Prototropic cyclization

Simple acetylenic allylic alcohols can be cyclized easily by tarf-butoxide, and since this base initiates prototropic shifts the vinylic link may.be E or Z such cyclizations proceed via exomethylene furans similar to 15.65 If necessary, UV irradiation can effect both the isomerization of an to a Z-alkene and the cyclization, leaving only the final adjustments to be made chemically.66 In a variation, methoxide plays the role of leaving group allowing very good yields to be attained (Scheme 10).67... 

The propargylic alcohol 102, prepared by condensation between 100 and the lithium acetylide 101, was efficiently reduced to the hydrocarbon 103, which on treatment with potassium tert-butoxide was isomerized to the benzannulated enyne-allene 104 (Scheme 20.22) [62], At room temperature, the formation of 104 was detected. In refluxing toluene, the Schmittel cyclization occurs readily to generate the biradical 105, which then undergoes intramolecular radical-radical coupling to give 106 and, after a prototropic rearrangement, the llJ-f-benzo[fo]fluorene 107. Several other HJ-f-benzo[fo]fluorenes were likewise synthesized from cyclic aromatic ketones. 

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

In addition to the example depicted in Scheme 20.40 and examples involving a prototropic rearrangement [61], the use of trimethylsilyl trifluoromethanesulfonate to induce the transformation of 212 afforded 213 bearing a keto substituent at the allenic terminus (Scheme 20.44) [81]. Thermolysis of 213 promoted the Myers-Saito cyclization leading to 216. 

These authors conclude that the problem of internal solvation is still an experimental and theoretical challenge GB measurements for this type of molecules of low volatility are not always in good agreement194. Molecular orbital calculations may help to solve the difficult experimental problems, but they have to take into account conformational isomerisms and the prototropic tautomerisms of the amidine and guanidine moieties. In light of the above discussion, the proton affinities deduced from the experimental GB values should be based on accurate estimations of the entropy of cyclization 86. 

The major product (21-37%) from the reaction of benzyne with N-phenylpyrrole is the 2 1 adduct (167), the formation of which is explicable in terms of the cyclization of either one of two intermediate zwitterions, 165 or 166. Alternatively, prototropic shift within the intermediate (166) accounts for the formation of the a-naphthylamine (147) (4-6% yield). Other benz[o]carbazole derivatives (168 and 169)... 

Dimethyl-l-butynyl(phenyl)iodonium tosylate has been employed with bis-(diphenylphosphino)methane to give the (terr-butyl)phospholium tosylate shown in equation 7892. The initial formation of an alkynylphosphonium ion with a free phosphino group has been proposed. Intramolecular cyclization of this intermediate followed by a 1,3-prototropic shift would lead to the observed product. Evidence for the probability of such an intermediate is provided by the fact that the alkynyliodonium tosylate, like the... 

The key step in the first reaction is, once again, a 1,4-dehydrohalogenation followed by a stereocontrolled prototropic shift and electrocyclic closure of the derived triene to a bicy-cloheptadiene (shown below) the dichlorocyclopropane then undergoes a typical sequence of 1,2-dehydrochlorination followed by prototropic shifts to lead to the [10]annulene. The chlorodiene 45 may be produced by a similar sequence of 1,4-dehalo-genation, prototropic shift and cyclization 00b. The mechanisms of these and related reactions have been the subject of labelling studies. 

The intramolecular oxime-alkene cyclizations, also known as tandem 1,2-prototropic-cycloadditions, with nonactivated alkenes was first reported by Oppolzer and Keller in 1970 <70TLiii7> but their use for the heterocycles of this chapter was first reported in the 1990s <91T4007>. The methodology is shown in Schemes 46 and 47 in an expedient synthesis of chiral, unfunctionalized... 

Octalone dienamines, e.g. 152, have shown a remarkable solvent dependence in the reaction with methyl vinyl ketone (equation 31)86. In methanol, reaction occurs primarily at the less reactive -position of the dienamine and the mechanism probably involves a prototropic shift in the initially formed enolate anion to give 153, and subsequent cyclization onto C-8a of the enimmonium salt to give 154. In toluene, the change in regioselectivity is complete and the product obtained is 157, which must arise from 156, formed in turn from cycloaddition to cross-conjugated dienamine 155. 

Although 7-alkyl substituted 6-heptynyllithiums do not cyclize at elevated temperatures, the phenyl-substituted analog affords an approximately 1 1 mixture of allene (from prototropic rearrangement) and cyclic product [13a,b]. Allene foimation can obviously be totally suppressed by introduction of a em-dimethyl group at the propargylic position (Scheme 7-24). 

Christy and coworkers observed a similar cyclization on condensing ketone 39 with hydroxylamine in hot ethanol to provide compound 41 (Scheme 9) (79JOC3117). Oxime 40 could be prepared under milder conditions, and was found to undergo a 1,2-prototropic shift followed by intramolecular cycloaddition to provide 41 on warming to 75 °C in toluene. 

First, derivatives of a-amino acids in which the amino group is part of an amide are considerably more prone to a-epimerization/racemization upon COOH activation than their carbamate congeners. Loss of stereochemical integrity is attributed to cyclization of a generic activated species, 23, to oxazolone 24, which exists in prototropic equilibrium with the aromatic tautomer 25 (Scheme 5). An amide being more nucleophilic than a carbamate, cyclization to an intermediate of type 24 is easier. Second, the tendency to cyclize is even more pronounced if the a-amido... 

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