alpha,beta-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles

Author(s)

Burtoloso, Antonio C. B. ^[1] ; Dias, Rafael M. P. ^[1] ; Bernardim, Barbara ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Quim Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

• Document type: Review article
• Source: ACCOUNTS OF CHEMICAL RESEARCH; v. 48, n. 4, p. 921-934, APR 2015.
• Web of Science Citations: 35

Abstract

Among the different types of diazocarbonyl substrates found in the literature to date, alpha,beta-unsaturated diazoketones have proven to be very promising as multifunctional intermediates. Possessing a diazo group, a ketone function and a double bond all together in a single molecule, these compounds constitute versatile building blocks for synthesis. For example, double bond functionalization, followed by intramolecular insertion reactions, can be a short alternative to prepare several rings or heterocyclic compounds. Although there are many efficient methods to prepare diazoketones, very few can be extended to the synthesis of the a,beta-unsaturated diazoketones; this is likely responsible for their limited application in synthesis. Unfortunately, the classical methods to prepare saturated- or aryl-diazoketones (acylation of diazomethane with acyl chlorides or mixed anhydrides) are not suitable for preparing a,beta-unsaturated diazoketones, since pyrazolines (dipolar cycloaddition products from the reaction between diazomethane and the double bond) are formed. Although Danheiser's two-step detrifluoroacetylative procedure (starting from a,beta-unsaturated methyl ketones) is considered the best general method, it cannot be applied to the synthesis of all types of alpha,beta-unsaturated diazoketones. For example, the synthesis of more complex unsaturated diazoketones, as well as those with epimerizable stereocenters in the gamma position, was never described before. Another point is related to the geometry of the double bond, since practically all examples described thus far refer to unsaturated diazoketones with E geometry. In recent years, our research group developed two new Horner-Wadsworth-Emmons reagents (containing a diazocarbonyl function) that could be easily applied in the one-step preparation of alpha,beta-unsaturated diazoketones from aldehydes. Not only were we able to selectively synthesize E- and Z-unsaturated diazoketones, but also to employ these useful platforms in the short synthesis of several nitrogen heterocycles such as indolizidines, quinolizidines, piperidines, and pyrrolidines. Our purpose in this Account is to introduce this class of diazoketone and provide a brief historical overview, culminating in how we developed a general methodology to prepare them. In continuation, we wish to call of the reader's attention to these important building blocks, showing how we could apply them to the synthesis of several nitrogen heterocycles, including the very short preparation of some popular alkaloids. The reader will also notice that the combination of these three important functions in the same molecule makes these compounds special as well as provides powerful platforms to access many important molecules in a direct fashion. (AU)

• FAPESP's process: 12/22274-2 - Study in the photochemical Wolff rearrangement from a,b-unsaturated diazoketones. Aplication in diversity synthesis of nitrogen and oxygen heterocycles
• Grantee: Barbara Bernardim de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/25504-1 - Development of new methodologies for the asymmetric a-functionalization of carbonyl compounds using chiral catalysts
• Grantee: Antonio Carlos Bender Burtoloso
• Support Opportunities: Regular Research Grants