One-pot catalytic enantioselective synthesis of functionalized tetrahydroquinolines by aza-michael/michael cascade reactions of N-protected 2-aminophenyl α,β-unsaturated esters with Nitroolefins

Article abstract of DOI:10.1055/s-0034-1379044

A highly enantioselective synthesis of functionalized tetrahydroquinolines with useful biological properties has been developed by means of asymmetric organocatalytic aza-Michael/Michael cascade reactions of nitroolefins with N-protected 2-aminophenyl α,β-unsaturated esters in the presence of a chiral thiourea catalyst. The reaction gave the corresponding highly functionalized tetrahydroquinolines in good yields, excellent diastereoselectivities (>30:1 dr), and high enantioselectivities (≤99% ee).

Full text of DOI:10.1055/s-0034-1379044

PAPER
▌3365
pOapnere-Pot Catalytic Enantioselective Synthesis of Functionalized Tetrahydro-
quinolines by Aza-Michael/Michael Cascade Reactions of N-Protected
2-Aminophenyl α,β-Unsaturated Esters with Nitroolefins
Functionalized Tetrahydroquinolines
Ki-Tae Kang, Sung-Gon Kim*
Department of Chemistry, College of Natural Science, Kyonggi University, 154-42 Gwanggyosan-ro, Yeongtong-gu, Suwon, 443-760,
Republic of Korea
Fax +82(31)2531165; E-mail: sgkim123@kyonggi.ac.kr
Received: 08.07.2014; Accepted after revision: 06.08.2014
co-workers successfully developed a three-component en-
Abstract: A highly enantioselective synthesis of functionalized tet-
antioselective Povarov reaction for the efficient synthesis
rahydroquinolines with useful biological properties has been devel-
of 2,3,4-trisubstituted tetrahydroquinolines from anilines,
oped by means of asymmetric organocatalytic aza-Michael/Michael
cascade reactions of nitroolefins with N-protected 2-aminophenyl
aldehydes, and ene carbamates as precursors.4c
α,β-unsaturated esters in the presence of a chiral thiourea catalyst.
The reaction gave the corresponding highly functionalized tetrahy-
tions6 have also been identified as potential methods for
droquinolines in good yields, excellent diastereoselectivities (>30:1
Organocatalytic5 enantioselective domino/cascade reac-
the asymmetric synthesis of functionalized tetrahydro-
quinolines. In particular, many organocatalytic reactions
dr), and high enantioselectivities (≤99% ee).
Key words: organocatalysis, Michael additions, cascade reactions,
asymmetric synthesis, tetrahydroquinolines
catalyzed by bifunctional thiourea derivatives of cinchona
alkaloids have been described.7 Recently, Xu and co-
workers reported an aza-Michael/Michael cascade reac-
tion of 2-aminophenyl α,β-unsaturated ketones with ni-
The tetrahydroquinoline core is a characteristic structural
troolefins to give 2,3,4-trisubstituted tetrahydroquinolines
motif in many biologically active natural products and
in high yields and excellent enantioselectivities, but with
pharmacologically relevant therapeutic agents.1 In partic-
only moderate to good diastereoselectivities.4a Because of
ular, chiral functionalized tetrahydroquinolines form the
the limited success of this approach, there is still a need to
structural cores of many natural products and pharmaceu-
develop an efficient enantioselective synthetic method for
ticals that exhibit a broad range of biological activities,
preparing highly functionalized tetrahydroquinolines. Re-
such as anti-HIV, antibacterial, antifungal, antimalarial,
cently, our group and Du and co-workers independently
antitumor, and cardiovascular effects.2 Consequently, the
reported an organocatalyzed aza-Michael/Michael cas-
asymmetric synthesis of functionalized tetrahydroquino-
cade reaction for the synthesis of chiral highly functional-
lines has been investigated intensively, and numerous ste-
ized tetrahydroquinolines by using 2-(tosylamino)phenyl
reoselective methodologies have been developed.3 In
α,β-unsaturated ketones and nitroolefins as the starting
particular, highly functionalized tetrahydroquinolines
materials to give the desired products in good yields and
with chiral centers at the 2-, 3-, and 4-positions have re-
excellent diastereoselectivities and enantioselectivities.8
ceived considerable attention and, as a result, there is an
To develop these findings further, we surmised that the
use of 2-(tosylamino)phenyl α,β-unsaturated esters in the
aza-Michael/Michael cascade reaction might give chiral
highly functionalized tetrahydroquinolines possessing
greater synthetic versatility, as the ester functional group
can be readily transformed into various other functional
increasing demand for the development of new methods
for their efficient asymmetric synthesis. A number of suc-
cessful examples that use ortho-amino aromatic com-
pounds as nucleophiles to react with a diverse range of
electrophiles to give highly functionalized tetrahydro-
quinolines have been reported.4 For example, Masson and
O
OR1
O
O
X
Aza-Michael/
Michael
reaction
OR1
NO2
R1O
NHPG
+
NO2
R2
catalyst
X
X
NO2
R2
N
R2
N
PG
PG
Scheme 1 Organocatalytic aza-Micheal/Micheal cascade reaction of N-protected 2-aminophenyl α,β-unsaturated esters with nitroalkenes
SYNTHESIS 2014, 46, 3365–3373
Advanced online publication: 10.09.2014
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DOI: 10.1055/s-0034-1379044; Art ID: ss-2014-f0428.eps
© Georg Thieme Verlag Stuttgart · New York

3366
K.-T. Kang, S.-G. Kim
PAPER
groups, such as carboxylic acid, aldehyde, or alcohol The choice of protecting group on the nitrogen atom of the
groups (Scheme 1).9
phenyl α,β-unsaturated ethyl ester significantly affected
the reactivity of the substrate in the aza-Michael/Michael
reaction. No reaction was observed when ethoxycarbonyl,
tert-butoxycarbonyl, or benzyloxycarbonyl protecting
groups were used (Table 1, entries 1–3). However, the re-
action proceeded smoothly to give the desired tetrahydro-
quinoline 3aa in good yield, excellent diastereoselectivity
(>30:1 dr), and good enantioselectivity (92% ee) when a
more strongly electron-withdrawing tosyl group was used
as the protecting group in ester 1 (Table 1, entry 4).
We began our studies by evaluating the cascade reaction
of N-protected-2-aminophenyl α,β-unsaturated ethyl es-
ters 1 with β-nitrostyrene (2a) using thiourea cinchona al-
kaloid Ia as the catalyst in dichloromethane at room
temperature (Table 1 and Figure 1).
