Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids

Article abstract of DOI:10.1021/ja204861a

A silver-mediated cross-coupling of trifluoromethoxide with aryl stannanes and arylboronic acids to give aryl trifluoromethyl ethers is reported. This is the first report of a transition-metal-mediated C_aryl-OCF₃ bond formation.

Full text of DOI:10.1021/ja204861a

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pubs.acs.org/JACS
Silver-Mediated Trifluoromethoxylation of Aryl Stannanes and
Arylboronic Acids
Chenghong Huang, Theresa Liang, Shinji Harada, Eunsung Lee, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
S Supporting Information
b
Scheme 1. Trifluoromethoxylation
ABSTRACT: A silver-mediated cross-coupling of trifluoro-
methoxide with aryl stannanes and arylboronic acids to
give aryl trifluoromethyl ethers is reported. This is the first
report of a transition-metal-mediated CarylÀOCF3 bond
formation.
O-(trifluoromethyl)-dibenzofuranium salts under photoirradia-
tion at À100 °C.11 And Kolomeitsev has reported the synthesis
of phenyl and naphthyl trifluoromethyl ether via addition of
trifluoromethoxide to in situ generated benzyne and R-naphthyne,
respectively.5a
luorine incorporation often improves the properties of
pharmaceuticals, agrochemicals, and materials.1 Previous
F
research has resulted in the development of several trifluoro-
methylation2 and fluorination3 reactions via transition-metal-
mediated and catalyzed cross-coupling reactions. Despite the
utility of trifluoromethoxy arenes in pharmaceuticals and agro-
chemicals, in part due to their high stability toward metabolism,4
transition-metal-mediated cross-coupling reactions for trifluor-
omethoxylation (CarylÀOCF3) are currently unavailable. Diffi-
culties in CÀOCF3 bond formation can be attributed to the
reversible decomposition of trifluoromethoxide anion in solution
above room temperature to afford carbonic difluoride (bp: À84 °C)
and fluoride,5 as well as β-fluoride elimination6 from transition
metalÀtrifluoromethoxide complexes. Earlier this year, Buchwald
reported a Pd-catalyzed CarylÀSCF3 cross-coupling reaction.7
Thus far, the analogous reaction to make aryl trifluoromethyl
ethers has not been developed via Pd-catalyzed cross-coupling,
possibly due to the commonly employed reaction conditions
involving basic media at elevated temperature typically used for
challenging CÀX bond forming reactions;3n such conditions
may lead to decomposition of trifluoromethoxide anion before
CÀO bond formation. Herein, we report a silver-mediated cross-
coupling reaction of trifluoromethoxide 1 with aryl stannanes and
arylboronic acids to give aryl trifluoromethyl ethers (ArÀOCF3)
(Scheme 1). The reported trifluoromethoxylation reaction pro-
vides access to several novel aryl trifluoromethyl ethers under
conditions tolerant of a variety of functional groups.
Aryl trifluoromethyl ethers are conventionally made from
phenols via fluoroformate or chlorothionoformate intermediates,
followed by nucleophilic fluorination with antimony trifluoride,
hydrofluoric acid, or sulfur tetrafluoride at 100À160 °C.8 Only
structurally simple phenol derivatives can tolerate such reaction
conditions. Togni and co-workers have reported the successful
trifluoromethylation of primary and secondary alcohols with
electrophilic hypervalent iodine reagents.9 Similar attempts to
trifluoromethylate 2,4,6-trimethylphenol afforded products pri-
marily resulting from carbon trifluoromethylation and up to 15%
yield of the desired aryl trifluoromethyl ether.10 Umemoto and
co-workers have reported trifluoromethylation of phenols using
Here, we report a new strategy for the synthesis of aryl
trifluoromethyl ethers: trifluoromethoxylation of aryl nucleo-
philes by CarylÀO bond formation. Treatment of aryl stannanes
with trifluoromethoxide 1, F-TEDA-PF6 (4), and silver(I) hexa-
fluorophosphate (AgPF6) in a THF/acetone mixture at À30 °C
afforded the desired aryl trifluoromethyl ethers in 59À88% yield
(Table 1). Reagent 1 was prepared in situ from trifluoromethyl
trifluoromethanesulfonate, a nonfuming, hydrolytically stable liquid
that is commercially available and synthesized from triflic acid in
one step (see Supporting Information) and tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF). The trifluoromethoxy-
lation reaction tolerates functional groups like alcohols, halogens,
esters, ethers, alkenes, and ketones and can be applied to electron-
rich, electron-poor, and ortho-substituted arenes. Trifluoromethoxy-
lation can also be accomplished from arylboronic acids (Table 2).
