Iridium-promoted, palladium-catalyzed direct arylation of unactivated arenes

Article abstract of DOI:10.1021/om401221v

A Pd-catalyzed cross-coupling reaction between Cp*(PMe ₃)IrBn₂ and aryl halides was developed. Examining the scope of this reaction led to the discovery that Cp*(PMe ₃)IrMeCl activates C-H bonds on arene substrates that undergo subsequent Pd-catalyzed cross-coupling with aryl iodides. This Ir-promoted, Pd-catalyzed direct arylation is notable for its distal selectivity on substituted arenes lacking directing groups or a particular electronic bias.

Full text of DOI:10.1021/om401221v

Communication
pubs.acs.org/Organometallics
Iridium-Promoted, Palladium-Catalyzed Direct Arylation of
Unactivated Arenes
Landon J. Durak and Jared C. Lewis*
Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: A Pd-catalyzed cross-coupling reaction between
Cp*(PMe3)IrBn2 and aryl halides was developed. Examining
the scope of this reaction led to the discovery that
Cp*(PMe3)IrMeCl activates C−H bonds on arene substrates
that undergo subsequent Pd-catalyzed cross-coupling with aryl
iodides. This Ir-promoted, Pd-catalyzed direct arylation is notable for its distal selectivity on substituted arenes lacking directing
groups or a particular electronic bias.
atalytic C−H functionalization has the potential to
a fundamental advance toward our ultimate goal of dual
catalytic C−H functionalization.
C
streamline chemical synthesis, enable the use of
inexpensive chemical feedstocks, and eliminate substrate
prefunctionalization (e.g., halogenation or metalation) and
waste associated with analogous cross-coupling processes.1−3
Most methods for metal-catalyzed C−H functionalization
require chelate assistance by a proximal directing group or a
strong electronic bias to enable C−H activation, which provides
a mechanism for selective functionalization.4,5 Relatively few
catalysts have been developed for selective functionalization of
C−H bonds distal to arene substituents,6 but such steric
control is exhibited by a number of metal complexes (M1) that
promote stoichiometric C−H bond activation.7−9
Studies on the transmetalation of hydrocarbyl ligands from
Cp*(PMe3)Ir(R1)2 complexes to electrophilic d8 Pt(II) and
Pd(II) complexes led to the discovery that Pd(II) catalyzes
oxidative homocoupling of benzyl ligands from 1a in the
presence of Ag2O.16 We hypothesized that changing the
stoichiometric oxidant from Ag(I) to an aryl halide would
enable catalytic cross-coupling reactions of Cp*(PMe3)IrIII
hydrocarbyl complexes.11,17 1a was therefore reacted with PhI
in the presence of different Pd catalysts and additives intended
to increase Pd electrophilicity via anion metathesis or
abstraction (Table 1).16 Initial trials using Pd(OAc)2 showed
that the addition of a noncoordinating anion led to formation
of the desired product, diphenylmethane, in up to 16% yield
(entries 1−3). Exploring Pd catalysts revealed that Pd(0) with a
This stoichiometric reactivity could be exploited for catalysis
if the activated organic fragment (R1) underwent trans-
metalation to a second metal (M2) for functionalization
(Scheme 1).10−15 We previously established that trans-
a
Table 1. Optimizing Pd-Catalyzed 1a/PhI Cross-Coupling
Scheme 1. Dual Catalytic Cycle for C−H Functionalization
b
b
entry
Pd source
additive
A, %
B, %
1
2
3
4
5
6
Pd(OAc)2
NaOAc
0
8
17
21
27
3
Pd(OAc)2
NaBF4
Pd(OAc)2
LiN(Tf)2
LiN(Tf)2
LiN(Tf)2
16
Pd2(dba)3
70
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
90
0
F
KBAr4
125
124
0
metalation of hydrocarbyl (R1) and trifluoroacetate (X) ligands
between Cp*(PMe3)Ir(R1)2 and (COD)Pt(Me)(X) complexes
was possible.16 Here, similar transmetalation chemistry is
exploited for Pd-catalyzed cross-coupling of Cp*(PMe3)Ir(Bn)2
(1a) with aryl halides (R2-X). Ir-promoted, Pd-catalyzed direct
arylation of unactivated arenes (R1-H) using aryl halides (R2-X)
can also be achieved. This reaction affords biaryl products in
good yields with regioselectivity for the sterically most
accessible distal position of the arene substrates and constitutes
c
F
7
KBAr4
0
a
b
Reactions were conducted at 0.01 M at 23 °C for 16 h. Yields were
calculated by GC analysis of crude reaction mixtures relative to 1,3,5-
trimethoxybenzene internal standard added after completion of the
c
reaction. Reaction was conducted in 1/1 PhMe/H2O.
