Convenient synthesis of ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3- carboxylates and 4-aryl-6-(trifluoromethyl)-2H-pyran-2-ones: Novel highly reactive CF3-containing building blocks

Article abstract of DOI:10.1021/ol800992z

(Chemical Equation Presented) An expedient synthesis of a series of 2-pyrones, bearing a CF₃ group at the 6-position and aryl group at position 4, from readily available aryl-4,4,4-trifluorobutane-1,3-diones, PCl₅, and sodium diethyl malonate is described.

Full text of DOI:10.1021/ol800992z

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2857-2859
Convenient Synthesis of Ethyl 4-Aryl-6-
(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates
and 4-Aryl-6-(trifluoromethyl)-2H-
pyran-2-ones: Novel Highly Reactive
CF3-Containing Building Blocks
Boris I. Usachev,*,† Dmitrii L. Obydennov,† Gerd-Volker Ro¨schenthaler,‡ and
Vyacheslav Ya. Sosnovskikh†
Department of Chemistry, Ural State UniVersity, 620083 Ekaterinburg, Russia, and
Institute of Inorganic & Physical Chemistry, UniVersity of Bremen, 28334 Bremen,
Germany
boris.usacheV@mail.ru
Received April 30, 2008
ABSTRACT
An expedient synthesis of a series of 2-pyrones, bearing a CF3 group at the 6-position and aryl group at position 4, from readily available
aryl-4,4,4-trifluorobutane-1,3-diones, PCl5, and sodium diethyl malonate is described.
6-(Trifluoromethyl)-2H-pyran-2-ones, poorly explored het-
erocyclic compounds, have successfully been used as con-
jugated dienes in Diels-Alder reactions with several dieno-
philes for the synthesis of CF3-anilines1 and cage antiviral
agents.2 Only a few methods for preparing some of these
compounds have been reported so far (Scheme 1).2–8
The methods A-H for the preparation of 6-CF3-2H-pyran-
2-ones of the general formula 1 often suffer from a narrow
scope of substrates (A-E), long reaction time (A), tedious
synthetic routes (A, D), drastic reaction conditions (E), low
yields (A, B), as well as a very limited variety of substituents
(A-E). Moreover, there are no approaches for the synthesis
of 6-CF3-2H-pyran-2-ones bearing an aryl group at the
4-position.
† Ural State University.
‡ University of Bremen.
In this paper, we describe the preparation of new 2-pyrones
substituted with CF3 group at the 6-position, aryl group at
the 4-position, and bearing an ethoxycarbonyl group or
hydrogen at position 3. All of the starting products are
commercially available or easily obtainable.9
(1) Tolmachova,; N, A.; Gerus, I. I.; Vdovenko, S. I.; Essers, M.;
Fro¨hlich, R.; Haufe, G. Eur. J. Org. Chem. 2006, 4704–4709.
(2) Whitney, J. G.; Gregory, W. A.; Kauer, J. C.; Roland, J. R.; Snyder,
J. A.; Benson, R. E.; Hermann, E. C. J. Med. Chem. 1970, 13, 254–260.
(3) Hoberg, H.; Schaefer, D. J. Organomet. Chem. 1982, 238, 383–
387
.
(4) German, L. S.; Sterlin, S. R.; Cherstkov, V. F. IzV. Akad. Nauk SSSR,
Ser. Khim. 1982, 1657-1659; Chem. Abstr. 1982, 97, 162758
.
(5) (a) Martin, P.; Streith, J.; Rihs, G.; Winkler, T.; Bellusˇ, D.
(7) Yamaguchi, M.; Ito, Y.; Shubayama, A.; Yamaji, Y.; Hanai, R.;
Uotsu, S.; Sadohara, H. PCT Int. Appl. WO 9728127, 1997; Chem. Abstr.
1997, 127, 190757
(8) Gerus, I. I.; Tolmachova, N. A.; Vdovenko, S. I.; Fro¨hlich, R.; Haufe,
G. Synthesis 2005, 1269–1278.
Tetrahedron Lett. 1985, 26, 3947–3950. (b) Martin, P.; Steiner, E.; Streith,
J.; Winkler, T.; Bellusˇ, D. Tetrahedron 1985, 41, 4057–4078
.
(6) Boulanger, W. A.; Katzenellenbogen, J. A. J. Med. Chem. 1986,
29, 1159–1163
.
10.1021/ol800992z CCC: $40.75
Published on Web 06/07/2008
2008 American Chemical Society

