Synthesis and elaboration of all-cis-1,2,4,5-tetrafluoro-3- phenylcyclohexane: A polar cyclohexane motif

Article abstract of DOI:10.1002/chem.201400354

A stereocontrolled synthesis of all-cis-1,2,4,5- tetrafluoro-3- phenylcyclohexane is developed as the first functionalised example of this polar cyclohexane motif. The dipolar nature of the ring, arising due to two 1,3-diaxial C-F bonds, is revealed in the solid-state (X-ray) structure. The orthogonal conformation of the aryl and cyclohexyl rings in all-cis-1,2,4,5- tetrafluoro-3-phenylcyclohexane, and in an ortho-nitro derivative, result in intramolecular ^1hJ_HF and ^2hJ_CFNMR couplings relayed through hydrogen bonding. The aryl group of all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane is elaborated in different ways to demonstrate the versatility of this compound for delivering the motif to a range of molecular building blocks. A stereocontrolled synthesis of all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane is developed as the first functionalised example of this polar cyclohexane motif. The dipolar nature of the cyclohexane ring is explored and the aryl ring is elaborated in different ways to demonstrate its versatility as a molecular building block (see figure).

Full text of DOI:10.1002/chem.201400354

DOI: 10.1002/chem.201400354
Communication
&
Synthetic Methods
Synthesis and Elaboration of All-cis-1,2,4,5-Tetrafluoro-3-
Phenylcyclohexane: A Polar Cyclohexane Motif
[a]
[a, b]
[a]
[a]
Alastair J. Durie, Tomoya Fujiwara,
Rodrigo Cormanich, Michael Bꢀhl, Alexandra
[a]
[a]
M. Z. Slawin, and David O’Hagan*
nable to X-ray structure analysis and it has a large calculated
Abstract: A stereocontrolled synthesis of all-cis-1,2,4,5-
tetrafluoro-3-phenylcyclohexane is developed as the first
functionalised example of this polar cyclohexane motif.
The dipolar nature of the ring, arising due to two 1,3-dia-
xial CÀF bonds, is revealed in the solid-state (X-ray) struc-
ture. The orthogonal conformation of the aryl and cyclo-
hexyl rings in all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohex-
ane, and in an ortho-nitro derivative, result in intramolecu-
[9]
dipole moment of 5.2 D. The polarity arises from the two 1,3-
diaxial CÀF bonds in the cyclohexane chair conformation,
which is maintained on ring inversion. NMR spectroscopy in
toluene indicates that the electropositive axial hydrogen
atoms, on the opposite face to the fluorine atoms, are shielded
and shifted ꢀ1.5 ppm in comparison with NMR spectroscopy
performed in dichloromethane, indicating CÀH···p(aryl) interac-
tions between these hydrogen atoms and the aromatic ring of
the solvent, and, thus, facial polarity of the cyclohexyl ring.
This finding is consistent with a calculated electrostatic surface
1h
2h
lar JHF and JCF NMR couplings relayed through hydro-
gen bonding. The aryl group of all-cis-1,2,4,5-tetrafluoro-3-
phenylcyclohexane is elaborated in different ways to dem-
onstrate the versatility of this compound for delivering
the motif to a range of molecular building blocks.
Selective fluorination of organic frameworks has long served
the fine chemicals industries in tuning the properties of organ-
[
1]
ic compounds to improve their performance. Aryl/hetero-
[
2]
[3]
[4]
[5]
aryl, -F, -CF3 and -XCF3 compounds are most commonly
encountered in this context, leading to these motifs finding
[6]
wide utility in pharmaceutical and agrochemical products.
Figure 1. The synthesis of all-cis-tetrafluorocyclohexane 1, with the crystal
However, aliphatic-ring motifs carrying fluorine atoms are also
emerging as attractive compounds in structure–activity pro-
structure and the calculated electrostatic surface profile
[9]
(
B3LYP/6-311+G(2d,p)). Red areas (Àve), blue areas (+ve).
