A facile one-pot regioselective synthesis of [1,2,4]triazolo[4,3-a]5(1H)-pyrimidinones via tandem Japp-Klingemann, smiles rearrangement, and cyclization reactions

Article abstract of DOI:10.1002/hc.10008

Coupling of active [(4-oxo-6-phenyl-3H-pyrimidin-2-yl)thio]methine compounds (3) with diazotized anilines in the presence of base gave [1,2,4]triazolo[4,3-a]pyrimidines (7). The latter products were also obtained by reactions of hydrazonoyl chlorides (10)

Full text of DOI:10.1002/hc.10008

Heteroatom Chemistry
Volume 13, Number 2, 2002
A Facile One-Pot Regioselective Synthesis
of [1,2,4]Triazolo[4,3-a]5(1H )-pyrimidinones
via Tandem Japp–Klingemann, Smiles
Rearrangement, and Cyclization Reactions
Ahmad S. Shawali, Magda A. Abdallah, Mosselhi A. N. Mosselhi,
and Thoraya A. Farghaly
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Received 14 February 2001; revised 23 July 2001
rearrangement, and cyclization reactions. Such a
ABSTRACT: Coupling of active [(4-oxo-6-phenyl-
sequence of reactions provides a facile one-pot
3H-pyrimidin-2-yl)thio]methine compounds (3) with
regioselective synthesis of the title compounds. The
diazotized anilines in the presence of base gave
latter compounds are of interest as many derivatives
[1,2,4]triazolo[4,3-a]pyrimidines (7). The latter prod-
of [1,2,4]triazolo[4,3-a]pyrimidine (7) have been
ucts were also obtained by reactions of hydrazonoyl
reported to be useful as calcium-channel blocking
chlorides (10) with either 6-phenyl-2-thiouracil (1) or
vasodilators and they have antihypertensive [2], car-
the 2-methylthio derivative 9. The mechanisms and
diovascular [3,4], anxiolytic [5] activities, as well as
the regiochemistry of the reactions studied are dis-
being components in photographic materials [6].
C
cussed. 2002 Wiley Periodicals, Inc. Heteroatom Chem
13:136–140, 2002; Published online in Wiley Interscience
RESULTS AND DISCUSSION
(www.interscience.wiley.com). DOI 10.1002/hc.10008
Reaction of 6-phenyl-2-thiouracil (1), prepared as
previously described [7], with the active chloro-
methylene compounds 2A–C in ethanol in the
presence of triethylamine at room temperature
yielded the S-alkylated derivatives 3A–C, respectively
(Scheme 1). The structure of the latter products were
INTRODUCTION
Tandem pericyclic reactions have attracted consid-
erable attention within the past decade because of
their utility in organic synthesis [1]. Other reac-
tions in tandem have received little, if any, attention.
We wish to disclose herein our finding that cou-
pling of active [(4-oxo-6-phenyl-3H-pyrimidin-2-
yl)thio]methine compounds (3) with diazotized ani-
lines afforded directly the respective 1H-[1,2,4]
triazolo[4,3-a]pyrimidin-5-ones via three in situ tan-
dem reactions, namely, Japp–Klingemann, Smiles
1
evidenced by their mass, IR, and H NMR spectra
(see Experimental). For example, their 1H NMR spec-
tra showed a singlet signal at -2.4 assignable to the
methine hydrogen. The formation of 3A–C from 1
and 2A–C respectively is analogous to S-alkylation
reactions exhibited by 2-thiouracil derivatives [8].
