Direct enantioselective access to 4-substituted tetrahydroquinolines by catalytic asymmetric transfer hydrogenation of quinolines

Article abstract of DOI:10.1039/c1ob05870c

A convenient protocol for the enantioselective synthesis of 4-substituted tetrahydroquinolines has been developed. Chiral BINOL phosphoric acids promote the reduction of a wide range of 4-substituted quinolines with Hantzsch esters with good to high level

Full text of DOI:10.1039/c1ob05870c

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PAPER
Direct enantioselective access to 4-substituted tetrahydroquinolines by
catalytic asymmetric transfer hydrogenation of quinolines†
Magnus Rueping,* Thomas Theissmann, Mirjam Stoeckel and Andrey P. Antonchick
Received 1st June 2011, Accepted 11th July 2011
DOI: 10.1039/c1ob05870c
A convenient protocol for the enantioselective synthesis of 4-substituted tetrahydroquinolines has been
developed. Chiral BINOL phosphoric acids promote the reduction of a wide range of 4-substituted
quinolines with Hantzsch esters with good to high levels of enantioselectivity.
Introduction
In recent years, chiral Brønsted acid catalyzed transfer hydrogena-
tion emerged as a generally applicable strategy for the enantioselec-
tive reduction of various acyclic as well as cyclic systems containing
carbon nitrogen double bonds.1,2 In this context, several successful
approaches have been disclosed for the efficient reduction of
acyclic imines, leading to chiral amines under mild reaction
conditions.3,4 Furthermore, notable achievements have also been
registered in the organocatalyzed reduction of cyclic imines and
various nitrogen-containing heteroaromatic systems which offer
access to diverse enantioenriched nitrogen heterocycles.5–9 Among
them, quinoline reduction5,6 constitutes a challenging field since
it allows formation of the corresponding tetrahydroquinolines,
which are common structural motifs in alkaloids and biologically
active compounds. Given the importance of this class of molecules,
considerable efforts have been made in order to develop improved
methods for their synthesis.
Although several methods have been developed for the asym-
metric reduction of 2-substituted quinolines (Scheme 1a), the 3-
and 4-substituted analogs have received considerably less attention
(Scheme 1b). To date, no direct approach for the generation
of optically active 4-substituted tetrahydroquinolines has been
described.10 Typically, synthetic routes consist of several steps
as, for instance, shown in the enantioselective synthesis of 4-
ethyl substituted tetrahydroquinoline (Scheme 1c).11 Given the
high industrial interest in enantioenriched 4-substituted tetrahy-
droquinolines we decided to develop a first general catalytic
asymmetric route.
Scheme 1 a, b) Asymmetric reduction of 2- and 3-substituted quinolines.
c) Asymmetric synthesis of 4-ethyltetrahydroquinoline.
Results and discussion
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg, 1,
D-52074, Aachen, Germany. E-mail: Magnus,Rueping@rwth-aachen.de
NOL phosphoric acids12–14 in the reduction of 4-methylquinoline
† Electronic supplementary information (ESI) available: 1H- and 13C-
NMR spectra and HPLC chromatograms are provided for all synthesized
compounds. See DOI: 10.1039/c1ob05870c
Our investigation started with the evaluation of various chiral BI-
(lepidine, 1a) using dihydropyridines as a hydride source. The
most successful catalyst previously employed for organocatalytic
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Table 1 Evaluation of different Brønsted acids
Table 2 Solvent and Hantzsch ester evaluation
Entrya
Catalyst
eeb (%)
Entrya
Substrate
HEH
Solvent
eeb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
35
36
14
48
54
41
66
58
33
11
33
67
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
5a
5a
5a
5a
5a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
CHCl3
Bu2O
C6H5CF3
C6H5CH3
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
57
69
65
66
67
64
64
62
61
88
90
91
91
89
9
9
10
11
12
3j
3k
3l
10
11
12
13
14
C6H6
C6H6
C6H6
a Reactions were performed with lepidine, HEH (Hantzsch 1,4-
dihydropyridine) 4a (2.4 equiv.) and 3 (5 mol%) at 60 ◦C. b Enantiomeric
excess was determined by HPLC using a Chiralcel OD-H column.
a Reactions were performed with quinolines 1a/5a, HEH 4a–e (2.4 equiv.)
and 3l (5 mol%) at 60 ◦C in 2 mL solvent. b Enantiomeric excess was
determined by HPLC using a Chiralcel OD-H column.
reductions proved less selective, yielding the desired product 2a
with just 66% ee (Table 1, entry 7). Hence, further work
was devoted to the synthesis of BINOL-phosphates bearing
bulkier residues in the 3,3¢-positions. To follow the known aryl-
substitution pattern (phenyl, naphthyl, phenanthryl), we synthe-
sized the pyrenyl derivative, but the result was disappointing
(Table 1, entry 8).
entries 6–9). In contrast to the alkyl-substituted quinolines, the
corresponding aryl-derivatives prefer sterically more hindered
Hantzsch esters 4c–d as the hydrogen source (Table 2, entries
12–13). It seems that the steric demand of the NADH-synthon
is diametrically opposed between alkyl- and aryl-4-substituted
quinolines.
