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Chemistry of the aminochromes. Part XII. Som e new aminochromes, and their derivatives1-3

R. A. HEACOCKND 0 . HUTZINGERAtlantic Regional Laboratory, National Research Council of Canada, Halifax, Nova Scotia

Received August 9, 1968The synthesis of a number of new arninochromes (and their rnonosernicarbazones) derived fromcatecholamines containing: (a) a primary amino group and (b) an alkoxy group in the p-position of theethylarnine side chain is reparted. Improved procedures for the prepara tion of some previously describedaminochrornes of these types including 7-iodonorepinochrome and adrenochrome methyl and ethylethers are also given.

Canadian Journal of Chemistry, 47, 2009 (1969)

In previous publications in this series thepreparation, physical properties, and chemicalreactivity of several new aminochromes havebeen described (1-3). This paper describesattempts to isolate a number of other new amino-chromes as crystalline solids from catechol-amines with: (a) a primary amino group and(b) an alkoxy group in the P-position of theethylamine side chain.Whilst the preparation of aminochromes fromcatecholamines containing a secondary aminogroup presents no particular problems (cf. reviewby Heacock, (4)) no simple non-halogenatedaminochromes have, as yet, been obtained, asfully characterized crystalline solids, fromprimary catecholamines. Marquardt and Carl(5) reported that noradrenochrome (1) could beobtained as an ill-defined red-brown powder oras "red rings on the side of the flask" whennoradrenaline (2) was oxidized with silver oxidein acetonitrile. The ultraviolet-visible absorptionspectrum of 1 was described, but no otherphysical or analytical data were reported (5).In view of the interest that has developed inrecent years in the physiological activity ofadrenochrome (cf. ref. 4, p. 379) it was con-sidered desirable to investigate also the physio-logical activity of pure samples of noradreno-chrome (1). However, attempts in the hands ofthe authors, to repeat and improve on the pro-cedure of Marquardt and Carl for the prepara-tion of 1 have met with little success. It was

'NRCC No. 10420.2Part XI. Can. J. Chern. This issue.3The preliminary phases of the work'described in thispaper were carried out by the authors in the laboratoriesof the Psychiatric Research Unit, University Hospital,Saskatoon, Saskatchewan.

also not possible to obtain crystalline 1 by theoxidation of noradrenaline (2) with silver oxidein methanol, using the method commonlyemployed for the preparation of adrenochromefrom adrenaline (6) or by oxidation of the basewith the calculated quantity of iodic acid inaqueous methanol (cf. 7), a method that hasbeen successfully used for the preparation ofadrenochrome. Whilst red solutions were ob-tained using both of these procedures, onlyunidentified black amorphous solids could beisolated in either case. Similarly all attempts toprepare crystalline 2-methylnoradrenochrome(3) by the oxidation of 3;4-dihydroxynorephe-drine (4 ) were unsuccessful.

7-Iodonoradrenochrome (5) was first preparedby Bu'Lock and Harley-Mason in 1951 (8) bythe oxidation of noradrenaline (2) with potassiumiodate in aqueous solution. It was later shownthat the copious formation of tarry by-products,that invariably occurred in this reaction, couldbe avoided if the reaction was carried out in moredilute solution under fairly strong acid conditions(9). A number of 7-halogenated aminochrome

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2010 CANADIAN JOURNAL OF CHEMISTRY. VOL. 47, 1969

monosemicarbazones have recently been pre-pared by direct halogenation of the correspond-ing aminochrome monosemicarbazones andshown t o exhibit poten t hypotensive activity (10).A potentially very interesting member of thisseries, from the physiological stand poin t, whichwas not reported in the original patent (lo), is7 - iodono rad renoch rome monos emica rbazone(6). This compound has now been prepared bydirect condensation of 7-iodonoradrenochrome(5) with semicarbazide.Whilst red products were definitely obtainedon the oxidation of noradrenaline methyl ether(7) with silver oxide either in methanol oracetonitrile it was not possible to isolate nor-adrenochrome methyl ether (8) as a crystallinesolid from such solutions. However, noradreno-chrome methyl ether monosemicarbazone (9)was obtained as a red microcrystalline solid fromaqueous solutions of noradrenaline methyl ether(7) which had been oxidized with potassiumferricyanide. All attempts to prepare crystalline7-iodonoradre nochrom e methyl ether (10) by theoxidation of 7 with potassium iod ate in aqueoussolution were unsuccessf~~l.here appears to belittle doubt however that the iodoaminochrome10 had form ed, since the violet color of thesolution was rapidly discharged by a scorbic acid,a reagent known to reduce aminochromes (cf.ref. 4, p. 253). 5,6-Diacetoxy-7-iodoindole (11)could be obtained by the ace tylation of the ether-soluble reduction products. This product wouldhave been expected since it is known tha t am ino-chrome s with a 3-alkoxy group, like those with a3-hydroxy group, give 5,6-dihydroxyindoles onredu ction (1 1).

