Preparation of 3-trifluoromethyl-2-cycloalkenones by the oxidative rearrangement of trifluoromethylated tertiary allylic alcohols with pyridinium chlorochromate

Article abstract of DOI:10.1016/S0022-1139(99)00159-1

Trifluoromethylated tertiary allylic alcohols, obtained from trifluoromethylation of several conjugated enones, undergo oxidative rearrangements to 3-trifluoromethyl-2-cycloalkenones with pyridinium chlorochromate in the presence of a small amount of conc

Full text of DOI:10.1016/S0022-1139(99)00159-1

Journal of Fluorine Chemistry 101 (2000) 199±202
Preparation of 3-tri¯uoromethyl-2-cycloalkenones by the
oxidative rearrangement of tri¯uoromethylated tertiary
allylic alcohols with pyridinium chlorochromate$
G.K. Surya Prakash*, Emily C. Tongco, Thomas Mathew,
Yashwant D. Vankar1, George A. Olah
Department of Chemistry, Loker Hydrocarbon Research Institute, University of Southern California,
Los Angeles, CA 90089-1661, USA
Received 9 May 1999; received in revised form 11 June 1999; accepted 14 June 1999
Abstract
Tri¯uoromethylated tertiary allylic alcohols, obtained from tri¯uoromethylation of several conjugated enones, undergo oxidative
rearrangements to 3-tri¯uoromethyl-2-cycloalkenones with pyridinium chlorochromate in the presence of a small amount of concentrated
H2SO4. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Tri¯uoromethyltrimethylsilane; Tri¯uoromethylated tertiary allylic alcohols; Pyridinium chlorochromate; 3-tri¯uoromethyl-2-cycloalkenones
1. Introduction
materials can also be used to prepare polycyclic compounds
containing angular tri¯uoromethyl groups and are of parti-
cular interest in steroid chemistry. Of the several possibilites,
we considered oxidative rearrangement of tertiary allylic
alcohols as a viable route to this effect (Dauben rearrange-
ment). This mainly stems from the fact that tri¯uoromethy-
lated tertiary allylic alcohols are readily available by the
addition of CF3SiMe3 to conjugated enones. The use of
oxochromium (VI) reagents for oxidative rearrangement of
tertiary allylic alcohols has been studied [12±14] for the past
two decades and has found diverse applications in natural
product synthesis [15]. This reaction has been extended to
include oxidative rearrangements of enynols [16], dienols
[17], vinylclopropylcarbinols [18], phosphorus-containing
tertiary allylic alcohols [19±21], and substrates bearing
sulfur substituents [15]. However, to our knowledge, oxida-
tive rearrangement of tertiary allylic tri¯uoromethyl alco-
hols has not been studied.
Organo¯uorine compounds have found rapidly increasing
use in the areas of agrochemicals, pharmaceuticals and
¯uoropolymers [1±4]. In addition to the introduction of
elemental ¯uorine, incorporation of a tri¯uoromethyl group
in organic compounds has received considerable attention in
recent years [1±5]. In connection with our ongoing studies to
develop synthetic methodologies for the synthesis of novel
compounds containing tri¯uoromethyl groups [6±8], we
now report the synthesis of 3-tri¯uoromethyl-2-cycloalke-
nones by oxidative rearrangement of the corresponding
tri¯uoromethylated tertiary allylic alcohols. Conjugated
enones have been used in (2 ‡ 2) [9] and (2 ‡ 3) [10,11]
cycloadditions to rapidly build up polycylic molecules. It
was, therefore, of interest to us to develop a general synthetic
method which allows preparation of conjugated enones
containing a tri¯uoromethyl group on the double bond. Such
$Considered Synthetic Methods and Reactions, Part. 204. For Part
203, see, G.A. Olah, E.R. Marinez, G.K.S. Prakash, Synlett, submitted
for publication. The work was presented at the International
Conference on Fluorine Chemistry 1999 Tokyo, 9±11 May 1999,
Yokohama, Japan.