Subsequently, in order to improve the enantioselectivity, chiral
phosphates 3i–k with elongated residues into the space, were syn-
thesized. However, all the acetylene-bridge extended derivatives
3i–k exhibited only a low level of selectivity (Table 1, entries
9–11). Compared to the phenanthryl derivative which afforded
the product with 66% ee, the acetylene elongated one yielded
the product with only 11% ee (Table 1, entry 7 vs. 10). A
slight increase in the selectivity (67% ee) has been observed with
the octahydro-BINOL-phosphate bearing triphenylsilyl residues
(Table 1, entry 12).
With the best catalyst 3l in hand, the subsequent investigation
concentrated on the influence of the solvent employed (Table 2).
Comparable results in terms of selectivity were obtained in both
aromatic solvents and dibutyl ether (Table 2, entries 2–5). In
addition, the influence of the reducing agent was also examined
(Table 2, entries 5–9). Various Hantzsch ester derivatives were
evaluated and the best result in the reduction of lepidine was
obtained with the ethyl derivative 4a (Table 2, entry 5). Bulkier
ester-derivatives 4b–e led to a decrease of the ee values (Table 2,
The effect of catalyst loading and temperature on the reaction
yield and selectivity was also analyzed. First the catalyst loading
was varied in the range of 10 to 0.1 mol%. Whereas the
enantiomeric excess is nearly constant over the whole range,
a better yield was obtained with 5 mol% catalyst. Regarding
the influence of the temperature, with lowering the temperature
(60→50→40 ◦C), the enantiomeric excess increased, but the
conversion of the reaction considerably decreased. Therefore,
the overall best conditions with regard to reaction time and
asymmetric induction are 5 mol% of catalyst at 50 ◦C in benzene
or toluene.
Under these optimized conditions we explored the scope of the
first asymmetric transfer hydrogenation of various 4-substituted
quinolines (Table 3). In general, high enantioselectivities and
good yields are observed for various 4-substituted alkyl- and
aryl-tetrahydroquinolines (Table 3, entries 1–7 and 8–17 re-
spectively). Especially the chloro-containing substrates could be
reduced with high enantioselectivities and excellent yields. In this
case, in addition to the activation by the catalyst, the electron
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Table 3 Scope of the catalytic enantioselective reduction
Regarding the mechanism of the reaction (Scheme 2), a first
step protonation of the substrate yields the corresponding iminium
ion. Hydride transfer from the HEH to the substrate takes place
selectively, from the less hindered face and gives a chiral enamine
intermediate along with a pyridinium salt which undergoes proton
transfer to liberate the catalyst. Isomerization of the enamine
yields the corresponding chiral iminium ion which is subjected
to second hydride transfer. Finally, protonation will regenerate
the catalyst.
Entrya
Product
R1
R2
Yieldb (%)
eec (%)
1d
2d
3d
4d
5d
6d
7
2a
2b
2c
2d
2e
2f
2g
6a
6b
6c
6d
6e
6f
Me
Me
Et
i-Pr
Bu
Bn
CO2Me
C6H5
H
67
85
88
81
82
96
67
96
84
92
77
95
90
92
80
98
96
73
85
85
90
84
84
75
92
81
91
83
90
72
92
82
90
75
Cl
Cl
Cl
Cl
Cl
H
Cl
H
Cl
H
Cl
H
Cl
H
Cl
Cl
8
9
C6H5
10
11
12
13
14
15
16
17
4-Me-C6H5
4-Me-C6H5
4-MeO-C6H5
4-MeO-C6H5
3-MeO-C6H5
3-MeO-C6H5
2-Naphthyl
4-Biphenyl
6g
6h
6i
6j
Scheme 2 Proposed mechanism for the asymmetric reduction.
a Reactions were performed with quinolines 1/5, HEH 4d (2.4 equiv.) and
3l (5 mol%) at 50 ◦C. b Yield after chromatography. c Enantiomeric excess
was determined by HPLC using Chiralcel OD-H or Chiralpak AD-H.
d HEH 4a was used.
Our initial catalyst evaluation revealed a strong correlation
between the steric bulk of the catalyst substituents in the 3,3-
position and the selectivity of the reaction, whereby larger
residues lead to superior enantioselectivities. Furthermore, when
comparing the catalysts bearing large groups directly attached
to the BINOL framework with the ones bearing an acetylene-
bridge or less bulky groups, better results were obtained with the
former. This result is explained by the position of the developing
stereocenter which is far away from the protonated nitrogen and
the catalytic center of the phosphoric acid catalyst. In the case of
BINOL derivatives 3l and 3g, the triphenylsilyl and phenanthryl
substituents are able to provide the necessary environment for
a selective reaction. In contrast, in the case of 3j and 3k, the
acetylene-bridge provides too much space around the substrate
and, therefore, none of the faces can be effectively shielded.
withdrawing effect of the chlorine atom most probably enhances
the electrophilicity of the substrate by decreasing the electron
density of the heteroaromatic ring, thus enabling the attack of
the H- nucleophile.
This rationale is best illustrated by the difference in yield
in the case of 2a and 2b which were obtained with 67 and
85% yield, respectively (Table 3, entries 1–2). In the case of
quinoline derivatives bearing aryl groups in the 4-position, the
electronic nature of this moiety plays a less relevant role since
electron donating groups are well tolerated in this reaction.
