International Journal of Organic Chemistry, 2011, 1, 47-52
doi:10.4236/ijoc.2011.12009 Published Online June 2011 (http://www.SciRP.org/journal/ijoc)
A Facile Synthesis of 2-Amino-5-cyano-4,
6-disubstitutedpyrimidines under MWI
Kishor S. Jain*, Swapnil K. Chaudhari, Nikhil S. More, Kapil D. More, Sachin A. Wakedkar,
M. K. Kathiravan
P. G. Research Centre, Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Pune, India.
Received May 21, 2011; revised June 20, 2011; accepted July 1, 2011
Abstract
Microwave Assisted Organic Synthesis (MAOS) is energy efficient and effective tool to speed up the syn-
thesis for drug discovery process. In the present study we report a novel protocol for the rapid, high
throughput synthesis of mononuclear 2-amino-5-cyano-4,6-disubstituted pyrimidines, adaptable to parallel
synthesis for compound libraries. The overall reaction time in hrs has been reduced to 25 - 50 minutes with
improved yields.
Keywords: Microwave Assisted Organic Synthesis (MAOS), 2-Amino-5-Cyano-2, 6-Disubstitutedpyrimidines,
α-Cyanoketene S,S-Acetals
1. Introduction
Mononuclear pyrimidines exhibit a wide range of me-
dicinal activities and are isomeric with two other forms
of diazine. Physiologically important nucleic acids bases
as well as some vitamins are pyrimidine derivatives [1,2].
The major approach to the synthesis of mononuclear
pyrimidines is the principal synthesis, involving the
condensation of N-C-N fragment with an appropriate
functionalized 3-carbon unit [3]. Various synthetic me-
thods and reaction conditions have been employed for
the synthesis of mononuclear pyrimidines in the litera-
ture [4-17].
The reported methods for the syntheses of mononu-
clear pyrimidines have one or the other limitations such
as more number of steps, use of carcinogenic reagents
like benzene, pyridine and lengthy reaction time. In
many syntheses volatile organic solvents are used, which
are detrimental to the environment and are to be recov-
ered.
The generalized method for the synthesis of mononu-
clear pyrimidines is by the cyclocondensation of α-
cyanoketene S,N-acetals with guanidine in DMF under
reflux for 24 - 36 hr. The α-cyanoketene S,N-acetals
were prepared through the nucleophilic displacement of
the 3-methylthio group of the corresponding α-cyanoke-
tene S,S-acetals with various amines [16].
Tominaga et al. [18] have further improved on the
synthesis of mononuclear pyrimidines by direct one pot
synthesis through Multi Component Reaction (MCR) of
α-Cyanoketenes S,S-acetals, appropriate amine and gua-
nidine carbonate (Scheme 1). The solvent employed was
pyridine and overall reaction time was 24 - 36 hr.
Microwave Assisted Organic Synthesis (MAOS) is an
invaluable technology for drug discovery applications as
it dramatically reduces reaction time, which makes it
ideal for rapid reaction scouting and optimization, al-
lowing rapid synthesis of large number of NCEs and
their libraries. It is an efficient synthetic tool and its
benefit has been well documented [19-22]. In continua-
tion to our ongoing work on green chemical techniques
[23], herein we report a novel, hitherto unreported pro-
tocol for the rapid synthesis of mononuclear 2-amino-5-
cyano-4,6-disubstituted-pyrimidines under MWI. (Mic-
rowave Irradiation)
2. Results and Discussion
The α-cyanoketene S,S-acetals such as di-(methylthio)
methylene malononitrile 1 and ethyl-2,2-di(methyl-
thio)methylene cyanoacetate 2 were prepared as per re-
ported method [16]. The α-cyanoketene S,S-acetals 1 and
2 were converted to corresponding S,N-acetals by reacting
with appropriate primary as well as secondary amine in
ethanol under microwave at 80 W (Scheme 2). Secondary
amine being more reactive underwent nucleophilic

