Development of a Direct Alkynylation of Carboxylic Acids
Final Report Abstract
The van Gemmeren lab aims to develop synthetic methods with which organic molecules can be accessed that would otherwise be challenging to obtain. Ideally, these methods are intended to complement existing methods, giving organic chemists additional tools for synthesis planning. The original aim of this project was to develop reagents that would enable the direct conversion of carboxylic acids into alkynes, in which one carbon atom would originate from the carboxylate moiety. While the originally designed reagents could not be generated, we could demonstrate that one of the envisaged key steps is inherently not feasible. For the alternative approach we could show that the key step does indeed generate alkynes under mild conditions. Subsequent studies enabled us to develop a method for the direct conversion of acyloins into alkynes. Combined with several fragment-coupling acyloin syntheses, we could thus access a useful two-step approach towards alkynes from separate organic compounds, each of which contributes on carbon atom to the alkyne. The protocol proved to feature a broad functional group tolerance, allows for aliphatic and aromatic substituent on the alkyne, as well as for symmetric and non-symmetric alkynes. At the same time, it only requires cheap and simple reagents that are present in many organic chemistry laboratories. Inspired by the knowledge gained in this study about providing driving force to desired reactions through condensation/fragmentation processes, we devised an olefination protocol that would deliver olefins from aldehydes and thiols through a mechanism involving a Ramberg-Bäcklundtype rearrangement as the key step. Towards this goal, a kinetically controlled formation of nonsymmetric bis-thioacetals was developed, which is in itself attractive for combinatorial chemistry applications and in dynamic covalent systems. Building upon this intermediate study, we could ultimately identify a protocol that enables the olefination of aldehydes with thiols as reaction partners. The protocol proved to be widely applicable including challenging substitution patterns on the olefin and thereby complements the well-established olefination methods form literature.
Publications
- The Direct Conversion of α-Hydroxyketones to Alkynes, J. Org. Chem. 2019, 84, 983-993
F. Ghiringhelli, L. Nattmann, S. Bognar, M. van Gemmeren
(See online at https://doi.org/10.1021/acs.joc.8b02941) - Direct Synthesis of Unsymmetrical Dithioacetals, Chem. Eur. J. 2021, 27, 4859-4863
S. Bognar, M. van Gemmeren
(See online at https://doi.org/10.1002/chem.202004835)
