On the synthesis and reactions of indole-2-carboxylic acid hydrazide

Article abstract of DOI:10.1007/s007060170091

Indole-2-carboxylic acid hydrazide was prepared and allowed to react with aromatic aldehydes in acidic medium to give the corresponding hydrazone derivatives in good yields. The hydrazones were cyclized to indolo[2,3-d]pyridazine derivatives by refluxing with acetyl chloride. The indole carbohydrazide was converted to 2-triazolylindoles which acted as starting materials for several indole derivatives. A number of new indole derivatives were also prepared and structurally confirmed.

Full text of DOI:10.1007/s007060170091

Monatshefte fuÈr Chemie 132, 753±763 (2001)
On the Synthesis and Reactions of Indole-2-
carboxylic Acid Hydrazide
Abd El-Wareth A. O. Sarhan
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Summary. Indole-2-carboxylic acid hydrazide was prepared and allowed to react with aromatic
aldehydes in acidic medium to give the corresponding hydrazone derivatives in good yields. The
hydrazones were cyclized to indolo[2,3-d]pyridazine derivatives by re¯uxing with acetyl chloride.
The indole carbohydrazide was converted to 2-triazolylindoles which acted as starting materials for
several indole derivatives. A number of new indole derivatives were also prepared and structurally
con®rmed.
Keywords. Indole alkaloids; Synthesis; Hydrazides; Indolopyridazines; Indolyltriazoles.
Introduction
Indole has been investigated as a starting material for the synthesis of organic
natural products as well as a precursor in alkaloid chemistry. Indole-2-carbo-
hydrazide derivatives have been shown to inhibit monoamine oxidase A activity
[1,2]. Some N-methylindole-3-hydrazones have shown antihypertensive activity in
spontaneously hypertensive rats [3]. Several 3-substituted indoles proved useful as
materials for alkaloids, agrochemicals, pharmaceuticals, and perfumes [4]. Indole
acetic acid has been shown to be active against E. coli [5]. Several indole-3-
carbohydrazide derivatives have been prepared and studied chemically [6, 7]. These
®ndings prompted the synthesis of a number of indole-2-carbohydrazide derived
systems of potential biological activity.
Results and Discussions
This work is focused on the synthesis and the chemical behavior of new indole
derivatives. Indole-2-carboxylic acid ethyl ester (1) was reacted with hydrazine
hydrate to give the corresponding indole-2-carboxylic acid hydrazide (2) in good
yield. The structure of 2 agreed with that reported in the literature [1, 2]. Upon
condensation of 2 with aromatic aldehydes, the hydrazone derivatives 3a±f were
obtained in varying yields. Re¯uxing 3b and 3c in acetyl chloride afforded the
corresponding indolo[2,3-d]pyridazine derivatives 4a,b rather than the indenotri-
azines 5 (Scheme 1).
The cyclization of 4a and 4b was substantiated by spectroscopic data and
1
microanalysis. The IR spectrum of 4b revealed two NH signals at 3295±3300 cm .

754
A. A. O. Sarhan
Scheme 1
1
An exchangeable NH proton could be denoted in the H NMR spectrum of 4b
which excluded the formation of 5. The mass spectrum of 4a provided the expected
molecular ion peak. Acetylation of 2 by re¯uxing in acetic acid afforded 2-
acetylhydrazinocarbonylindole (6) in high yield. Product 6 could be cyclized
directly by re¯uxing in dioxane containing POCl3 to the indolo[3,2-b]pyridazine
derivative 7 in low yield. On the other hand, re¯uxing 2 in formic acid for 5 hours
afforded the N-formyl derivative 8 in good yield. The indolo[3,2-b]pyridazine
derivative 9 has been known for several years as an azacarboline derivative [8]. Here
we present a different route for its synthesis. By ring closure of 8 upon heating
above its melting point for 10 minutes followed by re¯uxing in ethanol for further 3
hours, 9 was obtained in 43% yield (Scheme 2).
Upon condensation of 2 with acetylacetone in ethanol containing a catalytic
amount of acetic acid, the corresponding derivative 10 was obtained in 64% yield.
Reaction of 2 with ethyl acetoacetate without solvent gave the ester derivative 11 in
70% yield. 11 could be cyclized to the pyrazolone derivative 12 by heating above
its melting point for 10 minutes followed by re¯uxing in methanol for further 2
hours. Compound 12 was also obtained independently in 34% yield via direct
re¯uxing of 2 with ethyl acetoacetate in ethanol/acetic acid mixture for 5 hours
(Scheme 3).
