A cheap metal for a challenging task: nickel-catalyzed highly diastereo- and enantioselective hydrogenation of tetrasubstituted fluorinated enamides

Article abstract of DOI:10.1039/C8SC04002H

Nickel-catalyzed asymmetric hydrogenation of challenging tetrasubstituted fluorinated enamides has been achieved, affording chiral α-fluoro-β-amino esters in high yields with excellent diastereo- and enantioselectivities (up to 98% yield, >99?:?1 dr, up t

Full text of DOI:10.1039/C8SC04002H

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A cheap metal for a challenging task: nickel-
catalyzed highly diastereo- and enantioselective
hydrogenation of tetrasubstituted fluorinated
enamides†
Cite this: Chem. Sci., 2019, 10, 252
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Yu-Qing Guan, Zhengyu Han, Xiuxiu Li, Cai You, Xuefeng Tan, Hui Lv *acd
a
a
a
a
b
b
and Xumu Zhang
Nickel-catalyzed asymmetric hydrogenation of challenging tetrasubstituted fluorinated enamides has been
achieved, affording chiral a-fluoro-b-amino esters in high yields with excellent diastereo- and
enantioselectivities (up to 98% yield, >99 : 1 dr, up to >99% ee). Deuterium-labeling experiments and
control experiments were conducted to probe the mechanism, and the results indicated that the acidity
of the solvent plays a critical role in the control of diastereoselectivity by trapping the adduct of nickel
hydride to C]C bonds via protonolysis, giving the hydrogenation product with stereospecific syn-
selectivity. This protocol provides efficient access to chiral a-fluoro-b-amino esters which have
important potential applications in organic synthesis and medicinal chemistry.
Received 9th September 2018
Accepted 3rd October 2018
DOI: 10.1039/c8sc04002h
rsc.li/chemical-science
Highly efficient construction of chiral compounds in an envi- experienced rapid development, such as iron-, cobalt- and
ronmentally friendly and cost-effective manner is highly nickel-catalyzed asymmetric (transfer) hydrogenation of C]C,
3–5
signicant in organic synthesis and the pharmaceutical C]O, and C]N bonds. However, rst-row transition metal
1
industry. Asymmetric hydrogenation of tetrasubstituted catalyzed asymmetric hydrogenation of tetrasubstituted alkenes
alkenes provides ideal access to chiral compounds containing has not been achieved.
two contiguous stereocenters due to its perfect atom economy
and efficiency. Although great effort has been made so far, only ical and biological properties of organic molecules, introduction
a few successful examples of asymmetric hydrogenation of tet- of uorine atoms to nitrogen-containing molecules has emerged
Owing to the unique ability of uorine to modulate the phys-
2
6
7
rasubstituted olens have been reported via catalysts based on as an attractive strategy in drug discovery, and a series of
Rh, Ru, Ir, and Pd with high costs and deleterious environ- synthetic molecules containing chiral vicinal uoroamine motifs,
2
8a
8b
8c
mental impact. In contrast, catalysts based on cheap, earth- such as MK-0731, clofarabine, and sitaoxacin (Fig. 1a), have
abundant rst-row transition metals offer potential advan- been reported to exhibit important bioactivities. However, asym-
3
tages in terms of cost and sustainability. Consequently, metric synthetic routes to b-uoroamines with a vicinal stereo-
replacing precious metals with cheap, earth-abundant rst-row genic center are still very limited, and most of them involve the
transition metals in asymmetric hydrogenation of tetrasub- formation of C–F bonds and C–N bonds. As an alternative
9
–11
4
stituted alkenes is desirable. In the past few years, rst-row approach, transition metal catalyzed asymmetric hydrogenation
transition metal catalyzed asymmetric hydrogenation has of tetrasubstituted uorinated enamides, one of the most
12
powerful transformations available in synthetic chemistry, is
unexploited. There are several reasons that may account for the
a
Key Laboratory of Biomedical Polymers of Ministry of Education, College of Chemistry
and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R. China. absence of asymmetric hydrogenation in this transformation.
