Concise and Efficient Access to 5,7‐Disubstituted Pyrazolo[1,5‐a]pyrimidines by Pd‐Catalyzed Sequential Arylation, Alkynylation and SN_Ar Reaction

Abstract

A simple and efficient method for synthesis of 5,7‐disubstituted pyrazolo[1,5‐a]pyrimidines is reported. The synthetic route involved first a one‐pot two‐step synthesis of 7‐substituted pyrazolo[1,5‐a]pyrimidin‐5‐ones from the reaction of 3‐aminopyrazole 1 with activated alkynes. These compounds were used as key intermediates to access, with excellent yields, a library of new 5,7‐disubstituted pyrazolo[1,5‐a]pyrimidines, which are known for their wide range of biological activities, through C–O bond activation with PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate) as an activator reagent.

Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C–H Activation: Synthesis of Pyrazolo[1,5-a]pyrimidines

“…1 H and 13 C NMR spectra matched with previously reported literature. 17 1 H NMR (600 MHz, CDCl 3 ) δ 8.69 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 8.09–8.05 (m, 2H), 7.55–7.45 (m, 3H), 7.26 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 156.2, 148.5, 145.6, 137.1, 135.1, 130.5, 129.0, 127.2, 105.5, 97.0.…”

An Efficient Synthesis of New 7-Trifluoromethyl-2,5-disubstituted Pyrazolo[1,5-a]pyrimidines

“…26 More recently, we developed an exhaustive method for the synthesis of pyrazolo[1, 5-a]pyrimidines based on the condensation of 3-aminopyrazoles and alkynes. 27 Herein, and in continuation of our interest in the synthesis of new heterocycles bearing a fluoroalkyl group, we have applied this strategy for the straightforward synthesis of a new library of fluorinated pyrazolo[1, 5-a]pyrimidines using the condensation of various 3-aminopyrazoles 1 with ethyl 4,4,4-trifluorobut-2ynoate (2).…”

“…To achieve this goal, we initially developed a one-pot, two-step synthesis of fluorinated pyrazolo[1,5-a]pyrimidin-5-ones 3 via the condensation of commercially available 3-aminopyrazoles 1 with fluorinated alkyne 2. Following our reported procedure, 27 the reaction was carried out in a sealed tube for 2 hours at reflux in dioxane using microwave-assisted conditions, followed by the addition of 2 equivalents of sodium methoxide at room temperature and stirring for 12 hours (Scheme 1). 3-Aminopyrazole (1a) was reacted with fluorinated alkyne 2 to provide fluorinated pyrazolo[1,5-a]pyrimidin-5-one 3a as the only regioisomer in 63% yield.…”

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

“…Synthetically, although many approaches have been reported for the synthesis of non-fluorinated pyrazolo[1,5- a ]pyrimidines, the incorporation of fluorinated groups in this heterocycle remains limited [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Recently, we described the condensation of 5-substituted 3-aminopyrazoles with ethyl 4,4,4-trifluoro-2-butynoate, affording regioselectively the 2-substituted 7-(trifluoromethyl)pyrazolo[1,5- a ]pyrimidin-5-ones in fair to good yields [ 37 ]. Continuing our research directed towards the development of new heterocyclic compounds containing the fluorine atoms [ 38 , 39 , 40 , 41 ], we report herein an efficient approach for synthesizing 3,5-disubstituted 7-(trifluoromethyl)pyrazolo[1,5- a ]pyrimidines in good yields through S N Ar and Suzuki–Miyaura cross-coupling reactions, using 3-bromo-7-(trifluoromethyl)pyrazolo[1,5- a ]pyrimidin-5-one as a starting material.…”