Merging visible-light photocatalysis and transition-metal catalysis in the copper-catalyzed trifluoromethylation of boronic acids with CF3I

Article abstract of DOI:10.1021/ja301553c

This communication describes the development of a mild method for the cross-coupling of arylboronic acids with CF₃I via the merger of photoredox and Cu catalysis. This method has been applied to the trifluoromethylation of electronically diverse aromatic and heteroaromatic substrates and tolerates many common functional groups.

Full text of DOI:10.1021/ja301553c

Communication
pubs.acs.org/JACS
Merging Visible-Light Photocatalysis and Transition-Metal Catalysis
in the Copper-Catalyzed Trifluoromethylation of Boronic Acids with
CF3I
Yingda Ye and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
*
S Supporting Information
5
b,e,g
3b,5a
Togni’s reagent,
or TESCF3
]. Finally, many protocols
ABSTRACT: This communication describes the develop-
ment of a mild method for the cross-coupling of
exhibit limited substrate scope/generality.
One attractive approach to begin to address these limitations
would be to access alternative and potentially complementary
mechanistic manifolds. We reasoned that a radical pathway
(Scheme 1c) would be particularly interesting, since CF · can
be generated under mild, neutral conditions from commercially
arylboronic acids with CF I via the merger of photoredox
3
and Cu catalysis. This method has been applied to the
trifluoromethylation of electronically diverse aromatic and
heteroaromatic substrates and tolerates many common
functional groups.
3
7
available and relatively inexpensive CF I. In particular, we
3
noted recent reports by MacMillan demonstrating the
conversion of CF I to CF · at room temperature in the
3
3
rifluoromethyl substituents are widely prevalent in
pharmaceuticals and agrochemicals. Thus, the develop-
presence of a photocatalyst, visible light, and a reductant
1
8
T
(Scheme 2). On the basis of this work, we hypothesized that
ment of mild and versatile synthetic methods for generating
carbon−CF bonds has become a field of intense research
Scheme 2. Proposed New Pathway for Radical
Trifluoromethylation of Boronic Acids via Cu/Ru Catalysis
3
2,3
4,5
effort. Over the past three years, a variety of Pd and Cu -
based cross-coupling protocols have been developed for the
trifluoromethylation of aryl halides, arylboronic acids, and
aromatic carbon−hydrogen bonds. As exemplified in Scheme
1a,b for the Cu-catalyzed trifluoromethylation of boronic acids,
Scheme 1. Cu-Mediated/Catalyzed Trifluoromethylation of
Boronic Acids
the merger of visible-light photocatalysis (to generate CF ·)
3
with Cu catalysis (to generate reactive Cu−aryl species)
(
Scheme 2) might provide a mild and general method for the
trifluoromethylation of boronic acid derivatives.
Our initial investigations focused on the Cu-catalyzed/Ru-
photocatalyzed trifluoromethylation of 1,1′-biphenyl-4-ylbor-
onic acid with CF I to form 4-(trifluoromethyl)-1,1′-biphenyl
3
(
1a). We were delighted to find that Cu/Ru catalysis provided
product 1a in modest to excellent yields under a number of
conditions (Table 1). A variety of different bases (to promote
transmetalation) and reaction solvents were screened for this
reaction [see Table S1 in the Supporting Information (SI)],
and the use of K CO in N,N-dimethylformamide (DMF)
−
4c,e,l,5i
+
4f,5d,e
these transformations involve “CF ”
or “CF ”
3
3
reagents and are generally believed to proceed via nucleophilic
or electrophilic transfer of the CF group to the Cu center,
respectively. Many of these new methods represent significan6t
progress in comparison to the traditional Swarts reaction,
which requires highly reactive fluorinating reagents and harsh
conditions.
