Rhodium-catalyzed asymmetric hydrogenation of β-acetylamino acrylonitriles

Article abstract of DOI:10.1016/j.tetasy.2011.01.023

The rhodium-catalyzed asymmetric hydrogenation of β-acetylamino acrylonitriles was investigated by using monophosphine and bisphosphine ligands. It was found that an Rh-QuinoxP complex exhibited high enantioselectivities for β-aryl substituted β-acetylamino acrylonitriles and the Rh-JosiPhos CyPF-t-Bu complex was proven to be effective for the hydrogenation of tetrasubstituted olefins from cyclic β-acetylamino acrylonitriles.

Full text of DOI:10.1016/j.tetasy.2011.01.023

Tetrahedron: Asymmetry 22 (2011) 506–511
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Tetrahedron: Asymmetry
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Rhodium-catalyzed asymmetric hydrogenation of b-acetylamino acrylonitriles
Miaofeng Ma a,b,c, Guohua Hou b,c, Junru Wang a, , Xumu Zhang b,c,
⇑
⇑
a College of Science, Northwest Agriculture and Forestry University, Yangling, Shaanxi 712100, PR China
b Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
c Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 December 2010
Accepted 26 January 2011
The rhodium-catalyzed asymmetric hydrogenation of b-acetylamino acrylonitriles was investigated by
using monophosphine and bisphosphine ligands. It was found that an Rh-QuinoxP⁄ complex exhibited
high enantioselectivities for b-aryl substituted b-acetylamino acrylonitriles and the Rh-JosiPhos CyPF-
t-Bu complex was proven to be effective for the hydrogenation of tetrasubstituted olefins from cyclic
b-acetylamino acrylonitriles.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
finally proven to be an effective catalyst for tetrasubstituted olefins
of cyclic b-acetylamino acrylonitriles with good enantioselectivi-
Enantiopure b-amino nitriles are widely used as key intermedi-
ates or important building blocks in pharmaceuticals, for example,
in the synthesis of alkylnitrile quinoline and isoindoline com-
pounds.1 Moreover, b-amino nitrile constitutes a versatile synthon
that is readily transformed into b-amino carboxylic acids and 1,3-
diamines, which are also valuable structural motifs for the synthe-
sis of biologically active products.2 Due to their significance in
chemical synthesis, much effort has been devoted to the pursuit
of practical asymmetric routes to produce chiral b-amino nitriles.3
Recently, we have reported a highly efficient Rh-TangPhos com-
plex catalyst for the asymmetric hydrogenation of acyclic b-acetyl-
amino acrylonitriles.4 Although very good results have been
achieved for these substrates, TangPhos is extremely sensitive to
air and this drawback has prevented its widespread application
in asymmetric catalysis. Furthermore, this catalyzed system pro-
vides very low conversion and enantioselectivity for the tetrasub-
stituted olefin of 2-acety1amino-1-cyclopentene-1-carbonitrile
whose asymmetric hydrogenation is generally difficult and re-
mains an unexplored area. These results suggested that new effi-
cient catalysts were necessary for the development of the highly
enantioselective hydrogenation of b-acetylamino acrylonitriles to
give chiral b-acetylamino nitriles. We found that the enantioselec-
tivities which were achieved in the hydrogenation of b-aryl substi-
tuted b-acetylamino acrylonitriles with a Rh-QuinoxP⁄ complex
were comparable to those with the Rh-TangPhos complex. How-
ever, this catalyzed system was also unsuccessfully applied to
the asymmetric hydrogenation of 2-acety1amino-1-cyclopen-
tene-1-carbonitrile. In further studies, Rh-JosiPhos CyPF-t-Bu was
ties, up to 83% ee being achieved. It is notable that both QuinoxP⁄
and JosiPhos CyPF-t-Bu ligands are air-stable.
2. Results and discussion
The substrates for the asymmetric hydrogenation could be
readily prepared in two steps via intermolecular dimerization of
nitriles and intramolecular cyclization of dinitriles in the presence
of potassium tert-butoxide5 and then amino protection with acetic
anhydride (Scheme 1).6 We initially focused on the rhodium-cata-
lyzed asymmetric hydrogenation of 3-acetylamino-3-phenyl acry-
lonitrile 1a as a model substrate with a series of chiral ligands
(Table 1). Hydrogenation proceeded smoothly with QuinoxP⁄ and
gave 2a with 93% ee (entry 7) when the reactions were performed
at 40 °C under 100 atm of hydrogen pressure in MeOH. Other types
of ligand showed lower enantioselectivities or conversions (entries
1–6). Further studies indicated that changing the solvent (entries
8–12) led to poor results. The effect of the reaction hydrogen
H2N
R
AcHN
R
a
b
R
C
N
CN
NH2
CN
1a-j
NHAc
b'
n(H2C)
CN
CN
a'
n(H2C)
CN
n(H2C)
CN
1k,l
⇑
Corresponding authors. Fax: +86 029 87092226 (J.W.), +1 732 445 6321 (X.Z.).