Next, reaction of 3 with diazotized anilines was
investigated in ethanol in the presence of sodium ac-
etate at low temperature (0–5 C). Based on the previ-
ous literature on the Japp–Klingemann reaction [9],
we anticipated that the products of this coupling re-
action would be the thiohydrazonate esters (5) or
Correspondence to: Ahmad S. Shawali; e-mail: shawali@chem-
sci.cairo.eun.eg.
c
2002 Wiley Periodicals, Inc.
136

A Facile One-Pot Regioselective Synthesis of [1,2,4]Triazolo[4,3-a]5(1H )-pyrimidinones 137
diately ruled out and the isolated products were as-
signed structure 7. The assignment of the latter struc-
ture 7 is further evidenced by the similarity of their
carbonyl stretching frequencies ( (C O) = 1690–
1
1700 cm ) with those of pyrimidinones of type I.
For example, pyrimidinone derivatives of type I ex-
1
hibit their CO bands in the region 1680–1690 cm
whereas the IR spectra of type II show their CO
1
bands in the region 1640–1660 cm [11].
To account for the direct formation of the latter
products 7, the mechanism outlined in Scheme 1 is
proposed. According to this mechanism, the reaction
starts with the formation of azo coupling products 4,
which undergo Japp–Klingemann elimination of the
acetyl group to form the thiohydrazonates 5 [12].
The latter then undergo Smiles rearrangement to
yield the thiohydrazides 6 [10], which in turn un-
dergo in situ cyclization to give 7 as the end products
(Scheme 1). In all cases examined, attempts to iso-
late the intermediates 4–6 failed, however. This find-
ing indicates that such intermediates are consumed
as soon as they are formed under the reaction con-
ditions employed.
To substantiate further the assigned structure
7 for the isolated products and to provide an indi-
rect evidence for the involvement of the interme-
diates 4–6 and in turn the proposed mechanism,
we examined alternate syntheses of the products 7
(Scheme 2). In our hands, reactions of 1 with the
hydrazonoyl halides 9A–D in ethanol in the pres-
ence of sodium ethoxide afforded products identi-
cal in all respects (m.p., mixed m.p., and IR spectra)
with those obtained above. As it is well known that
hydrazonoyl halides react with thiols to give the re-
spective thiohydrazonate esters [12], which undergo
base-catalyzed Smiles rearrangement [10] to give the
respective thiohydrazides, it is not unreasonable to
assume that both reactions, namely, (3 + ArN+2 → 7 )
and (1 + 9 → 7) proceed via the same intermediates,
namely, 4–6 (Scheme 1).
The regioselective cyclization of the thiohy-
drazides 6 and, in turn, the assignment of structure 7
were further substantiated by alternate syntheses of
7 by reaction of 2-methylthiouracil (10) with hydra-
zonoyl halides (9). Thus, treatment of 10 with 9, in
ethanol, in the presence of sodium ethoxide, under
reflux, was found to give products proved to be iden-
tical in all respects with products 7 obtained above.
As both alkylation and acylation of 2-alkylthiouracil
usually occur at N3 rather than N1 [13], it is not
unreasonable to assume that reaction of 10 with
9 proceeds via the formation of the amidrazones
11, which, in turn, undergo cyclization with elim-
ination of methanethiol to give 7 as end products
(Scheme 2).
SCHEME 1
their Smiles rearrangement [10] products, namely,
the thiohydrazides (6). However, the mass spectral
and elemental analysis data of the isolated products
revealed that they were free of sulfur and thus the
three structures 4–6 were discarded from further
considerations (Scheme 1). The spectral and ana-
lytical data were unexpectedly consistent with ei-
ther of the two isomeric [1,2,4]triazolopyrimidines
7 or 8 (Scheme 1). Distinction between these two
structures was made on the basis of the 13C NMR
and IR spectra. Literature reports [11] have shown
that the chemical shift for the carbonyl carbon in 4-
pyrimidinone derivatives is markedly affected by the
nature of the adjacent nitrogen (pyridine type in our
structure 8 and pyrrole type in our structure 7). In
Chart 1, the reported chemical shift values of the an-
nelated 4-pyrimidinones I and II are compared with
the values found for the isolated products. Since the
values found for the isolated products are similar to
those of I, the regioisomeric structure 8 was imme-
CHART 1

138 Shawali et al.
temperature for 24 h, then the solvent was distilled
under reduced pressure and the residue was cooled.
