Asymmetric Friedel-Crafts alkylation of indoles with 3-nitro-2H-chromenes catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II) complexes

An efficient diastereo- and enantioselective Friedel-Crafts alkylation of indoles with 3-nitro-2H-chromenes catalyzed by diphenylamine-linked bis(oxazoline) and bis(thiazoline) Zn(II) complexes has been developed. This asymmetric Friedel-Crafts alkylation led to medicinally privileged indolyl(nitro)chromans in good yields with high enantioselectivities (up to 95% ee) and diastereoselectivities under mild reaction conditions.     

Chiral Pd-catalyzed enantioselective Friedel-Crafts reaction of indoles with γ,δ-unsaturated β-keto phosphonates

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with γ,δ-unsaturated β-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-Crafts alkylation adducts with excellent enantioselectivities (up to 99% ee).     

Organocatalytic enantioselective Friedel-Crafts alkylation of simple phenols with trifluoropyruvate

Enantioselective Friedel-Crafts alkylation of simple phenols (4a-j) with 3,3,3-trifluoropyruvate (3) was accomplished by using chiral cinchona alkaloid catalyst 2h (10 mol %). High yields and enantioselectivities (71-94% ee) of the Friedel-Crafts alkylation products were obtained.     

Highly enantioselective Friedel-Crafts alkylations of indoles with simple enones catalyzed by zirconium(IV)-BINOL complexes

Complexes of BINOL-based ligands with Zr(OtBu)4 catalyze the Friedel-Crafts alkylation reaction of indoles and pyrrole with nonchelating beta-substituted alpha,beta-enones at room temperature affording the expected products with good yields and ee above 95% in most of the studied examples.     

Ir-catalyzed regio- and enantioselective Friedel-Crafts-type allylic alkylation of indoles

Highly regio- and enantioselective Ir-catalyzed Friedel-Crafts type allylic alkylation of indoles have been realized using [Ir(COD)Cl]2/phosphoramidite ligand 1a, affording the branched products with up to >97/3 branched-linear ratio and 92% ee.     

Enantioselective Friedel-Crafts alkylation of indoles with 2-enoylpyridine-N-oxides catalyzed by glucoBOX-Cu(II) complex

The glucosamine derived glucoBOX-Cu(II) complex was found to be a unique catalytic system for enantioselective Friedel-Crafts alkylation of indoles with 2-enoylpyridine-1-oxides. A large number of 3-alkylated indole derivatives were prepared using 5 mol% glucoBOX-Cu(II) complex in excellent yields with high enantioselectivity up to 99% ee.     

Trisoxazoline/Cu(II)-catalyzed asymmetric intramolecular Friedel-Crafts alkylation reaction of indoles

Intramolecular Friedel-Crafts alkylation reaction of indoles catalyzed by trisoxazoline/copper(II) is described. This annulation provides an easy access to polycyclic indole derivatives with up to 90% ee in up to 99% yield.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Catalytic enantioselective Friedel-Crafts alkylations of indoles with alpha'-phosphoric enones

The C2-symmetric bis(oxazoline) copper(II) complex proves to be an excellent catalyst in the Friedel-Crafts alkylation of indoles with alpha'-phosphoric enones. The enantioselectivities of this reaction are obtained in up to 98% ee.     

A new type of bis(sulfonamide)-diamine ligand for a Cu(OTf)2-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes

Chiral bis(sulfonamide)-diamine served as new type of ligand for a Cu(OTf)(2)-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes. The desired products were obtained with up to 99% yield and 97% ee.     

A library of chiral imidazoline-aminophenol ligands: discovery of an efficient reaction sphere

A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)- or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a Friedel-Crafts alkylation of indole and nitroalkene to give the adduct in up to 83 % ee.     

Controllable enantioselective Friedel-Crafts reaction between indoles and alkylidene malonates catalyzed by pseudo-C3-symmetric trisoxazoline copperII complexes

Pseudo-C(3)-symmetric trisoxazoline copper(II) complexes prove to be excellent catalysts in the Friedel-Crafts alkylation of indoles with alkylidene malonates. The absolute stereochemistry of this reaction is shown to be dependent on the solvent. Reactions in isobutyl alcohol afford the Friedel-Crafts alkylation adducts in excellent yields and with up to +98% ee. In 1,1,2,2-tetrachloroethane (TTCE), however, the opposite enantiomers of the products are obtained in good yields with up to -89% ee. Water tolerance of chiral catalyst trisoxazoline 2a/Cu(OTf)(2) is examined, and it is found that the addition of up to 200 equiv of water relative to catalyst in isobutyl alcohol has almost no effect on enantioselectivity but slows down the reaction. The reaction scope is studied as well. The roles of alcohol as the solvent to accelerate the reaction are discussed. The stereochemical models of asymmetric induction for reactions both in isobutyl alcohol and in TTCE are also developed.     

