Friedel-Crafts acylation with heterocyclic

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. 

In Scheme 10, examples of eaiantioseleetive cycloadditions with formation of three-, four-, five-, and six-membered carbocyclic or heterocyclic rings are presented, to demonstrate the use of Ti-TADDOLates as Lewis acids. The Diels-Alder reaction has, so far, been studied most extensively, and many protocols have been proposed for the preparation of the Ti catalyst, of which as little as 5 mol-% and as much as several equivalents were employed (more often than not, Lewis acids bind strongly to the products of reactions they have mediated cf. the classical Friedel-Crafts acylation with AICI3 ). 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

It is known that certain Friedel-Crafts acylations of reactive aromatics may proceed with a small amount of catalyst or even, to some extent, with no catalyst at all.41 Effective catalysts are Fe, FeCl3, ZnCl2, iodine, and hydroiodic acid. However, satisfactory yields are usually obtained with activated and polynuclear aromatics, and heterocycles. The mixed anhydrides acyl triflates are also powerful acylating agents without catalyst.34... 

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. 

Friedel-Crafts acylation of t-butanol (Scheme 6) followed by treatment with ammonia gives a mixture of 2,7-naphthyridines (379 R = Me, Et, Pr", Pr, Bu) and pyridines (380) (38-91% yield) <84BSF449>. Heterocycles (379) are the major products in these reactions and pyrylium salts have been proposed as reaction intermediates. Unsymmetrical naphthyridines (382) have been obtained as the major products of the reaction of alkenones (381) under similar conditions (Scheme 6) <84BSF454>. 

Thio- and selenoacetals and esters are excellent substrates for mild Friedel-Crafts reactions, because of the affinity of sulfur and selenium for copper (Sch. 23). Anisole was readily acylated with methylselenoesters 94 at room temperature with activation by CuOTf to affordpnra-substituted (> 95 %) derivatives 95 [50,51]. Mercury(II) and copper(II) salts, which were effective for the activation of selenyl esters for reaction with alcohols, amines, and water, were not effective for the Friedel-Crafts reaction. Aromatic heterocycles 96 could be acylated in high yields, and the alkylation product 100 was obtained from dibutylthioacetal 99 and anisole. Vedejs has utilized this methodology in the cyclization of 101 to afford 102 in 77 % yield [52]. This intramolecular variant did not require the use of the more reactive bis copper triflate-benzene complex. 

Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution nitration, sulfonation, halogenation. Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/ mole somewhat less than the resonance energy of benzene (36 kcal/mde), but much greater than that of most conjugateci dienes (about Tlccal/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

Like other aromatic compounds, these five-membered heterocycles undergJ nitration, halogenation, sulfonation, and Friedel-Crafts acylation. They are mucji more reactive than benzene, and resemble the most reactive benzene derivatives (amines and phenols) in undergoing such reactions as the Reimer-Tiemann reaction, nitrosation, and coupling with diazonium salts. 

The pyridine 122 reacts with BuLi by I/Li exchange capture of the lithium derivative with propanal and oxidation gives the ketone 130 in the heterocyclic equivalent of a Friedel-Crafts acylation. The fluorine atom that was originally present to initiate the halogen dance from 120 to 121 can now be hydrolysed to give the pyridone 126. 

The few reactions that work well with heterocycles. The Heck reaction, Friedel-Crafts acylation and a mention oflithiation... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The Friedel-Crafts synthesis with acyl chlorides and anhydrides can be applied to all aromatic hydrocarbons and to many heterocyclic compounds, in particular to thiophene, furan, and pyrrol derivatives. Pyridine does not react,531,532 and hydrocarbons carrying electron-attracting substituents react with difficulty or not at all. 

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