A novel approach to biologically relevant oxazolo[5,4-d]pyrimidine-5,7-diones via readily available diazobarbituric acid derivatives

Diazo Glutaconimides: an Unexplored Type of Heterocyclic α‐Diazocarbonyl Compounds Conveniently Evolved into Pyridine‐2,6(1H,3H)‐diones and Oxazolo[5,4‐b]pyridin‐5(4H)‐ones

“…Metal carbene species generated catalytically from diazocarbonyl compounds can undergo dipolar [3+2] cycloaddition to double and triple bonds [25] . In particular, cycloaddition with nitriles leads to the formation of fused oxazoles, which we have been recently exemplified for α‐diazohomophthalimides 1 [11] and diazo barbituric acids 2 [14] . Extending this transformation to diazo glutaconimides, we reasoned, would provide a facile entry into the oxazolo[5,4‐ b ]pyridin‐5(4 H )‐one scaffold.…”

“…These efforts have led to the identification of α‐diazo homophthalimides ( 1 ) capable of undergoing Rh(II)‐catalyzed cycloaddition with nitriles, [11] spirocyclization with cyclic ethers [12] as well as halofluorination and arylation in superacidic medium [13] . Continuing this line of inquiry, diazo barbituric acids 2 were successfully prepared and involved in the preparation of biologically relevant oxazolo[5,4‐ d ]pyrimidine‐5,7‐diones via Rh(II)‐catalyzed condensation with nitriles [14] . Most recently, we [15] and others [16] introduced ( E )‐3‐arylidene‐4‐diazopyrrolidine‐2,5‐diones 3 also prepared via direct diazo transfer to readily available 3‐arylidene pyrrolidine‐2,5‐diones.…”

“…[13] Continuing this line of inquiry, diazo barbituric acids 2 were successfully prepared and involved in the preparation of biologically relevant oxazolo [5,4-d]pyrimidine-5,7-diones via Rh (II)-catalyzed condensation with nitriles. [14] Most recently, we [15] and others [16] introduced (E)-3-arylidene-4-diazopyrrolidine-2,5diones 3 also prepared via direct diazo transfer to readily available 3-arylidene pyrrolidine-2,5-diones. Compounds 3 have been shown to undergo metal carbene-mediated XÀ H insertion reactions [15] and [2 + 1] cycloaddition with aldehydes; [16] their synthetic potential continues being unraveled in our laboratories.…”

“…[25] In particular, cycloaddition with nitriles leads to the formation of fused oxazoles, which we have been recently exemplified for α-diazohomophthalimides 1 [11] and diazo barbituric acids 2. [14] Extending this transformation to diazo glutaconimides, we reasoned, would provide a facile entry into the oxazolo [5,4-b]pyridin-5(4H)-one scaffold. Oxazolo [5,4-b] pyridines in general are of high medicinal relevance considering their documented acting as MAOÀ B inhibitors, [26] sphingomyelin synthase inhibitors, [27] potential β-amyloid PET ligands, [28] α7 nAChR agonists, [29] IkB kinase inhibitors [30] as well as compounds endowed with photocytotoxic activity.…”

“…Relying on the previously developed protocols, [11,14] reactions were conducted using the respective nitrile as a solvent and Rh 2 (esp) 2 (1 mol%) as the catalyst. On moderate (80°C) heating, full conversion was achieved over 4-16 h and the desired oxazolo[5,4-b]pyridin-5(4H)-ones 8 were obtained in moderate to good yields (Table 3).…”