Photochemically Promoted Aza-Diels-Alder-Type Reaction: High Catalytic Activity of the Cr(III)/Bipyridine Complex Enhanced by Visible Light Irradiation

Article abstract of DOI:10.1021/acs.joc.7b00838

Aza-Diels-Alder-type cycloaddition reactions between a range of N-arylimines and functionalized alkenes were effectively catalyzed by the Cr(III)/bipyridine complex under irradiation of blue light, to give the corresponding 1,2,3,4-tetrahydroquinoline derivatives in high yields with excellent diastereoselectivity. Typically, the reaction of benzylideneaniline with 1-vinyl-2-pyrrolidinone proceeded smoothly with a substrate-to-catalyst molar ratio (S/C) of 1000 and completed within 4 h at room temperature (20-25 °C), affording the cycloaddition product in 97% yield.

Full text of DOI:10.1021/acs.joc.7b00838

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Note
Photochemically Promoted Aza-Diels-Alder-Type Reaction: High Catalytic
Activity of the Cr(III)/bipyridine Complex Enhanced by Visible Light Irradiation
Noriyoshi Arai, and Takeshi Ohkuma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00838 • Publication Date (Web): 27 Jun 2017
Downloaded from http://pubs.acs.org on June 27, 2017
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Photochemically Promoted Aza-Diels-Alder-Type Reaction: High Catalytic
Activity of the Cr(III)/bipyridine Complex Enhanced by Visible Light
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Irradiation
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Noriyoshi Arai*,† and Takeshi Ohkuma*,†,‡
†
Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Sapporo,
Hokkaido 060ꢀ8628, Japan
‡
Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo,
Hokkaido 060ꢀ8628, Japan
*Eꢀmail: nꢀarai@eng.hokudai.ac.jp; ohkuma@eng.hokudai.ac.jp
455 nm
[Cr(bpy)3](OTf)3
R4
R3
R2
R4
R1
R1
+
R3
R2
CH3CN
20–25 °C
N
N
H
Substrate / Cr compex = 150–1000
ABSTRACT:
AzaꢀDielsꢀAlderꢀtype cycloaddition reactions between a range of
Nꢀarylimines and functionalized alkenes were effectively catalyzed by the Cr(III)/bipyridine
complex under irradiation of blue light, to give the corresponding
1,2,3,4ꢀtetrahydroquinoline derivatives in high yields with excellent diastereoselectivity.
Typically, the reaction of benzylideneaniline with 1ꢀvinylꢀ2ꢀpyrrolidinone proceeded
smoothly with a substrateꢀtoꢀcatalyst molar ratio (S/C) of 1000 and completed within 4 h at
room temperature (20–25 °C), affording the cycloaddition product in 97% yield.
The tetrahydroquinoline framework is a quite common structural motif found in a number of
biologically active natural products and pharmaceuticals.1 Therefore, the development of new
synthetic methodologies for this important class of compounds has attracted much attention
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among researchers in the fields of drug discovery and medicinal chemistry as well as
synthetic chemistry.2 Among the numerous methods for preparing the tetrahydroquinoline
ring system, the azaꢀDielsꢀAlderꢀtype reaction between Nꢀarylimines and functionalized
alkenes is one of the most versatile approaches, because a wide range of diverse products can
be readily obtained with this reaction merely by changing the combination of imines and
alkenes.3 It is well known that the [4+2] cycloaddition reactions between Nꢀarylimines and
functionalized alkenes are catalyzed by Brønsted acids,4 or by Lewis acids that include
groupꢀ3 metal triflates,5 Sb2(SO4)3,6 SbCl3,7 InCl3,8 FeCl3,9 Al(OTf)3,10 and others.11,12 Some
of these reactions catalyzed by Lewis acids were extended to the asymmetric reaction by
combination with chiral ligands or by using chiral organocatalysts.13,14 It has also been
reported that the cycloaddition reaction is promoted via single electron transfer by using a
pyrrilium salt under UV irradiation,15 cerium(IV) salt,16 nitrosonium salt,17 or an aminium
cation radical.18 However, these methods also have some drawbacks from the view point of
efficient and practical catalytic reaction—namely, they require expensive rare metals with
relatively large catalyst loading (1–10 mol%, in many cases). Guo and coꢀworkers reported
that a triphenylmethylium cation catalyzed the azaꢀDielsꢀAlderꢀtype reaction with a catalyst
loading of 0.5 mol%.19 However, when the catalyst loading decreased to 0.05 mol%, the yield
of the product (60% after 12 h) was not satisfactory. We herein report a new catalytic system
for the azaꢀDielsꢀAlderꢀtype reaction by using a chromium/bipyridine complex under visible
light irradiation. The catalytic efficiency is quite high and the reaction completes within a few
hours under a substrateꢀtoꢀcatalyst molar ratio (S/C) of 1000 in the best case.
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[Cr(bpy)3](OTf)3 (1) is easily synthesized from CrCl3 according to the method described in
the literature.20 The complex behaves as a strong oxidizing reagent in its excited state, the
redox potential of which is calculated as E°(Cr3+(bpy)3*/Cr2+(bpy)3) = +1.45 (vs. SCE).21,22
The absorption maximum of lowest energy transition in the UVꢀVis spectrum of 1 is reported
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as 455 nm (blue light region).21 In spite of this attractive redox property, there have been few
reports on the synthetic use of complex 1. This situation prompted us to investigate the
azaꢀDielsꢀAlderꢀtype reaction by using 1 as a visibleꢀlight photocatalyst. Elegant
investigations into the DielsꢀAlderꢀtype reaction of dienes and alkenes with related
photooxidizing Cr/phenanthroline catalysts were previously reported by Rappé and Shores et
al.23
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At an initial attempt,
a
solution containing Nꢀphenylimine 2a (0.2 mmol),
1ꢀvinylꢀ2ꢀpyrrolidinone (3) (0.55 mmol), and Cr(III)/bpy complex 1 (0.004 mmol, S/C = 50)
in CH3CN (4 mL) was irradiated with 455 nm LED at room temperature for 3 h. To our
delight, most of the starting material 2a was consumed, giving the cycloaddition product
cisꢀ4a in 77% yield accompanied with small amounts of transꢀ4a (approximately <3%)
(Table 1, entry 1). It should be noted that neither RuCl3(bpy)3 nor [Ir(dFCF3ppy)2(bpy)]PF6,
which are very popular photocatalysts available in the blue light region,24–26 were effective,
and the reactions resulted in almost quantitative recovery of the starting materials under the
same reaction conditions (entries 2 and 3). No reaction occurred without 1 (entry 4).
Unexpectedly, small amounts of 4a were obtained even in the absence of photo irradiation
(entry 5). We guessed that the trace of residual acid contained in 1 brought about a relatively
slow reaction. In fact, the formation of adduct 4a was suppressed by the addition of
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine as a Brønsted base (entry 6).27
Table 1. Initial Attemptsa
hν (455 nm)
O
N
[Cr(bpy)3](OTf)3 (1)
O
+
N
CH3CN
N
Ph
N
H
Ph
20–25 °C, 3 h
2a
3
cis-4a
entry deviation from standard conditions
yield of cisꢀ4a (%)b
1
2
3
none
77
0c
0c
RuCl3(bpy)3, instead of 1
[Ir(dFCF3ppy)2(bpy)]PF6, instead
of 1
no 1
no light
4d
5e
6e
0c
35
2
no light, with
2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridinef
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a
Reactions were conducted at 20–25 °C using 0.2 mmol of 2a, 0.55
mmol of 3, and 0.004 mmol of 1 in 4 mL of solvent under irradiation
with 455 nm LED.
b
Determined by 1H NMR analysis using
c
1,3,5ꢀtrimethoxybenzene as an internal standard. Only 2a, 3, and
CH3CN were observed in 1H NMR analysis of the crude mixture.
d
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e
Carried out with 0.29 mmol of 3 and 2 mL of solvent. Carried out
with 0.25 mmol of 3, 0.002 mmol of 1, and 2 mL of solvent. f 15ꢀfold
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molar amounts of the base were added.
