,

Chemistry of the aminochromes. Part XII. Some new aminochromes and their derivatives1-3
R. A. HEACOCK 0. HUTZINGER AND
Atlantic Regional Laboratory, National Research Council o Canada, Halifax, Nova Scotia f Received August 9, 1968 The synthesis of a number of new arninochromes (and their rnonosernicarbazones) derived from catecholamines containing: (a) a primary amino group and (b) an alkoxy group in the p-position of the ethylarnine side chain is reparted. Improved procedures for the preparation of some previously described aminochrornes of these types including 7-iodonorepinochrome and adrenochrome methyl and ethyl ethers are also given.
Canadian Journal of Chemistry, 47, 2009 (1969)

In previous publications in this series the preparation, physical properties, and chemical reactivity of several new aminochromes have been described (1-3). This paper describes attempts to isolate a number of other new aminochromes as crystalline solids from catecholamines with: (a) a primary amino group and (b) an alkoxy group in the P-position of the ethylamine side chain. Whilst the preparation of aminochromes from catecholamines containing a secondary amino group presents no particular problems (cf. review by Heacock, (4)) no simple non-halogenated aminochromes have, as yet, been obtained, as fully characterized crystalline solids, from primary catecholamines. Marquardt and Carl (5) reported that noradrenochrome (1) could be obtained as an ill-defined red-brown powder or as "red rings on the side of the flask" when noradrenaline (2) was oxidized with silver oxide in acetonitrile. The ultraviolet-visible absorption spectrum of 1 was described, but no other physical or analytical data were reported (5). In view of the interest that has developed in recent years in the physiological activity of adrenochrome (cf. ref. 4, p. 379) it was considered desirable to investigate also the physiological activity of pure samples of noradrenochrome (1). However, attempts in the hands of the authors, to repeat and improve on the procedure of Marquardt and Carl for the preparation 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 this paper were carried out by the authors in the laboratories of the Psychiatric Research Unit, University Hospital, Saskatoon, Saskatchewan.

also not possible to obtain crystalline 1 by the oxidation of noradrenaline (2) with silver oxide in methanol, using the method commonly employed for the preparation of adrenochrome from adrenaline (6) or by oxidation of the base with the calculated quantity of iodic acid in aqueous methanol (cf. 7), a method that has been successfully used for the preparation of adrenochrome. Whilst red solutions were obtained using both of these procedures, only unidentified black amorphous solids could be isolated in either case. Similarly all attempts to prepare crystalline 2-methylnoradrenochrome (3) by the oxidation of 3;4-dihydroxynorephedrine (4) were unsuccessful.

7-Iodonoradrenochrome (5) was first prepared by Bu'Lock and Harley-Mason in 1951 (8) by the oxidation of noradrenaline (2) with potassium iodate in aqueous solution. It was later shown that the copious formation of tarry by-products, that invariably occurred in this reaction, could be avoided if the reaction was carried out in more dilute solution under fairly strong acid conditions (9). A number of 7-halogenated aminochrome

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monosemicarbazones have recently been prepared by direct halogenation of the corresponding aminochrome monosemicarbazones and shown to exhibit potent hypotensive activity (10). A potentially very interesting member of this series, from the physiological standpoint, which was not reported in the original patent (lo), is 7-iodonoradrenochrome monosemicarbazone (6). This compound has now been prepared by direct condensation of 7-iodonoradrenochrome (5) with semicarbazide. Whilst red products were definitely obtained on the oxidation of noradrenaline methyl ether (7) with silver oxide either in methanol or acetonitrile it was not possible to isolate noradrenochrome methyl ether (8) as a crystalline solid from such solutions. However, noradrenochrome methyl ether monosemicarbazone (9) was obtained as a red microcrystalline solid from aqueous solutions of noradrenaline methyl ether (7) which had been oxidized with potassium ferricyanide. All attempts to prepare crystalline 7-iodonoradrenochrome methyl ether (10) by the oxidation of 7 with potassium iodate in aqueous solution were unsuccessf~~l. There appears to be little doubt however that the iodoaminochrome 10 had formed, since the violet color of the solution was rapidly discharged by ascorbic acid, a reagent known to reduce aminochromes (cf. ref. 4, p. 253). 5,6-Diacetoxy-7-iodoindole (11) could be obtained by the acetylation of the ethersoluble reduction products. This product would have been expected since it is known that aminochromes with a 3-alkoxy group, like those with a 3-hydroxy group, give 5,6-dihydroxyindoles on reduction (1 1).

