One-pot synthesis of 2-trifluoromethylchromones

Article abstract of DOI:10.1016/j.tetlet.2011.01.045

We report a simple and suitable method for the preparation of useful 2-trifluoromethylchromones in one step, in high yields and avoiding the use of solvents. We were able to detect the intermediate of this reaction. Furthermore a mechanism for the formati

Full text of DOI:10.1016/j.tetlet.2011.01.045

Tetrahedron Letters 52 (2011) 1436–1440
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 2-trifluoromethylchromones
Isabel C. Henao Castañeda a,c, Sonia E. Ulic b,d, Carlos O. Della Védova a,b, Nils Metzler-Nolte e, Jorge L. Jios a,
⇑
a Laboratorio de Servicios a la Industria y al Sistema Científico (UNLP-CIC-CONICET), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La
Plata, 47 esq. 115, 1900 La Plata, Argentina
b CEQUINOR (UNLP-CONICET), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 esq. 115, 1900 La Plata, Argentina
c Departamento de Farmacia, Facultad de Química Farmacéutica, Universidad de Antioquia, calle 67 No Medellín, Colombia
d Departamento de Ciencias Básicas, Universidad Nacional de Luján, Rutas 5 y 7, 6700 Luján, Argentina
e Lehrstuhl für Anorganische Chemie I—Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse150, D-44801 Bochum, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a simple and suitable method for the preparation of useful 2-trifluoromethylchromones in one
step, in high yields and avoiding the use of solvents. We were able to detect the intermediate of this reac-
Received 29 November 2010
Revised 30 December 2010
Accepted 10 January 2011
Available online 18 January 2011
tion. Furthermore
a mechanism for the formation of the 7-methoxy-3-trifluoroacetyl-2-trif-
luoromethylchromone through the unexpected double trifluoroacetylation of 4-methoxy-2-
hydroxyacetophenone followed by dehydration is also proposed. All compounds are fully identified
and characterized by spectroscopic techniques.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
2-Trifluoromethylchromones
NMR characterization
One-pot synthesis
1. Introduction
the study of the synthesis and reactivity of 2-polyfluoroalkylchro-
mones.8 Additionally, a series of 2-trifluoromethylchromones has
Chromones are an important class of oxygen-containing hetero-
cyclic compounds. These kind of compounds have been extensively
studied and their occurrence in the nature is widespread.1 The
existence of chromones as parent compounds of fruit and flower
been synthesized in our laboratory.9 The introduction of the trifluo-
romethyl group into the C2 position of chromone causes activation
of the pyrone ring, due to the strong electron-withdrawing capacity
of the –CF3. Significant differences in reactivity between 2-alkyl-
and 2-trifluoromethylchromones with respect to nucleophilic re-
agents were observed.8 Besides, this strong electron-withdrawing
property of the trifluoromethyl group has been found to enhance
the electrophilic character at cationic sites in superelectrophiles
leading to greater positive-charge delocalization.10
2
pigments is well known and documented. 2-Methylchromones3
are usually readily cleaved at the pyrone ring via nucleophilic at-
tack at the C-2 position. This property has been utilized for the
preparation of a variety of rearranged products and heterocyclic
molecules.3,4
Contrastingly, the 2-perfluoroalkyl derivatives of chromone
have been never found in nature. The first 2-trifluoromethyl-
substituted chromones5 were prepared long time ago but
such fluorinated molecules have been scarcely studied. The
trifluoromethyl substituent is a very important group because their
presence in organic molecules increases their applicability as phar-
maceuticals or agrochemicals. Pharmacological properties, such as
fat solubility or metabolic stability are improved when aromatic
substrates are functionalized with this substituent6. Despite its
importance, there are no good general methods for the introduc-
tion of the trifluoromethyl group into organic molecules. Recently,
a catalytic reaction for the introduction of this useful trifluoro-
methyl group has been described with success.6,7 In the last decade
Sosnovskikh and his group have devoted considerable attention to
The previous reports, describing the synthesis of 2-perflu-
oroalkylchromones, require at least a two-step procedure with loss
of yield.5,8,11 Therefore, simpler and high yield approaches toward
fluorinated chromones would be desirable.
