Synthesis of 3-hetaryl-1H-isochromen-1-ones based on 3-(2-bromoacetyl)-1H- isochromen-1-one

Article abstract of DOI:10.1007/s10593-013-1183-7

A preparative method was developed for the synthesis of 3-(2-bromoacetyl)-1H-isochromen-1-one. Its heterocyclization to 3-(2-R-thiazol-4-yl)-, (3-quinoxalin-2-yl)-, and 3-(imidazo[1,2-a]pyridin-2-yl)- 1H-isochromen-1-ones was studied.

Full text of DOI:10.1007/s10593-013-1183-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS OF 3-HETARYL-1H-ISOCHROMEN-1-ONES
BASED ON 3-(2-BROMOACETYL)-1H-ISOCHROMEN-1-ONE
O. V. Shablykina1*, O. V. Shablykin1, V. V. Ishchenko1,
A. V. Voronaya1, and V. P. Khilya1
A preparative method was developed for the synthesis of 3-(2-bromoacetyl)-1H-isochromen-1-one. Its
heterocyclization to 3-(2-R-thiazol-4-yl)-, (3-quinoxalin-2-yl)-, and 3-(imidazo[1,2-a]pyridin-2-yl)-1H-
isochromen-1-ones was studied.
Keywords: 3-acetyl-1H-isochromen-1-one, 3-(2-bromoacetyl)-1H-isochromen-1-ones, 3-hetaryl-1H-iso-
chromen-1-ones, heterocyclization.
Investigations into 1H-isochromen-1-ones began way back in the nineteenth century [1]. The continuing
interest in the chemistry of hetaryl-substituted compounds of this class is due not only to the wide range of their
biological activity, but also to the numerous options for modification of the 1H-isochromen-1-one ring [1-4]. In
spite of this, however, among the large number of 1H-isochromen-1-one derivatives synthesized and isolated
from natural sources there are only a few examples of compounds, in which the isochromene ring is linked to
another heterocycle [5].
There are two possible approaches to construction of the 3-hetaryl-1H-isochromen-1-one system. One
of them involves the formation of the isochromene system from compounds containing another heterocyclic
fragment. Thus, for example, we synthesized a series of 3-hetaryl-1H-isochromen-1-ones by the condensation of
homophthalic acid derivatives with heterocyclic carboxylic acid chlorides [6].
O
O
O
Br2
O
O
O
+
AcOH
CH2Br
CHBr2
Me
O
O
O
1
2
3
According to the second method, the 3-hetaryl-1H-isochromen-1-ones are synthesized by construction
of a heterocycle onto an existing 1H-isochromen-1-one ring. In the present work, we have used this method for
the synthesis of 3-hetaryl-1H-isochromen-1-ones on the basis of 3-(2-bromoacetyl)-1H-isochromen-1-one.
For the first time we obtained the 3-(2-bromoacetyl)-1H-isochromen-1-one (2) by the reaction of
3-acetyl-1H-isochromen-1-one (1) with bromine in acetic acid solution.
_______
*To whom correspondence should be addressed, e-mail: shablykina@ukr.net.
1Kyiv Taras Shevchenko National University, 64 Volodymirska St., Kyiv 01601, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1736-1741, November, 2012.
Original article submitted January 16, 2012.
0009-3122/13/4811-1621©2013 Springer Science+Business Media New York
1621

1
As follows from the H NMR spectra, the reaction mixture obtained from equimolar amounts of the
reagents contained the desired product 2, the dibromo derivative 3, and the initial compound 1. By optimizing
the conditions it was possible to achieve a 70% yield of the monobromo derivative 2. Treatment of 3-acetyl-1H-iso-
chromen-1-one (1) with more than two equivalents of Br2 resulted in the exclusive formation of 3-(2,2-di-
bromoacetyl)-1H-isochromen-1-one (3) in almost quantitative yield.
