Stepwise preparation of all- cis 1,3,4-trifluoro-2-phenylcyclohexane, avoiding a phenonium intermediate

Article abstract of DOI:10.1021/jo501432x

The original synthesis of all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane resulted in a trifluorocyclohexene as a significant co-product of the final fluorination step. This product was notable in that an elimination reaction was accompanied by C-F bond formation that had occurred with a retention of configuration. In order to deconvolute this reaction, the two isomers of the ditriflate diol precursor were separated, and they were each treated independently with Et₃N·3HF. One gave the original all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane and the other the trifluorocyclohexene. A deuterium labeling experiment was carried out, resulting in a distribution of the isotope in the trifluorocyclohexene consistent with an intermediate (symmetrical) phenonium intermediate. Cognisant of this, a controlled elimination reaction of one of the diastereoisomers with DBU, followed by hydrogenation, gave a cyclohexane triflate, which, on fluorination, gave the all-cis 1,2,3-trifluoro-2-phenylcyclohexane now with an inversion of configuration.

Full text of DOI:10.1021/jo501432x

Article
pubs.acs.org/joc
Stepwise Preparation of All-cis 1,3,4-Trifluoro-2-phenylcyclohexane,
Avoiding a Phenonium Intermediate
Alastair J. Durie,† Tomoya Fujiwara,†,‡ Nawaf Al-Maharik,† Alexandra M. Z. Slawin,†
and David O’Hagan*,†
†University of St. Andrews, EastChem School of Chemistry, North Haugh, St. Andrews, KY16 9ST, U.K.
‡Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
S
* Supporting Information
ABSTRACT: The original synthesis of all-cis 1,2,4,5,-tetrafluoro-2-
phenylcyclohexane resulted in a trifluorocyclohexene as a significant
co-product of the final fluorination step. This product was notable in
that an elimination reaction was accompanied by C−F bond
formation that had occurred with a retention of configuration. In
order to deconvolute this reaction, the two isomers of the ditriflate
diol precursor were separated, and they were each treated
independently with Et3N·3HF. One gave the original all-cis 1,2,4,5,-
tetrafluoro-2-phenylcyclohexane and the other the trifluorocyclohex-
ene. A deuterium labeling experiment was carried out, resulting in a
distribution of the isotope in the trifluorocyclohexene consistent with
an intermediate (symmetrical) phenonium intermediate. Cognisant
of this, a controlled elimination reaction of one of the
diastereoisomers with DBU, followed by hydrogenation, gave a
cyclohexane triflate, which, on fluorination, gave the all-cis 1,2,3-trifluoro-2-phenylcyclohexane now with an inversion of
configuration.
however, polarized due to the molecular dipole moment
associated with the diaxial C−F bonds arrangement, which is
satisfied in each case, even with cyclohexane ring inversion.9
This confers facial polarity to these cyclohexanes with a −ve
electrostatic fluorine face and a +ve electrostatic hydrogen face.
Most recently, we have reported10 the synthesis of all-cis
1,2,4,5-tetrafluoro-3-phenylcyclohexane 3 (Scheme 1). Com-
pound 3 has potential as a polar building block for use in
discovery chemistry programs. Phenylcyclohexane 3 was readily
converted to a range of derivatives using standard electrophilic
aromatic substitution reactions. In developing a preparation of
3, different strategies were explored from syn-diepoxide 5. It
proved most efficient to mediate epoxide ring opening with
Et3N·3HF to generate a mixture of fluorohydrins 6 and 7. The
fluorohydrins were converted, as a mixture to triflates 8 and 9,
which, in turn, were treated, also as a mixture, with Et3N·3HF.
This gave rise to the desired product 3, but the reaction
generated olefin 10 as the major product. It was noteworthy
that the fluorination had occurred with a retention of
configuration in the generation of 10. There was no
trifluoroolefin with an inverted stereochemistry, suggesting
that elimination to the olefin and the fluorination with a
retention of configuration, were linked. In this paper, we
present evidence that the retention of configuration in
INTRODUCTION
■
Selectively fluorinated organic motifs continue to attract wide
attention in the development of performance organic
compounds.1−5 We have recently executed the syntheses of
cyclohexanes carrying arrays of vicinally distributed C−F bonds
(Figure 1).6−8 These include isomers of tetrafluorocyclohex-
Figure 1. Previously synthesized all-cis tetrafluorocyclohexane based
compounds 1, 2, and 3.6−8 Also, the target all-cis 1,2,4-trifluoro-3-
phenylcyclohexane 4.
