Regioselectivity-switchable hydroarylation of styrenes

Article abstract of DOI:10.1021/ja108809u

Cobalt-phosphine and cobalt-carbene catalysts have been developed for the hydroarylation of styrenes via chelationassisted C-H bond activation, to afford branched and linear addition products, respectively, in a highly regioselective fashion. Deuterium-la

Full text of DOI:10.1021/ja108809u

Published on Web 12/15/2010
Regioselectivity-Switchable Hydroarylation of Styrenes
Ke Gao and Naohiko Yoshikai*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological UniVersity, Singapore 637371, Singapore
Received September 30, 2010; E-mail: nyoshikai@ntu.edu.sg
interested in the hydroarylation of olefins, including styrenes. Thus
Abstract: Cobalt-phosphine and cobalt-carbene catalysts have
been developed for the hydroarylation of styrenes via chelation-
assisted C-H bond activation, to afford branched and linear
addition products, respectively, in a highly regioselective fashion.
Deuterium-labeling experiments suggested a mechanism involv-
ing reversible C-H bond cleavage and olefin insertion steps and
reductive elimination as the rate- and regioselectivity-determining
step.
we set out to explore catalytic systems for the addition of
2-phenylpyridine 1a to styrene 2a (1.2 equiv). Selected data of the
screening experiments are summarized in Table 1. A cobalt catalyst
generated from CoBr2 (10 mol %), PCy3 (10 mol %), and
tBuCH2MgBr (100 mol %) or Me3SiCH2MgCl (80 mol %) effected
the hydroarylation reaction in THF at 60 °C to afford a branched
product 3aa in 68% or 81% yield, respectively, with high
regioselectivity (b/l ) 98:2) (entries 1 and 2). The loading of the
cobalt catalyst could be reduced to 5 mol % (entry 3). Other
monodentate phosphine ligands such as Buchwald’s biaryl phos-
phines also afforded the branched product 3aa albeit in much lower
yields. The choice and the amount of Grignard reagent were also
critical. The use of other Grignard reagents as well as the reduction
of the amount of tBuCH2MgBr or Me3SiCH2MgCl resulted in much
lower yields (see Table S1 in the Supporting Information).
To our surprise, when the reaction in entry 1 was performed
using IMes•HCl (1,3-dimesitylimidazolium chloride), a precursor
of an N-heterocyclic carbene (NHC) ligand, instead of PCy3, a near
complete switch of the regioselectivity was observed (entry 4).7
Thus the reaction afforded the linear adduct 4aa in 84% yield with
a regioselectivity of 97:3. The reaction with the NHC ligand was
rather sensitive to the Grignard reagent and almost stopped when
Me3SiCH2MgCl was used (entry 5). The use of other common NHC
precursors afforded only small amounts of the hydroarylation
products (see Table S2).
The addition of aromatic C-H bonds to styrenes offers a
straightforward method for the synthesis of 1,1-(branched) and 1,2-
(linear) diarylethane derivatives, which are structural motifs often
found in biologically active compounds. There are two known major
types of reactions that can be used to achieve such transformations,
namely, Friedel-Crafts type alkylation by Lewis (or Brønsted) acid
catalysis1 and hydroarylation through C-H bond activation by
transition metal catalysts (Scheme 1a).2,3 The two types of
hydroarylation reactions are characterized by different substrate
scopes and regioselectivities. The former reaction takes place only
with electron-rich arenes and selectively affords the branched
adducts because of the positive charge on the R-position of styrene
that develops upon Lewis acid coordination. On the other hand,
the latter reaction usually requires a directing group or other
electronic perturbations (e.g., electron-poor heteroarenes) on the
arene and preferentially affords the linear adduct due to the steric
factors during the insertion of the CdC bond into the MsH bond,
with only a few exceptions.4 Here we report on cobalt-catalyzed,
