Heterocyclic synthesis seven-membered rings

Preparation of spirooxaziridines from cyclic ketones poses no problems nor does oxaziridine synthesis from cyclic Schiff bases, which was preferably carried out with pyrro-lines to give, for example (245) (59JCS2102) and, in connection with tranquilizer synthesis, with heterocyclic seven-membered rings to give, for example, (246) (63JOC2459). 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

Coquerel Y, Bensa D, Doutheau A, Rodriguez J (2006) Synthetic studies on the MARDi cascade stereoselective synthesis of heterocyclic seven-membered rings. Org Lett 8 4819-4822... 

Cyclative cleavage to five- and six-membered ring heterocycles is dominated by the synthesis of hydantoins and diketopiperazines, respectively. In the seven-membered ring case, it is the benzodiazepine nucleus that has attracted attention, due to its status as a privileged structure in drug discovery. In the precombinatorial days, Camps et al,33 reported a... 

The second method employed for the synthesis of telluraxanthene is similar to that widely used for the preparation of various tricyclic heterocycles containing one or two heteroatoms. It is based on the interaction of 2,2 -dilithiodiphenylmethane with powdered tellurium, by which reaction telluraxanthene 82 has been prepared in 50% yield [81JOM(205)167]. The reaction apparently proceeds through the intermediate bis(telluro-phenolate) 86 which is oxidized to the heterocyclic ditelluride 87. The latter compound eliminates tellurium from its stericaily strained seven-membered ring and converts to telluraxanthene. This mechanistic scheme seems to be corroborated by the observation that the treatment of lithi-oarenes ArLi usually ends in the formation of diarylditellurides Ar2Te2 (74MI1 83MI2). 

The full potential of ring-closing metathesis methodology in the synthesis of seven-membered heterocyclic systems is still to be realised, and there are many opportunities to investigate different substituents in the diene precursors. A combination of ring-closing metathesis with other reaction types in a cascade context is also likely to realise novel seven-membered ring based systems. 

In more modern times, the first successful anti-ulcer drug, cimetidine 3, with its ability to block histamine synthesis in the stomach, is an imidazole and the classical anti-depressant valium 4 has a seven-membered ring heterocycle that is not (quite) aromatic. 

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