Synthesis, reactions and antimicrobial activity of some new indolyl-1,3,4-oxadiazole, triazole and pyrazole derivatives

Article abstract of DOI:10.1002/jccs.200400023

Indole-3-carboxylic acid hydrazide 3 was prepared and was treated with aromatic aldehydes in ethanol to give the corresponding hydrazone derivatives 4-7 in good yields. The indole carbohydrazide was incorporated into the 3-indolyloxadiazoles 8-11 and 18, 3-indolyltriazoles 13-17 and 35, 3-indolylpyrazole derivatives 19-23 and carbamate derivatives 26-27. Furthermore, interaction of the carboazide 24 with hydrazine hydrate in refluxing toluene afforded the corresponding semicarbazide derivative 30. The thiadiazine derivative 34 was also prepared. Some of these compounds were screened in vitro for their antibacterial and antifungal activity.

Full text of DOI:10.1002/jccs.200400023

Journal of the Chinese Chemical Society, 2004, 51, 147-156
147
Synthesis, Reactions and Antimicrobial Activity of Some New
Indolyl-1,3,4-Oxadiazole, Triazole and Pyrazole Derivatives
Abdel-Rahman A. H. Farghaly
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Indole-3-carboxylic acid hydrazide 3 was prepared and was treated with aromatic aldehydes in ethanol to
give the corresponding hydrazone derivatives 4-7 in good yields. The indole carbohydrazide was incorpo-
rated into the 3-indolyloxadiazoles 8-11 and 18, 3-indolyltriazoles 13-17 and 35, 3-indolylpyrazole deriva-
tives 19-23 and carbamate derivatives 26-27. Furthermore, interaction of the carboazide 24 with hydrazine
hydrate in refluxing toluene afforded the corresponding semicarbazide derivative 30. The thiadiazine deriva-
tive 34 was also prepared. Some of these compounds were screened in vitro for their antibacterial and
antifungal activity.
Keywords: Monoamine oxidase; 3-Indolyloxadiazoles; 3-Indolytriazoles and pyrazoles.
INTRODUCTION
Indole derivatives have attracted particular attention
carried out using a Perkin-Elmer 240 C Microanalyzer, and
the results were in an acceptable range. The characterization
data of the newly synthesized compounds are listed in Table
1.
due to their various pharmacological activities.1,2 Several of
these derivatives possess potent central nervous system
(CNS) as well as anti-inflammatory properties.3-6 Indole-3-
carbohydrazide derivatives have been shown to inhibit
monoamine oxidase A activity.7-9 Some N-methylindol-3-
hydrazones have shown antihypertensive activity in sponta-
neously hypertensive rates.10 Moreover, it was reported that
several 3-substituted indoles were used as materials for alka-
loids, agrochemicals, pharmaceuticals and perfumes.11 In-
dolyl quinazolones possess potent anti-inflammatory as well
as CNS activity.12,13 Also, it has been reported that the substi-
tution by hetrocyclic moieties, i.e., oxadiazoles or triazoles at
positions 1 and 3 of the indole nucleus enhances these activi-
ties.14 All these findings prompted the synthesis of a number
of indole-3-carbohydrazide derived systems of anti-micro-
bial activity.
Ethyl 1-benzyl-1H-indole-3-carboxylate (2)
To a mixture of the compound 1 (0.189 g, 0.001 mol)
and K2CO3 (0.414 g, 0.003 mol) in dry DMF (10 mL) was
added benzyl chloride (0.139 g, 0.0011 mol). The mixture
was heated under reflux for 12 h. After cooling, the solvent
was removed under reduced pressure and the residue was
triturated with water, then the product was extracted with di-
chloromethane (3 ´ 50 mL). The combined extracts were
washed with water (3 ´ 50 mL), dried over Na2SO4 and con-
centrated under reduced pressure to give a buff solid product,
which was recrystallized from ethyl acetate/light petroleum
to afford buff needles.
1-Benzyl-1H-indole-3-carbohydrazide (3)
A mixture of compound 2 (5 g, 0.019 mol) and hy-
drazine hydrate (15 mL) was refluxed for 4 h. The excess of
hydrazine hydrate was removed in vacuo and the residue was
triturated with water, filtered off, dried and recrystallized
from ethanol to give colorless crystals.
EXPERIMENTAL
All melting points are uncorrected and were measured
on a Gallenkamp melting point apparatus. IR spectra were re-
corded on a Shimadzu 470 IR-Spectrophotometer (KBr; umax
N-Arylmethylene-1-benzyl-1H-indole-3-carbohydrazide
(4-7)
1
in cm-1). H NMR spectra were recorded on a Jeol LA 400
MHz FT-NMR spectrophotometer with TMS as internal stan-
dard (d values in ppm.). Mass spectra were obtained with a
Jeol JMS-600 mass spectrometer. Elemental analyses were
To a solution of 3 (0.265 g, 0.001 mol) in ethanol (15
mL), an ethanolic solution of appropriate aldehyde (0.001
mol) was added. The resulting mixture was refluxed for 2 h.

148 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Farghaly
Table 1. Characterization Data of the Synthesized Compounds
Compd M.P. (°C)/
Formula
(M.W.)
Spectral data and elemental analysis
(Yield: %)
2
3
66-68
(95)
C18H17NO2
(279.3)
IR: 2950 (CH aliphatic); 1680 (C=O). 1H NMR (CDCl3) d 8.35-8.30 (m, 1H, H-4); 7.79 (s, 1H,
H-2); 7.50-7.31 (m, 3H, H-5, H-6, H-7 and Ph-H); 5.43 (s, 2H, CH2); 3.98 (s, 3H, CH3). Anal.
Calcd. for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.28; H, 5.98; N, 4.89.
