Amine synthesis via iron-catalysed reductive coupling of nitroarenes with alkyl halides

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.

Introduction

Amines are among the most important organic compounds for the chemical, materials, pharmaceutical and agrochemical industries1,2,3. In particular, aromatic and heteroaromatic amines occupy a privileged position in the medicinal chemistry3,4, as exemplified in the top-selling drugs such as Abilify, Crestor, Gleevec and Lidoderm5. The most general methods to prepare aryl and heteroaryl amines are amine-carbonyl reductive amination6 (Fig. 1a), direct alkylation of amines with alkyl halides7 (Fig. 1b), and Buchwald–Hartwig8,9,10 and Ullman-type carbon–nitrogen (C–N) cross-coupling reactions11,12 (Fig. 1c). These amination methods employ amines, especially anilines, as the nitrogen source, which are usually prepared in advance by the hydrogenation of nitroarene derivatives13. Amine synthesis using directly nitro(hetero)arenes is attractive as it eliminates the hydrogenation step, saving time and cost. Moreover, functional groups such as amine, hydroxyl and thiol have orthogonal reactivity to the nitro group, so they may be tolerated without protection14. On the contrary, in amine synthesis using anilines, these groups have to be protected to avoid undesirable alkylation or arylation14. Recently, Baran and co-workers14developed a novel and elegant hydroamination approach to synthesize (hetero)aryl amines from nitro(hetero)arenes and olefins using an iron salt as catalyst, phenylsilane as hydrogen donor, and zinc (Zn) as reductant (Fig. 1d). Nevertheless, this approach was mostly efficient for the synthesis of (hetero)aryl amines substituted by a tertiary alkyl group15. General methods for amine synthesis from nitroarenes remain underdeveloped despite their potential advantages14,16,17.

Figure 1: Different approaches to (hetero)aryl amines.

(a) Reductive amination; (b) N-Alkylation of amine; (c) Buchwald–Hartwig and Ullmann-type coupling; (d) Baran’s hydroamination with nitro(hetero)arenes; (e) Current work using reductive coupling of nitro(hetero)arenes with alkyl halides. Fe(acac)3, iron(III) acetylacetonate; PhSiH3,phenylsilane; Zn, zinc; TMSCl, chlorotrimethylsilane.