2-substituted indoles

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Snyder and coworkers followed a completely different path to canthin-6-one (Fig. 23). Earlier they had shown that indole-substituted 1,24-triazine 66 could be heated in refluxing triisopropylbenzene (bp = 232 °C) to give /3-carboline 67 via an intramolecular cycloaddition/cycloreversion reaction [58]. Selective oxidation of 67 at C-6 was achieved through the use of triethylbenzylammonium permanganate [59]. Success of the reaction proved to be very sensitive to the solvent chosen. Heating 67 for 4 h at 70 °C in a 5 1 mixture of dichloromethane and acetic acid gave a 65% yield of 63, yet use of increasing amounts of dichloromethane slowed the reaction down (no reaction occurred in pure dichloromethane), while use of pure acetic acid led to an intractable mixture. 

The first total syntheses of these compounds were by Hibino and coworkers [91,92] and utilized palladium(0)-catalyzed coupling of 135 and 136 to produce indole-substituted imidazole 137 in 82% yield (Fig. 39). (A similar approach to closely related compounds was reported by Achab and coworkers at about the same time as the first report by Hibino) [93]. Ester 137 was hydrolyzed in near quantitative yield by reaction with sodium car-... 

The reaction between zinc-copper reagents and acid chlorides is very general and provides a useful synthesis of ketones [7, 34, 41, 42], This acylation has also been used to prepare various indoles substituted in position 2 (Scheme 2.42) [88],... 

This enzyme [EC 4.1.99.1], also known as L-tryptophan indole-lyase, catalyzes the hydrolysis of L-tryptophan to generate indole, pyruvate, and ammonia. The reaction requires pyridoxal phosphate and potassium ions. The enzyme can also catalyze the synthesis of tryptophan from indole and serine as well as catalyze 2,3-elimination and j8-replacement reactions of some indole-substituted tryptophan analogs of L-cysteine, L-serine, and other 3-substituted amino acids. 

A variety of syntheses are used to prepare indoles the most versatile for indoles substituted in the benzene ring is still the venerable Fischer indolization process. 

Cyclic versus non-cyclic replacements a. Cyclic replacements of non-cycllc functional groups e.g. phenol/Indole substitutions e.g.carboxylic acid/tetrazole substitutions ... 

Cr(CO)3 coordinates to the benzene ring of indole (181) selectively and the reaction occurs mainly at the normally inaccessible C(4) carbon to give 182, and substitution at C(7) to give 183 is a minor reaction [47]. With the uncomplexed indole, substitution at C(2) is common. 

In intermolecular cyclopropanations [100], it was found better to use a-bromoesters and amides as ylide precursors and a,/ -unsaturated ketones and esters as electron-deficient alkenes - rather than using a-haloketones as the ylide precursor. (For experimental details see Chapter 14.11.4). The reaction gives access to a range of 1,2-dicarbonyl-substituted cyclopropanes (see Fig. 10.5). The al-kene could have an aryl-, alkyl- or indole-substituted ketone, and a-substitution was also tolerated. Notably, Weinreb amides could be used as the ylide precursor and the product subsequently transformed into a diketocyclopropane. Both enan-... 

A consequence of this delocalisation is that the lone pair is not available for protonation under moderately acidic conditions so, like pyrrole, indole is another weakly basic heterocycle. Another similarity to pyrrole is that being an electron-rich heterocycle indole easily undergoes aromatic electrophilic substitution, and is also rather unstable to oxidative (electron-loss) conditions. However, an important difference emerges here, in that whereas pyrrole preferentially reacts with electrophiles at the C2/C5 positions, indole substitutes selectively at the C3 position. The reasons for this will be discussed later. 

Stephenson and coworkers applied reductive photoredox catalysis to trigger radical 6-exo cyclizations of co-pyrrole or co-indole-substituted a-bromocarbonyl compounds 124 [186] as well as radical 5-exo cyclizations of 2-bromo-2-(4-pentenyl)malonates 126 (Fig. 32) [187]. These cyclization processes provide bi- or tricyclic products 125 or cyclopentanecarboxylates 127 in moderate to excellent yields. The initial radical was formed with reduced ruthenium catalyst HOB generated similarly as above from 110 and a sacrificial amine... 

It was found that indole-substituted (9-pentafluorobenzoyl oximes 240 underwent... 

Unsubstituted and substituted o-bromo and o-chloroanilines are adequate substrates for obtaining indoles substituted with Me, Ph, or MeO groups in 50-90% yield [70a]. 

In an attempt to synthesize a component 50 of exochelin MN (51), the regioin-versed AA of imidazol acrylates 49 under the influence of the (DHQD)2AQN ligand was investigated (Scheme 9). While hydroxyphenyl-substituted substrates such as 48a and 48b gave satisfactory yields (45-55%), regioselectivities (3 1 — 1 0), and enantioselectivities (84-86% ee), no reaction was observed with imidazole-substituted substrates like 48c [71], However, the synthesis of the indole-substituted amino acid 52, a component of cyclomarin A (53), was achieved in 36% yield (Scheme 9) [72], The diastereoselectivity of the AA reaction was determined to be 95 5. 

The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-l//-indol-l-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JC0813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines. 

To date, NMR has been used to study (a) the structures of indoles, substituted in both heterocyclic as well as the benzenoid ring (recently, there have been a number of publications wherein NMR is used to elucidate the complicated structures of biologically important antibiotics95,110-112 and alkaloids113-117 containing the indole skeleton) (b) tautomeric structures and equilibria 96, 118-120 (c) the stereochemistry of side-chain substituents and (d) the protonation of indoles. It is hoped that in the future many significant applications of NMR in the indole field, such as a study of intermolecular and intramolecular reactions and the rates of fast reactions, will be found. 

Grieco improved the above methods, developing a general allylation method for indoles employing y,y-disubstituted allylic alcohols. Allylic alcohol 94 underwent no reaction under conditions similar to those affording effective allylation of 95 by use of y-aryl allylic alcohol 90. By contrast, in an LPDE solution containing a catalytic amount of AcOH (1 mol %), the rapid consumption of 94 proceeded to give the indole substitution product 96 in 77 % yield. Particularly noteworthy is that the iso-... 

Oxazolone itself can be easily obtained from oxazolidinone through electrochemical reduction as described in CHEC-II(1996). A similar sequence was utilized in the synthesis of indole-substituted 2(3//)-oxazolone 244 (Scheme 71) <1997CPB733>. Electrochemical oxidation of 2-oxazolidinone in methanol gave a 4-methoxy oxazolidinone 241, which reacted with an organomagnesium indole reagent 242 in the presence of BF3-Et20, followed by... 

To illustrate the methods, a culture medium that contains indole, pyruvic acid, tyrosine phenollyase and an ammonium salt, as well as the usual buffers and salts, will accumulate L-tryptophan or will produce an indole-substituted L-tryptophan if indole itself is replaced by a substituted indole. L-Dopa formed in a system employing tyrosinase from Aspergillus terreus provides a further example of this approach (Chattopadhyay and Das, 1990). 

Opioid receptor binding data have been reported for a series of 17-cyclopropyl-methylnoraminomorphindole derivatives (59, Fig. 13) [56]. All but the propyla-mino derivative (59b) had subnanomolar affinity for DOR which reduced its DOR selectivity compared with ethylamino- (59a) which was the only new ligand comparable in selectivity with naltrindole (58b). The indolic-substituted formyla-mino- derivatives were investigated as potential PET ligands for imaging studies of DOR. Alkylation of the indolic /V-atom allowed retention of high affinity for DOR. The fluoroethyl substituent (59d) had little effect on selectivity but fluoropropyl (59e) lowered selectivity. 

Figure 9 Indole Substitution Patterns Found in Aldrich Catalog...

Meanwell NA, Wallace OB, Fang H et al (2009) Inhibitors of HIV-1 attachment. Part 2 an initial survey of indole substitution patterns. Bioorg Med Chem Lett 19 1977-1981... 

Aroylindoles bind to the colchicine site of p-tubulin, however, and in contrast to colchicine (1), vincristine (2a), nocodazole (13) or taxol (3), they showed no significant influence on the GTPase activity up to 10 pM [48,49]. In addition, angiogenesis in the chick embryo chorioallantoic membrane (CAM) assay was inhibited by D-64131 and analogue. Since 2-aroylindoles are easy to synthesise (Scheme 2), the role of the indole substitution pattern was studied in more detail. 

Tryptophan is an indole-substituted alanine (Section 21.11). Like imidazole, indole is an aromatic compound. Because the lone pair on the nitrogen atom of indole is needed for the compound s aromaticity, indole is a very weak base. (The pi a of protonated indole is -2.4.) Therefore, the ring nitrogen in tryptophan is never protonated under physiological conditions. 

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