γ-Al2O3/triflic acid as cooperative catalysts for the tandem Michael addition/carbocyclization: An easy access to 2-substituted pyrrolo[2,1-a]isoquinolines and 3-substituted pyrrolidine-2,5-diones

Article abstract of DOI:10.1002/jhet.4266

A tandem Michael addition/carbocyclization of 3,4-dimethoxyphenethyl maleimide with carbon and sulfur nucleophiles is accomplished via a relay catalysis using γ-Al₂O₃/TfOH binary system. The X-ray Photoelectron Spectroscopy (XPS) ana

Full text of DOI:10.1002/jhet.4266

Received: 7 December 2020
DOI: 10.1002/jhet.4266
Revised: 16 March 2021
Accepted: 19 March 2021
A R T I C L E
γ-Al2O3/triflic acid as cooperative catalysts for the tandem
Michael addition/carbocyclization: An easy access to
2-substituted pyrrolo[2,1-a]isoquinolines and 3-substituted
pyrrolidine-2,5-diones
Ramana Sreenivasa Rao1 | Anita Sahani1 | Sheikh Haider Ali1
Sumanta Pradhan2 | Chinnasamy Ramaraj Ramanathan1
|
1Department of Chemistry, Pondicherry
Abstract
University, Puducherry, India
2Catalysis and Inorganic Chemistry,
Division, CSIR—National Chemical
Laboratory, Pune, India
A tandem Michael addition/carbocyclization of 3,4-dimethoxyphenethyl
maleimide with carbon and sulfur nucleophiles is accomplished via a relay
catalysis using γ-Al2O3/TfOH binary system. The X-ray Photoelectron Spec-
troscopy (XPS) analysis of binary system indicates the presence of AlF3,
AlO(OH) species. This approach provides an easy access to 2-aryl or 2-thio aryl
pyrrolo[2,1-a]isoquinolines in good yields in a tandem fashion. With suitable
ratio of γ-Al2O3/TfOH binary system, the Michael addition of N/C/S nucleo-
philes to N-benzyl maleimide is also achieved. A key to the success of these
reactions would be the generation of AlF3, AlO(OH) species from γ-Al2O3 and
TfOH, which might have delineated the disadvantageous background reactions
usually displayed by a strong Brønsted acid such as TfOH.
Correspondence
Chinnasamy Ramaraj Ramanathan,
Department of Chemistry, Pondicherry
University, Puducherry 605 014, India.
Email: crrnath.che@pondiuni.edu.in
Funding information
Science and Engineering Research Board,
Grant/Award Number: CRG/2019/002960;
DBT-IPLS Programme, Pondicherry
University; SERB, New Delhi, CSIR, New
Delhi
K E Y W O R D S
3-substituted pyrrolidine-2,5-diones, carbocyclization, Michael addition, pyrrolo[2,1-a]
isoquinolines, γ-Al2O3/TfOH binary system
1 | INTRODUCTION
to synthesize pyrroloisoquinoline skeletons.[1,3] Recently, our
group also contributed toward the synthesis of this class of
Pyrrolo[2,1-a]isoquinolines are fused tricyclic subunits occur
widely in natural products. (−)-Trolline, (+)-oleracein E, and
(+)-crispine A are some of the pyrrolo[2,1-a]isoquinoline
skeleton containing alkaloids (Figure 1). These alkaloids dis-
play remarkable biological activities such as antibacterial
activity, radical scavenging property, and anticancer prop-
erty.[1] Erythrina alkaloids are well-known for their sedative,
hypotensive, anticonvulsive, hypnotic, CNS depressing, and
curare-like properties.[2] Owing to their structural diversity
and the spectrum of biological activities, efforts have been
directed to develop an efficient methodologies utilizing
Bischler–Napierlski, Parham-type cyclization, 6-exo-trig cycli-
zation through imide carbonyl group activation, and so on,
alkaloids via imide carbonyl group activation and cyclization
strategy from phenethyl imides in the presence of either
AlBr3 or TfOH (Scheme 1).[4] The synthesis of at 2-substituted
pyrrolo[2,1-a]isoquinoline requires pre-installed substituents
in unsymmetrical succinimides.[4a] Therefore, the additional
steps are indeed required for the preparation of N-phenethyl
unsymmetrical succinimides. Unlike succinimides, due to the
presence of α,β-unsaturated system, the maleimide is prone
to be attacked by two nucleophiles in the presence of Lewis
acid or Brønsted acids. Thus by modulating the reactivity of
maleimide toward two nucleophiles in an intra- and inter-
molecular fashion would lead to the formation of
2-substituted pyrroloisoquinoline skeletons (Scheme 1).
J Heterocyclic Chem. 2021;1–14.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

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FIGURE 1 Selected
pyrroloisoquinoline based alkaloids and
pyrrolidine-2,5-diones
SCHEME 1 Synthesis of
2-substituted
pyrroloisoquinolines
Furthermore, the maleimides persist to attract synthetic
followed by reduction using NaBH4/MeOH. The desired
product pyrroloisoquinoline (A) was obtained only in 10%
yield (Scheme 1). This is perhaps the intrinsic property of
maleimides undergoing side reactions, for example, poly-
merization in the presence of strong Brønsted acid.
It is well known that the maleimides can exist as
dicationic species (Figure 2, dicationic species I and II)[16] in
the presence of strong Brønsted acid (TfOH). Therefore, we
intend to modulate the reactivity of dicationic species of
maleimide with nucleophiles and that may lead to
2-substituted pyrrolo-isoquinolines. Hence, the systematic
investigation on trapping the dicationic species with external
and internal nucleophiles may produce the desired product
(Scheme 1). Accordingly, 3,4-dimethoxy-phenethyl maleimide
was treated with 1,3,5-trimethoxy benzene in the presence of
TfOH, which failed to give the expected product.
chemists due to their intrinsic chemical reactivity toward var-
ious nucleophiles to generate natural products,[5]
pharmaceuticals,[6] functional materials,[7] antidepressant,[8]
anticonvulsant,[9] anti-tubercular agents,[10] cyclopeptide
alkaloids,[11] neurotoxic fungal metabolites,[12] anti-filarial,[13]
and anti-emetic agents[14] as well as antibiotics of the quino-
lone carboxylic acid series.[15]
In pursuit of exploring the TfOH mediated 6-exo-trig
cyclization, we herein, report the construction of
2-aryl/2-thioarylpyrroloisoquinoline units by exploiting
the dual reaction site nature of maleimide involving
Michael addition/carbocyclization strategy.
2 | RESULTS AND DISCUSSION
This may be due to the super acid's ability to proton-
ate not only maleimide but also trimethoxy benzene.[17]
Hence, controlling the reactivity of TfOH has become
essential. Presence of excess acid also favors the
We commenced our work to examine the cyclization
reaction of 3,4-dimethoxyphenethyl maleimide with
TfOH (8 equiv. as adopted for succinimides) at 0 ꢀC,

