A new approach to the synthesis of 3,4-dihydroisocoumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.08.024

A new, simple, one-step synthesis of 3-substituted 3,4-dihydroisocoumarins is developed. The products are obtained by the reaction of o-methoxycarbonyl arenediazonium bromides with unsaturated compounds in the presence of CuBr as a catalyst.

Full text of DOI:10.1016/j.tetlet.2009.08.024

Tetrahedron Letters 50 (2009) 6112–6115
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A new approach to the synthesis of 3,4-dihydroisocoumarin derivatives
*
Mykola D. Obushak , Vasyl S. Matiychuk, Victor V. Turytsya
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2009
Revised 23 July 2009
Accepted 14 August 2009
Available online 20 August 2009
A new, simple, one-step synthesis of 3-substituted 3,4-dihydroisocoumarins is developed. The products
are obtained by the reaction of o-methoxycarbonyl arenediazonium bromides with unsaturated com-
pounds in the presence of CuBr as a catalyst.
Ó 2009 Elsevier Ltd. All rights reserved.
Isocoumarin and 3,4-dihydroisocoumarin derivatives are well-
known compounds isolated from a wide variety of natural sources,
and which exhibit a broad range of biological properties1,2 such as
antifungal,3 antiallergic, antimicrobial,4 immunomodulatory,5 anti-
tumour and/or cytotoxic,6 anti-inflammatory,7 plant growth inhi-
bition8 and enzyme inhibitory9 activity. Isocoumarin derivatives
are important precursors in the synthesis of many naturally occur-
ring isoquinoline alkaloids and their analogues.10
A number of methods have been described for the synthesis of
isocoumarins. The most common synthetic approach involves
cyclization of homophthalic or 2-methylbenzoic acid derivatives.11
While these transformations are widely used, they suffer from sev-
eral notable disadvantages such as (i) the starting materials are of-
ten commercially unavailable, (ii) the reaction conditions are
difficult to control and (iii) all the reagents must be of a high purity
grade.
A two-step synthesis of 3-substituted 3,4-dihydroisocoumarins
based on the Meerwein arylation reaction was reported earlier.16,17
3-Cyano-3,4-dihydroisocoumarin was synthesized by the reaction
of sodium with 2-(2-chloro-2-cyanoethyl)benzoic acid, which
was obtained by the CuCl2-mediated Meerwein arylation of acrylo-
nitrile with 2-carboxybenzenediazonium chloride.16
Herein, we report a one-pot synthesis of 3,4-dihydroisocoum-
arin derivatives 3a–h via the CuBr-catalyzed reaction of o-
methoxycarbonyl benzenediazonium bromides 1a–d with
unsaturated compounds 2a–d (Table 1). The key step involves
intramolecular cyclization to give compounds 3a–h. The reac-
tions occurred under mild conditions in water–polar organic
solvent medium [water–acetone (1:2) was found to be the best].
o-Ethoxycarbonyl benzenediazonium bromides were also con-
verted into 3,4-dihydroisocoumarins 3a–h in a similar manner
to 1a–d.18
Another important method for the construction of the isocoum-
arin ring involves Sonogashira coupling followed by cyclization of
alkynes containing a carboxylate or other substituent in proximity
to the triple bond (Scheme 1).12
A number of isocoumarins have been prepared in good yields
via Pd-catalyzed annulation of internal alkynes.13 However, this
method is somewhat limited in synthetic scope since it is highly
selective for symmetrical disubstituted acetylenes. Furthermore,
2-iodobenzoic acid reacts with allene derivatives under palladium
catalysis to afford the corresponding isocoumarins.14
The purpose of our work was to study the syntheses of 3,4-
dihydroisocoumarins via the Meerwein arylation reaction. Various
approaches to the synthesis of benzoheterocycles from diazonium
salts have been investigated. Intramolecular cyclization occurred
in the reaction of unsaturated compounds with arenediazonium
salts, which contained a suitable substituent ortho- to the diazo-
nium group.15
In order to investigate the scope of this reaction, o-methoxy-
carbonyl benzenediazonium chloride 4 was reacted with methyl
acrylate, ethyl acrylate and acrylonitrile. In this case, the usual
Meerwein arylation products 5a–c were obtained (Scheme 2
and Table 2, entries 1–3), and no cyclic products were isolated.
19
Moreover, CuCl and FeCl2 were also used as catalysts in this
reaction which proceeded in a similar manner to give com-
pounds 5a–c.20
o-Carboxybenzenediazonium bromide 6 was examined in the
reactions with methyl and ethyl acrylates 2a,e, however, no cycli-
zation reaction was observed. Acids 7a,b were obtained using CuBr
as catalyst (Scheme 3 and Table 2, entries 4 and 5).21
R
Hal
Pd-cat
O
R
+
X
O
X = COOH, COOR1, CN
* Corresponding author. Tel.: +380 322600396.
E-mail address: obushak@in.lviv.ua (M.D. Obushak).
Scheme 1. Construction of the isocoumarin ring.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.024

