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
Chem. Eur. J. 2014, 20, 1 – 6
1
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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