Anionic cyclisation mechanism

The stereochemical contrast between radical and anionic cyclisations provides a useful test of mechanism which has been used on a number of occasions to elucidate the course of reactions whose mechanism is ambiguous. For example the results in table 7.2.2 show that the anionic cyclisation of 352 under certain conditions proceeds without a radical component. However,... 

The first alkyne cyclisations, from 377, 379 and 381, predate the early alkene cyclisations by a couple of years these three date from 1966173 and 1967,174 and illustrate the favourability of both exo and endo-dig cyclisation. All three generate benzylic vinyllithiums (378, 380 and 382), and both aryl (377, 379) and alkyl halides (381) are successful starting materials. Similar organomagnesium cyclisations were described at about the same time.175 However, it is not clear in these reactions how much of the product is due to participation of radicals in the mechanism - alkylbromides undergo halogen-metal exchange with alkyllithiums via radical intermediates (chapter 3).176 If it really is an anionic cyclisation, cyclisation to 378 is remarkable in being endo. Endo-dig anionic cyclisations are discussed below. 

A more recent paper by Cunningham and Schmir242 on the hydrolysis of 4-hydroxybutyranilide XL in neutral and alkaline solution suggests that intramolecular nucleophilic attack by the neighbouring hydroxyl group is followed by bifunctional catalysis by phosphate or bicarbonate buffers of the conversion of the tetrahedral intermediate to products. A quantitative comparison was made between the effects of buffer on the hydrolysis of 4-hydroxybutyranilide and on the hydrolysis of 2-phenyliminotetrahydrofuran, since both reactions proceed via identical intermediates. The mechanism suggested243 states that the cyclisation of the hydroxyanilide ion yields an addition intermediate whose anionic form may either cleave to products or revert to reactant and whose neutral form invariably gives aniline and butyrolactone, viz. 

Conversion of the trimer (80) to the seven-membered ring system (81) occurs readily with cesium fluoride [3,75], whereas in the presence of TAS fluoride, the di-anion (82) is trapped. These observations lead to the most likely mechanism for rearrangement as that in Scheme 37 [3]. The cyclisation step shown in Scheme 37 is made more easily accepted by the fact that the diene (83) (Scheme 38), undergoes rapid rearrangement in the presence of fluoride ion, giving the cyclic system (86) [77]. The ready cyclisation of a crowded anion (84) to give what appears to be a sterically unfavourable intermediate (85) would not be easily predictable ... 

Additional support for an alternative alkene first mechanism in these cyclisations came from the successful cyclisation of cyclopropyl ketone 26 with no observance of fragmentation products (Scheme 5.21).43 This suggests that a ketyl radical anion is not formed during the cyclisation and that reduction of the alkene leads to product formation. 

The reaction mechanism involved the cyclisation of ketyl radical anion 3 on to the methylenecyclopropane moiety in a 5-exo-trig manner. Ring opening of cyclopropane intermediate 4 gave rise to the cyclohexyl radical 5, which then cyclised in a 5-exo-dig fashion to form the second ring (Scheme 6.2).5,6... 

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