Enantioselective Catalytic Domino Aza-Michael-Henry Reactions: One-Pot Asymmetric Synthesis of 3-Nitro-1,2-dihydroquinolines via Iminium Activation

Article abstract of DOI:10.1002/ejoc.201501618

Asymmetric transformations arising from iminium activation of aromatic aldehydes are uncommon. In this work, an enantioselective organocatalytic domino aza-Michael-Henry reaction between N-(2-formylphenyl)sulfonamides and trans-β-nitro olefins through imi

Full text of DOI:10.1002/ejoc.201501618

DOI: 10.1002/ejoc.201501618
Full Paper
Asymmetric Catalysis
Enantioselective Catalytic Domino Aza-Michael–Henry
Reactions: One-Pot Asymmetric Synthesis of 3-Nitro-1,2-
dihydroquinolines via Iminium Activation
Hao Luo,[a,b] Xilong Yan,[a,b] Ligong Chen,[a,b] Yang Li,[a,b] Na Liu,[a,b] and Guohui Yin*[c]
Abstract: Asymmetric transformations arising from iminium hydroquinolines in high yields with up to 88 % ee under mild
activation of aromatic aldehydes are uncommon. In this work,
an enantioselective organocatalytic domino aza-Michael–Henry
reaction between N-(2-formylphenyl)sulfonamides and trans-ꢀ-
nitro olefins through iminium activation has been presented.
This reaction proceeded smoothly to give chiral 3-nitro-1,2-di-
conditions. Furthermore, a preliminary study showed that 2-
mercaptobenzaldehyde derivatives could participate in a thia-
Michael–Henry reaction with trans-ꢀ-nitro olefins to yield chiral
3-nitro-2H-thiochromenes.
Introduction
hypothesized to be enhanced by facile deprotonation of OH
and NH moieties.
Organocatalysis, the use of small organic molecules to catalyze
organic transformations, has been accepted as a fundamental
and effective tool for chiral molecule (or enantioselective) syn-
thesis since the two outstanding works by List[1] and MacMil-
lan[2] in 2000, respectively.[3] In this context, iminium activation
has been demonstrated to be one of the most powerful strate-
gies for asymmetric catalysis.[4,5] However, this activation mode
has generally focused on the functionalization of α,ꢀ-unsatu-
rated aldehydes by lowering their LUMO energy levels. By con-
trast, asymmetric transformations enabled by iminium activa-
tion of aromatic aldehydes have been rarely achieved.[6]
Inspired by the previous studies,[6a,6b] and based on our un-
derstanding of corresponding reaction mechanisms, we envi-
sioned that a domino aza-Michael–Henry reaction between N-
protected 2-aminobenzaldehydes and trans-ꢀ-nitro olefins
might take place to afford chiral 3-nitro-1,2-dihydroquinolines
(Scheme 1). In the protocol, an electron-withdrawing group
(EWG) was installed on the amino moiety of 2-aminobenzalde-
hyde to increase the N–H acidity, thus enabling deprotonation
and subsequently improved nucleophilicity. For 1,2-dihydro-
quinolines, although they are known as biologically active com-
pounds and useful synthetic intermediates in natural product
synthesis,[7,8] methods for their asymmetric catalytic synthesis
are limited.[6c,9] Thus, the development of a facile approach to
chiral 1,2-dihydroquinolines is highly desirable and very valu-
able.
In 2008, Xu et al. reported the first example of iminium catal-
ysis with aromatic aldehydes; enantioselective oxa-Michael–
Henry reactions of salicylaldehydes with trans-ꢀ-nitro olefins af-
forded chiral 3-nitro-2H-chromenes.[6a] Using a bifunctional
trans-4-hydroxy-L-prolinamide as the catalyst and employing 4-
nitrophenol as the cocatalyst, we have improved upon Xu's
method for the synthesis of chiral 3-nitro-2H-chromenes in
terms of both yield and enantioselectivity.[6b] Moreover, it was
found that the heteroaromatic aldehyde 2-formylpyrrole, could
also be activated by a transient iminium species.[6b] In these
cases, the formation of iminium intermediates would promote
the acidity of OH and NH moieties in salicylaldehydes and 2-
formylpyrrole, respectively. As a result, their nucleophilicity was
[a] School of Chemical Engineering and Technology, Tianjin University,
Tianjin 300072, P. R. China
[b] Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin),
Tianjin 300072, P. R. China
[c] School of Science, Tianjin University,
Tianjin 300072, P. R. China
E-mail: yingh21@tju.edu.cn
http://www.tju.edu.cn/science/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501618.
