CARBON–CARBON AND CARBON–HETEROATOM BOND FORMATION THROUGH C–H BOND FUNCTIONALIZATION A Dissertation Presented to the Faculty of the Department of Chemistry University of Houston In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy By Thanh V Truong August 2013 CARBON–CARBON AND CARBON–HETEROATOM BOND FORMATION THROUGH C–H BOND FUNCTIONALIZATION Thanh V. Truong APPROVED: Dr. Olafs Daugulis, Chairman Dr. Ognjen Miljanic Dr.
Zachary Ball Dr. Randolph Thummel Dr. Ding-Shyue Yang Dean, College of Natural Sciences and Mathematics ii ACKNOWLEDGMENTS I would like to thank: Advisor Prof. Olafs Daugulis Committee Members Prof.
Randolph Thummel Prof. Ognjen Miljanic Prof. Zachary Ball Prof. Ding-Shyue Yang All former and present Daugulis group members NMR Manager Dr.
Charles Anderson X-Ray Facilities Manager Dr. James Korp iii CARBON–CARBON AND CARBON–HETEROATOM BOND FORMATION THROUGH C–H BOND FUNCTIONALIZATION An Abstract of a Dissertation Presented to the Faculty of the Department of Chemistry University of Houston In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy By Truong V Thanh August 2013 iv ABSTRACT Direct C–H bond functionalization provides an efficient route by allowing the construction of C – C bonds directly from C–H bonds. In this dissertation, methods using first-row transition metals as catalysts for C–H bond functionalization have been developed. Furthermore, protocols for direct arylation via benzyne intermediates have been demonstrated.
A number of first-row transition metal salts such as nickel, cobalt, and manganese chlorides have been shown to catalyze deprotonative dimerization of acidic arenes. Five- or six-membered ring heterocycles as well as electron-poor arenes can be dimerized under oxygen atmosphere when tetramethylpiperidine or dicyclohexylamide bases are employed. An auxiliary-assisted, copper-catalyzed fluorination of benzoic derivative β-C-H bonds has been developed. The method employs silver(I) fluoride as fluorinating reagent, copper(I) iodide catalyst, and N-methylmorpholine oxidant.
By optimizing conditions, mono- or di-fluorination can be achieved selectively. The method provides an efficient alternative for preparation of aryl fluorides. An efficient method for base-promoted direct C-arylation of arenes such as heterocycles, alkynes, phenols, and anilines has been demonstrated. Under basic conditions, a variety of arenes can be arylated by aryl halides and aryl triflates.
A variety of functional groups, such as alkene, ether, dimethylamino, trifluoromethyl, ester, cyano, halide, hydroxyl, ketone, and silyl are tolerated. The reactions are carried out at mild temperatures and proceed via aryne intermediates. In addition, a general method for v trapping aryl lithium intermediates with various electrophiles has been described. Furthermore, new reaction between phenols and aryl halides forming helicenes has been discovered.
vi TABLE OF CONTENTS ACKNOWLEDGMENTS iii ABSTRACT v TABLE OF CONTENTS vii LIST OF ABBREVIATIONS xii LIST OF SCHEMES xiv LIST OF FIGURES xix LIST OF TABLES xx LIST OF RELATED PUBLICATIONS xxii Chapter 1 Biaryl Formation Via Oxidative Homocoupling Reactions 1 1. Transition-metal Catalysis 2 1. Homocoupling of Arenes 2 1. Homocoupling of Aryl Metals 2 1.2 Oxidative Homocoupling of Phenol and Aniline Derivatives 8 1.3 Oxidative Homocoupling of Arenes 11 1.
Nickel, Cobalt, and Manganese-catalyzed Deprotonative Arene Dimerization 15 1. Results and Discussion 16 1. Nickel Catalysis 16 vii 1. Experimental Section 23 References 37 Chapter 2 Transition-Metal-Catalyzed Sp2 C-F Bond Formation 41 2.
Sp2 C-F Bond Formation 42 2. Aryl Fluoride Formation from Aryl Metals 43 2.3 Aryl Fluoride Formation from Aryl Halides and Aryl Triflates 50 2. Direct Aryl Fluoride Formation from Arenes 54 2. Copper-catalyzed Direct Fluorination of Sp2 C-H Bonds 58 2.
