Efficient synthesis of methyl 4-chloro-6-fluoro-3-formyl-2H-chromene-2- carboxylate and its derivatives

Article abstract of DOI:10.1007/s00706-011-0595-2

Methyl 4-chloro-6-fluoro-3-formyl-2H-chro-mene-2-carboxylate was synthesized conveniently using Vilsmeier reagent. A series of new 2H-chromenes was prepared in high yields by introducing a corresponding β- halovinylaldehyde into condensation and cyclization reactions with active methylene compounds.

Full text of DOI:10.1007/s00706-011-0595-2

Monatsh Chem (2012) 143:165–170
DOI 10.1007/s00706-011-0595-2
ORIGINAL PAPER
Efficient synthesis of methyl 4-chloro-6-fluoro-3-formyl-2H-
chromene-2-carboxylate and its derivatives
•
Andrii I. Kysil Viktoria S. Moskvina
•
•
Marian V. Gorichko Volodimyr P. Khilya
Received: 8 March 2011 / Accepted: 16 July 2011 / Published online: 24 August 2011
Ó Springer-Verlag 2011
Abstract Methyl 4-chloro-6-fluoro-3-formyl-2H-chro-
mene-2-carboxylate was synthesized conveniently using
Vilsmeier reagent. A series of new 2H-chromenes was
prepared in high yields by introducing a corresponding
b-halovinylaldehyde into condensation and cyclization
reactions with active methylene compounds.
Results and discussion
In this paper, we report our results regarding the synthesis of
novel methyl 4-chloro-6-fluoro-3-formyl-2H-chromene-2-
carboxylate (6) from methyl 6-fluoro-4-oxochromane-2-
carboxylate (5) and studying its reactions with active
methylene compounds. It is well known that b-halo-
vinylaldehydes have been extensively employed as versatile
reactive intermediates in the synthesis of a large variety of
aliphatic, aromatic, and heterocyclic compounds [7]. It
should be noted that carboxylate 5 and its corresponding
carboxylic acid were used as key intermediates in the syn-
thesis of fidarestat, a potent inhibitor of aldose reductase
used to treat incurable complications of diabetes [8, 9].
Methyl 6-fluoro-4-oxochromane-2-carboxylate (5) [10]
reacted with Vilsmeier reagent to afford the corresponding
novel b-chlorocarboxyaldehydederivative6 only(Scheme 1).
Transformation via Vilsmeier’s methodology has
already been described for other simple benzopyranones,
but examples are scarce [11–13]. Literature sources also
contain data about the Vilsmeier formylation of 7-meth-
oxy-2,2,-dimethyl-4-chromanones, which were readily
converted into 4-chloro-6-formyl-7-methoxy-2,2-dimethyl-
2H-chromenes with high yields (up to 80%) [14, 15].
Methyl 4-chloro-6-fluoro-3-formyl-2H-chromene-2-car-
boxylate (6) was then introduced into the reaction, with
malononitrile and hetarylacetonitriles 8a–8i acting as 1,3-
C,N-binucleophiles.
Keywords Chromanes ꢀ Chromenes ꢀ
b-Halovinylaldehydes ꢀ Hetarylacetonitriles ꢀ Condensation
Introduction
Chromanes and 2H-chromenes constitute two important
classes of oxygen-containing heterocycles which have
attracted significant synthetic interest due to their reactivity
and biological activity of naturally occurring representa-
tives [1, 2]. Members of these classes, such as sorbinil (1)
[3] and 2 [4], have demonstrated aldose reductase inhibi-
tion properties which can be used in the treatment of
complications of diabetes; others such as antioxidants 3 [5]
or insulin secretion inhibitors 4 [6] possess the potential to
be biological ‘‘response modifiers’’ (Fig. 1). All of these
compounds contain the benzopyran moiety, but the limited
number of reported compounds prohibits an assessment of
how their key functional groups influence inhibitory
activity.
