264 PYMAN : ISOQUINOLINE DERIVATIVES. PART I\*.XXV~II.-isoQuinoli-I~c Deriva.tives. Part I V. ortho-Dih yd roxy-bases. The Cowvemion o f I -Keto-6 : ~ - d i m e t J ~ o x y - ~ - a l k . y l t e t c l . a h y d ~ ~ o ~ ~ o ~ ~ ~ ~ iw!o3 : 4 - D ih yd roxyplzcn y letl~y Zalky Zanaines.By FRANK LEE PYMAN.IN the preceding papers of this series (Trans., 1909, 95, 1266, 1610,1738) a number of 6 : 7-dimethoxgisoquinoline derivatives have beendescribed. Some of these proved t o be physiologically antivesubstances, and it was thought likely that the corresponding G : 7-di-hydroxy-bafies might be compounds of still more marked physiologicalaction.I n particular, it seemed possible that compounds of this type, such,for instance, as 6 : 7-dihydroxy-2-methyl-3 : 4-dihydroisoquinoliniumchloride (I), might praduce a pressor effect similar to thnt caused bPYMAW : ISOQUIXOLINE DERIVATIVES.PART 1V. 265p-3 : 4-trihydroxyphenyleth ylmethylamine (IT), the laevo-modification ofwhich is the active principle of the suprarenal gland, since they mouldbe in some respects similarly constituted :(1.1 (11.)With this object in view, several dimethoxyisoquinoline derivativeshave been converted by treatment with hydrochloric acid into thecorresponding dihydroxy-bases, which were then submitted tophysiological examination, but in no case where the isoquinoline ringremained intact had the resulting dihydroxy-base any marked pressorproperties. It was found, however, that the 1-keto-6 : 7-dimethoxy-2-alkyltetrahydroisoquinolines, when treated with hydrochloric acid a ta sufficiently high temperature, gave rise to bases of considerable pressorproperties, in which the isoquinoline ring was no longer preserved.1 -ket 0-6 : 7 - d i methox y-2 - met h yl tetrah y droisoquinoline(111) is heated with hydrochloric acid under pressure for three hoursat 175O, it is quantitatively converted into the hydrochloride of3 : 4-dill~yd~~oxyp7~snyZet~~ylmethyZanaine (VII).By working at tempera-tures lower than 175", however, two immediate products, 7(or 6)-hydroxy-l-kato-6(or 7)-methoxy-2-methyZtetrcthydroisoquinoZi~~e (IV) and6 : 7 - dihydroxy - 1 -&to - 2 - methyltetrahydroisoquinoline (V), may beisolated, and it is therefore evident that the mechanism of the changeat 175" consists in the successive hydrolysis of the two methoxylgroups, followed by hydration of the lactam, forming the correspond-ing amino-acid (VI), and subsequent decomposition of the latter intocarbon dioxide and the amine.The course of the reaction maytherefore be represented by the following scheme :Thus, whenCH2 CH,MeO/\/\CH, -+ Me H 1 \Ol O'\/\CH2 ' "Me --+ 31eob\, coCO\/A/ I lNMe(111.) (IV.)CH,(VII.266 PYMAN : ISOQUINOLINE DERIVATIVES. PART IV.It may be pointed out that the ring fission illustrated above isprecisely similar to that occurring in the formation of 8-aminovalericacid from a-piperidone (Schotten, Her. 1888, 21, 2242), whilst theloss of carbon dioxide from the resulting acid is a not uncommonproperty of hydroxybenzoic acids when ixnder the influence of hydro-chloric acid a t a high temperature. Proof of the presence of animino-group in the final product is afforded by the fact that it yieldsa neutral triacetyl derivative,CGHs( CH,*CO,),*CH,*CH,*N Me*CO*OH,.It was found that on increasing the size of tho alkyl group on thenitrogen atom, the ring fission and subsequent elimination of carbondioxide took place with greater difficulty ; thus, under the conditions(three hours at 175') which sufficed to convert I-keto-6 : 7-dimethoxy-2-methyltetrahydroisoquinoline almost completely into 3 : 4-dihydroxy-phenylethylmethylamine, the ethyl and propyl homologues were onlypartly converted into the corresponding 3 : 4-dihydroxyphenylethyl-alkylamines, the former giving 30 per cent.and the latter 79 per cent.of the theoretical yield of the corresponding 6 : 7-dihydroxy-1-keto-2-nl ky ltetrahy droisoquinoline.The similarity of structure between the 3 : 4-dihydroxyphenylethyl-alkylamiiies and p-3 : 4- trihydroxyphenylethylmethylamine (VIII) isobvious ; 3 : 4-dihydroxyphenylethylmethylamine (IX), in fact, differsonly from this valuable drug in being devoid of the alcoholic hydroxylgroup.The physiological action of this compound (and of the othersmentioned in this paper) has been examined by Dr. H. H. Dale of theWellcome Physiological Research Laboratories, to whom the author isindebted