E-mail addresses: wangjr07@163.com (J. Wang), xumu@rci.rutgers.edu (X.
Scheme 1. Synthesis of b-acetylamino acrylonitriles. Reagents and conditions: (a)
CH3CN, t-BuOK, toluene, ultrasound 4 h; (b) Ac2O, Et3N, toluene, reflux overnight;
(a0) t-BuOK, overnight; (b0) Ac2O, pyridine, reflux overnight; n = 1, 2.
Zhang).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.023

M. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 506–511
507
Table 1
Rhodium-catalyzed asymmetric hydrogenation of 1a under various conditionsa
NHAc
AcHN
[Rh(cod)L]BF4
H2, solvent
CN
Ph
*
Ph
CN
1a
Solvent
2a
Entry
Ligand
PH (atm)
T (°C)
Conv.b (%)
eec (%)
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(R)-MonoPhos
(R)-Mop
(R)-SegPhos
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
Toluene
Dioxane
CH2Cl2
CF3CH2OH
MeOH
MeOH
100
100
100
100
100
100
100
100
100
100
100
100
50
40
40
40
40
40
40
40
40
40
40
40
40
40
25
31
0
8
/
1
63
85
100
95
100
5
9
5
6
(R,S)-JosiPhos CyPF-t-Bu
(Sc,Rp)-DuanPhos
(R,R)-Et-DuPhos
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
(R,R)-QuinoxP⁄
1
90
80
93
7
8
35
75
84
93
/
94
90
0
100
a
b
c
All reactions were carried out with a substrate/catalyst ratio of 100:1, for 24 h.
Determined by GC methods.
The ee value of 2a was determined by chiral phase GC.
pressure and temperature was also examined, however, we found
that both the conversion and enantioselectivity decreased at a low-
er hydrogen pressure (entry 13), and that the reaction did not pro-
ceed at room temperature (entry 14).
respectively (entries 9 and 10). Compared with our previous stud-
ies, Rh-QuinoxP⁄ catalyst is slightly sensitive to the ratios of E/Z
isomers, and we found that substrates 1d–f, 1j with lower ratios
of E/Z isomers, which were hydrogenated by QuinoxP⁄, exhibited
lower enantioselectivities than those hydrogenated by TangPhos.4
Since Rh-TangPhos and Rh-QuinoxP⁄ catalysts have been
proved to be very successful for the hydrogenation of b-aryl substi-
tuted b-acetylamino acrylonitriles, cyclic b-acetylamino acryloni-
trile 1k with a tetrasubstituted olefin was hydrogenated by both
catalysts at 40 °C under 100 atm hydrogen pressure for 24 h (Ta-
ble 3, entries 1 and 2). However, very poor enantioselectivities
and conversions were achieved using either the TangPhos or Qui-
noxP⁄ ligand. We thus turned our attention to other types of li-
gands. One particular ligand, JosiPhos CyPF-t-Bu, could make the
Under the optimized reaction conditions, a variety of b-aryl
substituted b-acetylamino acrylonitriles 1 were examined using
an Rh-QuinoxP⁄ catalyst system (Table 2). We studied the effect
of the electronic properties of the substituents on the phenyl ring
of the substrates with regard to the enantiomeric excess of the
products. All substrates, except for 1f, bearing electron-donating
or electron-withdrawing substituents on the phenyl ring were
smoothly hydrogenated to the corresponding products with good
enantioselectivities (entries 2–6). Both the thiophen-2-yl and 2-
naphthyl substrates afforded products in 92% and 84% ee values,
Table 2
Rhodium-catalyzed asymmetric hydrogenation of 1a–j under the optimized reaction conditionsa
Bu-t
N
N
P
P
NHAc
AcHN
R
[Rh(cod)QuinoxP*]BF4
H2, MeOH
CN
Bu-t
R
*
CN
2a-j
1a-j
(R,R)-QuinoxP*
b
d
Entry
Substrate
E:Z
R
Product
eec (%) (config.)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
2.3:1
>99:1
>99:1
2.2:1
50:1
0.8:1
>99:1
>99:1
>99:1
50:1
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
93 (—)
89 (—)
89 (—)
82 (—)
84 (—)
77 (—)
90 (—)
90 (—)
92 (—)
84 (—)
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-FC6H4
p-CF3C6H4
m-MeC6H4
m-ClC6H4
Thiophen-2-yl
2-Naphthyl
10
1j
2j
a
b
c
All reactions were carried out with a substrate/catalyst ratio of 100:1 in MeOH at 40 °C under 100 atm hydrogen pressure for 24 h, 100% conversion.
Determined by 1H NMR.
The ee value was determined by GC or HPLC on a chiral phase.
