Synthesis of 2-Alkynoates by Palladium(II)-Catalyzed Oxidative Carbonylation of Terminal Alkynes and Alcohols

A homogeneous Pd(II) catalyst, utilizing a simple and inexpensive amine ligand (TMEDA), allows 2‐alkynoates to be prepared in high yields by an oxidative carbonylation of terminal alkynes and alcohols. The catalyst system overcomes many of the limitations of previous palladium carbonylation catalysts. It has an increased substrate scope, avoids large excesses of alcohol substrate and uses a desirable solvent. The catalyst employs oxygen as the terminal oxidant and can be operated under safer gas mixtures

Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13

Development of Pd-Catalyzed Alkyne Dimerization and Enyne Benzannulation Methodologies

Dimerization of alkynes represents a fundamental reaction for a straightforward construction of carbon–carbon bonds in atom-economical manner. A general highly regio- and stereoselective palladium-catalyzed head-to-head dimerization reaction of terminal alkynes has been developed. This methodology allows for efficient synthesis of a variety of 1,4-enynes as single E-stereoisomers. Furthermore, an alternative head-to-tail regioselectivity has been observed upon addition of carboxylate salts to the catalytic system. Detailed computational studies revealed that head-to-head dimerization under neutral reaction conditions proceeds via the hydropalladation pathway. It was also found that the regioselectivity of the process in the presence of carboxylate anion switches due to the redirection of the reaction from hydropalladation to carbopalladation pathway and destabilization of intermediate palladium complexes. Based on the DFT calculations, a clear correlation between mechanistic path and the reaction selectivity has been established. These findings are essential for the design of novel synthetic methods based on hydroalkynylation strategy in which hydro- and carbometallation are the competing reaction pathways. Chemo- and regioselective palladium-catalyzed [4+2] benzannulation reaction of conjugated enynes with various alkyne-containing enynophiles represent a powerful atom-economical method for construction of the aromatic ring from easily accessible starting materials. A highly efficient catalytic system for the Pd-catalyzed [4+2] benzannulation of enynes with diynes has been developed. Newly found conditions enabled synthesis of variety of densely substituted arylacetylenes via the cross-benzannulation reaction with turnover number of the catalyst up to 1800. This catalytic system also allowed expanding the scope of homo-benzannulation reaction. Moreover, an efficient method toward fluorinated and perfluoroalkylated densely substituted benzene derivatives based on the Pd-catalyzed [4+2] cross-benzannulation reaction has been established. The utility of obtained products has been also demonstrated by efficient synthesis of various aromatic and heteroaromatic compounds. Thus, this strategy offers a viable and very general alternative to the existing fluorination and perfluoroalkylation methods

Synthesis of Fluoro- and Perfluoroalkyl Arenes via Palladium-Catalyzed [4 + 2] Benzannulation Reaction

An efficient entry into densely substituted fluorinated and perfluoroalkylated benzene derivatives via chemo- and regioselective Pd-catalyzed [4 + 2] cross-benzannulation is presented. The synthetic utility of these products for the synthesis of various aromatic and heteroaromatic compounds is also demonstrated. This strategy offers a viable and quite general alternative to existing fluorination and perfluoroalkylation methods for securing these valuable molecules

General and Selective Head-to-Head Dimerization of Terminal Alkynes Proceeding via Hydropalladation Pathway

A general highly regio- and stereoselective palladium-catalyzed head-to-head dimerization reaction of terminal acetylenes is presented. This methodology allows for the efficient synthesis of a variety of 1,4-enynes as single <i>E</i> stereoisomers. Computational studies reveal that this dimerization reaction proceeds via the hydropalladation pathway

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

Selective carbon–carbon (C–C) bond formation in chemical synthesis generally requires pre-functionalized building blocks. However, the requisite pre-functionalization steps undermine the efficiency of multi-step synthetic sequences, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without pre-functionalized building blocks. This method is facilitated by a tailored P,N-ligand that enables regioselective coupling and suppresses secondary E/Z-isomerization of the product. The transformation enables several classes of unactivated internal acceptor alkynes to be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. The reaction is scalable and can operate effectively with 0.5 mol% catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle