Glasgow Theses Service http://theses.gla.ac.uk/ theses@gla.ac.uk Hewitt, Joanne F.M. (2014) Development of methodology for the palladium-catalysed synthesis of oxygen-containing heterocycles. PhD thesis. http://theses.gla.ac.uk/5096/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Development of Methodology for the Palladium-Catalysed Synthesis of Oxygen-Containing Heterocycles Joanne F. M. Hewitt (M. Sci) A thesis submitted in part fulfillment of the requirements of the degree of Doctor of Philosophy School of Chemistry College of Science and Engineering University of Glasgow April 2014 2 Abstract The opening chapter of this thesis gives an overview of the existing methods to functionalise palladium(II)-alkyl intermediates resulting from oxy- or carbopalladation of unactivated alkenes, outlining the range of heterocycles which can be formed using this type of methodology. A summary of Pd(IV) species in synthesis and catalysis follows, with a focus on Pd(IV) intermediates arising from oxidative addition of alkyl halides to Pd(II) and those suggested in alkene difunctionalisation reactions. As the subsequent formation of sp 3 –sp 3 C–C bonds from Pd(II)-alkyl intermediates was noted as a limitation of prevailing nucleopalladation methods, the second chapter of this thesis outlines the work towards development of an oxypalladation reaction of hydroxyalkenes, with concomitant formation of an sp 3 –sp 3 C–C bond. Allyl halides proved to be competent electrophiles for this transformation. The oxyallylation reaction was successfully applied to a range of hydroxyalkene substrates, with the methodology developed also applied to a 5-step synthesis of anti-depressant citalopram. The oxyallylation reaction constructs heterocycles substituted in the 2-position, forming two new bonds in a single step. Ensuing work, detailed in Chapter 3, focused on the development of an analogous carboallylation reaction, using aryl boronic acid derivatives. This transformation gives rise to the formation of two new C–C bonds in a single step, including the construction of a fully substituted carbon centre. Experimental procedures and data are summarised in Chapter 4. O NC N F Citalopram OH R 2 O R 2 Pd(hfacac) 2 (cat.) NaHCO 3 , toluene, 50 °C X R 1 R 1 >20 examples O Pd(hfacac) 2 (10 mol%), Na 2 CO 3 , DME, 50 °C, 20 h Cl BF 3 K O 3 Acknowledgements 5 Author’s Declaration 6 Abbreviations 7 1. Functionalisation of Alkenes: Synthesis of Oxygen Containing Heterocycles 10 1.1 Introduction 10 1.2 Oxypalladation of Alkenes 12 1.2.1 Wacker-Type Cyclisations 12 1.2.2 Difunctionalisation via Wacker-Type Cyclisations 14 1.3 Carbopalladation of Alkenes 23 1.3.1 Carbocyclisation−β-hydride Elimination 23 1.3.2 Carbocyclisation–C–X Bond Formation 25 1.3.3 Carbocyclisation–C–C Bond Formation 26 1.4 Pd(IV) Chemistry 29 1.4.1 Pd(IV) Species from Oxidative Addition of Alkyl Halides 30 1.4.2 Pd(IV) Species from Stoichiometric Oxidants 33 1.5 Summary 36 2. Synthetic Approaches Towards Heterocyclisation of Unactivated Alkenes 37 2.1 Introduction and Aims 37 2.1.1 Mechanistic Rationale 38 2.1.2 Substrate Design and Synthesis 38 2.2 Attempted Pd(II)−Pd(IV) Catalysed Heterocyclisation 39 2.2.1 Attempted Heterocyclisation Using Bromoalcohol 39 2.2.2 Attempted Heterocyclisation Using Benzylic Alcohol 43 2.2.3 Attempted Heterocyclisation Using Phenol 49 2.3 Oxyallylation of Unactivated Alkenes 58 2.3.1 Oxyallylation Reaction Development 58 2.3.2 Substrate Scope: Phenols 63 2.3.3 Substrate Scope: Alcohols 69 2.3.4 Reaction Limitations: Oxyallylation of Monosubstituted Alkenes 96 2.3.5 Reaction Limitations: Nitrogen-Containing Substrates 101 2.4 Synthesis of Citalopram 109 2.4.1 Selected Literature Syntheses of Citalopram and Escitalopram 109 2.4.2 Synthesis of Citalopram via an Oxyallylation Reaction 112 2.5 Oxyallylation Reaction Mechanism 115 2.6 Conclusions 120 4 2.7 Future Work 121 3. Synthetic Approaches Towards Carbocyclisation of Unactivated Alkenes 122 3.1 Introduction and Aims 122 3.2 Synthesis and Reactions of Boronic Acid 123 3.3 Synthesis and Reactions of Boronic Acid Derivatives 133 3.3.1 Synthesis of Boronic Acid Derivatives 133 3.3.2 Reactions of Boronic Acid Derivatives 135 3.4 Conclusions 140 3.5 Future Work 141 4. Experimental 142 4.1 General Experimental Information 142 4.2 Experimental Details 143 5. References 196 5 Acknowledgements I would like to extend my thanks to Dr. David France for giving me the opportunity to work in (and launch!) his research group and for all his advice and support over the course of my PhD. I am also grateful to my second supervisor, Dr. Andrew Sutherland, and Dr. Joëlle