US2414715A - Production of 3-indole aldehyde - Google Patents

Description

Patented Jan. 21, 1947 UNITED. STATES PAT-E PRODUCTION OF s-mnoLn ALDEHYIJE Edgar C. Britton, John E. Livak, and John C. Vander Weele, Midland, Mich., assignors to The Dow Chemical Company, corporation of Michigan Midland, Mich., a.

No Drawing. Application October 23, 1944, Serial N 0. 560,034

6 Claims. 1 This invention concerns an improved method for the production of 3-indole aldehyde.

It'is known that 3-indole aldehyde may be formed by reacting indole with a lower alkyl magnesium iodide to form indole magnesium iodide, adding ethyl formate and heating to 70 to 100 C. However, by-products, particularly N -formylindole, are formed in considerable amount and the yield of the aldehyde'is low. It has heretofore been usual practice to add, to a solution of the indole magnesium iodide, approximately five molecular equivalents of ethyl formate and to heat the resultant mixture at atmospheric pressure to the reaction temperature. Putochin, Ber. 59 1991 (1926) indicates that when operating in this manner, the yield of 3-indole aldehyde is between 27 and 33 per cent of theoretical.

It is an object or this invention to provide an improved method whereby 3-indole aldehyde may be produced more economically and/or in higher yield than by the known method just mentioned. A particular object is to provide an improved method which will permit the use of an alkyl magnesium bromide, instead of an alkyl magnesium iodide, as astarting material in the production of 3-indole aldehyde. Other objects will be apparent from the following description of the invention.

We have found that a lower alkyl magnesium bromide, instead of a corresponding iodide, may be used in producing 3-indole aldehyde by the general reactions just mentioned, provided the reactionibetween the indole magnesium bromide (obtained as an intermediate product) and a lower alkyl formate is carried out at an elevated temperature and pressure in the presence of diethyl ether as a medium for the reaction. Peculiarly, attempts on our part similarly to employ alkyl magnesium chlorides in the process have not resulted in the formation of 3-indole aldehyde in an appreciable yield. We have also found that by carrying out the reaction between indole magnesium bromide and a lower alkyl formate under pressure and in ethereal solution, 3-indole aldehyde maybe produced in a'yield considerably higher than has heretofore been reported. We have further found that the five-fold molecular excess of an alkyl formate over an indole magnesium halide, heretofore employed in the reaction ror formation of the 3-indole aldehyde, is unnecessary and that the aldehyde may be obtained in a good a yield when employing the for-. mate in amount molecularlyequivalent to, or only moderately in excess of, the indole magnesium halide. On a basis of these discoveries we have devised the following improved method for the production of 3-indo1e aldehyde.

A lower alkyl magnesium bromide is formed, as usual, by reacting magnesium with an ethereal solution of an alkyl bromide. The alkyl bromide employed is one containing not more than four carbon atoms in the alkyl group, i. e. the alkyl group is one corresponding to a normally gaseous parafiinic hydrocarbon. Diethyl ether, in amount suificient to dissolve the alkyl magnesium bromide, is used as a. medium for the reaction.

The resultant ethereal solution of the loweralkyl magnesium bromide is treated with indole in amount not exceeding the molecular equivalent of the alkyl-magnesium bromide. The indole and alkyl magnesium bromide react readily to form indole magnesium bromide and evolve a, parafiinic hydrocarbon corresponding to the alkyl group of the alkyl magnesium bromide. The reaction is preferably carried out in a closed reactor at room temperature or thereabout with cooling and gradual withdrawal of the gaseous hydrocarbon as it is formed, since loss of the ether by vaporization may thus be minimized. However, the reaction may be carried out at lower or higher temperatures. When operating on a large scale, the indole is preferably added gradually and with stirring until the gaseous hydrocarbon is no longer evolved, at which time introduction of the indole is discontinued. It is important that the indole be employed in amount not greatly exceeding the molecular equivalent of the alkyl magnesium bromide, since excess indole, if present, reacts with the indole magnesium bromide intermediate product and consumes a portion of the latter with for mation of undesired by-products.

The ethereal solution of indole magnesium bromide is treated with methyl formate, or preferably ethyl formate, in amount corresponding to between 0.8 and 2.5, preferably between 1.0 and 1.5, of the molecular equivalent of the indole magnesium bromide. The formate is usually added gradually and with stirring at room tem-- perature or thereabout, but it may be added while heating the reaction mixture if desired. In any case, it is necessary that the mixture be heated within a short time, e. g. less than 3 hours, after adding the formate since the latter and the indole magnesium bromide react slowly at room temperature or lower to form principally N-formylindole rather than the desired aldehyde. The reaction mixture is heated in a closed vessel, e. g. a bomb or autoclave, at temperatures between and 120 C., preferably at from to 0. Usually, from 20 to 40 minutes of heating is sulficient to complete the reaction.

Thereafter, the vessel is cooled, opened, and ether i separated from the resinous reaction product. The latter is decomposed to liberate 3-indole aldehyde by procedure usual in the treatment of other Grignard reaction products.

, For instance, it maybe ground or broken into small pieces, admixed with ice water and treated with an acid, preferably an aliphatic carboxylic acid such asrformim ac'eticg or propioniciaci'd; etc.-,c;

to effect hydrolysis and liberate thealdehyd N-formyl-indole, present as a by-product, may

be extracted from the aqueous mixture by agitat-g-cv ing the latter together with a liquid aromatic During the" extraction, 3

hydrocarbon solvent.

hydrocarbon phase. The major portion of the aqueous phase is then separatedand the remain.- ing mixture is filtered to recover the solid(3-;=.-

indole aldehyde. N-formyl-indole may be recovered, e. g. by fractionally distilling the extractfl The products may, of (course, be separated in otl1er1:way's: from; the reacted;mixture; For-win stance; the lattermayfirist'ibe filteredzor. decanted to: separate: 3-indole+v aldehyde inf crudegf-orm and the product may be .purified -by :zextracting; 1101 steam distilling,- Naformyl indole therefrom: H

The following example describesmne; wayin which :the principle .1 of *the invention. has; been applied; but, is notto;.beiconstruedeslimiting the ide was prepared. by a usual Grignardreaction 3 between 12.15"pa rts (0.5 atOmic'WeightYQf magnesium shavings and .5915 parts (0.55 mole) gof ethyl bromide in theipr esence of 107" parts'of diethyl ether.

