Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

Abstract

An efficient and original synthesis of various 3,5-disubstituted 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines is reported. A library of compounds diversely substituted in C-3 and C-5 positions was easily prepared from a common starting material, 3-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-one. In C-5 position, a SNAr type reaction was achieved by first activating the C–O bond of the lactam function with PyBroP (Bromotripyrrolidinophosphonium hexafluorophosphate), followed by the addition of amine or thiol giving monosubstituted derivatives, whereas in C-3 position, arylation was performed via Suzuki–Miyaura cross-coupling using the commercially available aromatic and heteroaromatic boronic acids. Moreover, trifluoromethylated analogues of potent Pim1 kinase inhibitors were designed following our concise synthetic methodology.

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

“…Jismy and co-workers developed protocols for PP derivatives synthesis based on 1,3-biselectrophilic ynones [ 47 , 48 , 49 ]. Unlike previous approximations, employing ynones delivers to hydroxy/enone substituents at position 5 of the fused pyrazole.…”

“…They produce an exchange of hydroxyl group for a chloride atom by a NAS reaction; thus, employing optimized conditions for the coupling reactions could achieve aryls at position 5 like in product 79 ( Scheme 25 a) [ 48 ]. The reaction was further applied in the amine 3-bromosubstituted 81 and was optimized, finding the highly reproducible conditions to obtain 82 ( Scheme 25 b) [ 47 ]. The reaction shows an improvement in reaction times, and also, regarding the previous work, the authors found that modifying the ligand and catalyst enables the functionalization of the nucleophilic site at the pyrazolic moiety.…”

“…The authors also obtain other two pyridine moieties in analogs of 106 employing the same methodology. Similarly, Jismy and co-workers developed a method to functionalized the aza-heterocyclic core at position 5 with wide scope [ 47 , 48 , 49 , 64 ]. Different from other authors, they generate the electrophilic coupling partner substituting the hydroxy/enone group at position 5 of 36d (and analogs), then using the proper alkyne, the reaction delivers the product 108 ( Scheme 29 b) [ 49 ].…”

“…Similarly, Jismy et al designed a methodology for the functionalization of position 5 employing PyBroP, probably with the formation of the intermediate species 121 , which facilitates the secondary amine 89 formation by the nucleophilic substitution of 122 over 121 ( Scheme 35 a) [ 47 , 49 ]. The authors employ this methodology in a one-pot manner achieving high yields.…”

“…Additionally, the authors evaluated the efficiency of first obtaining 81 and then performing a Suzuki coupling reaction at position 3, obtaining 82 (see Scheme 25 b above). As a result, the procedure done in that order delivers the final product in higher yields compared to the Suzuki coupling and then the aromatic nucleophilic substitution reaction [ 47 ]. Similarly, Berteina-Raboin developed a multicomponent method to obtain 112a analogs, controlling the equivalents of added amine (morpholine, Scheme 35 b); they were able to decrease the poisoning of the catalyst achieving good yields for various 7-aminoderivatives [ 72 ].…”