Organic Letters
Letter
method is the use of a general Pd(OAc)2 catalyst to obtain 4-
substituted pyridine derivatives, which are difficult to
synthesize with Rh-catalyzed methodology. This work comple-
ments previously reported pyridine synthetic methods, since 4-
unsubstituted pyridines can already be easily prepared with
alkenes by using a commercially available Rh-catalyst (Scheme
1b vs 1c).
We first examined the reaction between symmetrical α,β-
unsaturated O-methyl oxime 1a (Me) and methyl acrylate (2a)
in the presence of Pd(OAc)2 as a catalyst.6 With AgTFA as an
oxidant and dioxane as a solvent, the desired pyridine 3aa was
obtained in 17% yield, and no β-alkenylation product was
observed.
Based on our experience in the development of Pd-catalyzed
β-selective C−H functionalization of α,β-unsaturated oximes,4
we expected that the identification of a suitable catalyst ligand
would be the key to establish the optimal protocol. We chose
to examine the effect of pyridine derivatives, since they are
known to be useful ligands for Pd-catalyzed C−H alkenylation
of oxime derivatives (Table 1).7 Although simple organic
reactivity. Tricyclic quinoline-derived ligand L8 and acridine
(L9), developed by Yu and co-workers,8 led to loss of
reactivity. Anticipating a positive effect of a bulkier ligand, we
prepared L10 in one step from 2,6-difluoropyridine and 1-
adamantanol. To our delight, the use of L10 significantly
improved the reactivity and afforded 3aa in 50% yield. The
yield could not be further improved despite extensive ligand
screening with substrate 1a (Me).
Having identified two suitable ligands L4 and L10, we
turned our attention to exploring the structure−reactivity
relationship of the oxime ether moiety. Although various
oximes 1a bearing O-acetyl, O-pivaloyl, O-silyl, and O-SEM4
groups were examined, the reaction did not proceed at all (see
hindered O-tert-butyl oxime 1a (tBu), only the starting material
was recovered (Table 2, entry 2). However, O-isopropyl oxime
a
Table 2. Reaction Optimization
a
Table 1. Ligand Optimization
entry
R
1a
ligand
AgTFA (x equiv)
yield (%)
1
2
3
4
5
Me
tBu
iPr
iPr
iPr
1a (Me)
1a (tBu)
1a (iPr)
1a (iPr)
1a (iPr)
L4
L4
2.5
2.5
2.5
2.5
5.0
47
0
L4
69
76
85
L10
L10
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (3.0 equiv),
Pd(OAc)2 (10 mol %), ligand (30 mol %), AgTFA (x equiv), dioxane
(2.0 mL), 90 °C, 24 h. Isolated yield.
1a (iPr) improved the reactivity and the yield increased to 69%
(entry 3). To our delight, the use of the ligand L10 in place of
L4 further improved the yield from 69% to 76% (entry 4).
Finally, further screening of reaction conditions revealed that
5.0 equiv of AgTFA was optimal, affording 3aa in 85% yield
(entry 5).
With the optimal oxime moiety as well as reaction
conditions in hand, we surveyed the generality of this
multisubstituted pyridine synthesis by examining the reaction
of various α,β-unsaturated oximes with methyl acrylate (2a)
(Table 3). Symmetrical oximes bearing an electron-donating
group (1b and 1c), halogens (1d and 1e) and an electron-
withdrawing CF3 group (1f) at the para position of the phenyl
ring afforded the expected 2-allylpyridines (3ba−3fa) in good
yields (65−91%). Notably, unsymmetrical ketoximes were
available, affording the pyridines (3ga−3ka) in good yields
(64−80%). Oximes with heteroaromatics such as dibenzothio-
phene (1l) and carbazole (1m) were also acceptable and
furnished the desired pyridines 3la and 3ma in 48% and 55%
yields, respectively. This reaction also worked well with
cyclized oximes derived from benzylidene cyclopentanone
derivatives (1n−1p), giving the desired 2,3,4,6-tetrasubstituted
pyridines (3na−3pa) in good yields. Unfortunately, with the
exception of the cyclized oximes (1n−1p), neither α-
substituents nor β-alkyl substituents were generally tolerated
a
Reaction conditions: 1a (Me) (0.2 mmol, 1.0 equiv), 2a (3.0 equiv),
Pd(OAc)2 (10 mol %), ligand (30 mol %), AgTFA (2.5 equiv),
dioxane (2.0 mL), 90 °C, 24 h. Isolated yield.
bases, pyridine (L1)7a,b and 2,6-lutidine (L2), inhibited the
reaction, 2,6-dimethoxypyridine (L3)7c slightly improved the
reactivity and afforded the desired pyridine in 29% yield.
Interestingly, more sterically hindered 2,6-di-tert-butylpyridine
(L4) significantly increased the reactivity and 3aa was obtained
in 47% yield. Next, we tested a series of 2-alkoxylquinoline
derivatives (L5−L8), which are more electron-rich than the
pyridine series ligands (L1−L4). The use of 2-methoxyquino-
line (L5) did not improve the reactivity, but the product yield
was increased when a quinoline ligand bearing a bulkier side
chain, tert-butoxy (L6) or 1-adamantyloxy (L7), was used.
This substituent effect suggests that steric hindrance around
the nitrogen atom of the quinoline ligand is crucial for high
1660
Org. Lett. 2021, 23, 1659−1663