Water-Promoted Chlorination of 2-Mercaptobenzothiazoles

Abstract

Substituted benzothiazoles play an important role in medicinal chemistry due to their pharmacological properties. Their 2-substituted derivatives are often prepared from 2-chlorobenzothiazoles, which in turn can be synthesized from the 2-mercapto precursor using sulfuryl chloride. In practice, this seemingly straightforward and widely used reaction can be impeded by poor reproducibility and low reaction yields. In this communication, we report that the simple addition of water to the reaction leads to remarkable improvements in reaction efficiency. We attribute this effect to the formation of acid through partial hydrolysis of sulfuryl chloride. This hypothesis is supported by the observation that improved yields were also obtained in the presence of some anhydrous acidic additives. The simple combination of sulfuryl chloride and water reproducibly provides excellent yields for a range of chlorinated products.

Ionic Reactivity of 2-Isocyanoaryl Thioethers: Access to 2-Halo and 2-Aminobenzothia/Selenazoles

“…13 C{ 1 H} NMR (101 MHz, CDCl 3 ): δ 152.0, 138. 7,136.8,130.6,122.6,115.8,105.3,and 15.7. HRMS (ESI) 341.8669;found,341.8676.…”

“…13 C{ 1 H} NMR (101 MHz, CDCl 3 ): δ 169.2, 152. 7,136.0,127.3,122.9,120.2,119.7,66.2,48.4,. Purified by silica gel column chromatography (eluent: PE/EA = 30:1−10:1).…”

“…Recently, the halogenation of acidic C–H bonds in the 2-position of benzothiazoles was achieved by sequential deprotonation and halogenation with various halide electrophiles (Scheme b) . Additionally, some methodologies, such as chlorination of 2-hydroxy and 2-mercapto benzothiazoles, as well as bromination of 2-hydroxybenzothiazoles, are also developed as efficient and practical protocols to yield the corresponding 2-halobenzothiazoles. Although numerous methods for the synthesis of 2-halobenzothiazoles have been developed, from the viewpoint of synthetic methodology, these procedures are limited to using the preformed benzothiazoles as raw materials.…”

Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives

“…Earlier, this simple procedure gave low yields and was poorly reproducible. In [ 102 ], the authors have found that the simple addition of water substantially increases the effectiveness of the reaction. This effect was assigned to the formation of acid by partial hydrolysis of sulfuryl chloride.…”

“…The reaction does not depend on the substituents in the reagents. Later on [102], this method was applied to the synthesis of 2-mercaptobenzothiazoles 51d-n (Scheme 43). Their treatment with sulfuryl chloride gave 2-chlorobenzothiazoles 53d-n in excellent yield.…”