Modular Synthesis of Chiral -Aminophosphine P,N- Ligands and Their Applications in Asymmetric Catalysis by Yixiong Song A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Chemistry University of Toronto © Copyright by Yixiong Song 2015 Modular Synthesis of Chiral -Aminophosphine P,N-Ligands and Their Applications in Asymmetric Catalysis Yixiong Song Master of Science Graduate Department of Chemistry University of Toronto 2015 Abstract A series of chiral -aminophosphine ligands bearing different carbon backbones and electronically differentiated diarylphosphino groups were prepared using a modular approach. These P,N-ligands were found to induce a modest level of enantioselectivities in the Pd- catalyzed asymmetric decarboxylative allylation reaction. Thiourea-phosphine bifunctional catalysts derived from the chiral -aminophosphine building blocks were prepared and applied to the asymmetric Morita-Baylis-Hillman (MBH) reaction of methyl acrylate and 4- nitrobenzaldehyde. The electronically unmodified diarylphosphino-thiourea was found to be optimal for achieving high activity and enantioselectivity in this particular MBH reaction. We also reported the synthesis of a P-chiral C2-symmetric bisphosphine ligand. However, the utility of this Trost-type ligand remains to be explored in the future. ii Acknowledgments iii Table of Contents Chapter 1. Modular Synthesis of -Aminophosphine P,N-Ligands and Their Applications in the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ..................................... 1 1 Introduction ..................................................................................................................... 1 1.1 Overview of P,N-ligands in Asymmetric Catalysis .............................................. 1 1.2 Decarboxylative Allylation Reaction .................................................................10 2 Objectives .......................................................................................................................18 3 Results and Discussion ....................................................................................................19 3.1 Synthesis of -Substituted -Aminophosphines and Their appplications in the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ........................19 3.2 Attempted Synthesis of -Disubstituted -Aminophosphines ...........................26 3.3 Attempted C–H Activation of (R)-2-Phenylglycinol ............................................31 4 Experimental ...................................................................................................................36 4.1 Procedures and Compounds................................................................................36 4.1 1H NMR, 13C NMR and 31P NMR Spectra ..........................................................53 Chapter 2. Synthesis of Bifunctional Thiourea-Phosphine Organocatalysts and Their Applications in the Asymmetric Morita-Baylis-Hillman (MBH) Reaction ............................83 1 Introduction ....................................................................................................................83 1.1 Mechanism of the MBH Reaction ......................................................................83 1.2 The Asymmetric MBH Reaction........................................................................87 1.3 The Asymmetric aza-MBH Reaction ..................................................................91 1.4 Asymmetric Transformations Related to the MBH Reaction ................................95 2 Objectives .......................................................................................................................98 3 Results and Discussion ....................................................................................................98 4 Conclusion and Future Work ......................................................................................... 105 iv 5 Experimental ................................................................................................................. 106 5.1 Procedures and Compounds.............................................................................. 106 1 13 31 5.2 H NMR, C NMR and P NMR Spectra ........................................................ 116 5.3 X-Ray Crystallography Data ............................................................................ 