Advanced Nitroso Aldol Reaction: Metal-Free Cross-Coupling of Anilines with Silyl Enol Ethers en Route to α-Amino Ketones

Abstract

A practical and step-economical nitroso aldol reaction has been developed based on metal-free direct cross-coupling of ready-stock anilines with silyl enol ethers at room temperature affording α-amino ketones in high yields (up to 82%). The protocol features a one-pot cascade of nitroso compound generation, selective C-N bond formation, and N-O bond cleavage using solely inexpensive and user-friendly Oxone and displays remarkable functional group tolerance. The method was further extended to prepare densely functionalized indoles that are otherwise difficult to synthesize.

Ambident Reactivity of Nitroso Compounds for Direct Amination and Hydroxylation of Carbonyls

“…In 2017, we reported a direct cross-coupling of commercially available anilines and silyl enol ethers using Oxone as the sole reagent (Scheme 11). 24 Herein, Oxone plays a dual role; it oxidizes aniline to produce nitrosoarenes and also acts as a Brønsted acid to promote the cleavage of the N-O bond…”

“…The versatility of this synthetic protocol was further rationalized through a vinylogous α-amination cascade for the synthesis of peripherally decorated indole derivatives 56 (Scheme 12). 24 Anilines, e.g. 56, in the presence of Oxone and 1,2,3,4-tetrahydronaphthalen-1-ylidenemalononitrile (55) undergo an intermolecular vinylogous amination reaction to provide intermediate P. The nucleophilic attack of amino group present in P to the electrophilic nitrile group gives Q, which is followed by aromatization to provide the indole derivatives, e.g.…”

Selenomethoxylation of Alkenes Promoted by Oxone®

“…Moreover, it is commercially available as Oxone® in the form of a triple salt (2KHSO 5 · KHSO 4 · K 2 SO 4 ) containing about 50 % of active oxidant/mol, that is the anion peroxymonosulfate (HSO 5 – ). The active oxidant within the mixture has been efficiently used to perform a great number of organic transformations in polar solvents More recently, Oxone® was applied in the direct conversion of Baylis–Hillman alcohols to β‐chloro aldehydes, the α‐amination of ketones through nitroso aldol reaction, the oxidative chlorination of C sp3 –H bonds, in C sp3 –H hydroxylation, and the direct oxidative cascade cyclization of 2‐aminobenzoic acid and arylaldehydes . Furthermore, Oxone® was used to prepare different classes of organic compounds, such as indenochromenes, β‐fluoroporpholactones, α‐bromo‐ and α‐azidoketones …”

Recent advances in the synthesis of α-amino ketones

“…63 In 2017, Baidya published a convenient α-amination protocol involving the in situ generation of nitroso arenes from anilines (82) in the presence of super-stoichiometric amounts of Oxone® (Scheme 18). 64 These intermediates underwent a nitroso aldol reaction with silyl enol ethers (81), and the addition products (84) were easily converted to the desired α-amino ketones (83) in up to 82% yield by assistance of the disilyl protecting group. A related transformation developed by Hashimoto uses an imidoiodinane as the nitrogen electrophile in the presence of a polymer-supported dirhodium(II) catalyst.…”