A fast and large-scale synthesis of 3-formyl-2-mercaptoquinolines

Article abstract of DOI:10.1080/10426500600574796

A convenient, efficient, and inexpensive procedure for the synthesis of 3-formyl-2-mercaptoquinolines 2a-l has been developed by a simple one-pot reaction of 3-formyl-2-chloroquinolines 1a-l with sodium sulfide and hydrochloric acid in ethanol. The structures of all the synthesized compounds were elucidated on the basis of elemental analyses and IR, 1 H NMR, and mass spectral data. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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A Fast and Large-Scale
Synthesis of 3-Formyl-2-
mercaptoquinolines
Belalakatte P. Nandeshwarappa a , Doyijode B. Aruna
Kumar b , Halehatty S. Bhojya Naik a & Kittappa M.
Mahadevan b
a Department of Post Graduate Studies and Research
in Industrial Chemistry, Kuvempu University,
Shankaraghatta, Karnataka, India
b Department of PG Studies and Research in
Chemistry, Kuvempu University, Shankaraghatta,
Karnataka, India
Version of record first published: 21 Sep 2006.
To cite this article: Belalakatte P. Nandeshwarappa , Doyijode B. Aruna Kumar ,
Halehatty S. Bhojya Naik & Kittappa M. Mahadevan (2006): A Fast and Large-Scale
Synthesis of 3-Formyl-2-mercaptoquinolines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 181:9, 1997-2003
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Phosphorus, Sulfur, and Silicon, 181:1997–2003, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600574796
A Fast and Large-Scale Synthesis
of 3-Formyl-2-mercaptoquinolines
Belalakatte P. Nandeshwarappa
Department of Post Graduate Studies and Research in Industrial
Chemistry, Kuvempu University, Shankaraghatta, Karnataka, India
Doyijode B. Aruna Kumar
Department of PG Studies and Research in Chemistry, Kuvempu
University, Shankaraghatta, Karnatak, India
Halehatty S. Bhojya Naik
Department of PG Studies and Research in Industrial Chemistry,
Kuvempu University, Shankaraghatta, Karnataka, India
Kittappa M. Mahadevan
Department of PG Studies and Research in Chemistry, Kuvempu
University, Shankaraghatta, Karnatak, India
A convenient, efficient, and inexpensive procedure for the synthesis of 3-formyl-
2-mercaptoquinolines 2a–l has been developed by a simple one-pot reaction of
3-formyl-2-chloroquinolines 1a–l with sodium sulfide and hydrochloric acid in
ethanol. The structures of all the synthesized compounds were elucidated on the
basis of elemental analyses and IR, 1 H NMR, and mass spectral data.
Keywords 3-formy-2-mercaptoquinoline; 3-formy-2-chloroquinoline; hydrochloric acid;
sodium sulfide
INTRODUCTION
The conversion of aryl quinolines into mercaptoquinolines is of vi-
tal importance in synthetic organic chemistry. Aryl mercaptols are
Received July 28, 2005; accepted September 26, 2005.
The authors are thankful to V. P. Vaidya, professor and chairman, India, Department
of Chemistry and Industrial Chemistry, Kuvempu University, India, for providing labo-
ratory facilities. Authors are also thankful to H. S. Bhojya Naik, head, NMR Research
Center, Indian Institute of Science, Bangalore, India, for spectral data.
Address correspondence to Kittappa M. Mahadevan, Kuvempu University, Depart-
ment of PG Studies and Research in Chemistry, Shankaraghatta, Karnatak 577 451,
India. E-mail: mady kmm@yahoo.co.uk
1997

