Asymmetric transfer hydrogenation of quinolines using tethered Ru(II) catalysts

Article abstract of DOI:10.1016/j.tetasy.2010.03.053

The first report of an asymmetric transfer hydrogenation, in formic acid/triethylamine, of quinolines is described. Using a Ru(II) catalyst containing a 4-carbon tether, products of up to 73% ee were formed, whilst a Rh(III)-tethered catalyst gave products of up to 94% ee.

Full text of DOI:10.1016/j.tetasy.2010.03.053

Tetrahedron: Asymmetry 21 (2010) 1549–1556
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric transfer hydrogenation of quinolines using tethered Ru(II) catalysts
Vimal Parekh a, James A. Ramsden b, Martin Wills a,
*
a Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
b Dr. Reddy’s Laboratories, Unit 162, Cambridge Science Park, Milton Road, Cambridge CB4 0GH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The first report of an asymmetric transfer hydrogenation, in formic acid/triethylamine, of quinolines is
described. Using a Ru(II) catalyst containing a 4-carbon tether, products of up to 73% ee were formed,
whilst a Rh(III)-tethered catalyst gave products of up to 94% ee.
Received 8 March 2010
Accepted 31 March 2010
Available online 24 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor H. B. Kagan on his
80th birthday
1. Introduction
for hydrogenation of 2-methylquinoline 4 in organic solvents.
Using the Ir(III) complex, 2-methyltetrahydroquinoline 5 was
The asymmetric reduction of C@N bonds is a valuable method
for the asymmetric formation of chiral amines.1 Whilst several
methods exist for the asymmetric reduction of isolated C@N
groups,2 their reduction when they are a part of an aromatic ring
represents a more challenging objective. The conversion of quino-
lines to tetrahydroquinolines is a useful direct method for the syn-
thesis of chiral, non-racemic N-containing heterocycles from
readily available starting materials. A number of reports on the
pressure hydrogenation of quinolines have been published.3–17
formed in up to 99% ee.17 The use of an acidic additive was demon-
strated to be important for optimal activity. These results sug-
gested that the reduction of quinolines proceeds by an ionic
mechanism in which N-protonation was required to activate the
hydride addition process.16,17
Ru
H
Rh
Cl
Ir
Cl
TsN
Cl
TsN
TsN
N
2. Results and discussion
N
H
N
H
H
Ph
Ph
Ph
H
H
Ph
Ph
Ph
The first example of asymmetric quinoline hydrogenation em-
ployed chiral biaryldiphosphine ligands with an Ir(I) salt and gave
products with ees of up to 94%. Iodine was found to be an essential
additive.3 Several other iridium/diphosphine complexes have given
excellent results in this application.4–10 Supported versions of
these catalysts have been prepared and used successfully in recy-
clable catalyst systems.11,12 The activation of quinolines with chlo-
roformates has been reported to improve the rates of reactions.13
Other ligands which have been used in Ir-catalysed quinoline
hydrogenation include BINOL-derived diphosphonites14 and
ferrocenyloxazolines.15
The use of nitrogen-donor ligands, such as diamines, in this
application is less developed. In a recent report, the use of a Ru/
TsDPEN complex 1 as a catalyst for hydrogenation of 2-methyl-
quinoline 4 in an ionic liquid gave excellent results.16 In this pro-
cess, the ionic liquid was essential—reactions in methanol
proceeded with much lower activity. Switching to Rh(III) and Ir(III)
as the metal, however, led to the development of catalysts 2 and 3
1
2
3
In contrast, there are few reports on the use of asymmetric transfer
hydrogenation, which can offer advantages in terms of practicality,
in this particular application. Recently, Xiao et al. disclosed the use
of Rh-based catalyst 2 in aqueous solution.18 This gave impressive
results and required careful control of pH for full reduction to occur.
A racemic Ir(I)-catalysed transfer hydrogenation (using isopropanol
as the hydrogen source) has been reported.19 The closely related
reduction of quinolines using Hantzsch esters as the source of
hydrogen has, however, been reported to give excellent results in
both the metal-free20 and Ir/diphosphine-catalysed21 methods.
We therefore instigated a series of studies on the asymmetric
transfer hydrogenation for the asymmetric reduction of quinoline
and isoquinoline rings. Given the success demonstrated by 1–3 in
reduction by hydrogen gas and asymmetric transfer hydrogenation
in water, it was considered that these might also prove successful
in the closely related asymmetric transfer hydrogenation process
in formic acid/triethylamine azeotrope (formic acid/TEA),22 which
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.053

1550
V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
is known to work well with imines.23 In addition, we wished to
evaluate catalysts 6–12, which have recently been developed in
our group.24,25 Initial studies of the reduction of 2-methylquinoline
(Scheme 1) were carried out using the dropwise addition of formic
acid, the method reported by Blackmond for imines, in methanol
solvent.26 These studies indicated that catalyst 9 was particularly
active in this application (see SI). Further studies were conducted
using the Noyori procedure (i.e., in which a 5:2 formic acid/TEA
azeotrope is employed from the outset) and this was found to give
similar results. Hence this method was selected for extended
investigations.
higher conversion but lower ee. The tethered ligands 7–11 were
tested next and, of these, 9 and 10 proved to be the most active.25
In our previous studies, we have demonstrated that monomer cat-
alysts 7–11 are formed in situ from their dimer precursors and
both give identical results in asymmetric transfer hydrogenation
reactions.25 In the cases of 9 and 10, the dimer catalyst precursors
were, in practice, used directly in the experiments, although the
corresponding monomers are illustrated for ease of structural com-
parison. The 3C-tethered complex 8 was used in both dimer and
monomer forms to confirm reproducibility; both gave identical re-
sults within experimental error. All the catalysts were of (R,R)-con-
n
n
Ph
Ru
Ru
N
Ru
Cl
N
Cl
Cl
Rh
N
TsN
TsN
TsN
Cl
N
TsN
Ph
H
H
H
Ph
Ph
Ph
H
Ph
Ph
Ph
11 (n=2)
Ph
6
12
7
8
9
(n=0)
(n=1)
(n=2)
10
(n=3)
In order to optimise the outcome of the reaction, systematic varia-
tion of the conditions was carried out using 2-methylquinoline 4 as
a substrate and the 4C-tethered complex 9 as catalyst. The results of
solvent variation are shown in Table 1. Of these, methanol gave the
best result in terms of conversion and ee. A study of the effect of
temperature revealed that (in methanol) the ee dropped only
slightly at elevated temperature (to 43% at 60 °C).
figuration (illustrated) with respect to the diamine, with the
exception of the dimer of 8, which was of the (S,S)-configuration.
Catalyst 9, with a 4C tether, gave the highest conversion (24 h,
rt). 2-Methylquinoline 4 was reduced to 5 in 96% conversion, with
an ee of 43% (R configuration).
Catalysts 6–10 have already been reported,24,25 however, 11
was prepared specifically for use in this project and is new. In view
of the high conversion in reduction of 4 achieved using the 4C-
tethered complex 9, but the highest ee of 80% seen using the p-
cymene containing untethered complex 1, we sought to design a
catalyst which contained elements of both 1 and 9 in order to
achieve both high activity and ee, that is, 11.
0.5 % catalyst 1, 2, 6-12,
HCO2H, Et3N
H
Cosolvent, rt
see Table 1,2,4.
Me
N
H
N
Me
R-
4
5
Me
Cl
Cl
Scheme 1.
Ru
Cl
2
NHTs
Ph
NH
Ph
Me
HN
Alternative Ru(II) catalysts were tested for comparison with 9
(Table 2) over a fixed 24-h reaction time. In the event, complex 1
proved to be capable of reducing 2-methylquinoline 4 in high ee
but in very low conversion even after extended reaction times.
