4-Chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)coumarins as novel and efficient building blocks for the regioselective synthesis of 3,4-fused coumarins

Article abstract of DOI:10.1016/j.tet.2011.08.030

4-Chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)coumarins react with electron-rich aminoheterocycles, dimethyl 1,3-acetonedicarboxylate, hydrazines, alkyl thioglycolates, and methyl sarcosinate to give a variety of 3,4-heteroannulated coumarins.

Full text of DOI:10.1016/j.tet.2011.08.030

Tetrahedron 67 (2011) 7946e7955
Contents lists available at ScienceDirect
Tetrahedron
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4-Chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)coumarins as novel and
efficient building blocks for the regioselective synthesis of 3,4-fused coumarins
,
b
,
a
a
,
,c
Viktor O. Iaroshenko a , Friedrich Erben , Satenik Mkrtchyan c, Ani Hakobyan a
,
*
Marcelo Vilches-Herrera a, Sergii Dudkin a, Alina Bunescu a e, Alexander Villinger a,
,
Vyacheslav Ya. Sosnovskikh d, Peter Langer a
,e,
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kyiv, Ukraine
c Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
d Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russia
e
€
€
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2011
Received in revised form 9 August 2011
Accepted 10 August 2011
Available online 16 August 2011
4-Chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)coumarins react with electron-rich amino-
heterocycles, dimethyl 1,3-acetonedicarboxylate, hydrazines, alkyl thioglycolates, and methyl sarcosinate
to give a variety of 3,4-heteroannulated coumarins. The starting materials were prepared by the reaction
of 4-hydroxycoumarin with trifluoroacetic anhydride and methyl 2-chloro-2-oxoacetate in the presence
of trimethylsilylchloride. An NMR study and X-ray crystallographic analysis are reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Coumarins
Heterocyclisation
Dinucleophiles
Heterocycles
Regioselectivity
1. Introduction
topoisomerase II,5 and tyrosine kinase6 inhibitors. On the other
hand, they have also found application as photosensitizers, fluo-
Coumarins (2H-1-benzopyran-2-ones, 2H-chromen-2-ones) are
very attractive targets for combinatorial library synthesis due to
their wide range of valuable biological activities. Many natural and
synthetic coumarins have occupied an important place in drug
research, as a one of the so-called privileged drug scaffold.1 The
therapeutic potential of these compounds is immense. Coumarins
have been reported to exhibit antibacterial and antifungal activity
and to act as diuretics and analgesics.2 There have also been reports
that structures containing the coumarin ring reduce tissue swelling
due to various kinds of trauma or disease, display hypolipidaemic,
vasorelaxant, antiplatelet aggregation, antioxidant, antiin-
flammatory, and immunosuppressive activities.1 Coumarins also
exhibit a variety of anticancer activities, displaying antimutagenic,
and antitumor properties.3 In addition, this scaffold is present in
promising drug candidates as nonpeptidic HIV protease inhibitors,4
rescent, and laser dyes,7 and represent useful synthetic building
blocks in organic and medicinal chemistry.8
The biological and industrial importance of coumarins has led to
a considerable amount of synthetic work in the field of coumarins
with 3,4-carbocyclic- and 3,4-heterocyclic fused ring systems.9 For
these purposes the structure most commonly used is 4-chloro-3-
formylcoumarin (1a).10,11 Being essentially gem-activated alkene
with a good leaving group (chlorine atom), this compound exhibits
a variety of properties and can react with substituted anilines,12 aryl
isocyanides,13 arylhydrazines,10,14 amidines,15 hydroxylamine,14
benzylamines,16 sodium azide,17 ethyl cyanoacetate,18 ethyl 3-
aminocrotonate,19 1,3-bis(trimethylsilyloxy)-1,3-butadienes,20 Wit-
tig phosphoranes,21 and ethyl glycinates.22 Having electron-
withdrawing formyl group at the 3-position, 1a undergo conju-
gated additioneelimination reactions with dinucleophiles at the 4-
position of the coumarin system, followed by intramolecular cycli-
zation via electrophilic formyl function to coumarins 3,4-fused
to pyrazoles, isoxazoles, pyrimidines, pyrroles, pyridines, quino-
lines and other heterocycles (formal [3þ2] and [3þ3] cycloaddi-
tions). At the same time, very scarce information is available
* Corresponding authors. Tel.: þ49 381 4986410; fax: þ49 381 49864112; e-mail
addresses: viktor.iaroshenko@unirostock.de (V.O. Iaroshenko), peter.langer@
unirostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.030

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
7947
about the reactivity of 4-chloro-3-(methoxycarbonyl)coumarin (1b)
(Scheme 1). Only two papers describing its reactions with sodium
azide23 and S-methylisothiourea24 are present in the literature. It
should be noted that all these reactions proceed via nucleophilic 1,4-
or 1,2-addition to give coumarin derivatives without opening of the
coumarin ring.
secondly, acylation by trifluoroaceticanhydride or methyl 2-chloro-2-
oxoacetate delivers in situ the corresponding acetylated in-
termediates, which were treated with POCl3 to form 2a,b in excellent
yield. This reaction sequence is a straightforward and convenient
route to 4-chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)
coumarins (2a,b), which makes these previously unknown com-
pounds suitable for further investigations and has advantages with
regard to ease of operation and the ready availability of starting ma-
terials. Although the method represents a three-step process, it is
experimentallysimple and may be of valuein CF3-containing building
blocks chemistry.
Cl
O
Cl
O
H
OMe
O
1a
O
O
1b
O
4-Chloro-3-(trifluoroacetyl)coumarin (2a) is, as previously de-
scribed for 3-(trifluoroacetyl)coumarins,32 sensitive to moisture.
Therefore, all reactions and storage was performed under dry inert
atmosphere. Compounds 2a,b are stable in dry and inert solvents
under inert atmosphere at least for 48 h. This gave us a chance to
use NMR spectroscopy to confirm their structure and purity.25
Continuing our research program dedicated to the design and
synthesis of novel fused pyridines and in view of the unique bi-
ological properties displayed by many coumarin derivatives1 we
have started our investigation in this area by the study of the re-
actions of 2a,b with electron-rich aminoheterocycles 3e7 (Fig. 1) in
order to obtain the corresponding 5H-chromeno[3,4-c]pyridin-5-
one ring system. The latter represents an important synthetic tar-
get due to its interesting biological properties.9,19,33
OH
Cl
O
O
i, ii, iii
R
O
O
O
2a,b
i
iii
TMS
O
TMS
O
O
O
R
ii
O
O
O
R = CF3 (2a, 93%), R = CO2Me (2b, 94%)
Scheme 1. One-pot three step synthesis of 4-chloro-3-(trifluoroacetyl)- and 4-chloro-
3-(methoxalyl)coumarins (2a,b). Reagents and conditions: (i) 1,4-dioxane, Py
(2.1 equiv), 30 min, TMSCl (1.2 equiv), 60 min, rt; (ii) TFAA or ClCOCO2Me (1.3 equiv),
2 h, 80e90 ꢀC; (iii) POCl3 (1.0 equiv), 60 ꢀC, 2 h.
Me
S
N
N
S
R
NH2
N
NH2
We envisaged that introduction of such powerful electron-
withdrawing groups as trifluoroacetyl and methoxalyl into the 3-
position of 4-chlorocoumarin would increase its reactivity toward
nucleophilic reagents and open up a broad synthetic scope of this
important oxygen-containing heterocyclic system. So far, 4-chloro-
3-(trifluoroacetyl)coumarin (2a) and 4-chloro-3-(methoxalyl)
coumarin (2b) have not received much attention despite their
potential interest as building blocks in organic synthesis for
the construction of 3,4-fused coumarins (Scheme 1). To the best of
our knowledge, there has been only our preliminary communica-
tion on the synthesis of 2a and its reaction with aromatic amines.25
On the other hand, 3-substituted chromones (3-formyl-,26 3-
R
4a: R = NMe2
4b: R = N(CH2)5
3a: R = Ph
3b: R = Et
O
NC
Me
N
NH2
-Bu
N
R
O
N
Me
NH2
6
5a: R =
t
5b: R = cyclohexyl
5c: R = cyclopentyl
Me
5d: R =
5e: R =
p
-tolyl
trifluoroacetyl-,27 3-dichloroacetyl-,28 3-methoxalyl-,29 3-cyano-
N
n
-hexyl
NH2
N
Ph
30
and 3-nitrochromones31) are widely used as valuable synthetic
5f: R = 2-Me-cyclohexyl
5g: R = 4-MeO-benzyl
,
7
intermediates in the preparation of pharmacologically relevant
products and new heterocyclic systems.
Fig. 1. Electron-rich heterocyclic amines 3e7 used for the synthesis of 3,4-
Based on the retrosynthetic analysis and on our previous work
related to the development of new cyclocondensation reactions of
electron-rich aminoheterocycles and other dinucleophilic
reagents,27e31 we envisaged that compounds 2a,b are suitable
substrates for the synthesis of 3,4-heteroannulated coumarins. We
are reporting now on the formation of this type of heterocycles from
coumarins 2a,b as 1,3-dielectrophiles and various 1,3-dinucleophiles
(heterocyclic amines, morpholine-4-carboxamidine, dimethyl 1,3-
acetonedicarboxylate) and 1,2-dinucleophiles (hydrazines, alkyl
thioglycolates, methyl sarcosinate).
heteroannulated coumarins.
