The first synthesis of 4-unsubstituted 3-(trifluoroacetyl)coumarins by the knoevenagel condensation of salicylaldehydes with ethyl trifluoroacetoacetate followed by chromene-coumarin recyclization

Article abstract of DOI:10.1055/s-2007-1000867

A series of ethyl 6-substituted 2-hydroxy-2-(trifluoromethyl)-2H-chromene- 3-carboxylates was obtained in good yields via the Knoevenagel condensation of salicylaldehydes with ethyl trifluoroacetoacetate in the presence of piperidinium acetate. The subsequent recyclization of these chromenes proceeds smoothly in refluxing chlorobenzene in the presence of p-toluenesulfonic acid affording previously unknown 3-(trifluoroacetyl)coumarins in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000867

LETTER
281
The First Synthesis of 4-Unsubstituted 3-(Trifluoroacetyl)coumarins by the
Knoevenagel Condensation of Salicylaldehydes with Ethyl Trifluoroaceto-
acetate Followed by Chromene–Coumarin Recyclization
S
ynthesis of 4-Uns
m
ubstituted3-(Triflu
i
oroace
t
r
arins ii L. Chizhov,*a Vyacheslav Ya. Sosnovskikh,b Marina V. Pryadeina,a Yanina V. Burgart,a Victor I. Saloutin,a
Valery N. Charushina
a
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620041 Ekaterinburg,
Russian Federation
Fax +7(343)3693058; E-mail: dlchizhov@ios.uran.ru
Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
b
Received 17 October 2007
marin system and the carbonyl carbon of 3-polyfluoroacyl
group.
Abstract: A series of ethyl 6-substituted 2-hydroxy-2-(trifluoro-
methyl)-2H-chromene-3-carboxylates was obtained in good yields
via the Knoevenagel condensation of salicylaldehydes with ethyl
trifluoroacetoacetate in the presence of piperidinium acetate. The
subsequent recyclization of these chromenes proceeds smoothly in
refluxing chlorobenzene in the presence of p-toluenesulfonic acid
affording previously unknown 3-(trifluoroacetyl)coumarins in
moderate to good yields.
In view of the unique biological properties displayed by
many fluorinated heterocyclic compounds7 and as an ex-
tension of our continuing synthetic studies on the reactiv-
ity of RF-containing compounds,8 we have focussed our
attention on the 3-(trifluoroacetyl)coumarins as a new
class of polydentate electrophilic substrates. 3-Trifluoro-
acetyl-substituted coumarins, despite of their potential in-
terest as building blocks in organic synthesis for the
construction of more complex trifluoromethylated hetero-
cycles, have not received much attention, probably owing
to the lack of general methods for the synthesis of these
compounds. To the best of our knowledge, there has been
only one report on the preparation of 3-(trifluoroacetyl)-4-
(trifluoromethyl)-7-hydroxycoumarin 3 by reaction of
ethyl trifluoroacetoacetate with trimethylsilylated deriva-
tive of w-trifluoro-2,4-dihydroxyacetophenone.9 On the
other hand, 3-RFCO-chromones 4 isomeric to 3-RFCO-
coumarins 2 (Figure 1) were successfully employed for
the preparation of various RF-containing heterocycles,
such as isoxazoles, pyrazoles, fused pyrans, and pyr-
idines.10
Key words: ethyl trifluoroacetoacetate, salicylaldehydes, Knoeve-
nagel condensation, 3-(trifluoroacetyl)coumarins, chromene–cou-
marin recyclization
Derivatives of 2H-1-benzopyran-2-one, also known as
coumarins, are prominent natural products possessing a
wide range of valuable physiological activities. Cou-
marins have been reported to exhibit antibacterial and an-
tifungal activity and to act as diuretics and analgesics.1
There have also been reports that structures containing the
coumarin ring reduce tissue swelling due to various kinds
of trauma or disease, display hypolipidaemic, vasorelax-
ant, antiplatelet aggregation, antioxidant, anti-inflamma-
tory, and immunosuppressive activities.2 In addition, they
have also found application as photosensitizers, fluores-
cent and laser dyes,3 and represent useful synthetic build-
ing blocks in organic and medicinal chemistry.4
The importance of highly reactive substrates 4 prompted
us to develop a new general and efficient method for the
preparation of 3-(trifluoroacetyl)coumarins as useful pre-
cursors of a wide variety of heterocycles with CF3 group.
