Highly enantioselective Ir-catalyzed hydrogenation of exocyclic enamines

Article abstract of DOI:10.1016/j.tetasy.2009.03.037

[Ir(COD)Cl]₂/MeO-BiPhep/I₂ catalyst system is highly effective for the asymmetric hydrogenation of exocyclic enamines with high enantioselectivities (up to 96% ee).

Full text of DOI:10.1016/j.tetasy.2009.03.037

Tetrahedron: Asymmetry 20 (2009) 1040–1045
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective Ir-catalyzed hydrogenation of exocyclic enamines
*
Xiao-Bing Wang, Da-Wei Wang, Sheng-Mei Lu, Chang-Bin Yu, Yong-Gui Zhou
State Key of Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
[Ir(COD)Cl]2/MeO-BiPhep/I2 catalyst system is highly effective for the asymmetric hydrogenation of exo-
cyclic enamines with high enantioselectivities (up to 96% ee).
Received 20 January 2009
Accepted 4 March 2009
Available online 6 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
R1
R
R2
Ar
NH2
O
NH
O
N
R
N
R1
R2
R1
OR2
Optically active amines are very important for the synthesis of
biologically active natural products and pharmaceuticals.1 Transi-
tion metal-catalyzed asymmetric hydrogenation of functionalized
enamines is a well-known and important method for preparing
them.2 To date, a broad range of catalysts are available, which pro-
vide the desired N-acylamino acid with excellent enantioselectivi-
ties. It is widely accepted that N-acyl groups are important for high
reactivity and selectivity for the chelation requirement between
the substrate and metal.3 However, tedious modification of the
substrate and removal of the acyl groups under strongly acidic or
basic conditions have seriously limited its application. Developing
new catalysts that allow the asymmetric hydrogenation of simple
enamines is still in great demand. Recently, some progress has
been made in this area (Scheme 1). The pioneering work in asym-
metric hydrogenation of simple enamines involved the utilization
of [(S,S,S)-(EBTHI)TiO2-binaphthol] as the catalyst (up to 98% ee).4
In 2000, Börner et al. reported an asymmetric hydrogenation of
simple enamines with up to 72% ee using Rh(I)-bisphosphine.5 Sci-
entists at Merck reported that the asymmetric hydrogenation of
unprotected enamine esters and amides using Rh/Josiphos led to
the chiral amines with high ee.6 Zhang employed Rh/TangPhos
for the asymmetric hydrogenation of N-aryl b-enamino esters with
excellent ee’s.7 In 2006, Zhou et al. developed a highly enantiose-
lective hydrogenation of simple N-unprotected enamines with
Rh(I) complexes of chiral spiro phosphonite ligands, in which io-
dine and HOAc are crucial for the activity and enantioselectivity.8a
Very recently, Zhou et al. described the iridium-catalyzed asym-
metric hydrogenation of cyclic enamines with up to 97% ee.8b De-
spite the progresses that has been made for asymmetric
hydrogenation of enamines, the suitable catalytic system and sub-
strate scope are still rather limited.
R'
R1
N
N
Ar1
N
R
H
1
R2
Ar2
Scheme 1. The structures of some typical simple enamines.
asymmetric hydrogenation of ketones and imines have been made
by our group.11,12 As a part of our continuing efforts in asymmetric
hydrogenation, herein, we report our initial findings on the asym-
metric hydrogenation of simple exocyclic enamines 1 using the
[Ir(COD)Cl]2/MeO-BiPhep/I2 as
enantioselectivity.
a catalyst with up to 96%
2. Results and discussion
Asymmetric hydrogenation of exocyclic enamines 1 provides a
convenient route to synthesize chiral tetrahydroquinoline deriva-
tives, which are important synthetic intermediates, structural units
of natural products and biologically active compounds. Enamine
(Z)-2-(3,4-dihydroquinolin-2(1H)-ylidene)-1-phenylethanone 1a,
which can be conveniently synthesized by partial hydrogenation
of the corresponding quinoline derivatives, was selected as the
model substrate. Considering that iridium has been successfully
applied to asymmetric hydrogenation of imines, olefins, and quin-
olines,2a,11 we firstly examined [Ir(COD)Cl]2/(S)-MeO-Biphep/I2 for
hydrogenation of 1a. To our delight, the reaction proceeded
smoothly to give hydrogenation product with 96% ee. Then the sol-
vent effect was investigated, and the results are summarized in Ta-
ble 1 (entries 1–4). The conversions and ees of the products are
highly solvent dependent. Benzene and toluene were found to be
the optimal solvents. Iodine also plays a crucial role for enantiose-
lectivity and reactivity, and the reaction did not occur in the
absence of iodine (entry 5).
Recently, some significant progress on the asymmetric hydroge-
nation of heteroaromatic compounds9d,10 and Pd-catalyzed
* Corresponding author. Tel./fax: +86 411 84379220.
E-mail address: ygzhou@dicp.ac.cn (Y.-G. Zhou).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.037

X.-B. Wang et al. / Tetrahedron: Asymmetry 20 (2009) 1040–1045
1041
Table 1
Table 2
Condition optimization for Ir-catalyzed asymmetric hydrogenation of exocyclic
Ir-Catalyzed hydrogenation of exocyclic enamines 1a
enamines 1aa
R1
R1
[Ir(COD)Cl]2 / (S)-MeO-Biphep
[Ir(COD)Cl]2 /L* /I2
N
N
Benzene / I2 / H2 (600Psi), RT
R2
N
N
H
H
*
H2, Solvent
H
H
2
O
O
R2
1
2a
1a
O
Ph
O
Ph
R1/R2
Yieldb (%)
eec (%)
Entry
Solvent
Ligand
Covnb (%)
eec (%)
Entry
1
2
3
4
Toluene
CH2Cl2
THF
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
L-1
L-1
>95
58
>95
>95
<5
>95
>95
>95
68
>95
15
96
62
85
96
—
94
96
96
75
96
2
1
2
3
4
5
6
7
8
9
10
11
12
13
H/Ph 1a
H/Me 1b
97 2a
99 2b
93 2c
95 2d
94 2e
91 2f
94 2g
99 2h
91 2i
94 2j
96 2k
97 2l
97 2m
96 (R)
94 (R)
85 (R)
94 (R)
95 (R)
96 (R)
96 (R)
90 (R)
96 (R)
90 (R)
89 (R)
78 (R)
94 (R)
H/n-C3H7 1c
H/4-CF3–C6H4 1d
H/4-iPr-C6H4 1e
H/2-CH3–C6H4 1f
H/1-Naphthyl 1g
H/Phenethyl 1h
F/Ph 1i
Me/Ph 1j
H/Ome 1k
H/NEt2 1l
H/3,4-(MeO)2C6H4 1m
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
CF3CH2OH
Benzene
5d
6e
7f
8g
9h
10
11
12
13i
14j
>95
>95
>95
96
30
16
a
Conditions: [Ir(COD)Cl]2 (1 mol %), (S)-MeO-Biphep (2.2 mol %), I2 (10 mol %),
a
Reaction conditions: [Ir(COD)Cl]2 (1 mol %), ligand (2.2 mol %), I2 (10 mol %),
2 mL solvent, 16 h.
benzene, rt, 16 h.
b
Isolated yields.