[
7]
grams, particularly as there has been a steady creativity and
diversity in amenable syntheses and methodologies towards
[8]
[9]
such small-ring aliphatic compounds in recent years. We re-
profile of 1 (B3LYP/6-311+G(2d,p)) that demonstrates clear
facial polarity, as illustrated in Figure 1. In view of these proper-
ties, it became an objective to prepare an analogue of 1 that
could be functionalised to deliver building blocks and compo-
nents for structural diversity in compound libraries. Herein, we
report the synthesis and elaboration of phenyl derivative 3 as
a molecular fragment containing the all-syn-1,2,4,5-tetrafluoro-
cyclohexane motif, and we explore its potential as a building
block by exemplifying a range of elaborations of the aryl ring.
The synthesis of 3 (see Scheme 1) started with a Birch reduc-
cently reported the synthesis and analysis of all-cis-1,2,4,5-tet-
[
9]
rafluorocyclohexane 1. This compound was prepared by
ꢁ
direct treatment of cis-diepoxide 2 with Deoxo-Fluor (bis(2-
methoxy-
ethyl)aminosulfur trifluoride) or DAST (diethylaminosulfur tri-
fluoride), to generate 1 in a single step. Cyclohexane 1 has
some surprising properties for a small aliphatic fluorocarbon. It
is a solid material at room temperature (m.p.=1078C), is ame-
[10]
[
a] Dr. A. J. Durie, Dr. T. Fujiwara, R. Cormanich, Prof. M. Bꢀhl,
Prof. A. M. Z. Slawin, Prof. D. O’Hagan
School of Chemistry
tion of biphenyl 4 to generate diene 5. Treatment of 5 with
meta-chloroperbenzoic acid (mCPBA) generated the cis-diepox-
ide, 6, as the major diastereoisomer in a cis/trans ratio of 10:1.
The minor diastereoisomer was readily removed by chroma-
University of St Andrews
North Haugh, St Andrews KY169ST (United Kingdom)
E-mail: do1@st-andrews.ac.uk
[
11]
tography. Direct treatment of diepoxide 6 with DAST
Deoxo-Fluor
or
did not generate clean products, unlike the
transformation of 2 into 1. In view of this result, compound 6
ꢁ[12]
[b] Dr. T. Fujiwara
Graduate School of Medicine and Pharmaceutical Sciences
University of Toyama
Sugitani, Toyama 930-0194 (Japan)
[13]
was treated with Et N·3HF to give the two difluorohydrins, 7
3
and 8, as a 1.6:1 mixture. These isomers could not be separat-
ed by chromatography; instead they were treated together
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400354.
Chem. Eur. J. 2014, 20, 1 – 6
1
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
the phenyl ring, which lies equatorially, adopts an orientation
parallel to the two diaxial CÀF bonds. To assess the preference
for this orientation, a rotational energy profile was calculated
at the B3LYP/def2-TZVP level. This indicated that the solid-
state structure adopts a conformation close to the energy min-
imum in the gas phase, and that the barrier to phenyl ring ro-
À1
tation is ꢀ4.0 kcal.mol (see Figure 2). Examination of the mo-
lecular packing within the X-ray-derived unit cell reveals that
there is an intermolecular interaction between the aryl ring of
one molecule of 3 and the non-fluorous face of the cyclohexyl
ring in a neighbouring molecule, indicative of an electrosta-
tic···p interaction. This observation was reinforced by NMR ex-
periments. In a similar manner to that previously shown for 1,
1
selected H NMR signals of 3 show a very clear upfield shift in
[
D ]toluene when compared with the spectrum obtained in
8
CDCl (Figure 3). In particular, the axial protons H2 and H4 dis-
3
play upfield shifts (Ddꢀ1.1 and Ddꢀ1.0 ppm, respectively) of
around one ppm. The equatorial protons (H3 and H1b) also
experience upfield shifts in toluene of approximately half that
magnitude (Ddꢀ0.5 ppm). Notably, the signal for the axial
proton H1a, which is situated on the fluorine face of the cyclo-
hexane rings, does not shift significantly, indicating that the
anisotropic influence of toluene is felt only on the lower elec-
tropositive face of the cyclohexane ring. Therefore, both X-ray
crystallography and NMR spectroscopy indicate the facial po-
larity of this ring system. This comparative analysis was carried
out for all compounds, 12, 15–21 and 23, and a consistent pat-
tern was observed, in which the axial protons H2 and H4 in
the tetrafluorocyclohexane ring systems became shifted up-
field by ꢀ1.0 ppm in [D ]toluene, relative to CDCl (see Table
8
3
in the Supporting Information).