RAO ET AL.
3
FIGURE 2 Possible dicationic
species I and II of maleimides with TfOH
polymerization reaction instead of Michael addition.[18]
The 6-exo-trig cyclization essentially requires excess
TfOH, whereas, the Michael addition requires catalytic
quantity of either Brønsted acid or Lewis acid.[19] γ-Al2O3
is known to display multifunctional characteristics
(Lewis acidic and basic sites) upon treatment with super
acid[20] and consequently it could moderate the reactivity
of excess super acid. To test this hypothesis, the reaction
of 3,4-dimethoxyphenethyl maleimide along with exter-
nal nucleophile 1,3,5-trimethoxy benzene was carried out
with TfOH (8 equiv.) in the presence of γ-Al2O3 (1 equiv.)
in dichloromethane at −30 ꢀC. After 6 h, the expected
2-aryl substituted pyrroloisoquinoline 3a was obtained in
27% yield. Encouraged by this observation, the experi-
ments were performed by varying the equivalents of both
γ-Al2O3 and TfOH. The results are summarized in
Table 1. While decreasing the equivalents of γ-Al2O3 the
formation of tandem product is favored with eight equiva-
lents of TfOH (Table 1, entries 1–5). In the presence of
γ-Al2O3 (0.1 equiv.), the expected product 3a was obtained in
80% yield (Table 1, entry 5). With 0.1 equivalents of γ-Al2O3,
the reactions were carried out by varying the equivalents of
TfOH (8 to 12 equiv.). While increasing the TfOH equiva-
lents, the decrease in tandem product formation was
observed (Table 1, entries 6–7). On the other hand, by
retaining the equivalents of γ-Al2O3 (0.1) constant and
decreasing the equivalent of TfOH, lead to the formation of
Michael addition product (Table 1, entry 8). This observation
not only ascertains the involvement of relay catalytic process
but also the essential role played by γ-Al2O3. The first step
involves the Michael addition of 1,3,5-trimethoxy benzene on
to maleimide ring in 3,4-dimethoxyphenethyl maleimide trig-
gered by Lewis acid AlF3 generated from alumina.
TABLE 1 Optimization of reaction conditions a
S. No.
1.
TfOH (equiv.)
Al2O3 (equiv.)
Yield (%)b
8
8
1
27
52
67
72
80
27
21
68c
2.
0.5
0.2
0.15
0.1
0.1
0.1
0.1
3.
8
4.
8
5.
8
6.
10
12
4
7.
8.
aReaction conditions: maleimide 1 (1 mmol), 1,3,5-trimethoxybenzene
(1 mmol), DCE (3 mL), −30 ꢀC.
bYields are isolated product.
cMichael addition product (5).
The present method enabled the generation of 2-aryl
substituted phenyl succinimide 5 (Scheme 2), and thus all-
owing efficient synthesis of fused 2-aryl pyrroloisoquinolines
from readily accessible 3,4-dimethoxyphenethyl maleimide
1 with various C-nucleophiles in a relay catalytic process
(Figure 3). With this condition in hand, the scope of aromatic
and heteroaromatic nucleophiles have been examined in
presence of TfOH/γ-Al2O3 (8:0.1 ratio) and they smoothly
delivered the expected product in good to excellent yields
(Figure 3; 3a–3g). To prove the versatility of this tandem pro-
cess, the hetero nucleophiles such as thiol and amine were
examined. Interestingly, the sulfur nucleophile was installed
at C-2 carbon in pyrroloisoquinolines through tandem pro-
cess (Figure 3, entry 3h).
Unfortunately, the nitrogen nucleophile failed to
undergo this transformation. This may be due to the pro-
tonation of amine nucleophile by excess TfOH. Synthesis
of 3-substituted succinimides, for example, 3-aryl suc-
cinimides, are usually accomplished from maleimides
Subsequently, the precursor generated in situ underwent
regioselective cyclization in the presence of available TfOH
to furnish the tandem product, 2-aryl pyrroloisoquinoline 3a.

4
RAO ET AL.
FIGURE 3 Synthesis of
2-substituted pyrroloisoquinolines
through Michael addition[21] or transition metal cata-
lyzed reactions.[22] All these reactions are mainly utilized
to synthesize 3-aryl succinimides. Whereas, aza-Michael
addition was promoted by various Lewis acids.[23] On the
other hand, S-nucleophile is usually attached at C-3 posi-
tion in succinimide via Michael addition with maleimide
by using base mediated reactions.[24] The aza-Michael
addition is possible only when free amines are available
in the reaction medium and that is not feasible with
excess TfOH. Therefore, the equivalents of TfOH gradu-
ally reduced to one equivalent at room temperature to
witness again no Michael addition product. While
increasing the temperature of the reaction from room
temperature to 70 ꢀC in 1,2-dichloroethane, the forma-
tion of Michael adduct 4 was realized (Scheme 2, entry
4). This may be due to the generation of free amine from
ammonium triflate salt with reagent system γ-Al2O3/
TfOH (0.1/1) at 70 ꢀC. Since, the reaction at elevated tem-
perature in presence of γ-Al2O3 (0.1 equiv.) and TfOH
(1 equiv.) facilitated the Michael adduct formation with
nitrogen nucleophile, we intend to find out the outcome
of this condition with carbon and sulfur nucleophiles as
well and in both cases the expected Michael adducts were
obtained in good yields (Scheme 2, entries 4–6). To gener-
alize this condition, the model substrate N-
benzylmaleimide was successfully employed to demon-
strate the Michael addition reaction with various nitro-
gen nucleophiles (1ꢀ/2ꢀ amines), carbon nucleophiles
(arenes, heteroarenes, and active methylene compounds),
and sulfur nucleophiles (aryl thiols). This reaction gener-
ated 3-aryl pyrrolidine-2,5-diones, 3-amino pyrrolidine-2,-
5-diones, and 3-mercapto pyrrolidine-2,5-diones in good
yields (Scheme 2, entries 8a–8h, 9a–9g, and 10a–10c,
respectively). Chiral primary amine, R-(+)-α-methyl
benzylamine, smoothly furnished the Michael adduct
with 1:1 diastereomeric ratio (Scheme 2, entry 8 h). Simi-
larly, an active methylene compound, oxindole, also
underwent this reaction to form the diastereomeric mix-
ture in equal ratio (Scheme 2, entry 9g).
The active species involved in binary system have
been investigated through systematic analysis of mate-
rials generated from γ-Al2O3 and TfOH by using pyridine
IR (PY-IR) spectroscopy and X-ray Photoelectron Spec-
troscopy (XPS). The commercial γ-Al2O3 (Merck) was
pre-heated at 300 ꢀC (Al2O3) to avoid moisture contami-
nation and used for analysis as well as the preparation of
Al2O3-Tf sample [prepared from TfOH (1 mL) and pre-
heated γ-Al2O3 (100 mg) at room temperature] and
Al2O3-Tf-1 sample [obtained from pre-heated γ-Al2O3
(100 mg) and TfOH (0.1 mL) at 70 ꢀC]. The generation of
Lewis acidic sites (LPy) and Brønsted acidic sites (BPy)
were ascertained with help of Fourier Transform Infrared
(FT-IR) spectroscopy after pyridine adsorption (Py-PAS).
Pyridine was adsorbed on these samples at 423 K, and
the FT-IR spectra of pyridine-loaded and unloaded sam-
ples were recorded at room temperature (Figure 4).

