302
Y. Dürüst et al. / European Journal of Medicinal Chemistry 48 (2012) 296e304
(18), 139 (22), 109 (13), 75 (14). HRMS-TOF-MS ESþ:Measured;
247.0562, Calculated for C9H7N6O3; 247.0580.
(n-hexane:ethyl acetate; 1:1).IR (KBr, n
: cmꢀ1): 3074 (Arom. CeH),
1720 (C]O), 1653, 1593 (C]N), 1494, 1471, 1388, 1340, 1089, 850,
740.1H NMR (dH, 400 MHz, CDCl3): 7.91 (d, J ¼ 8.6 Hz, 2H), 7.37 (m,
6H), 7. (dd, J ¼ 2.8, 9.8 Hz, 2H), 5.84 (d, J ¼ 10.8 Hz, 1H), 5.51 (d,
J ¼ 17.8 Hz, 1H), 5.35 (d, J ¼ 17.8 Hz, 1H), 4.73 (d, J ¼ 10.8 Hz, 1H). 13C
NMR (dC, 100 MHz, CDCl3): 175.4 (C]O), 171.1 (C]O), 169.4 (C]N),
167.6 (C]N), 137.5, 131.2, 129.2, 129.0, 128.9, 126.3, 124.7 (eCH),
83.5 (eCH), 58.3(eCH), 44.3 (eCH2e).MS TOF APþ (m/z, %) ¼ 450
(M þ MeCNHþ, 9), 409 (M þ Hþ, 8), 117 (23), 100 (100). HRMS-
TOF-MS ESþ:Measured; 409.0823, Calculated for C19H13ClN6O3;
409.0816.
4.2.2.1.8. 5-(Azidomethyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole
(4h). Yellow oil (0.445 g, 100%). Rf: 0.83 (n-hexane:ethyl acetate;
1:1). IR (KBr,
n
: cmꢀ1): 3009 (Arom. CeH), 2108 (N]N]N), 1614,
1571 (C]N), 1483, 1425, 1342, 1174, 1008, 839, 752. 1H NMR (dH
,
400 MHz, CDCl3): 8.05 (d, J ¼ 8.5 Hz, 2H), 7.02 (d, J ¼ 8.6 Hz, 2H),
4.62 (s, 2H), 3.88 (s, 3H). 13C NMR (dC, 100 MHz, CDCl3): 173.6 (C]
N), 168.4 (C]N), 162.2, 129.2, 118.6, 114.4 (eCH), 55.4 (eCH2e), 45.1
(eCH3). MS (m/z, %): 231 (Mþ, 83), 203 (97), 133 (100), 90 (46), 50
(22). HRMS-TOF-MS ESþ:Measured; 232.0833, Calculated for
C10H10N5O2; 232.0834.
4.2.3.1.3. (3aS,6aR)-1-((3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl)
methyl)-5-phenyl-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-
dione (5c). White solid (0.080 g, 71%). M.p.:156e157 ꢁC.Rf: 0.62
4.2.2.1.9. 5-(Azidomethyl)-3-(4-(methylthio)phenyl)-1,2,4-oxadiazole
(4i). Yellow oil (0.213 g, 100%). Rf: 0.86 (n-hexane:ethyl acetate; 1:1). IR
(KBr,
n
: cmꢀ1): 2989 (Arom. CeH), 2108 (N]N]N), 1593, 1558 (C]N),
(n-hexane:ethyl acetate; 1:1). IR (KBr, n
: cmꢀ1): 3059 (Arom.
1471, 1408, 1340, 1162, 1089, 831, 746. 1H NMR (dH, 300 MHz, CDCl3):
8.00 (d, J ¼ 10.8 Hz, 2H), 7.30 (m, 2H), 4.62 (s, 2H), 2.52 (s, 3H). 13C NMR
CeH), 1722 (C]O), 1595, 1566 (C]N), 1498, 1471, 1383, 1342,
1190, 835, 742.1H NMR (dH, 400 MHz, CDCl3): 7.91 (d, J ¼ 8.7 Hz,
2H), 7.62 (d, J ¼ 8.5 Hz, 2H), 7.44 (d, J ¼ 7.5 Hz, 3H), 7.25 (t,
J ¼ 7.7 Hz, 2H), 5.83 (d, J ¼ 10.7 Hz, 1H), 5.52 (d, J ¼ 17.6 Hz, 1H),
5.37 (d, J ¼ 17.7 Hz, 1H), 4.72 (d, J ¼ 10.8 Hz, 1H). 13C NMR (dC,
100 MHz, CDCl3): 179.9 (C]O), 176.3 (C]O), 174.4 (C]N), 172.5
(C]N), 137.0, 136.9, 133.8, 131.3, 130.7, 130.0, 88.9 (eCH), 62.7
(eCH), 48.4 (eCH2e). MS TOF APþ (m/z, %): 453 (Mþ, 3), 117 (21),
100 (100). HRMS-TOF-MS ESþ:Measured; 459.0534, Calculated
for C19H13BrN6O3; 453.0311.
