Abstract Title of Document: DIVERSITY IN CATALYTIC REACTIONS OF PROPARGYLIC DIAZOESTERS Huang Qiu, Doctor of Philosophy, 2016 Directed By: Professor Michael P. Doyle, Department of Chemistry and Biochemistry Propargylic aryldiazoesters, which possess multiple reactive functional groups in a single molecule, were expected to undergo divergent reaction pathways as a function of catalysts. A variety of transition metal complexes including rhodium(II), palladium(II), silver(I), mercury(II), copper(I and II), and cationic gold (I) complexes have been examined to be effective in the catalytic domino reactions of propargylic aryldiazoesters. An unexpected Lewis acid catalyzed pathway was also discovered by using FeCl3 as the catalyst. Under the catalysis of selected gold catalysts, propargylic aryldiazoesters exist in equilibrium with 1-aryl-1,2-dien-1-yl diazoacetate allenes that are rapidly formed at room temperature through 1,3-acyloxy migration. The newly formed allenes further undergo a metal-free rearrangement in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H- pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture or quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. In the presence of a pyridine-N-oxide, both E- and Z-1,3-dienyl aryldiazoacetates are formed in high combined yields by Au(I)-catalyzed rearrangement of propargyl arylyldiazoacetates at short reaction times. Under thermal reactions the E-isomers form the products from intramolecular [4+2]-cycloaddition with H‡298 = 15.6 kcal/mol and S‡298= -27.3 cal/ (mol•degree). The Z-isomer is inert to [4+2]- cycloaddition under these conditions. The Hammett relationships from aryl-substituted diazo esters ( = +0.89) and aryl-substituted dienes ( = - 1.65) are consistent with the dipolar nature of this transformation. An unexpected reaction for the synthesis of seven-membered conjugated 1,4-diketones from propargylic diazoesters with unsaturated imines was disclosed. To undergo this process vinyl gold carbene intermediates generated by 1,2-acyloxy migration of propargylic aryldiazoesters undergo a formal [4+3]-cycloaddition, and the resulting aryldiazoesters tethered dihydroazepines undergo an intricate metal-free process to form observed seven-membered conjugated 1,4-diketones with moderate to high yields. Diversity in Catalytic Reaction of Propargylic Diazoesters By Huang Qiu Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, College Park, in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2016 Advisory Committee: Professor Lyle Isaacs, Chair Professor Andrei Vedernikov Professor Daniel Falvey Professor Yanjin Zhang Professor Michael P. Doyle Professor Wenhao Hu © Copyright by Huang Qiu 2016 ii Dedication To my wife, Lulu Ma for her tireless support throughout this entire process, to my granduncle Changji Qiu and my parents Baifa Qiu and Sumei Sheng. iii Acknowledgement I would like to express deepest gratitude to my advisor, Dr. Michael Doyle, for his support, patience, encouragement, and guidance throughout my entire graduate research program in the United States. His great passion on science has always motivated me, and his thoughtful criticisms have inspired me a lot. Without his great guidance and constant feedback this PhD dissertation would not have been achievable. To me, Dr. Michael Doyle is not only a great mentor in science but also an outstanding mentor in life. Also, I would like to extend my gratitude to Janice Doyle for her help to me and my family in United States. I would like to thank my advisor Professor Wenhao Hu at East China Normal University in China. He is a person who showed the beauty of organic chemistry to me and fostered my great interests in scientific research. I truly benefit from his insights on science as well as his advice both on my career development and my life. I would like to thank Professor Anderi Vedernikov, Professor Daniel Falvey, and Professor Lyle Isaacs for serving on Ph.D dissertation committee, and Professor Yanjin Zhang for serving as the Dean’s representative. I am really appreciated for their valuable time and advices. iv For members of the Doyle group, I would like give to my special gratitude to Dr. Kostiantyn Marichev, Dr. Harathi D. Srinivas, Michael Mandler, and Yifan Deng, who collaborated with me in the project of transition metal catalyzed reactions of propargyl aryldiazoacetates. I am also grateful to the help from other members of the Doyle group including Dr. Xinfang Xu, Dr. Xinchen Xu, Dr. Phong Truong, Dr. Ruby Liu, David Yim, Dr, Qiang Sha, Dr. Changcheng Jing, Dr. Yu Qian, Dr. Fernando Gama, Dr. Yongming Deng, Dr. Qingqing Cheng and all the new members. I would like to thank all the past and current Hu group members, Dr. Huadong Xu, Dr. Ming Li, Dr. Changwei Zhai, Dr. Jing Zhou, Xia Zhang, Renwei Zhang, Qing Zheng, Li, Zan, Dr. Xing Dong, Dr. Dan Zhang, Chaoqun Ma, Yonghui Wang, and all the new members at ECNU. I want to thank Professor Kendall Houk and his group members Abing Duan and Peiyuan Yu at UCLA for their collaboration on the project of intramolecular [4+2]-cycloaddition between 1,3-diene and diazo ester. A special thanks to Professor Wei Zhang and Professor Banglin Chen for their letters of recommendation. Also, I wish to thank all of my friends, especially Luning Wang, Dr. Bin Li, Dr. Hailong Wang, Dr. Huicai Huang. Last, but not least, I would like to thank grandparents, v granduncle, my parents, mother-in-law, father-in-law, brother, sister, and my wife for their support and love over the years. ii Table of Contents Abstract ...................................................................................................... ii Dedication .................................................................................................. ii Acknowledgement .................................................................................... iii List of Figures ........................................................................................... vi List of Tables ............................................................................................ ix List of Schemes ......................................................................................... xi List of Abbreviations ............................................................................... xv Chapter 1 : Catalyst Classification in Catalytic Reaction of Propargylic Diazoesters ................................................................................................. 1 I. Introduction ......................................................................................... 1 1.1 General Information for Diazo Compounds ................................. 1 1.2 Transition Metal-Catalyzed reactions of Diazo Compounds ........ 2 1.3 General Information for Alkynes ................................................ 14 1.4 My Research Goal ....................................................................... 16 II. Results and Discussion .................................................................... 23 2.1 Initial Assessments of Transition Metal Complexes ................... 23 2.2 Substrate Scope with CuPF6(MeCN)4 ......................................... 27 2.3 Proposed Mechanism for Copper-Catalyzed Carbene Domino Cascade Process ................................................................................ 29 2.4 The Lewis Acid Catalyzed Reactions of Propargyl Phenyldiazoesters .............................................................................. 30 III. Conclusion ...................................................................................... 33 IV. Experimental Section ...................................................................... 34 4.1 General Information .................................................................... 34 4.2 Materials ...................................................................................... 35 4.3 Experimental Procedures ............................................................. 36 iii 4.4 Characterization Data .................................................................. 41 V. References: ....................................................................................... 55 Chapter 2 : Unprecedented Rearrangement of Propargyl Aryldiazoacetates. Gold Catalysis Forms Allenes Whose Intramolecular Reaction with the Terminal Diazo Nitrogen Yields 1,5-Dihydro-4H- pyrazol-4-ones ......................................................................................... 62 I Introduction ........................................................................................ 62 1.1 Discovery of the Rearrangement Process ................................... 62 1.2 General Information for Gold Catalysis ...................................... 63 1.3 Gold-Catalyzed 1,3-Acyloxy Migration of Propargyl Esters and Subsequent Transformations ............................................................. 64 II. Results and Discussion .................................................................... 65 2.1 Initial Assessment of Gold Catalysts and Attempts to Determine the Structure of Rearrangement Products ......................................... 65 2.2 Optimization of Reaction Conditions and Monitoring the Reaction Process ................................................................................ 68 2.3 Reaction Mechanism ................................................................... 74 2.4 Substrate Scope ........................................................................... 82 III. Conclusion ...................................................................................... 85 IV. Experimental Section ...................................................................... 87 4.1 General Information .................................................................... 87 4.2 Materials ...................................................................................... 88 4.3 Experimental Procedures. ............................................................ 88 4.4 Kinetic Experiments .................................................................... 92 4.5 Characterization Data for New Compounds ............................... 97 4.6 X-ray Crystal Structure Information for 4 and 6’ ..................... 127 V References: ...................................................................................... 133 Chapter 3 : Unprecedented Intramolecular [4+2]-Cycloaddition Between a 1,3-Diene and a Diazo Ester ............................................................... 136 I. Introduction ..................................................................................... 136 iv 1.1 Isoelectronic Principle and Isoelectronic Systems: Diazo Compounds, Ketenes and Allenes ................................................... 136 1.3 Original Considerations of [4+2]-Cycloaddition of Diene with Diazo Compounds ........................................................................... 142 II. Results and Discussion .................................................................. 146 2.1 Initial Screening of Additives and Reaction Conditions ........... 146 2.2 Substrate Scope ......................................................................... 151 2.3 Kinetic Studies .......................................................................... 154 2.4 Reaction Mechanism ................................................................. 160 2.5 Further Applications of [4+2]-Cycloaddition Products ............ 167 III. Conclusion .................................................................................... 168 IV. Experimental Section .................................................................... 169 4.1 General Information .................................................................. 169 4.2 Materials .................................................................................... 170 4.3 Experimental Procedures ........................................................... 170 4.4 Characterization Data for New Compounds ............................. 177 4.5 X-ray Crystal Structure Information for 2f, (Z)-1e, and 5e ...... 208 V. References: ..................................................................................... 209 Chapter 4 : Unexpected [4+3]-Cycloaddition/Extrusion of Dinitrogen and Rearrangement in Gold-Catalyzed Reactions of Propargylic Diazoesters with Unsaturated Imines ........................................................................ 212 I. Introduction ..................................................................................... 212 1.1 Discovery of the Unexpected Cascade Process ........................ 212 1.2 Gold Catalyzed 1,2-Acyloxy Migration of Propargyl Esters and Subsequent Reactions ...................................................................... 213 1.3 [4+3]-Cycloaddition Reactions of Metal Vinylcarbenes with Unsaturated Imines .......................................................................... 215 1.4 Seven-Membered Carbocycles and Previous Synthesis ........... 217 II. Results and Discussion .................................................................. 218 2.1 Discovery of the Unexpected Cascade Process and Optimization of Reaction Conditions .................................................................... 218 2.2 Substrate Scope ......................................................................... 222 v 2.3 Isolation of [4+3]-Cycloaddition Products and Kinetic Studies 225 2.4 The Role of the Unsaturated Imines in Diketones Formation .. 228 2.5 Reaction Mechanism ................................................................. 231 III. Conclusion .................................................................................... 232 IV. Experimental Section .................................................................... 233 4.1 General Information .................................................................. 233 4.2 Materials .................................................................................... 234 4.3 Experimental Procedures. .......................................................... 234 4.4 Characterization Data for New Compounds ............................. 239 4.5 X-ray Crystal Structure Information for 4ha ............................. 260 V References: ...................................................................................... 273 Chapter 5 : Conclusions ......................................................................... 275 I. Diversity as a Function of Catalyst................................................. 275 II. Intramolecular Electrophilic Addition Reaction of Diazo Ester with an Allene ............................................................................................ 275. III. The Fisrt Discovery of Intramolecular [4+2]-Cycloaddition Between a 1,3-Diene and a Diazo Ester............................................. 276 IV. Intramolecular [3+2]-Cycloaddition with a Diazo with an Alkene and Subsequent Transformation ......................................................... 277 V. Future Work ................................................................................... 278 List of References .................................................................................. 280 vi List of Figures Figure 1.1 Resonance Structures of Diazo Compounds. .................... 1 Figure 1.2 Selected Chiral Ligands for Copper Catalysts. ................. 9 Figure 1.3 General Structural Formula for Homoleptic Dirhodium(II) Carboxylates (X = Y = O) and Carboxamidates (X = O; Y = N). .... 11 Figure 1.4 Representative Examples of Chiral Dirhodium(II) Carboxylates and Carboxamidates. ................................................... 11 Figure 1.5 Selected Chiral Ligands for Gold(I) Catalysts. ............... 13 Figure 1.6 Structures for AuCl3 and AuCl3(Pyridine). ..................... 13 Figure 1.7 Two Classes of Alkynes.................................................. 14 Figure 2.1 X-Ray Structures of 1,5-Dihydro-4H-Pyrazol-4-One 4 and Deacylation Product 6ʹ. .............................................................. 68 Figure 2.2 Time Course for the Formation of 3, 4, and 6 in DCE at 20 ⁰C. ................................................................................................. 70 Figure 2.3 Stacked 1 H NMR Spectra: Determination of Rate Constant for the Conversion of 8 to 10q at 20 ⁰C. ............................ 94 Figure 2.4 First-order Rate Constant at 20 ⁰C. ................................. 94 Figure 2.5 First-order Rate Constant at 40 ⁰C. ................................. 94 Figure 2.6 First-order Rate Constant at 45 ⁰C. ................................. 94 Figure 2.7 First-order Rate Constant at 60 ⁰C. ................................. 94 Figure 2.8 Arrhenius Plot: Compound 8 Activation Energy............ 95 Figure 3.1 Isoelectronic Systems: Allenes-Ketenes-Diazo Compounds ...................................................................................... 137 vii Figure 3.2 X-ray Structures of Diene (Z)-1e and Cycloaddition Product 2f. ....................................................................................... 151 Figure 3.3 Linear Relationship Between Reaction Time and Ln [(E)- 1a/(E)-1a0].. ..................................................................................... 155 Figure 3.4 Hammett Plot for the para-Substituted Aryldiazoesters. ......................................................................................................... 159 Figure 3.5 Hammett Plot for the para-Substituted Aryldienes. ..... 160 Figure 3.6 Energetics and Transition States of Intramolecular [4+2]- Cycloaddition (E vs Z) .................................................................... 166 Figure 3.7 Energetics and Transition States of [4+2]- and [3+2]- Cycloadditions ................................................................................. 167 Figure 3.8 X-Ray Structure of 5e. .................................................. 168 Figure 3.9 First-order Rate Constant at 49 o C. ............................... 177 Figure 3.10 First-order Rate Constant at 41 o C. .............................. 177 Figure 3.11 First-order Rate Constant at 30 o C. ............................. 177 Figure 3.12 First-order Rate Constant at 20 o C. ............................. 177 Figure 3.13 Arrhenius plot: (E)-1a Activation Energy. ................. 177 Figure 4.1 X-ray Structure of 4ha. ................................................. 222 Figure 4.2 1 H NMR Progress of the Gold-Catalyzed Reaction. .... 226 Figure 4.3 First-order Rate Constant at 61 o C. ............................... 228 Figure 4.4 First-order Rate Constant at 65 o C. ................................ 228 Figure 4.5 First-order Rate Constant at 71 o C. ............................... 228 Figure 4.6 First-order Rate Constant at 75 o C. ................................ 228 Figure 4.7 Arrhenius Plot: 16cb Activation Energy. ..................... 228 viii Figure 4.8 Representative SEM of Metallic Gold. ......................... 229 ix List of Tables Table 1.1 Catalysts Screening of the Reaction with Phenylpropargyl Phenyldiazoacetate 1a. ...................................................................... 26 Table 1.2 Substrates Scope for CuPF6(MeCN)4 Reaction with Propargyl Diazoacetates .................................................................... 28 Table 1.3 Lewis Acid Catalyzed Reactions of Propargyl Phenyldiazoesters .............................................................................. 31 Table 2.1 Solvent Screening for the Reaction of 1 with AuCl(C4H8S) ........................................................................................................... 69 Table 2.2 Temperature Screening for the Reaction of 1 with AuCl(C4H8S). .................................................................................... 71 Table 2.3 Screening of Gold(I) and Gold(III) Catalysts in Reactions with Phenylpropargyl Phenyldiazoacetate 1. .................................... 73 Table 2.4 Substrate Scope of Gold(I)-Catalyzed Reaction of Phenylpropargyl Aryldiazoacetates 9................................................ 82 Table 2.5 Deacylation of 10d and 11d by Nucleophiles .................. 91 Table 2.6 Data for Arrhenius Plot Measured within 20−60 ⁰C ........ 95 Table 2.7 Time Course for the Gold(I)-Catalyzed Reaction of 1 ..... 95 Table 2.8 Crystallographic data and structure refinement for cd1309 (4) and cd1383 (6') .......................................................................... 130 Table 3.1 Sreening the Additives for Gold-Catalyzed Reactions of Propargyl Phenyldiazoacetate 4a. ................................................... 147 Table 3.2 Optimization of Catalyst and Reaction Condition for Gold- Catalyzed Reactions of Propargyl Phenyldiazoacetate 4a. ............. 149 Table 3.3 Substrate Scope for Rearrangement Reaction. ............... 152 x Table 3.4 Product and Kinetic Studies of Intramolecular [4+2]- Cycloaddition. ................................................................................. 157 Table 3.5 Data for Arrhenius plot ................................................... 177 Table 4.1 Optimization of Gold-Catalyzed Reaction of Propargyl Phenyldiazoacetate 2a with trans-Cinnamyl Phenylimine 1b ........ 220 Table 4.2 Substrate Scope of Gold-Catalyzed Reactions of Propargylic Diazoesters with Unsaturated Imines .......................... 223 Table 4.3 Control Experiments ....................................................... 230 xi List of Schemes Scheme 1.1 General Reactions of Diazo Compounds. ....................... 2 Scheme 1.2 Transition Metal-Catalyzed Decomposition of the Diazo Compounds. ......................................................................................... 3 Scheme 1.3 Transition Metal-Catalyzed Reactions of Metal Carbenes Formed from Diazo Compounds. ........................................................ 4 Scheme 1.4 Generally Accepted Mechanism for Metal Catalyzed Decomposition of Diazo Compounds. ................................................ 5 Scheme 1.5 Classification of Substituted Metal Carbene Intermediates. ...................................................................................... 6 Scheme 1.6 General Reactivity Profiles of Metal Carbenes. ............. 6 Scheme 1.7 Synthesis of Donor/Acceptor Diazo Compounds and Transformations involving Donor/Acceptor Metal Carbenes. ............ 7 Scheme 1.8 Traditional Transformations of Alkynes. ...................... 15 Scheme 1.9 Transition Metal Complexes Catalyzed Reactions of Alkynes. ............................................................................................. 16 Scheme 1.10 Synthesis of Propargylic Phenyldiazoacetates. ........... 17 Scheme 1.11 Transition Metal Complexes-Catalyzed Domino Reactions of Diazo Compounds with Tethered Alkynes. ................. 19 Scheme 1.12 Rh2(OAc)4-Catalyzed Domino Reactions of Propargylic Phenyldiazoesters. ............................................................................. 20 Scheme 1.13 Competitive 1,2- and 1,3-Acyl Migration of Transition Metal Complexes Catalyzed Rearrangement of Propargylic Esters. 22 Scheme 1.14 Catalyst-Dependent Divergence of Reaction Pathway Based on -Bond Association with a Diazo Functional Group versus -Bond Association with an Alkyne. ................................................ 23 xii Scheme 1.15 Postulated Copper-Catalyzed Reaction Pathway. ....... 30 Scheme 1.16 FeCl3-Catalyzed Reaction of Propargyl Acetate with tert-Butyl Diazo Acetate. ................................................................... 32 Scheme 1.17 Proposed Mechanism for FeCl3-Catalyzed Reaction of 1a. ...................................................................................................... 33 Scheme 2.1 Catalysts Screening Leads to Discovery of the Rearrangement Process. .................................................................... 63 Scheme 2.2 Equation for Gold-Catalyzed Activation of Alkynes toward a variety of Nucleophiles. ..................................................... 64 Scheme 2.3 Formation of Allenes and Subsequent Transformations to Form Diverse Carbocycles and Heterocycles. .............................. 65 Scheme 2.4 Domino Reaction of Propargyl Phenyldiazoacetate 1 Catalyzed by Cationic Gold(I). ......................................................... 66 Scheme 2.5 Products from Gold(I)-Catalyzed Rearrangement of Phenylpropargyl Phenyldiazoacetate 1. ............................................ 67 Scheme 2.6 Proposed Mechanism for the Formation of 10, 11, and 12 from 9. ............................................................................................... 75 Scheme 2.7 Further Insight into the Mechanism of Au(I)-Catalyzed [3,3]-Rearrangements of Propargylic Esters ..................................... 77 Scheme 2.8 Intermolecular Electrophilic Addition of α-Diazoesters with Ketones. ..................................................................................... 79 Scheme 2.9 Synthesis of 2,3-Benzodiazepines from Benzocyclobutenes ............................................................................ 80 Scheme 2.10 Synthesis of 1,2-Diazepine from Enedione-Diazoester. ........................................................................................................... 80 Scheme 2.11 Formation of 1,3-diene from Gold-Catalyzed Propargyl Esters. ................................................................................................ 82 xiii Scheme 2.12 Substrate Scope of Gold(I)-Catalyzed Reaction of Arylpropargyl Aryldiazoacetates 9. .................................................. 84 Scheme 2.13 Outcome of Gold(I)-Catalyzed Reaction of Cyclobutyl Propargyl Reactant 9r. ...................................................................... 85 Scheme 3.1 [4+2]- versus [2+2]-Cycloaddition of 1,1-Difluoroallene and 1,3-Butadiene. ........................................................................... 138 Scheme 3.2 Divergent Outcomes of Transition Metal-Catalyzed [4+2]-Cycloaddition Reactions of Allenes with Dienes. ................ 139 Scheme 3.3 [4+2]-Cycloaddition Reaction of Diphenylketene and (E)-4-Methoxybut-3-en-2-one. ........................................................ 140 Scheme 3.4 Cinchona Alkaloid-Based Catalyst-Catalyzed [4+2]- Cycloaddition of o-Quinones with Ketene Enolates ....................... 141 Scheme 3.5 N-Heterocyclic Carbene-Catalyzed [4+2]-Cycloaddition Reaction of Ketenes with Enones. ................................................... 142 Scheme 3.6 Dipolar Cycloaddition and Cyclopropanation of 1,3- Dienes with Diazo Compounds. ...................................................... 143 Scheme 3.7 Intramolecular Cycloaddition of 1-Aza-2-Azoniaallene Salts. ................................................................................................ 144 Scheme 3.8 Proposed Intramolecular [4+2]-Cycloaddition of Dienes with Diazo Compounds. .................................................................. 145 Scheme 3.9 Synthesis of Diene-linked Aryldiazoacetates. ............ 146 Scheme 3.10 Proposed Mechanism for Gold(I)-Catalyzed Rearrangements in Presence of 4-Chloropyridine N-Oxide. .......... 161 Scheme 3.11 Gold-Catalyzed Isomerization of Unreactive Allenes into 1,3-Dienes. ............................................................................... 162 Scheme 3.12 Gold-Catalyzed Rearrangement of Diynes: Pyridine-N- Oxides as Mild Bases. ..................................................................... 163 xiv Scheme 3.13 Gold-catalyzed Rearrangement of 2-(1-Alkynyl)-2- Alken-1-Ones: Pyridine-N-Oxides as Mild Bases. ......................... 164 Scheme 3.14 Proposed Deuterium-Hydrogen Exchange Process. . 165 Scheme 3.15 Deuterium Labeling Experiments. ............................ 165 Scheme 4.1 Discovery of the Unexpected Cascade Process. ......... 213 Scheme 4.2 Formation of Gold Vinylcarbenes and Subsequent Transformations. .............................................................................. 215 Scheme 4.3 Rhodium-Catalyzed [4+3]-Cycloaddition Reaction of Styryldiazoacetates with α,β-Unsaturated Imines. .......................... 216 Scheme 4.4 Gold-Catalyzed [4+3]-Cycloaddition Reaction of Propargyl Esters with α,β-Unsaturated Imines. .............................. 217 Scheme 4.5 Various Routes to Seven-Membered Carbocycles. .... 218 Scheme 4.6 Control Experiments for the formation of 4bd from 3bd. ......................................................................................................... 227 Scheme 4.7 Proposed Mechanism for the Gold-Catalyzed Reaction of Propargyl Arylyldiazoacetates 1 with Unsaturated Imines 2. .... 232 xv List of Abbreviations p-ABSA 4-Acetamidobenzenesulfonyl azide Ar aromatic Bn benzyl t-Bu tert-butyl DCM dichloromethane DCE 1,2-dichloroethane dr diastereomeric ratio ee enantiomeric excess Et ethyl Et3N triethylamine EtOAc ethyl acetate equiv equivalent h hour xvi MLn transition metal with ligands Me methyl NMR nuclear magnetic resonance OAc acetate i-Pr iso-propyl RT room temperature SEM scanning electron microscope THF tetrahydrofuran TMS trimethylsilyl 1 Chapter 1: Catalyst Classification in Catalytic Reaction of Propargylic Diazoesters I. Introduction 1.1 General Information for Diazo Compounds Diazo compounds are high energy organic compounds bearing a C=N=N functional group. Their general formula can be described as R1R2C=N2. Two resonance contributing structures describe the general electronic characteristics of diazo compounds (Figure 1.1). These electronic structures describe an electropositive center on the central nitrogen and nucleophilic centers at the terminal nitrogen and the carbon. Figure 1.1 Resonance Structures of Diazo Compounds. Diazo compounds are capable of undergoing a variety of transformations, and numerous reactions involving diazo compounds have been studied over the past hundred years. In general, four types of reactions have been recognized and described in the literature (Scheme 1.1): (a) 1,3-dipolar cycloaddition reactions with alkenes or alkynes; 1 (b) 2 a surprising electrophilic addition to nucleophiles from the terminal nitrogen position; 2 (c) nucleophilic addition reactions with electrophiles that occur at the nucleophilic carbon position, 3 and (d) reactions involving (metal) carbene intermediates. 4 Scheme 1.1 General Reactions of Diazo Compounds. 1.2 Transition Metal-Catalyzed reactions of Diazo Compounds Catalytic decomposition of diazo compounds occurs by the extrusion of dinitrogen to produce a variety of reaction products dependent on the catalyst that is employed. 5 Because of back-bonding from electrophilic transition metals, their complexes produce 3 electrophilic metal-stabilized carbenes. 6 The proposed process involves the use of a transition metal complex as a Lewis acid by coordination to the negatively-polarized carbon of the diazo compound to produce an organometallic diazonium ion followed by loss of dinitrogen to furnish the metal-stabilized carbene. 6b,7 The metal-stabilized carbene may be depicted by two resonance contributing structures: one that describes a metal-carbon double bond, not unlike that used to depict stable Fischer carbene, 6-7 and another having a charge separated structure that places a formal positive charge on carbon and a formal negative charge on the metal (Scheme 1.2). 8 The depiction of the carbene as a charge-separated species (metal-stabilized carbocation), while deemphasizing back bonding from metal into the carbene, provides focus on their electrophilic reactivity. Scheme 1.2 Transition Metal-Catalyzed Decomposition of the Diazo Compounds. Due to their high electrophilic reactivity, metal-stabilized carbenes have been reported to undergo a wide array of transformations including 4 cyclopropanation, cyclopropenation, C-H insertion and ylide formation (Scheme 1.3). 5a,9 For these processes a simplified catalytic cycle is described in Scheme 1.4, and in some cases catalyst loading is under 0.1 mol %. 10 Addition to the carbon-carbon double bond to form cyclopropanes is perhaps the most studied transformation, but C-H insertion and ylide-derived transformations have emerged during the past two decades as viable and synthetically useful transformations. 5b,10-11 Scheme 1.3 Transition Metal-Catalyzed Reactions of Metal Carbenes Formed from Diazo Compounds. 5 Scheme 1.4 Generally Accepted Mechanism for Metal Catalyzed Decomposition of Diazo Compounds. 1.2.1 Classification of Metal Carbenes The reactivity profile of metal carbenes is greatly influenced by the electronic nature of the substituents that adorn the carbene center. 12 Because of their relative stabilities and general ease of formation and handling, diazocarbonyl compounds are the most commonly used metal carbene precursors. 13 Three types of metal carbenes have been classified and described by Davies and coworkers: acceptor, acceptor/acceptor, and donor/acceptor metal carbenes (Scheme 1.5); 5d,11b,11c the term “acceptor” refers to an electron-withdrawing group (keto, cyano, nitro, phosphonyl and sulfonyl) bonded to the carbene center, whereas “donor” refers to an electron-donating group (vinyl, aryl and heteroaryl) bonded to the 6 carbene center; both terms are relative to hydrogen in their electronic effects. Scheme 1.5 Classification of Substituted Metal Carbene Intermediates. Due to the electrophilic character of metal carbenes, the electron- donating group bonded to the carbene center will stabilize metal carbenes, which results in their increased selectivity compared to the acceptor and acceptor/acceptor metal carbenes (Scheme 1.6). 5b Scheme 1.6 General Reactivity Profiles of Metal Carbenes. For the past two decades, numerous efforts have been devoted to the study of catalytically selective reactions of donor/acceptor metal carbenes, especially aryldiazoacetates. 5c These donor/acceptor diazo 7 compounds are easily prepared from corresponding arylacetate esters via a diazo transfer reaction, usually with 4-acetamidobenzenesulfonyl azide (p-ABSA). 14 They are stable and storable at room temperature for extended periods of time; and they are capable of undergoing a variety of transformations ranging from cyclopropanation, cyclopropenation, C-H insertion, aromatic substitution, and ylide formation (Scheme 1.7). 