Methyl 2-methoxytetrafluoropropionate as a synthetic equivalent of methyl trifluoropyruvate in the Claisen condensation. The first synthesis of 2-(trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2009.06.067

2-(Trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones were obtained in good yields via the Claisen condensation of acetophenones with methyl 2-methoxytetrafluoropropionate, followed by sulfuric acid-mediated deprotection of

Full text of DOI:10.1016/j.tetlet.2009.06.067

Tetrahedron Letters 50 (2009) 4903–4905
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Methyl 2-methoxytetrafluoropropionate as a synthetic equivalent of
methyl trifluoropyruvate in the Claisen condensation. The first synthesis
of 2-(trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-
3(2H)-ones
b
b
Roman A. Irgashev a, Vyacheslav Ya. Sosnovskikh a, , Nataliya Kalinovich , Olesya Kazakova ,
*
Gerd-Volker Röschenthaler b
a Department of Chemistry, Ural State University, pr. Lenina 51, 620083 Ekaterinburg, Russian Federation
b Institute of Inorganic and Physical Chemistry, University of Bremen, 28334 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones were obtained
in good yields via the Claisen condensation of acetophenones with methyl 2-methoxytetrafluoropropio-
nate, followed by sulfuric acid-mediated deprotection of the reaction products.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 April 2009
Revised 22 May 2009
Accepted 12 June 2009
Available online 16 June 2009
Keywords:
Methyl 2-methoxytetrafluoropropionate
Acetophenones
Claisen condensation
Deprotection
Trifluoromethyl 1,2,4-triketones
Trifluoromethylated heterocycles continue to be of great aca-
demic and industrial interests. Replacement of hydrogen with fluo-
rine sometimes can lead to dramatic changes in the physical
properties, chemical reactivity, and biological activity of com-
pounds, as a result of the high electronegativity of fluorine and
the high C–F bond energy.1 In connection with this, the develop-
ment of new methods for incorporation of the CF3 group into or-
ganic compounds remains an important area of research. In view
of the unique biological properties displayed by many fluorinated
heterocyclic compounds,2 and as an extension of our continuing
synthetic studies in the field of 3-(trifluoroacetyl)chromones 1,3
we have focussed our attention on 2-(trifluoroacetyl)chromones
2 as a new class of polydentate electrophilic substrates (Fig. 1).
These compounds, despite their potential interest as building
blocks in organic synthesis for the construction of more complex
trifluoromethylated heterocycles, have received little attention. In
contrast to the well-known 2-acetylchromones,4 no data on the
preparation and chemical properties of 2-(trifluoroacetyl)chro-
mones 2 have been documented, probably owing to the lack of
general methods for their synthesis.
The importance of highly reactive substrates 2 prompted us
to develop a general and efficient method for their preparation
as useful precursors of a wide variety of heterocycles containing
a CF3 group. Our approach to these compounds follows the
same design as many earlier methods for the preparation of
2-substituted chromones and includes a Claisen condensation
of an appropriately substituted acetophenone with methyl
2-methoxytetrafluoropropionate.
Esters of trifluoropyruvic acid are used as trifluoromethylated
building blocks in organic chemistry. However, it is well known
that the reaction of methyl trifluoropyruvate 3 with methyl ke-
tones occurs only at the carbonyl adjacent to the CF3 group to give
the corresponding b-ketols 4 (aldol condensation),5 and not the
triketones 5 (Claisen condensation). On the other hand, the starting
material for the preparation of 3, methyl 2-methoxytetrafluoropro-
pionate 6, was found to be a very stable compound, especially
O
O
O
O
COCF3
R
R
COCF3
2
1
* Corresponding author. Fax: +7 343 261 59 78.
