An Efficient New Procedure for the One-Pot Conversion of Aldehydes into the Corresponding Nitriles

Abstract

A new and efficient procedure for the one-pot conversion of various aldehydes into the corresponding nitriles under mild reaction conditions has been developed. The ethyl dichlorophosphate/DBU-mediated dehydration of aldoxime intermediates was utilized as a key operation to effect the transformation.

Key words

aldehydes - nitriles - ethyl dichlorophosphate - DBU - ­dehydration

References and Notes

• 1 Friedrich K. Wallensfels K. The Chemistry of the Cyano Group   Rappoport Z. Wiley-Interscience; New York: 1970. 
• 2 Coskun N. Arikan N. Tetrahedron  1999,  55:  11943 
• 3 Boruah M. Knowar D. J. Org. Chem.  2002,  67:  7138 
• 4a Erman MB. Snow JW. Williams MJ. Tetrahedron Lett.  2000,  41:  6749 
• 4b Talukar S. Hsu JL. Chou TC. Fang JM. Tetrahedron Lett.  2001,  42:  1103 
• 5 Foley PJ. J. Org. Chem.  1969,  34:  2805 
• For examples, see:
• 6a Sandnya A. Synthesis  1982,  190 
• 6b Feng JC. Lin G. Dia L. Bian NS. Synth. Commun.  1998,  28:  3765 
• 6c Das B. Madhusudhan P. Venkataiah B. Synlett  1999,  1569 
• 6d Kumar HMS. Reddy BVS. Deddy PT. Yadav JS. Synthesis  1999,  586 
• 6e Sharghi H. Sarvari MH. Tetrahedron  2002,  58:  10323 
• 6f Koshima H. Hamada M. Tani M. Iwasaki S. Sato F. Heterocycles  2002,  57:  2145 
• 6g Srinivas KVNS. Mahender I. Das B. Chem. Lett.  2003,  32:  738 
• 6h Ballini R. Fiorini D. Palmieri A. Synlett  2003,  1841 
• 6i Sharghi H. Sarvari MH. Synthesis  2003,  243 ; and references cited therein
• 7 Kuo CW. Zhu JL. Wu JD. Chu CM. Yao CF. Shia KS. Chem. Commun.  2007,  301 
• 11 For the preparation of compound 3, see: Falorni M. Giacomelli G. Porcheddu A. Teddei M. J. Org. Chem.  1999,  64:  8962 
• 12 Monica CD. Randazzo A. Bifulco G. Cimino P. Aquino M. Izzo I. Riccardis F. Luigi GP. Tetrahedron Lett.  2002,  43:  5707 
• 13 Costello GF. James R. Shaw JS. Slater AM. Stutchbury NCJ. J. Med. Chem.  1991,  34:  181 
• 14 Liskamp R. M. J., Boiejen A.; Eur. J. Org. Chem.; 1999, 2127
• 15 Kohrt A., Hartke K.; Liebigs Ann. Chem.; 1992, 6: 595
• 16 A representative experimental procedure is described for the preparation of benzonitrile (2). To a solution of benzaldehyde (1, 0.2 g, 1.88 mmol) in CH₂Cl₂ (8 mL), powdered 3 Å MS (120 mg), 1.2 equiv of NH₂OH·HCl (0.157 g, 2.26 mmol) and 5 equiv of DBU (1.43 g, 9.42 mmol) were successively added in one portion. The reaction mixture was stirred at r.t. for 10 h, cooled in an ice-water bath to 5 °C, and 1.5 equiv of EtOPOCl₂ (0.46 g, 2.83 mmol) were added. Then, stirring at r.t. was continued for an additional 5 h. The mixture was then quenched with aq NH₄Cl, extracted with CH₂Cl₂ and subjected to chromatographic purification on silica gel (15% EtOAc in hexane) to afford 2 in 96% yield (0.186 g), whose spectral data (IR, ¹H NMR and ¹³C NMR) were identical to those of the authentic sample.Benzonitrile(2): IR (KBr): 2228, 1701, 1597, 1583, 1489, 1447 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.56-7.46 (m, 3 H), 7.43-7.32 (tm, J = 7.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 132.8, 132.0, 129.1, 118.8, 112.2. GC-MS: m/z = 103.5 [M]⁺.(S)-2-(tert-Butoxycarbonylamino)propanenitrile (4): IR (KBr): 3317, 2979, 2260, 1680 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 1.46 (s, 9 H), 1.53 (d, J = 7.2 Hz, 3 H), 4.61 (br s, 1 H), 4.99 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.6, 28.2, 37.6, 81.2, 119.6, 154.1. LC-MS (ES): m/z = 193 [M + 23]⁺; mp 105-106 °C; [α]_D ^{2 5} -24.5 (c 2.5, CHCl₃) {Lit.¹⁵ [α]_D ^{2 0} -24.6 (c 2.5, CHCl₃)}.(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanenitrile (6): IR (KBr): 3353, 3065, 2248, 1691 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (s, 9 H), 3.08 (m, 2 H), 4.84 (m, 1 H), 4.95 (m, 1 H), 7.25-7.40 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.2, 39.2, 43.4, 81.3, 118.4, 127.9, 129.0, 129.5, 133.9, 154.1. LC-MS (ES): m/z 246 [M]⁺; mp 114-115 °C; [α]_D ^{2 5} -16.4 (c 0.98, dioxane) {Lit.¹⁴ [α]_D ^{2 5} -16.4 (c 0.98, dioxane)}

8

Both PhCH=NOPO(OEt)₂ and PhCH=NOH were obtained as the single stereoisomers. The stereochemistry remains to be determined.

9

An optimized amount of 3 Å MS was used. It was found that at least 120 mg of 3 Å MS was required for a quantitative conversion of 1.50 mmol of benzaldehyde (1) into benzonitrile (2).

10

Satisfactory spectral and LC-MS analytical data were obtained for all products; all known nitriles showed physical and spectral properties identical to those reported in the literature.