4-Chloro-3-(trifluoroacetyl)coumarin as a novel building block for the synthesis of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones

Article abstract of DOI:10.1016/j.tetlet.2010.11.028

4-Chloro-3-(trifluoroacetyl)coumarin was synthesized for the first time via direct TMSCl-mediated acylation of 4-hydroxycoumarin with TFAA followed by the treatment with POCl₃. The reaction of 4-chloro-3-(trifluoroacetyl) coumarin with commercially available anilines is a two-step method, which affords a set of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones in good to excellent yields. Copy; 2010 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2010.11.028

Tetrahedron Letters 52 (2011) 373–376
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
4-Chloro-3-(trifluoroacetyl)coumarin as a novel building block
for the synthesis of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones
Viktor O. Iaroshenko a,b, , Sajid Ali a, Tariq Mahmood Babar a, Sergii Dudkin a, Satenik Mkrtchyan a,
⇑
Nasim Hasan Rama c, Alexander Villinger a, Peter Langer a,d,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
c Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
d Leibniz-Institut für Katalyse e.V. an der Universität Rostock, 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:
4-Chloro-3-(trifluoroacetyl)coumarin was synthesized for the first time via direct TMSCl-mediated acyl-
ation of 4-hydroxycoumarin with TFAA followed by the treatment with POCl3. The reaction of 4-chloro-3-
(trifluoroacetyl)coumarin with commercially available anilines is a two-step method, which affords a set
of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 August 2010
Revised 3 November 2010
Accepted 5 November 2010
Available online 21 November 2010
Keywords:
Cyclization
Coumarins
Anilines
Heterocycles
Fluorine
Chromeno[4,3-b]quinolines
Coumarins (2H-1-benzopyran-2-ones, 2H-chromen-2-ones) are
subunits of many natural products and a range of relevant pharma-
ceuticals with unique biological activities, constituting an impor-
tant class of heterocycles. These compounds are well known
aromatic lactones isolated from a variety of plant sources1 and
implicate diverse bioactivities.2,3 On the other hand, coumarin
framework is present in promising drug candidates as nonpeptidic
HIV protease inhibitors4, topoisomerase II5 and tyrosine kinase6
inhibitors. Many natural, semi-synthetic and synthetic coumarins
have occupied an important place in drug research, as a one of
the so-called privileged drug scaffold. Moreover, heterocyclic com-
posites, containing a coumarin subunit, are of particular interest as
fluorescence dyes which have gained a wide application in mate-
rial science.7 Fluorescent zounds containing a coumarin moiety
are currently used for DNA and RNA labelling.1
6H-chromeno[4,3-b]quinolines are also under investigation in
medicinal chemistry, for example, as a new series of oestrogen
receptor b-selective ligands.11
The attachment of fluorine-containing functional groups to bio-
molecules often results in the development of new physiologically
active compounds.12 In particular, we have undertaken this study
as a logical continuation of our recent achievements13 related to
the synthesis of fluorinated drug-like scaffolds. Herein, we would
like to present our recent results related to the synthesis of the 7-
(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-one ring system
by annulation of the pyridine ring to the aniline moiety. For this pur-
pose, we use the specially designed novel trifluoroacetyl-containing
building block 4a. The synthesis of 6H-chromeno[4,3-b]quinolines
by reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with
anilines, using a related strategy, was previously reported.14
In the initial study we have developed the synthesis of the
hitherto unknown 4-chloro-3-(trifluoroacetyl)-2H-chromen-2-one
4a15 starting from commercially available 4-hydroxy-2H-
chromen-2-one 1 by a one-pot procedure depicted in Scheme
1.16 The synthetic route consists of three steps: firstly, 4-hydroxy-
coumarin 1 was silylated by TMSCl in 1,4-dioxan using dry
pyridine as HCl acceptor; secondly, acylation by TFAA delivers
in situ the corresponding intermediate 3. The latter was treated
with POCl3 to form 4a (dF = À75.8 ppm) in 93% yield (Scheme 1).
4-Chloro-3-(trifluoroacetyl)coumarin 4a is, as previously described
Differently fused chromenopyridin-5-ones are also under inves-
tigation, due to their biological activities.8 Some of them constitute
the backbone of naturally occurring alkaloids, for example, of
santiagonamine.9 Several chromeno[4,3-b]pyridin-5-ones, both
natural and non-natural products are currently in clinical trials,10
and have attracted much attention in recent years. The related
⇑
Corresponding authors. Fax: +49 381 4986412.