Table 1 Exploration of the Aza-Michael/Michael Reactions of N-
Protected 2-Aminophenyl α,β-Unsaturated Esters with β-Nitrosty-
renea
O
Under analogous conditions, the cinchona alkaloid-based
catalysts Ib, Ic, and IIa gave similar results to catalyst Ia,
affording 3aa in moderate yield with excellent diastereo-
selectivity (>30:1 dr) and good enantioselectivity (entries
5, 6, and 8). Of the cinchona alkaloids tested, the thiourea
cinchona alkaloid IIb was found to be the optimal catalyst
in terms of the reactivity and stereoselectivity of the reac-
tion (entry 9). The Takemoto catalysts IIIa and IIIb10
gave inferior results to catalyst IIb (entries 5–8). Next, we
examined various solvents to optimize the reaction fur-
ther. The reaction medium had a marked effect on the con-
version efficiency of the reaction. Protic solvents gave
reduced reaction efficiencies (entries 15–18), probably
due to a reduction in the activity of the catalyst because
the aza-Michael/Michael reaction occurs through sub-
strate activation by the thiourea catalyst through hydro-
gen-bonding interactions. The solvent-screening studies
identified toluene as the optimal solvent for the reaction
(entry 14); however, we chose dichloromethane as the sol-
vent for further evaluation of this reaction, because most
of the substrates that we tested showed poor solubility in
toluene.
OEt
O
NHPG
EtO
1
catalyst (10 mol%)
NO2
+
solvent, r.t.
NO2
Ph
N
Ph
2a
PG
3
Entry PG
Catalyst Solvent Time Yield drc
(h) (%)b
eed
(%)
e
e
e
1
2
CO2Et
Ia
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
48
48
48
40
30
36
30
30
24
36
48
24
52
24
52
52
52
52
–
–
–
ndf nd
Boc
Cbz
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ia
nd
nd
nd
nd
3
Ia
4
Ia
85
57
53
85
66
86
91
8
>30:1 92
>30:1 93
>30:1 92
24:1 96
>30:1 92
>30:1 98
10:1 94
5
Ib
6
Ic
7
Id
Having identified the optimal reactions conditions [1 (1
equiv), 2 (2 equiv), catalyst IIb (10 mol%), CH2Cl2], we
examined the scope of the reaction with various sub-
strates. First, we examined the reaction of various 2-(to-
sylamino)phenyl α,β-unsaturated esters 1a–j with β-
nitrostyrene (2a; Table 2). The reaction proved insensitive
to the type of ester moiety and it proceeded smoothly to
give the corresponding tetrahydroquinolines 3aa–da in
good yields and excellent diastereo- and enantioselectivi-
ties. Furthermore, the sterically bulky tert-butyl ester 1d
presented no problems, and gave tetrahydroquinoline 3da
with >30:1 dr and 98% ee, albeit with a reduced yield (en-
try 4). The electronic nature, bulk, and position of the sub-
stituent in the phenyl ring of the 2-(tosylamino)phenyl
α,β-unsaturated ethyl esters had no obvious effect on the
efficiency, diastereoselectivity, or enantioselectivity of
the reaction (entries 5–10).
8
IIa
IIb
IIIa
IIIb
IIb
IIb
IIb
IIb
IIb
IIb
IIb
9
10
11
12
13
14
15
16
17
18
nd
nd
88
71
85
15
5
>30:1 97
>30:1 97
>30:1 99
25:1 95
toluene
MeCN
THF
nd
nd
nd
nd
nd
nd
MeOH
DMF
5
e
–
a All of the reactions were carried out in the appropriate solvent (0.3
M) with 1 (0.15 mmol) and β-nitrostyrene (2a, 0.30 mmol) in the pres-
ence of the catalyst (10 mol%) at r.t.
We also evaluated the catalytic aza-Michael/Michael cas-
cade reactions of various nitroolefins 2b–m (Table 3).
The electronic nature of nitroolefin 2 had little effect on
the reactivity or stereoselectivity of the reaction. Aromatic
nitroolefins with either electron-donating (Table 3, entries
1–5) or electron-withdrawing substituents (entries 6–10)
on the phenyl ring participated in the reaction with high
efficiency, regardless of the substitution pattern. All prod-
b Isolated yield after chromatographic purification.
c Determined by 1H NMR analysis.
d Determined by chiral-phase HPLC analysis.
e No reaction.
f Not determined.
Synthesis 2014, 46, 3365–3373
© Georg Thieme Verlag Stuttgart · New York

PAPER
Functionalized Tetrahydroquinolines
3367
R1
R1
CF3
H
N
H
N
S
HN
NH
F3C
N
N
H
H
Ar
Ar
N
N
N
R2
R2
N
S
S
N
H
H
Ia R1 = H, Ar = 3,5-(F3C)2C6H3
Ib R1 = H, Ar = Ph
Ic R1 = OMe, Ar = 3,5-(F3C)2C6H3
Id R1 = OMe, Ar = Ph
IIIa R2 = Me
IIIb R2 = H
IIa R1 = OMe, Ar = 3,5-(F3C)2C6H3
IIb R1 = OMe, Ar = Ph
Figure 1 Evaluated chiral organocatalysts
ucts were obtained in good yield with excellent diastereo- in excellent yield and diastereoselectivity, albeit with a
selectivities (from 25:1 to >30:1 dr) and slightly diminished enantioselectivity (entry 12).
enantioselectivities (94–99% ee). Much to our delight, the
hetaryl nitroolefin 2l was also tolerated and gave the high-
ly functionalized tetrahydroquinoline 3al in 83% yield
with >30:1 d.r. and 98% ee (entry 11). In addition, the al-
To determine the absolute configuration of the products,
we prepared single crystals suitable for X-ray crystallo-
graphic analysis from the tetrahydroquinoline 3ae. The
absolute stereochemistry of 3ae was unambiguously as-
iphatic nitroolefin 2m also gave the desired product 3am
Table 3 Enantioselective Aza-Michael/Michael Reactions of 2-
(Tosylamino)phenyl α,β-Unsaturated Ethyl Ester (1a) with Nitro-
alkenes 2b–m Catalyzed by Thiourea IIba
Table 2 Enantioselective Aza-Michael/Michael Reactions of 2-(To-
O
sylamino)phenyl α,β-Unsaturated Esters 1a–j with β-Nitrostyrene
(2a) Catalyzed by Thiourea IIba
O
OEt
O
EtO
NHTs
1a
R4
NO2
OR1
IIb (10 mol%)
O
+
R3
NHTs
1
N
R1
CH2Cl2, r.t.
R1O
NO2
R1
R2
Ph
R4
IIb (10 mol%)
Ts
NO2
Ph
+
2
3
CH2Cl2, r.t.
