Highly efficient Rh-catalyzed asymmetric hydrogenation of α,β-unsaturated nitriles

Article abstract of DOI:10.1021/jacs.5b06418

A highly efficient enantioselective hydrogenation of α,β-unsaturated nitriles catalyzed by Rh-(R,R)-f-spiroPhos complex has been developed. With Rh-(R,R)-f-spiroPhos catalyst and under mild conditions, a wide range of α,β-unsaturated nitriles including the (E)- and (Z)-isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl α,β-unsaturated nitriles were hydrogenated to the corresponding chiral nitriles with excellent enantioselectivities (up to 99.9% ee) and high turnover numbers (TON up to 10,000).

Full text of DOI:10.1021/jacs.5b06418

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Highly Efficient Rh-Catalyzed Asymmetric Hydrogenation of α,β-
Unsaturated Nitriles
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Qiaozhi Yan, Duanyang Kong, Meina Li, Guohua Hou,* and Guofu Zi*
College of Chemistry, Beijing Normal University, Beijing 100875, China
Asymmetric hydrogenation, Unsaturated nitriles, Chiral nitriles, Rhodium catalysts, Enantioselectivity, f-spiroPhos
ligand.
ABSTRACT: A highly efficient enantioselective hydrogenation of α,β-unsaturated nitriles catalyzed by Rh-(R,R)-f-
spiroPhos complex has been developed. With Rh-(R,R)-f-spiroPhos catalyst and under mild conditions a wide range of
α,β-unsaturated nitriles including the (E)- and (Z)-isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl α,β-unsaturated
nitriles were hydrogenated to the corresponding chiral nitriles with excellent enantioselectivities (up to 99.9% ee) and
high turnover numbers (TON up to 10,000).
1. INTRODUCTION
ido or carboxylate group attached to the C=C bond.11 More
recently, in combination with N,N-diisopropylethylamine
(DIPEA), a Ir/N,P complex exhibited a high reactivity and
enantioselectivity only for E-α,β-unsaturated nitriles, but
poor conversions or enantioselectivities were observed for
the corresponding Z-isomers.8
The chiral 3,3-disubstituted propionitriles are im-
portant synthetic intermediates for many biologically
active compounds and pharmaceuticals, such as ar-
turmerone,1 florhydral,2 Tolterodine,3 indatraline,4 and
5
arpromidine (Figure 1). In addition, these nitriles can be
readily converted to other useful compounds, such as
amines, aldehydes and carboxylic acids. Due to their sig-
nificance in chemical synthesis, the development of effi-
cient enantioselective synthetic protocols has attracted
considerable attentions. Among these, the metal-
catalyzed conjugate reduction of α,β-unsaturated nitriles
represents the predominant. However, presumably be-
cause of the intrinsic low reactivity of these substrates and
the linearity of the nitrile group,6, 7a, 8 which is not suitable
for the assistant coordination between the C=C bond and
metal catalyst, reports on efficient catalyst systems for the
asymmetric reduction of α,β-unsaturated nitriles have
been very limited so far. The Co-catalyzed conjugate re-
duction of these substrates with sodium borohydride pro-
vided saturated nitriles with only moderate enantioselec-
tivities, up to 69% ee.9 Higher enantioselectivities could
be achieved using the copper-josiphos catalyzed asym-
metric hydrosilylation with polymethylhydrosiloxane
(PMHS).7 Although the catalytic asymmetric hydrogena-
tion has been one of the most powerful approaches to
chiral compounds and great progress has been made,10
there are only a few examples involving asymmetric hy-
drogenation of α,β-unsaturated nitriles and high enanti-
oselectivities could only be achieved for the substrates
with an assistant coordinating group such as an acetam-
Figure 1. Key structural elements in chiral pharmaceuticals.
We have recently developed a new type of chiral di-
phosphine ligand f-spiroPhos based on privileged spirobi-
indane skeleton, which developed by Zhou and cowork-
ers,12 and demonstrated its iridium complex was highly
efficient for the hydrogenation of β-acylamino nitroole-
fins.13 When we evaluated this chiral diphosphine ligand
for the hydrogenation of α,β-unsaturated nitriles without
any additional chelating groups, we fortunately found its
rhodium complex showing excellent enantioselectivities
(up to 99.9% ee) and high reactivities (TON up to 10,000)
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for a wide range of substrates including both E- and Z-
3
4
5
isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl α,β-
unsaturated nitriles under mild reaction conditions
(Scheme 1).
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Scheme 1
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Figure 2. Structures of the phosphine ligands for hydrogena-
tion of (E)-3-phenylbut-2-enenitrile 1a.