Furthermore, quinoline 1g with an ester group, that might be
further functionalized, is also applicable in this procedure (Table 3,
entry 7).
The absolute configuration of the product 6j has been deter-
mined as R by X-ray crystal structure analysis (Fig. 1).
Conclusions
In summary, we have succeeded in developing the first asymmetric
hydrogenation of biologically relevant 4-substituted quinolines.
The protocol provides direct access to a large variety of 4-aryl-
and 4-alkyl-substituted tetrahydroquinolines in good yields and
good to high enantiomeric excesses. Further work will be devoted
to the application of this methodology in the synthesis of more
complex molecular architectures.
Experimental
General methods
All reactions were performed under an argon atmosphere. Unless
otherwise noted, all materials were obtained from commercial
suppliers and were used without further purification. Solvents for
extraction and chromatography were technical grade and distilled
Fig. 1 X-ray crystal structure of tetrahydroquinoline 6j.
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prior to use. Solvents used in reactions were reagent grade and
distilled from the indicated drying agents: benzene (Na). For
thin-layer chromatography (TLC), silica gel coated aluminum
plates (Merck, silica gel 60 F254) were used and chromatograms
were visualized by irradiation with UV light at 254 nm. Column
chromatography was performed using Merck silica gel 60 (particle
size 0.040–0.063 mm). Solvents mixtures are understood as
volume/volume.
1H-NMR and 13C-NMR were recorded on a Bruker AM 250
spectrometer in CDCl3. Data are reported in the following order:
chemical shift (d) in ppm; multiplicities are indicated as (bs
(broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet)); coupling constants (J) are in hertz (Hz). Field
Desorption (FD) mass spectra were obtained with Finnigan MAT
95 instrument. Infrared (IR) spectra were recorded on a Bruker
Tensor 27 FT-IR spectrometer and are reported in terms of fre-
quency of absorption (cm-1). The enantiomeric excesses were de-
termined by HPLC analysis using a chiral stationary phase column
(column, Daicel Co. CHIRALCEL OD-H and CHIRALPAK
AD-H; eluent: hexane/2-propanol). The chiral HPLC method
was calibrated with the corresponding racemic mixtures. Optical
rotations were measured on a Perkin Elmer 241 polarimeter.
(4S)-7-Chloro-4-ethyl-1,2,3,4-tetrahydro-quinoline (2c, Table 3,
entry 3). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 6.91 (d, J = 8.1 Hz, 1H), 6.55 (dd, J =
2.1, 8.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 3.91 (bs, 1H), 3.37–
3.18 (m, 2H), 2.66–2.55 (m, 1H), 1.96–1.42 (m, 4H), 0.97 (t, J =
7.4 Hz, 3H); 13C-NMR (CDCl3): d = 145.2, 132.0, 130.1, 123.6,
116.2, 113.3, 38.2, 36.8, 28.9, 25.4, 11.5; MS (FD): m/z (%) =
195.0 (100) [M+], 197.0 (Cl2 pattern); IR (KBr): 3393, 2958, 2921,
2844, 1602, 1497, 1093, 844, 798 cm-1. HPLC conditions: AD-H
column, n-hexane/2-propanol = 99/1, flow rate = 0.45 mL min-1,
major enantiomer: tR = 27.88 min; minor enantiomer: tR = 31.48
min; [a]2D5 -23.8 (c 0.5, CHCl3).
(4S)-7-Chloro-4-isopropyl-1,2,3,4-tetrahydro-quinoline
(2d,
Table 3, entry 4). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 6.89 (dd, J = 0.6, 8.1 Hz, 1H), 6.54 (dd,
J = 2.1, 8.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 3.89 (bs, 1H), 3.38–
3.22 (m, 2H), 2.53–2.42 (m, 1H), 2.05–1.85 (m, 2H), 1.82–1.68 (m,
1H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C-NMR
(CDCl3): d = 145.4, 132.0, 130.4, 122.6, 115.8, 113.2, 41.9, 39.1,
30.2, 22.6, 21.4, 18.6; MS (FD): m/z (%) = 209.0 (100) [M+]; IR
(KBr): 3390, 2955, 2928, 2851, 1603, 1496, 1090, 842, 799 cm-1.
HPLC conditions: AD-H column, n-hexane/2-propanol = 99/1,
flow rate = 0.45 mL min-1, major enantiomer: tR = 25.94 min;
minor enantiomer: tR = 37.14 min; [a]2D5 -9.1 (c 0.5, CHCl3).
General procedure for the transfer hydrogenation of quinolines
In a typical experiment quinoline 1/5, catalyst 3l (5 mol%),
Hantzsch dihydropyridine 4a/4d (2.4 equiv.) and benzene (2.0 mL)
were added to a screw-capped vial and the mixture was exposed to
an argon atmosphere. The resulting yellow solution was allowed
to stir at 50 ◦C for 35–50h. The solvent was evaporated under
vacuum, and the residue was purified by column chromatography
on silica gel to afford the corresponding amine. The yields and
enantiomeric excesses are given in Table 3.
