A Mild Synthesis of Nitriles by von Braun Degradation of Amides Using Triphenyl Phosphite-Halogen-Based Reagents

Abstract

A mild procedure for the synthesis of aromatic and aliphatic nitriles is disclosed. In the presence of bromotriphenoxyphosphonium bromide (TPPBr₂), N-alkyl and N,N-dialkyl amides undergo von Braun degradation to nitriles in good to excellent yields under the mildest conditions ever reported. The reaction proceeds via formation of an iminoyl bromide intermediate at -60 °C, which subsequently dealkylate upon refluxing in chloroform or even at room temperature. In the case of N-tert-butyl, N-α-phenylethyl and N-benzhydryl amides, chlorotriphenoxyphosphonium chloride (TPPCl₂) generated at -30 °C was also effective.

amide degradation - halotriphenoxyphosphonium halides - imidoyl halides - nitriles - triphenyl phosphite

References and Notes

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11

All compounds were characterized by ¹H NMR and EI-MS analysis. For new compounds, ¹³C NMR and elemental analysis were also performed.

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13

TPPBr ₂ -Promoted von Braun Degradation; General Procedure Bromine (0.31 mL, 6.0 mmol) was added to a solution of triphenyl phosphite (1.57 mL, 6.0 mmol) in anhyd CHCl₃ (20 mL) maintained at -60 °C under argon flow. After addition of dry Et₃N (0.9 mL, 6.5 mmol), the amide (5.0 mmol) was added to the pale orange clear solution (for tertiary amides, however, Et₃N was not used). After leaving to warm to r.t. over a period of 3-4 h, the reaction mixture was gently heated to reflux for 16 h, except when TLC analysis already showed complete disappearance of the starting amide (see Table [1] ). The solvent was then evaporated under reduced pressure and the resulting nitrile was purified by column chromatography on silica gel.

14

TPPX₂ is generated by reacting triphenyl phosphite with an equimolecular amount of Cl₂ or Br₂ at low temperature, viz. from -30 °C to -20 °C for chlorine or from -60 °C to -50 °C for bromine. Under such conditions, the predominant species is the halotriphenoxyphosphonium halide (PhO)₃P⁺X X^-, which is active for our synthetic scope. When generated at higher temperatures, increasing amounts of the synthetically inactive covalent species dihalo triphen-oxyphosphorane (PhO)₃PX₂ are also formed.^9a,12

15a

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