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

ABSTRACT: Pyrrolidine and 1,2,3,4-tetrahydroisoquinoline (THIQ) undergo redox-neutral ?-amidation with concurrent N-alkylation upon reaction with aromatic aldehydes and isocyanides. Reactions are promoted by acetic acid and represent a new variant of the Ugi reaction.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC4934885 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Zhu Zhengbo Z Seidel Daniel D

Organic letters 20160119 4

Pyrrolidine and 1,2,3,4-tetrahydroisoquinoline (THIQ) undergo redox-neutral α-amidation with concurrent N-alkylation upon reaction with aromatic aldehydes and isocyanides. Reactions are promoted by acetic acid and represent a new variant of the Ugi reaction. ...[more]

PMID: 26785064

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Project description:Ureido-functionalized compounds play an indispensable role in important biochemical processes, as well as chemical synthesis and production. Isocyanates, and KOCN in particular, are the preferred reagents for the ureido functionalization of amine-bearing compounds. In this study, we evaluate the potential of urea as a reagent to graft ureido groups onto amines at relatively low temperatures (<100 °C) in aqueous media. Urea is an inexpensive, non-toxic and biocompatible potential alternative to KOCN for ureido functionalization. From as early as 1864, urea was the go-to reagent for polyurea polycondensation, before falling into disuse after the advent of isocyanate chemistry. We systematically re-investigate the advantages and disadvantages of urea for amine transamidation. High ureido-functionalization conversion was obtained for a wide range of substrates, including primary and secondary amines and amino acids. Reaction times are nearly independent of substrate and pH, but excess urea is required for practically feasible reaction rates. Near full conversion of amines into ureido can be achieved within 10 h at 90 °C and within 24 h at 80 °C, and much slower reaction rates were determined at lower temperatures. The importance of the urea/amine ratio and the temperature dependence of the reaction rates indicate that urea decomposition into an isocyanic acid or a carbamate intermediate is the rate-limiting step. The presence of water leads to a modest increase in reaction rates, but the full conversion of amino groups into ureido groups is also possible in the absence of water in neat alcohol, consistent with a reaction mechanism mediated by an isocyanic acid intermediate (where the water assists in the proton transfer). Hence, the reaction with urea avoids the use of toxic isocyanate reagents by in situ generation of the reactive isocyanate intermediate, but the requirement to separate the excess urea from the reaction product remains a major disadvantage.

Dataset Information

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

Publications

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

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