E-mail address: vyacheslav.sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.067

4904
R. A. Irgashev et al. / Tetrahedron Letters 50 (2009) 4903–4905
against alkaline hydrolysis.6 Moreover, very recently7 this ester
was used as a carbonyl component in the condensation with cyclo-
hexanone. Bearing these facts in mind, we envisaged that the reac-
In marked contrast to the known 2-acetylchromones,4 chro-
mones 2a–c obtained in this work were prone to easy and revers-
ible covalent hydrate formation as observed from the 1H NMR
spectrum of 2a in CDCl3, which contained two sets of signals
(2a:20a = 83:17). The diagnostic signal for proton H-3 in chromone
2a, which appeared at d 7.18 ppm, was shifted upfield in its hy-
drate 20a (d 6.84 ppm). In DMSO-d6 solution, compounds 2 exist
in the gem-diol form 20, exclusively (dH3 = 6.60–6.66 ppm); the
CF3 group is bonded to the sp3-hybridized carbon atom and occurs
as a singlet at ca. 81 ppm (C6F6). The IR spectra (KBr) of 2 showed
intense absorption bands in the ranges 3340–3290 cmꢀ1 corre-
sponding to the hydroxy groups, 1642–1636 cmꢀ1 attributed to
the chromone carbonyl group, and 1597–1584 cmꢀ1 due to the
C@C double bond. Therefore, in the solid state chromones 2 exist
in the gem-diol form 20, as was observed in the case of 3-(trifluoro-
acetyl)chromones3 and 3-(trifluoroacetyl)coumarins.11
Acetophenone and p-methyl- and p-chloroacetophenones were
similarly reacted with methyl 2-methoxytetrafluoropropionate 6
under the same reaction conditions (refluxing ethanol and NaOEt
as catalyst). The final products 10a–c, which were fully enolic in
CDCl3 (dOH = 15.5–15.6 ppm), were produced in 60–79% yields after
work-up. Treatment of 10a–c with 96% H2SO4 in the presence of
SiO2 gave the corresponding triketones, which underwent sponta-
neous intramolecular cyclization at the COCF3 group to yield fura-
nones 11a–c in 64–75% yields (Scheme 3). The structures of
compounds 10 and 11 were confirmed by elemental analysis, 1H,
19F NMR, and IR spectroscopies, and mass spectrometry. This very
practical and convenient approach has never been applied to the
synthesis of CF3-containing 1,2,4-triketones, despite the fact that
methyl 2-methoxytetrafluoropropionate 6 is readily available.6,8
The synthesis of trifluoromethylated molecules is an ongoing
area of research due to the unique physical and biological proper-
ties imparted by the CF3 group.1,2 We envisaged that the presence
of a strongly electron-withdrawing CF3 group would render the
carbonyl moieties non-equivalent toward nucleophilic attack,
leading to high regiochemical control when reacted with suitable
nucleophiles. To demonstrate the ability of compounds 2 to under-
go regioselective heterocyclization reactions, chromone 2a was
reacted with ethylenediamine (MeOH, AcOH, 48 h, ꢁ20 °C) and
o-phenylenediamine (AcOH, 8 h, reflux). Our preliminary results
showed that 2a behaves as a latent 1,2-diketone, having a masked
aroyl fragment at the 3-position, and reacts with diamines to give
compounds 12 and 13 in good yields (57% and 83%, respectively).
In contrast with ethylenediamine, reaction of 2a with o-phenyl-
tion of ester
6 with methyl ketones would produce the
corresponding triketones 7 with one protected carbonyl group,
which could be converted into the trifluoromethyl 1,2,4-triketones
5 (Scheme 1).
As the Claisen reaction usually affords b-dicarbonyls, in the case
of 2-hydroxyacetophenones, we would expect the formation of
chromanones 8, whose acid-catalyzed dehydration would result
in chromones 9 with a masked trifluoroacetyl substituent at the
2-position. Indeed, we found that methyl 2-methoxytetrafluoro-
propionate 6, easily prepared from hexafluoropropene epoxide
and methanol,6,8 reacted with 2-hydroxyacetophenones under Cla-
isen reaction conditions (refluxing ethanol and NaOEt as catalyst or
refluxing THF and LiH as catalyst) affording, after hydrochloric acid
hydrolysis, chromones 9a–c in 57–87% yields.9 It should be noted
that the intermediates 8 could not be isolated and underwent
spontaneous dehydration to 9a–c. Deprotection of chromones
9a–c was carried out using 96% H2SO4 and SiO2, as previously re-
ported for the preparation of ester 3 from 6,8 to afford 2-(trifluoro-
acetyl)chromones 2a–c in 76–88% yields10 (Scheme 2).
F3C
R
R
MeO2C
OH
O
O
O
O
aldol
MeCOR
4
F3C
OMe
X
O
3
Claisen
F3C
O
5
H2SO4
H2SO4
O
O
O
F3C
F
F3C
F
MeCOR
Claisen
OMe
R
OMe
OMe
6
7
Scheme 1.
