Organic Letters
Letter
a
Scheme 1. Recent Advance in AH of 2-Substituted
Pyridinium Salts
Table 1. Optimization of the Reaction Conditions
b
c
entry
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
EtOAc
toluene
acetone
L
conv (yield) (%)
>99
ee of 2a (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L4
L4
L4
L4
L4
L4
L4
L4
90
91
92
94
94
69
45
d
92
87
52
83
70
90
82
d
>99
>99
>99 (86)
>99
>99
>99
20
>99
>99
88
80
90
10
11
12
13
14
15
16
CH CN
50
95
90
3
1,4-dioxane
MeOH
asymmetric hydrogenation of organic acid pyridinium salts
with high diastereoselectivities and good enantioselectivities
9
(
up to 83% ee) (Scheme 1c). Here, we reported a new type of
2
‑aryl-3-phthalimidopyridinium salts through Ir-diphosphine-
catalyzed asymmetric hydrogenation to provide chiral 2-aryl-3-
imidylpiperidine derivatives with high levels of diastereose-
lectivities and enantioselectivities (Scheme 1d).
We began our investigation with N-benzyl-2-phenyl-3-
pyridinium salt 1a, which was conveniently prepared by Suzuki
coupling of 2-chloro-3-aminopyridine and phenyl boronic acid,
then the amino group was protected by phthalic acid, followed
by treatment with benzyl bromide. The initial asymmetric
hydrogenation experiment was carried out by using 1a as a
standard substrate in 1,2-dichloroethane (DCE) at 60 °C for
2
4 h under H (55 bar) in the presence of catalyst [Ir(cod)Cl]
2
2
(
1 mol %) and (R)-BINAP (3 mol %) formed in situ, followed
by a basic workup, affording the corresponding chiral
piperidine derivative 2a bearing two contiguous chiral centers
with high levels of diastereoselectivity (>99:1) and enantiose-
lectivity (90% ee) (Table 1, entry 1). Subsequently, to improve
the enantioselectivity, we attempted to explore the effects of a
series of chiral diphosphine ligands, which are commercially
available or developed in our group; (R)-SynPhos gives 91% ee
respectively (Table 1, entries 9 and 10). The investigation of
EtOAc, toluene, acetone, CH CN, and 1,4-dioxane proceeded
3
with 50−95% conversions and moderate to good enantiose-
lectivities (52−90%) (Table 1, entries 11−15). When protic
solvent methanol was used, we only observed byproduct 3a
(Table 1, entry 16). Among the above results, we selected
DCE as the most favorable solvent for further exploration. To
reduce the byproduct, we removed the trace moisture on an
autoclave, reduced the reaction concentration (0.1 M), and
increased the hydrogen gas pressure (80 bar), and the target
product 2a was gained with a higher isolated yield (93%)
without erosion of the enantiomeric excess. In addition, the
absolute configuration of 2a was determined by X-ray
crystallographic analysis (CCDC no. 2013289).
(
Table 1, entry 2) and (R)-MeO-BIPHEP provides 92% ee
(Table 1, entry 3). Surprisingly, the same high enantiomeric
excess (94% ee) was obtained by using (S)-SegPhos and (S)-
C3-TunePhos (Table 1, entries 4 and 5). However, medium
enantioselectivities were attained for (R)-O-SDP and (S,R )-
1
8
19
P
2
0
ZhaoPhos, respectively, of 69% and 45% ee (Table 1, entries
and 7). Additionally, low conversion was given for (R,S)-
6
JosiPhos, and the ee of the trace product could not be
determined (Table 1, entry 8). Considering (S)-SegPhos is
commercially available, we selected it as the optimum ligand
for further optimization. In a survey of dichloromethane and
THF as solvent, full conversions were observed and the
enantioselectivities slightly decreased to 92% ee and 87% ee,
To explore the usefulness of the Ir/(S)-SegPhos catalytic
system, a wide range of 2-aryl-3-phathalimidopyridinium salts
1 were prepared and evaluated under the optimized conditions.
Substrates 1b, 1c, 1d, 1e, and 1f bearing electron-donating
substituents on the aromatic ring were hydrogenated with high
enantioselectivities (92−95% ee) and good to high yields (78−
B
Org. Lett. XXXX, XXX, XXX−XXX
Zhang, Xumu