The solid that formed was collected and crystallized
from dioxane–water mixture to give the respective
product 3.
Repitition of this procedure using sodium ethox-
ide in lieu of triethylamine afforded the respective 3
in almost the same yield.
3-Oxo-2[(6-phenyl-4-oxo-pyrimidin-2-yl)thio]but-
1
ananilide (3A). Yield 75%, m.p. 200–202 C. (cm )
3288, 3100 (NH), 1718, 1662 (CO). MS m/z (%) 379
(M+, 11), 336 (7), 286 (53), 217 (28), 171 (59), 129
(20), 93 (100). 1H NMR (DMSO-d6) 2.3 (s, 3H), 4.45
(s, 1H), 6.05 (s, 1H), 7.9–8.3 (m, 10H), 10.3 (s, 1H),
10.5 (s, 1H). Anal. Calcd. for C20H17N3O3S: C, 63.31;
H, 4.52; N, 11.07. Found: C, 63.6; H, 4.4; N, 11.3%.
3-[(6-Phenyl-4-oxo-pyrimidin-2-yl)thio]-2,4-pent-
anedione (3B). Yield, 70%, m.p. 212–214 C (Lit.
1
m.p. 214 C [17]).
(DMSO-d6)
(cm ) 1690. 1612. 1H NMR
2.0 (s, 6H), 3.3 (s,1H), 4.1 (s, 1H),
7.0–8.1 (m, 5H), 11.2 (s, 1H).
SCHEME 2
Synthesis of Ethyl 3-Oxo-2[(6-phenyl-4-oxo-
pyrimidin-2-yl)thio]butanoate (3C)
To a stirred solution of 1 (2.04 g, 10 mmol) in
ethanol (40 ml) and DMF (10 ml) was added potas-
sium hydroxide (0.56 g) previously dissolved in water
(10 ml), followed by ethyl 2-chloro-3-oxobutanoate
(2C) (1.38 ml, 10 mmol). The mixture was stirred for
24 h, then diluted with water. The solid that precipi-
tated was filtered off, washed with water, and finally
crystallized from ethanol to give 3C, m.p. 202–204 C
EXPERIMENTAL
Melting points were determined on a Gallenkamp
apparatus and are uncorrected. IR spectra were
recorded in potassium bromide using Fourier Trans-
form Infrared and Pye Unicam SP300 Infrared
spectrophotometers. H and 13C NMR spectra were
1
recorded in deuterated chloroform using a Varian
Gemini 200 NMR spectrometer. Mass spectra were
recorded on a GCMS-QP 1000 EX Varian MAT 711
and SSQ 7000 spectrometers. Elemental analyses
were carried out at the Microanalytical Laboratory
of Cairo University, Giza, Egypt.
1
(Lit. m.p. 206 C [17]). (cm ) 3197, 1732, 1707,
1
1687, 1615. H NMR (DMSO-d6) 1.1 (t, 3H), 1.9
(s, 3H), 2.8 (s,1H), 3.4 (q, 2H), 4.1 (s, 1H), 7.0–8.1
(m, 5H), 10.9 (s, 1H).
2,3-Dihydro-2-thioxo-6-phenylpyrimidin-4(1H)-
one (1) [7], the hydrazonoyl chlorides 9A–D [14],
2-methylthio-6-phenyl-3,4-dihydropyrimidin-4-one
(10) [15], and the active chloromethylene com-
pounds 2A–C [16] were prepared as previously
described.
Synthesis of [1,2,4]Triazolo[4,3-a]pyrimidines (7)
Method A: To a solution of the appropriate 3
(10 mmol) in ethanol (40 ml) and DMF (10 ml) was
added sodium acetate trihydrate (3 g), and the mix-
ture was cooled in an ice bath to 0–5 C while be-
ing stirred. To the resulting cold solution was added
portionwise a cold solution of benzenediazonium
chloride, prepared as usual by diazotizing aniline
(10 mmol) in hydrochloric acid (6 ml, 6M) with
sodium nitrite (0.7 g, 10 mmol) in water (10 ml).
