Dissimilar reactivities of diastereomeric 1,1,1-trifluoro-3-(4-methoxyphenyl)-2,3-diphenylpropan-2-ols in an attempted elimination reaction

Article abstract of DOI:10.1016/S0022-1139(01)00364-5

Attempted dehydration of a diastereomeric mixture of 1,1,1-trifluoro-3-(4-methoxyphenyl)-2,3-diphenyl-propan-2-ols (6a) with thionyl chloride in the presence of pyridine afforded the rearranged derivative 8 as the main product and only small amounts of the expected olefins (4, 5). Similar treatment of (2RS,3RS)-6a gave the rearrangement product 8 exclusively, while transformation of (2RS,3SR)-6a resulted in the formation of compounds 4, 5 and 8. The different reactivity of the diastereomers is rationalised.

Full text of DOI:10.1016/S0022-1139(01)00364-5

Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
Dissimilar reactivities of diastereomeric
,1,1-tri¯uoro-3-ꢀ4-methoxyphenyl)-2,3-diphenylpropan-2-ols
in an attempted elimination reaction
1
a
Gyula Horny a k , J o zsef Fetter , K a roly Lempert , L a szl o P a rk a nyi ,
b
a,b
c
d
G a bor N e meth , L a szl o Posz a v a cz , Gyula Simig
Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, Hungary
b
Department of Organic Chemistry, Technical University Budapest, H-1521 Budapest, Hungary
Institute of Chemistry, Chemical Research Centre of the Hungarian Academy of Sciences, H-1525 Budapest, Hungary
d
d,*
a
c
d
Chemical Research Division, EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary
Received 18 December 2000; accepted 8 February 2001
Abstract
Attempted dehydration of a diastereomeric mixture of 1,1,1-tri¯uoro-3-ꢀ4-methoxyphenyl)-2,3-diphenyl-propan-2-ols ꢀ6a) with thionyl
chloride in the presence of pyridine afforded the rearranged derivative 8 as the main product and only small amounts of the expected ole®ns
ꢀ
4, 5). Similar treatment of ꢀ2RS,3RS)-6a gave the rearrangement product 8 exclusively, while transformation of ꢀ2RS,3SR)-6a resulted in
the formation of compounds 4, 5 and 8. The different reactivity of the diastereomers is rationalised. # 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Diastereospeci®c reaction; Tri¯uoromethyl group substituent effect; Field effect; Wagner±Meerwein type rearrangement of 1-ꢀtri¯uoromethyl)-
1,2,2-triarylethanols; Destabilised carbocation
1
. Introduction
and 3 in the position of the hydroxy group. The observed
unexpected reactivity is rationalised also by the interaction
of the neighbouring aryl rings, which helps to stabilise a
cationic centre adjacent to a tri¯uoromethyl group. This
interaction obviously has a crucial effect on the outcome of
cationic reactions of 1,1,1-tri¯uoro-2,3,3-triarylpropanols
[1,2].
Recently we reported a new practical synthesis of pano-
mifene ꢀ1, EGIS-5650, GYKI-13504), a mammary-tumour
inhibiting antiestrogen [1]. We have also discussed there the
acid-catalysed dehydration of diastereomeric 3,3,3-tri¯uoro-
1
-ꢀ4-methoxyphenyl)-1,2-diphenylpropan-1-ols 2 and 3
demonstrating that either alcohol affords practically the
same 7.7:1 ratio of the E ꢀ4) and Z ꢀ5) isomers of the ole®nic
product ꢀScheme 1). The stereoselectivity of this dehydra-
tion has been explained by different stabilities of the con-
formers of the common carbenium ion intermediate. The
cation stabilising effect of the p-methoxyphenyl group is
assisted by the electron donating ®eld effect of the nearly
parallel adjacent phenyl group in conformer A contrary to
conformer B bearing the electron-withdrawing tri¯uoro-
methyl group in the same position.
2. Results and discussion
A mixture of the diastereomeric alcohols 6a was prepared
by the reaction of ketone 7a [2] with phenylmagnesium
bromide ꢀScheme 2). Dehydration of this alcohol mixture
proved dif®cult. The starting material was recovered when
using the same conditions as for dehydration of alcohols 2
and 3 ꢀhydrochloric acid in re¯uxing ethanol). Related a-
ꢀtri¯uoromethyl)triarylethanols were dehydrated with thio-
nyl chloride in pyridine [3]. When using these reagents in
re¯uxing chloroform the unexpected rearrangement product
In continuation of these studies, we report here the results
obtained in the course of attempted dehydration of the
diastereomeric alcohols 6, which differ from the pair 2
8 was obtained from 6a in 32% yield as a practically pure
single diastereomer ꢀfor the assignment of the stereostruc-
ture see below). Ole®ns 4 and 5 as minor products could be
*
Corresponding author. Tel.: ‡36-1-2655543; fax: ‡36-1-2655613.
E-mail address: simig@freemail.hu ꢀG. Simig).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ꢀ 0 1 ) 0 0 3 6 4 - 5

