Abstract
(Hetero)Aryl amines, an important class of organic molecules in medicinal chemistry, are most commonly synthesized from anilines, which are in turn synthesized by hydrogenation of nitroarenes. Amine synthesis directly from nitroarenes is attractive due to improved step economy and functional group compatibility. Despite these potential advantages, there is yet no general method for the synthesis of (hetero)aryl amines by carbon–nitrogen cross-coupling of nitroarenes. Here we report the reductive coupling of nitroarenes with alkyl halides to yield (hetero)aryl amines. A simple iron catalyst enables the coupling with numerous primary, secondary and tertiary alkyl halides. Broad scope and high functional group tolerance are demonstrated. Mechanistic study suggests that nitrosoarenes and alkyl radicals are involved as intermediates. This new C–N coupling method provides general and step-economical access to aryl amines.
Highlights
(Hetero)Aryl amines, an important class of organic molecules in medicinal chemistry, are most commonly synthesized from anilines, which are in turn synthesized by hydrogenation of nitroarenes
Inspired by Baran’s proposal that alkyl radical could add to nitrosoarene, formed by the reduction of nitroarene[14], we envisioned that reductive coupling of nitroarenes and alkyl halides might be used to form secondary alkyl aryl amines according to the following pathways (Fig. 2): an iron(II) precatalyst (Fe(II)) is reduced by zinc to Fe(I), which is able to activate an alkyl halide to give an alkyl radical and regenerate Fe(II)
The present method allows the synthesis of alkyl aryl amines from functionalized nitroarenes, which are often cheaper than functionalized anilines
Summary
Mechanistic study suggested that alkyl radical was involved as an intermediate, which added to terminal alkyne to form the C–C bond. The alkyl radical attacks the nitrogen atom of nitrosoarene to form the C–N bond[14], and reduction of the resulting intermediate by zinc in the presence of an oxophilic Lewis acid such as chlorotrimethylsilane (TMSCl) shall give the amine product (Fig. 2c). We commenced the study by examining the reaction of nitrobenzene (1a) with 2-iodooctane (2a) (Supplementary Tables 1–9). After a screening of reaction parameters, we found that the optimized conditions involved the use of N-methylpyrrolidone (NMP) as solvent, iron(II) chloride tetrahydrate (FeCl2 Á 4H2O) as catalyst (20 mol%), Zn (3 equiv.) as reductant, and TMSCl (2 equiv.) as co-reductant. FeCl2 Á 4H2O was the best catalyst (Supplementary Table 1, entries 1–16).
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