Synthetic and Mechanistic Investigations of Some Novel Organophosphorus Reagents Author Fairfull-Smith, Kathryn Elizabeth Published 2004 Thesis Type Thesis (PhD Doctorate) School School of Science DOI https://doi.org/10.25904/1912/3875 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/367534 Griffith Research Online https://research-repository.griffith.edu.au SYNTHETIC AND MECHANISTIC INVESTIGATIONS OF SOME NOVEL ORGANOPHOSPHORUS REAGENTS KATHRYN ELIZABETH FAIRFULL-SMITH (née ELSON) BSc (Hons) School of Science Faculty of Science Griffith University Submitted in fulfilment of the requirements of the Degree of Doctor of Philosophy May 2004 i Statement of Originality This work has not previously been submitted for a degree or diploma in any University. To the best of my knowledge and belief, this thesis contains no material previously published or written by another person except where due reference is made in the thesis itself. Kathryn Fairfull-Smith (née Elson) BSc (Hons) ii Preface Unless otherwise stated, the results in this thesis are those of the author. Parts of this work have appeared elsewhere. Refereed journal publications are submitted with the dissertation and are presented in Appendix Two. Refereed Journal Publications ‘The Hendrickson reagent and the Mitsunobu reaction : a mechanistic study’ Kathryn E. Elson, Ian D. Jenkins and Wendy A. Loughlin, Org. Biomol. Chem., 2003, 1, 2958-2965. ‘Cyclic analogues of the Hendrickson ‘POP’ reagent’ Kathryn E. Elson, Ian D. Jenkins and Wendy A. Loughlin, Aust. J. Chem., 2004, 57, 371-376. ‘Polymer-supported triphenylphosphine ditriflate : a novel dehydrating reagent’ Kathryn E. Elson, Ian D. Jenkins and Wendy A. Loughlin, Tetrahedron Lett., 2004, 45, 2491-2493. ‘Novel polymer-supported coupling/dehydrating reagents for use in organic synthesis’ Kathryn E. Fairfull-Smith (née Elson), Ian D. Jenkins and Wendy A. Loughlin, Org. Biomol. Chem., 2004, 2, 1979-1986. Conference Posters ‘Phosphonium Anhydrides as Alternative Mitsunobu Reagents: A Kinetic Study’ Kathryn E. Elson, Ian D. Jenkins and Wendy A. Loughlin, presented at the IUPAC International Chemistry Conference on Organic Synthesis, Christchurch, New Zealand, July, 2002. ‘Towards an Alternative Mitsunobu Protocol – Novel Cyclic Analogues of the Hendrickson ‘POP’ Reagent’ Kathryn E. Elson, Ian D. Jenkins and Wendy A. Loughlin, presented at the Brisbane Biological and Organic Chemistry Symposium, Brisbane, December, 2003. Conference Lectures ‘Mitsunobu Reactions without Azodicarboxylates? Use of the Hendrickson Reagent’ Kathryn E. Elson, presented at the RACI National Organic Chemistry Conference, Lorne, Victoria, July, 2003. iii Table of Contents Statement of Originality i Preface ii Table of Contents iii List of Figures vii List of Tables xii List of Abbreviations xv Acknowledgements xix Abstract xx Introduction 1 Preface 2 1.0 The Mitsunobu reaction 2 1.1 General overview 2 1.2 The mechanism of the Mitsunobu reaction 5 1.3 Modifications and alternative reagents in the Mitsunobu reaction 7 2.0 The Hendrickson reagent 15 2.1 General overview 15 2.2 Uses of the Hendrickson reagent 16 2.2.1 Reactions with carboxylic acids and O- and N-nucleophiles 16 2.2.2 Other reactions with carboxylic acids 