2. Experimental
1H, 13C and 19F NMR spectra were obtained in CDCl3
solutions on a Varian unity 300 (300 MHz) instrument and
*Corresponding author. Fax: ‡1-213-740-66679.
the chemical shifts referenced to TMS (for H, 13C NMR)
1
E-mail address: prakash@methyl.usc.edu (G.K.S. Prakash)
1Present address: Department of Chemistry, Indian Institute of
Technology, Kanpur 208016, India.
and CFCl3 (for 19F NMR). GC/MS data were obtained from
a Hewlett±Packard 5890 series spectrometer. HRMS data
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 5 9 - 1

200
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 101 (2000) 199±202
were obtained using chemical or electron ionization, and
performed by the Southern California Mass Spectroscopy
Facility at University of California Riverside. All starting
ketones were commercially available, and used without
further puri®cation. All solvents were freshly distilled prior
to use.
27 Hz); 121.2 (CH); 125.7 (CF3, q, JC±F ˆ 289 Hz); 127.5
(CH); 136.1 (Cquat); 144.4 (CH). 19F NMR (ꢀ): 77.6. Mass
spectra, m/z: 220 (M , 40); 109 (100); 91 (64).
‡
2.2. General procedure for oxidation of
trifluoromethylated alcohols with PCC
2.1. General procedure for the synthesis of
trifluoromethylated alcohols
The alcohol (2.5 mmol) was dissolved in CH2Cl2 (20 ml)
followed by addition of PCC (1.075 g, 5 mmol). To this
reaction mixture was added several drops (ꢀ8 drops) of
concentrated sulfuric acid until the solution becomes
brownish-black. Progress of the reaction was monitored
by TLC and GC/MS, but in all cases, complete conversion
to the rearranged ketone was not achieved. After overnight
stirring at room temperature, the reaction mixture was
diluted with diethyl ether, and carefully quenched with
saturated NaHCO3. The organic layer was extracted several
times with ether. The collected organic layer was washed
with NaHCO3, and with brine, and dried over MgSO4.
Evaporation of solvent gave the product as a mixture of
starting tri¯uoromethyl alcohol and the b-tri¯uoromethyl
carbonyl compound, which was puri®ed through column
chromatography on silica gel (hexane-methylene chloride).
3-Tri¯uoromethyl-2-cyclohexen-1-one (2a): Oil, 1H
NMR (ꢀ): 2.02 (2H, q, J ˆ 6 Hz); 2.37 (4H, t, J ˆ 6 Hz);
6.24 (1H, s). 13C NMR (ꢀ): 21.8, 22.7, 37.2 (CH2); 122.7
(CF3, q, JC±F ˆ 274 Hz); 128.1 (CH, q, JC±C±C±F ˆ 5 Hz);
147.4 (C±CF3, q, JC±C±F ˆ 32 Hz); 197.9 (CO). 19F NMR
(ꢀ): 71.4. IR (cm 1): 1711 (CO). Mass spectra, m/z: 164
To a Schlenk ¯ask equipped with a magnetic stirrer was
placed 2.5 mmol of the ketone in 5 ml THF, followed by
addition of CF3TMS (1.2 eq). Tetrabutylammonium ¯uor-
ide (TBAF, 1.0 M in THF solution) was added dropwise
until reaction becomes exothermic and the reaction mixture
becomes dark brown. The reaction was monitored by TLC.
Hydrolysis of the corresponding tri¯uoromethyl silyl ethers
was carried out either in 5 N HCl solution, or in 1 eq TBAF
solution. After hydrolysis is complete as shown by TLC, the
solvent was evaporated and the crude product ®ltered
through silica gel. The tri¯uoromethylated alcohols were
used in the subsequent oxidation step.