E-mail addresses: viktor.iaroshenko@uni-rostock.de, iva108@googlemail.com
(V.O. Iaroshenko).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.028

374
V. O. Iaroshenko et al. / Tetrahedron Letters 52 (2011) 373–376
O
O
Cl
O
Cl
O
O
O
OH
R
i, ii, iii
CF3
R
CF3
Cl
O
O
O
or
5
NH
O
O
O
NH2
i
O
i
O
CF3
4a
4b
CF3
1
iii
10
6
4
11
9
ii
R
TMS
O
TMS
12
7
8
O
O
O
O
O
N
1
7
2
CF3
CF3
6
O
ii
3
O
O
4
5
2
3
Scheme 1. One-pot three step synthesis of 4-chloro-3-(trifluoroacetyl)coumarin
4a. Reagents and conditions: (i) 1,4-dioxan, Py (2.1 equiv), 30 min, TMSCl
(1.2 equiv), 60 min, rt; (ii) TFAA (1.3 equiv), 2 h, 80–90 °C; (iii) POCl3 (1.0 equiv),
60 °C, 2 h.
Scheme 2. Reagents and conditions: (i) DMF/TMSCl, 120 °C, 12–24 h; (ii) concd
H2SO4, 70 °C, 2 h.
Table 1
Synthesis of compounds 6 and 7
for 3-(trifluoroacetyl)coumarins,17 sensitive to moisture. There-
fore, all reactions and storage was performed under dry inert atmo-
sphere. The compound is stable in dry and inert solvents under
inert atmosphere at least for 48 h. This gave us a chance to use
1D and 2D NMR methods to confirm its structure and purity.
The exact structure of product 4a had to be thoroughly estab-
lished. In principle, the compound can exist in the form of another
isomer, namely (E)-3-(1-chloro-2,2,2-trifluoroethylidene)chro-
man-2,4-dione 4b. The structure of 4a could be unambiguously
confirmed by X-ray crystal structure analysis. In principle, the for-
mation of a hydrate is possible. However, the X-ray structure
shows that product 4a exists in the nonhydrated form.18 As ex-
pected, the coumarin motif of 4a is planar. In the crystal, the tor-
sion angle C(1)C(2)–C(10)O(2) is 44.4o (Fig. 1).
With compound 4a in hand, we started to study its reactions
with a range of commercially available o-, m-, and p-substituted
anilines 5 to give 3-(trifluoroacetyl)-4-(arylamino)-2H-chromen-
2-ones 6 (Scheme 2, Table 1). First we have conducted this reaction
in dry solvents, such as DMF, CH2Cl2, toluene, 1,4-dioxan, with tri-
ethylamine as base, however the yields were less then 50%. On this
stage we have turned our attention towards the use of a new con-
densing media, namely DMF/TMSCl.19 These reaction conditions20
have shown the highest yields for the synthesis of 6 (Table 1).21
Concerning the second step, by the testing number of reaction
conditions we have identified concentrated sulfuric acid to be a
reaction media22 of choice for the intramolecular cyclization of 6
to deliver 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones
7 (dF = À53 ppm)23 (Scheme 2).
3
a
Anilines (5)
NH2
% (6)a
R (7)
% (7)a
64
—
86
b
c
d
e
f
H3C
Et
NH2
74
76
85
83
84
68
72
85
60
9-Me
9-Me
9-OMe
9-OEt
9-SMe
9-F
89
90
90
92
95
90
89
88
85
NH2
MeO
EtO
H3CS
F
NH2
NH2
NH2
g
h
i
NH2
Cl
NH2
9-Cl
Br
NH2
9-Br
j
O2N
Br
NH2
9-NO2
k
l
61
—
8-Br
85
65b
89
NH2
MeO
10-OMe
11-I
NH2
I
m
n
65
65
NH2
Br
11-Br
93
NH2
a
Yields of isolated products.
This compound was formed directly on the first step in DMF/TMSCl at 120 °C.
b
In the case of compound 6k, which contains a meta-substituted
aniline moiety, we have observed an unexpected ortho-regioselec-
tivity with formation of the corresponding 8-bromo-7-(trifluoro-
methyl)-6H-chromeno[4,3-b]quinolin-6-one 7k as a single isomer.
Figure 1. Ortep plot of 4-chloro-3-(trifluoroacetyl)-2H-chromen-2-one 4a.

V. O. Iaroshenko et al. / Tetrahedron Letters 52 (2011) 373–376
375
When we have set m-anisidine under investigation, the reaction of
4a in DMF/TMSCl gave 7-(trifluoromethyl)-10-methoxy-6H-chro-
meno[4,3-b]quinolin-6-one 7l in a single step (Table 1).
