Indole nucleus

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

Leptactina senegambica (Rubiaceas). The root-bark contains about 1 per cent, of alkaloids, including leptactinine, m.p. 264f-6°, which forms a picrate, m.p. 258° (dec.), picrolonate, m.p. 196°, and styphnate, m.p. 240-2°. The colour reactions with numerous alkaloidal reagents are recorded, some of which indicate that an indole nucleus is present. Pharmacological effects of an extract of the root bark are described (Paris and Bouquet, Ann. pharm. franc., 1946, 4, 233). 

The Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone 1 of an aldehyde or ketone by treatment with acid catalyst or effected thermally to form the indole nucleus 2. ... 

A number of reaction pathways have been proposed for the Fischer indolization reaction. The mechanism proposed by Robinson and Robinson in 1918, which was extended by Allen and Wilson in 1943 and interpreted in light of modem electronic theory by Carlin and Fischer in 1948 is now generally accepted. The mechanism consists of three stages (I) hydrazone-ene-hydrazine equilibrium (II) formation of the new C-C bond via a [3,3]-sigmatropic rearrangement (III) generation of the indole nucleus by loss of... 

Under acidic conditions, the first step involves protonation of the imine nitrogen followed by tautomerization to form an ene-hydrazine intermediate (7). After the tautomerization, a [3,3]-sigmatropic rearrangement occurs, which provides intermediate 8. Rearomatization then occurs via a proton shift to form the imine 9 which cyclizes to form the 5-membered ring 10. Finally, loss of ammonia from 11 generates the indole nucleus in 12. 

An example of the formation of a Grignard reagent on the benzene ring moiety of the indole nucleus has been described recently. Noland... 

Jardine and Brown reported that the product obtained on treatment of indole magnesium iodide in ether with deuterium oxide in tetrahydrofuran was deuterated to the extent of about 50% in both the 1- and 3-positions of the indole nucleus. ... 

Poti and Ruff have also reported recently that infrared spectroscopic studies indicate that the magnesium function in indole magnesium iodide is associated with the nitrogen atom of the indole nucleus and not the carbon atom in the 3-position. 

Alkylation takes an entirely unexceptional course. The nitrogen atom of the 7r-excessive five-membered ring of the indole nucleus resists alkylation, md-A-Alkylation with alkyl halides can be achieved only after forcing deprotonation with, for example, sodamide, potassium amide or ethoxide. In this manner... 

The iminium salt 165, derived from acid treatment of 1,4-dihydropyridine 164, on intramolecular cyclization on the indole nucleus gave pentacyclic compound 166 (83T3673). The tmns stereochemistry of H3 and H9 in 166 (biogenetic... 

New reactions of indole nucleus and their synthetic applications 99YZ35. 

Once an electron-withdrawing group is introduced onto the indole nucleus, no matter which position it is, 1-hydroxyindoles become stable (91YGK205, 99H1157). For the preparation of such stable 1-hydroxyindoles, various reagents and conditions can be employed and many approaches have been reported, as summarized in previous reviews (79MI1, 90AHC105). 

As for regioselectivity in the electrophilic substitution reactions, we have assumed that introducing a methoxy group to the 1 position of indole nucleus might alter its positional reactivity. 

No 1 -hydroxytryptamine or -tryptophan alkaloid that lacks a stabilizing group on the indole nucleus has been reported yet. However, isolation of37,38a, 38b, HUN-7293 (293) (96MI69), and apicidin (301) (96TL8077) offers indirect evidence for the existence of 1-hydroxytryptamines and/or 1-hydroxytryptophans in living organisms. We believe their isolation will be reported in the near future. 

In the early stages of the synthesis, the stable, aromatic veratryl group had served admirably as a masking device for the a-carbon of the indole nucleus. It permitted the processes leading to the for-... 

Curiously, the ring expansion fails in sulfuric, trifluoroacetic, trichloroacetic, and orthophos-phoric acid. The reaction is sensitive to substituents both in the TV-aryl group and in the 2-and 3-positions of the indole nucleus. For example, 3-methyl-l-phenylindole yields a mixture of 10-methyl-5//-dibenz[/t,/]azepine (34% mp 129-131X) and 2-mcthyl-l-phenylindole (57%). In contrast, 2-methyl-l-phenylindole and 2,3-dimethyl-l-phcnylindole fail to ring expand. The reaction also fails with electron-withdrawing groups (N02 and CF3) in the TV-phenyl ring. 

HT is metabolised primarily by MAO to 5-hydroxyindoleacetic acid (5-HIAA) (Fig. 9.4). In vitro, 5-HT is the preferred substrate for the MAOa, rather than the MAOb isoenzyme (see Chapter 8) and this appears to be the case in vivo since MAOa, but not MAOb, knock-out mice have increased concentrations of 5-HT in the brain. Obviously, because of its indole nucleus, 5-HT is not a substrate for the enzyme COMT which metabolises the catechol derivatives, dopamine and noradrenaline. However, other metabolic products of 5-HT are theoretically possible and one, 5-hydroxytryptophol,... 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

N-benzylation had occurred as expected rather than substitution at the 2-position of the indole nucleus. 

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