anes with an all-cis stereochemistry such that the fluorines are
orientated on one face of the cyclohexane ring.6,7 This imparts
polarity to the rings and generates polar structural motifs. For
example all-cis 1,2,4,5-17 and 1,2,3,4-26 tetrafluorocyclohexanes
are perhaps unexpectedly crystalline despite their aliphatic
nature without significant hydrogen bonding donor or acceptor
capacities and their relatively low molecular weight. They are,
Received: June 27, 2014
Published: August 7, 2014
© 2014 American Chemical Society
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Elimination clearly occurs due to the ability of the triflate C−O
bond to adopt an antiperiplanar arrangement to a methylene
C−H bond in 8. On the other hand, treatment of 9 with Et3N·
3HF gave a smooth conversion to 3. Only substitution occurs,
presumably because there is no C−H bond lying antiperiplanar
to the triflate groups in 9. There was no crossover in product
formation from the individual isomers, illustrating that the
product outcome was isomer-dependent. Thus, isomer 9 was
processed as anticipated, but isomer 8 behaved in an
unexpected manner. In order to explore the reaction of
ditriflate isomer 8 to olefin 10 more closely, a deuterium
labeling experiment was designed, using ditriflate [2H2]-8 as a
substrate. The required isotopically labeled precursor was
prepared as illustrated in Scheme 3 from [4,4′-2H2]-biphenyl,
Scheme 1. Previous Synthesis of Tetrafluorocyclohexane 3
and Trifluorocyclohexene 1010
Scheme 3. Isotope Incorporation and Synthesis of Ditriflate
[2H2]-8 from Biphenyl
generating 10 arises solely from 8 via a phenonium ion11−18
and that an obligate elimination precedes fluorination. By
controlling the elimination reaction, and separating it from the
fluorination event, then an efficient preparation of all-cis 1,3,4-
trifluoro-2-phenylcyclohexane 4 is achieved and provides access
to another attractive polar cyclohexane building block.
RESULTS AND DISCUSSION
■
It was an objective to deconstruct the fluorination reaction of
the mixture of triflate isomers 8 and 9 and understand how they
contribute to products 10 and 3, respectively. In order to
establish if each isomer generates a unique product, the isomers
were separated by careful chromatography (Scheme 2).
Treatment of 8 with Et3N·3HF gave the trifluoroolefin 10.
itself prepared by treatment of dibromide 11 with LiBu3Mg,
followed by a D2O quench.19 Birch reduction20 gave [2H2]-13,
followed by mCPBA-mediated diepoxidation to generate [2H2]-
5. Diepoxide [2H2]-5 was then converted to ditriflate [2H2]-8
following the three-step protocol illustrated in Scheme 1. This
material was a 1:1 mixture of diastereoisomers due to the lack
of any stereochemical bias of the deuterium situated at the 4-
position of the cyclohexane ring in 8.
Scheme 2. Separate Fluorinations of Ditriflates 8 and 9
Generate Unique Products 10 and 3, Respectively
Treatment of [2H2]-8 with Et3N·3HF led to an efficient
conversion to three observable (by 19F and 13C NMR)
populations of [2H]-10. The introduction of the double bond
requires elimination of the triflate group and the antiperiplanar
hydrogen/deuterium at C-4.12 Only 50% of the stereospecific
elimination will result in a deuterium retention. For the
molecules that retained deuterium in the cyclohexene ring, an
equal scrambling of the isotope was apparent between the
double bond carbons, C3 and C4, as deduced from the 1H, 13C,
and 19F NMR spectra. For 19F NMR, integrations were
consistent with 50% deuterium retention distributed over both
olefinic carbons. In the 13C NMR, 25% of each olefin carbon
signal was coupled to deuterium, and in the 19F{1H} NMR
spectrum (Figure 2), isotope induced shifts were consistent
with an equal distribution of deuterium across these carbons.
This isotope labeling pattern is illustrated in Scheme 4.
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Figure 2. 19F{1H} NMR of three isotope populations of 10 after the fluorination of [2H2]-8.
Scheme 4. Fluorination of Ditriflate [2H2]-8 Results in an Isotope Distribution Consistent with a Phenonium Intermediate 15
The equal distribution of the isotope across the double bond
of 10 is consistent with fluoride ion attack onto the symmetrical
phenonium ion intermediate 15. This intermediate appears to
form only after elimination has occurred to introduce the
double bond. There is no evidence for a fluorine substituted
product without elimination, or a tetrafluoro product arising
from double fluorination of ditriflate 8. We reasoned, however,
that, if a controlled elimination was carried out, under
nonfluorination conditions, then the product of elimination
might be isolated. To this end, when 8 is treated with DBU,
then cyclohexene 16 is generated in good yield, as shown in
Scheme 5.
