The design and synthesis of structurally related mercaptopurine analogues: Reaction of dimethyl N-cyanodithioiminocarbonate with 5-aminopyrazoles

Article abstract of DOI:10.1081/SCC-100106204

A novel synthesis of 4-methylthiopyrazolo[1,5-a]-1,3,5-triazines via reaction of dimethyl N-cyanodithioiminocarbonate with 5-aminopyrazoles is reported and the synthetic potential of the method is demonstrated.

Full text of DOI:10.1081/SCC-100106204

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THE DESIGN AND SYNTHESIS OF STRUCTURALLY
RELATED MERCAPTOPURINE ANALOGUES: REACTION
OF DIMETHYL N-CYANO-DITHIOIMINOCARBONATE
WITH 5-AMINOPYRAZOLES
Galal H. Elgemeie a , Samia R. El-Ezbawy a & Hany A. El-Aziz a
a Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, Cairo,
Egypt
Published online: 22 Aug 2006.
To cite this article: Galal H. Elgemeie , Samia R. El-Ezbawy & Hany A. El-Aziz (2001): THE DESIGN AND SYNTHESIS OF
STRUCTURALLY RELATED MERCAPTOPURINE ANALOGUES: REACTION OF DIMETHYL N-CYANO-DITHIOIMINOCARBONATE WITH
5-AMINOPYRAZOLES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:22, 3453-3458
To link to this article: http://dx.doi.org/10.1081/SCC-100106204
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SYNTHETIC COMMUNICATIONS, 31(22), 3453–3458 (2001)
THE DESIGN AND SYNTHESIS
OF STRUCTURALLY RELATED
MERCAPTOPURINE ANALOGUES:
REACTION OF DIMETHYL N-CYANO-
DITHIOIMINOCARBONATE
WITH 5-AMINOPYRAZOLES
Galal H. Elgemeie,* Samia R. El-Ezbawy,
and Hany A. El-Aziz
Chemistry Department, Faculty of Science,
Helwan University, Ain Helwan, Cairo, Egypt
ABSTRACT
A novel synthesis of 4-methylthiopyrazolo[1,5-a]-1,3,5-tria-
zines via reaction of dimethyl N-cyanodithioiminocarbonate
with 5-aminopyrazoles is reported and the synthetic potential
of the method is demonstrated.
Therapeutic attempts to inhibit the growth of cancer cells or certain
viruses have often employed administration of analogues of purines that
inhibit the synthesis of their DNA or RNA. Such compounds include
6-thioguanine and 6-mercaptopurine.1–2 Allopurinol, a purine analogue, is
*Corresponding author.
3453
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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ELGEMEIE,EL-EZBAWY,AND EL-AZIZ
widely used in the treatment of gout. As a part of our program directed
for development of new simple and efficient procedures for the synthesis
of purine analogues and other antimetabolites,3–5 we have recently reported
different successful approaches for the synthesis of pyrazolopyrimidines.6
Derivatives of this ring system are interesting because they are purine
analogues and as such they have useful properties as antimetabolites
in purine biochemical reactions. The present part deals with a novel
synthesis of 4-methylthiopyrazolo[1,5-a]-1,3,5-triazines by the reaction of
dimethyl N-cyanodithioiminocarbonate with 5-aminopyrazoles. Thus, it
has been found that dimethyl N-cyanodithioiminocarbonate 2 reacts with
5-aminopyrazoles 1 in refluxing ethanol containing catalytic amounts of
piperidine to give the corresponding 4-methylthiopyrazolo[1,5-a]-1,3,5-tria-
zines 5a–h in good yield. The structure of compounds 5 were established and
confirmed on the basis of their elemental analysis and spectral data (MS, IR,
1
and H NMR and 13C NMR). The analytical data for 5a revealed a mol-
1
ecular formula C12H11N5S (Mþ ¼ 257). H NMR spectroscopy was used to
1
confirm this structure for the product. Thus, H NMR revealed a band at d
2.49 ppm assignable to SCH3 group, a multiplet at d 7.44–8.05 ppm assigned
for aromatic protons and a broad singlet at d 8.65 ppm assignable for an
amino group. The formation of 5 from the reaction of 1 and 2 is assumed to
proceed via the intermediate 4, which cyclised to yield the end products 5.
Although, one may argue that the reaction of 2 with 5-aminopyrazoles 1 may
involve the exocyclic pyrazole nitrogen leading to the other possible 4-amino
regioisomers. However, it is known that the endocyclic ring nitrogen is the
most nucelophilic center in the molecule and in basic medium will initially
add to the unsaturated double bond of 2.7 Compounds 5 bearing latent
functional substituents were found useful for the synthesis of
other derivatives. Thus, it has been found that compounds 5 reacted with
hydrazine hydrate or aniline in refluxing ethanol containing catalytic
amounts of piperidine to afford the corresponding hydrazino or anilino
derivatives 6a–d, 6e–h, respectively. The structure of compounds 6 was
established on the basis of elemental analysis and spectral data. Thus,
the mass spectrum of 6a was compatible with the molecular formula
C11H11N7, and the 1H NMR spectrum contained two broad bands at
d 8.17 and 10.09 ppm assignable for two amino groups and a broad singlet
at d 9.15 ppm assignable for an NH group.
In summary, we have achieved a regiospecific synthesis of interesting
methylthiopyrazolo[1,5-a]-1,3,5-triazines by the reaction of dimethyl N-cya-
nodithioiminocarbonate with 5-aminopyrazoles. The compounds synthe-
sized are being subjected to biological testing.

