A multi-component synthesis of 3-aryl-1-(arylmethylideneamino)pyrrolidine-2,5-diones

Article abstract of DOI:10.1016/j.tet.2010.01.108

A multi-component synthesis of 3-aryl-1-(arylmethylideneamino)pyrrolidine-2,5-diones is described. A mixture of N-isocyaniminotriphenylphosphorane, an aldehyde, and Meldrum's acid undergo a 1:2:1 addition reaction under mild conditions to afford the title compounds in good to excellent yields.

Full text of DOI:10.1016/j.tet.2010.01.108

Tetrahedron 66 (2010) 2723–2727
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A multi-component synthesis of 3-aryl-1-(arylmethylideneamino)
pyrrolidine-2,5-diones
,
a
a
b
c
Mehdi Adib a , Samira Ansari , Solmaz Fatemi , Hamid Reza Bijanzadeh , Long-Guan Zhu
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
c Chemistry Department, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A multi-component synthesis of 3-aryl-1-(arylmethylideneamino)pyrrolidine-2,5-diones is described. A
mixture of N-isocyaniminotriphenylphosphorane, an aldehyde, and Meldrum’s acid undergo a 1:2:1
addition reaction under mild conditions to afford the title compounds in good to excellent yields.
Ó 2010 Published by Elsevier Ltd.
Received 27 October 2009
Received in revised form 23 December 2009
Accepted 27 January 2010
Available online 2 February 2010
Keywords:
N-Isocyaniminotriphenylphosphorane
Aldehydes
Meldrum’s acid
3-Aryl-1-(arylmethylideneamino)
pyrrolidine-2,5-diones
Multi-component reactions
1. Introduction
b
-turn conformations.7 It has also been shown that they can be
used as irreversible protease inhibitors.8 The bioactive natural
product andrimid (Fig. 1) was found to exhibit potent in vitro an-
tibacterial activity against methicillin resistant Staphylococcus au-
reus and a range of other antibiotic resistant human pathogens.9,10
The cytotoxic labdane alkaloid haterumaimide A (Fig. 1) has been
used as a protein synthesis inhibitor11 and antitumor drug.12
Multi-component reactions (MCRs) have become a significant
part of today’s arsenal of methods in combinatorial chemistry due to
their valued features, such as atom economy, straightforward re-
action design, and the opportunity to construct target compounds
by the introduction of several diversity elements in a single chem-
ical event. Typically, purification of products resulting from MCRs is
also simple since all the organic reagents employed are consumed
and are incorporated into the target compound.1 MCRs, leading to
interesting heterocyclic scaffolds, are particularly useful for the
construction of diverse chemical libraries of ‘drug-like’ molecules.
The isocyanide-based MCRs are especially important in this area.1d,e
Succinimides (pyrrolidine-2,5-diones) are an important class of
heterocyclic compounds with numerous applications in different
fields.2 In medicine, they have been used for the treatment of ar-
thritis, tuberculosis, convulsion, and epilepsy. They are considered
as bioisosteres of hydantoins,3 a heterocycle widely exploited in the
synthesis of combinatorial libraries.4,5 In organic synthesis they
have been used as valuable reagents and intermediates for the
synthesis of natural and non-natural compounds.6 Recently,
succinimide-based pseudopeptides have been shown to stabilize
O
H
N
O
O
H
OH
Ph
O
O
NH
Cl
Cl
N
N
H
H
O
O
OAc
H
andrimid
haterumaimide A
Figure 1. Examples of succinimide subunit containing natural products.