Hydrogenation of cyclohexene 16 proved to be straightfor-
ward and gave cyclohexane triflate 17, which, on treatment with
Et3N·3HF, resulted in a smooth conversion to all-cis
trifluorocyclohexane 4, in a reaction proceeding with an
inversion of configuration. No elimination occurs, as there are
no antiperiplanar C−H/triflate arrangements. There was no
evidence of diastereoisomer 18, with retained stereochemistry,
a reference sample of which could be generated separately by
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cyclohexane rings for inclusion in discovery chemistry
programs.
Scheme 5. Subsequent Transformations of 16 after the
Controlled Elimination Reaction of Ditriflate 8.
EXPERIMENTAL SECTION
■
2,5-Difluoro-3-phenylcyclohexane-1,4-diyl Bis(trifluoro-
methanesulfonate) (8) and 4,6-Difluoro-2-phenyl-
cyclohexane-1,3-diyl Bis(trifluoromethanesulfonate) (9). To a
solution of diepoxide 5 (565 mg, 3 mmol) in anhydrous THF (0.75
mL) at room temperature was added Et3N·3HF (3.91 mL, 24 mmol, 8
equiv). After 45 h stirring at 130 °C under an argon atmosphere, the
mixture was poured into sat. aq. sodium bicarbonate (150 mL) at 0 °C.
The mixture was extracted with CH2Cl2 (3 × 80 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified via silica gel
chromatography (2:5:5 petroleum ether/CH2Cl2/EtOAc) to afford a
mixture of difluorohydrins 6 and 7 (557 mg, 81%, 6:7 = 1.8:1) as a
colorless solid.
The aforementioned mixture was dissolved in anhydrous CH2Cl2
(19 mL), and trifluoromethanesulfonic anhydride (1.23 mL, 7.32
mmol, 3 equiv) and pyridine (0.79 mL, 9.76 mmol, 4 equiv) were
added subsequently under an argon atmosphere at −40 °C. The
mixture was allowed to warm to room temperature. After 24 h stirring,
the mixture was filtered through a small pad of silica gel (2:3:2
petroleum ether/CH2Cl2/EtOAc) and the filtrate was concentrated
under reduced pressure. The residue was purified via silica gel
chromatography (10:5:1 petroleum ether/CH2Cl2/Et2O) to afford the
asymmetric ditriflate 8 (746 mg, 62%) as a colorless crystalline solid;
hydrogenation of 10. Thus, it appears that the phenonium
intermediate 15 and the observed retention of configuration
only occur after the elimination to generate the cyclohexene.
Presumably, the presence of the double bond in 15 flattens the
six-membered ring and this accommodates phenonium ion
formation.
The ability to circumvent the phenonium ion participation by
a controlled elimination, followed by hydrogenation, allows
access to all-cis trifluorocyclohexane 4. The X-ray structure of 4
is shown in Figure 3, and it can be seen that the phenyl ring lies
1
mp 99.0−102.0 °C; H NMR (300 MHz, CDCl3) δ 7.45−7.36 (5H,
m, CH), 5.40 (1H, td, J = 11.2, 8.8 Hz, CH), 5.30 (1H, m, CH), 5.03
(1H, dddd, J = 49.1, 11.8, 8.8, 5.3 Hz, CHF), 4.94 (1H, m, CHF), 3.31
(1H, dd, J = 37.6, 11.7 Hz, CH), 2.79 (1H, m, CHAHB), 2.50 (1H, m,
CHAHB); 13C{1H} NMR (100 MHz, CDCl3) δ 131.9 (s, C), 129.4 (d,
J = 2.4 Hz, CH), 129.3 (s, CH), 129.2 (s, CH), 118.4 (q, J = 319.6 Hz,
CF3), 118.0 (q, J = 320.6 Hz, CF3), 89.8 (d, J = 181.6 Hz, CHF), 87.0
(d, J = 185.8 Hz, CHF), 85.1 (dd, J = 18.4, 2.6 Hz, CH), 79.8 (dd, J =
34.3, 13.2 Hz, CH), 46.1 (dd, J = 17.4, 5.1 Hz, CH), 30.9 (d, J = 22.8
Hz, CHAHB); 19F{1H} NMR (282 MHz, CDCl3) δ −74.9 (3F, s,
CF3), −75.1 (3F, d, J = 9.0 Hz, CF3), −188.1 (1F, q, J = 9.0 Hz,
CHF), −194.0 (1F, s, CHF); HRMS (EI-TOF) calcd for C14H12-
F8O6S2 (M+): 491.9948; found 491.9950.; MS (EI) m/z 492 ([M]+,
32%), 192 (100%), 173 (18%), 133 (20%), 115 (20%), 91 (28%); and
the symmetric ditriflate 9 (405 mg, 34%) as a colorless crystalline
Figure 3. X-ray structure of 4 showing the 1,3-diaxial C−F bonds and
the perpendicular orientation of the aryl ring.
