Reaction between N-isocyaniminotriphenylphosphorane, aldimines, Meldrum's acid and water: Diastereoselective synthesis of 3,4-disubstituted N-aminopyrrolidine-2,5-diones

Article abstract of DOI:10.1055/s-0030-1259696

A multicomponent synthesis of 3,4-disubstituted N-aminopyrrolidine-2,5- diones is described. A mixture of N-isocyan-iminotriphenylphosphorane, an aldimine and Meldrum's acid undergoes an addition reaction under mild conditions in aqueous THF to produce 1-

Full text of DOI:10.1055/s-0030-1259696

LETTER
619
Reaction between N-Isocyaniminotriphenylphosphorane, Aldimines,
Meldrum’s Acid and Water: Diastereoselective Synthesis of 3,4-Disubstituted
N-Aminopyrrolidine-2,5-diones
3
, 4-Disubstituted
N
-A
m
e
inopyrroli
h
dine-2, 5-dion
d
es i Adib,*a Samira Ansari,a Hamid Reza Bijanzadehb
a
b
Received 23 September 2010
O
Abstract: A multicomponent synthesis of 3,4-disubstituted N-ami-
nopyrrolidine-2,5-diones is described. A mixture of N-isocyan-
iminotriphenylphosphorane, an aldimine and Meldrum’s acid
undergoes an addition reaction under mild conditions in aqueous
THF to produce 1-amino-4-aryl-2,5-dioxo-N3-aryl-3-pyrrolidine-
O
Ph
O
NH
O
N
H
N
H
NH
O
O
andrimid
1
O
carboxamides diastereoselectively in good to excellent yields. H
H
NMR analysis showed that the two substituents on C-3 and C-4
OH
positions of the obtained pyrrolidine-2,5-diones are trans.
Cl
Key words: N-isocyaniminotriphenylphosphorane,
aldimines,
Meldrum’s acid, 3,4-disubstituted N-aminopyrrolidine-2,5-diones,
diastereoselective synthesis, multicomponent reactions
Cl
OAc
H
haterumaimide A
Figure 1 Examples of succinimide subunit containing natural
products
Succinimides (pyrrolidine-2,5-diones) are an important
class of heterocyclic compounds with numerous applica-
tions in different fields.1 Some pyrrolidine-2,5-diones
have been used in liquid crystalline systems.2 In medicine,
they have been used for the treatment of arthritis, tubercu-
losis, convulsion and epilepsy.3 In organic synthesis they
have been used as valuable reagents and intermediates for
the synthesis of natural and non-natural compounds such
as azaprostaglandins.4 Recently, succinimide-based
pseudopeptides have been shown to stabilize b-turn con-
formations.5 It has also been shown that they can be used
as irreversible protease inhibitors6 and selective inhibitors
of aromatase.7 The bioactive natural product andrimid
(Figure 1) was found to exhibit potent in vitro antibacteri-
al activity against methicillin-resistant Staphylococcus
aureus and a range of other antibiotic-resistant human
pathogens.8,9 Andrimid is a hybrid nonribosomal peptide-
polyketide antibiotic that blocks the carboxyl-transfer
reaction of bacterial acetyl-CoA carboxylase and thereby
inhibits fatty acid biosynthesis.10 The cytotoxic labdane
alkaloid haterumaimide A (Figure 1) has been used as a
protein synthesis inhibitor11 and antitumor drug.12
tals and maleic anhydride.18 However, introducing carbo-
nyl functionalities at 3- and/or 4-positions is not readily
feasible by most of these methods.
Recently, syntheses of 1,3,4-oxadiazepines19a and 2-aryl-
1,3,4-oxadiazoles19b have been reported using N-isocyan-
iminotriphenylphosphorane (1) in MCRs. Very recently,
we have described the synthesis of 2-aryl-5-hydroxy-
alkyl-1,3,4-oxadiazoles,20a 3-(1-hydroxyalkyl)[1,2,4]-
triazolo[4,3-c]quinazolines20b
and
3-aryl-1-(aryl-
methylideneamino)pyrrolidine-2,5-diones20c by use of 1
in MCRs.
