Carbon-heteroatom bond formation cross-coupling reactions

D.v. Carbon-Heteroatom Bond-Formation Cross-Coupling Reactions... 

The transition metal catalyzed synthesis of seven membered and larger heterocycles attracted considerably less attention than the preparation of their five and six membered analogues. Typical examples in this chapter include the formation of heterocycles in insertion reactions, or through carbon-heteroatom bond formation. Although the formation of some macrocyclic natural products was also achieved in cross-coupling reactions they will not be discussed in detail. 

From reading the other sections of this book, one readily sees that palladium complexes serve as catalysts for a variety of C—C bond-forming cross-coupling processes. This cross-coupling chemistry involves the metal-catalyzed reactions between nucleophiles and electrophiles that display a wide variety of steric and electronic properties. It is, therefore, surprising that carbon-heteroatom bond formation by cross-coupling processes lay close to dormant until roughly five years ago. 

Recent renaissance in Ulmann chemistry has opened new opportunities for successful implementation of novel cross-coupling approaches, especially useful for carbon-heteroatom bond formation under mild conditions with copper compounds. Numerous publications have appeared dealing with thiolation and selenation of aryl-and alkenyl halides using various Cu complexes as catalysts. A high reaction temperature of 200-300 °C [55] was significantly reduced, to 100 °C and less. Therefore, a simplified reaction technique and cheaper solvents may be utilized in synthetic procedures. Lower temperature was also of much importance to avoid side reactions. 

During the past few decades, transition metal-catalyzed cross-coupling reactions have become a powerful tool for the construction of C—C and C-heteroatom bonds [1]. This strategy allows the conceptually simple and yet powerful and reliable approach for synthesizing structurally complex pharmaceuticals and biologically active molecules. The two most vastly used transition metal catalysts in carbon-heteroatom bond formation are palladium (mainly depends on its ancillary ligands) and copper (depends on the optimization of the catalytic system as a whole copper source, solvent, base, concentrations, etc.). Besides, considerable developments have also been made with other transition metal catalysts such as nickel, iron, etc. 

Recently, interest in copper-catalyzed carbon-heteroatom bond-forming reactions has shifted to the use of boronic acids as reactive coupling partners [133], One example of carbon-sulfur bond formation is displayed in Scheme 6.65. Lengar and Kappe have reported that, in contrast to the palladium(0)/copper(l)-mediated process described in Scheme 6.55, which leads to carbon-carbon bond formation, reaction of the same starting materials in the presence of 1 equivalent of copper(II) acetate and 2 equivalents of phenanthroline ligand furnishes the corresponding carbon-sulfur cross-coupled product [113]. Whereas the reaction at room temperature needed 4 days to reach completion, microwave irradiation at 85 °C for 45 min in 1,2-dichloroethane provided a 72% isolated yield of the product. 

The synthesis of the promazine 444 class of antipsychotics was pursued by medicinal chemists firom Lundbeck Pharmaceuticals (Deerfield, EL). Although the C—N and C S bond formations have been separately developed and optimized to practical use, the formation of multiple carbon-heteroatom bonds has been challenging. To this end, the researchers developed a palladium-catalyzed, three-component cross-coupling reaction in which the formation of one C—S bond from thiophenol 441 and aromatic halogenide 443 and two C—N bonds from amines 442 were accomplished in a one-pot tandem reaction fashion (Scheme 46.50). 

Carbon-heteroatom double bonds can also participate in this reaction. These include both carbonyl compounds (Scheme 11.37) and imines (Scheme 11.38). Addition to aldehydes is co-catalysed by tin(II) or indium(III) salts. Under these conditions, tetrahydrofiirans are obtained. The presence or absence of the co-catalyst can also switch the reaction from one mode to another (Scheme 11.39). An indium cocatalysed cycloaddition to a 7-pyrone aldehyde 11.117 was used in a synthesis of aureothin 11.122 and A-acetylaureothamine 11.123 (Scheme 11.40). Cross-metathesis of the exo-cyc ic alkene 11.118 allowed a subsequent Suzuki coupling with a gem-dibromide 11.120 that showed the expected selectivity (Section 2.1.4.2). This reaction required the use of thallium ethoxide as the Lewis base to suppress the formation of side products. A Negishi coupling completed the synthesis of aureothin 11.122. Reduction and acylation of the nitro group yielded A-acetylaureothamine 11.123. The latter compound is active digainst Helicobacter pylori, a bacterium behind stomach ulcers. 

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