Recyclization reactions of 2-(1-benzoylpyrrolidin- 2-ylidene)malononitrile

Article abstract of DOI:10.1007/s10593-010-0469-2

Acylation of pyrrolidin-2-ylidenemalononitrile with benzoyl chloride leads to the formation of 2-(1-benzoylpyrrolidin-2-ylidene)malononitrile. The obtained product was used as starting material in the synthesis of γ- aminopropylpyrazoles and pyrimidines.

Full text of DOI:10.1007/s10593-010-0469-2

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
RECYCLIZATION REACTIONS
OF 2-(1-BENZOYLPYRROLIDIN-
2-YLIDENE)MALONONITRILE
K. V. Shvidenko1*, K. G. Nazarenko1, T. I. Shvidenko2, and A. A. Tolmachev3
Acylation of pyrrolidin-2-ylidenemalononitrile with benzoyl chloride leads to the formation of 2-(1-
benzoylpyrrolidin-2-ylidene)malononitrile. The obtained product was used as starting material in the
synthesis of γ-aminopropylpyrazoles and pyrimidines.
Keywords: ω-aminoalkylheterocycles, binucleophiles, cyclic enamines, recyclization.
For some time a large number of studies have been devoted to heterocycles containing an ω-aminoalkyl
fragment [1]. These compounds are used as intermediates for the synthesis of medicinal preparations, pesticides,
and corrosion inhibitors, and may also be used as promising building-blocks [2-5].
One of the approaches to the making of compounds of a similar nature is the use of the reaction of
recyclization of saturated lactam rings, lactim esters, cyclic amidines, and enamines by the reaction of
nucleophilic reagents [1]. A significant limitation of this method is the fact that the opening of the ring in the
initial compounds frequently occurs under the action of strong nucleophilic reagents and under the fairly rigid
conditions. Thus, recyclization of pyrrolidin-2-ylidenemalononitrile (1) into γ-aminopropylpyrazole readily
occurs on brief boiling of the starting material in a 60% excess of hydrazine hydrate [6]. At the same time the
authors mention that under milder conditions, boiling compound 1 in alcoholic solution, the analogous opening
of the saturated ring was not observed. There is no information in the literature on reactions of cyclic enamine 1
with other nucleophilic reagents.
It is known that the introduction of an electron-withdrawing group at the nitrogen atom in the heterocycle
increases the electrophilicity of the adjacent oxygen atom, and subsequent nucleophilic attack at this position may
lead to cleavage and/or recyclization of the initial compounds with the formation of linear structures or cyclic
products [7-9]. We showed previously that acylation of 2-(nitromethylene)azepane with carboxylic acid chlorides
in the presence of aqueous alkali is accompanied by opening of the saturated ring with the formation of derivatives
of 7-amino-1-nitroheptan-2-one [10]. While continuing investigations in this area we attempted to use an analogous
approach for the synthesis of γ-aminopropyl heterocycles from enamine 1.
_______
* To whom correspondence should be addressed, e-mail: shved@i.com.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
2National Agricultural University of Ukraine, Kiev 03041, Ukraine.
3Research and Development Center for Chemistry and Biology, Kiev T. Shevchenko National University, Kiev
01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67-71, January, 2010. Original
article submitted March 27, 2009.
56
0009-3122/10/4601-0056©2010 Springer Science+Business Media, Inc.