Due to the unique properties of succinimides, the develop-
ment of synthetic methods that enable facile access to
these useful entities is desirable. As part of our current
studies on the development of efficient methods for the
preparation of biologically active heterocyclic com-
pounds,21 herein we describe a novel, one-pot and multi-
component
synthesis
of
3,4-disubstituted
N-
aminopyrrolidine-2,5-diones. Thus a mixture of N-isocy-
animinotriphenylphosphorane (1), an aldimine 2 and Mel-
drum’s acid (3) underwent an addition reaction in aqueous
THF at ambient temperature to afford the corresponding
1-amino-4-aryl-2,5-dioxo-N3-aryl-3-pyrrolidinecarbox-
amides 4a–i in 83–96% yields (Scheme 1, Table 1). All
3,4-Disubstituted pyrrolidine-2,5-dione derivatives have
been prepared by the conventional methods such as con-
densation of succinic anhydride derivatives with
amines,13,14 Stobbe-type condensation,15 Diels–Alder
condensation of maleimides and dienes,16 ene reaction of
maleimides17 and condensation of a-oxoketene O,N-ace-
1
the reactions went to completion within 48 hours. H
NMR spectroscopic analysis of the reaction mixtures
clearly indicated formation of the corresponding pyrroli-
dine-2,5-diones 4 in good to excellent yields. Any product
other than 4 and triphenylphosphine oxide could not be
detected by NMR spectroscopy.22 The reaction was
SYNLETT 2011, No. 5, pp 0619–0622
Advanced online publication: 25.02.2011
DOI: 10.1055/s-0030-1259696; Art ID: D26010ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

620
M. Adib et al.
LETTER
O
Ar1
NHAr2
O
O
aq THF
r.t., 48 h
Ph3PO
+
Ph3P
N
N
C
Ar1HC NAr2
+
+
O
O
O
O
N
1
2
3
NH2
4
Scheme 1
stereoselective and led to one diastereoisomer. Our at- A plausible mechanism for the formation of the pyrroli-
tempts to detect the second diastereoisomer in the reaction dine-2,5-diones 4 is provided in Scheme 2. On the basis of
mixture were not successful.
the chemistry of isocyanides,24 it is reasonable to assume
that the 5-arylmethylidene Meldrum’s acid 5, formed
from the initial addition of Meldrum’s acid (3) to the ald-
imine 2 by removal of an amine molecule, could undergo
nucleophilic attack of N-isocyaniminotriphenylphospho-
rane (1) leading to the intermediate 6 by removal of an ac-
etone molecule. Then, this intermediate may be attacked
by the released amine and water molecules to form adduct
7, which may undergo cyclization via intramolecular ami-
dation of the carboxylic acid by the adjacent nitrogen
atom to form the N-iminotriphenylphosphorane pyrroli-
dine-2,5-dione intermediate 8. This iminophosphorane
could undergo hydrolysis to produce the isolated N-ami-
nopyrrolidine-2,5-dione 4 by removal of a triphenylphos-
phine oxide molecule.
The structures of the isolated products 4a–i were deduced
on the basis of IR, 1H NMR and 13C NMR spectroscopy,
mass spectrometry and elemental analysis. The IR spec-
trum of 4e showed absorptions at 3321, 3234, 3172 (NH),
1787, 1704 (C=O, imide), 1667 (C=O, amide) cm–1 indi-
cating the presence of the N-aminosuccinimide23 and
amide functionalities. The mass spectrum of 4e displayed
the molecular ion [M+] peaks at m/z = 345 (37Cl) and 343
(35Cl), which were consistent with the 1:1:1:1 adduct of
N-isocyaniminotriphenylphosphorane, N-phenyl-4-chloro-
benzaldimine, Meldrum’s acid and water losing an ace-
1
tone molecule and triphenylphosphine oxide. The H
NMR spectrum of 4e exhibited two doublets at d = 4.04
and 4.45 (3J = 5.3 Hz) for the two methine groups (at C-3
and C-4), in agreement with the trans geometry for these
protons.18 Two fairly sharp singlets were observed at d =
5.15 and 10.50 due to the amine and amide protons, re-
spectively. The characteristic signals for the nine aromatic
H atoms were seen with appropriate chemical shifts and