After some optimization, it was found that treatment of cou-
marins 2 with amines 3e6 (1.1 equiv) in dry DFM at 100e120 ꢀC for
2e12 h in the presence of TMSCl as a water scavenger resulted in
the formation of heteroannulated chromeno[3,4-c]pyridin-5-ones
8aer with an excellent regioselectivity and in good yields
(54e85%). In most cases, the reaction was complete after 6e8 h and
the products could be isolated by simple filtration of the precipitate
formed or by column chromatography over silica gel. The progress
of the reaction was monitored by TLC, and the results are sum-
marized in Scheme 2. Note that coumarin 2a is more reactive than
2b, which failed to react with 4a,b and 6. It is important that a wide
range of 2-aminopyrroles 5aeg can effectively participate in the
reaction with 2a,b, providing a variety of chromeno[4,3-d]pyrrolo
[2,3-b]pyridines 8fep in moderate to good yield (38e72%). The
analogous reaction of 4-chloro-3-formylcoumarin (1a) with 5a
gave compound 8q in 40% yield. The regiochemistry of 8b, 8f, and
2. Results and discussion
In the initial study we have developed the synthesis of the hitherto
unknown 4-chloro-3-(trifluoroacetyl)- and 4-chloro-3-(methoxalyl)
coumarins (2a,b) starting from commercially available 4-
hydroxycoumarin by a one-pot procedure depicted in Scheme 1.
The synthetic route consistsof threesteps: firstly, 4-hydroxycoumarin
was silylated by TMSCl in dioxane using dry pyridine as HCl acceptor;

7948
V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
8g was unambiguously confirmed by X-ray single crystal analyses
(Figs. 3e5). This result clearly shows that the present methodology
could be applicable to various types of heterocyclic amines, pro-
viding a rapid route to the synthesis of a wide range of the heter-
oannulated pyridines fused to 3,4-position of the coumarin,
including CF3-containing derivatives.
O
N
N
N
O
N
O
N
O
N
O
CF3
CF3
10a (60%)
10b (80%)
OH
Cl
O
O
N
O
Me
MeO2C
CO2Me
CF3
N
N
R
R
+
CF3
NH2
3-7
O
2a,b
O
8a-r
O
O
O
O
10c (88%)
11a (70%)
-H2O
-HCl
Ph
N
Ph
NH2
COR
NH
N
N
N
OH
R
CF3
CO2Me
O
A
O
O
B
O
O
O
O
O
11b (59%)
11c (62%)
Fig. 2. Structures of the products obtained.
S
R'
R'
N
N
N
S
Me
N
N
R
CF3
O
O
O
O
8a: R = CO2Me, R' = Et (74%)
8b: R = CF3, R' = Ph (85%)
8c: R = CO2Me, R' = Ph (82%)
8d: R' = NMe2 (54%)
8e: R' = N(CH2)5 (63%)
8f: R = CF3, R' =
t
-Bu (72%)
R'
N
8g: R = CO2Me, R' = -Bu (53%)
t
8h: R = CF3, R' = cyclohexyl (46%)
8i: R = CF3, R' = cyclopentyl (58%)
8j: R = CO2Me, R' = cyclopentyl (38%)
NC
N
R
8k: R = CO2Me, R' =
p-tolyl (42%)
8l: R = CF3, R' = -hexyl (45%)
n
O
O
O
8m: R = CF3, R' = 2-Me-cyclohexyl (44%)
8n: R = CO2Me, R' = 2-Me-cyclohexyl (40%)
8o: R =CF3, R' = 4-MeO-benzyl (41%)
8p: R =CO2Me, R' = 4-MeO-benzyl (55%)
8q: R = H, R' =
t
-Bu (40%)
Fig. 3. Molecular structure of compound 8b.
Ph
N
Me
O
Me
N
N
N
N
N
Me
CF3
CF3
O
O
O
O
8r (73%)
9
(51%)
Scheme 2.
Analyzing the crystal structures of compounds 8b, 8f, and 8g,
which at first glance should be planar, it was found that in the case
of CF3-substituted pyridines 8b and 8f the heterocyclic core is
twisted. The chiefly points of distortion in both structures are a-
pyrone rings; the corresponding dihedral angles for 8f are C(7)
C(6)eC(14)O(1) of 4.1(2)ꢀ, C(6)C(5)eC(16)C(15) of 12.4(2)ꢀ, and
C(14)C(6)eC(7)C(13) of 13.1(2)ꢀ. Distortion of the planar geometry
was also observed for 8b, the molecular conformation of which is
more twisted, dihedral angle C(13)C(12)eC(17)C(O2) is 10.8(2)ꢀ,
C(12)C(11)eC(15)C(16) is 17.8(1)ꢀ, and C(17)C(12)eC(13)C(14) is
16.4(1)ꢀ. In contrary, in the case of 8g, the core of heterocyclic
framework is planar, the carbonyl group is out of the plane of the
heterocycle, dihedral angle N(1)C(5)eC(13)O(1) was detected to be
Fig. 4. Molecular structure of compound 8f.

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
7949
X-ray diffraction analysis.15 Molecules of this type consist of five
planar ring fragments, however their molecular conformation ap-
parently cannot be planar due to repulsion of the hydrogen atoms
at C-1 and C-13. Hence, these molecules have a helical conforma-
tion and are chiral even though there are no asymmetric atoms,
possessing so-called helical chirality.
The reaction of coumarin 2a with dimethyl 1,3-acetonedi-
carboxylate in dioxane in the presence of triethylamine gave the
expected benzo[c]coumarin 10c in 88% yield, whereas the similar
reaction of 2b afforded a complex mixture of many unidentified
products as well as low quantities of the corresponding triester,
which was not isolated in a pure form (Fig. 2). The formation of
compounds 10aec can proceed via both the 1,4- and 1,2-addition of
the nitrogen or carbon atom of a 1,3-dinucleophile with subsequent
ring closure, however we prefer the first mechanism since only
4-anilino-3-(trifluoroacetyl)coumarins are formed in high yields in
the reaction of 2a with aromatic amines.25
Fig. 5. Molecular structure of compound 8g.
Further experiments were conducted to expand the utility of the
reaction and substrate scope with a series of 1,2-dinucleophiles,
such as hydrazines, alkyl thioglycolates, and methyl sarcosinate. We
found that coumarin 2a, when treated with methylhydrazine in
refluxing toluene, underwent transformation into 1-methyl-3-
(trifluoromethyl)chromeno[4,3-c]pyrazol-4(1H)-one 11a (70%
yield). This reaction exhibits high regioselectivity and pyrazole 11a
was isolated as the single product, the structures of which were
independently confirmed by X-ray crystal structure analysis (Fig. 6).
The formation of this pyrazole may be rationalized by initial 1,4-
addition of the more nucleophilic secondary nitrogen atom of
methylhydrazine on the C-4 atom of 2a with concomitant elimi-
nation of HCl followed by the intramolecular attack at the CF3CO
group by the primary amino group. Attempts to use coumarin 2b in
the reaction with methylhydrazine failed to produce the desired
product, affording a complex mixture of unidentified compounds.
It is of interest that coumarins 2a,b react in different manner
with phenylhydrazine to provide a completely different regio-
chemistry. Treatment of 2a,b with phenylhydrazine in refluxing
toluene produced 2-phenylchromeno[4,3-c]pyrazol-4-ones 11b,c
in 59e62% yields (Fig. 2). The choice between 2-phenyl- and 1-
phenylchromeno[4,3-c]pyrazoles was made in favor of the former
on the basis of spectroscopic data. It is known that a carbon adja-
cent to a substituted nitrogen (pyrrole-like) resonates upfield of the
signal of that same carbon in the other isomer (pyridine-like) in
isomeric pyrazoles.34 The 13C NMR spectra of 11a and 11b clearly
demonstrated their structures by comparison of the C-3 signals (for
11a 137.7 ppm, q, 2JC,F¼38.1 Hz; for 11b 132.4 ppm, q, 2JC,F¼41.0 Hz).
Moreover, a similar increase in 2JC,F values has been noted earlier for
N-substituted 3-CF3- and 5-CF3epyrazoles. On the whole, the
77.1(2)ꢀ. The logical explanation of this fact can be given by taking
into account the van der Waals radii of the CF3 group, which by the
overlapping with carbonyl group in its vicinity triggers visible
distortion of core geometry.
Because of the ambident character of heterocyclic amine, a nu-
cleophilic attack of nitrogen or carbon on coumarin 2 would lead to
different products. The first step of the reaction leading to 8 ap-
parently involves an attack of the internal enamine b-carbon (in
general, this atom is more nucleophilic than the primary amino
group) at C-4 of 2 with concomitant elimination of HCl (in-
termediate A). Subsequent intramolecular attack of the amino
group at the carbonyl group via intermediate B leads to the fused
coumarin derivatives 8. At the same time, for the initial attack of the
4-position by the amino group the reaction through the elimi-
nationering-closure sequence would result in isomeric
g-
CF3epyridines. This direction was observed only in the case of 5-
amino-3-methyl-1-phenylpyrazole (7), which reacts with couma-
rin 2a as an aromatic amine25 to give under the same conditions
compound 9 with a completely different regiochemistry pattern
(yield 51%, Scheme 2). The exact structure of 9 was established by
1H, 13C, and 19F NMR spectra, in which we have observed the ap-
pearance of a quartet of methyl protons at 2.75 ppm (6JH,F¼3.7 Hz),
quartet of methyl carbon at 16.9 ppm (5JC,F¼6.8 Hz), and quartet of
the CF3 group at ꢁ55.0 ppm (6JF,H¼3.7 Hz). This can be regarded as
a prove for structure 9, where the methyl and trifluoromethyl
groups are situated near each other.
Thus, the most important step determining the structure of
a product is the addition to the first center of dinucleophile. From
this point of view, it clearly appears that the less aromatic amino-
heterocycles 3e6 have a proclivity to the formation of fused
a-
CF3epyridines 8, while in aminopyrazole 7 and arylamines25 the
high degree of aromatization of the ring would be responsible for
their observed different reactivity. The reaction of heterocyclic
amines with coumarins 2 makes the latter compounds very useful
for a combinatorial approach to the synthesis of novel hetero-
annulated pyridines with potential biological activity. However, it is
necessary to mentioned that not all electron-rich aminohetero-
cycles reacted with 2 with the formation of the corresponding
pyridines; in the cases of ethyl 5-aminothiophene-2-carboxylate,
ethyl 5-aminofuran-2-carboxylate, and 5-aminouracil the reactions
failed or leaded to the mixture of inseparable regioisomers.
