Visible light mediated cyclization of tertiary anilines with maleimides using nickel(II) oxide surface-modified titanium dioxide catalyst

Article abstract of DOI:10.1021/jo502901h

Surface-modified titanium dioxides by highly dispersed NiO particles have an extended absorption in the visible light region and a reduced hole-electron pair recombination than unmodified TiO₂. They have now been successfully applied as highly active heterogeneous photocatalysts in the visible light mediated direct cyclization of tertiary anilines with maleimides to give tetrahydroquinoline products in moderate to high yields at ambient temperature. In contrast with unmodified titanium dioxide catalysts that are conventionally used in a stoichiometric amount in combination with UVA light, only a catalytic amount (1 mol %) of the surface-modified TiO₂ catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-metal complexes such as Ru(bpy)₃Cl₂ or Ir(ppy)₂(dtbbpy)PF₆, advantages of these surface-modified titanium dioxides as photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without significant decay of catalytic activity.

Full text of DOI:10.1021/jo502901h

Article
pubs.acs.org/joc
Visible Light Mediated Cyclization of Tertiary Anilines with
Maleimides Using Nickel(II) Oxide Surface-Modified Titanium Dioxide
Catalyst
Jian Tang,† Gunter Grampp,‡ Yun Liu,§ Bing-Xiang Wang,∥ Fei-Fei Tao,† Li-Jun Wang,†
̈
Xue-Zheng Liang,† Hui-Quan Xiao,† and Yong-Miao Shen*,†
†Key Laboratory of Clean Dyeing and Finishing Technology of Zhejiang Province, School of Chemistry and Chemical Engineering,
Shaoxing University, Shaoxing 312000, China
‡Physical and Theoretical Chemistry, Graz University of Technology, Stremayrgasse 9/Z2, A-8010 Graz, Austria
§Jiangsu Key Laboratory of Green Synthetic for Functional Materials, School of Chemistry and Chemical Engineering, Jiangsu
Normal University, Xuzhou, Jiangsu 221116, China
∥Jiangsu Key Laboratory of Biofunctional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing
210097, China
S
* Supporting Information
ABSTRACT: Surface-modified titanium dioxides by highly
dispersed NiO particles have an extended absorption in the
visible light region and a reduced hole−electron pair
recombination than unmodified TiO2. They have now been
successfully applied as highly active heterogeneous photo-
catalysts in the visible light mediated direct cyclization of
tertiary anilines with maleimides to give tetrahydroquinoline
products in moderate to high yields at ambient temperature. In
contrast with unmodified titanium dioxide catalysts that are
conventionally used in a stoichiometric amount in combina-
tion with UVA light, only a catalytic amount (1 mol %) of the
surface-modified TiO2 catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-
metal complexes such as Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6, advantages of these surface-modified titanium dioxides as
photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without
significant decay of catalytic activity.
catalyzed organic synthesis in general,5,6 and in C−H bond
INTRODUCTION
■
activation and C−C and C−heteroatom bond formation in
Visible light mediated photoredox catalysis is an effective and
particular,5,7 is still quite limited.
A limiting factor to the application of TiO2 as a photocatalyst is
that it has a band gap of ∼3.2 eV and absorbs chiefly in the UVA
versatile method for inert C−H bond activation and function-
alization.1 Especially, the functionalization of the sp3 C−H bond
adjacent to a tertiary nitrogen atom has attracted increasing
attention in recent years.2 The normally used photocatalysts for
region, while UV light constitutes only 4% of total solar
irradiation. This is also one of the main reasons why titanium
the visible light mediated photoredox reactions are ruthenium or
iridium complexes1 and organic dyes.1c,3 However, as homoge-
dioxide has not gained wide application in organic synthesis as
transition-metal complexes and organic dyes that have their
neous catalysts, these transition-metal complexes and organic
absorption maxima in the visible region of the electromagnetic
spectrum. There have been much effort in recent years to find
dyes suffer from the drawbacks of high cost, difficult recovery, and
an inability to be reused.3
ways to shift the band gap of TiO2 to make it more efficient for
Titanium dioxide (TiO2) as a redox active heterogeneous
photocatalyst has gathered much attention because of its easy
visible light absorption.8 In this respect, modification of TiO2
with metal oxide nanoclusters as recently investigated by Libera
et al.9 and Tada et al.10 has proven to be one of the most effective
means. Tada and co-workers found that surface modification of
TiO2 with such metal oxides as NiO, FeOX, or CuO could greatly
availability, high photochemical and thermal stability, and
nontoxicity. Furthermore, the solid catalyst can be easily
recovered by either filtration or centrifugation and may be
reused, providing remarkable advantages in view of economy,
environmental benignancy, and operational simplicity.4 Despite
the significant advantages of heterogeneous semiconductor
photocatalysts over homogeneous catalysts, their use in photo-
Received: December 22, 2014
© XXXX American Chemical Society
A
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enhance the visible light photocataltyic activity by narrowing the
band gap and reducing the hole−electron pair recombination.
Although these modified titanium dioxides with visible light
response have shown to be highly effective in photocatalytic
degradation of organic wastes, they have not found applications
in photocatalyzed C−C and C−heteroatom bond formation
reactions in organic synthesis. We envision that this narrowing of
the band gap through raising the edge of the valence band, and the
resulting decreased oxidizing ability, would have another
advantage by making them as milder photocatalysts to be used
to catalyze selective organic transformations of synthetic value,
instead of leading to comprehensive bond breaking and profound
degradation of the substrates as often happened when
unmodified titanium dioxide is used as photocatalyst.
Therefore, we decided to investigate the use of this type of
surface-modified TiO2 catalysts in the visible light mediated
functionalization of the sp3 C−H bond adjacent to a tertiary
nitrogen atom with the cyclization reaction of N,N-dimethylani-
line with maleimides to form tetrahydroquinoline products as a
model reaction. This type of transformation has recently been
achieved in thermal reactions using Mn(NO3)211 or CuCl212 as
single electron oxidant and in visible light mediated reaction with
Ru(bpy)3Cl213 as a photocatalyst.14 In this paper, we report the
result of using reusable and inexpensive surface-modified TiO2
with NiO as visible light responsible photocatalyst to carry out
this transformation (Scheme 1).
Figure 1. XRD patterns of (a) P25, (b) P25/NiO(1), (c) P25/NiO(2),
(d) P25/NiO(3), and (e) P25/NiO(4).
(200) plane, showing the formation of a P25/NiO composite,
and with the mass percentage of Ni ions increasing from 2.0% to
14.8%, the peak at 2θ = 43.265° for the P25/NiO successively
enhances. The NiO clusters (<2 nm) are well dispersed on the
surface of the P25 support in P25/NiO, as shown in Figure 2.10
Scheme 1
Figure 2. (a) TEM images of Degussa P25 and (b) P25/NiO with Ni
ions loading amount of 10.6%.
UV−visible absorption spectral measurements (Figure 3)
clearly show that, while TiO2 itself has no significant absorption
in the visible region, the surface-modified catalysts P25/NiO(1),
RESULTS AND DISCUSSION
■
The surface modification of TiO2 was achieved by the
chemisorption−calcination cycle (CCC) technique10 for form-
ing extremely small metal oxide clusters on commercially
available TiO2 Degussa P25. These synthesized photocatalysts
were characterized by means of X-ray powder diffraction (XRD),
high-resolution transmission electron microscopy (HRTEM),
and inductively coupled plasma spectroscopy (ICP). The Ni
loading amount was determined by ICP, and four different P25/
NiO(1), P25/NiO(2), P25/NiO(3), and P25/NiO(4) catalysts
were prepared, with mass percentage of Ni ions loading amounts
of 2.3, 6.5, 10.6, and 14.8%, respectively. Typical NiO crystal
structure can be found in all P25/NiO samples with different Ni
ions loading amounts, as in Figure 1, which can be indexed to the
Figure 3. UV−visible absorption spectra of P25/NiO samples with
varying Ni2+ loading amounts.
