A strategy for C-H activation of pyridines: Direct C-2 selective alkenylation of pyridines by Nickel/Lewis acid catalysis

Article abstract of DOI:10.1021/ja710766j

The C-2 selective alkenylation of pyridine derivatives is achieved with a catalyst consisting of nickel and Lewis acid. Use of diorganozinc compounds as the Lewis acid catalyst gives C-2 monoalkenylation products, whereas AlMe₃ changes the reaction course to afford C-2 dienylated products, which are derived from double insertion of alkynes into the C(2)-H bond. The reaction demonstrates a broad substrate scope and proceeds with high chemo-, regio-, and stereoselectivities under mild conditions compared with previous examples of direct C-H functionalization of pyridines. Copyright

Full text of DOI:10.1021/ja710766j

Published on Web 02/05/2008
A Strategy for C-H Activation of Pyridines: Direct C-2 Selective Alkenylation
of Pyridines by Nickel/Lewis Acid Catalysis
Yoshiaki Nakao,* Kyalo Stephen Kanyiva, and Tamejiro Hiyama*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received December 3, 2007; E-mail: nakao@npc05.kuic.kyoto-u.ac.jp; thiyama@npc05.kuic.kyoto-u.ac.jp
Scheme 1. Catalytic Direct C-2 Alkenylation of Pyridines by
Nickel-Lewis Acid Cooperative Catalysis
A large number of pharmaceuticals, natural products, and optical
materials contain a pyridine nucleus. Thus, the functionalization
of pyridines is an important transformation in organic synthesis.
However, due to the low reactivity of pyridine derivatives toward
aromatic electrophilic substitution reactions such as the Friedel-
Crafts reaction, additional steps including halogenation and meta-
lation are required to install substituents in a pyridine ring.1
Accordingly, the development of a direct C-H functionalization2
of pyridine catalyzed by transition metals has gained significant
attention and importance.3-6 Nevertheless, the limited number of
reported examples suffers from harsh reaction conditions of over
150 °C,3 limited scope of substrates,4 requires the presence of a
directing group,5 or employs N-oxides.6 We have also recently
reported the C-2 alkenylation of pyridine-N-oxides by mild nickel
catalysis.6c Since the enhanced reactivity of pyridine-N-oxides,
compared with that of parent pyridines, is apparently attributed to
an electron-deficient nitrogen that increases the acidity of the
C(2)-H bond, we envisioned that a similarly activated pyridine
species could be generated catalytically in situ by the coordination
of the nitrogen to a Lewis acid (LA) catalyst (Scheme 1). Herein,
we report that a combination of nickel and LA catalysts allows the
direct C-2 alkenylation of pyridines under mild conditions. More-
over, the single or double insertion of alkynes into the C(2)-H
bond of pyridines is successfully controlled by simply changing
the LA catalyst.
At the onset, we briefly examined effects of various LA catalysts
toward the reaction of pyridine (1a, 3.0 mmol) and 4-octyne (2a,
1.0 mmol) in the presence of Ni(cod)2 (3 mol %) and P(i-Pr)3 (12
mol %) in toluene at 50 °C and found that zinc and aluminum
catalysts with mild Lewis acidity were highly effective (Table 1).
Thus, the reaction in the presence of ZnMe2 (6 mol %) afforded
C-2 alkenylated product 3aa highly stereoselectively in 95% yield
(entry 1), whereas the absence of the LA or the nickel catalyst gave
no trace amount of the adduct. A small amount of C-2 dienylated
product 4aa was also observed, the formation of which was
suppressed by running the reaction at 80 °C (entry 2). ZnPh2 was
equally effective to give 3aa in 88% yield after isolation by silica
gel chromatography (entry 3). A stronger zinc LA catalyst, ZnCl2,
was completely ineffective.7 Although an equimolar reaction of 1a
with 2a resulted in a low yield of 3aa (55% by GC) due to
competitive trimerization of 2a, no trace amount of a C-2 and C-6
dialkenylated product was observed. On the other hand, the use of
AlMe3 as a LA catalyst dramatically changed the reaction course,
affording 4aa as a major adduct in 80% isolated yield (based on
2a as the limiting reagent) together with a small amount of 3aa
(entry 4). The identical reaction at 80 °C, however, gave a mixture
of 3aa and 4aa (entry 5), suggesting that a higher reaction
temperature preferred the formation of 3aa over 4aa irrespective
of the kind of LA catalysts used (entry 1 vs entry 2 and entry 4 vs
entry 5). Again, aluminum LA catalysts with a stronger Lewis
acidity were inferior.7 In either system, the direct C-H function-
alization of pyridine by nickel-LA dual catalysis under relatively
mild conditions at 50-80 °C is worth noting, compared with the
reported ruthenium and rhodium catalysis.3,8