It was also found that the condensation of coumarin 2a with 1,3-
N,N-dinucleophiles, such as 2-aminobenzimidazole and morpho-
line-4-carboxamidine, under the same reaction conditions affords
target products 10a and 10b in high yields. Previously, non-
fluorinated analogue of chromenopyrimidobenzimidazolone 10a
was obtained by the reaction of 2-aminobenzimidazole with 1a in
the presence of triethylamine and its structure was confirmed by
Fig. 6. Molecular structure of compound 11a.

7950
V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
constant 2JC,F for N-substituted 3-CF3epyrazoles ranges from 36 to
40 Hz, while that for 5-CF3epyrazoles is known to vary from 38 to
43 Hz.35 Additional support for the assignments was provided by
the 1H NMR spectra of 11aec on the basis of the H-9 signals, which
were observed at 8.23, 8.09, and 8.13 ppm, respectively. Because of
unfavorable steric interactions with the peri-H atom in the 1-
phenylchromeno[4,3-c]pyrazoles, the phenyl substituent should
predominantly be located in the non-planar position toward the
coumarin ring and exerts a shielding effect on the H-9 proton. As
a result, this proton should appear in a stronger field (in the series
of 1-phenylchromeno[4,3-c]pyrazol-4-ones it is observed at
6.9e7.5 ppm).34 Interestingly, although the chemistry of the tri-
cyclic chromeno[4,3-c]pyrazol-4-one system has been well docu-
mented,9,10,14,34,36 we have found that compounds 11aec are
hitherto unreported.
Fig. 7. Molecular structure of compound 12a.
Next, taking into account the above results and that the thio-
phene and pyrrole rings are important structural fragments of
many natural and biologically active substances,37 it was of interest
to evaluate the behavior of coumarins 2a,b in their reactions with
alkyl thioglycolates and methyl sarcosinate. In this context, two
papers are of interest when 4-hydroxycoumarin and 4-chloro-3-
formylcoumarin (1a) are reacted with these 1,2-dinucleophiles to
obtain the corresponding 3,4-fused coumarins.11,22 We anticipated
that alkyl thioglycolates and methyl sarcosinate might undergo
a similar [3þ2] cycloaddition with 2a,b to give 3,4-heteroannulated
coumarins 12. In fact, it was found that treatment of 2a,b with alkyl
thioglycolates or methyl sarcosinate (1.1e2.0 equiv) in dichloro-
methane or DMF in the presence of triethylamine at room tem-
perature for several hours resulted in the formation of the
previously unknown coumarin derivatives 12aee in variable yields
(24e83%).
In all cases, conjugated additioneelimination at the 4-position
takes place (intermediate A, Scheme 3) with subsequent annula-
tion of the thiophene or pyrrole core. The formation of the other
regioisomer is not observed in these examples. The structure of
the product 12a was confirmed by X-ray crystal structure analysis
(Fig. 7). In the case of 2a and methyl sarcosinate, compound 12f
was obtained as the only isolated product in 50% yield. In contrast
to the formation of chromeno[4,3-b]pyrrole 12e, no elimination of
the hydroxyl group and aromatization occurs; many attempts to
dehydrate this product failed (AcOH/reflux, p-TSA/EtOH, DMF/
TMSC). The X-ray crystal structure of 12f unambiguously con-
firmed that the CO2Me and CF3 groups are situated trans to each
other (Fig. 8).
Fig. 8. Molecular structure of compound 12f.
3. Conclusion
In conclusion, we have developed a simple and convenient
method for the synthesis of 3,4-heteroannulated coumarins by
formal [3þ3] and [3þ2] cyclocondensations of 4-chloro-3-
substituted coumarins with electron-rich aminoheterocycles, hy-
drazines, alkyl thioglycolates, and methyl sarcosinate. The products
constitute an important structural subunit of a variety of bi-
ologically active compounds, which are not readily available by
other methods. The biological evaluation of the synthesized com-
pounds is currently studied in our laboratories.
CO2R'
Cl
O
O
X
4. Experimental
4.1. General
R
HXCH2CO2R'
Et3N
R
O
2a,b
O
12a-e
O
NMR spectra were recorded on a Brucker AV 300 instruments. IR
spectra were recorded on a PerkineElmer FT IR 1600 spectrometer
(ATR). Mass spectra were obtained on a HewlettePackard HPGC/MS
5890/5972 instrument (EI, 70 eV) by GC inlet or on an MX-1321
instrument (EI, 70 eV) by direct inlet. Column chromatography
was performed on silica gel (63e200 mesh, Merck), silica gel Merck
60 F254 plates were used for TLC. All solvents were purified and
dried by standard methods. The starting 4-chloro-4-(tri-
fluoroacetyl)coumarin (2a) was prepared according to described
procedure.25
-HCl
-H2O
CO2Me
Me
X
CO2R'
COR
N
OH
CF3
O
A
O
O
O
12f (50%)
12a: X = S, R = CF3, R' = Me (83%)
12b: X = S, R = CO2Me, R' = Me (58%)
12c: X = S, R = CF3, R' = CH2CH(Et)Bu (47%)
12d: X = S, R = CO2Me, R' = CH2CH(Et)Bu (54%)
12e: X = N, R = CO2Me, R' = Me (24%)
4.1.1. Procedure for the synthesis of 4-chloro-4-(methoxalyl)couma-
rin (2b). Synthesis was conducted in a pressure tube. To the sus-
pension of 4-hydroxycoumarin (2.5 g, 15.4 mmol) in dry 1,4-
Scheme 3.

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
7951
dioxane (20 mL) was added dry pyridine (2.56 g, 32.4 mmol). After
a brief stirring, when the mixture became completely homoge-
neous, was added trimethylsilylchloride (2.01 g, 18.5 mmol). The
reaction mixture was stirred for 1 h at room temperature. Then was
added methyl oxalyl chloride (2.44 g, 20.0 mmol) and the mixture
was stirred for another 2 h at 80e90 ꢀC. To the cooled reaction mass
was added 2.36 g (15.4 mmol) of phosphorus oxychloride and the
mixture was stirred for 2 h at 60 ꢀC. Then the reaction mass was
diluted with ice water and extracted with chloroform (50 mL), the
chloroform layer was separated, and the water phase was extracted
two times with chloroform (50 mL). The combined extract was
dried under sodium sulfate, chloroform was removed and the res-
idue was dried in a high vacuum on a boiling water bath. Yield
3.83 g (94%), white solid, mp 110e112 ꢀC; 1H NMR (300 MHz, CDCl3)
2H); 13C NMR (63 MHz, DMSO-d6)
d
38.5, 52.9, 109.6, 114.1, 117.4,
122.2,124.7,125.8,128.6,129.4,129.5,132.8,134.1,148.3,149.0,151.3,
158.4, 166.1, 175.9, 179.4; MS (GC, 70 eV) m/z (%) 417 ([M]þ, 2), 317
(29), 260 (39), 43 (100); HRMS (ESI): calcd for C22H15N3O4S [MþH]þ
418.0856, found 418.0857; IR (ATR, cmꢁ1
)
n
2952 (w), 1739 (s), 1592
~
(m),1495 (w),1468 (w),1428 (m), 1366 (m), 1334 (m), 1301 (s), 1267
(m), 1217 (s), 1173 (m), 1146 (m), 1075 (m), 1040 (m), 1019 (s), 953
(m), 865 (w), 794 (m), 758 (s), 745 (s), 707 (s), 647 (m).
4.2.4. 2-(Dimethylamino)-5-(trifluoromethyl)-6H-chromeno[4,3-d]
[1,3]thiazolo[4,5-b]pyridin-6-one (8d). Yield 54%, light brown solid,
mp 251e252 ꢀC; 1H NMR (300 MHz, 80 ꢀC, DMSO-d6)
d 3.38 (s, 6H),
7.51 (d, 1H, J¼8.4 Hz), 7.57 (t, 1H, J¼7.2 Hz), 7.77 (t, 1H, J¼8.0 Hz),
8.22 (d, 1H, J¼8.0 Hz); 19F NMR (282 MHz, DMSO-d6)
ꢁ62.8 (CF3);
d
d
3.93 (s, 3H), 7.37e7.46 (m, 2H), 7.69e7.74 (m, 1H), 8.01 (dd, 1H,
MS (GC, 70 eV) m/z (%) 365 ([M]þ, 100), 350 (24), 336 (71), 330 (44),
J¼8.0, 1.4 Hz); 13C NMR (63 MHz, CDCl3)
d
53.5, 117.2, 117.7, 121.4,
316 (34); HRMS (ESI): calcd for C16H10F3N3O2S [MþH]þ 366.05186,
found 366.05212; IR (ATR, cmꢁ1
)
n
2953 (w),1742 (s),1611 (m),1586
~
125.6, 127.0, 135.2, 151.3, 152.7, 157.5, 161.1, 181.5; MS (GC, 70 eV) m/
z (%) 266 ([M]þ, 100); HRMS (EI): calcd for C12H7ClO5 [M]þ
(m), 1543 (m), 1510 (m), 1458 (w), 1433 (m), 1411 (m), 1392 (s), 1357
(m), 1309 (m), 1274 (m), 1211 (m), 1197 (m), 1178 (s), 1145 (s), 1066
(s), 985 (s), 910 (s), 855 (m), 840 (w), 802 (m), 756 (s), 733 (s), 700
(m), 676 (m), 657 (m).
