Synthesis of α,α-difluoroethyl aryl and heteroaryl ethers

Article abstract of DOI:10.1021/ol301696x

Fluorine plays a critical role in modern medicinal chemistry due to its unique properties, and new methods for its incorporation into target molecules are of high interest. An efficient new method for the preparation of aryl-α,α-difluoroethyl ethers (4) via addition of aryl and heteroaryl alcohols (1) to commercially available 2-bromo-1,1-difluoroethene (2) and subsequent hydrogenolysis is presented. This procedure is an attractive alternative to existing methods that employ harshly reactive fluorinating systems such as xenon difluoride and hydrogen fluoride.

Full text of DOI:10.1021/ol301696x

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3944–3947
Synthesis of r,r-Difluoroethyl Aryl and
Heteroaryl Ethers
Eddie Yang, Matthew R. Reese, and John M. Humphrey*
Pfizer Worldwide Research and Development, Eastern Point Road, Groton,
Connecticut 06340, United States
John.m.humphrey@pfizer.com
Received June 20, 2012
ABSTRACT
Fluorine plays a critical role in modern medicinal chemistry due to its unique properties, and new methods for its incorporation into target
molecules are of high interest. An efficient new method for the preparation of aryl-R,R-difluoroethyl ethers (4) via addition of aryl and heteroaryl
alcohols (1) to commercially available 2-bromo-1,1-difluoroethene (2) and subsequent hydrogenolysis is presented. This procedure is an
attractive alternative to existing methods that employ harshly reactive fluorinating systems such as xenon difluoride and hydrogen fluoride.
Fluorine plays a critical role in modern medicinal chem-
istry due to its unique stereoelectronic properties and
small size.1,2 Electron-rich aromatic rings that are prone
to oxidation by metabolic enzymes can be stabilized
through the judicious incorporation of electron-withdraw-
ingfluorine, andthehighCÀF bond energymakesfluorine
an attractive isostere for the replacement of hydrogen
atoms at specific metabolic soft spots including ArÀH
and hydrogen atoms R to heteroatoms (i.e., ÀCH2OR).3
Additionally, fluorine has been used as an isostere for
ethyl/isopropyl(CF3), carbonyl(CF2), hydroxyl (CF, CF2,
CF2H), and amide functionalities4À7 and can impart un-
ique structural effects relative to the parent hydrocarbon
chain thereby enabling access to alternative conforma-
tional space.8,9 Fluorine-induced changes in lipophilicity
and pKa can improve target binding, bioavailability, and/
or CNS exposure by reducing interaction with various
cytochrome P450s and efflux proteins.3 Approximately
30% of the 30 top selling small molecule drugs in recent
years contain fluorine, often as direct aryl substituents
(e.g., Lipitor, Crestor, Celebrex, Prozac) but also as aliphatic
fluorine (e.g., Prevacid, Protonix).10 Thus, the utility of
fluorine as a means to impart desirable properties to drug
molecules has fostered intense research on new methods
€
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Mendonca, R. V.; Springman, E.; McCarter, J.; Chung, T.; Cheung,
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Strickley, R. M.; Liu, L.; Venuti, M. C.; Percival, M. D.; Falgueyret,
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r
10.1021/ol301696x
Published on Web 07/20/2012
2012 American Chemical Society

