Direct metalation of heteroaromatic esters and nitriles using a mixed lithium-cadmium base. Subsequent conversion to dipyridopyrimidinones.
All pyridine nitriles and esters were metalated at the position next to the directing group using (TMP)(3)CdLi in tetrahydrofuran at room temperature. The 2-, 3-, and 4-cyanopyridines were treated with 0.5 equiv of base for 2 h to afford, after subsequent trapping with iodine, the corresponding 3-iodo, 2-iodo, and 3-iodo derivatives, respectively, in yields ranging from 30 to 61%. Cyanopyrazine was similarly functionalized at the 3 position in 43% yield. Ethyl 3-iodopicolinate and -isonicotinate were synthesized from the corresponding pyridine esters in 58 and 65% yield. Less stable ethyl 4-iodonicotinate also formed under the same conditions and was directly converted to ethyl 4-(pyrazol-1-yl)nicotinate in a two-step 38% yield. All three ethyl iodopyridinecarboxylates were involved in a one-pot palladium-catalyzed cross-coupling reaction/cyclization using 2-aminopyridine to afford new dipyrido[1,2-a:3',2'-d]pyrimidin-11-one, dipyrido[1,2-a:4',3'-d]pyrimidin-11-one, and dipyrido[1,2-a:3',4'-d]pyrimidin-5-one in yields ranging from 50 to 62%. A similar cross-coupling/cyclization sequence was applied to methyl 2-chloronicotinate using 2-aminopyridine, 2-amino-5-methylpyridine, and 1-aminoisoquinoline to give the corresponding tricyclic or tetracyclic compounds in 43-79% yield. Dipyrido[1,2-a:4',3'-d]pyrimidin-11-one and dipyrido[1,2-a:3',4'-d]pyrimidin-5-one showed a good bactericidal activity against Pseudomonas aeroginosa . Dipyrido[1,2-a:2',3'-d]pyrimidin-5-one and pyrido[2',3':4,5]pyrimidino[2,1-a]isoquinolin-8-one showed a fungicidal activity against Fusarium and dipyrido[1,2-a:4',3'-d]pyrimidin-11-one against Candida albicans . Ethyl 4-(pyrazol-1-yl)nicotinate and dipyrido[1,2-a:2',3'-d]pyrimidin-5-one have promising cytotoxic activities, the former toward a liver carcinoma cell line (HEPG2) and the latter toward a human breast carcinoma cell line (MCF7).
Bentabed-Ababsa
Ghenia
G
Chimie et Photonique Moléculaires, UMR 6510 CNRS, Université de Rennes 1, Batiment 10A, Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes, France.
Cheikh Sid Ely
Sidaty
S
Hesse
Stéphanie
S
Nassar
Ekhlass
E
Chevallier
Floris
F
Nguyen
Tan Tai
TT
Derdour
Aïcha
A
Mongin
Florence
F
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002104:Cadmium / Q000737:chemistry*; D002176:Candida albicans / Q000737:chemistry*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents; D003500:Cyclization; D004952:Esters; D005670:Fusarium / Q000737:chemistry*; D056945:Hep G2 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008094:Lithium / Q000737:chemistry*; D008670:Metals / Q000737:chemistry*; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D003432:Cross-Linking Reagents; D004952:Esters; D006571:Heterocyclic Compounds; D008670:Metals; D009570:Nitriles; D011725:Pyridines; D011744:Pyrimidinones; D002104:Cadmium; D008094:Lithium