Fluorinated cyclopropanes: Synthesis and chemistry of the aryl α,β,β-trifluorocyclopropane motif

Article abstract of DOI:10.1039/c8cc04964e

A general route to aryl α,β,β-trifluorocyclopropanes is reported and aryl oxidation gave the corresponding α,β,β-trifluorocyclopropane carboxylic acid. Reactions of the corresponding amides with phenol/thiophenol resulted in HF elimination and then conjugate addition. The partially fluorinated cyclopropane has a similar lipophilicity to -CF₃ despite three carbon atoms, and it emerges as a novel motif for drug discovery.

Full text of DOI:10.1039/c8cc04964e

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Fluorinated cyclopropanes: Synthesis and chemistry of the aryl
α,β,β-trifluorocyclopropane motif
Connor J. Thomson,a Qingzhi Zhang,a Nawaf Al-Maharik,a,b Michael Buehl,a David B. Cordes,a
Received 00th January 20xx,
Accepted 00th January 20xx
Alexandra M. Z. Slawina and David O’Hagana*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A general route to aryl α,β,β-trifluorocyclopropanes is
reported and aryl oxidation gave the corresponding α,β,β- product, however trifluorocyclopropane
trifluorocyclopropane carboxylic acid. Reactions of the product, which presumably arose by adventitious
corresponding amides with phenol/thiophenol resulted in HF difluorocarbene addition to an in-situ formed vinylfluoride
3. This gave the expected difluorocyclopropane
4 as the major
6
emerged as a side
5.
elimination and then conjugate addition. The partially fluorinated These are the only examples we are aware of for the
cyclopropane has a similar lipophilicity to –CF3 despite three preparation of this ring system and therefore the published
carbon atoms, and it emerges as a novel motif for drug discovery.
routes and range of examples are extremely limited.
F
Around 20% of pharmaceuticals and 35% of agrochemicals
contain fluorine largely from modifications for improving the
pharmacokinetics of bioactive leads.1,2 There are
consequences in changing to such an electronegative atom,
the most obvious of which is the introduction of polarity.3 In
the context of medicinal chemistry it is becoming recognised
that polarity increases with selective fluorination (eg –CH2F, -
OCH2F) on alkane substituents, and this is an attractive feature
for lowering Log P, whereas higher levels of fluorination (eg –
CF3, -OCF3) lead to increased lipophilicity. These observations
have stimulated our interest in partially fluorinated motifs as
potential starting points as library components for drug
F
F
NC
NC
F
PhHgCF3
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
1
2
CF3
CF3
O
OSiMe3
ClCF2CO2Na (6 equiv)
diglyme,180oC, 1h
O
OSiMe3
Ph
F
+
F
Ph
+
Ph
Ph
F
minor
product
F
F
F
5
6
3
4
Scheme 1. Previous syntheses of α,β,β-trifluorocyclopropanes.
discovery.4
We
have
introduced
all
cis-2,3,5,6-
In this paper we explore the addition of difluorocarbene generated
from the Ruppert-Prakash reagent9 to vinyl fluorides and find it a
straightforward method for the synthesis of α,β,β-
trifluorocyclopropanes. We also look at aryl oxidation of these
products to the corresponding α,β,β-trifluorocyclopropane
carboxylic acid and then explore the reactivity of the corresponding
amides with thiols and phenols.
tetrafluorocyclohexane in this regard.5 Also the ArSCF2CH3 and
ArOCF2CH3 substituents are mixed fluorinated motifs, which
are significantly less lipophilic than the corresponding RSCF3
and OCF3 groups respectively.6 In this paper we describe a
practical synthesis of 1,2,2-trifluorocyclopropanes as a partially
fluorinated cyclopropane motif. Only two previous reports
describe this ring system (Scheme 1). In an isolated example7
The preparation of aryl α,β,β-trifluorocyclopropanes 11 required
access to α-fluorostyrenes 10 as substrates. These could be
prepared from styrenes 8 followed by bromofluorination10 to
generate intermediates 9, and then hydrogen bromide elimination11
as illustrated in Scheme 2.
cyclopropane
from phenyl(trifluoromethyl)mercury to generate vinyl
fluoride , however in general mercuric reagents are not
2 was prepared by difluorocarbene addition
1
attractive due to their toxicity. The only other reported
synthesis8 involved difluorocarbene addition to silylenol ether
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using morpholine (Pd2(dba)3 and BINAP) gave the cross coupled
product 14 in excellent yield (93%).