The calculated minimum-energy conformer for 3 is not per-
fectly symmetrical, and has proximal ortho-H···F distances of
ax
[14]
2
.22 and 2.70 ꢃ. The former is particularly short, with a H···F
distance well within the van der Waals contact (ꢀ2.47 ꢃ). This
finding led us to explore the prospect of scalar NMR couplings
[15]
1h
2h
transmitted through these contacts. Thus, JHF and JCF cou-
pling constants were calculated for the lowest-energy con-
formers of structure 3. This study was extended to ortho-nitro
derivative 12, which has a significantly higher calculated barri-
À1
er to rotation (ꢀ12 kcalmol , see the Supporting Informa-
tion), owing to the steric influence of the nitro group and the
capacity for a hydrogen bond between the nitro group and
the H1 axial hydrogen. This increase in restricted rotation
should maximise intramolecular H···F coupling. The calculated
Scheme 1. Synthesis and X-ray structures of cis-1,2,4,5-tetrafluoro-3-phenyl-
cyclohexane 3 and trifluorocyclohexene 11. Tf O=triflic anhydride.
2
1h
2h
with triflic anhydride to generate a mixture of 9 and 10. The
JHF and
J
CF
1
coupling constants are shown in Table 1. The ex-
ditriflate mixture was then treated with Et N·3HF, at 1008C, to
perimental H NMR data for 3 and 12 shows small J cou-
3
HF
give 11 and 3, which could be separated by chromatography.
Their structures and stereochemistry were confirmed by X-ray
structure analysis. The structure and stereochemistry of 3 was
consistent with expectation. However, in the case of product
plings of ꢀ1 Hz, which are only observed when comparing the
1
19
1
difference between the H NMR and { F} H NMR spectra in
each case. Theory suggests maximum values of ꢀ3.67 Hz. The
magnitude of the experimental coupling is close to the value
5
11, an elimination had occurred, accompanied by a retention
that might be found for a through bond J coupling, there-
HF
1
h
of configuration of one of the original CÀO bonds during its
conversion to a CÀF bond, most probably via a phenonium-ion
intermediate.
fore, the F···H couplings do not convincingly suggest a JHF
2h
coupling. However, the experimental JCF couplings are much
13
more convincing. Coupling constants in the C NMR spectra
for the ortho-C carbon atom of 3 (triplet, 2.4 Hz) and 12 (trip-
let, 7.3 Hz) are significant, suggesting coupling relayed through
The X-ray structure of 3 revealed some insights into the
properties of this tetrafluorocyclohexane derivative. Notably,
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
2
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
an intramolecular hydrogen
bond. In the case of 12, the ex-
perimental value (7.3 Hz) is very
close to the average of the two
expected theoretical coupling
constants (13.4 Hz and 2.59 Hz),
consistent with restricted rota-
tion and
a maximum value.
There is no distal CF coupling
observed experimentally, this is
consistent with the theory calcu-
lations. For 3, the experimental
2h
JCF value (2.4 Hz) is a little
2
h
smaller than the average JCF
value (3.86 Hz) predicted by
theory, and is presumably re-
duced due to averaging associ-
ated with the more rapid aryl
ring rotation. However, we con-
clude that for 3, and certainly in
2
h
the case of 12, there are JCF
couplings (2.4 Hz and 7.3 Hz, re-
spectively), which are consistent
with scalar couplings relayed
through short F···H contacts.
It became an objective to ex-
plore the derivatisation of 3 so
that this motif could be elabo-
rated in different synthetic direc-
tions. In the first instance, 3 was
subjected to electrophilic aro-
matic substitution reactions. In
particular, nitration was ex-
plored. Nitration under different
Figure 2.
A) Rotational energy profile of 3 around the CÀPh bond calculated at the B3LYP/def2-TZVP level. B) Crystal pack-
ing showing the interaction of two molecules of 3 in the solid state, indicative of an electrostatic interaction be-
tween the p system of the phenyl ring and the non-fluorous face of the cyclohexane ring.
[16]
reaction conditions gave mix-
tures of ortho/meta/para prod-
ucts 12–14, as summarised in
Table 2.