K. S. JAIN ET AL. 48
CNNC
H
3
CS SCH
3
HN R
1
R
2
NH
H
2
NNH
2
24-36 hrs
pyridine
= aryl and cycloalkyl amines.
N
N
NH
2
NC
N
R
1
R
2
NH
2
HCO
3-
HN R
1
R
2
Scheme 1. MCR of α-cyanoketenes S,S-acetals, amine and guanidine carbonate.
NH
2
NH
2
NH
2
NH
2
Cl
CH
3
OCH
3
O
H
N
NH
2
Br
NH
2
F
NH
2
F
NH
2
CH
3
=
Cl
HN
R
1
R
2
CNX
SMeMeS +CN
X
SMeN
1, X = CN
2, X = COO C
2
H
5
EtOH
1a-i, X = CN
2a-i, X = COOC
2
H5
NH
R
2
R
1
R
2
R
1
MWI, 80W
5-10 min
Scheme 2. Synthesis of α-cyanoketene S,N-acetals (1a-i, 2a-i)E.
+
X
NC
SMeN
1a-i , X = CN
2a-i , X = COOC
2
H
5
DMF
3a-i , X = NH
2
4a-i , X = OH
R
2
R
1
MWI, 80W
25-50 minNC
N
R
2
R
1
N
N
NH
2
NH
2
NHH
2
N
X
Scheme 3. Synthesis of target compounds.
substitution with α-cyanoketene S,S-acetals in 5 minutes.
Also the amines possessing substitution like halogens as
well as electron donating groups such as methyl and
methoxy completed the displacement in shorter time (5
minutes) when compared with unsubstituted amine ow-
ing to its resonance effect.
There was not much difference in the reaction rate be-
tween the amines bearing substitution at meta and para
positions. The overall reaction time were 5 - 10 minutes.
The best yields were obtained for 1c, 96%. Over all yields
were in the range of 84% - 96% (Table 1).
In the subsequent step condensation of guanidine with
α-cyanoketene S,N-acetals for the synthesis of title com-
pounds were investigated. The reaction involved one-pot
yclocondensation of functionalized α-cyanoketene c
S,N-acetals with guanidine in the dimethylformamide.
Initially guanidine as a free base was generated in situ
from its salt form by treating with sodium hydride in DMF
under microwave irradiation for 1 minute at 20W. Once
the free base was generated, α-cyanoketene S,N-acetals
was added and subjected to MWI for 25 - 50 minutes at 80
W to afford the title 2-amino-5-cyano-4,6-disubstituted-
pyrimidines (Scheme 3). The reaction was completed in
just few minutes instead of the 18 hrs required under con-
ventional heating. The products were obtained in high
yield (76% - 90%), purity (>95%). (Table 2)
In comparison to the conventional heating method,
microwave heating affords more advantages such as high
yield, reduced reaction time, low cost, and simplicity in
reaction progress, reduced pollution and higher product