In this work we wish to report a high yield and simple one-pot
synthesis procedure of 2-perfluoromethylchromones. This opens a
new synthetic way to molecules containing the strongly electron-
withdrawing trifluoromethyl group.
2. Results and discussion
The structure and numbering of the 12 2-trifluoromethylchro-
mones 1 selected for this study are shown in Figure 1, while the
description of substituents and yields are described in Table 1.
The studied compounds showed 1H NMR spectra with the char-
acteristic singlet signals of the vinyl proton H-3 between 6.90 and
6.60 ppm, while in the 13C NMR spectra, the CF3, C-2 and C-3
⇑
Corresponding author. Tel.: +54 0221 471 4527; fax: +54 0221 471 4527
E-mail address: jljios@quimica.unlp.edu.ar (J.L. Jios).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.045

Isabel C. Henao Castañeda et al. / Tetrahedron Letters 52 (2011) 1436–1440
1437
O
CH3
β
O
O
+
O
R
C
CH3
α
α
β
8
5
OH
O
O
CF
3
α
(CF CO) O
7
6
3
2
R
–
O
Py, 3h, 80 °C
3
α
(i)
(ii)
β
β
Scheme 1. Electron delocalization in 2-methylchromone.
Figure 1. Reaction conditions, and numbering of the obtained 2-trif-
luoromethylchromones 1.
methoxy group and its location in para position to the carbonyl
group are crucial in the 3-trifluoroacetylation of the desired product.
The strength of the trifluoroacetic anhydride as acylating agent
on the one hand, and the electron delocalization toward the car-
bonyl oxygen promoted by the methoxyl group in para position,
on the other hand, favor the over trifluoracetylation of an interme-
diate, which ultimately produce the chromone 1i.
One possible mechanism that would explain the formation of 1i
is shown in Figure 2. After the initial esterification of the hydroxy-
acetophenone, the structures (a) and (b) are in resonance, but the
last structure increases its weight due to the favored electron delo-
calization of the methoxy group. The ionized structure (b) is ester-
ified by nucleophilic attack of the trifluoroacetic anhydride to
produce the intermediate (c). The removal of a proton catalyzed
by the trifluoroacetate anion gives the intermediate (d), which
after charge migration and rearrangement forms 1,3-diketone (e),
the latter intermediate was rearranged in the same manner to pro-
duce intermediate (f). Finally, the last intermediate cycles to chro-
mone (i) with loss of water.
carbon atoms are easily recognizable due to their coupling pattern
and J values. The chemical shifts of C-2 are in the range between
152.5 and 149.6 ppm (152.3 for 2-trifluoromethylchromone 1a)
while the same carbon atom in 2-methylchromone appears at
165.8 ppm.3 Noteworthy, the C-2 carbon is protected by a –CF3
group. This apparent anomaly could be explained if we consider
the resonance structures that can take place in the
carbonyl moiety (Scheme 1).
a,b-unsaturated
The weight of the resonance form (ii) in 2-trifluoromethylchro-
mones is strongly disadvantaged because it involves the generation
of a positive charge on one electron-deficient carbon atom. The
chemical shift of the C-3 carbon atom in 2-methylchromone
(110.0 ppm) is somewhat lower than in 2-trifluoromethylchro-
mone (110.5 ppm). This fact also agrees with the highest electron
delocalization postulated for 2-methylchromones. In the IR spec-
trum, the stretching carbonyl frequency provides additional evi-
dence to this conclusion. Values close to 1675 cmꢀ1 were found
for the title compounds, while in 2-methylchromone this fre-
quency falls to 1643 cmꢀ1 12
The effect of replacing CF3 by CH3 is
.
2.2. Detection of an intermediate: example in the preparation of
6-chloro-7-methyl-2-trifluoromethylchromone
the shift toward lower frequencies due to a lower double bond
character of the carbonyl group in the methyl derivatives reflecting
a higher extension of the conjugation.
