A Clean Conversion of Aldehydes to Nitriles Using a Solid-Supported Hydrazine

Abstract

A polymer-supported hydrazine reagent has been applied to the conversion of a range of aldehydes to nitriles, providing a clean and efficient route to more diverse building blocks for combinatorial chemistry programmes.

Key words

aldehydes - nitriles - polymer-supported reagents

References

• 2 For example by polymer-supported oxidation reagents, see: Ley SV. Baxendale IR. Bream RN. Jackson PS. Leach AG. Longbottom DA. Nesi M. Scott JS. Storer I. Taylor SJ. J. Chem. Soc., Perkin Trans. 1  2000,  3815 
• 3a Foley HG. Dalton DR. J. Chem. Soc., Chem. Commun.  1973,  628 
• 3b Rosini G. Baccolini G. Cacchi S. J. Org. Chem.  1973,  38:  1061 
• 3c Kukhar VP. Pasternak VI. Synthesis  1974,  563 
• 3d Vowinkel E. Bartel J. J. Chem. Ber.  1974,  107:  1221 
• 3e Olah GA. Keumi T. Synthesis  1979,  112 
• 3f Sosnovsky G. Krogh JA. Umhoefer SG. Synthesis  1979,  722 
• 3g Saednya A. Synthesis  1982,  190 
• 3h Shinozaki H. Imaizumi M. Tajima M. Chem. Lett.  1983,  929 
• 3i Meshram HM. Synthesis  1992,  943 
• 3j Fukuzawa S. Yamaishi Y. Furuya H. Terao K. Iwasaki F. Tetrahedron Lett.  1997,  38:  7203 
• 3k Sampath Kumar HM. Mohanty PK. Suresh Kumar M. Yadav JS. Synth. Commun.  1997,  27:  1327 
• 3l Yang SH. Chang S. Org. Lett.  2001,  3:  4209 
• 4 Misono A. Oda T. Koda S. Bull. Chem. Soc. Jpn.  1966,  39:  854 
• 5 Parameswaran KN. Friedman OM. Chem. Ind. (London)  1965,  988 
• 6 Nakagawa K. Mineo S. Kawamura S. Horikawa M. Tokumoto T. Mori O. Synth. Commun.  1979,  9:  529 
• 7a Fischer E. J. Prakt. Chem.  1965,  29:  199 
• 7b Brack-man W. Smit PJ. Rec. Trav. Chim. Pay-Bas  1963,  82:  757 
• 8a Capdeveille P. Lavigne A. Maumy M. Synthesis  1989,  451 
• 8b Menger FM. Tsuno T. J. Am. Chem. Soc.  1989,  111:  4903 
• 9 Chen F.-E. Fu H. Meng G. Cheng Y. Lu Y.-X. Synthesis  2000,  11:  1519 
• 10 Hinzen B. Lenz R. Ley SV. Synthesis  1998,  977 
• 11a

  Commercially available solid-supported hydrazines, such as PS-TsNHNH₂, whilst effective scavengers of aldehydes, did not oxidise upon treatment with mCPBA to release nitriles.

• 11b

  Polymer-supported hydrazine: Merrifield resin (Polymer Laboratories, 3.89 mmol/g, 18.60 g) was thoroughly washed [MeOH (50 mL), CH₂Cl₂ (50 mL), Et₂O (50 mL) this cycle was repeated 3 times] and dried in vacuo. The resin was cooled to 0 °C. Methyl hydrazine (100 g, 2.171 mol, 30 equiv) was added drop wise and the temperature maintained at 0 °C. The resin was filtered to remove excess methyl hydrazine, and stirred in a 2:1 mixture of CH₂Cl₂-NEt₃ (200 mL) for 1 h. The resin was filtered, washed [MeOH (50 mL), CH₂Cl₂ (50 mL), Et₂O (50 mL) this cycle was repeated 10 times] and dried in vacuo.

• 12 Smith PAS. In The Chemistry of Open Chain Organic Nitrogen Compounds   Vol II:  W. A. Benjamin; New York N.Y.: 1966.  p.126 
• 15 Mlochowski J. Kloc K. Kubicz E. J. Prakt. Chem.  1994,  336:  467 

1

Data courtesy of Available Chemicals Directory ACD 2001.

13

The loading was determined by scavenging a 1:1 mixture of benzaldehyde and benzyl alcohol for 1 h and comparing the ratio of alcohol to aldehyde in the NMR spectra of the starting solution and recovered mixture. Loadings of approximately 3 mmol/g were obtained.

14

Dimethyl dioxirane oxidation was also attempted but no oxidation was observed.

16

Typical procedure: Benzaldehyde (0.1 g, 0.942 mmol, 0.096 mL) was dissolved in CH₂Cl₂ (10 mL), and agitated for 1 h at r.t. with the polymer-supported hydrazine 1 (0.565 g, 1.130 mmol, 1.2 equiv). The polymer was separated from the reaction mixture by filtration, and the filtrate was concentrated in vacuo to yield recovered benzaldehyde (7.5 mg). The resin was washed thoroughly [MeOH (50 mL), CH₂Cl₂ (50 mL), Et₂O (50 mL) this cycle was repeated 3 times] then swelled in CH₂Cl₂ (10 mL), and agitated for 1 h at r.t. with mCPBA (0.358 g, 2.073 mmol, 2.2 equiv) and NaHCO₃ (50 mg). Polymer-supported polyvinylpyridine (Fluka, 0.545 g, 5.181 mmol, 5.5 equiv) was added to scavenge out remaining mCPBA and the reaction mixture was agitated for 1 h. The polymer was separated from the reaction mixture by filtration and the filtrate was washed with saturated sodium hydrogen carbonate (20 mL) to remove residual 3-chlorobenzoic acid. The organic fraction was concentrated in vacuo to yield the desired product, benzonitrile (0.049 g, 0.48 mmol, 55%) without further purification.