Indoles aminomethylation

Jap-KIingermarm reactions, 4, 301 oxidation, 4, 299 reactions, 4, 299 synthesis, 4, 362 tautomerism, 4, 38, 200 Indole, 5-amino-synthesis, 4, 341 Indole, C-amino-oxidation, 4, 299 tautomerism, 4, 298 Indole, 3-(2-aminobutyl)-as antidepressant, 4, 371 Indole, (2-aminoethyl)-synthesis, 4, 278 Indole, 3-(2-aminoethyl)-synthesis, 4, 337 Indole, aminomethyl-reactions, 4, 71 Indole, 4-aminomethyl-synthesis, 4, 150 Indole, (aminovinyl)-synthesis, 4, 286 Indole, 1-aroyl-oxidation, 4, 57 oxidative dimerization catalysis by Pd(II) salts, 4, 252 Indole, 1-aroyloxy-rearrangement, 4, 244 Indole, 2-aryl-nitration, 4, 211 nitrosation, 4, 210 synthesis, 4, 324 Indole, 3-(arylazo)-rearrangement, 4, 301 Indole, 3-(arylthio)-synthesis, 4, 368 Indole, 3-azophenyl-nitration, 4, 49 Indole, 1-benzenesulfonyl-by lithiation, 4, 238 Indole, 1-benzoyl photosensitized reactions with methyl acrylate, 4, 268 Indole, 3-benzoyl-l,2-dimethyl-reactions... 

Aminomethyl-1-methyl-5-chloro-3(o-fluorophenyl)indole HCI Chromic anhydride Ammonia Hydrogen chloride... 

A solution of 60 g of chromic anhydride in 40 ml of water was added dropwise to a suspension of 60 g of 2-aminomethyl-1 -methyl-5-chloro-3-(o-fluorophenyl)-indole hydrochloride in 600 ml of acetic acid. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1.1 liters of ether and 1 liter of water and then 800 ml of 28% ammonium hydroxide, in small portions. The ethereal layer separated, washed with water, dried, and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and 100 ml of 20% ethanollc hydrogen chloride was added to the solution and the mixture was cooled. The precipitate was collected by filtration to yield 46.5 g of 1 -methyl-7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, melt-... 

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 " ... 

This method, although described for indoles, probably also worlds with 5-OH-tryptamine (serotonin), and 5-OH-DMT (bufotenin) with compounds of the latter type, orally active psilocybin analogs will be obtained in one step. Dissolve 5 g 5-OH-indole (or analog) in 25 ml ethanol. Add 5.5 g 33% aqueous dimethylamine (or other amine, e.g., piperidine) and add slowly dropwise with stirring 3.5 g 38% aqueous formaldehyde. Two minutes after the end of the addition shake with water and CHCI3 dry and evaporate in vacuum the CHClj phase to get 5 g oily 4-dimethyl-aminomethyl-5-OH-indole (1) (can chromatograph on 100 g alumina and elute with ethyl acetate). It has been claimed that this method does not work. 

Molindone Molindone, 3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5F0-one (6.4.3), is synthesized by the nitrozation of diethylketone using nitric acid or methyl-nitrite into nitrozodiethylketone (6.4.1). Reduction of this product with zinc in acetic acid into 2-aminodiethylketone in the presence of cyclohexandion-1,3 gives 3-ethyl-2-methyl-4,5,6,7-tetrahydroindol-4-one (6.4.2). Aminomethylation of this product using morpholine and formaldehyde gives molindone (6.4.3) [51-52]. 

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

Carbocations stabilized by functional groups can also effect 3-alkylation of indoles. From a synthetic point of view the most important are iVJV-dialkyl-methyleneiminium ions which can be generated under Mannich conditions from formaldehyde and secondary amines[13]. The products, 3-(N,AI-dialkyl-aminomethyl)indoles, are useful synthetic intermediates (see Chapter 12). 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

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-... 

Support-bound indoles can be modified in several ways. N-Alkylation of polystyrene-bound indoles has been achieved by treatment with reactive alkylating agents (Mel, BnBr, BrCH2C02R) in conjunction with NaH or KOrBu as a base in DMF at room temperature (Entries 1 and 2, Table 15.7). The aminomethylation of indole at C-3 proceeds smoothly on cross-linked polystyrene. The resulting (aminomethyl)in-doles are thermally unstable and undergo substitution reactions with various carbon nucleophiles (e.g. cyanide or nitroacetates) at higher temperatures (Entry 4, Table... 

Like pyrrole, indole readily undergoes the Mannich reaction affording the aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an elimination followed by a 1,4-addition reaction, as in the preparation of acetate 7.27. 

Gramine (= 3-(Dimethyl-aminomethyl)-indole Donaxine) (indole)... 

The indole linker 1.11 (68), easily prepared from aminomethyl PS resin and N-carboxyalkylated indole-3-carboxaldehyde, was used to support amines and to transform them on SP, obtaining, by release with TFA-DCM 1/1 in 30 min, a variety of compounds, including amides, sulfonamides, guanidines, ureas, and carbamates. 

The amidomethylation reaction is suitable for the same purpose, as NH atnide.s, whieh are well-known substrates of Mannich synthesis, can also behave like amine reagents. Thus, the resultant amidomethyl derivative 21 (Fig. 15) can be then subjected to hydrolysis by means of hydrazine to give the primary amine product. - By this method the 6-aminomethyl indole derivative 22 has been obtained. ... 

Pyrrole is aminomethylated in position 2, that is, in the a position with respect to the heteroatom. - When the pyrrole ring is fused to another aromatic ring (e.g., indole d e -... 

Deaminomethylation of Mannich bases may also occur in the presence of electrophilic species, capable of replacing the aminomethyl group linked to the substrate moiety, such as, for example, diazonium salts acting on Mannich bases of phenols and indoles, or alcohols acting on cyclic O-Mannich bases. The deaminomethylation reaction is also prc.sent in. several equilibria afforded by aminomethyl derivatives of benzotriazole (sec 209, Chap. 1, C.6). 

Typical examples of this class of reaction are the C- or N-aminomcthylations of pynole and indole derivatives, the N- or S-aminomethylation of thioamides, etc. Aminomelhylated products may also easily undergo interconversions, as described below in Sec. C.6. 

---