Molecular Diversity

, Volume 13, Issue 4, pp 399–419 | Cite as

One hundred years of Meldrum’s acid: advances in the synthesis of pyridine and pyrimidine derivatives

  • Victoria V. Lipson
  • Nikolay Yu. GorobetsEmail author


A general review (138 references) focused on the recent advances in the application of Meldrum’s acid reactivity for synthesis of diverse pyridine and pyrimidine derivatives, mostly small and drug-like molecules is presented.


Meldrum’s acid Pyridine Pyrimidine Azoloazines Tandem reactions Multicomponent cyclocondensations 


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  1. 1.
    Meldrum AN (1908) A β-lactonic acid from acetone and malonic acid. J Chem Soc Trans 93: 598–601. doi: 10.1039/CT9089300598 CrossRefGoogle Scholar
  2. 2.
    Forster MO (1934) Obituary notices: Andrew Norman Meldrum, 1876–1934. J Chem Soc 1476–1478. doi: 10.1039/JR9340001468
  3. 3.
    Japp FR, Meldrum AN (1901) Homologues of anhydracetonebenzil. J Chem Soc Trans 79: 1024–1042. doi: 10.1039/CT9017901024 CrossRefGoogle Scholar
  4. 4.
    Meldrum AN, Perkin WH Jr (1908) The cis- and trans-modifications of 1-methylcyclohexan-2-ol-4-carboxylic acid and their conversion into 1 methyl-Δ1-cyclohexane-4-carboxylic acid. J Chem Soc Trans 93: 1416–1428. doi: 10.1039/CT9089301416 CrossRefGoogle Scholar
  5. 5.
    Byun K, Mo Y, Gao J (2001) New insight on the origin of the unusual acidity of Meldrum’s acid from ab initio and combined QM/MM simulation study. J Am Chem Soc 123: 3974–3979. doi: 10.1021/ja001369r PubMedCrossRefGoogle Scholar
  6. 6.
    Arnett EM, Harrelson JA Jr (1987) Ion pairing and reactivity of enolate anions. 7. A spectacular example of the importance of rotational barriers: the ionization of Meldrum’s acid. J Am Chem Soc 109: 809–812. doi: 10.1021/ja00237a028 CrossRefGoogle Scholar
  7. 7.
    Davidson D, Bernhard SA (1948) Structure of Meldrum’s supposed β-lactonic acid. J Am Chem Soc 70: 3426–3428. doi: 10.1021/ja01190a060 PubMedCrossRefGoogle Scholar
  8. 8.
    McNab H (1978) Meldrum’s acid. Chem Soc Rev 7: 345–358. doi: 10.1039/CS9780700345 CrossRefGoogle Scholar
  9. 9.
    Chen BC (1991) Meldrum’s acid in organic synthesis. Heterocycles 32: 529–597CrossRefGoogle Scholar
  10. 10.
    Gerencsér J, Dormán G, Darvas F (2006) Meldrum’s acid in multicomponent reactions: applications to combinatorial and diversity-oriented synthesis. QSAR Comb Sci 25: 439–448. doi: 10.1002/qsar.200540212 CrossRefGoogle Scholar
  11. 11.
    McNab H (2004) Chemistry without reagents: synthetic applications of flash vacuum pyrolysis. Aldrichim Acta 37:19–26. Google Scholar
  12. 12.
    Gaber AE-AM, McNab H (2001) Synthetic applications of the pyrolysis of Meldrum’s acid derivatives. Synthesis 14: 2059–2074. doi: 10.1055/s-2001-18057 CrossRefGoogle Scholar
  13. 13.
    Ivanov AS (2008) Meldrum’s acid and related compounds in the synthesis of natural products and analogs. Chem Soc Rev 37: 789–811. doi: 10.1039/b716020h PubMedCrossRefGoogle Scholar
  14. 14.
    Wang H, Tang Y, Wang L, Long C-L, Zhang Y-L (2007) ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr Med Chem 14: 133–155. doi: 10.2174/092986707779313390 PubMedCrossRefGoogle Scholar
  15. 15.
    Connon SJ (2006) Catalytic asymmetric acyl-transfer mediated by chiral pyridine derivatives. Lett Org Chem 3: 333–338. doi: 10.2174/157017806776611908 CrossRefGoogle Scholar
  16. 16.
    Saladino R, Ciambecchini U, Nencioni L, Palamara AT (2003) Recent advances in the chemistry of parainfluenza-1 (Sendai) virus inhibitors. Med Res Rev 23: 427–455. doi: 10.1002/med.10036 PubMedCrossRefGoogle Scholar
  17. 17.
    Baraldi PG, Cacciari B, Borea PA, Varani K, Pastorin G, Da Ros T, Tabrizi MA, Fruttarolo F, Spalluto G (2002) Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: a possible template for adenosine receptor subtypes. Curr Pharm Des 8: 2299–2332Google Scholar
  18. 18.
    Gros P, Fort Y (2002) nBuLi/lithium aminoalkoxide aggregates: new and promising lithiating agents for pyridine derivatives. Eur J Org Chem 3375–3383. doi: 10.1002/1099-0690(200210)2002:20<3375::AID-EJOC3375>3.0.CO;2-X
  19. 19.
    Rewcastle GW, Denny WA, Showalter HDH (2000) Synthesis of 4-(phenylamino)pyrimidine derivatives as ATP-competitive protein kinase inhibitors with potential for cancer chemotherapy. Curr Org Chem 4: 679–706CrossRefGoogle Scholar
  20. 20.
    Shaabani A, Bazgir A, Bijanzadeh HR (2004) A reexamination of Biginelli-like multicomponent condensation reaction: one-pot regioselective synthesis of spiro heterobicyclic rings. Mol Divers 8: 141–145. doi: 10.1023/B:MODI.0000025613.35304.25 PubMedCrossRefGoogle Scholar
  21. 21.