Sign of the specific rotation.
d

508
M. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 506–511
Table 3
Rhodium-catalyzed asymmetric hydrogenation of cyclic b-acety1amino acrylonitriles 1k–la
NHAc
NHAc
[Rh(cod)L]BF4
*
*
H2, solvent
CN
CN
cis-2k
1k
PtBu2
NHAc
NHAc
[Rh(cod)JosiPhosCyPF-t-Bu]BF4
*
Fe
*
PCy2
n(H2C)
CN
H2, MeOH
n(H2C)
CN
, n=1
1k
1l
cis-2k, n=1
cis-2l, n=2
(R,S)-JosiPhos CyPF-t-Bu
, n=2
Entry
Ligand
Substrate
Solvent
PH (atm)
T (°C)
Product
Conv.b (%)
eec (%)
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(S,S,R,R)-TangPhos
(R,R)-QuinoxP⁄
(R)-MonoPhos
(R)-Mop
(R)-SegPhos
(R,S)-Josiphos CyPF-t-Bu
(R,S)-JosiPhos
(R,R)-Et-DuPhos
(Sp,Rc)-DuanPhos
(S)-PhanePhos
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-Josiphos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
(R,S)-JosiPhos CyPF-t-Bu
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1l
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
Toluene
Dioxane
CH2Cl2
CF3CH2OH
MeOH
MeOH
MeOH
MeOH
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
70
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
25
25
25
25
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2k
2m
73
27
12
5
19
100
92
81
50
57
49
13
2
26
6
3
6
1
62
24
49
44
16
0
3
8
2
51
46
64
64
60
83
100
100
100
100
100
50
70
a
b
c
All reactions were carried out with a substrate/catalyst ratio of 100:1, for 24 h.
Determined by GC methods.
The ee value was determined by chiral phase GC.
substrate completely convert to the desired product with moderate
enantioselectivity (62% ee, entry 6). Further solvent screening (en-
tries 11–14) revealed that the use of other solvents led to lower
enantioselectivities and conversions. Although CF3CH2OH also gave
complete conversion, the enantioselectivity decreased dramati-
cally (entry 15). Subsequently, we investigated the effect of reac-
tion temperature on the hydrogenation; it was found that the
hydrogenation reaction proceeded completely and a slightly higher
ee value was observed when the reaction temperature was de-
creased from 40 °C to 25 °C (64% ee; entry 16). Finally, when
decreasing the hydrogen pressure to 70 atm (entry 17), we found
no evident effect on the enantioselectivity. Decreasing the hydro-
gen pressure further caused a minor decrease in the ee value (entry
18).
cyclic b-acety1amino acrylonitriles. Our future work will focus on
investigating asymmetric hydrogenation of other olefins bearing
an amine functionality to produce chiral amines which are useful
synthetic intermediates for pharmaceutical products.
4. Experimental
4.1. General
Unless otherwise noted, all reagents and solvents were pur-
chased from commercial suppliers and used without further puri-
fication. NMR spectra were recorded with a Varian spectrometer at
400 MHz (1H NMR) and 100 MHz (13C NMR) in acetone-d6 or
CDCl3. Chemical shifts are reported in ppm downfield from internal
Me4Si. Optical rotations were determined using a Perkin Elmer 341
MC polarimeter. HRMS were recorded on a quadrupole–hexapole–
quadrupole (QHQ) mass spectrometer. GC analyses were
performed using Hewlett Packard Model HP 7890 Series. HPLC
analyses were conducted on an Agilent 1200 Series instrument.
Column Chromatography was performed with silica gel Merck 60
(230–400 mesh).
The optimized reaction conditions were applied to the 6-mem-
bered analogue, 2-acety1amino-1-cyclohexene-1-carbonitrile 1l.
The substrate was found to give 83% ee (Table 3, entry 19), indicat-
ing that the hydrogenation was much better than that of 1k.
3. Conclusion
We have studied Rh-catalyst systems with different ligands for
the asymmetric hydrogenation of b-acety1amino acrylonitriles.
The experimental results indicate that QuinoxP⁄ exhibits high
activities and enantioselectivities to b-aryl substituted b-acety1a-
mino acrylonitriles, and JosiPhos CyPF-t-Bu was firstly proved to
be effective for the hydrogenation of tetrasubstituted olefins of
4.2. General procedures for the synthesis of b-enaminonitriles
4.2.1. Acyclic-b-enaminonitriles
To a solution of aromatic nitrile (50 mmol) and acetonitrile
(2.05 g, 50 mmol) in toluene (150 mL), powdered t-BuOK

M. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 506–511
509
(15.68 g, 140 mmol) was added. Then the mixture was ultrasound-
ed with 35 kHz frequency at room temperature for 4 h. After com-
pletion, the reaction mixture was poured into water, extracted
with diethyl ether, dried (anhydrous Na2SO4), and concentrated
in vacuo to afford the crude product. Recrystallization of a series
of the crude products from toluene gave acyclic-b-enaminonitriles
in 75–92% yields.
