Thorpe-Ziegler cyclization mechanism

The present review covers the Thorpe-Ziegler syntheses of 3-aminofurans, 3-aminopyrroles, 3-aminothiophenes, 3-aminoselenophenes, and diverse aminoazoles as well as the corresponding annulated systems that appeared from 1983 to 1996 but excludes examples considered in the 3-cyanopyridine review (92MI1). Moreover, examples are included that do not report a separate Thorpe-Ziegler cyclization but are likely to involve this type of reaction (e.g., cases in which precursors 1 were not isolated and identified but directly formed in the reaction mixture). Special attention is paid to synthetic aspects, although some reaction mechanisms are discussed too. 

The Thorpe-Ziegler cyclization is characterized by a relatively straightforward mechanism. As demonstrated below, deprotonation of dinitrile 1 results in the formation of the anionic species 2. Intramolecular cyclization in a manner similar to the well-known Dieckmann condensation yields 3. Workup under aqueous conditions then produces imine 4, which immediately tautomerizes to the conjugated enamine 5. 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

The formation of the 3H-3-morpholinopyrrole 82 from the cyanoazabu-tadiene 81 also involves a Thorpe-Ziegler type cyclization (Scheme 21) (for a further example in the tetrahydroindole series and the mechanism see Scheme 26) (87HCA187). 

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

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