Asymmetric Aza-Henry Reaction Under Phase Transfer Catalysis: An Experimental and Theoretical Study

Abstract

An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented. The method is based on the reaction of the respective nitroalkane with alpha-amido sulfones effected by CsOH x H2O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production of beta-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric synthesis of gamma-amino alpha,beta-unsaturated esters through a catalytic, highly enantioselective formal addition of functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO2 group of the nitrocompound.

Nitroalkanes as Key Compounds for the Synthesis of Amino Derivatives

“…The nature of the urea catalyst strongly affects the diastereopreference in the addition of primary nitroalkanes to N-Boc imines 51 (Scheme 16) [43,44] Phase transfer catalysis using chinchona-derived ammonium salts provides a formidable method to realize asymmetric azaHenry reactions. For this purpose, -amido sulfones 60 have been proved to be particularly effective since upon basic conditions they slowly release the corresponding N-carbamoyl imine, allowing addition of primary and secondary nitroalkanes 61 with formation of the corresponding adducts 63 with satisfactory diastereo-and enantioselectivity (Scheme 17) [45]. Catalyst 62 obtained from natural quinine, gives the best results over other modified cinchona alkaloids tested.…”

Organocatalytic Asymmetric Mannich Reactions in the Preparation of Enantioenriched β3-Amino Acid Derivatives

“…to the quaternary nitrogen atom in the catalyst [57] force the imine to approach the back side and thus favour selective addition to its Re face. Finally the superior efficiency of catalyst containing an ortho-substituted benzylic moiety, when used in combination with aqueous inorganic bases, can be interpreted by considering a well organized network of hydrogen bonds reinforced by a molecule of water [58].…”

Chiral Cu(ii)-amino alcohol based complexes for asymmetric aza-Henry reaction of N-Ts imines

“…[20][21][22] Due to the extensive applications of the enantio-pure product of the asymmetric aza-Henry reaction, several catalytic systems based on both metal and metal-free (organo-catalyst) have been explored in recent years. 23 Among them, BINOL, 24,25 bis-oxazolines, 26,27 phenyl bis oxazoline 28 and salen ligands with various metals (Cu, Zn, La, Ni, Yb) [29][30][31][32][33][34][35][36][37][38][39] and organocatalysts [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] have shown good catalytic activity in asymmetric aza-Henry reactions both in terms of yield and enantioselectivity at lower temperature, but there is a nagging issue of separation and recycling of the catalyst. Chiral catalysts are very expensive; hence their recyclability is of prime concern in offsetting the catalyst cost.…”