8
S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
(E)-2-ethoxycarbonyl-3-(2-naphthyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylate (E-50d): 1H NMR (400 MHz, DMSO-d6)
0.86 (t,
1324, 1294, 1253, 1143, 1090, 1071, 1013, 990 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
d
1.12 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz, 3H,
J¼7.1 Hz, 3H, Me), 3.85 (q, J¼7.1 Hz, 2H, CH2O), 7.12 (dd, J¼8.5,
1.6 Hz, 1H, H-3), 7.42e7.46 (m, 2H, H-6, H-7), 7.49 (s, 1H, H-1), 7.71
(d, J¼8.6 Hz, 1H, H-4), 7.73e7.77 (m, 1H, H-5/8), 7.80e7.84 (m, 1H,
Me), 4.14 (q, J¼7.1 Hz, 2H, CH2O), 4.17 (q, J¼7.1 Hz, 2H, CH2O), 7.17
(d, J¼8.6 Hz, 2H, Ar), 7.32 (d, J¼8.6 Hz, 2H, Ar), 7.80e11.20 (br s, 1H,
NH); 19F NMR (471 MHz, CDCl3)
d
ꢁ61.4 (s, CF3); 13C NMR (126 MHz,
H-8/5); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ55.0 (s, CF3).
CDCl3)
d
13.7, 13.8, 62.3, 62.4, 120.5 (q, 1JC,F¼269.2 Hz, CF3), 129.0,
129.8, 131.9, 135.1, 136.5, 136.7 (q, 2JC,F¼39.4 Hz), 140.8, 142.6, 163.8,
165.1. Anal. Calcd for C17H15ClF3N3O4: C, 48.87; H, 3.62; N, 10.06.
Found: C, 48.70; H, 3.62; N, 9.99.
4.5.5. (E)-2-Ethoxycarbonyl-3-p-tolyl-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (E-5e). Yield 91% (6 h), mp 199e201 ꢀC. IR
(ATR): 3241, 1717, 1673, 1623, 1605, 1526, 1508, 1450, 1408, 1374,
1314, 1300, 1245, 1223 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.04 (t,
4.6.3. Diethyl
(2-naphthyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)
J¼7.1 Hz, 3H, Me), 2.31 (s, 3H, Me), 4.09 (q, J¼7.1 Hz, 2H, CH2O), 7.01
(d, J¼8.0 Hz, 2H, Ar), 7.21 (d, J¼8.0 Hz, 2H, Ar),12.90e13.90 (br s,1H,
OH), 15.90e16.60 (br s, 1H, NH). Anal. Calcd for C16H14F3N3O4: C,
52.04; H, 3.82; N, 11.38. Found: C, 51.80; H, 3.96; N, 11.34.
methylenemalonate (6d). Yield 83%, light yellow viscous liquid. IR
(ATR): 3205, 2986, 2938, 1712, 1597, 1516, 1469, 1446, 1371, 1293,
1237, 1138, 1089, 1066, 1004, 988 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.00 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz, 3H, Me), 4.12 (q,
J¼7.1 Hz, 2H, CH2O), 4.14 (q, J¼7.1 Hz, 2H, CH2O), 7.28 (dd, J¼8.6,
1.8 Hz, 1H, H-3), 7.46e7.55 (m, 2H, H-6, H-7), 7.73 (d, J¼1.1 Hz, 1H,
4.5.6. 2-Ethoxycarbonyl-3-(2-thienyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (5f). Yield 50% (5 h, Z/E¼70:30), pale yellow
H-1), 7.75e7.83 (m, 3H, H-4, H-5, H-8), 8.10e11.50 (br s,1H, NH); 19
F
solid, mp 204e207 ꢀC. 1H NMR (400 MHz, CDCl3)
d
(Z): 1.22 (t,
NMR (471 MHz, CDCl3)
d
d
ꢁ61.4 (s, CF3); 13C NMR (126 MHz, CDCl3)
1
J¼7.1 Hz, 3H, Me), 4.27 (q, J¼7.1 Hz, 2H, CH2O), 6.98 (dd, J¼3.8,
1.1 Hz, 1H, H-3), 7.13 (dd, J¼5.1, 3.8 Hz, 1H, H-4), 7.85 (dd, J¼5.1,
1.1 Hz, 1H, H-5), 13.00e14.00 (br s, 1H, OH), 15.90e16.40 (br s, 1H,
NH); (E): 0.98 (t, J¼7.1 Hz, 3H, Me), 3.98 (q, J¼7.1 Hz, 2H, CH2O), 7.12
(dd, J¼3.8, 1.1 Hz, 1H, H-3), 7.14 (dd, J¼5.1, 3.8 Hz, 1H, H-4), 7.85 (dd,
J¼5.1, 1.1 Hz, 1H, H-5), 13.00e14.00 (br s, 1H, OH), 15.90e16.40 (br s,
13.7, 13.8, 62.1, 62.2, 120.6 (q, JC,F¼269.2 Hz, CF3), 125.2, 127.0,
127.6, 127.9, 128.5, 128.6, 128.7, 131.7, 132.9, 133.9, 134.1, 136.8 (q,
2JC,F¼39.3 Hz), 141.9, 142.7, 163.9, 165.5. Anal. Calcd for
C
21H18F3N3O4$0.25H2O: C, 57.60; H, 4.26; N, 9.60. Found: C, 57.48;
H, 4.07; N, 9.58.