Table 1. Asymmetric Hydrogenation of (E)-3-
phenylbut-2-enenitrile 1a, optimizing reaction condi-
tions.a
2. RESULTS AND DISCUSSION
2.1. Asymmetric Hydrogenation of (E)-3-alkyl-3-aryl
α,β-Unsaturated Nitriles.
Initially, (E)-3-phenylbut-2-enenitrile 1a was used as
the model substrate, and the hydrogenation was per-
formed under 60 atm of H2 in CH2Cl2 at room tempera-
ture using the complex of (R,R)-f-spiroPhos and
[Ir(COD)Cl]2, which was very efficient for the hydrogena-
tion of nitroalkenes.13 Despite full conversion, only mod-
erate enantioselectivity was achieved, 64% ee (Table 1,
entry 1). After investigation of the metal precursors, we
found that [Rh(COD)Cl]2 was the best choice and showed
both high enantioselectivity and activity, 96% ee and
complete conversion (entry 3). Furthermore, a brief
screening of chiral phosphorus ligands available in our
laboratory revealed that most of phosphorus ligands in-
cluding (S)-BINAP, (S,R)-DuanPhos, (R)-JosiPhos-1, (S,S)-
f-Binaphane, and (S)-MonoPhos, gave either low conver-
sions or poor enantioselectivities (up to 57% ee, entries
4−8). The effect of solvents was also explored. This hydro-
genation could be performed smoothly with good enanti-
oselectivities in most of solvents, such as THF, toluene,
and DME (entries 10−12), but not in methanol (entry 9).
In addition to CH2Cl2, dioxane is also suitable for the hy-
drogenation and comparable results were observed (96%
ee, entry 13). Interestingly, lower hydrogen pressures have
a negative effect on the enantioseletivity of this reaction.
Decreasing the hydrogen pressure from 60 atm to 5 atm
led to a decrease in enantioselectivity (entries 14−15),
while the conversion remains unchanged. Moreover, un-
der 50 atm of H2, this hydrogenation could be completed
in 30 minutes with unchanged enantioselectivity (entry
16).
entry ligand
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
conv.(%)b ee (%)c
1d
2e
3
(R,R)-f-spiroPhos
>99
61
64
58
96
57
24
9
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(S)-BINAP
>99
4
4
5
(S,R)-DuanPhos
(R)-JosiPhos-1
6
6
20
7
(S,S)-f-Binaphane CH2Cl2
89
47
14
8
(S)-MonoPhos
CH2Cl2
MeOH
THF
0.9
94
9
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
31
10
11
>99
>99
>99
>99
>99
>99
>99
86
74
93
96
91
Toluene
DME
12
13
14f
15g
16h
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
93
96
a
Reaction conditions: [Rh(COD)Cl]2/phosphine/substrate
b
ratio = 0.5 : 2.1 : 100, 60 atm H2, 12 h, rt. Determined by GC
c
analysis. Determined by chiral GC using a Supelco Alpha-
DexTM 225 column (30 m × 0.25 mm × 0.25 μm).
d
e
f
g
h
[Ir(COD)Cl]2. [Rh(COD)2]BF4. 5 atm H2. 20 atm H2. 50
atm H2, 30 min.
Under the optimal reaction conditions a variety of (E)-
3-alkyl-3-aryl α,β-unsaturated nitriles 1 were evaluated
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17d
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(E)-3-pyridinyl(1q) Me
2q
2r
2s
>99(96) 99(-)
>99(95) 96(-)
>99(98) 99(-)
>99(98) 98(-)
and provided the corresponding chiral nitriles with
95−99.7% ee (Table 2). The electron property and position
of the substituents in the phenyl ring of the substrates
had no obvious effect on both the reactivity and enanti-
oseleltivity. Generally, the substrates with electron-
withdrawing substituents on the phenyl ring gave rela-
tively higher enantioselectivity than those with electron-
donating substituents. For example, the substrate (E)-1f
with a para-methyl group gave 95% ee (entry 6), while the
substrates with a para-chloro ((E)-1c), bromo ((E)-1d) or
nitro group ((E)-1e) yielded 2c, 2d and 2e with as high as
97% ee (enties 3, 4 and 5). The substrates with substitu-
ents at meta- or ortho-position of the phenyl ring also
gave higher enantioselelctivities than those with substitu-
ents at para-position, and the substrate (E)-1l provided
product 2l with the highest ee value of 99.7% (entry 12).
