Asymmetric domino aza-Michael-Michael reaction of o-N-protected aminophenyl α,β-unsaturated ketones: Construction of chiral functionalized tetrahydroquinolines

Article abstract of DOI:10.1016/j.tet.2014.05.114

The diastereo- and enantioselective synthesis of 2,3,4-trisubstituted tetrahydroquinolines has been developed through organocatalytic domino aza-Michael-Michael reaction of o-N-tosylaminophenyl α,β-unsaturated ketones with nitroalkenes. This useful and simple domino process afforded diverse highly functionalized tetrahydroquinolines, some of which are not easily accessible using other methodologies, in good yields and with excellent diastereo- and enantioselectivities (up to >30:1 dr, >99% ee).

Full text of DOI:10.1016/j.tet.2014.05.114

Tetrahedron 70 (2014) 5114e5121
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric domino aza-MichaeleMichael reaction of
o-N-protected aminophenyl a,b-unsaturated ketones:
construction of chiral functionalized tetrahydroquinolines
*
Shinae Kim, Ki-Tae Kang, Sung-Gon Kim
Department of Chemistry, Kyonggi University, 154-42 Gwanggyosan-ro, Yeongtong-gu, Suwon 443-760, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2014
Received in revised form 28 May 2014
Accepted 31 May 2014
Available online 11 June 2014
The diastereo- and enantioselective synthesis of 2,3,4-trisubstituted tetrahydroquinolines has been de-
veloped through organocatalytic domino aza-MichaeleMichael reaction of o-N-tosylaminophenyl a,b-
unsaturated ketones with nitroalkenes. This useful and simple domino process afforded diverse highly
functionalized tetrahydroquinolines, some of which are not easily accessible using other methodologies,
in good yields and with excellent diastereo- and enantioselectivities (up to >30:1 dr, >99% ee).
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Domino reaction
Michael addition
Asymmetric catalysis
Tetrahydroquinoline
1. Introduction
developed for easy access to the synthesis of complex compounds.
Among the strategies, domino reactions,4,5 in which two or more
The development of methodologies for the synthesis of chiral
compound for the production of pharmaceuticals, agrochemicals,
and functional materials is one of the most briskly pursued areas in
synthetic chemistry.1 Among the developed methods, asymmetric
catalytic reaction, which includes enzymatic catalysis, metal ca-
talysis, and organocatalysis, is the most efficient tool for the prep-
aration of enantiomerically pure compound in regard to
economical approaches and green chemistries.2 In particular,
asymmetric organocatalysis, which results in better reproducibility
and greater operational simplicity than traditional metal catalysis,
has attracted considerable attention during the past decade.3
Organocatalysts have several important advantages in that they
are usually inexpensive, generally non-toxic, readily available, and
air-stable. Furthermore, asymmetric organocatalysis is a very
promising strategy that provides cost-efficient and environment-
friendly access to enantiomerically pure compounds in the syn-
thesis of natural products and biologically active compounds.
The synthesis of complex natural products and biologically ac-
tive compounds has attracted the attention of organic chemists for
a very long time. Many new types of chemical reactions have been
bond-forming transformations occur under identical reaction
conditions and the subsequent reactions occur as a consequence of
the functionality formed in the previous step, have received wide
acceptance because of the improved synthetic efficiency by re-
ducing the number of synthetic steps required and the quantities of
chemicals and solvents used. These benefits are of particular in-
terest in the efficient and stereoselective construction of complex
molecules from simple precursors in a single process. In this area,
domino Michael additions have especially emerged as one of the
most powerful method for the synthesis of various important cyclic
building blocks in the recent decades.6 Herein, we report the
organocatalytic asymmetric one-pot domino aza-MichaeleMichael
reaction of o-N-protected aminophenyl
a,b-unsaturated ketones
with nitroalkenes, thus affording highly functionalized tetrahy-
droquinolines in good yields and with excellent diastereo- and
enantioselectivities.
Tetrahydroquinolines are valuable building blocks found in
numerous biologically active natural products and pharmacologi-
cally relevant therapeutic agents.7 Molecules containing the tetra-
hydroquinoline scaffold exhibit a broad range of bioactivities, such
as anti-HIV, antibacterial, antifungal, antimalarial, antitumor, and
cardiovascular activities. In addition, the chiral tetrahydroquinoline
scaffold is found in several important biologically active natural
products and pharmaceutical compounds,8 with notable examples
* Corresponding author. Tel.: þ82 31 249 9631; fax: þ82 31 253 1165; e-mail
address: sgkim123@kyonggi.ac.kr (S.-G. Kim).
http://dx.doi.org/10.1016/j.tet.2014.05.114
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
5115
such as Peniprequinolone isolated from Penicillium simplicissimum
and the fungus Penicillium janczewskii, Benzastain D possessing
antiviral activity, which is isolated from Streptomyces sp., and Tor-
cetrapib, a potent cholesteryl ester transfer protein inhibitor (Fig.
1). In view of their immense significance, numerous synthetic
methods for tetrahydroquinolines with careful stereochemical
control have been reported.9 Consequently, the development of an
efficient enantioselective synthetic method for the tetrahy-
droquinoline scaffold still remains an active field of research.
similar results when only catalyst IIa was used (83% yield, 15% ee;
Table 1, entry 3) and found that this catalytic reaction was achieved
by activating the nitroalkene through hydrogen-bonding in-
teractions with the thiourea catalyst.
Fig. 1. Selected biologically active chiral tetrahydroquinolines.
Fig. 2. Structure of candidate organocatalysts.
Recently, we reported a novel method for the efficient prepa-
ration of chiral 4-substituted tetrahydroquinoline derivatives
through an organocatalytic conjugate addition-cyclization domino
reaction [Eq. 1].10 In this process, the methylene carbon of the
Table 1
Condition screening of the domino double Michael reactions of 1 and 2aa
dialkyl malonate attacks the b-position carbon of the o-N-protected
aminocinnamaldehyde to afford the Michael adduct first, followed
by hemiacetalization. To further investigate the synthesis of highly
functionalized tetrahydroquinoline and the utility of o-N-protected
aminophenyl a,b-unsaturated carbonyl compounds, we considered
a cascade MichaeleMichael reaction that provides chiral tetrahy-
droquinoline in a single step [Eq. 2].11 This reaction is initiated by
the attack of the protected amine to nitroalkene, and a high level of
stereocontrol is expected owing to the positive effect of the pro-
tecting group.
Entry
Cat.
R
PG
Time (h)
Yield (%)b
drc
ee %d
1
2
3
4
5
6
7
8
I
H
H
H
TS
TS
TS
TS
TS
TS
TS
TS
60
60
36
6
6
6
6
8
24
24
24
8
nd
nd
18
15
96
91
87
92
87
nd
nd
nd
IþIIa
IIa
IIa
IIb
IIIa
IIIb
IV
IIa
IIa
IIa
58
83
82
80
71
83
74
de
de
de
10:1
>30:1
>30:1
>30:1
>30:1
>30:1
24:1
nd
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
ð1Þ
9
10
11
CO2Et
Boc
Cbz
nd
nd
a
All of the reactions were carried out in CH2Cl2 (0.25 M) with 1 (0.10 mmol) and
-nitrostyrene (2a, 0.15 mmol) in the presence of 10 mol % catalyst at room
b
temperature.
b
Isolated yield after chromatographic purification.
c
Determined by 1H NMR analysis.
Determined by chiral-phase HPLC analysis.
No reaction.
ð2Þ
d
e
Having identified the hydrogen-bonding interactions as the
2. Results and discussion
activation mode for this domino double Michael reaction, we
turned our attention to o-N-tosylaminophenyl -unsaturated
a,b
First, the coupling of o-N-tosylaminophenyl
a,b-unsaturated
ketones as the starting materials. Surprisingly, excellent results
aldehyde and -nitrostyrene 2a was investigated in the presence of
b
were achieved in the reaction of (E)-1-phenyl-3-(2-(tosylamino)
diphenylprolinol TMS ether catalyst I (Fig. 2) that activated the
aldehyde through the iminium intermediate. However, this re-
action afforded the desired tetrahydroquinoline product with
a very low reaction efficiency (Table 1, entry 1). Next, the use of
a co-catalyst system comprising organocatalyst I activating the al-
dehyde through the iminium intermediate and bifunctional thio-
urea IIa12 activating the nitroalkene by hydrogen-bonding
interactions, afforded the desired product but still with low enan-
tioselectivity, albeit in a moderate yield and with good diaster-
eoselectivity (58% yield, 18% ee; Table 1, entry 2). We also obtained
phenyl)prop-2-en-1-one 1a with
b-nitrostyrene 2a catalyzed by
thiourea IIa (10 mol %) in CH2Cl2 at room temperature that afforded
the desired tetrahydroquinoline product 3aa in 82% yield and with
excellent diastereoselectivity (>30:1 dr) and enantioselectivity
(96% ee, Table 1, entry 4). Other cinchona alkaloid-derived thiourea
catalysts IIb, IIIa, and IIIb as well as Takemoto catalyst IV13 pro-
vided inferior results when catalyst IIa was used (Table 1, entries
5e8). The reaction did not occur when the protecting group on the
o-aminophenyl a,b-unsaturated ketone 1 was an ethoxycarbonyl,

5116
S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
Table 3
tert-butoxycarbonyl (Boc), or benzyloxycarbonyl (Cbz). This result
demonstrated that the more electron-withdrawing protecting
group (Tosyl), providing a sufficient level of acidity to the NH group
for the aza-Michael reaction, was necessary to activate this reaction
and to provide a high level of stereoselectivity.
Variation of the nitroalkenea
Next, other factors that influenced the reaction, such as solvent,
catalyst loading, and reaction temperature, were thoroughly in-
vestigated. The reaction medium slightly affected the conversion
and enantioselective induction. This asymmetric domino aza-
MichaeleMichael reaction could be smoothly performed in several
conventional solvents, thus affording the desired products in good
yields and with high enantioselectivities (72e86% yields, 89e97%
ee; Table 2, entries 1e8). The use of toluene resulted in the highest
enantioselectivity (97% ee; entry 4). The enantioselectivity of the
reaction was further improved to 98% ee by lowering the reaction
temperature to 0 ꢀC (Table 2, entry 9). However, lowering the cat-
alyst loading had a detrimental effect on the reaction rate and yield
(Table 2, entry 10).
