Microwave-assisted Domino Reaction in Organic Synthesis

The fields of combinatorial and automated medicinal chemistry have emerged to meet the increasing requirement of new compounds for drug discovery, where speed is of the essence (Loupy, 2002). In this regard, domino (or tandem, or cascade) reactions where “two or more bond-forming transformations take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step” are especially suitable for the generation of libraries of bioactive small molecules (Tietze, 1996, 2000, 2006; Domling, 2006). When performed intermolecularly, they are used to couple small fragments to larger units. In intramolecular reactions, they can bring about cyclizations or bicyclizations, and thus astonishing changes of molecular structures and increases in molecular complexity. This effect can even be enhanced by repeating the same reaction type several times or combining it with a different transformation in a domino fashion. Such sequential processes offer a wide range of possibilities for the efficient construction of high structural diversity and molecular complexity in the desired scaffolds in a single synthetic step simply by proper variation of precursors, thus avoiding time-consuming and costly processes for purification of various precursors and tedious steps of protection and deprotection of functional groups (de Meijere et al., 2005; Tietze et al., 2009). Additionally, they frequently occur with enhanced regio-, diastereo-, and even enantioselectivity for the overall transformation (Ikeda, 2000; Domling & Ugi, 2000; D'Souza & Mueller, 2007). Simultaneously, the emergence of sustainable microwave chemistry has further impacted synthetic chemistry significantly since the introduction of precision controlled microwave reactors. From the pioneering experiments of Gedye (Gedye et al., 1986) and Giguere (Giguere et al., 1986), the use of microwave irradiation as an energy-efficient heat source for accelerating chemical reactions including heterocycle-forming, condensation, and cycloaddition reactions has seen widespread application (Kappe, 2000; Kappe & Stadler, 2005, 2009; Loupy, 2006; Kappe et al., 2009). Therefore, the high density microwave irradiation has matured into a reliable and useful methodology for accelerating reaction processes for the collection of heterocycles. Not only is direct microwave heating able to reduce chemical reaction times from hours to minutes and seconds, but it is also known to reduce side reactions, increase yields, and improve reproducibility. As a result, many academic and industrial research groups are already using microwave-assisted organic