This work has been aimed to the study of insoluble polymer-bound (IPB) chiral organocatalysts to be used under continuous flow or batch conditions for enantioselective transformations. For the preparation of IPB chiral organocatalysts inside microreactors two different strategies were taken into consideration: (a) bottom-up approach, where proline derivatives were supported by CuAAC on methacrylic polymer brushes, grown by atom transfer radical polymerization (ATRP) on the inner walls of a microchip; (b) copolymerization of proline-bearing styrenic monomer with styrene and divinylbenzene (DVB) to produce a resin monolith within an empty HPLC column.
For the use in batch reactions we developed a novel pyrrolidine-sulfonamide organocatalyst supported by CuAAC on commercial Merrifield resin

LEONCINI, ANDREA

Electronic Thesis and Dissertation Archive - Università di Pisa

UNIVERSITÀ DEGLI STUDI DI PISA  FACOLTÀ DI SCIENZE MATEMATICHE, FISICHE E NATURALI DIPARTIMENTO DI CHIMICA E CHIMICA INDUSTRIALE      Corso di Laurea Magistrale in Chimica Classe LM-54 Tesi di Laurea  Supported chiral proline and pyrrolidine organocatalysts for enantioselective C-C bond formation reactions.   CANDIDATO: ANDREA LEONCINI   RELATORE:                                                                                                             CONTRORELATORE: Dr. A. MANDOLI                                             Prof.ssa A. RASPOLLI GALLETTI   ANNO ACCADEMICO 2012/2013          This work has been carried out at the Department of Chemistry and Industrial Chemistry of University of Pisa and at MESA+ Institute for Nanotechnology of University of Twente (UT).  EU’s Lifelong Learning Programme is acknowledged for the financial support of the exchange period in UT through the ERASMUS Student Mobility for Placements (SMP) grant. I Table of contents. ACRONYMS VII AIMS AND SUMMARY OF THE WORK. XI CHAPTER 1. INTRODUCTION. 1 1.1 Asymmetric catalysis and organocatalysis ............................................................. 1 1.2 Recoverable enantioselective catalysts. ................................................................ 5 1.2.1 Silica and zeolite surfaces functionalised with enantioselective catalysts ..................... 6 a ) Noncovalent Binding of Homogeneous Catalysts ...................................................................... 7 b ) Immobilization of Catalysts on the Surface Through Covalent Bonds ....................................... 8 1.2.2 Insoluble resin-supported catalyst ................................................................................ 12 1.3 Asymmetric transformations in flow. .................................................................... 16 1.3.1 Packed-bed CFRs. ....................................................................................................... 19 1.3.2 Monolithic CFRs. .......................................................................................................... 22 1.3.3 Wall-coated CFRs. ........................................................................................................ 31 1.4 Proline and pyrrolidine supported organocatalysts............................................... 32 1.4.1 Supported proline catalysts .......................................................................................... 32 a ) PEG-supported proline ................................................................................................................. 32 b ) Polystirene supported proline ....................................................................................................... 35 c ) Silica-supported proline ................................................................................................................ 37 d ) Proline and proline derivatives in ionic liquids .............................................................................. 38 e ) Proline in supported ionic liquid matrices ..................................................................................... 39 f ) Other supports ............................................................................................................................... 40 1.4.2 Supported proline catalysts for flow reactions .............................................................. 42 1.4.3 Pyrrolidine derivatives ................................................................................................... 45 a ) Supported pyrrolidine derivatives ................................................................................................. 47 CHAPTER 2. RESULTS AND DISCUSSION. 53 2.1 Flow reactors ....................................................................................................... 53 2.1.1 Bottom-up approach to the preparation of wall-coated CFRs for enantioselective catalysis. ................................................................................................................. 53 2.1.2 Preparation of L-Proline derivatives ............................................................................. 