15 Scheme 1.7 Synthesis of Donor/Acceptor Diazo Compounds and Transformations involving Donor/Acceptor Metal Carbenes. 1.2.2 Transition Metal Complexes for Metal Carbene Transformations 8 Transition metal complexes have played an important role in the development of synthetic methodology; 4b,16 and their applications to the decomposition of diazo compounds, as well as their subsequent transformations involving metal carbenes, are particular attractive. Transition metal complexes, including those of copper, rhodium, cobalt, iron, palladium, ruthenium, silver, iridium, 17 and gold have been reported to mediate these transformations effectively; 13b and recent results have shown that the ligands for these transition metals have great influence on the reactivity and selectivity. 18 Copper and rhodium complexes are well- established systems, and their activities and selectivities have been summarized in several excellent reviews. 6a,6b,9,11d 1.2.2.1 Copper Catalysts in the Decomposition of Diazo Compounds Since the first discovery of copper-catalyzed decomposition of diazo compounds over a century ago, 19 a variety of copper salts and complexes have been widely used in the catalytic reactions of diazo compounds. These copper salts include copper(I) halides, 20 copper(I) triflate, 21 copper(II) triflate, 22 copper(II) sulfate. 23 The commercial available and conveniently handled tetrakis(acetonitrile)copper(I) hexafluorophosphate [CuPF6(MeCN)4] 24 and 9 tetrakis(acetonitrile)copper(I) tetrafluoroborate [CuBF4(MeCN)4] 25 have shown advantages over other copper salts in several transformations. Copper(I) is understood to be the catalytically active oxidation state in copper catalyzed reactions of diazo compounds. 21 With four coordination sites copper(I) can be linked to ligands that influence its reactivity and selectivity in reactions with diazo compounds. The first effective chiral ligands used to control enantioselectivity were introduced on copper, 26a and the most effective of these ligands were multidentate. 5b, 26b Copper complexes formed from chiral ligands have been widely used in the asymmetric transformations including cyclopropanation, 27 C-H insertion, 28 and [3+3]-cycloaddition of diazo compounds, 29 and the major ligands used for copper(I) complexes are described in Figure 1.2. 30 Figure 1.2 Selected Chiral Ligands for Copper Catalysts. 1.2.2.2 Rhodium Complexes in Dinitrogen Extrusion from Diazo Compounds 10 Dirhodium(II) complexes have emerged as the dominant catalysts for reactions with diazo compounds. 5b,5d,10,15a,31 They possess a paddlewheel structure containing two rhodium atoms that are connected by a rhodium-rhodium single bond and four bidentate ligands that bridge two rhodium atoms in 16-electron rhodium complexes (Figure 1.3). The bridging ligands are most commonly carboxylates or carboxamidates, though catalysts based on phosphonate 32 and arylphosphine 33 ligands have also been reported. Dependent on the bridging ligands, they may have water solubility; but most uses have occurred in solvents of moderate polarity such as dichloromethane. Two open coordination sites exist at the axial positions of these paddlewheel complexes, and the axial coordination site is the electrophilic center at which reaction with diazo compounds occurs. 11 Figure 1.3 General Structural Formula for Homoleptic Dirhodium(II) Carboxylates (X = Y = O) and Carboxamidates (X = O; Y = N). Chiral dirhodium(II) carboxylates or carboxamidates can be easily prepared from rhodium acetate and corresponding enantiomerically pure amino-protected amino acids or enantiomerically pure amino acid- derived lactams. 8,34 Several excellent reviews describe their catalytic advantages. 5a,5b,5d,10 Recently, these chiral dirhodium(II) complexes have been broadly classified and well summarized according to generality and selectivity in the transformations of rhodium carbenes by a compressive review by Doyle and coworkers (Figure 1.4). 35 Figure 1.4 Representative Examples of Chiral Dirhodium(II) Carboxylates and Carboxamidates. 12 1.2.2.3 Gold Complexes in Reactions with Diazo Compounds Gold complexes have emerged in recent years as powerful catalysts for the construction of C–C, C–N, and C–O bonds in organic synthesis. 36 During the past decade, the chemical community has witnessed a rapidly increasing interest in the gold-catalyzed transformations of diazo compounds, especially α-diazocarbonyl compounds. 37 Gold(I) complexes, simply described as [LAuY], are two- coordinate, linear species; they are air- and moisture-stable. When Y is a coordinating anion (halides, carboxylates, sulfonates, and triflimide), they are neutral gold(I) complexes. Cationic gold(I) complexes with weakly coordinating anions (BF4 ¯ , PF6 ¯ , SbF6 ¯ , OTf ¯ , NTf2 ¯ BAr F 4 ¯ ), which can be generated in situ via ionization of neutral gold(I) complexes (LAuCl) with soluble silver or sodium salts (AgSbF6, AgBF4, NaBAr F 4), are the most commonly used gold complexes for reactions with α- diazocarbonyl compounds; and the reactivity profiles of formed gold carbene complexes is greatly dependent on the nature of the ligand that is bound to gold. Phosphines, phosphites, and N-heterocyclic carbenes are the most commonly used ligands. The most commonly used ligands are listed in Figure 1.5. 38 13 Figure 1.5 Selected Chiral Ligands for Gold(I) Catalysts. Beside the cationic gold(I) complexes, some simple gold(III) salts such as AuCl3 and AuCl3(pyridine), also have been reported as catalysts in decomposition of diazo compounds (Figure 1.6). These complexes are subject to disproportionation at higher temperatures, generally observed through the formation of metallic gold. Figure 1.6 Structures for AuCl3 and AuCl3(Pyridine). 1.2.2.4 Other Transition Metal Complexes in Reactions with Diazo Compounds For the past several decades, several other transition metals including cobalt, iron, palladium, ruthenium, silver, iridium also have been investigated, and important progress has been achieved. 6a, 6c, 11a, 17 It 14 is worthy noted that the ligands for these transition metal complexes always play an important role on the selectivity and reactivity in the transformations of diazo compounds. 18a,34e,39 1.3 General Information for Alkynes Alkynes are organic compounds containing a carbon-carbon triple bond. The simplest alkyne is acetylene with the formula C2H2, whose four atoms are linear; there are two π-bonds and one σ-bond between two carbon atoms; the hybridization on each carbon atom is sp. Based on the substituents of each acetylenic carbon, alkynes can be simply categorized as terminal and internal alkynes; both of them share the similar linear structure with acetylene (Figure 1.7). Figure 1.7 Two Classes of Alkynes. Alkynes have played an extremely important role in the history of organic chemistry. 40 Several traditional transformations including hydrogenation, additions of electrophilic reagents, 1,3-dipolar cycloaddition reactions, hydroboration and oxidations have been reported in the last century; these transformations have been commonly used 15 methods for constructing C-C, C-O, C-B, C-X (X = Cl, Br) bonds (Scheme 1.8). 40a, 40c, 40d Also, their applications in the total synthesis of natural products have been demonstrated by numerous examples. 41 Scheme 1.8 Traditional Transformations of Alkynes. The transition metal complexes catalyzed transformations of alkynes are particularly attractive because they provide a wide range of synthetically meaningful transformations with high efficiency under mild reaction conditions. 42 Transition metal alkyne complexes, which are formed through -coordination of an alkyne ligand (or two and more alkyne ligands) to a transition metal center, are proposed as key intermediates in many catalytic transformations. 41b,43 It should be noted 16 that the alkynes that coordinate to transition metal complexes are usually non-linear; the transition metal alkyne complexes can undergo a variety of transformations ranging from nucleophilic addition reactions, 44 electrophilic addition reactions, 45 and cycloaddition reactions (Scheme 1.9). 46 A wide range of transition metal complexes containing cobalt, 47 titanium, 48 zirconium, 49 iron, 50 molybdenum, 51 tungsten, 52 nickel, 53 rhodium, 54 ruthenium, 55 iridium, 56 palladium, 57 mercury, 58 platinum, 59 silver, 60 and gold 55a,59b have been reported. Scheme 1.9 Transition Metal Complexes Catalyzed Reactions of Alkynes. 1.4 My Research Goal 17 Since both diazo compounds and alkynes can react with a wide array of transition metal complexes to form reactive transition metal complexes which are capable of undergoing further transformations, we asked the question “Is there diversity in product formation if both acetylenic and diazo functionalities are present in the same molecule?” To answer this question, easily accessible propargylic phenyldiazoacetates that combines diazo functionality and a propargylic ester were synthesized for this evaluation. Scheme 1.10 Synthesis of Propargylic Phenyldiazoacetates. 1.4.1 Transition Metal Catalyzed-Domino Reactions involving Diazo Decomposition and Carbene/Alkyne Cascade. Domino reactions, which are also known as cascade reactions or tandem reactions, are defined as a consecutive series of transformations occurring in one step via highly reactive intermediates. 61 Transition metal complexes catalyzed domino reactions of diazo compounds with tethered 18 alkynes have been investigated over the past three decades; 4a the mechanism for these domino processes always involves dinitrogen extrusion and a subsequent carbene/alkyne cascade to produce a new cyclic metal carbene species, sometimes involving formation of a highly strained cyclopropene that can react with transition metal complex to produce the same cyclic metal carbene species. 64 The newly formed cyclic metal carbene species has been reported to undergo a variety of transformations that include cyclopropanation, C-H insertion, 62 , aromatic substitution 63 and 1,3-dipolar cycloaddition. 64 Transition metal complexes including Rh2(OAc)4, Pd(OAc)2, Ni(COD)2, Cu(hfacac)2, and other dirhodium(II) carboxylates have been reported as the catalysts for selected domino processes. 19 Scheme 1.11 Transition Metal Complexes-Catalyzed Domino Reactions of Diazo Compounds with Tethered Alkynes. Padwa and coworkers have reported that propargylic phenyldiazoesters can undergo intramolecular domino reactions to produce indene-fused lactone upon treatment with catalytic amount Rh2(OAc)4; the authors propose that the domino reaction proceeds through rhodium-catalyzed diazo decomposition, carbene/alkyne metathesis and subsequent aromatic substitution. 65 However, the substrate scope of this domino reaction was not fully investigated; other transition metal complexes that can catalyze decomposition of diazo compounds have not been examined in this domino reaction. 20 Scheme 1.12 Rh2(OAc)4-Catalyzed Domino Reactions of Propargylic Phenyldiazoesters. 1.4.2 Transition Metal Complexes-Catalyzed Reactions of Propargylic Esters Propargylic esters are one of the most easily accessible substrates for reactions with transition metals that are initiated at the carbon-carbon triple bond. Numerous examples have been reported; 66 and all involve rearrangement of the ester as the initial step. Two rearrangement pathways are common (Scheme 1.13). In one the transition metal complex coordinates with the triple bond to form alkyne complexes I, and then the carbonyl oxygen undergoes a 5-exo-dig cyclization to form intermediate II, which with back-bonding from gold and successive ring opening finally forms the vinyl transition metal-stabilized carbene intermediates III. An alternative pathway is also possible. Instead of 5- exo-dig cyclization, intermediate I undergoes a 6-endo-dig cyclization to generate a six-membered-ring intermediates IV, which forms allenylic 21 ester intermediate V via a similar back-bonding and ring opening process. In most cases outcomes of the transition metal complexes-catalyzed regioselectivity of propargylic esters can be predicted: if the R 3 unit is a hydrogen atom (terminal alkynes) or an electron-withdrawing group that includes ester, the formation of the metal vinylcarbene complexes though 5-exo-dig cyclization is preferred; alternatively, while when R 3 is an aryl group or alkyl group, allenyl esters, which are generated by 6-endo-dig cyclization, will be the corresponding reaction intermediates. However, a few cases that are not consistent with this simple rule have also been reported. 67 These results indicate that the outcome of regioselectivity can be also influenced by other factors ranging from the structure of transition metal complexes, the substitution pattern at the propargylic moiety, and reaction conditions. 22 Scheme 1.13 Competitive 1,2- and 1,3-Acyl Migration of Transition Metal Complexes Catalyzed Rearrangement of Propargylic Esters. Different transition metals including copper, 68 zinc, 69 silver, 68 palladium, 70 ruthenium, 71 rhodium, 66a platinum, 70,72 and gold 36b,66d,73 have been unveiled to be effective for those reactions of propargylic esters. However, propargylic esters bearing a diazo group have not yet been examined with these transition metal complexes. 1.4.3 Reactivity of Propargylic Phenyldiazoacetates Two divergent reaction pathways are possible for reactions of propargyl diazoacetates: (a) the diazo functionality reacts with the - bond acceptor to displace dinitrogen through back-donation and formation of a metal carbene, followed by addition to the carbon-carbon triple bond to form a derivative metal carbene that completes the domino transformation by electrophilic substitution into the aromatic ring of the original aryldiazoacetates; (b) -bond-forming reactions that occur initially at the carbon-carbon triple bond followed by nucleophilic addition at a carbonyl oxygen and 1,3-acyloxy migration to produce allene intermediates, 68,74 and then to undetermined product(s) based on subsequent reactions that, although diverse examples are known, the 23 possible outcome with propargylic diazoacetates is unknown. (Scheme 1.14) Scheme 1.14 Catalyst-Dependent Divergence of Reaction Pathway Based on -Bond Association with a Diazo Functional Group versus - Bond Association with an Alkyne. II. Results and Discussion 2.1 Initial Assessments of Transition Metal Complexes Assessments of transition metal complexes catalysis with phenylpropargyl phenyldiazoacetate 1a were performed at 20 ℃ in CH2Cl2 using 1-5 mol % of catalyst. With 1 mol% Rh2(OAc)4 the product (2) from the cascade transformation of an intermediate metal carbene was formed in 76% isolated yield (Table 1.1, entry 1). The more Lewis acidic catalyst Rh2(TFA)4 was also tested and gave improved yield (83% yield) indicating that dirhodium catalysts prefer the domino process (Table 1.1, 24 entry 2). Three commonly used palladium catalysts Pd(OAc)2, PdCl2(PhCN)2, and [Pd(η3-C₃H₅)Cl]₂,were further examined. Although all of them produced the cascade product 2a as the dominated product, their catalytic activities are much lower compared to Rh2(OAc)4. These reactions were monitored every 12 h by TLC (Thin Layer Chromatography), and the starting material 1a was completely consumed after 48 h. The cascade product was obtained in moderate yields (Table 1.1, entries 3-5), but an unexpected elimination product 3a was observed during the process. AgSbF6, which is widely used in decomposition of diazo compounds, also worked well in the domino cascade reaction. With 5 mol % AgSbF6, the cascade cascade product 2a was obtained in reasonable yield, and the elimination product 3a was isolated as another product (Table 1.1, entry 6). Au(JohnPhos)SbF6 and IPrAuBF4, recently were reported as effective catalysts in decomposition donor/acceptor diazoacetates, 75 were also surveyed. Au(JohnPhos)SbF6 gave the cascade product in 86% yield, whereas the cascade product 1a was obtained in 50% yield with IPrAuBF4 (Table 1.1, entries 7 and 8). When more Lewis acidic catalysts such as Hg(OTf)2 were employed, the competing product 3a was obtained as the dominant product, and only 10% of the domino product 2a was observed. With the Cu(OTf)2 catalysis, the cascade 25 product 2a and elimination product 3a almost were formed in similar yield (Table 1.1, entry 11). We found that CuBF4(MeCN)4 and CuPF6(MeCN)4 were very effective for this domino reaction (Table 1.1, entries 12-13); with 5 mol% CuPF6(MeCN)4 2a was obtained in 90% isolated yield (94% 1 H NMR yield) in DCM for 1 h at room temperature, and no other discernable product was observed. Under the catalysis of FeCl3, the elimination product 3a was isolated as the dominant product in 70% yield (Table 1.1, entry 14). Surprisingly, no cascade product 2a was observed but instead unexpected product 4a was obtained in 20% yield, which can be easily separated from 2a by normal phase column chromatography (this part will be discussed later). Moreover, reaction with tetrahydrothiophene gold(I) chloride, AuCl(C4H8S), was more complex, forming none of 2a but produced two isomeric 1H-pyrazolines as the dominant products (discussed in the chapter 2). We also performed several reactions of 1a under the catalysis of chiral catalysts including chiral dirhodium carboxylates such as Rh2(S-PTTL)4 and CuPF6(CH3CN)4 with chiral BOX ligands (i-Pr, t-Bu, Bn and etc.). Although 2a is formed in reasonable yield, the analyses from chiral HPLC have shown that the only racemic product 2a was observed. 26 Table 1.1 Catalysts Screening of the Reaction with Phenylpropargyl Phenyldiazoacetate 1a. Entry a Catalyst reaction time Conversion of 1a b , % Yield of 2a % Yield of 3a, % 1 Rh2(OAc)4 c 6 h >95 76 <5 2 Rh2(TFA)4 c 3 h >95 83 <5 3 Pd(OAc)2 48h >95 71 10 4 PdCl2(PhCN)2 48 h >95 76 11 5 [Pd(η3-C₃H₅)Cl]₂ 48 h >95 65 15 6 AgSbF6 1 h >95 65 30 7 Au(JohnPhos)SbF6 10 h >95 86 4 8 IPrAuBF4 10 h >95 50 16 9 Hg(OTf)2 48 h >95 10 80 27 10 HgCl2 24 h 50 15 76 11 Cu(OTf)2 6 h >95 40 50 12 CuBF4(MeCN)4 1 h >95 92 <5 13 CuPF6(MeCN)4 1 h >95 94 (90) d <5 14 FeCl3 e 12 h >95 <5 70 15 AuCl(C4H8S) 72h >95 <5 <5 a Reactions were carried out at 20 ℃ on a 0.20 mmol scale: a solution of 1a in 2.0 mL CH2Cl2 was added dropwise to a 5 mol % solution of -catalyst in 2.0 mL CH2Cl2 under a nitrogen atmosphere within 10 min, and the resulting reaction mixture was stirred for the stated reaction time. b The percent conversion of 1a, the yield of 2a and yield of 3a (in parenthesis) were determined by 1 H NMR spectroscopy using 2,4,6-trimethoxy-benzaldehyde as an internal standard. c Catalyst loading is 1 mol %. d Isolated yield. e Temperature was 60 o C and DCE was solvent. 2.2 Substrate Scope with CuPF6(MeCN)4 Since CuPF6(MeCN)4 has exhibited very high efficiency and excellent selectivity in formation of domino cascade reaction product during the catalyst screening of 1a, we became interested in the generality of CuPF6(MeCN)4 to the domino process The propargyl aryldiazoacetates 1b-1j with different substituents were prepared in the following investigation. First, the influence of substituents on the phenyl group at the para position was examined to further understand the formation of the cascade products. Substituents 1b-c with electron 28 donating groups (EDG) such as methoxy group and methyl group gave higher yields compared with 1a (Table 1.2, entries 1 and 2); bromo- and chloro-substituted propargylic aryldiazoacetates 1d-e resulted in corresponding products with slightly decreased yields because elimination product 3a was formed as a by-product (Table 1.2, entries 3 and 4); however, 1f with a nitro group, which is a strong electron- withdrawing group (EWG), only produced a trace of product (15% yield) under same reaction conditions (elimination product 3a was obtained in 65% yield separately; Table 1.2, entry 5) . Then, substrates with dimethyl as well as other carbocycles that include cyclohexyl and cyclobutyl 1g-i were found to be compatible in this domino cascade process and furnished the products 2g-i in good yields (Table 1.2, entries 6-8). The substituents on alkyne were also investigated: substrate 1j, which is derived from cyclopropylacetylene, produces corresponding cascade product 2j in 85% yield under the same reaction conditions (Table 1.2, entry 9). Table 1.2 Substrates Scope for CuPF6(MeCN)4 Reaction with Propargyl Diazoacetates 29 Entry a 1 and 2 R 1 R 2 R 3 yield of 2(%) b 1 b OMe -(CH2)4- Ph 98 2 c Me -(CH2)4- Ph 95 3 d Br -(CH2)4- Ph 86 (6) c 4 e Cl -(CH2)4- Ph 78 (12) c 5 f NO2 -(CH2)4- Ph 15 (65) c 6 g H Me Ph 90 7 h H -(CH2)3- Ph 90 8 i H -(CH2)5- Ph 80 9 j H -(CH2)4- cyclopropyl 85 a Reactions were performed at 20 ℃ on a 0.20 mmol scale: a solution of 1 in 2.0 mL CH2Cl2 was added dropwise to a 5 mol % solution of CuPF6(MeCN)4 in 2.0 mL solvent under a nitrogen atmosphere within 10 min, and the resulting reaction mixture was stirred for 1 h. b Isolated yield. c Isolated yield of elimination product 3a. 2.3 Proposed Mechanism for Copper-Catalyzed Carbene Domino Cascade Process As shown in Scheme 1.15, a plausible mechanism is proposed based on previous reports by Padwa and coworkers. 64,76 The Cu(I) complex reacts with phenyldiazoacetate A to produce metal carbene intermediate B, which readily undergoes a carbene/alkyne metathesis or cyclopropenation/spontaneous ring opening process to form the cyclic 30 vinyl carbene intermediate C, 77 followed by an intramolecular electrophilic aromatic substitution to furnish indene product E. Scheme 1.15 Postulated Copper-Catalyzed Reaction Pathway. 2.4 The Lewis Acid Catalyzed Reactions of Propargyl Phenyldiazoesters As mentioned before, under the catalysis of FeCl3 an unexpected reaction of 1a occurred with formation of unexpected lactone 4a albeit with relatively lower yield. However, the elimination product 3a was obtained as the dominant product under selected reaction conditions 31 (Table 1.3, entry 1). Other Lewis acids also were examined for this process. Sc(OTf)3, In(OTf)3, and Zn(OTf)2 failed to give the lactone 4a (Table 1.3, entries 2-4). With 10 mol% ZnBr2, lactone 4a was obtained in 4% yield (Table 1.3, entry 5); increasing the catalyst loading of ZnBr2 to 100 mol% resulted in higher yield (Table 1.3, entry 6). BF3•Et2O was also tested, and lactone 4a could be obtained in 20% yield at either 60 o C or 20 o C upon the consumption of starting material (Table 1.3, entries 7 and 8). However, the formation of elimination product 3a was always the dominant process with these Lewis acids. Table 1.3 Lewis Acid Catalyzed Reactions of Propargyl Phenyldiazoesters Entry a Lewis acid reaction time Conversion of 1a b Yield of 4a c Yield of 3a c 1 FeCl3 12 h >95% 21% 75% 2 Sc(OTf)3 10 h >95% <1% 80% 3 In(OTf)3 10 h >95% <1% 95% 4 Zn(OTf)2 24 h >95% <1% 80% 5 ZnBr2 24 h >95% 4% 90% 6 ZnBr2 d 12 h >95% 17% 75% 32 7 BF3•Et2O 1 h >95% 20% 80% 8 e BF3•Et2O 12 h >95% 20% 65% 9 e FeCl3 24 h 50% 3% 45% 10 f FeCl3 6 h >95% 15% 75% aReactions were performed at 60℃ on a 0.20 mmol scale: a solution of 1a in 2.0 mL ClCH2CH2Cl was added to a solution of 10 mol% of catalyst in 2.0 mL ClCH2CH2Cl under a nitrogen atmosphere, and the resulting reaction mixture was stirred for stated reaction time. bThe percent conversion of 1a was determined 1H NMR spectroscopy using 2,4,6-trimethoxy-benzaldehyde as an internal standard. cIsolated yield. d1.0 eq. of ZnBr2 was used. eReaction temperature was 20 ºC. fReaction temperature was 80 ºC. Major efforts were devoted to understanding the mechanism for this unique process. A control experiment was conducted by using propargyl acetate with tert-butyl diazoacetate under catalysis of FeCl3; the rearrangement product analog 4g was obtained in 17% isolated yield together with the major elimination product 3g (Scheme 1.16). Scheme 1.16 FeCl3-Catalyzed Reaction of Propargyl Acetate with tert- Butyl Diazo Acetate. Based on this experiment and previous reports, 78 we propose a plausible mechanism for the above rearrangement reaction as shown in 33 Scheme 1.17. Under the catalysis of FeCl3, ester C-O bond cleavage of A occurs, which forms cationic species G and anionic species F. The conversion of cationic species G to the allene carbocation H via Meyer−Schuster rearrangement has been documented 79. The allene carbocation H was proposed to be trapped by nucleophilic attack of F to produce a key intermediate aryl allene derived compound I, and finally cyclization of I furnishes product J. Also, the formed cationic species G is not stable; deprotonation of G occurs readily, which forms enyne L as another competing product. 80 Scheme 1.17 Proposed Mechanism for FeCl3-Catalyzed Reaction of 1a. III. Conclusion 34 In summary, we have disclosed that propargylic phenyldiazoesters were converted into three structurally different products as a function of catalysts. A variety of transition metal complexes that include rhodium(II), palladium(II), silver(I), mercury(II), copper(I and II), and cationic gold (I) complexes have been examined to be effective in the catalytic domino reactions of propargylic aryldiazoesters. CuPF6(MeCN)4 has been demonstrated as a superior catalyst in the domino cascade reaction for formation of indene derivatives. A Lewis acid catalyzed pathway was also discovered: FeCl3 works as a Lewis acid and selectively gives furanone 4 as a reaction product. Selected gold catalysts exhibit a unique catalytic reactivity, which not only selectively activates the alkyne group but also retains the dinitrogen in the final product, which has been thoroughly investigated and will be reported in the next three chapters. IV. Experimental Section 4.1 General Information Unless noted all reactions were carried out under inert atmosphere of dinitrogen in oven-dried glassware with magnetic stirring using freshly distilled solvents. All solvents were purified and dried using standard 35 methods. Analytical thin layer chromatography (TLC) plates were purchased from EM Science (silica gel 60 F254 plates). High-resolution mass spectra (HRMS) were performed on a microTOF-ESI mass spectrometer using CsI as the standard. Accurate masses are reported for the molecular ion [M+Cs] + , [M+Na] + , or [M+H] + . Melting points were determined on an Electrothermo Mel-Temp DLX 104 device and were uncorrected. Column chromatography was performed on CombiFlash ® Rf 200 purification system using normal phase disposable columns. IR spectra were recorded using Bruker Vectcr 22 spectrometer. All NMR spectra were recorded on a Bruker spectrometer at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR) or an Agilent spectrometer at 500 MHz ( 1 H NMR) and 125 MHz ( 13 C NMR). Chemical shifts are reported in ppm with the solvent signals as reference (in CDCl3 as solvent), and coupling constants (J) are given in Hertz (Hz). The peak information is described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite of magnetically non-equivalent protons. 4.2 Materials Rh2(OAc)4 was purchased from Pressure Chemical Co. and Rh2(TFA)4, Pd(OAc)2, PdCl2(PhCN)2, [Pd(η3-C₃H₅)Cl]₂, AgSbF6, Au(JohnPhos)SbF6, IPrAuBF4, Hg(OTf)2, Cu(OTf)2, CuBF4(MeCN), 36 CuPF6(MeCN)4, and FeCl3 were purchased from Sigma-Aldrich. AuCl(C4H8S) was purchased from Strem Chemicals. Other chemicals were obtained from commercial sources and used without further purification. 4.3 Experimental Procedures General Procedures for Preparation of 1- (Phenylethynyl)cyclopentyl α-Diazo-α-phenylacetate 1a: To a solution of phenylacetylene (1.02 g, 10.0 mmol) in dry THF (50 mL) was added n-BuLi ( 4.4 mL, 11.0 mmol) dropwise under nitrogen atmosphere at - 78 o C. After stirring at -78 o C for 1 h, cyclopentanone ( 924 mg, 11 mmol) was added, and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for another 10 h, the reaction mixture was quenched with aqueous NH4Cl solution (50 mL), and then extracted with diethyl ether (50 mL×2) and dried over anhydrous MgSO4. After evaporating the solvent, the crude product was purified by column 37 chromatography (hexane/ethyl acetate = 10/1) to give 1- (phenylethynyl)cyclopentan-1-ol as a white solid (1.76 g, 95% yield) To a solution of 1-(phenylethynyl)cyclopentan-1-ol (930 mg, 5 mmol), phenylacetic acid (816 mg, 6mmol) and DMAP (122 mg, 1 mmol) in dry DCM (30 mL) was added to a solution of DCC (1.24g, 6 mmol) in dry DCM (20 mL) via addition funnel over 20 min at 0 o C. The resulting mixture was allowed to warm to room temperature over 1 h, and stirred for another 10 h, and a white solid was formed in the process. The reaction solution was added to 30 mL of hexanes and filtered by Büchner funnel. After evaporating the solvent under reduced pressure, the resulting reaction mixture was purified by column chromatography (hexane/ethyl acetate = 25/1) to give 1-(phenylethynyl)cyclopentyl 2- phenylacetate as a colorless oil (1.29 g, 85% yield). To a solution of 1-(phenylethynyl)cyclopentyl 2-phenylacetate (1.29 g, 4.2 mmol) and 4-acetamidobenzenesulfonyl azide (p-ABSA) (1.20 g, 5 mmol) in dry CH3CN (30 mL) was added 1,8- diazabicycloundec-7-ene (DBU) (0.76g, 5mmol) dropwise at 0 o C. The resulting mixture was allowed to warm to room temperature over 30 min and stirred for another 10 h. The reaction was quenched with aqueous NH4Cl solution (60 mL) and then extracted with diethyl ether (50 mL×2) 38 and dried over anhydrous MgSO4. After evaporating the solvent, the resulting mixture was purified by column chromatography (hexane/ethyl acetate = 30/1) to give 1-(phenylethynyl)cyclopentyl α-diazo-α- phenylacetate 1a as a yellow solid (1.13 g, 82% yield). Compounds 1b – 1j were prepared from the corresponding arylacetic acids, ketones, or alkynes using the same synthetic procedure as 1a. General Procedure for Catalyst Screening: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, transition metal catalyst (0.010 mmol) and 2.0 mL DCM were added under nitrogen atmosphere [for Rh2(OAc)4 and Rh2(TFA)4, only 1 mol% catalyst was used]. . 1-(Phenylethynyl)cyclopentyl 2-diazo-2-phenylacetate 1a (0.20 mmol) dissolved in 2.0 mL of DCM was added in one portion into the solution under a flow of nitrogen. The resulting mixture was stirred at room temperature and monitored periodically by TLC. Upon consumption of the 2-diazo-2-phenylacetate 1a (1 – 48 h), the reaction 39 mixture was purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure 8'- phenylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]-3'(8'H)-one 2a and General Procedure for Copper-Catalyzed Domino Cascade Reaction of 1-(Phenylethynyl)cyclopentyl α-Diazo-α-phenylacetate 1a: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, CuPF6(MeCN)4 (0.010 mmol) and 2.0 mL DCM were added under nitrogen atmosphere. 1-(Phenylethynyl)cyclopentyl 2-diazo-2- phenylacetate 1a (0.20 mmol) dissolved in 2.0 mL of DCM was added in one portion into the solution under a flow of nitrogen. The resulting mixture was stirred for 1 h at room temperature (20 °C). The reaction mixture was purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure 8'- phenylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]-3'[8'H]-one 2a as a white solid (90% yield) The same procedure was used with other transition metal complexes. 40 General Procedure for FeCl3-Catalyzed Reaction of 1- (Phenylethynyl)cyclopentyl α-Diazo-α-phenylacetate 1a: To a flame- dried 10 mL Schlenk flask charged with a magnetic stirbar. FeCl3 (0.020 mmol) and 2.0 mL DCE were added under nitrogen atmosphere. 1- (Phenylethynyl)cyclopentyl 2-diazo-2-phenylacetate 1a (0.20 mmol) dissolved in 2.0 mL of DCE was added in one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 12 h at 60 °C; crude product was purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure 3a (70%) yield as colorless oil and 4a (20 % yield) as a white solid. 41 General Procedure for FeCl3-Catalyzed Reaction of tert-Butyl 2- Diazo-2-phenylacetate and 2-Methyl-4-phenylbut-3-yn-2-yl acetate: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar. FeCl3 (0.020 mmol) and 2.0 mL DCE were added under a nitrogen atmosphere. tert-Butyl 2-diazo-2-phenylacetate (0.20 mmol) and 2- methyl-4-phenylbut-3-yn-2-yl acetate (0.20 mmol) dissolved in 2.0 mL of DCE were added in one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 12 h at 60 °C; the reaction mixture was purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure 3g (70% yield) as colorless oil and 4g (12 % yield) as a white solid. 4.4 Characterization Data 1-(Phenylethynyl)cyclopentyl α-Diazo-α-phenylacetate 1a: 66% yield. Yellow solid, m.p. 52.7 – 54.1℃. 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.9 Hz, 2H), 7.47 – 7.43 (comp, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.31 – 7.27 (comp, 3H), 7.18 (t, J = 7.4 Hz, 1H), 2.46 – 3.39 (comp, 2H), 42 2.35 – 2.27 (comp, 2H), 1.89 – 1.80 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.50, 131.82, 128.85, 128.28, 128.11, 125.69, 125.63, 123.95, 122.66, 89.34, 85.08, 82.16, 40.77, 23.44. IR (neat) 2089, 1704, 1353, 1250, 1151, 905 cm -1 . HRMS (ESI) m/z calculated for C21H18N2O2Cs + [M+Cs] + 463.0417, found: 463.0419. 1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(4- methoxyphenyl)acetate 1b: 69% yield. Orange oil. 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 2H), 7.44 – 7.39 (comp, 2H), 7.33 – 7.28 (comp, 3H), 6.97 – 6.92 (comp, 2H), 3.82 (s, 3H), 2.42 (ddd, J = 12.3, 7.8, 3.7 Hz, 2H), 2.35 – 2.26 (comp, 2H), 1.90 – 1.78 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 164.06, 157.97, 131.84, 128.27, 128.11, 125.87, 122.72, 117.07, 114.56, 89.46, 85.01, 82.04, 55.35, 40.79, 23.46. IR (neat) 2954, 2075, 1702, 1512, 1255, 1145, 997 cm -1 ; HRMS (ESI) m/z calculated for C22H20N2O3Na [M+Na] + 383.1366, found: 383.1361. 43 1-(Phenylethynyl)cyclopentyl α-Diazo-α-(p-tolyl)acetate 1c: 64%. Yellow solid, m.p. 60.2 – 61.5℃. 1H NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.32 – 7.27 (comp, 3H), 7.21 (d, J = 8.1 Hz, 2H), 2.46 – 2.40 (comp, 2H), 2.35 (s, 3H), 2.34 – 2.26 (comp, 2H), 1.89 – 1.82 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.69, 135.50, 131.77, 129.55, 128.22, 128.06, 124.03, 122.66, 122.22, 89.39, 84.99, 82.01, 40.73, 23.41, 20.93. IR (neat) 2087, 1703, 1250, 1150, 906 cm -1 . HRMS (ESI) m/z calculated for C22H20N2O2Na + [M+Na] + 367.1417, found: 367.1431. 1-(Phenylethynyl)cyclopentyl 2-(4-Bromophenyl)-2- diazoacetate 1d: 68% yield. Yellow solid, m.p. 80.5 – 82℃. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 2H), 7.46 – 7.42 (comp, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.31 – 7.26 (comp, 3H), 2.45 – 2.36 (comp, 2H), 2.34 – 2.26 (comp, 2H), 1.86 – 1.78 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.12, 131.92, 131.81, 128.36, 128.14, 125.34, 124.87, 122.57, 119.20, 89.14, 85.24, 82.43, 40.77, 23.44. IR (neat) 2088, 1702, 1491, 44 1245, 1150, 903 cm -1 . HRMS (ESI) m/z calculated for C21H17N2O2BrNa + [M+Na] + 431.0366, found: 431.0381. 1-(Phenylethynyl)cyclopentyl 2-(4-Chlorophenyl)-2- diazoacetate 1e: 65% yield. Yellow solid, m.p. 56.5 – 58.1℃. 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.40 (comp, 4H), 7.34 (d, J = 7.1 Hz, 2H), 7.30 – 7.26 (comp, 3H), 2.44 – 2.38 (comp, 2H), 2.34 – 2.27 (comp, 2H), 1.87 – 1.79 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.18, 131.81, 131.33, 128.99, 128.34, 128.13, 125.06, 124.29, 122.57, 89.15, 85.21, 82.40, 40.76, 23.43. IR (neat) 2088, 1702, 1250, 1150, 745 cm -1 . HRMS (ESI) m/z calculated for C21H17N2O2ClCs + [M+Cs] + 497.0028, found: 497.0036. 1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(4-nitrophenyl)acetate 1f: 54% yield. Yellow solid, m.p. 113.4 – 114.5℃. 1H NMR (500 MHz, 45 CDCl3) δ 8.22 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.47 – 7.42 (comp, 2H), 7.32 – 7.27 (comp, 3H), 2.46 – 2.38 (comp, 2H), 2.35 – 2.28 (comp, 2H), 1.92 – 1.78 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 162.03, 144.95, 134.04, 131.80, 128.49, 128.18, 124.20, 123.18, 122.38, 88.72, 85.57, 83.07, 40.75, 23.42. IR (neat) 2095, 1708, 1594, 1335, 1245, 1152, 903 cm -1 . HRMS (ESI) m/z calculated for C21H17N3O4Na + [M+Na] + 398.1111, found: 398.1135. 2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazo-2-phenylacetate 1g: 63% yield. Orange oil. 1 H NMR (300 MHz, CDCl3) δ 7.53 – 7.43 (comp, 4H), 7.41 – 7.35 (comp, 2H), 7.32 – 7.27 (comp, 3H), 7.21 – 7.14 (m, 1H), 1.85 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 163.35, 131.85, 128.86, 128.39, 128.15, 125.73, 125.70, 124.03, 122.52, 89.95, 84.47, 73.81, 29.44. IR (neat) 2936, 2079, 1705, 1498, 1349, 1247, 1120, 754, 691 cm - 1 ; HRMS (ESI) m/z calculated for C19H16N2O2Na [M+Na] + 327.1104, found: 327.1102. 46 1-(Phenylethynyl)cyclobutyl 2-Diazo-2-phenylacetate 1h: 52% yield. Yellow solid, m.p. 76 – 77 °C. 1H NMR (500 MHz, CDCl3) δ 7.52 (dd, J = 8.5, 1.1 Hz, 2H), 7.50 – 7.45 (comp, 2H), 7.42 – 7.36 (comp, 2H), 7.34 – 7.29 (comp, 3H), 7.23 – 7.16 (m, 1H), 2.81 – 2.71 (comp, 2H), 2.62 (ddd, J = 12.7, 9.7, 2.6 Hz, 2H), 2.15 – 2.05 (m, 1H), 2.00 (qdd, J = 9.9, 8.6, 4.9 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 163.24, 131.94, 128.90, 128.43, 128.16, 125.80, 125.45, 123.98, 122.54, 89.16, 84.79, 73.26, 37.18, 14.65. IR (neat) 2952, 2081, 1704, 1497, 1351, 1242, 1144, 1088, 754, 691 cm -1 ; HRMS (ESI) m/z calculated for C20H16N2O2Na [M+Na] + 339.1104, found: 339.1107. 1-(Phenylethynyl)cyclohexyl 2-Diazo-2-phenylacetate 1i: 66% yield. Yellow solid, m.p. 50 – 51 °C. 1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 8.5, 1.1 Hz, 2H), 7.50 – 7.45 (comp, 2H), 7.42 – 7.36 (comp, 2H), 47 7.34 – 7.28 (comp, 3H), 7.21 – 7.16 (m, 1H), 2.36 – 2.21 (comp, 2H), 2.09 (comp, 2H), 1.81 – 1.65 (comp, 4H), 1.62 – 1.53 (m, 1H), 1.45 (ddd, J = 13.1, 8.5, 4.8 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 163.07, 131.87, 128.85, 128.32, 128.14, 125.79, 125.66, 124.02, 122.70, 89.06, 86.54, 77.10, 37.48, 25.17, 22.72. IR (neat) 2936, 2083, 1707, 1241, 754, 691 cm -1 ; HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na] + 367.1417, found: 367.1410. 1-(phenylethynyl)cyclopentyl 2-Diazo-2-phenylacetate 2a: 94% yield. White solid, m.p. 128 – 129 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.33 - 7.30 (comp., 3H), 7.27 - 7.24 (comp., 2H), 7.08 - 7.06 (comp., 2H), 4.80 (s, 1H), 2.11 - 2.08 (comp., 2H), 2.07 -2.02, (m, 1H), 2.01 - 1.98 (m, 1H), 1.98 – 1.82 m, 1H), 1.81 – 1.69 (m, 1H), 1.67 – 1.55 (m, 1H), 1.33-1.25 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 179.0, 166.4, 152.0, 136.1, 135.9, 134.3, 129.1, 128.1, 127.9, 127.7, 125.0,120.9, 95.5, 52.4, 38.5, 36.7, 24.4. HRMS 48 (ESI) m/z calculated for C21H18O2Na [M+Na] + 325.1199, found: 325.1200. 5'-Methoxy-8'-phenylspiro(cyclopentane-1,1'-indeno[1,2- c]furan)-3'(8'H)-one 2b: 98% yield. White solid, m.p. 152 – 153 °C.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J= 8.3 Hz, 1H), 7.22 - 7.20 (comp., 3H), 6.98 - 6.96 (comp., 2H), 6.81 - 6.78 (m, 1H), 6.70 - 6.69 (m, 1H), 4.65 (s, 1H), 3.66 (s, 3H), 1.98 - 1.94 (comp., 2H), 1.88 – 1.86 (m, 1H), 1.78 – 1.74 (m, 1H), 1.71 – 1.66 ( m, 1H),1.59 – 1.54 (m, 1H), 1.47 – 1.40 (m, 1H), 1.20-1.12 (m, 1H); 13 C NMR (100 MHz, CDCl3) 176.9, 166.5, 159.2, 153.9, 136.1, 135.6, 129.0, 128.1, 127.8, 127.0, 121.3, 112.6, 111.8, 95.4, 55.4, 52.4, 38.3, 36.7, 24.3. HRMS (ESI) m/z calculated for C22H21O3Na [M+Na] + 355.1305, found: 355.1309. 49 5'-Methyl-8'-phenylspiro[cyclopentane-1,1'-indeno[1,2- c]furan]-3'[8'H]-one 2c: 98% yield. White solid, m.p. 98 – 99 °C. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 1H), 7.24 - 7.18 (comp., 3H), 7.09 (d, J = 8.4 Hz, 1H), 6.98-6.95 (comp., 3H), 4.66 (s, 1H), 2.24 (s, 3H), 1.99 - 1.96 (comp., 2H), 1.93 – 1.86 (m, 1H), 1.82 – 1.75 (m, 1H), 1.73 – 1.64 (m, 1H), 1.63 - 1.56 (m, 4H),1.50-1.41 (m,1H),1.21-1.14 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 178.1, 166.6, 152.3, 136.9, 136.2, 136.0, 131.5, 129.1, 128.4, 128.1, 127.8, 125.8, 120.5, 95.4, 52.3, 38.4, 36.7, 24.3, 21.5. HRMS (ESI) m/z calculated for C22H20O2Na [M+Na] + 339.1361, found: 339.1371. 5'-Bromo-8'-phenylspiro(cyclopentane-1,1'-indeno[1,2- c]furan)-3'[8'H}-one 2d: 86% yield. White solid, m.p. 143 – 144 °C.1H 50 NMR (500 MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.34 – 7.32 (m, 1H), 7.33 – 7.29 (comp., 3H), 7.08 – 6.99 (comp., 2H), 4.77 (s, 1H), 2.10 – 2.04 (comp., 2H), 2.01 – 1.93 (m, 1H), 1.90 – 1.83 (m, 1H), 1.79 – 1.73 (m, 1H), 1.70 – 1.65 (m, 1H), 1.55 – 1.51, (m, 1H), 1.29 – 1.22 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 179.09, 165.92, 153.83, 135.45, 134.89, 133.20, 130.91, 129.27, 128.40, 128.19, 128.05, 122.04, 120.96, 95.44, 52.42, 38.41, 36.72, 24.42, 24.33. C21H17O2BrNa [M+Na] + 403.0310, found: 403.0306. 5'-Chloro-8'-phenylspiro[cyclopentane-1,1'-indeno[1,2- c]furan]-3'(8'H)-one 2e: 78% yield. White solid, m.p. 101 – 102 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 1H), 7.29-7.24 (comp., 4H), 7.19-7.12 (m, 1H), 6.98-6.96 (comp., 2H), 4.70 (s, 1H), 2.02 – 1.97 (comp., 2H), 1.93 – 1.87 (m, 1H), 1.83 – 1.77 (m , 1H), 1.72 – 1.67 (m, 1H), 1.64 – 1.57 (m, 1H), 1.51 - 1.45 (m, 1H), 1.23-1.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 179.1, 166.0, 153.6, 135.5, 135.0, 133.0, 51 132.8, 129.3, 128.2, 128.1, 125.6, 121.7, 95.5, 52.5, 38.5, 36.8, 24.5, 24.4. C21H17O2ClNa [M+Na] + 359.0815, found: 359.0821. 5'-Nitro-8'-phenylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]- 3'(8'H)-one 2f: 15% yield. White solid, m.p. 162 – 163 °C.1H NMR (500 MHz, CDCl3) δ 8.34 – 8.30 (m, 1H), 8.09 – 8.06 (m, 1H), 7.87 – 7.82 (m, 1H), 7.36 – 7.32 (m, 3H), 7.05 (s, 2H), 4.90 (s, 1H), 2.15 – 2.07 (m, 2H), 2.03 – 1.98 (m, 1H), 1.92 – 1.87 (m, 1H), 1.84 – 1.78 (m, 1H), 1.75 – 1.71 (m, 1H), 1.59 – 1.56 (m, 1H), 1.33 – 1.29 (m, 1H).13C NMR (125 MHz, CDCl3) δ 183.53, 165.26, 153.04, 146.99, 140.43, 135.21, 133.69, 129.60, 128.72, 128.05, 124.30, 121.13, 120.42, 95.84, 52.92, 38.64, 36.88, 24.54, 24.46. C21H17NO4Na [M+Na] + 370.1055, found: 370.1047. 52 2-Methyl-4-phenylbut-3-yn-2-yl 2-diazo-2-phenylacetate 2g: 90% yield; white solid, m.p. 88 – 89 °C.1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.32-7.28 (m, 1H), 7.24-7.14 (comp., 5H), 6.98-6.96 (comp., 2H), 4.70 (s, 1H), 1.54 (s, 3H), 1.03 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 181.9, 166.2, 151.6, 135.6, 135.1, 134.3, 129.1, 128.2, 127.9, 127.8, 127.0, 121.1, 85.4, 52.5, 26.4, 25.7. C19H16O2Na [M+Na] + 299.1043, found: 299.1050. 8'-Phenylspiro[cyclobutane-1,1'-indeno[1,2-c]furan]-3'(8'H)- one 2h: 90% yield; white solid, m.p. 150 – 151 °C.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J= 8.2 Hz, 1H), 7.38-7.32 (comp., 4H), 7.27-7.21 (comp., 2H), 7.15-7.13 (comp., 2H), 4.89 (s, 1H), 2.82-2.74 (m, 1H), 2.51-2.47 (comp., 2H), 1.84-1.73 (comp., 2H), 1.60-1.50(m, 1H); 13 C NMR (100 MHz, CDCl3) δ 178.2, 166.2, 152.2, 135.8, 135.5, 133.8, 129.0, 128.1, 127.9, 127.0, 125.0, 120.9, 85.9, 52.4, 33.3, 31.7, 12.2. C20H16O2Na [M+Na] + 311.1048, found: 311.1062. 53 8'-Phenylspiro[cyclohexane-1,1'-indeno[1,2-c]furan]-3'(8'H)- one 2i: 80% yield; white solid, m.p. 175 – 176 °C. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.33 – 7.29 (m, 3H), 7.24 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.07 – 7.03 (comp., 2H), 4.76 (s, 1H), 1.85 – 1.77 (comp., 3H), 1.75 – 1.46 (comp., 3H), 1.43 – 1.39 (comp., 2H), 1.19 – 1.08 (m, 1H), 1.06 – 0.97 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 182.00, 166.60, 151.83, 135.67, 135.23, 134.24, 129.05, 128.25, 127.85, 127.69, 126.94, 125.01, 121.01, 87.36, 52.66, 35.68, 34.67, 24.30, 22.09, 21.70. C22H20O2Na [M+Na] + 339.1361, found: 339.1364. 8'-Cyclopropylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]- 3'[8'H]-one 2j: 80% yield; White solid, m.p. 135 – 136 °C. 1H NMR 54 (500 MHz, CDCl3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 2.89 (d, J = 9.6 Hz, 1H), 2.57 – 2.47 (m, 1H), 2.17 – 1.89 (m, 7H), 0.93 – 0.83 (m, 1H), 0.81 – 0.69 (m, 3H), 0.46 (td, J = 9.6, 5.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 179.22, 150.67, 135.79, 134.10, 127.70, 126.46, 124.41, 120.80, 95.64, 51.79, 38.78, 36.84, 25.07, 24.92, 11.84, 4.82, 4.33. C18H18O2Na [M+Na] + 289.1024, found: 289.1026. 5-Cyclopentylidene-3,4-diphenylfuran-2[5H]-one 4a: 20% yield; White solid, m.p. 93 – 94 °C. 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.42 (comp., 3H), 7.41 – 7.37 (comp., 2H), 7.29 – 7.25 (comp., 2H), 7.25 – 7.19 (comp., 3H), 2.77 (t, J = 6.9 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.71 – 1.63 (comp., 2H), 1.62 – 1.56 (comp., 2H). 13C NMR (125 MHz, CDCl3) δ 168.88, 148.98, 141.50, 136.31, 132.76, 129.82, 128.96, 128.95, 128.39, 128.21, 128.08, 125.69, 32.54, 30.49, 27.32, 25.31. HRMS (ESI) m/z calculated for C21H18O2Na [M+Na] + 325.1199, found: 325.1191. 55 3,4-Diphenyl-5-(propan-2-ylidene)furan-2[5H]-one 4g: 17 % yield; White solid, m.p. 87 – 88 °C.1H NMR (500 MHz, CDCl3) δ 7.45 – 7.40 (m, 3H), 7.35 – 7.31 (m, 2H), 7.29 – 7.26 (m, 2H), 7.23 – 7.18 (m, 3H), 2.10 (s, 3H), 1.47 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 168.40, 148.80, 144.04, 133.33, 129.71, 129.03, 129.00, 128.90, 128.48, 128.24, 128.04, 127.18, 125.64, 21.19, 19.17. 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Tetrahedron Lett. 2002, 43, 1289-1293. 62 Chapter 2: Unprecedented Rearrangement of Propargyl Aryldiazoacetates. Gold Catalysis Forms Allenes Whose Intramolecular Reaction with the Terminal Diazo Nitrogen Yields 1,5-Dihydro-4H- pyrazol-4-ones I Introduction 1.1 Discovery of the Rearrangement Process Because of the positioning of their two reaction centers (diazo and alkyne), we have been intrigued with the reactions of propargyl diazoacetates since both reaction centers are known to initiate reaction processes that are characteristic of their requisite functional groups. In Chapter 1, we disclosed that a variety of transition metal complexes that include Rh2(OAc)4, Rh2(tfa)4, Pd(OAc)2, PdCl2(PhCN)2, [Pd(η 3 - C₃H₅)Cl]₂, AgSbF6, Au(JohnPhos)SbF6, IPrAuBF4, Cu(OTf)2, CuBF4(MeCN)4, and CuPF6(MeCN)4 undergo carbene/alkyne domino cascade reactions. During the screening of the transition metal complexes with propargyl phenyldiazoacetate, we found that the carbene/alkyne 63 domino cascade product was not observed under catalysis by AuCl(C4H8S); but, instead, two isomeric 1H-pyrazolines that retain dinitrogen were obtained (Scheme 2.1). Scheme 2.1 Catalysts Screening Leads to Discovery of the Rearrangement Process. 1.2 General Information for Gold Catalysis Gold catalysis provides powerful methodologies for unique metallo-organic transformations. 1 Activation of organic functional groups by gold(I) and gold(III) complexes initiates diverse pathways for often unique reactions. 2 Many of the transformations developed with gold complexes involve activating carbon-carbon unsaturated bonds as electrophiles. 3 Alkynes have been recognized as the most successful substrates in gold catalyzed reactions. 4 The most common reaction pattern involves the coordination of gold complexes with internal alkynes that lead to a loss of π-electron density, which allows nucleophilic attack 64 on the activated alkynes to produce trans-alkenyl gold complexes (Scheme 2.2). Scheme 2.2 Equation for Gold-Catalyzed Activation of Alkynes toward a variety of Nucleophiles. 1.3 Gold-Catalyzed 1,3-Acyloxy Migration of Propargyl Esters and Subsequent Transformations One of the most useful of these transformations has been that of propargyl esters, which form allenes by 1,3-acyloxy migration, then undergo varied catalytic reactions. 5 A wide array of subsequent transformations that involve this highly valuable intermediate have been widely used in constructing mono-, bicycles, and other important compounds over the past decade (Scheme 2.3). 6 65 Scheme 2.3 Formation of Allenes and Subsequent Transformations to Form Diverse Carbocycles and Heterocycles. II. Results and Discussion 2.1 Initial Assessment of Gold Catalysts and Attempts to Determine the Structure of Rearrangement Products Initial assessment of gold catalysis was evaluated with propargyl aryldiazoacetates using cationic gold(I) catalysts, including those formed from ligated gold(I) chloride and silver salts. Cationic gold catalysts are well-established -bond acceptors with aryldiazoacetates,7 and they have 66 been widely used for dinitrogen extrusion reactions of diazo compounds that are reported to produce the corresponding gold carbenes.8 Catalytic reactions of phenylpropargyl phenyldiazoacetate 1 with representative Au(I)+ catalysts formed the product from the carbene-initiated domino transformation 2 in good yield (Scheme 2.4). Complete conversion of the reactant was observed at room temperature, and no other discernable product was identified. Each of the gold catalysts was soluble in the reaction solution. Scheme 2.4 Domino Reaction of Propargyl Phenyldiazoacetate 1 Catalyzed by Cationic Gold(I). Neutral gold(I) and gold(III) compounds are reported to have varying influences on reactions with diazo and alkyne functional groups.9 A survey of representative compounds for reactions with 1 at 20 °C revealed that 5 mol % of chloro(tetrahydrothiophene)gold(I) [AuCl(C4H8S)] catalyzed its complete conversion to three discernable products in the highest yield (Scheme 2.5). The surprising conversion of 67 1 to 3 and 4 retained all of the atoms of the reactant but gave extensive rearrangement, including the conversion of the reactant ester to product 1,5-dihydro-4H-pyrazol-4-ones. Scheme 2.5 Products from Gold(I)-Catalyzed Rearrangement of Phenylpropargyl Phenyldiazoacetate 1. Compounds 3 and 4 were observed spectroscopically to be related as structural isomers, and the crystal structure of 4 was obtained (Figure 2.1a) after its isolation from the reaction mixture. Recognition of 3 and 4 as potential benzoyl transfer agents prompted us to convert 3 and 4, individually and as a mixture, quantitatively to the same 4- hydroxypyrazole 6 by treatment with nucleophilic bases that included hydrazines and amines (X-Ray structure of analog 6ʹ, Figure 2.1b). Compound 5, although present in very low yield, was confirmed by 68 spectral and chromatographic comparison with the characterized compound (discussed in the next chapter).10 Figure 2.1 X-Ray Structures of 1,5-Dihydro-4H-Pyrazol-4-One 4 and Deacylation Product 6ʹ. 2.2 Optimization of Reaction Conditions and Monitoring the Reaction Process Under the catalysis of 5 mol% AuCl(C4H8S), different solvents were examined in attempts to increase the yield of 1,5-dihydro-4H- pyrazol-4-ones as well as improve the ratios of 3:4 at room temperature. Use of chloroform and dichloromethane failed to increase product yields and resulted in the decreased 3:4 product ratios (Table 2.1, entries 2 and 3). Toluene gave the improved 3:4 product ratios compared to 1,2- dichloroethane, but the yield of 1,5-dihydro-4H-pyrazol-4-ones was only 29% (Table 2.1, entry 4). Polar solvents that include tetrahydrofuran and acetonitrile showed lower yield of product, but had a great influence on the 3:4 product ratios (Table 2.1, entries 5 and 6). Overall, examination of this reaction as a function of solvent did not provide any improvement in the product yield, but did show significant variation in the 3:4 product ratios. 69 Table 2.1 Solvent Screening for the Reaction of 1 with AuCl(C4H8S) Entry a Solvent b Conversion (%) 1 c Yield (%) 3+4 c Ratio 3:4 c Yield (%) 5 c 1 1,2- Dichloroethane >95 76 72:25 2 2 Chloroform >95 57 65:35 3 3 Dichloromethane >95 43 40:60 5 4 Toluene >95 29 80:20 10 5 Tetrahydrofuran >95 40 65:35 3 6 Acetonitrile >95 30 37:63 1 aReactions were carried out on 0.20 mmol scale: a solution of 1 (0.20 mmol) in 2.0 mL of solvent was added to a solution of 5 mol % AuCl(C4H8S) in 2.0 mL of solvent under a nitrogen atmosphere at 20 oC, and the resulting reaction mixture was stirred for 72 h. bNo reaction occurred for reactions performed in hexane or nitromethane. cConversion of 1, yields of (3+4), 5. Ratios 3:4 were determined by 1H NMR analysis of characteristic peaks using 2,4,6-trimethoxybenzene as the internal standard. To determine if this product variation could be due to an equilibrium between 3 and 4 under the reaction conditions, the formation of 3 and 4 in DCE was followed as a function of time over ten days at room temperature with high product accountability, and the results from this investigation (Figure 2.2) clearly show an equilibrium between 3 and 70 4. Slow deacylation resulting in 6 complicates the overall picture, but conclusions can be drawn that compound 3 is the product of kinetic control at room temperature, and 4 is the product of thermodynamic control. Figure 2.2 Time Course for the Formation of 3, 4, and 6 in DCE at 20 ⁰C. (Yields were determined by 1 H NMR and HPLC analyses of the reaction mixture after selected periods of time using 1,3,5-trimethoxybenzene as the internal standard; reported yields are the averages of two runs; reactions and analyses performed by Kostiantyn Marichev.) Experiments performed at higher temperatures (50 and 84 °C) are consistent with this interpretation (Table 2.2). Compound 4 is the major isomer even at lower conversions of diazo compound 1. At 50 °C the maximum total yield of 3+4 is 81% at a 12 h reaction time, and the ratio 3:4 is 2:3; whereas at 84 °C the reaction is complete (total yield of 3+4 is 80%) after 6 h, and 3:4 is 1:1. Continuing the reaction further at these higher temperatures leads to lower product yield as the result of deacylation from which 4-hydroxypyrazole 6 is formed. 71 Table 2.2 Temperature Screening for the Reaction of 1 with AuCl(C4H8S). Entry a Temp (°C) Time (h) Yield (%) (3+4) b Ratio 3:4 b 1 50 3 35 45:55 2 50 6 56 42:58 3 50 12 81 40:60 4 50 24 64 37:63 5 84 3 53 48:52 6 84 6 80 45:55 7 84 12 79 43:57 8 84 24 48 45:55 a Reactions were carried out on 0.20 mmol scale: a solution of 1 (0.20 mmol) in 2.0 mL of solvent was added to a solution of 5 mol % AuCl(C4H8S) in 2.0 mL of solvent under a nitrogen atmosphere at 20 o C, and the resulting reaction mixture was heated for defined periods of time. b Yields and ratios were determined by 1 H NMR analyses of the reaction mixture using 1,3,5-trimethoxybenzene as the internal standard. 72 Cationic gold(I) and the neutral chloro(tetrahydrothiophene)gold(I) catalysts are mutually exclusive for product formation from reactions with 1. Both catalysts are active at room temperature, and their application provides products from reactions at the diazo functional group [2 from cationic gold(I)] and the alkyne functional group [3, 4, and 5 from AuCl(C4H8S)] in good yields. Neutral gold(I) chloride complexes having strongly coordinating ligands (Table 2.3) show very low or negligible conversion of phenylpropargyl phenyldiazoacetate 1 under the same conditions, even to reaction times of three days. However, heating these complexes to the temperature of refluxing 1,2-dichloroethane for up to 48 h gives the domino reaction product 2 exclusively or as the major product (Table 2.3, entries 1-6), albeit usually with low product yield and, generally, low % conversion. The dimethylsulfide coordinated AuCl (Table 2.3, entries 9-10) is not as effective a catalyst as its tetrahydrothiophene analog (Table 2.3, entries 7-8) with product yields only about half those found with AuCl(C4H8S). Gold(III) catalysts (Table 2.3, entries 11-14) are also less efficient than the AuCl(R2S) catalysts in the formation of compounds 3 and 4, but they afford diene 5 in yields up to 39% and give no evidence for the formation of 2. 73 Table 2.3 Screening of Gold(I) and Gold(III) Catalysts in Reactions with Phenylpropargyl Phenyldiazoacetate 1. Entry a Gold Catalyst Temp (°C) Conversion (%) 1 Yield (%) 2 b Yield (%) 3+4 b Ratio 3:4 b Yield (%) 5 b 1 AuCl(IPr) 84 d (20) 68 (<5) 46 2 AuCl(CO) 84 (20) >95 (14) 16 (9) 14 47:53 9 3 AuCl[P(OMe)3] 84 c (20) 40 (<5) 25 3 4 AuCl(PPh3) 84 c (20) 35 (<5) 23 5 AuCl(PMe3) 84 c (20) 45 (<5) 20 8 40:60 6 6 84 c (20) 70 (<5) 57 7 AuCl(C4H8S) i 20 >95 76 75:25 2 8 AuCl(C4H8S) 84 >95 80 45:55 4 9 AuCl(Me2S) 20 >95 42 62:38 3 10 AuCl(Me2S) 84 >95 46 45:55 5 74 11 e AuPicCl2 j 20 >95 21 50:50 14 12 f AuPicCl2 j 84 >95 14 40:60 18 13 g AuCl3(Pyridine) j 20 >95 25 60:40 35 14 h AuCl3(Pyridine) j 84 >95 18 45:55 39 aReactions were performed on 0.10 mmol scale: a solution of 1 (0.10 mmol) in DCE (1.0 mL) was added to a solution of Au-catalyst (5 mol %) in DCE (1.0 mL) under a nitrogen atmosphere at 20 °C (% conversion in parenthesis for entries 1-6) or in refluxing DCE, and the resulting reaction mixture was stirred for defined periods of time. bConversion of 1, yields of 2, (3+4), 5, and ratios 3:4 were determined by 1H NMR analysis of characteristic peaks using 2,4,6-trimethoxybenzene as the internal standard. Reaction times were 72 h for the reactions carried out at 20 °C, and 6 h at 84 °C. Reaction times: c12 h; d48 h. Yield of product 6: e24%; f27%; g32%; h38%. iAt 50 °C after 12 h: 81% yield of 3+4 with 3:4 = 40:60. jReduction of the catalyst to elemental gold is significant. 2.3 Reaction Mechanism A stepwise mechanism for the neutral gold(I)-catalyzed rearrangement of arylpropargyl aryldiazoacetate 9 is given in Scheme 2.6. The AuCl(R2S) catalyzed 1,3-acyloxy rearrangement of 9 produces carboxyallene C that undergoes a unique rearrangement between allene C and the diazo functional group to form the observed 3 directly in a concerted fashion or stepwise through intermediate D. Diene 12 is formed from gold-activated carboxyallene A, presumably through gold- coordinated acylium ion intermediate B. Compound 10 is formed initially from A and undergoes acyl migration to reach equilibrium with 11. This mechanism explains the formation of 10 from carboxyallene C, the 75 equilibrium that exists between 10 and 11, and the formation of (Z)-diene 12. Scheme 2.6 Proposed Mechanism for the Formation of 10, 11, and 12 from 9. 2.3a Formation of Allene Close examination of the reaction process by NMR spectroscopy revealed that the key transformation in the formation of 3 and 4 was the generation of allene (Scheme 2.6), which occurred within 5 min at 20 C. For these investigations the dimethyl analog (7) of cyclopentylpropargyl phenyldiazoacetate 1 was used (Eq 1) to assess the course of the reaction. Allene 8 formation,6b which occurs by 1,3-acyloxy transfer, begins to 76 take place immediately upon addition of the catalyst [5 mol % AuCl(Me2S) or AuCl(C4H8S)] as the only reaction product, and reaches an apparent equilibrium (7:8 = 45:55 with either catalyst). With added gold catalyst up to 2 equiv. based on 7 no further change in the 7:8 ratio occurred. Confirmation of this process was made with phenyldimethylpropargyl benzoate under the same conditions (allene:alkyne = 3:2) and with 1 (allene:alkyne = 1:2). The validity of the reversibility of Au(I)-catalyzed [3,3]- rearrangements of propargylic esters has been reported by Toste and coworkers. 6h By introducing a stereochemically defined cyclopropane probe, the authors have disclosed both isomerization of the cyclopropyl moiety and propargyl moiety which indicates the reversibility of the gold(I)-catalyzed rearrangement propargylic esters. DFT studies on the reversibility of propargylic esters supported the experimental evidence. 77 Scheme 2.7 Further Insight into the Mechanism of Au(I)-Catalyzed [3,3]-Rearrangements of Propargylic Esters With propargyl diazoacetates additional stabilization by the diazo group of the cyclic carbocation intermediate on the pathway to allene formation could be expected. Furthermore, when the allene was isolated from the reaction mixture free of gold catalyst, the allene was observed to undergo slow conversion to the rearranged products corresponding to 3 and 4, but without any obvious formation of 5. This conversion was first order in 7 with a rate constant of 1.05 × 10−5 sec−1 at 20 °C, and addition of AuCl(Me2S) did not influence the reaction rate. The activation energy measured over 20−60 °C was 18.8 kcal/mol (R2 = 0.999) with ΔH‡ = 18.2 kcal/mol and ΔS‡ = −19.4 cal/deg-mol at 298 K (reaction and analysis performed by Kostiantyn Marichev). 2.3b Diazo Compounds as Electrophiles in Organic Transformations 78 Although diazo compounds are normally regarded as nucleophiles, with both the diazo carbon and the terminal nitrogen as nucleophilic centers,11 there are examples in which the terminal nitrogen atom of diazo compounds exhibits electrophilic reactivity.12 The formation of 10 can be considered to be initiated by intramolecular electrophilic addition of the N-terminus of the aryldiazoacetates onto the central carbon of the allene that is continued with hydrogen. Feng and coworkers discovered a scandium-catalyzed nucleophilic addition to α-diazoesters, in which ketones were the nucleophiles.13 With chiral N,N’-dioxide as the ligands for Sc(OTf)3, the reaction produces the addition products in excellent yields and enantioselectivities. To better understand this unusual process, the authors performed theoretical calculations, which showed that the positive charge on the terminal nitrogen atom greatly increases when the carbonyl oxygen of α- diazoesters coordinates with Sc(OTf)3 These reactions are intermolecular and involve obvious nucleophilic attack on the terminal nitrogen of 79 diazocarbonyl compounds and result in the formation of hydrazone derivatives (Scheme 2.8). Scheme 2.8 Intermolecular Electrophilic Addition of α-Diazoesters with Ketones. The intramolecular transformations that involve the electrophilic capability of diazo compounds are also documented in several other reports, 14 which are also referred to as electrocyclization of the diazo group. 15 For instance, in the process of investigating synthetic applications of benzocyclobutenes, Nemoto and coworkers have developed a one-pot reaction for synthesis of 2,3-benzodiazepines. In this reaction, the electrophilic capability of diazo compounds plays an important role in the formation of the cyclic product, which was obviously formed by intramolecular nucleophilic addition to the terminal nitrogen of the diazo group (Scheme 2.9). 15b Enolates were also reported as efficient nucleophiles in the reactions with diazo compounds by Doyle and coworkers, who have discovered that the enedione-diazoester undergoes intramolecular cycloaddition reaction to produce 1,2-diazepine 80 under basic conditions. The authors proposed a mechanism by which a similar intramolecular nucleophilic attack occurs on the terminal nitrogen process (Scheme 2.10). 15a Scheme 2.9 Synthesis of 2,3-Benzodiazepines from Benzocyclobutenes Scheme 2.10 Synthesis of 1,2-Diazepine from Enedione-Diazoester. 2.3c Formation of 1,3-Diene 81 Isomerization of allenes into 1,3-dienes under the catalysis of gold complexes has been reported previously.16 Gold-allene complexes are considered to be the initial intermediates in these transformations. Based on those reports,17 we propose a plausible mechanism for formation of 1,3-diene 12. The (Z)-diene 12 was considered to be generated from gold-allene complexes A, presumably through gold-coordinated acylium ion intermediate B. Acylium ion intermediate B underwent intermolecular 1,5-hydrogen shift, which produced the (Z)-diene-gold complex Bʹ, followed by a proton transfer process of the newly formed (Z)-diene-gold complex Bʹ, to furnish (Z)-diene 12. It should be noted that when the same reaction was performed in the presence of 4- chloropyridine-N-oxide, the isomeric (E)-diene could be observed (discussed in next chapter). Rearrangement of propargyl esters into 1,3-dienes in presence of gold catalysts has also been documented,18 and this rearrangement has been considered to occur though allene intermediates. Gevorgyan and coworkers developed a cascade process of double 1,3-acyloxy group migration/1,2-migration of hydrogen to produce (E)-1,3-dienes from alkynes via a gold-catalyzed cycloisomerization of propargylic esters. The authors proposed a pathway in which a gold-catalyzed 1,3-acyloxy 82 migration occurs via cyclic intermediates into allenes, followed by hydrogen migration to produce the (Z)-1,3-dienes (Scheme 2.11). Scheme 2.11 Formation of 1,3-diene from Gold-Catalyzed Propargyl Esters. 2.4 Substrate Scope The substrate scope of phenylpropargyl aryldiazoacetates 9a─k (Table 2.4) demonstrates that the AuCl(C4H8S)-catalyzed reaction is broadly appropriate for the synthesis of the 1,5-dihydro-4H-pyrazol-4- ones 10 and 11, and these reactions are tolerant of both electron-donating and electron-withdrawing substituents in the aryl group of the aryldiazoacetate. High total yields of the 10+11 composites are observed, and their 10:11 ratio is near 3:1 (Table 2.4). Substrate 9j with a 12- membered ring gives a high yield of the 10j+11j composite, but its 10:11 ratio is 3:2. Tetrahydropyranyl derivatives 10k+11k are obtained in only 46% yield and a 78:22 10:11 ratio. Table 2.4 Substrate Scope of Gold(I)-Catalyzed Reaction of Phenylpropargyl Aryldiazoacetates 9 a 83 9−11 Ar (Y = CH2) Yield (%) b, c Ratio 10:11 b a C6H5 76 75:25 b p-MeO-C6H4 75 72:28 c p-Me-C6H4 85 72:28 d p-Ph-C6H4 78 88:12 e p-Br-C6H4 87 85:15 f p-Cl-C6H4 83 83:17 g p-CF3-C6H4 73 70:30 h 2-C4H3S d 67 88:12 9−11 Y (Ar = C6H5) Yield (%) b, c Ratio 10:11 b i (CH2)2 73 78:22 j (CH2)8 86 59:41 84 k CH2O 46 78:22 aReactions were carried out at 20 °C on a 0.20 mmol scale: a solution of 1 in 2.0 mL DCE was added to a 5 mol % solution of AuCl(C4H8S) in 2.0 mL DCE under a nitrogen atmosphere, and the resulting reaction mixture was stirred for 72 h. bRatios and yields were determined by 1H NMR spectroscopy using 2,4,6- trimethoxybenzaldehyde as the internal standard. cIndividual compounds 10 and 11 were isolated and fully characterized (see Supporting Information). d2-C4H3S = 2-Thiophene. With substrates having electron-withdrawing or electron-donating groups (EWG or EDG) in both arene rings, the product outcome is quite similar (Scheme 2.12) to those presented in Table 2.4. However, having an EWG as Z and an EDG as X (compound 9o) results in a lower yield of 10o+11o (47%) but a higher 10:11 ratio of 89:11. High yield (79%) and almost exclusive formation of compound 10q (10:11 = 91:9) are observed from the dimethyl analog 9q, whereas the unsubstituted aryl analog 9p results in lower yield of 10p+11p (68%) with a 88:12 10:11 ratio. Scheme 2.12 Substrate Scope of Gold(I)-Catalyzed Reaction of Arylpropargyl Aryldiazoacetates 9. 85 The cyclobutyl analog 9r forms neither 10 nor 11. Instead, treatment of 9r with 5 mol % AuCl(C4H8S) affords 13 in good yield (70%), but only at 80 °C over 12 h. This product is consistent with initial formation of a gold-carbene intermediate through the diazo functional group. The alternate pathway through a strained allene intermediate is apparently too restrictive and, although the initial step in the 1,3-acyl rearrangement that produces the stabilized intermediate E is favorable, release of the C-O bond to form the allene does not occur (Scheme 2.13). Scheme 2.13 Outcome of Gold(I)-Catalyzed Reaction of Cyclobutyl Propargyl Reactant 9r. III. Conclusion We have discovered a unique gold(I)-catalyzed rearrangement of propargyl aryldiazoacetates and a platform on which catalytic activity of 86 gold complexes can be assessed. Phenylpropargyl phenyldiazoacetates have two reactive sites for reactions with gold complexes. If initial interaction occurs at the diazo carbon, a gold carbene is the outcome, and a subsequent cascade process results in the formation of a product that is uniquely characteristic of this pathway. If gold coordination occurs with the carbon-carbon triple bond, 1,3-acyloxy migration of the propargylic ester promoted by the diazoester takes place. The corresponding allene formed rapidly is a stable intermediate, and it determines the course of subsequent processes, one of which is to undergo gold-catalyzed formation of a gold-acylacylium ion intermediate to form stable products by cleavage or intramolecular hydrogen migration. Alternatively, the allene intermediate undergoes a complex transformation, not catalyzed by gold, in which the terminal nitrogen of the diazo functional group adds at the central carbon of the allene to initiate a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. As acyl transfer agents these unique products undergo intramolecular 1,3-acyl migration to form an equilibrium mixture of two isomeric 1,5-dihydro-4H-pyrazol-4-ones under the reaction conditions or quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. Cationic gold(I) complexes initiate 87 their reactions at room temperature exclusively with the diazo functional group of propargyl phenyldiazoacetates, whereas both AuCl(R2S) and gold(III) catalysts undergo initial reaction exclusively at the carbon- carbon triple bond. Neutral gold(I) chloride complexes having strongly coordinating ligands show very low or negligible conversion of propargyl phenyldiazoacetates at room temperature, but they undergo slow reaction at higher temperatures to give mainly the product from reaction at the diazo functional group, which may have occurred after chloride dissociation,19 sometimes in competition with products from reaction at the carbon-carbon triple bond. IV. Experimental Section 4.1 General Information Unless noted all reactions were carried out under inert atmosphere of dinitrogen in oven-dried glassware with magnetic stirring using freshly distilled solvents. All solvents were purified and dried using standard methods. Analytical thin layer chromatography (TLC) plates were purchased from EM Science (silica gel 60 F254 plates). High-resolution mass spectra (HRMS) were performed on a microTOF-ESI mass spectrometer using CsI as the standard. Accurate masses are reported for the molecular ion [M+Cs] + , [M+Na] + , or [M+H] + . Melting points were 88 determined on an Electrothermo Mel-Temp DLX 104 device and were uncorrected. Column chromatography was performed on CombiFlash ® Rf 200 purification system using normal phase disposable columns. IR spectra were recorded using Bruker Vector 22 spectrometer. All NMR spectra were recorded on a Bruker spectrometer at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR) or an Agilent spectrometer at 500 MHz ( 1 H NMR) and 125 MHz ( 13 C NMR). Chemical shifts are reported in ppm with the solvent signals as reference (in CDCl3 as solvent), and coupling constants (J) are given in Hertz (Hz). The peak information is described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite of magnetically non-equivalent protons. 