Entry
R1
Time (h)
3
Yield (%)b
drc
ee %d
1
2
3
4
5
6
7
8
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
p-MeC6H4
p-ClC6H4
6
8
6
6
36
6
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
90
96
94
86
88
95
85
94
94
87
65
94
97
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
25:1
98
97
97
99
98
97
98
95
94
98
98
98
91
2
o-ClC6H4
o-BrC6H4
12
18
6
48
18
8
9
10
11
12
13
p-NO2C6H4
2-Furanyl
2-Thienyl
>30:1
>30:1
>30:1
iPr
Table 2
a
Optimization of the reaction conditionsa
All of the reactions were carried out in toluene (0.25 M) with 1a (0.10 mmol) and
nitroalkene (2, 0.15 mmol) in the presence of 10 mol % catalyst IIa at 0 ꢀ C.
b
Isolated yield after chromatographic purification.
c
Determined by 1H NMR analysis.
d
Determined by chiral-phase HPLC analysis.
To further expand the substrate scope of our methodology,
a variety of o-N-tosylaminophenyl a,b-unsaturated ketone 1 was
synthesized and subjected to the reaction conditions. The elec-
tronic nature of the R2 group slightly affected the reaction effi-
ciencies with regard to stereoselectivities and yields. Both electron-
donating (Table 4, entries 1e2) and electron-withdrawing (Table 4,
entries 3e5) groups were well tolerated. For the R3 group, the re-
actions proceeded well with electron-donating substituents (Table
4, entries 6e7), as well as electron-withdrawing substituents (Table
4, entries 8e11). Notably, the ortho-halogen-substituent on the
phenyl R3 group afforded the corresponding product with lower
enantioselectivity than the meta- and para-halogen-substituents
Entry
Solvent
Time (h)
Yield (%)b
drc
ee %d
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
DCE
Toluene
Xylene
CH3CN
THF
EtOAc
Toluene
Toluene
6
6
6
6
6
82
80
82
84
86
72
76
80
86
72
>30:1
>30:1
>30:1
>30:1
>30:1
20:1
>30:1
>30:1
>30:1
>30:1
96
93
94
97
96
89
96
95
98
97
8
48
12
18
48
9e
10f
a
Unless otherwise specified, the reaction was carried out in solvent (0.25 M) with
-nitrostyrene (2a, 0.15 mmol) in the presence of 10 mol %
Table 4
Variation of the o-N-tosylaminophenyl a,b
-unsaturated ketonea
1a (0.10 mmol) and
b
catalyst IIa at room temperature.
b
Isolated yield after chromatographic purification.
c
Determined by 1H NMR analysis.
d
Determined by chiral-phase HPLC analysis.
e
The reaction was carried out at 0 ꢀC.
f
The reaction was carried out with 5 mol % catalyst at 0 ꢀC.
With the optimal conditions in hand (10 mol % thiourea IIa in
toluene at 0 ꢀC), the substrate scope of the reaction was in-
vestigated. First, this reaction was confirmed to be suitable for
a wide variety of nitroalkenes 2. The results are summarized in
Table 3. A wide range of nitroalkenes with diverse steric and elec-
tronic environments reacted smoothly with (E)-1-phenyl-3-(2-
(tosylamino)phenyl)prop-2-en-1-one 1a. Aromatic nitroalkenes
with both electron-donating (Table 3, entries 1e6) and electron-
withdrawing substituents (Table 3, entries 7e9) on the phenyl
ring participated in this reaction with high efficiency, regardless of
the substitution pattern. Excellent diastereoselectivity (>30:1 dr)
and enantioselectivity (94e99% ee) were observed in all the cases
except the nitro-substituted substrate with a slightly diminished
diastereoselectivity (25:1 dr). Heteroaromatic-substituted nitro-
alkenes were also tolerated (Table 3, entries 11e12), even though 2-
furanylnitroolefin required a slightly longer reaction time. A further
broadening of the substrate scope to aliphatic alkene also resulted
in an excellent yield and diastereoselectivity, albeit with a slightly
diminished enantioselectivity (Table 3, entry 13).
Entry R2
R3
Time (h)
3
Yield (%)b drc
ee %d
1
2
5-Me Ph
3-Me Ph
36
36
36
36
36
36
24
36
18
36
28
2
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
78
99
86
89
76
88
95
91
94
83
85
>30:1
>30:1
>30:1
>30:1
>30:1
96
97
98
99
98
3
4
5
6
5-Cl
4-Cl
5-Br
H
Ph
Ph
Ph
p-MeOC6H4
p-MeC6H4
p-ClC6H4
m-ClC6H4
o-ClC6H4
p-BrC6H4
2-Furanyl
t-Bu
>30:1 >99
7
H
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
99
97
96
84
98
94
92
95
78
8
H
9
H
3ja
3ka
3la
10
11
12
13
14
15
H
H
H
H
H
H
3ma 84
18
3na
3oa
3pa
91
97
83
Cyclopropyl 18
Me 36
a
All of the reactions were carried out in toluene (0.3 M) with 1 (0.10 mmol) and
b-
nitrostyrene (2a, 0.15 mmol) in the presence of 10 mol % catalyst IIa at 0 ꢀC.
b
Isolated yield after chromatographic purification.
c
Determined by 1H NMR analysis.
d
Determined by chiral-phase HPLC analysis.

S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
5117
(Table 4, entry 10 vs entries 8e9). When a heteroaromatic group
was introduced at the R3 position, the reaction proceeded quickly to
afford good stereocontrol (>30:1 dr, 94% ee; Table 4, entry 12).
o-N-tosylaminophenyl
using a cinchona alkaloid-derived thiourea catalyst. This domino
reaction proceeded well with a wide range of o-N-tosylamino-
a
,
b
-unsaturated ketones with nitroalkenes
Furthermore, the reactions of aliphatic
a
,
b
-unsaturated ketones
phenyl
ficient access to
tetrahydroquinolines in good yields and with excellent diastereo-
and enantioselectivities (up to >30:1 dr, 99% ee).
a
,
b
-unsaturated ketones and nitroalkene, and provided ef-
variety of highly functionalized
with a bulkier group, such as tert-butyl and cyclopropyl, proceeded
smoothly to afford the corresponding products with high yields and
excellent stereoselectivities (Table 4, entries 13e14), However,
a
methyl a,b-unsaturated ketone provided the desired product with
moderate enantioselectivity, albeit in a good yield and with ex-
cellent diastereoselectivity (83% yield, 78% ee; Table 4, entry 15).
These results indicated that the steric hindrance of the R3 group
had a very important role toward the enantiocontrol in this re-
4. Experimental section
4.1. General procedure for asymmetric domino aza-Mi-
chaeleMichael reaction of o-N-tosylaminophenyl a,b-un-
action as observed in the case of o-N-tosylaminophenyl
a
,b
-un-
saturated ketone with nitroalkene
saturated aldehyde (Table 1, entry 3).
The absolute configuration of the tetrahydroquinoline com-
pound 3fa was determined by X-ray structure analysis and found to
be 2S,3R,4S (Fig. 3).14 The absolute configuration for the remaining
examples was assigned by analogy as the same.
An amber 2-dram vial equipped with a magnetic stir bar, con-
taining catalyst IIa (0.01 mmol, 10 mol %), and o-N-tosylamino-
phenyl
a,b-unsaturated ketone 1 (0.10 mmol, 1.0 equiv) was
charged with toluene (0.4 mL) at 0 ꢀC. The solution was stirred for
5 min before the addition of nitroalkene 2a (0.15 mmol, 1.5 equiv).
The resulting mixture was stirred at constant temperature until
On the basis of these experimental results and previous pro-
posed dual activation model,15 a plausible transition state for this
asymmetric domino reaction is shown in Fig. 4. In our catalytic
complete consumption of o-N-tosylaminophenyl
a,b-unsaturated
15e
ꢀ
system, PaPai’s proposal
is more suitable than others. The ter-
ketone 1 was observed as determined by TLC. The resulting mixture
was directly purified by silica gel chromatography (25% EtOAc/
hexane) to afford the desired tetrahydroquinoline compound 3 as
white solid or colorless gum.
tiary amine group of catalyst IIa first deprotonate acidic proton of
tosylated amine in compound 1a, and the resulting anion might be
stabilized through multiple hydrogen bonding including the in-
teraction between carbonyl and thiourea moieties. Meanwhile,
nitroalkene 2a is activated by the NeH of the protonated amine in
catalyst IIa. In this model, the amine attacks the nitroalkene from
the Si face preferentially resulting in the S-configurated in-
termediate followed by intramolecular Michael addition to give
3aa.
