Highly efficient aluminum trichloride catalyzed michael addition of indoles and pyrroles to maleimides

Article abstract of DOI:10.1055/s-0033-1339515

A highly efficient synthetic strategy for Michael addition of indoles and pyrroles to maleimides has been developed using the Lewis acids zinc chloride or aluminum trichloride as the catalyst. The reactions generated 3-substituted indoles and 2-substitute

Full text of DOI:10.1055/s-0033-1339515

PAPER
▌2719
pHapiegr hly Efficient Aluminum Trichloride Catalyzed Michael Addition of Indoles
and Pyrroles to Maleimides
Lewis Acid Catalyzed Michael Addition
Yu-Long An, Zhi-Yu Shao, Jian Cheng, Sheng-Yin Zhao*
Department of Chemistry, Donghua University, No. 2999 North Renmin Road, Shanghai 201620, P. R. of China
Fax +86(21)67792608-805; E-mail: syzhao8@dhu.edu.cn
Received: 09.05.2013; Accepted after revision: 11.07.2013
reaction conditions to enhance reactivity such as heating,
Abstract: A highly efficient synthetic strategy for Michael addition
microwave irradiation,17 or ionic liquids.18 The majority
of indoles and pyrroles to maleimides has been developed using the
of these reactions were studied using highly nucleophilic
indoles, and even electron-poor indoles sometimes give
Lewis acids zinc chloride or aluminum trichloride as the catalyst.
The reactions generated 3-substituted indoles and 2-substituted pyr-
roles in high yields with excellent regioselectivity in the presence of unsatisfactory yields. Thus, an efficient, economical and
a catalytic amount of zinc chloride or aluminum trichloride under
mild reaction conditions. The method is simple, efficient, and prac-
tical.
environmentally benign Lewis acid catalyst is highly de-
sirable for this process.
Recently, there has been an increase in the use of alumi-
num trichloride in chemistry that has seen it emerged as a
Key words: Michael addition, indole, pyrrole, maleimide, alumi-
num trichloride
safe, economical, air and moisture tolerant, alternative
Lewis acid in various organic transformations.19 In con-
tinuation of our efforts to develop selective, efficient, and
Indole derivatives are ubiquitous structural features of
mild synthetic methodologies for the preparation of het-
many alkaloid natural products and drug candidates.1
erocycle derivatives, herein, we report the aluminum tri-
Among them, indolylsuccinimide rings are important
chloride catalyzed Michael addition of biologically and
building blocks in the synthesis of biologically active
chemically important indoles and pyrroles to maleimides.
compounds and natural products.2 Their derivatives are
In addition, the notable advantages of this methodology
important intermediates in organic synthesis and pharma-
are mild conditions, short reaction times, high yields, and
ceutical chemistry.3
no side reaction products.
Generally, indolylsuccinimides are prepared by the reac-
In the initial studies, we chose 1H-indole (1) as a model
tion of indoles with maleimides in acetic acid. However,
compound to study this reaction, because the product, 3-
the reaction requires long reaction times, and the products
indolylsuccinimide 3a, is solid and easy to purify. As
are obtained in low yields. 4 The acid-catalyzed conjugate
shown in Table 1, the reaction between 1H-indole (1) and
addition of indoles requires careful control of the acidity
maleimide (2) in the presence of Lewis acid is accom-
to prevent side reactions such as dimerization or polymer-
plished by heating the reagents in 1,2-dichloroethane at
ization.5 Recently, Michael addition and Friedel–Crafts-
reflux for eight hours. Since, Lewis acid catalyzed addi-
type alkylation of heteroaromatics with electron-deficient
tion of indole to maleimide has not previously been re-
α,β-unsaturated carbonyl compounds have been used as
ported in the literature, zinc triflate was initially chosen as
powerful methods for direct C–C bond formation in the
the catalyst. Unfortunately, zinc triflate and yttrium tri-
functionalization of these biologically important motifs.6
flate do not function as catalysts in this reaction (entries 1
The 3-position of indole is the preferred site for electro-
and 2) and the starting materials were recovered. Using
philic substitution reactions, and the resultant 3-alkyl- or
bismuth nitrate as the catalyst gave numerous products be-
3-acylindoles are versatile intermediates for the synthesis
cause of its oxidative properties (entry 3). Next, we exam-
of a wide range of indole derivatives. A simple and direct
ined the use of classic Lewis acids, such as ZnCl2, ZnBr2,
method for the synthesis of 3-alkylated indoles involves
Zn(OAc)2, FeCl3, and AlCl3. Zinc chloride was an effec-
the conjugate addition of indoles to α,β-unsaturated com-
tive catalyst (entry 4); 3-indolylsuccinimide 3a was
pounds in the presence of Lewis acids such as InBr3,7
formed in 88% yield in the presence of 0.1 equivalents of
CeCl3–NaI,8 Zn(OTf)2,9 ZrCl4,10 Au(III),11 Ru(III),12
zinc chloride. In contrast, using 0.1 equivalents of
Zn(OAc)2,13 Al-MCM-14,14 Bi(NO3)3,15 or I2,16 which
iron(III) chloride gave 3-indolylsuccinimide 3a in 53%
have been exploited with varying degrees of success.