On the other hand, reaction of 2 with KSCN in re¯uxing ethanol containing
catalytic amounts of HCl gave after work up the salt 13 which was converted

Reactions of Indole-2-carboxylic Acid Hydrazide
755
Scheme 2
Scheme 3
directly to 14 by heating in aqueous KOH followed by acidi®cation with HCl in
good yield. When 2 was re¯uxed with equimolecular amounts of alkyl/aryl-
isothiocyanates in ethanol the corresponding thiosemicarbazide derivatives 15a±d
were obtained in high yields. Cyclization of 15a±d using an aqueous solution of

756
A. A. O. Sarhan
Scheme 4
KOH followed by neutralization with HCl furnished 16a±d in excellent yields
(Scheme 4).
Alkylation of 16c using ethyl iodide or benzyl bromide in the presence of KOH
gave the S-ethyl and S-benzyl derivatives 17a and 17b in good yields. Upon reaction
of 16c with phenacylbromide derivatives in methanol containing KOH or fused
sodium acetate, the corresponding thioacetophenone derivatives 18a,b were obtained
in good yields. Furthermore, reaction of 16c with diethyl bromomalonate under the
same reaction conditions led to the corresponding thioester 19 (Scheme 5).
Scheme 5

Reactions of Indole-2-carboxylic Acid Hydrazide
757
Experimental
Melting points are uncorrected. IR Spectra were measured on a Shimadzu-470 spectrophotometer
using KBr discs. Elemental analyses were performed with a Perkin-Elmer elemental analyzer 240-C;
the results were in satisfactory agreement with the calculated values. 1H NMR spectra were recorded
on a Varian EM-390 spectrometer operating at 90 MHz; TMS was used as an internal standard.
Mass spectra were measured on a Shimadzu-GC-MS-QP 1000EX spectrometer using the direct
inlet system. Starting materials were commercially available. Solvents were distilled and dried
before use.
Indole-2-carboxylic acid hydrazide (2; C9H9N3O)
A mixture of 1 g 2-ethoxycarbonylindole (1; 5.3 mmol) and 2 cm3 hydrazine hydrate was re¯uxed in
20 cm3 ethanol for 4 h. The precipitate formed after cooling was collected by ®ltration to give 0.73 g
(98.5%) of colorless crystals of 2.
M.p.: 247±248ꢀC [1,2]; IR (KBr): ꢀ ˆ 3300m, 3200m, 3100w, 3080w, 2900w, 1640s, 1615s,
1
1550m, 780m, 740s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 11.7 (s, NHindole, exchangeable), 9.85
(bs, NHCO, exchangeable), 7.0±7.8 (m, 4Harom ‡ CHindole), 4.5 (bs, 2H, NH2) ppm; MS: m/z
(%) ˆ 177 [M‡2] (16), 176 [M‡1] (62), 160 (5), 158 (7), 147 (6), 145 (60), 127 (3), 118 (13), 117
(25), 116 (30), 111 (4), 92 (3), 68 (4), 57 (5), 50 (5).
2-Arylideneaminocarbonylindoles (general procedure)
A mixture of 1 g of 2 (5.7 mmol) and 6.28 mmol of aromatic aldehyde was re¯uxed in 25 cm3
ethanol/acetic acid (24:1) for 3 h. The precipitate resulting after cooling was collected by ®ltration
and recrystallized from EtOH to give the 2-arylideneaminocarbonylindoles 3a±f.
1H-Indole-2-carboxylic acid benzylidene-hydrazide (3a; C16H13N3O)
Yield: 74%; m.p.: 194±196ꢀC; IR (KBr): ꢀ ˆ 3400w, 3300w, 3050w, 2900w, 1650m, 1600s, 1565m,
1300s, 740 cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable), 11.2 (s, CONH,
exchangeable), 8.3 (s, N=CH), 6.9±7.8 (m, 9Harom ‡ CHindole) ppm.
1H-Indole-2-carboxylic acid (4-methoxy-benzylidene)-hydrazide (3b; C17H15N3O2)
Yield: 67%; m.p.: 220±222ꢀC; IR (KBr): ꢀ ˆ 3300s, 3050w, 1640s, 1600s, 1540s, 1500s, 1255s,
1025s, 740s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable), 9.3 (s, CONH,
exchangeable), 8.3 (s, N=CH), 7.0±7.8 (m, 8Harom ‡ CHindole), 3.85 (s, 3H, OCH3) ppm; MS: m/z
‡
(%) ˆ 294 [M‡1] (20), 293 [M ] (84), 276 (4), 263 (4), 235 (7), 177 (4), 160 (48), 150 (40), 144
(100), 134 (8), 117 (7), 116 (26), 89 (39), 77 (7), 63 (6), 51 (4).
1H-Indole-2-carboxylic acid (4-chloro-benzylidene)-hydrazide (3c; C16H12N3OCl)
1
Yield: 58%; m.p.: 251±252ꢀC; IR (KBr): ꢀ ˆ 3300s, 1630s, 1490m, 1540s, 1250s, 740s cm 1; H
NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable), 9.3 (s, CONH, exchangeable), 8.4 (s,
N=CH), 7.0±7.9 (m, 8Harom ‡ CHindole) ppm; MS: m/z (%) ˆ 299 [M‡2] (40), 298 [M‡1] (37), 297
‡
[M ] (66), 286 (9), 279 (7), 258 (7), 238 (13), 202 (9), 184 (6), 158 (44), 151 (22), 143 (100), 115
(74), 110 (75), 98 (12), 90 (51), 75 (26), 63 (46), 50 (15), 37 (23).

758
A. A. O. Sarhan
1H-Indole-2-carboxylic acid (2-nitro-benzylidene)-hydrazide (3d; C16H12N4O3)
Yield: 76%; m.p.: 231±233ꢀC; IR (KBr): ꢀ ˆ 3300s, 3050s, 1660w, 1610s, 1535s, 1510s, 1235s,
1
730s cm
;
1H NMR (DMSO-d6, ꢁ, 90 MHz); 11.8 (s, NHindole, exchangeable), 11.2 (s, CONH,
exchangeable), 8.9 (s, N=CH), 7.0±8.3 (m, 8Harom ‡ CHindole) ppm.
1H-Indole-2-carboxylic acid (4-N-dimethyl-benzylidene)-hydrazide (3e; C18H18N4O)
Yield: 72%; m.p.: 218±220ꢀC; IR (KBr): ꢀ ˆ 3400s, 3300s, 3050m, 2900w, 1620s, 1590s, 1590s,
1
1560s, 1510s, 1250s, 720s cm
;
1H NMR (TFA, ꢁ, 90 MHz): 8.1 (s, N=CH), 7.0±7.9 (m,
8Harom ‡ CHindole), 3.2 (s, 6H, NꢁCH3†2) ppm.
1H-Indole-2-carboxylic acid (2-methoxy-benzylidene)-hydrazide (3f; C17H15N3O2)
Yield: 67%; m.p.: 243±245ꢀC; IR (KBr): ꢀ ˆ 3325m, 3200m, 3050w, 2960w, 1665s, 1630m, 1520s,
1480s, 1255s, 1050s, 730s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable),
7.5 (s, N=CH), 6.3±7.4 (m, 8Harom ‡ CHindole), 3.5 (s, 3H, OCH3) ppm.
3-Acetyl-4-aryl-1,2,3,4-tetrahydro-indolo[2,3-d]pyridazin-1-ones (general procedure)
A mixture of 0.1 g of 3b or 3c was re¯uxed in 10 cm3 acetyl chloride for 3 h. The reaction mixture
was cooled, diluted with 50 cm3 H2O, and neutralized with Na2CO3 solution; the precipitate formed
was collected by ®ltration. The crude product was washed with H2O (3x) and crystallized from
EtOH.
3-Acetyl-4-(4-chloro-phenyl)-1,2,3,4-tetrahydro-indolo[2,3-d]pyridazin-1-one (4a; C18H14N3O2Cl)
Yield: 81%; m.p.: 200±201ꢀC; IR (KBr): ꢀ ˆ 3300s, 3210m, 3050w, 2910w, 1700m, 1660s, 1635s,
1
1545m, 1485s, 1250s, 1090s, 810s, 740s cm
;
1H NMR (DMSO-d6, ꢁ, 90 MHz): 6.9±7.8 (m,
8Harom ‡ CHpyridazine), 2.4 (s, 3H, COCH3) ppm; MS: m/z (%) ˆ 341 [M‡2] (30), 340 [M‡1] (24),
‡
339 [M ] (55), 296 (65), 279 (39), 266 (18), 252 (6), 237 (10), 232 (11), 219 (12), 217 (27), 204
(25), 199 (94), 186 (33), 165 (37), 160 (21), 155 (16), 145 (16), 144 (100), 149 (43), 137 (50), 129
(46), 116 (20), 114 (13), 111 (13), 102 (21), 92 (12), 89 (37), 77 (8), 74 (53), 63 (11), 50 (4), 43 (29).
3-Acetyl-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydro-indolo[2,3-d]pyridazin-1-one (4b; C19H17N3O3)
Yield: 76%; m.p.: 151±153ꢀC; IR (KBr): ꢀ ˆ 3290s, 3200m, 3050s, 2930w, 2820w, 1700s, 1660m,
1
1600s, 1540m, 1500s, 1245s, 1060s, 830s, 740s cm
;
1H NMR (CDCl3, ꢁ, 90 MHz): 10.1 (s,
NHpyridazinone, exchangeable), 11.1 (s, NHindole, exchangeable), 6.4±7.4 (m, 8Harom ‡ CHpyridazine), 3.8
(s, 3H, OCH3), 2.2 (s, 3H, COCH3) ppm.
1H-Indole-2-carboxylic acid N1-acetyl-hydrazide (6; C11H11N3O2)
A sample of 0.4 g 2 (2.2 mmol) was re¯uxed in 10 cm3 acetic acid for 5 h. The reaction mixture was
cooled, and the crystalline product was collected by ®ltration to give 0.35 g (72%) of 6.
M.p.: 273±275ꢀC; IR (KBr): ꢀ ˆ 3300s, 3250s, 3050m, 1670s, 1650s, 1540s, 1490s, 1250s, 740s,
1
700s cm
;
1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.9 (s, NHindole, exchangeable), 10.3 (s, NHCO,
exchangeable), 9.9 (s, NHCO, exchangeable), 7.0±7.9 (m, 4Harom ‡ CHindole), 2.0 (s, 3H, CH3) ppm;
‡
MS: m/z (%) ˆ 217 [M ] (3), 216 (27), 215 (96), 198 (6), 173 (27), 143 (100), 130 (12), 116 (34),
115 (80), 102 (8), 98 (99), 77 (9), 63 (45), 50 (7).

Reactions of Indole-2-carboxylic Acid Hydrazide
759
2,3-Dihydro-4-methyl-indolo[3,2-b]pyridazin-1-one (7; C11H9N3O)
A sample of 0.2 g 6 (0.92 mmol) was re¯uxed in 10 cm3 dioxane containing 1.0 cm3 phosphorus
trichloride for 3 h. The reaction mixture was cooled and diluted with ice-cold H2O, followed by
neutralization with NH4OH. The precipitate formed was collected by ®ltration and crystallized from
aqueous EtOH (50%) to give 43% of 7.
M.p.: 212±214ꢀC, 211±213ꢀC [10]; IR (KBr): ꢀ ˆ 3250m, 3050w, 2900w, 1650m, 1540s,
1
1260m, 740s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 6.9±7.5 (m, 4Harom), 2.0 (s, 3H, CH3) ppm.
1H-Indole-2-carboxylic acid N1-formyl-hydrazide (8; C10H9N3O2)
A sample of 0.21 g 2 (1.2 mmol) was re¯uxed in 15 cm3 formic acid for 6 h. The reaction mixture
was cooled, and the colourless crystals formed were collected by ®ltration to give 74% of 8.
M.p.: 230ꢀC; IR (KBr): ꢀ ˆ 3400s, 3250s, 3100s, 3000m, 2900s, 1665s, 1645s, 1540s, 1420m,
1230s, 740s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable), 10.6 (s, NHCO,
exchangeable), 10.3 (s, NHCO, exchangeable), 8.05 (s, 1H, HCO), 7.6±6.8 (m, 4Harom ‡ CHindole
)
‡
ppm; MS: m/z (%) ˆ 203 [M ] (100), 185 (1), 175 (3), 160 (2), 145 (7), 144 (66), 116 (3), 90 (1), 89
(10), 63 (1), 39 (1).
2,3-Dihydro-indolo[3,2-b]pyridazin-1-one (9; C10H7N3O)
A sample of 0.1 g 8 (0.5 mmol) was heated to 230ꢀC for 10 min and re¯uxed in 20 cm3 EtOH for
further 3 h. The reaction mixture was cooled and the precipitate obtained was collected by ®ltration
and crystallized from EtOH to give 43% of 9.
M.p.: 325±327ꢀC, 326±328ꢀC [9]; IR (KBr): ꢀ ˆ 3270s, 3180m, 3050m, 2900m, 1645s, 1530m,
1440s, 1400s, 1195s, 730s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 12.0 (s, NHindole, exchangeable),
10.7 (s, NH, exchangeable), 9.0 (s, CHpyridazine), 8.0±7.1 (m, 4Harom) ppm.
(3,5-Dimethyl-pyrazol-1-yl)-(1H-indol-2-yl)-methanone (10; C14H13N3O)
A mixture of 0.16 g 2 (0.9 mmol), 0.2 g acetylacetone (2.0 mmol), and 1.0 cm3 acetic acid was
re¯uxed in 10 cm3 EtOH for 5 h. The precipitate which formed after cooling was collected by
®ltration and recrystallized from EtOH to give 64% of 10 as colourless crystals.
