Indole derivatives lithiation

The direct lithiation of benzo fused heterocyclic systems in the benzo ring is often less easy than in the heterocyclic ring or even at a substituent phenyl group. Thus, while A7-phenyl indole undergoes lithiation at both the 2- and the 2 -positions, /3-lithiation at the 7-position does not occur. The first observation of lithiation at the 7-position of an indole derivative was seen with tricarbonyl(T7 -l-methyl-2-trimethylsilylindole)chromium(0) 26, even though the major site of reaction was at C-4 (Scheme 28)... 

Lithiation of a seven-membered azaheterocycle has also been observed with an azepino[5,4,3-cindole derivative (87JOC3319). Mono-... 

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]. 

To check the different reactivity for the carbolithiation reaction of a lithiated double bond by vinyl- or aryllithiums, tertiary amine 341 was synthesized and treated with 6 equivalents of f-BuLi and TMEDA. Subsequent deuteriolysis led to a 6 1 mixture of the dihydropyrrole derivative 342 and the indole derivative 343 in very good overall yield, showing that intramolecular carbolithiation reaction of a lithiated double bond by a vinyllithium is faster than the corresponding carbolithiation reaction by an aryllithium (Scheme 88)141. 

Metalation of the amine substrate 184, followed by annulation promoted by tetramethylethylenediamine (TMEDA), gave the intermediate 185, which could thereafter be converted to the fused 3-pyrroline system 186 (Scheme 22). Subsequent dehydrogenation with DDQ gave the corresponding fused pyrrole. This methodology was used for preparation of an extended set of related pyrroles, as well as a series of indole derivatives, which were accessed by lithiation of iV-bromoallyl-2-bromoanilines <2001CEJ2896>. 

In some cases, aniline or indole derivatives can be substituted meta to the nitrogen by lithiation of the appropriate chromium tricarbonyl complexes. " Examples are given in Scheme 3. One of the Cr—C=0 bonds eclipses the C—bond, and therefore the other carbonyls eclipse the meta C— bonds. Two suggestions have been offered for the meta selectivity (i) the butyllithium coordinates the chromium carbonyl oxygen and then removes the proximate proton (a kinetic effect) (ii) the eclipsed conformation produces a lower electron density at the meta position, which in turn renders the meta protons more acidic (a thermodynamic effect). ... 

Scheme 16 C2-lithiation of a resin-bound indole derivative...

Intramolecular versions of the Peterson reaction of a-sUylbenzyl anions are utilized to construct heteroaromatic frameworks [96]. Lithiation of the ortho-substituted benzylsilanes 55 with LDA and subsequent intramolecular Peterson reaction of the derived carbanions 56 with the carbonyl moiety leads directly to intramolecular cydization giving indole derivatives 57 (Scheme 2.37) [97]. 

A new route to 2-substituted indoles derived from 1-methoxyindole was recently described. Dimethyl sulfate proved to be the reagent of choice for the methylation of the unstable 1-hydroxyindole to give 1 -methoxyindole in 51 % yield (eq 10). The resulting methoxyindole undergoes 0-lithiation at the 2-posilion using n-Butyllithium, and can be trapped with appropriate electrophiles. It should be noted that methylation of 1-hydroxyindole using lodomethane afforded only very low yields of the desired methoxyindole. 

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. 

Introduction of an iodine to C-2 of indole can be accomplished using lithium derivatives. Since direct iodination tends to give mixtures it is essential to activate the 2-position at the expense of the inherently more reactive 3-position. This has been done by lithiating 1-f-butoxycarbonylin-doles (25) and then converting them into iodo derivatives before deprotection (85JHC505) (Scheme 19). Alternatively carbon dioxide can be used... 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

Much more versatile than the simple anilines are their anilide derivatives. PivalaniUdes, benzanilides and other non"° (or scarcely ) enolizable amides 549 are laterally lithiated on treatment with two equivalents of BuLi, and may be quenched with electrophiles to give 551. In the absence of an electrophile, the organoUthiums 550 cyclize to indoles 552 (Scheme 218). 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

Synthesis of 2-Substituted Indoles via a-LiTHiATioN of N-Protected Derivatives... 

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

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