Solvent-free synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a] pyrimidine-6-carboxylic esters catalyzed by sulfamic acid

Article abstract of DOI:10.1002/jhet.5570450609

(Chemical Equation Presented) The solvent-free synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic esters was performed and effectively catalyzed by sulfamic acid. Compared with conventional methods, this protocol features mild reaction conditions and high yields. Furthermore, it is solvent-free and thus ecofriendly.

Full text of DOI:10.1002/jhet.5570450609

Nov-Dec 2008
1609
Solvent-free Synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-
a]pyrimidine-6-carboxylic esters Catalyzed by Sulfamic Acid
Changsheng Yao, Song Lei, Cuihua Wang, Chenxia Yu, Shujiang Tu*
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology
on Medical Plant, Xuzhou, Jiangsu 221116, PR China
Received February 21, 2008
O
R1
N
O
O
N
SA
N
N
N
R1CHO
+
+
R2O
N
H3C
OR2
Solvent-free
N
N
H
H2N
N
H
4
1
3
2
The solvent-free synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic esters
was performed and effectively catalyzed by sulfamic acid. Compared with conventional methods, this
protocol features mild reaction conditions and high yields. Furthermore, it is solvent-free and thus eco-
friendly.
J. Heterocyclic Chem., 45, 1609 (2008).
INTRODUCTION
Biginelli reaction efficiently [27,28]. In continuing our
work related to the DHPM scaffold and optimization of
the Biginelli reaction [29,30], we report herein the
solvent-free synthesis of 5-methyl-7-aryl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylic esters catalyzed
by sulfamic acid (Scheme 1, Table 4).
In past decades, much attention has been devoted
towards dihydropyrimidine (DHPM) derivatives due to
their array of pharmacological and therapeutic properties
[1,2]. They have emerged as potential calcium channel
blockers [3], inhibitors of mitotic kinesin, Eg5 for treating
cancer [4,5], TRPA1 modulators for treating pain [6], etc.
Several marine alkaloids containing the dihydro-
pyrimidine core unit were found to show interesting
biological activities such as antiviral, antibacterial and
anti-inflammatory activity [7,8]. Hence the preparation of
this heterocyclic core unit has gained much importance.
Compounds containing the dihydrotetrazolo[1,5-a]-
pyrimidine (DHPM) scaffold include purine derivatives
which have been reported to have various biological
activities, such as antimicrobial activity [9], farnesyl
transferase inhibitory [10], fungicidal activity [5],
antihypertensive [11], KATP channel opening [12],
central nervous system stimulating [13], etc. In general,
three main methods for synthesizing these compounds
have been developed so far. The first one utilizes an azide
intermediate [14-17]. The second method starts with 2-
aminotetrazole and uses a three-component reaction
[18-23], and the third involves the reaction of 5-
aminotetrazole with ꢀ-oxo carbonyl compounds or ꢁ,ꢀ-
unsaturated carbonyl compounds [24-26]. However, most
of the synthetic protocols reported so far have many
drawbacks, including high temperatures, prolonged
reaction time, drastic reaction conditions, low yields and
the use of hazardous and often expensive acid catalysts.
Therefore, the development of simple, convenient and
environmentally benign approaches for the synthesis of
these compounds is still desirable. Recently, sulfamic acid
Scheme 1
O
R1
N
O
O
N
SA
N
N
N
R1CHO
+
+
R2O
N
H3C
OR2
Solvent-free
N
N
H
H2N
N
H
4
1
3
2
RESULTS AND DISCUSSION
The effect of solvent on the reaction was initially
examined by reacting ethyl 3-oxobutanoate (1 mmol), 1H-
tetrazol-5-amine hydrate (1 mmol) and phenyl aldehyde
(1 mmol) catalyzed by SA. It was found that if the
synthesis was performed in the organic solvent it gave the
expected product, 4w, in moderate to high yield (55-85%)
(Table 1).
Table 1
Solvent effect on the synthesis of 4w.
