The first example of a regioselective biginelli-like reaction based on 3-alkylthio-5-amino-1, 2, 4-triazole

Article abstract of DOI:10.1002/jhet.1

The three-component condensation of 3-amino-5-alkylthio-1, 2, 4-triazoles with aromatic aldehydes and β-ketoester was studied to develop a regioselective Biginelli-like reaction. The results indicated that the reaction solvent and the properties of the β-

Full text of DOI:10.1002/jhet.1

March 2009
The First Example of a Regioselective Biginelli-Like Reaction
Based on 3-Alkylthio-5-amino-1,2,4-triazole
139
Qiong Chen, Li-Li Jiang, Chao-Nan Chen, and Guang-Fu Yang*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, People’s Republic of China
*E-mail: gfyang@mail.ccnu.edu.cn
Received November 26, 2007
DOI 10.1002/jhet.1
Published online 18 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes
and b-ketoester was studied to develop a regioselective Biginelli-like reaction. The results indicated that
the reaction solvent and the properties of the b-ketoester component displayed great influence on the
regioselectivity. This is the first report about the regioselectivity of the aminotriazole-based Biginelli-
like reaction.
J. Heterocyclic Chem., 46, 139 (2009).
INTRODUCTION
triazole, in which products 5 and 6 could be produced
by regioselectivity depending on the reaction conditions.
In the last decades, dihydropyrimidinones (DHPMs)
and their sulfur analogs have attracted much attention
because of their wide range of biological activities. For
example, many DHPMs were reported to be calcium or/
and potassium channel blockers and openers [1], antihy-
pertensive agents [2], a-adrenergic antagonists [3], neu-
ropeptide Y (NPY) antagonists [4], and HIV gp-120-
CD4 inhibitors [5]. The most important and direct
method for the synthesis of DHPMs is based on the
Biginelli reaction reported first in 1893 [6]. The classi-
cal Biginelli reaction of an aldehyde, a b-ketoester, and
urea or thiourea requires strongly acidic conditions.
Recently, the Biginelli reaction was extended to the syn-
thesis of dihydrotriazolo-pyrimidine by replacing the
urea component with 5-amino-1,2,4-triazole [7–12].
Because the b-ketoester and 5-amino-1,2,4-triazole are
asymmetric, four possible products (4, 5, 6, and 7) could
be obtained theoretically (Scheme 1) according to the
mechanism of the traditional Biginelli reaction. How-
ever, so far no attention has been paid to the regioselec-
tivity of the aminoazole-based Biginelli reaction.
RESULTS AND DISCUSSION
First, the reaction of ethyl acetoacetate, 4-methoxy-
benzaldehyde, and 3-methylthio-5-amino-1,2,4-triazole
was selected as a model reaction. Some reported cata-
lysts or additives, such as H3BO3 [17], p-toluene sul-
fonic acid (TSA) [18], FeCl3 [19], InCl3 [20], and HCl
[21], and solvents, such as C2H5OH, DMF, H2O, THF,
HOAc, CH2Cl2, and CHCl3, were screened. As shown
in Table 1, the TSA/H2O system was found to give
almost equivalent amounts of products 5a and 6a with a
moderate overall yield (5a and 6a, 69%). Then, this sys-
tem was extended to other substrates, and the results are
listed in Table 2. As shown in Table 2, when ethyl ace-
toacetate and ethyl chloroacetoacetate acted as b-
ketoester components, two isomers were isolated in all
cases. Interestingly, only one isomer was isolated for the
reaction of ethyl trifluoroacetoacetate and 4-substituted
benzaldehyde. For example, the reactions of 4-methoxy-
benzaldehyde (Table 2, entry 15), 4-chlorobenzaldehyde
(Table 2, entry 16), 4-chlorobenzaldehyde (Table 2,
entry 17), 3,4-dichlorobenzaldehyde (Table 2, entry 18),
and 4-nitrobenzaldehyde (Table 2, entry 19) afforded
isomers 5o–s in isolated yields of 40, 48, 49, 51, and
55%, respectively. However, the reactions of benzalde-
hyde (Table 2, entry 21) and 4-methylbenzaldehyde (Ta-
ble 2, entry 22) afforded product 6u-v in isolated yields
of 80% and 60%, respectively. However, the reactions
of 2-fluorobenzaldehyde (Table 2, entry 20) also
The existing results about the aminoazole-based Bigi-
nelli-like reaction indicated that only product 5 was
obtained or only product 4 was obtained at first, which
then suffered subsequent dehydration to afford product 5
[7–12]. No reports about the formation of products 6 or
7 could be found in the existing literature. As a continu-
ation of our systematic research work on the synthesis
and biological activity of triazolopyrimidines [13–16],
we report herein the first example of regioselective Bigi-
nelli-like reactions based on 3-alkylthio-5-amino-1,2,4-
C
V
2009 HeteroCorporation

140
Q. Chen, L.-L. Jiang, C.-N. Chen, and G.-F. Yang
Vol 46
Scheme 1
afforded product 6t. From these results, we can con-
clude that the electronic property and the position of the
R1 group has the most important effect on the regiose-
lectivity of the aminotriazole-based Biginelli reaction in
H2O solution. Additionally, the effect of R2 group on
the regioselectivity is complex, whereas the R3 group
seems to have no obvious effect on the regioselectivity.
In addition, as shown in Table 1, the reaction under
the system of HCl/C2H5OH afforded regioselectivity iso-
mer 5a in a yield of 32%, a little higher than that in
DMF solution. Then, we studied the extension of this
reaction system to other substrates, and the results are
listed in Table 3. Additionally, microwave irradiation
has been proven to be a powerful technique for promot-
ing a variety of chemical reactions [22–25]. The main
benefits of performing reactions under microwave irradi-
ation conditions are significant rate enhancements and
higher yields. Recently, the technique of microwave
irradiation was also applied to improve the yields and
shorten the reaction time of Biginelli reactions [26–28].
So, the results in C2H5OH solution under microwave
irradiation were compared with those under conventional
heating as listed in Table 3, which indicated that the
yields under microwave irradiation were improved as
Table 1
Results of the model reaction under various conditions.
No.
Reaction conditions
Products
1
2
3
HBO3 (cat.), HOAc, reflux
FeCl3 (10%), THF, reflux
AlCl3 (cat.), THF, reflux
InCl3 (20%), THF, reflux
HCl (cat.), H2O, reflux
TSA, CH2Cl2, reflux
TSA, CHCl3, reflux
Very complex
Very complex
Very complex
Very complex
Very complex
No reaction
4
5
6
7
No reaction
8
TSA, H2O, reflux
HCl (cat.), C2H5OH, reflux
DMF, reflux
5a, 34%; 6a, 35%
5a, 32%
5a, 30%
9
10
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
The First Example of a Regioselective Biginelli-Like Reaction
Based on 3-Alkylthio-5-amino-1,2,4-triazole
141
Table 2
Results of the Biginelli-like reaction in H2O solution using TSA as catalyst.
No.
R1
R2
R3
Isolated yields of products (%)
5a (34) 6a (35)
1
2
CH3
CH3
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
2,4-Cl2C6H3
4-Pyridyl
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
SCH3
SCH3
SCH3
SCH3
SCH3
SCH2Ph
SCH2Ph
SCH2Ph
SCH3
5b (25)
5c (36)
5d (32)
5e (48)
5f (32)
5g (41)
5h (29)
5i (36)
5j (31)
5k (43)
5l (35)
5m (30)
5n (28)
5o (40)
5p (48)
5q (49)
5r (51)
5s (55)
5t (0)
6b (ꢀ5)a
6c (ꢀ5)a
6d (24)
6e (ꢀ5)a
6f (19)
6g (ꢀ5)a
6h (39)
6i (20)
6j (ꢀ5)a
6k (ꢀ5)a
6l (ꢀ5)a
6m (25)
6n (35)
6o (0)
6p (0)
6q (0)
6r (0)
6s (0)
6t (54)
6u (80)
6v (60)
3
4
CH3
CH3
5
6
CH3
CH3
7
CH3
CH3
8
9
ClCH2
ClCH2
ClCH2
ClCH2
ClCH2
ClCH2
CF3
CF3
CF3
CF3
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
SCH3
SCH3
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
SCH2Ph
SCH2Ph
SCH2Ph
SCH3
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
2-FC6H4
SCH3
SCH2Ph
SCH3
SCH3
SCH3
SCH3
SCH3
CF3
CF3
C6H5
4-CH3C6H4
5u (0)
5v (0)
CF3
a Detected by HPLC, but unable to be isolated.
expected by 3–10%, and the reaction time was also
shortened from 18 h to 30 min.
ever, the reactions in C2H5OH solution always pro-
ceeded first with the participation of N(2) to produce
regioselectivity of the isomer 5.
The structures of compounds 4–7 correspond to the
direction of the interaction established earlier in the
reactions between 3-amino-5-alkylthio-1,2,4-triazoles
and arylidenacetoacetates (8) (Scheme 2). Formation of
the pyrimidine ring with the participation of the aryli-
dene derivatives (8) occurs via interaction of the b-car-
bon atom of the acetoacetate with the carbonyl group of
the aldehydes. For example, in H2O solution with TSA
as catalyst, the reaction proceeded first with the partici-
pation of N(2) or 3-NH2 of the 3-amino-5-alkylthio-
1,2,4-triazoles to afford regioselectivity ethyl 7-aryl-2-
alkylthio-4,7-dihydro-1,2,4-triazolo-[1,5-a]pyrimidine-6-
carboxylate (5) or ethyl-7-hydroxy-7-alkyl-5-aryl-2-alkylthio-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylate
(6) depending on the property of the aromatic aldehydes
when ethyl trifluoroacetoacetate was used as the b-
ketoester component. When ethyl acetoacetate and ethyl
chloroacetoacetate acted as b-ketoester components, the
reaction always produced two isomers 5 and 6. How-
Recently, Chebanov et al. reported the three-compo-
nent condensation of 3-amino-5-alkylthio-1,2,4-triazoles
with aromatic aldehydes and acetoacetamides in
C2H5OH solution under microwave irradiation without
any catalyst [12]. Prompted by these results, we also
examined the microwave-assisted aminoazole-based
Biginelli-like reaction in C2H5OH solution without any
catalyst. The results shown in Table 3 indicated that the
yields were improved significantly compared with those
in the presence of HCl as catalyst. Further, it should be
noted that different from the situation in H2O solution
using TSA as catalyst, only isomer 5 was formed using
C2H5OH as reaction solvent no matter what b-ketoester
component was used. Additionally, the properties of the
R1 and R2 group displayed great effects on the yields of
product 5. Ethyl trifluoroacetoacetate always gave higher
yields than ethyl acetoacetate and ethyl chloroacetoace-
tate. Benzaldehydes with electron-withdrawing group
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

142
Q. Chen, L.-L. Jiang, C.-N. Chen, and G.-F. Yang
Vol 46
Table 3
Results of the Biginelli-like reaction in C2H5OH solution.
Conventional heating
Isolated
Microwave irradiation
No.
R1
R2
R3
yields (%)
Reaction time (h)
Isolated yields (%)
Reaction time (min)
1
2
CH3
CH3
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
2,4-Cl2C6H3
4-Pyridyl
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
SCH3
SCH3
5a
30
36
40
40
70
40
34
45
39
31
43
42
37
48
51
61
63
61
60
64
68
59
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
36a/52b
39a/55b
45a/60b
48a/62b
80a/82b
46a/60b
40a/54b
49a/53b
34a/50b
35a/51b
47a/61b
44a/60b
41a/56b
53a/67b
56a/61b
68a/75b
70a/78b
66a/72b
69a/73b
67a/68b
72a/79b
63a/68b
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
3
4
CH3
CH3
SCH3
SCH3
SCH3
SCH2Ph
SCH2Ph
SCH2Ph
SCH3
5
6
CH3
CH3
7
CH3
CH3
8
9
ClCH2
ClCH2
ClCH2
ClCH2
ClCH2
ClCH2
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
SCH3
SCH3
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
2-FC6H4
SCH2Ph
SCH2Ph
SCH2Ph
SCH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
SCH3
SCH2Ph
SCH3
SCH3
SCH3
SCH3
SCH3
5t
5u
5v
C6H5
4-CH3C6H4
a Yields of the reactions without any catalyst under conventional heating.
b Yields of the reactions without any catalyst under microwave irradiation.
1
always afforded higher yields of products than benzalde-
hydes with electron-donating groups. For example, the
reaction of 4-pyridylaldehyde (entry 5, Table 3) gave
the highest yield (80% in the presence of HCl, 82%
without any catalyst) among eight aromatic aldehydes
used in this study.
for 5-CH and 6-CH was observed in the H NMR spec-
trum of compound 6d. The peak for the 4-NH of com-
pound 6d appeared at 6.88 ppm. Ultimately, the struc-
tures of 5d and 6d were established on the basis of a X-
ray analysis as shown in Figure 1.
Structure determination. As shown in Scheme 1,
four possible products could be obtained theoretically,
but only two isomers, compounds 5 and 6, were identi-
fied in this study. The structures of 5 and 6 were
CONCLUSIONS
In summary, the three-component condensation of 3-
amino-5-alkylthio-1,2,4-triazoles with aromatic alde-
hydes and b-ketoester was studied. The obtained results
showed that the reaction solvent and the properties of
the b-ketoester components had a great influence on the
regioselect. In H2O solution with TSA as catalyst, the
reaction proceeded first with the participation of N(2) or
3-NH2 of the 3-amino-5-alkylthio-1,2,4-triazoles to
afford regioselectivity ethyl 7-aryl-2-alkylthio-4,7-
1
assigned by H NMR, 13C NMR, MS, and X-ray diffrac-
tion analysis to be ethyl 7-aryl-2-alkylthio-4,7-dihydro-
1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylate and ethyl
7-hydroxy-7-alkyl-5-aryl-2-alkylthio-4,5,6,7-tetrahydro-1,
2,4-triazolo[1,5-a]pyrimidine-6-carboxylate, respectively.
For example, compound 5d displayed two single peaks
at 6.77 and 10.90 ppm for 7-CH and 4-NH, respectively,
whereas an obvious AB system at 3.44 and 5.62 ppm
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
The First Example of a Regioselective Biginelli-Like Reaction
Based on 3-Alkylthio-5-amino-1,2,4-triazole
143
Scheme 2. The hypothetic mechanism of reaction.
