A novel synthesis of N-aryl-6-methylsulfanyl-4-pyrimidinones and purine analogues: The reaction of dimethyl N-cyanodithioiminocarbonate with cyanoacetanilides

Article abstract of DOI:10.1081/SCC-120021035

A novel and efficient method for the synthesis of N-aryl-6-methylsul-fanyl-4-oxopyrimidine-5-carbonitriles via the reaction of dimethyl N-cyanodithioiminocarbonate with substituted cyanoacetanilides has been investigated. (3)N-Aryl-2,5-diamino-7H-pyrazolo

Full text of DOI:10.1081/SCC-120021035

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A Novel Synthesis of N-Aryl-6-methylsulfanyl-4-
pyrimidinones and Purine Analogues: The Reaction
of Dimethyl N-Cyanodithioiminocarbonate with
Cyanoacetanilides
Galal H. Elgemeie a , Samia R. El-Ezbawy a & Soha A. Sood a
a Chemistry Department, Faculty of Science, Helwan University, Ain-Helwan, Cairo, Egypt
Published online: 17 Aug 2006.
To cite this article: Galal H. Elgemeie , Samia R. El-Ezbawy & Soha A. Sood (2003): A Novel Synthesis of N-Aryl-6-
methylsulfanyl-4-pyrimidinones and Purine Analogues: The Reaction of Dimethyl N-Cyanodithioiminocarbonate with
Cyanoacetanilides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:12, 2095-2101
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2095–2101, 2003
A Novel Synthesis of N-Aryl-6-methylsulfanyl-4-
pyrimidinones and Purine Analogues:
The Reaction of Dimethyl
N-Cyanodithioiminocarbonate
with Cyanoacetanilides
*
Galal H. Elgemeie, Samia R. El-Ezbawy, and Soha A. Sood
Chemistry Department, Faculty of Science, Helwan
University, Ain-Helwan, Cairo, Egypt
ABSTRACT
A novel and efficient method for the synthesis of N-aryl-6-methylsul-
fanyl-4-oxopyrimidine-5-carbonitriles via the reaction of dimethyl
N-cyanodithioiminocarbonate with substituted cyanoacetanilides
has been investigated. (3)N-Aryl-2,5-diamino-7H-pyrazolo[3,4-d]-
pyrimidin-4(3H)-one have also been prepared from the reaction of
6-sulfanylthio-N-aryl-4-pyrimidinones with hydrazines.
*Correspondence: GalalH. Elgemeie, ChemistryDepartment, FacultyofScience,
Helwan University, Ain-Helwan, Cairo, Egypt; E-mail: rughe@rusys.eg.net.
2095
DOI: 10.1081/SCC-120021035
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2096
Elgemeie, El-Ezbawy, and Sood
Key Words: Methylsulfanyl-pyridones; Cyanoacetanilides; N-
Cyanodithioiminocarbonate; Pyrazolo[3,4-d]pyrimidines; Antime-
tabolite agents.
During the course of our studies directed toward exploring the
synthetic potential of ketene dithioacetals for synthesizing new classes
of novel antimetabolites,[1–3] we have recently reported different
successful approaches for synthesis of mercaptopurine and thioguanine
analogues by the reaction of ketene dithioacetals with diazoles contain-
ing amino and active methylene functions.[4,5] In an extension of this
work, the present paper describes a new one-pot synthesis of N-aryl-6-
methylsulfanyl-4-oxopyrimidine-5-carbonitriles by the reaction of
dimethyl N-cyanodithioiminocarbonate with cyanoacetanilides. Thus,
ithas been found htatS
,S-dimethyl N-cyanodithioimidocarbonate 2
prepared by the reaction of cyanamide 1 with carbon disulfide and
methyl iodide in the presence of alkali, was treated with cyanocetani-
lides 3 in dioxane containing a catalytic amount of potassium hydro-
xide at room temperature to yield the 4-oxopyrimidine derivatives 6.
The structures of 6 were established on the basis of elemental analysis
1
and spectral data (IR, H NMR, 13C NMR and MS). The formation of
6 from the reaction of 2 with 3 is assumed to proceed via Michael
addition of active methylene of 3 to the double bond in 2. The formed
Michael adducts then cyclized smoothly via CH3SH elimination and
addition to the cyano group. Compounds 6, bearing methylthio group
and other latent functional substituent, were found to be useful for the
synthesis of fused derivatives. Thus, compounds 6 reacted with
aromatic amines in fusion to afford the corresponding 6-anilino
derivatives 7. The structure of compounds 7 were established on the
1
basis of elemental analysis and spectral data (IR, H NMR and MS).
When compounds 6 were subjected to the reaction with hydrazine, the
hydrazino derivatives could not be isolated, but cyclized to the
pyrazolo[3,4-d ]pyrimidin-4(3H )-one derivatives 8, whose structure
were established by elemental analysis and spectral data (IR,
1H NMR and MS).
In summary, we have achieved a regiospecific synthesis of interest-
ing 6-methylsulfanyl-N-aryl-4-oxopyrimidines and their corresponding
purine analogues by the reaction of dimethyl N-cyanodithioimino-
carbonate with cyanoacetanilides. The compounds obtained seems
promising as high potential intermediates for synthesizing antimetabo-
lite agents.