    Amini MM, Shaabani A, Bazgir A (2006) Tungstophosphoric acid (H3PW12O40): an efficient and eco-friendly catalyst for the one-pot synthesis of dihydropyrimidin-2(1H)-ones. Catal Commun 7: 843–847. doi: 10.1016/j.catcom.2006.02.027 CrossRefGoogle Scholar
  22. 22.
    Shaabani A, Bazgir A (2004) A novel pseudo four-component reaction: unexpected formation of densely functionalized pyrroles. Tetrahedron Lett 45: 2575–2577. doi: 10.1016/j.tetlet.2004.01.154 CrossRefGoogle Scholar
  23. 23.
    Byk G, Kabha E (2004) Anomalous regioselective four-member multicomponent Biginelli reaction II: one-pot parallel synthesis of spiro heterobicyclic aliphatic rings. J Comb Chem 6: 596–603. doi: 10.1021/cc049962i PubMedCrossRefGoogle Scholar
  24. 24.
    Byk G, Kabha E (2006) A solid-supported stereoselective multicomponent reaction: one-pot generation of three asymmetric carbons. Synlett 747–748. doi: 10.1055/s-2006-932498
  25. 25.
    D’yachenko EV, Glukhareva TV, Dyudya LV, Eltsov OV, Morzherin YY (2005) The tert-amino effect in heterocyclic chemistry. Synthesis of spiro heterocycles. Molecules, 10:1101–1108.
  26. 26.
    Schwartz A, Beke G, Kovári Z, Böcskey Z, Farkas Ö, Mátyus P (2000) Applications of tert-amino effect and a nitrone-olefin 1,3-dipolar cycloaddition reaction: synthesis of novel angularly annelated diazino heterocycles. J Mol Struct (Theochem) 528: 49–57. doi: 10.1016/S0166-1280(99)00399-1 CrossRefGoogle Scholar
  27. 27.
    Beke G, Gergely A, Szasz G, Szentesi A, Nyitray J, Barabas O, Harmath V, Mátyus P (2002) Synthesis and stereochemistry of dispiro substituted pyridazines: application of ellipticity-absorbance ratio spectra for proving enantiomeric relationship by HPLC-CD/UV detection. Chirality 14: 365–371. doi: 10.1002/chir.10096 PubMedCrossRefGoogle Scholar
  28. 28.
    Kaval N, Halasz-Dajka B, Vo-Thanh G, Dehaen W, Van der Eycken J, Mátyus P, Loupy A, Van der Eycken E (2005) An efficient microwave-assisted solvent-free synthesis of pyrido-fused ring systems applying the tert-amino effect. Tetrahedron 61: 9052–9057. doi: 10.1016/j.tet.2005.07.046 CrossRefGoogle Scholar
  29. 29.
    Melh-Cohn O, Suschiizky H (1996) The t-amino effect: heterocycles formed by ring closure of ortho-substituted t-anilines Adv Heterocycl Chem 65: 1. doi: 10.1016/S0065-2725(08)60294-9 Google Scholar
  30. 30.
    Ojea V, Muinelo I, Quintela JM (1998) Synthesis of fused pyrido[2,3-d]pyrimidines by thermal isomerization of 4-amino-5-vinylpyrimidines. Tetrahedron 54: 927–934. doi: 10.1016/S0040-4020(97)10334-9 CrossRefGoogle Scholar
  31. 31.
    Glukhareva TV, D’yachenko EV, Morzherin YY (2002) Synthesis of spiro derivatives of pyrrolo[1,2-a]quinoline. Chem Heterocycl Comp 1426–1427. doi: 10.1023/A:1022107332320
  32. 32.
    D’yachenko EV, Glukhareva TV, Nikolaenko EF, Tkachev AV, Morzherin YY (2004) tert-Amino effect in heterocyclic chemistry. Synthesis of hydrogenated spiro derivatives of quinolines. Russ Chem Bull Int Ed 53: 1240–1247. doi: 10.1023/B:RUCB.0000042280.71728.d0 CrossRefGoogle Scholar
  33. 33.
    Deeva EV, Glukhareva TV, Zybina NA, Morzherin YY (2005) Stereoselective synthesis of spiro derivatives of 2, 4-dimethyl-2, 3,4,4a,5,6-hexahydro-6H-benzo[c]quinolizine. Russ Chem Bull Int Ed 54: 1537–1538. doi: 10.1007/s11172-005-0444-8 CrossRefGoogle Scholar
  34. 34.
    Deeva EV, Glukhareva TV, Tkachev AV, Morzherin YY (2006) The stereo selective synthesis of spirofused 3-substituted 2,3,4,4a,5,6-hexahydro-6H-benzo[c]quinolizine by the using tert-amino effect. Mendeleev Commun 16: 82–83CrossRefGoogle Scholar
  35. 35.
    Paramonov IV, Belyaev NA, Glukhareva TV, Volkov AS, Deeva EV, Morzherin YY (2006) One-step synthesis of a novel heterocyclic system: spiro 1,4-thiazino[4,3-a]quinoline-5,5′-pyrimidine]. Chem Heterocycl Comp 42: 127–128. doi: 10.1007/s10593-006-0061-y CrossRefGoogle Scholar
  36. 36.
    Vlaskina NM, Suzdalev KF, Babakova MN, Mezheritskii VV, Kartsev VG (2006) Use of the tert-amino effect in the synthesis of spirocyclic fused α-carbolines. Russ Chem Bull 55: 384–386. doi: 10.1007/s11172-006-0265-4 CrossRefGoogle Scholar
  37. 37.
    Renslo AR, Danheiser RL (1998) Synthesis of substituted pyridines via regiocontrolled [4+2] cycloadditions of oximinosulfonates. J Org Chem 63: 7840–7850. doi: 10.1021/jo981014e CrossRefGoogle Scholar
  38. 38.
