Asymmetric synthesis of tetrahydroquinolines with quaternary stereocenters through the Povarov reaction

Article abstract of DOI:10.1002/chem.201102333

The asymmetric Povarov reaction with α-alkyl styrenes as dienophiles was catalyzed by an N,N′-dioxide L4-Sc(OTf)₃ complex. Enantiopure tetrahydroquinoline derivatives with a quaternary stereocenter at the C4 position were synthesized for the fi

Full text of DOI:10.1002/chem.201102333

DOI: 10.1002/chem.201102333
Asymmetric Synthesis of Tetrahydroquinolines with Quaternary
Stereocenters through the Povarov Reaction
Mingsheng Xie, Xiaohua Liu, Yin Zhu, Xiaohu Zhao, Yong Xia, Lili Lin, and
Xiaoming Feng*[a]
Abstract: The asymmetric Povarov re-
action with a-alkyl styrenes as dieno-
philes was catalyzed by an N,N’-dioxide
reaction, to give excellent diastereo-
(up to 99:1 d.r.) and enantioselectivi-
ties (92 to >99% ee). In addition, the
reaction could be performed on the
gram scale without any loss of yield,
diastereoselectivity, or enantioselectivi-
ty. An intermolecular hydrogen-shift
reaction was found to be a side reac-
tion, which offered a method to synthe-
size the corresponding quinoline deriv-
atives with chiral quaternary sterocen-
ters.
L4–Sc
ACHTUNGTRENNUNG(OTf)3 complex. Enantiopure tet-
rahydroquinoline derivatives with
a
quaternary stereocenter at the C4 posi-
tion were synthesized for the first time.
A wide variety of a-alkyl styrenes and
N-aryl aldimines were tolerated in the
Keywords: asymmetric catalysis
·
dioxides · Povarov reaction · scandi-
um · tetrahydroquinolines
Introduction
binaphthol–ytterbium complexes.[8] Subsequently, great en-
deavors have been devoted toward asymmetric Povarov re-
actions with various dienophiles.[9] In 2006, Akiyama and co-
workers reported the reaction with vinyl ethers as dieno-
philes promoted by a chiral phosphoric acid.[9b] Later, ene-
carbamates and vinylindoles were used as dienophiles in re-
actions with chiral phosphoric acids as catalysts by Zhu and
Massonꢀs group[9c] and Bernardi and Ricciꢀs group,[9d] respec-
tively. In 2010, Jacobsenꢀs group reported the Povarov reac-
tion with vinyl ethers, enecarbamates and enamides as dien-
ophiles through cooperative catalysis of strong Brønsted
acids with chiral ureas.[9e] Very recently, Jørgensen and co-
workers developed an intramolecular Povarov reaction cata-
lyzed by a prolinol silyl ether.[9h] However, the previous
studies could only afford chiral tetrahydroquinolines with a
tertiary stereocenter at the C4 position, and the construction
of chiral tetrahydroquinolines with a quaternary stereocen-
ter at the C4 position remains unreported.[10]
The asymmetric construction of molecules with quaternary
carbon stereocenters represents a highly challenging area in
organic synthesis.[1] Tetrahydroquinoline derivatives bearing
a quaternary carbon center at the C4 position exhibit poten-
tial biological activities. Representative examples[2] are
shown in Scheme 1. The Povarov reaction,[3] an inverse elec-
Scheme 1. Examples of biologically active tetrahydroquinoline deriva-
tives bearing a quaternary carbon center at the C4 position.