K. S. JAIN ET AL.49
Table 1. Physical Data of α-cyanoketene S,N-acetals (1a-i, 2a-i).
XNC
SCH3 R2R1N
Comp.No. X NR1R2 M.P. (˚C) Reaction time (min)
at 80 WYield Comp.
No X NR1R2 M.P. (˚C) Reaction
time (min)
at 80 W Yield
1a CN C6H5NH 170 - 172 10 90 2a COOC2H5C6H5NH 82 - 83 10 95
1b CN 4-morpholinyl 150 - 152 5 85 2b COOC2H54-morpholinyl 93 - 94 5 91
1c CN 4-CH3OC6H4NH148 - 150 10 96 2c COOC2H54-CH3OC6H4NH 96 - 98 10 86
1d CN 4-CH3C6H4NH 140 - 141 5 94 2d COOC2H54-CH3C6H4NH 112 - 114 10 87
1e CN 4-Br-C6H5NH 122 - 124 10 92 2e COOC2H54-Br-C6H5NH 120 - 121 10 84
1f CN 4-F-C6H4NH 135 - 137 5 88 2f COOC2H5
4-F-C6H4NH 128 - 130 5 95
1g CN 4-Cl-C6H4NH 160 - 162 10 86 2g COOC2H54-Cl-C6H4NH 140 - 142 5 92
1h CN 3-Cl,4-F-C6H5NH139 - 141 5 91 2h COOC2H53-Cl,4-F-C6H5NH 151 - 153 5 90
1i CN 3-CH3C6H4NH 106 - 108 10 88 2i COOC2H5
3-CH3C6H4NH 95 - 96 10 94
purity. Hence, the synthetic methodology reported herein
is a very efficient method for the parallel library synthe-
sis of 2-amino-5-cyano-4,6-disubstitutedpyrimidines.
3. Experimental
All reagents and chemicals used were of LR grade and
purchased from standard vendors and used as received.
Microwave synthesizer; (Questron Technologies Corp.,
Canada; model-ProM) having monomode open-vessel
was used for the synthesis. The 1H NMR spectra were
recorded in CDCl3 using NMR Varian Mercury YH-300
MHz spectrometer and chemical shifts are given in units
as per million, downfield from TMS (tetramethylsilane)
as an internal standard. Mass spectra were obtained on a
Shimadzu GCMS-QP2010 spectrometer. The Ultraviolet
absorption spectra were determined in methanol on
JASCO (Japan) V-530, UV-Visible double beam spec-
trophotometer. The IR spectra of the synthesized com-
pounds were recorded on Perkin Elmer (USA) spectrum
BX.FT-IR in potassium bromide discs.
3.1. The α-Cyanoketene S,S-Acetals were
Prepared as Per Literature Method
3.1.1. Synthesis of α-Cyanoketene S,N-Acetals (1a-i,
2a-i)
A mixture of appropriate α-cyanoketene S,S-acetal 1 or 2
(0.02 mol) and 0.02 mol of aromatic amine in 10 ml of
ethanol was subjected to microwave irradiation at 80 W
for 5 - 10 minutes. The progress of the reaction was
monitored by TLC. Upon completion the mixture was
cooled and the crystals obtained were filtered, washed
with chilled ethanol and air dried. The compounds were
pure for all practical purpose.
3.1.2. Synthesis of 2,4-Diamino-5-Cyano-6-
(Phenylaminopyrimidine (3a-I & 4a-i)
To the benzene washed suspension of sodium hydride
(50%) (0.01 mol) in DMF (10 ml), guanidine nitrate
(0.01 mol) was added and subjected to microwave irra-
diation at 20 W for 1 min. The solution was filtered and
to the filterate α-cyanoketene S,N-acetals (1a-i, 2a-i)
(0.01 mol) was added. The flask was subjected to MWI
at 80 W for 25 - 50 min. The progress of reaction was
monitored by TLC for every 5 minutes. On completion
of reaction, the reaction mixture was cooled to RT and
poured into ice water (50 ml). The solid precipitate ob-
tained was filtered and dried. The crude product was
recrystallized from DMF-ethanol to obtain the desired
product.
3.2. Representative Data of Target Compounds
2,4-Diamino-5-cyano-6-(phenylamino)pyrimidine 3a
1HNMR (400 MHz, DMSO-d6): δ 5.01(2H, s, NH2 at 4);
5.13(2H, s, NH2 at 2); 5.34(1H, s, NH 6); 7.11 - 7.62 (5H,
m, ArH). IR (KBr) cm–1: 3479, 3317[ 
NH], 2210[

