Asymmetric hydrogenation of unfunctionalized enamines catalyzed by iridium complexes of chiral spiro N,N-diarylphosphoramidites

Article abstract of DOI:10.1002/cjoc.201090293

Chiral spiro N,N-diarylphosphoramidites were synthesized. These new chiral spiro monophosphoramidites were efficient ligands for iridium-catalyzed asymmetric hydrogenation of unfunctionalized enamines derived from simple alkyl aryl ketones, providing chiral tertiary amines in good enantioselectivities (up to 90% ee).

Full text of DOI:10.1002/cjoc.201090293

FULL PAPER
Asymmetric Hydrogenation of Unfunctionalized Enamines
Catalyzed by Iridium Complexes of Chiral Spiro
N,N-Diarylphosphoramidites†
Yan, Pucha(严普查)
Xie, Jianhua(谢建华)
Zhou, Qilin*(周其林)
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
Abstract Chiral spiro N,N-diarylphosphoramidites were synthesized. These new chiral spiro monophos-
phoramidites were efficient ligands for iridium-catalyzed asymmetric hydrogenation of unfunctionalized enamines
derived from simple alkyl aryl ketones, providing chiral tertiary amines in good enantioselectivities (up to 90% ee).
Keywords Iridium, chiral phosphoramidite, enamine, asymmetric catalysis, hydrogenation
Introduction
ee, respectively.
In the study of the asymmetric hydrogenation of
simple enamines 3 derived from the alkyl aryl ketones
with secondary amines we first employed catalysts
Rh-(S)-1 and Ir-(Sa,R,R)-SIPHOS-pe and obtained low
conversions (＜ 38%) and low enantioselectivities
(＜ 10% ee). We then carefully modified the spiro phos-
phorus ligands and found that the spiro N,N-diarylphos-
phoramidite ligands (R)-2 were efficient for the iridium-
catalyzed asymmetric hydrogenation of simple
enamines 3. We herein report the detail of iridium-
catalyzed asymmetric hydrogenation of simple
enamines 3 with chiral spiro N,N-diarylphosphoramidite
ligands, offering the corresponding chiral tertiary
amines with high enantioselectivities (up to 90% ee,
Scheme 1).
Chiral tertiary amines are significant compounds
which are broadly used in the syntheses of biologically
active molecules and natural products. Catalytic
asymmetric hydrogenation of N,N-dialkyl/aryl
unfunctionalized enamines provides a direct approach to
the preparation of chiral tertiary amines. However, to
the best of our knowledge, only a few examples of
successful asymmetric hydrogenation of unfunctiona-
lized enamines have been reported so far. In 1994,
Buchwald and co-workers reported their pioneering
study on the asymmetric hydrogenation of 1-(dialkyl-
amino)-1-arylethenes catalyzed by chiral titanocene
complex [(S,S,S)-(EBTHI)TiO2-binaphtho] with high
enantioselectivities (up to 98% ee).1 In 2000, Börner et
al. used a chiral rhodium-diphosphine complex to cata-
lyze asymmetric hydrogenation of cyclic enamines and
obtained moderate enantioselectivities (up to 72% ee).2
Recently, we developed a highly efficient rhodium
catalyst with chiral spiro phosphonite ligand (S)-1 for
the asymmetric hydrogenation of enamines, (E)-1-(1-
pyrrolidinyl)-1,2-diarylethenes, providing the corre-
sponding tertiary amines with up to 99.9% ee.3 We also
demonstrated that iridium complexes of chiral spiro
phosphoramidite ligands (Ra,S,S) or (Sa,R,R)-SIPHOS-
pe were excellent catalysts for the enantioselective hy-
drogenation of cyclic enamines such as 1-alkyl-2-
arylpyrrolines (up to 97% ee)4 and N-alkyl-1-alkyli-
denetetrahydroisoquinolines (up to 98% ee)5 (Figure 1).
Andersson6 and Pfaltz7 independently introduced chiral
iridium complexes of chiral P,N-ligands into the asym-
metric hydrogenation of enamines, giving the corre-
sponding tertiary amines with up to 87% ee and 92.5%
Results and discussion
We initially chose the easily prepared 1-(1-phenyl-
vinyl)pyrrolidine 3a as a model substrate and the hy-
drogenation reaction was performed under the condi-
tions which are similar to the asymmetric hydrogenation
of cyclic enamines.4,5 By using chiral spiro monophos-
phoramidite ligand (R)-2a with two phenyl groups on
nitrogen atom, the enamine 3a was quantitatively hy-
drogenated under 5× 106 Pa of hydrogen in THF, and
chiral amine (S)-4a was obtained in 97% yield with
87% ee (Table 1, Entry 1). This result was better than
those obtained by using Ir catalysts with P,N-ligands
reported in the literatures (33% ee and 44% ee),6,7 and
encouraged us to study the effect of N-aryl group of the
ligands on the enantioselectivity of the hydrogenation of
enamines 3. A series of spiro phosphoramidite ligands
*
E-mail: qlzhou@nankai.edu.cn; Tel.: (+86)-22-2350-0011; Fax: (+86)-22-2350-6177
Received July 22, 2010; accepted August 11, 2010.
Project supported by the National Nature Science Foundation of China (No. 21032003), National Basic Research Program of China (973 Program, No.
2010CB833300), the “111” project (B06005) of the Ministry of Education of China.
†
Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
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Chin. J. Chem. 2010, 28, 1736— 1742

Asymmetric Hydrogenation of Unfunctionalized Enamines
Figure 1 Asymmetric hydrogenation of unfunctionalized enamines with chiral spiro catalysts.
