Indol-3-yl carbinols

The acid-catalyzed alkylation of indoles by carbonyl compounds is complicated by the fact that the resulting indol-3-yl carbinols are usually reactive under these conditions. The most common outcome is the formation of W -indolylmethanes, as is discussed in the next section. In some cases, the carbinol intermediates can be diverted to alkylation by reductive trapping using triethylsilane-TFA. This reaction gives good yields of 3-benzyl indoles and there are a few examples of 3-alkylatiOTi using N-substituted indoles [120]. 

These conditions were used to prepare a series of potential COX-2 inhibitors 

The presence of a strongly electron-attracting group, such as trifluoromethyl can both enhance the reactivity of the carbonyl group and stabilize the carbinol. As a result, such compounds have been the most successful in giving the carbinol product. One of the first successful enantioselective alkylation reactions was carried out using 3,3,3-trifluoropyruvate esters [122]. 

The same substituent effect is present with trifluoromethyl aryl ketones. N/J, AfW-Tetramethyl-N -(f-butyl)guanidine was an effective catalyst for reaction with trifluoromethyl ketones [123]. The reaction can be done enantioselectively using 3,3 -bw-(2,4,6,-tri-j-propyl-phenyl)BlNOL [ 124], 

A similar substituent effect operates in the reaction of indole with diethyl ketomalonate conducted by microwave irradiation oti montmorillonite K-10 clay [125]. Indole, its 1-methyl and 2-methyl derivatives, along with C-ring analogs, gave mixtures of both the 3-carbinol and te-indol-3-yl products. 

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Fused indole 232 resulted from the reaction of a donor-acceptor cyclopropane with an indole bearing a Michael acceptor at C2.The products were obtained in good yield with high diastereoselectivity (16 examples, 64-90% yield) (140L3954). Tetracyclic-fused indole 233 was prepared by a [3+3]-cycloaddition of an indol-2-yl carbinol with an azadiene (11 examples, 42-90% yield). This could be followed by an oxidative ring expansion promoted by (bis(trifluoroacetoxy)iodo)benzene to produce a series of indole azepinones (6 examples, 59-71% yield) (14CC11181). Fused indole 234 was synthesized by the first calcium(II)-promoted Nazarov cyclization (87% yield).The substituent a to the ester functionality could vary electron-rich arenes, heteroarenes, and secondary alkyl... 

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