4.3.3.5. 3-Acetylamino-3-(p-fluorophenyl)acrylonitrile 1e. Yield:
72%, E/Z = 50:1. 1H NMR (acetone-d6, 400 MHz) d 9.17 (br, 1H, NH),
7.54–7.49 (m, 2H, Ar-H), 7.16–7.11 (m, 2H, Ar-H), 6.57 [s, 1H, @CH
(E)], 5.49 [s, 1H, @CH (Z)], 2.04 (s, 3H, CH3).
4.3.3.6. 3-Acetylamino-3-(p-trifluoromethylphenyl)acrylonitrile
1f. Yield: 26.8%, E/Z = 0.8:1. 1H NMR (CDCl3, 400 MHz) d 7.71–7.69
[m, 1.5H, Ar-H(E)], 7.60 [s, 2H, Ar-H(Z)], 7.58 [s, 2H, Ar-H(Z)], 7.45–
7.43 [m, 1.9H, Ar-H(E)], 7.01 (br, 1H, NH), 6.74 [s, 1H, @CH(E)], 4.99
[s, 1H, @CH(Z)], 2.15 [s, 3H, CH3 (Z)], 2.13 [s, 3H, CH3 (E)].
4.2.2. Cyclic-b-enaminonitriles
A mixture of adiponitrile (5.40 g, 50 mmol) and powdered t-
BuOK (6.72 g, 60 mmol) was kept at room temperature overnight.
The crystalline solid that was formed by the addition of water to
the reaction mixture was filtered off and recrystallized from MeOH
to give 2-amino-1-cyclopentene-1-carbonitrile (4.26 g, 79%).
A mixture of pimelonitrile (6.10 g, 50 mmol) and powdered t-
BuOK (6.72 g, 60 mmol) was kept at 80 °C for 3 h and then at room
temperature overnight. Water was added to the reaction mixture
and the product extracted with ether. The solvent was evaporated
and the residual solid was recrystallized from MeOH to give 2-ami-
no-1-cyclohexene-1-carbonitrile (5.23 g, 80%).
4.3.3.7. 3-Acetylamino-3-(m-methylphenyl)acrylonitrile 1g. Yield:
1
31%, E/Z >99:1. H NMR (CDCl3, 400 MHz) d 7.29–7.19 (m, 4H, Ar-H),
7.04 (br, 1H, NH), 6.63 (s, 1H, @CH), 2.34 (s, 3H, CH3), 2.10 (s, 3H, CH3).
4.3.3.8. 3-Acetylamino-3-(m-chlorophenyl)acrylonitrile 1h. Yield:
55%, E/Z >99:1. 1H NMR (CDCl3, 400 MHz) d 7.53–7.50 (m, 1H, Ar-H),
7.49–7.48 (m, 1H, Ar-H), 7.46–7.45 (m, 2H, Ar-H), 7.20 (br, 1H, NH),
6.76 (s, 1H, @CH), 2.20 (s, 3H, CH3).
4.3.3.9. 3-Acetylamino-3-(thiophen-2-yl)acrylonitrile 1i. Yield:
24%, E/Z >99:1. 1H NMR (CDCl3, 400 MHz) d 7.54–7.52 (m, 1H,
Ar-H), 7.44–7.43 (m, 1H, Ar-H), 7.08–7.06 (m, 2H, Ar-H), 6.60 (s,
1H, @CH), 2.13 (s, 3H, CH3).
4.3. General procedures for the synthesis of compounds 1a–l
4.3.1. Compounds 1a–j
To a solution of acyclic-b-enaminonitriles (30 mmol) in toluene
(180 mL), Ac2O (15.30 g, 150 mmol) was added, after which Et3N
(6.06 g, 60 mmol) was dropped into the solution under stirring.
The reaction mixture was then heated to reflux and stirred for
24 h. The reaction mixture was cooled to room temperature,
washed with saturated sodium carbonate, water, and then dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
Finally, the product mixture was purified by column chromatogra-
phy using a mixture of hexane and ethyl acetate as eluent.
4.3.3.10. 3-Acetylamino-3-(2-naphthyl)acrylonitrile 1j. Yield:
35%, E/Z = 50:1. 1H NMR (CDCl3, 400 MHz) d 8.04 (s, 1H, Ar-H),
7.98–7.96 (m, 1H, Ar-H), 7.94–7.90 (m, 2H, Ar-H), 7.62–7.61 (m,
1H, Ar-H), 7.60–7.57 (m, 2H, Ar-H), 7.27 (br, 1H, NH), 6.82 [s, 1H,
@CH(E)], 5.23 [s, 1H, @CH(Z)], 2.22 (s, 3H, CH3).