B
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P25/NiO(2), P25/NiO(3), and P25/NiO(4) all have extended
absorption in the visible region compared to bare P25, and the
absorbability in the visible region increases with the increasing of
Ni ions loading on the surface of the P25 until the Ni ions loading
reaches 10.6%. The absorption spectra of P25/NiO show
significant band gap narrowing, which is caused by the surface
modification with NiO clusters. This red shift of the modified
TiO2 is induced by the rise in the VB top with nano NiO surface
modification.10f
be too high so that the oxidation ability of the catalyst may be too
weak to induce the redox process with the substrate. Next, we
turn our attention to the effect of the molar ratio of 2a and 1a and
found that, when this ratio was adjusted to 1:1.5 and 1:1.2, the
yield of 3a decreased. The reactions in different solvents were
then examined, and DMF turned out to be the best solvent. We
have further found that, when the reaction was carried out in the
absence of air in an argon atmosphere, no product formation can
be detected (entry 15). Furthermore, the reaction could be
accelerated in an oxygen atmosphere than in the air with a yield
up to 78% (entry 16). For convenience, however, all the reactions
were carried out under air atmosphere. Therefore, we choose the
optimized reaction conditions as irradiating maleimide and N,N-
dimethylaniline (2 equiv) in DMF in the presence of P25/
NiO(3) (referred to as P25/NiO hereinafter) (1 mol %) under
air.
Initially, the reaction between N,N-dimethylaniline (1a) and
N-phenylmaleimide (2a) was chosen for the optimization of
reaction conditions (Table 1). First, we tested the performance of
the four synthesized P25/NiO catalysts. We found that, under
visible light irradiation of a 3W blue LED, these catalysts are
highly active for the reaction between 1a and 2a, and only 1 mol %
of the catalyst is needed for effectively bringing the cyclization
process. Furthermore, when the mass percentage of nickel ions in
the photocatalyst was increased from ∼2% to ∼11%, the product
yield was increased from 48% to 83% (Table 1, entries 2−4).
However, a further increase of the Ni2+ loading amount in the
catalyst had a detrimental effect and led to a decreased yield of 3a
(entry 8). This kind of relationship between the photocatalytic
activity and the NiO loading amount is also found in P25/NiO-
catalyzed photodegradation of organic pollutants such as 2-
naphthol and p-cresol,10a,b where there is always an optimum
NiO loading, beyond which, a further increase of the NiO loading
results in a reversal of the catalytic activity. This phenomenon
shows that, while progressive increasing of NiO loading below the
optimized amount results in band gap narrowing by raising the
valence band edge to lead to increasing visible light absorption
and higher catalytic activity, a further increase of the NiO loading
exceeding the optimal amount would cause the valence band to
The photoreactions of a series of N,N-dimethylanilines 1 and
maleimides 2 with a range of substituents on the benzene ring of 1
and the N atom of 2, respectively, were next examined under the
Table 2. Visible Light Mediated Cyclization of Tertiary
Anilines and Maleimides with P25/NiO as Photocatalyst
a
b
entry
R1
R2
1
R3
2
3
yield/%
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
75
64
89
81
62
67
69
68
85
68
93
86
73
73
77
69
64
86
75
61
a
4-MeOPh
4-MePh
4-FPh
4-ClPh
Me
Table 1. Optimization Studies
3
4
5
6
7
t-Bu
2g
2h
2a
2b
2c
2d
2e
2f
3g
3h
3i
8
Bn
9
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-MeO
2-Me
4-F
Ph
b
entry
catalyst/mol %
molar ratio (2a:1a)
solvent
yield (3a)/%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-MeOPh
4-MePh
4-FPh
4-ClPh
Me
3j
1
2
P25/1.0
1:2
1:2
1:2
1:2
1:1.5
1:1.2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
acetone
DCM
EtOH
NMP
CH3CN
DMSO
DMF
DMF
23
48
54
83
62
43
39
28
29
7
3k
3l
P25/NiO(1)/1.0
P25/NiO(2)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/0.5
P25/NiO(4)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
P25/NiO(3)/1.0
3
3m
3n
3o
3p
3q
3r
4
5
Bn
2h
2a
2a
2a
2a
2a
2c
2e
2f
6
Ph
7
Ph
8
Ph
9
4-Cl
4-Br
4-Br
4-Br
4-Br
4-Br
H
Ph
3s
3t
10
11
12
13
14
15
16
1g
1g
1g
1g
1g
1h
1i
Ph
c
41
18
50
37
4-MePh
4-ClPh
Me
3u
3v
3w
3x
3y
3z
68
d
52
65
45
71
48
Bn
2h
2a
2c
c
ND
Ph
d
78
Ph
H
4-MePh
a
a
Reaction conditions: A mixture of 1a (0.25 mmol), 2a (0.125 mmol),
and metal oxide (1 mol % of 2a) in the solvent (5 mL) was irradiated
Reaction conditions: 1.25 mmol of 1a, 0.625 mmol of 2a, and 1 mol
% P25/NiO, in 25 mL of DMF, irradiation with 3 W blue LED lamp
for 12 h. Yield after chromatographic purification. A secondary
product 4u was also formed in 10% yield. A secondary product 4v
was also formed in 8% yield.
b
b
c
with a 3 W blue LED lamp in the air for 12 h. Determined by HPLC
c
d
(external standard method). Reaction in an argon atmosphere.
d
Reaction in an oxygen atmosphere (1 atm, balloon) for 5 h.
C
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optimized conditions (Table 2). It is seen that the N-alkyl
maleimide and N-aryl maleimide with either an electron-donating
or an electron-withdrawing group on the aryl all reacted well with
N,N-dimethylaniline to give the cyclization products in
satisfactory yields (entries 1−8). Similarly, N,N-dimethylanilines
with either an electron-donating or an electron-withdrawing
substituent at the benzene ring took part in the reaction smoothly
with various N-substituted maleimides 2a−2h, respectively, to
give the products in moderate to high yields (entries 9−26).
Steric effect turned out to be important for the reaction, and the
reaction of 2-methyl-N,N-dimethylaniline with 2a led to a much
lower product yield (64%) than the reaction of 4-methyl-N,N-
dimethylaniline (85%) (entries 17 and 9), indicating an
unfavorable effect of the 2-methyl in 1d to the cyclization
process. At the same time, a methyl group at the CC bond of
the maleimide seemed to have no significant impeding effect on
the cyclization, as shown by the fact that photoinduced reaction
of 4-methyl-N,N-dimethylaniline 1b with N-(chlorophenyl)-2-
methylmaleimide 2i afforded the cyclization product 5 in 82%
yield (Scheme 2). We also found that, in a few cases, the main
Scheme 3
Scheme 4
It is noteworthy that, while the CuCl2/O2 system12 failed to
catalyze the reaction of N,N-diethylaniline 11 with 1a, and
Ru(bpy)3Cl2/visible light system13 gave a pair of diastereoiso-
meric cyclization products (12a/22%, 12b/24%), under our
optimized reaction conditions, only one diastereomer 12a was
selectively formed with a 41% yield (Scheme 5).
Scheme 2
Scheme 5
products (3u and 3v) could further react with maleimide under
the reaction conditions to give the byproducts 4u and 4v (see the
Supporting Information) respectively, leading to a reduction of
the yield of the main products 3 (Table 2, entries 21 and 22).
Control experiments showed that the byproduct 4u can only be
formed by irradiation of N-(4-methylphenyl)maleimide with the
main product 3u in the presence of both P25/NiO catalyst and
oxygen, and no reaction took place between maleimide and 3u
when the irradiation was carried out in the absence of either P25/
NiO or oxygen. The necessity of the photocatalyst clearly
inducates that the byproduct was not formed by direct excitation
of the maleimide, followed by hydrogen abstraction of the excited
maleimide from 3u at the benzylic position and the ensuing
radical pair recombination. Meanwhile, the dependence on
oxygen presence further suggests that the hydrogen abstraction
event at the benzylic position of 3u may be induced by the
hydroperoxy radical (·OOH) formed by protonation of the
superoxide anion radical, which, in turn, is generated by electron
transfer between the excited photocatalyst and ground state
oxygen.15 Subsequent radical addition of the radical from 3u to
maleimide, followed by another H atom abstraction, affords the
byproduct 4u (Scheme 6).