Scheme 1. A plausible reaction pathway for the organocatalytic asymmetric
synthesis of 3-nitro-1,2-dihydroquinolines.
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Results and Discussion
lysts; 4-nitrophenol was identified as a suitable cocatalyst,
whereas other acidic additives gave inferior results with respect
to both yields and stereoselectivities (Table 2, Entries 1–6). The
remarkable performance of 4-nitrophenol as a cocatalyst may
be rationalized on the basis of its acidity, which appears to be
most amenable to generation of the iminium intermediate; its
conjugate base is relatively basic which facilitates the deproto-
nation of N–H moiety in the iminium intermediate. Moreover,
the regeneration of catalyst Ia might be effectively promoted
by 4-nitrophenol (Scheme 1). Notably, a control experiment
lacking cocatalyst was also performed, thus confirming the ne-
cessity of 4-nitrophenol in the domino reaction (Table 2, Entry
7). Subsequently, screening of different solvents revealed CHCl3
as the ideal reaction medium (Table 2, Entries 1, 8–14); the
model reaction with this solvent gave the highest yield and
enantioselectivity of those solvents tested. It is worth noting
that almost racemic mixtures of 3a were obtained when the
model reaction was performed in CH3OH, DMF or DMSO
(Table 2, Entries 10–12). Such data can be understood by realiz-
ing that highly polar or protonic solvents tend to disfavor the
required hydrogen-bonding interactions. However, nonpolar
solvents, though helpful from the standpoint of H-bonding, are
unconducive to stabilizing polar iminium intermediates. These
considerations help one to rationalize why CHCl3, with its mod-
erate polarity, proved to be the optimal solvent for these asym-
metric reactions.
To validate the feasibility of our hypothesis, N-tosyl-2-amino-
benzaldehyde 1a was first chosen to react with trans-ꢀ-nitro-
styrene 2a in the presence of organocatalyst Ia, together with
4-nitrophenol as a cocatalyst. Meanwhile, molecular sieves (MS,
4 Å) were added to facilitate the catalytic process by removing
water generated during the reaction. To our delight, the
expected domino aza-Michael–Henry reaction proceeded
smoothly in chloroform at room temperature and desired 3-
nitro-2-phenyl-1-tosyl-1,2-dihydroquinoline 3a was obtained in
95 % yield and with 88 % ee (Table 1, Entry 1). The absolute
configuration was assigned to be S based on comparisons of
HPLC traces of 3a with those reported previously in the litera-
ture.[9c] Apart from the substrate with a strong electron-with-
drawing sulfonyl 1a, other N-protecting groups such as acetyl
(Ac), Cbz, Boc and electron-donating benzyl (Bn) functionalized
2-aminobenzaldehydes were also tested in our study (Table 1,
Entries 2–5). However, it was found that these kinds of 2-amino-
benzaldehydes were incompatible with the domino reaction.
These observations might be rationalized by more difficult de-
protonation of N–H moiety in the corresponding iminium inter-
mediates due to the weak electron-withdrawing or -donating
abilities of Ac, Cbz, Boc and Bn substituents.
