Cu-Catalyzed Heterocycle Synthesis

Cu-catalyzed domino reactions have been used for the synthesis of carbocycles, as well as for heterocycles such as indoles, benzoxazoles, and quinoxalines. A very useful process is also the combination of the formation of allyl vinyl ethers, followed by a Claisen rearrangement. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

Gillingham DG, Hoveyda AH (2007) Chiral N-Heterocyclic Carbenes in Natural Product Synthesis Application of Ru-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis and Cu-Catalyzed Allylic Alkylation to Total Synthesis of Baconipyrone C. Angew Chem Int Ed 46 3860... 

Up to now, a variety of heterogeneous Cu-catalyzed cycloaddition reactions for the assembly of bioactive heterocycles have been reported. Most examples are the Huisgen-type 1,3-dipolar cycloadditions, but there are rare reports on the heterogeneous Cu-catalyzed synthesis of heterocycles through other types of cycloaddition reactions. 

Synthesis of Heterocycles via Heterogeneous Cu-Catalyzed Coupling Reactions... 

The domino reaction allows the formation of two or more bonds in one process and meets the requirements of the modem synthesis (Tietze et al., 2006). In contrast with the traditional stepwise synthesis, such a process provides a wide range of possibilities for the efficient assembly of complex molecules from simple starting materials in a single step, and the tedious workup and isolation procedures of intermediates are avoided. Moreover, additional solvents and reagents can be saved by using such a method. Recently, heterogeneous Cu-catalyzed domino reactions have been applied for the efficient and convenient elaboration of heterocyclic molecules. 

These pioneering achievements in heterogeneous Cu-catalyzed synthesis of heterocycles are just the tip of the iceberg, and much more remains to be discovered and explored. 

Recentiy, glyoxylyl chlorides 3, formed in situ by direct glyoxylation of electron-rich heterocycles such as indoles and pyrroles with oxalyl chloride, have been coupled in the Cu-catalyzed Stephen-Castro reaction to terminal arylacetylenes [11]. The resulting heterocycHc ynediones 4 are valuable electrophihc building blocks for the synthesis of various pharmaceutically relevant compounds (Scheme 9.3). 

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