Synthesis, characterization and spectral studies of various newer 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-hydrazides

Article abstract of DOI:10.1002/jhet.5570420537

4-Benzyloxyindole-2-carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in alcoholic medium in refluxing conditions to give 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-hydrazides, important synthetic intermediates for the syn

Full text of DOI:10.1002/jhet.5570420537

Synthesis, Characterization and Spectral Studies of Various Newer
Jul-Aug 2005
985
4-Benzyloxy-1H-indole-2-carboxylic Acid (Arylidene)-hydrazides
Asheesh Kumar Jain, Pradeep Kumar Gupta, Kumaran Ganesan, Ambuja Pande,
Deepak Pardasani, Ramesh Chandra Malhotra*
Synthetic Chemistry Division, Defence Research & Development Establishment,
Jhansi Road, Gwalior-474002, MP, India
Received November 2, 2004
4-Benzyloxyindole-2-carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in
alcoholic medium in refluxing conditions to give 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-
hydrazides, important synthetic intermediates for the synthesis of a newer class of pharmacologically active
compounds. We describe here the synthesis of various 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-
hydrazides by conventional as well as microwave irradiation techniques. The structures of these compounds
have been confirmed by spectroscopic techniques (FTIR, NMR and MS). Some of the interesting features of
the electron impact mass spectral fragmentation pattern of these compounds are also discussed.
J. Heterocyclic Chem., 42, 985 (2005).
The Indole nucleus is an important element of many
precursors is well documented [6]. Keeping in view their
biological and synthetic utility, much attention has been
paid to develop new methodologies for the construction of
this structural framework [7]. In the present course, we
have synthesized newer 4-benzyloxyindole-2-carboxylic
acid hydrazide (1) and 4-benzyloxy-1H-indole-2-car-
boxylic acid (arylidene)-hydrazide (2-10) using new eco-
friendly microwave irradiation technique as well as con-
ventional heating methods. All the above compounds were
characterized by spectral analysis.
Hydrazinolysis of 4-benzyloxyindole-2-carboxylic acid
hydrazide from corresponding methyl ester was carried out
by conventional method as well as by microwave technique.
The conventional method involved the refluxing of mixture
of corresponding ester and excess of hydrazine hydrate for
16 hours while in the case of the microwave technique, a
pharmacologically active compounds. It has been investi-
gated as a starting material for the synthesis of hallucino-
genic compounds i.e., psychochemical like bufotenin,
psilocin and dimethyltryptamine and various organic nat-
ural products as well as a precursor in alkaloid [1]. Some
N-methylindole-3-hydrazones have shown antihyperten-
sive activity in spontaneously hypertensive rat [2]. Most of
the 3-substituted indole acetic acid derivatives such as its
hydrazide and corresponding pyridazinone derivatives are
found to possess antimicrobial activity [3]. Hydrazone
derivatives of indole-2-carboxylic acid hydrazide are use-
ful as psychopharmacological agents and as monoami-
neoxidase (MAO) inhibitor [4]. From the synthetic point
of view, hydrazones are important synthons for several
transformations [5] and their synthesis from various

986
A. K. Jain, P. K. Gupta, K. Ganesan, A. Pande, D. Pardasani, R. C. Malhotra
Vol. 42
Table 1
Synthesis of 4-Benzyloxy-1H-indole-2-carboxylic Acid (Arylidene)-hydrazide
Product
Time
Yield of the product (%)
MW
Conventional
(hr)
MW
Conventional
(min)
O
C
10
16
86
50
PhH2CO
NH
NH
2
NH
1
O
C
PhH2CO
NHN CH
10
86
8
55
NH
2
O
C
PhH2CO
PhH2CO
PhH2CO
PhH2CO
NHN CH
Cl
NH
6
5
90
85
7
6
40
30
3
O
C
N
NH
CH
F
NH
4
O
C
CH
NHN
OH
6
5
85
88
8
30
35
NH
5
O
C
NHN CH
10
NH
6
OH
O
C
PhH2CO
NHN
CH
Cl
NH
3
87
85
8
45
40
7
F
O
C
PhH2CO
N
NH
CH
10
14
NH
8
OCH3
O
C
PhH2CO
CH
N
NH
10
10
89
86
12
16
33
40
NH
9
OCH3
O
C
PhH2CO
N
CH
NH
NH
O
10

Jul-Aug 2005
Synthesis, Characterization and Spectral Studies
987
1
mixture of ester and hydrazine hydrate (1:1 molar ratio) was
irradiated with microwaves for 10 minutes in the absence of
any solvent, catalyst and solid support. The results of the
two approaches (conventional and microwave technique)
are summarized in Table 1 (product 1).
