Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and 3, n -dihalobenzo[ b ]thiophenes

Abstract

A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in the presence of substituted 2-alkynylthioanisoles. The proposed method is facile, uses ethanol as a green solvent, and results in uniquely substituted benzo[b]thiophene structures with isolated yields up to 96%. The most useful component of this methodology is the selective introduction of bromine atoms at every available position (2–7) around the benzo[b]thiophene ring, while keeping position 3 occupied by a specific halogen atom such as Cl, Br or I. Aromatic halogens are useful reactive handles; therefore, the selective introduction of halogens at specific positions would be valuable in the targeted synthesis of bioactive molecules and complex organic materials via metal-catalyzed cross coupling reactions. This work is a novel approach towards the synthesis of dihalo substituted benzo[b]thiophene core structures, which provides a superior alternative to the current methods discussed herein.

Synthesis and Evaluation of 3-Halobenzo[b]thiophenes as Potential Antibacterial and Antifungal Agents

“…ACS-grade hexanes and ethyl acetate were used as the eluent for flash chromatography, and silica gel (60-120 mesh) was used as the stationary phase. Benzo[b]thiophenes 10-27 were synthesized according to procedures in the literature, and the characterization data were in good agreement with previously reported data [48,49].…”

“…We employed the green halocyclization reaction above to synthesize a series of 3-halo substituted benzo[b]thiophenes as depicted in Scheme 1. The synthesis of benzo[b]thiophenes 10-27 has already been reported earlier [48][49][50]. However, the synthesis of 2-cyclohexyl, 2-(1,1dimethylmethanol), and 2-cyclopentanol substituted 3-chloro and 3-bromobenzo[b]thiophenes derivatives 28-32 have not been reported in the literature, and we report their first synthesis herein.…”

“…Recently, Kesharwani and coworkers demonstrated that the seemingly difficult chlorocyclization of 2-alkynylthioanisole could easily be achieved using table salt as the source of electrophilic chlorine in the presence of copper sulfate in ethanol. This environmentally benign method has also been demonstrated to work for bromo-and iodocyclization by changing sodium chloride to sodium bromide and sodium iodide, respectively [48][49][50].…”

Step‐Economical Route to 2‐Amido‐3‐bromobenzo[b]thiophenes via Ynamide Formation and Selectfluor‐Mediated Oxidative Bromocyclization

“…Infrared spectra were recorded with a Smith Detection ATR‐FTIR. The known compounds 1 a , [6c] 2 b , [26] 2 c‐d , [27] 2 e , [28] 2 f , [29] 2 g , [30] 2 h , [31] 2 i , [32] 2 j , [33] 2 k , [34] 2 l‐p , [35] and the known intermediates required for synthesis of 1 are not characterized.…”

Copper-Catalyzed Electrophilic Chlorocyclization Reaction Using Sodium Chloride as the Source of Electrophilic Chlorine

“…17 We recently reported a potent method using relatively inexpensive CuSO 4 along with NaCl for generating 2,3-disubstituted benzo[ b ]thiophene derivatives with the desired chlorine moiety at the 3 position. 18 The yields were higher and reaction conditions were milder compared to previous methodologies, but an excess of CuSO 4 was required. The need for the development of a reduced amount of transition metal has prompted our research on the development of simple and high-yielding copper-catalyzed electrophilic chlorocyclization reactions for the synthesis of benzo[ b ]thiophenes and thiophenes.…”