Scheme 2. i.[CH3PPh3]Br, nBuLi, THF, 70°C, 4 h, 32-58%; ii. NBS, Et3N.3HF or
Pyr.HF, DCM, 0°C to rt, 4 h, 39-80%; iii. KOtBu, THF, 0°C to rt, 59-82%; iv.
TMSCF3, NaI, THF, 55°C, 20 h, 53-93%.
Scheme 4. Nitration of 11a affords a mixture of isomers. i) NH4NO3, TFA,
MeCN, 75°C, 4 h, 48%.
Bromofluorination generated a single regioisomer of products 9 for
all of the substrates explored except p-nitrostyrene (8f). In this case
the more acidic Pyr.HF (70%) rather than Et3N.3HF was required for
reaction and it gave rise to the mixture of regio-isomers 9f and 9f'
(2.8:1.0 ratio) as illustrated in Scheme 3.
Scheme 5. Palladium catalysed cross-coupling reactions of 11b. i) 12,
PdCl2PPh3, CuI, PPh3, Et3N, DMF, 80°C, 20h, 76%; ii) morpholine, Pd2(dba)3,
BINAP, Cs2CO3, toluene, 80oC, 36 h, 93%.
Methyl ether cyclopropane 11e was treated with boron
tribromide14 in an effort to prepare the corresponding phenol
however this generated phenolcyclopropanol 17 in excellent yield
(90%). This product appears to have arisen from a hydrolytic
reaction of intermediate 16 triggered by the electronic nature of
the phenol located para to the benzylic fluorine of the cyclopropane
ring and the expulsion of hydrogen fluoride from intermediate 15,
as illustrated in Scheme 6. This may emerge as an attractive feature
if incorporated into a drug scaffold as it offers the potential to
Scheme 3. Bromofluorination of p-nitrostyrene. i) NBS, HF:Pyr
(70%), CH2Cl2, 0°C to 25°C, 4 h, 39%.
A two-step telescoped approach to α−fluorostyrene 10a from
styrene 8a was explored and this led to a more efficient process
(76% vs. 61%). In this case an increased number of equivalents of
KOtBu (8.0 vs 1.5 eq) was required to drive the dehydrobromination
reaction to completion. α-Fluorostyrene 10e was also obtained in
this one-pot-two-step manner in the yield of 82%. The resultant α-
fluorostyrenes were then treated with TMSCF3/NaI9 to affect their
conversions to cyclopropanes 5 in modest to good isolated yields as
illustrated in Figure 1. This would appear to offer a straight forward
route to this rare motif.
release
a
reactive intermediate during metabolism. Such
approaches have been used for the development of electrophilic
cytotoxic pro-drugs which react with DNA.15
Scheme 6. Rational for the conversion of 11e to 17. i) BBr3, DCM, rt, 1h,
90oC, 90%.
One of the most informative predictors of druggability is logP.16 We
chose to measure Log Ps of comparative phenyl derivatives by
reverse phase HPLC in acetonitrile/water.17 Trifluorocyclopropane
11a is more polar than cyclopropylbenzene, consistent with partial
fluorination which polarises the cyclopropane hydrogens (Figure 2).
Notably, the trifluorocyclopropane 11a has the same log P as
trifluoromethylbenzene (logP = 3.2) suggesting that it may have use
as a larger aliphatic substituent than trifluoromethyl, containing
two more carbons, but without any increase in lipophilicity.
