Reduction of 3-(carboxyaryl)isocoumarins with sodium borohydride

Article abstract of DOI:10.1007/s10593-012-0896-3

Reduction of 3-(carboxyaryl)isocoumarins with sodium borohydride proceeds with formation of corresponding 3-carboxyaryl-3,4-dihydroisocoumarins or isomeric dihydrophthalides, 3-(2-carboxybenzyl)-2-benzofuran-1(3H)-ones. Derivatives at the carboxyl group of 3-carboxyaryl-3,4-dihydroisocoumarins and 3-(2-carboxybenzyl)-2-benzofuran-1(3H)-ones have been obtained. 0009-3122/12/4710-12122012 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-012-0896-3

Chemistry of Heterocyclic Compounds, Vol. 47, No. 10, January, 2012 (Russian Original Vol. 47, No. 10, October, 2011)
REDUCTION OF 3-(CARBOXYARYL)ISOCOUMARINS
WITH SODIUM BOROHYDRIDE
V. V. Ishchenko1, N. M. Voevoda1, O. V. Shablykina1*,
A. V. Turov1, and V. P. Khilya1
Reduction of 3-(carboxyaryl)isocoumarins with sodium borohydride proceeds with formation of
corresponding 3-carboxyaryl-3,4-dihydroisocoumarins or isomeric dihydrophthalides, 3-(2-carb-
oxybenzyl)-2-benzofuran-1(3H)-ones. Derivatives at the carboxyl group of 3-carboxyaryl-3,4-dihydro-
isocoumarins and 3-(2-carboxybenzyl)-2-benzofuran-1(3H)-ones have been obtained.
Keywords: amides, 3-aryl-3,4-dihydroisocoumarins, 3-arylisocoumarins, 3-(2-carboxybenzyl)-2-benzo-
furan-1(3H)-ones, carboxyl group, esters.
Compounds with a benzopyrone ring attract attention not only due to their biological activity [1, 2], but
also due to special features of their spectral-luminescent properties as a result of which they are promising for
use in quantum electronics and helioenergetics [3, 4]. In particular, there is interest in the reduced forms of
isocoumarins, the 3,4-dihydroisocoumarins with different substituents [5-9], particularly with functional groups
such as carboxyl group, enabling further modification [10, 11]. The effect of carboxyl group on the process of
isocoumarins reduction and on the structure of reaction products has not been practically studied.
O
O
O
O2N
O
O
COOH
O
COOH
2
COOH
3
1
O
O
COOH
O
O
O
4
O
COOH
5
CH3
_______
*To whom correspondence should be addressed, e-mail: shablykina@ukr.net.
1Kyiv Taras Shevchenko National University, 64 Volodymyrska St., Kyiv 01601, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1471-1484, October, 2011.
Original article submitted March 28, 2011.
1212
0009-3122/12/4710-1212©2012 Springer Science+Business Media, Inc.

Isocoumarins 1-5 were chosen for investigation of 3-(carboxyaryl)isocoumarins conversions under
treatment with sodium borohydride, and also with the aim to develop convenient preparative methods of
synthesis of 3-arylisocoumarins dihydro derivatives with carboxyl, ester or amide groups.
In this paper substances are studied which contain aromatic carboxyl group (acids 1 [12], 2, and 3 [11])
and aliphatic (compound 4) carboxyl group close to the reaction center, and aliphatic carboxyl group distant
from the reaction center (acid 5).
The choice of sodium borohydride as reducing agent [5-9] was caused by its ability to reduce an
isocoumarin to 3,4-dihydroisocoumarin without affecting other groups (COOH, NO2) [10, 13]. An alkaline
medium was necessary to carry out the reaction [5-8]. The isocoumarin ring was opened at the first stage, after
which ketone II was reduced by sodium borohydride to the corresponding alcohol III. Subsequently, in the
presence of acidic agents (sulfuric acid solution, acetic anhydride, thionyl chloride), cyclization occured, leading
to formation of 3,4-dihydroisocoumarin IV [5-8].
O
O
COOH
OH
COOH
O
OH–
H+
NaBH4
O
O
R
R
R
R
I
II
III
IV
Reduction of isocoumarins 1-3 was carried out in aqueous-alcoholic solution. When reducing
isocoumarins 1 and 3 a larger quantity of alkali was necessary (2 equiv. NaOH) to open the heterocycle.
Addition of alkali to isocoumarin 2 led to its destruction. However, due to electron-withdrawing influence of the
nitro group, opening of the ring occurred also in weakly alkaline medium produced by sodium borohydride.
Products 6a, 8a, and 10a were isolated from solution by acidification with diluted hydrochloric acid.
OH COO –
NaOH,
NaBH4
Na+
1
COO–Na+
H+
O
O
O
COOH
O
6a
7a
COOH
It should be specified that compounds of the type III, which were obtained by reduction of 3-substituted
isocoumarins, containing no functional groups free to dissociate, are unstable in the presence of additional
carboxyl group in the molecule. It was not possible to isolate the open form of isocoumarins 1-5 dihydro
derivatives. Formation of cyclic compounds 6a, 8a, and 10a was confirmed by lack of signals for a hydroxyl and
a second carboxyl group in 1H NMR spectra and by mass spectroscopy data, and also by a chemical behavior of
these substances; they were unchanged on treatment with various cyclizing agents (H2SO4, thionyl chloride).
