Pyrroles unsymmetrical, synthesis

A mild procedure which does not involve strong adds, has to be used in the synthesis of pure isomers of unsymmetrically substituted porphyrins from dipyrromethanes. The best procedure having been applied, e.g. in unequivocal syntheses of uroporphyrins II, III, and IV (see p. 251f.), is the condensation of 5,5 -diformyldipyrromethanes with 5,5 -unsubstituted dipyrromethanes in a very dilute solution of hydriodic add in acetic acid (A.H. Jackson, 1973). The electron-withdrawing formyl groups disfavor protonation of the pyrrole and therefore isomerization. The porphodimethene that is formed during short reaction times isomerizes only very slowly, since the pyrrole units are part of a dipyrromethene chromophore (see below). Furthermore, it can be oxidized immediately after its synthesis to give stable porphyrins. 

The most widely applicable method for synthesis of unsymmetrically substituted dipyrrylmethanes (129) requires the condensation of a 2-unsubstituted pyrrole (124) with a 2-acetoxymethylpyrrole (128). This reaction was originally carried out with sodium acetate in hot acetic acid (60JA4389), but subsequent developments have shown that the conditions can be much milder if a catalytic quantity of toluene-p-sulfonic acid (in warm methanol or acetic acid) is employed (73JCS(Pl)247l). 

In brief communications concerning the use of dialkyl ketoximes (79IZV2840 81MI7, 81MI8) in this reaction, no comprehensive synthetic procedures are described. The experimental details for the synthesis of 2,3-dialkyl-substituted pyrroles from symmetrical and unsymmetrical dialkyl ketoximes and dichloroethane in the KOH/DMSO system (Scheme 63) were first discussed by Trofimov et al. (85KGS59). 

Pure individual porphyrins such as (4)-(7) can, however, be synthesized using dipyrroles, and these approaches will be briefly discussed later in this section. If two dipyrrole units (8) and (9) with an appropriate future meso-carbon are reacted together with the intention of preparing porphyrin (10), there is actually a maximum of three possible products, (10) (12) (Scheme 3). This is because the two dipyrroles can either react with themselves, or (as required) with each other. If the dipyrroles do not possess attached (future) meso-carbon atoms (e.g., (13) and (14)) and also bear an unsymmetrical arrangement of substituents (indicated by the A and B labels on each pyrrole— oxidation levels, i.e., dipyrromethene or dipyrromethane, not defined), even greater mixtures can occur—in this case, porphyrins (15)-(20) (Scheme 4). Such symmetry problems are common with all so-called [2 + 2] syntheses. However, if a porphyrin synthesis involving two dipyrroles is to be attempted, the symmetry problems can often be overcome if one of the two dipyrroles is symmetrical about its interpyrrolic (5-) carbon atom (e.g., synthesis of (6) from (21) and (22), Scheme 5). 

Pyrroles 531 are formed from the chromium complex 529 and alkynes 530 (R = H, Me or Ph = Me, Ph or NEt2). The dicobaltoctacarbonyl-catalysed reaction of cyanotrimethylsilane with a variety of acetylenes R C=CR (R R = alkyl or Ph) furnishes pyrroles 532, in which the bulkier of the two substituents of unsymmetrical internal acetylenes appears at the position marked with an asterisk . An indole synthesis from o-iodo-aniline and alkynes R C=CR (R R =alkyl or Ph) in the presence of palladium(II) acetate, triphenylphosphine, lithium chloride and potassium carbonate has been described (equation 56). In the case of unsymmetrical alkynes, the bulkier substituent tends to be in position 2 of the indole. ... 

A significant improvement in the synthesis of unsymmetrical pyrromethanes in good yields involves the coupling of 2-acetoxymethyl pyrroles with 2-unsubsti-tuted pyrroles in methanol containing a catalytic amount of toluene-p-sulfonic acid. More recently the use of tin(IV) chloride has been described as a catalyst for similar reactions, and this is likely to be of particular utility with less reactive pyrroles. A variety of aminomethyl pyrromethanes, and the related cyclic lactams, have been prepared by standard routes for use in biosynthetic studies. The use of thioacetals as protecting groups for formyl pyrroles has enabled... 

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... 

There are several routes to a,c-biladienes. One was mentioned at the start of this section of porphyrin synthesis, i.e. condensation of two dipyrromethenes (one of which has an unsubstituted 5-position). Another route, to symmetrically substituted a,c-biladienes in particular, is by condensation of dipyrrylmethane-5,5 -dicarboxylic acids with two moles of a 2-formyl-5-pyrrole. This method can be used to construct the most unsymmetric porphyrins, e.g. isocoproporphyrin. ... 

While unsymmetrically substituted tetraaryl (and arylalkyl) porphyrins (for numbering see Fig. 1, Table 23) were prepared by reacting the corresponding aldehydes and separating the mixture via column chromatography [194] a solid phase synthesis was introduced for the preparation of tolylporphyrin [195], Polystyrene, crosslinked with 2% divinylbenzene, was reacted with 3-hydroxy-or 4-hydroxybenzaldehyde respectively and subsequently was treated with p-tolylaldehyde and pyrrole in hot propionic acid. Tetratolylporphyrin, also... 

Similar to the Paal-Knorr pyrrole synthesis, the Knorr pyrazole synthesis is the most common synthetic method for the preparation of pyrazoles. The Knorr pyrazole synthesis involves the cyclocondensation of an appropriate hydrazine, 1, which acts as a bidentate nucleophile, with the three carbon unit of a 1,3-dicarbonyl moiety, 2, featuring two electrophilic carbons. With unsymmetrical substrates having two electrophilic centers (Ra R4), mixtures of regioisomers 3a and 3b are often obtained in reactions with substituted hydrazines (Ri H). However, when Ri = H, the prototropic tautomerism of pyrazoles renders 3a equivalent to 3b. 

BODIPY has a rigid structure, which can be formed by boron insertion with BF3 OEt2 into a dipyrromethene unit. Generally, the synthesis of BODIPY derivatives starts from the dipyrromethene precursor. It is relatively easy to construct the precursor using the well-known pyrrole condensation reaction. There are two common synthetic strategies, especially for symmetric and unsymmetric BODIPY cores, respeetively. 

Many successM methods have been reported for the synthesis of porphyrinoids. Symmetric porphyrin synthesis is achieved by cyclic tetramerizalion using a-free pyrroles and aldehyde [6]. a-Hydroxymethylpyrroles are also employed suc-cessfiiUy in the cyclic tetramerization method [7]. For the synthesis of unsymmetric porphyrinoids, oligomeric pyrroUc units are condensed under acidic conditions. These mediods are categorized by the number of pyrroles (or five-membered heterocycles) in the units. The [2 + 2] and [3 -h 1 ] methods are common in the synthesis of porphyrins [8] the [3 - - 2] and [3+1 + 1] methods are employed for the synthesis of sap-phyrins [9] and the [2 + 2] method provided porphyrins and corroles [10]. For the preparation of 7t-expanded porphyrinoid precursors by using these methods, monomeric or oligomeric equivalents of isoindoles are required and these preparations are first introduced. 

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