In each case, mild conditions were used (heating during
20–30 min in i-PrOH or DMF), and products of conden-
sation 7 and 9a–9i were obtained with good yields
(Scheme 2, Table 1). Continuous reflux of product 9a in
DMF for 2 h led to the intramolecular nucleophilic sub-
A. I. Kysil ꢀ V. S. Moskvina (&) ꢀ M. V. Gorichko ꢀ
V. P. Khilya
Department of Chemistry, Kyiv National Taras Shevchenko
University, Kyiv, Ukraine
e-mail: v.moskvina@gmail.com
stitution of the chlorine atom and resulted in
a
heterocyclization product 10 (Scheme 3). Based on the
123

166
A. I. Kysil et al.
Me
H
Table 1 Reactions of chloroaldehyde 6 with hetarylacetonitriles 8
O
O
Hetarylacetonitrile 8a–8i Product 9a–9i
Solvent Time/
min
F
F
O
COOH
HO
HN
DMF
20
NH
O
NC
N
O
O
1
O
Me
N
H
8a
2
F
O
Me
Me
Cl
O
MeO
O
HN
OH
CN
N
F
HO
9a
HN
Me
O
O
DMF
20
3
4
Me
Me
O
NC
N
O
O
Me
Fig. 1 Biologically active compounds containing the chromane
skeleton
N
H
8b
F
Cl
HN
CN
O
O
O
N
O
O
O
Me
O
O
Vilsmeier reagent
r.t., 4-6 h
Me
Me
Me
9b
F
F
Cl
5
6
DMF
20
NC
O
N
N
Scheme 1
O
O
Me
Me
F
F
F
Cl
Me N
8c
O
CN
O
N
N
N
O
Malononitrile
9c
i-PrOH
Me
F
O
O
Cl
NC
O
DMF
20
CN
O
NC
O
N
N
7
Me
O
F
O
Me
O
Cl
F
O
6
F
8a-8i
O
Cl
i-PrOH or DMF
8d
Me
F2HC
N
CN
F
Cl
Het
CN
9d
9a-9i
Scheme 2
i-PrOH 30
O
NC
Ph
N
O
O
Me
mild conditions required for the reaction, the Z-configura-
tion was assigned to compound 9a; such heterocyclization
reaction would not be so easily possible for an E-isomer.
N
Cl
N
8e
Ph
1
CN
The vinyl proton signal in the H NMR spectra of 9a–9i is
found at 6.36–6.61 ppm, implying that the configuration is
the same for all of these compounds.
9e
The b-chlorocarboxyaldehyde derivative 6 also reacted
with methyl mercaptoacetate in methanol under reflux in
the presence of potassium bicarbonate to give methylthie-
nocarboxylic ester derivative 11 (Scheme 4).
123

Synthesis of methyl 4-chloro-6-fluoro-3-formyl-2H-chromene-2-carboxylate
Table 1 continued
167
O
O
O
O
O
Hetarylacetonitrile 8a–8i Product 9a–9i
Solvent Time/
min
O
COOMe
MeOH, KHCO3
O
HS
Me
Me
F
F
i-PrOH 30
S
Cl
NC
O
O
S
O
6
O
Me
Me
O
N
11
Me
F
Cl
S
8f
Scheme 4
CN
N
Conclusions
9f
Me
To summarize, we have developed an efficient synthetic
route to novel methyl-4-chloro-6-fluoro-3-formyl-2H-
chromene-2-carboxylate and have studied its condensation
and cyclization reactions with various active methylene
compounds. The initial and obtained compounds contain
the potentially bioactive 2H-chromene skeleton, and a study
targeted at learning their biological activity is in progress.
i-PrOH 30
O
N
NC
O
O
Me
F
8g
Cl
CN
N
9g
i-PrOH 30
Experimental
N
Me
O
NC
O
N
O
Me
Reaction flow and the identity of obtained compounds was
controlled by TLC on Merck F254 plates using chloro-
form:methanol (9:1, v/v) as the eluent. Melting points were
determined using a Kofler-type Leica Galen III micro hot
stage microscope. NMR spectra were recorded on a Mer-
cury-400 spectrometer (spectrometer frequency for 1H:
400 MHz, 13C: 100 MHz) from DMSO-d6 solutions. The
TMS signal was used as an internal standard. Elemental
analyses for C, H, and N were conducted using a Perkin-
Elmer C, H, N Analyzer; their results were found to be in
good agreement ( 0.2%) with the calculated values. Mass
spectra were recorded on an Agilent 1100 LC/MSD
instrument with chemical ionization (CI).
