Dihydroindoles, Friedel-Crafts

Less common 2-substituted indole derivatives can be prepared by Friedel-Crafts alkylation of 4,7-dihydroindoles with a,p-unsaturated aldehydes, followed by oxidation with p-benzoquinone [317]. 4,7-Dihydroindoles, which can be considered as 2,3-disubstituted pyrroles, react with a wide variety of aromatic and aliphatic enals... 

The ability of the less sterically hindered primary amines to perform iminium activation with challenging substrates such a,P-unsaturated ketones has been also applied to the Friedel-Crafts alkylation of 4,7-dihydroindoles using simple 1,2-vicinal diamines derived from L-leucine [329]. 

Primary-secondary diamine catalyst 14 was found to be useful in the Friedel-Crafts alkylation reaction (Scheme 3.20). In the presence of 14/trifluoroacetic acid (TFA), alkylation of 4,7-dihydroindoles 85 with a,(3-unsaturated enones 86 proceeded well, and the desired alkylation products were obtained in high yields and with excellent enantioselectivities [56]. 

Takenaka and coworkers used 2-aminopyridinium salts as dual hydrogen-bond donors for the activation of nitroalkenes. The 7-azaindolium salt 65 was found to be particularly effective for the Friedel-Crafts reaction of nitroalkenes with various electron-rich arenes as well as for intra- and intermolecular Diels-Alder reactions (Scheme 10.63) [163, 164]. The same concept was successfully applied to the enantioselective conjugate addition of 4,7-dihydroindoles to nitroalkenes using helical chiral 2-aminopyridinium salts (Scheme 10.64) [165]. The reaction was found to have a broad substrate scope, affording various 2-substituted indoles in good to high enantiomeric ratios. 

You and coworkers employed 4,7-dihydroindoles 79 instead of indoles 75 in the Friedel-Crafts reaction with nitroalkenes 77 (Scheme 11.22) [41]. Catalyst Ig with a 9-anthryl group displayed excellent performance. The notable point in this reaction is the use of the syringe pump technique to achieve high enantioselectivities and suppress the background reaction. Subsequent oxidation of Friedel-Crafts adducts 80 by p-benzoquinone afforded 2-substituted indole derivatives 81 in excellent yields without racemization. This approach and the simple asymmetric Friedel-Crafts reaction of indoles are complementary methods for obtaining the different substitution patterns of chiral indole derivatives. 

Scheme 11.22 Asymmetric Friedel-Crafts reaction of dihydroindole with nitroalkenes.

One interesting feature of these reactions is that the absolute configurations of the corresponding adducts were switched by employing the same (R)-phosphoric acid catalysts in both Friedel-Crafts reactions. In the case of dihydroindole, the enriched enantiomer was the (S)-enantiomer, whereas the (R)-isomer was the major product in the indole Friedel-Crafts reaction (Figure 11.5). 

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