Table 1. Screening of N-protected 2-aminobenzaldehydes for the domino aza-
Michael–Henry reaction.[a]
Table 2. Optimization of reaction conditions for the domino aza-Michael–
Henry reaction.[a]
Entry Cocatalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4-nitrophenol
benzoic acid
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
toluene
CH3OH
DMF
95
64
51
34
15
26
24
85
83
85
93
81
55
57
88
84
79
69
77
68
32
84
79
< 5
< 5
< 5
72
54
4-methoxybenzoic acid
4-nitrobenzoic acid
salicylic acid
2,4-dinitrophenol
–
4-nitrophenol
4-nitrophenol
4-nitrophenol
4-nitrophenol
4-nitrophenol
4-nitrophenol
4-nitrophenol
9
10
11
12
13
14
DMSO
THF
CH3CN
[a] All reactions were carried out with N-protected 2-aminobenzaldehyde (1;
0.1 mmol, 1.0 equiv.), trans-ꢀ-nitrostyrene (2a; 0.2 mmol, 2.0 equiv.), organo-
catalyst Ia (20 mol-%), 4-nitrophenol (20 mol-%), and molecular sieves (4 Å;
300 mg) in CHCl3 (1 mL) at room temperature for 3 d. [b] Isolated yields.
[c] Determined by chiral HPLC. [d] n.r.: no reaction.
[a] All reactions were carried out with N-tosyl-2-aminobenzaldehyde (1a;
0.1 mmol, 1.0 equiv.), trans-ꢀ-nitrostyrene (2a; 0.2 mmol, 2.0 equiv.), organo-
catalyst Ia (20 mol-%), cocatalyst (20 mol-%), and molecular sieves (4 Å;
300 mg) in solvent (1 mL) at room temperature for 3 d. [b] Isolated yields.
[c] Determined by chiral HPLC.
Using Ia as reaction catalyst, optimization of reaction condi-
tions was then carried out using a model reaction between N-
tosyl-2-aminobenzaldehyde 1a and trans-ꢀ-nitrostyrene 2a
With optimized conditions in hand, we next focused on es-
(Table 2). Acids usually play an important role in iminium cataly- tablishing the general applicability of the domino aza-Michael–
sis,[10] and accordingly, we surveyed a range of acidic cocata- Henry reaction by screening substrates with different substitu-
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ents; the results are summarized in Table 3. As revealed earlier
(Table 1), a strong electron-withdrawing sulfonyl moiety seems
to be essential for the domino reaction. Consequently, the influ-
ences of different sulfonyl groups on this asymmetric transfor-
mation were investigated. Tosyl, benzenesulfonyl and 4-
(methoxy)phenylsulfonyl protected 2-aminobenzaldehydes un-
derwent the reaction well, affording desired 3-nitro-1,2-dihydro-
quinolines in excellent yields with high enantioselectivities
(Table 3, Entries 1–3). In contrast, the methylsulfonyl protecting
group resulted in a comparable yield but significantly de-
creased reaction enantioselectivity (Table 3, Entry 4). The poor
enantioselectivity seen with the methanesulfonyl protected
substrate versus the arylated species probably stems from its
minor steric capabilities with regard to exerting stereocontrol.
Afterwards, a wide range of nitro olefins were reacted with N-
tosyl-2-aminobenzaldehyde 1a. Corresponding transformations
of aromatic nitro olefins generally gave high yields and good
enantioselectivities of 69–86 % ee (Table 3, Entries 5–10). On the
basis of these data it appears that the position and electronic
properties of substituents on the aromatic rings have very lim-
ited impact on reaction yields but can significantly affect the
observed enantioselectivities. For instance, a chloro group on
the para, meta or ortho positions of the phenyl ring of ꢀ-nitro-
styrenes led to noticeable differences in the ee values (Table 3,
Entries 5–7). As for heteroaromatic ꢀ-furyl-substituted nitro ole-
fin, the ꢀ-furyl group was tolerated and this substrate was con-
verted into 3-nitro-1,2-dihydroquinoline 3k in 88 % yield and
with 79 % ee (Table 3, Entry 11). When aliphatic trans-ꢀ-nitro
olefin derived from n-butyraldehyde was used as a substrate, 3l
was attained in moderate yield and with moderate enantiose-
lectivity (Table 3, Entry 12). Additionally, we found that the ee
values for generation of 3d and 3l were only slightly improved
when the corresponding reactions were carried out at 0 °C
(Table 3, Entries 4 and 12).