M.p.: 103±105ꢀC; IR (KBr): ꢀ ˆ 3330s, 3100w, 2960w, 2910w, 1665s, 1585s, 1510s, 1480s,
1
1430s, 1260s, 1095s, 735s cm 1; H NMR (CDCl3, ꢁ, 90 MHz): 11.2 (s, NHindole, exchangeable),
7.0±7.8 (m, 4Harom ‡ CHindole), 6.0 (s, CHpyrazole), 2.6 (s, 3H, CH3), 2.3 (s, 3H, CH3) ppm; MS: m/z
‡
(%) ˆ 239 [M ] (14), 238 [M 1] (71), 209 (16), 160 (2), 142 (37), 128 (2), 114 (51), 105 (3), 95 (8),
89 (44), 76 (3), 63 (9), 51 (3), 29 (6).
3-((1H-Indole-2-carbonyl)-hydrazono)-butyric acid ethyl ester (11; C15H17N3O3)
A mixture of 0.21 g 2 (1.2 mmol) and 0.2 g ethyl acetoacetate (1.6 mmol) was condensed without
solvent at 180±190ꢀC for 10 min. The reaction mixture was cooled and re¯ux in 25 cm3 EtOH for
2 h. The precipitate formed after cooling was collected by ®ltration and recrystallized from EtOH to
give 70% 11 as colourless crystals.
M.p.: 100±102ꢀC; IR (KBr): ꢀ ˆ 3300s, 3220w, 3050w, 2990w, 1725m, 1680s, 1635s, 1525s,
1
1470m, 1240s, 1200s, 1020s, 740s cm
; ,
1H NMR (CDCl3, ꢁ, 90 MHz): 11.6 (s, NHindole
exchangeable), 10.2 (s, CONH, exchangeable), 7.8±6.9 (m, 4Harom ‡ CHindole), 4.4±4.1 (q, J ˆ 7 Hz,
2H, CH2CH3), 3.4 (s, 2H, CH2), 2.2 (s, 3H, CH3), 1.5±1.3 (t, J ˆ 7 Hz, 3H, CH2CH3) ppm.

760
A. A. O. Sarhan
1-(1H-Indole-2-carbonyl)-5-methyl-1,2-dihydro-pyrazol-3-one (12; C13H11N3O2)
Method A: A mixture of 0.16 g 2 (0.9 mmol), 0.2 g ethyl acetoacetate, and 1.0 cm3 acetic acid was
re¯uxed in 10 cm3 EtOH for 5 h. The precipitate formed after cooling was collected by ®ltration and
recrystallized from EtOH to give colorless crystals of 12.
Yield: 34%; m.p.: 270±271ꢀC; IR (KBr): ꢀ ˆ 3350m, 3300s, 3050w, 1660s, 1640s, 1520s, 1480s,
1420s, 1240s, 1195s, 740s, 700s cm 1; 1H NMR (TFA, ꢁ, 90 MHz): 7.9±7.3 (m, 4Harom ‡ CHindole),
4.4 (d, J ˆ 7 Hz, CHpyrazolone), 1.5 (s, 3H, CH3) ppm; MS: m/z (%) ˆ 240 [M 1] (10), 197 (11), 166
(15), 160 (8), 158 (14), 142 (9), 127 (28), 115 (9), 96 (23), 80 (9), 77 (8), 66 (10), 64 (100), 41 (10),
30 (22).
Method B: A sample of 0.1 g 11 (0.35 mmol) was re¯uxed in EtOH:CH3COOH ˆ 10:2 for 8 h.
The reaction mixture was cooled, and the crystals formed were collected by ®ltration and crystallized
from EtOH to give 67% 12 as colourless crystals.
5-(1H-Indol-2-yl)-4H-[1,2,4]triazole-3-thiol (14; C10H8N4S)
A mixture of 0.5 g 2 (2.8 mmol) and 0.5 g KSCN (5.1 mmol) was re¯uxed in 25 cm3 ethanol
containing a few drops of conc. HCl for 3 h. The precipitate formed was collected by ®ltration and
dried to give 13 (75%) which was used without further puri®cation. A mixture of 0.4 g 13 (1.3 mmol)
and 0.1 g KOH (1.6 mmol) was re¯uxed in 25 cm3 H2O for 3 h. The reaction mixture was cooled and
then acidi®ed with HCl to give 30% 14.
M.p.: 294±296ꢀC; IR (KBr): ꢀ ˆ 3300s, 3200m, 3050w, 2920m, 1640s, 1590s, 1540s, 1490m,
1220m, 1195s, 740s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 13.9 (s, NHtriazole, exchangeable), 13.7
(s, NHtriazole, exchangeable), 11.9 (s, NHindole, exchangeable), 7.7±6.9 (m, 4Harom ‡ CHindole) ppm.
1H-Indole-2-carboxylic acid N1-thiaalkoyl/aroyl-hydrazides (general procedure)
A mixture of 0.5 g 2 (2.8 mmol) and 2.9 mmol alkyl/arylisothiocyanate derivative was re¯uxed in
25 cm3 EtOH for 3±5 h. The precipitate formed was collected by ®ltration and dried to give the
corresponding derivatives 15a±d.