RAO ET AL.
5
SCHEME 2 Synthesis of
3-substituted 1-phenethyl/benzyl
pyrrolidine-2,5-diones

6
RAO ET AL.
known to etch the γ-Al2O3 layer and leads to the forma-
tion of matrix. To understand this, the TfOH treated alu-
mina (Al2O3-Tf) was analyzed using XPS (Figure 5). The
Al 2p spectrum of untreated and treated samples
(γ-Al2O3 and Al2O3-Tf) could be deconvoluted to three
species corresponding to 74.2 eV as in Al2O3, 75.2 eV as
in AlO(OH), and 76.8 eV, which is the position of Al 2p
in AlF3. These binding energy values correlated well with
the literature reports.[26] Based on these results, a plausi-
ble mechanism for the Michael addition and cyclization
reaction is proposed (Scheme 3).
The presence of species Al(O) OH may probably
facilitate the Michael addition of nucleophiles such as
amines and thiols to maleimides (Scheme 4).
3 | CONCLUSION
FIGURE 4 Pyridine-IR spectrum
In conclusion, we have demonstrated a tandem Michael
addition/carbocyclization sequence using γ-Al2O3/TfOH
(0.1/8) binary catalytic system. Using this strategy, 2-aryl
or 2-thioaryl pyrroloisoquinoline derivatives are obtained
in good to excellent yields at low temperature. Whereas,
the binary system γ-Al2O3/TfOH (0.1/1 ratio) furnished
3-substituted succinimide derivatives with C/N/S nucleo-
philes at elevated temperature in good yields. The active
species involved in binary system were confirmed
through XPS, which are found to be AlO(OH), AlF3 along
with TfOH. Furthermore, PY-IR analysis reveals the
Lewis and Brønsted acidic nature of the binary system.
Exploration of the synthetic utility of this binary system
in other organic transformations is in progress in this
laboratory.
4 | EXPERIMENTAL
Melting points reported in this paper are uncorrected and
were determined using BUCHI M-560, Buchi Labortechnik
AG, Switzerland. Infrared spectra were recorded on Thermo
Nicolet 6700 FT-IR Spectrophotometer and are reported in
frequency of absorption (cm−1). Mass spectra were measured
FIGURE 5 Deconvoluted Al(2P) XPS spectra of treated sample
Al2O3-Tf (top) along with standard γ-Al2O3
The intensities of bands at about 1440 cm−1 (LPy),
1484 cm−1 (LPy + BPy), 1590 cm−1 (BPy), and 1610 cm−1
(LPy) in the normalized spectra were used to determine
the type of acidic sites semi-quantitatively.[25]
From PY-IR spectroscopy it is clear that the addition
of TfOH to the pre-heated γ-Al2O3 at room temperature,
the Lewis, and Brønsted acidic strength has got increased
when compared to the normal γ-Al2O3, which was fur-
ther enhanced when heated at 70 ꢀC. Due to this, the
binary system displayed co-operative catalysis to furnish
tandem and Michael addition products. Super acids are
with Agilent-6530 B Q-TOF (ESI-HRMS), H and 13C NMR
1
were recorded on Bruker AVANCE 400 spectrometer. NMR
spectra for all the samples were measured in CDCl3 using tet-
ramethylsilane (TMS) as an internal standard. The chemical
shifts are expressed in δ ppm down field from the signal of
internal TMS. Pyridine (FT-IR) spectroscopy recorded with
Nicolet iS50 spectrometer equipped with DTGS KBR detec-
tor. XPS was analyzed through Perkin-Elmer PHI
5300Thermo Scientific Kalpha+ XPS spectrometer.
Trifluoromethanesulfonic acid purchased from M/s. Sigma-
Aldrich and used without further purification. Aromatic/

RAO ET AL.
7
SCHEME 3 Plausible mechanism
for the formation of 2-aryl
pyrroloisoquinoline derivatives
with KBr. The samples were diluted with KBr in the
195:5 wt% ratio. The samples were mixed with 20 μL Pyr-
idine. Then spectra were recorded between 4000 and
400 cm−1 before and after Py adsorption at RT.
SCHEME 4 Plausible mechanism for the formation of
2-substituted pyrrolidine-2,5-diones
4.2 | XPS analysis
XPS experiments were performed in an ultrahigh vacuum
(UHV) chamber equipped with a Perkin-Elmer PHI 5300
Thermo Scientific K-alpha+ XPS spectrometer with a
position-sensitive detector and a hemispherical energy
analyzer. The Al Kα (beam energy = 1486.6 eV) X-ray
source of the XPS spectrometer was operated at 350 W
with 15 kV acceleration voltage used for photoemission.
hetero nucleophiles were also purchased from M/s. Sigma-
Aldrich and purified (liquid sample) by distillation under
reduced pressure. N-Benzyl[27] and 3,4-dimethoxy N-
phenethyl maleimides[4] were prepared from maleic anhy-
dride with benzyl amine and 3,4-dimethoxy N-phenethyl
amine, respectively, using the reported procedures.[27] Sol-
vents used for the reactions were dried using standard proce-
dures. Analytical Thin Layer Chromatographic (TLC) tests
were carried out using precoated aluminum TLC plates. The
spots were visualized by short exposure to iodine vapor or
UV light. Column chromatography was carried out using
M/s. Merck silica gel (100–200 mesh). All the glassware were
pre-dried at 120 ꢀC for 6 h and assembled while hot and
cooled under stream of dry nitrogen gas. In all experiments,
round bottom flasks of appropriate size were used.
4.3 | General procedure to synthesize
2-substituted pyrroloisoquinolinone
derivatives (3a–3h)
An oven-dried schlenk tube with side arm was fitted with
nitrogen balloon, septum, and equipped with stir bar was
cooled down to room temperature under a steady stream
of nitrogen gas flow. After reaching room temperature, the
septum was opened under nitrogen atmosphere and the
schlenk tube was charged with 3,4-dimethoxyphenethyl
maleimide 1 (1 mmol), π-nucleophile (or) thiophenol
(1 mmol), γ-Al2O3 (10 mol%), and dry dichloromethane
(5 mL). The contents were closed with septum under
nitrogen atmosphere and stirred at −30 ꢀC followed by
addition of TfOH (0.71 mL, 8 mmol). After stirring for 3 h
at −30 ꢀC, the reaction mixture was brought to room
4.1 | Pyridine FT-IR spectroscopy
Lewis acid sites (LPy) and Brønsted acid sites (BPy) were
studied with Nicolet iS50 spectrometer equipped with
DTGS KBR detector. The spectra were recorded in DRIFT
mode with 4 cm−1 resolution and 32 scans. Before record-
ing the samples, a background spectrum was recorded

