Highly efficient RhI-catalyzed asymmetric hydrogenation of β-amino acrylonitriles

Article abstract of DOI:10.1002/chem.201000325

(Figure Presented) It takes two to TangPhos: β-Amino acrylonitriles can be readily prepared from acetonitriles. Both of the E/Z isomers undergo hydrogenation with excellent enantioselectivity by using the Rh-TangPhos (TangPhos = l, 1'-ditert-butyl-(2, 2')-diphospholane) catalyst system. The products, chiral β-amino nitriles, are valuable chiral building blocks for many drugs.

Full text of DOI:10.1002/chem.201000325

COMMUNICATION
DOI: 10.1002/chem.201000325
Highly Efficient RhI-Catalyzed Asymmetric Hydrogenation of b-Amino
Acrylonitriles
Miaofeng Ma,[a, b] Guohua Hou,[b] Tian Sun,[b] Xiaowei Zhang,[b] Wei Li,[b]
Junru Wang,*[a] and Xumu Zhang*[b]
Enantiomerically pure b-amino nitriles and their deriva-
tives are important intermediates in organic synthesis and
pharmaceutical chemistry. The nitrile group is one of the
most versatile functional groups in organic chemistry and
can be readily transformed into a variety of valuable func-
tionalities,[1] including carboxyl; aldehyde; and amino
groups, and, hence, b-amino nitriles enable facile approaches
to b-amino acids, aldehydes, and 1,3-diamines. Therefore,
the synthesis of b-amino nitriles has attracted much atten-
tion in recent decades. The early preparation of b-amino ni-
triles started from b-amino alcohols and involves a reaction
with toxic cyanic reagents.[2] Some recent progress[3] includes
addition reactions of alkyl nitriles to imines catalyzed by
Cu,[4] Pd,[5] Ru,[6] or Lewis base[7] complexes, with good
yields. An alternative approach to b-amino nitriles is the
ring-opening of aziridines with trimethylsilyl cyanide
(TMSCN).[8]
b-amino acrylonitriles is achieving chemoselectivity between
the olefinic double bond and the nitrile group.[10]
Asymmetric hydrogenation catalyzed by transition metals
has proved to be a highly efficient method for the synthesis
of chiral amines. A number of chiral phosphine ligands have
been developed that improve the chemo- and enantioselec-
tivity of the hydrogenation reaction.[11] We envisioned that
the electron-donating, rigid, chiral ligands, such as Tang-
Phos, DuanPhos, and Binapine (shown here), developed in
To the best of our knowledge, there are few reports of the
direct preparation of chiral b-amino nitriles by asymmetric
hydrogenation of the corresponding b-amino acrylonitriles.[9]
This is mainly due to the electronic structure of nitriles,
which prefer the end-on coordination of metal ions, making
the conjugated double bond unsuitable for hydrogenation
reactions. Another challenge in the direct hydrogenation of
our research group,[11d] could be efficient ligands for the hy-
drogenation of b-amino acrylonitriles. Herein, we report the
first direct asymmetric hydrogenation of b-amino acryloni-
triles with a Rh–TangPhos catalyst, providing the corre-
sponding b-amino nitriles in excellent enantioselectivities
(up to 99.4% ee) and tolerating E/Z mixtures of
substrate.[11a]
b-Amino acrylonitriles can be readily prepared in two
steps with good yield (Scheme 1).[12] With (E)-3-acetylami-
no-3-phenylacrylonitrile [(E)-1a)] as a model substrate, we
screened several electron-donating ligands developed in our
group, and some commercially available chiral ligands, such
[a] M. Ma, Prof. J. Wang
College of Science
Northwest Agriculture and Forestry University
Yangling, Shaanxi 712100 (P.R.China)
Fax : (+86)029-87092226
E-mail: wangjr07@163.com
[b] M. Ma, Dr. G. Hou, T. Sun, X. Zhang, W. Li, Prof. X. Zhang
Department of Chemistry and Chemical Biology &
Department of Pharmaceutical Chemistry
Rutgers, the State University of New Jersey
Piscataway, New Jersey 08854 (USA)
Fax : (+1)732-445-6321
E-mail: xumu@rci.rutgers.edu
Scheme 1. Synthesis of b-acetylamino acrylonitriles. Reagents and condi-
tions: a) CH3CN, tBuOK, toluene, ultrasound, 4 h; b) Ac2O, Et3N, tolu-
ene, reflux, overnight.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000325.
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as 1,2-bis(2,5-dialkylphospholano)benzene (DuPhos) and
BINAP (shown). DuanPhos, Binapine, Et-DuPhos, and
enantioselectivity; this had no evident effect on the enantio-
selectivity of the product, but at 258C, incomplete conver-
sion was observed (Table 1, entry 12 and 13).
In asymmetric hydrogenation, lower enantioselectivities
