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

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• mixture of diastereomers). 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). Methyl isocyanoacetate 13a was used as an essential component in the first hydrazino-Ugi-azide reaction allowing consecutive Ugi reactions to take place. In the first step, 13a, hydrazides, aldehyde or ketone, trimethylsilyl azide (TMSN3) and ZnCl2 (10 mol %) in

• trifluoroethanol (TFE) were stirred at room temperature for 24 h to obtain acylhydrazino 1,5-disubstituted tetrazoles 14 in 30–100% yield. Attempts of this reaction without the use of catalyst provided the desired products in low yields. Subsequently, a hydrazinolysis reaction with hydrazine monohydrate led to the

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

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• 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. Keywords: acylhydrazines; consecutive Ugi reactions; 1,5-disubstituted tetrazoles; isocyanide-based multicomponent reactions (IMCRs

• are used as angiotensin receptor blockers (Figure 1) [8]. In recent years, the synthesis of 1,5-disubstituted tetrazoles has attracted the attention of several research groups around the world not only for their important pharmacological activities but also for being an excellent mimic of the cis

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• deprotected and cyclized the linear products towards the oxazole derivatives 146 in yields up to 73%. Tetrazoles In medicinal chemistry, tetrazoles are often used as carboxylic acid bio-isosteres due to their comparable acidity [114]. However, studies towards 1,5-disubstituted tetrazoles have shown that these