1998
B. P. Nandeshwarappa et al.
usually prepared via their corresponding halogenated derivatives.
More reactive heterocyclic halogenated derivatives, i.e., 3-formyl-2-
chloroquinolines into 3-formyl-2-mercaptoquinolines, are known.1,2
Such procedures are obviously accompanied by poor yields, undesired
side products, vigorous reaction conditions, long reaction times, ex-
pensive or toxic reagents, and tedious work-up. Therefore, there is
still a need to introduce new methods and inexpensive reagents for
such functional group transformations. In this context, we wish to
report an efficient and inexpensive method for the synthesis of 3-
formyl-2-mercaptoquinolines starting from easily accessible 3-formyl-
2-chloroquinoline by a reaction with sodium sulfide and hydrochloric
acid in a quantitative yield under remarkably soft conditions. We found
that the best results were achieved using concentrated hydrochloric
acid.
3-formyl-2-mercaptoquinoline compounds and the ring substituted
analogues are important starting materials to construct sulfur-
containing heterocycles, such as thiophene, thiopyrans, etc., fused with
a quinoline moiety, with very important functional groups, such as
COOR, COR, CN, and CONHR, at appropriate positions.3 These
functional groups have been utilized to build various pharmaceutically
important heterocycles.4–9 2-hydroxy, 2-mercaptoaromatic, and hetero-
cyclic aldehydes, and also their derivatives, such as oximes, and schiff
bases, have proven to be an important pharmaceutical agent.10–16
A
number of metal complexes of such compounds have also been re-
ported. Hence, there is a great deal of interest to synthesize 3-formyl-
2-mercaptoquinolines.
In continuation of our work on condensed heterocycles17–19and in
view of a growing interest in the field of anticancer agents, we wish to
report an efficient synthesis of novel title compounds 2a–l.
RESULTS AND DISCUSSION
The reaction is presumed to take place via an in situ formation of H2S
under strong acidic conditions. It was observed that reaction was com-
plete within 10 min. The synthesis of 3-formyl-2-mercaptoquinoline
(2a) from 1a with conc. HCl and sodium sulfide resulted in an excel-
lent yield (Scheme 1). The structure of 2a was assigned on the basis of
1
IR, H NMR, and mass spectral studies. As an example, the IR spec-
trum of 2a exhibited bands at 3480–3490 cm−1, which correspond to
NH and SH. This confirms the subsequent substitution by remov-
ing chlorine present at the 2-position on the quinoline nucleus of 2a.
Also, the absence of chlorine was confirmed by a Beilstein’s test. In

3-Formyl-2-Mercaptoquinolines
1999
SCHEME 1 The general synthetic procedure of 3-formyl-2-mercaptoquino-
lines derivatives 2a–l.
1
the H NMR spectra of 2a, a broad singlet occurred at δ 11.2 due to
the SH in the product. Furthermore, the structure assigned for 2a
was confirmed by its mass spectrum with a molecular ion peak at 189.
In addition, the structure of 2a was further supported by elemental
analysis. Compounds 2b–l were similarly prepared (see Experimental
section).
In conclusion, the present procedure catalyzed by conc. HCl on
substituted 3-formyl-2-chloroquinolines 1a–l provided a convenient
and selective method for the synthesis of substituted 3-formyl-2-
mercaptoquinolines 2a–l. The notable advantages of this procedure
are (a) a fast reaction, (b) high yields, and (c) good conversions. We
believe that this procedure will provide a better and more practical
alternative to the existing methodologies for the synthesis of 3-formyl-
2-mercaptoquinoline derivatives.