There are several reports on the use of N-isocyanimino
triphenylphosphorane 1 in the synthesis of metal complexes.13,14
However, applications of 1 in organic synthesis are rare. Recently,
a synthesis of 1,3,4-oxadiazepines via a three-component reaction
between 1, dialkyl acetylenedicarboxylates, and 1,3-diphenyl-
1,3-propanedione15 and a synthesis of 2-aryl-1,3,4-oxadiazoles
* Corresponding author. Tel./fax: þ98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.01.108

2724
M. Adib et al. / Tetrahedron 66 (2010) 2723–2727
from 1 and benzoic acids16 were reported. Very recently, we have
described a new synthesis of 2-aryl-5-hydroxyalkyl-1,3,4-oxadia-
zoles via a three-component reaction between 1, aldehydes, and
carboxylic acids.17
(CHAHBCHX) was observed for the two diastereotopic H atoms of the
methylene group
(
dA¼3.02 ppm, dd, 2J¼17.9 Hz, 3J¼5.8 Hz;
dB¼3.34 ppm, dd, 2J¼17.9 Hz, 3J¼9.5 Hz) and the adjacent methine H
atom (dX¼4.55 ppm, dd, 3J¼5.8 Hz, 3J¼9.5 Hz). The characteristic
signals for the eight H atoms of the two aryl substituents were seen
with appropriate chemical shifts and coupling constants. The 1H
decoupled 13C NMR spectrum of 4a showed characteristic signals at
2. Results and discussion
d
¼35.0 ppm (due to CH2), 43.8 ppm (arising from CH), 159.3 ppm
Due to the unique properties of succinimides, the development
of synthetic methods, which enable facile access to these useful
entities are desirable. As part of our current studies on the de-
velopment of efficient methods for the preparation of biologically
active heterocyclic compounds,18 herein we describe a novel,
one-pot, and multi-component synthesis of 3-aryl-1-(arylmethy-
(for the aldimine, N]CH) as well as two deshielded resonances at
d
¼171.7 and 173.0 ppm (due to the two carbonyl groups) along with
other eight distinct resonances for the two aryl substituents in
agreement with the proposed structure. Partial assignments of
these resonances are given in the Experimental section.
Single-crystal X-ray analysis of 4c conclusively confirmed its
structure, and by analogy those of 4a,b,d–j. An ORTEP diagram of 4c
is shown in Figure 2.19
lideneamino)pyrrolidine-2,5-diones. Thus
a mixture of N-iso-
cyaniminotriphenylphosphorane 1, an aldehyde 2, and Meldrum’s
acid 3 undergo a 1:2:1 addition reaction in THF at ambient tem-
perature to afford the corresponding 3-aryl-1-(arylmethylidenea-
mino)pyrrolidine-2,5-diones 4a–j in 81–92% yields (Scheme 1,
Table 1). All the reactions went to completion within 3 h. 1H NMR
spectroscopic analysis of the reaction mixtures clearly indicated
formation of the corresponding pyrrolidine-2,5-diones 4 in good to
excellent yields.
A plausible mechanism for the formation of the pyrrolidine-2,5-
diones 4 is provided in Scheme 2. On the basis of the chemistry of
isocyanides,1d,e,20–22 it is reasonable to assume that the 5-arylme-
thylidene Meldrum’s acid 5 formed from the initial condensation of
the aldehyde 2 and Meldrum’s acid 3 could undergo nucleophilic
attack of N-isocyaniminotriphenylphosphorane 1 leading to the
intermediate 6 by removal of an acetone molecule. Then, this in-
termediate may be attacked by a water molecule to form adduct 7,
which may undergo intramolecular addition of nitrogen atom to
the adjacent ketene moiety to produce the N-imino-
triphenylphosphorane pyrrolidine-2,5-dione intermediate 8. Aza
Wittig reaction of this intermediate with another aldehyde mole-
cule would afford the isolated 3-aryl-1-(arylmethylideneamino)-
pyrrolidine-2,5-dione 4 by removal of a triphenylphosphine oxide
molecule and decarboxylation.
O
O
O
THF
N
N
Ph3PO
C
Ph3P
ArCHO
+
+
+
N
N
r.t., 3 h
O
O
Ar
Ar
O
3
1
2
4
Scheme 1. One-pot synthesis of 3-aryl-1-(arylmethylideneamino)-pyrrolidine-2,5-di-
ones 4a–j.
Table 1
Synthesis of 3-aryl-1-(arylmethylidene amino)-pyrrolidine-2,5-diones 4a–j
3. Conclusion
4
Ar
Yielda (%)
In conclusion, we have developed
a one-pot and multi-
a
b
c
d
e
f
g
h
i
4-O2NC6H4
C6H5
92
90
91
92
89
81
83
91
86
88
component reaction between N-isocyaniminotriphenylphosphorane,
aldehydes, and Meldrum’s acid for the preparation of 3-aryl-1-
(arylmethylideneamino)pyrrolidine-2,5-diones, which are of poten-
tial chemical, synthetic and pharmacological interest. Good to
excellent yields of the products and mild reaction conditions are the
main advantages of this method.
4-BrC6H4
4-ClC6H4
4-CH3C6H4
3-CH3OC6H4
3-FC6H4
4-FC6H4
2-Furyl
2-Thienyl
j
4. Experimental
4.1. General
a
Isolated yield.
