Friedel-Crafts alkylation with heterocyclic

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel-Crafts alkylation. Heterocyclic rings are also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, a true alkylation of a pyridine or a quinoline has never been described.However, alkylation of pyridine and other nitrogen heterocycles can be accomplished by a free radical (14-23) and by a nucleophilic method (13-15). 

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

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. 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

The latter reagent also methylates certain heterocyclic compounds (e.g., quinoline) and certain fused aromatic compounds (e.g., anthracene, phenanthrene). The reactions with the sulfur carbanions are especially useful, since none of these substrates can be methylated by the Friedel-Crafts procedure (11-12). It has been reported that aromatic nitro compounds can also be alkylated, not only with methyl but with other alkyl and substituted alkyl groups as well, in ortho and para positions, by treatment with an alkyllithium compound (or, with lower yields, a Grignard reagent), followed by an oxidizing agent such as Bra or DDQ (P- 1511). 

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 outcome of the reaction of phenols with 5-alkylidene Meldrum s acids 25 catalysed by Yb triflate in the synthesis of O-heterocycles is dependent upon the nature of the alkylidene unit. Two distinct Friedel-Crafts sequences are apparent in this mild and simple route to coumarins and dihydrocoumarins and to chromones and chroman-4-ones (i) C-alkylation - (9-acylation and (ii) C-acylation - (9-alkylation <06JOC409>. 

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. ... 

It is comparatively rare for the construction of a benzanellated heterocycle to involve formation of the benzene ring as a final step, however benzo[c]thiophenes can be made by this strategy, utilising a double Friedel-Crafts-type alkylation of a 2,5-disubstituted (to prevent attack at a-positions) thiophene with a... 

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