With a-alkyl styrenes as dienophiles, the corresponding
tetrahydroquinoline adducts can be oxidized into quinoline-
3-one derivatives with the quaternary carbon center main-
tained;[11] comparatively, tetrahydroquinolines with the C4
position as a tertiary stereocenter would be converted into
quinolines[12] (Scheme 2). With the consideration that tetra-
hydroquinolines with the C4 position as a quaternary stereo-
center potentially exhibit biological activities, an effective
catalyst for this Povarov reaction is highly desirable. As ex-
cellent chiral scaffolds, N,N’-dioxide ligands[13] can coordi-
nate with various metals and have shown strong asymmetry-
inducing capability for many reactions, including the Povar-
ov reaction of cyclopentadiene.[9f] In an effort to develop a
practical approach toward the structural class of tetrahydro-
quinolines, we have expanded the scope of the asymmetric
Povarov reaction of a-alkyl styrenes. Herein, we report the
asymmetric synthesis of optically active tetrahydroquinoline
tron-demand aza Diels–Alder reaction[4–7] of N-aryl imines
(2-azadienes) with electron-rich alkenes (dienophiles), is
one of the most efficient routes to construct this kind of
privileged backbone. In 1996, Ishitani and Kobayashi devel-
oped the first catalytic asymmetric Povarov reaction with cy-
clopentadiene and vinyl ethers as dienophiles by using chiral
[a] M. S. Xie, Prof. Dr. X. H. Liu, Y. Zhu, X. H. Zhao, Y. Xia,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P. R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102333.
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Chem. Eur. J. 2011, 17, 13800 – 13805

FULL PAPER
Table 1. Screening of central metal ions in the asymmetric Povarov reac-
tion of N-aryl imine 4a and a-methylstyrene (5a).[a]
Entry
Metal
salt
Yield
[%][b]
trans/cis[c]
ee
[%][c]
1
2
3
4
5
6
7
8
Mg
Cu(OTf)2
Yb(OTf)3
(OTf)3
La(OTf)3
(OTf)3
(OiPr)3
(OTf)3
(OTf)3
Nd(OTf)3
(OTf)2
trace
trace
5
16
5
37
trace
20
ACHTUNGTRENNUNG
Scheme 2. The Povarov reaction and the oxidation of the products.
G
25/75
26/74
26/74
49/51
0
0
0
Y
E
G
derivatives with a quaternary stereocenter catalyzed by an
Sc
Sc
Ce
Pr
G
30
N,N’-dioxide–ScACHTUNGTRENNUNG
(OTf)3 complex[14] in good yields and with
R
N
26/74
27/73
0
0
excellent diastereoselectivities (up to 99:1 d.r.) and enantio-
selectivities (92 to >99% ee). The side reactions occurring
in the process were also studied in detail.
9
10
A
6
E
trace
[a] Unless otherwise noted, all reactions were carried out with 10 mol%
of L1/metal (1/1), 4a (0.2 mmol), and 5a (7.5 equiv, 200 mL) in CH2Cl2
(1.0 mL) under N2 at 308C for 22 h. [b] Yield of isolated product. [c] De-
termined by chiral HPLC analysis; the trans isomer was confirmed by
1H NMR spectroscopy; the ee value refers to the trans isomer.
Results and Discussion
Initially, l-pipecolic acid derived N,N’-dioxide L1
(Scheme 3) was complexed with various metal salts to cata-
lyze the Povarov reaction of N-aryl imine 4a with a-methyl-
Table 2. Screening of ligand and solvent effects in the asymmetric Povar-
ov reaction of N-aryl imine 4a and a-methylstyrene (5a).[a]
Entry
L
Solvent
Yield
[%][b]
trans/cis[c]
ee
[%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L4
L4
L4
L4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CHCl3
ClCH2CH2Cl
Cl2CHCH2Cl
37
27
32
39
trace
10
18
49/51
74/26
73/27
95/5
30
80
89
96
Scheme 3. Chiral ligands employed for the Povarov reaction.