1H-Indole-2-carboxylic acid N1-thiaacetyl-hydrazide (15a; C11H12N4OS)
Yield: 74%; m.p.: 242±243ꢀC; IR (KBr): ꢀ ˆ 3320s, 3200s, 2905m, 1635s, 1545s, 1520s, 1230s,
1
1200s, 730s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 11.8 (s, NHindole, exchangeable), 10.5 (s, NH,
exchangeable), 9.3 (s, NH, exchangeable); 6.8±7.5 (m, 4Harom ‡ CHindole), 2.8 (d, J ˆ 5 Hz, 3H,
CH3) ppm.
1H-Indole-2-carboxylic acid N1-thiapropionyl-hydrazide (15b; C12H14N4OS)
Yield: 89%; m.p.: 219±221ꢀC; IR (KBr): ꢀ ˆ 3350m, 3290s, 3230s, 2990m, 1660s, 1610s, 1530s,
1
1475s, 1440m, 1260s, 1040s, 740s cm
; ,
1H NMR (DMSO-d6, ꢁ, 90 MHz): 11.1 (s, NHindole
exchangeable), 9.7 (s, NH, exchangeable), 9.3 (s, NH, exchangeable), 8.2 (s, NH, exchangeable),
7.9±7.8 (m, 4Harom ‡ CHindole), 3.4 (dq, J ˆ 0:5 Hz, J ˆ 7 Hz, 2H, NHCH2CH3), 1.1 (t, J ˆ 7 Hz,
3H, CH2CH3) ppm.
1H-Indole-2-carboxylic acid N1-thiabenzoyl-hydrazide (15c; C16H14N4OS)
Yield: 87%; 221±223ꢀC; IR (KBr): ꢀ ˆ 3300s, 3200s, 2900w, 1650s, 1630w, 1590m, 1520s, 1190s,
1
730s cm 1; H NMR (TFA, ꢁ, 90 MHz): 7.0±7.6 (m, 9Harom ‡ CHindole) ppm; MS: m/z (%) ˆ 310

Reactions of Indole-2-carboxylic Acid Hydrazide
761
‡
[M ] (21), 309 [M 1] (58), 291 (6), 275 (20), 232 (5), 227 (9), 215 (83), 205 (2), 192 (11), 173
(100), 158 (16), 155 (18), 143 (99), 128 (12), 115 (82), 107 (22), 102 (27), 89 (100), 77 (86), 63 (78),
51 (29), 49 (70), 42 (28), 29 (57).
1H-Indole-2-carboxylic acid N1-cyclohexanthiocarbonyl-hydrazide (15d; C16H20N4OS)
Yield: 94%; m.p.: 225±227ꢀC; IR (KBr): ꢀ ˆ 3310s, 3240m, 3050w, 2915s, 1680s, 1610w, 1520s,
1
1460s, 1250s, 1180s, 740s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 12.05 (s, NHindole, exchange-
able), 10.5 (s, NH, exchangeable), 9.3 (s, NH, exchangeable), 6.8±7.9 (m, 4Harom ‡ CHindole), 4.1 (m,
1Hcyclohexyl), 1.1±2.0 (m, 10Hcyclohexyl) ppm.
5-(1H-Indol-2-yl)-4-alkyl/phenyl-4H-[1,2,4]triazole-3-thiols (general procedure)
A mixture of 0.5 g 15a±d and 25 cm3 alcoholic KOH was re¯uxed for 3 h. The reaction mixture was
cooled and acidi®ed with dilute HCl to give the corresponding s-triazoles 16a±d.
5-(1H-Indol-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (16a; C11H10N4S)
Yield: 91%; m.p.: 317±319ꢀC; IR (KBr): ꢀ ˆ 3310s, 3100s, 3050s, 2950s, 2800m, 1590s, 1565s,
1510s, 1475s, 1410s, 1230s, 1140s, 1100s, 730s, 700s cm 1; 1H NMR (DMSO-d6, ꢁ, 90 MHz): 13.3
(s, NHtriazole, exchangeable), 11.3 (s, NHindole, exchangeable), 6.9±7.7 (m, 4Harom ‡ CHindole), 3.8 (s,
3H, NCH3) ppm.
5-(1H-Indol-2-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol (16b; C12H12N4S)
Yield: 94%; m.p.: 279±281ꢀC; IR (KBr): ꢀ ˆ 3320s, 3100s, 2950s, 2925s, 2800m, 1600s, 1590s,
1
1510s, 1460s, 1280s, 1040s, 720s cm
; ,
1H NMR (DMSO-d6, ꢁ, 90 MHz): 13.1 (s, NHtriazole
exchangeable), 11.3 (s, NHindole, exchangeable), 7.7 (s, CHindole), 6.9±7.6 (m, 4Harom), 4.25 (q,
J ˆ 7 Hz, 2H, NCH2CH3), 1.4 (t, J ˆ 7 Hz, 3H, NCH2CH3) ppm.