8
RAO ET AL.
temperature and quenched with NaBH4 (2 mmol) and
MeOH (2.5 mL), and stirring was continued until the color
disappears. The contents were transferred to round bottom
flask and the schlenk tube was washed with dichloromethane
(2 × 20 mL). The solvent was evaporated under reduced pres-
sure. The trace amount of solvents dichloromethane and
methanol were removed under high vacuum. The residue
was then quenched with water and then extracted with dic-
hloromethane (2 × 10 mL). The combined organic layer was
dried over anhydrous Na2SO4 and filtered and the solvent
was removed under reduced pressure. The crude reaction
mixture was purified through silica gel column chromatogra-
phy using ethyl acetate and hexane (50:50) as eluent to fur-
nish 2-aryl pyrroloisoquinolinone derivatives 3a-3 h in
pure form.
4.6 | 8,9-Dimethoxy-
2-(4-methoxyphenyl)-1,5,6,10b-
tetrahydropyrrolo-[2,1-a]isoquinolin-3(2H)-
one (3c)
Colorless liquid, yield: 332 mg (94%), IR (KBr, cm−1):
2925, 2850, 1688, 1609, 1508, 1454, 1263, 1171, 1115,
1051, 1018, 876, 821, 724, 597; 1H NMR (400 MHz,
CDCl3): δ = 7.17–7.15 (m, 2H), 6.87–6.84 (m, 2H), 6.66 (s,
1H), 6.59 (s, 1H), 4.76–4.72 (m, 1H), 4.40–4.35 (m, 1H),
3.88 (s, 3H), 3.85 (s, 3H), 3.81–3.79 (m, 1H), 3.78 (s, 3H),
3.14–3.02 (m, 2H), 2.99–2.91 (m, 1H), 2.77–2.73 (m, 1H),
1.96–1.88 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ = 172.7, 155.2, 148.4, 148.3, 133.1, 132.5, 128.8, 128.7,
125.7, 112.2, 112.0, 111.9, 107.8, 56.4, 56.2, 54.5, 48.3,
38.0, 37.6, 28.4; HRMS-ESI (m/z): (M+H)+ calcd for
C21H24NO4: 354.1705; found: 354.1702.
4.4 | 8,9-Dimethoxy-2-(2,4,6-
trimethoxyphenyl)-1,5,6,10b-tetrahydro
pyrrolo[2,1-a]isoquinolin-3(2H)-one (3a)
4.7 | 2-(3-Bromo-4-methoxyphenyl)-
8,9-dimethoxy-1,5,6,10b-tetra-hydropyrrolo
[2,1-a]isoquinolin-3(2H)-one (3d)
Yellow liquid, yield: 330 mg (80%), IR (KBr, cm−1): 2922,
2851, 1686, 1609, 1506, 1452, 1261, 1173, 1113, 1050,
1
1016, 872, 820, 722, 596; H NMR (400 MHz, CDCl3):
Colorless liquid, yield: 401 mg (93%), IR (KBr, cm−1):
2925, 2850, 1688, 1609, 1508, 1454, 1263, 1171, 1115,
δ = 6.64 (s, 1H), 6.54 (s, 1H), 6.12 (d, J = 2.0 Hz, 1H),
6.04 (d, J = 2.4 Hz, 1H), 4.77–4.73 (m, 1H), 4.38–4.33 (m,
2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H),
3.49 (s, 3H), 3.06–3.00 (m, 1H), 2.95–2.87 (m, 1H), 2.85–
2.80 (m, 1H), 2.72–2.38 (m, 1 H), 2.04–1.96 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ = 174.6, 160.5, 159.3, 159.0,
148.2, 147.7, 130.5, 125.7, 111.7, 108.5, 107.9, 91.6, 90.9,
56.0, 55.5, 55.47, 54.9, 38.7, 37.9, 34.8, 28.5; HRMS-ESI
(m/z): (M+H)+ calcd for C23H27NO6: 414.1917; found:
414.1918.
1
1051, 1018, 876, 821, 778, 724, 597; H NMR (400 MHz,
CDCl3): δ = 7.41 (d, J = 2.0 Hz, 1H), 7.19–7.16 (m, 1H),
6.85 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 4.76–
4.72 (m, 1H), 4.38–4.34 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.85 (s, 3H), 3.81–3.76 (m, 1H), 3.13–3.03 (m, 2H), 3.00–
2.91 (m, 1H), 2.74 (d, J = 14.0 Hz, 1H), 1.90 (dd, J = 21.6,
12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 172.7,
155.2, 148.4, 148.3, 133.1, 132.5, 128.8, 128.7, 125.7, 112.3,
112.0, 111.9, 107.8, 56.5, 56.2, 56.1, 48.3, 38.1, 37.7, 28.4;
HRMS-ESI (m/z): (M+H)+ calcd for C21H22BrNO4:
432.0810; found: 432.0795.
4.5 | 8,9-Dimethoxy-2-(naphthalen-1-yl)-
1,5,6,10b-tetrahydropyrrolo-[2,1-a]
isoquinolin-3(2H)-one (3b)
4.8 | 2-(1-Ethyl-1H-indol-3-yl)-
8,9-dimethoxy-1,5,6,10b-tetrahydro-pyrrolo
[2,1-a]isoquinolin-3(2H)-one (3e)
Colorless liquid, yield: 243 mg (68%), IR (KBr, cm−1):
2925, 2850, 1688, 1609, 1508, 1454, 1263, 876, 821,
724, 597; 1H NMR (400 MHz, CDCl3): δ = 7.99–7.97
(m, 1H), 7.87–7.85 (m, 1H), 7.77–7.74 (m, 1H), 7.49–7.46
(m, 2H), 7.44–7.40 (m, 2H), 6.68 (s, 1H), 6.55 (s, 1H),
4.91-4.87 (m, 1H), 4.65–4.60 (m, 1H), 4.51–4.46 (m, 1H),
3.88 (s, 3H), 3.80 (s, 3H), 3.29–3.16 (m, 2H), 3.09–3.01
(m, 1H), 2.83–2.79 (m, 1H), 2.08–2.00 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ = 173.1, 148.3, 148.2, 135.3, 134.2,
132.1, 129.2, 129.1, 127.1, 126.2, 126.1, 125.9, 125.6, 123.2,
111.9, 107.7, 56.1, 54.8, 46.4, 38.1, 37.8, 28.4; HRMS-ESI
(m/z): (M+H)+ calcd for C24H24NO3: 374.1756; found:
374.1720.
Colorless liquid, yield: 292 mg (75%), IR (KBr, cm−1):
2926, 2852, 1691, 1611, 1515, 1451, 1362, 1261, 1223,
1177, 1118, 1057, 1016, 865, 725, 690, 607; 1H NMR
(400 MHz, CDCl3): δ = 7.50–7.47 (m, 1H), 7.30 (d,
J = 8.4 Hz, 1H), 7.20–7.15 (m, 2H), 7.07–7.03 (m, 1H),
6.66 (s, 1H), 6.58 (s, 1H), 4.81 (dd, J = 9.6, 6.8 Hz, 1H),
4.45–4.40 (m, 1H), 4.20–4.15 (m, 1H), 4.14–4.08 (m, 2H),
3.88 (s, 3H), 3.83 (s, 3H), 3.22–3.11 (m, 1H), 3.04–2.97 (m,
1H), 2.80–2.75 (m, 1H), 2.06–1.97 (m, 2H), 1.45–1.42 (m,
3H); 13C NMR (100 MHz, CDCl3): δ = 148.3, 139.7, 134.0,
133.6, 129.7, 126.7, 125.4, 123.1, 113.8, 112.7, 111.8, 107.6,

