Lithiated indoles

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. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Lithiated indoles are the most useful intermediates for direct preparation of 2-alkylin-doles. 1-Methylindole, 1-benzenesulfonylindole and 1-f-butoxycarbonylindole all provide... 

The antihypertensive agent 278 has been 14C-labelled by carbonation of the 2-lithiated indole, 279 (R = Li), with 14CC>2 and subsequent combination with a preformed peptide side chain. In 279 (R = H) the indole nitrogen has been converted into its benzenesulphonyl derivative to direct properly the lithiation while the 2-hydroxy-3-isopropylaminopropoxy side chain has been protected as oxazolidin-2-one290. 

Another way was used to synthesize pentathiepinoindoles <2001T7185>. Thus, the reactions of 2-lithiated indole and 1-methylindole with elemental sulfur were studied, leading, for example, to a rational approach to the corresponding pentathiepino[6,7-A]indoles 126 and 127. Treatment of the anions of the corresponding indoline-2-thiones with sulfur also gave both pentathiepinoindoles (Scheme 27). Pentathiepino[6,7-A]indole 126 can be isolated from reaction of P4S10 with isatin in pyridine (Scheme 27) <1994TL5279>. 

The use of different orf/io-lithiated indole derivatives (/V-methy I indole. 5 -me thox v-/V-me th vI i ndoIe and /V./V-di ineth vI am i noine th vI i ndoIe) led to novel titanocene dichlorides 27-29 with IC50 values of 71 pM, 37 pM and the impressive value of 8.4 pM for 28 (see Fig. 9). Again, this represents a nearly 250-fold increase in cytotoxic activity compared with Cp2TiCl2 [26]. 

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>. 

Reaction of 1,2-anhydro-mannose with lithiated indole in the presence of BF3-OEt2 as Lewis acid yielded a-C-mannosylindole, which was further transformed into C-mannosyltryptophan, a naturally occurring C-glycosyl amino acid found in some proteins (O Scheme 38) [59]. 

Lithio-l-arenesulfonyUndole intermediates are also prone to ring fragmentation. Lithiated 1-phenylsulfonylindole-2-carboxamides fragment at —78°C <86H(24)2127>. 3-Lithiated indoles with A-alkyl substituents are much less susceptible to fragmentation. This relative stability relationship presumably reflects the anion stabilization provided by the sulfonyl group. 

Fig. 4 Additional indole natural product targets synthesized via lithiated indole intermediates...

New synthetic sequences based on four-co-ordinate borate intermediates continue to be discovered. The carbonylation of B-R-9-BBN, resulting ultimately in quantitative one-carbon homologation of R to primary alcohol or aldehyde, is preferentially and rapidly effected by K [(Pr 0)3BH], which is stable and does not give undesirable by-products on work-up. The lithiated indole of Scheme 6... 

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