1
solid; mp 110.0 °C (dec., CH2Cl2); H NMR (300 MHz, CDCl3) δ
7.50−7.40 (3H, m, CH), 7.31−7.27 (2H, m, CH), 5.14−5.04 (2H, m,
CH), 4.93−4.68 (2H, m, CHF), 3.13 (1H, t, J = 11.4 Hz, CH), 2.96
(1H, dquint, J = 12.8, 5.2 Hz, CHAHB), 2.19 (1H, m, CHAHB);
13C{1H} NMR (100 MHz, CDCl3) δ 130.5 (s, C), 129.8 (s, CH),
129.6 (s, CH), 128.8 (s, CH), 117.9 (q, J = 319.6 Hz, CF3), 86.7 (dd, J
= 189.0, 15.1 Hz, CHF), 86.2 (d, J = 19.1 Hz, CH), 47.9 (t, J = 6.1 Hz,
CH), 31.7 (t, J = 21.5 Hz, CHAHB); 19F{1H} NMR (282 MHz,
CDCl3) δ −75.1 (6F, d, J = 9.0 Hz, CF3), −185.9 (2F, br d, J = 8.7 Hz,
CHF); HRMS (EI-TOF) calcd for C14H12F8O6S2 (M+): 491.9948;
found 491.9945; MS (EI) m/z 492 ([M]+, 22%), 192 (100%), 172
(16%), 147 (15%), 133 (18), 115 (22%), 91 (31%).
3,4,6-Trifluoro-5-phenylcyclohexene (10). To a solution of the
asymmetric ditriflate 8 (148 mg, 0.30 mmol) in anhydrous THF (0.5
mL) was added Et3N·3HF (1.20 mL, 7.50 mmol, 25 equiv) at room
temperature. After 69 h stirring at 100 °C under an argon atmosphere,
the mixture was poured into sat. aq. sodium bicarbonate (50 mL) at
room temperature. The mixture was extracted with CH2Cl2 (3 × 50
mL). The combined organic extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified via
silica gel column chromatography to give trifluorocyclohexenes 10 (39
mg, 62%).10
equatorial with two of the C−F bonds orientating 1,3-diaxial to
each other and rendering this also a polar organic motif. The
plane of the phenyl ring lies perpendicular to the plane of the
cyclohexane ring, in a manner explored in detail with 3.10,21
CONCLUSION
■
In this study, we have deconvoluted the relationship between
the ditriflate isomers 8 and 9 and their products of fluorination
10 and 3. Both are efficiently converted to their respective
products, and there is no product crossover in reaction of the
individual isomers. For the reaction of isomer 8, the unexpected
product outcome was shown to arise by a sequential
elimination and then a substitution reaction proceeding via a
phenonium intermediate. This was deduced by carrying out a
controlled elimination, and also a deuterium isotope experi-
ment with [2H2]-8. An understanding of this process has
enabled a synthetic protocol that decouples the elimination
from the fluorination reaction. Hydrogenation of the
elimination product then allows efficient access to the all-cis
trifluorocyclohexane 4. We present 4 in addition to 3 as polar
hydrophobic building blocks with unusual facially polarized
All-cis 1,2,4,5-Tetrafluoro-3-phenylcyclohexane (3). Fluorina-
tion of symmetric ditriflate 5 (690 mg, 1.40 mmol) with Et3N·3HF
(4.60 mL, 28.0 mmol, 20 equiv) in anhydrous THF (1 mL) according
to the procedure described for 4 gave tetrafluorocyclohexane 8 (297
mg, 91%).10
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6,4′-[2H2]-2-Phenyl-4,8-dioxatricyclo[5.1.0.03,5]octane
([2H2]-5). n-Butyllithium (10 mL, 2.3 M in THF, 23 mmol, 2.4 equiv)
was added to a solution of butylmagnesium bromide (5.7 mL, 2.0 M in
THF, 11.4 mmol, 1.2 equiv) in THF (20 mL) at 0 °C. After 15 min
stirring at 0 °C, a solution of 4,4′-dibromobiphenyl 11 (2.96 g, 9.5
mmol, 1 equiv) in THF (20 mL) was dropwise added to the reaction
mixture over 10 min, and the reaction mixture was stirred for an
additional 1 h before D2O (1 mL, 50 mmol, 5.3 equiv) was added. The
mixture was stirred for 1 h at 0 °C and then treated with sat. aq.
ammonium chloride (50 mL). The aqueous phase was extracted with
ethyl acetate (2 × 100 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated to give 4,4′-[2H2]-biphenyl
[2H2]-12.