The use of the N-benzylated TsDPEN ligand 624 gave a product in
13
Me
Me
Ph
CHO
Me
NHTs
Ph
Me
14
15
Table 1
Asymmetric transfer hydrogenation of 2-methylquinoline 4 to tetrahydroquinoline 5
(Scheme 1) using catalyst 9; variation of solventa
Table 2
Asymmetric transfer hydrogenation of 2-methylquinoline 4 to tetrahydroquinoline 5
eeb/% (R/S)
(Scheme 1); variation of catalysta
Entry
Solvent
Conversion/%
eeb/% (R/S)
1
2
3
4
5
6
7
8
9
MeOH
MeCN
H2O
EtOH
DCM
96
79
23
96
92
98
8
73
98
75
61
46 (R)
36 (R)
32 (R)
37 (R)
25 (R)
17 (R)
8 (R)
22 (R)
31 (R)
18 (R)
46 (R)
Entry
Catalyst
Conversion/%
1
2
3
4
5
6
7
8
1 (monomer)
6 (monomer)
7 (monomer)
8 (dimer)
8 (monomer)
9 (dimer)
17
66
27
63
59
96
87
29
80 (R)
29 (R)
68 (R)
43 (S)c
43 (R)
43 (R)
44 (R)
42 (R)
Et2O
Acetone
Toluene
iPrOH
EtOAc
Nonec
10 (dimer)
11 (dimer)
10
11
a
Conditions: 0.5 mol % of catalysts 6–11 wrt monomer form (i.e. 0.5 mol % of
a
Ru(II)). [quinoline] = 0.45 M, 60 °C, 24 h, MeOH solvent, 5:2 formic acid/TEA
Conditions: 0.5 mol % of catalyst 9 (dimer precursor used). [quinoline] = 0.45 M,
azeotrope.
28 °C, 24 h, 5:2 formic acid/TEA azeotrope.
b
b
ee determined by chiral GC (see SI).
(S,S)-Catalyst used.
ee determined by chiral GC (see SI).
Neat formic acid/TEA used.
c
c

V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
1551
Table 4
The synthetic approach to 11 required the synthesis of the dimer pre-
cursor 13 (converted in situ to 11 during asymmetric transfer hydro-
genation reactions). To achieve this, 14 (mixture of regioisomers)
was first prepared through Br/Li exchange on 3,5-dimethylbromo-
benzene and reaction with Br(CH2)4OTBDPS, then deprotection,
Birch reduction and oxidation. Reductive amination of 14 with
(R,R)-TsDPEN gave 15, which was reacted with RuCl3 to form the salt
13. Unfortunately 11 did not give superior results. In the reduction of
ketones, however, catalyst 11 was very efficient. Acetophenone was
reduced in 97% ee (R) and acetylcyclohexane in 74% ee (S) using
0.5 mol % (wrt Ru(II)) of 11 (28 °C, 5:2 formic acid/TEA).
Asymmetric transfer hydrogenation of 2-substituted quinolines to tetrahydroquino-
lines using catalyst 12a
Entry
Substrate
Time/h
Conversionc/%
eeb/% (R/S)
1
2
3
4
5
6
7
8
9
4
24
48
48
48
48
48
48
48
48
68 (85)
68 (35)
16 (43)
67 (76)
65 (73)
64 (76)
57 (65)
30 (29)
58 (69)
93 (R)
86 (S)
0 (–)
91 (R)
90 (R)
92 (R)
93 (R)
81 (R)
94 (R)
19
20
21
22
23
24
25
26
Other substrates were then examined including 1-methyliso-
quinoline 16, which was not reduced under these conditions. This
result suggests that the reduction mechanism of 4 may involve an
initial 1,4-addition of hydrogen to the protonated heterocycle to
give 17, followed by isomerisation to the imine 18, which is then
reduced enantioselectively to the observed product. This sequence,
which has previously been proposed for the closely related hydro-
genation of 4 in an ionic liquid,16 would not be applicable to iso-
meric heterocycle 16.
a
Conditions: 0.5 mol % of catalyst 12 wrt monomer form (i.e., 0.5 mol % of
Rh(III)). [quinoline] = 0.45 M, 28 °C, 24 h, MeOH solvent, 5:2 formic acid/TEA
azeotrope.
b
ee determined by chiral GC or HPLC (see SI).
Figures in parenthesis are those obtained with 2 mol % of catalyst 12.
c
Better results, in terms of enantioselectivity, in several cases
exceeding 90% ee, were achieved using the rhodium-tethered cat-
alyst 12, which has previous been used for ketone and imine reduc-
tions (Table 4). Using 0.5 mol % of 12, the reactions did not go to
full conversion after 48 h, although the use of a higher loading
(2 mol %) of catalyst increased the conversions in most cases. Fur-
ther work is required to optimise the reductions by these catalysts.
N
N
N
H
18
16
17
O
25 R=
26 R=
3. Conclusion
Br
O
OMe
N
R
In conclusion, we have demonstrated that tethered Ru(II) and
Rh(III) complexes are effective catalysts for the asymmetric trans-
fer hydrogenation of substituted quinolines, which are generally
regarded as challenging substrates for this application. To the best
of our knowledge, this is the first report of the use of such catalysts
in a solution of formic acid/triethylamine/methanol. As has been
observed in ketone reduction, the increased reactivity of tethered
complexes over the untethered ones appears to be key to their
capacity to work as effective catalysts in this application.
19 (R=Ph)
20 (R=tBu)
21 (R=Et)
22 (R=nPr)
23 (R=nBu)
24 (R=CH2CH2Ph)
27 (R=CO2Me)
OMe
N
MeO
MeO
N
Ph
N
N
28
29
30
4. Experimental
The reduction of a series of further quinolines 19–28 was examined
using tethered catalyst 9 (Table 3).
4.1. (4-Bromobutoxy)(tert-butyl)diphenylsilane27
Of these, the phenyl-substituted substrate 19 was reduced in
the highest ee of the series, whilst the tBu derivative 20 was suc-
cessfully reduced but only in racemic form. Other isoquinolines
were reduced in high conversion but only moderate-good ee. The
ester-substituted compound 27 was not reduced under the condi-
tions used. Heterocycles 29 (0% conversion) and 30 (17% conver-
sion) also proved resistant to reduction.
tert-Butyl-chlorodiphenylsilane (7.96 g, 7.53 ml, 28.97 mmol)
was added to a stirred solution of 4-bromo-1-butanol (4.03 g,
26.34 mmol) and imidazole (3.95 g, 57.95 mmol) in THF (150 ml)
under an argon atmosphere. The resulting mixture was stirred
for 72 h at rt and the reaction was quenched with water (150 ml)
followed by the addition of diethyl ether (150 ml). After phase sep-
aration and extraction of the aqueous phase with diethyl ether
(3 ꢀ 150 ml), the combined organic phases were dried (MgSO4),
concentrated and purified by flash chromatography (hexane/EtOAc
9:1) to afford the silyl alcohol as a colourless oil (3.23 g, 31%). 1H
NMR (300 MHz; CDCl3) d 7.52–7.51 (m, 4H), 7.45–7.30 (m, 6H),
3.75 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.8 Hz, 2H), 2.00 (m, 2H), 1.70
(m, 2H), 1.09 (s, 9H); 13C NMR (300 MHz; CDCl3) d 135.6, 133.8,
129.7, 127.7, 62.9, 34.0, 31.1, 29.5, 26.9, 20.0.