4.1.1. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-phenyl-1-
tosylquinolin-4-yl)-1-phenylethanone (3aa). White solid; mp
186e188 ꢀC; ½a 2D0
ꢁ
ꢂ12.5 (c 0.22, CHCl3); 98% ee; 1H NMR (700 MHz,
CDCl3)
d
7.88 (d, J¼7.7 Hz,1H), 7.83 (d, J¼7.7 Hz, 2H), 7.58 (d, J¼7.7 Hz,
3H), 7.46 (t, J¼7.7 Hz, 2H), 7.38 (t, J¼7.7 Hz, 1H), 7.23e7.32 (m, 7H),
7.18 (t, J¼7.7 Hz, 1H), 6.80 (d, J¼7.7 Hz, 1H), 4.87 (dd, J¼7.0, 10.5 Hz,
1H), 3.26 (dd, J¼8.4, 18.4 Hz, 1H), 3.05e3.10 (m, 1H), 2.86 (dd, J¼3.5,
18.4 Hz, 1H), 2.42 (s, 3H); 13C NMR (176 MHz, CDCl3)
d 195.2, 144.7,
139.6,135.9,135.7,135.3,133.7,131.3,129.9,129.1,128.8,128.5,128.4,
127.9, 127.2, 127.1, 126.2, 125.8, 94.3, 62.5, 37.0, 35.8, 21.7; IR (film)
2934, 1686, 1556, 1454, 1359, 1229, 1170, 1077 cmꢂ1; HRMS (ESI):
calcd for C30H26N2NaO5S [MþNa]þ: 549.1460 Found: 549.1457;
Chiralpak AD-H column and AD-H guard column (10% i-
PrOHehexanes, 1.0 mL/min flow,
tr¼12.1 min and minor-isomer tr¼23.1 min.
l
¼254 nm); major-isomer
4.1.2. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-2-(4-methoxyphenyl)-3-
nitro-1-tosylquinolin-4-yl)-1-phenylethanone (3ab). White solid;
mp 122e124 ꢀC;½a D23
ꢁ
ꢂ29.5(c0.17, CHCl3);98%ee;1HNMR(700MHz,
Fig. 3. X-ray crystal structure of compound 3fa.
CDCl3)
d
7.84 (t, J¼7.0 Hz, 3H), 7.56e7.63 (m, 3H), 7.45 (t, J¼7.7 Hz, 2H),
7.36 (t, J¼7.7 Hz, 1H), 7.29 (d, J¼7.7 Hz, 2H), 7.13e7.22 (m, 3H), 6.81 (d,
J¼8.4 Hz,3H), 6.02(d, J¼7.0Hz,1H), 4.86(dd, J¼7.0, 9.8 Hz,1H), 3.75(s,
3H), 3.27 (dd, J¼8.4, 18.2 Hz, 1H), 3.05 (br s, 1H), 2.87 (dd, J¼3.5,
18.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (176 MHz, CDCl3)
d 195.3, 159.5,
144.6, 135.9, 135.7, 135.3, 133.7, 131.7, 131.3, 129.9, 128.8, 128.4, 127.9,
127.5,127.2,127.1,127.0,125.8,114.5, 94.4, 62.3, 55.3, 37.0, 35.8, 21.7; IR
(film) 2928,1687,1554,1512,1485,1451, 1362,1247,1166, 1026 cmꢂ1
;
HRMS (ESI): calcd for C31H28N2NaO6S [MþNa]þ: 579.1566 Found:
579.1564; Chiralpak AD-H column and AD-H guard column (20% i-
PrOHehexanes, 1.0 mL/min flow,
tr¼18.2 min and minor-isomer tr¼45.5 min.
l
¼254 nm); major-isomer
4.1.3. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-2-(3-methoxyphenyl)-3-
nitro-1-tosylquinolin-4-yl)-1-phenylethanone (3ac). White solid;
Fig. 4. Plausible transition state.
mp 103e104 ꢀC; ½a D23
ꢁ
ꢂ7.2 (c 0.16, CHCl3); 97% ee; 1H NMR
(700 MHz, CDCl3)
d
7.89 (d, J¼8.4 Hz,1H), 7.82 (d, J¼7.0 Hz, 2H), 7.59
3. Conclusion
(d, J¼7.7 Hz, 3H), 7.45 (t, J¼7.7 Hz, 2H), 7.36 (t, J¼7.7 Hz, 1H), 7.29 (t,
J¼7.7 Hz, 2H), 7.20 (t, J¼7.7 Hz, 1H), 7.16 (t, J¼7.7 Hz, 1H), 6.81 (d,
J¼7.7 Hz, 2H), 6.78 (d, J¼7.0 Hz, 1H), 6.10 (d, J¼6.3 Hz, 1H), 4.89 (dd,
J¼7.0, 9.1 Hz, 1H), 3.70 (s, 3H), 3.26 (dd, J¼8.4, 18.2 Hz, 1H), 3.10 (br
In conclusion, we have developed a highly diastereo- and
enantioselective catalytic domino aza-MichaeleMichael reaction of

5118
S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
s, 1H), 2.85 (dd, J¼3.5, 18.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (176 MHz,
(m, 3H), 7.48 (t, J¼8.0 Hz, 2H), 7.39 (t, J¼7.6 Hz,1H), 7.32 (d, J¼8.0 Hz,
2H), 7.19 (dt, J¼0.8, 7.6 Hz, 1H), 7.10e7.16 (m, 4H), 6.83 (d, J¼7.6 Hz,
1H), 6.08 (d, J¼6.8 Hz, 1H), 4.89 (dd, J¼6.8, 10.0 Hz, 1H), 3.28 (dd,
J¼8.4,18.4 Hz,1H), 3.10 (dt, J¼4.0, 9.2 Hz,1H), 2.87 (dd, J¼4.0,18.4 Hz,
CDCl3)
d 195.3, 160.0, 144.7, 141.1, 135.9, 135.7, 135.3, 133.7, 131.1,
130.1, 129.8, 128.9, 128.5, 127.9, 127.4, 127.1, 126.8, 125.9, 118.3, 113.8,
111.8, 94.0, 62.3, 55.2, 37.2, 35.7, 21.7; IR (film) 2938, 1691, 1595,
1547, 1449, 1353, 1236, 1160, 1088, 1025 cmꢂ1; HRMS (ESI): calcd for
1H), 2.45 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 195.3,
C
31H28N2NaO6S [MþNa]þ: 579.1566 Found: 579.1566; Chiralpak
144.6,138.2,136.6,135.9,135.8,135.4,133.7,131.2,129.9,129.8,128.8,
128.4,127.9,127.2,127.0,126.9,126.1,125.8, 94.2, 62.4, 37.2, 35.7, 21.7,
21.1; IR (film) 2924, 1682, 1554, 1486, 1351, 1207, 1164, 1086,
986 cmꢂ1; HRMS (ESI): calcd for C31H28N2NaO5S [MþNa[þ: 563.1617
Found: 563.1613; Chiralpak AD-H column and AD-H guard column
AD-H column and AD-H guard column (20% i-PrOHehexanes,
1.0 mL/min flow,
isomer tr¼29.7 min.
l
¼254 nm); major-isomer tr¼16.4 min and minor-
4.1.4. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-2-(2-methoxyphenyl)-3-
nitro-1-tosylquinolin-4-yl)-1-phenylethanone (3ad). White solid;
(20% i-PrOHehexanes, 1.0 mL/min flow,
tr¼14.7 min and minor-isomer tr¼31.4 min.
l
¼254 nm); major-isomer
mp 214e216 ꢀC; ½a D25
ꢁ
60.3 (c 0.99, CHCl3); 97% ee; 1H NMR
7.99 (d, J¼8.0 Hz,1H), 7.81 (d, J¼7.2 Hz, 2H), 7.68
(400 MHz, CDCl3)
d
4.1.8. 2-((2S,3R,4S)-2-(4-Chlorophenyl)-1,2,3,4-tetrahydro-3-nitro-
(d, J¼8.0 Hz, 2H), 7.60 (dd, J¼7.2, 7.6 Hz, 1H), 7.23e7.51 (m, 7H), 7.16
(dd, J¼7.2, 7.6 Hz, 1H), 6.92 (dd, J¼7.2, 7.6 Hz, 1H), 6.85 (d, J¼7.6 Hz,
1H), 6.78 (d, J¼8.4 Hz, 1H), 6.49 (d, J¼5.6 Hz, 1H), 5.01 (dd, J¼7.2,
7.6 Hz, 1H), 3.62 (s, 3H), 3.18e3.30 (m, 2H), 2.89 (d, J¼14.8 Hz, 1H),
1-tosylquinolin-4-yl)-1-phenylethanone (3ah). Colorless gum; ½a D21
ꢁ
ꢂ23.7 (c 0.25, CHCl3); 98% ee; 1H NMR (700 MHz, CDCl3)
d 7.85 (t,
J¼7.0Hz, 3H), 7.55e7.63(m, 3H), 7.47(t, J¼7.0Hz, 2H), 7.38(t, J¼7.0 Hz,
1H), 7.25e7.35 (m, 4H), 7.18 (d, J¼7.0 Hz, 3H), 6.79 (d, J¼7.0 Hz, 1H),
6.02 (d, J¼6.3 Hz, 1H), 4.82 (t, J¼8.4 Hz, 1H), 3.28 (dd, J¼7.7, 17.5 Hz,
1H), 2.99 (br s, 1H), 2.89 (d, J¼17.5 Hz, 1H), 2.43 (s, 3H); 13C NMR
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 195.5, 156.0, 144.5, 136.7,
136.0, 135.6, 133.6, 130.4, 129.8, 129.6, 128.7, 128.2, 127.9, 127.8,
127.7, 127.4, 126.4, 126.1 (two signals overlapping), 120.9,110.7, 92.1,
59.0, 54.8, 37.8, 35.8, 21.7; IR (film) 2934, 1686, 1552, 1488, 1456,
1352, 1247, 1163, 1095 cmꢂ1; HRMS (ESI): calcd for C31H28N2NaO6S
[MþNa]þ: 579.1566 Found: 579.1569; Chiralpak AD-H column and
AD-H guard column (20% i-PrOHehexanes, 1.0 mL/min flow,
(176 MHz, CDCl3) d 195.1,144.9,138.2,135.8,135.5,135.0,134.4,133.8,
131.3, 130.0, 129.3, 128.8, 128.6, 127.9, 127.7, 127.3, 127.2, 127.1, 125.7,
94.3, 62.1, 36.6, 35.8, 21.7; IR (film) 2924,1686,1553,1489,1355,1162,
1087, 1013 cmꢂ1; HRMS (ESI): calcd for C30H25ClN2NaO5S [MþNa]þ:
583.1070 Found: 583.1065; Chiralpak AD-H column and AD-H guard
l
¼254 nm); major-isomer tr¼17.8 min and minor-isomer
column (20% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼14.8 min and minor-isomer tr¼22.3 min.
l
¼254 nm); major-
tr¼29.0 min.