RAO ET AL.
9
56.2, 56.1, 54.3, 42.4, 39.2, 37.7, 31.3, 28.3; HRMS-ESI
(m/z): (M+H)+ calcd for C24H27N2O3: 391.2022; found:
391.2016.
3.84 (s, 3H), 3.82 (s, 3H), 3.06–2.98 (m, 2H), 2.84–2.76 (m,
1H), 2.64 (dd, J = 15.6, 2.4 Hz, 1H), 1.91–1.83 (m, 1H),
13C NMR (100 MHz, CDCl3): δ = 170.4, 148.3, 148.1,
133.6, 132.6, 129.0, 128.3, 127.7, 125.5, 111.8, 107.6, 56.0,
54.4, 49.3, 37.8, 36.2, 28.0; HRMS-ESI (m/z): (M+H)+
calcd for C20H22NO3S: 356.1320; found: 356.1322.
4.9 | 8,9-Dimethoxy-
2-(1-[phenylsulfonyl]-1H-pyrrol-3-yl)-
1,5,6,10b-tetrahydropyrrolo[2,1-a]
isoquinolin-3(2H)-one (3f)
4.12 | General procedure for the
synthesis of 3-substituted pyrrolidine-
2,5-diones, 4–6, and 8a–8h, 9a–9h, 10a–10c
Green color liquid, yield: 370 mg (82%), IR (KBr, cm−1):
2928, 2846, 1687, 1609, 1515, 1458, 1363, 1266, 1221, 1116,
1019, 861, 742, 468; 1H NMR (400 MHz, CDCl3): δ = 7.83–
7.81 (m, 2H), 7.62–7.58 (m, 1H), 7.54–7.50 (m, 2H), 7.22
(dd, J = 3.6, 1.6 Hz, 1H), 6.63 (s, 1H), 6.54 (s, 1H), 6.26–
6.24 (m, 1H) 6.18–6.16 (m, 1H), 4.74–4.69 (m, 1H), 4.41–
4.31 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.27–3.21 (m, 1H),
3.11–3.04 (m, 1H), 2.97–2.89 (m, 1H), 2.72 (dd, J = 13.6,
2.0 Hz, 1H), 1.81–1.73 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ = 173.4, 148.3, 148.1, 136.4, 129.3, 127.4, 125.6,
125.3, 121.6, 119.3, 119.0, 111.8, 109.6, 107.7, 56.1, 54.7,
41.1, 40.1, 37.6, 37.5, 28.4; HRMS-ESI (m/z): (M+H)+
calcd for C24H25N2O5S: 453.1484; found: 453.1483.
An oven-dried schlenk tube with side arm was fitted with
nitrogen balloon, septum, and equipped with stir bar was
cooled down to room temperature under a steady stream
of nitrogen gas flow. After reaching room temperature,
the septum was opened under nitrogen atmosphere and
the schlenk tube was charged with 3-methoxyphenethyl
maleimide (1 mmol) or N-benzyl maleimide (1 mmol),
N/C/S-nucleophile (1 mmol), γ-Al2O3 (10 mol%), and dry
1,2-dichloroethane (3 mL). The contents were closed with
septum under nitrogen atmosphere and stirred at room
temperature followed by the addition of TfOH (1 mmol).
The reaction mixture was stirred at 70 ꢀC. After the con-
sumption of the starting material (16 to 24 h), the reac-
tion mixture was cooled to room temperature and
quenched with water (10 mL). Organic layer was sepa-
rated and the aqueous layer was extracted with dic-
hloromethane (2 × 10 mL). The combined organic layer
was washed with brine solution (2 × 10 mL), dried over
anhydrous Na2SO4, filtered and the solvent was removed
in vacuo. The crude reaction mixture was purified
through silica gel column chromatography using hexane
and ethyl acetate (80:20) as eluent to give 3-substituted
1-phenethyl/benzyl pyrrolidine-2,5-diones 4, 5 and 6/8a-
8h, 9a–9g and 10a–10c.
4.10 | 2-(Benzo[b]thiophen-2-yl)-
8,9-dimethoxy-1,5,6,10b-tetrahydro-pyrrolo
[2,1-a]isoquinolin-3(2H)-one (3g)
Yellow color liquid, yield: 285 mg (75%), IR (KBr, cm−1):
2923, 2855, 1687, 1514, 1422, 1264, 1171, 1113, 1021,
1
773, 725, 601; H NMR (400 MHz, CDCl3): δ = 7.85–7.83
(m, 1H), 7.71–7.69 (m, 1H), 7.34 (t, J = 3.6 Hz, 3H), 6.67
(s, 1H), 6.57 (s, 1H), 4.87–4.83 (m, 1H), 4.46–4.41 (m,
1H), 4.31–4.26 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.22–
3.13 (m, 2H), 3.05–2.96 (m, 3H), 2.08–2.01 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ = 172.1, 148.4, 140.8, 138.4,
133.2, 128.9, 125.6, 124.4, 124.1, 123.7, 123.1, 121.9, 111.9,
107.7, 56.1, 54.7, 43.6, 37.7, 36.5, 28.4; HRMS-ESI (m/z):
(M+H)+ calcd for C22H22NO3S: 380.1320; found:
380.1310.
4.13 | 1-(3,4-Dimethoxyphenethyl)-
3-((4-methoxyphenyl) amino)-pyrrolidine-
2,5-dione (4)
Yellow color liquid, yield: 249 mg (65%), IR (KBr, cm−1):
3035, 2839, 1704, 1514, 1452, 1404, 1346, 1242, 1151,
1028, 817, 761; 1H NMR (400 MHz, CDCl3): δ = 6.81–6.78
(m, 3H), 6.75–6.73 (m, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.17–
4.13 (dd, J = 8.0, 5.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 1H),
3.78 (d, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.16–3.09 (m, 1H),
2.89–2.85 (m, 2H), 2.56 (dd, J = 17.6, 5.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ = 177.0, 174.7, 153.6, 149.0,
147.9, 140.0, 130.0, 121.0, 115.6, 115.1, 112.1, 111.3, 55.9,
55.7, 53.6, 40.3, 38.0, 33.1; HRMS-ESI (m/z): (M+H)+
calcd for C21H25N2O5: 385.1763; found: 385.1781.
4.11 | 8,9-Dimethoxy-2-(phenylthio)-
1,5,6,10b-tetrahydro-pyrrolo[2,1-a]
isoquinolin-3(2H)-one (3h)
Yellow color liquid, yield: 309 mg (87%), IR (KBr, cm−1):
3060, 2928, 2841, 1771, 1694, 1611, 1515, 1434, 1361,
1
1326, 1263, 1220, 1166, 1115, 1019, 863, 740, 696, 559, H
NMR (400 MHz, CDCl3): δ = 7.51–7.49 (m, 2H), 7.25–
7.20 (m, 3H), 6.56 (s, 1H), 6.46 (s, 1H), 4.65 (t, J = 8.0 Hz,
1H), 4.33–4.28 (m, 1H), 4.06 (dd, J = 10.0, 8.8 Hz, 1H),

