Ligand-Controlled Para-Selective C-H Arylation of Monosubstituted Arenes

Article abstract of DOI:10.1021/acs.orglett.5b01802

In a Pd-catalyzed double C-H activation reaction, a pyridine-type ligand is identified, for the first time, to enable a highly para-selective C-H arylation of monosubstituted arenes. Excellent para-selectivity is achieved with a variety of arenes containing alkyl, methoxyl, and halo substituents.

Full text of DOI:10.1021/acs.orglett.5b01802

Letter
pubs.acs.org/OrgLett
Ligand-Controlled Para-Selective C−H Arylation of Monosubstituted
Arenes
Hui Xu,†,§ Ming Shang,†,§ Hui-Xiong Dai,*,† and Jin-Quan Yu*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: In a Pd-catalyzed double C−H activation reaction,
a pyridine-type ligand is identified, for the first time, to enable a
highly para-selective C−H arylation of monosubstituted arenes.
Excellent para-selectivity is achieved with a variety of arenes
containing alkyl, methoxyl, and halo substituents.
iaryls are an important structural motif in natural products,
biologically active compounds, drug molecules, and
by [ArPd(IV)F] species. However, achieving para-selectivity
using oxidants other than a stoichiometric F+ source has not
been successful. Herein, we report the use of a catalytic amount
of ligand that significantly enhances the para-selectivity in a
double C−H activation reaction without involving [ArPd(IV)-
F] species, thus demonstrating the feasibility of developing a
ligand for achieving para-selectivity (eq 2).
We have recently systematically established that Pd(II)-
catalyzed C−H activation can be drastically influenced by
pyridine- and quinoline-based ligands.10 The observed ligand
effects encouraged us to test if we could replace the fluoride at
the Pd(IV) center by a suitable ligand and still afford para-
selectivity in the C−H cleavage step. To test this hypothesis, we
began to investigate the regioselectivity of the well-established
C−H coupling of acetanide with toluene.5b,c,g In one of the
studies, a ortho/meta/para selectivity of 1/16/16 was
obtained.5b Preliminary screening of our pyridine ligands
afforded a significantly improved para to meta selectivity (15/
1) when pyridine (L3) was used as a ligand, albeit in low yield
(eq 3). The use of pivaloyl-protected aniline substrate
PhNHCO-t-Bu (1a) gave improved yield and selectivity,
while other directing groups were inferior (Scheme 1).
B
organic materials.1 Formation of biaryls via C−H/C−H
coupling is potentially an attractive method as the prefunction-
alization step is omitted.2 However, achieving regioselectivity
on both arene-coupling partners is challenging.3 Moderate
success has been achieved by combining ortho-directed C−H
activation with nondirected C−H activation.4−6 While the
ortho-selectivity of one of the two arenes is secured by the
directing group, regioselectivity on the monosubstituted arenes
containing no directing group remains to be substantially
improved.5 For example, para-selective C−H arylation of
monosubstituted electron-rich anisole has been reported with
encouraging para-regioselectivity.5b,d,g Recently, we reported a
Pd-catalyzed para-selective C−H arylation of monosubstituted
arene using F+ as the bystanding oxidant (eq 1).7 The observed
Using PhNHCO-t-Bu as the substrate, we further examined a
variety of ligands (Scheme 2). In the absence of ligand,
treatment of PhNHCO-t-Bu (1a) and toluene afforded arylated
products (mono and di) in 53% yield with a para/meta ratio of
para-selectivity is crucially dependent on the use of a
stoichiometric F+ reagent. Based on an earlier related study,8,9
we attributed this selectivity to a para-selective C−H cleavage
Received: June 23, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01802
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a d
−
structure of the ligands. Compared with para- and meta-
substitued pyridine, ortho-substitued pyridine only gave lower
regioselectivity. Meanwhile, the electron-withdrawing group at
the para- and meta-positions of pyridine showed a higher para/
meta ratio than the electron-donating group. Some other
nitrogen-containing heterocycles were also tested (L21−L27).
When bidentate ligand L28 was employed, no desired product
was formed. We further investigated the loading of ligand L13
and found that 30 mol % of ligand gave better result with a
para/meta ratio of 28/1 for 2a (see the Supporting
Information).
Scheme 1. Screening of Directing Group
a
Reaction conditions: 1a, A−C (0.2 mmol), Pd(OAc)2 (10 mol %),
pyridine (20 mol %), TFA (1.0 mmol), Na2S2O8 (0.6 mmol), toluene
b
(2 mL), 70 °C, 16 h. Yield is determined by 1H NMR analysis of the
c
crude reaction mixture using CH2Br2 as an internal standard. Mono-
