Azepine-tetrazoles

A library of piperazine containing fused azepine-tetrazoles 183 was built by Nixey et al. via Ugi reaction in the solution phase [55]. This library comprises an example of a building block introduced piperazine (Scheme 32). The reaction of A-Boc-a-amino aldehyde 184, methyl isocyanoacetate 185, substituted piperazines 186, and trimethylsilylazide 181 in methanol, followed by acid treatment, proton scavenging, and reflux affords bicyciic azepine-tetrazoles 183. This efficient protocol with three diversity points can be used to generate arrays of biologically... 

Scheme 32 Synthesis of piperazine incorporating fused azepine-tetrazoles 183 and two representative 3D conformations of 183A blue) and 183B cyan)...

Nixey T, Kelly M, Semin D, Huhne C (2002) Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Lett 43(20) 3681-3684... 

Scheme 12. Synthetic routes to fused 6,5-ketopiperazine-tetrazoles and 7,5-azepine-tetrazoles. Reagents and conditions (i) R2R2C = O (1.5 equiv., 0.1 M in MeOH), TMSN3 (1 equiv., 0.1 M in MeOH), R3NH2 (1 equiv., 0.1 M in MeOH), 92 (1 equiv., 0.1 M in MeOH), 24 h, RT. (ii) 10% TFA in CH2C12. (iii) PS-DIEA, DMF/dioxane, 1 1, reflux, (iv) PS-NCO, PS-TsNHNH2 THF/DCE, 1 1. (v) Reflux, MeOH.

Workers at Amgen further exploited this reaction in an attempt to access 6,5-fused ketopiperazine-tetrazoles 96 and 7,5-fused azepine-tetrazoles 94, respectively (Scheme 12). Thus, reaction of methyl-isocyanoacetates 92,... 

Triazidochlorosilane ClSi(N3)3 708, which is readily prepared in situ by reaction of three equivalents of NaN3 with SiCU 57 in acetonitrile, reacts with acetophenone to give the tetrazoles 709 and 710 and with cyclohexanone to 6,7,8,9-tetrahy-dro-5H-tetrazolo[l,5-a]azepine 711, Si02, and HCl [210] (Scheme 5.70). 

The preparation and chemistry of organic azides have been intensively investigated since about 1960 because of their importance in preparative heterocyclic chemistry and as a source of nitrenes [1]. Many nitrogen-containing heterocycles such as carbazoles, furoxans, azepines, A2-triazolines, triazoles [2], tetrazoles [3], aziridines [4, 5], and azirines have been obtained by either the addition or the decomposition of azides. 

The fused P-lactams 36 and 37, the fused oxazolidinones 38 and 39, [intermediates in Danishefsky s synthesis of staurosporine (see Chapter 24)], 41 and a precursor to this, namely 40, ° and 42. The X-ray structure of d-mannose derived azepine 43 shows this to adopt a pseudo-chair conformation. The glucose-based tetrazole 44 and fused heterocycle 45. ... 

---