Indole catalytic reduction

While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through 3if-indoleninm intermediates. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

The BOM group is introduced onto an indole with the chloromethyl ether and sodium hydride in 80-90% yield. It is cleaved in 92% yield by catalytic reduction followed by basic hydrolysis, or by CF3COOH, HBr or 6 M HCl at... 

Dihydroantirhine has also been reached from indole alkaloid strictosi-dine (224). Mild hydrolysis of 224, followed by subsequent sodium borohydride and catalytic reduction, supplied vallesiachotamine derivative 225. Hydrolysis and decarboxylation of 225 gave enamine 226, which could be izomerfzed to 227 by the use of acid. Sodium borohydride reduction of the thermodynamically less stable enamine 226 afforded (+)-18,19-dihydroantirhine selectively, while 227 yielded uniformly 3-epi-18,19-dihydroantirhine (203) (144). 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

The side chain on the fused five-membered ring can, interestingly, form part of a piperidine or piperazine ring. The scheme for preparing the first of these takes advantage of the reactivity of the indole 3 position. The relatively weak base, sodium hydroxide, thus catalyzes the addition of bromoindole (16-1) to the carbonyl group in 4-iV-methylpiperidone (16-2) to afford carbinol (16-3). This product dehydrates in the presence of acid catalytic reduction of the thus-produced olefin then affords the... 

Vigorous catalytic reduction of indole (H2/Pd/AcOH/HCI, 80°C) results in the formation of cis-octahydroindole. Catalytic reduction of isoindoles occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in ... 

Catalytic reduction of the C-alkenyl and -alkynyl substituents over palladium or Raney nickel can be effected without concomitant hydrogenation of the heterocyclic system to give the corresponding alkyl-pyrroles and -indoles (72HC(25-2)65, B-77MI30504). 

Indole synthesis.3 A general indole synthesis involves reaction of an o-nitrotoluene derivative with dimethylformamide dimethyl acetal in refluxing DMF with removal of the methanol to form a nitro N,N-dimethyl enamine. Reduction of the nitro group is accompanied by spontaneous cyclization to an indole. Catalytic hydrogenation is generally preferred for this step. 

The structure of the piperidine moiety and the presence of an unsubstituted tryptamine bridge in alkaloids of the mavacurine-pleiocarpamine class can be proved by a catalytic reduction to the corresponding indolines, which show very different spectra because now the main fragments contain ring D,los (212)- -(216)- -[2I7]-> [218]->[219]. The reduction of indole to indoline alkaloids seems an attractive route for the structure determination of those alkaloids.25... 

Catalytic reduction of the nitro-epoxide (8.1, R = COOMe) leads directly to the indole carboxylic ester but when R = H, reduction of the nitro-epoxide does not give the indole. However, cleavage of the epoxide and reduction of the nitro group gives the amine (8.2) which is cyclized by a strong base. 

Conversion of isatins into oxindoles can be achieved by catalytic reduction in acid, or by the Wolff-Kischner process.3-Substituted indoles result from Grignard addition at the ketone carbonyl, followed by lithium aluminium hydride reduction of the residual amide, then dehydration. The reaction of isatin with triphenylphosphine provides an easy synthesis of 3-(triphenylphosphorylidene)oxindole, a Wittig reagent. ... 

Aminoindole exists mainly as the 3H-tautomer, presumably because of the energy advantage conveyed by amidine-type resonance. 3-Aminoindole is very unstable, and easily autoxidised. Both 2- and 3-acylamino-indoles are stable and can be obtained by catalytic reduction of nitro-precursors in the presence of anhydrides. 1-Amino-indoles can be prepared by direct amination of the indolyl anion. ... 

The key processes which controlled the stereochemistry were as follows. Firstly, the catalytic reduction of (36) gave two stereoisomeric products, of which (37), in which hydrogen had been added on the side opposite to the bulky indole residue and cis [thus ensuring that hydrogens at C(21), C(20), and C(15)... 

Reduction of the heterocyclic ring is readily achieved under acidic conditions formerly, metal-acid combinations were used, but now much milder conditions employ relatively acid-stable metal hydrides such as sodium cyanoborohydride. Triethylsilane in trifluoroacetic acid is another convenient combination 2,3-disubstituted indoles give cis indolines by this method. Such reductions proceed by hydride attack on the p-protonated indole - the 3//-indolium cation. Catalytic reduction of indole, again in acid solution, produces indoline initially, further slower reduction completing the saturation. ... 

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