    Danheiser RL, Renslo AR, Amos DT, Wright GT (2003) Preparation of substituted pyridines via regiocontrolled [4+2] cycloadditions of oximinosulfonates: methyl 5-methylpyridine-2-carboxylate. Org Synth 80:133–143 Google Scholar
  39. 39.
    Katagiri N, Nochi H, Kurimoto A, Sato H, Kaneko C (1994) Synthesis of nucleosides and related compounds. XXXIV. Synthesis of 5-isonitroso-1,3-dioxane-4,6-diones and their reactions. Chem Pharm Bull 42:1251–1257 Google Scholar
  40. 40.
    Chou SY, Chang LS, Chen SF (1999) An anomalous preparing of a tetrahydro-2H-oxocine fused pyrrole derivative and its acid-catalyzed rearrangement. Heterocycles 51: 833–839CrossRefGoogle Scholar
  41. 41.
    Vanotti E, Amici R, Bargiotti A, Berthelsen J, Bosotti R, Ciavolella A, Cirla A, Cristiani C, D’Alessio R, Forte B, Isacchi A, Martina K, Menichincheri M, Molinari A, Montagnoli A, Orsini P, Pillan A, Roletto F, Scolaro A, Tibolla M, Valsasina B, Varasi M, Volpi D, Santocanale C (2008) Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships. J Med Chem 51: 487–501. doi: 10.1021/jm700956r PubMedCrossRefGoogle Scholar
  42. 42.
    Orsini P, Maccario A, Colombo N (2007) Regioselective γ-alkylation of tert-butyl 2,4-dioxopiperidine-1-carboxylate. Synthesis 2007: 3185–3190. doi: 10.1055/s-2007-990792 CrossRefGoogle Scholar
  43. 43.
    Casimir JR, Didierjean C, Aubry A, Rodriguez M, Briand J-P, Guichard G (2000) Stereoselective alkylation of N-Boc-protected-5-substituted δ-lactams: synthesis of α, δ-disubstituted δ-amino acids. Org Lett 2: 895–897. doi: 10.1021/ol9913136 PubMedCrossRefGoogle Scholar
  44. 44.
    Marin J, Didierjean C, Aubry A, Briand J-P, Guichard G (2002) Diastereoselective hydroxylation of 6-substituted piperidin- 2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related α-amino acids. J Org Chem 67: 8440–8449. doi: 10.1021/jo025950c PubMedCrossRefGoogle Scholar
  45. 45.
    Tian X, Chen X, Gan L, Hayes JC, Switzer AG, Solinsky MG, Ebetino FH, Wos JA, Pinney BB, Farmer JA, Crossdoersen D, Sheldon R J. (2006) Synthesis of Tic-D-Phe Ψ [CH2-CH2] isostere and its use in the development of melanocortin receptor agonists. Bioorg Med Chem Lett 16: 1721–1725. doi: 10.1016/j.bmcl.2005.12.005 PubMedCrossRefGoogle Scholar
  46. 46.
    Saczewski F, Gdaniec M (1996) Syntheses of novel fused heterocyclic systems by reactions of 1,2-dihydro-2-(4, 5-dihydroimidazol-2-yl)phtalazine-1-ol with active methylene compounds. Liebigs Ann 1996: 1673–1677. doi: 10.1002/jlac.199619961028 CrossRefGoogle Scholar
  47. 47.
    Benzing M, Vilsmaier E (1987) Reactions of diastereomeric aminobicycloalkyl Meldrum’s acid derivatives—sterically controlled transformations at the [4.1.0]-bicyclic systems. Chem Ber 120: 1873–1880. doi: 10.1002/cber.19871201116 CrossRefGoogle Scholar
  48. 48.
    Deb ML, Bhuyan PJ (2006) Synthesis of novel classes of pyrido[2,3-d]pyrimidines, pyrano[2,3-d]pyrimidines, and pteridines. Synth Commun 36: 3085–3090. doi: 10.1080/00397910600775622 CrossRefGoogle Scholar
  49. 49.
    Tietze LF, Evers H, Enno T (2001) A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: formation of N-betaines by multicomponent domino reactions. Angew Chem Int Ed 40: 903–905. doi: 10.1002/1521-3773(20010302)40:5<903::AID-ANIE903>3.0.CO;2-7 CrossRefGoogle Scholar
  50. 50.
    Bihlmayer GA, Derflinger G, Derkosch J, Polansky OE (1967) Cyclic acylals. XVII. Hydroxy- and aminomethylene derivatives of Meldrum’s acid. Monatsh Chem 98: 564–578. doi: 10.1007/BF00901364 CrossRefGoogle Scholar
  51. 51.
    Feldman KS, Coca A (2008) Synthesis of the pentacyclic core of lihouidine. Tetrahedron Lett 49: 2136–2138. doi: 10.1016/j.tetlet.2008.01.118 PubMedCrossRefGoogle Scholar
  52. 52.
    Teague SJ, Barber S, King S, Linda S (2005) Synthesis of benzimidazole based JNK inhibitors. Tetrahedron Lett 46: 4613–4616. doi: 10.1016/j.tetlet.2005.04.145 CrossRefGoogle Scholar
  53. 53.
    Kitahara Y, Mizuno T, Kubo A (2004) Synthetic studies of benzo[b]pyrrolo[4,3,2-de][1,10]phenanthroline. Tetrahedron 60: 4283–4288. doi: 10.1016/j.tet.2004.03.057 CrossRefGoogle Scholar
  54. 54.
    Watterson SH, Carlsen M, Dhar TGM, Shen Z, Pitts WJ, Guo J, Gu HH, Norris D, Chorba J, Chen P, Cheney D, Witmer M, Fleener CA, Rouleau K, Townsend R, Hollenbaugh DL, Iwanowicz EJ (2003) Novel inhibitors of IMPDH a highly potent and selective quinolone-based series. Bioorg Med Chem Lett 13: 543–546. doi: 10.1016/S0960-894X(02)00944-7 PubMedCrossRefGoogle Scholar
  55. 55.
