Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed C-O Cross-Coupling

Article abstract of DOI:10.1021/acs.orglett.0c02347

Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and-poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.

Full text of DOI:10.1021/acs.orglett.0c02347

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Letter
Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed
C−O Cross-Coupling
Robert Szpera, Patrick G. Isenegger, Maxime Ghosez, Natan J. W. Straathof, Rosa Cookson,
́
David C. Blakemore, Paul Richardson, and Veronique Gouverneur*
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ABSTRACT: Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols
using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short
reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method
provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.
luorinated alkyl aryl ethers are encountered in medicinal
chemistry and agrochemistry, due to the ability of fluorine
to modulate molecular properties including lipophilicity and
metabolic stability.1 Prominent molecules featuring these
motifs include the multibillion-dollar proton pump inhibitor
lansoprazole, the antiarrhythmic flecainide, and idalopirdine
(Figure 1). Approaches for fluoroalkyl aryl ether preparation
protocols include the use of stoichiometric transitions metals
(Cu(I) fluoroalkoxide procedure),8 limited substrate scope
(Pd-catalyzed procedure), long reaction times, and/or the
requirement of neat fluorinated alcohols (Cu-catalyzed
procedure).5
F
Shekhar and co-workers reported novel biaryl phosphor-
inane ligands for Pd-catalyzed C−O cross-coupling with
electron-rich and heteroaryl halides, but these ligands are
currently not commercially available.9 In this field of research,
the contribution of Buchwald and co-workers stands out by
providing an excellent procedure for C−O cross-coupling of
alcohols and aryl halides in the presence of NaOtBu in dioxane
and using commercially available precatalysts tBuBrettPhos Pd
G3 and AdCyBrettPhos Pd G3.10 For alcohols of reduced
nucleophilicity including 2,2,2-trifluoroethanol and 2,2,3,3,3-
pentafluoropropanol, superior yields were obtained using
AdCyBrettPhos Pd G3.
Given our interest in narrowing the gap between 19F- and
18F-chemistry,11−14 we considered applying this C−O cross-
coupling as a radiosynthetic route to install 18F-labeled
fluorinated alkyl aryl ethers motifs. For this purpose, it was
necessary to adapt the protocol to accommodate short reaction
Figure 1. Drugs containing fluorinated alkyl aryl ethers.
include Chan−Lam coupling of aryl boronic acids,2,3
Williamson ether synthesis,4 and transition metal mediated
cross-coupling of aryl halides with fluorinated alcohols.5−8
Copper mediated approaches include coupling of fluorinated
alcohols with aryl iodides under copper catalysis reported by
Bonnet-Delpon and co-workers5 and reaction of aryl bromides
with a copper(I) fluoroalkoxide complex reported by the Weng
group.8 The Singh group has reported palladium-catalyzed
coupling of fluorinated alcohols with aryl bromides bearing
para-electron-withdrawing groups.6,7 Limitations of these
Received: July 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02347
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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times (18F half-life = 109.7). In addition, it is important that no
large excess of fluorinated alcohol is required for effective
coupling considering that cyclotron-produced 18F-fluoride is
available in the picomolar range. Herein, we report the Pd-
coupled product was observed in 51% yield (entry 4). An
increase to 70% yield was observed using Buchwald’s Bu-
t
BrettPhos Pd G3 precatalyst (entry 5). Buchwald’s precatalysts
are air and moisture stable Pd(II)-palladacycles, which allow
for quantitative formation of the catalytically active LPd(0)
species in situ following base induced C−N reductive
elimination.17 Cs2CO3 gave superior results compared to
both sodium and potassium carbonate (entries 6 and 7).
K3PO4 was an effective base, affording the product in 70%
yield (entry 8). While Cs2CO3 was used for this study, use of
K3PO4 may be advantageous on a larger scale, as it is
significantly cheaper than Cs2CO3. The use of NaOtBu as base
with 1,4-dioxane as solvent10 resulted in a reduced yield (entry
9). While stronger bases such as NaOtBu can promote C−O
cross-couplings at lower temperatures than weaker inorganic
bases such as Cs2CO3, they can also lead to reduced yields for
base-sensitive substrates.18,19 Toluene afforded a higher yield
than 1,4-dioxane (entry 10) and tert-amyl alcohol (entry 11).
Reducing the reaction duration to 30 min or the temperature
to 80 °C resulted in lower yields (entries 12 and 13).
t
catalyzed C−O coupling of fluorinated alcohols using Bu-
BrettPhos Pd G3 with the mild base Cs2CO3 in toluene. This
protocol accommodates an extensive range of (hetero)aryl
bromide and fluorinated alcohols and was adapted for cross-
coupling with [18F]trifluoroethanol.
We investigated the Pd-catalyzed cross-coupling reaction
between trifluoroethanol and 1a, a demanding aryl bromide
considering the lack of an activating electron-withdrawing
group attached directly to the aromatic ring, and the presence
of mildly acidic protons α to the ketone (Table 1). We
Table 1. Reaction Optimization
The scope of the reaction with respect to the aryl bromide
was explored next (Scheme 1). Various electron-rich aryl
bromides underwent coupling with trifluoroethanol in high
yield after 0.5 to 2 h, with morpholinyl and methoxy
substitution well tolerated (2b to 2d). Product 2c was isolated
in 89% yield, while it has been reported to form in 69% NMR
yield using NaOtBu and 1,4-dioxane.10 The reaction conditions
were applied to the double C−O cross-coupling of 1,4-
dibromobenzene to yield 2f in a single step. Electron-deficient
aryl bromides also underwent coupling in excellent yields
(substrates 2h to 2k). A wide range of functional groups were
well tolerated including sulfone, ester, ketone, aldehyde, and
nitro groups, some bearing acidic α-protons. For many
substrates, the reaction temperature could be decreased to
80 °C without detrimental impact on reactivity. In contrast,
when electron-rich aryl bromides such as 1d were reacted with
trifluoroethanol at 80 °C, starting material was recovered
almost quantitatively. Heteroaryl bromides also underwent
coupling (2n−2r), with 80 °C being adequate for some
substrates. Pyridines, pyrimidine, quinoline, and quinoxaline
substrates all coupled effectively. This cross-coupling method
was applied to prepare the drug precursor N-Boc-flecainide
(2t).
Aryl chlorides were also investigated as substrates. The
activated aryl chloride fenofibrate 1v underwent C−O cross-
coupling in excellent yield. A control experiment excluding
tBuBrettPhos Pd G3 afforded no product, ruling out a
nucleophilic aromatic substitution mechanism. Contrarily,
electron-rich aryl chloride 1b(Cl) afforded only traces of the
coupled product. For preparing compounds 2a, 2u, and 2w,
the conditions reported herein were compared directly to use
of NaOtBu with 1,4-dioxane (NMRY for conditions herein vs
NMRY* for NaOtBu conditions, Scheme 1).10 In these cases,
higher yields were observed using Cs2CO3 and toluene.
Various other fluorinated alcohols were successfully coupled
to aryl bromides under our optimized conditions. Notably, in
contrast to 2,2,2-trifluoroethanol, coupling reactions of
electron-rich aryl bromides with 2,2-difluoroethanol could be
carried out at 80 °C. Furthermore, electron-poor aryl bromides
and heteroaryl bromides successfully coupled with 2,2-
difluoroethanol. 2-Fluoroethanol also reacted in high yield
(4d). In a competition experiment in which equimolar
quantities of 2,2,2-trifluorethanol, 2,2-difluoroethanol, and 2-
Yield
a
Entry
1
Catalyst
Solvent
Base
(%)
BrettPhos,
Pd2(dba)3
toluene
Cs2CO3
0
2
3
XPhos, Pd2(dba)3
toluene
toluene
Cs2CO3
Cs2CO3
0
0
tBuXPhos,
Pd2(dba)3
4
tBuBrettPhos,
Pd2(dba)3
toluene
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
51
70
0
5
tBuBrettPhos Pd
toluene
toluene
toluene
toluene
G3*
tBuBrettPhos Pd
6
G3*
7
tBuBrettPhos Pd
8
G3*
8
tBuBrettPhos Pd
K3PO4
70
48
61
33
34
48
G3*
9
tBuBrettPhos Pd
1,4-dioxane
(80 °C, 16 h)
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
G3*
10
11
12
13
tBuBrettPhos Pd
1,4-dioxane
G3*
tBuBrettPhos Pd
tert-amyl alcohol
toluene (80 °C)
toluene (30 mins)
G3*
tBuBrettPhos Pd
G3*
tBuBrettPhos Pd
G3*
a
Yields determined by 19F qNMR with PhCF3 as internal standard.