(4S)-7-Chloro-4-butyl-1,2,3,4-tetrahydro-quinoline (2e, Table 3,
entry 5). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 6.90 (d, J = 8.1 Hz, 1H), 6.55 (dd, J =
2.1, 8.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 3.91 (bs, 1H), 3.38–
3.19 (m, 2H), 2.74–2.64 (m, 1H), 1.96–1.72 (m, 2H), 1.70–1.22
(m, 6H), 0.92 (t, J = 7.0 Hz, 3H); 13C-NMR (CDCl3): d = 145.1,
131.9, 130.1, 123.9, 116.2, 113.3, 38.1, 36.1, 35.1, 29.1, 25.8, 22.8,
14.1; MS (FD): m/z (%) = 223.8 (100) [M+], 225.8 (Cl2 pattern); IR
(KBr): 3419, 2954, 2927, 2857, 1604, 1576, 1496, 1468, 1355, 1309,
1089, 839 cm-1. HPLC conditions: OD-H column, n-hexane/2-
propanol = 97/3, flow rate = 0.6 mL min-1, major enantiomer: tR =
12.35 min; minor enantiomer: tR = 11.38 min; [a]2D5 -8.6 (c 0.5,
CHCl3).
(4S)-4-Methyl-1,2,3,4-tetrahydro-quinoline (2a, Table 3, en-
try 1). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.08 (d, J = 7.6 Hz, 1H), 6.97 (t, J =
7.6 Hz, 1H), 6.63 (dt, J = 1.2, 7.4 Hz, 1H), 6.48 (dd, J = 1.2,
8.0 Hz, 1H), 3.85 (bs, 1H), 3.40–3.22 (m, 2H), 3.02–2.84 (m, 1H),
2.07–1.92 (m, 1H), 1.76–1.61 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H);
13C-NMR (CDCl3): d = 144.2, 128.4, 126.7, 126.6, 116.9, 114.1,
39.0, 30.2, 29.9, 22.6; MS (FD): m/z (%) = 147.8 (100) [M+]; IR
(KBr): 3407, 3051, 3016, 2955, 2925, 2864, 1606, 1498, 1315, 745
cm-1. HPLC conditions: OD-H column, n-hexane/2-propanol =
98/2, flow rate = 0.6 mL min-1, major enantiomer: tR = 17.15 min;
minor enantiomer: tR = 18.63 min; [a]2D5 -23.6 (c 1.0, CHCl3).
(4S)-7-Chloro-4-benzyl-1,2,3,4-tetrahydro-quinoline (2f, Table 3,
entry 6). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.27–7.06 (m, 5H), 6.76 (d, J = 8.1 Hz,
1H), 6.46 (dd, J = 2.1, 8.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H),
3.88 (bs, 1H), 3.35–3.23 (m, 1H), 3.19–3.09 (m, 1H), 3.02–2.86 (m,
2H), 2.69–2.54 (m, 1H), 1.78–1.56 (m, 2H); 13C-NMR (CDCl3): d =
145.2, 140.0, 132.3, 130.2, 129.3, 128.3, 126.1, 122.7, 116.4, 113.4,
42.9, 37.9, 37.1, 25.0; MS (FD): m/z (%) = 257.8 (100) [M+], 259.9
(Cl2 pattern); IR (KBr): 3404, 3042, 3024, 3000, 2953, 2932, 1605,
1504, 1310, 1084, 1028, 844, 796, 704 cm-1. HPLC conditions:
OD-H column, n-hexane/2-propanol = 90/10, flow rate = 0.6 mL
min-1, major enantiomer: tR = 15.62 min; minor enantiomer: tR =
13.73 min; [a]2D5 -115.9 (c 1.0, CHCl3).
(4S)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-quinoline
(2b,
Table 3, entry 2). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 6.94 (dd, J = 0.8, 8.1 Hz, 1H), 6.57
(dd, J = 2.1, 8.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 3.92 (bs,
1H), 3.39–3.21 (m, 2H), 2.93–2.79 (m, 1H), 2.01–1.88 (m, 1H),
1.72–1.58 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H); 13C-NMR (CDCl3):
d = 145.2, 132.0, 129.4, 124.8, 116.6, 113.3, 38.8, 29.9, 29.4, 22.4;
MS (FD): m/z (%) = 181.8 (100) [M+], 183.7 (Cl2 pattern); IR
(KBr): 3417, 2957, 2925, 2867, 1604, 1575, 1496, 1469, 1308,
1088, 1067, 872, 841, 792 cm-1. HPLC conditions: AD-H column,
n-hexane/2-propanol = 99/1, flow rate = 0.45 mL min-1, major
enantiomer: tR = 28.92 min; minor enantiomer: tR = 31.56 min;
[a]2D5 -18.0 (c 0.5, CHCl3).
(4S)-1,2,3,4-Tetrahydro-quinoline-4-carboxylic acid methyl ester
(2g, Table 3, entry 7)
Eluted from silica gel using hexane/ethylacetat in a ratio of 20 : 1
as eluent.
