Rapid access of some chloro-substituted isocoumarins and biological activity toward some pathogenic systems

Article abstract of DOI:10.1080/00397910500182416

Sulphuric acid-catalyzed chloralhydrate condensation with different m-substituted benzoic acids formed trichlorophthalides 1, from which Zn + AcOH reduction afforded various dichloro derivatives 2. These derivatives 2 on treatment with alkaline Hg(OAc)

Full text of DOI:10.1080/00397910500182416

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Rapid Access of Some
Chloro‐substituted
Isocoumarins and Biological
Activity Toward Some
Pathogenic Systems
H. N. Roy a & M. S. Sarkar a
a Department of Chemistry , University of Rajshahi ,
Rajshahi, Bangladesh
Published online: 18 Aug 2006.
To cite this article: H. N. Roy & M. S. Sarkar (2005) Rapid Access of Some
Chloro‐substituted Isocoumarins and Biological Activity Toward Some Pathogenic
Systems, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:16, 2177-2181
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Synthetic Communicationsw, 35: 2177–2181, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500182416
Rapid Access of Some Chloro-substituted
Isocoumarins and Biological Activity
Toward Some Pathogenic Systems
H. N. Roy and M. S. Sarkar
Department of Chemistry, University of Rajshahi, Rajshahi, Bangladesh
Abstract: Sulphuric acid–catalyzed chloralhydrate condensation with different m-sub-
stituted benzoic acids formed trichlorophthalides 1, from which Zn þ AcOH reduction
afforded various dichloro derivatives 2. These derivatives 2 on treatment with alkaline
Hg(OAc)2 þ I2 furnished different substituted isocoumarins 4.
Keywords: 2-(2,20-dichloroethenyl)-5-substituted benzoic acid, 3-chloro substituted
isocoumarins
Isocoumarins are widely distributed microbial metabolites in nature that are
associated with different structures[1] and biological profiles.[2–4] They are
also found to be associated with pesticidal activities.[4,5] Many synthesis of
isocoumarins and dihydroisocoumarins were reported. Larock et al.[6] have
reported a convenient route for the synthesis of some isocoumarins and
3,4-dihydroisocoumarins using the toxic metal thallium for thallation and
subsequent olefination of benzoic acids. In 1998 Mali et al.[7] devised the con-
densation of phthalides with butyraldehyde or acetaldehyde in the presence of
LDA and acid hydrolysis to obtain isocoumarins. Recently, a simple method
was devised by Purohit[8] for the fabrication of 3-aroyl-4-alkylisocoumarins
by refluxing o-acylbenzoic acid with phenaceyl bromide in the presence of
Received in India May 4, 2005
Address correspondence to H. N. Roy, Department of Chemistry, University of
Rajshahi, Rajshahi 6205, Bangladesh. E-mail: hnroy01@yahoo.com
2177

2178
H. N. Roy and M. S. Sarkar
anhyd. potassium carbonate. Undoubtedly, all the methods added to the field of
isocoumarins synthesis. We felt the need to develop a new method for the
synthesis of chloro-substituted isocoumarin, which is described herein.
RESULTS AND DISCUSSION
While performing the known reaction[9] of the Zn and AcOH reduction to
3-(trichloromethyl)-6-methoxyphthalide, we isolated a new compound,
2-(2,20-dichloroethenyl)-5-methoxybenzoic acid 2, and not the reported
1
compound 3. The H NMR and 13C NMR (Dept) spectral analyses proved
the structure of 2. In addition the mass spectrum also supported the
structure of 2. Further information by conducting Baeyer and Br2 þ water
tests were conclusive.
Subsequent reaction of 2a with alkaline Hg(OAc)2 in DMSO followed by
acid workup gave 4a in an 85% yield. In the infrared spectrum, peaks at 1728
1
and 1687 cm21 for the C55O group and double bond were observed. The H
NMR spectrum indicated peak because of methoxy at 3.81 ppm. In the 13C
NMR spectrum, ten carbons were detected with C55O at 170.23 ppm. The
double-bonded carbons were observed at 102.2 and 107.3 ppm. The HRMS
was in agreement with the given structure of 4a. Isocoumarins (4) were
screened for biological activity. In the MIC test all the compounds (4a–c)
showed moderate biological activity with respect to Shigella dysenteriae,
Bacillus subtilis, Salmonella typhi, and Escherichia coli at a molar concen-
tration of 20–25 mg/mL. Therefore, we state in conclusion that the present
article describes a simple strategy for the preparation of chloro-substituted iso-
coumarins (Scheme 1).
Scheme 1.

