Pyrroles Friedel-Crafts acylation

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... 

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. 

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... 

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. 

For the synthesis of isoindoles (benzo[c]pyrroles) by type la cyclization the required intermediate is an o -acylbenzylamine. The only viable route to these substances which has been developed starts with a -bromo-o -toluic acid which is converted first to a phthalimide and then to the acid chloride. The acid chloride is then elaborated to the requisite ketone by Friedel-Crafts acylation. Condensation to the isoindole occurs on liberation of the primary amino group using hydrazine (equation 18) (64JA4152). 

Some acyl halides are reactive enough to effect Friedel-Crafts acylation on the neutral heterocycles without a catalyst. For pyrrole such reactions are known, for example, with trifluoroacetyl chloride and trichloroacetyl chloride. Indole reacts smoothly in cold ether with oxalyl chloride and on heating with acetic anhydride. Some examples of these types of acylation are collected in Table 10. 

The synthesis of a pyrrole segment common to netropsin and distamycin is shown in Scheme 2ji°l Friedel-Crafts acylation of 1-methylpyrrole (1) followed by nitration at C4 provides 3 in 54% yield. After a haloform reaction, hydrogenolysis, N-protection with B0C2O, and saponification, the pyrrolecarboxylic derivative acid 7 was obtained in 30% overall yield from 3. This monomer is readily chain-extended to the pyrrole-imidazole derivative 9 (Scheme 3)J10 Furthermore, solid-phase synthesis with this and related pyrrole-containing building blocks leads to polyamides that have recently been used in the recognition of a 16 base-pair sequence in the minor groove of DNA.1" ... 

Dioxacorroles are 18-7r-electron aromatic systems like corroles. They exhibit basicity intermediate between that of porphyrin and corrole, and require 1 h at 100 °C in TFA for complete deuteration of the meso positions. The furan protons are also substituted by deuterium under the same conditions after lOOh. Friedel-Crafts acylation occurs at C-5 while alkyl halides attack on the pyrrolic nitrogens to give a mixture of mono- and di-alkyl derivatives. 

The Friedel-Crafts acylation and alkylation reactions are fundamental processes in aromatic chemistry. Pyrroles and furans are not stable to the Lewis acids necessary for these reactions, but thiophenes are stable to Lewis acids, and do undergo Friedel-Crafts acylation and alkylation. 

In spite of the fact that indoles do not undergo acylation at the pyrrole ring carbon atom under typical Friedel-Crafts acylation conditions, the pyrrolopyridines can be successfully acylated in this manner. 3-Formylation is the most useful acylation reaction of pyrrolopyridines <68AHC(9)27>. Scheme 6 shows the acylation of compound (2), which afforded 3-acetylpyrrolo[2,3-c]pyridine (34) in 71% yield <79CHE69>. 

The first three reactions are all electrophilic substitution a bromination of a pyrrole, the nitration quinoline, and a Friedel-Crafts acylation of thiophene. Bromination occurs on the pyrrole at only remaining site. Nitration of quinoline occurs on the benzene rather than the quinoline r-fi (actually giving a mixture of 5- and 8-nitroquinolines, but don t worry if you didn t see t- Mi p. 1174), and the acylation would occur next to sulfur. 

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