18 2.2.3 Other substitutions 18 2.2.4 Eliminations 21 2.2.5 Reductions 22 2.3 Variations of the Hendrickson reagent 23 3.0 Solid-phase chemistry 24 iv 3.1 General overview 24 3.2 Solid-phase organic synthesis (SPOS) 25 3.3 Polymer-assisted solution-phase synthesis (PASP) 27 3.3.1 Polymeric reagents 29 3.3.1.1 Nucleophilic substitution reactions with anionic resins 30 3.3.1.2 Dehydrations reactions 30 3.3.1.3 Amide bond formation 31 3.3.2 Polymeric catalysts 34 3.3.3 Polymer-supported scavengers, quenching agents and recognition 34 elements 3.3.4 Multistep organic synthesis 37 3.4 Choice of polymer support 38 4.0 Aims and scope of thesis 40 Chapter One – Use of the Hendrickson reagent in an alternative 43 Mitsunobu protocol 1.0 Reactions of the Hendrickson reagent 27 with primary alcohols 44 2.0 Reactions of the Hendrickson reagent 27 with secondary alcohols 47 3.0 Removal of the triflate salts from reactions using the Hendrickson 55 reagent 27 4.0 Addition of diisopropylethylamine and tetrabutylammonium triflates 57 to the standard Mitsunobu reaction 5.0 Investigation of the influence of the menthyl leaving group on the 68 reaction outcome – elimination versus substitution 6.0 Esterification of secondary alcohols with retention using the 70 Hendrickson reagent 27 and an activating agent v 7.0 General conclusions 71 Chapter Two – Cyclic analogues of the Hendrickson reagent 73 1.0 Synthesis and characterisation of five-, six- and seven-membered 74 cyclic analogues 90-92 2.0 Use of the cyclic analogues 90-92 for ester and amide formation 85 3.0 Kinetic studies 87 4.0 General conclusions 92 Chapter Three – Acyclic analogues of the Hendrickson reagent 94 1.0 Tributylphosphonium anhydride triflate 120 95 2.0 Tricyclohexylphosphonium anhydride triflate 130 104 3.0 Triphenylphosphonium anhydride tetrafluoroborate 42 107 4.0 Diphenyl-2-pyridylphosphonium anhydride triflate 137 109 5.0 General conclusions 118 Chapter Four – Polymer-supported reagents 120 1.0 Polymer-supported five-membered cyclic analogue 56 121 2.0 Polymer-supported triphenylphosphine ditriflate 157 127 3.0 General conclusions 145 Chapter Five – Further considerations of the Mitsunobu and 147 Hendrickson reagents 1.0 Phosphitylation via the Hendrickson reagent 27 148 2.0 Methylenation of catechols using the Mitsunobu reaction 151 3.0 Alternatives to azodicarboxylates in the Mitsunobu reaction 154 vi 4.0 General conclusions 158 Chapter Six – Concluding comments 159 Experimental 165 General procedures 166 Chapter One 169 Chapter Two 188 Chapter Three 204 Chapter Four 228 Chapter Five 249 References 258 Appendix One 276 Data and calculations for kinetic study of 4-nitrobenzyl 4-nitrobenzoate 61 formation using 27, 90-92. Appendix Two 287 Publications vii List of Figures Introduction Figure 1. Various uses of polymer supports in organic synthesis. 28 Figure 2. The opportunities for solid-supported reagents in synthesis. 