Ionic liquid-mediated one-pot synthesis of 5-(trifluoromethyl)-4,7- dihydrotetrazolo-[1,5-a]pyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2011.566460

(Chemical Equation Presented) A facile one-pot synthesis of 5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5- a]pyrimidine derivatives is described via a three-component reaction of aldehydes with 5-aminotetrazole and ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-trifluoro-1-phenylbutane- 1,3-dione in ionic liquid. This method has the advantages of short synthetic route, operational simplicities, good yields, ecofriendliness, and recyclability of the solvent. Copyright Taylor & Francis Group, LLC.

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Ionic Liquid–Mediated One-Pot
Synthesis of 5-(Trifluoromethyl)-4,7-
dihydrotetrazolo[1,5-a]pyrimidine
Derivatives
Tuan-Jie Li a , Chang-Sheng Yao a , Chen-Xia Yu a , Xiang-Shan Wang a
& Shu-Jiang Tu a
a School of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou Jiangsu, P. R. China
Accepted author version posted online: 31 Oct 2011.Version of
record first published: 29 May 2012.
To cite this article: Tuan-Jie Li, Chang-Sheng Yao, Chen-Xia Yu, Xiang-Shan Wang & Shu-Jiang Tu
(2012): Ionic Liquid–Mediated One-Pot Synthesis of 5-(Trifluoromethyl)-4,7-dihydrotetrazolo[1,5-
a]pyrimidine Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:18, 2728-2738
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Synthetic Communications1, 42: 2728–2738, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.566460
IONIC LIQUID–MEDIATED ONE-POT SYNTHESIS
OF 5-(TRIFLUOROMETHYL)-4,7-DIHYDROTETRAZOLO-
[1,5-a]PYRIMIDINE DERIVATIVES
Tuan-Jie Li, Chang-Sheng Yao, Chen-Xia Yu,
Xiang-Shan Wang, and Shu-Jiang Tu
School of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou Jiangsu, P. R. China
GRAPHICAL ABSTRACT
Abstract
A facile one-pot synthesis of 5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5-
a]pyrimidine derivatives is described via a three-component reaction of aldehydes with
5-aminotetrazole and ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-trifluoro-1-phenylbu-
tane-1,3-dione in ionic liquid. This method has the advantages of short synthetic route, oper-
ational simplicities, good yields, ecofriendliness, and recyclability of the solvent.
Keywords Cyclization; ionic liquid; tetrazolo[1,5-a]pyrimidine; trifluoromethylated
INTRODUCTION
In the past, ionic liquids as environmentally benign reaction media have been
used in many organic transformations because of their many fascinating properties
such as nonvolatility, recyclability, and nonflammability, and they offer homogenous
media. On the other hand, multicomponent reactions (MCRs)[1] have been an
increasingly valuable approach to drug-like heterocyclic compounds because of their
intrinsic convergence, operational simplicity, and energy efficiency. Many proce-
dures for the synthesis of heterocyclic compounds via MCRs in ionic liquids were
well documented in the literature.[2]
Received August 29, 2010.
Address correspondence to Chang-Sheng Yao, School of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou Jiangsu 221116, P. R. China. E-mail: csyao@xznu.edu.cn
2728

5-TRIFLUOROMETHYLATED TETRAZOLO[1,5-a]PYRIMIDINE
2729
Compounds with the tetrazolo[1,5-a]pyrimidine core unit are known to exhi-
bit various biological activities, such as antimicrobial activity,[3] anticonvulsant and
antidepressant activities,[4] and antituberculosis activity.[5] They are also used as
late sodium channel blockers,[6] transforming growth factor-b type I receptor
(ALK5) inhibitors,[7] and human neutrophil elastase inhibitors in the treatment of
pulmonary and cardiovascular diseases.[8] Hence, the synthesis of tetrazolo[1,5-
a]pyrimidine derivatives is of considerable interest for both organic chemistry
and medicinal chemistry.
