Coumarins, Friedel-Crafts alkylation

Subsequent intramolecular Friedel-Crafts alkylation and elimination yields the coumarin derivatives (See Scheme 14, Sect. 2.2). With 5 mol% of BiCl3, the desired products 21a-d have been obtained in high yields after short reaction times (1-2 h) (Scheme 17). 

A number of reactions relevant to fine chemicals manufacture can be catalyzed by superacids, for example, dehydration of carboxamides to nitriles, Friedel-Crafts alkylation and acylation, Fisher indole synthesis of coumarins, isomerization of limonene, condensation of hydroquinone with aniline, and esterification in general (Hino and Arata, 1980, 1985 Joshi and Rajadhyaksha, 1980 Rajadhyak-sha and Chaudhari, 1987 Kumbhar and Yadav, 1989 Rajadhyaksha and Joshi, 1991 Kumbhar et al., 1994). Two particularly important reactions are described here. 

In nature, the alkylation of aromatic rings most commonly proceeds using 5-adenosyhnethionine ( SAM, 31a) as the source of an electrophilic methyl group. Such alkylations are catalyzed by C-methyltransferase enzymes and are analogous to Friedel-Crafts alkylations. Two C-methyl-transferases, NovO and CouO (from Streptomyces spheroides and Streptomyces rishiriensis, respectively), have been expressed in recombinant E. coli and have been shown to have a synthetically useful substrate scope. Not only are they able to catalyze the regioselective alkylation of various coumarins 32 (X=0), 2-quinolones 32 (X=NH), and naphthalenediols 34-36, but in addition, they are able to accept nonnatural cofactors 31b-f in place of SAM and so can transfer various alkyl groups other than methyl to the substrates (Scheme 32.4) [26]. 

Finally, the replacement of the coumarine scaffold by naphthalene derivatives was envisaged, and conversions of 15% to 45% were obtained for the methylation of some naphthalenediols, opening new perspectives for this green and selective Friedel-Craft alkylation. 

A somewhat more complex coumarin that includes basic nitrogen has been used as a coronary vasodilator. The key reaction in the synthesis of this compound involves Friedel-Crafts-Uke reaction of the alkylation product (2-1) from ethyl acetoacetate... 

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>. 

A single-step benzoylation-oximation has been described on 4-hydroxy-coumarin by the use of PhCCl=NOH and EtjN in boiling methanol. When 7-methoxy-8-prenylcoumarin (osthol) or its epoxide was treated with various Lewis acids, several products were obtained. These resulted from migration or disappearance of the exocyclic double bond, abnormal Friedel-Crafts phenyl-ation, hydration, cyclization, or demethylation. A novel ring-opening of coumarins was effected by treatment with alkyl halides and NaH in THF. The c/5-o-alkoxycinnamic acid was obtained mainly or exclusively. 

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