    Beifuss U, Feder SG (2001) Efficient allylation of 4-silyloxyquinolinium triflates and other positively charged heteroaromatic systems. Tetrahedron 57: 1005–1013. doi: 10.1016/S0040-4020(00)01066-8 CrossRefGoogle Scholar
  56. 56.
    Delfourne E, Roubin C, Bastide J (2000) The first synthesis of the pentacyclic pyridoacridine marine alkaloids: arnoamines A and B. J Org Chem 65: 5476–5479. doi: 10.1021/jo000011a PubMedCrossRefGoogle Scholar
  57. 57.
    Walz AJ, Sundberg RJ (2000) Synthesis of 8-methoxy-1-methyl-1H-benzo[de]1,6-naphthyridin-9-ol (isoaaptamine) and analogues. J Org Chem 65: 8001–8010. doi: 10.1021/jo001080s PubMedCrossRefGoogle Scholar
  58. 58.
    Al-Awadi NA, Abdelhamid IA, Al-Etaibi AM, Elnagdi MH (2007) Gas-phase pyrolysis in organic synthesis: rapid green synthesis of 4-quinolinones. Synlett: 2205–2208. doi: 10.1055/s-2007-985573
  59. 59.
    Morgentin R, Pasquet G, Boutron P, Jung F, Lamorlette M, Maudet M, Ple P (2008) Strategic studies in the synthesies of novel 6, 7-substituted quinolones and 7- or 6-substituted 1,6- and 1, 7-naphthyridones. Tetrahedron 64: 2772–2782. doi: 10.1016/j.tet.2008.01.055 CrossRefGoogle Scholar
  60. 60.
    Blake AJ, McNab H, Morrow M, Rataj H (1993) Pyrazolo[1,2-a]-1,2,3-triazinium-4-olate. Chem Soc Chem Commun 840–842. doi: 0.1039/C39930000840J
  61. 61.
    Quiroga J, Hormaza A, Insuasty B, Saitz C, Julian C, Canete A (1998) Synthesis of pyrazolo[1,5-a]pyrimidines in the reaction of 5-amino-3-arylpyrazoles with methoxymethylene Meldrum’s acid derivative and thermolysis of their pyrazolylaminomethylenederivatives. J Heterocycl Chem 35: 61–64CrossRefGoogle Scholar
  62. 62.
    Cassis R, Tapia J, Valderrama A (1985) Synthesis of 4(1H)-quinolones by thermolysis of arylaminomethylene Meldrum’s acid derivatives. Synth Commun 15: 125–133. doi: 10.1080/00397918508076818 CrossRefGoogle Scholar
  63. 63.
    Singh B, Laskowski SC, Lesher GY (1990) An efficient and facile synthesis of novel 2-aryl-pyrido[2,3-d]pyrimidin-5(8H)-ones. Synlett 549–550 doi: 10.1055/s-1990-21163
  64. 64.
    Ravina I, Zicane D, Petrova M, Gudriniece E, Kalejs U (2002) Exotic amino acids. Part 6. Synthesis of substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines. Chem Heterocycl Comp 38: 836–839. doi: 10.1023/A:1020689805869 CrossRefGoogle Scholar
  65. 65.
    Dennin F, Blondeau D, Sliwa H (1989) Synthesis of new heterocyclic phenols: 9-hydroxypyrido[1,2-a]pyrimidin-4-one and 9-hydroxypyrimido[1,6-a]pyrimidin-4-one. Tetrahedron Lett 30: 1529–1530. doi: 10.1016/S0040-4039(00)99510-8 CrossRefGoogle Scholar
  66. 66.
    Horvath G, Hermecz I, Horvath A, Pongor-Csakvari M, Pusztay L, Kiss AI, Czako L, Abdirizak OH (1985) Electronic structure of 4H-pyrido[1,2-a]pyrimidin-4-ones. J Heterocycl Chem 22: 481–489CrossRefGoogle Scholar
  67. 67.
    Everson da Silva L, Carlos JA, Nunes RJ, Navakoski de Oliveira K (2008) Synthesis of tacrine analogs derived from N-aryl-5-amino-4-cyanopyrazoles. Synth Commun 38: 15–20. doi: 10.1080/00397910701648744 CrossRefGoogle Scholar
  68. 68.
    Eversonda Silva L, Joussef AC, Pacheco LK, Albino DBL, Duarte AMC, Steindel M, Rebelo RA (2007) Synthesis and antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis of chlorinated 1,7- and 1,8-naphthyridines. Lett Drug Des Discov 4: 154–159. doi: 10.2174/157018007779422550 CrossRefGoogle Scholar
  69. 69.
    Gomez L, Hack MD, Wu J, Wiener JJM, Venkatesan H, Santillan A, Pippel DJ, ManiN Morrow BJ, Motley ST, Shaw KJ, Wolin R, Grice CA, Jones TK (2007) Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis. Bioorg Med Chem Lett 17: 2723–2727. doi: 10.1016/j.bmcl.2007.03.003 PubMedCrossRefGoogle Scholar
  70. 70.
    Ye F-C, Chen B-C, Huang X (1989) Synthesis of 7-substituted 5-oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acids, 2-substituted 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acids, and 2,6-disubstituted 4-quinolones from Meldrum’s acid derivatives. Synthesis 4: 317–320. doi: 10.1055/s-1989-27241 CrossRefGoogle Scholar
  71. 71.
    Knight ZA, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K, Abraham RT, Shokat KM (2004) Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg Med Chem 12: 4749–4759. doi: 10.1016/j.bmc.2004.06.022 PubMedCrossRefGoogle Scholar
  72. 72.