240
G. Horny a k et al. / Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
Scheme 1.
Scheme 2.
1
detected in the mother liquor by TLC together with several
unidenti®ed compounds. Triphenylethanol 6b was also trea-
ted with thionyl chloride in re¯uxing chloroform in the
presence of pyridine. No rearrangement was observed in
this case, only elimination occurred and ole®n 4b ꢀ5b) was
obtained in 85% yield.
ꢀFig. 1). Formation of compound 8 can be explained by
Wagner±Meerwein rearrangement of alcohol 6a ꢀScheme 3).
The p-methoxyphenyl group migrates towards the cationic
centre destabilised by the trifluoromethyl substituent [4].
The new carbocation stabilises itself by recombination with
The constitution of chloride 8 is based on spectral data
and on its transformation to the benzyl compound 9 by
catalytic hydrogenation. The con®guration of compound 8
was determined by single crystal X-ray diffraction analysis
1
Crystallographic data for the structure reported in this paper have been
deposited at the Cambridge Crystallographic Data Centre. Copies of the
data can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

G. Horny a k et al. / Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
241
of 6a were separated. The structures of the individual
diastereoisomers were determined by single crystal X-ray
1
diffraction analysis ꢀFig. 2). As indicated by the H NMR
spectra, both diastereoisomers exist predominantly in the
same conformations in solution as in the crystalline state.
Since the bulky benzene rings on the neighbouring carbon
atoms are nearly parallel ꢀpropeller-like arrangement,
Fig. 2), their mutual anisotropic effects result in diamagnetic
shifts of the aromatic proton signals. This shift of the protons
of the p-methoxyphenyl ring is characteristic of the 2RS,3RS
isomer of 6a. Similar diamagnetic shifts of the protons of the
para-substituted benzene ring were observed for the diaster-
eoisomeric pairs of 1,1,2-triarylethanes, 1,1,2-triaryletha-
nols [8,9] and tri¯uoromethyl substituted 1,1,2-triaryl-
ethanols ꢀ2, 3) [1].
The two diastereomers of 6a reacted in a signi®cantly
different manner when treated with thionyl chloride in
re¯uxing chloroform in the presence of catalytic pyridine.
After re¯uxing for 2 h, the 2RS,3RS diastereomer gave
exclusively compound 8 as a single diastereomer in 76%
yield ꢀisolated). Conversion of the 2RS,3SR diastereomer
was much slower and resulted in a product mixture contain-
ing ole®ns 4, 5 ꢀ36%) and the rearranged product 8 ꢀ31%).
These experiments suggest that the 2SR,3SR diastereomer
of 6a possesses the structure required for rearrangement to 8
ꢀScheme 3). The observation that triphenylethanol 6b did
not afford a rearranged product indicates that the assistance
of the p-methoxyphenyl group in the departure of the leaving
group is essential for the rearrangement to take place. The
formation of a single diastereomer 8 can be explained by a
Fig. 1. Perspective view and atom labelling of the crystal structure of
2RS,3SR)-3-chloro-1,1,1-trifluoro-2-ꢀ4-methoxyphenyl)-2,3-diphenyl-
ꢀ
propane ꢀ8). Atomic displacement ellipsoids represent 50% probabilities.
the chloride anion. Similar rearrangements resulting in the
separation of the positive charge apart from the trifluoro-
methyl group are known from the literature [5±7].
In order to study the effect of the con®guration of 6a on
the outcome of the reaction with thionyl chloride in re¯uxing
chloroform in the presence of pyridine, the diastereoisomers
Scheme 3.