Thus, we found that complex 1 effectively catalyzes the azaꢀDielsꢀAlderꢀtype reaction
under blue light irradiation, and we next screened a series of solvents to identify a suitable
one for this reaction. The reactions were carried out by using 2a (0.2 mmol), 3 (0.25 mmol),
and 1 (0.002 mmol, S/C = 100) in CH3CN (2 mL), and discontinued in 3 h irrespective of
the consumption of the starting material. As can be seen from Table 2, the solvent employed
largely affected the result of the reaction. Acetonitrile was the solvent of choice, and gave
the adduct cisꢀ4a in good yield with a small recovery of 2a (entry 1). The stereoselectivity
was comparably high with that reported in the literature for the UVꢀirradiated cycloaddition
reaction between imines and 3.15 A moderate yield of 4a was obtained in nitromethane with
messy byproducts (entry 2). The reactions in solvents with medium polarity were rather
slow, partially due to the poor solubility of 1 in these solvents (entries 3–7). Adduct 4a was
also obtained in methanol and acetone, but the yield was low and was accompanied by
unidentified byproducts in both cases (entries 8 and 9).
Table 2. Solvent Screena
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h
ν
(455 nm)
[Cr(bpy)3](OTf)3 (1)
O
+
N
Solvent
8
N
Ph
20–25 °C, 3 h
9
2a
3
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O
O
N
N
+
N
H
Ph
N
H
Ph
cis-4a
trans-4a
entry solvent
yield or recovery (%)b
cisꢀ4a
78
45
35
9
22
5
8
transꢀ4a
2a
12
23
61
70
61
82
79
52
9
1
2
CH3CN
CH3NO2
CH2Cl2
PhCF3
3
2
1
3c
4c
5c
6c
7c
8
<1
1
<1
<1
<1
<1
THF
MTBE
AcOEt
CH3OH
acetone
13
23
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a
Reactions were conducted at 20–25 °C using 0.2 mmol of 2a, 0.25
mmol of 3, and 0.002 mmol of 1 in 2 mL of solvent under irradiation
b
with 455 nm LED.
Determined by 1H NMR analysis using
c
1,3,5ꢀtrimethoxybenzene as an internal standard. Complex 1 did not
completely dissolve in the solvent.
With the most suitable solvent for the reaction settled, we next applied this cycloaddition
reaction to a series of Nꢀarylimines 2. In these studies, twoꢀfold molar amounts of 3 with
respect to 2 were employed, and the reaction was continued until the imine was consumed
except when the reaction was very slow. The results are listed in Table 3. The reaction with
imine 2a proceeded well under the condition of S/C = 500 to afford the addition product 4a
in 95% isolated yield (entry 1). Notably, the same reaction was completed even under the
condition of S/C = 1000 with slightly prolonged reaction time, giving 4a in high yield
(entry 2). The reaction under more diluted conditions (initial substrate concentration = 0.1
M) gave comparable yield and stereoselectivity (entry 3). We presumed that the slight
decrease of the yield in entry 3 was caused by competitive hydrolysis of imine 2a, though
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commercial dehydrated grade solvent was used. The reaction was applicable to a range of
imines that were derived from paraꢀsubstituted anilines, 2b–2e, as well as unsubstituted 2a
to give the corresponding tetrahydroquinoline derivatives in excellent yields and
diastereoselectivities (entries 4–7). In contrast, an imine with a nitro group, 2f, was slow to
react, and gave the product 4f in low yield and medium cisꢀselectivity with a recovery of 2f
(33%) (entry 8). Fortunately, when the 4ꢀacetamideꢀsubstituted imine 2g was employed
instead of 2f, the reaction proceeded nicely, giving the product 4g in 95% yield and 98%
cisꢀselectivity (entry 9). This result allowed us to obtain tetrahydroquinoline derivatives
having nitrogen functionality at the 6ꢀposition. When the reaction was conducted with
imine 2h, which had bromine at the metaꢀposition, the 7ꢀbromotetrahyroquinoline
derivative 4h was obtained in moderate yield (entry 10). In this case, a hardly separable
mixture that might contain regio isomer of 4h was also obtained but the mixture was not
fully characterized. In contrast, the reaction with Nꢀarylimine from mꢀanisidine 2o gave
5ꢀmethoxytetrahydroquinoline 4o' as major product accompanied with a comparable
amount of 7ꢀisomer 4o (Scheme 1). The reaction with the sterically hindered imine 2i
derived from oꢀtoluidine afforded the 8ꢀmethyltetrahydroquinoline derivative 4i in 72%
yield (entry 11). The electronic properties of aromatic rings that came from aldehydes had
little impact on the product yields, though the reaction with the electron rich substrate 2k
was slower than that with 2j (entries 12 and 13). This reaction was also applicable to imines
that were prepared from aldehydes other than benzaldehyde derivatives. When the reaction
was carried out by using imine 2l derived from furfural, 2ꢀfuryltetrahydroquinoline 4l was
obtained in moderate yield (entry 14). This adduct, 4l, is known as a useful intermediate for
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the construction of isoindolo[2,1ꢀa]quinoline frameworks.28 The reaction with imine 2m
from pivalaldehyde proceeded smoothly to give the product 4m in almost perfect
diastereoselectivity (entry 15). The 2ꢀcyclopropyltetrahydroquinoline derivative 4n was
also stereoselectively produced in moderate yield from imine 2n (entry 16). Thus, our
reaction is also suitable for the preparation of 2ꢀalkylꢀsubstituted tetrahydroquinolines.
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Table 3. Substrate Screena
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h
ν
(455 nm)
R
6
7
8
9
[Cr(bpy)3](OTf)3 (1)
O
R1
R1
+
N
N
R2
N
H
R2
CH3CN
20–25 °C
3
2a–n
4a–n
substrate / catalyst = 500
R =
O
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N
entry
imine
time (h)
product (cis:trans)b
R
1
2c
3c,d
3
4
8
95% (97:3)
97% (96:4)
89% (97:3)
N
Ph
Ph
N
H
R
Ph
Ph
2a
2b
Cl
Cl
4
5
6
7
8
9
3
93% (99:1)
90% (95:5)
90% (98:2)
95% (95:5)
26% (81:19)e
95% (98:2)
61% (94:6)
72% (94:6)
84% (96:4)
N
N
H
R
MeO
Me
MeO
Me
8.5
5
N
N
N
Ph
Ph
Ph
N
H
R
Ph
Ph
Ph
2c
2d
2e
N
H
R
EtO2C
EtO2C
3
10
8
N
H
R
O2N
O2N
N
Ph
N
H
Ph
2f
R
H
AcN
H
AcN
N
H
R
Ph
Ph
Ph
N
N
Ph
Ph
2g
2h
10
10
10
3
Br
Br
N
H
R
11
12
13
14
15
16
N
Ph
N
H
Me
2i
Me
R
N
N
N
H
Cl
2j
Cl
R
10
10
3
89% (97:3)
N
H
R
OMe
O
2k
OMe
MeO
MeO
64% (94:6)f
O
N
N
H
2l
R
90% (>99:1)
55% (96:4)
N
t-Bu
N
H
t-Bu
2m
R
10
N
N
H
2n
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a
Reactions were conducted at 20–25 °C using 0.75 mmol of 2, 1.5
mmol of 3, and 0.0015 mmol of 1 in 2 mL of solvent under irradiation
b
c
with 455 nm LED. Isolated yield. Carried out with 1.5 mmol of 2
and 3 mmol of 3 (S/C = 1000). d Carried out with 15 mL of solvent.
e
2f was recovered in 33%. f 2l was recovered in 18%.
