Synthesis, spectral studies, and antimicrobial activities of [N-(un)alkylated-2-arylindol-3-yl]-thiocarboxamides

Article abstract of DOI:10.1080/10426500490485110

A series of [N-(un)alkylated-2-arylindol-3-yl]thiocarboxamides (6) have been synthesized by the condensation of alkyl [N-(un)alkylated-2-arylindol-3-yl] dithiocarboxylates (5) with appropriate secondary amines in absolute alcohol. Compound 5 was prepared

Full text of DOI:10.1080/10426500490485110

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Phosphorus, Sulfur, and Silicon
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SYNTHESIS, SPECTRAL STUDIES,
AND ANTIMICROBIAL ACTIVITIES
OF [N-(UN)ALKYLATED-2-
ARYLINDOL-3-
YL]THIOCARBOXAMIDES
Vijai N. Pathak a , Rahul Joshi & Neetu Gupta
a Department of Chemistry, University of Rajasthan ,
Jaipur, India
Published online: 16 Aug 2010.
To cite this article: Vijai N. Pathak , Rahul Joshi & Neetu Gupta (2004) SYNTHESIS,
SPECTRAL STUDIES, AND ANTIMICROBIAL ACTIVITIES OF [N-(UN)ALKYLATED-2-
ARYLINDOL-3-YL]THIOCARBOXAMIDES, Phosphorus, Sulfur, and Silicon and the Related
Elements, 179:11, 2365-2378, DOI: 10.1080/10426500490485110
To link to this article: http://dx.doi.org/10.1080/10426500490485110
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Phosphorus, Sulfur, and Silicon, 179:2365–2378, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490485110
SYNTHESIS, SPECTRAL STUDIES, AND
ANTIMICROBIAL ACTIVITIES OF
[N-(UN)ALKYLATED-2-ARYLINDOL-3-YL]-
THIOCARBOXAMIDES
Vijai N. Pathak, Rahul Joshi, and Neetu Gupta
Department of Chemistry, University of Rajasthan,
Jaipur, India
(Received July 3, 2003; accepted April 28, 2004)
A series of [N-(un)alkylated-2-arylindol-3-yl]thiocarboxamides (6) have
been synthesized by the condensation of alkyl [N-(un)alkylated-
2-arylindol-3-yl]dithiocarboxylates (5) with appropriate secondary
amines in absolute alcohol. Compound 5 was prepared by the reaction
of N-(un)alkylated-2-arylindoles with carbon disulphide in the pres-
ence of potassium-t-butoxide followed by alkyl iodide under nitrogen
atmosphere. All of the compounds have been characterized on the basis
of their elemental and spectral data and have been screened for their
antibacterial and antifungal activities. Some of the synthesized com-
pounds have shown promising activity.
Keywords: 2-Arylindoles; antimicrobial activity; PTC; thiocarboxylate;
thiocarboxamide
INTRODUCTION
The use of carbon disulphide as a solvent in Friedel-Crafts and other
reactions and as a solvent in spectroscopy is well known. Carbon disul-
phide is also used as a starting material for the synthesis of vari-
ous heterocyclic compounds. Condensation reactions of carbon disul-
phide with various types of nucleophiles has been reported.1–6 Various
sulphur-containing indole derivatives have been reported to possess
The authors would like to thank the head of the Department of Chemistry, University
of Rajasthan, Jaipur for providing necessary facilities, Dr. V. J. Ram, Dy. Director (retd.)
and Emeritus Scientist CDRI, Lucknow for valuable suggestions and for the help offered
in obtaining the various spectra, and CSIR (New Delhi) for the award of Senior Research
Fellowship to N. Gupta.
Address correspondence to Vijai N. Pathak, Department of Chemistry, University of
Rajasthan, Jaipur, 302 004, India. E-mail: pathakvijain@yahoo.com
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V. N. Pathak et al.
antibacterial,7,8 antimigraine,9 antiinflammatory,10,11 antiasthmatic,12
anticoagulant,13 antidiabetic,14 and antineoplastic15 activities. Encour-
aged by these observations, a number of [N-(un)alkylated-2-arylindol-
3-yl]thiocarboxamides have been synthesized and characterized.
DISCUSSION
2-Arylindoles (3) were prepared by the method of Joshi et al.16 utiliz-
ing Fischer Indole synthesis. 2-Arylindoles were than N-alkylated by
phase transfer catalysis method.17 N-(un)alkylated-2-arylindoles were
treated with CS2 in the presence of potassium-t-butoxide followed by
alkyl iodide under nitrogen atmosphere, which was in turn further
treated with appropriate secondary amines to afford [N-(un)alkylated-
2-arylindol-3-yl]thiocarboxamides (6a–h). The structure of the synthe-
sized compounds was established on the basis of their IR, 1H NMR, and
FAB mass spectral studies Physical and analytical data of compounds
5 and 6 are given in Tables I and II, respectively. The spectral data of
SCHEME 1

