An asymmetric organocatalytic povarov reaction with 2-hydroxystyrenes

Article abstract of DOI:10.1021/jo301174g

An organocatalytic asymmetric three-component Povarov reaction involving 2-hydroxystyrenes has been established to provide an efficient method to access structurally diverse cis-disubstituted tetrahydroquinolines in high stereoselectivities of up to >99:1 dr and 97% ee. This protocol also provides an easy access to tetrahydroquinolines with chiral quaternary stereocenters upon using α-alkyl 2-hydroxystyrenes as substrates. The theoretical studies revealed that the Povarov reaction proceeded through a sequential vinylogous Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as bifunctional catalyst to activate 2-hydroxystyrene and aldimine simultaneously.

Full text of DOI:10.1021/jo301174g

Article
pubs.acs.org/joc
An Asymmetric Organocatalytic Povarov Reaction with
2‑Hydroxystyrenes
Feng Shi,† Gui-Juan Xing,† Zhong-Lin Tao,‡ Shi-Wei Luo,*,‡ Shu-Jiang Tu,† and Liu-Zhu Gong*,‡
†School of Chemistry & Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, China
‡Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
S
* Supporting Information
ABSTRACT: An organocatalytic asymmetric three-compo-
nent Povarov reaction involving 2-hydroxystyrenes has been
established to provide an efficient method to access
structurally diverse cis-disubstituted tetrahydroquinolines in
high stereoselectivities of up to >99:1 dr and 97% ee. This
protocol also provides an easy access to tetrahydroquinolines
with chiral quaternary stereocenters upon using α-alkyl 2-
hydroxystyrenes as substrates. The theoretical studies revealed that the Povarov reaction proceeded through a sequential
vinylogous Mannich reaction and an intramolecular Friedel−Crafts reaction, wherein the phosphoric acid acted as bifunctional
catalyst to activate 2-hydroxystyrene and aldimine simultaneously.
cis-tetrahydroquinolines in high stereoselectivities (up to >99:1
dr, 97% ee) (eq 3).
INTRODUCTION
■
The prevalent appearance of tetrahydroquinoline skeleton in
natural products and unnatural bioactive molecules1 has led to a
great demand for efficient synthetic methods. The Povarov
reaction,2 an inverse electron-demand aza-Diels−Alder reaction
between 2-azadienes and electronically rich olefins catalyzed by
either a Lewis or Brønsted acid, represents the most facile and
synthetically practical approach to access 1,2,3,4-tetrahydroqui-
nolines in high structural diversity.
Although the development of efficient Povarov reaction has
drawn the attention from the chemists for a long time,2,3 the
reports describing successful asymmetric variants are still rather
limited.4 In particular, highly reactive olefins such as
enamides,4f,g,i,j enol ethers4a,e,i and cyclopentadiene4a,c are mostly
selected as substrates (eq 1). So far, there is only one example of
RESULTS AND DISCUSSION
■
The chiral phosphoric acids have proven to be privileged
organocatalysts that have enabled a large number of highly
enantioselective transformations.6 However, the nucleophiles
activated by the Lewis basic phosphoryl oxygen are commonly
enamides (enamines, enols) or their analogues and precursor-
s.6,4e−k Our continuous interest in the Brønsted acid-catalyzed
multicomponent reactions7 prompted us to envisage that the 2-
hydroxystyrene, structurally similar to an dienol species, is
principally able to participate in a vinylogous Mannich reaction
with an aldimine generated from an aldehyde and aniline under
the catalysis of a chiral phosphoric acid,8 forming a transient
intermediate I, which principally undergoes an intramolecular
Friedel−Crafts reaction (the 1,4-addition of aniline to the enone
functionality), again under the catalysis of the same phosphoric
acid9 to afford enantioenriched multiply substituted tetrahy-
droquinolines (Scheme 1).
highly enantioselective protocol catalyzed by a chiral scandium
complex describing the use of styrene derivatives as the olefin
component, very recently established by Feng and co-workers
(eq 2),4d while nearly no organocatalytic asymmetric alternatives
have been reported, yet.
Herein, we will report the chiral Brønsted acid-catalyzed
Povarov reaction involving 2-hydroxystyrene derivatives as the
dienophile component,5 giving a structurally diverse spectrum of
Received: June 6, 2012
© XXXX American Chemical Society
A
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Scheme 1. Proposed Reaction Pathway
a
Table 1. Screening of Catalysts and Optimization of Conditions
b
c
d
entry
4
5
solvent
MS (Å)
yield (%)
dr
ee (%)
1
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4baa
4baa
4baa
4baa
5a
5b
5c
5d
5e
5e
5e
5e
5e
5e
5e
5e
5e
5e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
3
3
3
3
3
4
5
5
5
86
97
93
80
19
64
73
74
77
77
39
33
39
69
14:1
5:1
68
−32
−15
0
2
3
4
5
6
7
8
9
6:1
3:1
16:1
6:1
94
85
5:1
92
e
6:1
95
ef
,
12:1
10:1
27:1
14:1
10:1
30:1
89
g
10
11
12
13
14
80
eh
,
5
5
5
5
82
eh
,
87
eh
,
PhCH3
PhCH3
92
ehi
, ,
90
a
Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in a solvent (1 mL) with MS (100 mg) for 60 h, and the ratio of 1/2a/3a
b
c
d
e
was 1.2/1/1.2. Isolated yield. The dr was determined by 1H NMR. The ee was determined by HPLC. Performed in anhydrous and under argon
condition with 150 mg of 5 Å MS. In the presence of 5 mol % 5e. In the absence of MS in anhydrous and under argon condition. The reaction
time was 84 h. The ratio of 1b/2a/3a was 1.2/1/2.
f
g
h
i
The initial attempt to validate our hypothesis examined a
three-component reaction of 4-nitrobenzaldehyde 1a, 4-
methoxyaniline 2a and 2-hydroxystyrene 3a, which was
performed in the presence of 10 mol % of chiral phosphoric
acids 5 in dichloromethane at room temperature (Table 1). The
preliminary results revealed that the 3,3′-triphenylsilyl binol-
based phosphoric acid 5e turned out to be much more promising
than other analogues in terms of stereochemical control, capable
of delivering the highest level of enantioselectivity of up to 94% ee
(entries 1−4 vs 5), whereas the yield was relatively much lower
(19%). Thus, further efforts were devoted to optimize the
reaction conditions to improve the yield and enantioselectivity.
The evaluation of molecular sieves (MS) found that the addition
of 5 Å MS rendered a much cleaner reaction that provided 73%
yield, but accompanying with a slight erosion of both
enantioselectivity and diastereoselectivity (entry 7). The
presence of more amounts of 5 Å MS and conducting the
reaction under argon resulted in a high yield of 74% and an
excellent enantioselectivity of 95% ee (entry 8). Lowering the
catalyst loading had no obvious effect on the yield, but led to a
decreased enantioselectivity, albeit with increased diastereose-
lectivity (entry 9). In the absence of 5 Å MS, the
enantioselectivity was sacrificed to some extent, while the yields
were nearly the same as that with 5 Å MS, which indicated that 5
Å MS played some important role in controlling the
enantioselectivity of the reaction (entry 10). However, the
application of the optimized reaction conditions as listed in entry
8 to an electronically neutral benzaldehyde 1b led to
unsatisfactory results (82% ee) (entry 11). Thus, the reaction
conditions for electronically neutral and rich aldehyde substrates
were subsequently reoptimized. The survey of the solvents found
that toluene was a more suitable reaction media, in which a high
enantioselectivity of 92% ee was offered, albeit in a low yield
(entry 13). To our delight, tuning the stoichiometry of 2-
B
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hydroxystyrene 3a rendered the reaction to proceed in a much
higher yield with an improved diastereoselectivity and nearly
maintained enantioselectivity (entry 14 vs 13).
With the optimal conditions in hand, the generality for
aldehydes 1 was then explored by the reaction with 4-
methoxyaniline 2a and 2-hydroxystyrene 3a. As shown in
Table 2, this protocol is amenable to a wide scope of aldehydes
phenylpropanal (entry 15). Increasing the loading of catalyst
5e resulted in a greatly improved enantioselectivity of 85% ee and
diastereoselectivity of 25:1 dr, but still with a low yield (entry 15,
in parentheses).
The substrate scope with respect to anilines was then explored
by the reaction with 4-nitrobenzaldehyde 1a and 2-hydroxystyr-
ene 3a (Table 3, entries 1−5). A variety of anilines substituted
with either electron-donating or -withdrawing groups served as
appropriate substrates, providing the corresponding products in
high yields (70−77%) and good enantioselectivities (82−95%
ees). The generality for 2-hydroxystyrenes was also examined by
the reaction with 4-nitrobenzaldehyde 1a and 4-methoxyaniline
2a (Table 3, entries 6−11). Both 2-hydroxystyrenes and α-alkyl
2-hydroxystyrenes bearing different substituents on their
aromatic rings were accommodated and led to the generation
of desired products in good to excellent stereoselectivities (6:1 to
>99:1 drs, 83−97% ees). Significantly, the use of the α-alkyl 2-
hydroxystyrenes afforded tetrahydroquinolines with an all-
carbon quaternary stereogenic center in high enantioselectivity.
