The Palladium-Catalyzed Synthesis of Aromatic Heterocycles

There is a wide range of methods available to construct aromatic heterocydes. Nevertheless, many of these rely upon relatively involved multistep processes, especially for the assembly of highly substituted products. In addition, these can sometimes suffer from harsh reaction conditions, or display limited product diversity. As such, there has been intense recent interest in the design of new and more efficient routes to these products. In this regard, metal catalysis, and in particular palladium catalysis, has played a central role. 

The use of palladium catalysis to synthesize aromatic heterocydes has been reviewed in a number of recent publications [1], As such, rather than a complete discussion of this large field, the thrust of this review will be to highlight general examples of how palladium catalysis has become used in heterocyde synthesis. This will focus on routes that direcdy assemble the aromatic heterocyclic core, rather than their subsequent functionalization or the use of palladium to assemble precursors for traditional cydocondensations, and on processes that involve generation of carbon-heteroatom bonds. 

Palladium Ji-Lewis Acidity Intramolecular Nucleophilic Attack on Unsatuiated Bonds 

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An alternative approach to multicomponent heterocycle synthesis involves the use of palladium catalysis to construct keto-alkynes for cycloaddition reactions. Muller has demonstrated the power of this approach in the construction of a range of aromatic heterocycles. For example, the palladium-catalyzed coupling of acid chlorides with terminal alkynes provides a method to assemble 36. The trapping of this substrate can provide routes to aromatic heterocycles. As an example, the addition of amidines provides a multicomponent synthesis of pyrimidines (Scheme 6.69) [97]. This same substrate 36 is available via the carhonylative coupling of aryl halides with terminal alkynes, providing a four-component synthesis of pyrimidines (98j. 36 can also be employed in 1,3-dipolar cydoaddition reactions. For example, cydoaddition... 

The following discussion focuses on the synthesis of aromatic heterocycles where a key palladium- or copper-catalyzed aryl halide (or equivalent) amination, etherification or thioetherification process is employed. Annulative routes utilizing anilines and related compounds with alkynes (Larock type) are also considered. Routes that do not lead to aromatic products or that rely on the functionalization of preexisting heterocycles have been discounted. Similarly, the synthesis of heterocycles via TT-allylpalladium chemistry or intramolecular cyclization of palladium Tr-olefin and TT-alkyne complexes is not featured. The discussion is structured predominantly around the type of bond being formed (C—N, C—O, or C—S) and is classified further by heterocycle type. Intramolecular and intermolecular C—X bond formations as well as tandem catalytic processes leading to aromatic heterocycle products are all discussed. 

Sultones are the internal esters of hydroxy sulfonic acids and are the sulfur analogs of lactones. Sultones are demanded scaffolds in medicinal chemistry research. Biological studies on sultones are mainly concerned with their toxicological, skin sensitization, and antiviral activities [20]. Sultones are synthetically useful heterocycles which can react with a variety of compounds to introduce the alkylsulfonic acid function and therefore used as sulfoalkylating agents [21]. There have been several new developments for the synthesis of sultones which have also been applied in the total synthesis of natural products. In recent years, the palladium-catalyzed direct arylation of several aromatics via a C-H bond activation using aryl halides has led to successes. An intramolecular version of this reaction has allowed the synthesis of several biaryls via the formation of five- to seven-membered rings. Thus, the sultones should be synthesized by C-H activation via two pathways (Scheme 4.14). 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Alcaide and Almendros have developed a novel palladium-catalyzed domino heterocyclization/cross-coupling reaction of various a-allenols and MBH acetates, furnishing [(2,5-dihydrofuran-3-yl)methyl]acrylate derivatives 489 and 490 and the acrylonitrile 491 in moderate to good yields (Scheme 3.216). " Ozonolysis of MBH adducts originating from aromatic aldehydes provides a-ketoesters 492 with different substitution patterns on the aromatic ring. Diastereoselective reduction of the a-ketoesters 492 affords the corresponding a,p-dihydroxy-esters 493 with excellent anti diastereoselectivity. This method provides an alternative approach for the synthesis of either a-ketoesters or a,p-dihydroxy esters (Scheme 3.217). ... 

Cascade palladium- and copper-catalyzed aromatic heterocycle synthesis The emergence of general precursors 13EJ0425. 

In 1993, Corriu et al. studied the synthesis of nitrogen-containing heterocycles from (Z)-3-(tribulylstannyl)allylamine, which was prepared by the reaction of Af-(trimethylsilyl)allylamine with 2 mol of ra-butyllithium followed by treatment with chlorotributyltin and subsequent hydrolysis. The unprotected (Z)-3-(tributylstannyl)allylamine underwent a palladium-catalyzed cross-coupling reaction with aromatic bromides affording a stereospecific preparation of substituted allylic amines with Z configuration of the carbon-carbon double bond. The reactions of o/t/zo-functionalized aryl bromides offer a one-step preparation of 7-membered nitrogen heterocycles in high yields (Scheme 4.18). 

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