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Scheme 1. Reaction with m-Methoxyphenylimine 2o.
hν (455 nm)
[Cr(bpy)3](OTf)3 (1)
+
3
CH3CN
MeO
N
Ph
20–25 °C, 4 h
2o
2o / 1 = 500
O
O
N
MeO
N
+
MeO
N
Ph
N
H
Ph
H
4o 38% (cis:trans = 84:16)
4o' 43% (cis:trans = 77:23)
We can employ functionalized alkenes other than 1ꢀvinylpyrrolidinꢀ2ꢀone (3). In the
reaction between imine 2b and acyclic alkenyl amide 5, the tetrahydroquinoline derivative
6b, which has acetamide functionality at the 4ꢀposition, was obtained in high yield (Scheme
2). It should be commented that amide 5 exists as a mixture of rotamers (approximately
3:1), which was also the case with the product 6b.
Scheme 2. Reaction with Acyclic Alkenyl Amide 5.
Ac
hν (455 nm)
N
Cl
Cl
[Cr(bpy)3](OTf)3 (1)
Ac
N
+
Ph
CH3CN
N
N
H
Ph
20–25 °C, 9 h
cis-6b 83%
trans-6b 7%
2b
5
2b / 1 = 500
In addition to the terminal alkenes described above, the internal alkenyl amide was also
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employable as a reaction partner of imine 2a, although the reactivity was relatively low.
When imine 2a was reacted with internal amide 7 under the conditions described in Table 3,
the corresponding cycloaddition products 8a and 9a were obtained in moderate yields
(Scheme 3). The relative configuration of 8a and 9a was determined by NOE experiments
(See Supporting Information).
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Scheme 3. Reaction with Internal Amide 7.
hν (455 nm)
[Cr(bpy)3](OTf)3 (1)
O
N
+
CH3CN
N
Ph
20–25 °C, 10 h
2a
7
2a / 1 = 500
O
O
N
N
+
N
H
Ph
N
H
Ph
8a 43%
9a 25%
The reaction was also applicable to an internal alkenyl ether. The reaction between imine
2a and 3,4ꢀdihydroꢀ2Hꢀpyrane (10) proceeded sluggishly, affording the corresponding
cycloadduct 11a in 43% yield with recovery of 2a (approximately 45%) after irradiation of
24 h with increased catalyst loading (Scheme 4).
Scheme 4. Reaction with Cyclic Alkenyl Ether 10.
hν (455 nm)
O
[Cr(bpy)3](OTf)3 (1)
+
CH3CN
N
Ph
O
N
H
Ph
20–25 °C, 24 h
cis-11a 23%
trans-11a 20%
2a
10
2a / 1 = 150
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It is known that the oxidation potentials of enamides (3: +1.12 V vs SCE,29 5: +1.55 V vs
SCE30) are lower than that of alkenyl ether 10 (+1.66 V vs SCE)31 from an electrochemical
point of view. As can be seen from the reactions described above, the reaction proceeded
more smoothly with readily oxidizable 3 or 5 than with 10. Though further investigations
will be needed to disclose the reaction mechanism, we surmise that the reaction proceeds
via single electron transfer from functionalized alkenes to the excited chromium complex,
as discussed in the literature on the azaꢀDielsꢀAlderꢀtype reactions via single electron
transfer.15,18
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In summary, we found that [Cr(bpy)3](OTf)3 (1) efficiently catalyzes the
azaꢀDielsꢀAlderꢀtype reaction between a range of imines and functionalized alkenes under
irradiation of blue light (455 nm) to give the corresponding cycloaddition products in high
yield. The reaction was completed with a substrate/catalyst molar ratio (S/C) as high as
1000 in the best case. This cycloaddition would be applicable to the preparation of
diversely substituted tetrahydroquinoline derivatives with very small amounts of catalyst
loading.
Experimental Section
General Remarks
NMR spectra were obtained on a JEOL JNMꢀECS400 spectrometer. Carbon multiplicity
(described as follows: methyl, CH3; methylene, CH2; methine, CH; quaternary, C) was
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assigned by a DEPT experiment. IR spectra were recorded on a JASCO FT/IRꢀ4100
spectrophotometer. Melting points were measured on a Yanaco Micro Melting Point
Apparatus MPꢀS3 and were uncorrected. Silica gel column chromatography was performed
using FL 60D or PSQ 60B silica gel from Fuji Silysia Chemical, Ltd. Preparative thin layer
chromatography was carried out with Wako Gel Bꢀ5F from Wako Pure Chemical Industries,
Ltd. Solvents for the cycloaddition reaction were of commercial dehydrated grade (Kanto
Chemical Co., Inc.) and used as received. Gel permeation chromatography (GPC) was
performed using an LCꢀ918 recycling preparative HPLC equipped with JAIGELꢀ1H and
ꢀ2H columns in series (Japan Analytical Industry Co., Ltd.). Mass spectrometry and
elemental analyses were carried out at the Instrumental Analysis Division, Global Facility
Center, Creative Research Institution, Hokkaido University.
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Preparation of the Catalyst and the Starting Materials
[Cr(bpy)3](OTf)3 (1) was prepared according to the procedure described in the literature.20
All of the starting materials used in this study are known compounds. NꢀBenzylideneaniline
(2a) is widely available from suppliers and was purified by recrystallization (from hexane)
before use. 1ꢀVinylꢀ2ꢀpyrrolidinone (3), NꢀmethylꢀNꢀvinylacetamide (5), and
3,4ꢀdihydroꢀ2Hꢀpyrone (10) are commercially available and were purified by distillation
before use. (E)ꢀ1ꢀ(1ꢀPropenyl)ꢀ2ꢀpyrrolidinone (7) was prepared according to the procedure
described in the literature.32 All imines except 2a and 2n were prepared by refluxing a
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benzene solution of an equimolar mixture of the corresponding amine and aldehyde with a
DeanꢀStark trap for several hours.33 The crude products were purified by recrystallization or
distillation. Imine 2n was synthesized according to the procedure described in the
literature.34 The physical and spectral data of imines 2b,35 2c,35 2d,35 2e,36 2f,37 2g,38 2h,39
2i,39 2j,40 2k,41 2l,42 2m,43 2n,34 and 2o44 showed good accordance with those described in
the literature.
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General Procedure for the Cycloaddition of Imines and Functionalized Alkenes
The reaction between 2a and 3 under S/C=500 (Table 1, entry 1) is representative.