Table 3. Domino aza-Michael–Henry reactions between N-sulfonyl-2-amino-
benzaldehydes 1 and trans-ꢀ-nitro olefins 2.[a]
The mechanism of the disclosed domino aza-Michael–Henry
reactions was also studied. Two critical intermediates, iminium
ion (M+: 458.1750) and tetrahydroquinoline with tethered cata-
lyst Ia ([M + H]+: 607.2205 and [M + Na]+: 629.2027), were de-
tected in the reaction mixture (after stirring for 1 d) using high-
resolution mass spectroscopy (HRMS). These HRMS data sup-
port the rationale of the proposed mechanism shown in
Scheme 1. Moreover, we hypothesize that regeneration of cata-
lyst Ia from tetrahydroquinoline might be rate-determining in
the catalytic cycle; this may be a reflection of the much lower
content of iminium ion observed during HRMS studies.
We next endeavored to apply iminium activation to other
aromatic aldehyde substrates and their asymmetric transforma-
tions. The structural similarity between 2-mercaptobenzalde-
hydes and N-sulfonyl-2-aminobenzaldehydes prompted us to
envisage that a thia-Michael–Henry reaction between 2-mer-
captobenzaldehydes and trans-ꢀ-nitro olefins might be feasible,
thus affording chiral 3-nitro-2H-thiochromenes. To the best of
our knowledge, there are very few reports on the asymmetric
synthesis of 2H-thiochromenes.[11] Accordingly, the above hy-
pothesis was tested by employing 2-mercaptobenzaldehyde
and trans-ꢀ-nitrostyrene as substrates (Scheme 2). Much to our
delight, 3-nitro-2-phenyl-2H-thiochromene 5 was obtained in
[a] All reactions were carried out with N-sulfonyl-2-aminobenzaldehydes (1;
0.1 mmol, 1.0 equiv.), trans-ꢀ-nitro olefins (2; 0.2 mmol, 2.0 equiv.), organocat-
alyst Ia (20 mol-%), 4-nitrophenol (20 mol-%), and molecular sieves (4 Å;
300 mg) in CHCl3 (1 mL) at room temperature for 3 d. [b] Isolated yields.
[c] Determined by chiral HPLC. [d] Performed at 0 °C.
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General Procedure for the Asymmetric Domino Aza-Michael–
Henry Reaction: trans-ꢀ-Nitro olefin 2 (0.2 mmol, 2.0 equiv.) was
added to a stirred mixture of molecular sieves (4 Å; 0.3 g), catalyst
Ia (20 mol-%), 4-nitrophenol (20 mol-%) and N-protected 2-amino-
benzaldehyde 1 (0.1 mmol, 1.0 equiv.) in chloroform (1 mL) at room
temperature. After stirring for 3 d, the solvent was removed in
vacuo, and the residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate, 20:1) on silica gel to give the
corresponding 3-nitro-1,2-dihydroquinolines (i.e., 3).
96 % yield with 41 % ee. Considering the relatively high reactiv-
ity of mercaptans,[12] the moderate enantioselectivity encoun-
tered en route to 5 probably stems from direct reaction of 2-
mercaptobenzaldehyde with trans-ꢀ-nitrostyrene which likely
competes with the process of iminium intermediate formation.
To improve the enantioselectivity for 5 production, a control
experiment at lower temperature (0 °C) was performed. How-
ever, decreases in both ee and yield were observed (32 % ee,
67 % yield). These results are likely best attributed to the fact
that the reactivity of the corresponding iminium intermediate
is more sensitive to temperature than is that of 2-mercapto-
benzaldehyde.
Procedure for the Asymmetric Domino Thia-Michael–Henry Re-
action: trans-ꢀ-Nitrostyrene 2a (0.2 mmol, 2.0 equiv.) was added to
a stirred mixture of molecular sieves (4 Å; 0.3 g), catalyst Ia (20 mol-
%), 4-nitrophenol (20 mol-%), and 2-mercaptobenzaldehyde 4
(0.1 mmol, 1.0 equiv.) in chloroform (1 mL) at room temperature.
After stirring for 3 d, the solvent was removed in vacuo, and the
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 300:1) on silica gel to give the corresponding
3-nitro-2H-thiochromene (i.e., 5).
Determination of the Absolute Configurations of Products: The
absolute configuration of 3a was determined by comparing the
HPLC traces of 3a with those reported in the literature,[9c] and the
absolute configuration of 3a was deduced accordingly. The configu-
rations of other quinolines were assigned by analogy.