E-mail: huilv@whu.edu.cn
Firstly, the combined effect of both the steric hindrance and
electron-decient nature of tetrasubstituted uorinated alkenes
greatly decreases the coordination ability of the alkene to the
metal, which leads to the low activity in asymmetric hydrogena-
b
Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science
and Technology, Shenzhen, Guangdong 518055, P. R. China
c
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of
Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
12
tion. Secondly, the competition between deuorination and
4
30072, China
13
d
hydrogenation makes this reaction more challenging. Especially,
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, the reaction might be further challenged by relatively low catalytic
Beijing, 100190, P. R. China
activity when a nickel complex is employed as the catalyst.
Moreover, the mechanism of Ni-catalyzed hydrogenation is
distinct from the rhodium dihydride and ruthenium
†
Electronic supplementary information (ESI) available: Experimental procedures
and NMR spectra of the compounds. CCDC 1845389. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c8sc04002h
252 | Chem. Sci., 2019, 10, 252–256
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Fig. 2 Structures of the phosphine ligands for hydrogenation of (E)-
ethyl-3-acetamido-2-fluoro-3-phenylacrylate (E)-1a.
Table 1 Reaction condition optimization of Ni-catalyzed asymmetric
hydrogenation of (E)-ethyl-3-acetamido-2-fluoro-3-phenylacrylate
a
(E)-1a
Fig. 1 Ni-catalyzed asymmetric hydrogenation of olefins.
b
Yield [%]
1
4
b
c
monohydride pathways. For example, hydrogenation of acrylates
involves the formation of O–nickel enolate through 1,4-conjugate
addition of Ni–H to acrylate or Ni–H insertion to C]C bonds and
Entry
Ligand
Solvent
2a + 3a
4a
2a : 3a
ee
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
TFE
TFE
TFE
TFE
72
88
28
12
0
0
0
NR
—
—
—
5
20
0
0
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
—
97
95
99
À72
>99
—
—
—
—
>99
—
>99
>99
5q,s
subsequent isomerization (Fig. 1b), and it is extremely difficult
to afford stereospecic syn-addition products by the protonation.
Given that the protonolysis of the carbon–metal bond may occur
with retention of conguration at carbon under suitable condi-
tions, we envisioned that if we could inhibit the formation of O–
nickel species or accelerate the protonolysis of C–nickel species by
acidic solvents or acids, syn hydrogenation products would be
obtained stereospecically (Fig. 1c). Herein, we report the rst 11
example of nickel-catalyzed asymmetric hydrogenation of tetra- 12
substituted uorinated enamides, giving a-uoro-b-amino esters
with excellent diastereo- and enantioselectivities.
Initially, asymmetric hydrogenation of (E)-ethyl-3-acet-
amido-2-uoro-3-phenylacrylate (E)-1a was investigated using
<10
<10
>99
NR
Trace
Trace
Trace
42
TFE
Toluene
THF
EtOAc
15
—
—
—
1 : 2
CH
2
Cl
2
10
MeOH
EtOH
TFE
25
>99
32
<1 : 20
>99 : 1
>99 : 1
d
d,e
13
TFE
a
Conditions: Ni(OAc) /(S)-Binapine/(E)-1a 1 : 1.1 : 20, in 0.5 mL of
solvent. The conversion and ratio were determined using H NMR
analysis. The ee values of 2a were determined using HPLC analysis
2
b
1
c
d
e
ꢀ
with a chiral stationary phase. 50 atm of H . 50 C.