The substrate (E)-1q with a heterocyclic pyridinyl ring
also afforded the product 2q with an excellent enantiose-
lectivity (99% ee), but higher hydrogen pressure and
longer reaction time were required to complete the reac-
tion (entry 17). This reduced activity may be attributed to
the strong inhibitory effect of the pyridinyl group on the
catalyst. The substrates with a larger 3-alkyl substituent
(E)-C6H5(1r)
(E)-C6H5(1s)
(E)-C6H5(1t)
Et
iPr
19
20
C5H9 2t
a
Unless otherwise mentioned, all reactions were carried
out with a [Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of
9
b
0.5 : 1.1 : 100, CH2Cl2, 50 atm H2, rt, 30 min. Determined by
1H NMR spectroscopy or GC analysis; data in parentheses are
isolated yields. c Determined by HPLC analysis using a chiral
stationary phase or chiral GC analysis. d 80 atm H2, 24 h.
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Furthermore, it is notable that this catalyst system was
also highly efficient for the hydrogenation of the (Z)-
isomers of the substrates 3, providing the corresponding
products 4 with good to excellent enantioslectivities
(89−97% ee) (Table 3). Although the enantioselectivities
of the hydrogenation of (Z)-isomers were relatively lower
than those obtained by the corresponding (E)-isomers
and with opposite configuration, this provided the first
example of highly efficient asymmetric hydrogenation of
both the (E)- and (Z)-isomers of α,β-unsaturated nitriles
to produce either desired enantiomer, (S) or (R)-
enantiomer of chiral nitriles with similar enantioselectivi-
ties.
i
such as Et, Pr and C5H9 ((E)-1r to 1t) also gave compara-
ble or even better enantioselelctivity than that provided
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of
by the model substrate (E)-1a (entries 18−20).
(Z)-3-alkyl-3-aryl α,β-unsaturated nitriles.a
Table 2. Rh-Catalyzed Asymmetric Hydrogenation of
(E)-3-alkyl-3-aryl α,β-unsaturated nitriles.a
conv.
(%)b
prod-
uct
product conv.(%)b ee(%)c
entry Ar
R
ee (%)c
entry Ar
R
1
(Z)-4-ClC6H4(3a) Me
(Z)-2-FC6H4(3b) Me
4a
4b
4c
4d
4e
4f
>99(96) 89(-)
>99(95) 94(+)
>99(97) 97(+)
>99(96) 95(+)
>99(95) 92(+)
>99(95) 93(+)
>99(96) 97(+)
1
(E)-C6H5(1a)
Me
Me
Me
Me
2a
2b
2c
2d
2e
2f
>99(98) 96(S)
>99(98) 95(-)
>99(98) 97(+)
>99(97) 97(+)
>99(96) 97(+)
>99(98) 95(S)
>99(96) 97(+)
>99(97) 97(+)
>99(97) 98(-)
>99(98) 98(-)
>99(98) 96(-)
>99(98) 99.7(-)
>99(97) 99.5(-)
>99(96) 99(+)
>99(97) 98(-)
>99(98) 96(+)
2
3
4
5
6
7
2
(E)-4-FC6H4 (1b)
(E)-4-ClC6H4(1c)
(E)-4-BrC6H4(1d)
(Z)-2-ClC6H4(3c) Me
(Z)-2-MeC6H4(3d) Me
(Z)-1-naphthyl(3e) Me
3
4
5
(E)-4-NO2C6H4(1e) Me
(E)-4-MeC6H4(1f) Me
(Z)-C6H5(3f)
(Z)-C6H5(3g)
Et
iPr
6
4g
7
(E)-3-ClC6H4(1g)
(E)-3-BrC6H4(1h)
Me
Me
2g
2h
2i
a
Unless otherwise mentioned, all reactions were carried
8
out with a [Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of
b
9
(E)-3-NO2C6H4(1i) Me
(E)-3-MeOC6H4(1j) Me
0.5 : 1.1 : 100, CH2Cl2, 50 atm H2, rt, 30 min. Determined by
10
11
12
13
14
15
16
2j
1H NMR spectroscopy or GC analysis; data in parentheses are
isolated yields. c Determined by HPLC analysis using a chiral
stationary phase or chiral GC analysis.