Table 3
Asymmetric transfer hydrogenation of 2-substituted quinolines to tetrahydroquino-
lines using catalyst 9a
Entry
Substrate
Time/h
Conversion/%
eeb/% (R/S)
1
2
3
4
5
6
7
8
9
19
20
21
22
23
24
25
26
27
28
168
48
30
144
144
48
48
48
48
24
68
57
95
94
93
90
86
93
0
73 (S)
0 (-)
41 (R)
42 (R)
41 (R)
50 (R)
47 (R)
67 (R)
-
4.2. tert-Butyl(4-(3,5-dimethylphenyl)butoxy)diphenylsilane
A Schlenk tube was dried with a heat gun under vacuum and
flushed with argon. 5-Bromo-m-xylene (1.53 g, 1.12 ml,
8.25 mmol) was injected into the tube followed by freshly distilled
THF (16.5 ml). The tube was then degassed three times. tBuLi
(1.7 M in pentane, 12.14 ml, 20.63 mmol) was added dropwise at
ꢁ78 °C and the tube was again degassed and flushed with argon.
10
46
50 (R)
a
Conditions: 0.5 mol % of catalyst 9 wrt monomer form (i.e., 0.5 mol % of Ru(II)).
[quinoline] = 0.45 M, 28 °C, MeOH solvent, 5:2 formic acid/TEA azeotrope.
b
ee determined by chiral GC or HPLC (see SI).

1552
V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
The mixture was stirred at rt for 1 h and then re-cooled to ꢁ78 °C.
(4-Bromobutoxy)(tert-butyl)diphenylsilane (3.23 g, 8.25 mmol)
was added dropwise to the reaction mixture and then degassed
and flushed with argon. The solution was heated to 40 °C and al-
lowed to stir at this temperature for 4 days. The mixture was al-
lowed to cool to rt and then partitioned between diethyl ether
(33 ml) and water (25 ml). The aqueous phase was extracted with
diethyl ether (2 ꢀ 16.5 ml) and then the combined organic phases
were dried over MgSO4, filtered and then evaporated in vacuo to
added at the same temperature. After stirring for 45 min at
ꢁ78 °C, triethylamine (1.73 ml, 12.40 mmol) was added and the
reaction mixture was allowed to warm up to rt. After 60 min, water
(10 ml) was added and the mixture was extracted with DCM
(3 ꢀ 5 ml). The combined organic layers were dried over magne-
sium sulfate, filtered and concentrated under reduced pressure to
give crude 4-(3,5-dimethylcyclohexa-1,4-dienyl)butanal as a light
orange oil (355 mg, 96%) which appeared to be a ca. 1:1 mixture
of isomers 14a and 14b. 1H NMR (400 MHz; CDCl3) d 9.88 (s,
0.5H), 9.85 (s, 0.5H), 5.30–5.20 (m, 2H), 2.80–2.76 (br s, 1H),
2.40–2.30 (m, 3H), 2.03–1.95 (m, 0.5H), 1.80–1.70 (m, 0.5H), 1.68
(br s, 4.5H), 1.30–1.20 (m, 3H), 1.01 (d, J = 7.7 Hz, 1.5H). This mate-
rial was directly used in the next step.
give a light yellow oil (2.4 g, 70%).
m
max/cmꢁ1 (thin film) 3071,
2931, 2858, 1606, 1472, 1462, 1428, 1390, 1361, 1261, 1189,
1105, 1008, 998, 975, 939, 846, 822, 739, 699; 1H NMR
(400 MHz; CDCl3) d 7.70–7.62 (m, 4H), 7.45–7.30 (m, 6H), 6.85 (s,
1H), 6.80 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H),
2.25 (s, 6H), 1.70 (m, 2H), 1.60 (m, 2H), 1.05 (s, 9H); 13C NMR
(400 MHz; CDCl3) d 142.6, 137.7, 136.8, 136.6, 135.6, 134.2,
134.1, 131.0, 129.5, 129.1, 127.6, 127.3, 126.3, 63.8, 35.5, 32.3,
29.5, 29.0, 27.6, 26.9, 21.3. m/z (ESI) 439 (M+Na); HRMS Found
(ESI): [M++Na] 439.2419, C28H36NaOSi requires 439.2428
(1.86 ppm error).
4.6. N-((1R,2R)-2-(4-(3,5-Dimethylcyclohexa-1,4-dienyl)-
butylamino)-1,2-diphenylethyl)-4-methylbenzene-sulfonamide
15
To a suspension of powdered molecular sieves (4 Å, 0.50 g) in
dry methanol (30 ml) were added 4-(3,5-dimethylcyclohexa-1,4-
dienyl)butanal 14 (355 mg, 2.00 mmol), (R,R)-TsDPEN (806 mg,
2.20 mmol) and glacial acetic acid (4 drops). The reaction mixture
was stirred at rt and monitored by TLC. After leaving for 2 h, the
imine had formed and sodium cyanoborohydride (590 mg,
9.38 mmol) was added. The reaction was left overnight at rt. The
molecular sieves were removed by filtration and the solution was
concentrated under reduced pressure. The residue was re-dis-
solved in DCM (40 ml). The organic phase was washed with NaH-
CO3 (satd, 40 ml) and brine (40 ml), dried over magnesium
sulfate and concentrated. The resulting residue was purified by
flash chromatography to afford N-((1R,2R)-2-(4-(3,5-dimethylcy-
clohexa-1,4-dienyl)butylamino)-1,2-diphenylethyl)-4-methylben-
4.3. 4-(3,5-Dimethylphenyl)butan-1-ol
Tetrabutylammonium fluoride (1 M solution in THF) (24 ml)
was added to a solution of tert-butyl(4-(3,5-dimethylphenyl)but-
oxy)diphenylsilane (2.0 g, 4.8 mmol) in THF (65 ml). The mixture
was allowed to stir for 3 days at 23 °C and the conversion was
checked by TLC. The crude mixture was purified by flash chroma-
tography (9:1 hexane:EtOAc to 5:5 hexane:EtOAc) to afford the
product as a colourless oil (776 mg, 91%). m
max/cmꢁ1 (thin film)
3326, 3014, 2928, 2860, 1606, 1459, 1377, 1060, 1036, 985, 933,
894, 843, 700; 1H NMR (400 MHz; CDCl3) d 6.82 (s, 1H), 6.80 (s,
2H), 3.65 (t, J = 6.2 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.30 (s, 6H),
1.75–1.55 (m, 4H), 1.35 (br s, 1H); 13C NMR (400 MHz; CDCl3) d
142.3, 137.8, 127.4, 126.3, 62.9, 35.5, 32.5, 27.6, 21.3; m/z (ESI)
201 (M+Na), 161, 102; HRMS found (ESI): [M+ +Na] 201.1247,
zene-sulfonamide 15 as
¼ ꢁ5:3 (c 0.5 CHCl3).
a
white oil (390 mg, 37% yield);
½
a 3D5
ꢂ
m
max/cmꢁ1 (thin film) 3299, 3030,
2926, 2856, 2257, 1600, 1495, 1455, 1433, 1380, 1352, 1327,
1305, 1184, 1160, 1119, 1093, 1054, 1020, 909, 846, 807, 755,
731, 698, 667; 1H NMR (400 MHz, CDCl3) d 7.38 (d, J = 11.2 Hz,
2H), 7.15–7.10 (m, 3H), 7.05–7.00 (m, 5H), 6.95–6.85 (m, 4H),
6.40–6.20 (br s, 1H), 5.35–5.25 (m, 2H), 4.25 (m, 1H), 3.60 (m,
1H), 2.77–2.60 (m, 1H), 2.35 (s, 3H), 2.45–2.25 (m, 3H), 1.92 (m,
1H), 1.70 (s, 4.5H), 1.45–1.20 (m, 6H), 1.05 (d, J = 7.2 Hz, 1.5H);
13C NMR (400 MHz, CDCl3) d 142.7, 139.4, 138.4, 137.0, 131.1,
129.1, 128.0, 127.6, 127.4, 127.3, 127.2, 125.2, 125.0, 123.4, 67.9,
63.1, 47.1, 36.8, 36.5, 34.0, 30.4, 29.6, 24.9, 23.1, 21.5. m/z 529
(M+H), 350; HRMS found (EI): [MꢁH]+ 529.2899, C33H41N2O2S re-
quires 529.2883 (ꢁ2.9 ppm error).