CN]. m/z

K. S. JAIN ET AL. 50
Table 2. Physical data of 2-amino-5-cyano-4,6-disubstitutedpyrimidines (3a-i, 4a-i).
N
N
X
N
R
1
R
2
NC
NH
2
Com. No. X
N
R
1
R
2
Yield (%)M.P. (˚C)
(Solv. of recryst)* Reaction time (Min) at 80 W
3a NH2 C
6H5NH 84 268 - 270
D - E 25
3b NH2 4-morpholinyl 82 226 - 227
D - E 35
3c NH2 4-CH3OC6H4NH88 259 - 262
D - E 40
3d NH2 4-CH3C6H4NH 78 253 - 254
D - E 45
3e NH2 4-Br C6H5NH 80 249 - 251
D - E 40
3f NH2 4-FC6H4NH 89 245 - 247
D - E 35
3g NH2 4-ClC6H4NH 81 2425 - 244
D - E 30
3h NH2 3-Cl,4F-C6H5N
H 79 227 - 229 D - E 35
3i NH2 3-CH3C6H4NH 76 264 - 266
D - E 30
4a OH C6H5NH 81 280 - 281
D - E 40
4b OH 4-morpholinyl 80 257 - 258
D - E 45
4c OH 4-CH3OC6H4NH84 270 - 272
D - E 50
4d OH 4-CH3C6H4NH 79 276 - 278
D-E 45
4e OH 4-Br C6H5NH 87 266 - 267
D-E 35
4f OH 4-FC6H4NH 88 259 - 261
D - E 30
4g OH 4-ClC6H4NH 85 247 - 250
D - E 45
4h OH 3-Cl,4F-C6H4N
H 82 278 - 280 D - E 35
4i OH 3CH3C6H4NH 90 260 - 263
D - E 35
*Solv.of recryst. D = Dimethylformamide, E = Ethanol.

K. S. JAIN ET AL.51
226 (M+). Anal. Calcd. for C11H10N6: C, 58.40; H, 4.46;
N, 37.15; found C, 58.76; H, 4.76; N, 37.43.
2,4-Diamino-5-cyano-6-(4-morpholinyl)pyrimidine
3b
1HNMR (400 MHz, DMSO-d6): δ 3.54 - 3.76(4H, m,
-NH(CH2-)2); 3.84-4.12 (4H, m, O-(CH2-)2]; 6.51(2H, s,
NH2 at 4); 6.69(2H, s, NH2 at 2). IR (KBr) cm–1: 3466,
3358[

NH], 2216[

CN]. m/z 220(M+). Anal. Calcd. for
C9H12N6O: C, 49.08; H, 5.49; N, 38.16; found C, 49.32;
H, 5.68; N, 38.29.
2,4-Diamino-5-cyano-6-[(4-methoxyphenyl)amino]p
yrimidine 3c
1HNMR (400 MHz, DMSO-d6): δ 3.73(3H, s, OCH3);
4.0 - 4.31(4H, s, NH2 at 2 and 4); 6.85 - 7.33 (4H, m,
Ar-H). IR (KBr) cm–1: 3416, 3374 [ 
NH], 2208 [

CN]. m/z
256(M+). Anal. Calcd. for C12H12N6O: C, 56.24; H, 4.72;
N, 32.79; found C, 56.35; H, 4.45; N, 32.93.
2,4-diamino-5cyano-6-[(4-methylphenyl)amino]pyri
midine 3d
1HNMR (400 MHz, DMSO-d6): δ 3.4(3H, s, ArCH3 at
6); 6.6(4H, m, NH2 at 2 and 4); 8.4(4H, m, ArH at 6). IR
(KBr) cm–1: 3474, 3289, 3153[

NH], 2188[

CN]. m/z
240(M+). Anal. Calcd. for C12H12N6: C, 59.99; H, 5.03;
N, 34.98 ; found C, 59.84; H, 5.34; N, 34.87.
2,4-diamino-5-cyano-6-[(4-chlorophenyl)amino]pyr
imidine 3g
1HNMR (400 MHz, DMSO-d6): δ 3.4(3H, s, ArCH3 at
6); 6.6(4H, m, NH2 at 2 and 4); 8.4(1H, s, ArH at 6). IR
(KBr) cm–1: 3324, 3178[

NH], 2190[

CN]. m/z 260(M+).
Anal. Calcd. for C11H9N6Cl: C, 50.68; H, 3.48; N, 32.24;
found C, 50.43; H, 3.62; N, 32.26.
2-amino-4-hydroxy-5-cyano-6-(4-morpholinyl)pyri
midine 4b
1HNMR (400 MHz, DMSO-d6): δ 2.9[s, -N(CH2-)2];
3.8[s, O-(CH2-)2]; 6 (2H, s, NH2 at 2); 7.4( s, 1H, OH at
4). IR (KBr) cm–1: 3357, 3115[