We obtained 2-(1-benzoylpyrrolidin-2-ylidene)malononitrile (2) by the action of benzoyl chloride on
compound 1 in pyridine. This compound was chosen as a model and its interaction with a series of nucleopohilic
and bisnucleophilc reagents has been investigated.
CN
CN
CN
PhCOCl
Py
N
CN
N
H
Ph
O
2
1
As might have been expected the electrophilic properties of benzoyl derivative 2 were expressed far
more strongly than for enamine 1. Thus compound 2 interacts smoothly with benzylamine in boiling toluene
(1 h) forming N-(4-benzylamino-5,5-dicyanopent-4-enyl)benzamide 3. Nucleophilic attrack in this case is
effected at the α-carbon of the enamine and is accompanied by cleavage of the saturated ring. The reaction of
benzoylenamine 2 with p-anisidine requires more prolonged boiling (5 h), and the nucleophilic attack is directed
at the benzoylamino group. In this case, deacylation of compound 2 occurs with regeneration of the initial
enamine 1 and the formation of 4-methoxybenzanilide. Compound 1 does not interact with amines under the
indicated conditions.
Ph
HN
CN
CN
H2NCH2Ph
H
Ph
N
CN
N
PhMe, ∆
O
CN
Ph
O
3
2
O
4-MeOC6H4NH2
CN
CN
N
OMe
Ph
+
H
N
H
The N-benzoyl derivative 2 was used as a 1,3-biselectrophile (C-2 and CN) in reactions with 1,2- and
1,3-bisnucleophilic reagents for obtaining γ-aminopropyl heterocycles, It was found that reaction of 2 with
arylhydrazines leads to the formation of N-[3-(5-amino-1-aryl-4-cyano-1H-pyrazol-3-yl)propyl]benzamides 5
containing a benzoylaminopropyl fragment. Reaction was readily effected on heating the initial compounds in
pyridine.
Ph
NH
Ph
NH
O
O
CN
R
NH2NHR
N
NH
CN
N
H
N
Ph
O
N
R
NC
NC
2
NH2
N
5 a–c
4
5 a R = Ph, b R = 4-FC6H4, c R = 4-MeC6H4
57

Evidently, as in the reaction of compound 1 with benzylamine, the first nucleophilic attack is directed at
the α-position of the enamine, which leads to opening of the saturated ring and the formation of the linear
intermediate 4. Subsequent intramolecular nucleophilic attack by the nitrogen atom of the hydrazine fragment at
the nitrile group leads to closing of the pyrazole ring and the formation of compounds 5.
Reaction with 1,3-bisnucleophilic reagents, alkyl and arylamidines, was carried out under standard
conditions, boiling in alcohol in the presence of sodium ethylate. As in the previous case the formation of a
heterocyclic nucleus is accompanied by opening of a saturated ring of the initial compound. N-[3-(2-R-6-amino-
5-cyanopyrimidin-4-yl)propyl]benzamides 6 were obtained in this way in moderate yield.
O
R
R
N
N
Ph
HN
NH2
H
N
2
NC
EtOH/EtONa
NH2
6 a–c
6 a R = Ph, b R = pyrid-3-yl, c R = Me
The structures of the obtained aminopropyl products 3, 5, and 6 were demonstrated by 1H NMR spectra,
1
and were confirmed by data of elemental analysis. It is necessary to note that in the H NMR spectra of these
compounds the signals of the protons of the methylene group next to the nitrogen atom of the amide group in the
case of 7-amino-1-nitroheptan-2-ones [10], are displaced towards higher field compared with the initial cyclic
compound. Thus in the initial benzoylenamine 2 the triplet at 3.99 ppm corresponds to the methylene group, and
in the aminopropyl products this signal is displayed as a multiplet at 3.20-3.40 ppm. Additional confirmation of
the presence of an aminoalkyl chain in compounds 3, 5, and 6 is the presence of a triplet at 8.5 ppm (J = 5.4 Hz),
corresponding to the amide group proton, absent from the initial cyclic benzoylenamine 2.
It has therefore been shown that 2-pyrrolidin-2-ylidenemalononitrile 1 is readily acylated by benzoyl
chloride. The obtained benzoylenamine 2 may be used as a starting material in the synthesis of γ-benzoyl-
aminopropylpyrazoles and pyrimidines.
EXPERIMENTAL
Melting points are not corrected. Commercially available reagents were used. Enaminonitrile 1 was
1
obtained by the procedure of [6]. Pyridine, benzene, and ethanol were purified by standard methods [11]. The H
NMR spectra were recorded on a Varian 300 instrument (300 MHz) in DMSO-d6, internal standard was TMS.
2-(1-Benzoylpyrrolidin-2-ylidene)malononitrile (2). Benzoyl chloride (0.45 ml, 3.8 mmol) was added
dropwise to a stirred solution of enaminonitrile 1 (0.5 g, 3.8 mmol) in freshly distilled pyridine (7 ml) in an
atmosphere of dry argon at 0oC. The reaction mixture was left overnight, then boiled for 1 h, cooled, and water
was added dropwise with stirring. The mixture was stirred for 1 h, the resulting brown solid was filtered off, and
1
washed with 2-propanol. Yield of compound 2 was 0.54 g (61%); mp 126-128oC (2-propanol). H NMR
spectrum, δ, ppm (J, Hz): 1.99-2.09 (2H, m, H-4); 3.19 (2H, t, J = 7.2, H-3); 3.99 (2H, t, J = 7.2, H-5); 7.52-7.58
(2H, m, Ar); 7.64-7.69 (1H, m, Ar); 7.76 (2H, d, J = 7.2, Ar). Found, %: C 70.97; N 17.93. C14H11N3O.
Calculated, %: C 70.87; N 17.71.
N-(Benzylamino-5,5-dicyanopent-4-enyl)benzamide (3). Benzylamine (0.23 ml, 2.1 mmol) was added
to a suspension of benzoylenamine 2 (0.5 g, 2.1 mmol) in dry toluene (15 ml) and the reaction mixture was
boiled for 1 h. The precipitated solid was filtered off. The yield of benzamide 3 was 0.47 g (65%); mp 170-172
1
oC (ethanol). H NMR spectrum, δ, ppm (J, Hz): 1.68-1.92 (2H, m, 2-CH2); 2.42-2.55 (2H, m, 3-CH2);
58

