Microwave-assisted reactions: Part 2Part 1: ref. 1. One-pot synthesis of pyrimido[1,2-a]pyrimidines

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  • Microwave-assisted reactions: Part 2 One-pot synthesis ofpyrimido[1,2-a]pyrimidines

    Fawi M. Abd El Latif,a Magda A. Barsy,a Amal Mmohamed Arefa and Kamal UsefSadek*b

    a Chemistry Deparment, Faculty of Science, South Valley University, Aswan, A. R, Egyptb Chemistry Deparment, Faculty of Science, Minia University, 61519 Mina, A. R, Egypt.

    E-mail: rumenia@enstinet.EG.net

    Received 22nd November 2001First published as an Advance Article on the web 8th February 2002

    A simple route for the synthesis of pyrimido[1,2-a]pyrimidines by condensation of 2-aminopyrimidine 1, aromaticaldehydes 2 and active methylene reagents 3 under microwave irradiation is reported.

    Introduction

    The importance of pyrimido[1,2-a]pyrimidines is well recog-nized by synthetic as well as biological chemists.2,3 Thedevelopment of pyrimido[1,2-a]pyrimidines as having hypo-glycemic and platelet aggregation-inhibitory activities,4 aspotential hosts in the enantioselective recognition of oxo anionsin polytopic abiotic receptors,5 anchor modules for oxo anionicfunctions of molecular guest species complexed by polytopicartificial receptors,6 and as efficient insecticides , acaricides andnematocides,7 have prompted us to investigate an efficient routefor the synthesis of this ring system.

    A previous synthesis for pyrimido[1,2-a]pyrimidines re-ported by Echavarren et al.8 involved a nine-step procedurefrom L-asparagine with a total yield of 5.1%. However, thisoverall yield was improved by Kurzmeier and Schmidtehen5 to20%. Most of the other syntheses are either multi-stage routes9or give only poor to moderate yields.10

    In recent years, microwave-induced rate acceleration tech-nology has become a powerful tool in organic synthesis1114 inview of the mild, clean, convenient, enhanced selectivity,spontaneity of the reaction process in comparison to theconvential solution phase reactions and the associated ease ofmanipulation. It is of note that this technique offers anenviromentally friendly process of organic synthesis.

    Results and discussion

    In connection with our interest in the synthesis and biologicalevaluation of condensed azines,15,16 we now report a novel andefficient route for the synthesis of pyrimido[1,2-a]pyrimidinederivatives under microwave irradiation. Simple addition of anequimolecular mixture of 2-aminopyrimidine 1, benzaldehyde2a and malononitrile 3a under microwave irradiation and in thepresence of piperidine as a catalyst gave either the 2-aminopyr-imidino[1,2-a]pyrmidine 8a or the 4-amino isomer 6a (Scheme1). Structure 6a was considered more likely based on analyticaland chemical data. 1H NMR spectra revealed a singlet at d 8.4that integrated for two protons. This was assigned to an aminofunction at C-4. The downfield shift of this amino functioncould be explained by the anisotropic effect of the ring nitrogen.It is difficult to rationalize this amino function if the reactionproduct was 8a. Moreover, pyrimidopyrimidine 6a was con-

    firmed chemically by its synthesis via another route by thereaction of 2-aminopyrimidine 1 with benzaldehyde 2a to affordSchiff base 9 which was then treated with malononitrile 3a indioxane in the presence of a catalytic amount of piperidine.Similarly, microwave irradiation of 2-aminopyrimidine 1 withaldehydes 2bd and active methylenes 3bd afforded 6bd,respectively. The structure assigned for these reaction productswere established from analytical and spectral data (see Experi-mental section). Two possible routes for the formation of 6adare postulated. The first route involves the condensation ofaldehyde with the active methylene reagent to afford thecorresponding b-arylacrylonitrile derivative (4) followed byaddition of the exocyclic amino function of 2-aminopyrimidine1 to the activated double bond system in 4 to form Michaeladduct 5 which undergoes intramolecular cyclization to give 6;alternatively, addition of the ring nitrogen to 4 to form Michaeladduct 7 will lead to the formation of 8. The second route is thecondensation of aldehyde 2 with 2-aminopyrimidine 1 to affordthe corresponding Schiff base 9 followed by the addition of theactive methylene moiety to form 6. We believe that the firstpathway is the predominant one through monitoring the reactionmixture. Thus, after microwave irradiation of a mixture of2-aminopyrimidine 1, benzaldehyde 2a and malononitrile 3afor 30 s and at 650 W, the corresponding b-arylacrylonitrilederivative 4 could be detected by TLC.