Thio-Carboxamides
2367
TABLE I Physical and Analytical Data of Alkyl [N-(un)-
alkylated-2-arylindol-3-yl]dithiocarboxylates (5)
Elemental analyses (%),
found (calc.)
Compd.
no.
m.p. Yield Molecular
R1 R2 Color (◦C) (%)
formula
X
C
H
N
S
5a
5b
5c
5d
5e
5f
4-Br
H
H
Et Orange 190 43 C17H14BrNS2 54.01 3.73 3.71 17.09
(54.25) (3.72) (3.72) (17.02)
4-Br
Me Orange 194 47
83 42
Et Orange 179 52
C
16H12BrNS2 52.80 3.32 3.86 17.76
(53.03) (3.31) (3.87) (17.68)
18H16BrNS2 55.12 4.12 3.58 16.48
(55.38) (4.10) (3.59) (16.41)
17H14ClNS2 61.28 4.24 4.21 19.39
(61.54) (4.22) (4.22) (19.31)
4-Br Et Me Red
C
4-Cl
4-Cl
H
H
C
Me Red
190 50 C16H12ClNS2 60.29 3.79 4.40 20.24
(60.47) (3.78) (4.41) (20.16)
4-Cl Me Me Orange 94 49
C
17H14ClNS2 61.29 4.24 4.23 19.38
(61.54) (4.22) (4.22) (19.31)
synthesized compounds (5 and 6) are given in Table III. Major mass
fragments along with their relative intensities and m/z values of com-
pounds 6 are given in Table IV. The synthesized compounds have been
screened for their antibacterial activity against gram-positive bacte-
ria Staphylococcus aureus and gram-negative bacteria Escherichia coli.
Antifungal activity was done against Candida albicans and Aspergillus
niger. Results of antibacterial and antifungal activities are tabulated
in Tables V and VI, respectively.
IR Spectra
The IR spectra of 2-arylindoles showed absorption bands at 3350–
3450 cm−1, which is attributed to >N H stretching vibration. In the IR
spectra of N-alkyl-2-arylindoles (4), >N H absorption band at 3350–
3450 cm−1 disappeared and an absorption band appeared at 2850 cm−1
due to aliphatic C H stretching vibration. IR spectra of alkyl [N-
(un)alkylated-2-arylindol-3-yl] dithiocarboxylates (5) exhibited >C S
and >C S absorptions in the region of 1161–1239 cm−1 and 1070–
1071 cm−1, respectively. The IR spectra of [N-(un)alkylated-2-arylindol-
3-yl]thiocarboxamides (6) exhibited >C S absorption in the region
of 1238–1298 cm−1, whereas >N H absorption was observed in the
range of 3423–3435 cm−1. Disappearance of C S absorption in
the range of 1070–1071 cm−1 and appearance of C N absorption in
the range of 1340–1350 cm−1 confirms the formation of compounds 6;
however, in some cases this C NR2 absorption coalesced with indolyl
C N absorption.