Chloro-substituted Isocoumarins
EXPERIMENTAL
General
2179
The melting points were determined on a capillary melting-point apparatus
and are uncorrected. Infrared spectra were recorded using KBr pellets for
solids and neat for liquids on FTIR-8400 and Perkin-Elmer 883 grating spec-
trometers. 1H NMR and 13C NMR spectra were taken on AC Bruker 200-MHz
spectrometer in CDCl3, containing TMS as the internal standard. Mass spectra
were taken on Kratos MS 80 and JEOL JMS-DX 303/JMA-DA-5000 system.
All J values are given in Hz, chemical shifts are all in d units. Reactions were
monitored by TLC and column chromatography carried out on 60–120 mesh
E. Merck silica gel. No hazardous chemicals or procedures have been adopted
during the work.
General Procedure for Dichloro Compounds:
2-(2,20-Dichloroethenyl)-5-methoxybenzoic Acid 2a
Trichloromethyl-6-methoxyphthalide[9] 1a (1 g, 3.55 mmol) acetic acid
(15 mL) and Zn dust (2 equiv., 0.46 g) were heated at 1168C for 3 h, and
then filtered and diluted with cold water. A white precipitate was cooled
and filtered to give 2a in a 90% yield (0.78 g). Mp. 166–1678C. IR: 1691,
1
1602 cm21; H NMR (d6-DMSO): 7.45–7.40 (m, 2 H, Ar-H), 6.90 (dd, 1
H, J ¼ 2, 8 Hz, Ar-H), 4.53 (s, 1 H, 55CH), 3.26 (s, 3 H, OMe); 13C NMR:
167.5, 158.9, 131.2, 130.4, 128.8, 126.7, 119.4, 117.5, 115.4, 55.1. Calcd.
for C10H8O3CI2: C, 48.58%; H, 3.24%; CI, 28.74%. Found C, 48.63%; H,
3.39%; CI, 28.78%. HRMS calculated for C10H8O3CI2, 247.0762; observed
247.0764.
2-(2,20-Dichloroethenyl)-5-hydroxybenzoic acid 2b. 75% (0.65 g). Mp
;
1838C. IR: 3475 (broad), 1680 cm21 1H NMR: (d6-DMSO), 7.47–7.35
(m, 2 H), 6.95 (dd, 1 H, J ¼ 2.6, 8.4 Hz, Ar-H), 4.79 (s, 1 H, Ar-OH), 4.61
(s, 1 H, 55CH); 13C NMR: 168.6, 157, 131.5, 130.5, 128.8, 125.9, 119.6,
119.3, 117.8. Calcd. for C9H6O3CI2: C, 46.35%; H, 3.43%; CI, 30.47%.
Found C, 46.40%; H, 3.48%; CI, 30.52%. HRMS calculated for
C9H6O3CI2, 233.0494; observed 233.0497.
2-(2,20-dichloroethenyl)-5-benzyloxybenzoic acid 2c. 70% (0.61 g). Mp
1
1458C. IR: 1687 cm21; H NMR (CDCI3): 8.03 (d, 1 H, J ¼ 8 Hz, Ar-H),
7.46–7.35 (m, 7 H, Ar-H), 5.12 (s, 2 H, –CH2–) 4.53 (s, 1 H, 55CH); 13C
NMR: 169, 156, 145, 136.3, 133 (3 ꢀ C), 128.5 (2 ꢀ C), 128.1, 127.5, 126
(2 ꢀ C), 122.3, 117, 71.2. Calcd. for C16H12O3CI2: C, 59.44%; H, 3.71%;
CI, 21.98%; Found C, 59.49%; H, 3.76%; CI, 22.03%. HRMS calculated
for C16H12O3CI2, 323.1738; observed 323.1739.

