One pot synthesis of pyrimidine-5-carbonitrile and pyrimidine-5-carboxamide using ammonium chloride under solvent free condition

Article abstract of DOI:10.1007/s12039-019-1633-6

Abstract: Pyrimidine-5-carbonitrile and pyrimidine-5-carboxamide were synthesized from the various substituted benzaldehyde, malononitrile and cyanoacetamide, urea/thiourea in the presence of ammonium chloride followed by characterization using IR, ¹

Full text of DOI:10.1007/s12039-019-1633-6

J. Chem. Sci.
(2019) 131:54
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1633-6
REGULAR ARTICLE
One pot synthesis of pyrimidine-5-carbonitrile and
pyrimidine-5-carboxamide using ammonium chloride under
solvent free condition
J S AHERa,∗, A V KARDELb, M R GAWAREc, D D LOKHANDEc and A M BHAGAREd
aDepartment of Chemistry, K R T Arts, B H Commerce and A M Science College, Shivaji Nagar,
Gangapur Road, Nashik, Maharashtra 422 002, India
bDepartment of Chemistry, KGDM Arts, Commerce and Science College, Niphad, District Nashik,
Maharashtra 422 303, India
cDepartment of Chemistry, KPG Arts, Commerce and Science College Igatpuri, District Nashik,
Maharashtra 422 402, India
dDepartment of Chemistry, KKW Arts, Commerce and Science College, Pimaplgaon (B.), District Nashik,
Maharashtra 422 209, India
E-mail: js_aher@rediffmail.com; anantkardel11@gmail.com
MS received 18 December 2018; revised 9 March 2019; accepted 14 March 2019
Abstract. Pyrimidine-5-carbonitrile and pyrimidine-5-carboxamide were synthesized from the various
substituted benzaldehyde, malononitrile and cyanoacetamide, urea/thiourea in the presence of ammonium
chloride followed by characterization using IR, 1H NMR spectroscopic technique.
Keywords. Ammonium chloride; Biginelli reaction; cyanoacetamide; malononitrile; substituted aromatic
aldehyde; thiourea/urea.
Dipen K Sureja et al.,8 documented the synthesis
of pyrimidine -5-carbonitrile in three different meth-
1. Introduction
ods such as the presence of conc. hydrochloric acid
and ethanol, conc. sulphuric acid and ethanol in the
microwave assisted method, CH3COONa and water by
green chemistry method approach. Nayan H. Bhuva9
and co-worker documented the synthesis of pyrimidine-
5-carboxamide as an intermediate step obtained by
three-component aromatic aldehyde, thiourea, and mal-
ononitrile in the presence of methanol and hydrochloric
acid resulting in pyrimidine-5-carbonitrile, which on
reaction with conc. sulphuric acid gives pyrimidine-5-
carboxamide. Dipti R Patil10 and co-workers in 2010
also documented the same synthesis in the presence of
phosphorus pentaoxide and ethanol. However, all the
reported methods suffered several drawbacks such as
long reaction time, harsh reaction conditions, anhydrous
conditions, stoichiometric amounts, hazardous radia-
tion, use of costly apparatus, and gave unsatisfactory
results. Therefore, in our present work, we have used
the least expensive and easily available catalyst as well
as a mild and neutral reaction condition for the synthesis
The increasing importance of pyrimidines and their
derivatives as intermediates for the synthesis of bio-
logically and industrially useful compounds prompted
us to synthesize pyrimidine-5-carbonitrile derivatives.
Pyrimidine and their derivatives are gaining the atten-
tion of the medicinal chemists in view of a long
and notable history from the day of their discovery.
The important pyrimidine compounds have a diverse
application like bactericidal,1 fungicidal,2 analgesic,3
anti-inflammatory,4 antitumor agents,5 antioxidant,6
anti-HIV.7 They are also used as a calcium channel
blocker. The pyrimidine and its fused derivatives have
been widely used as drugs to treat various diseases.
Pyrimidines occur in some pesticides and plant growth
regulators.
*
For correspondence
J. S. Aher: Affiliated to Savitribai Phule Pune University
(Formerly University of Pune), Maharashtra, India.
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1633-6) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