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ELGEMEIE,EL-EZBAWY,AND EL-AZIZ
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 and 13C NMR spectra were measured in a Varian 400 or
wilmad 270 MHzspectrometer for (CD 3)2SO solutions using SiMe4 as inter-
nal standard. Mass spectra were recorded in Varian MAT 112 spectrometer.
Analytical data were obtained from the Micro Analytical Data Center at
Cairo University.
2-Amino-7-aryl-4-(methylthio)pyrazolo[1,5-a]-1,3,5-triazines (5a–d)
General procedure: A suspension of dimethyl N-cyanodithioiminocar-
bonate 2 (0.01 mol) in ethanol (30 ml) was refluxed with 5-aminopyrazoles 1
(0.01 mol) and three drops of piperidine for 3 h, the reaction mixture was left
to cool to room temperature. The crystals separating on cooling were fil-
tered off and crystallized from the appropriate solvent.
5a: Yellow, m.p. 255ꢀC (from EtOH), yield (75%), IR (KBr)
1
n
max/cmꢁ1 3450 (NH2), H NMR (DMSO) d 2.49 (s, 3H, SCH3), 6.78 (s,
1H, CH), 7.44–8.05 (m, 5H, C6H5), 8.65 (s, br, 2H, NH2), C12H11N5S,
Calcd: C, 56.0; H, 4.3; N, 27.2. Found: C, 56.7; H, 3.7; N, 26.7%.
5b: Yellow, m.p. 260ꢀC (from EtOH), yield (81%), IR (KBr) nmax/cmꢁ1
1
3470 (NH2), H NMR (DMSO) d 2.37 (s, 3H, CH3), 2.48 (s, 3H, SCH3),
6.73 (s, 1H, CH), 7.30–7.95 (m, 4H, C6H4), 8.65 (s, br, 2H, NH2),
C13H13N5S, Calcd: C, 57.6; H, 4.8; N, 25.8. Found: C, 58.2, H, 5.2; N,
26.3%. 5c: Yellow, m.p. 241ꢀC (from EtOH), yield (72%), IR (KBr)
n
max/cmꢁ1 3465 (NH2), C13H13N5OS (Mþ ¼ 287), Calcd: C, 54.3; H, 4.5;
N, 24.4. Found: C, 53.8; H, 3.9; N, 24.0%. 5d: Yellow, m.p. 271ꢀC (from
EtOH), yield (87%), IR (KBr) nmax/cmꢁ1 3441 (NH2), H NMR (DMSO)
1
d 2.48 (s, 3H, SCH3), 6.79 (s, 1H, CH), 7.57–8.05 (m, 4H, C6H4), 8.69 (s, br,
2H, NH2). 13C NMR (DMSO) C12H10N5SCl, Calcd: C, 49.4; H, 3.4, N,
24.0. Found: C, 50.0; H, 2.8; N, 23.6%.
2-Amino-7-aryl-4-hydrazinopyrazolo[1,5-a]-1,3,5-triazines (6a–d)
General procedure: A mixture of 5 (0.01 mol), hydrazine (0.01 mol),
and piperidine (3 drops) in ethanol (30 ml) was refluxed for 2 h, cooled,
the precipitate was filtered off and crystallized from the appropriate solvent.