Received: December 23, 2013
Published: January 30, 2014
© 2014 American Chemical Society
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Communication
bulky phosphine ligand (Pd[P(t-Bu)3]2) increased the yield of
diphenylmethane to 90% (entries 3−5). Finally, combining
Different Cp*(PMe3)IrIII complexes were also explored.
When Cp*(PMe3)IrMeCl (1b) was reacted with 2-iodonaph-
thalene in 1/1 benzene/water, the expected cross-coupling
product was not observed. Instead, the major product resulted
from direct arylation of benzene using 2-iodonaphthalene
(Scheme 2). This reaction, though stoichiometric in Ir complex
1b, constitutes an unusual example of direct arylation18,19
without the need for a directing group6 on an unactivated
substrate.
F
Pd[P(t-Bu)3]2 and the weakly coordinating BAr4 anion
F−
(BAr4 = tetrakis(pentafluorophenyl)borate) led to yields in
excess of 100% relative to 1a due to the reaction of both benzyl
ligands (entry 6). Similar efficiency was observed using biphasic
water/toluene mixtures, which were intended to improve the
solubility of the salt additives investigated (entry 7). Reactions
conducted with Cp*(PMe3)IrBnX (X = Cl/I), the presumed Ir
product from transmetalation,16 provided significantly lower
yields than 1a; therefore, the reported yields reflect the
transmetalation of one benzyl ligand of 1a.
Scheme 2. Unexpected Ir-Mediated C−H Activation/Pd-
Catalyzed Cross-Coupling of Benzene with 2-
Iodonaphthalene
The optimized reaction conditions (2 mol % Pd, 1.3 equiv of
F
ArX, 1 equiv of KBAr4 , toluene solvent) were then used to
explore the substrate scope of the cross-coupling process
(Table 2). Both aryl iodides and aryl bromides were competent
coupling partners (entries 1−9), but aryl chlorides were
unreactive (entry 10). Electron-rich and electron-deficient aryl
halides, including examples with ortho substitution and ester,
pyridine, and ether functional groups, underwent cross-
coupling.
While this reaction proved highly sensitive to residual oxygen
and the method used to agitate the biphasic mixture, conditions
for reliable direct arylation were identified. The scope of this
process was explored using p-iodoanisole and various arene
substrates (Table 3, entries 1−8). Both electron-rich and
electron-deficient arenes are competent substrates, and the
regioselectivities observed in the biaryl products appear to
result primarily from steric, rather than electronic, effects. For
both ortho- and meta-disubstituted arenes, the meta C−H
bond is arylated, and monosubstituted substrates provide a
statistical mixture of meta- and para-functionalized products
(Table 3, entries 3 and 7). Para-disubstituted and 1,3,5-
trisubstituted arenes were unreactive. Our survey of the
substrates revealed that the regioselectivity is neither consistent
with that expected for electrophilic aromatic substitution
(Table 3, entry 1) nor reflective of a preference toward
cleavage of the most acidic C−H bond (Table 3, entry 7).
