Three-component reaction between 6-amino-N,N′ - Dimethyluracil and ammonium thiocyanate in the presence of aroyl chlorides under solvent-free conditions

Article abstract of DOI:10.1080/17415993.2011.619537

A novel method for the pyrimidine ring formation is established using the reaction of ammonium thiocyanate and aroyl chlorides with 6-amino-N,N′ -dimethyluracil under solvent-free conditions to afford the functionalized pyrimido[4,5-d]pyrimidines in excel

Full text of DOI:10.1080/17415993.2011.619537

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Three-component reaction between
6-amino-N, - dimethyluracil and
ammonium thiocyanate in the presence
of aroyl chlorides under solvent-free
conditions
Razieh Mohebat a , Mohammad H. Mosslemin a , Ali Dehghan-
Darehshiri a & Alireza Hassanabadi b
a Department of Chemistry, Islamic Azad University, Yazd Branch,
PO Box 89195-155, Yazd, Iran
b Department of Chemistry, Islamic Azad University, Zahedan
Branch, PO Box 98135-978, Zahedan, Iran
Published online: 03 Oct 2011.
To cite this article: Razieh Mohebat , Mohammad H. Mosslemin , Ali Dehghan-Darehshiri & Alireza
Hassanabadi (2011) Three-component reaction between 6-amino-N, - dimethyluracil and ammonium
thiocyanate in the presence of aroyl chlorides under solvent-free conditions, Journal of Sulfur
Chemistry, 32:6, 557-561, DOI: 10.1080/17415993.2011.619537
To link to this article: http://dx.doi.org/10.1080/17415993.2011.619537
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Journal of Sulfur Chemistry
Vol. 32, No. 6, December 2011, 557–561
Three-component reaction between 6-amino-N,Nꢀ-
dimethyluracil and ammonium thiocyanate in the presence of
aroyl chlorides under solvent-free conditions
Razieh Mohebata*, Mohammad H. Mosslemina, Ali Dehghan-Darehshiria and
Alireza Hassanabadib
aDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran;
bDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
(Received 21 July 2011; final version received 30 August 2011)
A novel method for the pyrimidine ring formation is established using the reaction of ammonium thio-
cyanate and aroyl chlorides with 6-amino-N,Nꢀ -dimethyluracil under solvent-free conditions to afford the
functionalized pyrimido[4,5-d]pyrimidines in excellent yields.
O
H3C
HN
CH3
O
O
N
N
H3C
H2N
CH3
O
O
Solvent-free
r.t., 8h
N
N
NH4SCN
+
+
Ar
Cl
S
N
Ar
Keywords: 6-amino-N,Nꢀ -dimethyluracil; aroyl chlorides; ammonium thiocyanate; pyrimidine;
solvent-free
1. Introduction
The pyrimidine ring system undoubtedly is one of the most important heterocycles in nature,
as it represents the main structure of many biologically significant compounds, including nucle-
osides and nucleotides. Consequently, many analogs and derivatives of pyrimidines have been
synthesized and developed as pharmacologically active compounds or drugs. Pharmacologically
active purine analogs include tricyclic structures such as imidazo[2,1-i]purinones (e.g. PSB-11, a
potentA3 adenosine receptor antagonist), pyrimido[4,5-b]indoles (e.g.APEPI, a potentA1 adeno-
sine receptor antagonist), and imidazo[2,1-a]purines (e.g. tricyclic ganciclovir analogs, which are
potent antiviral agents) (1). Since the isolation of pyrimidine derivatives, considerable attention
has been devoted to their chemistry and biological activity (2). In recent years, there has been
*Corresponding author. Email: rozitakalami@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2011.619537
http://www.tandfonline.com