For entries 1−4, 0.5 mol % of Pd2(dba)3 and 1.25 mol % of ligand
were used. For entries 6−13, 1 mol % of the precatalyst was used.
screened short reaction durations with the foresight of applying
the coupling for introducing 18F-labeled motifs. Under
conditions similar to those reported by Singh, using BrettPhos,
Pd2(dba)3, and Cs2CO3 in toluene, no coupled product was
formed after 1 h (entry 1).6 Switching the ligand to either
t
XPhos or BuXPhos also resulted in no product formation
(entries 2 and 3).15,16 Using BuBrettPhos as ligand, the
t
B
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Letter
The scalability of the C−O cross-coupling reaction was
demonstrated by the gram-scale coupling of 2,2,3,3-tetrafluor-
opropanol and 3-bromobenzaldehyde for the preparation of
2u, an intermediate in the synthesis of the drug idalopirdine
(Figure 1).20 For this scale-up, the catalyst loading was
reduced to 0.5 mol % without impacting the yield of isolated
product. On a larger scale, use of Pd2(dba)3 with tBuBrettPhos
Scheme 1. Pd-Catalyzed C−O Cross-Coupling of
Fluorinated Alcohols with Aryl Bromides (Yields of Isolated
Products Are Quoted)
t
rather than BuBrettPhos Pd G3, and K3PO4 rather than
Cs2CO3, may be preferable to reduce costs.
The short reaction time and high efficiency of incorporation
of the fluorinated alcohol encouraged the use of this cross-
coupling reaction for the introduction of 18F-labeled motifs,
specifically [18F]trifluoroethanol (Scheme 2A). Preparation of
Scheme 2. (A) Approaches to [18F]Trifluoroethyl Ethers;
(B) Previously Reported Synthesis of [18F]Trifluoroethanol
Requiring Multiple Distillations and AlH3; (C) Our
Approach for the Synthesis of [18F]Trifluoroethanol; (D)
Coupling of Aryl Bromides with [18F]Trifluoroethanol
a
2 mol % tBuBrettPhos Pd G3, 3 equiv of Cs2CO3 and
b
c
trifluoroethanol used. Yield determined by 19F qNMR. Reaction
duration of 4 h. NMRY = NMR yield under the conditions reported
herein. NMRY* = NMR yield using NaOtBu in 1,4-dioxane at 40 to
80 °C.
a
RCY = radiochemical yield, determined by integration of the radio-
HPLC trace (prior to HPLC for compound 9).
fluoroethanol were reacted with substrate 1d at 100 °C for 2 h
under the conditions reported herein, the trifluoroethyl,
difluoroethyl, and fluoroethyl ethers were formed in an
∼1:3:2 ratio, respectively. This supports decreased reactivity
of 2,2,2-trifluoroethanol relative to 2,2-difluoroethanol and 2-
fluoroethanol.
an 18F-trifluoroethyl ether has been reported by the Riss group
via alkylation of the corresponding phenol with [18F]-
trifluoroethyl tosylate (Scheme 2A).21−24 Here, we propose a
complementary approach that utilizes a C−O cross-coupling
event to prepare 18F-trifluoroethyl ethers [18F]2 from aryl
bromides and [18F]trifluoroethanol. [18F]Trifluoroethanol has
C
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previously been synthesized by nucleophilic radiofluorination
of ethyl bromodifluoroacetate 5 with [18F]KF/K2.2.2, followed
by reduction with AlH3 prepared in situ from LiAlH4 and
H2SO4 (Scheme 2B).25 The [18F]trifluoroethanol was not used
directly and required an additional step to generate [18F]-
trifluoroethyl triflate, which was then applied for amine
alkylation. Multiple distillations were used to purify ethyl
[18F]trifluoroacetate 7 and [18F]trifluoroethanol.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02347.
■
sı
Experimental data, characterization data, 18F-radiotraces
(PDF)
AUTHOR INFORMATION
Corresponding Author
We sought to develop an [18F]trifluoroethanol synthesis
without distillation, using instead HPLC purification. We also
aimed to replace AlH3 with NaBH4, a reducing agent readily
available and easy to handle. Our initial experiments showed
that ethyl trifluoroacetate [18F]6 is unstable under reversed-
phase HPLC conditions. Therefore, we targeted menthol
[18F]trifluoroacetate [18F]9, an ester which is more resistant to
hydrolysis and therefore amenable to purification by reversed-
■
́
Veronique Gouverneur − Chemistry Research Laboratory,
Oxford University, Oxford OX1 3TA, U.K.; orcid.org/
0000-0001-8638-5308; Email: veronique.gouverneur@
chem.ox.ac.uk
Authors
Robert Szpera − Chemistry Research Laboratory, Oxford
University, Oxford OX1 3TA, U.K.