266.01250, found 266.01255; IR (ATR, cmꢁ1
)
n
1761 (m), 1712 (s),
~
1604 (m), 1544 (m), 1496 (w), 1451 (m), 1355 (w), 1314 (m), 1294
(m), 1261 (m), 1205 (m), 1087 (m), 1036 (m), 1003 (m), 960 (m), 881
(w), 856 (m), 759 (s), 732 (s), 662 (m), 584 (m).
4.2.5. 2-(1-Piperidinyl)-5-(trifluoromethyl)-6H-chromeno[4,3-d][1,3]
thiazolo[4,5-b]pyridin-6-one (8e). Yield 63%, brown solid, mp
4.2. General procedure for the synthesis of compounds 8e10
244e245 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.79 (br s, 6H), 3.84 (br s,
Coumarin 2a or 2b (2 mmol) and the corresponding amino-
heterocycle (2.2 mmol) were placed in a pressure tube under the
flow of dry argon and dissolved in dry DMF (10 mL) containing 1 mL
of TMSCl. The mixture was heated at 100e120 ꢀC during 2e12 h
(controlled by TLC). Then this solution was evaporated under re-
duced pressure, treated with water, filtered, and dried on the air
and recrystallized from an appropriate solvent, or was subjected to
a column chromatography over silica gel.
4H), 7.34e7.42 (m, 2H), 7.57e7.63 (m, 1H), 8.00 (dd, 1H, J¼8.0,
0.8 Hz); 13C NMR (63 MHz, CDCl3)
d 24.0, 25.5, 50.1, 107.9, 115.3,
1
117.9, 120.2, 121.2 (q, JC,F¼274.2 Hz), 124.6, 125.8, 132.8, 138.9 (q,
2JC,F¼35.4 Hz), 152.6, 155.9, 158.7, 166.7, 171.8; 19F NMR (282 MHz,
CDCl3)
d
ꢁ64.3 (CF3); MS (GC, 70 eV) m/z (%) 405 ([M]þ, 100), 376
(54), 349 (29), 249 (15); HRMS (ESI): calcd for C19H14F3N3O2S
[MþH]þ 406.08316, found 406.08282; IR (ATR, cmꢁ1
)
n
2933 (w),
~
2867 (w), 1742 (s), 1601 (w), 1584 (m), 1543 (m), 1506 (m), 1453 (w),
1422 (s), 1393 (m), 1358 (m), 1333 (m), 1307 (m), 1262 (m), 1198 (s),
1174 (s), 1145 (s), 1168 (s), 1008 (m), 983 (s), 907 (w), 884 (m), 852
(m), 803 (m), 756 (s), 732 (s), 701 (m), 671 (m), 657 (m).
4.2.1. Methyl 3-ethyl-1-methyl-6-oxo-2-thioxo-1,2,3,6-
tetrahydrochromeno[4,3-d]imidazo[4,5-b]pyridine-5-carboxylate
(8a). Yield 74%, red solid, mp >375 ꢀC; 1H NMR (300 MHz, CDCl3)
d
1.45 (t, 3H, J¼7.0 Hz), 3.93 (s, 3H), 4.05 (s, 3H), 4.53 (q, 2H,
J¼7.0 Hz), 7.38e7.45 (m, 2H), 7.59e7.65 (m, 1H), 7.85 (dd, 1H, J¼8.0,
1.2 Hz); 13C NMR (63 MHz, CDCl3)
12.8, 38.5, 39.6, 53.4, 109.7,
4.2.6. 3-(tert-Butyl)-6-oxo-5-(trifluoromethyl)-3,6-dihydrochro-
meno[4,3-d]pyrrolo[2,3-b]pyridine-1-carbonitrile (8f). Yield 72%,
white solid isolated by preparative chromatography (heptane/
d
114.2, 118.2, 121.4, 124.4, 125.6, 128.3, 132.7, 148.5, 149.8, 152.0,
AcOEt 2:1), mp 267e269 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.93 (s,
158.6,166.8,175.6; MS (GC, 70 eV) m/z (%) 369 ([M]þ,100), 340 (30);
9H), 7.43e7.56 (m, 2H), 7.65e7.72 (m, 1H), 8.32 (s, 1H), 8.70 (dd, 1H,
HRMS (ESI): calcd for C18H15N3O4S [MþH]þ 370.08560, found
J¼8.1, 1.2 Hz); 13C NMR (63 MHz, CDCl3)
d 29.2, 60.7, 86.1, 110.6,
370.08576; IR (ATR, cmꢁ1
)
n
2925 (w), 1726 (s), 1643 (w), 1608 (w),
114.6, 115.8, 116.0, 117.3, 121.3 (q, 1JC,F¼275.1 Hz), 124.4, 129.2, 133.4,
~
2
1586 (w), 1480 (m), 1455 (m), 1426 (m), 1392 (s), 1284 (m), 1218 (s),
1145 (m), 1088 (m), 1047 (m), 1027 (m), 992 (s), 950 (m), 868 (m),
812 (m), 754 (s), 692 (s).
139.5, 140.7, 143.4 (q, JC,F¼36.6 Hz), 146.5, 152.0, 156.5; 19F NMR
(282 MHz, CDCl3)
d
ꢁ54.6 (CF3); MS (EI, 70 eV) m/z (%) 385 ([M]þ,
17), 330 (19), 329 (100), 309 (23); HRMS (ESI): calcd for
C20H14F3N3O2 [MþH]þ 386.11109, found 386.11134; IR (ATR, cmꢁ1
)
n
~
4.2.2. 1-Methyl-3-phenyl-2-thioxo-5-(trifluoromethyl)-2,3-dihydro-
chromeno[4,3-d]imidazo[4,5-b]pyridin-6(1H)-one (8b). Yield 85%,
3472 (w), 2981 (w), 2215 (m), 1747 (m), 1545 (m), 1362 (m), 1147 (s),
1008 (s), 757 (m), 747 (s).
yellow solid, mp >375 ꢀC; 1H NMR (300 MHz, CDCl3)
d 3.96 (s, 3H),
7.42e7.60 (m, 6H), 7.65e7.69 (m, 2H), 7.81e7.84 (m, 1H); 13C NMR
4.2.7. Methyl 3-(tert-butyl)-1-cyano-6-oxo-3,6-dihydrochromeno
[4,3-d]pyrrolo[2,3-b]pyridine-5-carboxylate (8g). Yield 53%, white
solid isolated by preparative chromatography (heptane/AcOEt 2:1),
(63 MHz, CDCl3)
d
38.3, 111.9, 114.0, 116.9, 121.2 (q, 1JC,F¼274.0 Hz),
123.8, 124.6, 127.5, 128.2, 128.4, 129.2, 129.4, 132.9, 133.9, 141.6 (q,
2JC,F¼35.5 Hz), 147.4, 151.1, 155.9, 176.3; 19F NMR (282 MHz, CDCl3)
mp 245e247 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.81 (s, 9H), 4.01 (s,
d
ꢁ60.3 (CF3); MS (GC, 70 eV) m/z (%) 427 ([M]þ, 92), 426 (100), 406
3H), 7.36 (dd, 1H, J¼8.1, 1.6 Hz), 7.40e7.46 (m, 1H), 7.54e7.61 (m,
(23), 204 (15); HRMS (EI): calcd for C21H12F3N3O2S [M]þ 427.05186,
1H), 8.18 (s, 1H), 8.79 (dd, 1H, J¼8.1, 1.7 Hz); 13C NMR (63 MHz
found 427.05165; IR (ATR, cmꢁ1
)
n
3038 (w), 1744 (m), 1592 (w),
CDCl3) d 29.2, 53.4, 60.5, 85.6, 109.2, 113.3, 116.2, 116.7, 117.7, 124.6,
~
1503 (w), 1475 (m), 1432 (m), 1374 (w), 1322 (m), 1305 (m), 1268
(w), 1246 (m), 1146 (s), 1075 (m), 1036 (m), 996 (m), 895 (w), 860
(m), 804 (w), 768 (s), 747 (s), 725 (s), 679 (s), 613 (m), 578 (s).
129.1, 133.1, 138.6, 138.9, 148.4, 149.3, 152.1, 159.2, 167.2; MS (EI,
70 eV) m/z (%) 375 ([M]þ, 27), 319 (50), 288 (46), 287 (100), 259
(25); HRMS (ESI): calcd for C21H17N3O4 [MþH]þ 376.12918, found
376.12883; IR (ATR, cmꢁ1
)
n
3438 (w), 2210 (m), 1728 (s), 1544 (s),
~
4.2.3. Methyl 1-methyl-6-oxo-3-phenyl-2-thioxo-1,2,3,6-tetrahydro-
1159 (s), 1058 (s), 748 (m), 734 (s).