The
regioselectivity
varied in different solvents, but
indicated that the tetrafluorocy-
clohexyl ring does not have
a dominating ortho-/para-direct-
ing effect.
After the nitration reactions,
the ortho isomer, 12, was readily
separated by chromatography
from the meta and para isomers,
13 and 14, which were recov-
ered as a mixture. However, the
meta/para isomer mixture could
be efficiently reduced to the cor-
responding anilines, 15 and 16,
and these products were easily
separated by chromatography
Figure 3.
1
1
3 8
A) shows the H NMR spectrum of 3 in CDCl , and B) shows the H NMR spectrum of 3 in [D ]toluene There are
(
Scheme 2).
significant upfield-shifted proton signals in toluene, consistent with a close interaction of the electropositive
lower-face protons interacting with the aromatic solvent, and indicative of facial polarity of the tetrafluorocyclo-
hexyl ring system.
The meta- and para-anilines,
15 and 16, were individually
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
3
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
Table 1. Calculated NMR spin–spin coupling constants (Hz) obtained for
minimum-energy conformers of 3 and 12 (at the BHandH/EPR-III level),
a
The F···H distances (ꢃ) are the shortest calculated in each lowest-energy
conformer. The dotted (*) ortho carbon atoms are those for which cou-
plings to fluorine are reported in the Table.
3
12
1.91
3.67
–
1
1
5
h
h
a
J(Hproximal, Fax
)
)
2.54
3.60
b
J(Hproximal, Fax
a
J(Hdistal, Fax
)
)
a
À0.10
0.25
5
b
Scheme 2. Synthesis of the amino and bromo derivatives of tetrafluoro-
phenylcyclohexane 3.
J(Hdistal, Fax
–
2
2
4
4
h
J(Cproximal, Fax
)
13.4
13.4
h
b
J(Cproximal, Fax
)
2.41
0.37
À0.74
2.59
À0.01
À0.54
a
J(Cdistal, Fax
)
)
b
J(Cdistal, Fax
Table 2. The conditions and results of the nitration of 3.
[
b]
Entry Conditions
Yield
Ratio
[
a]
[%]
12/13/14
[
c]
1
2
(NH
4
)
2
Ce(NO
3
)
6
(2 equiv), H
2
SO
4
/CH
2
Cl
2
, rt,
96
96
1.0:1.2:1.9
1.7:1.0:1.4
3.5 h
NH
4
NO
3
(2 equiv), (CF
3
CO)
2
O/CH
2
Cl
2
, rt to
reflux, 6 h
3
4
5
HNO
HNO
HNO
3
3
3
(20 equiv), H
(20 equiv), H
(20 equiv), H
2
2
2
SO
SO
SO
4
4
4
/CH
/PhNO
/MeNO
2
Cl
2
, rt, 2 h
, rt, 2 h
, rt, 2.5 h
98
96
99
1.8:1.0:1.6
1.0:1.0:2.0
1.0:1.1:2.0
2
2
Scheme 3. Elaboration of the tetrafluorophenylcyclohexane motifs 16 and
19.
1
9
[a] Combined yield of 12–14. [b] Determined by F NMR spectroscopy of
the product mixture. [c] Contains a trace amount of the dinitrated deriva-
tive.
[17]
1
6 was also treated under Paal–Knorr conditions to generate
pyrrole 21. A Sonogoshira reaction with para-bromide 19 and
alkyne 22 generated the coupled product 23 in an efficient re-
action. These elaborations of aniline 16 and arylbromide 19
are illustrated in Scheme 3.
converted to the corresponding bromides, 18 and 19, under
Sandmeyer conditions. Direct bromination of 3 with bromine
in the presence of iron gave a similar regioselectivity to that of
nitration. The ortho isomer, 17, was readily separated from the
meta and para isomers, 18 and 19. However, it was not possi-
ble to separate 18 and 19 by chromatography. Therefore, the
preparation of 18 and 19 was most conveniently achieved by
means of the Sandmeyer reaction protocol starting from 15
and 16, respectively.
In conclusion, aryl 3 has been introduced as a novel organo-
fluorine motif with unique structural and polar properties, and
its chemical elaboration into a variety of derivatives has been
demonstrated, exemplifying its utility as a building block for
fine chemical discovery programmes.