1H-NMR (CDCl3): d = 7.03 (d, J = 7.6 Hz, , 1H), 6.96 (t, J =
8.4 Hz, 1H), 6.56 (dt, J = 1.1, 7.6 Hz, 1H), 6.44 (dd, J = 1.1, 8.0 Hz,
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1H), 3.87 (bs, 1H), 3.72 (t, J = 5.0 Hz, 1H), 3.64 (s, 3H), 3.42–3.30
(m, 1H), 3.27–3.16 (m, 1H), 2.27–2.14 (m, 1H), 2.01–1.85 (m, 1H);
13C-NMR (CDCl3): d = 174.7, 144.4, 130.3, 128.1, 117.0, 114.7,
52.1, 41.7, 38.8, 24.6; MS (FD): m/z (%) = 191.0 (100) [M+]; IR
(KBr): 3407, 2951, 2926, 2855, 1731, 1601, 1503, 1194, 1164, 748
cm-1. HPLC conditions: AD-H column, n-hexane/2-propanol =
80/20, flow rate = 0.6 mL min-1, major enantiomer: tR = 10.82
min; minor enantiomer: tR = 13.01 min; [a]2D5 -61.2 (c 0.5, CHCl3).
(4R)-7-Chloro-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydro-quino-
line (6e, Table 3, entry 12). Eluted from silica gel using toluene
as eluent.
1H-NMR (CDCl3): d = 7.03 (d, J = 8.6 Hz, 2H), 6.84 (d, J =
8.8 Hz, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.54–6.58 (m, 2H), 4.04
(t, J = 6.0 Hz, 1H), 4.00 (bs, 1H), 3.79 (s, 3H), 3.34–3.15 (m,
2H), 2.21–2.07 (m, 1H), 2.05–1.92 (m, 1H); 13C-NMR (CDCl3):
d = 158.1, 145.8, 138.1, 132.5, 131.4, 129.4, 122.0, 116.7, 113.8,
113.4, 55.3, 41.5, 38.9, 30.7; MS (FD): m/z (%) = 273.0 (100) [M+],
275.0 (Cl2 pattern); IR (KBr): 3417, 2952, 2928, 2832, 1607, 1506,
1247, 1086, 1032, 844 cm-1. HPLC conditions: OD-H column,
n-hexane/2-propanol = 90/10, flow rate = 0.6 mL min-1, major
enantiomer: tR = 19.33 min; minor enantiomer: tR = 14.58 min;
[a]2D5 -77.3 (c 1.0, CHCl3).
(4R)-7-Chloro-4-phenyl-1,2,3,4-tetrahydro-quinoline
(6a,
Table 3, entry 8). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.26–7.10 (m, 3H), 7.05–7.00 (m, 2H),
6.57 (d, J = 7.7 Hz, 1H), 6.45–6.40 (m, 2H), 4.01 (t, J = 6.0 Hz,
1H), 3.93 (bs, 1H), 3.26–3.06 (m, 2H), 2.16–2.03 (m, 1H), 2.01–
1.88 (m, 1H); 13C-NMR (CDCl3): d = 146.0, 145.8, 132.6, 131.4,
128.5, 128.3, 126.3, 121.6, 116.7, 113.4, 42.3, 38.9, 30.6; MS (FD):
m/z (%) = 243.8 (100) [M+], 245.9 (Cl2 pattern); IR (KBr): 3418,
3058, 3024, 2948, 2924, 2854, 1602, 1494, 1311, 1087, 701 cm-1.
HPLC conditions: OD-H column, n-hexane/2-propanol = 90/10,
flow rate = 0.6 mL min-1, major enantiomer: tR = 21.58 min, minor
enantiomer: tR = 12.28 min; [a]2D5 -70.8 (c 1.0, CHCl3).
(4R)-4-(4-Methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline
(6f,
Table 3, entry 13). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.06 (d, J = 8.6 Hz, 2H), 6.99 (d, J =
7.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 7.3 Hz, 1H),
6.60–6.50 (m, 2H), 4.10 (t, J = 6.0 Hz, 1H), 3.93 (bs, 1H), 3.80 (s,
3H), 3.35–3.18 (m, 2H), 2.25–2.12 (s, 1H), 2.08–1.95 (m, 1H); 13C-
NMR (CDCl3): d = 157.9, 144.9, 138.8, 130.4, 129.6, 127.2, 123.8,
117.0, 114.2, 113.7, 55.3, 42.0, 39.2, 31.2; MS (FD): m/z (%) =
239.1 (100) [M+]; IR (KBr): 3338, 3028, 2948, 2926, 2832, 1607,
1497, 1247, 1033, 746 cm-1. HPLC conditions: OD-H column,
n-hexane/2-propanol = 90/10, flow rate = 0.6 mL min-1, major
enantiomer: tR = 22.54 min; minor enantiomer: tR = 25.68 min;
[a]2D5 -55.4 (c 1.0, CHCl3).
(4R)-4-Phenyl-1,2,3,4-tetrahydro-quinoline (6b, Table 3, entry 9).
Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.25–7.03 (m, 5H), 6.93 (t, J = 7.0 Hz,
1H), 6.67 (d, J = 7.3 Hz, 1H), 6.51–6.44 (m, 2H), 4.07 (t, J =
6.1 Hz, 1H), 3.85 (bs, 1H), 3.27–3.10 (m, 2H), 2.20–2.06 (m, 1H),
2.03–1.90 (m, 1H); 13C-NMR (CDCl3): d = 146.7, 145.0, 130.4,
128.7, 128.3, 127.3, 126.1, 123.4, 117.0, 114.2, 42.8, 39.2, 31.1; MS
(FD): m/z (%) = 209.9 (100) [M+]; IR (KBr): 3414, 3057, 3021,
2951, 2919, 2896, 2850, 2831, 1607, 1505, 1491, 1315, 741, 703
cm-1. HPLC conditions: OD-H column, n-hexane/2-propanol =
90/10, flow rate = 0.6 mL min-1, major enantiomer: tR = 22.32
min; minor enantiomer: tR = 14.61 min; [a]2D5 -60.8 (c 1.0, CHCl3).