Entry Solvent
Temp Time
(°C)
Yield
(h)
(ꢀ)
60
55
85
65
55
85
1
2
3
4
5
6
CH3CN
CHCl3
EtOH
HOAc
H2O
reflux
reflux
reflux
85
9
9
9
9
9
7
85
(NH2SO3H, SA),
a
commercially available and
solvent-free 85
inexpensive reagent, has been reported to catalyze the

1610
C. S. Yao, S. Lei, C. H. Wang, C. X. Yu, S. J. Tu
Vol 45
To screen for the optimal catalyst for the sovent-free
To find the best catalyst loading, the previous reaction
was run in 1 mmol scale of substrate using different
amounts of catalyst (Table 3). Table 3 shows that 10%
mol amount of sulfamic acid was optimal under the
experimental conditions used.
synthesis, the previous reaction was performed using
H2SO4, FeCl3·6H2O, MgSO4, SnCl2·2H2O, NiCl2, CrCl3,
Na2SO4, and SA as catalysts (10 mol%) (Table 2). As
shown in Table 2, SA was the best catalyst for this
reaction from the viewpoint of yield.
Moreover, the optimal temperature for the reaction
was found to be 85°C.
Table 2
Based on the optimized reaction conditions, a series of 5-
methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxylic esters were synthesized. The resultsꢁꢂ
summarized in Table 4, show that the reaction catalyzed by
sulfamic acid under solvent-free conditions gave the
corresponding products in moderate to good yields. As
shown in Table 4, this methodology can be applied to
aromatic aldehydes either with electron-withdrawing
groups (such as a nitro group, halogen) or electron-donating
groups (such as a methoxy group) with moderate to
excellent yields under the same conditions. Therefore, we
conclud that the electronic nature of substituents of the
aromatic aldehyde had no significant effect on the reaction.
However, when the aliphatic aldehyde was applied to this
reaction, no expected product was obtained. In addition,
yields were unaffected when methyl 3-oxobutanoate or
ethyl 3-oxobutanoate was used.
Catalyst optimization for the synthesis of 4w under solvent-free media.
Entry Catalyst
Temp ( °C) Time
(h)
Yield(ꢀ)
1
2
3
4
H2SO4
FeCl3·6H2O 85
MgSO4 85
SnCl2·2H2O 85
85
7
9
8
10
9
9
10
7
54
46
65
55
52
55
45
85
5
6
7
8
NiCl2
CrCl3
Na2SO4
SA
85
85
85
85
Table 3
The effect of catalyst loading on reaction under solvent-free media.
Entry Catalyst
(%)
Temp
(°C)
85
85
85
85
85
Time
(h)
8
8
8
8
8
Yield(ꢀ)
All of the compounds were characterized by elemental
1
2
3
4
5
0
5
10
15
20
52
75
85
72
65
1
analysis, FTIR and H NMR. . To further elucidate the
structure of products, a single crystal of compound 4c was
prepared and its structure was determined by X-ray
diffraction (Figure 1).
Table 4
SA catalyzed the synthesis of compound 4.
Compound No.
R1
R2
Time(h)
Yield (%)
Mp(°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
3,4-(CH3O)2C6H3
4-NO2C6H4
4-BrC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
8
9
7
8
8
9
9
8
8
7
7
8
9
9
8
7
8
8
9
9
7
8
7
78 218-220
82 230-232
79 220-222
84 253-255
87 178-180
80 213-215
77 200-202
83 223-224
82 184-186
81 230-232
84 197-198
87 226-228
80 >300
2,4-Cl2C6H3
3-FC6H4
3,4-(OCH2O)C6H3
3,4,5-(CH3O)3C6H2
2-FC6H4
3-ClC6H4
2-ClC6H4
4-FC6H4
3-NO2C6H4
3-(CHO)C6H4
3-NO2-4-HOC6H3
C6H5
79 247-249
82 189-191
89 237-238
87 257-259
85 196-198
88 199-201
86 210-212
81 184-186
83 206-208
85 204-205(Ref[21]:205-206)
4-BrC6H4
2,4-Cl2C6H4
3,4-(OCH2O)C6H3
3,4,5-(CH3O)3C6H2
3,4-(CH3O)2C6H3
3-ClC6H4
4t
4u
4v
4w
3-NO2C6H4
C6H5

Nov-Dec 2008
Solvent-free Synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-
1611
6-carboxylic esters esters Catalyzed by Sulfamic Acid
Methyl 5-methyl-7-(4-nitrophenyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4b). ir (potassium bromide):
3177, 3080, 2957, 1692, 1651, 1580, 1520, 1438, 1354, 1315,
1290, 1238, 1193, 1106, 993, 952, 830, 750, 735, 701, 666 cm-1;
1H nmr (DMSO-d6): ꢀ 2.48 (s, 3H, 5-methyl-H), 3.52 (s, 3H,
COOCH3), 6.86 (s, 1H, CH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 8.20
(d, J = 8.0 Hz, 2H, ArH), 11.48 (s, 1H, NH). Anal. Calcd. for
C13H12N6O4: C, 49.37; H, 3.82; N, 26.57. Found: C, 49.46; H,
3.77; N, 26.45.
