3-Indoleacetic acids

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetic acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3-dimethylaminomethylindole or gramine (II). The latter reacts in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleacet-amide (IV), part of which is further hydrolys 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). 

3-Indoleacetic acid In a 1-litre flask, fitted with a reflux condenser, place a solution of 35 2 g. of sodium cyanide in 70 ml. of water, then add 25 g. of gramine and 280 ml. of 95 per cent, ethanol. Reflux the mixture (steam bath) for 80 hours. Dilute the cooled reaction mixture with 35 ml. of water, shake with a little activated charcoal (e.gr., Norit), filter and concentrate to about 350 ml. under reduced pressure (water pump) in order to remove most of the alcohol. Cool to about 5°, filter off the solid and wash it with a little cold water keep the filtrate (A). Becrystallise the solid from alcohol-ether to give 5-0 g. of 3-indoleacetamide, m.p. 150-151.  

Cool the filtrate (A) to 5-10° and add concentrated hydrochloric acid dropwise and with vigorous stirring [FUME CUPBOARD hydrogen cyanide is evolved) to a pH of 1-2 (about 50 ml.) a crude, slightly pink 3-indoleacetic acid is precipitated. The yield of crude acid, m.p. 159-161°, is 20 g. Becrystallise from ethylene dichloride containing a small amount of ethanol 17 6 g. of pure 3-indoleacetic acid, m.p. 167-168°, are obtained. 

Hydrolyse the 5 g. of 3-indoleacetamide by heating it under reflux for 4 hours with a solution of 6 g. of sodium hydroxide in 40 ml. of water. Cool to 5°, treat with decolourising carbon (if necessary), filter, render strongly acid with concentrated hydrochloric acid (pH about 1-5). Collect the acid which precipitates and dry it at 70° the crude acid weighs 4 5 g. Purify as above. 

Polymerisation involves the chemical combination of a number of identical or similar molecules to form a complex molecule. The resulting polymer has a high molecular weight. The term synthetic polymer is usually employed to denote these coihpounds of very high molecular weight. 

Dimethylaminomethylindole (gramine). Cool 42 5 ml. of aqueous methylamine solution (5 2N ca. 25 per cent, w/v) contained in an 100 ml. flask in an ice bath, add 30 g. of cold acetic acid, followed by 17 -2 g. of cold, 37 per cent, aqueous formaldehyde solution. Pour the solution on to 23 -4 g. of indole use 10 ml. of water to rinse out the flask. Allow the mixture to warm up to room temperature, with occasional shaking as the indole dissolves. Keep the solution at 30-40° overnight and then pour it, with vigorous stirring, into a solution of 40 g. of potassium hydroxide in 300 ml. of water crystals separate. Cool in an ice bath for 2 hours, collect the crystalline solid by suction flltration, wash with three 50 ml. portions of cold water, and dry to constant weight at 50°. The yield of gramine is 34 g. this is quite suitable for conversion into 3-indoleacetic acid. The pure compound may be obtained by recrystaUisation from acetone-hexane m.p. 133-134°. 

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A solution of 1.330 g sodium hydroxide in 20 ml water is slowly admixed with 2.330 g hydroxylamine hydrochloride while cooling, whereupon 1 g chloride of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid is distempered in this neutral or slightly alkaline solution by vigorously stirring during a few minutes. 

Alternatively, dissolve 220 g 4-benzyloxy-3-indoleacetic acid (or equimolar amount other indoleacetic acid) in 2 L absolute methanol and reflux six hours in the presence of 20 g Dowex 50X8 sulfonic acid resin. Filter (decolor with carbon if desired) and concentrate below 35° until precipitation starts then cool to precipitate and filter to get 200 g of the methyl ester. Add 200 g of the ester to 600 ml 40% aqueous methylamine over twelve hours with vigorous stirring. Filter, wash precipitate with water and dry to get 187 g of the N-methyl-acetamide (reflux two hours in 500 ml benzene to remove unreacted ester). 24 g of the acetamide in 300 ml tetrahydrofuran is added dropwise to 10 g lithium aluminum hydride in 300 ml tetrahydrofuran reflux ten hours, cool to 15° and add dropwise with stirring 50 ml ethyl acetate. Reflux two hours and proceed as above to get 15 g (II) or analog. 

A 4 g 3-indoleacetic acid (I) in ether. I reat with PCi5 as described elsewhere here to get 2.7 g of the chloride (II). Dissolve 2.7 g (II) in 40 ml ethyl acetate and add 2 ml piperidine (or equimolar amount other amine), 3.5 ml N-ethyl-piperidine in 40 ml ethyl acetate. Let stand three hours at room temperature and filter. Wash filtrate with IN HCI, 10% Na carbonate and evaporate in vacuum to get 1 g of the amide (III) (test for activity). Add 1 g (111) in 25 ml ether to 1.4 g lithium aluminum hydride in 50 ml ether stir four hours at room temperature and reflux one-half hour. Cool and carefully add water until no more bubbling. Add 3 ml 20% NaOH and dry. evaporate in vacuum to get 1 g piperidine analog of DMT... 

SYNTHESIS (from indoleacetone) To a solution of 1.55 g NaOAc in 5 mL acetic anhydride there was added 2.0 g 3-indoleacetic acid and the mixture was heated at 135-140 °C for 18 h. Removal of all volatiles on the rotary evaporator under vacuum produced a pale yellow residue that was the 1-acetylindole-3-acetone. This was dissolved in MeOH to which 0.93 g MeONa was added, and the solution held a reflux several hours. After removal of the solvent under vacuum, the residue was suspended in H20 and extracted with several portions of Et20. These extracts were pooled, and removal of the solvent under vacuum gave 0.41 g (21%) indole-3-acetone as a white solid, mp 115-117 °C. MS (in m/z) indolemethylene+ 130 (100%) parent ion 173 (16%). IR (in cm-1) 691,753,761,780. 1017, 1110, 1172, and a broad C=0 at 1710. 

Important indole derivatives (see Scheme 2) include (i) indigo, a vat dye known and widely used since antiquity, and originally obtained from indican, a (3-glucoside of indoxyl which occurs in some plants. Indigo is now prepared synthetically. Tyrian purple, a natural dye used since classical times, is 6,6 -dibromoindigo (ii) the numerous indole alkaloids, with complex derivatives such as yohimbine and strychnine (iii) tryptophan, an essential amino acid found in most proteins. Its metabolites include skatole and tryptamine and (iv) 3-indoleacetic acid, which is important as a plant growth hormone. 

Complexes of 3-indoleacetic acid (60) and 1,2-dimethylbenzimidazole (61) have been described.439,440... 

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