Carbamate //- alkyl 1//-indole

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. 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 . A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton . 

Most carbamates used as protective groups for amines are either acid-labile or base-labile. Deprotection proceeds by the mechanisms outlined in Figure 10.8. During the deprotection of acid-labile carbamates, carbocations are formed, which can alkylate electron-rich structural elements in a given substrate (e.g. phenols, thiols, indoles,... 

A series of alkyl carbamates of 1-protected indole-3-methylamines 403 have been prepared from the corresponding acetamides 402 in good to excellent yields via (diacetoxyiodo)benzene-promoted Hofmann rearrangement (Scheme 3.161). This procedure has been further extended to the preparation of alkyl carbamates of thiophenylmethylamines and pyrrolylmethylamines [502]. 

This approach has been used to efficiently assemble 3-vinyl indoles 13 with alkenes (Scheme 6.20) [28]. It was observed in this case that the nature of the nitrogen substituent influences the ability to trap the 3-palladated indole, with carbamates providing the highest yields. The elimination of HX from the palladium after P-hydride elimination creates a Pd(0) complex that is unable to mediate subsequent cyclizations. As such, co-oxidants, such as stoichiometric copper(II) salts, are used in this reaction to regenerate the palladium(II) catalyst. However, by modifying reaction conditions, Lu has found that the addition of excess LiBr can inhibit P-hydride elimination, and instead allow the formation of the reduced product (Scheme 6.21) [29]. This not only allows access to 3-alkyl substituted indoles, but also eliminates the need for stoichiometric oxidants. 

Another double amination route to indoles 260 was reported by Willis (Scheme 9.91) [243]. Accordingly, tandem inter-/intramolecular-bisamination of 2-(2-haloalkenyl)-aryl halides 258 with an array of N-nudeophiles 259, such as anilines, amides, and carbamates, proceeded in the presence of different Cu(I) catalysts, providing N-functionalized indoles 260 in moderate to high yields. Conversely, employment of simple alkyl amines was far less efficient. 

Six Ring Nitrogen Systems.—ReducedPyridines. A -Substituted-l,2-dihydropyridines are of interest since they are implicated in indole-alkaloid biosynthesis. One of the few accessible derivatives is the carbamate (209), which on photolysis gives the 2-azabicyclo[2,2,0]hex-5-ene ester (210). Conditions for the conversion of the latter into the amine (211) have now been found, and several alkylations of this compound have been carried out thermolysis of these compounds has given jV-substituted... 

The next stage of the synthesis required introduction of the indolylethyl group and oxidative cyclization to afford the pentacyclic skeleton of reser-pine. First the carbamate was removed from decahydroisoquinoline 133 to give 134. Alkylation then gave 135. The next task was oxidative cyclization to provide the pentacyclic indole skeleton. At this point it becomes clear why loss of the enamide was unfortunate. 

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