M. D. Obushak et al. / Tetrahedron Letters 50 (2009) 6112–6115
6113
Table 1
Formation of 3,4-dihydroisocoumarins
O
O
R2
OMe
O
CuBr
R1
R1
+
R2
R3
R3
_
Me2CO-H2O, r.t.
N2+Br
2a-d
1a-d
3a-h
Entry
1
Diazonium salt
Olefin
Product
Yielda (%)
COOMe
O
COOMe
2a
47
O
+
-
3a
COOMe
Br
1aN
2
COOMe
Me
O
2
36
O
O 2b
+
3b
-
Br
1aN
2
Me
O
COOMe
O
O
3
4
39
56
2c
O
O
+
-
3c
Br
1aN
2
Ph
COOMe
Me
COOMe
2d
+
-
3d
Br
1aN
2
COOMe
Me
COOMe
O
COOMe
5
31
40
2a
+
O
-
3e
N2 Br
1b
Me
COOMe
Me
Me
Me
COOMe
O
O
COOMe
2a
6
7
Me
O
+
-
3f
COOMe
N2 Br
1c
1c
COOMe
Me
COOMe
2d
Me
Br
41
32
O
+
-
3g
COOMe
N2 Br
Me
Br
COOMe
O
COOMe
2a
8
O
+
-
3h
COOMe
N2 Br
1d
a
Yield after purification.
COOMe
COOMe
Cl
CuCl2
Me2CO-H2O, r.t.
R2
+
N2+Cl_
4
In summary, we have described a simple and efficient method
for the preparation of 3,4-dihydroisocoumarin derivatives. Cycliza-
tion occurred to yield 3,4-dihydroisocoumarins 3, when o-alkoxy-
carbonyl benzenediazonium bromides were used. In the case of o-
carboxybenzenediazonium bromides and o-alkoxycarbonyl benze-
nediazonium chlorides, acyclic products were obtained. Further
investigations on the scope and limitations of the reported method
are in progress.
R2
2a,e,f
5a-c
R2 = COOMe (a); COOEt (b), CN (c)
Scheme 2. Formation of the chloroarylation products. The reaction was carried out
with 4 (obtained from 0.1 equiv of methyl anthranilate, HCl (40 mL) and 0.12 equiv of
NaNO2), 0.1 equiv of the corresponding olefin, acetone (100 mL), CuCl2 (3.5 g), 0.5–1 h.

6114
M. D. Obushak et al. / Tetrahedron Letters 50 (2009) 6112–6115
Table 2
Synthesis of arylation products 5a–c and 7a,b
Entry
1
Diazonium salt
Olefin
Catalyst
CuCl2
Product
Yielda (%)
45
COOMe
COOMe
COOMe
2a
Cl
5a
COOMe
-
N2+Cl
4
4
4
CuCl2
CuCl2
CuBr
CuBr
COOMe
COOMe
Cl
COOEt
2e
2
3
4
5
35
40
36
30
5b
-
N2+Cl
COOEt
COOMe
COOMe
CN
2f
Cl
5c
CN
-
N2+Cl
COOH
COOH
Br
COOMe
2a
7a
-
N2+Br
COOMe
6
COOH
COOH
Br
COOEt
2e
7b
-
N2+Br
COOEt
6
a
Yield after purification.
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2a,e
+
_
N2+Br
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6
7a,b
R2 = COOMe (a); COOEt (b)
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Scheme 3. Formation of the bromoarylation products. The reaction was carried out
with 6 (obtained from 0.1 equiv of anthranilic acid, HBr (40 mL, 48%) and 0.12 equiv of
NaNO2), 0.1 equiv of the corresponding olefin, acetone (100 mL), CuBr (3.5 g), 0.5–1 h.
Acknowledgement
The authors are grateful to the Ministry of Education and Sci-
ence of Ukraine for financial support of this project
(0109U002073).
References and notes
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18. Typical procedure for the arylation reaction: A solution of sodium nitrite (8 g,
0.12 mol) in H2O (15 mL) was added dropwise to a stirred and ice-cold mixture
of methyl anthranilate (15.1 g, 0.1 mol, 12.9 mL), aqueous HBr (48%, 40 mL)
and H2O (40 mL) below 0–5 °C. The cold diazonium salt solution was slowly
added to a vigorously stirred solution of CuBr (3.5 g) and olefin 2a–d (0.1 mol)

