Pyrrole sulfonation

FIGURE 18 / 0 0 A heterocycle-release strategy was [433] applied to solid-supported a-tosyloxy ketones in the synthesis of a pentasubsti-tuted pyrrole. Sulfonic acid resin, prepared from commercially available sulfo-nyl chloride resin or polystyrene, was employed. 

The classical structures of pyrrole, furan and thiophene (31) suggest that these compounds might show chemical reactions similar to those of amines, ethers and thioethers (32) respectively. On this basis, the initial attack of the electrophile would be expected to take place at the heteroatom and lead to products such as quaternary ammonium and oxonium salts, sulfoxides and sulfones. Products of this type from the heteroaromatic compounds under consideration are relatively rare. 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the... 

Both pyrrole and furan can be sulfonated in the 2-position by treatment with the pyridine-sulfur trioxide complex (Scheme 14). Furan can be further sulfonated by this reagent to give the 2,5-disulfonate. 

Indole is sulfonated under similar conditions to pyrrole though in this case the 3-sulfonic acid is formed. Benzo[Z>]thiophene is also sulfonated in the 3-position (71AHC(13)235). 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

The chemistry of pyrrole is similar to that of activated benzene rings. In general, however, the heterocycles are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished. For example ... 

Besides the azo coupling reactions of 1-methyl- and 2,5-dimethylpyrrole with benzenediazonium-4-sulfonate mentioned above, Butler et al. (1977) synthesized almost all possible combination products of the unsubstituted and four 4-substituted benzenediazonium ions with pyrrole itself, with most isomeric mono-, di-, and trimethyl-pyrroles, and with 3-ethyl-2,4-dimethylpyrrole. These authors also investigated the kinetics of all these combinations (see Sec. 12.7). 

Kobayashi and Mutai75 have recently reported an interesting rearrangement of the 1,4-dithiin sulfone (53) to the thiophenes (54) and (55) (equation 12). While 54 presumably arises as a result of simple photoextrusion, the rearranged thiophene (55) is postulated to arise via the valence isomer (56), followed by cyclization to the thiophene, concomitant with, or preceded by, loss of S02. Some support for the intermediacy of the thioketone (56) was revealed by the isolation of the pyrrole (57), when the photolysis was conducted in n-butylamine. Compound 57 presumably arises by cyclization of the iV-butylimine analog of 56 initially formed. 

When the decomposition of N-phenyl-1,3,4,6-tetrahydrothieno-(3,4-c)-pyrrole-2,2-dioxide (II) was carried out in a sublimator a relatively high yield (80-95%) was obtained. However, under identical conditions, the decomposition of 5-(carboethoxyphenyl)-l,3,4,6-tetrahydrothieno(3,4-c)-pyrrole-2,2-dioxide yielded only 15% of diene product. This observation was found in agreement with the results reported by Alston (18). It was suggested that the yield from these sulfones depended on the relative volatility of the exocyclic diene formed since these dienes could undergo dimerization readily at the decomposition temperature of lbO C. 

In the tris-pentafluorophenyl analog (TFPC), in contrast to other Co corroles, aromatic amines can substitute PPh3 to form six-coordinate trivalent bis(amine) complexes.788 Bis-chlorosulfon-ation of TFPC occurs regioselectively to give the 2,17-(pyrrole)-bis-chlorosulfonated derivative fully characterized as its triphenylphosphinecobalt(III) complex.789 The amphiphilic bis-sulfonic acid was also obtained. 

Nitroalkenes can be replaced by u. i-unsaturated sulfones in the Barton-Zard pyrrole synthesis. Each method has its own merit. Nitroalkenes are more reactive than a,(3-unsaturated sulfones therefore, nitroalkenes should be used in less reactive cases. On the other hand, cyclic u.fi-unsaturated sulfones are more easily prepared than cyclic nitroalkenes pyrrole synthesis using sulfones is the method of choice in such cases, as shown in Eq. 10.41.46... 

In 1988, Ono and Maruyama reported a very simple synthesis of octaethylporphyrin (OEP) from 3,4-diethylpyrrole-2-carboxylate, as shown in Eq. 10.44 49 Reduction of this pyrrole with LiAlH4 gives 2-hydroxyethylpyrrole, which is converted into OEP on treatment with acid and an oxidizing agent. This route is very convenient for synthesis of porphyrins. This method is now used extensively for synthesis of P-substituted porphyrins.50 For example, a highly conjugated porphyrin, shown in Eq. 10.45, has been prepared by this route.51 The requisite pyrroles are prepared from nitro compounds or sulfones thus, various substituents are readily introduced into porphyrins. 

Although the most characteristic reaction of the pyrrole nucleus is the predominant addition of electrophiles to the C-2 position, it is interesting to note that contrary to previous assumptions, sulfonation of pyrrole and its 1-methyl derivative with sulfur trioxide-pyridine complex affords mainly the 3-sulfonated pyrroles <00TL6605>. As Mizuno wisely points out, it is likely that some of the pyrrole-2-sulfonates reported previously are actually pyrrole-3-sulfonates. 

Another approach is based on the condensation of lithiated sulfones to unsaturated nitrones (387). Good yields of single stereoisomers of unsaturated hydrox-ylamines (388) are obtained. They undergo a reverse-Cope elimination leading to a single enantiomer of pyrrol idine-/V -oxide (389) (Scheme 2.169) (626). 

FVP of the aza-bicyclic sulfone 236 at 700°C and 8xl0 2mbar resulted in 3//-pyrrolizin-3-one 237 <2004TL3889>. At same temperature and lower pressure, that is, 4 x 10-2 mbar, the same sulfone affords a mixture of 237 and vinyl pyrrole 238 in 44% and 27% yield, respectively. The latter was the only product obtained when the thermolysis of 236 was performed in a sealed tube in sulfolane. This result and others led Pinho e Melo et al. <2005JOC6629> to suggest the plausible eight-step mechanism shown in Scheme 61. 

A-alkylation, A-acylation, and A-sulfonation. Note particularly that whereas pyrrole reacts with electrophiles at carbon, usually C-2, the pyrrole anion reacts at the nitrogen atom. 

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