for the following report :3 : 4-DihydroxyphenylethylmethyIamine has the characteristicsuprarenal action in a high degree, being the nearest in action to thetrue active principle of any of the large series of related substanceswhich Dr.Dale has now examined; qualitatively there is littledifference in the action of the two on organs innervated by sympatheticnerves. The characteristic rise of blood-pressure ; acceleration andaugmentation of the heart's action ; contraction of the pregnant andinhibition of the non-pregnant uterus of the cat ; dilatation of thepupil; secretion of saliva-all are produced. A 1 in 1000 solutionproduced marked and sustained pallor of the conjunctival mucousmembrane when instilled into the eye.Quantitatively, by finding doses which produce rises of bloodPYMAK : ISOQUJNOLINE DERIVATIVES. PART IV. 267CH/+COpressure t o equal submnximal heights,* Dr. Dale has found that 3 : 4-dihydroxyphenylethylmethylamine has an activity approximately one-seventh of that of racemic @-3 : 4-t~rihydroxyphenylethylmethylamine,or one-tenth of that of the naturally-occurring lsvo-modification.The corresponding ethyl- and propyl-amines behave in a similarmanner, but to a lees extent, the ethylamine having about one-thirdand the propylamine less than one-twentieth of the activity of themethylamine.?The valuable properties of 3 : 4-dihydroxyphenylethylmefhylaminesuggested -the preparation of a trih ydroxyphenylethylmethylamine,and it was proposed to prepare such a compound by nitrating l-keto-6 : 7-dimethoxy-2-methyltetrahydroisoquinoline, reducing the nitro-compound, substituting a hydroxyl for the amino.group in the usualway, and decomposing the product with hydrochloric acid.Thissynthesis seemed a priori promising, since Freund ( B e y , , 1587, 20,2406) has described a nitro-oxyhydrastinine obtained by the action ofwarm dilute nitric acid on oxyhydrastinine. Unfortunately, theaction of this reagent on l-keto-6 : 7-dimethoxy-2-methyltetrahydroiso-quinoline (X) consisted not only in nitration, but also in simultaneousoxidation, two atoms of hydrogen being removed with the formationof a bright yellow nitro-compound having the formula C,,HI20,N,.This proved t o be 5(or S)-nitro-l-keto-6 : 7-dimethoxy-2-methyl-2 : 2-dihydroisoquinolinze$ (XI or XII), for it was readily obtained bynitrating 6 : 7-dimethoxy-N-methylisoquinolone (XIII) (l-koto-6 : 7CHMeO/\/\CHMeOl I "Me \/\/NO, coi NO., CH I NO, CH\/\/CH2MeO/\/%HMe01 I INMe OrUO C268 PYMAY : ISOQUTNOLINE DERIVATIVES.PART IV.dimethoxy-%met hyl-1 : ~-dihydroisoqlxinolin~), a compound preparedby Decker rand Pschorr (Rev., 1904, 37, 3401) by the oxidation ofN-met hy lisopapaverine.No further investigation of this compound was made, since 1-keto-2-alkyl-1 : 2-dihydroisoquinolines do not appear to become converted intophenylethylenealkylnmines under the influence of acids a t high tem-peratures ; thus, 1-keto-2-methyl-1 : 2-dihydroisoquinoline can be quanti-tatively recovered unchanged after heating with hydrochloric acidunder pressure for two hours at 1709Reference has already been made to the preparation of dihydroxy-bases containing the isoquinoline ring ; them are readily obtained ingood yield by the action of hydrochloric acid at 175O on the corre-sponding dimethoxy-compounds ; 6 : 7-dihyd~oxy-2-methyZtetrah ydro-isoquinoline (XIV) and 6 : 7-dihydroxy-2-methyl-3 : 4-dihydroiso-puinolinium chlovide (XV) have no decided physiological action :On tEe addition of sodium carbonate to a solution of the lattercompound, the phenolbekzine of the corresponding isoquinoliniumhydroxide is obtained.This compound has one of the two formulze(XVI) or (XVII), but no attexpt has been made to determine(XVI.) (XVI J. )which of the two is correctt, although for the purpose OF furtherdiscussion the former has been arbitrarily adopted throughout thiscommunication.This base exhibits the characteristic properties of phenol betaines(compare Decker and Dunant, Annden, 1908, 358, 396), amoagstothers that of forming the iodide of the corresponding methoxy-compound, 7(or 6)-hydroxy-6(or 7)-methoxy-2-methyZ-3 : 4-dihydroiso-puinolinum iodide (XVIII), when heated with methyl iodide.Atthe same time, a compound (XTX) of the latter with one moleculeof the phenolbetaine is found in accordance with the followingscheme PYMAK : ISOQUIKOLINE DERIVATIVES. PART 1V. 269(XVI.) (XVIII.)HO/\/\CH, MeO/\/\CH,01 ! "Me1 * HOI I jNMe-CH(XIS).CH, CH2\/\/ \/\/CHThis compound may be crystallised unchanged, and can be convertedinto the chloride by means of silver chloride, and crystallised assuch without breaking down, but is readily decomposed by hydr-iodic acid, the compounds from which it was formed being repro-duced.Mixed external phenolbetaines of this type do not appear tohave been previously observed, but simple external phenolbetaines ofthe type HO*RiN-O-RiNI have been obtained by Griess (Ber., 1880,13, 246) and by Claus and Hotvitx (J. pr. Chem., 1890, [ii], 42, 223)and their collaborators by the action of ammonia on substituted ammo-nium iodides of the type HOoRiNI ; a simple external phenolbetaine(XX) of this typo can be similarly obtained from 7(or 6)-hydroxy-6(or 7)-methoxy-2-methyl-3 : 4-dihydroisoquinoliniurn chloride (XVIII).Me0 '\I/)CH, a1 eO/\/\CH,CH2 CH,\/\/ 0) 1 IN3leCl' €10' NMe----CH\/\/CH(SX.)E x P E R I MENTAL.1 - Keto-6 : 7 -dimthoxy- 2 -nteth y Zte trah ydroiso pinoline.By the method of preparation of this compound by simultaneousoxidation and reduction of 4 : 5-dimethoxy-2-/3-methylaminoethylbenz-aldehyde (Trans., 1909, 95, 1272), only one-half of the originalmaterial is transformed into the above substance.It can, however,be prepared in almost theoretical yield from the same material bythe method devised by Freund (Bet-., 1889, 22, 457) for the conver-sion of hydrastinine into oxyhydrastinine, namely, by oxidation bypermanganate in the presence of alkali.Two grams of 6 : .7-dimethoxy-2-methy1-3 : 4-dihydroisoquinoliniumchloride were dissolved in 180 C.C. of water, rendered alkaline by theaddition of 20 C.C.of 10 per cent. aqueous sodium hydroxide, an270 PYMAN : ISOQUINOLINE DERIVATIVES. PART IV.mixed with a solution of 0.8 gram (a slight excess) oE potassiumpermanganate in 20 C.C. of water, After one hour, the solutionwas filtered from manganese dioxide, neutralised with dilute sulphuricacid, evaporated to low bulk, and extracted with ether. Afterevaporation of the solvent, 1.4 grams of pure 1-keto-6 : 7-dimethoxy-2-methyltetrahydroisoquinoline mere obtained, that is, 96 per cent.of the theoretical,To the description of this compovnd previously given (Zoc. cit.), thefollowing way be added. It can be distilled under diminishedpressure without decomposition, and passes over as a nearly colourlessoil, which solidifies on cooling, a t 24Qo(corr.)/16 mm.It is easily soluble in water, but, on agitating a strong aqueoussolution, an unstable hydrate separates as a mass of silky needles,which are sparingly soluble in water.When this bydrate is collectedand dried for half an hour on porous porcelain, it melts indefinitely a t40-70°, but on exposure to air for twelve hours becomes anhydrous,has the melting point 126' (corr.) of the anhydrous base, and is, asbefore, easily soluble in water.&(or 8)-Nitro-l-keto-6 ; 7-dimethoxg-2-methyZ-1 : 2-dihydroisopuitzoline(XI or XII, p. 267).Ten grams of 1 - ke to- 6 : 'I-dirne t hox y -2 -me t h y 1 te t rnhydroisoq uinolinewere dissolved in a solution of 10 grams of concentrated nitric acid in30 C.C. of water and heated on the water-bath. The liquor quicklybecame brown, and then effervesced vigorously with evolution of brownfumes, whilst a quantity of yellow needles continuously separated out.After a few minutes, the liquor was cooled, filtered from the separatedcrystals, and again heated, this time over a free flame, when a furtherquantity of crystals were obtained j these operations were againrepeated after the addition of another 5 C.C.of concentrated nitricacid, until no further quantity of the crystalline compound could beobtained.5 (or 8)-Nitro-6 ; 7-dimethoxy-2-methyl-1:: 2-dihydroisoquinoline crystal-lises from glacial acetic acid in fine bright, canary-yellow needles,which begin to soften at about 240' and melt at 244-245O (corr). Itis easily soluble in chloroform, fairly easily so in boiling glacial aceticacid or xylene, but almost insoluble in water or the other usual'organicsolvents :The total yield amounted to 6.4 grams.0*1521 gave 0.3032 CO, and 0.0641 H,O.C1,H1,O,N, requires C = 54.5 ; H = 4.6 per ccut.Like Freund's '' nitro-oxyhydrastinine " (Zoc.cib.), it is insoluble indilute acids or weak alkalis, but dissolves in warm aqueous sodiumC=54.4 ; H=4*7PYMAN : ISOQUINOLINE DERIVATIVES. PART IV. 271hydroxide, and is reprecipitated in a