The structure of compound 10a, in view of the symmetry of its open form, was determined
unequivocally. If open form of the dihydro derivative is unsymmetric (reduction of substrates 1, 2), then two
practically equiprobable routes of cyclization were possible with formation of a five- (compounds 6a, 8a) or six-
1213

membered (compounds 7a, 9a) heterocycle. It was considered previously that reduction of isocoumarin 1 leads
to dihydroisocoumarin 7a, but possibility of forming the five-membered ring 6a was generally not considered
1
[10]. From H and 13C NMR spectroscopy data, it was not possible to make a conclusion in favor of this or
another structure. Mass spectra and chemical behavior of the substance 6a also did not allow to determine,
which of the carboxyl groups was involved in formation of the heterocycle.
OH COO–
O2N
NaBH4
Na+
2
COO–
H+
Na+
O
O
NO2
O2N
O
COOH
O
9a
COOH
8a
O
O
H+
OH
NaOH,
NaBH4
3
COO –
COO –
COOH
Na+
10a
Na+
To solve this problem and to determine the structure of the obtained compound we used heteronuclear
1H–13C correlations of the specially synthesized methyl ester 6b of acid 6a.
O
O
O
COOMe
O
Me2SO4
K2CO3
Me2CO
7a
6a
1
7b
COOMe
6b
Assignment of the aromatic protons signals was made using two-dimensional COSY spectra for
compound assumed to have the structure 6b (Fig. 1).
1214

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
S
2
C16H9NO6
61.98
61.74
69.90
69.67
68.75
68.92
71.39
71.64
72.05
72.33
72.03
71.81
74.58
73.98
65.41
65.13
61.54
61.35
62.21
62.39
65.87
66.03
73.02
72.33
73.01
72.96
72.47
72.28
69.50
69.22
2.91
3.16
4.83
4.55
4.05
4.08
4.47
4.51
4.86
5.00
4.95
4.77
5.36
5.13
4.34
4.03
3.72
3.54
3.87
4.00
4.45
4.34
4.96
5.00
5.24
5.44
5.34
5.10
5.18
5.16
4.50
4.72
—
—
—
—
—
—
106-108
274-275
228-229
204-205
111-112
180-181
176-178
138-139
192-193
116-117
228-229
185-186
127-128
112-113
255-256
63
89
92
78
96
88
86
90
82
78
81
74
96
64
4
C18H14O5
—
—
—
—
5
C17H12O5
6a
6b
6c
6d
6е
C16H12O4
C17H14O4
C24H19NO5
С23H19NO4
C19H14N2O3S
C16H11NO6
C17H13NO6
C23H18N2O6
C17H14O4
3.49
3.94
3.75
8.16
7.99
4.63
4.47
4.46
4.28
6.80
6.70
8.97
9.15
8а
8b
8d
10а
10b
10c
17a
—
—
—
—
—
—
—
—
C18H16O4
—
C25H21NO5
С18Н16О5
3.56
3.37
—
87 (1),
90 (2),
85 (3),
94 (4)
17b
17d
17e
18a
C19H18O5
69.58
69.93
71.67
71.93
63.80
63.95
68.73
68.45
5.37
5.56
5.74
5.55
4.90
4.60
4.74
4.73
—
—
—
107-108
117-119
184-185
176-177
83
90
87
C25H23NO5
C21H18N2O4S
С17Н14О5
3.48
3.36
7.32
7.10
8.31
8.13
—
—
86 (1),
88 (2),
77 (3),
83 (4)
18b
18d
18e
13
C18H16O5
C24H21NO5
C20H16N2O4S
C19H16O5
C18H14O5
C18H16O6
С17Н14О6
C16H14O3
69.28
69.22
71.66
71.45
63.52
63.15
70.43
70.36
69.90
69.67
66.11
65.85
65.14
64.97
75.76
75.58
5.16
5.16
5.38
5.25
4.55
4.24
4.94
4.97
4.56
4.55
5.16
4.91
4.76
4.49
5.69
5.55
—
—
—
148-149
206-207
187-188
152-153
147-148
272-273
236-237
213-214
79
86
93
84
78
85
90
75
3.35
3.47
7.52
7.36
—
—
—
—
—
8.42
8.43
—
—
—
—
—
14
15
16
19
Further refinement of assignments was made on the basis of data obtained as a result of heteronuclear
1H-13C HMQC and HMBC correlations given in Table 2.
1215

7.98
H
O
7.56
H
H
7.55
H
7.46
H
O
133.2
130.3
7.71
7.42
5.86
H
H
H
H
3.95
7.60
H
3.31
CH OOC
H
3.913
8.07
Fig. 1. Correlations of proton signals in COSY spectra (
heteronuclear 1H and 13C correlations (
) for compound 6b.
) and some
Signals of carbon atoms of the phenyl group linked with the methoxycarbonyl substituent have
numerous correlations with signals of methylene protons, but not with the signal of methine group proton, what
makes possible to choose between the structures 7b and 6b in favor of the latter, containing the furan fragment
(Fig. 1).
