Hydrazine Hydrate in Asymmetric Synthesis: A Bifunctional Squaramide Catalytic Approach toward Fused Pyrazolines

Abstract

A unified strategy has been developed to utilize hydrazine hydrate in asymmetric organic synthesis by overcoming the rapid background reaction with dienone. The H-bond donor ability of the cinchona-alkaloid-derived squaramide catalyst unlocks this previously deemed infeasibility. The dissymmetric hydrazine addition to symmetrical dienones tolerates various substitutions, resulting in the formation of optically pure fused pyrazoline derivatives under mild reaction conditions. Furthermore, the scalability of this methodology and a successful demonstration of postsynthetic transformations have been accomplished.

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles

“…Notwithstanding these remarkable findings, to the best of our knowledge, the synthesis of polycyclic benzimidazole in a sequential stereoselective cascade manner under bifunctional organocatalytic conditions poses a formidable challenge and has never been documented. The demand for proficient organocatalytic synthesis of varied molecular architectures aided by the aza-Michael addition reaction is consistently rising. , In our ongoing efforts to leverage asymmetric Michael addition processes involving chiral organocatalysts, and drawing inspiration from our prior work, we hypothesized a one-pot odyssey toward the synthesis of polycyclic benzimidazoles employing o -diaminobenzene instead of TsNH 2 (Scheme C). We envision that a chiral cinchona-alkaloid-based bifunctional squaramide catalyst could be suitable for such a cascade reaction, which would yield fused chiral tricyclic benzimidazoles through on-site dihydrobenzimidazole formation, aza-Michael addition followed by oxidation reaction.…”

“…Our efforts to delineate the likely mechanism of this cascade reaction through control reaction, NMR studies, and mass spectrometric analysis have been fruitful (see the SI for more details). Based on mechanistic investigations, prior research, , and insights from chiral squaramide-catalyzed aza-Michael addition reactions, , the proposed transition state depicted in Scheme provides clarity on the observed absolute stereochemical outcomes. NiCl 2 (PPh 3 ) 2 acts as a Lewis acid, enhancing the enantioselectivity of the reaction from 92:8 to 95:5 (Table , entries 13 and 17).…”

Organocatalytic Asymmetric Construction of Spirooxazines via Chemoselective Cascade Addition of N-Substituted Hydroxylamine with Keto-bis-enone

“…The beauty relies on the simplicity of reaction conditions and highly stereocontrolled transformations. Using bifunctional catalysis, our group contributed substantially toward asymmetric hetero-Michael reactions . Hence, we envisioned introducing a nucleophile with two contiguous nucleophilic centers and reacting with a suitable substrate having multiple electrophilic centers; by modulating their chemoselectivity, a stereochemically complex architecture can be crafted.…”