Scheme 1a
Table 1. Preparation of Ethyl 4-Aryl-6-(trifluoromethyl)-2-oxo-
2H-pyran-3-carboxylates 3
aReagents, conditions, and substituents: (i)3 maleic anhydride, 40 °C, 2
weeks, R1 ) R2 ) Me, R3 ) CF3; (ii)2 CF3COMe, base, R1 ) CO2Et, R2
) R3 ) H; (iii)4 P2O5, ∆, R1 ) COCF3, R2 ) OH, R3 ) H; (iv)5 mesitylene,
reflux, R1 ) R3 ) H, R2 ) CO2Me; (v)6 SF4, HF, 120 °C, 4 h, R1 ) R2 )
R3 ) H; (vi)7 ArCH2CO2Et, R1 ) Ar, R2 ) Alk, R3 ) H, Me, CO2H,
CO2Et; (vii)8 R1CH2CO2H, Ac2O, R1 ) NHCOAr, R2 ) R3 ) H; (viii)8
R1CH2CO2H, Ac2O, ∆, R1 ) NHCOAr, R2 ) H, R3 ) CO2Et or COCF3.
We discovered that treatment of 1-aryl-4,4,4-trifluorobu-
tane-1,3-diones 2 with PCl5 and then sodium diethyl malonate
afforded ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-
carboxylates 3 in moderate yields (Table 1). The first stage
is a slow reaction, while the second stage is fast.
The reaction of 2 with 1.1 equiv of PCl5 (i.e., the first
stage) leads to a mixture of products containing a major
intermediate. Thus, four signals corresponding to the CF3-
bearing intermediates were observed in the 19F NMR spectra
of the reaction mixture of 2a and PCl5 (C6D6): δ -79.8 (3%),
δ < 2370.5 (8%), δ -70.0 (79%, major intermediate), δ
-63.5 (3%). The reaction mass also contained 6% of the
starting diketone 2a (δ -77.4). The 19F NMR spectral data
for the mixtures prepared from the other diketones and PCl5
were similar to those observed for the mixture of 2a and
PCl5.
Probably, the major intermediates with the signal at about
δ -70.0 are responsible for the formation of the intermediate
4-aryl-1,1,1-trifluorobut-3-yn-2-ones A, which then react with
sodium diethyl malonate to produce 3 through anions B.10
The reaction times for the first stage depend strongly on the
nature of the aryl substituent. As can be seen in Table 1, an
electron-withdrawing substituent (F, Cl, NO2) at the para
position of the aromatic ring retards the reaction, whereas
an electron-donating aromatic group (p-tolyl, 2-naphthyl,
2-thienyl) greatly accelerates it (entries b-d versus entries
e-g). The temperature level of the reactions should be as
low as possible (25-35 °C). Prolonged heating at higher
temperatures resulted in a more complex mixture of inter-
mediates and decrease in the yields of 3. Nevertheless, in
order to decrease the reaction time as much as possible, in
the case of diketone 2d the reaction was carried out at 45-50
°C to give pyrone 3d in 18% yield.
The reaction mass was then treated with sodium diethyl
malonate at -50 to 0 °C within 1 h (the second stage). After
several trials, we were pleased to find that the use of 4.5
equiv of sodium diethyl malonate relative to starting 2a, the
maximum yield of the sequential reaction product 3a was
reached (Table 1, entry a). In the other cases (entries b-g,
Table 1), 4.5 equiv of sodium diethyl malonate was also
found to be sufficient. No pyrone 3a was obtained, when
the same reaction was conducted using 1.1 or 9.5 equiv of
sodium diethyl malonate.
The structure of the synthesized 6-CF3-2H-pyran-2-ones
3a-g was confirmed by NMR, EI-MS, HRMS, IR spectra,
and elemental analysis. The proton H-5 appeared as a singlet
at about δ 6.8. In the 19F NMR, the signal at about δ -77.0
corresponding to the trifluoromethyl group was observed.
In the 13C NMR spectra of compound 3a, the characteristic
quartets of C-6 at δ 148.00 (2JC,F ) 39.7 Hz) and C-5 at δ
107.09 (4JC,F ) 3.6 Hz) were observed. In the EI-MS spectra,
characteristic fragmentation of 3 was presented by intense
ion peaks [M]+, [M - 28]+, [M - 45]+, [M - 28 - 69]+,
and by ion peak [CF3]+ (∼30%).
(9) (a) Reid, J. C.; Calvin, M. J. Am. Chem. Soc. 1950, 72, 2948–2952.
(b) Barkley, L. B.; Levine, R. J. Am. Chem. Soc. 1951, 73, 4625–4627.
(10) Korshunov, S. P.; Vereshyagin, L. I.; Bugerova, G. S.; Okhapkina,
L. L. Zh. Org. Khim. SSSR 1965, 1, 2212–2214.
2858
Org. Lett., Vol. 10, No. 13, 2008