Scheme 1 Asymmetric hydrogenation of N,N-dialkylenamines
with catalysts Ir-(R)-2
on the N-phenyl groups yielded product 4a in low con-
version (36%) with very low ee value (17% ee) (Entry
4). The ligands having different aryl groups on the ni-
trogen atom such as 2e and 2f or connecting a carbazole
(ligand 2g) gave lower enantioselectivity (Entries 5— 7).
Altering one of the N-phenyl groups of ligand 2a to hy-
drogen (ligand 2h) or methyl (ligand 2i) resulted in very
low conversion and enantioselectivities (Entries 8 and 9).
Modification of the ligand by adding two methyl groups
to the 6,6'-positions of the spirobiindane backbone
(ligand 2j) also led to a very low enantioselectivity
(27% ee) (Entry 10). Thus, the spiro N,N-diphenylphos-
phoramidite 2a was the choice of ligands for
Ir-catalyzed asymmetric hydrogenation of enamine 3a.
The addition of iodine was crucial for the reaction
and no hydrogenation took place without iodine (Entry
11). Although the combination of I2 with triethylamine
or acetic acid has no effect on the reactivity of reaction,
it slightly decreased the enantioselectivity of reaction
from 87% ee to 80% ee and 82% ee, respectively (En-
tries 12 and 13). A low conversion was observed by
adding KI, it worked effectively in the iridium-catalyzed
asymmetric hydrogenation of N-alkyl-1-alkylidenetetra-
hydroisoquinolines5 (Entry 14). Solvent experiments
showed that THF was the best choice of solvent in terms
of reactivity and enantioselectivity of reaction (Entry 1
vs. Entries 15— 18). The hydrogenation of enamine 3a
can also be carried out at 1× 106 Pa of hydrogen, giving
a comparable result (Entry 19). It is worthy noting that
the catalyst loading can be lowered to 0.1 mol% without
diminishing the enantioselectivity of reaction (Entry
20).
(R)-2 with different N-aryl or N,N-diaryl groups were
synthesized by our previous method.8 The ligands (R)-2
were compared in the hydrogenation of enamine 3a and
the results were listed in Table 1. Introduction of an
electron-withdrawing substituent such as a para-chloro
(ligand 2b) into N-phenyl groups of the ligand has little
effect on the enantioselectivity of the reaction (Table 1,
Entry 2). However, the electron-donating group such as
a para-methoxy on the N-phenyl groups (ligand 2c) led
to a small decrease in the enantioselectivity of reaction
(Entry 3). The steric effect of ligand 2 was also manifest,
for example, the ligand 2d having 3,5-dimethyl groups
Under the optimal conditions a variety of N,N-
dialkylenamines 3 have been hydrogenated by the cata-
lyst Ir-(R)-2a. As shown in Table 2 the alkyl groups at
the nitrogen atom of enamine substrates had a manifest
effect on both reactivity and enantioselectivity of the
reaction. The enamine 3a with a five-membered cyclic
amino group was completely hydrogenated to chiral
Chin. J. Chem. 2010, 28, 1736— 1742
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1737

Yan, Xie & Zhou
FULL PAPER
Table 1 Optimizing the reaction conditionsa
phenyl ring of substrate led to lower enantioselectivities
(Entries 12 and 13). Also for the reason of steric hin-
drance, β-substituted α-dialkylaminostyrene was not a
suitable substrate for this reaction, the asymmetric hy-
drogenation of 1-(1-phenylprop-1-enyl)pyrrolidine (3o)
at 5×106 Pa of H2 gave the corresponding amine 4o in
only 43% ee (Entry 15). The asymmetric hydrogenation
of cyclic enamines 3p—3r, flexibility- restricted sub-
strates, were also examined by using catalyst Ir-(R)-2a.
High enantioselectivities were obtained in the hydro-
genation of these cyclic substrates, with the
seven-membered cyclic enamine 3r being the highest
enantioselective (Entries 16—18).
Entry Ligand Solvent Additive Conv.b/%
eec/%
87
87
78
17
75
85
70
7
1
(R)-2a THF
(R)-2b THF
(R)-2c THF
(R)-2d THF
(R)-2e THF
I2
100
100
100
36
2
I2
3
I2
4
I2
5
I2
100
100
100
67
Conclusion
6
(R)-2f
THF
I2
7
(R)-2g THF
(R)-2h THF
I2
In summary, new iridium catalysts based on chiral
spiro N,N-diarylphosphoramidite ligands have been de-
veloped for the asymmetric hydrogenation of unfunc-
tionalized enamines derived from alkyl aryl ketones.
This reaction provides an efficient method for the syn-
thesis of chiral tertiary amines with good to high enan-
tioselectivities.
8
I2
9
(R)-2i
(R)-2j
THF
THF
I2
30
15
27
7
10
11
12d
13e
14
15
16
17
18
19f
20g
I2
100
5
(R)-2a THF
(R)-2a THF
(R)-2a THF
(R)-2a THF
(R)-2a Et2O
no
I2/Et3N
100
80
82
85
71
84
79
69
87
86
I2/HOAc 100
KI
I2
23
Experimental
10
General
(R)-2a CH2Cl2 I2
(R)-2a toluene I2
87
All reactions and manipulations were performed in
an argon-filled glovebox (VAC DRI-LAB HE 493) or
using standard Schlenk techniques. Melting points were
measured on a RY-I apparatus and uncorrected. Et2O,
THF and toluene were distilled from sodium benzophe-
none ketyl. DCM was distilled from calcium hydride.