Highly enantioselective yttrium(III)-catalyzed Friedel-Crafts alkylation of β-trichloro(trifluoro)methyl aryl enones with indoles

An efficient yttrium(III)-catalyzed highly enantioselective Friedel-Crafts alkylation of β-trichloro(trifluoro)methyl aryl enones is described. The reaction delivered a series of functionalized indoles with a chiral tertiary carbon center bearing a trichloro(trifluoro)methyl group in excellent results (up to 96% ee and 99% yield) under mild conditions.     

Catalytic and asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates. Application to the synthesis of tryptophan analogues

An asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates catalyzed by chiral (4R,5S)-DiPh-BOX (L1)-Cu(OTf)₂ complex (10 mol %) has been developed. The reactions provide tryptophan nitro-precursors in moderate diastereoselectivities (anti/syn up to 72:28) and good to excellent enantioselectivities (up to 99% ee). The alkylation products could be easily reduced to optically active tryptophan analogues with Zn/H⁺.     

Enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by bifunctional tridentate bis(oxazoline)-Zn(II) complex

[reaction: see text] A more practical and efficient catalytic asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes using bifunctional tridentate bis(oxazoline)-Zn(OTf)(2) as catalyst has been developed. Various types of the nitroalkylated indoles were obtained in excellent yields (85-99%) and high enantioselectivities (up to 98% ee).     

Asymmetric synthesis of chiral 9,10-dihydrophenanthrenes using Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee.     

Enantioselective synthesis of tertiary alcohols through a zirconium-catalyzed Friedel-Crafts alkylation of pyrroles with α-ketoesters

Chiral complexes of 1,1'-bi-2-naphthol-based ligands with zirconium tert-butoxide catalyze the Friedel-Crafts alkylation of pyrroles with α-ketoesters to afford tertiary alcohols in good yields and ee up to 98%. The reaction is also of application to 4,7-dihydroindole to give C2-alkylated indoles after oxidation with p-benzoquinone.     

Dy(OTf)3/Pybox-catalyzed enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones

The first catalytic enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones has been accomplished. The reaction was achieved in the presence of the Dy(OTf)₃/Pybox complex, producing the desired products in high yields (up to 99%) with good enantioselectivities (up to 86% ee). The absolute stereochemistry of the resulting adducts was determined by X-ray analysis.     

Iron-catalyzed oxidative coupling of alkylamides with arenes through oxidation of alkylamides followed by Friedel-Crafts alkylation

FeCl(3) in combination with t-BuOOt-Bu as an oxidant was found to be an efficient catalyst for oxidation of alkylamides to α-(tert-butoxy)alkylamides. FeCl(2) and CuCl showed, respectively, almost the same and slightly lower activities compared with FeCl(3) in the tert-butoxylation of N-phenylpyrrolidone (1a), whereas no tert-butoxylated product was obtained by use of Fe(OTf)(3), RuCl(3), or Zr(OTf)(4). FeCl(3) was found to be effective also as a catalyst for the Friedel-Crafts alkylation with thus obtained α-(tert-butoxy)alkylamides. The Friedel-Crafts alkylation proceeded smoothly also in the presence of a catalytic amount of Fe(OTf)(3), RuCl(3), or Zr(OTf)(4). In contrast, FeCl(2) and CuCl, which showed certain activity toward the tert-butoxylation, failed to promote the Friedel-Crafts alkylation. Among the transition metal complexes thus far examined, only FeCl(3) showed high catalytic activities for both the oxidation and the Friedel-Crafts alkylation. The bifunctionality of FeCl(3) was utilized for the oxidative coupling of alkylamides with arenes through a tandem reaction consisting of oxidation of alkylamides to α-(tert-butoxy)alkylamides and the following Friedel-Crafts alkylation. The FeCl(3)-catalyzed oxidative coupling is applicable to a wide variety of alkylamides and arenes, though a combination of FeCl(3) with Fe(OTf)(3) was found to be effective for the reaction of arenes with low nucleophilicity. A Fe(II)-Fe(III) catalytic cycle is concerned with the tert-butoxylation, whereas a Fe(III) complex as a Lewis acid catalyzes the Friedel-Crafts alkylation.     

Remarkable effect of N-substituent on enantioselective ruthenium-catalyzed propargylation of indoles with propargylic alcohols

Ruthenium-catalyzed enantioselective propargylation of indoles with propargylic alcohols affords the corresponding beta-propargylated indoles in good yields with a high enantioselectivity (up to 95% ee). A remarkable effect of the nature of the N-substituent of indoles is observed for the enantioselectivity of the propargylated indoles. The preparative method described in this paper may provide a novel protocol for asymmetric Friedel-Crafts alkylation of indoles using propargylic alcohols as a new type of electrophiles.