chromeno[4,3-d]imidazo[4,5-b]pyridine-5-carboxylate
82%, yellow solid, mp >375 ꢀC; 1H NMR (300 MHz, DMSO-d6)
3.92 (both s, 3H), 7.53e7.58 (m, 5H), 7.58e7.67 (m, 2H), 7.71e7.76 (m,
(8c). Yield
d
3.84,
4.2.8. 3-Cyclohexyl-6-oxo-5-(trifluoromethyl)-3,6-dihydrochromeno
[4,3-d]pyrrolo[2,3-b]pyridine-1-carbonitrile (8h). Yield 46%, white

7952
V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
solid isolated by preparative chromatography (heptane/AcOEt 2:1),
mp 288e290 ꢀC; 1H NMR (250 MHz, DMSO-d6)
1.33e2.17 (m,
(heptane/AcOEt 2:1), mp 259e261 ꢀC; 1H NMR (300 MHz, DMSO-
d6)
d
d
0.64 (d, 3H, J¼6.0 Hz), 1.34e1.63 (m, 3H), 1.77e2.05 (m, 6H),
10H), 4.79e5.26 (m, 1H), 7.34e7.61 (m, 2H), 7.61e7.80 (m, 1H), 8.60
(dd, 1H, J¼8.1, 1.6 Hz), 9.28 (s, 1H); 19F NMR (282 MHz, CDCl3)
4.59e4.88 (m, 1H), 7.43e7.55 (m, 2H), 7.66e7.78 (m, 1H), 8.65 (dd,
1H, J¼8.0, 1.0 Hz), 9.30 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d
ꢁ53.7 (CF3); MS (EI, 70 eV) m/z (%) 411 ([M]þ, 39), 330 (24), 329
d 12.0, 18.6, 25.1, 25.3, 32.2, 33.9, 57.7, 85.4, 110.2, 114.8, 116.2, 116.4,
(100); HRMS (ESI): calcd for C22H16F3N3O2 [MþH]þ 412.12674,
118.3, 122.8 (q, 1JC,F¼275.0 Hz), 124.7, 124.8, 124.9, 132.7, 144.7 (q,
2JC,F¼35.1 Hz), 148.1, 150.1, 151.5, 157.0; 19F NMR (282 MHz, DMSO-
d6) ꢁ53.6 (CF3); MS (EI, 70 eV) m/z (%) 425 ([M]þ, 33), 330 (72), 329
found 412.12743; IR (ATR, cmꢁ1
)
n
3124 (w), 2228 (m),1736 (s),1586
~
(s), 1180 (s), 1145 (s), 754 (m), 730 (s).
(100); HRMS (EI): calcd for C23H18F3N3O2 [M]þ 425.13456, found
425.13425; IR (ATR, cmꢁ1
)
n
2228 (m), 1746 (s), 1586 (s), 1397 (m),
~
4 . 2 . 9 . 3 - C y c l o p e n t yl - 6 - o x o - 5 - ( t r ifl u o r o m e t hyl ) - 3 , 6 -
dihydrochromeno[4,3-d]pyrrolo[2,3-b]pyridine-1-carbonitrile
(8i). Yield 58%, white solid isolated by preparative chromatography
(heptane/AcOEt 2:1), mp 256e258 ꢀC; 1H NMR (250 MHz, DMSO-
1367 (m), 1161 (s), 754 (s).
4.2.14. Methyl 1-cyano-3-(2-methylcyclohexyl)-6-oxo-3,6-
dihydrochromeno[4,3-d]pyrrolo[2,3-b]pyridine-5-carboxylate
(8n). Yield 40%, white solid isolated by preparative chromatogra-
phy (heptane/AcOEt 2:1), mp 230e232 ꢀC; 1H NMR (300 MHz,
d6)
d 1.63e1.82 (m, 2H), 1.84e2.10 (m, 4H), 2.18e2.37 (m, 2H),
5.23e5.41 (m, 1H), 7.41e7.60 (m, 2H), 7.68e7.82 (m, 1H), 8.59 (dd,
1H, J¼8.1, 1.1 Hz), 9.24 (s, 1H); 13C NMR (63 MHz, DMSO-d6)
d 23.6,
32.2, 57.1, 85.8, 110.6, 113.5, 115.6, 116.1, 116.9, 119.2, 121.4 (q, CF3,
1JC,F¼275.0 Hz), 124.0, 128.0, 129.0, 129.1, 133.5, 139.9, 142.6 (q,
2JC,F¼36.5 Hz), 145.8, 151.5, 156.1; 19F NMR (282 MHz, CDCl3)
DMSO-d6)
d
0.63 (d, 3H, J¼6.0 Hz), 1.30e1.60 (m, 3H), 1.67e2.18 (m,
6H), 4.05 (s, 3H), 4.68 (br s, 1H), 7.41e7.56 (m, 2H), 7.61e7.71 (m,
1H), 8.62 (d, 1H, J¼7 Hz), 9.08 (s, 1H); 13C NMR (63 MHz, DMSO-d6)
d
ꢁ52.2 (CF3); MS (EI, 70 eV) m/z (%) 397 ([M]þ, 25), 329 (100), 309
d 12.0, 18.5, 25.1, 25.3, 30.8, 32.3, 33.9, 52.5, 83.7, 108.1, 113.4, 115.8,
(42); HRMS (EI): calcd for C21H14N3F3O2 [M]þ 397.10326, found
116.9, 118.7, 124.2, 124.4, 124.9, 132.4, 136.2, 147.4, 149.1, 151.6, 159.2,
397.10325; IR (ATR, cmꢁ1
)
3142 (w), 2217 (m), 1746 (s), 1552 (s),
164.9; HRMS (EI): calcd for C24H21N3O4 (Mþ) 415.15326, found
~
n
415.15328; IR (ATR, cmꢁ1
)
n
3093 (w), 2930 (w), 2221 (m), 1739 (s),
~
1453 (m), 1359 (m), 1154 (s), 757 (s), 609 (m).
1582 (m), 1398 (m), 1210 (s), 1053 (s), 754 (s).
4.2.10. Methyl 1-cyano-3-cyclopentyl-6-oxo-3,6-dihydrochromeno
[4,3-d]pyrrolo[2,3-b]pyridine-5-carboxylate (8j). Yield 38%, white
solid isolated by preparative chromatography (heptane/AcOEt 2:1),
4.2.15. 3-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-3,6-
dihydrochromeno[4,3-d]pyrrolo[2,3-b]pyridine-1-carbonitrile
(8o). Yield 41%, white solid isolated by preparative chromatogra-
phy (heptane/AcOEt 2:1), mp 264e266 ꢀC; 1H NMR (300 MHz,
mp 225e227 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.77e1.95 (m, 6H),
2.23e2.40 (m, 2H), 4.02 (s, 3H), 5.34e5.48 (m, 1H), 7.30e7.51 (m,
2H), 7.55e7.64 (m, 1H), 8.12 (s, 1H), 8.87 (dd, 1H, J¼8.1, 1.0 Hz); 13C
DMSO-d6)
d 3.74 (s, 3H), 5.70 (s, 2H), 6.93e7.00 (m, 2H), 7.45e7.59
NMR (63 MHz, CDCl3)
d
24.0, 33.1, 53.4, 56.9, 87.0, 109.8, 112.1, 116.3,
(m, 4H), 7.67e7.85 (m, 1H), 8.63e8.71 (m, 1H), 9.28 (s, 1H); 19F NMR
116.7, 117.8, 124.7, 129.2, 133.2,138.0, 139.1, 148.2, 150.6, 152.3, 159.2,
(282 MHz, CDCl3)
d
ꢁ53.7 (CF3); MS (EI, 70 eV) m/z (%) 449 ([M]þ,
167.3; HRMS (ESI): calcd for C22H17N3O4 [MþH]þ 388.12918, found
25), 122 (16), 121 (100), 63 (18), 44 (11); HRMS (ESI): calcd for
388.12886; IR (ATR, cmꢁ1
)
n
3114 (w), 2218 (w), 1729 (s), 1549 (s),
C24H14F3N3O3 [M]þ 449.09818, found 449.09833; IR (ATR, cmꢁ1
)
~
~
n
1398 (m), 1216 (s), 763 (s).
3461 (w), 2220 (m), 1736 (s),1513 (s), 1145 (s),1008 (s), 762 (m), 757
(s).
4.2.11. Methyl 1-cyano-3-(4-methylphenyl)-6-oxo-3,6-
dihydrochromeno[4,3-d]pyrrolo[2,3-b]pyridine-5-carboxylate
(8k). Yield 42%, yellow solid isolated by preparative chromatog-
raphy (heptane/AcOEt 2:1), mp 245 ꢀC; 1H NMR (300 MHz, CDCl3)
4.2.16. Methyl 1-cyano-3-(4-methoxybenzyl)-6-oxo-3,6-
dihydrochromeno[4,3-d]pyrrolo[2,3-b]pyridine-5-carboxylate
(8p). Yield 55%, white solid isolated by preparative chromatogra-
phy (heptane/AcOEt 2:1), mp 227e229 ꢀC; 1H NMR (300 MHz,
d
2.47 (s, 3H), 4.04 (s, 3H), 7.37e7.59 (m, 6H), 7.66e7.75 (m, 1H),
8.34 (s, 1H), 8.96 (dd, 1H, J¼8.1, 1.1 Hz); 13C NMR (63 MHz, CDCl3)
CDCl3)
7.18e7.29 (m, 4H), 7.43e7.51 (m,1H), 7.78 (s,1H), 8.55 (dd,1H, J¼8.1,
1.7 Hz); 13C NMR (63 MHz, DMSO-d6)
48.3, 52.5, 55.0, 83.5, 108.1,
d 3.72, 4.10 (both s, 3H), 5.50 (s, 2H), 6.79e6.84 (m, 2H),
d
21.2, 53.3, 88.1, 110.2, 112.3, 116.1, 117.8, 124.4, 124.7, 125.0, 129.2,
130.3, 133.0, 133.4, 139.3, 139.4, 140.5, 148.0, 151.4, 152.3, 158.9,
d
166.9; MS (EI, 70 eV) m/z (%) 409 ([M]þ,100), 378 (44), 350 (59), 349
113.2, 114.1, 115.8, 116.8, 118.6, 124.2, 124.9, 127.9, 129.4, 129.7, 132.3,
(30), 322 (18); HRMS (EI): calcd for C24H15N3O4 [M]þ 409.10571,
136.2, 142.6, 147.5, 148.5, 151.5, 159.1, 164.8; HRMS (EI): calcd for
found 409.10597; IR (ATR, cmꢁ1
)
n
3136 (w), 2215 (m),1727 (s),1544
C25H17N3O5 [M]þ 439.11627, found 439.11640; IR (ATR, cmꢁ1
(w), 2217 (m), 1730 (s), 1514 (s), 1224 (s), 1168 (s), 753 (s).
