Pd-catalyzed oxidative ortho -C-H borylation of arenes

Article abstract of DOI:10.1021/ja2097095

The development of a Pd-catalyzed oxidative ortho-C-H borylation with N-arylbenzamides is reported. A modified dibenzylideneacetone (dba) ligand, a weak base, and a strong oxidant are critical for obtaining good yields. The reaction is tolerant of electro

Full text of DOI:10.1021/ja2097095

Communication
pubs.acs.org/JACS
Pd-Catalyzed Oxidative ortho-C−H Borylation of Arenes
Hui-Xiong Dai and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
a broad substrate scope. However, a critical challenge in
ABSTRACT: The development of a Pd-catalyzed oxida-
tive ortho-C−H borylation with N-arylbenzamides is
reported. A modified dibenzylideneacetone (dba) ligand,
a weak base, and a strong oxidant are critical for obtaining
good yields. The reaction is tolerant of electron-deficient
and electron-rich benzamides derived from readily
available benzoic acids. The borylated products can be
converted to various synthons via diverse transformations.
developing this catalytic process is the decomposition of the
arylboronic esters via transmetalation between the arylboronic
esters and Pd(II) species. Herein we report a Pd-catalyzed
oxidative borylation of N-arylbenzamides with a diboron reagent
via a Pd(II)/Pd(0) manifold (eq 4). The use of a powerful
directing group for C−H activation as well as a weak base
(TsONa), a strong oxidant (K2S2O8), and a modified dibenzyli-
deneacetone (dba) ligand (L-3) are crucial for this trans-
formation. The obtained arylboronic esters are shown to engage
in carbon−carbon, carbon−nitrogen, and carbon−halogen bond
formation5 with various reaction partners, providing access to
synthons that currently cannot be obtained using our previously
reported Pd-catalyzed C−H activation reactions.2
In our continuing effort to develop synthetically versatile
C−H activation reactions, we recently identified −CONHAr
[Ar = (4-CF3)C6F4] as a highly efficient auxiliary to assist a
diverse range of C−H activation reactions that are otherwise
elusive.11 Importantly, this amide auxiliary is applicable
to a wide range of carboxylic acids whose carbon skeletons
can be mapped onto both drug molecules and natural
products.11b We therefore decided to investigate C−H
borylation using N-arylbenzamide substrate 1a. We found that
C−H borylation of 1a with 2 equiv of 2 occurred in the
presence of 10 mol % Pd(OAc)2, 1.0 equiv of Ag3PO4, and 1.0
equiv of KH2PO4 in CH3CN to give the desired borylation
product 3a in 13% yield (Scheme 1). This initial result suggests
mong the various metal-catalyzed C−H functionalization
A
reactions, Pd catalysts have displayed encouraging
versatility in terms of the development of diverse carbon−
carbon and carbon−heteroatom bond-forming transforma-
tions.1 For instance, the Pd(II)/Pd(0) redox catalytic cycle
has been shown to be able to couple C−H bonds with alkyl,
aryl, and vinyl organometallic reagents as nucleophiles to forge
various carbon−carbon bonds.2 Because of the broad utility of
arylboron reagents in synthesis, we envision that an aryl C−H
borylation reaction using a Pd(II)/Pd(0) catalytic platform
would be highly valuable. Prevalent methods for the prepara-
tion of arylboronic esters involve the metal-catalyzed borylation
of aryl halides3,4 or the addition of aryllithium or magnesium
species to borates.5
Significant progress has been made in the past decade on
Ir- and Rh-catalyzed C−H borylation reactions, in which the
regioselectivity is controlled by either sterics6,7 or a directing
group (DG) (eq 1).8,9 Two isolated examples of Pd(0)-catalyzed
Scheme 1. Pd-Catalyzed Borylation of N-Arylbenzamides
that C−H activation could outcompete the decomposition of
the diboron by the Pd(II) catalyst.
An extensive screening of bases, oxidants, and solvents
showed that the use of K2S2O8 as the oxidant, TsONa as the
base, and CH3CN as the solvent provided 3a in 53% yield
(Table 1, entry 6). Poor yields were obtained with other
oxidants [see the Supporting Information (SI)]. The use of a
weak base such as TsONa was essential for obtaining good
borylation of benzylic or isoindolinyl C−H bonds under
reducing conditions have also been reported (eqs 2 and 3).10
Because of the versatile reactivity of Pd(II) catalysts in C−H
activation, the development of the oxidative Pd(II)/Pd(0)
manifold to effect C−H borylation has the potential to afford
Received: October 16, 2011
Published: December 9, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Evaluation of Reaction Conditions
Table 3. Pd-Catalyzed Borylation Reaction of
ab
,
N-Arylbenzamides
a
Conditions: 1a (0.1 mmol), 2 (0.2 mmol), Pd catalyst (10 mol %),
oxidant (0.2 mmol), base (0.15 mmol), CH3CN (1.0 mL), 80 °C,