Determined by HPLC analysis with chiral column.
Conversions were determined by 1H NMR analysis of the crude products.
Determined by HPLC analysis with OD-H column.
b
c
c
d
Without I2.
e
Run at 50 °C.
Run at 1200 psi of H2.
Run at 300 psi of H2.
[Ir(COD)Cl]2 (0.10 mol %), ligand (0.22 mol %), I2 (1.0 mol %).
Rh(COD)2BF4/MeO-Biphep/H2(6 atm)/TFA/50 °C.
Enamine (Z)-CH3(PMPNH)C@CHCO2Et was used
f
obtained regardless of the electronic and steric effects of the aryl
group (entries 4–6, and 13). The substrate with 1-naphthyl substi-
tuent can also give 96% ee value. However, when R2 was changed
to phenethyl, a slightly lower enantioselectivity was obtained
(90% ee, entry 8). The substrate with a 6-substituted heteroaro-
matic ring could also be hydrogenated. Both electro-donating
group such as Me and the electron-withdrawing group such as F,
gave excellent enantioselectivities (entries 9–10). For the exocyclic
enamine ester 11 and amide 12, 89% ee and 78% ee can be ob-
tained, respectively (entries 11 and 12).
g
h
i
j
O
O
O
MeO
MeO
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
P
P
O
O
L-4 (
O
:
S
)-SegPhos
L-3 (R,R)-Me-DuPhos
L-1 (
S
)-MeO-BiPhep L-2 (
S
)-SynPhos
Iridium-catalyzed asymmetric hydrogenation of exocyclic en-
amines provides a convenient route to synthesize optically active
alkaloids and chiral drugs (Scheme 2). For example, 2k is the key
intermediate for the synthesis of NMDA-glycine antagonists.13a
The naturally occurring tetrahydroquinoline alkaloid (S)-cuspare-
ine can also be conveniently synthesized starting from the hydro-
genation product 2m in two steps.13b
The pressure and temperature effects on the reaction were also
screened. The results showed that there is no obvious effect for the
reaction. Slightly lower enantioselectivity was observed under a
higher temperature (entry 6). The enantioselectivities of the reac-
tion can be retained at lower or higher pressure of hydrogen (en-
tries 7 and 8). However, when the catalyst loading was reduced
to 0.1 mol %, only 68% conversion with 75% ee was obtained (entry
9). Next, the effect of various chiral ligands on the asymmetric
hydrogenation of 1a was also studied. The results showed that
the axial chiral bisphosphine ligands exhibited excellent enanti-
oselectivities with full conversions (entries 4, 10–12), whereas a
lower conversion and poor enantioselectivity were achieved with
electron-rich Me-DuPhos (L-3, entry 11). It is noteworthy that
low enantioselectivity was observed using the Rh/(S)-MeO-Bip-
hep/TFA7 for hydrogenation of 1a. Thus, the optimized conditions
are: [Ir(COD)Cl]2/(S)-MeO-BiPhep/Benzene/I2.
COR
O
Ref 10a
N
O
R = OH
R = NHPh
N
H
OMe
Br
N
H
O
2k
O
1. TFA/Et 3SiH
OMe
OMe
N
N
Ar
2. HCHO/NaBH3CN
H
Me
Ar = 3,4-(MeO)2C6H3
4: (S)-Cuspareine
2m
Scheme 2. Formal synthesis of NMDA-glycine antagonists and synthesis of (S)-
cuspareine.
Hydrogenation of the simple acyclic enamine ester (Z)-
CH3(PMPNH)C@CHCO2Et was carried out smoothly under the
above optimized condition. However, the enantioselectivity is
rather low (only 16% ee, entry 14).
3. Conclusions
A variety of exocyclic enamines 1 could be successfully hydro-
genated using [Ir(COD)Cl]2/(S)-MeO-BiPhep/I2 catalyst system with
high to excellent ee values (Table 2). Firstly, a series of exocyclic
enamine ketone derivatives were screened. When the R2 substitu-
ent is methyl, 94% ee and 99% yield are obtained. When the R2 was
changed to n-C3H7, the ee value was dropped to 85%. When the R2
substituent is an aryl group, excellent enantioselectivities were
In summary, the first highly enantioselective Ir-catalyzed asym-
metric hydrogenation of unprotected exocyclic enamines has been
developed using the [Ir(COD)Cl]2/MeO-BiPhep/I2 catalyst system
with good reactivity and excellent enantioselectivities. This meth-
odology has been successfully applied to the synthesis of natural
products and chiral drugs. Further work will focus on the extension
of the catalyst system to a broader range of unprotected enamines.

1042
X.-B. Wang et al. / Tetrahedron: Asymmetry 20 (2009) 1040–1045
NMR (100 MHz, CDCl3): 24.2, 28.8, 92.6, 117.0, 123.7, 125.4, 125.5,
4. Experimental
4.1. General
127.6, 128.0, 128.4, 132.5, 136.4, 143.1, 160.0, 187.9; HRMS Calcd
for C18H15F3NO [M+H]+ 318.1106, found: 318.1111.
Unless otherwise noted, all experiments were carried out under
an inert atmosphere of dry nitrogen by using standard Schlenk-
type techniques, or performed in a nitrogen-filled glovebox. Com-
mercial reagents were used as received, unless otherwise stated.
All the reactions were monitored by TLC with silica gel coated
plates. Flash column chromatography was performed according
to standard technique. 1H and 13C NMR spectra were recorded on
a Bruker DRX-400 spectrometers with CDCl3 as the solvent and tet-
ramethylsilane (TMS) as a reference. Optical rotations were mea-
sured with a JASCOP-1010 polarimeter.
4.2.1.5. (Z)-2-(3,4-Dihydroquinolin-2(1H)-ylidene)-1-(4-iso pro-
pylphenyl)ethanone 1e. Yield 19%. 1H NMR (400 MHz, CDCl3):
d = 1.26 (s, 3H), 1.28 (s, 3H), 2.71 (t, J = 6.4 Hz, 2H), 2.86 (t,
J = 8.0 Hz, 2H), 2.94–2.97 (m, 1H), 5.86 (s, 1H), 6.92–6.97 (m,
2H), 7.08 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.28 (d,
J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 12.81 (br s, 1H); 13C NMR
(100 MHz, CDCl3): 23.8, 24.0, 24.5, 28.8, 34.3, 92.5, 116.8, 123.1,
125.2, 126.6, 127.4, 127.9, 128.3, 136.9, 137.6, 152.6, 158.6,
189.6; HRMS Calcd for C20H22NO [M+H]+ 292.1701, found:
292.1702.
