Imines Friedel-Crafts alkylation

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-... 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

LHASA pr icted that l-methyl-3,4-dihydroisoquinoline (18) could be synthesized from methyl phenyl N-(2-chloroetiiyl)imine via a Friedel-Crafts alkylation in the presence of a Lewis acid and heat. This prediction was based on a literature reference identified by LHASA. LHASA also predicted the Bischler-Napieralski synthesis of 18 from N-(2-phenylethyl)acetamide (19) in the presence of heat and acid (Scheme 5). 

For selected pioneering examples, see (a) D. Uraguchi, K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2004, 126, 11804-11805. Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. (b) T. Akiyama, H. Morita, J. Itoh, K. Fuchibe, Org. Lett. 2005, 7, 2583-2585. Chiral Br0nsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of a-amino phosphonates. 

Many structures included an aromatic subunit. At the time, synthetic aromatic chemistry was at its height and electrophilic aromatic substitution reactions (SE-reac-tions) such as Friedel-Crafts alkylations [37] and acylations [38], nitrations [39] and diazotisations [40] were effectively used. Vorlander and others centred most procedures for the elongation of rod-like structures on carbonyl-reactions. It must be noted, however, that the scope of most of these reactions had not been realized until the late 1940s. Typical preparations of imines/anils (azines) [41] via aldehyde/ketone-amine/ aniline (hydrazine) condensations have remained standard synthetic methods of today [42] (Scheme 3). 

On the other hand, Lee showed that 28 could activate N-sulfonyl imines through hydrogen-bonding interaction and could function as an efficient Br0nsted acid catalyst for the highly enantioselective Friedel-Crafts alkylation of indoles with the imines (Scheme 7.55) [83]. It was essential to wash the catalyst with dilute hydrochloric acid followed by water and brine prior to use to attain sufficient reactivity. 

Scheme 7.55 Asymmetric Friedel-Crafts alkylation of indoles with imines.

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... 

As mentioned above, a range of enantioselective transformations have been established using chiral phosphoric acids via the activation of imines and related nitrogen-substituted substrates. In contrast, the activation of carbonyl compounds, including a,P-unsaturated carbonyl compounds, by chiral phosphoric acids has been limited. In 2008, Zhou, He, and coworkers achieved the asymmetric Friedel-Crafts alkylation reaction of indole derivatives with 1,3-diaryl a,p-unsaturated... 

IrCl2H(cod)]2 catalyzed the synthesis of substituted quinolines, where the reachon of aniline derivahves, aromatic and alkyl aldehydes efficiently proceeds under an oxygen atmosphere (Scheme 11.34) [46]. The plausible mechanism consists of a Mannich reaction, a Friedel-Craft-type aromahc substituhon, dehydration, and dehydrogenation. This can be recognized as a formal [4+2] cycloaddition of N-aryl imine and enol (Scheme 11.35). 

In a variation of the Gatterman reaction an alkyl cyanide RCN is used in place of HCN as a useful way of preparing ketones from reactive aromatic species that do not react well under Friedel-Crafts conditions. The electrophile involved is effectively R—C NH+, although, perhaps, the imino chloride, R(C NH)C1, the analogue of an acyl chloride, RCOCl, is also involved. As in the Gatterman reaction, the imine is an intermediate. 

The retro-synthetic analysis ouflined in Scheme 6.1 shows that in addition to the Pictet-Spengler route previously used by discovery, several others are also possible. The Bischler-Napieralski condensation of 5-methyltryptamine and 2-cyclohexylacetic acid chloride as well as the Friedel-Crafts reaction of the N-protected 5-methyltryptamine allows preparation of the prochiral imine derivative 7. The 2-cyclohexylmethyl side chain may also be introduced via alkylating an unsubstituted THpC by 2-cyclohexylmethyl chloride. As shown in Scheme 6.1, all of these routes involve 5-methyltryptamine as a common building block. 

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