The use of malononitrile in the synthesis of novel α-amino nitriles

Article abstract of DOI:10.1081/SCC-100104341

Continuing earlier studies designed to obtain compounds of pharmaceutical interest, we used acetyl acetone (1, R = CH₃) and ethyl acetoacetate (1, R=OEt) for the preparation of some novel α-amino nitriles (3, 6 and 7). The structures of the new

Full text of DOI:10.1081/SCC-100104341

SYNTHETIC COMMUNICATIONS, 31(12), 1901–1905 (2001)
THE USE OF MALONONITRILE IN THE
SYNTHESIS OF NOVEL a-AMINO NITRILES
M. A. Metwally,* and M. Abdel Mogieb
Department of Chemistry, Faculty of Science, University of
Mansoura, Mansoura, Egypt
ABSTRACT
Continuing earlier studies designed to obtain compounds of
pharmaceutical interest, we used acetyl acetone (1, R ¼ CH3)
and ethyl acetoacetate (1, R ¼ OEt) for the preparation of
some novel a-amino nitriles (3, 6 and 7). The structures of
the new ring systems have been confirmed by IR, NMR and
mass spectral data.
Key Words: Synthesis; Malononitrile; Amino nitriles
The ready availability of b-diketones and the enhanced reactivity of
their electrophilic sites have made them the starting materials of choice for
a great variety of synthesis. As a further extension on the reaction of acetyl
acetone and ethyl acetoacetate with some reagents,1–7 thiocarbamoylation
followed by reaction of (1, R ¼ CH3) with malononitrile and the reaction of
(1, R ¼ OEt) with aniline and/or aryldiazonium salts and malononitrile were
investigated.
Application of thiocarbamoylation to (1, R ¼ CH3), gave 2-acetyl-
1-thioacetoacetanilide (2).8 Heating 2 with malononitrile in ethanol and
* Corresponding author.
1901
Copyright & 2001 by Marcel Dekker, Inc.
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piperidine as a catalyst gave 2-acetyl-3-phenylamino-4-cyano-5-aminophenol
(3) in a good yield. The structure of compound 3 was based on IR, 1H-NMR
and mass spectral data. The formation of compound 3 may be rationalized in
terms of carbanion attack at the thiocarbonyl carbon atom of 2 to give the
dicyanomethylidine intermediate (A). This intermediate undergoes a ring
closur to give intermediate (B) which rearranges to the final product 3.
The reaction of (1, R ¼ OEt), with aniline gave acetoacetanilide (4).9
Coupling of 4 with aryldiazonim salts resulted in the formation of the
arylazo derivatives (5).10 The reaction of 5 with malononitrile in ethanol-
piperidine gave 3-arylazo-1-phenyl-4-methyl-5-cyano-6-amino-2-pyridones
(6a–c) in a good yield.
An alternative approach to the pyridones (6a–c) was treating 4 with
malononitrile in ethanol-piperidine to give the 2-pyridone 7. Coupling of 7
with aryldiazonium salts gave pyridones (6a–c). Structure 7 was established
1
by H-NMRand mass spectral data. In the presence of alcohol the forma-
tion of 6 and 7 proceeds through cyanocarbon acid (C) intermediate, which
on subsequent cyclization gives intermediate (D) and finally 6 and 7.
EXPERIMENTAL
All melting points are uncorrected. Elemental analyses were performed
in the Microanalytical Unit, Mansoura and Cairo University. IRspectra
(in cmꢀ1) were recorded by means of pressed KBr on a Perkin-Elmer 883
1
Infrared Spectrophotometer. H-NMRspectra are obtained at 400 MHz
using TMS as an internal standard. Mass spectra were obtained using
Varian MAT 711 at 70 eV.
2-Acetyl-1-thioacetoacetanilide (2)
Thiscompoundwaspreparedaccordingtopreviouslyreportedmethod.8
2-Acetyl-3-phenylamino-4-cyano-5-aminophenol (3), 3-Arylazo-
1-phenyl-4-methyl-5-cyano-6-amino-2-pyridones (6a–c) and 1-Phenyl-
4-methyl-5-cyano-6-amino-2-pyridone (7)
General Procedure
To (0.005 mol) of each of 2,8 49or 510 in ethanol (25 mL) and 2–3 drops
of piperidine was added malononitrile (0.33 g, 0.005 mol). The reaction

