INTRODUCTION
Much attention has been recently paid to the synthesis of some thieno[1,2,4]triazolopyrimidines and thieno[1,2,4]tria-zolopyrimidinones because of their biological activities.
1
-
4
With this in mind and in continuation of our recent work on the synthesis of 2-phenylthieno[3,2-
e
][1,2,4]triazolo[1,5-
c
]pyrimidine derivatives
7
5
we describe here a facile synthesis of 2-phenylthieno[2,3-
e
][1,2,4]triazolo[1,5-
c
]pyrimidine derivatives
5
that have not been reported hitherto as a new ring system. Previous observations revealed that the thieno[3,2-
e
][1,2,4]triazolo[4,3-
c
]pyrimidines
6
can isomerizes in the presence of base to the thermodynamically more stable thieno[3,2-
e
][1,2,4]triazolo[1,5-
c
]pyrimidines
7
by Dimroth-type rearrangement. We, therefore, decided to apply this methodology also to the synthesis of
5
from
4
.
The compounds
4
were prepared through a series of reaction starting with 3-aminothiophene-2-carbonitrile (
1
) according to the modified procedure we have previously reported(
1
).
1
The required starting material
1
was obtained by adopting the new synthetic method.
6
Reaction of
1
with triethyl orthoformate and the successive hydrazine hydrate gave 4-hydrazinothieno[3,2-
d
]pyrimidine (
2
). The hydrazone derivatives
3
were synthesized by condensation of hydrazine compound
2
with the corresponding benzaldehydes in refluxing ethanol in the presence of catalytic amount of piperidine. The oxidative cyclization of the resultant hydrazone derivatives
3
to
4
was achieved using aluminasupported calcium hypochlorite (Ca(OCl)
2
/Al
2
O
3
= 1:1, grounded mixture) as a new oxidant. For instance, a maximum yield of 73% for
4a
in 1 h was achieved with 1:3 molar ratio of hydrazone to calcium hypochlorite. The use of alumina-supported calcium hypochlorite as a heterogeneous oxidant in this reaction has advantage of enhanced reaction rate and yield, simple work-up, low cost, and eco-friendly reagent when compared to other oxidants such as bromine,
7
lead tetraacetate,
8
iodobenzene diacetate
1
,
9
or copper dichloride.
10
When each of
4
was treated with sodium acetate in refluxing ethanol, it underwent a Dimroth-type rearrangement to give compounds
5
through a sequence of ring opening and ring closure reaction. For instance, the reaction of
4a
(1 mmol) with sodium acetate (2 mmol) in refluxing ethanol for 5 h afforded only one product,
5a
in 68% yield. The structures of all new compounds
5
were identified by elemental analyses and spectral data. The results are summarized in
1
. It was noticed that the two isomeric
4
and
5
showed no appreciable differences in the fragmentation pattern of MS spectra, however, the
1
H NMR spectra of
5
revealed that the most prominent pyrimidine proton showed signal little more downfield than the one of their isomeric
4
. These results were in agreement with those reported in earlier report.
5
The conversion of
4
into
5
is also analogous to rearrangement of thieno[2,3-
e
][1,2,4]triazolo[4,3-
c
]pyrimidin-5(6
H
)-ones in base to the isomeric thieno[2,3-
e
][1,2,4]triazolo[1,5-
c
]pyrimidin-5(6
H
)-ones.
4
In conclusion, we report a facile synthesis of 2-phenylthieno[2,3-
e
][1,2,4]triazolo[1,5-
c
]pyrimidine derivatives
5
via
rearrangement of 3-phenylthieno[2,3-
e
][1,2,4]triazolo [4,3-
c
]pyrimidines
4
.
Reagents and conditions; (A) (i) HC(OEt)3, reflux (ii) hydrazine hydrate/ethanol, reflux; (B) benzaldehydes, piperidine/ethanol, reflux; (C) Ca(OCl)2-Al2O3/methylene chloride, rt; (D) NaOAc/ethanol, reflux
Preparation of compounds5from4
EXPERIMENTAL
All products were characterized by IR,
1
H NMR, MS and elemental analysis. Melting points were measured by using the capillary tubes on Büchi apparatus and are uncorrected. Each compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F
254
and purified by column chromatography using Merck silica gel (70 - 230 mesh). IR spectra were recorded on the FT-IR Brucker Tensor 27. The
1
H NMR spectra were recorded on Bruker DRX-300 FT-NMR spectrometer (300 MHz) with Me
4
Si as internal standard and chemical shifts are given in ppm (δ). Electron ionization mass spectra were recorded on a HP 59580 B spectrometer. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.