The structures of the isolated products 4a–j were deduced on the
basis of IR, 1H and, 13C NMR spectroscopy, mass spectrometry, and
elemental analysis. The mass spectrum of 4a displayed the molec-
ular ion (Mþ) peak at m/z¼368, which was consistent with the
product structure. The 1H NMR spectrum of 4a exhibited a sharp
All the reagents and solvents were obtained from Merck (Ger-
many) and were used without further purification. N-Iso-
cyaniminotriphenylphosphorane 1 was prepared according to the
literature procedure.13 Melting points were measured on an Elec-
trothermal 9100 apparatus. Elemental analyses for C, H, and N were
singlet at
d¼9.36 ppm due to the aldimine H atom. An ABX system
Figure 2. ORTEP diagram of the molecular structure of 4c.

M. Adib et al. / Tetrahedron 66 (2010) 2723–2727
2725
_
O
O
O
O
.
_
H2O
O
O
_
_
O
O
O
(CH3)2CO
ArCHO
+
+
N
Ar
O
O
+
N
Ar
H2O
N
C
PPh3
PPh3
5
N
6
3
1
2
OH
O
O
O
O
O
.
HO
ArCHO
N
N
N
N
N
_
Ph3PO
PPh3
Ar
H
Ar
Ar
Ar
N
PPh3
_
CO2
O
O
O
4
7
8
Scheme 2. Proposed mechanism for the reaction.
performed using a Heraeus CHN-O-Rapid analyzer. Mass spec-
trometry was performed on a FINNIGAN-MATT 8430 mass spec-
trometer operating at an ionization potential of 20 eV. 1H NMR and
13C NMR spectra (DMSO-d6 solution) were recorded using a Bruker
DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz, re-
spectively. Infrared spectra were recorded on a Shimadzu IR-460
spectrometer. X-ray crystallography was performed on a Bruker
SMART diffractometer equipped with a CCD area detector with
4.28 (1H, dd, J¼5.3, 9.5 Hz, CH), 7.32 (1H, dd, J¼6.4, 6.5 Hz, CH),
7.36–7.43 (4H, m, 4CH), 7.51–7.60 (3H, m, 3CH), 7.87 (2H, d,
J¼7.0 Hz, 2CH), 9.04 (1H, s, CH). 13C NMR (125.8 MHz, DMSO-d6):
d
35.5 (CH2), 44.1 (CH), 127.5, 128.2, 128.3, 128.7, 129.1, and 132.3
(6CH), 132.8, and 137.7 (2C), 163.6 (CH), 172.1, and 173.8 (2C]O).
4.2.3. 1-(4-Bromobenzylideneamino)-3-(4-bromophenyl)pyrroli-
dine-2,5-dione (4c). Colorless crystals, mp 208–209 ꢀC, yield:
0.20 g, 91%. IR (KBr) (nmax/cmꢁ1): 1701, 1582, 1480, 1375, 1320, 1224,
1170,1059,1002, 945, 858, 817, 721, 658. MS, m/z (%): 438 (Mþ 81Br2,
1), 436 (Mþ 81Br79Br, 2), 434 (Mþ 79Br2, 1), 312 (6), 254 (35), 226
(25), 210 (21), 182 (67), 173 (100), 145 (13), 129 (12), 101 (39), 89
(23), 75 (28). Anal. Calcd for C17H12Br2N2O2 (436.10): C, 46.82; H,
2.77; N, 6.42. Found: C, 46.8; H, 2.8; N, 6.4%. 1H NMR (500.1 MHz,
graphite monochromatized Mo K
a radiation. Chromatography
columns were prepared from Merck silica gel 60 mesh.
4.2. General procedure
A mixture of N-isocyaniminotriphenylphosphorane (0.5 mmol)
and the appropriate aldehyde (1 mmol) was dissolved in hot THF
(5 mL). Then, Meldrum’s acid (0.5 mmol) was added to the reaction
mixture, which was stirred at ambient temperature for 3 h. Then,
the solvent was removed under the reduced pressure and the
residue was purified by column chromatography using n-hexane–
EtOAc (4:1) as eluent. The solvent was removed, and the product
was obtained as colorless crystals.
DMSO-d6):
d
2.90 (1H, dd, J¼5.5, 17.9 Hz, CH), 3.27 (1H, dd, J¼9.5,
17.9 Hz, CH), 4.30 (1H, dd, J¼5.5, 9.5 Hz, CH), 7.38 (2H, d, J¼8.4 Hz,
2CH), 7.56 (2H, d, J¼8.4 Hz, 2CH), 7.73 (2H, d, J¼8.4 Hz, 2CH), 7.81
(2H, d, J¼8.4 Hz, 2CH), 9.36 (1H, s, CH). 13C NMR (125.8 MHz,
DMSO-d6):
d 35.2 (CH2), 43.5 (CH), 120.7, and 125.8 (2C), 130.1,
130.5, and 131.5 (3CH), 132.1 (C), 132.2 (CH), 136.9 (C), 161.7 (CH),
171.9, and 173.4 (2C]O).
