Trifluoromethyl ketones from enolizable carboxylic acids via enediolate trifluoroacetylation/decarboxylation

Article abstract of DOI:10.1021/jo801737c

(Chemical Equation Presented) Primary and secondary (enolizable) carboxylic acids were converted in a single step to trifluoromethyl ketones. Treatment of the acid with 2.2 equiv of LDA generated an enediolate that was trifluoroacetylated with EtO₂CCF₃. Quenching the reaction mixture with aqueous HCl resulted in rapid decarboxylation and provided the trifluoromethyl ketone product in good yield. The process may be performed at -20°C with a slight reduction in yield. The reaction was extended to the preparation of pentafluoroethyl and chlorodifluoromethyl ketones.

Full text of DOI:10.1021/jo801737c

SCHEME 1. Pfeffer and Silbert’s Conversion of Carboxylic
Acids to Aldehydes
Trifluoromethyl Ketones from Enolizable
Carboxylic Acids via Enediolate
Trifluoroacetylation/Decarboxylation
Jonathan T. Reeves,* Jinhua J. Song, Zhulin Tan,
Heewon Lee, Nathan K. Yee, and Chris H. Senanayake
or expensive reagents.3 To support drug development activities,
we required a scalable synthesis of trifluoromethyl ketones
which would ideally employ starting substrates of the carboxylic
acid oxidation level. The two-step sequence of base-promoted
Claisen condensation of esters with ethyl trifluoroacetate and
subsequent acidic hydrolysis and decarboxylation to trifluoro-
methyl ketones has been known for over 50 years.4 Yields for
the Claisen condensation, however, are low with alkoxide bases,
and while higher yields are obtained with NaH or Na metal in
refluxing solvents, these conditions were undesirable for scaleup.
Olah and Prakash reported a one-step conversion of methyl
esters to trifluoromethyl ketones using TMSCF3 and catalytic
TBAF.5 Although this direct conversion is attractive, the high
cost of TMSCF3 and the requirement for anhydrous TBAF are
serious limitations to large-scale application. In addition, in our
hands this reaction was difficult to drive to completion, and the
unreacted starting ester proved impossible to separate from the
trifluoromethyl ketone product by nonchromatographic means.
The method of Zard and co-workers, in which a primary acid
chloride is treated with trifluoroacetic anhydride (TFAA) and
pyridine in CH2Cl2 followed by hydrolysis/decarboxylation on
addition of water, is attractive due to the low cost of reagents.6
Recently, we reported a variation on Zard’s method which
allowed for direct conversion of primary and secondary car-
boxylic acids to trifluoromethyl ketones using TFAA/pyridine
in toluene at 60-100 °C for 6-48 h followed by hydrolysis/
decarboxylation on addition of water.7 While this procedure
expanded the scope of amenable substrates, the long reaction
times, requirement for a large excess (4.5-6.0 equiv) of TFAA,
and modest yields obtained with secondary carboxylic acids
provided the impetus to search for a more general alternative
preparation.
Department of Chemical DeVelopment, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Old Ridgebury Road,
P.O. Box 368, Ridgefield, Connecticut 06877-0368
jonathan.reeVes@boehringer-ingelheim.com
ReceiVed August 4, 2008
Primary and secondary (enolizable) carboxylic acids were
converted in a single step to trifluoromethyl ketones. Treat-
ment of the acid with 2.2 equiv of LDA generated an
enediolate that was trifluoroacetylated with EtO2CCF3.
Quenching the reaction mixture with aqueous HCl resulted
in rapid decarboxylation and provided the trifluoromethyl
ketone product in good yield. The process may be performed
at -20 °C with a slight reduction in yield. The reaction was
extended to the preparation of pentafluoroethyl and chlo-
rodifluoromethyl ketones.
The trifluoromethyl group is an important structural motif in
many active pharmaceutical ingredients.1 Important precursors
for introduction of trifluoromethyl groups are trifluoromethyl
ketones.2 Several methods are available for the synthesis of
trifluoromethyl ketones, but many require multiple steps and/
In 1970, Pfeffer and Silbert reported a one-step synthesis of
aldehydes from carboxylic acids by treating the dianion of the
acid (from 2 equiv of LDA) with ethyl formate.8 The intermedi-
ate R-formylcarboxylate was not isolated but underwent spon-
taneous decarboxylation on neutralization (Scheme 1). The
(1) (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432–5446. (b)
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Hathaway, C. E.; Roberts, C. W. J. Am. Chem. Soc. 1956, 78, 4053–4057. (b)
Brown, P.; Burdon, J.; Smith, T. J.; Tatlow, J. C. Tetrahedron 1960, 10, 164–
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Angew. Chem., Int. Ed. 1998, 37, 820–821. For related methods involving CF3
addition to esters: (a) Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M.
J. Org. Chem. 1999, 64, 2873–2876. (b) Yokoyama, Y.; Mochida, K. Synlett
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Salvador, R. L.; Saucier, M. Tetrahedron 1971, 27, 1221–1226. (c) Creary, X.
J. Org. Chem. 1987, 52, 5026–5030. (d) Villuendas, I.; Parrila, A.; Guerrero, A.
Tetrahedron 1994, 50, 12673–12684. (e) Mun˜oz, L.; Rosa, E.; Bosch, M. P.;
Guerrero, A. Tetrahedron Lett. 2005, 46, 3311–3313. (f) Qiu, W.; Shen, Y. J.
Fluorine Chem. 1988, 38, 249–256. Oxidation of CF3 carbinols: (g) Imperiali,
B.; Abeles, R. H. Tetrahedron Lett. 1986, 27, 135–138. (h) Kesavan, V.; Bonnet-
Delpon, D.; Be´gue´, J. P.; Srikanth, A.; Chandrasekaran, S. Tetrahedron Lett.
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B.; Pedro, J. R.; Ruiz, R. Tetrahedron 2002, 58, 8565–8571. Radical based
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2511–2512. (k) Kim, S.; Kavali, R. Tetrahedron Lett. 2002, 43, 7189–7191.
Pd-catalyzed coupling of phenyl trifluoroacetate with organoboron compounds: (l)
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10.1021/jo801737c CCC: $40.75 2008 American Chemical Society
Published on Web 10/31/2008

