Synthesis of some 3-substituted isochromen-1-ones

Article abstract of DOI:10.1080/00397910701557796

An alternative method for the synthesis of 3-substituted isocoumarins from homophthalic acid and ester is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701557796

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Synthesis of Some 3‐Substituted
Isochromen‐1‐ones
S. Syed Tajudeen a & Dr. F. Nawaz Khan a
a Chemistry Division, School of Science and Humanities, Vellore Institute of
Technology, Vellore, Tamil Nadu, India
Published online: 05 Oct 2007.
To cite this article: S. Syed Tajudeen & Dr. F. Nawaz Khan (2007): Synthesis of Some 3‐Substituted
Isochromen‐1‐ones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:20, 3649-3656
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Synthetic Communicationsw, 37: 3649–3656, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557796
Synthesis of Some 3-Substituted
Isochromen-1-ones
S. Syed Tajudeen and F. Nawaz Khan
Chemistry Division, School of Science and Humanities, Vellore Institute
of Technology, Vellore, Tamil Nadu, India
Abstract: An alternative method for the synthesis of 3-substituted isocoumarins from
homophthalic acid and ester is described.
Keywords: acids, esters, isocoumarins, microwave, solvent free
Compounds containing the isocoumarin structure exhibit a broad range of bio-
logical activities including antiallergic and antimicrobial,[1,2] immunomodula-
tory,[3] cytotoxic,[4] antifungal,[5] anti-inflammatory,[6] and anti-angiogenic[7]
activity. Isocoumarins[8] are also useful intermediates in the synthesis of a
variety of important compounds such as carbocyclic and heterocyclic
compounds, including isocarbostyrils, iso-quinolines, isochromones,
pyridones, and various aromatic compounds.[9]
A number of methods have been reported in the literature for the synthesis
of isocoumarins.[10] For example, 3-substituted isocoumarins have been
synthesized either by a variety of traditional approaches[11] or by utilizing
transition-metal-catalyzed reactions.[12]
The synthesis of 3,4-disubstituted isocoumarins has received considerable
attention too,[6,13] and recently a number of these compounds have been
Received in India March 13, 2007
Address correspondence to Dr. F. Nawaz Khan, Chemistry Division, School of
Science and Humanities, Vellore Institute of Technology, Vellore 632104, Tamil
Nadu, India. E-mail: nawaz_f@yahoo.co.in
3649

3650
S. S. Tajudeen and F. N. Khan
prepared in good yields via palladium-catalyzed annulations of internal
alkynes.[13d]
However, these catalytic methods are somewhat limited in synthetic
scope because they are highly regioselective only for sterically hindered
alkynes. In continuation of our interest in microwave-assisted reactions and
carbon–carbon bond formation reactions,[14] the present article presents an
alternative method for the synthesis of 3-substitued isocoumarins by the
reaction of homophthalic acid and simpler ester derivatives (Scheme 1).
This methodology avoids the use of both highly expensive alkynes and
toxic acid chlorides prepared using thionylchloride reagents, which are
required for the synthesis.
As a preliminary study, a mixture of homophthalic acid 1 (20 mmol)
and benzoyl chloride 2a (80 mmol) was heated under reflux at 2008C in an
oil bath for 3 h. The completion of reaction was monitored by thin-layer
chromatography (TLC) and then chromatographed on silica gel to produce
3-phenylisocoumarin 3a in 80% yield. Compound 3a was characterized by
IR, 1H NMR, and 13C NMR. The same reaction was performed under
microwave irradition at 900 W for 4 min with a 94% yield of 3a.
The reaction of homophthalic acid with various acid chlorides 2a–g
was tabulated (Table 1). Although the reaction gave good yields, the
major disadvantage was acid chloride. To avoid these difficulties, the
next reaction between methyl benzoate 4a and homophthalic acid was
performed under the same conditions both in oil baths as well as in a
microwave oven, and the reaction was successful, giving 3a in 40% and
54% yields, respectively.
To improve the yield of homophthalic acid and methyl benzoate conden-
sation under conventional and nonconventional routes, sulphuric acid, hydro-
chloric acid, triethyl amine, diethyl amine, and other acid additives such as
acetic acid, monochloroacetic acid, (MCA), dichloroacetic acid (DCA), tri-
chloroacetic acid (TCA), and trifluoroacetic acid (TFA) were attempted
(Table 2, entries 1–9). Trichloroacetic acid indeed improved the yields to
67% and 79% in conventional and microwave irradiation respectively
(Table 2, entry 8).
Optimization for molar percentage of trichloroacetic acid found 200 mol%
was adequate (Tables 2, 3).
Scheme 1. Synthesis of 3-substituted isocoumarin.