150-52
(90)
C16H15N3O
(265.3)
IR: 3330-3200 (NHNH2); 1640 (C=O). 1H NMR (DMSO-d6): d 9.26 (s, 1H, NH); 8.19 (d, J4-5
8 Hz, 1H, H-4); 8.13 (s, 1H, H-2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.32-7.12 (m, 7H, H-5, H-6 and
Ph-H); 5.43 (s, 2H, CH2); 4.39 (s, 2H, NH2). Anal. Calcd. for C16H15N3O: C, 72.43; H, 5.70; N,
15.84. Found: C, 72.38; H, 5.58; N, 15.75.
=
4
5
6
7
8
9
183-85
(87).
C23H19N3O
(353.4)
IR: 3200 (NH); 1650 (C=O). 1H NMR (DMSO-d6): d 9.18 (s, 1H, NH); 8.17 (s, 1H, N=CH);
8.12-6.93 (m, 15H, Ar-H and H-2); 5.35 (s, 2H, CH2). Anal. Calcd. for C23H19N3O: C, 78.16; H,
5.42; N, 11.89. Found: C, 78.28; H, 5.58; N, 11.78.
227-29
(90)
C23H18N3Ocl IR: 3210 (NH0; 1630 (C=O). 1H NMR (DMSO-d6): d 9.18 (s, 1H, NH); 8.20 (s, 1H, N=CH);
(387.9)
8.13-6.83 (m, 14H, Ar-H and H-2); 5.35 (s, 2H, CH2). Anal. Calcd. for C23H18ClN3O: C, 71.22;
H, 4.68; N, 10.83; Cl, 9.14. Found: C, 71.28; H, 4.58; N, 10.76; Cl, 8.89.
223-25
(83)
C24H21N3O2
(383.5)
IR: 3200 (NH); 1630 (C=O). 1H NMR (DMSO-d6): d 9.18 (s, 1H, NH); 8.20 (s, 1H, N=CH);
8.15-6.84 (m, 14H, Ar-H and H-2); 5.38 (s, 2H, CH2); 3.78 (s, 3H, OCH3). Anal. Calcd. for
C24H21N3O2: C, 75.18; H, 5.52; N, 10.96. Found: C, 78.23; H, 5.54; N, 10.87.
IR: 3200 (NH); 1630 (C=O). 1H NMR (DMSO-d6): d 9.19 (s, 1H, NH); 8.20 (s, 1H, N=CH);
8.13-6.73 (m, 14H, Ar-H and H-2); 5.38 (s, 2H, CH2); 2.96 (s, 6H, N (CH3)2). Anal. Calcd. for
C25H24N4O: C, 75.73; H, 6.10; N, 14.13. Found: C, 75.68; H, 6.28; N, 14.29.
257-59
(81)
C25H24N4O
(396.5)
93-95
(61)
C25H21N3O2
(395.5)
IR: 1660 (C=O). 1H NMR (CDCl3): d 8.19-7.10 (m, 15 H, Ar-H and H-2); 5.28 (s, 2H, CH2);
2.30 (s, 3H, CH3); 2.10 (s, 1H, CH oxadiazole). Anal. Calcd. for C25H21N3O2: C, 75.93; H, 5.33;
N, 10.63. Found: C, 75.88; H, 5.28; N, 10.45.
113-115
(48)
C17H13N3O
(275.3)
IR: 3030 (CH aromatic). 1H NMR (DMSO-d6): d 8.18 (d, J4-5 = 8 Hz, 1H, H-4); 8.12 (s, 1H, H-
2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.34-7.14 (m, 7H, H-5, H-6 and Ph-H); 5.43 (s, 2H, CH2); 2.13
(s, 1H, CH oxadiazole). Anal. Calcd. for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
74.10; H, 4.60; N, 15.17.
10
11
12
13
203-205 C17H13N3OS
(87) (307.4)
IR: 3200 (NH). 1H NMR (DMSO-d6): d 13.4 (s, 1H, NH); 8.19 (d, J4-5 = 8 Hz, 1H, H-4); 8.13 (s,
1H, H-2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.32-7.12 (m, 7H, H-5, H-6 and Ph-H); 5.43 (s, 2H,
CH2). Anal. Calcd. for C17H13N3OS: C, 66.43; H, 4.26; N, 13.67. Found: C, 66.30; H, 4.18; N,
13.48.
202-204 C16H13N3O2
(93)
IR: 3200 (NH); 1780 (C=O). 1H NMR (DMSO-d6): d 13.4 (s, 1H, NH); 8.18 (d, J4-5 = 8 Hz, 1H,
H-4); 8.12 (s, 1H, H-2); 7.49 (d, J6-7 = 8 Hz, 1H, H-7); 7.34-7.14 (m, 7H, H-5, H-6 and Ph-H);
5.43 (s, 2H, CH2). Ms: 290 (M-1, 100%). Anal. Calcd. for C17H13N3O2: C, 70.09; H, 4.50; N,
14.42; S,10.98. Found: C, 70.20; H, 4.38; N, 14.35; S, 10.88.
(291.3)
175-77
(97)
C23H20N4OS
(401.5)
IR: 3400, 3250, 3150 (NH); 1640 (C=O). 1H NMR (DMSO-d6): d 10.05 (s, 1H, NH); 9.72 (s,
1H, NH); 8.26 (s, 1H, NH); 8.20 (d, J4-5 = 6.8 Hz, 1H, H-4); 7.57 (s, 1H, H-2); 7.47 (d, J6-7 = 8
Hz, 1H, H-7); 7.34-7.12 (m, 12H, H-5, H-6 and Ph-H); 5.49 (s, 2H, CH2). Anal. Calcd. for
C23H20N4OS: C, 68.98; H, 5.03; N, 13.99; S,8.01. Found: C, 68.87; H, 4.98; N, 13.79; S, 7.97.
