Nickel-Catalyzed Chemoselective Asymmetric Hydrogenation of α,β -Unsaturated Ketoimines: An Efficient Approach to Chiral Allylic Amines

Article abstract of DOI:10.1021/acs.orglett.9b03365

An efficient synthetic route to chiral allylic amines has been developed by nickel/(S,S)-Ph-BPE complex catalyzed chemoselective asymmetric hydrogenation of α,β-unsaturated ketoimines. Varieties of α,β-unsaturated ketoimines have been well tolerated in this transformation to give chiral allylic amines with high yields and excellent ee values (up to 99% yield, up to 99% ee). A gram-scale reaction with 0.2 mol % catalyst loading has also been achieved.

Full text of DOI:10.1021/acs.orglett.9b03365

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Chemoselective Asymmetric Hydrogenation of α,β-
Unsaturated Ketoimines: An Efficient Approach to Chiral Allylic
Amines
Xiang Zhao,† Feng Zhang,‡ Kai Liu,† Xumu Zhang,# and Hui Lv*,†,§
†Key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Engineering
Research Center of Organosilicon Compounds & Materials, Ministry of Education, Sauvage Center for Molecular Scieneces, Wuhan
University, Wuhan, Hubei 430072, China
‡College of Science, Hunan Agricultural University, Changsha 410128, China
§Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
#Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong
518055, China
S
* Supporting Information
ABSTRACT: An efficient synthetic route to chiral allylic
amines has been developed by nickel/(S,S)-Ph-BPE complex
catalyzed chemoselective asymmetric hydrogenation of α,β-
unsaturated ketoimines. Varieties of α,β-unsaturated ketoimines
have been well tolerated in this transformation to give chiral
allylic amines with high yields and excellent ee values (up to
99% yield, up to 99% ee). A gram-scale reaction with 0.2 mol %
catalyst loading has also been achieved.
hiral allylic amines are valuable chiral building units for
examples heavily rely on noble transition metal catalysts, which
Csynthesis of natural products, pharmaceuticals, and unavoidably suffered from some intrinsic shortcomings of
bioactive molecules.1 As a result, tremendous efforts have
noble metal catalyst, such as being expensive, poisonous, and
environmentally deleterious. Accordingly, a cheap and efficient
catalytic system for asymmetric hydrogenation is in urgent
demand in green chemistry.
been focused on the synthesis of chiral allylic amines, and a
great deal of methods have been well documented. The
representative methods include transition metal catalyzed
enantioselective allylic amination,2 asymmetric addition of
potassium alkenyltrifluoroborates to N-tosyl imines,3 asym-
metric reductive coupling of alkynes and imines,4 asymmetric
rearrangement of prochiral allylic imidates,5 and asymmetric
hydroamination of allenes or alkynes.6 However, most of these
approaches suffered from some drawbacks, such as poor
substrate generality, high catalyst loading, and tedious
operating procedures, which greatly impeded the applications
of these methods in organic synthesis. Hence, the development
of new synthetic methods for chiral allylic amines is highly
desirable.
In past decades, transition metal catalyzed asymmetric
hydrogenation has emerged as one of the most robust ap-
proaches to chiral molecules due to its high efficiency and
perfect atom economy.7 In this context, asymmetric hydro-
genation of α,β-unsaturated ketoimines and α-vinyl enamines
was regarded as a potential synthetic route to chiral allylic
amines, and it has intrigued organic chemists for years.
