Bergman cyclization experimental

These computational predictions have been tested experimentally. Kinetic measurements confirmed that both ortho-N02 and ortho-CHO substituents substantially decrease activation energies for the Bergman cyclization supporting earlier computational predictions.51... 

A very interesting experimental observation of Jones et al. illustrates a different effect of strain on the efficiency of photochemical Bergman cyclizations.43d Variations in the size of the cycle which does not incorporate the whole enediyne system, but only the vinyl part of the enediyne moiety (in contrast to the previously discussed data) affect the yield of the cycloaromatized product. Initially, an increase in the ring size leads to an increase in yield (Scheme 16). 

Kim and Russell synthesized 5,6-diethynyl-2,4-dimethoxypyrimidine (85) starting from iodination of 5-chloro-2,4-dimethoxypyrimidine [61], Very careful experimentation resulted in optimal conditions for the Sonogashira reaction of dihalopyrimidine 83 with trimethylsilylacetylene to provide bis-alkyne 84. The temperature appeared to be crucial. Only mono-substitution for the iodine was observed at lower temperature, whereas Bergman cyclization seemed to occur at temperatures higher than 120 °C. Subsequent desilylation of 84 then delivered diethynylpyrimidine 85. 

An interesting route to 98 was suggested by Cramer et al. " cyclization of isonitrile 110 could lead to 98 in a rearrangement analogous to the Bergman cyclization. The activation enthalpy for the only slightly exothermic reaction was estimated at 18 kcal/mol. However, this novel access to m-arynes could not be realized experimentally so far. 

One of the most important transannular reactions of cyclic alkynes is the Bergman cycliza-lion [67] of enediynes (Scheme 8-15). Nicolaou et al. have shown that the crucial distance between the termini of the enediyne system, allowing spontaneous Bergman cyclization at room temperature, is in the range of 3.1-3.2 A [9cj. Questions about the energy and structure of the biradicaloid intermediate and the mechanism of the biradical formation have stimulated considerable theoretical and experimental work [68]. These investigations and the importance of the Bergman cyclization reaction for the action of a new class of antitumor antibiotics will not be discussed here, as the enediynes are dealt with in considerable detail in Chapter 7. 

Extensive mechanistic studies of this cyclization reaction were carried out by Myers et al. and extended with theoretical work by Squire s et al. It is known that, in contrast to the Bergman cyclization of the ene-diyne (Chapter 4.2), this transformation proceeds as an exothermic process determined by the increased stability of a benzyl radical versus a phenyl radical. The barrier for cyclization from substrate to a diradical product is low and can further be reduced by an appropriate substitution at the allenic terminus of the substrate. The dichotomous (polar and free radical) reactivity is observed on pyrolysis in the presence of polar reactants. Both radical and polar products arise from a common intermediate, which is described as a polar diradical, a linear combination of limiting structure 7 and zwitterion 11. According to Squires, polar diradical singlet species are involved. Based on computational studies supported by experimental product distribution studies, it has been proposed that both the diradical 7 and... 

Zeidan, T.A., Kovalenko, S.V., Manoharan, M. and Alabugin, I.V. (2006) Ortho effect in the Bergman cyclization comparison of experimental approaches and dissection of cycloaromatization kinetics. Journal of Organic Chemistry, 71(3), 962-975. 

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