NO2
R3
Entry R1
Product Time Yield drc
ee%d
N
2a
(h)
(%)b
R2
Ts
3
1
2
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
3ab
3ac
3ad
24
24
24
24
24
24
24
24
24
24
24
24
52
88
61
73
78
72
92
74
80
76
83
94
>30:1 94
>30:1 96
>30:1 95
>30:1 99
>30:1 97
Entry R1
R2 R3
R4
Product Time Yield drc
(h) (%)b
eed
(%)
3
1
2
Et
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
3aa
3ba
3ca
3da
24 91
24 82
24 98
48 45
36 79
36 63
28 72
28 83
36 80
36 64
>30:1 98
4
3,4-(MeO)2C6H3 3ae
Me
Bn
H
H
H
H
H
>30:1 94
>30:1 98
>30:1 98
>30:1 97
>30:1 98
>30:1 94
>30:1 96
>30:1 97
25:1 94
5
4-MeC6H4
4-ClC6H4
2-ClC6H4
2-BrC6H4
4-FC6H4
4-O2NC6H4
2-thienyl
i-Pr
3af
3ag
3ah
3ai
3
6
28:1
96
4
t-Bu
Et
7
>30:1 97
>30:1 97
5
Me 3ea
8
6
Et
H
3fa
3ga
3ha
3ia
3ja
9
3aj
3ak
3al
28:1
25:1
96
94
7
Et
OCH2O
10
11
12
8
Et
H
Cl
H
Cl
>30:1 98
>30:1 70
9
Et
H
3am
10
Et
Br
a All of the reactions were carried out in CH2Cl2 (0.3 M) with 1 (0.15
mmol) and nitroalkene 2 (0.30 mmol) in the presence of catalyst IIb
(10 mol%) at r.t.
a All of the reactions were carried out in CH2Cl2 (0.3 M) with 1 (0.15
mmol) and β-nitrostyrene (2a, 0.30 mmol) in the presence of catalyst
IIb (10 mol%) at r.t.
b Isolated yield after chromatographic purification.
c Determined by 1H NMR analysis.
b Isolated yield after chromatographic purification.
c Determined by 1H NMR analysis.
d Determined by chiral-phase HPLC analysis.
d Determined by chiral-phase HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3365–3373

3368
K.-T. Kang, S.-G. Kim
PAPER
O
EtO
NO2
OMe
OMe
N
Ts
Figure 2 X-ray crystal structure of compound 3ae
signed as (2R,3S,4R) by means of single-crystal X-ray dif- dr). From these results, we surmise that the presence of a
fraction (Figure 2).11 By analogy, the other products were tosyl group is important for achieving a high level of dia-
assumed to have the same configuration.
stereoselectivity, although it decreases the observed reac-
tivity.
Finally, to confirm the role of the tosyl group and the α,β-
unsaturated ester moiety, as well as their combined effect, From our experimental results and a dual-activation mod-
we examined the catalytic reactions of 4-methoxyaniline el,12 we propose a simplified but plausible mechanism that
(4a), 4-methoxy-N-tosylaniline (4b), and the 2-aminophe- account for the observed stereoselectivity of the reaction
nyl α,β-unsaturated ethyl ester 4c with β-nitrostyrene (2a) (Scheme 3). Initially, the nitroolefin 2a is activated by hy-
in the presence of the thiourea cinchona alkaloid catalyst drogen bonding, including an interaction between the car-
IIb under our optimized reaction conditions (Scheme 2). bonyl and thiourea moieties of the bifunctional catalyst
The reaction of 4-methoxyaniline (4a) gave the desired IIb. Meanwhile, the tertiary amine moiety present in the
product 5 in 80% yield but as a racemate, indicating that catalyst acts as a base and activates the tosylated amine in
the α,β-unsaturated ester moiety is a key feature for chiral compound 1a. The amine in the 2-(tosylamino)phenyl
induction in the aza-Michael/Michael cascade reaction. α,β-unsaturated ethyl ester attacks activated β-nitrosty-
Notably, no reaction was observed when 4-methoxy-N-to- rene (2a) preferentially from the Re face, resulting in an
sylaniline (4b) was used, whereas the 2-aminophenyl α,β- intermediate with an R-configuration. The resulting α-car-
unsaturated ethyl ester 4c gave the desired product 6 in bon derived from the nitroalkene approaches the α,β-un-
good yield and high enantioselectivity (94% ee for the saturated ester group by an intramolecular Michael
major isomer), but with moderate diastereoselectivity (2:1 reaction to give the (2R,3S,4R)-product 3.
In conclusion, a highly diastereo- and enantioselective
catalytic aza-Michael/Michael cascade reaction of 2-(to-
MeO
sylamino)phenyl α,β-unsaturated ketones with nitroole-
fins in the presence of a cinchona alkaloid-derived
NH2
MeO
NO2
Ph
IIb
(10 mol%)
4a
+
thiourea was developed for the efficient preparation of
highly functionalized tetrahydroquinoline derivatives.
The cascade reaction proceeded well with a wide range of
nitroolefins and 2-(tosylamino)phenyl α,β-unsaturated es-
ters, and provided efficient access to a variety of highly
functionalized tetrahydroquinolines in good yields and
excellent diastereo- and enantioselectivities (up to >30:1
dr, 99% ee).
∗
N
CH2Cl2, r.t.
NO2
H
Ph
2a
5: 80% yield, racemic
MeO
NHTs
MeO
NO2
Ph
IIb
(10 mol%)
4b
+
∗
N
CH2Cl2, r.t.
All reactions were performed in flame- or oven-dried glassware un-
der an atmosphere of dry N2. Organic solvents were distilled before
use. Organic solutions were concentrated under reduced pressure
using a Büchi rotary evaporator. Chromatographic purification of
products was accomplished using forced-flow chromatography on
ICN 60 32–64 mesh silica gel 63. TLC was performed on 0.25 mm
silica gel 60-F plates (EM Reagents, Darmstadt). Developed chro-
matograms were visualized by fluorescence quenching and by
staining with anisaldehyde. 1H NMR spectra were recorded at 400
or 700 MHz and 13C NMR spectra were recorded at 100 MHz or 176
MHz on Bruker Avance II 400 or Avance III 700 spectrometers.
The NMR spectra were internally referenced to residual nondeuter-
ated solvent signals. Optical rotations were measured with a Perkin-
Elmer P241 polarimeter with a sodium lamp (589 nm) and a 1.0 dm
cell. High-resolution mass spectra were recorded by using a SYN-
APT G2 Q-TOF mass spectrometer. HPLC analysis was performed
NO2
Ph
Ts
6
2a
CO2Et
CO2Et
NH2
4c
+
∗
∗
MeO
NO2
Ph
IIb
(10 mol%)
∗
N
CH2Cl2, r.t.