C
12H18NaO requires 201.1250 (1.5 ppm error).
4.4. 4-(3,5-Dimethylcyclohexa-1,4-dienyl)butan-1-ol
solution of 4-(3,5-dimethylphenyl)butan-1-ol (513 mg,
A
2.8 mmol) in ethanol (2.5 ml) was slowly added to a refluxing solu-
tion of ammonia (50 ml) containing ethanol (10 ml) at ꢁ78 °C
while stirring. Small sodium pieces were added to the reaction
mixture until the blue colour persisted. After the addition of so-
dium over the course of 7 h with regular additions of ethanol
(2.5 ml), the reaction mixture was left overnight to evaporate
ammonia. The reaction was quenched carefully with ammonium
chloride (satd, 20 ml) and extracted by DCM (3 ꢀ 6 ml). The com-
bined organic layer was dried over magnesium sulfate, filtered
and concentrated under reduced pressure to afford crude 4-(3,5-
dimethylcyclohexa-1,4-dienyl)butan-1-ol as an orange red oil
(374 mg, 90%) which appeared to be a ca. 1:1 mixture of diene iso-
mers. 1H NMR (300 MHz; CDCl3) d 5.32 (br s, 2H), 3.60–3.55 (m,
2H), 2.71 (br s, 1H), 2.35–2.25 (m, 2H), 2.00–1.92 (m, 1H), 1.65
(br s, 4.5H), 1.50–1.20 (m, 6H), 0.95 (d, J = 7.6 Hz, 1.5H). This mate-
rial was directly used in the next step.
4.7. N-((1R,2R)-2-(4-(3,5-Dimethylphenyl)butylamino)-1,2-
diphenylethyl)-4-methylbenzenesulfonamide ammonium
chloride dimer 13
To a stirred solution of N-((1R,2R)-2-(4-(3,5-dimethylcyclo-
hexa-1,4-dienyl)-butylamino)-1,2-diphenylethyl)-4-methylbenzene-
sulfonamide 15 (200 mg, 0.38 mmol) in anhydrous DCM (5.5 ml)
was added hydrochloric acid (2 M in diethyl ether, 0.57 ml,
1.14 mmol) at 0 °C. The reaction mixture was stirred at rt for
20 min and subsequently concentrated under reduced pressure
to give a white residue. To a suspension of the residue in ethanol
(7.2 ml) was added hydrate ruthenium(III) trichloride hydrate
(62 mg, 0.30 mmol). The reaction mixture was refluxed overnight.
The precipitate was collected by filtration and washed with etha-
nol to give N-((1R,2R)-2-(4-(3,5-dimethylphenyl)butylamino)-1,2-
diphenylethyl)-4-methylbenzenesulfonamide ammonium chloride
dimer 13 (54 mg, 25%) as black crystals. The compound was too
dark to obtain optical rotation measurement. Mp 240–250 °C
4.5. 4-(3,5-Dimethylcyclohexa-1,4-dienyl)butanal 14
A solution of oxalylchloride (2 M in DCM, 1.35 ml, 2.69 mmol)
in anhydrous DCM (3 ml) was cooled to ꢁ78 °C and was slowly
added to a solution of dimethylsulfoxide (0.38 ml, 5.38 mmol) in
DCM (1.5 ml) by a syringe. The solution was stirred for 30 min at
ꢁ78 °C before a solution of 4-(3,5-dimethylcyclohexa-1,4-die-
nyl)butan-1-ol (375 mg, 2.07 mmol) in DCM (5 ml) was slowly
(dec.); m
max/cmꢁ1 (thin film) 3054, 1597, 1456, 1323, 1156, 1091,

V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
1553
1030, 925, 813, 763, 700, 669; 1H NMR (400 MHz, DMSO-d6) d 9.85
(br s, 2H), 9.85 (br s, 2H), 8.95 (br s, 2H), 8.55 (d, J = 8.5 Hz, 2H),
7.40–6.70 (m, 28H), 5.59–5.51 (m, 6H), 4.74–4.66 (m, 2H), 4.50–
4.40 (m, 2H), 2.80–2.70 (m, 4H), 2.55 (br s, 12H), 2.40–2.35 (m,
4H), 2.20 (s, 6H), 1.83–1.50 (m, 8H); 13C NMR (400 MHz, DMSO-
d6) d 142.3, 137.5, 135.4, 131.4, 129.2, 129.1, 128.9, 128.7, 127.7,
127.6, 127.2, 126.4, 126.1, 107.1, 104.1, 82.8, 82.2, 82.1, 64.4,
60.5, 56.0, 45.4, 31.6, 25.1, 24.5, 20.9, 18.6, 18.3. m/z 1321, 1307,
627 (0.5 M-2HCl-Cl), 353 (molecular ion not observed; fragmenta-
tion ions with Ru isotope patterns observed). HRMS found (EI):
tracted thrice with 75 ml portions of dichloromethane. The com-
bined organic layers were dried over MgSO4, and after
concentration yielded
(400 MHz, CDCl3) d 7.99 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.61
(dtd, J = 1.4, 1.5, 1.4 Hz, 1H), 7.39 (dmd, J = 1.0, 1.0 Hz, 1H), 7.25
(d, J = 8.5 Hz, 1H), 2.88 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.7 Hz, 3H);
13C NMR (400 MHz, CDCl3) d 163.4, 147.2, 135.8, 128.8, 128.2,
126.9, 126.1, 125.1, 120.3, 31.7, 13.0.
a
yellow oil (1.90 g, 69%). 1H NMR
4.8.4. 2-Propylquinoline 2229
627.1631;
C
33H37N2O2RuS requires 627.1622 (1.4 ppm error),
Prepared as for 2-ethylquinoline 21 as a yellow oil (1.83 g, 61%).
1H NMR (400 MHz, CDCl3) d 8.05 (dd, J = 3.6, 3.7 Hz, 2H), 7.78 (d,
J = 8.1 Hz, 1H), 7.68 (dtd, J = 1.4, 1.5, 1.4 Hz, 1H), 7.49 (dmd,
J = 1.0, 1.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 2.99 (sts, J = 1.6 Hz,
2H), 1.90 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H); 13C NMR (400 MHz,
CDCl3) d 163.0, 148.0, 136.2, 129.3, 128.9, 127.5, 126.8, 125.7,
121.4, 41.3, 23.3, 14.0.
314.0841, C33H38N2O2RuS(2+) requires 314.0847 (1.9 ppm error).
4.8. General procedure for quinoline synthesis
2-Methylquinoline and 2-phenylquinoline were purchased
from Sigma–Aldrich and Alfa Aesar.
4.8.1. 2-tert-Butylquinoline 2028
4.8.5. 2-Butylquinoline 2329
To a solution of 6-nitrobenzaldehyde (3.02 g, 20 mmol) in etha-
nol (60 ml) was added iron power (<10 lm, aldrich, 4.47 g,
Prepared as for 2-ethylquinoline 21 as a yellow oil (1.70 g, 92%).
1H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.5 Hz, 1H), 7.99 (d,
J = 8.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 7.43
(t, J = 7.1 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 2.98–2.94 (m, 2H),
1.83–1.75 (m, 2H), 1.43 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).
13C NMR (400 MHz, CDCl3) d 163.1, 147.9, 136.1, 129.3, 128.8,
126.7, 125.6, 121.3, 39.1, 32.2, 22.7, 14.0.
