Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

Abstract

The aza-Michael addition reaction is av ital transformation for the synthesis of functionalizedc hiral amines. Despite intensive research, enantioselective aza-Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote ah ighly selective aza-Michael reaction between primary alkyla mines and b-trifluoromethyl b-aryl nitroolefins.I nc ontrast to classical conjugate-addition reactions,astrategy of HOMOraising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 %ee).The asymmetric aza-Michael reaction is arguably one of the most straightforward methods for the synthesis of important 1,2-difunctionalized chiral building blocks,s uch as 1,2-diamines. [1] Many successful combinations of nitrogen nucleophiles and electron-deficient olefins have been reported, with either Lewis acid catalysts [2] or organocatalysts. [3] However, two key problems remain largely unsolved:t he use of alkyl amines as the nitrogen source,and the construction of tertiary stereocenters with anitrogen substituent. Simple alkyl amines tend to form stable complexes with Lewis acids,w hich not only deactivates the catalyst, but also renders the aza-Michael reaction reversible. [4] In the case of organocatalysis,p rimary and secondary amines interfere with both LUMO-lowering iminium activation (competing imine/iminium formation) and proton catalysis (acid-base neutralization). As ar esult, research efforts have been mostly concentrated on modulating the basicity of the donor nitrogen atom (Scheme 1). For example,M acMillan and co-workers used N-silyloxycarbamates as anonbasic nitrogen source for aza-Michael reactions of a,b-unsaturated aldehydes. [5] Jørgensen and co-workers reported the use of 1,2,4-triazoles as good amine surrogates for secondary-amine-catalyzed enantioselective aza-Michael reactions with a,b-unsaturated aldehydes. ] and imines [15] have also been reported as valid nitrogen sources for asymmetric aza-Michael reactions under iminium catalysis.Ooi and co-workers reported au nique arylaminophosphonium-catalyzed asymmetric addition of 2,4-dimethoxyanilines to nitroolefins. [16] Theonly reaction of this type involving abasic amine was reported by Sundararajan and Prabagaran, who used ap olymer-supported Lewis acid as the catalyst and found that benzyl amine reacted with ethyl cinnamate to give the product with 81 % ee. [17] However,t he arguably more useful reaction of unactivated alkyl amines has not been reported. Furthermore,n early all aza-Michael reactions rely on LUMO-lowering activation mechanisms with Lewis acids, amine catalysts,o rB r ønsted acids.H erein, we report an enantioselective aza-Michael reaction between primary alkyl amines and b-trifluoromethyl b-aryl nitroolefins for the Entry Catalyst Additive Solvent Yield [%] [b] ee [%] [c]

Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis

“…Beside commonly classical twoelectron pathways, NHC-catalyzed radical reactions via a single electron transfer (SET) pathway of aldehydes or esters, and their surrogates have also received continuous attention [42][43][44][45][46] . Besides the aforementioned use of NHC as Lewis base catalyst, the asymmetric Bronsted base catalysis with NHC has also made impressive advances, in which NHC can activate 1,3-dicarbonyl compounds, amines, and thiols to realize asymmetric reactions via noncovalent interactions [47][48][49][50][51] . In sharp contrast to the aforementioned well-developed NHC-activation of aldehydes, enals, and esters, NHC-activation of valuable amide and its derivatives has been largely underdeveloped (Fig.…”

Straightforward access to linear and cyclic polypeptides

“…Moreover, linear and cyclic block copolypeptides are easily accessible by tuning the type of initiator and by sequential addition of monomers. This bifunctional organocatalysis strategy was developed based on the conjecture that: 25,34,37 free NHCs can form a hydrogen bonding network with the initiating amines and the subsequently formed ω-amino terminus of the propagating chains (Fig. 2).…”