10
RAO ET AL.
4.14 | 1-(3,4-Dimethoxyphenethyl)-
3-(2,4,6-trimethoxyphenyl) pyrolidine-
2,5-dione (5)
1343, 1243, 1167, 1033, 936, 822, 107, 628; 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.38 (m, 2H), 7.33–7.28 (m,
3H), 6.77 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H),
4.66 (s, 2H), 4.30 (bs, 1H), 4.17 (dd, J = 8.4, 5.2 Hz, 1H),
3.72 (s, 3H), 3.08 (dd, J = 18.0, 8.4 Hz, 1H), 2.54 (dd,
J = 18.0, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ = 176.8, 174.4, 153.2, 139.9, 135.4, 128.8, 128.6, 128.0,
115.3, 114.8, 55.5, 53.4, 42.5, 37.4; HRMS-ESI (m/z): (M
+H)+ calcd for C18H18N2O3: 311.1396; found: 311.1421.
Yellow oily liquid, yield: 291 mg (68%), IR (KBr, cm−1):
2942, 1700, 1602, 1510, 1406, 1344, 1233, 1153, 1116,
1028, 811, 757; 1H NMR (400 MHz, CDCl3): δ = 6.85–6.80
(m, 3H), 6.12 (d, J = 20.0 Hz, 2H), 4.45–4.41 (m, 1H),
3.89 (s, 3H), 3.86 (s, 3H), 3.81–3.78 (m, 6H), 3.77–3.74 (m,
2 H), 3.65 (s, 3H), 3.00–2.93 (m, 1H), 2.88–2.84 (m, 2H),
2.65–2.59 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ = 179.8, 177.4, 161.1, 149.1, 147.8, 130.8, 120.9, 112.0,
111.4, 106.6, 91.1, 90.9, 56.0, 55.6, 55.5, 40.3, 36.0, 35.4,
33.5; HRMS-ESI (m/z): (M+H)+ calcd for C23H28NO7:
430.1866; found: 430.1885.
4.18 | 1-Benzyl-3-(diethylamino)
pyrrolidine-2,5-dione (8c)
Yellow color liquid, yield: 182 mg (70%), IR (KBr, cm−1):
3029, 2927, 2858, 1772, 1706, 1612, 1459, 1392, 1346,
1161, 1079, 810,757, 632, 1H NMR (400 MHz, CDCl3):
δ = 7.37 (d, J = 6.5 Hz, 2H), 7.32–7.28 (m, 3H), 4.70–4.61
(m, 2H), 4.02 (dd, J = 8.9, 5.2 Hz, 1H), 2.84–2.78 (m, 1H),
2.67–2.61 (m, 1H), 2.59–2.50 (m, 4H), 1.09–1.05 (m, 6H),
13C NMR (100 MHz, CDCl3): δ = 177.3, 175.2, 135.9,
129.0, 128.8, 128.1, 59.2, 44.8, 42.3, 32.1, 13.6, HRMS-ESI
(m/z): (M+H)+ calcd for C15H20N2O2: 261.1603; found:
261.1619.
4.15 | 1-(3,4-Dimethoxyphenethyl)-
3-(pyrimidin-2-ylthio) pyrrolidine-
2,5-dione (6)
Colorless liquid, yield: 310 mg (83%), IR (KBr, cm−1):
2938, 1775, 1705, 1557, 1514, 1450, 1388, 1234, 1153,
1
1027, 808, 758; H NMR (400 MHz, CDCl3): δ = 8.37 (d,
J = 4.8 Hz, 2H), 6.96 (t, J = 4.8 Hz, 1H), 6.75 (d,
J = 4.8 Hz, 3H), 4.15 (dd, J = 9.6, 5.6 Hz, 1H), 3.82 (s,
3H), 3.80 (s, 3H), 3.76–3.72 (m, 2H), 3.24–3.17 (m, 1H),
2.91 (d, J = 5.6 Hz, 1H), 2.87–2.80 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ = 175.2, 175.0, 169.8, 157.4, 148.9,
147.7, 130.2, 120.8, 117.4, 111.9, 111.3, 55.9, 41.1, 40.7,
36.2, 33.0; HRMS-ESI (m/z): (M+H)+ calcd for
C18H20N3O4S: 374.1175; found: 374.1190.
4.19 | 1-Benzyl-3-(4-phenylpiperazin-1-yl)
pyrrolidine-2,5-dione (8d)
Yellow color liquid, yield: 286 mg (82%), IR (KBr, cm−1):
3032, 2937, 2827, 1773, 1707, 1595, 1499, 1443, 1391,
1
1343, 1152, 1007, 930, 757, 702, 412, H NMR (400 MHz,
CDCl3): δ = 7.39–7.37 (m, 2H), 7.33–7.23 (m, 5H), 6.90–
6.84 (m, 3H), 4.66 (d, J = 4.0 Hz, 2H), 3.80 (dd, J = 8.8,
4.8 Hz, 1H), 3.18–3.16 (m, 4H), 2.94–2.91 (m, 2H), 2.84
(m, 1H), 2.71–2.61 (m, 3H), 13C NMR (100 MHz, CDCl3):
δ = 175.7, 174.7, 151.1, 135.8, 129.2, 128.9, 128.8, 128.1,
120.1, 116.3, 62.4, 49.3, 49.2, 42.3, 31.6, HRMS-ESI (m/z):
(M+H)+ calcd for C21H24N3O2: 350.1869; found:
350.1894.
4.16 | 1-Benzyl-3-morpholinopyrrolidine-
2,5-dione (8a)
Yellow color liquid, yield: 203 mg (74%), IR (KBr, cm−1):
2925, 2854, 1771, 1704, 1440, 1394, 1344, 1161, 1116, 1006,
1
944, 706; H NMR (400 MHz, CDCl3): δ = 7.37–7.35 (m,
2H), 7.33–7.25 (m, 3H), 4.66 (dd, J = 16.8, 14.0 Hz, 2H),
3.76–3.73 (m, 1H), 3.70 (t, J = 4.8 Hz, 4H), 2.87–2.76 (m,
3H), 2.66 (dd, J = 18.4, 4.8 Hz, 1H), 2.50–2.48 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ = 175.7, 174.6, 135.7, 129.0,
128.8, 128.2, 66.9, 62.6, 49.6, 42.4, 31.5; HRMS-ESI (m/z):
(M+H)+ calcd for C15H19N2O3: 275.1396; found: 275.1407.
4.20 | 1-Benzyl-3-([pyridin-2-ylmethyl]
amino)pyrrolidine-2,5-dione (8e)
Yellow color liquid, yield: 251 mg (85%), IR (KBr, cm−1):
3316, 2924, 2856, 1775, 1703, 1591, 1461, 1395, 1344,
1
1163, 754, 702; H NMR (400 MHz, CDCl3): δ = 8.56 (d,
4.17 | 1-Benzyl-3-((4-methoxyphenyl)
amino)pyrrolidine-2,5-dione (8b)
J = 4.4 Hz, 1H), 7.65 (td, J = 7.6, 2.0 Hz, 1H), 7.38–7.36
(m, 2H), 7.33–7.28 (m, 4H), 7.21–7.18 (m, 1H), 4.66 (s,
2H), 4.01 (d, J = 0.4 Hz, 2H), 3.82 (dd, J = 8.0, 4.0 Hz,
1H), 2.93 (dd, J = 18.0, 8.0 Hz, 1H), 2.7 (brs, 1H), 2.57
(dd, J = 18.0, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
Yellow color liquid, yield: 360 mg (90%); IR (KBr, cm−1):
3368, 2940, 2836, 1779, 1706, 1633, 1515, 1438, 1399,

RAO ET AL.
11
δ = 177.5, 175.0, 158.3, 149.6, 136.8, 135.6, 129.0, 128.8,
128.2, 122.6, 122.5, 55.8, 53.1, 42.6, 36.5; HRMS-ESI
(m/z): (M+H)+ calcd for C17H18N3O2: 296.1399; found:
296.1406.
4.24 | 1-Benzyl-3-(2,4,6-trimethoxyphenyl)
pyrrolidine-2,5-dione (9a)
Colorless liquid yield: 302 mg (85%), IR (KBr, cm−1):
2943, 2842, 1772, 1711, 1609, 1497, 1462, 1327, 1223,
1116, 1037, 952, 890, 815, 706, 629, 481; 1H NMR
(400 MHz, CDCl3): δ = 7.43 (d, J = 6.8 Hz, 2H), 7.24–7.16
(m, 3H), 6.05 (s, 1H), 5.94 (s, 1H), 4.64 (s, 2H), 4.41–4.37
(m, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.14 (s, 3H), 2.88 (dd,
J = 18.0, 9.6 Hz, 1H), 2.51 (dd, J = 18.0, 5.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ = 179.5, 177.1, 161.0, 158.8,
158.6, 136.5, 129.4, 128.5, 127.8, 106.5, 90.9, 90.7, 55.9,
55.4, 55.0, 42.9, 36.0, 35.4; HRMS-ESI (m/z): (M+H)+
calcd for C14H22NO5: 356.1498; found: 356.1487.
4.21 | 1-Benzyl-3-(dimethylamino)
pyrrolidine-2,5-dione (8f)
Yellow color liquid, yield: 150 mg (65%), IR (KBr, cm−1):
3031, 2934, 2864, 2787, 1772, 1705, 1441, 1395, 1345,
1163, 705; 1H NMR (400 MHz, CDCl3): δ = 7.37–7.35 (m,
2H), 7.31–7.23 (m, 3H), 4.69–4.61 (m, 2H), 3.77 (dd,
J = 8.8, 4.8 Hz, 1H) 2.82–2.75 (m, 1H), 2.64–2.58 (m, 1H),
2.33 (s, 6H); 13C NMR (100 MHz, CDCl3): δ = 177.2,
174.9, 135.8, 128.9, 128.7, 128.1, 62.7, 42.2, 41.3, 31.0;
HRMS-ESI (m/z): (M+H)+ calcd for C13H17N2O2:
233.1290; found: 233.1304.
4.25 | 1-Benzyl-3-(1-[phenylsulfonyl]-1H-
pyrrol-3-yl)pyrrolidine-2,5-dione (9b)
Colorless liquid, yield: 205 mg (52%), IR (KBr, cm−1): 2924,
1
4.22 | 1-Benzyl-3-(4-oxo-
2-thioxothiazolidin-3-yl)pyrrolidine-
2,5-dione (8g)
2856, 1776, 1704, 1583, 1359, 1176, 1083, 823, 695, 606; H
NMR (400 MHz, CDCl3): δ = 7.74–7.24 (m, 2H), 7.64–7.60
(m, 1H), 7.53–7.49 (m, 2H), 7.41–7.38 (m, 1H), 7.34–7.24
(m, 5H), 6.71 (s, 1H), 6.24–6.22 (m, 1H), 5.99 (dd, J = 3.2,
1.6 Hz, 1H), 4.71-4.68 (m, 3H), 4.49 (dd, J = 9.6, 5.2 Hz,
1H), 3.16 (dd, J = 18.4, 9.6 Hz, 1H), 2.65 (dd, J = 18.4,
5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 176.0, 175.2,
139.2, 135.6, 134.3, 131.1, 129.7, 129.0, 128.8, 128.5, 128.2,
128.0, 126.7, 124.0, 112.5, 42.9, 39.6, 38.2; HRMS-ESI (m/z):
(M+H)+ calcd for C21H19N2O4S: 395.1066; found: 395.1035.
Brownish liquid, yield: 217 mg (68%), IR (KBr, cm−1):
2932, 2253, 1729, 1629, 1465, 1395, 1347, 1159, 989, 908,
1
735, 637; H NMR (400 MHz, CDCl3): δ = 7.36–7.34 (m,
2H), 7.31–7.24 (m, 3H), 4.72-4.69 (m, 2H), 4.57–4.54 (m,
1H), 3.92 (s, 2H), 3.33–3.26 (m, 1H), 2.98–2.92 (m, 1H);
13C NMR (100 MHz, CDCl3): δ = 198.7, 186.2, 173.5,
172.9, 135.0, 128.7, 128.6, 128.0, 43.9, 43.3, 39.9, 36.4;
HRMS-ESI (m/z): (M+H)+ calcd for C14H12N2O3S2:
321.0368; found: 321.0382.
4.26 | 1-Benzyl-3-(2-[methylamino]
phenyl)pyrrolidine-2,5-dione (9c)
4.23 | 1-Benzyl-3-(([R]-1-phenylethyl)
amino)pyrrolidine-2,5-dione (8h)
Colorless liquid, yield: 171 mg (58%), IR (KBr, cm−1): 3315,
2928, 2856, 2818, 1778, 1706, 1597, 1500, 1440, 1395, 1343,
1168, 1125, 1081, 1042, 1003, 928, 812, 756, 694, 626, 573,
Colorless liquid, yield: 265 mg (86%), IR (KBr, cm−1):
3315, 3029, 2966, 2927, 2858, 1774, 1706, 1489, 1440,
438; H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 7.4 Hz,
1
1H), 7.23–7.11 (m, 6H), 6.82 (td, J = 7.4, 1.1 Hz, 1H), 6.65
(dd, J = 8.2, 0.6 Hz, 1H), 4.62–4.51 (m, 2H), 3.91 (d,
J = 9.4 Hz, 1H), 3.42 (dd, J = 11.5, 2.8 Hz, 1H), 3.30–3.24
(m, 1H), 2.97 (dd, J = 11.5, 4.6 Hz, 1H), 2.72 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 178.4, 176.5, 148.3, 135.6,
130.3, 128.74, 128.70, 128.5, 127.9, 120.0, 119.0, 112.8, 50.8,
43.6, 42.9, 42.1, 39.6; HRMS-ESI (m/z): (M+H)+ calcd for
C18H19N2O2: 295.1447; found: 295.1426.
1
1399, 1345, 1165, 761, 705; H NMR (400 MHz, CDCl3):
δ = 7.35–7.29 (m, 10H), 7.29–7.23 (m, 10H), 4.60 (s, 4H),
4.11–4.06 (m, 1H), 3.74 (dd, J = 13.6, 6.8 Hz, 1H), 3.60
(dd, J = 8.4, 5.2 Hz, 1H), 3.47 (dd, J = 8.0, 5.2 Hz, 1H),
2.75 (dd, J = 17.6, 8.0 Hz, 1H), 2.53 (dd, J = 18.0, 5.2 Hz,
1H), 2.45 (dd, J = 18.0, 8.0 Hz, 1H), 2.25 (brs, 2H), 2.18
(dd, J = 18.0, 5.2 Hz, 1H), 1.40 (d, J = 1.2 Hz, 3H), 1.39
(d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ = 178.2, 177.9, 175.0, 175.0, 144.3, 143.4, 135.6, 135.5,
129.0, 128.9, 128.9, 128.7, 128.1, 127.7, 127.2, 126.5, 58.6,
56.3, 55.7, 54.0, 42.5, 42.4, 37.7, 36.7, 24.3, 24.1; HRMS-
ESI (m/z): (M+H)+ calcd for C19H21N2O2: 309.1603;
found: 309.1628.
4.27 | 1-Benzyl-3-(4-methoxyphenyl)
pyrrolidine-2,5-dione (9d)
Colorless liquid yield: 251 mg (85%), IR (KBr, cm−1):
2930, 2843, 1772, 1702, 1611, 1509, 1431, 1394, 1345,

