CsF-catalyzed nucleophilic trifluoromethylation of trans-enones with trimethyl(trifluoromethyl)silane: A facile synthesis of trans-α-trifluoromethyl allylic alcohols

Article abstract of DOI:10.1021/ol990844r

(matrix presented) Reactions of trans-enones, R-C=C-COR′ (R = Ph, Me, -C=CH-CH=C-S; R′ = Ph, Me, Et, CF₃) (1a-e), with TMS-CF₃ in the presence of catalytic amounts of cesium fluoride (CsF) in ethylene glycol dimethyl ether led to the

Full text of DOI:10.1021/ol990844r

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1047-1049
CsF-Catalyzed Nucleophilic
Trifluoromethylation of trans-Enones
with Trimethyl(trifluoromethyl)silane: A
Facile Synthesis of
trans-r-Trifluoromethyl Allylic Alcohols
Rajendra P. Singh, Robert L. Kirchmeier, and Jean’ne M. Shreeve*
Department of Chemistry, UniVersity of Idaho, Moscow, Idaho 83844-2343
jshreeVe@uidaho.edu
Received July 21, 1999
ABSTRACT
Reactions of trans-enones, R−CdC−COR′ (R ) Ph, Me, −CdCH−CHdC−S; R′ ) Ph, Me, Et, CF3) (1a−e), with TMS-CF3 in the presence of
catalytic amounts of cesium fluoride (CsF) in ethylene glycol dimethyl ether led to the formation of the corresponding trans-r-trifluoromethyl
silyl ethers, R−CdC−C(OSiMe3)(CF3)R′ (R ) Ph, Me, −CdCH−CHdC−S; R′ ) Ph, Me, Et, CF3) (2a−e), in essentially quantitative yield.
On hydrolysis with aqueous HCl, the corresponding trans-r-trifluoromethyl allylic alcohols, R−CdC−C(OH)(CF3)R′ (R ) Ph, Me,
−CdCH−CHdC−S; R′ ) Ph, Me, Et, CF3) (3a−e), were formed in >90% isolated yield. Under similar reaction conditions, 2-cyclohexen-1-one
(1f) also gave trifluoromethyl allylic alcohols (3f) in 92% yield. The intermediates (2a−f) and products (3a−f) are liquids and were characterized
by IR, 1H, 19F and 13C NMR, MS, and high-resolution mass spectroscopy (HRMS).
Because fluorine is the most electronegative element and the
van der Waals radius of fluorine is close to that of hydrogen,
the introduction of a fluorine-containing group into an
organic molecule brings about some remarkable changes in
its physical and chemical properties.1 In addition, novel
reactivities are observed as a result of the introduction of
fluorine or fluorinated groups into organic molecules. Many
new fluorinated materials that take advantage of these useful
changes, e.g., drugs and agrochemicals, have been designed2
and synthesized.3
quently, reactions leading to the formation of allylic alcohols,
especially fluorinated alcohols are of great interest. A number
of methods are available for the preparation of allylic
alcohols,5 but techniques for the synthesis of R-trifluoro-
methyl allylic alcohols are rare.6 Shen et al. reported the
synthesis of some R-trifluoromethyl allylic alcohols by the
reaction of a ylide anion with aldehydes, but the yields were
low (46-55%).6
(3) Hudlicky´, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II. A Critical ReView; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995.
(4) (a) Gardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Chem. Soc., Chem.
Commun. 1982, 1308. (b) Harding, K. E.; Stephens, R.; Hollingsworth, A.
S. Tetrahedron Lett. 1984, 25, 2631. (c) Berkowitz, W. F.; Amarasekara,
A. S. Tetrahedron Lett. 1985, 26, 3663. (d) Tamura, Y.; Annoura, H.;
Fujioka, H. Tetrahedron Lett. 1987, 28, 5681.
Allylic alcohols are particularly useful intermediates for
the synthesis of biologically active compounds.4 Conse-
(1) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Filler, R., Kobayashi,
Y. Eds. Biomedical Aspects of Fluorine Chemistry; Kodansha Ltd., &
Elsevier Biochemical: Tokyo and Amsterdam, 1982.
(2) (a) Welch, J. T., Eswarakrishnan, S., Eds. Fluorine in Bioorganic
Chemistry; John Wiley & Sons: New York, 1991. (b) Goldman, P. Science
1969, 164, 1123.
(5) Ono, N.; Kamimura, A.; Kaji, A. Tetrahedron Lett. 1984, 25, 5319
and references therein.
(6) Shen, Y.; Wang, T. Tetrahedron Lett. 1989, 30, 7203.
10.1021/ol990844r CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/03/1999

