Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino-Isocyanates.
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.
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
Ryan A
RA
Ivanovich
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
Christian
C
Clavette
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
Jean-François
JF
Vincent-Rocan
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
Jean-Grégoire
JG
Roveda
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
Serge I
SI
Gorelsky
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada. andre.beauchemin@uottawa.ca.
André M
0000-0003-0667-6215
AM
Beauchemin
amination; amphoteric molecules; intramolecular aminocarbonylation; nitrogen-substituted isocyanates; synthetic methods