Similarly, all attempts to isolate crystalline 2methylnoradrenochrome methyl ether (12) or 7iodo-2-methylnoradrenochrome methyl ether (13) from solutions of oxidized a-methylnoradrenaline methyl ether (14) were not successful. As in the case of the oxidation products of noradrenaline methyl ether (7) however, it appeared that 7-iodo-2-methylnoradrenochrome methyl ether (13) was formed during the aqueous iodate oxidation since 5,6-diacetoxy-7-iodo-2methylindole (15) was obtained on acetylation of the ether-soluble reduction products of 13. The formation of a crystalline iodo derivative of norepinochrome was first reported in 1951 (12). At that time neither the details of the preparative procedure nor the position of the iodine atom in the molecule was defined. This compound has now been obtained as a wellcharacterized violet-brown crystalline solid by the oxidation of dopamine (16) with potassium iodate under the coeditions used to prepare 7-iodonoradrenochrome (5) (cf. 9). In common with all other iodoaminochromes the iodo derivative of norepinochrome is a 7-iodo derivative (i.e. 17) since it gave 5,6-diacetoxy-7iodoindole (11) on treatment with acetic anhydride and pyridine (cf. ref. 4, p. 242). . The iodoaminochrome 17 is probably the primary product obtained on oxidation of dopamine (16) with iodine, the reaction employed as the first stage of the commonly used estimation of dopamine in clinical chemistry. The chemistry of this method does not appear to be clearly understood (cf. ref. 4, p. 282). The methyl and ethyl ethers of adrenochrome (18 and 19) were first isolated as their mono-

HEACOCK A N D HUTZINGER: CHEMISTRY OF THE AMINOCHROMES. XI1

semicarbazones (13); the preparation of the crystalline aminochromes 18 and 19 in relatively poor yield was later reported by Heacock and Scott (1) who carried out the oxidation of adrenaline methyl and ethvl ether in acetonitrile with silver oxide. ~t has now been shown and 19 can be readily prepared by that carrying out the oxidation in a methanol-ether medium.

dopamine hydrochloride (0.5 g) in water (150 ml). The reaction mixture was stirred at room temperature for 1 h, after which time the pH of the solution was adjusted to 2 by the dropwise addition of concentrated hydrochloric acid: 7-iodonore~inochrome (0.28 -, totally decom~osed a: . withbut melting by 10604)was obtained as violet-brown crystalline solid after the deep red-violet solution had been allowed to stand in the refrigerator overnight. Anal. Calcd. for CsH61NOz: C, 34.94; H, 2.20; N, 5.09; I, 46.15. Found: C, 34.85; H, 2.11; N, 5.16; I, 45.97.

HO, HO

m, P l" R
NHCH(CH3),

The preparation of the methyl and ethyl ethers of N-isopropylnoradrenaline (i.e. 20 and 21) has recently been described (14). In view of the relatively small amount of research that has been carried out into the chemistry of the aminochrome ethers, attempts were made to prepare aminochromes (and their 7-iodo derivatives) from 20 and 21. Whilst it was not possible to obtain these aminochromes in crystalline form it was possible to isolate crystalline monosemicarbazones of 1-isopropylnoradr,enochrome methyl ether and 1-isopropylnoradrenochrome ethyl ether (i.e. 22 and 23). The results reported in this paper indicate some of the difficulties that are encountered in the synthesis of aminochromes derived from catecholamines containing a primary amino group or a P-alkoxy group in the ethylamine side chain. Experimental
7-lodonorepirzoclirome (17) Potassium iodate (0.8 g) was added to a solution of

