Indoles allylic alkylation

Table 11.1 lists some of the reaction conditions which have given prepara-tively useful yields of 3-alkylation. Entries 1-3 are typical alkylations using a magnesium salt and an alkyl halide. Even 2,3-disubstituted indoles are alkylated at C3 under these conditions (Entry 7). Entry 5 represents a more recently developed method in which an allylic alcohol and indole react in the... 

Scheme 1.80 N/S/P-ferrocenyl ligand for Pd-catalysed allylic alkylations of indoles.

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

Methyl-2-diphenylphosphino-3-(l -isoquinolyl)indole with pallada-cycle derived from dimethyl-1-naphthyl ethylamine and potassium hexa-fluorophosphate yields chelate 310 (97T4035). With [(r)3-PhCH = CH = CHPh)Pd( j.-Cl)]2, allyl 311 follows in the presence of silver tetrafluor-oborate. Addition of ligands 312 (R = R1 = H, Me) to [(r 3-PhCHCHCHPh)Pd (Cl) ]2 under conditions of allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate leads to the formation of P,N-chelates 313 (R = R1 = H, Me), the active species of the catalytic reaction (00T(A)4753). 

Scheme 6.78 Asymmetric allylic alkylation of indoles by using Pd/165 complex as catalyst reported by Chan.

Scheme 6.79 Asymmetric allylic alkylation of indoles catalyzed by Pd/(1 )-sulfur-MOP complex reported by Hoshi and Hagiwara.

In 2007, Chan and eo-workers reported the synthesis of a new class of chiral ferrocenyl heterobidentate P/S ligands, which are readily available from Ugi s amine, and they reported their applieation in Pd-catalyzed asymmetric allylic alkylation of l,3-diphenyl-2-propenyl acetate with indoles. The corresponding C3 alkylated indoles derivatives were produced in good yields with up to 96% ee (Scheme 6.78). 

In 2010, Hoshi, Hagiwara, and co-workers designed and synthesized various (/ )-sulfur-MOP ligands with aryl and alkyl substituents on sulfur. These ligands were applied in the Pd-catalyzed allylic alkylation of indoles. The allylation products from substituted indoles were obtained with up to 95% ee (Scheme 6.79). 

Subsequently, chiral binaphthyl-based terminal alkene-phosphine hybrid ligands were synthesized and employed in the Pd-catalyzed asymmetric allylic alkylation of indoles with 168 to give the desired products in high yields (72-99%) with good to excellent enantioselectivity (75-94% ee) (Scheme 6.80). To evaluate the effect of the alkene group of (S)-167, a ligand... 

Table 6.12 Allylic alkylation of indoles with unsymmetric 1,3-disubstituted allyl acetates reported by Liao.

In 2008, You and co-workers demonstrated the first example of Ir-catalyzed regio- and enantioselective FC-type allylic alkylation reaction of indoles. In the presence of a catalytic amount of [Ir(cod)Cl]2 and Feringa ligand (S,S,Sa)-170a, highly enantioenriched branched products 171B were afforded from indoles and monosubstituted allylic carbonates (Table 6.13). ... 

Scheme 6.83 Ir-catalyzed intramolecular asymmetric allylic alkylation reaction of indol-3-yl carbonates 180 reported by You.

Apart from reports on Ir-catalyzed intramolecular asymmetric allylic alkylation of substituted indoles with the linker attached on the C3 position,... 

Chen et al. developed the first asymmetric and chemoselective A-allylic alkylation of indoles with MBH carbonates. This method was realized by employing modified cinchona alkaloids (DHQD)2PHAL as organocatalysts. Either electron-rich or electron-deficient indoles could be employed and moderate to excellent enantioselectivity was achieved (62-93% ee) (Scheme 3.115). ... 

Franzen and coworkers described a series of indole-phos-phine-oxazoline (IndPHOX) ligands, 231-238 (Scheme 35). The power of these ligands is demonstrated by the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphe-nyl-2-propenyl acetate with dimethyl malonate with 98%... 

Enantioselectivities as high as 91% could be achieved by Chen and co-workers [118] in the chemoselective asymmetric V-allylic alkylation of indoles catalyzed by 10 mol% of (DHQD)2PHAL 26 (Scheme 11.38). The reaction showed excellent chemoselectivity (A-vs. C3-aIkylation 99 1). Reaction times were typically 1-3 days and the A-alkylation products were obtained with good yields (71-97%) and with enantiometic excesses higher than 80% using aromatic solvents (e.g., toluene, w-xylene or mesitylene). 

You et al. reported the iridium-catalyzed enantioselective functionalization of indoles and pyrroles. In the event, indole 181 is transformed, via an intramolecular allylic alkylation, into a spirocyclic intermediate at C3, which then undergoes selective methylene migration to form 182 with no loss of enantiopurity (up to 99% ee is obtained).The indole ring can tolerate substitution with various halogens or methoxy groups, while pyrroles can be substituted with alkyl or aryl groups (13JA8169). 

A detailed study of the enantioselective gold-catalysed allylic alkylation of substituted indoles (1) forming tertrahydrocarbazoles has been investigated both experimentally and theoretically at the B3LYP/LDBS level of theory. The results indicate that the reaction 0 occurs by an intramolecular 5n2 attack by C(2) of the indole ring on the double bond... 

Recent studies carried out by Casnati and coworkers 69, 70) seem to indicate that revision of the mechanism outlined above is necessary. These authors studied the reactivity of 3-alkylated indoles towards alkylation with allyl bromides and clearly showed that direct attack at position 2 of the indole nucleus is competitive with alkylation at position 3. In particular, with reagents of enhanced electrophilic character direct attack at the 2-position increases 69). It was suggested that the positional selectivity is determined by the electronic density of 3-alkyl-indoles. In fact, an alkyl group in an aromatic system decreases the electron density in the a-position and increases it in the p-position (272). 

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. 

Aniline, N-alkyl-o-allyl-indole synthesis from, 4, 321 Aniline, N-allyl-... 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

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