We reasoned that replacing the hydrogens of the 3-acetyl
group with fluorine atoms, which are strongly electroneg-
Coumarins can be synthesized by methods such as the
Perkin, Pechmann, and Wittig reactions as well as Knoev-
enagel condensation. The reaction of active methylene
compounds with salicylaldehydes under base catalysis, an
example of the Knoevenagel reaction,5 has been exten-
sively used as the first step in the synthesis of 3-substitut-
ed coumarins. With methylene compounds activated by
CO2R and CN groups, the reaction affords, almost invari-
able, coumarins 1 bearing different electron-withdrawing
substituents at the 3-position. However, in contrast to
well-known 3-acylcoumarins (1, X = COR),6 no data on
the chemical properties of 3-(polyfluoroacyl)coumarins 2
have been documented. This is quite surprising, especially
as these compounds should contain three strong electro-
philic centers, that is the C-2 and C-4 atoms of the cou-
X
CORF
R
O
O
O
O
1
2
X = COR, CO2R, CN, NO2
CF3
O
COCF3
CORF
R
HO
O
O
O
3
4
SYNLETT 2008, No. 2, pp 0281–0285
x
x.
x
x.
2
0
0
8
Advanced online publication: 21.12.2008
DOI: 10.1055/s-2007-1000867; Art ID: G31407ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Benzopyranones bearing different EWG substituents at
the 3-position

282
D. L. Chizhov et al.
LETTER
Table 1 Reaction of Ethyl Trifluoroacetoacetate with Salicylaldehydes 5a–d
Entry
Aldehyde
R
Solvent, catalysta
Timeb
Yield (%)c
Ratio of productsd
6
7 + 8
1
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
H
toluene, piperidine
toluene, PA
6 h
6 h
8 h
30 d
6 h
12 h
5 d
4 h
6 h
4 h
3 h
68
73
91
83
90
73
77
85
85
83
87
52
48
36
12
5
2
H
64
3
H
benzene, PA
benzene, PA (r.t.)
PA (110 °C)e
MeCN, Et3N
MeCN, PA (r.t.)
MeCN, PA
88
4
H
95
5
H
95
5
6
H
100
100
100
100
100
100
0
7
H
0
8
H
0
9
MeO
Br
NO2
MeCN, PA
0
10
11
MeCN, PA
0
MeCN, PA
0
a Refluxing, if not indicate otherwise.
b Monitoring by TLC.
c Isolated yield.
d Based on the 1H and 19F spectra of a crude reaction mixture.
e Under solvent-free conditions.
R
CHO
ative, would have a positive effect on the reactivity and
synthetic utility of these coumarin derivatives. Our ap-
proach to new 3-(trifluoroacetyl)coumarins follows the
same design as many older methods for the preparation of
3-substituted coumarins 1 and includes the Knoevenagel
condensation of an appropriately substituted salicylalde-
hyde 5 with ethyl trifluoroacetoacetate. Because the
Knoevenagel reaction usually affords a mixture of E- and
Z-isomers of substituted olefins, we could expect the for-
mation of two benzylidene derivatives A and B, whose in-
tramolecular ring closure should result in a mixture of
ethyl 2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-car-
boxylates 6 and 3-(trifluoroacetyl)coumarins 7. In this let-
ter, we wish to report the successful two-step approach to
coumarins 7, involving the condensation of ethyl trifluo-
roacetoacetate with salicylaldehydes 5 with the selective
formation of chromenes 6 and the recyclization of 6 to 7
under the thermodynamically controlled reaction condi-
tions.
