Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds

Abstract

Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C-C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (-NH₂) and hydroxyl (-OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom-transfer reagents. Here, we demonstrate the use of bench-stable N-H and N-alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions.

Figure 1. Current approaches to primary arylamine and phenol synthesis from arylmetals in the absence of transition-metal catalysts, impact of steric hindrance on kinetic acidity and the discovery of multifunctional oxaziridine reagents for heteroatom-transfer reactions

a–c, Known two-step procedures for the synthesis of primary arylamines (4) from the corresponding arylmetals (2 and 2c) using electrophilic aminating agents (1, 5 and 7). d, Conversion of arylmagnesium halides (2a) into phenols (12) using molecular oxygen in a flow system. e, Non-hindered amines undergo rapid proton exchange with arylmetals. f, Sterically bulky secondary amines, such as 13, do not undergo proton exchange with arylmetals. g, Our hypothesis: a sterically hindered electrophilic N source, such as an N–H oxaziridine, will undergo NH transfer rather than proton exchange when reacted with arylmetals. h,i, Camphor-derived N–Me and N–benzyl oxaziridine (19a (h) and 19b (i), respectively) react with 15 directly to give 2-naphthol (20) on workup. j,k, Camphor- and fenchone-derived N–H oxaziridines (16 (j) and 18 (k), respectively) react with 2-naphthylmagnesium bromide (15) directly at low temperature and under a protective argon atmosphere to afford 2-naphthylamine (17) on simple aqueous workup. Bn, benzyl; TMDEA, tetramethylethylenediamine.

Figure 2. Three-dimensional representation of competitive amination and proton-transfer transition states, and the proposed mechanism of N transfer and deuterium-trapping experiments

a, Free-energy barriers and enthalpy barriers (kcal mol⁻¹) (the top row numbers correspond to M06-2X and the bottom row to wB97X-D.) b, Proposed mechanism of the direct primary amination of arylmetals using bench-stable N–H oxaziridines: I, the strained three-membered oxaziridine ring is easy to open and 21a attacks the N–O σ* orbital; II, breakdown of the aminal intermediate to afford the magnesium amide of the arylamine product. c, Deuterium-trapping experiments using a delayed addition (2 h) at −78 °C in THF/toluene and then quenched with NH₄Cl (aq). The aryl-Grignard reagent 21b was titrated before use, approximately 0.2 mmol of 36 was present in the aryl-Grignard reagent because of inadvertent/unavoidable protonation during its preparation and the addition of the D₂O after only 5 s gave almost identical results.