139 v List of Abbreviations (m) Medium (s) Strong (w) Weak °C Degrees Celsius Ac Acetate acac Acetylacetone Ar Aryl Boc tert-Butyloxycarbonyl Bn Benzyl Bz Benzoyl cod 1,5-Cyclooctadiene DART Direct Analysis in Real Time dba Dibenzylideneacetone DCC Dicyclohexylcarbodiimide DMAP 4-Dimethylaminopyridine DMF Diastereomeric ratio ee Enantiomeric excess er Enantiomeric ratio eq. Equivalent ESI Electro-spray ionisation Et Ethyl EWG Electron withdrawing group g Grams HRMS High resolution mass spectrometry i-Pr iso-Propyl IR Infra red L Ligand Leu Leucine M Molar m- meta m/z Mass/charge ratio Me Methyl MeCN Acetonitrile mg Milligrams MHz Mega hertz min. Minutes mL Milliliters n-Bu normal-Butyl nbd Norbornadiene NMR Nuclear magnetic resonance Nu Nucleophile o- ortho p- para PMP para-methoxyphenyl vi TBAB Tetrabutylammonium bromide TBAB Tetrabutylammonium chloride TBS tert-Butyldimethylsilyl t-Bu tert-Butyl Tf Triflate THF Tetrahydrofuran Ts Tosyl v/v Volume per volume vii List of Tables Table 1. Scope for secondary phosphine oxides .......................................................................24 Table 2. Scope for -substituted--aminophosphine oxides .....................................................24 Table 3. Scope for -substituted--aminophosphines...............................................................25 Table 4. Screening of P,N-ligands for decarboxylative allylic alkylation ..................................26 Table 5. Decomposition products isolated in the reduction of aminophosphine oxide ...............30 Table 6. Scope for thiourea-phosphine catalysts ......................................................................98 Table 7. Screening of bifunctional catalysts in the MBH reaction ............................................98 Table 8. Screening of P-chiral bifunctional catalysts in the MBH reaction ............................. 102 Table 9. Screening of P-chiral C2-symmetrical bisphosphine ligand in Pd-catalyzed AAA reaction ................................................................................................................................ 103 viii List of Figures Figure 1. X-ray crystal data Pd -allyl complex ....................................................................... 2 Figure 2. The exo-endo equilibrium of the Pd-allyl complex ..................................................... 3 Figure 3. 31P NMR spectra of ring-opening reaction using KOtBu and NaOtBu .......................23 Figure 4. X-ray crystal structure of thiourea-phosphine-borane 2.28a .................................... 100 ix List of Schemes Scheme 1. Asymmetric allylic substitution reactions of 1,3-dialkylallyl acetates using PHOX ligand ...................................................................................................................................... 2 Scheme 2. Asymmetric allylic substitution of 1,3-dimethylallyl acetate with dimethyl malonate 4 Scheme 3. Asymmetric allylic substitution of cyclic substrates with dimethyl malonate............. 4 Scheme 4. Intermolecular asymmetric Heck reaction using PHOX and BINAP ligands ............. 5 Scheme 5. Ir-catalyzed asymmetric hydrogenation of non-functionalized olefins ....................... 5 Scheme 6. Asymmetric hydroboration-oxidation of arylalkenes using Rh-QUINAP .................. 5 Scheme 7. Asymmetric diboration-oxidation of olefins using Rh-QUINAP ............................... 6 Scheme 8. Asymmetric three component condensation employing QUINAP and its analog ....... 6 Scheme 9. Asymmetric Kumada coupling reaction using -aminophosphine ............................. 7 Scheme 10. Cu-catalyzed conjugated addition of diethylzinc to enones using iminophosphine ... 8 Scheme 11. Ru-catalyzed asymmetric tandem Michael addition/hydrogenation of cyclic enone . 8 Scheme 12. Fe-catalyzed hydrogenation of esters and N-heterocycles ....................................... 9 Scheme 13. Fe-catalyzed asymmetric hydrogenation of ketones and activated imines ................ 9 Scheme 14. The Tsuji reaction ................................................................................................10 Scheme 15. Proposed catalytic cycle of the decarboxylative allylic alkylation of allyl enol carbonates and allyl β-keto esters ............................................................................................11 Scheme 16. The initial report of enantioselective Tsuji reaction using Trost P,P-ligand and PHOX P,N-ligand ...................................................................................................................11 Scheme 17. Asymmetric decarboxylative allylic alkylation using Trost ligands ........................12 Scheme 18. Asymmetric decarboxylative allylic alkylation using PHOX 1.4 and 1.16 ..............13 x Scheme 19. Synthesis of chiral -fluoroketones through decarboxylative allylic alkylation ......14 Scheme 20. Enantioselective decarboxylative enolate alkylation cascade .................................14 Scheme 21. Ir-catalyzed allylic alkylation of -substituted β-ketoesters ...................................15