The bromo ketone 2 reacted readily with thioamides when refluxed in ethanol or isopropyl alcohol and
led to 3-(2-R-thiazol-4-yl)-1H-isochromen-1-ones 4a-g. The formation of thiazole ring was confirmed by
1H NMR spectra; in addition to the H-4 singlet characteristic of the 3-substituted isochromene system, a singlet
for the thiazole ring proton appeared in the region of 7.37-7.51 ppm (Table 1). The isochromene 2 reacted with
2-aminopyridine under analogous conditions, leading to 3-(imidazo[1,2-a]pyridin-2-yl)-1H-isochromen-1-one (5).
O
O
H2N
R
O
O
N
NH2
S
2
N
N
R
N
S
4a–g
5
4 a R = Me, b R = Ph, c R = 3-FC6H4, d R = 4-FC6H4, e R = 4-ClC6H4, f R = NH2, g R = CH2CN
Formation of this particular isomer of compound 5 (and not 3-(imidazo[1,2-a]pyridin-3-yl)-1H-iso-
chromen-1-one) was confirmed by the nuclear Overhauser effect (NOE) of the imidazole ring proton signal (a
downfield singlet at 8.35 ppm) with the doublet of the pyridine ring (8.47 ppm). The presence of a NOE
between the singlet of the isochromene ring H-4 proton at 7.35 ppm and one of the components of the multiplet
at 7.47-7.51 ppm (a doublet corresponding to the H-5 proton of the isochromene system) confirmed the
accuracy of the signal assignment in the 1H NMR spectrum of compound 5.
It was possible to obtain 3-(quinoxalin-2-yl)-1H-isochromen-1-one 6 by condensation of compound 2
with o-phenylenediamine, accompanied by oxidation of the intermediate product by atmospheric oxygen, but
better yields of the product were obtained through reaction with the dibromo ketone 3.
O
NH2
O
3
+
N
N
NH2
6
It should be noted that the N-nucleophiles used in the synthesis of compounds 5 and 6 did not lead to
opening of the isochromene ring.
The amides 7a,b were obtained by acylation of the thiazole ring amino group in compound 4f with
carboxylic acid chlorides.
O
O
RCOCl
4f
Py
N
NHCOR
S
7a,b
7 a R = Me, b R = Ph
1622

TABLE 1. Spectral Characteristics of Compounds 2-10
IR spectrum,
Com-
pound
1Н NMR spectrum, , ppm (J, Hz)
, cm–1
1
2
3
1720,
1705
4.66 (2Н, s, СH2Br); 7.75 (1Н, t, J = 8.0, H-7); 7.81 (1Н, s, H-4);
7.88 (1Н, d, J = 8.0, H-5); 7.91 (1Н, t, J = 8.0, H-6); 8.25 (1Н, d, J = 8.0, H-8)
2
(C=O)
1720,
1700
7.38 (1Н, s, СHBr2); 7.78 (1Н, t, J = 7.6, H-7); 7.89 (1Н, d, J = 7.6, H-5);