558 R. Mohebat et al.
increasing interest in the synthesis of pyrimidine derivatives, and there are some methods used
to synthesize the pyrimidine ring that allow access to a large number of multifunctionalized
pyrimidine derivatives (3).
Recently, several new methods have been developed that illustrate the utility of the last approach
(4–9). As part of our current studies on the development of new organic synthesis routes (10–
12), we report an efficient one-pot synthesis of the functionalized pyrimido[4,5-d]pyrimidines,
employing readily available starting materials.
2. Results and discussion
Reaction of 6-amino-N,Nꢀ-dimethyluracil 1 and aroyl chlorides 2 with ammonium thiocyanate 3
under solvent-free conditionsaffords the functionalized pyrimido[4,5-d]pyrimidines 4 in excellent
yields (Scheme 1).
O
H3C
HN
CH3
O
O
N
N
N
H3C
H2N
CH3
O
O
Solvent-free
r.t., 8 h
N
N
NH4SCN
+
+
Ar
Cl
S
Ar
1
2
3
4
b
f
c
3- CH3C6H4
90
d
e
a
4
Ar
%Yield*
C6H5
88
NO
2-CH
3-
2 C6H4
3 C6H4
4-Br C6H4 4-Cl C6H4
90
89
92
88
*Isolated yield.
Scheme 1. Three-component reaction between 6-amino-N,Nꢀ-dimethyluracil and ammonium
thiocyanate in the presence of aroyl chlorides.
Structures of compounds 4a–f were confirmed by IR, 1H NMR, 13C NMR, and mass spectral
1
data. For example, the H NMR spectrum of 4b shows three sharp lines (δ = 2.40, 3.21, and
3.36 ppm) corresponding to the protons of the methyl groups. The aromatic protons resonated
between 7.31 and 7.52 ppm and a singlet signal was observed at δ = 14.96 ppm for the NH proton
which disappeared after addition of a few drops of D2O to the DMSO solution of 4b.
The 13C NMR spectrum of compound 4b shows 15 distinct signals, which is consistent with
the proposed structure. The C S group resonance in the 13C NMR spectra of 4b appears at
=
191.24 ppm. The mass spectrum of 4b displayed the molecular ion peak at m/z = 314. The IR
spectrum of compound 4b also supports the suggested structure with strong absorption bands
observed at 3455, 1701, and 1621 cm−1, respectively, for the NH and two carbonyl groups. A
tentative mechanism for this transformation is proposed in Scheme 2.
It is conceivablethatthereaction startswiththeformationof aroyl thiocyanate 5, followedby the
addition of 6-amino-N,Nꢀ-dimethyluracil 1 to generate 6. Subsequent cyclization of intermediate
6 generates 7 that is converted to 4 by the elimination of water.
In conclusion, the reaction of 6-amino-N,Nꢀ-dimethyluracil and ammonium thiocyanate in the
presence of aroyl chlorides leads to the functionalized pyrimido[4,5-d]pyrimidines in excellent
yields. The present procedure has the advantage that the reaction is performed under neutral
conditions and the starting material can be used without any activation or modification.

Journal of Sulfur Chemistry 559
O
H3C
S
CH3
N
O
N
O
1
Ar
N
H
N
H
3
+
2
Ar
N
N
C
O
S
5
6
O
H3C
N
CH3
O
N
1, 3 H shift
–H2O
4
Ar
OH
S
N
H
7
Scheme 2. Suggested mechanism for the formation of compound 4.
3. Experimental
Melting points were determined with an electrothermal 9100 apparatus. Elemental analyses were
performed using a Costech ECS 4010 CHNS-O analyzer at the analytical laboratory of Islamic
Azad University Yazd branch. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass
spectrometer operating at an ionization potential of 70 eV. IR spectra were recorded on a Shi-
madzu IR-470 spectrometer.1H and13C NMR spectra were recorded on a Bruker DRX-500Avance
spectrometer in CDCl3 using TMS as the internal standard. The chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without further purification.
3.1. General procedure
Aroyl chloride (2 mmol) was added via a syringe to ammonium thiocyanate (0.15 g, 2 mmol) in
a 50 ml flask at room temperature (r.t.) The reaction mixture was stirred in a water bath at about
90◦C for 5 min. Then, 6-amino-N,Nꢀ-dimethyluracil (2 mmol) was added at this temperature. The
reaction mixture was allowed to cool to r.t. The resulting mixture was stirred at r.t. for 8 h. The
progress of the reaction was monitored by TLC. After completion of the reaction, 20 ml distilled
water was added over 5 min to the reaction mixture. The resulting precipitate was collected by
filtration on a Buchner funnel and washed with 10 ml of cold diethyl ether to afford the pure title
compounds.
3.1.1. 1,3-Dimethyl 5-(phenyl)7-thioxo-7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-2,4-dione
(4a)
Yellowpowder; m.p. 212–214◦C, IR(KBr)(νmax cm−1): 3395, 17011, 1649, 1547, 1446.Analyses:
Calcd. for C14H12N4O2S: C, 55.99; H, 4.03; N, 18.65%. Found: C, 55.85; H, 4.12; N, 18.49. MS
(m/z, %): 300 (M+, 3); 77 (100). 1H NMR (500 MHz, DMSO-d6): δ 3.23 and 3.35 (6 H, 2s, 2CH3),
7.57–7.95 (5 H, m, 5CH aromatic), 13.85 (1 H, s, NH) ppm.13C NMR (125.8 MHz, DMSO-d6):
δ 28.99 and 31.13 (2CH3), 93.60, 128.00, 129.55, 133.23, 135.13, 148.42, 159.26, 164.15, and
=
165.33 (9C), 191.00 (C S) ppm.