242
G. Horny a k et al. / Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
Fig. 2. Perspective view and atom labelling of the crystal structure of the 2S,3S and 2R,3S enantiomers ꢀtop and bottom, respectively) of 1,1,1-trifluoro-3-ꢀ4-
methoxyphenyl)-2,3-diphenylpropan-2-ol diastereomeric racemates ꢀ6a). Atomic displacement ellipsoids represent 40 and 50% probabilities, respectively.
concerted transformation of intermediate 10 to the ®nal
product 8 or to the bridged phenonium ion 11, which can
be opened by the chloride anion only from the less shielded
side.
donating ®eld effect of the adjacent b-aryl group, provided
that the two benzene rings on the neighbouring carbon atoms
are in gauche relation, resulting a nearly parallel, propeller-
like arrangement [1,10].
The dissimilar reactivities of the diastereomers 6a can be
explained by assuming a transition state, in which C±OSOCl
bond breaking somewhat precedes C±Ar bond making,
developing thereby some positive charge at the central
carbon atom. A very strong demand for stabilisation in
the transition state of the formation of a-tri¯uoromethyl
cation is expected. The stabilisation of the carbenium ion by
the a-aryl substituent is known to be assisted by the electron
Comparison of the antiperiplanar conformations of inter-
mediates 10 and 12 shows ꢀScheme 3) that only the inter-
mediate 10 derived from 2S,3S-6a exhibits a- and b-phenyl
groups in the required arrangement permitting more effec-
tive stabilisation of the partial positive charge in the transi-
tion state of the rearrangement, which results in a fast
transformation. In the case of intermediate 12 derived from
the 2R,3S diastereomer of 6a the steric requirements for a