5-(1H-Indol-2-yl)-4-phenyl-4H-[1,2,4]triazole-3-thiol (16c; C16H12N4S)
Yield: 93%; m.p.: 284±287ꢀC; IR (KBr): ꢀ ˆ 3350s, 3300s, 3100m, 2900s, 2800m, 1590s, 1570s,
1
1500s, 1460s, 1420s, 1400s, 1230s, 1080s, 740s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 14.4 (s,
NHtriazole, exchangeable), 12.1 (s, NHindole, exchangeable), 6.9±7.7 (m, 9Harom ‡ CHindole) ppm.
5-(1H-Indol-2-yl)-4-cyclohexyl-4H-[1,2,4]triazole-3-thiol (16d; C16H18N4S)
Yield: 98%; m.p.: 249±251ꢀC; IR (KBr): ꢀ ˆ 3330s, 3150w, 2950m, 2900w, 2820m, 1600s, 1560m,
1
1520s, 1240m, 1010s, 740s cm 1; H NMR (DMSO-d6, ꢁ, 90 MHz): 12.8 (s, NHtriazole, exchange-
able), 11.1 (s, NHindole, exchangeable), 6.9±7.8 (m, 4Harom ‡ CHindole), 4.7 (m, 1H, NCH), 1.0±2.0
(m, 10Hcyclohexyl) ppm.
2-(5-Ethyl/benzylsulfanyl-4-phenyl-4H-[1,2,4]triazol-3-yl)-1H-indoles (general procedure)
A mixture of 0.12 g 16c (0.4 mmol) and ethyl iodide (5.0 mmol) or benzyl bromide (4.0 mmol) in
10 cm3 EtOH was treated with aqueous KOH at room temperature for 20 min. The precipitate formed
was collected by ®ltration and crystallized from EtOH to give colourless crystals of 17a±b.

762
A. A. O. Sarhan
2-(5-Ethylsulfanyl-4-phenyl-4H-[1,2,4]triazol-3-yl)-1H-indole (17a; C18H16N4S)
Yield: 95%; m.p.: 229±230ꢀC; IR (KBr): ꢀ ˆ 3205s, 3050m, 2950w, 1590s, 1570s, 1490s, 1250m,
1120s, 785s, 730s cm 1; 1H NMR (CDCl3, ꢁ, 90 MHz): 11.4 (s, NHindole, exchangeable), 6.8±7.7 (m,
9Harom), 5.6 (s, CHindole), 3.4±3.1 (q, J ˆ 7 Hz, 2H, SCH2CH3), 1.3±1.5 (t, J ˆ 7 Hz, 3H, SCH2CH3)
ppm; MS: m/z (%) ˆ 319 [M 1] (100), 304 (4), 291 (55), 287 (16), 259 (2), 232 (6), 218 (14),
210 (13), 182 (10), 164 (2), 156 (4), 149 (18), 141 (29), 129 (4), 116 (16), 105 (30), 102 (5), 77 (38),
51 (8).
2-(5-Benzylsulfanyl-4-phenyl-4H-[1,2,4]triazol-3-yl)-1H-indole (17b; C23H18N4S)
Yield: 81%; m.p.: 218±221ꢀC; IR (KBr): ꢀ ˆ 3200w, 3030w, 2900w, 1610m, 1595w, 1520m,
1
1485m, 1310s, 1020m, 730s cm
CHindole), 4.1 (s, 2H, SCH2) ppm.
;
1H NMR (CDCl3, ꢁ, 90 MHz): 6.6±7.4 (m, 14Harom), 5.5 (s,
2-(5-(1H-Indol-2-yl)-4-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-aryl-ethanone (general procedure)
A mixture of 0.12 g of 16c (0.4 mmol) and the corresponding phenacyl bromide derivative
(0.42 mmol) in 10 cm3 EtOH was re¯uxed for 3 h in the presence of 0.2 g of anhydrous CH3COONa.
The precipitate formed was collected by ®ltration and washed with H2O (3x). The crude product was
recrystallized fom EtOH to give colorless crystals of 18a,b.
2-(5-(1H-Indol-2-yl)-4-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone
(18a; C25H20N4O2S)
Yield: 88%; m.p.: 258±261ꢀC; IR (KBr) ꢀ ˆ 3245s, 3050m, 2950w, 2900w, 2870w, 1680s, 1595s,
1570s, 1490s, 1250s, 1170s, 820s, 795s, 725s cm 1; 1H NMR (CDCl3, ꢁ, 90 MHz): 11.8 (s, NHindole
exchangeable), 6.8±7.8 (m, 13Harom), 5.5 (s, CHindole), 4.7 (s, 2H, SCH2), 3.8 (s, 3H, OCH3) ppm.