yield (entry 7). Compound 3a was also obtained in 80%
However, the reaction usually demands high catalyst
yield using aluminum trichloride as catalyst. The possible
loadings (>10 mol%), long reaction times ranging from
reason is that iron(III) chloride lead to the partial polym-
several hours to several days in some cases, strong acidic
erization of maleimide due to its oxidation. Using zinc
conditions, expensive and hazardous reagents, and special
chloride as the catalyst, the solvent was varied (entries 4
and 10–13); 3-indolylsuccinimide 3a was not formed us-
SYNTHESIS 2013, 45, 2719–2726
Advanced online publication: 06.08.2013
DOI: 10.1055/s-0033-1339515; Art ID: SS-2013-H0344-OP
© Georg Thieme Verlag Stuttgart · New York
ing N,N-dimethylformamide, tetrahydrofuran, or dioxane
as the solvent. These results demonstrate that zinc chlo-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2720
Y.-L. An et al.
PAPER
ride is a more effective catalyst than iron(III) chloride. It
should be noted that without any catalyst, the reaction did
not generate the desired product 3a (entry 9).
Table 1 Optimization of the Reaction Conditionsa
H
N
O
O
H
N
O
O
Lewis acid
+
N
H
N
H
1
2
3a
Entry
Catalyst
Solvent
Time (h) Yieldb (%)
1
2
Zn(OTf)2
Y(OTf)3
Bi(NO3)3
ZnCl2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMFc
THF
24
24
8
0
0
Figure 1 Effect of catalyst loading on yield. Reaction conditions:
indole (1, 3 mmol), maleimide (2, 3 mmol), 1,2-dichloroethane (15
mL), reflux, 8 h.
3
0
4
8
88
85
45
53
80
0
5
ZnBr2
8
also was unsuccessful due to polymerization of the ma-
leimides. Next, we examined the use of aluminum trichlo-
ride as the Lewis acid. The results suggest aluminum
trichloride is an efficient catalyst for the addition of elec-
tron-deficient indoles to maleimides (entries 9–12); 3-in-
dolylsuccinimides 3i–l were obtained ca. 90% yield.
6
Zn(OAc)2
FeCl3
24
8
7
8
AlCl3
8
9
no catalyst
ZnCl2
24
24
24
24
24
Crystals of compound 3b suitable for X-ray analysis was
obtained by slow evaporation of a solution of this com-
pound in a mixture of ethyl acetate and ethanol (1:1). The
crystal data suggested that the reaction was clean and gave
the C3-substitution product exclusively (Figure 2). No
C1-substitution product was isolated. Using pyrrole as
substrate, only C2-substitution products 3m,n were ob-
tained in ca. 90% yield. The packing view of 3b in the unit
cell and tables of X-ray crystallographic data can be found
in the Supporting Information. The target compounds 3a–
l were obtained in good to excellent yields with no forma-
tion of side products, such as polymers, that are frequently
encountered under the influence of strong protic acids.
10
11
12
13
0
ZnCl2
0
ZnCl2
dioxane
CHCl3
0
ZnCl2
38
a Reaction conditions: 1H-indole (1, 10 mmol), maleimide (2, 10
mmol), catalyst (10 mol%), solvent (50 mL), reflux, stirring.
b Isolated yield.
c Reaction temperature ~100–105 °C.