Scheme 2. Domino thia-Michael–Henry reaction between 2-mercaptobenz-
aldehyde and trans-ꢀ-nitrostyrene.
(S)-3-Nitro-2-phenyl-1-tosyl-1,2-dihydroquinoline (3a): Yellow
solid (95 % yield, 88 % ee), m.p. 173–174 °C. 1H NMR (600 MHz,
CDCl3): δ = 7.76 (d, J = 8.4 Hz, 1 H), 7.54 (s, 1 H), 7.45–7.48 (m, 1
H), 7.26–7.31 (m, 4 H), 7.24 (s, 5 H), 7.10 (d, J = 7.8 Hz, 2 H), 6.87 (s,
1 H), 2.36 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 144.7, 144.0,
135.1, 134.8, 134.2, 132.6, 129.9, 129.6, 128.8, 128.8, 128.7, 128.6,
127.6, 126.8, 126.7, 125.2, 55.5, 21.6 ppm. HRMS (ESI): calcd. for
Conclusions
In summary, we have reported an organocatalytic enantiose-
lective domino aza-Michael–Henry reaction, capable of trans-
forming a broad range of N-sulfonyl-2-aminobenzaldehydes
and trans-ꢀ-nitro olefins to chiral 3-nitro-1,2-dihydroquinolines
through an iminium activation mechanism. Additionally, a thia-
Michael–Henry reaction of 2-mercaptobenzaldehyde derivatives
with trans-ꢀ-nitro olefins was preliminarily studied, providing
an approach to chiral 3-nitro-2H-thiochromenes albeit with
moderate enantioselectivity. Further investigations into imin-
ium activation of aromatic aldehydes and its application to
other asymmetric processes are ongoing in our laboratory.
C
22H18N2O4SNa 429.0879 [M + Na]+, found 429.0877. The enantio-
meric excess was determined by HPLC with a Chiralpak ID column
(hexane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm): tR
(minor) = 16.1 min, tR (major) = 18.4 min. The enantiomeric excess
was also determined by HPLC with a Chiralpak AD-H column (hex-
ane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 254 nm): tR (mi-
nor) = 10.1 min, tR (major) = 11.5 min. [literature:[9c] tR (minor) =
13.0 min, tR (major) = 15.8 min].
(S)-3-Nitro-2-phenyl-1-(phenylsulfonyl)-1,2-dihydroquinoline
(3b): Yellow solid (92 % yield, 86 % ee), m.p. 173–175 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.77 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 7.2 Hz,
1 H), 7.51 (s, 1 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 2 H),
7.28–7.34 (m, 4 H), 7.24 (s, 5 H), 6.88 (s, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 143.9, 137.5, 134.9, 134.0, 133.7, 132.7, 130.0,
129.1, 128.9, 128.9, 128.7, 128.6, 127.8, 126.8, 126.6, 125.2, 55.5 ppm.
HRMS (ESI): calcd. for C21H16N2O4SNa 415.0723 [M + Na]+, found
415.0734. The enantiomeric excess was determined by HPLC with a
Chiralpak ID column (hexane/2-propanol, 99:1; flow rate: 1.0 mL/
min; λ = 380 nm): tR (major) = 14.2 min, tR (minor) = 21.2 min.
Experimental Section
General Information: All reagents were used as purchased from
commercial suppliers without further purification unless otherwise
noted. Solvents were dried and purified according to standard pro-
cedures before use. Flash column chromatography was performed
using 200–300 mesh silica gel. H NMR and 13C NMR spectra were
1
recorded with a Bruker Avance spectrometer (600 or 400 MHz), and
tetramethylsilane was used as a reference. 1H NMR spectroscopic
data are represented as follows: chemical shift (ppm), multiplicity
(s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m =
multiplet), integration, coupling constants in Hertz (Hz). 13C NMR
spectroscopic data are reported in ppm. High-resolution mass spec-
tra were measured with a Bruker Daltonics micrOTOF-Q II instru-
ment (ESI). Melting points were determined with a commercially
available melting point apparatus. Analytical chiral HPLC was per-
formed using Daicel ChiralPak ID, AS-H, AD-H or OD columns.