54 Page 2 of 4
J. Chem. Sci.
(2019) 131:54
NC
CN
R
3
NC
NH4Cl
1100C
N
CHO
H2N
N
XH
R
X
4a-j
+
O
H2N
NH2
R
H2N
CN
5
2
1
O
NH4Cl
1100C
H2N
H2N
N
N
XH
6a-j
R= C6H5, 2-(Cl)-C6H4, 4-(Cl)-C6H4, 4-(NO2)-C6H4, 4-(CH3)-C6H4. X= O, S
Scheme 1. Synthesis of Pyrimidine-5-Carbonitrile and Pyrimidine-5-Carboxamide.
of pyrimidine-5- carbonitrile. We have developed a new (0.18 g 3 mmol/L) and NH4Cl (0.36 g 0.8 mmol/L) were
heated in the oil bath under stirring at 110 ◦C for 4 h. The
method for synthesis of pyrimidine-5-carboxamide the
progress of the reaction was monitored using TLC. After
use of cyanoacetamide.
completion of the reaction, the reaction mixture was cooled
Various methods have been reported vis-à-vis the
at room temperature and poured in crushed ice to obtain the
synthesis of pyrimidine derivatives.11 Few one-pot syn-
solid product. The crude product was filtered and washed with
theses have been published using aromatic aldehyde
cold water and recrystallized from ethyl acetate: n-hexane at
cyano ethyl acetate and thiourea.12–14 Hence, we wish to
a 1:3 ratio to obtain an analytical sample for spectral analysis.
report the results obtained from the study of the prepa-
ration of pyrimidine-5-carbonitrile and pyrimidine-5-
carboxamide and its derivatives with ammonium chlo-
2.2 Spectral data of synthesized compounds
ride (NH4Cl) as easily available catalyst under neutral
and solvent-free conditions (Scheme 1). The procedure
gives the product in good yields and avoids the prob-
lems like cost and handling safety associated with the
use of the solvent. The method decreases reaction time
because of the increase in the reactivity of the reactant
in the solid state at the reaction temperature of 110 ◦C.
2.2a Entry-4a: 4-Amino-2-hydroxy-6-phenylpyrimidine-5
-carbonitrile: Yield: 82%; C11H8N4O: M.p. 179−181 ◦C (Lit
M.p. 179 ◦C) IR (cm−1):
3415,
1589,
3373,
1556,
νO−H
νC=N
νN−H
νAr−H
νC−N
νC≡N
νArC=C
3082, 3032,
2220,
1
1340; H NMR (δ, ppm in dmso-d6, 500 MHz): δ 8.55 (s,
2H,–NH2), δ 7.96 (s, 1H, –OH), δ 7.71–7.61 (m, 5H, Ar-H).
2.2b Entry-4b 4-Amino-6-(2-chlorophenyl)-2-hydroxy-
pyrimidine-5-carbonitrile: Yield: 75%; C11H7N4OCl: M.p.
162−164 ◦C (Lit M.p. 164 ◦C) IR (cm−1): O−H 3415,
ν
ν
Ar−H
2. Experimental
ν
ν
ν
ν
3091, 3049, C≡N 2225, C=N 1579, C−N 1286, Ar−Cl 1128;
1HNMR (δ, ppm in dmso-d6, 500 MHz): δ 8.68 (s, 2H, -NH2),
δ 8.02 (s, 1H, –OH) δ 7.71–7.57 (m, 4H, Ar-H).
The reagents used are of research grade and are purchased
from SD Fine-Chem and Merck laboratories. The melting
points have been recorded in an open capillary method and are
uncorrected. The melting points are compared with the liter-
ature report. The products are characterized by using Fourier
Transform Infrared spectra (FT-IR) and 1H Nuclear Magnetic
Resonance (1H NMR). The FT-IR spectra are recorded on
2.2c
Entry-4d
4-Amino-6-(4-nitrophenyl)-2-hydroxy-
pyrimidine-5-carbonitrile:◦Yield: 74%; C11H7N5O3: M.p.
221−223 ◦C (Lit M.p. 224 C) IR (cm−1): O−H 3369,
ν
ν
Ar−H
νC≡N
νC=N
νArC=C
νN−O
3034, 2920,
2218,
1589,
1566,
1440,
1317; 1H NMR (δ, ppm in dmso-d6, 500 MHz):
ν
C−N
1
Shimadzu FT-IR spectrometer while H NMR spectra have
δ 8.40 (s, 2H, - NH2), δ 7.99 (s, 1H, –OH), δ 7.97–7.18 (m,
been recorded on Bruker (500 MHz) using DMSO-d6 as a
solvent.
4H, Ar-H).
2.2d Entry-4 h 4-Amino-6-(4-chlorophenyl)-2-mercapto-
2.1 General procedure for the synthesis of
pyrimidine-5-carbonitrile and
pyrimidine-5-carboxamide
pyrimidine-5-cabonitrile: Yield: 81%; C11H7N4OCl M.p.
123−125 ◦C (Lit M.p. 125 ◦C) IR (cm−1): Ar−H 3032, 2953,
ν
νC≡N
ν
ν
ν
1317,
2218,
1602, 1566,
1180,
ArC=C
C−N
Ar−Cl
2610; 1H NMR (δ, ppm in dmso-d6, 500 MHz): δ 8.56
νS−H
In a 100 mL round bottom flask a mixture of benzaldehyde (s, 2H, - NH2), δ 7.96 (s, 1H, –OH), δ 7.94–7.71 (m, 4H,
(0.24 g 2 mmol/L), malononitrile (0.12 g 2 mmol/L), urea Ar-H).