Similarly, all attem pts to isolate crystallimethylnoradrenochrome methyl ether (12)iodo-2-methylnoradrenochrome methyl (13) from solutions of oxidized a-methyadrenaline methyl ether (14) were not succeAs in the case of the oxidation producnoradrenaline methyl ether (7) howeveappeared that 7-iodo-2-methylnoradrenochmethyl ether (13) was formed du ring th e aquiodate oxidation since 5,6-diacetoxy-7-iomethylindole (15) was obtained on acetylatithe ether-soluble reduction products of 13.The formation of a crystalline iodo derivof norepinochrome was first reported in (12). At that time neither the details opreparative procedure nor the position oiodine atom in the molecule was defined.compound has now been obtained as a characterized violet-brown crystalline solithe oxidation of dopamine (16) with potasiodate under the coeditions used to pr7-iodonoradrenochrome (5) (cf. 9). In comwith all other iodoaminochromes the derivative of norepinochrome is a 7derivative (i.e. 17) since it gave 5,6-diacetoiodoindole (11) on treatment with acetichydride and pyridine (cf. ref. 4, p. 242). .The iodoamin ochrom e 1 7 is probablyprimary product obtained on oxidation ofamine (16) with iodine, the reaction empas the first stage of the commonly used estion of dopamine in clinical chemistry.chemistry of this method does not appear clearly understood (cf. ref. 4, p. 282).The methyl and ethyl ethers of adrenoch(18 and 19) were first isolated as their m

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HEACOCK A N D HUTZINGER: CHEMISTRY O F THE AMINOCHROMES. XI1

semicarbazones (13); the preparation of the do pa mi ne hydro chloride (0.5 g) in water (150 ml). Thecrystalline aminochromes 18 and 19 in relatively react ion mixture was st i rred at room temperature for 1 h,after which time the pH of the solution was adjusted to 2poor yield was later reported by Heacock and by the dropwise addition of concentrated hy drochloricScott (1) who carried out the oxidation of ac id : 7- iodonore~inochrome0.28 a : to ta l ly deco m~ osed-,adrenaline methyl and ethvl ether in aceto- withbut melting by 10604) was o btained as a violet-brownnitrile with silver oxide. ~t has no w been shown crystalline solid after the deep red-violet solution hadthat and 19 ca n be readily prepared by been allowed to stan d in the refrigerator overnight.Anal . Calcd. for CsH 61N Oz: C, 34.94; H, 2.20; N,carrying out th e oxidation in a methanol-ether 5.09; I, 46.15. Fou nd : C, 34.85; H , 2.11; N, 5.16; I, 45.97.medium.

HO ,ml,"PRHO NHCH(CH3),The preparation of the methyl and ethyl ethers

of N-isopropylnoradrenaline (i.e. 20 and 21) hasrecently been described (14). In view of therelatively small amount of research that has beencarried out into the chemistry of the amino-chrome ethers, attempts were made to prepareaminochromes (and their 7-iodo derivatives)from 20 and 21. Whilst it was not possible toobtain these aminochromes in crystalline form itwas possible to isolate crystalline monosemi-carbazones of 1-i sopropylnoradr ,enochromemethyl ether and 1-isopropylnoradrenochromeethyl ether (i.e. 22 and 23).The results reported in this paper indicatesome of the difficulties that are encountered inthe synthesis of aminochromes derived fromcatecholamines containing a primary aminogroup or a P-alkoxy group in the ethylamine sidechain.Experimental

