Direct Arylation of Simple Azoles Catalyzed by 1,10-Phenanthroline Containing Palladium Complexes: An Investigation of C4 Arylation of Azoles and the Synthesis of Triarylated Azoles by Sequential Arylation

Abstract

Direct triarylation and sequential triarylation reactions of simple azoles catalyzed by [Pd(phen)(2)]PF(6) are described. Simple azoles, such as N-methylimidazole, thiazole, and oxazole, were observed to undergo triaryaltion reactions even at their C4 positions when treated with aryl iodides in the presence of [Pd(phen)(2)]PF(6) as a catalyst and a stoichiometric amount of Cs(2)CO(3) in DMA at 150 °C. Using excess amounts of azoles, selective C5 monoarylation was achieved by using the same catalytic system. Subsequent efforts demonstrated that C5 arylated azoles undergo exclusive C2 arylation using [Pd(phen)(2)]PF(6) as the catalyst with galvinoxyl as an additive. Finally, unprecedented C4 arylation reactions of 2,5-diaryl-azoles occur by using the new catalytic system to give the corresponding triarylated products in good to excellent yields. The results of mechanistic studies suggest that the C2 arylation process takes place by way of an electrophilic aromatic substitution (S(E)Ar) palladation pathway, while arylation reactions at the C4 position occur via a S(E)Ar palladation and/or radical mechanism. Finally, a concise, three-step synthesis of the Tie-2 Tyrosine Kinase Inhibitor has been executed starting with commercially available N-methylimidazole by a route that employs the new sequential arylation process.

A robust protocol for Pd(ii)-catalyzed C-3 arylation of (1H) indazoles and pyrazoles: total synthesis of nigellidine hydrobromide

“…16 Prior to our work, a single example of tristrifluoromethylphenylation of N-methylpyrazole in a moderate yield (52%) using [Pd(Phen) 2 ](PF 6 ) 2 catalyst was reported by Murai. 17 …”

Biaryl Synthesis through Metal‐Catalyzed C–H Arylation

“…Itami [89] found that a Pd II /bipy complex is effective for the C5-arylation of thiazoles, and finally Lee [119] found that Pd II /NHC ligand 85 is effective for the C5-selective arylation of imidazoles. [123] Scheme 17.24 Direct C-H arylation of 1,3-azoles with aryl halides, and applications of this methodology.…”

“…Subsequently, they accomplished the synthesis of Tie2 tyrosine kinase inhibitor 87 [122]. Murai and Shibahara [123] also synthesized this target via sequential C-H arylation from a simple imidazole using their robust catalyst, [Pd(phen) 2 ](PF 6 ) 2 . Sames [125] also reported multiple arylations of simple imidazoles using his own catalytic system.…”

Directing/Protecting‐Group‐Free Synthesis of Tetraaryl‐Substituted Pyrazoles through Four Direct Arylations on an Unsubstituted Pyrazole Scaffold

“…Notwithstanding the importance of multiaryl‐substituted pyrazoles, direct CH arylation based on pyrazoles has attracted somewhat less attention. Recently, direct CH arylation at the C3‐, C4‐, and C5‐positions of pyrazoles8a, 17 and at the C3‐position of indazoles18 have been reported. In particular, Sames achieved a multiaryl‐substituted pyrazole synthesis starting from 4‐bromopyrazole with the aid of a 2‐(trimethylsilyl)ethoxymethyl (SEM) group 17c.…”