4.2.1. 1-(4-Nitrobenzylideneamino)-3-(4-nitrophenyl)pyrrolidine-
2,5-dione (4a). Colorless crystals, mp 275 ꢀC, yield: 0.17 g, 92%. IR
(KBr) (nmax/cmꢁ1): 1712, 1596, 1511, 1334, 1179, 1104, 1046, 965, 845,
737, 692. MS, m/z (%): 368 (Mþ, <1), 220 (13), 178 (13), 165 (5), 152
(15), 151 (100), 150 (87), 119 (9), 105 (23), 104 (20), 92 (12), 77 (63),
65 (13), 51 (42). Anal. Calcd for C17H12N4O6 (368.30): C, 55.44; H,
3.28; N, 15.21. Found: C, 55.4; H, 3.4; N, 15.1%. 1H NMR (500.1 MHz,
4.2.4. 1-(4-Chlorobenzylideneamino)-3-(4-chlorophenyl)pyrrolidine-
2,5-dione (4d). Colorless crystals, mp 201 ꢀC, yield: 0.16 g, 92%. IR
(KBr) (nmax/cmꢁ1): 1708, 1586, 1560, 1490, 1378, 1329, 1233, 1178,
1167, 1088, 1069, 1049, 1012, 975, 947, 827. MS, m/z (%): 347 (Mþ,
<1), 322 (27), 279 (19), 266 (66), 238 (13), 220 (12), 205 (15), 167
(40), 149 (100), 138 (33), 122 (39), 97 (19), 83 (27), 69 (53). Anal.
Calcd for C17H12Cl2N2O2 (347.20): C, 58.81; H, 3.48; N, 8.07. Found:
DMSO-d6):
d
3.02 (1H, dd, J¼5.8, 17.9 Hz, CH), 3.34 (1H, dd, J¼9.5,
C, 58.7; H, 3.6; N, 7.9%. 1H NMR (500.1 MHz, DMSO-d6):
d 2.90 (1H,
17.9 Hz, CH), 4.55 (1H, dd, J¼5.8, 9.5 Hz, CH), 7.75 (2H, d, J¼8.8 Hz,
2CH), 8.14 (2H, d, J¼8.8 Hz, 2CH), 8.23 (2H, d, J¼8.8 Hz, 2CH), 8.34
(2H, d, J¼8.8 Hz, 2CH), 9.36 (1H, s, CH). 13C NMR (125.8 MHz,
dd, J¼5.5,17.9 Hz, CH), 3.27 (1H, dd, J¼9.5,17.9 Hz, CH), 4.32 (1H, dd,
J¼5.5, 9.5 Hz, CH), 7.41–7.48 (4H, m, 4CH), 7.59 (2H, d, J¼8.5 Hz,
2CH), 7.89 (2H, d, J¼8.5 Hz, 2CH), 9.09 (1H, s, CH). 13C NMR
DMSO-d6):
d
35.0 (CH2), 43.8 (CH), 123.7, 124.2, 129.3, and 129.9
(125.8 MHz, DMSO-d6): d 35.2 (CH2), 43.4 (CH), 128.6, 129.2, 129.9,
(4CH), 138.9, 144.9, 146.9, and 149.3 (4C), 159.3 (CH), 171.7, and
and 130.2 (4CH), 131.7, 132.2, 136.4, and 136.8 (4C), 161.6 (CH), 171.9,
173.0 (2C]O).
and 173.5 (2C]O).
4.2.2. 1-(Benzylideneamino)-3-phenylpyrrolidine-2,5-dione
4 . 2 . 5 . 1 - ( 4 - M e t h y l b e n z y l i d e n e a m i n o ) - 3 - ( 4 - m e t h yl -
phenyl)pyrrolidine-2,5-dione (4e). Colorless crystals, mp 175–
176 ꢀC, yield: 0.13 g, 89%. IR (KBr) (nmax/cmꢁ1): 1704, 1599, 1564,
1512, 1376, 1325, 1167, 1062, 977, 944, 811, 700. MS, m/z (%): 306
(Mþ, 9), 279 (8), 189 (27), 167 (18), 149 (45), 118 (100), 105 (18), 91
(16), 78 (12). Anal. Calcd for C19H18N2O2 (306.36): C, 47.05; H, 5.92;
N, 9.14. Found: C, 46.9; H, 6.0; N, 9.1%. 1H NMR (500.1 MHz, DMSO-
(4b). Colorless crystals, mp 158–159 ꢀC, yield: 0.12 g, 90%. IR (KBr)
(
nmax/cmꢁ1): 1703, 1602, 1570, 1492, 1450, 1378, 1319, 1162, 1072,
1033, 975, 943, 912, 753, 691. MS, m/z (%): 278 (Mþ, 2), 227 (9), 192
(3), 175 (18), 167 (7), 149 (17), 104 (100), 90 (16), 77 (13), 70 (3), 63
(4). Anal. Calcd for C17H14N2O2 (278.31): C, 73.37; H, 5.07; N, 10.07.
