A trifluoromethyl group directed semipinacol rearrangement: Synthesis of α-(trifluoroacetyl) diarylmethanes

Article abstract of DOI:10.1016/S0022-1139(97)00031-6

Semipinacol rearrangements of trifluoromethyl substituted vic-diol monomethyl ethers proceeded smoothly to give α-(trifluoroacetyl) diarylmethanes in good yields. The trifluoromethyl group gave specific orientation to the course of the rearrangement.

Full text of DOI:10.1016/S0022-1139(97)00031-6

Journal of Fluorine Chemistry 84 (1997) 49–51
A trifluoromethyl group directed semipinacol rearrangement: synthesis of
a-(trifluoroacetyl) diarylmethanes
U
Gyula Hornya´k a, , Jo´zsef Fetter b, Ga´bor Ne´meth c, L. Posza´va´cz c, Gyula Simig c
a Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, 1521 Budapest, Hungary
b Department of Organic Chemistry, Technical University Budapest, 1521 Budapest, Hungary
c Chemical Research Division, EGIS Pharmaceuticals Ltd., P.O. Box 100, 1475 Budapest, Hungary
Received 22 November 1996; accepted 28 February 1997
Abstract
Semipinacol rearrangements of trifluoromethyl substituted vic-diol monomethyl ethers proceeded smoothly to give a-(trifluoroacetyl)
diarylmethanes in good yields. The trifluoromethyl group gave specific orientation to the course of the rearrangement. q 1997 ElsevierScience
S.A.
Keywords: Pinacol rearrangement; Semipinacol rearrangement; a-(Trifluoroacetyl) diarylmethanes
1. Introduction
methyl ethers 1 (Scheme 2). The reaction conditions
employed for compound 1a were also suitable for the similar
transformations of substrates 1b and 1c to the corresponding
ketones 2b and 2c.
In the course of our efforts to explore new trifluoromethy-
lated building blocks [1] we found that treatment of a ben-
zene solution of vic-diol monomethyl ether 1a with
concentrated sulfuric acid at ambient temperature afforded
a-(trifluoroacetyl) diphenylmethane 2a in 87% yield, pre-
sumably via a semipinacol rearrangement (Scheme 1) [2–
4]. The term ‘semipinacol rearrangement’ has come to rep-
resent also all 1,2-migrations of 2-hetero-substitutedalcohols
related to pinacol rearrangement [4].
In this paper we report the synthesis of vic-diolmonoethers
1a–1c containing substituents with various electronic quali-
ties at the p-position of the phenyl ring attached to the sec-
ondary carbon and their rearrangement to a-(trifluoroacetyl)
diarylmethanes 2a–2c.
The course of the rearrangement can be explained by com-
paring the stabilities of the possible carbenium ion interme-
diates (Scheme 3). The tertiary carbenium ion 5 is
destabilized by the electron-withdrawing trifluoromethyl
group, therefore the formation of the secondary carbenium
ion 6 is favored. 1,2-shift of the phenyl group is supposed to
be accompanied by simultaneous demethylation of the ether
group, thus avoiding the formation of a-trifluoromethyl sub-
stituted carbenium ion 7. A concerted rearrangement of the
protonated molecule 8 also cannot be excluded.
To the best of our knowledge this is the first observation
of a trifluoromethyl group controlled pinacol type (semipi-
nacol) rearrangement. Furthermore, the reaction sequence
discussed represents a convenient synthesis of trifluoroace-
tylated diarylmethanes from the easily available Mosher’s
nitrile.
2. Results and discussion
Compounds 1 have been prepared conveniently from the
easily available ‘Mosher’s nitrile’ 3 [5] (Scheme 2). Gri-
gnard reactions of compound 3 with arylmagnesium bro-
mides afforded ketones 4. Sodium borohydride reduction of
ketones 4 gave mixtures of diastereomeric vic-glycol mono-
3. Experimental details
The melting points were determined on a Bu¨chi 535 appa-
ratus and are uncorrected. The IR spectra were recorded on
an Aspect 2000 computer controlled Bruker IFS-113v vac-
uum optic FT spectrometer, using KBr pellets for solids or
liquid films. The NMR spectra were run on a Bruker WM-
U Corresponding author. Department of Organic Chemistry, Technical
University Budapest, 1521 Budapest, Hungary. Phone: q36 1 463 1129;
Fax: q36 1 463 3297.
0022-1139/97/$17.00 q 1997 Elsevier Science S.A. All rights reserved
PII S0022-1139(97)00031-6