    Barbeau OR, Cano-Soumillac C, Griffin RJ, Hardcastle IR, Smith GCM, Richardson C, Clegg W, Harrington RW, Golding BT (2007) Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase. Org Biomol Chem 5: 2670–2677. doi: 10.1039/b705095j PubMedCrossRefGoogle Scholar
  73. 73.
    Sanghvi YS, Larson SB, Robins RK, Revankar GR (1990) A convenient synthesis of pyrazolo[3,4-b]pyridine nucleosides by convenient ring-closure procedures. X-ray crystal and molecular structure of 4-amino-1-(β-D-ribofuranosyl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one. J Chem Soc Perkin Trans 1 2943–2950. doi: 10.1039/P19900002943
  74. 74.
    Huang X, Liu Zh (2003) Synthesis of 1-(N-alkylidene or benzylideneamino)-1,6-dihydro-2-methylthio-6-oxo-pyrimidine from Meldrum’s acid derivatives. Synth Commun 33: 927–934CrossRefGoogle Scholar
  75. 75.
    Bibas H, Moloney DWJ, Neumann R, Shtaiwi M, Bernhardt PV, Wentrup C (2002) Chemistry of stable iminopropadienones, RN:C:C:C:O. J Org Chem 67: 2619–2631. doi: 10.1021/jo0110552 PubMedCrossRefGoogle Scholar
  76. 76.
    Emtenas H, Alderin L, Almqvist F (2001) An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones. J Org Chem 66: 6756–6761. doi: 10.1021/jo015794u PubMedCrossRefGoogle Scholar
  77. 77.
    Emtenas H, Ahlin K, Pinkner JS, Hultgren SJ, Almqvist F (2002) Design and parallel solid-phase synthesis of ring-fused 2-pyridinones that target pilus biogenesis in pathogenic bacteria. J Comb Chem 4: 630–639. doi: 10.1021/cc020032d PubMedCrossRefGoogle Scholar
  78. 78.
    Emtenas H, Taflin C, Almqvist F (2003) Efficient microwave assisted synthesis of optically active bicyclic 2-pyridinones via delta-2-thiazolines. Mol Divers 7: 165–169. doi: 10.1023/B:MODI.0000006800.46154.99 PubMedCrossRefGoogle Scholar
  79. 79.
    Sellstedt M, Almqvist F (2008) Synthesis of a novel tricyclic peptidomimetic scaffold. Org Lett 10: 4005–4007. doi: 10.1021/ol801506y PubMedCrossRefGoogle Scholar
  80. 80.
    Pemberton N, Pinkner JS, Edvinsson S, Hultgren SJ, Almqvist F (2008) Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones-targeting pilus biogenesis in uropathogenic bacteria. Tetrahedron 64: 9368–9376. doi: 10.1016/j.tet.2008.07.015 CrossRefGoogle Scholar
  81. 81.
    Aberg V, Das P, Chorell E, Hedenstroem M, Pinkner JS, Hultgren SJ, Almqvist F (2008) Carboxylic acid isosteres improve the activity of ring-fused 2-pyridones that inhibit pilus biogenesis in E. coli. Bioorg Med Chem Lett 18: 3536–3540. doi: 10.1016/j.bmcl.2008.05.020 CrossRefGoogle Scholar
  82. 82.
    Chorell E, Das P, Almqvist F (2007) Diverse functionalization of thiazolo ring-fused 2-pyridones. J Org Chem 72: 4917–4924. doi: 10.1021/jo0704053 PubMedCrossRefGoogle Scholar
  83. 83.
    Pemberton N, Pinkner JS, Edvinsson S, Hultgren SJ, Almqvist F (2008) Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones-targeting pilus biogenesis in uropathogenic bacteria. Tetrahedron 64: 9368–9376. doi: 10.1016/j.tet.2008.07.015 CrossRefGoogle Scholar
  84. 84.
    Aaberg V, Norman F, Chorell E, Westermark A, Olofsson A, Sauer-Eriksson AE, Almqvist F (2005) Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of Aβ-peptide aggregation inhibitors. Org Biomol Chem 3: 2817–2823. doi: 10.1039/b503294f CrossRefGoogle Scholar
  85. 85.
    Pemberton N, Jakobsson L, Almqvist F (2006) Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation. Org Lett 8: 935. doi: 10.1021/ol052998e PubMedCrossRefGoogle Scholar
  86. 86.
    Morita Y, Kamakura R, Takeda M, Yamamoto Y (1997) Convenient preparation of trifluoroacetyl Meldrum’s acid and its use as a building block for trifluoromethyl-containing compounds. Chem Commun 359–360. doi: 10.1039/a608104e
  87. 87.
    Nesterov VN, Krivokolysko SG, Dyachenko VD, Dotsenko VV, Litvinov VP (1997) Synthesis, properties and structures of ammonium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. Russ Chem Bull 46: 990–996. doi: 10.1007/BF02496132 CrossRefGoogle Scholar
  88. 88.
    Krivokolysko SG, Dotsenko VV, Litvinov VP (2000) New multicomponent condensation leading to sulfur-containing 1,2,3, 4-tetrahydro-2-pyridinones. Chem Heterocycl Comp 36: 1108–1109. doi: 10.1023/A:1002750402772 CrossRefGoogle Scholar
  89. 89.
    Dyachenko VD, Krivokolysko SG, Litvinov VP (1997) A new method for the synthesis of N-methylmorpholinium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates and their properties. Russ Chem Bull 46: 1758–1762. doi: 10.1007/BF02495131 CrossRefGoogle Scholar
  90. 90.
    Dyachenko VD, Krivokolysko SG, Litvinov VP (1997) Synthesis and some properties of 4-alkyl-5-cyano-6-mercapto-3, 4-dihydropyridin-2(1H)-ones. Russ Chem Bull 46: 1912–1915. doi: 10.1007/BF02503785 CrossRefGoogle Scholar
  91. 91.