and reagents for its incorporation.1,11À20 As stated by
G. K. Surya Prakash, “Fluorine has become a driving
force À it’s the new kingpin of drug discovery.”21
source of electrophilic difluoroethene, commercial 2-bro-
mo-1,1-difluoroethene (6b), would obviate the OTs/halide
conversion and provide a route to 8 via hydrogenolysis
(Scheme 1).
Our contribution tothisareaoriginatedfrom a desire for
an efficient, scaleable, and environmentally safe way to
replace an aryl ethoxy group with the R,R-difluoroethoxy
group to reduce the extent of oxidative metabolism R to
oxygen. Xenon difluoride (XeF2) is an established reagent
for the incorporation of this group by skeletal rearrange-
ment of aryl or heteroaryl carbonyls, but the conversion
involves excessive use of corrosive XeF2/HF and, espe-
cially with acetophenone substrates, suffers from low
yields.9,22À24 Limited commercial availability of aryl alde-
hydes and acetophenones also limits wide application of
this procedure. Other methods include conversion of
thionoesters into R,R-difluoroethers via the action of
nucleophilic fluorine sources such as DAST,25 BrF3,26 or
nBu4NH2F3.27 Drawbacks to these methods include em-
ployment of toxic and corrosive fluorinating agents. Here-
in we report an alternative method for the introduction of
the R,R-difluoroethoxygroupthatbeginswiththe addition
of aryl or heteroaryl alcohols to commercially available
2-bromo-1,1-difluorobromoethene. The resultant difluor-
obromoethyl group can be dehalogenated to cleave the
bromine atom, or conversely the bromine can be used as a
functional handle for further structural transformation
(Scheme 1).
In developing this method we considered a report by
Fang et al. whereby oxygen nucleophiles are added to 2,2-
difluorovinyl tosylate 6a to yield 1,1-difluoro-2-tosyl aryl
ethers such as 7a.28 In contrast to established methods, this
strategy would allow us to purchase the carbonÀfluorine
bond rather than install it with reactive fluorinating re-
agents. We reasoned that an attractive route to the R,R-
difluoroethoxy group could entail subsequent reductive
cleavage of the tosylate.29 Our pilot studies centered on
the addition of commercially available 2-aminopyridin-3-
ol (5) to the vinyltosylate 6a to yield 7a, followed by zinc/
NaI mediated reductive cleavage of the CÀOTs bond to
give the target ether 8 (Scheme 1). Deficiencies in the
strategy were soon apparent: requisite SN2 displacement
of ÀOTs with NaI was extremely sluggish, and the in situ
reduction required large amounts of zinc which would
complicate scaleup. We then considered that an alternative
Scheme 1. Synthetic Strategy
In practice treatment of 5 with 6b and KOH in acetoni-
trile produced the desired ether 7b in 84% yield, and
subsequent hydrodehalogenation provided the target 8 in
82% yield. In determining the generality of this method we
repeated the reaction conditions with simple 3-hydroxy-
pyridine 9: treatment with 6b and KOH in acetonitrile at
room temperature gave the desired product 10, but in this
case it also gave ∼25% of the elimination product 11
(Table 1).30 This side product was not observed with the
ÀOTs reagent.28 Replacement of KOH with a stronger or
weaker base (KOtBu/K2CO3) did not change the product
ratio, but the weaker base resulted in a much slower
reaction (∼24 h vs 2 h). The elimination result can be
explained mechanistically, as the anionic aryloxide inter-
mediate from 9 is poised to eliminate fluoride, whereas this
process is suppressed in the case of 5 due to the internal
proton donor(NH2). Given these results, weconductedthe
reaction in the presence of water as a green proton source
(Table 1). While small amounts of water gave a slower
reaction, the extent of elimination was drastically reduced
(entry 1 vs 2). In subsequent experiments we compensated
Table 1. Base and Solvent Effects
(19) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.;
Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494–1497.
(20) Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Olah, G. A. Org.
Lett. 2008, 10, 557–560.
(21) Ritter, S. K. Chem. Eng. News 2012, 90, 10–17.
(22) Zajc, B.; Zupan, M. J. Org. Chem. 1990, 55, 1099–102.
(23) Stavber, S.; Koren, Z.; Zupan, M. Synlett 1994, 265–6.
(24) Tamura, M.; Matsukawa, Y.; Quan, H.-d.; Mizukado, J.;
Sekiya, A. J. Fluorine Chem. 2004, 125, 705–709.
(25) Bunnelle, W. H.; McKinnis, B. R.; Narayanan, B. A. J. Org.
Chem. 1990, 55, 768–770.
entry
water
t (°C)
time (h)
10:11a
yielda
(1)
(2)
(3)
(4)
À
rt
2
36
5
76:24
97:3
93:7
96:4
71%
53%
74%
82%
5%
2.5%
5%
rt
50
50
(26) Rozen, S.; Mishani, E. J. Chem. Soc., Chem. Commun. 1993,
1761–1762.
10
(27) Kuroboshi, M.; Hiyama, T. Synlett 1994, 251–252.
(28) Fang, X.; Wu, Y.-M.; Deng, J.; Wang, S.-W. J. Fluor. Chem.
2004, 125, 1481.
a Product ratio determined by 1H NMR; yield reported is combined
yield after chromatography.
(29) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 3325–6.
Org. Lett., Vol. 14, No. 15, 2012
3945