F3C
CO2Et
+
O
OH
5a–d
+
–
– H2O
C5H10NH2 OAc
R
CO2Et
R
COCF3
CO2Et
+
COCF3
OH
OH
A
B
– EtOH
R
CO2Et
OH
R
COCF3
O
+
O
CF3
O
6a–d
7a–d
+
HO
OH
We found that ethyl trifluoroacetoacetate reacted with sal-
icylaldehyde 5a under the Knoevenagel reaction condi-
tions (refluxing toluene and piperidine as a catalyst)
affording a mixture of chromene 6a, coumarin 7a, and its
hydrate 8a in the ratio of 6a:(7a + 8a) = 52:48, based on
the 19F NMR spectrum of a crude reaction mixture
(Scheme 1, Table 1, entry 1). All our attempts to obtain 7a
(or its mixture with 8a) as the sole product were fruitless.
The use of piperidinium acetate (PA) and Et3N as well as
replacement of toluene by benzene or absence of any sol-
vents resulted in a mixture of chromene 6a with 7a + 8a
in various ratios (Table 1, entries 2–5). In these cases, the
R
CF3
O
O
8a–d
Scheme 1 Piperidinium acetate catalyzed Knoevenagel reaction of
ethyl trifluoroacetoacetate with salicylaldehydes 5a–d
reaction between the salicylaldehyde 5a and ethyl trifluo-
roacetoacetate gave the chromene 6a with only minor
quantities of 3-(trifluoroacetyl)coumarin 7a, that is the cy-
clization preferentially occurred by addition of the phen-
olic hydroxyl to the CF3CO group due to the powerful
Synlett 2008, No. 2, 281–285 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Unsubstituted 3-(Trifluoroacetyl)coumarins
283
inductive control of the CF3 group. This suggests that the
Knoevenagel condensation under these conditions is ste-
reoselective yielding E-styryl derivatives A as the main
intermediates in which the aromatic ring and the CF3CO
group are in the cis-configuration, thus facilitating selec-
tive cyclization. As expected, the intramolecular cycliza-
tion of Z-styryl derivative B under these conditions
resulted in the formation of coumarin 7a.
Table 2 Chromene–Coumarin Recyclization of 6 to 7
Coumarin
R
Time (h)
Yield (%)
7a
7b
7c
7d
H
12
10
13
17
74
76
73
54
MeO
Br
NO2
Next we found that chromene 6a can be obtained exclu-
sively in good yield when the Knoevenagel condensation
was carried out in the presence of Et3N (1 equiv) or PA
(2–5 mol%) in acetonitrile with or without refluxing
(Table 1, entries 6–8). The most suitable conditions
(Table 1, entry 8) were used to condense ethyl trifluoro-
acetoacetate with salicylaldehydes 5b–d and 6-substituted
chromenes 6b–d were obtained (Table 1, entries 9–11).11
Noticeably, the nature of the substituents not have any
major effect on the reaction outcome. Very recently,12 the
synthesis of 3-unsubstituted 2-hydroxy-2-(trifluorometh-
yl)-2H-chromenes, which turned out to be highly reactive
synthons, was achieved by intramolecular cyclization of
3-(trifluoromethyl)-3-phenoxypropenals in the presence
of aluminum chloride.