    Krivokolysko SG, Dyachenko VD, Litvinov VP (1999) Synthesis and alkylation of N-methylmorpholinium 5-cyano-4-(3- and 4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. Russ Chem Bull 48: 2308–2311. doi: 10.1007/BF02498278 CrossRefGoogle Scholar
  92. 92.
    Frolov KA, Dotsenko VV, Krivokolysko SG, Litvinov VP (2005) Three-component condensation in the synthesis of substituted tetrahydropyrimidinethiolates. Russ Chem Bull 54: 1335–1336. doi: 10.1007/s11172-005-0404-3 CrossRefGoogle Scholar
  93. 93.
    Dotsenko VV, Krivokolysko SG, ChernegaAN Litvinov VP (2002) Anilinomethylidene derivatives of cyclic 1,3-dicarbonyl compounds in the synthesis of new sulfur-containing pyridines and quinolines. Russ Chem Bull 51: 1556–1561. doi: 10.1023/A:1020939712830 CrossRefGoogle Scholar
  94. 94.
    Mermerian AH, Case A, Stein RL, Cuny DG (2007) Structure-activity relationship, kinetic mechanism, and selectivity for new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors. Bioorg Med Chem Lett 17: 3729–3732. doi: 10.1016/j.bmcl.2007.04.027 PubMedCrossRefGoogle Scholar
  95. 95.
    Yu C-Y, Yang P-H, Zhao M-X, Huang Z-T (2006) A novel one-pot reaction of heterocyclic ketene aminals: synthesis of a small library of tetrahydropyrimidone-fused 1,3-diazaheterocycles. Synlett 12: 1835–1840. doi: 10.1055/s-2006-947343 CrossRefGoogle Scholar
  96. 96.
    Ramin M, Ahmadreza M (2008) Dihydropyridines and atypical MDR: a novel perspective of designing general reversal agents for both typical and atypical MDR. Bioorg Med Chem 16: 8329–8334. doi: 10.1016/j.bmc.2008.07.025 CrossRefGoogle Scholar
  97. 97.
    Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL, Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W, Ye G, Semus SF, Evans CF, Harvey E, Jolivette LJ, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Bentley R, Doe CP, Hu E, Lee D (2007) Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors. J Med Chem 50: 6–9. doi: 10.1021/jm0609014 PubMedCrossRefGoogle Scholar
  98. 98.
    Suarez M, Verdecia Y, Ochoa E, Salfran E, Moran L, Martin N, Martinez R, Quinteiro M, Seoane C, Soto JL, Novoa H, Blaton N, Peeters OM, De Ranter C (2000) Synthesis and structural study of 3,4-dihydro-2(1H)-pyridones and isoxazolo[5,4-b]pyridin-6(7H)-ones. Eur J Org Chem 2079–2088. doi: 10.1002/1099-0690(200006)2000:11<2079::AID-EJOC2079>3.0.CO;2-#
  99. 99.
    Surez M, Ochoa E, Verdecia Y, Pita B, Morin O, Martin N, Quinteiro M, Seoane C, Soto JL, Novoa H, Blaton N, Peters OM (1999) A joint experimental and theoretical structural study of novel substituted 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinolines. Tetrahedron 55: 875–884. doi: 10.1016/S0040-4020(98)01078-3 CrossRefGoogle Scholar
  100. 100.
    Morales A, Ochoa E, Suarez M, Verdecia Y, Gonzalez L, Martin N, Quinteiro M, Seoane C, Soto JL (1996) Novel hexahydrofuro[3,4-b]-2(1H)-pyridones from 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones. J Heterocycl Chem 33: 103–107CrossRefGoogle Scholar
  101. 101.
    Verdecia Y, Suarez M, Morales A, Rodriguez E, Ochoa E, Gonzalez L, Martin N, Quinteiro M, Seoane C, Soto JL (1996) Synthesis of methyl 4-aryl-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates from methyl 4-aryl-6-methyl-2-oxo-1,2,3,4-tetrahydropyridine-5-carboxylates. J Chem Soc Perkin Trans 1: 947–951. doi: 10.1039/P1996000 CrossRefGoogle Scholar
  102. 102.
    Tu Sh, Fang F, Zhu S, Li T, Zhang X, Zhuang Q, Ji Sh, Zhang Y (2005) Microwave-assisted synthesis of phenylenedi(4′, 4′′-tetrahydroquinoline) and di(4′,4′′-tetrahydropyridine) derivatives. J Heterocycl Chem 42: 29–32CrossRefGoogle Scholar
  103. 103.
    Tu Sh, Miao Ch, Fang F, Feng Y, Li T, Zhuang Q, Zhang X, Zhu S, Shi D (2004) New potential calcium channel modulators: design and synthesis of compounds containing two pyridine, pyrimidine, pyridone, quinoline and acridine units under microwave irradiation. Bioorg Med Chem Lett 14: 1533–1536. doi: 10.1016/j.bmcl.2003.12.092 PubMedCrossRefGoogle Scholar
  104. 104.
    Rodriguez H, Suarez M, Perez R, Petit A, Loupy A (2003) Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones under microwave irradiation. Tetrahedron Lett 44: 3709–3712. doi: 10.1016/S0040-4039(03)00625-7 CrossRefGoogle Scholar
  105. 105.
    Fu G-Y, Zhang X-L, Sheng S-R, Wei M-H, Liu X-L (2008) Rapid microwave-assisted liquid-phase synthesis of 4-substituted-5-methoxycarbonyl-6-methyl-3,4-dihydropyridones on poly(ethyleneglycol) support. Synth Comm 38: 1249–1258. doi: 10.1080/00397910701873144 CrossRefGoogle Scholar
  106. 106.