With a catalytic amount of zinc chloride (≤10 mol% based
on indole), 1H-indole (1) reacted with maleimide (2) to
give 3-indolylsuccinimide 3a (Figure 1). As shown in Fig-
ure 1, increasing the loading of zinc chloride initially led
to a sharp increase in the yield and then it plateaued. Using
20 mol% of zinc chloride as the catalyst gave a ~95%
yield.
To further illustrate the utility of this method, a series of
substrates including indoles and pyrroles were used as
substrates. The results are summarized in Table 2. In some
cases, isolated yields were good and ranged from 82 to
95%. However, the methodology is unsuitable for the
Michael addition of electron-deficient indoles (5-nitro-
1H-indole and 5-bromo-1H-indole) to maleimides; using
zinc chloride as a catalyst under the optimized conditions
did not give the Michael product. Using chlorobenzene, a
high-boiling solvent, in the procedure instead of 1,2-di-
chloroethane in order to elevate the reaction temperature
Figure 2 ORTEP structure of the compound 3b, showing 50% prob-
ability ellipsoids
Synthesis 2013, 45, 2719–2726
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lewis Acid Catalyzed Michael Addition
2721
Table 2 Lewis Acid Catalyzed Michael Addition of Indoles and Pyrroles to Maleimidesa
Entry
Indole
Maleimide
Catalyst
ZnCl2
Time (h) Product
Yieldb (%)
H
N
O
O
O
O
H
N
O
O
O
O
O
O
1
8
88
90
92
91
95
N
H
N
H
3a
Me
N
O
Me
N
2
3
4
5
ZnCl2
ZnCl2
ZnCl2
ZnCl2
8
N
H
N
H
3b
Ph
N
O
Ph
N
8
N
H
N
H
3c
Bn
N
O
O
Bn
N
O
O
8
N
H
N
H
3d
H
N
O
O
H
N
O
O
8
N
N
Me
Me
3e
H
N
O
O
H
N
O
O
6
7
ZnCl2
8
89
95
N
H
N
H
3f
H
N
O
O
MeO
H
N
MeO
O
O
ZnCl2
8
N
H
N
H
3g
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2719–2726

2722
Y.-L. An et al.
PAPER
Table 2 Lewis Acid Catalyzed Michael Addition of Indoles and Pyrroles to Maleimidesa (continued)
Entry
Indole
Maleimide
Catalyst
ZnCl2
Time (h) Product
Yieldb (%)
Me
N
O
O
MeO
Me
MeO
N
O
O
O
O
8
8
90
O
O
O
O
N
H
N
H
3h
H
N
O
O
Br
H
N
Br
9
10
11
AlCl3
AlCl3
AlCl3
12
85
82
86
N
H
N
H
3i
H
N
O
O
H
N
12
N
CO2Et
H
N
CO2Et
H
3j
H
N
O
O
O2N
H
N
O2N
16
N
H
N
H
3k
Ph
N
O
O
O2N
Ph
N
O2N
O
O
12
AlCl3
16
89
N
H
N
H
3l
O
N
H
H
N
NH
O
O
O
13
14
ZnCl2
ZnCl2
8
92
96
N
H
3m
O
N
O
Bn
N
N
H
Bn
O
O
8
N
H
3n
a Reaction conditions: indole (10 mmol), maleimide (10 mmol), Lewis acid (1 mmol), reflux.
b Isolated yield.
Synthesis 2013, 45, 2719–2726
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lewis Acid Catalyzed Michael Addition
2723
With the compound 3a in hand, it was oxidized by 2,3-di- added to labile intermediate 6 to yield the corresponding
chloro-5,6-dicyano-1,4-benzoquinone to provide 3-in- Michael adduct 7, which upon subsequent electron reor-
dolylmaleimide 4.4a Then, compound 4 was subjected to ganization followed by hydrogen transfer yields com-
Michael addition with 5-methoxy-1H-indole in the pres- pound 3a, releasing the catalyst for next cycle. In the
ence of zinc chloride to give trans-bisindolylsuccinimide catalytic cycle, it is thought that aluminum trichloride pro-
5 in 90% yield (Scheme 1). This trans stereochemistry motes the reaction by increasing the electrophilic charac-
was deduced from the existence of the signal of succin- ter of the enal. A mechanistic study in our laboratory to
imide methine protons at δ = 3.52.3d,20 It provided a useful clarify the pathways for aluminum trichloride employing
intermediate for the synthesis of indolylmaleimides with Michael addition is under way.
heteroaromatic moieties.