Figure 1. Aryl-1,2,2-trifluorocyclopropane products 11. Yields represent the
cyclopropanation reaction from the corresponding α-fluorostyrene 10.
The aryl cyclopropanes 11 were explored in a range of aromatic
functionalisation reactions to assess the compatibility of the
partially fluorinated ring with mainstream reaction conditions. For
example nitration of 11a proceeded cleanly to give a mixture of the
o-, m- and p- nitroaromatic products (ratio 1.2 : 1.0 : 2.1) 11f, 11f'
and 11f" as illustrated in Scheme 4. The meta product 11f' was
most readily isolated by chromatography, while the ortho and para
isomers 11f and 11f" were recovered as a mixture. Sonogashira12
and Buchwald-Hartwig13 Pd-mediate cross coupling reactions were
carried out on the para-Br arylcyclopropane 11b (Scheme 4). A
Sonogashira coupling of 11b to 1-ethynyl-4-propylbenzene (12),
with
CuI
and Pd(PPh3)2Cl2,
furnished
4,4’-substituted
diphenylacetylene 13 in good (76%) yield and amination of 11b
2 | J. Name., 2012, 00, 1-3
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Figure 2. Comparison of experimentally derived Log P values of 11a relative
to some aryl derivatives and molecular dipole values and an ESP map of 11a.
yield. Reaction of 4-bromothiophenol with the amide under the
same conditions led to 23b a product that was readily crystallised.
The
Conformational analysis18 of aryl α,β,β-trifluorocyclopropane 11a
has revealed that the lowest energy conformer orients the C-F bond
perpendicular to the aryl ring (Figure S3). An electrostatic surface
potential map19 of this conformer is shown in Figure 2 and Figure
S4, illustrating the polar nature of the ring. Calculated molecular
dipole moments demonstrated a significant polarity for the partially
fluorinated cyclopropane, with the lower energy conformer (C-F
orthogonal) of 11a being the more polar (3.01 D versus 2.74 D).
Having
developed
a
synthesis
of
the
aryl-α,β,β-
trifluorocyclopropanes we then explored aryl oxidation. Treatment
of 11a with RuCl3/NaIO4 under the phase-transfer conditions first
described by Sharpless,20 resulted in an efficient oxidation to
generate the corresponding α,β,β-trifluorocyclopropane carboxylic
acid 18 (Scheme 7).
Figure 3. DFT (B3LYP/6-311+G** level), rotational energy profile of N-methyl
amide model 20. Full circles: gas phase, open circles: in a polarizable
continuum (CPCM). Conformation 20A is lowest in energy when the C-F and
C=O bonds oriented anti – parallel to each other.
F
F
F
H
N
i
ii
F
F
HO2C
F
R
F
F
O
F
18
11a
19a
R = Ph
structure is shown in Figure 4. These adducts demonstrate a
particular reactivity of the α,β,β,-trifluorocyclopropyl amide motif
which has potential in the design of mechanism based (suicide)
enzyme inhibitors.
19b R = Bn
F
H
N
Scheme 7. i) RuCl3 (cat), NaIO4, CH3CN/H2O/CCl4 , 90°C, 3 days, 60%; ii)
PhNH2 or PhCH2NH2, HOBt, EDCI, Et3N, rt, overnight, 86% and 82%. X-Ray
structures of 18, 19a and 19b are inset.