gelatinous form on the additionOF dilute acids.The same nitro-compound is readily obtained by warming 1 gram of1-keto-6 : 7-dimethoxy-2-methyl-1 : 2-dihydroisoquinoline with a mix-ture of 1 C.C. of concentrated nitric acid and 3 C.C. of water; theidentity of the product of this reaction with that described abovefollows from the fact that the two products and a mixture of both meltat the Eame temperature.7( or 6)-Hydroxy-l -keto-6 (or 7) -methoxy2 methgltetraiiydroiso-puinoline (IV, p.265).Five grams of 1 -keto-6 : 7-dimethoxy-2-methyltetrahydro~soquinolineand 30 C.C. of concentrated hydrochloric acid were heated togetherunder pressure for two hours at 130-135O. The product consisted ofa pale brown liquor containing a mass of cream-coloured needles, whichformed the hydrochloride of the new base. The solid matter wascollected, dissolved in a little hot water, and, after some time, 3.2grams of the base separated in spear-like crystals, which melted at200-208°, but contained some quantity of the dihydroxy-base, sincethey gave a green coloration with aqueous ferric chloride.After recrystallisation from absolute alcohol, 7(or 6)-hydroxy-l-ke to-6(or 7)-methoxy-2-methyltetrahydroisoquinoline forms colourless,glistening, diamond-shaped plates, which soften from ZOO0, melt at 210'(corr.), and give no coloration with aqueous ferric chloride :0.1529 gave 0.3562 CO, and 0.0864 H,O.C = 63.5 ; H = 6.3.0.1555 ,, 0.3635 CO, ,, 0.0880 H20. C=63*8 ; H= 6.3.C,,H,,O,N requires C = 63% ; H = 6.3 per cent.This compound is very sparingly soluble in cold water, sparingly soin hot water or cold alcoho1,readily so in hot alcohol, and sparinglyor very sparingly so in the other usual organic solvents. It is in-soluble in dilute acids, but soluble in aqueous sodium carbonate orammonia, and dissolves readily in aqueous sodium hydroxide, forming asodium salt which may be obtained as a crystalline mass by evaporatingthe solution to a very small bulk in a vacuum over sulphuric acid;this salt is very easily soluble in water or alcohol.6 : 7-Dih~drox~-l-ke~o-2-methyltetrahydroisoquinoline (V, p.265).Ten grams of 1-keto-6 : 7-dimethoxy-2-methyltetrahydroisoquinolineand 60 C.C. of concentrated hydrochloric acid were heated togetherunder pressure for three hours at 145-150'. The product consistedof a pale brown liquor containing pale brown needles; the latter werecollected and digested successively with warm water and a littl272 PP MAN : ISOQUINOLINE DERlVATlVES. PART IV.boiling alcohol. The residue amounted to 3.4 grams of nearly puredihydroxy-compound, and the alcohol deposited further small quantitiesof this compound.6 : 7-Dihydroxy-1-keto-2-methyltetrahydroisoquin-oline crystallises from absolute alcohol in beautiful colourless grains,which show a large number of sharply cut faces. I t begins to sinterat about 250°, and melts at 279' (corr.) :0.1504 gave 0.3400 GO, and 0.0788 H20.001555 ,, 10.2 C.C. N, at 25' and 768 mm. N = 7.4.This compound is sparingly soluble in boiling water or alcohol, andalmost insoluble in these solvents when. cold. It is insoluble in diluteacids, but easily soluble in aqueous ammonia, sodium carbonate, orsodium hydroxide, Forming ' yellow solutions which gradually darkenon exposure to air, Aqueous suspensions of this substance give, withferric chloride solution, a faint green coloration, which graduallydevelops to deep green as the substance dissolves.C = 61.7 ; H = 5.9.CloH,103N requires C = 62.1 ; H = 5.8 ; N = 7.3 per cent.3 ; 4-Dih~yd.roxyphenylethylmeth~lamine (VII, p.265).Ten grams of 1-lreto-6 : 7-dimethoxy-2-methyltetrahydroisoquinolineand 60 C.C. of concentrated hydrochloric acid were heated togetherunder pressure for three hours a t 170-175'.* The acid was thenremoved by distillation under diminished pressure, and the resultingslate-grey crystals of 3 : 4-dihydroxyphenylethylmethylamine hydro-chloride were washed with acetone. The yield amounted to 8.5 grams,that is, 92 per cent. of the theoretical, and the crude product waspurified by cry stallisation from water containing sulphurous acid.3 : 4-Dihydroxyphenylethyllnet~ykan~ine is liberated in a crystallineform on the addition of ammonia to an aqueous solution of the hydro-chloride.It crystallises from absolute alcohol in colourless clusters oftransparent spikes, which melt at 188-189O (corr.). It is sparicglysoluble in cold water, more easily so in hot water, sparingly so inboiling alcohol, and very sparingly so in cold alcohol and the usualorganic solvents :0.1524 gave 0.3611 CO, and 0.1090 H20.0.1567 ,, 11.0 C.C. N2 at 17" and 778 mm. N = 8.3.C,H130,N requires C = 64.6 ; H = 7.9 ; N = 8*4 per cent.Aqueous solutions of the salts of this base give with ferric chloridesolution a deep emerald-green coloration, which becomes orange-brownon the addition of aqueous sodium carbonate; such solutions reducewarm aqueous silver nitrate and boiling Fehling's solution ; they giveno precipitate with aqueous picric acid.