Indoles benzene-ring acylation

Acylation of the C3 position can also be accomplished with acid chlorides, as illustrated in the synthesis of indole 7.34, a drug for the treatment of depression. Reaction of indole 7.31 with oxalyl chloride affords C3-substituted product 7.32 even though the benzene ring is very electron-rich. Conversion to amide 7.33 is followed by reduction with lithium aluminium hydride which removes both carbonyl groups, affording the target indole 7.34. 

Bromo- and -iodoindoles, and the similarly reactive 2- and 3-triflates, " undergo palladium-catalysed couplings as normal aryl halides. Since 2- and 3-haloindoles are unstable it is expedient to employ their A -acyl derivatives. Halogen and triflate on the benzene ring of indoles take part unexceptionally in coupling reactions. 

In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents whereas it occurs in the 2-position with pyrrole. Halogenation, nitration, sulfonation, Friedel—Crafts acylation, and alkylation all occur cleanly at that position. 

The EW-effect of the acyl groups makes the pyrrole and indole ring more comparable to benzene... 

With both hemispheres 228 and 229 in hand, treatment of the TMS derivative of 228 with s-BuLi, followed by addition of 229 resulting in acylation and subsequent in situ hetero-Peterson olefination provided 227. Parikh-Doering oxidation, selective removal of the TMS and TES groups, followed by treatment with Sc(OTf)3 in benzene provided indole 243, assembling the AF ring system and installing the complete penitrem D carbon skeleton. Selective acylation, TIPS removal, selena-tion of the resulting primary alcohol, oxidative elimination and final hydrolytic removal of the acetate furnished (-)-penitrem D (226) (Scheme 43). 

The susceptibility of the pyrrole ring to electrophilic attack has been used in the synthesis of pyrrolo-fused 1,4-diazepines, for example, A-(3-acetylaminopropyI)-3-methyl indole underwent a Bischler-Napierelski-type cyclodehydration on treatment with phosphorous oxychloride in benzene to give ll-methyl-4,5-dihydro-3ff-l,4-diazepine[l,2-a]indole <91IJC(B)1018>. In another example the acyl azide (143) cyclized to the furo[2,3-e]pyrrolo[l,2-a]-l,4-diazepine-9-one (144) (Scheme 25) <92JHC1507>. 

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