The H NMR spectrum of 4-benzyloxyindole-2-car-
boxylic acid hydrazide displayed a singlet at δ 9.8 ppm due
to the NHCO proton. Presence of later was further sup-
13
ported by the appearance of a peak at 161.6 in its C NMR
spectrum. Another broad singlet at 4.2 (2H) corresponded
Various newer 4-benzyloxy-1H-indole-2-carboxylic acid
(arylidene)-hydrazide (2-10) were also prepared by the con-
densation of 1 with different aromatic aldehydes under
microwave irradiations and conventional methods. They
are prepared in conventional method by refluxing 1 with
the different aldehydes in alcohol and in microwave irradi-
ation technique without any solvent. The overall yield of
products obtained using the microwave irradiation tech-
nique is in the range of 85-90% as compared to the conven-
tional methods where the yields were 30-55%. The reaction
time is 3-10 minutes by microwave irradiation as compared
to conventional methods of 6-16 hours (Scheme 1).
to NH protons while a singlet at 10.5 resonated due to
2
indole NH proton. Benzylic CH protons appeared at 5.2 in
2
1
its H NMR spectrum while as a sharp singlet at 69.5 ppm
in its C NMR spectrum. Eight benzenoid protons and
13
one indolic CH proton appeared as multiplet at 7.0-7.8
ppm. Similar pattern for the proton resonances was also
1
observed in the H NMR spectrum of hydrazones. In addi-
tion, a singlet corresponding to N=CH proton appeared at δ
7.9-8.7 depending upon the substituent in the phenyl ring
of the aldehyde molecule. Also, broad singlet at 4.2 ppm
corresponding to the –NH protons in the spectrum of 10
2
was not observed in those of hydrazones.
In the EI mass spectra of 4-benzyloxyindole-2-car-
boxylic acid hydrazides and all the 4-benzyloxy-1H-
indole-2-carboxylic acid (arylidene)-hydrazides, molecu-
lar ion peaks were distinct. Fragment ion peak at m/z 250
Spectral Analysis.
The IR spectrum of 4-benzyloxyindole-2-carboxylic
acid hydrazide showed absorption bands at 1629 and 1100
-1
cm corresponding to C=O and C-N stretching vibrations.
could be attributed to the loss of NHNH and NHN=CH-
2
-1
Two bands at 3302 and 3225 cm appeared due to the
Ar radicals from the molecular ions of hydrazide and 4-
benzyloxy-1H-indole-2-carboxylic acid (arylidene)-
hydrazide respectively. The formation of fragment ion at
m/z 223 can be rationalized by the loss of neutral iso-
presence of –NH and –NH groups. The corresponding 4-
2
benzyloxy-1H-indole-2-carboxylic acid (arylidene)-
hydrazides showed similar spectra except that bands due to
-1
the NH group, instead of bands at 1565-1555 cm due to
cyanate (H N-N=C=O or ArCH=N-N=C=O) from molec-
2
2
C=N stretching, were observed.
ular ion as depicted in Scheme 2. The fragment ion peak at

988
A. K. Jain, P. K. Gupta, K. Ganesan, A. Pande, D. Pardasani, R. C. Malhotra
Vol. 42
indole CH), 5.1 (s, 2H, CH ). EIMS: m/z (%) = 403 (84)
m/z 158 could arise due to the loss of benzylic and H radi-
cal (either in concerted or stepwise manner) from the frag-
ment ion having m/z value of 250 (Scheme 2). In addition,
benzylic cleavage in the molecular ion gave rise to peaks at
m/z [M-91] as also m/z 91 due to characteristic tropylium
cation. The ion m/z 131 is obtained due to the loss of CO
from that of m/z 159.