560 R. Mohebat et al.
3.1.2. 1,3-Dimethyl 7-thioxo-5-o-tolyl 7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-2,4-dione
(4b)
Yellow powder; m.p. 195–197◦C, IR (KBr) (νmax cm−1): 3455, 1701, 1621, 1524, 1439.Analyses:
Calcd. for C15H14N4O2S: C, 57.31; H, 4.49; N, 17.82%. Found: C, 57.48; H, 4.34; N, 17.90. MS
(m/z, %): 314 (M+, 8); 91 (100). 1H NMR (500 MHz, DMSO-d6): δ 2.40, 3.21, and 3.36 (9 H,
3s, 3CH3), 7.31–7.52 (4 H, m, 4CH aromatic), 14.96 (1 H, s, NH) ppm.13C NMR (125.8 MHz,
DMSO-d6): δ 20.56, 29.24, and 31.48 (3CH3), 93.67, 126.95, 127.91, 131.60, 132.14, 136.76,
=
137.48, 148.79, 159.53, 164.12, and 168.19 (11C), 191.24 (C S) ppm.
3.1.3. 1,3-Dimethyl 7-thioxo-5-m-tolyl 7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-2,4-dione
(4c)
Yellow powder; m.p. 196–198◦C, IR (KBr) (νmax cm−1): 3460, 1700, 1621, 1529, 1430.Analyses:
Calcd. for C15H14N4O2S: C, 57.31; H, 4.49; N, 17.82%. Found: C, 57.48; H, 4.34; N, 17.90. MS
(m/z, %): 314 (M+, 11); 91 (100). 1H NMR (500 MHz, DMSO-d6): δ 2.39, 3.22, and 3.38 (9 H,
3s, 3CH3), 7.46–7.75 (4 H, m, 4CH aromatic), 15.43 (1 H, s, NH) ppm.13C NMR (125.8 MHz,
DMSO-d6): δ 20.51, 29.35, and 31.43 (3CH3), 93.61, 126.97, 127.85, 131.43, 132.25, 136.80,
=
137.67, 148.56, 159.42, 164.23, and 168.35 (11C), 191.28 (C S) ppm.
3.1.4. 5-(4-Bromophenyl) 1,3-dimethyl 7-thioxo-7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-
2,4-dione (4d)
Yellow powder; m.p. 202–204◦C, IR (KBr) (νmax cm−1): 3350, 1707, 1623, 1530, 1441.Analyses:
Calcd. for C14H11BrN4O2S: C, 44.34; H, 2.92; N, 14.77%. Found: C, 44.50; H, 3.05; N, 14.90.
MS (m/z, %): 379 (M+, 5); 381 (M+2, 4.97); 155 (100). 1H NMR (500 MHz, DMSO-d6): δ 3.19
and 3.34 (6 H, 2s, 2CH3), 7.64 (2 H, d, 3JHH = 8 Hz, 2 CH of C6H4Br), 7.91 (2 H, d, 3JHH = 8 Hz,
2 CH of C6H4Br), 15.51 (1 H, s, NH) ppm. 13C NMR (125.8 MHz, DMSO-d6): δ 29.38 and 31.53
(2CH3), 93.85, 123.48, 127.69, 133.14, 138.46, 149.46, 159.58, 164.26, and 164.49 (9C), 191.46
=
(C S) ppm.
3.1.5. 5-(4-Chlorophenyl) 1,3-dimethyl 7-thioxo-7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-
2,4-dione (4e)
Yellow powder; m.p. 207–209◦C, IR (KBr) (νmax cm−1): 3352, 1705, 1627, 1536, 1440.Analyses:
Calcd. for C14H11ClN4O2S: C, 50.23; H, 3.31; N, 16.74%. Found: C, 50.10; H, 3.44; N, 16.85.
MS (m/z, %): 334 (M+, 7); 336 (M+2, 2.2); 112 (100). 1H NMR (500 MHz, DMSO-d6): δ 3.21
and 3.35 (6 H, 2s, 2CH3), 7.57 (2 H, d, 3JHH = 8 Hz, 2 CH of C6H4Cl), 8.11 (2 H, d, 3JHH = 8 Hz,
2 CH of C6H4Cl), 15.51 (1 H, s, NH) ppm.13C NMR (125.8 MHz, DMSO-d6): δ 29.27 and 31.45
(2CH3), 93.62, 126.72, 129.95, 132.27, 135.22, 148.53, 159.17, 164.26, and 165.53 (9C), 194.28
=
(C S) ppm.
3.1.6. 5-(3-Nitrophenyl) 1,3-dimethyl 7-thioxo-7,8-dihydro1H-pyrimido[4,5,d]pyrimidine-
2,4-dione (4f)
Yellow powder; m.p. 200–202◦C, IR (KBr) (νmax cm−1): 3450, 1709, 1631, 1533, 1436, 1373.
Analyses: Calcd. for C14H11N5O4S: C, 48.69; H, 3.21; N, 20.28%. Found: C, 48.55; H, 3.30; N,
20.41. MS(m/z, %):345(M+, 5);122(100). 1HNMR(500 MHz, DMSO-d6):δ 3.23and3.34(6 H,
2s, 2CH3), 7.89–8.68 (4 H, m, 4CH aromatic), 15.59 (1 H, s, NH) ppm. 13C NMR (125.8 MHz,

Journal of Sulfur Chemistry 561
DMSO-d6): δ 29.22 and 31.45 (2CH3), 93.69, 121.82, 123.43, 130.85, 134.32, 136.78, 143.62,
=
148.67, 159.71, 164.23, and 168.45 (11C), 191.78 C S) ppm.
Acknowledgement
The authors gratefully acknowledge the financial support from the Research Council of Islamic Azad University of Yazd
and the Islamic Azad University of Zahedan of Iran.
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