Imines Friedel-Crafts addition

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

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. 

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). 

The analogy between imines and carbonyls was introduced earlier, and just as 1,3-dike-tonate complexes undergo electrophilic substitution reactions at the 2-position, so do their nitrogen analogues. Reactions of this type are commonly observed in macrocyclic ligands, and many examples are known. Electrophilic reactions ranging from nitration and Friedel-Crafts acylation to Michael addition have been described. Reactions of 1,3-diimi-nes and of 3-iminoketones are well known. The reactions are useful for the synthesis of derivatised macrocyclic complexes, as in the preparation of the nickel(n) complex of a nitro-substituted ligand depicted in Fig. 5-12. 

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. 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

Neopentyl glycol, polyesters use, 494 Nickel, MA bisadduct, 212 Nickel carbonyl, MA complex, 212 Nickel chloride, MA distillation additive, 22 Nickel oxide, oxidation catalyst, 31, 36 Nicotinic acid, use in polyesters, 490 Nitrile imines, dimethyl fumarate adduct, 225 Nitrile oxides, MA adducts, 225 Nitriles, Michael addition to maleates, 64 Nitrile sulfides MA adducts, 225 maleimide adducts, 227 p-Nitroaniline, permaleic acid oxidation, 77 Nitrobenzene, 180 ene reaction solvent, 166 Friedel-Crafts acylation solvent, 93, 97 2-Nitrofuran, 127... 

Ghosh, A. K., Martyr, C. D., Xu, C.-X. (2012). TiCl -promoted tandem carbonyl or imine addition and Friedel-Crafts cyclization Synthesis of benzo-fused oxabicyclooctanes and nonanes. Organic Letters, 14, 2002-2005. 

A simple and practical Cu(OTf)2-catalyzed synthesis of quinoline-2-carboxylates through tandem Grignard-type imine addition/Friedel-Crafts alkenylation of arenes with aryl or alkyl alkynes via activation of C-H bonds was reported in 2009 (Scheme 8.84). The quinoline-2-carboxylates products could be obtained in high yields from a number of readily available alkynes and imines at room temperature [154]. 

With respect to cupreidine, C9 0-benzoyl esters of this cinchona derivative were demonstrated to be the best catalysts for the nitroaldol reaction of a-ketoesters [55], the conjugate addition of anthrone to nitroalkenes [56], the Henry reaction with fluoromethyl ketones (Scheme 6.25) [57], and an aza-Friedel-Crafts reaction of naphthols with N-sulfonyl imines [58]. 

Enantioselective Friedel-Crafts reactions using metal-based chiral catalysts or chiral organocatalysts have been investigated extensively because the reactions directly provide alkylated arenes, a pharmacologically important substructure, in optically active forms. The chiral phosphoric acid catalyzed Friedel-Crafts reaction was first accomplished via the activation of imines but, currently, the scope of the electrophilic components has been broadened to include the Michael addition to nitroalkenes, a, 3-unsaturated carbonyl compounds, and so on. 

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