2000
B. P. Nandeshwarappa et al.
EXPERIMENTAL
General
All mps were recorded in an open capillary and were uncorrected. IR
spectra (cm−1) were recorded (as KBr pellets) on a Perkin Elmer 157
infrared spectrophotometer. The 1H NMR spectra (300 MHz) were mea-
sured in DMSO-d6 with a Bruker supercon FT NMR instrument using
TMS as an internal standard. Chemical shifts are expressed as δ val-
ues (ppm). Mass spectra were determined on a Jeol JMS-D 300 mass
spectrometer operating at 70 eV. The purity of compounds was checked
by TLC on silica gel, and the compounds were purified by column chro-
matography (silica gel).
The General Procedure for the Synthesis of
2-Mercapto-3-formylquinolin es 2a–l
A mixture of 3-formyl-2-chloroquinoline (1a, 5.73 g, 29.98 mmol) and
sodium sulfide (8.4 g, 9.2 mmol) was refluxed for 10 min on a water
bath in ethanol (50 mL). Conc. HCl (15 mL) was added dropwise to the
reaction mixture. The mercapto compound 2a precipitated out as a yel-
low crystalline solid. The mixture was poured into cold water (500 mL);
the resulting solid product 2a was collected by filtration, washed with
ethanol, dried, and recrystallized from ethyl acetate and benzene (8:2).
In a similar way, the same procedure produced 2b–l. The synthesized
1
compounds were easily characterized by IR, H NMR, and mass spec-
troscopy.
3-Formyl-2-mercaptoquinoline (2a)
Obtained in an 80% yield, solid; m.p. > 193◦C; (Found: C, 63.39; H,
3.71; N, 7.38; S, 16.85. C10H7NOS requires C, 63.47; H, 3.73; N, 7.40; S,
16.95); νmax/cm−1 3480–3490 (NH), 1640 (C S); δH7.6–8.3 (m, 5H, 6H,
7H, 8H), 8.83 (s, 4H), 10.35 (s, CHO), 11.2 (s, SH); m/z 189 (M+).
6-Methyl-3-formyl-2-mercaptoquinoline (2b)
Obtained in a 79% yield, solid; m.p. > 213◦C; (Found: C, 65.07; H, 4.39;
N, 6.78; S, 15.68. C11H9NOS requires C, 65.00; H, 4.46; N, 6.89; S, 15.78);
νmax/cm−1 3485–3493 (NH), 1635 (C S); δH 2.55 (s, CH3), 7.70 (d, J =
9Hz, 7H), 7.82 (s, 5H), 7.86 (d, J = 9Hz, 8H), 8. 68 (s, 4H), 10.44 (s,
CHO), 11.3 (s, SH); m/z 203 (M+).

3-Formyl-2-Mercaptoquinolines
2001
7-Methyl-3-formyl-2-mercaptoquinoline (2c)
Obtained in an 82% yield, solid; m.p. > 225◦C; (Found: C, 65.07; H,
4.39; N, 6.78; S, 15.68. C11H9NOS requires C, 65.00; H, 4.46; N, 6.89; S,
15.78); νmax/cm−1 3485–3494 (NH), 1642 (C S); δH2.60 (s, CH3), 7.49
(dd, J = 9Hz, 6H), 7.79 (dd. J = 9Hz, 8H), 7.95 (s, J = 9Hz, 5H), 8.71 (s,
4H), 10.47 (s, CHO), 11.2 (s, SH).
8-Methyl-3-formyl-2-mercaptoquinoline (2d)
Obtained in an 80% yield, solid; m.p. > 223◦C; (Found: C, 65.07; H,
4.39; N, 6.78; S, 15.68. C11H9NOS requires C, 65.00; H, 4.46; N, 6.89, S,
15.78); νmax/cm−1 3487–3492 (NH), 1636 (C S); δH2.73 (s, CH3), 7.55
(t, J = 8Hz, 6H), 7.75 (dd. J = 8 Hz, 7H), 7.92 (dd, J = 8Hz, 5H), 8.75
(s, 4H), 10.50 (s, CHO), 11.4 (s, SH).
6-Methoxy-3-formyl-2-mercaptoquinoline (2e)
Obtained in an 85% yield, solid; m.p. > 233◦C; (Found: C, 60.29; H,
4.15; N, 6.35; s, 14.69. C11H9NO2S requires C, 60.26; H, 4.14; N, 6.39;
S, 14.62); νmax/cm−1 3488–3498 (NH), 1635 (C S); δH3.94 (s, OCH3),
7.47 (dd, J = 8Hz, 7H), 7.91 (d, J = 8Hz, 8H), 7.17 (d, J = 8Hz, 5H),
8.75 (s, 4H), 10.50 (s, CHO), 11.3 (s, SH); m/z 219 (M+).
7-Methoxy-3-formyl-2-mercaptoquinoline (2f)
Obtained in an 88% yield, solid; m.p. > 236◦C; (Found: C, 60.29; H,
4.15; N, 6.35; S, 14.69. C11H9NO2S requires C, 60.26; H, 4.14; N, 6.39;
S, 14.62); νmax/cm−1 3480–3491(NH), 1638 (C S); δH3.97 (s, 4 .02 (s,
OCH3), 7.27 (dd, J = 9Hz, 6H), 7.33 (s. 8H), 8.03 (s, J = 9Hz, 5H), 8.72
(s, 4H), 10.97 (s, CHO), 11.3 (s, SH).
8-Methoxy-3-formyl-2-mercaptoquinoline (2g)
Obtained in an 85% yield, solid; m.p. > 241◦C; (Found: C, 60.29; H,
4.15; N, 6.35; S, 14.69. C11H9NO2S requires C, 60.26; H, 4.14; N, 6.39;
S, 14.62); νmax/cm−1 3485–3493 (NH), 1630 (C S); δH4.10 (s, OCH3),
7.25 (t, J = 9Hz, 6H), 7.47 (s, 7H), 7.55 (t, J = 9Hz, 5H), 8. 70 (s, 4H),
10.57 (s, CHO), 11.2 (s, SH).
6-Bromo-3-formyl-2-mercaptoquinoline (2h)
Obtained in an 83% yield, solid; m.p. > 243◦C; (Found: C, 44.89; H, 2.28;
N, 5.24; S, 11.86. C10H6BrNOS requires C, 44.79; H, 2.26; N, 5.22; S,

