Tetrazole-ketopiperazines

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 . A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 200 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 201, with sodium azide afforded aryl tetrazoles 202 . 

Scheme 33 Synthesis of fused tetrazole-ketopiperazines 187 and two representative 3D conformations of 187A (blue) and 187B (cyan)...

A library of fused tetrazole-ketopiperazines 187 was obtained by Nixey et al. via Ugi four-component reaction in the solution phase [56]. The reaction of an oxo component 188, primary amine 189, methyl isocyanoacetate 190, and trimethylsi-lylazide 181 in methanol at reflux affords bicyclic tetrazole-ketopiperazines 187 in good yield (Scheme 33). The cyclization to afford the tetrazole-ketopiperazines is performed spontaneously under the reaction conditions. 

Nixey T, Kelly M, Huhne C (2000) The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Lett 41(45) 8729-8733... 

By varying the nucleophilic component in the U-4CR, a variety of heterocyclic compoimds may be synthesized. Such an example is illustrated in the one-pot synthesis of fused tetrazole-ketopiperazines, as demonstrated by Hulme and co-workers. The treatment of trimethylsilyl azide (38) with amine 37, isonitrile 39, and aldehyde 40 gave the intermediate tetrazole 41 that underwent spontaneous lactamization to afford 42. In this report, the formation of [3.4.0]-bicycles proceeds in good to excellent yields for all examples. However, attempts to form [3.5.0]-bicyclic systems using methyl-P-isonitrile propionate resulted in significantly decreased yields. 

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,... 

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