Novel C-H functionalization of arenes: palladium-catalyzed synthesis of diaryl sulfides

A novel protocol for the direct arylthiolation of electron-rich arenes is described. Applying arylsulfonyl cyanides in the presence of catalytic amounts of Pd allows for a straightforward synthesis of diaryl sulfides.     

A convergent synthesis of polysubstituted aromatic nitriles via palladium-catalyzed C-H functionalization

A palladium-catalyzed C-H functionalization reaction for the synthesis of highly substituted aromatic nitriles is reported. The modularity of the reaction is demonstrated by the broad range of aryl iodides which can be coupled with metal cyanides and alkyl halides or aryl bromides.     

Double C-H activation: the palladium-catalyzed direct C-arylation of xanthines with arenes

The novel Pd-catalyzed C(sp(2))-H/C(sp(2))-H cross-coupling of unactivated xanthines with unactivated arenes utilizing a combination of Ag(I) and O(2) as oxidants exclusively yields C-8 arylated xanthines in a single synthetic operation.     

Twofold C-H functionalization: palladium-catalyzed ortho arylation of anilides

The ortho arylation of anilides to form biphenyls via a twofold C-H functionalization/C-C bond-forming process is described. The oxidative coupling takes place in the presence of 5-10 mol % of Pd(OAc)2, 10-20 mol % of DMSO, and 4-11 equiv of the aryl substrate in TFA under an oxygen atmosphere. No metal-containing cocatalyst is required.     

Gold-catalyzed chemo- and site-selective direct C-H functionalization of phenols with diazo compounds

<正>Phenols motifs are used as common versatile synthons in organic synthesis due to their wide availability and low cost.Thus, C-H functionalization of phenols is highly attractive to the community of synthetic chemistry. In the past decade, many methods have been developed via installing a protective group on the hydroxyl to allow for ortho/meta/para functionalization of phenols. One of the most effective methods for direct C-H functionalization is the carbene     

Insights into directing group ability in palladium-catalyzed C-H bond functionalization

This paper describes a detailed investigation of factors controlling the dominance of a directing group in Pd-catalyzed ligand-directed arene acetoxylation. Mechanistic studies, involving reaction kinetics, Hammett analysis, kinetic isotope effect experiments, and the kinetic order in oxidant, have been conducted for a series of different substrates. Initial rates studies of substrates bearing different directing groups showed that these transformations are accelerated by the use of electron-withdrawing directing groups. However, in contrast, under conditions where two directing groups are in competition with one another in the same reaction flask, substrates with electron-donating directing groups react preferentially. These results are discussed in the context of the proposed mechanism for Pd-catalyzed arene acetoxylation.     

C-H functionalization logic in total synthesis

In this critical review, the strategic and economic benefits of C-H functionalization logic will be analyzed through the critical lens of total synthesis. In order to illustrate the dramatically simplifying effects this type of logic can potentially have on synthetic planning, we take the reader through a series of case studies in which it has already been successfully applied. In the first section, a chronological look at key historical syntheses will be examined, leading into modern day examples. In the second section, our own experience with applying and executing synthesis with a C-H functionalization "mindset" will be discussed (114 references).     

Chemical libraries via sequential C-H functionalization of phenols

Phenols provide a useful template for diversification via sequential hydroarylation reactions. Specifically, a protocol has been developed that begins with the hydroarylation of cinnamic acids by 3,5-dimethoxyphenol to produce dihydrocoumarins. This activated ester undergoes facile ring-opening with amines to form a C-N bond and regenerate a phenol. The resulting phenol can be further functionalized via a second hydroarylation reaction. Thus, in 3-4 steps, a phenol is coupled with a cinnamic acid, an amine, and a cinnamic or propiolic acid.     

Highly diastereoselective synthesis of tetrahydropyridines by a C-H activation-cyclization-reduction cascade

A versatile reaction cascade leading to highly substituted 1,2,3,6-tetrahydropyridines has been developed. It comprises rhodium(I)-catalyzed C-H activation-alkyne coupling followed by electrocyclization and subsequent acid/borohydride-promoted reduction. This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity.     

