Synthesis 2018; 50(10): 2027-2032
DOI: 10.1055/s-0036-1591553
paper
© Georg Thieme Verlag Stuttgart · New York

Water-Promoted Chlorination of 2-Mercaptobenzothiazoles

Laurin Wimmer
a   Global Drug Development, Chemical & Analytical Development, Novartis Pharma AG, Basel, Switzerland
,
Michael Parmentier
a   Global Drug Development, Chemical & Analytical Development, Novartis Pharma AG, Basel, Switzerland
,
Bernard Riss
a   Global Drug Development, Chemical & Analytical Development, Novartis Pharma AG, Basel, Switzerland
,
Tobias Kapferer
a   Global Drug Development, Chemical & Analytical Development, Novartis Pharma AG, Basel, Switzerland
,
Chao Ye
b   Global Drug Development, Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu 215537, P. R. of China   Email: jialiang.li@novartis.com
,
Lei Li
b   Global Drug Development, Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu 215537, P. R. of China   Email: jialiang.li@novartis.com
,
Hongyong Kim
b   Global Drug Development, Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu 215537, P. R. of China   Email: jialiang.li@novartis.com
,
Jialiang Li*
b   Global Drug Development, Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu 215537, P. R. of China   Email: jialiang.li@novartis.com
› Author Affiliations
Further Information

Publication History

Received: 10 November 2017

Accepted after revision: 22 February 2018

Publication Date:
09 April 2018 (online)


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.

Supporting Information

 
  • References

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  • 3 Both SO2Cl2 and POCl3 react with water in a violent, exothermic reaction with evolution of gas. However, the high density and limited miscibility of POCl3 with water makes its use particularly hazardous: During the quench with water a delayed onset of the hydrolysis reaction can occur resulting in a dangerous accumulation and potential run-away of the reaction.
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  • 5 The addition of one, two or three equivalents of water led to the same reaction performance. After these initial experiments, we decided to use 2 equivalents of water as standard conditions.
  • 6 The rapid decomposition of heterocyclic sulfinic acids through loss of SO2 under acidic conditions is well documented. See for example: Evans RM. Jones PG. Palmer PJ. Stephens FF. J. Chem. Soc. 1956; 4106
  • 7 When quenching excess reagent from a reaction containing 5 g of mercaptobenzothiazole in 25 g of sulfuryl chloride, 6 liters of gaseous by-products (mainly hydrogen chloride) were released.