An aliquot of the just prepared reaction mixture before heating
was analyzed by CG–MS spectroscopy. The chromatogram shows
the absence of chromone and a new peak whose mass spectrum
has a molecular ion 18 amu heavier than the molecular weight of
chromone. This result is consistent with the formation of an inter-
mediated ester produced by acylation of the hydroxyl group, as
usually occurs in the Baker–Venkataraman procedure. After heat-
ing, the chromatogram shows the complete disappearance of this
intermediate and the formation of the chromone by loss of one
molecule of water (18 amu).
2.1. Unexpected trifluoroacetylation of 7-methoxy-2-
trifluoromethylchromone: synthesis of 7-methoxy-3-
trifluoroacetyl-2-trifluoromethylchromone (1i)
The reported synthesis of 7-methoxy-2-trifluoromethylchro-
mone (mp 136 °C) was achieved from 4-methoxy-2-hydroxyaceto-
phenone, sodium, and ethyl trifluoroacetate5 or from (2Z)-4,4,4-
trifluor-3-(3-methoxyphenoxy)butenoic acid.13
All attemptsto obtainthis compoundunder ourinvestigated con-
ditions were unsuccessful. However, we obtained 7-substituted 2-
trifluoromethylchromones with groups other than methoxy (see
entries 1c, 1h and 1j). Moreover, it was possible to obtain 6-meth-
oxy-2-trifluoromethylchromone (1l) in very good yields (90%).
These results show that both the strong donor character of the
Actually, the detected intermediate could be some of the iso-
mers that take place in the Baker–Venkataraman procedure as
shown in the Scheme 2.
We postulate the 2-acetyl-4-chloro-5-methylphenol trifluoro-
acetyl ester as the detected intermediate (Scheme 2a), since the
formation of both compounds b and c requires basic catalysis.
Table 1
Substituents and yields of 2-Trifluoromethylchromones 1
Entry
Compound
R
Yielda
3
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2-Trifluoromethylchromone
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–CH3
–H
–C6H5
–H
–H
–H
–H
–H
–H
–H
98
95
92
89
96
92
79
85
94
95
80
90
6-Methyl-2-trifluoromethylchromone
7-Methyl-2-trifluoromethylchromone
6-Phenyl-2-trifluoromethylchromone
2-Trifluoromethyl-b-naphthochromone
–CH3
–H
–CH@CH–CH@CH–
–H
–H
2-Trifluoromethyl-
a
-naphthochromone
–CH@CH–CH@CH–
–H
–H
–H
–H
–H
–CH3
–H
6-Fluoro-2-trifluoromethylchromone
7-Fluoro-2-trifluoromethylchromone
7-Methoxy-3-trifluoroacetyl-2-trifluoromethylchromone
6-Chloro-7-methyl-2-trifluoromethylchromone
6,8-Dimethyl-2-trifluoromethylchromone
6-Methoxy-2-trifluoromethylchromone
–H
–H
–H
–H
–H
–H
–F
–H
–H
–Cl
–CH3
–OCH3
–F
–COCF3
–H
–H
–OCH3
–CH3
–H
1j
1k
1l
–H
–H
a
Yields after removal of solvent from the isolated product or flash chromatography.

1438
Isabel C. Henao Castañeda et al. / Tetrahedron Letters 52 (2011) 1436–1440
O
CF3
O
O
O
CH3
CF3
O
CH3
H3C
O
O
COCF3
H3C O
OCOCF3
(b)
(a)
O
O
CF3
CF3
O
O
CH2
H
CH2
O
H3C O
OCOCF3
H3C
O
OCOCF3
O
F3C
(d)
(c)
O
H3CO
O
O
CF3
CF3
- H2O
CF3
C
H2
O
O
H3C O
O
COCF3
(f)
(e)
Figure 2. Postulated mechanism for the obtention of 7-methoxy-3-trifluoroacetyl-2-trifluoromethylchromone 1i.
O
O
O
Cl
Cl
Cl
O
CF
3
CF
O
3
OH
CF
O
OH
O
3
a
b
c
Scheme 2. Isomeric structures as possible intermediates in the synthesis of 6-chloro-7-methyl-2-trifluoromethylchromone 1j.
