Indole Mannich reaction

Another electrophilic substitution which indole undergoes with ease is aminoalkylation (Mannich reaction). Indole, formaldehyde and dimethylamine in acetic acid interact with formation of the natural product gramine [(3-dimethylaminomethyl)indole], which has been isolated from grasses (earlier gramineae now poaceae) ... 

Colourless solid m.p. 132-134 C. An important intermediate for preparing indole derivatives, produced by treating indole under Mannich reaction conditions with methanal and dimethylamine. 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

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. 

Indole, 4,5,6,7-tetrahydro-4,7-dioxo-structure, 4, 303 Indole, tetrahydro-3-methyl-synthesis, 4, 109 Indole, 2-(2-thienyl)-nitration, 4, 211 Indole, 3-thio-synthesis, 4, 368 Indole, 2-thioalkyl-synthesis, 4, 152 Indole, 3-thiocyano-synthesis, 4, 368 Indole, 1-tosyloxy-rearrangement, 4, 302 Indole, 1,2,3-trialkyl-Mannich reactions, 4, 228 Indole, 3-(tricyanovinyl)-nucleophilic addition reactions, 4, 281 reactions... 

An indole protected by a Mannich reaction with formaldehyde and dimethyl-amine is stable to lithiation. The protective group is removed with NaBH4 (EtOH, THE, reflux). The related piperidine analogue has been used similarly for the protection of a triazole. ... 

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

Oxyiminium cations formed from iV,0-diaIkyhydroxylamines and formaldehyde are sufficiently reactive for Mannich reactions with activated arenes. Mannich reactions of oxyiminium cations with indoles (e.g. 74, equation 48) " as well as pyrroles and furans but not phenol and thiophene have been reported. 

The mechanism of the Mannich reaction is similar to that of the Vilsmeier reaction as the electrophile is also a methyleniminium cation, formed this time from a condensation of dimethylamine and formaldehyde in acetic acid solution (Scheme 7.7a). This reacts with indole to yield 3-(A, 7V-dimethylaminomethyl)indole (although not shown, it is possible that initial attack occurs at N-1 and rearrangement of the side chain to C-3 takes place in a follow-up step) (Scheme 7.7b). Scheme 7.7... 

To make use of the Mannich reaction it is possible to methylate the N-atom of the new side chain and eliminate trimethylamine. The product, a 3-methyleneindoleninium salt, can then be trapped with suitable nucleophiles. In the example shown in Scheme 7.7b, cyanide ion is used, and reduction of the resultant nitrile yields the important amine trypta-mine. Indol-3-ylacetonitrile is also the source of indol-3-ylacetic acid and other biologically useful compounds (see Section 7.1.7). 

The Mannich reaction is another example of electrophilic aromatic substitution where indole can produce an aminomethyl derivative. 

Support-bound C-nucleophiles have also been successfully added to imines. Poly-styrene-bound thiol esters can be converted into ketene acetals by O-silylation, and then alkylated with imines in the presence of Lewis acids. Further examples include Mannich reactions of support-bound alkynes and indoles (Table 10.10). Some Man-nich-type products (e.g. 3-(aminomethyl)indoles, 2-(aminomethyl)phenols, (3-amino ketones) are unstable and can decompose upon treatment with acids. 3-(Amino-... 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

Other compounds containing active hydrogen atoms similarly undergo the Mannich reaction, and a further interesting example is provided by the synthesis of dimethylaminomethylindole (gramine), in which indole is the reactive component (cognate preparation in Expt 6.147). 

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