27849-99-6Relevant academic research and scientific papers
Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino-Isocyanates
Ivanovich, Ryan A.,Clavette, Christian,Vincent-Rocan, Jean-Fran?ois,Roveda, Jean-Grégoire,Gorelsky, Serge I.,Beauchemin, André M.
, p. 7906 - 7916 (2016)
The ubiquity of nitrogen heterocycles in biologically active molecules challenges synthetic chemists to develop a variety of tools for their construction. While developing metal-free hydroamination reactions of hydrazine derivatives, it was discovered that carbazates and semicarbazides can also lead to alkene aminocarbonylation products if nitrogen-substituted isocyanates (N-isocyanates) are formed in situ as reactive intermediates. At first this reaction required high temperatures (150-200 °C), and issues included competing hydroamination and N-isocyanate dimerization pathways. Herein, improved conditions for concerted intramolecular alkene aminocarbonylation with N-isocyanates are reported. The use of βN-benzyl carbazate precursors allows the effective minimization of N-isocyanate dimerization. Diminished dimerization leads to higher yields of alkene aminocarbonylation products, to reactivity at lower temperatures, and to an improved scope for a reaction sequence involving alkene aminocarbonylation followed by 1,2-migration of the benzyl group. Furthermore, fine-tuning of the blocking (masking) group on the N-isocyanate precursor, and reaction conditions relying on base catalysis for N-isocyanate formation from simpler precursors resulted in room temperature reactivity, consequently minimizing the competing hydroamination pathway. Collectively, this work highlights that controlled reactivity of aminoisocyanates is possible, and provides a broadly applicable alkene aminocarbonylation approach to heterocycles possessing the β-aminocarbonyl motif. Unusual cycloadditions: Rare N-substituted isocyanates are shown to provide efficient access to cyclic heterocycles containing β-aminocarbonyl motifs through an alkene aminocarbonylation reaction. This study includes an investigation using DFT and the development of several reaction variants. These provide controlled reactions of reactive N-isocyanate intermediates, resulting in milder conditions, improved yields, and a better substrate scope (see scheme).