Methyl 7-(4-bromophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4c). ir (potassium bromide):
3245, 3059, 2949, 1710, 1648, 1574, 1488, 1432, 1413, 1385,
1302, 1278, 1227, 1190, 1153, 1103, 1072, 1012, 839, 813, 772,
1
725, 686 cm-1; H nmr (DMSO-d6): ꢀ 2.46 (s, 3H, 5-methyl-H),
3.52 (s, 3H, COOCH3), 6.69 (s, 1H, CH), 7.28 (d, J = 8.0 Hz,
2H, ArH), 7.55 (d, J = 8.0 Hz, 2H, ArH), 11.38 (s, 1H, NH).
Anal. Calcd. for C13H12BrN5O2: C, 44.59; H, 3.45; N, 20.00.
Found: C, 44.65; H, 3.35; N, 20.16.
Figure 1. The crystal structure of 4c.
Methyl 7-(2,4-dichlorophenyl)-5-methyl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidine-6-carboxylate (4d). ir (potassium
bromide): 3181, 3057, 2953, 1717, 1691, 1649, 1582, 1473,
1436, 1387, 1342, 1315, 1286, 1230, 1190, 1149, 1104, 1049,
953, 851, 818, 780, 731, 690 cm-1; 1H nmr (DMSO-d6): ꢀ 2.46
(s, 3H, 5-methyl-H), 3.50 (s, 3H, COOCH3), 7.03 (s, 1H, CH),
7.43 (s, 2H, ArH), 7.67 (s, 1H, ArH), 11.46 (s, 1H, NH). Anal.
Calcd. for C13H11Cl2N5O2: C, 45.90; H, 3.26; N, 20.59. Found:
C, 45.75; H, 3.37; N, 20.44.
In summary, we have developed an efficient,
economical, safe and environmentally benign procedure
for synthesizing derivatives of dihydrotetrazolo[1,5-a]-
pyrimidine.ꢀ The results show that SA is an efficient
catalyst that could, in principle, be used as a catalyst in
organic reactions requiring acid catalysis.
EXPERIMENTAL
Methyl 7-(3-fluorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4e). ir (potassium bromide):
3176, 3057, 2955, 1689, 1651, 1579, 1489, 1437, 1390, 1342,
1315, 1285, 1258, 1238, 1189, 1153, 1136, 1103, 993, 952, 934,
811, 775, 701, 704 cm-1; 1H nmr (DMSO-d6): ꢀ 2.47 (s, 3H, 5-
methyl-H), 3.53 (s, 3H, COOCH3), 6.49 (s, 1H, NH), 6.71 (s,
1H, CH), 7.15~7.22 (m, 3H, ArH), 7.38~7.43 (m, 1H, ArH).
Anal. Calcd. for C13H12FN5O2: C, 53.98; H, 4.18; N, 24.21.
Found: C, 53.86; H, 4.26; N, 24.32.
Common reagents and materials were purchased from
commercial sources and purified by recrystallization or
distillation. NMR spectra were recorded on a Bruker DPX 400,
Data for 1H are reported as follows: chemical shift (ppm),
integration, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad), coupling constant (Hz) and
number. Infrared (IR) spectra were recorded on a TENSOR 27
spectrophotometer in KBr pellet and are reported in terms of
frequency of absorption (cm-1). Elemental analyses were
performed on a Perkin-Elmer 240 II elementary analyzer.
Melting points were determined in open capillaries and are
uncorrected. The single crystal diffraction data were gathered on
a Rigaku Saturn diffractometer.
Methyl 7-(benzo[d][1,3]dioxol-5-yl)-5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4f). ir (potassium
bromide): 3238, 3177, 3085, 2949, 1711, 1686, 1653, 1584,
1493, 1434, 1379, 1333, 1315, 1251, 1189, 1146, 1101, 1038,
1
963, 924, 795, 734, 692 cm-1; H nmr (DMSO-d6): ꢀ 2.46 (s,
3H, 5-methyl-H), 3.54 (s, 3H, COOCH3), 6.01 (s, 2H, OCH2O),
6.60 (s, 1H, CH), 6.79 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H, ArH),
6.86 (d, J = 8.0 Hz, 1H, ArH), 6.87 (d, J = 1.6Hz, 1H, ArH),
11.28 (s, 1H, NH). Anal. Calcd. for C14H13N5O4: C, 53.33; H,
4.16; N, 22.21. Found: C, 53.46; H, 4.28; N, 22.35.