EXPERIMENTAL
dihydro-1,2,4-triazolo-[1,5-a]pyrimidine-6-carboxylate (5)
or ethyl-7-hydroxy-7-alkyl-5-aryl-2-alkylthio-4,5,6,7-tet-
rahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylate (6)
depending on the property of the aromatic aldehydes
when ethyl trifluoroacetoacetate was used as the b-
ketoester component. When ethyl acetoacetate and ethyl
chloroacetoacetate acted as b-ketoester components, the
Melting points are uncorrected. Mass spectra were measured
on a Finnigan Trace MS spectrometer. NMR spectra were
recorded in CDCl3 on a Varian Mercury 400 spectrometer, and
resonances are given in ppm (d) relative to TMS. HPLC analy-
ses were performed on an Agilent 1100 MWD instrument.
Microwave irradiation reactions were carried out on a Smith-
synthesizerTM instrument.
reaction always produced two isomers
5 and 6.
General procedure for the three-component reaction in
H2O solution. A solution of b-ketoester (1 mmol), aromatic
aldehyde (1 mmol), and 3-amino-5-alkylthio-1,2,4-triazoles (1
mmol) in H2O (3 mL) containing a catalytic amount of TSA
was heated under 80ꢁC for 10 h. The resulting mixture was
extracted with CH2Cl2 (10 mL ꢂ 3), and then the extract was
dried over sodium sulfate and filtered. The filtrate was con-
densed under reduced pressure, and the residue was purified
by chromatography on SiO2 (Vacetone/Vpetroleum ether ¼ 1/10) to
afford products 5 and 6.
However, the reactions in C2H5OH solution always
proceeded first with the participation of N(2) to produce
regioselectivity isomer 5. The yields of the reaction in
C2H5OH solution in the absence of any catalyst were
improved significantly when compared with those in
the presence of HCl as catalyst. Additionally, compared
with the conventional heating, microwave irradiation
improved the yields of the reaction in C2H5OH solution
and shortened the reaction time to a great extent. To
our knowledge, this is the first report about the
regioselectivity of aminotriazole-based Biginelli-like
reactions.
General procedure for the three-component reaction in
C2H5OH solution using HCl as catalyst. A solution of b-
ketoester (1 mmol), aromatic aldehyde (1 mmol), and 3-
amino-5-alkylthio-1,2,4-triazoles (1 mmol) in EtOH (3 mL)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

144
Q. Chen, L.-L. Jiang, C.-N. Chen, and G.-F. Yang
Vol 46
Figure 1. Crystal structures of products 5d and 6d. [Color figure can be viewed in the online issue, which is available at www.interscience.
wiley.com.]
containing 10 lL of concentrated HCl (37%) were refluxed for
18 h. The reaction mixture was cooled to room temperature,
and the precipitate was filtered and recrystallized from ethanol
to give pure product 5.
measured reflections, T ¼ 292(2) K on a Brucker-Nonius
(SHELXS 97) and refined with SHELXK 97 final R [F2 > 2r
kappa CCD. The structure was solved using direct methods
(F2)] ¼ 0.064 and wR ¼ [w ¼ 1/[r2(Fo ) þ (0.0865P)2
þ
2
2
2
General procedure for the three-component reaction in
C2H5OH solution using HCl as catalyst under microwave
irradiation. A mixture of b-ketoester (1 mmol), aromatic
aldehyde (1 mmol), and 3-amino-5-alkylthio-1,2,4-triazoles
(1 mmol) in EtOH (3 mL) containing 10 lL of concentrated
HCl (37%) was added into a microwave tube. The sealed tube
was placed in a SmithsynthesizerTM and irradiated at 150ꢁC
for 30 min. The reaction mixture was cooled to room tempera-
ture, and the precipitate was filtered and recrystallized from
ethanol to give pure product 5.
General procedure for the reaction in C2H5OH solution
without any catalyst under microwave irradiation. A mix-
ture of b-ketoester (1 mmol), aromatic aldehyde (1 mmol), and
3-amino-5-alkylthio-1,2,4-triazoles (1 mmol) in EtOH (3 mL)
was added into a microwave tube. The sealed tube was placed
in a SmithsynthesizerTM and irradiated at 150ꢁC for 30 min.
The reaction mixture was cooled to room temperature, and the
precipitate was filtered and recrystallized from ethanol to give
pure product 5.
1.8162P], where P ¼ (Fo þ2Fc )/3.
CCDC 639763 and 639764 contain the supplementary crys-
tallographic data for compounds 5d and 6d, respectively, from
this article. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.
Data for characterizations of 5 and 6.
Compound 5a. White solid, mp 219–220; H NMR (CDCl3,
1
400 MHz) d (ppm): 1.15 (t, 3H, J ¼ 6.8 Hz), 2.50 (s, 3H),
2.60 (s, 3H), 3.78 (s, 3H), 4.07 (q, 2H, J ¼ 6.8 Hz), 6.32 (s,
1H), 6.82–7.23 (m, 4H), 10.26 (s, 1H); 13C NMR (CDCl3, 100
MHz) d (ppm): 14.10, 14.41, 19.30, 55.19, 59.45, 60.01,
99.36, 113.68, 128.55, 133.65, 145.74, 148.26, 158.95, 159.32,
165.72; EI-MS (70Ev, m/z) (relative intensity %): 362 (20),
360 (Mþ, 99), 345 (25), 331 (66), 313 (100), 287 (57), 259
(26), 253 (98), 240 (31), 225 (67), 207 (15), 180 (12), 179
(28), 159 (19), 143 (12), 127 (15), 115 (36), 108 (31); Elemen-
tal Anal. Calcd. for C17H20N4O3S: C, 56.65; H, 5.59; N,
15.54; Found: C, 56.89; H, 5.32; N, 15.79.
1
Determination of the X-ray crystal structure of com-
pounds 5d and 6d. Crystals of 5d and 6d were grown by
slowly evaporating an acetone solution at room temperature.
Compound 5d, C16H16Cl2N4O2S (Mr ¼ 399.29), Monoclinic
Compound 5b. White solid, mp 227–228; H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 7.2 Hz), 2.31 (s, 3H),
2.49 (s, 3H), 2.62 (s, 3H), 4.07 (q, 2H, J ¼ 7.2 Hz), 6.33 (s,
1H), 7.19–7.22 (m, 4H), 10.76 (s, 1H); 13C NMR (CDCl3, 100
MHz) d (ppm): 14.10, 14.43, 19.32, 21.15, 59.78, 60.03,
99.49, 127.24, 129.10, 137.88, 138.38, 145.75, 148.28, 158.97,
165.67; EI-MS (70Ev, m/z) (relative intensity %): 346 (20),
344 (Mþ, 94), 315 (45), 297 (100), 271 (30), 253 (99), 225
(86), 207 (11), 179 (26), 161 (10), 141 (12), 128 (18), 115
(17); Elemental Anal. Calcd. for C17H20N4O2S: C, 59.28; H,
5.85; N, 16.27; Found: C, 59.55; H, 5.64; N, 16.40.