* On opening the tube, a large volume of gases containing a quantity of carbondioxide escaped.C = 64.6 ; H = 8.0PYMAN : ISOQUINOLINE DERIVATIVES.PART IV. 273The hydrochZo?*ide crystallises from water in long, colourless prisms,which melt at 179-180O (corr,), This salt is anhydrous, and is easilysoluble in water or hot alcohol, but somewhat sparingly so in coldalcohol :0.1505 gave 0.2944 CO, and 0.0939 H,O. C = 53.3 ; H = 7.0.0.1843 ,, 0.1281 AgCI. C1=17*2.C,H,,O,N,HCl requires C = 53.1 ; H = 6.9 ; C1= 17.4 per cent.The sulphate cry stallises from water in colourless, transparent prisms,which melt to a brown liquid at 289-290' (corr,), after commencingto soften and turn brown several degrees earlier.This salt isanhydrous, and is somewhat sparingly soluble in cold water :0.1524 gave 0.2779 CO, and 0.0905 H20.(C,Hl,02N),,H,S04 requires C = 50.0 ; H = 6.5 per cent.The oxalate separates from water i n colourless, hexagonal plates,which melt a t 194-195O (corr,). This salt is anhydrous, and issparingly soluble in cold water :C=49*7; H=6*6.0.1524 gave 0.3168 CO, and 0,0938 H,O. C = 56.7 ; H = 6.9.(C,H130,N),,C,H,04 requires C = 56.6 ; H = 6.7 per cent.3 : 4- Diacetoxy-N-acet~l~henylethylmeth~Z~~~n~,(CH3*C0,),C,H3*CH2*CH2*NMe*CO*CH,.Two grams of 3 : 4-dihydroxyphenylethylmethylamine hydrochloride,5 grams of fused sodium acetate, and 20 C.C.of acetic anhydride wereboiled for half an hour under a reflux condenser. The product wasstirred into 100 C.C. of water, the resulting clear solution renderedalkaline with sodium carbonate, and extracted with ether. On dis-tilling the ether to low bulk and setting aside, 2.1 grams of the purecompound crystallised out, and a further small quantity was obtainedfrom the mother liquor.3 : 4-Diaicetoxy-N-acetylphen~ZethyZmethyZamine crgstallises from abso-lute alcohol in shimmering, hexagonal, monoclinic plates, which softenat 11 1" and melt a t 113-1 14O (corr.). I t is very sparingly solublein water or dilute acids, but dissolves slowly in dilute aqueousammonia or sodium hydroxide, giving respectively greenish-yellow andstramberryred solutions.It is sparingly soluble in cold alcohol orether :0.1728 gave 0-3895 CO, and 0.1006 H,O.0.1522 ,, 6.1 C.C. N, at 21' and 775 mm. N = 4.7.C = 61.5 ; H = 6.5.C,,H,,O,N requires C = 61 *4 ; H = 6.5 ; N = 4.8 per cent,VOL. XCVII. 274 PYMAN : ISOQUINOLINE DFRIVATlVES. PART IV.Action of HydroclJoric Acid at 175" on I -Keto-6 : 7-dimethoxy-2-etl~yl-tetrahydroisoquinoline.Four and a-half. grams of 1-keto-6 : 7-dimethoxy-2-ethyltetrahydro-isoquinoline and 30 C.C. of concentrated hydrochloric acid were heatedtogether under pressure for three hours at, 1'75'. The resulting clearbrown liquor was evaporated to dryness under diminished pressureand dissolved in 15 C.C. of water, when 0-8 gram of 6 : 7-dihydroxy-1-keto-2-ethyltetrahydroisoquinoline separated in pale brown crystals ;after removing these, the process was repeated, when a furtherquantity of 0.4 gram of the same product was obtained.The motherliquor gave on evaporation 3 : 4-dihydroxyphenylethylethylaminehydrochloride, of which 1.5 grams were obtained in a pure. form bycrystallisation from water.6 : 7-DiT~~d~~ox~-l-ksto-2-e~?~yltetra?