Pd-Catalyzed Oxy- and Aminoalkynylation of Olefins

Continuous progress in organic synthesis significantly relies on the design of novel efficient, selective and flexible synthetic methods to access molecular targets of increasing complexity. The metal-catalyzed multifunctionalization of non-activated alkenes constitutes an effective approach to the generation of complex structures from simple, readily available starting materials. Unprecedented in this context, the development of palladium-catalyzed intramolecular alkene heteroalkynylation reactions is herein reported for the effective synthesis of propargyl heterocycles.

The exceptionally large number of reactions available for the derivatization of acetylenes accounts for their increasing importance not only in organic synthesis, but also in other research domains, including chemical biology and material science. Although the classical strategies for the introduction of alkynyl groups are based on the nucleophilic character of terminal acetylenes, new synthetic opportunities have been disclosed by recent achievements in the field of electrophilic acetylene transfer. Alkynyl halides and hypervalent iodine compounds have been successfully used in the alkynylation of carbon nucleophiles, often with the aid of palladium catalysis.

On the other hand, the use of palladium catalysis has been extensively investigated as an efficient strategy for the difunctionalization of alkenes. Both PdII/PdIV and Pd0/PdII catalytic systems have been reported for these transformations, in which the suitable functionalization of a putative PdII-alkyl intermediate is achieved prior to β-hydride elimination. In the present dissertation, palladium catalysis was employed to couple the electrophilic alkynylation of C=C double bonds with the formation of new carbon-heteroatom bonds.

The Pd-catalyzed oxyalkynylation of ortho-allyl phenols using hypervalent iodine alkynylation reagents was initially investigated. Best results were obtained with triisopropylsilyl 1-ethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as the source of electrophilic acetylene. An electron-poor palladium catalyst (PdII hexafluoroacetyl acetonate, Pd(hfacac)2) and dichloromethane as the solvent were required for the successful outcome of the reaction, which could be efficiently run under open-flask conditions (no need for inert atmosphere or anhydrous solvent). A large variety of propargyl dihydrobenzofurans were obtained in good to excellent yields. The method could be further extended to the synthesis of propargyl lactones by cyclization of alkenyl carboxylic acids. The reaction worked especially well with pentenoic acids. In this case, the oxyalkynylation of monosubstituted C=C double bond afforded excellent yields in spite of the competing β-hydride elimination. A possible mechanism for this transformation relies on a PdII/PdIV catalytic cycle involving oxidative alkynyl transfer from TIPS-EBX to the PdII nucleopalladation intermediate followed by reductive elimination from the resultin