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. 2024 Sep 3;15(38):15835-15840.
doi: 10.1039/d4sc03874f. Online ahead of print.

2 H-Thiazolo[4,5- d][1,2,3]triazole: synthesis, functionalization, and application in scaffold-hopping

Ryuya Miyazaki  1 , Fumito Takada  1 , Takunari Kikuchi  1 , Yuya Oguro  2 , Makoto Kamata  2 , Takafumi Yukawa  2 , Kenta Kato  1 , Kei Muto  3 , Junichiro Yamaguchi  1
Affiliations

2 H-Thiazolo[4,5- d][1,2,3]triazole: synthesis, functionalization, and application in scaffold-hopping

Ryuya Miyazaki et al. Chem Sci. .

Abstract

This manuscript unveils the synthesis of 2H-thiazolo[4,5-d][1,2,3]triazole (ThTz), an unprecedented [5-5]-fused heteroaromatic system, and established a scalable synthetic procedure for producing large quantities of the ThTz ring bearing a sulfone group on the thiazole ring. The sulfone moiety proves to be a versatile reactive tag, facilitating diverse transformations such as SNAr reactions, metal-catalyzed couplings, and radical-based alkylations. Furthermore, functionalization of the triazole ring highlights the potential of this newly developed heteroaromatic compound as a valuable heteroaryl building block, promoting scaffold hopping strategies in medicinal chemistry.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) [5-5]-Bicyclic heteroarenes in bioactive compounds. (B) 2H-Thiazolo[4,5-d][1,2,3]triazole (ThTz): an innovative and previously unexplored aromatic system. (C) Sulfonylated ThTz (1): synthesis, functionalization, and application in scaffold-hopping.
Scheme 1
Scheme 1. (A) Retrosynthetic analysis of sulfonylated ThTz (1). (B) Synthesis of 1. (C) Amination of PMB-triazole 5.
Scheme 2
Scheme 2. Functionalization of 1 by the SNAr reaction. aConditions: amine (2.0 equiv.), THF, 60 °C. bConditions: alcohol or thiol (2.0 equiv.), NaH (2.0 equiv.), THF, 0 °C. cConditions: carbonyl compound, base, RT. dConditions: NaBH4 (2.0 equiv.), MeOH/THF, 0 °C.
Scheme 3
Scheme 3. Arylation and alkylation of 1.
Scheme 4
Scheme 4. Functionalization on the triazole ring.
Scheme 5
Scheme 5. Heteroarene replacement of bioactive molecules.
See this image and copyright information in PMC

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