In summary, aluminum trichloride and zinc chloride have
been demonstrated to be a highly selective and efficient
catalyst for the Michael addition of a variety of indoles
H
H
N
O
O
N
O
O
and pyrroles to N-substituted maleimides. The reactions
were performed smoothly to generate the desired products
3-substituted indolylsuccinimides in good yields under
safe experimental conditions. The notable advantages of
this methodology are mild conditions, short reaction
times, high yields, and the absence of side products. This
method offers one of the important motifs for synthesis of
3-substituted indoles, as natural products, biologically ac-
tive compounds, and pharmaceutical agents.
ZnCl2
DDQ
5-methoxyindole
N
N
H
H
4
3a
H
N
O
O
OMe
N
N
H
H
Melting points were determined with RY-1 apparatus and are un-
corrected. IR spectra were determined as KBr pellets on a Shimadzu
5
1
model 470 spectrophotometer. H and 13C NMR spectra were re-
Scheme 1
corded using a Bruker AV 400 MHz spectrometer in DMSO-d6 and
CDCl3 with TMS as internal standard. EI mass spectra were record-
ed on Shimadzu QP-2010 GC-MS system and Waters Micromass
GCT system. Maleimides were purchase from TCI China. All
chemicals and reagents were purchased from known commercial
We believe that aluminum trichloride functions as a cata-
lyst in our Michael addition protocol for both electron-
donating and electron-deficient indoles. A plausible
mechanism for 3-indolylmaleimide compounds is pro-
posed in Scheme 2. Although we do not have additional
evidence for this, we hypothesized that aluminum trichlo-
ride readily coordinates to the oxygen and nitrogen atoms
of maleimide.21 Rapid formation of 7 may be due to the
initial formation of intermediate 6 from aluminum trichlo-
ride and maleimide, which presumably reduces the activa-
tion energy required for Michael addition. Next, indole is
1
suppliers and used without further purification. Mp and H NMR
data of known compounds is in accord with that reported in the lit-
erature. The purity of substrates and the monitoring of reactions
were performed by TLC on silica gel polygram SILG/UV 254
plates.
Crystals of 3-(1H-indole-3-yl)-1-methylpyrrolidine-2,5-dione (3b)
were obtained by dissolving 3b (0.2 g) in EtOAc (3 mL) and EtOH
(3 mL) and evaporating the solvent slowly at r.t. over 2 d. The data
were collected on CAD-4 diffractometer equipped with graphite-
monochromatic MoKα radiation (λ = 0.71037 Å) by using an ω
scan mode at 293(2) K. The structure of 3b is shown in Figure 2. X-
ray crystallographic data for compound 3b can be found in the Sup-
porting Information.
H
N
O
O
H
AlCl3
N
O
O
Michael Addition of Indoles to Maleimides Catalyzed by Zinc
Chloride; General Procedure
2
A mixture of the indole (10 mmol), maleimide (10 mmol), and an-
hyd ZnCl2 (1 mmol) in 1,2-dichloroethane (40 mL) was stirred and
refluxed for the specified time (TLC monitoring). After completion
of the reaction, the mixture was cooled to r.t., and H2O (15 mL) was
added. The mixture was extracted with EtOAc (2 × 15 mL), and the
combined organic phases were washed with H2O (2 × 10 mL), and
dried (Na2SO4). The solvent was removed and the residue was re-
crystallized (EtOH) to yield the product. For compounds 3i–l, an-
hyd AlCl3 was used instead of anhyd ZnCl2. The mp and 1H NMR
data of known products are in accord with that reported in the liter-
ature.
