Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Abstract

1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C-N bond is a facile condensation between the amine and an ortho-quinone, which triggers redox isomerization to an ortho-iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho-oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Copper catalysis with redox-active ligands

“…Building on their previously discussed phenol oxidation methodology (Scheme 5 and Scheme 6), Lumb and co-workers have targeted subsequent C-N bond formation to access oxindoles [34], and perform C-H functionalization through aerobic dearomatization of phenols [35]. These broad synthetic outcomes further led to a unified approach for the preparation of 1,2-oxy-aminoarenes by phenol-amine couplings (Scheme 10) [36].…”

Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo‐ and Regioselective Oxidation

“…This leads us to propose a steric bias for oxygenation at C4 that results from an unfavorable interaction between the C1 phenyl group and a tert ‐butyl group of the DBED ligand (i.e. TS1 , Scheme B) . This interaction would be decreased in TS2 , where the relatively planar biaryl bond at C4a would remain orthogonal to the plane of atom transfer.…”

“…Related azo switches possess red‐shifted absorbance properties and fast thermal relaxation, which are attractive for fast information transmission in biologically relevant contexts . Alternatively, coupling with dihydropyrrole affords N ‐aryl pyrrole 16 following condensation and redox isomerization, whereas the addition of phenylglycine methyl ester affords angularly fused benzoxazinone 17 following a similar cascade terminated by lactonization (structure confirmed by X‐ray, see the Supporting Information) …”

Nature is the Cure: Engineering Natural Redox Cofactors for Biomimetic and Bioinspired Catalysis

“…A recent approach to molecular diversity relying on oxidative biosynthetic pathways makes clever use of the fact that phenols are precursors in the biosynthesis of ortho‐quinones (Scheme ). The TTQ cascade serves as a source of inspiration for the synthesis of substituted quinones, ortho‐quinones, and 1,2‐oxy‐aminoarenes . Through a bioinspired copper catalyzed approach, the phenol substrate binds to the copper center and becomes a proradical ligand .…”

“…The TTQ cascade serves as a source of inspiration for the synthesis of substituted quinones, [20] orthoquinones, [21] and 1,2-oxy-aminoarenes. [22] Through a bioinspired copper catalyzed approach, the phenol substrate binds to the copper center and becomes a proradical ligand. [23] Ligand redox 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 non-innocence then translates into chemical reactivity at the ligand and allows efficient access to a variety of products.…”