Fluorine containing cyclopropanes: Synthesis of aryl substituted all-: cis 1,2,3-trifluorocyclopropanes, a facially polar motif

Article abstract of DOI:10.1039/c9cc05749h

The syntheses of substituted all-cis-1,2,3-trifluorocyclopropanes are described for the first time. The three fluorines located on each of the cyclopropyl carbons with a stereochemistry where they are all on the same face of the cyclopropane, imparts a significant polarity to the molecule, and the inherent conformational rigidity and lowering of logP makes this motif attractive for exploration as a substituent for pharmaceuticals and agrochemicals research.

Full text of DOI:10.1039/c9cc05749h

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DOI: 10.1039/C9CC05749H
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Fluorine containing cyclopropanes: Synthesis of aryl substituted
all-cis 1,2,3-trifluorocylopropanes, a facially polar motif
Zeguo Fang,a David B. Cordes,a Alexandra M. Z. Slawina and David O’Hagan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
pentafluoroaryl substrates3b to the corresponding all-cis
1,2,3,4,5-pentafluorocyclohexyl derivatives.
The synthesis of substituted all-cis-1,2,3-trifluorocylopropanes are
described for the first time. The three fluorines located on each of
the cyclopropyl carbons with a stereochemistry where they are all
on the same face of the cyclopropane, imparts a significant polarity
to the molecule, and the inherent conformational rigidity and
lowering of Log P makes this motif attractive for exploration as a
substituent for pharmaceuticals and agrochemicals research.
With this background we became interested in preparing
derivatives of all-cis- 1,2,3-trifluorocylopropane 2. Progressing
from a cyclohexane to a cyclopropane reduces the carbon count
and with that the lipophilicity and unlike cyclohexane,
cyclopropane has a rigid conformation which favours entropic
factors in binding to proteins (Fig 1a). Similar to the properties
of cyclohexane 1, cyclopropanes such as 2 are predicted to have
the unusual property of facial polarity4 with different
coordinating preferences for the fluorine and hydrogen faces.
Fluorine is widely used in bioactive pharmaceutical and
agrochemical products to refine pharmacokinetic profiles as a
lead compound is progressed through development.1 Although
the incorporation of fluorine is synonymous with increasing
lipophilicity, this is almost entirely confined to the replacement
of an aryl or heterocyclic hydrogen by –F or -CF3 and higher
levels of fluorination.2 Selective fluorination generally increases
polarity, particularly where there are adjacent geminal and
vicinal hydrogens, which become polarised due to the
electronegative fluorine and therefore aliphatic fluorination
actually lowers Log P values.2d This adds another attractive
feature associated with the introduction of fluorine in the arena
of bioactives discovery, where Log P values require to be
contained as a lead compound is developed. An extreme
example of this polarity phenomenon is found in 1,2,3,4,5,6-all-
cis hexafluorocyclohexane 1, a molecule with a fluorine on each
of the six carbons, and with a stereochemistry where all the
fluorines are on one face of the ring.3a Cyclohexane 1 is among
the most polar aliphatic motifs known. It has attracted
significant attention in its ability to coordinate both anionic and
cationic species to the hydrogen and fluorine faces respectively,
and it has clear prospects in supramolecular chemistry.4 The
potential for derivatives of cyclohexane 1 in drug discovery is in
its infancy, but looks attractive as the ring should coordinate
electropositive and electronegative substituents on proteins.
These prospects have improved recently as substituted ring
systems are now available due to direct hydrogenation of
(a)
F
-
F
F
F
F
F
F
F
R
F
F
F
+
R
F
2
= H
3a
4a
1
= Ph
= p-biphenyl
(b)
O
N
O
C7H15
H2N CO2H
H
O
F
CO2H
F
N
Cl
O
6
H2N
Cl
F
NH3
F
5
CF3
7
Figure 1. (a) Facially polarised fluorocycloalkanes. (b) Fluorocyclopropanes
in medicinal chemistry.
