Indole 3-dimethylaminomethyl

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. 

Essentially the present procedure converted 1-methylindole to l-methyl-3-(N,N-dimethylaminomethyl)indole and a-methyl-styrene to o -(N,N-dimethylaminoethyl)styrene. ... 

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... 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethylaminomethyl-indole (gramine) (353) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 62). 

To exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, f-butylcarbamoyl, benzenesulfonyl, dimethylamino and dimethylaminomethyl have been used (81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (396) (81JOC3760). Another useful process involves the /V-lithiation, carbonation, and C-2 lithiation of indoles, which leads for example to 2-haloindoles in excellent yields (92JOC2495). 

Gramine - 3-(dimethylaminomethyl)indole (14) - is a readily obtainable derivative of indole and is produced with a quantitative yield by the Mannich reaction. In [19] it was phosphorylated with diethyl chlorophosphite. 3-(Dimethylaminomethyl)-l-(triethoxyphosphito)indole (15) was obtained also by the method in [20] using diethyl penten-3-on-2-yl phosphite. Compound 15 readily adds sulfur with the formation of the corresponding gramine 1-thiophosphate 16 and reacts with chloral according to the scheme of the Perkow reaction, forming phosphate 17 ... 

To exploit the reactions of the C-lithio derivatives of N-unsubstituted pyrroles and indoles, N-protecting/masking groups such as ferf-butoxycarbonyl, terZ-biitylcarbamoyl, benzenesulfonyl, dimethylamino, and dimethylaminomethyl must be used. This is illustrated by a route to G-acylated pyrroles 441. Another very useful process involves N-lithiation, N-carbonation, and lithiation of the resulting indol-l-ylcarboxylate at C(2) reaction with an electrophile and loss of carbon dioxide during work-up give N-unsubstituted 2-substituted indoles, for example, 2-haloindoles in excellent yields. 

This compound, 111-D, has been synthesized79 in the course of preparation of deuterium-labelled 3-(dimethylaminomethyl)indole-2-D, 112-D (equation 47), utilizing... 

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) ... 

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