29 Chapter One Figure 3. The effect of equivalents of Hendrickson reagent 27 on yield (by 45 1H NMR) of 4-nitrobenzyl 4-nitrobenzoate 61. Figure 4. (–)-Menthyloxytriphenylphosphonium triflate 35, formed by 53 1 reaction of the Hendrickson reagent 27 with (–)-menthol in CD2Cl2. (a) H NMR spectrum (400 MHz) of signal due to H1 in 35. (b) 1H {31P} NMR spectrum (400 MHz) of signal due to H1 in 35. Figure 5. Mitsunobu reaction (PPh3, DIAD, (–)-menthol and 4-nitrobenzoic 59 acid in CD2Cl2) in the presence of diisopropylethylammonium triflate (1.0 equiv.). (a) 31P NMR spectrum (162 MHz) at 25oC following DIAD addition. (b) 31P NMR spectrum (162 MHz) at 25oC after standing at room temperature for 24 hours. Figure 6. Mitsunobu reaction (PPh3, DIAD, (–)-menthol and 4-nitrobenzoic 60 acid in CD2Cl2) in the presence of diisopropylethylammonium triflate (2.0 equiv.). (a) 31P NMR spectrum (162 MHz) at 25oC following DIAD addition. (b) 31P NMR spectrum (162 MHz) at 25oC after standing at room temperature for 24 hours. viii Figure 7. Mitsunobu reaction (PPh3, DIAD, (–)-menthol and 4-nitrobenzoic 62 31 acid in CD2Cl2) in the presence of n-Bu4NOTf (1.0 equiv.). (a) P NMR spectrum (162 MHz) at 25oC following DIAD addition. (b) 31P NMR spectrum (162 MHz) at 25oC after standing at room temperature for 24 hours. Figure 8. The effect of added n-Bu4NOTf on the outcome of the Mitsunobu 63 reaction between (–)-menthol and 4-nitrobenzoic acid. Menthenes 36 and 37 ( ), (–)-menthol (z), neomenthyl 4-nitrobenzoate 67 ({). Conditions: PPh3 (1.0 equiv.), DIAD (1.0 equiv.), (–)-menthol (0.85 equiv.), 4- nitrobenzoic acid (0.85 equiv.), n-Bu4NOTf (Figure 8(a) 0.0-2.0 equiv.; Figure 8(b) 0.0-0.2 equiv.) and DCM (8 mL); 24 hours at room temperature. Figure 9. 1H NMR spectra (400 MHz) of menthenes 36 and 37 formed by 67 (a) thermolysis of menthol diphenylphosphate ester20; (b) Mitsunobu reagents (Organic Syntheses conditions)16; (c) Hendrickson reagent 27 (Table 2, entry 3) and (d) Hendrickson reagent 27 (Table 2, entry 8). Chapter Two Figure 10. 31P NMR stack spectra (162 MHz) showing the addition of triflic 78 anhydride to a solution of 1,2-bis(diphenylphosphinyl)ethane 93 in CD2Cl2 at -80oC. Figure 11. 31P NMR spectrum (162 MHz) at -80oC of (a) five-membered 80 cyclic reagent 90 in CD2Cl2 and (b) following the addition of 4- chlorophenol (0.5 equiv.). ix Figure 12. The effect of solvent polarity on the rate of 4-nitrobenzyl 4- 88 nitrobenzoate 61 formation using the Hendrickson reagent 27. DCM/toluene 1:1 (□), DCM (●), DCM/CH3CN 1:1 (○). Reaction conditions: Hendrickson reagent 27 (1.0 equiv.), 4-nitrobenzyl alcohol (1.0 equiv.), 4-nitrobenzoic acid (5.0 equiv.), diisopropylethylamine (5.0 equiv.), solutions 0.013 M in 27, 0oC. Figure 13. A comparison of 4-nitrobenzyl 4-nitrobenzoate 61 formation 91 over time using reagents 27, 90-92 in DCM. Five-membered cyclic analogue 90 (○), Hendrickson reagent 27 (■), seven-membered cyclic analogue 92 (●), six-membered cyclic analogue 91 (□). Reaction conditions: reagents 27, 90-92 (1.0 equiv.), 4-nitrobenzyl alcohol (1.0 equiv.), 4-nitrobenzoic acid (5.0 equiv.), diisopropylethylamine (5.0 equiv.), solutions 0.013 M in reagent 27, 90, 91 or 92, 0oC. Chapter Three Figure 14. 1H NMR spectrum (400 MHz) of 97 benzylaminotributylphosphonium triflate 122. (a) benzyl CH2 at δ 4.12 ppm (c) benzyl CH2 at δ 4.12 ppm with phosphorus decoupling (b) NH at δ 5.76 ppm (d) NH at δ 5.76 ppm with phosphorus decoupling. Figure 15. (a) 13C NMR spectrum (100 MHz, δ 20.7-25.7 ppm) of (–)- 100 menthyloxytributylphosphonium triflate 123.