The following derivatives were synthesized in order to confirm the structure of phthalides 6a, 8a and
isocoumarin 10a: methyl esters 6b, 8b, 10b and amides 6c-e, 8d, 10c. Compound 6b mentioned above and also
esters 8b and 10b were obtained using dimethyl sulfate in the presence of potassium carbonate (see
EXPERIMENTAL).
When attempting to obtain the acid chlorides of acids 6a, 8a, and 10a using SOCl2 even under mild
conditions a mixture of products difficult to identify was obtained. Consequently carbonyldiimidazole (CDI)
was used for synthesis of amides 6c-e, 8d, and 10c.
1H NMR spectra of amide 8d were informative enough for confirming its structure. The greatest shift in
the spectra of amide 8d, in comparison with the spectrum of the starting substrance 8a, was undergone by the
protons of the methylene group and the aromatic ring linked with the nitro group (Table 4), which is possible only
on formation of the five-membered ring.
TABLE 2. Heteronuclear 1H-13C Correlations in Compound 6b
1Н, δ, ppm
HMQC 13С, δ, ppm
HMBC 13С, δ, ppm
8.07
7.98
7.71
7.60
7.56
7.55
7.46
7.42
5.86
3.95
3.91
3.31
131.3
125.7
134.6
123.3
129.9
132.8
133.2
127.8
82.0
168.0; 138.8; 132.8
170.2; 134.6; 150.3
150.3; 125.7; 82.0 (w)
129.9; 126.5; 82.0
126.5; 123.3; 150.3; 170.2 (w)
138.9; 131.3
130.3; 127.8; 168.0; 39.9
133.2; 130.3
170.2; 150.3; 138.8; 134.6; 126.5; 123.3; 39.9
150.3; 138.8; 133.2; 130.3; 82.0
168.0
39.9
52.5
39.9
150.3; 138.2; 133.2; 130.3; 82.0
1216

O
O
O
O
1. CDI
2. R1NH2
1. CDI
2. R1NH2
6a, 8a
10a
CONHR1
R1HNOC
R
6c-e, 8d
10c
6c–e R = H; 6, 10 c R1 = 2,3-dihydro-1,4-benzodioxin-6-yl, 6d R1 = 4-MeOC6H4,
6e R1 = thiazol-2-yl;
8d R = NO2, R1 = 4-MeOC6H4
O
O
O
O
Me
HO
11
OH
12
BrCH2CO2Me,
K2CO3, Me2CO
BrCH2CO2Me,
K2CO3, Me2CO
O
O
1) OH– ;
1) OH– ;
2) NaBH4;
2) NaBH4;
O
O
Me
3) H+
3) H+
OCH2CO2Me
MeO2CCH2O
14
1) OH– ;
2) H+
13
1) OH– ;
2) H+
1) NaBH4;
2) H+
CO2H
CO2H
1) NaBH4;
2) H+
O
O
Me
HO2CCH2O
OCH2CO2H
16
H +
15
H +
5
4
1) OH– ;
+
2) NaBH ;
3) H
1) OH– ;
3) H+
4
2) NaBH4;
O
O
O
O
Me
OCH2CO2H
HO2CCH2O
18a
17a
1217

1
In the H NMR spectra of 3,4-dihydroisocoumarin 10a and its derivatives 10b and 10c (Table 4)
chemical shifts of the proton signals of the heterocycle methylene group and of the methylene group of the
benzyl substituent, although not identical, were all very close. This fact further confirms that on the basis of
1
methylene group signals position in the H NMR spectrum of compound 6a it is impossible to verify if this
group is included in the cyclic system (compound 7a) or not (compound 6a).
Acids 4 and 5 were synthesized starting from hydroxyphenylisocoumarins 11 [14] and 12 [15]. Further
treatment of the obtained esters 13 and 14 with alkali resulted in formation of the open forms of isocoumarins 15
and 16. Treatment of the latter with acid led to the formation of acids 4 and 5.
Substituted 3,4-dihydroisocoumarins 17a and 18a were obtained as a result of isocoumarins 4 and 5
reduction. As in the case of 3,4-dihydroisocoumarins 6a, 8a, and 10a, isolation of the open form (alcohols of
type III) of substances 17a and 18a was unsuccessful.
Compounds 17a and 18a could also be obtained from 2-[(2-carboxyphenyl)acetyl]phenoxyacetic acids
15 and 16. This is an additional confirmation of the fact that reduction of isocoumarins with sodium borohydride
proceeds through the heterocycle opening stage.
Dihydroisocoumarins 17a and 18a may be obtained by sequential treatment of esters 13, 14 with alkali
and sodium borohydride, by-passing stages of products 15, 16 and 4, 5 isolation, what increases the yield of the
desired compounds and simplifies the synthetic scheme. Such one-pot way of synthesis therefore has an
advantage also over alternative reactions sequence: reduction of hydroxyisocoumarins 11 and 12 to the
corresponding dihydroisocoumarins 19, 20 [16], alkylation with bromoacetic acid ester, alkaline hydrolysis
(acidic proceeds in a heterogeneous system) of esters 17b and 18b with subsequent acidification of the obtained
solution leading to isolation of acids 17a, 18a.