Cl2
N
H
HCl
Al
3a
N
O
O
Cl2
Al
6
N
H
O
O
HCl
3-(1H-Indole-3-yl)pyrrolidine-2,5-dione (3a)4a
N
White crystalline solid; yield: 1.88 g (88%); mp 192–194 °C.
H
N
H
7
IR (KBr): 3425, 3139, 3056, 2782, 1770, 1707, 1554, 1456, 743
cm–1.
1
1H NMR (400 MHz, DMSO-d6): δ = 2.76 (dd, J = 18.0, 5.6 Hz, 1 H,
CH2), 3.18 (dd, J = 18.0, 9.5 Hz, 1 H, CH2), 4.34 (dd, J = 9.5, 4.7
Scheme 2 Proposed catalytic cycle for the reaction of indole and ma-
leimide catalyzed by aluminum trichloride
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2719–2726

2724
Y.-L. An et al.
PAPER
Hz, 1 H, CH), 7.00 (t, J = 7.2 Hz, 1 H, HAr), 7.10 (t, J = 7.0 Hz, 1 H,
HAr), 7.32 (s, 1 H, HAr), 7.37 (d, J = 7.8 Hz, 1 H, HAr), 7.42 (d,
J = 7.7 Hz, 1 H, HAr), 11.01 (s, 1 H, NH), 11.28 (s, 1 H, NH).
MS (EI): m/z = 214 [M]+, 162, 156, 143, 115, 105, 89.
3-(5-Methoxy-1H-indole-3-yl)pyrrolidine-2,5-dione (3g)22,25
White crystalline solid; yield: 2.31 g (95%); mp 206–209 °C.
IR (KBr): 3349, 3191, 3072, 2943, 1777, 1690, 1583, 1486, 804
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.75 (dd, J = 18.1, 4.0 Hz, 1 H,
CH2), 3.18 (dd, J = 17.6, 9.4 Hz, 1 H, CH2), 3.74 (s, 3 H, CH3), 4.30
(s, 1 H, CH), 6.76 (d, J = 8.2 Hz, 1 H, HAr), 6.91 (s, 1 H, HAr), 7.25–
7.27 (m, 2 H, HAr), 10.88 (s, 1 H, NH), 11.29 (s, 1 H, NH).
3-(1H-Indole-3-yl)-1-methylpyrrolidine-2,5-dione (3b)4a,22
White crystalline solid; yield: 2.06 g (90%); mp 170–172 °C.
IR (KBr): 3467, 3332, 2936, 1765, 1682, 1557, 1443, 748 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.79 (dd, J = 18.1, 5.4 Hz, 1 H,
CH2), 2.92 (s, 3 H, CH3), 3.23 (dd, J = 17.8, 9.2 Hz, 1 H, CH2), 4.35
(dd, J = 9.2, 5.4 Hz, 1 H, CH), 7.00 (d, J = 7.0 Hz, 1 H, HAr), 7.08
(d, J = 7.1 Hz, 1 H, HAr), 7.33 (s, 1 H, HAr), 7.38 (br s, 2 H, HAr),
11.02 (s, 1 H, NH).
MS (EI): m/z = 244 [M]+, 228, 202, 173, 147, 132, 104, 97, 89.
3-(5-Methoxy-1H-indole-3-yl)-1-methylpyrrolidine-2,5-dione
(3h)22
White crystalline solid; yield: 2.32 g (90%); mp 138–140 °C.
MS (EI): m/z = 228 [M]+, 199, 170, 162, 143, 115, 89.
IR (KBr): 3360, 3126, 3024, 2968, 2938, 1770, 1698, 1578, 1457,
867, 840 cm–1.
3-(1H-Indole-3-yl)-1-phenylpyrrolidine-2,5-dione (3c)23
White crystalline solid; yield: 2.67 g (92%); mp 149–151 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.78 (dd, J = 18.0, 3.4 Hz, 1 H,
