Heterocycles synthesis using benzene

Radicals can be generated from aromatic compounds by different methods and can be used for heterocycles synthesis. This is illustrated by the synthesis " in modest yield (45%) of benzoquinolones (phenan-thridones) starting with 2-aminobenzanilides (such as 4.43, Scheme 4.47). The amino group is converted to the stable (even when dry) dia-zonium fluoroborate (4.44) from which an aiyl radical is generated by action of metallic copper. The radical then adds to a double bond of the second benzene ring (Scheme 4.47) to form radical 4.45, which is resonance delocalized. An oxidative step (even just exposure to air) is then required to achieve the fully aromatic system of the phenanthridone (4.46). 

Dipoles can also be built into heterocyclic systems, and though of limited use, they may also be utilized for the synthesis of [5,6] ring-fused systems. Reaction of 2 3H)-benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic pyridinone (418) was obtained, presumably by elimination of COS from the intermediate cycloadduct (417) (80JOC2474). 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Despite that the thiophene ring is considered as a bioisoster of the benzene ring, the synthesis and chemistry of thiophene analogs of heterocycles with therapeutic interest remain poorly studied. One of the most recent examples concerns the synthesis of new substituted thioisatoic anhydrides (6 and 7-arylthieno[3,2-d] [1,3]oxazine-2,4-diones), which were prepared on a large scale under microwave irradiation conditions. A small library of thiophene ureidoacids was easily performed using a Normatron microwave reactor (500 W) with high yields and good purity [4,5] (Scheme 4). 

Synthesis ofAzo Dyes. Processes to all the major benzene and naphthalene intermediates that are used in the commercial manufacture of azo dyes have been extensively reviewed. Description of the synthetic routes to heteroaromatic diazo components, such as those shown in Figure 2.8, are well covered in literature reviews, ° as are all the major heterocyclic coupling components. 

In order to outline the scope of this chemistry, Sections 4.8.2 and 4.8.3 will discuss the catalysts and carbenoid precursors used. This will be followed by reactions of caibenoids with ir-systems, organized according to the ir-system involved, alkenes (Section 4.8.4), alkynes (Section 4.8.5), benzenes and electron-rich heterocycles (Section 4.8.6). Particular emphasis will be placed on the stereochemical outcome of these reactions with reference to applications in organic synthesis. 

In a convenient experimental procedure, nitrogen heterocycles 3 are alkylated by a mixture of a carboxylic acid 4 and [bis(trifluoroacetoxy)iodo]benzene in boiling benzene or under irradiation in dichloromethane at room temperature (Scheme 2) [11, 12]. A similar procedure has been used for the stereoselective synthesis of C-nucleosides and their analogs via photolysis of the gulonic acid derivatives, (diacetoxy)iodobenzene, and the appropriate heteroaromatic bases [13]. 

The use of the hypervalent iodine reagent [bis(trifluoroacetoxy)iodo]benzene has been reported to be effective in the synthesis of C-nucleoside-like compounds. Radical decarboxylation of a suitably protected uronic acid, initiated photochem-ically, followed by addition of a heterocyclic base provided the C-nucleoside in high yield.154 The mode of action involves initial radical formation of 122 (Scheme 33), followed by introduction of the base and radical coupling.155 The anomeric selectivity was high in some examples, and low in others—lepidine gave the highest proportion of the ( anomer. Isolated yields were poor to moderate. 

The (V-oxide derivatives (235)-(240) have all found use in the synthesis of bicyclic heterocycles. 2-Chloronitroethene reacted with (V-oxide (235) in benzene at reflux temperature giving a mixture... 

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