To a Pyrex® test tube containing imine 2a (146.0 mg, 0.806 mmol), alkenyl amide 3 (176.0
mg, 1.58 mmol), and Cr catalyst 1 (1.5 mg, 0.0015 mmol) under argon, acetonitrile (2 mL)
that had been degassed by three freezeꢀthaw cycles was added via a syringe. The solution
was irradiated by a 240 mW (radiant flux) blue LED (455 nm) externally for 3 h. The
reaction mixture was concentrated under reduced pressure. Purification of the crude
materials by silica gel column chromatography (PSQ 60B, hexane/ethyl acetate; initially
2:1, then 1:1, and finally 1:2) gave pure cisꢀ4a (225.5 mg) and a mixture of cisꢀ4a and
transꢀ4a (21.4 mg) as colorless viscous oil. Dichloromethane was used to combine the
fractions. A small amount of solvent remained in these samples even after a long period of
evacuation. The molar amounts of 4a (cisꢀ4a: 0.741 mmol; transꢀ4a: 0.024 mmol) were
calculated by subtracting those of solvent based on the 1H NMR integrals.
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In the several cases listed below, the cisꢀproduct was spontaneously precipitated in the
reaction mixture. Filtration followed by washing with cold acetonitrile gave a
diastereomerically pure sample. The filtrate was concentrated and purified by silica gel
column chromatography or preparative thin layer chromatography. The yields and the
diastereomeric ratios shown in Table 3 were calculated from combined amounts of these
samples.
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Physical and Spectral Data of the Products
(2R*,4R*)-1,2,3,4-Tetrahydro-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline (cis-4a)15a
Colorless viscous oil or foamy amorphous solid. IR (KBr) 3313, 3027, 2950, 1671, 1605,
1489, 1420, 1313, 1285, 1268, 751, 701 cm–1. 1H NMR (400 MHz, CDCl3) δ 1.98–2.14 (m,
4H), 2.42–2.58 (m, 2H), 3.18–3.28 (m, 2H), 4.00 (br s, 1H), 4.60–4.63 (m, 1H), 5.71–5.75
(m, 1H), 6.58 (dd, J=8.0, 1.0 Hz, 1H), 6.69–6.73 (m, 1H), 6.88 (d, J=7.6 Hz, 1H),
7.04–7.09 (m, 1H), 7.29–7.45 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 18.2 (CH2), 31.4
(CH2), 35.2 (CH2), 42.3 (CH2), 48.4 (CH), 56.4 (CH), 114.9 (CH), 118.2 (CH), 118.8 (C),
126.4 (CH), 126.8 (CH), 128.0 (CH), 128.2 (CH), 128.8 (CH), 143.0 (C), 145.9 (C), 175.8
(C).
(2R*,4R*)-6-Chloro-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
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(cis-4b)15a
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Compound 4b was obtained from imine 2b (163.2 mg, 0.757 mmol) according to the
general procedure. Colorless solid (cisꢀ4b, 190.2 mg, 0.582 mmol) was isolated as a
precipitate. Purification of the filtrate by preparative thin layer chromatography (developed
with CHCl3/MeOH = 40:1, 2 times) gave pale yellow oil (46.8 mg with a small amount of
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inseparable 3). H NMR analysis revealed that the oil contained 0.116 mmol of cisꢀ4b and
0.0070 mmol of transꢀ4b. The combined yield was 93% (cis:trans = 99:1). IR (KBr) 3357,
2951, 1673, 1601, 1491, 1458, 1433, 1364, 1341, 1296, 1255, 819, 769, 705 cm–1. 1H NMR
(400 MHz, CDCl3) δ 2.00–2.13 (m, 4H), 2.42–2.60 (m, 2H), 3.18–3.28 (m, 2H), 4.02 (br s,
1H), 4.57–4.61 (m, 1H), 5.66–5.70 (m, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.82 (obscured d, J=2
Hz, 1H), 6.99–7.02 (m, 1H), 7.30–7.43 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 18.2 (CH2),
31.2 (CH2), 34.8 (CH2), 42.2 (CH2), 48.2 (CH), 56.3 (CH), 116.1 (CH), 120.5 (C), 122.8
(C), 126.3 (CH), 126.4 (CH), 128.1 (CH), 128.2 (CH), 128.8 (CH), 142.6 (C), 144.4 (C),
175.8 (C).
(2R*,4R*)-1,2,3,4-Tetrahydro-6-methoxy-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4c)15a
Compound 4c was obtained from imine 2c (159.8 mg, 0.756 mmol) according to the
general procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 1:1, then 1:2) gave colorless solid
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(cisꢀ4c, 193.3 mg, 0.600 mmol) and pale yellow oil (27.1 mg with a small amount of
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residual ethyl acetate). H NMR analysis revealed that the oil contained 0.0468 mmol of
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cisꢀ4c and 0.0328 mmol of transꢀ4c. The combined yield was 90% (cis:trans = 95:5). IR
(KBr) 3354, 2992, 2950, 2828, 1679, 1497, 1472, 1429, 1286, 1270, 1234, 1041, 822, 767,
705 cm–1. 1H NMR (400 MHz, CDCl3) δ 1.98–2.14 (m, 4H), 2.41–2.57 (m, 2H), 3.18–3.28
(m, 2H), 3.73 (s, 3H), 3.80 (br s, 1H), 4.52–4.56 (m, 1H), 5.72 (dd, J=11.0, 7.0 Hz, 1H),
6.48 (dd, J=2.8, 1.0 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 6.68–6.71 (m, 1H), 7.29–7.45 (m, 5H).
13C NMR (100 MHz, CDCl3) δ 18.2 (CH2), 31.4 (CH2), 35.2 (CH2), 42.3 (CH2), 48.6 (CH),
55.9 (CH3), 56.7 (CH), 112.2 (CH), 114.4 (CH), 116.1 (CH), 120.2 (C), 126.5 (CH), 127.9
(CH), 128.7 (CH), 140.1 (C), 143.1 (C), 152.6 (C), 175.8 (C).
(2R*,4R*)-1,2,3,4-Tetrahydro-6-methyl-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4d)6
Compound 4d was obtained from imine 2d (147.1 mg, 0.753 mmol) according to the
general procedure. Colorless solid (cisꢀ4d, 136.1 mg, 0.444 mmol) was isolated as a
precipitate. Purification of the filtrate by silica gel column chromatography (FL 60D,
hexane/ethyl acetate = 1:2) gave pale yellow oil (72.3 mg with a small amount of
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inseparable 3 and residual ethyl acetate). H NMR analysis revealed that the oil contained
0.217 mmol of cisꢀ4d and 0.0135 mmol of transꢀ4d. The combined yield was 90%
(cis:trans = 98:2). IR (KBr) 3342, 3027, 2954, 2913, 1661, 1504, 1300, 816, 768, 704 cm–1.
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1H NMR (400 MHz, CDCl3) δ 1.98–2.13 (m, 4H), 2.22 (s, 3H), 2.42–2.59 (m, 2H),
3.17–3.27 (m, 2H), 3.88 (br s, 1H), 4.55–4.58 (m, 1H), 5.68–5.73 (m, 1H), 6.51 (d, J=8.0
Hz, 1H), 6.68 (br s, 1H), 6.86–6.89 (m, 1H), 7.29–7.44 (m, 5H). 13C NMR (100 MHz,
CDCl3) δ 18.2 (CH2), 20.6 (CH3), 31.4 (CH2), 35.4 (CH2), 42.3 (CH2), 48.4 (CH), 56.5
(CH), 115.1 (CH), 118.9 (C), 126.5 (CH), 127.1 (CH), 127.5 (C), 127.9 (CH), 128.7 (CH),
128.9 (CH), 143.2 (C), 143.6 (C), 175.8 (C).