After all of the diazonium salt solution had been
added, the reaction mixture was stirred for a fur-
ther 30 min with cooling in the ice bath. The solid
that precipitated was filtered off, washed with water,
Syntheses of Active Methine Compounds
3A and 3B
General method: To a mixture of equimolar quan-
tities of pyrimidinethione 1 and the appropriate
chloromethylene compound 2 (10 mmol each) in
absolute ethanol (60 ml) was added triethylamine
(1.4 ml, 10 mmol). The mixture was stirred at room

A Facile One-Pot Regioselective Synthesis of [1,2,4]Triazolo[4,3-a]5(1H )-pyrimidinones 139
1
air dried, and finally crystallized from the appropri-
(43), 129 (43), 104 (20), 91 (19), 77 (72). H NMR
(DMSO-d6) 6.8 (s, 1H), 7.2–8.3 (m, 14H), 11.7 (s,
1H). Anal. Calcd. for C24H16ClN5O2: C, 65.24; H,
3.65; N, 15.85. Found: C, 65.3; H, 3.4; N, 15.6%.
ate solvent to give the corresponding derivatives 7.
Method B: To an ethanolic sodium ethoxide solu-
tion, prepared from sodium metal (0.23 g, 10 mmol)
and absolute ethanol (30 ml), was added the thione
1 (10 mmoles) with stirring. To the resulting solu-
tion, was added the appropriate hydrazonoyl chlo-
ride (9) (10 mmol), and the mixture was stirred
at room temperature for 24 h. During this period
compound 9 dissolved and a new product precipi-
tated. The latter was filtered off, washed with water,
dried, and crystallized from an appropriate solvent
to give the respective 7. The latter products proved
to be identical in all respects with those obtained by
method A.
3-Phenylcarbamoyl-1-(4-nitrophenyl)-7-phenyl-1,
2,4-triazolo[4,3-a]-5(1H)-pyrimidinone (7Ad). Yield
1
78%, m.p. 268 C (Dioxane/H2O). (cm ) 3180, 1701,
1674. MS m/z (%) 452 (M+, 89), 407 (64), 347 (100),
332 (48), 171 (36), 129 (53), 104 (26), 91 (38), 77
(87). H NMR (DMSO-d6) 6.9 (s, 1H), 7.2–8.7 (m,
14H), 11.6 (s, 1H). Anal. Calcd. for C24H16N6O4: C,
63.71; H, 3.56; N, 18.58. Found: C, 63.6; H, 3.8;
N, 18.4%.
1
Method C: To a stirred ethanolic solution of
sodium ethoxide, prepared from sodium metal
(0.23 g, 10 mmol) and absolute ethanol (20 ml), was
added 10 (10 mmol). After 10 min, the appropriate
hydrazonoyl chloride (9) was added. The reaction
mixture was refluxed until methanethiol ceased to
evolve (24–40 h), and then it was cooled. The pre-
cipitated solid was filtered off, washed with water,
and finally crystallized from the appropriate solvent
to give the respective 7. The products 7Aa, 7Ba, and
7Ca, prepared by this method, proved to be identi-
cal in all respects with those obtained by methods A
and B.
3-Acetyl-1,7-diphenyl-1,2,4-triazolo[4,3-a]-5(1H)-
pyrimidinone (7Ba). Yield 67%, m.p. 170–172 C
1
(Dioxane/H2O).
(cm ) 1701, 1680. MS m/z (%)
331 (M+, 98), 288 (24), 261 (19), 171 (18), 129 (24),
104 (13), 91 (43), 77 (100). H NMR (DMSO-d6)
1
2.5(s, 3H), 6.9 (s, 1H), 7.5–8.2 (m, 10H). Anal. Calcd.
for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96. Found:
C, 69.0; H, 4.3; N, 16.5%.
