Studies on multicomponent reactions: New 4- and 5-component routes to aminoacid diamides and 3-component routes to substituted indoles by modification of the classical Ugi and Fischer indole reactions.

摘要

Multicomponent reactions (MCRs) provide a convenient route to structurally diverse compounds in a single step. The increased demand for high-throughput screening of compounds and the biological relevance of most MCR products has led to a renaissance in MCR research. Towards this end, a retrosynthetic intermediate analysis (RIA) approach was developed with the goal of creating new, and improving known, MCRs.; The Ugi synthesis of dipeptides is one of the most widely used MCRs. RIA revealed that the imine intermediate, typically formed from a carbonyl and amine, could also be accessed by the addition of organometallic reagents to nitrites. This discovery led to a novel four-component Ugi synthesis of N-unsubtituted dipeptides in moderate to good yields. In an extension of the aforementioned chemistry, the dimensionality of the Ugi reaction was also increased to five components using a transimination step to form N-substituted imincs. Using this chemistry, a five-component Ugi reaction was developed that produced N-substituted dipeptides in moderate to good yields.; To assess the applicability of RIA beyond known MCRs, the approach was applied to the bimolecular Fischer indole reaction. RIA revealed that a suitable replacement for the arythydrazone intermediate, typically derived from a carbonyl and arylhydrazine, may also be formed by reacting a nitrite, organometallic reagent, and arylhydrazine. This approach led to the development of a novel three-component Fischer indole reaction. Indoles and indolenines were obtained in moderate to good yields using a variety of starting materials.; Another variation of the Fischer indole reaction was based on similarities between nitronates and imines, both of which contain the C=N moiety. A one-pot Fischer indole reaction was developed from nitroalkanes, producing indoles and indolenines in good yields. Further investigation of the reaction suggested that it proceeded through a Nef type reaction, whereby ketone and oxime intermediates converged to produce the desired indole.