Aceiylaiiotz of 7-lodonorepinochrotne (17); Preparaiiotz of 5,6-Diaceioxy-7-iodoindole (11) 7-Iodonorepinochrome (1.2g) was dissolved in a mixture of acetic anhydride (35 ml) and dry pyridine (35 ml) and the solution was allowed to stand at room temperature overnight. The reaction mixture was then added dropwise to a stirred ice-water mixture (1500 ml) and the aqueous reaction product was extracted with ether5 (6 x 150 ml). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (until free of acetic acid) and with water (2 x 100 ml). The yellow oily residue, which remained on concentration of the dried (NaZS04) solution, in vacuo, gave after recrystallization from benzene - light petroleum (b.p. 8&10O0), pale-fawn colored crystals (0.41 g; m.p. 123126") of crude 5,6-diacetoxy-7-iodoindole.This product was purified first by chromatography on a short silica gel6 column with benzene - light petroleum (b.p. 6&80) (2:l) as eluant and finally by further recrystallization from benzene - light petroleum (b.p. 8&100). In this (0.25 manner a pure sample of 5,6-diacetoxy-7-iodoindole g; m.p. 127-128") was obtained as a colorless crystalline solid. The melting point of a sample of 5,6-diacetoxy-7iodoindole prepared by acetylation of the reduction product of 7-iodoadrenochrome (cf. 15) was undepressed on admixture with a sample of the same compound, prepared by the method described above. 7-lodonoradrenochrome Monosemicarbazotze (6) A suspension of 7-iodonoradrenochrome (0.3 g), prepared by the method of Heacock and Scott (9), sodium acetate (0.5 g; anhydrous), and semicarbazide hydrochloride (0.5 g) in water (2.5 ml) was stirred at room temperature for 2 h. The crude product, an orange-brown solid (0.23 g), was filtered off, washed with a little cold water, and air dried. The residue was repeatedly extracted with boiling ethanol. The combined extracts were concentrated to small volume and a n equal quantity of dry

4The decomposition points were measured o n a Leitz hot-stage instrument. 5Peroxide-free ether was used throughout this investigation. 61n this and subsequent experiments the chromatographic silica gel used was obtained from the Koch-Light Laboratories Ltd. (200/300 mesh size).

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benzene added. 7-Sodonoradrenochrome monosemicarbazone (0.04 g) was obtained as a deep cherry red crystalline solid (totally decomposed by 158"). Anal. Calcd. for C9H9IN4O3: 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 ) Oxidation with Silver Oxide N o crystalline products could be isolated from solutions of noradrenaline methyl ether hydrochloride, in either methanol or.acetonitrile, which had been oxidized with silver oxide. (ii) Oxidation with Potassium Ferricyanide; Preparation of Noradrenochrotne Methyl Ether Monosemicarbazone ( 9 ) A solution of noradrenaline methyl ether hydrochloride (0.5 g, (14)) in water (2.5 ml) was oxidized with a solution of potassium ferricyanide (2.35 g) and sodium bicarbonate (0.75 g) in water (6.2 ml). After the oxidation had been allowed t o proceed for 5 min a solution of ~~micarbazide hydrochloride (0.25 g) and sodium acetate (0.25 g) in water (1.5 ml) was added t o the deep-red solution containing noradrenochrome methyl ether. A brown precipitate (0.25 g) separated after the reaction mixture had been allowed to stand at 4" overnight. Eventually a small quantity of noradrenochrome methyl ether monosemicarbazone was obtained as a deep-red microcrystalline powder (totally decomposed by 208") by repeated recrystallization of the crude product from aqueous alcohol. Anal. Calcd. for CI0HlZN4O3:C, 50.84; H, 5.12; N, 23.72. Found: C, 50.52; H, 5.29; N, 23.55. (iii) Oxidatiotz with Potassium Iodate (a) Potassium iodate (0.8 g) was added to a solution of noradrenaline methyl ether hydrochloride (0.5 g; (14)) in water (150 ml). The reaction mixture was stirred at room temperature for 39 h, after which time the deep-purple solution was filtered from a little dark-colored amorphous insoluble material. No significant precipitation occurred after the reaction mixture had been allowed t o stand in the refrigerator overnight. The p H of the solution was then adjusted t o 2 and it was allowed to stand at 4' for several hours; however, n o crystalline iodoaminochrome was obtained. The solution, presumed to contain 7-iodonoradrenochrome methyl ether (lo), was treated with a n excess of ascorbic acid and rapidly extracted with ether (4 x 60 ml). A mixture of acetic anhydride (10 ml) and dry pyridine (10 ml) was added to the dried (Na2S04)ethereal extracts. After removal of the ether in uacuo the acetylation mixture was allowed t o stand at room temperature overnight and was then poured dropwise with stirring into a n icewater mixture. The aqueous reaction mixture was ether extracted (4 x 60 ml) and the combined ether extracts washed free of acetic acid with 5 % aqueous sodium bicarbonate and water. Benzene (50 ml) was added to the dried (Na,S04) ether solution and the ether removed it1 uacuo. The crude product (in benzene solution) was purified chromatographically o n a short silica gel column by adsorption from benzene - light petroleum (b.p. 60-80") (1:l) and elution with a mixture (5:l) of these solvents. 5,6-Diacetoxy-7-iodoindole(0.13 g ; m.p. 126127") was obtained when the partially purified product,

obtained o n concentration of the combined eluates, was recrystallized from benzene - light petroleum (b.p. 80-100"). This material did not depress the melting points of samples of 5,6-diacetoxy-7-iodoindole obtained from dopamine (see above) or noradrenaline (15). (b) N o crystalline products were obtained when more concentrated aqueous solutions of noradrenaline methyl ether hydrochloride were oxidized with potassium iodate in water at 0". Repeated filtration from initially formed tarry by-products and adjustment of the p H of the solution to 2 were of no avail.
Oxidation of a-Methylnoradrenaline Met/zyl Ether (14) An attempt t o prepare 7-iodo-2-methylnoradrenochrome methyl ether (13) from a-methylnoradrenaline methyl ether hydrochloride (0.5 g), by a method analogous to that described above for the corresponding noradrenaline derivative was also unsuccessful. The deeppurple solution of the crude iodoaminochrome was reduced and the products acetylated as described previously. O n pouring the acetylation mixture into icewater a pale-brown solid was obtained. The product was dissolved in a mixture of benzene and light petroleum (b.p. 80-100") (1 :I) and adsorbed o n a short silica gel column (2.5 x 2.2cm). Elution of the column with benzene - light petroleum (b.p. 80-100") (5 :1) gave a solid product, which, on recrystallization from benzene light petroleum (b.p. 100-120"), gave 5,6-diacetoxy-7iodo-2-methylindole (0.055 g), m.p. 161-162", undepressed o n admixture with a sample prepared from a-methylnoradrenaline hydrochloride (16). Adrenochrome Methyl Ether (18) Freshly prepared silver oxide (5 g) was added t o a solution of adrenaline methyl ether hydrochloride (1 g; (13)) in dry methanol (10 ml). The reaction mixture was shaken vigorously for 3 4 min and then filtered with suction through a Dowex-l (Cl-) resin bed.7 Dry ether (30 ml) was addedsto the deep-red filtrate, which was cooled to -80". After standing for several hours at this temperature adrenochrome methyl ether was obtained as a deep-red microcrystalline solid (m.p. softens at 81"; totally decomposed by 86"; undepressed o n admixture with a sample of this compound prepared by the method previously described (1)). A second crop was obtained from the mother liquors after they had been allowed to stand at -80' overnight (total yield, 0.19 g). Anal. Calcd. for C l o H l l N 0 3 : C, 62.16; H, 5.74. Found: C, 62.04; H , 5.71. Adrenochronze Ethyl Ether (12) Adrenochrome ethyl ether (0.25 g) was prepared a s a deep-red microcrystalline solid (m.p. 79.5-81.5" with decomposition, undepressed on admixture with a sample of this compound prepared by the method previously described (1)) from adrenaline ethyl ether hydrochloride (1 g) by a method analogous t o that described above for the preparation of adrenochrome methyl ether. Anal. Calcd. for C,lH,3N03: C, 63.75; H , 6.32; N, 6.76. Found: C, 63.60; H: 6.32; N, 6.77.