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N-Aryl-6-methylsulfanyl-4-pyrimidinones and Purine Analogues
2097
EXPERIMENTAL
All melting points were determined in open glass capillaries on
Gallenkamp melting point apparatus and are uncorrected. Their spectra
were obtioned (KBr disc) on a Perkin Elmer/1650. FT-IR instrument.
1
The H NMR and 13C NMR. Spectra were measured in a Varian 400 or

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2098
Elgemeie, El-Ezbawy, and Sood
Wilmad 270 MHZ spectrometer for (CD3)2 SO solutions using SiMe4 as
internal standard. Mass spectra were recorded in a Varian MAT 112
spectrometer. Analytical data were obtained from the Micro Analytical
Data Center at Cairo University.
Compounds 2 and 3 were prepared following literature procedures.[6,7]
2-Amino-(3)N-aryl-3,4-dihydro-6-methylthio-
4-oxopyrimidine-5-carbonitriles (6a–e)
General Procedure
Dimethyl N-cyanodithioiminocarbonate 2 (0.01 mol) was added to a
stirred solution of cyanoacetanilides 3 (0.01 mol) in a dry dioxane (50 mL)
containing potassium hydroxide (0.01 mol). After stirring under dry con-
ditions at room temperature for 24 h, the reaction mixture was diluted
with cold water (50 mL). The resulting solid product was collected by
filtration and recrystallized from the appropriate solvent.
6a. Rose, m.p. 225ꢀC (from EtOH), yield (80%). IR (KBr) ꢀmax/cmꢁ1
1
3446 (NH2), 2168 (CN) and 1627 (C¼O). H NMR (DMSO) ꢁ 2.65 (s,
3H, SCH3), 7.01–7.49 (m, 5H, C6H5), 7.52 (s, br, 2H, NH2). 13C NMR
(DMSO) ꢁ 16.54 (SCH3), 119.03 (CN), 128.75–129.32 (phenyl carbons),
139.00 (C-5), 157.21 (C-6), 162.60 (C-2), 169.26 (C-4). C12H10N4OS,
(Mþ ¼ 258), Calcd.: C, 55.81; H, 3.87; N, 21.70; S, 12.40. Found: C,
56.1; H, 3.9; N, 21.8; S, 12.5%.
6b. Buff, m.p. 210ꢀC (from EtOH), yield (79%). IR (KBr) ꢀmax/cmꢁ1
1
3628 and 3446 (NH2), 2205 (CN) and 1630 (C¼O). H NMR (DMSO) ꢁ
2.24 (s, 3H, CH3), 2.60 (s, 3H, SCH3), 7.00–7.52 (m, 4H, C6H5), 7.96 (s,
br, 2H, NH2). 13C NMR (DMSO) ꢁ 16.48 (CH3), 20.73 (SCH3), 118.98
(CN), 128.14–131.4 (phenyl carbons), 155.41 (C-5), 159.41 (C-6), 162.36
(C-2), 173.83 (C-4). C13H12N4OS, Calcd.: C, 57.35; H, 4.41; N, 20.58; S,
11.76. Found: C, 57.7; H, 4.5; N, 20.8; S, 11.7%.
6c. Colorless, m.p. 225ꢀC (from EtOH), yield (85%). IR (KBr)
ꢀ
max/cmꢁ1 3394 and 3309 (NH2), 2205 (CN) and 1677 (C¼O).
1H NMR (DMSO) ꢁ 2.49 (s, 3H, SCH3), 3.86 (s, 3H, OCH3), 7.05–7.61
(m, 4H, C6H5), 7.75 (s, br, 2H, NH2). 13C NMR (DMSO) ꢁ 12.13 (SCH3),
55.28 (OCH3), 115.15 (CN), 126.21–129.58 (phenyl carbons), 152.31
(C-5), 55.63 (C-6), 159.46 (C-2), 173.90 (C-4). C13H12N4O2S, Calcd.:
C, 54.16; H, 4.16; N, 19.44; S, 11.11. Found: C, 54.0; H, 4.1; N, 19.2;
S, 11.1%.
6d. Rose, m.p. 240ꢀC (from EtOH), yield (84%). IR (KBr) ꢀmax/cmꢁ1
1
3487 and 3381 (NH2), 2215 (CN) and 1671 (C¼O). H NMR (DMSO)