TABLE 1. One-Step Synthesis of Trifluoromethyl Ketones from
Enolizable Carboxylic Acids
SCHEME 2. Optimal Reaction Conditions
procedure was also applied to the synthesis of nitro compounds
by quenching with n-propylnitrate. We postulated the analogous
trapping of a carboxylic acid dianion with ethyl trifluoroacetate
would give an intermediate R-trifluoroacetyl carboxylate that
would readily decarboxylate on acidification to give a triflu-
oromethyl ketone.9 This proved to be the case, and herein we
present the scope of this reaction.
Exploratory experiments were performed on adamantane-1-
acetic acid 1 (Scheme 2). Enediolate formation was best effected
by addition of LDA (1.5 M in cyclohexane) to a -20 °C solution
of 1 in THF, warming to 20 °C, and aging for 4 h.10 The reaction
mixture was then cooled to -65 °C and treated with EtO2CCF3
(1.5 equiv). On quenching the reaction mixture with aqueous
HCl, an immediate evolution of gas was observed. Extractive
workup and chromatographic purification of the crude product
gave the desired trifluoromethyl ketone 2 in 68% yield.7 The
majority of the mass balance was the starting acid 1 (22%
recovery). None of the intermediate R- trifluoroacetyl acid was
detected, indicating decarboxylation of this species is facile.
Increasing the time for enolization did not increase the yield,
while decreasing the enolization period to 1 h gave a 59% yield
of 2. When an inverse quenching protocol was employed, i.e.
the enediolate solution was added dropwise to a -65 °C solution
of EtO2CCF3 (3.0 equiv) in THF, the yield of 2 increased to
75%. The inverse quench protocol was preferred not only for
the increased yield, but also for the greater control it imparts
over the exothermicity of the enediolate trifluoroacetylation,
particularly in large-scale reactions. In addition, the EtO2CCF3
quench could be performed at -20 °C instead of -65 °C with
only a slightly lower yield (65%).
The scope of the reaction was explored as depicted in Table
1. Both primary (entries 1-7) and secondary (entries 8-13)
carboxylic acids give consistently good yields of trifluoromethyl
ketones. Conveniently, carboxylate salts may be used, allowing
the LDA charge to be reduced to 1.1 equiv (entry 2). Silyl ether
(entry 6) and R-phenylthio (entry 7) substituents were tolerated.
Key advantages of this procedure over the TFAA/pyridine
protocol are the consistently good yields for both primary and
secondary carboxylic acids, even highly hindered substrates, and
the uniform reaction times for all substrates.
The reaction was successfully extended to the synthesis of
pentafluoroethyl ketone 15 and chlorodifluoromethyl ketone 16
a Isolated yields after chromatography on SiO2. b Lithium 4-cyclo-
hexylbutyrate used as starting material with 1.1 equiv of LDA.
(9) For the reaction of carboxylic acid dianions with esters to give
ꢀ-ketocarboxylic acids: Kuo, Y.-N.; Yahner, J. A.; Ainsworth, C. J. Am. Chem.
Soc. 1971, 93, 6321–6323.
(10) Petragnani, N.; Yonashiro, M. Synthesis 1982, 521–578.
(11) Yang, D.; Wong, M.-K.; Wang, X.-C.; Tang, Y.-C. J. Am. Chem. Soc.
1998, 120, 6611–6612.
(Table 2).15,17 In these cases, the reaction was conducted by
using the same procedure developed for trifluoromethyl ketones,
except that ethyl pentafluoropropionate and ethyl chlorodifluo-
roacetate were used for the quench. As with the trifluoromethyl
ketone substrates, decarboxylation was spontaneous on acidi-
fication of the quenched reaction mixture, and good yields of
the products were obtained. This procedure offers a direct and
(12) Greif, D.; Riedel, D.; Feindt, A.; Pulst, M. J. Prakt. Chem. 1995, 337,
34–37.
(13) For the synthesis of 12-(tert-butyldimethylsilyloxy)dodecanoic
acid: Mohanraj, S.; Ford, W. T. J. Org. Chem. 1985, 50, 1616–1620.
(14) Linderman, R. J.; Graves, D. M. J. Org. Chem. 1989, 54, 661–668.
(15) Qiu, W.; Shen, Y. J. Fluorine Chem. 1988, 38, 249–256.
(16) Hornyak, G.; Fetter, J.; Nemeth, G.; Poszavacz, L.; Simig, G. J. Fluorine
Chem. 1997, 84, 49–51.
(17) Kimura, M.; Tominaga, T.; Kitazume, T. J. Fluorine Chem. 2005, 126,
135–139.
J. Org. Chem. Vol. 73, No. 23, 2008 9477