˚
space group Pbca, Z ¼ 4, a ¼ 10.7044(10) A, b ¼ 22.128(2)
ꢁ
ꢁ
ꢁ
˚
˚
A, c ¼ 8.2341(8) A, a ¼ 90 , b ¼ 110.663(2) , c ¼ 90 , V ¼
3
1824.9(3) A , Mo Ka radiation, 1.84 < y < 26.99ꢁ, 15129
measured reflections, T ¼ 292(2) K on a Brucker-Nonius
kappa CCD. The structure was solved using direct methods
ꢁ
˚
(SHELXS 97) and refined with SHELXK 97 final R [F2 > 2r
2
(F2)] ¼ 0.066 and wR ¼ [w ¼ 1/[r2(Fo ) þ (0.0737P)2
þ
2
2
1
1.1468P], where
P
¼
(Fo
þ
2Fc )/3. Compound 6d,
Compound 5c. White solid, mp 254–255; H NMR (CDCl3,
C16H18Cl2N4O3S (Mr ¼ 417.30), Monoclinic space group
400 MHz) d (ppm): 1.15 (t, 3H, J ¼ 7.2 Hz), 2.49 (s, 3H),
2.63 (s, 3H), 4.07 (q, 2H, J ¼ 7.2 Hz), 6.33 (s, 1H), 7.25–7.30
(m, 4H), 10.66 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
14.10, 14.37, 19.43, 59.49, 60.23, 99.06, 128.68, 128.81,
˚
˚
Pbca, Z ¼ 4, a ¼ 11.9765(10) A, b ¼ 8.7314(8) A, c ¼
ꢁ
ꢁ
ꢁ
˚
18.7954(16) A, a ¼ 90 , b ¼ 91.3200(10) , c ¼ 90 , V ¼
3
1824.9(3) A , Mo Ka radiation, 2.00 < y < 25.99ꢁ, 13069
ꢁ
˚
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
The First Example of a Regioselective Biginelli-Like Reaction
Based on 3-Alkylthio-5-amino-1,2,4-triazole
145
134.09, 139.60, 145.98, 147.97, 159.13, 165.38; EI-MS (70Ev,
m/z) (relative intensity %): 366 (30), 364.5 (Mþ, 94), 349 (10),
337 (22), 335 (48), 318 (100), 289 (23), 275 (11), 253 (71),
244 (11), 225 (46), 207 (8), 179 (17), 154 (4), 127 (13), 111
(5); Elemental Anal. Calcd. for C16H17ClN4O2S: C, 52.67; H,
4.70; N, 15.36; Found: C, 52.78; H, 4.92; N, 15.09.
128.91, 134.02, 137.20, 139.75, 146.23, 148.00, 157.71,
165.43; EI-MS (70Ev, m/z) (relative intensity %): 444 (6), 442
(25), 440 (Mþ, 100), 407 (60), 395 (5), 361 (19), 349 (26),
329 (21), 317 (21), 289 (11), 275 (5), 247 (9), 207 (12), 189
(10), 163 (10), 123 (43); Elemental Anal. Calcd. for
C22H21ClN4O2S: C, 59.92; H, 4.80; N, 12.71; Found: C,
60.23; H, 4.51; N, 12.84.
1
Compound 5d. White solid, mp 242–243; H NMR (CDCl3,
1
400 MHz) d (ppm): 1.12 (t, 3H, J ¼ 7.2 Hz), 2.48 (s, 3H),
2.65 (s, 3H), 4.04 (q, 2H, J ¼ 7.2 Hz), 6.77 (s, 1H), 7.18–7.38
(m, 3H), 10.90 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
14.10, 14.32, 19.39, 56.84, 60.19, 97.94, 127.52, 129.63,
130.71, 134.18, 134.53, 137.27, 146.9, 147.9, 159.2, 165.2; EI-
MS (70Ev, m/z) (relative intensity %): 403 (10), 401 (16), 399
(Mþ, 32), 398 (87), 371 (52), 369 (80), 363 (55), 353 (25),
333 (9), 325 (12), 317 (8), 287 (15), 253 (100), 225 (56), 207
(12), 179 (19), 161 (17), 126 (7); Elemental Anal. Calcd. for
C16H16Cl2N4O2S: C, 48.13; H, 4.04; N, 14.03; Found: C,
48.32; H, 3.86; N, 14.29.
Compound 5i. White solid, mp 292–293; H NMR (CDCl3,
400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 6.8 Hz), 2.32 (s, 3H),
2.51 (s, 3H), 4.11 (q, 2H, J ¼ 7.2 Hz), 4.95 (d, 1H, J ¼ 12.4
Hz), 5.14 (d, 1H, J ¼ 12.4 Hz), 6.36 (s, 1H), 7.11–7.22 (m,
4H), 10.42 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
13.94, 14.50, 21.19, 40.21, 59.82, 60.90, 101.76, 127.25,
129.34, 137.22, 138.50, 142.39, 147.19, 159.34, 164.38; EI-
MS (70Ev, m/z) (relative intensity %): 381 (32), 379 (Mþ, 99),
342 (100), 331 (19), 313 (51), 297 (20), 287 (69), 267 (37),
255 (36), 223 (29), 194 (9), 177 (11), 153 (8), 141 (14) 126
(13), 115 (21); Elemental Anal. Calcd. for C17H19ClN4O2S: C,
53.89; H, 5.05; N, 14.79; Found: C, 54.13; H, 5.28; N, 14.91.
1
Compound 5e. White solid, mp 243–244; H NMR (CDCl3,
1
400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 7.2 Hz), 2.49 (s, 3H),
2.66 (s, 3H), 4.10 (q, 2H, J ¼ 7.2 Hz), 6.36 (s, 1H), 7.27 (d,
2H, J ¼ 6.4 Hz), 8.59 (d, 2H, J ¼ 6.0 Hz), 11.15 (s, 1H); 13C
NMR (CDCl3, 100 MHz) d (ppm): 14.10, 14.22, 19.43, 58.87,
60.33, 97.49, 122.34, 147.21, 148.38, 149.50, 149.92, 159.39,
165.23; EI-MS (70Ev, m/z) (relative intensity %): 333 (10),
331 (Mþ, 60), 287 (35), 253 (100), 225 (59), 207 (24), 180
(29), 159 (19), 143 (12), 127 (36), 115 (29); Elemental Anal.
Calcd. for C15H17N5O2S: C, 54.36; H, 5.17; N, 21.13; Found:
C, 54.59; H, 5.46; N, 21.44.
Compound 5j. White solid, mp 286–287; H NMR (CDCl3,
400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 7.2 Hz), 2.52 (s, 3H),
3.78 (s, 3H), 4.11 (q, 2H, J ¼ 7.2 Hz), 4.95 (d, 1H, J ¼ 12.0
Hz), 5.13 (d, 1H, J ¼ 12.0 Hz), 6.36 (s, 1H), 6.83–7.27 (m,
4H), 10.78 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
13.9,7 14.58, 40.19, 55.25, 59.55, 60.850, 101.72, 126.98,
128.62, 132.57, 142.51, 147.38, 159.56, 159.73, 164.46; EI-
MS (70Ev, m/z) (relative intensity %): 397 (13), 395 (Mþ,
100), 358 (99), 329 (36),313 (29), 287 (62), 271 (41), 251
(27), 240 (15), 222 (27), 194 (14), 177 (10), 158 (9), 145 (10),
115 (14), 108 (18), 77 (10); Elemental Anal. Calcd. for
C17H19ClN4O3S: C, 51.71; H, 4.85; N, 14.19; Found: C,
51.93; H, 5.07; N, 14.43.