NO2
H
Ph
6: 75% yield, 2:1 d.r.
major: 94% ee
2a
minor: 90% ee
Scheme 2 The effects of tosyl and α,β-unsaturated ester functional
groups in organocatalytic aza-Micheal/Micheal reactions
Synthesis 2014, 46, 3365–3373
© Georg Thieme Verlag Stuttgart · New York

PAPER
Functionalized Tetrahydroquinolines
3369
OMe
H
N
NH
O
Ph
N
O
S
N
EtO
H
NO2
IIb
OEt
NO2
+
Ph
aza-Michael/
Michael reaction
NHTs
1a
N
Ph
2a
Ts
3aa
N
∗
+
N
S
MeO
H
S
N
N
H
N
H
H
EtO
N
N
O
Ar
H
N
O–
O –
O–
+N
H
N
O
+
N
Ts
Ph
Ts
Ph
intra-Michael
Si-face attack
CO2Et
inter-aza-Michael
Re-face attack
Scheme 3 A proposed mechanism for the asymmetric aza-Micheal/Micheal reaction
on a Hewlett-Packard 1100 Series chromatograph by using an AD-
H (25 cm) column and an AD-H guard (5 cm) column.
Methyl [(2R,3S,4R)-3-Nitro-2-phenyl-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl]acetate (3ba)
20
White solid; yield: 59 mg (82%); mp 148–150 °C; [α]D –16.1 (c
Alkyl [(2R,3S,4R)-3-Nitro-1-tosyl-1,2,3,4-tetrahydroquinolin-4-
yl]acetates 3; General Procedure
1.4, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 7.6 Hz, 1 H), 7.57 (d,
J = 8.0 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.20–7.36 (m, 8 H), 7.02
(d, J = 8.0 Hz, 1 H), 6.02 (d, J = 7.2 Hz, 1 H), 4.79 (dd, J = 7.2, 10.8
Hz, 1 H), 3.64 (s, 3 H), 2.70–2.77 (m, 1 H), 2.58 (dd, J = 8.4, 17.2
Hz, 1 H), 2.44 (s, 3 H), 2.36 (dd, J = 3.6, 17.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.3, 144.5, 139.6, 135.8, 135.5,
131.4, 129.9, 129.1, 128.8, 128.5, 127.8, 127.5, 127.2, 126.2, 124.9,
94.8, 62.8, 52.1, 36.5, 32.3, 21.7.
A 2-dram amber vial equipped with a magnetic stirrer bar was
charged at r.t. with catalyst IIb (0.015 mmol, 10 mol%) and enoate
1 (0.15 mmol, 1.0 equiv), followed by toluene (0.5 mL) The solu-
tion was stirred for 5 min and then nitroalkene 2 (0.30 mmol, 2.0
equiv) was added. The mixture was stirred at r.t. until enoate 1 was
completely consumed (TLC). The mixture was then directly puri-
fied by chromatography (silica gel, 20% EtOAc–hexane).
Ethyl [(2R,3S,4R)-3-Nitro-2-phenyl-1-tosyl-1,2,3,4-tetrahydro-
quinolin-4-yl]acetate (3aa)
HRMS (ESI): m/z [M + Na]+ calcd for C25H24N2NaO6S: 503.1253;
found: 503.1252.
White solid; yield: 68 mg (91%); mp 147–148 °C; [α]D26 –8.0 (c 1.0,
CHCl3).
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
21.5 min; major isomer: tR = 26.4 min; 94% ee.
1H NMR (400 MHz, CDCl3): δ = 7.87 (dd, J = 5.2, 8.0 Hz, 1 H),
7.57 (d, J = 8.4 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.20–7.36 (m, 8
H), 7.03 (d, J = 8.0 Hz, 1 H), 6.02 (d, J = 7.2 Hz, 1 H), 4.82 (dd, J =
7.2, 10.8 Hz, 1 H), 4.11 (dq, J = 2.0, 7.2 Hz, 2 H), 2.74 (ddd, J = 4.0,
8.8, 12.0 Hz, 1 H), 2.56 (dd, J = 8.4, 17.2 Hz, 1 H), 2.43 (s, 3 H),
2.37 (dd, J = 4.0, 17.2 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 144.5, 139.7, 135.8, 135.5,
131.4, 129.9, 129.1, 128.7, 128.5, 127.7, 127.4, 127.2, 126.2, 125.0,
94.7, 62.8, 61.0, 36.5, 32.5, 21.6, 14.1.
Benzyl [(2R,3S,4R)-3-Nitro-2-phenyl-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl]acetate (3ca)
Colorless gum; yield: 82 mg (98%); [α]D22 –19.0 (c 1.03, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.56 (d,
J = 8.4 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.19–7.39 (m, 13 H), 6.97
(d, J = 7.6 Hz, 1 H), 6.03 (d, J = 6.8 Hz, 1 H), 5.09 (dd, J = 12.0,
20.4 Hz, 2 H), 4.83 (dd, J = 7.2, 10.8 Hz, 1 H), 2.77 (ddd, J = 4.0,
8.8, 11.6 Hz, 1 H), 2.61 (dd, J = 8.4, 17.2 Hz, 1 H), 2.38–2.58 (m, 4
H).
HRMS (ESI): m/z calcd for C26H26N2NaO6S [M + Na]+: 517.1409;
found: 517.1403.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
13.3 min; major isomer: tR = 24.2 min; 98% ee.
13C NMR (100 MHz, CDCl3): δ = 169.7, 144.6, 139.6, 135.8, 135.4,
135.3, 131.2, 129.9, 129.1, 128.8, 128.6, 128.5, 128.4, 128.3, 127.7,
127.3, 127.2, 126.2, 125.1, 94.6, 66.8, 62.7, 36.5, 32.6, 21.6.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3365–3373

3370
K.-T. Kang, S.-G. Kim
PAPER
HRMS (ESI): m/z [M + Na]+ calcd for C31H28N2NaO6S: 579.1566;
found: 579.1565.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 6.4 Hz, 2 H), 7.29–
7.37 (m, 6 H), 7.22 (dd, J = 2.0, 8.0 Hz, 2 H), 6.50 (s, 2 H), 6.05 (dd,
J = 1.2, 12.0 Hz, 2 H), 5.96 (d, J = 6.8 Hz, 1 H), 4.75 (dd, J = 7.2,
10.8 Hz, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 2.34–2.56 (m, 6 H), 1.23 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 147.6, 147.2, 144.5, 139.8,
135.4, 129.9, 129.6, 129.1, 128.5, 127.2, 126.2, 125.6, 109.6, 104.7,
102.0, 95.3, 63.0, 61.1, 36.7, 32.4, 21.6, 14.1.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 220 nm); minor isomer: tR =
19.5 min; major isomer: tR = 34.0 min; 98% ee.
tert-Butyl [(2R,3S,4R)-3-Nitro-2-phenyl-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl]acetate (3da)
Colorless gum; yield: 36 mg (45%); [α]D22 –17.9 (c 1.3, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C27H26N2NaO8S: 561.1308;
found: 561.1304.
