Friedel Crafts indole

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Section C of Table 11,5 gives some examples of Friedel-Crafts and Vilsmeier-Haack acylations of indoles. 

Aromatics containing electron releasing groups such as phenols, dim ethyl am in oben 2en e and indole are formylated by 2-ethoxy-l,3-dithiolane in the presence of boron trifluoroetherate, followed by hydrolysis (114). The preformed dithiolanium tetrafluoroborate also undergoes Friedel-Crafts reaction with aromatics such as dim ethyl am in oben 2en e and indole (115), and was used to generate dithiolanium derivatives (formyl precursors) from the enoltrimethylsilyl ether derivatives (116). 

A/-sulfonated ayiridines have also been used in Friedel-Crafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with a2itidines has also been reported ... 

Birch reduction of indole with lithium metal in THF in the presence of trimethylsilyl chloride followed by oxidation with p-benzoquinone gave l,4-bis(trimethylsilyl)indoIe (106). This is readily converted in two steps into l-acetyl-4-trimethylsilylindole. Friedel-Crafts acylation of the latter compound in the presence of aluminum chloride yields the corresponding 4-acylindole (107) (82CC636). 

Vilsmeier-Haack and Friedel-Crafts reactions, bromination, debromination, debenzylation in indole series and their synthetic application 99YZ35. 

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...

The first compounds of this class46 have been obtained via Route A. The initial condensation of phthalic anhydride with dimethylaniline requires a Friedel-Crafts catalyst, while condensation of the resulting benzophenone with the indole requires acetic anhydride. For Route B preparation of the intermediate l,2-dimethyl-3-(2-carboxybenzoyl)indole has also been described47 by condensation of the two components in the presence of aluminum chloride. However, in our experience, aluminum chloride is, in this case, unnecessary, thus rendering this route the method of choice. 

The reaction of indole and /V-mcthylpyrrole via Friedel-Crafts reactions with 0CHC02Et in various aqueous solutions generated substituted indoles and pyrroles without using any metal catalyst (Eq. 7.8).18... 

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 fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

Derivatives 30 (R OH, R2 = iV-acetyl-indol-3-yl-(CH2)2 and (R = OEt, R2 = Ph-(CH2) (n — 2, 3)) were transformed into intramolecular Friedel-Crafts type reactions involving A-acyliminium cation intermediates into the cis-and trans-isomeric mixtures of the corresponding fused derivatives on treatment with strong acid <2000TL2745, 2001JOC5731>. 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

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>. 

Asides from the application of imines on conjugate addition reactions, Deng [87, 88] reported the first asymmetric chiral thiourea catalyzed Friedel-Crafts reaction of indoles with iV-tosyl imines (Scheme 35). The reaction was receptive to various aromatic, heteroaromatic, and aliphatic imines in good yield and high enantioselec-tivity (Scheme 36). 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

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 49 Friedel-Crafts reaction of enecarbamates and indoles...

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],... 

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