4.3.3.11. 2-Acety1amino-1-cyclopentene-1-carbonitrile 1k. Yield:
52%. 1H NMR (CDCl3, 400 MHz) d 8.06 (br, 1H, NH), 3.16–3.11 (m,
2H, CH2), 2.55–2.51 (m, 2H, CH2), 2.15 (s, 3H, CH3), 2.05–1.97 (m,
2H, CH2).
4.3.2. Compounds 1k and 1l
To a solution of cyclic-b-enaminonitriles (30 mmol) in dry pyr-
idine (18 mL), Ac2O (6.12 g, 60 mmol) was added. The reaction
mixture was heated at reflux for 16 h and cooled to room temper-
ature. It was then poured into a mixture of ice (about 50 g) and
60 mL of 6 molar hydrochloric acid and extracted with chloroform.
After being washed with water, the extract was dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. Finally,
the product mixture was purified by column chromatography
using the mixture of hexane and ethyl acetate as eluent.
4.3.3.12. 2-Acety1amino-1-cyclohexene-1-carbonitrile 1l. Yield:
78%. 1H NMR (CDCl3, 400 MHz) d 7.32 (br, 1H, NH), 2.78–2.75 (m,
2H, CH2), 2.22–2.20 (m, 2H, CH2), 2.05 (s, 3H, CH3), 1.63–1.55 (m,
4H, 2 ꢀ CH2); 13C NMR (CDCl3, 100 MHz): d 168.16, 151.81,
118.01, 90.52, 27.66, 25.45, 24.70, 21.41, 20.98; MS (ESI): 165
(M++1); HRMS Calcd for C9H13N2O 165.1028; Found 165.1023.
4.4. General procedures for the asymmetric hydrogenation of
compounds 1a–l
4.3.3. NMR and HRMS data of compounds 1a–l
4.3.3.1. 3-Acetylamino-3-phenyl acrylonitrile 1a. Yield: 55%, E/
Z = 2.3:1. 1H NMR (CDCl3, 400 MHz) d 7.46–7.42 (m, 5H, Ar-H),
7.02 (br, 1H, NH), 6.61 [s, 1H, @CH (E)], 5.22 [s, 1H, @CH(Z)], 2.06
(s, 3H, CH3).
4.4.1. Asymmetric hydrogenation of compounds 1a–j
A stock solution of [Rh(COD)2]BF4 (COD = cycloocta-1,5-diene)
and QuinoxP⁄ at a 1:1.1 molar ratio was stirred in MeOH at room
temperature for 10 min in a nitrogen-filled glovebox. The required
amount of catalyst solution (0.1 mL, 0.001 mmol) was then trans-
ferred by syringe into the vials charged with different substrates
(0.1 mmol for each) in MeOH (2.9 mL). All of the vials were placed
together in a steel autoclave into which hydrogen gas was charged.
After the solution was stirred at 40 °C under 100 atm hydrogen
pressure for 24 h, the hydrogen was released slowly. The solution
was concentrated, and then the crude product was eluted by EtOAc
through a plug of silica gel to remove the metal complex. The puri-
fied product mixture was analyzed by chiral GC or HPLC to deter-
mine the ee value.
4.3.3.2. 3-Acetylamino-3-(p-methylphenyl)acrylonitrile 1b. Yield:
33%, E/Z >99:1. 1H NMR (CDCl3, 400 MHz) d 7.45 (d, J = 8.0 Hz, 2H, Ar-
H), 7.31 (d, J = 8.0 Hz, 2H, Ar-H), 7.07 (br, 1H, NH), 6.72 (s, 1H, @CH),
2.43 (s, 3H, CH3), 2.20 (s, 3H, CH3).
4.3.3.3. 3-Acetylamino-3-(p-methoxyphenyl)acrylonitrile1c. Yield:
26%, E/Z >99:1. 1H NMR (CDCl3, 400 MHz) d 7.40 (d, J = 8.0 Hz, 2H, Ar-H),
7.07 (br, 1H, NH), 6.90 (d, J = 8.0 Hz, 2H, Ar-H), 6.55 (s, 1H, @CH), 3.78 (s,
3H, CH3), 2.09 (s, 3H, CH3).
4.4.2. Asymmetric hydrogenation of compounds 1k and 1l
A stock solution of [Rh(COD)2]BF4 and JosiPhos CyPF-t-Bu at a
1:1.1 molar ratio was stirred in MeOH at room temperature for
10 min in a nitrogen-filled glovebox. The required amount of cata-
lyst solution (0.1 mL, 0.001 mmol) was then transferred by syringe
4.3.3.4. 3-Acetylamino-3-(p-chlorophenyl)acrylonitrile 1d. Yield:
84%, E/Z = 2.2:1. 1H NMR (acetone-d6, 400 MHz) d 9.20 (br, 1H, NH),
7.48 (d, J = 8.0 Hz, 2H, Ar-H), 7.40 (d, J = 8.0 Hz, 2H, Ar-H), 6.57 [s, 1H,
@CH (E)], 5.49 [s, 1H, @CH (Z)], 2.03 (s, 3H, CH3).

