Friedel Crafts pyrrole

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

Thiophene is also readily acylated under both Friedel-Crafts and Vilsmeier-Haack conditions and similarly to pyrrole and furan gives 2-acylated products. An almost quantitative conversion of thiophene into its 2-benzoyl derivative is obtained by reaction with 2-benzoyloxypyridine and trifluoroacetic acid. The attempted preparation of 2-benzoylthiophene under standard Friedel-Crafts conditions, however, failed (80S139). 

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 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 ... 

Whereas pyrroles normally undergo substitution at the C-2 position, 1-arylsulfonylpyrroles display a tunable reactivity in Friedel-Crafts acylations, wherein substitution occurs at C-3 in the presence of "hard acids" such as aluminum chloride but mainly at C-2 when catalyzed by weaker acids <81TL4899,81TL4901>. An alternative route to 3-aroylpyrroles 38 has been introduced via irradiation of 1-acetyl- or 1-phenylsulfonylpyrrole (36) with arenethiocarboxamides <96H(43)463>. The proposed mechanism involves formation and scission of a thietane intermediate 37, followed by hydrolysis of the resultant imine. 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

The reaction of indole and /V-mcthylpyrrole via Friedel-Crafts reactions with 0CHC02Et in various aqueous solutions generated substituted indoles and pyrroles without using any metal catalyst (Eq. 7.8).18... 

Nevertheless, we can interpret the reactions of furan and thiophene by logical consideration as we did for pyrrole. In electrophilic substitutions, there is again a preference for 2- rather than 3-substitution, and typical electrophilic reactions carried out under acidic conditions are difficult to control. However, because of lower reactivity compared with pyrrole, it is possible to exploit Friedel-Crafts acylations, though using less-reactive anhydrides rather than... 

Moreover, phosphoric acid (5)-3r (5 mol%, R = SiPhj) bearing a bulky triphe-nylsilyl group turned out to be a suitable catalyst for the asymmetric Friedel-Crafts alkylation of iV-alkyl pyrroles 31 with M-benzoyl-protected aldimines 32 (Scheme 12) [23]. 2-Pyrrolyl amines 33 were obtained in high yields (66-97%) and moderate to high enantioselectivities (42 to >99% ee). 

Typical electrophilic reactions, such as nitration, halogenation with a Lewis acid (as a carrier ), Friedel-Crafts C-alkylation and -acylation, that work well with benzene, cannot be applied to pyrrole, because heating with strong acids, or a Lewis acid, destroys the heterocycle. However,... 

The possibility of acetylating the pyrrole nitrogen atom of 9a was investigated. The reaction was performed in the presence of different bases, and the highest yield of the corresponding compound 9b was achieved for potassium tert-butoxide. As should be expected, even trace amounts of this compound are absent from the acylation products of thienopyrrole 9a under Friedel-Crafts conditions <20020L387>. 

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

The monosubstitution products of the Friedel-Crafts reaction and of the nitration reaction have been interrelated to show that the substituent group is introduced at the same position in each case. A further correlation with the adduct (Id) from indolizine and methyl propiolate provides evidence that this is the 1-position as predicted.56 Acylation of 2-methoxycarbonyl-3-phenylcycl[3,2,2]azine (Is) takes place in the pyrrole part of the molecule.51... 

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 case of sulfonation and nitration milder reagents can be employed, i.e. the pyridine-sulfur trioxide complex and acetyl nitrate, respectively. Attempts to carry out the Friedel-Crafts alkylation of furan are often unsuccessful because the catalysts required cause polymerization. 

Intramolecular acylation of l-benzyl-2-(2-carboxybenzoyl)pyrrole under Friedel-Crafts conditions yields l//-benz[/]indole-4,9-dione (79KGS1564). When the 1-position is unsubstituted, cyclization occurs to that position (B-77MI30502). 

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