Besides, 1,3-diketone compounds like b are yellow due to their
strong delocalized charges and present yellow solutions. Moreover,
all reactions that we investigated showed colorless solutions and
products.
the formation of side products occurring in this reaction. Also,
we presented evidences of the formation of the intermediate
2-trifluoroacetyloxyacetophenone.
The isolation procedure applied to the reaction causes the hydro-
lysis of the intermediate regenerating the o-hydroxyacetophenone.
We conclude that 2-acetyl-4-chloro-5-methylphenol trifluoro-
acetyl ester is first formed at room temperature and subsequently
trifluoracetic acid is generated by heating with traces of moisture.
This medium could reasonably act as a catalyst for the cyclization
of the ester and subsequent dehydration to chromone.
4. Experimental
Solvents were evaporated from solutions in a rotary evaporator
Heidolph Laborota 4010 equipped with a ROTAVAP valve control.
Melting points (mp) were recorded with a Netzsch DSC 200 PCPhox
or in an Electrothermal 9100 apparatus. The mass spectra were
measured with a CG–MS Shimadzu QP-2010 spectrometer with
HP-5 column. The infrared spectra were recorded in KBr pellets
in the range of 4000 and 400 cmꢀ1 on a Thermo-Nicolet IR200
FT-IR spectrometer (2 cmꢀ1 resolution). The 1H (250.13 MHz) and
13C (62.98 MHz) NMR spectra of the title compounds were mea-
sured at 298 K on a Bruker AC 250 spectrometer. The compounds
were dissolved in CDCl3. Chemical shifts, d, are given in ppm rela-
tive to TMS (d = 0 ppm) and are referenced by using the residual
undeuterated solvent signal. Coupling constants, J, are reported
in Hz, multiplicities being marked as: singlet (s), broad singlet
(br s), doublet (d), double double doublet (ddd), triplet (t), double
triplet (dt) or multiplet (m).
3. Conclusion
Continuing with our studies of biologically active compounds
containing fluorine, we report here a new method to obtain 2-trif-
luoromethylchromones in a single step. The developed procedure
avoids the use of solvents and large excess of some of the reagents
used in other reported methods. Besides, the reaction conditions
and high yields simplify the isolation stage. Under these condi-
tions, we have not been able to obtain the 7-substituted chro-
mones. However, we present a possible mechanism to explain

Isabel C. Henao Castañeda et al. / Tetrahedron Letters 52 (2011) 1436–1440
1439
4.1. Optimized preparation procedure
CF3); 117.1 (C5a
); 113.4 (q, 3J = 3 Hz, C3); 113.4 (C4a); MS m/z
264 (100%, M+), 236 (53%, MꢀCO+), 265, (15%, M+1+).
2-Hydroxyacetophenone (0.01 mol) was dissolved in trifluoro-
acetic anhydride (0.02 mol) and pyridine (0.01 mol) was added to
this dissolution. The reaction mixture was heated at 80 °C and stir-
red for three hours. After cooling the reaction mixture was treated
with 1 M hydrochloric acid (5 ml) and methylene chloride (5 ml)
and washed thoroughly with distilled water. The organic layer
was dried over sodium sulfate anhydride, the solvent removed in
a rotary evaporator and the residue dried in vacuum. If necessary
the desired chromone was separated from starting materials
through flash chromatography using 10% ethyl acetate in hexane.
4.1.6. 2-Trifluoromethyl-
Colorless crystals, mp 120.2 °C (DSC); 92% yield; FT-IR (KBr)
1675 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 8.50 (1H,
dd, J = 9 and 2 Hz, H8 ); 8.10 (1H, d; J = 9 Hz, H5); 7.95 (1H, dd,
J = 7 and 2 Hz, H7
a-naphthochromone (1f)
m
a
a
); 7.80 (1H, d, J = 9 Hz, H6); 7.80–7.69 (2H, m,
H7b and H8b); 6.90 (1H, s, H3); 13C NMR (CDCl3, 62.98 MHz) d
(ppm) 176.6 (C4); 153.3 (C8a); 151.7 (q, 2J = 39 Hz, C2); 136.2
(C7); 130.1 (C7b); 128.2 (C7
a); 127.7 (C8b); 126.6 (C5); 123.4
(C8); 122.3 (C8
a
); 120.5 (C4a); 120.2 (C6); 118.7 (q, 1J = 275 Hz,
CF3); 111.8 (q, 3J = 2 Hz, C3); MS m/z 264 (100%, M+), 236 (39%,
MꢀCO+), 265 (15%, M+1+).