IR: 3280, 3180 (NH2); 3100 (NH). 1H NMR (DMSO-d6): d 13.3 (s, 1H, NH); 8.19 (d, J4-5 = 8
Hz, 1H, H-4); 8.13 (s, 1H, H-2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.32-7.12 (m, 7H, H-5, H-6 and
Ph-H); 5.20 (s, 2H, NH2); 5.35 (s, 2H, CH2). Ms: 321 (M+, 4%). Anal. Calcd. for C17H15N5S: C,
63.53; H, 4.70; N, 21.79; S,9.98. Found: C, 63.48; H, 4.86; N, 21.69; S, 9.87.
IR: 3200 (NH). 1H NMR (DMSO-d6): d 13.7 (s, 1H, NH); 8.25-7.10 (m, 15H, Ph-H and H-2);
5.40 (s, 2H, CH2). Anal. Calcd. for C23H18N4S: C, 72.23; H, 4.74; N, 14.65; S, 8.38. Found: C,
72.08; H, 4.67; N, 14.69; S, 8.47.
126-28
(98)
C17H15N5S
(321.4)
14
15
110-112
(78)
C23H18N4S
(382.5)
125-27
(66)
C17H15N5O
(305.3)
IR: 3280, 3170 (NH2); 3100 (NH). 1H NMR (DMSO-d6): d 13.10 (s, 1H, NH); 8.23 (d, J4-5 = 8
Hz, 1H, H-4); 8.13 (s, 1H, H-2); 7.40 (d, J6-7 = 8 Hz, 1H, H-7); 7.22-7.12 (m, 7H, H-5, H-6 and
Ph-H); 5.20 (s, 2H, NH2); 5.35 (s, 2H, CH2). Anal. Calcd. for C17H15N5O: C, 66.87; H, 4.95; N,
22.94; S, 5.24. Found: C, 66.78; H, 4.87; N, 5.19; S, 8.47.
16
168-70
(52)
C29H31N5S
(481.7)
IR: 2950 (CH aliphatic). 1H NMR (CDCl3): d 8.24-8.21 (m, 1H, H-4); 7.68 (s, 1H, H-2); 7.32-
6.92 (m, 13 H, H-5, H-6, H-7 and Ph-H); 5.30 (s, 2H, CH2); 3.54 (t, J = 7.4 Hz, 2H, SCH2); 3.01
(t, J = 7.4 Hz, 2H, SCH2CH2 NEt2); 2.66 (q, J = 7.2 Hz, 4H, SCH2CH2 N(CH2CH3)2); 1.06 (t, J =
7.2 Hz, 6H, SCH2CH2 N(CH2CH3)2). Ms: 486 (M+2, 12%). Anal. Calcd. for C29H31N5S: C,
72.32; H, 6.49; N, 14.54; S, 6.66. Found: C, 72.22; H, 6.33; N, 14.43; S, 6.50.

Indolyl-1,3,4-Oxadiazole, Triazole and Pyrazole
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 149
17
18
78-80
(57)
C29H29N5OS
(495.7)
IR: 2950 (CH aliphatic). 1H NMR (CDCl3): d 8.23-8.20 (m, 1H, H-4); 7.70 (s, 1H, H-2); 7.32-
6.92 (m, 13 H, H-5, H-6, H-7 and Ph-H); 5.30 (s, 2H, CH2); 3.68 (t, J = 4.5 Hz, 4H, OCH2); 3.43
(t, J = 8 Hz, 2H, SCH2); 2.82 (t, J = 8 Hz, 2H, SCH2CH2 N); 2.53 (t, J = 4.5 Hz, 4H, NCH2).
Anal. Calcd. for C29H29N5OS: C, 70.28; H, 5.90; N, 14.13; S, 6.47. Found: C, 70.14; H, 5.79; N,
14.04; S, 6.39.
105-107 C23H24N4O2S IR: 2950 (CH aliphatic). 1H NMR (CDCl3): d 8.23-8.20 (m, 1H, H-4); 7.69 (s, 1H, H-2); 7.32-
(71)
(420.5)
6.92 (m, 8H, H-5, H-6, H-7 and Ph-H); 5.30 (s, 2H, CH2); 3.68 (t, J = 4.5 Hz, 4H, OCH2); 3.43
(t, J = 8 Hz, 2H, SCH2); 2.82 (t, J = 8 Hz, 2H, SCH2CH2 N); 2.53 (t, J = 4.5 Hz, 4H, NCH2). Ms:
418 (M-2, 10%). Anal. Calcd. for C23H24N4O2S: C, 65.69; H, 5.75; N, 13.32; S, 7.62. Found: C,
65.58; H, 5.66; N, 13.22; S, 7.56.
19
21
22
23
238-40
(60)
C20H17N3O2
(331.4)
IR: 3150 (NH); 1660 (C=O). 1H NMR (DMSO-d6): d 8.98 (s, 1H, NH); 8.27 (d, J4-5 = 8 Hz, 1H,
H-4); 7.58 (s, 1H, H-2); 7.33-7.29 (m, 8H, H-5, H-6, H-7 and Ph-H); 6.03 (s, 1H, CH
pyrazolone); 5.61 (s, 2H, CH2); 2.42 (s, 3H, CH3). Anal. Calcd. for C20H17N3O2: C, 72.49; H,
5.17; N, 12.68. Found: C, 72.33; H, 7.11; N, 12.54.
107-109
(85)
C21H19N3O
(329.4)
IR: 2900 (CH aliphatic); 1660 (C=O). 1H NMR (CDCl3): d 8.72 (s, 1H, H-2); 8.50 (d, J4-5 = 7.8
Hz, 1H, H-4); 7.30-7.14 (m, 8H, H-5, H-6, H-7 and Ph-H); 5.99 (s, 1H, CH pyrazole); 5.37 (s,
2H, CH2); 2.66, 2.27 (2s, 6H, 2CH3). Anal. Calcd. for C21H19N3O: C, 76.57; H, 5.81; N, 12.76.