However, owing to the formidable difficulty in retaining the
C−C double bonds during reduction, the successful examples
on the preparation of chiral allylic amines by enantioselective
hydrogenation are rare.8 Furthermore, all these successful
Recently, nickel-catalyzed asymmetric hydrogenation, be-
cause of its inherent advantages in cost and sustainability, has
attracted great interest.9 In this context, Hamada reported his
pioneering work on nickel catalyzed asymmetric hydrogenation
of ketones.10 Subsquently, Zhou,11 Chirik,12 Zhang,13 and our
group14 developed Ni-catalyzed enantioselective hydrogena-
tion of imines and alkenes, which exhibited the great potential
of nickel catalysts in asymmetric hydrogenation. However, to
date, Ni-catalyzed chemoselective and enantioselective reduc-
tion of α,β-unsaturated ketoimines has not been reported. The
possible reason lies in the fact that both ketoimines and
conjugated alkenes can be well hydrogenated by nickel
catalysts (Scheme 1a and 1b), which makes the chemoselective
reduction of the imine group of α,β-unsaturated ketoimine
extremely difficult. In addition, the reaction was further
challenged by over-reduction. Inspired by our previous work
on Rh-catalyzed chemoselective asymmetric hydrogenation of
α-vinyl ketone/enamide8b,c,14 and our recent work on nickel-
catalyzed enantioselective hydrogenation of enamides,15 we
Received: September 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Ni-Catalyzed Asymmetric Hydrogenation
Figure 1. Structures of the phosphine ligands for asymmetric
hydrogenation of 1a.
a
Table 2. Solvent Screening
a
Table 1. Ligand Screening
b
c
entry
solvent
TFE
HFIP
MeOH
EtOH
IPA
DCM
DCE
1,4-dioxane
THF
EtOAc
toluene
conv (%)
2a/3a
ee (%)
1
2
3
4
5
6
7
8
>99
99
25
8
3
NR
NR
NR
NR
NR
NR
>98:2
>98:2
>98:2
>98:2
NA
99
96
>99
>99
>99
NA
NA
NA
NA
NA
NA
b
c
entry
ligand
conv (%)
2a/3a
ee of 2a (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L4
>99
>99
88
>99
NR
46
62:38
50:50
98:2
>98:2
NA
98:2
98:2
NA
90
95
98
99
NA
−87
−79
NA
NA
NA
NA
NA
NA
NA
9
10
11
73
NR
a
d
Unless otherwise noted, all reactions were carried out with 1a (0.1
8
mmol), Ni(OAc)2 (5 mol %), and (S,S)-Ph-BPE (5.5 mol %) in
a
b
Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), Ni(OAc)2 (5 mol %), and ligand (5.5 mol %) in CF3CH2OH
solvent (1 mL) under H2 (80 atm) at 25 °C for 24 h. The ratio was
c
determined by 1H NMR analysis. Determined by HPLC analysis
b
(1 mL) under H2 (80 atm) at 25 °C for 24 h. The ratio was
using a chiral stationary phase. NR = no reaction, NA = not available.
c
determined by 1H NMR analysis. Determined by HPLC analysis
d
using a chiral stationary phase. No H2 was used. NR = no reaction,
ketoimines, was employed, and the reaction proceeded
smoothly, although significant over-reduction product 3a was
detected (entry 1). Other Pchiral ligands, such as (RC, SP)-
DuanPhos, also exhibited poor chemoselectivity in this
transformation albeit with excellent catalytic activity and
enantiocontrol (entry 2). To our delight, excellent chemo-
and enantioselectivity were obtained when planar chiral
phosphine ligand (R,S)-tBu-Josiphos was employed (entry 3).
Further ligand screening disclosed that (S,S)-Ph-BPE is the
best choice for this transformation, specifically affording chiral
allylic amine 2a in excellent yields with high ee values (entries
4−7). No target product was detected when the reaction was
conducted without H2, which ruled out the transfer hydro-
genation pathways (entry 8).
NA = not available.
think ligands may play a critical role in nickel catalyzed
asymmetric hydrogenation of α,β-unsaturated ketoimines,
making it possible to achieve the modulation of chemo-
selectivity by choosing a proper ligand and suitable reaction
conditions. Herein, we report an efficient synthetic approach to
chiral allylic amines via chemo- and enantioselective hydro-
genation of α,β-unsaturated ketoimines.
Initial investigations began with the optimization of
conditions for the asymmetric hydrogenation of N-Ms
protected (E)-1,3-diphenylbut-2-en-1-imine 1a (Table 1).