R
CO2Et
OH
R
COCF3
TsOH
PhCl,
O
CF3
O
O
6a–d
7a–d
H+
– EtOH, – H+
OH
R
CO2Et
OH
COCF3
O
H
CF3
O
OEt
R
H
A
C
~H+
OH
R
OH
Taking into account the high stability of the coumarin sys-
tem compared to that of the chromene system and the fact
that alkylideneacetoacetates are prone to E/Z isomeriza-
tion on heating or treating with Lewis acids,13 we attempt-
ed to transform 6 into 7. It was found that chromenes 6
rearrange to coumarins 7 smoothly in the presence of
TsOH (10 mol%) in refluxing chlorobenzene for 10–17
hours (Scheme 2, Table 2).14 The progress of the reaction
was monitored by TLC. Compounds 7a–d were obtained
in good yields (54–76%), however, in marked contrast to
the known 3-acylcoumarins,6 the coumarins obtained in
this work were prone to the facile and reversible covalent
hydrate formation as observed from their 1H NMR and 19F
NMR spectra, which contained two sets of signals. The di-
agnostic signal for the proton H-4 in coumarins 7a–d,
which appeared at d = 8.4–8.6 ppm, was shifted upfield in
hydrates 8a–d (d = 8.2–8.4 ppm). The facile formation of
hydrates 8 probably arises from the high hydrophilicity of
coumarins 7 due to the electrophilic character of the
carbonyl carbon atom connected to a trifluoromethyl
substituent as it was observed in the case of 3-(trifluoro-
acetyl)chromones.10 As can be seen from the Table 2, the
electron-withdrawing nitro group of chromene 6d compli-
cates the rearrangement (the reaction time is longer, and
the yield is lower), probably due to the lower nucleophi-
licity of the phenolic hydroxyl. At the same time, elec-
tron-donating methoxy group at the 6-position slightly
facilitates this reaction.
CO2Et
CF3
CO2Et
CF3
O
H
O
H
B
R
Scheme 2 Synthesis of 3-(trifluoroacetyl)coumarins 7a–d
was observed. This result indicates that the acid has an im-
portant role in the Z → E isomerization during the trans-
formation of chromenes 6 into the corresponding
coumarins 7. This approach is the first example of suc-
cessful synthesis of 4-unsubstituted 3-(trifluoro-
acetyl)coumarins 7 and has advantages with regard to ease
of operation and the ready availability of starting materi-
als. Although the method represents a two-step process, it
is experimentally simple and may be of value in RF-con-
taining building-block chemistry since coumarins 7 could
be regarded as a,b-unsaturated trifluoromethylketones.15
A plausible pathway leading to the formation of these
compounds is outlined in Scheme 2. The formation of
coumarins 7 is strictly linked to their high stability and
could be explained by protonation of the heterocyclic oxy-
gen (cation A) followed by opening of the pyran ring to
cation B, isomerization B → C, and subsequent intramo-
lecular cyclization between ortho-hydroxyl and ethoxy-
carbonyl groups with elimination of ethanol (Scheme 2).
The structures of the chromenes 6 and coumarins 7 were
confirmed by elemental analysis, H, 19F, 13C NMR, and
1
Coumarins 7a–d were isolated in analytically pure form
by the azeotropic water removal with toluene followed by
sublimation; however, on storing for three months they
added water again and the content of hydrate 8 reached
40%. It should be mentioned that when chromene 6a was
refluxed in chlorobenzene for 36 hours without an acidic
catalyst or in the presence of Et3N, no recyclization to 7a
IR spectroscopy.11,14 The IR spectra of 6 showed intensive
absorption bands in the ranges 3230–3260 cm–1 corre-
sponding to the hydroxyl group, 1680–1690 cm–1 attribut-
ed to the ethoxycarbonyl group, and 1560–1580 cm–1 due
to the C=C double bond. A characteristic feature of the 1H
NMR spectra in CDCl3 is the appearance of a singlet at
Synlett 2008, No. 2, 281–285 © Thieme Stuttgart · New York

284
D. L. Chizhov et al.
LETTER
(5) (a) Jones, G. Org. React. (N. Y.) 1967, 15, 204. (b) Tietze,
L. F.; Beifuss, U. In Comprehensive Organic Synthesis, Vol.
2; Trost, B. M.; Fleming, I.; Heathcock, C. H., Eds.;
Pergamon Press: Oxford, 1991, 341. (c) Bigi, F.; Chesini,
L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999, 64, 1033.
(d) Fringuelli, F.; Permatti, O.; Pizzo, F. Synthesis 2003,
2331.
(6) (a) Selim, M. R. J. Chem. Res., Synop. 1998, 84.
(b) O’Callaghan, C. N.; McMurry, T. B. M. J. Chem. Res.,
Synop. 1997, 78. (c) O’Callaghan, C. N.; McMurry, T. B. M.