4.1.5. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-2-(3,4-dimethoxyphenyl)-3-
4.1.9. 2-((2S,3R,4S)-2-(2-Chlorophenyl)-1,2,3,4-tetrahydro-3-nitro-
nitro-1-tosylquinolin-4-yl)-1-phenylethanone (3ae). White solid;
1-tosylquinolin-4-yl)-1-phenylethanone (3ai). White solid; mp
mp 128e129 ꢀC; ½a D24
ꢁ
ꢂ12.7 (c 0.18, CHCl3); 99% ee; 1H NMR
211e213 ꢀC; ½a 2D5
ꢁ
21.2 (c 1.3, CHCl3); 95% ee; 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
7.82e7.89 (m, 3H), 7.58e7.65 (m, 3H), 7.47 (t,
CDCl3)
d
7.88 (dd, J¼1.2, 9.2 Hz, 1H), 7.83 (dd, J¼1.2, 8.4 Hz, 2H),
J¼8.0 Hz, 2H), 7.37 (t, J¼7.6 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H), 7.19 (dt,
J¼1.2, 7.6 Hz, 1H), 6.72e6.88 (m, 4H), 6.12 (d, J¼6.4 Hz, 1H), 4.97 (dd,
J¼6.4, 9.6 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.29 (dd, J¼8.0, 18.0 Hz,
1H), 3.18 (dt, J¼3.6, 9.2 Hz, 1H), 2.91 (dd, J¼4.0, 18.0 Hz, 1H), 2.44 (s,
7.59e7.66 (m, 3H), 7.46 (dd, J¼7.6, 8.8 Hz, 2H), 7.40 (dd, J¼7.6, 8.8 Hz,
1H), 7.32e7.38 (m, 3H), 7.18e7.28 (m, 4H), 6.86 (d, J¼8.0 Hz,1H), 6.45
(d, J¼7.2 Hz, 1H), 5.02 (dd, J¼7.6, 9.6 Hz, 1H), 3.26 (dd, J¼8.4, 18.0 Hz,
1H), 3.18 (dt, J¼3.6, 9.2 Hz, 1H), 2.87 (dd, J¼3.6, 18.0 Hz, 1H), 2.46 (s,
3H); 13C NMR (100 MHz, CDCl3)
d
195.4, 149.3, 149.0, 144.6, 135.9,
3H); 13C NMR (100 MHz, CDCl3)
d 195.3, 144.8, 137.3, 136.3, 135.9,
135.8, 135.5, 133.8, 132.0, 131.1, 129.9, 128.8, 128.4, 127.9, 127.3, 126.9,
126.5,126.1,118.6,111.4,109.3, 93.9, 62.2, 55.9, 55.8, 37.3, 35.7, 21.7; IR
134.9, 133.8, 132.4, 130.4, 130.3, 130.0, 129.8, 129.0, 128.8, 128.5, 127.9,
127.6, 127.4, 126.8, 126.5, 126.2, 91.9, 59.7, 37.4, 35.6, 21.7; IR (film)
(film) 2942, 1683, 1552, 1516, 1449, 1354, 1259, 1161, 1087, 1023 cmꢂ1
;
2926, 1686, 1554, 1488, 1446, 1366, 1225, 1170, 1088, 1022 cmꢂ1
;
HRMS (ESI): calcd for C32H30N2NaO7S [MþNa]þ: 609.1671 Found:
HRMS (ESI): calcd for C30H25ClN2NaO5S [MþNa]þ: 583.1070 Found:
609.1671; Chiralpak AD-H column and AD-H guard column (20% i-
583.1068; Chiralpak AD-H column and AD-H guard column (5%
PrOHehexanes, 1.0 mL/min flow,
tr¼17.3 min and minor-isomer tr¼40.4 min.
l
¼254 nm); major-isomer
EtOHehexanes, 1.0 mL/min flow,
tr¼22.0 min and major-isomer tr¼32.6 min.
l
¼254 nm); minor-isomer
4.1.6. 2-((2S,3R,4S)-2-(Benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-
4.1.10. 2-((2S,3R,4S)-2-(2-Bromophenyl)-1,2,3,4-tetrahydro-3-nitro-
3-nitro-1-tosylquinolin-4-yl)-1-phenylethanone (3af). White solid;
1-tosylquinolin-4-yl)-1-phenylethanone (3aj). White solid; mp
mp 158e160 ꢀC; ½a D
ꢁ
25 15.1 (c 0.83, CHCl3); 98% ee; 1H NMR (400 MHz,
198e201 ꢀC; ½a 2D5
ꢁ
30.9 (c 1.0, CHCl3); 94% ee; 1H NMR (400 MHz,
CDCl3)
d
7.88 (d, J¼7.6 Hz, 3H), 7.56e7.64 (m, 3H), 7.49 (t, J¼7.6 Hz,
CDCl3)
d
7.89 (d, J¼8.0 Hz, 1H), 7.83 (d, J¼7.2 Hz, 2H), 7.65 (d,
2H), 7.40 (d, J¼7.6 Hz,1H), 7.32 (t, J¼8.0 Hz, 2H), 7.21 (t, J¼7.6 Hz,1H),
6.81 (d, J¼8.0 Hz,1H), 6.74 (s, 2H), 6.69 (s,1H), 5.96 (d, J¼7.6 Hz,1H),
5.94 (d, J¼8.4 Hz, 2H), 4.82 (dd, J¼7.6, 10.8 Hz, 1H), 3.31 (dd, J¼8.4,
18.0 Hz,1H), 3.00 (dd, J¼3.2,10.8 Hz,1H), 2.90 (dd, J¼3.6,18.4 Hz,1H),
J¼8.4 Hz, 2H), 7.61 (d, J¼7.6 Hz, 1H) 7.54 (d, J¼8.0 Hz, 1H), 7.47 (t,
J¼8.0 Hz, 2H), 7.41 (t, J¼7.2 Hz, 1H), 7.34 (d, J¼8.4 Hz, 2H), 7.13e7.30
(m, 4H), 6.88 (d, J¼8.0 Hz,1H), 6.46 (d, J¼7.2 Hz, 1H), 5.03 (dd, J¼7.2,
8.4 Hz, 1H), 3.20e3.31 (m, 2H), 2.82e2.92 (m, 1H), 2.46 (s, 3H); 13
C
2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
195.1, 148.3, 147.7, 144.7,
NMR (100 MHz, CDCl3) d 195.4, 144.8, 139.1, 136.3, 135.9, 134.9,
135.9,135.7,135.2,133.7,133.6,131.4,129.9,128.5,127.9,127.3,127.2,
125.6, 120.1, 108.6, 106.6, 101.3, 94.6, 62.7, 36.7, 35.8, 29.7, 21.7; IR
(film) 2930, 1688, 1555, 1486, 1447, 1347, 1246, 1160, 1085,
1032 cmꢂ1; HRMS (ESI): calcd for C31H26N2NaO7S [MþNa[þ:
593.1358 Found: 593.1360; Chiralpak AD-H column and AD-H guard
133.8, 133.6, 130.3, 130.0, 129.0, 128.8, 128.5, 128.3, 127.9, 127.5,
126.8, 126.4, 126.3, 122.3, 91.9, 61.2, 37.5, 35.5, 21.7; IR (film) 2924,
1685, 1557, 1486, 1448, 1360, 1228, 1168, 1086, 1020 cmꢂ1; HRMS
(ESI): calcd for C30H25BrN2NaO5S [MþNa]þ: 627.0565 Found:
627.0569; Chiralpak AD-H column and AD-H guard column (10%
column (15% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼24.0 min and minor-isomer tr¼32.8 min.
l
¼254 nm); major-
EtOHehexanes, 1.0 mL/min flow,
tr¼15.3 min and major-isomer tr¼26.8 min.
l
¼254 nm); minor-isomer
4.1.7. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-p-tolyl-1-
4.1.11. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-(4-nitrophenyl)-1-
tosylquinolin-4-yl)-1-phenylethanone (3ag). White solid; mp
tosylquinolin-4-yl)-1-phenylethanone (3ak). White solid; mp
89e91 ꢀC; ½a 2D4
ꢁ
ꢂ21.2 (c 0.15, CHCl3); 97% ee; 1H NMR (400 MHz,
198e200 ꢀC; ½a 2D4
ꢁ
ꢂ34.8 (c 0.17, CHCl3); 98% ee; 1H NMR (400 MHz,
CDCl3)
d
7.89 (dd, J¼0.8, 8.0 Hz,1H), 7.85 (d, J¼7.2 Hz, 2H), 7.58e7.64
CDCl3)
d
8.20 (d, J¼8.8 Hz, 2H), 7.87e7.83 (m, 3H), 7.63 (t, J¼7.6 Hz,

S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
5119
1H), 7.58 (d, J¼8.4 Hz, 2H) 7.42e7.51 (m, 5H), 7.34 (d, J¼8.0 Hz, 1H),
7.25 (ddd, J¼0.4, 7.6, 8.4 Hz, 1H), 6.82 (d, J¼7.6 Hz, 1H), 6.12 (d,
J¼7.6Hz,1H), 4.88 (dd, J¼4.8, 9.2 Hz,1H), 3.34(dd, J¼8.8,18.8 Hz,1H),
CDCl3)
d
7.85 (d, J¼7.6 Hz, 2H), 7.78 (d, J¼8.4 Hz, 1H), 7.56e7.66 (m,
3H), 7.48 (t, J¼7.6 Hz, 2H), 7.25e7.36 (m, 7H), 7.19 (d, J¼8.0 Hz, 1H),
6.63 (s, 1H), 6.12 (d, J¼6.8 Hz, 1H), 4.89 (dd, J¼6.8, 10.0 Hz, 1H), 3.27
(dd, J¼8.0, 14.0 Hz, 1H), 3.06e3.13 (m, 1H), 2.89 (dd, J¼4.0, 14.0 Hz,
2.92e3.01 (m, 2H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 194.9,
147.8,146.7,145.2,135.8,135.2,134.6,133.9,131.4,130.1,128.9,128.8,
127.9,127.7,127.6,127.4,127.2,125.7,124.4, 94.1, 62.2, 36.1, 36.0, 21.7;
IR (film) 2928, 1686, 1597, 1555, 1520, 1487, 1449, 1346, 1167,
1087 cmꢂ1; HRMS (ESI): calcd for C30H25N3NaO7S [MþNa]þ:
594.1311 Found: 594.1309; Chiralpak AD-H column and AD-H guard
1H), 2.45 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 195.4,
144.5, 139.8, 136.9, 136.1, 135.5, 133.7, 133.2, 131.0, 129.9, 129.2,
129.1, 128.9, 128.4, 127.9, 127.3, 126.9, 126.4, 126.2, 94.3, 62.5, 37.1,
35.7, 21.7, 21.3; IR (film) 2980, 2931, 1686, 1557, 1493, 1356, 1221,
1169, 1076 cmꢂ1; HRMS (ESI): calcd for C31H28N2NaO5S [MþNa]þ:
563.1617 Found: 563.1613; Chiralpak AD-H column and AD-H guard
column (20% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼10.4 min and minor-isomer tr¼15.0 min.
