Off the Beaten Track: The Use of Secondary Amines in the Ugi Reaction

Abstract

Although the Ugi multicomponent reaction is more than 40 years old, there is still room for its application to the discovery of new multicomponent transformations, even within the constraints of its classic four‐reactant menu (aldehyde, amine, carboxylic acid, and isocyanide). Replacement of a primary amine with a secondary one thus allows the Mumm‐like rearrangement step to be avoided, freezing the reaction course at the stage of an imino‐anhydride intermediate susceptible to alternative nucleophilic trapping. Mainstream post‐transformation strategies can then add a further level of complexity. The potential of this approach to expedite access to molecular scaffolds of biological relevance and to create unprecedented chemical diversity is outlined.

An Ugi Reaction Incorporating a Redox-Neutral Amine C–H Functionalization Step

“…1 Reactions of isocyanides with secondary amines and aldehydes/ketones represent a special case, as the prototypical Mumm rearrangement cannot take place. 2 …”

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

“…Many noval MCRs [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] have meanwhile become part of the range of syntheses, e.g. boron-mediated [62,66], photo-induced [67] and carbenebased MCRs [72] such as N-heterocyclic carbenes (NHCs).…”

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

“…In summary,wehave developed anovel chiral phosphoric acid catalyzed enantioselective reaction between isonitriles (3)and 3-(arylamino)isobenzofuran-1(3H)-ones (7)toafford Angewandte 3-oxo-2-arylisoindoline-1-carboxamides (4)i nh igh yields with good to high enantioselectivities.Acatalytic enantioselective Ugi reaction of 2-formylbenzoic acids (1), anilines (2), and isonitriles (3)w as subsequently developed for the first time and lead to the same heterocycles 4.Mechanistic studies indicate that the observed enantioselectivity results from aDKR of the primary Ugi adduct rather than from the CÀC bond-forming process.W hile ag reat number of DKRs have been developed dealing with specific substrates, [25] DKR of ar eaction intermediate as am eans to achieving enantioselectivity remains an underexploited field. [26] Acknowledgments Financial supports from National Natural Science Foundation of China (21320102002, 21502202) and the EPFL (Switzerland) are gratefully acknowledged.…”

“…Indeed, its presence renders the development of an enantioselective process extremely difficult since carboxylic acid is not only areactant, but also acatalyst for the classic Ugi reaction. We report herein an ovel CPA-catalyzed enantioselective reaction between isonitriles (3)a nd 3-(arylamino)isobenzofuran-1(3H)-ones (7), as well as the first examples of the Ugi fourcenter three-component reaction of 2-formylbenzoic acids (1), anilines (2), and isonitriles (3)f or the synthesis of enantioenriched 3-oxoisoindoline-1-carboxamides (4). [15] We also document that the observed enantioselectivity results from the dynamic kinetic resolution (DKR) of the primary Ugi adduct, rather than from the CÀCbond-forming step.The heterocycle 4 is known for its analgesic properties [16] and has [17] and medicinally relevant compounds,s uch as (R)-pazinaclone,asedative and anxiolytic drug.…”

“…[1] Ther eaction generates one C À C, one C = O, and two C À Nbonds with water as the only byproduct. While the prototypical Ugi 4CR provides al inear peptide-like adduct, many heterocycles [2] and even macrocycles [3] are now readily accessible by modification of this versatile and powerful reaction. Since one stereogenic center is generated in this transformation, the ability to control the stereochemical outcome would expand significantly its synthetic utilities.H owever,t he development of ac atalytic, enantioselective Ugi reaction remains an unsolved problem in spite of the progress recorded in the field of asymmetric Passerini reactions, [4][5][6][7][8][9] ac losely related three-component condensation of an aldehyde,carboxylic acid, and isonitrile.…”