Indoles and imines

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

Two years later, thiourea 21, functionalized with a cinchona alkaloid, was efficiently used in the synthesis of 3-indolylmethanamines in good yields and selec-tivities (up to 96% ee) [25]. The transformation takes place in the presence of aromatic, aliphatic, and heteroaromatic imine analogs. Chiral phosphoric acids 26a, mf-26d, and ent-26f were also identified as efficient catalysts for the F-C alkylation between indoles and imines [35, 38, 40]. In these cases, in contrast with thiourea 21, the processes were only successful in the presence of aromatic imines. More recently, the fmitful use of a thiourea supported on mesoporous silica (heterogeneous bifunctional catalyst) was reported [61]. The catalyst can be easily separated from the reaction mixture by simple filtration and reused several times without erasing the enantioselectivity. 

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-... 

While lanthanide triflates have been demonstrated to promote the reaction of indoles with imines <99SL498>, Johannsen has developed a new synthesis of optically active p-indolyl N-tosyl a-amino acids 110 via the enantioselective addition of A-tosylimnio esters of ethyl glyoxylate 109 to indoles 108 bearing both electron-donor and electron-acceptor substituents at C-5 using 1-5 mol% of a chiral copper(I)-Tol-BINAP catalyst <99CC2233>. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

One of the most important condensed ring systems is indole. Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the intermediate by the nitrogen without disruption of the benzene aromaticity. Indole can exist in two tautomeric forms, the more stable enam-ine and the 3-H-indole or imine forms. C-2 to C-3 pi-bond of indole is more capable of cycloaddition reactions then the other pi bonds of the molecule. Inter molecular cyclo additions are not favorable, whereas intramolecular variants are often high-yielding. 

This limitation was overcome, when Dy(OTf)3 was used in place of In(OTf)3. This catalyst exhibited similar activity in both [C4Ciim][BF4] and [C4Ciim][PF6], and afforded better yields and reaction rates in these solvents relative to aqueous media.[63] With either hexanal or acetone as substrates, only a slight deterioration in activity occurred after six catalytic runs. The dysprosium salt also catalysed the reaction between the indole and various imines, but with relatively low selectivity towards the condensation product. 

Processes based on metallation are also useful for the synthesis of indoles. For example, a series of substituted indoles and earbazoles has been synthesized from 2-fluorophenyl imines. Thus for instance, treatment of the imine 88 with LDA in refluxing THF gave the thienoindole 89. Based on labelling experiments, it was suggested that the reaction is probably proceeding via the benzyne intermediate 90 <03S1661>. 

C. Pyrroles, Indoles, and Isoindoles Naphthalen-1,4-imines and Anthracen-9,10-imines... 

The reactions of indole with Ae imines derived from acetaldehyde and r-butylamine and isopropylamine have been reported using acetic acid as the proton source in benzene. A poor yield (15%) is obtained with ethylidene-t-butylamine but a better yield (60%) results with the isopropylamine analog (equation 44). A one pot reaction using indole, acetaldehyde and isopropylamine gives the same product in 40% yield. This type of reaction depends for its success on the stability of the aldimine under the acidic reaction conditions. However, while the more sterically demanding primary amines afford the most stable imines, it appears that this can lead to too great a steric demand in the transition state leading to reaction with, for example, indole, and hence the low yield reported in the f-butylamine reaction. 

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