The remarkably high catalytic activity of the P25/NiO catalyst
is also manifested by the result of a solar light induced reaction of
1a with 2a under otherwise the same conditions. This experiment
was carried out on a clear day (Oct. 25, 2014) on a balcony at
Shaoxing University (30°00′ north latitude and 120°34′ east
longitude, 11 m above the sea level). It was found that the
reaction proceeded swiftly under solar irradiation and it took only
2 h (from 12 at noon to 14 p.m., local time) to reach a completion
to give the product 3a in 70% yield.
After studying the scope of the reaction, we examined the
recycling of the surface-modified TiO2 photocatalyst. Exper-
imentally, the catalyst is easily removed from the system after
reaction by a simple centrifugal separation (see the Supporting
Information, Figure 2s) and the catalyst was reused without
further treatment (Table 3). Remarkably, we have found that the
photocatalyst could be efficiently recycled in nine consecutive
catalytic cycles without significant loss of reactivity and
selectivity, indicating the efficiency of P25/NiO as a visible
light photocatalyst for this reaction.
In order to get information about the catalyst structure before
and after use in the photoredox oxidative cyclization reaction, we
examined the P25/NiO catalyst by transmission electron
microscopy (TEM). From these measurements, no significant
morphological changes with regard to the shape and structure of
the catalyst were found (Figure 4). This explained why the
catalyst can be recycled for several times without loss of activity.
On the basis of these experimental results, a plausible reaction
pathway for this visible light induced oxidative cyclization
It was envisaged that a doubly annelated product 7 might be
conveniently synthesized from commercially available 1,2-
bismaleimidoethane 6 and N,N-dimethylaniline 1a (Scheme 3).
However, when 1a (4 eqiv) and 6 (1 eqiv) were irradiated for 12 h
under the optimized conditions, only a monocyclized compound
8 (see the Supporting Information) was formed. The same
situation happened in the reaction of 1a with 4,4′-methylenebis-
(N-phenylmaleimide) 9 (Scheme 4).
D
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a
Table 3. Catalyst Recycling in the Visible Light Mediated Direct Cyclization Reaction
cycle
1
2
3
4
5
6
7
8
9
b
yield of 3a (%)
80
83
82
79
81
78
75
79
78
a
Reaction conditions: 0.25 mmol of 1a, 0.125 mmol of 2a, and 1 mol % of P25/NiO, in 5 mL of DMF, irradiation with 3 W blue LED lamp in the air
b
for 12 h. Determined by HPLC (external standard method).
hydrogen atom from N,N-dimethylaniline to contribute another
pathway to the formation of the α-aminoalkyl radical B.13
CONCLUSION
■
In summary, we have used surface-modified titanium dioxide
(TiO2/NiO) as an efficient visible light responsive photocatalyst
in sp3 C−H bond activation in tertiary amines to perform the
direct cyclization between a wide range of tertiary anilines with
maleimides. To our knowledge, this is the first time that surface-
modified TiO2 is used beyond an environmental purpose to
selectively catalyze synthetic organic reactions. In contrast to
previously reported TiO2 catalyzed organic reactions that
typically use a stoichiometric amount ofconventional unmodified
TiO2 (Degussa P25) in combination with UVA light, the
extended absorption in the visible light region and the reduced
hole−electron pair recombination of the NiO surface-modified
catalysts allow them to be used in a catalytic amount as small as 1
mol % together with visible light irradiation to achieve high
catalytic efficiency. Furthermore, the high thermal and photo-
chemical stability of these modified photocatalysts enables them
to be easily recovered by centrifugation and to be reused for at
least nine times without significant decay of the catalytic activity.
Figure 4. TEM analyses of P25/NiO before use (a) and after use for nine
times (b).
reaction catalyzed by surface-modified TiO2 is proposed in
Scheme 6. Single electron transfer (SET) from the tertiary amine
Scheme 6. Proposed Reaction Mechanism for the Photoredox
of Tertiary Anilines and Maleimides with Surface-Modified
TiO2
EXPERIMENTAL SECTION
■
General Methods. All reagents were used without further
purification. All solvents were dried according to standard procedures.
Melting points are uncorrected. 1H and 13C NMR spectra were recorded
at 400 and 100 MHz, using CDCl3 as solvent. IR spectra were taken with
an FT-IR spectrometer. Mass spectra were obtained using ESI
techniques. For X-ray crystallographic analysis, the X-ray diffraction
intensities and the unit cell parameters were determined on a CCD
diffractometer employing graphite-monochromated (Mo−Kα) radia-
tion (λ = 0.71073 Å).
Synthesis of P25/NiO Catalyst.10e 1 g of P25 particles had been
added to of a Ni(acac)2(H2O)2 solution (solvent: 100 mL of ethanol/n-
hexane = 3:17 v/v); they were subjected to mechanical agitation for 24 h
at 298 K. The concentration of the Ni(acac)2(H2O)2 was maintained at
6.5 × 10−4 mol/L. The resulting samples were washed repeatedly with
the same solvent to remove physisorbed complexes and then dried,
followed by heating in air at 773 K for 1 h. The complex adsorption and
the subsequent heating were repeated to increase the Ni loading amount.
General Procedure for the Visible Light Mediated Cyclization
of Tertiary Anilines and Maleimides Reaction. In a vial (16 × 125
mm, 10 mL), P25/NiO (1 mol %), tertiary anilines 1 (1.25 mmol), and
maleimides 2 (0.625 mmol) were dissolved in 25 mL DMF. The reaction
mixture was stirred, and the vial was placed beside a 3 W blue LED lamp
with an edge-to-edge distance of 2 cm for irradiation. After the reaction
was completed, the catalyst was recovered by a simple centrifugal
separation, and then the reaction mixture was poured into 50 mL of
water. The aqueous layer was extracted with EtOAc (15 mL × 3). The
combined organic layers were dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the crude mixture was
directly charged on silica gel and purified by column chromatography
with petroleum ether/ethyl acetate as eluents (gradient elution).
(3aS*,9bR*)-5-Methyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-pyrrolo-
[3,4-c]quinoline-1,3(2H)-dione (3a). Yield (137.0 mg, 75%). White
solid: Rf = 0.41 (petroleum ether/ethyl acetate 6:1); mp 202−204 °C;13
1H NMR (400 MHz, CDCl3) δ 2.84 (s, 3H), 3.13 (dd, 1H, J = 11.6, 4.4
1 to the hole of the excited semiconductor catalyst leads to the
amine cation radical A, while SET from the conducting band of
the catalyst to ground state oxygen generates superoxide anion
radical. Proton transfer from the amine cation radical A to the
superoxide anion radical gives the α-aminoalkyl radical B and
hydroperoxy radical. Radical addition of B to the maleimide,
followed by intramolecular cyclization, leads to radical C. SET
oxidation of C by oxygen or by the excited semiconductor catalyst
to a carbocation, followed by deprotonation, furnishes the
product. Meanwhile, the ·OOH radical may also abstract a
Hz), 3.53−3.57 (m, 1H), 3.62 (dd, 1H, J = 11.6, 2.6 Hz), 4.17 (d, 1H, J =
E
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9.6 Hz), 6.75 (d, 1H, J = 8.4 Hz), 6.91 (t, 1H, J = 7.6 Hz), 7.22−7.28 (m,
3H), 7.36 (t, 1H, J = 7.2 Hz), 7.43 (t, 2H, J = 7.6 Hz), 7.53 (d, 1H, J = 7.6
Hz).
for data collection 2.50 ≤ θ ≤ 26.65°, 5398 measured reflections, 2358
independent reflections, 1518 reflections with I > 2σ(I), Rint = 0.0436,
157 refinable parameters, R[F2 > 2σ(F2)] = 0.0433, wR2 (F2) = 0.0921.