OH
O
O
enediamine afforded
a mixture of two tautomeric forms
Me
CF3
OMe
MeO
+
(13A:13B = 59:41) as was observed previously for 2-ketomethyl-
quinolines.12 These results clearly indicate that C-2 of chromones
2, due to the electron-withdrawing effect of the CF3CO group, is
very susceptible to nucleophilic attack, which makes them useful
F
6
R
1) EtONa, EtOH
2) HCl
O
O
O
R
R
O
O
OH
CF3
CF3
-H2O
Me
CF3
O
9a-c
+
MeO
8
F
OMe
F
OMe
F
OMe
R
6
1) EtONa, EtOH
2) HCl
H2SO4 SiO2
O
O
O
O
H
O
O
R
R
OH
H2O
-H2O
CF3
CF3
H2SO4
SiO2
O
CF3
O
2a-c
COCF3
F OMe
R
R
2'a-c HO OH
10a-c
11a-c
R = H (a), Me (b), Cl (c)
R = H (a), Me (b), Cl (c)
Scheme 2.
Scheme 3.

R. A. Irgashev et al. / Tetrahedron Letters 50 (2009) 4903–4905
4905
for constructing highly functionalized biologically and medicinally
Acknowledgment
important products. In addition, chromone 2a reacted smoothly
with indole at 85 °C in 5 h to produce the expected adduct 14 in
75% yield (Scheme 4).
This work was financially supported by a DFG (Grant No. 436
RUS 113/901/0-1).
Reaction of furanone 11a with o-phenylenediamine also oc-
curred in refluxing AcOH to give a 55:45 mixture of tautomers
15A and 15B in 68% yield. Treatment of 11a in refluxing AcOH with
N2H4ꢂ2HCl (2 equiv) resulted in the formation of 6-phenyl-3-(tri-
fluoromethyl)pyridazin-4(1H)-one 1613 (yield 60%) which exists
as a mixture of two tautomeric forms (95:5) in DMSO-d6 solution
(Scheme 5). It should be noted that isomeric 6-phenyl-4-(trifluoro-
methyl)pyridazin-3(2H)-one can be prepared from acetophenone,
methyl trifluoropyruvate, and hydrazine hydrate.5d
The structures of 12–16 were confirmed with the aid of spectral
and analytical data. For example, in the 19F NMR spectra of 13 and
15, the CF3 group of tautomer A appeared as a triplet (5JF,H = 1.3–
1.6 Hz) at 98.8 ppm and the CF3 group of B appeared as a doublet
(5JF,H = 1.8–1.9 Hz) at 96.1–96.8 ppm (C6F6).
In summary, we have developed a simple and convenient
two-step synthesis of 2-(trifluoroacetyl)chromones and 5-aryl-2-
hydroxy-2-(trifluoromethyl)furan-3(2H)-ones starting from com-
mercially available acetophenones and hexafluoropropene epoxide
via introduction of a CF3COCO group into methylketones. Hexaflu-
oropropene epoxide is advantageous as a starting material in that
it is stable, readily available, comparatively inexpensive, and
environmentally safe. The compounds obtained are of interest as
precursors for the synthesis of other useful organic materials.
Further studies on the synthetic application of this methodology
and on the reactivity of the described chromones and furanones
are in progress.
References and notes
1. Hiyama, T. Organofluorine Compounds. Chemistry and Application; Springer-
Verlag: Berlin, 2000.
2. (a) Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157; (b) Bégué, J.-P.; Bonnet-
Delpon, D. J. Fluorine Chem. 2006, 127, 992.
3. (a) Sosnovskikh, V. Y.; Irgashev, R. A.; Barabanov, M. A. Synthesis 2006, 2707; (b)
Sosnovskikh, V. Y.; Irgashev, R. A.; Kodess, M. I. Tetrahedron 2008, 64, 2997; (c)
Sosnovskikh, V. Y.; Moshkin, V. S.; Kodess, M. I. Tetrahedron 2008, 64, 7877; (d)
Sosnovskikh, V. Y.; Khalymbadzha, I. A.; Irgashev, R. A.; Slepukhin, P. A.
Tetrahedron 2008, 64, 10172.