NH], 2922[

C-H], 2182[

CN],
1628[ 
CONH]. m/z 221(M+). Anal. Calcd. for C9H11N5O2: C,
48.86; H, 5.01; N, 31.66; found C, 48.74; H, 5.44; N,
31.34.
2-amino-4-hydroxy-5-cyano-6-[(4-flurophenyl)ami
no]pyrimidine 4f
1HNMR (400 MHz, DMSO-d6): δ 4.2(2H, s, NH2 at 4);
5.07(1H, s, OH); 6.72(5H,m, Ar-H ). IR (KBr) cm–1: 3476,
3296[ 
NH], 2916.12[

C-H], 2211[

CN] 1654, 1618[

CONH]. m/z
245(M+). Anal. Calcd. for C11H8N5OF: C, 53.88; H, 3.29;
N, 28.56; found C, 53.73; H, 3.08; N, 28.32.
4. Conclusions
We have described a new, rapid and a versatile approach
by MAOS for the synthesis of 2-amino-5-cyano-4,6-
disubstitutedpyrimidines in a highly efficient way. Fur-
ther work is in progress with respect to diversity oriented
synthesis of mononuclear pyrimidines and their biologi-
cal screening.
5. Acknowledgements
The authors acknowledge the contributions of Prof. M. N.
Navale, President, & Dr. (Mrs.) S. M. Navale, Secretary,
Sinhgad Technical Education Society, Pune for provid-
ing facilities to carry out the synthetic work and basic
spectroscopic analysis. The Mass and NMR were done at
Department of Chemistry, Saurashtra University, Rajkot,
India and University of Pune, India, respectively.
6. References
[1] K. S. Jain, T. S. Chitre, P. B. Miniyar, M. K. Kathiravan,
V. Bendre, V. Veer, S. Shahane and C. Shishoo, “Bio-
logical and Medical Significance of Pyrimidines,” Cur-
rent Science, Vol. 90, 2006, pp. 793-799.
[2] R. Butler, “The Structure, Reactions, Synthesis, and Uses
of Heterocyclic Compounds,” In: A. Katritzky and C.
Rees, Ed., Comprehensive Heterocyclic Chemistry, Per-
gamon Press, Oxford, Vol. 5, 1984, pp. 796-798.
[3] D. Brown, “Pyrimidines and Their Benzo Derivatives,” In:
A. Katritzky and C. Rees, Ed., Comprehensive Heterocyc-
lic Chemistry, Pergamon Press, Oxford, Vol. 2, 1984, pp.
57-61. doi:10.1016/B978-008096519-2.00035-7
[4] R. J. Vishnu, V. Berge and A. Dirk, “Synthesis of
Pyrimidines and Fused Pyrimidines as Leishmanicides
and Herbicides,” Advanced Synthesis and Catalysis, Vol.
331, No. 6, 1989, pp. 893-905.
doi:10.1002/prac.19893310603
[5] H. Kristison and O. Kristinson, “Substituted Pyrimidi-
nes,” Chemical Abstract, 1988, Vol. 108, Article ID:
186761.
[6] B. Detlef, G. Wagner and Z. Chem, Vol. 25, 1985, p. 141.
[7] E. Kniner, F. Eberhard and K. Regina, Chemical Abstract,
Vol. 98, 1983, Article ID: 215609.
[8] J. Bagli, “Amino-Pyrimidine Derivatives,” Chemical
Abstract, Vol. 103, 1985, Article ID: 6358.
[9] M. Perez, J. Soto, “Synthesis of 6-Alkoxy-2-amino-5-
cyanopyrimidines through Sodium Alkoxide-Induced Re-
giospecific Cyclization of 1,3-Dicarbonitriles,” Synthesis,
Vol. 12, 1981, pp. 955-958. doi:10.1055/s-1981-29654
[10] A. Kumar, V. Agrawal, H. Ila and H. Jujappa, “A Novel
and Convenient Synthesis of 2-Amino-4-(N-alkyl-N-
arylamino)-pyrimidines using Poolarized Ketene S,S- and
S,N-Acetals,” Synthesis, Vol. 9, 1980, pp. 748-751.
doi:10.1055/s-1980-29200
[11] J. Asserka, H. Schwelmlan and J. Perine, Chemical Ab-
stract, Vol. 122, 1995, Article ID: 239716.
[12] Z. Folki and A. Salaman, “Chemische Berichte,” Euro-
pean Journal of Inorganic Chemistry, Vol. 74, No. 7,
1941, p. 1126.
[13] S. Nishiqate, K. Senqa, K. Arda, T. Takabatake and F.
Yosuda, “Condensation Reactions of Ethyl Ethoxy-

