Regioselective substitution chemistry

Regioselective Substitution Chemistry. The 1,3,2V-dioxaphospholanes are valuable precursors in other novel synthetic transformations. For example, the benzoylation of 1,2-propanediol employing triphenylphosphine/benzoyl peroxide is... 

Aran, Goya, and Ochoa (Institute of Medicinal Chemistry, Madrid, Spain) contribute the first comprehensive review of heterocycles containing the sulfamide moiety, covering a wide diversity of heterocyclic ring systems. The chapter by Comins and O Connor, on regioselective substitution in aromatic six-membered nitrogen heterocycles, describes exciting work contributed by their laboratory and also includes a broad literature survey. 

Regioselective substitution on indole is one of the most important goals in heterocyclic chemistry owing to the great importance of indoles in the preparation of biologically active products. The 2- and 3-positions of the ring are the normal sites of attack in the electrophilic substitution, including acylation because of their much more nucleophilic activity. ... 

In further studies, Chou and colleagues found that the sulfolene nucleus could be regioselectively substituted with alkyl chains incorporating an alkene bond. Alkylations with allylic halides were particularly effective (Scheme 6.25, Table 6.8). They utilized this chemistry in neat syntheses of simple terpenes (see Section 6.4). In some cases the alkene bond of the side-chain was utilized as a dienophile in an intramolecular Diels-Alder reaction [43,46,69,109]. 

Evans and coworkers developed a rhodium-catalyzed allylic substitution of chiral acyclic tertiary allylic carbonates with acyl anion equivalents. This substitution pathway provides a route to undergo a stereo- and regioselective substitution to provide the quaternary carbon 73. The enantioenriched product is isolated in greater than 95 5 selectivity and 87% yield. This pathway provides a product that could be obtained through enolate chemistry, only lacking the same atom economy obtained with rhodium-catalysis. 

The problems associated with predicting regioselectivity in quinone Diels-Alder chemistry have been studied, and a mechanistic model based on frontier molecular orbital theory proposed (85). In certain cases of poor regioselectivity, eg, 2-methoxy-5-methyl-l,4-ben2oquinone with alkyl-substituted dienes, the use of Lewis acid catalysts is effective (86). 

Recent progress of basic and application studies in chitin chemistry was reviewed by Kurita (2001) with emphasis on the controlled modification reactions for the preparation of chitin derivatives. The reactions discussed include hydrolysis of main chain, deacetylation, acylation, M-phthaloylation, tosylation, alkylation, Schiff base formation, reductive alkylation, 0-carboxymethylation, N-carboxyalkylation, silylation, and graft copolymerization. For conducting modification reactions in a facile and controlled manner, some soluble chitin derivatives are convenient. Among soluble precursors, N-phthaloyl chitosan is particularly useful and made possible a series of regioselective and quantitative substitutions that was otherwise difficult. One of the important achievements based on this organosoluble precursor is the synthesis of nonnatural branched polysaccharides that have sugar branches at a specific site of the linear chitin or chitosan backbone [89]. 

Recently, an example of green chemistry in the formation of a nitrone in aqueous medium, using a surfactant, was reported in 1,3-dipolar cycloadditions to ethyl acrylate (776). The control of regioselectivity in this reaction favors the formation of trans -5-substituted isoxazolidines. 

Several classes of silyl ethers have been shown to be excellent substrates for the C-H insertion chemistry of donor/ acceptor-substituted carbenoids.81 Effective C-H insertions predominantly occur at methylene sites. Primary sites are not sufficiently activated electronically while tertiary sites are sterically too crowded. Rl -DOSP -catalyzed functionalization of the allyl silyl ether 3 resulted in a highly diastereoselective transformation, leading to the formation of the /3-hydroxyester 4 in 94% yield and 82% ee (Equation (17)).81 This example illustrates the regioselectivity of this chemistry, because 3 contains two allylic sites but only the methylene site adjacent to the siloxy group was functionalized. Even better substrates are the commercially available tetraalkoxysilanes such as 5, because with these substrates, the high diastereoselectivity was retained while the enantioselectivity was increased (Equation (18)).81... 

To summarize, electrophilic substitutions and metalations of thiophenes take place preferably at the a-positions due to the electronegativity of the sulfur atom. This is the consequence of the more effective incorporation of lone pair electrons on the sulfur into the aromatic system. Although regioselective reactions are routinely performed for oc,p-dihalofurans, regioselectivity is not as easily achieved in Pd-mediated chemistry with oc,p-dihalothiophenes. 

Allylic substitutions with nonstabilized C-nucleophiles are an important domain of organocopper chemistry [51]. However, on close inspection of the literature, it becomes apparent that regioselectivity in favor of the branched allylic alkylation products is only obtained with alkyl copper compounds, while aryl copper compounds mainly give the linear alkylation products. This observation was an incentive for Alexakis et al. [52] to probe the reactions of aryl zinc hahdes in the Ir-catalyzed allylic substitution (Scheme 9.18). 

The synthesis and chemistry of metal complexes of thiophenes have been reported including the electrophilic additions to osmium-thiophene complexes <9902988> and nucleophilic additions to ruthenium-thiophene complexes <99JOMC242>. The selectivity for the insertion of ruthenium into 3-substituted thiophenes was studied <99CC1793>. For example, treatment of 3-acetylthiophene (84) with Ru(cod)(cot) led to a regioselective 1,2-insertion of ruthenium giving thiaruthenacycle 85. 

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