BORAH , H N

BORUAH , R C

SANDHU , J S

IR@NEIST - North East Institute of Science and Technology (CSIR)

Microwave-induced One-pot Synthesis ofN-carboxyalkyl Maleimides and Phthalimides$Harsha N. Borah, Romesh C. Boruah and Jagir S. Sandhu*Organic Chemistry Division, Regional Research Laboratory, Jorhat-6, Assam 785006, IndiaMaleic and phthalic anhydride condenses with amino acids and alkylamines under microwave irradiation to affordN-substituted maleimides and phthalimides in excellent yields.Maleimides constitute an important class of chemically andbiologically significant compounds.1 Reagents containing amaleimido ligand tethered to an active ester group are inhigh demand in modern chemistry and biotechnology.2In addition, N-alkylphthalimides have received renewedinterest 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 anhydrideor n-alkylation of maleimide using Mitsunobo reactionconditions.4 Maleimide-linked esters are prepared by cyclo-condensation of maleimino acids in the presence of aceticanhydride and sodium acetate or from N-(ethoxy-carbonyl)maleimide and amino acids.5 However, thesemethods have limitations of general applicability owingto low yield, extensive by-product formation and harshreaction conditions.6There has been a growing interest in the use of microwaveirradiation for heating in organic synthesis.7 This resultsin better selectivity, rate enhancement and reduction ofthermally degradative products when compared withconventional heating. In addition, microwave-mediated syn-thesis without a solvent oers advantages for reducinghazardous explosions and the removal of high boilingaprotic solvents from the reaction mixture.8 Recently micro-wave irradiation has been utilized for N-alkylation ofphthalimide in dry media under phase-transfer catalysis.9Although the synthesis of N-arylmaleimides proceeds inexcellent yields, the synthesis of N-alkylmaleimides underidentical conditions is less satisfactory.10 In this report wedescribe a microwave-induced fast synthesis of potentiallybiologically active carboxyalkyl maleimides in a one-potreaction by condensing functionalized amines with maleicanhydrides.Equimolecular amounts of maleic anhydride (1) andamino acid (3, R2=H, Me, Ph; R3=CO2H, CO2Me) wereplaced in an open Erlenmeyer flask and heated in a domesticmicrowave oven for an appropiate time (Table 1) toobtain N-carboxyalkyl maleimides (4–6) in excellent yields(90–96%). Under identical conditions phthalic anhydride (2)reacted with alkylamine (3, R2=H, R3=Ph) and aminoacids (3, R2=H, R3=CO2H) aording N-substitutedphthalimides (9 and 10, respectively) in 89–95% yields.Interestingly, our procedure of microwave heating excludespolymerization.6 Further, alkylamines (3, R2=H, R3=Ph,vinyl) eciently undergo one-pot condensation with 1 and2, aording 7 and 8, respectively. All the products wereidentified by spectral and microanalytical analysis.In conclusion we have described a microwave-mediatedfacile and fast synthesis of N-carboxyalkyl- and N-alkyl-maleimides that may be biologically active. The reportedone-pot procedure is economical because of its high selec-tivity, solvent-less condition and absence of dehydratingagent.ExperimentalMps were uncorrected and recorded on a Buchi apparatus.IR spectra were obtained on a Perkin-Elmer 237B and 580B infra-red spectrometer in KBr discs. The 1H NMR spectra were recordedon Varian T-60 and JEOL JNM FX90Q spectrometers using Me4Sias internal standard (d/ppm). Mass spectra were recorded ona AEIMS-30 spectrometer at 70 eV. Microanalytical data were per-formed on a Perkin-Elmer Series II 2400 instrument. Reactionswere conducted in a commercial microwave oven model ER 5054 Dof Microwave Products (India) Ltd.General Procedure.