The introduction of a trifluoromethyl group into organic molecules often
changes their physical, chemical, and physiological properties, which might result
in an entirely new complementary biological activity. Subsequently, the interest of
the pharmaceutical industry in trifluoromethyl-containing compounds has grown
significantly.[9] Although many tetrazolo[1,5-a]pyrimidine derivatives were prepared
by the Biginelli-like reactions of aromatic aldehyde and 5-aminotetrazole with acet-
oacetic acid derivatives or cyclic b-diketones,[10] only limited publications have
been devoted to the synthesis of trifluoromethylated tetrazolo[1,5-a]pyrimidine.
Pryadeina et al.[11] and Abelman et al.[12] respectively reported the syntheses of
5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine derivatives via the reac-
tions of ethyl 4,4,4-trifluoro-3-oxobutanoate with aldehyde and 5-aminotetrazole.
In their procedures, the cyclocondensations were realized by using corrosive hydro-
chloric acid and p-toluenesulfonic acid[11] and Et3N[12] as catalysts, respectively. Fur-
thermore, these reactions required harmful organic solvents and have some
drawbacks such as tedious workup, poor yields, the narrow application scope of sub-
strates, and two-stage routines. Therefore, the development of simple, convenient,
and environmentally benign approaches for the synthesis of these compounds is still
desirable.
However, to date, the preparation of 5-(trifluoromethyl)-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine derivatives by MCRs in ionic liquids was seldom
described. With the aim of broadening the diversity of the heterocyclic compound
library and in continuation of our recent interest in the synthesis of heterocyclic com-
pounds via MCRs in ionic liquids,[13,2c,2d] herein we report an efficient and simple
procedure for the direct synthesis of 5-(trifluoromethyl)-7-aryl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidine derivatives from the one-pot reaction of aldehydes with 5-ami-
notetrazole and ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-trifluoro-1-
phenylbutane-1,3-dione in ionic liquid (Scheme 1).
Scheme 1. Three-component synthesis of 5-(trifluoromethyl)-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine
derivatives.

2730
T.-J. LI ET AL.
RESULTS AND DISCUSSION
To search for the optimal solvent, the reaction of 4-bromobenzaldehyde
(1 mmol) with 5-aminotetrazole (1 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate
(1 mmol) was examined in different solvents at 100 ꢀC. The results in Table 1 show
that the [bmimþ][BFꢁ4 ] is the best solvent for the synthesis of target product 4aa
among those examined. Thus, to further evþaluate the effect of reaction temperature,
the same reaction was performed in [bmim ][BFꢁ4 ] at temperatures ranging from 80
to 130 ꢀC, with an increment of 10 ꢀC each time. The results are summarized in
Table 2. From the results, it can be seen that the yield of product 4aa was increased,
and the reaction time was shortened with the temperature increasing from 80 to
110 ꢀC, whereas the yield was significently decreased when the temperature was
further increased to 120 and 130 ꢀC. Therefore, 110 ꢀC was chosen as optimal reac-
tion temperature for all further MCR reactions in ionic liquid.
Under these optimized reaction conditions ([bmimþ][BF4ꢁ], 110 ꢀC), various kinds
of benzaldehydes were reacted with
2 and 3 to give the corresponding
5-(trifluoromethyl)-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine derivatives 4, and rep-
resentative examples are shown in Table 3 (4aa–4al). To expand the scope of this
method, the replacement of ethyl 4,4,4-trifluoro-3-oxobutanoate with 4,4,4-trifluoro-1-
phenylbutane-1,3-dione was examined. To our delight, the reactions proceeded steadily
to yield a series of new tetrazolo[1,5-a]pyrimidine compounds 4ba–4bg (Table 3) with
good yields at 80ꢀC. The results reveal that all of the benzaldehydes gave expected
Table 1. Solvent effect on the synthesis of 4aaa
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
[bypþ][BFꢁ4 ]
[bmimþ][BFꢁ4 ]
CH3CN
EtOH
7
7
9
7
8
8
79
85
75
73
68
70
HOAc
DMF
a[bypþ][BFꢁ4 ],1-butylpyridinium tetrafluoroborate, [bmimþ][BFꢁ4 ], 3-butyl-1-
methyl-1H-imidazol-3-ium tetrafluoroborate.
bIsolated yield.
