Organic Letters
Letter
directed functionalization of C−H bonds to allow the
conversion of simple styrene building blocks into an array of
functionalized intermediates (Figure 1c).
Table 1. Optimization of Nitrile-Directed C−H
Acetoxylation
The detailed scope of the copper-catalyzed cyanoborylation
of styrenes and related vinyl arenes was recently described
through work independently developed by Buchwald4 and our
lab,6 with mechanistic details elucidated through computa-
tional work by Liu.5 In order to explore the opportunity for
cyano-directed C−H functionalizations, a small set of 1,2-
diarylethanes were assembled either through Suzuki couplings
of the cyanoborylation products or by independent synthesis of
simpler derivatives through traditional olefination/hydro-
genation sequences or other standard organic transformations.
The model systems 3a−c, derived from vinyl arenes, can be
accessed in two steps in good overall yields (Figure 2).
Pd(OAc)2
(mol %)
additive
(equiv)
yield of meta product
m:p:o
a
a
entry
(%)
ratio
bc
,
1
2
3
4
5
6
7
8
10
10
20
20
20
20
20
20
−
−
−
48
51
78
29
36
70
55
−
9:2:1
12:4:1
20:1:4
11:1:1
10:1:1
7:1:1
15:2:1
AgOAc (3.0)
AgOAc (2.0)
AgOAc (1.0)
AgOAc (0.2)
AgTFA (0.2)
d
77 (74 )
a
Yields and regioselectivity ratios were determined by GC−MS and
b
GC-FID. The reaction was carried out with 2.0 equiv of PhI(OAc)2.
c
d
The reaction was carried out without Ac-Gly-OH ligand. 1.0 mmol-
scale reaction; isolated yield of a mixture of acetoxylation products in
a 2.0:1.0 meta:minor regioisomer ratio.
transformation was synthetically useful, challenges associated
with the separation of regioisomers prompted us to examine a
variety of additives to increase the selectivity for the distal
meta-acetoxylation (Table 1). Silver salts were examined
because of their ability to form heterobimetallic species that
are poised for C−H functionalization.28,29 Previous studies
have demonstrated that Lewis acids may lower the ring strain
and energy barrier for the formation of the necessary nitrile-
coordinated macrocyclic transition state. Although the
selectivity benefited from the inclusion of silver acetate
(AgOAc), the resulting yield was compromised (Table 1,
entry 4). Lowering the loading of AgOAc to 1.0 equiv restored
the chemical yield and maintained the selectivity, but lower
loadings of AgOAc were less effective (Table 1, entries 6 and
7). Ultimately, silver trifluoroacetate (AgTFA) proved to be
beneficial to the reaction and could be used in substoichio-
metric amounts to give a good yield (77%) and high selectivity
(15:2:1 m:p:o) (Table 1, entry 8). Previous template-directed
chemistry reports utilized MPAA ligands.30 We found that an
MPAA ligand (Ac-Gly-OH), was necessary for our method as
well, improving both the reactivity and selectivity of the
transformation (Table 1, entry 2). This class of ligands has
been shown to simultaneously stabilize the palladium species
and potentially aid in the C−H abstraction.30 Finally, control
studies showed not only that the position of the nitrile (ortho
to the linker) is important for the selectivity of the reaction but
also that substrates lacking the nitrile provide unselective and
slower oxidation (Scheme S1). Assessment of the general
reaction selectivity on this model substrate 3a then allowed for
further investigation of the synthetic utility of the meta-
acetoxylation in the context of other bibenzyls.
Figure 2. Representative synthetic strategy for access to 1,2-
diarylethylene derivatives. From ref 6.
a
Copper-catalyzed cyanoborylation followed by C(sp2)−C(sp3)
Suzuki cross-coupling of an aryl bromide allows a variety of
substituted benzonitriles to be accessed, as illustrated by the
conversion of styrene, 4-methylstyrene, and 2-vinylnaphthalene
to products 3a−c.6 This model scaffold not only represents
substructures of natural products, and pharmaceuticals
currently on the market,21 but the nitrile functionality is
present in a number of these motifs, as it can render unique
biological characteristics.22−26
With an efficient modular synthetic method in hand for the
synthesis of substituted cyanobenzenes with an appended
phenethyl group, we hypothesized that this template would be
an ideal system for examining the directing capabilities of the
nitrile group in late-stage functionalization across different
arenes in a molecule. Selectively employing multiple trans-
formations via a single innate directing group, especially one
that is an inherently versatile handle in organic chemistry, is a
highly attractive strategy for complex synthesis. Drawing
inspiration from monoprotected amino acid (MPAA)-
promoted C−H functionalizations developed by Yu,7,11,27
selective C−H oxidation of 3a was observed at the meta
position on the distal arene to give 4a with the use of
Pd(OAc)2, Ac-Gly-OH, PhI(OAc), and Ac2O in hexafluor-
oisopropanol (HFIP) at 90 °C for 18 h (Table 1, entry 1).
Moving forward with the optimization, we found that
increasing the catalyst and oxidant loadings boosted the yield
significantly, leading to a 78% yield of the meta-functionalized
product (Table 1, entry 3). Although the yield of this
With the optimized conditions in hand, the transformation
was applied to a variety of diarylethanes (Scheme 1). Selective
distal meta-C−H acetoxylation was observed for substrates
bearing electron-withdrawing and electron-donating substitu-
ents on both the distal and proximal aromatic rings (products
4b−g). Furthermore, we were able to extend the length of the
carbon chain between the arenes (product 4i) and maintain
good yield and meta selectivity. Several substrates with
heteroatoms in the linker were also compatible with the
B
Org. Lett. XXXX, XXX, XXX−XXX