Reactions of chlorocarbonyl isocyanate with 5-aminopyrazoles and active methylene nitriles: A novel synthesis of pyrazolo[1,5-a]-1,3,5-triazines and barbiturates

Article abstract of DOI:10.1081/SCC-100106205

Reactions of chlorocarbonyl isocyanate and chlorosulfonyl isocyanate with aminopyrazoles and active methylene nitriles are reported. They lead to novel pyrazolo[1,5-a]-1,3,5-triazines and barbituric acid derivatives. The structures of the products and the mechanisms of their formation are reported.

Full text of DOI:10.1081/SCC-100106205

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REACTIONS OF CHLOROCARBONYL ISOCYANATE
WITH 5-AMINOPYRAZOLES AND ACTIVE METHYLENE
NITRILES: A NOVEL SYNTHESIS OF PYRAZOLO[1,5-
a]-1,3,5-TRIAZINES AND BARBITURATES
Galal H. Elgemeie a , Samia R. El-Ezbawy a & Hany A. Ali a
a Chemistry Department, Faculty of Science, Helwan University, Ain-Helwan, Cairo,
Egypt
Version of record first published: 22 Aug 2006.
To cite this article: Galal H. Elgemeie, Samia R. El-Ezbawy & Hany A. Ali (2001): REACTIONS OF CHLOROCARBONYL
ISOCYANATE WITH 5-AMINOPYRAZOLES AND ACTIVE METHYLENE NITRILES: A NOVEL SYNTHESIS OF PYRAZOLO[1,5-a]-1,3,5-
TRIAZINES AND BARBITURATES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:22, 3459-3467
To link to this article: http://dx.doi.org/10.1081/SCC-100106205
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SYNTHETIC COMMUNICATIONS, 31(22), 3459–3467 (2001)
REACTIONS OF
CHLOROCARBONYL ISOCYANATE
WITH 5-AMINOPYRAZOLES AND
ACTIVE METHYLENE NITRILES:
A NOVEL SYNTHESIS OF
PYRAZOLO[1,5-a]-1,3,5-TRIAZINES
AND BARBITURATES
Galal H. Elgemeie,* Samia R. El-Ezbawy,
and Hany A. Ali
Chemistry Department, Faculty of Science,
Helwan University, Ain-Helwan, Cairo, Egypt
ABSTRACT
Reactions of chlorocarbonyl isocyanate and chlorosulfonyl
isocyanate with aminopyrazoles and active methylene nitriles
are reported. They lead to novel pyrazolo[1,5-a]-1,3,5-tria-
zines and barbituric acid derivatives. The structures of the
products and the mechanisms of their formation are reported.
*Corresponding author.
3459
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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ELGEMEIE, EL-EZBAWY, AND ALI
Chlorocarbonyl isocyanate is versatile and increasingly used in a vari-
ety of organic syntheses, in particular in the synthesis of new types of
heterocyclic compounds.1 In continuation of our work on the synthesis of
purine and pyrimidine analogues as potential antimetabolites in purine
biochemical reactions,2–5 we investigated the reactivity of chlorocarbonyl
isocyanate towards various aminopyrazoles and active methylene nitriles.
We have found that these reactions constitute a facile method for the syn-
thesis of several novel pyrazolo[1,5-a]-1,3,5-triazine-2,4-dione and uracil
derivatives. Our method is superior, due to the milder reaction conditions
employed. These reactions take place in a relatively shorter time and afford
the products in a high degree of purity and in a good yield. Thus, it has been
found that addition of one equivalent of chlorocarbonyl isocyanate to a
stirred solution of 5-aminopyrazoles 1 in methylene chloride containing
catalytic amounts of triethylamine at room temperature affords the
1,2,3,4-tetrahydropyrazolo[1,5-a]-1,3,5-triazine-2,4-diones 5. The formation
of 5 from the reaction of chlorocarbonyl isocyanate with 1 is assumed to
proceed via the intermediacy of 6. Although one may argue that the reaction
of 5-aminopyrazoles 1 with chlorocarbonyl isocyanate may involve exocyc-
lic or endocyclic pyrazole-N, involvement of endocyclic or exocyclic pyra-
zole-N will lead to the same product. The structure of 5 was established
1
based on elemental analysis and spectral data (MS, IR, H NMR). The
analytical data for 5a revealed
a molecular formula C11H8N4O2
1
(Mþ ¼ 228). H NMR revealed two broad bands at d 10.1 and 11.65 ppm
assignable to two NH groups. For further evidence in support of structure 5
and in order to clarify the mechanism of this conversion, we examined the
reaction of 5-aminopyrazoles 1 with chlorosulphonyl isocyanate under the
same conditions. The products 5 obtained were shown to be the same as those
obtained from the reaction of 1 with chlorocarbonyl isocyanate by their
melting points and spectral data. The mechanism of the reaction of 1 and
chlorosulphonyl isocyanate is assumed to proceed through the formation of
the initial adduct 2, which leads to the intermediate 4 and hence to the
product 5 as produced by the reaction of 1 with chlorocarbonyl isocyanate.
In order to investigate the scope of this reaction further we studied the
reaction of chlorocarbonyl isocyanate with 2-cyanomethylbenzothiazole 7
in dioxane-triethylamine under mild conditions (room temperature, 24 h).
The reaction proceeded to yield the 1,3-dioxo-2H-pyrimido[6,1-b]benzothia-
zole-4-carbonitrile 8. The formation of 8 in this reaction might be assumed
to proceed via addition of chlocarbonyl isocyanate and HCl elimination
under the basic reaction conditions to yield the finally isolated product 8.
The structure of compound 8 was established on the basis of its elemental
analysis and spectral data. Thus, structure 8 is supported by its mass
which revealed a molecular formula C11H5N3O2S (Mþ ¼ 243) and 1H NMR