Methyl 5-methyl-7-(3,4,5-trimethoxyphenyl)-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4g). ir (potassium
bromide): 3241, 3179, 3096, 2839, 1715, 1684, 1651, 1583,
1507, 1463, 1385, 1337, 1280, 1234, 1189, 1129, 1009, 956,
816, 774, 734, 719, 699 cm-1; 1H nmr (DMSO-d6): ꢀ 2.47 (s, 3H,
5-methyl-H), 3.57 (s, 3H, COOCH3), 3.64 (s, 3H, CH3O), 3.73
(s, 6H, 2ꢁCH3O), 6.56 (s, 2H, ArH), 6.63 (s, 1H, CH), 11.28 (s,
1H, NH). Anal. Calcd. for C16H19N5O5: C, 53.18; H, 5.30; N,
19.38. Found: C, 53.26; H, 5.18; N, 19.47.
Methyl 7-(2-fluorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4h). ir (potassium bromide):
3180, 3050, 2957, 1696, 1654, 1580, 1493, 1435, 1388, 1336,
1316, 1284, 1244, 1228, 1180, 1152, 1106, 1075, 992, 961, 854,
788, 755, 733, 678 cm-1; 1H nmr (DMSO-d6): ꢀ 2.45 (s, 3H, 5-
methyl-H), 3.52 (s, 3H, COOCH3), 6.89 (s, 1H, CH), 7.18~7.23
(m, 2H, ArH), 7.36~7.42 (m, 2H, ArH), 11.42 (s, 1H, NH).
General Procedure for the synthesis of 5-methyl-7-aryl-
4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic
esters
(4a-4w). Acetoacetate ester 1 (1 mmol), 1H-tetrazol-5-amine
hydrate 2 (0.103 g, 1 mmol) and aryl aldehyde 3 (1 mmol) were
triturated together in an agate mortar for 5 minutes. Then the
mixture was kept at 85 °C for a certain time (monitored by
TLC). The resulting mixture was cooled to room temperature,
washed with water and recrystallized from ethanol (95%) to give
pure product 4. A similar procedure was used in preparing the
following compounds.
Methyl 7-(3,4-dimethoxyphenyl)-5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4a). ir (potassium
bromide): 3185, 3060, 2958, 1692, 1661, 1594, 1519, 1439,
1383, 1333, 1313, 1261, 1229, 1138, 1104, 1020, 992, 954, 876,
1
804, 783, 747, 684 cm-1; H nmr (DMSO-d6): ꢀ 2.46 (s, 3H, 5-
methyl-H), 3.54 (s, 3H, COOCH3), 3.72 (s, 3H, CH3O), 3.74 (s,
3H, CH3O), 6.20 (s, 1H, CH), 6.73 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz,
1H, ArH), 6.89 (d, J = 8.4 Hz, 1H, ArH), 6.93 (d, J=1.6Hz, 1H,
ArH), 11.26 (s, 1H, NH). Anal. Calcd. for C15H17N5O4: C, 54.38;
H, 5.17; N, 21.14. Found: C, 54.26; H, 5.05; N, 21.28.

1612
C. S. Yao, S. Lei, C. H. Wang, C. X. Yu, S. J. Tu
Vol 45
Anal. Calcd. for C13H12FN5O2: C, 53.98; H, 4.18; N, 24.21.
Found: C, 53.86; H, 4.22; N, 24.36.
CH), 7.06 (s, 1H, CH), 7.83 (d, J = 8.0 Hz, 2H, ArH), 8.15 (d, J
= 8.0 Hz, 2H, ArH), 11.48(s, 1H, NH). Anal. Calcd. for
C13H13N5O2: C, 57.56; H, 4.83; N, 25.82. Found: C, 57.55; H,
4.83; N, 25.85.