3-Acetyl-1-(4-methylphenyl)-7-phenyl-1,2,4-triaz-
olo[4,3-a]-5(1H)-pyrimidinone (7Bb). Yield 64%,
1
m.p. 200–203 C (Dioxane/H2O). (cm ) 1705, 1680.
MS m/z (%) 344 (M+, 100), 301 (43), 275 (24), 171
1
(22), 129 (25), 104 (36), 91 (48), 77 (54). H NMR
3-Phenylcarbamoyl-1,7-diphenyl-1,2,4-triazolo[4,
(DMSO-d6) 2.3 (s, 3H), 2.76 (s, 3H), 6.84 (s, 1H),
7.2–8.2 (m, 9H). Anal. Calcd. for C20H16N4O2: C,
69.76; H, 4.68; N, 16.20. Found: C, 70.0; H, 4.8;
N, 16.5%.
3-a]-5(1H)-pyrimidinone (7Aa). Yield 75%; m.p.
1
228–229 C (Dioxane/H2O).
(cm ) 3382, 1701,
1668. MS m/z (%) 407 (M+, 79 ), 302 (64), 287 (48),
171 (11), 145 (21), 129 (27), 104 (32), 91 (50), 77
1
(100). H NMR (DMSO-d6) 6.82 (s, 1H), 7.2–8.4
(m, 15H), 11.68 (s, 1H). 13C NMR (DMSO-d6) 96.7,
119.4, 120.8, 124.5, 127.1, 128.6, 129.0, 129.7, 130.9,
133.6, 135.7, 137.5, 138.3, 147.3, 153.0, 156.6, 162.6,
163.3. Anal. Calcd. for C24H17N5O2: C, 70.75; H, 4.21;
N, 17.19. Found: C, 70.7; H, 4.5; N, 17.1%.
3-Acetyl-1-(4-chlorophenyl)-7-phenyl-1,2,4-triaz-
olo[4,3-a]-5(1H)-pyrimidin-one (7Bc). Yield 80%,
1
m.p. 148–149 C (EtOH). (cm ) 1700, 1682. MS
m/z (%) 364 (M+, 100), 321 (35), 296 (31), 171
1
(37), 129 (47), 104 (15), 91 (36), 77 (50). H NMR
(DMSO-d6) 2.76 (s, 3H), 6.86 (s, 1H), 7.2–8.3 (m,
9H). Anal. Calcd. for C19H13ClN4O2: C, 62.56; H,
3.59; N, 15.36. Found: C, 62.8; H, 3.7; N, 15.2%.
3-Phenylcarbamoyl-1-(4-methylphenyl)-7-phenyl-
1,2,4-triazolo[4,3-a]-5(1H)-pyrimidinone (7Ab). Yield
1
80%, m.p. 238 C (EtOH). (cm ) 3110, 1697, 1668.
MS m/z (%) 421 (M+, 80 ), 316 (100), 301 (49), 171 (m,
3-Acetyl-1-(4-nitrophenyl)-7-phenyl-1,2,4-triazolo
14H) (20), 129 (50), 104 (44%), 91 (93), 77 (93%).
[4,3-a]-5(1H)-pyrimidinone (7Bd). Yield 75%, m.p.
1
1H NMR (DMSO-d6)
2.46 (s, 3H), 6.8 (s, 1H),
222 C (Dioxane/H2O). (cm ) 1700, 1674. MS m/z
7.2–8.2 (m, 14H), 11.8 (s, 1H). Anal. Calcd. for
C25H19N5O2: C, 71.30; H, 4.51; N, 16.6. Found: C,
71.7; H, 4.5; N, 16.5%.