7-lodonorepirzoclirome ( 17 )Potassium iodate (0.8 g) was added to a solution of

Aceiylaiiotz of 7-lodonorepinochrotne (17) ; Preparaiiotz of5,6-Diaceioxy-7-iodoindole11 )7-Iodonorepinochrome (1.2g) was dissolved in amixture of acetic anhydride (35 ml) an d dry pyridine (35ml) and the solution was allowed to stand at roomtemperature overnight. The reaction mixture was thenadd ed drop wise to a stirred ice-water mixture (1500 ml)and the aqueous react ion product was extracted withether5 (6 x 150 ml). Th e comb ined ether extracts werewashed with saturated aqueous sodium bicarbonate(until free of acetic acid) and with water (2 x 100 ml).Th e yellow oily residue, which remained on conce ntrationof the dried ( Na ZS0 4) solut ion, in vacuo, gave afterrecrystallization from benzene - ight petroleum (b.p.8&10O0), pale-fawn colored crystals (0.41 g; m .p. 123-126") of crude 5,6-diacetoxy-7-iodoindole. his productwas purified first by chrom atograph y on a shor t silica gel6column with benzene - ight petroleum (b.p. 6&80)(2:l) as eluant and finally by further recrystallization

from benzene - ight petroleum (b.p. 8&100). In thismanner a pure sample of 5,6-diacetoxy-7-iodoindole0.25g ; m.p . 127-128") was obta ined a s a colorless crystallinesolid. The melting point of a sample of 5,6-diacetoxy-7-iodoindole prepared by acetylation of the reductionproduc t of 7-iodoadrenochrome (cf. 15) was undepressedon admixture with a sample of the same compound,prepared by the method described above.7-lodonoradrenochrome Monosemicarbazotze (6)A suspension of 7-iodon oradreno chrom e (0.3 g),prepared by the method of Heacock and Scott (9), sod iumacetate (0.5 g; anhyd rous), an d semicarbazide hyd ro-chlo ride (0.5 g) in wa ter (2.5 ml) was stirred at ro omtemperature for 2 h. T he crude product , an orange-brownsolid (0.23 g), was filtered off, washed w ith a little coldwater, and a ir dried. Th e residue was repeatedly extractedwith boiling ethanol. The combined extracts were concen-trated to small volume and an equal quanti ty of dry

4The decomposition points were measured o n a Leitzhot-stage instrument.5Peroxide-free ether was used th rougho ut this investi-gat ion.61n this and subsequent experiments the chromato-graphic silica gel used was obtained from th e Koch-L ightLaboratories Ltd. (200/300 mesh size).

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2012 CANADIAN JOURNAL OF (ZHEMISTRY. VOL. 47, 1969benzene added. 7-Sodonoradrenochrome monosemicarb-azone (0.04 g) was obtained as a d eep cherry red crystal-line solid (totally decomposed by 158").Anal . Calcd . fo r C9 H9IN 4O3 : C , 31 .05 ; H , 2 .61; N,16.10; 1, 36.40. Found: C, 31.30; H, 2 .73; N, 16.41; I,36.49.Oxidation of Noradrenaline Methyl Ether (7)

( i ) O xidation with Silver OxideN o crystalline products could be isolated from solu-tions of noradrenaline methyl ether hydrochloride, ineither methanol or.acetonitrile, which ha d been oxidizedwith silver oxide.(ii ) Oxidation with Potassium Ferricyanide;Preparation of Noradrenochrotne Methyl EtherMonosemicarbazone (9 )A solution of noradrenaline methyl ether hydro-chlorid e (0.5 g, (14)) in water (2.5 m l) was oxidized with asolution of po tassium ferricyanide (2.35 g) an d sod iumbicarbonate (0 .75 g) in water (6 .2 ml). After the o xidationhad been allowed to proceed fo r 5 min a so lution of