(
dC, 75 MHz, CDCl3): 174.1 (C]N), 168.6 (C]N), 143.7, 128.0, 126.0,
122.5 (eCH), 45.3 (eCH2e), 15.2 (eCH3). MS (m/z, %): 247 (Mþ, 100),
219 (67), 165 (62), 149 (88), 106 (17), 90 (12), 69 (12). HRMS-TOF-
MS ESþ:Measured; 247.0527, Calculated for C10H9N5OS; 247.0528.
4.2.2.1.10. 5-(Azidomethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-
oxadiazole (4j). Yellow oil (0.307 g, 93%). Rf: 0.88 (n-hexane:ethyl
acetate; 1:1). IR (KBr,
n
: cmꢀ1): 2933 (Arom. CeH), 2100 (N]N]N),
1597, 1573 (C]N), 1485, 1419, 1329, 1174, 1066, 854, 759. 1H NMR
(
dH, 400 MHz, CDCl3): 8.24 (d, J ¼ 8.8 Hz, 2H), 7.77 (d, J ¼ 8.8 Hz, 2H),
4.2.3.1.4. (3aS,6aR)-1-((3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)
methyl)-5-phenyl-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-
dione (5d). White solid (0.067 g, 52%). M.p.:155e157 ꢁC.Rf: 0.52 (n-
4.66 (s, 2H). 13C NMR (dC, 100 MHz, CDCl3): 174.8 (C]N), 168.0 (C]
N), 133.7, 129.7, 128.2, 126.3 (eCF3-), 45.3 (eCH2e). MS (m/z, %): 269
(Mþ, 100), 241 (9), 187 (100), 168 (18), 139 (22) 109 (13), 75 (14).
hexane:ethyl acetate; 1:1).IR (KBr, n
: cmꢀ1): 3059 (Arom. CeH),1724
HRMS-TOF-MS
C10H6N5OF3; 269.0524.
ESþ:Measured;
269.0519,
Calculated
for
(C]O), 1606, 1581 (C]N), 1479, 1417, 1383, 1342, 1190, 852, 740. 1H
NMR (dH, 300 MHz, CDCl3): 8.04 (m, 2H), 7.45 (m, 3H), 7.30 (m, 4H),
5.93 (d, J ¼ 10.8 Hz, 1H), 5.59 (d, J ¼ 17.6 Hz, 1H), 5.40 (d, J ¼ 17.9 Hz,
1H), 4.82 (d, J ¼ 10.8 Hz,1H).13C NMR (dC, 75 MHz, CDCl3): 174.5 (C]
O),171.2 (C]O),169.4 (C]N),167.6 (C]N),130.9,129.9,129.3,129.2,
126.3, 123.4, 122.4, 116.4 (eCH), 83.4 (eCH), 57.6 (eCH), 44.4
(eCH2e). MS TOFAPþ (m/z, %): 434 (M þ MeCNHþ, 33), 393 (M þ Hþ,
38), 117 (55), 100 (100). HRMS-TOF-MS ESþ:Measured; 393.1115,
Calculated for C19H13FN6O3; 393.1111.
4.2.2.1.11. 5-(Azidomethyl)-3-(4-(N,N-dimethylamino)phenyl)-1,2,4-
oxadiazole (4k). Yellow solid (0.169 g, 99%). M.p.:61e62 ꢁC. Rf: 0.83 (n-
hexane:ethyl acetate; 1:1). IR (KBr, n
: cmꢀ1): 2914 (Arom. CeH), 2098
(N]N]N),1614,1587 (C]N),1491,1435,1375,1276,1197, 821, 756.1H
NMR (dH, 400 MHz, CDCl3): 7.96 (d, J ¼ 9.1 Hz, 2H), 6.76 (d, J ¼ 9.1 Hz,
2H), 4.60 (s, 2H), 3.06 (s, 6H). 13C NMR (dC, 100 MHz, CDCl3): 173.1 (C]
N), 168.8 (C]N), 152.4, 133.4, 128.8, 111.7 (eCH), 45.1 (eCH2e), 40.1
(eNCH3). MS (m/z, %): 244 (Mþ, 59), 215 (65), 145 (100), 102 (13).
HRMS-TOF-MS ESþ:Measured; 244.1070, Calculated for C11H12N6O1;
244.1073.