50
G. Hornya´k et al. / Journal of Fluorine Chemistry 84 (1997) 49–51
3.2. Preparation of 3,3,3-trifluoro-2-methoxy-1-aryl-2-
phenylpropanols (1): general procedure
In a typical experiment 3,3,3-trifluoro-2-methoxy-1,2-
diphenylpropan-1-one (4a, 29.7 g, 101 mmol) was dissolved
in ethanol (450 ml) and sodium borohydride (17.8 g, 468
mmol) was added to the stirred solution. It was refluxed for
20 min, acidified by addition of aqueous hydrogen chloride
solution (10%) to pH 6 and evaporated. Water (600 ml) was
added to the residue and the mixture was extracted with dich-
loromethane (3=300 ml), treated with charcoal and evap-
orated to give 1a (29.6 g, 99%). The product was shown by
its 1H NMR spectrum to be a practically pure 2:1 mixture of
the two diastereomers and was subjected to the semipinacol
rearrangementwithoutfurtherpurification.1HNMR(CDCl3,
200 MHz) d: 7.42–6.72 (10H, m), 4.95 (1H, bs), 3.42 and
Scheme 1.
250 FT, or a Varian Gemini-200, or a Varian Unity Inova
400 spectrometer. Mass spectra were obtained by EI (70 eV,
evaporation temperature 120 8C) using a KRATOS MS 902
mass spectrometer.
3.1. Preparation of 3,3,3-trifluoro-2-methoxy-1-aryl-2-
phenylpropan-1-ones (4): general procedure
5
In a typical experiment a-trifluoromethyl-a-methoxy-
phenylacetonitrile (3, 29.0 g, 130 mmol) was added to a
solution of phenylmagnesium bromide (prepared from mag-
nesium (4.6 g, 192 mmol) and bromobenzene (17.0 ml, 29.0
g, 135 mmol) in ether (150 ml)) and the mixture was
refluxed for 5 h. The solvent was evaporated and the residue
was dissolved in ethanol (550 ml). Water (30 ml) and con-
centrated hydrochloric acid (30 ml) were added and the mix-
ture was refluxed for 5 h. After evaporation of the ethanol,
water (90 ml) was added and the pH was adjusted to 8 with
aqueous sodium hydroxide (40%) solution. The mixture was
extracted with ether (3=150 ml), the combined ethereal
solution wasextracted withbrine, driedonmagnesiumsulfate
and evaporated. The residual oil was distilled to give 3,3,3-
trifluoro-2-methoxy-1,2-diphenylpropan-1-one (4a). The
physical and spectral data of compounds 4 are shown in
Table 1.
3.36 (3H, ratio ca. 1:2, 2=q, JHFs1.8 Hz, through space
coupling), 3.20 and 3.00 (1H, ratio ca. 1:2, bs); high reso-
lution MS (EI) calculated for C16H15F3O2 (Mq) m/z
296.1024, found 296.1027.
Compounds 1b and 1c were prepared by a similar
procedure.
3,3,3-Trifluoro-2-methoxy-1-(4-methoxyphenyl)-2-
phenylpropanol (1b): yield 99%, 4:1 mixture of the two
1
diastereomers. H NMR (CDCl3, 250 MHz) d: 7.55–6.55
(9H, m), 4.92 (1H, bs), 3.77 and 3.73 (3H, ratio ca. 1:4,
2=s), 3.46 and 3.42 (3H, ratio ca. 1:4, 2=q, 5JHFs1.8 Hz,
through space coupling), 4.02 and 3.81 (1H, ratio ca. 1:4,
2=d, Js6.5 and 5.0 Hz); high resolution MS (EI) calcu-
lated for C17H17F3O3 (Mq) m/z 326.1130, found 326.1123.
3,3,3-Trifluoro-1-(4-fluorophenyl)-2-methoxy-2-phenyl-
propanol (1c): yield 92%, 3:1 mixture of the two diastereo-
mers. 1H NMR (CDCl3, 200 MHz) d: 7.45–6.75 (9H, m),
Scheme 2.
Scheme 3.