1H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 0.8, 8.0 Hz, 1 H),
7.55 (d, J = 8.4 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.20–7.35 (m, 8
H), 7.08 (d, J = 8.0 Hz, 1 H), 6.01 (d, J = 7.2, 10.8 Hz, 1 H), 4.84
(dd, J = 7.2, 10.8 Hz, 1 H), 2.66 (ddd, J = 4.0, 8.8, 10.8 Hz, 1 H),
2.45 (dd, J = 8.0, 17.2 Hz, 1 H), 2.42 (s, 3 H), 2.30 (dd, J = 4.0, 17.2
Hz, 1 H), 1.39 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 168.9, 144.5, 139.8, 135.8, 135.3,
131.7, 129.8, 129.1, 128.6, 128.4, 127.5, 127.2, 127.1, 126.2, 125.2,
94.6, 81.6, 62.8, 36.7, 33.5, 27.9, 21.6.
HPLC: Chiralpak AD-H column and AD-H guard column (20%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
10.2 min; major isomer: tR = 23.5 min; 94% ee.
Ethyl [(2R,3S,4R)-6-Chloro-3-nitro-2-phenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ha)
White solid; yield: 66 mg (83%); mp 131–133 °C; [α]D24 +33.3 (c
1.1, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C28H30N2NaO6S: 545.1722;
found: 545.1719.
1H NMR (700 MHz, CDCl3): δ = 7.81 (d, J = 9.1 Hz, 1 H), 7.59 (d,
J = 7.7 Hz, 2 H), 7.40 (dd, J = 1.4, 8.4 Hz, 1 H), 7.28–7.37 (m, 5 H),
7.20 (d, J = 7.0 Hz, 2 H), 7.03 (s, 1 H), 6.04 (d, J = 7.0 Hz, 1 H),
4.89 (dd, J = 6.3, 10.5 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 2.72–2.78
(m, 1 H), 2.51 (dd, J = 7.7, 17.5 Hz, 1 H), 2.44 (s, 3 H), 2.34 (dd,
J = 7.7, 16.8 Hz, 1 H), 1.24 (t, J = 7.0 Hz, 3 H).
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
9.02 min; major isomer: tR = 14.1 min; 98% ee.
13C NMR (176 MHz, CDCl3): δ = 169.5, 144.8, 139.1, 135.2, 134.4,
133.0, 130.0, 129.2 (two peaks overlapping), 128.9, 128.6, 128.5,
127.2, 126.2, 125.6, 93.8, 62.6, 61.2, 36.4, 32.5, 21.7, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25ClN2NaO6S:
551.1020; found: 551.1024.
Ethyl [(2R,3S,4R)-6-Methyl-3-nitro-2-phenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ea)
White solid; yield: 60 mg (79%); mp 136–138 °C; [α]D25 +16.7 (c
0.98, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 1 H), 7.58 (d,
J = 8.4 Hz, 2 H), 7.21–7.37 (m, 8 H), 6.83 (s, 1 H), 6.00 (d, J = 6.8
Hz, 1 H), 4.80 (dd, J = 2.8, 6.8 Hz, 1 H), 4.11 (q, J = 7.2 Hz, 2 H),
2.69–2.76 (m, 1 H), 2.55 (dd, J = 8.4, 17.2 Hz, 1 H), 2.43 (s, 3 H),
2.32–2.39 (m, 4 H), 1.23 (t, J = 7.2 Hz, 3 H).
HPLC: Chiralpak AD-H column and AD-H guard column (20%
EtOH, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR = 6.6 min;
major isomer: tR = 8.0 min; 96% ee.
13C NMR (100 MHz, CDCl3): δ = 169.8, 144.3, 139.8, 137.3, 135.6,
133.2, 131.2, 129.8, 129.4, 129.1, 128.4, 127.5, 127.2, 126.2, 125.5,
94.8, 62.8, 60.9, 36.5, 32.6, 21.6, 21.4, 14.1.
Ethyl [(2R,3S,4R)-7-Chloro-3-nitro-2-phenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ia)
White solid; yield: 63 mg (80%); mp 109–110 °C; [α]D25 +27.8 (c
0.96, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO6S: 531.1566;
found: 531.1569.
1H NMR (700 MHz, CDCl3): δ = 7.91 (d, J = 1.4 Hz, 1 H), 7.61 (d,
J = 8.4 Hz, 2 H), 7.29–7.38 (m, 5 H), 7.26 (dd, J = 1.4, 7.7 Hz, 1 H),
7.21 (d, J = 7.0 Hz, 2 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.08 (d, J = 7.0
Hz, 1 H), 4.89 (dd, J = 7.0, 10.5 Hz, 1 H), 4.10 (dq, J = 2.1, 7.0 Hz,
2 H), 2.78–2.83 (m, 1 H), 2.51 (dd, J = 7.7, 17.5 Hz, 1 H), 2.44 (s,
3 H), 2.32 (dd, J = 4.9, 17.5 Hz, 1 H), 1.22 (t, J = 7.0 Hz, 3 H).
13C NMR (176 MHz, CDCl3): δ = 169.7, 144.9, 139.0, 136.9, 135.2,
134.3, 130.0, 129.3, 129.2, 128.7, 127.3, 127.2, 126.8, 126.4, 126.2,
93.6, 62.5, 61.2, 36.1, 32.9, 21.7, 14.1.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
8.9 min; major isomer: tR = 10.8 min; 97% ee.
Ethyl [(2R,3S,4R)-8-Methyl-3-nitro-2-phenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3fa)
White solid; yield: 56 mg (63%); mp 77–78 °C; [α]D24 –40.9 (c 0.49,
CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.0 Hz, 2 H), 7.28–
7.39 (m, 7 H), 7.05 (dd, J = 3.6, 7.6 Hz, 2 H), 6.94 (d, J = 7.2 Hz, 1
H), 5.80 (d, J = 7.6 Hz, 1 H), 4.79 (dd, J = 7.6, 12.0 Hz, 1 H), 4.13
(q, J = 7.2 Hz, 2 H), 2.71–2.79 (m, 1 H), 2.57 (dd, J = 4.0, 17.2 Hz,
1 H), 2.40–2.51 (m, 7 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 144.7, 139.7, 139.3, 135.6,
134.8, 134.5, 131.4, 130.0, 129.0, 128.6, 128.2, 127.9, 126.7, 122.4,
94.7, 63.8, 60.9, 36.9, 32.1, 21.6, 19.5, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25ClN2NaO6S:
551.1020; found: 551.1019.