G. Horny a k et al. / Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
243
similar stabilisation are missing. However, the slow forma-
tion of 8 from 2RS,3SR-6a indicates that, prior to the
rearrangement, a slow epimerisation is taking place at the
was added to a solution of phenylmagnesium bromide,
prepared from magnesium ꢀ0.98 g, 40 mmol) and bromo-
benzene ꢀ4.2 ml, 6.28 g, 40 mmol) in ether ꢀ40 ml). The
mixture was stirred for 30 min at ambient temperature and
saturated aqueous ammonium chloride solution ꢀ40 ml) was
added. The ethereal solution was washed with brine, dried
over magnesium sulphate and evaporated to dryness. The
residual oil was distilled in vacuo ꢀ0.2 Hgmm, vapour
temperature 140±1458C) to give a 2:1 diastereomeric mix-
ture of alcohols ꢀ2RS,3SR)-6a and ꢀ2RS,3RS)-6a ꢀ6.5 g,
88%). 3.25 g of this oil was dissolved in hexane at ambient
temperature. ꢀ2RS,3SR)-6a ꢀ1.48 g, diastereomeric purity
ꢂ90%) separated on standing, mp 139±1408C ꢀhexane).
2
-position. A similar procedure, racemisation of optically
active a-tri¯uoromethyl tri¯ate, is known from the literature
10]. In addition to the slow epimerisation-rearrangement
[
sequence a competing elimination process leading to 4 and 5
is also occurring in this case.
3
. Experimental section
Melting points were determined on a B uÈ chi 535 appara-
tus. IR spectra were recorded on an aspect 2000 computer
controlled Bruker IFS-113v vacuum optic FT spectrometer,
using KBr pellets for solids or liquid ®lms. NMR spectra
were run on Bruker WM-250 FT, Varian Gemini-200 and
Varian Unity Inova 400 spectrometers. Mass spectra were
obtained by EI ꢀ70 eV, evaporation temperature 1208C)
using a KRATOS MS 902 mass spectrometer.
1H NMR ꢀCDCl , 400 MHz) d 7.60±6.90 ꢀ14H, m), 4.93
3
ꢀ1H, s), 3.75 ꢀ3H, s), 3.09 ꢀ1H, s). The mother liquor of this
product was evaporated to dryness and the residue was
dissolved in pentane at ambient temperature. ꢀ2RS,3RS)-
6a ꢀ0.96 g, diastereomeric purity >98%) separated on stand-
1
ing, mp 108±1098C ꢀpentane). H NMR ꢀCDCl , 400 MHz)
3
d 7.60±7.10 ꢀ12H, m), 6.57 ꢀ2H, d, J ˆ 8:8 Hz), 4.91 ꢀ1H, s),
3.62 ꢀ3H, s), 3.08 ꢀ1H, s).
3
.1. Structure determinations by X-ray crystallography
3.3. 1,1,1-Trifluoro-2,3,3-triphenylpropan-2-ol ꢀ6b)
Intensity data were collected at room temperature on an
Enraf Nonius CAD4 diffractometer. The structures were
solved by direct methods [12,13] ꢀsee footnote).
Compound 6b was prepared as described above for 6a,
starting from 1,1,1-tri¯uoro-3,3-diphenylpropan-2-one ꢀ7b
8
: C H ClF O, M ˆ 390:81, colourless, prism, size:
[2], 22.3 g, 84.4 mmol): yield 69.2%, b.p. 138±1408C
2
2
18
3
1
0
:50 mm  0:30 mm  0:20 mm, monoclinic, space group
ꢀ0.1 Hgmm), mp 134±1358C. H NMR ꢀCDCl , 200 MHz)
3
Ê
Ê
Ê
Cc; a ˆ 13:555ꢀ2† A, b ˆ 21:069ꢀ4† A, c ˆ 7:515ꢀ1† A,
d 7.60±6.95 ꢀ15 H, m), 4.97 ꢀ1H, s), 3.12 ꢀ1H, s). High
ꢁ
3
‡
Ê
b ˆ 100:56ꢀ1† , V ˆ 1849:0ꢀ5† A , Z ˆ 4, Dcalc ˆ 1:404
resolution MS ꢀEI) calcd for C H F O ꢀM ) m/z 342.1231,
found 342.1198.
2
1 17 3
3
2
Mg/m . Re®nement [13] on F values for all non-hydrogen
atoms yielded R1 ˆ 0:0397 and wR2 ˆ 0:0952 for 5219
[
I > 2sꢀI†] observations, R1 ˆ 0:0725 and wR2 ˆ 0:1029
3.4. Reactions of 1,1,1-trifluoro-2,3,3-triarylpropan-
2-ols ꢀ6) with thionyl chloride
for all 8079 data.
a ꢀ2RS,3RS): C H F O , M ˆ 372:37, colourless,
6
2
2 19 3 2
prism, size: 0:60 mm  0:50 mm  0:45 mm, triclinic, space
3.4.1. 1,1,1-Trifluoro-3-ꢀ4-methoxyphenyl)-2,3-
Ê
Ê
group P1, a ˆ 9:605ꢀ1† A, b ˆ 11:804ꢀ1† A, c ˆ 17:356ꢀ1†
diphenylpropan-2-ol ꢀ6a, mixture of diastereomers)
A solution of 6a ꢀmixture of diastereomers, 1.5 g,
4.0 mmol), thionyl chloride ꢀ3.0 ml, 1.83 g, 42 mmol) and
pyridine ꢀ0.2 ml) in chloroform ꢀ15 ml) was re¯uxed for 2 h.
The solvent was evaporated to dryness and the residue was
triturated with methanol ꢀ5 ml) to give ꢀ2RS,3SR)-3-chloro-
1,1,1-tri¯uoro-2-ꢀ4-methoxyphenyl)-2,3-diphenyl-propane
ꢁ
ꢁ
ꢁ
Ê
A, a ˆ 90:27ꢀ1† , b ˆ 102:62ꢀ1† , g ˆ 105:44ꢀ1† ,
3
3
Ê
V ˆ 1846:8ꢀ3† A ,Z ˆ 4,Dcalc ˆ 1:339 Mg/m .Re®nement
2
[
13] on F for all non-hydrogen atoms yielded R1 ˆ 0:0415
and wR2 ˆ 0:1303 for 5551 [I > 2sꢀI†] observations,
R1 ˆ 0:0454 and wR2 ˆ 0:1338 for all 6236 data.
6
a ꢀ2RS,3SR): C H F O , M ˆ 372:37, colourless,
2
2 19 3 2
prism, size: 0:60 mm  0:20 mm  0:08 mm, monoclinic,
ꢀ8, 0.5 g, 32%). Diastereomeric purity ꢂ95%, mp 130±
Ê
Ê
3
1
space group P2 , a ˆ 12:015ꢀ1† A, b ˆ 6:206ꢀ1† A,
1318C ꢀmethanol). H NMR ꢀCDCl , 200 MHz) d 7.55±
1
3
ꢁ
Ê
Ê
c ˆ 12:129ꢀ1† A, b ˆ 92:38ꢀ1† , V ˆ 903:62ꢀ18† A ,
6.65 ꢀ14H, m), 6.08 ꢀ1H, s), 3.87 ꢀ3H, s). High resolution MS
‡
3
2
Dcalc ˆ 1:369 Mg/m . Re®nement [13] on F for all non-
hydrogen atoms yielded R1 ˆ 0:0333 and wR2 ˆ 0:0944 for
ꢀEI) calcd for C H ClF O ꢀM ) m/z 390.0998, found
2
2
18
3
390.0988.
3
all 3571 data.
349 [I > 2sꢀI†] and R1 ˆ 0:0361 and wR2 ˆ 0:0968 for
3.4.2. ꢀ2RS,3RS)-1,1,1-trifluoro-3-ꢀ4-methoxyphenyl)-2,3-
diphenylpropan-2-ol [ꢀ2RS,3RS)-6a]
3.2. 1,1,1-Trifluoro-3-ꢀ4-methoxyphenyl)-2,3-
diphenylpropan-2-ol ꢀ6a)
A solution of ꢀ2RS,3RS)-6a ꢀ0.5 g, 1.3 mmol), thionyl
chloride ꢀ1.0 ml, 0.61 g, 14 mmol) and pyridine ꢀ0.07 ml)
in chloroform ꢀ5 ml) was re¯uxed for 2 h. The solvent
was evaporated to dryness and the residue was triturated
with methanol ꢀ5 ml) to give compound 8 ꢀ0.4 g, 76%,
A solution of 1,1,1-tri¯uoro-3-ꢀ4-methoxyphenyl)-3-phe-
nylpropan-2-one ꢀ7a [2], 6.0 g, 20.4 mmol) in ether ꢀ30 ml)

