Published on Web 10/16/2009
Direct Alkenylation and Alkylation of Pyridone Derivatives by Ni/AlMe3 Catalysis
Yoshiaki Nakao,* Hiroaki Idei, Kyalo Stephen Kanyiva, and Tamejiro Hiyama*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received August 26, 2009; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp; thiyama@z06.mbox.media.kyoto-u.ac.jp
Pyridone derivatives constitute a core of various important biologically
active compounds, and therefore, methods for rapid access to the
heterocycles substituted at specific positions are of interest to synthetic
and medicinal chemists.1 Whereas significant progress has been made in
protocols for constructing the ring systems with a diverse range of
substitution patterns,1a,2 regioselective introduction of substituents to
existing pyridone derivatives requires prefunctionalization by stoichiometric
metalation or halogenation. On the other hand, an increasing number of
direct C-H functionalizations of heterocycles that allow facile and
regioselective direct installation of new C-C bonds are available.3
Nevertheless, related transformations of pyridone derivatives remain
elusive. Reactions of pyridones with electrophiles are known to proceed
exclusively at the C(5) position (Scheme 1),4 and this inherent reactivity
of the heterocycles has been applied to electrophilic palladation at C(5),
allowing a few precedents for C(5) selective direct arylation and oxidative
alkenylation in the presence of stoichiometric and catalytic palladium(II).5,6
We report herein unprecedented C(6)-selective functionalization of pyri-
done derivatives through inter- and intramolecular insertion of unsaturated
bonds into the C(6)-H bond by nickel/Lewis acid (LA) catalysis as a
complementary protocol for accessing substituted pyridones.
group at the C(3) or C(4) position did not affect the reaction (entries 2-4),
whereas the C(5) methyl group of 1e retarded the reaction, presumably
because of steric repulsion (entry 5). N-Methylisoquinolone (1f), -pyrimi-
done (1g), and -quinazolone (1h) also participated in the alkenylation, albeit
with modest yield or stereoselectivity (entries 6-8).9 The formal trans
adducts observed with 3ga and 3gh having R,ꢀ-unsaturated imine
substructures are likely derived from isomerization of the initial cis adducts,
possibly through a phosphine-catalyzed process, given the fact that an
isolated sample of (E)-3ha readily isomerizes to (Z)-3ha (E/Z ) 57:43
after 1.5 h) under the reaction conditions in the presence of 1a and 2a.
On the other hand, N,N-dimethyluracil (1i) underwent the alkenylation
reaction with a range of alkynes with perfect stereo- and regioselectivities,
with the heterocycle being introduced trans to a bulkier alkyne substituent
(entries 9-14). Moreover, 1-phenyl-1,3-butadiene (2g) reacted with 1i,
albeit in modest yields, and the use of a carbene ligand allowed the insertion
of vinyl arene 2h into the C(6)-H bonds of 1d and 1i, giving the
corresponding C(6)-alkylated products shown in entries 15-17.
Whereas intermolecular alkylation did not take place with terminal
alkenes other than vinyl arenes under these conditions, intramolecular
addition across tethered alkenes proceeded mainly in an exo-trig fashion
to give bicyclic products 5 and 6 in good yields (eq 1):
Scheme 1. Direct Functionalization of 2-Pyridones
We recently disclosed a direct C-H alkenylation of pyridines and
formamides that takes advantage of nickel/LA catalysis.7 Pyridines and
formamides coordinating to a LA cocatalyst through the nitrogen and the
carbonyl oxygen are likely responsible for oxidative addition to nickel(0)
by C(2)-H and formyl C-H bonds, respectively, that are located R to a
formally positively charged nitrogen (Scheme 2). We therefore envisioned
that the C(6)-H bond of pyridones could also be activated by nickel(0)
upon coordination to a LA catalyst at the more basic carbonyl oxygen.
The present nickel/LA catalysis is presumably initiated by η2 coordina-
tion (A in Scheme 3) followed by oxidative addition of the activated
pyridones to give nickel hydride B. Coordination of alkynes to the nickel
center (C) in the direction that avoids steric repulsion between the bulkier
R2 group and the heterocycle, followed by hydronickelation, gives
alkenylnickel intermediate D, which upon reductive elimination affords
3. Coordination and subsequent migratory insertion of 1,3-dienes 2g and
vinyl arene 2h into the H-Ni bond likely give π-allyl- and benzylnickel
intermediates E and F, respectively, which are responsible for the observed
regiochemistry of the alkylations (entries 15-17 of Table 1).
Scheme 2. Plausible C(6)-H Activation of 2-Pyridones by Ni/LA
On the basis of the above mechanism, one could imagine the use of
a simple enamide (e.g. 7), a pyridone substructure, as a substrate for these
Scheme 3. Plausible Mechanism
To test the above viability, we first examined the reaction of N-methyl-
2-pyridone (1a, 1.0 mmol) and 4-octyne (2a, 1.2 mmol) in the presence
of Ni(cod)2 (5 mol %), P(i-Pr)3 (10 mol %), and AlMe3 (20 mol %) in
toluene at 80 °C and found that (E)-N-methyl-6-octen-4-yl-2-pyridone
(3aa) was obtained in 90% yield after 6 h through exclusive C(6)-H
activation (Table 1, entry 1). The cis stereochemisty of the addition reaction
was unambiguously identified by nuclear Overhauser effect experiments
on 3aa.8 The absence of the LA catalyst gave no trace amount of the
adduct.8 Dialkenylation at the C(4) and C(6) positions was also observed
in a small amount (5%).8 An N-benzyl substituent (entry 2) and a methyl
9
15996 J. AM. CHEM. SOC. 2009, 131, 15996–15997
10.1021/ja907214t CCC: $40.75 2009 American Chemical Society
Nakao, Yoshiaki
