Abstract
An efficient, mild and environmentally benign protocol has been developed for the synthesis of aminouracil-tethered tri-substituted methane derivatives. The three-component reaction of 2-hydroxy-1,4-naphthaquinone, 6-amino-1,3-dimethyluracil and aldehydes in the presence of molecular iodine as catalyst under reflux conditions resulted in aminouracil-tethered tri-substituted methane derivatives 4 in aqueous medium. Similarly, the four-component reaction of 2-hydroxy-1,4-naphthaquinone, o-phenylenediamine, aldehydes and aminouracil derivatives resulted in aminouracil-tethered tri-substituted methane derivatives 6 under the same reaction conditions. The notable features of this protocol are simple experimental procedure, cheap catalyst, readily available starting materials, moderate-to-good yields of the products having biologically active important moieties such as aminouracil, hydroxy-naphthaquinone/benzophenazine.
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Parker WB (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 109:2880–2893. https://doi.org/10.1021/cr900028p
Bradshaw TK, Hutchinson DW (1977) 5-Substituted pyrimidine nucleosides and nucleotides. Chem Soc Rev 6:43–62. https://doi.org/10.1039/CS9770600043
Noia JD, Neuberger MS (2002) Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419:43–48. https://doi.org/10.1038/nature00981
Dinner AR, Blackburn GM, Karplus M (2001) Uracil-DNA glycosylase acts by substrate autocatalysis. Nature 413:752–755. https://doi.org/10.1038/35099587
Isobe Y, Tobe M, Inoue Y, Isobe M, Tsuchiya M, Hayashi H (2003) Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Bioorg Med Chem 11:4933–4940. https://doi.org/10.1016/j.bmc.2003.09.012
Zhi C, Long Z-Y, Gambino J, Xu W-C, Brown NC, Barnes M, Butler M, LaMarr W, Wright GE (2003) Synthesis of substituted 6-aminouracils and their inhibition of DNA polymerase IIIC and gram-positive bacterial growth. J Med Chem 46:2731–2739. https://doi.org/10.1021/jm020591z
Muller CE, Shi D, Manning M, Daly JW (1993) Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors. J Med Chem 36:3341–3349. https://doi.org/10.1021/jm00074a015
Bills CW, Gebura SE, Meek JS, Sweeti OJ (1962) New synthesis of uric acid and dimethyluric acid. J Org Chem 27:4633–4635. https://doi.org/10.1021/jo01059a501
Wells JN, Garst JE, Kramer GL (1981) Inhibition of separated forms of cyclic nucleotide phosphodiesterase from pig coronary arteries by 1,3-disubstituted and 1,3,8-trisubstituted xanthines. J Med Chem 24:954–958. https://doi.org/10.1021/jm00140a008
Buckle DR, Arch JRS, Connolly BJ, Fenwick AE, Foster KA, Murray KJ, Readshaw SA, Smallridge M, Smith DG (1994) Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis (cyclo propylmethyl)xanthine. J Med Chem 37:476–485. https://doi.org/10.1021/jm00030a007
Azizian J, Mohammadizadeh MR, Teimouri F, Mohammadi AA, Karimi AR (2006) Reactions of 6-aminouracils: the first simple, fast, and highly efficient synthesis of bis(6-Amino pyrimidonyl)methanes (BAPMs) using thermal or microwave-assisted solvent-free methods. Synth Commun 36:3631–3638. https://doi.org/10.1080/00397910600943832
Das S, Thakur AJ (2011) A clean, highly efficient and one-pot green synthesis of aryl/alkyl/heteroaryl-substituted bis(6-amino-1,3-dimethyluracil-5-yl)methanes in Water. Eur J Org Chem 2011:2301–2308. https://doi.org/10.1002/ejoc.201001581
Brahmachari G, Banerjee B (2015) Ceric ammonium nitrate (CAN): an efficient and eco-friendly catalyst for the one-pot synthesis of alkyl/aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)methanes at room temperature. RSC Adv 5:39263–39269. https://doi.org/10.1039/c5ra04723d
Emmadi NR, Atmakur K, Bingi C, Godumagadda NR, Chityal GK, Nanubolu JB (2014) Regioselective synthesis of 3-benzyl substituted pyrimidino chromen-2-ones and evaluation of anti-microbial and anti-biofilm activities. Bioorg Med Chem Lett 24:485–489. https://doi.org/10.1016/j.bmcl.2013.12.038