K. S. JAIN ET AL. 52
methylenecyanoacetate with Amidines,” Chemical and
Pharmaceutical Bulletin, Vol. 18, No. 5, 1970, pp.
1003-1007.
[14] P. Juby, T. Hudyma, M. Brown, M. Essery and R. Par-
tyka, “Antiallergy Agents. 2. 2-Phenyl-5-(1H-tetrazol-5-yl
pyrimidin-4(3H)-ones,” Journal of Medicinal Chemistry,
Vol. 25, No. 10, 1982, pp. 1145-1150.
doi:10.1021/jm00352a009
[15] A. Abd-Elfattah, S. Hussain, A. El-Reedy and N. Yousif,
“Reactions with α-Substituted Cinnamonitriles: A Novel
Synthesis of Prylpyrimidines,” Tetrahedron, Vol. 39, No.
19, 1983, pp. 3197-3199.
doi:10.1016/S0040-4020(01)91566-2
[16] V. Bhadti, Ph.D Thesis, Gujrat University, 1985.
[17] S. Goswami. A. Hazra and S. Jana, “One-Pot Two-Step
Solvent-Free Rapid and Clean Synthesis of 2-(Substituted
Amino)-pyrimidines by Microwave Irradiation,” Bulletin
of the Chemical Society of Japan, Vol. 82, No. 9, 2009,
pp. 1175-1181. doi:10.1246/bcsj.82.1175
[18] Y. Tominaga and Y. Matsuda, “Synthesis of Heterocyclic
Compounds Using Nitro Ketene Dithioacetal,” Journal of
Heterocyclic Chemistry, Vol. 22, No. 4, 1985, pp. 937-
949. doi:10.1002/jhet.5570220401
[19] J. Bariwal, J. Trivedi and E. Van der Eycken, “Micro-
wave Irradiation and Multicomponent Reactions,” In: R.
V. A. Orru, Ed., Top Heterocyclic Chemistry, Springer-
Verlag, Berlin Heidelberg, 2010, Vol. 25, pp. 169-230.
[20] C. Kappe, A. Stadler, R. Mannhold, H. Kubinyi and G.
Folkers, “Methods and Principles in Medicinal Chemistry:
Microwaves in Organic and Medicinal Chemistry, Vol-
ume 25,” Wiley, New Jersey, 2005, pp. 9-24.
[21] C. Kappe and D. Dallinger, “The Impact of Microwave
Synthesis on Drug Discovery,” Nature Reviews Drug
Discovery, Vol. 5, 2006, pp. 51-63. doi:10.1038/nrd1926
[22] K. Jain, R. Kulkarni, J. Bariwal and D. Jain, “Impact of
Microwave Assisted Heating on the Combinatorial and
Parallel Syntheses of Compound Libraries for New Drug
Discovery,” Indian Drugs, Vol. 46, 2009, pp. 747-771.
[23] K. Jain, J. Bariwal, M. Kathiravan, V. Raskar, G. Wank-
hede, N. Londhe and S. Dighe, “An Efficient and Rapid
Synthesis of 2-Amino-4-arylthiazoles Employing Micro-
wave Irradiation in Water,” Green and Sustainable
Chemistry, Vol. 1, No. 2, 2011, pp. 35-38.
doi:10.4236/gsc.2011.12007