We report the palladium-catalyzed gem-difluoroallylation of aryl halides and pseudo halides with 3,3-difluoroallyl boronates in high yield with high regioselectivity, and we report the preparation of the 3,3-difluoroallyl boronate reactants by a copper-catalyzed defluorinative borylation of inexpensive gaseous 3,3,3-trifluoropropene with bis(pinacolato)diboron. The gem-difluoroallylation of aryl and heteroaryl bromides proceeds with low catalyst loading (0.1 mol % [Pd]) and tolerates a wide range of functional groups, including primary alcohols, secondary amines, ethers, ketones, esters, amides, aldehydes, nitriles, halides, and nitro groups. This protocol extends to aryl iodides, chlorides, and triflates, as well as substituted difluoroallyl boronates, providing a versatile synthesis of gem-difluoroallyl arenes that we show to be valuable intermediates to a series of fluorinated building blocks.The difluoromethylene (CF 2 ) unit can be used to fine-tune the physical, chemical, and biological properties of pharmaceuticals, agrochemicals, and materials. [1] This unit can serve as a bioisostere for an ether linkage or a keto group in pharmaceuticals, [2] and, when positioned at a benzylic site, it can block metabolic oxidation at otherwise labile benzylic CÀH bonds. [2] Difluoromethylene groups also have been used to alter the lipophilicity and ground-state conformation of organic molecules. [2] Compounds containing difluoromethylene groups even serve as valuable reactants, for example undergoing CÀF bond activation during reactions that form alkyl fluorides. [3] However, the installation of a difluoromethylene group poses synthetic challenges. Classical approaches to access 1,1difluoroalkanes, such as the deoxyfluorination of ketones with DAST or Deoxo-Fluor , [4] the fluorodesulfurzation of dithianes, [5] and the hydrofluorination of alkynes, [6,7] typically proceed in low yield and exhibit poor functional group tolerance. Recently, difluoroalkylations catalyzed by transition-metal complexes have provided an alternative, convergent route to access compounds containing the difluoro-methylene group. [8] Among these, difluoroallylations are notable for their ability to simultaneously install a difluoromethylene group and a versatile alkene functional group. In 2014, Zhang et al. reported the palladium-catalyzed coupling of arylboron reagents 1 and 3-bromo-3,3-difluoropropene (2) to provide synthetically versatile gem-difluoroallyl arenes 3 (Scheme 1 a). [9] Similarly, Feng et al. demonstrated that aryl boronic acids 4 undergo cross-coupling with 2-aryl difluoroallyl quaternary ammonium salts 5 to provide 2-aryl difluoroallyl arenes 6 (Scheme 1 b). [10] However, the arylboron reagents used in these reactions as the source of the aryl group are much less available than aryl halides and the 3bromo-3,3-difluoropropene reagent used as the source of the difluoroallyl group in one protocol is expensive; [11] it is prepared from dibromodifluoromethane and ethylene by Scheme 1. Background on the difluoroallylation of a...

The direct, catalytic arylation of simple arenes in small excess with aryl bromides is disclosed. The developed method does not require the assistance of directing groups and relies on a synergistic catalytic cycle in which phosphine-ligated silver complexes cleave the aryl C−H bond, while palladium catalysts enable the formation of the biaryl products. Mechanistic experiments, including kinetic isotope effects, competition experiments, and hydrogen-deuterium exchange, support a catalytic cycle in which cleavage of the C−H bond by silver is the rate-determining step.

The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (-)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe-Schmitt reaction and an oxa-Pictet-Spengler reaction. The hetero-Diels-Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested.

An asymmetric Claisen rearrangement using Oppolzer’s camphorsultam was developed. Under thermal conditions, a geraniol-derived substrate underwent the rearrangement with good stereoselectivity. The absolute configuration of the newly formed all-carbon quaternary stereocenter was confirmed by the total synthesis of (+)-bakuchiol from the rearrangement product.