2002
B. P. Nandeshwarappa et al.
11.96); νmax/cm−1 3489–3498 (NH), 1636 (C S); δH7.95 (s, 8H); 7.97 (s,
7H), 10.55 (s, CHO), 8.18 (s, 5H), 8. 68 (s, 4H), 11.3 (s, SH); m/z 268
(M+).
6-Chloro-3-formyl-2-mercaptoquinoline (2i)
Obtained in an 85% yield, solid; m.p. > 248◦C; (Found: C, 53.69; H,
2.69; N, 6.18; S, 14.28. C10H6ClNOS requires C, 53.70; H, 2.70; N, 6.26;
S, 14.34); νmax/cm−1 3485–3496 (NH), 1635 (C S); δH7.80 (dd, J = 9Hz,
7H), 7.96 (s, 5H), 8.03 (d, 8H), 8. 68 (s, 4H), 10.55 (s, CHO), 11.2 (s, SH);
m/z 223 (M+).
7-Chloro-3-formyl-2-mercaptoquinoline (2j)
Obtained in an 87% yield, solid; m.p > 251◦C; (Found: C, 53.69; H, 2.69;
N, 6.18; S, 14.28. C10H6ClNOS requires C, 53.70; H, 2.70; N, 6.26; S,
14.34); νmax/cm−1 3486–3495 (NH), 1645 (C S); δH 7.58 (dd, J = 9Hz,
6H), 7.95 (d, J = 9Hz, 5H), 8.01 (s. 8H), 8. 73 (s, 4H), 10.51 (s, CHO),
11.3 (s, SH).
6,7-Dimethoxy-3-formyl-2-mercaptoquinoline (2k)
Obtained in an 85% yield, solid; m.p > 247◦C; (Found: C, 57.76; H,
4.37; N, 5.59; S, 12.85. C12H11NO3S requires C, 57.82; H, 4.45; N, 5.62,
S, 12.86); νmax/cm−1 3486–3496 (NH), 1630 (C S); δH 4.00 (s, OCH3),
4.02 (s, OCH3), 7.07 (s, 5H), 7.30 (s, 8H), 8.84 (s, 4H), 10.42 (s, CHO),
11.4 (s, SH); m/z 249 (M+).
5,6,7-Trimethoxy-3-formyl-2-mercaptoquinoline (2l)
Obtained in a 76% yield, solid; m.p > 242◦C; (Found: C, 55.85; H, 4.75;
N, 5.06; S, 11.37. C13H13NO4S requires C, 55.90; H, 4.69; N, 5.01; S,
11.48); νmax/cm−1 3488–3498 (NH), 1635 (C S); δH4.05 (s, OCH3), 4.14
(s, OCH3), 4.22 (s, OCH3), 7.10 (s, 8H), 8.84 (s, 4H), 10.59 (s, CHO),
11.2 (s, SH); m/z 279 (M+).
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