styrene (5a) in CH2Cl2 at 308C. The central metal ion was
found to significantly affect the enantioselectivity of the re-
93/7
91/9
89/11
86
91
83
action. As shown in Table 1, when Mg
were tested, trace amounts of tetrahydroquinoline 6a were
obtained (Table 1, entries 1 and 2). Yb(OTf)3, Y(OTf)3, and
La(OTf)3 gave the racemic tetrahydroquinoline 6a in poor
yields with the cis isomer as the major product (Table 1, en-
tries 3–5). When Sc(OTf)3 was tested as the metal salt,
ACHUTNGTRNENUG(OTf)2 or CuACHTUGNTERN(NUNG OTf)2
17
[a] Unless otherwise noted, all reactions were carried out with 10 mol%
of L/Sc(OTf)3 (1/1), 4a (0.2 mmol), and 5a (7.5 equiv, 200 mL) in solvent
(1.0 mL) under N2 at 308C for 22 h. [b] Yield of isolated product. [c] De-
termined by chiral HPLC analysis; the trans isomer was confirmed by
1H NMR spectroscopy; the ee value refers to the trans isomer.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
nearly equal amounts of the cis and trans isomers were ob-
tained with 37% yield of the total products 6a and 30% ee
for the trans isomer (Table 1, entry 6). In addition, the coun-
L2 with bulkier isopropyl groups, could raise the diastereo-
selectivity and enantioselectivity of the trans product (74:26
d.r. and 80% ee; Table 2, entry 2 versus entry 1). Further-
more, the l-ramipril derived N,N’-dioxide L4 exhibited su-
perior stereoselectivity (95:5 d.r. and 96% ee) compared
with the l-proline and l-pipecolic acid derived ones, and it
afforded the best results (Table 2, entry 4 versus entries 2
and 3). On the encouraging basis of these initial results, vari-
terion also affected the reactivity greatly, and ScACHTNUTRGNEUNG(OiPr)3
gave trace amounts of tetrahydroquinoline 6a (Table 1,
entry 7 versus entry 6). Other lanthanide metal salts were
also employed, but no better results were obtained (Table 1,
entries 8–10). As a result, ScACHTNUGTRENUNG(OTf)3 was selected as the
metal salt for the further examination.
Further optimization of the reaction conditions was aimed
at exploring the effect of complexes of other N,N’-dioxide li-
ous solvents were tested in the presence of L4–ScACHTUNGTRENNUNG(OTf)3
(Table 2, entries 5–8). Tetrahydrofuran reduced the catalytic
activity greatly, and only traces of product 6a were observed
(Table 2, entry 5). When chloroform, 1,2-dichloroethane,
gands with Sc
ACHTUNGTRENNUNG(OTf)3 (Table 2). An increase in the steric hin-
drance of the amide subunits of the N,N’-dioxide, such as in
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X. M. Feng et al.
Table 4. The scope of 2-azadienes 4 tolerated in the asymmetric Povarov
and 1,1,2-trichloroethane were used as solvents, excellent
diastereoselectivities and enantioselectivities could also be
obtained, but the yields were low (Table 2, entries 6–8).
Therefore, CH2Cl2 was established as the best solvent for
the further optimization.
reactions.[a]
With CH2Cl2 as the solvent and the L4–ScACTHNURGTNE(GNU OTf)3 complex
as the catalyst, however, the isolated yield of 6a is only
39% (Table 3, entry 1) and a large amounts of 2-aminophe-
Entry
R1
t
Yield
[%][b]
trans/cis[c]
ee
[h]
[%][c]
Table 3. Screening of the effects of additives and the hydroxy group in
N-aryl imine 4a in the asymmetric Povarov reaction of N-aryl imine 4a
and a-methylstyrene (5a).[a]
1
2
3
4
5
Ph
38
18
44
69
21
45
42
42
69
69
69
69
93
95
93
46
75 (6a)
93 (6b)
76 (6c)
82 (6d)
84 (6e)
88 (6 f)
92 (6g)
85 (6h)
81 (6i)
88 (6j)
66 (6k)
51 (6l)
22 (6m)
67 (6n)
35 (6o)
33 (6p)
94/6
93/7
95/5
96/4
94/6
94/6
96/4
95/5
93/7
95/5
94/6
95/5
91/9
96/4
89/11
61/39
96
92
95
>99
94
94
>99
98
99
94
97
99
98
>99
96
95
2-ClC6H4
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
3-BrC6H4
4-BrC6H4
4-FC6H4
4-CF3C6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
2-naphthyl
2-thienyl
cyclohexyl
6
7[d]
8
9
10
11[e]
12
13
14
15
16[e,f]
Entry
4a
Additive
Yield
[%][b]
trans/cis[c]
ee
[%][c]
1
4a
4a
4a
4a
4a
4a
4a
4aa
4ab
–
39
58
62
75
69
65
65
40
72
95/5
96/4
95/5