A Sandmeyer reaction of para-aniline 16 using water as a nu-
cleophile generated the corresponding phenol 20. Para-aniline
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
4
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
[
1] a) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308–319; b) K. Mꢀller, C. Faeh,
F. Diederich, Science 2007, 317, 1881–1886.
Experimental Section
[
2] a) P. Tang, W. Wang, T. Ritter, J. Am. Chem. Soc. 2011, 133, 11482–11484;
b) D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢅa-Fortanet, T.
Kinzel, S. L. Buchwald, Science 2009, 325, 1661–1664.
All-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane (3) and 3,4,6-
trifluoro-5-phenylcyclohexene (11)
[
3] a) F. Sladojevich, S. I. Arlow, P. Tang, T. Ritter, J. Am. Chem. Soc. 2013,
Et N·3HF (9.50 mL, 57.9 mmol, 8.0 equiv) was added to a solution
3
1
35, 2470–2473; b) D. O’Hagan, J. Org. Chem. 2012, 77, 3689–3699.
of diepoxide 6 (1.36 g, 7.24 mmol, 1.0 equiv) in dried THF (2 mL) at
room temperature. After stirring at 1308C under argon atmosphere
for 40 h, the mixture was cooled to room temperature and was
poured into saturated aqueous sodium bicarbonate (200 mL) at
[
4] a) G. Landelle, A. Panossian, S. Pazenok, J.-P. Vors, F. R. Leroux, Beilstein J.
Org. Chem. 2013, 9, 2476–2536; b) D. A. Nagib, D. W. C. MacMillan,
Nature 2011, 480, 224–228; c) W. K. Hagmann, J. Med. Chem. 2008, 51,
4
359–4369.
[5] a) F. R. Leroux, B. Manteau, J.-P. Vors, S. Pazenok, Beilstein J. Org. Chem.
008, 4, 13; b) V. N. Boiko, Beilstein J. Org. Chem. 2010, 6, 880–921.
[6] a) P. Kirsch, in Modern Fluoroorganic Chemistry: Synthesis Reactivity, Ap-
plications, 2nd Ed., Wiley-VCH, Weinheim, Germany, 2013; b) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–
0
8C. The mixture was extracted with CH Cl (4ꢄ100 mL). The com-
2 2
bined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/CH Cl /
2
2
2
EtOAc=1:2:2) to give a mixture of difluorohydrins 7 and 8 (1.51 g,
1%, 7/8=ca. 1.6:1) as a colourless powder.This mixture of 7 and
was dissolved in dried CH Cl2 (50 mL) under an argon atmos-
3
30; c) P. Jeschke, ChemBioChem 2004, 5, 570–589.
7] S. Hruschka, S. Yoshida, K. L. Kirk, G. Haufe, J. Fluorine Chem. 2008, 129,
75–880.
8] a) S. A. Kꢀnzi, B. Morandi, E. M. Carreira, Org. Lett. 2012, 14, 1900–1901;
b) B. Morandi, J. Cheang, E. M. Carreira, Org. Lett. 2011, 13, 3080–3081;
c) F. Wang, T. Luo, J. B. Hu, Y. Wang, H. S. Krishnan, P. V. Jog, S. K.
Ganesh, G. K. S. Prakash, G. A. Olah, Angew. Chem. 2011, 123, 7291–
7295; Angew. Chem. Int. Ed. 2011, 50, 7153–7157.
9
[
[
8
2
8
phere. Pyridine (2.14 mL, 26.4 mmol, 4.0 equiv) and trifluorometha-
nesulfonic anhydride (3.33 mL, 19.8 mmol, 3.0 equiv) were added
to the solution at À408C and the mixture was allowed to warm to
room temperature. After stirring for 21 h, the mixture was filtered
through a small pad of silica gel (petroleum ether/CH Cl /EtOAc=
2
2
1
:1:1) and concentrated under reduced pressure. The residue was
[9] A. J. Durie, A. M. Z. Slawin, T. Lebl, P. Kirsch, D. O’Hagan, Chem.
Commun. 2012, 48, 9643–9645.
10] P. A. Baguley, L. V. Jackson, J. C. Walton, J. Chem. Soc. Perkin Trans.
purified by silica gel column chromatography (petroleum ether/
CH Cl /diethyl ether=8:4:1) to give a mixture of ditriflates 9 and
1
[
2
2
1
2002, 304–309.