11
12
+
–
3) H+
1) OH– ;
2) NaBH ;
3) H
1) OH ;
2) NaBH4;
4
O
O
O
O
Me
HO
19
OH
20
BrCH2CO2Me
K2CO3, Me2CO
BrCH2CO2Me
K2CO3, Me2CO
O
O
O
O
Me
MeO2CCH2O
OCH2CO2Me
17b
18b
18a
1) OH– ;
+
2) H
2) H+
–
1) OH ;
17a
1218

1219

TABLE 4. 1H NMR Spectra of Compounds 6, 8, 10, 15-20
Com-
Chemical shifts, , ppm (J, Hz)
pound
1
2
6a
3.16 (1H, dd, J = 13.6, J = 8.4) and 3.90 (1H, dd, J = 13.6, J = 3.6, СН2);
5.78 (1Н, dd, J = 8.4, J = 3.6, H-3); 7.35 (1Н, d, J = 7.6, Н-6'); 7.39 (1Н, t, J = 7.6, Н-4');
7.48-7.52 (2Н, m, Н-4,6); 7.57 (1Н, t, J = 7.6, H-5); 7.73 (1Н, t, J = 7.6, Н-5');
7.81 (1Н, d, J = 7.6, H-7); 7.98 (1Н, d, J = 7.6, Н-3'); 12.8 (1Н, br. s, СО2Н)
6c
3.30 (1H, dd, J = 14.0, J = 8.8) and 3.65 (1H, dd, J = 14.0, J = 3.6, СН2);
4.37 (4Н, m, 2СН2); 5.85 (1H, dd, J = 8.8, J = 3.6, H-3); 6.73 (1Н, d, J = 8.4, Н-5'');
7.13 (1H, dd, J = 8.4, J = 2.4, Н-6''); 7.35-7.41 (3Н, m, H-6,6',2'');
7.43 (1Н, t, J = 7.6, H-4'); 7.47 (1Н, d, J = 7.6, H-4); 7.55 (2Н, m, H-5,3');
7.68 (1Н, t, J = 7.6, H-5'); 7.78 (1Н, d, J = 7.6, H-7); 10.10 (1Н, s, NH)
6d
6е
8a
8b
8d
3.15 (1H, dd, J = 14.0, J = 6.0) and 3.67 (1H, dd, J = 14.0, J = 2.0, СН2);
3.77 (3Н, s, 4''-ОСН3); 5.87 (1Н, dd, J = 6.0, J = 2.0, Н-3); 6.85 (2Н, d, J= 8.4, Н-3'',5'');
7.41-7.49 (4Н, m, Н-4,6,4',6'); 7.55 (1Н, t, J = 7.6, Н-5); 7.59 (1Н, d, J = 6.8, Н-3');
7.64-7.70 (3Н, m, Н-5',2'',6''); 7.79 (1Н, d, J = 7.2, Н-7); 10.16 (1Н, s, NH)
3.16 (1H, dd, J = 14.0, J = 8.8) and 3.90 (1H, dd, J = 14.0, J = 2.8, СН2);
5.84 (1Н, dd, J = 8.8, J = 2.8); 7.15 (1Н, d, J = 2.8, Н-4''); 7.39-7.45 (2Н, m, H-6,4');
7.51-7.54 (3Н, m, H-4,6',5''); 7.55 (1Н, t, J = 7.6, H-5); 7.67 (1Н, t, J = 7.6, H-5');
7.72 (1Н, d, J = 7.6, H-3'); 7.79 (1Н, d, J = 7.6, H-7); 12.57 (1Н, s, NH);
3.32 (1H, dd, J = 13.6, J = 9.2) and 4.07 (1H, dd, J = 13.6, J = 2.8, СН2);
5.81 (1Н, dd, J = 9.2, J = 2.8, H-3); 7.58-7.62 (2Н, m, H-4,6); 7.71 (1Н, d, J = 8.4, H-6');
7.77 (1Н, t, J = 7.6, H-5); 7.81 (1Н, d, J = 7.6, H-7); 8.35 (1Н, dd, J = 8.4, J = 2.4, H-5');
8.73 (1Н, d, J = 2.4, H-3'); 13.67 (1Н, br. s, СООН)
3.36 (1H, dd, J = 13.6, J = 9.2) and 4.01 (1H, dd, J = 13.6, J = 2.4, СН2);
3.96 (3Н, s, СО2СН3); 5.77 (1Н, dd, J = 9.2, J = 2.4, Н-3); 7.60 (1Н, t, J = 7.6, Н-6);
7.68 (1Н, d, J = 7.6, Н-4); 7.82-7.75 (3Н, m, Н-5,7,6'); 8.37 (1Н, br. d, J = 8.0, Н-5');
8.67 (1Н, br. s, Н-3')
3.23 (1H, m) and 3.77-3.82 (4Н, m, СН2, 4''-ОСН3); 5.90 (1Н, m, Н-3);
6.88 (2Н, d, J = 8.8, Н-3'',5''); 7.58-7.56 (2Н, m, H-4,6); 7.64 (2Н, d, J = 8.8, Н-2'',6'');