coupling constants. The 1H decoupled 13C NMR spectrum
of 4e exhibited two signals at d = 46.93, 54.39 for the two
CH groups and three deshielded resonances at d = 164.75,
171.00 and 174.27 (due to the three carbonyl groups)
along with other eight distinct resonances (5 × CH and 3
× C) in the downfield region of the spectrum in agreement
with the proposed structure.22
O
O
O
O
– Ar2NH2
O
O
– Me2CO
Ar1HC NAr2
+
_
Ar1
+
N
O
O
N
C
PPh3
5
1
2
3
NH2Ar2
O
O–
O
O
Ar2NH
O
OH
N
– H2O
PPh3
Ar1
Ar1
H2O
N
+
N
PPh3
Table 1 Synthesis of 1-Amino-4-aryl-2,5-dioxo-N3-aryl-3-pyrro-
lidinecarboxamides 4a–i
N
O
H
6
7
O
4
a
b
c
d
e
f
Ar1
Ar2
Yield (%)a
Ar1
NHAr2
H2O
– Ph3PO
Ph
Ph
91
93
86
94
96
92
89
83
87
4
O
O
Ph
4-ClC6H4
N
N
PPh3
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
4-O2NC6H4
3,4-(MeO)2C6H3
Ph
8
Ph
Scheme 2
Ph
Ph
Surprisingly, when the reaction was performed using
equivalent ratios of N-isocyaniminotriphenylphosphorane
(1), 4-chlorobenzaldehyde, aniline, and Meldrum’s acid
(3) under the same reaction conditions (aq THF), TLC and
1H NMR analysis of the reaction mixture indicated the
formation of 1-(4-chlorobenzylideneamino)-3-(4-chlo-
rophenyl)pyrrolidine-2,5-dione (9)20c and 1-amino-4-(4-
chlorophenyl)-2,5-dioxo-N3-phenyl-3-pyrrolidinecarbox-
amide (4e) in 42% and 16% yields, respectively
g
h
i
4-ClC6H4
4-ClC6H4
2,4-(MeO)2C6H3
a Isolated yield.
Synlett 2011, No. 5, 619–622 © Thieme Stuttgart · New York

LETTER
3,4-Disubstituted N-Aminopyrrolidine-2,5-diones
621
Cl
Cl
O
CHO
Cl
NHPh
THF
+
+
+
PhNH2
1
3
O
+
O
Ph3PO
+
N
N
O
O
r.t., 48 h
N
NH2
CH
Cl
9
4e
Scheme 3
(8) 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.
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J. Org. Chem. 1994, 59, 2058. (b) Oclarit, J. M.; Okada, H.;
Ohta, S.; Kaminura, K.; Yamaoka, Y.; Iizuka, T.; Miyashiro,
S.; Ikegami, S. Microbios. 1994, 78, 7.
(Scheme 3). But, when the same reaction was carried out
in anhydrous THF, the yields changed to 49 and 5% for 9
and 4e, respectively. The released water from the conden-
sation of the aldehyde and aniline can justify the forma-
tion of 4e.
In conclusion, we have developed a one-pot and multi-
component reaction between N-isocyaniminotriphe-
nylphosphorane, aldimines, Meldrum’s acid and water for
the diastereoselective synthesis of 1-amino-4-aryl-2,5-di-
oxo-N3-aryl-3-pyrrolidinecarboxamides which are of po-
tential chemical, synthetic and pharmacological interest.
1H NMR analysis showed that the two substituents on C-
3 and C-4 positions of the prepared pyrrolidine-2,5-diones
are trans. Good to excellent yields of the products and
mild reaction conditions are the main advantages of this
method. The reactions were performed under neutral con-
ditions, and the starting materials and reagents have been
mixed without any activation or modification. The sim-
plicity of this method makes it an interesting alternative to
other 3,4-disubstituted pyrrolidine-2,5-diones syntheses.
(10) Liu, X.; Fortin, P. D.; Walsh, C. T. Proc. Natl. Acad. Sci.
U.S.A. 2008, 105, 13321.
(11) Robert, F.; Gao, H. Q.; Donia, M.; Merrick, W. C.; Hamann,
M. T.; Pettetier, J. RNA 2006, 12, 717.
(12) Malochet-Grivois, C.; Roussakis, C.; Robillard, N.; Biard,
J. F.; Riou, D.; Debitus, C.; Verbist, J. F. Anticancer Drug
Des. 1992, 7, 493.
(13) Sandler, S. R.; Karo, W. In Organic Functional Group
Preparations, Vol. 3, 3rd ed.; Blomquist, A. T.; Wasserman,
H., Eds.; Academic Press: New York, 1972, 241.
(14) Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem.
1997, 62, 2652; and references cited therein.
(15) (a) Zerrer, R.; Simchen, G. Synthesis 1992, 922. (b) Darcy,
P. J.; Heller, H. G.; Patharakorn, S.; Piggott, R. D.; Whittall,
J. J. Chem. Soc., Perkin Trans. 1 1986, 315; and references
cited therein.