4.2. Experimental procedures
4.2.1.6. (Z)-2-(3,4-Dihydroquinolin-2(1H)-ylidene)-1-o-tolyl
ethanone 1f. Yield 31%. 1H NMR (400 MHz, CDCl3): d = 2.50 (s, 3H),
2.66 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H), 5.48 (s, 1H), 6.96 (t,
J = 8.4 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 7.16–7.21 (m, 3H), 7.24–
7.29 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 12.64 (br s, 1H); 13C NMR
(100 MHz, CDCl3): 20.4, 24.4, 28.6, 96.6, 116.8, 123.2, 125.2,
125.6, 127.5, 127.9, 128.3, 129.4, 131.2, 136.1, 136.8, 141.7,
158.4, 194.9; HRMS Calcd for C18H18NO [M+H]+ 264.1388, found:
264.1395.
4.2.1. General procedure for the synthesis of exocyclic
enamines 1
Exocyclic enamines 1 can be prepared according to the known
literature.14a Exocyclic enamines 1 can also be prepared according
to the procedure as below: a mixture of [Ir(COD)Cl]2 (3.4 mg,
0.005 mmol) and (rac)-MeO-BiPhep (6.4 mg, 0.011 mmol) in
CH2Cl2 (4 mL) was stirred at room temperature for 10 min in a
glovebox, then the mixture was transferred by a syringe to stain-
less steel autoclave, in which I2 (12.8 mg, 0.05 mmol) and substrate
(1.0 mmol) were placed beforehand. The hydrogenation was per-
formed at room temperature under H2 (400 psi) for 14 h. After
carefully releasing the hydrogen, the reaction mixture was purified
by a silica gel column eluted with ethyl acetate/petroleum to give
pure products 1 (17–43%) and the corresponding tetrahydroquino-
line side products (which can be used as racemic compounds of 2).
4.2.1.7. (Z)-2-(3,4-Dihydroquinolin-2(1H)-ylidene)-1-(naphtha-
len-1-yl)ethanone 1g. Yield 20%.1H NMR (400 MHz, CDCl3):
d = 2.69 (t, J = 6.8 Hz, 2H), 2.87 (t, J = 7.6 Hz,2H), 5.65 (s, 1H), 6.98
(d, J = 7.2 Hz, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.18–7.20 (m, 1H),
7.45–7.53 (m, 3H), 7.68 (d, J = 7.2 Hz, 1H), 7.87 (t, J = 8.8 Hz, 2H),
8.48 (d, J = 8.4 Hz, 1H), 12.83 (br s, 1H); 13C NMR (100 MHz, CDCl3):
24.4, 28.6, 97.3, 116.9, 123.3, 124.9, 125.3, 125.6, 126.1, 126.8,
127.9, 128.4, 130.3, 130.4, 134.0, 136.7, 139.9, 158.7, 194.1; HRMS
Calcd for C21H18NO [M+H]+ 300.1388, found: 300.1390.
4.2.1.1. (Z)-2-(3,4-Dihydroquinolin-2(1H)-ylidene)-1-phenyl
ethanone 1a. Known compound.14a Yield 43%. 1H NMR (400 MHz,
CDCl3): d = 2.72 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 7.6 Hz, 2H), 5.87 (s,
1H), 6.95 (q, J = 8.0 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.18 (t,
J = 7.6 Hz, 1H), 7.41–7.47 (m, 3H), 7.91 (d, J = 6.8 Hz, 2H), 12.84 (br
s, 1H); 13C NMR (100 MHz, CDCl3): 24.4, 28.8, 92.6, 116.8, 123.3,
125.3, 127.3, 127.9, 128.4, 128.5, 131.3, 136.8, 139.9, 159.0, 189.7.
4.2.1.8. (Z)-1-(3,4-Dihydroquinolin-2(1H)-ylidene)-4-phenyl
butan-2-one 1h. Yield 18%. 1H NMR (400 MHz, CDCl3): d = 2.56 (t,
J = 6.8 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 2.97 (t,
J = 8.4 Hz, 2H), 5.15 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.93–6.95 (m,
1H), 7.05 (d, J = 7.2 Hz, 1H) 7.13–7.30 (m, 6H), 12.30 (br s, 1H);
13C NMR (100 MHz, CDCl3): 24.4, 28.3, 31.6, 44.0, 95.5, 116.5,
122.9, 125.0, 126.0, 127.8, 128.3, 128.5, 128.6, 136.9, 141.9,
157.3, 198.9; HRMS Calcd for C19H20NO [M+H]+ 278.1545, found:
278.1534.
4.2.1.2. (Z)-1-(3,4-Dihydroquinolin-2(1H)-ylidene)propan-2-
one 1b. Yield 18%. 1H NMR (400 MHz, CDCl3): d = 2.11 (s, 3H), 2.56
(t, J = 6.8 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 5.15 (s, 1H), 6.84 (d,
J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.14
(t, J = 7.6 Hz, 1H), 12.25 (br s, 1H); 13C NMR (100 MHz, CDCl3):
24.4, 28.2, 29.6, 96.0, 116.5, 122.8, 125.0, 127.8, 128.2, 136.9,
157.0, 197.4; HRMS Calcd for C12H14NO [M+H]+ 188.1075, found:
188.1082.
4.2.1.9. (Z)-2-(6-Fluoro-3,4-dihydroquinolin-2(1H)-ylidene)-
1-phenylethanone 1i. Yield 22%. 1H NMR (400 MHz, CDCl3):
d = 2.71 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 7.6 Hz,2H), 5.87 (s, 1H), 6.83
(d, J = 6.4 Hz, 1H), 6.88 (d, J = 6.4 Hz, 2H), 7.42–7.50 (m, 3H), 7.90
(d, J = 6.8 Hz, 2H), 12.89 (br s, 1H); 13C NMR (100 MHz, CDCl3):
24.6, 28.4, 92.5, 114.3 (d, J = 90.8 Hz), 115.1 (d, J = 91.2 Hz), 117.1
(d, J = 32.8 Hz), 127.0 (d, J = 30.8 Hz), 127.2, 128.5, 131.3, 132.9,
139.8, 157.6, 158.6, 160.0, 189.7; HRMS Calcd for C17H15NOF
[M+H]+ 268.1138, found: 268.1132.