TABLE 2. Extension to Pentafluoroethyl and
Chlorodifluoromethyl Ketones
Experimental Section
General Procedure: 2,2,2-Trifluoro-1-indan-2-yl-ethanone
(11). To a solution of indane-2-carboxylic acid (1.62 g, 10.0 mmol)
in THF (20 mL) at -20 °C was added dropwise LDA (14.7 mL,
22.0 mmol, 1.5 M in cyclohexane) over 10 min. The temperature
of the reaction mixture was allowed to rise to 10 °C during the
addition of LDA. The reaction mixture was then aged at 20 °C for
4 h. In a separate flask, a solution of ethyl trifluoroacetate (3.6 mL,
30.0 mmol) and THF (10 mL) was cooled to -65 °C. The
enediolate solution was added dropwise via cannula to the ethyl
trifluoroacetate solution. Upon completion of the addition, the
reaction mixture was aged for 15 min at -65 °C and then quenched
with 6 N HCl (20 mL) [Caution: CO2 is evolved during the quench].
The reaction mixture is diluted with EtOAc (10 mL), the layers
are separated, and the organic phase was dried over MgSO4, filtered,
and concentrated. Column chromatography on SiO2 (hexanes) gave
11 (1.48 g, 69% yield) as a colorless oil. IR (neat) 3028, 2955,
a Isolated yields after chromatography on SiO2.
efficient entry to higher perfluoroalkyl ketones from carboxylic
acids and commercially available perfluoroalkyl esters.
In conclusion, an efficient and general one-step conversion
of primary and secondary carboxylic acids to trifluoromethyl
ketones has been reported. The method employs cheap, com-
mercially available reagents and the procedure is operationally
simple. While optimal yields are obtained by quenching with
EtO2CCF3 at low temperature (-65 °C), the quench may be
performed at -20 °C with only a slight decrease in yield. The
method is equally well suited to the preparation of pentafluo-
roethyl and chlorodifluoromethyl ketones. This procedure should
prove to be a method of choice for the preparation of primary
and secondary trifluoromethyl ketones.
1
2859, 1755, 1486, 1450, 1205, 1115 cm-1; H NMR (400 MHz,
CDCl3) δ 7.24-7.14 (m, 4 H), 3.80 (p, J ) 8.7 Hz, 1 H), 3.34-3.23
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ 192.7 (q, J ) 34 Hz),
140.2, 126.9, 124.3, 115.9 (q, J ) 290 Hz), 45.5, 34.9. Anal. Calcd
for C11H9F3O: C, 61.68; H, 4.24. Found: C, 61.39; H, 4.13.
Supporting Information Available: Characterization data
for 6, 7, 10, and 11 and copies of 1H and 13C NMR spectra for
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801737C
9478 J. Org. Chem. Vol. 73, No. 23, 2008