Ring systems cyclization, nitrogen nucleophiles

Intramolecular nucleophilic displacement of the bromo group by an azine-nitrogen occurs in the cyclization of A-2-quinaldyl-2-bromo-pyridinium bromide (248) to give the naphthoimidazopyridinium ring system. The reaction of 2-bromopyridine and pyridine 1-oxide yields l-(2-pyridoxy)pyridinium bromide (249) which readily undergoes an intramolecular nucleophilic substitution in which departure of hydrogen as a proton presumably facilitates the formation of 250 by loss of the JV-oxypyridyl moiety. 

Additions to l,3-dienes6 (12, 367-368 14, 249-250 15, 245). This reaction can be used to effect intramolecular cyclization of cyclic 1,3-dienes substituted by a suitable nitrogen nucleophile. Thus reaction of the amido diene 1 with lithium acetate catalyzed by Pd(OAc)2 (with benzoquinone as reoxidant) provides the ds-fused heterocycle cis-2, in which the acetoxy group is cis to the ring fusion, formed by an overall trans-1,4-oxyamidation of the diene system. Addition of a trace of LiCl improves the yield and results in an overall cis- 1,4-oxyamidation (equation I). Acetamides and carbamates can also be used in place of amides. 1,4-Chloroamidation can also be effected by use of 2 equiv. of LiCl. 

Cyclization of an indolylethyl-tetrahydropyridine derivative is also a key stage in an extremely brief and elegant synthesis of the yohimbine ring system and a number of ajmalicinoid bases by Wenkert and his collaborators.78 Thus, internal nucleophilic attack by enolate anion at the y-position to the nitrogen atom in (122) gave a tetrahydropyridine derivative which readily cyclized to the pentacyclic enamine (123), reduction of which gave (db)-pseudoyohimbone (124) (Scheme 11). 

In the presence of a palladium catalyst, allyl epoxides (113) react with nitrogen nucleophiles at the al-kenic carbon atom remote from the oxirane ring to give 1,4-adducts (114)." In the absence of a palladium catalyst, azide ion attacks the oxirane ring affording 1,2-adducts (115 Scheme 52 and Table 2)." Vinyl epoxide (116) gave 1,2- and 1,4-azido alcohol in a ratio of 1 1.5 irrespective of the reaction system. " Intramolecular cyclization of vinyl epoxide (117) in the presence of a palladium catalyst afforded isoquinuclidine (118 Scheme 52). ... 

The use of intramolecular nitrogen nucleophiles in such schemes holds much promise for the formation of nitrogenous heterocycles. This is especially the case when a second radical ring closure may be built in tandem-wise (Scheme 29) [53]. The stereochemistry of the two major products (35) and (36) here is best explained by transition states for the radical cyclization which put the phenyl ring on the exosurface of the developing bicyclic system. tra y-Selectivity in cyclization of benzyl radicals is standard [54] and provides the major product (35). 

Cyclization can also be performed via nucleophilic attack of nitrogen nucleophiles as shown for the release of cyclic urea derivatives. Dressman et al. examined a methodology to cleave hydantoins 222 via treatment of carbamate linkers with an intramolecular amide functionahty and base [188]. In the case of resin-bound substrate 221 (Scheme 33), the resulting heterocycle is a five-membered ring system but other heterocycles containing a urea-type unit can also be synthesized as published by diverse other groups (c.f. benzimidazolone-synthesis of li et al. [199]). 

In the latter example, cyclization occurs exclusively to the carbonyl carbon rather than with nucleophilic displacement of chloride at the a-carbon. Intramolecular alkylation of nitrogen does occur in other systems the 3-chloropropylsulfonylhydrazide (194), for example, ring closes to give the 1,2,3-thiadiazine dioxide (195) on treatment with base (62JPR(19)56). 

Betainic alkaloids and nucleobases, 85, 67 Bicyclic 6/5 ring-fused systems with bridgehead nitrogen, 49, 193 Bifunctional nucleophiles cyclizations and ring transformations on reaction of azines with, 43, 301... 

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