Lu G-P, Cai C (2014) A one-pot, efficient synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines and uncyclized adducts by aldehydes, 1,3-dicarbonyl compounds, and 6-aminouracil. J Heterocycl Chem 51:1595–1602. https://doi.org/10.1002/jhet.1704
Pérez-Sacau E, Díaz-Peñate RG, Estévez-Braun A, Ravelo AG, García-Castellano JM, Pardo L, Campillo M (2007) Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line. J Med Chem 50:696–706. https://doi.org/10.1021/jm060849b
Berghot MA, Kandeel EM, Abdel-Rahman AH, Abdel-Motaal M (2014) Synthesis, antioxidant and cytotoxic activities of novel naphthoquinone derivatives from 2,3-dihydro-2,3-epoxy-1,4- naphthoquinone. Med Chem 4:381–388. https://doi.org/10.4172/2161-0444.1000169
Moorthy NSHN, Karthikeyan C, Trivedi P (2009) Synthesis, cytotoxic evaluation and in silico pharmacokinetic prediction of some benzo[a] phenazine-5-sulfonic acid derivatives. Med Chem 5:549–557. https://doi.org/10.2174/157340609790170533
Lavaggi ML, Cabrera M, de los Ángeles Aravena M, Olea-Azar C, de Ceráin AL, Monge A, Pachón G, Cascante M, Bruno AM, Pietrasanta LI, González M, Cerecetto H (2010) Study of benzo[a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation. Bioorg Med Chem 18:4433–4440. https://doi.org/10.1016/j.bmc.2010.04.074
Sasada T, Kobayashi F, Sakai N, Konakahara T (2009) An unprecedented approach to [4,5-d] pyrimidine derivatives by a ZnCl2-Catalyzed three-component coupling reaction. Org Lett 11:2161–2164. https://doi.org/10.1021/ol900382j
Gopalsamy A, Yang H, Ellingboe JW, Tsou HR, Zhang N, Honores E, Powell D, Miranda M, McGinnis JP, Robindran SP (2005) Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: parallel synthesis for lead optimization of amide region. Bio Org Med Chem 15:1591–1594. https://doi.org/10.1016/j.bmcl.2005.01.066
Kandhasamy S, Ramanathan G, Muthukumar T, Thyagarajan S, Umamaheshwari N, Santhanakrishnan VP, Sivagnanam UT, Perumal PT (2017) Nanofibrous matrixes with biologically active hydroxybenzophenazine pyrazolone compound for cancer theranostics. Mater Sci Eng C 74:70–85. https://doi.org/10.1016/j.msec.2017.01.001
Paengsri W, Lee VS, Chong WL, Wahab HA, Baramee A (2012) Synthesis, antituberculosis activity and molecular docking studies for novel naphthoquinone derivatives. Int J Biol Chem 6:69–88. https://doi.org/10.3923/ijbc.2012.69.88
Dömling A (2005) In: Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 76–94
Tejedor D, Garcia-Tellado F (2007) Chemo-differentiating ABB′ multicomponent reactions. Privileged building blocks. Chem Soc Rev 36:484–491. https://doi.org/10.1039/B608164A
Ibarra IA, Islas-Jácome A, González-Zamora E (2018) Synthesis of polyheterocycles via multicomponent reactions. Org Biomol Chem 16:1402–1418. https://doi.org/10.1039/C7OB02305G
Ismaili L, Carreiras MC (2017) Multicomponent reactions for multitargeted compounds for Alzheimer’s disease. Curr Top Med Chem 17:3319–3327. https://doi.org/10.2174/1568026618666180112155424
Cioc RC, Ruijter E, Orru RVA (2014) Multicomponent reactions: advanced tools for sustainable organic synthesis. Green Chem 16:2958–2975. https://doi.org/10.1039/C4GC00013G
Boukis AC, Reiter K, Frölich M, Hofheinz D, Meier MAR (2018) Multicomponent reactions provide key molecules for secret communication. Nat Commun 9:1439. https://doi.org/10.1038/s41467-018-03784-x
Azizi N, Ahooie TS, Hashemi MM (2017) Multicomponent domino reactions in deep eutectic solvent: an efficient strategy to synthesize multisubstituted cyclohexa-1,3-dienamines. J Mol Liq 246:221–224. https://doi.org/10.1016/j.molliq.2017.09.049
Felluga F, Benedetti F, Berti F, Drioli S, Regin G (2018) Efficient Biginelli synthesis of 2-aminopyrimidines under microwave irradiation. Synlett 29:1047–1054. https://doi.org/10.1055/s-0036-1591900
