Palladium-Catalyzed Regioselective Arylation of Imidazo[1,2-a]pyrimidine

Abstract

Imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of base and a catalytic amount of palladium. This provides an efficient one-step synthesis of 3-arylimidazo[1,2-a]pyrimidines from the unsubstituted heterocycle. [reaction: see text]

Direct transition metal-catalyzed functionalization of heteroaromatic compounds

“…A method for direct arylation and heteroarylation of imidazopyrimidine 66 was reported by Li (Scheme 28). 43 The protocol involved employment of the Pd(OAc) 2 /PPh 3 catalytic system in the presence of Cs 2 CO 3 in dioxane, affording the corresponding aryl derivatives 67 with good to excellent yields (Scheme 28). 43 It was suggested that this arylation proceeds via Miura's electrophilic mechanism.…”

“…43 The protocol involved employment of the Pd(OAc) 2 /PPh 3 catalytic system in the presence of Cs 2 CO 3 in dioxane, affording the corresponding aryl derivatives 67 with good to excellent yields (Scheme 28). 43 It was suggested that this arylation proceeds via Miura's electrophilic mechanism. 3 Gevorgyan reported an efficient and regioselective method for C-3 arylation and heteroarylation of indolizines 68 (Scheme 29).…”

“…This mechanism has often been considered as the most probable mechanism for arylation of heterocycles. 3,5,13,14 Naturally, the absence of an isotope effect in the arylation of 11 (Scheme 6) does not contradict pathway A, as the deprotonation event in the electrophilic mechanisms is not a rate-limiting step. 15 Additionally, it is well known that the pyrrole ring of an indolizine is electron-rich and easily undergoes electrophilic substitution reactions.…”

Catalytic Direct Arylation of Heteroaromatic Compounds

“…29 The reaction has been employed as a key step in the synthesis of a potential GABA agonist drug candidate, 2 0 ,4-difluoro-5 0 -(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile. The arylation of oxazolo [4,5-b]pyridine can be carried out under mild conditions (Scheme 26).…”

8-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor

“…The pK a values were determined by analysing the UV chromophores during a pH titration (using Sirius SGA technology) and, for the compounds 7 and 9, the values obtained are very close to those previously published in the literature. 20,21 Interestingly, in both the unsubstituted and 7-isopropanol series, it is clear that the C-F unit (in 11 and 12) alters the pK a in an identical manner to an azine nitrogen (in 9 and 10), that is, by approximately two units. Log D 7.4 values were determined using the traditional 'shake-flask' method with partitioning between octanol and a pH 7.4 buffer.…”