More generally the cyclopropyl ring has been used widely in
drug development programmes.5 As a subset, some fluorinated
cyclopropanes have featured in medicinal chemistry however
examples are confined almost exclusively to mono-fluorinated
cyclopropanes (Fig 1b).6 Fluorocyclopropyl-amines are the
most common variant of this class such as the cyclopropane
found in the 6-fluoroquinolone antibiotic sitafloxin 5, and LY-
341,495 6 a selective orthosteric antagonist.7 There has been
extensive exploration by Haufe and coworkers into the
a. University of St Andrews, School of Chemistry, North Haugh, St Andrews, KY16
9ST, UK.
b. E-mail: do1@st-andrews.ac.uk
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
F
synthesis, physical chemistry and bioactivity of monofluorinated
phenylcyclopropylamines such as 7, particularly as candidate
monoamine oxidase inhibitors.8 Jubault’s lab have made recent
contributions to the synthesis of more highly functionalised
monofluorocyclopropanes.9 Good methods have developed to
prepare -difluorocyclopropanes through difluorocarbene
addition to olefins,10 and a very wide range of such compounds have
been prepared, and this category of fluorinated cyclopropane
dominates entries in the chemical and patent literature. Vicinal -
or ’-di-fluorocyclopropanes are rarely quoted, where the
fluorines are located on two adjacent carbons, rather than as a CF2
group. Again there are some patent claims to vicinal difluoro
cyclopropanes, but examples in the primary literature are confined
to theory studies where properties are computationally predicted.11
The focus of this study was to explore synthesis routes to substituted
all-cis-1,2,3-trifluorocyclopropanes 3a and 4a. We are not aware of
any derivatives of all-cis 1,2,3-trifluorocyclopropanes 2 having been
reported, however both isomers of the unsubstituted parent 1,2,3,-
trifluorocyclopropane, 2a and 2b have been prepared at analytical
levels.12 The isomers emerge as minor products of the ozonolysis of
cis-1,2-difluoroethene. Analytical samples of each isomer were
secured by preparative gas chromatography and their integrity and
stereochemistry was assigned by vibrational and microwave
spectroscopy.12a In this paper we report the first preparations of
derivatives of all-cis-1,2,3-trifluorocyclopropanes. In this context the
phenyl 3a and para-biphenyl 4a derivatives, as well as their trans
isomers 3b and 4b are reported. We also compare the relative
polarity (Log Ps) of the phenyl derivative 3a and 3b to other
selectively fluorinated phenylcyclopropanes and demonstrate that
3a is the most polar of the series.
View Article Online
F
F
F(H)
H(F)
DOI: 10.1039/C9CC05749H
F
F
F
R
3(4)a/b
a)
R
18
19
R = H (40 %)
R = Ph (48 %)
b)
c)
F
F
R
F
e)
16
17
R = H
R = Ph
F
F
F(Cl)
Cl(F)
F
F(Br)
Br(F)
d)
R
R
23a + b
24a + b
R = H (21 %)
R = Ph (26 %)
20a+b
21a+b
R = H (25 %)
R = Ph (30 %)
F
F
F(I)
I(F)
Ph
22a+b
(38 %)
19
22b
Scheme 2. Fluorocarbene reactions and X-ray structures of 19 and 22b.
Conditions: a) CHFI2, ZnEt2, PE, 0 ⁰C; b) TMSCF3, NaI, THF, reflux; c) CFCl3, TiCl4,
LiAlH4, THF, 0-RT; d) CHFI2, TEBAB (Benzyltriethylammonium Bromide),
NaOH·H20, DCM, 0-RT; e) CHFBr2, TEBAB, NaOH·H20, DCM, 0-RT
nucleophiles and the CHF carbene is not so electrophilic.
Consistent with this, the more electrophilic fluorohalocarbenes
(:CXF, where X = Cl, Br and I) all successfully reacted with (Z)-
-difluorostyrenes 16 and 17 at room temperature, and also
with the less electrophilic carbene (:CF2), generated from the
Ruppert-Prakash (TMS-CF3) reagent16 but at high temperature.
