Heck Reaction of 2-Oxyacrylates with Aryl Bromides: A Common Route to Monoaryl Pyruvates and Ortho Ester-Protected Monoaryl Pyruvates.

A palladium-catalyzed Heck reaction between 2-oxyacrylates and aryl bromides was developed, where DavePhos was a unique ligand that efficiently promoted the reaction. The products, 2-oxycinnamates, served as excellent precursors, providing synthetically useful monoaryl pyruvates or ortho ester-protected monoaryl pyruvates depending on the nature of the 2-oxy group. The formation of such ortho esters via alkoxide addition is novel, and computational studies identified a plausible mechanism with an oxyallyl zwitterion as the key intermediate.

Fluoroenesulphonamides: N-sulphonylurea isosteres showing nanomolar selective cancer-related transmembrane human carbonic anhydrase inhibition.

After hydrofluorination of ynesulphonamides in superacid or in the presence of hydrofluoric acid/base reagents, a series of α-fluoroenamides has been synthesised and tested for the inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms. This study reveals a new, highly selective family of cancer-related transmembrane human (h) CA IX/XII inhibitors. These original fluorinated ureido isosters do not inhibit the widespread cytosolic isoforms hCA I and II and selectively inhibit the transmembrane cancer-related hCA IX and XII, offering interesting new leads for future studies.

Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects.

3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors.

Synthesis of aryl tri- and difluoromethyl thioethers via a C-H-thiocyanation/fluoroalkylation cascade.

An AlCl3 -catalyzed CH thiocyanation was discovered and combined with a Langlois-type trifluoromethylation to afford aryl trifluoromethyl thioethers directly from arenes, N-thiocyanatosuccinimide (NTS) and Ruppert-Prakash reagent. An analogous combination with a copper-mediated difluoromethylation gives access to aryl difluoromethyl thioethers. Both processes proceed with exceptional regioselectivity for the most electron-rich, sterically least hindered position of the arene. The sulfur and fluoroalkyl groups originate from different sources, so that the use of expensive, preformed fluoroalkylthiolation reagents is avoided.

Synthesis of difluoromethyl thioethers from difluoromethyl trimethylsilane and organothiocyanates generated in†situ.

A copper-CF2 H complex generated in situ from copper thiocyanate and TMSCF2 H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups-a largely unexplored substituent with highly promising properties-into drug-like molecules.

Chemo- and stereoselective synthesis of fluorinated enamides from ynamides in HF/pyridine: second-generation approach to potent ureas bioisosteres.

(E)- and (Z)-α-fluoroenamides could be easily prepared with high levels of chemo- and regioselectivities by hydrofluorination of readily available ynamides with HF/pyridine. The scope and limitations of this new process for the hydrofluorination of ynamides, as well as the stability of the resulting α-fluoroenamides, have been extensively studied. Theoretical calculations at the MP2 and B3LYP levels of theory showed that the resulting fluoroenamides exhibit geometrical and electronic properties that partially mirror those of ureas, therefore demonstrating that the hydrofluorination of ynamides provides a general, straightforward, and user-friendly approach to bioisosteres of ureas, potent building blocks for biological studies and medicinal chemistry.

Sandmeyer difluoromethylation of (hetero-)arenediazonium salts.

A Sandmeyer-type difluoromethylation process has been developed that allows the straightforward conversion of (hetero-)arenediazonium salts into the corresponding difluoromethyl (hetero-)arenes under mild conditions. The actual difluoromethylating reagent, a difluoromethyl-copper complex, is formed in situ from copper thiocyanate and TMS-CF2H. The diazonium salts are either preformed or generated in situ from broadly available aromatic amines.

Unprecedented synthesis of alkynylphosphine-boranes through room-temperature oxidative alkynylation.

An original and user-friendly synthesis of alkynylphosphine-boranes, useful building blocks in organic synthesis, based on an oxidative P-alkynylation reaction with readily available copper acetylides is reported. The ability of a secondary phosphine protected with a borane to undergo oxidative coupling without oxidation of the P-moiety is demonstrated for the first time. The reaction, which proceeds at room temperature, is applicable to the preparation of enantioenriched and structurally complex alkynylphosphine-boranes.

Stereoselective hydrofluorination of ynamides: a straightforward synthesis of novel α-fluoroenamides.

α-Fluoroenamides, potent rigid fluorinated bioisosters of ureas, have been synthesized by a highly regio- and stereo-selective hydrofluorination of ynamides in anhydrous HF. This reaction provides the first general entry to α-fluoroenamides and can easily be applied to a wide range of substrates.

Copper-catalyzed coupling of 1,1-dibromo-1-alkenes with phenols: a general, modular, and efficient synthesis of ynol ethers, bromo enol ethers, and ketene acetals.

An efficient and general copper-catalyzed method is reported for the synthesis of phenol-derived 1-bromoenol ethers, ynol ethers, and ketene acetals by chemodivergent copper-catalyzed cross-coupling between readily available 1,1-dibromo-1-alkenes and phenols.

Copper-catalyzed alkynylation of amides with potassium alkynyltrifluoroborates: a room-temperature, base-free synthesis of ynamides.

An efficient copper-mediated method for the coupling of potassium alkynyltrifluoroborates with nitrogen nucleophiles is reported. This reaction provides the first base-free and room-temperature synthesis of ynamides and allows for an easy preparation of these useful building blocks.

Ynamides: versatile tools in organic synthesis.

Ynamides display an exceptionally fine balance between stability and reactivity. They also offer unique and multiple opportunities for the inclusion of nitrogen-based functionalities into organic molecules, and are emerging as especially useful and versatile building blocks for organic synthesis. Recent breakthroughs in the preparation of these substrates have revitalized interest in nitrogen-substituted alkynes, and the beginning of the 21st century has witnessed an ever-increasing number of publications reporting the development of new reactions or synthetic sequences starting from ynamides. This Review highlights major developments in this area.

Scope and limitations of imidazolium-based ionic liquids as room temperature glycosylation promoters.

The scope and limitations of imidazolium-based ionic liquids as room temperature glycosylation promoters have been studied. Herein, we report the effects of modifying the structure of the imidazolium cation and how important the choice of counter ion becomes on model glycosylation reactions of thioglycosides at room temperature in the presence of N-iodosuccinimide (NIS).