Table 2. Temperature effect on the synthesis of 4aaa
Entry
Temp. (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
80
90
10
9
73
77
85
89
81
78
100
110
120
130
7
7
6
6
a[bmimþ][BFꢁ4 ] was used as solvent.
bIsolated yield.

5-TRIFLUOROMETHYLATED TETRAZOLO[1,5-a]PYRIMIDINE
Table 3. Synthesis of 4 in ionic liquid ([bmimþ][BF4ꢁ])
2731
Products
Ar
R
Time (h)
Yielda (%)
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4-BrC6H4
2,4-Cl2C6H3
3-FC6H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
C6H5
7
8
8
7
8
8
7
8
7
8
8
9
9
8
8
7
7
8
9
89
85
85
80
79
86
85
84
87
81
88
85
82
83
86
81
80
81
78
3-OH-4-NO2C6H3
4-N(CH3)2C6H4
2-FC6H4
3-BrC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4aj
4ak
4ba
4bb
4bc
4bd
4be
4bf
4bg
4bh
4-NO2C6H4
4-NO2C6H4
3,4-(OCH2O)C6H3
3-FC6H4
C6H5
C6H5
3-BrC6H4
2-ClC6H4
C6H5
C6H5
2-FC6H4
3-NO2C6H4
3,4,5-(CH3O)3C6H3
C6H5
C6H5
C6H5
aIsolated yield.
products in good yields, either bearing electron-withdrawing groups (such as halide,
nitro) or electron-donating groups (such as alkyl group, alkoxyl group) under the same
reaction conditions. Therefore we concluded that the electronic nature of the substitu-
ents has no significant effects on this reaction. The structure of the products 4aa was
established by x-ray crystallographic analysis, as shown in Fig. 1.
Figure 1. Crystal structure of 4ap.

2732
T.-J. LI ET AL.
Table 4. Study on the reuse of ionic liquid ([bmimþ][BF4ꢁ])
Round
4aa yielda (%)
1
2
3
4
89
86
84
80
aIsolated yield.
To test the recyclability of the reaction solvent ([bmimþ][BF4ꢁ]), after com-
pletion of the model reaction of 4-bromobenzaldehyde, 5-aminotetrazole, and ethyl
4,4,4-trifluoro-3-oxobutanoate, the mixture was cooled to room temperature and
poured into water, and precipitated products were separated by filtration. The fil-
trate was washed with acetic ester, concentrated under reduced pressure, and dried
in vacuo at 100 ꢀC for several hours to obtain the reusable solvent. The obtained sol-
vent was used in subsequent reactions with a modest loss in its efficiency (Table 4).
In summary, we report here a facile, one-pot, three-component synthesis of
5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine derivatives from readily
available aldhyde, 5-aminotetrazole, and ethyl 4,4,4-trifluoro-3-oxobutanoate or
4,4,4-trifluoro-1-phenylbutane-1,3-dione in ionic liquid. This method has the advan-
tages of short synthetic route, operational simplicities, good yields, ecofriendliness,
and the recyclability of the solvent.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Tensor 27 spectrophotometer in KBr
pellets and are reported in terms of frequency of absorption (cmꢁ1). 1H NMR spec-
tra were recorded on a Bruker DPX 400 instrument; elemental analyses were deter-
mined by using a Perkin-Elmer 240c elemental analysis instrument. Melting points
were determined in open capillaries and are uncorrected. The single-crystal diffrac-
tion data were gathered on a Rigaku Saturn diffractometer.
General Procedure for the Synthesis of Ethyl
5-(Trifluoromethyl)-4,7-dihydro-7-aryltetrazolo[1,5-
a]pyrimidine-6-carboxylate and (5-(Trifluoromethyl)-4,7-
dihydro-7-aryltetrazolo[1,5-a]pyrimidin-6-yl)(phenyl)methanone (4)
AryL aldehyde 1 (1.0 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-
trifluoro-1-phenylbutane-1,3-dion 2 (1.0 mmol), and 5-aminotetrazole 3 (1.0 mmol)
were mixed in 3 mL[bmimþ][BF4ꢁ] and stirred for a certain time (monitored by
thin-layer chromatography, TLC) at 110 ꢀC or 80 ꢀC. The mixture was cooled to
room temperature and poured into 20 mL of water. The solid product was collected
by filtration and recrystallized from ethanol to give the pure compound 4. The fil-
trate was washed with acetic ester several times, concentrated under reduced press-
ure, and dried in vacuo at 100 ꢀC for several hours to give the reusable solvent.