J. Chem. Res., Synop. 1999, 458. (d) Bogdal, D. J. Chem.
Res., Synop. 1998, 468. (e) Buu-Hoi, N. P.; Saint-Ruf, G.;
Loc, T. B.; Xuong, N. D. J. Chem. Soc. 1957, 2593.
(f) Specht, D. P.; Martic, P. A.; Farid, S. Tetrahedron 1982,
38, 1203. (g) Su, C.; Chen, Z.-C.; Zheng, Q.-G. Synthesis
2003, 555. (h) Prakash Rao, H. S.; Sivakumar, S. J. Org.
Chem. 2006, 71, 8715.
d = 7.69–7.82 ppm for the olefinic proton H-4 (for 6a dou-
blet with J = 0.4 Hz) and a singlet at d = 7.40–7.55 ppm
for the OH group, which disappeared in the presence of
CD3CO2D. In the 19F NMR spectra of 6 the trifluorometh-
yl group appeared as a singlet at d = 74.50–74.66 ppm
(C6F6). The intensive absorption bands in the IR spectra in
the ranges 1740–1752, 1696–1719, and 1548–1566 cm–1
were attributed to the ester and ketone carbonyl groups,
and the C=C double bond of coumarins 7, respectively. In
comparison with chromenes 6, shifts of the olefinic proton
H-4 of 7 are more deshielded in the 1H NMR spectra (d =
8.41–8.56 ppm). Noteworthy, that signals of other aro-
matic protons are shifted downfield as well (Dd = 0.36–
0.43 ppm). In the 19F NMR spectra the CF3 group of 7
manifests itself as a singlet at d = 88.16–88.40 ppm
(C6F6).
(7) (a) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Hiyama, T. Organofluorine Compounds. Chemistry and
Application; Springer: Berlin, 2000. (c) Persy, J. M. Top.
Curr. Chem. 1997, 193, 131.
In conclusion, we have shown that the Knoevenagel con-
densation of ethyl trifluoroacetoacetate with salicylalde-
hydes provides a simple and convenient approach from
readily available starting material to ethyl 2-hydroxy-2-
(trifluoromethyl)-2H-chromene-3-carboxylates and 3-
(trifluoroacetyl)coumarins, which may be considered as
useful CF3-containing substrates for the synthesis of a
wide variety of heterocyclic compounds with potential bi-
ological activity. Further studies on the synthetic applica-
tion of this method are now in progress.
(8) (a) Sosnovskikh, V. Ya.; Korotaev, V. Yu.; Chizhov, D. L.;
Kutyashev, I. B.; Yachevskii, D. S.; Kazheva, O. N.;
Dyachenko, O. A.; Charushin, V. N. J. Org. Chem. 2006, 71,
4538. (b) Korotaev, V. Yu.; Kutyashev, I. B.; Sosnovskikh,
V. Ya. Heteroat. Chem. 2005, 16, 492. (c) Chizhov, D. L.;
Ratner, V. G.; Pashkevich, K. I. Russ. Chem. Bull. 1999, 48,
758; Izv. Akad. Nauk, Ser. Khim. 1999, 762. (d)Yachevskii,
D. S.; Chizhov, D. L.; Ratner, V. G.; Pashkevich, K. I. Russ.
Chem. Bull., Int. Ed. 2001, 50, 1233; Izv. Akad. Nauk, Ser.
Khim. 2001, 1176. (e) Chizhov, D. L.; Pashkevich, K. I.;
Röschenthaler, G.-V. J. Fluorine Chem. 2003, 123, 267.
(f) Pryadeina, M. V.; Kuzueva, O. G.; Burgart, Ya. V.;
Saloutin, V. I.; Lyssenko, K. A.; Antipin, M. Yu. J. Fluorine
Chem. 2002, 117, 1. (g) Pryadeina, M. V.; Kuzueva, O. G.;
Burgart, Ya. V.; Saloutin, V. I. Russ. J. Org. Chem. 2002, 38,
224; Zh. Org. Khim. 2002, 38, 244. (h) Pryadeina, M. V.;
Burgart, Ya. V.; Kodess, M. I.; Saloutin, V. I. Russ.