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(2R*,4R*)-Ethyl
1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)-2-phenyl-6-quinolinecarboxylate (cis-4e)
Compound 4e was obtained from imine 2e (193.1 mg, 0.762 mmol) according to the
general procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 2:1, then 1:1, and finally 1:2) gave
colorless solid (cisꢀ4e, 227.5 mg with a trace of residual ethyl acetate, 0.617 mmol net) and
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colorless oil (33.3 mg with a small amount of residual ethyl acetate). H NMR analysis
revealed that the oil contained 0.0751 mmol of cisꢀ4e and 0.0345 mmol of transꢀ4e. The
combined yield was 95% (cis:trans = 95:5). Mp 177–179 °C. IR (KBr) 3338, 2981, 1693,
1667, 1610, 1511, 1364, 1291, 1244, 1177, 1132, 1102, 767, 700 cm–1. 1H NMR (400 MHz,
CDCl3) δ 1.36 (t, J=7.1 Hz, 3H), 1.98–2.17 (m, 4H), 2.46 (ddd, J=17.0, 9.3, 8.0 Hz, 1H),
2.58 (ddd, J=17.0, 9.2, 5.7 Hz, 1H), 3.18–3.28 (m, 2H), 4.27–4.35 (m, 2H), 4.43 (br s, 1H),
4.69 (dd, J=10.9, 3.3 Hz, 1H), 5.69 (dd, J=11.6, 6.0 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H),
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7.31–7.43 (m, 5H), 7.56 (br s, 1H), 7.74–7.76 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 14.4
(CH3), 18.3 (CH2), 31.3 (CH2), 34.7 (CH2), 42.2 (CH2), 48.0 (CH), 56.0 (CH), 60.3 (CH2),
113.7 (CH), 117.6 (C), 119.3 (C), 126.3 (CH), 128.2 (CH), 128.5 (CH), 128.8 (CH), 130.2
(CH), 142.1 (C), 149.5 (C), 166.6 (C), 175.9 (C). HRMS (ESIꢀorbitrap) m/z: [M + Na]+
Calcd for C22H24N2O3Na 387.1679; Found 387.1682.
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(2R*,4R*)-1,2,3,4-Tetrahydro-6-nitro-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4f)12
Compound 4f was obtained from imine 2f (171.2 mg, 0.757 mmol) according to the general
procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 2:1, then 1:1, and finally 1:2)
followed by preparative thin layer chromatography (developed with CHCl3/MeOH = 50:1)
gave two portions of yellow viscous oil (cisꢀ4f, 55.0 mg, transꢀ4f, 12.3 mg each with a
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small amount of residual ethyl acetate). H NMR analysis revealed that the portions
contained 0.158 mmol of cisꢀ4f and 0.0346 mmol of transꢀ4f, respectively. The combined
yield was 26% (cis:trans = 81:19). IR (KBr) 3308, 2954, 1674, 1610, 1584, 1531, 1507,
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1468, 1417, 1294, 1248, 1164, 1092, 824, 751, 696 cm–1. H NMR (400 MHz, CDCl3) δ
2.03–2.20 (m, 4H), 2.48 (ddd, J=17.0, 9.4, 8.1 Hz, 1H), 2.62 (ddd, J=17.0, 9.4, 5.3 Hz, 1H),
3.24–3.28 (m, 2H), 4.75 (dd, J=11.0, 3.3 Hz, 1H), 4.81 (br s, 1H), 5.69 (dd, J=11.8, 5.5 Hz,
1H), 6.53 (d, J=8.8 Hz, 1H), 7.34–7.44 (m, 5H), 7.76 (s, 1H), 7.97–8.00 (m, 1H). 13C NMR
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(100 MHz, CDCl3) δ 18.2 (CH2), 31.0 (CH2), 34.1 (CH2), 42.1 (CH2), 47.7 (CH), 56.1 (CH),
113.4 (CH), 117.8 (C), 122.8 (CH), 125.2 (CH), 126.3 (CH), 128.5 (CH), 129.0 (CH),
138.2 (C), 141.2 (C), 151.0 (C), 176.0 (C).
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(2R*,4R*)-6-Acetamido-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4g)
Compound 4g was obtained from imine 2g (179.3 mg, 0.752 mmol) according to the
general procedure. Colorless solid (cisꢀ4g, 229.9 mg, 0.658 mmol) was isolated as a
precipitate. Purification of the filtrate by preparative thin layer chromatography (developed
with CHCl3/MeOH = 30:1, 2 times, then 15:1, 2 times) gave colorless oil (20.7 mg with a
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small amount of residual ethyl acetate). H NMR analysis revealed that the oil contained
0.0419 mmol of cisꢀ4g and 0.0126 mmol of transꢀ4g. The combined yield was 95%
(cis:trans = 98:2). Mp 250–251 °C. IR (KBr) 3319, 3288, 3095, 2975, 1656, 1601, 1558,
1501, 1314, 1289, 1245, 829, 762, 705 cm–1. 1H NMR (400 MHz, CDCl3) δ 1.99–2.13 (m,
4H), 2.13 (s, 3H), 2.42–2.59 (m, 2H), 3.21–3.31 (m, 2H), 3.96 (br s, 1H), 4.56–4.60 (m,
1H), 5.66–5.70 (m, 1H), 6.54 (d, J=8.5 Hz, 1H), 6.91 (obscured d, J=2 Hz, 1H), 7.08 (br s,
1H), 7.21 (dd, J=8.5, 2.3 Hz, 1H), 7.30–7.43 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 18.3
(CH2), 24.3 (CH3), 31.4 (CH2), 35.1 (CH2), 42.4 (CH2), 48.4 (CH), 56.4 (CH), 115.2 (CH),
119.1 (C), 119.5 (CH), 121.6 (CH), 126.4 (CH), 128.0 (CH), 128.8 (CH), 128.9 (C), 142.8
(C), 142.9 (C), 168.2 (C), 176.0 (C). HRMS (ESIꢀorbitrap) m/z: [M + Na]+ Calcd for
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C21H23N3O2Na 372.1683; Found 372.1677.
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(2R*,4R*)-7-Bromo-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4h)
Compound 4h was obtained from imine 2h (159.8 mg, 0.756 mmol) according to the
general procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 2:1, then 1:1, and finally 1:2) gave
three portions of colorless viscous oil (#1, 41.0 mg, #2, 138.2 mg, and #3, 19.6 mg each
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with a small amount of residual solvents). H NMR analysis revealed that these portions
contained 0.432 mmol of cisꢀ4h and 0.0265 mmol of transꢀ4h. The combined yield was
61% (cis:trans = 94:6). Spectral data of portion #2 were shown. IR (KBr) 3296, 3031, 2960,
2927, 1656, 1598, 1486, 1456, 1440, 1338, 1307, 1286, 1240, 846, 706 cm–1. 1H NMR (400
MHz, CDCl3) δ 1.98–2.13 (m, 4H), 2.41–2.57 (m, 2H), 3.15–3.26 (m, 2H), 4.06 (br s, 1H),
4.60 (dd, J=10.5, 3.5 Hz, 1H), 5.64 (dd, J=11.2, 6.5 Hz, 1H), 6.70–6.72 (m, 2H), 6.80 (dd,
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J=8.2, 1.9 Hz, 1H), 7.30–7.42 (m, 5H). C NMR (100 MHz, CDCl3) δ 18.2 (CH2), 31.3
(CH2), 34.9 (CH2), 42.2 (CH2), 48.0 (CH), 56.2 (CH), 117.2 (CH), 117.8 (C), 120.8 (CH),
121.7 (C), 126.4 (CH), 128.1 (CH), 128.9 (CH), 142.4 (C), 147.0 (C), 175.8 (C). One of the
aromatic methine signals should contain two signals. HRMS (ESIꢀorbitrap) m/z: [M + Na]+
Calcd for C19H1979BrN2ONa: 393.0573; Found 393.0576.