319.5 Hz, CF3), 90.0 (d, J = 181.8 Hz, CHF), 87.2 (d, J = 185.7 Hz,
CHF), 85.3 (d, J = 18.4 Hz, CH), 79.9 (dd, J = 34.7, 13.2 Hz, CH),
46.2 (dd, J = 17.4, 5.1 Hz, CH), 30.3 (q, J = 20.8 Hz, CHD); 19F{1H}
NMR (471 MHz, CDCl3) δ −74.5 (3F × 2, s, CF3), −74.7 (3F × 2, d,
J = 9.0 Hz, CF3), −187.7 (1F, q, J = 9.0 Hz, CHF), −187.8 (1F, q, J =
9.0 Hz, CHF), −193.6 (1F, s, CHF), −193.6 (1F, s, CHF); HRMS
(APCI-ion trap mass analysis) calcd for C14H10F8O6S2D2 (M+):
494.0068; found 494.0064; MS (APCI) m/z 524(100%), 494 ([M]+,
5%), 437 (25%), 427 (25%), 195 ([M − 2OTf + H]+, 20%), 175 ([M
− 2OTf − HF + H]+, 20%).
1/2,4′-[2H2]-3,4,6-Trifluoro-5-phenylcyclohexene ([2H2]-10)
and 4′-[2H]-3,4,6-Trifluoro-5-phenylcyclohexene ([2H]-10). A
solution of [2H2]-8 (30 mg, 0.061 mmol, 1 equiv) in Et3N·3HF (1.0
mL, 6.1 mmol, 100 equiv) was stirred at 100 °C in a Teflon flask for 60
h. The reaction mixture was cooled down to room temperature,
quenched with sat. aq. sodium bicarbonate (50 mL), and extracted
with ethyl acetate (4 × 50 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated. The brown solid was
then purified via silica gel chromatography, (4:1 petroleum ether/
Et2O) to afford [2H2]-10 (11 mg, 85%), an isotopic mixture, as a
The crude 4,4′-[2H2]-biphenyl [2H2]-12 was dissolved in anhydrous
diethyl ether (50 mL) and added to liquid ammonia (100 mL) at −78
°C. Lithium (150 mg, 21.3 mmol, 2.2 equiv) was added portionwise to
the reaction mixture over 10 min, resulting in the formation of a deep
blue-brown color. The reaction mixture was warmed to −25 °C,
stirred for 30 min, and then quenched by addition of solid ammonium
chloride (8 g), resulting in a colorless suspension. After warming to
room temperature, water (50 mL) and diethyl ether (50 mL) were
added subsequently. The aqueous phase was washed with diethyl ether
(50 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to offer 6,4′-[2H2]-
3-phenyl-1,4-cyclohexadiene [2H2]-13 as a colorless oil.
