Tin‐Catalyzed Synthesis of 5‐Substituted 1H‐Tetrazoles from Nitriles: Homogeneous and Heterogeneous Procedures

Abstract

The preparation of 5-substituted 1H-tetrazoles was efficiently achieved by reaction of trimethylsilylazide with nitriles using a triorganotin alkoxide precatalyst. The reaction mechanism was first investigated using a homogeneous tributyltin derivative and was explored through experimental investigations and DFT calculations. A heterogeneous version was then developed using a polymer-supported organotin alkoxide and afforded an efficient method for the preparation of tetrazoles in high yields with an easy work-up and a residual tin concentration in the desired products compatible for pharmaceutical applications (less than 10 ppm).

Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles by Continuous Flow: Application to the Synthesis of Valsartan

“…The preparation of the latter and its use in batch for the synthesis of 5-substituted 1H-tetrazole has been recently reported by our group. 13 We demonstrated that the tin alkoxy moiety grafted on insoluble polystyrene afforded good conversions in batch for a large range of nitrile derivatives and allows a facile procedure to recover the reaction products. However, this procedure suffered from long reaction times (18 h).…”

“…Solvent systems and flash column chromatography are reported as percent by volume values. 1 H, 13 C and 119 Sn NMR spectra were recorded on Bruker Avance 300 or Bruker ARX 400 instruments. Chemical shifts are given in ppm as  values related to tetramethylsilane ( 1 H, 13 C) and coupling constants are given in Hz.…”

“…1 H, 13 C and 119 Sn NMR spectra were recorded on Bruker Avance 300 or Bruker ARX 400 instruments. Chemical shifts are given in ppm as  values related to tetramethylsilane ( 1 H, 13 C) and coupling constants are given in Hz. Carbon chemical shifts were internally referenced to the deuterated solvent signals in DMSO (δ 39.52 ppm).…”

“…[10][11][12] From our side, we have recently reported a versatile synthesis of 5H-substituted 1H-tetrazoles 2 through the reaction of trimethylsilylazide with nitriles using a triorganotin alkoxide precatalyst 1, a strategy which was found to be efficient both for substituted aryl or alkyl tetrazoles. 13 This procedure involves the in situ generation of a triorganotin azide acting as the effective reaction catalyst. Moreover, a heterogeneous version of the reaction was also developed by using a polystyrene-supported organotin reagent.…”

“…Moreover, a heterogeneous version of the reaction was also developed by using a polystyrene-supported organotin reagent. 13,14 This methodology limits efficiently the amount of residual tin in the reaction product. 15,16 The high temperatures required for the preparation of tetrazoles in batch associated to the inherent hazardous nature of azides, prompted us to explore a continuous flow approach of our technology.…”