Bergmann cyclization

The Sonogashira reaction is used a lot because of the great potential of ene-diyne antibiotics. Symmetrical ene-diynes may be synthesized in one step from two molecules of a terminal alkyne and Z-dihaloethene. The ene-diyne part of the molecule does the remarkable Bergmann cyclization to give a benzene diradical the ene-diyne is able to penetrate DNAand the diradical is able to react with it. These compounds are anticancer drugs of some promise. 

A variation of this process is the Bergmann cyclization, where an ene-diyne cyclizes to a biradical (103) and then aromatizes as shown. 

This reaction is related to the Bergmann Cyclization and Myers-Saito Cyclization. 

Enediynes can condense to 1,4-benzene biradicals, known as the Bergmann cyclization, and abstract hydrogens from, e.g., the sugar backbone of DNA to form benzene (Fig. 2.45), and are thus often used in antibiotic studies [122, 123]. The cyclization rate strongly depends on the distance between the acetylene termini (J), which can be decreased by metal complexation [124]. 

Metal complexation of o-dppeb readily affords the 9-membered macrocycles [MCl2(o-dppeb)] (116a M = Pd 116b M = Pt 116c M = Hg) that have shortened distances between the alkyne termini (Fig. 2.46) [125]. Whereas a distance of 3.34 A is taken as the threshold for the Bergmann cyclization to occur, compounds with d <3.2 A cyclize spontaneously [123, 126]. The Pd and Pt-complexes of 6>-dppeb have an intermediate d of csl. 3.3 A and therefore cyclize at moderate temperatures (Table 2.1) to form naphtyl biradicals 117, which are trapped by... 

Fig. 2.46 Formation of monomeric (116a-c) and dimeric (119a-c) [MChio-dppeb)] macrocycles and subsequent Bergmann cyclization...

Table 2.1 Bergmann cyclization temperatures (7b) for 6>-dppeb and complexes thereof ...

Bergmann and Meyer264 cyclized the 1,1-diarylpropenes (55 R = H or Cl) to the corresponding benzo[6]thiophene-1,1 -dioxides (56 R = H or Cl) using sulfuric acid. 3-Phenylbenzo[6]thiophene-l,l-dioxide is obtained by cyclization of the trans isomer of 57 under Friedel-Crafts conditions.265-266 Similar cyclization of 58 (R = H 267 or CH2CH2Ph268) affords the corresponding 2,3-dihydrobenzo[6]thio-phene-1,1-dioxide. Thioindoxy 1-1,1-dioxide (60) is obtained in 81%... 

Norrish reaction Pericyclic elimination Tandem cationic cyclization Bergmann cycloaromatization... 

The new N-terminal residue can then be removed as a phenylhydantoin in a second cycle of phenylcarbamoylation and cyclization. This method of stepwise degradation, while discovered several decades earlier (Bergmann et al. 1927), reached practicality only in 1950 when Edman modified the reagent and applied chromatographic procedures for identification of the cyclic products. The improved reagent, phenylisothiocyanate, smoothly converts the peptide to the phenylthiocarbamoyl derivative which is cyclized and cleaved by the action of hydrochloric acid (dissolved in an organic solvent such as dioxane) ... 

It is interesting that when the enyne-allene moiety is incorporated into a bicyclic system, such as [7.3.2]-eneyne-allene 30, cyclization does not proceed. In contrast, the Bergmann cycloaromatization has been observed for a related substrate, [7.4.1]-enediyne (not illustrated). ... 

Weizmann and Bergmann treated MA with an excess of benzyl, ethyl, and butyl Grignards. In each case, a mixture of acidic and neutral products was obtained. The acidic fraction contained y, y-dialkyl-y-hydroxycrotonic acid 94. The latter cyclized spontaneously to give 95 but could be trapped... 

M. Bergmann was presumably the first to exploit this possibility (54). He prepared N-benzoyldehydrodipeptides (33) by azlactone synthesis, and used ketene or acetic anhydride to effect cyclization to N-benzoyl-dehydropiperazinediones (34). 

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