α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles

Abstract

Among the different types of diazocarbonyl substrates found in the literature to date, α,β-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,β-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,β-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,β-unsaturated methyl ketones) is considered the best general method, it cannot be applied to the synthesis of all types of a,β-unsaturated diazoketones. For example, the synthesis of more complex unsaturated diazoketones, as well as those with epimerizable stereocenters in the γ 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 α,β-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.

Traditional and New methods for the Preparation of Diazocarbonyl Compounds

“…Padwa and co-workers described the use of ethyl 2-diazomaalonyl chloride in the diazoacetylation reaction with different nucleophiles to afford a variety of diazocarbonyl compounds (Marino et al 1994) ( Figure 55). Recently, our group showed that the α,βunsaturated diazoketones can be modified to another diazocarbonyl derivative by Michael addition with a broad range of amines, remaining intact the diazo functional group for the next transformation (Burtoloso et al 2015, Dias et al 2017 (Figure 56). α,β-unsaturated diazoketones could also be functionalized by means of a Sharpless Asymmetric dihydroxylation to furnish α,βdihydroxy diazoketones, an interesting substrate for the short synthesis of substituted furanones (Talero and Burtoloso 2017).…”

“…Diazocarbonyl compounds, containing two functional groups, "diazo and keto", are very versatile intermediates and can perform a number of chemical transformations. For example, these compounds can undergo C-H and C-X insertion reactions, the Wolf rearrangement, cyclopropanations and dipolar cycloaddition ( Figure 1) (Burtoloso et al 2015). In addition, the use of diazocarbonyl compounds has showed significant developments in chemical biology such as the alkylation of DNA, RNA and proteins (Mix et al 2016, Ford et al 2015.…”

Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide

“…Importantly, cleavage of the N–C bond was not observed, which likely results from the complementary Sm(II) reagent system employed. This transformation, which rapidly delivers chiral β-amino alcohol units, represents a powerful method for the construction of piperidine, indolizidine and quinolizidine alkaloids from readily available α-amino acid derivatives ( Scheme 16 B) [ 71 , 72 ].…”

Rapid Synthesis of Bicyclic N‐Heterocyclic Cores from N‐Terminal α,β‐Unsaturated Diazoketones

“…Because of the importance of N‐heterocycles, especially in the pharmaceutical industry, the development of synthetic methods to access these cores with different substitution patterns is highly desired. Since 2010, our research group has been involved with the chemistry of α,β‐unsaturated diazoketones to target the direct preparation of O‐ and N‐heterocycles . For example, the synthesis of the popular pyrrolidine alkaloid preussin could be accomplished in just three steps from decanal by employing an unsaturated diazoketone as the key intermediate (Scheme A) .…”