Nickel-Catalyzed Asymmetric Hydrogenation of Hydrazones

Article abstract of DOI:10.1002/ejoc.202100642

An efficient nickel-catalyzed asymmetric hydrogenation of hydrazones to chiral hydrazines has been realized with up to 99 % yield and 99.4 : 0.6 er. Deuterium labelling experiments indicated that the hydrazone substrates undergo imine-enamine tautomerizat

Full text of DOI:10.1002/ejoc.202100642

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Nickel-Catalyzed Asymmetric Hydrogenation of Hydrazones
Authors: Bowen Li, Dan Liu, Yanhua Hu, Jianzhong Chen, Zhenfeng
Zhang, and Wanbin Zhang
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01/2020

10.1002/ejoc.202100642
European Journal of Organic Chemistry
COMMUNICATION
Nickel-Catalyzed Asymmetric Hydrogenation of Hydrazones
Bowen Li,[a] Dan Liu,[a] Yanhua Hu,[a] Jianzhong Chen,[a] Zhenfeng Zhang,*[b] and Wanbin Zhang*[a,b,c]
[a]
B. Li, D. Liu, Y. Hu, Dr. J. Chen, Prof. W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs
Frontiers Science Center for Transformative Molecules
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P. R. China)
E-mail: wanbin@sjtu.edu.cn
https://wanbin.sjtu.edu.cn/
[b]
[c]
Dr. Z. Zhang, Prof. W. Zhang
School of Pharmacy
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P. R. China)
E-mail: zhenfeng@sjtu.edu.cn
Prof. W. Zhang
College of Chemistry
Zhengzhou University
75 Daxue Road, Zhengzhou 450052 (P. R. China)
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient nickel-catalyzed asymmetric hydrogenation of
hydrazones to chiral hydrazines has been realized with up to 99%
yield and 99.4:0.6 er. Deuterium labelling experiments indicated that
the hydrazone substrates undergo imine-enamine tautomerization in
the mixed solvents. Studies on the effects of acids revealed that the
required acid assistance promoted the dissociation of the active nickel
catalyst in the catalytic cycle.
earth-abundant transition metal catalysts for use in asymmetric
hydrogenation has great potential due to their low cost and
environmental friendliness. Recently, catalytic asymmetric
hydrogenation using earth-abundant transition metals,[9] such as
Mn,[10] Fe,[11] Co,[12] Ni[13] and Cu,[14] has been developed rapidly
for the synthesis of various chiral compounds. However, only a
few of these metal catalysts have been applied to the asymmetric
hydrogenation of hydrazones.[12h,15] In 2015, Zhou and co-workers
reported a Ni-catalyzed asymmetric transfer hydrogenation of
hydrazones using a HCOOH/Et3N hydrogen source, affording
chiral hydrazines with excellent results.[15] In 2019, we also
Optically active hydrazines and their derivatives are privileged
structural motifs for the construction of various functional
compounds in pharmaceutical, agrochemical and organic
reagents (Scheme 1).[1] Such N−N bond containing compounds
can be synthesized by several methods, such as N−N bond
formation from chiral amines, rearrangement from chiral halide
ureas, and the alkylation of hydrazines with chiral haloalkanes,
etc.[2] As an asymmetric approach, the transition metal-catalyzed
asymmetric hydrogenation of hydrazones has emerged to be the
most direct method for the synthesis of chiral hydrazines.[3-8]
disclosed
a
highly efficient Co-catalyzed asymmetric
hydrogenation of hydrazones based on H2 gas (Scheme 2).[12h]
Inspired by our recent works in transition metal-catalyzed
asymmetric hydrogenations[16] and nickel-catalyzed asymmetric
reactions,[13f-h,17] herein we report the first nickel-catalyzed
asymmetric hydrogenation of hydrazones using H2 gas as the
hydrogen source for the efficient synthesis of chiral hydrazines
(Scheme 2).
Scheme 2. Synthesis of chiral hydrazines via transition metal-catalyzed
asymmetric hydrogenation of hydrazones.
Scheme 1. Representative chiral hydrazine-based compounds.
Initially, N'-(1-phenylethylidene)benzohydrazide (1a) was
selected as the model substrate to explore the feasibility of this
nickel-catalyzed asymmetric hydrogenation of hydrazones.
Preliminary solvent screening showed that the hydrogenation
failed to proceed in commonly used solvents but worked smoothly
in a mixed solvent system consisting of 2,2,2-trifluoroethanol
(TFE) and acetic acid (see SI for details). Next, several
commercially available chiral bisphosphine ligands were
screened (Table 1). When electron-rich chiral dialkyl phosphine
In 1992, Burk and co-workers reported the first
enantioselective reduction of hydrazones via a Rh/DuPhos
catalyst.[4] Since then, many noble transition metal catalysts have
been developed for the asymmetric hydrogenation of hydrazones,
with the majority being Rh catalysts[5] and fewer examples of Pd,[6]
Ir[7] and Ru[8] catalysts (Scheme 2). However, these metal
catalysts are very expensive and environmentally harmful so their
broader applications are hindered. Therefore, the development of
1
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10.1002/ejoc.202100642
European Journal of Organic Chemistry
COMMUNICATION
[a] Reaction conditions otherwise noted: 1a (0.2 mmol), solvent (1 mL), the
absolute configuration of product was determined as R by comparison of the
specific rotations with the literature data[12h]. [b] The conversions were detected
by 1H NMR spectra and the er values were determined by HPLC using a chiral
stationary phase.
ligand (R,R)-QuinoxP* was used, full conversion with 92:8 er was
achieved. Other chiral dialkyl phosphine ligands, such as (R,R)-
BenzP*, (Rc, Sp)-DuanPhos, (S,S)-Ph-BPE and (R,R)-DuPhos,
also worked well for this reaction (50-99% conv., 69:31-93:7 er),
albeit not performing as well as (R,R)-QuinoxP*. In contrast, no
reaction occurred when using chiral diaryl phosphine ligands,
such as (S)-BINAP, (S)-SegPhos and (R,Sp)-JosiPhos. These
results indicate that the electron-rich ligands could enhance the
activities of the nickel catalysts in accordance with literature
reports and our previous research.[13]
Table 1. Ligands screening.[a]
[a] Conditions: 1a (0.2 mmol), solvent (1 mL). The conversions were calculated
from 1H NMR spectra. The er values were determined by HPLC using chiral
stationary phases.
Further investigations focused on the solvent effect in the
presence of acetic acid (Table 2). Replacing TFE with other protic
solvents, such as MeOH, EtOH and iPrOH, resulted in a
significant decrease in the reactivity, albeit with a slight increase
in the enantioselectivity (entries 1-4). The special role of TFE in
this reaction is similar to that in some metal-catalyzed reactions;
the TFE is suspected of acting as a stabilizer of the active catalyst,
or hydrogen bond donor of the substrate.[18] Similar to previous
studies,[13f-h] the hydrogenation did not proceed in aprotic solvents,
such as THF, PhMe and CH2Cl2 (entries 5-7). Different ratios of
AcOH were also tested (entries 8-12), with the comparatively best
results (92:8 er) being obtained when the reaction was carried out
in a solution of TFE/AcOH (v/v =10:1, entry 9).
Scheme 3. Substrate scope. Reaction conditions: 1 (0.2 mmol), Ni(OAc)2·4H2O
(0.002 mol), (R,R)-QuinoxP* (0.002 mmol), TFE/AcOH (10:1, v/v, 1 mL), H2 (30
bar), 50 °C, 24 h; Isolated yields; The er values were determined by chiral HPLC.
Table 2. Reaction Optimization.[a]
With the optimized conditions in hand (Table 2, entry 9), the
scope of the nickel-catalyzed asymmetric hydrogenation of
hydrazones was studied (Scheme 3). At first, a number of
acetophenone-derived hydrazones with different protecting
groups were synthesized and tested. Acetyl protected hydrazone
1b gave the same results as 1a (99% yield and 92:8 er). Other
protecting groups from COtBu to diacyl were also investigated,
but the corresponding products were obtained with the
enantioselectivities not as good as the model substrate (2c-f).
Thus, the substrates bearing Bz group were mainly studied. As
shown in Scheme 3, both electron-rich and electron-poor
substituents on the aryl rings were well tolerated regardless of
their position, giving the desire products in high yields and good
enantioselectivities (2g-n, 96-99% yields, 91:9-93:7 er).
Disubstituted substrates were also successfully reacted to
provide good enantioselectivities (2o, p). Replacing the phenyl
Entry
1
2
3
4
5
6
7
8
Solvent (v/v)
Conv. (%)[b]
er (%)[b]
92:8
93:7
93:7
-
TFE/AcOH = 4:1
MeOH/AcOH = 4:1
EtOH/AcOH = 4:1
iPrOH/AcOH = 4:1
THF/AcOH = 4:1
Tolene/AcOH = 4:1
CH2Cl2/AcOH = 4:1
TFE/AcOH = 2:1
TFE/AcOH = 10:1
TFE/AcOH = 20:1
TFE/AcOH = 40:1
TFE/AcOH = 100:1
99
23
13
5
0
Trace
Trace
99
99
99
-
-
-
92:8
92:8
91:9
91:9
91:9
9
10
11
12
99
93
2
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10.1002/ejoc.202100642
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group with a 1- or 2-naphthyl substituent provided moderate
enantioselectivities (2q, r). The reaction was also applicable to
heteroaryl substrates (1s, t) affording the corresponding products
with the same 77:23 er. Changing the methyl group to other alkyl
groups did not affect the reaction activity, but the
enantioselectivity decreased significantly (2u, v). It should be
noted that dialkyl substrates were also explored and the tert-butyl-
substituted product was obtained with an excellent 99.4: 0.6 er
(2w, x).
To demonstrate the synthetic utility of this method, an
asymmetric hydrogenation of 1a was conducted on a gram scale
(Scheme 4a). The reaction was carried out with the catalytic
system of a higher ratio of nickel salts according to our previous
studies,[13f,h] affording the desired product 2a in 97% yield and
92:8 er. Additionally, the synthetic application of this protocol was
also demonstrated in the asymmetric synthesis of hydrazine 2y,
a key intermediate for the preparation of a hrFAAH inhibitor
enantiomer, in which hydrazone 1y was hydrogenated to chiral