are often observed for E and Z stereoisomers of sub-
strates.[11,13] It is notable that the Rh–TangPhos catalytic
system is efficient for the hydrogenation of both the E and
Z isomers of substrates. For example, under the optimized
reaction conditions, both (Z)-1a and (Z)-1b are hydrogenat-
ed by the Rh–TangPhos catalyst to the desired products
with higher enantioselectivities (>99% ee, Table 2, entries 2
BINAP only showed low conversions and enantioselectivi-
ties (Table 1, entries 2–5). To our delight, the Rh–TangPhos
complex proved to be highly enantioselective. However, by
Table 2. Rhodium-catalyzed asymmetric hydrogenation of b-amino
acryloACHTUNGTRNEUNG
nitriles 1.[a]
Table 1. Rhodium-catalyzed asymmetric hydrogenation of (E)-1a under
various conditions.[a]
[d]
Entry Substrate E:Z[b]
R
Product ee [%][c] +/À
1
2
3
4
5
6
7
8
9
(E)-1a
(Z)-1a
1a
(E)-1b
(Z)-1b
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1a
–
–
C6H5
C6H5
2a
2a
2a
2b
2b
2b
2c
2d
2e
2 f
2g
2h
2i
96
99
98
95
99.4
96
95
96
96
92
98
97
94
33
20
93
97
82
93
À
À
À
À
À
À
À
À
À
À
À
À
À
À
À
À
À
+
À
2.3:1 C6H5
–
–
p-ClC6H4
p-ClC6H4
Entry Ligand
Solvent PH
T
Conversion ee
2
AHCTUNGTRENNUNG
[atm] [oC] [%][b]
[%][c]
2.2:1 p-ClC6H4
>99:1 p-MeC6H4
>99:1 p-MeOC6H4
50:1 p-FC6H4
12.5:1 p-BrC6H4
0.8:1 p-CF3C6H4
>99:1 m-MeC6H4
>99:1 m-ClC6H4
>99:1 o-ClC6H4
>99:1 o-MeC6H4
50:1 2-naphthyl
1
2
3
4
5
6
7
8
9
10
11
12
13
(S, S, R, R)-TangPhos CH2Cl2 70
60
60
60
60
60
60
60
60
60
60
60
40
25
64
38
24
22
3
100
84
100
70
100
100
100
94
93
80
20
59
29
93
36
19
8
94
96
96
94
A
CH2Cl2 70
CH2Cl2 70
CH2Cl2 70
CH2Cl2 70
E
(S)-BINAP
(S)-Binapine
10[e]
11
12
13
14[f]
15[f]
16
17
18
19[g]
(S, S, R, R)-TangPhos MeOH 70
(S, S, R, R)-TangPhos THF 70
(S, S, R, R)-TangPhos toluene 70
(S, S, R, R)-TangPhos dioxane 70
(S, S, R, R)-TangPhos MeOH 30
(S, S, R, R)-TangPhos MeOH 10
(S, S, R, R)-TangPhos MeOH 10
(S, S, R, R)-TangPhos MeOH 10
2j
2k
2l
>99:1 thiophen-2-yl 2m
>99:1 Me
2.3:1 C6H5
2n
2a
[a] All reactions were carried out with a substrate/catalyst ratio of 100:1,
for 24 h. [b] Determined by GC methods. [c] The ee of 2a was deter-
mined by chiral phase GC.
[a] Unless mentioned otherwise, reactions were carried out with a sub-
strate/catalyst ratio of 100:1, in MeOH, at 408C, under 10 atm of hydro-
gen, for 24 h and resulted in 100% conversion. [b] Determined by
1H NMR spectroscopy. [c] The ee was determined by GC or HPLC on a
chiral phase. [d] The sign of the optical rotation. [e] 50 atm of H2, 48 h,
100% conversion. [f] 50 atm of H2, 72 h, 100% conversion. [g] Substrate/
catalyst=1000.
using 70 atm of H2, at room temperature, in dichlorome-
thane, TangPhos only gave a very poor result with <5%
conversion (result not shown). However, when this reaction
was performed at 608C, very promising results were ob-
tained (64% conversion, 93% ee) (Table 1, entry 1). Subse-
quently, the effect of the solvent was investigated. It was
found that only in MeOH was substrate 1a converted to the
desired product with full conversion and good enantioselec-
tivity (93% ee; Table 1, entry 6). Other solvents, such as
THF and dioxane, gave much lower enantioselectivities
(Table 1, entries 7–9). Although the hydrogenation proceed-
ed smoothly in toluene, the enantioselectivity decreased dra-
matically (Table 1, entry 8). The effect of the pressure of H2
was also tested; if the hydrogen pressure was reduced to
10 atm, the milder reaction conditions gave a slightly higher
ee (96% ee; Table 1, entry 11). Finally, we attempted to de-
crease the reaction temperature to further improve the
and 5) than the corresponding E isomers (Table 2, entries 1
and 4). Even the hydrogenation of an E/Z mixture of 1a or
b still retains comparable ee (Table 2, entries 3 and 6), which
makes it unnecessary to isolate the isomers to produce high
enantioselectivities and is a more practical method for or-
ganic synthesis.
Encouraged by the promising results obtained for the hy-
drogenation of 1a and b, we applied the Rh–TangPhos-cata-
lyzed asymmetric hydrogenation to a variety of b-amino
acrylonitriles, with various E/Z isomer ratios, 1c–n. The de-
sired b-amino nitriles, were obtained in full conversion and
excellent enantioselectivity (Table 2). The electronic proper-
ties of the substituents on the aryl group of b-amino acrylo-
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Chem. Eur. J. 2010, 16, 5301 – 5304

