N-, O-arylation using diaryliodonium salts in continuous flow

Abstract

The work presented herein describes a novel and practical methodology for the synthesis of diarylamines and diarylethers using diaryliodonium salts and the selectivity between N-, and O-nucleophiles using continuous flow chemistry protocols with the FlowSyn™ automated reaction system (Scheme 1). 1 Scheme 1: N-, O-Arylation using diaryliodonium salts The translation from batch conditions successfully reduced the time for the reaction (24 h to 80 min) and a further refinement of using a copper coil as both reactor and catalyst generated the desired products under even milder conditions (130 °C to RT). Scheme 2: Diaryliodonium salt synthesis The diaryliodonium salts were easily synthesised from commercial, inexpensive, starting materials and purified by recrystallization (Scheme 2).2, 3 The stability of these salts allowed us to investigate a range of diaryliodonium salts to determine which aromatic ring reacted with the nucleophile, their solubility and that of the aniline/phenol in DMF allowed us to use flow chemistry as the reaction mixture was homogeneous.Scheme 3: Selectivity of N-, O-arylation using diaryliodonium salts The methodology was extended to also investigate the arylation of O-nucleophiles under the same reaction conditions using the FlowSyn™ (Scheme 1) however the selectivity between the two types of nucleophiles was unknown and a range of hydroxyanilines were used to explore this (Scheme 3). The method gave high yields of the arylated product with a notable preference for N-arylation over O-arylation, although some N, O-diarylation was observed. Of particular interest was the production of N-phenylazaquinone 82% when 4-hydroxyaniline was used with two equivalents of diphenyliodonium trifluoroacetate indicating a two-step process was present, the first equivalent resulting in N-arylation and the second oxidising the product.4, 5 Scheme 4: Arylation of aliphatic amines The methodology has also proven to be valuable for the arylation of aliphatic amines for instance those examples shown in Scheme 4, however the yield of the desired product was lower than that obtained for the aromatic amines. This project has indicated that aromatic amines are more suitable substrates for arylation with diaryliodonium salts and in the case where both N- and O-nucleophiles are present the nitrogen was always selectively arylated over the oxygen nucleophile.The translation of the reaction methodology to flow chemistry protocols has also allowed us to scale up the production, for example 3, 4-dimethoxydiphenylamine was prepared in a high yield (80%) at room temperature using diphenyliodonium trifluoroacetate (13.79 g, 35 mmol) and 3,4-dimethoxyaniline (5.36 g, 35 mmol). Simple washing of the precipitated product with ether gave the pure material (Fig. 1