(S)-1-[(4-Methoxyphenyl)sulfonyl]-3-nitro-2-phenyl-1,2-di-
hydroquinoline (3c): Yellow solid (89 % yield, 88 % ee), m.p. 169–
1
171 °C. H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 7.8 Hz, 1 H), 7.57
(s, 1 H), 7.44–7.47 (m, 1 H), 7.32 (d, J = 9.0 Hz, 2 H), 7.28–7.30 (m, 2
H), 7.24 (s, 5 H), 6.87 (s, 1 H), 6.76 (d, J = 9.0 Hz, 2 H), 3.81 (s, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 163.6, 144.0, 135.2, 134.2,
132.6, 129.9, 129.3, 128.8, 128.8, 128.8, 128.7, 128.7, 127.7, 126.8,
125.2, 114.2, 55.7, 55.5 ppm. HRMS (ESI): calcd. for C22H18N2O5SNa
445.0829 [M + Na]+, found 445.0833. The enantiomeric excess was
determined by HPLC with a Chiralpak ID column (hexane/2-prop-
anol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm): tR (minor) =
25.3 min, tR (major) = 28.7 min.
N-Protected 2-aminobenzaldehydes used in this work were ob-
tained via oxidation of corresponding alcohols,[13a] and these alco-
hols were synthesized according to literature procedures.[13b–13e]
Additionally, the procedure for preparing organocatalyst Ia can
been seen in our previous report.[6b]
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(S)-1-(Methylsulfonyl)-3-nitro-2-phenyl-1,2-dihydroquinoline
(3d): Yellow solid (94 % yield, 52 % ee), m.p. 168–169 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.52 (d,
J = 7.8 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H),
7.26 (s, 5 H), 6.88 (s, 1 H), 2.78 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 144.7, 135.5, 134.4, 133.1, 130.7, 129.5, 129.1, 129.0,
7.49 (m, 1 H), 7.29–7.33 (m, 2 H), 7.25 (d, 2 H), 7.20–7.22 (m, 2 H),
7.11 (d, J = 7.8 Hz, 2 H), 6.91–6.94 (m, 2 H), 6.83 (s, 1 H), 2.36 (s, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 144.8, 143.7, 134.6, 133.9,
132.7, 130.9, 130.0, 129.7, 128.8, 128.7, 128.7, 128.5, 127.8, 126.6,
125.0, 115.9, 115.7, 54.9, 21.6 ppm. HRMS (ESI): calcd. for
C
22H17FN2O4SNa 447.0785 [M + Na]+, found 447.0792. The enantio-
127.3, 126.7, 126.4, 124.1, 55.7, 38.6 ppm. HRMS (ESI): calcd. for meric excess was determined by HPLC with a Chiralpak ID column
C16H14N2O4SNa 353.0566 [M + Na]+, found 353.0573. The enantio-
meric excess was determined by HPLC with a Chiralpak AS-H col-
umn (hexane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm):
tR (major) = 24.8 min, tR (minor) = 45.6 min.
(hexane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm): tR
(minor) = 13.9 min, tR (major) = 15.3 min.
(S)-2-(4-Methoxyphenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline
(3j): Yellow solid (99 % yield, 70 % ee), m.p. 144 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.74 (d, J = 7.8 Hz, 1 H), 7.52 (s, 1 H), 7.45–
7.47 (m, 1 H), 7.26–7.32 (m, 4 H), 7.09–7.15 (m, 4 H), 6.81 (s, 1 H),
6.75 (d, J = 7.8 Hz, 2 H), 3.72 (s, 3 H), 2.35 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 160.0, 144.6, 144.2, 134.8, 134.1, 132.5, 129.8,
129.6, 128.6, 128.4, 128.2, 127.6, 127.0, 126.6, 125.2, 114.2, 55.2, 55.1,
21.6 ppm. HRMS (ESI): calcd. for C23H20N2O5SNa 459.0985 [M + Na]+,
found 459.0986. The enantiomeric excess was determined by HPLC
with a Chiralpak ID column (hexane/2-propanol, 90:10; flow rate:
1.0 mL/min; λ = 380 nm): tR (minor) = 31.5 min, tR (major) =
33.9 min.