56 II 2.1.3 Preparation of azide-functionalised polymer brushed on flat surface and on the inner walls of a microchip reactor .................................................................................... 59 a ) Polymerization and functionalization of polymer brushes grown on a silicon flat surface. ............ 59 b ) Polymerization and functionalization of polymer brushes grown on the inner walls of a chip-type microreactor. ................................................................................................................... 63 2.1.4 Copolymerization approach to the preparation of monolithic CFRs ............................. 64 2.2 IPB proline derivatives for batch reactions ........................................................... 69 2.2.1 Supportation of (2S,4R)-2-carboxy-4-(prop-2-yn-1-yloxy)pyrrolidin-1-ium trifluoroacetate on amphiphilic PS-PEG resin. ....................................................... 69 2.2.2 Preparation of aminomethyl pyrrolidine sulfonamide supported on PS. ....................... 72 a ) Synthesis of alkyne-functionalised sulfonamide ............................................................................ 73 b ) Synthesis of soluble model of chiral sulfonamide ......................................................................... 74 2.2.3 Supportation of novel sulfonamide catalyst on polystyrene .......................................... 76 2.2.4 Catalytic activity of the supported chiral sulfonamides ................................................. 78 a ) Aldol addition of cyclohexanone to 4-nitrobenzaldehyde .............................................................. 79 b ) α-Amination of 3-methylbutanal with dibenzyl azodicarboxylate ................................................... 81 c ) Conjugate addition of propionaldehyde to β-nitrostyrene .............................................................. 82 CHAPTER 3. CONCLUSIONS 85 CHAPTER 4. EXPERIMENTAL SECTION. 87 4.1 General. .............................................................................................................. 87 4.2 Lithium azide (111).210 ......................................................................................... 88 4.3 Benzylazide (112). ............................................................................................... 89 4.4 tris((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (83).196, 211 ................................ 89 4.5 (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (75).193... 90 4.6 (2S,4R)-1-(tert-Butoxycarbonyl)-4-(prop-2-yn-1-yloxy)pyrrolidine-2-carboxylic acid (71)............................................................................................................... 90 4.7 (2S,4R)-2-Carboxy-4-(prop-2-yn-1-yloxy)pyrrolidin-1-ium trifluoroacetate (73).195 91 4.8 (2S,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-(prop-2-yn-1-yloxy)pyrrolidine-2-carboxylic acid (72). .................................................................................. 91 4.9 Click-anchoring of 73 onto resin P1: preparation of supported (S)-proline trifluoroacetate 73 (88).175 ............................................................................. 92  III 4.10 Deprotection of 88 (89).161 ................................................................................... 93 4.11 Aldol addition of cyclohexanone to 4-nitrobenzaldehyde in batch conditions with resin 88.161 ................................................................................................... 93 4.12 General procedure for the α-amination reaction with 88 or 89.147a ....................... 94 4.13 (2S,4R)-4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (84).175 .................................... 94 4.14 (2S,4R)-1-(tert-Butoxycarbonyl)-4-((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)pyrrolidine-2-carboxylic acid (84).175 ........................................... 95 4.15 (2S,4R)-di-tert-Butyl 4-(prop-2-yn-1-yloxy)pyrrolidine-1,2-dicarboxylate (87).213 .. 96 4.16 (2S,4R)-di-tert-Butyl 4-((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)pyrrolidine-1,2-dicarboxylate (86).175 .............................................................................. 96 4.17 4-Azidomethyl styrene (85).198 ............................................................................. 97 4.18 General procedure for the preparation of chiral resin monolith within HPLC column (GP1).128....................................................................................................... 97 4.18.1 Preparation. .................................................................................................................. 97 4.18.2 In-flow deprotection of proline units.195 ......................................................................... 99 4.19 General procedure for the aldol addition in flow condition in column (GP2).161..... 99 4.20 (S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (96).199 ...................... 100 4.21 (S)-tert-Butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (97).199 ................... 100 4.22 (S)-tert-Butyl 2-(azidomethyl)pyrrolidine-1-carboxylate (98).199 .......................... 