2
5
8
mol% Ni(OAc) and 5.5 mol% ligand under 70 atm of H at
2 2
0 C in CF CH OH for 24 h. A variety of diphosphine ligands
ꢀ
3
2
(
Fig. 2) developed by our group and some commercially avail-
asymmetric hydrogenation of (E)-1a. Subsequently, the solvent
effect was investigated, and the results revealed that solvents
play critical roles in this reaction, affecting the catalytic activity
and selectivity greatly. When toluene, tetrahydrofuran (THF),
able chiral ligands were examined (Table 1). When (R ,S )-
C
P
DuanPhos and (R)-BINAP were employed for this reaction, both
of them showed excellent reactivities and enantioselectivities,
but an undesired deuorination product was observed (Table 1,
entries 1–2). (S,S)-Me-DuPhos and (S,S)-Ph-BPE exhibited low
catalytic activity for this transformation albeit with good
enantioselectivities (Table 1, entries 3–4). To our delight, full
conversion and excellent ee were obtained by using (S)-Binapine
as the ligand (Table 1, entry 5, >99% conversion and >99% ee).
Notably, no deuorination or diastereoisomer products were
2 2
ethyl acetate (EtOAc) and dichloromethane (CH Cl ) were used
as solvents, the reactions were totally inhibited or only trace
products were detected (Table 1, entries 7–9). When the reac-
tions were conducted in MeOH or EtOH, the deuorination
product was observed with poor yields, affording 3a as the
major product (Table 1, entries 10–11). The effect of H pressure
2
for this reaction was also evaluated. Full conversion with an
unchanged ee value was obtained when the reaction was carried
2
detected in this process, which indicated that the Ni(OAc) /(S)-
Binapine catalytic system is efficient and effective for the
out in CF
3
CH
2
OH under a lower hydrogen pressure of 50 atm
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ꢀ
Table 1, entry 12). When the temperature decreased to 50 C, amyl, the reaction also proceeded smoothly, affording b-amido-
(
the reaction proceeded with 32% conversion (Table 1, entry 13). a-uoro esters with good yields and high enantioselectivities
Therefore, the optimized reaction conditions involved the use (2n–2p). Moreover, in order to determine the absolute cong-
of Ni(OAc) /(S)-Binapine as a catalyst under 50 atm of H pres- uration of the products, X-ray analysis of 2b was conducted, and
2
3
2
ꢀ
16
sure in CF
CH
2
OH at 80 C for 24 h.
the conguration was determined as (2R,3S).
To obtain insight into this catalytic system, a series of
With the optimized reaction conditions in hand, a series of
b-enamido-a-uoro esters were examined to evaluate the isotopic labeling studies were conducted. Firstly, when 1b was
ꢀ
substrate scope and generality of this catalytic reaction. As hydrogenated with 50 atm of D
2
in CF
3
CH
2
OH at 80 C, the
shown in Scheme 1, compounds (E)-1 with different ester deuterium atom was solely added at the b position (Scheme 2a).
groups were found to be good substrates to give the desired b- Then, when the experiment was carried out with 70 atm of H in
2
amido-a-uoro esters in excellent yields with outstanding ster- CD OD, the deuterium atoms were incorporated at the a posi-
3
eocontrol (2a and 2b). A wide range of b-aryl-b-enamido-a-uoro tion of the ester (Scheme 2b). Finally, when 2b was stirred in
ꢀ
esters with electron-rich or -poor aryl groups were examined. a mixture of 1 : 1 CD
3
OD/CF
3
CH
2
OH at 80 C, the deuterium
High yields and excellent enantioselectivities were observed in atoms were found at ester and amido groups, excluding the H/D
most cases, regardless of the substitution position (2c–2k). exchange at the a position of the ester aer the product was
17
Moreover, excellent enantioselectivity was obtained with the formed (Scheme 2c).
substrate containing the naphthyl group (2l). In addition, when In order to ascertain the role of solvent in modulation of
the acetyl group, the protection group of the amino group, was diastereoselectivity, we conducted this reaction in MeOH by
changed to a benzoyl group, high yield and excellent enantio- adding different ratios of acetic acid (Table 2), and the results
selectivity were also achieved (2m). Notably, when the aryl group revealed that the yields and diastereoselectivities were gradually
was changed to an alkyl group, such as methyl, i-butyl, or n- improved as the ratios of acetic acid increased. Joyfully, when 15
equivalents of acetic acid were added, only the syn hydrogenation
product was obtained. These results suggested that the acidic
proton plays a critical role in the control of diastereoselectivity.
