SOME PHENOLIC DERIVATIVES OF P-PHENYLETHYLAMINE. 2253CCXXXVII.--Some Phenolic Dwivatives of P-Phenyl-et h y lamine.By GEORGE BARUER AND ARTHUR JAMES EWINS.~HYDROXY-P-PHENYLETHYLANINE, OH*C,H,*CB,*CH,*N.B,, whichis formed by the action of micro-organisms from tyrosine and fromproteins containing tyrosine, has been shown to have a pronouncedphysiological activity (Earger and Walpole, J. Physiol., 1909, 38, 343) ;it is, for instance, one of the active constituents of ergot extracts(Barger, Trans., 1909, 96, 1123).Since the effect of this base on the vascular system and on certainorgans is essentially similar to that of adrenaline (Dale and Dixon, J2254 BARGER AND EWINS: SOME PHENOLICPhysiol., 1909, 39, 25), to which phydroxy-P-phenylethylamine is alsochemically related, an examination of a considerable number ofsimilarly constituted amines was undertaken by Dale in order to traceas far as possible the connexion between physiological activity andchemical structure within the limits of this group (Barger and Dale, J.Physiol., 1910, 41, 19).The present paper deals with the synthesis of some of these amines.They were chosen for the following reasons :(1) Since the bactericidal action of phenol is greatly enhanced bythe introduction of a methyl group into the benzene ring (yieldingcresol), we prepared 3-methyl-4-hydroxy-P-phenylethylamine.Thepressor action of this base was found, however, to be only about onehalf as great as that of the parent substance.(2) One of the differences bet ween p-hydroxy-P-phenylethylamineand adrenaline (I) is that the former substance has only a singlephenolic hydroxyl group as compared with two in the latter substance.We therefore prepared 3 : 4-dihydroxy-P-phenylethylamine (11), whichwas found to be scarcely more active than the monophenolic aminealthough its N-methyl derivative, obtained by Pyman from an oxida-tion product of laudanosine (this vol., p.268), approximates muchmore closely to adrenaline.(3) Since in several cases the introduction of a second phenolichydroxyl group greatly increases the physiological activity of bases ofthis type, me wished to trace the effect of introducing yet anotherphenolic hydroxyl group, and for this purpose prepared 2 : 3 : 4-trih ydroxy-P-phenylethylamine (111) and o-aminoga ZZacet ophenone (I V).HO/'\HOI ICO*CH,*NH,OH HOHOf)HO\/CH,*CH,*NH, \/(111.) (IV. 1Both these bases were somewhat less active than the correspondingdihydroxy-bases (namely, 3 : 4 - dihydroxy - P - phenylethylamine ando-aminoacetylcatechol ).The close chemical relationship of the bases (I), (11), (111), and (IV) isfurther illustrated by the fact that they all give the colour reactionshitherto described as characteristic for adrenaline (I) (Ewins, J. Physiol,1910, 40, 317).The synthesis of 4 - h y d r o t t . y - P - m - t o l y ~ ~ t ~ y ~ a ~ ~ ~ ~ ~ started with m-tolyl-acetonitrile, and was completely analogous to t h a t of p-hydroxy-/3DERIVATIVES OF P-PHENYLETHYLAMINE. 2265phenylethylamine from phenylacetonitrile (Barger, Trans., 1909, 95,1123).3 : 4-Dihydroxy-p-phenylethylamine was obtained from its dimethylether, and has already been described by Mannich (Ber,, 1910, 43,196).The production of the pyrogallol bases (111 and IV) at first gaveconsiderable difficulty.The 2 : 3 : 4-trihydrosybenzaldehyde requiredfor (111) had to be prepared with anhydrous hydrogen cyanide accordingto Gattermann’s method. It was found impossible to obtain 2: 3 : 4-trimethoxy-P-phenylethylnmine from 2 : 3 : 4-trimethoxyphenylpropion-amide by Hofmann’s reaction, although this method was employed inpreparing the corresponding dimethoxy-base. We therefore had touse Curtius’s method, starting from 2 : 3 : 4-trimethoxyphenylpropionyl-h ydrazide.I n the case of o-aminogallacetophenone (IV) we found it quiteimpossible to isolate a pure substance when o-chlorogallacetophenonewas acted on by ammonia, although this method is employed technicallyin the case of w-chloroacetylcatechol ; the substance is destroyed tooreadily in alkaline solution.We therefore had recourse to an indirectmethod ; o-chlorogallacetophenone reacts readily with sodium azide,and from the o-triaxogallacetophenone, C6H2(OH)3*CO*CH2*N,, thusproduced the required amine is obtainable by reduction.I n the course of our work on this subject we have also pre-pared p-phenylethylmethylamine, C,H,-CH,*CH2*NH*CH3, of whichadrenaline is the trihydroxy-derivative. Two methods for preparingthis base will be mentioned, although it is not a phenolic amine, and wasrecently prepared by Johnson and Guest (Amer.Chem. J., 1909, 42,340) according to a third method (methylation of benzenesulphonyl-phenylethylamine and subsequent hydrolysis).EX PE a I Y ENTA L.p- Phenylethylmethylamine, C,H,*CH,* CH,*NH*CH,.As the direct methylation of P-phenylethylamine yields a quaternaryiodide, we condensed methylamine (in 33 per cent, aqueous solution)with phenylacetaldehyde by means of sodium hydroxide, and reducedthe crude condensation product, which separated out, with sodium andalcohol.A second, and more convenient, method consists in acting ona-chloro-P-phenylethane, C,H,*CH,*CH,CI (Barger, Trans, 1909, 95,2194), with an excess of a 33 per cent. alcoholic solution of methyl-amine at 100’ for several hours.The base thus obtained was distilled(b. p. 205O), and its hydrochloride was analysed. (Found, C1-20.7.Calc., C1= 20.4 per cent,)The base was isolated as the oxalate2256 BARGER AND EWINS: SOME PHENOLICPreparation of 4- Hydroxy-P-m-tolylethylamins,OH<\CW,*CH,*NH,. -/C'H,p-Nitro-m-tolylacetonitde, NO,/ \CH,.CN.-Ten grams ofm-tolylacetonitrile (Sehkowski, Molzatsh., 1888, 9, 854) were droppedinto 40 C.C. of nitric acid (D 1.5) at a temperature below - 5O. Theacid solution was then poured into water and extracted with ether.After washing with sodium carbonate, drying, and distilling, a fractionboiling at 201-205O/22 mm. was collected, which solidified, and oncrystallisation from ether and light petroleum melted at 52".Theyield was 80 per cent. of the theoretical :C= 61.2 ; H = 4.6.CH3-\/0.1584 gave 0.3554 CO, and 0.0665 H,O.p -Amino - m - tolylacetonitrile,CgH802N2 requires C = 61 *4 ; H = 4.5 per cent,NH,*C6H,Me*CH,*CN.-p - Nitro-m-tolylacetonitrile (19 grams) was dissolved in alcohol (240 c.c.), tin-foil (25 grams), and then gradually concentrated hydrochloric acid(120 c.c.) was added. The temperature was a t first kept below 60°,finally being raised to 100". After extraction with ether, the base wasdistilled, and 8.5 grams (60 per cent.) boiling at 175--185O/20 mm.were obtained. On crystallisation from benzene, the substance melteda t 8 7 O :0.1552 gave 0.4204 CO, and 000902 H,O.The hydrochloride, prepared by addiDg alcoholic hydrogen chloride to0.2082 gave 001620 AgCl.The oxalats melts a t 164-165' :0.1884 gave 24 C.C.N, (moist) at 20' and 768 mm.(CgH~oN2)2,H2C204 requires N = 14.7 per cent.p-Hydroxy-m-tolylacetonitrile, OH*C6H,Me*CH2*CN.-3*9 Grams ofsodium nitrite dissolved in ia little water were slowly added to a boilingsolution of 8.5 grams of the amino-compound dissolved in 200 C.C. ofdilute sulphuric acid (210 C.C. of water and 17 C.C. of concentratedsulphuric acid). On extracting the acid solution with ether, 2.5 grams(30 per cent.) of a substance were obtained, which distilled at162-164"/2 mm. and crystallised in the receiver. It crystailisesfrom benzene in leaflets melting a t 84" :C = 73.9 ; H = 6.5.C,H,,N, requires C = 74.0 ; H = 6.8 per cent.the ethereal solution of the base, melts at 247-248O :C1= 19.3.CSH,,N,,HC1 requires C1= 19.4 per cent.N= 14.7DERIVATIVES OF P-PHENYLETHYLAMINE. 