Prunet for their helpful thoughts and discussions on my research. I would like to express my gratitude to the department staff, academic, technical and administrative, for their support. Many thanks to the France boyz Lewis, Craig and David for their diligent thesis proof reading efforts. I’d also like to thank all the France, Prunet and Marquez group members, past and present, for some truly hilarious moments in the Raphael lab. Particular thanks to Helen, Toni, Pooja, Mhairi and Anna for great chat and keeping the testosterone levels in the lab slightly lower! Outwith the department: for cocktails, mocktails, Sunday runs and endless cups of tea, the experience wouldn’t have been quite the same without the witches Victoria, Leigh and Laura and running buddy Michael. Writing up wouldn’t have been half as entertaining without random chat, thesis avoidance and procrastination with Jonathan. For keeping me sane by getting me away from chemistry to explore Scotland and beyond through running, cycling and swimming (and eating good food and cake!), many thanks to Glasgow Triathlon Club, especially the tri girls Hannah, Lexy, Christine, Elizabeth, Caroline and Fiona. I am appreciative of the endless support and encouragement from my family: my Mum, sister Jennie, brother Iain and all the other Allan nutters. Financial support from the University of Glasgow, WestCHEM and EPSRC is gratefully acknowledged. Finally, I’d like to thank Douglas Adams for giving me the answer to the great question of life, the universe and everything. 6 Author’s Declaration This thesis represents the original work of Joanne Frances Mary Hewitt unless otherwise explicitly stated in the text. The research was carried out at the University of Glasgow in the Raphael Laboratory under the supervision of Dr. David France during the period of October 2010 to September 2013. Portions of the work described herein have been published elsewhere, as below: Hewitt, J. F. M.; Williams, L.; Aggarwal, P.; Smith, C. D.; France, D. J. Chem. Sci. 2013, 4, 3538–3543. 7 Abbreviations Å angstrom(s) Ac acetyl acac acetylacetonate aq. aqueous Ar aryl BBN borabicyclo[3.3.1]nonane bipy bipyridine Bn benzyl Boc tert-butoxycarbonyl BOXAX bis(oxazolyl)-binaphthyl br broad BRSM based on recovered starting material BSA bis(trimethylsilyl)acetamide Bu butyl Bz benzoyl °C degrees centigrade cat. catalytic CI chemical ionisation conc. concentration/concentrated COP cobaltocenyloxazoline palladacycle COSY correlation spectroscopy Cy cyclohexyl d doublet dba dibenzylideneacetone DCE dichloroethane DIBAL-H diisobutylaluminium hydride DIPEA diisopropyl ethyl amine dppf diphenylphosphorylferrocene dppp diphenylphosphorylpropane DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide dtbpy di-tert-butylpyridine er enantiomeric ratio EI electron impact equiv equivalents 8 ESI electrospray ionisation Et ethyl Et 2 O diethyl ether EtOAc ethyl acetate EWG electron withdrawing group FAB fast atom bombardment FTIR Fourier transform infrared spectroscopy g gram(s) h hour(s) hfacac hexafluoroacetylacetonate HMBC heteronuclear multiple bond correlation HPLC high performance liquid chromatography HRMS high resolution mass spectrometry HSQC heteronuclear single-quantum correlation Hz hertz IPA 2-propanol IR infrared J NMR spectra coupling constant L ligand LDA lithium diisopropylamide M molar m multiplet mdtbpy 4-methyl-2,6-di-tert-butylpyridine Me methyl MeCN acetonitrile MeOH methanol mg milligram(s) MHz megahertz MIDA methyliminodiacetic acid min minute(s) mL millilitre(s) mmHg millimetres mercury mmol millimole(s) mol mol(es) MOM methoxymethyl Ms methanesulfonyl MS molecular sieves m/z mass to charge ratio NMR nuclear magnetic resonance 9 NBS N-bromosuccinimide NMO N-methylmorpholine N-oxide NMP N-methylpyrrolidinone nOe nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Nu nucleophile PBQ p-benzoquinone PG protecting group Ph phenyl phen phenanthroline ppm parts per million iPr isopropyl py pyridine q quartet quant. quantitative s singlet sat. saturated SERT serotonin transporter SET single electron transfer sp sparteine SPRIX spiro bis(isoxazoline) SSRI selective serotonin reuptake inhibitor R f retention factor RT room temperature t triplet TBAF tetra-n-butylammonium fluoride TBDPS tert-butyldiphenylsilyl TBME tert-butyl methyl ether TEMPO 2,2,6,6-tetramethylpiperidinyloxy Temp temperature TFA trifluoroacetic acid THF tetrahydrofuran TIPS-EBX triisopropylsilyl ethynylbenziodoxolone TLC thin layer chromatography Tf trifluoromethanesulfonyl Ts 4-toluenesulfonyl µL microlitre(s) µw microwave % wt. percentage by weight [...]