4.2.1.3. (Z)-1-(3,4-Dihydroquinolin-2(1H)-ylidene)pentan-2-
one 1c. Yield 19%. 1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.6 Hz,
3H), 1.62–1.69 (m, 2H), 2.32 (t, J = 7.6 Hz, 2H), 2.55–2.59 (m, 2H),
2.80 (t, J = 8.0 Hz, 2H), 5.15 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.92
(t, J = 7.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H),
12.31 (br s, 1H); 13C NMR (100 MHz, CDCl3): 14.2, 19.3, 24.5,
28.3, 44.6, 95.6, 116.5, 122.8, 125.0, 127.8, 128.3, 137.0, 157.0,
200.6; HRMS Calcd for C14H18NO [M+H]+ 216.1388, found:
216.1380.
4.2.1.10. (Z)-2-(3,4-Dihydro-6-methylquinolin-2(1H)-ylidene)-
1-phenylethanone 1j. Yield 17%. 1H NMR (400 MHz, CDCl3):
d = 2.29 (s, 3H), 2.70 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H),
5.58 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 6.98 (d,
J = 8.0 Hz, 1H), 7.41–7.46 (m, 3H), 7.90 (d, J = 6.8 Hz, 2H), 12.85
(br s, 1H); 13C NMR (100 MHz, CDCl3): 21.0, 24.4, 28.9, 92.3,
116.7, 125.2, 127.2, 128.4, 128.5, 129.0, 131.2, 132.9, 134.3,
140.0, 159.1, 189.4; HRMS Calcd for C18H18NO [M+H]+ 264.1388,
found: 264.1395.
4.2.1.4. (Z)-1-(4-(Trifluoromethyl)phenyl)-2-(3,4-dihydroquin-
olin-2(1H)-ylidene)ethanone 1d. Yield 24%. 1H NMR (400 MHz,
CDCl3): d = 2.74 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 5.85 (s,
1H), 6.95–7.02 (m, 2H), 7.11 (d, J = 7.6 Hz, 1H), 7.18–7.25 (m, 1H),
7.68 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 12.89 (br s, 1H); 13C

X.-B. Wang et al. / Tetrahedron: Asymmetry 20 (2009) 1040–1045
1043
4.2.1.11. (Z)-Methyl 2-(3,4-dihydroquinolin-2(1H)-ylidene) ace-
tate (1k). Yield 19%. 1H NMR (400 MHz, CDCl3): d = 2.56 (t,
J = 6.8 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 3.68 (s, 3H), 4.67 (s, 1H),
6.67 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz,
1H), 7.12 (t, J = 7.6 Hz, 1H), 10.40 (br s, 1H); 13C NMR (100 MHz,
CDCl3): 24.7, 28.7. 50.5, 84.2, 115.7, 121.9, 124.2, 127.7, 128.2,
137.3, 156.5, 170.7; HRMS Calcd for C12H14NO2 [M+H]+ 204.1025,
found: 204.1027.
(400 MHz, CDCl3): d = 0.93 (t, J =7.4 Hz, 3H), 1.59–1.68 (m, 3H),
1.88–1.89 (m, 1H), 2.39(t, J = 7.4 Hz, 2H), 2.59–2.61 (m, 2H),
2.68–2.79 (m, 1H), 2.80–2.87 (m, 1H), 3.72–3.76 (m, 1H), 4.48 (br
s, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 6.92–6.97
(m, 2H); 13C NMR (100 MHz, CDCl3): 13.9, 17.3, 25.8, 28.1, 45.5,
47.0, 49.1, 114.8, 117.4, 121.0, 127.0, 129.3, 144.4, 210.9; HRMS
Calcd for C14H20NO [M+H]+ 218.1545, found: 218.1541; HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8
mL minꢁ1): t1 = 6.7 min; t2 = 7.5 min.
4.2.1.12. (Z)-N,N-Diethyl-2-(3,4-dihydroquinolin-2(1H)-ylidene)
acetamide 1l. Yield 25%. 1H NMR (400 MHz, CDCl3): d = 1.18–1.25
(m, 6H), 2.58 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 3.37 (br s,
4H), 4.78 (s, 1H), 6.67–6.83 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 7.09 (t,
J = 7.6 Hz, 1H), 11.50 (br s, 1H); 13C NMR (100 MHz, CDCl3): 13.7,
13.9, 25.2, 29.3, 83.8, 115.5, 120.8, 124.0, 127.5, 127.9, 137.9, 153.6,
169.5;HRMSCalcdforC15H21N2O[M+H]+ 245.1654, found:245.1647.
4.2.2.4. (R)-1-(4-(Trifluoromethyl)phenyl)-2-(1,2,3,4-tetrahydro-
quinolin-2-yl)ethanone 2d. Colorless oil, 94% ee, ½a D25
¼ ꢁ80:0 (c
ꢀ
1.12, CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.78–1.87 (m, 1H),
2.02–2.06 (m, 1H), 2.76–2.80 (m, 1H), 2.86–2.91 (m, 1H), 3.20 (d,
J = 6.0 Hz, 2H), 3.96–3.98 (m, 1H), 4.55 (br s, 1H), 6.49 (d, J = 8.2 Hz,
1H), 6.63 (t, J = 7.0 Hz, 1H), 6.96–6.99 (m, 2H), 7.73 (d, J = 7.7 Hz,
2H), 8.06 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): 25.7, 28.3,
45.6, 47.2, 114.9, 117.7, 121.0, 125.9, 126.2, 127.1, 128.6, 129.4,
134.7, 139.5, 144.2, 198.7; HRMS Calcd for C18H17NOF3 [M+H]+
320.1262, found: 320.1248; HPLC (OD-H column, n-hexane/2-propa-
nol = 80/20, flow rate = 0.8 mL minꢁ1): t1 = 10.1 min; t2 = 17.0 min.
4.2.1.13. (Z)-2-(3,4-Dihydroquinolin-2(1H)-ylidene)-1-(3,4-dime-
thoxyphenyl)ethanone 1m. Yield 28%. 1H NMR (400 MHz, CDCl3):
d = 2.72 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 7.6 Hz,2H), 3.93 (s, 3H), 3.96 (s,
3H), 5.85 (s, 1H), 6.87–6.93 (m, 3H), 6.95 (d, J = 7.2 Hz, 1H), 7.10 (t,
J = 7.6 Hz, 1H), 7.51–7.56 (m, 2H), 12.78 (br s, 1H); 13C NMR
(100 MHz, CDCl3): 24.5, 28.8, 56.1, 56.2, 92.1, 110.0, 110.3, 116.7,
120.8, 123.0, 125.1, 127.9, 128.3, 132.8, 136.8, 149.0, 151.9, 158.4,
188.6; HRMS Calcd for C19H20NO3 [M+H]+ 310. 1443, found: 310.1448.