Found: C, 73.3; H, 5.0; N, 9.8%. 1H NMR (500.1 MHz, DMSO-d6):
d
2.89 (1H, dd, J¼5.3, 17.9 Hz, CH), 3.29 (1H, dd, J¼9.5, 17.9 Hz, CH),
d6):
d
2.29 and 2.37 (6H, 2s, 2CH3), 2.83 (1H, dd, J¼5.2, 17.9 Hz, CH),

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M. Adib et al. / Tetrahedron 66 (2010) 2723–2727
3.26 (1H, dd, J¼9.4,17.9 Hz, CH), 4.21 (1H, dd, J¼5.2, 9.4 Hz, CH), 7.17
(2H, d, J¼7.9 Hz, 2CH), 7.26 (2H, d, J¼8.0 Hz, 2CH), 7.33 (2H, d,
J¼7.9 Hz, 2CH), 7.75 (2H, d, J¼8.0 Hz, 2CH), 8.94 (1H, s, CH). 13C NMR
C
13H10N2O4 (258.23): C, 60.47; H, 3.90; N, 10.85. Found: C, 60.5; H,
3.9; N, 10.8%. 1H NMR (500.1 MHz, DMSO-d6):
d
2.93 (1H, dd, J¼5.3,
17.8 Hz, CH), 3.19 (1H, dd, J¼9.5, 17.8 Hz, CH), 4.42 (1H, dd, J¼5.3,
9.5 Hz, CH), 6.45 (1H, dd, J¼2.1, 2.3 Hz, CH), 6.49 (1H, d, J¼3.1 Hz,
CH), 6.73 (1H, dd, J¼1.0, 1.8 Hz, CH), 7.25 (1H, d, J¼3.4 Hz, CH), 7.64
(1H, dd, J¼0.6, 0.8 Hz, CH), 8.01 (1H, s, CH), 8.87 (1H, s, CH). 13C NMR
(125.8 MHz, DMSO-d6):
d 20. 6 and 21.1 (2CH3), 35.5 (CH2), 43.7
(CH), 127.9, 128.3, 129.2, and 129.6 (4CH), 130.1, 134.7, 136.6, and
142.4 (4C), 163.6 (CH), 172.1, and 173.9 (2C]O).
(125.8 MHz, DMSO-d6):
d 32.8 (CH2), 38.1 (CH), 108.1, 110.7, 112.7,
4. 2. 6. 1-(3-Methoxybenzylideneamino)-3-(3-methox-
yphenyl)pyrrolidine-2,5-dione (4f). Colorless crystals, mp 172 ꢀC,
yield: 0.13 g, 81%. IR (KBr) (nmax/cmꢁ1): 1701,1595,1492,1455,1382,
1321, 1251, 1174, 1092, 1033, 970, 882, 782, 689. MS, m/z (%): 338
(Mþ, 6), 279 (18), 205 (18), 167 (39), 149 (100), 134 (31), 122 (9), 113
(9), 104 (11), 91 (11), 71 (18). Anal. Calcd for C19H18N2O4 (338.36): C,
67.44; H, 5.36; N, 8.28. Found: C, 67.6; H, 5.5; N, 8.1%. 1H NMR
119.3,143.0, and 147.5 (6CH),148.9, and 149.4 (2C),151.5 (CH), 171.4,
and 171.7 (2C]O).