4.2.3.1.5. (3aS,6aR)-5-Phenyl-1-((3-p-tolyl-1,2,4-oxadiazol-5-yl)
methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-dione
(5e). White solid (0.060 g, 68%). M.p.:138e140 ꢁC.Rf: 0.43 (n-
hexane:ethyl acetate; 1:1).IR (KBr, n
: cmꢀ1): 3049 (Arom. CeH),
4.2.3. Synthesis of dihydropyrrolo triazoles 5aek
4.2.3.1. General procedure for the preparation of 5aek
1720 (C]O), 1597, 1572 (C]N), 1483, 1383, 1342, 1107, 740.1H
NMR (dH, 400 MHz, CDCl3): 7.93 (d, J ¼ 8.2 Hz, 2H), 7.45 (m, 3H),
7.28 (m, 4H), 5.88 (d, J ¼ 10.8 Hz, 1H), 5.60 (d, J ¼ 17.8 Hz, 1H), 5.32
(d, J ¼ 17.8 Hz, 1H), 4.80 (d, J ¼ 10.8 Hz, 1H), 2.44 (s, 3H).13C NMR (dC,
100 MHz, CDCl3): 173.4 (C]O), 170.7 (C]O), 168.7 (C]N), 168.5
(C]N), 130.6, 129.7, 129.4, 129.3, 128.4, 127,5, 126.2, 123.1 (eCH),
83.0 (eCH), 57.2(eCH), 44.4 (eCH2e), 21.6 (eCH3-). MS TOF ESþ
(m/z, %): 427 (M þ Kþ, 5), 359 (M-Nþ2 , 6), 274 (100), 146 (90), 129
(19), 105 (33). HRMS Measured; 389.2153 Calculated for
C20H16N6O3; 389.1362.
4.2.3.1.1. (3aS,6aR)-5-Phenyl-1-((3-phenyl-1,2,4-oxadiazol-5-yl)
methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-dione
(5a). A mixture of N-phenyl maleimide (0.044 g, 0.252 mmol) and 5-
(azidomethyl)-3-phenyl-1,2,4-oxadiazole (4a) (0.050 g, 0.240 mmol)
were stirred in benzene (25 mL) and the mixture was heated under
reflux for 2-4 d. The reaction was monitored by TLC. The reaction
mixture was concentrared in vacuo, and the crude residue was
washed with n-hexane to give (5a) as a white solid (0.048 g, 54%).
M.p.:162e164 ꢁC; Rf: 0.74 (n-hexane:ethyl acetate; 1:1). IR (KBr,
n:
4.2.3.1.6. (3aS,6aR)-1-((3-(4-Iodophenyl)-1,2,4-oxadiazol-5-yl)
methyl)-5-phenyl-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-
dione (5f). White solid (0.064 g, 84%). M.p.:161e163 ꢁC.Rf: 0.61 (n-
cmꢀ1): 3068 (Arom. CeH),1716 (C]O),1597,1500 (C]N),1475,1444,
1384, 1348, 1188, 933, 717.1H NMR (dH, 400 MHz, CDCl3): 8.06 (d,
J ¼ 6.8 Hz, 2H), 7.73 (m, 7H), 7.26 (m,1H), 5.92 (d, J ¼ 10.8 Hz, 1H), 5.65
(d, J ¼ 17.8 Hz,1H), 5.37 (d, J ¼ 17.8 Hz,1H), 4.83 (d, J ¼ 10.8 Hz, 1H).13C
NMR (dC, 100 MHz, CDCl3): 175.4 (C]O), 171.6 (C]O), 170.1 (C]N),
168.2 (C]N),131.7,129.2,129.1,129.0,128.5,127,5,126.8,100.0 (eCH),
83.8 (eCH), 58.2(eCH), 44.5 (eCH2e). MS TOF APþ (m/z, %) ¼ 416
(M þ MeCNHþ, 3), 375 (M þ Hþ, 7), 117 (8), 100 (100). HRMS-TOF-
MS ESþ:Measured; 375.1201, Calculated for C19H14N6O3; 375.1206.
4.2.3.1.2. (3aS,6aR)-1-((3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)
methyl)-5-phenyl-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-
dione (5b). White solid (0.068 g, 78%). M.p.:164e165 ꢁC.Rf: 0.50
hexane:ethyl acetate; 1:1).IR (KBr, n
: cmꢀ1): 3053 (Arom. CeH),
1716 (C]O), 1689, 1558 (C]N), 1498, 1402, 1384, 1334, 1195, 837,
742. 1H NMR (dH, 300 MHz, CDCl3): 7.80 (m, 5H), 7.38 (m, 4H), 5.93
(d, J ¼ 10.8 Hz, 1H), 5.60 (d, J ¼ 17.6 Hz, 1H), 5.41 (d, J ¼ 17.9 Hz, 1H),
4.81 (d, J ¼ 10.8 Hz, 1H). 13C NMR (dC, 75 MHz, CDCl3): 174.7 (C]O),
171.2 (C]O), 169.4 (C]N), 167.9 (C]N), 138.2, 130.9, 129.3, 129.2,
129.1, 126.4, 125.6, 98.5 (eCH), 83.5 (eCH), 57.6 (eCH), 44.4
(eCH2e). MS TOF ESþ (m/z, %): 541 (M þ MeCNHþ, 22), 521 (100),
478 (9), 391 (39). HRMS-TOF-MS ESþ:Measured; 501.0194, Calcu-
lated for C19H13IN6O3; 501.0172.