Alkyl-Indoles

Only alkyl groups at indole a-positions show any special reactions. Many related observations confirm that in a series of equilibria, P-protonation can lead to 2-aUcylidene-indolines, and hence reactivity towards electrophiles at an a-, but not a P-alkyl group, for example in DCl at 100 °C 2,3-dimethylindole exchanges H for D only at the 2-methyl. This same phenomenon is seen in Mannich condensation and trifluoro-acetylation of 1,2,3-trimethylindole at the a-methyl. 

Side-chain lithiation is again specific for an a-substituent, via an iV-lithium carboxylate, or even without Af-protection.  

A quite different side-chain acylation can be achieved with aluminium chloride catalysis here, association of the Lewis acid with the indole a-position is assumed to lead to a styrene intermediate, which is acylated.  

---

Tabatabaeian, K., Mamaghani, M., Mahmoodi, N.O., and Khorshidi, A. 2008. Solvent-free, ruthenium-catalyzed, regioselective ring-opening of epoxides, an efficient route to various 3-alkylated indoles. Tetrahedron Letters, 49 1450-54. 

A related sequence is involved in the lithium aluminium hydride reduction of indol-3-yl-carbinols (which can be obtained from the corresponding ketones using milder reducing agents), with formation of the alkyl-indole. This constitutes a useful synthesis of 3-alkyl-indoles. The one-pot conversion of 3-formylindole into 3-cyanomethylindole with a mixture of sodium cyanide and sodium borohydride probably involves a comparable elimination from the cyanohydrin, then reduction. ... 

A palladium-catalyzed allylation of indoles with allyl carbonates furnished 3-alkylated indoles <04OL3199>. An intramolecular variation with indolyl carbonates provided a novel synthesis of tetrahydro-p-carbolines and pyrazinoll,2-a indoles. 

The preparation of indoles by the benzyne route is illustrated by the base-induced cyclization of the amino-alcohols (171 R = H or Me) to indole and 3-methylin-dole, respectively/ The photochemical reaction of o-bromo- or o-iodo-aniline with the enolates (172 R = H, Me, or PrO leads to indoles (173)/ The salt (174), generated by the action of lithium di-isopropylamide on o-tolyl isocyanide, serves as a source of diverse indole derivatives (i) it cyclizes spontaneously to 1-lithioindole, which forms 3-alkyl-indoles on treatment with alkyl halides in the presence of magnesium iodide, (ii) it reacts with allyl esters RC02CH2CH=CH2 (R = alkyl or aryl) to give the ketones (175), which cyclize... 

With limitations, this method is applicable to synthesis of cycloheptanones. Indole synthesis. o-Tolyl isocyanide (1) is lithiated by treatment with LDA (2 equiv.) in diglyme at —78° on warming to 20°, indole (2) is obtained in almost quantitative yield. The intermediate a can also be used for preparation of 3-alkyl-indoles (4). ... 

The observation of in vitro metabolic activation of the 3-benzylindole moiety in zafirlukast, an anti-asthma drug, to give the glutathione adduet is an indication that the 3-methyl-indole activation pathway applies to other activated 3-alkyl indoles as well. ... 

A-vinylindoles took place. Moreover, the gold-catalyzed cyclization of 2-alkynylanilines can be combined with a gold-catalyzed Michael addition to enones, which afforded 3-alkylated indoles with good yield. Gold-catalyzed hydroamination/hydroarylation cascades of polyenyne-substituted anilines leading to condensed aromatics have been described recently. ... 

The enantioenriched 3-alkylated indoles 204 were isolated in high-to-excellent stereoselectivity upon a Friedel-Crafts/Sf 2 addition-elimination sequence, which also allowed recovering the less reactive starling material (/ )-203 with high optical purity. 

A mixture of indole derivative (1 1 mmol), 1,3-dicarbonyl compound (2 1 mmol) and molecular iodine (10 mol%) was stirred at room temperature in a round-bottom flask for 2-3 h. After completion of the reaction (as monitored by TLC) a saturated aqueous solution of Na2S203 (2x5 mL) was added, and the mixture was extracted with EtOAc (3x5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product of 3-alkenylated indole (3)/3-alkylated indole (4) which was then purified using column chromatography. Each of the products (3 and 4) was characterized on the basis of spectral and elemental analyses. 

Recent studies carried out by Casnati and coworkers 69, 70) seem to indicate that revision of the mechanism outlined above is necessary. These authors studied the reactivity of 3-alkylated indoles towards alkylation with allyl bromides and clearly showed that direct attack at position 2 of the indole nucleus is competitive with alkylation at position 3. In particular, with reagents of enhanced electrophilic character direct attack at the 2-position increases 69). It was suggested that the positional selectivity is determined by the electronic density of 3-alkyl-indoles. In fact, an alkyl group in an aromatic system decreases the electron density in the a-position and increases it in the p-position (272). 