(%) 375 (M+, 100), 332 (11), 328 (10), 305 (19), 171
1
(20), 129 (13), 103 (42), 90 (13), 77 (18). H NMR
(DMSO-d6) 2.77 (s, 3H), 6.8 (s, 1H), 7.5–7.9 (m,
9H). 13C NMR (DMSO-d6) 20.5, 97.0, 119.8, 121.1,
124.7, 127.3, 128.8, 129.8, 131.0, 136.0, 137.7, 153.0,
156.6, 162.8, 192.1. Anal. Calcd. for C19H13N5O4:
C, 60.80; H, 3.49; N, 18.66. Found: C, 60.8; H, 3.2;
N, 18.5%.
3-Phenylcarbamoyl-1-(4-chlorophenyl)-7-phenyl-
1,2,4-triazolo[4,3-a]-5(1H)-pyrimidinone (7Ac). Yield
1
72%, m.p. 260 C (EtOH). (cm ) 3184, 1733, 1672.
MS m/z (%) 441(M+, 31), 337 (26), 322 (25), 171

140 Shawali et al.
Ethyl 1,7-Diphenyl-1,2,4-triazolo[4,3-a]-5(1H)-
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138 C (Dioxane/H2O). (cm ) 1751, 1695. MS m/z
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1
Yield 75%, m.p. 136–138 C (EtOH). (cm ) 1751,
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171 (12), 129 (26), 103 (21), 91 (32), 77 (26). 1H
NMR (CDCl3) 1.5 (t, 3H), 4.6 (q, 2H), 6.6 (s, 1H),
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[15] Brown, T. H.; Blakemore, R. C.; Durant, G. J.;
Emmett, J. C.; Ganellin, C. R.; Parsons, M. E.;
Rawlings, D. A.; Walkes, T. F. Eur J Med Chem 1988,
23, 53.
Ethyl 1-(4-Nitrophenyl)-7-phenyl-1,2,4-triazolo[4,
3-pta]-5(1H)-pyrimidinone-3-carboxylate(7Cd). Yield
1
75%, m.p. 210–212 C (EtOH). (cm ) 1753, 1701.
MS m/z (%) 405 (M+, 100), 360 (10), 332 (10), 279
(14), 171 (11), 129 (26), 105 (10), 91 (27), 77 (22).
1H NMR (DMSO-d6) 1.5 (t, 3H), 4.62 (q, 2H), 6.68
(s, 1H), 7.2–8.7 (m, 9H). 13C NMR (DMSO-d6) 13.2,
63.3, 97.9, 120.3, 125.0, 127.3, 128.7, 131.0, 135.5,
135.7, 140.9, 145.1, 147.8, 155.2, 156.2, 162.2. Anal.
Calcd. for C20H15N5O5: C, 59.26; H, 3.73; N, 17.28.
Found: C, 59.0; H, 3.5; N, 17.0%.
1,3,7-Triphenyl-1,2,4-triazolo[4,3-a]-5(1H)-pyrimi-
dinone (7Da). Yield 72%, m.p. 180–181 C (MeOH).
1
(cm ) 1700. MS m/z (%) 365 (74), 364 (80), 233
(10), 194 (5), 103 (25), 91 (100), 77 (35), 64 (36).
1H NMR (DMSO-d6) 6.6 (s, 1H), 7.4–8.3 (m, 15H).
13C NMR (DMSO-d6)
97.1, 120.6,126.1, 127.0,
[16] (a) Hodgkinson, A. J.; Staskun, B. J Org Chem
1969, 34, 1709; (b) Takamizawa, A.; Hamashima, Y.
Yakugaky Zasshi 1964, 54, 1113; (c) Aylward, J. B.;
Scott, F. L. J Chem Soc B, 1969, 1080.
[17] Attaby, F. A.; Eldin, S. M. Z Naturforsch 1999, 54B,
788.
127.1, 127.4, 128.7, 129.3, 130.3, 130.4, 130.7, 136.1,
136.5, 144.1, 148.3, 156.7, 161.4. Anal. Calcd. for
C23H16N4O: C, 75.81; H, 4.43; N, 15.37. Found: C,
76.0; H, 4.3; N, 15.2%.