The research group of Prof. Arjan W. Kleij has developed an effective one-pot three-component reaction strategy for the coupling of oxetanes, amines and CO2 to afford a variety of functionalized carbamates with excellent chemoselectivity and good yields.
Carbamates are organic compounds with substantial synthetic potential illustrated by their wide use in insecticides, agrochemicals, cosmetics and pharmaceuticals, among others. As for carbamates used in human pharmacotherapy, relevant examples include Meprobamate and its derivatives Carisoprodol and Felbamate that are used as anxiolytic and muscle relaxant drugs. The direct formation of carbamates from oxetanes, CO2 and amines has been rather unexplored and the only example reported to date is a non-catalytic approach that suffers from many limitations such as the harsh reaction conditions, long reactions times and low yields.
General scheme for the catalytic one-pot oxetane to carbamate conversion and molecular stucture of Carisoprodol
In this context, Prof. Kleij research group has designed and synthesized an Al-based catalyst for the intermediate formation of a six-membered carbonate from various (substituted) oxetanes and CO2. Then, the in situ aminolysis of the carbonate allows for direct formation of functionalized carbamates. Efficient Al-catalysis offers faster reactions, significantly reduced by-product formation and more benign reaction conditions.
“This work validates that carbon dioxide, if appropriately combined with suitable partners under efficient catalysis, offers new opportunities for synthetic chemists; these and other results in the field may inspire colleagues to further explore the use of this renewable carbon resource. In this respect, functionalized cyclic carbonates offer new unexplored potential for the preparation of useful pharma- and polymer-relevant building blocks” -says Prof. Kleij.
The developed methodology has also been succesfully applied towards the formal synthesis of Carisoprodol and the mono-carbamate of Felbamate, two molecules used in the treatment of several diseases. Carisoprodol is a centrally acting skeletal muscle relaxant indicated in the treatment of injuries and other conditions. On the other hand, Felbamate is used in the treatment of epilepsy and also to treat generalized seizures associated with Lennos-Gastaut syndrome in children.
The work has been published in Advanced Synthesis & Catalysis where has been selected for the journal cover.
Catalytic One-Pot Oxetane to Carbamate Conversions: Formal Synthesis of Drug Relevant Molecules
W. Guo, V. Laserna, J. Rintjema, A. W. Kleij
Adv. Synth. Catal., 2016, 358, 1602-1607