4.1.1. 2-Trifluoromethylchromone (1a)
Colorless crystals, mp 95.0–95.7 °C (lit.14 88–90 °C); 98% yield;
FT-IR (KBr)
m
1673 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d
4.1.7. 6-Fluoro-2-trifluoromethylchromone (1g)
(ppm) 8.20 (1H, dd, J = 8 and 2 Hz, H5), 7.79 (1H, ddd, J = 8, 7 and
2 Hz, H7), 7.55 (1H, br d, J = 8 Hz, H8), 7.48 (1H, dt, J = 8 and
1 Hz, H6), 6.72 (1H, s, H3); 13C NMR (CDCl3, 62.98 MHz) d (ppm)
176.8 (C4); 155.7 (C8a); 152.3 (q, 2J = 39 Hz, C2); 134.9 (C7);
126.3 (C6); 126.0 (C5); 124.1 (C4a); 118.6 (q, 1J = 272, CF3); 118.4
(C8); 110.5 (q, 3J = 3 Hz, C3); 19F NMR (CDCl3, 235.2 MHz) d
(ppm) 16.36 (CF3); MS m/z 214 (100%, M+), 186 (55%, MꢀCO+).
Colorless crystals, mp 76.5 °C (DSC); 79% yield; FT-IR (KBr) m
1675 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 7.73 (1H,
dd, J = 8 and 3 Hz, H5); 7.51 (1H, dd, J = 9 and 4 Hz, H8); 7.41
(1H, dq, J = 9, 7 and 3 Hz, H7); 6.63 (1H, s, H3); 13C NMR (CDCl3,
62.98 MHz) d (ppm) 176.0 (d, 4J = 2 Hz, C4); 160.0 (d, 1J = 249 Hz,
C6); 152.5 (q, 2J = 39 Hz, C2); 151.2 (d, 4J = 2 Hz, C8a); 125.2 (d,
3J = 8 Hz, C4a); 123.2 (d, 2J = 25 Hz, C7); 120.6 (d, 3J = 8 Hz, C8);
118.5 (q, 1J = 274 Hz, CF3); 111.9 (d, 2J = 24 Hz, C5); 109.7 (q,
3J = 3 Hz, C3); MS m/z 232 (100%, M+), 204 (38%, MꢀCO+), 185
(8%, MꢀCOꢀF+), 69 (6%, CF3+).
4.1.2. 6-Methyl-2-trifluoromethylchromone (1b)
Colorless crystals, mp 55.5 °C (DSC); (lit.5 53 °C); 95% yield; FT-
IR (KBr)
m
1673 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm)
6.70 (1H, s, H3); 7.98 (1H, d, J = 1 Hz, H5); 7.6 (1H, dd, J = 9 and
2 Hz, H7); 7.4 (1H, br d, J = 9 Hz, H8); 2.5 (3H, s, CH3); 13C NMR
(CDCl3, 62.98 MHz) d (ppm) 177.0 (C4); 154.0 (C8a); 152.2 (q,
2J = 39 Hz, C2); 136.6 (C7); 136.0 (C6); 125.3 (C5); 123.7 (C4a);
118.7 (q, 1J = 274 Hz, CF3); 118.1 (C8); 110.4 (q, 3J = 3 Hz, C3);
20.9 (CH3); MS m/z 228 (100%, M+); 227 (28%, MꢀH+); 199 (25%,
MꢀHꢀCO+).