Me
F
Cl
N
8h
Me
CN
N
Me
9h
DMF
30
N
O
NC
O
HN
O
Me
Br
F
O
Cl
HN
8i
O
CN
N
4-Chloro-6-fluoro-3-formyl-2H-chromene-2-carboxylate
(6, C12H8ClFO4)
Br
9i
To a mixture of 4.18 g DMF (57 mmol) and 7 g POCl3
(46 mmol) in an ice bath at 0–5 °C, a solution of 6.2 g 5
(28 mmol) in 30 cm3 CH2Cl2 was added dropwise while
maintaining the reaction temperature below 20 °C. After
addition was completed, the reaction was continued at
50 °C for 2 h and then poured over crushed ice. The
aqueous layer was extracted twice with 50 cm3 CH2Cl2.
The combined CH2Cl2 extracts were dried over sodium
sulfate and evaporated under reduced pressure. Purification
by recrystallization from MeOH afforded the title com-
pound as an off-white solid (5.8 g, 77%). M.p.: 126–
128 °C; 1H NMR (400 MHz, DMSO-d6): d = 10.12
O
O
O
O
N
O
O
DMF
2 h
Me
Me
F
F
Cl
HN
CN
CN
N
N
9a
10
3
4
(s, 1H, CHO), 7.44 (dd, JHF = 8.0 Hz, JHH = 3 Hz,
3
1H), 7.30 (td, JHF = 8.0 Hz, JHH = 3 Hz, JHH = 8 Hz,
4
3
Scheme 3
123

168
A. I. Kysil et al.
4
3
4
8.0 Hz, JHH = 3 Hz, JHH = 8 Hz, 1H), 7.37 (s, 1H),
3
1H), 7.12 (dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H), 5.87
(s, 1H), 3.62 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 193.4, 172.6, 155.3, 153.2, 150.1, 137.9, 127.6,
117.4, 115.3, 112.6, 78.4, 54.2 ppm; MS: calcd. for
C12H8ClFO4 270.64, found 270.64.
4
3
7.25 (dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H), 6.61 (s, 1H),
3.71 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 172.6, 155.1, 153.2, 141.5,
146.4, 135.6 (2C), 134.1, 130.2 (2C), 127.9, 127.4, 118.4,
115.7, 115.8, 115.2 (2C), 112.2, 111.7, 82.3, 52.4, 21.0
(2C) ppm; MS: calcd. for C23H17ClFN3O3 437.85, found
437.85.
General procedure for the reaction
of b-chlorocarboxyaldehyde 6 with nitriles
Methyl 4-chloro-3-[(Z)-2-cyano-2-(1-methyl-1H-
benzimidazol-2-yl)vinyl]-6-fluoro-2H-chromene-
2-carboxylate (9c, C22H15ClFN3O3)
To a mixture of 10 cm3 i-PrOH or DMF (see Table 1) and
0.27 g chloroaldehyde 6 (1 mmol), the nitrile (1.2 mmol)
was added with stirring. The resulting mixture was refluxed
and stirred for 20–30 min and evaporated to dryness. The
residue was subjected to appropriate purification.