Results and Discussion 59 2. Experimental Section 65 References 94 Chapter 3 Direct Arylation of C-H Bonds via Aryne Intermediates 96 Introduction 97 viii Chapter 3-1. Direct Arylation of Acidic sp2 C-H Bonds via Benzyne Intermediates 98 3. Transition-metal-catalyzed Arylation of Acidic sp2 C-H Bonds 98 3.
Arylation via Aryne Intermediates 100 3. Other Procedures for Transition-metal-free Biaryl Formation 104 3. Direct Arylation of Acidic sp2 C-H Bonds via Benzyne Intermediates 108 3. Results and Discussion 108 3.
Experimental Section 115 References 133 Chapter 3-2. Direct Arylation of Terminal Alkynes via Benzyne Intermediates 136 3. Transition-metal-catalyzed Arylation of Terminal Alkynes 136 3. Alkynylation via Arynes 137 3.
Direct Arylation of Terminal Alkynes via Benzyne Intermediates 139 3. Results and Discussion 139 3. Mechanistic Studies 145 ix 3.5 Experimental Section 148 References 169 Chapter 3-3. Arylation of Acidic sp2 C-H Bonds Followed by Trapping of Aryllithium Intermediates 172 3.Results and Discussion 175 3.
Expansion of Reaction Scope for Arylation of Arenes 176 3. Arylation of Heteroarenes 179 3. (Hetero)Arene Arylation with Subsequent Aryl Lithium Intermediate Trapping 182 3. Experimental Section 192 References 231 Chapter 3-4.
ortho-Arylation of Phenols and Anilines via Benzyne Intermediates 235 3. Transition-metal-catalyzed C-Arylation of Phenols and Anilines 235 3. Transition-metal-free ortho-Arylation of Anilines 240 3. Results and Discussion 241 x 3.
Reactions of Arynes with Phenols: Formation of 2- Arylphenols and Helicenes 250 3. Results and Disscussion 250 3. Transition-metal-free ortho-Arylation of Anilines 262 3. Reactions Between Arynes and Phenols: 2-Arylphenols and Helicenes Synthesis 291 References 323 xi LIST OF ABBREVIATIONS Ac acetyl acac acetylacetone Alk alkyl Ar aryl Bn benzyl Bu butyl Bz benzoyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.0]undec-7-ene DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMA dimethylacetamide DMF dimethylformamide DMSO dimethyl sulfoxide ee enantiomeric excess Et ethyl L ligand Me methyl M metal NMR nuclear magnetic resonance OTf triflate Ph phenyl xii Phen phenanthroline Piv pivaloyl TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl BINAPH 1,1′-binaphthyl-2,2′-diamine BINOL 1,1'-bi-2-naphthol TBAF tetra-n-butylammonium fluoride mCPBA meta-chloroperoxybenzoic acid PET positron emission tomography NMO N-methylporpholine oxide Pr propyl THF tetrahydrofuran Et2O diethyl ether TMEDA N,N,N’,N’-tetramethylethylenediamine Ts tosyl RT room temperature N-FTPT N-fluoro-2,4,6-trimethylpyridinium triflate TMPH 2,2,6,6-tetramethylpiperidine LDA lithium diisopropyl amide Cy2NLi lithium dicyclohexyl amide xiii LIST OF SCHEMES Scheme 1.
Biphenyl formation by irradiation of aryl lithium 3 Scheme 1. Biaryl formation via organogold species 3 Scheme 1. Homocoupling of aryl boronic acids under palladium catalysis 4 Scheme 1. Copper-catalyzed homocoupling of organosilicon compounds 4 Scheme 1.
Iron-catalyzed dimerization of aryl Grignards 5 Scheme 1. Iron-catalyzed homocoupling of aryl Grignard 5 Scheme 1. Homocoupling using atmospheric oxygen as oxidant 6 Scheme 1. Tentative mechanism for Mn-catalyzed dimerization under oxygen 7 Scheme 1.
Homocoupling under cobalt catalysis 7 Scheme 1. Dimerization of aryl Grignard with TEMPO catalyst under oxygen 8 Scheme 1. Mn-mediated phenol dimerization 9 Scheme 1. Copper-mediated dimerization of phenols and anilines 9 Scheme 1.
Dimerization of 2-naphtholate under copper catalysis 10 Scheme 1. Copper-catalyzed dimerization of phenols under oxygen 10 Scheme 1. Iron-catalyzed homocoupling of naphthols using m-CPBA oxidant 11 Scheme 1. Alumina supported-copper catalyzed dimerization of phenols 11 Scheme 1.
Palladium-catalyzed homocoupling of arenes under aerobic oxidation 12 Scheme 1. Dimerization of arenes under gold catalysis 13 Scheme 1. Unsymmetric homocouplings of indoles using palladium catalyst 13 xiv Scheme 1. Proposed mechanisms for oxidative dimerization of 2- phenylpyridine 14 Scheme 1.
Ruthemium-catalyzed, directing group assisted dimerization of arenes 15 Scheme 1. Copper-catalyzed dimerization of acidic arenes 16 Scheme 1. Formation of phenol byproducts in dimerization 17 Scheme 1. Base sythesis 17 Scheme 1.
Control experiments 22 Scheme 2. Traditional routes to aryl fluorides 42 Scheme 2. Ar-F reductive elimination from Pd complexes with bulky ligands 43 Scheme 2. Fluorination of boronic acids via palladium complexes 44 Scheme 2.
Silver-mediated electrophilic fluorination of aryl stannanes 45 Scheme 2. Silver-mediated fluorination of aryl boronic acids 45 Scheme 2. Transmetalation from boron to silver during reaction 46 Scheme 2. Silver-mediated fluorination of aryl silanes 46 Scheme 2.
Synthesis of Ni(II) aryl complexes and their reactivity toward fluorination 47 Scheme 2. Copper-mediated fluorination of aryl stannanes and aryl trifluoborates 48 Scheme 2. Copper-mediated fluorination of arylboronate esters 49 Scheme 2. Proposed mechanism for the fluorination of ArBPin with (tBuCN)2CuOTf 49 xv Scheme 2.
Pd-catalyzed fluorination of aryl triflates 51 Scheme 2. Fluorination of an aryl bromide via benzyne intermediate 51 Scheme 2. Deoxyfluorination of phenols 52 Scheme 2. Catalytic fluorination of macrocyclic Ar-X (X = Cl, Br) 53 Scheme 2.
Copper-mediated fluorination of aryl iodides 53 Scheme 2. ortho-Lithiation/fluorination of arenes 54 Scheme 2. Fluorobenzene formation via copper (II) fluoride 55 Scheme 2. Pd-catalyzed fluorination of 2-phenylpyridine derivatives 56 Scheme 2.
Pd-catalyzed ortho-fluorination of benzylamine derivatives 57 Scheme 2. Pd-catalyzed fluorination of 8-methylquinoline derivatives 57 Scheme 2. Copper-catalyzed sulfenylation and amination of sp2 C-H bonds 59 Scheme 2. Removal of directing group 64 Scheme 3.
Formation of higher oligomers of thiophene 98 Scheme 3. Phenylation of 1,3-dinitrobenzene 99 Scheme 3. Palladium-catalyzed arylation of heterocycles 99 Scheme 3. Copper-catalyzed arylation of acidic arenes 100 Scheme 3.
C-Arylation of 2-methylquinoline and fluorene 101 Scheme 3. Carbon arylation of enamine 101 Scheme 3. Reaction of benzyne and indoles 102 Scheme 3. Reaction of aryne and pyridine-N-oxide 102 Scheme 3.
Formation of p-terphenyl derivatives via benzyne intermediates 103 xvi Scheme 3. 2-Bromo-2′-iodobiphenyl formation from 1-bromo-2- iodobenzene 104 Scheme 3. Reactions of arynes with N-alkylimidazoles 104 Scheme 3. Oxidative cross-coupling using PhI(OH)OTs oxidant 105 Scheme 3.
tBuOK-promoted arylation of N-heterocycles 106 Scheme 3. Biaryl formation via organocatalysis 106 Scheme 3. Photo-induced arylation 107 Scheme 3. Involment of benzyne intermediates in copper-catalyzed arylation 109 Scheme 3.
Sequential diarylation of N-methylimidazole 114 Scheme 3. Sonogashira reactions 136 Scheme 3. Aryne alkynylation using aryl bromides in KNH2/NH3 137 Scheme 3. Polyalkynylation and polyalkenylation via benzyne 138 Scheme 3.
