One pot synthesis of 1-(s-triazolo[4,3-c]pyrimidin-3-Yl)substituted polyols

Article abstract of DOI:10.1081/SCC-120004057

2-N,N-Diphenylamino-4-hydrazino-6-trifluoromethylpyrimidine (5) was reacted with some aldoses to give the corresponding hydrazones (6), which on bromine oxidation cyclized to afford 1-(s-triazolo[4,3-c]pyrimidin-3-yl)substituted polyols (7).

Full text of DOI:10.1081/SCC-120004057

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
ONE POT SYNTHESIS OF 1-(S-TRIAZOLO[4,3-
c]PYRIMIDIN- 3-YL)SUBSTITUTED POLYOLS
A. H. Ismail
To cite this article: A. H. Ismail (2002) ONE POT SYNTHESIS OF 1-(S-TRIAZOLO[4,3-c]PYRIMIDIN-
3-YL)SUBSTITUTED POLYOLS, Synthetic Communications, 32:12, 1791-1795, DOI: 10.1081/
SCC-120004057
To link to this article: http://dx.doi.org/10.1081/SCC-120004057
Published online: 17 Oct 2011.
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SYNTHETIC COMMUNICATIONS, 32(12), 1791–1795 (2002)
ONE POT SYNTHESIS OF
1-(S-TRIAZOLO[4,3-c]PYRIMIDIN-
3-YL)SUBSTITUTED POLYOLS
A. H. Ismail
Chemistry Department, Faculty of Science,
Menoufiya University, Shebin El-Koom, Egypt
ABSTRACT
2-N,N-Diphenylamino-4-hydrazino-6-trifluoromethylpyrimi-
dine (5) was reacted with some aldoses to give the corre-
sponding hydrazones (6), which on bromine oxidation
cyclized to afford 1-(s-triazolo[4,3-c]pyrimidin-3-yl)substi-
tuted polyols (7).
[1,2,4]-Triazolo[4,3-c]pyrimidine derivatives represent a new class of
bicyclic antogonists having potent oral antihypertensive activity in the
renal artery-ligated rat model.[1,2] Triazolo[4,3-c]pyrimidines are generally
prepared by cyclization of 4-hydrazinopyrimidine with various reagents
such as orthoesters,[3] cyanogen chloride,[4] carbon disulfide,[5] isothio-
cyanates[6] and ethylchloroformates.[7]
We now report a one-pot synthesis of 1-(s-triazolo[4,3-c]pyrimidin-3-
yl)substituted polyols (7), starting from commercially available aldoses
which does not require any protective and consequently deprotective steps.
2-N,N-Diphenylamino-4-chloro-6-trifloromethylpyrimidine (4), which was
prepared from 2-N,N-diphenylamino-6-trifluoromethylpyrimidin-4-ol[8] (3),
1791
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ISMAIL
and was refluxed in excess hydrazine hydrate to afford 2-N,N-diphenyl-
amino-4-hydrazino-6-trifluoromethylpyrimidine (5) (Scheme 1).
In the presence of acid catalyst the hydrazinopyrimidine (5) was
reacted with aldoses in methanol to give the corresponding hydrazones.[9]
Cyclization of aldosehydrazones (6) into the corresponding 1(s-triazolo
[4,3-c]pyrimidinyl)substituted polyols (7) was achieved by the addition of
the methanolic bromine to the reaction mixture (Scheme 2).[10,11]
Scheme 1.
Scheme 2.

