Synthesis of 3-alkyl-6-methyl-1,2,4,5-tetrazines via a Sonogashira-type cross-coupling reaction.

1,2,4,5-Tetrazines have become extremely useful tools in chemical biology. However, the synthesis of some challenging substrates such as asymmetrically disubstituted alkyltetrazines is still a limitation for the widespread use of this class of compounds. Herein we describe an efficient route to these compounds based on the Sonogashira coupling of 3-bromo-6-methyl-1,2,4,5-tetrazine and 3-bromo-6-phenyl-1,2,4,5-tetrazine with terminal alkynes. The preparation of the starting reagents has also been optimized. The alkynyl products have been used as intermediates for the synthesis of dialkyl-tetrazines through a sequence of hydrogenation and re-oxidation with unprecedented yields. The synthetic applicability of this new approach is showcased through the preparation of several unnatural amino acids bearing alkynyl- and alkyl-1,2,4,5-tetrazine fragments.

Dialkylammonium tert-Butylmethylphosphinites: Stable Intermediates for the Synthesis of P-Stereogenic Ligands.

The preparation of shelf-stable crystalline salts of tert-butylmethylphosphinous acid borane 1 is described. X-ray analysis of diisopropylammonium tert-butylmethylphosphinite borane 6 revealed the presence of a cyclic hydrogen-bond network in the solid state which accounts for an increased melting point and stability. Dialkylammonium phosphinite boranes are convenient precursors of the chiral tert-butylmethylphosphine fragment. Compound 6 can be used directly in SN2@P reactions with various nucleophiles to yield valuable P-stereogenic intermediates and ligands.

P-Stereogenic bisphosphines with a hydrazine backbone: from N-N atropoisomerism to double nitrogen inversion.

The synthesis of P-stereogenic bisphosphine ligands starting from a phosphinous acid chiral synthon and hydrazine is reported. The dialkylation of the hydrazine backbone yielded atropo- and nitrogen inversion isomers which are in slow exchange. The crystallization of one of the isomers allowed us to study the reaction kinetics of the equilibria. The new ligands were tested in the Rh catalysed asymmetric hydrogenation of various benchmark substrates attaining up to 99% ee.

Silacyclopropylideneplatinum(0) Complex as a Robust and Efficient Hydrosilylation Catalyst.

The base-stabilized silacyclopropylidene 1 behaves as a versatile strongly nucleophilic ligand toward transition metals. The strong silylene-metal binding related to both increased σ-donating and π-accepting character of silylene 1 compared to N-heterocyclic carbenes (NHCs) allowed the synthesis of robust and air-stable silylene complexes. Of particular interest, the corresponding platinum(0) complex 6 exhibits high stability and a high level of selectivity and catalytic activity in hydrosilylation reactions that is superior to that of the related NHC-Pt(0) complexes.

Well-Defined and Robust Rhodium Catalysts for the Hydroacylation of Terminal and Internal Alkenes.

A Rh-catalyst system based on the asymmetric ligand (t)Bu2PCH2P(o-C6H4OMe)2 is reported that allows for the hydroacylation of challenging internal alkenes with ß-substituted aldehydes. Mechanistic studies point to the stabilizing role of both excess alkene and the OMe-group.

Biomedical properties of a series of ruthenium-N-heterocyclic carbene complexes based on oxidant activity in vitro and assessment in vivo of biosafety in zebrafish embryos.

N-Heterocyclic carbene (NHC) ligands have attracted great interest over the last decade for their use in the design of homogenous catalysts. NHC-based metal complexes have interesting potential biomedical applications, such as in antimicrobial and cancer therapy, which are beginning to be explored more fully. We have studied here the oxidant activities of a series of Ru(II) complexes in vitro and zebrafish (Danio rerio) have been used as a model in vivo to investigate and characterize the toxicity of some of these compounds. Dual behavior was observed for the NHC-based complexes as they behaved as antioxidants at low concentrations but showed pro-oxidant capacity at higher concentrations. Zebrafish embryos were exposed to Ru(II) complexes under several different conditions (0 or 24 h postfertilization, with or without the chorion) and various parameters, such as viability, edema, heart rate, blood coagulation, pigmentation, scoliosis, malformation, and hatching, were tested. In general, zebrafish embryos were not harmed by exposure to Ru(II) complexes whatever the experimental conditions. Several toxicity profiles were observed depending upon the chemical structure of the compound in question. Their characteristics as pro-oxidant and/or antioxidant agents together with their biosafety may point to their having biomedical applications as antitumoral or neuroprotective drugs.

A simple catalyst for the efficient benzylation of arenes by using alcohols, ethers, styrenes, aldehydes, or ketones.

One catalyst fits all! One catalyst is active for a wide set of benzylating reactions (see scheme). A tandem process allows the use of aldehydes and ketones as benzylating agents.The compound [IrCp*(OTf)(2)(I(nBu))] (I(nBu)=1,3-di-n-butyl-imidazolylidene) is an effective catalyst in the benzylation of arenes with different benzylating agents, such as alcohols, ethers and styrenes, representing an unprecedented highly versatile catalyst for this type of process. The same compound also catalyses a remarkable tandem process that allows the use of aldehydes and ketones as benzylating agents, through the base-free hydrogenation of C==O bonds with iPrOH and further use of the resulting primary or secondary alcohols as benzylating agents.

[IrCl(2)Cp*(NHC)] complexes as highly versatile efficient catalysts for the cross-coupling of alcohols and amines.

A comparative study on the catalytic activity of a series of [IrCl(2)Cp*(NHC)] complexes in several C-O and C-N coupling processes implying hydrogen-borrowing mechanisms has been performed. The compound [IrCl(2)Cp*(I(nBu))] (Cp*=pentamethyl cyclopentadiene; I(nBu)=1,3-di-n-butylimidazolylidene) showed to be highly effective in the cross-coupling reactions of amines and alcohols, providing high yields in the production of unsymmetrical ethers and N-alkylated amines. A remarkable feature is that the processes were carried out in the absence of base, phosphine, or any other external additive. A comparative study with other known catalysts, such as Shvo's catalyst, is also reported.