- General procedure for the preparation of 2-phenylthieno [2,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives (5)
To a solution of each 3-phenylthieno[2,3-
e
][1,2,4]triazolo [4,3-
c
]pyrimidine
4
(1 mmol) in ethanol (30 mL) was added sodium acetate (0.164 g, 2 mmol) and the mixture was refluxed for 5 h and cooled. The precipitated solid was filtered, washed with water, dried and finally crystallized from ethanol to give the respective 2-phenylthieno[2,3-
e
][1,2,4]triazolo[1,5-
c
]pyrimidine
5
.
- 2-Phenylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5a)
Yield 68%; mp 105 - 107 ℃; IR (KBr): 3045, 1620 cm
-1
;
1
H NMR (CDCl
3
): δ 9.32 (s, 1H, H-4), 8.36-8.33 (m, 2H, H-2’ and H-6’), 7.88 (d, 1H,
J
= 5.9 Hz, H-7), 7.65 (d, 1H,
J
= 5.9 Hz, H-6), 7.55-7.52 (m, 3H, H-3’, H-4’ and H-5’); MS: (
m/z
) 252 (M
+
, 100), 149 (15), 134 (20), 118 (16).
Anal.
Calcd. for C
13
H
8
N
4
S: C, 61.89; H, 3.20; N, 22.21. Found: C, 61.69; H, 3.39; N, 22.48.
- 2-(4-Chlorophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5b)
Yield 70%; mp 250 - 252 ℃; IR (KBr): 3052, 1620 cm
-1
;
1
H NMR (CDCl
3
): δ 9.30 (s, 1H, H-4), 8.29 (d, 2H, H-2’ and H-6’), 7.88 (d,
J
= 5.9 Hz, 1H, H-7), 7.65 (d,
J
= 5.9 Hz, 1H, H-6), 7.51 (d, 2H, H-3’ and H-5’); MS: (
m/z
) 287 (M
+
, 100), 149 (30), 134 (22).
Anal.
Calcd. for C
13
H
7
ClN
4
S: C, 54.45; H, 2.46; N, 19.54. Found: C, 54.29; H, 2.31; N, 19.71.
- 2-p-Tolylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5c)
Yield 55%; mp 203 - 205 ℃; IR (KBr): 3050, 2973, 1620, 1370 cm
-1
;
1
H NMR (CDCl
3
): δ 9.30 (s, 1H, H-4), 8.23 (d, 2H, H-2’ and H-6’), 7.86 (d,
J
= 5.9 Hz, 1H, H-7), 7.63 (d,
J
= 5.9 Hz, 1H, H-6), 7.34 (d, 2H, H-3’ and H-5’), 2.44 (s, 3H, Me); MS: (
m/z
) 266 (M
+
, 99), 149 (35), 134 (20).
Anal.
Calcd. for C
14
H
10
N
4
S: C, 63.14; H, 3.78; N, 21.04. Found: C, 63.30; H, 3.59; N, 21.22.
- 2-(4-Methoxyphenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5d)
Yield 62%; mp 201 - 203 ℃; IR (KBr): 3044, 2980, 1622, 1375 cm
-1
;
1
H NMR (CDCl
3
): δ 9.27(s, 1H, H-4), 8.26 (d, 2H, H-2’and H-6’), 7.85 (d,
J
= 5.9 Hz, 1H, H-7), 7.62 (d,
J
= 5.9 Hz, 1H, H-6), 7.03 (d, 2H, H-3’ and H-5’), 3.89 (s, 3H, OMe); MS: (
m/z
) 282 (M
+
, 100), 149 (15), 134(22).
Anal.
Calcd. for C
14
H
10
N
4
OS: C, 59.56; H, 3.57; N, 19.85. Found:C, 59.44; H, 3.66; N, 19.93.
