Pyridine-directed asymmetric hydrogenation of 1 1-diarylalkenes

Article abstract of DOI:10.1021/acs.orglett.7b02262

Highly enantioselective pyridine-directed rhodium-catalyzed asymmetric hydrogenation of challenging 1 1-diarylalkenes is achieved by using [Rh(NBD)DuanPhos]BF4 as a precatalyst. Various types of 2-pyridine substituted 1 1-diarylalkenes could be hydrogenated with good to excellent enantioselectivities which provide an efficient route to the synthesis of pharmaceutically and biologically active compounds containing a 2-pyridyl ethane unit.

Full text of DOI:10.1021/acs.orglett.7b02262

Letter
pubs.acs.org/OrgLett
Pyridine-Directed Asymmetric Hydrogenation of 1,1-Diarylalkenes
Hailong Yang,† Erfei Wang,† Ping Yang,† Hui Lv,*,†,‡ and Xumu Zhang*,§
†Key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, Hubei 430072, China
‡Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular
Sciences, Wuhan University, Wuhan, Hubei 430072, China
§Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
S
* Supporting Information
ABSTRACT: Highly enantioselective pyridine-directed rho-
dium-catalyzed asymmetric hydrogenation of challenging 1,1-
diarylalkenes is achieved by using [Rh(NBD)DuanPhos]BF4
as a precatalyst. Various types of 2-pyridine substituted 1,1-
diarylalkenes could be hydrogenated with good to excellent
enantioselectivities, which provide an efficient route to the
synthesis of pharmaceutically and biologically active com-
pounds containing a 2-pyridyl ethane unit.
n recent decades, homogeneous asymmetric hydrogenation
of alkenes has attracted great interest,1 and transition metal-
species.5 Direct asymmetric hydrogenation of alkenes contain-
ing 2-pyridine group is still a challenge.
I
catalyzed asymmetric hydrogenation of multiple-substituted
CC bonds has become one of the most important methods
to prepare enantiopure compounds because of its advantages of
high efficiency and being environmentally friendly.2 In this
context, a variety of alkenes have been hydrogenated with
excellent enantioselectivities.
However, there are only a few reports about asymmetric
hydrogenation of 1,1-diarylalkenes bearing 2-pyridine group3
despite the fact that 1,1-diarylalkane scaffolds, especially the 2-
pyridine substituted chiral 1,1-diarylalkanes, are important
intermediates in the synthesis of pharmaceuticals and natural
products,4 such as 2-(1-phenylethyl)pyridine and R-dimethin-
dene analogues (Figure 1). Furthermore, only poor to
Recently we found that the 2-pyridine group could act as a
directing group to achieve rhodium-catalyzed asymmetric
hydrogenation of 2-pyridine ketones, affording 2-pyridine
alcohols with high yields and excellent ee’s.6 We envision that
the directing effect of the pyridine group can also play an
important role in the asymmetric hydrogenation of 2-pyridine
substituted alkenes under the right conditions, which is
beneficial for the reaction to work smoothly and generate the
desired products with high enantioselectivities. Herein, we
disclose pyridine-directed rhodium-catalyzed asymmetric hy-
drogenation of 1,1-diarylalkenes.
In our initial studies, we chose the 2-(1-(p-tolyl)-vinyl)-
pyridine (1a) as the standard substrate and the asymmetric
hydrogenation was carried with Rh(COD)2BF4 under 10 bar of
H2 in CH2Cl2. First, (R)-Binapine, the best ligand for the
asymmetric hydrogenation of 2-pyridine ketones, was exam-
ined. To our disappointment, it gave the desired product with
very poor enantioselectivities, albeit with excellent activity
(Table 1, entry 1). Then, other chiral diphosphorus ligands
(Figure 2) were evaluated. Fortunately, we found that the
DuanPhos, an electron-donating rigid bisphosphine ligand
developed in our group, achieved 87% ee with full conversion
(Table 1, entry 4). And other ligands, except TangPhos (62%
ee, Table 1, entry 3) and Quinoxp* (65% ee, Table 1, entry 6),
all gave less than 50% ee. Subsequently, the effect of metal
precursors was evaluated. To our surprise, the iridium, which
was frequently used in the asymmetric hydrogenation of
alkenes, gave the desired product with excellent yield but no
enantioselectivity (Table 2, entry 1). The anions of the
Figure 1. Pharmaceutical and biological active compounds containing
2-pyridyl ethane unit.
moderate enantioselectivities have been obtained for asym-
metric hydrogenation of 2-pyridyl alkenes.3,5 The main reason
can be attributed to the coordination effect of pyridine, which
degrades the catalyst’s activity and stereocontrol ability to some
extent. In addition, the small difference between aryl groups
and pyridine groups also makes it difficult to achieve high
enantioselectivities. To solve this problem, the 2-pyridine
substituted alkenes were always hydrogenated as N-oxide
Received: July 23, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02262
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Organic Letters
Letter
Table 1. Ligands Screening for the Asymmetric
Hydrogenation of 1a
Table 2. Condition Optimization of Asymmetric
Hydrogenation of 1a
a
a
b
c
b
c
entry
ligand
(R)-Binapine
conversion (%)
ee (%)
entry
metal precursor
solvent
CH2Cl2
conversion (%) ee (%)
1
2
>99