1
Compound 5f. White solid, mp 165–166; H NMR (CDCl3,
400 MHz) d (ppm): 1.15 (t, 3H, J ¼ 7.2 Hz), 2.24 (s, 3H),
2.56 (s, 3H), 4.06 (q, 2H, J ¼ 6.8 Hz), 4.14 (d, 1H, J ¼ 12.8
Hz), 4.26 (d, 1H, J ¼ 12.8 Hz), 6.33 (s, 1H), 7.19–7.22 (m,
9H), 10.76 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
14.09, 19.40, 21.17, 36.49, 59.92, 60.03, 99.26, 127.24,
127.29, 128.37, 128.97, 129.12, 137.35, 137.86, 138.40,
145.82, 148.13, 157.45, 165.67; EI-MS (70Ev, m/z) (relative
intensity %): 422 (18), 420 (Mþ, 100), 387 (58), 376 (10), 359
(5), 341 (26), 329 (42), 297 (45), 283 (9), 269 (15), 251 (11),
239 (8), 224 (11), 205 (16), 169 (11), 141 (15), 128 (15), 123
(39), 115 (14); Elemental Anal. Calcd. for C23H24N4O2S: C,
65.69; H, 5.75; N, 13.32; Found: C, 65.37; H, 5.96; N, 13.54.
1
Compound 5k. White solid, mp 270–271; H NMR (CDCl3,
400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 7.2 Hz), 2.51 (s, 3H),
4.12 (q, 2H, J ¼ 7.2 Hz), 4.96 (d, 1H, J ¼ 12.0 Hz), 5.12 (d,
1H, J ¼ 12.0 Hz), 6.37 (s, 1H), 7.26–7.31 (m, 4H), 10.85 (s,
1H); 13C NMR (CDCl3, 100 MHz) d (ppm): 13.95, 14.57,
39.80, 59.39, 60.98, 100.81, 128.79, 128.84, 134.45, 138.76,
143.67, 147.60, 159.68, 164.16; EI-MS (70Ev, m/z) (relative
intensity %): 402 (11), 400 (44), 399 (Mþ, 21), 398 (81), 362
(80), 353 (10), 333 (36), 317 (17), 287 (100), 275 (45), 259
(23), 251 (10), 223 (22), 208 (5), 194 (5), 177 (9), 162 (7),
149 (10), 140 (6), 127 (9); Elemental Anal. Calcd. for
C16H16Cl2N4O2S: C, 48.13; H, 4.04; N, 14.03; Found: C,
47.87; H, 4.27; N, 13.86.
1
Compound 5g. White solid, mp 191–192; H NMR (CDCl3,
400 MHz) d (ppm): 1.15 (t, 3H, J ¼ 6.8 Hz), 2.57 (s, 3H),
3.80 (s, 3H), 4.07 (q, 2H, J ¼ 6.8 Hz), 4.14 (d, 1H, J ¼ 12.8
Hz), 4.27 (d, 1H, J ¼ 12.8 Hz), 6.33 (s, 1H), 7.19–7.22 (m,
9H), 10.76 (s, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm):
14.11, 19.41, 36.47, 55.26, 59.65, 60.07, 99.48, 113.80,
127.27, 128.39, 128.60, 128.98, 133.56, 137.33, 145.47,
147.89, 157.41, 159.49, 165.65; EI-MS (70Ev, m/z) (relative
intensity %): 438 (31), 436 (Mþ, 100), 403 (44), 389 (7), 357
(12), 345 (38), 329 (11), 313 (35), 285 (10), 267 (8), 241 (5),
229 (8), 197 (8), 185 (6), 159 (6), 123 (17); Elemental Anal.
Calcd. for C23H24N4O3S: C, 63.28; H, 5.54; N, 12.83; Found:
C, 63.04; H, 5.28; N, 13.06.
1
Compound 5l. White solid, mp 297–298; H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 6.8 Hz), 2.34 (s, 3H),
4.12 (q, 2H, J ¼ 7.2 Hz), 4.16 (d, 1H, J ¼ 12.8 Hz), 4.27 (d,
1H, J ¼ 12.8 Hz), 4.88 (d, 1H, J ¼ 12.0 Hz), 5.09 (d, 1H, J ¼
12.0 Hz), 6.36 (s, 1H), 7.11–7.23 (m, 9H), 10.42 (s, 1H); 13C
NMR (CDCl3, 100 MHz) d (ppm): 13.93, 21.18, 36.67, 39.87,
59.86, 60.79, 101.31, 127.25, 127.29, 128.36, 128.97, 129.29,
137.22, 137.49, 138.31, 143.25, 147.64, 157.94, 164.43; EI-
MS (70Ev, m/z) (relative intensity %): 456 (19), 454 (Mþ, 59),
418 (59), 385 (20), 363 (10), 357 (13), 339 (12), 327 (11), 297
(6), 267 (8), 227 (6), 212 (6), 168 (4), 141 (8), 123 (12); Ele-
mental Anal. Calcd. for C23H23ClN4O2S: C, 60.72; H, 5.10; N,
12.31; Found: C, 60.54; H, 4.87; N, 12.09.
1
Compound 5h. White solid, mp 204–205; H NMR (CDCl3,
400 MHz) d (ppm): 1.14 (t, 3H, J ¼ 7.2 Hz), 2.58 (s, 3H),
4.06 (q, 2H, J ¼ 7.2 Hz), 4.12 (d, 1H, J ¼ 13.2 Hz), 4.26 (d,
1H, J ¼ 13.2 Hz), 6.32 (s, 1H), 7.19–7.30 (m, 9H), 10.87 (s,
1H); 13C NMR (CDCl3, 100 MHz) d (ppm): 14.10, 19.47,
36.28, 59.57, 60.19, 98.62, 127.34, 128.37, 128.65, 128.81,
Compound 5m. White solid, mp 293–294; 1H NMR
(CDCl3, 400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 6.8 Hz), 3.80 (s,
3H), 4.11 (q, 2H, J ¼ 6.8 Hz), 4.16 (d, 1H, J ¼ 12.8 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

146
Q. Chen, L.-L. Jiang, C.-N. Chen, and G.-F. Yang
Vol 46
4.28 (d, 1H, J ¼ 12.8 Hz), 4.90 (d, 1H, J ¼ 12.0 Hz), 5.07 (d,
1H, J ¼ 12.0 Hz), 6.35 (s, 1H), 6.84–7.24 (m, 9H), 10.99 (s,
1H); 13C NMR (CDCl3, 100 MHz) d (ppm): 13.95, 36.67,
39.83, 55.25, 59.56, 60.77, 101.29, 113.91, 127.26, 128.36,
128.64, 128.97, 132.71, 137.22, 143.25, 147.61, 157.84,
159.64, 164.44; EI-MS (70Ev, m/z) (relative intensity %): 472
(10), 470 (Mþ, 40), 462 (7), 434 (70), 401 (16), 373 (10), 355
(12), 327 (12), 313 (21), 283 (24), 267 (23), 241 (22), 228
(25), 197 (20), 185 (20), 172 (14), 158 (12), 123 (28), 115
(10), 91 (100); Elemental Anal. Calcd. for C23H23ClN4O3S: C,
58.65; H, 4.92; N, 11.90; Found: C, 58.88; H, 5.12; N, 12.05.
