An improved synthesis of 4-aminobutanenitrile from 4-azidobutanenitrile and comments on room temperature stability

Abstract

4-Aminobutanenitrile (1) is an important synthetic intermediate for neurological disorder therapeutics including Parkinson’s and Alzheimer’s diseases, and is an industrial precursor to pyrroline and pyrrolidine. Synthesis of 1 by Co(II) catalyzed reduction of 4-azidobutanenitrile (2) with NaBH₄, or by a one-pot Staudinger reduction of 2 in THF, was low yielding. ¹H-NMR analysis of the Staudinger reduction revealed the formation of iminophosphorane intermediate (3) after 22 h at rt, and that increasing the reaction temperature from rt to 40 °C promoted hydrolysis of 3 to 1. A modified Staudinger reduction of 2 involving pyridine as solvent, addition of water 3 h after triphenylphosphine, and a temperature increase to 40 °C, gave rise to 1 in 69% yield. 1 is unstable at rt, thus the hydrochloride salt of 1 (1⋅HCl) was prepared by bubbling HCl_(g) through a solution of 1 in chloroform. 1⋅HCl is stable at rt and is hence the preferred form for storage.

Graphical Abstract

Keywords:

• Aminonitriles
• nuclear magnetic resonance spectroscopy
• stability
• staudinger reduction

Acknowledgments

The authors acknowledge support from the Australian Research Council Centre of Excellence for Nanoscale Biophotonics (CE140100003). PKC would like to acknowledge PhD scholarship support from the MF and MH Joyner Scholarship in Science, and the Norman and Patricia Polglase Supplementary Scholarship. The authors would like to thank Philip Clements for assistance with NMR collection and analysis. This work was performed in part at the Optofab node of the Australian National Fabrication Facility utilizing Commonwealth and SA State Government funding.