Alkylation of indoles

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

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]. 

Scheme 4 FeCb catalyzed Friedel-Crafts alkylations of indoles with alcohols...

Fig. 34 Catalytic asymmetric Friedel-Crafts alkylation of indoles catalyzed by 60...

Huang H, Peters R (2009) A highly strained planar chiral platinacycle for catalytic activation of internal olefins in the Eriedel-Crafts alkylation of indoles. Angew Chem Int Ed 48 604-606... 

Whittlesey, Williams and co-workers fnrther developed the catalytic indirect Wittig reaction and fonnd that the more electron-rich NHC present in complex 18 provided a more reactive catalyst [8]. Catalyst 18 was used to convert benzyl alcohol 8 and phosphoninm ylide 19 into the product 20 under slightly milder reaction conditions and in a shorter time than in previous work (Scheme 11.4). Other C-C bond-forming reactions from alcohols using a borrowing hydrogen approach have been reported, with Peris and co-workers using Ir-NHC complexes for the C-3 alkylation of indoles with alcohols [9]. 

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

Pseudo-C3-symmetrical trisoxazoline copper(II) complexes prove to be excellent catalysts in the Friedel-Crafts alkylation of indoles with alkylidene malonates (Eq. 7.13). Water tolerance of chiral catalyst trisoxazoline/Cu(OTf)2 was examined, and it was found that the addition of up to 200 equivalents of water relative to the catalyst in /,vo-butyl... 

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>. 

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

A closely related dicationic platinum complex has been shown to transform efficiently /3-citronellene into cis-thujane in a highly diastereoselective manner, which mimics terpene biosynthesis.362 Also, using platinum(n) catalysis, Widenhoefer has reported an intramolecular alkylation of indoles with unactivated olefins, which can be carried out in an enantioselective fashion (Scheme 99).363... 

As we have seen earlier in this chapter, palladium is often employed to effect JV-alkylation of indoles. Trost and Molander found that indole reacts with vinyl epoxide 375 to give indole 376 [468]. The utility of such AZ-alkylations remains to be established. 

N-ALKYLINDOLES FROM THE ALKYLATION OF INDOLE SODIUM IN HEXAMETHYLPHOSPHORAMIDE 1-BENZYLINDOLE... 

The alkylation of indole sodium generated from indole and sodium amide in liquid ammonia has been used as the general method for the... 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

Experimental Procedure 4.2.3. Alkylation of Indole by Intermolecular C-H Insertion 3-( l//-3-Indolyl)-2,4-pyrrolidinedione... 

Grigg et al. also reported the alkylation of indole at the C3-position with alcohols, catalyzed by the 1/KOH system (Scheme 5.32) [69]. A variety of indole derivatives having an alkyl substituent at the C3-position were synthesized by this methodology. The same group also developed a Cp lr-catalyzed process for successive carbon-nitrogen and carbon-carbon bond formation, starting with 2-amino-phenethyl alcohol (also see Scheme 5.22). 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Scheme 65 Alkylation of indoles using a chiral anion/chrral amine combination...

In 2007, two groups independently described asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylations of indoles. While You et al. chose the conventional approach and employed imines as substrates (Scheme 11), Terada and coworkers came up with a different concept and used electron-rich alkenes as precursors (Scheme 49) [73]. Enecarbamates 125 reacted with indoles 29 in the presence of BINOL phosphate (R)-io (5 mol%, R = bearing 2,4,6-triisopropyl-... 

Scheme 50 Friedel-Crafts alkylation of indoles with ( )- or (Z)-enecarbamates...

Shortly after the discovery of the first asymmetric phosphoric acid-catalyzed transformation of enecarbamates, Zhou et al. expanded the scope of the Friedel-Crafts alkylation of indoles 29 with electron-rich alkenes to enamides 127 (Scheme 51) [74],... 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

Scheme 6.7 Product range of 9- and urea 16-catalyzed Friedel-Crafts alkylations of indole and methyl indoles.

Scheme 6.127 Typical Fhedel-Crafts adducts resulted from the 121- and 124-catalyzed alkylation of indols with N-protected aldimines. The configurations of the products were not determined.

Figure 6.46 (A) Hydroxy-protected thiourea 141 and 142 lacking the hydroxy function and their catalytic efficiency in the Friedel-Crafts alkylation of indole with frans-P-nitrostyrene (139 78% yield 85% ee under identical conditions). (B) Proposal for the key hydrogen-bonding interactions between 139 and the model substrates.

The first, and one of the most straightforward, syntheses of racemic 69 was that of Schach von Wittenau and Els ° after they had determined the stmcmre. Friedel-Crafts alkylation of indole with ethyl 2,3-epoxybutyrate gave the a-indolmycenic acid ester 119a. Cyclization of 119a with Af,//-dimethylguanidine yielded both 69 and isoindolmycin 120 (Scheme 6.32). In this case, facile epimerization of H-5 had occurred under the basic cyclization conditions. 

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