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Review
. 2019 Sep 30;9(53):30835-30867.
doi: 10.1039/c9ra05687d. eCollection 2019 Sep 26.

Bicyclic 6 + 6 systems: the chemistry of pyrimido[4,5- d]pyrimidines and pyrimido[5,4- d]pyrimidines

M Monier  1   2 , Doaa Abdel-Latif  1   2 , Ahmed El-Mekabaty  2 , Khaled M Elattar  2
Affiliations
Review

Bicyclic 6 + 6 systems: the chemistry of pyrimido[4,5- d]pyrimidines and pyrimido[5,4- d]pyrimidines

M Monier et al. RSC Adv. .

Abstract

The present study provides an overview of the chemistry and biological significance of pyrimido[4,5-d]pyrimidine and pyrimido[5,4-d]pyrimidine analogs as types of bicyclic [6 + 6] systems. The main sections include: (1) synthesis methods; (2) the reactivities of the substituents linked to the ring carbon and nitrogen atoms; and (3) biological applications. A discussion demonstrating the proposed mechanisms of unexpected synthetic routes is intended. The aim of this study is to discuss the synthetic significance of the titled compounds and to establish the biological characteristics of this class of compounds as studied to date, where the compounds have been applied on a large scale in the medical and pharmaceutical fields. This survey will help researchers in the fields of synthetic organic and medicinal chemistry to undertake and improve new approaches for the construction of new standard biological components.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Structures of the potent bioactive components.
Scheme 1
Scheme 1. Synthesis of 2-thioxo-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one.
Scheme 2
Scheme 2. Synthesis route from ethyl 4-amino-2-thioxo-1,2-dihydropyrimidine-5-carboxylate.
Scheme 3
Scheme 3. Synthesis of 6-chloropyrimido[5,4-d]pyrimidin-4(3H)-one.
Scheme 4
Scheme 4. Synthesis of 1,3,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (19).
Scheme 5
Scheme 5. Synthesis of 1-butyl-1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetraone.
Scheme 6
Scheme 6. Synthesis of 1,3-dialkyl-1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetraone.
Scheme 7
Scheme 7. Synthesis of 7-alkyl-1,3-dipentyl-1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetra-ones.
Scheme 8
Scheme 8. Synthesis of N7-alkyl-heteryl-1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetraone.
Scheme 9
Scheme 9. Synthesis of 7-thioxo-4,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidine-2,5(1H,3H)-diones.
Scheme 10
Scheme 10. Synthesis of 5,7-dichloro-2-aryl-2,4a-dihydropyrimido[4,5-d]pyrimidine-4(3H)-thiones.
Scheme 11
Scheme 11. Synthesis of 2-aminopyrimidopyrimidinones.
Scheme 12
Scheme 12. Synthesis of 5-(1H-indol-3-yl)-5,8-dihydropyrimido[4,5-d]pyrimidines.
Scheme 13
Scheme 13. Synthesis of 5-aryl-(7-thioxo and 7-oxo)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-diones.
Scheme 14
Scheme 14. Synthesis of 5-aryl-7-(thioxo and oxo)-hexahydropyrimido[4,5-d]pyrimidine-2,4-diones.
Scheme 15
Scheme 15. Synthesis of 5-aryl-tetrahydro-pyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,4aH)-triones.
Scheme 16
Scheme 16. Synthesis of 1,3-dimethyl-5-aryl-tetrahydropyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,4aH)-triones.
Scheme 17
Scheme 17. Multicomponent synthesis of 1,3-dimethyl-5,6,7-triaryl-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidine-2,4(1H,3H)-diones.
Scheme 18
Scheme 18. Synthesis of hexahydro- and 5,6-dihydro-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones.
Scheme 19
Scheme 19. Synthesis of 1,3-dialkyl-6-amino-(naphthalen-1-ylmethyl)pyrimido[4,5-d]pyrimidine-2,4,5-(1H,3H,6H)-trione.
Scheme 20
Scheme 20. Synthesis of 7-alkylaryl-1,3-dialkyl-pyrimido[4,5-d]pyrimidine-2,4,5(1H,3H,6H)-triones.
Scheme 21
Scheme 21. Synthesis of 5,6-diaryl-1-alkyl-3-methyl-7-thioxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidine-2,4(1H,3H)-diones.
Scheme 22
Scheme 22. Catalytic multicomponent synthesis of 2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidinones.
Scheme 23
Scheme 23. Four-component synthesis of 5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones.
Scheme 24
Scheme 24. The proposed mechanistic route for the synthesis of 5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones.
Scheme 25
Scheme 25. Synthesis of hexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione.
Scheme 26
