Organic synthesis | EPFL Graph Search

Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one of the most important branches of organic chemistry. There are several main areas of research within the general area of organic synthesis: total synthesis, semisynthesis, and methodology. Total synthesis Total synthesis A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available petrochemical or natural precursors. Total synthesis may be accomplished either via a linear or convergent approach. In a linear synthesis—often adequate for simple structures—several steps are performed one after another until the molecule is complete; the chemical compounds made in each step are called synthetic intermediates. Most often, each step in a synthesis ref

Ligand synthesis for homogeneous catalysis

Michael Maurin

Organophosphorus compounds found applications in varied fields of the organic chemistry: they are particularly present in natural compounds such as the deoxyribonucleic acid (DNA) and in the field of catalysis in which their utility is also proven. Thus, this thesis work first focused on the preparation of various phosphorus ligands utilizable in transition metal catalysed reactions. Being given the importance of this type of reaction in organic synthesis, it appears essential to have many ligands at disposal in order to fine-tune and to optimize the reaction conditions as much as possible. Thus, the first objective of this work was to propose a simple and general method for the preparation of monodentate phosphorus ligands. Based on the use of phosphites in substitution for the usual phosphorus trihalides, this method was initially tested during the preparation of different simple triarylphosphines. Thereafter, this method was extended to the synthesis of new ligands having more complex structures. The yields obtained for the latter as well as the variety of the substrates authorized by this method confirmed its value and suggested its application to the synthesis of new heteroaromatic phosphines. The preparation of bidentate phosphorus ligands based on chiral biphenyl motifs was then addressed. For that purpose, the 2,2',6,6' -tetrabromobiphenyl was chosen as a pivot substrate for the development of a modular synthetic approach. Indeed, by means of successive halogen/metal permutational exchanges and after treatment with the suitable electrophile, it was possible to functionalize this substrate, isolate each atropisomer in enantiomerically pure form, and finally convert each one of those into chiral biphenylbisphosphines. In addition, it was also possible, during the synthesis of these ligands, to evaluate the rotational stability of some enantiomerically pure dilithiobiphenyls by means of dynamic nuclear magnetic resonance experiments.

EPFL2007

In Situ Tethering Strategies for the 3-Component Synthesis of Vicinal Amino Alcohols and Diamines via Pd-Catalyzed Carboetherification and Carboamination

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

One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ Aminal Formation and Carboamination

Ugo Jonathan Orcel, Jérôme Waser

A synthesis of vicinal diamines via in situ aminal formation and carboamination of allyl amines is reported. Employing highly electron-poor trifluoromethyl aldimines in their stable hemiaminal form was key to enable both a fast and complete aminal formation as well as the palladium-catalyzed carboamination step. The conditions developed allow the introduction of a wide variety of alkynyl, vinyl, aryl, and hetereoaryl groups with complete regioselectivity and high diastereoselectivity. The reaction exhibits a high functional-group tolerance. Importantly, either nitrogen atom of the imidazolidine products can be selectively deprotected, while removal of the aminal tether can be achieved in a single step under mild conditions to reveal the free diamine. We expect that this work will promote the further use of mixed aminal tethers in organic synthesis.

2016