8506
A. Kudelko / Tetrahedron 67 (2011) 8502e8508
28.81 cmꢁ1 Mꢁ1), 223 (16.78); dH (300 MHz, DMSO-d6, Me4Si) 4.67
(1H, s, CH), 4.76 (1H, s, CH), 7.35e7.43 (10H, m, 2Ph), 11.50 (2H, br s,
2$OH); dC (DMSO-d6) 57.2 (CH), 56.4 (CH), 128.3, 128.6, 128.7, 135.7
(2Ph), 171.0 (2$CO).
Me4Si) 5.83 (1H, s, CH), 7.32e7.42 (5H, m, Ph), 9.17 (1H, s, HeC5); dC
(DMSO-d6) 43.8 (CHePh), 128.0, 128.2, 129.0, 134.9 (Ph), 155.1 (C5),
164.5 (C2); m/z (EI) 56, 63, 89, 121, 159, 191, 317, 350 (Mþ); nmax
(ATR) 3116, 2947, 1556, 1504, 1486, 1455, 1326, 1301, 1261, 1231,
1094, 1076, 1033, 974, 961, 874, 856, 832, 758, 723, 697 cmꢁ1
.
4.4. Synthesis of dimethyl 1,10-diphenylthiodiacetate 4
4.6.2. 2-Benzyl-1,3,4-oxadiazole (7a). Colourless liquid, yield: 10%;
Rf (benzene/ethyl acetate, 1:3 v/v) 0.66; [Found: C, 67.40; H, 5.00; N,
17.41. C9H8N2O requires C, 67.48; H, 5.04; N, 17.48%]; lmax (MeOH):
1,10-Diphenyl-2,20-thiodiacetic acid 3 (24.2 g, 80 mmol), 120 mL
of methanol and p-TsOH (0.50 g, 2.9 mmol) were heated under
reflux for approximately 5 h. The methanol was then removed on
the rotary evaporator. The residue was dissolved in 150 mL of
diethyl ether, washed with a saturated aqueous Na2CO3 solution
(50 mL) and then finally washed with water (50 mL). The organic
layer was dried over anhydrous MgSO4 and concentrated on the
rotary evaporator, yielding crude dimethyl 1,10-diphenylth-
iodiacetate 4 as a yellow oil that crystallised upon resting. It was
recrystallised from isopropanol.
208 nm (
3
ꢂ10ꢁ3 7.65 cmꢁ1
M
ꢁ1); dH (300 MHz, DMSO-d6, Me4Si)
4.28 (2H, s, CH2), 7.23e7.36 (5H, m, Ph), 9.13 (1H, s, HeC5); dC
(DMSO-d6) 31.1 (CH2ePh), 127.9, 129.4, 129.5, 135.2 (Ph), 155.4 (C5),
165.8 (C2); m/z (EI) 51, 63, 65, 77, 78, 89, 90, 91, 103, 104, 105, 118,
119, 131, 132, 159, 160 (Mþ); nmax (ATR) 3137, 3031, 1571, 1518, 1495,
1455, 1422, 1223, 1180, 1039, 980, 849, 878, 724, 695, 670 cmꢁ1
.