The aforementioned crude product was dissolved in CH2Cl2 (50
mL) at 0 °C, and mCPBA (3.44 g, 70%, 19.9 mmol, 2.1 equiv) was
then added. After 14 h stirring at room temperature, the mixture was
quenched with 10% KOH (50 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated to give a colorless crystalline
solid. This was purified via silica gel chromatography (4:1 hexane/
ethyl acetate) to afford [2H2]-5 (1.2 g, 66%) as a colorless crystalline
solid containing a 1:1 mixture of diastereoisomers with respect to the
deuterium: mp 129.5−130.5 °C (CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.43−7.39 (2H × 2, m, CH), 7.33−7.30 (2H × 2, m, CH),
3.97 (1H × 2, s, CH), 3.22−3.19 (2H × 2, m, CHO), 3.13−3.10 (2H
× 2, m, CHO), 2.91 (1H, s, CHxDy), 2.44−2.41 (1H, m, CDxHy);
13C{1H} NMR (125 MHz, CDCl3) δ 138.3 (s, C), 129.2 (s, CH),
1
colorless crystalline solid: mp 122.0−124.0 °C (CHCl3); H NMR
(500 MHz, CDCl3) δ 7.42−7.39 (2H, m, CH), 7.38−7.35 (2H, m,
CH), 6.16−6.07 (2H, m, CH), 5.44−5.21 (2H, m, CHF), 5.07−4.94
(1H, m, CHF), 3.23−3.11 (1H, m, CH); 13C{1H} NMR (125 MHz,
CDCl3) δ 134.9 (s, C), 131.1−130.6 (m, CH/D), 129.3 (s, CH),
128.7 (s, CH), 127.8 (t, J 24.4 Hz, CD), 127.4−127.0 (m, CH/D),
92.0−90.3 (m, CHF), 89.3 (dd, J = 182.1, 19.0 Hz, CHF), 88.2−86.6
(m, CHF), 48.5 (td, J = 19.6, 7.3 Hz); 19F{1H} NMR (471 MHz,
CDCl3) δ −176.0 (1F, d, J = 10.5 Hz, CHF), −176.0 (1F, d, J = 10.5
Hz, CHF), −176.0 (1F, d, J = 10.5 Hz, CHF), −185.1 (1F, dd, J =
14.5, 10.5 Hz, CHF), −185.1 (1F, dd, J = 14.4, 10.5 Hz, CHF),
−185.3 (1F, dd, J = 13.5, 11.2 Hz, CHF), −194.7− (−194.8) (1F × 3,
m, CHF); HRMS m/z (APCI-ion trap mass analysis) calcd for
C12H9F3D2 ([M]+): 214.0933; found 214.0928; MS (APCI) m/z 287
(50%), 286 (45%), 214 ([M(2H2)]+, 5%), 213 ([M(2H1)]+, 5%), 195
([M(2H2) + H − HF]+, 70%), 194 ([M(2H1) + H − HF]+, 55%), 175
([M(2H2) + H − 2HF]+, 75%), 174 ([M(2H1) + H − 2HF]+, 100%).
3,6-Difluoro-5-phenylcyclohexen-4-yl Trifluoromethane-
sulfonate (16). To a solution of the asymmetric ditriflate 8 (492
mg, 1.00 mmol) in anhydrous THF (4 mL) at 0 °C under an argon
atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.160 mL,
1.05 mmol, 1.05 equiv). The resulting solution was allowed to warm
up to room temperature, stirred for 1 h, and then concentrated under
reduced pressure. The residue was purified via silica gel chromatog-
raphy (8:2:1 petroleum ether/CH2Cl2/Et2O) to afford cyclohexenyl
monotriflate 16 (334 mg, 98%) as a colorless crystalline solid; mp
128.6 (s, CH), 127.7 (t, J = 24.3 Hz, CD), 53.6 (s, CHO), 53.6 (s,
CHO), 49.4 (s, CHO), 49.3 (s, CHO), 23.5 (t, J = 19.2 Hz, CHD);
HRMS (APCI − ion trap mass analysis) calcd for C12H11O2D2 ([M +
H]+): 191.1036; found 191.1032.; MS (APCI) m/z 381 ([2M + H]+,
60%), 191 ([M + H]+, 100%), 173 ([M + H − H2O]+, 55%), 155
(20%), 146 (80%).
6,4′-[2H2]-2,5-Difluoro-3-(phenyl)cyclohexane-1,4-diyl Bis-
(trifluoromethanesulfonate) ([2H2]-8). A solution of [2H2]-5
(200 mg, 1.1 mmol, 1 equiv) in Et3N·3HF (2.5 mL, 2.5 g, 15
mmol, 14 equiv) was stirred at 150 °C in a Teflon flask for 14 h. The
reaction mixture was cooled down to room temperature, quenched
with sat. aq. (50 mL), and extracted with ethyl acetate (4 × 50 mL).
The combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure to give a crude product as a
brown crystalline solid.
1
83.0−84.0 °C (dec., CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.45−
7.35 (5H, m, CH), 6.24−6.11 (2H, m, CH), 5.64 (1H, m, CH), 5.34
(1H, m, CHF), 5.08 (1H, m, CHF), 3.22 (1H, dddd, J = 30.1, 12.5,
3.0, 1.1 Hz, CH); 13C{1H} NMR (75 MHz, CDCl3) δ 133.1 (s, C),
130.1 (dd, J = 23.0, 10.0 Hz, CH), 129.8 (d, J = 3.1 Hz, CH), 128.8 (s,
CH), 128.7 (s, CH), 127.4 (dd, J = 17.0, 8.9 Hz, CH), 118.1 (q, J =
319.6 Hz, CF3), 89.9 (dd, J = 178.6, 3.6 Hz, CHF), 86.6 (dd, J = 175.0,
1.4 Hz, CHF), 84.5 (d, J = 18.8 Hz, CH), 48.6 (dd, J = 19.3, 5.8 Hz,
CH); 19F{1H} NMR (282 MHz, CDCl3) δ −75.1 (3F, d, J = 9.8 Hz,
CF3), −175.3 (1F, d, J = 10.0 Hz, CHF), −183.4 (1F, dq, J = 10.0, 9.8
Hz, CHF); HRMS m/z (EI-TOF) Found: [M]+ 342.0348.