Found: C, 76.44; H, 5.76; N, 12.68.
228-30
(91)
C20H15N5O
(341.4)
IR: 3400, 3300 (NH2); 2210 (C=N); 1660 (C=O). 1H NMR (CDCl3): d 8.89 (s, 1H, H-2); 8.47 (d,
J4-5 = 8 Hz, 1H, H-4); 7.70 (s, 1H, CH pyrazole); 7.33-7.23 (m, 9H, H-5, H-6, NH2 and Ph-H);
7.13 (d, J6-7 = 8 Hz, 1H, H-7); 5.37 (s, 2H, CH2). Anal. Calcd. for C20H15N5O: C, 70.37; H, 4.43;
N, 20.52. Found: C, 70.25; H, 4.33; N, 20.45.
143-45
(85)
C22H20N4O3
(388.4)
IR: 3450, 3350 (NH2); 1680 (C=O). 1H NMR (CDCl3): d 8.91 (s, 1H, H-2); 8.48 (d, J4-5 = 8 Hz,
1H, H-4); 7.72 (s, 1H, CH pyrazole); 7.33-7.23 (m, 9H, H-5, H-6, NH2 and Ph-H); 7.13 (d, J6-7
8 Hz, 1H, H-7); 5.36 (s, 2H, CH2); 4.29 (q, J = 7.07 Hz, 2H, CH2CH3); 1.35 (t, J = 7 Hz, 3H,
=
CH2CH3). Anal. Calcd. for C22H20N4O: C, 68.03; H, 5.19; N, 14.42. Found: C, 67.97; H, 5.05; N,
14.34.
24
26
27
29
30
31
32
33
34
35
112-14
(90)
C16H12N4O
(276.1)
IR: 2150 (N3); 1650 (C=O). 1H NMR (CDCl3): d 8.91 (s, 1H, H-2); 8.48 (d, J4-5 = 8 Hz, 1H, H-
4); 7.33-7.23 (m, 7H, H-5, H-6, and Ph-H); 7.13 (d, J6-7 = 8 Hz, 1H, H-7); 5.35 (s, 2H, CH2).
Anal. Calcd. for C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.48; H, 4.24; N, 20.151.
IR: 3300 (NH); 1680 (C=O). 1H NMR (CDCl3): d 7.50 (d, J4-5 = 8 Hz, 1H, H-4); 7.27 (s, 1H, H-
2); 7.30-7.13 (m, 7H, H-5, H-6, and Ph-H); 7.10 (d, J6-7 = 8 Hz, 1H, H-7); 6.66 (s, 1H, NH); 5.26
(s, 2H, CH2); 4.26 (q, J = 7.16 Hz, 2H, CH2CH3); 1.34 (t, J = 6.96 Hz, 3H, CH2CH3).
IR: 3300 (NH); 1680 (C=O). 1H NMR (CDCl3): d 7.49 (d, J4-5 = 8 Hz, 1H, H-4); 7.26 (s, 1H, H-
2); 7.29-7.12 (m, 7H, H-5, H-6, and Ph-H); 7.10 (d, J6-7 = 8 Hz, 1H, H-7); 6.58 (s, 1H, NH); 5.24
(s, 2H, CH2); 4.03 (quant, J = 6.10 Hz, 1H, CH (CH3)2); 1.33, 1.31 (2s, 6H, 2CH3).
IR: 3300 (NH); 1635 (C=O). 1H NMR (DMSO-d6): d 8.54 (s, 1H, NH); 7.68 (s, 1H, H-2); 7.56
(d, J4-5 = 7.50 Hz, 1H, H-4); 7.45 (d, J6-7 = 8.08 Hz, 1H, H-7); 7.29-7.03 (m, 7H, H-5, H-6 and
Ph-H); 5.35 (s, 2H, CH2).
141-43
(72)
C18H18N2O2
(294.3)
128-30
(72)
C19H20N2O2
(308.2)
233-35
(35)
C31H26N4O
(470.2)
198-200
(71)
C16H16N4O
(280.1)
IR: 3400-3200 (NH and NH2); 1680 (C=O). 1H NMR (DMSO-d6): d 8.65 (s, 1H, NH); 8.37 (s,
1H, NH); 7.57 (s, 1H, H-2); 7.52 (d, J4-5 = 7.50 Hz, 1H, H-4); 7.41 (d, J6-7 = 8.08 Hz, 1H, H-7);
7.28-6.97 (m, 7H, H-5, H-6 and Ph-H); 5.34 (s, 2H, CH2); 4.35 (s, 2H, NH2).
IR: 3400 (NH); 1580 (C=O). 1H NMR (CDCl3): d 7.67 (d, J4-5 = 7.50 Hz, 1H, H-4); 7.39 (s, 1H,
H-2); 7.26-7.10 (m, 9H, H-5, H-6, H-7, NH and Ph-H); 5.26 (s, 2H, CH2); 3.60 (t, unresolved,
4H, N(CH2)2); 1.62-1.57 (m, 6H, 3CH2).
78-80
(65)
C21H23N3O
(333.2)
98-100
(50)
C20H21N3O2
(335.2)
IR: 3400 (NH); 1600 (C=O). 1H NMR (CDCl3): d 7.67 (d, J4-5 = 7.50 Hz, 1H, H-4); 7.39 (s, 1H,
H-2); 7.26-7.10 (m, 9H, H-5, H-6, H-7, NH and Ph-H); 5.26 (s, 2H, CH2); 3.68 (t, unresolved,
4H, OCH2); 2.53 (t, 4H, NCH2).