4.2.2.5. (R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-(4-isopropyl
phenyl)ethanone 2e. Pale yellow oil, 95% ee, ½a D25
¼ ꢁ70:3 (c 1.32,
ꢀ
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.24–1.28 (m, 6H), 1.79–
1.82 (m, 1H), 1.99–2.03 (m, 1H), 2.74–2.79 (m, 1H), 2.84–2.98
(m, 2H), 3.13–3.15 (m, 2H), 3.90–3.93 (m, 1H), 4.58 (br s, 1H),
6.47 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 6.94 (m, 2H), 7.30
(d, J = 7.9 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 23.8, 25.9, 28.4, 34.4, 45.1, 47.4, 114.9, 117.4, 121.0,
126.9, 127.0, 128.5, 128.7, 129.3, 134.9, 144.5, 155.1, 199.3; HRMS
Calcd for C20H24NO [M+H]+ 294.1858, found: 294.1855; HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8
mL minꢁ1): t1 = 7.5 min; t2 = 9.7 min.
4.2.2. Typical procedure for the Ir-catalyzed asymmetric
hydrogenation of exocyclic enamines 1
A mixture of [Ir(COD)Cl]2 (0.9 mg, 0.00125 mmol) and (S)-MeO-
Biphep (1.6 mg, 0.00275 mmol) in benzene (2 mL) was stirred at
room temperature for 10 min in a glovebox, then the mixture
was transferred by a syringe to stainless steel autoclave, in which
I2 (3.2 mg, 0.0125 mmol) and substrate (0.125 mmol) were placed
beforehand. The hydrogenation was performed at room tempera-
ture under H2 (600 psi) for 16 h. After carefully releasing the
hydrogen, the reaction mixture was purified by a silica gel column
eluted with petroleum/EtOAc to give pure product. The enantio-
meric excesses were determined by chiral HPLC with chiral col-
umns (OD-H, OJ-H and AD-H).
4.2.2.6. (R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-o-tolyl-etha-
none (2f). Pale yellow oil, 96% ee, ½a D25
¼ ꢁ94:9 (c 1.06, CHCl3);
ꢀ
1H NMR (400 MHz, CDCl3): d = 1.77–1.80 (m, 1H), 1.97–2.01
(m, 1H), 2.52 (s, 3H), 2.73–2.78 (m, 1H), 2.83–2.87 (m, 1H),
3.10 (d, J = 6.3 Hz, 2H), 3.89–3.92 (m, 1H), 4.57 (br s, 1H), 6.49
(d, J = 7.8 Hz, 1H), 6.61 (t, J = 7.3 Hz, 1H), 6.94–6.98 (m, 2H),
7.24–7.27 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.64 (d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): 21.6, 25.8, 28.3, 47.6, 47.9,
114.9, 117.4, 121.1, 125.9, 127.0, 128.8, 129.4, 131.8, 132.3,
137.7, 138.4, 144.4, 203.7; HRMS Calcd for C18H20NO [M+H]+
266.1545, found: 266.1537; HPLC (OD-H column, n-hexane/2-
4.2.2.1. (R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-phenyletha-
none 2a. Pale yellow oil, 96% ee, ½a D25
ꢀ
¼ ꢁ96:6 (c 0.54, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 1.80–1.84 (m, 1H), 2.00–2.04 (m, 1H),
2.74–2.80 (m, 1H), 2.84–2.88 (m, 1H), 3.16–3.18 (m, 2H), 3.92–
3.96 (m, 1H), 4.58 (br s, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.61 (t,
J = 7.4 Hz, 1H), 6.96 (t, J = 7.2 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.57
(t, J = 7.0 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 25.8, 28.4, 45.2, 47.3, 114.9, 117.4, 121.0, 127.0, 128.2,
128.8, 129.4, 133.6, 137.0, 144.4, 199.6; HRMS Calcd for C17H17NO-
Na [M+Na]+ 274.1208, found: 274.1204; HPLC (OD-H column, n-
propanol = 80/20,
flow
rate = 0.8 mL minꢁ1):
t1 = 8.1 min;
t2 = 9.0 min.
4.2.2.7. (R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-(naphthalen-
hexane/2-propanol = 80/20,
flow
rate = 0.8 mL minꢁ1):
1-yl)ethanone 2g. Colorless oil, 96% ee, ½a D25
¼ ꢁ145:7 (c 1.12,
ꢀ
t1 = 8.8 min; t2 = 10.6 min.
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.79–1.85 (m, 1H), 2.00–
2.04 (m, 1H), 2.74–2.80 (m, 1H), 2.84–2.90 (m, 1H), 3.25–3.27
(m, 2H), 3.98–4.02 (m, 1H), 4.65 (br s, 1H), 6.51 (d, J = 7.8 Hz,
1H), 6.63 (t, J = 7.3 Hz, 1H), 6.95–6.99 (m, 2H), 7.46–7.53(m, 2H),
7.55–7.62 (m, 1H), 7.87 (d, J = 7.0 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H),
8.64 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): 25.8, 28.3,
47.9, 48.5, 114.9, 117.5, 121.1, 124.5, 125.8, 126.7, 127.0, 128.1,
128.3, 128.7, 129.4, 130.2, 133.2, 134.1, 135.7, 144.4, 203.9; HRMS
Calcd for C21H20NO [M+H]+ 302.1545, found: 302.1556; HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8
mL minꢁ1): t1 = 14.7 min; t2 = 18.9 min.
4.2.2.2. (R)-1-(1,2,3,4-Tetrahydroquinolin-2-yl)propan-2-one
2b. Pale yellow oil, 94% ee, ½a D25
ꢀ
¼ ꢁ87:3 (c 1.06, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 1.63–1.72 (m, 1H), 1.88–1.91 (m, 1H), 2.17
(s, 3H), 2.64–2.72 (m, 3H), 2.79–2.84 (m, 1H), 3.72–3.75 (m, 1H),
4.44 (br s, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.60 (t, J = 7.1 Hz, 1H),
6.92–6.97 (m, 2H); 13C NMR (100 MHz, CDCl3): 25.7, 28.0, 30.7,
47.0, 50.0, 114.8, 117.5, 121.0, 127.0, 129.3, 144.3, 208.6; HRMS
Calcd for C12H15NONa [M+Na]+ 212.1051, found: 212.1056; HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8 -
mL minꢁ1): t1 = 8.6 min; t2 = 9.5 min.