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N-Aryl-6-methylsulfanyl-4-pyrimidinones and Purine Analogues
2099
ꢁ 2.62 (s, 3H, SCH3), 7.28–7.58 (m, 4H, C6H4), 7.62 (s, br, 2H, NH2).
13C NMR (DMSO) ꢁ 12.15 (SCH3), 115.75 (CN), 128.41–136.03 (phenyl
carbons), 150.22 (C-5), 154.99 (C-6), 159.11 (C-2), 174.36 (C-4).
C12H9ClN4OS, Calcd.: C, 49.23 ; H, 3.07; N, 19.15; S, 10.94. Found:
C, 49.3; H, 3.0; N, 19.2; S, 11.0%.
6e. Yellow, m.p. 125ꢀC (from EtOH), yield (77%). IR (KBr)
g
C12H9N5O3S, Calcd.: C, 47.52; H, 2.97; N, 23.10; S, 10.56. Found:
C, 47.8; H, 3.1; N, 23.2; S, 10.7%.
max/cmꢁ1 3418 and 3361 (NH2), 2171 (CN) and 1631 (C¼O).
2-Amino-(3)N-aryl-3,4-dihydro-6-anilino-
4-oxopyrimidine-5-carbonitriles (7a–e)
General Procedure
A mixture of equivalent amounts (0.01 mol) of 6a–e and aniline were
heated at 150ꢀC, (bath temperature) for 30 min, after cooling, the result-
ing solid poduct was triturated with water, filtered off and crystallized
from the appropriate solvent.
7a. Colorless, m.p. 300ꢀC (from EtOH), yield (76%). IR (KBr)
ꢀ
max/cmꢁ1 3275 and 3352 (NH2, NH), 2210 (CN) and 1660 (C¼O).
C17H13N5O, Calcd.: C, 68.12; H, 4.29; N, 23.10. Found: C, 67.8; H,
4.5; N, 23.3%.
7b. Buff, m.p. 245ꢀC (from EtOH), yield (83%). IR (KBr) ꢀmax/cmꢁ1
3488, 3374 and 3312 (NH2, NH), 2221 (CN) and 1671 (C¼O).
C18H15N5O, Calcd.: C, 68.14; H, 4.73; N, 22.08. Found: C, 67.1; H,
4.5; N, 22.2%.
7c. Colorless, m.p. 165ꢀC (from EtOH), yield (85%). IR (KBr) ꢀmax
/
cmꢁ1 3471, 3361 and 3310 (NH2, NH), 2213 (CN) and 1668 (C¼O).
C18H15N5O2, Calcd.: C, 64.86 ; H, 4.50; N, 21.02. Found: C, 65.0; H,
4.7; N, 21.3%.
7d. Buff, m.p. 220ꢀC (from EtOH), yield (83%). IR (KBr ꢀmax
/
cmꢁ1 3459 and 3326 (NH2, NH), 2211 (CN) and 1529 (C¼O).
C17H12ClN5O, Calcd.: C, 60.04; H, 3.56; N, 20.74. Found: C, 60.0; H,
3.6; N, 20.9%.
7e. Yellow, m.p. 135ꢀC (from EtOH), yield (75%). IR (KBr)
max/cmꢁ1 3480, 3361 and 3219 (NH2, NH), 2219 (CN) and 1631
ꢀ
(C¼O). 1H NMR (DMSO) ꢁ 6.59 (s, br, 2H, NH2), 6.74 (s, br, 1H,
NH), 7.84–7.98 (m, 9H, C6H4 and C6H5). C17H12N6O3, Calcd.: C,
58.62; H, 3.45; N, 24.14. Found: C, 58.9; H, 3.50; N, 24.4%.