—A mixture of either maleic anhydride (1) orphthalic anhydride (2, 0.02 mol) and glycine (3, R2=H, R3=CO2H,0.02 mol) was placed in an Erlenmeyer flask fitted with a loose topcap and heated in a commercial microwave oven operating at2450 MHz by setting the power range to medium high (70% oftotal power). The reaction mixture turned red. After cooling, thereaction mixture was extracted with chloroform (2 30 ml) andwshed with cold water (2 10 ml), dried (Na2SO4), filtered and thesolvent removed.N-Carboxymethylmaleimide 4: yield 94%, mp 112–13 8C; max/cmÿ1 (KBr) 3050, 1710; dH (CDCl3) 6.70 (s, 2 H, olefinic), 3.75 (s, 2H, methylene); m/z 111 (MÿCO2) (Found: 46.5; H, 3.15; N, 9.1.C6H5NO4 requires C, 46.44; H, 3.25; N, 9.01%).N-(a-Carboxyethyl )maleimide 5: yield 90%, mp 97–98 8C; max/cmÿ1 (KBr) 3060, 1710; dH (CD3COCD3) 6.85 (s, 2 H, olefinic),3.80 (q, 1 H, methine), 2.1 (d, 3 H, methyl); m/z 125 (MÿCO2)(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 87–89 8C (lit.4(c), 88 8C); max/cmÿ1 (KBr) 3010, 1725, 1710; dH (CDCl3)7.25–8.25 (m, 5 H, aromatic), 6.90 (s, 2 H, olefinic), 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) 69.5–70.5 8C); max/cmÿ1 (KBr) 3050, 1705; dH (CDCl3) 7.20–7.40 (m,5 H, aromatic), 6.70 (s, 2 H, olefinic) 4.68 (s, 2 H, methylene); m/z237 (M).N-Allylmaleimide 8: yield 82%, mp 42–43 8C (lit.,4(c) 42.5–43 8C);max/cmÿ1 (KBr) 3000, 1710; dH(CDCl3) 6.72 (s, 2 H, olefinic), 5.80(m, 1 H, vinylc), 5.12–5.24 (m, 2 H, vinylic), 4.10 (dt, 2 H, J5.6 Hz, vinylic); m/z 137 (M).N-Benzylphthalimide 9: yield 89%, mp 119–20 8C (lit.,4(c) 118.5–119.5 8C); max/cmÿ1 (KBr) 3060, 1700; dH (CDCl3) 7.65–7.88 (m, 4H, aromatic), 7.20–7.45 (m, 5 H, aromatic), 4.80 (s, 2 H, olefinic);m/z 237 (M).N-Carboxymethylphthalimide 10: yield 95%, mp 110–11 8C; max/cmÿ1 (KBr) 3040, 1720; dH (CD3COCD3) 7.60–7.95 (m, 4 H,aromatic), 4.70 (s, 2 H, methylene); m/z 161 (MÿCO2). (Found:C, 58.6, H, 3.3, N, 6.9. C10H7NO4 requires C, 58.52, H, 3.44,N, 6.83%).J. Chem. Research (S),1998, 272–273$$This is a Short Paper as defined 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).*To receive any correspondence.272 J. CHEM. RESEARCH (S), 1998Received, 5th December 1997; Accepted, 19th January 1998Paper E/7/07961CReferences1 J. E. T. Corrie, J. Chem. Soc., Perkin Trans 1, 1994, 2975.2 T. Kitagawa, T. Kawasaki and H. Munechika, J. Biochem.,1982, 92, 585.3 D. D. Pietro, R. M. Borzilleri and S. M. Weinreb, J. Org.Chem., 1994, 59, 5856.4 (a) G. B. Gill, G. B. James, K. V. Oates and G. J. Pattenden,J. Chem. Soc., Perkin Trans. 1, 1993, 2567; (b) M. A. Walker,J. Org. Chem., 1995, 60, 5352; (c) P. Y. Reddy, S. Kondo,T. Toru and Y. Ueno, J. Org. Chem., 1997, 62, 2652.5 O. Nielsen and O. Buchardt, Synthesis, 1991, 819 and referencescited therein.6 M. P. Stevens, J. Polym. Sci. Polym. Lett. Ed., 1984, 22, 467.7 (a) R. Laurent, A. Leporterie, J. Dubac, J. Berlan, S. Lauverieand F. M. Audhuy, J. Org. Chem., 1992, 57, 7099 and referencescited therein; (b) S. Caddick, Tetrahedron, 1995, 51, 10403.8 (a) G. Bram, A. Loupy and D. Villemerin, in Solid Supports andCatalysts in Organic Chemistry, Ellis Horwood, London, 1992;(b) A. Boruah, M. Baruah, D. Prajapati and J. S. Sandhu,Chem. Lett., 1996, 965.9 D. Bogda and J. Pielichiowski, Synlett, 1996, 873.10 (a) N. B. Metha, A. P. Phillips, F. F. Lui and R. E. Brooks,J. Org. Chem., 1960, 25, 1012; (b) D. H. Rich, P. D. Gesellchen,D. Paul, A. Tong, T. A. Cheung and C. K. Buckner, J. Med.Chem., 1975, 18, 1004.Table 1 Condensation of maleic and phthalic anhydrides with aminesEntry Substrate ProductReaction time(t/min)Solvent ofcrystallization1 Glycine N-Carboxymethylmaleimide (4) 3 Water2 Alanine N-(a-Carboxyethyl)maleimide (5) 3 Water3 2-Phenylglycine methyl ester N-(a-Methoxycarbonylbenzyl)maleimide (6) 2 Methanol4 Benzylamine N-Benzylmaleimide (7) 2 Chloroform5 Allylamine N-Allylmaleimide (8) 2 Methanol6 Benzylamine N-Benzylphthalimide (9) 3 Water7 Glycine N-(Carboxymethyl)phthalimide (10) 3 ChloroformJ. CHEM. RESEARCH (S), 1998 273

Microwave induced one-pot synthesis of N-carboxyalkyl maleimides and phthalimides

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Microwave induced one-pot synthesis of N-carboxyalkyl maleimides and phthalimides

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