Friedel-Crafts reaction imines

The FeCls-catalyzed Friedel-Crafts reactions of electron-rich arenes with imines or aziridines provide a facile and convenient route for the synthesis of p-aryl... 

Mesoxalates are highly reactive substrates because of their strongly polarized carbon-oxygen bond. They have been used in pericyclic processes (e.g. Diels-Alder reactions,8 ene reactions,9 [3+2]10 and [2+2]11 cycloadditions), in aldol12 and Wittig as well as Friedel-Crafts reactions.13 Further applications arise from the use of the corresponding imines in hetero Diels-Alder reactions14 and electrophilic cyclizations.15... 

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). 

Mechanistically, the Brpnsted acid-catalyzed Friedel-Crafts reaction presumably involves a tantomerism of enamide 127 to the corresponding A -acetyl-protected imine. Snbseqnent addition of indole 29 affords amide 128 (Scheme 52). 

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-... 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Sertraline (16) is an antidepressant that inhibits the uptake of serotonin in the central nervous system.148 It is marketed by Pfizer under the name Zoloft.149 One methodology that can be used relies on an asymmetric reduction (see also Chapter 16) (Scheme 31.11).150-156 The lactone can be used as a chiral starting material for the Friedel-Crafts reaction. The established stereogenic center in the tetralone controls the reduction of the imine.157 The alternative is a resolution approach (Scheme 31.12).148-153-158-161... 

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

The 3-indolyl methanamine structural motif 503 is embedded in numerous indole alkaloids and synthetic indole derivatives . An efficient catalytic asymmetric Friedel-Crafts reaction of indoles 501 with imines 502 provides a direct, convergent, and versatile method for the highly enantioselective construction of 3-indolyl methanamines 503 from readily accessible achiral precursors (Scheme 101) <2006JA8156 and references therein>. 

The work-up with aqueous Na2C03 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel-Crafts reaction. 

Jorgensen, K. A. Asymmetric Friedel-Crafts reactions Cataiytic enantioselective addition of aromatic and heteroaromatic C-H bonds to activated aikenes, carbonyi compounds, and imines. Synthesis 2003,1117-1125. 

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. 

Various routes to 1,1,3-trisubstituted 1//-isoindoles have been reviewed.5 Thus, the triphenyl derivative 53 is available from the reaction of benzo-phenone imine with diphenyldichloromethane or by the Friedel-Crafts reactions between benzene and l,l,3-trichloro-lf/-isoindole. Recently, another route, which involves heating the cyclotriphosphatriazene 54 with benzophenone, has been described.86 The nitrone derivative 55 of the isoindolenine 53 may be obtained by treating the isoindolenine with m-chloroperbenzoic acid. This nitrone has also been obtained by the isomerization of the oxaziran 56 in the presence of a Lewis acid (Scheme 11).87... 

Research progress in Friedel—Crafts reactions of indoles and imines 12CJ0462. 

The chiral phosphoric acid catalyst 121 forms hydrogen bonds with enethiourea 203 and the imine, formed in situ from amine 201 and aldehyde 202. The enethiourea 203 attacks then that imine in a pseudointramolecular manner from the si-face to form iminium ion depicted in TS-5. After intramolecular aza-Friedel-Crafts reaction, hexahydropyrroloquinolines 204 were obtained. 

For other examples of use of chiral phosphoric acid as catalyst in the synthesis of indole derivatives, see (a) Q. Kang, Z.-A. Zhao, S.-L. You, Tetrahedron 2009, 65, 1603-1607. Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines. (b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. Int. Ed. 2009, 48, 2553-2556. Activation of hemiaminal ethers by chiral Brpnsted acids for facile access to enantioselective two-carbon homologation using enecarbamates. 

Sc(OTf)3 was widely used as a Lewis acid catalyst in Friedel-Crafts acylation [38-40], amination [41], chloromethylation [42], and nitration of aromatic compounds [43]. It also exhibited a superior catalytic activity for one-pot three-component phenol-imine Friedel-Crafts reactions to give the corresponding amino acid derivatives. Among various Lewis acids including La(OTf)3, Yb(OTf)3, YbCl3, InCl3, SnCU, and TiCU, Sc(OTf)3gave the best results (Scheme 12.21) [44]. 

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