In summary, we have developed the synthesis of 4-chloro-3-
(trifluoroacetyl)coumarin 4a, a novel fluorine-containing 1,3-CCC-
dielectrophile on the basis of commercially available 4-hydroxy-
coumarin. The reaction of 4a with a number of o-, m- and p-substi-
tuted anilines was studied. The method reported herein provides a
straightforward approach to biologically relevant 4-(trifluoro-
methyl)-5H-chromeno[4,3-b]pyridin-5-ones which are not easily
accessible by other methods.
In order to confirm the structure of compounds 7l and 7k we
have undertaken the study by means of H–H, C–H (HMQC, HMBC,
NOESY) correlation spectroscopy. By these NMR methods we have
assigned all protons and carbon atoms of the 7-(trifluoromethyl)-
6H-chromeno[4,3-b]quinolin-6-one framework. This study reveals
that for compound 7l the proton at the 8-position appears as a
doublet of quartets at 8.05 ppm, the first coupling constant on
H(9) is J = 8.1 Hz and the second coupling constant of J = 1.8 Hz is
a through space coupling constant on the fluorine atoms of the
neighbouring CF3-group. At the same time, the same 2D methods
have proven that bromine atom in the case of compound 7k situ-
ates in position 8.
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern
(scholarships for S.M.), by the European Regional Development
Fund (EFRE), and by the State of Pakistan (HEC scholarship for
T.M.B., and S.A.) is gratefully acknowledged. Funding for Dr. V. O.
I by the German Ministry of Education and Research (BMBF) is
gratefully acknowledged (Grant No. 03IS2081A).
The structure of scaffolds 624 and 725 was unambiguously estab-
lished by the crystal structure investigation (Figs. 2 and 3). The
structure of 6e contains intermolecular hydrogen bond between
H at N(1) and the oxygen O(3) (Fig. 2). The dihedral angle C(3)–
N(1)–C(12) is 129.3° for 6e, the plane of aryl substituent is termed
on 55° regarding the coumarin plane. The corresponding torsion an-
gle C(13)C(12)–N(1)C(3) is 55.2°. The geometry of 7i is not planar, it
is twisted, the dihedral angle C(1)C(2)–C(10)C(17) is about 20.7°.
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15. 4-Chloro-3-(trifluoroacetyl)-2H-chromen-2-one (4a): white solid (3.94 g, 93%),
mp 115–117 °C. 1H NMR (300 MHz, CDCl3): d = 7.42–7.50 (m, 2H), 7.73–7.78
(m, 1H), 7.97–8.00 (m, 1H). 13C NMR (62.9 MHz, DMSO): d = 114.4 (q,
J = 290 Hz), 116.9, 117.4, 120.8, 125.8, 126.7, 135.5, 150.2, 152.9, 155.9, 180.9
(q, J = 40 Hz). 19F NMR (282.4 MHz, CDCl3): d = À75.8 (s, CF3). MS (EI, 70 eV): m/
z (%) = 276 (M+, 15), 209 (33), 208 (12), 207 (100), 135 (18), 123 (11). HRMS
(ESI): calcd for C11H4ClF3O3 (M+H) 277.0072, found 277.0070. IR (ATR, cmÀ1):
20. General procedure for the synthesis of compounds 6. Synthesis was carried out in
a pressure tube. To a solution of compound 4 (0.3 g, 1.08 mmol) and equimolar
amount of aniline in DMF (15 ml) was added TMSCl (1 ml) dropwise. The
reaction was heated for 12–24 h at 110–120 °C (controlled by TLC). After
cooling the pressure tube, the reaction mixture was poured into water. The
precipitate formed was filtered and dried. The product was purified on column
chromatography. The products 6 were obtained in good to excellent yield (60–
85%).
21. 4-(4-(Methylthio)phenylamino)-3-(trifluoroacetyl)-2H-chromen-2-one
(6f).