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3461
spectra which included one broad band near d 12.27 ppm assigned to the
one NH proton. The interesting course of the reaction between the chlor-
ocarbonyl isocyanate and amino functionalized azoles prompted us to
investigate this reaction with amino functionalized nitriles. Thus, it has
been found that chlorocarbonyl isocyanate reacted with cyanoacetohydra-
zide in dioxane containing catalytic amounts of triethylamine at room
temperature to give the N-amino-barbituric acid derivative 10 in good
yield. Structure 10 was supported by its mass (Mþ ¼ 168), which agreed
with its molecular formula C5H4N4O3; its 1H NMR spectrum displayed
signals at d 6.1 (s, br, N-NH2). The formation of 10 from the reaction of
chlorocarbonyl isocyanate and cyanoacetohydrazide is assumed to proceed
via intermediacy of the acyclic adduct 9, which cyclized to yield the
final N-aminobarbiturate derivative 10. Although one may argue that
the reaction of cyanoacetohydrazide with chlorocarbonyl isocyanate
may involve active methylene or NH function, involvement of either will
lead to the same product. Similarly, it has been found that reaction of
chlorocarbonyl isocyanate with cyanothioacetamide under the same con-
ditions gave the novel thiobarbituric acid derivative 13, the structure of
which was established on the basis of elemental analysis and spectral
evidence. Thus, a CN absorption was present from the IR spectrum
at 2220 cmÀ1 and a carbonyl group at 1712 cmÀ1, whilst the mass spectrum
was compatible with the molecular formula C5H3N3O2S (Mþ ¼ 169); the
1H NMR spectrum showed signals at d 4.8 (s, CH) and (2 NH) at 6.85
and 7.36 ppm.
In summary, by the reaction of chlorocarbonyl isocyanate with 5-ami-
nopyrazoles and amino functionalized nitriles we have achieved a regiospe-
cific synthesis of novel antimetabolites, compounds which have both
chemical and biological potential.
EXPERIMENTAL
All melting points were determined in open glass capillaries on
Gallenkamp melting point apparatus and are uncorrected. Their spectra
were obtained (KBr disc) on a Perkin–Elmer/1650. FT-IR instrument.
1
The H NMR spectra were measured in a Varian 400 or wilmad 270 MHz
spectrometer for (CD3)2SO 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.