C13H11F5O3S+ requires m/z 342.0349; MS (EI) m/z 342 ([M]+,
45%), 252 (75%), 192 (31%), 172 (21%), 154 (19%), 133 (17%), 119
(100%), 115 (14%), 91 (88%).
Triflic anhydride (0.53 mL, 0.89 g, 3.2 mmol, 3 equiv) and pyridine
(0.34 mL, 0.33 g, 4.2 mmol, 4 equiv) were added subsequently to a
solution of the aforementioned crude product in CH2Cl2 (20 mL) at 0
°C. After 20 h stirring at room temperature, the reaction mixture was
treated with sat. aq. CuSO4 (50 mL). The aqueous phase was extracted
with CH2Cl2 (2 × 50 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated. The brown solid was purified
via silica gel chromatography, (2:1 petroleum ether/CH2Cl2) to afford
[2H2]-8 (72 mg, 14%) as a colorless crystalline solid containing a 1:1
mixture of diastereoisomers with respect to the deuterium: mp 98.0−
99.5 °C (CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.45−7.36 (4H × 2,
m, CH), 5.46−5.36 (1H × 2, m, CH), 5.33−5.28 (1H × 2, m, CH),
5.10−4.89 (2H × 2, m, CHF), 3.32 (1H × 2, dd, J = 37.7, 11.8 Hz,
CH), 2.77 (1H, s, CHADB), 2.53−2.44 (1H, m, CDAHB); 13C{1H}
NMR (125 MHz, CDCl3) δ 132.1 (s, C), 129.5 (d, J = 2.4 Hz, CH),
129.4−128.8 (m, CH, CD), 118.5 (q, J = 319.7 Hz, CF3), 118.1 (q, J =
3,4,6-Trifluoro-5-phenylcyclohexene (10). Fluorination of
cyclohexenyl monotriflate 16 (51 mg, 0.150 mmol) with Et3N·3HF
(0.490 mL, 3.00 mmol, 20 equiv) in anhydrous THF (0.49 mL)
according to the procedure described for 8 gave trifluorocyclohexene
10 (20 mg, 61%).10
3,6-Difluoro-5-phenylcyclohexan-4-yl Trifluoromethane-
sulfonate (17). 10% palladium on activated carbon (14 mg) was
added to a solution of cyclohexenyl monotriflate 16 (0.20 g, 0.584
mmol) in EtOAc (7 mL). After 2.5 h stirring under a hydrogen
atmosphere, the mixture was filtered through a pad of Celite and
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dx.doi.org/10.1021/jo501432x | J. Org. Chem. 2014, 79, 8228−8233

The Journal of Organic Chemistry
Article
concentrated under reduced pressure. The residue was purified via
silica gel column chromatography (10:2:1 petroleum ether/CH2Cl2/
Et2O) to give 17 (195 mg, 97%) as a colorless crystalline solid; mp
95.0−96.0 °C (dec., CHCl3/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
7.42−7.32 (5H, m, CH), 5.42 (1H, td, J = 11.1, 8.7 Hz, CH), 4.90
(1H, m, CHF), 4.75 (1H, m, CHF), 2.95 (1H, dd, J = 34.7, 11.6 Hz,
CH), 2.35−2.11 (3H, m, CH2), 1.72 (1H, m, CH2); 13C{1H} NMR
(75 MHz, CDCl3) δ 134.4 (s, C), 129.2 (d, J = 3.0 Hz, CH), 128.8 (s,
CH), 128.5 (s, CH), 118.0 (q, J = 319.5 Hz, CF3), 91.4 (dd, J = 178.0,
1.8 Hz, CHF), 91.2 (d, J = 185.1 Hz, CHF), 87.7 (dd, J = 18.2, 1.9 Hz,
CH), 51.4 (dd, J = 17.8, 4.9 Hz, CH), 27.8 (dd, J = 21.7, 11.3 Hz,
CH2), 24.8 (dd, J = 19.3, 1.9 Hz, CH2); 19F{1H} NMR (282 MHz,
CDCl3) δ −75.3 (3F, d, J = 8.8 Hz, CF3), −179.6 (1F, q, J = 8.8 Hz,
CHF), −194.4 (1F, s, CHF); HRMS m/z (EI-TOF) Found: [M]+
344.0503. C13H13F5O3S+ requires m/z 344.0506; MS (EI) m/z 344
([M]+, 32%), 194 (57%), 174 (15%), 148 (100%), 135 (16%), 129
(25%), 115 (25%), 91 (43%).
