Miscellaneous reactions

Isomerizations of double bonds and tautomerizations (interconversion of isomers) are useful organic transformations. These also can be enhanced by microwave irradiation. Loupy et al. have used microwave-induced, solvent-free, solid-liquid-phase transfer catalysis (PTC), which employs a salt (in this case, potassium t-butoxide) and a phase transfer catalyst (tetrabutylammoniumbromide, TBAB), to isomerize eugenol to isoeugenol (Scheme 135).708 An example of a microwave-enhanced double bond isomerization followed by enol – keto tautomerization is shown in Scheme 136.10,223

Scheme 135

Scheme 136

Dealkoxycarbonylation, also known as the Krapcho reaction, completely removes an ester group directly from the carbon alpha to a carbonyl. These reactions are difficult to achieve with conductive heating, and they usually require very high temperatures with DMSO as the solvent. Loupy uses PTC with LiBr/TBAB to transform malonic esters to monoesters (Scheme 137).709

Scheme 137

Hydrosilylation of alkenes is another reaction that proceeds poorly with conventional heating. The example shown below in Scheme 138 normally requires 18 hours of thermal heat and provides only a 5% product yield. With six 30-second bursts of microwave irradiation, the 2-vinylpyridine is silylated with a 75% yield of product.381

Scheme 138

The Wittig reaction is probably the most reliable olefin-forming reaction in synthetic organic chemistry. In this reaction, an aldehyde or a ketone reacts with a phosphorus ylide, forming an oxaphosphetane intermediate. The four-membered ring collapses and produces the alkene and a phosphine oxide byproduct. Wittig reactions, traditionally, can require up to 24 hours of reflux in high boiling point solvents. There has been some research performed on the microwave-assisted synthesis of both the Wittig reagent (ylide)710 and the reaction itself 711-719. Scheme 139 exhibits successful Wittig transformations on benzaldehyde derivatives that occurred in five minutes.711

Scheme 139

The Peterson olefination, also known as the silyl-Wittig reaction, utilizes a trialkylsilylmethyl lithium (or magnesium) reagent that adds to a ketone or aldehyde. The β-hydroxysilane intermediate, which can be isolated, eliminates water upon acid or base catalysis. Depending on the stability of the β-hydroxysilane, these reactions can require many hours of reflux. A Peterson reaction in which the silylmethyl anion was generated in situ with cesium fluoride on clay was successful in ten minutes with microwave heating (Scheme 140).721

Scheme 140

The role of microwave synthesis in drug discovery and development will only increase over the next several years. There is a need for a very simple, flexible, and compact microwave system that can be used in synthesis laboratories. As with most new technology, various levels of automation will be demanded and introduced to the market to support needs in drug discovery and library generation. This technology will eventually replace hot plates, heating mantles, and block heaters, allowing chemists to begin using microwave energy on a broad scale, as affordable instrumentation becomes readily available. Academia, drug discovery, and lead optimization are the areas expected to receive the most benefit from this new technology. As microwave synthesis instrumentation continues to evolve, new applications will be developed for a variety of chemistries and process developing needs. This will naturally accelerate as the technology is adopted. Undoubtedly, microwave-enhanced synthesis will be a valuable tool for chemists in a variety of fields and specialties for many years to come.