4.2 Materials AuCl(PPh3), AuCl(PMe3), AuCl[P(OMe)3], Chloro[2- dicyclohexyl(2′,6′-dimethoxybiphenyl)phosphine] gold(I), and AuPicCl2 were purchased from Sigma-Aldrich; AuCl(C4H8S), AuCl(Me2S), AuCl(CO), (IPr)AuCl, and AuCl3(Py) were purchased from Strem Chemicals. All other chemicals were obtained from commercial sources and used as received without further purification. 4.3 Experimental Procedures. 89 General Procedure for Gold(I)-Catalyzed Domino Cascade Transformation of Phenylpropargyl Phenyldiazoacetates 1: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar cationic gold(I) catalyst (0.010 mmol) and 2.0 mL DCM were added under nitrogen atmosphere. 1-(Phenylethynyl)cyclopentyl 2-diazo-2- phenylacetate 1 (0.20 mmol) dissolved in 2.0 mL of DCM was added in one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 12 h at room temperature (20 °C); the reaction mixture was purified by column chromatography (100:1 to 10:1 gradient of hexanes:ethyl acetate as eluents) to afford pure 8'- phenylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]-3'[8'H]-one (2) as a white solid. 90 General Procedure for the Synthesis of 1,5-Dihydro-4H- pyrazol-4-ones 10 and 11: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, AuCl(C4H8S) catalyst (0.010 mmol) and 2.0 mL DCE were added under nitrogen atmosphere. Propargyl aryldiazoacetate 1 or 9 (0.20 mmol) dissolved in 2.0 mL of DCE was added in one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 72 h at room temperature (20 °C). Solvent was evaporated, and products were purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure compounds 10 and 11. Procedure for the Synthesis of 6d from a Reaction Mixture Containing 10d and 11d: To the reaction mixture after the gold(I)- catalyzed reaction of 9d that contained 1,5-dihydro-4H-pyrazol-4-ones 10d and 11d (156 mg, 0.384 mmol) of in DCE (8.0 mL) benzylamine (49.4 mg, 0.461 mmol) dissolved in DCE (0.5 mL) was added in one portion under a nitrogen atmosphere. The resulting mixture was stirred at 20 °C for 2 h, and the white precipitate of 6' was formed. The precipitate 91 of 6' was dissolved by adding methanol (5.0 mL); the solution was filtered through Celite to remove gold particles. Solvents were evaporated, and the obtained mixture of products 6' and N- benzylbenzamide was separated by column chromatography using hexanes/ethyl acetate (v/v 2:1) as the eluent to afford 3-([1,1'-biphenyl]- 4-yl)-5-(cyclopent-1-en-1-yl)-1H-pyrazol-4-ol 6'. Procedure for the Synthesis of 6' from Pure 10d: To a solution of 10d (81.0 mg, 0.200 mmol) in DCE (4.0 mL) benzylamine (25.7 mg, 0.240 mmol) dissolved in DCE (0.3 mL) was added in one portion under a nitrogen atmosphere. The resulting mixture was stirred at 20 °C for 2 h. Afterward, DCE was evaporated, and the obtained mixture of products 6' and N-benzylbenzamide was separated by column chromatography using hexanes/ethyl acetate (v/v 2:1) as the eluent to afford compound 6' (54.0 mg, 89% yield). Table 2.5 Deacylation of 10d and 11d by Nucleophiles Entry Substrate Nucleophile Isolated yield (%) 6' 1 a 10d+11d PhNHNH2 80 2 a 10d+11d BnNH2 87 92 3 a,b 10d+11d MeOH 63 4 10d BnNH2 89 5 11d BnNH2 88 6 10d CyNH2 90 7 11d CyNH2 86 aIsolated yields are given only for the deacylation reaction. bThe reaction was carried out at 65 °C for 12h. 4.4 Kinetic Experiments Rate constants for the conversion of 8 to 10q were determined by 1 H NMR spectroscopy. The equilibrium mixture 7+8 was formed by treatment of 7 (0.1 mmol) with 5 mol % AuCl(Me2S) in DCM. After 5 min the mixture 7+8 was separated from gold via silica gel column chromatography (with 19:1 to 9:1 gradient of hexanes:ethyl acetate as eluents). Solvents were evaporated under vacuum at room temperature to afford pure mixture 7+8 (See 1 H NMR and 13 C NMR spectra confirming the formation of allene 8 below; reactions and analyses performed by Kostiantyn Marichev.) 93 Data collection for the intramolecular conversion of 8 to 10p was performed at at 20 ⁰C: since 7 is stable in CDCl3 in the absence of catalyst and not self-reactive, we decided to use the mixture 7+8 for data collection with 7 as the internal standard. The obtained mixture of 7+8 was dissolved in 0.35 mL CDCl3 and placed in an NMR tube. The ratio of 7 [following peak at δ 1.86 (s, 6H, CH3) ppm] to 8 [following peak at δ 1.98 (s, 6H, CH3) ppm] and % conversion of 8 to 10p (Figure 2.3) were determined by 1 H NMR analysis (Agilent spectrometer at 500 MHz, 1 H NMR). The first-order rate constant k = 1.05 × 10 -5 s -1 at 20 ⁰C was calculated from the plot of ln[8]/[8t=0] vs. time (Figure 2.4). Other first-order rate constants at different temperatures [40 ⁰C (Figure 2.5), 45 ⁰C (Figure 2.6), 60 ⁰C (Figure 2.7)] were determined in the same way: an NMR tube with CDCl3 solution of 7+8 was placed into an oil bath with a temperature stability of ±1 ⁰C. Temperature control at 94 60 ⁰C was provided by the Agilent 500 MHz spectrometer with a temperature stability of ±0.1 ⁰C. An Arrhenius plot (Table 2.6, Figure 2.8) was obtained from the first-order rate constants determined at the corresponding temperatures. The activation energy Eact = 18.8 kcal/mol (R 2 = 0.999) was calculated from the slope of Arrhenius plot (Eact = −slope × R). ΔH ‡ = 18.2 kcal/mol and ΔS‡ = −19.4 cal/deg-mol were determined from Eyring equation.20 Figure 2.3 Stacked 1 H NMR Spectra: Determination of Rate Constant for the Conversion of 8 to 10q at 20 ⁰C; Reaction and Analysis Performed by Kostiantyn Marichev. Figure 2.4 First-order Rate Constant at 20 ⁰C. (k = 1.05 × 10-5 s-1) Figure 2.5 First-order Rate Constant at 40 ⁰C. (k = 7.67 × 10-5 s-1) Figure 2.6 First-order Rate Constant at 45 ⁰C. (k = 1.19 × 10-4 s-1) Figure 2.7 First-order Rate Constant at 60 ⁰C. (k = 5.17 × 10-4 s-1) 95 Table 2.6 Data for Arrhenius Plot Measured within 20−60 ⁰C lnk −11.46 −9.48 −9.04 −7.57 1/T, K -1 0.003413 0.003195 0.003145 0.003003 Figure 2.8 Arrhenius Plot: Compound 8 Activation Energy. Table 2.7 Time Course for the Gold(I)-Catalyzed Reaction of 1 a Time (h) Yield (%) 3 Yield (%) 4 Yield (%) 6 Total yield (%) a 3+4+6 0 0 0 0 0 3 13 2 1 16 6 19 5 2.5 26.5 96 12 26.5 7 3 36.5 24 39.5 9.5 4 53 36 47 12.5 4 63.5 48 51 15.5 4 70.5 60 54 17.5 4 75.5 72 56 20 5 81 84 55 22.5 5 82.5 96 50.5 25.5 7 83 108 45 29.5 8 82.5 120 40.5 32 10 82.5 132 37 33 11 81 144 35 34 11 80 156 33 34 12 79 168 31.5 35.5 12 79 180 30 36.5 12.5 79 97 192 29 38 12.5 79.5 204 28 39 13 80 216 28 40 12.5 80.5 228 28 40 12.5 80.5 240 28 40 12.5 80.5 aRecords the formation of 3, 4, and 6 in DCE at 20 ºC in reactions of 1 with 5 mol % AuCl(C4H8S). Yields were determined by 1H NMR analyses of the reaction mixture at the recorded times in the presence of 1,3,5- trimethoxybenzene as the internal standard. Reported yields are the averages of two runs. aYield of 5 was about 2−3% and remained constant within 10 days. 4.5 Characterization Data for New Compounds 1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(thiophen-2-yl)acetate 9h: 52% yield. Dark-red oil. 1 H NMR (500 MHz, CDCl3) δ 7.46 (dd, J = 6.4, 2.9 Hz, 2H), 7.34 – 7.28 (m, 4H), 7.07 – 7.03 (m, 1H), 6.84 (d, J = 3.6 Hz, 1H), 2.49 – 2.41 (m, 2H), 2.31 (dt, J = 15.3, 7.7 Hz, 2H), 1.87 – 1.81 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 163.38, 131.85, 128.34, 128.12, 126.90, 125.92, 125.44, 122.61, 120.88, 89.03, 85.33, 82.90, 98 40.76, 23.43. IR (neat) 2928, 2076, 1701, 1443, 1285, 1231, 1127, 974, 691 cm -1 ; HRMS (ESI) m/z calculated for C19H16N2O2SNa [M+Na] + 359.0825, found: 359.0822. 1-(Phenylethynyl)cyclododecyl 2-Diazo-2-phenylacetate 9j: 62% yield. Yellow solid, m.p. 92.5 – 93.5 °C. 1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 0.9 Hz, 2H), 7.50 – 7.44 (comp, 2H), 7.42 – 7.35 (comp, 2H), 7.34 – 7.27 (comp, 3H), 7.19 (ddd, J = 8.6, 2.2, 1.1 Hz, 1H), 2.37 – 2.23 (comp, 2H), 2.12 – 1.98 (comp, 2H), 1.68 (d, J = 8.8 Hz, 2H), 1.43 (comp, 16H). 13 C NMR (126 MHz, CDCl3) δ 163.08, 131.87, 128.85, 128.31, 128.14, 125.79, 125.66, 124.01, 122.71, 89.38, 86.21, 79.61, 33.36, 26.08, 25.86, 22.29, 22.07, 19.44. IR (neat) 2928, 2079, 1705, 1470, 1241, 1146, 1006, 754 cm -1 ; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na] + 451.2356, found: 451.2343. 99 4-(Phenylethynyl)tetrahydro-2H-pyran-4-yl 2-Diazo-2- phenylacetate 9k: 65% yield. Yellow solid, m.p. 85 – 86 °C. 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.45 (comp, 4H), 7.44 – 7.36 (comp, 2H), 7.36 – 7.28 (comp, 3H), 7.23 – 7.17 (m, 1H), 3.93 (dt, J = 9.2, 4.4 Hz, 2H), 3.85 (ddd, J = 11.9, 9.0, 2.9 Hz, 2H), 2.45 – 2.38 (comp, 2H), 2.23 (ddd, J = 13.1, 9.0, 4.0 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 163.00, 131.92, 128.92, 128.70, 128.24, 125.89, 125.43, 124.07, 122.15, 87.48, 87.46, 74.12, 64.51, 37.96. IR (neat) 2960, 2086, 1707, 1498, 1241, 1140, 755 cm -1 ; HRMS (ESI) m/z calculated for C21H18N2O3Na [M+Na] + 369.1214, found: 369.1210. 100 1-((4-Methoxyphenyl)ethynyl)cyclopentyl 2-Diazo-2-(4- methoxyphenyl)acetate 9n: 58% yield. Orange oil. 1 H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 10.1, 9.0 Hz, 4H), 6.94 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 2.46 – 2.37 (m, 2H), 2.34 – 2.24 (m, 2H), 1.87 – 1.78 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 164.08, 159.61, 157.94, 133.33, 125.86, 117.13, 114.84, 114.54, 113.75, 88.06, 84.91, 82.25, 55.34, 55.25, 40.83, 23.45. IR (neat) 2956, 2080, 1703, 1511, 1248, 1147, 830, 734 cm -1 ; HRMS (ESI) m/z calculated for C23H22N2O4Na [M+Na] + 413.1472, found: 413.1483. 1-((4-Methoxyphenyl)ethynyl)cyclopentyl 2-Diazo-2-(4- (trifluoromethyl)phenyl)acetate 9o: 55% yield. Orange oil. 1 H NMR (500 MHz, CDCl3) δ 7.72 – 7.52 (comp, 4H), 7.40 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 2.50 – 2.37 (comp, 2H), 2.37 – 2.22 (comp, 2H), 1.85 (comp, 4H). 13 C NMR (126 MHz, CDCl3) δ 162.76, 159.72, 133.34, 130.32, 127.47 (q, J = 32.5 Hz), 125.73 (q, J = 3.8 Hz), 101 123.45, 114.62, 113.79, 87.63, 85.31, 82.90, 77.26, 77.00, 76.75, 55.25, 40.82, 23.44. IR (neat) 2957, 2087, 1706, 1509, 1323, 1244, 1070, 832 cm -1 ; HRMS (ESI) m/z calculated for C23H19F3N2O2Na [M+Na] + 451.1240, found: 451.1225. 2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazo-2-(4- methoxyphenyl)acetate 9q: 68% yield. Orange oil. 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.34 – 7.28 (comp, 3H), 6.95 (d, J = 9.0 Hz, 2H), 3.82 (s, 3H), 1.85 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 163.90, 157.97, 131.85, 128.36, 128.14, 125.94, 122.56, 117.15, 114.55, 90.05, 84.39, 73.66, 55.35, 29.45. IR (neat) 2988, 2079, 1705, 1514, 1258, 1122, 998, 827 cm -1 ; HRMS (ESI) m/z calculated for C20H18N2O3Na [M+Na] + 357.1210, found: 357.1209. 102 5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-phenyl-1,5-dihydro-4H- pyrazol-4-one 3: 57% yield. Yellow solid, m.p. 115–116 °C. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 7.9, 1.2 Hz, 2H), 8.08 (dd, J = 7.9, 1.2 Hz, 2H), 7.90 (br, 1H), 7.62 – 7.57 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 – 7.36 (comp, 3H), 5.88 – 5.84 (m, 1H), 2.50 – 2.41 (comp, 3H), 2.35 – 2.29 (m, 1H), 1.98 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.05, 189.74, 143.83, 138.50, 133.97, 133.43, 131.63, 130.71, 129.19, 129.09, 128.49, 128.35, 125.98, 81.54, 32.43, 32.42, 22.96. IR (neat) 3358, 1721, 1674, 1246, 903 cm -1 ; HRMS (ESI) m/z calculated for C21H18N2O2Na [M+Na] + 353.1260, found: 353.1247. 5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-phenyl-1,5-dihydro-4H- pyrazol-4-one 4: 19% yield. Yellow solid, m.p. 130–131 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 2H), 7.66 (br, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 – 7.33 (comp, 7H), 6.84 – 6.80 (m, 1H), 2.75 – 2.70 (comp, 2H), 2.56 – 2.49 (comp, 2H), 1.96 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.74, 189.45, 143.16, 135.74, 134.05, 133.70, 133.07, 131.98, 130.94, 129.49, 128.79, 128.46, 126.49, 81.80, 34.07, 103 32.68, 22.20. IR (neat) 3343, 1732, 1675, 1447, 1231, 738 cm -1 ; HRMS (ESI) m/z calculated for C21H18N2O2Na [M+Na] + 353.1260, found: 353.1249. 5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(4-methoxyphenyl)-1,5- dihydro-4H-pyrazol-4-one 10b: 54% yield. Yellow solid, m.p. 44– 46 °C. 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.3 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.73 (s, 1H), 7.62 – 7.56 (m, 1H), 7.50 – 7.44 (comp, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.87 – 5.82 (m, 1H), 3.84 (s, 3H), 2.52 – 2.39 (comp, 3H), 2.31 (dddd, J = 17.5, 9.3, 5.8, 2.1 Hz, 1H), 2.02 – 1.84 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 192.53, 189.89, 160.49, 144.20, 138.71, 133.93, 133.48, 131.43, 130.72, 128.34, 127.58, 121.69, 113.96, 81.31, 55.30, 32.46, 32.43, 22.96. IR (neat) 3338, 2931, 1712, 1674, 1608, 1510, 1251, 1176, 835 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O3 [M−H] − 359.1401, found: 359.1396. 104 5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-(4-methoxyphenyl)-1,5- dihydro-4H-pyrazol-4-one 11b: 21% yield. Yellow solid, m.p. 60.5– 61.5 °C. 1 H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.73 (s, 1H), 7.53 – 7.47 (m, 1H), 7.36 (dd, J = 11.7, 4.0 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.82-6.81 (m, 1H), 3.80 (s, 3H), 2.76 – 2.68 (m, 2H), 2.52 (d, J = 5.6 Hz, 2H), 1.96 – 1.88 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 193.12, 189.71, 159.84, 143.16, 133.85, 133.64, 133.12, 132.07, 131.02, 128.42, 127.87, 127.78, 114.89, 81.58, 55.31, 34.07, 32.69, 22.21. IR (neat) 3344, 2954, 1736, 1673, 1608, 1510, 1252, 692 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O3 [M−H] − 359.1401, found: 359.1406. 105 5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(p-tolyl)-1,5-dihydro-4H- pyrazol-4-one 10c: 61% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.19 – 8.14 (comp, 2H), 7.97 – 7.92 (comp, 2H), 7.78 (s, 1H), 7.60 – 7.56 (m, 1H), 7.47 – 7.43 (comp, 2H), 7.21 – 7.18 (comp, 2H), 5.85 – 5.82 (m, 1H), 2.46 – 2.38 (comp, 3H), 2.36 (s, 3H), 2.31 – 2.26 (m, 1H), 1.96 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.31, 189.84, 144.23, 139.34, 138.63, 133.95, 133.46, 131.52, 130.73, 129.21, 128.42, 128.34, 125.96, 81.40, 32.45, 32.42, 22.96, 21.42. IR (neat) 3344, 1722, 1676, 1231, 951 cm -1 ; HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na] + 367.1417, found: 367.1404. 5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-(p-tolyl)-1,5-dihydro-4H- pyrazol-4-one 11c: 24% yield. Yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.88 – 7.80 (comp, 2H), 7.67 (s, 1H), 7.51 – 7.47 (m, 1H), 7.37 – 7.32 (comp, 2H), 7.24 – 7.16 (comp, 4H), 6.83 – 6.78 (m, 1H), 2.74 – 2.68 (comp, 2H), 2.55 – 2.48 (comp, 2H), 2.34 (s, 3H), 1.96 – 1.88 (comp, 106 2H). 13 C NMR (126 MHz, CDCl3) δ 192.94, 189.61, 143.22, 138.79, 133.91, 133.65, 133.11, 132.85, 132.04, 131.03, 130.19, 128.42, 126.40, 81.81, 34.07, 32.68, 22.21, 21.14. IR (neat) 3348, 1737, 1675, 1230, 809 cm -1 ; HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na] + 367.1417, found: 367.1407. 3-([1,1'-Biphenyl]-4-yl)-5-benzoyl-5-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 10d: 69% yield. Yellow solid, m.p. 49– 51 °C. 1 H NMR (500 MHz, CDCl3) δ 8.23 – 8.15 (comp, 2H), 7.98 (s, 1H), 7.68 – 7.58 (comp, 6H), 7.47 (dt, J = 12.5, 7.9 Hz, 5H), 7.37 (t, J = 7.4 Hz, 1H), 5.89 (m, 1H), 2.59 – 2.40 (comp, 3H), 2.35 (ddd, J = 15.2, 11.0, 4.0 Hz, 1H), 2.04 – 1.86 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.14, 189.76, 143.50, 141.83, 140.49, 138.50, 134.02, 133.48, 131.68, 130.73, 128.82, 128.39, 128.08, 127.58, 127.18, 127.03, 126.38, 81.61, 32.46, 23.00. IR (neat) 3346, 2957, 1725, 1674, 1233, 907, 733 cm -1 ; HRMS (EI) m/z calculated for C27H21N2O2 [M−H] − 405.1609, found: 405.1610. 107 5-([1,1'-Biphenyl]-4-yl)-5-benzoyl-3-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 11d: 9% yield. Yellow solid, m.p. 80–81 °C. 1 H NMR (500 MHz, CDCl3) δ 7.92 – 7.88 (comp, 2H), 7.78 (s, 1H), 7.67 – 7.61 (comp, 3H), 7.60 – 7.55 (comp, 2H), 7.52 (dd, J = 11.1, 3.7 Hz, 1H), 7.48 – 7.42 (comp, 3H), 7.38 (dd, J = 15.9, 7.7 Hz, 3H), 6.88 – 6.83 (m, 1H), 2.79 – 2.72 (comp, 2H), 2.58 – 2.51 (comp, 2H), 1.98 – 1.90 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 192.83, 189.49, 143.22, 141.67, 140.00, 134.63, 134.15, 133.79, 133.14, 132.02, 130.95, 128.86, 128.55, 128.15, 127.73, 127.08, 126.93, 81.60, 34.11, 32.72, 22.24. IR (neat) 3342, 2953, 1728, 1674, 1487, 1229, 1008, 735, 696 cm -1 ; HRMS (EI) m/z calculated for C27H21N2O2 [M−H] − 405.1609, found: 405.1604. 108 5-Benzoyl-3-(4-bromophenyl)-5-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 10e: 74% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.19 – 8.14 (comp, 2H), 7.97 – 7.92 (comp, 3H), 7.61 – 7.57 (m, 1H), 7.52 – 7.49 (comp, 2H), 7.47 – 7.43 (comp, 2H), 5.86 – 5.83 (m, 1H), 2.47 – 2.39 (comp, 3H), 2.32 – 2.26 (m, 1H), 1.96 – 1.89 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 191.68, 189.49, 142.70, 138.29, 134.09, 133.31, 131.82, 131.68, 130.75, 128.39, 128.07, 127.39, 123.36, 81.67, 32.45, 32.43, 22.94. IR (neat) 3336, 1724, 1673, 1231, 1009 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaBr [M+Na] + 431.0366, found: 431.0350. 5-Benzoyl-5-(4-bromophenyl)-3-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 11e: 13% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.83 – 7.79 (comp, 2H), 7.62 (s, 1H), 7.54 – 7.50 (comp, 3H), 7.39 – 7.35 (comp, 2H), 7.26 – 7.23 (comp, 2H), 6.83 – 6.80 (m, 1H), 2.74 – 2.68 (comp, 2H), 2.54 – 2.50 (comp, 2H), 1.95 – 1.89 (comp, 109 2H). 13 C NMR (126 MHz, CDCl3) δ 192.40, 189.05, 143.33, 134.67, 134.55, 133.94, 132.88, 132.62, 131.85, 130.77, 128.66, 128.17, 123.20, 80.98, 77.25, 77.00, 76.75, 34.10, 32.66, 22.19. IR (neat) 3338, 1719, 1674, 1230, 908 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaBr [M+Na] + 431.0366, found: 431.0345. 5-Benzoyl-3-(4-chlorophenyl)-5-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 10f: 69% yield. Yellow solid, m.p. 77.5– 78.5 °C. 1 H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (s, 1H), 7.62 – 7.57 (m, 1H), 7.49 – 7.45 (comp, 2H), 7.38 – 7.34 (comp, 2H), 5.87 – 5.83 (m, 1H), 2.49 – 2.39 (comp, 3H), 2.33 – 2.26 (m, 1H), 1.97 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.75, 189.51, 142.73, 138.33, 135.04, 134.09, 133.32, 131.79, 130.73, 128.73, 128.39, 127.62, 127.17, 81.66, 32.45, 32.43, 22.94. IR (neat) 3345, 1716, 1673, 1231, 1116 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na] + 387.0871, found: 387.0857. 110 5-Benzoyl-5-(4-chlorophenyl)-3-(cyclopent-1-en-1-yl)-1,5- dihydro-4H-pyrazol-4-one 11f: 14% yield. Yellow solid, m.p. 94–95 °C. 1 H NMR (500 MHz, CDCl3) δ 7.84 – 7.80 (comp, 2H), 7.67 (s, 1H), 7.55 – 7.51 (m, 1H), 7.40 – 7.36 (comp, 4H), 7.34 – 7.30 (comp, 2H), 6.85 – 6.81 (m, 1H), 2.75 – 2.69 (comp, 2H), 2.56 – 2.51 (copm, 2H), 1.96 – 1.90 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.48, 189.12, 143.30, 134.99, 134.50, 134.13, 133.92, 132.89, 131.86, 130.77, 129.67, 128.63, 127.89, 80.94, 34.09, 32.66, 22.19. IR (neat) 3344, 1717, 1671, 1228, 933 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na] + 387.0871, found: 387.0858. 111 5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-[4- (trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one 10g: 51% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.22 – 8.16 (comp, 4H), 8.07 (br, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.60 – 7.56 (m, 1H), 7.50 – 7.47 (comp, 2H), 5.88 – 5.86 (m, 1H), 2.47 – 2.40 (comp, 3H), 2.33 – 2.27 (m, 1H), 1.98 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.37, 189.33, 141.91, 138.11, 134.17, 133.55, 133.27, 132.76, 132.61, 131.92 (q, J = 30.0 Hz), 129.30, 128.42, 127.85, 125.40 (q, J = 3.8 Hz) 124.51 (q, J = 278.8 Hz), 81.91, 32.44, 32.39, 22.95. IR (neat) 3334, 1709, 1673, 1321, 1120 cm -1 ; HRMS (ESI) m/z calculated for C22H17N2O2F3Na [M+Na] + 421.1134, found: 421.1116. 5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-[4- (trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one 11g: 22% yield. Yellow solid, m.p. 45.5–46.5 °C. 1H NMR (500 MHz, CDCl3) δ 7.82 – 7.76 (comp, 2H), 7.68 – 7.63 (comp, 3H), 7.55 – 7.50 (comp, 3H), 112 7.38 (t, J = 7.8 Hz, 2H), 6.85 – 6.83 (m, 1H), 2.75 – 2.69 (comp, 2H), 2.56 – 2.51 (comp, 2H), 1.97 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.14, 188.85, 143.30, 139.33, 134.84, 134.07, 132.86, 131.76, 130.99 (q, J = 32.5 Hz) 130.59, 128.78, 126.90, 126.37 (q, J = 3.8 Hz), 121.54 (q, J = 270 Hz) 80.84, 34.11, 32.67, 22.18. IR (neat) 3335, 1729, 1675, 1119, 907 cm -1 ; HRMS (ESI) m/z calculated for C22H17N2O2F3Na [M+Na] + 421.1134, found: 421.1119. 5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(thiophen-2-yl)-1,5- dihydro-4H-pyrazol-4-one 10h: 59% yield. 6 Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.3 Hz, 2H), 7.82 (s, 1H), 7.80 (dd, J = 3.7, 0.8 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 5.1 Hz, 1H), 7.08 (dd, J = 4.9, 3.8 Hz, 1H), 5.88 – 5.84 (m, 1H), 2.48 – 2.37 (comp, 3H), 2.37 – 2.26 (m, 1H), 1.91 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 190.69, 189.48, 141.61, 138.34, 134.05, 130.72, 128.39, 127.65, 126.69, 81.21, 32.44, 22.96. IR (neat) 3337, 2926, 1722, 1674, 113 1228, 731, 692 cm -1 ; HRMS (ESI) m/z calculated for C19H16N2O2SNa [M+Na] + 359.0825, found: 359.0823. 5-Benzoyl-5-(cyclohex-1-en-1-yl)-3-phenyl-1,5-dihydro-4H- pyrazol-4-one 10i: 57% yield. Yellow oil. 1 H NMR (300 MHz, CDCl3) δ 8.18 (dd, J = 5.3, 3.3 Hz, 2H), 8.13 – 7.95 (m, 2H), 7.84 (s, 1H), 7.59 (ddd, J = 6.7, 4.0, 1.3 Hz, 1H), 7.52 – 7.43 (comp, 2H), 7.42 – 7.32 (comp, 3H), 5.84 (t, J = 2.7 Hz, 1H), 2.11 (comp, 2H), 1.63 (comp, 6H). 13 C NMR (126 MHz, CDCl3) δ 192.26, 190.41, 143.73, 134.13, 133.91, 133.45, 130.83, 129.18, 129.10, 128.54, 128.46, 128.33, 128.24, 127.72, 125.95, 84.94, 25.90, 25.48, 22.57, 21.58. IR (neat) 3343, 2927, 1729, 1674, 1447, 1231, 695 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O2 [M−H]− 343.1452, found: 343.1449. 114 5-Benzoyl-3-(cyclohex-1-en-1-yl)-5-phenyl-1,5-dihydro-4H- pyrazol-4-one 11i: 16% yield. Yellow solid, m.p. 63–64 °C. 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (br, 1H), 7.49 (dd, J = 10.5, 4.4 Hz, 1H), 7.41 – 7.31 (comp, 7H), 7.02 (m, 1H), 2.40 (comp, 2H), 2.18 (comp, 2H), 1.76 – 1.55 (comp, 4H). 13C NMR (126 MHz, CDCl3) δ 193.10, 189.61, 145.03, 135.93, 133.67, 133.12, 131.49, 130.95, 129.45, 128.74, 128.46, 127.74, 126.52, 82.13, 25.72, 25.17, 22.25, 21.92. IR (neat) 3339, 2927, 1732, 1675, 1447, 1231, 698 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O2 [M−H] − 343.1452, found: 343.1448. 5-Benzoyl-5-(cyclododec-1-en-1-yl)-3-phenyl-1,5-dihydro-4H- pyrazol-4-one 10j: 51% yield. Yellow solid, m.p. 69–70 °C. 1H NMR (500 MHz, CDCl3) δ 8.15 – 8.05 (comp, 2H), 7.89 (s, 1H), 7.64 – 7.31 (comp, 8H), 5.48 – 5.42 (m, 1H), 2.69 – 2.44 (comp, 2H), 2.32 – 2.18 (m, 1H), 2.09 – 1.96 (m, 1H), 1.55 – 1.19 (comp, 16H). 13C NMR (126 MHz, CDCl3) δ 192.16, 190.33, 143.53, 143.47, 135.73, 135.03, 133.72, 131.61, 115 131.36, 129.03, 128.45, 128.23, 127.84, 127.05, 125.94, 85.65, 26.43, 25.53, 25.48, 25.09, 25.05, 24.74, 24.72, 24.10, 22.64, 22.37. IR (neat) 3351, 2928, 1699, 1677, 1448, 1344, 693 cm -1 ; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na] + 451.2356, found: 451.2347. 5-Benzoyl-3-(cyclododec-1-en-1-yl)-5-phenyl-1,5-dihydro-4H- pyrazol-4-one 11j: 35% yield. Yellow solid, m.p. 71–72 °C. 1H NMR (500 MHz, CDCl3) δ 7.85 (dt, J = 8.5, 1.5 Hz, 2H), 7.66 (s, 1H), 7.52 – 7.47 (m, 1H), 7.44 – 7.31 (comp, 7H), 6.79 (t, J = 8.1 Hz, 1H), 2.57 (t, J = 6.8 Hz, 2H), 2.30 – 2.17 (comp, 2H), 1.67 – 1.59 (comp, 2H), 1.54 (dt, J = 9.6, 7.2 Hz, 2H), 1.49 – 1.41 (comp, 4H), 1.40 – 1.31 (comp, 6H), 1.30 – 1.23 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 193.42, 189.63, 144.99, 135.98, 135.37, 133.64, 133.23, 130.88, 129.94, 129.45, 128.72, 128.48, 126.47, 81.94, 26.57, 26.11, 25.60, 25.19, 25.14, 24.89, 24.62, 23.69, 22.93, 22.24. IR (neat) 3347, 2924, 2850, 1729, 1672, 1447, 1229, 116 737, 696 cm -1 ; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na] + 451.2356, found: 451.2349. 5-Benzoyl-5-(3,6-dihydro-2H-pyran-4-yl)-3-phenyl-1,5- dihydro-4H-pyrazol-4-one 10k: 36% yield. Yellow solid, m.p. 67– 68 °C. 1 H NMR (500 MHz, CDCl3) δ 8.23 – 8.12 (comp, 2H), 8.10 – 8.03 (m, 1H), 7.84 (dd, J = 6.3, 3.1 Hz, 1H), 7.56 – 7.30 (comp, 5H), 7.27 (comp, 2H), 5.91 – 5.88 (m, 1H), 4.22 (dd, J = 5.3, 2.6 Hz, 2H), 3.89 (ddt, J = 16.8, 11.9, 6.2 Hz, 1H), 3.78 – 3.64 (m, 1H), 2.70 – 2.41 (m, 1H), 2.37 – 2.05 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 191.76, 189.62, 144.05, 134.20, 131.68, 131.58, 130.95, 130.67, 129.36, 128.57, 128.53, 126.70, 126.03, 83.53, 65.33, 64.00, 25.78. IR (neat) 3332, 2925, 2085, 1710, 1677, 1447, 1232, 700 cm -1 ; HRMS (EI) m/z calculated for C21H17N2O3 [M−H] − 345.1245, found: 345.1243. 117 5-Benzoyl-3-(3,6-dihydro-2H-pyran-4-yl)-5-phenyl-1,5- dihydro-4H-pyrazol-4-one 11k: 10% yield. Yellow solid, m.p. 70– 71 °C. 1 H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.52 (td, J = 7.6, 1.0 Hz, 1H), 7.44 – 7.33 (comp, 7H), 6.99 (m, 1H), 4.29 (comp, 2H), 3.89 (dd, J = 10.5, 5.2 Hz, 2H), 2.54 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 192.57, 189.28, 143.24, 135.56, 133.80, 133.03, 130.94, 129.56, 128.91, 128.52, 128.51, 126.43, 125.14, 82.38, 65.39, 64.08, 25.06. IR (neat) 3322, 2923, 2085, 1708, 1675, 1447, 1232, 1131, 694 cm -1 ; HRMS (EI) m/z calculated for C21H17N2O3 [M−H] − 345.1245, found: 345.1239. 5-(4-Chlorobenzoyl)-5-(cyclopent-1-en-1-yl)-3-phenyl-1,5- dihydro-4H-pyrazol-4-one 10l: 62% yield. Yellow solid, m.p. 85–86 °C. 1 H NMR (500 MHz, CDCl3) δ 8.21 – 8.15 (comp, 2H), 8.08 – 8.03 (comp, 2H), 7.92 (s, 1H), 7.46 – 7.43 (comp, 2H), 7.41 – 7.37 (comp, 3H), 5.85 – 5.82 (m, 1H), 2.47 – 2.40 (comp, 3H), 2.29 – 2.24 (m, 1H), 1.97 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.00, 188.67, 118 143.90, 140.74, 138.43, 132.36, 132.06, 131.50, 129.28, 128.97, 128.70, 128.53, 125.98, 81.58, 77.26, 77.01, 76.75, 32.50, 32.44, 22.92. IR (neat) 3347, 1724, 1674, 1114, 1010 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na] + 387.0871, found: 387.0855. 5-(4-Chlorobenzoyl)-3-(cyclopent-1-en-1-yl)-5-phenyl-1,5- dihydro-4H-pyrazol-4-one 11l: 18% yield. Yellow solid, m.p. 92–93 °C. 1 H NMR (500 MHz, CDCl3) δ 7.84 – 7.80 (comp, 2H), 7.77 (s, 1H), 7.40 – 7.36 (comp, 3H), 7.33 – 7.30 (comp, 2H), 7.28 – 7.26 (comp, 2H), 6.82 – 6.79 (m, 1H), 2.75 – 2.71 (comp, 2H), 2.55 – 2.51 (comp, 2H), 1.95 – 1.89 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 192.74, 188.42, 143.28, 140.46, 135.69, 134.13, 132.65, 131.96, 131.03, 129.62, 128.97, 128.75, 126.69, 82.19, 77.25, 77.00, 76.75, 34.09, 32.69, 22.20. IR (neat) 3342, 1741, 1676, 1091, 907 cm -1 ; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na] + 387.0871, found: 387.0856. 119 5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-phenyl-1,5- dihydro-4H-pyrazol-4-one 10m: 48% yield. Yellow solid, m.p. 53– 54 °C. 1 H NMR (500 MHz, CDCl3) δ 8.29 – 8.18 (comp, 2H), 8.11 – 8.02 (comp, 2H), 7.98 (s, 1H), 7.43 – 7.33 (comp, 3H), 6.98 – 6.90 (comp, 2H), 5.88 – 5.79 (m, 1H), 3.89 (s, 3H), 2.52 – 2.37 (comp, 3H), 2.32 – 2.24 (m, 1H), 2.00 – 1.84 (comp, 2H). 13C NMR (126 MHz, cdcl3) δ 192.59, 187.77, 164.22, 144.01, 138.98, 133.58, 131.38, 129.19, 129.12, 128.47, 126.06, 125.99, 113.58, 81.57, 55.53, 32.55, 32.44, 22.96. IR (neat) 3336, 2932, 2842, 1714, 1663, 1596, 1244, 1171, 1028, 842, 732 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O3 [M−H] − 359.1401, found: 359.1397. 120 3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-phenyl-1,5- dihydro-4H-pyrazol-4-one 11m: 29% yield. Yellow solid, m.p. 72– 73 °C. 1 H NMR (500 MHz, CDCl3) δ 7.94 – 7.84 (comp, 2H), 7.78 (s, 1H), 7.50 – 7.42 (m, 1H), 7.41 – 7.34 (comp, 2H), 7.33 – 7.29 (comp, 2H), 6.86 – 6.77 (comp, 3H), 3.81 (s, 3H), 2.77 – 2.69 (comp, 2H), 2.53 (ddd, J = 9.6, 4.8, 2.2 Hz, 2H), 1.93 (dt, J = 15.0, 7.4 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 193.38, 187.75, 163.91, 143.41, 136.43, 133.87, 133.84, 132.10, 129.43, 128.87, 128.66, 126.73, 125.50, 113.68, 82.22, 55.47, 34.07, 32.70, 22.22. IR (neat) 3310, 2933, 2841, 1736, 1667, 1599, 1510, 1247, 1172, 733 cm -1 ; HRMS (EI) m/z calculated for C22H19N2O3 [M−H]− 359.1401, found: 359.1394. 121 5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-(4- methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one 10n: 55% yield. Yellow solid, m.p. 52–53 °C. 1H NMR (500 MHz, CDCl3) δ 8.29 – 8.17 (comp, 2H), 8.07 – 7.98 (comp, 2H), 7.90 (s, 1H), 6.97 – 6.87 (comp, 4H), 5.86 – 5.78 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.51 – 2.36 (comp, 3H), 2.28 (dddd, J = 15.3, 9.3, 5.8, 2.1 Hz, 1H), 1.99 – 1.84 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 193.04, 187.90, 164.17, 160.41, 144.19, 139.17, 133.52, 131.11, 127.55, 126.15, 121.83, 113.93, 113.56, 81.34, 55.51, 55.28, 32.54, 32.43, 22.97. IR (neat) 3340, 2956, 2840, 1717, 1665, 1598, 1508, 1248, 1172, 1029, 837 cm -1 ; HRMS (EI) m/z calculated for C23H21N2O4 [M−H] − 389.1507, found: 389.1501. 122 3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-(4- methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one 11n: 24% yield. Yellow solid, m.p. 67–68 °C. 1H NMR (500 MHz, CDCl3) δ 7.94 – 7.86 (comp, 2H), 7.83 (s, 1H), 7.24 – 7.17 (comp, 2H), 6.92 – 6.85 (comp, 2H), 6.86 – 6.77 (comp, 3H), 3.81 (s, 3H), 3.80 – 3.77 (s, 3H), 2.77 – 2.67 (comp, 2H), 2.56 – 2.46 (comp, 2H), 1.96 – 1.87 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 193.71, 187.98, 163.84, 159.70, 143.27, 133.91, 133.57, 132.17, 128.46, 128.06, 125.55, 114.81, 113.62, 81.97, 55.46, 55.29, 34.05, 32.70, 22.22. IR (neat) 3337, 2933, 2839, 1721, 1663, 1596, 1508, 1241, 1169, 1027, 839, 734 cm -1 ; HRMS (EI) m/z calculated for C23H21N2O4 [M−H] − 389.1507, found: 389.1497. 123 5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-[4- (trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one 10o: 42% yield. Yellow solid, m.p. 35–36 °C. 1H NMR (500 MHz, CDCl3) δ 8.23 (comp, 5H), 7.63 (d, J = 8.3 Hz, 2H), 6.99 – 6.91 (comp, 2H), 5.89 – 5.83 (m, 1H), 3.89 (s, 3H), 2.51 – 2.39 (comp, 3H), 2.33 – 2.24 (m, 1H), 2.00 – 1.87 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.90, 187.39, 164.36, 141.88, 138.55, 133.60, 131.74, 130.47 (q, J = 32.8 Hz), 125.91, 125.36 (q, J = 3.8 Hz), 113.64, 81.95, 55.54, 32.52, 32.43, 22.95. IR (neat) 3326, 2930, 2845, 1663, 1596, 1321, 1243, 1164, 1065, 842 cm -1 ; HRMS (EI) m/z calculated for C23H18F3N2O3 [M−H] − 427.1275, found: 427.1274. 124 3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-[4- (trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one 11o: 5% yield. Yellow solid, m.p. 67 – 68 °C. 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 9.3, 2.6 Hz, 2H), 7.71 (s, 1H), 7.66 (dd, J = 8.5, 2.5 Hz, 2H), 7.48 (dd, J = 8.5, 2.5 Hz, 2H), 6.92 – 6.76 (comp, 3H), 3.84 (s, 3H), 2.82 – 2.67 (comp, 2H), 2.61 – 2.42 (comp, 2H), 2.00 – 1.84 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.82, 187.09, 164.19, 143.61, 140.05, 134.63, 133.59, 131.88, 130.83 (q, J = 34.0 Hz), 127.65, 127.13, 126.34 (q, J = 3.8 Hz), 125.21, 125.13, 113.99, 81.24, 55.55, 34.11, 32.68, 22.20. IR (neat) 3337, 2930, 1725, 1667, 1598, 1323, 1243, 1170, 1120, 1070, 841 cm -1 ; HRMS (EI) m/z calculated for C23H18F3N2O3 [M−H] − 427.1275, found: 427.1277. 125 5-Benzoyl-3-phenyl-5-(prop-1-en-2-yl)-1,5-dihydro-4H- pyrazol-4-one 10p: 60% yield. 6 Yellow solid, m.p. 39 – 40 °C. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 7.4 Hz, 2H), 8.08 (d, J = 6.7 Hz, 2H), 7.93 (s, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.43 – 7.35 (comp, 3H), 5.27 (s, 1H), 5.20 (s, 1H), 1.91 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 191.96, 189.85, 143.73, 140.34, 134.10, 133.37, 130.72, 129.26, 129.01, 128.51, 128.45, 126.03, 116.67, 84.14, 20.00. IR (neat) 3339, 1727, 1671, 1447, 1229, 692 cm -1 ; HRMS (ESI) m/z calculated for C19H16N2O2Na [M+Na] + 327.1104, found: 327.1098. 5-Benzoyl-3-(4-methoxyphenyl)-5-(prop-1-en-2-yl)-1,5- dihydro-4H-pyrazol-4-one 10q: 72% yield. 6 Yellow solid, m.p. 44– 45 °C. 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.4 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.74 (s, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.25 (s, 1H), 5.18 (s, 1H), 3.83 (s, 3H), 1.90 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 192.41, 189.98, 160.52, 144.08, 140.53, 134.05, 133.39, 130.72, 128.43, 127.61, 121.59, 116.51, 126 113.97, 83.89, 55.30, 20.02. IR (neat) 3342, 2934, 1730, 1674, 1251, 1231, 1173, 835, 690 cm -1 ; HRMS (EI) m/z calculated for C20H17N2O3 [M−H]− 333.1245, found: 333.1251. 5-(Cyclopent-1-en-1-yl)-3-phenyl-1H-pyrazol-4-ol 6: 90% yield. White solid, m. p. 198 – 200 °C (decomp.). 1H NMR (500 MHz, CD3OD) δ 7.85 (dd, J = 8.1, 0.9 Hz, 2H), 7.43 (dd, J = 10.6, 4.8 Hz, 2H), 7.34 (ddd, J = 6.8, 2.4, 1.2 Hz, 1H), 6.48 (dt, J = 4.2, 2.1 Hz, 1H), 2.78 (ddd, J = 9.8, 4.4, 2.1 Hz, 2H), 2.57 (tdd, J = 7.5, 4.8, 2.4 Hz, 2H), 2.07 – 1.93 (comp, 2H). 