)
n
3131
~
~
(s), 1415 (m), 1225 (s), 756 (m), 660 (s).
4.2.12. 3-Hexyl-6-oxo-5-(trifluoromethyl)-3,6-dihydrochromeno[4,3-
d]pyrrolo[2,3-b]pyridine-1-carbonitrile (8l). Yield 45%, white solid
isolated by preparative chromatography (heptane/AcOEt 2:1), mp
4.2.17. 3-(tert-Butyl)-6-oxo-3,6-dihydrochromeno[4,3-d]pyrrolo[2,3-
b]pyridine-1-carbonitrile (8q). Yield 40%, yellow solid isolated by
preparative chromatography (heptane/AcOEt 2:1), mp 252e254 ꢀC;
177 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
0.86 (t, 3H, J¼6.3 Hz),
1H NMR (300 MHz, DMSO-d6)
d
1.86 (s, 9H), 7.41e7.56 (m, 2H),
7.65e7.80 (m, 1H), 8.76 (dd, 1H, J¼8.1, 1.1 Hz), 8.93 (s, 1H), 9.18 (s,
1H); 13C NMR (63 MHz, DMSO-d6)
28.6, 59.9, 83.6, 111.6, 112.1,
1.24e1.37 (m, 6H), 1.90e1.99 (m, 2H), 4.45e4.54 (m, 2H), 7.37e7.56
(m, 2H), 7.62e7.72 (m, 1H), 8.51 (d, 1H, J¼8.1 Hz), 9.15 (s, 1H); 13C
d
NMR (75.5 MHz, DMSO-d6)
d
13.8, 21.9, 25.5, 28.8, 30.6, 45.3, 84.7,
116.4,117.6, 124.1,128.5, 132.0, 132.8, 136.2, 140.9,145.8,149.6,151.9,
109.8, 114.6, 115.5, 116.3, 118.1, 122.8 (q, CF3, 1JC,F¼275.0 Hz), 124.4,
159.9; HRMS (EI): calcd for C19H15N3O2 [M]þ 317.11588, found
124.7, 128.9, 132.6, 146.4 (q, 2JC,F¼36.5 Hz), 147.9, 149.8, 151.4, 156.9;
317.11601; IR (ATR, cmꢁ1
)
n
3132 (w), 2216 (w), 1726 (s), 1592 (m),
~
19F NMR (282 MHz, DMSO-d6)
d
ꢁ53.7 (CF3); MS (EI, 70 eV) m/z (%)
1364 (m), 1181 (s), 1081 (m), 758 (s), 745 (s).
413 ([M]þ, 100), 384 (22), 329 (83); HRMS (EI): calcd for
C22H18F3N3O2 [M]þ 413.13456, found 413.13447; IR (ATR, cmꢁ1
)
n
4.2.18. 2,4-Dimethyl-6-(trifluoromethyl)-1H-chromeno[40,30:4,5]pyr-
ido[2,3-d]pyrimidine-1,3,7(2H,4H)-trione (8r). Yield 73%, white
~
2229 (m), 1727 (s), 1589 (s), 1389 (m), 1365 (m), 1145 (s), 755 (s).
solid, mp >250 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.37, 3.66 (both s,
4.2.13. 3-(2-Methylcyclohexyl)-6-oxo-5-(trifluoromethyl)-3,6-dihy-
drochromeno[4,3-d]pyrrolo[2,3-b]pyridine-1-carbonitrile (8m).
Yield 44%, white solid isolated by preparative chromatography
3H), 7.27e7.33 (m,1H), 7.43 (dd,1H, J¼8.4,1.1 Hz), 7.67e7.73 (m,1H),
8.15 (dd, 1H, J¼8.4, 1.4 Hz); 19F NMR (282 MHz, DMSO-d6)
d
ꢁ64.3
(CF3); MS (GC, 70 eV) m/z (%) 377 ([M]þ, 100); HRMS (ESI): calcd for

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
7953
C17H10F3N3O4 [MþH]þ 378.06962, found 378.06916; IR (ATR, cmꢁ1
)
1561 (w),1497 (w),1454 (w),1421 (w),1358 (w),1317 (w),1243 (m),
1205 (m), 1161 (m), 1146 (m), 1124 (m), 972 (m), 893 (w), 850 (m),
810 (m), 755 (s), 702 (s), 643 (s).
~
n
1757 (m), 1715 (s), 1660 (s), 1589 (m), 1552 (s), 1461 (s), 1366 (m),
1289 (w),1231 (s),1214 (s),1193 (s),1155 (s),1134 (m),1081 (m),1011
(s), 970 (w), 935 (m), 823 (w), 775 (s), 733 (s), 684 (s).
4.3. General procedures for the synthesis of compounds 11
4.2.19. 8-Methyl-10-phenyl-7-(trifluoromethyl)chromeno[4,3-b]pyr-
azolo[4,3-e]pyridin-6(10H)-one (9). Yield 51%, yellow solid, mp
To a toluene solution of coumarin 2a or 2b (1 mmol) was slowly
added the corresponding hydrazine (2.2 mmol) and the reaction
mixture was reflux for 3e4 h. After the reaction was finished (TLC
control), the solvent was removed, the residue was treated with
water and finally dried in vacuum. The purification was performed
by column chromatography (silica gel).
6
219 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
2.75 (q, 3H, JH,F¼3.7 Hz),
7.30e7.41 (m, 3H), 7.53e7.62 (m, 3H), 8.22e8.26 (m, 2H), 8.51 (dd,
1H, J¼7.9, 1.5 Hz); 13C NMR (300 MHz, DMSO-d6)
d 16.9 (q,
5JC,F¼6.8 Hz), 109.6, 114.8, 116.8, 118.4, 121.5, 121.9 (q,
1JC,F¼276.6 Hz), 124.8, 125.6, 126.9, 129.2, 133.2, 136.6 (q,
2JC,F¼36.6 Hz), 138.1, 144.0, 151.8, 152.0, 152.5, 157.4; 19F NMR
(282 MHz, DMSO-d6)
d
ꢁ55.0 (q, 6JF,H¼3.7 Hz, CF3); MS (GC, 70 eV)
4.3.1. 1-Methyl-3-(trifluoromethyl)chromeno[4,3-c]pyrazol-4(1H)-
one (11a). Yield 70%, yellow solid, mp 231e232 ꢀC; 1H NMR
(250 MHz, DMSO-d6) d 4.39 (s, 3H), 7.44e7.53 (m, 2H), 7.65e7.72
m/z (%) 395 ([M]þ, 100); HRMS (ESI): calcd for C21H12F3N3O2
[MþH]þ 396.09544, found 396.09499; IR (ATR, cmꢁ1
)
n
3072 (w),
~
1738 (s), 1593 (w), 1568 (s), 1498 (m), 1466 (m), 1420 (m), 1390
(w), 1364 (m), 1275 (w), 1242 (m), 1213 (s), 1175 (s), 1136 (s), 1075
(m), 991 (w), 886 (m), 835 (w), 797 (w), 768 (s), 752 (s), 686 (m),
656 (m).
(m, 1H), 8.23 (d, 1H, J¼8.0 Hz); 13C NMR (63 MHz, DMSO-d6)
d 40.9,
104.4, 110.8, 117.6, 120.1 (q, 1JC,F¼269.0 Hz), 123.8, 124.9, 132.1, 137.7
(q, 2JC,F¼38.1 Hz), 142.9, 152.3, 154.1; 19F NMR (282 MHz, DMSO-d6)
d
ꢁ56.0 (CF3); MS (GC, 70 eV) m/z (%) 268 ([M]þ, 100); HRMS (ESI):
calcd for C12H7F3N2O2 [MþH]þ 269.0532, found 269.0533; IR (ATR,
4.2.20. 7-(Trifluoromethyl)-6H-chromeno[30,40:5,6]pyrimido[1,2-a]
benzimidazol-6-one (10a). Yield 60%, brown solid, mp 275e276 ꢀC;
cmꢁ1
)
3108 (s), 1740 (m), 1614 (m), 1556 (w), 1511 (w), 1442 (w),
~
n
1327 (m), 1291 (m), 1237 (w), 1181 (s), 1132 (s), 1040 (m), 1019 (s),
982 (s), 891 (s), 759 (s), 729 (s), 705 (m), 663 (m).
1H NMR (300 MHz, DMSO-d6)
d 7.51e7.59 (m, 2H), 7.68e7.76 (m,
2H), 7.96 (t, 1H, J¼7.2 Hz), 8.08 (d, 1H, J¼8.2 Hz), 8.16 (d, 1H,
J¼8.5 Hz), 8.53 (d, 1H, J¼7.5 Hz); 13C NMR (63 MHz, DMSO-d6)
4.3.2. 2-Phenyl-3-(trifluoromethyl)chromeno[4,3-c]pyrazol-4(2H)-
one (11b). Yield 59%, pink solid, mp 166e167 ꢀC; 1H NMR
1
d
101.6, 116.4, 117.6, 118.3, 120.2 (q, JC,F¼278.1 Hz), 120.9, 123.0,
123.9, 125.6, 127.9, 128.6, 132.9, 136.5, 145.8, 148.5 (q, 2JC,F¼38.0 Hz),
(300 MHz, DMSO-d6)
d
7.44 (dt, 1H, J¼7.3, 1.0 Hz), 7.52 (dd, 1H,
151.4, 152.9, 155.0; 19F NMR (282 MHz, DMSO-d6)
d
ꢁ65.1 (CF3); MS
J¼8.3, 0.8 Hz), 7.62e7.71 (m, 6H), 8.09 (dd, 1H, J¼7.8, 1.5 Hz); 13C
(GC, 70 eV) m/z (%) 355 ([M]þ, 100), 326 (10); HRMS (EI): calcd for
NMR (75.5 MHz, DMSO-d6) d 107.5, 113.0, 117.2, 118.4 (q,
C18H8F3N3O2 [Mþ] 355.05630, found 355.06687; IR (ATR, cmꢁ1
)
n
1JC,F¼268.0 Hz), 122.5, 125.1, 126.3, 129.4, 130.8, 131.6, 132.4 (q,
~
3077 (w), 1745 (s), 1675 (w), 1604 (m), 1590 (m), 1562 (w), 1497 (m),
1479 (m), 1453 (m), 1374 (m), 1313 (m), 1266 (w), 1253 (m), 1229
(w), 1183 (s), 1145 (s), 1087 (m), 1044 (m), 1027 (m), 1010 (m), 958
(m), 920 (m), 885 (w), 842 (w), 794 (w), 754 (s), 746 (s), 663 (w),
622 (w).