1
1-Tri¯uoromethyl-2-cyclohexen-1-ol (1a): H NMR (ꢀ):
1.52±2.37 (7H, m); 5.73 (1H, br. d, J ˆ 10 Hz); 6.17 (1H,
m). 13C NMR (ꢀ): 17.2, 24.8, 28.9 (CH2); 70.1 (C±CF3, q,
JC±C±F ˆ 30 Hz); 126.0 (CF3, q, JC±F ˆ 284 Hz); 122.8,
136.4 (ole®nic CH). 19F NMR (ꢀ): 83.3. Mass spectra,
‡
m/z: 166 (M , 0.4); 97 (100); 69 (16).
1-Tri¯uoromethyl-4,4-dimethyl-2-cyclohexen-1-ol (1b):
1H NMR (ꢀ): 1.04 (3H, s); 1.25 (3H, s); 1.51±1.97 (4H, m);
2.41 (1H, br); 5.55 (1H, br. d, J ˆ 10 Hz); 5.84 (1H, br. d,
J ˆ 10 Hz). 13C NMR (ꢀ): 26.2 (CH2); 26.9, 29.7 (CH3);
31.6 (CH2); 70.4 (C±CF3, q, JC±C±F ˆ 29 Hz); 120.2 (CH);
125.8 (CF3, q, JC±F ˆ 284 Hz); 146.1 (CH). 19F NMR (ꢀ):
83.1. Mass spectra, m/z: 176 (M 18, 13); 125 (100); 69
(11).
‡
(M , 22); 136 (100); 67 (40). HRMS, m/z: Calc. 164.0449
(M ); Found 164.0449.
‡
3-Tri¯uoromethyl-6,6-dimethyl-2-cyclohexen-1-one(2b):
Oil, 1H NMR (ꢀ): 1.11 (6H, s); 1.91 (2H, t, J ˆ 6 Hz); 2.47
(2H, br. t, J ˆ 6 Hz); 6.25 (1H, s). 13C NMR (ꢀ): 20.2 (CH2);
23.5 (CH3); 35.2 (CH2); 41.1 (Cquat); 124.3 (CF3, q, JC±F
ˆ
274 Hz); 126.8 (CH, q, JC±C±C±F ˆ 5 Hz); 145.6 (C±CF3, q,
JC±C±F ˆ 32 Hz); 202.8 (CO). 19F NMR (ꢀ): 71.1. IR
1-Tri¯uoromethyl-4-(2-propenyl)-2-cyclohexen-1-ol(1c):
1H NMR (ꢀ): 1.61±2.53 (m, 5H); 1.74 (3H, s); 1.82 (3H, s);
2.45 (1H, s); 4.75 (2H, d, J ˆ 8 Hz); 5.81 (1H, br. m). 13C
NMR (ꢀ): 17.4, 20.4 (CH3); 30.7, 36.8 (CH2); 37.4 (CH);
74.3 (C±CF3, q, JC±C±F ˆ 28 Hz); 109.7 (CH2); 125.8 (CF3,
q, JC±F ˆ 287 Hz); 129.8 (Cquat); 130.7 (CH); 147.7 (Cquat).
‡
(cm 1): 1695 (CO). Mass spectra, m/z: 192 (M , 14);
‡
136 (100); 67 (19). HRMS, m/z: Calc. 192.0762 (M );
Found 192.0760.
3-Tri¯uoromethyl-6-(2-propenyl)-2-cyclohexen-1-one
1
(2c): Oil, H NMR (ꢀ): 1.76 (3H, s); 1.93±1.95 (2H, m);
19F NMR (ꢀ): 76.2. Mass spectra, m/z: 220 (M , 0.7); 202
2.33±2.45 (2H, m); 2.60±2.67 (3H, m); 4.78 (1H, s); 4.85
(1H, s). 13C NMR (ꢀ): 11.3, 20.3 (CH3); 30.0 (CH2); 40.5
(CH); 42.1, 111.4 (CH2); 123.8 (CF3, q, JC±F ˆ 277 Hz);
137.4 (Cquat); 140.5 (C±CF3, q, JC±C±F ˆ 30 Hz); 145.3
(Cquat); 198.3 (CO). 19F NMR (ꢀ): 63.3. IR (cm 1):
‡
(100); 109 (89).
