Indole hydroxyalkylation

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

A wide vanety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [55, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [56], Gngnard [57, 59], organocadmiura, and organozmc compounds [56], undergo C-hydroxyalkylation with trifluoropynivates to yield derivatives of a-trifluoromethyi a-hydroxy acids. 

The enamine-imine tautomerism of the indolenine system gives rise to rearrangement reactions of interest in indole alkaloid chemistry. Thus the synthesis of dihydroburnamicine (625) utilized the rearrangement of an acetoxyindolenine to an a-hydroxyalkyl indole, presumably through an intermediate enamine. Similarly 2,3-dialkyl indoles undergo oxidations to 2-acyl indoles (626-631). 

The Reimer-Tiemann reaction is not an effective route to formyl-pyrroles or -indoles (see Section 3.05.1.6) and the oxidation of alkyl and hydroxyalkyl derivatives of the heterocycles and the reduction of carboxylic acid derivatives are discussed in Sections 3.05.2.2 and 3.05.2.4, respectively. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

The various substituents (R) of glucosinolate (R-glucosinolate) compounds include alkyl, hydroxyalkyl, aryl (e.g. Phe-CH2, jft-HO-Phe, Phe-(CH2)2), indol-3-yl (Phe pyrrole), methylsulfonyl alkyl (GH3—S02—(GH2) ), methylsulfinylalkyl (GH3—SO—(CH2) ) and methylthioalkyl (CH3—S—(CH2) ) groups. These give rise to the corresponding isothiocyanates (R—N=C=S) that can have particular bioactivities such as insect attractant, insect deterrent, cytotoxic, lachrymatory, tastant and odorant activities. 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Indoles react with epoxides and aziridines in the presence of Lewis acids (see section 17.5 for reaction of indolyl anions with such reactants) with opening of the three-membered ring and consequent 3-(2-hydroxyalkylation) and 3-(2-amino-alkylation) of the heterocycle. Both ytterbium triflate and phenylboronic acid are good catalysts for reaction with epoxides under high pressure " silica gel is also an effective catalyst, but slow at normal pressure and temperature." Lewis acid-mediated reaction with aziridines can be catalysed by zinc triflate or boron trifluoride.More reactive alkylating electrophiles react at lower temperatures, at room temperature with dimethylallyl bromide for example. ... 

The above reaction sequence (Scheme 11), sometimes called the Katritzky method, has been exploited by a number of research groups for the preparation of 2-substituted IV-unsubstituted indoles [83, 102, 130, 218, 240-245], Gribble and Bergman used this chemistry to prepare 2-bromoindole and 2-iodoindole [246-248]. Bergman and Janosik further explored this sequence to prepare indol-2-yl sulfides and selenides [57,249,250]. Hudkins has used this chemistry to prepare 2-hydroxyatkylindoles en route to indolocarbazole derivatives [251, 252], The first step in Bergman s short total synthesis of yuehchukene used the Katritzky method and aldehyde 59, which gave 2-(hydroxyalkyl)indole 60 (Scheme 12) [253, 254]. 

Primarily, the product 19 of an acid-catalyzed hydroxyalkylation should be formed, which on protonation and loss of H2O produces the azafulvenium ion 18 alkylation of a second indole moiety by 18 affords the bis(indolyl)methanes 20 as final products. 

Scheme 35.7 Cinchona alkaloid catalyzed hydroxyalkylation of indoles.

The scope of this F-C hydroxyalkylation of indoles was extended to a range of different carbonyl compounds, giving rise to the desired compounds in high yields (up to 97%) and enantioselechvities (up to 99% ee) in the presence of catalysts 13 and 14 [18]. Catalyst 14 also proved to be highly selective when carrying out the first example of cinchona alkaloid mediated F-C alkylation of phenols with 45 (Scheme 35.8) [58]. Chiral phosphoric acids were also used to mediate F-C alkylation in the presence of ethyl trifluoropyravate [31], trifluoroacetate [59], and trif-luoromethyl ketones [60]. 

Microwave-assisted decarboxylative Claisen rearrangement reactions of substituted acetate derivatives of 3-(hydroxyalkyl)indoles give dearomatised products (Camp et al., 2011). The reactivity of the resultant compounds was evaluated. 

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