13 C NMR (126 MHz, CD3OD) δ 136.70, 135.08, 134.32, 131.59, 130.43, 128.71, 128.19, 127.49, 126.13, 32.87, 32.62, 22.39. IR (neat) 3249 (br), 1635, 1482, 1274, 1026, 845 cm -1 ; HRMS (ESI) m/z calculated for C14H15N2O [M+H] + 227.1179, found: 227.1181. 127 3-([1,1'-biphenyl]-4-yl)-5-(cyclopent-1-en-1-yl)-1H-pyrazol-4-ol 6’: 87% yield. White solid, m. p. > 300 °C (decomp.). 1H NMR (300 MHz, DMSO-d6) δ 12.54 (br, 1H), 8.04 – 8.01 (comp, 3H), 7.69 (d, J = 7.3 Hz, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.29 (s, 1H), 2.70 – 2.68 (comp, 2H), 2.49 – 2.47 (comp, 2H), 1.99 – 1.78 (comp, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 140.27, 138.71, 135.96, 129.39, 127.79, 127.05, 126.88, 126.30, 126.00, 33.41, 33.31, 22.76. IR (neat) 3246 (br), 1634, 1487, 1269, 1016, 844, 767 cm -1 ; HRMS (ESI) m/z calculated for C20H19N2O [M+H] + 303.1492, found: 303.1496. NMR graphs will be obtained from the supporting information of the upcoming published paper. 4.6 X-ray Crystal Structure Information for 4 and 6’ 128 129 Single crystals of C21H18N2O2 (4) and C20H18N2O (6') were prepared by slow evaporation of 4 solution in hexane/dichloromethane (4:1) and 6' solution in methanol respectively. A suitable green needle- like crystal (for C21H18N2O2), with dimensions of 0.42 mm × 0.06 mm × 0.01 mm, and a suitable colorless prism-like crystal (for C20H18N2O), 130 with dimensions of 0.37 mm × 0.27 mm × 0.07 were mounted, using Paratone oil, onto a glass fiber. The data were collected at 98(2) K using a Rigaku AFC12 / Saturn 724 CCD fitted with MoKα radiation (λ = 0.71075 Å). Data collection and unit cell refinement were performed using CrystalClear software. 9 The total number of data were measured in the range 5.2° < 2θ < 50.1° and 4.5° < 2θ < 50.1° using ω scans, respectively. Data processing and absorption correction, giving minimum and maximum transmission factors of 0.407 and 1.000 for C21H18N2O2 and 0.474 and 1.00 for C20H18N2O, were accomplished with CrystalClear 10 and ABSCOR 10 respectively. The structure, using Olex2, 11 was solved with the ShelXT 12 structure solution program using direct methods and refined (on F 2 ) with the ShelXL 13 refinement package using full-matrix, least-squares techniques. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atom positions were determined by geometry and refined by a riding model. Table 2.8 Crystallographic data and structure refinement for cd1309 (4) and cd1383 (6') 131 Identification code cd1309 cd1383 Empirical formula C21H18N2O2 C20H18N2O Formula weight 330.37 302.36 Crystal system Monoclinic Orthorhombic Space group P 1 21/c 1 P n a 21 a (Ǻ) 17.920(7) 6.727(9) b (Ǻ) 6.022(2) 23.55(3) c (Ǻ) 15.745(6) 9.860(13) α (°) 90 90 β (°) 99.297(6) 90 γ (°) 90 90 Volume (Ǻ3) 1676.8(11) 1562(4) Z 4 4 ρ (calc.) 1.309 1.286 λ 0.71075 0.71075 Temp. (K) 98(2) 98(2) 132 F(000) 696 640 μ (mm-1) 0.085 0.080 Tmin, Tmax 0.407, 1.000 0.474, 1.000 2θrange (°) 5.2 to 50.1 4.5 to 50.1 Reflections collected 8256 6848 Independent reflections 2953 [R(int) = 0.094] 2538 [R(int) = 0.067] Completeness 99.4% 97.6% Data / restraints / parameters 2953 / 0 / 226 2538 / 1 / 209 Observed data [I > 2σ(I)] 1994 1788 wR(F 2 all data) 0.1761 0.1984 R(F obsd data) 0.0785 0.0900 Goodness-of-fit on F 2 1.015 1.04 Largest diff. peak and 0.48/−0.48 0.37 / −0.37 133 hole (e Å −3 ) wR2 = { Σ [w(Fo2 – Fc2)2] / Σ [w(Fo2)2] }1/2 R1 = Σ ||Fo| – |Fc|| / Σ |Fo| V References: (1) (a) Hashmi, A. S. K.; Toste, F. D. (Eds.) Modern Gold Catalyzed Synthesis; Wiley-VCH: Weinheim, Germany, 2012. (b) Toste, F. D.; Michelet, V. (Eds.) Gold Catalysis: An Homogeneous Approach (Catalytic Science Series – Vol. 13); Imperial College Press, 2014. (2) (a) Ranieri, B.; Escofet, I.; Echavarren, A. M. Org. Biomol. Chem. 2015, 13, 7103-7118; (b) Qian, D.; Zhang, J. Chem. Soc. 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Introduction 1.1 Isoelectronic Principle and Isoelectronic Systems: Diazo Compounds, Ketenes and Allenes The term, isoelectronic, is used to describe chemical entities (atoms, molecules, or ions) that have the same number of electrons and the same number of heavy-atoms. 1 The “isoelectronic principle” states that when two or more molecular entities are isoelectronic, they tend to have similar physical and chemical properties. 2 For instance, carbon dioxide and nitrous oxide are isoelectronic with each other; and their physical properties including critical pressure, critical temperature, density of liquid, and dielectric constant of liquid are found to be remarkably similar. 3 More importantly, the isoelectronic principle provides an opportunity for chemists to predict some possible properties and reactions of compounds as being isoelectronic with some already known ones. 137 Diazo compounds, ketenes and allenes are isoelectronic and share similar electronic structures of cumulated double-bond systems (Figure 3.1). 4 Based on the isoelectronic principle, the rich chemistry of allenes and ketenes might provide some clues for us to discover possible properties and reactions of diazo compounds that have not been explored. Figure 3.1 Isoelectronic Systems: Allenes-Ketenes-Diazo Compounds 1.2 [4+2]-Cycloaddition of Dienes with Allenes or Ketenes The Diels-Alder reaction is noted for its ability to construct unsaturated six-membered rings and has been extensively used in synthesis of drugs, natural products, and compounds with biological activity. 5 Allene and ketene have been reported to undergo these reactions and have received considerable attention. 6 However, in the long history of Diels-Alder reactions there has not been a reported example of [4+2]-cycloaddition between a diene and a diazo compound. 7 1.2.1 4+2]-Cycloaddition of Diene with Allene 138 Concerted thermal [4+2]-cycloaddition reactions of dienes with highly polarized allenes were extensively investigated in the last century, but favorable competing stepwise [2+2]-cycloaddition reactions diminished their importance. 8 For instance, Houk and coworkers have investigated the cycloaddition reaction of 1,1-difluoroallene and 1,3- butadiene. Although the total yield of [4+2]-adduct and [2+2]-adduct is high, the selectivity in product formation is only moderate (Scheme 3.1). 9 Scheme 3.1 [4+2]- versus [2+2]-Cycloaddition of 1,1-Difluoroallene and 1,3-Butadiene. Transition metal complex catalyzed allene-diene cycloaddition reactions, although recent in their discovery, have circumvented this competition and become a mainstay of new process developments. 10 Under catalysis of transition metal complexes these [4+2]-cycloaddition reactions were proposed to proceed through a multistep mechanism that always involved organometallic complexes as reaction intermediates; the nature of these transition metal complexes has a great influence on the selectivity of [4+2]-cycloaddition reactions of allenes which have two reactive carbon-carbon double bonds. 11 For instance, Wender and 139 coworkers reported a transition metal-catalyzed intramolecular [4+2]- cycloaddition of diene-allene. 12 They found, interestingly, that treatment of the diene-allene with Ni(COD)2/P(O-o-BiPh)3 gave products with 6,6- fused rings, while when [RhCl(COD)]2/P(O-o-BiPh)3 was used as the catalyst, products with 6,5-fused rings were obtained in good yields (Scheme 3.2). 12 Scheme 3.2 Divergent Outcomes of Transition Metal-Catalyzed [4+2]- Cycloaddition Reactions of Allenes with Dienes. 1.2.2 [4+2]-Cycloaddition of Dienes with Ketenes The development of [4+2]-cycloaddition reactions of ketenes has been a challenge for a long period of time. 13 One major problem is that ketenes readily undergo [2+2]-cycloaddition reactions with one double bond of dienes. 14 However, diene equivalents that include α,β- unsaturated ketones bearing a strong electron-donating group (EWG) at the α position react with ketenes to produce [4+2]-cycloaddition products under thermal reaction conditions (Scheme 3.3). 15 140 Scheme 3.3 [4+2]-Cycloaddition Reaction of Diphenylketene and (E)-4- Methoxybut-3-en-2-one. Recently, organocatalysis has emerged as a powerful method in organic synthesis. 16 Organocatalyzed [4+2]-cycloaddition reactions of ketenes have also been explored. 17 These transformations involve zwitterionic “ketene” enolates that are generated in situ from the reactions of cinchona alkaloids or N-heterocyclic carbenes with ketenes. 17f These organocatalysts have not only expanded upon the substrate scope of dienes, but have also permitted access to the asymmetric version of these [4+2]-cycloaddition reactions. Cinchona alkaloid-based catalysts were first applied in the [4+2]-cycloaddition reaction of o-quinones with ketene enolates, which are derived in situ from readily available acid chlorides. 17b To inhibit the [2+2]- cycloaddition products, o-quinones were used as the dienes so that restoration of aromaticity occurs by [4+2]-cycloaddition (Scheme 3.4). Ye and coworkers have developed a chiral N-heterocyclic carbene- catalyzed formal [4+2]-cycloaddition of disubstituted ketenes with enones to produce δ-lactones with a quaternary-β-tertiary stereocenter in 141 good yields with high diastereo- and enantioselectivities. 17f The authors proposed that the [4+2]-cycloaddition reaction initiated by the nucleophilic addition of N-heterocyclic carbene (NHC) to ketenes produce ketene enolates, which could undergo an inverse electron demand Diels–Alder reaction to afford triazolium zwitterionic intermediates, followed by elimination of the NHC to furnish the corresponding δ–lactones (Scheme 3.5). Scheme 3.4 Cinchona Alkaloid-Based Catalyst-Catalyzed [4+2]- Cycloaddition of o-Quinones with Ketene Enolates 142 Scheme 3.5 N-Heterocyclic Carbene-Catalyzed [4+2]-Cycloaddition Reaction of Ketenes with Enones. 1.3 Original Considerations of [4+2]-Cycloaddition of Diene with Diazo Compounds Compared with allenes or ketenes, diazo compounds commonly react with one double bond of dienes by dipolar cycloaddition or, following dinitrogen extrusion, by cyclopropanation, but not by [4+2]- cycloaddition (Scheme 3.6). 7 143 Scheme 3.6 Dipolar Cycloaddition and Cyclopropanation of 1,3-Dienes with Diazo Compounds. That [4+2]-cycloaddition reactions occur with allenes and ketenes, but not with diazo compounds suggested to us that the facility with which diazo compounds undergo dipolar cycloaddition prevent [4+2]- cycloaddition and that, if dipolar cycloaddition could be electronically and/or sterically inhibited, perhaps [4+2]-cycloaddition should be observed. Inhibition of dipolar cycloaddition with deactivation of the carbon-carbon double bond towards dipolar cycloaddition would require constraints in the alignment of the diazo functional group with either one of the double bonds of the diene. To design such a system we were encouraged by a recent report by M. Brewer and coworkers of a polar intramolecular [4 ○+ +2]-cycloaddition of aryl-1-aza-2-azoniaallene salts that produced protonated azomethine imines. 18 When they used heteroallenes as starting materials, [3○+ +2]-cycloaddition products, 5,5- bridged bicyclic diazenium salts, 19 were not observed, but instead, [4○+ +2]-cycloaddition products, tricyclic azomethine imine salts containing a 1,2,3,4-tetrahydrocinnoline scaffold, were obtained in good yields. To further understand this transformation, Brewer and Houk have employed computational studies indicating that the formation of a four-membered 144 ring transition state prevents the formation of the [3○+ +2]-cycloaddition product and favors the [4○++2]-cycloaddition (Scheme 3.7). 20 Scheme 3.7 Intramolecular Cycloaddition of 1-Aza-2-Azoniaallene Salts. One such structural design appropriate for intramolecular [4+2]- cycloaddition between a diene and a diazocarbonyl compound (Scheme 3.8) would produce a dipolar azomethine species (2) that could serve as a suitable stabilized product. Add to this design activation of the diene with electron-donating substituents, as well as further stabilization of the dipolar azomethine product; and this cycloaddition reaction appears feasible. However, additional constraints that include the linkage between the diene and the diazo units, as well as the geometry of attachment to the diene, remain unresolved. 145 Scheme 3.8 Proposed Intramolecular [4+2]-Cycloaddition of Dienes with Diazo Compounds. For this investigation we chose to synthesize diene-linked aryldiazoacetates 1 (Scheme 3.9). This structure contains the elements of activation and stabilization that we believe to be requirements for diene- diazo [4+2]-cyclization. Gold-catalyzed 1,3-acyloxy migration of propargylic carboxylates is known to form allene intermediates (3) suitable for diene formation, and the generation of dienes from propargylic esters through a gold(I)-catalyzed 1,3-migratory cascade involving allene intermediates has been established. 21 146 Scheme 3.9 Synthesis of Diene-linked Aryldiazoacetates. II. Results and Discussion 2.1 Initial Screening of Additives and Reaction Conditions Treatment of propargyl phenyldiazoacetate 4a with a broad selection of neutral gold catalysts under various conditions of temperatures and solvents gave either no reaction or 1,5-dihydro-4H- pyrazol-4-ones as dominant products (discussed in Chapter 2) and minor amounts of diene (Z)-1a, although not in high yield. Sensing that proton transfer might be limiting this process, a variety of inorganic bases, organic bases, and organic acids were used as additives. Results are shown in Table 3.1. Organic bases that include triethylamine (NEt3), pyridine, and 1,8-diazabicycloundec-7-ene (DBU) were found to poison the gold catalyst (Table 3.1, entries 1-3). With sodium hydroxide as the base, the starting material 4a was also recovered in over 95% after 4 days under the same reaction conditions (Table 3.1, entry 4). Sodium acetate and sodium bicarbonate changed the yields of (Z)-1a slightly with over 95% conversion of 4a (Table 3.1, entries 5 and 6). Another mild Lewis base, nitrosobenzene (PhNO), was also tested and was found to slightly deactivate the gold catalyst (Table 3.1, entry 7). Interestingly, when 1.0 equivalent of dimethyl sulfoxide (DMSO) was added, the reaction 147 resulted in the formation of (Z)-1a and a product anticipated from a diene-diazo [4+2]-cycloaddition (2a) in a combined yield of 30% (Table 3.1, entry 8). Further investigations of other organic-oxide-containing bases including triphenylphosphine oxide and pyridine-N-oxide have shown that pyridine-N-oxide gave improved results (Table 3.1, entry 9 and 10). The use of benzoic acid did not yield the [4+2]-cycloaddition product 2a (Table 3.1, entry 11). Table 3.1 Sreening the Additives for Gold-Catalyzed Reactions of Propargyl Phenyldiazoacetate 4a. Entry a Additive Conversion b Yield c (Z)-1a:2a c 1 NEt3 <10 <10 - d 2 Pyridine <10 <5 - d 3 DBU <10 <10 - d 4 NaOH <10 <10 - d 5 NaOAc >95 15 >20:1 148 6 NaHCO3 >95 18 >20:1 7 PhNO 80 23 >20:1 8 DMSO >95 30 60:40 9 Ph3PO >95 10 >20:1 10 Pyridine-N- oxide >95 74 65:35 11 Benzoic acid 90% 9 >20:1 aTo a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, AuCl(SMe2) (2.90 mg, 0.010 mmol), an additive (0.20 mmol) and 2.0 mL of toluene were added sequentially under nitrogen atmosphere. Then 4a (0.20 mmol) dissolved in 3.0 mL of toluene was added sequentially into the solution under the flow of nitrogen. The resulting mixture was allowed to stir for 48 h at room temperature. bThe percent conversion of 4a was determined 1H NMR spectroscopy using 2,4,6-trimethoxybenzaldehyde as an internal standard. cThe total yields of [(Z)-1a+2a] and the ratios were determined by the 1H NMR analyses of characteristic absorptions. dNot determined. Pyridine-N-oxides with different substituent groups including nitro, methoxy, and chloro at the para-position were also tested (Table 3.2, entries 1-4). 4-Chloropyridine-N-oxide was optimal. 4-Nitropyridine-N- oxide 6c did not give the product from [4+2]-cycloaddition, which might be because of its decreased basicity; however, 4-methoxypyridine-N- oxide, which is a stronger base compared to pyridine-N-oxide, was found to deactivate the gold catalyst and resulted in a lower yield of products. With 4-chloropyridine-N-oxide, gold catalysts that include AuCl, AuCl3, IPrAuCl, PPh3AuCl were examined, but did not give improved results 149 (Table 3.2, entries 5-8). A variety of solvents that include hexanes, tetrahydrofuran (THF), acetonitrile (CH3CN), and toluene were examined subsequently (Table 3.2, entries 9-12): all of the solvents were tolerated, but their use did give significant variation in the (Z)-1a:2a product ratios. Finally, AuCl(Me2S) and 4-chloropyridine-N-oxide were optimal for the reaction performed in toluene at 20℃. Table 3.2 Optimization of Catalyst and Reaction Condition for Gold- Catalyzed Reactions of Propargyl Phenyldiazoacetate 4a. Entrya [Au] solvent 6 conversion (%)b yield (%)c (Z)- 1a:2ad 1 AuCl(SMe2) CH2Cl2 6a >95 74 65:35 2 AuCl(SMe2) CH2Cl2 6b >95 80 62:38 3 AuCl(SMe2) CH2Cl2 6c >95 <10 - d 150 4 AuCl(SMe2) CH2Cl2 6d 50 31 65:35 5 AuCl CH2Cl2 6b >95 76 65:35 6 AuCl3 CH2Cl2 6b >95 52 67:33 7 IPrAuCl CH2Cl2 6b <5 trace - d 8 PPh3AuCl CH2Cl2 6b <5 trace - d 9 AuCl(SMe2) hexane 6b >95 42 52:48 10 AuCl(SMe2) THF 6b >95 81 62:38 11 AuCl(SMe2) CH3CN 6b >95 55 65:35 12 AuCl(SMe2) toluene 6b >95 85 (80) e 43:57 (40:60)f aReactions were performed at 20℃ on a 0.20 mmol scale: a solution of 4a in 2.0 mL solvent was added to the solution of 6 (1.0 equiv) and 5 mol% of catalyst 3.0 mL of solvent under a nitrogen atmosphere, and the resulting reaction mixture was stirred for 4 days. bThe percent conversion of 4a was determined 1H NMR spectroscopy using 2,4,6-trimethoxybenz-aldehyde as an internal standard. cThe total yields of [(Z)-1a + 2a] and the ratios were determined by the 1H NMR analyses of characteristic absorptions. dNot determined. eThe combined isolated yield of (Z)-1a and 2a. fThe ratio (Z)-1a:2a of the isolated product. Structures for both the diene (Z)-1e and cycloaddition product 2f were confirmed by X-ray diffraction (Figure 3.2). Neither the cascade reaction anticipated from initial dinitrogen extrusion by the catalyst at the diazo carbon nor the product(s) from dipolar cycloaddition between the diazo compound and diene were observed, and the absence of the cascade 151 reaction product indicated a high preference of the gold catalyst for reaction at the carbon-carbon triple bond rather than with the phenyldiazoacetate. Figure 3.2 X-ray Structures of Diene (Z)-1e and Cycloaddition Product 2f. 2.2 Substrate Scope Using optimum reaction conditions (Table 3.2, entry 12) the influence of substituents on the arylpropargyl aryldiazoacetate was examined to further understand the formation of diene-linked aryldiazoacetates and the diene-diazo [4+2]-cycloaddition process. As shown in Table 3.3, arylacetic acid-derived substituents – including ethers, halides, nitro, trifluoromethyl, alkyl, aryl – underwent the rearrangement reaction smoothly within 4 days at 20oC, affording the diene and cycloaddition products in good to excellent combined yields (Table 3.3, entries 1-8). o-Bromophenylacetic acid-derived compound 4j (Table 3.3, entry 9) underwent reaction much slower than the p- bromophenylacetic acid-derived substitutent 4e, suggesting a possible 152 steric influence. We also examined arylacetylene-derived substituents. Generally, those with electron-donating substituents in the para-position (Table 3.3, entries 10 and 11) underwent rearrangement reaction faster than 4a. However, those with electron-withdrawing substituents were potential challenges because of the reduced nucleophilicity of (E)-1 dienes that are suggested to be the precursors to cycloaddition products 2. The success of the p-fluorophenylacetylene-substituted 4n encouraged us to examine more electron-deficient substituents (4o and 4p). The dienes and cycloaddition products from these reactants were successfully obtained in reasonable yields after 20 days at room temperature (Table 3.3, entries 14 and 15). However, the p-nitrophenylacetylene-substituted 4q failed to deliver the corresponding diene and cycloaddition product (Table 3.3, entry 16) even after 20 days. Table 3.3 Substrate Scope for Rearrangement Reaction. Entrya 4 Ar 1 Ar2 reaction time (day)b conversion (%)c yield of (Z)-1 and 2 (%)d (Z)- 1:2e 153 1 4b Ph 4 >95 92 41:59 2 4c 4-MeC6H4 Ph 4 >95 94 42:58 3 4d 4-PhC6H4 Ph 4 >95 91 42:58 4 4e 4-BrC6H4 Ph 4 >95 89 44:56 5 4f 4-ClC6H4 Ph 4 >95 88 41:59 6 4g 4-FC6H4 Ph 4 >95 84 40:60 7 4h 4-CF3C6H4 Ph 4 90 77 42:58 8 4i 4-NO2C6H4 Ph 4 85 70 26:74 9 4j 2-BrC6H4 Ph 20 >95 75 27:73 10 4k Ph 4-OMeC6H4 2.5 >95 82 50:50 11 4l Ph 4-MeC6H4 3 >95 86 48:52 12 4m Ph 4-ClC6H4 7 >95 85 47:53 13 4n Ph 4-FC6H4 9 >95 81 45:55 14 4o Ph 4- MeO2CC6H4 20 >95 81 45:55 15 4p Ph 4- (OHC)C6H4 20 >95 77 47:53 154 16 4q Ph 4-NO2C6H4 20 45% <10% - f aReactions were performed at 20℃ on 0.20 mmol scale: the solution of 4 in 2.0 mL toluene was added to the solution of 6b and 5 mol % of AuCl(SMe2) in 3.0 mL of toluene under a nitrogen atmosphere, and the resulting reaction mixture was stirred for the stated reaction time. bThe reaction time was determined from the disappearance of 4 by thin-layer chromatography or no improved conversion with longer times. cThe % conversion of 4 was determined by 1H NMR analysis using 2,4,6-trimethoxybenzaldehyde as the internal standard. dIsolated combined yields. eIsolated ratios. fNot determined. 2.3 Kinetic Studies To determine if both (E)-1 and (Z)-1 were formed initially after which (E)-1 underwent cycloaddition to 2 we examined the gold catalyzed reaction at shorter reaction times. If (E)-1 was the precursor to 2, this diene should be observed as an initially formed product. Fortunately, during 6-12 h reaction time at room temperature with relatively low conversion of 4, both (E)-1 and (Z)-1 were obtained at apparent equivalent rates. Isolation of (E)-1a by column chromatography at room temperature provided sufficient material to examine if this diene could undergo uncatalyzed formation of 2a or if cycloaddition required the intervention of a catalyst. In the absence of catalyst, isolated (E)-1a underwent quantitative conversion to cycloaddition product 2a in toluene at room temperature for 4 days. Furthermore, compound (E)-1a was dissolved in CDCl3 and the progress of the reaction was monitored by 1H NMR spectroscopy. Reaction was first order in (E)-1a with kobs = 9.6×10 - 5 s-1 at 41℃ in CDCl3 (Figure 3.3); and the addition of the gold catalyst 155 in amounts similar to those used for reactions with propargyl aryldiazoacetates 4 did not influence the rate of conversion of (E)-1a to 2a, confirming that the cycloaddition reaction was uncatalyzed. The variation of the rate constant over temperatures ranging from 20℃ to 49℃ provided Eact = 16.2 kcal/mol, H ‡ 298 = 15.6 kcal/mol and S ‡ 298 = - 27.3 cal/(mol•degree).22 Multiple determinations of reaction rates after separations of (E)-1a from different reaction mixtures were made to ensure that there was consistency in results. Cycloaddition occurred with rate constants that were independent of the batch source of (E)-1a. Figure 3.3 Linear Relationship Between Reaction Time and Ln [(E)- 1a/(E)-1a0]. Reaction Performed in CDCl3 at 41℃. y = -0.000096x + 0.003189 R² = 0.9996 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0 2000 4000 6000 8000 10000 12000 Ln [ ( E) -1 a/ ( 1 (E )- 1 a 0 ] Reaction time/sec 156 Surprisingly, the geometrical isomer of (Z)-1a did not undergo [4+2]-cycloaddition. Stable at room temperature in the absence of catalyst for more than 7 days in toluene, (Z)-1a underwent complete decomposition resulting in complex mixtures at 60℃ in CDCl3 for 24 h that did not include evidence for 2a or similar cycloaddition products. In contrast, (E)-1a underwent what is a facile [4+2]-cycloaddition reaction that occurred without evidence for formation of a dipolar cycloaddition product. The design of (E)-1 with its strategically placed phenyl groups allows the examination of the influence substituents on the rates for cycloaddition for both the dienophile and the diene in the same compound. To perform these determinations we isolated (E)-1 from a representative series of gold-catalyzed reactions of 4, determined the yields for their conversion to [4+2]-cycloaddition product, and measured the rates for their conversion to 2 at constant temperature. As shown in Table 3.4, the intramolecular [4+2]-cycloaddition reaction of (E)-1 gave 2 in high yields with complete diastereocontrol. Reaction rates were dependent on compounds (E)-1 with arylacetic acid-derived substituents Ar1 and with arylacetylene-derived aryl substituents Ar2. The p- methylsubstituent slightly decreased the reaction rate (Table 3,4, entry 157 2); other substituents, such as p-Ph, p-Br, p-Cl, and p-F, increased the reaction rate (Table 3,4, entries 3-6); moreover, the aryldiazoacetate with the strongly electron-withdrawing p-NO2 group gave the highest reaction rate (Table 3.4, entry 7). In contrast, electron-withdrawing groups on the benzene ring of the phenylacetylene-derived substituents decreased the reaction rate (Table 3.4, entries 11-14), whereas electron-donating groups increased the reaction rate (Table 3.4, entries 9 and 10). Hammett plots of the intermolecular [4+2]-cycloaddition reaction of (E)-1 showed good correlations between σ values and log (kX/kH) with -values of +0.89 (R 2 = 0.96) for the para-substituted aryldiazo esters and -1.65 (R2 = 0.95) for the para-substituted aryldienes (Figures 3.4 and 3.5).23 The diazo functional group exhibits electrophilic character in these reactions (discussed in Chapter 2) while the diene is its nucleophilic partner. In addition, the o-bromo substituent underwent a much slower reaction than did the p-bromo-derived compound, suggesting a possible steric inhibition (Table 3.4, entry 8). Table 3.4 Product and Kinetic Studies of Intramolecular [4+2]- Cycloaddition. 158 Entrya (E)-1 and 2 Ar1 Ar2 timeb (days) yield of 2 from (E)-1c rate constantd (s -1 ) 1 a Ph Ph 4 90 e 1.50×10-5 2 c 4- MeC6H4 Ph 4 92e 1.47×10-5 3 d 4- PhC6H4 Ph 4 93e 2.57×10-5 4 e 4- BrC6H4 Ph 4 90e 3.41×10-5 5 f 4-ClC6H4 Ph 4 88 e 3.04×10-5 6 g 4-FC6H4 Ph 4 91 e 2.38×10-5 7 i 4- NO2C6H4 Ph 2 85e 9.82×10-5 8 j 2- BrC6H4 Ph 21 87 0.33×10-5 9 k Ph 4-OMeC6H4 4 92 e 3.71×10-5 10 l Ph 4-MeC6H4 4 90 e 3.04×10-5 159 11 m Ph 4-ClC6H4 7 88 e 0.72×10-5 12 n Ph 4-FC6H4 7 88 e 0.86×10-5 13 o Ph 4- MeO2CC6H4 15 89 0.45×10-5 14 p Ph 4- (OHC)C6H4 21 87 0.30×10-5 aReactions were performed at 20 ± 0.5℃ on a 0.05 mmol scale: under a nitrogen atmosphere. The solution of (E)-1 in 0.5 mL CDCl3 was monitored by 1H NMR spectroscopy every a period of time until over 80% of (E)-1 was converted into the cycloaddition product 2. bThe reaction time was determined from the disappearance of (E)-1 by 1H NMR spectroscopy. cIsolated yields from the conversions of (E)-1 to 2. dDetermined by 1H NMR. eThe solution of (E)-1 and (Z)-1 in 0.5 mL CDCl3 was monitored by 1H NMR spectroscopy. Figure 3.4 Hammett Plot for the para-Substituted Aryldiazoesters. p-Me H p-F p-Ph p-Cl p-Br p-NO2 y = 0.8907x + 0.0934 R² = 0.9586 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 -0.2 0 0.2 0.4 0.6 0.8 1 lo g( K X /K H ) σ 160 Figure 3.5 Hammett Plot for the para-Substituted Aryldienes. 2.4 Reaction Mechanism A plausible mechanism for the neutral gold(I)-catalyzed formation of diene-diazo and cycloaddition product is outlined in Scheme 3.10. Gold-catalyzed 1,3-acyloxy rearrangement of 4a produces gold- coordinated carboxyallene A (discussed in Chapter 2). In the presence of 4-chloropyridine N-oxide, subsequent protonation of gold-coordinated carboxyallene A produces (E)- and (Z)-gold-coordinated diene-diazo intermediates B and C, which are protodeaurated by protonated 4- chloropyridine N-oxide (Pry-OH ○+ ) to produce (E)- and (Z)-1a and regenerate gold catalyst and 4-chloropyridine N-oxide. The (E)-1a further undergoes an intramolecular [4+2]-cycloaddition to furnish the dipolar azomethine species 2a. 161 Scheme 3.10 Proposed Mechanism for Gold(I)-Catalyzed Rearrangements in Presence of 4-Chloropyridine N-Oxide. 2.4a Gold-Catalyzed Isomerization of Allenes into 1,3-Dienes with an Additive As discussed in Chapter 2, gold-coordinated carboxyallene A, which is initially formed by gold-catalyzed 1,3-acyloxy rearrangement of 162 4a, is the key intermediate for further transformation. Gold-catalyzed synthesis of 1,3-dienes via allene intermediates has been reported previously (also discussed in Chapter 2). In some cases, additives play an important role in these transformations. For instance, Liu and coworkers found that in presence of AuCl3 and nitrosobenzene, the (3- methylbuta-1,2-dien-1-yl)benzene undergoes isomerization and furnishes (E)-(3-methylbuta-1,3-dien-1-yl)benzene in good yield. Nitrosobenzene is found to be essential to this transformation; no 1,3-diene is formed in absence of nitrosobenzene. In the paper, the authors suggested that the role of nitrosobenzene is as a mild base accelerating proton transfer for this isomerization (Scheme 3.11). 24 Scheme 3.11 Gold-Catalyzed Isomerization of Unreactive Allenes into 1,3-Dienes. 2.4b Pyridine N-Oxides as Mild Bases in Gold Catalysis Although pyridine-N-oxides are noted for their role in oxygen transfer that provides access to α-oxo gold carbenes,25 uses of pyridine- N-oxides as mild bases rather than as oxygen transfer agents have also 163 been reported. 26 For instance, studies of reactions using diynes as substrates with pyridine-N-oxides in presence of BrettPhosAuNTf afforded tricyclicindenes instead of oxidation products. Zhang and coworkers proposed a mechanism which describes the N-oxide as a mild base to facilitate the deprotonation of the terminal alkyne to form alkynylgold E with subsequent coordination with another BrettPhosAu cation to produce F, which further undergoes complex transformations to form intermediate G, which react with protonated pyridine N-oxide (Pry- OH○+) to produce the tricyclicindenes, and regenerate the gold catalysts and pyridine N-oxides (Scheme 3.12). 27 Scheme 3.12 Gold-Catalyzed Rearrangement of Diynes: Pyridine-N- Oxides as Mild Bases. 164 In another example, Zhang and co-workers reported a novel strategy for in situ generation of furan-based ortho-quinodimethanes from 2-(1-alkynyl)-2-alken-1-ones with catalytic amount of pyridine N-oxides and Ph3PAuCl. They demonstrated that pyridine-N-oxide plays a key role in this transformation and serves as the mild base. Interestingly, replacement of pyridine-N-oxide with a series of inorganic and organic bases including K2CO3, 1,4-diazabicyclo[2,2,2]octane (DABCO), Et3N, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) failed to produce the any desired products (Scheme 3.13). 28 Scheme 3.13 Gold-catalyzed Rearrangement of 2-(1-Alkynyl)-2-Alken- 1-Ones: Pyridine-N-Oxides as Mild Bases. 2.4c Deuterium Labeling Experiments Based on the proposed mechanism, we hypothesized that protonated 4-chloropyridine N-oxide (Pry-OH○+) may undergo deuterium- 165 hydrogen exchange with external deuterium source such as deuterium oxide (D2O) to form deuterated 4-chloropyridine N-oxide (Pry-OD○+); if this proposed process occurs, the deuterated dienes should be observed. Scheme 3.14 Proposed Deuterium-Hydrogen Exchange Process. To test our hypothesis, deuterium oxide (D2O) was added to the reaction mixtures under optimized reaction conditions. And the results were reported in Scheme 3.15. Both deuterated diene-diazo and [4+2]- cycloaddition products were obtained; and the percentage of two deuterated products was almost the same even with changing the amount of deuterium oxide (D2O). Scheme 3.15 Deuterium Labeling Experiments. 166 2.4d Theoretical Study To further understand this unique intramolecular [4+2]- cycloaddition reaction, we are collaborating with Professor Kenneth Houk’s group at UCLA, whose calculated results fit our observations very well. Although there is an intrinsic preference for diazoketones and dienes to give the 1,3-dipolar cycloaddition [3+2]-cycloaddition products, our reaction strongly favors the intramolecular [4+2] across the diazo N=N bond because the tether distortion is much less than that of the 1,3- dipolar cycloaddition (this work will published) . Figure 3.6 shows the energetics and transition states of intramolecular [4+2] cycloaddition across the N=N double bond of diazo ester for (E)- and (Z)-alkenes. The (E)-alkene is 2.5 kcal/mol stable than the (Z)-alkene. The observed product from (E)-alkene is formed with a barrier of only 26.9 kcal/mol. The reaction of the (Z)-alkene has a much high barrier (39.2 kcal/mol), and the product is slightly unstable compared to the reactant. Figure 3.6 Energetics and Transition States of Intramolecular [4+2]- Cycloaddition (E vs Z) 167 Figure 3.7 shows the two possible competing [4+2] and [3+2] cycloadditions. The observed [4+2] cycloaddition has a lower barrier (by 4 kcal/mol) compared to the (3+2) cycloaddition. Therefore, only the [4+2] product was observed experimentally, although the (3+2) product is more stable. Figure 3.7 Energetics and Transition States of [4+2]- and [3+2]- Cycloadditions 2.5 Further Applications of [4+2]-Cycloaddition Products The [4+2]-cycloaddition products formed from (E)-1 are stable dipolar species, and their suitability for dipolar cycloaddition with reactive alkenes and alkynes was examined.29 Treatment of 2e with N- phenylmaleimide at room temperature for 6 h gave the nitrogen-fused pentacyclic compound 5e in 85% yield with complete diastereocontrol (eq 2). The structure of 5e was confirmed by X-ray diffraction (Figure 3.8). 