94/6
94/6
91/9
95/5
21/79
10/90
96
97
97
96
96
93
97
0
2
PhCHO
3[d]
PhCHO, MgSO4
PhCHO, MgSO4
PhCHO, MgSO4
PhCHO, MgSO4
PhCHO, MgSO4
PhCHO, MgSO4
PhCHO, MgSO4
[a] Unless otherwise noted, all reactions were carried out with 10 mol%
of L4/Sc(OTf)3 (1/1), 4 (0.2 mmol), 5a (7.5 equiv, 200 mL), the aldehyde
4[d,e]
5[d,e,f]
6[d,e,g]
7[d,e,h]
8[d,e]
9[d,e]
AHCTUNGTRENNUNG
(0.5 equiv) from which the N-aryl imine 4 was derived, and MgSO4
(10.0 mg) in CH2Cl2 (0.6 mL) under N2 at 308C. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis; the trans isomer was
confirmed by 1H NMR spectroscopy; the ee value refers to the trans
isomer. [d] The absolute configuration of adduct 6g was determined to
be (2S,4S) by X-ray diffraction analysis. [e] The imine was formed in situ
from aldehyde (1.5 equiv) and 2-aminophenol (0.2 mmol). [f] 20mol% of
0
[a] Unless otherwise noted, all reactions were carried out with 10 mol%
of L4/Sc(OTf)3 (1/1), 4 (0.2 mmol), 5a (7.5 equiv, 200 mL), and PhCHO
ACHTUNGTRENNUNG
(0.5 equiv, 11.5 mL) in CH2Cl2 (1.0 mL) under N2 at 308C for 22 h.
[b] Yield of isolated product. [c] Determined by chiral HPLC analysis;
the trans isomer was confirmed by 1H NMR spectroscopy; the ee value
refers to the trans isomer. [d] MgSO4 (10.0 mg) was added. [e] CH2Cl2
(0.6 mL) was used and the reaction time was 38 h. [f] Imine formed in
situ. [g] 5 mol% of the catalyst was used. [h] Reaction was performed
under air and moisture.
L4/ScACTHNUGETRN(NUG OTf)3 (2:1) was used at 08C.
Under the optimized conditions (Table 3, entry 4), the
substrate scope of 2-azadienes in the Povarov reaction was
examined (Table 4). Regardless of the steric hindrance of
the substituents on the electron-deficient imines, tetrahydro-
quinolines with a quaternary stereocenter were obtained in
nol was detected. It is possible that the cause is decomposi-
tion of imine 4a in the presence of a Lewis acid. In order to
decrease the decomposition of imine 4a, benzaldehyde and
MgSO4 were added, which greatly improved the yield (62%
yield; Table 3, entries 2 and 3). Extensive screening of the
reaction conditions, including the concentrations in the reac-
tion system, a three-component version, and the catalyst
loading, showed that the optimal conditions were 10 mol%
high yields with excellent diaACHTNUTRGNEsUNG tereo- and enantioselectivities
(92 to >99% ee; Table 4, entries 1–9). It would appear that
the electron-donating substituent on the aromatic imine en-
riches the electron density and thus decreases the reactivity.
In the case of imines derived from methyl-substituted ben-
zaldehydes, moderate to good yields with excellent diaster-
eo- and enantioselectivities (94–99% ee) could also be ob-
tained (Table 4, entries 10–12). When an electron-donating
4-methoxy-substituted imine was used, excellent enantiose-
lectivity (98% ee) was observed, but the yield was substan-
tially reduced (Table 4, entry 13). In addition, the 2-naph-
thaldehyde-derived imine served as a good 2-azadiene com-
ponent to form the tetrahydroquinoline 6n with >99% ee
(Table 4, entry 14). Meanwhile, imines derived from hetero-
aromatic and aliphatic aldehydes were also suitable sub-
strates to afford the desired adducts with high enantioselec-
tivities (95–96% ee) but low yields (Table 4, entries 15 and
16). The absolute configuration of tetrahydroquinoline 6g
of the L4–ScACHTUNGTRENNUNG(OTf)3 complex, 0.2 mmol of N-aryl imine 4a,
and benzaldehyde and MgSO4 as additives in 0.6 mL CH2Cl2
at 308C (Table 3, entries 4–6). If the reaction was performed
under air and moisture, the diastereo- and enantioselectivity
could be maintained, although the yield was slightly de-
creased (Table 3, entry 7). It is also worth pointing out that
only racemic tetrahydroquinolines were obtained if N-aryl
imines derived from aniline or 2-methoxyaniline were
tested, which indicates the crucial role of the hydroxy group
of N-aryl imine 4a in the stereorecognition process (Table 3,
entries 8 and 9).