b-Amino Acrylonitriles
COMMUNICATION
nitriles 1 have limited influence on the conversion and the
enantioselectivity of the products. Very high enantioselectiv-
ities were obtained with substrates bearing either an elec-
tron-donating or an electron-withdrawing group at the para
or meta position of the benzene ring (92–98% ee; Table 2,
entries 7–13). Both 2-naphthyl and thiophen-2-yl b-amino
acrylonitriles afforded the b-amino nitrile products, with 93
and 97% ee, respectively (Table 2, entries 16 and 17). In
contrast, we found that the presence of either a methyl or
chloro substituent at the ortho-position resulted in dramati-
cally reduced reactivity and enantioselectivity, which may be
due to the steric hindrance caused by the ortho-substituents.
Notably, 82% ee was achieved for the hydrogenation of an
alkyl b-amino acrylonitrile 1n (Table 2, entry 18).
amine compounds is currently in progress and will be re-
ported in a due course.
Experimental Section
General procedure for the synthesis of compounds 1: Et3N (2.0 equiv)
was added dropwise to a solution of a b-enaminonitrile (1.0 equiv) and
Ac2O (5.0 equiv) in toluene under stirring. The reaction mixture was
then heated to reflux and stirred for 24 h. After it was cooled to room
temperature, the reaction solution was consecutively washed with saturat-
ed sodium carbonate, water, and brine and then dried over anhydrous
Na2SO4. After removing the solvent, the crude product was purified by
column chromatography using ethyl acetate and hexane as the eluent.
General procedure for the hydrogenation of 1: A stock solution of the
catalyst was made by mixing [RhACHTNUTRGNE(UNG cod)2]BF4 with TangPhos (1:1.1 molar
To explore the potential of the Rh–TangPhos-catalyzed
asymmetric hydrogenation of b-amino acrylonitriles as a
practical method to synthesize chiral b-amino nitriles, the
catalyst loading was decreased to 0.1 mol% (turnover
number=1000). The model substrate 1a is still smoothly hy-
drogenated under these mild reaction conditions albeit with
a slightly lower enantioselectivity of 93% ee, (Table 2,
entry 19). Hence, this Rh–TangPhos catalyst system provides
an efficient enantioselective catalytic approach to chiral b-
amino nitriles, which frequently occur in pharmaceutical and
biological molecules. For example, in important chiral drugs
like alkylnitrile quinolines 3,[14] which are NK-3 receptor li-
gands used for the treatment of peripheral and central nerv-
ous system diseases or disorders, and isoindoline compounds
4,[15] which are used for the treatment, prevention, and man-
agement of diseases mediated by PDE4 inhibition or associ-
ated with abnormal TNF-a levels, can be readily prepared
by using this methodology (Scheme 2).
ratio) in MeOH, at room temperature, for 10 min, in a nitrogen-filled
glovebox. This catalyst solution (0.1 mL, 0.001 mmol) was then trans-
ferred, by syringe, into vials charged with different substrates (0.1 mmol
each) in MeOH (2.9 mL). All the vials were placed in a steel autoclave
and then hydrogen gas was added. After stirring at 408C for 24 h (except
1 f (48 h), j (72 h) and k (72 h)), the hydrogen was released slowly, the so-
lution concentrated and subjected to a short silica gel column to remove
the metal complex. The purified solution was analyzed by chiral GC or
HPLC to determine the ee.
Acknowledgements
We thank the National Institutes of Health (GM58832), the China Schol-
arship Council, and the Northwest Agriculture & Forestry University for
financial support. The Bruker 400 MHz NMR spectrometer used in these
studies was purchased with a grant from the National Center for Re-
search Resources (NCRR; No. 1S10RR023698-01A1), a component of
the NIH. Mass spectrometry was provided by the Mass Spectrometry
Lab, School of Chemical Sciences, University of Illinois at Urbana Cham-
paign.
Keywords: acrylonitriles
·
enantioselectivity
·
hydrogenation · P ligands · rhodium
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Received: February 5, 2010
Published online: March 31, 2010
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