80 mmol) followed by 0.1 N aq HCl (10 ml, 1 mmol) and the result-
ing mixture was vigorously stirred at 95 °C (oil bath) for 2 h. TLC
analysis revealed that the reduction reaction was complete and
so 3,3-dimethyl-2-butanone (2.0 g, 2.5 ml, 20 mmol) and pow-
dered KOH (1.35 g, 24 mmol) were added successively in portions
(caution! potential exotherm; add KOH slowly). The reaction mix-
ture was stirred at 95 °C, then cooled to rt, diluted with DCM
(600 ml) and filtered through a Celite pad. The filtrate was washed
with water (100 ml) and the aqueous phase was back-extracted
with DCM (2 ꢀ 40 ml). The combined organic phases were dried
over MgSO4, filtered and concentrated in vacuo to give 2-tert-
butylquinoline 20 as an orange red oil (3.7 g, 100%). 1H NMR
(400 MHz, CDCl3) d 8.03 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H),
7.65 (t, J = 7.0 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.45 (t, J = 7.1 Hz,
1H), 1.49 (s, 9H); 13C NMR (400 MHz, CDCl3) d 169.3, 147.5,
135.9, 129.5, 129.0, 127.2, 126.5, 125.6, 118.2, 38.2, 30.2.
4.8.6. 2-Phenylethylquinoline 2429
Prepared as for 2-ethylquinoline 21 as a yellow oil (3.02 g,
74%).1H NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.4 Hz, 1H), 7.97 (d,
J = 8.4 Hz, 1H), 7.73 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.37–7.24 (m,
5H), 7.18 (d, J = 8.4 Hz, 1H), 3.38–3.34 (m, 2H), 3.26–3.22 (m,
2H); 13C NMR (400 MHz, CDCl3) d 161.8, 148.1, 141.6, 136.2,
129.0, 128.6, 128.6, 126.9, 126.2, 125.9, 121.6, 41.1, 36.0.
4.8.7. 2-(3,5-Dimethoxyphenethyl)quinoline 2629
Prepared as for 2-ethylquinoline 21 as an orange oil (2.29 g,
78%). 1H NMR (300 MHz, CDCl3) d 8.05 (t, J = 8.5 Hz, 2H), 7.77
(dd, J = 8.1, 1.2 Hz, 1H), 7.69 (t, J = 6.9 Hz, 1H), 7.49 (t, J = 7.0 Hz,
1H), 7.24 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 2H), 6.32 (t,
J = 2.3 Hz, 1H), 3.74 (s, 6H), 3.31–3.26 (m, 2H), 3.12–3.07 (m,
4.8.2. 6,7-Dimethoxy-2-methylquinoline 2828
To a solution of 6-nitroveratraldehyde (2.11 g, 10 mmol) in eth-
anol (30 ml) was added iron power (<10 lm, aldrich, 2.23 g,
40 mmol) followed by 0.1 N aq HCl (5 ml, 0.5 mmol) and the result-
ing mixture was vigorously stirred at 95 °C (oil bath) for 2 h. TLC
analysis revealed that the reduction reaction was complete and
so acetone (0.58 g, 0.73 ml, 10 mmol) and powdered KOH (0.67 g,
12 mmol) were added successively in portions (caution! potential
exotherm; add KOH slowly). The reaction mixture was stirred at
95 °C, then cooled to rt, diluted with DCM (300 ml) and filtered
through a Celite pad. The filtrate was washed with water (50 ml)
and the aqueous phase was back-extracted with DCM (2 x
20 ml). The combined organic phases were dried over MgSO4, fil-
tered and concentrated in vacuo to give 6,7-dimethoxy-2-methyl-
quinoline 28 as brown crystals (1.55 g, 76 %). 1H NMR (400 MHz,
CDCl3) d 7.88 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 7.10 (d, J = 8.3 Hz,
1H), 6.95 (s, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 2.70 (s, 3H); 13C NMR
(400 MHz, CDCl3) d 156.5, 152.3, 149.1, 144.8, 134.5, 121.7,
120.1, 107.5, 105.1, 56.1, 56.0, 25.0.
2H); m
max/cmꢁ1 (thin film) 3057, 2998, 2935, 2837, 1735, 1594,
1563, 1504, 1459, 1427, 1349, 1310, 1295, 1204, 1147, 1115,
1065, 826, 750, 690; 13C NMR (300 MHz, CDCl3) d 161.1, 160.2,
147.4, 143.3, 135.6, 135.5, 128.8, 128.2, 126.9, 126.2, 125.2,
121.0, 105.9, 97.6, 54.6, 40.2, 35.6. m/z (ESI) 294 (M+H). HRMS
Found (EI): [M++H] 294.1486, C19H20NO2 requires 294.1489
(1.0 ppm error).
4.8.8. 2-(2-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethyl)quinoline
2529,30
Prepared as for 2-ethylquinoline 21 as white crystals (1.65 g,
46%). 1H NMR (300 MHz, CDCl3) d 8.05 (d, J = 8.3 Hz, 2H), 7.77
(dd, J = 8.2, 1.5 Hz, 1H), 7.68 (t, J = 6.9 Hz, 1H), 7.48 (t, J = 6.9 Hz,
1H), 7.27 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.72 (s, 1H), 5.91 (s, 2H),
3.24–3.15 (m, 4H); 13C NMR (300 MHz, CDCl3) d 135.7, 128.8,
128.3, 126.9, 125.2, 121.0, 112.1, 109.6, 100.9, 38.7, 35.5.
4.8.3. 2-Ethylquinoline 2129
4.9. General procedure for the asymmetric transfer
hydrogenation of ketones25d
2-Methylquinoline (2.50 g, 17.5 mmol) 5 was dissolved in dry
THF (35 ml). The reaction vessel was cooled to ꢁ78 °C and n-butyl-
lithium in hexanes (1.6 M, 10.9 ml, 17.5 mmol) was added. After
30 min, methyliodide (3.26 g, 1.43 ml, 23 mmol) was added via a
syringe. The mixture was allowed to gradually warm to rt while
being stirred overnight. The resulting light yellow solution was
concentrated, diluted with water (75 ml) and brine (25 ml) and ex-
A solution of ruthenium dimer (0.0025 mmol) in formic acid/tri-
ethylamine (5:2) azeotrope (0.5 ml) was stirred in a flame-dried
schlenk tube at 28 °C for 30 min. Ketone (1 mmol) was added.
The reaction mixture was stirred at 28 °C and monitored by TLC.
After the starting material was consumed, the reaction mixture

1554
V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
was diluted by DCM (6.7 ml) and washed with NaCO3 solution
(3 ꢀ 5 ml). The organic phase was dried over MgSO4 and concen-
trated under reduced pressure.
CHCl3) 91% ee (S); 1H NMR (300 MHz, CDCl3) d 6.98–6.94 (m,
2H), 6.60 (td, J = 7.4, 1.1 Hz, 1H), 6.47 (dd, J = 8.6, 1.3 Hz, 1H),
3.77 (br s, 1H), 3.19–3.13 (m, 1H), 2.85–2.69 (m, 2H), 2.00–1.94
(m, 1H), 1.63–1.48 (m, 3H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR
(300 MHz, CDCl3) d 144.1, 128.6, 126.1, 120.8, 116.3, 113.4, 52.4,
28.8, 27.0, 25.8, 9.5. Reduction of 21 using catalyst 12; 91% ee
and 67% conversion: enantiomeric excess by HPLC analysis and
conversion by NMR analysis (Chiralcel OD-H, hexane/isopropa-
nol = 90:10, flow rate 0.2 ml/min, 254 nm, 17.0 °C): tR = 26.8 min
(major), tS = 30.5 (minor).