chelation-assisted hydroarylation reactions of styrenes, which
uniquely allow for switching of the branched/linear regioselectivity
by ligand control (Scheme 1b).
Table 1. Cobalt-Catalyzed Reaction of 2-Phenylpyridine 1a and
Styrene 2aa
Entry
Ligand (mol %)
RMgX (mol %)
Yield (3aa:4aa)b
1
2
3
4
5
PCy3 (10)
PCy3 (10)
PCy3 (5)
IMes•HCl (10)
IMes•HCl (10)
tBuCH2MgBr (100)
Me3SiCH2MgCl (80)
Me3SiCH2MgCl (50)
tBuCH2MgBr (100)
Me3SiCH2MgCl (100)
68% (98:2)
81% (98:2)
88% (96:4)d
84% (3:97)d
3% (<1:99)
Scheme 1. Hydroarylation Reactions to Styrenes
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), CoBr2 (10
mol %), ligand, RMgX, THF (0.3 M), 60 °C, 12 h. b Determined by GC
using n-tridecane as an internal standard. c 5 mol % of CoBr2 were used.
d Isolated yields.
The above two catalytic systems were applicable to a variety of
arylpyridine derivatives (Table 2). The substrates bearing electron-
donating substituents at the 4- or 3-positions, under Co-PCy3 and
Co-IMes catalyzed conditions, reacted with styrene to afford the
corresponding branched and linear products, respectively, in moder-
ate to good yields with a regioselectivity greater than 90:10 (entries
1-4). The 3-substituted substrates underwent C-C bond formation
exclusively at the less hindered position (entries 3 and 4). A slight
decrease in the regioselectivity was observed with a 4-fluoro
substituent (entry 5). With a highly electron-withdrawing CF3 group,
the regioselectivity of the Co-PCy3 catalysis decreased to 79:21
(entry 6). Moreover, the Co-IMes catalysis afforded the branched
We recently reported on hydroarylation reactions of internal
alkynes through chelation-assisted or heteroatom-directed C-H
bond activation by cobalt-phosphine-Grignard ternary catalytic
systems.5,6 As a natural extension of this chemistry we became
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400 J. AM. CHEM. SOC. 2011, 133, 400–402
10.1021/ja108809u  2011 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cobalt-Catalyzed Addition of 2-Phenylpyridine to Various
product as the major product with a regioselectivity of 85:15. These
observations suggest that the reaction pathways to the branched
and linear products are competing with each other (vide infra), and
the competition is affected not only by the ligand but also by the
electronic nature of the substrate. It was also notable that the
presence of a 2-methyl group completely stopped the Co-PCy3
catalysis but did not interfere with the Co-IMes catalysis (entry
7). On the other hand, steric hindrance at the pyridyl ring did not
interfere with the reaction (entry 8).
Styrene Derivativesa
Yield (3:4)b
Entry
R
Co-PCy3 catalysis
Co-IMes catalysis
69% (1:99)c
60% (6:94)c
78% (<1:99)c
72% (9:91)
74% (10:90)
69% (2:98)
62% (7:93)d
84% (2:98)c
68% (39:61)
39% (<1:99)c
Table 2. Cobalt-Catalyzed Addition of 2-Arylpyridine Derivatives to
1
2
3
4
5
6
7
8
9
4-MeC6H4 (2b)
3-MeC6H4 (2c)
2-MeC6H4 (2d)
4-PhC6H4 (2e)
4-MeOC6H4 (2f)
4-FC6H4 (2g)
3-FC6H4 (2h)
2-FC6H4 (2i)
93% (>99:1)
87% (99:1)
34% (92:8)d
80% (99:1)
68% (99:1)
86% (94:6)d
66% (>99:1)d
N.R.
Styrenea
2-Naphthyl (2j)
tBu (2k)
88% (>99:1)
7% (<1:99)
10
a The reaction was performed on
a
0.3 mmol scale. Co-PCy3
catalysis: CoBr2 (10 mol %), PCy3 (10 mol %), Me3SiCH2MgBr (80
mol %), 60 °C, 12-52 h; Co-IMes catalysis: CoBr2 (10 mol %),
IMes•HCl (10 mol %), tBuCH2MgBr (100 mol %), 60 °C, 12-48 h.
b Isolated yield. Regioselectivity was determined by 1H NMR or
GC. N.R.
)
No reaction. c Dialkylation products (5-13%) were
obtained. d Loadings of CoBr2, the ligand, and the Grignard reagent
were doubled.
catalyst loading (20 mol %). The Co-PCy3 catalysis, followed by
acidic hydrolysis, afforded the branched ketone products in moder-
ate to good yields with high regioselectivity. On the other hand,
the Co-IMes catalysis was sensitive to the nature of both the imine
and olefin, resulting in varying yields and regioselectivities. Note
