Cu,8,9 and Ni10 promoted nucleophilic fluorinations. Most
relevant to the current work, Hartwig recently disclosed the
CuI/III-mediated fluorination of ArI with AgF at 140 °C.8b
However, this method is limited by the requirement for a
noble metal fluoride source, superstoichiometric quantities
of Cu, and high temperatures.
Table 1. Reaction Optimizationa
We hypothesized that Cu salts could potentially catalyze
the fluorination of diaryliodonium salts. Such a transfor-
mation would offer several key advantages over known
nucleophilic fluorination methods.11 First, the highly elec-
trophilic Ar2Iþ salts are expected to undergo fast oxidative
addition to CuI (the rate limiting step in Hartwig’s ArI
reactions).8b This should enable the use of much milder
reaction conditions compared to the related ArI fluorina-
tions. Second, [MesꢀIꢀAr]þ (Mes = mesityl) derivatives
are well-known to undergo sterically controlled oxidative
addition at CuI, with selective transfer of the smaller aryl
group.11,12 Such selectivity would be highly complemen-
tary to the analogous uncatalyzed fluorinations of
[MesꢀIꢀAr]þ13 and could potentially enable the fluorina-
tion of challenging electron rich substrates. Finally, the
desired [MesꢀIꢀAr]þ reagents are readily synthetically
accessible from commercially available MesI(OAc)2 and
aryl boronic acids.14
time
yield
(%)b
entry
[Cu]
(h)
additive
none
1:2
1
2
3
4
5
(tBuCN)2CuOTf
18
18
18
3
71
57
85
81
30
96:4
96:4
98:2
97:3
20:80
CuOTf benzene
none
3
Cu(OTf)2
Cu(OTf)2
none
none
18-crown-6
18-crown-6
3
a Conditions: [MesꢀIꢀPh]BF4 (1 equiv), [Cu] (0.2 equiv), KF
(1.1 equiv), additive (0 or 0.4 equiv), DMF (0.1 M), 60 °C. b Combined
yield of 1 and 2 determined by 19F NMR.
opposite selectivity under these conditions (ratio of
1:2 = 20:80, entry 5).13
We next investigated the scope of this transformation
with substrates of general structure [MesꢀIꢀAr]BF4
(Ar = electron rich (hetero)aromatic ring), as these are
typically the most challenging substrates for nucleophilic
fluorination reactions.1,2 As summarized in Figure 1,
fluorinated products 3ꢀ16 were obtained in good yield
and high selectivity. All products with boiling points over
180 °C were isolated, and the purity of isolated products
was >98% unless otherwise noted. Remarkably, even
2-fluorothiophene (16) could be formed, albeit under more
forcing conditions (130 °C for 2 h).5 With these electron
rich substrates, the analogous Cu-free reactions proceeded
in modest yields and provided MesꢀF (2) as the major
product.
Substrates bearing electron-withdrawing substituents
on the Ar ring were also investigated. When the sub-
stituents were moderately electron-withdrawing, Cu cata-
lysis resulted in significant enhancements in yield and
selectivity (e.g., Figure 1, 18ꢀ22) relative to the uncata-
lyzed fluorination reaction. In contrast, substrates with
stronglyelectron withdrawing groups (e.g., 24ꢀ26) reacted
in good yield and selectivity in both the presence and
absence of Cu. This trend is consistent with prior
reports of uncatalyzed fluorination of diaryliodonium
reagents.13
We initially examined (tBuCN)2Cu(OTf) as a catalyst
for the fluorination of [MesꢀIꢀPh]BF4. This Cu complex
was selected because it proved optimal in Hartwig’s ArI
fluorination.8b Evaluation of a number of different condi-
tions and fluoride sources (see Supporting Information for
full details) revealed that this reaction proceeds smoothly
over 18 h at just 60 °C using 20 mol % Cu and 1.1 equiv of
KF. (tBuCN)2Cu(OTf) afforded a 71% yield and good
selectivity for PhF (1) over MesF (2) (96:4 ratio of 1:2)
(Table 1, entry 1). Both CuI(OTf) benzene and CuII(OTf)2
3
were also effective catalysts (entries 2 and 3), with the latter
providing the highest yield (85%) and selectivity (98:2).
The reaction time could be lowered from 18 to 3 h by the
addition of 40 mol % of 18-crown-6 with only minimal
erosion of yield and selectivity (entry 4). Under these
conditions, fluorination proceeded in 81% yield with
97:3 selectivity for 1 over 2. The background reaction
(without Cu(OTf)2) proceeded in low yield (30%) and
(9) Cu-mediated fluorination with Fþ reagents: (a) Ye, Y.; Sanford,
M. S. J. Am. Chem. Soc. 2013, 135, 4648. (b) Fier, P. S.; Luo, J.; Hartwig,
J. F. J. Am. Chem. Soc. 2013, 135, 2552.
(10) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134,
17456.
(11) Examples of Cu-catalyzed reactions with Ar2Iþ: (a) Lubriks, D.;
Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436. (b) Phipps,
R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am.
Chem. Soc. 2012, 134, 10773. (c) Zhu, S.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2012, 134, 10815. (d) Phipps, R. J.; Grimster, N. P.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e) Kang, S. K.; Yamaguchi, T.;
Kim, T. H.; Ho, P. S. J. Org. Chem. 1996, 61, 9082.
(12) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(13) Reactions of nucleophiles with unsymmetrical diaryliodonium
salts generally afford selective substitution of the more hindered (i.e.,
ortho-substituted) and more electron-deficient aryl group. (a) Grushin,
V. V. Acc. Chem. Res. 1992, 25, 529. (b) Grushin, V. V.; Demkina, I. I.;
Tolstaya, T. P. J. Chem. Soc., Perkin Trans. 2 1992, 505. (c) Chun, J. H.;
Lu, S.; Lee, Y. S.; Pike, V. W. J. Org. Chem. 2010, 75, 3332.
(14) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052.
One particularly noteworthy substrate in this series is
chloropyridine 23. Cu-catalyzed fluorination generated
23 in a modest 33% yield but with high selectivity for
fluorination at the 5-position. This substitution pattern is
often challenging to access in nucleophilic fluorination
reactions due to the high propensity of 2-chloropyridines
to participate in SNAr.3
As expected, a steep erosion in selectivity was observed
with electron rich substrates bearing ortho-substituents
(eq 1). For instance, 27 underwent unselective fluorination
to provide a 62% yield of a 50:50 mixture of 28 and 2.
In contrast, the electronically similar, but less hindered,
B
Org. Lett., Vol. XX, No. XX, XXXX