Regioselective 1,3‐Dipolar Cycloadditions of Diazoalkanes with Heteroatom‐Substituted Alkynes: Theory and Experiment

• Published in: European journal of organic chemistry 2018-06, Vol.2018 (20-21), p.2477-2485
• Main Authors: Breugst, Martin, Huisgen, Rolf, Reissig, Hans‐Ulrich
• Format: Article
• Language: English
• Subjects: Alkynes; Carboxylates; Constitution; Cycloaddition; Decarboxylation; Density functional calculations; Density functional theory; Diazo compounds; Diazomethane; Mathematical analysis; Pyrazole; Reaction mechanisms; Regioselectivity; Substitutes
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201800100

The 1,3‐dipolar cycloadditions of diazomethane and diazoethane with methyl 3‐(diethylamino)propiolate were investigated experimentally and computationally by employing density functional theory (DFT). The experiments provided methyl 3‐(diethylamino)‐pyrazole‐4‐carboxylates as the only isolated regioisomers. The constitution of these cycloadducts was secured by independent synthesis and decarboxylation to 3‐(diethylamino)pyrazoles. The calculations fully support the experimental findings. For the preferred pathway of the diazomethane cycloaddition with the alkyne, a kinetic preference of 9.6 kJ mol–1 was calculated in Et2O solution. The computational analysis was extended to other alkynes, for instance to heteroatom‐substituted alkynes such as ethoxyethyne and (ethylthio)ethyne. Again, the calculations nicely explain the switch in regioselectivity of the 1,3‐dipolar cycloadditions of diazomethane with these two alkynes, which has been reported earlier by the group of Arens. The regioselective 1,3‐dipolar cycloaddition of a series of heteroatom‐substituted alkynes with diazomethane was experimentally investigated and interpreted by DFT calculations that nicely explain the observed reactivities and regioselectivities.