1-Tri¯uoromethyl-2-cyclohepten-1-ol (1d): 1H NMR (ꢀ):
1.53±2.30 (9H, m); 5.71 (1H, d, J ˆ 12 Hz); 6.05±6.13 (1H,
m). 13C NMR (ꢀ): 22.7, 26.8, 27.4, 31.3 (CH2); 76.0 (C±
CF3, q, JC±C±F ˆ 27 Hz); 125.9 (CF3, q, JC±F ˆ 286 Hz);
128.2 (CH); 137.9 (CH). 19F NMR (ꢀ): 83.4. Mass spectra,
‡
1689 (CO). Mass spectra, m/z: 218 (M , 3); 150 (100);
122 (34). HRMS, m/z: Calc. 219.0997 (M ‡ 1); Found
‡
m/z: 180 (M , 0.6); 162 (79); 111 (100).
219.1008 (M ‡ 1).
1-Tri¯uoromethyl-2-methyl-6,6-dimethyl-2,4-cyclohep-
tadien-1-ol (4): 1H NMR (ꢀ): 1.14 (3H, s); 1.19 (3H, s); 1.97
(3H, s); 2.09 (1H, d, J ˆ 15 Hz); 2.25 (1H, d, J ˆ 15 Hz);
2.32 (1H, s); 5.53±5.59 (1H, m); 5.68 (1H, d, J ˆ 11 Hz);
5.86 (1H, br. d, J ˆ 7 Hz). 13C NMR (ꢀ): 21.6, 26.0, 32.3
3-Tri¯uoromethyl-2-cyclohepten-1-one (2d): Oil, 1H
NMR (ꢀ): 1.71±1.93 (4H, m); 2.52±2.67 (4H, m); 6.43
(1H, s). 13C NMR (ꢀ): 21.2, 24.9, 26.2, 42.5 (CH2);
123.7 (CF3, q, JC±F ˆ 274 Hz); 131.9 (CH, q, JC±C±C±F
ˆ
5 Hz); 142.8 (C±CF3, q, JC±C±F ˆ 29 Hz); 202.5 (CO). 19F
NMR (ꢀ): 70.9. IR (cm 1)1682 (CO). Mass spectra, m/z:
(CH3); 35.4 (Cquat); 48.9 (CH2); 77.2 (C±CF3, q, JC±C±F
ˆ

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 101 (2000) 199±202
201
‡
178 (M , 26); 136 (71); 109 (100); 81 (72). HRMS, m/z:
‡
procedure. It is noteworthy that PCC alone or only with a
drop of H2SO4 did not give any rearranged products. On the
other hand, one equivalent (or more) of H2SO4 led to
excessive decomposition of PCC without any improvement
in the yields of the ®nal rearranged products. Substitution of
sulfuric acid with Na®on-H (a solid polymeric sulfonic acid
catalyst) [28,29] did not give any rearrangement product.
Furthermore, the present reaction was found to be generally
limited to cyclic enones. Thus, for example, tri¯uoromethy-
lated allylic alcohols derived from chalcone, 4-phenyl-
buten-2-one, a-ionone, and 4-hexen-3-one did not give
the rearrangement products.
Calc. 178.0605 (M ); Found 178.0602.
5-Tri¯uoromethyl-3, 3, 6-trimethyl-8-oxa-bicyclo[3.2.1]-
1
octa-6-ene-2-one (5): Oil, H NMR (ꢀ): 1.19 (3H, s); 1.32
(3H, s); 1.80 (1H, d, J ˆ 14 Hz); 1.93 (3H, s); 2.26 (1H, d,
J ˆ 14 Hz); 4.75 (1H, s); 5.93 (1H, s). 13C NMR (ꢀ): 12.0,
30.3, 30.8 (CH3); 36.8 (CH2); 42.5 (Cquat); 85.3 (CH); 87.2
(C±CF3, q, J ˆ 32 Hz); 123.3 (CF3, q, JC±F ˆ 281 Hz);
126.1 (CH); 143.3 (Cquat); 206.3 (CO). 19F NMR (ꢀ):
79.2. IR (cm 1): 1715.6 (CO). Mass spectra, m/z: 234
‡
‡
(M , 11); 150 (100); 81 (14). HRMS, m/z: Calc. 234.0878
‡
(M ); Found 234.0869 (M ).