168 Figure 3.8 X-Ray Structure of 5e. III. Conclusion In summary, aryl-substituted 1-(1,3-dienyl) aryldiazoacetates were formed selectively and in moderate to high yields by Au(I)-catalyzed rearrangement of propargyl phenyldiazoacetates performed in the presence of a pyridine-N-oxide. Complete selectivity for Au(I) activation of the alkyne rather than metallocarbene formation from the diazoacetate occurred, and both aryl-substituted 1-(1,3-dienyl) aryldiazoacetates and the products from intramolecular [4+2]-cycloaddition of the diazo N=N bond to the diene were formed. Aryl-substituted (E)-1-(1,3-dienyl) 169 aryldiazoacetates underwent intramolecular [4+2]-diene-diazo cycloaddition under mild conditions without catalysis by the Au(I) reagent used in its formation and without evidence of a competing dipolar cycloaddition.30 Cycloaddition was first order in the substrate, and both the activation parameters and the Hammett relationships for the conversion of (E)-1 to 2 are consistent with those for other intramolecular Diels-Alder reactions.31 IV. Experimental Section 4.1 General Information Unless noted all reactions were carried out under inert atmosphere of dinitrogen in oven-dried glassware with magnetic stirring using freshly distilled solvents. All solvents were purified and dried using standard methods. Analytical thin layer chromatography (TLC) plates were purchased from EM Science (silica gel 60 F254 plates). High-resolution mass spectra (HRMS) were performed on a microTOF-ESI mass spectrometer using CsI as the standard. Accurate masses are reported for the molecular ion [M+Cs] + , [M+Na] + , or [M+H] + . Melting points were determined on an Electrothermo Mel-Temp DLX 104 device and were uncorrected. Column chromatography was performed on CombiFlash ® Rf 200 purification system using normal phase disposable columns. IR 170 spectra were recorded using Bruker Vectcr 22 spectrometer. All NMR spectra were recorded on a Bruker spectrometer at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR) or an Agilent spectrometer at 500 MHz ( 1 H NMR) and 125 MHz ( 13 C NMR). Chemical shifts are reported in ppm with the solvent signals as reference (in CDCl3 as solvent), and coupling constants (J) are given in Hertz (Hz). The peak information is described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite of magnetically non-equivalent protons. 4.2 Materials AuCl, AuCl3, (PPh3)AuCl, (IPr)AuCl were purchased from Sigma- Aldrich. AuCl(C4H8S) and AuCl3(C5H6N) were purchased from Strem Chemicals. Pyridine N-oxides were purchased from Sigma-Aldrich or prepared according to the literature procedures. 32 Other chemicals were obtained from commercial sources and used without further purification. 4.3 Experimental Procedures Synthesis of 1-[(4-chlorophenyl)ethynyl]cyclopentyl α-diazo-α- phenylacetate (4m). 171 To a solution of Et2NH (20 mL) in an oven-dried flask equipped with a magnetic stirring bar was added 1-ethynylcyclopentan-1-ol (1.10 g, 10.0 mmol), 1-chloro-4-iodobenzene (2.62 g, 11.0 mol), Pd(PPh3)2Cl2 (700 mg, 1.0 mmol), CuI (38 mg, 2.0 mmol), and the reaction mixture was degassed with nitrogen. After stirring under refluxing conditions for 24 h, the solvent of the reaction mixture was removed with the use of a vacuum pump. The residue was purified by column chromatography (hexane/ethyl acetate = 10/1) to give 1-((4- chlorophenyl)ethynyl)cyclopentan-1-ol as a colorless oil (1.98 g, 90% yield). To a solution of 1-[(4-chlorophenyl)ethynyl]cyclopentan-1-ol (1.10 mg, 5 mmol), phenylacetic acid (816 mg, 6 mmol) and DMAP (122 mg, 1 mmol) in dry DCM (30 mL) was added to a solution of DCC (1.24 g, 6 mmol) in dry DCM (20 mL) via addition funnel over 20 min at 0 o C. The 172 resulting mixture was allowed to warm to room temperature, and stirred for another 10 h, and a white solid was formed in the process. The reaction solution was added to 30 mL of hexanes and then filtered through a Büchner funnel. After evaporating the solvent, the resulting reaction mixture was purified by column chromatography (hexane/ethyl acetate = 25/1) to give the 1-[(4-chlorophenyl)ethynyl]cyclopentyl 2- phenylacetate as a colorless oil (1.39 g, 82% yield). To a solution of 1-[(4-chlorophenyl)ethynyl]cyclopentyl 2- phenylacetate (1.29 g, 4.1 mmol) and p-ABSA (1.20 g, 5 mmol) in dry CH3CN (30 mL) was added DBU (0.76g, 5mmol) dropwise at 0 o C. The resulting mixture was allowed to warm to room temperature, and stirred for another 10 h. The reaction was quenched with aqueous NH4Cl solution (60 mL), and then extracted with diethyl ether (50 mL×2) and dried over anhydrous MgSO4. After evaporating the solvent, the reaction mixture was purified by column chromatography (hexane/ethyl acetate = 30/1) to give the 1-[(4-chlorophenyl)ethynyl]cyclopentyl α-diazo-α- phenylacetate 4m as a yellow oil (1.30 g, 85% yield). Compounds 4n – 4q were prepared from corresponding iodo(bromo)- arenes using the same synthetic procedure with 4m. 173 General Procedure for Gold Catalyzed Rearrangement of Propargyl Aryldiazoacetates in the Presence of 4-Chloropyridine N-Oxide: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, AuCl(SMe2) (2.90 mg, 0.010 mmol), 4-chloropyridine N- oxide 6b (25.9 mg, 0.20 mmol) and 2.0 mL toluene were added sequentially under nitrogen atmosphere. Then 4 (0.20 mmol) dissolved in 3.0 mL of toluene was added at once into the solution under the flow of nitrogen. The resulting mixture was allowed to stir for the stated time at room temperature, then purified by column chromatography (with 100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to give isolated (Z)- 1 and 2. General Procedure for Deuterium Labeling Experiments To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, AuCl(SMe2) (2.90 mg, 0.010 mmol), 4-chloropyridine N- oxide 6b (25.9 mg, 0.20 mmol), x (x = 1.0, 2.0, 5.0, 10.0) equiv. of deuterium oxide (D2O) and 2.0 mL toluene were added sequentially under nitrogen atmosphere. Then 4a (0.20 mmol) dissolved in 3.0 mL of toluene was added at once into the solution under the flow of nitrogen. The resulting mixture was allowed to stir for the 4 days at room temperature, then purified by column chromatography (with 100:1 to 174 10:1 gradient of hexanes: ethyl acetate as eluents) to give isolated (Z)-1a and 2a. The percentage of deuterated products was determined by 1 H NMR analysis. Kinetic Measurements: Isolation of (E)-1a: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, AuCl(SMe2) (2.90 mg, 0.010 mmol), 4- chloropyridine-N-oxide (25.9 mg, 0.20 mmol) and 2.0 mL toluene were added sequentially under nitrogen atmosphere. Then 4 (0.20 mmol) dissolved in 3.0 mL of toluene was added at once into the solution under the flow of nitrogen. The resulting mixture was allowed to stir for 6 - 12 h at room temperature. The mixture of diene (E)-1a with (Z)-1a was isolated following the separation on the silica gel column chromatography (with 100:1 to 30:1 gradient of hexanes:ethyl acetate as eluents) and removal solvents in a water bath at 5 - 10 o C under vacuum. The mixture of diene (E)-1a with (Z)-1a was obtained as light yellow oil and kept under nitrogen atmosphere at -78 o C. Pure diene (E)-1a could be isolated by preparative TLC plates. Data collection for the intermolecular cycloaddition reaction: Because (E)-1a is inert to [4+2]-cycloaddition and stable in CDCl3 at room temperature, we decided to use the mixture of diene (E)-1a with 175 (Z)-1a for data collection. The mixture of diene (E)-1a with (Z)-1a (0.1 M for combined concentration) was diluted in CDCl3 and placed in an NMR tube. The ratio of diene (E)-1a [δ 6.39 (s, 1H), 5.84 (t, J = 2.2 Hz, 1H) with (Z)-1a (1:1) [δ 6.55 (s, 1H), 5.90 (t, J = 2.4 Hz, 1H) was determined by 1 H NMR analysis (Agilent spectrometer at 500 MHz for 1 H NMR). The NMR tube was placed in an oil bath at 41 o C with temperature stability of ±0.5 o C for 10.0 min and quenched by dry ice- acetone bath. The 1 H NMR spectra were recorded after the heating of each 10.0 (or 30.0) min. A control experiment was carried out which proved that the presence of (Z)-1a had no effect on the rate of intramolecular [4+2]-reaction or on the yield of products. Computational methods for determining the progress of the intramolecular cycloaddition reaction: The amount of (E)-1a was determined by the integration of (E)-1a olefinic protons at δ = 6.39 (s, 1H, normalized as “1.00”), 5.84 (t, J = 2.2 Hz, 1H), and the difference was less than 5%. The amount of (E)-1a0 was calculated by combined integration of (E)-1a with 2a [δ 8.69 (d, J = 8.5, 2H), 6. 57 – 6.54 (m, 1H)] or the integration of (Z)-1a [δ 6.63 (s, 1H), 5.98 (t, J = 2.4 Hz, 1H), and the difference of two methods was less than 5%. 176 For other substituted derivatives: The mixture of diene (E)-1 with (Z)-1 was isolated following the same procedure as 1a and was used directly for data collection of the intermolecular cycloaddition reaction. The amount of (E)-1 was determined by the integration of (E)-1 olefinic protons δ = 6.45 – 6.35 (s, 1H, normalize as “1.00”), 5.85 – 5.75, (t, 1H) and the difference was less than 5%. The amount of (E)-10 was calculated by combined integration of (E)-1 with 2 [δ 8.80 – 8.60 (d, 2H), 6. 60 – 6.50 (m, 1H)] or the integration of (Z)-1a [δ 6.70 – 6.50 (s, 1H), 5.95 – 5.87 (t, 1H), and the difference of two methods was less than 5%. First-order rate constants at different temperatures (20 o C, 41 o C, 49 o C) were obtained by the same procedure: the time in oil bath ranged from every 5 min (49 o C) to 1 h (20 o C) with a temperature stability of ±0.5 o C (Figure 3.9 to Figure 3.12). This intramolecular process was recorded at least 8 times. An Arrhenius plot was obtained from the kinetic rate constants that were obtained and their corresponding temperature (Table 3.5 and Figure 3.13). The activation energy Eact was calculated from the slope of Arrhenius plot (Eact = -slope × R). H ‡ 298 and S‡298 were calculated by the Eyring equation. 177 Table 3.5 Data for Arrhenius plot lnk -11.09 -10.12 -9.25 -8.52 1/T 0.003411 0.003299 0.003183 0.003104 Figure 3.9 First-order Rate Constant at 49 o C. Figure 3.10 First-order Rate Constant at 41oC. Figure 3.11 First-order Rate Constant at 30 o C. Figure 3.12 First-order Rate Constant at 20 o C. Figure 3.13 Arrhenius plot: (E)-1a Activation Energy. 4.4 Characterization Data for New Compounds (The characterization data for 4a, 4a-g has been reported on Chapter 1 and 2.) 178 1-(Phenylethynyl)cyclopentyl 2-(benzo[d][1,3]dioxol-5-yl)-2- diazoacetate 4b: 63% yield. Red solid, m.p. 69.1 – 71.0℃. 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.39 (comp, 2H), 7.31 – 7.24 (comp, 3H), 7.10 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.96 (s, 2H), 2.44 – 2.35 (comp, 2H), 2.33 – 2.25 (comp, 2H), 1.86 – 1.75 (comp, 4H). 13 C NMR (125 MHz, CDCl3) δ 163.79, 148.31, 145.92, 131.81, 128.27, 128.10, 122.64, 118.71, 117.71, 108.73, 105.68, 101.19, 89.33, 85.05, 82.13, 40.75, 23.42. IR (neat) 2085, 1700, 1492, 1235, 903 cm -1 . HRMS (ESI) m/z calculated for C22H18N2O4Na + [M+Na] + 397.1159, found: 397.1174. 1-(Phenylethynyl)cyclopentyl 2-Diazo-2-[4-(trifluoromethyl)- phenyl]acetate 4h: 58% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.68 – 7.57 (comp, 4H), 7.47 – 7.43 (comp, 2H), 7.33 – 7.25 (comp, 3H), 2.48 – 2.38 (comp, 2H), 2.37 – 2.26 (comp, 2H), 1.90 – 1.79 (comp, 4H). 13 C NMR (125 MHz, CDCl3) δ 162.73, 131.82, 130.27, 128.42, 128.17, 127.47 (q, J = 32.5 Hz), 125.73 (q, J = 3.8 Hz), 124.09 (q, J = 179 270.2 Hz), 123.45, 122.53, 89.02, 85.39, 82.68, 40.78, 23.45. IR (neat) 2092, 1704, 1325, 1125, 1070, 903 cm -1 . HRMS (ESI) m/z calculated for C22H17N2O2F3Na + [M+Na] + 421.1134, found: 421.1131. 1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(4-nitrophenyl)acetate 4i: 54% yield. Yellow solid, m.p. 113.4 – 114.5℃. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.47 – 7.42 (comp, 2H), 7.32 – 7.27 (comp, 3H), 2.46 – 2.38 (comp, 2H), 2.35 – 2.28 (comp, 2H), 1.92 – 1.78 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 162.03, 144.95, 134.04, 131.80, 128.49, 128.18, 124.20, 123.18, 122.38, 88.72, 85.57, 83.07, 40.75, 23.42. IR (neat) 2095, 1708, 1594, 1335, 1245, 1152, 903 cm -1 . HRMS (ESI) m/z calculated for C21H17N3O4Na + [M+Na] + 398.1111, found: 398.1135. 180 1-(Phenylethynyl)cyclopentyl 2-(2-Bromophenyl)-2- diazoacetate 4j: 60% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.47 – 7.43 (comp, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.31 – 7.27 (comp, 3H), 7.19 (t, J = 7.7 Hz, 1H), 2.43 – 2.37 (comp, 2H), 2.33 – 2.25 (comp, 2H), 1.86 – 1.78 (comp, 4H). 13 C NMR (125 MHz, CDCl3) δ 163.77, 133.28, 132.80, 131.80, 129.86, 128.24, 128.08, 127.55, 125.86, 122.69, 89.39, 85.01, 82.29, 40.72, 23.40. IR (neat) 2098, 1700, 1153, 902 cm -1 . HRMS (ESI) m/z calculated for C21H17N2O2BrNa + [M+Na] + 431.0366, found: 431.0386. 1-[(4-Methoxyphenyl)ethynyl]cyclopentyl α-Diazo-α-phenyl- acetate 4k: 52% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.7 Hz, 2H), 7.43 – 7.36 (comp, 4H), 7.18 (t, J = 8.5 Hz, 1H), 6.84 – 6.80 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 2.47 – 2.40 (comp, 2H), 2.35 – 2.27 (comp, 2H), 1.88 – 1.80 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.43, 159.56, 133.24, 128.77, 125.59, 123.86, 114.70, 113.68, 87.89, 84.95, 82.31, 55.15, 40.75, 23.37. IR (neat) 2087, 1702, 1510, 1247, 181 1149, 903 cm -1 . HRMS (ESI) m/z calculated for C22H20N2O3Na + [M+Na] + 383.1366, found: 383.1364. 1-(p-Tolylethynyl)cyclopentyl α-Diazo-α-phenylacetate 4l: 60% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) 7.51 (d, J = 8.1 Hz, 2H), 7.40 – 7.32 (comp, 4H), 7.19 – 7.15 (m, 1H), 7.09 (d, J = 8.1 Hz, 2H), 2.46 – 2.38 (comp, 2H), 2.35 – 2.26 (comp, 5H), 1.88 – 1.79 (comp, 4H). 13 C NMR (125 MHz, CDCl3) δ 163.49, 138.35, 131.71, 128.86, 128.83, 125.66, 123.95, 119.58, 88.61, 85.21, 82.29, 40.78, 23.43, 21.43. IR (neat) 2079, 1703, 1598, 1498, 1244, 1142, 1003 cm -1 . HRMS (ESI) m/z calculated for C22H20N2O2Na + [M+Na] + 367.1417, found: 367.1426. 1-[(4-Chlorophenyl)ethynyl]cyclopentyl α-Diazo-α- phenylacetate 4m: 62% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.7 Hz, 2H), 7.41 – 7.36 (comp, 4H), 7.27 (d, J = 7.7 Hz, 182 2H), 7.19 (t, J = 9.6 Hz, 1H), 2.47 – 2.38 (comp, 2H), 2.36 – 2.28 (comp, 2H), 1.89 – 1.80 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.48, 134.30, 133.03, 128.86, 128.44, 125.74, 125.52, 123.93, 121.16, 90.33, 83.96, 81.97, 40.71, 23.44. IR (neat) 2087, 1701, 1149, 903 cm -1 . HRMS (ESI) m/z calculated for C21H17N2O2ClNa + [M+Na] + 387.0871, found: 387.0883. 1-[(4-Fluorophenyl)ethynyl]cyclopentyl α-Diazo-α-phenyl- acetate 4n: 61% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 2H), 7.45 – 7.40 (comp, 2H), 7.40 – 7.35 (comp, 2H), 7.18 (t, J = 7.5, 1H), 7.98 (t, J = 7.5, 1H), 2.45 – 2.38 (comp, 2H), 2.33 – 2.25 (comp, 2H), 1.87 – 1.79 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.51, 162.52 (d, J = 249.9 Hz), 133.74 (d, J = 8.3 Hz), 128.87, 125.73, 125.58, 123.95, 118.74(d, J = 3.5 Hz), 115.39 (d, J = 22.4 Hz), 89.05, 84.03, 82.07, 40.74, 23.44. IR (neat) 2085, 1702, 1505, 1246, 1147, 905 cm -1 . HRMS (ESI) m/z calculated for C21H17N2O2FNa + [M+Na] + 371.1166, found: 371.1179. 183 Methyl 4-[(1-(2-Diazo-2-phenylacetoxy)cyclopentyl]ethynyl benzoate 4o: 57% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.52 – 7.48 (comp, 4H), 7.38 (t, J = 7.9 Hz, 2H), 7.18 (t, J = 10.6, 1H), 3.90 (s, 3H), 2.45 – 2.37 (comp, 2H), 2.35 – 2.25 (comp, 2H), 1.88 – 1.79 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 166.50, 163.49, 131.69, 129.54, 129.28, 128.88, 127.39, 125.77, 125.48, 123.94, 92.38, 84.35, 81.86, 52.16, 40.71, 23.46. IR (neat) 2081, 1703, 1605, 1273, 1145, 1004 cm -1 . HRMS (ESI) m/z calculated for C23H20N2O4Na + [M+Na] + 411.1315, found: 411.1314. 1-[(4-Formylphenyl)ethynyl]cyclopentyl α-Diazo-α-phenyl- acetate 4p: 53% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 9.99 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 2.46 – 2.40 184 (comp, 2H), 2.36 – 2.29 (comp, 2H), 1.89 – 1.83 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 191.41, 163.48, 135.47, 132.28, 129.34, 128.97, 128.89, 125.80, 125.42, 123.93, 93.49, 84.23, 81.75, 40.69, 23.47. IR (neat) 2087, 1709, 1497 cm -1 . HRMS (ESI) m/z calculated for C22H18N2O3Na + [M+Na] + 381.1210, found: 381.1219. 1-[(4-Nitrophenyl)ethynyl]cyclopentyl α-Diazo-α-phenylacetate 4q: 47% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 2.47 – 2.39 (comp, 2H), 2.35 – 2.28 (comp, 2H), 1.88 – 1.82 (comp, 4H). 13C NMR (125 MHz, CDCl3) δ 163.49, 147.07, 132.48, 129.60, 128.91, 125.86, 125.33, 123.92, 123.37, 94.81, 83.30, 81.56, 40.65, 23.48. IR (neat) 2090, 1703, 1521, 1346, 1150, 906 cm -1 . HRMS (ESI) m/z calculated for C21H17N3O4Na + [M+Na] + 398.1111, found: 398.1124. 185 (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl α-Diazo-α-phenyl- acetate 1a: 32% yield. 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 – 7.18 (m, 1H), 7.15 – 7.12 (m, 1H), 6.55 (s, 1H), 5.90 (t, J = 2.4 Hz, 1H), 2.60 (t, J = 6.4 Hz, 2H), 2.32 (dt, J = 7.6, 2.4 Hz, 2H), 1.90 – 1.80 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.24, 143.72, 138.56, 135.57, 135.44, 129.03, 128.62, 128.23, 126.09, 124.79, 124.47, 123.83, 115.08, 33.06, 32.19, 23.82. HRMS (ESI) m/z calculated for C21H18N2O2Cs + [M+Cs] + 463.0417, found: 463.0437. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-(Benzo[d][1,3]- dioxol-5-yl)-2-diazoacetate 1b: 38% yield. 1 H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 2H), 7.29 – 7.27 (m, 1H), 7.14 – 7.09 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.61 (s, 1H), 5.97 (t, J = 2.0 Hz, 1H), 5.96 (s, 2H), 2.67 (t, J = 6.3 Hz, 2H), 2.40 (dt J = 7.3, 2.0 Hz, 2H), 1.97 – 1.90 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 163.61, 148.50, 146.27, 143.75, 138.55, 135.58, 135.42, 128.62, 128.23, 124.47, 124.38, 117.82, 115.06, 108.87, 105.63, 186 101.33, 33.06, 32.20, 23.83. HRMS (ESI) m/z calculated for C22H18N2O4Cs + [M+Cs] + 507.0316, found: 507.0319. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl α-Diazo-α-(p-tolyl)- acetate 1c: 40% yield. 1 H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.31 -7.28 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.63 (s, 1H), 5.98 (t, J = 2.3 Hz, 1H), 2.68 (t, J = 6.5 Hz, 2H), 2.40 (dt, J = 7.5, 2.3 Hz, 2H), 2.35 (s, 3H), 1.92 – 1.83 (comp, 2H). 13 C NMR (125 MHz, CDCl3) δ 163.48, 143.76, 138.60, 136.03, 135.61, 135.38, 129.75, 128.60, 128.20, 124.47, 123.94, 121.40, 115.05, 33.05, 32.19, 23.82, 20.99. HRMS (ESI) m/z calculated for C22H20N2O2Cs + [M+Cs] + 477.0574, found: 477.0592. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-([1,1'-Biphenyl]-4- yl)-2-diazoacetate 1d: 38% yield. 1 H NMR (500 MHz, CDCl3) δ 7.66 – 7.62 (comp, 3H), 7.61 – 7.57 (comp, 3H), 7.51 – 7.47 (comp, 2H), 7.43 – 187 7.46 (comp, 2H), 7.37 – 7.33 (comp, 3H), 7.30 – 7.28 (m, 1H), 6.64 (s, 1H), 5.99 (t, J = 2.4 Hz, 1H), 2.69 (t, J = 6.5 Hz, 2H), 2.41 (dt, J = 7.5, 2.4 Hz, 2H), 1.88 (tt, J = 7.5, 6.5 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 163.27, 143.73, 140.21, 138.93, 138.55, 135.56, 135.52, 128.84, 128.65, 128.26, 127.68, 127.43, 126.87, 124.48, 124.15, 123.64, 115.12, 33.08, 32.20, 23.84. HRMS (ESI) m/z calculated for C27H22N2O2Cs + [M+Cs] + 539.0730, found: 539.0757. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-(4-Bromophenyl)- 2-diazoacetate 1e: 39% yield. 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.36 – 7.32 (comp, 2H), 7.29 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 5.98 (t, J = 2.2 Hz, 1H), 2.65 (t, J = 6.3 Hz, 2H), 2.40 (dt J = 8.2, 2.2 Hz, 2H), 1.96 – 1.91 (comp, 2H). 13 C NMR (125 MHz, CDCl3) δ 162.97, 143.61, 138.40, 135.65, 135.44, 132.10, 128.65, 128.30, 125.23, 124.43, 123.98, 119.67, 115.15, 33.05, 32.18, 23.80. HRMS (ESI) m/z calculated for C21H17N2O2BrCs + [M+Cs] + 540.9522, found:540.9539. 188 (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-(4-Chlorophenyl)- 2-diazo-acetate 1f: 36% yield. 1 H NMR (500 MHz, CDCl3) δ 7.48 (comp, 4H), 7.38 – 7.33 (comp, 4H), 7.29 (t, J = 7.3 Hz, 1H), 6.62 (s, 1H), 5.99 (t, J = 2.5 Hz ,1H), 2.66 (t, J = 6.6 Hz, 2H), 2.40 (dt, J = 7.6, 2.5 Hz, 2H), 1.97 – 1.90 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.00, 143.64, 138.42, 135.64, 135.47, 131.83, 129.19, 128.66, 128.31, 124.99, 124.45, 123.41, 115.16, 33.06, 32.19, 23.81. HRMS (ESI) m/z calculated for C21H17N2O2ClCs + [M+Cs] + 497.0028, found:497.0047. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-Diazo-2-(4-fluoro- phenyl)-acetate 1g: 34% yield. 1 H NMR (500 MHz, CDCl3) δ 7.53 – 7.44 (comp, 4H), 7.34 (t, J = 7.5 Hz, 1H), 7.30 – 7.26 (comp, 1H), 7.10 (d, J = 7.5 Hz, 2H), 6.62 (s, 1H), 6.97 (t, J = 2.5 Hz ,1H), 2.66 (t, J = 6.5 Hz ,2H), 2.40 (dt, J = 7.6, 2.5 Hz, 2H), 1.98 – 1.89 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.33, 161.20 (d, J = 247.9 Hz), 143.70, 138.48, 189 135.56, 135.53, 128.65, 128.29, 125.81(d, J = 7.8 Hz), 124.46, 120.52 (d, J = 1.9 Hz), 116.15 (d, J = 21.9 Hz), 115.13, 33.07, 32.20, 23.83. HRMS (ESI) m/z calculated for C21H17N2O2FCs + [M+Cs] + 481.0323, found:481.0338. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-Diazo-2-[4- (trifluoromethyl)phenyl]acetate 1h: 32% yield. 1 H NMR (500 MHz, CDCl3) δ 7.69 – 7.64 (comp, 4H), 7.48 (d, J = 8.3 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.32 – 7.28 (m, 1H), 6.65 (s, 1H), 6.01 (t, , J = 2.6 Hz, 1H), 2.67 (t, J = 6.7 Hz, 2H), 2.42(dt, J = 7.8 Hz, 2.6 Hz, 2H), 1.98 – 1.92 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 162.57, 143.55, 138.33, 135.83, 135.37, 129.36, 128.69, 128.41, 127.91 (q, J = 32.4 Hz), 125.93 (q, J = 3.8 Hz), 124.44, 123.96 (q, J = 270.2 Hz), 123.42, 115.24, 33.06, 32.19, 23.81. HRMS (ESI) m/z calculated for C22H17N2O2F3Cs + [M+Cs] + 531.0291, found: 531.0317. 190 (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-Diazo-2-(4-nitro- phenyl)-acetate 1i: 18% yield. 1 H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.32 - 7.28 (m, 1H), 6.64 (s, 1H), 6.01 (t, J = 2.4 Hz, 1H), 2.65 (t, J = 6.4 Hz, 2H), 2.41 (dt, J = 7.5, 2.4 Hz, 2H), 1.97 – 1.91 (comp, 2H). 13 C NMR (125 MHz, CDCl3) δ 162.00, 145.34, 143.46, 138.17, 136.11, 135.22, 133.05, 128.75, 128.48, 124.43, 124.37, 123.30, 115.36, 33.09, 32.20, 23.81. HRMS (ESI) m/z calculated for C21H17N3O4Cs + [M+Cs] + 508.0268, found: 508.0286. (Z)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl 2-(2-Bromophenyl)- 2-diazo-acetate 1j: 20% yield. 1 H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.41 – 7.33 (comp, 3H), 7.31 – 7.27 (m, 1H), 7.26 – 7.23 (m, 1H), 6.59 (s, 1H), 5.97 (t, J = 2.2 Hz, 1H), 2.75 – 2.65 (comp, 2H), 2.40 (dt, J = 7.0, 2.2 Hz, 2H), 2.00 – 1.92 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.78, 144.00, 138.59, 135.56, 135.27, 135.23, 133.34, 130.52 130.51, 128.58, 191 128.19, 127.83, 124.52, 114.95, 114.91, 33.21, 32.24, 23.80. HRMS (ESI) m/z calculated for C21H17N2O2BrCs + [M+Cs] + 540.9522, found: 540.9552. (Z)-2-(Cyclopent-1-en-1-yl)-1-(4-methoxyphenyl)vinyl α-Diazo- α-phenylacetate 1k: 42% yield. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.9 Hz, 2H), 7.42– 7.38 (comp, 4H), 7.21 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 6.51 (s, 1H), 5.93 (t, J = 2.4 Hz, 1H), 3.80 (s, 3H), 2.66 (t, J = 6.8 Hz, 2H), 2.39 (dt, J = 7.8, 2.4 Hz, 2H), 1.95 – 1.89 (comp, 2H). 13 C NMR (125 MHz, CDCl3) δ 159.69, 143.65, 138.59, 134.37, 129.02, 128.24, 126.06, 125.90, 124.84, 123.82, 114.09, 113.90, 113.42, 55.30, 33.10, 32.15, 23.83. HRMS (ESI) m/z calculated for C22H20N2O3Cs + [M+Cs] + 493.0523, found: 493.0539. (Z)-2-(Cyclopent-1-en-1-yl)-1-(p-tolyl)vinyl α-Diazo-α-phenyl- acetate 1l: 41% yield. 1 H NMR (500 MHz, CDCl3) δ 7.55(d, J = 8.0 Hz, 2H), 7.42 – 7.36 (comp, 4H), 7.21 (t, J = 7.57, 1H), 7.15 (d, J = 7.7 Hz, 192 2H), 6.58 (s, 1H), 5.95 (t, J = 2.0 Hz, 1H), 2.67 (t, J = 6.6 Hz, 2H), 2.39 (dt, J = 7.6, 2.0 Hz, 2H), 2.34 (s, 3H), 1.97 – 1.89 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.25, 143.90, 138.61, 138.23, 134.88, 132.79, 129.36, 129.02, 126.05, 124.85, 124.41, 123.82, 114.20, 33.10, 32.17, 23.84, 21.20. HRMS (ESI) m/z calculated for C22H20N2O2Cs + [M+Cs] + 477.0574, found: 477.0587. (Z)-1-(4-Chlorophenyl)-2-(cyclopent-1-en-1-yl)vinyl α-Diazo-α- phenyl-acetate 1m: 40% yield. 1 H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2H), 7.44 – 7.38 (comp, 4H), 7.34 – 7.29 (d, J = 7.4 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.61 (s, 1H), 6.00 (t, J = 2.4 Hz, 1H), 2.67 (t, J = 6.3 Hz, 2H), 2.41 (dt, J = 7.7, 2.4 Hz, 2H), 1.98 – 1.91 (comp, 2H). 13C NMR (125 MHz, CDCl3) δ 163.17, 142.69, 138.40, 136.12, 134.22, 134.02, 129.08, 128.84, 126.21, 125.75, 124.60, 123.84, 115.58, 32.99, 32.22, 23.81. HRMS (ESI) m/z calculated for C21H17N2O2ClCs + [M+Cs] + 497.0028, found: 497.0048. 193 (Z)-2-(Cyclopent-1-en-1-yl)-1-(4-fluorophenyl)vinyl α-Diazo-α- phenylacetate 1n: 36% yield. 1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 2H), 6.56 (s, 1H), 5.97 (t, J = 2.5 Hz, 1H), 2.67 (t, J = 6.5 Hz, 2H), 2.40 (dt, J = 7.9, 2.5 Hz, 2H), 1.98 – 1.90 (comp, 2H). 13 C NMR (125 MHz, CDCl3) δ 163.20, 162.65 (d, J = 247.1 Hz), 142.86, 138.40, 135.73 (d, J = 3.3 Hz), 131.90, 129.07, 126.35(d, J = 8.1 Hz), 126.19, 124.64, 123.84, 115.65 (d, J = 21.8 Hz), 115.02, 33.02, 32.19, 23.81. HRMS (ESI) m/z calculated for C21H17N2O2FCs + [M+Cs] + 481.0323, found: 481.0332. Methyl (Z)-4-(2-(Cyclopent-1-en-1-yl)-1-[(2-diazo-2-phenyl- acetoxy)vinyl]benzoate 1o: 36% yield. 1 H NMR (500 MHz, CDCl3) δ 8.01(d, J = 8.6 Hz, 2H), 7.56 – 7.52 (comp, 4H), 7.44 – 7.38 (comp, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.58 (s, 1H), 6.08 – 6.05 (m, 1H), 3.91 (s, 3H), 194 2.71 – 2.65 (comp, 2H), 2.45 – 2.39 (comp, 2H), 1.99 – 1.91 (comp, 2H). 13 C NMR (126 MHz, CDCl3) δ 166.59, 163.15, 142.69, 139.92, 138.48, 137.27, 129.97, 129.09, 126.24, 124.56, 124.23, 123.87, 117.18, 52.12, 32.95, 32.30, 23.82. HRMS (ESI) m/z calculated for C23H20N2O4Cs + [M+Cs] + 521.0472, found: 521.0494. (Z)-2-(Cyclopent-1-en-1-yl)-1-(4-formylphenyl)vinyl α-Diazo-α- phenylacetate 1p: 36% yield. 1 H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.23 (t, J = 7.7 Hz, 1H), 6.79 (s, 1H), 6.10 (t, J = 2.5 Hz, 1H), 2.69 (t, J = 7.3 Hz, 2H), 2.43 (dt, J = 7.5, 2.5 Hz, 2H), 1.95 (dd, J = 15.0, 7.4 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 191.41, 163.05, 142.42, 141.42, 138.49, 138.02, 135.66, 130.11, 129.12, 126.31, 124.79, 124.46, 123.87, 118.02, 32.91, 32.35, 23.82. HRMS (ESI) m/z calculated for C22H18N2O3Cs + [M+Cs] + 491.0366, found: 491.0393. 195 2-Oxo-3,9a-diphenyl-2,5a,6,7,8,9a-hexahydrocyclopenta[e]- oxazolo[3,2-b]pyridazin-4-ium-5-ide 2a: 48% yield. Light yellow solid, 100 ℃(dec.); 1H NMR (400 MHz, CDCl3) δ 8.69 d, J = 8.5, 2H), 7.69 – 7.42 (comp, 2H), 7.41 – 7.10 (comp, 6H), 6. 57 – 6.54 (m, 1H), 3.82 (t, J = 8.2 Hz, 1H), 2.66 – 2.36 (comp, 3H), 2.16 – 1.85 (comp, 2H), 1.83 – 1.61 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 163.94, 148.42, 135.16, 130.09, 128.89, 128.10, 127.70, 127.61, 126.01, 125.43, 115.87, 104.8, 96.70, 68.15, 32.15, 29.41, 24.42. HRMS (ESI) m/z calculated for C21H19N2O2 + [M+H] + 331.1441, found: 331.1461. 3-(Benzo[d][1,3]dioxol-5-yl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a- hexahydro-cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2b: 54% yield. Yellow solid, 100 ℃(dec.); 1H NMR (500 MHz, CDCl3) δ 8.32 (d, 196 J = 8.8 Hz, 2H), 7.42 – 7.32 (comp, 3H), 7.28 (d, J = 7.3 Hz, 2H), 6.96 – 6.92 (m, 1H), 6.56 – 6.52 (m, 1H), 6.01 (s, 2H), 3.78 (t, J = 8.6 Hz, 1H), 2.59 – 2.44 (comp., 3H), 2.05 - 1.90 (comp, 2H), 1.80 – 1.74 (m, 1H).13C NMR (125 MHz, CDCl3) δ 163.93, 148.52, 147.28, 146.79, 135.30, 130.04, 128.87, 125.96, 121.87, 120.26, 115.83, 108.13, 105.56, 101.05, 101.01, 96.45, 67.96, 32.23, 29.42, 24.41. HRMS (ESI) m/z calculated for C22H19N2O4 + [M+H] + 375.1339, found: 375.1358. 2-Oxo-9a-phenyl-3-(p-tolyl)-2,5a,6,7,8,9a-hexahydrocyclo- penta[e]-oxazolo[3,2-b]pyridazin-4-ium-5-ide 2c: 54% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 8.2 Hz, 2H), 7.39 – 7.36 (m, 1H), 7.36 – 7.27 (comp, 6H), 6.56 – 6.53 (m, 1H), 3.78 (t, J = 8.7 Hz, 1H), 2.58 – 2.44 (comp, 3H), 2.40 (s, 3H), 2.04 – 1.98 (comp, 1H), 1.97 – 1.90 (m, 1H), 1.80 – 1.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.99, 148.46, 137.67, 135.32, 130.03, 128.86, 128.80, 126.02, 125.44, 124.90, 115.86, 105.61, 96.56, 68.03, 32.21, 29.43, 24.42, 21.49. HRMS (ESI) m/z calculated for C22H21N2O2 + [M+H] + 345.1598, found: 345.1616. 197 3-([1,1'-Biphenyl]-4-yl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a- hexahydro-cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2d: 53% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.69 – 7.66 (comp, 2H), 7.49 – 7.45 (comp, 2H), 7.41 – 7.36 (comp, 3H), 7.36 – 7.33 (comp, 3H), 6.60 – 6.57 (m, 1H), 3.84 (t, J = 8.7 Hz, 1H), 2.63 – 2.44 (comp, 3H), 2.10 – 2.01 (m, 1H), 2.00 – 1.91 (m, 1H), 1.85 – 1.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.95, 148.45, 140.65, 140.00, 135.16, 130.12, 128.91, 128.80, 127.38, 126.97, 126.73, 126.69, 126.01, 125.76, 115.88, 105.38, 96.75, 68.22, 32.18, 29.42, 24.43. HRMS (ESI) m/z calculated for C27H23N2O2 + [M+H] + 407.1754, found: 407.1765. 198 3-(4-Bromophenyl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]-oxazolo[3,2-b]pyridazin-4-ium-5-ide 2e: 50% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 8.8 Hz,, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.40 – 7.30 (comp, 3H), 7.28– 7.24 (comp, 2H), 6.54 – 5.51 (m, 1H), 3.76 (t, J = 8.7 Hz, 1H), 2.60 – 2.42 (comp, 3H), 2.03 – 1.89 (comp, 2H), 1.80 – 1.72 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.71, 148.46, 134.99, 131.24, 130.21, 128.97, 126.89, 126.67, 125.97, 121.20, 115.83, 104.87, 96.98, 68.32, 32.15, 29.42, 24.42. HRMS (ESI) m/z calculated for C21H18N2O2Br + [M+H] + 409.0546, found: 409.0565. 3-(4-Chlorophenyl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2f: 52% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 6.55 – 6.52 (m, 1H), 3.79 (t, J = 8.6 Hz, 1H), 2.60 – 2.44 (comp, 3H), 2.04 – 1.92 (comp, 2H), 1.78 (m, 1H). 199 13 C NMR (125 MHz, CDCl3) δ 163.78, 148.45, 134.95, 132.90, 130.20, 128.95, 128.27, 126.64, 126.21, 125.95, 115.79, 104.79, 96.93, 68.26, 32.13, 29.39, 24.41. HRMS (ESI) m/z calculated for C21H18N2O2Cl + [M+H] + 365.1051, found: 365.1071. 3-(4-Fluorophenyl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2g: 50% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 8.7 Hz, 2H),, 7.41 – 7.32 (comp, 3H), 7.29 (t, J = 7.4 Hz, 2H), 7.15 (d, J = 7.4 Hz, 2H), 6.57– 6.53 (m, 1H), 3.79 (t, J = 8.2 Hz, 1H), 2.62 – 2.40 (comp, 3H), 2.05 – 1.90 (comp, 2H), 1.82 – 1.73 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.93, 161.60 (d, J=248.2 Hz), 148.51, 135.07, 130.15, 128.92, 127.54 (d, J=7.5 Hz), 125.96, 123.98, 115.5 (d, J=21.3 Hz), 114.99, 104.90, 96.82, 68.07, 32.16, 29.40, 24.40. HRMS (ESI) m/z calculated for C21H18N2O2F + [M+H] + 349.1347, found: 349.1365. 200 2-Oxo-9a-phenyl-3-(4-(trifluoromethyl)phenyl)-2,5a,6,7,8,9a- hexahydrocyclopenta[e]oxazolo [3,2-b]pyridazin-4-ium-5-ide 2h: 52% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 6.57 – 6.54 (m, 1H), 3.83 (t, J = 8.8 Hz, 1H), 2.60 – 2.47 (comp, 3H), 2.06 – 2.01 (m, 1H), 1.98 – 1.93 (m, 1H), 1.82 – 1.77 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.72, 148.39, 134.70, 131.00, 130.33, 129.03, 128.67 (q, J = 32.2 Hz), 128.47 (q, J = 276.4 Hz), 125.89, 125.17, 124.97 (q, J = 3.4 Hz), 115.76, 104.53, 97.19, 68.54, 32.05, 29.38, 24.41. HRMS (ESI) m/z calculated for C22H17N2O2F3 + [M+H] + 399.1315, found: 399.1326. 201 3-(4-Nitrophenyl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2i: 42% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.90 (d, J = 9.0 Hz, 2H), 8.30 (d, J = 9.0 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.3 Hz, 2H), 6.59 – 6.55 (m, 1H), 3.86 (t, J = 9.0 Hz, 1H), 2.62 – 2.55 (comp, 2H), 2.54 – 2.46 (m, 1H), 2.10– 2.05 (m, 1H), 2.02– 1.95 (m, 1H), 1.86 – 1.79 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.48, 148.35, 145.62, 142.78, 134.34, 133.83, 130.53, 129.14, 125.93, 125.25, 123.52, 115.73, 97.57, 68.95, 31.99, 29.36, 24.43. HRMS (ESI) m/z calculated for C21H17N3O4Cs + [M+Cs] + 508.0268, found: 508.0280. 3-(2-Bromophenyl)-2-oxo-9a-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2j: 55% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 7.69 – 7.65 (m, 1H), 7.63 – 7.53 (comp, 3H), 7.44 – 7.36 (comp, 4H), 7.29 – 2.25 (m, 1H), 6.54 – 6.51 (m, 1H), 3.81 – 3.76 (m, 1H), 2.62 – 2.55 (m, 1H), 2.53 202 – 2.45 (m, 1H), 2.44 – 2.38 (m, 1H), 1.96 – 1.86 (comp, 2H), 1.71 – 1.78 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 163.80, 148.53, 133.35, 132.58, 130.45, 130.22, 128.83, 128.75, 128.04, 127.38, 126.39, 125.01, 115.63, 105.83, 97.98, 68.01, 32.00, 29.32, 24.31. HRMS (ESI) m/z calculated for C21H18N2O2Br + [M+H] + 409.0546, found: 409.0557. 9a-(4-Methoxyphenyl)-2-oxo-3-phenyl-2,5a,6,7,8,9a- hexahydro-cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2k: 42% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 8.1 Hz, 2H), 7.31 (t, J = 8.1 Hz, 1H), 7.24(d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 6.52 – 6.50 (m, 1H), 3.81 (t, J = 8.6 Hz, 1H), 3.78 (s, 3H), 2.59 – 2.44 (m, 3H), 2.04 – 1.99 (m, 1H), 1.96 – 1.90 (m, 1H), 1.79 – 1.76 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 164.10, 160.84, 148.33, 128.10, 127.79, 127.70, 127.54, 127.01, 125.43, 116.00, 114.16, 105.25, 96.77, 68.13, 55.38, 32.14, 29.41, 24.49. HRMS (ESI) m/z calculated for C22H21N2O3 + [M+H] + 361.1547, found: 361.1557. 203 2-Oxo-3-phenyl-9a-(p-tolyl)-2,5a,6,7,8,9a-hexahydrocyclo- penta[e]-oxazolo[3,2-b]pyridazin-4-ium-5-ide 2l: 45% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 8.3 Hz, 2H), 7.47 (t, J = 8.3 Hz, 2H), 7.32 (t, J = 8.3 Hz, 1H), 7.21(d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.54 – 6.51 (m, 1H), 3.81 (t, J = 8.2 Hz, 1H), 2.60 – 2.41 (comp, 3H), 2.33 (s, 3H), 2.04 – 1.98 (m, 1H), 1.96 – 1.90 (m, 1H), 1.80 – 1.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 164.05, 148.26, 140.32, 132.20, 129.53, 128.09, 127.79, 127.55, 126.02, 125.44, 115.99, 105.36, 96.81, 68.13, 32.14, 29.40, 24.46, 21.17. HRMS (ESI) m/z calculated for C22H21N2O2 + [M+H] + 345.1598, found: 345.1606. 9a-(4-Chlorophenyl)-2-oxo-3-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2m: 45% yield. 204 Light yellow solid, 100 ℃(dec.); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H), 7.35 – 7.29 (comp, 3H), 7.25 (t, J = 7.8 Hz, 2H), 6.55 - 6.52 (m, 1H), 3.78 (t, J = 8.6 Hz, 1H), 2.60 – 2.42 (comp, 3H), 2.05 – 1.91 (comp, 2H), 1.82 – 1.75 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 163.68, 148.95, 136.31, 133.76, 129.16, 128.15, 127.80, 127.51, 125.46, 115.55, 105.40, 95.95, 68.23, 32.17, 29.44, 24.39. HRMS (ESI) m/z calculated for C21H18N2O2Cl + [M+H] + 365.1051, found: 365.1063. (5aR,9aR)-9a-(4-fluorophenyl)-2-oxo-3-phenyl-2,5a,6,7,8,9a- hexahydro-cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2n: 45% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 8.1 Hz, 2H), 7.36 – 7.30 (comp, 3H), 7.04 (t, J = 8.5 Hz, 2H), 6.54 – 6.51 (m, 1H), 3.79 (t, J = 8.6 Hz, 1H), 2.59 – 2.45 (comp, 3H), 2.05 – 2.00 (m, 1H), 1.98 – 1.93 (m, 1H), 1.81 – 1.76 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 163.76, 163.50 (d, J = 249.6 Hz), 148.83, 131.17 (d, J = 3.3 Hz), 128.25, 128.14, 127.76, 205 127.56, 125.45, 115.98 (d, J = 21.9 Hz), 115.73, 105.37, 96.05, 68.20, 32.16, 29.43, 24.41. HRMS (ESI) m/z calculated for C21H18N2O2F + [M+H] + 349.1347, found: 349.1359. 