4. (a) Brown, R. C.; Cairns, H. J. Chem. Soc., Perkin Trans. 1 1976, 1553; (b) Bevan, P.
S.; Ellis, G. P.; Wilson, H. K. J. Chem. Soc., Perkin Trans. 1 1981, 2552.
5. (a) Golubev, A. S.; Galakhov, M. V.; Kolomiets, A. F.; Fokin, A. V. Izv. Akad. Nauk
ˇ
SSSR, Ser. Khim. 1989, 2127; (b) Palecek, J.; Paleta, O. Synthesis 2004, 521; (c)
Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.; Petrenko, A. E. Synthesis
2004, 2545; (d) Sibgatulin, D. A.; Volochnyuk, D. M.; Kostyuk, A. N. Synlett 2005,
1907.
6. Sianesi, D.; Pasetti, A.; Tarli, F. J. Org. Chem. 1966, 31, 2312.
7. Sevenard, D. V.; Khomutov, O. G.; Boltachova, N. S.; Filyakova, V. I.; Vogel, V.;
Lork, E.; Sosnovskikh, V. Ya.; Iaroshenko, V. O.; Roschenthaler, G.-V. Z.
Naturforsch. 2009, 64b, 541.
´
ˇ
ˇ
8. Dolensky, B.; Kvícala, J.; Palecek, J.; Paleta, O. J. Fluorine Chem. 2002, 115, 67.
9. 2-(1,2,2,2-Tetrafluoro-1-methoxyethyl)chromone (9a): A mixture of methyl 2-
methoxytetrafluoropropionate 6 (25.0 g, 0.132 mol) and 2-hydroxyacetophenone
(17.4 g, 0.128 mol) was added dropwise to an alcoholic solution of NaOEt
obtained by dissolution of sodium (8.6 g, 0.374 mol) in anhydrous EtOH
(150 mL). The resulting reaction mixture was refluxed with stirring for 5 h.
Concentrated HCl (65 mL) was added to the disodium salt, and the mixture was
refluxed with stirring for 1 h. The cooled mixture was quenched by addition of
water (200 mL) and the solvent was concentrated under reduced pressure. The
organic product thus obtained was extracted with ether (3 ꢃ 100 mL) and the
combined extracts were washed with 5% KOH (60 mL) and water (60 mL), dried
over anhydrous MgSO4, and evaporated to afford a colorless solid. The solid
was recrystallized from hexane–ether (10:1) to give 9a in 57% yield (20.0 g),
mp 95–96 °C. 1H NMR (400 MHz, CDCl3) d 3.60 (d, 3H, MeO, 4JH,F = 0.8 Hz), 6.77
O
4
(d, 1H, H-3, JH,F = 1.8 Hz), 7.49 (ddd, 1H, H-6, J = 8.0, 7.2, 1.0 Hz), 7.56 (dd, 1H,
H
OH
O
N
NH
H-8, J = 8.5, 1.0 Hz), 7.76 (ddd, 1H, H-7, J = 8.5, 7.2, 1.7 Hz), 8.23 (dd, 1H, H-5,
J = 8.0, 1.7 Hz); 19F NMR (376 MHz, CDCl3/C6F6) d 25.05 (m, F), 79.94 (d, CF3,
3JF,F = 4.0 Hz); MS (EI), m/z (%) 276 [M]+ (100), 207 [MꢀCF3]+ (100). Anal. Calcd
for C12H8F4O3: C, 52.19; H, 2.92. Found: C, 52.16; H, 3.30.