When the reaction was conducted with 5 mol % Ni(OAc)2
in TFE under 80 bar of H2 at room temperature, various chiral
diphosphine ligands were screened (Figure 1). First, (S)-
Binapine, the privileged ligand, which exhibits excellent
performance in nickel-catalyzed asymmetric hydrogenation of
Subsequently, the sovlent effects were evaluated and the
results disclosed that the conversion of this reaction was
extensively affected by the acidity of solvents. As shown in
Table 2, when the acidic protic solvents, such as TFE and
B
DOI: 10.1021/acs.orglett.9b03365
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Organic Letters
Letter
unsaturated ketoimines, furnishing a chiral allylic amine in high
yields with excellent chemo- and enantioselectivities. When the
protecting group of α,β-unsaturated ketoimines was changed
from Ms to −SO2NMe2 or Ts, the reaction was not affected
and proceeded very smoothly, affording target products in 97−
99% yields with 97−98% ee (2a−2c). When R1 and R3 both
are aryl groups, the substituents on the benzene ring have no
effects on the reaction, all of them furnishing chiral allylic
amines with high yields and excellent ee values. When R1 was
changed to a 2-naphthyl or 2-furanyl group, the reaction
proceeded smoothly, albeit the yields decreased slightly (2m−
2n). The reaction also worked very well when a methyl group
replaced R1 (2o). Notably, chalconeimines were also tolerated
in this transformation to give target molecules (2p, 2q) with
moderate yields and excellent enantioselectivitities.16,17
Scheme 2. Substrate Scope of Chemo- and Enantioselective
Hydrogenation of α,β-Unsaturated Ketoimines
a
To demonstrate the synthetic potential of this methodology,
the gram-scale reaction was investigated with a low catalyst
loading. To our delight, α, β-unsaturated ketoimine 1i was
hydrogenated with high chemoselectivity in the presence of 0.2
mol % catalyst loading, giving the corresponding product 2i
with 89% yield and 99% ee (Scheme 3).
In conclusion, we have developed nickel/(S,S)-Ph-BPE
catalyzed highly chemo- and enantioselective hydrogenation
of α,β-unsaturated ketoimines, giving corresponding chiral
allylic amines in high yields and high ee’s. Moreover, the
reaction proceeded smoothly with 0.2 mol % catalyst loading at
room temperature, which indicated that the method has
potential applications in organic synthesis. Further studies on
Ni-catalyzed enantioselective hydrogenation are in progress.
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.9b03365.
Experimental details and characterization data (PDF)
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), Ni(OAc)2 (5 mol %), and (S,S)-Ph-BPE (5.5 mol %) in
AUTHOR INFORMATION
■
b
CF3CH2OH (1 mL) under H2 (80 atm) at 25 °C for 24 h. Yield of
Corresponding Author
*E-mail: huilv@whu.edu.cn.
ORCID
c
the isolated product. Determined by HPLC analysis using a chiral
d
e
f
stationary phase. At 50 °C. Two h. 48 h.
Scheme 3. Gram-Scale Reaction
Hui Lv: 0000-0003-1378-1945
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21871212,
21402145), the Natural Science Foundation of Hubei Province
(2018CFB430), and the open foundation of CAS Key
Laboratory of Molecular Recognition and Function.
HFIP, were used, the reaction worked smoothly, specifically
delivering the chiral allylic amine 2a with excellent
enantioselectivities (entries 1−2). Other protic solvents with
less acidity, such as MeOH, EtOH, and i-PrOH, lead to a sharp
decrease in yield, albeit with high enantioselecvity (entries 3−
5). Aprotic solvents CH2Cl2, ClCH2CH2Cl, 1,4-dioxane, THF,
EtOAc, and toluene also have detrimental effects to this
transformation, causing the reaction to be completely inhibited
(entries 6−11).
Under the optimized reaction conditions, we examined the
substrate scope of Ni-catalyzed chemoselective asymmetric
hydrogenation of α,β-unsaturated ketoimines (Scheme 2).
Generally, the reaction exhibited good tolerance to various α,β-
REFERENCES
■
(1) (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689−
1708. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921−
2943. (c) Nugent, T. C. Chiral Amine Synthesis: Methods, Develop-
ments and Applications; Wiley-VCH: Weinheim, Germany, 2010.
