Anionic cyclization 5-endo-trig

According to Baldwin s rules, the anionic 5-endo-trig cyclization is a disfavoured process, but it has been found to be facilitated by the introduction of two fluorine atoms at the terminal carbon atom. ° Extensive ab initio calculations (Gaussian 94 and Mulliken) for homoallylic alkoxides found that the highly electronegative fluorine atoms stabilized both transition state and product. 

Yamazaki T, Hiraoka S, Sakamoto J, Kitazume T. Anionic 5-endo-trig cyclization of terminally difluorinated homoaUyhc alkoxides. J. Phys. Chem. A 1999 103 6820-6824. 

Endo-trig cyclization of anion 29, formed from 3-methylpyridazine by LDA in THF with methyl 3-propynoate provided 6H-pyrido[l,2-fc]pyrida-zin-6-one 30 (06TL5063). 

Cyclocondenzation of 2-pyridylacetonitrile and ethoxycarbonyl isothiocyanate in MeCN gave 4-cyano-l-oxo-2,3-dihydro-lH-pyrido[l,2-c]pyrimi-dine-3-thione in 18% yield (08MI2). 6-Endo-trig cyclization of anion, formed from 4-methylpyrimidine by LDA in THF at —78 °C, with methyl 3-propynoate provided 8-methyl-6H-pyrido[2,l-c]pyrimidin-6-one in 47% yield (06TL5063). 

Grigg, R. Kemp, J. Malone, J. Tangthong-kum, A. 5-Endo-trig cyclization and 1,3-anion-ic cycloaddition in arylimine derivatives of a-amino acid esters. J. Chem. Soc. Chem. Commun. 1980, 648-650. 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

Reactions of Monocyclic Azepines. The enolate anion (18) cyclizes to give (20) via what is apparently a 5-endo-trig process (Baldwin disfavoured), so either this rule applies with less rigour to the formation of bridged systems or an alternative mechanism is operating - possibly prior tautomerization to (19) and a 5-exo-trig cyclization. ... 

Since the Baldwin mles are not exclusive, disfavored cyclization can take place when the reaction conditions are properly changed. In basic medium the enone form of 2 reacts, and the alkoxy anion approaches the P-C atom of the C=C bond in the disfavored 5-endo-trig mode. In the acidic medium, protonation of the carbonyl group promotes the formation of enol in equilibrium with enone. This reactive species enters cyclization in 5-exo-trig mode (Scheme 7.17). TM 7.10 is isolated in 84% yield on prolonged heating in dichloroethane in the presence of a catalytic amount of p-TsOH. 

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