9a-(4-(Methoxycarbonyl)phenyl)-2-oxo-3-phenyl-2,5a,6,7,8,9a- hexahydrocyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2o: 45% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 7.5 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 6.56 – 6.53 (m, 1H), 3.91 (s, 3H), 3.76 (t, J = 8.6 Hz, 1H), 2.58 – 2.45 (comp, 3H), 2.06 – 2.00 (m, 1H), 1.97 – 1.92 (m, 1H), 1.81 – 1.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 165.98, 163.62, 149.00, 139.65, 131.75, 130.15, 128.17, 127.87, 127.49, 126.10, 125.51, 115.56, 105.52, 95.94, 68.26, 52.39, 32.21, 29.45, 24.36. HRMS (ESI) m/z calculated for C23H21N2O4 + [M+H] + 389.1496, found: 389.1504. 206 9a-(4-Formylphenyl)-2-oxo-3-phenyl-2,5a,6,7,8,9a-hexahydro- cyclopenta[e]oxazolo[3,2-b]pyridazin-4-ium-5-ide 2p: 41% yield. Light yellow solid, 100 ℃ (dec.); 1H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.69 (d, J = 7.7 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.52 – 7.47 (comp, 4H), 7.36 (t, J = 7.7 Hz, 1H), 6.58 – 6.55 (m, 1H), 3.78 (t, J = 8.7 Hz, 1H), 2.62 – 2.46 (comp, 3H), 2.08 – 2.02 (m, 1H), 2.00 – 1.94 (m, 1H), 1.83 – 1.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 191.41, 163.05, 142.42, 141.42, 138.49, 138.02, 135.66, 130.11, 129.12, 126.31, 124.79, 124.46, 123.87, 118.02, 105.60, 32.91, 32.35, 23.82. HRMS (ESI) m/z calculated for C22H19N2O3 + [M+H] + 359.1390, found: 359.1410. (E)-2-(Cyclopent-1-en-1-yl)-1-phenylvinyl α-Diazo-α-phenyl- acetate 1a: 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 4H), 7.39 – 7.34 (comp, 5H), 7.18 (t, J = 7.4 Hz, 1H), 6.39 (s, 1H), 5.84 (t, J = 2.2 Hz, 207 1H) 2.34 – 2.30 (comp, 2H), 2.02 - 1.91 (comp, 2H), 1.79 – 1.74 (comp, 2H).: 13 C NMR (125 MHz, CDCl3) δ 163.83, 146.02, 137.87, 135.16, 134.87, 129.80, 128.92, 128.82, 127.71, 125.94, 125.12, 123.93, 118.69, 33.58, 32.30, 24.11. (The 13 C NMR for 1a contains around 10% of cycloaddition product 2a because (E)-1a was converted to 2a in process of acquiring data.) HRMS (ESI) m/z calculated for C21H18N2O2Cs + [M+Cs] + 463.0417, found: 463.0428. (±)-(3aS,3bR,5aR,9aR,9cS)-3b-(4-bromophenyl)-2,5a-diphenyl- 3a,5a,8,9,9a,9c-hexahydro-1H,7H-5-oxa-2,3b1,9b-triazapentaleno- [1,2,3-cd]-s-indacene-1,3,4(2H,3bH)-trione 5e: 85% yield. White solid, 80 ℃ (dec.), .); 1H NMR (500 MHz, CDCl3) δ 7.41 –7.37 (comp, 3H), 7.35 –7.25 (comp, 4H), 7.09 –7.01 (comp, 5H), 6.80 – 6.76 (m, 1H), 6.68 – 6.64 (m, 1H), 5.57 – 5.55 (m, 1H), 4.55 –4.50 (comp, 2H), 4.10 (d, J = 7.5 Hz, 1H), 2.65–2.50 (comp, 3H), 2.04 – 1.97 (m, 1H), 1.93 – 1.87 (m, 1H), 1.70 – 1.61 (m, 1H). 13C NMR (126 MHz, cdcl3) δ 166.59, 166.17, 208 163.54, 142.16, 131.11, 124.27, 123.83, 123.77, 122.92, 122.07, 121.68, 121.12, 120.75, 120.66, 118.57, 115.73, 110.53, 93.01, 70.76, 54.53, 54.31, 44.47, 22.95, 21.53, 14.79. 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Soc. 2003, 125, 16310-16321; (c) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224-232. (32) (a) Maerker, G.; Case, F. H. J. Am. Chem. Soc. 1958, 80, 2745-2748; (b) Kulkarni, A. A. Beilstein J. Org. Chem. 2014, 10, 405- 424. 212 Chapter 4: Unexpected [4+3]- Cycloaddition/Extrusion of Dinitrogen and Rearrangement in Gold-Catalyzed Reactions of Propargylic Diazoesters with Unsaturated Imines I. Introduction 1.1 Discovery of the Unexpected Cascade Process With access to metal carbenes from both diazo and acetylenic precursors we considered whether we could selectively form one of two metal carbene intermediates and, in doing so, either retain the unreacted functional group or expect a synergy between the two groups that, like the cascade reactions developed from previously reported reactions of diazo compounds with both functional groups, provides unique access to complex chemical structures (see examples in Chapter 2 and Chapter 3). Using the gold-catalyzed reaction process for [4+3]-cycloaddition established by Toste and coworkers, 1 we have employed the slightly modified propargyl system in which benzoate is replaced by phenyldiazoacetate (2a) that was expected to produce dihydroazepines (3) 213 which retained the phenyldiazoacetate functionality. Instead, an unexpected cascade [4+3]-cycloaddition/extrusion of dinitrogen and rearrangement occurred that reorganized the reactant atoms, including conversion of the reactant ester to a diketone. Scheme 4.1 Discovery of the Unexpected Cascade Process. 1.2 Gold Catalyzed 1,2-Acyloxy Migration of Propargyl Esters and Subsequent Reactions For the past several decades, alkynes have been reported to effectively serve as precursors to metal carbenes via direct reactions with transition metal complexes. 2 Gold catalyzed 1,2-acyloxy migration of propargyl esters is a highly versatile route to access gold vinylcarbene intermediates and has received considerable attention from several 214 research groups. 3 Similar to other transition metal complex-catalyzed rearrangements of propargyl esters, which have been described in Chapter 1, the outcomes of the regioselectivity in the gold catalyzed of propargylic esters are mainly dependent on the R 3 group: if R 3 is a hydrogen atom, the formation of the gold vinylcarbene complexes is preferred. 4 These gold vinylcarbene intermediates are capable of undergoing a variety of intermolecular transformations including cycloaddition, insertion and ylide formation. 4-5 215 Scheme 4.2 Formation of Gold Vinylcarbenes and Subsequent Transformations. 1.3 [4+3]-Cycloaddition Reactions of Metal Vinylcarbenes with Unsaturated Imines Cycloaddition reactions of imines with metal carbene species provide access to a wide range of nitrogen-containing heterocyclic compounds with remarkable selectivities and high yields under mild reaction conditions. 6 These reactions typically involve reactive azomethine ylide intermediates. 7 In the process of investigating rhodium- catalyzed azomethine ylide-derived reactions of vinyldiazo compounds with imines, Doyle and coworkers have discovered the first example of a [4+3]-cycloaddition reaction of styryldiazoacetates with α,β-unsaturated imines. This reaction provides rapid entry into substituted dihydroazepine derivatives from easily obtained starting materials. A stepwise mechanism involving addition of α,β-unsaturated imines to a rhodium vinylcarbene intermediate has been proposed. 8 216 Scheme 4.3 Rhodium-Catalyzed [4+3]-Cycloaddition Reaction of Styryldiazoacetates with α,β-Unsaturated Imines. By analogy with to the [4+3]-cycloaddition reaction of rhodium vinylcarbenes with α,β-unsaturated imines, Toste and coworkers have demonstrated that propargyl esters can serve as gold vinylcarbene precursors, which undergo similar [4+3]-cycloaddition reactions with α,β-unsaturated imines. Similar to the mechanism proposed by Doyle and coworkers, this formal [4+3]-cycloaddition reaction proceeds via a stepwise process involving addition of the α,β-unsaturated imines to a gold vinylcarbene intermediate to form an allyl−gold intermediate, which undergoes intramolecular cyclization to produce the [4+3]-adduct and regenerates the gold catalyst. 1 217 Scheme 4.4 Gold-Catalyzed [4+3]-Cycloaddition Reaction of Propargyl Esters with α,β-Unsaturated Imines. 1.4 Seven-Membered Carbocycles and Previous Synthesis Seven-membered carbocycles exist in many natural products, and some of them are potential therapeutic compounds, such as ingenol, cortistatin guanacastepene family tropolonoids. 9 However, constructing seven-membered carbocycles is considered to be generally more challenging in comparison to five- and six-membered carbocycles. 10 Although several synthetic approaches that lead to seven-membered carbocycles have been developed over the past decades, discovering novel synthetic methods to highly functionalized seven-membered carbocycles is still in high demand. 11 218 Scheme 4.5 Various Routes to Seven-Membered Carbocycles. II. Results and Discussion 2.1 Discovery of the Unexpected Cascade Process and Optimization of Reaction Conditions With 5 mol% AuPicCl2 as the catalyst, treatment of propargyl phenyldiazoacetate 2a with α-methyl-trans-cinnamyl phenylimine 1a, which was the optimum cinnamylimine previously used in reactions with ,-dimethylpropargyl benzoate (Scheme 4.4), resulted in a complex product mixture that occurred with complete reaction of propargyl phenyldiazoacetate 2a within 30 minutes at room temperature but with <10% production of the anticipated [4+3]-cycloaddition product 3aa (Table 4.1, entry 1). The use of alternative Au(I) catalysts, including 219 AuCl, Au(JohnPhos)SbF6, and IPrAuBF4 that are commonly used in the transformations of propargyl esters, also failed to give the desired [4+3]- cycloaddition product 3aa. Replacing α-methyl-trans-cinnamyl N- phenylimine 1a with trans-cinnamyl N-phenylimine 1b, which was disfavored in reactions with ,-dimethylpropargyl benzoate, under the same reaction conditions for 72 h resulted in a 40% conversion of propargyl phenyldiazoacetate 2a, but gave as the predominant product 4ba in 10% isolated yield a compound that did not have the diazo functional group or the anticipated ester functionality and was highly colored (Table 4.1, entry 2). Cationic gold catalysts that include (ArO)3PAuSbF6, Au(IPr)SbF6 and Au(JohnPhos)SbF6 failed to give 4ba at room temperature in dichloromethane (DCM) with low conversion of 1a (Table 4.1, entries 3-5). The use of neutral AuCl produced this unexpected product but in low yield (Table 4.1, entry 6), However, increasing the reaction temperature dramatically increased percent conversion and the yield of this product, as well as reducing the reaction time (Table 4.1, entries 7-9). At 80ºC in 1,2-dichloroethane (DCE) for 6 h in the presence of 5 mol% PicAuCl2 this highly colored product was obtained in 62% isolated yield. A further increase in temperature slightly decreased the yield of this product (Table 4.1, entry 10). Changing the 220 solvent to toluene, acetonitrile, or N,N-dimethylformamide did not provide improvement (Table 4.1, entries 11-13). Table 4.1 Optimization of gold-catalyzed reaction of propargyl phenyldiazoacetate 2a with trans-cinnamyl phenylimine 1b Entry a imines [Au] Temperature ( o C) /time (h) solvent Conversion of 2a b (%) yield of 4ba c (%) 1 e 1a PicAuCl2 20/0.5 DCM >95 -- d 2 1a Ph3PAuSbF6 20/72 DCM <10 <5 3 1a IPrAuSbF6 20/24 DCM <10 <5 4 1a (ArO)PAuSbF6 20/24 DCM <10 <5 5 1a AuCl 20/24 DCM 25 8 6 1a PicAuCl2 20/72 DCM 40 10 7 1b PicAuCl2 40/48 DCE 60 31 221 aReactions were performed on 0.20 mmol scale: a solution of 2a (0.24 mmol) in 2.0 mL solvent was added to a solution of 1b (or 1a) (0.20 mmol) and 5 mol% of selected catalyst in 2.0 mL of solvent under a nitrogen atmosphere at stated temperature, and the resulting reaction mixture was stirred for the stated time. bThe percent conversion of 2a was determined by 1H NMR spectroscopy using 2,4,6-trimethoxybenzaldehyde as the internal standard. cThe yield of 4ba was determined by 1H NMR analyses of characteristic absorptions. d Neither 3aa nor 4aa was observed. e The isolated yield of 4ba. Ar = 2,4-di-tert-butylphenyl. Attempts to determine the structure of 4 spectroscopically gave partial connectivities, demonstrated the loss of dinitrogen, and pointed to the conversion of the ester to ketones, but its final confirmation awaited X-ray determination. Various derivatives were prepared, but only with 4ha from the reaction between propargyl phenyldiazoacetate 2a, and cinnamyl 1-naphthylimine 1h was a compound suitable for single crystal analysis obtained. X-ray diffraction revealed a structure in which the carbon atoms of the original propargyl phenyldiazoacetate were rearranged, that the ester was converted to a diketone, and depicted the presence of an intramolecular hydrogen bond between nitrogen and a 8 1b PicAuCl2 60/12 DCE 85 47 9 1b PicAuCl2 80/6 DCE >95 65 (62) e 10 1b PicAuCl2 100/2 DCE >95 57 11 1b PicAuCl2 80/6 toluene >95 25 12 1b PicAuCl2 80/6 CH3CN 80 38 13 1b PicAuCl2 80/6 DMF <20 <5 222 carbonyl group (Figure 4.1). Extrusion of dinitrogen from propargyl phenyldiazoacetate 2a and the fact that the carbon atoms of seven- membered ring came from three parts of the starting materials demonstrated extensive structural rearrangement. Figure 4.1 X-ray Structure of 4ha. 2.2 Substrate Scope In efforts to determine the scope of the gold-catalyzed reaction, structural modifications on both the propargyl aryldiazoacetates and the cinnamyl arylimines were investigated under the optimized reaction conditions (Table 4.1, entry 9). Propargylic aryldiazoacetates 2 with electron-donating groups and electron-withdrawing groups at the para position underwent the gold-catalyzed transformation smoothly in 6 h with moderate to high yields (Table 4.2, entries 1-4). Ortho substituted propargylic aryldiazoacetates (2f and 2g) gave reasonable yields of 4bf and 4bg (Table 4.2, entries 5 and 6). Unsaturated imines 1c-1g with 223 arylimine-derived para substituents Ar 1 – including ethers, phenols, and halides –underwent this cycloaddition favorably under the stated reaction conditions (Table 4.2, entries 7-11). Sterically hindered 1- naphthylamine-derived 1h also underwent this transformation smoothly and gave the product 4ha in 68% yield (Table 4.2, entry 12). Imine 1i with a bulky N-mesityl group gave the highest yield in all cases (Table 4.2, entry 13). That p-nitrocinnamylaldehyde-derived and p- methoxycinnamylaldehyde-derived unsaturated imines 1j and 1k gave the corresponding products 4ja and 4ka in comparable yields shows electronic tolerance in the reactant trans-cinnamyl phenylimines (Table 4.2, entries 14 and 15). Using cyclopentylpropargyl phenyldiazoacetate, which was easily obtained from 1-ethynylcyclopentanol, the rearranged product 4bg was formed in basically the same yield as its dimethyl analog 4ba (Table 4.2, entry 16). Table 4.2 Substrate Scope of Gold-Catalyzed Reactions of Propargylic Diazoesters with Unsaturated Imines 224 entry 1 Ar 2/ Ar 3 2 Ar 1 /R 4 yield of 4 (%) 1 1c 4-HOC6H4/Ph 2b 4-MeOC6H4/Me 4cb 68 2 1b Ph/Ph 2c 4-MeC6H4/Me 4bc 65 3 1b Ph/Ph 2d 4-BrC6H4/Me 4bd 55 4 1b Ph/Ph 2e 4-NO2C6H4/Me 4be 43 5 1b Ph/Ph 2f 2-BrC6H4/Me 4bf 52 6 1b Ph/Ph 2g 2-NO2C6H4/Me 4bg 55 7 1c 4-HOC6H4/Ph 2a Ph/Me 4ca 64 8 1d 4-MeOeC6H4/Ph 2a Ph/Me 4da 65 9 1e 4-BrC6H4/Ph 2a Ph/Me 4ea 61 10 1f 4-ClC6H4/Ph 2a Ph/Me 4fa 60 11 1g 4-FC6H4/Ph 2a Ph/Me 4ga 56 12 1h 2-Naphthyl/Ph 2a Ph/Me 4ha 68 13 1i 2,4,6-Me3C6H2/Ph 2a Ph/Me 4ia 70 14 1j Ph/4-MeOC6H4 2a Ph/Me 4ja 67 225 15 1k Ph/4-NO2C6H4 2a Ph/Me 4ka 59 16 1b Ph/ Ph 2g Ph/-(CH2)4- 4bg 65 aReactions was performed on a 0.20 mmol scale: a solution of 2 (0.24 mmol) in 2.0 mL solvent was added to a solution of 1 (0.20 mmol) and 5 mol% of PicAuCl2 in 2.0 mL of DCE under a nitrogen atmosphere at 20 oC, and the resulting reaction mixture was stirred at 80 ºC for 6 h. Yields are isolated yields after chromatography. 2.3 Isolation of [4+3]-Cycloaddition Products and Kinetic Studies The extraordinary structural rearrangement that was uncovered in this investigation obviously occurred after the combination of the imine reactant with an intermediate formed by a gold catalyzed reaction with the propargyl phenyldiazoacetate. 1 We understood that gold catalysis occurred with the acetylenic functional group rather than with the diazo group, but was this rearrangement the result of a transformation from the gold-catalyzed [4+3]-cycloaddition product? To address this question propargyl phenyldiazoacetate 2a was reacted with N-phenyl cinnamylimine 1b at the lower reaction temperature of refluxing CDCl3 in presence of 5 mol% AuPicCl2. An intermediate 3ba was observed within 5 min that was completely converted to 4ba after 12 h (Figure 4.2). To obtain the separable and relatively stable [4+3]-adducts for further investigation of this cascade process, a variety of reactions with 226 different starting materials as well as reaction conditions was performed. Fortunately, [4+3]-cycloaddition product 3cb was isolated by silica-based columns in 36% yield from 1c and 2b by quenching the reaction after 5 min at 80ºC in DCE. To determine if intermediate 3 was converted to diketone 4 by a metal-free process or required a catalyst, 3cb was allowed to react in the absence and presence of 5 mol% AuPicCl2. The stable product 4cb was obtained in 90% isolated yield from the solution of 3cb in DCE at 80 o C for 6 h in the absence of any catalysts. However, when the [4+3]-cycloaddition 3cb was treated with 5 mol% PicAuCl2 in DCE at 80 o C, decomposition occurred within 1 h and resulted in a complex product mixture in which only a trace (less than 10%) of 4cb was observed (Scheme 4.6). Figure 4.2 1 H NMR Progress of the Gold-Catalyzed Reaction. 227 Scheme 4.6 Control Experiments for the formation of 4bd from 3bd. Furthermore, we carried out a series of kinetic studies with the isolated [4+3]-cycloaddition product 3cb for the subsequent transformation. The transformation was first order in 3cb with a rate constant kobs =3.6×10 −4 sec −1 at 61 °C in DCE. The variation of the rate constant over temperatures ranging from 61℃ to 75℃ provided Eact = 22.6 kcal/mol, H‡298 = 22.0 kcal/mol and S ‡ 298 = -9.21 cal/(mol•℃) (Figure 4.3-4.7). 12 228 Figure 4.3 First-order Rate Constant at 61 o C. Figure 4.4 First-order Rate Constant at 65 o C. Figure 4.5 First-order Rate Constant at 71 o C. Figure 4.6 First-order Rate Constant at 75 o C. Figure 4.7 Arrhenius Plot: 16cb Activation Energy. 2.4 The Role of the Unsaturated Imines in Diketones Formation y = -0.00036 x + 0.00114 R² = 0.99891 -2.5 -2 -1.5 -1 -0.5 0 0 1000 2000 3000 4000 5000 6000 Ln [1 7 cb ]/ [1 7 cb ] 0 Time (s) T = 61oC y = -0.00049 x - 0.01628 R² = 0.99363 -2.5 -2 -1.5 -1 -0.5 0 0 1000 2000 3000 4000 5000 Ln [1 7 cb ]/ [1 7 cb ] 0 Time (s) T = 65oC 229 As shown in precious section, the [4+3]-cycloaddition product 3cb undergoes a metal free process to form the rearranged products. However, the AuPicCl2, which is capable of destroying the [4+3]-cycloaddition product 3cb, exists in the reaction mixture. We speculated that there is a base (it might be the unsaturated imine), which prevented the gold species from decomposing the [4+3]-cycloaddition product 3cb in the reaction mixture. Thus, we carried out several control experiments, and four types of bases were tested in the presence of 5 mol% AuPicCl2. From the Table 4.3, we can easily find that: a) adding base increased the yields of diketone 4cb; and b) decreasing the amount of base resulted in a decreasing the yield of diketone 4cb. These results supported that the imines also served as a base, which assists in the formation of 4cb in presence of 5 mol% AuPicCl2. We also found the formation of metallic gold in the presence of imines (A2 to A4), which was confirmed by a SEM (Scanning Electron Microscope) examination. Figure 4.8 Representative SEM of Metallic Gold. 230 Table 4.3 Control Experiments Entry a additive equiv of additive (mol%) 1 HNMR yield (%) 1 A1 50 56 2 A2 50 40 3 A3 50 72 231 4 A4 50 73 5 A4 40 69 6 A4 30 63 7 A4 20 55 8 A4 10 45 aReactions was performed on a 0.05 mmol scale: a solution of 3cb (0.05 mmol) in 0.5mL DCE was added to a solution of stated amount of additive and 5 mol% of PicAuCl2 in 0.5 mL of DCE under a nitrogen atmosphere at 20oC, and the resulting reaction mixture was stirred at 80 ºC for 6 h. Yield is determined by 1H NMR analyses of characteristic absorptions. 2.5 Reaction Mechanism Based on these observations and previous reports, 1 a plausible mechanism for the formation of seven-membered conjugated 1,4- diketones 4 is shown in Scheme 4.7. The vinyl gold carbene intermediates generated by 1,2-acyloxy migration of propargylic aryldiazoesters undergo formal [4+3]-cycloaddition with unsaturated imines 2 to afford phenyldiazoacetate-tethered dihydroazepines 3. We propose that 3 can undergo an intramolecular [3+2]-cycloaddition to form pyrazolines. 13 (The formal [3+2]-cycloaddition might be stepwise, which involves diazo group as an electrophile that has been discussed in Chapter 2, and followed by subsequent ring-closing to produce the [3+2]- adducts.) The resulting pyrazolines undergo nitrogen extrusion, 14 acyloxy 232 migration followed by a nucleophilic attack at carbonyl carbon, retro- Michael addition 15 and tautomerization, 16 as shown in Scheme 4.7, and finally afford 4 under thermal conditions. Scheme 4.7 Proposed Mechanism for the Gold-Catalyzed Reaction of Propargyl Arylyldiazoacetates 1 with Unsaturated Imines 2. III. Conclusion In conclusion, we have developed a general and efficient method for the synthesis of seven-membered conjugated 1,4-diketones 4 from easily synthesized materials. To undergo this process vinyl gold carbene intermediates generated by 1,2-acyloxy migration of propargylic aryldiazoesters undergo a formal [4+3]-cycloaddition, and the resulting aryldiazoesters tethered dihydroazepines 3 undergo an intricate metal- free process to form observed 4 with moderate to high yields. Current 233 efforts aimed at understanding the metal-free process in detail and utilizing propargylic aryldiazoesters as switchable carbene precursors in other transformations are ongoing in our lab. IV. Experimental Section 4.1 General Information Unless noted all reactions were carried out under inert atmosphere of dinitrogen in oven-dried glassware with magnetic stirring using freshly distilled solvents. All solvents were purified and dried using standard methods. Analytical thin layer chromatography (TLC) plates were purchased from EM Science (silica gel 60 F254 plates). High-resolution mass spectra (HRMS) were performed on a microTOF-ESI mass spectrometer using CsI as the standard. Accurate masses are reported for the molecular ion [M+Cs] + , [M+Na] + , or [M+H] + . Melting points were determined on an Electrothermo Mel-Temp DLX 104 device and were uncorrected. Column chromatography was performed on CombiFlash ® Rf 200 purification system using normal phase disposable columns. IR spectra were recorded using Bruker Vector 22 spectrometer. All NMR spectra were recorded on a Bruker spectrometer at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR) or an Agilent spectrometer at 500 MHz ( 1 H 234 NMR) and 125 MHz ( 13 C NMR). Chemical shifts are reported in ppm with the solvent signals as reference (in CDCl3 as solvent), and coupling constants (J) are given in Hertz (Hz). The peak information is described as: br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite of magnetically non-equivalent protons. The wavelength of maximum absorbance and molar extinction coefficients measurements were performed on a Carey 50 Bio UV-vis spectrometer (200-800 nm) in DCM at room temperature. 4.2 Materials AuCl(PPh3), AuCl[P(OMe)3], Chloro[2-dicyclohexyl(2′,6′- dimethoxybiphenyl)phosphine] gold(I), and AuPicCl2 were purchased from Sigma-Aldrich; AuCl was purchased from Strem Chemicals. Unsaturated imines 17 and propargylic diazoesters 18 were prepared according to the literature procedures. All other chemicals were obtained from commercial sources and used as received without further purification. 4.3 Experimental Procedures. 235 General Procedure for Gold Catalyzed Reaction of Propargylic Diazoesters with Unsaturated Imines: To a flame-dried 10 mL Schlenk flask charged with a magnetic stirring bar, N-aryl imine 2 (0.20 mmol), 1,2-dichloroethane (DCE) (2.0 mL) and AuPicCl2 (3.9 mg, 0.01 mmol) were sequentially added under a nitrogen atmosphere. Propargyl diazoester 1 (0.24 mmol) dissolved in 2.0 mL of DCE was added in one portion into the solution under the flow of nitrogen. The mixture was stirred for 6h at 80 o C. Solvent was evaporated, and products were purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure compounds 4 as red solids or liquids. 236 General Procedure for Synthesis of 3cb: To a flame-dried 10 mL Schlenk flask charged with a magnetic stir bar, N-aryl imine 1c (0.20 mmol), 1,2-dichloroethane (DCE) (2.0 mL) and AuPicCl2 (3.9 mg, 0.01 mmol) were sequentially added under nitrogen atmosphere. Propargyl diazoester 2b (0.24 mmol) dissolved in 2.0 mL of DCE was added in one portion into the solution under the flow of nitrogen. The mixture was stirred for 5 min at 80 o C. The reaction mixture was directly purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure compound 3cb in 36% isolated yield as a light yellow oil. 237 General Procedure for Synthesis of 4cb from 3cb without Gold Catalyst: To a flame-dried 10 mL Schlenk flask charged with a magnetic stir bar, 3cb (0.1 mmol) dissolved in 2.0 mL of DCE was added under nitrogen atmosphere, The reaction mixture was stirred for 6h at 80 o C. Solvent was evaporated, and products were purified by column chromatography (100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure compound 4cb in 90% isolated yield. 238 General Procedure for Synthesis of 4cb from 3cb with Gold Catalyst: To a flame-dried 10 mL Schlenk flask charged with a magnetic stir bar, 3cb (0.1 mmol) dissolved in 2.0 mL of DCE and AuPicCl2 (2.0 mg, 0.005 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred for 5 min at 80 o C. The color of reaction mixture turned dark black. Checking the reaction mixture shows that the starting material was consumed completely, and the yield of 4cb was less than 10%. General Procedure for Control Experiment: To a flame-dried 10 mL Schlenk flask charged with a magnetic stir bar, a solution of 3cb (0.05 mmol) in 0.05 mL of DCE was added to a solution of 1c (A4) and 5 mol% of PicAuCl2 in 0.5 mL of DCE under a nitrogen atmosphere at 20 o C. The reaction mixture was stirred for 6 h at 80 o C. The solvent was 239 evaporated; the yield of 4cb was determined by 1 H NMR analysis using 2,4,6-trimethoxybenzaldehyde as an internal standard. Other stated additives were also tested using the same procedure. 4.4 Characterization Data for New Compounds 2-Methylbut-3-yn-2-yl 2-Diazo-2-phenylacetate 2a: 80% yield. Yellow solid, m.p. 70.2 – 71.4℃. 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 8.5 Hz, 2H), 7.19 (t, J = 8.5 Hz, 1H), 2.62 (s, 1H), 1.78 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 163.45, 128.84, 125.75, 125.44, 123.96, 84.51, 72.84, 72.77, 29.21. IR (neat) 2082, 1701, 1286, 1145 cm -1 ; HRMS (ESI) m/z calculated for C13H12N2O2Na + [M+Na]+ 251.0791, found: 251.0796. 240 2-Methylbut-3-yn-2-yl 2-Diazo-2-(4-methoxyphenyl)acetate 2b: 75% yield. Red solid, 67.0 – 68.5℃. 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 9.1 Hz, 2H), 6.93 (d, J = 9.1 Hz, 2H), 3.80 (s, 3H), 2.59 (s, 1H), 1.76 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 164.03, 158.00, 125.89, 116.87, 114.54, 84.62, 72.71, 72.68, 55.34, 29.24. IR (neat) 2084, 1702, 1127, 903 cm-1; HRMS (ESI) m/z calculated for C14H14N2O3Na [M+Na] + 281.0897, found: 281.0900. 2-Methylbut-3-yn-2-yl 2-Diazo-2-(p-tolyl)-acetate 2c: 78% yield. Yellow solid, 58.0 – 59.2℃. 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 2.61 (s, 1H), 2.35 (s, 3H), 1.78 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 163.70, 135.60, 129.57, 124.08, 122.07, 84.58, 72.70, 29.22, 20.95. IR (neat) 2083, 1702, 1124, 906 cm-1; HRMS (ESI) m/z calculated for C14H14N2O2Na + [M+Na] + 265.0947, found 265.0953. 241 2-Methylbut-3-yn-2-yl 2-(4-Bromophenyl)-2-Diazoacetate 2d: 82% yield. Yellow solid, 90.1 – 91.5℃. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 2.62 (s, 1H), 1.77 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 163.08, 131.93, 125.33, 124.69, 119.28, 84.35, 73.12, 72.93, 29.20. IR (neat) 2087, 1703, 1126, 907 cm -1 ; HRMS (ESI) m/z calculated for C13H12N2O2BrNa + [M+Na] + 328.9896, found 328.9891. 2-Methylbut-3-yn-2-yl 2-Diazo-2-(4-nitrophenyl)acetate 2e: 65% yield. Yellow solid, 107.2 – 108.5℃. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 7.1 Hz, 2H), 2.64 (s, 1H), 1.80 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 161.98, 145.00, 133.85, 124.19, 123.18, 84.00, 73.78, 73.28, 29.14. IR (neat) 2095, 1710, 1334, 904 cm-1; HRMS (ESI) m/z calculated for C13H11N3O4Na + [M+Na] + 296.0642, found 296.0634. 242 2-Methylbut-3-yn-2-yl 2-(2-Bromophenyl)-2-Diazoacetate 2f: 65% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.0, 7.7 Hz, 1H), 7.18 (dd, J = 7.8, 7.7 Hz, 1H), 2.60 (s, 1H), 1.74 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 163.58, 133.16, 132.73, 129.81, 127.44, 125.55, 124.13, 84.39, 72.88, 72.68, 29.05. IR (neat) 2091, 1699, 1117, 754 cm-1; HRMS (ESI) m/z calculated for C13H12N2O2BrNa + [M+Na] + 328.9896, found 328.9893. 2-Methylbut-3-yn-2-yl 2-Diazo-2-(2-nitrophenyl)acetate 2g: 52% yield. Yellow oil. 1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 7.9, 2.3 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.2, 2.3 Hz, 1H), 2.58 (s, 1H), 1.70 (s, 7H). 13 C NMR (125 MHz, CDCl3) δ 162.94, 147.17, 133.12, 130.96, 128.74, 125.60, 121.01, 84.18, 73.74, 72.94, 28.97. IR (neat) 2085, 1702, 1513, 1259, 903 cm-1; HRMS (ESI) m/z calculated for C13H11N3O4Na + [M+Na] + 296.0642, found 296.0637. 243 Ethynylcyclopentyl 2-Diazo-2-phenylacetate 2h: 81% yield. Yellow solid, m.p. 31.8 – 33.0℃. 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.47 (m, 2H), 7.39 – 7.35 (m, 2H), 7.20 – 7.15 (m, 1H), 2.64 (s, 1H), 2.37 – 2.30 (m, 2H), 2.27 – 2.20 (m, 2H), 1.82 – 1.76 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 163.64, 128.84, 125.75, 125.37, 123.91, 83.97, 81.27, 73.36, 40.59, 23.32. IR (neat) 2081, 1701, 1598, 1286, 907 cm-1; HRMS (ESI) m/z calculated for C15H14N2O2Na + [M+Na] + 277.0947, found 277.0946. (Z)-5,5-Dimethyl-2,6-diphenyl-7- [(phenylamino)methylene]cyclohept-2-ene-1,4-dione 4ba: 63% yield. Red viscous oil. TLC Rf =0.3 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.60 (d, J = 12.3 Hz, 1H), 7.58 (d, J = 12.3 Hz, 1H), 7.41 – 7.34 (comp, 5H), 7.34 – 7.27 (comp, 6H), 7.26 – 7.21 (m, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H), 6.55 (s, 1H), 4.10 (s, 1H), 1.50 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.6, 189.7, 149.2, 147.1, 140.0, 139.8, 138.9, 131.1, 129.8, 129.8, 128.7, 128.4, 128.3, 244 126.8, 124.2, 116.7, 111.4, 54.5, 52.5, 27.9, 23.2; IR (neat) 2977, 2248, 1625, 1596 cm -1 ; HRMS (ESI) m/z calculated for C28H26NO2 + [M+H] + 408.1958, found: 408.1944; UV/vis absorption spectra of 4ba recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 308 nm, 411 nm, and corresponding molar extinction coefficients are 308 = 10362 M −1 cm −1 , 411 = 9534 M −1 cm −1 . (Z)-7-[(4-hydroxyphenyl)amino]methylene-2-(4- methoxyphenyl)-5,5-dimethyl-6-phenylcyclohept-2-ene-1,4-dione 4cb: 68% yield. Red viscous oil. TLC Rf = 0.15 (5:1 hexanes/EtOAc). 1 H NMR (500 MHz, CDCl3) δ 12.72 (d, J = 12.3 Hz, 1H), 7.47 (d, J = 12.3 Hz, 1H), 7.36 – 7.28 (m, 4H), 7.28 – 7.23 (m, 4H), 6.91 – 6.83 (m, 4H), 6.78 – 6.73 (m, 2H), 6.53 (d, J = 1.1 Hz, 1H), 5.86 (s, 1H), 4.10 (s, 1H), 3.81 (s, 3H), 1.48 (s, 3H), 1.21 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 207.32, 189.05, 160.19, 153.08, 149.13, 148.13, 140.06, 133.10, 131.12, 129.89, 129.88, 129.47, 128.35, 126.72, 118.49, 116.55, 113.82, 110.71, 245 55.34, 54.35, 52.77, 27.87, 23.06. HRMS (ESI) m/z calculated for C29H28NO4 + [M+H] + 454.2018, found: 454.2014; UV/vis absorption spectra of 4cb recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 303 nm, 419 nm, and corresponding molar extinction coefficients are 303 = 9762 M −1 cm −1 , 419 = 8121 M −1 cm −1 . (Z)-5,5-Dimethyl-6-phenyl-7-[(phenylamino)methylene]-2-(p- tolyl)cyclohept-2-ene-1,4-dione 4bc: 65% yield. Red viscous oil. TLC Rf = 0.25 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.61 (d, J = 12.2 Hz, 1H), 7.56 (d, J = 12.2 Hz, 1H), 7.37 – 7.28 (comp, 6H), 7.25 – 7.22 (m, 1H), 7.19 – 7.15 (comp, 4H), 7.08 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H), 6.54 (s, 1H), 4.09 (s, 1H), 2.36 (s, 3H), 1.49 (s, 3H), 1.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.8, 189.9, 149.3, 147.0, 140.0, 139.9, 138.9, 136.0, 130.5, 129.8, 129.8, 129.0, 128.4, 128.3, 126.7, 124.2, 116.7, 111.5, 54.5, 52.5, 27.9, 23.2, 21.3; IR (neat) 2973, 1628, 1598 cm -1 ; HRMS (ESI) m/z calculated for C29H28NO2 + [M+H] + 246 422.2115, found: 422.2118; UV/vis absorption spectra of 4bc recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 311 nm, 405 nm, and corresponding molar extinction coefficients are 311 = 9517 M −1 cm −1 , 405 = 8119 M −1 cm −1 . (Z)-2-(4-Bromophenyl)-5,5-dimethyl-6-phenyl-7- [(phenylamino)-methylene]cyclohept-2-ene-1,4-dione 4bd: 55% yield. Red viscous oil. TLC Rf =0.3 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.60 (d, J = 12.3 Hz, 1H), 7.59 (d, J = 12.3 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.35 – 7.28 (comp, 6H), 7.25 – 7.21 (m, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.5 Hz, 2H), 6.50 (s, 1H), 4.04 (s, 1H), 1.50 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.2, 188.9, 148.2, 147.4, 139.9, 139.6, 137.8, 131.4, 131.3, 130.0, 129.8, 129.7, 128.4, 126.8, 124.4, 123.1, 116.8, 111.4, 54.6, 52.3, 27.9, 23.5; IR (neat) 2975, 1625, 1597 cm -1 ; HRMS (ESI) m/z calculated for C28H25BrNO2 + [M+H] + 486.1063, found: 486.1052; UV/vis absorption spectra of 4bd recorded at 20 o C in dichloromethane (DCM): UV (λ max) 247 = 311 nm, 411 nm, and corresponding molar extinction coefficients are 311 = 14924 M −1 cm −1 , 411 = 11984 M −1 cm −1 . (Z)-5,5-Dimethyl-2-(4-nitrophenyl)-6-phenyl-7-[(phenylamino)- methylene]cyclohept-2-ene-1,4-dione 4be: 43% yield. Red viscous solid. TLC Rf =0.4 (5:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.61 (d, J = 12.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 12.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.38 – 7.30 (comp, 6H), 7.29 – 7.22 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 6.53 (s, 1H), 4.00 (s, 1H), 1.53 (s, 3H), 1.27 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 205.6, 187.9, 148.0, 147.7, 147.3, 145.7, 139.8, 139.4, 132.8, 129.9, 129.6, 129.5, 128.5, 126.9, 124.7, 123.4, 117.0, 111.5, 54.7, 52.2, 27.9, 23.8; IR (neat) 2926, 1626, 1596 cm -1 ; HRMS (ESI) m/z calculated for C28H25N2O4 + [M+H] + 453.1809, found: 408.1813; UV/vis absorption spectra of 4be recorded at 20 o C in dichloromethane (DCM): UV (λ max) 248 = 288 nm, 420 nm, and corresponding molar extinction coefficients are 288 = 14841 M −1 cm −1 , 420 = 6549 M −1 cm −1 . (Z)-2-(2-Bromophenyl)-5,5-dimethyl-6-phenyl-7-[(phenyl- amino)-methylene]cyclohept-2-ene-1,4-dione 4bf: 52% yield. Red viscous solid. TLC Rf =0.2 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.44 (d, J = 12.3 Hz, 1H), 7.59 (s, 2H), 7.43 – 7.37 (comp, 3H), 7.37 – 7.34 (comp, 2H), 7.34 – 7.27 (comp, 4H), 7.25 – 7.21 (m, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.5 Hz, 2H), 6.46 (s, 1H), 4.37 (s, 1H), 1.49 (s, 3H), 1.24 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.6, 188.2, 149.5, 147.4, 140.7, 139.9, 139.8, 132.9, 132.5, 131.1, 130.0, 129.9, 129.7, 128.5, 127.5, 126.9, 124.1, 122.0, 116.6, 110.4, 54.3, 52.6, 27.5, 22.2; IR (neat) 2975, 1759, 1624, 1597 cm -1 ; HRMS (ESI) m/z calculated for C28H25BrNO2 + [M+H] + 486.1063, found: 486.1020; UV/vis absorption spectra of 4bf recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 311 nm, 410 nm, and corresponding molar extinction coefficients are 311 = 8329 M −1 cm −1 , 410 = 8494 M −1 cm −1 . 