Patrick G. Isenegger − Chemistry Research Laboratory, Oxford
University, Oxford OX1 3TA, U.K.
Maxime Ghosez − Chemistry Research Laboratory, Oxford
University, Oxford OX1 3TA, U.K.
Natan J. W. Straathof − Chemistry Research Laboratory,
Oxford University, Oxford OX1 3TA, U.K.
Rosa Cookson − Medicines Research Centre, GlaxoSmithKline
plc, Stevenage, Hertfordshire SG1 2NY, U.K.
David C. Blakemore − Medicine Design, Pfizer Inc., Groton
Connecticut 06340, United States
Paul Richardson − Medicine Design, Pfizer Inc., San Diego,
California 92121, United States
phase HPLC (Scheme 2C). Under conditions slightly modified
26
́
from those previously reported by Szabo and Schou,
synthesis of [18F]9 was achieved in 27 10% radiochemical
yield (RCY) using [18F]TBAF and DBU in 1,3-dimethyl-2-
imidazolidinone (DMI).27 After HPLC purification and
reformulation into 1,4-dioxane, reduction using NaBH4
afforded [18F]trifluoroethanol in 98
1% RCY. Menthol,
formed during the reduction step, was found to be unreactive
under the conditions applied for C−O cross-coupling, and
therefore a purification step by filtration to remove salts was
sufficient. 1,4-Dioxane was used as the reaction solvent, as it
afforded high yields for the reduction (toluene performed
poorly) and proved highly suitable for the subsequent C−O
cross-coupling (Table 1, entry 10). This modification was
advantageous by avoiding a second reformulation step.
Under slightly modified coupling conditions, [18F]-
trifluoroethanol was coupled with aryl bromide 1a and
naphthyl bromide 1l to afford the desired cross-coupled
[18F]trifluoroethyl ethers (Scheme 2D). Radio-HPLC showed
clean reaction profiles, with mainly the 18F-labeled product and
unreacted [18F]trifluoroethanol. Extending the reaction
duration beyond 20 minutes did not increase the RCY. Our
study showed that the coupling was sensitive to the water
content in the [18F]trifluoroethanol solution; drying of
menthol [18F]trifluoroacetate [18F]9 under a flow of nitrogen
was essential prior to reformulation in 1,4-dioxane.27 While Pd-
mediated C−N and C−C cross-coupling has been used for
introduction of 18F-labeled motifs,28 this work supports the
feasibility of 18F-radiolabeling by Pd-mediated C−O cross-
coupling.
In conclusion, we have developed a protocol for Pd-
catalyzed cross-coupling between fluorinated alcohols and
(hetero)aryl bromides using the mild base Cs2CO3; the
reaction tolerates various electronic patterns on the arene ring,
a wide range of functional groups including those with mildly
acidic α-protons, and proceeds over a short duration. An
activated aryl chloride has also been shown to couple
effectively. In addition, K3PO4 was found to be a cheaper
alternative base to Cs2CO3. The utility of the coupling has
been further demonstrated with a new disconnection approach
to 18F-labeled trifluoroethyl ethers consisting of C−O cross-
coupling of aryl bromides with [18F]trifluoroethanol.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02347
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1) for a
studentship to R.S. (Oxford University), generously supported
by AstraZeneca, Diamond Light Source, Defence Science and
Technology Laboratory, Evotec, GlaxoSmithKline, Janssen,
Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. We also
acknowledge the Swiss National Foundation
(P2BSP2_178609, P.G.I., Oxford University), ERASMUS
(M.G., Oxford University), and the EPSRC (EP/R511742/1,
N.J.W.S., Oxford University) for funding. We acknowledge
Jeroen B. I. Sap (Oxford University) and Florian Guibbal
(Oxford University) for assistance with radiochemical experi-
ments. We also acknowledge Stephen Hyde (Oxford
University) for conducting preliminary experiments, Adeline
W. J. Poh (Oxford University) for synthesizing an
intermediate, and Eddie Toma (Oxford University) for
assistance using the glovebox.
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