>99
>99
>99
8
24
19
62
87
28
65
45
37
2
1
[Ir(COD)Cl]2
[Rh(COD)Cl]2
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(NBD)2BF4
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
0
25
87
89
90
88
78
86
89
84
91
(R)-Josiphos
2
CH2Cl2
EA
3
(1S,1S′,2R,2R′)-TangPhos
(Sc, Rp)-DuanPhos
(S)-Segphos
3
4
4
EtOH
5
5
MeOH
ClCH2CH2Cl
CHCl3
6
Quinoxp*
Me-Duphos
>99
37
6
7
7
8
f-BinaPhane
>99
32
8
iPrOH
9
C3-TunePhos
DTBM-Biphep
9
CF3CH2OH
THF
10
48
40
10
11
a
MeOH
Unless otherwise noted, all reactions were carried out with a
[Rh(COD)2BF4]/ligand/substrate (0.1 mmol) ratio of 1:1.1:100 in 1
mL of CH2Cl2 at room temperature under hydrogen (10 bar) for 20 h.
a
Unless otherwise noted, all reactions were carried out with a metal
precursor/ligand/substrate (0.1 mmol) ration of 1:1.1:100 in 1 mL of
solvent at room temperature under hydrogen (10 bar) for 20 h.
b
c
1
Determined by H NMR. Determined by HPLC analysis using a
b
c
1
chiral stationary phase.
Determined by H NMR. Determined by HPLC analysis using a
chiral stationary phase.
electronic property and the position of substituent group on the
benzene ring have an effect on the enantioselectivity. Generally,
electron-withdrawing substituents have a positive effect on
enantioselectivity for this reaction and gave a slightly higher ee
than that with electron-donating groups (2f−g, 2l vs 2a, 2c,
2k). When a substituent was introduced to the ortho position of
the phenyl group, it delivered the desired product with slightly
lower enantioselectivities (2d, 2j). It was worth noting that the
directing effect could distinguish the 2-pyridine and 3-piridine
groups precisely, giving excellent enantioselectivity (98% ee,
Scheme 1, 2m). Asymmetric hydrogenation of trisubstituted 2-
pyridine alkenes was also conducted. Although the reactions
proceeded smoothly, the enantioselectivities of the products
decreased significantly. (Z)-2-(1-(p-Tolyl)prop-1-en-1-yl)-
pyridine (2n) gave a 60% ee, and the (E)-2-(1-(p-tolyl)prop-
1-en-1-yl)pyridine (2o) only gave a 73% ee with opposite
optical rotation.
To determine if the directing effect of the pyridine group
actually played a critical role in the asymmetric hydrogenation
of 2-pyridine ethenes, substrates 1p−1r were synthesized and
hydrogenated (Scheme 1). When 3-pyridine ethene 1p was
tested under the same conditions, the asymmetric hydro-
genation reaction did not work. When the 2-pyridine group was
replaced with a phenyl group (1q) or other heterocyclic groups,
such as thiophene (1r), these alkenes also showed no reactivity.
All these results indicated that the 2-pyridine group actually
functioned as a directing group in the asymmetric hydro-
genation to improve the reactivity and enantioselectivity.
In summary, with the directing function of the pyridine
groups, highly enantioselective rhodium-catalyzed asymmetric
hydrogenation of 2-pyridine 1,1-diarylethenes was achieved,
giving 2-pyridine substituted 1,1-diarylalkanes with excellent
yields and enantioselectivities (up to 99% yield, up to 98% ee).
This protocol provided an efficient method to prepare chiral 2-
(1-arylethyl)pyridines and their derivatives. Further investiga-
tions on asymmetric hydrogenation by using the directing
strategy are underway.
Figure 2. Ligands screened in the asymmetric hydrogenation of 1a.
rhodium salts also greatly effected the enantioselectivities.
When [Rh(COD)Cl]2 was used, the ee of the product
decreased significantly from 87% to 25% (Table 2, entry 2).
We have also investigated the solvent effects and found the
methanol was the most suitable solvent for this reaction. Other
solvents had little effect on the enantioselectivities (Table 2,
entries 3−10). When the reaction was conducted in methanol
by using the (Sc, Rp)-DuanPhos/Rh(NBD)2BF4 complex as
catalyst, the best results were obtained (Table 2, entry 11).
With the optimized conditions in hand, the substrate scope
of asymmetric hydrogenation of 1,1-disubstituted 2-pyridine
alkenes was investigated. As shown in Scheme 1, a series of 2-
(1-arylvinyl)pyridines were hydrogenated very well and gave 2-
(1-arylethyl)pyridines with good to excellent enantioselectiv-
ities (86−98% ee, 2a−2m).7 These results disclosed that the
B
DOI: 10.1021/acs.orglett.7b02262
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Organic Letters
Letter
Notes
Scheme 1. Rhodium Catalyzed Asymmetric Hydrogenation
of 1,1-Diarylalkenes
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21402145,
21432007, and 21372179), the Youth Chen-Guang Science
and Technology Project of Wuhan City (2015071704011640),
the Natural Science Foundation of Hubei Province
(2014CFB181), the Fundamental Research Funds for Central
Universities (2042017kf0177), the Important Sci-Tech In-
novative Project of Hubei Province (2015ACA058), and the
“111” Project of the Ministry of Education of China.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02262.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: huilv@whu.edu.cn.
*E-mail: zhangxm@sustc.edu.cn.
ORCID
Hui Lv: 0000-0003-1378-1945
Xumu Zhang: 0000-0001-5700-0608
C
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D
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