Synthesis and application of stereogenic nitrogen- containing ammonium salts as phase-transfer catalysts By Mark Jason Dutton A thesis submitted to The University of Birmingham For a degree of DOCTOR OF PHILOSOPHY School of Chemistry College of Engineering and Physical Sciences University of Birmingham August 2014 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract The chirality of nitrogen was at the forefront of chemistry over 110 years ago. Since then it has been widely under-acknowledged as a potential chirality source in organic synthesis. This thesis demonstrates the diastereoselective formation of stereogenic nitrogen-containing ammonium salts. Over 150 compounds were synthesised and employed as phase-transfer catalysts in order to assess the chiral-at-nitrogen influence on the outcome of two common phase-transfer-catalysed reactions. Several X-ray crystal structures of single diastereoisomer chiral-at-nitrogen ammonium salts were isolated as well as the synthesis of a library of secondary and tertiary amines. ii This thesis is dedicated to Tiernan Kerr Probably the bravest boy I know iii Abbreviations R/S Rectus/sinister 1st gen First-generation compounds 2nd gen Second-generation compounds 3D Three dimensional 3rd gen Third-generation compounds Acac Acetylacetone AIBN Azobisisobutyronitrile app apparent Ar Aryl Aux Auxiliary BINOL 1,1'-Bi-2-naphthol Bn Benzyl Bu / tBu Butyl/tert-butyl o C2 180 plane of symmetry around the z axis ca. circa Cbz carboxybenzyl CD Circular dichroism cf. Confer Cy Cyclohexyl d.r. Diastereomeric ratio DAS Diastereomeric ammonium salt DCE 1,2-Dichloroethane DCM Dichloromethane DiPAMP 1,2-Bis[(2-methoxyphenyl)(phenylphosphino)]ethane DMAP 4-Dimethylamino pyridine DMC Dimethyl carbonate viii DME Dimethyl ether DMF Dimethylformamide DNA Deoxyribonucleic acid e.g. For example e.r. Enantiomeric ratio ee Enantiomeric excess Et al. Et alia (and others) HBTU N, N, N ,N-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HOBt Hydroxybenzotriazole HPLC High pressure liquid chromatography IR Infra red Me Methyl MeCN Acetonitrile MS Mass spectrometry MTPACl α-Methoxytrifluoromethylphenylacetyl chloride NBS N-bromo succinimide NIR Nitrogen inversion barrier NMR Nuclear magnetic resonance nOe Nuclear overhauser effect nPr Propyl Ph Phenyl phen phenanthroline Pr Propyl PTC Phase-transfer catalyst rac Racemic SN2 Bi-molecular nucleophilic substitution TBAB Tetra butyl ammonium bromide TBAF Tetra butyl ammonium fluoride ix TEA Triethylamine Tf Trifluoromethanesulfonyl THF Tetrahydrofuran TLC Thin layer chromatography TS Transition state VT Variable temperature w/w Weight/weight x Contents 1 Introduction ........................................................................................................................... 3 1.1 Stereogenic nitrogen ........................................................................................................ 3 1.1.1 Introduction to heteroatom-centred chirality ............................................................... 3 1.1.2 Pyramidal nitrogen containing molecules ................................................................... 7 1.1.3 Tetrahedral nitrogen .................................................................................................. 19 1.1.4 Applications of nitrogen chirality .............................................................................. 31 1.2 Previous work ................................................................................................................ 42 2 Aims ...................................................................................................................................... 46 3 Results and Discussion ........................................................................................................ 47 3.1 Enzymatic resolution ..................................................................................................... 47 3.2 First-generation ammonium salts .................................................................................. 50 st 3.2.1 Separation of 1 Gen DAS ........................................................................................ 57 3.3 Second generation ammonium salts .............................................................................. 59 3.3.1 Work towards chiral-only-at-nitrogen ammonium salts ............................................ 63 3.4 Third generation ammonium salts ................................................................................. 68 3.5 Application of stereogenic nitrogen in PTC .................................................................. 92 3.5.1 Alkylation of glycine Schiff base .............................................................................. 97 3.5.2 Epoxidation of chalcone .......................................................................................... 100 4 Conclusions ........................................................................................................................ 103 4.1 Summary ...................................................................................................................... 103 4.2 Conclusions ................................................................................................................. 104 5 Future Work ...................................................................................................................... 107 6 Experimental ..................................................................................................................... 108 6.1 General......................................................................................................................... 108 6.2 General Experimental procedures ............................................................................... 110 6.3 Determination of d.r. for ammonium salts .................................................................. 111 st 6.4 1 generation experimental .......................................................................................... 120 nd 6.5 2 Generation experimental ........................................................................................ 129 rd 6.6 3 Generation experimental ........................................................................................ 139 7 Appendices ......................................................................................................................... 212 1 st 7.1 Representative H NMR of 1 gen ammonium salts ................................................... 212 7.2 X-ray crystal structure data tables ............................................................................... 215 7.2.1 Compound 160f ....................................................................................................... 215 7.2.2 Compound 182 (NS) ................................................................................................. 217 1 7.2.3 Compound 208f (NR) ............................................................................................... 219 7.2.4 Compound 177l ....................................................................................................... 221 7.2.5 Compound 212e (NS) ............................................................................................... 223 7.2.6 Compound 216b (NR) .............................................................................................. 225 8 References .......................................................................................................................... 227 2 1 Introduction 1.1 Stereogenic nitrogen 1.1.1 Introduction to heteroatom-centred chirality In 1902 Pope addressed an audience of his peers, his first sentence was: “The subject on which I want to say a few words this evening must, I venture to think, ever be regarded as one of the most remarkable developments recorded in the history of science of modern chemistry.”1 Of course this was the description of the asymmetric carbon atom. With the newly established technique of polarimetry, it had become far simpler to identify optically active compounds. In paying homage to such distinguished luminaries of the chemistry world, such as Pasteur and Van’t Hoff, the discussion began considering the properties of light. In essence, a short tutorial on the working of polarimetry and then how this tool provided insight into enantiomorphism and proof for the resolution of saccharides and other asymmetric carbon atom-containing molecules. Pope concluded efforts towards resolving tetravalent sulfur and tin compounds, before encroaching onto the quinquilevance of nitrogen, namely ammonium iodides (Figure 1).2 Figure 1 Pope successfully resolved stereogenic-at-nitrogen ammonium salts in 1899 What was Pope’s area of expertise, having been the first to achieve resolution of a quaternary nitrogen stereogenic centre (where the only asymmetric component in the molecule was nitrogen) by fractional recrystallisation