Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

Abstract

Isocyanide-based multicomponent reactions (IMCRs) allow the construction of relatively complex molecules through a one-pot synthesis. The combination of IMCRs in a consecutive or sequential fashion further extends the complexity of the molecules obtained. Herein, we report the efficient application of this approach to the synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi-azide four-component reaction; second a hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to excellent yields. The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles.

Tetrazoles via Multicomponent Reactions

“…Similarly to the work of Dömling et al 170 in employing hydrazine in UT-4CR, Andrade et al. 207 reported two consecutive hydrazine UT-4CR incorporating acylhydrazines within 1,5-disubstituted tetrazoles 102 . Their strategy was based on a one-pot hydrazino UT-4CR ( 100 ) using protected acyl hydrazines (Boc or Cbz) followed by hydrazinolysis ( 101 ) by aqueous hydrazine and finally an additional hydrazino UT-4CR (Scheme 40).…”

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

“…Recently, our research group [22] carried out the synthesis of bis(1,5-disubstituted tetrazoles) 14 using two consecutive Ugi reactions (Scheme 4). The synthetic strategy was based on two hydrazino-Ugi-azide reactions and a hydrazinolysis step for the synthesis of acylhydrazino bis(1,5-disubstituted tetrazoles).…”

“…Synthesis of acylhydrazino bis(1,5-disubstituted tetrazoles) through two hydrazine-Ugi-azide reactions and a hydrazinolysis step [22]. …”

Synthesis of bis(1,5‐disubstituted tetrazoles) via double four component Azido‐Ugi reaction

“…Because they are abundant in the structure of active drug compounds. [5][6][7][8][9] For example, Cilostazol (A) as an antiinflammatory, Pentylenetetrazol (B) as a circulatory and respiratory stimulant, Nojiritetrazole (C) as an antidiabetic, Cefmetazol (D) and Latamoxef (E) as an antibiotic, are drugs having the 1,5-DT cores (Figure 1). Also, 1,5-DTs have a substantial interest in drug discovery programs, because tetrazole group is an amide bond isosteres.…”