(3aS*,9bR*)-2-(tert-Butyl)-5-methyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3g). Yield (117.4 mg, 69%).
White solid: Rf = 0.43 (petroleum ether/ethyl acetate 6:1); mp 76−78
°C; IR (KBr) ν 2918, 1702, 1577, 1444, 1340, 1162, 1134, 754, 650
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H), 2.80 (s, 3H), 3.00
(dd, 1H, J = 11.2, 4.4 Hz), 3.21 (ddd, 1H, J = 7.6, 4.4, 3.0 Hz), 3.43 (dd,
1H, J = 11.4, 3.0 Hz), 3.83 (d, 1H, J = 9.6 Hz), 6.71 (d, 1H, J = 8.0 Hz),
6.88 (td, 1H, J = 7.6, 1.2 Hz), 7.21 (td, 1H, J = 8.2, 1.4 Hz), 7.44 (d, 1H, J
= 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 28.3, 39.4, 42.1, 43.1, 50.9,
58.7, 112.3, 119.2, 119.3, 128.4, 130.3, 148.3, 177.9, 179.6; ESI-MS M/Z
[M + H]+: Calcd for C16H20N2O2: 273.16, found 273.17. EA found: C
70.53, H 7.44, N 10.32. Requires: C 70.56, H 7.40, N 10.29.
(3aS*,9bR*)-2-(4-Methoxyphenyl)-5-methyl-3a,4,5,9b-tetrahy-
dro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3b). Yield (128.9 mg,
64%). White solid: Rf = 0.38 (petroleum ether/ethyl acetate 4:1); mp
222−224 °C; IR (KBr) ν 2960, 1783, 1712, 1577, 1511, 1439, 1251,
1201, 1163, 833, 620 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.82 (s, 3H),
3.09 (dd, 1H, J = 11.6, 4.4 Hz), 3.50 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.58
(dd, 1H, J = 11.6, 2.8 Hz), 3.78 (s, 3H), 4.12 (d, 1H, J = 9.6 Hz), 6.73 (dd,
1H, J = 8.4, 0.8 Hz), 6.88−6.94 (m, 3H), 7.16 (dt, 2H, J = 5.4, 3.4 Hz),
7.20−7.25 (m, 1H), 7.51 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 39.5, 42.1, 43.5, 50.7, 55.5, 112.6, 114.3, 118.7, 119.7, 124.6,
127.6, 128.7, 130.3, 148.5, 159.4, 176.0, 178.0; ESI-MS M/Z [M + H]+
Calcd for C19H18N2O3 323.14, found 323.17. EA found: C 70.71, H 5.68,
N 8.62. Requires: C 70.79, H 5.63, N 8.69.
(3aS*,9bR*)-2-Benzyl-5-methyl-3a,4,5,9b-tetrahydro-1H-pyrrolo-
[3,4-c]quinoline-1,3(2H)-dione (3h). Yield (130.2 mg, 68%). White
solid: Rf = 0.42 (petroleum ether/ethyl acetate 5:1); mp 126−128 °C; IR
(KBr) ν 2949, 2866, 1770, 1701, 1570, 1560, 1430, 1161, 998, 699, 628
cm−1; 1H NMR (400 MHz, CDCl3) δ 2.77 (s, 3H), 3.00 (dd, 1H, J =
11.6, 4.4 Hz), 3.31 (ddd, 1H, J = 7.6, 4.8, 2.8 Hz), 3.46 (dd, 1H, J = 11.6,
2.8 Hz), 3.94 (d, 1H, J = 9.6 Hz), 4.62 (q, 2H, J = 14.3 Hz), 6.69 (d, 1H, J
= 8.0 Hz), 6.87 (td, 1H, J = 7.6, 1.2 Hz), 7.17−7.29 (m, 6H), 7.44 (d, 1H,
J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 39.3, 42.0, 42.7, 43.6, 50.7,
112.4, 118.8, 119.6, 127.7, 128.3, 128.5, 130.2, 135.5, 148.4, 176.4, 178.3;
ESI-MS M/Z [M + H]+ Calcd for C19H18N2O2 307.14, found 307.25. EA
found: C 74.51, H 5.95, N 9.12. Requires: C 74.49, H 5.92, N 9.14.
(3aS*,9bR*)-5,8-Dimethyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3i). Yield (162.8 mg, 85%).
White solid: Rf = 0.48 (petroleum ether/ethyl acetate 7:1); mp 193−195
°C;13 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.80 (s, 3H), 3.06 (dd,
1H, J = 11.2, 4.4 Hz), 3.52 (ddd, 1H, J = 6.8, 4.4, 2.6 Hz), 3.59 (dd, 1H, J =
11.2, 2.6 Hz), 4.12 (d, 1H, J = 9.6 Hz), 6.65 (d, 1H, J = 8.0 Hz), 7.04 (dd,
1H, J = 8.0, 2.0 Hz), 7.26−7.28 (m, 2H), 7.33−7.40 (m, 2H), 7.41−7.45
(m, 2H).
(3aS*,9bR*)-2-(4-Methoxyphenyl)-5,8-dimethyl-3a,4,5,9b-tetra-
hydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3j). Yield (143.0
mg, 68%). White solid: Rf = 0.31 (petroleum ether/ethyl acetate 5:1);
mp 180−182 °C;13 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.80 (s,
3H), 3.05 (dd, 1H, J = 11.2, 4.4 Hz), 3.50 (ddd, 1H, J = 9.5, 4.3, 2.6 Hz),
3.58 (dd, 1H, J = 11.6, 2.8 Hz), 3.80 (s, 3H), 4.10 (d, 1H, J = 9.6 Hz), 6.65
(d, 1H, J = 8.4 Hz), 6.92−6.95 (m, 2H), 7.04 (dd, 1H, J = 8.4, 2.0 Hz),
7.16−7.20 (dt, 2H, J = 5.6, 3.6 Hz), 7.34 (d, 1H, J = 1.6 Hz).
(3aS*,9bR*)-5,8-Dimethyl-2-(p-tolyl)-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3k). Yield (186.2 mg, 93%).
White solid: Rf = 0.47 (petroleum ether/ethyl acetate 6:1); mp 207−209
°C; IR (KBr) ν 2955, 1713, 1577, 1511, 1444, 1195, 1164, 815, 650
cm−1; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.35 (s, 3H), 2.79 (s,
3H), 3.03 (dd, 1H, J = 11.6, 4.4 Hz), 3.49 (ddd, 1H, J = 6.8, 4.4, 2.8 Hz),
3.56 (dd, 1H, J = 11.4, 2.6 Hz), 4.09 (d, 1H, J = 9.6 Hz), 6.64 (d, 1H, J =
8.4 Hz), 7.03 (dd, 1H, J = 8.4, 1.6 Hz), 7.13 (d, 2H, J = 8.4 Hz), 7.22 (d,
2H, J = 8.0 Hz), 7.33 (d, 1H, J = 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ
20.5, 21.2, 39.6, 42.2, 43.6, 51.0, 112.5, 118.6, 126.2, 129.0, 129.2, 129.4,
129.6, 130.8, 138.5, 146.4, 176.0, 178.0; ESI-MS M/Z [M + H]+ Calcd
for C20H20N2O2 321.16, found 321.25. EA found: C 74.93, H 6.31, N
8.75. Requires: C 74.98, H 6.29, N 8.74.
(3aS*,9bR*)-2-(4-Fluorophenyl)-5,8-dimethyl-3a,4,5,9b-tetrahy-
dro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3l). Yield (174.3 mg,
86%). White solid: Rf = 0.41 (petroleum ether/ethyl acetate 7:1); mp
157−159 °C;13 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.79 (s,
3H), 3.03 (dd, 1H, J = 11.4, 4.2 Hz), 3.50 (ddd, 1H, J = 9.6, 4.2, 2.6 Hz),
3.57 (dd, 1H, J = 11.4, 2.6 Hz), 4.10 (d, 1H, J = 9.2 Hz), 6.65 (d, 1H, J =
8.4 Hz), 7.04 (dd, 1H, J = 8.4, 1.6 Hz), 7.08−7.12 (m, 2H), 7.24−7.27
(m, 2H), 7.32 (d, 1H, J = 1.6 Hz).