column (20% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼27.6 min and minor-isomer tr¼44.8 min.
l
¼254 nm); major-
l¼254 nm); major-
4.1.12. 2-((2S,3S,4R)-2-(Furan-2-yl)-1,2,3,4-tetrahydro-3-nitro-1-
tosylquinolin-4-yl)-1-phenylethanone (3al). Colorless gum;
½
a 2D4
7.88 (dd,
ꢁ
4.1.16. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-8-methyl-3-nitro-2-phenyl-
ꢂ37.9 (c 0.17, CHCl3); 98% ee; 1H NMR (400 MHz, CDCl3)
d
1-tosylquinolin-4-yl)-1-phenylethanone (3ca). White solid; mp
J¼1.6, 8.8 Hz, 2H), 7.78 (dd, J¼1.2, 8.4 Hz,1H), 7.60e7.66 (m, 3H), 7.49
(t, J¼8.0 Hz, 2H), 7.24e7.35(m, 4H), 7.16 (dt, J¼1.2, 7.6 Hz,1H), 6.88 (d,
J¼7.6 Hz, 1H), 6.41 (d, J¼3.6 Hz, 1H), 6.36 (d, J¼5.6 Hz, 1H), 6.32 (dd,
J¼2.0, 3.6 Hz, 1H), 5.17 (dd, J¼5.6, 8.8 Hz, 1H), 3.24e3.46 (m, 2H),
217e219 ꢀC; ½a 2D6
ꢁ
4.8 (c 0.84, CHCl3); 97% ee; 1H NMR (400 MHz,
7.94 (d, J¼7.2 Hz, 1H), 7.72 (d, J¼7.6 Hz, 2H), 7.63 (t,
CDCl3)
d
J¼7.2 Hz, 1H), 7.51 (t, J¼7.6 Hz, 2H), 7.41 (d, J¼8.4 Hz, 1H), 7.30e7.37
(m, 4H), 7.19 (t, J¼7.6 Hz, 1H), 7.10e7.17 (m, 2H), 6.70 (d, J¼7.6 Hz,
1H), 5.87 (d, J¼7.6 Hz, 1H), 4.81 (dd, J¼7.6, 12.0 Hz, 1H), 3.36 (dd,
2.78e2.87 (m, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 195.4,
150.7,144.8,143.0,135.9,135.3,135.0,133.7,130.0,129.9,128.8,128.2,
127.9, 127.4, 126.7, 126.4, 125.8, 110.9, 108.9, 89.5, 56.5, 38.2, 34.9,
21.7; IR (film) 2934, 1689, 1556, 1522, 1484, 1359, 1165 cmꢂ1; HRMS
J¼9.2, 18.4 Hz, 1H), 2.95e3.05 (m, 1H), 2.48 (s, 3H), 2.45 (s, 3H); 13
C
NMR (100 MHz, CDCl3)
d 195.1, 144.8, 139.6 (two signals over-
lapping), 136.2, 135.6, 134.9, 134.7, 133.7, 131.3, 130.2, 129.0, 128.8,
128.6,128.0,127.9 (two signals overlapping),126.7,123.0, 95.2, 63.9,
36.7, 36.1, 21.7, 19.6; IR (film) 2933, 1689, 1550, 1447, 1361, 1208,
1169, 1090 cmꢂ1; HRMS (ESI): calcd for C31H28N2NaO5S [MþNa]þ:
563.1617 Found: 563.1616; Chiralpak AD-H column and AD-H guard
column (20% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼9.7 min and minor-isomer tr¼12.8 min.
(ESI): calcd for
539.1251; Chiralpak AD-H column and AD-H guard column (20% i-
C
28H24N2NaO6S [MþNa]þ: 539.1253 Found:
PrOHehexanes, 1.0 mL/min flow,
tr¼11.8 min and minor-isomer tr¼28.6 min.
l
¼254 nm); major-isomer
l¼254 nm); major-
4.1.13. 2-((2S,3S,4R)-1,2,3,4-Tetrahydro-3-nitro-2-(thiophen-2-yl)-1-
tosylquinolin-4-yl)-1-phenylethanone (3am). White solid; mp
172e174 ꢀC; ½a 2D4
ꢁ
ꢂ6.1 (c 1.3, CHCl3); 98% ee; 1H NMR (400 MHz,
4.1.17. 2-((2S,3R,4S)-6-Chloro-1,2,3,4-tetrahydro-3-nitro-2-phenyl-
CDCl3)
d
7.90 (dd, J¼0.8, 8.0 Hz, 2H), 7.83 (dd, J¼0.8, 8.0 Hz, 1H),
1-tosylquinolin-4-yl)-1-phenylethanone (3da). White solid; mp
7.58e7.65 (m, 3H), 7.49 (t, J¼8.0 Hz, 2H), 7.38 (t, J¼7.6 Hz,1H), 7.32 (d,
J¼8.4 Hz,1H), 7.18e7.25 (m, 2H), 6.99 (dd, J¼0.8, 3.6 Hz,1H), 6.94 (dd,
J¼3.6, 4.8 Hz, 1H), 6.82 (d, J¼8.0 Hz, 1H), 6.42 (dd, J¼0.8, 6.4 Hz, 1H),
4.99 (dd, J¼6.4, 10.8 Hz, 1H), 3.36 (dd, J¼8.4, 18.0 Hz, 1H), 3.06 (dt,
J¼3.6,10.8 Hz,1H), 2.94 (dd, J¼3.6,18.4 Hz,1H), 2.45 (s, 3H); 13C NMR
203e205 ꢀC; ½a 2D4
ꢁ
ꢂ67.4 (c 0.74, CHCl3); 98% ee; 1H NMR (400 MHz,
CDCl3)
d
7.86 (d, J¼8.8 Hz,1H), 7.80 (dd, J¼1.2, 8.4 Hz, 2H), 7.59e7.65
(m, 3H), 7.47 (t, J¼7.6 Hz, 2H), 7.24e7.38 (m, 8H), 6.85 (d, J¼1.6 Hz,
1H), 6.19 (d, J¼6.4 Hz,1H), 4.99 (dd, J¼2.4, 9.2 Hz,1H), 3.16e3.24 (m,
2H), 2.84e2.93 (m, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d
195.1,144.8,143.4,135.9,135.2,134.9,133.8,131.4,
d 195.1, 144.9, 139.0, 135.8, 135.2, 134.3, 133.9, 132.7, 132.4, 130.1,
130.0,128.9,128.5,128.0,127.9,127.5,127.3,127.2,125.9,125.7,125.3,
94.7, 59.1, 36.9, 35.7, 21.7; IR (film) 2928,1686,1551,1458,1352,1228,
1167, 1091 cmꢂ1; HRMS (ESI): calcd for C28H24N2NaO5S2 [MþNa]þ:
555.1024 Found: 555.1022; Chiralpak AD-H column and AD-H guard
129.3, 128.8, 128.6, 128.5, 127.9, 127.5, 127.3, 126.5, 126.2, 93.0, 62.2,
37.5, 35.4, 21.7; IR (film) 2945, 1683, 1560, 1476, 1360, 1229, 1169,
1080 cmꢂ1; HRMS (ESI): calcd for C30H25ClN2NaO5S [MþNa]þ:
583.1070 Found: 583.1072; Chiralpak AD-H column and AD-H
guard column (20% i-PrOHehexanes, 1.0 mL/min flow,
column (20% i-PrOHehexanes, 1.0 mL/min flow,
isomer tr¼13.0 min and minor-isomer tr¼40.6 min.
l
¼254 nm); major-
l¼254 nm); major-isomer tr¼11.8 min and minor-isomer
tr¼19.6 min.