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(2R*,4R*)-1,2,3,4-Tetrahydro-8-methyl-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4i)6
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Compound 4i was obtained from imine 2i (148.4 mg, 0.760 mmol) according to the general
procedure. Colorless solid (cisꢀ4i, 83.3 mg, 0.272 mmol) was isolated as a precipitate.
Purification of the filtrate by silica gel column chromatography (FL 60D, hexane/ethyl
acetate = 2:1) gave colorless solid (cisꢀ4i, 67.2 mg with a trace of residual solvents, 0.216
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mmol net) and colorless oil (17.6 mg with a small amount of residual ethyl acetate). H
NMR analysis revealed that the oil contained 0.0237 mmol of cisꢀ4i and 0.0328 mmol of
transꢀ4i. The combined yield was 72% (cis:trans = 94:6). IR (KBr) 3363, 3028, 2974, 1681,
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1601, 1504, 1475, 1433, 1310, 1285, 755, 698 cm–1. H NMR (400 MHz, CDCl3) δ
1.97–2.13 (m, 4H, containing s, 3H at 2.11), 2.42–2.58 (m, 2H), 3.17–3.26 (m, 2H), 3.83
(br s, 1H), 4.62–4.65 (m, 1H), 5.74–5.79 (m, 1H), 6.66 (t, J=7.5 Hz, 1H), 6.78 (d, J=7.5 Hz,
1H), 6.97–6.99 (m, 1H), 7.31–7.42 (m, 3H), 7.46–7.49 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 17.4 (CH3), 18.2 (CH2), 31.4 (CH2), 35.1 (CH2), 42.3 (CH2), 48.6 (CH), 56.3
(CH), 117.4 (CH), 118.3 (C), 121.9 (C), 124.5 (CH), 126.5 (CH), 127.9 (CH), 128.8 (CH),
129.3 (CH), 143.3 (C), 143.9 (C), 175.7 (C).
(2R*,4R*)-2-(4-Chlorophenyl)-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)quinoline
(cis-4j)6
Compound 4j was obtained from imine 2j (163.9 mg, 0.760 mmol) according to the general
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procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate = 2:1) gave cisꢀ4j (colorless solid, 199.4 mg
with a small amount of residual solvents, 0.594 mmol net), transꢀ4j (colorless solid, 5.2 mg,
0.016 mmol), and a mixture of cisꢀ and transꢀ4j (colorless oil, 9.2 mg with a small amount
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of residual ethyl acetate). H NMR analysis revealed that this oil contained 0.020 mmol of
cisꢀ4j and 0.0071 mmol of transꢀ4j. The combined yield was 84% (cis:trans = 94:6). IR
(KBr) 3334, 3047, 2917, 1667, 1603, 1487, 1461, 1437, 1309, 1288, 1256, 1085, 824, 776,
748 cm–1. 1H NMR (400 MHz, CDCl3) δ 1.98–2.11 (m, 4H), 2.42–2.58 (m, 2H), 3.17–3.26
(m, 2H), 3.96 (br s, 1H), 4.58 (dd, J=10.2, 3.7 Hz, 1H), 5.71 (dd, J=11.0, 6.9 Hz, 1H), 6.58
(dd, J=8.0, 1.0 Hz, 1H), 6.71 (dt, Jt=7.6 Hz, Jd=1.0 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H),
7.03–7.08 (m, 1H), 7.31–7.37 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 18.1 (CH2), 31.3
(CH2), 35.2 (CH2), 42.2 (CH2), 48.2 (CH), 56.7 (CH), 115.0 (CH), 118.3 (CH), 118.7 (C),
126.7 (CH), 127.8 (CH), 128.2 (CH), 128.8 (CH), 133.4 (C), 141.5 (C), 145.6 (C), 175.8
(C).
(2R*,4R*)-1,2,3,4-Tetrahydro-2-(4-methoxyphenyl)-4-(2-oxopyrrolidin-1-yl)quinoline
(cis-4k)16
Compound 4k was obtained from imine 2k (161.8 mg, 0.766 mmol) according to the
general procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 2:1, then 1:1, and finally 1:2) gave
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cisꢀ4k (colorless foamy solid, 186.0 mg with a small amount of residual ethyl acetate,
0.548 mmol net) and a mixture of cisꢀ and transꢀ4k (colorless oil, 46.9 mg with a small
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amount of residual ethyl acetate). H NMR analysis revealed that this oil contained 0.111
mmol of cisꢀ4k and 0.0211 mmol of transꢀ4k. The combined yield was 89% (cis:trans =
97:3). IR (KBr) 3315, 2951, 1672, 1606, 1513, 1489, 1421, 1312, 1286, 1246, 1173, 1035,
830, 751 cm–1. H NMR (400 MHz, CDCl3) δ 1.98–2.13 (m, 4H), 2.42–2.58 (m, 2H),
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3.18–3.28 (m, 2H), 3.82 (s, 3H), 3.95 (br s, 1H), 4.53–4.59 (m, 1H), 5.70–5.74 (m, 1H),
6.55–6.58 (m, 1H), 6.68–6.72 (m, 1H), 6.86–6.92 (m, 3H), 7.03–7.07 (m, 1H), 7.33–7.36
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(m, 2H). C NMR (100 MHz, CDCl3) δ 18.1 (CH2), 31.3 (CH2), 35.2 (CH2), 42.2 (CH2),
48.4 (CH), 55.2 (CH3), 55.7 (CH), 114.0 (CH), 114.8 (CH), 118.0 (CH), 118.7 (C), 126.7
(CH), 127.5 (CH), 128.1 (CH), 135.0 (C), 145.9 (C), 159.2 (C), 175.7 (C).
(2R*,4R*)-2-(2-Furyl)-1,2,3,4-tetrahydro-6-methoxy-4-(2-oxopyrrolidin-1-yl)quinoline
(cis-4l)28
Compound 4l was obtained from imine 2l (153.9 mg, 0.765 mmol) according to the general
procedure. Colorless solid (cisꢀ4l, 87.0 mg, 0.279 mmol) was isolated as a precipitate.