(3aS*,9bR*)-5-Methyl-2-(p-tolyl)-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3c). Yield (155.1 mg, 89%).
White solid: Rf = 0.43 (petroleum ether/ethyl acetate 7:1); mp 212−214
°C; IR (KBr) ν 3000, 1713, 1576, 1423, 1135, 951, 649, 619 cm−1; 1H
NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.83 (s, 3H), 3.11 (dd, J = 11.2,
4.4 Hz, 1H), 3.50−3.54 (m, 1H), 3.60 (dd, 1H, J = 11.6, 2.8 Hz), 4.14 (d,
1H, J = 9.6 Hz), 6.74 (dd, 1H, J = 8.4, 0.4 Hz), 6.90 (td, 1H, J = 7.2, 1.0
Hz), 7.12−7.14 (m, 2H), 7.21−7.25 (m, 3H), 7.52 (d, 1H, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3) δ 21.2, 39.4, 42.1, 43.6, 50.7, 112.5, 118.6,
119.6, 126.2, 128.7, 129.3, 129.7, 130.3, 138.6, 148.5, 175.9, 177.8; ESI-
MS M/Z [M + H]+ Calcd for C19H18N2O2 307.14, found 307.17. EA
found: C 74.47, H 5.95, N 9.12. Requires: C 74.49, H 5.92, N 9.14.
(3aS*,9bR*)-2-(4-Fluorophenyl)-5-methyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3d). Yield (157.1 mg,
81%). White solid: Rf = 0.39 (petroleum ether/ethyl acetate 6:1); mp
172−174 °C; IR (KBr) ν 2922, 1712, 1577, 1509, 1400, 1199, 1151,
1043, 813, 757, 619 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H),
3.10 (dd, 1H, J = 11.6, 4.4 Hz), 3.52 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.60
(dd, 1H, J = 11.4, 2.6 Hz), 4.15 (d, 1H, J = 9.6 Hz), 6.74 (d, 1H, J = 8.4
Hz), 6.91 (td, 1H, J = 7.4, 0.8 Hz), 7.07−7.13 (m, 2H), 7.21−7.28 (m,
3H), 7.51 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 38.4, 41.1,
42.6, 49.6, 111.6, 114.9, 115.1, 117.4, 118.7, 127.2, 127.7, 129.3, 147.5,
159.8, 162.3, 174.7, 176.7; ESI-MS M/Z [M + H]+ Calcd for
C18H15FN2O2 311.12, found 311.25. EA found: C 69.61, H 4.91, N
9.01. Requires: C 69.67, H 4.87, N 9.03.
(3aS*,9bR*)-2-(4-Chlorophenyl)-5-methyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3e). Yield (126.6 mg,
62%). White solid: Rf = 0.35 (petroleum ether/ethyl acetate 5:1); mp
188−190 °C; IR (KBr) ν 2861, 1783, 1713, 1575, 1493, 1398, 1201,
1018, 757, 619 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H), 3.10
(dd, 1H, J = 11.4, 4.2 Hz), 3.53 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.60 (dd,
1H, J = 11.4, 2.6 Hz), 4.15 (d, 1H, J = 9.6 Hz), 6.74 (dd, 1H, J = 8.2, 0.6
Hz), 6.91 (td, 1H, J = 7.4, 1.1 Hz), 7.22−7.26 (m, 3H), 7.37−7.40 (m,
2H), 7.51 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 39.5, 42.1,
43.6, 50.6, 112.6, 118.4, 119.8, 127.6, 128.8, 129.2, 130.3, 130.4, 134.2,
148.5, 175.5, 177.5; ESI-MS M/Z [M + H]+ Calcd for C18H15ClN2O2
327.09, found 327.08. EA found: C 66.18, H 4.66, N 8.53. Requires: C
66.16, H 4.63, N 8.57.
(3aS*,9bR*)-2,5-Dimethyl-3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-
c]quinoline-1,3(2H)-dione (3f). Yield (116.6 mg, 67%). White solid: Rf
= 0.41 (petroleum ether/ethyl acetate 5:1); mp 170−172 °C; IR (KBr) ν
1
2869, 1778, 1698, 1577, 1498, 1437, 1126, 762 cm−1; H NMR (400
MHz, CDCl3) δ 2.79 (s, 3H), 2.98 (s, 3H), 3.03 (dd, 1H, J = 11.6, 4.4
Hz), 3.36 (ddd, 1H, J = 6.8, 4.4, 2.4 Hz), 3.53 (dd, 1H, J = 11.6, 2.4 Hz),
4.00 (d, 1H, J = 9.6 Hz), 6.69 (d, 1H, J = 8.4 Hz), 6.89 (td, 1H, J = 7.6, 1.2
Hz), 7.21 (td, 1H, J = 7.6, 1.2 Hz), 7.47 (d, 1H, J = 7.6 Hz); 13C NMR
(100 MHz, CDCl3,) δ 25.4, 39.4, 42.0, 43.6, 50.5, 112.5, 118.7, 119.6,
128.6, 130.2, 148.4, 176.8, 178.8; ESI-MS M/Z [M + H]+ Calcd for
C13H14N2O2 231.11, found 231.08. EA found: C 67.83, H 6.18, N 12.13.
Requires: C 67.81, H 6.13, N 12.17.
X-ray Structure Analysis. C13H14N2O2 M = 230.26. Orthorhombic,
space group P2(1)2(1)2(1), a = 7.9707(19) Å, b = 8.873(2) Å, c =
16.273(4) Å, α = 90°, β = 90°, γ = 90°, V = 1150.9(5) Å, Z = 4, Dc = 1.329
g cm−3, F(000) = 488.0, absorption coefficient 0.091 mm−1, scan range
(3aS*,9bR*)-2-(4-Chlorophenyl)-5,8-dimethyl-3a,4,5,9b-tetrahy-
dro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3m). Yield (155.5 mg,
73%). White solid: Rf = 0.36 (petroleum ether/ethyl acetate 5:1); mp
178−180 °C;13 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.80 (s,
3H), 3.04 (dd, 1H, J = 11.4, 4.2 Hz), 3.51 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz),
3.58 (dd, 1H, J = 11.4, 2.6 Hz), 4.11 (d, 1H, J = 9.6 Hz), 6.65 (d, 1H, J =
F
DOI: 10.1021/jo502901h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
8.4 Hz), 7.04 (dd, 1H, J = 8.0, 2.0 Hz), 7.23−7.26 (m, 2H), 7.33 (d, 1H, J
= 2.0 Hz), 7.37−7.40 (m, 2H).
(3aS*,9bR*)-2,5,8-Trimethyl-3a,4,5,9b-tetrahydro-1H-pyrrolo-
[3,4-c]quinoline-1,3(2H)-dione (3n). Yield (142.0 mg, 73%). White
solid: Rf = 0.43 (petroleum ether/ethyl acetate 5:1); mp 173−176 °C;12
1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.76 (s, 3H), 2.95−2.99 (m,
4H), 3.34 (ddd, 1H, J = 6.6, 4.2, 2.2 Hz), 3.51 (dd, 1H, J = 11.4, 2.2 Hz),
3.96 (d, 1H, J = 9.6 Hz), 6.61 (d, 1H, J = 8.4 Hz), 7.01 (dd, 1H, J = 8.2, 1.8
Hz), 7.29 (d, 1H, J = 1.6 Hz).