More interestingly, the α-alkyl 2-hydroxystyrenes provided a
cleaner reaction than 2-hydroxystyrenes, giving much higher
yields but with slightly lower enantioselectivities (entries 8−11 vs
1, 6−7). Notably, in the case of 4-ethoxyaniline 2b as a reaction
component, α-methyl 2-hydroxystyrenes 3d exhibited higher
reactivity, delivering a higher yield of 87% and a higher
enantioselectivity of 94% ee than 2-hydroxystyrene 3a (entry
12 vs 2). In addition, 3,4-dichlorobenzaldehyde 1i was employed
instead of 4-nitrobenzaldehyde 1a as aldehyde component to
react with aniline 2a and α-alkyl 2-hydroxystyrene 3f, affording
tetrahydroquinoline 4iaf in excellent yield and good stereo-
selectivity, which could form a single crystal with >99% ee (entry
13).
The absolute configuration of compounds 4faa, 4aag and 4iaf
(>99% ee after recrystallization) were unambiguously deter-
mined to be (2S,4S) by single-crystal X-ray diffraction analysis.10
Moreover, the relative configurations of compounds 4faa, 4eaa,
4haa, 4aad, 4aag and 4iaf were all confirmed to be cis by their X-
ray structures.10 The relative and absolute configurations of other
tetrahydroquinolines were assigned by analogy. It is interesting
to mention that the relative configurations of tetrahydroquino-
lines 4 generated from our protocol (eq 3) are different from
those obtained by Feng’s procedure (eq 2),4d which always
afforded trans-tetrahydroquinolines with high enantioselectivity.
In order to examine the utility of our protocol, the reaction to
prepare tetrahydroquinoline 4aad bearing a quaternary stereo-
center was performed at 1 mmol scale under the optimized
conditions, which is 10 times larger than the scale of the original
reaction shown in Table 3, entry 8. The result revealed that the
protocol could be successfully scaled up with an increased yield
and enantioselectivity, albeit with a slightly decreased diaster-
eoselectivity (Scheme 2).
a
Table 2. Scope of the Aldehydes
yield
b
c
d
entry
4
R
(%)
dr
ee (%)
95
e
1
4aaa
4-NO2C6H4 (1a)
3-NO2C6H4 (1c)
74
82
6:1
2
4caa
20:1
25:1
7:1
93
91
92
94
90
91
92
91
90
83
86
3
4daa
2-NO2C6H4 (1d) 77
4
4eaa
4-CNC6H4 (1e)
4-Cl C6H4 (1f)
4-BrC6H4 (1g)
4-CF3C6H4 (1h)
3,4-Cl2C6H3 (1i)
3,4-F2C6H3 (1j)
Ph (1b)
71
43
54
76
63
77
69
43
5
4faa
9:1
6
4gaa
8:1
7
4haa
8:1
8
4iaa
14:1
15:1
30:1
31:1
20:1
9
4jaa
10
11
12
13
14
4baa
4kaa
3-MeC6H4 (1k)
4laa
3-MeOC6H4 (1l) 57
f
f
f
4maa 4-MeC6H4 (1m)
21 (85)
20 (55)
26:1 (33:1)
88 (83)
94 (86)
g
g
4naa
2-Thiophenyl
>99:1
g
(1n)
(>99:1)
h
h
h
15
4oaa
PhCH2CH2 (1o)
21 (20)
11:1 (25:1)
72 (85)
a
Unless indicated otherwise, the reaction was carried out in 0.1 mmol
scale in toluene (1 mL) with 5 Å MS (150 mg) for 84 h under argon,
b
c
and the ratio of 1/2a/3a was 1.2/1/2. Isolated yield. The dr was
d
determined by 1H NMR. The ee was determined by HPLC.
e
Performed in dichloromethane (1 mL) for 60 h, and the ratio of
f
g
1a/2a/3a was 1.2/1/1.2. The ratio of 1m/2a/3a was 1.2/1/4. The
ratio of 1n/2a/3a was 1.2/1/7. In the presence of 20 mol % 5e.
h
including benzaldehydes bearing either of an electronically poor,
neutral, or rich substituent, heteroaromatic and aliphatic
aldehydes in high enantioselectivities (up to 95% ee) and
diastereoselectivities (up to >99:1 dr). Basically, the benzalde-
hydes substituted with an electron-withdrawing group partici-
pated in the reaction to give relatively higher stereoselectivities
(entries 1−7, 90−95% ees, 6:1−25:1 drs) and good yields.
Moreover, disubstituted benzaldehydes appeared to be suitable
substrates, offering high yields and good stereoselectivities
(entries 8−9). More importantly, even if electronically rich
benzaldehydes and a heteroaromatic aldehyde were applied, high
stereoselectivities could also be delivered (entries 11−14, 83−
94% ees, 20:1−>99:1 drs). However, in some cases the relatively
lower yields were observed because of the low reactivity
associated with the aldehydes (entries 13−14). The presence
of excess amounts of 2-hydroxylstyrene 3a was found to
efficiently enhance the yields but leading to a slight erosion of
the enantioselectivity (entries 13−14, in parentheses). More
interestingly, aliphatic aldehydes can also be applied to this
reaction in moderate to high enantioselectivity and diaster-
eoselectivity but with a low yield, as exemplified by 3-
As proposed in Scheme 1, the phosphoric acid 5e acted as a
bifunctional catalyst to activate both 2-hydroxystyrenes and
imines by hydrogen-bonding interaction. To illustrate the crucial
role of O−H group in 2-hydroxystyrenes and to test our
hypothesis on the activation mode shown in Scheme 1, a control
experiment was carried out with 2-methoxystyrene 3h (Scheme
3). However, no reaction occurred, indicating that the O−H
group in 2-hydroxystyrenes 3 was essentially important for both
the enantioselectivity and reactivity.
To understand the stereochemistry experimentally observed,
theoretical calculations were performed on key intermediates
and transition states (TS) of the 2-hydroxystyrene-involved
C
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a
Table 3. Scope of Anilines and Styrenes
b
c
d
entry
4
R
R1
R2
yield (%)
dr
ee (%)
95
e
1
4aaa
4aba
4aca
4ada
4aea
4aab
4aac
4aad
4aae
4aaf
4aag
4abd
4iaf
MeO (2a)
EtO (2b)
PhO (2c)
Me (2d)
H
H (3a)
74
70
70
74
77
45
44
75
86
89
95
87
92
6:1
>99:1
6:1
e
2
H
H (3a)
90
89
95
82
97
91
93
83
84
88
94
e
3
H
H (3a)
f
4
H
H (3a)
4:1
g
5
F (2e)
H
H (3a)
8:1
e
6
MeO (2a)
MeO (2a)
MeO (2a)
MeO (2a)
MeO (2a)
MeO (2a)
EtO (2b)
MeO (2a)
H
Me (3b)
MeO (3c)
H (3d)
42:1
6:1
e
7
H
h
8
Me
Me
Me
Et
54:1
8:1
h
9
Me (3e)
MeO (3f)
H (3g)
h
10
25:1
>99:1
17:1
>99:1
h
11
h
12
Me
Me
H (3d)
hi
,
j
13
MeO (3f)
85 (>99)
a
b
Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in solvent (1 mL) with 5 Å MS (150 mg) under argon for 60 h. Isolated
c
d
e
yield. The dr was determined by 1H NMR. The ee was determined by HPLC. Performed in dichloromethane at 25 °C, and the ratio of 1a/2/3
was 1.2/1/1.2. Performed in toluene at 25 °C, and the ratio of 1a/2d/3a was 1.2/1/4. Performed in toluene at 25 °C, and the ratio of 1a/2e/3a
was 1.2/1/3. Performed in toluene at 0 °C for 84 h, and the ratio of 1/2/3 was 1.2/1/4.8. 3,4-Dichlorobenzaldehyde (1i) was employed as
aldehyde component. After recrystallization.
f
g
h
i
j
Scheme 2. Large Scale Synthesis of Tetrahydroquinoline 4aad
Scheme 3. Control Experiment Involving 2-Methoxystyrene
Povarov reaction. On the basis of our previous studies,7f,g the
hybrid density functional theory (DFT) B3LYP method11
combined with the 6-31G(d) basis set,12 as implemented in
the Gaussian03 program,13 was used for geometry optimization
of all intermediates and TS structures, although the B3LYP
functional was reported in certain instances not to account for
attractive dispersion forces properly.14 To save computing
resource, unsubstituted benzaldehyde and aniline was used to
model the intermediate imine and unsubstituted 2-hydroxystyr-
ene for TS structures.
isomer by about >6 kcal/mol, indicating that the observed
products resulted mainly from the E-imine. However, the 2-
hydroxystyrene could assume various conformations as indicated
by the located structures with different stabilization by predicted
relative energetic difference less than 1 kcal/mol. This implied
that 2-hydroxystyrene may take S-cis or S-trans orientations in the
transition state when reacting with E-imine in the chiral Brønsted
acid-catalyzed Povarov reaction pathway.