    Fan XS, Li YZ, Zhang XY, Qu GR, Wang JJ, Hu XY (2006) An efficient and green synthesis of 1,4-dihydropyridine derivatives through multi-component reaction in ionic liquid. Heteroat Chem 17: 382–388. doi: 10.1002/hc.2022 CrossRefGoogle Scholar
  107. 107.
    Tu S, Zhu X, Zhang J, Xu J, Zhang Y, Wang Q, Jia R, Jiang B, Zhang J, Yao C (2006) New potential biologically active compounds: design and an efficient synthesis of N-substituted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-diones under micro- wave irradiation. Bioorg Med Chem Lett 16: 2925–2928. doi: 10.1016/j.bmcl.2006.03.011 PubMedCrossRefGoogle Scholar
  108. 108.
    Svetlik J, Golijer I, Turecek F (1990) Oxygen-bridged tetrahydropyridines and dihydropyridones via a Hantzsch-like synthesis with 4-(2-hydroxyphenyl)but-3-en-2-one. J Chem Soc Perkin Trans 1: 1315–1318. doi: 10.1039/P19900001315 CrossRefGoogle Scholar
  109. 109.
    Cho H, Shima K, Hayashimatsu M, Ohnaka Y, Mizuno A, Takeuchi Y (1985) Synthesis of novel dihydropyrimidines and tetrahydropyrimidines. J Org Chem 50: 4227–4230. doi: 10.1021/jo00222a009 CrossRefGoogle Scholar
  110. 110.
    Katritzky AR, Yousaf TI (1986) A carbon-13 nuclear magnetic resonance study of the pyrimidine synthesis by the reactions of 1,3-dicarbonyl compounds with amidines and ureas. Can J Chem 64: 2087–2093. doi: 10.1139/v86-34 CrossRefGoogle Scholar
  111. 111.
    Ostras KS, Gorobets NYu, Desenko SM, Musatov VI (2006) An easy access to 2-amino-5,6-dihydro-3H-pyridin-4-one building blocks: the reaction under conventional and microwave conditions. Mol Divers 10: 483–489. doi: 10.1007/s11030-006-9045-1 PubMedCrossRefGoogle Scholar
  112. 112.
    Lipson VV, Orlov VD, Desenko SM, Karnozhitskaya TM, Shirobokova MG (1999) Reaction of arylidene derivatives of Meldrum’s acid with 3-amino-1,2,4-triazole. Chem Heterocycl Comp 35: 595–599. doi: 10.1007/BF02324645 CrossRefGoogle Scholar
  113. 113.
    Ivanova O, Poltorak V, Gorbenko N, Lipson V (2001) Novel antioxidant L-2264 prevents insulin resistance development in dexamethazone treated rats. Diabetologia 44(Suppl 1): A226Google Scholar
  114. 114.
    Ivanova O, Gorbenko N, Poltorak V, Gladkich A, Leshchenko Z (2004) Antiaterogenic effect of new antioxidant L-2264 in diabetic rabbits. Diabetologia 47(Suppl 1): A278Google Scholar
  115. 115.
    Lipson VV, Desenko SM, Borodina VV, Shirobokova MG, Karnozhitskaya TM, Musatov VI, Kravchenko SV (2005) 2-Methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5- and −7-ones. Chem Heterocycl Comp 41: 216–220. doi: 10.1007/s10593-005-0130-7 CrossRefGoogle Scholar
  116. 116.
    Lipson VV, Borodina VV, Shirobokova MG (2005) Cyclocondensation of 3,5-diamino-1,2,4-triazole with benzaldehydes and Meldrum’s acid. Ukrainskii Khimicheskii Zhurnal (Russian Edition) 71:95–99. CAN 143:172828Google Scholar
  117. 117.
    Lipson VV, Borodina VV, Musatov VI (2006) Cyclocondensation of 3,4,5-triamino-1,2,4-triazole with para-substituted benzaldehydes and Meldrum’s acid. Zh Org Farm Khim 4: 62–65. CAN 147:235114Google Scholar
  118. 118.
    Lipson VV, Orlov VD, Desenko SM, Shishkina SV, Shishkin OV, Shirobokova MG (2001) 1,2,3,4-Tetrahydropyrimido[1,2-a] benzimidazol-2- and −4-ones. Chem Heterocycl Comp 36: 1039–1043. doi: 10.1023/A:1002777714158 CrossRefGoogle Scholar
  119. 119.
    Quiroga J, Hormaza A, Insuasty B, Marquez M (1998) Reaction of 5-amino-1-aryl-3-methylpyrazoles with benzylidene derivatives of Meldrum’s acid: synthesis and characterization of pyrazolo[3,4-b]pyridinones. J Heterocycl Chem 35: 409–412CrossRefGoogle Scholar
  120. 120.
    Lipson VV, Desenko SM, Shirobokova MG, Shishkin OV, Shishkina SV (2006) Heterocyclizations of 3-amino-5-methylpyrazole with unsaturated arylalyphatic acid derivatives. Russ J Org Chem 42: 1022–1027. doi: 10.1134/S1070428006070153 CrossRefGoogle Scholar
  121. 121.
    Lipson VV, Shirobokova MG, Musatov VI (2005) Synthesis and chemical properties of partially hydrogenated 3-methyl-4-aryl(heteryl)pyrazolo[3,4-b]pyridin-6-ones. Zh Org Farm Khim 3:64–69. CAN 145:249136Google Scholar
  122. 122.
    Lipson VV, Svetlichnaya NV, Shishkina SV, Shishkin OV (2008) Cascade cyclization of 1,2-diamino-4-phenylimidazole with aromatic aldehydes and Meldrum’s acid. Mendeleev Commun 18: 141–143CrossRefGoogle Scholar
  123. 123.
