Indole derivatives reactivity

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

The reactivity of certain indole derivatives, such as ox indole and indoxyl... 

Triple bonds are in general more reactive than double bonds as is exemplified in the following process (1.2.).13 The active catalyst is HPdOAc, which is formed by the oxidative addition of acetic acid onto Pd(0). The organic substrate is attached to the palladium in a regio- and stereospecific step that is followed by an oxidative addition (N.B. Pd(II)-Pd(IV) transition) and reductive elimination, or alternatively carbopalladation and reductive elimination, to give the indole derivative. 

Gonzalez and Galvez269 have described an improved method for the preparation of 3-diazoindoles (174), using PTC. Indole derivatives 173 react in position 3 because of the ambident reactivity of the molecule. Yields are 75-90% when R is acyl or heteroaryl. 

Several examples of the cyclization of indole derivatives with alkenic side chains in the 3-position have been reported.6 In these examples, palladium chloride in combination with silver tetrafluoroborate is the cyclizing agent. The palladium tetrafluoroborate, presumably formed, should be a very reactive palladating species and probably is the reason why these reactions proceed at room temperature, although the mechanism is not yet completely clear. These reactions were worked up reductively (by addition of sodium borohydride) in order to reduce the expected alkenic product or any relatively stable organopalladium complexes that may have been formed (equation 4).6... 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

The mechanism of melatonin s interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through a radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4, and C7 and nitrosation [169]. The mechanisms by which melatonin protects against LP most likely involve direct or indirect antioxidant and free-radical scavenging activities of this indoleamine [169,171]. 2-Phenyl indole derivatives have redox properties because of the presence of an electron-rich aromatic ring system that allows the indoleamine to easily function as an electron donor. For these derivatives, the possible antioxidant mechanism might be most probably toward carbon-centered radicals described by Antosiewicz et al. [172]. 

To check the different reactivity for the carbolithiation reaction of a lithiated double bond by vinyl- or aryllithiums, tertiary amine 341 was synthesized and treated with 6 equivalents of f-BuLi and TMEDA. Subsequent deuteriolysis led to a 6 1 mixture of the dihydropyrrole derivative 342 and the indole derivative 343 in very good overall yield, showing that intramolecular carbolithiation reaction of a lithiated double bond by a vinyllithium is faster than the corresponding carbolithiation reaction by an aryllithium (Scheme 88)141. 

Bnciocx hi. E. and Schiroli, A., Sidechain reactivity of indole derivatives. The reaction of 3-indolylmethyltrimethy lammonium meth-ylsulphate with sodium toluenc-p-thiolate, J. Chem.. StK. B. 401, 1968. 

In general, the side chain derivatives of azaindoles undergo reactions analogous to those with indoles. The azagramines and 3-carboxaldehydes are the most useful, leading to many other azalogs of indole derivatives of biological importance. Unfortunately, most of the reactions and compounds involve the more accessible 7-azaindoles, so few comparisons in reactivity differences can be made. 

Chlorophenol is also reactive and irradiation in water leads to its conversion into resorcinoP" or in methanol to yield 3-methoxyphenol in 94% yield. Photoamidation with N-methylacetamide of 3-chlorophenol is also efficient and resnlts in the formation of the phenol 241 in a yield of 77%. Intramolecnlar amidation arises on irradiation of 242 in basic methanol. This resnlts in the formation of the indole derivative 243 as well as the methoxylated prodnct 244. More complex halophenols such as 245 are also photochemically reactive, but this yields a complex mixture of products including a benzofuran. The formation of this must be similar to the cychzations described earlier and involves the attack of a radical, produced by the C—I bond fission, on the other ring . 3-Nitrophenol is converted on irradiation in aqueous solution into a variety of products such as nitrocatechols, nitroresorcinol and resorcinol itself... 

A distinction between physical and reactive quenching is drawn in a study of the interaction of O2 with indolic derivatives. Kinetic studies on anthralin photoxidation show that O2 preferentially reacts with the trihydroxyanion . 

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