Cobalt-catalyzed hydroarylation of alkynes through chelation-assisted C-H bond activation

Article abstract of DOI:10.1021/ja106814p

Ternary catalytic systems consisting of cobalt salts, phosphine ligands, and Grignard reagents promote addition of arylpyridines and imines to unactivated internal alkynes with high regio- and stereoselectivities. Deuterium-labeling experiments suggest that the reaction involves chelation-assisted oxidative addition of the aryl C-H bond to the cobalt center and insertion of the C-C triple bond into the Co-H bond, followed by reductive elimination of the resulting diorganocobalt species.

Full text of DOI:10.1021/ja106814p

Published on Web 08/16/2010
Cobalt-Catalyzed Hydroarylation of Alkynes through Chelation-Assisted C-H
Bond Activation
Ke Gao, Pin-Sheng Lee, Takeshi Fujita, and Naohiko Yoshikai*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological UniVeristy, 21 Nanyang Link, Singapore 637371
Received July 30, 2010; E-mail: nyoshikai@ntu.edu.sg
product, 4aa, in 83% yield, together with a small amount of a
Abstract: Ternary catalytic systems consisting of cobalt salts,
monoalkenylated product, 3aa (Scheme 1a and Table 1, entry 1).
phosphine ligands, and Grignard reagents promote addition of
arylpyridines and imines to unactivated internal alkynes with high
regio- and stereoselectivities. Deuterium-labeling experiments
suggest that the reaction involves chelation-assisted oxidative
addition of the aryl C-H bond to the cobalt center and insertion
of the C-C triple bond into the Co-H bond, followed by reductive
elimination of the resulting diorganocobalt species.
The syn-addition product was confirmed by nuclear Overhauser
effect experiments. A small amount (<3%) of an ortho-methylated
product was also detected by gas chromatography and gas chro-
matography/mass spectrometry (vide infra). The amount of MeMgCl
could be reduced to 60 mol % without noticeable decrease of the
product yield after 12 h, while the reaction rate became slightly
lower (entry 2). The reaction became very sluggish with 50 mol %
MeMgCl (entry 3) and eventually stopped with less than 40
mol % MeMgCl (see Supporting Information). The use of
Chelation-assisted C-H bond cleavage by a transition metal
complex is well established as a versatile strategy for regioselective
C-H bond functionalization.1 Among such transformations, alkyl-
ation and alkenylation through C-H addition to C-C multiple
bonds represent the simplest atom-economical reactions. Since the
groundbreaking work of Murai and co-workers,2 second-row
transition metals such as ruthenium and rhodium have been the
catalysts of choice.1a,e,h,3 On the other hand, first-row metals,
regardless of their availability,4 have been rarely exploited for such
C-H addition reactions,5-7 while a number of relevant elementary
reactions, e.g., cyclometalation reactions, have been found to date.8
We report here cobalt-catalyzed addition of arylpyridines and imines
to unactivated internal alkynes that stereoselectively afford trisub-
stituted olefins through syn-addition of the ortho C-H bond across
the C-C triple bond (Scheme 1).9
CoBr2(PMePh2)2 as the precatalyst resulted in a similar catalytic
performance (entry 4). While low-valent cobalt complexes are well
known to catalyze cyclotrimerization of alkynes,10 only a trace
amount of such a product was detected under the above conditions.
Other monodentate phosphines such as PPh3, PMe2Ph, and PCy3
were much less effective (entries 5-7), and bidentate phosphines
(dppe, dppp, dppf, etc.) completely stopped the reaction. The use
of Grignard reagents other than MeMgCl resulted in much lower
yields of the alkenylation products (entries 8-11). Other reducing
agents such as BuLi and Et2Zn did not perform well. CoBr2 worked
best among common cobalt precatalysts including CoCl2, Co(acac)2,
and Co(acac)3.11 Other precatalysts (e.g., Mn, Fe, Ni, Cu, Ru, Rh,
Pd, and Ir salts) did not catalyze the reaction under otherwise
identical conditions (see Supporting Information).
Table 1. Cobalt-Catalyzed Reaction of 2-Phenylpyridine (1a) and
4-Octyne (2a)a
Scheme 1. Cobalt-Catalyzed Hydroarylation of Internal Alkyne
yield (%)b
entry
ligand
RMgX (mol %)
3aa
4aa
1
2
PMePh2
PMePh2
PMePh2
MeMgCl (100)
MeMgCl (60)
MeMgCl (50)
3 [29] (4)
77 [45] (83)
4 [45]
54
8
76 [31]
3
19
73
0
34
0
20
36
0
4c
5
MeMgCl (100)
MeMgCl (100)
MeMgCl (100)
MeMgCl (100)
nBuMgBr (100)
iPrMgBr (100)
tBuMgBr (100)
tBuCH2MgBr (100)
PPh3
PMe2Ph
PCy3
PMePh2
PMePh2
PMePh2
PMePh2
36
45
2
41
29
19
42
6
7
8
9
10
11
9
a Reaction conditions: 1a (0.3 mmol), 2a (2.5 equiv), CoBr2 (10 mol
%), ligand (20 mol %), RMgX, THF (0.4 M), 100 °C in sealed vessel,
12 h. b Determined by GC using n-tridecane as an internal standard. In
brackets and parentheses are shown yields at 1 h and isolated yields,
respectively. c CoBr2(PMePh2)2 (10 mol %) was used instead of CoBr2
and PMePh2.
We initially chose 2-phenylpyridine (1a) and 4-octyne (2a) as
model substrates. Extensive screening of cobalt precatalysts, ligands,
and reducing agents led us to find that 1a reacts with 2a in the
presence of a cobalt catalyst generated in situ from CoBr2 (10 mol
%), PMePh2 (20 mol %), and MeMgCl (100 mol %) at 100 °C
(bath temperature) in THF for 12 h to give an ortho-dialkenylated
Chart 1 illustrates the scope and limitation of the present reaction.
In general, the reaction showed excellent cis-stereoselectivity
(E/Z > 99/1) with a few exceptions (see 3ie and 3kh). Arylpyridines
bearing methoxy, dimethylamino, fluoro, and trifluoromethyl groups
9
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J. AM. CHEM. SOC. 2010, 132, 12249–12251 12249