4.2.10. 1-((Thiophen-2-yl)methyleneamino)-3-(thiophen-2-yl)pyrro-
lidine-2,5-dione (4j). Colorless crystals, mp 135–136 ꢀC, yield:
0.12 g, 88%. IR (KBr) (nmax/cmꢁ1): 1700, 1592, 1426, 1381, 1340, 1183,
1091, 1043, 977, 928, 701. MS, m/z (%): 290 (Mþ, 20), 181 (22), 167
(20), 149 (57), 138 (16), 110 (100), 96 (19), 69 (31). Anal. Calcd for
C13H10N2O2S2 (290.36): C, 53.77; H, 3.47; N, 9.64. Found: C, 53.5; H,
(500.1 MHz, DMSO-d6):
d
2.89 (1H, dd, J¼5.3, 17.9 Hz, CH), 3.27 (1H,
dd, J¼9.5, 17.9 Hz, CH), 3.76 and 3.81 (6H, 2s, 2OCH3), 4.25 (1H, dd,
J¼5.3, 9.5 Hz, CH), 6.88 (1H, dd, J¼2.2, 8.0 Hz, CH), 6.94 (1H, d,
J¼7.6 Hz, CH), 6.98 (1H, d, J¼1.9 Hz, CH), 7.14–7.16 (1H, m, CH), 7.28
(1H, t, J¼7.9 Hz, CH), 7.42 (1H, d, J¼2.2 Hz, CH), 7.44 (2H, d, J¼5.0 Hz,
3.7; N, 9.5%. 1H NMR (500.1 MHz, DMSO-d6):
d
3.00 (1H, dd, J¼5.5,
17.8 Hz, CH), 3.32 (1H, dd, J¼9.3, 17.8 Hz, CH), 4.55 (1H, dd, J¼5.5,
9.3 Hz, CH), 7.03 (1H, dd, J¼4.7, 5.0 Hz, CH), 7.15 (1H, d, J¼3.2 Hz,
CH), 7.23 (1H, dd, J¼3.8, 4.7 Hz, CH), 7.49 (1H, d, J¼5.1 Hz, CH), 7.74
(1H, d, J¼3.6 Hz, CH), 7.88 (1H, d, J¼5.0 Hz, CH), 9.17 (1H, s, CH). 13C
2CH), 9.00 (1H, s, CH). 13C NMR (125.8 MHz, DMSO-d6):
d 35.5
(CH2), 44.1 (CH), 55.1, and 55.2 (2OCH3), 112.3, 113.0, 113.9, 118.4,
120.3, 121.1, 129.7, and 130.2 (8CH), 134.2, 139.1, 159.5, and 159.6
(4C), 163.3 (CH), 172.1, and 173.7 (2C]O).
NMR (125.8 MHz, DMSO-d6):
d 35.5 (CH2), 39.2 (CH), 125.7, 126.0,
127.0,128.3,132.2, and 135.3 (6CH),137.1, and 138.6 (2C),157.7 (CH),
171.5, and 172.5 (2C]O).
4.2.7. 1-(3-Flurobenzylideneamino)-3-(3-flurophenyl)pyrrolidine-
2,5-dione (4g). Colorless crystals, mp 143 ꢀC, yield: 0.13 g, 83%. IR
(KBr) (nmax/cmꢁ1): 1702, 1581, 1487, 1445, 1377, 1310, 1250, 1148,
1071, 976, 899, 866, 780, 688. MS, m/z (%): 314 (Mþ, 3), 193 (27), 167
(8), 149 (24), 122 (100), 108 (23), 96 (15), 75 (9), 69 (8). Anal. Calcd
for C17H12F2N2O2 (314.29): C, 64.97; H, 3.85; N, 8.91. Found: C, 65.0;
Acknowledgements
This research was supported by the Research Council of the
University of Tehran as research project (6102036/1/03).
H, 3.8; N, 8.9%. 1H NMR (500.1 MHz, DMSO-d6):
d 2.93 (1H, dd,
References and notes
J¼5.6, 17.9 Hz, CH), 3.28 (1H, dd, J¼9.5, 17.9 Hz, CH), 4.35 (1H, dd,
J¼5.6, 9.5 Hz, CH), 7.15 (1H, ddd, J¼2.1, 8.4, 8.8 Hz, CH), 7.25 (1H, d,
J¼7.7 Hz, CH), 7.34 (1H, ddd, J¼1.8, 2.1, 10.2 Hz, CH), 7.39–7.44 (2H,
m, 2CH), 7.58 (1H, ddd, J¼2.0, 6.0, 8.0 Hz, CH), 7.66–7.69 (1H, m,
1. (a) Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Wein-
heim, 2005; (b) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70,
575–579; (c) Ramo´ n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634;
(d) Do¨mling, A. Chem. Rev. 2006, 106, 17–89; (e) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3169–3210.
2. Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Chem. Rev. 1970, 70, 439–469.
3. Comprehensive Medicinal Chemistry; Hansh, C., Sammes, P. G., Taylor, J. B., Eds.;
Pergamon: Oxford, 1990; Vol. 1, p 55.