7.93 (1Н, t, J = 7.6, H-6); 7.98 (1Н, s, H-4); 8.26 (1Н, d, J = 7.6, H-8)
3
(C=O)
1723
(C=O)
2.77 (3Н, s, СH3); 7.37 (1Н, s, H-4); 7.56 (1Н, t, J = 7.6, H-7);
7.68 (1Н, d, J = 7.6, H-5); 7.79 (1Н, t, J = 7.6, H-6); 7.86 (1Н, s, H-5');
8.18 (1Н, d, J = 7.6, H-8)
4a
4b
4c
4d
4e
4f
1745
(С=О)
7.46-7.51 (4Н, m, Н-4,3'',4'',5''); 7.55 (1Н, t, J = 7.6, H-7);
7.69 (1Н, d, J = 7.6, H-5); 7.79 (1Н, t, J = 7.6, H-6);
7.98-8.03 (3Н, m, H-5',2'',6''); 8.20 (1Н, d, J = 8.0, H-8)
1745
(С=О)
7.27 (1Н, br. t, J = 8.4, H-5''); 7.51 (1Н, s, H-4); 7.52-7.59 (2Н, m, Н-7,6''),
7.71 (1Н, d, J = 8.0, H-5); 7.78-7.84 (3Н, m, Н-6,2'',4''); 8.11 (1Н, s, H-5');
8.18 (1Н, d, J = 8.0, H-8)
1745
(С=О)
7.28 (2Н, br. t, J = 8.4, H-2'',6''); 7.47 (1Н, s, H-4); 7.57 (1Н, t, J = 7.6, H-7);
7.69 (1Н, d, J = 7.6, H-5); 7.81 (1Н, t, J = 7.6, H-6);
8.03-8.08 (3Н, m, H-5',3'',5''); 8.20 (1Н, d, J = 7.6, H-8)
1755,
7.47 (1Н, s, H-4); 7.51 (2Н, d, J = 8.4, H-2'',6''); 7.56 (1Н, t, J = 7.6, H-7);
1745(С=О) 7.69 (1Н, d, J = 7.6, H-5); 7.80 (1Н, t, J = 7.6, H-6); 8.01 (2Н, d, J = 8.4, H-3'',5'');
8.06 (1Н, s, H-5'); 8.18 (1Н, d, J = 7.6, H-8)
3420,
3300
7.02 (1Н, s, H-5'); 7.07–7.10 (3Н, m, Н-4, NH2); 7.51 (1Н, t, J = 7.6, H-7);
7.64 (1Н, d, J = 7.6, H-5); 7.76 (1Н, t, J = 7.6, H-6); 8.13 (1Н, d, J = 7.6, H-8)
(NH);
1723
(С=О)
2265
(CN);
1720
4.54 (2Н, s, СH2CN); 7.41 (1Н, s, H-4); 7.57 (1Н, t, J = 7.6, H-7);
7.74 (1Н, d, J = 7.6, H-5); 7.80 (1Н, t, J = 7.6, H-6); 8.06 (1Н, s, H-5');
8.18 (1Н, d, J = 7.6, H-8)
4g
5
(С=О)
1742
(С=О)
6.83 (1Н, t, J = 6.8, H-6'); 7.23 (1Н, br. t, J = 7.6, H-7'); 7.35 (1Н, s, H-4);
7.47-7.51 (2Н, m, Н-7,8'); 7.63 (1Н, d, J = 7.6, H-5); 7.74 (1Н, t, J = 7.6, H-6);
8.17 (1Н, d, J = 7.6, H-8); 8.35 (1Н, s, H-3'); 8.47 (1Н, d, J = 7.6, H-5')
1730
(С=О)
7.71 (1Н, t, J = 7.6, H-7); 7.85–7.92 (4Н, m, Н-5,6,6',7'); 8.00 (1Н, s, H-4);
8.12-8.17 (2Н, m, Н-5',8'); 8.28 (1Н, d, J = 7.6, H-8); 9.49 (1Н, s, H-3')
6
3125
(NH);
1767
2.17 (3Н, s, СH3); 7.16 (1Н, s, H-5'); 7.51-7.56 (2Н, m, Н-4,7);
7.68 (1Н, d, J = 8.0, H-5); 7.78 (1Н, t, J = 8.0, H-6);
8.15 (1Н, d, J = 8.0, H-8); 12.31 (1Н, s, NHCO)
7a
(С=О)
3055
(NH);
1728
7.25 (1Н, s, H-5'); 7.48-7.54 (3Н, m, Н-3'',4'',5''); 7.61 (1Н, t, J = 7.6, H-7);
7.62 (1Н, s, H-4); 7.69 (1Н, d, J = 7.6, H-5); 7.77 (1Н, t, J = 7.6, H-6);