Several additional aryl halides were subjected to the reaction
conditions (entries 8−10). Unlike the aforementioned cross-
coupling reactions, the direct arylation does not tolerate aryl
bromides or functional groups, including esters, alcohols, or
amines, on either the arene or the aryl halide. However, the
examples in Table 3 show regioselectivity trends similar to
those observed for Ir-catalyzed C−H borylation,6b,21 Pd-
catalyzed C−H amination,22 and several dehydrogenative
cross-coupling reactions.6a,c,d The lack of a strong electronic
effect on the regioselectivity of this reaction differs significantly
from that observed for reported examples of Pd-catalyzed direct
arylation;4,18,19 however, a Pt-catalyzed direct arylation
exhibiting both steric and electronic control of regioselectivity
has recently been reported.23 The differences in reactivity
between these reported systems and the bimetallic system
described herein suggest that distinct modes of C−H activation
will provide a means to functionalize a broad range of
substrates with unique selectivities. Currently, the selectivity
of this system for cross-coupling over homocoupling is
generally modest (ca. (2−3):1), but some substrates do
provide good levels of cross-coupling products (entries 7 and
8). Further studies, including a broader survey of Pd catalysts,
ligands, and additives, are underway to clarify these effects and
improve reaction selectivity.
Table 2. Scope of Pd-Catalyzed 1a/Aryl Halide Cross-
Coupling
a
1
Key to these efforts will be a detailed understanding of the
reaction mechanism. Both metals were required for efficient
direct arylation; omitting Pd[P(t-Bu)3]2 led to trace product
Yield determined by H NMR analysis of crude reaction mixtures
relative to one benzyl ligand of 1a (1,3,5-trimethoxybenzene internal
standard).
621
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Communication
Table 3. Scope of Bimetallic Direct Arylation of Arenes
Using Aryl Iodides
Scheme 3. Mechanistic Hypothesis for C−H Activation/
Cross-Coupling of Arenes and Aryl Iodides
reaction conditions. Control experiments showed that no C−H
F
activation occurred in the presence of either KBAr4 or water
alone, even at elevated temperatures. Complex 5 could then
undergo transmetalation with Pd complex 6 directly (as shown
in Scheme 3) or as a neutral species following reaction with
halide generated during the reaction. Reductive elimination of
Pd complex 7 would afford the biaryl product and regenerate
Pd(0) in analogy to conventional cross-coupling reactions.27
Specific details regarding the elementary steps of this proposed
mechanism, particularly those involving the fate of Ir, remain
unclear and are the focus of ongoing studies in our laboratory.
In conclusion, we have developed conditions for Pd-catalyzed
cross-coupling of Cp*(PMe3)Ir(Bn)2 and aryl halides as well as
Ir-promoted, Pd-catalyzed direct arylation of arenes using aryl
F−
iodides. In both cases including the weakly coordinating BAr4
anion was crucial to achieving good to high yields. The
bimetallic direct arylation is notable for its distal regioselectivity
on unactivated arenes. Future work will focus on developing a
mechanistic understanding of the C−H activation/cross-
coupling that will hopefully lead to a more selective process
and ultimately one that is catalytic in both metals, as shown in
Scheme 1.
ASSOCIATED CONTENT
* Supporting Information
Text and figures giving experimental procedures and character-
ization data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail for J.C.L.: jaredlewis@uchicago.edu.
■
Notes
a
1
The authors declare no competing financial interest.
Yields determined by H NMR analysis of crude reaction mixtures
using 1,3,5-trimethoxybenzene as an internal standard relative to 1b.
b
Product ratios determined by GC analysis of reaction mixtures.20
ACKNOWLEDGMENTS
This work was supported by The University of Chicago Louis
Block Fund for Basic Research and Advanced Study.
■
formation, while only aryl iodide homocoupling resulted in the
absence of 1b. Our current working hypothesis is therefore
based on the transmetalation pathway outlined in Scheme 1.
Within this context, the initial C−H activation step can be
rationalized in analogy to the known reactivity of Cp*(PMe3)-
IrCl224 and Cp*(PMe3)IrMeOTf25 toward hydrocarbons. It has
been suggested that D2O promotes ionization of Cp*(PMe3)-
IrCl2 to form [Cp*(PMe3)IrCl]+Cl−, which catalyzes H/D
exchange in organic substrates.24 Similarly, Cp*(PMe3)-
IrMeOTf ionizes via loss of OTf− to generate Cp*(PMe3)-
IrMe+, which reacts with arenes (ArH) to form Cp*(PMe3)-
IrAr+ and CH4.25 On the basis of this precedent, we propose
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