Applications of Boronic Acids in Organic Synthesis A dissertation presented by Pavel Starkov in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY at UNIVERSITY COLLEGE LONDON Department of Chemistry Christopher Ingold Laboratories University College London 20 Gordon Street WC1H 0AJ London Declaration This dissertation is the result of my own work. Where information has been derived from other sources it has been clearly indicated so and acknowledged accordingly. /Pavel Starkov/ ii Abstract This thesis describes progress on the application of boronic acids and borate esters as catalysts and reagents in synthetic organic synthesis, focusing on two areas: one-pot enolate formation/aldol reactions and amide bond formation. Chapter 1 introduces the reader to boronic acids and derivatives thereof, their methods of preparation and their use in synthetic organic chemistry as reactants, reagents and catalysts. Chapter 2 covers current chemical methods and cellular alternatives for amide bond formation. Here, we also discuss our use of boron reagents for the activation of carboxylic acids as well as amides. Chapter 3 introduces a new concept in catalytic aldol reactions, i.e. an alternative strategy to access boron enolates in situ. The work covers successful demonstration of the feasibility of such an approach on an intramolecular system. A novel variation of aerobic Chan–Evans– Lam coupling, an intramolecular coupling of an aliphatic alcohol with a boronic acid using catalytic copper, is also introduced Chapter 4 builds on our observations on gold catalysis and especially that in relation to electrophilic halogenations. Chapter 5 contains full details of the experimental procedures. iii Contents Declaration ii Abstract iii Contents iv Abbreviations vi Acknowledgements vii 1 Boronic Acids in Organic Synthesis 1 1.1 Introduction 2 1.2 Preparation 5 1.2.1 Arylboronic Acids 5 1.2.2 Other Boronic Acids 10 1.3 Boronic Acids as Reactants 12 1.3.1 Transition Metal Catalysed Reactions 12 1.3.2 Chan–Evans–Lam Coupling 15 1.3.3 Converting Boronic Acids 18 1.4 Boronic Acids as Reagents and Catalysts 18 1.4.1 Activation of Carboxylic Acids 21 1.5 Summary 27 2 Development of Boron Based Reagents and Catalysts for 30 Activation of Carboxylic Acids and Amides 2.1 Amide Bond Formation: An Overview 31 2.1.1 Methods for Amide Bond Formation 33 2.1.1.2 Activation of Carboxylic Acids 34 2.1.1.3 Alternative Methods 37 2.1.1.4 Catalytic Methods 38 2.1.1.5 Emerging Methods 38 2.1.2 Amide Bond Formation in Nature 44 2.1.2.1 Ribosomal Peptide Bond Formation 46 2.1.2.2 Nonribosomal Peptide Synthetases 47 2.1.2.3 Acyl Transferases 48 2.1.2.4 Lipases 50 iv 2.2 Results and Discussion 53 2.2.1 Introduction 53 2.2.2 Aims and Objectives 55 2.2.3 Synthesis of Boronic Acids 57 2.2.3.1 Synthesis of (1-Hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic Acid 57 2.2.3.2 Synthesis of “Sulfur-Armed” Boronic Acid 63 2.2.4 Evaluation of Boronic Acids and Borates for Catalytic Amide Bond Formation 64 2.2.5 Borates as a Novel Class of Coupling Reagents for Amide Bond Formation 74 2.2.6 Tris(2,2,2-trifluoroethyl) Borate as a Reagent for the Activation of Primary Amides 78 2.2.7 Mechanistic Considerations 80 2.2.8 Conclusions and Outlook 82 3 Gold-Catalysed Boron Enolate Formation 87 3.1 Background 89 3.2 Aims and Objectives 95 3.3 Results and Discussions 97 3.3.1 Gold-Catalysed Boron Enolate Formation 97 3.3.2 One-Pot Boron Enolate Formation/Aldol Reaction 100 3.3.3 Elaboration of Aldol Products: Oxidation, Suzuki, and Chan–Evans–Lam 112 3.3.4 Miscellaneous 116 3.4 Summary and Outlook 118 4 Observations on the Role of Cationic Gold and Brønsted Acids in Electrophilic Halogenation 122 4.1 Results and Discussion 123 4.2 Summary and Outlook 133 5 Experimental 134 5.1 General 135 5.2 Procedures for Chapter 2 136 5.2.1 Synthesis of Boron and Silicone Based Reagents 136 5.2.2 Direct Carboxamidation 147 5.2.3 Transamidations of Primary Amides 154 v 5.3 Procedures for Chapter 3 156 5.3.1 Synthesis of ortho-Alkynylphenylboronic Acids 156 5.3.2 Boron Enolate Formation 161 5.3.3 One-Pot Boron Enolate Formation/Aldol Reaction 164 5.3.4 Aldol/Oxidation 165 5.3.5 Aldol/Suzuki–Miyaura Coupling 168 5.3.6 Aldol/Intramolecular Chan–Evans–Lam Coupling 170 5.3.7 Aldol/Protodeboronation 172 5.4 Procedures for Chapter 4 173 References 175 Appendix 196 vi Abbreviations General ACS American Chemical Society aq aqueous bp boiling point cat catalytic conc concentrated conv conversion DFT density functional theory DMG directed metalation group DoE design of experiments ee enantiomeric excess EI electron ionisation equiv equivalent ESI electrospray ionisation EWG electron withdrawing group h hour(s) HMBC heteronuclear multiple bond connectivity HMQC heteronuclear multiple quantum connectivity HRMS high resolution mass spectrometry IR infrared spectrometry J coupling constant LA Lewis acid lit literature value LUMO lowest unoccupied orbital m meta M+ parent molecular ion min minute(s) mp melting point MS mass spectrometry MS molecular sieves MW microwave NMR nuclear magnetic resonance vii NRPS nonribosomal peptide synthetase o ortho p para PNA peptide nucleic acid ppm part(s) per million ref reference rds rate determining step RT room temperature sat saturated tRNA transport ribonucleic acid quant quantitative UV ultraviolet Reagents, ligands and solvents acac acetylacetonate AIBN 2,2’-azobis(isobutyronitrile) BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. bmim 1-butyl-3-methylimidazolium BOP (benzotriazol-1-yloxy)tris(dimethylamino) hexafluorophosphate BPO benzoyl peroxide. BQ 1,4-benzoquinone CDI carbonyldiimidazole cod 1,5-cyclooctadiene CuMeSal copper(I) 3-methylsalicylate CuTC copper(I) thiophen-2-carboxylate CYC cyanuric chloride dba dibenzylideneacetone dtby di-tert-butylbipyridine DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCB o-dichlorobenzene DCM dichloromethane DHA dihydroxyacetone DHAP dihydroxyacetone phosphate DIC diisopropylcarbodiimide DIPEA N,N-diisopropylethylamine DMAD dimethyl acetylenedicarboxylate viii DMAP 4-(N,N-dimethylamino)pyridine DMSO dimethylsulfoxide DO dioxane dppe 1,1-bis(diphenylphosphino)ethane dppf 1,1'-bis(diphenylphosphino)ferrocene dppm 1,1-bis(diphenylphosphino)methane dppp 1,3-bis(diphenylphosphino)propane dtby di-tert-butylbipyridine DTNO di-tert-butyl nitroxide EDCl [3-(dimethylamino)propyl]ethylcarbodiimide hydrochloride HATU O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate HEH Hantzsch ester HOAt 1-hydroxy-7-azabenzo[d][1,2,3]triazole HOBt 1-hydroxybenzo[d][1,2,3]triazole HOI