5-TRIFLUOROMETHYLATED TETRAZOLO[1,5-a]PYRIMIDINE
2733
Ethyl 7-(4-Bromophenyl)-5-(trifluoromethyl)-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxylate 4aa
Pale white crystals, mp 230–232 ꢀC. IR (KBr): 3190, 3064, 2979, 2926, 1736,
1650, 1588, 1488, 1440, 1408, 1344, 1283, 1257, 1177, 1101, 1072, 1012, 999, 835,
1
772, 735, 704, 644 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t, J ¼ 7.2 Hz, 3H,
CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.83 (s, 1H, CH), 7.35 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.62 (d, J ¼ 8.4 Hz, 2H, ArH), 12.08 (br, 1H, NH). Anal. calcd. for
C14H11BrF3N5O2: C, 40.21; H, 2.65; N, 16.75. Found: C, 40.33; H, 2.77; N, 16.57.
Ethyl 7-(2,4-Dichlorophenyl)-5-(trifluoromethyl)-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxylate 4ab
Pale white crystals, mp 206–207ꢀC. IR (KBr): 3172, 3064, 2966, 1737, 1709, 1594,
1561, 1475, 1433, 1371, 1342, 1290, 1056, 1194, 1104, 1051, 996, 863, 848, 761, 732, 699,
1
667, 637 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t, J¼ 7.2 Hz, 3H, CH3), 4.00 (q,
J ¼ 6.8 Hz, 2H, CH2), 7.15 (s, 1H, CH), 7.52 (d, J ¼ 8.0 Hz, 1H, ArH), 7.61 (d,
J ¼ 8.0 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 12.12 (br, 1H, NH). Anal. calcd. for
C14H10Cl2F3N5O2: C, 41.20; H, 2.47; N, 17.16. Found: C, 41.11; H, 2.36; N, 17.21.
Ethyl 5-(Trifluoromethyl)-7-(3-fluorophenyl)-
4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4ac
Pale white crystals, mp 195–196 ꢀC. IR (KBr): 3173, 3069, 2988, 2931, 1715,
1607, 1558, 1489, 1469, 1454, 1435, 1374, 1339, 1308, 1259, 1232, 1189, 1164,
1
1084, 1017, 996, 918, 866, 804, 791, 758, 692, 648 cmꢁ1; H NMR (DMSO-d6) (d,
ppm): 1.00 (t, J ¼ 7.2 Hz, 3H, CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.85 (s, 1H,
CH), 7.32–7.29 (m, 2H, ArH), 7.48 (d, J ¼ 7.2 Hz, 2H, ArH), 12.06 (br,1H, NH).
Anal. calcd. for C14H11F4N5O2: C, 47.07; H, 3.10; N, 19.60. Found: C, 47.10; H,
3.17; N, 19.54.
Ethyl 5-(Trifluoromethyl)-4,7-dihydro-7-(3-hydroxy-4-
nitrophenyl)tetrazolo [1,5-a]pyrimidine-6-carboxylate 4ad
Pale white crystals, mp 211–213 ꢀC. IR (KBr): 3180, 3071, 2963, 1716, 1610,
1543, 1489, 1470, 1452, 1425, 1311, 1256, 1194, 1108, 1086, 1084, 996, 920, 843,
825, 791, 760, 688, 675, 646 cmꢁ1; 1H NMR (DMSO-d6) (d, ppm): 1.00 (t, J ¼ 7.2 Hz,
Hz, 3H, CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.87 (s, 1H, CH), 7.20 (s, 1H, ArH), 7.52
(s, 1H, ArH), 8.00 (s, 1H, ArH), 9.62 (s, 1H, OH), 12.04 (br, 1H, NH). Anal. calcd. for
C14H11F3N6O5: C, 42.01; H, 2.77; N, 21.00. Found: C, 42.12; H, 2.68; N, 21.10.