(4R)-7-Chloro-4-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-quino-
line (6g, Table 3, entry 14). Eluted from silica gel using toluene
as eluent.
1H-NMR (CDCl3): d = 7.22 (t, J = 7.9 Hz, 1H), 6.79–6.64 (m,
4H), 6.54–6.48 (m, 2H), 4.06 (t, J = 6.0 Hz, 1H), 4.00 (bs, 1H), 3.77
(s, 3H), 3.34–3.16 (m, 2H), 2.24–1.96 (m, 2H); 13C-NMR (CDCl3):
d = 159.6, 147.7, 145.8, 132.6, 131.5, 129.3, 121.5, 121.0, 116.8,
114.6, 113.4, 111.3, 55.2, 42.4, 38.9, 30.5; MS (FD): m/z (%) =
273.0 (100) [M+], 275.0 Cl2 pattern; IR (KBr): 3415, 2951, 2925,
2834, 1603, 1494, 1312, 1256, 1087, 1046 cm-1. HPLC conditions:
OD-H column, n-hexane/2-propanol = 90/10, flow rate = 0.6 mL
min-1, major enantiomer: tR = 27.35 min; minor enantiomer: tR =
15.72 min; [a]2D5 -70.7 (c 1.0, CHCl3).
(4R)-7-Chloro-4-p-tolyl-1,2,3,4-tetrahydro-quinoline
(6c,
Table 3, entry 10). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.11 (d, J = 7.9 Hz, 2H), 7.00 (d, J =
8.1 Hz, 2H), 6.66 (d, J = 7.7 Hz, 1H), 6.53–6.47 (m, 2H), 4.05
(t, J = 6.0 Hz, 1H), 4.00 (bs, 1H), 3.33–3.18 (m, 2H), 2.33 (s,
3H), 2.22–2.10 (m, 1H), 2.07–1.94 (m, 1H); 13C-NMR (CDCl3):
d = 145.9, 143.0, 135.8, 132.5, 131.4, 129.1, 128.4, 121.9, 116.7,
113.4, 41.9, 38.9, 30.7, 21.0; MS (FD): m/z (%) = 257.0 (100)
[M+], 259.0 (Cl2 pattern); IR (KBr): 3391, 2956, 2919, 2855, 1604,
1493, 1302, 1088, 816, 796, 536 cm-1. HPLC conditions: OD-H
column, n-hexane/2-propanol = 98/2, flow rate = 0.6 mL min-1,
major enantiomer: tR = 24.83 min; minor enantiomer: tR = 16.75
min; [a]2D5 -70.9 (c 1.0, CHCl3).
(4R)-4-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline
(6h,
Table 3, entry 15). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.22 (t, J = 7.9 Hz, 1H), 7.01 (t, J =
7.6 Hz, 1H), 6.79–6.69 (m, 4H), 6.61–6.51 (m, 2H), 4.12 (t, J =
6.1 Hz, 1H), 3.93 (s, 1H), 3.77 (s, 3H), 3.36–3.19 (m, 2H), 2.28–2.15
(m, 1H), 2.13–2.00 (m 1H); 13C-NMR (CDCl3): d = 159.6, 148.3,
144.9, 130.4, 129.2, 127.3, 123.2, 121.2, 117.0, 114.7, 114.2, 111.2,
55.2, 42.9, 39.3, 31.0; MS (FD): m/z (%) = 239.1 (100) [M+]; IR
(KBr): 3408, 3059, 2999, 2951, 2922, 2892, 2830, 1277, 1253, 746
cm-1. HPLC conditions: OD-H column, n-hexane/2-propanol =
90/10, flow rate = 0.6 mL min-1, major enantiomer: tR = 30.19
min; minor enantiomer: tR = 23.32 min; [a]2D5 -51.0 (c 1.0, CHCl3).
(4R)-4-p-Tolyl-1,2,3,4-tetrahydro-quinoline (6d, Table 3, en-
try 11). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.13–6.97 (m, 5H), 6.77 (d, J = 8.1 Hz,
1H), 6.60–6.53 (m, 2H), 4.12 (t, J = 6.1 Hz, 1H), 3.93 (bs, 1H),
3.36–3.19 (m, 2H), 2.34 (s, 3H), 2.28–2.12 (m, 1H), 2.10–1.97 (m,
1H); 13C-NMR (CDCl3): d = 145.0, 143.7, 135.6, 130.4, 129.0,
128.6, 127.2, 123.6, 117.0, 114.2, 42.4, 39.2, 31.2, 21.0; MS (FD):
m/z (%) = 223.0 (100) [M+]; IR (KBr): 3403, 3050, 3020, 2947,
2922, 2852, 1605, 1502, 1313, 741 cm-1. HPLC conditions: OD-H
column, n-hexane/2-propanol = 90/10, flow rate = 0.6 mL min-1,
major enantiomer: tR = 15.41 min; minor enantiomer: tR = 13.38
min; [a]2D5 -57.8 (c 1.0, CHCl3).