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ELGEMEIE, EL-EZBAWY, AND ALI
7,8-Disubstituted-2,4-dioxo-1,2,3,4-tetrahydropyrazolo
[1,5-a]-1,3,5-triazines 5a–k
Generalprocedure: Chlorocarbonyl isocyanate (0.01 mole) or chloro-
sulfonyl isocyanate (0.02 mole) was added to a stirred solution of substituted
aminopyrazoles 1 (0.01 mole) in a dry methylene chloride (20 ml) containing
few drops of triethylamine at 0ꢀC. After stirring under dry conditions for 1 h
at room temperature, the reaction mixture was left to stand over night at
room temperature. Water (1 ml) was added and the solid product formed
was collected by filtration and recrystallized from the appropriate solvent.
5a: Yellow, m.p. 295ꢀC (from EtOH), yield (85%), IR (KBr)
n
max/cmÀ1 3728 (NH), 1710 (C¼O), 1H NMR (DMSO) d 6.32 (s, 1H,
CH), 7.37–7.95 (m, 5H, C6H5), 10.1 (s, br, 1H, NH), 11.65 (s, br, 1H,
NH), C11H8N4O2 (Mþ ¼ 228), Calcd: C, 57.9; H, 3.5; N, 24.6. Found: C,
58.2; H, 3.9; N, 25.0%. 5b: Yellow, m.p. 300ꢀC (from EtOH), yield (82%),
IR (KBr) nmax/cmÀ1 3217 (NH), 1703 (C¼O), H NMR (DMSO) d 2.36 (s,
1
3H, CH3), 6.28 (s, 1H, CH), 7.27–7.85 (m, 4H, C6H4), 11.6 (s, br, 1H, NH),
12.1 (s, br, 1H, NH), C12H10N4O2, Calcd: C, 59.5; H, 4.1; N, 23.1. Found:
C, 60.1; H, 3.7; N, 22.5%. 5c: Yellow, m.p. 325ꢀC (from EtOH), yield
(88%), IR (KBr) nmax/cmÀ1 3234 (NH), 1703 (C¼O), H NMR (DMSO)
1
d 3.81 (s, 3H, OCH3), 6.24 (s, 1H, CH), 7.0–7.9 (m, 4H, C6H4), 11.5 (s, br,
1H, NH), 11.98 (s, br, 1H, NH), C12H10N4O3, Calcd: C, 55.8; H, 3.9; N,
21.7. Found: C, 56.3; H, 4.2; N, 21.4%. 5d: Yellow, m.p. > 300ꢀC (from
EtOH), yield (80%), IR (KBr) nmax/cmÀ1 3425, 3208 (NH, NH2), 1725
(C¼O), C11H7N4O2Cl (Mþ ¼ 262), Calcd: C, 50.3; H, 2.7; N, 21.3. Found:
C, 49.9; H, 3.2; N, 20.8% 5e: Orange, m.p. 165ꢀC (from EtOH), yield (83%),
IR (KBr) nmax/cmÀ1 3421, 3300 (NH, NH2), 1718 (C¼O), C11H9N7O2,
Calcd: C, 48.7; H, 3.3; N, 36.1. Found: C, 49.3; H, 2.8; N, 35.5%.
5f: Orange, m.p. 185ꢀC (from EtOH), yield (81%). IR (KBr) nmax/cmÀ1
3440, 3220 (NH, NH2), 1735 (C¼O), C11H8N7O2Cl, Calcd: C, 43.2; H,
2.6; N, 32.0 Found: C, 42.8; H, 3.2; N, 31.7%. 5g: Orange, m.p. 190ꢀC
(from EtOH), yield (80%), IR (KBr) nmax/cmÀ1 3732, 3350, 3400 (NH2,
NH), 1720 (C¼O), C12H11N7O2, Calcd: C, 50.5; H, 3.9; N, 34.4. Found:
C, 50.2; H, 3.5; N, 33.8%. 5h: Orange, m.p. 157ꢀC (from EtOH), yield
(88%), IR (KBr) nmax/cmÀ1 3420, 3215 (NH, NH2), 1715 (C¼O),
1H NMR (DMSO) d 2.51 (s, 3H, CH3), 7.1 (s, br, 2H, NH2), 7.27–7.77
(m, 4H, C6H4), 11.2 (s, br, 1H, NH), 12.1 (s, br, 1H, NH), C12H11N7O2
(Mþ ¼ 285), Calcd: C, 50.5; H, 3.9; N, 34.4. Found: C, 50.2; H, 4.2; N,
33.8%. 5i: Orange, m.p. 160ꢀC (from EtOH), yield (89%), IR (KBr)
n
Calcd: C, 47.8; H, 3.7; N, 32.6. Found: C, 48.2; H, 3.2; N, 33.1%.
max/cmÀ1 3751, 3068 and 3030 (NH2, NH) 1707 (C¼O), C12H11N7O3,
5j: Orange, m.p. 170ꢀC (from EtOH), yield (79%), IR (KBr) nmax/cmÀ1

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3463

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ELGEMEIE, EL-EZBAWY, AND ALI