Anhydrous MeOH was distilled from magnesium. Hy-
drogen gas (99.999%) was purchased from Boc Gas Inc.
NMR spectra were recorded with a Varian spectrometer
at 400 MHz (1H NMR) and 100 MHz (13C NMR) or a
Bruker AV 300 spectrometer at 300 MHz (1H NMR) and
75 MHz (13C NMR) in CDCl3. Chemical shifts were
reported in ppm down field from internal Me4Si and
external 85% H3PO4, respectively. Optical rotations
were determined using a Perkin Elmer 341 MC po-
larimeter. HRMS were recorded on IonSpec FT-ICR
mass spectrometer with ESI resource. GC analyses were
performed using Hewlett Packard Model HP 6890 Se-
ries. HPLC analyses were performed using Hewlett
Packard Model HP 1100 Series. The enamines were
prepared using literature methods.1,9
92
(R)-2a MeOH
(R)-2a THF
(R)-2a THF
I2
I2
I2
91
100
100
a Recation conditions: Ir/L/add./subs.＝1∶2.2∶5∶100, [subs.]
－
＝0.1 mol•L , 5×106 Pa H2, 0 ℃, 24 h. Determined by GC.
1
b
c
d
e
Determined by chiral GC. 20 mol% Et3N. 20 mol% HOAc.
f 1×106 Pa H2. g 0.05 mol% [Ir(COD)Cl]2 (S/C＝1000).
amine 4a within 12 h with 87% ee (Table 2, Entry 1).
The enamine 3b with a six-membered piperidine ring
needed 24 h for complete hydrogenation, and the enan-
tiomeric excess of amine product became 67% ee (Entry
2). However, the enamine 3c with a morpholine moiety
was reluctant to be hydrogenated under standard condi-
tions. It was only hydrogenated under 5×106 Pa of hy-
drogen at 50 ℃, providing chiral amine 4c with 34% ee
(Entry 3). The enamines 3d and 3e, both having an
acyclic amino group, also showed low reactivity in the
hydrogenation, requiring 24 h or 40 h at 5×106 Pa of
hydrogen for full conversion (Entries 4 and 5). The
electronic property of substituents on the phenyl ring of
the enamines 3 has a visible effect on the enantioselec-
tivity of reaction. The substrates with an electron-
donating group at meta- or para-position of the phenyl
ring have high enantioselectivity (Entries 6, 7, 10 and
11). The substrates with an electron-withdrawing group
at para-position of the phenyl ring gave lower enantio-
selectivity (Entries 8 and 9). Presumably due to the
steric hindrance, a group on the ortho-position of the
Synthesis of chiral spiro phosphoramidite ligands8
N,N-Diphenyl-[(R)-1,1'-spirobiindane-7,7'-diyl]-
phosphoramidite ((R)-2a) A solution of (R)-1,1'-
spirobiindane-7,7'-diol (1.0 g, 4.0 mmol)) and Et3N (834
mg, 8.2 mmol) in 40 mL THF was cooled to 0 ℃, and a
freshly distilled PCl3 (566 mg, 4.1 mmol) was added.
The reaction mixture was stirred at 0 ℃ for 0.5 h, then
warmed to room temperature and stirred overnight. The
mixture was filtered under nitrogen and the filtrate was
1738
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1736— 1742

Asymmetric Hydrogenation of Unfunctionalized Enamines
Table 2 Asymmetric hydrogenation of enamines 3 with catalyst Ir-(R)-2aa
Substrate
Entry
Product
Time/h
eeb/%
R1, R2
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
R4
1
(CH2)4
(CH2)5
(CH2)2O(CH2)2
Et, Et
H
4a
4b
4c
4d
4e
4f
12
24
48
24
40
12
12
12
12
12
12
12
12
12
24
87
67
34
71
57
87
89
52
67
80
85
60
67
76
43
2
H
3c
4d
5d
6
H
H
Me, Ph
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
H
4-Me
4-MeO
4-Cl
4-F
7
4g
4h
4i
8
9
10
11
12
13
14
15d
3-Me
3-MeO
2-Me
2-MeO
3,4-OCH2O
H
4j
4k
4l
4m
4n
4o
16
17
18
4p
4q
4r
12
12
12
80
88
90
－
1
a Recation conditions: Ir/L/add./subs.＝1∶2.2∶5∶100, [subs.]＝0.1 mol•L , 1×106 Pa H2, 0 ℃, 100% conversion, ＞90% isolated
yield. b Determined by chiral GC or HPLC. c 5×106 Pa H2, 50 ℃. d 5×106 Pa, 15—18 ℃.
evaporated under reduced pressure. The residue was
resolved in 40 mL THF, cooled to －78 ℃, and treated
with lithium diphenylamide prepared from diphenylamine
(677 mg, 4.0 mmol) and 2.0 mL (4.4 mmol) butyllith-
100 MHz) δ: 147.3, 147.2, 145.9, 145.5, 145.3, 144.4,
144.3, 141.8, 140.6, 129.3, 128.6, 128.4, 124.9, 123.7,
121.6, 121.0, 117.7, 58.9, 38.1, 37.9, 30.8, 30.4; 31P
NMR (CDCl3, 162 MHz) δ: 118.1 (s). HRMS (ESI+)
calcd for C29H24NO2PH+ 450.1617, found 450.1615.