M. D. Obushak et al. / Tetrahedron Letters 50 (2009) 6112–6115
6115
in acetone (100 mL) at room temperature. The reaction was exothermic and
the rate of addition was adjusted such that nitrogen gas was evolved at a rate
of 2–3 bubbles/s (0.5–1 h). The resultant homogeneous solution was stirred
for 30 min at 40 °C and then diluted with H2O (150 mL). The organic phase
was dried over Na2SO4 and concentrated. The residue was purified by
distillation under reduced pressure to give isocoumarins 3a–h as pale-yellow
solids.
Methyl 1-oxo-3,4-dihydro-1H-isochromene-3-carboxylate 3a: Yield 47%, bp
176–180 °C (1 mmHg), mp 83–84 °C (EtOH); 1H NMR: (300 MHz, DMSO-
d6 + CCl4): d = 3.25 (dd, 2J = 16.9 Hz, 3J = 5.4 Hz, 1H), 3.49 (dd, 2J = 16.9 Hz,
3J = 5.7 Hz, 1H), 3.69 (s, 3H), 5.34 (t, J = 5.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H),
7.43 (t, J = 7.5 Hz, 1H) 7.57–7.62 (m, 1H), 7.95 (d, J = 7.5 Hz 1H); 13C NMR:
(50 MHz, CDCl3): d = 27.50, 53.34, 74.66, 125.12, 127.67, 127.98, 135.96,
136.38, 136.45, 164.10, 170.45; MS, m/z = 207 (M++1); Anal. Calcd for
C11H10O4: C, 64.08; H, 4.89. Found: C, 63.83; H, 4.72.
J = 7.6 Hz, 1H), 7.48–7.51 (m, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.96 (d, J = 7.6 Hz,
1H); 13C NMR: (100 MHz, CDCl3): d = 40.06, 43.89, 52.98, 118.30, 129.08,
130.09, 131.50, 133.33, 133.52, 136.30, 167.39; MS m/z = 224 (M++1); Anal.
Calcd for C11H10ClNO2: C, 59.07; H, 4.51; N, 6.26. Found: C, 58.95; H, 4.60; N,
6.13.
21. 2-(2-Bromo-2-methoxycarbonylethyl)benzoic acid 7a: Yield 36%, mp 90–91 °C
(EtOH); 1H NMR: (300 MHz, DMSO-d6): d = 3.55 (dd, 2J = 13.2 Hz 3J = 7.2 Hz
1H), 3.65–3.75 (m, 4H), 4.63 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.34 (t,
J = 7.2 Hz, 1H), 7.41–7.47 (m, 1H), 7.96 (d, J = 7.5 Hz, 1H). 13C NMR: (100 MHz,
CDCl3): d = 30.14, 46.51, 53.51, 128.26, 128.49, 128.65, 129.75, 134.66, 138.32,
164.12, 168.99; MS m/z = 287 (M++1, 79Br), 289 (M++1, 81Br); Anal. Calcd for
C11H11BrO4: C, 46.02; H, 3.86; Br, 27.83. Found: C, 45.89; H, 3.69; Br, 27.60.
2-(2-Bromo-2-ethoxycarbonylethyl)benzoic acid 7b: Yield 30%, mp 124–125 °C
(EtOH); 1H NMR: (400 MHz, DMSO-d6 + CCl4): d = 1.17 (t, J = 7.6 Hz, 3H), 3.56
(dd, 2J = 13.2 Hz, 3J = 7.4 Hz, 1H), 3.67 (dd, 2J = 13.2 Hz, 3J = 7.8 Hz, 1H), 4.07–
4.15 (m, 2H), 4.62 (t, J = 7.6 Hz, 1H), 7.28–7.50 (m, 3H), 7.94 (d, J = 7.8 Hz, 1H).
13C NMR: (100 MHz, CDCl3): d = 14.44, 30.14, 47.44, 61.87, 126.20, 127.35,
129.51, 132.25, 132.50, 136.30, 164.11, 168.07; MS m/z = 301 (M++1, 79Br), 303
(M++1, 81Br); Anal. Calcd for C12H13BrO4: C, 47.86; H, 4.35. Found: C, 47.80; H,
4.60.
19. (a) Obushak, N. D. Russ. J. Org. Chem. 1999, 35, 309–310; (b) Obushak, N. D. Russ.
J. Gen. Chem. 1998, 68, 443–445; (c) Ganushchak, N. I.; Obushak, N. D.;
Polishchuk, O. P. J. Org. Chem. USSR 1982, 18, 633–639.
20. Methyl 2-(2-chloro-2-cyanoethyl)benzoate 5c: Yield 40%, mp 61–62 °C (EtOH);
1H NMR: (400 MHz, DMSO-d6): d = 3.73 (d, J = 7.6 Hz, 2H), 3.84 (s, 3H), 5.44 (t,