C19H17BrN2O2 385.06, found 385.17. Found: C 59.20, H 4.43, N 7.24.
Requires: C 59.23, H 4.45, N 7.27.
(3aS*,9bR*)-8-Bromo-2-(4-chlorophenyl)-5-methyl-3a,4,5,9b-tet-
rahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3v). Yield (131.8
mg, 52%). White solid: Rf = 0.32 (petroleum ether/ethyl acetate 5:1);
mp 178−180 °C; IR (KBr) ν 3435, 1716, 1639, 1575, 1494, 1414, 1176,
811, 646 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.81 (s, 3H), 3.10 (dd,
1H, J = 11.6, 4.4 Hz), 3.53 (ddd, 1H, J = 9.6, 4.2, 2.6 Hz), 3.60 (dd, 1H, J =
11.4, 2.6 Hz), 4.10 (d, 1H, J = 9.6 Hz), 6.61 (d, 1H, J = 8.8 Hz), 7.23−
7.26 (m, 2H), 7.32 (dd, 1H, J = 8.8, 2.4 Hz), 7.39−7.42 (m, 2H), 7.63
(dd, 1H, J = 2.2, 0.6 Hz); 13C NMR (100 MHz, CDCl3) δ 39.5, 41.8, 43.3,
50.3, 111.8, 114.3, 120.2, 127.5, 129.2, 130.3, 131.6, 132.7, 134.4, 147.5,
174.9, 177.0; ESI-MS M/Z [M + H]+ Calcd for C18H14BrClN2O2
405.00, found 405.00. EA found: C 53.25, H 3.43, N 6.88. Requires: C
53.29, H 3.48, N 6.91.
(3aS*,9bR*)-8-Bromo-2,5-dimethyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3w). Yield (125.1 mg, 65%).
White solid: Rf = 0.33 (petroleum ether/ethyl acetate 5:1); mp 188−190
°C; IR (KBr) ν 2872, 1770, 1692, 1572, 1494, 1432, 1320, 1121, 1024,
810, 625 cm−1; 1HNMR (400 MHz, CDCl3) δ 2.78 (s, 3H), 2.99 (s, 3H),
3.02 (dd, 1H, J = 11.6, 4.4 Hz), 3.21 (ddd, 1H, J = 7.2, 4.4, 2.4 Hz), 3.53
(dd, 1H, J = 11.6, 2.4 Hz), 3.95 (d, 1H, J = 9.6 Hz), 6.56 (d, 1H, J = 8.8
Hz), 7.28 (dd, 1H, J = 8.8, 2.4 Hz), 7.59 (d, 1H, J = 2.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 25.5, 39.4, 41.7, 43.3, 50.2, 111.6, 114.2, 120.6,
131.3, 132.6, 147.4, 176.1, 178.3 ; ESI-MS M/Z [M-H]− Calcd for
C13H13BrN2O2 307.01, found 307.08. EA found: C 50.45, H 4.28, N 9.03.
Requires: C 50.50, H 4.24, N 9.06.
(3aS*,9bR*)-2-Benzyl-8-bromo-5-methyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3x). Yield (108.4 mg,
45%). White solid: Rf = 0.37 (petroleum ether/ethyl acetate 5:1); mp
148−150 °C; IR (KBr) ν 2925, 1699, 1578, 1495, 1438, 1340, 1145, 810,
716, 620 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.77 (s, 3H), 3.03 (dd,
1H, J = 11.6, 4.8 Hz), 3.35 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.47 (dd, 1H, J =
11.6, 2.8 Hz), 3.92 (d, 1H, J = 9.6 Hz), 4.64 (q, 2H, J = 14.1 Hz), 6.57 (d,
1H, J = 8.4 Hz), 7.26−7.30 (m, 6H), 7.57 (d, 1H, J = 2.4, 0.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 39.4, 41.7, 42.9, 43.4, 50.5, 111.7, 114.1,
120.7, 127.9, 128.4, 128.6, 131.3, 132.7, 135.4, 147.5, 175.2, 177.9; ESI-
MS M/Z [M + H]+ Calcd for C19H17BrN2O2 385.06, found 385.17. EA
found: C 59.20, H 4.49, N 7.25. Requires: C 59.23, H 4.45, N 7.27.
(3aS*,9bR*)-5-Ethyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-pyrrolo-
[3,4-c]quinoline-1,3(2H)-dione (3y). Yield (135.9 mg, 71%). White
solid: Rf = 0.43 (petroleum ether/ethyl acetate 6:1); mp 196−198 °C;13
1H NMR (400 MHz, CDCl3) δ 1.17 (t, 3H, J = 7.0 Hz), 3.16 (dd, 1H, J =
(3aS*,9bR*)-2-Benzyl-5,8-dimethyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3o). Yield (154.2 mg, 77%).
White solid: Rf = 0.44 (petroleum ether/ethyl acetate 6:1); mp 120−122
°C;13 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.76 (s, 3H), 2.98 (dd,
1H, J = 11.4, 4.6 Hz), 3.34 (ddd, 1H, J = 7.2, 4.8, 2.8 Hz), 3.47 (dd, 1H, J =
10.8, 2.6 Hz), 3.95 (d, 1H, J = 9.6 Hz), 4.65 (q, 2H, J = 14.7 Hz), 6.62 (d,
1H, J = 8.0 Hz), 7.02 (dd, 1H, J = 8.2, 2.2 Hz), 7.23−7.32 (m, 6H).
(3aS*,9bR*)-8-Methoxy-5-methyl-2-phenyl-4,5-dihydro-2H-
pyrrolo[3,4-c]quinoline-1,3(3aH,9bH)-dione (3p). Yield (139.0 mg,
69%). White solid: Rf = 0.31 (petroleum ether/ethyl acetate 4:1); mp
164−166 °C;13 1H NMR (400 MHz, CDCl3) δ 2.79 (s, 3H), 3.03 (dd,
1H, J = 11.4, 4.2 Hz), 3.51 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.56 (dd, 1H, J =
11.2, 2.8 Hz), 3.79 (s, 3H), 4.12 (d, 1H, J = 9.6 Hz), 6.68 (d, 1H, J = 9.2
Hz), 6.81 (dd, 1H, J = 9.0, 3.0 Hz), 7.13 (d, 1H, J = 2.8 Hz), 7.26−7.28
(m, 2H), 7.35 (tt, 1H, J = 7.4, 1.2 Hz), 7.40−7.45 (m, 2H).
(3aS*,9bR*)-5,6-Dimethyl-2-phenyl-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3q). Yield (122.5 mg, 64%).
White solid: Rf = 0.45 (petroleum ether/ethyl acetate 5:1); mp 119−120
°C; IR (KBr) ν 2935, 1712, 1577, 1442, 1384, 1173, 766, 650 cm−1; 1H
NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 2.76 (s, 3H), 3.40 (dd, 1H, J =
13.4, 6.6 Hz), 3.50−3.59 (m, 2H), 4.18 (d, 1H, J = 8.8 Hz), 7.08 (t, 1H, J
= 7.4 Hz), 7.16 (d, 1H, J = 7.2 Hz), 7.25−7.28 (m, 2H), 7.39 (tt, 1H, J =
7.4, 1.2 Hz), 7.44−7.49 (m, 2H), 7.58 (d, 1H, J = 7.6 Hz); 13C NMR (100
MHz, CDCl3,) δ 17.7, 38.9, 41.6, 42.0, 51.3, 122.9, 123.8, 126.3, 128.4,
128.7, 129.2, 130.5, 132.0, 132.8, 146.7, 175.8, 177.8; ESI-MS M/Z [M +
H]+ Calcd for C19H18N2O2 307.14, found 307.25. EA found: C 74.46, H
5.97, N 9.16. Requires: C 74.49, H 5.92, N 9.14.
