Unsymmetrical 3,4-disubstituted pyrroles

Although it was not attempted, the second bromine atom could presumably have been replaced by a second lithiation step prior to the hydrolysis, thereby giving rise to a variety of unsymmetrical 2,5-disubstituted pyrroles. 

Perhaps the most important new development in the ac-biladiene route has been the synthesis of discrete unsymmetrical tripyrrene intermediates. Russian workers had shown that a,a -disubstituted pyrromethanes could be condensed successively with one and two formyl pyrrole units to form first a tripyrrene and then a symmetrical ac-biladiene, which could be cyclized to porphyrin. The Liverpool group, however, showed that by use of unsymmetrical differentially protected pyrromethane diesters, condensation could be effected with two different formyl pyrroles to yield first tripyrrenes and then unsymmetrical ac-bi-ladienes. Cyclization of the latter afforded unsymmetrically substituted porphyrins. This procedure represents the first truly stepwise rational porphyrin synthesis, as exemplified by the synthesis of isocoproporphyin (26) (cf. Scheme... 

Dalla Croce and La Rosa examined the 1,3-dipolar cycloaddition reactions of unsymmetrical munchnones with terminal alkynes to give pyrroles 156 and 157 (Table 4.8). The reaction is generally regioselective the major pyrrole isomer from the monosubstituted munchnones have adjacent hydrogens, irrespective of the munchnone substituent. With the disubstituted munchnones, the major regioisomer is derived from attachment of C-4 of the munchnone and the p-carbon of the alkyne, except for phenylacetylene, which shows the opposite regiochemistry. The authors interpreted this behavior as a consequence of the electron-rich nature of phenylacetylene as a dipolarophile with a larger LUMO coefficient on the a carbon. 

Dihetarylethene 81 with two pyrrole cycles was obtained by the consecutive interaction of the corresponding bromide 80 with BuLi and CsFg in THF in 11 % yield [89] (Scheme 31). Later French authors [90] succeeded in optimizing the reaction conditions, increasing the yield to 74 %, and synthesizing the whole range of symmetrical and unsymmetrical 5,5 -disubstituted derivatives 82. 

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