Novel Convenient Approach to 6-, 7-, and 8-Numbered Nitrogen Heterocycles Incorporating Endocyclic Sulfonamide Fragment

Abstract

A new effective method for the construction of nitrogen heterocycles incorporating endocyclic pharmacophore sulfonamide fragment, based on the use of easy accessible N-(chlorosulfonyl)imidoyl chloride, CCl3C(Cl)=NSO2Cl (1), has been developed. Thus, a reaction of 1 as bielectrophilic 1,3-C–N–S reagent with benzylamines that act as 1,4-N–C–C-C binucleophiles, affords respective 1,2,4-benzothiadiazepine-1,1-dioxides. On the other hand, 1 reacts with alkenyl amines with the formation of respective N-alkenyl amidines undergoing Lewis acids initiated intramolecular cyclization to afford derivatives of 1,2,4-thiadiazines and 1,2,4-thiadiazocines bearing a halomethyl group able for further functionalization. The first examples of electrophilic heterocyclization of the chlorosulfonyl group onto an alkenyl or alkynyl group have been revealed.

Efficient Synthesis of Fused Heterocycles Incorporating Pyrazole/Thiadiazine or Pyrazole/Thiadiazepine Fragments Using N‐Chlorosulfonyltrihaloacetimidoyl Chlorides

“…Initially, the primary reaction product, A, undergoes intramolecular sulfonylation [12] at the electron enriched C-4 position of the pyrazole ring, resulting in the formation of a spiroheterocycle, B. Subsequently, ring opening occurs, leading to the formation of the chloromethyl derivative, C. This compound then undergoes dehydrochlorination and hydrolysis of the methylene imine D, ultimately converting into the final product, amidine 14, whose structure was confirmed by X-ray diffraction study (Figure 4).…”

“…Initially, the primary reaction product, A , undergoes intramolecular sulfonylation [12] at the electron enriched C‐4 position of the pyrazole ring, resulting in the formation of a spiro‐heterocycle, B . Subsequently, ring opening occurs, leading to the formation of the chloromethyl derivative, C .…”

“…In our recent works, we have developed a convenient method for preparing a CÀ N-S-bielectrophilic reagent, Nchlorosulfonyltrichloroacetimidoyl chloride 1 a, and demonstrated its versatility in the synthesis of monocyclic and condensed nitrogen heterocycles bearing 6-, 7-, and 8-membered rings, all of which incorporate an endocyclic sulfonamide fragment. [11][12][13] In this study, we present the synthesis of another novel CÀ N-S-bielectrophilic reagent, BrCF 2 C(Cl) = NSO 2 Cl 1b, and the use of both chlorosulfonyl imidoyl chlorides 1 a and 1 b to construct pyrazolothiadiazine and pyrazolothiadiazepine ring systems, expanding the scope of our synthetic methodology.…”