Obtained from chloroaldehyde 6 in 0.38 g (90%) yield
after column chromatography (CH2Cl2 as the eluent) as an
orange solid. M.p.: 168–170 °C; 1H NMR (400 MHz,
Methyl 4-chloro-3-(2,2-dicyanovinyl)-6-fluoro-
DMSO-d6): d = 8.19 (s, 1H, CHC(CN)), 7.66 (dd, 3JHH
=
4
6.4 Hz, JHH = 2.8 Hz, 2H), 7.40 (dd, JHF = 8.0 Hz,
3
2H-chromene-2-carboxylate (7, C15H8ClFN2O3)
Obtained from chloroaldehyde 6 in 0.3 g (96%) yield after
column chromatography (CH2Cl2 as the eluent) as a yellow
3
4
4JHH = 3 Hz, 1H), 7.32 (td, JHF = 8.0 Hz, JHH = 3 Hz,
3JHH = 8 Hz, 1H), 7.27 (dd, JHH = 6.4 Hz, JHH
=
3
4
1
4
3
solid. M.p.: 173–175 °C; H NMR (400 MHz, DMSO-d6):
2.8 Hz, 2H), 7.15 (dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H),
6.55 (s, 1H), 4.04 (s, 3H), 3.74 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 172.8, 155.1, 153.2, 141.5,
146.1, 138.9, 134.4, 134.0, 127.9, 127.4, 123.0 (2C), 118.6,
115.7, 115.8, 115.2 (2C), 112.2, 111.7, 82.2, 52.4,
35.9 ppm; MS: calcd. for C22H15ClFN3O3 423.83, found
423.83.
3
d = 8.30 (s, 1H, CHC(CN)2), 7.53 (dd, JHF = 8.0
4
Hz, JHH = 3 Hz, 1H), 7.46 (td, JHF = 8.0 Hz, JHH
3
4
=
3
4
3 Hz, JHH = 8 Hz, 1H), 7.24 (dd, JHF = 4.0 Hz,
3JHH = 8 Hz, 1H), 6.40 (s, 1H), 3.66 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 172.6, 155.4, 153.4,
153.6, 134.4, 127.6, 127.9, 115.8, 115.4, 113.6 (2C), 112.5,
105.3, 81.5, 52.5 ppm; MS: calcd. for C15H8ClFN2O3
318.69, found 318.69.
Methyl 4-chloro-3-[(Z)-2-cyano-2-[1-(difluoromethyl)-
1H-benzimidazol-2-yl]vinyl]-6-fluoro-2H-chromene-2-
carboxylate (9d, C22H13ClF3N3O3)
Methyl 3-[(Z)-2-(1H-benzimidazol-2-yl)-2-cyanovinyl]-
4-chloro-6-fluoro-2H-chromene-2-carboxylate
(9a, C21H13ClFN3O3)
Obtained from chloroaldehyde 6 in 0.44 g (96%) yield
after column chromatography (CH2Cl2 as the eluent) as an
orange solid. M.p.: 144–146 °C; 1H NMR (400 MHz,
DMSO-d6): d = 8.37 (t, 2JHF = 57.6 Hz, 1H, CHF2), 7.99
Obtained from chloroaldehyde 6 in 0.38 g (95%) yield after
column chromatography (CH2Cl2 as the eluent) as an orange
1
2
solid. M.p.: 201–204 °C; H NMR (400 MHz, DMSO-d6):
(s, 1H, CHC(CN)), 7.91 (d, JHH = 8 Hz, 1H), 7.86
2
(d, JHH = 8 Hz, 1H), 7.56 (dd, JHF = 8.0 Hz, JHH
3
4
d = 13.21 (br s, 1H, NH), 8.28 (s, 1H, CHC(CN)), 7.65 (dd,
=
=
4
3
2
2
3 Hz, 1H), 7.53 (d, JHH = 8 Hz, 1H), 7.50 (d, JHH
3JHH = 6.4 Hz, JHH = 2.8 Hz, 2H), 7.49 (dd, JHF = 8.0
4
3
4
3
4
Hz, JHH = 3 Hz, 1H), 7.37 (td, JHF = 8.0 Hz, JHH
3 Hz, 3JHH = 8 Hz, 1H), 7.33 (dd, 3JHH = 6.4 Hz, 4JHH
=
=
8 Hz, 1H), 7.44 (td, JHF = 8.0 Hz, JHH = 3 Hz,
3JHH = 8 Hz, 1H), 7.29 (dd, 4JHF = 4.0 Hz, 3JHH = 8 Hz,
1H), 6.57 (s, 1H), 3.74 (s, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 172.8, 155.1, 153.2, 141.6, 146.0, 138.9,
138.6, 134.2, 134.0, 127.9, 127.4, 122.8 (2C), 118.8, 115.6,
115.8, 115.4 (2C), 112.3, 111.6, 82.1, 52.3 ppm; MS:
calcd. for C22H13ClF3N3O3 459.81, found 459.81.