(2) For selected examples on asymmetric allylic amination, see:
(a) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 1411−1420. (b) Ohmura, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164−1565. (c) Kiener,
C
DOI: 10.1021/acs.orglett.9b03365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 14272−14273. (d) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007,
129, 774−775. (e) Roggen, M.; Carreira, E. M. J. Am. Chem. Soc.
2010, 132, 11917. (f) Ye, K.-Y.; He, H.; Liu, W. B.; Dai, L.-X.;
Helmchen, G.; You, S.-L. J. Am. Chem. Soc. 2011, 133 (46), 19006−
19014. (g) Zhuo, C.-X.; Zhang, X.; You, S.-L. ACS Catal. 2016, 6,
5307−5310.
(3) (a) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850−
3851. (b) Gopula, B.; Chiang, C.-W.; Lee, W. Z.; Kuo, T.-S.; Wu, P.-
Y; Henschke, J. P.; Wu, H.-L. Org. Lett. 2014, 16, 632−635. (c) Li, Y.;
Liu, B.; Xu, M.-H. Org. Lett. 2018, 20, 2306−2310.
(4) (a) Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J. Am. Chem.
Soc. 1991, 113, 2321. (b) Patel, S. J.; Jamison, T. F. Angew. Chem., Int.
Ed. 2004, 43, 3941. (c) Skucas, E.; Kong, J. R.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 7242.
(5) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412−12413. (b) Overman, L. E.; Owen, C. E.; Pavan, M. M.;
Richards, C. J. Org. Lett. 2003, 5, 1809−1810. (c) Anderson, C. E.;
Donde, Y.; Douglas, C. J.; Overman, L. E. J. Org. Chem. 2005, 70,
648−657. (d) Weiss, M. E.; Fischer, D. F.; Xin, Z. Q.; Jautze, S.;
Schweizer, W. B.; Peters, R. Angew. Chem., Int. Ed. 2006, 45, 5694−
5698. (e) Jautze, S.; Seiler, P.; Peters, R. Angew. Chem., Int. Ed. 2007,
46, 1260−1264.
(13) Li, B.; Chen, J.; Zhang, Z.; Gridnev, I. D.; Zhang, W. Angew.
Chem., Int. Ed. 2019, 58, 7329−7334.
(14) Gao, W.; Wang, Q.; Xie, Y.; Lv, H.; Zhang, X. Chem. - Asian J.
2016, 11, 231−233.
(15) (a) Gao, W.; Lv, H.; Zhang, T.; Yang, Y.; Chung, L. W.; Wu, Y.-
D.; Zhang, X. Chem. Sci. 2017, 8, 6419−6422. (b) Li, X.; You, C.; Li,
S.; Yang, Y.; Lv, H.; Zhang, X. Org. Lett. 2017, 19, 5130−5133.
(c) Long, J.; Gao, W.; Guan, Y.; Lv, H.; Zhang, X. Org. Lett. 2018, 20,
5914−5917. (d) Guan, Y.-Q.; Han, Z.; Li, X.; You, C.; Tan, X.; Lv,
H.; Zhang, X. Chem. Sci. 2019, 10, 252−256.
(16) Only trace over-reduction product was detected in this
transformation, and the low isolated yield was attributed to low
conversion. Full conversion can be obtained by increasing the
temperature, but over-reduction product dramatically increased,
which made purification very difficult.
(17) The absolute configuration of compound 2q has been
established by comparison with literature data (for R-2q in ref 2a:
([α]D25 = −31.4 (c 1.0, CHCl3), 95% ee for R; our experiment result
20
of 2q: [α]D = −20.6 (c = 1.0, CHCl3) (90% ee)). All the other
configurations are uncertain and based on the assumption that the
configuration follows that of 2q.
(6) (a) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 1622−1623. (b) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452−2453. (c) Narsireddy,
M.; Yamamoto, Y. J. Org. Chem. 2008, 73, 9698−9709. (d) Chen, Q.-
A.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc. 2015, 137, 8392−8395.