This gave the various trifluorohalocyclopropanes 18 - 24. In the
case of the chlorocyclopropanes 20 and 21 the required :CClF
carbene was generated from CFCl3, using the method of
Dolbier,17 and the iodo- 22 and bromo- cyclopropanes 23 and
24 were generated from CHFI2 and CHFBr2 18 derived fluorohalo
carbenes respectively, following the methods developed by
Weyerstahl et al.19,20 For these reactions it proved necessary to
prepare the required haloform precursors CHFI2 and CHFBr2 as
they are not commercially available. These reactions are
summarised in Scheme 2.
Given that the monofluorocarbene reactions with 16 and 17
were unsuccessful and the fluorohalocarbene additions were
more fruitful, our approach towards the target 1,2,3-
trifluorocyclopropanes 3 and 4 envisaged reductive removal of
the non-fluorine halogen from the product cyclopropanes 20 -
24. In the first instance reductive removal of the chlorine from
cyclopropanes 20 and 21 was investigated. The individual a
(fluorines all cis) and b (fluorine trans) isomers of 20 and 21
were not easily separated and the mixture was explored in each
case for dehalogenation (Bu3SnH/AIBN).20 In the event this
required high temperatures and led to product mixtures,
although containing the desired cyclopropanes (as determined
by 19F-NMR) but with significant levels of unidentifiable
products. Due to this poor selectivity, attention turned to the
iodo cyclopropanes 22a/b. Isomers 22a and 22b, were
separated and treated individually. Each could be reduced at a
Our synthesis approach to the all-cis-1,2,3-cyclopropane motif
envisaged either direct monofluorocarbene (:CHF) or
fluorohalocarbene (:CFX) addition to (Z)--difluorostyrene 16 or
the corresponding p-biphenyl-(Z)- -difluorostyrene 17. The p-
biphenyl series was developed to render products less volatile and
crystalline. The required styrenes were prepared from -
fluoroketones 12 and 13 following the protocol of Leroy.13 The -
fluoroketones were prepared efficiently from vinyl azides 10 and
1114a using recent methodology developed by Wu,14b and they were
then treated with DAST to generate the aryltrifluoroethyl products
14 and 15. A stereoselective base (tBuOK) induced hydrogen fluoride
elimination from 14 and 15, gave the required (Z)--
difluorostyrenes 16 and 17, with the fluorines in the required syn
arrangement.13 The route is summarised in Scheme 1.
At the outset we explored reactions of 16 and 17 with
monofluorocarbene (:CHF) generated from CHFI215, to try to
generate 3a/b and 4a/b directly, but these reactions were
unsuccessful presumably because these olefins are poor
Selectfluor
NaHCO3
Ag2CO3
TMSN3
N3
H2O, CH3CN
H2O, DMSO
R
R
R = H
R = Ph
8
9
R = H, 72%
R = Ph, 70%
10
11
O
F
F F
F
t-BuOK
DAST
F
BuOH
F
R
R
R
16
17
12
13
R = H, 65%
R = Ph, 70%
R = H, 48% 14
R = H, 32%
R = Ph, 28%
R = Ph, 50%
15
Scheme 1 Route to (Z)--difluorostyrenes.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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COMMUNICATION
Log P
F
F
View Article Online
F
I
F
Bu3SnH
DOI: 10.1039/C9CC05749H
F
F
AIBN,RT
Ph
Ph
29 3.40
22b
4b
(75 %)
F
F
F
F
F
F
O
F
F
F
Bu3SnH
F
F
I
AIBN,RT
18
2.94
28
2.91
Ph
Ph
22a
25
(63 %)
F
F
F
F
F
F
F
27
2.75
3b
2.74
26
2.73
25
Scheme 3. Reductive deiodination of cyclopropanes 22a and 22b.