101 4.23 (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (99).200 ......................... 101 4.24 (Prop-2-yn-1-yloxy)benzene (100).201 ................................................................ 102 4.25 4-(Prop-2-yn-1-yloxy)benzene-1-sulfonyl chloride (91). ..................................... 102 4.26 (hex-5-yn-1-yloxy)benzene (92).214 .................................................................... 103 4.27 Attempted preparation of 4-(hex-5-yn-1-yloxy)benzene-1-sulfonyl chloride (Errore. L'origine riferimento non è stata trovata.) by chlorosulphonation of 92. ...... 103 4.28 (S)-tert-Butyl 2-((4-(prop-2-yn-1-yloxy)phenylsulfonamido)methyl)pyrrolidine-1-carboxylate (90).215 ..................................................................................... 104 4.29 (S)-tert-Butyl 2-((4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenylsulfonamido)methyl)pyrrolidine-1-carboxylate (102).175 .. 104 IV 4.30 (S)-2-((4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenylsulfonamido)methyl)pyrrolidin-1-ium 2,2,2-trifluoroacetate (103).161 ...................................................................................................... 105 4.31 (S)-4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-N-(pyrrolidin-2-ylmethyl)benzenesulfonamide (104). .......................................................... 105 4.32 Aldol addition of cyclohexanone to 4-nitrobenzaldehyde using the soluble organocatalyst 104.161 ................................................................................ 106 4.33 Conjugate addition of propionaldehyde to β-nitrostyrene using catalyst 104.216 . 107 4.34 Azido-Merrifield resin (106).202 ........................................................................... 107 4.35 Colorimetric test for active chlorides (T1).203 ...................................................... 108 4.36 Colorimetric test for azides (T2).204 .................................................................... 108 4.37 Generic procedure for the supportation of 90 on resin 106 (GP3).175 ................. 108 4.38 General procedure for the preparation of trifluoroacetic acid salt of catalytic unit on resin (GP4).161 ............................................................................................ 109 4.39 General procedure for the preparation of the catalyst as free amine on resin (GP5).161 ..................................................................................................... 109 4.39.1 Method A ..................................................................................................................... 110 4.39.2 Method B ..................................................................................................................... 110 4.40 HCl solution in THF.217 ....................................................................................... 110 4.41 General procedure for the preparation of hydrochloric acid salt of the supported sulphonamide organocatalyst (GP6).161 ...................................................... 110 4.42 General procedure for the determination of the basic moieties content on resin using Gisin method an UV spectrophotometry (GP7). 198, 212....................... 111 4.43 General procedure for the aldol addition of cyclohexanone to 4-nitrobenzaldehyde in batch conditions (GP8).161 ...................................................................... 112 4.44 General procedure for the aldol addition of cyclohexanone to aromatic aldehydes in batch conditions (GP9).161 ...................................................................... 112 4.45 General procedure for the α-amination of 3-methylbutanal with dibenzyl azodicarboxylate (GP10).215, 218 .................................................................. 113 4.46 General procedure for the conjugate addition of propionaldehyde to β-nitrostyrene (GP11).216 ................................................................................................... 113  V 4.47 Preparation of racemic standards ...................................................................... 114 4.47.1 rac-2-(Hydroxy(4-nitrophenyl)methyl)cyclohexanone (115).219 .................................. 114 4.47.2 General procedure for the preparation of racemic products of aldol addition of cyclohexanone to aromatic aldehydes (GP12).220 ................................................ 115 a ) rac-2-(4-Fluorophenyl)(hydroxy)methyl)cyclohexanone (116).219c ......................................... 115 b ) rac-2-(Hydroxy(phenyl)methyl)cyclohexanone (117).219c ....................................................... 115 c ) rac-2-((4-Chlorophenyl)(hydroxy)methyl)cyclohexanone (118).219c ....................................... 115 d ) rac-2-(Hydroxy(p-tolyl)methyl)cyclohexanone (119).219c ........................................................ 115 e ) rac-2-(Hydroxy(4-methoxyphenyl)methyl)cyclohexanone (120).219c ...................................... 116 4.48 Preparation of polymer brushes ......................................................................... 