2
+
[C
H
N O Cl] , 367 (8), 312 (100), 276 (8), 250 (24), 235
23 18
3 2
(10), 223 (12) 158 (44), 131 (25), 91 (100), 65 (22).
4-Benzyloxy-1H-indole-2-carboxylic Acid (-2-Fluoro-benzyli-
dene)-hydrazide (4).
This compound has a mp of 188-190 °C, IR (KBr) = 3422,
-1
1
3298, 3070, 2970, 1634, 1560, 1364, 1245, 748 cm ; H NMR
In conclusion, we described the microwave-assisted
synthesis of newer 4-benzyloxyindole-2-carboxylic acid
hydrazide and various newer 4-benzyloxy-1H-indole-2-
carboxylicacid (arylidene)-hydrazide were prepared using
the same technique. Spectral properties and mass spectral
fragmentation pattern of these hydrazides and hydrazones
were also discussed.
(400 MHz, DMSO-d ): δ 11.5 (s, 1H, NH indole, exchangeable),
6
11.0 (s, 1H, CONH, exchangeable), 8.7 (s, 1H, N=CH), 7.1-7.8
(m, 12 x Ar-H, 1 x indole CH), 5.2 (s, 2H, CH ); EIMS: m/z (%)
2
+
= 387 (84) [C
H
N O F] , 296 (100), 281 (10), 250 (22), 223
23 18
3 2
(12), 158 (38), 131 (22), 91 (84), 65 (12).
4-Benzyloxy-1H-indole-2-carboxylic Acid (-2-Hydroxy-benzyli-
dene)-hydrazide (5).
This compound has a mp of 250-252 °C, IR (KBr): 3298,
-1
1
EXPERIMENTAL
3250, 3064, 2966, 1651, 1622, 1560, 1360, 1258, 748 cm ; H
NMR (400 MHz, DMSO-d ): δ 11.5 (s, 1H, OH), 11.2 (s, 1H, NH
6
4-Benzyloxyindole-2-carboxylic Acid Hydrazide (1).
indole exchangeable), 10.8 (s, 1H, CONH, exchangeable), 8.4 (s,
1H, N=CH) 7.0-7.7 (m, 12 x Ar-H, 1 x indole CH), 5.12 (s, 2H,
4-Benzyloxyindole-2-carboxylic acid methyl ester (10 mmol)
was dissolved in 99% hydrazine hydrate (10 mmol) in a conical
flask and was placed in a domestic microwave oven. After irradi-
ating at 450 watt for 10 minutes, the solid product was washed
with the ethanol to give the 4-benzyloxyindole-2-carboxylic acid
hydrazide 1 (86 %); mp: 248-250 °C. IR (KBr) = 3316 & 3282 (-
+
CH ); MS: m/z (%) = 385 (82) [C
H
N O ] , 294 (12), 250
2
23 19
3
3
(22), 223 (8),160 (84), 131 (22), 91 (100), 65 (18).
4-Benzyloxy-1H-indole-2-carboxylic Acid (4-Hydraoxy-ben-
zylidene)-hydrazide (6).
