Reactions of C-metallated Indoles

One of the most convenient A-protecting groups to be used in indole a-lithia-tions is carbon dioxide because the A-protecting group is installed in situ and, further, falls off during normal work-up. This technique has been used to prepare 2-haloindoles and to introduce a variety of substituents by reaction with appropriate electrophiles - aldehydes, ketones, chloroformates, etc. 

Given below is a selection of a-substitutions achieved with various A-block-ing/activating groups.  

Amazingly, metal-halogen exchange can be achieved with 5-bromoindole without A-protection the indole is first converted into its N-potassio-salt.  

Bromo- and iodoindoles, and the similarly reactive triflates, undergo palladium-catalysed couplings as normal aryl halides. Since 2- and 3-haloindoles are unstable it is expedient to employ their A-acyl derivatives.  

When an organometallic derivative of indole is required for a coupling reaction, boronic acids are to be preferred, although some zinc derivatives can be used. 

3-Lithioindoles can be prepared by halogen exchange the iV-7-butyldimethylsi-lyl derivative is regiostable, even at whereas 3-lithio-l-phenylsulfonylindole 

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The C-phenylation reaction of 3-unsubstituted indoles by Ph3Bi(OCOCF3)2 was catalyzed by metallic copper or copper(H) salts to give a 3-phenylated product in 50-96% yield (Scheme 9) [25], The same reaction did not proceed with Ph3Bi (OCOCH3)2. The reaction is believed to proceed through Cu(III) intermediates. 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

The (5)-tryptophan-derived oxazaborolidenes utilized in this aldol study have been previously examined by Corey as effective catalysts for enantioselective Diels-Alder cycloaddition reactions [6]. Corey has documented unique physical properties of the complex and has proposed that the electron-rich indole participates in stabilizing a donor-acceptor interaction with the metal-bound polarized aldehyde. More recently, Corey has formulated a model exemplified by 7 in which binding by the aldehyde to the metal is rigidified through the formation of a hydrogen-bond between the polarized formyl C-H and an oxyanionic ligand [7], The model illustrates the sophisticated design elements that can be incorporated into the preparation of transition-metal complexes that lead to exquisite control in aldehyde enantiofacial differentiation. 

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