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Thio-Carboxamides
2375
1H NMR Spectra
The 1H NMR spectra of ethyl [2-(4-bromophenyl)indole-3-yl]dithio-
carboxylate (5a), exhibited triplet at δ 1.56 (t, 3H, J = 7.13 Hz) and
quartet at δ 3.42 (q, 2H, J = 7.13 Hz), which is attributed to CH3 and
CH2 protons of S CH2 CH3 group. 1H NMR spectra of compound 5a
showed multiplet at δ 7.38 due to aromatic protons and singlet at δ 8.26
ppm due to >NH proton. Compound 5c exhibited triplet at δ 1.25 (t,
3H, J = 7.14 Hz) and quartet at δ 4.18 (q, 2H, J = 7.14 Hz) due to CH3
and CH2 protons of NCH2CH3 group, respectively, and a singlet at δ
1.54 ppm and multiplet at δ 7.37 due to protons of S CH3 group and
aromatic protons, respectively.
1H NMR spectra of compounds 6a–h revealed the anisochronous na-
ture of a pair of alkyl groups on a thioamide nitrogen. One set of signals
is obtained due to alkyl groups cis to the sulphur atom, and another set
1
is due to the alkyl groups trans to the sulphur atom. For example, H
NMR spectra of compound 6c exhibited four sets of signals due to mor-
pholino protons, a triplet centered at δ 3.31 due to trans NCH2 protons,
and another triplet centered at δ 3.41 due to cis NCH2 protons with
respect to sulphur. Similarly, one triplet centered at δ 3.52 is ascribed
to trans OCH2 protons, while another triplet centered at δ 3.59 is as-
cribed to cis OCH2 protons with respect to sulphur. 1H NMR spectra of
compound 6 exhibited complex multiplet due to aromatic protons in the
range of δ 7.04–7.64. All other NMR spectral data are given in Table III.
13C NMR Spectra
Results of 13C NMR spectra of compound 6 are also in harmony with
1
results of H NMR spectra. 13C NMR spectra of compound 6c exhib-
ited four signals due to four carbon of morpholino group. One signal is
obtained at δ 40.86 due to trans NCH2 carbon, and a second signal is
obtained at δ 46.05 due to cis NCH2 carbon with respect to sulphur. A
third signal is obtained at δ 66.15 ascribed to trans OCH2 carbon, and
a fourth signal is obtained at δ 66.33 ascribed to cis OCH2 carbon with
respect to sulphur. This is also in accordance with the anisochronous
behavior of alkyl groups on thioamide nitrogen.
Fast Atom Bombardment (FAB) Mass Spectra
All FAB mass spectra of synthesized compounds exhibited M+ + 1 peak
due to transfer of proton from matrix. Compound 5a exhibited (M+
+
1) peak at m/z 376/378 of relative intensity of 15.0% and moleculor ion
peak (M+) at m/z 375/377 of relative intensity of 10.0%. Compound 5a

2376
V. N. Pathak et al.
exhibited a base peak at m/z 271 (100.0%)/273 (100.0%) corresponding
to the molecular formula C14H10 79BrN/C14H10 81BrN. Compound 5c
exhibited (M+ + 1) peak at m/z at 390 (15.0%)/392 (5.0%) and molecular
ion peak (M+) at m/z 389 (12.0%)/391 (12.0%). FAB mass spectra of
compounds 6 exhibited (M+ + 1) peak and (M+) peak. Details are given
in Tables II and III.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are uncor-
rected (Tempo melting point apparatus). The purity of the synthesized
compounds was checked by thin layer chromatography (TLC) on silica
gel in various nonaqueous solvent systems. IR spectra were recorded in
KBr on a Perkin Elmer 557 spectrometer, PMR spectra were recorded in
CDCl3 on a Brucker spectrometer (200 MHz) using tetramethylsilane
(TMS) as an internal reference, and FAB mass spectra were recorded
on Jeol SX-102 (FAB) spectrometer.
1. Various 2-arylindoles were prepared by the literature method.16
2. 2-Arylindoles were N-alkylated by phase transfer catalysis
procedure.17
Alkyl [N-(un)alkylated-2-arylindol-3-yl]dithio-
carboxylates (5a–f): Ethyl[2-(4-bromophenylindol-3-yl]
Dithiocarboxylate (5a)
A mixture of 2-(4-bromophenyl)indole (10 mmol, 2.72 g) and potassium-
t-butoxide (10 mmol, 1.12 g) was taken in 100 ml round-bottomed flask
connected with vacuum manipole and nitrogen atmosphere. Then dry
tetrahydrofuran (THF) (20 ml) was added to it, and the resultant dark
brown solution was stirred at 5–10◦C. After 30 min, carbon disulphide
(10 mmol, 0.76 g) was added and the reaction mixture was stirred for
an additional hour to afford orange solution of the reaction mixture
followed by addition of ethyl iodide (10 mmol, 1.56 g), and the stirring
was continued for 2 h. The resulting reaction mixture thus obtained was
poured into a beaker containing crushed ice (50 g). The solid separated
was filtered and was then recrystallized from ethanol to give orange
crystals of ethyl[2-(4-bromophenyl)indol-3-yl] dithiocarboxylate. Yield
1.6 g (43%) 5a, m.p. 190◦C. All other compounds (5b–f) are prepared
using the same procedure and are given in Table I along with their
characteristics and analytical data.