-1
1
This compound has a mp of 260-262 °C; IR (KBr) = 3304,
NH ), 3120, 2929, 1637 (CO), 1230, 1097, 759, 732 cm ; H
2
1
1
3259, 3064, 2936, 1614, 1544, 1382, 1254, 761 cm- ; H NMR
NMR (400 MHz, DMSO-d ): δ 10.5 (s, 1H, indole NH,
6
(400 MHz, DMSO-d ): δ 11.4 (s, 1H, OH), 11.0 (s, 1H, NH
exchangeable), 9.8 (s, 1H, -NHCO, exchangeable), 7.0-7.8 (m, 8
6
indole, exchangeable), 10.8 (s, 1H, CONH, exchangeable), 8.4 (s,
x Ar-H, 1 x indole CH), 5.25(s, 2H, -OCH ), 4.2 (bs, 2H, -NH );
2
2
13
1H, N=CH), 7.0-7.8 (m, 12 x Ar-H, 1 x indole CH), 5.1 (s, 2H,
C NMR (100 MHz, DMSO-d ): δ 69.55 (-OCH ), 100.10 (C-
7), 101.09 (C-5), 106.07 (C-3), 118.89 (C-8), 124.58 (C-6),
128.03 (C-2'/6'), 128.24 (C-4'), 128.88 (C-3'/5'), 129.55 (C-2),
6
2
+
CH ); MS: m/z (%) = 385 (40) [C
H
N O ] , 294 (38), 250
2
23 19
3
3
(8), 223 (8), 158 (22), 136 (18), 91 (100), 65 (18).
137.81 (C-1'), 138.22 (C-9), 152.99 (C-4), 161.60 (CO); EI-MS:
4-Benzyloxy-1H-indole-2-carboxylic Acid (-2-Chloro-5-fluoro-
benzylidene)-hydrazide (7).
+
m/z (%) = 281 (51), [C
H
N O ] , 250 (20), 223 (12), 190
16 15
3 2
(40), 159 (20), 131 (18), 91 (100), 76 (8), 65 (16), 51 (8).
This compound has a mp of 186-188 °C; IR (KBr) = 3474,
General Procedure for the Synthesis of 4-Benzyloxy-1H-indole-
2-carboxylic Acid (Arylidene)-hydrazide.
-1
1
3295, 2964, 1644, 1544, 1382, 1254, 761 cm ; H NMR (400
MHz, DMSO-d ): δ 10.5 (s, 1H, NH indole, exchangeable), 9.8
6
(s, 1H, CONH, exchangeable), 8.5 (s, 1H, N=CH), 7.0-7.8 (m, 11
Carboxylic acid hydrazide (5 mmol) was mixed with aldehyde
(5 mmol) in a glass tube and the mixture was irradiated with
microwaves for the time period specified in Table 1 at a power
setting of 100 Watts. The reaction was monitored by TLC. After
completion of the reaction, the solid product was recrystallized
from the ethanol to give the pure hydrazones.
x Ar-H, 1 x indole CH), 5.1 (s, CH ). MS: m/z (%) = 421 (12)
2
+
[C
H
N O FCl] , 158 (8), 131(16), 91 (100).
23 17
3 2
4-Benzyloxy-1H-indole-2-carboxylic Acid (-3-Methoxy-ben-
zylidene)-hydrazide (8).
This compound has a mp of 178-180 °C; IR (KBr): 3308, 3238,
4-Benzyloxy-1H-indole-2-carboxylicacidbenzylidene-hydrazide
(2).
-1
1
3052, 2992, 1631, 1547, 1365, 1272, 1171, 753 cm ; H NMR
(400 MHz, DMSO-d ): δ 9.7 (s, 1H, CONH, exchangeable), 7.9
6
(s, 1H, N=CH), 6.9-7.8 (m, 12 x Ar-H, 1 x indole CH), 5.1 (s, 2H,
This compound has a mp of 216-218 °C, IR (KBr): 3445,
+
-1
1
CH ); MS: m/z (%) = 399 (100) [C H N O ] , 308 (84), 294
3178, 3029, 1628, 1526, 1510, 1360, 1258, 1241, 756 cm ; H
2
24 21 3 3
(38), 250 (22), 223 (12), 158 (22), 131 (18), 91 (78), 65 (20).