CH2), 2.92 (s, 3 H, CH3), 3.23 (dd, J = 17.9, 9.3 Hz, 1 H, CH2), 3.73
(s, 3 H, CH3), 4.32 (dd, J = 9.3, 6.6 Hz, 1 H, CH), 6.76 (d, J = 8.7
Hz, 1 H, HAr), 6.87 (s, 1 H, HAr), 7.25–7.27 (m, 2 H, HAr), 10.88 (s,
1 H, NH).
IR (KBr): 3402, 3344, 3053, 2866, 1778, 1704, 1555, 1495, 745
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.97 (dd, J = 18.1, 5.4 Hz, 1 H,
CH2), 3.41 (dd, J = 18.1, 9.6 Hz, 1 H, CH2), 4.55 (d, J = 9.6, 4.2 Hz,
1 H, CH), 7.03 (d, J = 9.6 Hz, 1 H, HAr), 7.13 (t, J = 13.4 Hz, 1 H,
HAr), 7.35 (d, J = 6.7 Hz, 2 H, HAr), 7.41–7.44 (m, 3 H, HAr), 7.50–
7.52 (m, 3 H, HAr), 11.08 (s, 1 H, NH).
MS (EI): m/z = 258 [M]+, 243, 173, 158, 130, 115, 89.
3-(5-Bromo-1H-indole-3-yl)pyrrolidine-2,5-dione (3i)4a,22
White crystalline solid; yield: 2.48 g (85%); mp 210–213 °C.
MS (EI): m/z = 290 [M]+, 219, 173, 162, 143, 129, 117, 90.
IR (KBr): 3347, 3053, 2927, 1769, 1706, 1558, 1460, 877, 801
cm–1.
1-Benzyl-3-(1H-indole-3-yl)pyrrolidine-2,5-dione (3d)
White crystalline solid; yield: 2.76 g (91%); mp 119–122 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.82 (dd, J = 17.9, 4.7 Hz, 1 H,
CH2), 3.18 (dd, J = 18.0, 9.4 Hz, 1 H, CH2), 4.35 (dd, J = 9.3, 6.6
Hz, 1 H, CH), 7.22 (d, J = 8.5 Hz, 1 H, HAr), 7.35 (d, J = 8.6 Hz, 1
H, HAr), 7.41 (s, 1 H, HAr), 7.65 (s, 1 H, HAr), 11.26 (s, 1 H, NH),
11.30 (s, 1 H, NH).
IR (KBr): 3442, 3326, 3037, 2937, 1769, 1698, 1588, 1493, 744
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.86 (d, J = 17.7 Hz, 1 H,
CH2), 3.33 (dd, 1 H, CH2), 4.44 (d, J = 17.7 Hz, 1 H, CH), 4.65 (s,
2 H, CH2), 6.91 (d, J = 6.5 Hz, 1 H, HAr), 7.08 (s, 1 H, HAr), 7.18–
7.55 (m, 8 H, HAr), 11.03 (s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 36.3, 38.1, 42.1, 111.1, 112.1,
118.8, 119.1, 121.8, 123.9, 126.2, 127.9, 128.2, 128.9, 136.7, 136.9,
176.9, 178.9.
MS (EI): m/z = 292, 294 [M]+, 221, 223, 195, 171, 143, 115, 88.
Ethyl 3-(2,5-Dioxopyrrolidin-3-yl)-1H-indole-2-carboxylate
(3j)
White crystalline solid; yield: 2.34 g (82%); mp 102–104 °C.
IR (KBr): 3563, 3472, 3316, 3054, 2984, 1764, 1701, 1568, 1441,
750 cm–1.
MS (EI): m/z = 304 [M]+, 213, 206, 187, 171, 143, 115, 89.
HRMS (EI): m/z [M]+ calcd for C19H16N2O2: 304.1212; found:
1H NMR (400 MHz, DMSO-d6): δ = 1.36–1.30 (m, 3 H, CH3), 2.70
(dd, J = 17.6, 6.1 Hz, 1 H, CH2), 3.11 (dd, J = 17.6, 9.6 Hz, 1 H,
CH2), 4.31 (q, J = 12.0 Hz, 2 H, CH2), 4.90 (dd, J = 9.3, 6.6 Hz, 1
H, CH), 7.12 (dd, J = 14.3, 7.0 Hz, 1 H, HAr), 7.30 (t, J = 7.6 Hz, 1
H, HAr), 7.48 (d, J = 8.0 Hz, 1 H, HAr), 7.64 (d, J = 7.7 Hz, 1 H, HAr),
11.32 (s, 1 H, NH), 11.87 (s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 14.6, 38.3, 38.6, 61.0, 113.2,
118.7, 120.1, 120.5, 123.8, 125.6, 127.6, 136.4, 161.6, 178.3, 180.1.