(S)-2-(4-Chlorophenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline
(3e): Yellow solid (96 % yield, 86 % ee), m.p. 168–170 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 1 H), 7.55 (s, 1 H), 7.48–
7.50 (m, 1 H), 7.31–7.34 (m, 3 H), 7.25 (s, 1 H), 7.22 (d, J = 8.4 Hz, 2
H), 7.17 (d, J = 7.8 Hz, 2 H), 7.11 (d, J = 7.8 Hz, 2 H), 6.82 (s, 1 H),
2.36 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 144.9, 143.4, 134.8,
134.6, 133.9, 133.7, 132.8, 130.0, 129.7, 129.0, 128.9, 128.6, 128.2,
127.8, 126.6, 124.9, 54.9, 21.6 ppm. HRMS (ESI): calcd. for
C22H17ClN2O4SNa 463.0490 [M + Na]+, found 463.0496. The enantio-
meric excess was determined by HPLC with a Chiralpak ID column
(hexane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm): tR
(minor) = 12.9 min, tR (major) = 14.5 min.
(R)-2-(Furan-2-yl)-3-nitro-1-tosyl-1,2-dihydroquinoline (3k):
Brown solid (88 % yield, 79 % ee), m.p. 128–130 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.80 (d, J = 8.4 Hz, 1 H), 7.49–7.52 (m, 1 H),
7.47 (s, 1 H), 7.26–7.34 (m, 5 H), 7.09 (d, J = 7.8 Hz, 2 H), 6.96 (s, 1
H), 6.19 (s, 1 H), 6.11 (s, 1 H), 2.35 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 147.7, 144.8, 143.7, 142.0, 134.7, 134.3, 132.6, 130.1,
129.6, 128.8, 128.1, 127.6, 126.7, 124.8, 110.5, 109.2, 50.6, 21.6 ppm.
HRMS (ESI): calcd. for C20H16N2O5SNa 419.0672 [M + Na]+, found
419.0661. The enantiomeric excess was determined by HPLC with a
Chiralpak ID column (hexane/2-propanol, 90:10; flow rate: 1.0 mL/
min; λ = 380 nm): tR (minor) = 20.1 min, tR (major) = 22.9 min.
(S)-2-(3-Chlorophenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline
(3f): Yellow solid (93 % yield, 80 % ee), m.p. 159–161 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 1 H), 7.56 (s, 1 H), 7.48–
7.51 (m, 1 H), 7.30–7.34 (m, 2 H), 7.28 (s, 2 H), 7.17–7.23 (m, 3 H),
7.10–7.15 (m, 3 H), 6.83 (s, 1 H), 2.36 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 144.9, 143.2, 137.2, 134.8, 134.6, 133.9, 132.8,
130.1, 129.7, 129.1, 129.1, 128.6, 127.8, 127.0, 126.6, 125.0, 124.9,
54.9, 21.6 ppm. HRMS (ESI): calcd. for C22H17ClN2O4SNa 463.0490 [M
+ Na]+, found 463.0493. The enantiomeric excess was determined
by HPLC with a Chiralpak ID column (hexane/2-propanol, 90:10; flow
rate: 1.0 mL/min; λ = 380 nm): tR (minor) = 13.2 min, tR (major) =
15.8 min.
(S)-3-Nitro-2-propyl-1-tosyl-1,2-dihydroquinoline (3l): Yellow
solid (62 % yield, 53 % ee), m.p. 129–131 °C. 1H NMR (600 MHz,
CDCl3): δ = 7.85 (d, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.34 (t,
J = 7.8 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.17–7.20 (m, 3 H), 7.05 (d,
J = 7.8 Hz, 2 H), 5.61–5.63 (m, 1 H), 2.32 (s, 3 H), 1.45–1.56 (m, 3 H),
1.34–1.40 (m, 1 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 146.0, 144.4, 134.9, 133.9, 132.3, 129.8, 129.4, 128.7,
127.6, 126.9, 126.5, 125.3, 53.1, 33.4, 21.5, 18.1, 13.2 ppm. HRMS
(ESI): calcd. for C19H20N2O4SNa 395.1036 [M + Na]+, found 395.1042.