4.1.8. 7-Fluoro-2-trifluoromethylchromone (1h)
Colorless crystals, mp 75.2 °C (DSC); 85% yield; FT-IR (KBr)
m
1674 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 8.15 (1H,
br t, H5); 7.17 (1H, d, J = 8 Hz, H8); 7.15 (1H, t, J = 8 Hz, H6); 6.64
(1H, s, H3); 13C NMR (CDCl3, 62.98 MHz) d (ppm) 175.7 (C4);
166.2 (d, 1J = 258 Hz, C7); 156.6 (d, 3J = 13 Hz, C8a); 152.5 (q,
2J = 39 Hz, C2); 128.7 (d, 3J = 11 Hz, C5); 120.8 (d, 4J = 2 Hz, C4a);
118.4 (q, 1J = 274 Hz, CF3); 115.2 (d, 2J = 23 Hz, C6); 110.8 (q,
3J = 3 Hz, C3); 105.2 (d, 2J = 26 Hz, C8); MS m/z 232 (100%, M+),
204 (49%, MꢀCO+).
4.1.3. 7-Methyl-2-trifluoromethylchromone (1c)
Colorless crystals, mp 81.2 °C (DSC); 92% yield; FT-IR (KBr)
m
1674 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 8.00 (1H,
br d, J = 8 Hz, H5); 7.40 (1H, br s, H8); 7.30 (1H, d, J = 8 Hz, H6);
6.70 (1H, s, H3); 2.50 (3H, s, CH3); 13C NMR (CDCl3, 62.98 MHz) d
(ppm) 176.8 (C4); 155.8 (C8a); 152.1 (q, 2J = 39 Hz, C2); 146.7
(C7); 127.8 (C6); 125.5 (C5); 121.8 (C4a); 118.7 (q, 1J = 274 Hz,
CF3); 118.1 (C8); 110.5 (q, 3J = 3 Hz, C3); 21.7 (CH3); MS m/z 228
(100%, M+), 227 (29%, MꢀH+), 199 (25%, MꢀHꢀCO+).
4.1.9. 7-Methoxy-2-trifluoromethylchromone
Alls attempts to obtain the 7-methoxy-2-trifluoromethylchro-
mone under the optimized preparation procedure were unsuccess-
ful. In all cases, the reaction between 2-hydroxy-4-
methoxyacetophenone and trifluoroacetic anhydride led to the for-
mation of 7-methoxy-3-trifluoroacetyl-2-trifluoromethylchro-
mone (1i) as the unique isolated compound.
4.1.4. 6-Phenyl-2-trifluoromethylchromone (1d)
Colorless crystals, mp 106.3–106.5 °C; 89% yield; FT-IR (KBr)
m
4.1.10. 7-Methoxy-3-trifluoroacetyl-2-
trifluoromethylchromone (1i)
1675 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 8.38 (1H,
br d, J = 2 Hz, H5); 7.98 (1H, dd, J = 6 and 2 Hz, H7); 7.63 (2H, dd,
J = 5 and 2 Hz, H20–H60); 7.60 (1H, d, J = 6 Hz, H8); 7.50–7.39 (3H,
m, H30, H40 and H50); 6.70 (1H, s, H3); 13C NMR (CDCl3,
62.98 MHz) d (ppm) 176.9 (C4); 154.9 (C8a); 152.2 (q, 2J = 38 Hz,
C2); 139.5 (C10); 138.6 (C6); 133.9 (C7); 129.0 (C30 and C50);
128.2 (C5); 127.1 (C20 and C60); 125.1 (C4a); 124.1 (C40); 118.8
(C8); 118.6 (q, 1J = 275 Hz, CF3); 110.4 (q, 3J = 3 Hz, C3); MS m/z
290 (100%, M+), 262 (14%, MꢀCO+).
