Substituted, conversion to indoles

AcEIYLKETENE, 21, 64 Acetylsalicylyl chloride, 23, 66 Acetylsalicylyl peroxide, 23, 66 Acetyl-o-toluidine, 22, 94 substituted, conversion to indoles, 22, 95... 

As o-substituted aniline starting materials are commonly appHed in indole synthesis and can be used in combination with a broad range of catalysts, Messerle and coworkers [346] showed that this transformation provided the basis for a high-throughput screening approach in catalyst discovery. Using a UV/Vis method, a cationic Rh complex was shown to realize complete conversion to indole within 12 min (Scheme 15.110). 

The Batcho indole synthesis involves the conversion of an o-nitrotoluene to a (3-dialkyl-amino-o-nitrostyrene with dimethylformamide acetal, followed by reductive cyclization to indoles. This provides a useful strategy for synthesis of substituted indoles (Eq. 10.49).63... 

Excellent ee-values (up to 94%) have been obtained for the hydrogenation of various 2-substituted N-acetyl indoles with an in-situ prepared rhodium catalyst modified with the trans-chelating diphosphine (S,S)-(R,R)-2,2"-bis[l-(diphenyl-phosphino)ethyl]-1,1"-biferrocene (Scheme 16.23) [88]. A strong base was required as co-reagent to observe both high conversion (TOFs of 50-100) and en-... 

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Akermark first reported the efficient oxidative coupling of diphenyl amines to carbazoles 37 with Pd(OAc)2 in refluxing acetic acid [45]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO2), and 20 years later Akermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 38 to carbazole-l,4-quinones 39 [46]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6,11-quinones (e.g., 40). 

A related Heck reaction of substituted o-bromoacetanilides with styrenes followed by selenium-induced cyclization of the resulting o-styiylacetanilides gives 2-arylindoles [378], Substituted o-bromonitrobenzenes react with ethyl vinyl ether under the influence of Pd(OAc)2 to give the corresponding o-ethoxyethenylnitrobenzenes. Zinc reduction then yields indoles [379]. The one-step Pd-catalyzed conversion of o-bromoanilines to indoles 302 with enamines (or with A/-vinyl-2-pyrrolidone) has been reported [380]. 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

The most frequent application of Larock s method is undoubtedly the conversion of o-haloanilines to indoles. The scope of this transformation covers a wide range of disubstituted acetylenes and anilines including both TV-substituted and unsubstituted derivatives. A schematic representation of... 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

Incorporation studies with isotopes showed that when anthranijate was converted to tryptophan, the carboxyl group df anthranilate was lost as carbon dioxide, but the nitrogen was retained. Because the enzymes in the tryptophan biosynthetic pathway have only a limited specificity, it was possible to substitute 4-methyl-anthranilate in E. coli extracts that could convert anthranilate to indole. This nonisotope label was conserved during the conversion to yield 6-methyl indole. 

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. 

Yet another use for (A-protected) grammes is conversion into 3-bromo-indoles this involves P-bromination and then retro-Mannich loss of the original substituent. Combined with the directing ability of the original dimethylamino group (20.5.1) this provides a route to 4-substituted 3-bromo-indoles. 

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