Regioselective Synthesis of 2,4‐Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4‐d]pyrimidines through Sequential Pd‐Catalyzed Arylation and S_NAr Reactions

Abstract

The synthesis and regioselective functionalization of rare 2,4‐disubstituted‐pyrido[1′,2′:1,5]pyrazolo[3,4‐d]pyrimidine derivatives is reported. C‐4 aminations were performed by chlorine nucleophilic substitution SNAr reactions, and their efficiencies were compared with those for direct one‐pot amide C–O activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) as a reagent. The latter method was used to perform palladium‐catalyzed C‐4 (het)arylation. Finally, two C‐4 amino and aryl derivatives were prepared on a large scale and engaged in desulfurative Liebeskind–Srogl‐type reactions under microwave irradiation to afford the envisioned compound library. Each step was optimized, and the results are discussed.

Aminations and arylations by direct C–O activation for the design of 7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidines

“…To take advantage of the lactam, we began our methodological study by a one-pot amination at the C-2 position using C-O direct activation involving PyBroP and Et 3 N. [35][36][37] In this tandem reaction, the rst in situ step generated the O-phosphonium leaving group, which was then displaced with the adequate nucleophile. In a rst attempt, the reactivity was examined by treating 4-phenyl-pyrido[3,2-d]pyrimidinone 8 with n-propylamine and several reaction parameters (temperature, duration) were screened to reach an acceptable level of reaction efficiency (Table 1).…”

Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines

“…Compound 8 was obtained via a 7-step sequence partially based on our previous work. 7,8 Dimethyl 5-chloropyrazolo[1,5- a ]pyridine-2,3-dicarboxylate 2 was obtained after a [3 + 2] cycloaddition between the 1-amino-4-chloropyridinium iodide 1 ( ref. 9 and 10 ) with dimethyl acetylenedicarboxylate (DMAD).…”

“…In order to build C-2 and C-4 disubstituted PPPy derivatives, we developed a straightforward strategy which included successive C-4 in situ C–O activation and a C-2 desulfurization through Liebeskind–Srogl cross-coupling reactions. 7 To provide a versatile platform we then sought to design a new flexible route to access 2,4,6-trisubstituted PPPy's I from a unique intermediate i.e. the 6-chloro-2-(methylthio)pyrido[1′,2′:1,5]pyrazolo[3,4- d ]pyrimidin-4(3 H )-one 8.…”

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions

“…For several years, our group has been developing efficient methodologies to selectively functionalize heterocycles such as azaindoles [ 7 , 8 , 9 ], pyridopyrimidines [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], and more recently, tricyclic heterocycles containing a bridgehead nitrogen, such as pyrido[1′,2′:1,5]pyrazolo[3,4- d ] pyrimidines or pyridazines [ 17 , 18 , 19 , 20 , 21 ].…”