Purification of the filtrate by silica gel column chromatography (FL 60D, hexane/ethyl
acetate; initially 2:1, then 1:1, then 1:2, and finally 1:3) gave unreacted 2l (27.5 mg, 18%
recovery), cisꢀ4l (pale yellow oil, 52.6 mg, 0.168 mmol), and a mixture of cisꢀ and transꢀ4l
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(yellow oil, 19.5 mg with a small amount of an impurity). H NMR analysis revealed that
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the mixture contained 0.0179 mmol of cisꢀ4l and 0.0275 mmol of transꢀ4l. The combined
yield was 64% (cis:trans = 94:6). IR (KBr) 3348, 3109, 2997, 1680, 1501, 1470, 1432,
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1290, 1274, 1254, 1223, 1035, 1018, 818, 772 cm–1. H NMR (400 MHz, CDCl3) δ
1.98–2.06 (m, 2H), 2.15–2.30 (m, 2H), 2.43–2.57 (m, 2H), 3.14–3.20 (m, 1H), 3.23–3.29
(m, 1H), 3.72 (s, 3H), 3.90 (br s, 1H), 4.60 (dd, J=11.1, 2.6 Hz, 1H), 5.68 (dd, J=11.5, 6.6
Hz, 1H), 6.26 (d, J=3.2 Hz, 1H), 6.35 (dd, J=3.2, 1.8 Hz, 1H), 6.46–6.47 (m, 1H), 6.57 (d,
J=8.6 Hz, 1H), 6.67–6.70 (m, 1H), 7.39 (dd, J=1.8, 0.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 18.2 (CH2), 31.2 (CH2), 31.4 (CH2), 42.3 (CH2), 48.0 (CH), 50.0 (CH), 55.8
(CH3), 105.5 (CH), 110.2 (CH), 112.1 (CH), 114.5 (CH), 116.6 (CH), 120.5 (C), 139.2 (C),
142.0 (CH), 152.9 (C), 155.2 (C), 175.8 (C).
(2R*,4R*)-2-(tert-Butyl)-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)quinoline (cis-4m)
Compound 4m was obtained from imine 2m (122.8 mg, 0.762 mmol) according to the
general procedure. Colorless solid (cisꢀ4m, 87.0 mg, 0.407 mmol) was isolated as a
precipitate. Purification of the filtrate by silica gel column chromatography (FL 60D,
hexane/ethyl acetate; initially 2:1, then 1:1, and finally 1:3) gave cisꢀ4m (colorless solid,
75.5 mg, 0.277 mmol). The combined yield was 90% (cis:trans = >99:1). Mp 191–192 °C.
IR (KBr) 3350, 3050, 2962, 1676, 1605, 1492, 1427, 1364, 1312, 1283, 741 cm–1. 1H NMR
(400 MHz, CDCl3) δ 0.97 (s, 9H), 1.72 (q, J=12 Hz, 1H), 1.95–2.07 (m, 3H), 2.45–2.59 (m,
2H), 3.14–3.29 (m, 3H), 3.81 (br s, 1H), 5.55 (dd, J=12, 5.8 Hz, 1H), 6.54 (dd, J=8.0, 1.0
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Hz, 1H), 6.62–6.66 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.99–7.04 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 18.2 (CH2), 25.9 (CH3), 27.1 (CH2), 31.5 (CH2), 33.2 (C), 42.3 (CH2), 48.6
(CH), 60.1 (CH), 114.9 (CH), 117.6 (CH), 119.1 (C), 126.5 (CH), 128.0 (CH), 146.2 (C),
175.7 (C). Anal. Calcd for C17H24N2O: C, 74.96%; H, 8.88%; N, 10.28%. Found: C,
74.94%; H, 8.90%; N, 10.31%.
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(2R*,4R*)-2-Cyclopropyl-1,2,3,4-tetrahydro-4-(2-oxopyrrolidin-1-yl)quinoline (cis-4n)
Compound 4n was obtained from imine 2n (110.0 mg, 0.758 mmol) according to the
general procedure. Purification of the concentrated reaction mixture by silica gel column
chromatography (FL 60D, hexane/ethyl acetate; initially 3:1, then 2:1, then 1:1, and finally
1:2) gave a mixture of 4n and an unidentified byproduct (135.6 mg). Further purification of
the mixture by preparative thin layer chromatography (developed with hexane/ethyl acetate
= 1:1 once, then 2:1, 2 times) gave a mixture of cisꢀ and transꢀ4n (faintly yellow solid,
107.0 mg, 0.417 mmol). The yield was 55% (cis:trans = 96:4). Mp 149–151 °C. IR (KBr)
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3339, 3081, 3000, 2952, 1664, 1605, 1492, 1423, 1312, 1284, 1262, 747 cm–1. H NMR
(400 MHz, CDCl3) δ 0.21–0.30 (m, 2H), 0.49–0.60 (m, 2H), 0.84–0.93 (m, 1H), 1.87–2.06
(m, 3H), 2.12–2.17 (m, 1H), 2.44–2.59 (m, 3H), 3.15–3.20 (m, 1H), 3.24–3.30 (m, 1H),
3.99 (br s, 1H), 5.51 (dd, J=12.0, 6.1 Hz, 1H), 6.54 (dd, J=8.0, 1.0 Hz, 1H), 6.63–6.67 (m,
1H), 6.79–6.82 (m, 1H), 7.00–7.04 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 1.76 (CH2),
2.93 (CH2), 16.7 (CH), 18.1 (CH2), 31.4 (CH2), 32.3 (CH2), 42.2 (CH2), 47.9 (CH), 57.1
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(CH), 114.4 (CH), 117.6 (CH), 118.8 (C), 126.6 (CH), 128.0 (CH), 145.5 (C), 175.6 (C).
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HRMS (ESIꢀorbitrap) m/z: [M + Na]+ Calcd for C16H20N2ONa: 279.1468; Found 279.1465.
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(2R*,4R*)-1,2,3,4-Tetrahydro-7-methoxy-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4o)
Compounds 4o and 4o' were obtained from imine 2o (161.6 mg, 0.765 mmol) according to
the general procedure. Purification of the concentrated reaction mixture by silica gel
column chromatography (FL 60D, hexane/ethyl acetate; initially 2:1, then 1:1, and finally
1:2) gave six portions (#1–6) as colorless viscous oil, all of which contained a small
amount of residual ethyl acetate. #1: 37.6 mg, cisꢀ4o. #2: 41.7 mg, cisꢀ4o and transꢀ4o
(96:4). #3: 7.2 mg, cisꢀ4o and transꢀ4o (57:43). #4: 13.6 mg, transꢀ4o and transꢀ4o' (76:24).
#5: 33.7 mg, transꢀ4o' and unidentified compounds. #6: 85.5 mg, cisꢀ4o'. Further
purification of #5 by preparative thin layer chromatography (developed with hexane/ethyl
acetate = 1:2) gave transꢀ4o' (24.9 mg). The combined yield of 4o was 38% (cis:trans =
84:16) and that of 4o' was 43% (cis:trans = 77:23). cis-4o: IR (KBr) 3319, 3081, 3029,
2952, 1670, 1618, 1491, 1462, 1421, 1285, 1265, 1207, 1169, 731, 702 cm–1. 1H NMR (400
MHz, CDCl3) δ 1.97–2.13 (m, 4H), 2.41–2.56 (m, 2H), 3.17–3.26 (m, 2H), 3.75 (s, 3H),
4.00 (br s, 1H), 4.58 (dd, J=10.5, 3.4 Hz, 1H), 5.67 (dd, J=10.9, 6.6 Hz, 1H), 6.13 (d, J=2.5
Hz, 1H), 6.30 (dd, J=8.5, 2.5 Hz, 1H), 6.78 (dd, J=8.5, 1.0 Hz, 1H), 7.29–7.44 (m, 5H). 13C
NMR (100 MHz, CDCl3) δ 18.2 (CH2), 31.4 (CH2), 35.4 (CH2), 42.2 (CH2), 48.0 (CH),
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55.1 (CH3), 56.4 (CH), 99.8 (CH), 104.3 (CH), 111.4 (C), 126.4 (CH), 127.86 (CH), 127.91
(CH), 128.7 (CH), 142.9 (C), 146.9 (C), 159.7 (C), 175.8 (C). HRMS (ESIꢀorbitrap) m/z:
[M + Na]+ Calcd for C20H22N2O2Na: 345.1574; Found 345.1576.