22570.1526 gave 0.4093 CO, and 0-0807 H20.C = 73.1 ; H = 5.9.0-1718 ,, 14.2 C.C. Nz (moist) at 2 2 O and 760 mm. N= 9.4.C,H,ON requires C = 73.5 ; H = 6.1 ; N = 9.5 per cent.CH3L/ /-\CH2*CH2*NH2.-O*9 Gram 4-Hydroxy-/?-m-toZyZethyZamine, OHof p-hydroxy-rn-tolylacetonitrile yielded, on reduction with 4 grams ofsodium in boiling alcoholic solution, 0 -62 gram of a crude hydrochloride,which was crystallised by adding ether to its concentrated solution inalcohol. From this the free base was obtained; it crystallised fromxylene, and, after sublimation in a vacuum, melted at 132-133' :0*1290 gave 0.3364 CO, and 0-0910 H,O.CgHl,ON requires C = 71.5 ; H = 8.6 per cent.The hydrochloride was also analysed :0*1226 gave 0.0956 AgCl.C1= 19.3.C,H,,ON,HCI requires C1= 19.0 per cent.The dibenzoyl derivative crystallised from dilute alcohol in long,thin needles, melting a t 130-131°.The quaternary iodide, OH*C6H,Me*CH2*CH2*NMe,'T, was obtainedby boiling the base with a little methyl alcohol and a large excess ofmethyl iodide. It melts at 231-232O, and closely resembles hordeninemethiodide in solubility and other properties.4-Hydroxy-P-rn-tolylet hg lamine resembles p- hydroxy-P-phen yle thyl-amine in behaviour and derivatives.The physiological action of the former base is about one-half of thelatter. Both bases give Millon's reaction, but it is significant that,unlike phydroxy-P-phenylethylamine, the tolyl compound does notgive Morner's reaction (green coloration after heating with sulphuricacid and formaldehyde).It would appear that substitution in thephenolic ring prevents this reaction from taking place.C = 71-2 ; H = 7.9.Pveparation of 3 ; 4-Dihydro~-pphenyZ~thy~a~ine,HO<)HO\/C H,*CH,*NH,3 : 4-Dimethoxy-P-pheny IethyIamine was prepared from vanillinaccording to the method described in detail by Pictetand Finkelstein(Ber., 1909, 42, 1979), and 5.2 grams of the amine boiling at164-166'/13 mm. were obtained from 20.5 grams of homoveratricacid.The amine was hydrolysed by heating with ten parts of concentratedhydrochloric acid to 170° for two hours. The hydrochloride so obtainedcrystallised from 90 per cent.alcohol in glistening, almost colourles2258 BARGER AND EWINS: SOME PHENOLICplates, melting and decomposing at 240-2419 Yield, 45 per cent. ofthe theoretical. (Found, C = 50.6 ; H = 6.2. Calc., C = 50.7 ; H = 6.2per cent.The hydrobromide was obtained by heating the dimethoxy-amine to130' for two hours with ten times its weight of concentrated aqueoushydrobromic acid. The crystalline hydrobromide was obtained quitepure in the same manner as that employed in the preparation of thehydrochloride.0.1212 gave 0.0984 AgBr. Br = 34.5.CSH,,O2NBr requires Br = 34.2 per cent.The aqueous solution of the salts of 3 : 4-dihydroxy-/?-phenylethyl-amine gave an intense green coloration with ferric chloride.The quaternary chloride, C,H,(OH),*CH2*CH,*NMe,Cl, was pre-pared in order to compare its action with that of hordenine methiodide,OH-C6H4*CH,*CH2*NMe,I.The action of the two substances is verysimilar, like that of nicotine, and unlike that of adrenaline.3 : 4-Bihydroxy-~-phenyle~hyZtrimet~yla~nmonium chloride was ob-tained from 3 : 4-dimet hoxy -P-phenylethylamine. The quaternaryiodide obtained by treating the latter base with methyl iodide wastransformed into the chloride by digestion with silver chloride, andwas then hydrolysed by concentrated hydrochloric acid at 1 7 0 O . Onremoval of the latter, the residue crystallised from alcohol and ether,and melted at 201'.The salt crystallises in plates, melting a t 212O :Prepayation of 2 : 3 : 4-Trihydroxy-P-phelzylethylamine,C,H,(OH),*CH,*CH,*NH,.2 : 3 : 4-T&methoxybensaZdehyde, C6H,(OMe),*CH0.