Compound 5n. White solid, mp > 300; 1H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 7.2 Hz), 4.11 (q, 2H, J ¼
7.2 Hz), 4.15 (d, 1H, J ¼ 13.6 Hz), 4.27 (d, 1H, J ¼ 13.6 Hz),
4.92 (d, 1H, J ¼ 12.0 Hz), 5.07 (d, 1H, J ¼ 12.0 Hz), 6.36 (s,
1H), 7.17–7.32 (m, 9H), 10.92 (s, 1H); 13C NMR (CDCl3, 100
MHz) d (ppm): 13.95, 36.54, 39.80, 59.52, 60.95, 100.63,
127.34, 128.37, 128.81, 128.86, 128.92, 134.46, 137.12,
138.87, 143.75, 147.59, 158.28, 164.18; EI-MS (70Ev, m/z)
(relative intensity %): 478 (14), 476 (54), 474 (Mþ, 73), 438
(57), 405 (31), 391 (23), 377 (10), 362 (17), 327 (9), 288 (10),
258 (13), 246 (14), 228 (9), 162 (7), 149 (8), 133 (34), 105
(22), 91 (100); Elemental Anal. Calcd. for C22H20Cl2N4O2S:
C, 55.58; H, 4.24; N, 11.79; Found: C, 55.41; H, 4.51; N,
11.63.
4.16 (m, 2H), 6.39 (s, 1H), 7.14–7.45 (m, 3H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.60, 14.11, 59.58, 61.92,
104.87, 114.19, 115.54, 118.33, 121.08, 123.79, 126.80,
129.61, 130.93, 131.37, 131.82, 132.22, 132.51, 133.03,
133.42, 138.44, 147.06, 161.54, 162.80; EI-MS (70Ev, m/z)
(relative intensity %): 454 (100), 452 (Mþ, 88), 423 (32), 405
(84), 383 (43), 359 (10), 307 (39), 279 (26), 251 (6), 233 (10),
201 (5), 165 (7), 109 (6); Elemental Anal. Calcd. for
C16H13Cl2F3N4O2S: C, 42.40; H, 2.89; N, 12.36; Found: C,
42.50; H, 3.05; N, 12.05.
Compound 5s. Yellow solid, mp 209–210; 1H NMR
(CDCl3, 400 MHz) d (ppm): 1.19 (t, 3H, J ¼ 7.2 Hz), 2.45 (s,
3H), 4.15 (m, 2H), 6.54 (s, 1H), 7.51–8.25 (m, 4H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.60, 14.02, 59.83, 62.14,
104.58, 115.49, 118.30, 120.87, 124.13, 128.61, 131.88,
132.22, 132.60, 132.93, 144.79, 147.20, 148.14, 161.73,
162.68; EI-MS (70Ev, m/z) (relative intensity %): 244 (3), 227
(2), 199 (2), 138 (20), 107 (33), 77 (100); Elemental Anal.
Calcd. for C16H14F3N5O4S: C, 44.76; H, 3.29; N, 16.31;
Found: C, 45.02; H, 3.38; N, 16.05.
1
Compound 5t. White solid, mp 155–156; H NMR (CDCl3,
400 MHz) d (ppm): 1.15 (t, 3H, J ¼ 7.2 Hz), 2.45 (s, 3H),
4.04 (m, 2H), 6.65 (s, 1H), 7.03–7.35 (m, 4H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.54, 14.10, 55.83, 61.68,
104.53, 115.56, 115.89, 116.22, 118.40, 121.13, 123.83,
124.44, 125.46, 125.60, 129.82, 130.87, 131.61, 131.92,
132.27, 132.58; EI-MS (70Ev, m/z) (relative intensity %): 402
(Mþ, 53), 373 (13), 353 (27), 333 (22), 307 (12), 279 (9), 266
(10), 249 (22), 198 (14), 168 (99), 139 (100), 124 (92), 106
(32); Elemental Anal. Calcd. for C16H14F4N4O2S: C, 47.76; H,
3.51; N, 13.92; Found: C, 48.02; H, 3.76; N, 14.15.
1
Compound 5o. White solid, mp 154–155; H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 7.2 Hz), 2.46 (s, 3H),
3.79 (s, 3H), 4.12 (m, 2H), 6.38 (s, 1H), 6.86–7.26 (m, 4H);
13C NMR (CDCl3, 100 MHz) d (ppm): 13.60, 14.16, 55.21,
60.11, 61.66, 106.45, 114.11, 115.73, 118.48, 121.22, 123.97,
128.78, 130.15, 130.52, 130.87, 147.11, 159.98, 160.76,
163.17; EI-MS (70Ev, m/z) (relative intensity %): 416 (5), 414
(Mþ, 100), 385 (25), 367 (78), 341 (44), 325 (12), 294 (10),
279 (16), 233 (6), 213 (9), 170 (4), 85 (4); Elemental Anal.
Calcd. for C17H17F3N4O3S: C, 49.27; H, 4.13; N, 13.52;
Found: C, 49.42; H, 4.36; N, 13.69.
1
Compound 5u. White solid, mp 179–180; H NMR (CDCl3,
400 MHz) d (ppm): 1.14 (t, 3H, J ¼ 7.2 Hz), 2.46 (s, 3H),
4.04 (m, 2H), 6.43 (s, 1H), 7.30–7.38 (m, 3H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.60, 14.11, 60.58, 60.72, 61.74,
106.19, 115.68, 118.48, 121.19, 123.90, 127.43, 128.83,
129.04, 130.51, 130.79, 131.20, 131.57, 138.33, 147.29,
160.81, 163.10; EI-MS (70Ev, m/z) (relative intensity %): 385
(19), 384 (Mþ, 100), 355 (20), 337 (50), 315 (19), 307 (25),
279 (19), 133 (8); Elemental Anal. Calcd. for C16H15F3N4O2S:
C, 50.00; H, 3.93; N, 14.58; Found: C, 50.08; H, 4.00; N,
14.30.
1
Compound 5p. White solid, mp 188–189; H NMR (CDCl3,
400 MHz) d (ppm): 1.17 (t, 3H, J ¼ 7.2 Hz), 2.45 (s, 3H),
4.13 (m, 2H), 6.40 (s, 1H), 7.25–7.35 (m, 4H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.60, 14.12, 60.02, 61.87, 92.29,
105.74, 115.60, 118.36, 121.11, 123.86, 128.87, 129.09,
130.83, 131.20, 131.57, 135.05, 136.76, 147.06, 161.17,
162.92; EI-MS (70Ev, m/z) (relative intensity %): 420 (29),
418 (Mþ, 100), 389 (32), 371 (62), 349 (32), 307 (21), 279
(17), 263 (3), 233 (8), 217 (5), 182 (3), 111 (5); Elemental
Anal. Calcd. for C16H14ClF3N4O2S: C, 45.88; H, 3.37; N,
13.38; Found: C, 45.62; H, 3.47; N, 13.11.
1
Compound 5v. White solid, mp 156–157; H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 7.2 Hz), 2.33 (s, 3H),
2.46 (s, 3H), 4.12 (m, 2H), 6.38 (s, 1H), 7.15 (dd, 2H, J ¼ 8.4
Hz), 7.19 (dd, 2H, J ¼ 8.0 Hz); 13C NMR (CDCl3, 100 MHz)
d (ppm): 13.60, 14.12, 21.17, 60.39, 61.57, 106.44, 115.73,
118.54, 121.16, 123.92, 127.33, 129.48, 130.41, 130.72,
131.14, 131.50, 135.45, 138.93, 147.23, 160.83, 163.12; EI-
MS (70Ev, m/z) (relative intensity %): 400 (5), 398 (Mþ, 100),
369 (25), 351 (81), 329 (28), 307 (30), 278 (31), 233 (8), 197
(4), 165 (3), 115 (7); Elemental Anal. Calcd. for
C17H16F4N4O2S: C, 49.04; H, 3.87; N, 13.46; Found: C,
49.25; H, 3.67; N, 13.19.