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2100
Elgemeie, El-Ezbawy, and Sood
3,6-Diamino-5-aryl-1,5-dihydro-4H-pyrazolo-
[3,4-d ]pyrimidin-4-ones (8a–e)
General Procedure
A mixture of 6 (0.01 mol) and hydrazine (0.01 mol) in ethanol
(30 mL) containing a catalytic amounts of piperidine was refluxed
for 3 h, cooled, the preciptate was filtered off and crystallized from the
appropriate solvent.
8a. Colorless, m.p. >300ꢀC (from EtOH), yield (82%). IR (KBr)
ꢀ
max/cmꢁ1 3511, 3428 and 3313 (NH2, NH) and 1677 (C¼O).
C11H10N6O, Calcd.: C, 54.54; H, 4.13; N, 34.71. Found: C, 54.7; H,
4.4; N, 34.9%.
8b. Buff, m.p. 240ꢀC (from EtOH), yield (78%). IR (KBr) ꢀmax/cmꢁ1
1
3494, 3434 and 3345 (NH2, NH) and 1680 (C¼O). H NMR (DMSO) ꢁ
2.38 (s, 3H, CH3), 5.07 (s, br, 2H, NH2), 6.36 (s, br, 2H, NH2), 7.13–7.37
(m, 4H, C6H4), 11.47 (s, br, 1H, NH). C12H12N6O, Calcd.: C, 56.25; H,
4.68; N, 32.81. Found: C, 56.1; H, 4.4; N, 32.6%.
8c. Colorless, m.p. >300ꢀC (from EtOH), yield (70%). IR (KBr)
1
ꢀ
max/cmꢁ1 3490, 3430 and 3310 (NH2, NH) and 1660 (C¼O). H NMR
(DMSO) ꢁ 3.80 (s, 3H, OCH3), 5.12 (s, br, 2H, NH2), 6.23 (s, br, 2H,
NH2), 7.01–7.91 (m, 4H, C6H4), 11.34 (s, br, 1H, NH). 13C NMR
(DMSO) ꢁ 55.26 (OCH3), 127.77–130.47 (phenyl carbons), 152.80
(C-9), 154.77 (C-5), 156.31 (C-8), 158.52 (C-2), 159.24 (C-4).
C12H12N6O2, Calcd.: C, 52.94; H, 4.41; N, 30.88. Found: C, 53.0; H,
4.6; N, 31.0%.
8d. Buff, m.p. >350ꢀC (from EtOH), yield (83%). IR (KBr)
ꢀ
max/cmꢁ1 3313 (NH2). C11H9ClN6O, Calcd.: C, 47.74; H, 3.25; N,
30.37. Found: C, 48.0; H, 3.0; N, 30.7%.
8e. Colorless, m.p. >300ꢀC (from EtOH), yield (75%). IR (KBr)
max/cmꢁ1 3480, 3361 and 3219 (NH2, NH) and 1631 (C¼O).
ꢀ
C11H9N7O3, Calcd.: C, 45.99; H, 3.13; N, 34.15. Found: C, 46.1; H,
3.3; N, 34.2%.
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N-Aryl-6-methylsulfanyl-4-pyrimidinones and Purine Analogues
2101
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Received in the USA September 16, 2002

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