Chem.Bull. Int. Ed. 2005, 54, 2841; Izv. Akad. Nauk. Ser.
Khim. 2005, 2745.
Acknowledgment
This research was financially supported by the Programme for the
Support of Leading Scientific School (grant N 9178.2006.3). Spec-
troscopic investigations and elemental analysis have been made in
the Institute of Organic Synthesis, Ural Branch of the RAS, Eka-
terinburg, Russian Federation.
References and Notes
(9) Voznyi, Ya. V.; Dekaprilevich, M. O.; Yufit, D. S.;
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(b) Sosnovskikh, V. Ya.; Irgashev, R. A.; Barabanov, M. A.
Synthesis 2006, 2707. (c) Sosnovskikh, V. Ya.; Irgashev, R.
A. Heteroat. Chem. 2006, 17, 99. (d) Sosnovskikh, V. Ya.;
Moshkin, V. S.; Irgashev, R. A. Tetrahedron Lett. 2006, 47,
8543. (e) Sosnovskikh, V. Ya.; Irgashev, R. A.;
(1) Bonsignore, L.; Cottiglia, F.; Lavagna, S. M.; Loy, G.; Secci,
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(11) Typical Procedure for Preparation of 6
A mixture of salicylaldehyde (5.0 mmol), ethyl trifluoro-
acetoacetate (5.0 mmol) and piperidinium acetate (4 mg, 5
mol%) was refluxed in MeCN (10 mL) for 3–4 h and then
diluted with H2O (30 mL). The precipitate that formed was
filtered, washed with warm H2O (50 °C, 5 × 10 mL) and
dried on air to give 6.
Data for Compounds 6a,d
Compound 6a: colorless crystals; mp 102–103 °C (hexane).
IR (mull): n = 3294, 1686, 1635, 1607, 1576 cm–1. 1H NMR
(400 MHz, CDCl3): d = 1.40 (t, J = 7.2 Hz, 3 H, Me), 4.38
(q, J = 7.2 Hz, 2 H, OCH2), 7.01–7.06 (m, 2 H, H-6, H-8),
7.26 (dd, J = 7.9, 1.7 Hz, 1 H, H-5), 7.39 (ddd, J = 8.2, 7.5,
1.7 Hz, 1 H, H-7), 7.50 (s, 1 H, OH), 7.78 (s, 1 H, H-4). 19
F
Synlett 2008, No. 2, 281–285 © Thieme Stuttgart · New York

LETTER
NMR (376 MHz, CDCl3): d (C6F6) = 74.50 (s, CF3). 13
Synthesis of 4-Unsubstituted 3-(Trifluoroacetyl)coumarins
285
C
solution was refluxed with a Dean–Stark trap for 5 h, the
solvent was evaporated in vacuo and the residue was
sublimed affording 7.
NMR (100 MHz, CDCl3): d = 14.02 (Me), 62.54 (CH2),
95.29 (q, 2JCF = 35.3 Hz, C-2), 114.74, 116.00 (CH), 117.55,
122.66 (q, 1JCF = 292.0 Hz, CF3), 122.68 (CH), 129.51 (CH),
133.94 (CH), 139.36 (CH), 152.62 (C-8a), 166.80 (C=O).
Anal. Calcd for C13H11F3O4 (%): C, 54.18; H, 3.85; F, 19.77.
Found: C, 54.20; H, 3.85; F, 19.82.