4.6.3. 2-Benzoyl-1,3,4-oxadiazole (8a). Colourless solid, yield: 8%;
mp 74e76 ꢀC; Rf (benzene/ethyl acetate, 1:3 v/v) 0.59; [Found: C,
61.99; H, 3.41; N, 16.02. C9H6N2O2 requires C, 62.05; H, 3.48; N,
4.4.1. Dimethyl 1,10-diphenylthiodiacetate (4). Colourless solid,
yield: 85%; mp 64e66 ꢀC (lit.:35 mp 69e71 ꢀC); Rf (benzene/ethyl
acetate,1:3 v/v) 0.74; [Found: C, 65.48; H, 5.46. C18H18O4S requires C,
16.08%]; lmax (MeOH): 203 nm (
3
ꢂ10ꢁ3 10.36 cmꢁ1
M
ꢁ1), 220
(6.47), 269 (10.50); dH (300 MHz, DMSO-d6, Me4Si) 7.63 (2H, t, J
7.8 Hz, H30, H50), 7.78 (1H, t, J 7.8 Hz, H40), 8.36 (2H, d, J 7.8 Hz, H20,
H60), 9.58 (1H, s, HeC5); dC (DMSO-d6) 128.8, 130.5, 134.2, 134.8
(Ph), 155.7 (C5), 160.4 (C2), 177.7 (CO); m/z (EI) 51, 77, 90, 105, 146,
174 (Mþ); nmax (ATR) 3144, 1658, 1592, 1574, 1521, 1496, 1448, 1344,
1237, 1176, 1164, 1116, 1076, 1001, 978, 971, 911, 884, 810, 740,
65.42; H, 5.50%]; lmax (MeOH): 206.0 nm (
3
ꢂ10ꢁ3 31.43 cmꢁ1 Mꢁ1),
289 (0.43), 301 (0.25); dH (300 MHz, DMSO-d6, Me4Si) 3.64 (6H, s,
2OCH3), 4.79 (2H, s, 2CH), 7.28e7.36 (10H, m, 2Ph); dC (DMSO-d6)
52.4 (OCH3), 73.1 (CH), 127.1, 127.4, 128.9, 128.9, 129.0, 130.0, 136.1,
136.1 (2Ph), 170.8, 171.1 (2$COAc).
684 cmꢁ1
.
4.5. Synthesis of 1,10-diphenylthiodiacetic acid dihydrazide 5
4.6.4. Bis(5-methyl-1,3,4-oxadiazol-2-yl-phenylmethyl) sulfide (6b).
Colourless solid, yield: 70%; mp 120e123 ꢀC; Rf (benzene/ethyl
acetate, 1:3 v/v) 0.34; [Found: C, 63.39; H, 4.70; N, 14.71.
C20H18N4O2S requires C, 63.45; H, 4.80; N, 14.80%]; lmax (MeOH):
Dimethyl 1,10-diphenylthiodiacetate 4 (21.5 g, 65 mmol) was
dissolved in 150 mL of methanol. Then, 15 mL of hydrazine hydrate
(310 mmol) was added, and the mixture was agitated at room
temperature for 24 h. The white precipitate was removed by fil-
tration, washed with diethyl ether and dried with air, yielding the
crude dihydrazide with a melting point of 203e204 ꢀC. The product
was purified by crystallisation from methanol to give compound 5.
207 nm (
3
ꢂ10ꢁ3 37.44 cmꢁ1
M
ꢁ1), 287 (0.55), 305 (0.47); dH
(300 MHz, DMSO-d6, Me4Si) 2.42 (3H, s, CH3), 5.75 (1H, s, CH),
7.27e7.44 (5H, m, Ph); dC (DMSO-d6) 11.1 (CH3), 44.6 (CHePh),
128.8, 128.9, 129.6, 135.9 (Ph), 165.1 (C2), 165.4 (C5); m/z (EI) 56, 63,
89, 121, 135, 147, 160, 173, 205, 345, 378 (Mþ); nmax (ATR) 3226,
3030,1670, 1587, 1558, 1495, 1454, 1368, 1261, 1225, 1076, 1031, 975,
4.5.1. 1,10-Diphenylthiodiacetic acid dihydrazide (5). Colourless
needles, yield: 76%; mp 209e210 ꢀC, Rf (benzene/ethyl acetate, 1:3
v/v) 0.10; [Found: C, 58.25; H, 5.57; N, 16.88. C16H18N4O2S requires
954, 844, 737, 695, 681 cmꢁ1
.