b
1
12 h. Determined by H NMR analysis of the crude productd using
c
CH2Br2 as an internal standard. 2 (0.1 mmol).
a
Table 2. C−H Borylation Promoted by dba Ligands
a
Conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd(OAc)2 (10 mol %), L-3
(30 mol %), K2S2O8 (0.2 mmol), TsONa (0.15 mmol), CH3CN
b
c
(1 mL), 80 °C, 24 h. Isolated yields are shown. 2 (0.3 mmol).
reagent was beneficial for obtaining good yields (entries 6 and
16) (see the SI).
Among various Pd catalysts tested, Pd2(dba)3 was found to
be equally effective as Pd(OAc)2 (Table 1, entry 15). Since the
electronic properties of substituents on the aryl groups of dba
are known to modulate the Suzuki−Miyaura cross-coupling of
organohalides with arylboronic acids,12 we tested a variety of
dba analogues in combination with Pd(OAc)2 to investigate
their influence on this reaction (Table 2). While nonsubstituted
dba had a negligible effect (entries 2−5), the use of electron-
deficient dba ligand L-3 significantly improved the yield of
the borylation reaction with good monoselectivity (entry 7).
When the reaction time was prolonged to 24 h, the yield was
improved to 78% (entry 11). However, the use of 3 equiv of
diboron reagent resulted in significant formation of the
diborylated product (entry 12).
With these optimized conditions in hand, we surveyed the
substrate scope of this borylation reaction (Table 3).
Methylated arenes gave yields of 85 and 82% (3b and 3c),
whereas MeO- and AcO-substituted arenes afforded lower
yields (3d−f). Borylation of fluorinated and chlorinated arenes
proceeded smoothly to give their corresponding products
(3g−l) in yields of 73−81%. The presence of an electron-
withdrawing CF3 group on the arene reduced the yield to 62%
a
Conditions: 1a (0.1 mmol), 2 (0.2 mmol), Pd(OAc)2 (10 mol %),
K2S2O8 (0.2 mmol), TsONa (0.15 mmol), CH3CN (1.0 mL), 80 °C,
12 h. Determined by H NMR analysis of the crude products using
CH2Br2 as an internal standard. 24 h. 2 (0.3 mmol).
b
1
c
d
yields (entries 2−6), as both the diboron reagent and the
arylboronate decomposed in the presence of K3PO4. While
the diboron reagent was stable when TsONa was used, slow
decomposition of the arylboronate product still occurred during
the reaction. Therefore, the use of 2.0 equiv of the diboron
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Journal of the American Chemical Society
Communication
amination reactions are particularly valuable because direct
cyanation and amination of C−H bonds still remain a
significant challenge.
Scheme 2. Versatile Transformations of the Borylated
Products
a
At this stage, the detailed mechanism of each elementary step
remains to be ascertained. Following C−H cleavage by the
Pd(II) catalyst, intermediate A could undergo transmetalation
with the diboron reagent to form the ArPdB intermediate B
(Scheme 3). Subsequent C−B reductive elimination would
afford the borylated product (path a) and Pd(0). The
effectiveness of Pd2(dba)3 is consistent with this pathway.
Intriguingly, the requirement of a strong oxidant such as
K2S2O8 appears to suggest that B could be oxidized to Pd(IV)
species C prior to the C−B reductive elimination (path b). Path
c is unlikely to be operative since the formation of the
acetoxylated product was not observed, as would be expected
from facile C−O reductive elimination of Pd(IV) species D.
In summary, we have developed the first Pd-catalyzed boryla-
tion of arenes under oxidative conditions. The N-arylbenza-
mides are readily accessible from benzoic acids. The borylated
products can be converted to various valuable synthons using
known transformations.
a
Conditions: (a) 3a (0.05 mmol), oxone (0.05 mmol) in H2O
(1.0 mL), acetone (1.0 mL), rt, 2 h. (b) 3a (0.05 mmol), CuCN
(0.05 mmol), K2CO3 (0.15 mmol), DMF (1.0 mL), 60 °C, 4 h. (c) 3a
(0.05 mmol), isopropylamine (0.06 mmol), Cu(OAc)2 (10 mol %),
4 Å molecular sieves (MS), O2 (1 atm), CH2Cl2 (1.0 mL), 40 °C, 12 h.
(d) 3a (0.05 mmol), aniline (0.06 mmol), Cu(OAc)2 (10 mol %), 4 Å
MS, O2 (1 atm), CH2Cl2 (1.0 mL), 40 °C, 12 h. (e) 3a (0.05 mmol),
CuCl2 (0.15 mmol) in H2O (1.0 mL), CH3OH (1.0 mL), 90 °C, 24 h.
(f) 3a (0.05 mmol), CuBr2 (0.15 mmol) in H2O (1.0 mL), CH3OH
(1.0 mL), 80 °C, 24 h.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 3. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
ACKNOWLEDGMENTS
We gratefully acknowledge The Scripps Research Institute, the
U.S. NSF (CHE-1011898), and Novartis for financial support.
■
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NOTE ADDED AFTER ASAP PUBLICATION
■
This article was published ASAP on December 19, 2011.
Reference 10 (c) has been added. The revised version was
posted on December 29, 2011.
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