The Research Of New Double Axially Chiral Bronsted Acid Catalyzed Enantioselective Friedel-crafts Reaction

Friedel-Crafts reaction is one of the most important carbon-carbon bond-formingreactions, and asymmetric Friedel-Crafts reaction is a direct way to synthesize chiralaryl derivatives. In this thesis, we synthesized a series of new double axially chiralbisphosphorylimide Br nsted acid catalyst, applied them to three types of asymmetricFriedel-Crafts reaction, and achieved good catalytic results.The optically pure2,2’-diphenyl-[3,3’-biphenanthrene]-4,4’-diol (VAPOL) wassynthesized via a cyclization, coupling, chiral resolution and reduction sequence from2-Naphthaleneacetic acid. Further synthesis to obtain (R)-VAPOL derived phosphorylchloride and phosphoric amide.(R)-VAPOL phosphoryl chloride and (R)-1,1’-bi-2-naphthol(BINOL) phosphoryl chloride reacted with (R)-VAPOLphosphoryl amide to get the double axially chiral bisphosphorylimide Br nsted acidcatalysts. The melting point, optical rotation,1H NMR,13C NMR,31P NMR, IR,HRMS of catalysts were all characterized.The eleven double axially chiral bisphosphorylimide catalysts derived from (R)-VAPOL and (R)-BINOL were applied to catalytic asymmetric Friedel-Crafts reactionof indoles and aryl N-tosyl imines. The effect of several factors, such as the activityand dosages of catalysts, the amount of substrate, the influence and dosages ofadditives, on reactivities and stereoselectivities of this reaction were investigated.Under the optimal conditions (Room temperature, toluene as reaction medium,1eq. indole,1eq. imine,2mol%bisphosphorylimide derived from (R)-BINOL which3,3’-position is1-naphthyl as catalyst,0.2mol%4-dimethylamiopryidine(DMAP) asadditive),24kinds of aryl imines,5kinds of indoles were also investigated. Resultly,the products of asymmetric Friedel-Crafts reaction from aryl N-tosyl imines withindoles were obtained in high enantioselectivities (98->99%ee) with high yields(90-99%). Experiments were performed on gram scales between indole and2-bromobenzaldehyde imine, at which the catalyst loading could be further reduced to0.5mol%and the product was obtained without any loss of enantioselectivity andyield. In addition, five characteristics of this Friedel-Crafts should be underlined:1)the catalytic reaction can be carried out at room temperature and easy to operate;2)The use of a very small amount of DMAP in successfully inhibited the formation ofbis (indolyl) methane byproducts, the amount of indole was reduced from common2-5equivalents to1equivalent;3) A wide range of aryl imines bearing eitherelectron-withdrawing or electron-donating groups on the phenyl ring furnished theresulting chiral3-indolymethanamines with high yields and excellentenatioselectivities in all cases;4) When the amount of the catalyst is reduced to0.5mol%, for the gram-scale reaction, the reaction can still be carried out smoothly;5)Our catalytic system was capable of promoting the Friedel–Crafts reaction ofortho-substituted aldimines with high efficiency and selectivity, whereas systems inprevious reports showed considerable chemoselective or stereoselective limitations.Then, the four double axially chiral bisphosphorylimide catalysts derived from (R)-VAPOL and (R)-BINOL were applied to catalytic asymmetric Friedel-Crafts reactionof indoles and alkyl N-tosyl imines. The effect of several factors, such as the activityand dosages of catalysts, the amount of substrate, the influence and dosages ofadditives, the reaction temperature, on reactivities and stereoselectivities of thisreaction were investigated. Under the optimal catalytic conditions (0℃or-40℃,toluene as reaction medium,1eq. indole,4eq. imine,0.25mol%bisphosphorylimidederived from (R)-VAPOL as catalyst,0.025mol%DMAP as additive),5kinds ofalkyl imines were also investigated. Resultly, the products of asymmetric Friedel-Crafts reaction from alkyl N-tosyl imines with indoles were obtained in highenantioselectivities (96->99%ee) with high yields (88-93%). Experiments wereperformed on gram scales between indole and isobutyraldehyde imine, at which theenantioselectivity of the product remain unchanged, and the yield was improved. Inaddition, three characteristics of this Friedel-Crafts should be underlined:1) Theamount of catalyst is0.25mol%, is very small;2) Enantioselectivity of the catalyticproduct is the highest in so far reports;3) DMAP in use not only suppress theformation of byproducts, but also improve the enantioselectivity of the product.In addition, the twelve double axially chiral bisphosphorylimide catalysts derivedfrom (R)-5,5’,6,6’,7,7’,8,8’-octahydro-1,1-bi-2-naphtol(H8-BINOL),(R)-BINOL and(R)-VAPOL were applied to catalytic asymmetric Friedel-Crafts reaction of pyrrolesand aryl N-tosyl imines. The effect of several factors, such as the activity and dosagesof catalysts, the solvents, the influence and dosages of additives and the reactiontemperature, on reactivities and stereoselectivities of this reaction were investigated.Under the optimal catalytic conditions (-60℃, toluene(0.3M) as reaction medium,1.1eq. pyrrole,1eq. imine,0.3mol%bisphosphorylimide derived from(R)-H8-BINOL which3,3’-position is3,5-bis (trifluoromethyl) phenyl as catalyst,5mg5molecular sieve as additive),23kinds of aryl imines were also investigated.Resultly, the products of asymmetric Friedel-Crafts reaction from aryl N-tosyl imineswith pyrrole were obtained in high enantioselectivities (93->99%ee) with moderateyields (40-99%).5molecular sieve added to shorten the reaction time.Finally, the seven double axially chiral bisphosphorylimide catalysts derived from(R)-BINOL,(R)-VAPOL and (R)-H8-BINOL were applied to catalytic asymmetricFriedel-Crafts reaction of pyrroles and α-aryl enamides. The effect of several factors,such as the activity and dosages of catalysts, the solvents, the influence and dosagesof additives, on reactivities and stereoselectivities of this reaction were investigated.Under the optimal catalytic conditions(Room temperature, dioxane as reactionmedium,1.1eq. pyrrole,1eq. enamide,2mol%bisphosphorylimide derived from (R)-H8-BINOL which3,3’-position is2-naphthyl as catalyst,90mg5molecularsieve as additive),18kinds of α-aryl enamides were also investigated. Resultly, theproducts of asymmetric Friedel-Crafts reaction from aryl N-tosyl imines with pyrrolewere obtained in high enantioselectivities (72-98%ee) with high yields (83-96%).5molecular sieve added to effectively suppressed the formation of byproducts.Overall, the fifteen double axially chiral bisphosphorylimide catalysts wereapplied to catalytic three types of asymmetric Friedel-Crafts reaction.77catalyticasymmetric Friedel-Crafts reaction instances were investigated. Via the researchingwork of this dissertation, it can provide experimental data for the application of thedouble axially chiral bisphosphorylimide catalysts. Moreover, some of the additives incatalytic reactions attempts play a unique role, and we hope that it can provide somenew ideas for asymmetric organic synthesis.