116 4.48.1 3-Azidopropanol (77).190a ............................................................................................ 116 4.48.2 3-azidopropyl methacrylate (69).190a ........................................................................... 116 4.48.3 General procedure for the surface activation of silicon wafers (GP13).189a ................ 117 4.48.4 General procedure for the radical initiator monolayer deposition on wafer surface (GP14).189a ............................................................................................................ 117 4.48.5 General procedure for the preparation of polymerization solutions (GP15).190a ......... 118 a ) Method A ............................................................................................................................... 118 b ) Method B ............................................................................................................................... 118 4.48.6 General procedure for the polymer brushes ATRP on silicon wafer surface (GP16). 118 a ) Method A ............................................................................................................................... 118 b ) Method B ............................................................................................................................... 119 4.48.7 General procedure for the epoxide ring opening on GMA polymer brushes on silicon wafer (GP17). ....................................................................................................... 119 4.48.8 General procedure for the CuAAC of proline derivatives on silicon wafer (GP18).190a 119 4.48.9 General procedure for the surface activation of the inner walls of a microchip (GP19).189a ............................................................................................................ 120 4.48.10 General procedure for the radical initiator monolayer deposition on the inner walls of a microchip (GP20).189a ........................................................................................... 120 4.48.11 General procedure for the polymer brushes ATRP on the inner walls of a microchip (GP21).190a ............................................................................................................ 121 a ) Method A ............................................................................................................................... 121 b ) Method B ............................................................................................................................... 121 4.48.12 General procedure for the epoxide ring opening on GMA polymer brushes in microchip (GP22). ................................................................................................................. 122 VI 4.48.13 General procedure for the CuAAC with proline derivatives in microchip (GP23).190a . 122 ACKNOWLEDGEMENTS. 123 REFERENCES. 125   VII Acronyms (DHQ)2PHAL  phthalazine adduct with dihydroquinine. A3 coupling transition-metal catalyzed three-component coupling of an aldehyde, an alkyne and an amine AIBN Azobisisobutyronitrile ATRP Atom Transfer Radical Polymerization BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1'-bi-2-naphthol bmim butylmethylimidazolium BnBr Benzylbromide Boc2O di-tert-butyl dicarbonate BOX bis(oxazoline) ligand bpy 2,2'-bipyridine CL Crosslinker NP Nanoparticle CFR Catalytic flow reactor CMR Catalytic microreactor COD Cyclooctadiene CSP-HPLC Chiral stationary phase high pressure liquid chromatography CuAAC Copper(I) catalyzed Azide-Alkyne Cycloaddition DBAD Dibenzyl azodicarboxylate DIPEA Ethyldiisopropylamine DMF Dimethylformamide DMSO Dimethylsulfoxide DVB Divinylbenzene Fmoc-OSu N-(9-Fluorenylmethoxycarbonyloxy) succinimide VIII FTIR Fourier Transform Infrared Spectroscopy GC Gas chromatography GMA Glycidyl Methacrylate HIPE High internal phase emulsion HPLC High Pressure Liquid Chromatography IL Ionic Liquid IPB Insoluble Polymer-Bound L-DOPA L-3,4-dihydroxyphenylalanine MeOPEG Methoxy polyethylene glycol NBD norbornadiene NMR Nuclear magnetic resonance PAzPMA poly(3-azidopropyl methacrylate) PASSflow Polymer Assisted Solution-Phase Synthesis flow-through technique PDMS poly(dimethylsiloxane) PEG polyethylene glycol PEO polyethylene oxide PgBr Propargylbromide PGMA poly(glycidyl methacrylate) PMO periodic mesoporous organosilica PS Polystyrene PS–PEG  (polystyrene–poly(ethylene glycol)) PTFE Polytetrafluoroethylene RCM Olefin ring-closing metathesis ROMP Ring opening metathesis polymerization RT Room Temperature Salen N,N’-Ethylenebis(salicylimine), condensation product of ethylenediamine and salicylaldehyde  IX SI-ATRP Surface initiated atom transfer radical polymerization TADDOL α,α,α’,α’-Tetraaryl-1,3-dioxolan-4,5-dimethanol TBTA tris((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)amine TEOS Tetraethoxysilane TFA Trifluoroacetic Acid THF Tetrahydrofurane TLC Thin Layer Chromatography TON Turnover Number TsCl 4-Toluenesulfonyl chloride 

Supported chiral proline and pyrrolidine organocatalysts for enantioselective C-C bond formation reactions.

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