3
2
3
I
proved optimal. Cu catalysts generally performed better than
II
Cu salts, and the highest yield of 1a (76%) was obtained with
CuOAc. The optimal conditions were as follows: 1 equiv of
Despite these important advances, most current strategies for
boronic acid 1, 5 equiv of CF I, 1 equiv of K CO , 20 mol %
3
2
3
aryl−CF cross-coupling suffer from one or more limitations. In
CuOAc, and 1 mol % Ru(bpy) Cl ·6H O with irradiation from
3
3 2 2
2
b,3a,b,4d
some cases, temperatures greater than 100 °C
and/or
two 26 W household light bulbs. The major side product was 4-
3a
t
4j
strong acids or bases (trifluoroacetic acid or BuOK ) are
necessary. Other methods require expensive trifluoromethylat-
Received: February 16, 2012
3a,4f,5d
ing reagents [e.g., S-(trifluoromethyl)thiophenium salts,
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja301553c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Reaction Between 1 and CF3I
Scheme 3. Substrate Scope for Cu/Ru-Catalyzed
a
Trifluoromethylation of Boronic Acids
a
General conditions: substrate (0.05 mmol, 1 equiv), CF I (5 equiv),
3
[
Cu] (0.2 equiv), Ru(bpy) Cl ·6H O (0.01 equiv), base (1 equiv),
3
2
2
DMF (0.17 M in substrate), 60 °C, 12 h, 26 W compact fluorescent
light bulb. 1 F NMR yields are shown. General conditions, but with
9
b
c
d
no light. General conditions, but with no CuOAc. General
conditions, but with no Ru(bpy) Cl ·6H O.
3
2
2
iodo-1,1′-biphenyl (formed in 9% yield under the optimal
conditions).
This Cu/Ru-catalyzed coupling between 1 and CF I is
3
practical and easily scalable. The reaction in Table 1, entry 6
was performed on a 0.05 mmol scale and provided a 76% yield
1
9
as determined by F NMR spectroscopy and GC−MS. Nearly
identical isolated yields (72 and 70%) were obtained on 1 and 5
mmol scales, respectively.
A variety of control reactions were conducted to establish the
role of each component of the reaction mixture. As shown in
Table 1, entries 10−12, when light, CuOAc, or Ru-
a
General conditions: substrate (1 equiv), CF I (5 equiv), [Cu] (0.2
3
equiv), Ru(bpy) Cl ·6H O (0.01 equiv), K CO (1 equiv), DMF (0.17
M in substrate), 60 °C, 12 h, 26 W compact fluorescent light bulb.
Isolated yields (≥95% purity) are shown, unless otherwise noted.
NMR yield. 0.5 equiv of CuOAc. Isolated as a 1:1 mixture with
inseparable protodeboronated product. 0.1 equiv of CuOAc. Isolated
as a 10:1 mixture with inseparable protodeboronated product. 3 equiv
of CF I. Reaction run at 70 °C. Reaction run at 40 °C. 0.05 equiv of
CuOAc.
3
2
2
2
3
(
bpy) Cl ·6H O was excluded under otherwise identical
3 2 2
9
b
19
F
conditions, ≤3% yield of 1a was obtained. These results
clearly indicate the necessity that all three components be
present to achieve high yields under these conditions,
consistent with the major pathway to 1a proceeding via dual
Cu/Ru catalysis (see below). The iodinated side product 4-
iodo-1,1′-biphenyl was also subjected to the reaction conditions
to establish whether it is an intermediate in the boronic acid
trifluoromethylation process. A <2% yield of the aryl−CF3
product was formed, strongly suggesting that the major
pathway to 1a does not involve an iodinated intermediate.
Finally, the reactivity of boronic acid substrate 1 was
investigated under conditions reported by Baran and
MacMillan to promote C−H trifluoromethylation reactions
c
d
e
f
g
h
i
j
3
embedded in the estrone framework underwent trifluorome-
thylation to generate 22a in 80% isolated yield. Most
remarkably, 4-iodophenylboronic acid underwent selective
trifluoromethylation to form 7a, leaving the aryl iodide intact
for subsequent functionalization. This demonstrates the
complementarity of this method to many other Cu-catalyzed
trifluoromethylation protocols.
10
5a,c,f
via in situ generation of CF ·. In both cases, a <2% yield of 1a
Furthermore, it provides
3
was observed. These results indicate that 1a is not formed by
additional evidence against the possibility of aryl iodide
intermediates in this transformation.
the direct reaction of CF · with the boronic acid.