8.12-8.17 (3Н, m, Н-8,2'',6''); 12.76 (1Н, s, NHCO)
7b
(С=О)
8a*
8b
1720
(С=О)
7.68-7.74 (2Н, m, Н-7,5); 7.75 (1Н, s, H-4); 7.84-7.91 (2Н, m, Н-6'',8'');
8.04-8.10 (3Н, m, Н-6,5'',7''); 8.56 (1Н, d, J = 8.0, H-8); 8.65 (1Н, s, H-5');
9.62 (1Н, s, H-4'')
1720
(С=О)
7.59 (1Н, d, J = 7.6, H-5); 7.79 (1Н, s, H-4); 7.87-7.93 (2Н, m, Н-7,8'');
8.08-8.16 (2Н, m, Н-6,7''); 8.20 (1Н, s, H-5''); 8.59 (1Н, d, J = 8.0, H-8);
8.72 (1Н, s, H-5'); 9.56 (1Н, s, H-4'')
1720
(С=О)
7.82 (1Н, s, H-4); 7.85–7.94 (3Н, m, Н-7,5,8''); 8.11 (1Н, t, J = 8.0, H-6);
8.60 (1Н, d, J = 8.0, H-8); 8.79 (1Н, s, H-5');
8c
8.86 (1Н, dd, 3J = 9.2, 4J = 2.4, H-7''); 9.02 (1Н, d, J = 2.4, H-5'');
9.71 (1Н, s, H-4'')
3240
6.81 (1Н, br. s, Н-8''); 6.88 (1Н, br. d, J = 8.8, Н-6''); 7.53 (1Н, s, H-4);
7.57 (1Н, t, J = 7.6, H-7); 7.70 (1Н, d, J = 7.6, H-5); 7.76 (1Н, d, J = 8.8, H-5'');
7.84 (1Н, t, J = 7.6, H-6); 8.08 (1Н, s, H-5'); 8.19 (1Н, d, J = 8.0, H-8);
8.99 (1Н, s, H-4''); 10.84 (1Н, br. s, ОН)
8d
(OH);
1733,
1695
(С=О)
1623

TABLE 1 (continued)
1
2
3
1734
(С=О)
2.56 (3H, s, ОСОСН3); 7.50 (1H, dd, 3J = 8.4, 4J = 1.6, Н-6'');
7.58 (1H, d, J = 1.6, H-8''); 7.75 (1Н, s, H-4); 7.84–7.90 (2Н, m, Н-5,7);
8.05-8.11 (2Н, m, Н-6,5''); 8.56 (1Н, d, J = 7.6, H-8); 8.66 (1Н, s, Н-5');
9.60 (1Н, s, Н-4'')
9a
1755,
1715
(С=О)
7.62-7.67 (3Н, m, Н-6'',3''',5'''); 7.70 (1Н, br. s, Н-8''); 7.76 (1Н, s, H-4);
7.80-7.96 (3Н, m, Н-5,7,4'''); 8.08 (1Н, t, J = 7.6, H-6);
8.16 (1Н, d, J = 8.8, H-5''); 8.33 (2Н, d, J = 7.6, Н-2''',6''');
8.57 (1Н, d, J = 7.6, H-8); 8.67 (1Н, s, H-5'); 9.65 (1Н, s, H-4'')
9b
10
1760,
1727
(С=О)
2.77 (3Н, s, ОСH3); 7.18 (1Н, br. s, Н-8''); 7.30 (1Н, br. d, J = 8.8, Н-6'');
7.71 (1Н, s, H-4); 7.83–7.89 (2Н, m, Н-5,7); 7.97 (1Н, d, J = 8.8, H-5'');
8.06 (1Н, t, J = 7.6, H-6); 8.51 (1Н, s, H-5'); 8.55 (1Н, d, J = 7.6, H-8);
9.50 (1Н, s, H-4'')
_______
*In the 1H NMR spectra of compounds 8-10 the protons of the
1H-isochromen-1-one system are denoted as H-3,4, etc., the proton of the
thiazole ring as H-5', and the protons of the 2H-chromen-2-one system as
H-3",4", etc.
Compounds 8a-d, in which the 2H-chromen-2-one and 1H-isochromen-1-one rings are linked by a
thiazole ring [8], were obtained by condensation of the thiazolylacetonitrile 4g with salicylaldehydes at the
active methylene group [7].
