2‐Bromo‐2‐chloro‐3‐arylpropanenitriles as C‐3 Synthons for the Synthesis of Functionalized 3‐Aminothiophenes

Abstract

2‐Bromo‐2‐chloro‐3‐arylpropanenitriles can be prepared by Meerwein reaction from 2‐chloroacrylonitrile and various aryldiazonium salts under copper(II) bromide catalysis. They proved to be stable compounds which form 2‐chlorocinnnamonitriles upon treatment with bases. Reaction of the title compounds with substituted thioglycolates gave substituted 3‐aminothiophenes which have not yet been accessible by other routes. Three‐component reactions with the title compound, sodium sulfide and bromonitromethane, chloroacetonitrile, or ethyl 4‐chloroacetoacetate gave 2‐nitro‐ and 2‐cyano‐substituted 3‐aminothiophenes, and thienopyridinediones in high yields and in one single step, respectively.

Bromoarylation of Methyl 2-Chloroacrylate under Meerwein Conditions for the Synthesis of Substituted 3-Hydroxythiophenes

“…In continuation of our interest in heterocycle synthesis, 28 catalytic thiophene synthesis, 29 and Meerwein reactions, 30,31 we report here an effective and reliable synthesis of a variety of 5-aryl-3-hydroxythiophenes starting from methyl 3-aryl-2-bromo-2-chloropropanoates A (Scheme 1). Starting material A can be smoothly obtained by Meerwein arylation of methyl 2-chloroacrylate (B) with arenediazonium salts derived from various anilines C. This method proved to be superior to the earlier reported chlorination and subsequent oxidation of 2-(1-bromo-2-phenylethyl)-4methyl-1,3-dioxolane.…”

“…34 The method described here therefore allows for the synthesis of 3-hydroxythiophenes which are difficult to prepare by other methods and which supplements our synthesis of substi-tuted 3-amino-5-arylthiophenes starting from 2-bromo-2chloro-3-phenylpropanenitriles as products of Meerwein arylations. 30 Methyl 2-chloroacrylate (B, Scheme 1) was obtained in two steps from methyl acrylate by chlorination followed by dehydrochlorination of the resulting methyl dichloropropionate. 35 To prepare the title thiophenes, anilines 1a-g were easily converted into their diazonium salts by aqueous solutions of hydrogen bromide, cooling to -5 °C, and subsequent addition of a saturated solution of sodium nitrite in water (Scheme 2).…”

Recent Development of Aryl Diazonium Chemistry for the Derivatization of Aromatic Compounds

“…Traditional radical addition to alkenes from aryl diazonium salts needs the participation of copper salts or other transition metals. A practical application of this strategy was disclosed through a Cu­(II)-catalyzed bromoarylation reaction using 2-chloroacrylonitrile 16 with in situ formed aryl diazonium salts, accessing the preparation of 2-bromo-2-chloro-3-arylpropanenitriles 17 with moderate to good yields in acetone/water (Scheme , up) . Another similar protocol involved the Fe­(II)-catalyzed oxyarylation of electron-rich olefins 18 , including styrenes, vinyl pyrrolidinone, and vinyl oxazolidinone with aryl diazonium tetrafluoroborates, furnishing corresponding carbohydroxylated and carbomethoxylated products 19 , including functionalized dihydroisocoumarin and dihydrobenzofuran derivatives (Scheme , below) .…”

Current Advances in Meerwein-type Radical Alkene Functionalizations

“…Within a synthetic study on a new access to 3-aminothiophenes, a Meerwein-type carbobromination 19,70,75 was recently employed as a useful tool to prepare the required precursors 55, starting from chloroacrylonitriles 54, in a single reaction step (Scheme 23). 76 Scheme 23 Copper-catalyzed bromoarylation of chloroacrylonitrile 76 Remarkably, a catalyst loading as low as 0.45 mol% enabled efficient product formation. In copper(II)-catalyzed reactions, reduction of the diazonium salt 53 to generate the aryl radical typically occurs due to traces of copper(I) ions being present in the reaction mixture, while the later construction of the carbon-bromine bond from alkyl radical XLII is enabled by bromine atom transfer from CuBr 2 .…”

“…Within a synthetic study on a new access to 3-aminothiophenes, a Meerwein-type carbobromination 19 70 75 was recently employed as a useful tool to prepare the required precursors 55 , starting from chloroacrylonitriles 54 , in a single reaction step (Scheme 23 ). 76…”