7.68-7.74 (2Н, m, H-5,6'); 7.79 (1Н, d, J = 7.6, H-7); 8.30 (1Н, br. d, J = 7.6, H-5');
8.41 (1Н, br. s, H-3'); 10.45 (1Н, s, NH)
10a
10b
10c
2.93-3.13 (2Н, m) and 3.93-3.51 (2Н, m, 2СН2); 4.76-4.80 (1Н, m, H-3);
7.29-7.40 (4Н, m, H-5,7,4',5'); 7.48-7.57 (2Н, m, Н-6,6'); 7.88-7.94 (2Н, m, Н-8,3');
12.74 (1Н, br. s, СО2Н)
2.90-3.03 (2Н, m) and 3.38-3.49 (2Н, m, 2СН2); 3.84 (3H, s, 2'-СО2СН3);
4.76-4.80 (1Н, m, H-3); 7.29-7.44 (4Н, m, H-5,7,4',6'); 7.54 (2Н, m, Н-6,5');
7.90 (2Н, m, Н-8,3')
2.99 (2Н, m, СН2); 3.24 (2Н, m, СН2); 4.37 (4Н, m, 2СН2); 4.82-4.86 (1Н, m, H-3);
6.71 (1Н, d, J = 8.4, Н-5''); 7.09 (1H, dd, J = 8.4, J = 1.6, Н-6'');
7.29-7.45 (6Н, m, H-5,7,3',4',5',2''); 7.51 (1H, d, J = 8.0, H-6'); 7.56 (1Н, t, J = 7.6, H-6);
7.88 (1Н, d, J = 7.6, H-8); 10.08 (1Н, s, CONH)
15
2.31 (3Н, s, 5'-СН3); 4.73 (2Н, s, 4-СН2); 4.75 (2Н, s, 2'-ОСН2);
6.93 (1H, d, J = 8.4, H-3'); 7.25-7.30 (2H, m, H-3,4'); 7.32-7.37 (2H, m, H-5,6');
7.49 (1H, t, J = 7.6, H-4); 7.95 (1H, d, J = 7.6, H-6); 12.70 (2H, br. s, СО2Н)
16
4.67 (2Н, s, СН2); 4.72 (2Н, s, 4'-ОСН2); 7.00 (2H, d, J = 8.8, H-3',5');
7.26 (1H, d, J = 7.6, H-3); 7.36 (1H, t, J = 7.6, H-5); 7.48 (1H, t, J = 7.6, H-4);
7.95 (1H, d, J = 7.6, H-6); 7.98 (2H, d, J = 8.8, H-2',6'), 12.8 (2H, br. s, СО2Н).
17a
2.33 (3Н, s, 5'-СН3); 3.19 (1Н, dd, J = 16.4, J = 12.0) and
3.30 (1Н, dd, J = 16.4, J = 3.2, 4-СН2); 4.63 (2Н, s, 2'-ОСН2);
5.91 (1Н, dd, J = 12.0, J= 3.2, H-3); 6.84 (1H, d, J = 8.4, H-3'); 7.08 (1H, d, J = 8.4, H-4');
7.33 (1H, br. s, H-6'); 7.41 (1Н, d, J = 7.6, H-5); 7.44 (1Н, t, J = 7.6, H-7);
7.60 (1Н, t, J = 7.6, H-6); 7.99 (1Н, d, J = 7.6, H-8)
17b
2.33 (3Н, s, 5'-СН3); 3.17 (1Н, dd, J = 16.0, J = 11.2) and
3.28 (1Н, dd, J = 16.0, J = 2.8, 4-СН2); 3.71 (3Н, s, СООСН3); 4.77 (2Н, br. s, 2'-ОСН2);
5.89 (1Н, dd, J = 11.2, J = 2.8, H-3); 6.84 (1H, d, J = 8.8, H-3');
7.09 (1H, d, J = 8.8, H-4'); 7.34-7.39 (2H, m, H-5,6'); 7.44 (1Н, t, J = 7.6, H-7);
7.61 (1Н, t, J = 7.2, H-6); 8.00 (1Н, d, J = 7.2, H-8)
1220

TABLE 4 (continued)
1
2
17d
2.37 (3Н, s, 5'-СН3); 3.15 (1Н, dd, J = 16.4, J = 12.0) and
3.38 (1Н, dd, J = 16.4, J = 1.8, 4-СН2); 3.77 (3Н, s, 4''-ОСН3); 4.70 (2Н, s, 2'-ОСН2);
6.08 (1Н, dd, J3,4α = 12.0, J3,4β = 1.8, H-3); 6.82 (2Н, d, J = 8.8, H-3'',5'');
6.93 (1Н, d, J = 8.4, Н-3'); 7.14 (1Н, d, J = 8.4, Н-4'); 7.38 (1Н, br. s, Н-6');
7.42 (1Н, d, J = 7.2, Н-5); 7.46-7.50 (3Н, m, Н-7,2'',6''); 7.64 (1Н, t, J = 7.2, Н-6);
