A New Synthetic Route of 2-Aroyl- and 2-Benzyl-Benzofurans and their Application in the Total Synthesis of a Metabolite Isolated from Dorstenia gigas

Abstract

The Lewis acid-catalyzed cyclization of the (Z)-3-(dimethylamino)-2-aryloxy-1-arylprop-2-en-1-ones 4a–h leads to a regioselective and short synthesis of 2-aroylbenzofurans 2a–h. The Wolff–Kishner reduction of the latter yielded a series of substituted 2-benzylbenzofurans 3a–h. This methodology was applied in the first total synthesis of the metabolite 2-(4-hydroxybenzyl)-6-methoxybenzofuran 1, which was isolated from the tropical plant Dorstenia gigas, and obtained through a six-step route and in a 24% overall yield.

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

“…For instance, irradiation of the signal assigned to the methyl protons of the dimethylamino group of compound 4e produced an enhancement of the signals corresponding to the phenylthioxy ring. This stereoselective preference, also observed in similar systems , is probably due to the higher stability gained by the planar π‐conjugated acrylate moiety when the bulky dimethylamino group is located at the opposite side of the double bond. This hypothesis is also supported by the X‐ray structure of compound 4e (Fig.…”

“…2‐Alkoxycarbonyl‐, 2‐acyl‐, and 2‐aroyl‐benzo[ b ]‐fused five‐membered heterocyclic rings 1a , 1b , 1c , 1d , 1e , 1f , 1g , 1h , 1i , 1j and 2a , 2b , 2c , 2d , 2e , 2f , 2g , 2h , 2i , 2j , 2k , 2l , 2m , 2n were synthesized according to the sequence of reactions illustrated in Schemes and and Tables . Thus, the aryloxycarbonylic, 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , and the arylthiocarbonylic, 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k , 6l , 6m , 6n , compounds were prepared in moderate to good yields (41–99%) by a reaction between the substituted phenols 7a , 7b , 7c , 7d , 7e , 7f or thiophenols 8a , 8b , 8c , 8d , 8e with the corresponding α‐haloesters ( 9a , 9b ) or α‐haloketones ( 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j , 9k ), in the presence of potassium carbonate in acetone at reflux for 12 h (Scheme ). 2‐Bromoacetophenones 9d , 9e , 9f , 9g , 9h , 9i , 9j , 9k are commercially available or can be prepared by bromination of the corresponding acetophenones, 10a–h , with bromine in the presence of zinc powder in H 2 O , or using N ‐bromosuccinimide in the presence of p ‐toluenesulfonic acid, in good yields (65–88%) (Scheme ).…”

“…Recently, we reported a novel straightforward synthesis of benzo[ b ]furans , through an intramolecular cyclization of properly functionalized enaminones, which was successfully extended to the preparation of indoles and coumarins . With the aim of optimizing and extending our methodology to other kinds of benzo[ b ]heterocycles, we hereby describe the development of alternative conditions for the preparation of benzo[ b ]furans 1 , and the synthesis of benzo[ b ]thiophenes 2 , by using enaminones 3 and 4 as their precursors, respectively (Scheme ).…”

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.…”

“…18 Additionally, they form the basic structure of many alkaloids and their synthetic derivatives, and these exhibit diverse biological activities. 19 Previously, we designed a new method for the preparation of benzofurans, 20 via a cyclization of functionalized enaminones. This strategy was successfully applied to the synthesis of indoles 21 and coumarins 22 (Scheme 1).…”