HPLC: Chiralpak AD-H column and AD-H guard column (5%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); major isomer: tR =
14.3 min; minor isomer: tR = 17.6 min; 97% ee.
Ethyl [(2R,3S,4R)-6-Bromo-3-nitro-2-phenyl-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ja)
White solid; yield: 55 mg (64%); mp 128–130 °C; [α]D25 +49.9 (c
0.96, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO6S: 531.1566;
found: 531.1566.
1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.0 Hz, 1 H), 7.59 (d,
J = 8.0 Hz, 2 H), 7.54 (dd, J = 1.6, 7.6 Hz, 1 H), 7.28–7.37 (m, 5 H),
7.19–7.23 (m, 3 H), 6.05 (d, J = 6.8 Hz, 1 H), 4.91 (dd, J = 6.4, 10.0
Hz, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.76–2.83 (m, 1 H), 2.51 (dd, J =
8.0, 17.2 Hz, 1 H), 2.44 (s, 3 H), 2.33 (dd, J = 1.2, 17.2 Hz, 1 H),
1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.5, 144.8, 139.1, 135.3, 135.0,
133.1, 131.8, 130.0, 129.2, 129.1, 128.7, 128.6, 127.2, 126.2, 120.7,
93.7, 62.5, 61.2, 36.3, 32.7, 21.6, 14.1.
HPLC: Chiralpak AD-H column and AD-H guard column (5%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
8.5 min; major isomer: tR = 10.4 min; 98% ee.
Ethyl {(6R,7S,8R)-7-Nitro-6-phenyl-5-tosyl-5,6,7,8-tetrahy-
dro[1,3]dioxolo[4,5-g]quinolin-8-yl}acetate (3ga)
White solid; yield: 58 mg (72%); mp 171–173 °C; [α]D25 +82.4 (c
0.86, CHCl3).
Synthesis 2014, 46, 3365–3373
© Georg Thieme Verlag Stuttgart · New York

PAPER
Functionalized Tetrahydroquinolines
3371
HRMS (ESI): m/z [M + Na]+ calcd for C26H25BrN2NaO6S:
595.0514; found: 595.0517.
Ethyl [(2R,3S,4R)-2-(3,4-Dimethoxyphenyl)-3-nitro-1-tosyl-
1,2,3,4-tetrahydroquinolin-4-yl]acetate (3ae)
27
White solid; yield: 61 mg (73%); mp 87–89 °C; [α]D +26.0 (c
HPLC: Chiralpak AD-H column and AD-H guard column (5%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
12.0 min; major isomer: tR = 15.8 min; 94% ee.
0.33, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.6 Hz, 1 H), 7.57 (d,
J = 8.4 Hz, 2 H), 7.41 (t, J = 8.4 Hz, 1 H), 7.24–7.32 (m, 3 H), 7.05
(d, J = 7.6 Hz, 1 H), 6.68–6.81 (m, 3 H), 6.00 (d, J = 6.8 Hz, 1 H),
4.87 (dd, J = 6.8, 10.8 Hz, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 3.85 (s, 3
H), 3.78 (s, 3 H), 2.77–2.84 (m, 1 H), 2.57 (dd, J = 8.0, 17.2 Hz, 1
H), 2.42 (s, 3 H), 2.39 (dd, J = 4.4, 17.2 Hz, 1 H), 1.22 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 149.2, 149.0, 144.5, 135.9,
135.6, 132.1, 131.4, 129.8, 128.7 (two signals overlapping), 127.3,
127.2, 125.2, 118.6, 111.3, 109.2, 94.5, 62.5, 61.0, 56.0, 55.8, 36.5,
32.6, 21.6, 14.1.
Ethyl [(2R,3S,4R)-2-(4-Methoxyphenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ab)
26
White solid; yield: 41 mg (52%); mp 124–125 °C; [α]D –0.13 (c
0.71, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 0.8, 8.0 Hz, 1 H),
7.56 (d, J = 8.4 Hz, 2 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.11–7.19 (m, 3
H), 7.12 (d, J = 7.6 Hz, 2 H), 7.03 (dd, J = 0.8, 7.6 Hz, 1 H), 6.84
(d, J = 8.8 Hz, 2 H), 5.95 (d, J = 6.8 Hz, 1 H), 4.76 (dd, J = 7.2, 8.4
Hz, 1 H), 4.10 (dq, J = 2.0, 7.6 Hz, 2 H), 3.79 (s, 3 H), 2.73 (ddd,
J = 4.0, 8.4, 10.8 Hz, 1 H), 2.56 (dd, J = 8.0, 17.2 Hz, 1 H), 2.43 (s,
3 H), 2.38 (dd, J = 4.0, 17.2 Hz, 1 H), 1.22 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 159.6, 144.4, 135.8, 135.5,
131.8, 131.5, 129.8, 128.7, 127.7, 127.6, 127.3, 127.2, 124.9, 114.4,
94.8, 62.5, 61.0, 55.3, 36.5, 32.5, 21.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C28H30N2NaO8S: 577.1621;
found: 577.1617.
HPLC: Chiralpak AD-H column and AD-H guard column (20%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 220 nm); minor isomer: tR =
16.2 min; major isomer: tR = 39.8 min; 99% ee.
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO7S: 547.1515;
found: 547.1513.
Ethyl [(2R,3S,4R)-3-Nitro-2-(4-tolyl)-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl]acetate (3af)
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
21.5 min; major isomer: tR = 26.4 min; 94% ee.
27
White solid; yield: 60 mg (78%); mp 154–156 °C; [α]D –8.4 (c
0.90, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 0.8, 8.0 Hz, 1 H),
7.56 (d, J = 8.4 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.26–7.33 (m, 3
H), 7.09–7.16 (m, 4 H), 7.44 (d, J = 8.0 Hz, 1 H), 5.98 (d, J = 7.2
Hz, 1 H), 4.81 (dd, J = 7.2, 9.2 Hz, 1 H), 4.11 (dq, J = 2.0, 7.2 Hz,
2 H), 2.70–2.79 (m, 1 H), 2.56 (dd, J = 7.6, 17.2 Hz, 1 H), 2.43 (s,
3 H), 2.37 (dd, J = 4.0, 17.2 Hz, 1 H), 2.33 (s, 3 H), 1.22 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 144.4, 138.3, 136.7, 135.9,
135.6, 131.5, 129.8, 129.7, 128.7, 127.7, 127.3, 127.2, 126.2, 124.9,
94.8, 62.7, 61.0, 36.5, 32.6, 21.6, 21.1, 14.1.
