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.

Key words

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

References and Notes

• 1 Wöhler F. von Liebig J. Justus Liebigs Ann. Chem.  1832,  3:  267 
• 2a Mowry DT. Chem. Rev.  1948,  42:  189 
• 2b Sandler SR. Karo W. Organic Functional Group Preparations In Organic Chemistry   2nd ed., Vol. 12-I:  Wasserman HH. Blomquist AT. Academic Press; San Diego: 1983.  Chapt. 17. p.549-584  
• 2c Subramanian LR. In Science of Synthesis   Vol. 19:  Thieme; Stuttgart: 2004.  p.79 
• 3a The Chemistry of the Cyano Group   Rappoport Z. Wiley-Interscience; New York: 1970. 
• 3b Larock RC. Comprehensive Organic Transformations   2nd ed.:  Wiley-VCH; New York: 1999. 
• 4 Geyer AM. Gdula RL. Wiedner ES. Johnson MJA. J. Am. Chem. Soc.  2007,  129:  3800 
• 5 von Braun J. Ber. Dtsch. Chem. Ges.  1904,  37:  3210 
• 6a Leonard NJ. Nommensen EW. J. Am. Chem. Soc.  1949,  71:  2808 
• 6b Vaughan WR. Carlson RD. J. Am. Chem. Soc.  1962,  84:  769 
• For instance, see:
• 7a Prelog V. Zalan E. Helv. Chim. Acta  1944,  27:  535 
• 7b Götz M. Bögri T. Gray AH. Tetrahedron Lett.  1961,  2:  707 
• 7c Sallay I. Ayres RH. Tetrahedron  1963,  19:  1397 
• 7d Fodor G. Bauerschmidt E. Cymerman CJ. Can. J. Chem.  1969,  47:  4393 
• 7e Butruille D. Fodor G. Saunderson Huber C. Letourneau F. Tetrahedron  1971,  27:  2055 
• 8a Fodor G. Ryan JJ. Letourneau F. J. Am. Chem. Soc.  1969,  91:  7768 
• 8b Blum J. Fisher A. Tetrahedron Lett.  1970,  23:  1963 
• 8c Dennis WE. J. Org. Chem.  1970,  35:  3253 
• 8d Perni BR. Gribble GW. Org. Prep. Proced. Int.  1983,  15:  297 
• 9a Spaggiari A. Blaszczak LC. Prati F. Org. Lett.  2004,  6:  3885 
• 9b Spaggiari A. Blaszczak LC. Prati F. Ars. Pharm.  2005,  46:  167 
• 9c Spaggiari A. Davoli P. Blaszczak LC. Prati F. Synlett  2005,  661 
• 9d Spaggiari A. Vaccari D. Davoli P. Prati F. Synthesis  2006,  995 
• 9e Vaccari D. Davoli P. Bucciarelli M. Spaggiari A. Prati F. Lett. Org. Chem.  2007,  4:  319 
• 10a Phillips BA. Fodor G. Gal J. Letourneau F. Ryan JJ. Tetrahedron  1973,  29:  3309 
• 10b Fodor G. Nagubandi S. Tetrahedron  1980,  36:  1279 
• 12 Spaggiari A. Vaccari D. Davoli P. Torre G. Prati F. J. Org. Chem.  2007,  72:  2216 
• 15a

  Reaction of optically pure (S)-α-phenylethyl amide 1g, [α]_D +54.1 (c 1.3, acetone); lit.^15b [α]_D +57.0 afforded tolunitrile along with (R)-phenylethyl bromide, [α]_D +28.4 (c 2.1, CHCl₃); lit.^15c [α]_D +111.5.

• 15b Nerdel F. Goetz H. Wendenburg J. Liebigs Ann. Chem.  1959,  627:  106 
• 15c Lau KSY. Wong PK. Stille JK. J. Am. Chem. Soc.  1976,  98:  5832 

11

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

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