244
G. Horny a k et al. / Journal of Fluorine Chemistry 108 ꢀ2001) 239±244
diastereomeric purity ꢂ95%) identical with the sample
palladium on charcoal ꢀ0.2 g) at atmospheric pressure and
ambient temperature. The catalyst was ®ltered off, the
obtained above.
®
from methanol to give 1,1,1-tri¯uoro-2-ꢀ4-methoxyphenyl)-
ltrate evaporated to dryness and the residue crystallised
3
.4.3. ꢀ2RS,3SR)-1,1,1-trifluoro-3-ꢀ4-methoxyphenyl)-2,3-
diphenylpropan-2-ol [ꢀ2RS,3SR)-6a]
2,3-diphenyl-propane ꢀ9, 0.30 g, 84%), mp 110±1118C.
1
A solution of ꢀ2RS,3SR)-6a ꢀ0.5 g, 1.3 mmol), thionyl
chloride ꢀ1.0 ml, 0.61 g, 14 mmol) and pyridine ꢀ0.07 ml) in
chloroform ꢀ5 ml) was re¯uxed for 10 h. After evaporation
to dryness the residue was separated by preparative TLC
H NMR ꢀCDCl , 250 MHz) d 7.42±6.60 ꢀ14H, m), 3.80
3
ꢀ3H, s), 3.72 ꢀ2H, s). High resolution MS ꢀEI) calcd for
‡
C H F O ꢀM ) m/z 356.1388, found 356.1384.
22 19 3
ꢀ
repeated elutions with a mixture of hexane and ethyl
acetate, 10:0.1) to give compound 8 ꢀ0.16 g, 31%, diaster-
eomeric purity ꢂ95%) identical with the sample obtained
above, and a 92:8 mixture of ole®ns 4 and 5 ꢀ0.17 g, 36%) as
indicated by GC measurements, the H NMR spectrum and
comparison with the spectra and GC of authentic samples
References
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3
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[
‡
calcd for C H F ꢀM ) m/z 324.1126, found 324.1128.
2
1
15
3
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3.5. Catalytic hydrogenation of ꢀ2RS,3SR)-3-chloro-1,1,1-
trifluoro-2-ꢀ4-methoxyphenyl)-2,3-diphenyl-propane ꢀ8)
193.
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