Benzylic Arylation of 2-Methyl-5-membered Heterocycles Using TMP-Bases

Abstract

A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires Li-, Mg-, or Zn-TMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the corresponding arylated heterocycles.

Recent Developments in Negishi Cross-Coupling Reactions

“…30 The use of TMPMgCl•LiCl (35) 31 and the related zinc base TMPZnCl•LiCl (36) 32 proved to be the most useful. Thus, 2,5-dichlorothieno [3,2-b]thiophene (37) is readily magnesiated by the addition of TMPMgCl•LiCl (35). Transmetalation with ZnCl 2 , followed by a Negishi crosscoupling reaction with 1-chloro-4-iodobenzene leads to the monoarylated thienothiophene (38) in 41% yield (Scheme 11).…”

“…33 Interestingly, 1,2-dimethylimidazole (39) is selectively magnesiated at the lateral methyl group furnishing the zinc reagent (40) after transmetalation with ZnCl 2 , which then undergoes a smooth cross-coupling with an aryl bromide affording benzylated imidazole (41) in 91% yield (Scheme 10). 35 In the case of aromatic substrates bearing C−H bonds of moderate acidity or sensitive functional groups, the use of TMP 2 Mg•2LiCl can be advantageous. Thus, the magnesiation of the salicylic derivative (42) proceeds with TMP 2 Mg•2LiCl, and after transmetalation with ZnCl 2 and Negishi crosscoupling with (E)-1-iodocyclohexene, the natural product (43) present in the essential oil of Pelargonium sidoides DC is obtained after deprotection (Scheme 12).…”

Cross‐Coupling Arylations: Precedents and Rapid HistoricalReview of the Field

“…Knochel's group has been active in this field [170]. In 2012, the group published a report on the arylation of 2-methyl-5-membered heterocycles with 2,2,6,6-tetramethylpiperidyl (TMP) bases [170].…”

“…1 51. Pd-catalyzed benzylic Negishi-Baba coupling arylation of 1,2-dimethylimidazole by Knochel and coworkers[170].…”

Advances in LiCl-Promoted Preparation of Polyfunctional Grignard Reagents and the Applications

“…2 Knochel-Hauser 碱除了可以实现芳环和芳香杂环的 C-H 键镁化反应以外, 也可以对丙烯腈、丙烯酸酯、 环状烯醇磷酸酯的不饱和 C-H 键进行选择性的镁化反 应 [32] . Knochel-Hauser 碱除了应用于上述芳烃、 烯烃等 sp 2 杂化碳的 C-H 键镁化反应以外, 芳香杂环的苄位也可 以实现类似反应 [33] . 例如, 1,2-二甲基咪唑在 1.5 equiv.…”