107-109 C18H19N3O2
(58)
IR: 3300 (NH); 1660 (C=O). 1H NMR (DMSO-d6): d 8.65 (s, 1H, NH); 8.37 (s, 1H, NH); 8.19
(d, J4-5 = 8 Hz, 1H, H-4); 8.13 (s, 1H, H-2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.32-7.12 (m, 7H, H-
5, H-6 and Ph-H); 5.43 (s, 2H, CH2); 3.79-3.35 (m, 5H, 2CH2 and OH).
(309.2)
115-17
(61)
C25H19N5S
(421.53)
IR: 3040 (CH aromatic). 1H NMR (DMSO-d6): d 8.19 (d, J4-5 = 8 Hz, 1H, H-4); 8.13 (s, 1H, H-
2); 7.50 (d, J6-7 = 8 Hz, 1H, H-7); 7.87-7.17 (m, 12H, H-5, H-6 and 2Ph-H); 5.35 (s, 2H, CH2);
4.30 (s, 2H, CH2 thidiazine).
100-104 C20H19N5OS
(51) (377.5)
IR: 3400, 3300 (NH2); 1700 (C=O). 1H NMR (CDCl3): d 8.71 (s, 1H, H-2); 8.50 (d, J4-5 = 7.8
Hz, 1H, H-4); 7.30-7.23 (m, 7H, H-5, H-6 and Ph-H); 7.15 (d, J6-7 = 8 Hz, 1H, H-7); 5.70 (s, 2H,
N-NH2); 5.30 (s, 2H, NCH2); 3.30 (s, 2H, SCH2); 2.13 (s, 3H, CH3).

150 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Farghaly
After cooling, the solid precipitate was collected by filtration
and recrystallized from ethanol to afford the title compounds
as white crystals of 4-7.
hydrate 99% (2 mL, 0.04 mol) in ethanol (10 mL) was re-
fluxed for 6 h. After cooling, the precipitate formed was col-
lected and recrystallized from ethanol to afford white crys-
tals.
4-Acetyl-4,5-dihydro-2-(1-benzyl-1H-indol-3-yl)-5-phenyl-
1,3,4-oxadiazole (8)
3-(1-Benzyl-1H-indol-3-yl)-4-phenyl-1,2,4-triazole-2-thione
(14)
Compound 3 (0.353 g, 0.001 mol) and redistilled acetic
anhydride (10 mL) was heated under reflux for 5 h. The reac-
tion mixture was cooled, poured onto water and allowed to
stand at room temperature for 3 h. The solid product formed
was collected and recrystallized from petroleum ether/ethyl
acetate mixture as white crystals.
Compound 12 (0.4 g, 0.001 mol), in an ethanolic potas-
sium hydroxide solution 4% (10 mL), was heated under re-
flux for about 4 h. The solvent was concentrated, diluted with
water and neutralized with diluted HCl at 0-5 °C. The crude
product was filtered off, washed with water and recrystal-
lized from ethanol to give white crystals.
2-(1-Benzyl-1H-indol-3-yl)-1,3,4-oxadiazole (9)
A mixture of 3 (0.265 g, 0.001 mol) and triethylorth-
formate (5 mL) was refluxed for 8 h. The solvent was evapo-
rated and the residue was triturated with ethanol. The solid
product obtained was filtered off and recrystallized from eth-
anol to give buff crystals.
4-Amino-3-(1-benzyl-1H-indol-3-yl)-1,2,4-triazol-5(1H)-
one (15)
A mixture of 11 (0.29 g, 0.001 mol) and hydrazine hy-
drate 99% (2 mL, 0.04 mol) in ethanol (10 mL) was refluxed
for 6 h. After cooling, the precipitate formed was collected
and recrystallized from ethanol to afford rosy pink crystals.
2-(1-Benzyl-1H-indol-3-yl)-1,3,4-oxadiazole-5(4H)-thione
(10)
5-(2¢-Diethylaminoethylthio)-3-(1-benzyl-1H-indol-3-yl)-4-
phenyl-1,2,4-triazole (16)
A mixture of 3 (0.265 g, 0.001 mol) and carbon disul-
fide (3 mL) in pyridine was refluxed on a water bath for 7 h,
then cooled and poured onto ice-cold water. The precipitate
formed was filtered off and recrystallized from ethanol to
give yellow crystals.
To a mixture of the thione 14 (0.382 g, 0.001 mol) and
sodium acetate (0.4 g, 0.005 mol) in ethanol (10 mL) was
added 2-diethylaminoethyl chloride hydrochloride (0.172 g,
0.001 mol). The mixture was refluxed for 7 h. and the reac-
tion was monitored by TLC. The solvent was removed under
reduced pressure and the residue was dissolved in water. The
product formed was collected and recrystallized from ethanol
as greenish white crystals.
2-(1-Benzyl-1H-indol-3-yl)-1,3,4-oxadiazol-5(4H)-one (11)
A mixture of the hydrazide compound 3 (0.265 g, 0.001
mol) and 1,1¢-carbonyldiimidazole (0.162 g, 0.001 mol) in
dry dioxane (10 mL) was heated under reflux for 6 h. After
cooling, the solvent was removed under reduced pressure and
the residue was triturated with cold water (20 mL). The solid
product was filtered off, dried and recrystallized from ethanol
to afford colorless crystals.
5-(2¢-Morpholinoethylthio)-3-(1-benzyl-1H-indol-3-yl)-4-
phenyl-1,2,4-triazole (17)
A mixture of the thione 14 (0.382 g, 0.001 mol), sodium
acetate (0.4 g, 0.005 mol) in ethanol (10 mL) and 4-(2-chloro-
ethyl) morpholine hydrochloride (0.188 g, 0.001 mol) was
refluxed for 6 h. The solvent was removed under reduced
pressure, the residue washed with water and the precipitate
obtained was filtered off and recrystallized from petroleum
ether/ethyl acetate mixture to give greenish white crystals.