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Tetrahydroquinolines with Quaternary Stereocenters
FULL PAPER
Scheme 4. The gram scale synthesis of tetrahydroquinoline 6a.
Figure 1. The structure of (2S,4S)-6g determined by X-ray analysis.
4ac was generated from the reduction of the substrate imine
4a. Comparative experiments were performed to investigate
the real reductive reagent. Equivalent amounts of pure tet-
rahydroquinoline 6a and imine 4a in the presence of
ScACHTUNTRGNEUNG(OTf)3 under an N2 atmosphere yielded quinoline deriva-
tive 7a and aniline 4ac with the same yield (Scheme 5). No-
was unambiguously determined to be (2S,4S) by single-crys-
tal X-ray diffraction analysis (Figure 1).[15]
Subsequently, the substrate scope of the a-alkyl styrenes
was tested. Both electron-rich and electron-poor dienophiles
were applied and resulted in excellent diastereoselectivities
and enantioselectivities (93/7–99/1 trans/cis, 93–98% ee;
Table 5, entries 1–6). Comparatively, an electron-deficient
Table 5. The scope of dienophiles 5 tolerated in the asymmetric Povarov
reactions.[a]
Entry
R2
R3
t
Yield
[%][b]
trans/cis[c]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Me
Me
Me
Et
38
27
33
27
41
41
27
48
35
75 (6a)
83 (6q)
81 (6r)
89 (6s)
63 (6t)
70 (6u)
85 (6v)
40 (6w)
54 (6x)
94/6
95/5
99/1
97/3
95/5
97/3
99/1
93/7
95/5
96
96
98
96
93
98
96
96
95
3-MeC6H4
4-MeC6H4
3,4-Me2C6H3
3,4-(MeO)2C6H3
4-FC6H4
2-naphthyl
Ph
Scheme 5. The intermolecular hydrogen-shift reaction and the crystal
structure of 8a determined by X-ray analysis.
Ph
H
[a] Reaction conditions: 10 mol% of L4/Sc
(OTf)3 (1/1), 4a (0.2 mmol), 5
tably, quinoline derivative 7a could be easily oxidized into
the quinoline-3-one under air. The quaternary carbon center
was maintained in product 8a, which was confirmed by
single-crystal X-ray diffraction analysis (Scheme 5).[15] It is
(200 mL or 7.5 equiv for solid), PhCHO (0.5 equiv), and MgSO4 (10.0 mg)
in CH2Cl2 (0.6 mL) under N2 at 308C. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis; the trans isomer was confirmed
1
by H NMR spectroscopy; the ee value refers to the trans isomer.
reasonable to conclude that ScACHTNUGTRENUNG(OTf)3 could promote hydro-
gen transfer from the tetrahydroquinoline to the imine,
which offers a method to synthesize the corresponding quin-
oline derivatives with quaternary stereocenters.[17]
styrene gave a slightly lower yield than the others (Table 5,
entry 6 versus entries 1–4). In addition, 2-(2-naphthyl)-pro-
pene was tolerated well to give the adduct 6v with excellent
results (Table 5, entry 7). The reactions with a-ethylstyrene
and styrene as dienophiles also afforded the desired tetrahy-
droquinolines with 96 and 95% ee values, respectively
(Table 5, entries 8 and 9).
Conclusion
In summary, we have developed an efficient asymmetric Po-
For the purpose of examining the utility of the catalytic
system, gram scale quantities of 2-azadiene 4a were treated
with 5a under the optimized reaction conditions. The tetra-
hydroquinoline 6a was obtained without any loss of yield,
diastereoselectivity, or enantioselectivity (Scheme 4).