4.9.1. Reduction of acetophenone using catalyst 11
Enantiomeric excess and conversion by GC analysis: 97% ee (R)
(Chrompac cyclodextrin-b-236M-19 50 m, T = 115 °C, P = 15 psi,
ketone 22.2 min, R isomer 33.5 min, S isomer 36.7 min); 1H NMR
(300 MHz, CDCl3) d 7.34–7.21 (m, 5H), 4.79 (q, J = 6.5, 1H), 2.62
(s, 1H), 1.44 (d, J = 6.5, 3H); dC (300 MHz; CDCl3) 145.9, 128.5,
127.4, 125.5, 70.3, 25.2.
4.11.3. (R)-2-Propyl-1,2,3,4-tetrahydroquinoline
4.9.2. Reduction of acetylcyclohexane using catalyst 11
Reduction of 22 using catalyst 9; 42% ee and 94% conversion:
Enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD, hexane/isopropanol = 90:10, flow rate
0.2 ml/min, 254 nm, 18.0 °C): tR = 23.6 min (major), tS = 26.8 (min-
Enantiomeric excess and conversion by GC analysis: 74% ee (S)
(Chrompac cyclodextrin-b-236 M-19 50 m, T = 115 °C, P = 15 psi,
ketone 18.8 min, R isomer 28.1 min, S isomer 31.0 min); 1H NMR
(400 MHz, CDCl3) d 3.59–3.51 (m, 1H), 1.88–1.62 (m, 5H), 1.37
(br s, 1H), 1.15 (d, J = 6.3 Hz, 3H), 0.91–1.31 (m, 6H); 1H NMR
(400 MHz, CDCl3) d 72.2, 45.1, 28.7, 28.4, 26.5, 26.2, 26.1, 20.4.
or); ½a 2D4
ꢂ
¼ þ54:1 (c 0.5, CHCl3) 42% ee (R) (lit.32
½
a 2D1
ꢂ
¼ ꢁ70:8 (c
1.1, CHCl3) 80% ee (S); 1H NMR (400 MHz, CDCl3) d 6.97–6.94 (m,
2H), 6.59 (t, J = 7.3 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.76 (br s, 1H),
3.28–3.21 (m, 1H), 2.85–2.69 (m, 2H), 1.98–1.92 (m, 1H), 1.64–
1.54 (m, 1H), 1.51–1.39 (m, 4H), 0.96 (t, J = 6.6 Hz, 3H); 13C NMR
(400 MHz, CDCl3) d 144.8, 129.3, 126.7, 121.4, 116.9, 114.1, 51.3,
38.9, 28.2, 26.5, 19.0, 14.3. Reduction of 22 using catalyst 12;
90% ee and 65% conversion: enantiomeric excess by HPLC analysis
and conversion by NMR analysis (Chiralcel OD-H, hexane/isopro-
panol = 90:10, flow rate 0.2 ml/min, 254 nm, 14.5 °C): tR = 24.5 min
(major), tS = 28.1 (minor).
4.10. General procedure for the asymmetric transfer
hydrogenation of Quinolines22a
A
solution of ruthenium dimer (0.0025 mmol) and imine
(1 mmol) in Methanol (1.6 ml) was stirred in a flame-dried Schlenk
tube at 28 °C for 10 min. Formic acid/triethylamine (5:2) azeotrope
(0.5 ml) was then added. The reaction mixture was stirred at 28 °C
and monitored by TLC. After the starting material was consumed,
NaHCO3 solution (5 ml) was added and was extracted with DCM
(3 ꢀ 6.7 ml). The organic phase was dried over MgSO4 and concen-
trated under reduced pressure.
4.11.4. (R)-2-Butyl-1,2,3,4-tetrahydroquinoline
Reduction of 23 using catalyst 9; 41% ee and 93% conversion:
enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD, hexane:isopropanol = 90:10, flow rate
0.2 ml/min, 254 nm, 18.5 °C): tR = 21.8 min (major), tS = 24.4 (min-
4.11. General procedure for the racemic standards3b
or); ½a 2D6
ꢂ
¼ þ46:6 (c 0.5, CHCl3) 41% ee (R) (lit.31
½
a 2D5
ꢂ
¼ ꢁ78:2 (c
To reaction bottle (A) were added [Ru(p-cymene)Cl2]2 (0.0028 g,
0.0045 mmol) and undistilled THF (2 ml). The mixture was stirred
until the solution was homogeneous. At the same time, to the reac-
tion bottle (B) were added quinoline (0.13 g, 0.12 ml, 0.89 mmol)
and I2 (0.012 g, 0.045 mmol) followed by THF (1 ml). The mixture
was stirred until the iodine was dissolved. Then to the reaction
bottle (B) was added the solution of [Ru(p-cymene)Cl2]2 of THF
in bottle (A). The final mixture was pressurised to 600 psi hydrogen
and stirred at 20 °C for 20 h. The reaction mixture was concen-
trated to afford the crude product and a sample was taken for GC
analysis.
0.53, CHCl3) 89% ee (S); 1H NMR (400 MHz, CDCl3) d 6.96–6.93
(m, 2H), 6.59 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 3.72 (br s,
1H), 3.24–3.18 (m, 1H), 2.84–2.68 (m, 2H), 1.98–1.91 (m, 1H),
1.63–1.53 (m, 1H), 1.51–1.45 (m, 2H), 1.41–1.32 (m, 4H), 0.94–
0.91 (m, 3H); 13C NMR (400 MHz, CDCl3) d 144.8, 129.3, 126.7,
121.4, 116.9, 114.1, 51.6, 36.5, 28.2, 28.0, 26.5, 22.9, 14.1. Reduc-
tion of 23 using catalyst 12; 92% ee and 64% conversion: Enantio-
meric excess by HPLC analysis and conversion by NMR analysis
(Chiralcel OD-H, hexane/isopropanol = 90:10, flow rate 0.2 ml/
min, 254 nm, 14.0 °C): tR = 22.8 min (major), tS = 25.6 (minor).
4.11.5. (S)-2-Phenyl-1,2,3,4-tetrahydroquinoline
4.11.1. (R)-2-Methyl-1,2,3,4-tetrahydroquinoline 5
21 Reduction of 19 using catalyst 9; 73% ee and 68% conversion:
Enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD, hexane/isopropanol = 90:10, flow rate
0.5 ml/min, 254 nm, 21.0 °C): tS = 17.0 min (major), tR = 21.1 (min-
Reduction of 4 using catalyst 9; 46% ee and 96% conversion,
reduction of 4 using catalyst 12; 93% ee and 68% conversion: Enan-
tiomeric excess and conversion by GC analysis (Chrompac cyclo-
dextrin-b-236M-19 50 m, T = 125 °C, P = 15 psi, gas He. imine
43.9 min, S isomer 67.5 min (minor), R isomer 68.6 min (major);
or); ½a 2D7
ꢂ
¼ ꢁ31:3 (c 0.5, CHCl3) 73% ee (S) (lit.31
½
a 2D5
ꢂ
¼ þ71:2 (c
1.0, CHCl3) 72% ee (R); 1H NMR (400 MHz, CDCl3) d 7.40–7.26 (m,
5H), 7.00 (m, 2H), 6.65 (t, J = 6.7 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H),
4.43 (dd, J = 3.3, 3.3 Hz, 1H), 4.04 (br s, 1H), 2.97–2.88 (m, 1H),
2.73 (tt, J = 4.8, 4.8 Hz, 1H), 2.15–2.09 (m, 1H), 2.04–1.94 (m,
1H); 13C NMR (400 MHz, CDCl3) d 144.8, 144.7, 129.3, 128.6,
127.5, 126.9, 126.6, 120.9, 117.2, 114.0, 56.3, 31.0, 26.4. Reduction
of 19 using catalyst 12; 86% ee and 30% conversion: Enantiomeric
excess by HPLC analysis and conversion by NMR analysis (Chiralcel
OD-H, hexane/isopropanol = 90:10, flow rate 0.5 ml/min, 254 nm,
19.0 °C): tS = 17.1 min (major), tR = 21.5 (minor).