(4R)-7-Chloro-4-naphthalen-2-yl-1,2,3,4-tetrahydro-quinoline
(6i, Table 3, entry 16). Eluted from silica gel using toluene as
eluent.
1H-NMR (CDCl3): d = 7.86–7.72 (m, 3H), 7.53–7.40 (m, 3H),
7.30 (dd, J = 1.8, 8.5 Hz, 1H), 6.68 (dd, J = 0.6, 8.1 Hz, 1H),
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6.58–6.48 (m, 2H), 4.25 (t, J = 6.1 Hz, 1H), 4.05 (bs, 1H), 3.37–
3.19 (m, 2H), 2.30–2.07 (m, 2H); 13C-NMR (CDCl3): d = 145.7,
143.3, 133.4, 132.7, 132.2, 131.6, 128.1, 127.7, 127.6, 127.4, 126.6,
126.0, 125.5, 121.7, 117.1, 113.7, 42.5, 39.0, 30.5; MS (FD): m/z
(%) = 293.9 (100) [M+], 296.1 (Cl2 pattern); IR (KBr): 3418, 3051,
2923, 2853, 1602, 1495, 1310, 1087, 820, 755, 743, 477 cm-1. HPLC
conditions: OD-H column, n-hexane/2-propanol = 90/10, flow
rate = 0.6 mL min-1, major enantiomer: tR = 21.03 min; minor
enantiomer: tR = 16.54 min; [a]2D5 -89.0 (c 1.0, CHCl3).
5 Examples of organocatalytic quinoline reduction: (a) M. Rueping, T.
Theissmann and A. P. Antonchick, Synlett, 2006, 1071; (b) M. Rueping
and W. Ieawsuwan, Synlett, 2007, 247; (c) M. Rueping, A. P. Antonchick
and T. Theissmann, Angew. Chem., Int. Ed., 2006, 45, 3683; (d) M.
Rueping, M. Stoeckel, E. Sugiono and T. Theissmann, Tetrahedron,
2010, 66, 6565. For the quinoline reduction in aqueous solution, see;
(e) M. Rueping and T. Theissmann, Chem. Sci., 2010, 1, 473; (f) M.
Rueping, T. Theissmann, S. Raja and J. W. Bats, Adv. Synth. Catal.,
2008, 350, 1001; (g) Q. S. Guo, D. M. Du and J. Xu, Angew. Chem., Int.
Ed., 2008, 47, 759.
6 Examples of asymmetric metal catalyzed reduction of 2-substituted
quinolines: (a) W.-B. Wang, S.-M. Lu, P. Y. Yang, X.-W. Han and Y.-G.
Zhou, J. Am. Chem. Soc., 2003, 125, 10536; (b) S.-M. Lu, X.-W. Han
and Y.-G. Zhou, Adv. Synth. Catal., 2004, 346, 909; (c) L. Xu, K. H.
Lam, J. Li, J. Wu, Q.-H. Fan, W.-H. Lo and A. S. C. Chan, Chem.
Commun., 2005, 1390; (d) K. H. Lam, L. Xu, L. Feng, Q.-H. Fan, F. L.
Lam, W.-H. Lo and A. S. C. Chan, Adv. Synth. Catal., 2005, 347, 1755;
(e) S.-M. Lu, Y.-Q. Wang, X.-W. Han and Y.-G. Zhou, Angew. Chem.,
Int. Ed., 2006, 45, 2260; (f) M. T. Reetz and X. Li, Chem. Commun.,
2006, 2159; (g) Z.-J. Wang, G.-J. Deng, Y. Li, Y.-M. He, W.-J. Tang and
Q.-H. Fan, Org. Lett., 2007, 9, 1243; (h) W.-J. Tang, S.-F. Zhu, L.-J.
Xu, Q.-L. Zhou, Q.-H. Fan, H.-F. Zhou, K. Lam and A. S. C. Chan,
Chem. Commun., 2007, 613; (i) C. Deport, M. Buchotte, K. Abecassis,
H. Tadaoka, T. Ayad, T. Ohshima, J.-P. Genet, K. Mashima and V.
Ratovelomanana-Vidal, Synlett, 2007, 2743; (j) N. Mrsic, L. Lefort, B.
Laurent, A. F. Jeroen, A. J. Minnaard, B. L. Feringa and J. G. de Vries,
Adv. Synth. Catal., 2008, 350, 1081; (k) Z. W. Li, T. L. Wang, Y. M. He,
Z. J. Wang, Q. H. Fan, J. Pan and L. J. Xu, Org. Lett., 2008, 10, 5265;
(l) H. Zhou, Z. Li, Z. Wang, T. Wang, L. Xu, Y. He, Q.-H. Fan, J. Pan, L.
Gu and A. S. C. Chan, Angew. Chem., Int. Ed., 2008, 47, 8464; (m) S.-M.