510
M. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 506–511
into the vials charged with different substrates (0.1 mmol for each)
in MeOH (2.9 mL). All of the vials were placed together in a steel
autoclave into which hydrogen gas was charged. After the solution
was stirred at 25 °C under 70 atm hydrogen pressure for 24 h,
hydrogen was released slowly, the solution was concentrated,
and then the crude product was eluted by EtOAc through a plug
of silica gel to remove the metal complex. The purified product
mixture was analyzed by chiral GC to determine the ee value.
J = 8.0 Hz, 2H, Ar-H), 7.43 (d, J = 8.0 Hz, 2H, Ar-H), 6.58–6.56 (br,
1H, NH), 5.31–5.26 (m, 1H, CH), 2.95 (dd, J = 6.4 Hz, 16.8 Hz, 1H,
CH), 2.82 (dd, J = 5.2 Hz, 16.8 Hz, 1H, CH), 1.96 (s, 3H, CH3).
4.4.3.7. 3-Acetylamino-3-(m-methylphenyl)propionitrile 2g.
½
a 2D0
ꢁ
¼ ꢂ50:2 (c 1.0, CH2Cl2), 90% ee. Enantiomeric excess was
determined by GC, Supelco Gama Dex™ 225 column
m), He 1.0 mL/min, programmed from
(30 m ꢀ 0.25 mm ꢀ 0.25
l
130 °C to 180 °C at 2.0 °C/min, hold 40 min at 180 °C; tR = 41.6 min
(minor), tR = 44.9 min (major). 1H NMR (CDCl3, 400 MHz) d 7.25–
7.19 (m, 1H, Ar-H), 7.12–7.10 (m, 3H, Ar-H), 6.01–6.00 (br, 1H,
NH), 5.15–5.10 (m, 1H, CH), 2.98 (dd, J = 6.8 Hz, 16.4 Hz, 1H, CH),
2.82 (dd, J = 4.4 Hz, 16.8 Hz, 1H, CH), 2.31 (s, 3H, CH3), 1.97 (s,
3H, CH3).
4.4.3. The NMR, specific rotation and HRMS data of compound 2
4.4.3.1. 3-Acetylamino-3-phenyl propionitrile 2a.
(c 1.0, CH2Cl2), 93% ee. Enantiomeric excess was determined by GC,
m), He
½
a 2D0
ꢁ
¼ ꢂ78:2
Supelco Gama Dex™ 225 column (30 m ꢀ 0.25 mm ꢀ 0.25
l
1.0 mL/min, programmed from 130 °C to 180 °C at 2.0 °C/min, hold
40 min at 180 °C; tR = 39.8 min (minor), tR = 43.8 min (major). 1H
NMR (CDCl3, 400 MHz) d 7.36–7.34 (m, 1H, Ar-H), 7.33–7.31 (m,
3H, Ar-H), 7.30–7.28 (m, 1H, Ar-H), 6.13–6.11 (br, 1H, NH), 5.20–
5.15 (m, 1H, CH), 2.98 (dd, J = 6.4 Hz, 16.8 Hz, 1H, CH), 2.82 (dd,
J = 4.4 Hz, 16.8 Hz, 1H, CH), 1.97 (s, 3H, CH3).
4.4.3.8. 3-Acetylamino-3-(m-chlorophenyl)propionitrile 2h.
½
a 2D0
ꢁ
¼ ꢂ35:6 (c 1.0, CH2Cl2), 90% ee. Enantiomeric excess was
determined by HPLC, Chiralcel OD-H column, n-hexane/2-propa-
nol = 85:15, 1.0 mL/min, 222 nm UV detector, tR = 13.4 min (min-
or), tR = 18.1 min (major). 1H NMR (CDCl3, 400 MHz) d 7.29–7.27
(m, 3H, Ar-H), 7.21–7.18 (m, 1H, Ar-H), 6.24–6.22 (br, 1H, NH),
5.21–5.16 (m, 1H, CH), 2.94 (dd, J = 4.8 Hz, 16.8 Hz, 1H, CH), 2.82
(dd, J = 4.8 Hz, 16.8 Hz, 1H, CH), 1.98 (s, 3H, CH3).
4.4.3.2. 3-Acetylamino-3-(p-methylphenyl)propionitrile 2b.
½
a 2D0
ꢁ
¼ ꢂ49:0 (c 1.0, CH2Cl2), 89% ee. Enantiomeric excess was deter-
mined by GC, Supelco Gama Dex™ 225 column (30 m ꢀ
0.25 mm ꢀ 0.25 m), He 1.0 mL/min, programmed from 130 °C to
180 °C at 2.0 °C/min, hold 40 min at 180 °C; tR = 45.9 min (minor),
tR = 49.6 min (major). 1H NMR (CDCl3, 400 MHz)
7.18 (d,
l
4.4.3.9. 3-Acetylamino-3-(thiophen-2-yl)propionitrile 2i.