Ethyl 7-(4-(Dimethylamino)phenyl)-5-(trifluoromethyl)-
4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4ae
Pale white crystals, mp 211–213 ꢀC. IR (KBr): 3173, 3062, 2950, 2021,1721,
1602, 1561, 1532, 1476, 1442, 1425, 1365, 1341, 1292, 1250, 1196, 1105, 1087, 994,
1
873, 816, 785, 740, 704, 648, 627 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t,

2734
T.-J. LI ET AL.
J ¼ 7.2 Hz, 3H, CH3), 2.94 (s, 6H, N(CH3)2), 4.00 (q, J ¼ 7.6 Hz, 2H, CH2), 6.63 (s,
1H,CH), 7.00 (d, J ¼ 8.0 Hz, 2H, ArH), 7.25 (d, J ¼ 8.0 Hz, 2H, ArH), 11.52 (br, 1H,
NH). Anal. calcd. for C16H17F3N6O2: C, 50.26; H, 4.48; N, 21.98. Found: C, 50.31;
H, 4.31; N, 21.87.
Ethyl 5-(Trifluoromethyl)-7-(2-fluorophenyl)-
4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4af
Pale white crystals, mp 163–164 ꢀC. IR (KBr): 3175, 3072, 2984, 2861, 1717,
1612, 1556, 1494, 1459, 1434, 1371, 1307, 1254, 1235, 1194, 1164, 1098, 1084, 993,
1
956, 881, 859, 787, 759, 730, 702, 686, 644 cmꢁ1; H NMR (DMSO-d6) (d, ppm):
1.00 (t, J ¼ 7.2 Hz, 3H, CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.99 (s, 1H, CH),
7.11–7.17 (m, 2H, ArH), 7.32–7.37 (m, 2H, ArH), 11.96 (br, 1H, NH). Anal. calcd.
for C14H11F4N5O2: C, 47.07; H, 3.10; N, 19.60. Found: C, 47.11; H, 3.21; N, 19.56.
Ethyl 7-(3-Bromophenyl)-5-(trifluoromethyl)-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4ag
Pale white crystals, mp 219–220 ꢀC. IR (KBr): 3176, 3067, 2976, 2936, 1730,
1602, 1562, 1478, 1434, 1366, 1346, 1287, 1252, 1165, 1143, 1105, 1091, 1018, 996,
1
886, 797, 776, 736, 723, 693, 670, 652 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00
(t, J ¼ 7.2 Hz, 3H, CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.84 (s, 1H, CH),
7.35–7.39 (m, 2H, ArH), 7.59–7.64 (m, 1H, ArH), 7.68 (s, 1H, ArH), 11.99 (br,
1H, NH). Anal. calcd. for C14H11BrF3N5O2: C, 40.21; H, 2.65; N, 16.75. Found:
C, 40.18; H, 2.71; N, 16.73.
Ethyl 5-(Trifluoromethyl)-7-(4-fluorophenyl)-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4ah
Pale white crystals, mp 206–208 ꢀC. IR (KBr): 3217, 3065, 2994, 2934, 1735,
1609, 1561, 1513, 1468, 1433, 1343, 1290, 1239, 1202, 1160, 1102, 1082, 999, 878,
1
837, 784, 735, 704, 642 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t, J ¼ 8.0 Hz,
3H, CH3), 4.00 (q, J ¼ 7.6 Hz, 2H, CH2), 6.79 (s, 1H, CH), 7.06–7.10 (m, 2H,
ArH), 7.37 (d, J ¼ 8.0 Hz, 2H, ArH), 11.78 (br, 1H, NH). Anal. calcd. for
C14H11F4N5O2: C, 47.07; H, 3.10; N, 19.60. Found: C, 47.11; H, 3.07; N, 19.55.