We have found that ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-
2H-pyran-3-carboxylates 3 can be decarbethoxylated in high
yields to 6-(trifluoromethyl)-4-aryl-2H-pyran-2-ones 4 by
refluxing in aqueous acetic acid with H2SO4 (Table 2). The
Scheme 2. Some Reactions of 3a
Table 2. Preparation of 4-Aryl-6-(trifluoromethyl)-2H-pyran-
2-ones 4 by Decarbethoxylation of 3
presence of antiaromatic cyclopentadienone fragment, showed
high reactivity relative to weak nucleophiles such as water.
Thus, usual recrystallization of 7 from aqueous ethanol led
to the formation of (E)-3-(3,3,3-trifluoro-2-oxopropylide-
ne)indan-1-one 8 in 33% yield. In the 1H NMR spectrum of
8, chemical shift of the proton H-4 at the benzene ring
(doublet at δ 8.0, J ) 7.8 Hz) confirms its E-isomer
structure.12 A possible mechanism of the transformation of
7 into 8 includes attack by a molecule of water on the pyrone
ring leading to the formation of the intermediate ꢀ-ketoacid
C, which easily decarboxylates to indanone 8.
In summary, we have demonstrated a new and efficient
approach to 6-CF3-2H-pyran-2-one derivatives via readily
available 1-aryl-4,4,4-trifluorobutane-1,3-diones, PCl5, and
diethyl malonate. The synthesized 6-CF3-2H-pyran-2-ones
3 and 4 can be used as essential building blocks for the
construction of trifluoromethylated heterocycles and bicyclic
systems.
structure of pyrones 4a-g was confirmed by conventional
spectroscopic methods.
To demonstrate the principal possibility of the application
of pyrones 3 in organic synthesis, we examined reactivity
of 3a under nucleophilic and electrophilic conditions: am-
monolysis with excess of NH4OAc, reaction with 2,3-
dihydrofuran, and treatment with H2SO4 (Scheme 2). Thus,
the reaction of 3a with NH4OAc in refluxing aqueous DMF,
involving loss of the ethoxycarbonyl group at the 3-position,
afforded the pyridinol derivative 5 in 69% yield. The solvent-
free inverse electron-demand Diels-Alder reaction of 3a
with 2,3-dihydrofuran gave bicyclic lactone 6 in 61% yield.
The characteristic coupling constant J 7.8 Hz for the vicinal
protons Ha-Hb confirms the endo-configuration of 6.11a Very
high regio- and stereoselectivity of the cycloaddition reaction
is in agreement with previous observations for the transfor-
mation of structurally related pyrones into the corresponding
bicyclic lactones.11 Remarkably, treatment of 3a with H2SO4
at125°Cfor10minaffordedtheintramolecularFriedel-Crafts
reaction product 7 in 41% yield. 3-(Trifluoromethyl)in-
deno[2,1-c]pyran-1,9-dione 7, the first representative of a
novel polynuclear fused heterocyclic system, due to the
Acknowledgment. This research was supported by the
Deutsche Forschungsgemeinschaft (Grant No. 436 RUS 113/
901/0-1). We are very grateful to Dr. T. Du¨lcks, Institute of
Organic Chemistry, University of Bremen (Germany), for
recording the mass spectra.
Supporting Information Available: Experimental pro-
cedures, spectral data, and elemental analysis for 3a, 4a, and
5-8. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) (a) Marku¨, I. E.; Evans, G. R.; Declercq, J.-P. Tetrahedron 1994,
50, 4557–4574. (b) Marku¨, I. E.; Evans, G. R. Tetrahedron Lett. 1993, 34,
7309–7312. (c) Marku¨, I. E.; Evans, G. R. Tetrahedron Lett. 1994, 35, 2767–
2770. (d) Marku¨, I. E.; Evans, G. R. Tetrahedron Lett. 1994, 35, 2771–
2774.
OL800992Z
(12) Sevenard, D. V.; Sosnovskikh, V. Ya.; Schroeder, G.; Ro¨schentha-
ler, G.-V. Aust. J. Chem. 2001, 54, 335–341.
Org. Lett., Vol. 10, No. 13, 2008
2859