C, 58.15; H, 5.50; N, 16.94%]; lmax (MeOH): 212 nm (
3
ꢂ10ꢁ3
4.6.5. 2-Benzyl-5-methyl-1,3,4-oxadiazole (7b). Colourless liquid,
yield: 18%, Rf (benzene/ethyl acetate, 1:3 v/v) 0.44; [Found: C,
68.88; H, 5.75; N, 16.01. C10H10N2O requires C, 68.94; H, 5.80; N,
31.80 cmꢁ1 Mꢁ1); dH (300 MHz, DMSO-d6, Me4Si) 4.27 (2H, s, NH2),
4.32 (1H, s, CH), 7.22e7.36 (5H, m, Ph), 9.37 (1H, s, NH); dC (DMSO-
d6) 51.9 (CH), 128.3, 128.8, 128.9, 138.2 (Ph), 168.9 (CO); m/z (EI) 63,
89, 121, 149, 181, 297, 298, 330 (Mþ); nmax (ATR) 3322, 3275, 1680,
1644, 1614, 1515, 1451, 1345, 1243, 1214, 1087, 995, 948, 921, 784,
16.07%]; lmax (MeOH): 208 nm (
3
ꢂ10ꢁ3 11.1 cmꢁ1
M
ꢁ1); dH
(300 MHz, CDCl3, Me4Si) 2.45 (3H, s, CH3), 4.14 (2H, s, CH2),
7.29e7.31 (5H, m, Ph); dC (CDCl3) 10.9 (CH3), 31.7 (CH2ePh), 127.5,
128.7, 128.8, 133.9 (Ph), 164.1 (C5), 165.4 (C2); m/z (EI) 51, 63, 65, 77,
78, 83, 89, 90, 91, 103, 104, 105, 117, 118, 119, 131, 132, 145, 173, 174
(Mþ); nmax (ATR) 3031, 2919, 1594, 1567, 1496, 1455, 1426, 1391,
739, 713, 697 cmꢁ1
.
4.6. Reactions of 1,10-diphenylthiodiacetic acid dihydrazide
with triethyl orthoestersdgeneral procedure
1351,1224,1167,1076,1048,1029, 971, 959, 795, 728, 695, 667 cmꢁ1
.
The starting 1,10-diphenylthiodiacetic acid dihydrazide 5 (3.30 g,
10 mmol) was added to a mixture of the appropriate triethyl
orthoester (100 mmol) and 0.4 mL (0.40 g, 7 mmol) of glacial AcOH.
The mixture was kept under reflux until the starting hydrazide was
consumed (TLC, 5e15 h). After cooling and filtrating, the excessive
orthoester and AcOH were evaporated under reduced pressure. The
crude products were purified by column chromatography with
silica gel and an eluent of benzene/AcOEt (1:3). Pure products were
crystallised from benzene/hexane mixtures.
4.6.6. 2-Benzoyl-5-methyl-1,3,4-oxadiazole (8b). Colourless solid,
yield: 10%; mp 103e105 ꢀC; Rf (benzene/ethyl acetate, 1:3 v/v) 0.68;
[Found: C, 63.75; H, 4.23; N, 14.80. C10H8N2O2 requires C, 63.82; H,
4.30; N, 14.88%]; lmax (MeOH): 203 nm (
3
ꢂ10ꢁ3 12.58 cmꢁ1
M
ꢁ1),
270 (11.97); dH (300 MHz, DMSO-d6, Me4Si) 2.65 (3H, s, CH3),
7.60e7.80 (3H, m, H30, H40, H50), 8.37 (2H, d, J 7.8 Hz, H20, H60); dC
(DMSO-d6) 11.4 (CH3), 127.1, 129.5, 131.1, 135.4 (Ph), 161.8 (C2), 166.6
(C5), 178.3 (CO); m/z (EI) 51, 77, 90, 104, 105, 160, 188 (Mþ); nmax
(ATR) 3218, 3069, 1666, 1596, 1575, 1558, 1524, 1451, 1394, 1364,
1306, 1261, 1229, 1171, 1092, 1049, 1003, 975, 913, 840, 804, 753,
4.6.1. Bis(1,3,4-oxadiazol-2-yl-phenylmethyl) sulfide (6a). Colour-
less solid, yield: 80%; mp 198e200 ꢀC; Rf (benzene/ethyl acetate,
1:3 v/v) 0.50; [Found: C, 61.60; H, 4.00; N, 15.89. C18H14N4O2S re-
738, 703, 687, 668 cmꢁ1
.
4.6.7. Bis(5-ethyl-1,3,4-oxadiazol-2-yl-phenylmethyl) sulfide (6c).
Colourless solid, yield: 65%; mp 132e133 ꢀC; Rf (benzene/ethyl
acetate, 1:3 v/v) 0.45; [Found: C, 64.92; H, 5.43; N, 13.79.
quires C, 61.69; H, 4.03; N, 15.98%]; lmax (MeOH): 214 nm (
3
ꢂ10ꢁ3
30.92 cmꢁ1
M
ꢁ1), 261 (1.61), 268 (1.26); dH (300 MHz, DMSO-d6,