Enantioselective transformations and continuous-flow synthesis of fluorinated diazoalkanes
Final Report Abstract
This research project focused on the application of fluorinated donor/acceptor diazoalkanes in organic synthesis methodology. These fluorinated donor/acceptor diazoalkanes differ significantly in their chemical reactivity from ester-substituted donor/acceptor diazoalkanes and led to the discovery of novel opportunities in organic synthesis. In one part of this research project, we could identify that such fluorinated diazoalkanes are excellent precursors for the introduction of gem-difluoro olefins via a C-H functionalization and fluoride elimination reaction cascade using Pd(II)- or Cu(I)-based catalysts. This approach allowed the access of a variety of important gem-difluoro olefins with important applications in drug discovery and medicinal chemistry. The further exploration of C-H functionalization reaction of heterocycles led to the discovery of Au(I)-catalyzed, site-selective C-H functionalization of unprotected carbazole as well as multi-C-H functionalization reactions that consist of up to six C-H functionalization reaction events. In the presence of Rh(II)-catalysts, we were could identify that highly efficient stereoselective cyclopropenation reactions can be achieved, where we could show a markedly distinct reactivity of fluorinated and estersubstituted donor/acceptor diazoalkanes in oligo-cyclopropenation reactions. Further research was focused on rearrangement reactions of organoselenium compounds, where we observed a poor reactivity of fluorinated donor/acceptor diazoalkanes. In contrast, these reactions could be readily achieved when using ester-substituted diazoalkanes. In another part of this research project, we could identify that photochemical properties of diazoalkanes can be used in cyclopropenation reactions of terminal alkynes via free carbene intermediates. Such reactivity could be expected, however, there had been very little precedence in the organic synthesis literature on the photochemical applications of diazoalkanes in organic synthesis. This unexpected result was not planned in this research proposal, but opened up an important research program in our group and world-wide with several research groups focusing on photochemical reactions of diazoalkanes today.
Publications
- “Blue-light induced carbene-transfer reactions of diazoalkanes” Angew. Chem. Int. Ed. 2019, 58, 1203–1207; Angew. Chem. 2019, 131, 1216–1220
R. Hommelsheim, Y. Guo, Z. Yang, C. Empel, R. M. Koenigs
(See online at https://doi.org/10.1002/anie.201811991 https://doi.org/10.1002/ange.201811991) - “C−H functionalization reactions of unprotected N-heterocycles by gold-catalyzed carbene transfer” ACS Catal. 2020, 10, 9925−9931
S. Jana, C. Empel, C. Pei, P. Aseeva, T. V. Nguyen, R. M. Koenigs
(See online at https://doi.org/10.1021/acscatal.0c02230) - “Synthesis of gem-difluoro olefins through C−H functionalization and β-fluoride elimination reactions” Angew. Chem. Int. Ed. 2020, 59, 5572–5576; Angew. Chem. 2020, 132, 5620-5624
Z. Yang, M. Möller, R. M. Koenigs
(See online at https://doi.org/10.1002/anie.201915500 https://doi.org/10.1002/ange.201915500) - “Synthesis of trifluoromethylated tetrasubstituted allenes via palladium-catalyzed carbene transfer reaction” Org. Lett. 2020, 22, 7300−7304
C. Pei, Z. Yang, R. M. Koenigs
(See online at https://doi.org/10.1021/acs.orglett.0c02638)