4.2.2.8. (R)-1-(1,2,3,4-Tetrahydroquinolin-2-yl)-4-phenylbutan
4.2.2.3. (R)-1-(1,2,3,4-Tetrahydroquinolin-2-yl)pentan-2-one
-2-one 2h. Colorless oil, 90% ee, ½a D25
ꢀ
¼ ꢁ57:8 (c 1.12, CHCl3); 1H
2c. Colorless oil, 85% ee, ½a D25
ꢀ
¼ ꢁ93:1 (c 1.01, CHCl3); 1H NMR
NMR (400 MHz, CDCl3): d = 1.64–1.66 (m, 1H), 1.86–1.89 (m, 1H),

1044
X.-B. Wang et al. / Tetrahedron: Asymmetry 20 (2009) 1040–1045
2.59–2.60 (m, 2H), 2.66–2.81 (m, 4H), 2.89–2.93 (m, 2H), 3.73–3.75
(m, 1H), 4.41 (br s, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.61 (t, J = 7.6 Hz,
1H), 6.94 (m, 2H), 7.17–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3):
25.7, 28.1, 29.8, 45.0, 47.0, 49.4, 114.9, 117.5, 121.0, 126.4, 127.0,
128.5, 128.7, 129.4, 140.9, 144.3, 209.8; HRMS Calcd for
Calcd for C19H22NO3 [M+H]+ 312.1600, found: 312.1605; HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8
mL minꢁ1): t1 = 18.2 min; t2 = 23.6 min.
4.2.3. (S)-2-(3,4-Dimethoxyphenethyl)-1,2,3,4-tetrahydro-
quinoline 3. Compound 3 was prepared according to the litera-
ture.14b To a stirred solution of 2m (74 mg, 0.25 mmol) in 1.0 mL
trifluoroacetic acid, triethylsilane (1.78 mmol) was added drop-
wise. After the addition, the solution was stirred for 24 h at room
temperature. The reaction mixture was evaporated to give the
crude product. The crude product was dissolved in CH2Cl2 and then
washed with three 10 mL portions of 1 N KOH. The solution was
dried over potassium carbonate and was evaporated in vacuo. Puri-
fication was performed by a silica gel column eluted with ethyl
acetate/petroleum to give the product 3 with 47% yield and recov-
C19H22NO
[M+H]+
280.1701,
found:
280.1689;
HPLC
(OD-H column, n-hexane/2-propanol = 80/20, flow rate = 0.8
mL minꢁ1): t1 = 13.7 min; t2 = 18.0 min.
4.2.2.9. (R)-2-(6-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)-1-phe-
nylethanone 2i. Pale yellow oil, 96% ee, ½a D25
¼ ꢁ48:9 (c 0.50,
ꢀ
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.78–1.81 (m, 1H), 1.99–
2.02 (m, 1H), 2.72–2.77 (m, 1H), 2.84–2.88 (m, 1H), 3.11–3.22
(m, 2H), 3.87–3.91 (m, 1H), 4.51 (br s, 1H), 6.40 (m, 1H), 6.66–
6.70 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.96
(d, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): 26.1, 28.2, 45.0,
47.6, 113.4, 113,7, 115.3, 115.6, 115.7, 128.2, 128.9, 133.6, 136.9,
140.6, 157.0, 199.6; HRMS Calcd for C17H17NOF [M+H]+ 270.1294,
found: 270.1286; HPLC (OD-H column, n-hexane/2-propa-
nol = 80/20, flow rate = 0.8 mL minꢁ1): t1 = 8.8 min; t2 = 9.3 min.
ered starting material 2m (45%). 94% ee, ½a D25
¼ ꢁ59:9 (c 1.00,
ꢀ
CHCl3); 1H NMR (400 MHz, CDCl3) 1.65 (m, 1H), 1.81 (m, 2H),
1.98 (m, 1H), 2.67 (m, 4H), 2.77 (m, 1H), 3.28 (m, 1H), 3.85 (s,
3H), 3.86 (s, 3H), 6.44 (d, J = 8.0 Hz, 1H), 6.59 (m, 1H), 6.74 (m,
3H), 6.94 (m, 2H); 13C NMR (100 MHz, CDCl3): 26.6, 28.5, 32.3,
38.8, 51.7, 56.3, 56.4, 111.8, 112.1, 114.6, 117.5, 120.6, 121.7,
127.2, 129.7, 134.9, 144.9, 147.8, 149.4; HPLC (OD-H, n-hexane/
2-propanol = 80/20, 0.8 mL minꢁ1), t1 = 14.6 min, t2 = 16.9 min.
4.2.2.10. (R)-2-(1,2,3,4-Tetrahydro-6-methylquinolin-2-yl)-1-
phenylethanone 2j. Colorless oil, 90% ee, ½a D25
¼ ꢁ48:7 (c 0.34,
ꢀ
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.79–1.83 (m, 1H), 1.99–
2.03 (m, 1H), 2.20 (s, 3H), 2.72–2.77 (m, 1H), 2.82–2.86 (m, 1H),
3.16–3.18 (m, 2H), 3.90–3.92 (m, 1H), 4.45 (br s, 1H), 6.42 (d,
J = 3.6 Hz, 1H), 6.77 (d, J = 6.3 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.58
(t, J = 7.4 Hz, 1H), 7.95 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 20.6, 25.8, 28.6, 45.1, 47.5, 115.1, 121.1, 126.7, 127.6,
128.2, 128.8, 129.9, 133.5, 137.0, 142.0, 199.7; HRMS Calcd for
C18H20NO [M+H]+ 266.1545, found: 266.1547; HPLC (OD-H col-
umn, n-hexane/2-propanol = 80/20, flow rate = 0.8 mL minꢁ1):
t1 = 8.2 min; t2 = 8.8 min.
4.2.4. (S)-Cuspareine 4. To a stirred solution of (S)-2-(3,4-dimethoxy-
phenethyl)-1,2,3,4-tetrahydroquinoline (74 mg, 0.25 mmol) and 0.2 mL
(2.5 mmol) of 37% aqueous formaldehyde in 2.5 mL of acetonitrile was
added 48 mg of sodium cyanoborohydride. Glacial acetic acid (250 lL)
was added, and the reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was poured into 30 mL of ether and
then washed with three 10 mL portions of 1 N KOH and one portion of
brine. The ether solution was dried over potassium carbonate and evap-
orated in vacuo to give crude product as a yellow oil, purification was
performed by a silica gel column eluted with ethyl acetate/petroleum
13C
4.2.2.11. (R)-Methyl 2-(1,2,3,4-tetrahydroquinolin-2-yl)acetate
2k, known compound, see: Ref 3. Colorless oil, 89% ee,
to give pure (S)-cuspareine (76 mg, 98% yield).