Thio-Carboxamides
2377
[N-(un)alkylated-2-arylindol-3-yl]thiocarboxamides
(6a–h): [2-(4-Bromophenyl)indol-3-yl]-
piperidinothiocarboxamide (6a)
A mixture of ethyl [2-(4-bromophenyl)indol-3-yl] dithiocarboxylate
(5 mmol, 1.88 g) and piperidine (5 mmol, 0.425 g) in ethanol (20 ml)
was refluxed for about 7–8 h. The resultant reaction mixture was poured
into a beaker containing crushed ice (50 g). The product separated was
extracted with chloroform. The chloroform layer was separated and the
combined chloroform extract was dried over Na2SO4 (anhydrous) and
filtered. The filtrate was evaporated to drynes to afford yellow-green
residue, which was recrystallized from chloroform to give yellow-green
crystals of [2-(4-bromophenyl) indol-3-yl] piperidinothiocarboxamide.
Yield: 0.87 g (44%) 6a, m.p. 110◦C. All other compounds (6b–h) are pre-
pared using same procedure and are given in Table II along with their
characteristics and analytical data.
Antibacterial and Antifungal Activities
Representative compounds were screened for their antibacterial activ-
ity against gram-negative bacteria E. coli and gram-positive bacteria
S. aureus at 200, 400, and 800 ppm concentration. Antifungal activity
was done against C. albicans and A. niger at 200, 400, and 800 ppm
concentration. Streptomycin and ketoconazole were used as standard
drugs for antibacterial and antifungal evaluations, respectively. The
compounds were screened for their biological activity using inhibition
zone technique.18 The results obtained for antibacterial and antifungal
activities are given in Tables V and VI respectively.
REFERENCES
[1] T. Takeshima, N. Fukada, M. Muraoka, and T. Miyauchi, Yuki Gousei Kagaku
Kyokaishi (J. Synth. Org. Chem. Japan), 31, 808 (1973).
[2] T. Takeshima, W. Muraoka, and N. Fukada, Yuki Gousei Kagaku Kyokaishi (J.
Synth. Org. Chem. Japan), 40, 123 (1982).
[3] W. O. Foye, J. Chem. Education, 46, 841 (1969).
[4] M. Yokoyama and T. Imamoto, Synthesis, 797 (1984).
[5] Y. Tominaga, J. Heterocyclic Chem., 26, 1167 (1989).
[6] Y. Tominaga, Y. Matsuda, and G. Kobayashi, Yakugaku Zasshi, 95, 1073 (1975).
[7] G. D. Cuny, J. R. Hauske, D. L. Heefner, M. Z. Hoemann, G. Kumaravel, A. Melikian-
Badalian, R. F. Rossi, and R. L. Xie, PCT Int. Appl. WO 0034, 265 (2000); C.A. 133,
43453g (2000).
[8] M. Yamada, S. Hamamoto, K. Hayashi, K. Takaoka, H. Matsukura, M. Yotsuji,
K. Yonezawa, K. Ojima, T. Takamatsu, K. Taya, H. Yamamoto, T. Kiyoto, and H.
Kotsubo, PCT Int. Appl. WO 99 21, 849 (1999); C.A., 130, 311706u (1999).
[9] R. J. Ogilvie, PCT Int. Appl. WO 02 50, 063 (2002); C.A. 137, 47115d (2002).

2378
V. N. Pathak et al.
[10] S. Barbey, C. Boyer-Joubert, M. Finet, R. Hanf, G. G. Le Filliatre, N. Prual, S. Yannic-
Arnoult, and J. L. Torregrosa, Fr. Demande FR 2, 814, 166 (2002); C.A., 137, 33209a
(2002).
[11] A. W. Faull and J. Kettle, PCT Int. Appl. WO 00 46, 198 (2000); C.A., 133, 150462f
(2000).
[12] A. Gutman, G. Nisnevich, I. Zaltzman, V. Ponomarev, and M. Sotrihin, PCT Int.
Appl. WO 02 46, 153 (2002); C.A., 137, 33210u (2002).
[13] E. Defossa, U. Heinelt, O. Klingler, G. Zoller, F. Al-Obeidi, A. Walser, P. Wildgoose,
and H. Matter, PCT Int. Appl. WO 99 33, 800, (1999); C.A., 131, 87814p (1999).
[14] M. L. Jones, D. Gunn, J. H. Jones, and M. C. Van Zandt, PCT Int. Appl. WO 99 50,
268 (1999); C.A., 131, 257442k (1999).
[15] R. Pamukku and G. A. Piazza, U.S. Patent 6, 410, 584 (2002); C.A., 137, 47109e
(2002).
[16] K. C. Joshi, V. N. Pathak, and P. Chand, J. Prakt. Chemie., 320(4), 701 (1978).
[17] K. C. Joshi, V. N. Pathak, and R. Gupta, Ind. J. Heterocycl. Chem., 2, 15 (1992).
[18] M. C. Bryant, Antibiotics and Their Laboratory Control (Butterworth, London,
1968).