4.1.14. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-2-isopropyl-3-nitro-1-
tosylquinolin-4-yl)-1-phenylethanone (3an). White solid; mp
4.1.18. 2-((2S,3R,4S)-7-Chloro-1,2,3,4-tetrahydro-3-nitro-2-phenyl-
1-tosylquinolin-4-yl)-1-phenylethanone (3ea). White solid; mp
125e127 ꢀC; ½a 2D4
ꢁ
ꢂ16.1 (c 1.1, CHCl3); 91% ee; 1H NMR (400 MHz,
CDCl3)
d
7.92 (d, J¼7.6 Hz, 2H), 7.79 (d, J¼7.6 Hz, 1H), 7.63 (t,
181e183 ꢀC; ½a 2D5
ꢁ
ꢂ49.0 (c 0.83, CHCl3); 99% ee; 1H NMR (400 MHz,
J¼7.6 Hz, 1H), 7.55 (d, J¼7.6 Hz, 2H), 7.50 (t, J¼7.6 Hz, 2H), 7.37 (t,
J¼7.6 Hz, 1H), 7.25 (d, J¼8.0 Hz, 2H), 7.18 (t, J¼7.6 Hz, 1H), 6.75 (d,
J¼8.0 Hz, 1H), 4.79 (dd, J¼5.2, 8.0 Hz, 1H), 4.72 (dd, J¼5.2, 7.6 Hz,
1H), 3.35 (dd, J¼8.8, 18.4 Hz, 1H), 3.04 (dd, J¼2.4, 18.4 Hz, 1H), 2.75
(t, J¼8.8 Hz, 1H), 2.41 (s, 3H), 1.80 (septet, J¼6.8 Hz, 1H), 1.03 (d,
CDCl3)
d
7.96 (d, J¼2.4 Hz,1H), 7.79 (dd, J¼1.2, 6.0 Hz, 2H), 7.58e7.67
(m, 3H), 7.46 (t, J¼8.0 Hz, 2H), 7.24e7.35 (m, 7H), 7.15 (dd, J¼2.0,
8.0 Hz, 1H), 6.80 (d, J¼8.0 Hz, 1H), 6.21 (d, J¼6.4 Hz, 1H), 4.99 (dd,
J¼6.4, 8.8 Hz, 1H), 3.17e3.26 (m, 2H), 2.80e2.91 (m, 1H), 2.45 (s,
3H); 13C NMR (100 MHz, CDCl3)
d 195.3, 145.0, 138.9, 136.7, 135.8,
J¼6.8 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
195.2,144.3,136.1,136.0,
135.1, 134.0, 133.9, 130.0, 129.3, 129.1, 128.8, 128.6, 127.9, 127.4,
127.3, 126.8, 126.2, 125.9, 92.8, 62.1, 37.8, 35.2, 21.7; IR (film) 2930,
1684, 1595, 1560, 1448, 1364, 1230, 1171, 1077 cmꢂ1; HRMS (ESI):
calcd for C30H25ClN2NaO5S [MþNa]þ: 583.1070 Found: 583.1069;
Chiralpak AD-H column and AD-H guard column (20% i-
135.9, 133.7, 132.1, 129.7, 128.8, 128.4, 128.3, 127.9, 127.5, 127.2,
125.2, 93.0, 65.4, 36.2, 35.9, 34.6, 21.6, 19.0, 18.6; IR (film) 2988,
2930, 1686, 1548, 1449, 1349, 1231, 1162, 1078 cmꢂ1; HRMS (ESI):
calcd for C27H28N2NaO5S (MþNa)þ: 515.1617 Found: 515.1617;
Chiralpak AD-H column and AD-H guard column (20% i-
PrOHehexanes, 1.0 mL/min flow,
tr¼13.7 min and minor-isomer tr¼19.8 min.
l
¼254 nm); major-isomer
PrOHehexanes, 1.0 mL/min flow,
tr¼6.9 min and minor-isomer tr¼9.0 min.
l
¼254 nm); major-isomer
4.1.19. 2-((2S,3R,4S)-6-Bromo-1,2,3,4-tetrahydro-3-nitro-2-phenyl-
4.1.15. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-6-methyl-3-nitro-2-phenyl-
1-tosylquinolin-4-yl)-1-phenylethanone (3fa). White solid; mp
1-tosylquinolin-4-yl)-1-phenylethanone (3ba). White solid; mp
108e109 ꢀC; ½a 2D6
ꢁ
ꢂ65.4 (c 0.76, CHCl3); 98% ee; 1H NMR (400 MHz,
175e177 ꢀC; ½a 2D6
ꢁ
ꢂ34.8 (c 0.75, CHCl3); 96% ee; 1H NMR (400 MHz,
CDCl3)
d
7.81 (d, J¼8.4 Hz, 1H), 7.79 (d, J¼8.0 Hz, 2H), 7.56e7.67 (m,

5120
S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
3H), 7.44e7.53 (m, 3H), 7.23e7.37 (m, 7H), 7.01 (s, 1H), 6.21 (d,
J¼6.4 Hz, 1H), 5.00 (dd, J¼6.4, 8.8 Hz, 1H), 3.15e3.28 (m, 2H), 2.87
(dd, J¼4.0, 17.6 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
CDCl3)
d
7.91 (d, J¼7.6 Hz, 1H), 7.80 (t, J¼1.6 Hz, 1H), 7.20 (d,
J¼8.0 Hz, 1H), 7.56e7.64 (m, 3H), 7.38e7.45 (m, 2H), 7.25e7.36 (m,
7H), 7.21 (t, J¼7.6 Hz, 1H), 6.81 (d, J¼8.0 Hz, 1H), 3.25 (dd, J¼8.0,
18.0 Hz, 1H), 3.11 (ddd, J¼4.0, 10.8, 13.2 Hz, 1H), 2.86 (dd, J¼4.0,
d
195.1, 144.9, 138.9, 135.8, 135.2, 134.8, 133.8, 132.8, 131.5, 130.1,
129.5, 129.3, 128.8, 128.5, 127.9, 127.5, 127.4, 126.2, 120.1, 92.7, 62.1,
37.7, 35.3, 21.7; IR (film) 2980, 1683, 1558, 1475, 1359, 1228, 1167,
1085 cmꢂ1; HRMS (ESI): calcd for C30H25BrN2NaO5S [MþNa]þ:
627.0565 Found: 627.0568; Chiralpak AD-H column and AD-H
guard column (20% i-PrOHehexanes, 1.0 mL/min flow,
18.0 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 194.1, 144.7,
139.5, 137.4, 135.7, 135.3, 135.2, 133.7, 130.9, 130.2, 130.0, 129.2,
128.6, 128.5, 128.1, 127.3, 127.1, 127.0, 126.2, 126.0, 125.8, 94.0, 62.4,
37.3, 35.7, 21.7; IR (film) 2921, 1682, 1555, 1486, 1347, 1160,
1069 cmꢂ1; HRMS (ESI): calcd for C30H25ClN2NaO5S [MþNa]þ:
583.1070 Found: 583.1069; Chiralpak AD-H column and AD-H
guard column (20% i-PrOHehexanes, 1.0 mL/min flow,
l
¼254 nm); major-isomer tr¼11.8 min and minor-isomer
tr¼18.1 min.
l
¼254 nm); major-isomer tr¼12.2 min and minor-isomer
4.1.20. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-phenyl-1-
tr¼19.7 min.
tosylquinolin-4-yl)-1-(4-methoxyphenyl)ethanone
(3ga). White
solid; mp 86e88 ꢀC; ½a D24
ꢁ
ꢂ6.1 (c 0.98, CHCl3); >99% ee; 1H NMR
4.1.24. 1-(2-Chlorophenyl)-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-
(400 MHz, CDCl3)
d
7.90 (dd, J¼1.2, 8.0 Hz, 1H), 7.83 (d, J¼8.8 Hz,
2-phenyl-1-tosylquinolin-4-yl)ethanone (3ka). White solid; mp
2H), 7.61 (d, J¼8.4 Hz, 1H), 7.39 (t, J¼7.6 Hz, 1H), 7.17e7.34 (m, 8H),
6.94 (d, J¼8.8 Hz, 2H), 6.86 (d, J¼8.0 Hz,1H), 4.92 (dd, J¼6.8,10.0 Hz,
1H), 3.89 (s, 3H), 3.23 (dd, J¼8.4, 18.0 Hz, 1H), 3.10 (dt, J¼3.6,
10.0 Hz, 1H), 2.83 (dd, J¼3.6, 18.0 Hz, 1H), 2.44 (s, 3H); 13C NMR
85e86 ꢀC; ½a 2D4
ꢁ
15.1 (c 0.96, CHCl3); 84% ee; 1H NMR (400 MHz,
CDCl3)
d
7.90 (d, J¼8.0 Hz, 1H), 7.60 (d, J¼8.0 Hz, 2H), 7.40e7.45 (m,
4H), 7.23e7.37 (m, 9H), 6.97 (d, J¼7.6 Hz, 1H), 6.13 (d, J¼6.8 Hz, 1H),
4.89 (dd, J¼7.2, 10.0 Hz, 1H), 3.28 (dd, J¼8.0, 19.2 Hz, 1H), 2.93e3.03
(100 MHz, CDCl3)
d
193.8, 163.9, 144.7, 139.7, 135.7, 135.3, 131.4,
(m, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 197.9, 144.7,
130.3, 129.9, 129.1, 129.0, 128.5, 128.4, 127.3, 127.1, 126.9, 126.2,
125.9, 113.9, 94.3, 62.6, 55.6, 36.7, 35.9, 21.7; IR (film) 2980, 1681,
1604, 1552, 1454, 1351, 1230, 1159, 1068 cmꢂ1; HRMS (ESI): calcd for
139.6, 137.9, 135.8, 135.3, 132.4, 130.9 (two signals overlapping),
130.8,129.9,129.3,129.1,128.6,128.4,127.3,127.2,127.1,127.0,126.2,
125.9, 94.1, 62.5, 41.1, 36.1, 21.7; IR (film) 2928, 1680, 1585, 1553,
C
31H28N2NaO6S [MþNa]þ: 579.1566 Found: 579.1565; Chiralpak
1486, 1348, 1159, 1068 cmꢂ1
;
HRMS (ESI): calcd for
AD-H column and AD-H guard column (20% i-PrOHehexanes,
C
30H25ClN2NaO5S [MþNa]þ: 583.1070 Found: 583.1067; Chiralpak
1.0 mL/min flow,
isomer tr¼33.6 min.
l
¼254 nm); major-isomer tr¼17.3 min and minor-
AD-H column and AD-H guard column (15% i-PrOHehexanes,
1.0 mL/min flow,
isomer tr¼25.2 min.
