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

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 S_NAr 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.

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. (A) Retrosynthetic analysis of sulfonylated ThTz (1). (B) Synthesis of 1. (C) Amination of PMB-triazole 5.

Scheme 2. Functionalization of 1 by the S_NAr 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. Arylation and alkylation of 1.

Scheme 4. Functionalization on the triazole ring.

Scheme 5. Heteroarene replacement of bioactive molecules.