Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

A unique C–H allylation has been discovered with unbiased aliphatic olefins. An intimate M–L affiliation between a high-valent cobalt catalyst and amino-quinoline derived benzamides has been found to be crucial for this unprecedented selectivity. An exemplary set of aliphatic olefins, high yields coupled with excellent regio- and stereoselectivity, and wide functional group tolerances are noteworthy. In addition, a catalytically competent organometallic Co­(III) species has been identified through X-ray crystallography. This study is expected to facilitate new synthetic designs toward unconventional allylic selectivity with aliphatic olefins.

Palladium-catalyzed coupling between aryl halides and alkenes (Mizoroki-Heck reaction) is one of the most popular reactions for synthesizing complex organic molecules. The limited availability, problematic synthesis, and higher cost of aryl halide precursors (or their equivalents) have encouraged exploration of direct olefination of aryl carbon-hydrogen (C-H) bonds (Fujiwara-Moritani reaction). Despite significant progress, the restricted substrate scope, in particular noncompliance of unactivated aliphatic olefins, has discouraged the use of this greener alternative. Overcoming this serious limitation, we report here a palladium-catalyzed chelation-assisted ortho C-H bond olefination of phenylacetic acid derivatives with unactivated, aliphatic alkenes in good to excellent yields with high regio- and stereoselectivities. The versatility of this operationally simple method has been demonstrated through drug diversification and sequential C-H olefination for synthesizing divinylbenzene derivatives.

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Visible-light induced, palladium catalyzeda lkylations of a,b-unsaturated acids with unactivated alkyl bromides are described. Av ariety of primary,s econdary,a nd tertiary alkylb romides are activated by the photoexcited palladium metal catalyst to provide aseries of olefins at room temperature under mild reaction conditions.Mechanistic investigations and density functional theory (DFT) studies suggest that ap hotoinduced inner-sphere mechanism is operative in whichabarrierless,single-electron transfer oxidative addition of the alkyl halide to Pd 0 is key for the efficient transformation.Cross-coupling reactions are one of the most important synthesis tools for the formation of C À Co rC-heteroatom bonds.C onventionally,t hree key steps are involved in the cross-coupling reaction:o xidative addition, transmetalation, and reductive elimination. Often challenges arise in the individual steps,d epending on the coupling partners,m etal catalysts or reaction conditions employed. In recent decades, numerous catalysts,aswell as ligands,have been developed in order to reduce the energy barrier in the bond-forming and breaking steps.More recently,ithas been shown that visiblelight enhances cross-couplings employing radicals. [1] This methodology allows single-electron transfer (SET) to replace the conventional two electron transfer process by using photoredox and transition metal dual-catalytic systems,t hus significantly reducing the barrier for each step in crosscoupling reactions. [2] Despite developments made in crosscoupling chemistry,t he conventional oxidative addition of alkyl electrophiles to Pd 0 remains sluggish, even at elevated temperature,o wing to the electron-rich nature of the alkyl halide bond. [3] In fact, computational studies have revealed that the alkyl bromide oxidative addition to Pd 0 is endothermic with ah igh energy barrier of 41.6 kcal mol À1 .F urther, alkyl-palladium(II) species that are formed through at wo-electron transfer are considerably less stable because of the lack of p-electrons interacting with the empty d-orbitals of the metal. This results in fast b-hydride (b-H) elimination from salkyl-palladium(II) intermediates which outcompetes the required olefin insertion in decarboxylative alkylation crosscoupling reactions. [3,4] In contrast to the photoredox dual-catalysis strategy which promotes cross-coupling by lowering the energy barrier, we now report the use of am echanistically distinct, SET barrierless oxidative addition strategy for alkylation of vinylic acids,using Pd complexes as both photosensitizer and cross-coupling catalyst. [5] This lowers the oxidative addition barrier resulting in an alkyl radical and aP d I intermediate (Figure 1) which can add to an a,b-unsaturated acids. Subsequent carbon dioxide elimination provides the akylated olefin and the regenerated catalyst. To the best of our knowledge,avisible light-induced palladium catalyzed decarboxylative C(sp 3 ) À C(sp 2 )c ross-coupling alkylation has not been reported.Vinylic acids are readily available and stable,...

An efficient method for stereoselective nitroaminoxylation of alkyne has been reported. The reaction enjoys a broad substrate scope, good functional group tolerance, and high yields. Synthetically useful α-nitroketones can be accessed through these products in a single step.

Photoacoustic imaging (PAI) is increasingly employed in (pre‐) clinical research, thus, development of suitable contrast agents, in particular fluorescence‐quenched chromophores, for PAI is of high importance. Small molecule dyes are appropriate due to favorable circulation, excretion properties, and ease of conjugation to targeting moieties. The BODIPY chromophores have been widely used in bioimaging, yet they are not ideal for PAI due to high fluorescence. Hence, here nonfluorescent BODIPY are designed by 1H‐pyrrole conjugation (PyBODIPY) to apply as probes for PAI. The PyBODIPYs exhibit absorption maxima up to 800 nm, and PA signal could be detected in concentrations of 1 nmol mL−1 and 35 pmol mm−3, by tube and tissue phantom, respectively. In addition to nonfluorescent, PyBODIPYs are non‐phototoxic, photostable, and show high molar extinction coefficients, as well as inertness toward nucleophilic addition. PyBODIPYs are modified with PEG‐400, to improve aqueous solubility and to enable in vivo imaging. Thus, PyBODIPY is an attractive small molecule to use as PA contrast agent, which could be coupled to targeting ligands for in vivo use. In addition, 1H‐pyrrole conjugation might be applied to the design of novel near‐infrared ranged quenchers suitable for PAI, and promote the development of probes for clinical translation.