F
F
F
3a
2.56
lower
chlorocyclopropanes. The trans isomer 22b resulted in trans-
1,2,3-trifluorocyclopropane 4b with retention of
temperature
than
the
corresponding
3a
Figure 2. Log P values of selectively fluorinated phenylcyclopropanes
(approximately scaled), and an electrostatic surface potential map of
3a.
stereochemistry, however the cis-isomer 22a lead to the
formation of the -unsaturated ketone 25 as the only
isolatable product, the nature of which was confirmed by X-ray
structure analysis (Scheme 3).
potential map of 3a is shown in Figure 2 and this clearly illustrates
the different electrostatic profile on each face of the cyclopropane
ring. To explore polarity in the context of bioactives discovery Log P
values for the selectively fluorinated cyclopropanes 3a, 3b, 26-2822
as well as phenylcyclopropane 29 as a reference, were evaluated
experimentally by reverse phase HPLC on a C18 coated silica column,
a method which has been widely validated.23 The selected phenyl
cyclopropanes are directly compared as they differ only by the
degree of fluorination on the cyclopropane ring. From this analysis it
emerged that all of the partially fluorinated cyclopropanes 3a, 3b,
26-28 are more polar than phenylcyclopropane 29 itself consistent
with the fluorine polarising geminal, and to a lesser extend vicinal,
hydrogens around the ring. The all cis-1,2,3- trifluorocyclopropane
3a (Log P 2.56) is the most polar of the series, and more polar than
the trans isomer 3b (Log P 2.74) where in the latter case the anti
fluorine is compromising the overall polarity. Notably cyclopropanes
18 and 28 which contain CF2 groups are significantly more lipophilic
than those with their fluorines in fluoromethylene (CHF) groups,
indicating that geminal CHF hydrogens are particularly polarised and
contribute significantly to lowering Log P.
Due to the inability to access cis-1,2,3-trifluorocyclopropane 4a
from the iodine series, attention turned to the
bromocyclopropanes 23 and 24. The isomer mixture of 23a and
23b was also subjected to reductive dehalogenation to generate
the anticipated 1,2,3-trifluorocylopropanes 3a and 3b (scheme
4). These product isomers could be readily separated by
chromatography. The all-cis isomer 3a has characteristic second
order 1H- and 19F-NMR spectra associated with the symmetry of
the nuclei on the cyclopropane ring (see SI). A similar reduction
was carried out on isomers 24a and 24b, which gave rise to the
all-cis isomer 4a and the trans isomer 4b respectively. In the
case of 4a a suitable crystal was selected for X-ray structure
analysis as illustrated in Scheme 4. This confirmed the all-cis
configuration of the three C-F bonds.
It was anticipated that the all-cis phenyl-1,2,3-trifluorocyclopropane
3a would display a significant polarity relative to phenylcyclopropane
29, following from our previous observations with all–cis
multifluorocyclohexanes.21 A calculated electrostatic surface
In conclusion, all-cis-1,2,3-trifluorocyclopropanes 3a and 4a
have been prepared by halofluorocarbene addition to -
difluorostyrenes, and then by removal of the non-fluoro
halogen by reductive dehalogenation. The study was stimulated
by a recognition that the facially polarised characteristics of
such a cyclopropyl ring system could offer unique polar
properties for an alicyclic ring. This tendency was demonstrated
by evaluation of Log P’s across a series of selectively fluorinated
phenylcyclopropanes where the all cis isomer 3a was the least
hydrophobic of the series. The study reports the first synthetic
access to cyclopropanes of this class and demonstrates
attractive characteristics for optimizing pharmacokinetic
profiles in bioactive discovery programmes.
F
F
F
F
F
F
F
Br
F
F
F
F
Bu3SnH
Br
+
F
+
AIBN,RT
R
R
R
R
23a/b
24a/b
R = H, (1 : 1.1, 21 %)
R = Ph, (1 : 1.1, 26 %)
3a/b
4a/b
R = H, (1 : 1.3, 37.5 %)
R = Ph, (1 : 1.3, 42 % )
4a
Scheme 4. Reductive debromination and structure of all-cis
trifluorocyclopropane 4a.
We thank the EPSRC for financial support (GR: EP/R013799/1)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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There are no conflicts to declare.
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