Microwave instrumentation

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

Finally, the introduction of focused microwave instruments further enabled to speed up the synthesis of libraries, by reducing the actual time needed for reaction [28-34]. The combination of using dedicated microwave instruments and sohd or solution phase tagging subsequently became a very powerful tool for PASP and SPOS apphcations [25,26,33-51]. 

The growing interest in MAOS during the mid-1990s led to increased demand for more sophisticated microwave instrumentation, offering, for example, stirring of the reaction mixture, temperature measurement, and power control features. For scientifically valuable, safe, and reproducible work, the microwave instruments utilized should offer the following features ... 

Since the early applications of microwave-assisted synthesis were based on the use of domestic multimode microwave ovens, the primary focus in the development of dedicated microwave instruments was inevitably the improvement of multimode... 

Recent advances and further improvements have led to a broad variety of applications for single-mode microwave instruments, offering flow-through systems as well as special features such as solid-phase peptide synthesis or in situ on-line analy-... 

Fig. 3.18 Prolabo single-mode microwave instruments Synthewave 402 (left) and Synthewave 1000 (right). Reproduced with permission from [14].

Since the first appearance of industrially designed microwave instruments for organic synthesis in the early 1990s, the interest in microwave-assisted synthesis has grown tremendously. 

The immobilized carbamates (40 pmol) were transferred to a sealable 96-well Weflon plate, and admixed with 10 pmol each of various primary or secondary amines dissolved in 400 iL of anhydrous toluene. After sealing, the plate was irradiated in a multimode microwave instrument, first generating a ramp to reach 130 °C within 45 min and then holding this temperature for an additional 15 min. After cooling, the resins were filtered with the aid of a liquid handler and the filtrates were concentrated to obtain the desired substituted ureas in good purity and reasonable yields. Anilines reacted rather sluggishly and 2-substituted benzyl carbamates afforded somewhat inferior results. 

Finally, another related study from the Sun laboratory concerned the synthesis of hydantoins utilizing acryloyl chloride to prepare a suitable polymer support [87]. All steps were carried out under reflux conditions in a dedicated microwave instrument utilizing 50-mL round-bottomed flasks. Identical reactions under classical thermal heating did not proceed in the same time period. 

Fig. 13.1 Microwave heating profile of organic solvents using a Prolabo Synthewave S402 microwave instrument (5 cm3 at 300 W)...

Carboxy-substituted benzofurans have been prepared under solventless phase-transfer conditions (solid potassium carbonate/tetrabutylammonium bromide) by condensation of a substituted salicylaldehyde with chloroacetic acid esters (Scheme 3.1)2. Similarly, 2-carboxyaryl-substituted benzofurans were prepared by condensation of a set of salicylaldehydes with a-tosyloxyketones in the presence of solid potassium fluoride doped alumina (Scheme 3.1)3. In each case, a domestic microwave instrument was employed. 

A 48-membered library of 2-arylbenzoxazoles has been prepared by the condensation of substituted 2-aminophenols with a series of acid chlorides. The reactions proceeded in the absence of a base in sealed tubes in an automated microwave instrument, which used sequential rather than parallel reaction processing. Comparisons to the conventional thermal conditions demonstrated the importance of the high temperatures and pressures achieved under microwave heating, which ensured that the reactions proceeded efficiently (Scheme 3.16)26. An analogous synthesis ofbenzoxazolesby the cyclocondensation reaction of 2-aminophenols with S-methylisothioamide hydroiodides on silica gel, under microwave irradiation, has also been reported (Scheme 3.16)27. 

The final step in the synthesis ofthe pyridopyrimidinones (Scheme 7.10a) involved the release of the products from the solid support by intramolecular cyclisation, whereupon the pure products were obtained in solution. All reaction steps were carried out in a dedicated single-mode microwave instrument under sealed vessel conditions. 

The combination of microwave-assisted chemistry and solid-phase synthesis applications is a logical consequence of the increased speed and effectiveness offered by microwave dielectric heating. While this technology is heavily used in the pharmaceutical and agrochemical research laboratories already, a further increase in the use of microwave-assisted solid-phase synthesis both in industry and in academic laboratories can be expected. This will depend also on the availability of modern microwave instrumentation specifically designed for solid-phase chemistry, involving for example dedicated vessels for bottom filtration techniques. 

Abstract An overview of the application of microwave irradiation in natural product synthesis is presented, focusing on the developments in the last 5-10 years. This contribution covers the literature concerning the total synthesis of natural products and their analogues, the synthesis of alkaloids and the construction of building blocks of interest for natural product synthesis. As microwave irradiation appeared on the scene only recently, we are at an early stage of its application in natural product chemistry, even though some nice examples have been communicated recently. The application of dedicated microwave instruments as well as domestic microwave ovens is discussed, giving emphasis to the microwave-enhanced transformations. 

As dedicated microwave instruments appeared rather recently on the market and several interesting applications of microwave irradiation for natural product synthesis were described applying domestic microwave ovens, we decided to include also research performed with domestic ovens, although one could argue that some of these experiments lack reproducibility. On the other hand, the development of safe and reproducible synthetic routes for domestic instruments, which are cheap and at the disposal of every research lab all over the world, is a challenge worth the task as this should tremendously speed up the introduction of microwave irradiation in organic synthesis in general. 

Scheme 7 Scale-up of Pd-catalyzed Buchwald-Hartwig aminations utilizing different microwave instruments...

The microwave region of the electromagnetic spectrum lies between 1 cm and 1 m and in order to avoid interfering with radar and telecommunication activities that operate within this region, most domestic and commercial microwave instruments operate at 2.45 GHz. The heating effect utilized in microwave-assisted organic... 

---