3-alkyl substituted indoles

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. 

Other Alkylations. NCS and allylic sulfides react with 3-unsubstituted indoles at —20 °C to give initially 3-sulfonium salts which on warming to 20 °C rearrange to 2-allyl-3-thiomethyl-indoles (eq 13). These are readily desulfurized, either with or without concomitant reduction of the allylic double bond, to give 3-allyl or 3-alkyl substituted indoles. ... 

Nitration of indole by benzoyl nitrate gives 3-nitroindole (35%) [68JCS(C)2145]. Nitration of some alkyl-substituted indoles by nitric acid/ sulfuric acid (63JOC2262 79JOU528) takes place upon the protonated species, and in such cases the rates pass through a maximum at 90% sulfuric acid in the usual way. 2-Methyl-, 1,2-dimethyl-, 2-f-butyl-, and 2,3-dimethylindole are each nitrated at the 5-position, the former two compounds in 84 and 82% yield, respectively, the latter two compounds at similar rates. This rate similarity suggests that in the protonated species the 5-position is much the most reactive of the benzenoid ring positions. In the protonated species it is probably the 3-position that has become... 

Enantiomerically pure 4-alkyl substituted derivatives of tryptophan required for the asymmetric syntheses of ergot alkaloids has been obtained [35]. The author used the method [36] to produce 4-alkyl substituted indoles and combined this organometallic reaction with an enantioselective enzymatic transformation. An efficient eight stage synthesis ofN-benzenesulphonyl-3-(3 -methoxyprop-2 -en-r-yl)-4-(r-hydroxy-2 -trimethylsilymethyl-prop-2 -en-r-yl)-indoles from 4-carbomethoxyindole has been described [37]. The use of these benzylic alcohols for intramolecular cation-olefine cycloadditions yielding either a tetracyclic or a tricyclic product was also demonstrated. 

Simple alkyl-substituted indoles (41) react with dioxygen in the presence of the cobalt porphyrins Co(TPP), Co(TPP)Br and Co(DPDME) at room temperature and 1 atm 0, affording ketoamides 42 [216,217]. 

Muratake, H., Mikawa, A., Serno, T., and Natsume, M. (1994) Preparation of alkyl-substituted indoles in the benzene portion. Part 11. Total synthesis of (6J ,8S)-herbindole A, (6R,8S)-herbindole B, (6R,8S)-herbindole C, (6R,8S)-ds-trikentrin A, (6R,8S)-cis-trikentrin B, (6R,8R)-trans-trikentrm B, and (6R,8R)-iso-troras-trikentrin B. Determination of the absolute structures of natural herbindole and trikentrins. Chem. Pharm. Bull., 42, 854—864. 

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

The Bartoli process has been employed effectively in the synthesis of 7-substituted indoles including 7-alkoxy (15), 7-alkyl (18) , and 7-formal indoles (21). Although the yields are only moderate, this process does provide a simple entry into indoles which were heretofore difficult to obtain. 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

Taber and Tian have employed the Neber protocol to prepare a-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-... 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

Indoles can be also be converted into their radical cations by the use of C1C>2 as the oxidant produced by pulse radiolysis. From the reactivity of the resultant cation it was possible to establish the one-electron reduction potential of the indole in question. Typical results from this are illustrated in Table 234. As can be seen, the one-electron reduction potential is influenced by alkyl substitution. 

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