(e) Fang, Y. Q.; Tadross, P. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2014, 136, 17966−17968. (f) Bernar, I.; Fiser, B.; Blanco-Ania, D.;
́
Gomez-Bengoa, E.; Rutjes, F. P. J. T. Org. Lett. 2017, 19, 4211−4214.
(7) Selected reviews for recent advances on transition-metal-
catalyzed asymmetric hydrogenation, see: (a) Xie, J.; Zhu, S.; Zhou,
Q. Chem. Rev. 2011, 111, 1713−1760. (b) Ager, D. J.; de Vries, A. H.
M.; de Vries, J. G. Chem. Soc. Rev. 2012, 41, 3340−3380. (c) Xie, J.;
Zhou, Q. Huaxue Xuebao 2012, 70, 1427−1438. (d) Wang, D.-S.;
Chen, Q.-A.; Lu, S.-M. Chem. Rev. 2012, 112, 2557−2590. (e) Liu, Y.;
Wang, Z.; Ding, K. Huaxue Xuebao 2012, 70, 1464−1470.
̀
́
(f) Verendel, J. J.; Pamies, O.; Dieguez, M.; Andersson, P. G.
Chem. Rev. 2014, 114, 2130−2169. (g) Zhang, Z.; Butt, N. A.; Zhang,
W. Chem. Rev. 2016, 116, 14769−14827. (h) Kraft, S.; Ryan, K.;
Kargbo, R. B. J. Am. Chem. Soc. 2017, 139, 11630−11641. (i) Zhu, S.;
Zhou, Q. Acc. Chem. Res. 2017, 50, 988−1001. (j) Meemken, F.;
Baiker, A. Chem. Rev. 2017, 117, 11522−11569. (k) Margarita, C.;
Andersson, P. G. J. Am. Chem. Soc. 2017, 139, 1346−1356.
(8) (a) Liu, T.-L.; Wang, C.-J.; Zhang. Angew. Chem., Int. Ed. 2013,
52, 8416−8419. (b) Zhou, M.; Liu, T.-L.; Cao, M.; Xue, Z.; Lv, H.;
Zhang, X. Org. Lett. 2014, 16, 3484−3487. (c) Wang, Q.; Gao, W.;
Lv, H.; Zhang, X. Chem. Commun. 2016, 52, 11850−11853. (d) Hu,
Q.; Hu, Y.; Liu, Y.; Zhang, Z.; Liu, Y.; Zhang, W. Chem. - Eur. J. 2017,
23, 1040−1043. (e) Selva, E.; Sempere, Y.; Ruiz-Martínez, D.; Pablo,
́
O.; Guijarro, D. J. Org. Chem. 2017, 82, 13693−13699.
(9) Zhang, Z.; Butt, N. A.; Zhou, M.; Liu, D.; Zhang, W. Chin. J.
Chem. 2018, 36, 443−454.
(10) (a) Hamada, Y.; Koseki, Y.; Fujii, T.; Maeda, T.; Hibino, T.;
Makino, K. Chem. Commun. 2008, 46, 6206−6208. (b) Hibino, T.;
Makino, K.; Sugiyama, T.; Hamada, Y. ChemCatChem 2009, 1, 237−
240.
(11) (a) Yang, P.; Xu, H.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53,
12210−12213. (b) Guo, S.; Yang, P.; Zhou, J. Chem. Commun. 2015,
51, 12115−12117. (c) Guo, S.; Zhou, J. Org. Lett. 2016, 18, 5344−
5347. (d) Xu, H.; Yang, P.; Chuanprasit, P.; Hirao, H.; Zhou, J.
Angew. Chem., Int. Ed. 2015, 54, 5112−5116. (e) Yang, P.; Lim, L. H.;
Chuanprasit, P.; Hirao, H.; Zhou, J. Angew. Chem., Int. Ed. 2016, 55,
12083−12087.
(12) Shevlin, M.; Friedfeld, M. R.; Sheng, H.; Pierson, N. A.; Hoyt, J.
M.; Campeau, L.-C.; Chirik, P. J. J. Am. Chem. Soc. 2016, 138, 3562−
3569.
D
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