N1-(1-Benzyl-1H-indol-3-oyl)-N4-phenylthiosemicarbazide
(12)
A mixture of compound 3 (0.265 g, 0.001 mol) and
phenyl isothiocyanate (0.13 mL, 0.001 mol) in ethanol (10
mL) was refluxed for 5 h. The reaction mixture was left to
cool and the white solid product formed was filtered off and
recrystallized from ethanol to give colorless crystals.
5-(2¢-Morpholinoethylthio)-2-(1-Benzyl-1H-indol-3-yl)-
1,3,4-oxadizole (18)
To a solution of the oxadiazolethione 10 (0.307 g, 0.001
mol), sodium acetate (0.4 g, 0.005 mol) and 4-(2-chloroethyl)
morpholine hydrochloride (0.188 g, 0.001 mol) in ethanol
(10 mL) was refluxed for 5 h. The solvent was evaporated and
4-Amino-3-(1-benzyl-1H-indol-3-yl)-1,2,4-triazole-5(1H)-
thione (13)
A suspension of 10 (0.307 g, 0.001 mol) and hydrazine

Indolyl-1,3,4-Oxadiazole, Triazole and Pyrazole
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 151
the residue was diluted with water and the solid product
formed was collected and recrystallized from petroleum
ether/ether mixture to afford white crystals.
reflux in ethanol (10 mL) for 5 h. The solvent was removed
under vacuum and the residue was recrystallized from etha-
nol as brownish yellow crystals.
1-(1-Benzyl-1H-indole-3-yl) carbonyl-1,2-dihydro-5-
methyl pyrazol-3-one (19)
Isopropyl N-(1-benzyl-1H-indol-3-yl) carbamate (27)
This compound was obtained via the above procedure
using isopropyl alcohol (10 mL) instead of ethanol. The prod-
uct resulted was recrystallized from the same alcohol to af-
ford the title compound as buff crystals.
A mixture of hydrazide derivative 3 (0.265 g, 0.001
mol) and ethyl acetoacetate (5 mL) was heated under reflux
for about 8 h. The excess of the solvent was removed in vacuo
and the residue was collected and recrystallized from ethanol
as buff crystals.
1,3-Bis-(1-benzyl-1H-indol-3-yl) urea (29)
A mixture of 24 (0.265 g, 0.001mol) and tertiary butyl
alcohol (10 mL) was refluxed for 4 h. After cooling, the sol-
vent was removed under reduced pressure and the solid prod-
uct obtained was recrystallized from tertiary butyl alcohol to
give white crystals.
(1-Benzyl-1H-indol-3-yl)-(3,5-dimethyl pyrazol-1-yl)
methanone (21)
A suspension of 3 (0.265 g, 0.001 mol) and acetyl-
acetone (2 mL, 0.02 mol) was gently refluxed for 2 h. After
cooling, the reaction mixture was triturated with ethanol and
the resulting product was collected and recrystallized from
methanol/ethyl acetate mixture as white crystals.
N4-(1-Benzyl-1H-indol-3-yl) semicarbazide (30)
A mixture of 24 (0.276 g, 0.001 mol) in dry toluene was
refluxed for 2 h. After cooling, hydrazine hydrate (2 mL, 0.04
mol) was added and the resulting mixture was heated under
reflux for 2 h. The solid precipitate formed was collected and
recrystallized from ethanol as brown crystals.
5-Amino-1-(1-benzyl-1H-indol-3-yl) carbonyl-1H-pyr-
azole-4-carbonitrile (22)
A mixture of 3 (0.265 g, 0.001 mol) and ethoxymeth-
ylene malononitrile (0.122 g, 1 mol) in absolute ethanol (10
mL) was heated under reflux for 6 h. After cooling, the sol-
vent was removed in vacuo and the solid residue was recrys-
tallized from ethanol to give white crystals.
Reaction of acid azide 24 with amines: Formation of the
derivatives 31-33
General procedure
A mixture of 24 (0.276 g, 0.001 mol) and an excess
(0.02 mol) of the respective amine (Piperdine, morpholine
and ethanol amine) was gently heated at 100-110 ºC for 2 h.
The reaction mixture then was triturated with ethanol and left
to cool. The crystalline solid precipitate was collected and
recrystallized.
Ethyl 5-amino-1-(1-benzyl-1H-indol-3-yl) carbonyl)-1H-
pyrazole-4-carboxylate (23)
A mixture of the hydrazide 3 (0.265 g, 0.001 mol) and
ethyl ethoxymethylene cyanoacetate (0.169 g, 0.001 mol) in
absolute ethanol (10 mL) was refluxed for 6 h. After cooling,
the solvent was removed under reduced pressure and the solid
residue was recrystallized from ethanol/light petroleum (1:2)
to afford colorless crystals.
1-Benzyl-3-piperidinocarbonylamino-1H-indole (31)
This compound was yielded employing the above pro-
cedure as buff crystals from petroleum ether/ethyl acetate
(1:1).
1-Benzyl-1H-indole-3-carbonylazide (24)
To a cold solution of 3 (2.65 g, 0.01 mol) in glacial ace-
tic acid (10 mL), sodium nitrite solution 10% (7 mL, 0.01
mol) was added. The reaction mixture was stirred at room
temperature over 15 min. The buff solid product formed was
filtered off, air dried and used in the next reaction without pu-
rification.
1-Benzyl-3-morpholinocarbonylamino-1H-indole (32)
This compound was yielded employing the above pro-
cedure as buff crystals from petroleum ether/ethyl acetate
(2:1).
N1-(1-Benzyl-1H-indol-3-yl)-N3-(2-hydroxyethyl) urea (33)
This compound was yielded employing the above pro-
cedure as buff crystals from methanol/ethyl acetate (1:1).