12
RAO ET AL.
1250, 1164, 1031, 889, 833, 720, 629, 524; 1H NMR
(400 MHz, CDCl3): δ = 7.32 (d, J = 7.6 Hz, 2H), 7.26–7.19
(m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H),
4.68–4.59 (m, 2H), 3.88 (dd, J = 9.2, 4.8 Hz, 1H), 3.71 (s,
3H), 3.09 (dd, J = 18.4, 9.6 Hz, 1H), 2.69 (dd, J = 18.8,
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 177.8,
175.9, 159.3, 135.9, 129.2, 128.9, 128.8, 128.5, 128.1, 114.6,
55.4, 45.2, 42.7, 37.3; HRMS-ESI (m/z): (M+H)+ calcd for
C18H18NO3: 296.1287; found: 296.1276.
4.72–4.60 (m, 2H), 4.13 (dd, J = 6.4, 1.2 Hz, 2H), 3.68–
3.53 (m, 2H), 2.84–2.65 (m, 2H), 2.40–2.34 (m, 1H), 1.86
(dd, J = 17.6, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ = 177.8, 177.5, 177.0, 176.9, 175.4, 141.9, 135.5, 129.3,
129.2, 129.2, 128.9, 128.7, 128.6, 128.3, 127.9, 126.0, 124.6,
123.9, 123.7, 123.2, 123.0, 110.5, 110.3, 46.4, 45.7, 42.9,
42.8, 40.7, 40.4, 31.8, 30.0; HRMS-ESI (m/z): (M+H)+
calcd for C19H17N2O3: 321.1239; found: 321.1258.
4.31 | 1-Benzyl-3-(phenylthio)
pyrrolidine-2,5-dione (10a)
4.28 | 1-Benzyl-3-(5-hydroxy-
2-methoxyphenyl)pyrrolidine-2,5-dione (9e)
Yellow color liquid, yield: 267 mg (90%); IR (KBr, cm−1):
3062, 2935, 2857, 2250, 1960, 1776, 1718, 1577, 1484,
Black color liquid yield: 186 mg (60%), IR (KBr, cm−1):
3440, 2927, 2358, 1773, 1701, 1602, 1517, 1437, 1395,
1
1394, 1347, 1162, 1079, 1028, 895, 825, 741, 698, 631; H
1
1347, 1274, 1164, 1030, 703, H NMR (400 MHz, CDCl3):
NMR (400 MHz, CDCl3): δ = 7.38–7.36 (m, 2H), 7.28–
7.24 (m, 6H), 7.19–7.15 (m, 2H), 4.53 (s, 2H), 3.95 (dd,
J = 9.2, 4.0 Hz, 1H), 3.06 (dd, J = 18.8, 9.2 Hz, 1H), 2.60
(dd, J = 18.8, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ = 175.3, 174.1, 135.2, 134.2, 130.1, 129.2, 129.1, 128.8,
128.6, 127.9, 43.7, 42.6, 35.7; HRMS-ESI (m/z): (M+H)+
calcd for C17H16NO2S: 298.0902; found: 298.0919.
δ = 9.35 (s, 1H), 7.35–7.25 (m, 5H), 6.77-6.72 (m, 3H),
4.67–4.57 (m, 2H), 4.11–4.07 (m, 1H), 3.66 (s, 3H),
3.77-3.07 (m , 1H), 2.73–2.67 (m, 1H) 2.51-2.49 (m, 1H);
13C NMR (100 MHz, CDCl3): δ = 178.4, 176.6, 152.0,
148.8, 136.4, 128.4, 127.3, 125.3, 116.7, 115.8, 113.7, 55.4,
43.4, 41.6, 35.7; HRMS-ESI (m/z): (M+H)+ calcd for
C18H18NO4: 312.1236; found: 312.1245.
4.32 | 1-Benzyl-3-(pyrimidin-2-ylthio)
pyrrolidine-2,5-dione (10b)
4.29 | 1-Benzyl-3-(3-hydroxy-
4-methoxyphenyl)pyrrolidine-2,5-dione (9f)
Yellow color liquid, yield: 267 mg (89%), IR (KBr, cm−1):
3037, 2927, 2856, 1780, 1695, 1557, 1496, 1391, 1346, 1163,
Black color liquid, yield: 155 mg (50%), IR (KBr, cm−1):
3441, 2930, 2854, 1772, 1708, 1602, 1517, 1437, 1394,
1
1078, 897, 810, 759, 698, 634, 484; H NMR (400 MHz,
1
1347, 1273, 1162, 1077, 1030, 922, 890, 816, 703, 625; H
CDCl3): δ = 7.84 (d, J = 4.8 Hz, 2H), 7.41–7.38 (m, 2H),
7.21 (dd, J = 6.4, 3.6 Hz, 3H), 6.74 (t, J = 4.8 Hz, 1H), 4.69
(s, 2H), 4.01 (dd, J = 8.0, 4.0 Hz, 1H), 3.23–3.16 (m, 1H),
2.83 (dd, J = 18.4, 5.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ = 175.1, 174.9, 169.4, 157.3, 135.7, 129.7, 128.6,
127.9, 117.1, 43.1, 41.2, 36.1; HRMS-ESI (m/z): (M+H)+
calcd for C15H14N3O2S: 300.0807; found: 300.0801.
NMR (400 MHz, CDCl3): δ = 7.42–7.40 (m, 2H), 7.33–
7.26 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 6.63 (dd, J = 8.0,
2.0 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.71 (brs, 1H) 4.76–
4.68 (m, 2H), 3.93 (dd, J = 9.2, 4.4 Hz, 1H), 3.75 (s, 3H),
3.21–3.14 (m, 1H), 2.80–2.74 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ = 177.8, 176.1, 147.1, 145.5, 136.0,
129.1, 128.9, 128.8, 128.1, 120.2, 115.0, 109.7, 55.9, 45.6,
42.8, 37.4; HRMS-ESI (m/z): (M+H)+ calcd for
C18H17NO4: 312.1236; found: 312.1244.
4.33 | 1-Benzyl-3-(p-tolylthio)pyrrolidine-
2,5-dione (10c)
4.30 | 11-Benzyl-3-(2-oxoindolin-3-yl)
pyrrolidine-2,5-dione (9g)
Yellow color liquid, yield: 280 mg (90%), IR (KBr, cm−1):
3030, 2926, 2858, 1776, 1711, 1596, 1492, 1437, 1394,
1346, 1164, 1087, 1028, 897, 812, 701, 632; 1H NMR
(400 MHz, CDCl3): δ = 7.27–7.25 (m, 7H), 6.98-6.96 (m,
2H), 4.55 (s, 2H), 3.92 (dd, J = 9.2, 4.4 Hz, 1H), 3.08 (dd,
J = 18.8, 9.2 Hz, 1H), 2.68-2.62 (m, 1H), 2.29 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 175.5, 174.4, 139.8, 135.4,
135.1, 130.2, 129.0, 128.7, 128.0, 126.0, 44.1, 42.8, 35.7,
21.3; HRMS-ESI (m/z): (M+H)+ calcd for C18H18NO2S:
312.1058; found: 312.1073.
Yellow color liquid, yield: 256 mg (80%), IR (KBr, cm−1):
3293, 2926, 2358, 1775, 1706, 1621, 1473, 1398, 1343,
1
1166, 750; H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1H),
8.64 (s, 1H), 7.43–7.40 (m, 2H), 7.35–7.34 (m, 3H), 7.30–
7.29 (m, 1H), 7.24–7.21 (m, 2H), 7.16–7.12 (m, 2H), 7.0–
6.87 (m,, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 8.0 Hz,
1H), 6.37 (d, J = 7.2 Hz, 1H), 4.77 (d, J = 14.0 Hz, 1H),

RAO ET AL.
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ACKNOWLEDGMENTS
We thank SERB, New Delhi, CSIR, New Delhi and DBT-
IPLS Programme, Pondicherry University for financial
support. RSR thanks the UGC, New Delhi for SRF. We
gratefully acknowledge CIF, Pondicherry University for
NMR/IR data. The authors wish to acknowledge Dr. C. P.
Vinod (CSIR-NCL) for helpful discussions.
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DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
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ORCID
Chinnasamy Ramaraj Ramanathan https://orcid.org/
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14
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How to cite this article: Rao RS, Sahani A,
Ali SH, Pradhan S, Ramanathan CR. γ-Al2O3/triflic
acid as cooperative catalysts for the tandem
Michael addition/carbocyclization: An easy access
to 2-substituted pyrrolo[2,1-a]isoquinolines and 3-
substituted pyrrolidine-2,5-diones. J Heterocyclic
Chem. 2021;1–14. https://doi.org/10.1002/jhet.4266
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