(E)-2-FC6H4(1k)
(E)-2-ClC6H4(1l)
Me
Me
2k
2l
Most importantly, this is a very highly efficient method
for the synthesis of chiral nitriles. With Rh-(R,R)-f-
spiroPhos catalyst and performed the hydrogenation of
the easily obtained (E)-1i at a catalyst loading of 0.02 mol%
under 110 atm of initial H2 pressure at room temperature,
(E)-2-MeC6H4(1m) Me
(E)-2-NO2C6H4(1n) Me
(E)-1-naphthyl(1o) Me
(E)-2-naphthyl(1p) Me
2m
2n
2o
2p
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CN
CN
CN
CN
2i was obtained in >99% conversion with 99.3% ee. Fur-
Cl
Cl
3
4
5
ther deceasing the catalyst loading to 0.01 mol%, >99%
conversion and 98% ee were also obtained under the
same initial H2 pressure at 40 C (Scheme 2). This result
5b
5c
5d
5a
o
yield.96%; ee.97% (-)
yield.96%; ee.97% (+)
yield.98%; ee.98% (S)
yield.95%; ee.94% (+)
6
7
8
9
indicated that Rh-(R,R)-f-spiroPhos was exceptional high-
ly efficient for the hydrogenation of α,β-unsaturated ni-
triles and could provide turnover numbers (TON) ap-
proaching 10,000.
CN
CN
NC
F
CN
F
O
5e
5f
5g
5h
yield.98%; ee.99% (S)
yield.98%; ee.99.8% (-)
yield.95%; ee.96% (+)
yield.95%; ee.94% (S)
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CN
CN
CN
Cl
CN
Cl
Scheme 2
O
O
F
5i
5j
5k
5l
yield.95%; ee.99% (+)
yield.97%; ee.97% (+)
CN
yield.98%; ee.99.7% (-)
NC
yield.98%; ee.99.4% (+)
NC
NC
Cl
O2N
O
Cl
N
N
5oc
5nb
5p
5m
yield.96%; ee.99.7% (+) yield.99%; ee 99.9% (S)
yield.98%; ee.99% (+)
yield.97%; ee.99.7% (-)
a
Unless otherwise mentioned, all reactions were carried
out with a [Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of
0.5 : 1.1 : 100, CH2Cl2, 50 atm H2, rt, 6 h. The conversion was
determined by H NMR spectroscopy; the enantioselectivity
was determined by HPLC analysis using a chiral stationary.
2.2. Asymmetric Hydrogenation of (E) and (Z)-3,3-
Diarylacrylonitriles.
1
Encouraged by the promising results obtained by the
asymmetric hydrogenation of the (E)- and (Z)-isomers of
3-alkyl-3-aryl α,β-unsaturated nitriles 1 and 3, we then
studied the asymmetric hydrogenation of 3,3-
diarylacrylonitriles with Rh-(R,R)-f-spiroPhos catalyst. To
date, only a few catalysts showed high activity and good
enantioselectivity for the hydrogenation of the unsaturat-
ed substrates bearing diaryl substituents at the C=C, C=O
or C=N bond.14 To the best of our knowledge, no example
b
40 oC, 12 h. c 12 h.
2.3. Asymmetric Hydrogenation of 3,3-dialkyl and
2-alkyl-3-aryl α,β-unsaturated nitriles 7 and 9.
In addition, the asymmetric hydrogenation of 3,3-
dialkyl and 2-alkyl-3-aryl α,β-unsaturated nitriles were
also evaluated with Rh-(R,R)-f-spiroPhos catalyst (Scheme
3). Under the similar conditions for the hydrogenation of
1 and 3, (E)-3,3-dialkyl α,β-unsaturated nitriles 7a and 7b
were hydrogenated to chiral nitriles 8a and 8b in full con-
versions with 91 and 95% ee, respectively, after reacted at
for
the
asymmetric
hydrogenation
of
3,3-
diarylacrylonitriles has been reported so far, and we
found Rh-(R,R)-f-spiroPhos catalyst was also very highly
efficient for this type of substrates.
o
−15 C for 6 h. With a substituent group at the α-position
Based on the optimal conditions for the hydrogenation
of 3-alkyl-3-aryl α,β-unsaturated nitriles 1 and 3, we found
that prolonging the reaction time from 0.5 h to 6 h a wide
range of (E)-3,3-diarylacrylonitriles could be hydrogenat-
ed to the corresponding products 6 in >99% conversions
with 94−99.9% ee (Table 4). These results revealed that
the electronics and the steric hindrance of substituents on
the aryl groups had no obvious effect on the enantioselec-
tivities. Remarkably, even for the hydrogenation of (Z)-
3,3-diarylacrylonitriles, such as 5f and 5o, the catalyst sys-
tem provides the desired products with excellent enanti-
oselectivities, 96% and 99.7% ee respectively, with a re-
versal of the absolute configuration. The performance of
the new Rh-f-spiroPhos catalyst system in the asymmetric
hydrogenation of 3,3-diarylacrylonitriles was also evaluat-
ed on a gram scale. Under optimized reaction conditions,
substrate 5k (1.0 g) was smoothly hydrogenated providing
the corresponding product in excellent yield (99% isolat-
ed yield) almost without any loss of enantioselectivity,
99.4% ee.
of the α,β-unsaturated nitriles, the reaction became slug-
gish. The asymmetric hydrogenation of (E)-3-aryl substi-
tuted methacrylonitriles 9a and 9b gave incomplete con-
version with 19% and 45% ee, respectively.