In some cases shown in Tables 4 and 5, the low yield of
the product is a partial consequence of the generation of by-
products.[16] Under the catalytic reaction conditions, aniline
varov reaction with a-alkyl styrenes as the dienophiles cata-
lyzed by an N,N’-dioxide L4–ScACHTNUGTRENUNG(OTf)3 complex. A wide vari-
ety of tetrahydroquinolines with a quaternary stereocenter
at the C4 position were obtained with excellent diastereo-
and enantioselectivities (up to >99:1 d.r. and 92 to
>99% ee). In addition, the reaction could be performed on
the gram scale without any loss of yield, diastereoselectivity,
or enantioselectivity. The intermolecular hydrogen-shift re-
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13803

X. M. Feng et al.
in CH2Cl2 (13 mL) in a 50 mL dried flask under nitrogen. Subsequently,
benzaldehyde (2.6 mmol, 263.5 mL) and CH2Cl2 (2.6 mL) were added,
and the reaction was stirred at 308C. After 0.5 h, a-methylstyrene (5a;
5.2 mL) was added, and the reaction mixture was stirred at 308C for
50 h. The residue was purified by flash chromatography on silica gel
(ethyl acetate/petroleum ether, 1/8) to afford 6a (1.21 g, 74% yield, 95:5
d.r., 98% ee).
action was found to be a side reaction, which offers a
method to synthesize the corresponding quinoline deriva-
tives with quaternary stereocenters. Further studies about
the intermolecular hydrogen-shift reaction and the applica-
tion of the catalyst to other reactions are underway.
Experimental Section
Acknowledgements
Typical experimental procedure for the asymmetric Povarov reaction
with N-aryl imine 4a and a-alkyl styrene 5a: ScACTHNUGTRENUNG(OTf)3 (9.8 mg,
We appreciate the National Natural Science Foundation of China
(nos. 20732003, 20872097, and 21021001), and National Basic Research
Program of China (973 Program: no. 2010CB833300) for financial sup-
port. We also thank Sichuan University Analytical & Testing Center for
NMR and X-ray diffraction analysis.
0.02 mmol), N,N’-dioxide ligand L4 (14.0 mg, 0.02 mmol), N-aryl imine
4a (39.4 mg, 0.2 mmol), and dried MgSO4 (10.0 mg) were stirred in
CH2Cl2 (0.5 mL) under nitrogen. Subsequently, PhCHO (10.5 mL,
0.1 mmol) and CH2Cl2 (0.1 mL) were added, and the reaction was stirred
at 308C. After 0.5 h, a-methylstyrene (5a; 200 mL) was added. The reac-
tion mixture was stirred at 308C for 38 h and then directly purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate, 8/1) to
afford the desired product 6a as a yellow amorphous solid in an insepara-
ble diastereomeric mixture: 1H NMR (600 MHz, CDCl3): d=7.34–7.28
(m, 5H), 7.25 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.11 (d, J=7.2 Hz, 2H),
7.10–6.10 (m, 3H), 4.59 (s, 1H), 4.48–4.18 (brs, 1H), 4.02 (brs, 1H), 2.27
(m, 1H), 2.17 (t, J=12.0 Hz, 1H), 1.76 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=150.46, 128.58, 128.19, 128.01, 127.56, 127.35,
127.16, 126.77, 125.84, 116.28, 48.13, 41.80, 29.76 ppm; HRMS (ESI-
TOF): calcd for C22H21NO [M+H+]: 316.1696; found: 316.1696; the ee
value was determined by chiral HPLC analysis on an Daicel Chiralcel IB
column by comparison with authentic racemates: eluent: n-hexane/2-
propanol, 90/10; flow rate: 1.0 mLminÀ1; l=254 nm; retention times:
5.62 (trans, minor), 6.06 (cis), 6.94 (cis), 7.80 min (trans, major).