N,N-Bis(4-chlorophenyl)-[(R)-1,1'-spirobiindane-
7,7'-diyl]-phosphoramidite ((R)-2b) Ligand (R)-2b
was synthesized by the same procedure as that for
(R)-2a. White solid, 70%, m.p. 152—154 ℃, [α]1D2
ium (2.2 mol•L－ solution in hexane) in 10 mL THF at
1
－78 ℃. The resulting solution was warmed to room
temperature and stirred for 24 h. The solvent was re-
moved in vacuum and the residue was purified by
chromatography on a silica gel column with ethyl ace-
tate/petroleum ether (1/40, V/V) as eluent to afford
(R)-2a as a white solid (1.4 g, 78%). m.p. 159—161 ℃,
1
＋127 (c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ:
7.20 (t, J＝8.0 Hz, 1H), 7.13—7.05 (m, 7H), 6.90 (d,
J＝8.0 Hz, 1H), 6.65—6.59 (m, 5H), 3.09—3.01 (m,
2H), 2.86—2.74 (m, 2H), 2.23—2.15 (m, 2H), 1.98—
1.90 (m, 1H), 1.78—1.70 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ: 146.9, 146.8, 146.0, 145.7, 145.1, 145.0,
142.8, 142.7, 141.7, 140.6, 129.4, 128.8, 128.7, 128.5,
[α]1D2 ＋203 (c 1.0, CH2Cl2); H NMR (CDCl3, 400
1
MHz) δ: 7.21—7.13 (m, 5H), 7.10—7.00 (m, 5H), 6.92
(d, J＝8.0 Hz, 1H), 6.70 (d, J＝7.6 Hz, 5H), 3.08—2.99
(m, 2H), 2.85—2.71 (m, 2H), 2.22—2.11 (m, 2H), 1.99
—1.91 (m, 1H), 1.76—1.69 (m, 1H); 13C NMR (CDCl3,
Chin. J. Chem. 2010, 28, 1736— 1742
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Yan, Xie & Zhou
FULL PAPER
126.0, 121.9, 121.3, 121.2, 120.9, 120.8, 58.9, 38.1,
38.0, 30.8, 30.4; 31P NMR (CDCl3, 162 MHz) δ: 115.7
(s). HRMS (ESI+) calcd for C29H22Cl2NO2PH+ 518.0838,
found 518.0837.
Hz, 3H), 7.10—7.01 (m, 4H), 6.93— 6.85 (m, 4H), 6.73
—6.71 (m, 2H), 3.09—2.98 (m, 2H), 2.84—2.73 (m,
2H), 2.22—2.10 (m, 2H), 2.00—1.92 (m, 1H), 1.77—
1.69 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 147.3,
147.2, 145.9, 145.6, 145.5, 145.4, 144.9, 144.7, 141.8,
141.1, 140.7, 133.7, 130.5, 128.8, 128.6, 128.2, 127.4,
127.3, 125.9, 125.6, 124.9, 124.3, 124.2, 123.5, 122.9,
121.7, 121.6, 121.2, 121.0, 59.0, 38.1, 38.0, 30.8, 30.5;
31P NMR (CDCl3, 162 MHz) δ: 116.5 (s). HRMS (ESI+)
calcd for C33H26NO2PH+ 500.1774, found 500.1768.
N,N-Diphenyl-[(R)-1,1'-spirobiindane-6,6'-
N,N-Bis(4-methoxyphenyl)-[(R)-1,1'-spirobiindane-
7,7'-diyl]-phosphoramidite ((R)-2c) Ligand (R)-2c
was synthesized by the same procedure as that for
(R)-2a. White solid, 75%, m.p. 146—148 ℃, [α]1D2
1
＋234 (c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ:
7.19 (t, J＝7.6 Hz, 1H), 7.11—7.02 (m, 3H), 6.93 (d,
J＝8.0 Hz, 1H), 6.74—6.64 (m, 9H), 3.75 (s, 6H), 3.09
—3.00 (m, 2H), 2.85—2.73 (m, 2H), 2.22—2.14 (m,
2H), 1.99—1.91 (m, 1H), 1.83—1.75 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 156.1, 147.6, 147.5, 146.0,
145.6, 145.5, 141.9, 140.7, 138.0, 137.9, 128.6, 128.4,
126.5, 126.4, 121.8, 121.6, 121.2, 121.0, 113.9, 59.0,
55.4, 38.2, 38.1, 30.9, 30.5; 31P NMR (CDCl3, 162 MHz)
δ: 117.3 (s). HRMS (ESI+) calcd for C31H28NO4PH+
510.1829, found 510.1834.
dimethyl-7,7'-diyl]-phosphoramidite
((R)-2j)
Ligand (R)-2j was synthesized by the same procedure as
that for (R)-2a. White solid, 72%, m.p. 136—138 ℃,
[α]1D8 ＋240 (c 1.0, CH2Cl2); H NMR (CDCl3, 400
1
MHz) δ: 7.13 (t, J＝7.6 Hz, 4H), 7.06 (d, J＝7.6 Hz,
1H), 6.99 (t, J＝7.2 Hz, 2H), 6.94 (d, J＝7.2 Hz, 2H),
6.87 (d, J＝7.2 Hz, 1H), 6.76 (brs, 4H), 2.98—2.90 (m,
2H), 2.78—2.60 (m, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 2.11
—2.02 (m, 2H), 1.92—1.85 (m, 1H), 1.70—1.62 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ: 145.7, 144.3,
144.2, 142.4, 141.6, 140.3, 129.9, 129.2, 128.5, 128.4,
124.6, 123.6, 121.1, 120.5, 59.4, 38.6, 37.8, 30.2, 29.8,
16.9, 16.4, 16.3; 31P NMR (CDCl3, 162 MHz) δ: 114.0
(s). HRMS (ESI+) calcd for C31H28NO2PH+ 478.1930,
found 478.1924.