While in general arylboronic acids are preferred reagents over
aryltin reagents, a two-step, one-pot procedure is required for the
presented trifluoromethoxylation of arylboronic acids. Treat-
ment of arylboronic acids with sodium hydroxide in methanol
followed by AgPF6 gave the corresponding aryl silver complexes,
which afforded aryl trifluoromethyl ethers upon addition of 1 and
4 in a THF/acetone solvent mixture. Currently, aryl nucleophiles
(both arylboronic acids and aryl stannanes) containing basic
nitrogen functional groups such as pyridine afford trifluoromethyl
ethers in substantially lower yield. For example, trifluoromethox-
ylation of 6-(tributylstannyl)quinoline gives 6-(trifluoromethoxy-
quinoline in 16% yield.
Both trifluoromethoxide salt and solvent have a significant
impact on the yield of trifluoromethoxylation. Deviation from
the reaction conditions described in Table 1 leads to byproducts,
which result from fluorodestannylation, hydroxydestannylation,
protodestannylation, and biaryl formation via homocoupling in
Received: May 26, 2011
Published: August 09, 2011
r
2011 American Chemical Society
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Table 1. Trifluoromethoxylation of Aryl Stannanes
Table 2. Trifluoromethoxylation of Arylboronic Acids
a Yield was determined by 19F NMR with 3-nitrofluorobenzene as
internal standard.
up to 50% combined yield. Byproduct formation was mini-
mized by reaction optimization (see Supporting Information),
but remains challenging for some substrates. For example, tri-
fluoromethoxylation of morphine derivative 25, the substrate
that affords the lowest yield among the examples shown in
Table 1, gave 24% of the corresponding fluorodestannylated and
10% the corresponding protodestannylated product, respec-
tively. Byproducts could be separated in all cases by column
chromatography.
The ability to form carbonÀheteroatom bonds at a lower
temperature thanusuallyemployedfor challengingCÀheteroatom
cross-coupling reactions3n,7 was key to the development of
trifluoromethoxylation because irreversible fluoride dissociation
from trifluoromethoxide could be prevented. The ability to effect
challenging carbonÀheteroatom bond transformations from
silver complexes may be a consequence of synergistic metalÀ
metal interactions that can lower activation barriers, as identified
for bimetallic catalysis.12 We hypothesize that trifluoromethox-
ylation proceeds from discrete high-valentsilver complexes, formed
via oxidation of aryl silver complexes with F-TEDA-PF6 (4),
followed by fluoride to trifluoromethoxide ligand exchange. The
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COMMUNICATION
use of 2 equiv of AgPF6 gave the highest observed yields of
trifluoromethoxylation, which could suggest a dinuclear silver
complex as a key intermediate in CÀOCF3 bond formation.
Bimetallic silver redox behavior has previously been proposed for
the Ag-mediated fluorination of aryl stannanes.3j,o,r In the
fluorination reaction, catalysis could be achieved but required
heating to 65 °C. A similar approach to achieve silver catalysis
for trifluoromethoxylation was not successful, presumably due
to the thermal instability of trifluoromethoxide.
In conclusion, a Ag-mediated trifluoromethoxylation of func-
tionalized aryl stannanes and arylboronic acids is reported. The
inability to efficiently trifluoromethoxylate arenes with basic
functional groups such as amines and pyridines is currently a
limitation of the reaction. In addition, the necessity for toxic
arylstannanes and the two-step procedure from arylboronic acids
currently limits the practicality of the presented trifluoromethoxy-
lation reaction. Currently, however, no other method is available
to trifluoromethoxylate aryl nucleophiles via cross-coupling. We
have addressed the fundamental challenges associated with
CarylÀOCF3 bond formation via silver redox chemistry. Future
efforts in the field should be directed at the development of more
practical reactions with broader functional group tolerance.
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectroscopic characterization for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
ritter@chemistry.harvard.edu
’ ACKNOWLEDGMENT
We thank Pingping Tang (Harvard), Jean Reynaud (Harvard),
and Ian Mangion (Merck) for helpful discussions as well as NSF
(CHE-0952753), the Massachusetts Life Science Center, NIH-
NIGMS (GM088237), and Merck for funding. T.R. is a Sloan
fellow, a Lilly Grantee, an Amgen Young Investigator, and an
AstraZeneca Awardee.
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