½
a 2D0
ꢁ
¼ ꢂ39:6 (c 1.0, CH2Cl2), 92% ee. Enantiomeric excess was
d
determined by HPLC, Chiralpak AS column, n-hexane/2-propa-
nol = 60:40, 1.0 mL/min, 222 nm UV detector, tR = 9.3 min (minor),
tR = 14.6 min (major). 1H NMR (CDCl3, 400 MHz) d 7.25–7.23 (m,
1H, Ar-H), 7.07–7.06 (m, 1H, Ar-H), 6.96–6.94 (m, 1H, Ar-H),
6.08–6.07 (br, 1H, NH), 5.47–5.42 (m, 1H, CH), 3.04 (dd,
J = 6.4 Hz, 16.8 Hz, 1H, CH), 2.89 (dd, J = 4.4 Hz, 16.8 Hz, 1H, CH),
1.98 (s, 3H, CH3).
J = 8.0 Hz, 2H, Ar-H), 7.13 (d, J = 8.0 Hz, 2H, Ar-H), 6.25–6.23 (br,
1H, NH), 5.14–5.09 (m, 1H, CH), 2.94 (dd, J = 6.4 Hz, 16.8 Hz, 1H,
CH), 2.79 (dd, J = 4.8 Hz, 16.8 Hz, 1H, CH), 2.28 (s, 3H, CH3), 1.94 (s,
3H, CH3).
4.4.3.3. 3-Acetylamino-3-(p-methoxyphenyl)propionitrile 2c.
½
a 2D0
ꢁ
¼ ꢂ66:6 (c 1.0, CH2Cl2), 89% ee. Enantiomeric excess was
determined by GC, Supelco Gama Dex™ 225 column (30 m
m), He 1.0 mL/min, programmed from 130 °C to
4.4.3.10. 3-Acetylamino-3-(2-naphthyl)propionitrile 2j.
½
a 2D0
ꢁ
¼ ꢂ46:5 (c 1.0, CH2Cl2), 84% ee. Enantiomeric excess was
ꢀ 0.25 mm ꢀ 0.25
l
determined by HPLC, Chiralpak AD column, n-hexane/2-propa-
nol = 90:10, 1.0 mL/min, 254 nm UV detector, tR = 12.2 min (min-
or), tR = 17.1 min (major). 1H NMR (CDCl3, 400 MHz) d 7.83–7.81
(m, 1H, Ar-H), 7.79–7.77 (m, 3H, Ar-H), 7.47–7.44 (m, 2H, Ar-H),
7.39–7.36 (m, 2H, Ar-H), 6.10 (br, 1H, NH), 5.37–5.32 (m, 1H,
CH), 3.08 (dd, J = 6.4 Hz, 16.8 Hz, 1H, CH), 2.93 (dd, J = 4.4 Hz,
16.8 Hz, 1H, CH), 2.00 (s, 3H, CH3).
180 °C at 2.0 °C/min, hold 100 min at 180 °C; tR = 81.9 min (minor),
tR = 89.5 min (major). 1H NMR (CDCl3, 400 MHz) d 7.24 (d, J = 8.8 Hz,
2H, Ar-H), 6.86 (d, J = 8.8 Hz, 2H, Ar-H), 5.94–5.93 (br, 1H, NH), 5.13–
5.08 (m, 1H, CH), 3.75 (s, 3H, OCH3), 2.97 (dd, J = 6.8 Hz, 16.4 Hz, 1H,
CH), 2.82 (dd, J = 4.4 Hz, 16.8 Hz, 1H, CH), 1.97 (s, 3H, CH3).
4.4.3.4. 3-Acetylamino-3-(p-chlorophenyl)propionitrile 2d.
½
a 2D0
ꢁ
¼ ꢂ55:8 (c 1.0, CH2Cl2), 82% ee. Enantiomeric excess was
4.4.3.11. cis-2-Acety1amino-1-cyclopentane-1-carbonitrile
determined by HPLC, Chiralpak AD column, n-hexane/2-propa-
nol = 90:10, 1.0 mL/min, 222 nm UV detector, tR = 10.2 min (minor),
tR = 14.3 min (major). 1H NMR (CDCl3, 400 MHz) d 7.30 (d, J = 8.2 Hz,
2H, Ar-H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 6.40–6.38 (br, 1H, NH), 5.20–
5.15 (m, 1H, CH), 2.93 (dd, J = 6.4 Hz, 16.8 Hz, 1H, CH), 2.79 (dd,
J = 5.2 Hz, 16.8 Hz, 1H, CH), 1.96 (s, 3H, CH3).
