One‐Pot Synthesis of α‐Amino Nitrile Units through Alkylative Strecker Cyanation from Formamides

Abstract

In this work, we describe the one-pot synthesis of α-amino nitrile units by the concomitant addition of alkyl (or aryl) Grignard reagents and TMS cyanide through alkylative Strecker cyanation from readily available formamides. The reaction is broad in scope and the conditions are mild, inexpensive, and easy to set-up, providing numerous α-amino nitriles in good yields (34 examples, 41-94 % yield).

KOtBu-Mediated Reductive Cyanation of Tertiary Amides for Synthesis of α-Aminonitriles

“…Compounds 2a – 2c , 2f , 2i – 2j , 2n – 2o , and 2q – 2r were prepared according to the previously reported procedures. ,,, Citations to the references containing characterization data for these compounds 2a , 2b , 2c , 2f , 2i , 2j , 2n , 2o , 2q , and 2r are consistent with the previous reports.…”

“…According to the experimental results as well as some previous publications, − a proposed mechanism for the reduction is illustrated in Scheme . It is proposed that the hydrosilane is activated with KO t Bu to form a pentacoordinate silicon intermediate, which allows the transfer of the hydride to the amide carbonyl to generate an O -silylated hemiaminal intermediate A .…”

“…Moreover, in 2021, the Li group reported the FeI 2 -catalyzed reductive Strecker cyanation of formamides to produce amino acetonitriles (Scheme D) . In 2021, the Sorin group described the one-pot synthesis of α-aminonitrile units by the concomitant addition of Grignard reagents and TMSCN through alkylative Strecker cyanation (Scheme D) . Finally, in 2020, the Chida group reported the reductive Strecker reactions of tertiary amides by NaH/NaI composite, in situ treatment with trimethylsilyl chloride, and subsequent coupling with tetrabutylammonium cyanide (Scheme E) .…”

A Journey from June 2018 to October 2021 with N,N-Dimethylformamide and N,N-Dimethylacetamide as Reactants

“…The reactions disclosed in Scheme 38(g 1 ) and Scheme 45 differ strongly from that previously reported under oxygen and Ni/Cu catalysis which provided 2-(quinolin-8-yl)isoindoline-1,3-diones via carbonylation using DM as the carbon source of carbonyl group [2,3,147]. Concomitant addition of Grignard reagents and TMSCN to DMF leading to α-amino nitriles was promoted with Ti(Oi-Pr)4 catalysis (Scheme 46(a1)) through, according to Lannou/Sorin's team, the addition of the Grignard reagent, transmetallation followed by reaction with TMSCN as depicted in Scheme 46(a2) [148]. Concomitant addition of Grignard reagents and TMSCN to DMF leading to α-amino nitriles was promoted with Ti(Oi-Pr) 4 catalysis (Scheme 46(a 1 )) through, according to Lannou/Sorin's team, the addition of the Grignard reagent, transmetallation followed by reaction with TMSCN as depicted in Scheme 46(a 2 ) [148].…”

“…Concomitant addition of Grignard reagents and TMSCN to DMF leading to α-amino nitriles was promoted with Ti(Oi-Pr)4 catalysis (Scheme 46(a1)) through, according to Lannou/Sorin's team, the addition of the Grignard reagent, transmetallation followed by reaction with TMSCN as depicted in Scheme 46(a2) [148]. Concomitant addition of Grignard reagents and TMSCN to DMF leading to α-amino nitriles was promoted with Ti(Oi-Pr) 4 catalysis (Scheme 46(a 1 )) through, according to Lannou/Sorin's team, the addition of the Grignard reagent, transmetallation followed by reaction with TMSCN as depicted in Scheme 46(a 2 ) [148]. Concomitant addition of Grignard reagents and TMSCN to DMF leading to α-amino nitriles was promoted with Ti(Oi-Pr)4 catalysis (Scheme 46(a1)) through, according to Lannou/Sorin's team, the addition of the Grignard reagent, transmetallation followed by reaction with TMSCN as depicted in Scheme 46(a2) [148].…”