~ ~ m i c a r b a z i d eydrochloride (0.25 g) and sodiu m acetate(0.25 g) in w ater (1 .5 ml) w as ad ded to the deep-redso lu t ion con tain ing noradrenochrome methy l e ther . Abrow n p recipitate (0.25 g) separated after th e reactionmixture had been allowed to stand at 4" overnight.Eventually a small quantity of noradrenochrome methylether monosemicarbazone was obtained as a deep-redmicrocrystalline powder (totally decomposed by 208") byrepeated recrystallization of the crude produ ct fromaqueous alcohol.A n a l. C a lcd . fo r C I0 H lZ N 4 O 3 :C, 50.84; H, 5 .12; N,23.72. Fou nd: C, 50.52; H, 5 .29; N, 23.55.(iii ) Oxidatiotz with Potassium Iodate(a ) Potassium iod ate (0.8 g) was added to a solution ofnoradrenaline methyl ethe r hydrochloride (0.5 g; (14)) inwater (150 ml). The reaction mixture was stirred at roo mtemperature for 39 h, after which time the dee p-purplesolution was filtered from a lit t le dark-colored a mo rph ou sinsoluble material. N o significant precipitation occurredafter the reaction mixture had been allowed t o stand inthe refrigerator overnight. The pH of the solution wasthen adjusted to 2 and it was allowed to stand a t 4' forseveral hours; however, n o crystalline iodo amin ochro mewas obtained.The so lu t ion , p resumed to con tain 7 - iodonoradreno-chrome methy l e ther (lo), was treated with an excess ofascorbic acid and rapidly extracted with ether (4 x 60 ml).A m ixture of acetic anhy dride (10 ml) an d dry py ridine(10 ml) was added to the d r ied (Na2 S04 )ethereal extracts.After removal of the ether in uacuo the acetylation mix-tu re was a l lowed to s tand at room temperatu re overn igh tand was then poured dropwise with stirring into an ice-water mixture. The aqueous reaction mixture was etherextracted (4 x 60 ml) an d the combined ether ex tractswashed f ree o f acet ic acid wi th 5 % aqueou s sod iumbicarbonate a nd water. Benzene (50 ml) was added to thedr ied (Na,S04) e ther so lu t ion and th e e ther removed it1uacuo. The crude p roduct ( in benzene so lu t ion ) waspurified chromatographically o n a sh ort silica gel colum nby adsorption from benzene - ight petroleum (b.p.60-80") (1:l) and elution with a mixture (5:l) of thesesolvents. 5,6-Diacetoxy-7-iodoindole 0.13 g ; m.p. 126-127") was obtain ed when th e partially purified prod uct,

ob tained o n concen tration o f the combined eluaterecrystallized from benzene - ight petroleum 80-100"). This material did n ot depress th e melting of samples of 5,6-diacetoxy-7-iodoindolebtaineddopa mine (see above) or noradrenaline (1 5).( b ) N o crystalline products were obtained whenconcentrated aqu eous solutions of noradrenaline mether hydrochloride were oxidized with potassium in water at 0". Repeated filtration from initially fotarry by-p roducts and ad justmen t o f th e pH o f thetion to 2 were of no avail.Oxidation of a-Methylnoradrenaline Met/zyl Ether (A n a t t em p t t o p rep a re 7-iodo-2-methylnoradchrome methy l e ther (13) f rom a-methy lnoradrenmethyl ether hydrochloride (0.5 g), by a meth od gous to that described above for the corresponoradrenaline derivative was also unsuccessful. T hepurp le so lu t ion o f the crude iodoaminochromreduced and the products acetylated as despreviously. O n pourin g the acetylation mixture intwater a pale-brown solid was obtained. The produdissolved in a mixture of benzene and light petr(b.p. 80-100") (1 : I ) and adsorbed on a shor t s i l icolumn (2.5 x 2 .2cm). E lu t ion o f the co lumnbenzene - ight petroleum (b.p. 80-100") (5: ) gsolid product, which, on recrystallization from benlight petroleum (b.p. 100-120"), gave 5,6-diacetoiodo-2-methy lindole (0.055 g), m.p. 161-162", p ressed o n adm ix tu re wi th a sample p repared a-methylnoradrenaline hydrochloride (16).Adrenochrome Methyl Ether (18)Freshly prepared silver oxide (5 g) was add edsolution of adrenaline methyl ether hydrochloride(13)) in dry m ethanol (10 ml). The reaction mixtush ak en vigo rou s ly fo r 3 4 min and then filteredsuction through a Dowex-l (Cl-) resin bed.7 Dry(30 ml) was addedsto the deep -red filtrate, whiccooled to -80". After standing for several hours temperatu re ad renochrom e methy l e ther was ob taia deep-red microcrystalline solid (m.p. softens atotally decompo sed by 86"; undepressed o n admwith a sample o f th is compound p repared by the mpreviously described (1)). A second crop was obfro m the mother liquors after they had been allowsta nd at -80' over night (total yield, 0.19 g).Anal. Calcd . fo r Clo Hl lN 03 : C , 62 .16 ; H,Foun d : C , 62 .04; H , 5 .71.Adrenochronze Ethyl Ether (1 2)Adren ochro me ethyl ether (0 .25 g) was preparedeep-red microcrystalline solid (m.p. 79.5-81.5" decomposition, undepressed on admixture with a sof this compo und prepared by the method prevdescribed (1)) from adrenaline ethyl ether hy droch(1 g) by a method analogous to that described abothe p reparat ion o f ad renochrom e methy l e ther .Anal . Calcd . fo r C , lH ,3N 03 : C , 63 .75 ; H, 6 .36.76. Foun d: C, 63.60; H: 6 .32; N, 6 .77.