C O M M U N I C A T I O N S
at the para position smoothly reacted with 4-octyne to give the
corresponding dialkenylated products 4ba-4ea in good yields of
73-86%. Substrates bearing meta-substituents (Me, CF3, and
OTBS) were alkenylated exclusively at the less hindered position
to give the products 3fa-3ha in 55-62% yields. A methyl group
at the 3-position of the pyridine ring also prevented dialkenylation,
and the product 3ia was obtained in 75% yield. An ortho-methyl
group significantly slowed the reaction to give 3ja in 35% yield.
The reaction of benzo[h]quinoline under the standard conditions
was sluggish, while modified conditions employing P(4-MeOC6H4)3
and neopentylmagnesium bromide at 60 °C gave the product 3ka
in 68% yield. Heteroarenes such as pyrrole and thiophene also
participated in the reaction (see 4la and 3ma). A pyrazolyl group,
although not as good as a pyridyl group, also served as a directing
group to afford a mixture of mono- (3na) and dialkenylation (4na)
products.
A variety of internal aliphatic alkynes participated in the reaction
to give the alkenylated products 3ib-3if in moderate to good yields.
Unsymmetrical alkynes underwent C-C bond formation at steri-
cally less hindered positions. While the reaction of 2-hexyne resulted
in a modest regioselectivity (71:29), perfect regioselectivity was
observed when the bulkier substituent on the alkyne was a secondary
or tertiary alkyl group (see 3ib-3id). The presence of silyl and
benzyloxy groups could be tolerated (see 3ie, 3if). A silylalkyne
also participated in the reaction, albeit in a low yield (see 3ig).
The reaction of diphenylacetylene was rather sluggish under the
standard conditions, while the modified conditions (vide supra) gave
the products 3ah and 3kh in 57% and 78% yields, respectively.
Terminal alkynes such as phenylacetylene and 1-octyne did not
participate in the reaction.
Aryl imines 1o and 1p, which were derived from the corre-
sponding ketones and p-anisidine, were also amenable to hydroaryl-
ation reaction by a cobalt/phosphine/Grignard ternary catalytic
system (Scheme 1b). While the original system (i.e., CoBr2/PMePh2/
MeMgCl, 100 °C) did not tolerate the imine functionality, an
alternative system consisting of CoBr2 (5 mol %), P(3-ClC6H4)3
(10 mol %), and tBuCH2MgBr (50 mol %) as essential catalyst
precursors and pyridine (80 mol %) as an additive promoted addition
of 1o and 1p to diphenylacetylene 2h under remarkably mild
conditions (20 °C).12 After hydrolysis, the alkenylated ketones 3oh
and 3ph were obtained in good yields and stereoselectivities
(E/Z ) ca. 9/1).
To gain insight into the reaction mechanism, several mechanistic
experiments were carried out. First, the reaction of a 1:1 mixture
of 1a-d5 and 1b with 4-octyne afforded 4aa-d5 and 4ba in 52%
and 74% yield, respectively, without any H/D crossover (Scheme
2a). This result clearly shows that the aryl group and the olefinic
hydrogen atom in the product molecule come from the same reactant
molecule and excludes a deprotonation mechanism for the ortho
C-H bond cleavage. Second, a competitive reaction of 1a/1a-d5
with 4-octyne, which was performed at 40 °C and quenched at the
early stage, gave a mixture of 3aa and 3aa-d5 in 19% and 9% yields
(3aa/3aa-d5 ) 2.1), respectively (Scheme 2b). The intermolecular
kinetic isotope effect value of 2.1 suggests that either C-H bond
cleavage or C-H bond formation is a kinetically important first
irreversible step of the reaction.13 Finally, a stoichiometric reaction
of 1a, CoBr2(PMePh2)2 (1 equiv), and MeMgCl (10 equiv) at 0 °C