3.28-3.36 (2H, m, 1-CH2); 4.50 and 4.74 (2H, m, N–CH2Ph); 7.18-7.52 (8H, m, Ar); 7.82 (2H, t, J = 6.9, Ar);
8.48-8.52 (1H, m, PhCONH); 9.17 and 9.29 (1H, m, NHBz). Found, %: C 73.39; N 16.33. C21H20N4O.
Calculated, %: C 73.23; N 16.27.
N-[3-(5-Amino-4-cyano-1-phenyl-1H-pyrazol-3-yl)propyl]benzamide (5a). Phenylhydrazine (0.17 ml,
1.6 mmol) was added to benzoylenamine 2 (0.39 g, 1.6 mmol) in freshly distilled pyridine (7 ml) and the
reaction mixture was boiled for 2 h. The pyridine was evaporated, and the residue triturated with water. Yield of
1
pyrazole 5a was 0.34 g (61%); mp 160-162oC (2-propanol). H NMR spectrum, δ, ppm (J, Hz): 1.87-1.97 (2H,
m, 2-CH2); 2.60 (2H, t, J = 7.8, 3-CH2); 3.34 (2H, q, J = 7.8, 1-CH2); 6.53 (2H, s, NH2); 7.35-7.49 (8H, m, Ar);
7.82 (2H, d, J = 7.2, Ar); 8.45 (1H, t, J = 5.4. NH). Found, %: C 69.45; N 20.12. C20H19N5O. Calculated, %:
C 69.55; N 20.28.
N-[3-(5-Amino-4-cyano-1-(4-fluorophenyl)-1H-pyrazol-3-yl)propyl]benzamide (5b) was obtained
analogously to compound 5a from benzoylenamine 2 (0.4 g, 1.6 mmol) and 4-fluorophenylhydrazine
hydrochloride (0.28 g, 1.6 mmol) in a yield of 0.41 g (67%); mp 185-187oC (2-propanol). 1H NMR spectrum, δ,
ppm (J, Hz): 1.87-1.97 (2H, m, 2-CH2); 2.57 (2H, t, J = 7.8, 3-CH2); 3.32 (2H, q, J = 7.8, 1-CH2); 6.63 (2H, s,
NH2); 7.30-7.34 (2H, m, Ar); 7.42-7.51 (5H, m, Ar); 7.82 (2H, d, J = 7.5, Ar); 8.50 (1H, t, J = 5.4, NH). Found,
%: C 66.31; N 19.42. C20H18FN5O. Calculated, %: C 66.10; N 19.27.
N-[3-(5-Amino-4-cyano-1-(4-methylphenyl)-1H-pyrazol-3-yl)propyl]benzamide (5c) was obtained
analogously to compound 5a from benzoylenamine 2 (0.4 g, 1.6 mmol) and 4-methylphenylhydrazine
hydrochloride (0.28 g, 1.6 mmol) in a yield of 0.35 g (58%); mp 175-177oC (2-propanol). 1H NMR spectrum, δ,
ppm (J,Hz): 1.87-1.97 (2H, m, 2-CH2); 2.34 (3H, s, CH3); 2.57 (2H, t, J = 7.8, 3-CH2); 3.32 (2H, q, J = 7.8.
1-CH2); 6.54 (2H, s, NH2); 7.29 (2H, d, J = 8.0, Ar); 7.34 (2H, d, J = 8.0, Ar); 7.43 (2H, t, J = 7.0, Ar); 7.50
(1H, t, J = 7.0, Ar); 7.82 (2H, d, J = 7.0, Ar); 8.50 (1H, t, J = 5.4, NH). Found, %: C 70.31; N 19.62. C21H21N5O.