,
2-(5-(1H-Indol-2-yl)-4-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-chloro-phenyl)-ethanone
(18b; C24H17N4OSCl)
Yield: 67%; m.p.: 238±241ꢀC; IR (KBr): ꢀ ˆ 3240s, 3050m, 2960w, 2910w, 2870w, 1685s, 1590s,
1570s, 1495s, 1250s, 1160s, 820s, 795s, 730s cm 1; 1H NMR (CDCl3, ꢁ, 90 MHz): 11.8 (s, NHindole
exchangeable), 6.7±7.7 (m, 13Harom), 5.5 (s, CHindole), 4.75 (s, 2H, SCH2) ppm.
,
2-(5-(1H-Indol-2-yl)-4-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-malonic acid diethyl ester
(19; C23H22N4O4S)
A mixture of 0.12 g 16c (0.4 mmol) and bromodiethyl malonate (0.4 mol) in 10 cm3 EtOH was
re¯uxed in the presence of 0.2 g anhydrous CH3COONa for 3 h. The precipitate formed was
collected by ®ltration and washed with H2O (3x). The crude product was recrystallized from EtOH
to give colorless crystals.
Yield: 81%; m.p.: 181±183ꢀC; IR (KBr): ꢀ ˆ 3240s, 3050m, 2970w, 2800w, 1740s, 1630s,
1600s, 1580s, 1490s, 1300s, 1260s, 1170s, 795s, 740s cm 1; 1H NMR (CDCl3, ꢁ, 90 MHz): 11.4 (s,
NHindole, exchangeable), 6.9±7.7 (m, 4Harom), 5.75 (s, 1H, SCH), 5.45 (s, CHindole), 4.1±4.3 (q,
J ˆ 7 Hz, 4H, 2CH2), 1.2±1.4 (t, J ˆ 7 Hz, 6H, 2CH3) ppm.
Acknowledgment
We are grateful thank to Prof. H. Falk, Chemistry Department, University of Linz, A-4040 Linz,
Austria, for helpful discussion. Thanks are also due to Prof. T. Izumi, Department of Chemistry and

Reactions of Indole-2-carboxylic Acid Hydrazide
763
Chemical Engineering, Faculty of Engineering, Yamagata University, Yonezawa 992-8510, Japan,
for her kind assistance, Assiut University, Assiut and to the Chemistry Department, 71516, Egypt, for
support of this work.
References
[1] a) Fernandez-Alvarez E, Lone M, Monge A (1969) Bull Soc Chim Fr 1932; b) Marco JL (1998)
J Heterocycl Chem 35: 475
[2] a) Perez S, Lasheras B, Oset C, Monge A (1997) J Heterocycl Chem 34: 1527; b) Cruces MA,
Elorriaga C, Fernandes-Alvarez E (1991) Eur J Med Chem 26: 33; c) Cruces MA, Elorriaga C,
Fernandes-Alvarez E (1990) Biochem Pharmacol 40: 535
[3] Monge Vega A, Palop JA, Gracia CI, Fernandez AE (1982) An Acad Farm 48 (2): 213
[4] Kasahara A (1987) Jpn Kokai Tokkyo Koho JP 62, 153, 271
[5] Ebright RH, Wong JR (1981) Proc Natl Acad Sci USA 78 (7): 4011
Á
[6] Alemany A, Bernabe M, Elorriaga C, Fernandez-Alvarez E, Tamayo ML, Lopez ON (1966) Bull
Soc Chim Fr 2486
[7] a) Doyle FP, Ferrier W, Holland DO, Mehta MD, Nayler JHC (1956) J Chem Soc 2853; b) Kelarev
VI, Shvekhgeimer GA (1982) Chem Heterocycl Compd (Engl Transl) 18 (3): 258
[8] a) Nogrady T, Morris L (1969) Can J Chem 47: 1999; b) Monge Vega A, Aldana I, Fernandez-
Alvarez E (1978) Eur J Med 13: 573; c) Kobayashi G, Furukawa S (1964) Chem Pharm Bull 12:
1129; d) Monge Vega A, Huarte V, Palop JA, Martinez MT, Fernandez-Alvarez E (1977) Ann
Quim 73: 278; e) Monge Vega A, Palop JA, Martinez MT, Fernandez-Alvarez E (1979) Ann Quim
75: 889
[9] Monge A, Aldana I, Lezamiz I, Fernandez-Alvarez E (1984) Synthesis 160
Received October 17, 2000. Accepted (revised) December 12, 2000