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3465

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ELGEMEIE, EL-EZBAWY, AND ALI
1
3784, 3751 and 3142 (NH2, NH), 1720 (C¼O), H NMR (DMSO) d 7.15
(s, br, 2H, NH2), 7.50–7.9 (m, 4H, C6H4), 11.2 (s, br, 1H, NH) 12.1 (s, br,
1H, NH), C11H8N7O2Cl (Mþ ¼ 305), Calcd: C, 43.2; H, 2.6; N, 32.0. Found:
C, 42.6; H, 2.1; N, 31.6%. 5k: Red, m.p. 175ꢀC (from EtOH), yield (88%),
IR (KBr) nmax/cmÀ1 3732, 3350 and 3300 (NH2, NH), 1720 (C¼O),
C11H8N8O4, Calcd: C, 41.8; H, 2.5; N, 35.4. Found: C, 42.1; H, 2.9;
N, 34.8%.
1,3-Dioxo-2H-pyrido[6,1-a]benzothiazol-4-carbonitrile 8
Generalprocedure: To a stirred solution of the 2-cyanomethylben-
zothiazole 7 (0.01 mole) in dry dioxane (20 ml) containing few drops of
triethylamine at 0ꢀC was added chlorocarbonyl isocyanate (0.01 mole).
The reaction mixture was stirred for 30 min at room temperature
ðꢁ 258CÞ. The solution was left to stand over night at room temperature,
the solid precipitated was collected by filtration and crystallized from the
appropriate solvent.
8: Orange, m.p. 205ꢀC, (from EtOH), yield (85%), IR (KBr)
n
max/cmÀ1 3190 (NH), 2218 (CN), 1732 (C¼O), 1H NMR (DMSO)
d 7.48–8.56 (m, 4H, C6H4), 12.27 (s, br, 1H, NH), C11H5N3O2S (Mþ ¼ 243).
Calcd: C, 54.3; H, 2.0; N, 17.3. Found: C, 55.0; @H, 1.8; N, 16.9%.
1-N-Amino-3-cyanobarbituric Acid 10
Generalprocedure: To a stirred solution of the cyanoacetohydrazide
(0.01 mole) in dry dioxane (20 ml) containing few drops of triethylamine at
0ꢀC was added chlorocarbonyl isocyanate (0.01 mole). The reaction mixture
was stirred for 30 min at room temperature ðꢁ 258CÞ. The solution was left
to stand over night at room temperature, the solid precipitated was collected
by filtration and crystallized from the appropriate solvent.
10: colorless, m.p. 195ꢀC (from EtOH/DMF), yield (70%), H NMR
1
(DMSO) d 4.2 (s, 1H, pyrimidine H-5), 6.1 (s, 2H, N-NH2), 9.2 (s, br, 1H,
NH). C5H4N4O3 (Mþ ¼ 168), Calcd: C, 35.7; H, 2.4; N, 33.3. Found:
C, 36.3; H, 1.8; N, 32.8%.
5-Cyano-4-thiobarbituric Acid 13
Generalprocedure: To a stirred solution of the cyanothioacetamide
(0.01 mole) in dry dioxane (20 ml) containing a few drops of triethylamine

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3467
at 0ꢀC was added chlorocarbonyl isocyanate (0.01 mole). The reaction mix-
ture was stirred for 30 min at room temperature ðꢁ 258CÞ. The solution was
left to stand over night at room temperature. The solid precipitated was
collected by filtration and crystallized from the appropriate solvent.
13: Yellow, m.p. 289ꢀC, (from EtOH), yield (80%), IR (KBr)
n
max/cmÀ1 3180 (NH), 2220 (CN), 1712 (C¼O), 1H NMR (DMSO)
d 4.76–4.97 (s, br, 3H, 2 OH, pyrimidine H-5), 6.85 (s, br, 1H, NH), 7.36
(s, br, 1H, NH). C5H3N3O2S (Mþ ¼ 169). Calcd: C, 35.5; H, 2.2; N, 24.9.
Found: C, 34.9; H, 2.5; N, 25.3%.
REFERENCES
1. Bunnenberg, R.; Jochims, J.C. Chem. Ber. 1981, 114, 2064–2074.
2. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Ahmed, S.A.
J. Chem. Soc. Perkin Trans. 1 1997, 3285–3289.
3. Elgemeie, G.H.; Attia, A.M.; Farag, D.S.; Sherif, S.M. J. Chem. Soc.
Perkin Trans. 1 1994, 1285–1288.
4. Elgemeie, G.H.; El-Ezbawy, S.E.; Ali, H.A.; Mansour, A.K. Bull.
Chem. Soc. Jpn. 1994, 67, 738–741.
5. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Masoud, W.A.
J. Chem. Res. (S) 1998, 164–165.
Received in the UK May 2, 2000

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