249 (Z)-5,5-Dimethyl-2-(2-nitrophenyl)-6-phenyl-7-[(phenylamino)- methylene]cyclohept-2-ene-1,4-dione 4bg: 55% yield. Red viscous solid. TLC Rf =0.3 (5:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.30 (d, J = 12.4 Hz, 1H), 8.19 (dd, J = 8.2, 1.3 Hz, 1H), 7.72 (td, J = 7.5, 1.3 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.52 – 7.44 (comp, 4H), 7.40 – 7.34 (comp, 2H), 7.31 – 7.26 (comp, 2H), 7.26 – 7.23 (m, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.5 Hz, 2H), 6.58 (s, 1H), 1.49 (s, 3H), 1.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.5, 187.0, 148.4, 147.7, 147.5, 140.2, 139.6, 135.0, 134.0, 132.2, 131.5, 129.8, 129.7, 129.6, 128.6, 127.0, 124.6, 124.3, 116.8, 110.2, 27.2; IR (neat) 2976, 1623, 1597 cm -1 ; HRMS (ESI) m/z calculated for C28H25N2O4 + [M+H] + 453.1809, found: 453.1802; UV/vis absorption spectra of 4bg recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 292 nm, 413 nm, and corresponding molar extinction coefficients are 292 = 9321 M −1 cm −1 , 413 = 7601 M −1 cm −1 . 250 (Z)-7-[(4-Hydroxyphenyl)amino]methylene-5,5-dimethyl-2,6- diphenylcyclohept-2-ene-1,4-dione 4ca: 64% yield. Red viscous solid. TLC Rf =0.2 (5:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.71 (d, J = 12.3 Hz, 1H), 7.47 (d, J = 12.3 Hz, 1H), 7.39 – 7.32 (comp, 6H), 7.31 – 7.27 (comp, 3H), 7.26 – 7.21 (m, 1H), 6.88 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.53 (s, 1H), 5.23 (br, 1H), 4.06 (s, 1H), 1.49 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.9, 188.8, 152.8, 149.5, 148.2, 140.1, 139.1, 133.3, 130.9, 129.8, 128.7, 128.4, 128.4, 128.3, 126.7, 118.5, 116.5, 110.8, 54.6, 52.6, 27.8, 23.2; IR (neat) 3321, 2975, 1733, 1620 cm -1 ; HRMS (ESI) m/z calculated for C28H26NO3 + [M+H] + 424.1907, found: 424.1889; UV/vis absorption spectra of 4ca recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 305 nm, 418 nm, and corresponding molar extinction coefficients are 305 = 9592 M −1 cm −1 , 418 = 8307 M −1 cm −1 . 251 (Z)-7-[(4-Methoxyphenyl)amino]methylene-5,5-dimethyl-2,6- diphenylcyclohept-2-ene-1,4-dione 4da: 65% yield. Red viscous solid. TLC Rf =0.5 (5:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.71 (d, J = 12.3 Hz, 1H), 7.47 (d, J = 12.3 Hz, 1H), 7.39 – 7.32 (comp, 6H), 7.31 – 7.27 (comp, 3H), 7.26 – 7.21 (m, 1H), 6.88 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.53 (s, 1H), 5.23 (br, 1H), 4.06 (s, 1H), 1.49 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.9, 188.8, 152.8, 149.5, 148.2, 140.1, 139.1, 133.3, 130.9, 129.8, 128.7, 128.4, 128.4, 128.3, 126.7, 118.5, 116.5, 110.8, 54.6, 52.6, 27.8, 23.2; IR (neat) 2919, 2850, 1622 cm -1 ; HRMS (ESI) m/z calculated for C29H28NO3 + [M+H] + 438.2064, found: 438.2057; UV/vis absorption spectra of 4da recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 305 nm, 420 nm, and corresponding molar extinction coefficients are 305 = 10691 M −1 cm −1 , 420 = 9478 M −1 cm −1 . 252 (Z)-7-[(4-Bromophenyl)amino]methylene-5,5-dimethyl-2,6- diphenylcyclohept-2-ene-1,4-dione 4ea: 61% yield. Red viscous solid,; TLC Rf = (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.55 (d, J = 12.2 Hz, 1H), 7.49 (d, J = 12.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.39 – 7.31 (comp, 7H), 7.31 – 7.27 (comp, 2H), 7.26 – 7.22 (m, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 4.09 (s, 1H), 1.50 (s, 3H), 1.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.4, 190.2, 149.0, 146.4, 139.8, 139.0, 138.8, 132.7, 131.3, 129.8, 128.8, 128.4, 128.4, 128.3, 126.9, 118.2, 116.7, 111.9, 54.5, 52.4, 27.9, 23.2; IR (neat) 2976, 1623, 1590 cm -1 ; HRMS (ESI) m/z calculated for C28H25BrNO2 + [M+H] + 486.1063, found: 486.1035; UV/vis absorption spectra of 4ea recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 301 nm, 413 nm, and corresponding molar extinction coefficients are 301 = 12017 M −1 cm −1 , 413 = 11837 M −1 cm −1 . 253 (Z)-7-[(4-Chlorophenyl)amino]methylene-5,5-dimethyl-2,6- diphenylcyclohept-2-ene-1,4-dione 4fa: 60% yield. Red viscous solid. TLC Rf =0.2 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.57 (d, J = 12.1 Hz, 1H), 7.49 (d, J = 12.1 Hz, 1H), 7.39 – 7.36 (comp, 3H), 7.35 – 7.31 (comp, 4H), 7.31 – 7.27 (comp, 3H), 7.26 – 7.23 (comp, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.56 (s, 1H), 4.10 (s, 1H), 1.50 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.5, 190.1, 149.0, 146.6, 139.8, 138.8, 138.5, 131.3, 129.8, 129.8, 129.3, 128.8, 128.4, 128.4, 128.3, 126.9, 117.8, 111.8, 54.5, 52.4, 27.9, 23.2; IR (neat) 2976, 1623, 1595 cm -1 ; HRMS (ESI) m/z calculated for C28H25ClNO2 + [M+H] + 442.1568, found: 442.1573; UV/vis absorption spectra of 4fa recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 300 nm, 410 nm, and corresponding molar extinction coefficients are 300 = 6217 M −1 cm −1 , 410 = 5461 M −1 cm −1 . 254 (Z)-7-[(4-Fluorophenyl)amino]methylene-5,5-dimethyl-2,6- diphenylcyclohept-2-ene-1,4-dione 4ga: 56% yield. Red viscous solid. TLC Rf =0.2 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.64 (d, J = 12.2 Hz, 1H), 7.47 (d, J = 12.2 Hz, 1H), 7.39 – 7.36 (comp, 3H), 7.35 – 7.33 (comp, 2H), 7.32 – 7.31 (m, 1H), 7.31 – 7.26 (comp, 3H), 7.25 – 7.22 (m, 1H), 7.06 – 6.98 (comp, 2H), 6.98 – 6.92 (comp, 2H), 6.55 (s, 1H), 4.09 (s, 1H), 1.50 (s, 3H), 1.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.5, 189.7, 159.55 (d, J = 244.2 Hz), 149.1, 147.5, 139.9, 138.9, 136.2 (d, J = 2.8 Hz), 131.2, 129.8, 128.8, 128.4, 128.4, 128.3, 126.8, 118.25 (d, J = 8.0 Hz), 116.59 (d, J = 23.1 Hz), 111.4, 54.5, 52.5, 27.9, 23.2; IR (neat) 2975, 1735, 1624, 1600 cm -1 ; HRMS (ESI) m/z calculated for C28H25FNO2 + [M+H] + 426.1864, found: 426.1867; UV/vis absorption spectra of 4ga recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 299 nm, 408 nm, and corresponding molar extinction coefficients are 299 = 8565 M −1 cm −1 , 408 = 7098 M −1 cm −1 . 255 (Z)-5,5-Dimethyl-7-(naphthalen-1-ylamino)methylene-2,6- diphenylcyclohept-2-ene-1,4-dione 4ha: 68% yield. Red viscous solid TLC Rf =0.3 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 13.43 (d, J = 11.8 Hz, 1H), 8.16 – 8.08 (m, 1H), 7.89 – 7.81 (m, 1H), 7.77 (d, J = 11.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.55 – 7.50 (comp, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.42 – 7.31 (comp, 9H), 7.29 – 7.23 (m, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.22 (s, 1H), 1.54 (s, 3H), 1.25 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 206.9, 190.2, 149.2, 148.3, 139.9, 138.8, 136.2, 134.2, 131.0, 129.9, 128.9, 128.5, 128.5, 128.4, 128.4, 126.8, 126.8, 126.8, 125.7, 124.9, 124.8, 121.1, 112.3, 111.7, 54.4, 52.8, 27.9, 23.0; IR (neat) 2975, 2268, 1616 cm -1 ; HRMS (ESI) m/z calculated for C32H28NO2 + [M+H] + 458.2115, found: 458.2088; UV/vis absorption spectra of 4ha recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 325 nm, 424 nm, and corresponding molar extinction coefficients are 325 = 3967 M −1 cm −1 , 424 = 4629 M −1 cm −1 . 256 (Z)-7-(Mesitylamino)methylene-5,5-dimethyl-2,6-diphenyl- cyclohept-2-ene-1,4-dione 4ia: 70% yield. Red viscous solid. TLC Rf =0.3 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.13 (d, J = 12.5 Hz, 1H), 7.41 – 7.34 (comp, 5H), 7.34 – 7.26 (comp, 4H), 7.24 – 7.18 (m, 1H), 7.06 (d, J = 12.5 Hz, 1H), 6.87 (s, 2H), 6.57 (s, 1H), 4.19 (s, 1H), 2.26 (s, 3H), 2.16 (s, 6H), 1.49 (s, 3H), 1.19 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 207.8, 189.1, 155.2, 149.0, 140.3, 138.8, 135.9, 135.9, 131.7, 130.3, 129.9, 129.5, 128.7, 128.4, 128.4, 128.3, 126.6, 109.3, 53.8, 53.2, 27.7, 22.3, 20.8, 18.5; IR (neat) 2974, 1622, 1602 cm -1 ; HRMS (ESI) m/z calculated for C31H32NO2 + [M+H] + 450.2428, found: 450.2401; UV/vis absorption spectra of 4ia recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 300 nm, 393 nm, and corresponding molar extinction coefficients are 300 = 12797 M −1 cm −1 , 393 = 7917 M −1 cm −1 . 257 (Z)-6-(4-methoxyphenyl)-5,5-dimethyl-2-phenyl-7-[(phenyl- amino)methylene]cyclohept-2-ene-1,4-dione 4ja: 67% yield. Red viscous solid. TLC Rf =0.30 (10:1 hexanes/EtOAc); 1 H NMR (500 MHz, CDCl3) δ 12.60 (d, J = 12.1 Hz, 1H), 7.57 (d, J = 12.1 Hz, 1H), 7.41 – 7.36 (comp., 3H), 7.35 – 7.30 (comp., 4H), 7.30 – 7.25 (comp., 4H), 7.10 – 7.07 (m, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.56 (s, 1H), 4.10 (s, 1H), 3.81 (s, 3H), 1.48 (s, 3H), 1.21 (s, 3H).; 13 C NMR (125 MHz, CDCl3) δ 206.90, 189.82, 158.22, 149.17, 147.05, 139.87, 138.91, 131.88, 130.96, 130.85, 129.79, 128.76, 128.44, 128.33, 124.21, 116.76, 113.76, 111.56, 55.25, 53.71, 52.79, 27.83, 22.85.; IR (neat) 2927, 1621, 1427 cm -1 ; HRMS (ESI) m/z calculated for C29H28NO3 + [M+H] + 438.2064, found: 438.2061; UV/vis absorption spectra of 4ja recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 301 nm, 391 nm, and corresponding molar extinction coefficients are 296 = 17213 M −1 cm −1 , 413 = 16721 M −1 cm −1 . 258 (Z)-5,5-Dimethyl-6-(4-nitrophenyl)-2-phenyl-7-[(phenyl- amino)methylene]cyclohept-2-ene-1,4-dione 4ka: 59% yield. Red viscous solid. TLC Rf =0.15 (10:1 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.66 (d, J = 12.3 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 12.3 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.40 – 7.32 (comp, 5H), 7.25 – 7.20 (comp, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.53 (s, 1H), 4.01 (s, 1H), 1.52 (s, 3H), 1.31 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 204.8, 188.9, 149.9, 148.1, 147.5, 146.4, 139.4, 138.8, 131.4, 130.3, 129.9, 129.0, 128.4, 128.3, 124.8, 123.4, 117.0, 110.6, 55.1, 51.6, 28.0, 24.4; IR (neat) 2925, 1625, 1595 cm -1 ; HRMS (ESI) m/z calculated for C28H25N2O4 + [M+H] + 453.1809, found: 453.1810; UV/vis absorption spectra of 4ka recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 296 nm, 413 nm, and corresponding molar extinction coefficients are 296 = 36223 M −1 cm −1 , 413 = 23233 M −1 cm −1 . 259 (Z)-8,11-Diphenyl-10-[(phenylamino)methylene]spiro[4.6]- undec-7-ene-6,9-dione 4bh: 65% yield. Red viscous solid. TLC Rf =0.2 (10:0 hexanes/EtOAc); 1 H NMR (400 MHz, CDCl3) δ 12.53 (d, J = 12.3 Hz, 1H), 7.61 (d, J = 12.3 Hz, 1H), 7.40 – 7.33 (comp, 2H), 7.31 – 7.28 (m, 1H), 7.27 – 7.21 (comp, 6H), 7.17 – 7.11 (comp, 4H), 7.06 – 7.01 (comp, 2H), 6.21 (s, 1H), 3.72 (s, 1H), 2.89 – 2.79 (m, 1H), 2.08 – 1.96 (m, 1H), 1.93 – 1.83 (comp, 3H), 1.78 – 1.67 (comp, 2H), 1.66 – 1.55 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 205.0, 189.2, 149.8, 147.1, 141.5, 139.8, 139.7, 132.2, 129.8, 128.3, 128.3, 128.3, 128.1, 128.0, 126.2, 124.2, 116.7, 112.5, 62.2, 54.9, 40.0, 38.2, 26.3, 24.8; IR (neat) 2949, 1625, 1595 cm -1 ; HRMS (ESI) m/z calculated for C30H28NO2 + [M+H] + 434.2115, found: 434.2134; UV/vis absorption spectra of 4bh recorded at 20 o C in dichloromethane (DCM): UV (λ max) = 298 nm, 419 nm, and corresponding molar extinction coefficients are 298 = 8390 M −1 cm −1 , 419 = 5328 M −1 cm −1 . 260 1-(4-hydroxyphenyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H- azepin-3-yl 2-diazo-2-(4-methoxyphenyl)acetate 3cb: 36% yield. Yellow oil. 1 H NMR (500 MHz, cdcl3) δ 7.30 (dd, J = 16.4, 8.3 Hz, 5H), 7.24 (d, J = 6.6 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.82 – 6.77 (m, 2H), 6.39 (d, J = 9.9 Hz, 1H), 6.37 (s, 1H), 5.33 (s, 1H), 4.92 (dd, J = 9.8, 6.6 Hz, 1H), 3.80 (s, 3H), 3.57 (d, J = 6.4 Hz, 1H), 1.19 (s, 3H), 1.04 (s, 3H). 13 C NMR (126 MHz, cdcl3) δ 165.96, 158.08, 152.62, 144.09, 140.75, 138.84, 129.65, 129.17, 127.69, 126.27, 125.86, 124.75, 122.96, 116.62, 115.85, 114.63, 107.79, 55.35, 54.90, 43.75, 28.36, 25.01. IR (neat) 3406, 2086, 1671, 1152, 1253 cm -1 ; HRMS (ESI) m/z calculated for C29H28N3O4 + [M+H] + 482.2080, found: 482.2086. NMR spectra will be obtained from the Supporting Information of the published paper. 4.5 X-ray Crystal Structure Information for 4ha 261 Crystal Structure Report for 4ha A specimen of C32H27NO2, approximate dimensions 0.07 mm × 0.08 mm × 0.47 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured on a Bruker APEX-II CCD system equipped with a graphite monochromator and a MoKα sealed tube (λ = 0.71073 Å). Data collection temperature was 150 K. The total exposure time was 17.78 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a monoclinicunit cell yielded a total of 15657 reflections to a maximum θ angle of 24.99° (0.84 Å resolution), of which 4299 were independent (average redundancy 3.642, completeness = 100.0%, Rint =7.86%) and 2251 (52.36%) were greater than 2σ(F2). The final cell constants of a = 18.041(4) Å, b = 12.292(3) Å, c = 11.066(2) Å, β = 94.663(3)°, V = 2445.9(9) Å3, are based upon the refinement of the XYZ-centroids of 1326 reflections above 20 σ(I) with 5.328° < 2θ < 41.67°. Data were corrected for absorption effects using the multi-scan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.8840 and 0.9940. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P21/c, with Z = 4 for the formula unit, C32H27NO2. The final anisotropic full-matrix least-squares refinement on F 2 with 404 variables converged at R1 = 5.44%, for the observed data and wR2 = 9.80% for all data. The goodness-of-fit was 1.069. The largest peak in the final difference electron density synthesis was 0.199 e - /Å 3 and the largest hole was -0.182 e - /Å 3 with an RMS deviation of 0.043 e - /Å 3 . On the basis of the final model, the calculated density was1.243 g/cm 3 and F(000), 968 e - . 262 APEX2 Version 2010.11-3 (Bruker AXS Inc.) SAINT Version 7.68A (Bruker AXS Inc., 2009) SADABS Version 2008/1 (G. M. Sheldrick, Bruker AXS Inc.) XPREP Version 2008/2 (G. M. Sheldrick, Bruker AXS Inc.) XS Version 2008/1 (G. M. Sheldrick, Acta Cryst. (2008). A64, 112-122) XL Version 2012/4 (G. M. Sheldrick, (2012) University of Gottingen, Germany) Platon (A. L. Spek, Acta Cryst. (1990). A46, C-34). Table 1. Sample and crystal data for 4ha. Identification code 2608 Chemical formula C32H27NO2 Formula weight 457.54 Temperature 150(2) K Wavelength 0.71073 Å Crystal size 0.07 × 0.08 × 0.47 mm Crystal system monoclinic Space group P21/c Unit cell dimensions a = 18.041(4) Å α = 90° b = 12.292(3) Å β = 94.663(3)° c = 11.066(2) Å γ = 90° Volume 2445.9(9) Å 3 Z 4 Density (calculated) 1.243 Mg/cm 3 Absorption coefficient 0.077 mm -1 F(000) 968 Table 2. Data collection and structure refinement for 4ha. Diffractometer Bruker APEX-II CCD Radiation source sealed tube, MoKα Theta range for 2.01 to 24.99° 263 data collection Index ranges -20 ≤ h ≤ 21, -14 ≤ k ≤ 14, -13 ≤ l ≤ 13 Reflections collected 15657 Independent reflections 4299 [R(int) = 0.0786] Coverage of independent reflections 100.0% Absorption correction multi-scan Max. and min. transmission 0.9940 and 0.8840 Structure solution technique direct methods Structure solution program ShelXS-97 (Sheldrick, 2008) Refinement method Full-matrix least-squares on F 2 Refinement program ShelXL-2014 (Sheldrick, 2014) Function minimized Σ w(Fo 2 - Fc 2 ) 2 Data / restraints / parameters 4299 / 0 / 404 Goodness-of-fit on F 2 1.069 Final R indices 2251 data; I>2σ(I) R1 = 0.0544, wR2 = 0.0797 all data R1 = 0.1294, wR2 = 0.0980 Weighting scheme w=1/[σ2(Fo 2 )+(0.0150P) 2 +0.7500P], P=(Fo 2 +2Fc 2 )/3 264 Largest diff. peak and hole 0.199 and -0.182 eÅ -3 R.M.S. deviation from mean 0.043 eÅ -3 Rint = Σ|Fo 2 - Fo 2 (mean)| / Σ[Fo 2 ] R1 = Σ||Fo| - |Fc|| / Σ|Fo| GOOF = S = {Σ[w(Fo 2 - Fc 2 ) 2 ] / (n - p)} 1/2 wR2 = {Σ[w(Fo 2 - Fc 2 ) 2 ] / Σ[w(Fo 2 ) 2 ]} 1/2 Table 3. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å 2 ) for 4ha. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x/a y/b z/c U(eq) C1 0.27599(16) 0.2147(2) 0.2860(3) 0.0371(8) C2 0.22310(14) 0.2913(2) 0.2500(2) 0.0353(7) C3 0.15699(15) 0.3060(3) 0.3262(3) 0.0405(8) C4 0.08121(15) 0.2776(3) 0.2558(3) 0.0437(8) C5 0.05480(17) 0.3616(3) 0.1603(3) 0.0450(8) O5 0.98856(11) 0.36475(18) 0.12510(18) 0.0610(7) C6 0.10421(17) 0.4408(3) 0.1064(3) 0.0414(8) C7 0.17840(15) 0.4432(2) 0.1021(2) 0.0371(7) C8 0.23122(15) 0.3540(2) 0.1442(2) 0.0367(7) O8 0.28433(10) 0.34054(14) 0.07800(16) 0.0399(5) N1 0.33667(12) 0.19550(19) 0.2260(2) 0.0347(6) C10 0.39469(15) 0.1210(2) 0.2515(2) 0.0339(7) C11 0.39531(17) 0.0481(2) 0.3448(3) 0.0420(8) C12 0.45455(18) 0.9744(3) 0.3645(3) 0.0497(9) C13 0.51227(19) 0.9752(3) 0.2931(3) 0.0481(9) C14 0.51321(15) 0.0486(2) 0.1947(3) 0.0377(7) 265 x/a y/b z/c U(eq) C15 0.57043(16) 0.0470(3) 0.1146(3) 0.0414(8) C16 0.56868(17) 0.1134(3) 0.0167(3) 0.0428(8) C17 0.50969(16) 0.1871(3) 0.9935(3) 0.0414(8) C18 0.45387(16) 0.1925(2) 0.0701(3) 0.0355(7) C19 0.45329(14) 0.1229(2) 0.1721(2) 0.0322(7) C31 0.16207(16) 0.4125(3) 0.3967(2) 0.0431(8) C32 0.22399(17) 0.4283(3) 0.4791(3) 0.0418(8) C33 0.23266(19) 0.5202(3) 0.5496(3) 0.0479(9) C34 0.1796(2) 0.6015(3) 0.5389(3) 0.0581(10) C35 0.1182(2) 0.5894(3) 0.4567(3) 0.0667(11) C36 0.10933(19) 0.4956(3) 0.3885(3) 0.0604(11) C41 0.08874(15) 0.1693(2) 0.1860(3) 0.0525(9) C42 0.02121(16) 0.2602(3) 0.3450(3) 0.0674(11) C71 0.21405(16) 0.5340(2) 0.0407(3) 0.0384(7) C72 0.18490(18) 0.5762(3) 0.9299(3) 0.0436(8) C73 0.2208(2) 0.6586(3) 0.8740(3) 0.0565(10) C74 0.2857(2) 0.7021(3) 0.9282(3) 0.0616(10) C75 0.3140(2) 0.6625(3) 0.0386(3) 0.0562(10) C76 0.27907(17) 0.5803(3) 0.0947(3) 0.0459(8) Table 4. Bond lengths (Å) for 4ha. C1-N1 1.347(3) C1-C2 1.376(4) C1-H1 0.98(2) C2-C8 1.419(3) C2-C3 1.526(3) C3-C31 1.524(4) C3-C4 1.557(4) C3-H3 1.00(2) C4-C5 1.525(4) C4-C42 1.539(4) C4-C41 1.550(4) C5-O5 1.227(3) C5-C6 1.479(4) C6-C7 1.344(4) C6-H6 0.98(2) C7-C71 1.481(4) C7-C8 1.502(4) C8-O8 1.264(3) N1-C10 1.402(3) N1-H1A 0.91(3) C10-C11 1.367(4) C10-C19 1.428(3) 266 C11-C12 1.405(4) C11-H11 0.97(2) C12-C13 1.357(4) C12-H12 0.98(3) C13-C14 1.414(4) C13-H13 0.95(3) C14-C15 1.415(4) C14-C19 1.422(3) C15-C16 1.355(4) C15-H15 0.98(2) C16-C17 1.405(4) C16-H16 1.00(2) C17-C18 1.370(4) C17-H17 0.97(2) C18-C19 1.416(4) C18-H18 0.94(2) C31-C36 1.394(4) C31-C32 1.397(4) C32-C33 1.375(4) C32-H32 0.98(2) C33-C34 1.383(4) C33-H33 0.98(3) C34-C35 1.382(4) C34-H34 0.99(2) C35-C36 1.380(4) C35-H35 1.01(3) C36-H36 0.99(3) C41-H41A 0.98 C41-H41B 0.98 C41-H41C 0.98 C42-H42A 0.98 C42-H42B 0.98 C42-H42C 0.98 C71-C76 1.394(4) C71-C72 1.394(4) C72-C73 1.376(4) C72-H72 0.94(3) C73-C74 1.379(4) C73-H73 0.99(3) C74-C75 1.375(4) C74-H74 0.96(3) C75-C76 1.367(4) C75-H75 0.95(3) C76-H76 0.98(2) Table 5. Bond angles (°) for 4ha. N1-C1-C2 123.4(3) N1-C1-H1 114.2(13) C2-C1-H1 122.3(13) C1-C2-C8 119.7(2) C1-C2-C3 118.4(3) C8-C2-C3 121.9(3) C31-C3-C2 111.6(2) C31-C3-C4 117.6(2) C2-C3-C4 113.0(2) C31-C3-H3 106.9(13) C2-C3-H3 104.7(13) C4-C3-H3 101.5(13) C5-C4-C42 110.0(2) C5-C4-C41 105.7(2) C42-C4-C41 107.2(3) C5-C4-C3 114.0(3) C42-C4-C3 110.2(2) C41-C4-C3 109.4(2) 267 O5-C5-C6 117.0(3) O5-C5-C4 118.9(3) C6-C5-C4 124.1(3) C7-C6-C5 131.6(3) C7-C6-H6 117.1(14) C5-C6-H6 111.3(14) C6-C7-C71 120.3(3) C6-C7-C8 125.6(3) C71-C7-C8 113.9(2) O8-C8-C2 122.8(3) O8-C8-C7 114.0(2) C2-C8-C7 123.2(2) C1-N1-C10 129.7(3) C1-N1-H1A 111.5(18) C10-N1-H1A 118.7(18) C11-C10-N1 122.7(3) C11-C10-C19 121.0(3) N1-C10-C19 116.3(2) C10-C11-C12 120.0(3) C10-C11-H11 120.4(15) C12-C11-H11 119.7(15) C13-C12-C11 121.0(3) C13-C12-H12 121.7(17) C11-C12-H12 117.3(17) C12-C13-C14 120.7(3) C12-C13-H13 122.6(17) C14-C13-H13 116.7(16) C13-C14-C15 121.9(3) C13-C14-C19 119.3(3) C15-C14-C19 118.8(3) C16-C15-C14 121.5(3) C16-C15-H15 119.2(15) C14-C15-H15 119.3(15) C15-C16-C17 120.2(3) C15-C16-H16 122.6(15) C17-C16-H16 117.2(15) C18-C17-C16 120.1(3) C18-C17-H17 120.2(16) C16-C17-H17 119.7(16) C17-C18-C19 121.2(3) C17-C18-H18 117.7(14) C19-C18-H18 121.0(14) C18-C19-C14 118.2(3) C18-C19-C10 123.6(3) C14-C19-C10 118.1(3) C36-C31-C32 116.5(3) C36-C31-C3 125.8(3) C32-C31-C3 117.7(3) C33-C32-C31 122.2(3) C33-C32-H32 120.1(14) C31-C32-H32 117.7(14) C32-C33-C34 119.9(3) C32-C33-H33 119.2(16) C34-C33-H33 120.8(16) C35-C34-C33 119.4(3) C35-C34-H34 117.1(15) C33-C34-H34 123.3(16) C36-C35-C34 120.1(4) C36-C35-H35 118.5(17) C34-C35-H35 121.4(17) C35-C36-C31 121.9(3) C35-C36-H36 118.0(17) C31-C36-H36 120.1(17) C4-C41-H41A 109.5 C4-C41-H41B 109.5 H41A-C41- H41B 109.5 268 C4-C41-H41C 109.5 H41A-C41- H41C 109.5 H41B-C41- H41C 109.5 C4-C42-H42A 109.5 C4-C42-H42B 109.5 H42A-C42- H42B 109.5 C4-C42-H42C 109.5 H42A-C42- H42C 109.5 H42B-C42- H42C 109.5 C76-C71-C72 118.0(3) C76-C71-C7 119.5(3) C72-C71-C7 122.5(3) C73-C72-C71 120.8(3) C73-C72-H72 120.4(16) C71-C72-H72 118.8(16) C72-C73-C74 120.3(3) C72-C73-H73 121.0(17) C74-C73-H73 118.7(17) C75-C74-C73 119.3(4) C75-C74-H74 122.2(18) C73-C74-H74 118.5(18) C76-C75-C74 120.9(4) C76-C75-H75 118.1(17) C74-C75-H75 120.8(17) C75-C76-C71 120.7(3) C75-C76-H76 122.4(15) C71-C76-H76 116.9(15) Table 6. Torsion angles (°) for 4ha. N1-C1-C2-C8 0.3(4) N1-C1-C2-C3 - 179.6(3) C1-C2-C3-C31 108.0(3) C8-C2-C3-C31 -71.9(3) C1-C2-C3-C4 - 116.9(3) C8-C2-C3-C4 63.2(4) C31-C3-C4-C5 59.3(3) C2-C3-C4-C5 -72.9(3) C31-C3-C4-C42 -64.9(3) C2-C3-C4-C42 162.9(3) C31-C3-C4-C41 177.5(2) C2-C3-C4-C41 45.3(3) C42-C4-C5-O5 -34.9(4) C41-C4-C5-O5 80.5(3) C3-C4-C5-O5 - 159.3(3) C42-C4-C5-C6 145.0(3) C41-C4-C5-C6 -99.6(3) C3-C4-C5-C6 20.7(4) O5-C5-C6-C7 - 162.0(3) C4-C5-C6-C7 18.1(5) 269 C5-C6-C7-C71 179.8(3) C5-C6-C7-C8 6.4(5) C1-C2-C8-O8 2.4(4) C3-C2-C8-O8 - 177.7(3) C1-C2-C8-C7 - 176.7(3) C3-C2-C8-C7 3.3(4) C6-C7-C8-O8 142.0(3) C71-C7-C8-O8 -31.8(3) C6-C7-C8-C2 -38.9(4) C71-C7-C8-C2 147.4(3) C2-C1-N1-C10 - 180.0(3) C1-N1-C10-C11 3.8(4) C1-N1-C10-C19 - 177.7(3) N1-C10-C11- C12 179.0(3) C19-C10-C11- C12 0.6(4) C10-C11-C12- C13 1.1(5) C11-C12-C13- C14 -1.8(5) C12-C13-C14- C15 - 176.2(3) C12-C13-C14- C19 0.8(4) C13-C14-C15- C16 176.2(3) C19-C14-C15- C16 -0.9(4) C14-C15-C16- C17 0.8(4) C15-C16-C17- C18 0.3(4) C16-C17-C18- C19 -1.4(4) C17-C18-C19- C14 1.3(4) C17-C18-C19- C10 - 176.7(3) C13-C14-C19- C18 - 177.4(3) C15-C14-C19- C18 -0.2(4) C13-C14-C19- C10 0.8(4) C15-C14-C19- C10 177.9(2) C11-C10-C19- C18 176.5(3) N1-C10-C19- C18 -2.0(4) C11-C10-C19- C14 -1.5(4) N1-C10-C19- C14 - 180.0(2) C2-C3-C31-C36 121.6(3) C4-C3-C31-C36 -11.2(4) C2-C3-C31-C32 -59.9(3) C4-C3-C31-C32 167.2(2) C36-C31-C32- C33 0.5(4) C3-C31-C32- C33 - 178.1(3) C31-C32-C33- -0.9(5) C32-C33-C34- -0.2(5) 270 C34 C35 C33-C34-C35- C36 1.7(6) C34-C35-C36- C31 -2.1(6) C32-C31-C36- C35 1.0(5) C3-C31-C36- C35 179.5(3) C6-C7-C71-C76 137.2(3) C8-C7-C71-C76 -48.7(4) C6-C7-C71-C72 -42.5(4) C8-C7-C71-C72 131.6(3) C76-C71-C72- C73 2.2(4) C7-C71-C72- C73 - 178.1(3) C71-C72-C73- C74 -1.3(5) C72-C73-C74- C75 -0.1(5) C73-C74-C75- C76 0.5(5) C74-C75-C76- C71 0.4(5) C72-C71-C76- C75 -1.8(4) C7-C71-C76- C75 178.5(3) Table 7. Anisotropic atomic displacement parameters (Å 2 ) for 4ha. The anisotropic atomic displacement factor exponent takes the form: -2π2[ h2 a*2 U11 + ... + 2 h k a * b * U12 ] U11 U22 U33 U23 U13 U12 C1 0.0311(18) 0.056(2) 0.0235(17) 0.0004(15) - 0.0017(14) - 0.0018(16) C2 0.0251(16) 0.056(2) 0.0253(16) 0.0015(14) 0.0034(13) 0.0041(15) C3 0.0301(18) 0.065(2) 0.0264(17) 0.0026(16) 0.0037(14) 0.0051(16) C4 0.0273(18) 0.073(2) 0.0311(17) - 0.0013(16) 0.0022(14) - 0.0047(16) C5 0.0284(19) 0.071(2) 0.0351(18) - 0.0074(16) 0.0010(15) 0.0042(17) O5 0.0268(13) 0.0972(18) 0.0579(15) 0.0080(12) - 0.0029(11) 0.0034(12) C6 0.0326(19) 0.057(2) 0.0340(18) - 0.0007(16) - 0.0014(15) 0.0059(17) C7 0.0319(18) 0.053(2) 0.0260(16) - 0.0072(14) - 0.0029(14) 0.0069(16) 271 U11 U22 U33 U23 U13 U12 C8 0.0317(17) 0.047(2) 0.0311(17) - 0.0018(14) 0.0008(14) 0.0022(15) O8 0.0303(12) 0.0548(13) 0.0357(12) 0.0046(10) 0.0093(10) 0.0075(10) N1 0.0271(14) 0.0497(17) 0.0275(15) 0.0035(12) 0.0029(12) 0.0057(12) C10 0.0274(17) 0.0410(18) 0.0320(17) - 0.0017(14) - 0.0063(13) 0.0013(14) C11 0.037(2) 0.054(2) 0.0349(19) 0.0070(16) 0.0022(16) 0.0061(17) C12 0.049(2) 0.058(2) 0.041(2) 0.0092(17) - 0.0049(17) 0.0065(18) C13 0.042(2) 0.050(2) 0.050(2) 0.0017(17) - 0.0051(18) 0.0140(18) C14 0.0295(17) 0.0411(19) 0.0417(19) - 0.0090(15) - 0.0027(14) 0.0027(14) C15 0.0269(18) 0.047(2) 0.049(2) - 0.0123(17) - 0.0028(16) 0.0058(16) C16 0.032(2) 0.048(2) 0.048(2) - 0.0134(17) 0.0072(16) - 0.0048(16) C17 0.036(2) 0.045(2) 0.044(2) - 0.0047(16) 0.0076(16) - 0.0029(16) C18 0.0281(18) 0.0364(19) 0.0413(19) - 0.0050(14) - 0.0014(15) 0.0026(15) C19 0.0258(17) 0.0387(18) 0.0311(17) - 0.0062(13) - 0.0044(13) - 0.0021(14) C31 0.0265(17) 0.075(2) 0.0285(17) - 0.0004(16) 0.0047(14) 0.0063(17) C32 0.0303(19) 0.058(2) 0.0373(19) 0.0060(17) 0.0021(15) 0.0046(18) C33 0.035(2) 0.071(3) 0.037(2) 0.0018(18) - 0.0048(16) - 0.0036(19) C34 0.062(3) 0.070(3) 0.042(2) - 0.0152(19) 0.0037(19) 0.010(2) C35 0.056(3) 0.096(3) 0.047(2) -0.022(2) - 0.0058(19) 0.033(2) C36 0.041(2) 0.097(3) 0.041(2) -0.022(2) - 0.0065(17) 0.025(2) C41 0.038(2) 0.072(2) 0.046(2) 0.0050(18) - - 272 U11 U22 U33 U23 U13 U12 0.0045(16) 0.0088(17) C42 0.036(2) 0.127(3) 0.040(2) 0.006(2) 0.0097(17) -0.005(2) C71 0.0296(18) 0.046(2) 0.0393(18) - 0.0024(15) 0.0009(15) 0.0072(15) C72 0.038(2) 0.054(2) 0.037(2) - 0.0063(17) - 0.0090(16) 0.0040(18) C73 0.071(3) 0.052(2) 0.044(2) 0.0075(18) -0.007(2) 0.001(2) C74 0.067(3) 0.053(3) 0.065(3) 0.010(2) 0.004(2) -0.006(2) C75 0.045(2) 0.061(2) 0.061(3) 0.000(2) -0.008(2) -0.008(2) C76 0.041(2) 0.054(2) 0.041(2) 0.0041(17) - 0.0036(17) 0.0041(17) Table 8. Hydrogen atomic coordinates and isotropic atomic displacement parameters (Å 2 ) for 4ha. x/a y/b z/c U(eq) H1 0.2742(12) 0.1728(18) 0.361(2) 0.033(7) H3 0.1620(12) 0.2461(17) 0.387(2) 0.023(7) H6 0.0758(13) 0.5023(19) 0.069(2) 0.037(8) H1A 0.3371(15) 0.238(2) 0.158(2) 0.053(10) H11 0.3548(14) 0.0468(19) 0.398(2) 0.047(8) H12 0.4526(16) -0.077(2) 0.432(3) 0.067(10) H13 0.5541(15) -0.072(2) 0.307(2) 0.058(10) H15 0.6123(14) -0.003(2) 0.130(2) 0.043(8) H16 0.6072(14) 0.1108(19) - 0.043(2) 0.047(8) H17 0.5090(14) 0.235(2) - 0.077(2) 0.051(9) H18 0.4145(13) 0.2415(18) 0.050(2) 0.031(8) H32 0.2611(13) 0.3695(19) 0.488(2) 0.034(8) H33 0.2754(15) 0.525(2) 0.610(2) 0.052(9) H34 0.1845(14) 0.671(2) 0.584(2) 0.048(9) H35 0.0798(17) 0.649(2) 0.443(3) 0.076(11) 273 x/a y/b z/c U(eq) H36 0.0647(16) 0.489(2) 0.331(3) 0.070(10) H41A 0.0398 0.1470 0.1494 0.079(6) H41B 0.1085 0.1129 0.2422 0.079(6) H41C 0.1227 0.1797 0.1221 0.079(6) H42A -0.0267 0.2457 0.2997 0.083(6) H42B 0.0172 0.3257 0.3946 0.083(6) H42C 0.0349 0.1981 0.3977 0.083(6) H72 0.1413(15) 0.545(2) - 0.108(2) 0.050(9) H73 0.2004(16) 0.689(2) - 0.205(3) 0.074(11) H74 0.3099(16) 0.759(2) - 0.113(3) 0.067(10) H75 0.3560(15) 0.696(2) 0.082(2) 0.057(10) H76 0.2979(14) 0.5512(19) 0.173(2) 0.042(8) Table 9. Hydrogen bond distances (Å) and angles (°) for 4ha. Donor- H Acceptor- H Donor- Acceptor Angle N1- H1A ... O8 0.91(3) 1.78(3) 2.550(3) 141.0 V References: (1) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244-9245. (2) (a) Zhang, L. Acc. Chem. Res. 2014, 47 , 877–888; (b) Qian, D.; Zhang, J. Chem. Soc. Rev. 2015, 44, 677-698. (3) Shu, X.-Z.; Shu, D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev. 2012, 41, 7698-7711. 274 (4) Kazem Shiroodi, R.; Gevorgyan, V. Chem. Soc. Rev. 2013, 42, 4991-5001. (5) Obradors, C.; Echavarren, A. M. Acc. Chem. Res. 2014, 47, 902–912 (6) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127- 2198; (b) Söderberg, B. C. G. Coord. Chem. Rev. 2006, 250, 300-387. (7) Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. J. Am. Chem. Soc. 2003, 125, 4692-4693. (8) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 3741-3744. (9) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244- 2266. (10) Nguyen, T. V.; Hartmann, J. M.; Enders, D. Synthesis 2013, 45, 845-873. (11) (a) Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323-2326; (b) Komagawa, S.; Takeuchi, K.; Sotome, I.; Azumaya, I.; Masu, H.; Yamasaki, R.; Saito, S. J. Org. Chem. 2009, 74, 3323-3329; (c) Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838-12839; (d) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O.; Ray, J. E. J. Org. Chem. 1994, 59, 6567-6587; (e) Trillo, B.; López, F.; Gulías, M.; Castedo, L.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2008, 47, 951-954; (f) Stark, C. B. W.; Pierau, S.; Wartchow, R.; Hoffmann, H. M. R. 2000, 6, 684-691; (g) Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc.1992, 114, 10978-10980; (h) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc.2009, 131, 6614-6617; (i) Krainz, T.; Chow, S.; Korica, N.; Bernhardt, P. V.; Boyle, G. M.; Parsons, P. G.; Davies, H. M. L.; Williams, C. M. Eur. J. Org. Chem. 2016, 2016, 41-44. (12) Eyring, H. J. Chem. Phys. 1935, 3, 107-115. (13) Lee, S. I.; Kim, K. E.; Hwang, G.-S.; Ryu, D. H. Org. Biomol. Chem. 2015, 13, 2745-2749. (14) Deng, Y.; Jing, C.; Doyle, M. P. Chem. Commun. 2015, 51, 12924-12927. 275 Chapter 5: Conclusions I. Diversity as a Function of Catalyst Divergent-oriented synthesis (DOS) is a strategy that emphasizes efficiency of chemical library synthesis of small molecules with complexity as well as skeletal diversity. Since both diazo compounds and alkynes can react with a wide array of transition metal complexes to form reactive transition metal complexes that are capable of undergoing further transformations, we asked the question “Is there diversity in product formation if both acetylenic and diazo functionalities are present in the same molecule?” To answer the question, we synthesized propargyl phenyldiazoacetates, which have a possibility to react with either functional group to form reactive transition metal complexes. Catalyst surveys under a variety of reaction conditions led to the discovery of the catalyst-directed divergent outcomes of propargylic diazoeacetates were discussed in Chapter 1. II. Intramolecular Electrophilic Addition Reaction of Diazo Ester with an Allene Under catalysis by neutral gold complexes, phenylpropargyl diazoacetates exist in equilibrium with 1-phenyl-1,2-dien-1-yl 276 diazoacetate allenes that are rapidly formed at room temperature through gold-catalyzed 1,3-acyloxy migration. Interestingly, these gold catalysts react solely with the π-donor rather than with the diazo group. The newly formed allene-aryldiazoacetates subsequently undergo a slow rearrangement that is not catalyzed by gold in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5- dihydro-4H-pyrazol-4-ones were found to undergo an intramolecular 1,3- acyl migration to form an equilibrium mixture or quantitatively transfer the acyl group to an external nucleophile with formation of 4- hydroxypyrazoles (Chapter 2). III. The Fisrt Discovery of Intramolecular [4+2]- Cycloaddition Between a 1,3-Diene and a Diazo Ester In the process of studying propargyl phenyldiazoacetate with a broad selection of gold catalysts under various conditions of temperature, solvents and additives, we found reactions using a 4-chloropyridine-N- oxide in stoichiometric amounts resulted in the formation of (Z)-diene and a product anticipated from diene-diazo [4+2]-cycloaddition. This led to the discovery of the first intramolecular. [4+2]-cycloaddition between 277 a 1,3-diene and a diazo ester. We successfully isolated the (E)-diene that was the presumed precursor to the cycloaddition product and studied the kinetic version of this reaction. Thermal reactions with the E-isomer form the product from [4+2]-cycloaddition with Eact = 16.2 kcal/mol, H ‡ 298 = 15.6 kcal/mol and S‡298 = -27.3 cal/ (mol•deg). The Z-isomer is inert to [4+2]-cycloaddition under these conditions; Hammett plots of this unique reaction were also created. In addition, to better understand this intramolecular [4+2]-cycloaddition reaction, we are collaborating with Professor Kenneth Houk’s group at UCLA from the viewpoint of computational chemistry, and the calculated results fit our observations very well (Chapter 3). IV. Intramolecular [3+2]-Cycloaddition with a Diazo with an Alkene and Subsequent Transformation Cascade reaction, a consecutive series of transformations occurred in one step, is noted for efficient construction of molecular complex, high atom economy and economies of time, labor, and resource management. Due to these benefits, discovery of novel cascade reactions has been in high demand as well as a challenging task of modern organic synthesis. Substrates with multiple functional groups are considered crucial and 278 fundamental to discovering cascade reactions. Inspired by gold-catalyzed [4+3]-cycloaddition of propargyl esters and unsaturated imines, we decided to use a modified propargyl system in which benzoate is replaced by phenyldiazoacetate that was expected to produce the azepine product that retained the phenyldiazoacetate functionality. Instead, a new and unexpected transformation occurred that reorganized the reactant atoms from the reactant ester to a diketone and rearranged the reactant atoms. To further understand this extensive process, we used the NMR spectroscopy to monitor the process. An intermediate, observed within 5 min that rapidly rearranged to diketone, was isolated by quenching the reaction after 5 min. Purified by silica gel chromatography, the isolated product was converted to the previously observed diketone at 80ºC in 90% yield without added catalyst. Furthermore, we carried out a series of kinetic studies with the isolated [4+3]-cycloaddition product for the subsequent transformation. The transformation was first order in with a rate constant kobs =3.6×10 −4 sec −1 at 61 °C in DCE. The variation of the rate constant over temperatures ranging from 61℃ to 75℃ provided Eact = 22.6 kcal/mol, H‡298 = 22.0 kcal/mol and S ‡ 298 = -9.21 cal/(mol•℃). This work was discussed in Chapter 4. V. Future Work 279 This work has demonstrated convincingly that the concept of “diversity as a function of catalyst” can be used in the discovery of novel transformations. The product diversity in a catalytic reaction and divergent reaction pathways could be achieved by the choice of catalysts. 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