1
Compound 5q. White solid, mp 160–161; H NMR (CDCl3,
400 MHz) d (ppm): 1.16 (t, 3H, J ¼ 7.2 Hz), 4.12 (m, 2H),
4.12 (d, 1H, J ¼ 13.2 Hz), 4.24 (d, 1H, J ¼ 13.2 Hz), 6.39 (s,
1H), 7.18–7.34 (m, 9H); 13C NMR (CDCl3, 100 MHz) d
(ppm): 13.59, 35.77, 59.99, 61.84, 105.47, 115.57, 118.32,
121.07, 123.82, 127.22, 128.27, 128.90, 129.07, 129.82,
130.94, 131.31, 131.68, 132.04, 135.01, 136.77, 146.96,
159.64, 162.94; EI-MS (70Ev, m/z) (relative intensity %): 496
(32), 494 (Mþ, 100), 461 (65), 449 (4), 415 (12), 403 (6), 390
(4), 217 (3), 172 (4), 121 (7), 91 (99); Elemental Anal. Calcd.
for C22H18ClF3N4O2S: C, 53.39; H, 3.67; N, 11.32; Found: C,
53.62; H, 3.84; N, 11.08.
1
Compound 6a. White solid, mp 154–155; H NMR (CDCl3,
400 MHz) d (ppm): 0.96 (t, 3H, J ¼ 7.2 Hz), 1.89 (s, 3H),
2.43 (s, 3H), 3.04 (d, 1H, J ¼ 11.2 Hz), 3.81 (s, 3H), 3.95 (m,
2H), 4.95 (d, 1H, J ¼ 11.2 Hz), 5.93 (s, 1H), 6.87–7.34 (m,
4H); 13C NMR (CDCl3, 100 MHz) d (ppm): 13.71, 14.30,
25.69, 53.84, 55.33, 57.10, 61, 50, 81.83, 114.12, 129.08,
129.74, 153.14, 159.09, 160.10, 169.87; EI-MS (70Ev, m/z)
1
Compound 5r. White solid, mp 188–189; H NMR (CDCl3,
400 MHz) d (ppm): 1.20 (t, 3H, J ¼ 7.2 Hz), 2.47 (s, 3H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
The First Example of a Regioselective Biginelli-Like Reaction
Based on 3-Alkylthio-5-amino-1,2,4-triazole
147
(relative intensity %): 379 (8), 378 (Mþ, 32), 360 (12), 335
(7), 313 (9), 289 (8), 247 (100), 233 (41), 200 (38), 174 (24),
161 (64), 146 (61), 129 (64), 115 (23); Elemental Anal. Calcd.
for C17H22N4O4S: C, 53.95; H, 5.86; N, 14.80; Found: C,
53.76; H, 6.04; N, 14.92.
61.73, 83.61, 113.88, 127.11, 128.26, 128.86, 129.37, 137.24,
154.13, 158.30, 160.04, 169.11; EI-MS (70Ev, m/z) (relative
intensity %): 324 (16), 291 (8), 282 (17), 233 (89), 206 (38),
189 (9), 173 (24), 161 (22), 137 (19), 115 (50), 91 (100); Ele-
mental Anal. Calcd. for C23H25ClN4O4S: C, 56.49; H, 5.15; N,
11.46; Found: C, 56.78; H, 5.06; N, 11.57.
1
Compound 6d. White solid, mp 151–152; H NMR (CDCl3,
400 MHz) d (ppm): 0.97 (t, 3H, J ¼ 7.2 Hz), 1.86 (s, 3H),
13
1
Compound 6n. White solid, mp 150–151; H NMR (CDCl3,
2.43 (s, 3H), 3.44 (d, 1H, J ¼ 11.2 Hz), 4.01 (m, 2H), 5.62 (d,
400 MHz) d (ppm): 0.97 (t, 3H, J ¼ 7.2 Hz), 3.51 (d, 1H, J ¼
11.2 Hz), 3.87 (d, 1H, J ¼ 11.2 Hz), 3.94 (m, 2H), 4.03 (d,
1H, J ¼ 13.2 Hz), 4.15 (d, 1H, J ¼ 13.2 Hz), 4.34 (d, 1H, J ¼
11.2 Hz), 4.93 (d, 1H, J ¼ 11.2 Hz), 6.78 (s, 1H), 7.23–7.39
(m, 9H); 13C NMR (CDCl3, 100 MHz) d (ppm): 13.60, 35.91,
45.86, 51.69, 53.40, 61.87, 83.73, 127.32, 128.45, 128.86,
129.02, 129.64, 135.03, 135.87, 137.11, 154.10, 158.50,
169.14; EI-MS (70Ev, m/z) (relative intensity %): 493 (Mþ,
1), 419 (1), 366 (2), 328 (61), 295 (43), 286 (21), 251 (4), 237
(99), 206 (100), 190 (10), 173 (45), 165 (33), 136 (23), 115
(29), 101 (25); Elemental Anal. Calcd. for C22H22Cl2N4O3S:
C, 53.55; H, 4.49; N, 11.36; Found: C, 53.78; H, 4.72; N,
11.70.
1H, J ¼ 11.2 Hz), 6.88 (s, 1H), 7.25–7.50 (m, 3H); C NMR
(CDCl3, 100 MHz) d (ppm): 13.69, 14.30, 24.38, 49.63, 52.14,
61.88, 82.10, 127.61, 129.67, 133.89, 139.11, 153.69, 159.52,
169.83; EI-MS (70Ev, m/z) (relative intensity %): 418 (4), 416
(Mþ, 7), 373 (5), 327 (9), 287 (23), 251 (100), 223 (21),199
(15), 170 (8), 13 0 (28), 114 (8); Elemental Anal. Calcd. for
C16H18Cl2N4O3S: C, 46.05; H, 4.35; N, 13.43; Found: C,
46.33; H, 4.08; N, 13.80.
1
Compound 6f. White solid, mp 140–141; H NMR (CDCl3,
400 MHz) d (ppm): 0.96 (t, 3H, J ¼ 7.2 Hz), 1.80 (s, 3H),
2.31 (s, 3H), 3.05 (d, 1H, J ¼ 11.2 Hz), 3.92 (m, 2H), 4.20 (d,
1H, J ¼ 13.2 Hz), 4.27 (d, 1H, J ¼ 13.2 Hz), 4.94 (d, 1H, J ¼
11.2 Hz), 5.86 (s, 1H), 7.13–7.37 (m, 9H); 13C NMR (CDCl3,
100 MHz) d (ppm): 13.60, 21.11, 25.69, 36.13, 54.33, 56.74,
61.48, 81.87, 127.21, 127.72, 128.44, 129.13, 129.49, 134.52,
137.47, 138.86, 152.90, 157.88, 170.12; EI-MS (70Ev, m/z)
(relative intensity %): 438 (Mþ, 5), 369 (2), 308 (50), 275
(30), 231 (27), 217 (72), 206 (65), 187 (21), 173 (24), 143
(28), 115 (51), 102 (16), 90 (100); Elemental Anal. Calcd. for
C23H26N4O3S: C, 62.99; H, 5.98; N, 12.78; Found: C, 62.77;
H, 6.17; N, 12.94.