8.04 (1Н, d, J = 7.6, H-8);
17e
2.33 (3Н, s, 5'-СН3); 3.20 (1Н, dd, J = 16.4, J = 12.0) and
3.36 (1Н, dd, J = 16.4, J = 2.8, 4-СН2); 4.90 (2Н, br. s, 2'-ОСН2);
6.03 (1Н, dd, J = 12.0, J = 2.8, H-3); 6.83 (1Н, d, J = 8.4, Н-3');
7.07-7.11 (2Н, m, Н-4', H-4''); 7.36 (1Н, br. s, Н-6');
7.41-7.43 (2Н, m H-5,5''); 7.45 (1Н, t, J = 7.6, H-7); 7.61 (1Н, t, J = 7.6, H-6);
8.01 (1Н, d, J = 7.6, H-8)
18a
18b
18d
3.02 (1Н, dd, J = 16.4, J = 2.8) and 3.27 (1Н, dd, J = 16.4, J = 8.8, 4-СН2);
4.36 (2Н, br. s, 4'-СН2О); 5.41 (1Н, dd, J = 8.8, J = 2.8, H-3);
6.89 (2H, d, J = 8.8, H-3',5'); 7.28-7.34 (3H, m H-5,2',6'); 7.39 (1Н, t, J = 7.6, H-7);
7.57 (1Н, t, J = 7.2, H-6); 7.93 (1Н, d, J = 7.6, H-8); 12.60 (1Н, br. s, СО2Н)
3.18 (1Н, dd, J = 16.0, J = 1.6) and 3.35 (1Н, dd, J = 16.0, J = 12.0, 4-СН2);
3.75 (3Н, s, СО2СН3); 4.75 (2Н, s, 4'-СН2О); 6.95 (2H, d, J = 8.8, H-3',5');
5.57 (1Н, dd, J = 12.0, J = 1.6, H-3); 7.39 (1Н, d, J = 7.2, H-5);
7.41-7.45 (3H, m, H-7,2',6'); 7.61 (1Н, t, J = 7.2, H-6); 7.99 (1Н, d, J = 7.6, H-8)
3.19 (1Н, d, J = 16.0) and 3.37 (1Н, dd, J = 16.0, J = 12.4, 4-СН2); 3.75 (3Н, s, 4''-ОСН3);
4.64 (2Н, s, 4'-СН2О); 5.59 (1Н, d, J= 12.4, H-3);
6.84 (2Н, d, J = 8.0, H-3'',5''); 7.05 (2H, d, J = 7.6, H-3',5'); 7.39 (1Н, d, J = 7.2, H-5);
7.44-7.47 (3H, m, H-7,2',6'); 7.54 (2Н, d, J = 8.0, H-2'',6''); 7.62 (1Н, t, J = 7.2, H-6);
7.98 (1Н, d, J = 7.2, Н-8)
18e
19
3.17 (1Н, dd, J = 16.0, J = 12.4) and 3.36 (1Н, dd, J = 16.0, J = 0.8, 4-СН2);
4.84 (2Н, s, 4'-СН2О); 5.58 (1Н, dd, J = 12.4, J = 0.8, H-3); 6.99 (2H, d, J = 8.4, H-3',5');
7.10 (1Н, d, J = 3.2, Н-4''); 7.38 (1Н, d, J = 7.6, H-5); 7.42-7.47 (4Н, m, H-7,2',6',5'');
7.60 (1Н, t, J = 7.6, H-6); 7.98 (1Н, d, J = 7.6, H-8); 12.27 (1Н, s, NH)
2.28 (3Н, s, 5'-СН3); 3.16-3.26 (2Н, m, 4-СН2); 5.78 (1Н, dd, J = 10.8, J = 4.0, Н-3);
6.75 (1Н, d, J = 8.0, Н-3'); 6.91 (1Н, d, J = 8.0, Н-4'); 7.21 (1Н, br. s, Н-6');
7.38 (1Н, d, J = 7.6, Н-5); 7.44 (1Н, t, J = 7.4, Н-7); 7.61 (1Н, t, J = 7.4, Н-6);
7.99 (1Н, d, J = 7.6, Н-8); 9.40 (1Н, s, 2-ОН)
20
3.15 (1Н, dd, J = 16.4, J = 2.4) and 3.35 (1Н, dd, J = 16.4, J = 11.6, 4-СН2);
5.49 (1Н, dd, J = 11.6, J = 2.4, Н-3); 6.78 (2H, d, J = 8.0, H-3',5');
7.28 (2H, d, J = 8.0, H-2',6'); 7.38 (1Н, d, J = 7.6, Н-5); 7.43 (1Н, t, J = 7.6, Н-7);
7.60 (1Н, t, J = 7.6, Н-6); 7.98 (1Н, d, J = 7.6, Н-8); 9.35 (1Н, s, 4-ОН)
Amides 17d,e and 18d,e were synthesized in order to obtain new derivatives of dihydroisocoumarins.
