Syntheses of some 3-substituted isothiochromen-1-ones

Full text of DOI:10.1007/s10593-010-0419-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
LETTERS TO THE EDITOR
SYNTHESES OF SOME 3-SUBSTITUTED
ISOTHIOCHROMEN-1-ONES
U. M. V. Basvanag1, S. Mohana Roopan1, F. Nawaz Khan1*
Keywords: dicarboxylic acid, isothiochromen-1-one, intramolecular cyclization.
Isocoumarins and their derivatives such as dihydroisocoumarins are secondary metabolites of a wide
variety of microbial plant and insect sources and can be used in the synthesis of other medicinal compounds
[1-4]. A number of substituted thioisocoumarins has been prepared [5]. They also occur as mycotoxins, fungal
metabolites, and a principal sweetness component of the Japanese sweet tea [6–8]. Most methods available for
the construction of the thioisocoumarin and thiocoumarin nucleus suffer from one or more drawbacks, such as a
multi-step procedure, low yields [9, 10], and long reaction time required to obtain a good yield of the desired
product, or the use of expensive and hazardous reagents and solvents. For example, 3-arylisocoumarins were
transformed into 3-aryl-1-thioisocoumarins by the reaction with phosphorus pentasulfide, which were converted
first into 3-aryldithioisocoumarins in a few steps, and then oxidized to 3-aryl-2-thioisocoumarins by potassium
permanganate [11, 12].
Monolkyl and dialkyl homophthalates can be converted into 3-alkoxy- or 3-(alkylthio)dithioiso-
coumarins, which are readily oxidized to the corresponding 2-thioisocoumarins by potassium permanganate or
benzonitrile N-oxide [13].
Finding an efficient method for the synthesis of isothiochromen-2-one is still a challenge.
In continuity of our interest [14–18] we have developed a new method for the synthesis of 3-substituted
isothiochromen-2-ones from 2-(mercaptocarbonylmethyl)benzothioic acid and various aromatic or aliphatic acid
chlorides. Homophthalic acid 1 was treated with thionyl chloride to give 2-(chlorocarbonylmethyl)benzoyl
chloride 2. Its reaction with potassium hydrogen sulfide followed by hydrolysis gave 2-(mercapto-
carbonylmethyl)benzothioic S-acid 3. The treatment of product 3 with different acid chlorides 4 gave
3-substituted 1H-isothiochromen-1-ones 5.
The elaborated route to 2-thioisocoumarins is a simple method proceeding without formation of any side
products such as dithioisocoumarins with the additional advantage of easy isolation of products.
_______
* To whom correspondence should be addressed, e-mail: nawaz_f@yahoo.co.in.
1Organic Chemistry Division, School of Science and Humanities, VIT – University, Vellore 632 014, Tamil
Nadu, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1586-1588, September, 2009.
Original article received November 9, 2008. In revised form September 21, 2009.
1276
0009-3122/09/4510-1276©2009 Springer Science+Business Media, Inc.

The 1H and 13C NMR spectra were recorded on a Bruker spectrometer at 400 and 100 MHz, respectively,
in CDCl3 (TMS as an internal reference). GC/MS analyses were performed with Agilent GC/MS-5973 Inert
MSD series.
KSH
KOH + H2S
O
O
O
OH
Cl
SK
HO
O
Cl
H2O
HCl
KS
O
KSH
SOCl2
O
1
2
O
SH
O
HS
RCOCl
4
S
O
R
3
5
R = Me, Ph, p-MeC6H4, p-ClC6H4
2-(Mercaptocarbonylmethyl)benzothioic acid (3). Homophthalic acid 1 (0.1 mol) was converted to its
chloride 2 by stirring with SOCl2 (0.15 mol) and then mixed with a solution containing ethanol/KOH, then
stirred under 10°C by passing H2S gas continuously overnight. The resulting solution was filtered off, and the
filtrate was distilled and evaporated to dryness. The residue was then mixed with cold water and extracted using
benzene to remove any neutral material. The aqueous solution was finally acidified, and the solid formed was
separated and extracted with ether. The ether was distilled under vacuum to give compound 3 (95%); mp
1
183-185°C. H NMR spectrum, δ, ppm: 2.56 (2H, s); 3.56 (2H, s); 7.24-7.22 (2H, m); 7.74 (1H, d); 7.35
(1H, m). GC/MS, m/z: 212.1128. C9H8O2S2 (212.28).
3-Substituted isothiochromen-1-ones 5a–d were synthesized from benzothioic acid 3 (1 mmol) and
acid chloride 4a–d (4 mmol) by heating under reflux at 200oC in an oil bath. The products obtained were
recrystallized from ether using activated charcoal and identified by NMR spectroscopy.
3-Phenyl-1H-isothiochromen-1-one (5a) was synthesized using benzoyl chloride in 95% yield; mp
105°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.1 (1H, s, H-4); 7.2-7.3 (4H, m, Ar); 7.41-7.42 (2H, d, J = 6.3, Ar);
7.58-7.60 (2H, d, J = 8, Ar); 7.7 (1H, m, Ar). 13C NMR spectrum, δ, ppm: 102.58 (C=CR); 120.30, 125.36,
127.06, 128.71, 129.06, 129.33, 129.50, 129.71, 130.49, 132.08, 135.85, 137.75 (C=CR); 152.89, 161.78
(C=O). GC/MS, m/z: 239 [M+]. Found, %: C 75.47; H 4.32; O 6.67; S 13.34. C15H10OS. Calculated, %: C 75.60;
H 4.23; O 6.71; S 13.46.
3-Methyl-1H-isothiochromen-1-one (5b) was synthesized using acetyl chloride in 95% yield; mp
110°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.7 (3H, s, Ar); 6.7 (1H, s, H-4); 7.3 (1H, m, Ar); 7.41-7.50 (2H, m,
Ar); 7.93-7.95 (1H, d, J = 8, Ar). 13C NMR spectrum, δ, ppm: 9.64 (CH3); 103.53 (C=CCH3); 119.94, 124.84,
127.55, 129.53, 134.73, 137.65 (C=CCH3); 154.57, 163.01 (–C=O). GC/MS, m/z: 177 [M+]. Found, %: C 68.27;
H 4.51; O 9.19; S 18.03. C10H8OS. Calculated, %: C 68.15; H 4.58; O 9.08; S 18.19.
3-(4-Chlorophenyl)-1H-isothiochromen-1-one (5c) was synthesized using p-chloro- benzoyl chloride in
94% yield; mp 145°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.2 (1H, s, H-4); 7.25 (2H, m, Ar); 7.28 (1H, m, Ar);
13
7.3 (2H, m, Ar); 7.5 (1H, m, Ar); 7.6 (1H, m, Ar); 7.94-7.92 (1H, d, J = 7.6, Ar). C NMR spectrum, δ, ppm:
102.09 (C=CR); 120.58, 126.04, 126.51, 2×(128.42); 129.13, 129.76, 130.47, 2×(134.99); 136.02, 137.27
1277

