Synthesis Of New Bifunctional Organic Catalysts And Research On Catalytic Asymmetric Michael Addition Reactions

Michael addition reaction is one of the most important carbon-carbonbond-forming reactions, which can provide many important precursors in organicsynthesis. Synthesis and applications of high active and selective organic smallmolecule catalysts is a hot research field of asymmetric organic synthesis. In thispaper, we dedicated to the design and synthesis of two types of new bifunctionalorganic catalysts, and applied them to three types of catalytic asymmetric Michaeladdition reactions.Aminobenzimidazole, aminoperimidine and diphenyl guanidine as hydrogenbond donors were introduced into the structure of the pyrrolidine, thereby four newbifunctional secondary amine catalysts [target catalysts:(S)-N-(1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxamide,(S)-N-(pyrrolidin-2-ylmethyl)-1H-benzo[d]imidazol-2-amine,(S)-N-(pyrrolidin-2-ylmethyl)-1H-perimidin-2-amine,(S,Z)-1,2-diphenyl-3-(pyrrolidin-2-ylmethyl)guanidine] containing double N-H bonds unit weredesigned. Different chiral intermediates which were derived from L-proline as thechiral source coupled with corresponding hydrogen bond donor(2-aminobenzimidazole,2-chlorobenzimidazole,2-chloroperimidine and diphenylthiourea), so four target catalysts were synthesized by the removal of correspondingprotecting groups subsequently. After4,7,7and8synthetic steps respectively,corresponding compounds were obtained in62%,30%,10%and51%yields. Themelting point, optical rotation,¹H NMR,¹3C NMR, IR, HRMS of these compoundswere all characterized. The four bifunctional secondary amine catalysts were applied to catalyticasymmetric Michael addition reactions for aldehydes and ketones with nitroolefins.The effect of many factors, such as catalysts, solvents, additives, dosages and reactiontemperature, on reactivities and stereoselectivities of products were investigated. Inthe optimal catalytic conditions (25oC, brine as reaction medium,1eq. nitroolefin,2eq. cyclohexanone,10mol%(S)-N-(pyrrolidin-2-ylmethyl)-1H-benzo[d]imidazol-2-amine as catalyst,10mol%4-CH3O-PhCOOH as additive),13kinds ofnitroolefins,5kinds of aldehydes or ketones were also investigated. Resultly, theaddition products from cyclohexanone with nitroolefins were obtained in high yields(80-93%) with high enantioselectivities (88-99%ee) and diastereoselectivities(88/12to99/1dr). In addition, two characteristics of this Michael addition should beunderlined:1) the catalytic reaction can be carried out at room temperature in theaqueous phase;2) the amount of Michael donor was reduced from common10-20equivalents to2equivalents. Therefore, the Michael addition reaction is not only easyto operate, but also more green.Then, the four bifunctional secondary amine catalysts were applied to catalyticasymmetric Michael addition reactions for nitroalkane with α, β-unsaturated ketones.The effect of many factors, such as additives, catalysts, solvents, dosages and reactiontemperature, on reactivities and stereoselectivities of products were investigated. Inthe optimal catalytic conditions (25oC,1eq. α, β-unsaturated ketone,0.5mL CH₃NO₂,10mol%(S)-N-(pyrrolidin-2-ylmethyl)-1H-benzo[d]imidazol-2-amine as catalyst,10mol%CF₃COOH as additive),19kinds of α, β-unsaturated ketones were alsoinvestigated. Resultly, the addition products from nitromethane with α, β-unsaturatedketones were obtained in moderate yields (60-81%yields) with highenantioselectivities (84-92%ee). This expanded the scope of application of thecatalysts further.In addition, L-threonine was selected as chiral skeleton. After modification in theamino, carboxyl and hydroxyl of L-threonine, eight new bifunctional acid-basecatalysts [target catalysts:1-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(dimethylamino)butan-2-yl)-3-phenylthiourea,1-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(di ethylamino)butan-2-yl)-3-phenylthiourea,1-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(pyrrolidin-1-yl)butan-2-yl)-3-phenylthiourea,1-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(piperidin-1-yl)butan-2-yl)-3-phenylthiourea,1-phenyl-3-((2R,3R)-1-(piperidin-1-yl)-3-(triphenylsilyloxy)butan-2-yl)thiourea,1-((2R,3R)-3-(tert-butyldiphenylsilyloxy)-1-(piperidin-1-yl)butan-2-yl)-3-phenylthiourea,1-phenyl-3-((2R,3R)-1-(piperidin-1-yl)-3-(triisopropylsilyloxy)butan-2-yl)thiourea,1-(3,5-bis(trifluoromethyl)phenyl)-3-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(piperidin-1-yl)butan-2-yl)thiourea] containing tertiary amine-thiourea unit were designed. From L-threonineas chiral source, eight target catalysts were synthesized through seven synthetic steps(Boc protecting of amino, conformation of amide, hydroxyl protection, amidereduction, deprotection, nuclephilic addition and hydroxyl silyl ether protection). Andfrom L-valine as chiral source, catalyst [(S)-1-(1-(dimethylamino)-3-methylbutan-2-yl)-3-phenylthiourea)] containing two regulatory sites was synthesizedthrough five synthetic steps (Boc protecting of amino, conformation of amide,deprotection, amide reduction, nuclephilic addition). The corresponding compoundswere obtained in18%,21%,14%,19%,19%,19%,18%,15%and29%yieldsrespectively. The melting point, optical rotation,1H NMR,13C NMR, IR, HRMS ofthese compounds were all characterized.The nine bifunctional acid-base catalysts were applied to catalytic asymmetricMichael addition reaction for2-hydroxy-1,4-naphthoquinone with nitroolefins. Theeffect of many factors, such as catalysts, solvents, dosages and reaction temperature,on reactivities and enantioselectivities of products were investigated. In the optimalcatalytic conditions (0oC,4mL PhCH3as reaction solvent,1eq.2-hydroxy-1,4-naphthoquinone,1.2eq. nitroolefin,3mol%1-((2R,3R)-3-(tert-butyldimethylsilyloxy)-1-(piperidin-1-yl)butan-2-yl)-3-phenylthiourea as catalyst),24kinds ofnitroolefins were also investigated. Resultly, the addition products from2-hydroxy-1,4-naphthoquinone with nitroolefins were obtained in moderate to highyields (32-93%yields) with high enantioselectivities (92->99%ee). Not only thistype of catalysts have shown high stereoselectivities under low catalyst loading, butalso simple and easy-to-operate synthetic route made these catalysts fine-tunable and versatile in their catalytic performance, which provide a solid foundation for furtherwide application of these catalysts.Overall,13bifunctional organic catalysts were synthesized and applied to3typesof asymmetric Michael addition reactions.68catalytic asymmetric Michael additioninstances were investigated. Via the researching work of this dissertation, it canprovide experimental data for the synthesis and application of bifunctional organiccatalysts, and we hope that it can provide some new ideas for asymmetric organicsynthesis.