Indoles nucleophilic substitution

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. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

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). 

Recently, the Bartoli indole synthesis was extended to solid supports. In contrast to the earlier reports in the liquid phase, o,o-unsubstituted nitro analogs (see 25) prove to be useful substrates. In addition, fluoro/chloro substituted nitro derivatives are well tolerated, which typically undergo nucleophilic substitution under Bartoli conditions in the liquid phase. 

Nucleophilic substitution of C-hydrogen in five-member ring of indoles 99PHC45. 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

When we proposed the possibility of nucleophilic substitution reactions on indole nitrogen in our hypothesis, we were taken to be eccentric. Fortunately, we have been able to demonstrate examples that seem to accord with the prediction. 

Two reaction mechanisms, such as SN1 and SN2 mechanisms, seem to be possible for explaining formations of 158a-c (Scheme 25). The former requires a resonance-stabilized indolyl cation 165 as an intermediate, while the latter indicates the presence of a transition state like 167. The introduction of a methoxy group into the 5 position of 165 should stabilize the corresponding cation 166, in which nucleophilic substitution on indole nitrogen would become a predominant pathway. 

Highly electron-deficient 1,3,6-trinitrobenzene (145) treated with phenyl acet-amidines 146 in ethanol provided low yields of a dinitroindole derivatives, probably 4,6-dinitroindoles 148 (77JOC435). Formation of indole derivatives 148 can be explained by nucleophilic substitution of the activated aromatic hydrogen leading to intermediates 147, which then cyclized to the final products 148 (Scheme 22). 

A paper concerned with the synthesis of pyridazino[3,4-fe]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work <06T121>. 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

Substituted 3,5-dihydro-4//-pyridazino[4,5-, ]indol-4-ones 50 <2001H(55)1105, 2002T10137> and 2,5-dihydro-l/7-pyridazino[4,5-7]indol-l-ones 52 <2006T121> have been synthesized from 5-(2-aminophenyl)pyridazin-3(2/0-ones 49 and 4-(2-aminophenyl)pyridazin-3(27/)-ones 51, respectively. For this purpose diazotization of the amino groups was followed by a nucleophilic substitution with sodium azide affording aryl azides. Upon heating of these compounds, the ring-closed products were obtained most probably via the formation of an electrophilic nitrene (Scheme 10). 

The analogous reaction of 5-iodopyridazin-3(2H)-one led to the formation of pyridazino[4,5-6]indoles (3.82.) in a two step nucleophilic substitution, palladium catalysed intramolecular carbon-carbon bond formation sequence. The same reaction has also been carried out in one-... 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

The halogenoacetyl derivatives of pyrrole and indole undergo normal nucleophilic substitution reactions and with bifunctional nucleophiles they yield the expected heterocyclic derivatives, as, for example, in the formation of the thiazolylindole from the reaction of 3-(chloroacetyl)indole with thioacetamide (77IJC(B)473>. 

In contrast with the relatively facile nucleophilic substitution reactions at the 2-position of the indole system, only 3-iodoindole has been reported to react with silver acetate in acetic acid to yield 3-acetoxyindole (59JOC117). This reaction is of added interest as 3-iodo-2-methylindole fails to react with moist silver oxide (72HC(25-2)127). It is also noteworthy that the activated halogen of ethyl 3-bromo-4-ethyl-2-formylpyrrole-5-carboxylate is not displaced during the silver oxide oxidation of the formyl group to the carboxylic acid (57AC(R)167>. 

As is true for other classes of aromatic nucleophilic substitution, the halogen displacement can frequently be catalyzed by copper or copper(I) salts. Using sodium hydride as the base and copper(I) iodide as catalyst, a series of o-bromophenylethylamine derivatives, including both amides and carbamates, have been cyclized. Oxidation to the indole can be effected with manganese dioxide (81JCS(P1)290). 

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