Heteroarene Friedel-Crafts acylation

Cross-linked polystyrene can be acylated with aliphatic and aromatic acyl halides in the presence of A1C13 (Friedel-Crafts acylation, Table 12.1). This reaction has mainly been used for the functionalization of polystyrene-based supports, and only rarely for the modification of support-bound substrates. Electron-rich arenes (Entry 3, Table 12.1) or heteroarenes, such as indoles (Entry 5, Table 15.7), undergo smooth Friedel-Crafts acylation without severe deterioration of the support. Suitable solvents for Friedel-Crafts acylations of cross-linked polystyrene are tetrachloroethene [1], DCE [2], CS2 [3,4], nitrobenzene [5,6], and CC14 [7]. As in the bromination of polystyrene, Friedel-Crafts acylations at high temperatures (e.g. DCE, 83 °C, 15 min [2]) can lead to partial dealkylation of phenyl groups and yield a soluble polymer. 

The selective functionalization of heterocycles is of particular importance, because of the ubiquity of these structures in natural products and pharmaceutical agents. Direct utilization of a C-H bond [1] of heterocycles is a promising method for the preparation of heterocycles because no pre-functionalization is required. Although Friedel-Crafts acylation is the most commonly used method for introduction of keto functionality on an aromatic ring, it is not often applicable to N-heteroarenes because of deactivation of the Lewis acids by the coordination of N-heteroarenes and the electron-deficient aromatic character of N-heteroarenes. 

Late-transition metal salts have been utilized as catalysts to promote Friedel-Crafts acylation of arenes and heteroarenes with anhydrides. A mismatch between their soft metal center and the hard carbonyl oxygen atoms of the products avoids the formation of a kinetically inert complex and results in catalytic turnovers. Although late-transition metal salts exhibit, a priori, rather poor Lewis acidity, sufficient reactivity can be gained by rendering them cationic. The acylation of variously substituted... 

Acyl-, carbamoyl- and alkoxycarbonyl radicals have been shown to add to protonated heteroarenes with high efficiency [2, 10]. The regioselectivity of these reactions is very similar to the regioselectivities obtained in the analogous alkylations discussed above. In contrast to the Friedel-Crafts acylation, where the acylated product is highly deactivated toward further acylation, the acylated heteroarenes are more reactive towards a second radical acylation. This is because of the higher electrophilicity of the protonated heteroarene after initial acylation. To suppress... 

Hf(OTf)4 was also reported for Friedel-Crafts acylation of ferrocenes and heteroarenes as well as in Friedel-Crafts acylations in the biphasic medium of an ionic liquid and supercritical carbon dioxide. ... 

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See also in sourсe #XX -- [ ]

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