NBS reacts with the indole nucleus following the normal pattern of electrophilic substitution attack at the 3-position is favored. When this position is blocked substitution occurs at the 2-position. Indole and 3-alkylated indoles exposed to one mole of NBS under anhydrous conditions yield 3-bromoindole and 2-bromo-3-alkylindoles respectively 175,394). By contrast, halogenation in hydroxylic solvents often leads directly to oxindoles and both 2- and 3-halo-indoles readily form... 

Alkyl indoles (characteristic rearrangement ion) Cinnamates (C6H5CH=CH—)... 

Similarly, acylation of the dipeptide 410 with bromoacetyl chloride followed by base-induced cyclization gives the pyrazinylacetate ester 411 <2001BML1251>. Compound 410 is itself cyclized with />-toluenesulfonic acid to give the (iV-alkylated indole) equivalent of 406 <200JME3518>. 

The use of dimethyl sulphoxide as a dipolar aprotic solvent is well known,7 and the present method can be regarded as a model procedure and has been applied to the preparation of a number of N-w-alkyl-pyrroles and N-w-alkyl indoles.8 The yield of N-benzylindole is considerably higher than in previously reported preparations and is as good as that reported for the preparation of N-methylindole in liquid ammonia.4 The present method is, however, less laborious and quicker to carry out. Very high yields are obtained in reactions using w-alkyl halides and moderately good yields with secondary alkyl halides. The reactions should be compared with those recently reported for pyrryl-thallium.9... 

The borate intermediate was also coupled with aryl halides. When a ynyl group is present, coupling is followed by a tandem cyclization which leads to 2-[ t-(cycloalkylidene)alkyl]indoles. <95CC409>... 

Indole and alkyl-indoles (38) are protonated in position 3 by the action of strong mineral acids.198,197 The tendency of the enamine salts to assume the immonium structure is very general the salts of ethyl j3-aminoerotonate are derived from the imino form at the expense of the conjugation between the carbonyl group and the double bond.12,198... 

Stanovnik, B., Tisler, M. and Carlock, J.T. (1976) Heterocycles, CLIX. A novel synthesis of alkyl indole-3-carboxylates. Synthesis, (11), 754—755. 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

The structures previously proposed for bromohexahydroechinulin and nitro-hexahydroechinulin are invalid, as they were based on an erroneous structure for echinulin. A recent 13C n.m.r. study of several model alkyl-indoles and these two... 

A better view is possible through the analysis of Hinman22 of the protonation behavior of alkylated indoles (equation 5)31. Pertinent pA H+ values are given in Table 5. As... 

N-Alkylation of 3-aroylindole 97 carried out at 80 °C with alkyl halides from ethyl through -hexyl, gives mixtures of products 98 and 99 in yields of 41-90% (Equation 15) <1998JOC4510>. In addition to the expected N-alkylated indoles 98, a substantial fraction of the product was formed by additional replacement of the methoxy group by an alkoxy group. The reaction is very temperature dependent, since a decrease of only 5 °C completely suppresses the formation of the 0-alkylation products with the ethyl or -propyl halide. However, -hexyl bromide provided a 75% yield of hexyl ether 99 under these conditions. 

N-Aminoalkylation of l//-pyrrole was achieved with 2-chloroethylamine under phase-transfer conditions (TEAS, NaOH, MeCN) <2004JOC8668>. Synthesis of N-alkylated indoles 121 (e.g., RO 60-0175, R = 5-F-6-Cl), that are selective 5HT2C agonists with potential therapeutic utility in the treatment of obsessive compulsive disorder... 

Various N-protected aziridines have been reacted with N-lithiated indoles to afford N-alkylated and 3-alkylated products, the exact ratios depending on the reaction solvent and the nature of the N-protecting group <1989CB2397>. Indoles and V-alkyl indoles afford tryptamine derivatives on reaction of aziridines under Lewis acid catalysis <1998SL754>. An improved technical process for the efficient N-alkylation of indoles 119 using the N-protected homochiral aziridine 123 has been developed (Equation 20) <20030PD22>. 

Using an acetonitrile/2-propanol system led to high-yield transformation of N-alkylated indoles 317 into the fluorinated targets 318 (Equation 71) <2002TL6573>. 

The observation that enamines may be reduced by NBH in acetic acid/ THF ° and sodium cyanoborohydride coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205) in high yield. //-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of l-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline (207) via an intermeuiate 3,2 dimer (206). ... 

A general synthetic method for production of alkyl-indols is that of Emil Fischer. 

Pirrung, M. C., Wedel, M., Zhao, Y. 7-Alkyl indole synthesis via a convenient formation/alkylation of lithionitrobenzenes and an improved Bartoli reaction. Syniett 2002, 143-145. 

Replacement of the aminoalkyl substituent by an alkyl chain results in N-alkyl indoles (non-AAIs) (e.g., 41, Fig. 10). The SAR of cannabimimetic 2-methylindoles indicates that compounds with N-alkyl substituents from w-propyl to n-hexyl have good affinities for both CBi and (TT receptors with a preference for CB2. The in vivo potencies of these compounds were reported to be consistent with their receptor affinities (Huffmann et al. 1994 Wiley et al. 1998). 

---