(3aS*,9bR*)-8-Fluoro-5-methyl-2-phenyl-4,5-dihydro-2H-
pyrrolo[3,4-c]quinoline-1,3(3aH,9bH)-dione (3r). Yield (166.8 mg,
86%). White solid: Rf = 0.34 (petroleum ether/ethyl acetate 4:1); mp
172−174 °C;13 1H NMR (400 MHz, CDCl3) δ 2.81 (s, 3H), 3.08 (dd,
1H, J = 11.2, 4.4 Hz), 3.53 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.59 (dd, 1H, J =
11.4, 2.6 Hz), 4.12 (d, 1H, J = 9.6 Hz), 6.67 (dd, 1H, J = 9.0, 4.6 Hz), 6.94
(td, 1H, J = 8.8, 3.2 Hz), 7.25−7.29 (m, 3H), 7.37 (tt, 1H, J = 7.4, 1.4 Hz),
7.41−7.46 (m, 2H).
(3aS*,9bR*)-8-Chloro-5-methyl-2-phenyl-4,5-dihydro-2H-
pyrrolo[3,4-c]quinoline-1,3(3aH,9bH)-dione (3s). Yield (153.2 mg,
75%). White solid: Rf = 0.36 (petroleum ether/ethyl acetate 4:1); mp
157−159 °C;13 1H NMR (400 MHz, CDCl3) δ 2.82 (s, 3H), 3.10 (dd,
1H, J = 11.2, 4.4 Hz), 3.53 (ddd, 1H, J = 7.0, 4.2, 2.8 Hz), 3.61 (dd, 1H, J =
11.6, 2.8 Hz), 4.11 (d, 1H, J = 9.6 Hz), 6.66 (d, 1H, J = 8.8 Hz), 7.18 (dd,
1H, J = 8.8, 2.4 Hz), 7.25−7.28 (m, 2H), 7.35−7.39 (m, 1H), 7.42−7.46
(m, 2H), 7.51 (d, 1H, J = 2.0 Hz).
(3aS*,9bR*)-8-Bromo-5-methyl-2-phenyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3t). Yield (141.5 mg, 61%).
White solid: Rf = 0.33 (petroleum ether/ethyl acetate 5:1); mp 159−161
°C;13 1H NMR (400 MHz, CDCl3) δ 2.81 (s, 3H), 3.10 (dd, 1H, J = 11.2,
4.2 Hz), 3.52 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.60 (dd, 1H, J = 11.2, 2.8
Hz), 4.09 (d, 1H, J = 9.6 Hz), 6.60 (d, 1H, J = 8.8 Hz), 7.24−7.27 (m,
2H), 7.31 (dd, 1H, J = 8.4, 2.4 Hz), 7.34−7.38 (m, 1H), 7.41−7.45 (m,
2H), 7.63 (dd, 1H, J = 2.2, 0.6 Hz).
(3aS*,9bR*)-8-Bromo-5-methyl-2-(p-tolyl)-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3u). Yield (163.7 mg,
68%). White solid: Rf = 0.45 (petroleum ether/ethyl acetate 6:1); mp
195−196 °C; IR (KBr) ν 2960, 1709, 1574, 1495, 1411, 1321, 1179, 813,
618 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.82 (s, 3H), 3.10
(dd, 1H, J = 11.6, 4.4 Hz), 3.52 (ddd, 1H, J = 7.2, 4.4, 2.8 Hz), 3.60 (dd,
1H, J = 11.6, 2.8 Hz), 4.09 (d, 1H, J = 9.6 Hz), 6.60 (d, 1H, J = 8.8 Hz),
7.12−7.15 (m, 2H), 7.23 (d, 2H, J = 8.4 Hz), 7.31 (dd, 1H, J = 8.8, 2.4
Hz), 7.64 (dd, 1H, J = 2.4, 0.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.3,
39.5, 41.8, 43.3, 50.4, 111.7, 114.2, 120.5, 126.1, 129.2, 129.7, 131.5,
132.8, 138.8, 147.5, 175.3, 177.4; ESI-MS M/Z [M + H]+ Calcd for
11.8, 4.2 Hz), 3.22−3.78 (m, 2H), 3.53 (ddd, 1H, J = 7.2, 4.4, 3.2 Hz),
3.64 (dd, 1H, J = 11.6, 2.8 Hz), 4.13 (d, 1H, J = 9.6 Hz), 6.77 (d, 1H, J =
8.4 Hz), 6.85 (td, 1H, J = 7.2, 0.8 Hz), 7.18−7.26 (m, 3H), 7.33−7.37(m,
1H) 7.40−7.44 (m, 2H), 7.51 (d, 1H, J = 7.4 Hz).
(3aS*,9bR*)-5-Phenyl-2-(p-tolyl)-3a,4,5,9b-tetrahydro-1H-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (3z). Yield (110.5 mg, 48%).
White solid: Rf = 0.38 (petroleum ether/ethyl acetate 5:1); mp 196−198
°C; IR (KBr) ν 2922, 1712, 1576, 1397, 1334, 1276, 1200, 816, 754, 698,
623 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 3.64 (ddd, 1H, J
= 7.2, 4.4, 2.8 Hz), 3.70 (dd, 1H, J = 11.8, 4.6 Hz), 4.19 (dd, 1H, J = 11.8,
3.0 Hz), 4.22 (d, 1H, J = 9.2 Hz), 6.77 (dd, 1H, J = 8.4, 1.2 Hz), 6.96 (td,
1H, J = 7.4, 1.2 Hz), 7.04 (dt, 2H, J = 4.0, 2.2 Hz), 7.07−7.11 (m, 4H),
7.21 (d, 2H, J = 8.0 Hz), 7.30−7.35 (m, 2H), 7.59 (d, 1H, J = 6.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.2, 42.4, 44.5, 48.4, 117.3, 120.6, 121.5,
122.9, 123.8, 126.1, 128.3, 129.2, 129.5, 129.7, 130.7, 138.7, 146.2, 146.4,
175.8, 177.2; ESI-MS M/Z [M + H]+ Calcd for C24H20N2O2 369.16,
found 369.25. EA found: C 78.19, H 5.52, N 7.65. Requires: C 78.24, H
5.47, N 7.60.
(3aS*,9bR*)-8-Bromo-9b-((S)-2,5-dioxo-1-(p-tolyl)pyrrolidin-3-
yl)-5-methyl-2-(p-tolyl)-3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]-
quinoline-1,3(2H)-dione (4u). Yield (17.9 mg, 10%). White solid: Rf =
0.32 (petroleum ether/ethyl acetate 3:1); mp 276−278 °C; IR (KBr) ν
2926, 1712, 1573, 1416, 1137, 811, 645, 621 cm−1; 1H NMR (400 MHz,
CDCl3) δ 2.367 (s, 3H), 2.374 (s, 3H), 2.87 (s, 3H), 2.92 (d, 1H, J = 6.4
Hz), 2.98 (d, 1H, J = 9.2 Hz), 3.37 (dd, 1H, J = 12.0, 5.6 Hz), 3.58 (dd,
1H, J = 11.6, 4.0 Hz), 3.74 (t, 1H, J = 4.8 Hz), 4.06 (dd, 1H, J = 9.2, 6.4
Hz), 6.63 (d, 1H, J = 8.8 Hz), 7.09 (dd, 4H, J = 11.6, 8.4 Hz), 7.23−7.27
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(m, 4H), 7.35 (dd, 1H, J = 8.8, 2.4 Hz), 7.76 (d, 1H, J = 2.4 Hz); 13
C
(m, 9H), 7.53 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 39.4,
41.1, 42.1, 43.6, 50.7, 112.5, 118.5, 119.6, 119.7, 126.1, 126.4, 128.7,
129.6, 129.7, 130.2, 130.3, 134.2, 140.3, 140.9, 148.5, 169.5, 169.6, 175.8,
177.7, 177.8; ESI-MS M/Z [M + H]+ Calcd for C29H23N3O4 478.18,
found 478.18. EA found: C 72.90, H 4.81, N 8.85. Requires: C 72.94, H
4.85, N 8.80.