3. Results and discussion
The required tri¯uoromethylated tertiary allylic alcohols
were synthesized following the procedure developed by
Prakash and Yudin [6]. Initial studies to effect the oxidative
rearrangement with reagents like pyridinium chlorochro-
mate (PCC) [22] pyridinium dichromate (PDC) [23], Col-
lins [24] and Jones reagents [25], failed to give the expected
enones. Use of PCC on alumina [26] or ultrasound promoted
PCC oxidation [27] also gave no encouraging results.
Interestingly, however, when the reaction was carried out
with PCC in the presence of a small amount of concentrated
sulfuric acid, the rearrangement took place leading to the
formation of the expected 3-tri¯uoromethyl-2-cycloalke-
nones, albeit in preparatively low yields (Table 1). However,
such low yields are still acceptable as valuable tri¯uoro-
methyl-substituted dienophiles are obtained in a one-pot
In an attempt to extend the scope of this reaction,
eucarvone 3 was chosen as a substrate. Addition of
CF3SiMe3 gave the expected tri¯uoromethylated alcohol
4 in 60% yield. Reaction of 4 with PCC under the above
described conditions gave a product with an exact mass
which was 16 masses higher than the expected oxidation
1
product. Analyses of H and 13C NMR spectra show the
likely product to have the dihydrofuran structure 5. It is
Table 1
PCC oxidation of a,b-unsaturated trifluoromethylated alcohols
Entry
Starting alcohol
Product
Yields (%)a
1a
2a
2b
28
1b
1cb
1d
25
34
20
2c
2d
aIsolated yields.
bDiastereomeric mixture.

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G.K.S. Prakash et al. / Journal of Fluorine Chemistry 101 (2000) 199±202
[2] J.F. Liebman, J.A. Greenberg, W.R. Dolbier, Jr. (Eds.), Fluorine-
containing Molecules. Structure, Reactivity, Synthesis, and Applica-
tions, VCH, New York, 1988.
possible that PCC under acidic conditions hydroxylates the
farthest double bond, creating a carbocationic center that is
subsequently attacked by the hydroxyl geminal to the tri-
¯uoromethyl group. The resulting intermediate alcohol
bearing the dihydrofuran ring is oxidized to the ®nal
product 5.
[3] R. Filler, Y. Kobayashi (Eds.), Biomedical Aspects of Organo-
fluorine Chemistry, Elsevier, Amsterdam, 1983.
[4] F.A. Smith, Handbook of Experimental Pharmacology, vol. XX, part
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[7] E.C. Tongco, G.K.S. Prakash, G.A. Olah, Synlett (1997) 1193.
[8] J. Weidemann, T. Heiner, G. Mloston, G.K.S. Prakash, G.A. Olah,
Angew. Chem. Int. Ed. Engl. 37 (1998) 820.
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references cited therein.
In summary, we report a relatively simple route to 3-
tri¯uoromethyl-2-cycloalkenones by the oxidative rearran-
gement of tri¯uoromethylated tertiary allylic alcohols,
obtained from tri¯uoromethylation of several conjugated
enones with pyridinium chlorochromate in the presence of a
small amount of concentrated H2SO4. This reaction is,
however, limited to cyclic enones.
[16] D. Liotta, D. Brown, W. Hoekstra, R. Monihan, Tetrahedron Lett.
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È
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Acknowledgements
Support of our work by the Loker Hydrocarbon Research
Institute is gratefully acknowledged.
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