that the CdN bond of the imine remained untouched under the
present reaction conditions.
a The reaction was performed with 0.3 mmol of the arene and 0.36
mmol of styrene. Co-PCy3 catalysis: CoBr2 (10 mol %), PCy3 (10 mol
%), Me3SiCH2MgBr (80 mol %), 40-80 °C, 12-72 h; Co-IMes
catalysis: CoBr2 (10 mol %), IMes•HCl (10 mol %), tBuCH2MgBr (100
mol %), 40-80 °C, 12-72 h. For detailed conditions for each substrate,
see Supporting Information. b Isolated yield. Regioselectivity was
Scheme 2. Addition of Aryl Iminesa
determined by H NMR or GC. N.R. ) No reaction. c tBuCH2MgBr was
1
used instead of Me3SiCH2MgCl. d Dialkylation product was obtained in
18% yield. e Loadings of CoBr2, the ligand, and the Grignard reagent
were doubled.
Table 3 summarizes the addition reactions of 1a to various
styrene derivatives. Styrenes bearing electron-donating or neutral
substituents generally performed well for both of the catalytic
systems in terms of efficiency and regioselectivity (>90:10) (entries
1-5), except that a methyl group at the 2-position slowed the
Co-PCy3 catalysis. Some of the Co-IMes catalyzed reactions were
accompanied by small amounts (5-13%) of dialkylation products.
Note that R-methylstyrene failed to react under the Co-PCy3
catalysis, while the Co-IMes catalysis gave its linear adduct in
26% yield (data not shown). The reactions of fluorine-substituted
styrenes were relatively sluggish and required a higher catalyst
loading (20 mol %) in some cases, yet afforded the products in
reasonable yields with high regioselectivity (>90:10), except
2-fluorostyrene, which failed to participate in the reaction under
the Co-PCy3 catalysis (entries 6-8). The Co-IMes catalysis of
2-vinylnaphthalene resulted in a significant decrease in the regi-
oselectivity (b/l ) 39:61), while perfect regioselectivity was
achieved with the Co-PCy3 catalysis (entry 9). Alipahtic olefins
such as tert-butylethylene exclusively afforded the linear product
in low yield regardless of the catalytic system (entry 10).
a The reaction was performed with 0.3 mmol of the imine and 0.36 mmol
of the olefin. PMP ) p-Methoxyphenyl. Co-PCy3 catalysis: CoBr2 (20 mol
%), PCy3 (20 mol %), Me3SiCH2MgBr (160 mol %), 60 °C, 72 h; Co-
IMes catalysis: CoBr2 (20 mol %), IMes•HCl (20 mol %), tBuCH2MgBr
(200 mol %), 60 °C, 72 h. In parentheses is shown the b/l ratio.
To gain insight into the reaction mechanism, deuterium-labeling
experiments were performed (Scheme 3). Thus, the reactions of
1a-d5 with 4-vinylbiphenyl 2e under the Co-PCy3 and Co-IMes
catalyzed conditions were stopped at an early stage. 1H NMR
analysis of the recovered starting materials and the hydroarylation
products revealed extensive H/D scrambling between 1a-d5 and 2e
prior to product formation. Thus we observed a significant decrease
in the deuterium content at the ortho position of 1a-d5 and a
considerable degree of deuterium incorporation into the R- and
ꢀ-positions of 2e in both of the catalytic systems. As a natural
consequence of this the products bore deuterium atoms at both the
R- and ꢀ-positions. Note that, under the Co-PCy3 catalysis, the
deuterium content was higher at the ꢀ-position than at the R-position
and that this trend was reversed for the Co-IMes catalysis.
The addition of an aromatic imine to styrene was also achieved
(Scheme 2), while the reaction was sluggish and required a higher
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J. AM. CHEM. SOC. VOL. 133, NO. 3, 2011 401

C O M M U N I C A T I O N S
Scheme 3. Deuterium-Labeling Experimentsa
Acknowledgment. We thank the National Research Foundation,
Singapore (NRF-RF2009-05 to N.Y.) and Nanyang Technological
University for generous financial support.
Supporting Information Available: Details of experimental pro-
cedures and physical properties of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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