hydrazine 2y at a lower catalyst loading (S/C = 500), with 91%
yield and 84:16 er (Scheme 4b).[19]
Figure 1. Deuterium labeling experiments.
In order to explore the role of the acid, other different organic
acids, taking into consideration their solubility in TFE, were
investigated on a 2 eq. scale (Table 3). No reaction occurred in
the absence of acid (entry 1). The tested weak acids all worked
well to give comparable results to that obtained with AcOH,
regardless of their steric hindrance and chirality (entries 2-7).
When strong acids were added to the reaction, such as TsOH and
TFA, only decomposed complex was discovered, even when the
amount of TsOH was reduced to 0.2 equiv. (entries 8-10). The
control experiments suggest that the reaction can be slightly
poisoned by the addition of product (entries 11-12). Considering
the hydrazine products possess the basic N-N bonds that
deactivate the catalyst, we hypothesize that the addition of weak
acid could promote the dissociation of the active nickel catalyst.
Table 3. Influence of acid.[a]
Scheme 4. Gram scale reaction.
To probe the reaction pathway of this asymmetric
hydrogenation, a series of deuterium labeling experiments were
conducted (Figure 1). Firstly, the reaction was carried out in
TFE/AcOH solution under 20 bar of D2. Deuterium (77%) was
incorporated on the prochiral carbon atom and trace deuterium
incorporation was observed at the α-methyl group (Figure 1a).
When the above experiment was repeated with TFE-d1/AcOD
and H2, the deuterium positions were reversed, in which
deuterium incorporation on the prochiral carbon atom was 7% and
81% at the α-methyl group (Figure 1b). Performing the
hydrogenation reaction in TFE-d1/AcOD under 20 bar of D2
resulted in the corresponding product with the deuterium being
incorporated at both the prochiral carbon atom and α-methyl
group (95% and 77% respectively, Figure 1c). Finally, the
hydrogenation reaction was conducted without the nickel catalyst,
and the substrate 1a was obtained with 93% deuterium
incorporation at the α-methyl group (Figure 1d). These results
indicate that the hydrogen on the prochiral carbon mainly
originates from H2(D2) gas and the hydrazone substrates undergo
imine-enamine tautomerization in the mixed solvent system.
entry
acid additive
(2 equiv.)
pKa
(H2O)
-
conv.
(%)[b]
Trace
99
99
95
99
99
99
er (%)[c]
1
2
3
4
5
6
7
8
9
-
-
91:9
91:9
89.5:10.5
91:9
91:9
91:9
-
AcOH
EtCOOH
tBuCOOH
PhCOOH
4.76
4.88
5.03
4.20
4.34
4.34
-2.80
-0.25
-2.80
-
(S)-2-Phenylpropanoic acid
(R)-2-Phenylpropanoic acid
TsOH∙H2O
TFA
TsOH∙H2O (0.2 equiv)
[d]
-
[d]
-
-
-
[e]
10
11[f]
12[g]
-
-
-
94
74
83:17
86:14
-
[a] Reaction conditions otherwise noted: 1a (0.2 mmol), solvent (1 mL); [b] The
conversions were detected by 1H NMR spectra. [c] The er values were
determined by HPLC using a chiral stationary phase. [d] The substrate was
decomposed. [e] No product was detected and 5% of substrate was
decomposed. [f] 30 mol% catalyst was used. [g] 30 mol% catalyst was used in
the presence of 30 mol% product 2a (92:8 er). TsOH: p-toluenesulfonic acid,
TFA: CF3COOH.
3
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10.1002/ejoc.202100642
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COMMUNICATION
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(Figure 2). Complex 3 coordinates with substrate 1a to form
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Figure 2. Proposed mechanism.
[6]
In summary, an efficient asymmetric hydrogenation of
hydrazones was developed using an earth-abundant metal nickel
catalyst. A series of chiral hydrazines were synthesized with up to
99% yield and 99.4:0.6 er. An imine-enamine tautomerization of
the hydrazone substrates was observed as evidenced by the
deuterium labelling experiments. Mechanistic studies indicated
that the addition of acid promoted the dissociation of the active
nickel catalyst in the catalytic cycle.
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Acknowledgments
We would like to thank National Key R&D Program of China
(No. 2018YFE0126800), National Natural Science Foundation of
China (Nos. 21620102003, 21991112, 21702134), Shanghai
Municipal Education Commission (No. 201701070002E00030),
and Science and Technology Commission of Shanghai
Municipality (19JC1430100) for financial support. We thank the
Instrumental Analysis Center of SJTU for characterization.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: asymmetric hydrogenation • nickel • hydrazones •
chiral hydrazines • imine-enamine tautomerization
4
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10.1002/ejoc.202100642
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
An asymmetric hydrogenation of hydrazones with a unique nickel catalyst has been developed for the synthesis of chiral hydrazines
with up to 99% yield and 99.4:0.6 er and a broad substrate scope.
6
This article is protected by copyright. All rights reserved.