Enantioselective NHC-Catalyzed [3+3] Annulation of α-Bromoenals with 2-Aminobenzimidazoles

Abstract

A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido­[1,2-a]­benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies indicated that the formed pyrimido­[1,2-a]­benzimidazole exhibited moderate cytotoxic activity against tumor cells.

Unexpected Ring Opening During the Imination of Camphor‐Type Bicyclic Ketones

“…Benzimidazoles, benzoxazoles, and benzothiazoles are important bioactive heterocyclic scaffolds and exhibit a broad spectrum of biological and pharmacological properties [2–7] including anti‐bacterial, [8–11] antiviral, [12–16] anti‐fungal, [17–19] anti‐inflammatory, [20–22] anti‐cancer [23–25] . There is considerable interest in the synthesis and biological evaluation of novel benzimidazole derivatives, including chiral ones, due to their wide range of biological activities [26–28] . There are two classical methods for the synthesis of 2‐substituted benzimidazoles, benzoxazoles, and benzothiazoles: the Phillips‐Ladenburg reaction based on the reaction of substituted anilines with carboxylic acids and the Weidenhagen reaction based on the reaction of substituted anilines with aldehydes [29] .…”

“…[23][24][25] There is considerable interest in the synthesis and biological evaluation of novel benzimidazole derivatives, including chiral ones, due to their wide range of biological activities. [26][27][28] There are two classical methods for the synthesis of 2-substituted benzimidazoles, benzoxazoles, and benzothiazoles: the Phillips-Ladenburg reaction based on the reaction of substituted anilines with carboxylic acids and the Weidenhagen reaction based on the reaction of substituted anilines with aldehydes. [29] The first approach is the coupling of o-phenylenediamines and carboxylic acids or their derivatives, which commonly require strong acidic conditions.…”

NHC‐Catalyzed Oxidative Annulation of α,β‐unsaturated Aldehydes with Benzyl Ketones: Direct Access to 4,5,6‐Trisubstituted Dihydropyranones

“…[8] Since the pioneers of Glorius [9] and Bode [10] independently reported the extended umpolung strategy, the NHC catalyzed annulation via homoenolate or enol intermediates have been made tremendous progress. [11] So far, several types of substrates including enals, [12] ynals, [13] α-bromoenals, [14] αaroyloxyaldehydes, [15] α,β-unsaturated esters, [16] α,β-unsaturated acyl compounds, [17] have been well explored.The start of the art in preparing dihydropyranones under NHC-catalysis was represented by Chi, [18] which was limited to activated dicarbonyl functionalities (Scheme 1a). [18a] In particular, Chi and co-workers reported an elegant method for the construction of dihydropyranones from enals and chalcones, in which acid as co-catalyst play a vital role in control of the reaction pathway (Scheme 1b).…”

“…The screening of various bases reveal that K 2 CO 3 was the best choice (Table 1, entries [8][9][10][11][12]. Sequencely, a rapid solvent testing results show that toluene gave the best result (Table 1, entry 4 vs entries [13][14][15]. Due to the results of the three solvents (toluene, DCM and CH 3 CN) were similar.…”

“…Due to the results of the three solvents (toluene, DCM and CH 3 CN) were similar. We then investigated the influence of different bases in the same solvent (Table 1, entries [14][15][16][17][18][19]. After further screening of the reaction, the best results could be achieved in the presence of catalyst D (20 mmol%), K 2 CO 3 (20 mmol%), and DQ (1.2 equiv) in toluene at rt.…”