Ethyl 7-(2-Chlorophenyl)-5-(trifluoromethyl)-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate 4ai
Pale white crystals, mp 160–162 ꢀC. IR (KBr): 3195, 3062, 2981, 1740, 1600,
1566, 1476, 1440, 1394, 1343, 1289, 1251, 1168, 1103, 1050, 1021, 995, 869, 797,
1
754, 734, 707, 680, 651 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t, J ¼ 8.0 Hz,
3H, CH3), 4.00 (q, J ¼ 7.6 Hz, 2H, CH2), 7.18 (s, 1H, CH), 7.29–7.32 (m, 2H,
ArH), 7.74–7.78 (m, 2H, ArH), 11.92 (br, 1H, NH). Anal. calcd. for
C14H11ClF3N5O2: C, 44.99; H, 2.97; N, 18.74. Found: C, 44.87; H, 2.83; N, 18.85.

5-TRIFLUOROMETHYLATED TETRAZOLO[1,5-a]PYRIMIDINE
2735
Ethyl 7-(3-Chlorophenyl)-5-(trifluoromethyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxylate 4aj
Pale white crystals, mp 203–204 ꢀC. IR (KBr): 3177, 3068, 2978, 2937, 1731,
1603, 1562, 1480, 1438, 1393, 1368, 1347, 1288, 1253, 1164, 1143, 1105, 1020, 996,
1
891, 867, 798, 777, 737, 694, 652 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t,
J ¼ 8.0 Hz, 3H, CH3), 4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 6.77 (s, 1H, CH), 7.28 (s, 1H,
ArH), 7.35–7.38 (m, 3H, ArH), 11.59 (br, 1H, NH). Anal. calcd for
C14H11ClF3N5O2: C, 44.99; H, 2.97; N, 18.74. Found: C, 44.85; H, 2.81; N, 18.96.
Ethyl 5-(Trifluoromethyl)-4,7-dihydro-7-(4-nitrophenyl)tetrazolo-
[1,5-a]pyrimidine-6-carboxylate 4ak
Pale white crystals, mp 216–217 ꢀC. IR (KBr): 3189, 3064, 2984, 1735, 1649,
1590, 1530, 1439, 1351, 1286, 1244, 1179, 1145, 1101, 1021, 999, 824, 780, 750,
1
725, 691, 649 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 1.00 (t, J ¼ 7.2 Hz, 3H, CH3),
4.00 (q, J ¼ 6.8 Hz, 2H, CH2), 7.03 (s, 1H, CH), 7.72 (d, J ¼ 8.4 Hz, 2H, ArH),
8.26 (d, J ¼ 8.4 Hz, 2H, ArH), 12.10 (br,1H, NH). Anal. calcd. for C14H11F3N6O4:
C, 43.76; H, 2.89; N, 21.87. Found: C, 43.63; H, 2.78; N, 21.75.
(5-(Trifluoromethyl)-4,7-dihydro-7-(4-nitrophenyl)tetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4ba
Pale white crystals, mp 215–217 ꢀC. IR (KBr): 3184, 3089, 2849, 1673, 1597,
1531, 1451, 1432, 1400, 1349, 1284, 1255, 1198, 1175, 1146, 1088, 1000, 823, 760,
1
734, 697, 615 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 6.83 (s, 1H, CH), 7.42–7.39
(m, 5H, ArH), 7.66 (d, J ¼ 7.6 Hz, 2H, ArH), 8.16 (d, J ¼ 7.6 Hz, 2H, ArH), 12.10
(br, 1H, NH). Anal. calcd. for C18H11F3N6O3: C, 51.93; H, 2.66; N, 20.19. Found:
C, 51.81; H, 2.71; N, 20.25.
(7-(Benzo[d][1,3]dioxol-5-yl)-5-(trifluoromethyl)-
4,7-dihydrotetrazolo[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bb
Pale white crystals, mp 231–232 ꢀC. IR (KBr): 3178, 3065, 2873, 1662, 1622,
1565, 1501, 1449, 1407, 1351, 1312, 1272, 1206, 1125, 1086, 1039, 998, 928, 802,
749, 655, 629 cmꢁ1;1H NMR (DMSO-d6) (d, ppm): 5.98 (d, J ¼ 6.4 Hz, 2H, OCH2O),
6.65 (dd, J ¼ 8.01, 1.29 Hz, 1H, ArH), 6.70 (s, 1H, CH), 6.79 (d, J ¼ 8.0 Hz, 1H,
ArH), 6.84 (d, J ¼ 1.2 Hz, 1H, ArH), 7.50 (t, J ¼ 7.6 Hz, 2H, ArH), 7.67 (t,
J ¼ 7.2 Hz, 1H, ArH), 7.88 (d, J ¼ 7.6 Hz, 2H, ArH), 12.04 (br, 1H, NH). Anal.
calcd. for C19H12F3N5O3: C, 54.95; H, 2.91; N, 16.86. Found: C, 54.87; H, 2.83;
N, 16.95.