N-hydroxyindolin-2-one Im imidazole IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene iPP2BH di(isopropylprenyl)borane LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide lut lutidine MIDA N-methyliminodiacetic acid MCPBA m-chloroperoxybenzoic acid MTBE methyl tert-butyl ether PE petroleum ether (boiling range 60–80 °C) phen 1,10-phenanthroline PhMe toluene Pro proline PTSA p-toluenesulfonic acid PyBOP (benzotriazol-1-yloxy)tris(pyrrolidinophosphonium) hexafluorophosphate nbd norbornadiene NBP N-butyl-2-pyrrolidinone NBS N-bromosuccinimide NHC N-heterocyclic carbene NMO N-methylmorpholine-N-oxide NMP N-methyl-2-pyrrolidinone ix PFP pentafluorophenyl PNO pyridine N-oxide PNP p-nitrophenol SIPr N,N'-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol)-2-ylidene TCP 2,4,6-trichlorophenyl TBD 1,5,7- triazabicyclo[4.4.0]dec-5-ene TEA triethylamine TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl TFA trifluoroacetic acid THF tetrahydrofuran Substituents Ac acetyl All allyl An anisyl, 4-methoxyphenyl Ar aryl Bn benzyl Boc tert-butoxycarbonyl Bu n-butyl iBu isobutyl sBu sec-butyl tBu tert-butyl Bz benzoyl cat catecholate Cbz benzyloxycarbonyl Cp cyclopentadienyl Cy cyclohexyl Cyp cyclopentyl dan derivative of 1,8-diaminonaphthalene Et ethyl Fur furanyl Hal halide Me methyl Mes mesityl, 2,4,6-trimethylphenyl MOM methoxymethyl neop neopentandiolate OTf triflate x PFP pentafluorophenyl Ph phenyl pin pinacolato iPr isopropyl pza 2-pyrazol-5-ylanilinyl Sia siamyl, sec-isoamyl, TCP 2,4,5-trichlorophenyl Tf triflyl, trifluoromethanesulfonyl Tol tolyl Tr trityl, triphenylmethyl Ts tosyl, p-toluenesulfonyl xi Acknowledgements I would like to thank Dr Tom Sheppard, my PhD thesis supervisor, for his time, patience and extensive advice. Also, Dr Abil Aliev and Dr Lisa Harris for help with NMR and MS, respectively. I thank friends that from time to time have encouraged and/or questioned me, and were always there with at least a helpful suggestion or a glass of wine, a pint of beer or a shot: Mikk, Anton, Nadja, Uno, Cindy and Armando, Sonya, Olya, John, Lena, Selene, Albin, Boaz, Lynsey, Karina, Jon, Sasha, James, Victoria, Lizzie. Also, the guys in the Sheppard lab (Oz, Fil, Martin, Sam, Matt and the summer students) and the Motherwell group (Matt, Josie, Helen, Sandra, Chi, Yumi). Last and definitely not least, my family. Financial support from EPSRC (EP/E052789/1), Estonian Ministry of Education and Research and Archimedes Foundation is acknowledged. xii On päris kindel: jalge alla jääb sul tuge liiga vähe, kui sa kõik tõkked teelt ei talla ja mööda enesest ei lähe. Kui suur on korraga su isu! Hing, ära ohus karda hukku, vaid senisest end lahti kisu ja keera vanad uksed lukku! Sind ümbritsevad jäised tuuled, ööst kerkib tühi mägiahel. Sa aimad sügavust ja kuuled metsloomi kaljuseinte vahel. Kui sa nüüd minna julgeks! Sillaks su ees siis kuristikud kaanduks, hall kivi raskeid vilju pillaks ja kiskjad alandlikult taanduks. Betti Alver. "Ekstaas" xiii v Chapter 1 Chapter 1 1 Boronic Acids and Other Boron-Centred Reagents in Organic Synthesis 1.1 Introduction The first boronic acid, ethylboronic acid, was discovered back in 1860,[1] but it took a long time for boronic acids to become widely applied in either industrial or academic settings.