Palladium-Catalyzed Functionalization of Olefins and Alkynes: From Oxyalkynylation to Tethered Dynamic Kinetic Asymmetric Transformations (DYKAT)

This review presents an account of the palladium-catalyzed functionalizations of alkenes and alkynes developed at the Laboratory of Catalysis and Organic Synthesis (LCSO). Starting from the intramolecular oxy- and aminoalkynylation of alkenes, tethered methods were then developed to functionalize allylic amines and alcohols, as well as propargylic amines. Finally, a new dynamic kinetic asymmetric transformation was developed based on the use of a 'one-arm' Trost-type ligand, giving access to enantiopure amino alcohols. Each section is a personal account by the researcher(s) who performed the work. 1 Introduction, 2 Oxy- and Aminoalkynylation of Olefins, 3 In Situ Tethering Strategies for the Synthesis of Vicinal Amino Alcohols and Diamines, 4 Carboamination of Allylic Alcohols, 5 Carbooxygenation of Propargylic Amines, 6 Enantioselective Carboetherification/Hydrogenation via a Catalytically Formed Chiral Auxiliary, 7 Conclusion

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

Cyclopropanes and Hypervalent Iodine Reagents: High Energy Compounds for Applications in Synthesis and Catalysis

Jonathan Brand, Filippo De Simone, Stefano Nicolai, Jérôme Waser

One of the major challenges faced by organic chemistry is the efficient synthesis of increasingly complex molecules. Since October 2007, the Laboratory of Catalysis and Organic Synthesis (LCSO) at EPFL has been working on the development of catalytic reactions based on the Umpolung of the innate reactivity of functional groups. Electrophilic acetylene synthons have been developed using the exceptional properties of ethynyl benziodoxolone (EBX) hypervalent iodine reagents for the alkynylation of heterocycles and olefins. The obtained acetylenes are important building blocks for organic chemistry, material sciences and chemical biology. The ring-strain energy of donor-acceptor cyclopropanes was then used in the first catalytic formal honno-Nazarov cyclization. In the case of aminocyclopropanes, the method could be applied in the synthesis of the alkaloids aspidospermidine and goniomitine. The developed methods are expected to have a broad potential for the synthesis and functionalization of complex organic molecules, including carbocycles and heterocycles.

2011

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.