- 2-(4-Bromophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5e)
Yield 68%; mp 207 - 208 ℃; IR (KBr): 3033, 1625 cm
-1
;
1
H NMR (CDCl
3
): δ 9.30 (s, 1H, H-4), 8.22 (d, 2H, H-2’ and H-6’), 7.88 (d,
J
= 5.9 Hz, 1H, H-7), 7.69 (d,
J
= 5.9 Hz, 1H, H-6), 7.65 (d, 2H, H-3’ and H-5’); MS: (
m/z
) 331 (M
+
, 98), 149 (12), 134 (10).
Anal.
Calcd. for C
13
H
7
BrN
4
S: C, 47.14; H, 2.13; N, 16.92. Found: C, 46.99; H, 2.34; N, 17.14.
- 2-(3-Chlorophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5f)
Yield 63%; mp 140 - 142 ℃; IR (KBr): 3035, 1629 cm
-1
;
1
H NMR (CDCl
3
): δ 9.30 (s, 1H, H-4), 8.55 (s, 1H, H-2’), 8.04 (m, 1H, H-6’), 7.72 (d,
J
= 5.9 Hz, 1H, H-7), 7.53 (d,
J
= 5.9 Hz, 1H, H-6), 7.46-7.39 (m, 2H, H-4’ and H-5’); MS: (
m/z
) 287 (M
+
, 100), 149 (16), 134 (20).
Anal.
Calcd. for C
13
H
7
ClN
4
S: C, 54.45; H, 2.46; N, 19.54. Found: C, 54.66; H, 2.30; N, 19.69.
- 2-m-Tolylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5g)
Yield 60%; mp 164 - 166 ℃; IR (KBr): 3036, 1625, 1375 cm
-1
;
1
H NMR (CDCl
3
): δ 9.30 (s, 1H, H-4), 8.18-8.14 (m, 2H, H-2’ and H-6’), 7.87 (d,
J
= 5.9 Hz, 1H, H-7), 7.64 (d,
J
= 5.9 Hz, 1H, H-6), 7.42 (t, 1H, H-5’), 7.33 (d, 1H, H-4’), 2.48 (s, 3H, Me); MS: (
m/z
) 266 (M
+
, 100), 149 (10).
Anal.
Calcd. for C
14
H
10
N
4
S: C, 63.14; H, 3.78; N, 21.04. Found: C, 63.29; H, 3.65; N, 21.11.
- 2-(3-Bromophenyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5h)
Yield 65%; mp 134 - 136 ℃; IR (KBr): 3034, 1622 cm
-1
;
1
H NMR (CDCl
3
): δ 9.29 (s, 1H, H-4), 8.58 (s, 1H, H-2’), 8.05 (d, 1H, H-6’), 7.74 (d,
J
= 5.9 Hz, 1H, H-7), 7.59 (d,
J
= 5.9 Hz, 1H, H-6), 7.54 (d, 1H, H-4’), 7.36 (t, 1H, H-5’); MS: (
m/z
) 331 (M
+
, 100), 149 (11), 134 (20).
Anal.
Calcd. for C
13
H
7
BrN
4
S: C, 47.14; H, 2.13; N, 16.92. Found: C, 47.28; H, 2.26; N, 17.11.
- 2-(2-Methoxyphenyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5i)
Yield 50%; mp 127 - 129 ℃; IR (KBr): 3030, 2975, 1620, 1375 cm
-1
;
1
H NMR (CDCl
3
): δ 9.28 (s, 1H, H-4), 8.14-8.10 (m, 2H, H-4’ and H-6’), 7.88 (d,
J
= 5.9 Hz, 1H, H-7), 7.55 (d,
J
= 5.9 Hz, 1H, H-6), 7.33 (t, 1H, H-5’), 7.24 (d, 1H, H-3’), 2.47 (s, 3H, OMe); MS: (
m/z
) 282 (M
+
, 100), 149 (14), 134 (18).
Anal.
Calcd. for C
14
H
10
N
4
OS: C, 59.56; H, 3.57; N, 19.85. Found: C, 59.69; H, 3.42; N, 19.62.
Bower J. D.
,
Doyle F. P.
1957
J. Chem. Soc.
727 -