Scheme 3
2.4. Application of the Rh-(R,R)-f-spiroPhos Cata-
lyst in the Synthesis of Biologically Active Com-
pounds and Pharmaceuticals.
Table 4. Rh-Catalyzed Asymmetric Hydrogenation of
3,3-diarylacrylonitriles 5.a
Furthermore, this method was successfully applied to
the enantioselective preparation of (S)-(+)-ar-turmerone
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as a spice flavor of turmeric in high yield and enantiose-
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lectivity. The produced (S)-(+)-ar-turmerone can be con-
verted to (+)-bisacumol, which is usually isolated from
the rhizome of Curcuma Xanthorrhiza as a member of the
aromatic bisabolane sesquiterpene family, and (S)-ar-
himachalene, a pheromone component of the flea beetle.15
The key intermediate 11 for the synthesis of indatraline,
which is a potent psychoactive compound with high in-
hibitory activity for monoamine reuptake,4 can also be
readily prepared by this method from 3,3-
diarylacrylonitrile 5p in high yield with excellent enanti-
oselectivity, 99% ee (Scheme 4). Importantly, this strategy
is more efficient than others reported in the literature. 7b, 16
10
11
12
13
14
15
16
17
18
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Scheme 4
H2 (50 atm)
1 mol% Rh-(R,R)-f-spiroPhos
CN
CN
KOH
HO(CH2)2OH
99%
CH2Cl2, rt, 40 min
98%
1f (0.5 g)
(S)-2f, 93% ee
O
MeNHOMe.HCl
EDC, DMAP
iPr2NEt, CH2Cl2
Me2C=CHMgBr
OMe
COOH
N
THF, 20 oC, to
rt, 2 h
Me
89%
88%
OH
(+)-bisacumol
Cl
O
or
(S)-ar-himachalene
(S)-(+)-ar-turmerone
92% ee
NC
CN
ref.[7b]
AcOH
H2SO4
H2 (50 atm)
Cl
Cl
1 mol% Rh-(R,R)-f-spiroPhos
H2O, reflux
NHCH3
CH2Cl2, rt, 6 h
99% yield
Cl
5p
CONCLUSION
6p
99.8% ee
O
In conclusion, we have developed a highly efficient
method for enantioselective hydrogenation of α,β-
unsaturated nitriles to optical active saturated nitriles.
With a rhodium complex bearing a spirobiindane-based
chiral diphosphine (R,R)-f-spiroPhos ligand a wide range
of α,β-unsaturated nitriles including the (E)- and (Z)-
isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl α,β-
unsaturated nitriles were hydrogenated to the corre-
sponding chiral nitriles with excellent enantioselectivities
(up to 99.9% ee) and high turnover numbers (TON up to
10,000). Further studies are underway and will be report-
ed in due course.
COOH
ref.[7b]
Cl
ref.[16]
Cl
Cl
Cl
Cl
ClSO3H
CH2Cl2
Cl
11
indatraline
91% yield for two steps
99% ee
According to the reported mechanism of rhodium and
iridium catalyzed asymmetric hydrogenation reactions,17 a
plausible mechanism of this transformation and possible
enantio-determining transition model were also proposed
(Scheme 5). The ferrocenyl group of the ligand blocked
one side of the complex and the substrate could only co-
ordinate to rhodium from the other side. The enantio-
determining transition model showed that the coordina-
tion of the (E)-substrate to rhodium was much more fa-
vorable from the Re-face of the α,β-unsaturated nitriles,
which led to the (S) products. For the (Z)-substrate, the
coordination was more favorable from the Si-face to af-
ford the (R) products. These were in agreement with the
stereochemical outcome of the hydrogenation products.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Scheme 5. proposed mechanism and stereorecognition
model for Rh-catalyzed asymmetric hydrogenation of α,β-
unsaturated nitriles.
*ghhou@bnu.edu.cn
gzi@bnu.edu.cn
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(Grant No. 21272026, 21172022, 21472013), the Fundamental
Research Funds for the Central Universities, Specialized Re-
search Fund for the Doctoral Program of Higher Education of
China, Program for Changjiang Scholars and Innovative Re-
search Team in University, and Beijing Municipal Commis-
sion of Education for generous financial support. We also
thank Prof. Qi-Lin Zhou and Jian-Hua Xie for helpful discus-
sions.
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