可见光氧化还原催化制备β-硝基酮

Synthesis ofβ-nitro ketone by visible light photoredox catalysis

β-胺基酮在天然产物和药物合成方面具有极其重要的价值.Mannich反应是合成β-胺基酮的重要方法,但仍然存在局限性:无法合成-NH_(2)未被修饰的β-氨基酮或-NH_(2)连在β-季碳上的酮.本文利用可见光诱导的氧化还原催化,由烯醇三甲基硅醚与偕溴代硝基烃在温和条件下制备各种β-硝基酮,包括硝基连在β-季碳上的酮.这些结构新颖的β-硝基酮很容易转化为β-NH_(2)酮、1,3-氨基醇、α,β-不饱和酮、β-氰基酮和γ-硝基酮.

β-Amino ketones are invaluable for the synthesis of natural products and pharmaceutical agents.Mannich reaction is an important method for the synthesis ofβ-amino ketones,but still has some limits:It is inaccessible to a ketone bearing a nudeβ-NH_(2) group or aβ-quaternary carbon with nude-NH_(2) group.Harnessing the power of visible light-induced photoredox catalysis,we prepared variousβ-nitro ketones,including those bearing aβ-quaternary carbon,from geminal bromonitroalkanes and trimethylsilyl enol ethers under mild conditions,which were easily converted intoβ-amino ketones,1,3-amino alcohols,α,β-unsaturated ketones,β-cyano ketones andγ-nitro ketones.We prepared quaternary and tertiary gem-halonitroalkanes by halogenation of ketoximes and primary nitroalkanes,respectively,and prepared trimethylsilyl enol ethers by silylation of the enolates of various methyl and methylene ketones.Under blue light irradiation,these gem-halonitroalkanes reacted smoothly with the trimethylsilyl(TMS)enol ethers in the presence of 0.5%(mol/mol)fac-Ir(ppy)_(3) at room temperature.Generally,theβ-nitro ketones were obtained in moderate to high yields.In several cases,elimination of HNO_(2) occurred to give theα,β-unsaturated ketones.The TMS or TBS enol ethers ofα-halo,α-phenyl andα,α-dimethyl ketones,5-methoxy-2-tetralone,2-indanone,tetrahydro-4H-pyran-4-one,acetone,aldehydes and esters failed to give any coupling product.To demonstrate the practicability and versatility of our new synthetic method,a gram-scale coupling reaction was established and theβ-nitro ketone was easily derivatized.The reaction mechanism was studied carefully and elucidated clearly.Control experiments verified that both visible light and the photoredox catalyst were necessary for the coupling reaction to proceed.Radical-trapping experiments indicated thatα-nitroalkyl radicals were possible intermediates.^(1 )H NMR monitoring the reaction between 2-bromo-2-nitropropane and 1-phenyl-1-trimethylsiloxyethylene clearly showed that trimethylsilyl bromide was the by-product.Stern-Volmer quenching analysis supported that electron transfer between fac-Ir(ppy)_(3) and gem-bromonitroalkane should take place during the coupling reactions,and no such process was involved between fac-Ir(ppy)_(3) and TMS enol ether.Based on the above facts,we proposed thatα-nitro radical,generated by single-electron-transfer from fac-Ir(ppy)_(3) to gembromonitroalkane,added to the C=C double bond of TMS enol ether resulting in anα-siloxy radical,which was then oxidized by photogenerated fac-[Ir(ppy)_(3)]^(+)to give a carbocation species.With the aid of Br^(−),liberation of TMS-Br was achieved to give theβ-nitro ketone product.