Double cyclization substituent effects

This similarity in reactivities probably derives from a fortuitous cancellation of substituent effects in 11. Fluorination increases chain stiffness and creates an unfavorable polarity mismatch between an electrophilic radical and an electron-poor double bond, but this is offset by the significant decrease of 7r-bond energy in 11. The vinyl ether 12 analog cyclizes about seven times faster than 11, which is consistent with the known lower 7r-bond energy and higher free-radical reactivity of perfluorovinyl ethers vs perfluoroalkenes [142]. 

Due to their ready isomerization simple cyclopentenones present a particular challenge in the Nazarov cyclization. In all of the cases studied in a- and -monosubstituted and a, -disubstituted systems the cy-clopentenone product contained the double bond in the less substituted position, as required by loss of the silicon electrofuge (Scheme 17). The relative conBguration of substituents in disubstituted cases is controlled by kinetic protonation and weakly favors the cis isomers. Substituent effects in rate were particularly noted in these cases where substitution with a- and -alkyl groups greatly accelerated and decelerated the reactions, respectively. 

When this stereoelectronic requirement is combined with a calculation of the steric and angle strain imposed on the transition state, as determined by MM-type calculations, preferences for the exo versus endo modes of cyclization are predicted to be as summarized in Table 12.3. The observed results show the expected qualitative trend. The observed preferences for ring formation are 5 > 6, 6 > 7, and 8 > 7, in agreement with the calculated preferences. The relationship only holds for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity as a result of a steric effect. 

Entry 11 involves generation and cyclization of an alkoxymethyl radical from a selenide. The cyclization mode is the anticipated 5-exo with a cis ring juncture. This is a case in which the electronic characteristics of the radical are not particularly favorable (ERG oxygen in the radical), but cyclization nevertheless proceeds readily. The reaction in Entry 12 was used to prepare a precursor of epibatidine. Entry 13 shows a 6-endo cyclization that is favored by steric factors. The 6-endo cyclization is also favored with a tetrahydropyranyloxy substituent in place of the ester, indicating that the electronic effect is not important. Entries 14 to 16 involve acyl radicals generated from selenides. The preferred 6-endo cyclization in Entry 15 is thought to be due to the preference for the less-substituted end of the double bond. Entry 17 is an example of a 5-exo-dig cyclization. 

An interesting feature of the cyclization of y, -unsaturated alcohols is the marked effect on product isomer distribution by the nature of substituents remote from the double bond (cf. 42 and Scheme 59).98 Complete stereospecificity is observed for the phenyl derivative 42a in contrast to 42b and c, and the isomer ratio is reversed for 42d. The suggested mechanism98 is shown in Scheme 60 the trisubstituted alkene (45) is mainly converted into a pyran (46) rather than a tetrahydrofuran derivative (Scheme 61). 

Barluenga and coworkers42 studied in recent years the behavior of 2-lithioallyl and 2-lithioaryl amines, as well as of 2-lithioaryl ethers43, in their anionic cyclizations onto unactivated double bonds. They reported the effect of different substituents at the terminal... 

The Nazarov cyclization is well suited for the construction of simple cyclopentenones adorned with various substitution patterns. A collection of representative structures prq>aied from either allyl vinyl or divinyl ketones is shown in Scheme 10. Many different alkyl groups are compatible with the substitution patterns. Aromatic substituents, especially at the a-position, have a beneficial effect on the reaction rate and yield. In all of those cases where a choice is possible, the double bond resides in the thermodynamically most stable position. 

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