4
3
2.8 Hz, 2H), 7.21 (dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H),
6.59 (s, 1H), 3.67 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 172.8, 155.3, 153.4, 141.6, 146.3, 138.9 (2C),
134.2, 127.9, 127.4, 123.0 (2C), 116.4, 115.7, 115.8, 115.3
(2C), 112.3, 111.6, 82.4, 52.6 ppm; MS: calcd. for
C21H13ClFN3O3 409.80, found 409.81.
Methyl 3-[(Z)-2-(1-benzyl-1H-imidazol-2-yl)-2-
cyanovinyl]-4-chloro-6-fluoro-2H-chromene-2-
carboxylate (9e, C24H17ClFN3O3)
Methyl 4-chloro-3-[(Z)-2-cyano-2-(5,6-dimethyl-1H-
benzimidazol-2-yl)vinyl]-6-fluoro-2H-chromene-2-
carboxylate (9b, C23H17ClFN3O3)
Obtained from chloroaldehyde 6 in 0.37 g (84%) yield
after column chromatography (CH2Cl2 as the eluent) as a
yellow solid. M.p.: 78–80 °C; 1H NMR (400 MHz,
DMSO-d6): d = 7.59 (s, 1H), 7.53 (s, 1H), 7.38 (m, 3H),
7.31 (m, 2H), 7.20 (s, 1H, CHC(CN)), 7.15 (dd,
Obtained from chloroaldehyde 6 in 0.4 g (91%) yield after
recrystallization from i-PrOH as an orange solid. M.p.:
1
229–230 °C; H NMR (400 MHz, DMSO-d6): d = 13.28
(br s, 1H, NH), 8.27 (s, 1H, CHC(CN)), 7.52 (s, 1H), 7.50
3
4
(dd, JHF = 8.0 Hz, JHH = 3 Hz, 1H), 7.41 (td, JHF
3
4
3
=
3JHF = 8.0 Hz, JHH = 3 Hz, 1H), 7.10 (td, JHF
=
123

Synthesis of methyl 4-chloro-6-fluoro-3-formyl-2H-chromene-2-carboxylate
169
8.0 Hz, 4JHH = 3 Hz, 3JHH = 8 Hz, 1H), 7.08 (dd, 4JHF
=
d = 172.6, 164.9, 164.8, 163.4, 155.1, 153.2, 146.2, 134.2,
127.9, 127.4, 118.6, 115.8, 115.5, 111.6, 112.5, 112.2,
82.2, 52.2, 25.5 (2C) ppm; MS: calcd. for C20H15ClFN3O3
399.81, found 399.81.
4.0 Hz, 3JHH = 8 Hz, 1H), 6.36 (s, 1H), 5.52 (s, 2H, CH2),
3.57 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 172.4, 157.8, 156.5, 149.7, 140.6, 138.2, 137.2,
129.8, 129.2, 129.1, 128.1, 126.7, 126.1, 123.8, 121.5,
121.4, 120.2, 118.7, 116.3, 112.8, 105.1, 82.9, 53.2,
52.2 ppm; MS: calcd. for C24H17ClFN3O3 449.86, found
449.86.
