Indoles from ketones

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

Many aryhydrazones provide two or more isomers when subjected to the conditions of the Fischer indole cyclization. The product ratio and the direction of indolization can also be affected by different reaction conditions (i.e. catalysts and solvents), which is attributed, at least in part, to the relative stabilities of the two possible tautomeric ene-hydrazine intermediates. Generally, strongly acidic conditions favor formation of the least substituted ene-hydrazine, while cyclization carried out in weak acids favors the most substituted ene-hydrazine. Eaton s acid (10% P2O5 in MeSOsH) has been demonstrated to be an effective catalyst for the preparation of 3-unsubstituted indoles from methyl ketones under strongly acidic conditions. Many comprehensive reviews on this topic have appeared. ... 

For a general, simple high yield indole synthesis from anilines and methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508 (1973). For indoles from N-( /3 -hydroxy-ethyl aniline esters see BSC 2485(1973). For a 2-acyl-indoles in one step from orthoamino-ketones and alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-aminocarbonyls see JOC 38,3622-24(1972). Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het. Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972). 

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... 

An interesting paper reports the combined synthesis of 3-vinylindoles from ketones with the vinylindole synthesis of tetrahydrocarbazoles in one flask by using indole (1 equivalent) and excess ketone precursor as the solvent, usually at reflux with maleic acid (1 equivalent), both as the catalyst for 3-vinylindole formation and as the dienophile for the Diels-Alder reaction. These reactions constitute an in situ vinylindole synthesis of tetrahydrocarbazoles (79JOC4402). 

Figure 6.23 Formation of indoles from dissymmetric ketones by the Fischer indole synthesis.

Examples of the syntheses of fused indoles by the SRN1 mechanism are depicted in Scheme 10.45. The photoinduced reactions of 22 with the enolate anions of cyclic ketones afford the corresponding indoles from moderate to good yields [61],... 

M. A. Yurovskaya, A. V. Karchava, A. Z. Afanas ev, and Yu. G. BundeT, Indoles from 3-nitropyridinium salts. 9. Methyl ethyl ketone A-methylimine in the indolization of l-methyl-3-nitropyridinium salts, Chem. Heterocycl. Cpds., 1992, 409-413. 

Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids. 

Fischer indole synthesis Preparation of indoles from arylhydrazones of ketones and aldehydes in the presence of protic or Lewis acid catalyst. 172... 

Indoles are an important class of fine chemicals derivatives find application as fragrance chemicals. The indole nucleus is present in many biologically active molecules including plant-growth regulators, proteins and pharmaceuticals. The selective synthesis of indole derivatives constitutes an important area of drug research. The well-known Fischer indole synthesis provides a versatile method for synthesizing substituted indoles from the arylhydrazones of aldehydes or ketones... 

Cyclizations. Synthesis of substituted indoles from o-haloanilines by condensation with ketones or nitriles is promoted by r-BuOK in DMSO. 

Indole synthesis. Lalloz and Caubere have reported a new synthesis of indoles from a halogenated aryl anil of type (1), prepared by condensation of a haloaniline with a ketone. Treatment of the anils with this complex base... 

In some cases it is possible to obtain Diels-Alder adducts from vinylindole intermediates which are generated in situ. The yields in such reactions are usually not very high but the simplicity of operation is a compensating factor. For example, heating indole, a ketone and maleic acid together gives l,2,3,4-tetrahydrocarbazole-2-carboxylic acids in around 20% yield (Equation (143))... 

The intermediate carbenes generated from ketones and TMSC-(Li)N2 have also been shown to undergo 1,5 0-Si and N-H insertion to produce 5-trimethylsilyl-2,3-dihydrofurans and 2-pyrrolines or 3-substituted indoles, respectively (eqs 61 and 62). Azulene 1-carboxylic esters may be generated in moderate yield by the reaction of TMSC(Li)N2 with alkyl 4-aryl-2-oxobutanoates, followed by oxidation with manganese dioxide. ... 

Subsequent to their synthesis of tabersonine from intermediate 4 (Scheme 1), Rawal and colleagues demonstrated the utility of their new indolization method in the regi-ocontrolled preparation of indoles from cyclic ketones via... 

Pictet-Spengler ring closure with ketones l,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indoles from tryptamines... 

Scheme 2.14 Pd-catalyzed synthesis of indoles from amines and ketones.

Scheme 2.114 Pd-catal) ed s mthesis of indoles from o-iodoanilines and ketones.

Bis(3-indolyl)methanes (69) were synthesized from the reaction of indole with ketones catalyzed by ZrCU in good to excellent yields (Equation 28) [33]. 

The most studied approaches to ring closure reactions is the S j l substitution of aromatic substrates that have an appropriate substituent in a position ortho to the leaving group. An important example of this approach is the synthesis of substituted indoles by the photoinduced substitution reaction of o-haloanilines (bromo, iodo) with carbanions from ketones, followed by spontaneous ring closure in the reaction media ... 

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