2JC,F¼41.0 Hz), 138.4, 148.5, 152.3, 154.3; 19F NMR (282 MHz, DMSO-
d6)
d
ꢁ54.9 (CF3); MS (GC, 70 eV) m/z (%) 330 ([M]þ, 100), 309 (11),
77 (18); HRMS (ESI): calcd for C17H9F3N2O2 [MþH]þ 331.0689,
found 331.0692; IR (ATR, cmꢁ1
)
n
1754 (s), 1619 (w), 1592 (w), 1592
~
(w), 1567 (w), 1520 (w), 1497 (w), 1448 (w), 1393 (w), 1328 (m),
1220 (m), 1191 (s), 1158 (m), 1125 (s), 1082 (m), 1033 (m), 999 (s),
982 (m), 898 (s), 769 (m), 754 (s), 687 (s), 661 (m).
4.2.21. 2-Morpholino-4-(trifluoromethyl)-5H-chromeno[4,3-d]pyr-
imidin-5-one (10b). Yield 80%, yellow solid, mp >375 ꢀC; 1H NMR
(300 MHz, DMSO-d6)
d
3.04 (br s, 8H, CH2), 7.45e7.71 (m, 2H),
4.3.3. Methyl 4-oxo-2-phenyl-2,4-dihydrochromeno[4,3-c]pyrazole-
8.22e8.50 (m, 2H); 19F NMR (282 MHz, DMSO-d6)
d
ꢁ65.0 (CF3); MS
3-carboxylate (11c). Yield 62%, pink solid, mp 255e256 ꢀC; 1H NMR
(GC, 70 eV) m/z (%) 351 ([M]þ, 100); HRMS (EI): calcd for
(300 MHz, CDCl3)
d
3.93 (s, 3H), 7.32 (dt, 1H, J¼7.8, 1.1 Hz), 7.39 (dd,
C16H12F3N3O3 [M]þ 351.0825, found 351.0826; IR (ATR, cmꢁ1
)
n
1H, J¼8.3, 0.9 Hz), 7.47e7.57 (m, 6H), 8.13 (dd, 1H, J¼7.8, 1.5 Hz); 13C
~
3072 (w), 1737 (s), 1593 (w), 1568 (m), 1497 (m), 1466 (m), 1419 (m),
1390 (w), 1365 (m), 1341 (w), 1275 (w), 1241 (s), 1212 (s), 1175 (s),
1136 (s), 1074 (m), 1021 (m), 886 (m), 835 (w), 797 (s), 768 (s), 751
(s), 730 (m), 686 (s), 656 (s).
NMR (63 MHz, CDCl3) d 53.6, 108.2, 113.9, 117.5, 122.9, 124.6, 124.7,
129.4, 129.8, 131.0, 135.7, 138.9, 149.0, 153.0, 156.0, 159.4; MS (GC,
70 eV) m/z (%) 320 ([M]þ, 100), 289 (21), 261 (11), 143 (11), 77 (28);
HRMS (ESI): calcd for C18H12N2O4 [MþH]þ 321.08698, found
321.08716; IR (ATR, cmꢁ1
)
n
3062 (s), 1755 (w), 1721 (s), 1620 (m),
~
4.2.22. Dimethyl 9-hydroxy-6-oxo-7-(trifluoromethyl)-6H-benzo[c]
chromene-8,10-dicarboxylate (10c). To a dry 1,4-dioxane solution
(10 mL) of 4-chloro-3-(trifluoroacetyl)coumarin 2a (0.25 g,
0.9 mmol) were added dimethyl 1,3-acetonedicarboxylate (0.174 g,
1 mmol) and triethylamine (0.136 g, 1.35 mmol) and the reaction
mixture was refluxed for 3 h. After the reaction was completed (TLC
control), the solvent was removed and the residue was washed
with water to remove the salts. Then the crude product was puri-
fied by column chromatography (silica gel, ethyl acetate, Rf¼0.51
ethyl acetate/MeOH¼20:1) to give 10c. Yield 88% (0.312 g), white
1593 (m), 1557 (m), 1515 (w), 1496 (m), 1447 (m), 1427 (m), 1393
(m), 1325 (m), 1275 (m), 1235 (s), 1163 (m), 1041 (s), 1015 (s), 983
(m), 945 (m), 912 (w), 897 (m), 830 (m), 786 (m), 758 (s), 743 (s),
732 (m), 701 (m), 688 (s).
4.4. General procedures for the synthesis of compounds 12
The coumarin derivative (1.0 mmol) was dissolved in 3 mL of dry
dichloromethane, then 1.1e2.0 equiv of the corresponding alkyl
thioglycolate or methyl sarcosinate in a small amount of dichloro-
methane and 4e5 equiv of NEt3 were added dropwise at 0 ꢀC. After
removal of the ice bath the solution was stirred at w20 ꢀC for
several hours (3e16 h). Subsequently water was added and the
mixture was extracted with dichloromethane or ethyl acetate. The
combined organic layers were dried over Na2SO4 and the solvent
was removed under reduced pressure. The residue was purified by
washing with acetone or by column chromatography to give the
desired products as white solids.
solid, mp 198e199 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
3.84, 3.93
(both s, 3H), 7.35e7.43 (m, 2H), 7.59e7.64 (m, 2H); 13C NMR
(63 MHz, DMSO-d6)
d 52.9, 53.1, 115.5, 117.3, 121.6, 122.6 (q,
2
1JC,F¼274.2 Hz), 124.5, 124.9, 129.4 (q, JC,F¼34.0 Hz), 131.9, 135.6,
150.7, 155.9, 159.9, 160.1, 165.4, 167.4, 175.5; 19F NMR (282 MHz,
DMSO-d6)
d
ꢁ54.3 (CF3); MS (GC, 70 eV) m/z (%) 396 ([M]þ, 10), 321
(100); HRMS (ESI): calcd for C18H11F3O7 [MþH]þ 397.0513, found
397.0514; IR (ATR, cmꢁ1
)
n
3340 (m), 1740 (w), 1719 (m), 1577 (w),
~

7954
V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 7946e7955
cmꢁ1
)
n
3459 (w), 3391 (w), 3118 (w), 3033 (w), 2949 (m), 2926 (m),
~
4.4.1. Methyl 4-oxo-3-(trifluoromethyl)-4H-thieno[3,2-c]chromene-
2-carboxylate (12a). Yield 83% (196 mg), mp 222e223 ꢀC; 1H NMR
2871 (m), 2860 (m), 1737 (s), 1699 (s), 1608 (m), 1585 (m), 1542 (m),
1502 (m),1484 (m),1464 (m),1456 (m),1441 (m),1402 (m),1392 (m),
1331 (m), 1293 (s),1275 (m),1238 (s), 1219 (s), 1190 (m),1163 (m),1139
(s), 1119 (m), 1080 (m), 1036 (m), 1013 (m). Anal. Calcd for C22H24O6S
(416.49): C, 63.44; H, 5.81. Found: C, 63.47; H, 6.04.
(300 MHz, DMSO-d6)
d
3.95 (s, 3H), 7.44 (m, 1H), 7.53 (dd, 1H, J¼8.2,
0.8 Hz), 7.70 (m, 1H), 8.05 (dd, 1H, J¼7.7, 1.5 Hz); 13C NMR (63 MHz,
1
DMSO-d6)
d
54.3, 115.0, 117.1, 120.4 (q, JC,F¼272.7 Hz), 121.4 (q,
3JC,F¼1.4 Hz), 124.5, 125.4, 128.1 (q, JC,F¼37.7 Hz), 135.7 (q,
2
3JC,F¼3.7 Hz), 133.0, 151.2, 151.3, 153.6, 160.4; 19F NMR (282 MHz,
DMSO-d6)
d
ꢁ55.7 (CF3); MS (EI, 70 eV) m/z (%) 328 ([M]þ, 100), 297
4.4.5. Dimethyl 1-methyl-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrole-
2,3-dicarboxylate (12e). 4-Chloro-3-(methoxalyl)coumarine 2b
(250 mg, 0.94 mmol) and methyl sarcosinate hydrochloride
(136 mg, 1.03 mmol) were dissolved in 5 mL of dry DMF and cooled
to 0 ꢀC. Then NEt3 (0.63 mL, 4.69 mmol) was added dropwise. The
reaction mixture was stirred for 5 h at 20 ꢀC and subsequently
poured onto water. The resulting precipitate was washed with ac-
etone to give 6e as a white solid. Yield 24% (70 mg), mp
(99), 225 (13), 213 (15), 169 (9), 144 (10); HRMS (EI): calcd for
C14H7O4F3S [M]þ 328.00117, found 328.00074; IR (ATR, cmꢁ1
)