N,N-Bis(3,5-dimethylphenyl)-[(R)-1,1'-spirobiin-
dane-7,7'-diyl]-phosphoramidite ((R)-2d)
Ligand
(R)-2d was synthesized by the same procedure as that
for (R)-2a. White solid, 76%, m.p. 180—182 ℃, [α]1D2
1
＋326 (c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ:
7.19 (t, J＝7.6 Hz, 1H), 7.13—7.05 (m, 3H), 6.92 (d,
J＝8.0 Hz, 1H), 6.72—6.68 (m, 3H), 6.31 (s, 4H), 3.15
—3.02 (m, 2H), 2.87—2.79 (m, 2H), 2.29—2.19 (m,
14H), 2.02—1.94 (m, 1H), 1.91—1.83 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 147.6, 147.5, 145.8, 145.7,
145.6, 145.4, 144.2, 144.1, 141.9, 141.8, 140.8, 138.0,
128.5, 125.6, 123.0, 121.9, 121.5, 121.3, 121.2, 121.1,
59.0, 38.1, 30.8, 30.6, 21.2; 31P NMR (CDCl3, 162 MHz)
δ: 117.3 (s). HRMS (ESI+) calcd for C33H32NO2PH+
506.2243, found 506.2248.
General procedure for asymmetric hydrogenation of
enamines and analytical data for the hydrogenation
products
To a dry reaction tube equipped with a stirring bar
was added [Ir(COD)Cl]2 (1.7 mg, 2.5 µmol), (R)-2a (4.9
mg, 11 µmol) and anhydrous THF (5.0 mL) under an
nitrogen atmosphere. After the mixture was stirred at
room temperature for 30 min, iodide (6.4 mg, 25 µmol)
and enamines (0.5 mmol) were added. The reaction tube
was then put into an autoclave. The nitrogen atmosphere
in the tube was replaced by hydrogen three times and
the reaction solution was stirred at 0 ℃ under 1×106
Pa H2 pressure for 12 h. After releasing hydrogen, the
resulted mixture was filtered through a short silica plug
and submitted to analysis for conversion and enanti-
omeric excess by GC with chiral column. The analytical
data for the hydrogenation products are listed below.
(S)-1-(1-Phenylethyl)pyrrolidine (4a)1 Yellow oil,
97% yield, 87% ee, [α]1D8 －53.4 (c 1.0, CHCl3), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 1.0 mL/min, programmed from 100 ℃ to
120 ℃ at 0.5 ℃/min; tR＝27.55 min (R) and tR＝
N-(4-Methoxy-2-methylphenyl)-N-phenyl-[(R)-1,1'-
spirobiindane-7,7′-diyl]-phosphoramidite
((R)-2e)
Ligand (R)-2e was synthesized by the same procedure as
that for (R)-2a. White solid, 81%, m.p. 145—147 ℃,
[α]1D2 ＋84.7 (c 1.0, CH2Cl2); H NMR (CDCl3, 400
1
MHz) δ: 7.09 (q, J＝8.4 Hz, 3H), 7.00—6.93 (m, 3H),
6.84—6.76 (m, 4H), 6.62—6.59 (m, 2H), 6.24 (dd, J＝
1.6, 8.4 Hz, 1H), 5.21 (brs, 1H), 3.62 (s, 3H), 2.98—
2.88 (m, 2H), 2.74—2.64 (m, 2H), 2.12—2.08 (m, 1H),
2.10 (s, 3H), 2.01 (dd, J＝6.0, 11.6 Hz, 1H), 1.89—1.82
(m, 1H), 1.65—1.57 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ: 157.8, 147.2, 147.1, 146.1, 145.9, 145.7, 145.3,
145.2, 141.8, 140.6, 138.7, 133.1, 133.0, 131.1, 128.9,
128.5, 128.3, 121.6, 121.4, 120.9, 120.7, 116.8, 116.7,
115.2, 111.3, 58.9, 55.1, 38.1, 37.8, 30.8, 30.4, 18.8; 31P
NMR (CDCl3, 162 MHz) δ: 118.9 (s). HRMS (ESI+)
calcd for C31H28NO3PH+ 494.1880, found 494.1875.
N-(Naphthalen-2-yl)-N-phenyl-[(R)-1,1'-spirobiin-
dane-7,7'-diyl]-phosphoramidite ((R)-2f) Ligand
(R)-2f was synthesized by the same procedure as that for
(R)-2a. White solid, 78%, m.p. 142—144 ℃, [α]1D2
1
28.00 min (S). H NMR (CDCl3, 400 MHz) δ: 7.35—
7.28 (m, 4H), 7.25—7.21 (m, 1H), 3.17 (q, J＝6.8 Hz,
1H), 2.58—2.51 (m, 2H), 2.40—2.33 (m, 2H), 1.81—
1.71 (m, 4H), 1.41 (d, J＝6.8 Hz, 3H).