The located TS structures confirmed our proposed reaction
pathway in Scheme 1. The 3,3′-bi(triphenylsilyl)phosphoric acid
5e acted as a bifunctional catalyst to activate both 2-
hydroxystyrene and E-imine by hydrogen-bonding interaction,
and 2-hydroxystyrene may take S-cis or S-trans orientations to
The optimized structures of key intermediate Z- and E-imines
and 2-hydroxystyrene with different orientations were shown in
Figure 1. The E-imine was predicted to be more stable than Z-
D
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Figure 1. Full optimized intermediate structures and relative energies in enthalpy (blue) and Gibbs free energy (red) in kcal/mol.
Figure 2. Located transition state structures with distance parameters in Angstroms and relative energies in enthalpy (blue) and Gibbs free energy (red)
in kcal/mol.
approach the E-imine from its R-face or S-face (Figure 2). Four
transition states were identified, as shown in Figure 2, in which
both o-OH of the styrenes and key intermediate E-imine were
activated simultaneously by the phosphoric acid 5e by means of
hydrogen-bonding interaction and thereby accelerating the
vinylogous Mannich reaction and the subsequent intramolecular
Friedel−Crafts reaction.15 The located TS structure TS-SproS,
corresponding to the major product experimentally observed,
was predicted to be more preferable than the other three ones by
about ∼4 kcal/mol because of the steric repulsion between the
phenol ring of the 2-hydroxystyrene and triphenylsilyl group of
the catalyst 5e. As a result, the experimentally observed SS-
configured product was predominantly formed.
CONCLUSION
■
In summary, we have established an efficient organocatalytic
asymmetric Povarov reaction with 2-hydroxystyrenes. This
protocol combines the merits of both organocatalysis and
multicomponent reactions, tolerating a wide range of aldehydes,
anilines and styrenes to furnish structurally diverse cis-
E
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Chirapak AD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 11.573 min (minor), tR = 13.674 min (major).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-phenylquinolin-
4-yl)phenol (4baa). Data: Flash column chromatography eluent,
petroleum ether/ethyl acetate = 8/1; reaction time = 84 h; yield 69%
tetrahydroquinolines in high stereoselectivities of up to >99:1 dr
and 97% ee. Moreover, the current protocol not only provides a
facile access to tetrahydroquinolines with chiral quaternary
stereocenters upon using α-alkyl 2-hydroxystyrenes as substrates,
but also furnishes an efficient method to synthesize cis-
disubstituted tetrahydroquinolines with high enantioselectivity.
The theoretical studies revealed that the Povarov reaction
proceeded through a sequential vinylogous Mannich reaction
and an intramolecular Friedel−Crafts reaction, wherein the
phosphoric acid acted as a bifunctional catalyst to activate the
reaction components and intermediates involved by hydrogen-
bonding interaction.
20
(22.9 mg); 30/1 dr; pale yellow sticky oil; [α]D = −82.5 (c 0.46,
1
CHCl3); H NMR (CDCl3, 400 MHz) δ (ppm) 7.40−7.33 (m, 2H),
7.30−7.24 (m, 2H), 7.23−7.18 (m, 1H), 7.08 (dd, J = 7.5, 1.6 Hz, 1H),
7.04 (td, J = 7.6, 1.6 Hz, 1H), 6.79 (td, J = 7.5, 1.2 Hz, 1H), 6.72 (dd, J =
8.0, 1.0 Hz, 1H), 6.62−6.57 (m, 1H), 6.51 (d, J = 8.6 Hz, 1H), 6.38 (d, J
= 2.1 Hz, 1H), 5.07 (s, 1H), 4.49−4.34 (m, 2H), 3.98 (s, 1H), 3.54 (s,
3H), 2.25−2.15 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 152.7,
151.8, 142.5, 138.6, 129.8, 129.3, 127.6, 127.0, 126.7, 125.7, 119.9, 115.9,
115.1, 113.4, 112.9, 57.0, 54.7, 39.8, 38.4; IR (KBr) γ 3372, 3017, 2922,
2853, 2833, 1708, 1593, 1502, 1453, 1267, 1231, 1035, 807, 756, 702,
666 cm−1; ESI FTMS exact mass calcd for (C22H21NO2 + H)+ requires
m/z 332.1651, found m/z 332.1645; Enantiomeric excess 90%,
determined by HPLC (Daicel Chirapak OD-H, hexane/isopropanol =
90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 13.064 min
(major), tR = 16.459 min (minor).
EXPERIMENTAL SECTION
■
General Information. NMR spectra were measured at 400 and 100
MHz, respectively. The solvent used for NMR spectroscopy was CDCl3,
using tetramethylsilane as the internal reference. HRMS spectra were
measured with electrospray ionization (ESI) and Orbitrap mass
analyzer. Enantiomeric excesses (ee) were determined by chiral high-
performance liquid chromatography (chiral HPLC). The chiral columns
used for the determination of enantiomeric excesses by chiral HPLC
were Chiralpak OD, IC, IA and AD columns. Optical rotation values
were measured with instruments operating at λ = 589 nm,
corresponding to the sodium D line at the temperatures indicated.
Analytical grade solvents for the column chromatography and
commercially available reagents were used as received. Toluene and
dichloromethane were dried and distilled prior to use.
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(3-nitrophenyl)-
quinolin-4-yl)phenol (4caa). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1 then 5/1; reaction time = 84
20
h; yield 82% (30.8 mg); 20/1 dr; yellow sticky oil; [α]D = −61.5 (c
0.62, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.25 (d, J = 1.7 Hz,
1H), 8.05 (dd, J = 8.1, 2.1 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.43 (t, J =
7.9 Hz, 1H), 7.10−7.00 (m, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 8.0
Hz, 1H), 6.61 (dd, J = 8.7, 2.8 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.35 (d,
J = 2.5 Hz, 1H), 4.95 (s, 1H), 4.54 (dd, J = 10.5, 3.5 Hz, 1H), 4.52−4.43
(m, 1H), 3.86 (s, 1H), 3.55 (s, 3H), 2.27−2.12 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 152.6, 152.0, 147.5, 145.0, 137.9, 131.9,
129.3, 128.6, 127.1, 123.1, 121.7, 120.7, 120.1, 115.7, 115.3, 113.4, 112.9,
56.0, 54.7, 40.5, 38.5; IR (KBr) γ 3364, 2934, 2835, 1734, 1708, 1594,
1530, 1500, 1349, 1233, 1043, 808, 756, 737, 689 cm−1; ESI FTMS exact
mass calcd for (C22H20N2O4 + H)+ requires m/z 377.1501, found m/z
377.1496; Enantiomeric excess 93%, determined by HPLC (Daicel
Chirapak OD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 15.508 min (major), tR = 19.569 min (minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(2-nitrophenyl)-
quinolin-4-yl)phenol (4daa). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1; reaction time = 84 h; yield
Typical Procedure for the Asymmetric Povarov Reaction with
α-Unsubstituted Styrenes. After a solution of aldehydes 1 (0.12
mmol), anilines 2 (0.1 mmol), the catalyst 5e (0.01 mmol), and 5 Å
molecular sieves (150 mg) in toluene (0.5 mL) was stirred at room
temperature for 20 min (1 h for aldehyde 1o) under argon, the solution
of styrenes 3a−3c (0.2 mmol) in toluene (0.5 mL) was added. In most
reactions involving 4-nitrobenzaldehyde 1a, dichloromethane was used
as solvent instead of toluene, and the ratio of 1a/2/3 was 1.2/1/1.2.
After being stirred at 25 °C for 60−84 h under argon, the reaction
mixture was filtered to remove molecular sieves, and the solid powder
was washed with ethyl acetate. The resultant solution was concentrated
under the reduced pressure to give the residue, which was purified
through flash column chromatography on silica gel to afford pure
products.
Typical Procedure for the Asymmetric Povarov Reaction with
α-Alkyl Styrenes. After a solution of aldehydes 1 (0.12 mmol), anilines
2 (0.1 mmol), the catalyst 5e (0.01 mmol), and 5 Å molecular sieves
(150 mg) in toluene (0.5 mL) was stirred at room temperature for 20
min under argon, the solution of α-alkyl styrenes 3d−3g (0.48 mmol) in
toluene (0.5 mL) was added. After being stirred at 0 °C for 84 h under
argon, the reaction mixture was filtered to remove molecular sieves, and
the solid powder was washed with ethyl acetate. The resultant solution
was concentrated under the reduced pressure to give the residue, which
was purified through flash column chromatography on silica gel to afford
pure products.
