Journal of the American Chemical Society
Communication
reactants at ambient temperature. The method utilizes
rationally designed bis(carboxylate) anions, palladium(II)
precatalysts, and iodine(III) arylation reagents and avoids
additives such as silver(I) salts.43−48
bridging mode. The crystal structure of the constrained
bis(carboxylic) acid H2La (spacer = 2,7-naphthyl) confirms
that the carboxylate groups are arranged approximately in a
plane, which is parallel to that of the central arene spacer.
Palladium precatalysts 1 and arylation reagents 2, which
contain nonafluoro-tert-butoxide anions, were designed with
the goal of avoiding the use of silver(I) compounds and any
other potentially interfering additives or anions (Figure 2a).
The bulky monodentate (CF3)3CO−, which does not
participate in the six-membered CMD process, can be
displaced from palladium by H2La (see Supporting Informa-
tion) and act as a mild base50 to remove H+ after the C−H
activation step, as demonstrated by the Larossa group.51−54
The potential of the proposed spatial anion control to
address challenging C−H functionalization reactions with
palladium was examined by performing the nondirected
arylation of arenes as limiting reactants. The constrained
bis(carboxylic) acid H2La and palladium precatalyst 1a enabled
catalytic C−H arylation of arene 3a with diaryl iodonium
reagent 2a at ambient temperature, yielding 4a in 39% yield
(Figure 2b, Figure S2). In contrast, H2Lb and H2Lc afforded 4a
in 17% and 1% yield, respectively, whereas with H2Ld and
simpler carboxylates,22,55−57 no product was observed (Figure
2c, see Figure S1 for additional screening and control
experiments), which attests to the relevance of the relative
spatial positioning of the two carboxylate groups for the
catalytic reactivity. Furthermore, a derivative of H2La, which
lacks the shielding mesityl groups, exhibited no reactivity
The geometric parameters of the carboxylate coordination
on palladium, namely, the O−Pd−O angles and Pd−O
distances, change significantly in the CMD transition state
(Figure 1b). We envisioned that the controlled spatial
arrangement of constrained bis(anions) could modulate the
coordination parameters, as exemplified in Figure 1c, left. The
spatial anion control could lead to stabilization of the geometry
required for the CMD transition state over, for example, κ2-
coordination in the palladium-bis(carboxylate) catalyst, thus
lowering the barrier for C−H activation. This approach can be
compared with the well-established spatial control of neutral
donors in transition-metal catalysis where parameters, such as
the bite angle, are influenced by the geometric requirements of
the ligand backbone (Figure 1c, right).49
Our anion design for spatial anion control on palladium, as
shown in Figure 2a, utilizes two 1-naphthyl carboxylic acid-
derived side-arms, which are structurally constrained by a
central aromatic spacer group. The size and geometry of the
spacer modulates the relative spatial arrangement of the four
carboxylate oxygen atoms, while sterically demanding mesityl
groups prevent the carboxylate groups from coordinating in a
−
−
(Figure S1b). Diaryl iodonium salts with BF4 and CF3SO3
anions have been used previously for the nondirected
functionalization of arenes, but high temperature, an acid
cosolvent, and an excess of arene were required.24,27 In our
system, the common diaryl iodonium salts were unsuitable,
while other palladium precatalysts proved to be inferior to 1a,
thereby demonstrating the importance of the (CF3)3CO−
anion (Figure 2c).
The constrained anion-enabled catalytic C−H arylation is
applicable to a wide range of arenes 3 at 26 °C (Scheme 1).
C−H arylation of substrate 3a with increased precatalyst
loading provided biaryl product 4a in 55% isolated yield, while
C−H functionalization of benzene using 5 mol % of H2La and
10 mol % of 1a afforded monoarylation and bis-arylation
products in a combined yield of 58% after 1 day (4b). Arenes
with strongly activating groups undergo efficient arylation at
the sterically exposed electron-rich C−H site (4c, 4d). Aryl
and bulky alkyl substituents effectively suppress ortho C−H
activation (4e−g), although arylation next to smaller alkyl
groups, such as methyl, is possible unless an additional meta
substituent is present (4h). Halogen-substituted arenes are
similarly functionalized at the meta and para positions to the
halogen group (4i−n). Iodoarenes and aryl triflates can be
used as substrates, demonstrating complementary reactivity of
the current system to common Pd-catalyzed carbon−carbon
bond-forming processes (4l−o).6 Fused (hetero)arenes are
suitable substrates, and yields of up to 86% could be obtained
with naphthalene derivatives (4p−s). In cases where two
equivalent C−H bonds are present, bis-functionalization is
observed (4p, 4q, 4s), which further demonstrates the
potential for polyarylation reactions (4p-bis).
The direct C−H arylation is compatible with electrophilic
functional groups, such as activated ketones and epoxides (4t,
4u), and is suitable for late-stage functionalization of
functionally rich molecules, as demonstrated with tryptophan
Figure 2. Development of a catalytic system for mild C−H arylation.
aFor details, see Supporting Information.
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX