Indole derivatives 3- alkylation

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

The Ciamician-Dennstedt reaction has been used to prepare macrocycles. Reaction of 2,3-alkyl linked indole derivatives 10, 11, 13, and 15 with phenyl(trichloromethyl)-... 

The most widely used procedures for the preparation of the indole magnesium halides are based on the method originally described by Oddo in 1911, and consist of adding a solution of indole or an indole derivative, in dry diethyl ether, to a solution of an alkyl magnesium... 

Pharmacokinetic studies of Ai-pyridinyl-indole-3-(alkyl)carboxamides and derivatives 95... 

Grigg et al. also reported the alkylation of indole at the C3-position with alcohols, catalyzed by the 1/KOH system (Scheme 5.32) [69]. A variety of indole derivatives having an alkyl substituent at the C3-position were synthesized by this methodology. The same group also developed a Cp lr-catalyzed process for successive carbon-nitrogen and carbon-carbon bond formation, starting with 2-amino-phenethyl alcohol (also see Scheme 5.22). 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Reduced indole derivatives can be synthesized by using the phenolic oxidation approach. Thus, A-alkyl-A-benzoyltyramines 120, on treatment with IBTA in trifluoroethanol (TFE), followed by aqueous workup, afford the hexahydroindol-6-ones 122. The formation of 122 is rationalized by intramolecular Michael-type addition of amino group to the double bond of the intermediate dienone 121 (91JOC435) (Scheme 33). 

Especially interesting is the alkylation of 3 (R = CH2OCH3) with 4-bromo-l-chlorobutane to afford the chloroalkyl derivative with very high enantioselectivity46. Depending on the mode of deprotection of both nitrogen atoms, tetracyclic indole derivatives 5 or 6 were obtained. 

Lonza Cie191 has recently patented a selective O-alkylation reaction of an indole derivative starting not from hydroxy- but from trimethylsilyloxy-indole (124). 

For example, although only trace amounts (ppm levels) of nitrogen are found in the mid-distillates, both neutral and basic nitrogen compounds have been isolated and identified in fractions boiling below 345°C (650°F). Pyrrole derivatives and indole derivatives account for the about two thirds of the nitrogen while the remainder is found in the basic pyridine and quinoline compounds. Most of these compounds cany alkyl chains. 

The enantioselective alkylation of indoles catalyzed by C2-symmetric chiral bisoxazoline-metal complexes 90 encouraged many groups to develop superior asymmetric catalysts which are cheap, accessible, air-stable and water-tolerant. Other analogs of the bisoxazoline-metal complex 90 as chiral catalysts and new Michael acceptors have also been studied. The enantioselective alkylations of indole derivatives with of-hydroxy enones using Cu(II)-bis(oxazoline) catalysts 93 and 94 provided the adducts in good yields... 

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... 

C-Alkylation of pyrroles and indoles can be mediated by alumina in association with the appropriate halide. 3-Indolyl sugar derivatives have been obtained by alkylation reactions of indolylmagnesium bromide. This type of alkylation has been extended to ring-fused indoles 105 and yields 3//-indole derivatives 106 in good yields. 

The alkylation of pyrroles 131 with epichlorohydrin using potassium carbonate as a catalyst affords l-(2-oxiranyl-methyl)-l/7-pyrroles 132 in modest to high yields (Equation 22) <2002BMC2511>. A similar synthetic route led to indole derivatives 133 (Equation 23). Both compounds 132 and 133 are precursors of isopropanolamines, potential anti-HIV-l-PR agents. 

Suvorov, N. N., Velezheva, V. S Vampi-lova, V. V., and Gordeev, E. N., Indole derivatives. XII. Alkylation of barbituric acids by Mannich bases, Khim. Geterotsikl. Soedin.. 515, 1974 Chem. Abstr.. 81, 37532, 1974. 

The substrate arachidonic aeid, whieh often leads to formation of inflammatory prostaglandins, is stored in tissues as one of a number of phospholipids these compounds, as the name indicates, comprise complex phosphate-containing esters. The antiinflammatory corticosteroids inhibit the action of the enzyme, phospholipase A2, that frees arachidonic acid. The many undesired effects of those steroids has led to the search for non-steroidal inhibitors of that enzyme. A highly substituted indole derivative has shown good activity as a phospholipase A2 inhibitor. Alkylation of the anion from treatment of indole (32) with benzyl chloride affords the corresponding A-benzylated derivative (33). The methyl ether at the 4 position is then cleaved by means of boron tribromide to yield 34. Alkylation of the enolate from reaction of the phenol with sodium hydride with tert-butylbromoacetate affords the corresponding... 

In a new simple synthesis of pyrazino[l,2-a]indole derivatives, 3-methylindole 157 was A-alkylated to 158, followed by treatment with formaldehyde and benzotriazole to produce the system 159. Displacement of the benzotriazolyl moiety with various nucleophiles gave the final products 160 <03JOC4938>. 

Although considered mild in comparison with other metals, copper(I) and (II) Inflates are suitable Lewis acids for affecting Friedel-Crafts alkylation and acylation reactions (Sch. 22). The intramolecular acylaminoalkylation of the indole derivative 88 afforded the cyclized product 89 in high yield [49]. The nitrogen functionality was not a requirement for formation of the benzylic cation, because the benzylic alcohol 90 reacted similarly with 91, even with an electron-withdrawing ester group adjacent to the cationic center. 

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