20
77% (29.0 mg); 25/1 dr; yellow sticky oil; [α]D = −60.9 (c 0.58,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.88 (dd, J = 7.9, 1.2 Hz,
1H), 7.74 (dd, J = 8.1, 1.2 Hz, 1H), 7.53 (td, J = 7.9, 1.1 Hz, 1H), 7.38−
7.29 (m, 1H), 7.10 (dd, J = 7.6, 1.6 Hz, 1H), 7.08−7.01 (m, 1H), 6.81
(td, J = 7.5, 1.1 Hz, 1H), 6.71 (dd, J = 8.0, 1.1 Hz, 1H), 6.60 (ddd, J = 8.7,
2.8, 0.6 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 2.7 Hz, 1H), 5.10
(s, 1H), 4.85 (dd, J = 11.0, 2.4 Hz, 1H), 4.46 (dd, J = 11.5, 6.3 Hz, 1H),
3.84 (s, 1H), 3.54 (s, 3H), 2.42 (ddd, J = 13.1, 6.3, 2.5 Hz, 1H), 2.25−
2.12 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 152.7, 152.1,
148.2, 138.1, 137.1, 132.3, 129.4, 129.3, 127.7, 127.3, 127.1, 123.1, 120.0,
115.9, 115.6, 113.2, 113.1, 54.7, 51.3, 39.8, 37.2; IR (KBr) γ 3488, 3356,
2926, 1711, 1595, 1525, 1500, 1454, 1349, 1228, 1037, 855, 754 cm−1;
ESI FTMS exact mass calcd for (C22H20N2O4 + H)+ requires m/z
377.1501, found m/z 377.1496; Enantiomeric excess 91%, determined
by HPLC (Daicel Chirapak IA, hexane/isopropanol = 85/15, flow rate
1.0 mL/min, T = 30 °C, 254 nm); tR = 16.338 min (major), tR = 19.019
min (minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(4-nitrophenyl)-
quinolin-4-yl)phenol (4aaa). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1; reaction time = 60 h; yield
20
74% (27.9 mg); 6/1 dr; yellow sticky oil; [α]D = −72.1 (c 0.18,
4-((2S,4S)-1,2,3,4-Tetrahydro-4-(2-hydroxyphenyl)-6-me-
thoxyquinolin-2-yl)benzonitrile (4eaa). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 4/1; reaction
time = 84 h; yield 71% (25.3 mg); 7/1 dr; white solid; mp 215−217 °C;
[α]D20 = −63.3 (c 0.37, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm)
7.56 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.06 (dd, J = 11.9, 4.5
Hz, 2H,), 6.81 (td, J = 7.5, 1.1 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.62
(dd, J = 8.7, 2.3 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.36 (d, J = 2.0 Hz,
1H), 4.87 (s, 1H), 4.50−4.44 (m, 2H), 3.82 (s, 1H), 3.55 (s, 3H), 2.26−
2.09 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 153.7, 153.1,
149.2, 139.0, 132.6, 130.4, 128.2, 127.6, 121.2, 118.8, 116.9, 116.4, 114.4,
114.1, 111.6, 57.6, 55.8, 40.5, 39.5; IR (KBr) γ 3365, 2931, 2854, 1720,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.20 (d, J = 8.8 Hz, 2H),
7.64 (d, J = 8.7 Hz, 2H), 7.19−7.09 (m, 2H), 6.89 (td, J = 7.5, 1.1 Hz,
1H), 6.80 (d, J = 8.0 Hz, 1H), 6.73−6.67 (m, 1H), 6.63 (d, J = 8.7 Hz,
1H), 6.44 (d, J = 2.0 Hz, 1H), 4.95 (s, 1H), 4.62 (dd, J = 10.6, 3.3 Hz,
1H), 4.57 (dd, J = 11.0, 6.9 Hz, 1H), 3.93 (s, 1H), 3.63 (s, 3H), 2.38−
2.15 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 153.6, 153.1,
151.2, 147.5, 138.8, 130.3, 128.2, 127.6, 123.9, 121.2, 116.8, 116.3, 114.4,
114.0, 57.2, 55.7, 40.2, 39.4; IR (KBr) γ 3504, 3364, 2934, 2843, 1598,
1517, 1501, 1456, 1346, 1226, 1111, 1036, 854, 755 cm−1; ESI FTMS
exact mass calcd for (C22H20N2O4 + H)+ requires m/z 377.1501, found
m/z 377.1498; Enantiomeric excess 95%, determined by HPLC (Daicel
F
dx.doi.org/10.1021/jo301174g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1653, 1618, 1590, 1493, 1455, 1229, 819, 754 cm−1; ESI FTMS exact
mass calcd for (C23H20N2O2 + H)+ requires m/z 357.1603, found m/z
357.1600; Enantiomeric excess 92%, determined by HPLC (Daicel
Chirapak AD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 8.968 min (minor), tR = 13.107 min (major).
2-((2S,4S)-2-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-methox-
yquinolin-4-yl)phenol (4faa). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 9/1; reaction time = 84 h; yield
43% (15.8 mg); 9/1 dr; colorless solid; mp 171−173 °C; [α]D20 = −70.8
(c 0.22, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.39 (d, J = 8.4
Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.18−7.09 (m, 2H), 6.88 (td, J = 7.5,
1.2 Hz, 1H), 6.80 (dd, J = 8.0, 1.1 Hz, 1H), 6.70−6.64 (m, 1H), 6.59 (d, J
= 8.7 Hz, 1H), 6.47−6.41 (m, 1H), 5.10 (s, 1H), 4.56−4.47 (m, 1H),
4.45 (dd, J = 10.0, 4.1 Hz, 1H), 3.88 (s, 1H), 3.62 (s, 3H), 2.31−2.18 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 153.7, 153.0, 142.1, 139.3,
133.4, 130.6, 130.4, 128.8, 128.1, 124.0, 121.0, 117.0, 116.2, 114.4, 114.0,
57.3, 55.7, 40.9, 39.4; IR (KBr) γ 3327, 2931, 2856, 1596, 1497, 1464,
1348, 1257, 1089, 1014, 829, 814, 754, 738, 686 cm−1; ESI FTMS exact
mass calcd for (C22H20ClNO2 + H)+ requires m/z 366.1261, found m/z
366.1256; Enantiomeric excess 94%, determined by HPLC (Daicel
Chirapak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 10.752 min (minor), tR = 14.044 min (major).
2-((2S,4S)-2-(4-Bromophenyl)-6-methoxy-1,2,3,4-tetrahy-
droquinolin-4-yl)phenol (4gaa). Data: Flash column chromatog-
raphy eluent, petroleum ether/ethyl acetate = 9/1; reaction time = 84 h;
yield 54% (22.3 mg); 8/1 dr; pale yellow sticky oil; [α]D20 = −71.2 (c
0.26, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.39 (d, J = 8.4 Hz,
2H), 7.26 (d, J = 8.4 Hz, 2H), 7.11−7.03 (m, 2H), 6.81 (td, J = 7.5, 1.1
Hz, 1H), 6.72 (dd, J = 8.0, 1.0 Hz, 1H), 6.60 (ddd, J = 8.0, 2.8, 0.8 Hz,
1H), 6.52 (d, J = 8.7 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 5.04 (s, 1H),
4.49−4.40 (m, 1H), 4.36 (dd, J = 10.1, 4.0 Hz, 1H), 3.80 (s, 1H), 3.54 (s,
3H), 2.23−2.08 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 152.7,
151.9, 141.6, 138.3, 130.7, 129.6, 129.3, 127.4, 127.1, 123.0, 120.4, 120.0,
115.8, 115.2, 113.3, 112.9, 56.3, 54.7, 39.7, 38.4; IR (KBr) γ 3364, 2940,
1727, 1654, 1625, 1597, 1496, 1452, 1235, 1040, 1012, 816, 759 cm−1;
ESI FTMS exact mass calcd for (C22H20BrNO2 + H)+ requires m/z
410.0756, found m/z 410.0754; Enantiomeric excess 90%, determined
by HPLC (Daicel Chirapak OD-H, hexane/isopropanol = 70/30, flow
rate 1.0 mL/min, T = 30 °C, 254 nm); tR =5.813 min (major), tR = 8.019
min (minor).
2-((2S,4S)-2-(4-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-
6-methoxyquinolin-4-yl)phenol (4haa). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 9/1; reaction
time = 84 h; yield 76% (30.2 mg); 8/1 dr; white solid; mp 158−160 °C;
[α]D20 = −71.8 (c 0.38, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm)
7.56−7.47 (m, 4H), 7.06 (ddd, J = 15.4, 7.6, 1.5 Hz, 2H), 6.81 (td, J =
7.5, 1.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.7, 2.7 Hz, 1H),
6.53 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 5.01 (s, 1H), 4.49−4.44
(m, 2H), 3.83 (s, 1H), 3.55 (s, 3H), 2.25−2.11 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 152.6, 151.9, 146.7, 138.1, 129.3 (J = 15.6
Hz), 128.8, 127.1, 126.0, 125.0, 123.0, 121.7, 120.1, 115.9, 115.2, 113.4,
112.9, 56.5, 54.7, 39.5, 38.4. IR (KBr) γ 3331, 2926, 2851, 1618, 1591,
1499, 1454, 1325, 1164, 1124, 1067, 1017, 840, 754; ESI FTMS exact
mass calcd for (C23H20F3NO2 + H)+ requires m/z 400.1524, found m/z
400.1518; Enantiomeric excess 91%, determined by HPLC (Daicel
Chirapak OD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 5.01 min (major), tR = 7.117 min (minor).