-This aldehydedoes not appear to have been described before, although F.Mauthner(Ber., 1909, 42, 188) has stated that it can be obtained from 2 : 3 : 4-trimethoxyphenylglyoxylic acid by the action of aniline, Themethylation of 2 : 3 : 4-trihydroxybenzaldehydo, which was preparedfrom pyrogallol and anhydrous hydrocyanic acid according to Gatter-mann and Kmbner's method (Ber., 1899, 32, 281), was carried out inan atmosphere of hydrogen by the method employed by Perkin andRobinson (Trans., 1907, 91, ,1079) for the preparation of Vera-traldehyde from vanillin, Twenty-five grams of 2 : 3 : 4-trihydroxy-benzaldehyde were dissolved in 80 C.C. of methyl alcohol, and to thissolution was added 24 grams of sodium hydroxide dissolved in theminimum quantity of water.The solution became very dark brownin colour. Eighty grams of methyl sulphate were then added, andwhen the vigorous reaction had nearly subsided, a further 66 grams insmall quantities alternately with small quantities of sodium hydroxidewere added a t such a rate that a vigorous reaction was maintainedDERIVATIVES OF &PHENYLETHYLAMINE. 2259The mixture was kept for half an hour, and then poured into 500 C.C.of water. An oil separated, which was extracted by means of ether,and, after drying and removal of the solvent, the residue was distilled,18.5 Grams of a colourless liquid, boiling at 168-170°/12 mm., werethus obtained. The distillate solidified after some time to a crystallinemass of long, thin needles, melting at 30" :0.1840 gave 0.4126 CO, and 0.1020 H,O.C = 61.1 ; H = 6.2,CloH1204 requires C = 61.2 ; H = 6.1 per cent.2 : 3 : 4-Trirnethoxy-/3-phertylpropionic Acid,C,H,(OMe),*CH,*CH,*CO,H.Twenty grams of 2 : 3 : 4-trimethoxybenzaldehyde were dissolved in35 grams of ethyl acetate, and the solution added to 3.3 grams offinely divided sodium contained in a large flask provided with a refluxcondenser. A vigorous reaction ensued. The product was kept forone hour, and then a solution of 14 grams of sodium hydroxide inmethyl alcohol was added. After the reaction had ceased, 250 C.C. ofwater were added. The alcohol was then removed by evaporation ona water-bath, water being added from time to time to avoid undueconcentration.The alkaline solution was then reduced by theaddition of 500 grams of 24 per cent. sodium amalgam in smallportions, concentrated hydrochloric acid being added from time to timeto neutraliso the excess of sodium hydroxide formed in the reaction.The resulting solution was filtered, and acidified with hydrochloricacid. A yellow oil separated, which slowly erystallised. The acidwas purified by distillation under diminished pressure (it boils at200-203°/2 mm.) and subsequent crystallisation from ether and lightpetroleum, from which it separated in clusters of prisms, melting at76". Yield, 50 per cent. of the theoretical :0.2150 gave 0.4722 CO, and 0.1282 H,O. C = 69.9 ; H = 6.6.CI2Hl6O5 requires C = 60.0 ; H = 6.7 per cent.Ethyl 2 : 3 : 4-Trimethoxy-~-phenylpropionat~,C,H2( OMe),*CH,*CH,* C0,Et.The acid obtained as above was converted into the correspondingethyl ester by dissolving in five times its weight of 5 per cent.alcoholichydrogen chloride and boiling under reflux for six hours. The alcoholand hydrochloric acid were evaporated off, and the residue wasdistilled. The ester boils at 200-201°/20 mm. Yield, 70 per cent. ofthe theoretical :0.2074 gave 0.4797 CO, and 0.1390 H,O. C = 63.1 ; H = 7.4.C1,H,oO, requires C = 62-7 ; H = 7.4 per cent2260 SOME PHENOLIC DERIVATIVES OF ,&PHENYLETHY LAMINE.2 ; 3 : 4-Trimethoxy-~-phenylpropion~Zhydrazide HydrochZoride,C,H2(OMe),*CH2*CH2*CO~NH*NH2,HCl,Two grams of the above ester mere gradually added to 0.6 gram ofboiling hydrazine hydrate.Solution was complete a t the end of onehour, and the solution was boiled under reflux for several hours longer.The excess of hydrazine was removed by evaporation in a vacuum oversulphuric acid. The syrupy residue could not be crystallised, but ondissolving in alcohol and adding a little alcoholic hydrogen chloride acrystalline precipitate separated, which was increased by the additionof ether. The hydrochloride thus obtained mas recrystallised from98 per cent. alcohol, separating in the form of hexagonal plates, whichmelted a t 155’ :0,1679 gave 0.3020 CO, and 0.0947 H20.The solution of this salt readily reduced ammoniacal silver in theCe49.0 ; H = 6.3.C,,HI,O,N,C1 requires C = 48.8 ; H = 6.5 per cent.cold, and Fehling’s solution on boiling.2 : 3 : 4-~rihydroxy-/3-phenylethylamine Hydroch Zoride,C,H2(0H),*CH2*CH2*NH,,H CI.The hydrazide obtained as described above was diazotised at Oo.The crude azide, obtained by extraction with ether, was converted intothe corresponding urethane derivative by boiling in absolute alcoholicsolution for twelve hours under reflux.The alcohol was then distilledoff, and the residue hydrolysed by heating in a sealed tube withconcentrated hydrochloric acid to 1 70-180° for three hours. Thevery dark-coloured contents of the tube were evaporated to dryness,dissolved in a little water, boiled with animal charcoal, filtered, andthe solution evaporated nearly to dryness. From the dark brownsyrupy product, crystals slowly separated.These mere pressed on aplate, and recrystallised from absolute alcohol by addition of ether.The crystals, which melted a t 162-163’, were still dark brown incolour. The aqueous solution gives with ferric chloride a deep purple-brown coloration, which rapidly fades :0*1000 gave 0*0700 AgC1. C1= 17-32.C8H,r0,NCl requires C1= 17.35 per cent.HO/\KOPreparation of o-Amilzogallucetop~~one, HOI ‘CO*CH2*NH2. \/o-Tria~ogallacetophanone, C6H2(OH),*CO*CH2*N,.-Seven grama ofo-chlorogallacetophenone, prepared according to Nencki’s methoTHE FORMATlON AND REACTIONS OF IMINO-COMPOUNDS. 2261(J. Buss. Phy8. Chem, Xoc., 1883, 25, 182), were dissolved in50 C.C. of hot water, and a hot solution of 2.5 grams of sodiumazide in a little water added, On cooling, a crystalline solidseparated. This was collected and recrystallised from xylene, whenrhomb-shaped plates, melting at 155O, were obtained. Yield, 50 percent. of the theoretical :0,2460 gave 44.2 C.C. N, (moist) a t 19O and 758 mm. N = 20.7.C,H70,N, requires N = 20.1 per cent.o- A rninog allacet ophenone Hydrochloride,C,H,( OH),*CO* CH,*NH,, HCl.-Five grams of w-triazogallacetophenone were dissolved in absolutealcohol. Ten grams of tin-foil were then placed in the liquid, and60 C.C. of concentrated hydrochloric acid added in small portions. Asreduction proceeded, the hydrochloride of the base separated out insmall, rectangular plates. The yield was 1.2 grams, or 25 per cent. ofthe theoreticalFor analysis, the salt was recrystallised from alcohol and ether, whenit melted at 259-260' :0.1916 gave 10.8 C.C. N, (moist) at 17O and 754 mm.0.1275 ,, 0*0838 AgC1. Cl= 16.2 ; N= 6.5.C,H,,O,NCl requires N = 6.4 ; C1= 16.1 per cent.The salt is readily soluble in water ; i t aqueous solution darkens onkeeping, and with very dilute ferric chloride solution gives a dirtygreen coloration, which rapidly changes to a brownish-yellow.THE WELLCOME PHYSIOLOGICAL RESEARCH LABORATORIES,HERNE HILL, S.E