Ugo Jonathan Orcel
Vicinal amino alcohols and diamines are privileged motifs in organic chemistry. As such, they have been targets of choice for exploring and developing novel and more efficient strategies in organic synthesis. In this context, the difunctionalization of olefins provides a rapid and efficient access to these pivotal motifs. In this field, palladium catalysis has been extensively investigated and successful. Methods enabling the concomitant formation of both a C-Heteroatom and a C-C bonds are highly valuable but still rely on tethering strategies. However, extra steps and purifications are often required to install and remove the tether, which is a major limitation. In situ tethering strategies have emerged to circumvent this issue. Nevertheless, such strategies are so far limited to few transformations, especially regarding difunctionalization reactions. In this regard, the goal of my PhD was first to investigate the synthesis of amino alcohols from allylamines via in situ formation of a hemiaminal tether, using an aldehyde, and subsequent Pd-catalyzed carbo-oxygenation of the olefin. Aliphatic secondary allylamines and highly electrophilic trifluoroacetaldehyde ethyl hemiacetal as tethering reagent were identified as a promising combination to access vicinal amino alcohols via the formation of oxazolidines. The optimized conditions involved silyl-protected bromoalkynes as electrophilic partner, [(cinnamyl)PdCp] as palladium source, DPEPhos, XANTPhos or tri(2-furyl)phosphine as ligand, cesium carbonate as base and toluene as solvent. Good diastereoselectivities could be obtained when branched allylamines were employed. The scope was extended to aliphatic alkynyl bromides and slightly activated aryl and vinyl bromides. The obtained oxazolidine products could be conveniently deprotected to access orthogonally the terminal alkyne, the free alcohol, the free amine, and importantly, the free amino alcohol in high yields. This strategy was next applied to the synthesis of 1,2-diamines via the formation of aminal tethers. Carbamate protected trifluoromethyl aldimines in their stable hemiaminal form were identified as highly efficient reagents for both in situ aminals formation from allylamines, and the Pd-catalyzed carboamination process. The optimized conditions involved Pd2dba3 as palladium source, tri(2-furyl)phosphine or PhDavePhos as ligand, cesium carbonate as base and toluene as solvent. Primary and secondary allylamines were efficient partners. Importantly, cesium triflate as additive was key to enable full conversion for amines substituted at their allylic position. Furthermore, the use of this additive in combination with tri(2-furyl)phosphine allowed to introduce a wide variety of aryls and heteroaryls and a vinyl onto the olefin. The imidazolidines obtained could be efficiently and orthogonally deprotected. Notably, full cleavage of the aminal tether could be achieved in excellent yields and without the need of purification by simple treatment of imidazolidines with trifluoroacetic acid at room temperature, followed by addition of methanol. Finally, the latter method was expanded to allyl alcohols in order to access amino alcohols via hemiaminal formation and Pd-catalyzed carboamination reactions. Preliminary results of this in situ process led to moderate yields but pave the way for the development of a highly modular and efficient synthesis of amino alcohols from simple and readily available allyl alcohols.
EPFL2017