Table 1. Direct C-2 Alkenylation of 1a with 2a Catalyzed by
Nickel-Lewis Acida
temp
C)
yield of
3aab (%)
yield of
4aab (%)
entry
LA
(
°
1
2
3
4
5
ZnMe2
ZnMe2
ZnPh2
AlMe3
AlMe3
50
80
50
50
80
95
3
<1
3
95c
96 (88)d
5
82 (80)d
56d,e
17d
a The reactions were carried out using 1a (3.0 mmol), 2a (1.0 mmol),
n-C11H24 (internal standard, 0.50 mmol), Ni(cod)2 (3.0 mol %), P(i-Pr)3
(12 mol %), and a Lewis acid (6.0 mol %) in toluene (2.5 mL). b Determined
by GC based on 2a as the limiting reagent. c E/Z ) 93:7. d Isolated yields.
e ZE/EE/others ) 52:43:5.
With the binary catalyst systems effective for the C-2 selective
alkenylation of pyridines, we further tested the scope of the present
transformation (Table 2). A range of electron-withdrawing and
-donating substituents on the 4-position of pyridine tolerated the
reaction conditions to give the corresponding adducts in good yields
(entries 1-5). Some of the substituted pyridines also participated
in the dienylation reaction under nickel-AlMe3 catalysis (entries
6 and 7). Excellent regioselectivities were observed with 3-substi-
tuted pyridines 1g and 1h, which were alkenylated at the C-6
position exclusively (entries 8 and 9). The sensitivity of the reaction
toward a steric environment of substrates was also observed with
2-picoline (1i), corresponding adduct 3ia being obtained in a modest
yield even at 100 °C (entry 10). Quinoline (1j) and pyrazine (1k)
also underwent the present C-2 alkenylation reaction (entries 11
and 12). The use of other alkynes in this reaction was also briefly
examined. Bis(silylmethyl)acetylene 2b underwent the reaction with
1a to give pyridyl-substituted allylsilane 3ab (entry 13), whereas
the addition across diphenylacetylene (2c) was sluggish (entry 14).
The reactions of unsymmetrical internal alkynes, 4,4-dimethyl-2-
pentyne (2d) and trimethyl(phenylethynyl)silane (2e), were highly
regioselective to give the corresponding adducts having a smaller
9
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J. AM. CHEM. SOC. 2008, 130, 2448-2449
10.1021/ja710766j CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
The pyridines activated by coordination to a LA10 would be
responsible for the oxidative addition of the C(2)-H bond to nickel-
(0) species A,11 a plausible initiation step of the present catalysis
(Scheme 2).12 Hydronickelation across the alkyne coordinating to
the nickel center in the direction avoiding a steric repulsion between
the bulkier R3 and the pyridyl group in B takes place to give C,
which upon reductive elimination affords 3 in the presence of zinc
LA catalysts (path A). The use of AlMe3, a stronger Lewis acid
than diorganozincs,10 or lower reaction temperature retards the
reductive elimination and/or promotes the second insertion of an
additional alkyne into either of the C-Ni bonds in C to give D or
E, resulting in the formation of dienylated product 4 upon reductive
elimination (path B).13 Another mechanistic scenario involving a
metallacycle formation14 (not shown) could be conceivable. Ex-
perimental and theoretical mechanistic analyses will be further
investigated in detail.
Table 2. Nickel-Lewis Acid Catalyzed Direct C-2 Alkenylation of
Pyridines
In conclusion, we have demonstrated the divergent direct C-2
alkenylation of pyridines by nickel-LA cooperative catalysis to
synthesize a wide variety of 2-alkenylated pyridines in chemo-,
regio-, and stereoselective manners under mild conditions. Develop-
ment of other C-H functionalizations by nickel-LA dual catalysis
is in progress in our laboratories.
Acknowledgment. We thank Professor James P. Stambuli for
proof reading the manuscript and helpful comments. This work has
been supported financially by a Grant-in-Aid for Creative Scientific
Research and that for Priority Areas “Chemistry of Concerto
Catalysis” from MEXT, The Sumitomo Foundation, and The
Uehara Memorial Foundation. K.S.K. acknowledges Honjo Inter-
national Scholarship Foundation for financial support.
Supporting Information Available: Detailed experimental pro-
cedures including spectroscopic and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 2. Plausible Mechanism
(7) See Supporting Information for details.
(8) The mild reaction conditions of the present protocol could also be derived
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substituent on the same side as the pyridyl group (entries 15 and
16), although silyl-substituted adduct 3ae isomerized under the
reaction conditions to give a stereoisomeric mixture.9 Terminal
alkynes were not applicable to this transformation due to rapid oligo-
and/or trimerization.
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