(5-(Trifluoromethyl)-7-(3-fluorophenyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bc
Pale white crystals, mp 246–248 ꢀC. IR (KBr): 3171, 3115, 3060, 2929, 2854,
1678, 1660, 1555, 1500, 1438, 1407, 1354, 1342, 1277, 1265, 1180, 1135, 1041, 991,

2736
T.-J. LI ET AL.
791, 694, 616 cmꢁ1; 1H NMR (DMSO-d6) (d, ppm): 6.84 (s, 1H, CH), 7.21–7.29 (m,
2H, ArH), 7.46–7.55 (m, 4H, ArH), 7.66 (t, J ¼ 8.0 Hz, 1H, ArH), 7.89 (d, J ¼ 7.2 Hz,
2H, ArH), 12.00 (br, 1H, NH). Anal. calcd. for C18H11F4N5O: C, 55.53; H, 2.85; N,
17.99. Found: C, 55.47; H, 2.71; N, 18.12.
(7-(3-Bromophenyl)-5-(trifluoromethyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bd
Pale white crystals, mp 229–230ꢀC. IR (KBr): 3172, 3062, 2932, 2857, 1662, 1658,
1523, 1487, 1457, 1355, 1326, 1279, 1265, 1219, 1135, 1088, 996, 792, 697, 686,
1
624 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 6.84 (s, 1H, CH), 7.05 (d, J¼ 8.0 Hz, 1H,
ArH), 7.20–7.10 (m, 2H, ArH), 7.31–7.37 (m, 1H, ArH), 7.48 (t, J¼ 8.0 Hz, 2H, ArH),
7.66 (t, J¼ 7.2 Hz, 1H, ArH), 7.87 (d, J¼ 7.6 Hz, 2H, ArH), 12.00 (br, 1H, NH). Anal.
calcd. for C18H11BrF3N5O: C, 48.02; H, 2.46; N, 15.56. Found: C, 48.11; H, 2.32; N, 15.61.
(7-(2-Chlorophenyl)-5-(trifluoromethyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4be
Pale white crystals, mp 198–199 ꢀC. IR (KBr): 3215, 3175, 3018, 2861, 1661,
1608, 1561, 1477, 1449, 1355, 1341, 1315, 1281, 1244, 1201, 1181, 1153, 1088, 995,
1
921, 846, 814, 769, 757, 719, 703, 687, 634 cmꢁ1; H NMR (DMSO-d6) (d, ppm):
7.10 (s, 1H, CH), 7.28 (s, 2H, ArH), 7.32–7.36(m, 1H, ArH), 7.40 (d, J ¼ 8.0 Hz,
1H, ArH), 7.50 (t, J ¼ 7.6 Hz, 2H, ArH), 7.67 (t, J ¼ 7.2 Hz, 1H, ArH), 7.89 (d,
J ¼ 7.6 Hz, 2H, ArH), 12.16 (br, 1H, NH). Anal. calcd. for C18H11ClF3N5O: C,
53.28; H, 2.73; N, 17.26. Found: C, 53.19; H, 2.69; N, 17.35.
(5-(Trifluoromethyl)-7-(2-fluorophenyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bf
Pale white crystals, mp 192–194 ꢀC. IR (KBr): 3173, 3068, 2856, 1656, 1605,
1558, 1494, 1459, 1450, 1341, 1319, 1234, 1200, 1098, 1086, 890, 846, 762, 694,
1
635 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 6.98 (s, 1H, CH), 7.11–7.19 (m, 2H,
ArH), 7.24–7.28(m, 1H, ArH), 7.36–7.43(m, 1H, ArH), 7.50(t, J ¼ 7.6 Hz, 2H,
ArH), 7.67 (t, J ¼ 7.2 Hz, 1H, ArH), 7.88(d, J ¼ 7.2 Hz, 2H, ArH), 12.00(br, 1H,
NH). Anal. calcd. for C18H11F4N5O: C, 55.53; H, 2.85; N, 17.99. Found: C,
55.61; H, 2.77; N, 18.03.