NMR (400 MHz, DMSO-d ): δ 7.9 (s, 1H, N=CH), 6.9-7.7 (m,
6
13 x Ar-H, 1 x indole CH), 5.2 (s,-OCH ). EIMS: m/z (%) = 369
2
4-Benzyloxy-1H-indole-2-carboxylic Acid (-4-Methoxy-ben-
zylidene)-hydrazide (9).
+
(98) [C
H
N O ] , 278 (98), 250 (22), 223 (12),159 (22) 158
23 19
3 2
(36), 130 (29), 103 (12), 91 (100) ,65 (8).
This compound has a mp of 210-212 °C; IR (KBr): 3308,
4-Benzyloxy-1H-indole-2-carboxylic Acid (-2-Chlorobenzyl-
idene)-hydrazide (3).
-1
1
3238, 3052, 2992, 1631, 1547, 1365, 1272, 1171, 753 cm ; H
NMR (400 MHz, DMSO-d ): δ 11.2 (s, 1H, NH indole,
6
exchangeable), 10.8 (s, 1H, CONH, exchangeable), 8.3 (s, 1H,
This compound has a mp of 220-222 °C, IR (KBr) = 3436,
-1
1
N=CH), 7.1-7.8 (m, 12 x Ar-H, 1 x indole CH), 5.1 (s, 2H, CH );
1633, 1556, 1433, 1263, 758 cm ; H NMR (400 MHz, DMSO-
2
+
EIMS: m/z (%) = 399 (100) [C
H
N O ] , 308 (86), 294 (38),
d ): δ 11.4 (s, 1H, NH indole exchangeable), 10.5 (s, 1H, CONH,
24 21
3 3
6
250 (12), 223 (8), 158 (22), 136 (18), 91 (100), 65 (20).
exchangeable), 8.5 (s, 1H, N=CH), 7.0-7.8 (m, 12 x Ar-H, 1 x

Jul-Aug 2005
Synthesis, Characterization and Spectral Studies
989
[b] C. Szantay, Pure Appl. Chem. 62, 1299 (1990).
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Fernandez, An. Acad. Farm., 48, 213 (1982).
4-Benzyloxy-1H-indole-2-carboxylic Acid Furan-3-ylmethyl-
ene-hydrazide (10).
This compound has a mp of 180-182 °C; IR (KBr) = 3448,
[3] S. E. D. Nabaweya, Acta. Pharm. 49, 127 (1999).
3179, 3035, 1628, 1578, 1512, 1357, 1266, 1240, 1160, 1064, 757
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[c] W. Sucrow, Org. Prep. Proced. Int., 14, 93 (1982); [d] R. Fusco
and F. Sannicolo, Tetrahedron., 36, 161 (1980).
-1 1
cm ; H NMR (400 MHz, DMSO-d ): δ = 11.3 (s, 1H, NH indole,
6
exchangeable), 10.8 (s, 1H, CONH, exchangeable), 8.5 (s, 1H,
N=CH), 6.5-7.7 (m, 8 x Ar-H, 1 x indole CH, 3 x furan CH), 5.12
+
(s, 2H, CH ); MS: m/z (%) = 359 (82) [C H N O ] , 268 (60)
2
21 17 3 3
+
[M-91] , 250 (22), 223 (12), 159 (22), 131 (22), 91 (100), 65 (16).
Acknowledgement.
Authors sincerely thank Mr. K. Sekhar, Director, Defence
Research and Development Establishment, Gwalior for keen inter-
est and encouragement. We are also thankful to Dr. R. P. Semwal,
Mrs. Mamta Sharma and R. C. Meena for recording spectra.
[6a] B. K. Banik, K. J. Barakat, W. R. Wagle, M. S. Manhas
and A. K. Bose, J. Org. Chem., 64, 5746 (1999); [b] S. Gadhwal, M.
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REFERENCES AND NOTES
*
Corresponding author; email: rcmalhotra@hotmail.com &
mramesh1946@rediffmail.com; Fax: +91 751 2341148.
[1a] S. Hibino and T. Choshi, Nat. Prod. Rep., 19, 148 (2002);