½
a 2D5
ꢀ
¼ ꢁ27:2 (c 0.87,
CHCl3); 1H NMR (400 MHz, CDCl3) 1.78 (m, 1H), 1.98 (m, 3H), 2.57 (m,
1H), 2.69 (m, 2H), 2.83 (m, 1H), 2.94 (s, 3H), 3.31 (m, 1H), 3.88 (s, 3H),
3.90 (s, 3H), 6.58 (d, J = 8.2 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H), 6.78 (m,
2H), 6.84 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): 23.8, 24.6, 32.1, 33.3, 38.3, 56.1, 56.2,
58.6, 110.8, 11.5, 111.8, 115.6, 120.3, 121.9, 127.3, 128.9, 134.9, 145.5,
147.4, 149.1.
½
a 2D5
ꢀ
¼ ꢁ77:2 (c 0.74, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 1.68–1.74 (m, 1H), 1.93–1.97 (m, 1H), 2.51–2.52 (m, 2H),
2.69–2.75 (m, 1H), 2.79–2.83 (m, 1H), 3.68–3.74 (m, 4H), 4.46 (br
s, 1H), 6.49 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 6.93–6.98
(m, 2H); 13C NMR (100 MHz, CDCl3): 25.7, 28.1, 40.8, 47.9, 51.9,
114.7, 117.5, 121.0, 127.0, 129.4, 144.1, 172.9; HPLC (OD-H col-
umn, n-hexane/2-propanol = 90/10, flow rate = 0.8 mL minꢁ1):
t1 = 9.8 min; t2 = 11.0 min.
Acknowledgments
4.2.2.12. (R)-N,N-Diethyl-2-(1,2,3,4-tetrahydroquinolin-2-yl)-
We are grateful for the financial support from National Natural
Science Foundation of China (20621063 and 20672112) and Chi-
nese Academy of Sciences.
acetamide 2l. Colorless oil, 78% ee, ½a D25
ꢀ
¼ ꢁ69:8 (c 1.00, CHCl3); 1H
NMR (400 MHz, CDCl3): d = 1.10–1.17 (m, 6H), 1.70 (m, 1H), 1.92
(m, 1H), 2.48 (m, 2H), 2.72 (m, 1H), 2.85 (m, 1H), 3.24–3.31 (m,
2H), 3.35–3.41 (m, 2H), 3.75–3.76 (m, 1H), 4.97 (br s, 1H), 6.48
(d, J = 7.8 Hz, 1H), 6.58 (t, J = 7.4 Hz, 1H), 6.91–6.96 (m, 2H); 13C
NMR (100 MHz, CDCl3): 13.2, 14.2, 26.0, 28.5, 39.6, 40.1, 41.9,
48.1, 114.8, 117.0, 121.0, 126.8, 129.1, 144.7, 170.6; HRMS Calcd
for C15H22N2ONa [M+Na]+ 269.1630, found: 269.1624; HPLC
(OJ-H column, n-hexane/2-propanol = 90/10, flow rate = 0.8
mL minꢁ1): t1 = 11.9 min; t2 = 15.3 min.
References
1. (a) Drey, C. N. In Chemistry and Biochemistry of the Amino Acids; Barrett, G. C.,
Ed.; Chapman and Hall: New York, 1985. Chapter 3; (b) Spzatola, A. F. In
Weinstein, B., Ed.; Chemistry and Biochemistry of Amino Acids, Peptides and
Proteins; Marcel Dekker: New York, 1983; Vol. 7, p 331; (c) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173.
2. (a) Tang, W.-J.; Zhang, X. Chem. Rev. 2003, 103, 3029; (b) You, J.; Drexler, H.;
Zhang, S.; Fischer, C.; Heller, D. Angew. Chem., Int. Ed. 2003, 42, 913; (c) Zhou, Y.-
G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952;
(d) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570; (e) Drexel, H.;
You, J.; Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.; Heller, D. Org.
Process Res. Dev. 2003, 7, 355.
3. (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543;
(b) Halpern, J. Science 1982, 217, 401.
4. Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985.
5. Taraov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Börner, A. Tetrahedron Lett.
2000, 41, 2351.
4.2.2.13. (R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-(3,4-dimeth-
oxyphenyl)ethanone 2m. Yellow oil, 94% ee, ½a D25
¼ ꢁ53:9 (c 1.21,
ꢀ
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.79–1.83 (m, 1H), 1.99–
2.04 (m, 1H), 2.75–2.80 (m, 1H), 2.84–2.88 (m, 1H), 3.12–3.14 (m,
2H), 3.91–3.96 (m, 7H), 4.57 (br s, 1H), 6.47 (d, J = 8.4 Hz, 1H),
6.61(t, J = 7.2 Hz, 1H), 6.86 (dd, J = 2.0, 8.4 Hz, 1H), 6.94–6.98 (m,
2H), 7.53–7.55 (m, 1H), 7.55–7.60 (m, 1H); 13C NMR (100 MHz,
CDCl3): 25.8, 28.4, 44.6, 47.6, 56.1, 56.2, 110.1, 11.0.2, 114.8, 117.4,
121.0, 123.0, 127.0, 129.3, 130.3, 144.4, 149.2, 153.7, 198.2; HRMS
6. Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.;
Armstrong, J. D., III; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am.
Chem. Soc. 2004, 126, 9918.

X.-B. Wang et al. / Tetrahedron: Asymmetry 20 (2009) 1040–1045
1045
7. Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343.
26, 737; (e) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. J. Organomet. Chem. 2007, 692,
3065; (f) Wang, D.-W.; Zeng, W.; Zhou, Y.-G. Tetrahedron: Asymmetry 2007, 18,
1103; (g) Wang, X.-B.; Zhou, Y.-G. J. Org. Chem. 2008, 73, 5640; (h) Yang, P.-Y.;
Zhou, Y.-G. Tetrahedron: Asymmetry 2004, 15, 1145; (i) Wang, Y.-Q.; Lu, S.-M.;
Zhou, Y.-G. Org. Lett. 2005, 7, 3235; (j) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006,
1189; (k) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729; (l)
Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10,
2071; (m) Wang, D.-W.; Lu, S.-M.; Zhou, Y.-G. Tetrahedron Lett. 2009, 50, 1282;
(n) Wang, D.-W.; Wang, X.-B.; Wang, D.-S.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem.
2009, 74, 2780.
8. (a) Hou, G.-H.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128,
11774; (b) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009,
131, 1366; (c) Donoghue, P. J.; Helquist, P.; Norrby, P.-O.; Wiest, O. J. Am. Chem.
Soc. 2009, 131, 410; (d) Cheruku, P.; Church, T. L.; Trifonova, A.; Wartmann, T.;
Andersson, P. G. Tetrahedron Lett. 2008, 49, 7290.
9. For recent reviews on the hydrogenation of aromatic compounds, see: (a)
Glorius, F. Org. Biomol. Chem. 2005, 3, 4171; (b) Lu, S.-M.; Han, X.-W.; Zhou, Y.-
G. Chin. J. Org. Chem. 2005, 25, 634; (c) Dyson, P. J. Dalton Trans. 2003, 2964; (d)
Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357; (e) Kuwano, R. Hetereocycles 2008,
76, 909.