Table 2. Reaction Scope
a Combined yield after silica gel chromatography. b KOH was replaced by K2CO3, and the reaction duration was extended to 30 h.
for the reduced reaction rate by raising the reaction
temperatureto50°C (entry 2vs3and 4), andtheoptimized
conditionsprovided a 96:4 ratio of 10and 11in a combined
yield of 82% (entry 4).
These optimal conditions were applied to a variety of aryl
and heteroaryl rings and, in general, gave good-to-excellent
yields (84À97%) with <5% elimination (Table 2).31 We at-
tribute the poorer product ratio of entry 12 to steric effects im-
parted by the isopropoxy group in 22 that hinder proton trans-
fer, and lower yields in select cases to reduced nucleophilicity of
the aryloxide (entry 13) or to competing nitrile hydrolysis by
KOH (entries 14, 15). In the latter case, better product yields
were obtained with K2CO3, which required an extended
reaction time but gave a much improved yield (entry 16).
(30) The structure of 11 was determined by NMR and MS.
(31) In a typical reaction, a stock solution was prepared by bubbling
1,1-difluorobromoethene gas via a cannula into an ice cold tarred flask
of acetonitrile to achieve a concentration of ∼1 M. In a second flask
containing 3.0 mmol of the aryl alcohol in acetonitrile was added 9.3
mmol of KOH followed by 3.0 mmol of 1,1-difluorobromoethene
transferred via syringe from the stock solution. The resultant mixture
was heated to 50 °C for 12 h. On completion as assessed by TLC and
LCMS, the mixture was cooled, passed through a plug of silica gel, and
concentrated to yield the product mixture.
(32) Bordwell, F. G.; Brannen, W. T., Jr. J. Am. Chem. Soc. 1964, 86,
4645–4650.
3946
Org. Lett., Vol. 14, No. 15, 2012

A few simple transformations further demonstrate the
utility of this method (Scheme 2). In the first example,
hydrogenation of bromodifluoro ether 7b provided the R,
R-difluoroethyl ether 8 in 83% yield. Consistent with the
literaturereport,28 wehavefound thatthesearyl/heteroaryl
R,R-difluoroethyl ether products are stable to aqueous
workup and silica chromatography and thus may con-
stitute reasonable pharmaceutical targets. In fact, our
attempts to hydrolyze these compounds under forcing con-
ditions (aqueous NaOH or HCl, 70 °C) further demon-
strated the resistance of this functionality to hydrolysis. In
contrast, alkyl R,R-difluoroethyl ethers are reportedly quite
susceptible to hydrolysis and must be handled carefully.25À27
provides a route to fused morpholines such as 26. How-
ever, other attempts to displace the bromine atom of 16
intermolecularly with pyrrolidine (DMF, 120 °C) failed,
yielding only starting material and suggesting impediment
of an intermolecular SN2 attack by the geminal adjacent
fluorine atoms.32
In conclusion we have described a new method for the
incorporation of the R,R-difluorobromoethoxy group into
aryl and heteroaryl systems in high yield. Competing
elimination of fluoride to yield the 1-fluoro-2-bromo vinyl
ether can be reduced by introducing water as a proton
source. The product 2-bromo-1,1-difluoroethyl ether can
be further manipulated by hydrogenolysis of bromine to
provide ready access to the R,R-difluoroethyl ethers, or
alternatively, intramolecular displacement of the bromine
atom byaninternalnucleophile can provideaccesstofused
morpholines. This method should prove useful as an
additional tool for the incorporation of fluorine in phar-
maceutical and agrochemical applications.
Scheme 2
Acknowledgment. The authors thank Professor E. J.
Corey, Harvard University, for consultation and support.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds,
including fluorine NMR spectra for representative struc-
tures. This material is available free of charge via the
Internet at http://pubs.acs.org.
In another demonstration of the utility of this method,
intramolecular displacement by an ortho-amine group
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
3947