N
O
O
CF3
HO CF3
10. 2-(Trifluoroacetyl)chromone (2a) and 2-(2,2,2-trifluoro-1,1-dihydroxyethyl) chromone
(20a). To a suspension of SiO2 (850 mg, 14 mmol) in concentrated sulfuric acid
(22 mL) chromone 9a (11.7 g, 42.4 mmol) was added in small portions with
stirring. The resulting yellow solution was heated with stirring at 125–130 °C
for 1 h. The cooled mixture was poured into water (300 mL) and extracted with
ethyl acetate (4 ꢃ 50 mL). The combined extracts were washed with water
(3 ꢃ 50 mL) and evaporated under reduced pressure. The solid that formed was
recrystallized from toluene–ethyl acetate (5:1) to give 2a in 88% yield (9.0 g),
12
14
2a + 2'a
H
N
OH
O
N
OH
mp 158 °C. IR (KBr) 3288, 1636, 1617, 1584, 1568, 1482 cmꢀ1 1H NMR
;
N
N
+
(400 MHz, CDCl3) (2a, 83%) d 7.18 (s, 1H, H-3), 7.52 (ddd, 1H, H-6, J = 8.0, 7.2,
1.0 Hz), 7.62 (dd, 1H, H-8, J = 8.6, 1.0 Hz), 7.81 (ddd, 1H, H-7, J = 8.6, 7.2, 1.7 Hz),
8.22 (dd, 1H, H-5, J = 8.0, 1.7 Hz); (20a, 17%) d 6.84 (s, 1H, H-3), 6.87 (s, 2H, 2OH),
7.45 (ddd, 1H, H-6, J = 8.0, 7.2, 1.0 Hz), 7.50 (d, 1H, H-8, J = 8.6 Hz), 7.71 (ddd, 1H,
H-7, J = 8.6, 7.2, 1.7 Hz), 8.18 (dd, 1H, H-5, J = 8.0, 1.6 Hz); 1H NMR (400 MHz,
DMSO-d6) (20a, 100%) d 6.64 (s, 1H, H-3), 7.54 (ddd, 1H, H-6, J = 8.0, 7.2, 1.0 Hz),
7.69 (dd, 1H, H-8, J = 8.5, 1.0 Hz), 7.86 (ddd, 1H, H-7, J = 8.5, 7.2, 1.7 Hz), 8.07
(dd, 1H, H-5, J = 8.0, 1.7 Hz), 8.37 (s, 2H, 2OH); 19F NMR (376 MHz, DMSO-d6/
C6F6) (20a, 100%) d 80.84 (s, CF3); MS (EI), m/z (%) 242 [M]+ (100), 173 [MꢀCF3]+
(36), 145 [MꢀCOCF3]+ (33), 101 (10), 92 (8), 89 (43), 69 [CF3]+ (8). Anal. Calcd for
C11H5F3O3ꢂH2O: C, 50.78; H, 2.71. Found: C, 50.76; H, 2.35.
CF3
CF3
13A
13B
Scheme 4.
O
OH
O
CF3
CF3
11. Chizhov, D. L.; Sosnovskikh, V. Y.; Pryadeina, M. V.; Burgart, Y. V.; Saloutin, V. I.;
Charushin, V. N. Synlett 2008, 281.
12. (a) Greenhill, J. V.; Loghmani-Khouzani, H. Tetrahedron 1988, 44, 3319; (b)
Greenhill, J. V.; Loghmani-Khouzani, H.; Maitland, D. J. J. Chem. Soc., Perkin
Trans. 1 1991, 2831.
OH
CF3
11a
N
N
Ph
O
Ph
N
H
Ph
N
16
13. 6-Phenyl-3-(trifluoromethyl)pyridazin-4(1H)-one (16): To a solution of furanone
11a (350 mg, 1.43 mmol) in AcOH (5 mL) was added N2H4ꢂ2HCl (300 mg,
2.87 mmol). The reaction mixture was refluxed for 8 h, cooled, and diluted with
water (15 mL). The solid was filtered, washed with water, and dried to give 16
in 81% yield (300 mg), mp 260–261 °C (sublimed). 1H NMR (400 MHz, DMSO-
d6) (major tautomer, 95%) d 6.96 (s, 1H, H-5), 7.57–7.66 (m, 3H, Ph), 7.78–7.84
(m, 2H, Ph), 14.07 (br s, 1H, NH); (minor tautomer, 5%) d 7.08 (s, 1H, H-5), 7.43–
7.55 (m, 3H, Ph), 7.87–7.90 (m, 2H, Ph), 14.48 (br s, 1H, OH); 19F NMR
H
O
O
N
N
+
N
N
Ph
Ph
(376 MHz, DMSO-d6/C6F6) (major tautomer, 95%)
d 95.21 (s, CF3), (minor
CF3
CF3
15A
15B
tautomer, 5%) d 97.30 (s, CF3); 13C NMR (100 MHz, DMSO-d6) (major tautomer)
d 117.50, 121.09 (q, 1JC,F = 274.8 Hz), 127.45, 129.20, 130.20, 131.40, 142.72 (q,
2JC,F = 30.6 Hz), 152.42, 166.97.
Scheme 5.