2.3- Disubstituted pyrroles, synthesis

Scheme 3 Synthesis of 1,4-disubstituted pyrroles via Paal-Knorr reaction...

Disubstituted thiophenes 96 and 1,2,5-tri- and 2,5-disubstituted pyrrole derivatives 97 are available readily from m-3,6-disubstituted-3,6-dihydro-l,2-dioxins in a one-pot synthesis. The reaction proceeds by an initial Kornblum-de la Mare rearrangement of the 3,6-dihydro-l,2-dioxin to its isomeric 1,4-diketone followed by the condensation with Lawesson s reagent, ammonium carbonate, or a primary amine (Scheme 21) <2002TL3199>. 

The [,4 + 2] cycloaddition of dienophiles with 1-substituted pyrroles is also a reversible reaction, which has been utilized in the synthesis of 3,4-disubstituted pyrroles (b-77MI305oq) and, via the initial reaction of the pyrrole with benzyne, for the synthesis of isoindoles (81 AHC(29>341). The retro-reaction can be controlled and aided by a 1,3-dipolar cycloaddition of the intermediate adduct with benzonitrile oxide (74TL2163, 76RTC67) (Scheme 61). 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

Russian workers have recently described an interesting synthesis of 1,3-disubstituted pyrroles which consists of the following 3-step procedure, illustrated for the preparation of 1-benzyl-3 -ethylpyrrole (from which 3-ethylpyrrole is easily available by Na/NH3 reductive removal of the benzyl group) ... 

Aelterman, W. De Kimpe, N. Tyvorskii, V. Kulinkovich, O. Synthesis of 2,3-disubstituted pyrroles and pyridines from 3-halo-l-azaallylic anions./. Org. Chem. 2001, 66, 53-58. 

Cycloaddition between N-tosyl-protected 3,4-disubstituted pyrroles 1084 and electron-deficient dienophiles (e.g., DMAD, which was also used as solvent) leads to aza-bicyclic systems 1085 (Equation 254), which were used in the synthesis of new highly functionalized cyclotrimers for future derivatization and application in supramolecular chemistry <20050L1003>. 

RegiocontroUed synthesis of 2,4-disubstituted pyrroles is achieved using the alkylation of a protected cyanohydrin with an alkynyl bromide (equation 15). ... 

Treatment of azidoketones 8 with triphenylphosphine led to the formation of pyrrolidine 9 via a Staudiner-aza-Wittig reductive cyclization <05JOC4751>. The latter were converted into 2,3-disubstituted pyrroles 10 upon heating. Azidoketones 8 were prepared by the novel condensation of 1,3-bis-sUyl enol ethers 6 with azidoacetal 7. This sequence was exploited for the synthesis of a cyclododecyl-fused pyrrole. 

We can now look at specific examples, and see how the principles above can lead to the aromatic heterocycles. In the first of the two broad categories, where only C-heteroatom bonds need to be formed, and for the synthesis of five-membered heterocycles, precmsors with two carbonyl groups related 1,4 are required, thus 1,4-diketones react with ammonia or primary amines to give 2,5-disubstituted pyrroles two successive heteroatom-to-carbonyl carbon additions and loss of two molecules of water produce the aromatic ring, though the exact order of these several steps is never certain. 

The Paal-Knorr synthesis, in which 1,4-dicarbonyl compounds are treated with NH3 or primary amines (or with ammonium or alkylammonium salts) in ethanol or acetic acid, leads to 2,5-disubstituted pyrroles, and is universally applicable. For instance, hexane-2,5-dione 8 reacts with NH3 to yield 2,5-dimethylpyrrole 9 ... 

Symmetrical 3,4-di-alkylpyrroles (2) may be prepared by heating aliphatic (or aromatic) azines (1) in the presence of nickel or cobalt chlorides. Unsym-metrical 3,4-disubstituted pyrroles (e.g., 5) are available by a versatile new route s involving 1,3-dipolar addition of p-toluene sulfonylmethylisocyanide (3) to suitably activated alkanes, for example, 4. Improvements in the synthesis of... 

Disubstituted pyrroles lacking substituents at the 3- and S-positions are often required in porphyrin synthesis, and these can now be prepared from pyrrole itself. Thus, trichloroacetylation or trifluoroacetylation of pyrrole affords the 2-trihaloacetylpyrrole 8, which can be converted into the corresponding esters 9, carboxylic acids, or amides. The amides have been acetylated, or formylated, at the 4-position specifically, and the resulting acyl pyrroles (10) have been reduced to the alkyl pyrroles (11). This general procedure has now been improved by direct Friedel-Crafts formylation of the trichloroacetylpyrrole (8a) with dichloromethyl methyl ether (aluminium chloride) to the diacylpyrroles... 

Substituted dipyrranes Synthesis and reactivity 12CSR3780. Synthesis of 3,4-disubstituted pyrroles 130PP171. 

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