2-((2S,4S)-2-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-me-
thoxyquinolin-4-yl)phenol (4iaa). Data: Flash column chromatog-
raphy eluent, petroleum ether/ethyl acetate = 9/1; reaction time = 84 h;
yield 63% (25.3 mg); 14/1 dr; pale yellow sticky oil; [α]D20 = −51.7 (c
0.24, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.57 (d, J = 2.0 Hz,
1H), 7.40 (d, J = 8.3 Hz, 1H), 7.28 (dd, J = 8.3, 2.0 Hz, 1H), 7.15−7.10
(m, 2H), 6.88 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.68
(ddd, J = 8.7, 2.8, 0.7 Hz, 1H,), 6.60 (d, J = 8.7 Hz, 1H), 6.43 (dd, J = 2.7,
0.7 Hz, 1H), 4.95 (s, 1H), 4.51 (dd, J = 10.9, 7.0 Hz, 1H), 4.45 (dd, J =
10.6, 3.3 Hz, 1H), 3.86 (s, 1H), 3.62 (s, 3H), 2.29−2.14 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 153.6, 153.0, 144.0, 139.0, 132.7,
131.5, 130.6, 130.4, 130.3, 128.7, 128.1, 126.1, 124.0, 121.1, 116.8, 116.3,
114.4, 114.0, 56.8, 55.7, 40.5, 39.4; IR (KBr) γ 3504, 3364, 2926, 1612,
1594, 1500, 1467, 1452, 1331, 1225, 1031, 824, 754 cm−1; ESI FTMS
exact mass calcd for (C22H19Cl2NO2 + H)+ requires m/z 400.0871,
found m/z 400.0866; Enantiomeric excess 92%, determined by HPLC
(Daicel Chirapak AD-H, hexane/isopropanol = 80/20, flow rate 1.0
mL/min, T = 30 °C, 254 nm); tR = 8.845 min (minor), tR = 10.892 min
(major).
2-((2S,4S)-2-(3,4-Difluorophenyl)-1,2,3,4-tetrahydro-6-me-
thoxyquinolin-4-yl)phenol (4jaa). Data: Flash column chromatog-
raphy eluent, petroleum ether/ethyl acetate = 9/1; reaction time = 84 h;
20
yield 77% (28.1 mg); 15/1 dr; white solid; mp 124−126 °C; [α]D
=
1
−77.8 (c 0.43, CHCl3); H NMR (CDCl3, 400 MHz) δ (ppm)7.22
(ddd, J = 11.3, 7.7, 1.9 Hz, 1H), 7.12−7.00 (m, 4H), 6.81 (td, J = 7.5, 1.1
Hz, 1H), 6.71 (dd, J = 7.9, 0.9 Hz, 1H), 6.60 (ddd, J = 8.7, 2.8, 0.6 Hz,
1H), 6.52 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.94 (s, 1H), 4.44
(dd, J = 10.9, 6.9 Hz, 1H), 4.37 (dd, J = 10.8, 3.1 Hz, 1H), 3.77 (s, 1H),
3.54 (s, 3H), 2.22−2.06 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 152.6, 151.9, 150.7 (J = 12.7 Hz), 149.9 (J = 12.7 Hz), 148.2 (J =
12.7 Hz), 147.5 (J = 12.8 Hz), 139.8, 138.1, 129.4 (J = 17.8 Hz), 127.1,
123.0, 121.5, 120.1, 116.3 (J = 17.1 Hz), 115.8, 115.2, 114.6 (J = 17.7
Hz), 113.1 (J = 43.0 Hz), 55.9, 54.7, 39.5, 38.6; IR (KBr) γ 3372, 2926,
2855, 1609, 1501, 1455, 1436, 1355, 1275, 1216, 1112, 1034, 816, 757
cm−1; ESI FTMS exact mass calcd for (C22H19F2NO2 + H)+ requires m/
z 368.1462, found m/z 368.1456; Enantiomeric excess 91%, determined
by HPLC (Daicel Chirapak OD-H, hexane/isopropanol = 85/15, flow
rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 9.610 min (major), tR =
13.934 min (minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-m-tolylquinolin-
4-yl)phenol (4kaa). Data: Flash column chromatography eluent,
petroleum ether/ethyl acetate = 10/1; reaction time = 84 h; yield 43%
20
(14.9 mg); 31/1 dr; pale yellow sticky oil; [α]D = −5.4 (c 0.29,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.20 (s, 1H), 7.16 (d, J =
5.1 Hz, 2H), 7.09 (dd, J = 7.5, 1.6 Hz, 1H), 7.07−7.01 (m, 2H), 6.80 (td,
J = 7.5, 1.1 Hz, 1H), 6.73 (dd, J = 8.0, 1.0 Hz, 1H), 6.60 (dd, J = 8.5, 2.6
Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 2.2 Hz, 1H), 5.22 (s, 1H),
4.42 (t, J = 9.0 Hz, 1H), 4.38−4.31 (m, 1H), 4.04 (s, 1H), 3.55 (s, 3H),
2.28 (s, 3H), 2.25−2.19 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 152.7, 151.8, 142.4, 138.6, 137.3, 129.8, 129.3, 127.5, 127.0,
126.3, 122.8, 120.0, 115.9, 115.2, 113.4, 112.9, 56.9, 54.7, 40.0, 38.3,
20.4; IR (KBr) γ 3298, 2926, 2851, 1608, 1592, 1492, 1454, 1263, 1226,
1092, 1034, 801, 755 cm−1; ESI FTMS exact mass calcd for (C23H23NO2
+ H)+ requires m/z 346.1807, found m/z 346.1800; Enantiomeric
excess 83%, determined by HPLC (Daicel Chirapak OD-H, hexane/
isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR =
5.032 min (major), tR = 6.374 min (minor).
2-((2S, 4S)-1,2, 3,4-Tetrahydro-6-methoxy-2-(3-
methoxyphenyl)quinolin-4-yl)phenol (4laa). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 8/1; reaction
20
time = 84 h; yield 57% (20.7 mg); 20/1 dr; pale yellow sticky oil; [α]D
= −61.1 (c 0.28, CHCl3);1H NMR (CDCl3, 400 MHz) δ (ppm) 7.21−
7.15 (m, 1H), 7.08 (dd, J = 7.9, 1.6 Hz, 1H), 7.04 (td, J = 7.9, 1.7 Hz,
1H), 6.98−6.92 (m, 2H), 6.80 (td, J = 7.4, 1.2 Hz, 1H), 6.77−6.71 (m,
2H), 6.60 (dd, J = 8.7, 2.8 Hz, 1H), 6.53 (t, J = 8.6 Hz, 1H), 6.37 (d, J =
2.2 Hz, 1H), 5.05 (s, 1H), 4.47−4.40 (m, 1H), 4.38 (dd, J = 10.0, 4.1 Hz,
1H), 4.01 (s, 1H), 3.73 (s, 3H), 3.55 (s, 3H), 2.30−2.13 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 158.9, 152.7, 151.8, 144.2, 138.5,
129.7, 129.3, 128.6, 127.0, 119.9, 118.0, 115.8, 115.2, 113.4, 112.9, 112.3,
111.0, 56.9, 54.7, 54.3, 39.9, 38.3; IR (KBr) γ 3372, 3009, 2934, 2844,
1597, 1500, 1452, 1337, 1260, 1226, 1153, 1039, 851, 788, 755, 697, 665
cm−1; ESI FTMS exact mass calcd for (C23H23NO3 + H)+ requires m/z
362.1756, found m/z 362.1750; Enantiomeric excess 86%, determined
by HPLC (Daicel Chirapak AD-H, hexane/isopropanol = 90/10, flow
rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 25.643 min (major), tR =
29.178 min (minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-p-tolylquinolin-
4-yl)phenol (4maa). Data: Flash column chromatography eluent,
petroleum ether/ethyl acetate = 10/1; reaction time = 84 h; yield 21%
(7.4 mg); 26/1 dr; yellow sticky oil; [α]D20 = −76.4 (c 0.11, CHCl3); 1H
NMR (CDCl3, 400 MHz) δ (ppm) 7.26 (d, J = 8.0 Hz, 2H), 7.11−7.07
(m, 3H), 7.04 (dd, J = 7.7, 1.6 Hz, 1H), 6.80 (td, J = 7.5, 1.0 Hz, 1H),
6.74 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.6, 2.7 Hz, 1H), 6.51 (d, J = 8.6
G
dx.doi.org/10.1021/jo301174g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.13 (s, 1H), 4.41 (t, J = 9.0 Hz, 1H),
4.35 (t, J = 7.3 Hz, 1H), 3.88 (s, 1H), 3.55 (s, 3H), 2.27 (s, 3H), 2.24−
2.18 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 152.7, 151.9,
139.4, 138.6, 136.4, 129.8, 129.3, 128.3, 127.0, 125.6, 119.8, 115.9, 115.2,
113.4, 112.9, 56.8, 54.7, 40.1, 38.3, 20.1; IR (KBr) γ 3397, 2926, 1594,
1500, 1456, 1265, 1230, 1038, 817, 754 cm−1; ESI FTMS exact mass
calcd for (C23H23NO2 + H)+ requires m/z 346.1807, found m/z
346.1801; Enantiomeric excess 88%, determined by HPLC (Daicel
Chirapak OD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 5.018 min (major), tR = 6.342 min (minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(thiophen-2-yl)-
quinolin-4-yl)phenol (4naa). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 8/1; reaction time = 84 h; yield
20% (6.8 mg); >99:1 dr; pale yellow sticky oil; [α]D20 = −23.0 (c 0.11,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.16 (dd, J = 5.1, 1.0 Hz,
1H), 7.11−7.04 (m, 2H), 6.99 (d, J = 3.0 Hz, 1H), 6.90 (dd, J = 5.0, 3.5
Hz, 1H), 6.82 (td, J = 7.5, 1.1 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.60 (dd,
J = 8.7, 2.3 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H),
5.03 (s, 1H), 4.74 (dd, J = 10.8, 3.1 Hz, 1H), 4.45 (dd, J = 11.0, 7.1 Hz,
1H), 3.99 (s, 1H), 3.55 (s, 3H), 2.39−2.22 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 152.7, 152.0, 146.3, 137.9, 129.4, 127.1, 125.6,
123.3, 122.8, 120.0, 115.3, 113.3, 112.9, 54.7, 52.4, 39.3; IR (KBr) γ
3364, 3009, 2926, 2851, 1591, 1502, 1454, 1240, 1103, 1035, 850, 809,
757, 705 cm−1; ESI FTMS exact mass calcd for (C20H19NO2S + H)+
requires m/z 338.1215, found m/z 338.1210; Enantiomeric excess 94%,
determined by HPLC (Daicel Chirapak IC, hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.851 min (minor),
tR = 8.380 min (major).
