Azacycles, formation

Heterocyclizations. An n-donor atom at a proper distance to an a-diazomethyl ketone participates in metal-catalyzed decomposition of the functional group, giving rise to a heterocyclic ketone. For medium azacycle formation the soluble Cu(acac)2 complex is much superior to Rh2(OAc)4- Oxacycles are similarly accessible using the hexafluoroacetylacetonate. ... 

Scheme 25 Sequential formation of 13- and 8-membered azacycles in Martin s total synthesis of ircinal A (129) and related manzamine alkaloids [78]...

Scheme 26 Sequential formation of 8- and 15-membered azacycles in total synthesis of enf-nakadomarin A (145) [80]...

Initial studies focused on lanthanocene-based catalyst systems that proofed to be efficient in the exo-specific cyclization of terminal aminoalkenes to form five-, six-, and seven-membered azacycles (Scheme 2). The reactions are predictably faster for the formation of smaller five-membered rings and in the presence of em-dialkyl substituents [117]. An increasing metal ionic radius and a more open coordination sphere, for example, in onra-lanthanocenes, are also beneficial for higher cyclization rates [103]. A further increase in catalytic activity is observed when sterically more open and more electrophilic CGC 17 (Fig. 15) are applied [118]. 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme 25).57,58 It is important to note that under identical conditions amines (62) and (63) did not cyclize but afforded the corresponding IVjV-dimethylamines. With regard to the alkene participant these results are in full accord with Baldwin s rules for ring formation.2 However, the formation of pyrrolidine (61) demonstrates that 5-endo-trig cyclizations2 can take place with respect to the iminium ion n-participant. The observed regioselectivity and the failure of (63) to cyclize are in accord with obligatory formation of an intermediate with tertiary carbocation character. 

Further examples of the formation of bridged azacyclic systems from the reaction of (65) with aryl Ketones are illustrated by the conversion of indanone (66) into (67) with ammonium acetate in ethanol. 67... 

An analogous pathway could be involved in the formation of 4-formyl-2-azacycl[3.2.2]azine (180) in 14% yield by treatment of 5-methylimidazo[l,5-fl]pyridine (179) with butyllithium and DMF, but the route suggested (75JOC1210), via the dialdehyde, (181) is also possible. 

Abstract Recent advances in strategies for the synthesis of manzamine-related alkaloids are summarized and discussed. We particularly focus on strategies for the formation of a complex central ring core, especially substituted hydroquinoline, and the formation of medium and large azacycles. 

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