1
Compound 6t. White solid, mp 158–159; H NMR (CDCl3,
400 MHz) d (ppm): 0.88 (t, 3H, J ¼ 7.2 Hz), 2.33 (s, 3H),
3.78 (d, 1H, J ¼ 4.0 Hz), 3.84 (m, 2H), 5.44 (d, 1H, J ¼ 4.0
Hz), 7.12–7.46 (m, 4H); 13C NMR (DMSO, 100 MHz) d
(ppm): 13.54, 47.03, 48.10, 60.43, 60.61, 81.23, 81.46, 115.25,
115.44, 121.42, 123.74, 123.79, 124.23, 124.67, 127.88,
130.50, 153.93, 155.62, 157.67, 158.33, 159.40, 160.77,
164.65, 165.52; EI-MS (70Ev, m/z) (relative intensity %): 422
(6), 420 (Mþ, 100), 401 (20), 373 (7), 353 (12), 277 (14), 235
(72), 217 (83), 184 (5), 149 (25), 134 (27), 115 (22); Elemen-
tal Anal. Calcd. for C16H16F4N4O3S: C, 45.71; H, 3.84; N,
13.33; Found: C, 45.54; H, 4.05; N, 13.56.
1
Compound 6h. White solid, mp 152–153; H NMR (CDCl3,
400 MHz) d (ppm): 0.96 (t, 3H, J ¼ 7.2 Hz), 1.78 (s, 3H),
3.01 (d, 1H, J ¼ 11.2 Hz), 3.92 (m, 2H), 4.12 (d, 1H, J ¼
13.2 Hz), 4.20 (d, 1H, J ¼ 13.2 Hz), 4.96 (d, 1H, J ¼ 11.6
Hz), 6.63 (s, 1H), 7.23–7.35 (m, 9H); 13C NMR (CDCl3, 100
MHz) d (ppm): 13.70, 25.61, 35.92, 53.68, 56.84, 61.73,
81.85, 127.20, 128.44, 128.91, 129.04, 129.29, 134.77, 136.32,
137.28, 152.91, 157.83, 169.64; EI-MS (70Ev, m/z) (relative
intensity %): 458 (Mþ, 2), 328 (64), 295 (48), 251 (49), 237
(36), 217 (42), 206 (100), 189 (9), 173 (46), 165 (37), 141
(11), 115 (11), 101 (18); Elemental Anal. Calcd. for
C22H23ClN4O3S: C, 57.57; H, 5.05; N, 12.21; Found: C,
57.82; H, 5.30; N, 12.09.
1
Compound 6u. White solid, mp 143–144; H NMR (CDCl3,
400 MHz) d (ppm): 0.88 (t, 3H, J ¼ 7.2 Hz), 2.26 (s, 3H),
3.59 (d, 1H, J ¼ 4.0 Hz), 3.85 (m, 2H), 5.10 (d, 1H, J ¼ 4.4
Hz), 7.32–7.40 (m, 5H); 13C NMR (CDCl3, 100 MHz) d
(ppm): 13.60, 14.22, 49.89, 54,14, 61.12, 81.87, 82.32, 121.24,
124.13, 126.65, 126.91, 136.14, 155.10, 160.83, 165.44; EI-
MS (70Ev, m/z) (relative intensity %): 402 (Mþ, 8), 369 (4),
272 (3), 230 (4), 217 (100), 203 (5), 184 (9), 171 (6), 139
(15), 115 (22); Elemental Anal. Calcd. for C16H17F3N4O3S: C,
47.76; H, 4.26; N, 13.92; Found: C, 48.04; H, 4.02; N, 14.15.
1
Compound 6i. White solid, mp 147–148; H NMR (CDCl3,
1
Compound 6v. White solid, mp 153–154; H NMR (CDCl3,
400 MHz) d (ppm): 0.93 (t, 3H, J ¼ 7.2 Hz), 2.36 (s, 3H),
2.39 (s, 3H), 3.55 (d, 1H, J ¼ 11.6 Hz), 3.88 (d, 1H, J ¼ 12.0
Hz), 3.94 (m, 2H), 4.36 (d, 1H, J ¼ 11.6 Hz), 4.93 (d, 1H, J
¼ 11.2 Hz), 5.82 (s, 1H), 7.17–7.34 (m, 4H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.52, 14.20, 21.24, 46.08, 51.73,
54.14, 61.88, 83.63, 127.81, 129.50, 134.08, 139.22, 153.91,
159.79, 169.90; EI-MS (70Ev, m/z) (relative intensity %): 396
(Mþ, 6), 360 (2), 273 (3), 266 (6), 251 (6), 231 (100), 217
(53), 185 (5), 164 (4), 145 (13), 130 (36), 115 (47), 103 (9);
Elemental Anal. Calcd. for C17H21ClN4O3S: C, 51.45; H, 5.33;
N, 14.12; Found: C, 51.57; H, 5.05; N, 14.34.
400 MHz) d (ppm): 0.92 (t, 3H, J ¼ 7.2 Hz), 2.29 (s, 3H),
2.34 (s, 3H), 3.56 (d, 1H, J ¼ 4.0 Hz), 3.87 (q, 2H, J ¼ 7.2
Hz), 5.06 (d, 1H, J ¼ 4.0 Hz), 7.07–7.24 (m, 4H); 13C NMR
(CDCl3, 100 MHz) d (ppm): 13.22, 13.58, 14.20, 49.87, 53.90,
61.23, 81.91, 82.19, 118.22, 121.14, 123.88, 126.55, 127.64,
129.61, 132.88, 138.83, 139.74, 155.13, 160.89, 165.54; EI-
MS (70Ev, m/z) (relative intensity %): 416 (Mþ, 6), 286 (2),
271 (3), 231 (100), 217 (8), 184 (5), 139 (9), 130 (14), 115
(19); Elemental Anal. Calcd. for C17H19F3N4O3S: C, 49.03; H,
4.60; N, 13.45; Found: C, 49.37; H, 4.63; N, 13.13.
Compound 6m. White solid, mp 147–148; 1H NMR
(CDCl3, 400 MHz) d (ppm): 0.94 (t, 3H, J ¼ 7.2 Hz), 3.52 (d,
1H, J ¼ 11.6 Hz), 3.76 (s, 3H), 3.87 (d, 1H, J ¼ 12.0 Hz),
3.96 (m, 2H), 4.02 (d, 1H, J ¼ 12.8 Hz), 4.16 (d, 1H, J ¼
12.8 Hz), 4.34 (d, 1H, J ¼ 11.6 Hz), 4.91 (d, 1H, J ¼ 11.6
Hz), 6.33 (s, 1H), 6.85–7.36 (m, 9H); 13C NMR (CDCl3, 100
MHz) d (ppm): 13.60, 35.82, 46.19, 51.89, 53.04, 55.22,
Acknowledgments. This work was supported by the National
NSFC grants (Nos. 20572030, 20432010, 20528201, and
20702018), the Cultivation Fund of the Key Scientific and Tech-
nical Innovation Project, Ministry of Education of China
(No.705039), and Program for Excellent Research Group of
Hubei Province (No. 2004ABC002).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

148
Q. Chen, L.-L. Jiang, C.-N. Chen, and G.-F. Yang
Vol 46
2003, 39, 1194; (b) Lipson, V. V.; Desenko, S. M.; Shishkina, S. V.;
Shirobokova, M. G.; Shishkin, O. V.; Orlov, V. D. Chem Heterocycl
Compd (Engl Transl) 2003, 39, 1041.
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DOI 10.1002/jhet