Substituted heteroaromatic

A research team at Rhone-Poulenc reported a four-component procedure for the synthesis of variously substituted heteroaromatic tetrazolo[l,5-zz]pyrazines <1998TL2735>. Thus, aldehydes, primary amines, trimethylsilyl azide, and methyl /3-(iV,iV-dimethylamino)-a-isocyanoacrylates 117 were reacted in a methanolic solution at room temperature to yield the product 119 in high yields. The reaction was rationalized to proceed via the formation of intermediate 118. The procedure proved to be efficient for combinatorial chemical applications. 

Thus, the unsubstituted starting compound 69 was treated with resorcinol in the presence of trifluoroacetic acid (TFA) to yield 70. Then, reaction of 69 with the cyclic a,/3-unsaturated ketone in the presence of lithium hydride gave the 7-substituted heteroaromatic compound 71, and ethyl cyanoacetate afforded the cross-conjugated product 72, whereas reaction with pyrimidine-2,4,6-trione in the presence of triethylamine yielded the addition product 73. Indole also been reacted with 69, and heating of the dichloromethane solution for 90 min in the presence of TFA yielded the addition product 74 in excellent yield (95%) <1998ZOR450> (Scheme 12). 

These authors found that nucleophilic additions to the unsubstituted ring system 1 can be carried out to yield a number of 7-substituted dihydro products or, in some cases, where an oxidation can follow this addition, also 7-substituted heteroaromatic derivatives (Scheme 6). Thus, reaction of 1 with indole under acidic conditions (in trifluoroacetic acid) yields 7-(177-indol-3-yl)-7,8-dihydrotetrazolo[l,5- ][l,2,4]triazine 24 <1998ZOR450>. Reaction of 1 with 3,4-difluoroacetophenone in the presence of potassium /frt-butoxide in tetrahydrofuran followed by... 

The substituted heteroaromatic compounds provide excellent opportunities for mechanistic studies of the interaction between the nitro group and other substituents. This is due... 

In a paper pnblished in the early 1950s Touster found that sodio derivatives of many alkyl-substituted heteroaromatic compounds or of allyl-substituted benzenes 30 can be oximated with alkyl nitrites in refluxing anhydrous liquid ammonia at atmospheric pressure... 

Subsequently, Kato and Goto have reported the synthesis of 2- and 4-pyridinecarbox-aldoximes from 2- and 4-picoline with potassium amide and amyl nitrite in liquid ammonia at — 33°C, although they failed to obtain either of these oximes when the reaction was carried ont with sodium amide in liquid ammonia at room temperature in a sealed tube. Finally, in 1964, aUcyl-substituted heteroaromatic compounds and allyl-substituted benzenes were oximated in liquid ammonia at —33 °C with sodamide and an alkyl nitrite . 

Substantially fewer studies have been published for the reactions of alkyl-substituted heteroaromatics, although these compounds also have implications for coal combustion. Several references discussed in the previous section contain information on methylated heteroaromatic rings. Mackie and coworkers completed experimental and theoretical studies of the pyrolytic decomposition of 2-picoline (2-methylpyridine). They concluded that decomposition proceeded mainly through o-pyridinyl and 2-picolinyl radicals. The former tended to decompose predominantly to yield cyanoacetylene, while the latter favored decomposition to a cyano-functionalized cyclopentadiene (Fig. 16). 

Despite the authors assertion that alkylated heteroaromatic compounds provide a better model for fuel-bound nitrogen than do the unsubstituted heterocycles, their pyrolytic study remains the most comprehensive look at substituted heteroaromatic chemistry, even several years later/ Kinetic studies are more common in the literature Frerichs et al. examined the reaction of the picolines with oxygen atom, while Yeung and Elrod studied reactions of HO with pyridine and its methyl- and ethyl-substituted derivatives.Both groups noted that the presence of nitrogen did not demonstrably affect the species chemistry generally, reactivity is comparable to toluene. 

Table 1 Thermodynamic and spin density information for methyl hydrogen atom loss reactions of methyl-substituted heteroaromatic rings. Enthalpies and energies in kcal/mol, obtained at the B3LYP/6-31 l+G //B3LYP/6-31G (designated as B3LYP) and CBS-QB3 (designated as CBS) levels...

IG ) for alkyl group loss reactions of methyl- and ethyl-substituted heteroaromatic rings... 

Fig. 17 Variation of reaction free energy (kcal/mol) with temperature (K) for alkyl C—H hydrogen atom loss in (a) five-membered ring methyl-substituted heteroaromatic rings and (b) six-membered ring methyl-substituted heteroaromatic rings.

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

The procedures discussed for aromatics can readily be adopted for the efficient preparation of fluoro-substituted heteroaromatics.141,143,149 150 Fluorodediazoniations of 2-ainino-, 3-amino-, 4-amino- and 2.6-diamino-substituted pyridines and some of the chloro or bromo derivatives have been carried out in liquid hydrogen fluoride with anhydrous sodium nitrite. About 1.2 equivalents of nitrite are used per amino group, and ammonium hydrogen fluoride has also been added. The corresponding fluoropyridines or their hydrochlorides have been obtained in 49-89% yield.150 For example, the reported synthesis150 is suitable for the preparation of larger quantities of 4-fluoropyridine hydrochloride (54% yield mp 100 C) examples are given by the formation of 5-7.150... 

The exploration of DoM chemistry in haloheteroaromatics is valuable for two reasons (a) halo derivatives can be readily prepared from acessible amino, hydroxy, and, at times, unsubstituted systems, and (b) halogens can be subsequently induced to undergo a variety of funcionalizations via addition-elimination, metal-halogen exchange, SRN1, and cross coupling reactions. Some of these transformations are more facile than in the aromatic series. Thus, DoM tactics may lead to diverse substituted heteroaromatics, which can be difficult to obtain by more classical means. 

Noyce has also reported a very extensive series of investigations into the reactivity of substituted heteroaromatic compounds. Although the... 

Finally, dianils of aromatic dialdehydes may react with 2 moles of a p-tolyl-substituted heterocycle. For example, 5-phenyl-2-(p-tolyl)-1,3,4-oxadiazole (71) reacts with Schiff s base from 2 moles of p-chloroaniline and 4,4 -diformylbiphenyl (72) to give 4,4 -bis[4-(5-phenyl-l,3,4-oxadiazol-2-yl)styryl]biphenyl (73).43 Along with further p-tolyl-substituted heteroaromatics, a number of carbocyclic aromatics have... 

Mamaev, V. P., Shkurko, O. P., Baram, S. G., Electron Effects of Heteroaromatic and Substituted Heteroaromatic Groups,... 

Terashima, M., Ishikura, M., Boron-substituted Heteroaromatic Compounds, 46, 143. 

Biological pyrimidines, tautomerism and electronic structure of, 18, 199 Bipyridines, 35, 281 Boron-substituted heteroaromatic compounds, 46, 143 Bridgehead nitrogen saturated bicyclic 6/5 ring-fused systems with, 49, 193... 

Electronic effects of heteroaromatic and substituted heteroaromatic groups,... 

In 1993 Murai et al. [16] reported a rare example of the catalytic C-C bond formation between aromatic ketones or acyl-substituted heteroaromatics and cy-cloalkenes via activation of the C-H bond in the ortho position to the ketone functionality. These reactions are described in the chapter Activation of Inert C-H Bonds . 

Trifluoromethylthio-substituted heteroaromatic systems are available by a multistep procedure, namely photochlorination of the corresponding methyl thioether and subsequent halogen exchange on treatment with antimony trifluoride (52ZOB2216 54ZOB887) (Scheme 18). 

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