(S)-1-(1-Phenylethyl)piperidine (4b)10 Yellow oil,
98% yield, 67% ee, [α]1D8 －17.7 (c 1.0, CHCl3), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 1.0 mL/min, programmed from 100 ℃ to
130 ℃ at 0.5 ℃/min; tR＝37.04 min (R) and tR＝
1
＋285 (c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ:
7.71 (d, J＝7.6 Hz, 1H), 7.61 (d, J＝8.8 Hz, 1H), 7.52
(d, J＝7.6 Hz, 1H), 7.40—7.33 (m, 2H), 7.18 (q, J＝7.6
1740
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Chin. J. Chem. 2010, 28, 1736— 1742

Asymmetric Hydrogenation of Unfunctionalized Enamines
1
1
37.55 min (S). H NMR (CDCl3, 400 MHz) δ: 7.33—
nor) and tR＝95.67 min (major). H NMR (CDCl3, 400
7.29 (m, 4H), 7.27—7.21 (m, 1H), 3.40 (q, J＝6.8 Hz,
1H), 2.41—2.35 (m, 4H), 1.58—1.53 (m, 4H), 1.41—
1.35 (m, 2H), 1.38 (d, J＝6.8 Hz, 3H).
MHz) δ: 7.26 (s, 4H), 3.14 (q, J＝6.4 Hz, 1H), 2.55—
2.48 (m, 2H), 2.36—2.31 (m, 2H), 1.77—1.74 (m, 4H),
1.36 (d, J＝6.4 Hz, 3H).
(S)-4-(1-Phenylethyl)morpholine (4c)11
Yellow
(－ )-1-(1-(4-Fluorophenyl)ethyl)pyrrolidine (4i)
Yellow oil, 95% yield, 67% ee, [α]2D5 －46.8 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
100 ℃ to 130 ℃ at 0.5 ℃/min; tR＝32.28 min (mi-
oil, 96% yield, 34% ee, [α]2D6 －14.2 (c 1.0, EtOH), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 1.0 mL/min, programmed from 105 ℃ to
145 ℃ at 0.5 ℃/min; tR＝40.80 min (R) and tR＝
1
1
41.56 min (S). H NMR (CDCl3, 300 MHz) δ: 7.32—
nor) and tR＝32.88 min (major). H NMR (CDCl3, 400
7.22 (m, 5H), 3.69 (t, J＝4.8 Hz, 4H), 3.30 (q, J＝6.8
Hz, 1H), 2.50—2.48 (m, 2H), 2.38—2.33 (m, 2H), 1.35
(d, J＝6.8 Hz, 3H).
MHz) δ: 7.30—7.26 (m, 2H), 6.99—6.95 (m, 2H), 3.15
(q, J＝6.4 Hz, 1H), 2.54—2.50 (m, 2H), 2.35—2.30 (m,
2H), 1.76—1.73 (m, 4H), 1.36 (d, J＝6.4 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ: 163.3, 160.1, 141.6, 128.5,
128.4, 115.0, 114.8, 65.1, 52.8, 23.4, 23.3. HRMS (ESI+)
calcd for C12H16FNH+ 194.1340, found 194.1346.
(S)-N,N-Diethyl-1-phenylethanamine
(4d)1
Yellow oil, 94% yield, 71% ee, [α]1D8 －20.9 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
80 ℃ to 110 ℃ at 0.5 ℃/min; tR＝35.89 min (S) and
( － )-1-(1-m-Tolylethyl)pyrrolidine (4j)1 Yellow
oil, 92% yield, 80% ee, [α]2D5 －40.3 (c 1.0, CHCl3), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 1.0 mL/min, programmed from 90 ℃ to
110 ℃ at 0.2 ℃/min; tR＝69.63 min (minor) and tR＝
1
tR＝36.79 min (R). HNMR (CDCl3, 400 MHz) δ: 7.37
—7.29 (m, 4H), 7.24—7.21 (m, 1H), 3.79 (q, J＝6.8 Hz,
1H), 2.63—2.45 (m, 4H), 1.34 (d, J＝6.8 Hz, 3H), 0.99
(t, J＝7.2 Hz, 6H).
1
70.29 min (major). H NMR (CDCl3, 400 MHz) δ: 7.21
(－ )-N-Methyl-N-(1-phenylethyl)aniline
(4e)3
—7.11 (m, 3H), 7.05 (d, J＝7.2 Hz, 1H), 3.13 (q, J＝6.4
Hz, 1H), 2.57—2.53 (m, 2H), 2.38—2.32 (m, 2H), 2.35
(s, 3H), 1.78—1.75 (m, 4H), 1.40 (d, J＝6.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ: 145.8, 137.7, 128.1,
127.8, 127.6, 124.4, 66.1, 53.1, 23.5, 23.3, 21.5. HRMS
(ESI+) calcd for C13H19NH+ 190.1590, found 190.1591.
(－ )-1-(1-(3-Methoxyphenyl)ethyl)pyrrolidine (4k)
Yellow oil, 93% yield, 85% ee, [α]2D5 －56.9 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
90 ℃ to 125 ℃ at 0.2 ℃/min; tR＝125.69 min (mi-
nor) and tR＝126.40 min (major). 1H NMR (CDCl3, 400
MHz) δ: 7.21 (t, J＝7.8 Hz, 1H), 6.93—6.91 (m, 2H),
6.78—6.76 (m, 1H), 3.80 (s, 3H), 3.14 (q, J＝6.8 Hz,
1H), 2.57—2.53 (m, 2H), 2.40—2.35 (m, 2H), 1.79—
1.72 (m, 4H), 1.39 (d, J＝6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ: 159.7, 147.6, 129.2, 119.6, 112.7,
112.2, 66.0, 55.2, 52.9, 23.5, 23.2. HRMS (ESI+) calcd
for C13H19NOH+ 206.1539, found 206.1539.