4. (a) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40, 2493–2496; (b) Boejen,
A.; Kruijtzer, J. A. W.; Liskamp, R. M. Bioorg. Med. Chem. Lett. 1998, 8, 2375–
2380; (c) Matthews, J.; Rivero, R. A. J. Org. Chem. 1997, 62, 6090–6092; (d) Patel,
D. V.; Chao, C.; Ngu, K.; Xiao, X. J. Org. Chem. 1997, 62, 6968–6973; (e) Dressman,
B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937–940; (f)
Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 5835–5838.
5. Nefzi, A.; Ostresh, J. M.; Giulianotti, M.; Houghten, R. A. Tetrahedron Lett. 1998,
39, 8199–8202.
6. Brie`re, J. F.; Charpentier, P.; Dupas, G.; Que`guiner, G.; Bourguignon, J. Tetrahe-
dron 1997, 53, 2075–2086; (b) Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org.
Chem. 1997, 62, 2652–2654.
7. Obrecht, D.; Abrecht, C.; Altorfer, M.; Bohdal, U.; Grieder, A.; Kleber, M.; Pfyffer,
P.; Mu¨ ller, K. Helv. Chim. Acta 1996, 79, 1315–1337.
8. Abell, A. D.; Oldham, M. D. J. Org. Chem. 1997, 62, 1509–1513.
9. Fredenhagen, A.; Tamura, S. Y.; Kenny, P. T. M.; Komura, H.; Naya, Y.; Nakanishi,
K.; Nishiyama, K.; Sugiura, M.; Kita, H. J. Am. Chem. Soc. 1987, 109, 4409–4411.
10. (a) Needham, J.; Kelly, M. T.; Ishige, M.; Andersen, R. J. J. Org. Chem. 1994, 59,
2058–2063; (b) Oclarit, J. M.; Okada, H.; Ohta, S.; Kaminura, K.; Yamaoka, Y.;
Iizuka, T.; Miyashiro, S.; Ikegami, S. Microbios 1994, 78, 7–16.
11. Robert, F.; Gao, H. Q.; Donia, M.; Merrick, W. C.; Hamann, M. T.; Pettetier, J. RNA
2006, 12, 717–724.
12. Malochet-Grivois, C.; Roussakis, C.; Robillard, N.; Biard, J. F.; Riou, D.; Debitus,
C.; Verbist, J. F. Anticancer Drug Des. 1992, 7, 493–502.
13. Stolzenberg, H.; Weinberger, B.; Fehlhammer, W. P.; Pu¨hlhofer, F. G.; Weiss, R.
Eur. J. Inorg. Chem. 2005, 21, 4263–4271.
14. Chiu, T. W.;Liu,Y. H.;Chi,K.M.;Wen, Y. S.;Lu, K.L.Inorg.Chem.2005, 44, 6425–6430.
15. Souldozi, A.; Ramazani, A.; Bouslimani, N.; Welter, R. Tetrahedron Lett. 2007, 48,
2617–2620.
16. Souldozi, A.; Ramazani, A. Tetrahedron Lett. 2007, 48, 1549–1551.
17. Adib, M.; Riazati Kesheh, M.; Ansari, S.; Bijanzadeh, H. R. Synlett 2009,1575–1578.
18. Adib, M.; Sheibani, E.; Zhu, L. G.; Bijanzadeh, H. R. Tetrahedron Lett. 2009, 50,
4420–4422; Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron
2008, 64, 10681–10686; Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett
2008, 3180–3182; Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008,
177–180; Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2007, 63, 11135–11140; Adib, M.; Aali Koloogani, S.; Abbasi, A.;
CH), 7.72 (1H, d, J¼7.7 Hz, CH), 9.13 (1H, s, CH). 13C NMR (125.8 MHz,
4
DMSO-d6):
d
35.1 (CH2), 43.7 (d, JFC¼1.2 Hz, CH), 114.1 (d,
2JFC¼22.6 Hz, CH), 114.3 (d, 2JFC¼21.0 Hz, CH), 115.1 (d, 2JFC¼22.2 Hz,
CH), 119.0 (d, 2JFC¼21.3 Hz, CH), 124.6 (d, 4JFC¼1.2 Hz, CH), 124.7 (d,
4JFC¼2.6 Hz, CH), 130.5 (d, JFC¼8.4 Hz, CH), 131.2 (d, JFC¼8.0 Hz,
3
3
3
3
CH), 135.3 (d, JFC¼7.9 Hz, C), 140.1 (d, JFC¼7.8 Hz, C), 161.4 (d,
4JFC¼2.7 Hz, CH), 162.2 (d, 1JFC¼243.7 Hz, C), 162.3 (d, 1JFC¼245.1 Hz,
C), 171.8, and 173.3 (2C]O).
