BARUAH , S D

LASKAR , N C

SARMAH , D

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

Mol Divers (2011) 15:257–261DOI 10.1007/s11030-010-9247-4SHORT COMMUNICATIONGreen chemistry approaches to the regioselective synthesis of spiroheterobicyclic rings using iodine as a new and efficient catalystunder solvent-free conditionsDipak Prajapati · Debajyoti Bhuyan ·Mukut Gohain · Wenhao HuReceived: 1 August 2009 / Accepted: 14 March 2010 / Published online: 3 April 2010© Springer Science+Business Media B.V. 2010Abstract Iodine catalyzes the pseudo four-componentreaction of an aldehyde, a urea or thiourea, and cyclic 1,3-dicarbonyl compounds under microwave irradiation in asolvent-free condition to yield various σ symmetric spiroheterobicyclic rings in excellent yields.Keywords Biginelli-like reaction · Barbituric acid ·Spiro fused heterocycles · 1, 3-dicarbonyl compounds ·Iodine · MCR · Multicomponent · Microwave synthesisIntroductionIn recent years, interest has been focused on Biginelli-like reactions [1] in which open chain β-dicarbonyl com-pounds have been extended to cyclic β-diketones [2],β-ketolactones [3], β-diamides [4–6], or cyclic β-diesters[4], benzocyclic ketones, and α-keto acids [7] under a vari-ety of conditions, and the spiro heterocycles thus obtainedexhibit a wide range of biological activities, such as antivi-ral, antitumor, antihypertensive, and neuropeptide Y(NPY)antagonism [4–6]. This is an impressive profile that bodeswell for the interaction of this heterocyclic building blockwith a variety of biological targets of interests. However,D. Prajapati (B) · D. Bhuyan · M. GohainMedicinal Chemistry Division, North East Institute of Science andTechnology, Jorhat, Assam 785 006, Indiae-mail: dr_dprajapati2003@yahoo.co.ukW. HuDepartment of Chemistry, East China Normal University,Shanghai 200062, People’s Republic of Chinathe practical application of these methods suffers fromdisadvantages such as the use of expensive or less easily avail-able reagents, vigorous reaction conditions, prolonged stand-ing, and tedious manipulations in the isolation of the pureproducts.Moreover, iodine is an electrophilic reagent that addsto alkenes and alkynes to give diiodides [8]. Alkenyl car-boxylic acids react to give iodolactones and alkenylamideslead to iodolactams [9]. Iodine dehydrogenates amines andreacts with ketones in the presence of base to giveα-iodo ketones [10]. Carboxylic acids are converted to α-iodo acid derivatives and carbanions react to give the substi-tuted iodides [11], organoboranes can give alkyliodides [12],and vinyl boranes lead to substituted alkenes [13]. Iodineis also an important spotting reagent for TLC analysis. Wehypothesized that the drawbacks of the catalysts employedin the Biginelli-like reaction may be avoided if we usediodine as a mild reagent. However, attention has so farbeen mainly paid to using open chained 1,3-dicarbonyl com-pounds to afford dihydropyrimidinone derivatives while theuse of cyclic 1,3-dicarbonyl compounds has been seldomlyreported (see Scheme 1)Herein, we have developed a practical and general greenchemistry approach for the Biginelli-type reactions usingnon-toxic and mild Lewis acid molecular iodine under micro-wave irradiation in solvent-free conditions. This method pro-vides an efficient and much improved modification of arecently reported Biginelli-like scaffold in terms of higheryields, and catalyst role [14]. We employed microwaveenergy because the potential application of microwave tech-nology in organic synthesis [15,16], particularly in solidstate, is increasing rapidly due to its reaction simplicity,reduced polluting, and minimum reaction time