2180
H. N. Roy and M. S. Sarkar
General Preparation Procedure for Isocoumarins: 7-Methoxy-3-
chloro Isocoumarin 4a
2-(2,20-Dichloroethenyl)-5-methoxybenzoic acid 2a (0.05 g, 0.203 mmol) and
I2 (0.025 g) were dissolved in DMSO (10 mL). Solid NaHCO3 (0.017 g) and
Hg(OAc)2 (0.06 g) were added and the reaction mixture was heated between
70–808C for 4 h (monitored by TLC). It was neutralized with 2 M of HCI,
DMSO was removed, and the residue was extracted with EtOAc, washed
with H2O, dried over Na2SO4, and evaporated. The crude product was chro-
matographed on silica gel by eluting with n-hexane/ethylacetate (5 : 1) to
1
afford 4a (0.036 g, 85%), mp 131–1328C. IR: 1728, 1687 cm21; H NMR
(CDCI3): 7.57 (d, 1 H, J ¼ 2 Hz), 7.51 (d, 1 H, J ¼ 8 Hz), 7.41 (s, 1 H,
55CH), 7.06 (dd, 1 H, J ¼ 2, 8 Hz), 3.81 (s, 3 H, OMe); 13C NMR: 170.23,
166, 163, 144, 138, 107.3, 105, 104, 102.2, 52.3; HRMS calculated for
C10H7O3CI, 210.6153; observed 210.6150.
7-Hydroxy-3-chloro isocoumarin 4b. 78% (0.033 g), mp 103–1048C. IR:
1
3405 (broad), 1729, 1681 cm21, H NMR (CDCI3): 7.84–7.44 (m, 2 H),
7.50 (s, 1 H, 55CH), 7.30 (s, 1 H, Ar-OH), 7.01 (dd, 1 H, J ¼ 2, 8 Hz); 13C
NMR: 170.5, 163, 143, 137, 135, 133, 122, 107, 103; HRMS calculated for
C9H5O3CI, 196.5885; observed 196.5883.
7-Benzyloxy-3-chloro isocoumarin 4c. 80% (0.036 g), mp 109–1118C. IR:
1
1731, 1687; H NMR (CDCI3): 7.43–7.33 (m, 5 H), 6.86 (dd, 1 H, J ¼ 2.4,
8 Hz), 6.73 (d, 1 H, J ¼ 2.4 Hz), 6.69 (s, 1 H, 55CH), 6.49 (dd, 1 H,
J ¼ 2.4, 8 Hz), 5.09 (s, 2 H); 13C NMR: 172, 164, 161, 151, 141, 135.7,
128.7 (2 ꢀ C), 128.3, 127.5 (2 ꢀ C), 105.6, 104, 102.7, 102, 70.2; HRMS
calculated for C16H11O3CI, 286.7129; observed 286.7132.
ACKNOWLEDGMENT
The authors are grateful to the Department of Chemistry, University of
Rajshahi, Bangladash, for required chemicals and instruments, and to
M. Motiur Rahman, a research fellow at Yonsei University in Korea, for
necessary spectra.
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Yoshida, S.; Takahashi, N. Agric. Biol. Chem. 1971, 35, 363.
2. Massayassu, K.; Masaya, K. Chem. Abstr. 1977, 86, 155511s.

Chloro-substituted Isocoumarins
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