Catalytic enantioselective decarboxylative protonation

We report a highly enantioselective, general catalytic system for the facile synthesis of tertiary stereocenters by protonation adjacent to cyclic ketones. The method relies on catalytic decarboxylative protonation of readily accessible racemic quaternary beta-ketoesters. A range of substituted cycloalkanone compounds can be accessed through this process with high levels of enantioselectivity.     

Palladium-catalyzed decarboxylative sp3-sp3 coupling of nitrobenzene acetic esters

Allylic esters of nitrobenzene acetic acids undergo facile palladium-catalyzed decarboxylative coupling. Both mono- and dinitroarene substrates give high yields of the coupled products. Moreover, the rates of the reactions suggest that decarboxylation is rate-limiting and substrates that sterically disfavor attainment of the reactive conformation for decarboxylation are not viable. Finally, reduction of the product nitroarenes to the corresponding anilines provides access to a variety of heterocycles including quinolines and dihydroquinolones.     

Synthesis of valsartan via decarboxylative biaryl coupling

An efficient synthesis of the angiotensin II inhibitor valsartan (Diovan) is presented. Two routes were evaluated, both making use of an advanced version of our decarboxylative coupling for the construction of the biaryl moiety. Thus, in the presence of a catalyst system consisting of copper(II) oxide, 1,10-phenanthroline, and palladium(II) bromide, 2-cyanocarboxylic acid was coupled with 1-bromo(4-dimethoxymethyl)benzene in 80% yield and with 4-bromotoluene in 71% yield. The valsartan synthesis using 1-bromo(4-dimethoxymethyl)benzene was completed in four steps overall with a total yield of 39%, via a novel route that presents substantial economical and ecological advantages over the literature process, as it is more concise and stoichiometric amounts of expensive organometallic reagents are avoided.     

Synthesis of allyl selenides by palladium-catalyzed decarboxylative coupling

This communication details the Pd-catalyzed decarboxylation of selenocarbonates; use of a chiral nonracemic catalyst affords enantioenriched allyl selenides which undergo stereospecific [2,3]-sigmatropic rearrangements to form enantioenriched allylic amines and chlorides.     

Palladium-catalyzed decarboxylative coupling of isatoic anhydrides with arylboronic acids

The decarboxylative coupling of isatoic anhydrides with arylboronic acids was realized for the first time in the presence of Pd(2)(dba)(3) and DPEphos, achieving aryl o-aminobenzoates with yields ranging from moderate to good. The efficiency of this procedure was demonstrated by good compatibility with fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, formacyl, acetyl, thienyl, and naphthyl groups. Preliminary mechanistic experiments using deuterium labeling showed that the oxygen atom was derived from dioxygen.     

A domino desulfitative coupling and decarboxylative coupling of 3, 4-dihydropyrimidine-2-thiones with copper(I) carboxylates

A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between 3,4-dihydropyrimidine-2-thiones and copper(I) carboxylates were performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative reagents but also as sources of carbon nucleophiles. A wide array of highly substituted and functionalized pyrimidines scaffolds were synthesized in good yields.     

Palladium-catalyzed decarboxylative coupling of potassium nitrophenyl acetates with aryl halides

A palladium-catalyzed decarboxylative cross-coupling of potassium 2- and 4-nitrophenyl acetates with aryl chlorides and bromides has been developed. Because the nitro group can be readily converted to many other functional groups, the new reaction provides a useful method for the preparation of diverse 1,1-diaryl methanes and their derivatives.     

Regioselective Cu(I)-catalyzed tandem A3-coupling/decarboxylative coupling to 3-amino-1,4-enynes

An efficient and novel copper-mediated protocol for the synthesis of 3-amino-1,4-enynes from glyoxylic acid, an amine, and an alkyne was developed. This new reaction involving two sequential C-C bond formations is air and moisture tolerant and proceeds via a tandem A(3)-coupling and a selective decarboxylative coupling.     

Copper-catalyzed decarboxylative coupling reactions for the synthesis of propargyl amines

When aryl alkynyl carboxylic acids were allowed to react with amines and aldehydes in CH₃CN at 80 °C in the presence of 10 mol % CuI, the desired propargyl amines were formed in good yields. This coupling reaction demonstrated to work across a broad range of reagents including functionalized aryl alkynyl carboxylic acids, aliphatic and aromatic aldehydes, and cyclic and acyclic amines.     

