Base promoted cyclisations

Another important investigation of a quantitative nature of the pre-war era is that of Ziegler et al. (1937), who studied the kinetics of the base-promoted cyclisation of o-(co-bromoalkoxy)phenols (43) in ethanol solution... 

A summary of the in situ use of the azobenzene probases is given in Table 2. Apart from the generation of ylid, referred to above, the main applications have been for N- and C-alkylation of weak nitrogen and carbon acids, for the promotion of condensation and substitution reactions involving carbanions such as the cyano-methyl anion, for an interesting carboxylation reaction (entries 4 and 17), and for base-promoted cyclisations (entries 5 and 6). 

The base-promoted cyclisations have also been effected by electrogenerated tri-chloromethyl anion (Scheme 10) but in this case nucleophilic substitution is a significant competing reaction. This complication is avoided by the use of azobenzene as probase. 

The cyclisation of 2-(2-phenylethynyl)benzoic acid can give a phthalide by a 5-exo-dig process or an isocoumarin through a 6-endo-dig route. It has now been established that base-promoted cyclisation leads to the former, but under acidic conditions isocoumarins are exclusively produced. This approach has been successfully applied to a synthesis of thunberginol A (Scheme 34) <06OL5517>. 

A thiiranium ion intermediate is involved in the phase transfer catalysed base-promoted cyclisation of (332) to azetidinone (333)244. (332)... 

CL128>. Based on a Diels-Alder reaction between a 2-bromobenzoquinone and a 2-methylbutadiene and a subsequent base-promoted ynone cyclisation, the anthra[l,2-b]pyran-4,7,12-trione system 33 has been synthesised <06AG(E)6990> and the methodology used in an enantioselective total synthesis of the pluramycin antibiotic, y-indomycinone <06OL5873>. 

Most of the phosphinate substrates (entries 1-7) are efSciently cyclised with good to excellent enantioselectivities. Homodimers, formed by intermolecular metathesis, were also detected in the crude reaction mixtures. In entries 1 and 6, with a substrate containing an allyloxy arm, no reaction was observed with any of the catalysts studied. This can be due to the formation of an unreactive alkylidyne via chelation of the P(0) group and Lewis-base-promoted... 

Temperature control during pressure hydrogenation of cis- or tram-isomers is essential, since at 155°C violent decomposition to carbon, hydrogen and carbon monoxide with development of over 1 kbar pressure will occur. The material should not be heated above 100°C, particularly if acid or base is present, to avoid exothermic polymerisation [1], The m-isomer is readily cyclised to 2,3-dimethylfuran, which promotes lire and explosion hazards. These were measured for the cis- and tram-isomers, and for fram-3-methyl-l-penten-4-yn-3-ol [2],... 

The cyclisation of (22) to the /J-lactam system, which is a thermodynamically unfavourable reaction, is promoted by using sodium hydride as the base in a dichloromethane-dimethylformamide solvent system at high dilution. 

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

An efficient synthesis of 1,4-oxazepines has been developed based on iodine-sodium bicarbonate-promoted intramolecular cyclisation of the enamides 237, which were derived in turn from the p-formyl enamides 236 by sodium borohydride reduction. Reductive removal of the iodo-substituent in 238 was readily achieved using sodium sulfite. The R1 and R2 groups were part of a ring system, for example a steroid system [01SC3281],... 

Notably, when the same cyclisation was carried out using sodium cobalt(I)salophen, the reaction became selective for toddaquinoline methyl ether <00TL6681>. This apparent diehotomy was attributed to the formation of a Lewis acid - Lewis base complex between cobalt(II)salophen and the pyridine moiety. Loss of bromide from the radical anion 151 generates aryl radieal 152 which adds to the proximal pyridine giving 153. Dehydrocobaltation to toddaquinoline methyl ether 149 completes the sequence (Scheme 42). Notably, as the pyridine ring is activated by complexation to the Lewis acidic Co(II), the eyelisation is more akin to a Minisci reaction. Consequently, cyclisation to C6 is promoted in this case <01T4447>. 

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