providingrapid access to large libraries of diverse small molecules[17].123258 Mol Divers (2011) 15:257–261ArCHO   +   NH2CXNH21 2+N NOOR2R1O3IodinemicrowaveN NOOR2R1O4HN NHArArXNN NHNHOOO ArR2R1Ar = C6H5, 4-ClC6H4-, 4-MeC6H4-X  = O, SR1 = R2 H, MeO OR2R11   +   NH2CONH2   +65IodineNHNHOO ArR27R1R1 = R2 = H, MeScheme 1 Formation of spiro heterobicyclic compounds 4 and dehy-dropyrimidinones 7ExperimentalGeneralMaterials were obtained from commercial suppliers and wereused without further purification. Melting points were deter-mined by using a Buchi melting point apparatus and areuncorrected. IR spectra were recorded using KBr discs on aPerkin-Elmer 240C analyser. 1H NMR spectra were recordedon a Varian EM-360L NMR spectrometer and the chemicalshifts are reported in δ units (ppm) relative to Me4Si as theinternal standard. The 300 MHz NMR spectra were recordedusing tetramethylsilane as internal standard (by RSIC, Shil-long). Mass spectra were recorded on an AEIMS-30 spec-trometer. Elemental analyses were performed on a Hitachi026 CHN analyser. The microwave-assisted reactions werecarried out in a Synthwave 402 Microwave reactor manu-factured bv Prolabo [18]. All solvents were distilled beforeuse. The progress of most reactions was monitored by TLCand flash chromatographic purification was performed withsilica gel 60 (120 mesh, Merck).SynthesisIodine-catalyzed Biginelli-type condensation undermicrowave irradiations: general procedureIn a typical procedure, a mixture of barbituric acid (1.30 g,10 mmol), benzaldehyde (3.20 g, 30 mmol), urea (0.6 g, 10mmol), and iodine (0.01 g, 0.1 mmol) was placed in a reac-tion vessel and irradiated in a Prolabo Synthwave Micro-wave Reactor for 4 min. After completion, (monitored byTLC) the reaction mixture was cooled to room temperatureand poured onto ice-cold water (30 mL). The resulting solidwas filtered, washed with water, and then recrystallized fromethanol to afford pure spiro-(2-oxo-4,6-diphenylhexahydro-pyrimidine-5,5′-barbituric acid) 4a, Mp 240−241◦ C (lit. Mp241 − 242◦ C [14]) in 94% yield. Similarly other substitutedaldehydes, barbituric acids or substituted barbituric acids,and urea or thiourea were reacted together to produce the cor-responding spiroheterocycles 4b-j in high yields. The resultsare summarized in the Table 1.Spiro-(2-oxo-4,6-diphenylhexahydropyrimidine-5,5′-barbituric acid): 4aMp 240 − 241◦ C (d). IR (KBr), 3360, 3150 (NH), 1735 and1690 (CO) cm−1. 1H NMR (400 MHz, DMSO − d6) : δH,5.30 (s, 2H, 2CH), 7.10–7.50 (m, 10H, aromatic), 7.65 (s,2H, NH), 11.02, 11.36 (2s, 2H, NH). 13C NMR (100 MHz,DMSO-d6) : δ c 57.5 (C-spiro), 62.2 (2CH), 127.8, 129.0,129.5, 137.1, 150.1, 156.1, 166.5, and 170.5 (4CO). Anal.Calcd for C19H16N4O4 : C, 62.64; H, 4.40; N, 15.38. Found:C, 62.73; H, 4.49; N, 15.33.Spiro-[2-oxo-4,6-diphenylhexahydropyrimidine-5,5′-(1′-methylbarbituric acid)]: 4dMp 234 − 236◦ C (d). IR (KBr), 3195, 3300 (NH), 1730 and1688 (CO) cm−1. 1H NMR: δH, 2.70 (3H, s, NMe), 5.35 (2H,s, 2CH), 7.08–7.35 (10H, m, aromatic), 8.80 (2H, s, NH). 13CNMR: δ c 28.8, 56.5, 62.8, 126.8, 128.8, 130.2, 136.2, 150.6,154.8, 167.2, and 171.1. Anal. Calcd for C20H18N4O4 : C,63.49; H, 4.76; N, 14.81. Found: C, 63.40; H, 4.83; N, 14.76.Similarly dimedone and cyclohexane 1,3-dicarbonyl com-pounds were reacted with urea and aldehydes in presenceof iodine under microwave irradiation and the correspond-ing 3,4-dihydropyrimidinones 7 were obtainded in 85–96%yields.7a: Mp 226 − 230◦ C (d) IR (KBr), 3330, 2960, 1705,1640, and 1380 cm−1. 