Considering that the reaction was conducted at relatively
high temperature, and anti-selective product 3a was the major
product in ethanol or methanol, we assumed that the proton-
ation of nickel enolate was a thermodynamically controlled
process, which was benecial for the formation of the major
18
product with anti-selectivity. Based on these results and
analysis, we proposed the plausible reaction pathway (Fig. 3).
5
q,s
2
The heterolytic cleavage of H gave the NiH complex followed
by reaction with enamide to form nickel intermediate I. There
were two possible reaction pathways from intermediate I. When
the reaction was conducted in CF CH OH, the acidity of the
3
2
solvent greatly accelerated the stereospecic protonolysis of
nickel species I, which led to the inhibition of conversion of I to
II, generating the syn hydrogenation product (path A). When
a less acidic solvent (methanol) was used, the reaction rate of
isomerization of intermediate
I to II was faster than
a
Scheme 1 Substrate scope. Unless otherwise mentioned, all reac-
tions were carried out with a Ni(OAc)
: 1.1 : 20, in 0.5 mL of CF CH
2
/(S)-Binapine/substrate ratio of
ꢀ
1
3
2
OH, at 80 C, under hydrogen (50 atm)
b
c
for 24 h. Yield of the isolated product. Determined by HPLC analysis
d
e
using a chiral stationary phase. Under 70 atm of H
2
. Under 100 atm of
f
g
H
2
. Defluorination product was detected. The reaction was con-
ducted with a Ni(OAc)
2
/(S)-Binapine/substrate ratio of 1 : 1.1 : 10 under Scheme 2 Deuterium labeling studies of asymmetric hydrogenation
ꢀ
h
9
0 atm of H
2
at 80 C for 46 h. The ee was not possible to detect.
of 1b.
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Table 2 Solvent effect on asymmetric hydrogenation of compound scale with 1 mol% catalyst loading, and the desired product (2b)
a
(E)-1a
was obtained with 90% yield and >99% ee (Scheme 3).
Conclusions
2
In conclusion, a Ni(OAc) /(S)-Binapine complex catalyzed asym-
metric hydrogenation of tetrasubstituted b-enamido-a-uoro
esters has been achieved in high yields with excellent diastereo-
and enantioselectivities (up to 98% yield, up to >99% ee, and up
to >99 : 1 dr). More importantly, this investigation reveals the
critical role of acidic solvent in modulating the reaction pathway
and in the control of diastereoselectivity, which throws a new
light on the reaction mechanism. This method features a broad
substrate scope, excellent stereoselectivity and diaster-
eoselectivity, and provides an efficient and concise route to a-
Yield/%
Ratio
Entry
HOAc (x equiv.)
2a + 3a
4a
2a : 3a
1
2
3
4
5
—
42
51
61
>99
>99
5
1 : 2
1 : 1
68 : 32
93 : 7
>99 : 1
0.5
1.0
5.0
15.0
<1
<1
<1
0

uoro-b-amino esters. Further investigations on nickel-catalyzed
a
All reactions were carried out with a Ni(OAc)
CH
2
/(S)-Binapine/substrate
OH, at 80 C, under hydrogen
ꢀ
asymmetric hydrogenation are in progress in our lab.
ratio of 1 : 1.1 : 20, in 0.5 mL of CF
70 atm) for 24 h.
3
2
(
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (Grant No. 21871212, 21402145
and 21432007), the Natural Science Foundation of Hubei
Province (2018CFB430), the Fundamental Research Funds for
the Central Universities (2042017kf0177), the Important Sci-
Tech Innovative Project of Hubei Province (2015ACA058) and
the “111” Project of the Ministry of Education of China.
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in column chromatography; thus no NDAc was detected in
NMR experiments.
7
8
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256 | Chem. Sci., 2019, 10, 252–256
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