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
8 See reference 1a and references cited therein.
9 4 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
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/.
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
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.
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