3
This transformation was next applied to a variety of different
aryl- and heteroarylboronic acid derivatives. The representative
examples shown in Scheme 3 were selected to highlight not
The use of sterically hindered substrates such as 1-naphthyl-
and 2,4,6-trimethylphenylboronic acid is typically challenging
12
for copper-mediated cross-coupling reactions. As shown in
Scheme 3, similar effects were seen in the current trans-
formation, with products 9a and 10a being formed in modest
yields (42 and 39%, respectively). In these cases, competing
protodeboronation was problematic, and the major side
products were naphthalene and mesitylene, respectively.
Heteroaromatic substrates are of particular relevance to the
pharmaceutical and agrochemical industries because of the
11
only the broad scope but also the limitations of this method.
Aromatic boronic acids bearing either electron-donating (tert-
butyl, methoxy) or electron-withdrawing (cyano, trifluorometh-
yl, fluoro, methyl ester) substituents underwent trifluorome-
thylation in high yield. A variety of different potentially reactive
functional groups (aromatic alcohols, ketones, aldehydes, esters,
and amides) were quite well-tolerated. A boronic acid
B
dx.doi.org/10.1021/ja301553c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
1
3
III
prevalence of heteroarenes in biologically active compounds.
Cu (CF ) intermediate. Subsequent base-promoted trans-
3
III
Boronic acids derived from pyridine, quinoline, furan, and
thiophene all underwent trifluoromethylation in modest to
metalation between Cu and the arylboronic acid would afford
III
Cu (aryl)(CF ), which could undergo aryl−CF bond-forming
3
3
1
0
good yields. In some of these cases, modification of the
catalyst loading and/or reaction temperature was needed to
achieve the optimal yield. Importantly, with all of these
substrates, trifluoromethylation of the boronic acid moiety
outcompeted uncatalyzed C−H trifluoromethylation of the
reductive elimination to release the organic product and
I
15
regenerate the Cu catalyst.
In summary, this communication describes a mild and
general approach for the Cu-catalyzed/Ru-photocatalyzed
trifluoromethylation and perfluoroalkylation of arylboronic
acids. This method takes advantage of visible-light photoredox
heterocycle with CF ·. Thus, this method provides an attractive
route for the site-selective installation of CF substituents into
3
catalysis to generate R · under mild conditions and merges it
3
F
these scaffolds.
with copper-catalyzed arylboronic acid functionalization. The
combination has enabled the trifluoromethylation of a wide
variety of aromatic and heteroaromatic substrates bearing many
common functional groups. This transformation demonstrates
the feasibility of achieving Cu-catalyzed trifluoromethylation via
a radical pathway. Furthermore, it represents a new example of
combining organometallic and photoredox catalysis to achieve
Related conditions could also be applied to analogous
perfluoroalkylation reactions. This is a significant advantage of
the current method, since perfluoroalkyl analogues of other
common trifluoromethylating reagents [e.g., R SiCF , S-
3
3
(
trifluoromethyl)thiophenium salts, or Togni’s reagent] are
expensive and/or not commercially available. As shown in
Scheme 4, perfluorobutyl and perfluorodecyl iodides reacted
with 1 to afford products 1b and 1c, respectively, in good yields
under the Cu/Ru-catalyzed conditions.
16
synthetically useful organic transformations.
ASSOCIATED CONTENT
Supporting Information
■
*
S
a
Experimental details and spectroscopic and analytical data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 4. Cu/Ru-Catalyzed Perfluoroalkylation of 1
AUTHOR INFORMATION
Corresponding Author
mssanfor@umich.edu
■
Notes
The authors declare no competing financial interest.
a
General conditions: substrate (1 equiv), CuOAc (0.5−1 equiv),
Ru(bpy) Cl ·6H O (0.01 equiv), K CO (1 equiv), DMF (0.17 M in
substrate), 60 °C, 12 h, 26 W compact fluorescent light bulb. Isolated
yields are shown. 5 equiv of C F I, 0.5 equiv of CuOAc. 1.2 equiv of
3
2
2
2
3
ACKNOWLEDGMENTS
■
b
c
We thank the NIH NIGMS (GM073836) for financial support
and Dr. Rebecca Loy and Dr. Brannon Gary for helpful
discussions.
4
9
C F I, 1 equiv of CuOAc.
10 21
While a detailed mechanistic picture of this transformation
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(
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dx.doi.org/10.1021/ja301553c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX