Aromatization, by loss

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

When benzyne is generated in the absence of another reactive molecule it dimerizes to biphenylene.132 In the presence of dienes, benzyne is a very reactive dienophile and [4+2] cycloaddition products are formed. The adducts with furans can be converted to polycyclic aromatic compounds by elimination of water. Similarly, cyclopentadienones can give a new aromatic ring by loss of carbon monoxide. Pyrones give adducts that can aromatize by loss of C02, as illustrated by Entry 7 in Scheme 11.9. 

Aphrodisiac, reputed, 347 Appetite depressants, 47 Aprindine, 208 Arbuzov reaction, 420 Aromatization, by loss of methyl group, 147, 149 Arrhythmias, cardiac, 33 Aspirin, 63, 89 Atenolol, 109... 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

Treatment of piperazine-2,5-diones, unsubstituted on the nitrogen atoms, with phosphorous oxychloride results in chlorination with simultaneous aromatization by loss of two hydrogen atoms [82JCS(P1)953] as shown in Scheme 16. 

Recently we have developed a more general approach to molecules exemplified by III. Thus the Diels-Alder cycloaddition of alkyne II and ct-pyrone, followed by aromatization by loss of carbon dioxide, led to the isolation of III (72%) (5). Alkyne II was obtained in high yields, in two steps from dichloroacetylene and triethylphosphite via Arbuzov-type reactions (5). Since the intermediate chloroalkyne phosphonate I was isolable (90%), phosphorus nucleophiles other than triethylphosphite could be used to give unsymmetrical alkyne diphosphoryl species. We have demonstrated this approach by the reaction of I with PhaPOEt and PhP(OEt)2 (5). 

Since the hydride is a very poor leaving group, the role of the oxidant is to provide, in a redox-type reaction, two electrons to convert this anionic adduct into a cationic species, which aromatizes into the amino product by proton elimination (Scheme 2). It cannot be excluded that under these conditions a one-electron process occurs, yielding a pyrimidyl radical, that aromatizes by loss of a hydrogen atom. 

Anions of isocyanides, especially tosylmethyl isocyanide (TsMIC) and esters of isocyanoacetic acid, form pyrroles by addition to electrophilic alkenes and alkynes. For example, addition of TsMIC to acrylate esters in the presence of NaH is followed by cyclization at the isocyanide carbon leading to an intermediate which can aromatize by loss of sulfinate (Scheme 76) <80Mi 203-01 >. 

An intermolecular Diels-Alder reaction of 3,4-pyridyne has been used in a short synthesis of the important anticancer alkaloid eUipticine. In this case the diene is an a-pyrone the initial Diels-Alder adduct is not isolated since it spontaneously aromatizes by loss of carbon dioxide. Unfortunately, the Diels-Alder reaction is not regioselective and an equal amount of the product arising from the alternative direction of addition to 3,4-pyridyne is formed (Scheme 7.35). 

A remarkably simple two-stage synthesis of 2-aryl-pyridines from cyclo-pentadienes has been reported. The 4a,7a-dihydrocyclopenta[ ][l,2]oxazines (10), available from cyclopentadiene and a-halogeno-ketoximes, at 200 °C undergo successive electrocyclic ring-opening and ring-closure to form the acyl-dihydropyridines (11), which aromatize by loss of acetaldehyde as illustrated in Scheme 2. 

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