... oxyalkynylation of aliphatic alcohol 1.28 To summarise, the oxypalladation of alkenes to afford oxygen-containing heterocycles is a well-studied area of research that has seen a recent revitalisation of interest In addition to the development of asymmetric examples of Wacker-type cyclisations, the contributions of 23 the Wolfe and Waser groups has seen an expansion in the scope of the C–C bond formation... Wacker-type cyclisation of o-allyl phenol sodium salt 1.9 Hosokawa and co-workers subsequently reported that use of Pd(OAc)2 as the Pd(II) source allowed the phenols to be used directly (Scheme 1.4).17 In the cyclisation of disubstituted alkene 1.11, the authors observed that use of the acetate salt of palladium in place of the chloride salt resulted in the formation of a 1:1 mixture of the direct β-hydride... in xylenes During the reaction development, the authors found that use of a chelating bis(phosphine) ligand was essential to suppress competing reduction of the aryl halide.38 Another common side reaction was the formation of ethers from O-arylation or O–vinylation The formation of these side products was most problematic when primary alcohol substrates were employed, hence 1.62 was formed in only 32%... the product of direct palladium-catalysed carbonylation of the bromoalkene 1.128, β-hydride elimination from the carbopalladated intermediate to afford 1.129 could also occur The simple solution of increasing the pressure of CO used could not be employed as this could lead to direct trapping product 1.128 The authors reasoned that the use of an electron rich phosphine ligand should favour binding of. .. addition of an aryl or alkenyl halide to Pd(0), which can then undergo intramolecular carbopalladation The resulting Pd(II) intermediate can then be participate in a range of transformations to afford substituted heterocycles One of the remaining challenges in multi-component and multiple bond forming processes, highlighted in some of the carbocyclisations detailed herein, is controlling the sequence of. .. a stereoselective synthesis of the methyl ester of a glandular secretion from the civet cat 1.38 (Scheme 1.9).32 In addition to the synthesis of 1.38, the authors demonstrated that a range of substitution patterns could be tolerated in the substrate The formation of 6-membered rings was found to proceed in a highly stereoselective fashion, affording the products as a single diastereomer PdCl2 (10 mol%),... Heterocyclisation of 1.28 with construction of new sp –sp C–C bond 1.3 Carbopalladation of Alkenes In addition to facilitating the addition of oxygen nucleophiles to alkenes, as in the heterocyclisation reactions described in Section 1.2, palladium(II) can also facilitate the addition of carbon nucleophiles to alkenes However, the problem associated with the development of these reactions is the readiness... must often be used Many examples of carbocyclisation reactions give rise to the formation of all-carbon rings; however, this type of chemistry can also be used to access heterocycles via Pd(II)catalysed carbopalladation of alkenes containing a heteroatom tether 1.100 (Scheme 1.24) 46 The resulting Pd(II) species 1.101 can then undergo β-hydride elimination, or further functionalisation to afford heterocycles. .. d.r O CO2Me H 1.39 Scheme 1.9: Synthesis of the methyl ester of civet cat secretion 1.38 This oxycarbonylation methodology was employed by the Tietze group as a key step in the enantioselective total synthesis of (−)-diversonol 1.43 (Scheme 1.10) 33 Thus, treatment of phenol 1.40 with catalytic Pd(TFA)2 and (S,S)-Bn-boxax 1.41 under an atmosphere of CO in methanol afforded chroman product 1.42 in 80%... (Figure 1.1) To synthesise heterocycles such as those shown in Figure 1.1, in addition to acid catalysed cyclisations and ring closing metathesis,5 many of these ring systems are constructed via haloetherification of hydroxyalkenes of an appropriate chain length 6 Although haloetherifications result in the formation of a new C–X bond, which can be elaborated through standard C–C bond formation techniques, . Glasgow Theses Service http://theses.gla.ac.uk/ theses@gla.ac.uk Hewitt, Joanne F.M. (2014) Development of methodology for the palladium-catalysed synthesis of oxygen-containing heterocycles. . Development of Methodology for the Palladium-Catalysed Synthesis of Oxygen-Containing Heterocycles Joanne F. M. Hewitt (M. Sci) A thesis submitted in part fulfillment of the. cyclisation of disubstituted alkene 1.11, the authors observed that use of the acetate salt of palladium in place of the chloride salt resulted in the formation of a 1:1 mixture of the direct