Ethyl N-(1-benzyl-1H-indol-3-yl) carbamate (26)
Compound 24 (0.265 g, 0.001 mol) was heated under

152 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Farghaly
3-(1-Benzyl-1H-indol-3-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazine (34)
our previous work directed to the synthesis of new pyrida-
zino[4,5-b]indole derivatives of pharmaceutical interest,15
the author reports herein the synthesis of oxadiazolo, triazolo
and pyrazolo compounds derived from indole. The starting
material 29 was prepared by the reaction of ethyl 1H-indol-3-
carboxylate with benzyl chloride in presence of anhydrous
potassium carbonate. Treatment of the ethyl 1-benzylindol-
2-carboxylate with hydrazine hydrate afforded the carbohy-
drazide derivative 3. Compound 3 proved to be a versatile
compound for the synthesis of a variety of oxdiazole and s-
triazole derivatives 8-18. The vast pharmaceutical activity of
the indole hydrazones10 encouraged us to synthesis a number
of new arylidene derivatives of potential biological interest.
Thus, condensation of the hydrazide 3 with aromatic alde-
hydes gave the corresponding arylidene derivatives 4-7.
Cyclization of the benzylidene compound 4 by its boiling
with acetic anhydride afforded the oxadizole derivative 8
(Scheme I).
A mixture of compound 13 (0.321 g, 0.001 mol),
phenacyl bromide (0.198 g, 0.001 mol) and sodium acetate
(0.4 g, 0.005 mol) in ethanol (10 mL) was refluxed for 7 h.
The solvent was evaporated, the residue was poured onto wa-
ter and the white solid product formed was filtered off and
recrystallized from ethanol to give yellow crystals.
4-Amino-3-(1-benzyl-1H-indol-3-yl)-5-acetonylthio-1,3,4-
triazole (35)
A mixture of compound 13 (0.321 g, 0.001mol), chloro
acetone (0.93 g, 0.001 mol) and sodium acetate (0.4 g, 0.005
mol) in ethanol (10 mL) was refluxed for 7 h. The solvent was
evaporated, the residue was poured onto water and the white
solid product formed was filtered off and recrystallized from
benzene to give brown crystals.
Biological Screening
The interaction of hydrazide 3 with triethylorthofor-
mate yielded the oxadiazole derivative 9, whereas its reaction
with carbon disulfide in boiling pyridine gave the corre-
sponding oxadiazolthione 10 in 87% yield. A convenient syn-
thesis for its oxygen analogue was done. Thus the oxadi-
azolone 11 was accomplished by treatment of the hydrazide 3
with 1,1¢-carbonyldiimidazolyl (CDI) in refluxing dioxane
(93% yield).
The filter paper disc method was performed in nutrient
agar for bacteria and Czapek’s Dox agar for fungi. These agar
media were inculcated with 0.5 mL of the 24 h liquid cultures.
Filter paper discs (5 mm diameter) saturated with each com-
pound solution (10 mg/1 mL of N,N-dimethylformamide,
DMF) were placed on the indicated agar media. The incuba-
tion time was 48 h (at 37 C for bacteria and 28 C for fungi).
Discs saturated with DMF were used as control. The diame-
ters of inhibition zones (mm) were measured and recorded.
Furthermore, when compound 3 was allowed to react
with phenyl isothiocyanate, the product was identified as
N1-(1-Benzyl-1H-indol-3-oyl)-N4-phenylthiosemicarbazide
12. The latter compound was subjected to a cyclization reac-
tion by refluxing with an ethanolic potassium hydroxide solu-
tion to give the s-triazolthione 14. The amino triazolo deriva-
tives 13 and 15 were obtained by treatment of the precursors
RESULTS AND DISCUSSION
With all the above facts in mind and in continuation of
Scheme I
COOEt
COOEt
CONHNH2
N2H4.H2O
PhCH2Cl
K2CO3 / DMF
N
EtOH
N
N
H
1
2
3
Ph
Ph
ArCHO
EtOH
COCH3
N
N
Ph
H
CONHN=CHAr
Ac2O
O
4, Ar = C6H5
Ar = Ph
N
5, Ar = C6H4Cl(p)
6, Ar = C6H4OCH3(p)
7, Ar = C6H4N(CH3)2(p)
N
Ph
8
Ph

Indolyl-1,3,4-Oxadiazole, Triazole and Pyrazole
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 153
Scheme II
oxadiazolo derivatives 10 and 11 with hydrazine hydrate via
ring opening reaction (Scheme II). The ring opening of 10
and 11 was substantiated by spectroscopic data. The IR spec-
trum of compound 13 or 15 showed bands at 3280, 3180 cm-1
(NH2) and 3100 cm-1 (NH).
85% yield. Interestingly, the hydrazide 3 was used as a deriv-
ative of hydrazine hydrate to prepare new pyrazole deriva-
tives 22 and 23. Thus, interaction of the 3 with ethoxymeth-
ylene malononitrile and ethyl ethoxymethylenecyanoacetate
furnished the corresponding pyrazolyl derivatives 22 and 23,
respectively.
Interestingly, the thione function in compound 14
should offer the possibility for further elaboration by alkyla-
tion reaction, e.g. the introduction of the basic side chains as
potentially pharmacophoric substructures. Thus 14 was
treated with diethylaminoethyl chloride hydrochloride and
with 4-(2-chloroethyl) morpholine hydrochloride in reflux-
ing ethanol in the presence of anhydrous sodium acetate to
give the corresponding s-alkylated products 16 and 17, re-
spectively. Similarly, interaction of 10 with 4-(2-chloroethyl)
morpholine hydrochloride under the same reaction condi-
tions gave the s-alkylated product 18 in good yield (Scheme
III).
Diazotization of 3 with an equimolar quantity of so-
dium nitrite in glacial acetic acid produced the carboazide
compound 24. On refluxing 24 in ethanol or isopropyl alco-
hol, it underwent Curtius rearrangement where the isocya-
nate derivative 25 was formed as intermediate (Scheme V).
