A Practical Strategy for Differentiated N- and S-Alkylation to Prepare Benzothiazolium Salts and Use in Synthesizing Cyanine Dyes

Dedication

Dedicated to the memory of Mr. George Verhagen, an enthusiastic practitioner of synthetic chemistry.

Abstract

Benzothiazolium salts are key intermediates in the synthesis of cyanine dyes and related functional materials, yet their preparation is often complicated by alkyl scrambling arising from equilibrium with benzothiazole-2-thione species. Unexpected salt mixtures observed during N-alkylation are rationalized through halide- or heteroatom-mediated cleavage of S-alkyl groups, regenerating reactive alkyl halides and thione intermediates. Herein, we report a practical and scalable strategy that enables complete control over N- and S-alkyl group differentiation. The method proceeds via initial S-alkylation, catalytic rearrangement to the corresponding thione, and mild recrystallization of the desired benzothiazolium salt. This approach allows gram-scale access to structurally diverse dialkylbenzothiazolium salts, which are subsequently employed in the efficient synthesis of thiazole orange derivatives under low-temperature conditions that suppress salt degradation. The insights and methodology presented provide a general solution to long-standing challenges in benzothiazolium salt synthesis and cyanine dye preparation.

Keywords

Benzothiazole - Cyanine dyes - Benzothiazolium salts - Alkylation - Rhodamine - Mercaptobenzothiazole - Dimethylaminopyridine - Rotor dyes

Publication History

Received: 08 January 2026

Accepted after revision: 28 January 2026

Article published online:
11 February 2026

• References

• 1 Henary M, Paranjpe S, Owens EA. Heterocycl Commun 2013; 19 (01) 1-11
• 2 Tariq S, Kamboj P, Amir M. Arch Pharm 2019; 352 (01) 1-17
• 3 Brooker LGS, Keyes G, Williams W. J Am Chem Soc 1942; 64: 199
• 4a Lee L, Chen C, Chiu L. Cytometry 1986; 7: 508-517
• 4b Fei X, Gu Y, Ban Y, Liu Z, Zhang B. Bioorg Med Chem 2009; 17 (02) 585-591
• 5 Fry DJ, Kendall JD. J Chem Soc 1951; 1716
• 6 General procedure for the preparation of salts (see SI for details)
• 7 Into dichloromethane, 2-mercaptobenzothiazole, ethyl iodide, and triethylamine were added. The mixture was covered in foil and was left stirring at room temperature for 24 h. The reaction was quenched with saturated ammonium chloride. The organics were separated and washed with 50% brine. Organics were concentrated in vacuo, and the residue (alkylation product, quantitative yield) was used without further purification. This 2-ethylthiobenzothiazole residue and 3–5 equiv of ethyl iodide were added into a high-pressure vessel. The sealed vessel was heated with stirring. The vessel was then allowed to rest at room temperature. Upon crystallization, the mixture was quenched with diethyl ether and washed with another aliquot of diethyl ether. The product was obtained as yellow needle crystals. The alkylation were accomplished with a modification of conditions described in: Li X, Srinivasan SR, Connarn J. et al. ACS Med Chem Lett 2013; 4 (11) 1042-1047
• 8 Petersen M, Hamed AA, Pedersen EB, Jacobsen JP. Bioconjug Chem 1999; 10: 66-74
• 9 Alganzory HH, Arief MMH, Amine MS, Ebeid EM. J Chem Pharm Res 2014; 6 (12) 143-161
• 10 Ethyl/Ethyl Dye (9a) has been prepared previously: Zhou X, Peng Z, Geise HJ. et al. J Imaging Sci Technol 1995; 39 (03) 244-252
• 11 General procedure for the preparation of dyes (see SI for details): 1-Ethyl-2-methylpyridinium iodide and 2 equiv of triethylamine were added into a round bottom flask with dichloromethane (roughly 0.28 M concentration of starting materials) at room temperature. This mixture was stirred until everything dissolved. To this solution, dimethyl aminopyridine (25% catalytic loading) and benzothiazolium salt were added. The round bottom flask was sealed, then transferred to the refrigerator (5 °C). The dye product crystallized out and did not require further purification upon filtration