4.2.8. 1-(4-Flurobenzylideneamino)-3-(4-flurophenyl)pyrrolidine-
2,5-dione (4h). Colorless crystals, mp 135 ꢀC, yield: 0.14 g, 91%. IR
(KBr) (nmax/cmꢁ1): 1703, 1596, 1504, 1376, 1314, 1225, 1152, 1017,
943, 835, 702. MS, m/z (%): 314 (Mþ, 4), 279 (7), 193 (13), 167 (14),
149 (39), 122 (100), 108 (21), 96 (7), 69 (14). Anal. Calcd for
C17H12F2N2O2 (314.29): C, 64.97; H, 3.85; N, 8.91. Found: C, 65.1; H,
3.9; N, 8.7%. 1H NMR (500.1 MHz, DMSO-d6):
17.9 Hz, CH), 3.27 (1H, dd, J¼9.5, 17.9 Hz, CH), 4.31 (1H, dd, J¼5.5,
d
2.88 (1H, dd, J¼5.5,
3
3
9.5 Hz, CH), 7.19 (2H, dd, JFH¼8.8 Hz, JHH¼8.8 Hz, 2CH), 7.37 (2H,
3
3
4
dd, JFH¼8.8 Hz, JHH¼8.8 Hz, 2CH), 7.45 (2H, dd, JFH¼5.5 Hz,
3JHH¼8.8 Hz, 2CH), 7.94 (2H, dd, JFH¼5.6 Hz, JHH¼8.8 Hz, 2CH),
4
3
9.04 (1H, s, CH). 13C NMR (125.8 MHz, DMSO-d6):
d 35.4 (CH2), 43.3
2
2
(CH), 115.4 (d, JFC¼21.6 Hz, CH), 116.2 (d, JFC¼22.1 Hz, CH), 129.4
(d, 4JFC¼2.8 Hz, C), 130.2 (d, 3JFC¼8.3 Hz, CH), 130.7 (d, JFC¼9.0 Hz,
3
CH), 133.7 (d, 4JFC¼2.9 Hz, C), 161.5 (d, 1JFC¼243.7 Hz, C), 162.2 (CH),
164.4 (d, 1JFC¼250.5 Hz, C), 171.9, and 173.7 (2C]O).
4.2.9. 1-((Furan-2-yl)methyleneamino)-3-(furan-2-yl)pyrrolidine-
2,5-dione (4i). Colorless crystals, mp 139 ꢀC, yield: 0.11 g, 86%. IR
(KBr) (nmax/cmꢁ1): 1722, 1595, 1468, 1388, 1353, 1293, 1161, 1968,
1008, 936, 885, 820, 756, 678. MS, m/z (%): 258 (Mþ, 42), 165 (19),
149 (23), 94 (100), 81 (10), 71 (7), 66 (19). Anal. Calcd for

M. Adib et al. / Tetrahedron 66 (2010) 2723–2727
2727
Bijanzadeh, H. R. Synthesis 2007, 3056–3060; Adib, M.; Sheibani, E.; Mostofi, M.;
Ghanbary, K.; Bijanzadeh, H. R. Tetrahedron 2006, 62, 3435–3438; Adib, M.;
Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.; Bijanzadeh, H. R. Synlett 2006, 1765–
1767; Adib, M.; Haghighat Jahromi, A.; Tavoosi, N.; Mahdavi, M.; Bijanzadeh, H.
R. Tetrahedron Lett. 2006, 47, 2965–2967.
108 and for all data R1¼0.082, wR2¼0.126. CCDC 746984 contains the supple-
mentary crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.
uk/data_request/cif.
20. Ugi, I. Isonitrile Chemistry; Academic: London, 1971.
21. Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810–819.
22. Walborsky, H. M.; Periasamy, M. P. In The Chemistry of Functional Groups,
Supplement C; Patai, S., Rappaport, Z., Eds.; Wiley: New York, NY, 1983; Chapter
20, pp 835–837.
19. Selected X-ray crystallographic data for compound 4c: C17H12N2O2Br2, triclinic,
space group¼P-1, a¼5.6060(12) Å, b¼8.6946(19) Å, c¼16.922(4) Å,
a
¼100.
217(3)ꢀ,
b
¼92.498(3)ꢀ,
g
¼91.331(3) ꢀ, V¼810.6(3) Å3, T¼295(2) K, Z¼2, Dcalcd¼1.
787 g cmꢁ3
,
m
¼5.01 mmꢁ1, 1865 observed reflections, final R1¼0.045, wR2¼0.