2-((2R,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-phenethylquino-
lin-4-yl)phenol (4oaa). Data: Flash column chromatography eluent,
petroleum ether/ethyl acetate = 8/1; reaction time = 84 h; yield 20%
(7.3 mg); 25/1 dr; yellow sticky oil; [α]D20 = −17.0 (c 0.11, CHCl3); 1H
NMR (CDCl3, 400 MHz) δ (ppm) 7.32−7.27 (m, 2H), 7.23−7.18 (m,
3H), 7.16−7.10 (m, 2H), 6.88 (td, J = 7.4, 1.0 Hz, 1H), 6.81 (d, J = 7.8
Hz, 1H), 6.63 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 6.40 (d,
J = 2.2 Hz, 1H), 4.89 (s, 1H), 4.30 (dd, J = 10.7, 7.1 Hz, 1H), 3.94 (s,
1H), 3.59 (s, 3H), 3.41−3.30 (m, 1H), 2.77−2.69 (m, 2H), 2.24 (ddd, J
= 13.2, 6.9, 2.7 Hz, 1H), 2.00−1.91 (m, 1H), 1.86 (dd, J = 14.4, 7.7 Hz,
2H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 153.8, 152.9, 141.6, 139.2,
131.2, 130.4, 128.6, 128.4, 128.0, 126.1, 120.8, 117.1, 116.2, 114.3, 113.8,
55.7, 52.7, 40.7, 38.1, 36.5, 32.1; IR (KBr) γ 3364, 2967, 2926, 2851,
1721, 1560, 1500, 1455, 1261, 1089, 1035, 804, 754, 700 cm−1; ESI
FTMS exact mass calcd for (C24H25NO2 + H)+ requires m/z 360.1964,
found m/z 360.1957; Enantiomeric excess 85%, determined by HPLC
(Daicel Chirapak AD-H, hexane/isopropanol = 70/30, flow rate 1.0
mL/min, T = 30 °C, 254 nm); tR = 6.465 min (major), tR = 8.535 min
(minor).
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.21 (d, J = 8.8 Hz, 2H),
7.65 (d, J = 8.7 Hz, 2H), 7.26−7.20 (m, 2H), 7.14−7.07 (m, 2H), 6.97
(t, J = 7.4 Hz, 1H), 6.89−6.83 (m, 3H), 6.81−6.73 (m, 2H), 6.65 (d, J =
8.6 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.81 (s, 1H), 4.70 (dd, J = 10.3, 3.5
Hz, 1H), 4.67−4.56 (m, 1H), 4.07 (s, 1H), 2.31−2.24 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 158.7, 153.5, 151.0, 148.4, 147.5,
141.3, 130.1, 129.9, 129.4, 128.1, 127.5, 124.5, 123.9, 121.9, 121.3, 121.0,
119.9, 116.9, 116.5, 116.1, 57.0, 39.2, 30.9; IR (KBr) γ 3504, 3381, 3066,
3025, 2926, 2851, 1602, 1520, 1488, 1457, 1348, 1262, 1219, 1164,
1105, 1015, 953, 855, 754, 695 cm−1; ESI FTMS exact mass calcd for
(C27H22N2O4 + H)+ requires m/z 439.1658, found m/z 439.1654;
Enantiomeric excess 89%, determined by HPLC (Daicel Chirapak AD-
H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254
nm); tR = 8.672 min (minor), tR = 10.185 min (major).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methyl-2-(4-nitrophenyl)-
quinolin-4-yl)phenol (4ada). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 10/1; reaction time = 60 h; yield
20
74% (26.5 mg); 4/1 dr; yellow sticky oil; [α]D = −48.4 (c 0.39,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.21 (d, J = 8.7 Hz, 2H),
7.64 (d, J = 8.7 Hz, 2H), 7.18−7.13 (m, 2H), 6.93−6.88 (m, 2H), 6.82
(d, J = 7.9 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.82 (s, 1H),
4.65 (dd, J = 9.2, 4.7 Hz, 1H), 4.57−4.47 (m, 1H), 4.00 (s, 1H), 2.29−
2.23 (m, 2H), 2.14 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm)
153.8, 151.9, 148.3, 142.6, 130.6, 130.5, 129.3, 128.9, 128.7, 128.3, 127.7,
124.1, 121.3, 117.1, 115.6, 57.5, 41.4, 40.6, 20.7; IR (KBr) γ 3438, 2926,
1604, 1520, 1506, 1456, 1344, 1102, 855, 752 cm−1; ESI FTMS exact
mass calcd for (C22H20N2O3 + H)+ requires m/z 361.1552, found m/z
361.1547; Enantiomeric excess 95%, determined by HPLC (Daicel
Chirapak OD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 8.133 min (major), tR = 14.449 min (minor).
2-((2S,4S)-6-Fluoro-1,2,3,4-tetrahydro-2-(4-nitrophenyl)-
quinolin-4-yl)phenol (4aea). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 8/1; reaction time = 60 h; yield
20
77% (28.0 mg); 8/1 dr; yellow sticky oil; [α]D = −67.8 (c 0.28,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.21 (d, J = 8.7 Hz, 2H),
7.64 (d, J = 8.8 Hz, 2H), 7.17−7.09 (m, 2H), 6.91 (td, J = 7.5, 1.2 Hz,
1H), 6.83−6.74 (m, 2H), 6.59 (dd, J = 8.7, 4.8 Hz, 1H), 6.53 (dd, J = 9.6,
2.3 Hz, 1H), 4.84 (s, 1H), 4.67 (dd, J = 10.3, 3.6 Hz, 1H), 4.64−4.54 (m,
1H), 4.03 (s, 1H), 2.33−2.18 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 157.6, 155.2, 153.5, 150.9, 147.5, 140.9, 129.9 (J = 30.4 Hz),
129.6, 128.2, 127.5, 123.9, 121.3, 116.1, 115.8, 115.4, 115.1, 114.5, 114.3,
67.9, 57.0, 39.0; IR (KBr) γ 3504, 3381, 3075, 3034, 2926, 2860, 1604,
1519, 1499, 1453, 1344, 1259, 1216, 1174, 1147, 1111, 1042, 1016, 950,
854, 812, 752, 700, 674 cm−1; ESI FTMS exact mass calcd for
(C21H17FN2O3 + H)+ requires m/z 365.1301, found m/z 365.1296;
Enantiomeric excess 82%, determined by HPLC (Daicel Chirapak OD-
H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254
nm); tR = 6.671 min (major), tR = 8.590 min (minor).
2-((2S,4S)-6-Ethoxy-1,2,3,4-tetrahydro-2-(4-nitrophenyl)-
quinolin-4-yl)phenol (4aba). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 8/1; reaction time = 60 h; yield
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(4-nitrophenyl)-
quinolin-4-yl)-4-methylphenol (4aab). Data: Flash column chro-
matography eluent, petroleum ether/ethyl acetate = 7/1; reaction time
= 60 h; yield 45% (17.6 mg); 42/1 dr; yellow sticky oil; [α]D20 = −68.8 (c
0.17, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.20 (d, J = 8.8 Hz,
2H), 7.64 (d, J = 8.7 Hz, 2H), 6.97−6.89 (m, 2H), 6.69 (d, J = 7.8 Hz,
2H), 6.63 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 4.82 (s, 1H), 4.62
(dd, J = 9.6, 4.3 Hz, 1H), 4.55−4.47 (m, 1H), 3.99 (s, 1H), 3.63 (s, 3H),
2.30−2.25 (m, 2H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 153.1, 151.3, 151.2, 147.5, 138.7, 130.7, 130.4, 129.9, 128.6,
127.5, 123.9, 116.6, 116.3, 114.4, 113.9, 57.3, 55.7, 40.3, 39.4, 20.5; IR
(KBr) γ 3372, 3281, 2934, 1604, 1510, 1498, 1352, 1257, 1108, 1016,
859, 817 cm−1; ESI FTMS exact mass calcd for (C23H22N2O4 + H)+
requires m/z 391.1658, found m/z 391.1652; Enantiomeric excess 97%,
determined by HPLC (Daicel Chirapak AD-H, hexane/isopropanol =
85/15, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 23.637 min
(minor), tR = 27.618 min (major).