'The resin (200/400 mesh size) was prepareextensive washing with: ( I ) 3 N hydrochloric( 2 ) with water un t i l neu tral to l i tmus; a nd (3) finallydry methan ol. Colu mn diame ter, 2 .5 cm ; height, 1

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HEACOCK AN D HUTZINGER: CHEMISTRY OF THE AMINOCHROMES. XI1 201 3I-IsopropylnoradrenocI~ro~~~eerllyl Ether.Monosemicarbazone (22)A solution of N-isopropylnoradrenaline methyl etherhydrochloride (0.25 g; (14)) in water (1.3 rnl) was oxidizedwith a solution of potassium ferricyanide (1.17 g) andsodium bicarbonate (0.37 g) in water (3.1 rnl). A solutioncontaining sernicarbazide hydrochloride (0.13 g) andsodium acetate (0.13 g) in water (0.7 rnl) was added to thedeep-red arninochrorne solution; the resulting orange-colored solution deposited an orange-brown crystallinesolid, m.p. 184-185" (decornp.) after being allowed tostand at 4" overnight. Recrystallization from waterafforded 1-isopropylnoradrenochrorne methyl ether serni-carbazone (0.2 g) in reddish-orange elongated prisms,rn.p. 190.5-191" (decornp.).Anal. Calcd. for C13H18N403:C, 56.10; H, 6.52; N,20.13. Found: C, 55.95; H, 6.56; N, 19.96.I-Isopropylnoradrenocl~romeEtlzyl EtherMonosemicarbazone (23)1-Isopropylnoradrenochrorne thyl ether rnonoserni-carbazone (0.21 g) (very small orange prisms; m.p.187.5-188.5" (decornp.) was prepared from N-isopropyl-noradrenaline ethyl ether hydrochloride (0.25 g; (14)) ina manner analogous to that described above for thecorresponding methyl ether.Anal. Calcd. for C14H20N403: , 57.52; H, 6.90; N,19.17. Found: C , 57.32; H, 6.84; N, 19.07.

AcknowledgmentThe technical assis tance of Mrs. B. D. Scott of

the Psychiatric Research Unit, University Hos-pital, Saskatoon, Saskatchewan is gratefullyacknowledged.1. R. A. HEACOCKnd B. D. Scorr. Can. J. Chern.38, 516 (1960).2. R. A. HEACOCKnd 0. HUTZINGER. an. J. Chern.43, 2535 (1965).3. 0. HUTZINGERnd R. A. HEACOCK.Can. J. Chern.This issue.4. R. A. HEACOCK.Advan. Heterocyclic Chern. 5,205(1965).5. P. MARQUARDTnd E. CARL. Naturwiss. 39, 210(1 952).6. R. A. HEACOCK,. NERENBERG,nd A. N. PAYZA.Can. J. Chern. 36, 853 (1958).7. E. M A c c ~ o r r ~ . azz. Chirn. Ital. 81, 485 (1951).8. J. D. Bu 'L oc ~ nd J. HARLEY-MASON.. Cheni.SOC.712 (1951).9. R. A. HEACOCKnd B. D. SCOTT. Experientia, 17,347 (1961).10. N. BARSEL.U. S. Patent No. 3,098,858. July 23,

1963. Chern Abstr. 60, 506 (1964).11. R. A. HEACOCK.Chern. Ind. London, 752 (1959).12. R. BARER, . BLASCHKO,nd H. LANGEMAN..Physiol. London, 112, 21P (1951).13. J. HUKKI nd N. SEPPALAINEN.cta Chern. Scand.12. 1231 (1958).14. R.'A. H ~ A C O ~ K . . HUTZINGER.nd B. D. Scorr.- - . -- - - - -Can. J. Chern. 43,2437 (1965). '15. R. A. HEACOCK, . E. MAHON, nd B. D. Scorr.Can. J. Chern. 39, 231 (1961).16. R. A. HEACOCK,. HUTZINGER,. D. SCOTT,J. W.DALY. nd B. WITKOP. J. Am. Chern. Soc. 85.1825