Scheme 26. Synthesis of 2,2,7-trisubstituted-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones.
Scheme 27
Scheme 27. Synthesis of 4,5,8a-trisubstituted-hexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-diones.
Scheme 28
Scheme 28. Multicomponent synthesis of 4,5-diaryl-4,5,6,8-tetrahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-diones and thiones.
Scheme 29
Scheme 29. Synthesis of 1,3,4,7-tetrahydropyrimido[5,4-d]pyrimidine-2,8-diones.
Scheme 30
Scheme 30. Synthesis of hexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-diones.
Scheme 31
Scheme 31. Synthesis of cyclopentyl-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione.
Scheme 32
Scheme 32. Synthesis of 2,5-disubstituted-pyrimido[4,5-d]pyrimidines.
Scheme 33
Scheme 33. Synthesis of 5-imino-7-(methylthio)-1,3,6-triphenyl-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dithione.
Scheme 34
Scheme 34. Synthesis of 5-imino-7-(methylthio)-1,3,6-triphenyl-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4-(1H,3H)-dithione.
Scheme 35
Scheme 35. Synthesis of tetrahydro-4H-dipyrimido[1,2-a:4′,5′-d]pyrimidin-4-ones.
Scheme 36
Scheme 36. Synthesis of 7,8-dihydro-1H-pyrimidoquinazoline-2,5(3H,6H)-diones.
Scheme 37
Scheme 37. Synthesis of 5-aryl-2-phenyl-3,5-dihydro-4H-pyrido[1,2-a]pyrimido[5,4-e]pyrimidin-4-ones.
Scheme 38
Scheme 38. Synthesis of 3-phenylbenzo[4,5]imidazo[1,2-c]pyrimido[5,4-e]pyrimidine-6(5H)-thione.
Scheme 39
Scheme 39. Synthesis of polycyclic pyrimido[4,5-d]pyrimidines.
Scheme 40
Scheme 40. Synthesis of N′-(8-(aryl-amino)pyrimido[5,4-d]pyrimidin-4-yl)substituted-hydrazides.
Scheme 41
Scheme 41. Reactions of 9-substituted-9H-purine-6-carbonitriles with different amines.
Scheme 42
Scheme 42. Synthesis of 3,8-disubstituted-amino-4-iminopyrimido[5,4-d]pyrimidines.
Scheme 43
Scheme 43. Synthesis of 7-methyl-2,4-disubstituted-4,10-dihydropyrimido[4′,5′:4,5]pyrimido[1,2-d]-[1,3,4]-thiadiazines.
Scheme 44
Scheme 44. Synthesis of bis-pyrimidopyrimidines.
Scheme 45
Scheme 45. Synthesis of bis(1,3-dimethyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones).
Scheme 46
Scheme 46. Synthesis of bis-1,3,4,7-tetrahydropyrimido[5,4-d]pyrimidine-2,8-diones.
Scheme 47
Scheme 47. Bromination of hexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione.
Scheme 48
Scheme 48. Synthesis of 4,8-dihydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dithiones.
Scheme 49
Scheme 49. Nucleophilic substitution reactions.
Scheme 50
Scheme 50. Synthesis of diamines.
Scheme 51
Scheme 51. Synthesis of mono- and disubstituted-amines.
Scheme 52
Scheme 52. Reactivity of 7-mercapto-1,2-dihydropyrimido[4,5-d]pyrimidin-4-ol.
Scheme 53
Scheme 53. Synthesis of 7-substituted-5-imino-1,3,6-triphenyl-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4-(1H,3H)-dithiones.
Scheme 54
Scheme 54. Synthesis of tetra-substituted-amines.
Scheme 55
Scheme 55. Synthesis of tri- and tetra-substituted-amines of pyrimido[5,4-d]pyrimidines.
Scheme 56
Scheme 56. Synthesis of nucleosides incorporated with a pyrimido[5,4-d]pyrimidine core.
Fig. 2
Fig. 2. The structure of 2,4,6,8-tetrakis(substituted-phenoxy)pyrimido[5,4-d]pyrimidines.
Scheme 57
Scheme 57. Reactivity of the ring substituents.
Scheme 58
Scheme 58. Synthesis of 1,3,5,7-tetra-substituted-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones.
Scheme 59
Scheme 59. Synthesis of 7-(alkylthio)-5-imino-1,3,6-triphenyl-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4-(1H,3H)-dithiones.
Scheme 60
Scheme 60. Reactivity of cyclopentyl-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione.
Scheme 61
Scheme 61. Reactivity of chlorine atoms attached to the ring carbon atoms.
Scheme 62
Scheme 62. Synthesis of the pyrimido[5,4-d]pyrimidine skeleton incorporating nucleosides.
Scheme 63
Scheme 63. Synthesis of N-alkyl- and hydrazine-substituents.
Scheme 64
Scheme 64. Synthesis of 3-aryl-5,10a-dihydropyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidines.
Scheme 65
Scheme 65. Synthesis of polymers bearing alkylamino groups.
Fig. 3
Fig. 3. The structures of the two probable monomeric conformers as base pair motifs.
Fig. 4
Fig. 4. A comparison of the different areas of research in the last decade.
None
M. Monier
None
Doaa Abdel-Latif
None
Ahmed El-Mekabaty
None
Khaled M. Elattar
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