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1-(S-TRIAZOLO[4,3-c]PYRIMIDIN-3-YL)SUBSTITUTED POLYOLS
1793
EXPERIMENTAL
Melting points were determine with Electothermal melting point appa-
ratus and are uncorrected. The H-NMR spectra were obtained with a
Varian Gemini 250 spectrometer with DMSO-d6 as solvent and TMS as
internal reference. Mass spectra were recorded with a Micromass Kratos
MS Tc. Microanalysis: C,H,N-Automat Cario Ebra 1106.
2-Chloro-6-ethoxy-4-triflouromethylpyrimidine (1): This compound was
prepared from 2,6-dichloro-4-trifluoromethylpyrimidine.[8]
2-N,N-Diphenylamino-4-ethoxy-6-trifluoromethylpyrimidine (2):
A
solution of diphenylamine (16.9 g, 100 mmol) in ethanol (5 ml) was added
in portions to a solution of 2-chloro-4-ethoxy-6-trifluoromethylpyrimidine
(11.36 g, 50 mmol )in ethanol (20 ml) at 0ꢀC. The mixture was heated gra-
dually to 70ꢀ and refluxed for 48 h. The solvent was removed under vacuo.
The crude product was crystallized from ethanol; yield (61%); m.p. 116ꢀC
(decomp.). MS, m/z ¼ 359 (Mþ); Calcd for C19H16F3N3O: C, 63.51; H, 4.49;
N, 11.69. Found: C, 63.72; H, 4.32; N, 11.71.
2-N,N-Diphenylamino-6-trifluoromethyl pyrimidin-4-ol (3): A suspen-
sion of compound (2) (3.59 g, 10 mmol) in 6 N hydrochloric (20 ml) acid
was heated under reflux for 40 h. After cooling, the precipitate was filtered
off, washed with water and crystallized from ethanol; yield (73%); m.p.
128–130ꢀC (decomp.); MS, m/z ¼ 331(Mþ); Calcd for C17H12F3N3O:
C, 61.63; H, 3.65; N, 12.68. Found: C, 61.82; H, 3.71; N, 12.56.
4-Chloro,2-N,N-diphenylamino–6-trifluoromethyl pyrimidine (4): A sus-
pension of (3) (3.31 g, 10 mmol ) in 20 ml of phosphorus oxychloride was
heated under reflux for 8 h. The phosphorus oxychloride was removed under
vacuo and the residue was poured into an ice-water (50 g). The crude prod-
uct formed was crystallized from ethanol; yield (60%); m.p. 97ꢀC; Calcd for
C17H11ClF3N3: C, 58.38; H, 3.17; N, 12.01. Found: C, 58.29; H, 3.00;
N, 12.30. MS, m/z ¼ 349 (Mþ).
2-N,N-Diphenylamino-4-hydrazino-6-trifluoromethylpyrimidine
(5):
In excess hydrazine hydrate (10 ml) compound (4) (1.75 g, 5 mmol) was
refluxed for 4h. After cooling the content were added to 50 ml of
ice-cold water. The precipitate was filtered, washed with water and used
as such in the next step; yield (68%); m.p. 137ꢀC; MS, m/z ¼ 345 (Mþ);
Calcd for C17H14F3N5: C, 59.13; H, 4.09; N, 20.28. Found: C, 59.40; H,
4.33; N, 20.
General procedure for prepration of (s-Triazolo [4,3-c]pyridmin-3-yl)
substituted polyols (7a–d): General procedure, A mixture of aldoses
(5 mmol), hydrazinopyrimidine (5) (5 mmol), methanol 20 ml and 3 drops
of conc. HCl was refluxed for 4h, cooled to 20 ꢀC, and added (0.26 ml,
5 mmol) bromine in 5 ml methanol with stirring 3 h. The solvent was

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1794
ISMAIL
removed under vacuo, the residue was titrated with 30 ml ethanol 1 h at
room temperature to give yellow cyrstalls.
1-(s-Triazolo[4,3-c]pyrimidin-3-yl)D-xylo-tetritol (7a): Yield ¼ 62%
m.p. 180ꢀC.1H-NMR (DMSO-d6) ꢀ ¼ 3.30–3.41 (2H, m, CH2), 3.50–3.56
(2H, m, H-3 and H-2), 4.80 (1H, d, H-1, J ¼ 5.2), 5.46 (H, br s. OH-1),
6.81 (1H, s, H-50), 7.1–7.6 (10H, m, Aryl) ppm; MS, m/z ¼ 475 (Mþ); Calcd
for C22H20F3N5O4: C, 55.58; H, 4.24; N, 14.73. Found: C, 55.71; H, 4.30;
N, 14.51.
1-(s-Triazolo[4,3-c]pyrimidin-3-yl)D-ribo-tetritol (7b): Yield (67%);
m.p. 179ꢀC. H-NMR (DMSO-d6) ꢀ ¼ 3.41–3.49 (2H, m, CH2), 3.56–3.78
1
(2H, m, H-2 and H-3), 4.39 (H, d, H-1, J ¼ 3.1), 6.88 (H,s, H-50), 7.25–7.68
(10H, m, Aryl) ppm.; MS, m/z ¼ 475 (Mþ); Calcd for C22H20F3N5O4:
C, 55.58; H, 4.24; N, 14.73. Found: C, 55.66; H, 4.39; N, 14.80.
1-(s-Triazolo[4,3-c]pyrimidin-3-yl)D-gluco-pentitol (7c): Yield (58%);
m.p. 170ꢀC. H-NMR (DMSO-d6) ꢀ ¼ 3.15–3.37 (2H, m, CH2), 3.60–3.82
1
(3H, m, H-2, H-3 and H-4), 4.50 (1H, d, H-1, J ¼ 7.3), 5.4(1H, d, J ¼ 6.1 Hz,
OH-1), 6.88 (1H, s, H-50), 7.51–7.90 (10H, m, Aryl) ppm; MS, m/z ¼ 505
(Mþ); Calcd for C23H22F3N5O5: C, 54.65; H, 4.39; N, 13.86. Found:
C, 54.51; H, 4.32; N, 14.00.
1-(s-Triazolo[4,3-c]pyrimidinyl–3)D-manno-pentitol (7d): Yield (65%)
m.p. 169ꢀC. H-NMR (DMSO-d6) ꢀ ¼ 3.05–3.23 (2H, m, CH2) 3.51–3.72
1
(3H, m, H-2, H-3 and H-4), 4.31 (H, d, H-1, J ¼ 4.2), 5.04 (H, br s,
OH-1), 6.70 (H, s, H-50), 7.41–7.77 (10H, m, Aryl) ppm;. MS, m/z ¼ 505
(Mþ). Calcd for C23H22F3N5O5: C, 54.65; H, 4.39, N, 13.86. Found: C,
54.43; H, 4.50; N, 13.95.
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©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Received in the UK March 12, 2001