for 30 min resulted in ortho-methylation of 1a in 41% yield (see
Supporting Information).14 Although the mechanism of the me-
thylation reaction is not clear at present, this observation suggests
that the C-H bond cleavage is a rather facile step in the present
catalytic hydroarylation reaction.
Chart 1. Scope of Arylpyridines and Alkynesa
Scheme 2. Deuterium-Labeling Experiments
On the basis of the above results, we speculate that the reaction
involves chelation-assisted oxidative addition of the aromatic C-H
bond (cyclometalation) to the cobalt center,15,16 insertion of the
alkyne into the Co-H bond, and reductive elimination of the
resulting alkenylarylcobalt intermediate. While the detailed nature
of the catalytically active cobalt species remains elusive at this stage,
the necessity of a larger amount (>40 mol %) of the Grignard
reagent than required for reduction of cobalt(II) to cobalt(0) (20
mol %) and the considerable effect of the Grignard reagent on the
catalytic activity (Table 1) suggest possible involvement of an
organocobalt(0)ate species as the reactive species.17
a Reaction was performed under the conditions shown in Table 1, entry
1, using either 2.5 equiv (for dialkenylation) or 1.5 equiv (for monoalk-
enylation) of alkyne for 12-24 h. E/Z ratio was >99:1 unless otherwise
indicated. b P(4-MeOC6H4)3 (20 mol %) and tBuCH2MgBr (100 mol %)
was used instead of PMePh2 and MeMgCl, and the reaction was performed
c
at 60 °C. Major regioisomer is shown (ratio ) 71:29). d E/Z ) 16:84.
In summary, we have reported cobalt-catalyzed addition reactions
of arylpyridines and imines to internal alkynes to give trisubstituted
e E/Z ) 84:16.
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C O M M U N I C A T I O N S
(6) For chelation-assisted reactions other than C-H addition to olefins/alkynes,
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J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925–2928.
(7) For C-H addition to olefins/alkynes without chelation assistance, see: (a)
Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1997, 119, 3165. (b)
Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1998, 120,
6965. (c) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem.
Soc. 2006, 128, 8146–8147. (d) Nakao, Y.; Kanyiva, K. S.; Hiyama, T.
J. Am. Chem. Soc. 2008, 130, 2448–2449. (e) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170–16171.
(f) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 5070–5071. (g) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama,
T. J. Am. Chem. Soc. 2009, 131, 15996–15997.
olefins with high regio- and stereoselectivities. Having demonstrated
the feasibility of chelation-assisted C-H addition to a C-C multiple
bond with a first-row transition metal catalyst, we consider that
extension of the present cobalt catalysis will lead to cost-effective
alternatives to a variety of existing C-H/olefin and C-H/alkyne
coupling reactions under rhodium and ruthenium catalysis.1a,e,h,9
Expansion of the substrate scope and further mechanistic studies
are in progress and will be reported in due course.
Acknowledgment. We thank National Research Foundation,
Singapore (NRF-RF2009-05 to N.Y.), and Nanyang Technological
University for generous financial support.
(8) Albrecht, M. Chem. ReV. 2010, 110, 576–623, and references cited therein.
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(11) High-purity (99.99%) and normal-grade (99%) CoBr2 gave similar catalytic
activities (see Supporting Information).
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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