[1] For reviews on the construction of chiral tetrasubstituted carbon
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Typical experimental procedure for the intermolecular hydrogen-shift re-
action of tetrahydroquinoline 6a and N-aryl imine 4a: ScACHTNUTRGNEUNG(OTf)3 (9.8 mg,
¯
Omura, Org. Lett. 2005, 7, 5701–5704; c) R. Uchida, R. Imasato, Y.
0.02 mmol), tetrahydroquinoline 6a (63.0 mg, 0.2 mmol), and N-aryl
imine 4a (39.4 mg, 0.2 mmol) were stirred under nitrogen, then CH2Cl2
(0.6 mL) was added, and the reaction was stirred at 308C under nitrogen
for 65 h. The residue was then purified by flash chromatography on silica
gel (petroleum ether/ethyl ether, 100/1) to afford the quinoline derivative
7a as a yellow amorphous solid: 1H NMR (400 MHz, CDCl3): d=7.96–
7.93 (m, 2H), 7.62 (m, 1H), 7.44–7.38 (m, 3H), 7.25–7.15 (m, 4H), 7.10
(t, J=7.6 Hz, 1H), 6.92 (dd, J=7.6, 1.2 Hz, 1H), 6.63 (dd, J=7.6, 1.2 Hz,
1H), 3.41 (d, J=16.8 Hz, 1H), 2.94 (d, J=16.4 Hz, 1H), 1.67 ppm (s,
3H); 13C NMR (101 MHz, CDCl3): d=163.44, 152.05, 146.20, 138.22,
135.44, 130.92, 130.69, 128.50, 128.48, 128.20, 126.67, 126.64, 126.50,
116.86, 112.81, 40.79, 40.21, 26.99 ppm.
¯
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The quinoline derivative 7a could be easily oxidized into the quinoline-3-
one 8a under air: 1H NMR (400 MHz, CDCl3): d=7.90–7.77 (m, 2H),
7.63 (s, 1H), 7.47–7.34 (m, 3H), 7.32 (t, J=8.0 Hz, 1H), 7.29–7.26 (m,
1H), 7.23 (m, 2H), 7.10–6.97 (m, 3H), 6.87 (d, J=7.6 Hz, 1H), 1.91 ppm
(s, 3H); 13C NMR (101 MHz, CDCl3): d=197.53, 155.78, 153.96, 139.21,
137.47, 133.74, 131.12, 130.99, 129.01, 128.74, 128.41, 128.35, 128.02,
127.16, 118.77, 114.43, 55.41, 21.81 ppm; the oxidation reaction of tetra-
hydroquinoline 7a under air could be detected with chiral HPLC analysis
on a Daicel Chiralcel IA column: n-hexane/2-propanol, 95/5; flow rate:
1.0 mLminÀ1; l=254 nm; retention times: 8.28 (8a), 11.21 (7a), 12.31
(8a), 14.10 min (7a).
The residue was purified by flash chromatography on silica gel (petrole-
um ether/ethyl acetate, 8/1) to afford the reduced aniline 4ac as a yellow
viscous liquid: 1H NMR (400 MHz, CDCl3): d=7.51–7.36 (m, 5H), 6.99–
6.90 (m, 1H), 6.81 (d, J=7.7 Hz, 1H), 6.77–6.66 (m, 2H), 5.18 (s, 2H),
4.43 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): d=143.73, 139.46,
137.15, 128.74, 127.74, 127.34, 121.65, 118.13, 114.73, 112.63, 48.69 ppm;
HRMS (ESI-TOF): calcd for C13H13NO [M+H+]: 200.1070; found:
200.1077.
Typical experimental procedure for the scaled-up reaction: ScACTHNUTRGNE(NUG OTf)3
(255.8 mg, 0.52 mmol), N,N’-dioxide ligand L4 (364.5 mg, 0.52 mmol), N-
aryl imine 4a (1.02 g, 5.2 mmol), and dried MgSO4 (260 mg) were stirred
13804
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Chem. Eur. J. 2011, 17, 13800 – 13805

Tetrahydroquinolines with Quaternary Stereocenters
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Received: July 28, 2011
Published online: November 14, 2011
Chem. Eur. J. 2011, 17, 13800 – 13805
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13805