COMMUNICATION
DOI: 10.1002/chem.201301350
Nickel-Catalyzed Direct Alkylation of Heterocycles with a-Bromo Carbonyl
Compounds: C3-Selective Functionalization of 2-Pyridones
[
a]
Akihiro Nakatani, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Pyridone derivatives constitute an important class of com-
dppp (cod=1,5-cyclooctadiene, dppp=1,3-bis(diphenylphos-
[1]
pounds in pharmaceutical and medicinal chemistry. In par-
ticular, acetic acids that contain 2-pyridone cores at the posi-
phino)propane) catalyst system with K PO as a base pro-
3
4
moted the reaction of 1a with 2a in heated ortho-xylene to
afford the alkylated 2-pyridone 3aa in good yield
(Scheme 1, conditions A). A combination of hexamethyl-
[2]
tion a to carbonyl groups show unique biological activity.
The palladium, nickel, and copper-catalyzed a-arylation of
carbonyl compounds with halogenated pyridones appear to
[3]
be attractive approaches to the target molecules. However,
the reaction with electron-rich heterocyclic halides is still re-
[4]
stricted in efficiency and selectivity. The metal-promoted
CÀH functionalization chemistry of heterocycles has recent-
ly received significant attention, and the traditional homo-
lytic radical aromatic substitution (HAS) is now revisited as
an efficient and direct functionalization methodology for
[5]
heterocycles. For example, Ru- and Ir-based photoredox
catalysts are applied to the HAS of electron-rich indoles
and pyrroles with a-halo carbonyl compounds and provides
a complementary access to a-heterocyclic acetic acid deriva-
Scheme 1. Reaction conditions for nickel-catalyzed C3-selective alkyla-
tion of N-methyl-2-pyridone (1a) with butyl 2-bromopropanoate (2a).
[6,7]
tives.
However, these photocatalysis reactions still suffer
A
H
U
G
R
N
U
G
(urotropine)
and
2-methyl-2-butanol
from a somewhat narrow substrate scope of a-halo carbon-
yls; only highly activated systems, such as 2-bromomalonate
esters, can be used owing to the limitation of their redox po-
tentials. Although the HAS reaction with xanthates has
been reported, preactivation of a-haloacetates into the cor-
responding xanthates is inevitable, and an excess amount of
peroxide is required. Thus, there remains a challenge to
develop the HAS-type direct alkylation of electron-rich het-
erocycles with less activated a-halo carbonyl compounds.
Herein, we report a nickel-catalyzed HAS-type reaction
with a-bromoacetates. The nickel catalyst enables the alkyl-
(tAmOH) also gave a comparable yield (Scheme 1, condi-
tions B). Particularly notable is that the CÀC bond forma-
tion occurred exclusively at the C3 position of 2-pyridone
and no regioisomers were detected. Such a high C3 selectivi-
[10]
ty is not trivial, and C5- and C6-selective functionaliza-
[11]
[12]
tions are possible under Pd and Ni/Al bimetallic cata-
lysts, respectively.
[8]
By using the conditions A or B shown in Scheme 1, we
performed the direct alkylation of an array of 2-pyridone
derivatives with 2a (Table 1). Regardless of the substitution
pattern on the pyridone ring, the exclusive C3 selectivity
was uniformly observed. Namely, 4-methyl, 5-methyl, and 6-
methyl-2-pyridones (1c–e) also underwent the alkylation,
and the corresponding C3-alkylated products 3ca–ea were
obtained as the single regioisomers (Table 1, entries 3–8).
On the other hand, when the methyl group was introduced
to the C3 position, no reaction took place (Table 1, entries 1
and 2). In addition to the simple methyl group, a trifluoro-
methyl group at the C4 or C5 positions was tolerated, albeit
with somewhat lower efficiencies (Table 1, entries 9 and 10).
The nickel catalysis accommodated the benzyl substituent
on nitrogen, which can be a useful synthetic handle for fur-
ther manipulations after an appropriate deprotection
ACHTUNGTRENNUNGa tion of 2-pyridones, as well as indoles, benzofuran, and cou-
marin, to directly form the corresponding a-heterocyclic
acetic acids. Moreover, in the reactions of 2-pyridones,
unique C3 selectivity is observed.
We first chose N-methyl-2-pyridone (1a) and butyl 2-bro-
mopropanoate (2a) as model substrates and extensively
screened various reaction parameters, such as catalysts, li-
[9]
gands, bases, and solvents. It was found that a Ni ACHTGNUTERNN(UNG cod) /
2
[
a] A. Nakatani, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-7362
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
(
Table 1, entry 11). A benzene-fused N-methyl-2-quinoli-
none (1i) was also available for use (Table 1, entry 12).
Moreover, an oxygen analogue, coumarin (1j), could be em-
ployed for the alkylation reaction; as shown in the reaction
with 2-pyridones, the C3-alkylated coumarin (3ja) was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301350.
Chem. Eur. J. 2013, 19, 7691 – 7695
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7691