Monosubstituted Malononitriles: Efficient One-Pot Reductive Alkylations of Malononitrile with Aromatic Aldehydes

Abstract

A powerful new one-pot method has been developed for the reductive alkylation of malononitrile with aromatic aldehydes. This new procedure has vastly improved the yield and efficiency of the process, and increased the scope of the aromatic aldehydes. Incorporating water as the catalyst in ethanol for the condensation step allows stoichiometric amounts of malononitrile and aldehyde to be employed. The reduction step takes place quickly and efficiently with sodium borohydride to give monosubstituted malononitriles via filtration or extraction. The product from 2-quinolinecarboxaldehyde quickly rearranges to a novel indolizine, while alkylation of the monosubstituted derivative provides an unsymmetrically disubstituted malononitrile that does not rearrange.

Key words

malononitrile - aldehydes - condensation - reduction - heterocycles

References

• 1a Li C.-J. Chem. Rev.  2005,  105:  3095 
• 1b Fagnou K. Lautens M. Chem. Rev.  2003,  103:  169 
• 1c Culkin DA. Hartwig JF. Acc. Chem. Res.  2003,  36:  234 
• 1d Mayr H. Kempf B. Ofial AR. Acc. Chem. Res.  2003,  36:  66 
• 1e Sammelson RE. Kurth MJ. Chem. Rev.  2001,  101:  137 
• 2a Wu Z.-L. Li Z.-Y. J. Org. Chem.  2003,  68:  2479 
• 2b Grossman RB. Varner MA. J. Org. Chem.  1997,  62:  5235 
• 3a Reddy BM. Patil MK. Rao KN. Reddy GK. J. Mol. Catal. A: Chem.  2006,  258:  302 
• 3b Saravanamurugan S. Palanichamy M. Hartmann M. Murugesan V. Appl. Catal. A  2006,  298:  8 
• 3c Wang X.-S. Zeng Z.-S. Li Y.-L. Shi D.-Q. Tu S.-J. Wei X.-Y. Zong Z.-M. Synth. Commun.  2005,  35:  1915 
• 3d Deb ML. Bhuyan PJ. Tetrahedron Lett.  2005,  46:  6453 
• 3e Pande A. Ganesan K. Jain AK. Gupta PK. Malhotra RC. Org. Process Res. Dev.  2005,  9:  133 
• 4a Xue D. Chen Y.-C. Cui X. Wang Q.-W. Zhu J. Deng J.-G. J. Org. Chem.  2005,  70:  3584 
• 4b Sammelson RE. Allen MJ. Synthesis  2005,  543 
• 4c Ranu BC. Samanta S. J. Org. Chem.  2003,  68:  7130 
• 4d Ranu BC. Samanta S. Tetrahedron  2003,  59:  7901 
• 4e Zhang B. Zhu X.-Q. Lu J.-Y. He J. Wang PG. Cheng J.-P. J. Org. Chem.  2003,  68:  3295 
• 4f Garden SJ. Guimaraes CRW. Correa MB. de Oliveira CAF. Pinto AC. de Alencastro RB. J. Org. Chem.  2003,  68:  8815 
• 4g Xue D. Chen Y.-C. Cui X. Wang Q.-W. Zhu J. Deng J.-G. J. Org. Chem.  2005,  70:  3584 
• 5 Dunham JC. Richardson AD. Sammelson RE. Synthesis  2006,  680 
• 6 Zhang Z. Gao J. Xia J.-J. Wang G.-W. Org. Biomol. Chem.  2005,  3:  1617 
• 7 Jung Y. Marcus RA. J. Am. Chem. Soc.  2007,  129:  5492 
• 9 Extreme caution must be employed in handling benzylidenemalononitriles (intermediates before NaBH₄ reduction). The 2-chloro derivative, 2-chlorobenzal-malononitrile (Table 1, entry 7), is known as CS, which has been used as the active ingredient in riot control and anti-personnel devices. See: Jones GRN. Nature  1972,  235:  257 
• 11a Smith CR. Bunnelle EM. Rhodes AJ. Sarpong R. Org. Lett.  2007,  9:  1169 
• 11b Liu Y. Song Z. Yan B. Org. Lett.  2007,  9:  409 
• 11c Kaloko J. Hayford A. Org. Lett.  2005,  7:  4305 
• 12 Marchalin S. Baumlova B. Baran P. Oulyadi H. Daich A. J. Org. Chem.  2006,  71:  9114 
• 13a Hofmann M, Bastiaans HMM, Langewald J, Oloumi-Sadeghi H, and Culbertson DL. inventors; PCT Int. Appl. WO  2007017414.  ; Chem. Abstr. 2007, 146, 229359
• 13b Daihei D. inventors; Jpn. Kokai Tokkyo Koho JP  2007031422.  ; Chem. Abstr. 2007, 146, 228960
• 13c Otaka T, and Ohira D. inventors; Jpn. Kokai Tokkyo Koho JP  2004099597.  ; Chem. Abstr. 2004, 140, 303517
• 13d Otaka K, Suzuki M, and Oohira D. inventors; PCT Int. Appl. WO  2002089579.  ; Chem. Abstr. 2002, 137, 369842
• 16 Castedo L. Riguera R. Anal. Quim.  1980,  C76:  24 ; Chem. Abstr. 1980, 94, 191412
• 17 Lin C.-F. Yang J.-S. Chang C.-Y. Kuo S.-C. Lee M.-R. Huang L.-J. Bioorg. Med. Chem.  2005,  13:  1537 
• 18 Sammelson RE. Gurusinghe CD. Kurth JM. Olmstead MM. Kurth MJ. J. Org. Chem.  2002,  67:  876 
• 19 Chung CWY. Toy PH. J. Comb. Chem.  2007,  9:  115 
• 20 Sammelson RE. Casida JE. J. Org. Chem.  2003,  68:  8075 

8

See reference 1a and references cited therein.

10

The X-ray data of 26 and 27 have been deposited at the Cambridge Crystallographic Database Centre under CCDC # 661126 and 661127, respectively. They can be retrieved from the web address http://www.ccdc.cam.ac.uk/products/csd/request/.

14

The reaction outcome for this example has no advantages over our previously reported work⁵ where condensation was not performed as a separate step.

15

No acid was added to work up reactions containing nitrogen containing heterocycles.