Radical cyclization tetrahydropyridines

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

Radical cyclizations of tetrahydropyridine scaffolds have been used to access diverse skeletal frameworks.An example of tandem radical cyclizations with two C-C bond formation is shown in Reaction (82). Treatment... 

An unusual 4-exo-trig cyclization accompanied by a later rearrangement was observed with aryl enolether 13 (Scheme 6) [48], The benzoxetane 14, which is formed in the initial cyclization step, undergoes ring-opening to form the phenoxy radical 15. 5-Endo cyclization of 15 and reduction of the resulting benzylic radical leads to the spirocycle 16. Diverse polycyclic products have also recently been obtained by intramolecular aryl radical cyclizations to tetrahydropyridines [49]. 

Sultams can also be accessed by intramolecular cyclization of compounds containing preformed C-S-N-C-C fragments with a C-C bond formation as demonstrated in a one-pot synthesis of tricyclic sultam 236 <05SL577>. Tetrahydropyridine 235, obtained from 77,7/-bis(allyl)sulfonamide 234 by ring-closure-metathesis (RCM) followed by isomerization, undergoes radical cyclization in the presence of tris(trimethylsilyl)silane (TTMSS) to give tricycle sultam 236. 

A regioselective free radical initiated reaction between 1,2,5,6-tetrahydropyridine and thiiranes has been shown to produce /3-aminothiols (311), which cyclize on boiling under reflux with di-/-butyl peroxide in chlorobenzene to give perhydrothiazolo[3,2-a]pyridine derivatives (312) (82TL5039). 

Indolylacyl radicals have also been used to access the 1,5-methanoazocino [4,3-A]indole system found in the uleine and Strychnos alkaloids [115, 116]. In several examples, Bennasar and coworkers utilized tributyltin hydride and EtsB to affect 6-exo and 6-endo cyclizations of the radicals, which were derived from the corresponding seleno esters, onto tetrahydropyridine double bonds. The example shown below illustrates the utility of the reaction sequence in the preparation of the uleine alkaloid isodasycarpidone (219). As such, seleno ester 218 was synthesized easily from indole and 2-cyanotetrahydropyridine and then further converted to the natural product in fair yield. 

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