Methyl 7-(3-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4i). ir (potassium bromide):
3272, 3187, 3058, 2956, 1672, 1579, 1476, 1433, 1388, 1339,
1302, 1285, 1235, 1193, 1146, 1100, 1078, 1000, 980, 955, 876,
791, 771, 736, 706, 687 cm-1; 1H nmr (DMSO-d6): ꢀ 2.47 (s, 3H,
5-methyl-H), 3.53 (s, 3H, COOCH3), 6.71 (s, 1H, CH),
7.28~7.31 (m, 1H, ArH), 7.38~7.42 (m, 3H, ArH), 11.39 (s, 1H,
NH). Anal. Calcd. for C13H12ClN5O2: C, 51.07; H, 3.96; N,
22.91. Found: C, 51.15; H, 4.07; N, 22.86.
Ethyl 7-(4-bromophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4p). ir (potassium bromide):
3251, 3182, 3101, 3058, 2979, 1702, 1655, 1568, 1487, 1407,
1387, 1309, 1282, 1225, 1147, 1103, 1071, 1011, 839, 801, 770,
1
738, 699 cm-1; H nmr (DMSO-d6): ꢀ 1.00 (t, J = 6.8 Hz, 3H,
OCH2CH3), 2.46 (s, 3H, 5-methyl-H), 3.94 (q, J = 6.8 Hz, 2H,
OCH2CH3), 6.66 (s, 1H, CH), 7.28 (d, J = 7.6Hz, 2H, ArH), 7.54
(d, J = 7.6Hz, 2H, ArH), 11.35 (s, 1H, NH). Anal. Calcd. for
C14H14BrN5O2: C, 46.17; H, 3.87; N, 19.23. Found: C, 46.28; H,
3.76; N, 19.32.
Ethyl 7-(2,4-dichlorophenyl)-5-methyl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidine-6-carboxylate (4q). ir (potassium
bromide): 3233, 3169, 3060, 2954, 1706, 1655, 1574, 1472,
1388, 1365, 1301, 1284, 1227, 1142, 1100, 1077, 1048, 852,
804, 728, 691cm-1; 1H nmr (DMSO-d6): ꢀ 0.98 (t, J = 6.8 Hz,
3H, OCH2CH3), 2.47 (s, 3H, 5-methyl-H), 3.92 (q, J = 6.8 Hz,
2H, OCH2CH3), 7.03 (s, 1H, CH), 7.44~7.47 (m, 2H, ArH), 7.67
(s, 1H, ArH), 11.42 (s, 1H, NH). Anal. Calcd. for
C14H13Cl2N5O2: C, 47.47; H, 3.70; N, 19.77. Found: C, 47.36; H,
3.66; N, 19.64.
Methyl 7-(2-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4j). ir (potassium bromide):
3180, 3055, 2952, 1682, 1654, 1588, 1474, 1438, 1381, 1337,
1314, 1282, 1236, 1189, 1147, 1106, 1078, 1042, 991, 840, 754,
1
732, 703, 689 cm-1; H nmr (DMSO-d6): ꢀ 2.46 (s, 3H, 5-
methyl-H), 3.49 (s, 3H, COOCH3), 7.02 (s, 1H, CH), 7.33~7.40
(m, 3H, ArH), 7.46~7.49 (m, 1H, ArH), 11.41 (s, 1H, NH).
Anal. Calcd. for C13H12ClN5O2: C, 51.07; H, 3.96; N, 22.91.
Found: C, 50.96; H, 4.02; N, 22.78.
Methyl 7-(4-fluorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4k). ir (potassium bromide):
3177, 3079, 2952, 1172, 1689, 1649, 1605, 1576, 1510, 1435,
1387, 1335, 1313, 1284, 1228, 1190, 1158, 1104, 1079, 993,
962, 856, 819, 792, 767, 734, 696 cm-1; 1H nmr (DMSO-d6): ꢀ
2.46 (s, 3H, 5-methyl-H), 3.52 (s, 3H, COOCH3), 6.70 (s, 1H,
CH), 7.15 (t, J = 8.4 Hz, 2H, ArH), 7.36 (dd, J1= 8.4Hz, J2 =
5.4Hz, 2H, ArH), 11.38 (s, 1H, NH)ꢀꢁ Anal. Calcd. for
C13H12FN5O2: C, 53.98; H, 4.18; N, 24.21. Found: C, 53.87; H,
4.24; N, 24.36.
Ethyl 7-(benzo[d][1,3]dioxol-5-yl)-5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4r). ir (potassium
bromide) 3233, 3169, 3060, 2954, 1706, 1655, 1574, 1472,
1388, 1365, 1301, 1284, 1227, 1142, 1100, 1077, 1048, 852,
1
804, 728, 691 cm-1; H nmr (DMSO-d6): ꢀ 1.18 (t, J = 7.2 Hz,
3H, OCH2CH3), 2.45 (s, 3H, 5-methyl-H), 3.96 (q, J = 7.2 Hz,
2H, OCH2CH3), 6.00 (s, 2H, OCH2O), 6.59 (s, 1H, CH),
6.82~6.86 (m, 3H, ArH), 11.26 (s, 1H, NH). Anal. Calcd. for
C15H15N5O4: C, 54.71; H, 4.59; N, 21.27. Found: C, 54.68; H,
4.64; N, 21.16.
Methyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4l). ir (potassium bromide):
3224, 3178, 3066, 2952, 1720, 1684, 1652, 1576, 1576, 1535,
1437, 1349, 1311, 1286, 1230, 1194, 1147, 1101, 1079, 737, 713
1
cm-1; H nmr (DMSO-d6): ꢀ 2.49 (s, 3H, 5-methyl-H), 3.52 (s,
Ethyl
5-methyl-7-(3,4,5-trimethoxyphenyl)-4,7-dihydro-
3H, COOCH3), 6.92 (s, 1H, CH), 7.67 (d, J = 6.8Hz, 1H, ArH),
7.80 (d, J = 6.8Hz, 1H, ArH), 8.20 (s, 2H, ArH), 11.48 (s, 1H,
NH). Anal. Calcd. for C13H12N6O4: C, 49.37; H, 3.82; N, 26.57.
Found: C, 49.28; H, 3.72; N, 26.66.
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4s). ir (potassium
bromide): 3238, 3176, 2936, 1682, 1650, 1579, 1507, 1464,
1423, 1390, 1365, 1322, 1281, 1237, 1128, 1004, 825, 773, 734,
697 cm-1; 1H nmr (DMSO-d6): ꢀ 1.04 (t, J = 7.2 Hz, 3H,
OCH2CH3), 2.47 (s, 3H, 5-methyl-H), 3.78 (s, 3H, OCH3), 3.85
(s, 6H, 2ꢁOCH3), 3.97 (q, J = 7.2 Hz, 2H, OCH2CH3), 6.58 (s,
2H, ArH), 6.61 (s, 1H, CH), 11.24 (s, 1H, NH). Anal. Calcd. for
C17H21N5O5: C, 54.39; H, 5.64; N, 18.66. Found: C, 54.28; H,
5.46; N, 18.72.
Dimethyl 7,7'-(1,3-phenylene)bis(5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate) (4m). ir (potassium
bromide): 3251, 3182, 3102, 2955, 1712, 1655, 1578, 1433,
1381, 1311, 1287, 1230, 1190, 1144, 1101, 1077, 990, 811, 787,
763, 736, 715, 694 cm-1; 1H nmr (DMSO-d6): ꢀ 2.45 (s, 6H, 2ꢁ5-
methyl-H), 3.44 (s, 6H, 2ꢁCOOCH3), 6.68 (s, 2H, 2ꢁCH), 7.16
(d, J = 7.6Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.30 (t, J = 7.6Hz,
1H, ArH), 11.35 (s, 2H, 2ꢁNH). Anal. Calcd. for C20H20N10O4:
C, 51.72; H, 4.34; N, 30.16. Found: C, 51.66; H, 4.42; N, 30.28.
Methyl 7-(4-hydroxy-3-nitrophenyl)-5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxylate (4n). ir (potassium
bromide): 3249, 3052, 2956, 1695, 1630, 1580, 1541, 1489,
1436, 1386, 1338, 1314, 1240, 1181, 1106, 1079, 827, 764 cm-1;
1H nmr (DMSO-d6): ꢀ 2.46 (s, 3H, 5-methyl-H), 3.54 (s, 3H,
COOCH3), 6.72 (s, 1H, CH), 7.10 (d, J = 8.4 Hz, 1H, ArH), 7.47
(d, J = 8.4Hz, 1H, ArH), 7.56 (s, 1H, ArH), 11.18 (s, 1H, OH),
11.36 (s, 1H, NH). Anal. Calcd. for C13H12N6O5: C, 46.99; H,
3.64; N, 25.29. Found: C, 46.88; H, 3.54; N, 25.36.