NMR (100 MHz, CDCl3) δ 21.2, 32.2, 39.3, 44.9, 45.2, 47.3, 48.5, 111.0,
114.6, 120.7, 125.9, 126.1, 128.56, 128.60, 129.8, 129.9, 130.4, 132.5,
139.1, 146.3, 173.7, 174.8, 175.6, 176.1; ESI-MS M/Z [M + H]+ Calcd
for C30H26BrN3O4 572.12; found 572.17. EA found: C 62.90, H 4.63, N
7.30. Requires: C 62.94, H 4.58, N 7.34.
(3aR*,4S,9bR*)-5-Ethyl-4-methyl-2-phenyl-3a,4,5,9b-tetrahydro-
1H-benzo[e]isoindole-1,3(2H)-dione (12a). Yield (81.8 mg, 41%).
White solid: Rf = 0.39 (petroleum ether/ethyl acetate 6:1); mp 199−201
°C;13 1H NMR (400 MHz, CDCl3) δ 1.03 (d, 3H, J = 6.8 Hz), 1.28 (t,
3H, J = 7.2 Hz), 3.15 (qd, 1H, J = 14.2, 7.0 Hz), 3.48 (qd, 1H, J = 14.0, 7.0
Hz), 3.63 (dd, 1H, J = 9.0, 5.8 Hz), 4.00 (t, 1H, J = 6.4 Hz), 4.07 (d, 1H, J
= 8.8 Hz), 6.79 (d, 1H, J = 7.2 Hz), 6.88 (t, 1H, J = 7.2 Hz), 7.21−7.30
(m, 3H), 7.38−7.43 (m, 1H), 7.46−7.50 (m, 2H), 7.78 (d, 1H, J = 7.6
Hz).
(3aS*,9bR*)-8-Bromo-2-(4-chlorophenyl)-9b-((S)-1-(4-chloro-
phenyl)-2,5-dioxopyrrolidin-3-yl)-5-methyl-3a,4,5,9b-tetrahydro-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (4v). Yield (15.3 mg, 8%).
White solid: Rf = 0.37 (petroleum ether/ethyl acetate 4:1); mp 258−260
°C; IR (KBr) ν 3001, 1713, 1578, 1426, 1166, 819, 649 cm−1; 1H NMR
(400 MHz, CDCl3) δ 2.88 (s, 3H), 2.95 (d, 2H, J = 8.0 Hz), 3.39 (dd, 1H,
J = 11.8, 5.8 Hz), 3.55 (dd, 1H, J = 11.8, 4.6 Hz), 3.84 (t, 1H, J = 5.2 Hz),
4.02 (t, 1H, J = 8.0 Hz), 6.65 (d, 1H, J = 8.8 Hz), 7.19 (dd, 4H, J = 11.4,
8.6 Hz), 7.37 (dd, 1H, J = 8.8, 2.4 Hz), 7.43 (td, 4H, J = 6.4, 2.0 Hz), 7.71
(d, 1H, J = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 32.2, 39.3, 44.8, 45.4,
47.3, 48.4, 111.1, 114.8, 120.3, 127.4, 127.5, 129.4, 129.5, 129.6, 129.7,
130.3, 132.7, 134.8, 146.3, 173.1, 174.2, 175.4, 175.8; ESI-MS M/Z [M +
H]+ Calcd for C28H20BrCl2N3O4 612.01, found 612.00. EA found: C
54.88, H 3.35, N 6.82. Requires: C 54.84, H 3.29, N 6.85.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H of all compounds and 13C NMR spectra of 18 new
compounds. X-ray crystal structure data for 8, 3f, and 4v in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
X-ray Structure Analysis. C28H20BrCl2N3O4, 0.5(C4H8O2) M =
657.32. Triclinic, space group P1, a = 7.5950(4) Å, b = 13.7694(8) Å, c =
̅
15.7113(12) Å, α = 64.051(2)°, β = 88.667(3)°, γ = 76.613(2) °, V =
1431.54(16) Å, Z = 2, Dc = 1.525 g cm−3, F(000) = 668.0, absorption
coefficient 1.668 mm−1, scan range for data collection 3.01 ≤ θ ≤ 25.10°,
11 496 measured reflections, 4958 independent reflections, 3784
reflections with I > 2σ(I), Rint = 0.0386, 461 refinable parameters,
R[F2 > 2σ(F2)] = 0.0421, wR2 (F2) = 0.1105.
AUTHOR INFORMATION
Corresponding Author
*E-mail: shenyongmiao@usx.edu.cn (Y.-M.S.).
■
Notes
(3aS*,9bR*)-2-(4-Chlorophenyl)-5,8,9b-trimethyl-3a,4,5,9b-tetra-
hydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (5). Yield (181.9 mg,
82%). White solid: Rf = 0.47 (petroleum ether/ethyl acetate 7:1); mp
204−206 °C; IR (KBr) ν 2975, 1781, 1718, 1577, 1493, 1444, 1205,
1129, 824, 649 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.81 (s, 3H), 2.28
(s, 3H), 2.85 (s, 3H), 3.09 (t, 1H, J = 3.2 Hz), 3.14 (dd, 1H, J = 11.4, 3.4
Hz), 3.67 (dd, 1H, J = 11.2, 2.8 Hz), 6.61 (d, 1H, J = 8.4 Hz), 7.01 (dd,
1H, J = 8.4, 2.0 Hz), 7.21 (dt, 2H, J = 9.6, 2.4 Hz), 7.37 (dt, 2H, J = 9.4, 2.3
Hz), 7.43 (d, 1H, J = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 20.5, 26.4,
39.7, 44.3, 47.7, 50.7, 112.4, 122.0, 127.5, 128.3, 129.1, 129.2, 129.5,
130.5, 134.1, 144.6, 175.9, 178.9; ESI-MS M/Z [M + H]+ Calcd for
C20H19ClN2O2 355.12, found 355.08. EAfound: C 67.68, H 5.45, N 7.91.
Requires: C 67.70, H 5.40, N 7.89.
(3aS*,9bR*)-2-(2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-5-
methyl-3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-
dione (8). Yield (64.7 mg, 61%). White solid: Rf = 0.32 (petroleum
ether/ethyl acetate 4:1); mp 176−178 °C; IR (KBr) ν 2935, 1705, 1577,
1499, 1435, 1152, 1133, 828, 650 cm−1; 1H NMR (400 MHz, CDCl3) δ
2.79 (s, 3H), 3.02 (dd, 1H, J = 11.6, 4.4 Hz), 3.33 (ddd, 1H, J = 6.8, 4.4,
2.4 Hz), 3.49 (dd, 1H, J = 11.6, 2.4 Hz), 3.64−3.78 (m, 4H), 3.96 (d, 1H,
J = 9.2 Hz), 6.61 (s, 2H), 6.69 (d, 1H, J = 7.8 Hz), 6.86 (td, 1H, J = 7.6, 1.2
Hz), 7.20 (td, 1H, J = 7.6, 1.2 Hz), 7.42 (d, 1H, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 35.8, 37.9, 39.3, 41.9, 43.5, 50.1, 112.5, 118.3,
119.4, 128.6, 130.1, 134.1, 148.3, 170.5, 176.8, 178.7; ESI-MS M/Z [M +
H]+ Calcd for C18H17N3O4 340.13, found 340.15. EA found: C 63.67, H
5.10, N 12.35. Requires: C 63.71, H 5.05, N 12.38.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (NSFC 21202101 and 51372154), the
Zhejiang Provincial Natural Science Foundation of China
(Y15B020012), and the Key Laboratory for Advanced
Technology in Environmental Protection of Jiangsu Province
(AE201306).
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3H), 3.12 (dd, 1H, J = 11.2, 4.4 Hz), 3.54 (ddd, 1H, J = 7.0, 4.2, 2.6 Hz),
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DOI: 10.1021/jo502901h
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