Increasing synthetic efficiency via direct C-H functionalization: formal synthesis of an inhibitor of botulinum neurotoxin

A new and efficient scheme for the synthesis of one of the best known inhibitors of botulinum neurotoxin serotype A (BoNTA) is reported herein. The synthetic route involves two palladium-catalyzed C-H functionalization reactions, formally activating three C-H bonds.     

Palladium-catalyzed C-N bond formation via direct C-H bond functionalization. Recent developments in heterocyclic synthesis

The formation of carbon-nitrogen bonds by reaction between a nitrogen atom and an unactivated carbon-hydrogen bond is a highly atom-economical process that attracted the attention of the chemists in the last two decades. The widely useful amination and hydroamination reactions, which furnish acyclic or cyclic products, give access to various nitrogen-containing basic and fine chemicals. This review highlights recent progress in the development of palladium-catalyzed reactions that occur by direct functionalization of simple carbon-hydrogen bonds to give heterocyclic products. Pd(0)- and Pd(II)-catalyzed reactions are described separately, emphasizing the different behavior of the metal in these two oxidation states.     

Synthesis of unsymmetrically substituted bipyridines by palladium-catalyzed direct C-H arylation of pyridine N-oxides

Substituted bipyridines were efficiently prepared by direct coupling between pyridine N-oxides and halopyridines using a palladium catalyst. Pyridine N-oxides with electron-withdrawing substituents gave the best yields. This method allows the convenient preparation of 2,2'-, 2,3'-, and 2,4'-bipyridines which are useful as functionalized ligands for metal complexes or as building blocks for supramolecular architectures.     

Zipper-mode double C-H activation: palladium-catalyzed direct construction of highly-fused heterocyclic systems

Direct construction of fused aromatic ring systems by "zipper-mode" double C-H bond activation is described. Treatment of (Z)-3-bromo-N-(2-bromo-3-phenylprop-2-enyl)aniline derivatives with a catalytic amount of Pd(OAc)2 and PCy3.HBF4 in the presence of Cs2CO3 in dioxane affords 4,5-naphtho[3,2,1-cd]indole derivatives in good yields. Introduction of heterocycles such as benzofuran, benzothiophene, or indole moieties into the substrates leads to the efficient construction of highly fused heterocyclic aromatic ring systems via C-H bond activation of the heteroaromatic rings.     

Synthesis of nitroxyl radical by direct nucleophilic functionalization of a C-H bond in the azadiene systems

Cyclic dinitrones underwent nucleophilic substitution of the hydrogen atom in the reaction with a paramagnetic carbanion, the lithium derivative of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl 3-oxide, to give polyfunctional nitronyl nitroxyls.     

Silver-mediated palladium-catalyzed direct C-H arylation of 3-bromoisothiazole-4-carbonitrile

Silver(I) fluoride-mediated Pd-catalyzed C-H direct arylation/heteroarylation of 3-bromoisothiazole-4-carbonitrile (1a) gives twenty-four 5-aryl/heteroaryl-3-bromoisothiazole-4-carbonitriles. The reaction was partially optimized with respect to catalyst, ligand, and base. During this study 3,3'-dibromo-5,5'-biisothiazole-4,4'-dicarbonitrile (3a) was isolated as a byproduct and subsequently prepared via the silver-mediated Pd-catalyzed oxidative dimerization of 3-bromoisothiazole-4-carbonitrile in 67% yield. The analogous phenylation and oxidative dimerization of 3-chloroisothiazole-4-carbonitrile (1b) gave 3-chloro-5-phenylisothiazole-4-carbonitrile (4) and 3,3'-dichloro-5,5'-biisothiazole-4,4'-dicarbonitrile (3b) in 96% and 69% yields, respectively.     

Catalytic C-H functionalization driven by CO as a stoichiometric reductant: application to carbazole synthesis

[reaction: see text] A palladium-catalyzed regioselective C-H bond functionalization driven by CO as the stoichiometric reductant is described. Nitrogen heterocycles, e.g., carbazoles, are accessible in good to excellent yields with use of palladium acetate and 70 psig of carbon monoxide at 140 degrees C.