Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products

Abstract

The remote electronic effects of chiral N-heterocyclic carbene catalysts on the asymmetric intramolecular Stetter reaction are investigated. The reaction rate and enantioselectivity were markedly influenced by a substituent at a...

Remote Electronic Effect of Chiral N‐Heterocyclic Carbene Catalyst on an Asymmetric Benzoin Reaction

“…The remote electron‐withdrawing substituents were also beneficial to prevent racemization of highly enolizable products. The results are consistent with the two conclusions that the rate‐limiting step with triazolinylidene NHC is interchangeable as in the reaction with thiazolinylidene, [5] and that the remote electronic effect is operative as we previously proposed [43–45,49] . DFT calculations and NCI analysis confirmed that the origin of the enantioselectivity is the orientation of the aldehyde aryl group with respect to the diaminoenol aryl group in the C−C bond forming TS as proposed in the literature.…”

“…The results are consistent with the two conclusions that the rate-limiting step with triazolinylidene NHC is interchangeable as in the reaction with thiazolinylidene, [5] and that the remote electronic effect is operative as we previously proposed. [43][44][45]49] DFT calculations and NCI analysis confirmed that the origin of the enantioselectivity is the orientation of the aldehyde aryl group with respect to the diaminoenol aryl group in the CÀ C bond forming TS as proposed in the literature. Moreover, the distortion/interaction analysis suggested that the distortion of the diaminoenol intermediate moieties of the TS caused by the remote electron-withdrawing substituents could be responsible for the increased enantioselectivity.…”

“…The slower reaction with 3a , bearing an electron‐donating group, indicates that the rate‐limiting step of the reaction is step B, in which deprotonation of the carbinol proton of II is involved. The electron‐withdrawing substituents in 3c – 3e are expected to increase the acidity of the carbinol proton [46,49] . In the reaction with 3d , involving intermediate II with a highly acidic carbinol proton, the tautomerization step would not be rate‐limiting.…”

“…The advantage of the remote substitution is that the substituents are located far from the carbene carbon atom, causing less steric or electrostatic interference in reactions [43] . We recently applied the electronically remote‐tuned chiral NHCs to an asymmetric intramolecular Stetter reaction and found that the electronic tuning of chiral NHC affected not only the reaction rate but also the enantioselectivity [49] . Herein, we report the remote electronic effect of chiral NHC on the asymmetric benzoin reaction, another typical Umpolung reaction of aldehydes.…”

Remote Electronic Tuning of Chiral N‐Heterocyclic Carbenes

“…We investigated the performance of the series of NHCs bearing variable remote substituents in an intramolecular Stetter reaction of α,β‐unsaturated esters 21 (Table 4). [13d] When α,β‐unsaturated ester 21a was subjected to the reaction with 1b and proton sponge in 1,2‐dichloroethane at 0 °C for 100 min, cyclized product 22a was produced in 53 % yield with 96 % ee (entry 2). After investigating NHCs with various substituents at the indane ring, we found that the more electron‐deficient NHC provided better conversion (entries 1–5).…”