Ketones heteroaryl

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Pd-catalyzed carbonylation of heteroaryl halides provides a quick entry to heteroaryl carbonyl compounds such as heteroaryl aldehydes, carboxylic acids, ketones, esters, amides, a-keto esters and a-keto amides. In addition, Pd-catalyzed alkoxycarbonylation and aminocarbonylation are compatible with many functional groups, and therefore, are more advantageous than conventional methods for preparing esters and amides [78],... 

Pyridylstannanes have been cross-coupled with numerous aryl- and heteroaryl halides as well as various other electrophiles. For example, an extension of Stille s original methodology to 3-trimethylstannylpyridine and acid chloride 73 gave the corresponding ketone 74, which was then converted to 2S-(+)-nicotinylalanine 75, a neuroprotection agent [62],... 

Of all the hydrocarbon-based PEMs, this group most likely has the largest variety of different systems. This is probably due to the wealth of prior knowledge of the nonsulfonated analogues that have been developed over the last several decades as well as the general expectation of higher thermal stability, better mechanical properties, and increased oxidative stability over polystyrene-based systems. Within the context of this section, polyarylenes are systems in which an aryl or heteroaryl ring is part of the main chain of the polymer. This section will, therefore, include polymers such as sulfonated poly (ether ether ketone) and sulfonated poly(imides) but will not include systems such as sulfonated polystyrene, which will be covered in Section 3.3.I.3. 

Danheiser et al. developed a new aromatic annotation methodology for the total s)mthesis of hyellazole (245) by irradiation of the heteroaryl a-diazo ketone 675 in the presence of 1-methoxypropyne (590). This reaction proceeds via the photochemical Wolff rearrangement of the heteroaryl a-diazo ketone 675 to generate a vinylketene, followed by a cascade of three pericyclic reactions. 

Carbonylative cross-coupling of various iodonium salts bearing transferable aryl, heteroaryl, alkenyl, alkynyl residues with phenylboronic acid takes place under mild conditions giving the respective ketones in high yields (Equation (16)). The yields of competing cross-coupling do not exceed 8%. 

No product was formed in this reaction in the absence of the soluble lanthanide salt or even in the presence of CeCL. Heteroaryl Grignard reagents react smoothly in the presence of LaCl3 2LiCl even with highly sterically hindered ketones like 211 (equation 137). 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

Regioselective fluorodestannylation of alkenyl and heteroaryl molecules to give 34 can be achieved under mild conditions with cesium fluoroxysulfate, while x-fluoro ketones, e.g. 35, are formed when the tin group is attached to the benzylic position.42 The pyrrole ring in indole derivatives is also successfully fluorinated using this method, e.g. formation of 36.42-45... 

The Schotten-Baumann acylation of pyrroles and indoles is discussed in Section 3.05.1.2.6 and reactions of the heteroaryl anions with aldehydes and ketones are presented in Section... 

Vinylpyrroles and vinylindoles are extremely sensitive to acid-catalyzed dimerization and polymerization and it is significant that much of the early research was conducted on systems which were produced in situ. Even by this approach, the dimerization of, for example, 2-(3-indolyl)propene and l-(3-indolyl)-l-phenylethylene was difficult to prevent (see the formation of 110 and 120, Section 3.05.1.2.8). Similarly, although it is possible to isolate ethyl 2-(2- and 3-indolyl)propenoates, they appear to be extremely unstable at room temperature even in the absence of acid (81UP30500) to give [ 4 + 2] cycloadducts of the type (348) (cf. 77JCS(P1)1204>. For many years simple vinylpyrroles also eluded isolation, on account of their facile acid-catalyzed polymerization. Application of the Wittig reaction, however, permits the synthesis of vinyl-pyrroles and -indoles under relatively mild and neutral conditions (see Section 3.05.2.5). In contrast, heteroarylvinyl ketones, esters, nitriles and nitro compounds, obtained by condensation of the appropriate activated methylene compound with the heteroaryl aldehydes (see Section 3.05.2.5), are thermally stable and... 

Table 2 Yields of a-Heteroarylated Ketones Formed in Photostimulated Reaction of Ketone Enolates with...

It is noticeable from the data in Table 1, that the number of examples of reactions involving the enolates of aryl alkyl ketones is limited. Bromo- and iodo-benzene were reported not to react with the enolate of acetophenone112 but the reaction with iodobenzene under more intense and longer irradiation was reported to give a 67% yield of phenacylbenzene.45 Sufficient examples of the ot-arylation of the enolates of aryl (and heteroaryl) alkyl ketones have been cited to indicate that these reactions are worth further investigation. 

A substantial number of important syntheses that depend on the attack of ketone enolates on ortho-functionalized aryl or heteroaryl halides, and that lead to cyclized products are discussed in Section 2.2.4.2. 

A useful synthesis of heteroaryl ketones uses the photostimulated a-cyanoalkylation reaction followed by oxidation (Scheme 4). The oxidation of products formed from phenylacetonitrile (R = Ph in Scheme 4) proceeded in over 90%.110... 

Reduction of ketones other than 48 to dimers has been examined. Ethyl pyridyl ketone (51) gave a poor yield of the corresponding pinacol (52).79 Pinacols can also be made from crossed coupling of ketones with 3-(48).80 Finally, a study of the radical anions formed from the isomeric benzoylpyr-idines (53) was done, and the rates of rotation of the pyridyl ring were determined.81 The mechanism of reduction of the oxime and thiosemicar-bazone derivatives of 53 was determined by voltammetry techniques.82 The monoimine derivative of the pyridil 54 was reduced to the a-amino ketone 55 (Scheme 18).83 Unsaturated pyridyl ketones and heteroaryl pyridyl ketones have also been studied by voltammetry.84,85... 

A new, metal-free protocol involving (heteroaryl)oxazoline catalysts for the enantioselective reduction of aromatic ketones (up to 94% ee) and ketimines (up to 87% ee) with trichlorosilane has been developed. The reaction is characterized by an unusual, long-ranging chiral induction.The enantiodifferentiation is presumed to be aided by aromatic interactions between the catalyst and the substrate.360 Asymmetric reduction of A-arylketimines with trichlorosilane is catalysed by A-methyl-L-amino acid-derived Lewis-basic organocatalysts with high enantioselectivity (up to 92% ee) 61... 

A closely related reaction is seen in the copper-mediated oxygenation of bis(2-ben-zimidazolyl)methanes to bis(2-benzimidazolyl)ketones (Fig. 9-31). This is a general reaction shown by many bis(heteroaryl)methanes. The reaction of the iron(n) complex... 

Figure 9-31. The transfer of oxygen atoms by copper/dioxygen reagents is not limited to aromatic substrates. Many bis(heteroaryl)methanes are converted to the corresponding ketones upon reaction with dioxygen in the presence of copper salts.

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