Award. We would also like to thank EPSRC UK National Mass
Spectrometry Facility (NMSF), Swansea, for mass spectrom-
etry analysis.
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colorless crystalline solid; mp 122.0−123.0 °C (CHCl3); H NMR
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(300 MHz, CDCl3) δ 7.49 (2H, br d, J = 6.9 Hz, CH), 7.40−7.30 (3H,
m, CH), 5.10 (1H, dd, J = 51.7, 8.7 Hz, CHF), 4.89 (1H, m, CHF),
4.64 (1H, ddddd, J = 45.6, 25.7, 12.1, 4.8, 2.2 Hz, CHF), 2.70 (1H, t, J
= 38.1 Hz, CH), 2.52−2.29 (2H, m, CHAHB), 1.98 (1H, m, CHAHB),
1.70 (1H, m, CHAHB); 13C{1H} NMR (75 MHz, CDCl3) δ 137.5 (s,
C), 129.2 (t, J 2.4 Hz, CH), 128.6 (s, CH), 127.6 (s, CH), 90.6 (dd, J
= 187.6, 17.2 Hz, CHF), 90.2 (dd, J = 184.5, 19.3 Hz, CHF), 89.0 (d, J
= 181.3 Hz, CHF), 48.3 (td, J = 18.1, 5.4 Hz, CH), 28.5 (dd, J = 22.6,
12.0 Hz, CHAHB), 20.4 (dd, J = 20.2, 3.3 Hz, CHAHB); 19F{1H} NMR
(282 MHz, CDCl3) δ −183.3 (1F, d, J = 14.2 Hz, CHF), −191.6 (1F,
d, J = 26.1 Hz, CHF), −210.1 (1F, dd, J = 26.1, 14.2 Hz, CHF);
HRMS (EI-TOF) calcd for C12H13F3 (M+): 214.0969; found
214.0970; MS (EI) m/z 214 ([M]+, 100%), 194 (10%), 153 (28%),
135 (37%), 122 (30%), 115 (23%), 109 (22%), 91 (55%).
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3,4,6-Trifluoro-5-phenylcyclohexane (18). Catalytic hydroge-
nation of trifluorocyclohexene 10 (42 mg, 0.200 mmol) with 10%
palladium on activated carbon (3 mg) in EtOAc (2.5 mL) according to
the procedure described for 9 gave 18 (40 mg, 93%) as a colorless
crystalline solid; mp 108.0−109.0 °C (CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 7.43−7.30 (5H, m, CH), 5.12 (1H, dddd, J = 51.3, 12.8,
11.4, 8.3 Hz, CHF), 4.84 (1H, m, CHF), 4.75 (1H, m, CHF), 2.90
(1H, dt, J = 35.7, 10.1 Hz, CH), 2.29−2.01 (3H, m, CH2), 1.70 (1H,
m, CH2); 13C{1H} NMR (75 MHz, CDCl3) δ 136.2 (s, C), 128.7 (d, J
= 1.7 Hz, CH), 128.6 (s, CH), 127.7 (s, CH), 93.7−90.6 (m, CHF),
51.3 (td, J = 18.6, 6.4 Hz, CH), 28.0 (ddd, J = 21.6, 11.4, 1.2 Hz,
CH2), 24.5 (ddd, J = 19.5, 6.9, 2.0 Hz, CH2); 19F{1H} NMR (282
MHz, CDCl3) δ −183.0 (1F, d, J = 15.8 Hz, CHF), −194.4 (1F, d, J =
15.8 Hz, CHF), −195.0 (1F, s, CHF); HRMS m/z (EI-TOF) Found:
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̈
+
[M]+ 214.0965. C12H13F3 requires m/z 214.0969; MS (EI) m/z 214
([M]+, 100%), 194 (10%), 153 (20%), 135 (32%), 122 (19%), 115
(21%), 109 (23%), 91 (58%), 78 (10%).
ASSOCIATED CONTENT
* Supporting Information
Crystallographic files and NMR spectra. This material is
■
S
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: do1@st-andrews.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC and ERC for financial support and
D.O’H. thanks the Royal Society for a Wolfson Research Merit
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