27
*
½
a D
ꢂ
¼ þ46:7 (c 0.5, CHCl3) 43% ee (R) (lit.31
½
a 2D5
ꢂ
¼ ꢁ78:3 (c
0.76, CHCl3) 91% ee (S); 1H NMR (300 MHz, CDCl3) d 6.98–6.95
(m, 2H), 6.61 (t, J = 7.2 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 3.70 (br s,
1H), 3.44–3.38 (m, 1H), 2.85–2.74 (m, 2H), 1.94–1.91 (m, 1H),
1.64–1.55 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H); 13C NMR (300 MHz,
CDCl3) d 144.2, 128.7, 126.1, 120.5, 116.4, 113.4, 46.6, 29.5, 26.0,
*
22.0.
[a] determined on sample with 43% ee.
D
4.11.2. (R)-2-Ethyl-1,2,3,4-tetrahydroquinoline
Reduction of 21 using catalyst 9; 41% ee and 95% conversion:
enantiomeric excess and conversion by GC analysis (Chrompac
cyclodextrin-b-236 M-19 50 m, T = 115 °C, P = 15 psi, gas He. imine
94.6 min, S isomer 174.0 min (minor), R isomer 176.4 min (major);
4.11.6. (R)-2-Phenethyl-1,2,3,4-tetrahydroquinoline
Reduction of 24 using catalyst 9; 50% ee and 90% conversion:
Enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD, hexane:isopropanol = 90:10, flow rate
½
a 2D8
ꢂ
¼ þ35:6 (c 0.5, CHCl3) 41% ee (R) (lit.31
½
a 2D5
ꢂ
¼ ꢁ73:2 (c 0.24,

V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
1555
0.5 ml/min, 254 nm, 20.0 °C): tR = 17.8 min (major), tS = 19.5 (min-
116.5, 113.6, 112.7, 112.1, 109.1, 101.0, 50.3, 36.4, 31.6, 27.2,
25.6. HRMS Found (EI): [M++H] 360.0596, C18H19BrNO2 requires
360.0594 (-0.7 ppm error). Reduction of 25 using catalyst 12;
81% ee and 30% conversion: Enantiomeric excess by HPLC analysis
and conversion by NMR analysis (Chiralcel OD-H, hexane/isopro-
panol = 80:20, flow rate 0.6 ml/min, 254 nm, 19.0 °C): tS = 21.1 min
(major), tR = 29.1 (minor). The absolute configuration has not been
determined, but can be compared with the reduction product of
substrate 24.
or); ½a 2D5
ꢂ
¼ þ45:5 (c 0.5, CHCl3) 50% ee (R) (lit.31
½
a 2D5
ꢂ
¼ ꢁ73:1 (c
0.55, CHCl3) 92% ee (S); 1H NMR (300 MHz, CDCl3) d 7.30–7.16
(m, 5H), 6.97–6.92 (m, 2H), 6.59 (td, J = 7.4, 1.1 Hz, 1H), 6.42 (dd,
J = 8.6, 1.3 Hz, 1H), 3.80 (br s, 1H), 3.31–3.22 (m, 1H), 2.85–2.66
(m, 4H), 2.01–1.92 (m, 1H), 1.84–1.77 (m, 2H), 1.71–1.59 (m,
1H); 13C NMR (300 MHz, CDCl3) d 143.9, 141.3, 128.7, 127.9,
127.8, 126.1, 125.4, 120.7, 116.4, 113.5, 50.5, 37.7, 31.6, 27.4,
25.6. Reduction of 24 using catalyst 12; 93% ee and 57% conver-
sion: Enantiomeric excess by HPLC analysis and conversion by
NMR analysis (Chiralcel OD-H, hexane/isopropanol = 90:10, flow
rate 0.5 ml/min, 254 nm, 15.0 °C): tR = 19.7 min (major), tS = 21.7
(minor).
*
Acknowledgements
We thank the EPSRC and Dr. Reddy’s Laboratories (Cambridge)
for financial support of V.P. (via the Collaborative Training Account
grant held at Warwick University). Dr. Martin Fox (Dr. Reddy’s) is
acknowledged for the original observation of the presence of a par-
tially reduced quinoline as a by-product in an attempted ketone
reduction using 9. Dr. B. Stein and colleagues of the EPSRC National
Mass Spectroscopic service (Swansea) are thanked for HRMS anal-
ysis of certain compounds. We acknowledge the use of the EPSRC
Chemical Database Service.33 The sample of catalyst 1 used in this
project was prepared by Dr. Silvia Gosiewska and the sample of
catalyst 6 was prepared by Dr. José E. D. Martins.
4.11.7. 2-tert-Butyl-1,2,3,4-tetrahydroquinoline
Reduction of 20 using catalyst 9; 0% ee and 57% conversion:
enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD-H, hexane/isopropanol = 90:10, flow rate
0.5 ml/min, 254 nm, 15.0 °C): tR = 20.5 min, tS = 27.5; 1H NMR
(300 MHz, CDCl3) d 6.98–6.94 (m, 2H), 6.52 (td, J = 7.4, 1.1 Hz,
1H), 6.45 (d, J = 7.7 Hz, 1H), 3.78 (br s, 1H), 3.00–2.96 (m, 1H),
2.83–2.70 (m, 2H), 2.00–1.95 (m, 1H), 1.60–1.55 (m, 1H), 0.98 (s,
9H); 13C NMR (300 MHz, CDCl3) d 144.8, 128.4, 126.1, 120.9,
116.1, 113.4, 60.3, 32.8, 26.8, 25.4, 22.5. Reduction of 20 using cat-
alyst 12; 0% ee and 16% conversion; HPLC (Chiralcel OD-H, hexane/
isopropanol = 90:10, flow rate 0.2 ml/min, 254 nm, 14.0 °C):
tR = 20.6 min, tS = 27.9.
References
1. (a) Blaser, H.-U.; Spindler, F. In Chapter 6.2 of Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Heidelberg, 2004; (b)Catalytic Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.;
Wiley-VCH, 2000; (c) Capprio, V.; Williams, J. M. J. Catalysis in Asymmetric
Synthesis; John Wiley and Sons: Chichester, 2008. Chapter 3.
2. Wills, M. In Modern Reduction Methods; Andersson, P. G., Munslow, I. J., Eds.;
Wiley-VCH: Weinheim, 2008; pp 271–296. Chapter 11.
3. (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X. W.; Zhou, Y.-G. J. Am. Chem. Soc.
2003, 125, 10536–10537; (b) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. J. Organomet.
Chem. 2007, 692, 3065–3069.
4.11.8. (R)-2-(3,5-Dimethoxyphenethyl)-1,2,3,4-tetrahydro-
quinoline
Reduction of 26 using catalyst 9; 67% ee and 93% conversion:
Enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD-H, hexane:isopropanol = 80:20, flow rate
0.6 ml/min, 254 nm, 18.0 °C): tR = 28.1 min (major), tS = 36.8 (min-
4. Lam, K. H.; Xu, L.; Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W.-H.; Chan, A. S. C. Adv.
Synth. Catal. 2005, 347, 1755–1758.
24
*
or);
½
a D
ꢂ
¼ þ39:5 (c 0.5, CHCl3) 67% ee (R);
m
max/cmꢁ1 (thin film)
5. 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, 5955–5965.
6. Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka, Y.; Ratovelomanana-
Videl, V.; Genet, J. P.; Mashima, K. Organometallics 2006, 25, 2505–2513.
7. 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, 613–615.
8. Jahjah, M.; Alame, M.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron: Asymmetry
2007, 18, 2305–2312.
9. Deport, C.; Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.;
Genet, J.-P.; Mashima, K. Synlett 2007, 2743–2747.
10. Chan, S. H.; Lam, K. H.; Li, Y.-M.; Xu, L.; Tang, W.; Lam, F. L.; Lo, W. H.; Yu, W. Y.;
Fan, Q.; Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 2625–2631.
11. Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H. Chem. Commun. 2005, 1390–
1392.
12. Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-H. Org. Lett. 2007, 9,
1243–1246.
13. Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45,
2260–2263.
14. Reetz, M. T.; Li, X. Chem. Commun. 2006, 2159–2160.
3675, 3396, 2935, 2838, 1594, 1460, 1428, 1351, 1309, 1276,
1254, 1203, 1148, 1114, 1056, 924, 830, 746, 718, 696, 667; 1H
NMR (300 MHz, CDCl3) d 6.98–6.90 (m, 2H), 6.60 (td, J = 7.4,
1.1 Hz, 1H), 6.45 (dd, J = 8.2, 1.4 Hz, 1H), 6.38–6.35 (m, 2H), 6.32–
6.28 (m, 1H), 3.77 (s, 6H), 3.34–3.25 (m, 1H), 2.81–2.72 (m, 2H),
2.69–2.63 (m, 2H), 2.2–1.94 (m, 1H), 1.85–1.75 (m, 2H), 1.72–
1.60 (m, 1H). 13C NMR (300 MHz, CDCl3) d 160.9, 144.3, 129.3,
126.8, 121.3, 117.0, 114.2, 106.5, 97.9, 55.3, 51.1, 38.0, 32.5, 28.0,
26.2. HRMS Found (EI): [M++H] 298.1798, C19H24NO2 requires
298.1802 (1.3 ppm error). Reduction of 26 using catalyst 12; 94%
ee and 58% conversion: Enantiomeric excess by HPLC analysis
and conversion by NMR analysis (Chiralcel OD-H, hexane:isopro-
panol = 80:20, flow rate 0.6 ml/min, 254 nm, 19.0 °C): tR = 27.4 min
*
(major), tS = 35.9 (minor). The absolute configuration has not been
determined, but can be compared with the reduction product of
substrate 27.
15. (a) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. Adv. Synth. Catal. 2004, 346, 909–912; (b)
Wang, D.-S.; Zhou, J.; Wang, D.-W.; Guo, Y.-L.; Zhou, Y.-G. Tetrahedron Lett.
2010, 51, 525–528.
16. Zhou, H.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; He, Y.; Fan, Q.-H.; Pan, J.; Gu, L.;
Chan, A. S. C. Angew. Chem., Int. Ed. 2008, 47, 8464–8467.
17. Li, Z.-W.; Wang, T.-L.; He, Y.-M.; Wang, Z.-J.; Fan, Q.-H.; Pan, J.; Xu, L.-J. Org. Lett.
2008, 10, 5265–5268.
18. Wang, C.; Li, C. Q.; Wu, X. F.; Pettman, A.; Xiao, J. L. Angew. Chem., Int. Ed. 2009,
48, 6524–6528.
19. Fujita, K.-I.; Kitatsuji, C.; Furukawa, S.; Yamaguchi, R. Tetrahedron Lett. 2004, 45,
3215–3217.
20. Reuping, M.; Theissmann, T.; AntonChick, A. P. Synlett 2006, 1071–1074.
21. Wang, D.-W.; Zeng, W.; Zhou, Y.-G. Tetrahedron: Asymmetry 2007, 18, 1103–
1107.
22. (a) Noyori, R. Adv. Synth. Catal. 2003, 345, 15–32; (b) Noyori, R.; Sandoval, C. A.;
Muniz, K.; Ohkuma, T. Philos. Trans. R. Soc. London, Ser. A 2005, 363, 901–912;
(c) Hedberg, C. In Modern Reduction Methods; Andersson, P. G., Munslow, I. J.,
Eds.; Wiley-VCH, 2008. Chapter 5; (d) Noyori, R.; Kitamura, M.; Ohkuma, T.
Proc. Nat. Acad. Sci. 2004, 101, 5356–5362; (e) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2006, 40, 40–73; (f) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563; (g) Fujii, A.; Hashiguchi,
4.11.9. (R)-2-(2-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethyl)-
1,2,3,4-tetrahydroquinoline
Reduction of 25 using catalyst 9; 47% ee and 86% conversion:
Enantiomeric excess by HPLC analysis and conversion by NMR
analysis (Chiralcel OD-H, hexane/isopropanol = 80:20, flow rate
0.6 ml/min, 254 nm, 19.0 °C): tS = 21.2 min (major), tR = 29.2 (min-
25
*
or);
½
a D
ꢂ
¼ þ25:6 (c 0.5, CHCl3) 47% ee (R);
m
max/cmꢁ1 (thin film)
3664, 3410, 2912, 1606, 1585, 1500, 1473, 1434, 1408, 1353,
1309, 1275, 1227, 1111, 1066, 1035, 964, 931, 858, 832, 746,
718, 657; 1H NMR (300 MHz, CDCl3) d 7.02–6.92 (m, 3H), 6.70 (s,
1H), 6.59 (td, J = 7.4, 1.2 Hz, 1H), 6.45 (dd, J = 8.3, 1.3 Hz, 1H),
5.90 (s, 2H), 3.84 (br s, 1H), 3.38–3.30 (m, 1H), 2.88–2.72 (m,
4H), 2.10–2.00 (m, 1H), 1.88–1.72 (m, 2H), 1.60 (s, 1H); 13C NMR
(300 MHz, CDCl3) d 146.8, 143.9, 133.5, 128.6, 126.1, 120.7,

1556
V. Parekh et al. / Tetrahedron: Asymmetry 21 (2010) 1549–1556
S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522;
(h) Koike, T.; Ikariya, T. Adv. Synth. Catal. 2004, 346, 37–41; (i) Ikariya, T.;
2007, 9, 4659–4662; (e) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006,
71, 7035–7044.
Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393–406; (j) Gladiali, S.;
Alberico, E. Chem. Soc. Rev. 2006, 36, 226–236.
23. (a) Uematsu, N.; Fujii, A.; Hasjiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 4916–4917; (b) Williams, G. D.; Wade, C. E.; Wills, M. Chem.
Commun. 2005, 4735–4737; (c) Williams, G. D.; Pike, R. A.; Wade, C. E.; Wills,
M. Org. Lett. 2003, 22, 4227–4230.
24. Martins, J. E. D.; Clarkson, G. J.; Wills, M. Org. Lett. 2009, 11, 847–850.
25. (a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005,
127, 7318–7319; (b) Matharu, D. S.; Morris, D. J.; Kawamoto, A. M.; Clarkson, G.
J.; Wills, M. Org. Lett. 2005, 7, 5489–5491; (c) Matharu, D. S.; Clarkson, G. J.;
Morris, D. J.; Wills, M. Chem. Commun. 2006, 3232–3234; (d) Cheung, F. K.; Lin,
C. X.; Minissi, F.; Criville, A. L.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett.
26. Blackmond, D. G.; Ropic, M.; Stefinovic, M. Org. Proc. Res. Dev. 2006, 10, 457–463.
27. Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa, B. L. J. Am. Chem.
Soc. 2006, 128, 14977–14985.
28. Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.; Dong, H.-Q.; Jin, M.; Ma, L.;
Panicker, B.; Siu, K. W.; Steinig, A. G.; Stolz, K. M.; Tavares, P. A. R.; Volk, B.;
Weng, Q.; Werner, D.; Mulvihill, M. J. Org. Biomol. Chem. 2007, 5, 61–64.
29. Stevens, R. V.; Canary, J. W. J. Org. Chem. 1990, 55, 2237–2240.
30. Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron 2002, 58, 3387–3400.
31. Wang, X.; Zhou, Y. J. Org. Chem. 2008, 73, 5640–5642.
32. Lu, S.-M.; Bolm, C. Adv. Synth. Cat. 2008, 350, 1101–1105.
33. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36,
746–749.