Colorless crystals, mp 140.1–140.7 °C; 94% yield; FT-IR (KBr)
m
1659 cmꢀ1 (C@O); 1768 cmꢀ1 (C@O–CF3); 1H NMR (CDCl3,
m
250 MHz) d (ppm) 8.10 (1H, d, J = 9 Hz, H5); 7.11 (1H, dd, J = 9
and 2 Hz, H6); 6.99 (1H, d, J = 2 Hz, H8); 3.97 (3H, s, OCH3); 13C
NMR (CDCl3, 62.98 MHz) d (ppm) 181.1 (q, 2J = 41 Hz, CO–CF3);
173.4 (q, 4J = 2 Hz, C4); 166.0 (C7); 157.0 (C8a); 149.6 (q,
2J = 40 Hz, C2); 127.4 (C5); 119.5 (C4a); 117.9 (q, 1J = 274 Hz,
CF3); 116.9 (C6); 116.4 (q, 3J = 4 Hz, C3); 114.6 (q, 1J = 290 Hz,
F3C–CO); 100.5 (C8); 56.2 (CH3); MS m/z 340 (29%, M+), 271
(100%, MꢀCF3+), 272 (14%, M+HꢀCF3+), 243 (10%, MꢀC(O)CF3+).
4.1.5. 2-Trifluoromethyl-b-naphthochromone (1e)
Colorless crystals, mp 126.4–127.0 °C; 96% yield; FT-IR (KBr)
1673 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 9.90 (1H,
d, J = 9 Hz, H5 ); 8.20 (1H, d; J = 8 Hz, H7); 7.90 (1H, dd, J = 7 and
1 Hz, H6 ); 7.80 (1H, ddd, J = 9, 7 and 1 Hz, H5b); 7.70 (1H, ddd,
m
4.1.11. 6-Chloro-7-methyl-2-trifluoromethylchromone (1j)
a
Colorless crystals, mp 81.4 °C (DSC); 95% yield; FT-IR (KBr) m
a
1687 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm) 8.10 (1H, s,
H5); 7.50 (1H, s, H8); 6.70 (1H, s, H3); 2.50 (3H, s, CH3); 13C NMR
(CDCl3, 62.98 MHz) d (ppm) 175.7 (C4); 153.8 (C8a); 152.3 (q,
2J = 39 Hz, C2); 144.7 (C7); 133.2 (C6); 125.6 (C5); 122.9 (C4a);
120.1 (C8); 119.1 (q, 1J = 274 Hz, CF3); 110.4 (q, 3J = 3 Hz, C3);
J = 9, 7 and 1 Hz, H6b); 7.60 (1H, d, J = 9 Hz, H8); 6.90 (1H, s, H3);
13C NMR (CDCl3, 62.98 MHz) d (ppm) 178.4 (C4); 157.0 (C8a);
150.0 (q, 2J = 39 Hz, C2); 136.8 (C7); 130.8 (C5); 129.9 (C6); 129.9
(C6a
); 128.4 (C5b); 127.4 (C8); 126.9 (C6b); 118.6 (q, 1J = 275 Hz,

1440
Isabel C. Henao Castañeda et al. / Tetrahedron Letters 52 (2011) 1436–1440
20.9 (CH3); MS m/z 262 (100%, M+), 227 (25%, Mꢀ35Cl+), 234 (9%,
MꢀCO+).
Komitee e.V., APA Programm, Wiesbaden, Germany), for the provi-
sion of an FT-IR 200 equipment. J.L.J. and S.E.U. acknowledge the
DAAD for the grant provided for the purchase of a rotary evapora-
tor equipment.
4.1.12. 6,8-Dimethyl-2-trifluoromethylchromone (1k)
Colorless crystals, mp 89.4 °C (DSC); 80% yield; 1H NMR (CDCl3,
250 MHz) d (ppm) 7.82 (1H, s, H5); 7.41 (1H, s, H7); 6.70 (1H, s,
H3); 2.47 (3H, s, CH3); 2.43 (3H, s, CH3); 13C NMR (CDCl3,
62.98 MHz) d (ppm) 177.5 (C4); 152.5 (C8a); 152.0 (q, 2J = 39 Hz,
C2); 137.3 (C7); 136.0 (C6); 127.7 (C8); 123.6 (C4a); 122.8 (C5);
118.7 (q, 1J = 274 Hz, CF3); 110.1 (q, 3J = 2 Hz, C3); 20.9 (CH3-C6);
15.2 (CH3-C8).