G. Hornya´k et al. / Journal of Fluorine Chemistry 84 (1997) 49–51
51
Table 1
Yields, boiling points, IR, 1H NMR, 13C NMR and high resolution MS spectra of 2 and 4
Entry
Boiling point (8C (mmHg))
84–86 (0.2)
Yield (%)
Spectrum
n (cmy1) or d (ppm) or exact mass (Mq, m/z)
2a
87%
IR
KBr
400 MHz
50.3 MHz
1763
1H NMR
13C NMR
7.38–7.17 (10H, m), 5.52 (1H, s)
190.0 (q, 2JCFs34 Hz), 135.6, 129.1, 128.9, 128.1, 116.0 (q,
1JCFs294 Hz), 57.8
calculated for C15H11F3O 264.0762, found 264.0753
1730
HRMS
IR
EI
KBr
400 MHz
2b
2c
108–110 (0.2)
76–78 (0.1)
71%
83%
1H NMR
7.46–7.20 (5H, m), 7.16 (2H, d, Js8.4 Hz), 6.88 (2H, d, Js8.4
Hz), 5.46 (1H, s), 3.79 (3H, s)
13C NMR
100.6 MHz
190.0 (q, 2JCFs33.6 Hz), 159.4, 136.0, 130.0, 129.0, 128.7, 128.0,
127.4, 116.0 (q, 1JCFs293.7 Hz), 114.5, 57.0, 55.3
calculated for C16H13F3O2 294.0868, found 294.0874
1764
HRMS
IR
EI
KBr
200 MHz
1H NMR
7.42–7.30 (3H, m), 7.29–7.15 (4H, m), 7.03 (2H, t-like m, Js8.7
Hz), 5.51 (1H, s)
13C NMR
50.3 MHz
189.8 (q, 2JCFs34.4 Hz), 162.6 (d, 1JCFs248 Hz), 135.4, 131.5
(d, 4JCFs3.4 Hz), 130.6 (d, 3JCFs8.4 Hz), 129.2, 128.8, 128.3,
116.0 (q, 1JCFs294 Hz), 116.0 (d, 2JCFs21.7 Hz), 57.0
calculated for C15H10F4O 282.0668, found 282.0857
1670
HRMS
IR
EI
KBr
250 MHz
4a
4b
109–110 (0.1)
128–130 (0.2)
77%
75%
1H NMR
7.95–7.80 (2H, m), 7.65–7.22 (8H, m), 3.53 (3H, q, 5JHFs1.8 Hz,
through space coupling)
193.6, 133.9, 133.8, 133.7, 130.1, 129.5, 128.6, 128.5, 128.3, 127.4,
126.8, 123.7 (q, 1JCFs292 Hz), 87.0 (q, 2JCFs25 Hz), 56.2
calculated for C16H13F3O2 294.0868, found 294.0869
1650
7.91 (2H, d, Js9.0 Hz), 7.54 (2H, m), 7.35 (3H, m), 6.77 (2H, d,
Js9.0 Hz), 3.78 (3H, s), 3.55 (3H, q, 5JHFs1.7 Hz, through space
coupling)
192.0, 163.8, 134.3, 132.6, 129.3, 128.5, 126.8, 126.7, 123.8 (q,
1JCFs291 Hz), 113.7, 86.8 (q, 2JCFs25 Hz), 56.0 (q, 4JCFs2.3
Hz), 55.3
13C NMR
62.9 MHz
HRMS
IR
EI
KBr
400 MHz
1H NMR
13C NMR
50.3 MHz
HRMS
IR
EI
KBr
200 MHz
calculated for C17H15F3O3 324.0973, found 324.0964
1692
4c
102–104 (0.2)
55%
1H NMR
7.91 (2H, dd-like m, Js9.2 and 5.6 Hz), 7.58–7.48 (2H, m), 7.42–
7.32 (3H, m), 6.98 (2H, t-like m, Js8.7 Hz), 3.55 (3H, q,
5JHFs1.8 Hz, through space coupling)
13C NMR
HRMS
50.3 MHz
EI
192.1, 165.9 (d, 1JCFs257 Hz), 133.8, 133.0 (d, 3JCFs9 Hz),
130.1, 129.6, 128.6, 126.8, 123.6 (q, 1JCFs291 Hz), 115.7 (d,
2JCFs22 Hz), 86.8 (q, 2JCFs25 Hz), 56.1 (q, 4JCFs2 Hz)
calculated for C16H12F4O2 312.0773, found 312.0783
4.97 (1H, bs), 3.47 and 3.40 (3H, ratio ca. 1:3, 2=q,
5JHFs1.8 Hz, through space coupling), 3.08 and 2.91 (1H,
ratio ca. 1:3, 2=d, Js7.0 and 2.9 Hz); high resolution MS
(EI) calculated for C16H14F4O2 (Mq) m/z 314.0930, found
314.0925.
was distilled to give 1,1,1-trifluoro-3,3-diphenylpropan-2-
one (2a). The physical and spectral data of compounds 2 are
shown in Table 1.
References
3.3. Preparation of 1,1,1-trifluoro-3-aryl-3-phenylpropan-
2-ones (2): general procedure
´
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In a typical experiment 3,3,3-trifluoro-2-methoxy-1,2-
diphenylpropanol (1a, 29.5 g, 100 mmol, a mixture of two
diastereomers, obtained as described above) was dissolved
in benzene (250 ml) and concentrated sulfuric acid (16 ml)
was added. After 30 min at ambient temperature the mixture
was extracted with water (2=50 ml) and brine (50 ml),
dried (magnesium sulfate) and evaporated. The residual oil
´
[3] M. Barto´k, A. Molna´r, Dehydration of diols, in: S. Patai (Ed.), The
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