Calculated, %: C 70.18; N 19.48.
N-[3-(6-Amino-5-cyano-2-phenylpyrimidin-4-yl)propyl]benzamide (6a). Benzamidine hydro-
chloride (0.33 g, 2.1 mmol) and compound 2 (0.5 g, 2.1 mmol) were added to a solution of sodium ethylate
(0.14 g, 2.0 mmol) in anhydrous ethanol (15 ml). The mixture was boiled for 3 h. The solvent was evaporated in
vacuum, and the residue triturated with water. Yield of pyrimidine 6a was 0.3 g (41%); mp 225-227oC (ethanol).
1H NMR spectrum, δ, ppm: 1.91-2.15 (2H, m, 2-CH2); 2.64-2.91 (2H, m, 3-CH2); 3.24-3.42 (2H, m, 1-CH2);
7.37-7.92 (10H, m, Ar + NH2); 8.25-8.55 (3H, m, Ar + NH). Found, %: C 70.35; N 19.65. C21H19N5O.
Calculated, %: 70.57; N 19.59.
N-{3-[6-Amino--5-(cyanopyrimidin-4-yl)-2-(pyrid-3-yl)]propyl}benzamide (6b) was obtained
analogously to compound 6a from benzoylenamine 2 (0.4 g, 1.6 mmol) and pyridine-3-carboxamidine
hydrochloride (0.26 g, 1.6 mmol) in a yield of 0.25 g (35%); mp 234-236oC (a mixture of ethanol–DMF).
1H NMR spectrum, δ, ppm (J, Hz): 2.03-2.06 (2H, m, 2-CH2); 2.87 (2H, t, J = 7.0, 3-CH2); 3.37 (2H, m, 1-CH2);
7.42 (2H, t, J = 7.5, Ar); 7.48-7.54 (2H, m, Ar); 7.81 (2H, d, J = 7.5, Ar); 7.60-8.20 (2H, br. s, NH2), 8.51 (1H, t,
J = 5.5, NH); 8.56 (1H, d, J = 7.5, H-4 Py); 8.70 (1H, d, J = 4.5, H-6 Py); 9.43 (1H, s, H-2 Py). Found, %:
C 67.24; N 23.67. C20H18N6O. Calculated, %: C 67.03; N 23.45.
N-[3-(6-Amino-5-cyano-2-methylpyrimidin-4-yl)propyl]benzamide (6c) was obtained analogously to
6a from benzoylenamine 2 (0.7 g, 2.8 mmol) and acetamidine hydrochloride (0.27 g, 2.8 mmol) in a yield of
0.22 g (25%); mp 219-221oC (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 1.88-1.91 (2H, m, 2-CH2); 2.34 (3H,
s, CH3); 2.71 (2H, t, J = 7.0, 3-CH2); 3.30 (2H, q, J = 7.0, 1-CH2); 7.44 (2H, t, J = 7.0, Ar); 7.50 (1H, t, J = 7.0,
Ar); 7.55-7.75 (2H, br. s, NH2); 7.82 (2H, d, J = 7.0, Ar); 8.51 (1H, t, J = 5.5, NH). Found, %: C 65.24; N 23.69.
C16H17N5O. Calculated, %: C 65.07; N 23.71.
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