Ethyl [(2R,3S,4R)-2-(3-Methoxyphenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ac)
White solid; yield: 69 mg (88%); mp 95–97 °C; [α]D27 –16.8 (c 0.99,
CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.87 (dd, J = 0.8, 8.0 Hz, 1 H),
7.57 (d, J = 8.0 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.21–7.32 (m, 4
H), 7.04 (d, J = 8.0 Hz, 1 H), 6.75–6.87 (m, 3 H), 6.02 (d, J = 7.2
Hz, 1 H), 4.82 (dd, J = 6.8, 10.8 Hz, 1 H), 4.11 (dq, J = 1.6, 7.2 Hz,
2 H), 3.76 (s, 3 H), 2.73–2.81 (m, 1 H), 2.56 (dd, J = 8.4, 17.2 Hz,
1 H), 2.43 (s, 3 H), 2.37 (dd, J = 4.0, 17.2 Hz, 1 H), 1.22 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 160.0, 144.5, 141.2, 135.9,
135.5, 131.3, 130.2, 129.8, 128.7, 127.5, 127.3, 127.2, 125.0, 118.4,
113.9, 111.9, 94.6, 62.6, 61.0, 55.2, 36.5, 32.6, 21.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO6S: 531.1566;
found: 531.1565.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
11.0 min; major isomer: tR = 12.5 min; 97% ee.
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO7S: 547.1515;
found: 547.1515.
Ethyl [(2R,3S,4R)-2-(4-Chlorophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ag)
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 220 nm); minor isomer: tR =
19.5 min; major isomer: tR = 34.0 min; 96% ee.
27
White solid; yield: 57 mg (72%); mp 181–183 °C; [α]D –15.1 (c
0.95, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.84 (dd, J = 0.8, 8.0 Hz, 1 H),
7.55 (d, J = 8.4 Hz, 2 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.26–7.34 (m, 5
H), 7.16 (d, J = 8.4 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1 H), 5.96 (d, J =
7.2 Hz, 1 H), 4.78 (dd, J = 4.8, 6.8 Hz, 1 H), 4.11 (dq, J = 1.6, 7.2
Hz, 2 H), 2.69 (ddd, J = 3.6, 8.0, 11.2 Hz, 1 H), 2.56 (dd, J = 8.0,
17.2 Hz, 1 H), 2.38–2.48 (m, 4 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 144.7, 138.2, 135.6, 135.2,
134.5, 131.4, 129.9, 129.3, 128.9, 127.8, 127.7, 127.6, 127.2, 124.9,
94.5, 62.3, 61.1, 36.5, 32.3, 21.6, 14.1.
Ethyl [(2R,3S,4R)-2-(2-Methoxyphenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ad)
White solid; yield: 48 mg (61%); mp 116–117 °C; [α]D27 –100.9 (c
0.35, CHCl3).
1H NMR (700 MHz, CDCl3): δ = 7.93 (d, J = 8.4 Hz, 1 H), 7.61 (d,
J = 8.4 Hz, 2 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.21–7.29 (m, 5 H), 6.99
(d, J = 7.7 Hz, 1 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.82 (d, J = 7.7 Hz, 1
H), 6.34 (d, J = 7.0 Hz, 1 H), 4.78 (dd, J = 6.3, 9.8 Hz, 1 H), 4.06
(dq, J = 3.5, 7.0 Hz, 2 H), 3.62 (s, 3 H), 2.49–2.52 (m, 1 H), 2.52
(dd, J = 8.4, 16.8 Hz, 1 H), 2.40 (s, 3 H), 2.33 (dd, J = 3.5, 16.8 Hz,
1 H), 1.18 (t, J = 7.0 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C26H25ClN2NaO6S:
551.1020; found: 551.1020.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
11.7 min; major isomer: tR = 13.0 min; 96% ee.
13C NMR (176 MHz, CDCl3): δ = 170.0, 156.0, 144.3, 136.8, 135.8,
130.8, 129.7, 129.6, 128.4, 127.9, 127.7, 127.3, 127.1, 126.8, 125.0,
120.8, 110.6, 93.4, 60.9, 59.3, 54.7, 36.7, 33.1, 21.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C27H28N2NaO7S: 547.1515;
found: 547.1514.
Ethyl [(2R,3S,4R)-2-(2-Chlorophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ah)
22
White solid; yield: 73 mg (92%); mp 143–144 °C; [α]D –63.5 (c
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
16.2 min; major isomer: tR = 19.7 min; 95% ee.
1.1, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3365–3373

3372
K.-T. Kang, S.-G. Kim
PAPER
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.6 Hz, 1 H), 7.59 (d,
J = 8.4 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.39 (dd, J = 1.2, 8.0 Hz,
1 H), 7.13–7.33 (m, 6 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.39 (d, J = 7.6
Hz, 1 H), 4.94 (dd, J = 7.6, 10.4 Hz, 1 H), 4.10 (dq, J = 4.0, 7.2 Hz,
2 H), 2.70–2.77 (m, 1 H), 2.52 (dd, J = 8.0, 17.2 Hz, 1 H), 2.44 (s,
3 H), 2.33 (dd, J = 4.4, 17.2 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C26H25N3NaO8S: 562.1260;
found: 562.1257.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
27.0 min; major isomer: tR = 32.8 min; 94% ee.
13C NMR (100 MHz, CDCl3): δ = 169.9, 144.7, 137.3, 136.3, 135.0,
132.4, 130.3, 130.2, 129.9, 129.8, 128.9, 128.7, 127.6, 127.4, 127.0,
126.9, 125.4, 92.1, 61.1, 59.6, 36.3, 33.0, 21.7, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25ClN2NaO6S:
551.1020; found: 551.1018.
Ethyl [(2S,3S,4R)-3-Nitro-2-(2-thienyl)-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl]acetate (3al)
White solid; yield: 62 mg (83%); mp 144–145 °C; [α]D24 +10.5 (c
0.70, CHCl3).
1H NMR (700 MHz, CDCl3): δ = 7.89 (d, J = 7.7 Hz, 1 H), 7.58 (d,
J = 7.7 Hz, 2 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.28–7.33 (m, 3 H), 7.24
(d, J = 4.9 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 6.92–6.98 (m, 2 H),
6.34 (d, J = 6.3 Hz, 1 H), 4.93 (dd, J = 6.3, 11.2 Hz, 1 H), 4.09–4.17
(m, 2 H), 2.71–2.76 (m, 1 H), 2.61 (dd, J = 8.4, 17.5 Hz, 1 H), 2.41–
2.47 (m, 4 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C NMR (176 MHz, CDCl3): δ = 169.8, 144.6, 143.4, 135.4, 135.0,
131.5, 129.9, 128.7, 128.4, 127.8, 127.3, 127.2, 125.9, 125.3, 124.9,
95.0, 61.1, 59.2, 36.4, 32.5, 21.6, 14.1.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
13.8 min; major isomer: tR = 18.1 min; 97% ee.