1H NMR: δH 0.72–1.12 (6H, s, 2CH3),1.95–2.25 (4H, d, 2CH2), 5.10 (1H, s, CH), 6.90–7.42 (5H,m, ArH), 8.55 (1H, s, NH), 8.75 (1H, s, NH); 13C NMR: δ c25.8, 27.4, 33.6, 40.8, 49.6, 53.2, 107.8, 127.8, 129.0, 129.5,140.5, 151.8, 155.8, and 193.8.7b: Mp 238 − 242◦ C (d) IR (KBr), 3250, 3090, 2960,1705, 1655, 1610, and 1470 cm−1. 1 H NMR: δH, 0.84–1.22(6H, s, 2CH3), 2.02–2.28 (4H, d, 2CH2), 5.15 (1H, s, CH),7.04–7.52 (4H, m, ArH), 8.60 (1H, s, NH), 8.82 (1H, s, NH);13C NMR: δ c 26.4, 28.2, 32.8, 39.6, 50.4, 51.8, 106.5, 127.8,129.0, 130.6, 132.4, 146.2, 150.1, 155.8, 192.8.7c: Mp > 290◦ C, IR (KBr), 3280, 3260, 3065, 2970,1710, and 1680 (CO) cm−1. 1H NMR: δH, 1.92–2.36 (6H,m, CH2), 5.25 (1H, s, CH), 7.54 (2H, m, ArH), 7.76 (3H,m, ArH), 8.65 (1H, s, NH), 8.84 (1H, s, NH). 13C NMR:δ c 32.4, 39.6, 48.8, 52.8, 106.6, 127.8, 129.0, 129.5, 130.8,132.8, 146.2, 150.1, 155.8, 166.5.123Mol Divers (2011) 15:257–261 259Table 1 Iodine catalysed synthesis of spiro heterobicyclic compounds 4 and dehydropyrimidinones 7Entry Productsa Ar R1 R2 X Reaction time Yieldsb (%) Mp (◦C) Lit. M.p.microwave ( min) microwave (◦C)1 4a Ph H H O 4.5 94 240–241 241–242 [12]2 4b 4-ClC6H4 H H O 4.0 95 289–291 289–291 [12]3 4c 4-MeC6H4 H H O 4.5 93 245–248 246–248 [12]4 4d Ph H CH3 O 4.0 95 234–236 –5 4e 4-ClC6H4 H CH3 O 4.5 92 269–272 –6 4f 4-MeC6H4 H CH3 O 4.5 90 266–268 –7 4g Ph CH3 CH3 O 4.0 95 231–232 231–232 [12]8 4h 4-ClC6H4 CH3 CH3 O 4.0 96 270–273 271–273 [12]9 4i 4-MeC6H4 CH3 CH3 O 4.5 94 226–228 227–229 [12]10 4j Ph H H S 4.5 50 245–247 245–247 [12]11 4k Ph CH3 CH3 S 4.5 52 242–244 242–244 [12]12 7a Ph CH3 CH3 O 1.5 95 226–230 (d) –13 7b 4-ClC6H4 CH3 CH3 O 1.5 96 238–240(d)–14 7c Ph H H O 1.5 86 >290(d) −a All the compounds were characterized by IR, NMR, MS, and Mpb Isolated yieldsBiginelli-type reaction catalyzed by iodine underthermolytic conditions: general procedureThe reaction was carried out similarly by heating the reac-tion mixture in the solid state at 60 ◦C in an oil bath and oncompletion and after usual work-up the corresponding spiroheterocycles 4 were obtained in 75–85% yields.Results and discussionWe performed a pseudo four-component Biginelli-type reac-tion using barbituric acid derivatives in place of the usuallyused open chain β-dicarbonyl compounds. The reaction wascarried out by heating a mixture of barbituric acid, urea, andan aldehyde in presence of 1 mol% iodine under microwaveirradiation for 4.0–4.5 min. After work-up the correspondingspiropyrimidine barbituric acid derivative 4a was exclusivelyobtained in 94% yield without the formation of classic Bigi-nelli-derived product 5.Treatment of 1 equiv each of barbituric acid, urea and alde-hyde under microwave irradiation in presence of iodine didnot produce the desired spiropyrimidine derivative 4 in goodyields. However, the reaction proceeds efficiently, withoutthe formation of any side products when 2 equiv of alde-hyde and 1 equiv of urea and barbituric acid were employed.During our investigation, it was observed that 1 mol% ofiodine is sufficient to perform the reaction as the conver-sion decreased when a smaller amount of iodine was used.When the same reaction is carried out under thermal heat-ing at 60 ◦C the corresponding spiro heterobicyclic products4a–i are obtained in 75–85% yields. The structure of allthe symmetrical spiroheterocyclic compounds obtained wereconfirmed by spectral analyses and by comparison against anauthentic sample. From spectroscopic studies it is observedthat the reaction is driven by a regiospecific condensationof two moles of aldehyde with one mole of urea and onemole of barbituric acid to afford exclusively the cis config-uration of the spiro pyrimidine barbituric acid. In the casewhere thiourea was used under similar microwave irradi-ation conditions only spiro[2-thioxo-4,6-diphenyl