Catalytic wittig reactions of semi- and nonstabilized ylides enabled by ylide tuning.

The first examples of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert-butyl carbonate, and/or ylide tuning. The acidity of the ylide-forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.

Breaking the ring through a room temperature catalytic Wittig reaction.

One ring no longer rules them all: Employment of 2.5-10 mol % of 4-nitrobenzoic acid with phenylsilane led to the development of a room temperature catalytic Wittig reaction (see scheme). Moreover, these enhanced reduction conditions also facilitated the use of acyclic phosphine oxides as catalysts for the first time. A series of alkenes were produced in moderate to high yield and selectivity.

Part I: the development of the catalytic Wittig reaction.

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96%) by using a precatalyst loading of 4-10 mol%. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,ß-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74% yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions.

Micro-photochemistry: photochemistry in microstructured reactors. The new photochemistry of the future?

The use of a confined space in which to carry out reactions has proven popular in recent years, as demonstrated by the large volume of work published on 'molecular microreactors' such as zeolites, micelles and nanoparticles. This article looks at reactions in microstructured reactors, also known as microchannelled reactors or microreactors. In general, these consist of a 'chip' with narrow channels etched into it. Microstructured reactors have been the subject of several review articles to date, focusing on preparation, types of reactions that may be carried out and on the potential for 'green' applications. However, the use of microstructured reactor technology in photochemistry has, until now, not been subject to review. This perspective aims to outline the work done to date in this area and in particular to demonstrate the advantages and future prospectives of this technology in photochemical processes. Photochemistry in microstructured reactors is an emerging area of interest and to date has demonstrated significant potential as a viable alternative to traditional photochemical synthesis.