O
O
O
O
DIC,
DIC,
18a
17a
Me
RNH2
RNH2
RHNOCCH2O
O
18d,e
CH2CONHR
17d,e
17, 18 d R = 4-MeOC6H4; e R = thiazol-2-yl
As in the case of amides of phthalides 6a, 8a synthesis, use of SOCl2 led to a mixture of unidentifiable
products. Therefore diisopropylcarbodiimide (DIC) was used for reaction of acids 17a, 18a with heterocyclic
and aromatic amines.
Thus, the reduction of 3-(carboxyaryl)isocoumarins with sodium borohydride has been studied. It was
shown that reduction of 3-(2-carboxyphenyl)isocoumarins was accompanied by recyclization with formation of
3-(2-carboxybenzyl)-2-benzofuran-1(3H)-ones (and not 3-(2-carboxyphenyl)-3,4-dihydroisocoumarins) and new
derivatives at the carboxyl group of the obtained dihydroisocoumarins and dihydrophthalides have been
synthesized.
1221

EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian Mercury 400 instrument (at 400 MHz) in DMSO-d6
(for compound 6b in a mixture of DMSO-d6–C6D6, 1:1), internal standard was TMS. Mass spectra were
recorded on Agilent 1100LC/MSD (CI, 200 eV) spectrometer. Elemental analysis was carried out on a Vario
Micro Cube instrument. Melting points were measured (at "equilibrium" according to Kofler) on a Boetius type
miniature hot stage with VEB Analytik PHMK 05 eye-piece. Progress of reactions and products purity was
controlled by TLC on Silufol UV-254 plates, eluting system was chloroform–methanol, 19:1.
2-(1-Oxo-1H-isochromen-3-yl)benzoic acid (1) was synthesized by the procedure of [12], 3-(2-hydroxy-
5-methylphenyl)-1H-isochromen-1-one (11) according to [14], 3-(4-hydroxyphenyl)-1H-isochromen-1-one (12)
according to [15], 3-(4-hydroxyphenyl)-3,4-dihydro-1H-isochromen-1-one (20) according to [16], and
4-nitrohomophthalic acid according to [17]. Physical constants and spectral data corresponded with the
literature.
2-(7-Nitro-1-oxo-1H-isochromen-3-yl)benzoic Acid (2). A mixture of 4-nitrohomo-phthalic acid (4.5 g,
0.02 mol), phthalic anhydride (4.4 g, 0.03 mol), and sodium acetate (0.4 g) was melted at 170oC for 3 h. After
cooling, the mixture was suspended in 2% NaHCO3 solution (75 ml), and left for 48 h at room temperature. The
solid was then filtered off, washed with water, and recrystallized from a mixture DMF–2-PrOH, 1:2.
2-[(1-Oxo-1H-isochromen-3-yl)methyl]benzoic Acid (3). Homophthalic anhydride (8.1 g, 0.05 mol) and
triethylamine (14 ml, 0.1 mol) were refluxed for 2 h in toluene (40 ml), the solvent was evaporated, and the
residue treated with 5% H2SO4 (200 ml). The solid was filtered off, washed with water, and recrystallized from a
mixture DMF–2-PrOH, 1:2. Yield 94%; mp 209-210oC (lit. 210-211oC [11]).
[2-(1-Oxo-1H-isochromen-3-yl)-4-methylphenoxy]acetic Acid (4) and [4-(1-Oxo-1H-isochromen-
3-yl)phenoxy]acetic Acid (5). A suspension of acid 15 or 16 (0.013 mol) in 20% H2SO4 (50 ml) was boiled for
6-8 h. The solid was filtered off, washed with water, and recrystallized from ethanol.
2-[(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)methyl]benzoic Acid (6a) and 2-[(1-Oxo-3,4-dihydro-1H-
isochromen-3-yl)methyl]benzoic Acid (10a). Isocoumarin 1 or 3 (8 mmol) was dissolved at 60oC with stirring
in ethanol (10 ml) and 2.5% aqueous NaOH (40 ml), after which a suspension of NaBH4 (1 g, 26 mmol) in
ethanol (10 ml) was added. The reaction mixture was stirred at 60oC for 2 h, the solution obtained was cooled
and acidified with dilute hydrochloric acid. The precipitated solid was filtered off, washed with water, and
recrystallized from 70% aqueous ethanol. Mass spectra, m/z (Irel, %): compound 6a – 268 [M]- (20), 267 [M-H]-
(100); compound 10a – 282 [M]- (15), 281 [M-H]- (85).
5-Nitro-2-[(3-oxo-1,3-dihydro-2-benzofuran-1-yl)methyl]benzoic Acid (8a). A suspension of NaBH4
(0.5 g, 13 mmol) in ethanol (10 ml) was added with stirring to a suspension of isocoumarin 2 (1.25 g, 4 mmol)
in water (50 ml), after that stirring was continued for another 1.5 h. The solution obtained was filtered, and
acidified with dilute hydrochloric acid, the solid was filtered off, washed with water, and recrystallized from
ethanol. Mass spectrum, m/z (Irel, %): 313 [M]- (20), 312 [M-H]- (100).