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6a: Yellow, m.p. 292ꢀC (from EtOH), yield (71%), IR (KBr)
1
n
max/cmꢁ1 3441, 3114 (NH, NH2), H NMR (DMSO) d 6.78 (s, 1H, CH),
7.97–8.03 (m, 5H, C6H5), 8.17 (s, br, 2H, NH2), 9.51 (s, br, 1H, NH), 10.09
(s, br, 2H, NH2), C11H11N7 (Mþ ¼ 241), Calcd: C, 54.8; H, 4.6, N, 40.6.
Found: C, 55.3; H, 3.9; N, 41.0%. 6b: Yellow, m.p. 284ꢀC (from EtOH),
yield (77%), IR (KBr) nmax/cmꢁ1 3500, 3350 (NH, NH2), C12H13N7, Calcd:
C, 56.5; H, 5.1; N, 38.4. Found: C, 56.1; H, 4.7; N, 37.8%. 6c: Yellow, m.p.
268ꢀC (from EtOH), yield (81%), IR (KBr) nmax/cmꢁ1 3450, 3365 (NH,
NH2), C12H13N7O, Calcd: C, 53.1; H, 4.8; N, 36.2. Found: C, 52.7; H,
5.1; N, 36.6%. 6d: Yellow, m.p. 342ꢀC (from EtOH), yield (83%),
1
IR (KBr) nmax / cmꢁ1 3374, 3300 (NH, NH2), H NMR (DMSO) d 6.41
(s, 1H, CH), 7.47–7.76 (m, 4H, C6H4), 8.04 (s, br, 2H, NH2), 9.31 (s, br, 1H,
NH), 9.83 (s, br, 2H, NH2), C11H10N7Cl, Calcd: C, 47.9; H, 3.6; N, 35.8.
Found: C, 48.3; H, 4.0; N, 36.2%.
2-Amino-7-aryl-4-anilinopyrazolo[1,5-a]-1,3,5-triazines (6e–h)
General procedure: A mixture of 5 (0.01 mol) and aniline (0.01 mol)
were heated at 150ꢀC (bath temperature) for 30 min, the resulting solid
product was triturated with ether, filtered off and crystallized from the
appropriate solvent.
6e: Yellow, m.p. 245ꢀC (from EtOH), yield (73%), IR (KBr)
1
n
max/cmꢁ1 3469, 3320 (NH, NH2), H NMR (DMSO) d 6.79 (s, 1H, CH),
7.44–8.06 (m, 10H, 2C6H5), 8.13 (s, br, 2H, NH2), 8.25 (s, br, 1H, NH),
C17H14N6, Calcd: C, 67.6; H, 4.6; N, 27.8. Found: C, 68.2; H, 3.9; N, 28.3%.
6f: Yellow, m.p. 275ꢀC (from EtOH), yield (79%), IR (KBr) nmax/cmꢁ1
3560, 3390 (NH, NH2), C18H16N6, Calcd: C, 68.4; H, 5.1; N, 26.6.
Found: C, 67.7; H, 4.8; N, 26.1%. 6g: Yellow, m.p. 295ꢀC (from EtOH),
yield (79%), IR (KBr) nmax / cmꢁ1 3530, 3340 (NH, NH2), C18H16N6, Calcd:
C, 65.1; H, 4.8; N, 25.3. Found: C, 64.8; H, 5.3; N, 25.7%. 6h: Yellow, m.p.
291ꢀC (from EtOH), yield (82%), IR (KBr) nmax/cmꢁ1 3495, 3365 (NH,
1
NH2), H NMR (DMSO) d 6.79 (s, 1H, CH), 7.55–8.06 (m, 9H, C6H5 and
C6H4), 8.29 (s, br, 2H, NH2), 8.65 (s, br, 1H, NH), C17H13N6Cl, Calcd: C,
60.6; H, 3.9; N, 25.0. Found: C, 61.2; H, 4.2; N, 24.7%.
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2. Otsuka, M.; Matsuda, Y.; Fox, J.L.; Higuchi, W.I. Pharm. Pharmacol.
Lett. 1995, 5, 18.

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3. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Ahmed, S.A.
J. Chem. Soc. Perkin Trans. 1 1997, 3285.
4. Elgemeie, G.H.; Hussain, B.A. Tetrahedron 1994, 50, 199.
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Eds. Barton, D.; Ollis, W.D. Pergmon Press, Oxford.
Received in the UK March 20, 2000

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