Compound 6d: light-yellow crystals; mp 120–120.5 °C
(benzene). IR (mull): n = 3230, 1686, 1619, 1578, 1527,
1345 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.43 (t, J = 7.2
Hz, 3 H, CH3), 4.42 (q, J = 7.2 Hz, 2 H,OCH2), 7.18 (br.d,
J = 9.0 Hz, 1 H, H-8), 7.55 (s, 1 H, OH), 7.82 (s, 1 H, H-4),
8.23 (d, J = 2.6 Hz, 1 H, H-5), 8.29 (dd, J = 9.0, 2.6 Hz, 1 H,
Data for Compounds 7a,d
Compound 7a: pale yellow crystals; mp 117–118 °C. IR
(mull): n = 1752, 1696, 1605, 1558 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.38–7.45 (m, 1 H, H-8, H-6), 7.70 (dd,
J = 7.8, 1.6 Hz, 1 H, H-5), 7.76 (ddd, J = 8.2, 7.6, 1.6 Hz, 1
H, H-7), 8.52 (s, 1 H, H-4). 19F NMR (376 MHz, CDCl3): d
(C6F6) = 88.37 (s, CF3). 13C NMR (100 MHz, CDCl3):
d = 115. 65 (q, 1JCF = 290.6 Hz, CF3), 116.93 (CH), 117.24,
119.03, 125.49 (CH), 130.63 (CH), 136.25 (CH), 151.07 (C-
4), 155.48 (C-8a), 155.90 (C-2), 178.36 (q, 2JCF = 37.7 Hz,
COCF3). Anal. Calcd for C11H5F3O3 (%): C, 54.56; H, 2.08;
F, 23.54. Found: C, 54.55; H, 2.30; F, 23.53.
H-7). 19F NMR (376 MHz, CDCl3): d (C6F6) = 74.80 (s).13
NMR (100 MHz, CDCl3): d = 13.82 (s, Me), 63.07 (s,
OCH2), 95.96 (q, 2JCF = 35.8 Hz, C-2), 116.79 (s, CH),
117.13, 117.63, 122.11 (q, 1JCF = 291.5 Hz, CF3), 125.02
(CH), 128.81 (CH), 137.09 (CH), 142.79, 156.69 (s, C-8a),
165.98 (s, C=O). Anal. Cald for C13H10NF3O6 (%): C, 46.86;
H, 3.03; F, 17.10; N, 4.20. Found: C, 46.73; H, 3.16; F,
16.97; N, 4.29.
C
Compound 7d: yellowish crystals; mp 115.5–116 °C
(sublim.). IR (mull): n = 1751, 1719, 1611, 1566, 1342
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.58 (dm, J = 9.1 Hz,
1 H, H-8), 8.58 (s, 1 H, H-4), 8.60 (dd, J = 9.1, 2.6 Hz, 1 H,
H-7), 8.65 (d, J = 2.6 Hz, 1 H, H-5). 19F NMR (376 MHz,
CDCl3): d (C6F6) = 88.16 (s). 13C NMR (100 MHz, CDCl3):
d = 115.47 (q, 1JCF = 290.1 Hz, CF3), 117.15, 118.19, 118.53
(CH), 126.08 (CH), 130.06 (CH), 144.68, 149.00 (q,
4JCF = 1.2 Hz, C-4), 154.24 (s, C-8a), 158.55 (C-2), 177.96
(q, 2JCF = 38.6 Hz, COCF3). Anal. Calcd for C11H4NF3O5
(%): C, 46.01; H, 1.40; N, 4.88; F, 19.85. Found: C, 46.00;
H, 1.15; N, 4.72; F, 19.94.
(12) El Kharrat, S.; Laurent, P.; Blancou, H. J. Org. Chem. 2006,
71, 8637.
(13) Inokuchi, T.; Kawafuchi, H. J. Org. Chem. 2006, 71, 947.
(14) General Procedure for Preparation of 7
A mixture of chromene 6 (0.5 mmol) and TsOH·H2O (10
mg, 10 mol.%) was refluxed in chlorobenzene (5 mL) for
10–17 h and then concentrated to ca. 2 mL in volume. The
resulting reaction mixture was dried in vacuo, dissolved in
toluene (15 mL) and washed with H2O (3 × 5 mL). Toluene
(15) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.
Tetrahedron 2007, 63, 7753.
Synlett 2008, No. 2, 281–285 © Thieme Stuttgart · New York

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