n
~
3446 (w), 3026 (w), 2953 (w), 2846 (w), 1738 (s), 1610 (m), 1586
(m), 1536 (m), 1503 (m), 1482 (m), 1438 (m), 1402 (m), 1369 (w),
1317 (m), 1281 (m), 1261 (m), 1250 (m), 1229 (s), 1170 (s), 1133 (s),
1078 (m), 1030 (m). Anal. Calcd for C14H7F3O4S (328.26): C, 51.22; H,
2.15. Found: C, 51.00; H, 2.33.
245e247 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.85, 3.86 (both s, 3H),
4.4.2. Dimethyl 4-oxo-4H-thieno[3,2-c]chromene-2,3-dicarboxylate
4.36 (s, 3H), 7.46 (m,1H), 7.54 (dd,1H, 3J¼8.2 Hz, 4J¼1.1 Hz), 7.64 (m,
(12b). Yield 58% (139 mg), mp 229e231 ꢀC; 1H NMR (300 MHz,
1H), 8.32 (dd, 1H, 3J¼8.2 Hz, 4J¼1.1 Hz); 13C NMR (75 MHz, DMSO-
DMSO-d6)
d
3.89, 3.91 (both s, 3H), 7.43 (dt, 1H, J¼7.6, 0.9 Hz), 7.52
d6) d 36.0, 52.7, 52.8, 106.2, 113.2, 118.0, 122.1, 123.8, 124.8, 125.1,
(dd, 1H, J¼8.5, 0.8 Hz), 7.68 (m, 1H), 8.04 (dd, 1H, J¼7.8, 1.4 Hz); 13C
130.8, 137.4, 152.4, 156.1, 159.8, 164.3; HRMS (ESI-TOF/MS): calcd for
NMR (63 MHz, DMSO-d6)
d
53.4, 53.7, 115.7, 117.6, 122.6, 125.0,
C16H13NO6 [MþNa]þ 338.06351, found 338.06332; IR (ATR, cmꢁ1
)
n
~
125.6, 129.4, 133.1, 138.3, 151.6, 152.0, 155.1, 160.1, 163.5; MS (EI,
3436 (w), 3077 (w), 3051 (w), 3009 (w), 2955 (w), 2845 (w), 1741
(s), 1727 (s), 1715 (s), 1651 (w), 1633 (w), 1610 (w), 1583 (w), 1554
(w),1511 (m),1457 (m),1429 (m),1403 (w),1379 (m),1311 (w),1293
(m),1253 (m),1227 (s),1211 (s),1197 (s),1170 (m),1144 (s),1119 (m),
1105 (s), 1063 (m), 1050 (s), 1011 (s). Anal. Calcd for C16H13NO6
(315.28): C, 60.95; H, 4.16; N, 4.44. Found: C, 61.06; H, 4.41; N, 4.33.
70 eV) m/z (%) 318 ([M]þ, 83), 287 (100), 259 (6), 229 (8), 202 (14),
144 (9); HRMS (ESI-TOF/MS): calcd for C15H10O6S [MþH]þ 319.0271,
found 319.0272; IR (ATR, cmꢁ1
)
n
3020 (w), 2961 (w), 1747 (m), 1735
~
(m),1709 (s),1606 (m),1583 (m),1537 (m),1494 (m),1481 (m),1440
(m), 1425 (m), 1403 (m), 1332 (w), 1293 (s), 1275 (m), 1238 (s), 1218
(s), 1187 (m), 1161 (m), 1139 (s), 1118 (m), 1082 (m), 1059 (m), 1037
(m), 1007 (s). Anal. Calcd for C15H10O6S (318.30): C, 56.60; H, 3.17.
Found: C, 56.49; H, 3.38.
4.4.6. Methyl 3-hydroxy-1-methyl-4-oxo-3-(trifluoromethyl)-1,2,3,4-
tetrahydrochromeno[4,3-b]pyrrole-2-carboxylate (12f). Yield 50%
(156 mg), mp 198e200 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.42,
4.4.3. 2-Ethylhexyl 4-oxo-3-(trifluoromethyl)-4H-thieno[3,2-c]chro-
mene-2-carboxylate (12c). 4-Chloro-3-(trifluoroacetyl)coumarin 2a
(200 mg, 0.72 mmol) and 2-ethylhexylthioglycolate (0.2 mL,
0.95 mmol) were dissolved in 6 mL of dry DMF and cooled to 0 ꢀC.
Then NEt3 (0.44 mL, 3.17 mmol) was added dropwise. After stirring
at 20 ꢀC for 16 h, TMSCl (0.46 mL, 3.60 mmol) was added. The
mixture was stirred at 100 ꢀC for 6 h and then poured onto ice water.
The resulting precipitate was washed with water and purified by
column chromatography (heptane/EtOAc¼30:1/15:1) to give 12c
as a white solid. Yield 47% (145 mg), mp 104e105 ꢀC; 1H NMR
3.74 (both s, 3H), 4.92 (s, 1H), 7.19 (s, 1H), 7.33e7.40 (m, 1H), 7.42
(dd, 1H, J¼8.3, 0.9 Hz), 7.69e7.76 (m, 1H), 8.24 (dd, 1H, J¼8.3,
1.1 Hz); 13C NMR (75 MHz, DMSO-d6)
d 36.4, 52.6, 74.5, 79.6 (q,
1
2JC,F¼32.3 Hz), 92.8, 111.8, 117.7, 124.0, 124.8 (q, JC,F¼285.7 Hz),
125.6, 133.9, 155.8, 156.3, 158.7, 166.3; 19F NMR (282 MHz, DMSO-
d6)
d
ꢁ77.8 (CF3); MS (EI, 70 eV) m/z (%) 343 ([M]þ, 14), 274 (100),
267 (33), 266 (22), 215 (62), 214 (22), 207 (26); HRMS (ESI): calcd
for C15H12F3NO5 [MþH]þ 344.0740, found 344.0733; IR (ATR, cmꢁ1
)
~
n
3169 (w), 3098 (w), 3002 (w), 2951 (w), 2909 (w), 2849 (w), 1743
(s), 1682 (s), 1612 (m), 1592 (m), 1532 (s), 1477 (w), 1454 (w), 1438
(w), 1417 (w), 1383 (m), 1326 (m), 1299 (m), 1280 (s), 1259 (m), 1245
(s), 1220 (s), 1197 (s), 1177 (m), 1149 (s), 1134 (s), 1121 (s), 1076 (w),
1052 (s), 1023 (m). Anal. Calcd for C15H12F3NO5 (343.25): C, 52.49;
H, 3.52; N, 4.08. Found: C, 52.35; H, 3.64; N, 3.81.
(300 MHz, CDCl3) d 0.8e1.0 (m, 6H), 1.50e1.2 (m, 8H), 1.71 (sept, 1H,
J¼5.8 Hz), 4.30 (d, 2H, J¼5.7 Hz), 7.34 (t, 1H, J¼7.6 Hz), 7.41 (d, 1H,
J¼8.3 Hz), 7.70 (d, 1H, J¼7.7 Hz), 7.57 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 10.9, 14.0, 22.9, 23.7, 28.8, 30.2, 38.7, 69.7, 115.1, 117.5, 120.1
1
3
(q, JC,F¼273.1 Hz), 121.9 (q, JC,F¼1.1 Hz), 123.4, 125.0, 130.1 (q,
2JC,F¼38.7 Hz), 132.5, 136.1 (q, 3JC,F¼3.3 Hz), 150.8, 151.6, 153.6, 160.4;
4.5. X-ray crystallographic data
19F NMR (282 MHz, CDCl3)
d
ꢁ56.7 (CF3); MS (EI, 70 eV) m/z (%) 426
([M]þ, 11), 316 (8), 315 (30), 314 (100), 297 (31), 70 (13); HRMS (EI):
X-ray crystallographic data (excluding structure factors) for the
structures 8b, 8f, 8g, 11a, 12a, and 12f, reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 834695e834700, can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 (1223) 336033; e-mail: depos-
it@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif.
calcd for C21H21F3O4S [M]þ 426.11072, found 426.11019; IR (ATR,
cmꢁ1
)
n
3121 (w), 3058 (w), 3028 (w), 2961 (m), 2931 (m), 2874 (m),
~
1811 (w), 1756 (s), 1693 (s), 1609 (m), 1590 (m), 1532 (w), 1501 (m),
1483 (m), 1468 (m), 1434 (m), 1393 (m), 1289 (s), 1277 (s), 1232 (s),
1175 (s), 1139 (s), 1095 (m), 1034 (m). Anal. Calcd for C21H21F3O4S
(426.45): C, 59.15; H, 4.96. Found: C, 59.28; H, 4.92.
4.4.4. 2-(2-Ethylhexyl) 3-methyl 4-oxo-4H-thieno[3,2-c]chromene-
Acknowledgements
2,3-dicarboxylate (12d). Yield54% (168 mg), mp 113e114 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
0.91 (t, 3H, J¼6.8 Hz), 0.94 (t, 3H, J¼7.4 Hz), 1.5e1.2
Financial support by the DAAD (scholarships for S.M., M.V.-H.,
and S.D.) is acknowledged.
(m, 8H), 1.69 (sept, 1H, J¼6.0 Hz), 4.04 (s, 3H), 4.26 (m, 2H), 7.34 (dt,
1H, J¼7.6,1.0 Hz), 7.42 (dd,1H, J¼8.6,1.0 Hz), 7.57 (m,1H), 7.73 (dd,1H,
J¼7.8, 1.5 Hz); 13C NMR (63 MHz, CDCl3)
d 10.9, 14.0, 22.9, 23.6, 28.8,
References and notes
30.2, 38.7, 53.4, 68.9,115.8,117.8,123.1,123.8,125.1,130.6,132.3,138.3,
151.6, 151.8, 155.1, 160.1, 163.9; MS (EI, 70 eV) m/z (%) 416 ([M]þ, 18),
304 (100), 287 (30), 273 (71), 229 (55), 202 (38); HRMS (ESI-TOF/MS):
calcd for C22H24O6S [MþNa]þ 439.1186, found 439.1187; IR (ATR,
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