O
1) Piperidine
CHO
OH
O
O
2) H +
O
R
4g
+
N
S
8a–d
8 a R = H, b R = 6-Br, c R = 6-NO2, d R = 7-OH
R
As in the case of the amine 4f, the acetate 9a and the benzoate 9b were synthesized from compound 8d
containing a hydroxy group. Treatment of compound 8d with dimethyl sulfate in the presence of potassium
carbonate likewise gave the methoxy derivative 10.
Het
O
Het
Me2SO4
K2CO3
RCOCl
Py
8d
O
O
O
OCOR
OMe
9a,b
10
9 a R = Me, b R = Ph; Het = 4-(1-оxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl
Thus, our investigations have demonstrated the possibility of using 3-(2-bromoacetyl)-1H-isochromen-
1-one for the synthesis of various 3-hetaryl-1H-isochromen-1-ones, including those containing active groups
capable of further functionalization. It is remarkable that in spite of the fact that 1H-isochromen-1-one is a
lactone, ring opening by the action of fairly strong nucleophiles did not occur in the heterocyclization reactions
that we investigated.
1624

EXPERIMENTAL
1
The H NMR spectra were recorded in CF3COOH (compounds 8a-c, 9b) and DMSO-d6 (the other
compounds) on a Varian Mercury 400 instrument (400 MHz) with TMS as internal standard. Elemental analysis
was performed on a Vario MICRO Cube instrument. The melting points were determined (in Koffler
“equilibrium”) on a small-scale Boetius hot stage with a VEB Analytik PHMK 05 viewing device. The reaction
progress and the purity of the compounds were monitored by TLC on Silufol UV-254 plates with 19:1 CHCl3–
MeOH as an eluent.
3-Acetyl-1H-isochromen-1-one (1) was synthesized by the methods in [9] and [10].
3-(2-Bromoacetyl)-1H-isochromen-1-one (2). 3-Acetyl-1H-isochromen-1-one (1) (5 g, 0.027 mol) was
dissolved in AcOH (60 ml) with stirring at room temperature, and Br2 (1.5 ml, 0.029 mol) was added dropwise
over 1 h (exothermic reaction). The reaction mixture was stirred for a further 15 min, after which it was left for
2 h. The precipitate was filtered off and washed successively with acetic acid (5 ml) and a large amount of
hexane. Yield 5.05 g (70%). Colorless crystals; mp 164-165°C. Found, %: С 49.67; Н 2.59; Br 29.78.
C11H7BrO3. Calculated, %: С 49.47; H 2.64; Br 29.92.
3-(2,2-Dibromoacetyl)-1H-isochromen-1-one (3). 3-Acetyl-1H-isochromen-1-one (1) (2 g, 0.011 mol)
was dissolved in AcOH (20 ml) at 60°C with stirring, and Br2 (1.4 ml, 0.027 mol) was added dropwise over 1 h
(exothermic reaction, the reaction mixture boiled). After cooling, water (100 ml) was added. The precipitate was
filtered off and washed with water. Yield 3.62 g (95%). Fine, light-beige crystals that became darker after
prolonged storage in air; mp 127-128°C (decomp.). Found, %: С 38.05; Н 1.82; Br 45.98. C11H6Br2O3.
Calculated, %: С 38.19; H 1.75; Br 46.19.
3-Hetaryl-1H-isochromen-1-ones 4a-e,g, 5, 6 (General Method). 3-(2-Bromoacetyl)-1H-isochromen-
1-one (2) (1.34 g, 5.0 mmol) and the corresponding thioamide (5.5 mmol) (for the preparation of compounds
4a-e,g), or the bromoketone 2 (1.34 g, 5.0 mmol) and 2-aminopyridine (0.52 g, 5.5 mmol) (for compound 5), or
dibromo ketone 3 (1.73 g, 5.0 mmol) and phenylenediamine (0.60 g, 5.5 mmol) (for compound 6) were refluxed
with stirring in 2-PrOH (30 ml) (15 ml for compound 4a) for 2 h. When the reaction mixture had cooled, the
precipitate was filtered off and washed with EtOH. The product was recrystallized from a 1:1 mixture of EtOH
and DMF.