Recently, we reported several highly successful new
cesium fluoride-catalyzed nucleophilic trifluoromethylation
reactions.7-10 We have now extended this chemistry to the
facile synthesis of trans-R-trifluoromethyl allylic alcohols
in excellent isolated yields by the CsF-catalyzed nucleophilic
trifluoromethylation of enones with TMS-CF3. Initially, we
studied the optimization of the reaction conditions (Scheme
1) by using trans-chalcone (benzylideneacetophenone) (1a)
enones 1b-e were reacted with TMS-CF3 in the presence
of catalytic amounts of CsF to give the corresponding
R-trifluoromethyl silyl ethers 2b-e. Hydrolysis of the silyl
ethers with 6 N HCl at room temperature formed the
R-trifluoromethyl allylic alcohols 3b-e (Scheme 1) in >90%
isolated yield (Table 1). We also found that cyclic enones,
such as 2-cyclohexen-1-one (1f), reacted in an identical
fashion with TMS-CF3 and 6 N HCl to give the trifluoro-
methylated allylic alcohol (3f).
Scheme 1
Table 1. Trifluoromethylation of Enones with TMS-CF3
as a substrate. Reactants 1a and TMS-CF3 were dissolved
in ethylene glycol dimethyl ether. The mixture was cooled
to 0 °C, and a catalytic amount of CsF was added. The
reaction mixture was allowed to warm slowly to room
temperature over 1 h. The reaction was monitored by 19F
NMR and was found to be complete in 3 h, giving the trans-
1,1,1-trifluoro-2,4-diphenyl-3-buten-2-trimethylsilyl ether (2a)11
intermediate, in 99% yield. Hydrolysis was carried out at
room temperature with 6 N HCl for 3 h to form trans-1,1,1-
trifluoro-2,4-diphenyl-3-buten-2-ol (3a)12 in 96% isolated
yield. However, since at room temperature the reaction
proceeded smoothly in ethylene glycol dimethyl ether over
3 h followed by acid hydrolysis to give the same product
(3a) in 96% isolated yields, all further reactions were carried
out at 25 °C. Using the same reaction conditions, trans-
a
All reactions were carried out with 5 mmol of substrate, 5.25
mmol of TMS-CF3, and 0.1 mmol of CsF in 5 mL of ethylene
glycol dimethyl ether. b Isolated.
The nucleophilic reaction mechanism for the trifluoro-
methylation of these trans-enones with TMS-CF3 is most
likely the same as that reported for ketones.13
(7) Singh, R. P.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999,
64, 2579.
(8) Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem.
1999, 64, 2873.
(9) Singh, R. P.; Vij, A.; Kirchmeier, R. L.; Shreeve, J. M. J. Fluorine.
Chem. 1999, in press.
The trans-R-trifluoromethyl allylic alcohols that we have
prepared (Table 1) are liquids. They are soluble in common
organic solvents and very stable to air and moisture. The
liquid-phase infrared spectra of 3a-f showed a broad peak
in the region 3300-3600 cm-1 due to the ν(OH) vibration
and a sharp peak in the region 1630-1690 cm-1 arising from
the (CdC) stretching vibration. In the 19F NMR spectra, a
single peak was observed in all cases in the range from δ
-83 to -77 for the CF3 moiety. 1H NMR spectra for 3a-f
clearly showed the presence of the hydroxyl proton. This
resonance disappeared upon addition of D2O. In the 13C NMR
spectra, the R-CdO peak that appeared at δ 199 in 1a shifted
upfield to δ 77.7 in 3a. This resonance appears as a quartet
(10) Singh, R. P.; Vij, A.; Kirchmeier, R. L.; Shreeve, J. M. Inorg. Chem.
Submitted.
(11) Spectral data for 2a: IR (neat) 1650 (s, CdC) cm-1 1H NMR
;
(CDCl3) δ 0.19 (s, 9H), 6.04 (d, 1H, J ) 16.3 Hz), 6.84 (d, 1H, J ) 16.3
Hz), 7.40 (m, 8H), 7.64 (m, 2H); 13C NMR (CDCl3) δ 2.0, 80.1 (q, JC-C-F
) 28.8 Hz), 125.2 (q, JC-F ) 286.4 Hz), 126.9, 127.0, 128.0, 128.6, 128.7,
128.9, 135.4, 135.8, 138.1; 19F NMR (CDCl3) δ -77.5 (s); MS (EI) m/z
(species, rel int) 350 (M+, 30), 281 (M+ - CF3, 98), 260 (M+ - Me3-
SiOH, 100), 73 (SiMe3, 43).
(12) Spectral data for 3a: IR (neat) 3545 (b, OH), 1651 (s, CdC) cm-1
;
1H NMR (CDCl3) δ 3.03 (s, broad, 1H), 6.82 (d, 1H, J ) 16.1 Hz), 6.98
(d, 1H, J ) 16.1 Hz), 7.44 (m, 8H), 7.75 (m, 2H); 13C NMR (CDCl3) δ
77.7 (q, JC-C-F ) 29 Hz), 125.6 (q, JC-F ) 283 Hz), 126.5, 126.9, 127.0,
128.4, 128.7, 128.8, 128.9, 133.7, 135.6, 137.5; 19F NMR (CDCl3) δ -78.7
(s); MS (EI) m/z (species, rel int) 278 (M+, 10), 260 (M+ - H2O, 3), 209
(M+ - CF3, 100), 103 (PhCHdCH, 36), 77 (Ph, 7); HRMS calcd for
C16H13F3O 278.0918, found 278.0898. Anal. Calcd for C16H13F3O: C, 69.06;
H, 4.71. Found: C, 69.02; H, 4.69.
(13) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984.
1048
Org. Lett., Vol. 1, No. 7, 1999

with JC-C-F ) 29 Hz. This upfield shift resulted from the
formation of the OH group and introduction of the CF3
moiety. The CF3 carbon appeared as a quartet at about δ
125.6 for 3a with JC-F ) 283 Hz. Similar results were
observed in the 13C NMR spectra of 3b-f.
In summary, we have developed a very efficient method
for the synthesis of trans-R-trifluoromethyl allylic alcohols
via the direct nucleophilic trifluoromethylation of trans-
enones with TMS-CF3. The reaction is very selective.
Reaction conditions are very mild, and the isolated yields
are excellent.
Acknowledgment. This work was supported by the
National Science Foundation (Grant No. CHE-9720365). We
would like to thank Dr. Gary Knerr for obtaining HRMS.
Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 2b-f and
3b-f; IR, NMR (1H, 13C and 19F), MS. High-resolution mass
spectroscopic (HRMS) data for 2e, 3b, 3c, and 3e.
OL990844R
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