A solution of '50. partsWOASmole) of indole in*71.4 parts of 'diethyl ether was addedf to the ethyl magnesiumbromide solution over a period of 'minutes while maintaining th-mix-*- ture in a closed-vessel at temperatures between" 20 and30' C. and withdrawing ethane-asit was formed .by'the reaction-which occurred. Introductiongof the indole'solution was discontinued-- when the evolution of ethane ceased. Approxiadded over a period of 30 minutes-to the ethereal solution of indole -magnesium" bromide thus formed and the resultant mixture was heated in an iron autoclave at a temperature of 95 Cffor-- 30 minutes. The mixture 'was allowedto stand overnight without further heating, after-which" the autoclave was opened: The mixture comprised .a hard reddish brow'n resinous' substance which has separated-irom the etherr Theeether was :poured from the :resinous substance and the of E-indole aldehyde and. N-zformyl-indole; The-" slurry was .treated: with ."88rparts aof-. :benzene and: the mixture-agitatedi treatment with henzeneiresulted in dissolvingoithe N-formyleindole: by thebenzene andzconcentration of the; -3-indo1e I aldehyde in solid: ;form; at athe interface of-the aqueous, and'in therbenzeneplayer. qThe aqueous layer wasseparated. and-the benzene layer-filtered to separate the 3indole aldehyde. JIhere: was obtained 25.5. parts,.or..41.per.oent of the ,theoretical yieid of 3-indole aldehyde. The benzene solution obtained as filtratejwas analyzed and found I to contain 25 parts, or a 40 per cent yield, of N-j' formyl indole;

Other modes of applying the principle of the invention may beemployed instead of those ex-- change -being-made as regards the plained,

method herein disc1osed, provided*the step or steps stated by anyof the following claims or the mately il parts (0.55 mole) of-ethyl formate'was' "'fihic hydrocarbon-'as it is formed, continuing the addition .until. .the-.,.gaseous hydrocarbon is no longer. evolved, adding to the resultant ethereal solutionofindole magnesium bromide between 0.8 and-'- molecular equivalents of an alkyl formate selected from the class consisting of methyl --formate and: ethyl .formate per moletof the indolemagnesium-bromide; heatingith'e emixi-i-il ture in a "closedwvessel and atvther-autogenous' pressure to "a :reaction' 'temperaturerbetweensfiO and' 120 C. ,'hydro1yzing:ther solid reaction; prod not to fOlm'3-indD1e'aldhydfiiand separatingzt latter;

'2. .The' meth0d,- as' 'described in" claim; 1, wherein;.:& the alkylzf'ormate is ethyl formate; between 1 and 1.5 molecular equivalentsof ethyliformatetis :em ployed pep; mol .of. indolei magnesium: bromide; and the reaction .ebetweem the .ind'ole magnesiuinari bromide 'fand' the ethyl formats is :carried outiatxi. a temperaturebetween-709and 1710?. c,

3. Ida method of imalringz'3-indole aldehydejsiv the steps .of. gradually adding indol'elto I an: ethe real solution :of an:alkyrmagnesiumubromide con-.1 taming not more: than fouraacarb'on atoms inithe alkyl radical awhile: withdrawing' gaseous araf-i 1.

'finic :hydrocarbonias'lit is formed: continuing'the addition" until tithegaseous hydrocarbon c is no longer, evolved; adding Y to the resulting. ethereal solution. *of :indo'le iimagn'esium; :bromide ;:'-betwe'en;; =1 0.8 :and I 2.5: :molecula'r equivalents, lzof van alk'ylix formate selected :from their class "consisting-x0111 methyl iormate and ethyl; formate :per2- mole -of the indole 'magne'sium i bromide, heating-the mix-.2 i ture in a closed vessel and at the autogen'ousa. pressure --to ;a reaction: temperature between 60 and @120 C.; thereafter: separatingv -a .resultan-t' solid product-: from; the ether;'3;hydrolyzing=-.the-.i product to form a mixture comprising: B-indol aldehyde and N -iormyl :indole; extracting-:the- -1at ter; from themiixture'witha liquid-aromatic hy drocarbon, and sfseparating B-indole; aldehyde-1 from the remaining mixture-a I i. The method which comprises-reacting indole 2 magnesium 1- bromjide with an :alkyL formats see- 1 lected frompthe class: consisting pf "methyland ethyl. .forma-tesw in the: presence. of diethyl setheri as a reaction .:-medium -by hea'ting the TCaCtiOHw? mixture in-a closed vessel at. the. autogenous pres-w sure to a reaction. temperature :between 1 60- ;-and.-- 120? C.

5. A method; as described: in :claim'3, wherein:- indole magnesium bromide and. between 0.8 i and; J 2.5 molecular.:equivalents I of ethyl .formate are. employed i as ,reactants. and theethereal reaction mixtureris heated-ma closed vessel to a reaction. A

.temperature-between7'70 and.1109 C.

-a reaction temperature-between..70 and. .C. I

EDGAR TCjBRITTONi '1 JOHN E. ZLIVAK.: JOHN 9C." VANDER'EWEEIDEL