272 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 272±273$
Microwave-induced One-pot Synthesis of
N-carboxyalkyl Maleimides and Phthalimides$
Harsha N. Borah, Romesh C. Boruah and Jagir S. Sandhu*
Organic Chemistry Division, Regional Research Laboratory, Jorhat-6, Assam 785006, India
Maleic and phthalic anhydride condenses with amino acids and alkylamines under microwave irradiation to afford
N-substituted maleimides and phthalimides in excellent yields.
Maleimides constitute an important class of chemically and
biologically signi®cant compounds.1 Reagents containing a
maleimido ligand tethered to an active ester group are in
high demand in modern chemistry and biotechnology.2
In addition, N-alkylphthalimides have received renewed
interest as a source of functionalized b-lactams.3 In general,
most methods of cyclic imide synthesis involve Lewis-acid-
mediated condensation of an amine with maleic anhydride
or n-alkylation of maleimide using Mitsunobo reaction
conditions.4 Maleimide-linked esters are prepared by cyclo-
condensation of maleimino acids in the presence of acetic
anhydride and sodium acetate or from N-(ethoxy-
carbonyl)maleimide and amino acids.5 However, these
methods have limitations of general applicability owing
to low yield, extensive by-product formation and harsh
reaction conditions.6
reacted with alkylamine (3, R2=H, R3=Ph) and amino
acids (3, R2=H, R3=CO2H) aording N-substituted
phthalimides (9 and 10, respectively) in 89±95% yields.
Interestingly, our procedure of microwave heating excludes
polymerization.6 Further, alkylamines (3, R2=H, R3=Ph,
vinyl) eciently undergo one-pot condensation with 1 and
2, aording 7 and 8, respectively. All the products were
identi®ed by spectral and microanalytical analysis.
In conclusion we have described a microwave-mediated
facile and fast synthesis of N-carboxyalkyl- and N-alkyl-
maleimides that may be biologically active. The reported
one-pot procedure is economical because of its high selec-
tivity, solvent-less condition and absence of dehydrating
agent.
Experimental
Mps were uncorrected and recorded on
a Buchi apparatus.
There has been a growing interest in the use of microwave
irradiation for heating in organic synthesis.7 This results
in better selectivity, rate enhancement and reduction of
thermally degradative products when compared with
conventional heating. In addition, microwave-mediated syn-
thesis without a solvent oers advantages for reducing
hazardous explosions and the removal of high boiling
aprotic solvents from the reaction mixture.8 Recently micro-
wave irradiation has been utilized for N-alkylation of
phthalimide in dry media under phase-transfer catalysis.9
Although the synthesis of N-arylmaleimides proceeds in
excellent yields, the synthesis of N-alkylmaleimides under
identical conditions is less satisfactory.10 In this report we
describe a microwave-induced fast synthesis of potentially
biologically active carboxyalkyl maleimides in a one-pot
reaction by condensing functionalized amines with maleic
anhydrides.
IR spectra were obtained on a Perkin-Elmer 237B and 580B infra-
red spectrometer in KBr discs. The 1H NMR spectra were recorded
on Varian T-60 and JEOL JNM FX90Q spectrometers using Me4Si
as internal standard (d/ppm). Mass spectra were recorded on
a AEIMS-30 spectrometer at 70 eV. Microanalytical data were per-
formed on a Perkin-Elmer Series II 2400 instrument. Reactions
were conducted in a commercial microwave oven model ER 5054 D
of Microwave Products (India) Ltd.
General Procedure.ÐA mixture of either maleic anhydride (1) or
phthalic anhydride (2, 0.02 mol) and glycine (3, R2=H, R3=CO2H,
0.02 mol) was placed in an Erlenmeyer ¯ask ®tted with a loose top
cap and heated in a commercial microwave oven operating at
2450 MHz by setting the power range to medium high (70% of
total power). The reaction mixture turned red. After cooling, the
reaction mixture was extracted with chloroform (2 Â 30 ml) and
wshed with cold water (2 Â 10 ml), dried (Na2SO4), ®ltered and the
solvent removed.
N-Carboxymethylmaleimide 4: yield 94%, mp 112±13 8C; ꢀmax
/
1
cm (KBr) 3050, 1710; dH (CDCl3) 6.70 (s, 2 H, ole®nic), 3.75 (s, 2
H, methylene); m/z 111 (M
C6H5NO4 requires C, 46.44; H, 3.25; N, 9.01%).
CO2) (Found: 46.5; H, 3.15; N, 9.1.
N-(a-Carboxyethyl)maleimide 5: yield 90%, mp 97±98 8C; ꢀmax
/
1
cm (KBr) 3060, 1710; dH (CD3COCD3) 6.85 (s, 2 H, ole®nic),
3.80 (q, 1 H, methine), 2.1 (d, 3 H, methyl); m/z 125 (M
CO2)
(Found: C, 49.8; H, 4.2; N, 8.2. C7H7NO4 requires C, 49.69; H,
4.17; N, 8.25%).
N-(a-Methoxycarbonylbenzyl)maleimide 6: yield 95%, mp 87±
1
89 8C (lit.4(c), 88 8C); ꢀmax/cm (KBr) 3010, 1725, 1710; dH (CDCl3)
7.25±8.25 (m, 5 H, aromatic), 6.90 (s, 2 H, ole®nic), 4.85 (s, 1 H,
methylene), 3.75 (s, 3 H, ester methyl); m/z 221 (M ).
N-Benzylmaleimide 7: yield 96%, mp 69±70 8C (lit.,4(c) 69.5±
1
70.5 8C); ꢀmax/cm (KBr) 3050, 1705; dH (CDCl3) 7.20±7.40 (m,
5 H, aromatic), 6.70 (s, 2 H, ole®nic) 4.68 (s, 2 H, methylene); m/z
237 (M ).
N-Allylmaleimide 8: yield 82%, mp 42±43 8C (lit.,4(c) 42.5±43 8C);
1
Equimolecular amounts of maleic anhydride (1) and
amino acid (3, R2=H, Me, Ph; R3=CO2H, CO2Me) were
placed in an open Erlenmeyer ¯ask and heated in a domestic
microwave oven for an appropiate time (Table 1) to
obtain N-carboxyalkyl maleimides (4±6) in excellent yields
(90±96%). Under identical conditions phthalic anhydride (2)
ꢀ
(m, 1 H, vinylc), 5.12±5.24 (m, 2 H, vinylic), 4.10 (dt, 2 H, J
max/cm (KBr) 3000, 1710; dH(CDCl3) 6.72 (s, 2 H, ole®nic), 5.80
5.6 Hz, vinylic); m/z 137 (M ).
N-Benzylphthalimide 9: yield 89%, mp 119±20 8C (lit.,4(c) 118.5±
1
119.5 8C); ꢀmax/cm (KBr) 3060, 1700; dH (CDCl3) 7.65±7.88 (m, 4
H, aromatic), 7.20±7.45 (m, 5 H, aromatic), 4.80 (s, 2 H, ole®nic);
m/z 237 (M ).
N-Carboxymethylphthalimide 10: yield 95%, mp 110±11 8C; ꢀmax
/
1
*To receive any correspondence.
cm
(KBr) 3040, 1720; dH (CD3COCD3) 7.60±7.95 (m, 4 H,
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
aromatic), 4.70 (s, 2 H, methylene); m/z 161 (M CO2). (Found:
C, 58.6, H, 3.3, N, 6.9. C10H7NO4 requires C, 58.52, H, 3.44,
N, 6.83%).