The latter intermediate reacted concomitantly with ethanol
and isopropyl alcohol, used as a solvent to give the corre-
sponding ethyl and isopropyl carbamate 26 and 27, respec-
tively. Interestingly, refluxing of the carboazide 24 with ter-
tiary butyl alcohol did not give the tertiary butyl carbamate
28 but afforded the urea derivative 29, which was prepared
independently by boiling 24 with water. When the alcohols
was replaced by amines, the corresponding urea derivatives
31-33 were obtained. It is noteworthy that when the acid
azide 24 was heated in an excess of hydrazine hydrate,
Curtius rearrangement did not occur and the product was
Treatment of 3 with ethyl acetoacetate without solvent
did not afford the ester derivative 20 but gave the cyclized
product, pyrazolone derivative 19. On the other hand, con-
densation of the hydrazide with acetyl acetone in refluxing
ethanol gave the corresponding pyrazolyl derivative 21 in

154 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Farghaly
Scheme III
H
N
N
S
N
Ph
N
14
O
N(CH2)2Cl.HCl
Ph
O
Et2N(CH2)2Cl.HCl
AcONa / EtOH
AcONa / EtOH
CH3
CH3
N
N
N
N
N
N
S
N
S
N
Ph
Ph
N
N
17
16
O
Ph
Ph
H
N
N
N
N
N
S
O
S
O
N(CH2)2Cl.HCl
AcONa / EtOH
O
N
N
10
18
Ph
Ph
Scheme IV
O
CH3
O
CH3
N
CH3COCH2COOEt
N
N
H
CH3COCH2COCH3
EtOH
3
N
O
N
N
CH3
O
CH3
20
Ph
EtCOOCH=CN(R2)
EtOH
Ph
21
O
CH3
O
NH2
N
R2
N
HN
N
N
N
O
Ph
19
Ph
22, R2 = CN,
23, R2 = COOEt
identified as acid hydrazide 3. However, when 24 was boiled
first in dry toluene to insure the Curtius rearrangement of 24
into the isocyanate 25 followed by addition of an excess of
hydrazine hydrate, the expected semicarbazide 30 was ob-
tained in 71% yield.
thiadiazine 34. Whereas, its reaction with chloro acetone did
not give the thiadiazine 36 but gave the corresponding
acetonylthio derivative 35.
Antimicrobial activity
Finally, refluxing the triazolthione 13 with phenacyl
bromide in ethanol produced the corresponding 3-(1-Benzyl-
1H-indol-3-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-b][1,3,4]
Some selected representatives of the newly synthesized
compounds were screened in vitro for their antimicrobial
activities against four strains of bacteria* (Staphylococcus
*All bacteria are from Assiut University, not purchased from ATCC

Indolyl-1,3,4-Oxadiazole, Triazole and Pyrazole
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 155
Scheme V
NHCOOR3
N=C=O
CON3
R3OH
D
NaNO2 / HCl
3
N
N
N
25
24
Ph
Ph
26-27
Ph
R4H
26, R3 = C2H5
27,
NHCOR4
D
N2H4.H2O
Toluene
R3 = CH(CH3)2
H2O
(CH3)3COH
D
N
NHCONHNH2
Ph
H
H
N
NHCOOC(CH3)3
31-33
N
N
30
N
31, R4 =
O
N
N
N
Ph
28
29
32, R4 =
N
O
Ph
Ph
Ph
33, R4 = NHCH2CH2OH
Scheme VI
H
N
N
N
N
N
N
S
S
N
N
CH3COCH2Cl
EtOH
N
PhCOCH2Br
EtOH
S
N
N
NH2
N
N
N
CH3
Ph
13
34
Ph
36
Ph
Ph
N
N
S
N
NH2
N
O
35
CH3
Ph
aureus, Serratia marcescens, Streptococcus, Pseudomonas
aeruginosa) and two species of fungi (Aspergillus parasitcus,
Penicillium oxalicum) using the filter paper disc method.16
The screening results given in Table 2 indicated that most of
the compounds tested exhibit considerable activities against
two bacterial species, Serratia marcescens and Streptococ-
cus. Compound 33 exhibits a moderate activity against
Staphylococcus aureus. All the screened compounds were in-
active against Pseudomonas aeruginosa. As far as the
anti-fungal activity is concerned, only compound 7 showed a
Table 2. The Antibacterial and Antifungal Activities of Some Compounds Synthesized
(Diameter of inhibition zone in mm)
Compd
Pseudo.
Staph.
aureus
Streptoc.
Serratia
Penicill.
oxalicum
Asperg.
aeruginosa
marcescns
parasitcus
3
7
10
30
33
-
-
-
-
-
-
-
-
-
9
7
13
-
-
-
-
9
13
14
-
-
7
-
-
-
-
-
-
-
-
-: No inhibition

156 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Farghaly
7. (a) Fernandez-Alvarez, E.; Lone, M.; Monge, A. Bull. Soc.
Chim. Fr. 1969, 1932. (b) Marco, J. L. J. Heterocycl. Chem.
1998, 35, 475.
moderate activity against Penicillium oxalicum. The other
compounds tested showed no activity against the two fungal
species.
8. (a) Perez, S.; Lasheras, B.; Oset, C.; Monge, A. J.
Heterocycl. Chem. 1997, 34, 1527. (b) Cruces, M. A.;
Elorriaga, C.; Fernandez-Alvarez, E. Eur. J. Med. Chem.
1991, 26, 33. (c) Cruces, M. A.; Elorriaga, C.; Fernandez-
Alvarez, E. Biochem. Pharmacol. 1990, 40, 535.
9. Alemany, A.; Fernandez-Alvarez, E.; Henandez-Sanchez, R.
An. Quim. 1975, 71(1), 88.
Received March 25, 2003.
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