Formal [3 + 4] Annulation of α,β-Unsaturated Acyl Azoliums: Access to Enantioenriched N–H-Free 1,5-Benzothiazepines

Abstract

An unprecedented formal [3 + 4] annulation of α,β-unsaturated acyl azoliums with 2-aminobenzenethiols has been utilized to synthesize enantioenriched N-H-free 1,5-benzothiazepines, which are recognized as privileged structures in numerous biologically active scaffolds. This protocol offers a rapid and direct pathway to access the target compounds with high enantioselectivities and has been applied in the concise synthesis of chiral drug (R)-thiazesim.

Recent advances in the synthetic chemistry of 1,5‐benzothiazepines: A minireview

“…The substrate scope was explored and the reaction was successfully upgraded to gram scale (1 g) without the loss of stereoselectivity (Scheme 7). [38] In continuation of their previous findings, Yin and coworkers reported the synthesis of chiral NH-unprotected 2,3-dihydro-1,5-benzothiazepinones (37) via Rh/Zhaophos complex catalyzed asymmetric hydrogenation of unsaturated cyclic NH lactams (36). Reaction conditions were optimized and it was noticed that use of [Rh(NBD) 2 ]BF 4 as a catalyst in the presence of DCM as the reaction medium under the environment of H 2 gas at 45 C for 36 hours turn out to be the optimized reaction conditions for obtaining final derivatives in high yields and with high ee.…”

“…The developed protocol was successfully utilized for the synthesis of (R)-thiazesim (a natural antidepressant drug) with 91% yield and 93% ee, (Scheme 6, entry 1). [36] A highly efficient synthesis of pharmacologically versatile asymmetric 1,5-benzothiazepinone derivatives ( (30) and o-aminothiophenol (1) were reacted in the presence of chiral N,N 0 -dioxide (31)/Yb(OTf) complex as the reaction catalyst and Sodium acetate as base to give final compound 32. Under the optimized reaction conditions, the scheme was able to provide excellent yields (up to 99%) of title compounds with high enantioselectivity, that is, up to 96% ee.…”

“…[39] Li et al developed an highly efficient method for the enantioselective reduction of racemic 1,5-benzothiazepinones into chiral 1,5-benzothiazepinones (38). Required intermediates (36) were synthesized from commercially available oaminothiophenol and phenylpropiolic acid under the argon environment at 120 C in 12 hours. These intermediates were than subjected to catalytic hydrogenation in the presence of hexane suspension of [Ru(cod)(2-methyl allyl)]/(R,R)-SIN-pEtÁHBF as a catalyst and KO t Bu as a base under the atmosphere of H 2 gas at 100 bar for 24 to 48 hours.…”

Direct and Enantioselective Synthesis of N−H‐Free 1,5‐Benzodiazepin‐2‐ones by an N‐Heterocyclic Carbene Catalyzed [3+4] Annulation Reaction

“…To date, the employment of nitrogen‐centered nucleophiles for β‐functionalization of α,β‐unsaturated acylazoliums in [3+4] annulations has not yet been explored, although N‐protected hydrazides have been previously used as nitrogen‐centered nucleophiles for the β‐functionalization of α,β‐unsaturated acylazoliums in a [3+2] annulation by Chi′s group . In continuation of our studies on the exploration of NHC‐catalyzed [3+ m ] annulations, we hypothesized that it might be possible to realize a formal [3+4] annulation of α,β‐unsaturated acylazoliums with readily accessible substituted aryl 1,2‐diamines for the direct synthesis of enantioenriched N−H‐free 1,5‐benzodiazepin‐2‐ones 4 that can easily undergo subsequent N‐functionalization (Scheme b). However, there are two competing reaction pathways when 2‐bromoenals 3 and aryl 1,2‐diamines 2 are used as the substrates with NHC catalysis.…”

Carbene-catalyzed asymmetric Friedel–Crafts alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids

“…Carbonyl activation of enones by Lewis/ Brønsted acids and activation of enals via iminiums are prevalent activation modes ( Fig. 2a) [8][9][10][11][12] Additionally, the use of heteroatoms (N or S) as nucleophiles to react with α,β-unsaturated acyl azoliums has also been disclosed [52][53][54][55][56] . Despite these elegant reports, using α,βunsaturated acyl azolium as the basic enal activation mode to achieve indole Friedel-Crafts alkylation remains a significant challenge to date ( Fig.…”