and diarylation (mono + di) is shown in parentheses. Regioselectivity
d
With these optimized conditions in hand, we began with a
survey of variously substituted anilide substrates. As shown in
Scheme 3, anilides containing electron-donating methyl and
of 2a is determined by GC analysis.
a c
−
Scheme 2. Screening of Ligands
a c
−
Scheme 3. Scope of Anilides
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol %), L (20
a
Reaction conditions: 1a−o (0.2 mmol), Pd(OAc)2 (10 mol %), L13
mol %), TFA (1.0 mmol), Na2S2O8 (0.6 mmol), toluene (2 mL), 70
(30 mol %), TFA (1.0 mmol), Na2S2O8 (0.6 mmol), toluene (2 mL).
b
1
°C, 16 h. Yield determined by H NMR analysis of crude reaction
b
Isolated yields are given. Mono- and diarylation (mono + di) is
mixture using CH2Br2 as an internal standard. Mono- and diarylation
c
shown in parentheses. Regioselectivity is determined by GC analysis.
c
(mono + di) is shown in parentheses. Regioselectivity of 2a is
d
e
L3 (30 mol %), TFA (2.0 mmol). TFA (2.0 mmol).
determined by GC analysis.
3/2 for monoproduct 2a. Since the F+ reagents used to achieve
the para-selectivity in our previous study contain amines and
amides L1−L2, we also tested these ligands and obtained poor
regioselectivity (L1−L2). Among the various tested pyridine-
and quinoline-based ligands, we found that 3-acetylpyridine
(L13) and methyl nicotinate (L15) gave the best result in terms
of both para-selectivity and yields. The regioselectivity of the
nondirected C−H activation sensitively depends on the
methoxy groups were arylated with toluene to give the
corresponding biaryl product with an excellect para/meta
ratio (≥22/1) with respect to toluene. By increasing the
amount of TFA and/or using L3 as ligand, anilides containing
electron-withdrawing fluoro, chloro, bromo, and trifluorometh-
yl groups also reacted with toluene to give the biaryl products
in good yields but slightly lower regioselectivity. The chloro
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DOI: 10.1021/acs.orglett.5b01802
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and bromo groups in products 2i−l are useful handles for
further structural elaborations.
Scheme 5. Kinetic Isotope Effect
This protocol is also applied to the other substituted arenes
containing alkyl, methoxyl, and halo groups, and high levels of
para-selectivity and moderate to good yields are obtained
(Scheme 4). In sharp contrast to the meta-selectivity observed
a c
−
Scheme 4. Scope of Substituted Arenes
Scheme 6. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01802.
a
■
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol %), L13 (30
S
mol %), TFA (1.0 mmol), Na2S2O8 (0.6 mmol), ArH (2 mL).
b
c
Isolated yields are given. Regioselectivity is determined by GC
d
e
analysis. TFA (2.0 mmol). L3 (30 mol %).
Experimental procedure and characterization of all new
compounds (PDF)
in the [RhIIICp*]-catalyzed ortho-coupling of benzamides with
monohalogenated benzene (meta/para ratio 2.6/1−4.7/1),5f
our reaction gives highly para-selective product with a para/
meta ratio of 15/1−20/1.
AUTHOR INFORMATION
Corresponding Authors
■
Since the cyclopalladated complex of the first C−H
activation step involving anilide directing group is well-
known,5d,11 we focused on the second C−H activation step.
A lack of kinetic isotope effect determined by intermolecular
competition experiments between toluene and toluene-d8 infers
that the second C−H activation step most likely involves an
electrophilic palladation by the ligand-supported Pd(II)3d,4a,d,e
or Pd(IV)5d,7−9 species (Scheme 5 and 6). It is known that the
π-acceptor character of pyridine ligands could increase the
electrophilicity of Pd centers.12 Presumably, the ligand-bearing
Pd center is sterically hindered and prefers to react at the para-
position via an electrophilic palladation pathway.
In conclusion, we have developed a ligand that can drastically
improve the para-selectivity of Pd-catalyzed ortho-arylation of
monosubstituted arenes without using stoichiometric F+
reagent. This finding paves the way for further development
of ligand-controlled regioselective arylation of monosubstituted
arene with or without directing groups.
*E-mail: hxdai@sioc.ac.cn.
*E-mail: yu200@scripps.edu.
Author Contributions
§H.X. and M.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research
Teams, NSFC-21121062, China Postdoctoral Science Founda-
tion 2013M541572, and The Recruitment Program of Global
Experts for financial support. We gratefully acknowledge The
Scripps Research Institute for financial support. This work was
supported by the NSF under the CCI Center for Selective C−
H Functionalization, CHE-1205646.
C
DOI: 10.1021/acs.orglett.5b01802
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