~ydroisoqzlinoline,CH2HO(\/\CH,HOv()NEtcoThis compound crystallises from absolute alcohol in beautifullycrptalline rods, which begin to sinter at about 200°, and melt a t214-218' (corr.). Its chemical properties and solubilities aresimilar t o those of the methyl homologue, with the exception of itssolubility in absolute alcohol, which is greater :0.1524 gave 0.3573 CO, and 0.0866 H20.C = 63.9 ; H = 6.4.CllH,,O,N requires C = 63.8 ; H = 6-3 per cent.3 : 4-Dihydroxyphenylthylethylamine,HO/)CH,*CH2=NHEtHOI \/The hydrochloride crystallises from water in prismatic needles,which melt a t 177-17S0 (corr.). Its chemical properties and solu-bilities are similar to those of the methyl homologue, except that itsaqueow solution does not yield a precipitate of the corresponding baseon the addition of ammonia :0.1519 gave 0.3057 CO, and 0.1024 H,O. C=55*0; H=7.6.0.1819 ,, 0.1239 AgC1. C1=16*8.C1,H,,02N,HCl requires C = 55.1 ; H = 7.4 ; Cl = 16.3 per centPPMAh' : ISOQUINOLINE DERIVATIVES. PART 1V. 275Action of Hydrochloric Acid at 175' on 1-Keto-6 : 7-dimethoxy-2-propyl-letrahydroisoquinoli?ze.Two grams of 1-keto-6 : 7-dimethoxy-2-propyltetrah ydroisoquinolineand 15 C.C.of concentrated hydrochloric acid, heated together underpressure for three hours a t 175', and worked up as in the precedingcase, gave 1 *4 grams of 6 : 7-dihydroxy-1 -keto-2-propyltetrahydrobo-quinoline and 0 +4 gram of 3 : 4-dihydroxyphenylethylpropylaminehydrochloride.6 : 7 -Bih ydroxy-l -keto- 2-propyltetrahydroisopuinolin e,CH2HOA/\CH,\/\/ HOI 1 INPr'GOThis compound separates from absolute alcohol in oblong, rect-Its chemical pro- angular plates, which melt at 184-185' (corr.).perties and solubilities are similar to those of the ethyl homologue :0,1548 gave 0.3677 CO, and 0,0959 H,O. C = 64.8 ; H = 6.9.U12H,503N requires C = 65.1 ; H = 6.9 per cent.3 : 4 -Dih y drox yplielz yleth y lprop y lamine,The hydrochloride crystallises from water in clusters of transparent,irregular prisms, which melt a t 184-185' (corr,), Its chemicalproperties and solubilities are similar t o those of the ethyl homologue :0-1540 gave 0*3200 CO, and 0.1091 H20, C = 56.7 ; H = 7.9.C,,HI7O,N,HC1 requires C r= 57.0 ; H = 7.9 per cent.G ; 7-Dihydroxy-2 -met?b y Ztetrah ydroisoquino Zine (XIV, p.2 6 8).Eight and a-half grams of 6 : 7-dimethoxy-2-methyltetrahydroiso-quinoline hydrochloride (containing 3 molecules of water of crystal-lisation) and 30 C.C. of concentrated hydrochloric acid were heated ina sealed tube for five hours at 170'. On cooling, 4.7 grams of6 : 7-dihydrouy-2-methyltetrahydroi~oquinoline hydrochloride separatedin grey needles, that is, 76 per cent.of the theoretical.6 : 7 - Dih ydroxy-2-meth yltetrahydroisoquinoline separates on theaddition of sodium carbonate to an aqueous solution of tbe bydro-chloride. It crystallises from water in nearly colourless (pale buff)T 276 PYMAN : ISOQUINOLINE DERIVATIVES. PART IV.needles, which melt at 221-222' (corr.), and contain one molecule ofwater of crystallisation. It is very sparingly soluble in water and theusual organic solvents.Aqueous solutions of its salts give with ferric chloride a deep greencoloration, which becomes mauve on the addition of sodium carbonate.They reduce hot silver nitrate and also boiling Fehling's solution :C = 67.1 ; H = 7.4.0.1833" lost 0.0172 at 100'.0.1500 ? gave 0.3693 CO, and 0.0987 H20.H20=9'4.C,,H,,O,N,H,O requires H20 = 9.1 per cent.C1,H1,02N requires C = 67.0 ; H = 7.3 per cent.The hydrochloride crystallises from water in coloi~rless needles, whichIt is fairly easily soluble in are anhydrous and melt at 27'7' (corr.).water, but sparingly so in alcohol :0.1522 gave 0.3093 CO, and 0.0937 H20.C = 55.4 ; H = 6.9.0.1731 ,, 0.1144 AgCl. C1= 16.4.CloHl,02N,HCl requires C = 55.7 ; H = 6.6 ; C1= 16.4 per cent.The picrate crystallises from alcohol in transparent, yellow, monoclinic(hexagonal) plates, which melt at 191-192' (corr.).Phenolbetaim of 6 : 7-Dihydroxy-2-methyl-3 ; 4-dihydroisoquinoliniumHplyoxide (XVI or XVII, p. 268).Ten grams OF 6 : 7-dimethoxy-2-methyl-3 : 4-dihydroisoquinoliniumchloride and 60 C.C.of concentrated hydrochloric acid were heatedtogether under pressure for four hours at 170". The product wasevaporated to dryness under diminished pressure, and the crystallineresidue well washed with acetone. 6.5 Grams of nearly pureanhydrous 6 : 7-dihydroxy-2-methyl-3 : 4-dihydroisoquinolinium chloridewere obtained, the yield thus amounting to 93 per cent. of thetheoretical.The phenolbetaine of 6 ; 7-dihyd~oxy-2-methyl-3 : 4-dihydroisoquino-Zinium hydroxide separates in long, deep yellow needles containing oneand a-quarter molecular .proportions of water oE crystallisation on theaddition of the calculated quantity of aqueous sodium hydroxide, or anexcess of sodium carbonate to a strong solution of its chloride :0,1816 * lost 0.0201 at 100'.C1,Hl102N, 1 $H,O requires H,O = 1 1-3 per cent.After recry stallisation from moist alcohol it forms deep yellow,monoclinic plates, which melt to a reddish-black liquid, decompose at322' (corr.), and contain 1 molecule of water of crystallisation :H,O= 11.1.0.1543 * gave 0,2667 CO, and 0.0746 H20.C = 61.5 ; H = 7.0.* Air-dried. t Dried at 100"PYMAN : ISOQUINOLINE DERIVATIVES. PART IV. 2770.1380 * gave 0.3096 CO, and 0.0839 H20.CloHl,O,N,H,O requires C = 61 *5 ; H = 6.8 per cent.0.1388 t gave 0.3448 CO, and 0.0795 H20.CloHllO,N requires C = 67.8 ; H = 6.3 per cent.The phenolbetaine crystallises from absolute alcohol in anhydrous,yellowish-brown, serrated spikes, which have the same melting point asthe hydrated base, is moderately easily soluble in cold water, no$ moreso in aqueous sodium carbonate or ammonia, but readily in diluteacids or aqueous sodium hydroxide.It is rather sparingly soluble incold alcohol or chloroform, and very sparingly so in the other usualorganic solvents. Aqueous solutions of its salts give with aqueousferric chloride a deep green coloration, and on the subsequent additionof sodium carbonate yield a pale reddish-brown suspension, the super-natant liquor appearing a dull yellow after the settlement of the ferrichydroxide. Aqueous solutions of the salts of this base reduce hotsilver nitrate, but do not reduce Fehling's solution even on boiling.The chloride crystxllises from moist acetone in primrose needles,which contain one and a-half molecular proportions of water ofcrystallisation.After drying at looo, this salt melts and decomposesat 276' (corr.). It is easily soluble in water, but sparingly so inalcohol :C = 61.2 ; H = 6.8.C = 67.7 ; H = 6.4.0.4060, air-dried salt, lost 0.0437 at 100".0-1468 T gave 0.3019 GO, and 0.0743 H,O.0.1593 t ,, 0*1081 AgC1. C1= 16.8.The picrate crystallises from alcohol in yellow, transparent, irregularplates, which melt and decompose at 236' (corr.).The sodium salt separates in clusters of beautiful crimson needles onthe addition of alcohol t o a solution of the phenolbetaine in thecalculated quantity of 2N-aqueous sodium hydroxide. It is easilysoluble in water or alcohol.This salt contains 6 molecules of waterof crystallisation, of which five are lost after prolonged heatingat 120':H20 = 10.8.C,oHl,0,NC1,1~H20 requires H,O = 11.2 per cent.C = 56.1 ; H = 5.7.Cl,Hl,O,NC1 requires C = 56-2 ; H = 5.7 ; C1= 16.6 per cent.0.2530 * gave 0.0562 Na,SO,. Na = 7.2.0.2541 * lost 0.0763 at 120". H,O = 30.0.C,oHl,0,NNa,6H,0 requires Na = 7.5 ; loss of 5H,O = 29.3 per cent.Action of MethTlyZ Iodide on the Phenot?betatim of 6 ; 7-Bihydroxy-2-nzethyZ-3 : 4-dil~ydroisoq~ino~~n~~m Hydroxide.Eight grams of the phenolbetaine, which had been dried for sometime a t loo", were heated together with 16 grams of methyl iodide for* Air-dried, t Dried at 100"278 PYMAN : ISOQUINOLINE DERIVATIVES. PART IV.three hours a t 100".The crystalline product obtained was separatedby fractional crystallisation from absolute alcohol into :(1) 7.2 grams of 'i(or 6)-hydroxp-G(or 7)-msthoxy-2-methyZ-3 : 4-dihydl.oisoquii2olinium iodide, melting at 21 3' (corr.).(2) 2.0 grams of 6(or 7)-methozy-7(or 6)-[6 : 7-dihydroxy-2-metAyZ-3 : 4-di~yd~oisoqzcinoliniumox?/l-2-met~~yZ-3~~ 4-hydroisoquinolinium iodide,melting a t 181-182' (corr,), and( 3 ) a small quantity of a brown, gummy residue.I n a second experiment, in which the phenolbetaine was notpreviously dried at loo", a larger proportion of the latter compoundwas obtained, 11 grams of hydrated phenolbetaine and 25 grams ofmethyl iodide yielding 4.4 grams of the first-mentioned iodide and5-1 grams of the latter, besides an oily residue which was neglecteld.7(or 6)-Hydroxy-G(or 7)-methoxy-2-methyl-3 : 4-dihydroisoquinoliniumSalts (XVIII, p.269).The iodide crystallises from alcohol in fine long, golden needles,It is anhydrous, and isC = 41.5 ; H = 4.5.which melt and decompose at 218' (corr.).sparingly soluble in water or alcohol :0.1536 gave 0.2336 CO, and 0.061 1 E20.0.1876 ,, 0.1370 AgI. I = 3 9 * 5 .0.3046 ,, by Zeisel's method 0.2098 AgI. OMe = 9 . 1 .C11H,,02NI requires C = 41.4 ; H = 4.4 ; I = 39.8 ; OMe = 9.7 per cent.The chloride was obtained from the iodide by double decompositionwith silver chloride. It crystallises from aqueous acetone in yellowneedles, which contain one molecule of water of crystallisation, andeffervesce at 155" (corr.), after sintering from about 140'; afterdrying at loo', it decomposes a t 198' (corr.).It is easily soluble inwater or hot alcohol, and its aqueous solution gives no coloration withferric chloride solution :0.2011 * lost 0.0146 at 100".0-1400 T gave 0.2970 CO, and 0*0815 H,O. C = 57.9 ; H = 6.5.C,,E,,O,NCl requires C = 58.0 ; H = 6.2 ; C1= 15.6 per cent.On dissolving this salt in warm concentrated aqueous ammonia, adeep red solution is obtained, which deposits, on cooling, orange crystalsof the chloride of the external phenolbetaine, namely, 6(or 'I)-~nethoxy-7 (or 6)-[7( or 6)-h ydroxy-6 (or 7)-methoxy-2-methyl-3 : 4-dih ydroisoquino-liiziumoxy]-2-methyZ-3 : 4-dihydroisopuinoliniuvn chloride (XX, p. 269).After recrystallisation from absolute alcohol, this salt forms brightH,O= 7.3.C,,H,,02NCl,H,0 requires H20 = 7 .3 per cent.0.1818 + ,, 0.1134 AgC1. C1= 15.4* Air-dried. .1. Dried at 100"PYMAN : ISOQUINOLINE DERIVATlVES. PART 1V. 279orange prisms, which contain 3&H,O and melt and decompose at 1 3 5 O(corr.). It is easily soluble in water, but sparingly so in cold absolutealcohol; it, contains chlorine. On heating this salt a t loo', it firstbecomes crimson, and then melts to a deep red gum which retainsabout 1 per cent. of water of crystallisation :0.1413 *gave 0.2831 CO, and 0,0933 H,O.0.1193 * lost 0.0146 a t 100'. H20=12*2.0.1047 T gave 02397 CO, and 0.0624 H20.C=54*6 ; H = 7.3.C2,H,70,N2C1,3~H20 requires C = 54.8 ; H = 7.1 ; H20 = 13.1 per cent.C2,H270,N,Cl requires C = 63.1 ; H = 6.5 per cent.C = 62.4; H = 6.6.6(or 7)-Methoxy-7(or 6)-[6 : 7-dih ydroxy-2-methyl-3 : 4-dihydroisoquino-linizcmoxy]-2-meth?/l-3 : 4-dihydroisoquinolinizcln Salt8 (XIX, p.269).The iodide crystallises from absolute alcohol in hard, orange grains,It is anhydrous andIts aqueouswhich melt and decompose at 181-182O (corr.).easily solpble in water, but sparingly so in cold alcohol.solution gives a deep green coloration with ferric chloride solution :0.1524 gave 0.2826 CO, and 04713 H,O. C = 50.6 ; H = 5.2.C2,H2,0,N21 requires C = 50-8 ; H = 5.1 ; I = 25.6 per cent.On adding a molecular proportion of hydriodic acid to the deeporange aqueous solution of 2 grams of this salt, a pale yellow solutionwas obtained. On evaporating this to low bulk and adding absolutealcohol, 0.9 gram of 7(or 6)-hydroxy-6(or 7)-methoxy-Z-methyl-3 : 4-dihydroisoquinolinium iodide separated ; after recrystallisation, thismelted a t 218O(corr.), both alone and whenmixed with the pure salt, andgave no coloration with aqueous ferric chloride.On then addingammonia to the mother liquor, a small quantity of the phenolbetaineof 6 : 7-dihydroxy-2-methyl-3 : 4-dihydroisoquinolinium hydroxideseparated ; after recrystallisation from alcohol, this compound meltedat 222O (corr.), and its melting point suffered no depression when thecompound was mixed with the pure phenolbetaine.The chlorih was prepared from the iodide by double decompositionwith silver chloride. It crystallises from absolute alcohol in deepyellow, glistening prisms, which melt a t 186-1 87' (corr.), and containone molecule of water of crystallisation :0.1867 ,, 0.0896 AgI. I = 25.9.0.3360 * lost 0.0169 at 100'.0,1416 t gave 0.3251 CO, and 0*0810 H,O.H,0=5-0.C21H250,N2C1,H20 requires H,O = 4.3 per cent.C,,H,,O,N,CI requires C = 62.3 ; H = 6.2 per cent.C= 62.6 ; H= 6.4.* Air-dried. t Dried at 100280 HOMER AND PURVIS: THE ABSORPTION SPECTRA OFPhenolbetaine of 6 ; 7-di~ydroxy-2-ethyZ-3 : 4-dihydroisoquinoliniumHyd *oxid@,I IThe preparation and properties of this compound and its salts aresimilar to those of the corresponding met hyl-homologue.The phenolbetaine of 6 ; 7-dihydroxy-2-ethyl-3 : 4-dihydroisoquino-Zinium hydroxide crystallises from absolute alcohol in deep yellow rods,which melt and decompose at 235' (corr.). It is anhydrous :0,1442 gave 0.3661 CO, and 0.0919 H20.Cl1H1,0,N requires C = 69-1 ; H = 6.9 per cent.The chloride crystallises from water in fine yellow needles, whichmelt at 104' (corr), and contain 2 molecules of water of crystallisation.After drying at loo', this salt melts and decomposes at 201-202'(corr.) :C=69*2; H=7*1.0.2170 * lost 0°0300 at 100'.0.1517 + gave 0.3221 C 0 2 and 0.0845 H20.0'1475 t ,, 0.0943 AgCI. C1= 15.8.The picrate crystallises from alcohol in clusters of golden, spear-likeH20 = 13.8.C,,Hl,02NC1,2H20 requires H,O = 13.7 per cent.C = 58.0 ; H = 6.2.C1lH1,O,NC1 requires C = 58.0 ; H = 6.2 ; C1= 15.6 per cent.needles, which melt and decompose a t 191' (corr.).THE WELLCOME CHEMICAL WORKSDARTFORD, KENT