20
70% (27.2 mg); >99:1 dr; yellow sticky oil; [α]D = −43.3 (c 0.26,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.20 (d, J = 8.8 Hz, 2H),
7.64 (d, J = 8.7 Hz, 2H), 7.16−7.09 (m, 2H), 6.88 (td, J = 7.5, 1.1 Hz,
1H), 6.79 (d, J = 7.9 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.62 (d, J =
8.6 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 4.98 (s, 1H), 4.62 (dd, J = 10.5, 3.3
Hz, 1H), 4.55 (dd, J = 10.6, 7.0 Hz, 1H), 4.01 (s, 1H), 3.87−3.79 (m,
2H), 2.31−2.25 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 153.6, 152.4, 151.2, 147.5, 138.8, 130.3, 128.2,
127.5, 123.9, 121.2, 116.8, 116.3, 115.2, 114.7, 64.0, 57.2, 40.4, 39.5,
14.8; IR (KBr) γ 3496, 3372, 2975, 2925, 2860, 1598, 1519, 1501, 1457,
1346, 1265, 1225, 1171, 1114, 1043, 1016, 958, 856, 753, 700 cm−1; ESI
FTMS exact mass calcd for (C23H22N2O4 + H)+ requires m/z 391.1658,
found m/z 391.1652; Enantiomeric excess 90%, determined by HPLC
(Daicel Chirapak OD-H, hexane/isopropanol = 70/30, flow rate 1.0
mL/min, T = 30 °C, 254 nm); tR = 8.712 min (major), tR = 10.662 min
(minor).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-2-(4-nitrophenyl)-
quinolin-4-yl)-4-methoxyphenol (4aac). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 6/1 then 5/
1; reaction time = 60 h; yield 44% (18.0 mg); 6/1 dr; yellow sticky oil;
[α]D20 = −54.7 (c 0.16, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm)
2-((2S,4S)-1,2,3,4-Tetrahydro-2-(4-nitrophenyl)-6-phenoxy-
quinolin-4-yl)phenol (4aca). Data: Flash column chromatography
eluent, petroleum ether/ethyl acetate = 8:1; reaction time = 60 h; yield
20
70% (30.7 mg); 6/1 dr; yellow sticky oil; [α]D = −14.8 (c 0.25,
H
dx.doi.org/10.1021/jo301174g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
8.20 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.5 Hz,
1H), 6.72−6.66 (m, 3H), 6.62 (d, J = 8.7 Hz, 1H), 6.44 (d, J = 2.2 Hz,
1H), 5.06 (s, 1H), 4.62 (dd, J = 9.7, 4.1 Hz, 1H), 4.54−4.47 (m, 1H),
3.92 (s, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 2.29−2.22 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 154.0, 153.1, 147.5, 131.3, 127.6, 123.9,
117.5, 116.4, 115.8, 114.3, 114.0, 113.0, 57.2, 55.7, 39.2, 30.9; IR (KBr) γ
33752, 3017, 2934, 2835, 1604, 1503, 1345, 1110, 1039, 853, 807, 754,
700, 672 cm−1; ESI FTMS exact mass calcd for (C23H22N2O5 + H)+
requires m/z 407.1607, found m/z 407.1601; Enantiomeric excess 91%,
determined by HPLC (Daicel Chirapak AD-H, hexane/isopropanol =
80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 24.357 min
(minor), tR = 27.423 min (major).
chromatography eluent, petroleum ether/ethyl acetate = 15/1; reaction
time = 84 h; yield 95% (38.3 mg); >99:1 dr; yellow solid; mp 192−195
°C; [α]D20 = −113.7 (c 0.41, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
(ppm) 8.17 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.39 (dd, J = 7.9,
1.5 Hz, 1H), 7.13 (ddd, J = 8.9, 7.7, 1.6 Hz, 1H), 6.92 (td, J = 7.8, 1.4 Hz,
1H), 6.79 (dd, J = 8.0, 1.3 Hz, 1H), 6.73 (dd, J = 8.7, 2.8 Hz, 1H), 6.67
(d, J = 8.7 Hz, 1H), 6.43 (d, J = 2.7 Hz, 1H), 5.33 (s, 1H), 4.68 (dd, J =
11.9, 3.2 Hz, 1H), 4.09 (s, 1H), 3.63 (s, 3H), 2.43−2.31 (m, 2H), 2.25−
2.18 (m, 1H), 1.95 (dd, J = 14.1, 3.3 Hz, 1H), 1.08 (t, J = 7.3 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ (ppm) 154.1, 152.9, 151.2, 147.5, 137.7,
132.9, 128.2, 127.5, 127.3, 124.9, 123.9, 120.4, 118.6, 116.6, 114.7, 114.3,
55.7, 54.2, 43.5, 43.3, 33.9, 9.8; IR (KBr) γ 3447, 3381, 2934, 2885, 1604,
1523, 1499, 1459, 1348, 1267, 1249, 1232, 1211, 1159, 1109, 1037, 862,
850, 818, 757, 702, 679 cm−1; ESI FTMS exact mass calcd for
(C24H24N2O4 + H)+ requires m/z 405.1814, found m/z 405.1810;
Enantiomeric excess 88%, determined by HPLC (Daicel Chirapak AD-
H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254
nm); tR = 7.622 min (minor), tR = 9.913 min (major).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-4-methyl-2-(4-
nitrophenyl)quinolin-4-yl)phenol (4aad). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 10/1; reaction
time = 84 h; yield 75% (29.2 mg); 54/1 dr; yellow solid; 199−202 °C;
20
1
[α]D = −138.9 (c 0.47, CHCl3); H NMR (CDCl3, 400 MHz) δ
(ppm) 8.18 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 7.9,
1.5 Hz, 1H), 7.16 (td, J = 7.9, 1.6 Hz, 1H), 6.95 (td, J = 7.7, 1.3 Hz, 1H),
6.79 (dd, J = 8.0, 1.3 Hz, 1H), 6.72 (dd, J = 8.7, 2.8 Hz, 1H), 6.66 (d, J =
8.7 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.84 (s, 1H), 4.68 (dd, J = 11.8, 2.7
Hz, 1H), 4.07 (s, 1H), 3.61 (s, 3H), 2.47 (dd, J = 13.3, 12.2 Hz, 1H), 1.86
(s, 3H), 1.80 (dd, J = 13.7, 2.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 153.5, 153.3, 151.0, 147.5, 137.4, 134.1, 128.4, 127.6, 127.2,
126.8, 123.9, 120.6, 118.2, 116.6, 114.7, 113.2, 55.6, 53.8, 45.0, 40.2,
31.1; IR (KBr) γ 3471, 3363, 2967, 2934, 2851, 1603, 1520, 1499, 1345,
1274, 1231, 1209, 1170, 1109, 1037, 1012, 851, 815, 754, 704, 672 cm−1;
ESI FTMS exact mass calcd for (C23H22N2O4 + H)+ requires m/z
391.1658, found m/z 391.1653; Enantiomeric excess 93%, determined
by HPLC (Daicel Chirapak OD-H, hexane/isopropanol = 85/15, flow
rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 12.691 min (minor), tR =
14.253 min (major).
2-((2S,4S)-6-Ethoxy-1,2,3,4-tetrahydro-4-methyl-2-(4-
nitrophenyl)quinolin-4-yl)phenol (4abd). Data: Flash column
chromatography eluent, petroleum ether/ethyl acetate = 8/1; reaction
20
time = 84 h; yield 87% (35.0 mg); 17/1 dr; yellow sticky oil; [α]D
=
−135.5 (c 0.45, CHCl3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.18 (d,
J = 8.8 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.46 (dd, J = 7.9, 1.5 Hz, 1H),
7.16 (td, J = 7.5, 1.6 Hz, 1H), 6.95 (td, J = 7.7, 1.3 Hz, 1H), 6.79 (dd, J =
8.0, 1.3 Hz, 1H), 6.71 (dd, J = 8.7, 2.8 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H),
6.43 (d, J = 2.7 Hz, 1H), 4.85 (s, 1H), 4.68 (dd, J = 11.8, 2.6 Hz, 1H),
4.06 (s, 1H), 3.87−3.76 (m, 2H), 2.53−2.39 (m, 1H), 1.85 (s, 3H), 1.80
(dd, J = 13.7, 2.8 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 153.6, 152.6, 151.0, 147.5, 134.2, 128.4, 127.6,
126.9, 123.9, 120.6, 118.2, 116.7, 115.4, 114.1, 63.9, 53.9, 45.1, 40.3,
31.2, 14.8; IR (KBr) γ 3472, 3372, 2976, 2926, 2867, 1604, 1519, 1502,
1346, 1272, 1229, 1204, 1176, 1112, 1045, 853, 814, 754 cm−1; ESI
FTMS exact mass calcd for (C24H24N2O4 + H)+ requires m/z 405.1814,
found m/z 405.1810; Enantiomeric excess 94%, determined by HPLC
(Daicel Chirapak AD-H, hexane/isopropanol = 70/30, flow rate 1.0
mL/min, T = 30 °C, 254 nm); tR = 7.413 min (minor), tR = 8.985 min
(major).