Ethyl [(2R,3S,4R)-2-(2-Bromophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3ai)
23
White solid; yield: 64 mg (74%); mp 133–135 °C; [α]D –76.3 (c
0.20, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.55–
7.64 (m, 3 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.06–7.34 (m, 7 H), 6.40 (d,
J = 7.6 Hz, 1 H), 4.95 (dd, J = 7.6, 10.0 Hz, 1 H), 4.10 (dq, J = 3.6,
7.2 Hz, 2 H), 2.86–3.03 (m, 1 H), 2.52 (dd, J = 8.0, 17.2 Hz, 1 H),
2.44 (s, 3 H), 2.33 (dd, J = 4.4, 17.2 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 3
H).
HRMS (ESI): m/z [M + Na]+ calcd for C24H24N2NaO6S2: 523.0973;
found: 523.0973.
HPLC: Chiralpak AD-H column and AD-H guard column (20%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
8.4 min; major isomer: tR = 20.3 min; 98% ee.
13C NMR (100 MHz, CDCl3): δ = 169.9, 144.7, 139.1, 136.3, 135.0,
133.5, 130.1, 129.9, 128.9, 128.7, 128.3, 127.4, 127.0, 126.8, 125.6,
122.3, 92.2, 61.2, 61.1, 36.2, 33.1, 21.7, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25BrN2NaO6S:
595.0514; found: 595.0518.
Ethyl {(2R,3S,4R)-2-Isopropyl-3-nitro-1-tosyl-1,2,3,4-tetrahy-
droquinolin-4-yl}acetate (3am)
White solid; yield: 65 mg (94%); mp 99–101 °C; [α]D25 –5.4 (c 1.0,
CHCl3).
1H NMR (700 MHz, CDCl3): δ = 7.78 (d, J = 7.7 Hz, 1 H), 7.52 (d,
J = 8.4 Hz, 2 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.27 (t, J = 7.7 Hz, 1 H),
7.21 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 7.7 Hz, 1 H), 4.74 (dd, J = 4.9,
7.7 Hz, 1 H), 4.69 (dd, J = 4.9, 11.2 Hz, 1 H), 4.08 (dq, J = 3.5, 7.0
Hz, 2 H), 2.56 (dd, J = 7.7, 16.8 Hz, 1 H), 2.47–2.53 (m, 2 H), 2.39
(s, 3 H), 1.73 (septet, J = 7.0 Hz, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 1.00
(dd, J = 6.3, 7.0 Hz, 6 H).
13C NMR (176 MHz, CDCl3): δ = 170.0, 144.1, 136.1, 136.0, 131.9,
129.6, 128.5, 128.4, 127.6, 127.2, 124.6, 92.6, 65.4, 60.9, 36.6,
34.5, 32.1, 21.6, 19.0, 18.6, 14.1.
HPLC: Chiralpak AD-H column and AD-H guard column (10%
i-PrOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
17.4 min; major isomer: tR = 20.6 min; 97% ee.
Ethyl [(2R,3S,4R)-2-(4-Fluorophenyl)-3-nitro-1-tosyl-1,2,3,4-
tetrahydroquinolin-4-yl]acetate (3aj)
27
White solid; yield: 62 mg (80%); mp 163–165 °C; [α]D –20.4 (c
0.96, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.84 (dd, J = 0.8, 8.0 Hz, 1 H),
7.55 (d, J = 8.4 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.19–7.35 (m, 5
H), 6.99–7.06 (m, 3 H), 5.97 (d, J = 7.2 Hz, 1 H), 4.79 (dd, J = 7.2,
10.8 Hz, 1 H), 4.11 (dq, J = 1.6, 7.2 Hz, 2 H), 2.69 (ddd, J = 3.6, 8.0,
10.8 Hz, 1 H), 2.56 (dd, J = 8.0, 17.2 Hz, 1 H), 2.38–2.46 (m, 4 H),
1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 144.6, 135.6, 135.3, 131.6,
129.9, 128.8, 128.2, 128.1, 127.8, 127.6, 127.2, 124.9, 116.2, 116.0,
94.7, 61.3, 61.1, 36.5, 32.3, 21.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28N2NaO6S: 483.1566;
found: 483.1568.
HPLC: Chiralpak AD-H column and AD-H guard column (5%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
7.0 min; major isomer: tR = 8.5 min; 70% ee.
Acknowledgment
HRMS (ESI): m/z [M + Na]+ calcd for C26H25FN2NaO6S: 535.1315;
found: 535.1311.
This research was supported by Nano-Material Development Pro-
gram and Basic Science Research Program through the National
Research Foundation of Korea (NRF), funded by the Ministry of
Education, Science, and Technology (NRF-2012M3A7B4049648
and NRF-2013R1A1A2009850)
HPLC: Chiralpak AD-H column and AD-H guard column (10%
EtOH–hexanes, 1.0 mL/min flow, λ = 254 nm); minor isomer: tR =
9.2 min; major isomer: tR = 10.5 min; 96% ee.
Ethyl [(2R,3S,4R)-3-Nitro-2-(4-nitrophenyl)-1-tosyl-1,2,3,4-tet-
rahydroquinolin-4-yl]acetate (3ak)
Supporting Information for this article is available online
White solid; yield: 62 mg (76%); mp 167–169 °C; [α]D24 +29.0 (c
0.51, CHCl3).
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1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.89 (d,
J = 7.6 Hz, 1 H), 7.41–7.59 (m, 5 H), 7.26–7.38 (m, 3 H), 7.05 (d,
J = 8.0 Hz, 1 H), 6.05 (d, J = 7.2 Hz, 1 H), 4.83 (dd, J = 7.2, 11.2
Hz, 1 H), 4.10 (dq, J = 1.6, 7.2 Hz, 2 H), 2.54–2.71 (m, 2 H), 2.39–
2.49 (m, 4 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.6, 147.9, 146.6, 145.0, 135.3,
134.8, 131.3, 130.0, 129.1, 127.9, 127.8, 127.4, 127.2, 125.0, 124.4,
94.1, 62.3, 61.2, 36.6, 31.9, 21.6, 14.1.
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© Georg Thieme Verlag Stuttgart · New York

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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3365–3373