Colorless oil, 87% yield, 57% ee, [α]D8 －90.6 (c 1.0,
CHCl3), HPLC condition: Chiralcel OJ-H column (25
cm×0.46 cm ID), n-hexane/2-propanol＝98∶2, 1.0
mL/min, 254 nm UV detector, tR＝14.58 min (major)
and tR＝21.69 min (minor). 1H NMR (CDCl3, 400 MHz)
δ: 7.35—7.32 (m, 4H), 7.27—7.23 (m, 3H), 6.84 (d, J＝
8.0 Hz, 2H), 6.73 (t, J＝7.2 Hz, 1H), 5.13 (q, J＝6.8 Hz,
1H), 2.68 (s, 3H), 1.55 (d, J＝6.8 Hz, 3H).
(－ )-1-(1-p-Tolylethyl)pyrrolidine (4f) Yellow oil,
95% yield, 87% ee, [α]1D8 －45.7 (c 1.0, CHCl3), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 1.0 mL/min, programmed from 100 ℃ to
130 ℃ at 0.5 ℃/min; tR＝40.56 min (minor) and tR＝
1
40.97 min (major). H NMR (CDCl3, 300 MHz) δ: 7.22
(d, J＝7.8 Hz, 2H), 7.11 (d, J＝7.8 Hz, 2H), 3.15 (q,
J＝6.6 Hz, 1H), 2.56—2.51 (m, 2H), 2.39—2.35 (m,
2H), 2.33 (s, 3H), 1.77—1.73 (m, 4H), 1.39 (d, J＝6.6
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 142.7, 136.3,
128.9, 127.1, 65.6, 53.0, 23.5, 23.2, 21.1. HRMS (ESI+)
calcd for C13H19NH+ 190.1590, found 190.1591.
( － )-1-(1-o-Tolylethyl)pyrrolidine (4l)1 Yellow
oil, 90% yield, 60% ee, [α]3D2 －62.1 (c 1.0, CHCl3), the
enantiomeric excesses of the amine was determined by
(－ )-1-(1-(4-Methoxyphenyl)ethyl)pyrrolidine (4g)1
Yellow oil, 92% yield, 89% ee, [α]1D8 －60.6 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
100 ℃ to 130 ℃ at 0.2 ℃/min; tR＝105.21 min
1
analysis of H NMR spectra of the diastereomeric salts
with (R)- or (S)-O-acetylmandelic acid. 1H NMR
(CDCl3, 400 MHz) δ: 7.53 (d, J＝7.6 Hz, 1H), 7.22—
7.17 (m, 1H), 7.11 (d, J＝4.0 Hz, 2H), 3.46 (q, J＝6.4
Hz, 1H), 2.55—2.52 (m, 2H), 2.45—2.42 (m, 2H), 2.36
(s, 3H), 1.79—1.76 (m, 4H), 1.34 (d, J＝6.4 Hz, 3H).
(－ )-1-(1-(2-Methoxyphenyl)ethyl)pyrrolidine (4m)
Yellow oil, 92% yield, 67% ee, [α]3D0 －32.3 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
100 ℃ to 135 ℃ at 0.2 ℃/min; tR＝128.85 min
1
(minor) and tR＝106.00 min (major). H NMR (CDCl3,
400 MHz) δ: 7.24 (d, J＝8.4 Hz, 2H), 6.84 (d, J＝8.4
Hz, 2H), 3.79 (s, 3H), 3.13 (q, J＝6.4 Hz, 1H), 2.54—
2.52 (m, 2H), 2.35—2.33 (m, 2H), 1.77—1.73 (m, 4H),
1.38 (d, J＝6.4 Hz, 3H).
(－ )-1-(1-(4-Chlorophenyl)ethyl)pyrrolidine (4h)1
Yellow oil, 94% yield, 52% ee, [α]2D5 － 40.7 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
100 ℃ to 130 ℃ at 0.2 ℃/min; tR＝94.46 min (mi-
1
(minor) and tR＝130.41 min (major). H NMR (CDCl3,
400 MHz) δ: 7.51 (dd, J＝7.6, 1.6 Hz, 1H), 7.21—7.17
(m, 1H), 6.96 (t, J＝7.6 Hz, 1H), 6.86 (d, J＝8.0 Hz,
Chin. J. Chem. 2010, 28, 1736— 1742
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1741

Yan, Xie & Zhou
FULL PAPER
1H), 3.81 (q, J＝6.8 Hz, 1H), 3.81 (s, 3H), 2.58—2.55
(m, 2H), 2.48—2.45 (m, 2H), 1.78—1.75 (m, 4H), 1.35
(d, J＝6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ:
156.4, 133.4, 127.9, 127.3, 120.8, 110.5, 56.8, 55.4,
52.6, 23.5, 22.1. HRMS (ESI+) calcd for C13H19NOH+
206.1539, found 206.1540.
