Direct heteroaromatic compounds

Reactions of tc-excessive heteroaromatic compounds such as pyrroles, thiophenes and furans with carbenoids have been known for several years 6-10>u>. Recent activities were directed towards further synthetic applications of already known reactions, evaluation of the efficacy of novel catalysts and towards mechanistic insights. 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

The Brpnsted acid catalyzed hydrogenation of quinolines with Hantzsch dihydropyridine as reducing agent provides a direct access to a variety of substituted tetrahydroquinolines (Table 4.2). The mild reaction conditions of this metal-free reduction of heteroaromatic compounds, high yields, operational simplicity and practicability, broad scope, functional group tolerance and remarkably low catalyst loading render this environment-friendly process an attractive approach to optically active tetrahydroquinolines and their derivatives (Table 4.3) (see page 176). ... 

Aryl halides normally do not react with phosphines. However, under forcing temperature conditions, most frequently at 170-250 °C in the absence of solvents, it is possible to achieve direct arylation of tertiary phosphines by several halogenated aromatic or heteroaromatic compounds, especially when they are activated26 (reactions 20 and 21). New examples of such arylations have been described for nitrogen heterocycles255 256,... 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

As described in Section III.1.4.1.1, the catalytic direct arylation reactions of aromatic compounds occurs effectively via C-H bond cleavage when the substrates are appropriately functionalized. On the other hand, various five-membered heteroaromatic compounds involving one or two heteroatoms, even without a functional group, are known to undergo arylation, usually at their 2- and/or 5-posi-tion(s), on treatment with aryl halides under the action of palladium catalysis. The coupling has recently been developed significantly [1, 2]. Representative examples with some mechanistic discussion are summarized in this section. 

Seregin IV, Gevorgyan V (2007) Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem Soc Rev 36 1173-1193... 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Xanthate 446 undergoes cyclization in the presence of camphorsulfonic acid via a radical chain reaction initiated by a small amount of lauroyl peroxide to give pyrroloimidazoles 449 in 56% yield. The use of an acid and anhydrous medium inhibits nucleophilic attack of the basic heterocycles at the xanthate moiety and allows radical reactions to occur. Fused heteroaromatic compounds can also be prepared directly from benzimidazole carrying an N-alkenyl substituent and xanthates by a tandem radical addition/cyclization to provide, for example, pyrrolobenzimidazole 453 in 57% yield (Scheme 106) <2002OL4345>. 

Direct interaction of a nitro substituent with electron-rich and electron-poor side-chains in ort o-substituted nitroaromatic and nitro-heteroaromatic compounds is a well-documented and fruitful source of novel heterocycliza-tion reactions. In this context, efficient solution-phase pyrolytic transformations of 4-nitro-l//-imidazol-5-ylethano-ates 356 and 3-nitropyridinyl- and 5-nitropyrimidinyl-ethanoates 358 gave 3,4-fused isoxazoles 357 and 359, plausibly through ketene intermediates (Scheme 87) <2002ARK80>. 

On the other hand, five-membered heteroaromatic molecules are the model structures first employed for kinetic investigation of the reaction mechanism in gas-phase heteroaromatic substitutions. While comparison of the relevant kinetic data with most common ion-neutral body collision theories and with theoretical predictions appears quite promising, nevertheless, accurate modeling of intrinsic reactivity properties of heteroaromatic compounds demands a more complete research effort, mainly directed to comparing the kinetic behavior of heteroaromatic compounds toward electrophilic and nucleophilic species (83IJM225 84JOC764) in the gas phase and in solution. 

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