Indolylacyl radicals

Scheme 3.81. Domino 2-indolylacyl radical addition/cyclization reaction.

The Bennasar group has reported a regioselective 6-endo reductive cyclization of 2-indolylacyl radicals, generated from 154, to afford entry into the tetracyclic ring system 155 found within guatambuine 156 <06JOC1746,06OL561>. 

Se-Ph selenoester is a good precursor of an acyl radical where it behaves as a nucleophilic radical. Treatment of Se-Ph selenoester (20) and benzyl acrylate with Bu3SnH generates a y-keto ester (21) as shown in eq. 4.1 la. 2-Indolylacyl radical can be generated from Se-Ph selenoester (22) by this method (eq. 4.11b) [25-30]. 

Indolylacyl radicals participate in a productive cascade reaction featuring an intermolecular alkene addition-indole cyclization sequence to give the cyclopenta[ >]indole... 

INTRAMOLECULAR REACTIONS OF 2-INDOLYLACYL RADICALS WITH ALKENES... 

As expected, the higher alkene substitution present in the 2-indolylacyl radical derived from 14a retarded the usually favored 5-exo cyclization in favour of the 6-endo mode. Thus, the tram fused tetracycle 15a was isolated as the major product in 75% yield along with... 

In contrast with the clean 1-exo cyclization of benzoyl radicals (e.g., selenoester 9, n = 3), no cyclization was observed from 2-indolylacyl radicals derived from selenoesters 33-35. Only the respective indole-2-carbaldehydes were isolated from the reaction mixtures, indicating that both exo and endo ring closures leading to 7- or 8-membered carbocycles fused to the indole ring are too slow for the radical chain to be productive <04OL759 07JOC4562>. 

Indolylacyl radicals undergo intramolecular reactions with benzene <04TL5605>, pyridine <05JOC9077> and quinoline <06OL561> rings with moderate to excellent efficiency, enabling the assembly of polycyclic aryl or heteroaryl indolyl ketones related to natural and synthetic bioactive compounds. 

Ellipticine quinones have an intrinsic interest as antitumor agents <04JME4958> and are also known intermediates in the synthesis of ellipticines <02CRV4303>. For instance, ellipticine quinones 53b and 53c have been transformed into the alkaloid ellipticine <80JA1457 90J(P1)1319 98H(48)1593>. Hence, these homolytic pyridine acylations by 2-indolylacyl radicals also constitute formal syntheses of the natural product. 

The reductive cyclization protocol was then applied to a suitably A-protected radical precursor to allow further access to the alkaloid calothrixin B. Satisfactorily, 2-indolylacyl radicals derived from A-(methoxymethyl) selenoester 57 underwent cyclization under TTMSS-AIBN conditions with an even higher efficiency than their A-methyl counterparts. The reaction nevertheless followed a different course as, after the radical addition and quinoline rearomatization, pentacyclic phenol 58, a fully aromatic tautomeric form of ketone P, was isolated in 90% yield. The same phenol 58 was isolated although in lower yields (50-70%) using either stannane-AIBN or AIBN-irradiation protocols. 

Indolylacyl radicals are extremely useful reactive intermediates that participate in inter-and intramolecular reactions with alkenes and (hetero)aromatic systems. This radical methodology gives easy access to a wide range of indolic structures, including simple indolyl ketones as well as more complex polycyclic compounds embodying the 2-acylindole moiety. 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines <05T941> and indolo[3,2-d][l]benzazepin-6-ones <05T5489>. 3,3-... 

The generation and reactivity of 2-indolylacyl radicals has been studied <04OL759, 04TL5605>. For example, irradiation of selenoester 188 and hexabutylditin produced... 

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