(5-(Trifluoromethyl)-4,7-dihydro-7-(3-nitrophenyl)tetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bg
Pale white crystals, mp 234–236 ꢀC. IR (KBr): 3170, 3069, 2930, 2877, 1683,
1657, 1608, 1539, 1482, 1450, 1422, 1353, 1281, 1264, 1199, 1166, 1085, 999, 932,
1
908, 931, 821, 809, 754, 733, 696, 684, 625 cmꢁ1; H NMR (DMSO-d6) (d, ppm):
7.08 (s, 1H, CH), 7.48 (t, J ¼ 8.0 Hz, 2H, ArH), 7.60–7.68 (m, 2H, ArH), 7.76 (d,
J ¼ 7.6 Hz, 1H, ArH), 7.90 (d, J ¼ 7.6 Hz, 2H, ArH), 8.14–8.17(m, 1H, ArH), 8.20
(t, J ¼ 1.6 Hz, 1H, ArH), 11.89 (br, 1H, NH). Anal. calcd. for C18H11F3N6O3: C,
51.93; H, 2.66; N, 20.19. Found: C, 51.81; H, 2.59; N, 20.27.

5-TRIFLUOROMETHYLATED TETRAZOLO[1,5-a]PYRIMIDINE
2737
(5-(Trifluoromethyl)-7-(3,4,5-trimethoxyphenyl)-4,7-dihydrotetrazolo-
[1,5-a]pyrimidin-6-yl)(phenyl)methanone 4bh
Pale white crystals, mp 231–232 ꢀC. IR (KBr): 3181, 3061, 2938, 2840, 1655,
1618, 1560, 1508, 1466, 1426, 1350, 1330, 1282, 1239, 1186, 1126, 1085, 1010, 820,
1
753, 653, 632 cmꢁ1; H NMR (DMSO-d6) (d, ppm): 3.53 (s, 3H, OCH3), 3.61 (s,
6H, 2 ꢂ OCH3), 6.50 (s, 1H, CH), 6.89 (s, 2H, ArH), 7.46 (t, J ¼ 8.0 Hz, 2H,
ArH), 7.63 (t, J ¼ 8.0 Hz, 1H, ArH), 7.87 (d, J ¼ 8.0 Hz, 2H, ArH), 11.84 (br, 1H,
NH). Anal. calcd. for C21H18F3N5O4: C, 54.67; H, 3.93; N, 15.18. Found: C,
54.55; H, 3.84; N, 15.28.
X-Ray Crystallography for 4aa
Empirical formula C14H11BrF3N5O2, FW ¼ 418.19, T ¼ 113(2) K, monoclinic,
˚
˚
˚
˚
space group P 1 21=c 1, a ¼ 18.773(2) A, b ¼ 10.4716(11) A, c ¼ 7.8700(8) (4) A,
3
3
ꢀ
˚
b ¼ 92.27(3) , V ¼ 1545.9(3) A , Z ¼ 4, Dc ¼ 1.797 Mg=m , k(MoKa) ¼ 0.71073 A,
m ¼ 2.713 mmꢁ1
,
F(000) ¼ 832. 2.17 ꢀ <h < 27.86 ꢀ, R ¼ 0ꢁ.03295, wR ¼ 0.0714.
˚
S ¼ 0.941, Largest diff. Peak and hole: 0.431 and ꢁ0.823 e ꢃ A
.
ACKNOWLEDGMENTS
We are grateful for financial support by the Natural Science Foundation of
China (Nos. 20672090 and 200810102050), the Major Basic Research Project of
the Natural Science Foundation of the Jiangsu Higher Education Institutions
(09KJA430003), the Natural Science Foundation of Xuzhou City (XM09B016),
the Graduate Foundation of Xuzhou Normal University (09YLB030), and the Qing
Lan Project (08QLT001).
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