12. For other group’s work on asymmetric hydrogenation of quinolines, see: (a) Xu,
L. J.; Lam, K. H.; Ji, J. X.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C. Chem. Commun.
2005, 1390; (b) Lam, K. H.; Xu, L. J.; Feng, L. C.; Fan, Q.-H.; Lam, F. L.; Lo, W.-H.;
Chan, A. S. C. Adv. Synth. Catal. 2005, 347, 1755; (c) Wu, J.; Chan, A. S. C. Acc.
Chem. Res. 2006, 39, 711; (d) Tang, W.-J.; Zhu, S.-F.; Xu, L.-J.; Zhou, Q.-L.; Fan,
Q.-H.; Zhou, H.-F.; Lam, K.; Chan, A. S. C. Chem. Commun. 2007, 613; (e) Chan,
S.-H.; Lam, K.-H.; Li, Y.-M.; Xu, L.-J.; Tang, W.-J.; Lam, F.-L.; Lo, W.-H.; Yu, W.-Y.;
Fan, Q.-H.; Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 2625; (f) Reetz, M.
T.; Li, X.-G. Chem. Commun. 2006, 12, 2159; (g) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam,
W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem.
Soc. 2006, 128, 5955; (h) Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.;
Fan, Q.-H. Org. Lett. 2007, 9, 1243; (i) Li, Z.-W.; Wang, T.-L.; He, Y.-M.; Wang, Z.-
J.; Fan, Q.-H.; Pan, J.; Xu, L.-J. Org. Lett. 2008, 10, 5265; (j) Zhou, H.-F.; Li, Z.-W.;
Wang, Z.-J.; Wang, T.-L.; Xu, L.-J.; He, Y.-M.; Fan, Q.-H.; Pan, J.; Gu, L.-Q.; Chan,
A. S. C. Angew. Chem., Int. Ed. 2008, 47, 8464; (k) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683; (l) Rueping, M.;
Theissmann, T.; Antonchick, A. P. Synlett 2006, 1071; (m) Rueping, M.;
Theissmann, T.; Raja, S.; Bats, J. W. P. Adv. Synth. Catal. 2008, 350, 1001; (n)
Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759; (o) Lu, S.-M.;
Bolm, C. Adv. Synth. Catal. 2008, 350, 1101; (p) Mrsic, N.; Lefort, L.; Boogers, J. A.
F.; Minnaard, A. J.; Feringa, B. L.; Vries, J. G. Adv. Synth. Catal. 2008, 350, 1081;
(q) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka, Y.;
Ratovelomanana-Vidal, V.; Genet, J. P.; Mashima, K. Organometallics 2006, 25,
2505; (r) Jahjah, M.; Alame, M.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron:
Asymmetry 2007, 18, 2305; (s) Deport, C.; Buchotte, M.; Abecassis, K.; Tadaoka,
H.; Ayad, T.; Ohshima, T.; Genet, J.-P.; Mashima, K.; Ratovelomanana-Vidal, V.
Synlett 2007, 2743; (t) Fache, F. Synlett 2004, 2827; (u) Fujita, K.-I.; Kitatsuji, C.;
Furukawa, K.; Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215; (v) You, S.-L.
Asian J. Chem. 2007, 2, 820.
10. For the asymmetric hydrogenation of quinoxalines, see: (a) Bianchini, C.;
Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M. Organometallics 1998,
17, 3308; (b) Henschke, J. P.; Burk, M. J.; Malan, C. G.; Herzberg, D.;
Peterson, J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G. Adv. Synth. Catal.
2003, 345, 300; For some examples on asymmetric hydrogenation of
indole derivatives: (c) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito,
Y. J. Am. Chem. Soc. 2000, 122, 7614; (d) Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213; (e) Kuwano, R.;
Kashiwabara, M. Org. Lett. 2006, 8, 2653; (f) Kuwano, R.; Kashiwabara,
M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17,
521; For the asymmetric hydrogenation of pyridine derivatives: (g)
Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W.
Angew. Chem., Int. Ed. 2004, 43, 2850; (h) Legault, C. Y.; Charette, A. B.
J. Am. Chem. Soc. 2005, 127, 8966; (i) Lei, A.-W.; Chen, M.; He, M.-S.;
Zhang, X.-M. Eur. J. Org. Chem. 2006, 4343; (j) Studer, M.; Wedemeyer-
Exl, C.; Spindler, F.; Blaser, H.-U. Monatsh. Chem. 2000, 131, 1335; (k)
Blaser, H.-U.; Hornig, H.; Studer, M.; Wedemeyer-Exl, C. J. Mol. Catal. A:
Chem. 1999, 139, 253; (l) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson,
B. F. G.; Bell, R. G.; Mantle, M. D. Chem. Commun. 2000, 1925; (m)
Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562; (n)
Wang, X.-B.; Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2008, 49, 4922; (o)
Legault, C. Y.; Charette, A. B.; Cozzi, P. G. Hetereocycles 2008, 76, 1271;
For the asymmetric hydrogenation of furans: (p) Ohta, T.; Miyake, T.;
Seido, N.; Kumobayashi, H.; Takaya, H. J. Org. Chem. 1995, 60, 357; (q)
Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45, 5194;
(r) Feiertag, P.; Albert, M.; Nettekoven, U.; Spindler, F. Org. Lett. 2006, 8,
4133; For the asymmetric hydrogenation of pyrrole: (s) Kuwano, R.;
Kashiwabara, M.; Ohsumi, M.; Kusano, H. J. Am. Chem. Soc. 2007, 129,
808.
13. (a) Katayama, S.; Ae, N.; Nagata, R. Tetrahedron: Asymmetry 1998, 9, 4295; (b)
Houghton, P. J.; Woldemariam, T. Z.; Watanabe, Y.; Yates, M. Planta Med. 1999,
65, 250; (c) Rakotoson, J. H.; Fabre, N.; Jacquemond-Collet, I.; Hannedouche, S.;
Fouraste, I.; Moulis, C. Planta Med. 1998, 64, 762.
14. (a) Greenhill, V.; Loghmani-Khouzani, H. Tetrahedron 1988, 44, 3319; (b) Ma, T.;
Kojima, T.; Matsuda, Y. Bull. Chem. Soc. Jpn. 2000, 73, 747.
11. For our work on asymmetric hydrogenation of quinolines and imines, see: (a)
Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc.
2003, 125, 10536; (b) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. Adv. Synth. Catal. 2004,
346, 909; (c) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int.
Ed. 2006, 45, 2260; (d) Zhao, Y.-J.; Wang, Y.-Q.; Zhou, Y.-G. Chin. J. Catal. 2005,