4-ethoxy-2-trifluoromethylbutanoate 4i and ethyl 6-pivalooxy-
2-trifluoromethylhexanoate 4j were formed. The reason for
choosing a pivaloyl ester as a protecting group is its tolerance
toward strong bases, which are required for the activation of the a-
position in the 1 ? 2 transformation. This is also the reason why
ketones must first be protected as ketals (e.g. 1k ? 1l), but after the
formation of 2l this protecting group could be removed. The ketone
2k was thus reacted with BrF3 with no complications to produce
methyl 7-oxo-2-trifluoromethyloctanoate 4k.
In conclusion, we have demonstrated for the first time a general
method for constructing various types of a-trifluoromethyl car-
boxylic acids suitable also for incorporation of the positron emitting
isotope 18F into such molecules.
We thank the USA-Israel Binational Science Foundation (BSF),
Jerusalem, Israel for financial support.
Scheme 2
The scope of this reaction was investigated and is summarized in
Table 1. The straight chain methyl heptanoate 1c, methyl
undecanoate 1d and methyl tetradecanoate 1e were a-trifluoro-
methylated to produce 4c,16 4d17 and 4e, respectively, in 65 – 70%
overall yield. Both cyclic derivatives 1f and 1g reacted rapidly to
form the unknown methyl 3-cyclopentyl-2-trifluoromethylpropa-
noate 4f and methyl 4-cyclohexyl-2-trifluoromethylbutanoate 4g.
Bromine trifluoride is known to substitute chlorine atoms as
demonstrated by the synthesis of the anaesthetic sevoflurane, but
again the complexation and the fast reaction with the sulfur atoms
in the reaction of 2h leave the chlorine intact and methyl 5-chloro-
2-trifluoromethylpentanoate 4h was eventually obtained. It is
known that unprotected alcohols are quickly oxidized by BrF3 to
acyl fluorides,18 but when protected, either as ethers or pivaloyl
esters (e.g. 1i or 1j), the reaction proceeds as expected and ethyl
Notes and references
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G. K. S. Prakash, M. Mandal and G. A. Olah, Angew. Chem., Int. Ed.,
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3 R. Fernandez, E. M. Zamora, C. Pareja, J. Vazquez, E. Diez, A. Monge
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4 J. A. Ma and D. Cahard, J. Org. Chem., 2003, 68, 8726.
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6 D. F. Halpern and M. L. Robin, US Pat., 4,996,371, 1991; K. Ramig,
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Table 1 Percentage yields for investigation of the reaction method B
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Overall yield
Compound
Ra
of 4b (%)
c
d
e
CH3(CH2)4
CH3(CH2)8
CH3(CH2)11
6516
7017
65
f
65
g
65
60
55
60
50
h
ic
jc
k
Cl(CH2)3
EtO(CH2)2
t-BuCOO(CH2)4
CH3CO(CH2)4
13 N. Ishikawa and T. Yokozawa, Bull. Chem. Soc. Jpn., 1983, 56, 724.
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found to be the most efficient one.
15 E. Anselmi, J. C. Blazejewski and C. Wakselman, Tetrahedron Lett.,
1998, 39, 9651.
l
16 K. Tomoya, Jap. Pat., 02,238,896, 1990 (Chem. Abstr., 1991, 114,
120301t).
17 K. Iseka, Y. Kuroki, T. Nagai and Y. Kobayashi, Chem. Pharm. Bull.,
1996, 44, 477.
a For spectral characterization of some representative compound 9s, 10s,
and all 11s see the ESI. b All a-trifluoromethyl esters of type 4 are oils. They
are fully characterized by IR, 1H, 13C, 19F NMR, HRMS and microanalysis.
c These compounds are ethyl esters.
18 S. Rozen and I. Ben-David, J. Fluorine Chem., 1996, 76, 145.
C h e m . C o m m u n . , 2 0 0 4 , 5 9 4 – 5 9 5
595