Synthesis of Amides 6c-e, 8d, 10c (General Method). Acid 6a, 8a, or 10a (2 mmol) and
carbonyldiimidazole (0.37 g, 2.25 mmol) was dissolved in dry DMF (5 ml). The mixture was stirred at room
temperature for 1 h, the correspoding amine (2.25 mmol) was added and the mixture was stirred at 40oC for
another 3-6 h. The reaction mixture was poured into water (50 ml), the solid was filtered off, and recrystallized
from a mixture DMF–2-PrOH, 1:2.
[2-(1-Oxo-3,4-dihydro-1H-isochromen-3-yl)-4-methylphenoxy]acetic Acid (17a) and [4-(1-Oxo-3,4-
dihydro-1H-isochromen-3-yl)phenoxy]acetic Acid (18a).
1. Acid 4 or 5 (8 mmol) in a mixture of methanol (10 ml) and 2.5% aqueous NaOH (40 ml) was stirred
while boiling until dissolving, after that a suspension of NaBH4 (1 g, 26 mmol) in methanol (10 ml) was added
and the mixture was refluxed for another 2-3 h. The solution obtained was cooled and acidified with dilute
hydrochloric acid. The precipitated solid was filtered off, washed with water and recrystallized from 70%
aqueous ethanol.
1222

2. Acid 15 or 16 (8 mmol) was dissolved in a mixture of methanol (10 ml) and 2.5% aqueous NaOH
(40 ml), after that a suspension of NaBH4 (1 g, 26 mmol) in methanol (10 ml) was added, and the mixture was
refluxed for 2-3 h. The reaction mixture was processed analogously to the previous experiment.
3. Methyl ester 13 or 14 (8 mmol) was mixed with methanol (10 ml) and 5% aqueous NaOH (40 ml) and
stirred while boiling until dissolving, after that a suspension of NaBH4 (1 g, 26 mmol) in methanol (10 ml) was
added and the mixture was refluxed for another 2-3 h. The reaction mixture was processed analogously to
experiment 1.
4. Methyl ester 17b or 18b (8 mmol) was dissolved by boiling in a mixture of ethanol (5 ml) and 2.5%
aqueous NaOH (40 ml). The obtained solution was cooled and acidified with dilute hydrochloric acid. The
precipitated solid was filtered off, washed with water and recrystallized from 70% aqueous ethanol.
Compound 17a: Mass spectrum, m/z (Irel, %): 312 [M]- (15), 311 [M-H]- (100).
Compound 18a: Mass spectrum, m/z (Irel, %): 298 [M]- (10), 297 [M-H]- (100).
Esters 6b, 8b, 10b (General Method). Dimethyl sulfate (0.5 ml, 5.3 mmol) was added to a mixture of
acid 6a, 8a, or 10a (3 mmol) and calcined potassium carbonate (1 g, 7.2 mmol) in acetone (20 ml), and the
mixture was refluxed with stirring for 1-1.5 h. The reaction mixture was poured into water (100 ml), the solid
was filtered off and recrystallized from 70% aqueous ethanol.
Amides of (1-Oxo-3,4-dihydro-1H-isochromen-3-yl)phenoxyacetic Acids 17d,e and 18d,e (General
Method). Diisopropylcarbodiimide (0.39 ml, 2.25 mmol) was added to a mixture of acid 17a or 18a (2 mmol)
and the corresponding amine (2.2 mmol) in dioxane (10 ml) with stirring. The reaction mixture was stirred at room
temperature for 4-6 h, poured into water (100 ml), the solid was filtered off and recrystallized from a mixture DMF–
2-PrOH, 1:2.
Esters of Phenoxyacetic Acids 13, 14, 17b, 18b (General Method). Bromoacetic acid methyl ester
(0.4 ml, 4 mmol) was added to a mixture of dihydroisocoumarin 19, 20, or isocoumarin 11, 12 (3 mmol) and
calcined potassium carbonate (1 g, 7.2 mmol) in acetone (20 ml) and the mixture was refluxed with stirring for
1-1.5 h. The reaction mixture was poured into water (100 ml), the solid was filtered off and recrystallized from
70% aqueous ethanol.
2-{2-[2-(Carboxymethoxy)-5-methylphenyl]-2-oxoethyl}benzoic
Acid
(15)
and
2-{2-[4-
(Carboxymethoxy)phenyl]-2-oxoethyl}benzoic Acid (16). Methyl ester 13 or 14 (8 mmol) was dissolved by
boiling in a mixture of ethanol (5 ml) and 2.5% aqueous NaOH (40 ml). The solution obtained was cooled and
acidified with dilute hydrochloric acid. The precipitated solid was filtered off, washed with water and purified
by recrystallization from a saturated aqueous solution of sodium bicarbonate with 10% hydrochloric acid.
3-(2-Hydroxy-5-methylphenyl)-3,4-dihydro-1H-isochromen-1-one (19). A suspension of NaBH4
(0.4 g, 11 mmol) in ethanol (10 ml) was added to a suspension of isocoumarin 11 (1 g, 4 mmol) in ethanol (20
ml) and the mixture was stirred at 40oC for 2 h. 20% H2SO4 (50 ml) was added to the reaction mixture and
heated at 60oC with stirring for 1 h. The mixture was cooled, the solid was filtered off and recrystallized from
70% aqueous ethanol.
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1224