Bimetallic nickel aluminun mediated para -selective alkenylation of pyridine: Direct observation of φ2,φ1-pyridine Ni(0)-Al(III) intermediates prior to C-H bond activation

Article abstract of DOI:10.1021/ja1061246

We have presented new amino-NHC Ni-Al complex mediated para C-H bond activation for pyridine and quinolin, and isolated for the first time the intermediate structure of a bimetallic φ²,φ¹- pyridine nickel aluminum complex prior to its C-H activation, which serves as key evidence for bimetallic catalysis.

Full text of DOI:10.1021/ja1061246

Published on Web 08/06/2010
Bimetallic Nickel Aluminun Mediated Para-Selective Alkenylation of Pyridine:
Direct Observation of η2,η1-Pyridine Ni(0)-Al(III) Intermediates Prior to C-H
Bond Activation
Chung-Chih Tsai,† Wei-Chih Shih,† Cyong-Hui Fang,† Chia-Yi Li,† Tiow-Gan Ong,*,† and
Glenn P. A. Yap‡
Institute of Chemistry, Academia Sinica, Nangang, Taipei, Taiwan, Republic of China and Department of Chemistry
and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received July 10, 2010; E-mail: tgong@chem.sinica,edu.tw
Table 1. Direct Para and Meta Alkenylation of 10 with 2 Mediated
by Nickel-Lewis Acid Supported by Amino Pendant Linked NHCa
Abstract: We have presented new amino-NHC Ni-Al complex
mediated para C-H bond activation for pyridine and quinolin, and
isolated for the first time the intermediate structure of a bimetallic
η2,η1-pyridine nickel aluminum complex prior to its C-H activation,
which serves as key evidence for bimetallic catalysis.
Transition-metal-catalyzed aromatic C-H bond functionalization
constitutes a hot area of research,1 representing an economical and
greener synthetic platform for the assembly of biologically and
industrially relevant aromatic molecules. Recent elegant work by
Hiyama’s group utilizes bifunctional catalysts consisting of nickel
and a Lewis acid to derivatize the C-H bond of heterocyclic
compounds.2 This is in contrast to the conventional protocol relying
on the assistance of directing groups to facilitate C-H bond
transformations.3 Nonetheless, the exact synergistic effect invoked
by this bimetallic complex and its reaction pathway remain an
enigma. The employment of N-heterocyclic carbenes (NHCs) in
metal mediated C-H activation is still very much in its infancy,4
despite its ubiquity in homogeneous transition metal catalysis. We
wish to report the para C-H bond activation of pyridine and
quinoline using amino-linked NHC 3 as a supporting platform for
a Ni-Al bimetallic catalyst. This offers a complementary approach
different from the general ortho-selectivity observed via directing
functional groups.5 Furthermore, providing a key to unlock the
complexity of this chemistry, an intermediate has been successfully
isolated prior to the C-H bond cleavage and is characterized as
an η2,η1-Pyridine Ni(0)-Al(III) complex.
a The reactions were carried out using 10 (1 equiv) and 2 (2 equiv)
determined by 1H NMR analysis. b Isolated yield based on heterocyclic
substrate as the limiting reagent. c Para/meta selectivities are in
brackets.
Table 2. Expanded Scope of Nickel-AlMe3 Amino-NHC 3 Mediated
C-4/C-3 Alkenylation of Heterocyclic Compounds (Het-cyc)a
The results of our initial investigation of the alkenylation of
pyridine (10) by 4-octyne (2), using 20 mol % AlMe3-amino-NHC
(3-Al)6 in the presence of 10 mol % Ni[COD]2 at 80 °C, are outlined
in Table 1. To our delight, the desired coupling products 10 were
obtained in good yield (83%). A similar catalytic yield could also
be achieved by adding all of the necessary components in situ
without resorting to the preparation of complex 3-A1. Detailed
NMR spectroscopic analysis into the distribution of the products
revealed a 10:3 ratio of 10aa and 10bb7 with no detection of ortho
product 10cc. Substitution of AlMe3 for other Lewis acids, such as
ZnMe2 and BH3, yielded only disappointing outcomes.
With the optimized reaction conditions in hand, we further
studied the scope and limitations of the dual catalyst Ni-AlMe3
(Table 2). Excellent para-regioselectivity was observed for 2-pi-
coline (11), 3-picoline (12), and methoxypyridine derivatives (15)
and (16). However, diminishing yields were witnessed for 4-picoline
a The reactions were carried out using 1 (1 equiv) and 2 (2 equiv)
and determined by 1H NMR analysis. Isolated yields are based on the
heterocyclic substrate as the limiting reagent. para:meta selectivities are
in brackets. b 3 equiv of 2 was used in this reaction.
(13) and 3,5-lutidine (14), suggesting sensitivity of the reaction
toward a steric environment. 3-Phenylpyridine (18) gave ap-
proximately equal amounts of para and meta functionalization with
a satisfactory yield of 71%. The electron-withdrawing effect of the
phenyl group may lead to greater meta activation. Quinoline (19)
and 6-methylquinoline (20) also participated in the catalytic reaction,
giving mostly para-alkenylated products in good yields. It is worth
noting that the C-H transformations of the phenyl-pyridine and
quinoline derivatives proceeded exclusively on the pyridyl ring,
which is in sharp contrast to other reported examples.8
† Academia Sinica.
‡ University of Delaware.
9
10.1021/ja1061246  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 11887–11889 11887