(C=CR); 152.58, 162.05 (C=O). GC/MS, m/z: 258.24 [M+2]. Found, %: C 66.17; H 3.27; O 5.76; S 11.71.
C15H9ClOS (256.68). Calculated, %: C 66.05; H 3.33; Cl 13.00; O 5.87; S 11.76.
3-p-Tolyl-1H-isothiochromen-1-one (5d) was synthesized using p-methylbenzoyl chloride in 85%
1
yield; mp 160°C. H NMR spectrum, δ, ppm (J, Hz): 2.34 (3H, s, CH3); 7.12 (2H, m, Ar); 7.2 (1H, s, H-4);
7.28–7.31 (2H, m, Ar); 7.5 (1H, m, Ar); 7.6 (2H, m, Ar); 7.9 (1H, s, Ar). 13C NMR spectrum, δ, ppm: 21.39
(CH3); 101.08 (C=CR); 120.42, 125.19, 2×(125.84); 127.91, 129.20, 2×(129.55); 129.65, 134.82, 137.73
(C=CR); 140.28, 153.86, 162.45 (C=O). GC/MS, m/z: 256.18 [M+]. Found, %: C 76.27; H 4.67; O 6.41;
S 12.79. C16H12OS (256.26). Calculated, %: C 76.16; H 4.79; O 6.34; S 12.71.
REFERENCES
1.
2.
3.
4.
5.
G. A. Olah, Friedel-Crafts and Related Reactions, Vol. III, Interscience, New York, 1964, Part I.
H. Szmant, Organic Building Blocks of the Chemical Industry, Wiley, New York, 1989.
J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992.
P. Manivel, S. Mohana Roopan, and F. Nawaz Khan, J. Chil. Chem. Soc., 53, 1126 (2008).
G. B. Henerson and R. A. Hill, J. Chem. Soc., Perkin Trans. 1, 1111 (1982).
I. Bunge, G. Derheimer, and R. Roschentaler, Biochem. Biophys. Res. Commun., 83, 398 (1978).
G. A. Kraus, J. Org. Chem., 46, 201 (1981).
6.
7.
8.
9.
K. Nozawa, S. Makajima, M. Yamada, and K. I. Kawai, Chem. Pharm. Bull., 28, 1622 (1980).
M. A. Kinder, J. Kopf, and P. Margaretha, Tetrahedron, 56, 6763 (2000).
M. A. Kinder and P. Margaretha, Photochem. Photobiol. Sci., 2, 1220 (2003).
L. Legrand and N. Lozac'h, Bull. Soc. Chim. Fr., 1787 (1964).
10.
11.
12.
13.
14.
L. Legrand and N. Lozac'h. Bull. Soc. Chim. Fr., 2227 (1970).
J. Lemoine, L. Legrand and N. Lozac'h, Phosphorus, Sulfur, Relat. Elem., 3, 321 (1977).
Venkatesha R. Hathwar, P. Manivel, F. Nawaz Khan, and T. N. Guru Row, Acta Crystallogr., E63,
o3707 (2007).
15.
Venkatesha R. Hathwar, P. Manivel, F. Nawaz Khan, and T. N. Guru Row, Acta Crystallogr., E63,
o3708 (2007).
16.
17.
18.
S. Mohana Roopan and F. Nawaz Khan, Indian J. Heterocycl. Chem., 18, 183 (2008).
S. Mohana Roopan, T. Maiyalagan, and F. Nawaz Khan, Phosphorus, Sulphur, Silicon, 86, 1019 (2008).
Venkatesha R. Hathwar, P. Manivel, F. Nawaz Khan, and T. N. Guru Row., Cryst. Eng. Commun.,
11, 284.
1278