3-(2-Methyl-1,3-thiazol-4-yl)-1H-isochromen-1-one (4a). Yield 0.77 g (63%). Light-beige needle-
shaped crystals; mp 119-120°C. Found, %: С 63.93; Н 3.59; N 5.87; S 13.07. C13H9NO2S. Calculated, %:
С 64.18; H 3.73; N 5.76; S 13.18.
3-(2-Phenyl-1,3-thiazol-4-yl)-1H-isochromen-1-one (4b). Yield 1.28 g (84%). Fine light-beige
crystals; mp 204-205°C. Found, %: С 71.06; Н 3.52; N 4.75; S 10.68. C18H11NO2S. Calculated, %: С 70.80;
H 3.63; N 4.59; S 10.50.
3-[2-(3-Fluorophenyl)-1,3-thiazol-4-yl]-1H-isochromen-1-one (4c). Yield 1.23 g (76%). Colorless
needle-shaped crystals; mp 216-218°C. Found, %: С 67.05; Н 3.09; N 4.52; S 10.16. C18H10FNO2S. Calculated,
%: С 66.86; H 3.12; N 4.33; S 9.92.
3-[2-(4-Fluorophenyl)-1,3-thiazol-4-yl]-1H-isochromen-1-one (4d). Yield 1.41 g (87%). Colorless
needle-shaped crystals; mp 236-237°C. Found, %: С 67.13; Н 3.25; N 4.17; S 9.74. C18H10FNO2S. Calculated,
%: С 66.86; H 3.12; N 4.33; S 9.92.
3-[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]-1H-isochromen-1-one (4e). Yield 1.51 g (89%). Colorless
needle-shaped crystals; mp 202-203°C. Found, %: 63.81; Н 2.99; Cl 10.27; N 4.32; S 9.27. C18H10ClNO2S.
Calculated, %: С 63.62; H 2.97; Cl 10.43; N 4.12; S 9.44.
2-[4-(1-Oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]acetonitrile (4g). Yield 0.91 g (68%). Coarse
light-brown crystals; mp 180-182°C. Found, %: С 62.56; Н 3.06; N 10.64; S 12.12. C14H8N2O2S. Calculated, %:
С 62.67; H 3.01; N 10.44; S 11.95.
1625

3-(Imidazo[1,2-a]pyridin-2-yl)-1H-isochromen-1-one (5). Yield 0.81 g (62%). Fine light-beige
crystals; mp 218-219°C. Found, %: С 73.08; Н 4.07; N 10.44. C16H10N2O2. Calculated, %: С 73.28; H 3.84;
N 10.68.
3-(Quinoxalin-2-yl)-1H-isochromen-1-one (6). Yield 1.17 g (85%). Coarse light-brown crystals; mp
186-187°C. Found, %: С 74.63; Н 3.66; N 10.45. C17H10N2O2. Calculated, %: С 74.45; H 3.67; N 10.21.
3-(2-Amino-1,3-thiazol-4-yl)-1H-isochromen-1-one (4f). The bromo ketone 2 (2.68 g, 10 mmol) and
thiourea (0.84 g, 12 mmol) in 2-PrOH (30 ml) were refluxed with stirring for 2 h. A 2% NaHCO3 solution (50 ml)
was then added, and the mixture was refluxed for a further 30 min. When the reaction mixture had cooled, the
precipitate was filtered off and washed with water. The product was recrystallized from a 1:1 mixture of EtOH
and DMF. Yield 2.03 g (83%). Fine, colorless crystals that became yellowish after prolonged storage in air; mp
241-242°C. Found, %: С 59.22; Н 3.30; N 11.25; S 13.16. C12H8N2O2S. Calculated, %: С 59.00; H 3.30;
N 11.47; S 13.13.
Preparation of Acyl Derivatives 7, 9a,b (General Method). The corresponding acyl chloride (3 mmol)
was added to a suspension of the amine 4f or phenol 8d (2.5 mmol) in pyridine (5 ml). The mixture was heated
with stirring at 80-90°C until a transparent solution had formed, and left overnight at room temperature. Then
H2O (50 ml) was added, and the precipitate was filtered off and washed with water. The product was
recrystallized from a 1:1 mixture of EtOH and DMF (compounds 7a,b), or from DMF (compounds 9a,b).