    Hollick JJ, Rigoreau LJM, Cano-Soumillac C, Cockcroft X, Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR, Hickson I, Hummersone MG, Menear KA, Martin NMB, Matthews I, Newell DR, Ord R, Richardson CJ, Graeme CM, Graeme CM, Griffin RJ (2007) Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure–activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. J Med Chem 50: 1958–1972. doi: 10.1021/jm061121y PubMedCrossRefGoogle Scholar
  124. 124.
    Snider BB, Neubert BJ (2004) A novel biomimetic route to the 3-acyl-5-hydroxy-3-pyrrolin-2-one and 3-acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one ring systems. J Org Chem 69: 8952–8955. doi: 10.1021/jo048605r PubMedCrossRefGoogle Scholar
  125. 125.
    Sorensen US, Falch E, Krogsgaard-Larsen P (2000) A novel route to 5-substituted 3-isoxazolols. Cyclization of N,O-diBoc β-keto hydroxamic acids synthesized via acyl Meldrum’s acids. J Org Chem 65: 1003–1007. doi: 10.1021/jo991409d PubMedCrossRefGoogle Scholar
  126. 126.
    Pak CS, Yang HC, Choi EB (1992) Aminolysis of 5-acyl-2, 2-dimethyl-1,3-dioxan-4,6-diones (acyl Meldrum’s acids) as a versatile method for the synthesis of β-oxo carboxamides. Synthesis 12: 1213–1214. doi: 10.1055/s-1992-26338 CrossRefGoogle Scholar
  127. 127.
    Weber L, Iaiza P, Biringer G, Barbier P (1998) Solid-phase synthesis of 3-acyltetramic acids. Synlett 10: 1156–1158. doi: 10.1055/s-1998-1862 CrossRefGoogle Scholar
  128. 128.
    Itoh T, Taguchi T, Kimberley MR, Booker-Milburn KI, Stephenson GR, Ebizuka Yu, Ichinose K (2007) Actinorhodin biosynthesis: structural requirements for post-PKS tailoring intermediates revealed by functional analysis of actVI-ORF1 reductase. Biochemistry 46: 8181–8188. doi: 10.1021/bi700190p PubMedCrossRefGoogle Scholar
  129. 129.
    Venturi F, Venturi C, Liguori F, Cacciarini M, Montalbano M, Nativi C (2004) A new scaffold for the stereoselective synthesis of α-O-linked glycopeptide mimetics. J Org Chem 69: 6153–6155. doi: 10.1021/jo049441h PubMedCrossRefGoogle Scholar
  130. 130.
    Kikuchi H, Sasaki K, Sekiya J, Maeda Y, Amagai A, Kubohara Y, Oshima Y (2004) Structural requirements of dictyopyrones isolated from Dictyostelium spp. in the regulation of Dictyostelium development and in anti-leukemic activity. Bioorg Med Chem 12: 3203–3214. doi: 10.1016/j.bmc.2004.04.001 PubMedCrossRefGoogle Scholar
  131. 131.
    Bach T, Hoefer F (2001) Photochemical deconjugation of chiral 3-methyl-2-butenoates derived from carbohydrate-based alcohols: the influence of the sugar backbone on the facial diastereoselectivity. J Org Chem 66: 3427–3434. doi: 10.1021/jo001740t PubMedCrossRefGoogle Scholar
  132. 132.
    Xu F, Armstrong JD, Zhou GX, Simmons B, Hughes D, Ge Z, Grabowski EJJ (2004) Mechanistic evidence for an α-oxoketene pathway in the formation of β-ketoamides/esters via Meldrum’s acid adducts. J Am Chem Soc 126: 13002–13009. doi: 10.1021/ja046488b PubMedCrossRefGoogle Scholar
  133. 133.
    Raillard SP, Weiwei Chen, Sullivan E, Bajjalieh W, Bhandari A, Baer TA (2002) Preparation and improved stability of N-Boc-α -amino-5-acyl Meldrum’s acids, a versatile class of building blocks for combinatorial chemistry. J Comb Chem 4: 470–474. doi: 10.1021/cc0200033 PubMedCrossRefGoogle Scholar
  134. 134.
    Tadesse S, Bhandari A, Gallop MA (1999) Solid-phase synthesis of highly functionalized 2,2′-bipyridines. J Comb Chem 1: 184–187. doi: 10.1021/cc980035j CrossRefGoogle Scholar
  135. 135.
    Gordeev MF, Patel DV, Wu J, Gordon EM (1996) Approaches to combinatorial synthesis of heterocycles: solid phase synthesis of pyridines and pyrido[2,3-d]pyrimidines. Tetrahedron Lett 37: 4643–4646. doi: 10.1016/0040-4039(96)00923-9 CrossRefGoogle Scholar
  136. 136.
    Bhandari A, Bei L, Gallop MA (1999) Solid-phase synthesis of pyrrolo[3,4-b]pyridines and related pyridine-fused heterocycles. Synthesis 11: 1951–1960. doi: 10.1055/s-1999-3618 CrossRefGoogle Scholar
  137. 137.
    Sun G, Fecko CJ, Nicewonger RB, Webb WW, Begley TP (2006) DNA-protein cross-linking: model systems for pyrimidine- aromatic amino acid cross-linking. Org Lett 8: 681–683. doi: 10.1021/ol052876m PubMedCrossRefGoogle Scholar
  138. 138.
    Sato M, Oda T, Iwamoto K, Murakami E (2003) Highly efficient methods for metacyclophane synthesis. Tetrahedron 59: 2651–2655. doi: 10.1016/S0040-4020(03)00326-0 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.State Institution “V.Ya. Danilevsky Institute of Endocrine Pathology Problems”Academy of Medical Sciences of UkraineKharkovUkraine
  2. 2.Department of Chemistry of Heterocyclic CompoundsState Scientific Institution “Institute for Single Crystals”, National Academy of Sciences of UkraineKharkovUkraine
  3. 3.AG Limbach, Institute for Organic ChemistryFree University of BerlinBerlinGermany

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