Mild copper-mediated fluorination of aryl stannanes and aryl trifluoroborates

Article abstract of DOI:10.1021/ja400300g

This communication describes a mild copper-mediated fluorination of aryl stannanes and aryl trifluoroborates with N-fluoro-2,4,6-trimethylpyridinium triflate. This protocol demonstrates broad substrate scope and functional group tolerance, and does not require the use of any noble metal additives. The reaction is proposed to proceed via an arylcopper(III) fluoride intermediate.

Full text of DOI:10.1021/ja400300g

Communication
pubs.acs.org/JACS
Mild Copper-Mediated Fluorination of Aryl Stannanes and Aryl
Trifluoroborates
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
Scheme 1. Strategies for Cu-Mediated Aryl−F Coupling
ABSTRACT: This communication describes a mild
copper-mediated fluorination of aryl stannanes and aryl
trifluoroborates with N-fluoro-2,4,6-trimethylpyridinium
triflate. This protocol demonstrates broad substrate
scope and functional group tolerance, and does not
require the use of any noble metal additives. The reaction
is proposed to proceed via an arylcopper(III) fluoride
intermediate.
ryl fluorides are extremely important structural motifs that
A
feature prominently in pharmaceuticals, agrochemicals,
1
organic materials, and biological imaging agents. As a result,
significant recent effort has focused on the development of new
2
synthetic procedures for the generation of CAryl−F bonds.
sources without introducing extra ligands that might lead to
unproductive competing reductive elimination from the metal
center.
To test this hypothesis, we initially explored the Cu-mediated
fluorination of aryl stannane 1 with commercial electrophilic
Transition metal-mediated and/or catalyzed aryl−fluoride
coupling reactions are of particular interest, because the rate,
selectivity, and functional group tolerance of these trans-
formations can often be modulated by changing the metal and
4
−6,8−10
3
its ligand environment. Over the past 6 years, several different
fluorinating reagents. These studies revealed that the
4
t
palladium and silver-based protocols have been developed to
combination of 1, ( BuCN) CuOTf, and N-fluoro-2,4,6-
2
effect aryl−fluoride bond formation via cross-coupling with aryl
trimethylpyridinium triflate (NFTPT) in EtOAc at 25 °C for
12 h afforded modest (6%) yield of the desired product 1a
(Scheme 2a; see Tables S1−S4 for full optimization details).
The major byproduct of this transformation is biaryl 1b derived
from unproductive homocoupling of the aryl stannane. We
5
,6
7
8
C−H bonds, aryl triflates, aryl stannanes, aryl boronic
9
10
acids, and aryl silanes. In several cases, these methods have
been successfully applied to the late-stage fluorination of
complex molecules. However, despite these significant
advances, the reactions generally remain limited by the
requirement for expensive and toxic noble metals.
reasoned that its formation could be circumvented by initial
t
oxidation of ( BuCN) CuOTf with NFTPT to form putative
2
A key unmet need in the field is a mild and general aryl
Cu(III)−F intermediate B (Scheme 1) followed by addition of
the stannane 1. As shown in Scheme 2b, this sequential
addition protocol resulted in dramatically improved yield of 1a
(74%) along with <4% of 1b. Notably, the control reaction (in
the absence of Cu) did not afford a detectable quantity of 1a.
We next applied this room temperature fluorination protocol
to a variety of different aryl stannanes. As shown in Scheme 3,
aryl stannanes bearing electron-donating and withdrawing
substituents underwent fluorination in good to excellent yields
under these conditions. The presence of ortho-substituents was
also well-tolerated. Notably, in all of the examples shown in
Scheme 3, no fluorination products were detected in the
absence of Cu (see Table S5 for the results of these control
experiments).
fluorination protocol mediated by an earth abundant first row
1
1
metal such as Cu. In a seminal report in 2011, Ribas and co-
workers demonstrated a proof-of-concept example of aryl−F
1
2,13
bond formation at a macrocyclic aryl−Cu(III) complex.
More recently, Fier and Hartwig reported the Cu-mediated
conversion of a broader scope of aryl iodides to aryl fluorides
14
using AgF as the fluoride source at 140 °C. As shown in
Scheme 1a, this transformation is also believed to proceed via a
III
Cu (aryl)(fluoride) intermediate A formed by oxidative
addition of Ar−I to Cu(I) and subsequent reaction with AgF.
Inspired by these exciting advances, we sought to develop a
milder and more versatile Cu(III)-mediated aromatic fluorina-
tion protocol. We hypothesized that an intermediate analogous
to A could be formed under less forcing conditions via the
With this proof of principle in hand, we next investigated
replacing the aryl stannanes with less toxic aryl−boron reagents.
+
combination of an electrophilic fluorinating reagent (F ) and an
5
,15,16
aryl organometallic species (Scheme 1b).
Importantly,
literature precedent in Pd- and Ag-catalyzed fluorination
reactions has shown that F reagents can serve as fluorine
Received: January 10, 2013
+
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja400300g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Cu-Mediated Fluorination of Aryl Stannanes