1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
(Z): ꢁ59.59 (s, CF3); (E):
4.7. General procedure for the synthesis of compounds 7aed
ꢁ59.64 (s, CF3). Anal. Calcd for C13H10F3N3O4S$0.5H2O: C, 42.17; H,
2.99; N, 11.35. Found: C, 42.29; H, 2.84; N, 11.34.
A solution of acid 5 (0.3 mmol) in 2 mL of an aqueous 1 N NaOH
was allowed to stand during overnight at room temperature. The
reaction mixture was then diluted with 1 mL of concd HCl to give
the target product 8 as a colourless solid.
4.5.7. (E)-3-(4-Bromophenyl)-2-ethoxycarbonyl-3-(5-(1,1,2,2-
tetrafluoroethyl)-1,2,3-triazol-4-yl)acrylic acid (E-5g). Yield 30%
(5 h), mp 159e161 ꢀC. IR (ATR): 3318, 1698, 1631, 1586, 1487, 1411,
1393, 1370, 1302, 1266, 1227, 1211, 1183, 1143, 1106, 1091, 1074, 1011,
4.7.1. Phenyl(5-trifluoromethyl-1,2,3-triazol-4-yl)methylenemalonic
acid (7a). Yield 92%, mp 214e216 ꢀC (with decarboxylation). IR
(ATR): 3398, 1716, 1687, 1645, 1586, 1497, 1447, 1410, 1320, 1273,
990 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
4.08 (q, J¼7.1 Hz, 2H, CH2O), 6.72 (t, JH,F¼52.2 Hz, 1H, CF2H), 7.05
(d, J¼8.3 Hz, 2H, Ar), 7.61 (d, J¼8.3 Hz, 2H, Ar), 12.90e13.90 (s, 1H,
OH), 15.80e16.40 (s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
1.03 (t, J¼7.1 Hz, 3H, Me),
2
1247, 1228, 1210, 1165, 1141, 1103, 1069, 1017 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6) d 7.19 (m, 2H, Ph), 7.31e7.50 (m, 3H, Ph), 13.38
d
ꢁ137.0 (s, CF2), ꢁ111.3 (s, CF2H). Anal. Calcd for C16H12BrF4N3O4: C,
(br s, 2H, OH), 16.08 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
41.22; H, 2.59; N, 9.01. Found: C, 40.92; H, 2.51; N, 8.84.
d
ꢁ58.9 (s, CF3); 13C NMR (101 MHz, DMSO-d6)
d 120.9 (q,
1JC,F¼268.3 Hz, CF3), 127.9, 128.6, 129.7, 132.7e135.1 (br s), 133.6,
135.7e138.5 (br s), 136.7, 141.7e144.7 (br s), 164.5, 166.4. Anal.
Calcd for C13H8F3N3O4$0.5H2O: C, 46.44; H, 2.70; N, 12.50. Found: C,
46.56; H, 2.84; N, 12.44.
4.6. General procedure for the synthesis of compounds 6aed
A solution of corresponding (E)-3-aryl-2-(ethoxycarbonyl)-3-(5-
trifluoromethyl-1,2,3-triazol-4-yl)acrylic acid (Z)-5 (0.3 mmol) and
0.3 mL 96% H2SO4 in2 mLofethanol wasrefluxed for 5 h. Thereaction
mixture was then diluted with water and the product was extracted
with CHCl3 (3ꢂ2 mL). The extract was dried with Na2SO4, filtered and
then evaporated. The resulting diester was purified by flash-
chromatography on silica gel using CHCl3/EtOH gradient system.
4.7.2. (4-Chlorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
enemalonic acid (7b). Yield 97%, mp 203e204 ꢀC (with de-
carboxylation). IR (ATR): 3404, 1715, 1689, 1648, 1589, 1493, 1405,
1325, 1279, 1228, 1210, 1170, 1146, 1104, 1092, 1071, 1018 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6)
d
7.19 (d, J¼8.5 Hz, 2H, Ar), 7.38 (d,
J¼8.4 Hz, 2H, Ar), 13.18 (br s, 2H, 2OH), 15.87 (s, 1H, NH); 19F NMR
4.6.1. Diethyl
phenyl(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
(376 MHz, DMSO-d6þCCl4)
d
ꢁ59.1 (s, CF3); 13C NMR (101 MHz,
enemalonate (6a). Yield 90%, colourless viscous liquid. IR (ATR):
DMSO-d6þCCl4)
d
120.7 (q, 1JC,F¼268.6 Hz, CF3), 128.4, 129.6, 134.0,
3213, 2987, 2941, 1729, 1626, 1517, 1494, 1446, 1393, 1372, 1327,
134.5, 132.8e137.9 (br s, 2C), 135.6, 140.3e144.2 (br s, 3C), 164.2,
166.0. Anal. Calcd for C13H7ClF3N3O4$0.5H2O: C, 42.12; H, 2.18; N,
11.34. Found: C, 42.04; H, 2.09; N, 11.24.
1294, 1251, 1221, 1198, 1162, 1141, 1095, 1071, 1004, 989 cmꢁ1 1H
;
NMR (500 MHz, CDCl3)
d
1.05 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz,
3H, Me), 4.129 (q, J¼7.1 Hz, 2H, CH2O), 4.132 (q, J¼7.1 Hz, 2H, CH2O),
7.19e7.25 (m, 2H, Ph), 7.31e7.40 (m, 3H, Ph); 19F NMR (376 MHz,
4.7.3. (4-Fluorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
enemalonic acid (7c). Yield 92%, mp 216e217 ꢀC (with de-
carboxylation). IR (ATR): 3406, 1714, 1684, 1645, 1604, 1584, 1511,
1405, 1324, 1276, 1243, 1228, 1210, 1164, 1140, 1101, 1070,
CDCl3)
d
ꢁ60.2 (s, CF3); 13C NMR (101 MHz, CDCl3)
d 13.7, 13.8, 62.1,
62.2, 120.5 (q, 1JC,F¼269.3 Hz, CF3), 128.4, 128.7, 130.2, 131.5, 136.6
2
(q, JC,F¼39.2 Hz), 136.7, 142.0, 142.6, 163.9, 165.4. Anal. Calcd for
C
17H16F3N3O4$0.66H2O: C, 51.64; H, 4.42; N, 10.63. Found: C, 51.53;
1017 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.18e7.31 (m, 4H, Ar), 13.46
H, 4.22; N, 10.39.
(br s, 2H, 2OH), 16.13 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ111.3 (br s, F), ꢁ59.0 (s, CF3); 13C NMR (126 MHz, DMSO-d6)
2
1
4.6.2. Diethyl (4-chlorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)
methylenemalonate (6b). Yield 91%, colourless viscous liquid. IR
(ATR): 3212, 2987, 2941, 1729, 1593, 1517, 1491, 1447, 1400, 1372,
d
115.8 (d, JC,F¼21.7 Hz, C-3, C-5); 120.9 (q, JC,F¼268.2 Hz, CF3),
3
130.4 (d, JC,F¼8.8 Hz, C-2, C-6), 133.0e135.5 (br s), 133.2, 133.8,
135.6e136.2 (br s), 142.2e144.4 (br s), 162.7 (d, 1JC,F¼247.9 Hz, C-4),