Ethyl 7-(3,4-dimethoxyphenyl)-5-methyl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidine-6-carboxylate (4t). ir (potassium
bromide): 3230, 3166, 3055, 2962, 1693, 1655, 1573, 1521,
1467, 1453, 1426, 1384, 1365, 1310, 1288, 1260, 1163, 1122,
1
1098, 1074, 1023, 982, 821, 806, 783, 757, 710 cm-1; H nmr
(DMSO-d6): ꢀ 1.05 (t, J = 6.8 Hz, 3H, OCH2CH3), 2.45 (s, 3H,
5-methyl-H), 3.74 (s, 6H, 2ꢁOCH3), 3.97 (q, J = 6.8 Hz, 2H,
OCH2CH3), 6.60 (s, 1H, CH), 6.75~6.77 (m, 1H, ArH),
6.89~6.95 (m, 2H, ArH), 11.22 (s, 1H, NH). Anal. Calcd. for
C16H19N5O4: C, 55.64; H, 5.55; N, 20.28. Found: C, 55.56; H,
5.48; N, 20.36.
Ethyl 7-(3-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate (4u). ir (potassium bromide):
3230, 3166, 3058, 2942, 1699, 1656, 1575, 1473, 1435, 1387,
1365, 1337, 1302, 1284, 1262, 1231, 1198, 1148, 1126, 1100,
1020, 981, 896, 836, 793, 770, 733, 719, 693 cm-1; 1H nmr
(DMSO-d6): ꢀ 1.00 (t, J = 6.8 Hz, 3H, OCH2CH3), 2.47 (s, 3H,
5-methyl-H), 3.93 (q, J = 6.8 Hz, 2H, OCH2CH3), 6.70 (s, 1H,
Methyl 4,7-dihydro-5-methyl-7-phenyltetrazolo[1,5-a]-
pyrimidine-6-carboxylate (4o). ir (potassium bromide): 3152,
3102, 2923, 1642, 1623, 1509, 1442, 1290, 1223, 1184, 1102,
1
987, 949, 823, 745, 729, 695, 639 cm-1; H nmr (DMSO-d6):
ꢀ 2.42 (s, 3H, 5-methyl-H), 3.55 (s, 3H, COOCH3), 6.84 (s, 1H,

Nov-Dec 2008
Solvent-free Synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-
1613
6-carboxylic esters esters Catalyzed by Sulfamic Acid
[10] Lansbury, P. T.; Liu, Z. H. Austria Patent 2,006,230,674,
2006; Chem. Abstr. 2007, 146, 309356.
CH), 7.26 (t, J = 4.4Hz, 1H, ArH), 7.39 (d, J = 4.4Hz, 2H, ArH),
7.44 (s, 1H, ArH), 11.36 (s, 1H, NH). Anal. Calcd. for
C14H14ClN5O2: C, 52.59; H, 4.41; N, 21.90. Found: C, 52.59; H,
4.35; N, 21.88.
[11] Ismail, M. A.-H.; Aboul-Einein, M. N. Y.; Abouzid, K. A.
M.; Kandil, S. B. A. Alex. J. Pharm. Sci. 2002, 16, 143.
[12] Drizin, I.; Holladay, M. W.; Yi, L.; Zhang, H. Q.;
Gopalakrishnan, S.; Gopalakrishnan, M.; Whiteaker, K. L.; Buckner, S.
A.; Sullivan, J. P.; Carroll, W. Bioorg. Med. Chem. Lett. 2002, 12, 1481.
[13] Nagai, S.-I.; Ueda, T.; Sugiura, S.; Nagatsu, A.; Murakami,
N.; Sakakibara, J.; Fujita, M.; Hotta, Y. J. Heterocycl. Chem. 1998, 35,
325.
[14] Ahmed, E.; Ameen, M.; Abdel-latif, F. Phosphorus, Sulfur
Silicon Relat. Elem. 2006, 181, 497.
[15] Sharma, R. L.; Kumar, S.; Sachar, A.; Singh, J.; Kour, D.
Indian J. Heterocycl. Chem. 2005, 15, 101.
Ethyl 5-methyl-7-(3-nitrophenyl)-4,7-dihydrotetrazolo[1,5-
a]pyrimidine-6-carboxylate (4v). ir (potassium bromide):
3182, 3090, 2924, 1720, 1654, 1578, 1534, 1475, 1443, 1348,
1309, 1277, 1261, 1225, 1141, 1119, 1099, 1075, 1020, 989,
808, 774, 737, 716, 675 cm-1; 1H nmr (DMSO-d6): ꢀ 1.00 (t, J =
6.8 Hz, 3H, OCH2CH3), 2.47 (s, 3H, 5-methyl-H), 3.95 (q, J =
6.8 Hz, 2H, OCH2CH3), 6.90 (s, 1H, CH), 7.66 (s, 1H, ArH),
7.78 (s, 1H, ArH), 8.22 (s, 2H, ArH), 11.45 (s, 1H, NH). Anal.
