Friedel 3-substituted indoles

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... 

Subsequently, the research groups of Terada and AntiUa reported highly enan-tioselective Friedel-Crafts reactions between N-substituted indoles and N-acyl aryl imines (Scheme 5.9) [17]. Interestingly, Antilla states that under his reaction condi-... 

Indoles can be used as radical acceptors instead of 63 [120, 121]. Simple and twofold reactions giving either 3-alkylindoles [120] or l,l-bis(3-indolyl)alkanes [121] were observed in 16-72% and 54-90% yield, respectively. In both methods the indole is subject to radical addition in 3-position. The resulting a-amino radical undergoes a further oxidation and deprotonation to the 3-substituted indole. In the case of twofold additions, the second indole unit is introduced by a subsequent polar Friedel-Crafts-type alkylation. 

The Friedel-Crafts alkylation of the parent pyrrole and of substituted indoles with a,P-unsaturated acyl phospho-nates 468 <2003JA10780> and 2-acyl iV-methylimidazoles 469 catalyzed by the chiral bis(oxazolinyl)pyridine (pybox)/scandium(lIl) triflate complex 467 exhibits good enantioselectivities over a broad range of substrates (Scheme 97, Equation 113) <2005JA8942>. The desired alkylation products 470-472 were formed in good yields and enantioselectivities. 

Murakami, Y, Tani, M., Ariyasu, T., Nishiyama, C., Watanabe, T., and Yokoyama, Y, The Friedel-Crafts acylation of ethyl pyrrole-2-carboxylate. Scope, limitations, and apphcation to synthesis of 7-substituted indoles, Hetemcycles, 27, 1855, 1988. 

A tandem, double Friedel-Crafts reaction of 2-formylbiphenyl (182) with 2-substituted indoles leading to 9-(3-indolyl)fluorene derivatives (183) with up to 96% ee which was catalyzed by chiral phosphoric acid ( S)-(184), have been reported by You and co-workers (Scheme 50). ... 

Less common 2-substituted indole derivatives can be prepared by Friedel-Crafts alkylation of 4,7-dihydroindoles with a,p-unsaturated aldehydes, followed by oxidation with p-benzoquinone [317]. 4,7-Dihydroindoles, which can be considered as 2,3-disubstituted pyrroles, react with a wide variety of aromatic and aliphatic enals... 

Enantioselective Friedel-Crafts alkylation reactions were performed between substituted indoles and methyl trifluoropyruvate, using a chiral nonracemic ( -symmetric 2,2 -bipyridyl copper triflate complex as catalyst. The active copper(II) catalyst was... 

Takenaka and coworkers used 2-aminopyridinium salts as dual hydrogen-bond donors for the activation of nitroalkenes. The 7-azaindolium salt 65 was found to be particularly effective for the Friedel-Crafts reaction of nitroalkenes with various electron-rich arenes as well as for intra- and intermolecular Diels-Alder reactions (Scheme 10.63) [163, 164]. The same concept was successfully applied to the enantioselective conjugate addition of 4,7-dihydroindoles to nitroalkenes using helical chiral 2-aminopyridinium salts (Scheme 10.64) [165]. The reaction was found to have a broad substrate scope, affording various 2-substituted indoles in good to high enantiomeric ratios. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

You and coworkers employed 4,7-dihydroindoles 79 instead of indoles 75 in the Friedel-Crafts reaction with nitroalkenes 77 (Scheme 11.22) [41]. Catalyst Ig with a 9-anthryl group displayed excellent performance. The notable point in this reaction is the use of the syringe pump technique to achieve high enantioselectivities and suppress the background reaction. Subsequent oxidation of Friedel-Crafts adducts 80 by p-benzoquinone afforded 2-substituted indole derivatives 81 in excellent yields without racemization. This approach and the simple asymmetric Friedel-Crafts reaction of indoles are complementary methods for obtaining the different substitution patterns of chiral indole derivatives. 

The Friedel Crafts amidoalkylation of indoles (119) with N-Ts substituted aryl aldimines (120) has been developed by Shen et al. utilising diphenyl phosphates (121) as organocatalysts to provide the 3-substituted indoles (122) in high yields (Scheme 30). ... 

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]. 

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]. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

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