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METWALLY AND ABDEL MOGIEB
mixture was refluxed for 4–6 hrs, left to cool and the solid product
that separated in each case was filtered off, dried and recrystallized
from ethanol.
Compound 3: obtained as colourless crystals, yield (70%), m.p. 110ꢁC.
Analysis: C14H13N3O2 (267.27)
Calcd: C 67.40 H 4.90 N 15.72
Found: C 67.55 H 4.98 N 15.59
IR: ꢀ ¼ 1650 (C ¼ O bonded), 2200 (C ꢂ N), 3200–3300 (br, NH and
NH2) and 3420 cmꢀ1 (OH). 1H-NMR: d ¼ 2.25 (s, 3H, CH3CO-), 5.09
(s, 2H, NH2), 7.1 (s, 1H, H-6), 7.25 (s, 1H, -NH) and 7.55–7.7
(m, 5H, ArH). - M.S. m/z (rel. int.) 266 (M+-1) (2), 241 (M+-CN)
(93), 241 (M+-HCN) (100), 226 (19), 178 (19.5), 141 (17), 77 (20), 55 (21).
Compound 6a: obtained as orange crystals, yield (85%), m.p. 169ꢁC.
Analysis: C20H17N5O2 (359.38)
Calcd: C 66.83 H 4.76 N 19.48
Found: C 66.95 H 4.91 N 19.26
IR: ꢀ ¼ 1665 (C ¼ O), 2270 (C ꢂ N), 3050–3200 (br, NH2).
Compound 6b: obtained as yellow crystals, yield (65%), m.p. 145ꢁC.
Analysis: C19H15N5O2 (345.35)
Calcd: C 66.07 H 4.37 N 20.28
Found: C 66.11 H4.21 N 20.15
IR: ꢀ ¼ 1670 (C ¼ O), 2245 (C ꢂ N), 3100–3250 (NH2), 3420 (OH).
Compound 6c: obtained as brown crystals, yield (81%), m.p. 125ꢁC.
Analysis: C20H17N5O (343.38)
Calcd: C 69.95 H 4.99 N 20.39
Found: C 70.09 H 4.91 N 20.43
IR: ꢀ ¼ 1665 (C ¼ O), 2235 (C ꢂ N), 3120–3210 (NH2).-M.S. m/z (rel.
int.) 343 (M+) (0,5), 295 (3), 225 (100), 197 (95), 182 (18), 93 (20), 77 (38).
Compound 7: obtained as colourless crystals, yield (71%), m.p. 295ꢁC.
Analysis: C13H11N3O (225.24)
Calcd: C 69.31 H 4.92 N 18.65
Found: C 69.43 H 4.81 N 18.51
IR: ꢀ ¼ 1675 (C ¼ O), 2200 (C ꢂ N), 3300, 3450 (NH2).-1H-NMR: d ¼ 2.26
(s, 3H, CH3), 5.15 (s, 2H, NH2), 5.87 (s, 1H, H-3, olefinic proton), 7.25–7.7
(m, 5H, ArH).- M.S. (rel. int.): 225 (M+) (100), 197 (92), 169 (18), 104 (16),
93 (20), 77 (39).

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REFERENCES
1. Etman, H.A; Sadek, E.G. and Metwally, M.A. Arch. Pharm. Res.
1990, 17(1), 36.
2. Etman, H.A.; Sadek, E.G. and Metwally, M.A. J. Indian Chem. Soc.
1990, 67, 211.
3. Hammouda, M.; Etman, H.A. and Metwally, M.A. J. Serb. Chem.
Soc. 1992, 57(3), 165.
4. Moustafa, M.A.; Eisa, H.M.; El-Emam, A.A. and Metwally, M.A.
Arch. Pharm. Res. 1990, 13(2), 204.
5. Metwally, M.A.; Yousif, M.Y.; Ismaiel, A.M. and Etman, H.A.
Heterocycles 1985, 23(9), 2251.
6. Metwally, M.A.; Yousif, M.Y.; Ismaiel, A.M. and Amer, F.A. J. Indian
Chem. Soc. 1985, LXII, 54.
7. Metwally, M.A. and Amer, F.A. Pakist. J. Sci. Ind. Res. 1981,
24(4), 135.
8. Borisevich, A.N.; Grabenko, A.D. and Pel’Kis, P.S. Zh. Obshch. Khim
1963, 33(7), 2223; Chem. Abstr. 1963, 59, 13874.
9. Taneja, A.D. and Srivastava, P.K. Chimia 1971, 25, 92.
10. Burr, A.H. and Rowe, F.M. J. Soc. Dyers and Colourists 1928, 44, 205;
Chem. Abstr. 1928, 22, 3400.
Received in the USA August 23, 2000

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