N-Substituted indole

In a process starting with the stereospecific Homer-Wadsworth-Emmons reaction of phosphonoglycinates 99 with 2-iodobenzaldehydes to afford the corresponding (Z)-didehydro-phenylalanine derivatives 100, Brown similarly utilized an intramolecular palladium-catalyzed animation of 100 (Y = 2-chloro-3-pyridyl, Ph, OBn) to form the N-substituted indole carboxylates 101 <00TL1623>. 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

Directed -lithiation of N-substituted indoles at the 3-position has been achieved with some 2-substituted indoles. Thus for example, N-t-Bu-1-methylindole-2-carboxamide can be lithiated at C-3 with 5-BuLi and TMEDA, but when a similar reaction was attempted with the 1-ben-zenesulfonyl analog, cleavage to an acetylene occurred readily, even at -78°C (Scheme 20)(86H2127). 

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-... 

The evidence for transient radical-cations from N-substituted indoles has been furnished by the observation of regiocontrolled anodic cyanation of the indole ring.193,194 Substitution in the 2-position dominates, although some 3-substitution takes place. When the 1,2,3-positions of indole were blocked, no cyanation occurred, but the products of anodic oxidation have not been isolated.194... 

Also, AMI and N-substituted indole esters (Fig. 3), which were reported to be COX-2 enzyme inhibitors, have inhibitory activity on LP and superoxide anion production [91]. Especially pyrrolidine and o-methylphenyl groups were found to be the most important side chains (Ri group) that elevated both activities for indole esters. 

Based on IPA, N-H, and N-substituted indole-3-propanamide derivatives (Fig. 11) have been prepared and their efficiencies were investigated towards SOD and LP. Compounds have very significant activity on inhibiting SOD as well as LP [125]. 

Indole 125 was alkylated with the triflate 126 giving N-substituted indole 127, intermediate in the synthesis of the antitumor agent FR-900482, in 44% yield (Equation 21) <1997JOC1083>. 

A type Ilae reaction has been reported by Willis and co-workers who prepared N-substituted indoles via Pd-catalyzed coupling of 2-(2-haloalkenyl)-aryl halides with a variety of amines <06ASC851>. In an alternative intermolecular approach to ring construction, Tang and Hu have reported a Pd-catalyzed coupling of o-alkynylhalobenzenes with amines to afford 1,2-disubstituted indoles <06ASC846>. 

Radicals such as benzyl and hydroxyl are unselective in their interaction with indoles, resulting in mixtures of products, so such reactions are of little synthetic use. On the other hand, benzoyloxylation of N-substituted indoles gives benzoates of indoxyl, i.e. it effectively oxidises the indole heterocyclic ring, via p-attack by the strongly electrophilic benzoyloxy-radical. In contrast, the weakly electrophilic radical derived from malonate reacts selectively at C-2, via an atom-transfer mechanism." "... 

The oxidative coupling reactions of benzofuran and N-substituted indoles with benzene and derivatives have also been achieved using oxygen as an oxidant (Equation 11.37) [76]. This methodology for synthesizing heterocoupled biaryls... 

Other N-substituted indoles have also been reported to undergo a photo-Fries type rearrangement of the substituent to other positions in the indole nucleus. The substituents that have been shown to migrate in this fashion include tosyl [34], alkoxy [34], aminocarbonylmethyl [38], and methoxycarbonylmethyl [38] (Scheme 6). 

Snyder and co-workers tried to utilize cycloadditions of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 to N-substituted indoles 325 as the key step in the attempted preparation of carbazoles <1997TL8611>. However, unlike previous examples reported by Haider and Wanko with 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 <1994ACO205, 1994H(38)1805>, the initially formed dimethyl 5//-pyridazino[4,5-3]indole-l,4-dicarboxylates 326 did not react further with any dienophile. On the other hand, they underwent reductive ring contraction readily with zinc in acetic acid to furnish dimethyl 5//-pyridazino[4,5-3]indole-l,4-dicarboxylates 327 (Scheme 78) <1997TL8611>. 

The acid-catalyzed alkylation of indoles by carbonyl compounds is complicated by the fact that the resulting indol-3-yl carbinols are usually reactive under these conditions. The most common outcome is the formation of W -indolylmethanes, as is discussed in the next section. In some cases, the carbinol intermediates can be diverted to alkylation by reductive trapping using triethylsilane-TFA. This reaction gives good yields of 3-benzyl indoles and there are a few examples of 3-alkylatiOTi using N-substituted indoles [120]. 

Muthusamy and coworkers [67, 68] have examined the regioselectivity (with respect to dipole orientation) of intermolecular cycloadditions of carbonyl ylides with a variety of N-substituted indoles. l-Diazo-3,3-dimethylpentane-2,4-dione (126), upon treatment with rhodium (11) acetate and simple indole derivatives (125), might be expected to give a mixture of regioisomers 127 and 128 however, only hexahydro-2//-carbazol-2-ones 127 were observed in 86-97% (Scheme 31). 

Cleavage of indoles. Singlet oxygen cleaves both N-unsubstituted and N-substituted indoles. 

Nageswar et al. used nano-CuO for the efficient assembly of N-substituted indoles from indolines via the aromatization/C-N coupling process. No external ligand was... 

Reddy, K. H. V., Satish, G., Ramesh, K., Kamakar, K., and Nageswar, Y. V. D. 2012. An efficient synthesis of N-substituted indoles from indoline/indoline carboxylic acid via aromatization followed by C-N cross-coupling reaction by using nano copper oxide as a recyclable catalyst. Tetrahedron Lett. 53(24) 3061-3065. 

A similar Cu(I)-catalyzed arylation protocol leading to the formation of differently N-substituted indole-3-carboxylates 233 was recently reported by Karchava and coworkers (Scheme 9.82) [235]. The corresponding indole precursors 232 can be easily accessed in nearly quantitative yields by the amination of the respective common 1,3-dicarbonyl compound. A variety of primary alkyl- and aryl-amines, including sterically hindered ones, can be employed in this reaction, affording indole products 233 in good to high yields. 

Daugulis [67] reported a palladium-catalyzed C-H arylation of heteroarenes with aryl chlorides. Although a number of methods of direct arylation of five-membered heteroarenes with aryl halides, including less reactive aryl chlorides, had been reported, thus, the direct arylation of N-substituted indoles, pyrroles, and furans with aryl chloride had been elusive except for Ohta s work [5]. Ohta s group succeeded in the C-H arylation of such heteroarenes with aryl chlorides using a combination of Pd(OAc)2, a bulky Buchwald ligand, and inorganic bases (Scheme 17.14). 

N-Substituted indole 159 was prepared by May via the condensation of amine 158 with aldehyde 157 the intermediate imine undergoes subsequent intramolecular imino arylation in the presence of copper(I) and a base. The sequence proceeds smoothly with a tremendous variety of amines including substituted aryl, alkyl, ethereal, and adamantyl (130L1666). 

A novel [3-I-3]-benzannulation process occurs in the coupling of alkynylcarbene complexes (e.g., 160, Scheme 17.27) and heteroaromatic aldehyde-derived imines (e.g., 201) [83]. Furan, benzofuran, and N-substituted indole derivatives led to benzannulation products, heteroaromatic-fused benzenes (e.g., 204). The mechanism proposed involves electrophilic aromatic substitution at the 3-position of the heterocyclic ring, resulting in the complex 202, followed by a simultaneous 1,2-shift of the metal and nucleophilic addition to the iminium salt. 

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