New method for the synthesis of 3,4-dihydroisocoumarin

Full text of DOI:10.1007/s10593-007-0245-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 12, 2007
LETTERS TO THE EDITOR
NEW METHOD FOR THE SYNTHESIS
OF 3,4-DIHYDROISOCOUMARIN
V. S. Matiychuk, V. V. Turytsya, and N. D. Obushak
Keywords: isocoumarin, arylation, intramolecular cyclization, Meerwein reaction.
Derivatives of isocoumarin and 3,4-dihydroisocoumarin display a broad range of biological activity
[1, 2]. Many compounds containing the isocoumarin fragment are natural products [1, 3-7]. Most of the classical
methods for the synthesis of isocoumarin are based on the intramolecular cyclization of homophthalic acid
derivatives [2, 8, 9], which must also first be synthesized. Recently, variants have been developed for the
formation of the lactone ring in isocoumarins using reactions catalyzed by transition metals [2, 10-14], in
particular, alkyne annelation catalized by palladium. However, this reaction is not always regioselective in the
case of asymmetric disubstituted acetylenes [14].
We have developed a new method for the synthesis of 3-substituted 3,4-dihydroisocoumarins, not
requiring not readily available reagents or catalysts. Diazotization of methyl anthranilate 1 gives
o-methoxycarbonylbenzoyldiazonium chloride (2), which reacts with acrylates 3a,b under Meerwein reaction
conditions. Treatment of chloroacrylation products 4a,b with ethanolic KOH gives 3,4-dihydro-
isocoumarin-3-carboxylic acid (5), which is a convenient reagent for obtaining compounds with the
3,4-dihydroisocoumarin fragment.
OR
O
O
O
Me
Me
3a,b
NaNO2, HCl
0-5°C
O
O
_
+
Me2CO–H2O, CuCl2
O
NH2
N2 Cl
1
2
O
Me
O
KOH, EtOH
O
Cl
OH
OR
O
5
4a,b
O
a R = Me, b R = Et
__________________________________________________________________________________________
Ivan Franko Lviv National University, Lviv 79005, Ukraine; e-mail: obushak@in.lviv.ua. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1875-1876, December, 2007. Original article
submitted October 5, 2007.
0009-3122/07/4312-1589©2007 Springer Science+Business Media, Inc.
1589

The 1H NMR spectra were taken on a Bruker AC-300 spectrometer at 300 MHz with the residual signals
of the undeuterated solvent as the internal standard. The electron impact mass spectra were taken on a Shimadzu
QP 1000 mass spectrometer at 70 eV.
Methyl 2-(2-chloro-2-methoxycarbonylethyl)benzoate (4a). Methyl anthranilate 1 (30.2 g, 0.2 mol) was
dissolved in concentrated hydrochloric acid (40 ml) and water (40 ml). The mixture was cooled to from 0 to -10°C
and a solution of NaNO3 (14 g) in water (30 ml) was added dropwise with stirring, maintaining the temperature not
exceeding 5°C. The solution obtained of 2-methoxycarbonylbenzoyldiazonium chloride (2) was added dropwise
with stirring to a mixture of acetone (200 ml), methyl acrylate (3a) (18 ml, 0.2 mol), and CuCl2·2H2O (3.5 g). The
reaction was continued until no further nitrogen evolved. The organic layer was separated, dried, and distilled in
1
vacuum to give 23.1 g (45%) 4a, bp 195-200°C (2 mm Hg). H NMR spectrum in CDCl3, δ, ppm (J, Hz): 3.48
(1H, dd, 2J = 13.6, 3J = 7.8, CH2); 3.72 (1H, dd, 2J = 13.6, 3J = 6.6, CH2); 3.75 (3H, s, OCH3); 3.87 (3H, s, OCH3);
4.75 (1H, dd, 3J = 7.6, 3J = 6.6, CH); 7.28-7.34 (2H, m, Ar); 7.44 (1H, pseudo t, Ar); 7.95 (1H, d, J = 7.0, Ar). Found,
%: C 56.28; H, 5.16. C12H13ClO4. Calculated, %: C 56.15; H 5.10.
Methyl 2-(2-chloro-2-ethoxycarbonylethyl)benzoate (4b) was synthesized analogously in 42% yield
(22.7 g); bp 186-190°C (1 mm Hg). 1H NMR spectrum in CDCl3, δ, ppm (J, Hz): 1.19 (3H, t, J = 7.4, CH3); 3.44
2
3
2
3
(1H, dd, J = 13.2, J = 8.0, CH2); 3.69 (1H, dd, J = 13.2, J = 6.6, CH2); 3.88 (3H, s, OCH3); 4.15 (2H, q,
3
3
J = 7.4, OCH2); 4.65 (1H, dd, J = 8.0, J = 6.6, CH); 7.27-7.34 (2H, m, Ar); 7.43 (1H, pseudo t, Ar); 7.96 (1H,
d, J = 6.8, Ar). Found, %: C 57.84; H 5.63. C13H15ClO4. Calculated, %: C 57.68; H 5.59.
3,4-Dihydroisocoumarin-3-carboxylic acid (5). A solution of ester 4a or 4b (0.05 mol) in ethanol
(50 ml) was added to a solution of KOH (8.4 g) in water (25 ml) and heated at reflux for 3-3.5 h. The mixture
was cooled and acidified by adding hydrochloric acid. The precipitate of acid 5 was filtered off and
recrystallized from water to give 5 in 84-87% yield, mp 153-154°C (mp 152.5-153.5°C [15]). 1H NMR spectrum
in DMSO-d6, δ, ppm (J, Hz): 3.25 (1H, dd, 2J = 16.8, 3J = 4.8, CH2); 3.48 (1H, dd, 2J = 16.8, 3J = 5.4, CH2); 5.20
(1H, pseudo t, CH); 7.35 (1H, d, J = 8.1, Ar); 7.41 (1H, pseudo t, Ar); 7.58 (1H, pseudo t, Ar); 7.94 (1H, d,
J = 7.2, Ar). Mass spectrum, m/z (Irel, %): 192 [M]+ (8), 147 (100), 119 (80), 91 (84), 65 (15). Found, %:
C 62.38; H 4.16. C10H8O4. Calculated, %: C 62.50; H 4.20.
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