Efficient Synthetic Approach to Substituted Benzo[b]furans and Benzo[b]thiophenes by Iodine‐Promoted Cyclization of Enaminones

Abstract

An efficient synthetic approach to the substituted benzo[b]furan and benzo[b]thiophene scaffolds by iodine‐mediated cyclization of the corresponding enaminones is described. This protocol was applied to a large series of these latter precursors to afford the respective benzoheterocycles substituted at the C‐2 position by a carbonyl group functionality. A study of the factors that control this process reveals that the reactivity depends on the presence of electron‐donor groups in the aryl ring of the aryloxycarbonylic and arylthiocarbonylic moieties.

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

“…[20][21][22]24 In the absence of a Lewis acid, poor or no reaction is observed even at a high temperature. In the synthetic strategy, for the preparation of indoles 1a-p proposed herein (Scheme 2), the last step of the route involves the iodine-assisted cyclization of the key enaminone precursors 3a-p.…”

“…31 However, we previously provided evidence that other species derived from iodine, such as structurally unknown HI/I 2 associated species or HI 3 , 32 were mainly involved in promoting such cyclization during the syntheses of benzofurans and benzothiophenes. 24 A similar mechanism can be proposed for the formation of indoles 1 and 2 (Scheme 3). These iodine-associated species, [I], can then be coordinated to the carbonyl group (intermediate A) of enaminones 3 promoting the polarization of the enaminone system (intermediate B) and favoring the attack of the aryl ring to yield the heterocyclic species C. Rearomatization of the aryl ring and elimination of the dimethylamino group of the latter, probably as a protonated species (thus forming a more favorable leaving group), will lead to the indole product 1.…”

“…2-Bromoacetophenones 6c-d were prepared by bromination of acetophenones 7a-b with N-bromosuccinimide (NBS) in the presence of p-toluenesulfonic acid in good yields (90-95%). 22,24,26 …”

“…23,27 In the course of our studies, we have found that molecular iodine (I 2 ) efficiently promote the intramolecular cyclization of enaminones to afford benzofurans and benzothiophenes. 24 Therefore, we applied it to the cyclization of enaminones 3 to assist their annulation to the desired indoles 1.…”

“…In order to optimize this methodology, we found that iodine 23 was an efficient promoter in the annulation of the respective enaminones to obtain benzofurans and benzothiophenes. 24 Iodine-mediated intramolecular reactions are well documented. 25 Scheme 1.…”