(16) Hatakeyama, S.; Sugawara, K.; Takano, S. J. Chem. Soc.,
Chem. Commun. 1992, 953.
(17) Leigh, W. J.; Mitchell, D. S. J. Am. Chem. Soc. 1992, 114,
5005.
(18) Furukawa, I.; Abe, T.; Fujisawa, H.; Ohta, T. Tetrahedron
1997, 53, 17643.
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
(19) (a) Souldozi, A.; Ramazani, A.; Bouslimani, N.; Welter, R.
Tetrahedron Lett. 2007, 48, 2617. (b) Souldozi, A.;
Ramazani, A. Tetrahedron Lett. 2007, 48, 1549.
(20) (a) Adib, M.; Riazati Kesheh, M.; Ansari, S.; Bijanzadeh,
H. R. Synlett 2009, 1575. (b) Adib, M.; Ansari, S.; Feizi, S.;
Bijanzadeh, H. R. Synlett 2010, 921. (c) Adib, M.; Ansari,
S.; Fatemi, S.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron
2010, 66, 2723.
References and Notes
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1970, 70, 439.
(2) Galatina, A. I.; Derkach, L. G.; Kilimenchuk, H. D.;
Kondratyeva, R. V.; Novikova, N. S.; Jarovoy, J. K. Liq.
Cryst. 2000, 27, 1229.
(21) (a) Adib, M.; Mohamadi, A.; Sheikhi, E.; Ansari, S.;
Bijanzadeh, H. R. Synlett 2010, 1606. (b) Adib, M.; Ansari,
S.; Mohamadi, A.; Bijanzadeh, H. R. Tetrahedron Lett.
2010, 51, 30. (c) Adib, M.; Ansari, S.; Feizi, S.;
Asgarian Damavandi, J.; Mirzaei, P. Synlett 2009, 3263.
(d) Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2008, 64, 10681. (e) Adib, M.; Mohammadi,
B.; Bijanzadeh, H. R. Synlett 2008, 3180. (f) Adib, M.;
Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 177.
(g) Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.;
Zhu, L. G. Tetrahedron 2007, 63, 11135.
(22) General Procedure for the Preparation of Compounds
4a–i: A mixture of N-isocyaniminotriphenylphosphorane (1
mmol), the appropriate imine (1 mmol) and Meldrum’s acid
(1 mmol) in THF (5 mL) was stirred at ambient temperature
for 48 h. The progress of the reaction was monitored by
TLC. Then, the solvent was removed under the reduced
pressure and the residue was purified by column
(3) (a) Malawska, B. Curr. Top. Med. Chem. 2005, 5, 69.
(b) Kornet, M. J. J. Pharm. Sci. 1983, 73, 405.
(c) Kaminski, K.; Obniska, J. Acta Pol. Pharm. Drug Res.
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(4) (a) Brière, J. F.; Charpentier, P.; Dupas, G.; Quèguiner, G.;
Bourguignon, J. Tetrahedron 1997, 53, 2075. (b) Reddy,
P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997, 62,
2652. (c) King, R. W. Tetrahedron Lett. 1981, 22, 2837.
(d) Reuschling, D.; Mitzlaff, M.; Kühlein, K. Tetrahedron
Lett. 1976, 4467.
(5) Obrecht, D.; Abrecht, C.; Altorfer, M.; Bohdal, U.; Grieder,
A.; Kleber, M.; Pfyffer, P.; Müller, K. Helv. Chim. Acta
1996, 79, 1315.
(6) Abell, A. D.; Oldham, M. D. J. Org. Chem. 1997, 62, 1509.
(7) Whomsley, R.; Smith, H. J.; Nicholls, P. J.; Nazareth, W.;
Ahmadi, M. J. Enzyme Inhib. Med. Chem. 1993, 6, 317.