J. Chem. Sci.
(2019) 131:54
Page 3 of 4
54
Table 1. Synthesis of pyrimidine-5-carbonitrile and 4. Conclusions
pyrimidine-5-carboxamide using ammonium chloride under
solvent-free condition.
In conclusion, we have developed a simple, quick
and eco-friendly method for synthesis of pyrimidine-5-
carbonitrile and pyrimidine-5-carboxamide with short
reaction time. It is also inexpensive with the easily
available catalyst under the neutral and solvent-free con-
ditions.
Compound
Ar
X
Yield %
M.p. (◦C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
O
O
O
O
O
S
S
S
S
S
O
O
O
O
O
S
S
S
S
S
82
75
84
74
72
90
85
81
82
84
79
86
89
86
84
75
78
84
81
80
179−181 ◦C
180−182 ◦C
162−164 ◦C
221−223 ◦C
148−150 ◦C
152−154 ◦C
148−150 ◦C
123−125 ◦C
190−192 ◦C
150−152 ◦C
120−122 ◦C
176−178 ◦C
218−220 ◦C
209−210 ◦C
191−193 ◦C
118−120 ◦C
161−163 ◦C
222−224 ◦C
210−212 ◦C
150−152 ◦C
2-(Cl)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
4-(CH3)-C6H4
C6H5
2-(Cl)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
4-(CH3)-C6H4
C6H5
2-(Cl)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
4-(CH3)-C6H4
C6H5
2-(Cl)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
4-(CH3)-C6H4
Supplementary Information (SI)
Supplementary information is available at www.ias.ac.in/
chemsci.
4j
6a
6b
6c
6d
6e
6f
6g
6h
6i
Acknowledgements
The authors are thankful to Maratha Vidya Prasarak Samaj,
Nashik for providing infrastructure for research and spec-
tral data. The authors also express their sincere thanks to the
Principal, K.R.T. Arts B. H. Commerce and A.M. Science
(KTHM) College, Gangapur Road, Nashik and the Princi-
pal, K. G. D. M. Arts, Commerce and Science College,
Niphad.
6j
2.2e Entry-6a 4-Amino-2-hydroxy-6-phenylpyrimidine-5
-carboxamide: Yield: 79%; C11H10N4O2 M.p. 120−122 ◦C
References
IR (cm−1):
3396,
1492,
3350,
3157,
νO−H
νN−H
νAr−H
νArC=C
1
ν
C=N
ν
1689, 1595,
1371; H NMR (δ, ppm in
C−N
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The presence of electron donating and electron with-
drawing group in the aromatic ring has played a
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From Table 1 it is observed that due to the presence
of electron donating group exhibiting (+I) effect in
pyrimidine-5-carbonitrile, the yield of the product has
decreased, while the presence of electron withdrawing
group possessing (-I) effect has enhanced the yield of
the product. This explains the nucleophilic attack or
more positively carbonyl carbon. Similar trends have
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reported a unique, simple and solvent-free contem-
porary synthesis strategy for pyrimidine-5-carbonitrile
and pyrimidine-5-carboxamide. Besides the correct val-
1
ues of IR, the H NMR of compounds are in good
agreement with the assigned structure. In addition,
the latter compound was used as a good source to
enrich the synthesis of heterocyclic chemistry with
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