MS (EI): m/z = 286 [M]+, 240, 213, 189, 169, 143, 115, 89.
HRMS (EI): m/z [M]+ calcd for C15H14N2O4: 286.0954; found:
304.1210.
3-(1-Methyl-1H-indole-3-yl)pyrrolidine-2,5-dione (3e)24
White crystalline solid; yield: 2.17 g (95%); mp 139–141 °C.
IR (KBr): 3265, 3069, 2936, 1775, 1712, 1616, 1544, 1517, 1475,
737 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.72 (dd, J = 18.0, 4.6 Hz, 1 H,
CH2), 3.19 (dd, J = 18.0, 9.6 Hz, 1 H, CH2), 3.74 (s, 3 H, CH3),
4.35–4.31 (m, 1 H, CH), 7.04 (t, J = 7.2 Hz, 1 H, HAr), 7.17 (t,
J = 7.4 Hz, 1 H, HAr), 7.31 (s, 1 H, HAr), 7.43 (t, J = 6.7 Hz, 2 H,
HAr), 11.31 (s, 1 H, NH).
286.0950.
3-(5-Nitro-1H-indole-3-yl)pyrrolidine-2,5-dione (3k)
White crystalline solid; yield: 2.45 g (86%); mp 224–226 °C.
MS (EI): m/z = 228 [M]+, 199, 179, 157, 142, 130, 115, 89.
IR (KBr): 3396, 3073, 1775, 1705, 1518, 1468, 817 cm–1.
3-(2-Methyl-1H-indole-3-yl)pyrrolidine-2,5-dione (3f)4b
White crystalline solid; yield: 2.03 g (89%); mp 230–232 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.97 (dd, J = 18.0, 5.1 Hz, 1 H,
CH2), 3.25 (dd, J = 7.9, 9.4 Hz, 1 H, CH2), 4.58 (dd, J = 9.3, 6.6 Hz,
1 H, CH), 7.60 (d, J = 9.0 Hz, 1 H, HAr), 7.70 (s, 1 H, HAr), 8.07 (d,
J = 9.0 Hz, 1 H, HAr), 8.59 (s, 1 H, HAr), 11.41 (s, 1 H, NH), 11.86
(s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 37.2, 38.9, 112.6, 114.3,
116.7, 117.2, 126.2, 127.4, 140.0, 140.9, 178.3, 179.9.
IR (KBr): 3364, 3189, 3062, 2921, 1771, 1706, 1497, 1457, 741
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.32 (s, 3 H, CH3), 2.64 (dd,
J = 18.1, 4.2 Hz, 1 H, CH2), 3.13 (dd, J = 18.1, 9.8 Hz, 1 H, CH2),
4.32 (dd, J = 8.3, 4.2 Hz, 1 H, CH), 6.93 (d, J = 7.2 Hz, 1 H, HAr),
7.01 (t, J = 7.3 Hz, 1 H, HAr), 7.12 (d, J = 7.7 Hz, 1 H, HAr), 7.27–
7.29 (m, 1 H, HAr), 10.94 (s, 1 H, NH), 11.40 (s, 1 H, NH).
MS (EI): m/z = 259 [M]+, 229, 188, 158, 142, 115, 89.
HRMS (EI): m/z [M]+ calcd for C12H9N3O4: 259.0593; found:
MS (EI): m/z = 228 [M]+, 213, 183, 157, 130, 115, 89.
259.0596.
Synthesis 2013, 45, 2719–2726
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lewis Acid Catalyzed Michael Addition
2725
3-(5-Nitro-1H-indole-3-yl)-1-phenylpyrrolidine-2,5-dione (3l)
1H NMR (400 MHz, DMSO-d6): δ = 3.52 (d, J = 16.2 Hz, 2 H, 2
CH), 3.60 (s, 3 H, CH3), 6.70–6.75 (m, 2 H, HAr), 6.87 (s, 1 H, HAr),
7.04 (s, 1 H, HAr), 7.18–7.25 (m, 2 H, HAr), 7.30–7.32 (m, 2 H, HAr),
7.36 (d, J = 7.6 Hz, 1 H, HAr), 10.86 (s, 1 H, NH), 11.01 (s, 1 H,
NH), 11.41 (s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 55.7, 60.2, 102.8, 111.2,
112.2, 112.7, 114.9, 115.3, 119.0, 120.2, 121.5, 123.8, 124.3, 125.8,
126.2, 132.7, 137.4, 153.1, 177.4, 180.4.
MS (EI): m/z = 359 [M]+, 329, 318, 288, 258, 243, 214, 173, 137,
128, 115, 109.
HRMS (EI): m/z [M]+ calcd for C21H17N3O3:359.1270; found:
359.1273.
White crystalline solid; yield: 2.98 g (89%); mp 106–109 °C.
IR (KBr): 3396, 3073, 1775, 1705, 1518, 1468, 900, 817 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.15 (dd, J = 18.0, 5.1 Hz, 1 H,
CH2), 3.45 (dd, J = 17.9, 9.4 Hz, 1 H, CH2), 4.75 (m, 1 H, CH),
7.36–7.53 (m, 6 H, HAr), 7.77 (s, 1 H, HAr), 8.03 (d, J = 9.0 Hz, 1 H,
HAr), 8.63 (s, 1 H, HAr), 11.91 (s, 1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 36.3, 37.9, 112.6, 114.1,
116.7, 117.3, 126.2, 127.6, 127.7, 128.8, 129.4, 133.0, 140.0, 141.0,
175.9, 177.5.
MS (EI): m/z = 335, 215, 207, 188, 142, 115, 89.
HRMS (EI): m/z [M]+ calcd for C18H13N3O4: 335.0906; found:
335.0907.
Acknowledgement
3-(1H-Pyrrole-2-yl)pyrrolidine-2,5-dione (3m)
White crystalline solid; yield: 1.50 g (92%); mp 86–88 °C.
The authors acknowledge financial support from the National Natu-
ral Science Foundation of China (Grant 21072029), Shanghai
Municipal Natural Science Foundation (Grant 10ZR1400700), and
the Fundamental Research Funds for the Central Universities from
the Ministry of Education of China (No. 11D-10523 and No. 11D-
10544) for financial support.
IR (KBr): 3403, 3315, 3083, 2883, 1784, 1696, 1537, 730 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.67 (dd, J = 17.9, 6.0 Hz, 1 H,
CH2), 3.04 (dd, J = 17.8, 9.5 Hz, 1 H, CH2), 4.09 (br s, 1 H, CH),
5.92 (br s, 2 H, HAr), 6.66 (s, 1 H, HAr), 10.79 (s, 1 H, NH), 11.17 (s,
1 H, NH).
13C NMR (101 MHz, DMSO-d6): δ = 37.3, 40.9, 106.2, 107.7,
118.2, 127.2, 178.1, 179.1.
MS (EI): m/z = 164 [M]+, 135, 119, 105, 93.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (EI): m/z [M]+ calcd for C8H8N2O2:164.0586; found:
164.0587.
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1-Benzyl-3-(1H-pyrrole-2-yl)pyrrolidine-2,5-dione (3n)
White crystalline solid; yield: 2.43 g (96%); mp 152–154 °C.
IR (KBr): 3302, 3138, 2950, 1766, 1686, 1528, 740, 694 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.84 (dd, J = 18.0, 5.6 Hz, 1 H,
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A soln of DDQ (456 mg, 2 mmol) in dioxane (20 mL) was slowly
added to a soln of 3a (428 mg, 2 mmol) in dioxane (20 mL). The
mixture was stirred at r.t. for 12 h. After filtration and removal of
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IR (KBr): 3433, 3347, 3240, 3057, 1751, 1702, 1601, 740 cm–1.
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trans-3-(1H-Indole-3-yl)-4-(5-methoxy-1H-indole-3-yl)pyrro-
lidine-2,5-dione (5)
White crystalline solid; yield: 0.45 g (90%); mp 150–152 °C.
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Synthesis 2013, 45, 2719–2726
© Georg Thieme Verlag Stuttgart · New York