Calcd. for C14H14N6O4: C, 50.91; H, 4.27; N, 25.44. Found: C,
50.88; H, 4.38; N, 25.56.
[16] Abdelhamid, A. O.; Al-Atoom, A. A. Phosphorus, Sulfur
Silicon Relat. Elem. 2005, 180, 1629.
Ethyl 4,7-dihydro-5-methyl-7-phenyltetrazolo[1,5-a]-
pyrimidine-6-carboxylate (4w). ir (potassium bromide): 3180,
3094, 2943, 1712, 1592, 1525, 1429, 1342, 1259, 1234, 1221,
1128, 1119, 1105, 1082, 1022, 988, 812, 780, 746, 716, 652
cm-1; 1H nmr (DMSO-d6): ꢀ 1.00 (t, J = 6.8 Hz, 3H, OCH2CH3),
2.45 (s, 3H, 5-methyl-H), 3.91 (q, J= 6.8Hz, 2H, OCH2CH3),
6.95 (s, 1H, CH), 7.26 (s, 1H, ArH), 7.60 (s, 1H, ArH), 7.88 (s,
1H, ArH), 8.25 (s, 2H, ArH), 11.44 (s, 1H, NH). Anal. Calcd. for
C14H15N5O2: C, 58.94; H, 5.30; N, 24.55. Found: C, 58.92; H,
5.34; N, 24.58.
[17] Abdel-Hafez, S. H., Russ. J. Org. Chem. 2005, 41, 396.
[18] Chebanov, V. A.; Sakhno, Y. I.; Desenko, S. M.; Shishkina,
S. V.; Musatov, V. I.; Shishkin, O. V.; Knyazeva, I. V. Synthesis 2005,
2597.
[19] Pryadeina, M. V.; Burgart, Y. V.; Saloutin, V. I.; Kodess, M.
I.; Ulomskii, E. N.; Rusinov, V. L. Russ. J. Org. Chem. 2004, 40, 902.
[20] Gein, V. L.; Gein, L. F.; Tsyplyakova, E. P.; Rozova, E. A.
Russ. J. Org. Chem. 2003, 39, 753.
[21] Fedorova, O. V.; Zhidovinova, M. S.; Rusinov, G. L.;
Ovchinnikova, I. G. Russ. Chem. Bull. 2003, 52, 1768.
[22] Desenko, S. M.; Gladkov, E. S.; Sirko, S. N.; Khanetskiy, B.
B. Visnik Kharkivs'kogo Natsional'nogo Universitetu im. V. N. Karazina
2003, 596, 56.
[23] Metwally, M. A.; Abdel-Mogib, M. Heterocycl. Commun.
1999, 5, 423.
[24] Chebanov, V. A.; Desenko, S. M.; Sakhno, Y. I.; Panchenko,
E. S.; Saraev, V. E.; Musatov, V. I.; Konev, V. F. Fiziol. Akt. Rechovini.
2002, 10-13.
[25] Desenko, S. M.; Gladkov, E. S.; Komykhov, S. A.; Shishkin,
O. V.; Orlov, V. D. Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2001,
37, 747.
[26] Metwally, M. A.; El-Hussiny, M. S.; El-Ablak, F. Z.; Khalil,
A. M. Pharmazie 1989, 44, 261.
Acknowledgement. We are thankful to the National Natural
Science Foundation of China (No. 20672090), the Nature
Science Foundation of the Jiangsu Province (No. BK2006033),
Six Kinds of Professional Elite Foundation of the Jiangsu
Province (No. 06-A-039), the Natural Science Foundation of
Xuzhou City (No. XJ07065) for financial support.
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[31] The single-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was was performed using a
Rigaku Saturn diffractometer. Crystal data for 4c: C13H12BrN5O2, crystal
dimension 0.16 x 0.14 x 0.10 mm, Monoclinic, space group P21/c, a =
17.907(2), b = 10.1825(12), c = 7.5055(3) Å, ꢀ = 92.166 (6)ꢀ, V =
1367.6(3) Å3, Mr = 350.19, Z = 4, Dc = 1.701 g/cm3, ꢀ = 0.71070 Å, μ
(Mokꢁ) = 3.018mm-1, F(000) = 704, S = 0.992, R1= 0.0350, wR2
=
[9] Aly, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181,
1285.
0.0832