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(2R*,4R*)-1,2,3,4-Tetrahydro-5-methoxy-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(cis-4o')
IR (KBr) 3303, 2952, 1667, 1604, 1494, 1477, 1459, 1435, 1421, 1286, 1247, 1118, 763,
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734, 701 cm–1. H NMR (400 MHz, CDCl3) δ 1.69–1.89 (m, 2H), 2.10–2.18 (m, 1H),
2.26–2.39 (m, 3H), 2.82–2.88 (m, 1H), 3.04–3.09 (m, 1H), 3.75 (s, 3H), 4.02 (br s, 1H),
4.42 (dd, J=10.6, 2.6 Hz, 1H), 5.61 (dd, J=9.7, 7.5 Hz, 1H), 6.260 (d, J=8.1 Hz, 1H), 6.264
(d, J=8.1 Hz, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.27–7.43 (m, 5H). 13C NMR (100 MHz, CDCl3)
δ 18.1 (CH2), 31.3 (CH2), 36.0 (CH2), 42.9 (CH2), 45.3 (CH), 55.45 (CH3), 55.50 (CH),
100.1 (CH), 107.1 (C), 108.3 (CH), 126.3 (CH), 127.6 (CH), 128.6 (CH), 128.9 (CH),
142.9 (C), 149.2 (C), 158.9 (C), 174.8 (C). HRMS (ESIꢀorbitrap) m/z: [M + Na]+ Calcd for
C20H22N2O2Na: 345.1574; Found 345.1576.
(2R*,4S*)-1,2,3,4-Tetrahydro-5-methoxy-4-(2-oxopyrrolidin-1-yl)-2-phenylquinoline
(trans-4o')
IR (KBr) 3312, 2954, 2837, 1666, 1607, 1494, 1456, 1418, 1284, 1264, 1237, 1129, 1108,
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753, 732, 701 cm–1. H NMR (400 MHz, CDCl3) δ 1.86–2.05 (m, 3H), 2.32–2.37 (m, 1H),
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2.38–2.51 (m, 2H), 3.00–3.06 (m, 1H), 3.32–3.38 (m, 1H), 3.78 (s, 3H), 4.17 (br s, 1H),
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4.32 (dd, J=12.5, 2.9 Hz, 1H), 5.32 (dd, J=4.5, 2.1 Hz, 1H), 6.23 (d, J=8.1 Hz, 1H), 6.24 (d,
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J=8.1 Hz, 1H), 7.08 (t, J=8.1 Hz, 1H), 7.28–7.40 (m, 5H). C NMR (100 MHz, CDCl3) δ
18.5 (CH2), 31.6 (CH2), 37.6 (CH2), 43.5 (CH), 47.6 (CH2), 52.7 (CH), 55.4 (CH3), 98.9
(CH), 105.1 (C), 107.4 (CH), 126.7 (CH), 127.8 (CH), 128.6 (CH), 129.4 (CH), 143.2 (C),
146.2 (C), 158.7 (C), 174.5 (C). HRMS (ESIꢀorbitrap) m/z: [M + Na]+ Calcd for
C20H22N2O2Na: 345.1574; Found 345.1569.
(2R*,4R*)-6-Chloro-1,2,3,4-tetrahydro-4-(N-methylacetamido)-2-phenylquinoline
(cis-6b)
Compound 6b was obtained from imine 2b (122.8 mg, 0.762 mmol) and 5 (151.5 mg, 1.53
mmol) according to the general procedure. Colorless solid (cisꢀ6b, 172.2 mg, 0.547 mmol)
was isolated as a precipitate. Purification of the filtrate by preparative thin layer
chromatography (developed with CHCl3/MeOH = 20:1) gave a mixture of cisꢀ and transꢀ6b
(51.6 mg). Further purification by preparative thin layer chromatography (developed with
toluene/ethyl acetate = 4:1, 2 times) afforded cisꢀ6b (faintly yellow solid, 27.5 mg with a
small amount of residual ethyl acetate) and transꢀ6b (pale yellow oil, 17.4 mg with a small
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amount of residual ethyl acetate). H NMR analysis revealed that the portions contained
0.0834 mmol of cisꢀ6b and 0.0522 mmol of transꢀ6b, respectively. All products were a
mixture of amide rotamers (3:1). The combined yield was 90% (cis:trans = 92:8). Mp
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206–207 °C. IR (KBr) 3327, 2962, 1631, 1602, 1486, 1454, 1399, 1296, 813, 769, 704
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cm–1. H NMR (400 MHz, CDCl3) δ 1.95–2.04 (m, 0.75H), 2.08–2.14 (m, 1H), 2.17–2.28
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(m, 0.25H, including s, 0.25×3H at 2.20 and s, 0.75×3H at 2.26), 2.71 (s, 0.25×3H), 2.77 (s,
0.75×3H), 3.99 (br s, 0.75H), 4.04 (br s, 0.25H), 4.56–4.61 (m, 1H), 5.22–5.27 (m, 0.25H),
6.17–6.21 (m, 0.75H), 6.49–6.52 (m, 1H), 6.84 (br d, 0.75H), 6.91 (br s, 0.25H), 6.98–7.05
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(m, 1H), 7.30–7.45 (m, 5H). C NMR (100 MHz, CDCl3) δ 21.6 (CH3), 22.2 (CH3), 28.4
(CH3), 31.1 (CH3), 34.7 (CH2), 35.7 (CH2), 50.3 (CH), 55.8 (CH), 56.3 (CH), 56.5 (CH),
116.0 (CH), 120.4 (C), 121.1 (C), 122.8 (C), 123.0 (C), 126.2 (CH), 126.4 (CH), 126.46
(CH), 126.53 (CH), 128.00 (CH), 128.03 (CH), 128.3 (CH), 128.6 (CH), 128.8 (CH), 128.9
(CH), 142.1 (C), 142.6 (C), 144.2 (C), 145.0 (C), 170.9 (C), 171.7 (C). Clearly minor
signals are written in italics. HRMS (ESIꢀorbitrap) m/z: [M + Na]+ Calcd for
C18H1935ClN2ONa: 337.1078; Found 337.1077.
(2R*,3S*,4R*)-1,2,3,4-Tetrahydro-3-methyl-4-(2-oxopyrrolidin-1-yl)-2-phenylquinolin
e (8a)
Compound 8a was obtained from imine 2a (138.0 mg, 0.761 mmol) and enamide 7 (188.9
mg, 1.51 mmol) according to the general procedure. Purification of the concentrated
reaction mixture by silica gel column chromatography (PSQ 60B, hexane/ethyl acetate;
initially 3:1, then 2:1, and finally 1:2) gave 8a (colorless solid, 100.2 mg, 0.327 mmol,
43%) and a mixture of 9a and an unidentified compound (71.2 mg). This mixture was
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