Palladium-catalyzed decarboxylative coupling of benzoic acid derivatives using hydrazone ligands

Palladium-catalyzed decarboxylative coupling of benzoic acid derivatives with arylboroxins gave biaryls using a catalytic amount of Pd(TFA)₂–hydrazone 1d system with Ag₂CO₃ at 80 °C in good yields. We also found that decarboxylative coupling with aryl(trialkoxy)silanes gave biaryls using a Pd(TFA)₂–hydrazone 1g system with AgF in good yields.     

Copper-catalyzed decarboxylative Se insertion coupling of indoles and propiolic acids

A novel and efficient copper-catalyzed decarboxylative alkynylselenation of indoles with Se powder and propiolic acids has been developed. The outstanding advantages of this protocol not only nicely avoid the use of prefabricated arylselenation reagent and address the facile over-selention issues, but also enrich the chemistry of selenium powder. Importantly, this reaction could be extended to pyrrole, and the practical utility of this transformation has been demonstrated in gram-scale synthesis and late-stage indolylselenation of Clofibrate-derived propiolic acid.     

Nickel-catalyzed decarboxylative coupling of an alkynyl carboxylic acid with aryl iodides

A decarboxylative coupling reaction with an alkynyl carboxylic acid and aryl iodides in the presence of a nickel catalyst was developed. When the reaction was conducted with NiCl₂ (10 mol%), Xantphos (15 mol%), Mn (1.0 equiv), and Cs₂CO₃ (1.5 equiv), the desired diaryl alkynes were formed in moderated to good yields. Furthermore, this method does not produce the diyne, which is formed in the homocoupling of alkynyl carboxylic acids.     

Copper-catalyzed decarboxylative C(sp2)-C(sp3) coupling reactions via radical mechanism

We have successfully developed an example of copper-catalyzed decarboxylative C(sp(2))-C(sp(3)) coupling reactions via C-H functionalization for the first time. It is noteworthy that our catalytic system is very stable, low-cost, palladium-free, ligand-free, and easily accessible.     

Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates with aryl halides

A new strategy for the regiospecific construction of unsymmetrical biaryls is presented, in which easily available salts of carboxylic acids are decarboxylated in situ to give arylmetal species that serve as the nucleophilic component in a catalytic cross-coupling reaction with aryl halides. The catalyst system consists of a copper phenanthroline complex that mediates the extrusion of CO2 from aromatic carboxylates to generate arylcopper species, and a palladium complex that catalyzes the cross-coupling of these intermediates with aryl halides. This bimetallic system allows the direct coupling of various aryl, heteroaryl, or vinyl carboxylic acids with aryl or heteroaryl iodides, bromides, or chlorides at 160 degrees C in the presence of a mild base such as potassium carbonate. The present scope and potential economic impact of the reaction are demonstrated by the synthesis of 42 biaryls, some of which are of substantial industrial relevance. Remaining challenges and future perspectives of the new transformation are discussed.     

Highly effective copper-catalyzed decarboxylative coupling of aryl halides with alkynyl carboxylic acids

We have developed a highly effective copper-catalyzed decarboxylative coupling of alkynylcarboxylic acids with various aryl and alkyl halides at 2 mol% loading of copper. This method is simple, economical and practical for the synthesis of disubstituted alkyne compounds.     

Copper-catalyzed decarboxylative coupling of aryl halides with alkynyl carboxylic acids performed in water

Most alkynes are volatile liquids, which are relatively difficult to use and to transport. In contrast, alkynyl carboxylic acids offer a stable and attractive alternative for the alkynylation reactions. Here, we employed alkynyl carboxylic acids as reaction partners for the alkynylation of aryl halides. Copper-catalyzed decarboxylative coupling, including various challenging aryl bromides with phenylpropiolic acid, was performed in water without using co-solvents with good yields. Our approach provides a low-loading, low-cost, stable and environmentally friendly copper catalyst system for decarboxylative coupling.