Narayan S, Muldoon J, Finn MG, Fokin VV, Kolb HC, Sharpless KB (2005) “On water”: unique reactivity of organic compounds in aqueous suspension. Angew Chem Int Ed 44:3275–3279. https://doi.org/10.1002/anie.200590069
Das P, McLeod D, McNulty J (2011) A direct synthesis of functionalized styrenes and terminal 1,3-dienes via aqueous Wittig chemistry with formalin. Tetrahedron Lett 52:199–201. https://doi.org/10.1016/j.tetlet.2010.10.090
Yi-M Ren, Cai C, Yang R-C (2013) Molecular iodine-catalyzed multicomponent reactions: an efficient catalyst for organic synthesis. RSC Adv 3:7182–7204. https://doi.org/10.1039/c3ra23461d
Parvatkar PT, Parameswaran PS, Tilve SG (2012) Recent developments in the synthesis of five- and six-membered heterocycles using molecular iodine. Chem Eur J 18:5460–5489. https://doi.org/10.1002/chem.201100324
Jereb M, Vrazic D, Zupan M (2011) Iodine-catalyzed transformation of molecules containing oxygen functional groups. Tetrahedron 67:1355–1387. https://doi.org/10.1016/j.tet.2010.11.086
Reddy GR, Reddy TR, Joseph SC, Reddy KS, Pal M (2012) Iodine catalyzed four-component reaction: a straightforward one-pot synthesis of functionalized pyrroles under metal-free conditions. RSC Adv 2:3387–3395. https://doi.org/10.1039/C2RA00982J
Ramachandran G, Karthikeyan NS, Giridharan P, Sathiyanarayanan KI (2012) Efficient iodine catalyzed three components domino reaction for the synthesis of 1- ((phenylthio)(phenyl)methyl)pyrroli din-2-one derivatives possessing anticancer activities. Org Biomol Chem 10:5343–5346. https://doi.org/10.1039/C2OB25530H
Bharti R, Kumari P, Parvin T, Choudhury LH (2018) Recent advances of aminopyrimidines in multicomponent reactions. Curr Org Chem 22:417–445. https://doi.org/10.2174/1385272822666171212152406
Panday AK, Mishra R, Jana A, Parvin T, Choudhury LH (2018) Synthesis of pyrimidine fused quinolines by ligand-free copper catalyzed domino reactions. J Org Chem 83:3624–3632. https://doi.org/10.1021/acs.joc.7b03272
Jana A, Panday AK, Mishra R, Parvin T, Choudhury LH (2017) Synthesis of thio and selenoethers of cyclic β-hydroxy carbonyls and amino uracils: a metal-free regioselective I2/DMSO mediated reaction. ChemistrySelect 2:9420–9424. https://doi.org/10.1002/slct.201702066
Choudhury LH, Parvin T (2011) Recent advances in the chemistry of imine-based multicomponent reactions (MCRs). Tetrahedron 67:8213–8228. https://doi.org/10.1016/j.tet.2011.07.020
Bharti R, Parvin T (2015) One-pot synthesis of highly functionalized tetrahydropyridines: a camphoresulfonic acid catalyzed multicomponent reaction. J Heterocycl Chem 52:1806–1811. https://doi.org/10.1002/jhet.2268
Bharti R, Parvin T (2015) Diversity oriented synthesis of tri-substituted methane containing aminouracil and hydroxynaphthoquinone/hydroxycoumarin moiety using organocatalysed multicomponent reactions in aqueous medium. RSC Adv 5:66833–66839. https://doi.org/10.1039/c5ra13093j
Bharti R, Kumari P, Parvin T, Choudhury LH (2017) Molecular diversity from the three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes and 6-aminouracils: a reaction condition dependent MCR. RSC Adv 7:3928–3933. https://doi.org/10.1039/c6ra18828a
Bharti R, Parvin T (2016) Multicomponent synthesis of diverse pyrano-fused benzophenazines using bifunctional thiourea-based organocatalyst in aqueous medium. Mol Divers 20:867–876. https://doi.org/10.1007/s11030-016-9681-z
Acknowledgements
We are thankful to NIT Patna and Department of Science and Technology, India, for financial support with Sanction No. EMR/2016/000960. We are also grateful to SAIF-Panjab University and SAIF-IIT Patna for providing analytical facilities.
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Kumari, P., Bharti, R. & Parvin, T. Synthesis of aminouracil-tethered tri-substituted methanes in water by iodine-catalyzed multicomponent reactions. Mol Divers 23, 205–213 (2019). https://doi.org/10.1007/s11030-018-9862-z
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DOI: https://doi.org/10.1007/s11030-018-9862-z