The enantiomeric excess was determined by HPLC with a Chiralpak
ID column (hexane/2-propanol, 95:5; flow rate: 1.0 mL/min; λ =
380 nm): tR (minor) = 13.1 min, tR (major) = 14.4 min.
(S)-2-(2-Chlorophenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline
(3g): Yellow solid (95 % yield, 73 % ee), m.p. 161–163 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 7.45–
7.49 (m, 2 H), 7.31–7.37 (m, 3 H), 7.18–7.23 (m, 3 H), 7.08 (d, J =
8.4 Hz, 2 H), 6.90–6.93 (m, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 2.36 (s, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 144.7, 144.2, 134.4, 134.3,
134.1, 132.7, 131.5, 131.1, 130.5, 129.7, 129.5, 129.4, 129.0, 128.2,
127.8, 127.2, 126.8, 126.1, 53.1, 21.6 ppm. HRMS (ESI): calcd. for
C22H17ClN2O4SNa 463.0490 [M + Na]+, found 463.0492. The enantio-
meric excess was determined by HPLC with a Chiralpak ID column
(hexane/2-propanol, 90:10; flow rate: 1.0 mL/min; λ = 380 nm): tR
(minor) = 26.0 min, tR (major) = 29.0 min.
3-Nitro-2-phenyl-2H-thiochromene (5): Yellow solid (96 % yield,
1
40 % ee), m.p. 108–110 °C. H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1
H), 7.47 (d, J = 7.6 Hz, 1 H), 7.31–7.34 (m, 1 H), 7.20–7.25 (m, 7 H),
5.55 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.7, 140.0,
132.4, 132.3, 132.2, 129.0, 128.5, 128.2, 127.4, 126.4, 126.2, 39.9 ppm.
HRMS (ESI): calcd. for C15H11NO2SNa 292.0403 [M + Na]+, found
292.0404. The enantiomeric excess was determined by HPLC with a
Chiralpak OD column (hexane/2-propanol, 99:1; flow rate: 1.0 mL/
min; λ = 380 nm): tR (major) = 10.0 min, tR (minor) = 17.0 min.
(S)-2-(4-Bromophenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline
(3h): Yellow solid (96 % yield, 84 % ee), m.p. 163 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 1 H), 7.55 (s, 1 H), 7.47–
7.50 (m, 1 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.29–7.33 (m, 2 H), 7.25 (s, 2
H), 7.11 (d, J = 7.2 Hz, 4 H), 6.80 (s, 1 H), 2.36 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 144.9, 143.4, 134.6, 134.2, 133.9, 132.8, 132.0,
130.0, 129.7, 128.9, 128.5, 127.8, 126.6, 124.9, 123.1, 55.0, 21.6 ppm.
HRMS (ESI): calcd. for C22H17BrN2O4SNa 508.9985 [M + Na]+, found
508.9970. The enantiomeric excess was determined by HPLC with a
Chiralpak ID column (hexane/2-propanol, 90:10; flow rate: 1.0 mL/
min; λ = 380 nm): tR (minor) = 15.7 min, tR (major) = 18.3 min.
Supporting Information (see footnote on the first page of this
article): Copies of the 1H NMR and 13C NMR spectra of 3a–3l and
5, and the HPLC spectra of 3a–3l and 5.
Acknowledgments
(S)-2-(4-Fluorophenyl)-3-nitro-1-tosyl-1,2-dihydroquinoline (3i):
Yellow solid (90 % yield, 74 % ee), m.p. 165–167 °C. 1H NMR
This work was financially supported by the National Natural Sci-
(600 MHz, CDCl3): δ = 7.75 (d, J = 8.4 Hz, 1 H), 7.54 (s, 1 H), 7.47– ence Foundation of China (NSFC) (grant number 21476163). The
Eur. J. Org. Chem. 2016, 1702–1707
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Full Paper
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Keywords: Organocatalysis · Asymmetric catalysis · Domino
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Received: December 29, 2015
Published Online: February 23, 2016
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