C O M M U N I C A T I O N S
Scheme 1
Scheme 2. Plausible Mechanism
In order to gain more insight into the regioselectivity and
mechanism of this reaction, Ni[COD]2 was treated stoichiometrically
with 3-Al and pyridine at room temperature. 3-Al was completely
consumed within a few hours (Scheme 1), and a new nickel complex
(4) was formed as a single organometallic product.9 The structure
of 4 was unambiguously confirmed by X-ray crystallography
(Figure 1), displaying a three-coordinate nickel (0) σ-bound to two
amino-NHCs with normal bond lengths of 1.8949(8) and 1.9224(17)
Å. One η2-bound pyridine (via C3-C4 of the ring) completes the
coordination sphere of Ni. The long bond length of C39-C40
(1.455 Å) signifies a high degree of π-back-donation from the metal
to the pyridine moiety. Interestingly, AlMe3 is bridged to the nickel
complex by coordination at the pyridine nitrogen (Al-N(7)
1.996(2)), illustrating the rationale for the para/meta-selectivity over
ortho-selectivity in our system. Performing the reaction with
pyridine using 4 in catalytic or stoichiometric amounts generated
the alkenylated product in good yield, implying that 4 is not the
resting state in the catalytic cycle. To our knowledge, this represents
the first structurally isolated example of C-H bond activation via
a synergistic effect played by a Ni-Al interaction, a proof of
concept that Lewis acids augment the C-H acidity of the pyridine,
as proposed by Hiyama.2
amino side arm. Finally, a competition experiment was performed
in order to obtain the kinetic isotope effect between the pyridine
10 and deuterated-10.11 A small primary KIE of 1.25 indicates that
the C-H bond breaking step is not the rate-limiting step of the
reaction.12 The result is consistent with the X-ray diffraction
findings (Vide supra) highlighting the importance of pyridine
π-coordination prior to C-H bond activation.13 On the basis of
the above studies and the precedent reports, a mechanistic proposal
of the present Ni-Al catalysis is depicted in Scheme 2. It can be
assumed that addition of (NHC)AlMe3 and pyridine leads to
complex 4. The following oxidative addition process is proposed
to afford the Ni hydride intermediate 6 upon coordination of alkyne.
The subsequent alkyne insertion and reductive elimination of the
nickel pyridyl 7 would deliver the product 10aa along with the
generation of (NHC)Ni for the next catalytic cycle.
In summary, we have presented a new amino-NHC Ni-Al
system that mediates para C-H bond activation of pyridine and
quinoline derivatives and have also isolated the structure of a
bimetallic η2,η1-pyridine Ni(0)-Al(III) intermediate (4) prior to the
C-H bond activation step. Further exploration of the synergistic
bimetallic catalysis on the scope of the reaction and detailed
mechanistic studies are ongoing in our laboratory, to be reported
in due course.
Acknowledgment. This communication is dedicated to the
memory of Professor Keith R. Fagnou. We are grateful to the
Taiwan National Science Council (NSC: 97-2113-M-001-024-MY2)
and Academia Sinica for their generous financial support. We also
thank Prof. Dr. Pierre Dixneuf (University of Rennes) and Prof.
Dr. Jennifer Scotts (Royal Military College of Canada, Kingston,
Ontario) for helpful suggestions and discussions.
Figure 1. ORTEP diagram of Ni-Al complex 4 with ellipsoids drawn at
30% probability level. All other hydrogen atoms have been omitted for
clarity.
Supporting Information Available: Detailed experimental proce-
dures, including spectroscopic and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Several observations in this reaction are worth mentioning. First,
our examination of different Al adducts revealed an inverse
relationship between the Al electrophilicity and the yield of the
reaction.10 1H NMR monitoring of the catalytic reaction employing
AlMe2Cl as a Lewis acid shows the formation of a trace amount
of species 5, an aluminum ion pair that has been confirmed by single
crystal X-ray analysis (Scheme 1).9 Performing the catalytic reaction
with 5 under similar conditions furnished a disappointingly low
conversion (29%).10 These findings suggest that the stronger Al-
NHC binding and stable ion pair species may retard the formation
of Ni-NHC and pyridine-Al species, key ingredients in the catalytic
cycle. Second, we hypothesized that the hard donor amino side
arm may have acted as a hemilable anchor, briefly stabilizing the
reactive nickel center before being displaced by small molecule
substrates. Control experiments using a series of classical unsatur-
ated and saturated symmetrical NHCs lacking an amino side arm
led to an average yield of 28%,11 validating the importance of the
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