Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts.

Alaa Zidan,Ali Khalil Ali,Nour E A Abd El-Sattar,Abeer M El-Naggar,Laurent El Kaïm

doi:10.3389/fchem.2019.00020

Abstract

We report here selective Tsuji-Trost type allylation of Ugi adducts using a strategy based on the enhanced nucleophilicity of amide dianions. Ugi adducts derived from aromatic aldehydes were easily allylated at their peptidyl position with allyl acetate in the presence of palladium catalysts. These substitutions were compared to more classical transition metal free allylations using allyl bromides.

Highlights

Since its discovery and even more after the 1980’s, the Ugi reaction has fascinated chemists with the high diversity brought by its four components nature together with its impressive functional tolerance (Dömling and Ugi, 2000; Hulme and Gore, 2003; Orru and De Greef, 2003; Zhu and Bienaymé, 2005; Dömling, 2006; Dömling et al, 2012; Zhu et al, 2014; Boyarskiy et al, 2015; Váradi et al, 2016; Lei et al, 2018)
Following our interest in Tsuji-Trost reactions involving isocyanide based MCRs (Dos Santos and El Kaïm, 2014; Cordier et al, 2015; El Mamouni et al, 2016), we decided to explore the behavior of Ugi adducts dianions toward allyl acetate
Ugi adduct 1a was selected due to its good behavior in our previous studies with propargyl bromide and diiodomethane. It was prepared in 89% yield from 4-chloro-benzaldehyde, propylamine, acetic acid and tertbutylisocyanide (Table 1)

Summary

Introduction

Since its discovery and even more after the 1980’s, the Ugi reaction has fascinated chemists with the high diversity brought by its four components nature together with its impressive functional tolerance (Dömling and Ugi, 2000; Hulme and Gore, 2003; Orru and De Greef, 2003; Zhu and Bienaymé, 2005; Dömling, 2006; Dömling et al, 2012; Zhu et al, 2014; Boyarskiy et al, 2015; Váradi et al, 2016; Lei et al, 2018). Following our interest in Tsuji-Trost reactions involving isocyanide based MCRs (Dos Santos and El Kaïm, 2014; Cordier et al, 2015; El Mamouni et al, 2016), we decided to explore the behavior of Ugi adducts dianions toward allyl acetate. When 1a was heated with allyl acetate in THF using 2.5 equivalents of potassium tert-butoxide together with a Pd(dba)2/PPh3 catalytical couple, we were delighted to observe a selective C-allylation of 1a giving 3a in 65% isolated yield after 2 h refluxing (entry 1, Table 1).

Results

Conclusion