l
¼254 nm); major-isomer tr¼20.5 min and minor-
4.1.21. 2-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-phenyl-1-
tosylquinolin-4-yl)-1-p-tolylethanone (3ha). White solid; mp
4.1.25. 1-(4-Bromophenyl)-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-
2-phenyl-1-tosylquinolin-4-yl)ethanone (3la). White solid; mp
110e111 ꢀC; ½a 2D4
ꢁ
ꢂ3.7 (c 1.1, CHCl3); 99% ee; 1H NMR (400 MHz,
CDCl3)
d
7.90 (d, J¼8.0 Hz, 1H), 7.76 (d, J¼8.0 Hz, 2H), 7.40 (t,
89e91 ꢀC; ½a 2D0
ꢁ
ꢂ14.3 (c 0.37, CHCl3); 98% ee; 1H NMR (400 MHz,
J¼7.6 Hz, 1H), 7.26e7.35 (m, 9H), 7.20 (t, J¼7.6 Hz, 1H), 6.84 (d,
J¼7.6 Hz, 1H), 6.13 (d, J¼6.8 Hz, 1H), 4.92 (dd, J¼6.8, 10.0 Hz, 1H),
3.27 (dd, J¼8.4, 18.0 Hz, 1H), 3.10 (dt, J¼3.6, 11.2 Hz, 1H), 2.86 (dd,
J¼3.6, 18.0 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d
7.90 (dd, J¼1.4, 8.4 Hz, 1H), 7.58e7.72 (m, 6H), 7.40 (t,
J¼8.0 Hz,1H), 7.24e7.35 (m, 7H), 7.20 (dt, J¼1.4, 8.0vHz,1H), 6.80 (d,
J¼7.6 Hz, 1H), 6.13 (d, J¼6.8 Hz, 1H), 4.89 (dd, J¼6.8, 10.0 Hz, 1H),
3.24 (dd, J¼8.0, 18.0 Hz, 1H), 3.07e3.13 (m, 1H), 2.83 (dd, J¼4.0,
CDCl3)
d
194.9, 144.7, 139.7, 135.7, 135.3, 133.5, 131.4, 130.0, 129.5,
18.0 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 194.3, 144.7,
129.2, 128.5, 128.4,128.1, 127.3, 127.1, 127.0, 126.3,125.9 (two signals
overlapping), 94.4, 62.6, 36.9, 35.8, 21.7, 21.6; IR (film) 2922, 1681,
1604,1552,1454,1350,1240,1150,1068 cmꢂ1; HRMS (ESI): calcd for
139.6, 135.8, 135.3, 134.6, 132.1, 130.9, 129.9, 129.4, 129.0, 128.6,
128.5, 127.3, 127.1, 127.0, 126.2, 125.8, 94.1, 62.5, 37.1, 35.7, 21.7; IR
(film) 2980, 1687, 1585, 1552, 1456, 1359, 1167, 1082 cmꢂ1; HRMS
(ESI): calcd for C30H25BrN2NaO5S [MþNa]þ: 627.0565 Found:
627.0560; Chiralpak AD-H column and AD-H guard column (15% i-
C
31H28N2NaO5S [MþNa]þ: 563.1617 Found: 563.1615; Chiralpak
AD-H column and AD-H guard column (20% i-PrOHehexanes,
1.0 mL/min flow,
isomer tr¼26.1 min.
l
¼254 nm); major-isomer tr¼14.7 min and minor-
PrOHehexanes, 1.0 mL/min flow,
tr¼22.4 min and minor-isomer tr¼39.1 min.
l
¼254 nm); major-isomer
4.1.22. 1-(4-Chlorophenyl)-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-
4.1.26. 1-(Furan-2-yl)-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-2-
2-phenyl-1-tosylquinolin-4-yl)ethanone (3ia). White solid; mp
phenyl-1-tosylquinolin-4-yl)ethanone (3ma). White solid; mp
100e102 ꢀC; ½a 2D1
ꢁ
ꢂ21.4 (c 0.98, CHCl3); 97% ee; 1H NMR (400 MHz,
156e158 ꢀC; ½a 2D4
ꢁ
ꢂ7.2 (c 1.2, CHCl3); 94% ee; 1H NMR (400 MHz,
CDCl3)
d
7.90 (dd, J¼1.2, 8.4 Hz, 1H), 7.78 (d, J¼8.8 Hz, 2H), 7.61 (d,
CDCl3)
d
7.90 (dd, J¼1.2, 8.4 Hz, 1H), 7.69 (dd, J¼0.8, 4.8 Hz, 1H),
J¼8.4 Hz, 2H), 7.45 (d, J¼8.4 Hz, 2H), 7.40 (t, J¼7.6 Hz,1H), 7.24e7.36
(m, 7H), 7.20 (dt, J¼1.2, 7.6 Hz, 1H), 6.81 (d, J¼7.6 Hz, 1H), 6.14 (d,
J¼7.2 Hz, 1H), 4.99 (dd, J¼7.2, 10.4 Hz, 1H), 3.25 (dd, J¼8.4, 18.4 Hz,
1H), 3.11 (ddd, J¼4.0, 8.8, 11.6 Hz, 1H), 2.84 (dd, J¼4.0, 18.4 Hz, 1H),
7.57e7.62 (m, 3H), 7.41 (t, J¼8.0 Hz, 1H), 7.20e7.36 (m, 8H), 7.15 (dd,
J¼3.6, 4.8 Hz, 1H), 6.94 (d, J¼7.6 Hz, 1H), 4.89 (dd, J¼6.8, 10.4 Hz,
1H), 3.21 (dd, J¼8.4, 17.6 Hz, 1H), 3.07 (ddd, J¼3.6, 9.2, 12.0 Hz, 1H),
2.84 (dd, J¼3.6, 17.6 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
194.1, 144.7, 140.3, 139.6,
d 188.2, 144.7, 143.0, 139.6, 135.7, 135.3, 134.4, 132.1, 131.1, 129.9,
135.8,135.3,134.2,131.0,129.4,129.2,129.1,128.6,128.5,127.3,127.1,
127.0, 126.2, 125.8, 94.1, 62.5, 37.1, 35.7, 21.7; IR (film) 2980, 1687,
1589, 1556, 1486, 1345, 1164, 1089 cmꢂ1; HRMS (ESI): calcd for
129.2, 128.6, 128.5, 128.3, 127.2, 127.1, 127.0, 126.2, 125.9, 94.3, 62.5,
37.7, 35.8, 21.7; IR (film) 2980, 1675, 1551, 1468, 1351, 1162,
1092 cmꢂ1; HRMS (ESI): calcd for C28H24N2NaO6S [MþNa]þ:
539.1253 Found: 539.1253; Chiralpak AD-H column and AD-H
guard column (15% i-PrOHehexanes, 1.0 mL/min flow,
C
30H25ClN2NaO5S [MþNa]þ: 583.1070 Found: 583.1074; Chiralpak
AD-H column and AD-H guard column (20% i-PrOHehexanes,
1.0 mL/min flow,
isomer tr¼32.7 min.
l
¼254 nm); major-isomer tr¼17.8 min and minor-
l
¼254 nm); major-isomer tr¼14.4 min and minor-isomer
tr¼26.4 min.
4.1.23. 1-(3-Chlorophenyl)-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-
4.1.27. 1-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-phenyl-1-
2-phenyl-1-tosylquinolin-4-yl)ethanone (3ja). White solid; mp
tosylquinolin-4-yl)-3,3-dimethylbutan-2-one (3na). White solid;
96e98 ꢀC; ½a 2D0
ꢁ
ꢂ7.8 (c 0.28, CHCl3); 96% ee; 1H NMR (400 MHz,
mp 132e134 ꢀC; ½a D25
ꢁ
12.0 (c 0.98, CHCl3); 92% ee; 1H NMR

S. Kim et al. / Tetrahedron 70 (2014) 5114e5121
5121
3. For selected reviews on organocatalysis, see: (a) Pellissier, H. Recent De-
velopments in Asymmetric Organocatalysis; RSC: Cambridge, UK, 2010; (b)
Asymmetric Organocatalysis; List, B., Ed.Topics in Current Chemistry; Springer:
Berlin/Heidelberg, 2010; vol. 291; (c) Dalko, P. I. Enantioselective Organo-
(400 MHz, CDCl3)
d
7.87 (dd, J¼0.8, 8.0 Hz, 1H), 7.59 (d, J¼8.4 Hz,
2H), 7.20e7.39 (m, 9H), 6.80 (d, J¼8.0 Hz, 1H), 6.14 (d, J¼6.4 Hz, 1H),
4.89 (dd, J¼6.4, 9.6 Hz, 1H), 2.86e2.93 (m, 1H), 2.77 (dd, J¼7.2,
18.8 Hz, 1H), 2.47 (dd, J¼4.4, 18.8 Hz, 1H), 2.39 (s, 3H), 1.09 (s, 9H);
€
catalysis; Wiley-VCH: Weinheim, Germany, 2007; (d) Berkessel, A.; Groger, H.
13C NMR (100 MHz, CDCl3)
d 211.6, 144.6, 139.5, 135.6, 135.4, 130.9,
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005; (e) Ber-
telsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178; (f) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (g)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (h) Pellissier, H.
Tetrahedron 2007, 63, 9267; (i) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
129.9, 129.1, 128.4, 128.3, 127.3, 126.7, 126.4, 126.3, 125.8, 93.5, 62.2,
44.2, 35.4, 35.2, 26.6, 21.6; IR (film) 2980, 1693, 1553, 1453, 1339,
1238, 1158, 1087 cmꢂ1; HRMS (ESI): calcd for C28H30N2NaO5S
[MþNa]þ: 529.1773 Found: 529.1771; Chiralpak AD-H column and
AD-H guard column (15% i-PrOHehexanes, 1.0 mL/min flow,
€
Chem. Rev. 2007, 107, 5471; (j) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev.
2007, 107, 5416.
4. For selected reviews on domino reactions, see: (a) MacMillan, D. W. C.; Walji,
A. M. Synthesis 2007, 1477; (b) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1; (c)
Pellissier, H. Tetrahedron 2006, 62, 2143; (d) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. C. Angew. Chem., Int. Ed. 2006, 45, 7134; (e) Guo, H. C.; Ma, J. A. Angew.
Chem., Int. Ed. 2006, 45, 354; (f) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
5. For selected reviews on organocatalytic domino reaction, see: (a) Pellissier, H.
Asymmetric Domino Reactions; RSC: Cambridge, UK, 2013; (b) Pellissier, H. Adv.