N-[4-(1-Oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]acetamide (7a). Yield 0.62 g (86%). Fine light-
beige crystals; mp 317-319°C (decomp.). Found, %: 58.93; Н 3.53; N 9.86; S 11.33. C14H10N2O3S. Calculated,
%: С 58.73; H 3.52; N 9.78; S 11.20.
N-[4-(1-Oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]benzamide (7b). Yield 0.79 g (91%). Fine
colorless crystals; mp 202-203°C. Found, %: 65.78; Н 3.62; N 8.27; S 9.06. C19H12N2O3S. Calculated, %:
С 65.50; H 3.47; N 8.04; S 9.20.
2-Oxo-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-7-yl Acetate (9a). Yield 0.96
g (89%). Yellow needle-shaped crystals; mp 252-253°C. Found, %: С 64.27; Н 3.15; N 3.12; S 7.28.
C23H13NO6S. Calculated, %: С 64.03; Н 3.04; N 3.25; S 7.43.
2-Oxo-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-7-yl Benzoate (9b). Yield
1.14 g (92%). Bright-yellow needle-shaped crystals; mp 295-297°C. Found, %: С 68.41; Н 3.17; N 2.77;
S 6.73. C28H15NO6S. Calculated, %: С 68.15; Н 3.06; N 2.84; S 6.50.
Preparation of Compounds 8a-d (General Method). The nitrile 4g (1.34 g, 5.0 mmol) and the
corresponding aldehyde (5.5 mmol) were dissolved with heating in the minimum amount of 2-PrOH. Then
piperidine (0.1 ml) was added, and the mixture was left overnight. Then 3% H2SO4 (50 ml) was added and the
mixture was refluxed for 6 h. The precipitate was filtered off and washed with H2O. The product was
recrystallized from DMF.
3-[4-(1-Oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-2-one (8a). Yield 1.53 g (82%).
Light-yellow needle-shaped crystals; mp 284-285°C. Found, %: 67.33; Н 3.18; N 3.98; S 8.37. C21H11O4S.
Calculated, %: С 67.55; Н 2.97; N 3.75; S 8.59.
6-Bromo-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-2-one (8b). Yield 1.99 g
(88%). Light-yellow needle-shaped crystals; mp >330°C. Found, %: С 55.97; Н 2.22; Вr 17.46; N 2.93; S 7.21.
C21H10BrNO4S. Calculated, %: С 55.77; Н 2.23; Вr 17.67; N 3.10; S 7.09.
6-Nitro-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-2-one (8c). Yield 1.78 g
(85%). Yellow needle-shaped crystals; mp >330°C. Found, %: С 60.37; Н 2.42; N 6.68; S 7.63. C21H10N2O6S.
Calculated, %: С 60.29; Н 2.41; N 6.70; S 7.66.
7-Hydroxy-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-2-one (8d). Yield 1.40 g
(72%). Fine dark-yellow crystals; mp >330°C. Found, %: С 64.51; Н 2.94; N 3.52; S 8.35. C21H11O5S.
Calculated, %: С 64.78; Н 2.85; N 3.60; S 8.23.
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7-Methoxy-3-[4-(1-oxo-1H-isochromen-3-yl)-1,3-thiazol-2-yl]-2H-chromen-2-one (10). A suspension of
compound 8d (0.97 g, 2.5 mmol), Me2SO4 (0.35 ml, 3.5 mmol), and K2CO3 (0.70 g, 5.0 mmol) was refluxed
with stirring in acetone (20 ml) for 2-2.5 h. Water (50 ml) was added, and the precipitate was filtered off and
washed with water. The product was recrystallized from DMF. Yield 0.87 g (86%). Fine yellow crystals; mp >
330°C (decomp.). Found, %: С 65.34; Н 3.38; N 3.32; S 7.86. C22H13NO5S. Calculated, %: С 65.50; Н 3.25;
N 3.47; S 7.95.
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