Table 1. Synthesis of 3-substituted isocoumarin by the reaction between homophthalic acid and various acid chlorides
Conventional heating
Temp. (8C) Time (h) Product, R
Ph, 3a
Nonconventional heating
Yield (%) Watts Time (min) Product, R
Ph, 3a
Entry
Acid chloride, R
Yield (%)
1
2
3
4
5
6
7
Ph, 2a
200
200
200
200
200
200
200
4
4
4
4
4
4
4
80
73
69
75
79
72
74
900
900
900
900
900
900
900
4
4
8
5
5
6
6
94
85
70
80
84
78
81
p-CH3-C6H4, 2b
p-NO2-C6H4, 2c
p-Cl-C6H4, 2d
p-OCH3-C6H4, 2e
n-Bu, 2f
p-CH3-C6H4, 3b
p-NO2-C6H4, 3c
p-Cl-C6H4, 3d
p-OCH3-C6H4, 3e
n-Bu, 3f
p-CH3-C6H4, 3b
p-NO2-C6H4, 3c
p-Cl-C6H4, 3d
p-OCH3C6H4, 3e
n-Bu, 3f
1-Cyclohexenyl, 2g
1-Cyclo hexenyl, 3g
1-Cyclo hexenyl, 3g

Table 2. Optimization of synthesis of 3-substituted isocoumarin by the reaction between homophthalic acid and methyl benzoate
Conventional heating
Nonconventional heating
Additives
(100 mol%)
Entry
Esters, R
Time (h)
Product
Yield (%)
Watts
Time (min)
Product
Yield (%)
1
2
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
Ph, 4a
H2SO4
HCl
6
6
6
6
6
6
6
6
6
6
6
6
6
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
—
10
5
900
900
900
900
900
900
900
900
900
900
900
900
900
3
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
Ph, 3a
—-
13
9
5
3
Diethyl amine
Triethy amine
Acetic acid
MCA
10
10
10
10
10
10
10
10
10
10
10
4
7
12
34
43
57
79
64
66
57
43
80
5
25
37
51
67
54
60
49
32
74
6
7
DCA
TCA
TFA
8
9
10
11
12
13
TCA- 75 mol%
TCA- 50 mol%
TCA- 25 mol%
TCA 200 mol%

Table 3. Synthesis of 3-substituted isocoumarin by reaction between homophthalic acid and various esters under conventional and nonconventional
techniques
Conventional heating
Nonconventional heating
Entry
Esters, R
Ph, 4a
Temp (8C)
Time (h)
Product
Yield (%)
Watts
Time (min)
Product
Yield (%)
1
3
4
5
6
7
8
200
230
230
230
230
200
200
6
6
6
6
6
6
6
3a
3b
3c
3d
3e
3f
74
66
61
64
67
73
74
900
900
900
900
900
900
900
10
12
12
12
12
10
10
3a
3b
3c
3d
3e
3f
89
72
63
70
74
81
79
p-CH3-C6H4, 4b
p-NO2-C6H4, 4c
p-Cl-C6H4 4d
p-OCH3-C6H4, 4e
n-Bu, 4f
1-Cyclohexenyl, 4g
3g
3g