Synth. Catal. 2012, 354, 237; (c) Albrecht, q.; Jiang, H.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2011, 50, 8492; (d) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem.
2010, 2, 167; (e) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037; (f) Enders,
l
¼254 nm); major-isomer tr¼8.2 min and minor-isomer
tr¼12.6 min.
4.1.28. 1-Cyclopropyl-2-((2S,3R,4S)-1,2,3,4-tetrahydro-3-nitro-2-
phenyl-1-tosylquinolin-4-yl)ethanone (3oa). White solid; mp
145e146 ꢀC; ½a 2D5
ꢁ
11.9 (c 1.2, CHCl3); 95% ee; 1H NMR (400 MHz,
CDCl3)
d
7.87 (d, J¼8.0 Hz, 1H), 7.58 (d, J¼7.6 Hz, 1H), 7.40 (t,
J¼7.6 Hz, 1H), 7.20e7.36 (m, 8H), 6.88 (d, J¼7.6 Hz, 1H), 6.07 (d,
J¼6.8 Hz, 1H), 4.80 (dd, J¼7.2, 8.8 Hz, 1H), 2.81e2.89 (m, 2H), 2.54
(dd, J¼7.2, 21.2 Hz, 1H), 2.41 (s, 3H), 1.73e1.81 (m, 1H), 0.83e1.05
€
D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
ꢀ
6. For selected recent Michael addition reviews, see: (a) Cordova, A. Catalytic
Asymmetric Conjugate Reactions; Wiley-VCH: Weinheim, Germany, 2010; (b)
Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E. Organocatalytic Enantioselective
Conjugate Addition Reactions; RSC: Cambridge, UK, 2010; (c) Almas¸ i, D.; Alonso,
(m, 4H); 13C NMR (100 MHz, CDCl3)
d 206.0, 144.5, 139.7, 135.7,
134.4,131.3,129.9,129.1,128.5,128.4,127.3,127.2,127.1,126.2,125.6,
94.4, 62.6, 41.5, 35.7, 21.6, 21.4, 11.3, 11.2; IR (film) 2978, 1694, 1550,
1455, 1338, 1160, 1090 cmꢂ1; HRMS (ESI): calcd for C27H26N2NaO5S
[MþNa]þ: 513.1460 Found: 513.1455; Chiralpak AD-H column and
AD-H guard column (15% i-PrOHehexanes, 1.0 mL/min flow,
ꢀ
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299; (d) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
7. For reviews on tetrahydroquinolines, see: (a) Sridharan, V.; Suryavanshi, P. A.;
ꢀ
Menendez, J. C. Chem. Rev. 2011, 111, 7157; (b) Zhou, Y.-G. Acc. Chem. Res. 2007,
40, 1357; (c) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 17,
2862; (d) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl. Chem.
1998, 35, 761; (e) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52,
15031.
l
¼254 nm); major-isomer tr¼13.2 min and minor-isomer
tr¼22.9 min.
8. (a) DePasquale, M.; Cadelina, G.; Knight, D.; Loging, W.; Winter, S.; Blasi, E.;
Perry, D.; Keiser, J. Drug Dev. Res. 2009, 70, 35; (b) Sikorski, J. A. J. Med. Chem.
2006, 49, 1; (c) He, J.; Lion, U.; Sattler, I.; Gollmick, F. A.; Grabley, S.; Cai, J.;
4.1.29. 1-((2S,3R,4S)-1,2,3,4-Tetrahydro-3-nitro-2-phenyl-1-
€
Meiners, M.; Schunke, H.; Schaumann, K.; Dechert, U.; Krohn, M. J. Nat. Prod.
tosylquinolin-4-yl)propan-2-one
(3pa). White
solid;
mp
2005, 68, 1397; (d) Kusano, M.; Koshino, H.; Uzawa, J.; Fujioka, S.; Kawano, T.;
Kimura, Y. Biosci. Biotechnol. Biochem. 2000, 64, 2559; (e) Jacquemond-Collet, I.;
186e188 ꢀC; ½a 2D6
ꢁ
10.4 (c 0.84, CHCl3); 78% ee; 1H NMR (400 MHz,
ꢀ
Hannedouche, S.; Fabre, N.; Fouraste, I.; Moulis, C. Phytochemistry 1999, 51,
CDCl3)
d
7.88 (d, J¼8.0 Hz, 1H), 7.57 (d, J¼8.4 Hz, 1H), 7.42 (t,
1167; (f) Morimoto, Y. J. Heterocycl. Chem. 1998, 35, 279.
J¼7.6 Hz, 1H), 7.20e7.37 (m, 8H), 6.83 (d, J¼8.0 Hz, 1H), 6.06 (d,
J¼7.2 Hz, 1H), 4.71 (dd, J¼7.2, 10.4 Hz, 1H), 2.82 (ddd, J¼3.6, 10.4,
13.2 Hz, 1H), 2.72 (dd, J¼8.4, 18.0 Hz, 1H), 2.43 (s, 3H), 2.36 (dd,
9. (a) Jia, Z.-X.; Luo, Y.-C.; Wang, Y.; Chen, L.; Xu, P.-F.; Wang, B. Chem.dEur. J. 2012,
18, 12958; (b) Tan, H. R.; Ng, H. F.; Chang, J.; Wang, J. Chem.dEur. J. 2012, 18,
3865; (c) Dagousset, G.; Zhu, J.-P.; Masson, G. J. Am. Chem. Soc. 2011, 133, 14804;
(d) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133,
6166; (e) Jia, Z.-X.; Luo, Y.-C.; Xu, P.-F. Org. Lett. 2011, 13, 832; (f) Kang, Y. K.; Kim,
S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847; (g) Xie, M.; Chen, X.; Zhu, Y.;
Gao, B.; Lin, L.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2010, 49, 3799; (h) Xu, H.;
Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986; (i) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009, 131,
J¼3.6, 18.0 Hz, 1H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 203.8,
144.6, 139.6, 135.8, 135.4, 131.2, 129.9, 129.1, 128.7, 128.5, 127.4, 127.2
(two signals overlapping), 126.2, 125.4, 94.4, 62.5, 41.8, 35.7, 29.6,
21.6; IR (film) 2980, 1712, 1548, 1487, 1360, 1306, 1165, 1095 cmꢂ1
;
HRMS (ESI): calcd for C25H24N2NaO5S [MþNa]þ: 487.1304. Found:
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4598; (j) Fustero, S.; Moscardo, J.; Jimenez, D.; Perez-Carrion, M. D.; Sanche-
ꢀ
487.1303; Chiralpak AD-H column and AD-H guard column (20% i-
Rosello, M.; del Pozo, C. Chem.dEur. J. 2008, 14, 9868; (k) Rueping, M.; An-
tonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683.
PrOHehexanes, 1.0 mL/min flow,
tr¼13.5 min and minor-isomer tr¼35.8 min.
l¼254 nm); major-isomer
10. Heo, S.; Kim, S.; Kim, S.-G. Tetrahedron Lett. 2013, 54, 4978.
11. (a) During our initial studies, Xu and co-workers disclosed organocatalytic aza-
MichaeleMichael cascade reactions of o-aminophenyl a,b-unsaturated ketones
and limited nitroalkenes in which only moderate to good diastereoselectivities
in most cases were reported, see: Ref. 9a. (b) During the preparation of this
manuscript Du and co-workers reported chiral squaramide-catalyzed aza-Mi-
Acknowledgements
chaeleMichael cascade reactions of o-N-tosyl aminophenyl
a,b-unsaturated
This research was supported by Nano-Material Development
Program 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).
ketones and -methyl- -nitrostyrene, see: Yang, W.; He, H.-X.; Gao, Y.; Du, D.-
b
b
M. Adv. Synth. Catal. 2013, 355, 3670.
12. For selected reviews on bifunctional thiourea catalysts, see: (a) Marques-Lopez,
E.; Herrera, R. P. In New Strategies in Chemical Synthesis and Catalysis; Pignataro,
B., Ed.; Wiley-VCH: Weinheim, Germany, 2010; p 175; (b) Han, B.; Li, J.-L.; Xiao,
Y.-C.; Zhou, S.-L.; Chen, Y.-C. Curr. Org. Chem. 2011, 15, 4128; (c) Takemoto, Y.
Chem. Pharm. Bull. 2010, 58, 593; (d) Song, C. E. Cinchona Alkaloids in Synthesis &
Catalysis; Wiley-VCH: Weinheim, Germany, 2009.
Supplementary data
13. (a) Sakamoto, S.; Inokuma, T.; Takemoto, Y. Org. Lett. 2011, 13, 6374; (b) Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.05.114.
14. CCDC 983605 (3la) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
15. (a) Li, X.; Yang, C.; Jin, J.-L.; Xue, X.-S.; Cheng, J.-P. Chem.dAsian J. 2013, 8, 997;
(b) Zhu, J. L.; Zhang, Y.; Liu, C.; Zheng, A.-M.; Wang, W. J. Org. Chem. 2012, 77,
References and notes
ꢀ
9813; (c) Basle, O.; Raimondi, W.; Duque, M. M. S.; Bonne, D.; Constantieux, T.;
Rodriguez, J. Org. Lett. 2010, 12, 5246; (d) Tan, B.; Lu, Y.; Zeng, X.; Chua, P. J.;
1. (a) Carreira, E. M.; Kvaerno, L. Classics in Stereoselective Synthesis; Wiley-VCH:
Weinheim, Germany, 2009; (b) Nicolaou, K. C.; Montagnon, T. Molecules That
Changed the World; Wiley-VCH: Weinheim, Germany, 2008.
ꢀ
ꢀ
Zhong, G. Org. Lett. 2010, 12, 2682; (e) Hamza, A.; Schubert, G.; Soos, T.; Papai, I.
J. Am. Chem. Soc. 2006, 128, 13151; (f) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
2. Ojima, P. Catalytic Asymmetric Synthesis; Wiley: New Jersey, 2010.