2k.
was determined by GC, Supelco Gama Dex™ 225 column
(30 m ꢀ 0.25 mm ꢀ 0.25 m), He 1.0 mL/min, programmed from
½
a 2D0
ꢁ
¼ ꢂ35:7 (c 1.0, CH2Cl2), 64% ee. Enantiomeric excess
l
130 °C to 180 °C at 2.0 °C/min, hold 20 min at 180 °C; tR = 24.8 min
(minor), tR = 28.2 min (major). 1H NMR (CDCl3, 400 MHz) d 6.12
(br, 1H, NH), 4.34–4.26 (m, 1H, CH), 3.23–3.19 (m, 1H, CH), 2.04–
1.99 (m, 2H, CH2), 1.97 (s, 3H, CH3), 1.95–1.92 (m, 1H, CH), 1.91–
1.81 (m, 1H, CH), 1.69–1.60 (m, 1H, CH), 1.59–1.52 (m, 1H, CH);
13C NMR (CDCl3, 100 MHz) d 170.46, 120.36, 52.13, 34.33, 29.98,
28.75, 23.05, 21.52; MS (ESI): 153 (M++1); HRMS Calcd for
C8H13N2O 153.1028, Found 153.1022.
4.4.3.5. 3-Acetylamino-3-(p-fluorophenyl)propionitrile 2e.
½
a 2D0
ꢁ
¼ ꢂ43:1 (c 1.0, CH2Cl2), 84% ee. Enantiomeric excess was
determined by HPLC, Chiralpak AD column, n-hexane/2-propa-
nol = 90:10, 1.0 mL/min, 254 nm UV detector, tR = 9.9 min (minor),
tR = 13.8 min (major). 1H NMR (CDCl3, 400 MHz) d 7.32–7.29 (m,
2H, Ar-H), 7.06–7.02 (m, 2H, Ar-H), 5.92–5.90 (br, 1H, NH), 5.20–
5.15 (m, 1H, CH), 3.99 (dd, J = 6.8 Hz, 16.8 Hz, 1H, CH), 2.83 (dd,
J = 4.4 Hz, 16.8 Hz, 1H, CH), 1.99 (s, 3H, CH3).
4.4.3.12. cis-2-Acety1amino-1-cyclohexane-1-carbonitrile 2l.
½
a 2D0
ꢁ
¼ ꢂ109:7 (c 1.0, CH2Cl2), 83% ee. Enantiomeric excess was
determined by GC, Supelco Gama Dex™ 225 column
m), He 1.0 mL/min, programmed from
(30 m ꢀ 0.25 mm ꢀ 0.25
l
4.4.3.6. 3-Acetylamino-3-(p-trifluoromethylphenyl)propionitrile 2f.
130 °C to 180 °C at 2.0 °C/min, hold 20 min at 180 °C; tR = 21.8 min
(minor), tR = 24.4 min (major). 1H NMR (CDCl3, 400 MHz) d 5.81
(br, 1H, NH), 3.87–3.80 (m, 1H, CH), 3.29–3.28 (m, 1H, CH), 1.96
(m, 1H, CH), 1.94 (s, 3H, CH3), 1.81–1.72 (m, 2H, CH2), 1.64–1.53
(m, 2H, CH2), 1.52–1.44 (m, 2H, CH2), 1.36–1.26 (m, 1H, CH); 13C
½
a 2D0
ꢁ
¼ ꢂ33:9 (c 1.0, CH2Cl2), 77% ee. Enantiomeric excess was
determined by HPLC, Chiralpak AD column, n-hexane/2-propa-
nol = 90:10, 1.0 mL/min, 222 nm UV detector, tR = 9.2 min (minor),
tR = 13.6 min (major). 1H NMR (CDCl3, 400 MHz)
d 7.58 (d,

M. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 506–511
511
4821; (c) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Richards, M. R.; Powell,
D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 7574; (d) Tian, Z.; Jiang, Z.; Li, Z.;
Song, G.; Huang, Q. J. Agric. Food Chem. 2007, 55, 143.
NMR (CDCl3, 100 MHz) d 169.75, 120.04, 48.35, 33.87, 28.49, 27.40,
24.55, 23.20, 21.21; MS (ESI): 167 (M++1); HRMS Calcd for
C9H15N2O 167.1184, Found 167.1179.
3. (a) Yazaki, R.; Nitabaru, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008,
130, 14477; (b) Yin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610;
(c) Aydin, J.; Conrad, C. S.; Szabó, K. J. Org. Lett. 2008, 10, 5175; (d) Kumagai, N.;
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Acknowledgments
We thank the National Institutes of Health (GM58832), China
Scholarship Council, and Northwest Agriculture & Forestry Univer-
sity for financial support.
4. Ma, M.; Hou, G.; Sun, T.; Zhang, X.; Li, W.; Wang, J.; Zhang, X. Chem. Eur. J. 2010,
16, 5301.
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