Methyl 3-[(Z)-2-(6-bromo-3,4-dihydro-4-oxoquinazolin-2-
yl)-2-cyanovinyl]-4-chloro-6-fluoro-2H-chromene-2-
carboxylate (9i, C22H12BrClFN3O4)
Obtained from chloroaldehyde 6 in 0.48 g (93%) yield after
recrystallization from i-PrOH as an orange solid. M.p.:
Methyl 4-chloro-3-[(Z)-2-cyano-2-(4-methyl-1,3-thiazol-
2-yl)vinyl]-6-fluoro-2H-chromene-2-carboxylate
(9f, C18H12ClFN2O3S)
1
[250 °C; H NMR (400 MHz, DMSO-d6): d = 13.19 (br
s, 1H), 8.27 (s, 1H, CHC(CN)), 8.21 (s, 1H), 8.10 (d,
2JHH = 8.8 Hz, 1H), 7.68 (d, 2JHH = 8.4 Hz, 1H), 7.47 (dd,
3JHF = 8.0 Hz, 4JHH = 3 Hz, 1H), 7.38 (td, 3JHF = 8.0 Hz,
4JHH = 3 Hz, 3JHH = 8 Hz, 1H), 7.21 (dd, 4JHF = 4.0 Hz,
3JHH = 8 Hz, 1H), 6.47 (s, 1H), 3.65 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 172.8, 160.6, 156.8,
155.2, 153.2, 151.4, 146.1, 136.4, 134.2, 132.5, 127.9,
127.4, 124.6, 123.2, 121.8, 116.8, 115.8, 115.4, 112.5,
112.2, 82.1, 52.4 ppm; MS: calcd. for C22H12BrClFN3O4
516.70, found 516.70.
Obtained from chloroaldehyde 6 in 0.37 g (97%) yield
after column chromatography (CH2Cl2 as the eluent) as a
yellow solid. M.p.: 165–167 °C; 1H NMR (400 MHz,
DMSO-d6): d = 8.14 (s, 1H, CHC(CN)), 7.56 (s, 1H), 7.43
3
4
(dd, JHF = 8.0 Hz, JHH = 3 Hz, 1H), 7.33 (td,
4
3
3JHF = 8.0 Hz, JHH = 3 Hz, JHH = 8 Hz, 1H), 7.18
4
3
(dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H), 6.47 (s, 1H), 3.65
(s, 3H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 172.4, 161.0, 158.9, 156.5, 155.1, 149.9, 135.5,
133.8, 123.6, 121.6, 120.7, 118.9, 116.2, 113.0, 108.3,
82.2, 53.6, 17.3 ppm; MS: calcd. for C18H12ClFN2O3S
390.82, found 390.82.
Methyl 8-cyano-2-fluoro-6H-chromeno[30,40:5,6]-
pyrido[1,2-a]benzimidazole-6-carboxylate
(10, C21H12FN3O3)
Methyl 4-chloro-3-[(E)-2-cyano-2-(pyridin-2-yl)vinyl]-
6-fluoro-2H-chromene-2-carboxylate
(9g, C19H12ClFN2O3)
A solution of 0.4 g 9a (1 mmol) in 5 cm3 dry DMF was
refluxed for 2 h with stirring and evaporated to dryness.
The residue was recrystallized from i-PrOH to give 0.3 g
1
Obtained from chloroaldehyde 6 in 0.34 g (91%) yield
after column chromatography (CH2Cl2 as the eluent) as a
yellow solid. M.p.: 135–137 °C; 1H NMR (400 MHz,
(82%) of 10 as a yellow solid. M.p.: [250 °C; H NMR
2
(400 MHz, DMSO-d6): d = 9.54 (s, 1H), 8.35 (d, JHH
8 Hz, 1H), 8.29 (dd, JHF = 8.0 Hz, JHH = 3 Hz, 1H),
=
3
4
2
2
7.91 (d, JHH = 8 Hz, 1H), 7.60 (t, JHH = 8.4 Hz, 1H),
2
DMSO-d6): d = 8.71 (d, JHH = 4 Hz, 1H), 8.52 (s, 1H,
2
CHC(CN)), 8.00 (t, JHH = 8 Hz, 1H), 7.79 (d,
2
3
7.49 (t, JHH = 8.4 Hz, 1H), 7.47 (td, JHF = 8.0 Hz,
4JHH = 3 Hz, 3JHH = 8 Hz, 1H), 7.32 (dd, 4JHF = 4.0 Hz,
3JHH = 8 Hz, 1H), 6.28 (s, 1H), 3.60 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 169.9, 162.9, 155.7,
153.0, 141.8, 139.6, 138.5, 135.2, 132.2, 123.8, 123.0,
123.1, 117.2, 116.1, 115.7, 115.2, 115.3, 116.7, 106.4,
87.2, 52.4 ppm; MS: calcd. for C21H12FN3O3 373.34,
found 373.34.
