Gram Scalable Method to Synthesize Biscarbodiimides and Asymmetric Monocarbodiimides: A Platform to Access an Array of Phosphaguanidines, Amidines, and Guanidines.

A mild, broadly functional group tolerant methodology has been developed to access a variety of mono- and bis-carbodiimides in good yield and high purity on multigram scale. Direct addition into these versatile motifs facilitated the rapid synthesis of a library of novel amidinines, guanidines, and phosphaguandines.

Stereoretentive Pd-catalyzed Kumada-Corriu couplings of alkenyl halides at room temperature.

Stereoselective palladium-catalyzed Kumada-Corriu reactions of functionalized alkenyl halides and a variety of Grignard reagents, including those bearing ß-hydrogen atoms and sensitive functional groups, can be carried out at room temperature using a new combination of reagents.

Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room Temperature: Heck, Suzuki-Miyaura and Negishi reactions carried out in the absence of organic solvents, enabled by micellar catalysis.

Palladium-catalysed cross-couplings, in particular Heck, Suzuki-Miyaura and Negishi reactions developed over three decades ago, are routinely carried out in organic solvents. However, alternative media are currently of considerable interest given an increasing emphasis on making organic processes 'greener'; for example, by minimising organic waste in the form of organic solvents. Water is the obvious leading candidate in this regard. Hence, this review focuses on the application of micellar catalysis, in which a 'designer' surfactant enables these award-winning coupling reactions to be run in water at room temperature.

Highly selective reactions of unbiased alkenyl halides and alkylzinc halides: Negishi-Plus couplings.

High yielding stereo- and chemoselective Pd-catalyzed cross-couplings in THF at room temperature of alkenyl iodides and bromides with primary and secondary alkyl zinc iodides have been developed with the aid of N-methyimidazole as the key additive.

Ligand effects on Negishi couplings of alkenyl halides.

Negishi couplings at olefinic centers do not always occur with the anticipated maintenance of stereochemistry. The source of erosion has been traced to the ligand, and a modified method has been developed that solves the stereochemical issue and significantly improves yields of Negishi couplings in general.

TPGS-750-M: a second-generation amphiphile for metal-catalyzed cross-couplings in water at room temperature.

An environmentally benign surfactant (TPGS-750-M), a diester composed of racemic α-tocopherol, MPEG-750, and succinic acid, has been designed and readily prepared as an effective nanomicelle-forming species for general use in metal-catalyzed cross-coupling reactions in water. Several "name" reactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-like couplings, have been studied using this technology, as have aminations, C-H activations, and olefin metathesis reactions. Physical data in the form of DLS and cryo-TEM measurements suggest that particle size and shape are key elements in achieving high levels of conversion and, hence, good isolated yields of products. This new amphiphile will soon be commercially available.

"On water" sp3-sp2 cross-couplings between benzylic and alkenyl halides.

Organic-solvent-free cross-couplings between benzylic and alkenyl halides have been developed. Various alkenyl halides can be efficiently benzylated by combining the precursor halides in the presence of Zn dust and a Pd catalyst at room temperature, in water as the only medium.

Organozinc Chemistry Enabled by Micellar Catalysis. Palladium-Catalyzed Cross-Couplings between Alkyl and Aryl Bromides in Water at Room Temperature.

Negishi-like cross-couplings between (functionalized) alkyl and aryl bromides are described. Despite the fact that organozinc reagents are intolerant of water, their formation as well as their use in an aqueous micellar environment is discussed herein. Each component of this complex series of events leading up to C-C bond formation has an important role which has been determined insofar as the type of zinc, amine ligand, surfactant, and palladium catalyst are concerned. In particular, the nature of the surfactant has been found to be crucial in order to obtain synthetically useful results involving highly reactive, moisture-sensitive organometallics. Neither organic solvent nor heat is required for these cross-couplings to occur; just add water.

Stereoselective Negishi-like couplings between alkenyl and alkyl halides in water at room temperature.

Mix in water and then stir. That is all that is required in this new approach to stereoselective sp(3)-sp(2) cross-couplings between an alkyl and alkenyl halide. Prior formation of organozinc reagents is not required.

Cross-couplings between benzylic and aryl halides "on water": synthesis of diarylmethanes.

A remarkably simple entry to unsymmetrical diarylmethanes has been developed that relies on an in situ organozinc-mediated, palladium-catalyzed cross-coupling. Thus, by mixing a benzyl and aryl halide together in the presence of Zn metal and a Pd catalyst, diarylmethanes are formed at room temperature without assistance by a surfactant; hence, "on water".

Zn-mediated, Pd-catalyzed cross-couplings in water at room temperature without prior formation of organozinc reagents.

Mix in water, stir. That is all that is required in this new approach to sp(3)-sp(2) cross-couplings between an alkyl iodide and an aryl bromide, both potentially bearing functionality. They react under catalysis by Pd(0) in the presence of zinc powder, aided by a nonionic amphiphile, to give the alkylated aromatic. No organic solvents and no heating; just add water.

New synthetic technologies for the construction of heterocycles and tryptamines.

New synthetic methods for the construction of novel heterocycles and tryptamines are described. Thus, N-Boc anilines (I) are sequentially converted to heterocycles II ((3-(2-aminophenyl)pyrrolidin-3-ol) derivatives), III (substituted 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines), and VI (2-(4,5-dihydro-1H-pyrrol-3-yl)aniline) derivatives through a route involving t-BuLi induced ortho-metalation/LaCl(3).2LiCl metal exchange, reaction with N-Boc pyrrolidin-3-one (5), and subsequent decarboxylative fragmentation. Labile intermediates VI are effectively converted to tryptamines Xa and Xb under controlled protic acid conditions. In addition to providing expedient access to the 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines (III), the method is applicable to the synthesis of the corresponding 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-piperidine series of spirocycles (e.g., 42) and their precursors (3-(2-aminophenyl)piperidin-3-ol derivatives, e.g., 43) by using N-Boc-protected piperidin-3-one (40). Applications of the developed synthetic technologies to the synthesis of regioisomeric spirocycles 87 and 90, tryptamines 88 and 91, Corey's aspidophytine tryptamine (97), and efavirenz (1) are also described.

Selective mono- and 1,2-difunctionalisation of cyclopentene derivatives via Mg and Cu intermediates.

A single Br/Mg exchange of 1,2-dibromocyclopentene with iPrMgCl LiCl provides the corresponding beta-bromocyclopentenylmagnesium reagent, which can then be reacted with various electrophiles (yields: 65-82 %). In the presence of a secondary alkylmagnesium halide and Li2CuCl4 (2 mol %), these 2-bromoalkenylmagnesium compounds undergo bromine substitution and can then further react with electrophiles to give 1,2-difunctionalised cyclopentenes (63-79 %). The mechanism of this process is discussed.

The Mg-oppenauer oxidation as a mild method for the synthesis of aryl and metallocenyl ketones.

Magnesium alkoxides undergo a hydride-transfer oxidation with benzaldehyde as the oxidant. This magnesium variant of the Oppenauer oxidation was used for the synthesis of polyfunctional biaryl ketones. LiCl was found to promote this reaction by enhancing the solubility of magnesium alkoxides. This mild oxidation method was especially useful for preparing ketones bearing a metallocenyl unit as well as various new ferrocenyl ketones and tricarbonylchromium complexes. This last class of ketones was reduced with the CBS catalyst (CBS=Corey-Bakshi-Shibata, diphenyl oxazaborolidine) to chiral benzhydrol complexes with high enantioselectivity enabling an asymmetric synthesis of electron-rich or -poor benzhydryl alcohols (up to 94 % ee).