Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets

Abstract

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

“Snapshot” Trapping of Multiple Transient Azolyllithiums in Batch

“…[1] Their physical properties depend on the functional groups and their substitution patterns. [2] Regioselective functionalization of an azole ring is still required [3] as a complementary method to the established cyclization strategy. [4] Azoles are categorized as electron-deficient aromatic rings; however, the azole nitrogen acts as a base.…”

Directed regioselective ortho,ortho′-magnesiations of aromatics and heterocycles using sBu2Mg in toluene

“…20 This new metalation procedure occurred twice as fast as the previously reported TMPMgBu base. 3 1,2,3-Triazoles 22a and 22b were isolated in 93% and 67% yields respectively aer Negishi cross-couplings with only 0.83 equiv. of aryl bromide.…”

“…of aryl bromide. 3 Copper-catalyzed acylation 11 with benzoyl chloride lead to products 22c and 22d in 55-58% yield and quenching with various aldehydes afforded compounds 22e-h in 69-80% yield.…”

“…2 Recently, we have examined the regioselective metalation of various pharmaceutically relevant aryl azoles such as 1. 3 We found that standard metal amides such as LDA or TMPLi (TMP ¼ 2,2,6,6-tetramethylpiperidyl) gave the lithiated products 2 with poor regioselectivity, due to a competitive deprotonation at the 5-position of the triazole ring of 1. The best result was achieved in toluene 4 using the alkylmagnesium amide TMPMgBu 5 prepared from commercial Bu 2 Mg, which provided aer cross-coupling with aryl bromides various products of type 3.…”

Preparation and reactions of polyfunctional magnesium and zinc organometallics in organic synthesis

“…Thus, designing a new toluene soluble base (BuMgTMP) allowed a regioselective kinetic metalation of various aryl azoles at the ortho -position of the aryl ring resulting in products of great interest for pharmaceutical research ( Scheme 7 ). 27 …”