Yellow solid (0.35 g, 84%), mp 176–177 °C. 1H NMR (300 MHz, CDCl3):
d = 2.54 (s, 3H, SCH3), 6.9 (dt, 2H, J = 7.5, 1.2 Hz), 7.16 (d, 2H, J = 8.5 Hz), 7.24
(d, 1H, J = 8.4, 1.2 Hz), 7.28–7.31 (m, 2H), 7.54 (dt, 1H, J = 7.3, 1.4 Hz), 12.9 (s,
1H, NH). 13C NMR (75 MHz, CDCl3): d = 15.6, 95.8, 112.5, 117.1 (q, J = 287.8 Hz),
118.5, 123.3, 125.6, 127.5, 128.1, 135.2, 135.4, 140.1, 155.2, 158.2, 160.9, 181.2
(J = 37.1 Hz). 19F NMR (282 MHz, CDCl3): d = À72.7 (s, CF3). GC–MS (EI, 70 eV):
m/z (%) = 379 (M+, 100), 361 (89), 310 (42), 295 (40), 235 (13). HRMS (ESI):
calcd for C18H13F3NO3S (M+H) 380.0563, found 380.0562. IR (ATR, cmÀ1):
m
= 3084 (w), 1727 (m), 1605 (w), 1584 (m), 1480 (w), 1453 (m), 1315 (s), 1276
(w), 1237 (w), 1195 (m), 1170 (s), 1156 (s), 1135 (m), 1073 (m), 1034 (w), 974
(m), 851 (m), 820 (m), 766 (s), 723 (s), 657 (m), 625 (w), 606 (w), 582 (m).
22. General procedure for the synthesis of compounds 7. The intermediate
6
(0.05 mmol) was heated at 70 °C for 2 h in concd H2SO4 under inert
atmosphere. Then reaction mixture was poured into cold water and the
formed precipitate was filtered off, washed with diluted sodium carbonate
solution, then water and finally dried. The product was purified by column
chromatography. The product 7 was obtained in excellent yield (85–95%).
m
= 3084 (w), 1727 (m), 1605 (w), 1584 (m), 1480 (w), 1453 (m), 1315 (s), 1276
23. 9-(Methylthio)-7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-one
(7f).
(w), 1237 (w), 1195 (m), 1170 (s), 1156 (s), 1135 (m), 1073 (m), 1034 (w), 974
(m), 851 (m), 820 (m), 766 (s), 723 (s), 657 (m), 625 (w), 606 (w), 582 (m).
16. Procedure for the synthesis of compound 4a. Synthesis was conducted in a
pressure tube. To the suspension of 4-hydroxycoumarin (2.5 g, 15.4 mmol) in
dry 1,4-dioxane was added 2.56 g (32.4 mmol) of dry pyridine. After a brief
stirring, when the mixture became completely homogeneous, were added
2.01 g (18.5 mmol) of trimethylsilylchloride. The reaction mixture was stirred
for 1 h at room temperature. Then was added 4.21 g (20.0 mmol) of
trifluoroacetic anhydride and the mixture was stirred for another 2 h at 80–
90 °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 sulphate, chloroform was removed and the residue was
dried in a high vacuum on a boiling water bath. Yield 3.94 g (93%). To obtain
product of extra high purity sublimation in vacuum was used. In this case, the
yield is 3.29 g (77%).
Yellow solid (0.17 g, 95%), mp 192–194 °C. 1H NMR (300 MHz, CDCl3):
d = 2.55 (s, 3H, SCH3), 7.24 (dd, 1H, J = 8.3, 0.8 Hz), 7.31 (dt, 1H, J = 7.8,
1.1 Hz), 7.46–7.51 (m, 1H), 7.64 (dd, 1H, J = 9.2 Hz, J = 1.1 Hz), 7.79–7.83 (m,
1H), 7.98 (d, 1H, J = 9.0 Hz), 8.57 (dd, 1H, J = 8.0, 1.5 Hz). 13C NMR (62.9 MHz,
CDCl3): d = 14.0, 114.9 (q, J = 1.8 Hz), 116.9, 118.3, 118.7, 123.2 (q, J = 277.5 Hz),
124.6, 125.0, 125.5, 130.1, 132.6, 132.7, 135.8, 141.7, 148.6, 150.1, 152.2, 157.7.
19F NMR (282 MHz, CDCl3): d = À53.6 (s, CF3). MS (EI, 70 eV): m/z (%) = 361 (M+,
100), 346 (11), 326 (7), 302 (9). HRMS (ESI): calcd for C18H11F3NO2S (M+H)
362.0457, found 362.0453.
24. CCDC-794413 for 6e contains all crystallographic details of this publication and
is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can
be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
25. CCDC-794414 for 7i contains all crystallographic details of this publication and
is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can
be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
17. Chizhov, D. L.; Sosnovskikh, V. Y.; Pryadeina, M. V.; Burgart, Y. V.; Saloutin, V. I.;
Charushin, V. N. Synlett 2008, 281–285.