Preparation of Polyfunctionalized Aromatic Nitriles from Aryl Oxazolines

Abstract

A selective ortho,ortho'-functionalization of readily available aryl oxazolines by two successive magnesiations with sBu 2 Mg in toluene followed by trapping reactions with electrophiles, such as (hetero)aryl iodides or bromides, iodine, tosyl cyanide, ethyl cyanoformate or allylic bromides (39 examples, 62-99 % yield) is reported. Treatment of these aryl oxazolines with excess oxalyl chloride and catalytic amounts of DMF (50 °C, 4 h) provided the corresponding nitriles (36 examples, 73-99 % yield). Conversions of these nitriles to valuable heterocycles are reported, and a tentative mechanism is proposed.

Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade

“…The high cost and unreliable availability of TMPMgCl•LiCl and its TMP precursor on industrial scale prompted us to explore alternative magnesium bases. A preliminary survey of cost-effective alternatives that included n-Bu 2 Mg, Turbo-Grignard reagent i-PrMgCl•LiCl, and (i-Pr 2 N) 2 Mg 21,22 identified the less commonly employed base i-Pr 2 NMgCl•LiCl (MgDA) 23−25 to be optimal, giving comparable performance to TMPMgCl•LiCl in batch mode (vide infra). According to literature-known protocols, the synthesis of MgDA from diisopropylamine (DIPA) using i-PrMgCl•LiCl typically requires long reaction times of >1 h at room temperature.…”