(－ )-1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)pyrroli-
dine (4n) Yellow oil, 91% yield, 76% ee, [α]3D0 －49.1
(c 1.0, CHCl3), GC condition: Varian CP7502 column
(25 m×0.25 mm×0.25 µm), N2 1.0 mL/min, pro-
grammed from 100 ℃ to 160 ℃ at 0.5 ℃/min; tR＝
84.05 min (minor) and tR＝84.61 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 6.88 (d, J＝1.2 Hz, 1H), 6.76—
6.71 (m, 2H), 5.92 (s, 2H), 3.09 (q, J＝6.8 Hz, 1H), 2.54
—2.50 (m, 2H), 2.38—2.34 (m, 2H), 1.76—1.73 (m,
4H), 1.35 (d, J＝6.8 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ: 147.6, 146.2, 140.0, 120.1, 107.8, 107.4, 100.8,
65.6, 52.8, 23.4, 23.3. HRMS (ESI+) calcd for
C13H17NO2H+ 220.1332, found 220.1336.
programmed from 120 ℃ to 160 ℃ at 1.0 ℃/min; tR
1
＝29.86 min (minor) and tR＝30.70 min (major). H
NMR (CDCl3, 400 MHz) δ: 7.38 (d, J＝7.2 Hz, 1H),
7.18—7.09 (m, 3H), 3.57 (t, J＝4.8 Hz, 1H), 2.96—2.89
(m, 1H), 2.80—2.67 (m, 3H), 2.51—2.48 (m, 2H), 2.17
—2.08 (m, 1H), 2.01—1.94 (m, 1H), 1.84—1.68 (m,
6H); 13C NMR (CDCl3, 75 MHz) δ: 138.7, 137.7, 129.4,
129.1, 126.7, 125.0, 60.8, 50.4, 29.1, 24.8, 23.8, 19.4.
HRMS (ESI+) calcd for C14H19NH＋ 202.1590, found
202.1593.
(－ )-1-(6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-
yl)pyrrolidine (4r) Yellow oil, 96% yield, 90% ee,
[α]2D5 －50.7 (c 1.0, CHCl3), GC condition: Varian
CP7502 column (25 m×0.25 mm×0.25 µm), N2 1.0
mL/min, programmed from 120 ℃ to 170 ℃ at 1.0
℃/min; tR＝29.49 min (minor) and tR＝30.48 min (ma-
jor). 1H NMR (CDCl3, 400 MHz) δ: 7.15—7.05 (m, 4H),
3.48 (t, J＝12.6 Hz, 1H), 3.15 (d, J＝6.0 Hz, 1H), 2.57
—2.51 (m, 3H), 2.18—2.02 (m, 4H), 1.92—1.88 (m,
1H), 1.79—1.63 (m, 6H), 1.38 (q, J＝12.2 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ: 144.1, 143.5, 129.7, 129.3,
126.8, 125.4, 71.9, 53.0, 35.4, 32.5, 28.6, 25.9, 23.7.
HRMS (ESI+) calcd for C15H21NH+ 216.1747, found
216.1748.
(－ )-1-(1-Phenylpropyl)pyrrolidine (4o) Yellow
oil, 93% yield, 43% ee, [α]1D8 －20.2 (c 1.0, CHCl3), GC
condition: Varian CP7502 column (25 m×0.25 mm×
0.25 µm), N2 0.5 mL/min, programmed from 100 ℃ to
110 ℃ at 0.1 ℃/min; tR＝81.20 min (minor) and tR＝
1
82.24 min (major). H NMR (CDCl3, 400 MHz) δ: 7.32
—7.20 (m, 5H), 2.94 (dd, J＝3.6, 10.0 Hz, 1H), 2.57—
2.52 (m, 2H), 2.36—2.31 (m, 2H), 2.03—1.93 (m, 1H),
1.78—1.65 (m, 5H), 0.66 (t, J＝7.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ: 143.2, 128.2, 128.0, 126.8, 72.8,
52.8, 28.6, 23.3, 10.5. HRMS (ESI+) calcd for
C13H19NH+ 190.1590, found 190.1592.
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2
3
4
5
6
Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
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Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.;
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Qiao, X.-C.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2009, 20, 1254.
(＋)-1-(2,3-Dihydro-1H-inden-1-yl)pyrrolidine (4p)
Yellow oil, 90% yield, 80% ee, [α]3D0 ＋25.4 (c 1.0,
CHCl3), GC condition: Varian CP7502 column (25 m×
0.25 mm×0.25 µm), N2 1.0 mL/min, programmed from
120 ℃ to 140 ℃ at 0.2 ℃/min; tR＝37.69 min (mi-
1
nor) and tR＝38.61 min (major). H NMR (CDCl3, 400
MHz) δ: 7.37 (d, J＝6.8 Hz, 1H), 7.26—7.15 (m, 3H),
4.21 (t, J＝5.6 Hz, 1H), 3.09—3.01 (m, 1H), 2.84—2.77
(m, 1H), 2.69—2.56 (m, 4H), 2.19—2.10 (m, 2H), 1.82
—1.73 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ: 144.3,
143.6, 127.4, 125.8, 125.7, 124.8, 67.3, 50.3, 30.9, 28.5,
23.6. HRMS (ESI+) calcd for C13H17NH＋ 188.1434,
found 188.1437.
7
8
9
Barluenga, J.; Fernández, M. A.; Aznar, F.; Valdés, C. Chem.
Eur. J. 2004, 10, 494.
10 Beaufort-Droal, V.; Pereira, E.; Théry, V.; Aitken, D. J.
Tetrahedron 2006, 62, 11948.
11 Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
14286.
( ＋ )-1-(1,2,3,4-Tetrahydronaphthalen-1-yl)pyrro-
lidine (4q) Yellow oil, 94% yield, 88% ee, [α]1D8
＋30.2 (c 1.0, CHCl3), GC condition: Varian CP7502
column (25 m×0.25 mm×0.25 µm), N2 1.0 mL/min,
(E1007222 Cheng, F.)
1742
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1736— 1742