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-4-methyl-2-(4-
nitrophenyl)quinolin-4-yl)-4-methylphenol (4aae). Data: Flash
column chromatography eluent, petroleum ether/ethyl acetate = 8/1;
reaction time = 84 h; yield 86% (34.8 mg); 8/1 dr; yellow sticky oil;
20
1
[α]D = −105.7 (c 0.48, CHCl3); H NMR (CDCl3, 400 MHz) δ
(ppm) 8.18 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.25 (s, 1H),
6.95 (dd, J = 8.1, 1.6 Hz, 1H), 6.73−6.67 (m, 2H), 6.64 (d, J = 8.7 Hz,
1H), 6.43 (d, J = 2.8 Hz, 1H), 4.67 (dd, J = 11.8, 2.6 Hz, 1H), 4.61 (s,
1H), 4.06 (s, 1H), 3.61 (s, 3H), 2.51−2.42 (m, 1H), 2.32 (s, 3H), 1.84
(s, 3H), 1.79 (dd, J = 13.6, 2.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 153.3, 151.3, 151.1, 147.5, 133.9, 129.6, 128.8, 127.6, 127.5,
123.9, 118.1, 116.6, 114.7, 113.3, 55.7, 53.9, 45.1, 40.2, 31.2, 20.9; IR
(KBr) γ 3472, 3364, 2926, 1604, 1522, 1501, 1345, 1270, 1109, 1039,
851, 813, 754, 704, 662 cm−1; ESI FTMS exact mass calcd for
(C24H24N2O4 + H)+ requires m/z 405.1814, found m/z 405.1810;
Enantiomeric excess 83%, determined by HPLC (Daicel Chirapak OD-
H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254
nm); tR = 6.337 min (minor), tR = 8.087 min (major).
2-((2S,4S)-2-(3,4-Dichlorophenyl)-6-methoxy-4-methyl-
1,2,3,4-tetrahydroquinolin-4-yl)-4-methoxyphenol (4iaf). Data:
Flash column chromatography eluent, petroleum ether/ethyl acetate =
18/1; reaction time = 84 h; yield 92% (40.7 mg); >99/1 dr; yellow solid;
mp 152−154 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.48 (d, J = 2.0
Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 8.3, 2.0 Hz, 1H), 6.98 (d,
J = 2.6 Hz, 1H), 6.69−6.60 (m, 3H), 6.54 (d, J = 8.7 Hz, 1H), 6.33 (d, J =
2.8 Hz, 1H), 4.42 (dd, J = 11.8, 2.6 Hz, 1H), 4.17 (s, 1H), 3.72 (s, 3H),
3.53 (s, 3H), 2.43−2.33 (m, 1H), 1.72 (s, 3H), 1.68 (dd, J = 13.6, 2.7 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 152.4, 152.1, 146.4, 142.8,
136.7, 134.7, 131.6, 130.5, 129.5, 127.7, 126.0, 125.1, 117.6, 115.5, 113.7,
113.0, 112.0, 110.9, 54.7, 54.6, 52.2, 43.7, 39.4, 28.6; IR (KBr) γ 3471,
3370, 2961, 2926, 2852, 2832, 1500, 1483, 1464, 1423, 1392, 1260,
1169, 1103, 1031, 866, 796, 739, 678 cm−1; ESI FTMS exact mass calcd
for (C24H23Cl2NO3 + H)+ requires m/z 444.1133, found m/z 444.1118;
Enantiomeric excess 85%, determined by HPLC (Daicel Chirapak AD-
H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254
nm); tR = 7.977 min (minor), tR = 9.194 min (major).
Typical Procedure for the Large Scale Synthesis of
Tetrahydroquinoline 4aad. After a solution of aldehydes 1a (1.2
mmol), anilines 2a (1 mmol), the catalyst 5e (0.1 mmol), and 5 Å
molecular sieves (1.5 g) in toluene (8 mL) was stirred at room
temperature for 40 min under argon and then was cooled to 0 °C, the
cooled solution (0 °C) of α-alkyl styrene 3d (4.8 mmol) in toluene (2
mL) was added. After being stirred at 0 °C for 72 h under argon, the
reaction mixture was filtered to remove molecular sieves, and the solid
powder was washed with ethyl acetate. The resultant solution was
concentrated under the reduced pressure to give the residue, which was
purified through flash column chromatography on silica gel to afford
pure product 4aad.
2-((2S,4S)-1,2,3,4-Tetrahydro-6-methoxy-4-methyl-2-(4-
nitrophenyl)quinolin-4-yl)-4-methoxyphenol (4aaf). Data: Flash
column chromatography eluent, petroleum ether/ethyl acetate = 8:1;
reaction time = 84 h; yield 89% (37.4 mg); 25/1 dr; yellow solid; mp
20
1
93−96 °C; [α]D = −100.8 (c 0.62, CHCl3); H NMR (CDCl3, 400
MHz) δ (ppm) 8.17 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.06 (d,
J = 2.4 Hz, 1H), 6.76−6.67 (m, 3H), 6.64 (d, J = 8.7 Hz, 1H), 6.42 (d, J =
2.7 Hz, 1H), 4.67 (dd, J = 11.8, 2.5 Hz, 1H), 4.45 (s, 1H), 4.07 (s, 1H),
3.79 (s, 3H), 3.61 (s, 3H), 2.50 (t, J = 12.7 Hz, 1H), 1.82 (s, 3H), 1.78
(dd, J = 13.6, 2.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 153.6,
153.3, 151.1, 147.5, 137.5, 135.6, 127.6, 127.1, 123.9, 118.7, 116.7, 114.8,
114.1, 113.1, 112.0, 55.7, 53.8, 44.7, 40.5, 31.0; IR (KBr) γ 3472, 3364,
2926, 2851, 2835, 1604, 1517, 1502, 1421, 1344, 1276, 1222, 1207,
1168, 1112, 1061, 1040, 849, 810, 753, 700, 679 cm−1; ESI FTMS exact
mass calcd for (C24H24N2O5 + H)+ requires m/z 421.1763, found m/z
421.1758; Enantiomeric excess 84%, determined by HPLC (Daicel
Chirapak OD-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 °C, 254 nm); tR = 8.156 min (minor), tR = 11.553 min (major).
2-((2S,4S)-4-Ethyl-1,2,3,4-tetrahydro-6-methoxy-2-(4-
nitrophenyl)quinolin-4-yl)phenol (4aag). Data: Flash column
I
dx.doi.org/10.1021/jo301174g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Chem. Rev. 2007, 107, 5744. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (e) Terada, M. Chem. Commun. 2008, 4097. (f) Terada,
M. Synthesis 2010, 1929.
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data (including H, 13C NMR and HPLC
1
(7) For a review, see: (a) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res.
2011, 44, 1156. For selected examples: (b) Guo, Q.-X.; Liu, H.; Guo, C.;
Luo, S.-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 3790.
(c) Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Angew. Chem., Int.
Ed. 2008, 47, 2458. (d) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am.
Chem. Soc. 2008, 130, 5652. (e) Yu, J.; He, L.; Chen, X.-H.; Song, J.;
Chen, W.-J.; Gong, L.-Z. Org. Lett. 2009, 11, 4946. (f) Shi, F.; Luo, S.-W.;
Tao, Z.-L.; He, L.; Yu, J.; Tu, S.-J.; Gong, L.-Z. Org. Lett. 2011, 13, 4680.
(g) He, L.; Chen, X.-H.; Wang, D.-N.; Luo, S.-W.; Zhang, W.-Q.; Yu, J.;
Ren, L.; Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504.
spectra) for all products, crystal data (CIF) of compounds 4faa,
4aag, 4iaf, 4eaa, 4haa, and 4aad, and computational data for
transition state. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gonglz@ustc.edu.cn; luosw@ustc.edu.cn.
■
(8) (a) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631.
(b) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2008, 350, 399. (c) Giera, D. S.; Sickert, M.; Schneider, C. Org. Lett.
2008, 10, 4259.
(9) For the phosphoric acid-catalyzed F−C reaction to unsaturated
carbonyl compounds, see: (a) Rueping, M.; Nachtsheim, B. J.; Moreth,
S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593. (b) Zeng, M.; Kang,
Q.; He, Q.-L.; You, S.-L. Adv. Synth. Catal. 2008, 349, 2169. (c) Gu, Q.;
Rong, Z.-Q.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056.
(10) CCDC 879362 for 4faa, CCDC 891219 for 4aag, CCDC 891220
for 4iaf, CCDC 879360 for 4eaa, CCDC 879361 for 4haa, CCDC
879359 for 4aad. See the Supporting Information for details.
(11) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from MOST (973 Project
2009CB82530), Ministry of Education and NSFC (21072181
and 21002083).
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dx.doi.org/10.1021/jo301174g | J. Org. Chem. XXXX, XXX, XXX−XXX