Organic Letters
Letter
a
availability of the alkylation reagents, and functional group
tolerance.
Table 1. Optimization of Reaction Conditions
The availability, stability, diversity, and low cost of alkyl
9
carboxylic acids has resulted in their widespread use. Since the
pioneering work of Minisci, the decarboxylative alkylation of
heteroarene C−H bonds with alkyl carboxylic acids has been a
1
0,11
topic of sustained interest.
These reactions exhibit
b
substrate-controlled site selectivity. Transition-metal catalysis
yield of 3aa
entry
deviation
(%)
with directing groups, however, enable greater C−H selectivity
12
and functionalization. The first chelation-assisted alkylation
of N-pyrimidyl indolines, 2-phenylpyridines, and azobenzenes
with alkyl carboxylic acids via decarboxylation was achieved by
Jain’s group using a Pd(II) catalyst. The catalyst loading,
excessive oxidant, and narrow scope of alkyl carboxylic acid
1
2
3
4
5
6
7
8
9
none
[Rh(COD)Cl] instead of [Rh(CO) Cl]
2
92
22
57
14
33
21
73
54
0
2
2
[Rh(COD) ]OTf instead of [Rh(CO) Cl]
2
2
2
DCE as the solvent
toluene as the solvent
PhCl as the solvent
Reaction temperature 120 °C
13
coupling partner left room for improvement. Shi and Sun
and their co-workers, as well as our team, recently disclosed
Rh(I)-catalyzed chelation-assisted decarbonylative C−H alky-
lation of pyridyl-substituted arenes, cyclic enamines, and
indoles with alkyl anhydrides in the absence of added oxidant
[Rh(CO)
Cl]
2
(1 mol %)
Cl]
2
without [Rh(CO)
2
2
c
10
in situ generation of anhydride from PivCl and
AcOH
in situ generation of anhydride from Piv O and
32
1
4a−c
(
Scheme 1b).
The alkyl anhydride partners were
c
1
1
2
90
39
91
2
conveniently generated from carboxylic acids. In one example,
Shi and co-workers realized the Rh(I)-catalyzed directed C7-
selective decarbonylative methylation of indoles using acetic
AcOH
c
1
in situ generation of anhydride from Boc O and
2
AcOH
14d
c
,
d
anhydride as the methyl group source. This procedure was
incompatible with other alkyl anhydrides, possibly due to β-
hydride elimination. We recently achieved the Rh(I)-catalyzed
regioselective and stereoselective C6-alkenylation of 1-(2-
pyridyl)-2-pyridones with alkenyl and conjugated polyenyl
13
in situ generation of anhydride from Boc O, PivOH,
2
and AcOH
a
General reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol),
[Rh(CO) Cl] (2 mol %), 1,4-dioxane (2.0 mL), 130 °C, 8 h.
2
c
2
b
Isolated yield. AcOH (0.22 mmol) and activator (0.24 mmol) and
d
7
n
were employed. AcOH (0.22 mmol), Boc O (0.24 mmol), and
carboxylic acids. We next envisage that 1-(2-pyridyl)-2-
pyridones might undergo Rh(I)-catalyzed decarbonylative C6-
alkylation with alkyl carboxylic acids or anhydrides. Such a
method could offer facile access to 6-alkylated 2-pyridones.
Herein, we describe development of a selective C6-alkylation
of 1-(2-pyridyl)-2-pyridones that proceeds in high yields with a
wide substrate scope and good functional group tolerance
2
PivOH (0.24 mmol) were employed.
corrosive or toxic reagents. To circumvent these shortcomings,
researchers have used carboxylic acids in combination with in
For our chemistry, we explored the
feasibility of in situ formation of acetic anhydride from acetic
acid and several activators. Among activators tested (Table 1,
entries 10−12), commercially available Piv O proved the best
choice (Table 1, entry 11). Interestingly, the combination of
Boc O, PivOH and AcOH also performed very well, affording
3aa in 91% yield (Table 1, entry 13). In view of the high price
1
4,16
situ activation.
(
Scheme 1c).
Considering the importance of methylation reactions in
15
medicinal chemistry, the methylation of 1-(2-pyridyl)-2-
pyridone (1a) with acetic anhydride (2a) was selected for the
identification of the optimal alkylation conditions (Table 1).
By evaluating different parameters, the optimal reaction
conditions were [Rh(CO) Cl] (2 mol %) in 1,4-dioxane at
2
2
2
2
of Piv O, the combination of Boc O and PivOH was used
2
2
1
30 °C for 8 h, leading to product 6-ethyl-2H-[1,2′-bipyridin]-
moving forward.
2
-one (3aa) in 92% isolated yield (Table 1, entry 1). Other
We next proceeded to explore the methylation of a series of
2-pyridones with 2a. As illustrated in Scheme 2, a range of 3-
and 4-substituted 2-pyridones (1b−1l) bearing electron-rich
and electron-deficient groups underwent smooth methylation
to deliver products 3ba−3la in 81%−92% yields. The structure
of 3ga was confirmed by single-crystal X-ray diffraction
(CCDC 1834644, Scheme 2). Importantly, a variety of
functional groups (OBn, F, Cl, Br, CF , CN, and CO Me)
were tolerated. Despite the steric hindrance, the 5-substituted
2-pyridones (1m−1q) delivered products 3ma−3qa in 54%−
86% yield. In these reactions, electron-rich 2-pyridones
generally exhibited slightly better yields. Furthermore, the
disubstituted 2-pyridones 1r−1s) provided products 3ra−3sa
in 72% and 81% yields. It is noteworthy that the installation of
substituents on the pyridyl directing group did not affect the
methylation, and products 3ta−3va were obtained in 85%−
89% yields. The versatility of this system was further reflected
by the methylation of 3-(pyridin-2-yl)quinazolin-4(3H)-one
(1w), 1-(pyridin-2-yl)quinolin-4(1H)-one (1x), and 4H-[1,2′-
bipyridin]-4-one (1y) in 71%−82% yields.
frequently employed Rh(I) complexes proved to be ineffective
Table 1, entries 2 and 3). Using [Rh(CO) Cl] and switching
(
2
2
solvents from 1,4-dioxane to DCE, toluene, or PhCl resulted in
lower yields (14%−33%; see Table 1, entries 4−6). Lowering
the reaction temperature to 120 °C or halving the catalyst
loading decreased the yield of 3aa by more than 20% (Table 1,
entries 7 and 8). Not surprisingly, control experiments in the
absence of [Rh(CO) Cl] did not provide 3aa (Table 1, entry
3
2
2
2
9
). Notably, using free 2-pyridone or 2-pyridone substrates
bearing other substituents on the nitrogen (Me, Bn, Ph, 2-
pyrimidyl, Ac, Piv, or Ts) did not form coupling products,
highlighting the importance of the 2-pyridyl directing group
under these conditions (see Table S3 in the Supporting
Information).
While alkyl carboxylic anhydrides are potentially useful
starting materials for alkylation reactions, there are drawbacks
to their use. These include (1) they are rarely commercially
available, (2) they are hydrolytically unstable, and (3) their
preparation and isolation is often tedious and/or employs
B
Org. Lett. XXXX, XXX, XXX−XXX