Deuteration Experiments 145 Scheme 3. Metalation-Benzyne Formation Sequence 147 Scheme 3. Mechanism of base-promoted arylation of heterocycle and arene C-H bonds 173 Scheme 3. Reactions of o-bromoiodoarenes with arylmagnesium bromide followed by iodine quenching 173 Scheme 3.
(Dialkylphosphino)biphenyl ligand synthesis via benzynes 174 Scheme 3. Aryne in total synthesis of clavilactone B 174 xvii Scheme 3. Addition of magnesium amide to aryne and trapping of intermediates 175 Scheme 3. Buchwald’s Sphos ligand synthesis via one-pot reaction 188 Scheme 3.
Reactions of heterocyclic arynes 191 Scheme 3. Miura’s ortho-arylation of phenol derivatives 235 Scheme 3. ortho-Arylation of 2-substituted phenols 235 Scheme 3. C-Arylation of phenol esters and carbamates 236 Scheme 3.
Phenol and aniline ortho-arylation with silicon-base tether directing groups 237 Scheme 3. Copper-catalyzed para-arylation of phenols and anilines 238 Scheme 3. Palladium-catalyzed ortho-arylation of anilides 239 Scheme 3. Ti-catalyzed C-arylation of unprotected anilines 239 Scheme 3.
Formation of o-phenylaniline 241 Scheme 3. o-Phenylation of enantiopure binaphthyldiamine 249 Scheme 3. Hexahelicene synthesis 254 Scheme 3. Reaction intermediates 255 Scheme 3.
Reaction mechanism 256 Scheme 3. Direct C-arylation of binols 260 xviii LIST OF FIGURES Figure 3. ORTEP view of 6a-phenyl-6a-hydro-12b- methoxybenzophenanthrene 322 xix LIST OF TABLES Table 1. Dimerization under Nickel Catalysis 18 Table 1.
Dimerization under Cobalt Catalysis 19 Table 1. Dimerization under Manganese Catalysis 21 Table 2. Optimization of Reaction Conditions 59 Table 2. Monofluorination Reaction Scope 61 Table 2.
Difluorination of Carboxylic Acid Derivatives 63 Table 3. Arylation Scope with Respect to Aryl Halides 110 Table 3. Arylation Scope with Respect to Heterocycles and Arenes 112 Table 3. Alkynylation Scope with Respect to Aryl Chlorides 140 Table 3.
Alkynylation Scope with Respect to Alkynes 142 Table 3. Optimization of Benzyne Formation 176 Table 3. Arylation Scope with Respect to Arenes 177 Table 3. Arylation Scope with Respect to Heterocycles 180 Table 3.
Trapping of Intermediate Reaction Optimization 182 Table 3. Use of Various Electrophiles 184 Table 3. Arylation of (Hetero)Arenes and Trapping of Aryllithium Intermediates 185 Table 3. Intermediate Trapping with Copper Salts and Further Transformations 188 Table 3.
Optimization of Reaction Conditions 242 xx Table 3. Arylation of 2-Naphthylamine 244 Table 3. Arylamine Phenylation 247 Table 3. Optimization of Reaction Conditions 251 Table 3.
Helicene Synthesis 252 Table 3. Optimization of Phenol Arylation 257 Table 3. Phenol Arylation 258 Table 3. Reaction Optimization in Details 294 Table 3.
Optimization of Phenol o-Arylation 307 xxi LIST OF RELATED PUBLICATIONS 1. “Nickel, Manganese, Cobalt and Iron-Catalyzed Deprotonative Arene Dimerization” Org. “Base-Mediated Intermolecular sp2 C−H Bond Arylation via Benzyne Intermediates” J. ‘‘Transition-Metal-Free Alkynylation of Aryl Chlorides’’ Org.
‘‘Directed Functionalization of C-H Bonds: Now also meta Selective’’Angew.‘‘Divergent Reaction Pathway for Phenol Arylation by Arynes: Synthesis of Helicenes and 2-Arylphenols’’Chem. ‘‘Direct Intermolecular Aniline Ortho-Arylation via Benzyne Intermediates’’ Org. ‘‘Copper-Catalyzed, Directing Group- Assisted Fluorination of Arene and Heteroarene C-H Bonds’’ J. xxii Chapter 1 Biaryl Formation Via Oxidative Homocoupling Reactions 1 1.
Transition-metal Catalysis 1.