Palladium-Catalyzed Cyclocarbonylation of Pyridinylated Vinylogous Amides and Ureas to Generate Ring-Fused Pyridopyrimidinones

Abstract

As part of a program aimed at generating new heterocyclic frameworks for medicinal chemistry exploration, an efficient approach to the assembly of novel ring-fused pyridopyrimidinones was undertaken. Specifically, a collection of 11 H-pyrido[2,1- b]quinazoline-1,11(2 H)-diones and 2,3-dihydropyrido[1,2- a]pyrrolo[3,4- d]pyrimidine-1,10-diones was generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%.

Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using pKa-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam

“…Given our interest in similar heterocycles, 17 we initially focused on generating the γ-lactam-fused, N-methyl 4-quinolinone core representative of the quinolactacins. In our case, C3 substitution of the lactam ring was unnecessary (cf., C3labeled 1, Figure 2), thereby enabling the use of a simplified, enolizable partner such as known 28 N-Boc tetramic acid 26a (Table 1).…”

“…Starting materials 9a , 21a–d , 21f–k , 26c , and 26f–h were purchased and used as received. Known compounds ( 26a , 26b , 26d , 26e , and 21e ) were synthesized according to literature procedures; characterization matched previous reports. With the exception of 9u , various syntheses of anhydrides 9b–v have been reported.…”

“…Six-membered, annulated variants such as floxacrine 7 and pyranoquinolinone 8 show antimalarial and AChE inhibitory activities, respectively. As part of a program aimed at the efficient assembly and application of unique, bioactive heterocycles, , we sought a general and efficient synthetic strategy that would enable the construction of a diverse collection of previously unknown, ring-fused, N-substituted-4-quinolinones for biological screening. We first took note of literature precedents leading to the construction of some of these scaffolds, starting with lactam-fused derivatives (Figure ).…”

Palladium‐catalyzed Synthesis of Fused Carbo‐ and Heterocycles

“…Golden group synthesized a method for cyclocarbonylation of pyridinylated vinylogous amides and ureas through palladium‐catalysis to provide ring‐fused pyridopyrimidinones (Scheme 51). [63] Under optimal reaction conditions, substrates containing pyridine ring substitutions of 2‐aminopyridyl‐NH‐cyclohexenones 162 in presence of 10 mol% palladium acetate, 20 mol% PPh 3 , 3 equiv. potassium persulfate in acetonitrile at 80 °C delivered ring‐fused pyridopyrimidinones 163 .…”

“…Synthesis of ring-fused pyridopyrimidinones by Golden group. [63] in addition to linear dienes with substituted phenyl rings. The aminoallyl precursor was also found to cyclize with a linear alkyl diene with a benzyl ether in good yield.…”