Lu and C. Bolm, Adv. Synth. Catal., 2008, 350, 1101; (n) H. Tadaoka,
D. Cartigny, T. Nagao, T. Gosavi, T Ayad, J.-P. Genet, T. Ohshima,
V. Ratovelomanana-Vidal and K. Mashima, Chem.–Eur. J., 2009, 15,
9990; (o) M. Eggenstein, A. Thomas, J. Theuerkauf, G. Francio and
W. Leitner, Adv. Synth. Catal., 2009, 351, 725; (p) Z.-J. Wang, H.-F.
Zhou, T.-L. Wang, Y.-M. He and Q.-H. Fan, Green Chem., 2009, 11,
767; (q) M. Rueping and R. M. Koenigs, Chem. Commun., 2011, 47,
304. For an overview see: Y.-G. Zhou, Acc. Chem. Res., 2007, 40, 1357.
7 Asymmetric organocatalytic reduction of other nitrogen-containing
cyclic systems: (a) M. Rueping, A. P. Antonchick and T. Theissmann,
Angew. Chem., Int. Ed., 2006, 45, 6751; (b) M. Rueping and A. P.
Antonchick, Angew. Chem., Int. Ed., 2007, 46, 4562; (c) M. Rueping, F.
Tato and F. R. Schoepke, Chem.–Eur. J., 2010, 16, 2688; (d) M. Rueping,
C. Brinkmann, A. P. Antonchick and I. Atodiresei, Org. Lett., 2010,
12, 4604; (e) M. Rueping, E. Merino and R. M. Koenigs, Adv. Synth.
Catal., 2010, 352, 2629; (f) Z.-Y. Han, H. Xiao and L.-Z. Gong, Bioorg.
Med. Chem. Lett., 2009, 19, 3729; (g) C. Metallinos, F. B. Barrett and
S. Xu, Synlett, 2008, 720. For a metal/Brønsted acid catalytic system
used in the enantioselective hydrogenation of quinoxalines, see: Q.-A.
Chen, D.-S. Wang, Y.-G. Zhou, Y. Duan, H.-J. Fan, Y. Yang and Z.
Zhang, J. Am. Chem. Soc., 2011, 133, 6126.
(4R)-4-Biphenyl-4-yl-7-chloro-1,2,3,4-tetrahydro-quinoline (6j,
Table 3, entry 17). Eluted from silica gel using toluene as eluent.
1H-NMR (CDCl3): d = 7.62–7.50 (m, 4H), 7.44 (t, J = 7.3 Hz,
2H), 7.34 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.71 (d,
J = 8.4 Hz, 1H), 6.55–6.50 (m, 2H), 4.14 (t, J = 5.9 Hz, 1H), 4.03
(bs, 1H), 3.38–3.18 (m, 2H), 2.29–2.14 (m, 1H), 2.13–2.00 (m, 1H);
13C-NMR (CDCl3): d = 145.9, 145.1, 140.9, 139.3, 132.7, 131.5,
128.9, 128.7, 127.1, 127.1, 127.0, 121.5, 116.8, 113.5, 42.0, 38.9,
30.6; MS (FD): m/z (%) = 320.0 (100) [M+], 322.0 (Cl2 pattern);
IR (KBr): 3419, 2954, 2925, 2867, 1604, 1496, 1308, 1088 cm-1.
HPLC conditions: OD-H column, n-hexane/2-propanol = 90/10,
flow rate = 0.6 mL min-1, major enantiomer: tR = 24.90 min; minor
enantiomer: tR = 17.84 min; [a]2D5 -64.0 (c 0.8, CHCl3).
Acknowledgements
Financial support by the DFG (SPP 1179) is gratefully acknowl-
edged.
Notes and references
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13 Examples of Brønsted acid catalyzed reactions from our group: (a) M.
Rueping, E. Sugiono and C. Azap, Angew. Chem., Int. Ed., 2006, 45,
2617; (b) M. Rueping and C. Azap, Angew. Chem., Int. Ed., 2006,
45, 7832; (c) M. Rueping, W. Ieawsuwan, A. P. Antonchick and B. J.
Nachtsheim, Angew. Chem., Int. Ed., 2007, 46, 2097; (d) M. Rueping, E.
Sugiono, T. Theissmann, A. Kuenkel, A. Kockritz, A. Pews-Davtyan,
N. Nemati and M. Beller, Org. Lett., 2007, 9, 1065; (e) M. Rueping,
E. Sugiono and S. A. Moreth, Adv. Synth. Catal., 2007, 349, 759;
(f) M. Rueping, E. Sugiono and F. R. Schoepke, Synlett, 2007, 1441;
(g) M. Rueping, A. P. Antonchick and C. Brinkmann, Angew. Chem.,
Int. Ed., 2007, 46, 6903; (h) M. Rueping and A. P. Antonchick, Org.
Lett., 2008, 10, 1731; (i) M. Rueping and A. P. Antonchick, Angew.
Chem., Int. Ed., 2008, 47, 10090; (j) M. Rueping, T. Theissmann, A.
Kuenkel and R. M. Koenigs, Angew. Chem., Int. Ed., 2008, 47, 6798;
(k) M. Rueping, A. P. Antonchick, E. Sugiono and K. Grenader, Angew.
Chem., Int. Ed., 2009, 48, 908; (l) M. Rueping and W. Ieawsuwan,
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