References and notes
1. Ellis, G. P. Naturally Occurring Chromones. In The Chemistry of Heterocyclic
Compounds, Weissberger, A., and Taylor, E. C. Eds.; Chromenes, Chromanes, and
Chromones; John Wiley: New York, 1977; Vol. 31, Chapter VII, pp 455–480.
2. (a) Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481–504; (b)
Picman, A. K.; Schneider, E. F.; Picman, J. Biochem. Syst. Ecol. 1995, 23, 683–693.
3. Ibrahim, M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A. ARKIVOC 2010, i, 98–
135.
4.1.13. 6-Methoxy-2-trifluoromethylchromone (1l)
4. (a) Szabó, V.; Borbély, J.; Theisz, E.; Nagy, S. Tetrahedron 1986, 42, 4215–4222;
(b) Khilya, V. P.; Grishko, L. G.; Davidkova, T. L. Chem. Heterocycl. Compd. 1980,
16, 685–690; (c) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. J. Heterocycl.
Chem. 2000, 37, 1629–1634.
Colorless crystals, mp 87.0 °C (DSC); (lit.14 84–86 °C); 90% yield;
FT-IR (KBr)
m
1675 cmꢀ1 (C@O); 1H NMR (CDCl3, 250 MHz) d (ppm)
7.54 (1H, d, J = 3 Hz, H5); 7.48 (1H, d, J = 9 Hz, H8); 7.33 (1H, dd,
J = 9 and 3 Hz, H7); 6.70 (1H, s, H3); 3.90 (3H, s, OCH3); 13C NMR
(CDCl3, 62.98 MHz) d (ppm) 176.8 (C4); 157.7 (C6); 152.1 (q,
2J = 39 Hz, C2); 150.4 (C8a); 125.0 (C7); 124.7 (C4a); 119.8 (C5);
118.7 (q, 1J = 274 Hz, CF3); 109.6 (q, 3J = 2 Hz, C3); 105.0 (C8);
56.0 (OCH3).
5. Whalley, W. B. J. Chem. Soc. 1951, 3235–3238.
6. Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L.
Science 2010, 328, 1679–1681.
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8. (a) Sosnovskikh, V. Ya.; Usachev, B. I. Russ. Chem. Bull. 2001, 50, 1426–1429; (b)
Sosnovskikh, V. Ya.; Usachev, B. I. Russ. Chem. Bull. 2001, 50, 453–455; c)
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A.; Sizov, A. Yu. Russ. Chem. Bull. 2002, 51, 1280–1291; (e) Sosnovskikh, V. Ya.;
Usachev, B. I.; Sevenard, D. V.; Roschenthaler, G.-V. Tetrahedron 2003, 59, 2625–
2630; (f) Sosnovskikh, V. Ya.; Usachev, B. I.; Sevenard, D. V.; Roeschenthaler, G.-
V. J. Org. Chem. 2003, 68, 7747–7754; (g) Sosnovskikh, V. Ya.; Usachev, B. I.;
Sizov, A. Yu.; Barabanov, M. A. Synthesis 2004, 942–948; (h) Sosnovskikh, V. Ya.;
Sizov, A. Yu.; Usachev, B. I.; Kodess, M. I.; Anufriev, V. A. Russ. Chem. Bull. 2006,
55, 535–542.
9. Henao Castañeda Isabel, C. Doctoral Thesis, La Plata, 2009.
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Ch.; Klumpp, D. A. J. Am. Chem. Soc. 2010, 132, 3266–3267.
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Acknowledgments
The authors acknowledge the Consejo Nacional de Investigaci-
ones Científicas y Técnicas (CONICET), Comisión de Investigaciones
Científicas de la Provincia de Buenos Aires (CIC), Facultad de Cien-
cias Exactas (UNLP), Agencia Nacional de Promoción Científica y
Técnica (ANPCYT), Fundación Antorchas, Alexander von Humboldt
Foundation, DAAD (Deutscher Akademischer Austauschdienst,
Germany). I.C.H.C. specially acknowledges the CONICET for the
doctoral scholarship to Latin-American students. J.L.J. acknowl-
edges the WUS organization (Word University Service, Deutsches