Olivier Gager

Copper-Catalyzed Cross-Coupling of Alkyl and Aryl Grignard Reagents with Alkynyl Halides†

Alkyl–alkynyl cross-coupling can be achieved through one of two pathways. The first one consists in alkylating a metal acetylide with a primary alkyl iodide or bromide. Sodium, potassium, or lithium acetylides have been extensively used, but the reaction suffers from some limitations. As an example, the substitution reaction does not tolerate the presence of reactive functional groups such as esters or nitriles. On the other hand, b-branched primary, secondary, or tertiary alkyl halides mainly undergo an elimination reaction and do not lead to the substitution product, or in only poor yields. The coupling of tertiary alkyl halides with alkynylalanes was reported. However, the method is not general, and only one of the three alkynyl groups is transferred. The alkyl–alkynyl cross-coupling can also be performed according to a second pathway, which involves reacting an alkylmetal with an alkynyl halide. The first attempts were carried out by reacting iodoor bromoalkynes with Grignard reagents in the presence of cobalt salts, or organocopper derivatives. However, poor to moderate yields are generally obtained. Later, a few trialkylaluminium reagents were coupled successfully with alkynyl bromides under nickel catalysis, however only one alkyl group was transferred in moderate to good yields. An interesting general method was described by Yeh and Knochel in 1989, in which functionalized organocuprate reagents, AlkFg–Cu(CN)ZnI (Fg = functional group), react with simple bromoor iodoalkynes to afford functionalized alkynes in good yields. However, the reaction conditions (12–16 h at 65 8C), and the use of a stoichiometric amount of copper are not very convenient for large-scale preparations. The aryl–alkynyl coupling is generally performed by using the well-known Sonogashira reaction between aromatic halides and terminal alkynes in the presence of both copper and palladium salts. In contrast, the coupling of an arylmetal with an alkynyl halide has been almost ignored until now. In 1972, Oliver and Walton studied the reaction of arylcopper reagents with iodo-trimethylsilylacetylene, but the reaction has not been extended to other substrates. In fact, it should be noted that as a rule, no general procedure is currently available to couple aryl or alkyl Grignard reagents with alkynyl halides. Herein we report the first efficient copper-catalyzed alkynylation of alkyl and aryl Grignard reagents. Weedon and co-workers reported that the coppercatalyzed coupling of alkyl Grignard reagents with alkynyl halides only gives poor yields of the substitution product. As mentioned by Normant and co-workers, the halogen/ magnesium exchange generally takes place predominantly. Recently, in the light of our experience in copper-catalyzed cross-coupling reactions with Grignard reagents, we decided to reinvestigate this reaction and we discovered that, in fact, satisfactory yields can be obtained by slowly introducing the Grignard reagent to the reaction mixture. As an example, in the presence of 3 mol % CuCl2 in THF at 0 8C, the addition of nBuMgCl (12 mmol) to heptynyl bromide (10 mmol) over a 45 minute period gave 73 % of 5-undecyne (Table 1, entry 1). To improve this result, we have tested the

Iron Thiolate Complexes: Efficient Catalysts for Coupling Alkenyl Halides with Alkyl Grignard Reagents

Ironing out the kinks: Efficient new catalytic systems based on iron thiolates are described for the iron-catalyzed cross-coupling of alkyl Grignard reagents with alkenyl halides. The reaction is highly chemo- and stereoselective. With this new procedure, the use of N-methylpyrrolidone as a co-solvent is no longer required.

Towards potential nanoparticle contrast agents: Synthesis of new functionalized PEG bisphosphonates

Summary The use of nanotechnologies for biomedical applications took a real development during these last years. To allow an effective targeting for biomedical imaging applications, the adsorption of plasmatic proteins on the surface of nanoparticles must be prevented to reduce the hepatic capture and increase the plasmatic time life. In biologic media, metal oxide nanoparticles are not stable and must be coated by biocompatible organic ligands. The use of phosphonate ligands to modify the nanoparticle surface drew a lot of attention in the last years for the design of highly functional hybrid materials. Here, we report a methodology to synthesize bisphosphonates having functionalized PEG side chains with different lengths. The key step is a procedure developed in our laboratory to introduce the bisphosphonate from acyl chloride and tris(trimethylsilyl)phosphite in one step.

Bifunctional Tripeptide with a Phosphonic Acid as a Bronsted Acid for Michael Addition: Mechanistic Insights

Enamine catalysis is a widespread activation mode in the field of organocatalysis and is often encountered in bifunctional organocatalysts. We previously described H-Pro-Pro-pAla-OMe as a bifunctional catalyst for Michael addition between aldehydes and aromatic nitroalkenes. Considering that opposite selectivities were observed when compared to H-Pro-Pro-Glu-NH2 , an analogue described by Wennemers, the activation mode of H-Pro-Pro-pAla-OMe was investigated through kinetic, linear effect studies, NMR analyses, and structural modifications. It appeared that only one bifunctional catalyst was involved in the catalytic cycle, by activating aldehyde through an (E)-enamine and nitroalkene through an acidic interaction. A restrained tripeptide structure was optimal in terms of distance and rigidity for better selectivities and fast reaction rates. Transition-state modeling unveiled the particular selectivity of this phosphonopeptide.

Peptides holding a phosphonic acid: Easily recyclable organocatalysts for enantioselective C–C bond creation

GRAPHICAL ABSTRACT ABSTRACT A novel bifunctional organocatalysts library was developed as efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes. Therefore, a phosphonic acid was used for the very first time as activating moiety in the field of organocatalysis. H-R-Pro-S-Pro-R-pAla-OMe (pAla stands for phosphonoalanine) was identified as the most effective one with up to 95:5 d.r. and 93:7 e.r over 12 GABA precursors examples. This catalyst was easily recycled and reused over 10 cycles without any significant loss of selectivity.