Free-Radical Addition to Ketimines Generated In Situ. New One-Pot Synthesis of Quaternary α-Aminoamides Promoted by a H₂O₂/TiCl₄−Zn/HCONH₂ System

Abstract

A free radical multicomponent reaction mediated by an acidic TiCl(4)-Zn/H(2)O(2) system allows the assembly of an amine, a ketone, and formamide in one pot, affording instant access to quaternary alpha-amino acid derivatives.

Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)

“…The key intermediate in the synthesis of 33 was gem -dimethyl α-amino amide 64 , which was obtained in a one-pot free radical multicomponent reaction 38 from aniline 63 . Exposure of 64 to 2,6-diisopropylphenyl isocyanate at high temperature 39 effected carbonylative ring closure to hydantoin 33 .…”

Multicomponent versus domino reactions: One-pot free-radical synthesis of β-amino-ethers and β-amino-alcohols

“…In a manner similar to the procedures of [ 25 ] and [ 27 ], a homogeneous solution of CH 2 Cl 2 (5 mL), containing an aryl amine (2 mmol), a cyclic or acyclic ketone (5 mmol), and TiCl 4 (2.5 mL of 1 M solution in CH 2 Cl 2 , 2.5 mmol), was stirred at room temperature under N 2 atmosphere. After approximately 30 min, Zn powder (300 mg, ca.…”

“…The basic approach consists of the simple mixing of an aniline, an aldehyde or ketone, and a suitable source of nucleophilic radicals (Nu–H = formamide [ 24 – 25 ], methanol [ 26 – 27 ], ethers [ 28 ]), in the presence of titanium chlorides, and slowly dropping a solution of hydroperoxide (H 2 O 2 or tert -butyl hydroperoxide ( t -BuOOH)) into the reaction medium ( Scheme 1 ).…”

“…Aqueous TiCl 3 proved particularly effective for promoting the formation and functionalization of aldimines ( Scheme 1 , entry a), but was necessarily replaced with the redox TiCl 4 (CH 2 Cl 2 )/Zn system when operating in the presence of ketones ( Scheme 1 , entry b), as the corresponding ketimines were more sensitive to the aqueous medium [ 25 , 27 ].…”

New Advances in Titanium-Mediated Free Radical Reactions

“…It is because of this low stability under non-anhydrous conditions that the TiCl 3 /ROOH system resulted ineffective when an aniline, a ketone and formamide were assembled in one-pot with the intention of promoting the formation of quaternary α -amino amides. Nevertheless, we recently reported an optimization of the previously discussed protocol, consisting in the replacement of the aqueous TiCl 3 with an anhydrous solution of TiCl 4 in CH 2 Cl 2 in combination with Zn powder ( Scheme 8 a) [ 42 ]. The same protocol was successfully applied in methanol solvent for the selective hydroxymetylation of ketimines, affording the corresponding β , β -disubstituted- β -amino alcohols ( Scheme 8 b) [ 43 ].…”