0 (3.20 g, 98%, 9/10=ca. 1.6:1) as a colourless powder.Et N·3HF
3
[
[
11] W. J. Middleton, J. Org. Chem. 1975, 40, 574–578.
(
21.0 mL, 130 mmol, 20 equiv) was added to a solution of this mix-
12] a) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H. Cheng, J. Org.
Chem. 1999, 64, 7048–7054; b) G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M.
Prozonic, Chem. Commun. 1999, 215–216.
ture of ditriflates 9 and 10 in dried THF (5 mL) at room tempera-
ture. After stirring at 1008C under argon atmosphere for 60 h, the
mixture was cooled to room temperature and was poured into sa-
turated aqueous sodium bicarbonate (300 mL) at 08C. The mixture
was extracted with CH Cl (4ꢄ90 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under re-
duced pressure. The residue was purified three times by silica gel
chromatography (petroleum ether/diethyl ether=1:1, petroleum
ether/CH Cl =3:2, and petroleum ether/diethyl ether=2:1, respec-
[
13] G. Haufe, J. Prakt. Chem./Chem.-Ztg. 1996, 338, 99–113.
[14] a) J. A. K. Howard, V. J. Hoy, D. O’Hagan, G. T. Smith, Tetrahedron 1996,
52, 12613–12622; b) J. D. Dunitz, R. Taylor, Chem. Eur. J. 1997, 3, 89–98;
c) S. J. Borwick, J. A. K. Howard, C. W. Lehmann, D. O’Hagan, Acta Crys-
tallogr. C 1997, C53, 124–126.
2
2
[
15] a) G. T. Giuffredi, V. Gouverneur, B. Bernet, Angew. Chem. Int. Ed. 2013,
2, 10524–10528; b) S. Jaime-Figueroa, L. J. Kurz, Y. Liu, R. Cruz, Spectro-
5
2
2
chim. Acta Part A 2000, 56, 1167–1178; c) A. Mele, B. Vergani, F. Viani,
S. V. Meille, A. Farina, P. Bravo, Eur. J. Org. Chem. 1999, 187–196; d) A.
Mele, G. Salani, F. Viani, P. Bravo, Mag. Res. Chem. 1997, 35, 168–174;
e) G. W. Gribble, W. J. Kelly, Tetrahedron Lett. 1985, 26, 3779–3782.
16] a) J. V. Crivello, J. Org. Chem. 1981, 46, 3056–3060; b) J. M. Mellor, S.
Mittoo, R. Parkes, R. W. Millar, Tetrahedron 2000, 56, 8019–8024.
tively) to give (1RS,2SR,3RS,4RS,5SR)-1,2,4,5-tetrafluoro-3-phenylcy-
clohexane 3 (471 mg, 31%) and (3RS,4SR,5SR,6SR)-3,4,6-trifluoro-5-
phenylcyclohexene 11 (579 mg, 42%).
[
Acknowledgements
[17] N. Azizi, A. Khajeh-Amiri, H. Ghafuri, M. Bolourtchian, M. R. Saidi, Synlett
009, 2245–2248.
2
DOH thanks the ERC for an Advanced Investigator Grant
(GO802567) and EPSRC for financial support. We are also grate-
ful to the EPSRC National Mass Spectrometry service, Swansea.
Keywords: aromatic transformations
fluorinations · organofluorine compounds · polar organic
·
cyclohexane
·
Received: January 27, 2014
Revised: March 15, 2014
motifs
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
A. J. Durie, T. Fujiwara, R. Cormanich,
M. Bꢀhl, A. M. Z. Slawin, D. O’Hagan*
&& – &&
Synthesis and Elaboration of All-cis-
,2,4,5-Tetrafluoro-3-
1
Phenylcyclohexane: A Polar
Cyclohexane Motif
A stereocontrolled synthesis of all-cis-
,2,4,5-tetrafluoro-3-phenylcyclohexane
hexane ring is explored and the aryl
ring is elaborated in different ways to
demonstrate its versatility as a molecular
building block (see figure).
1
is developed as the first functionalised
example of this polar cyclohexane
motif. The dipolar nature of the cyclo-
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!