hexahy-dropyrimidine-5,5′-(barbituric acid)] 4j was obtained (50%yield). Longer reaction times (e.g., 10 min) did not improveyields, and resulted in decomposition of starting material.Remarkably, when the same reaction was carried out withoutmicrowave energy in the solid state at 60 ◦C, the correspond-ing spiro heterocyclic ring 4j was obtained in 81% yields.To explore the synthetic scope of this Biginelli-like reac-tion further, various para-substituted benzaldehydes, ureaor thiourea, N-substituted or unsubstituted barbituric acidswere employed under microwave irradiation. Contrary toearlier reports [14], with our system this reaction proceedsefficiently with electron-releasing or electron-withdrawingpara-substituted benzaldehydes (90–96% yields). Notably,when we employed cyclic 1,3-dicarbonyl compounds such asdimedone or cyclohexane-1,3-dione 6 in the above reaction,under identical condition we did not observe the formation ofany spiro heterobicyclic rings, rather we got the correspond-ing dihydropyrimidinones 7 [7] as observed by Abelman etal. with α and β-tetralones.123260 Mol Divers (2011) 15:257–261ArCHO + NH2CXNH2 ArCH = NCXNH233 +N NO OOMeMe3N NO OOMeMeAr NHNH2X4ArCHON NO OOMeMeAr NHN=CHArX5N NO OOMeMeHN NHX4ArArScheme 2 Mechanism for the formation of spiro heterobicyclic com-pounds 4Although the mechanism of this reaction has not beenexperimentally elucidated, it is likely that N-acylimine spe-cies 3′ is formed first by the reaction of urea and aldehyde viaa nucleophilic addition and dehydration [19,20]. Subsequentaddition of the iminium ion to barbituric acid derivatives inpresence of iodine catalyst produces an open chain ureide 4′.The second molecule of aldehyde is then added to the ureide4′ to furnish intermediate 5′, which subsequently cyclizes toprovide spiro heterobicyclic ring 4 (Scheme 2). Alternatively,aldehyde and barbituric acid may react via a Knoevenagelcondensation reaction [20,21], followed by a Michael typereaction with urea to produce ureide 4′. This then reacts witha second molecule of aldehyde, which ultimately cyclizes tothe desired product. Further work is in progess to understandthe exact mechanism of the reaction.ConclusionIn conclusion, the present method discloses a new and simplemethod for the synthesis of various symmetrical spiro hete-robicyclic compounds using molecular iodine in excellentyields under microwave irradiations. This iodine-catalyzedone-pot synthesis is simple, high yielding, time saving, andenvironment friendly. In addition to its simplicity and selec-tivity this reaction has one salient feature in its ability totolerate a variety of aldehydes and constitutes a useful alter-native to the commonly accepted procedures.Acknowledgement We thank the CSIR, New Delhi and NSFC Chinafor granting the INDO-CHINA joint collaborative project. We alsothank the Director, North East Institute of Science and Technology,Jorhat for his keen interest and constant encouragement.References1. Biginelli P (1893) Synthesis of tetrahydropyrimidinones by theacid catalyzed condensation of an aldehyde, a β-ketoester and urea.Gazz Chim Ital 23:360–4162. Yarim M, Sarac S, Kilic FS, Erol K (2003) Synthesis and in vitrocalcium antagonist activity of 4-aryl-7,7-dimethyls1,7, 7,-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione deriva-tives. Il Farmaco 58:17–24. doi:10.1016/S0014-827X(02)00009-53. 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Copolymers of bulky fumarate: synthesis and their properties

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Copolymers of bulky fumarate: synthesis and their properties

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