Table 1. Cu-Mediated Fluorination of Aryl Boron Reagents
Scheme 3. Substrate Scope for Cu-Mediated Fluorination of
a
Aryl Stannanes
a
General conditions: stannane (0.025 mmol, 1 equiv),
(tBuCN) CuOTf (1 equiv), NFTPT (2 equiv), EtOAc (0.1 M in
2
boron reagent), 25 °C, 12 h. Copper salt and NFPTP were prestirred
in solvent for 5 min, followed by addition of the substrate. Yields
determined by 19F NMR spectroscopy. Reaction conducted using
MeCN as solvent.
b
Substrates containing ortho-substituents also underwent
efficient fluorination under these optimized conditions. This
protocol is compatible with a variety of common functional
groups. Substrates bearing aryl aldehydes, ketones, amides, and
esters produced the aryl fluorides in good yields. Control
reactions (without added Cu) were conducted for all of the
1
7
a
t
substrates in Scheme 4. As shown in Table S10, the electron
deficient aryl trifluoroborates showed no background reaction
under these conditions. Furthermore, only traces of background
fluorination products (2−6%) were observed with the electron
General conditions: stannane (0.25 mmol, 1 equiv), ( BuCN) CuOTf
2
(
1 equiv), NFTPT (2 equiv), EtOAc (0.1 M in stannane), 25 °C, 12 h.
Copper salt and NFTPT were prestirred in solvent for 5 min, followed
by addition of the stannane.
spectroscopy. Isolated yield.
b
19
Yield determined by F NMR
d
c
Isolated product contained 8% of
e
rich substrates p-MeOC H BF K, MesBF K, and naph-
biphenyl (derived from protodestannylation). 1.2 equiv of
6
4
3
3
t
(
BuCN) CuOTf.
thlylBF K.
2
3
In summary, this communication describes a new method for
the Cu-mediated fluorination of aryl stannanes and aryl
trifluoroborates with an electrophilic fluorinating reagent. The
reactions proceed under very mild conditions (in many cases at
room temperature) and exhibit a broad substrate scope and
A series of p-FC H BX derivatives were examined under
6
4
n
identical conditions to those in Scheme 3. As shown in Table 1,
the aryl boron reagents generally afforded low to modest yields
under these conditions. In most cases, the major byproducts
were either unreacted starting material or fluorobenzene from
1
7
18
protodeboronation. The best result (46% yield) was obtained
with the aryl trifluoroborate substrate (entry 5). Optimization
of this reaction showed that changing the solvent to MeCN
resulted in an improvement in the yield to 58% (entry 6; see
Tables S6−S9 for full optimization details).
functional group tolerance. A Cu(I/III) mechanism is
III
proposed with a Cu (aryl)(fluoride) (A in Scheme 1) serving
19
as a likely intermediate. Importantly, this strategy takes
advantage of the dual role of the electrophilic fluorinating
20
reagent as both an oxidant for Cu(I) and a fluorine source.
The substrate scope for the copper-mediated fluorination of
aryl trifluoroborates is shown in Scheme 4. Aryltrifluoroborates
bearing electron-donating and electron-withdrawing substitu-
ents reacted to generate the aryl−F products in good yields.
Ongoing work is focused on effecting analogous fluorination
reactions using alternative oxidants in conjunction with
4a,e,21
nucleophilic fluoride sources.
B
dx.doi.org/10.1021/ja400300g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 4. Substrate Scope for Cu-Mediated Fluorination of
Aryl Trifluoroborates
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c
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(
(
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ASSOCIATED CONTENT
Supporting Information
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.
(
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■
*
S
(
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4
Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50, 3936.
(18) Inert atmosphere and dry reagents are required for all the
reactions in Schemes 3 and 4. Reactions conducted in air with
nondried reagents showed significantly reduced yields. See Supporting
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AUTHOR INFORMATION
Corresponding Author
mssanfor@umich.edu
■
(19) 19F NMR analysis of the reaction of ( BuCN) CuOTf with
t
2
NFTPT in EtOAc at room temperature shows a resonance at −123.0
ppm, which may correspond to a Cu(III)−F; however, this species is
formed in low yield (∼1%), so it is unclear whether it is responsible for
the observed reactivity. When this same reaction was conducted in the
presence of 10 equiv of THF, the Cu(III) complex recently
characterized by Hartwig [ref 15] was detected by F NMR
spectroscopy, albeit also in modest (∼18%) yield. See Supporting
Information for relevant spectra. Ongoing efforts are focused on
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
9
We thank the Dow Chemical Company for financial support.
We thank Dr. Douglas Bland and Dr. Gary Roth from Dow
Chemical for helpful discussions.
C
dx.doi.org/10.1021/ja400300g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
gaining further insights into the organometallic intermediates and the
mechanistic complexities of this transformation.
(
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Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 17456.
1
(
D
dx.doi.org/10.1021/ja400300g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX