Indoles nucleophilic substitution, mechanism

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. 

Gramme is a common precursor for indol-3-ylmethylation of enolates and other nucleophiles. Such reactions normally occur by an elimination-addition mechanism. Following development of procedures for 4-substitution via directed lithiation with l-(tri-/w-propylsilyl)-gramine, Iwao and Motoi have developed conditions for tandem nucleophilic substitution of the dimethylamino group. Quatemization followed by reaction with a nucleophile in the presence of TBAF leads to alkylation. <95TL5929> The carbon nucleophiles which were successfully used include nitromethane, methyl acetoacetate, diethyl malonate and diethyl 2-(acetamido)malonate. Phthalimide, thiophenol, TMS-CN and TMS-Nj were also used as sources of nucleophiles. 

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. 

In the various reactions involving 4,6-dimethoxyindolin-2- one 73 and phosphoryl chloride, there is the possibility that the likely intermediate, 2-chloro-4,6-dimethoxyindole 102, could react with itself, as it is both electrophilic at C-2 and nucleophilic at C-3 and C-7. Even though no products of such a self-condensation process were observed in any of the reactions with indoles, an investigation of this combination of reactants was carried out. The reaction was indeed quite slow, but eventually very small yields (2 and 1%) of the rather interesting heterocyclic system 103 and its further substituted product 104 were isolated44 (Scheme 29). A possible mechanism is indicated in Scheme 29. A similar 1-methylindole trimer has been synthesized from 2-iodo-1-methylindole by both direct and stepwise routes.39,40 So far attempts to generalize the phosphoryl chloride reaction and improve the product yields have not met with success. 

Alternatively, the SrnI mechanism can be coupled to nucleophilic additions as was the case during the formation of substituted indole 212 [182], an interesting variation on a reaction first reported by Beugelmans and Roussi [183]. 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

C-Ring substituted indoles, including 4-nitroindole, are also allylated under these conditions. The reaction is believed to proceed by an Sa I mechanism, with the Zn(03SCF3)2 acting as a Lewis acid catalyst. There may also be some N-H deprotonation by the amine. 1-Methylindole reacts under these conditions, but with reduced yield. The Zn(03SCF3)2-mediated reaction was used in tandem with intramolecular nucleophilic capture to synthesize the flustramine structure [89]. 

In 1970, Bunnett and Kim reported a new nucleophilic aromatic substimtion reaction the S l mechanism (substitution, radical-nucleophilic, first order) [77-80]. Nine years later, Bunnett [81] and Beugelmans [82,83] independently discovered the application of the S l reaction to the synthesis of indoles (Scheme 10). In Bunnett s work (equation 1) the aeetone enolate (and others) was generated from acetone and potassium tert-butoxide (tert-butyl alcohol) in the presence of potassium amide in liquid ammonia [81]. Indoles 16 to 18 were also prepared by Bard and Bunnett. Beugelmans and Roussi employed a similar... 

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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