    In contrast, the reaction of 2-aminopyrimidine 1 withaldehyde 2g and cyanothioacetamide 3g gave a completelydifferent product than 6a. Structure 8a was assigned for thisreaction product based on analytical and spectral data. Thus, theIR spectrum of the reaction product revealed both amino andcyano functions at n 3250 and 2200 cm21. 1H NMR revealed aband at d 4.64 that integrated for one proton. This was assignedto CH-4. It is difficult to rationalize this signal if the reactionproduct was 6a. This product was assumed to be formed via

    Part 1: ref. 1.

    Green ContextReducing the number of steps in organic synthesis can be avery effective way of achieving many green chemistryreductions (of materials consumed, auxiliaries used, energyinput and waste produced). Thus one-pot reactions involv-ing several substrates have considerable appeal. Here thereactions of multiple substrates to important biologicallyactive compounds are achieved with a small amount ofcatalyst via microwave activation. JHC

    This journal is The Royal Society of Chemistry 2002

    196 Green Chemistry, 2002, 4, 196198 DOI: 10.1039/b110723m

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    http://dx.doi.org/10.1039/b110723mhttp://pubs.rsc.org/en/journals/journal/GChttp://pubs.rsc.org/en/journals/journal/GC?issueid=GC004003

  • intermediacy of 10 and subsequent cyclisation via H2Selimination. Similarly, 2-aminopyrimidine 1 reacted withaldehydes 2ei and active methylenes 3ei to afford 8ei,respectively. In contrast, attempts at condensation of 2-amino-pyrimidine 1 with aldehydes 2j, k and active methylenes 3j, kresulted in the formation of b-arylacrylonitriles 4j, k. This wasestablished based on spectral and chemical data and viasynthesis through condensation of aldehydes 2j, k with activemethylenes 3j, k under the same reaction conditions (seeExperimental section).

    Conclusion

    In conclusion we have shown that both the amino function andring nitrogen in 2-aminopyrimidine are active sites of nucleo-philic attack on a, b-unsaturated nitriles. Accordingly, alter-native structures should always be considered and strongarguments should be introduced when assigning structures tothe products of these reactions. The difference in behaviour of2,3j, k can be rationalised in terms of the relative activities ofthe ylidenic bond and the transition states leading to the endproducts. It is assumed that the Michael adduct formed from thereaction of 2,3j, k with 1 is in equilibrium with its constituentsand its cyclisation via water elimination is thermodynamicallyunfavarable.

    Experimental

    All melting points are uncorrected. IR spectra were recorded inKBr with Shimadzu 470 spectrophotometer. 1H NMR spectrawere recorded on a Varian EM-390 400 MHz spectrometer in[2H6]DMSO as solvent and TMS as internal standard, chemicalshifts are reported in d units (ppm). Mass spectra were measuredon a JOEL JMS 600 at 70 eV. Microanalytical data wereobtained from the microanalytical Data Unit at Cairo Uni-versity.

    General procedure for the reaction of 2-aminopyrimidine1, aromatic aldehyde 2 and active methylene reagents 3

    A mixture of 2-aminopyrimidine 1 (0.951 g, 0.01 mmol), (0.01mmol) of aromatic aldehyde 2ak and (0.01 mmol) activemethylene reagents 3ak in the presence of a catalytic amountof piperidine was irradiated in microwave oven for 3 min at 650W. After cooling to room temperature, the solid product formedwas collected by filtration, dried and recrystallized fromethanol.

    4-Amino-2-phenylpyrimido[1,2-a]pyrimidine-3-carbonitrile 6a

    Yield: 2.11 g (85%); mp 250 C. IR (KBr) nmax: 3340 (NH2),2200 (CN), 1580 cm21 (CNN). MS (EI, 70 eV): m/z 250 (M +1, 20%). 1H NMR (DMSO), dH 8.4 (s, 2H, NH2), 7.27.8 (m,9H, arom-H). C14H11N5 (249.27): calc. C 67.45, H 4.44, N28.09; found C 67.44, H 4.50, N 28.2%.

    Procedure for the preparation of compound 6a; anotherroute:

    A mixture of 2-aminopyrimidine 1 (0.95 g, 0.01 mmol) andaromatic aldehyde 2a afforded Schiff base 9 which was treatedwith active methylene reagent 3a in dioxane in the presence ofa catalytic amount of piperidine under reflux for 5 h. Aftercooling to room temperature the solid product formed wascollected by filtration, dried and recrystallized from ethanol.The reaction product was found to be identical with compound6a, (mixed mp and IR).

    4-Amino-2-(4-chlorophenyl)pyrimido[1,2-a]-pyrimidine-3-carbonitrile 6b

    Yield: 2.35 g (83%); mp 240 C. IR (KBr) nmax: 3350 (NH2),2200 (CN), 1550 cm21 (CNN). MS (EI, 70 eV): m/z 284 (M+,

    Scheme 1

    Green Chemistry, 2002, 4, 196198 197

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  • 7%). 1H NMR (DMSO), dH 7.327.63 (m, 8H, arom-H).C14H10N5Cl (283.72): calc. C 59.26, H 3.55, N 24.68, Cl 12.49;found C 59.32, H 3.49, N 24.66, Cl 12.44%.

    4-Amino-2-(2-furyl)pyrimido[1,2-a]-pyrimidine-3-carboxylate 6c

    Yield: 2.31 g (81%); mp 230 C. IR (KBr) nmax: 3400 (NH2),1700 (ester CO), 1580 cm21 (CNN). Insoluble in commonlyused 1H NMR solvents. C14H14N4O3 (286.29): calc. C 58.73, H4.92, N 19.57; found C 58.74, H 4.50, N 19.66%.

    4-Amino-2-(3-nitrophenyl)pyrimido[1,2-a]-pyrimidine-3-carboxylate 6d

    Yield: 2.86 g (84%); mp 135 C. IR (KBr) nmax: 3400 (NH2),1710 (ester CO), 1600 cm21 (CNN). MS (EI, 70 eV): m/z 342(M + 1, 32%). 1H NMR (DMSO), dH 8.9 (s, 1H, arom-H),7.68.4 (m, 7H, arom-H), 4.3 (q, 2H, CH2), 1.13 (t, 3H, CH3).C16H15N5O4 (341.33): calc. C 56.30, H 4.42, N 20.51; found C56.33, H 4.44, N 20.66%.

    2-Amino-4-(4-methoxyphenyl)pyrimido[1,2-a]-pyrimidine-3-carbonitrile 8e

    Yield: 2.29 g (82%); mp 150 C. IR (KBr) nmax: 3340 (NH2),2200 (CN), 1570 cm21 (CNN). MS (EI, 70 eV): m/z 280 (M +1, 5%). 1H NMR (DMSO), dH 8.4 (s, 2H, NH2), 7.27.66 (m,7H, arom-H), 4.54 (s, 1H, CH-4). C15H13N5O (279.30): calc. C64.50, H 4.69, N 25.07; found C 64.55, H 4.72, N 25.11%.

    2-Amino-4-(3-nitrophenyl)pyrimido[1,2-a]-pyrimidine-3-carbonitrile 8f

    Yield: 2.44 g (83%); mp 165 C. IR (KBr) nmax: 3330 (NH2),2200 (CN), 1610 cm21 (CNN). MS (EI, 70 eV): m/z 295 (M +1, 35%). Insoluble in commonly used 1H NMR solvents.C14H10N6O2 (294.27): calc. C 57.14, H 3.42, N 28.55; found C57.22, H 3.45, N 28.65%.

    2-Amino-4-phenylpyrimido[1,2-a]-pyrimidine-3-carbonitrile 8g

    Yield: 2.11 g (85%); mp 155 C. IR (KBr) nmax: 3340 (NH2),2200 (CN), 1610 cm21 (CNN). MS (EI, 70 eV): m/z 250 (M +1, 25%). 1H NMR (DMSO), dH 8.4 (s, 2H, NH2), 7.927.66 (m,

    8H, arom-H), 4.6 (s, 1H, CH-4). C14H11N5 (249.27): calc. C67.45, H 4.44, N 28.09; found C 67.52, H 4.45, N 28.22%.

    2-Amino-4-(4-chlorophenyl)pyrimido[1,2-a]-pyrimidine-3-carbonitrile 8h

    Yield: 2.26 g (80%); mp 170 C. IR (KBr) nmax: 3340 (NH2),2200 (CN), 1610 cm21 (CNN). MS (EI, 70 eV): m/z 284 (M +1, 7%). Insoluble in commonly used 1H NMR solvents.C14H10N5Cl (283.72): calc. C 59.26, H 3.55, N 24.68; found C59.33, H 3.52, N 24.67%.

    2-Amino-4-(2-furyl)pyrimido[1,2-a]-pyrimidine-3-carbonitrile 8i

    Yield: 1.96 g (82%); mp > 300 C. IR (KBr) nmax: 3320 (NH2),2200 (CN), 1560 cm21 (CNN). MS (EI, 70 eV): m/z 240 (M+,26%). Insoluble in commonly used 1H NMR solvents.C12H9N5O (239.23): calc. C 60.24, H 3.79, N 29.27; found C60.35, H 3.82, N 29.33%.

    Compounds 4j, k were found to be identical with authenticsamples (mixed mp and IR spectra).

    References

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    198 Green Chemistry, 2002, 4, 196198

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