2JHH = 4 Hz, 1H), 7.51 (dd, 3JHF = 8.0 Hz, 4JHH = 3 Hz,
1H), 7.44 (dd, 2JHH = 7.6 Hz, 1H), 7.33 (td,
4
3
3JHF = 8.0 Hz, JHH = 3 Hz, JHH = 8 Hz, 1H), 7.19
4
3
(dd, JHF = 4.0 Hz, JHH = 8 Hz, 1H), 6.52 (s, 1H), 3.64
(s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 172.4,
155.8, 155.2, 153.4, 148.8, 145.9, 137.4, 134.2, 127.9,
127.4, 122.6, 120.6, 118.8, 115.7, 115.8, 115.1, 112.4,
82.2, 52.3 ppm; MS: calcd. for C19H12ClFN2O3 370.76,
found 370.76.
Dimethyl 8-fluoro-4H-thieno[3,2-c]chromene-2,4-
dicarboxylate (11, C15H11FO5S)
Methyl 4-chloro-3-[(Z)-2-cyano-2-(4,6-dimethylpyrimidin-
2-yl)vinyl]-6-fluoro-2H-chromene-2-carboxylate
(9h, C20H15ClFN3O3)
Methyl mercaptoacetate (0.13 g, 1.2 mmol) was added to a
solution of 0.27 g 6 (1 mmol) and 0.12 g potassium
bicarbonate (1.2 mmol) in 10 cm3 MeOH. The reaction
mixture was refluxed for 3 h and evaporated to dryness.
Then, 10 cm3 H2O were added to the residue, and the
mixture was stirred for 15 min. The precipitate was filtered
off, washed with H2O (2 9 5 cm3), and dried to give 0.3 g
Obtained from chloroaldehyde 6 in 0.36 g (90%) yield
after column chromatography (CH2Cl2 as the eluent) as a
yellow solid. M.p.: 195–197 °C; 1H NMR (400 MHz,
3
DMSO-d6): d = 8.75 (s, 1H, CHC(CN)), 7.45 (dd, JHF
8.0 Hz, JHH = 3 Hz, 1H), 7.36 (td, JHF = 8.0 Hz,
=
4
3
1
(93%) of 11 as a white solid. M.p.: 172–174 °C; H NMR
4JHH = 3 Hz, JHH = 8 Hz, 1H), 7.31 (s, 1H), 7.20 (dd,
(400 MHz, DMSO-d6): d = 7.67 (s, 1H), 7.25 (dd,
3
4JHF = 4.0 Hz, JHH = 8 Hz, 1H), 6.58 (s, 1H), 3.65 (s,
3JHF = 8.0 Hz, JHH = 3 Hz, 1H), 7.11 (td, JHF
=
3
4
3
3H), 2.35 (s, 6H) ppm; 13C NMR (100 MHz, DMSO-d6):
4
8.0 Hz, JHH = 3 Hz, JHH = 8 Hz, 1H), 7.04 (dd,
3
123

170
A. I. Kysil et al.
3
4JHF = 4.0 Hz, JHH = 8 Hz, 1H), 6.17 (s, 1H), 3.87 (s,
3H), 3.68 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 169.8, 160.6, 155.4, 152.8, 142.1, 138.7, 134.2, 132.9,
123.8, 116.8, 116.4, 116.3, 88.7, 52.4, 51.6 ppm; MS: calcd.
for C15H11FO5S 322.33, found 322.33.
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14. Brown PE, Marcus WY, Anastasis P (1985) J Chem Soc Perkin
Trans 1:1127
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