F
O
S
21
H
putative reactive intermediate
N
F
O
F
23a
ii
F
H
This carboxylic acid could be converted to amides with amines
under standard conditions, a reaction which was exemplified using
aniline and benzylamine as illustrated in Scheme 7. The structures
of carboxylic acid 18 and amides 19a and 19b were confirmed by X-
ray structure analysis (Scheme 7). The α-fluorine of the cyclopropyl
ring and the carbonyl oxygens point in opposite directions (F-C-C=O
torsions angles of 161.0o and 167.2o for 19a and 19b respectively), a
conformation consistent with the established preference of α-
fluoroamides.21 This was further confirmed by a DFT theory study
exploring the conformation of a truncated N-methylamide 20
model. The resultant rotational energy profile, rotating around the
(F)C-C(O)N bond, is shown in Figure 3, and gas phase, and a
O
Br
N
F
i
H
N
F
S
Br
O
F
ii
H
N
O
F
22
19a
F
O
F
23b
iii
S(O)CH3
S(O2)CH3
SCH3
F
H
H
H
iv
v
N
N
F
N
F
O
F
O
F
O
F
25
24
23c
Scheme 8. Reactions of amide 19a with phenol and thiols. i) 4-bromophenol,
K2CO3, CH3CN, 60°C, overnight 18 h, 32%; ii) 2-naphthalenethiol or 4-
bromothiophenol, NaH, THF, 0°C to rt, 16 h 72 and 65%; iii) MeSK, CH3CN, rt,
16 h, 71%; iv) air, CH3CN, 60°C, partial oxidation; v) mCPBA, DCM, 0°C to rt,
4h, 81%.
dielectric continuum to simulate
a polar solvent (H2O) are
compared. There is a significant energy minimum (~5.0 kcal mol-
1
(gas) or ~3.5 kcal mol-1(H2O)) in each case for the conformation with
the C-F and C=O bonds oriented anti – parallel to each other. Several experiments were performed to try to observe
cyclopropene intermediate 21 by 19F-NMR, however these were
Together, with the X-Ray structures of 13a and 13b this suggests a
preferred conformation for this cyclopropyl amide motif.
unsuccessful. Treating amide 19a with sodium hydride at 0°C to rt in
THF or with K2CO3 at 50-60°C in acetonitrile led to a disappearance
of amide 19a (in situ VT-19F-NMR) along with the formation of a
gummy residue suggesting polymerisation.
The reactivity of amide 19a was explored with nucleophiles in view
of the inherently polar nature of the α,β,β-trifluorocyclopropyl ring,
particularly in conjugation with the amide. Treatment of 19a with 4-
bromophenol in acetonitrile and K2CO3 at 60oC generated
a
complex mixture from which phenol ether 22 was isolated and
crystallised for X-ray structure determination (Scheme 8 and Figure
4). The product can be rationalised by progressing through a base
induced dehydrofluorination, and then attack of in situ phenoxide
to generate putative cyclopropene intermediate 21 shown in
Scheme 8. A similar reaction with β-naphthiol and sodium hydride
Figure 4. X-ray derived structures of 22 and 23b
in THF was more efficient, and generated thioether 23a in excellent
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M. Z. Slawin, D. O’Hagan, Chem. Eur. J., 2014, 20, 6259 –
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Amide was also reacted with KSMe in acetonitrile, as both a base
and a nucleophile. The resultant adduct proved labile to oxidation
and generated sulfoxide 24. Complete oxidation of this adduct with
mCPBA afforded the sulfonyl derivative 25. In the course of 1H-NMR
analysis of sulfone 25 in MeOD as the solvent it was clear that there
was a gradual exchange of two C-H protons on the ring. The proton
alpha to the amide group (δH 4.2 ppm) exchanged more rapidly
(hours) than that alpha (C-3) of the sulfonyl (days) (Figure S1). The
introduction of deuterium was also evident in the 19F{1H}-NMR
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spectrum where fluorine signals experience isotope induced
-shifts of between 0.12-0.22 ppm (Figure S2). This isotope
exchange could be completely reversed in MeOH.
This study has established general route to the α,β,β
trifluorocyclopropane motif. Aryl oxidation of the
trifluorocyclopropane derivative generated carboxylic acid 18 which
could be converted to amides. The amides had clear
α- and
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β
a
-
a
conformational preference and underwent an elimination addition
reaction with phenols and thiophenols, which suggests a potential
role in mechanism based inhibition of enzymes.
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Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1-3
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F
F
F
F
F
F
Log P
3.2
3.2
SAr
F
F
F
F
ArSH
RHN
RHN
O
RHN
F
O
F
O
F