Synlett 2011, No. 5, 619–622 © Thieme Stuttgart · New York

622
M. Adib et al.
LETTER
chromatography using n-hexane–EtOAc (3:1) as eluent. The
solvent was removed and the product was recrystallized
from n-hexane–EtOAc (1:1).
d = 4.04 (d, J = 5.3 Hz, 1 H, CH), 4.45 (d, J = 5.3 Hz, 1 H,
CH), 5.15 (s, 2 H, NH2), 7.09 (t, J = 7.4 Hz, 1 H, CH), 7.33
(dd, J = 8.1, 7.7 Hz, 2 H, 2 × CH), 7.38 (d, J = 8.5 Hz, 2 H,
2 × CH), 7.45 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.59 (d, J = 7.7
Hz, 2 H, 2 × CH), 10.50 (s, 1 H, NHCO). 13C NMR (125.8
MHz, DMSO-d6): d = 46.93, 54.39 (2 × CH), 119.30,
124.09, 128.76, 128.89, 130.25 (5 × CH), 132.56, 135.34,
138.27 (3 × C), 164.75, 171.00, 174.27 (3 × C=O). EI–MS:
m/z (%) = 345 (13) [M+ + 37Cl], 343 (35) [M+ + 35Cl], 315
(31), 295 (11), 284 (7), 273 (17), 236 (15), 223 (53), 207
(32), 196 (29), 179 (24), 165 (48), 152 (17), 137 (33), 111
(22), 102 (33), 93 (47), 83 (43), 77 (45), 69 (80), 57 (100),
43 (98), 41 (84). Anal. Calcd for C17H14ClN3O3 (343.77): C,
59.40; H, 4.10; N, 12.22. Found: C, 59.4; H, 4.0; N, 12.1.
(23) (a) Matsuo, T. Bull. Chem. Soc. Jpn. 1964, 37, 1844.
(b) Stamboliyska, B. A.; Binev, Y. I.; Radomirska, V. B.;
Tsenov, J. A.; Juchnovski, I. N. J. Mol. Struct. 2000, 516,
237.
(24) (a) Ugi, I. Isonitrile Chemistry; Academic Press: London,
1971. (b) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21,
810. (c) Walborsky, H. M.; Periasamy, M. P. In The
Chemistry of Functional Groups, Supplement C; Patai, S.;
Rappaport, Z., Eds.; Wiley: New York, 1983, Chap. 20,
835–837. (d) Dömling, A. Chem. Rev. 2006, 106, 17.
(e) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3169.
1-Amino-4-(4-methylphenyl)-2,5-dioxo-N3-phenyl-3-
pyrrolidinecarboxamide (4c):
yield: 0.28 g (86%); colorless crystal; mp 152–154 °C. IR
(KBr): 3340, 3275, 3192 (NH), 1772, 1693 (C=O), 1600,
1534, 1438, 1312, 1191, 1106, 903, 815, 748, 691 cm–1. 1H
NMR (500.1 MHz, DMSO-d6): d = 2.28 (s, 3 H, Me), 4.01
(d, J = 5.0 Hz, 1 H, CH), 4.34 (d, J = 5.0 Hz, 1 H, CH), 5.16
(br s, 2 H, NH2), 7.09 (t, J = 7.4 Hz, 1 H, CH), 7.17–7.21 (m,
4 H, 4 × CH), 7.33 (dd, J = 8.1, 7.7 Hz, 2 H, 2 × CH), 7.59
(d, J = 7.7 Hz, 2 H, 2 × CH), 10.49 (s, 1 H, NHCO). 13C NMR
(125.8 MHz, DMSO-d6): d = 20.53 (Me), 47.26, 54.72 (2 ×
CH), 119.19, 123.97, 127.95, 128.79, 129.30 (5 × CH),
133.41, 137.02, 138.21 (3 × C), 164.82, 171.06, 174.59 (3 ×
C=O). EI–MS: m/z (%) = 323 (10) [M+], 279 (13), 236 (9),
203 (21), 167 (31), 149 (86), 115 (17), 97 (23), 83 (37), 71
(42), 69 (78), 57 (89), 55 (65), 43 (100), 41 (72). Anal. Calcd
for C18H17N3O3 (323.35): C, 66.86; H, 5.30; N, 13.00.
Found: C, 67.0; H, 5.4; N, 12.8.
1-Amino-4-(4-chlorophenyl)-2,5-dioxo-N3-phenyl-3-
pyrrolidinecarboxamide (4e): yield: 0.33 g (96%);
colorless crystal; mp 172–174 °C. IR (KBr): 3321, 3234,
3172 (NH), 1787, 1704, 1667 (C=O), 1603, 1537, 1493,
1440, 1414, 1321, 1257, 1215, 1094, 1051, 1007, 965, 830,
790, 743, 693, 658 cm–1. 1H NMR (500.1 MHz, DMSO-d6):
Synlett 2011, No. 5, 619–622 © Thieme Stuttgart · New York

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