3654
S. S. Tajudeen and F. N. Khan
DATA
3-Phenylisocoumarin (3a)
1
IR (KBr) (cm21): 3071, 1738, 1687, 2671, 2554. H NMR (CDCl3): d 6.96
(s, 1H), 7.45 (d, 1H), 7.46 (t, 2H), 7.49 (t, 1H), 7.6 (t, 1H), 7.8 (t, 1H), 8.14
(d, 1H), 8.12 (d, 1H). 13C NMR (CDCl3): d 172.27, 138.20, 135.02, 133.93,
130.31, 120.12, 128.95, 128.60, 125.36, 101.95.
3-p-Tolylphenylisocoumarin (3b)
1
IR (KBr) (cm21): 3444, 2543, 753. H NMR (CDCl3): d 2.17 (3H, s), 6.88
(1H, s), 7.23 (1H, d), 7.46 (1H, t), 7.4 (1H, d), 7.7 (1H, t), 8.0 (1H, d), 8.26
(1H, d). 13C NMR (CDCl3): d 200.50, 156.99, 140.77, 135.09, 132.87,
132.41, 130.08, 129.68, 128.93, 128.52, 126.33, 125.35, 103.95, 21.45.
3-p-Nitrophenylisocoumarin (3c)
IR (KBr) (cm21): 3060, 2924, 1688, 2551, 2671, 1347, 1425. 1H NMR
(CDCl3): d 7.15 (s, 1H), 7.58–7.63 (m, 2H), 7.80 (d, 1H), 8.07–8.09
(m, 2H), 8.34–8.38 (m, 3H). 13C NMR (CDCl3): d 161.47, 151.10, 148.35,
137.76, 136.54, 135.24, 129.94, 129.40, 126.56, 125.91, 124.20, 121.05,
104.84.
3-p-Chlorophenylisocoumarin (3d)
IR (KBr) (cm21): 3094, 1681, 2552, 1928, 851, 761. 1H NMR (CDCl3): d 6.96
(s, 1H), 7.32 (d, 1H), 7.44–7.46 (m, 3H), 7.53 (m, 2H), 7.73 (1H, m), 7.80
(m, 2H), 8.32 (m, 1H). 13C NMR (CDCl3): d 162.05, 152.58, 137.27,
136.02, 134.99, 129.76, 129.13, 128.42, 126.51 120.58, 102.09.
3-Anisylisocoumarin (3e)
IR (KBr) (cm21): 3018, 1731, 1657. 1H NMR (CDCl3): d 8.29–8.27 (m, 1H),
7.84–7.75 (m, 1H), 7.44–7.42 (m, 1H), 7.45 (d, J ¼ 7.8 Hz, 1H), 6.95 (s, 1H),
3.86 (s, 3H). 13C NMR (CDCl3): d 162.49, 161.09, 153.75, 137.92, 134.82,
129.65, 127.67, 126.84, 125.69, 124.57, 120.17, 114.25, 100.24, 55.42.
3-Butylisocoumarin (3f)
IR (KBr) (cm21): 2958, 1725, 1647. 1H NMR (CDCl3): d 8.27–8.25 (m, 1H),
7.68–7.65 (m, 1H), 7.44–7.42 (m, 1H), 7.35 (d, J ¼ 7.8 Hz, 1H), 6.15 (s, 1H),

3-Substituted Isochromen-1-ones
3655
2.53 (t, J ¼ 7.52 Hz, 2H), 1.74–1.66 (m, 2H), 1.46–1.36 (m, 2H), 0.95
(t, J ¼ 7.52 Hz, 3H). 13C NMR (CDCl3): d 158.3, 137.7, 135.9, 134.7,
130.1, 129.5, 127.5, 123.0, 102.9, 37.6, 28.9, 22.1, 13.7.
3-Cyclohexenylisocoumarin (3g)
IR (KBr) (cm21): 2978, 1695, 1657. 1H NMR (CDCl3): d 8.20–8.18 (m, 1H),
7.62–7.59 (m, 1H), 7.39–7.34 (m, 1H), 6.78 (d, J ¼ 7.8 Hz, 1H), 6.31 (s, 1H),
2.27–2.24 (m, 2H), 2.23–2.13 (m, 2H), 1.76–1.59 (m, 5H). 13C NMR
(CDCl3): d 163.5 137.76, 134.63, 129.45, 127.48, 125.23, 120.28, 100.88,
41.68, 30.58, 25.94, 25.88.
The spectral and C, H, N data of these compounds were reported pre-
viously,[12] and our results have been compared for authenticity.
ACKNOWLEDGMENT
The authors express their gratitude to the Indian Institute of Science, sophicas-
ticated analytical instruments facility (SAIF), Bangalore, and Spic Science
Foundation, Tuticorin, for NMR spectra.
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