'The resin (200/400 mesh size) was prepared b y extensive washing with: ( I ) 3 N hydrochloric ac!d; ( 2 ) with water until neutral to litmus; and (3) finally wlth dry methanol. Column diameter, 2.5 cm; height, 1 cm.

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I-IsopropylnoradrenocI~ro~~~e Merllyl Ether. Monosemicarbazone (22)

A solution of N-isopropylnoradrenaline methyl ether hydrochloride (0.25 g; (14)) in water (1.3 rnl) was oxidized with a solution of potassium ferricyanide (1.17 g) and sodium bicarbonate (0.37 g) in water (3.1 rnl). A solution containing sernicarbazide hydrochloride (0.13 g) and sodium acetate (0.13 g) in water (0.7 rnl) was added to the deep-red arninochrorne solution; the resulting orangecolored solution deposited an orange-brown crystalline solid, m.p. 184-185" (decornp.) after being allowed to stand at 4" overnight. Recrystallization from water afforded 1-isopropylnoradrenochrorne methyl ether sernicarbazone (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 Ether Monosemicarbazone (23) 1-Isopropylnoradrenochrorne ethyl ether rnonosernicarbazone (0.21 g) (very small orange prisms; m.p. 187.5-188.5" (decornp.) was prepared from N-isopropylnoradrenaline ethyl ether hydrochloride (0.25 g; (14)) in a manner analogous to that described above for the corresponding methyl ether. Anal. Calcd. for C14H20N403: 57.52; H, 6.90; N, C, 19.17. Found: C , 57.32; H, 6.84; N, 19.07.

t h e Psychiatric Research U n i t , University Hospital, S a s k a t o o n , Saskatchewan is gratefully acknowledged. and 1. R. A. HEACOCK B. D. Scorr. Can. J. Chern. 38, 516 (1960). 2. R. A. HEACOCK 0. HUTZINGER. and Can. J. Chern. 43, 2535 (1965). 3. 0. HUTZINGER R. A. HEACOCK.Can. J. Chern. and This issue. Advan. Heterocyclic Chern. 5,205 4. R. A. HEACOCK. (1965). 5. P. MARQUARDT E. CARL. Naturwiss. 39, 210 and (1952). 6. R. A. HEACOCK, NERENBERG, A. N. PAYZA. C. and Can. J. Chern. 36, 853 (1958). . 7. E. M A c c ~ o r r ~Gazz. Chirn. Ital. 81, 485 (1951). 8. J. D. B u ' L o c ~and J. HARLEY-MASON. Cheni. J. SOC.712 (1951). 9. R. A. HEACOCK B. D. SCOTT. Experientia, 17, and 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, H. LANGEMAN. H. and J. Physiol. London, 112, 21P (1951). 13. J. HUKKI N. SEPPALAINEN. Chern. Scand. and Acta 12. 1231 (1958). 14. . and B. D. Scorr. . . R.'A. H ~ A C O ~ K0. HUTZINGER. --. Can. J. Chern. 43,2437 (1965). ' 15. R. A. HEACOCK, E. MAHON, M. and B. D. Scorr. Can. J. Chern. 39, 231 (1961). 16. R. A. HEACOCK, HUTZINGER, D. SCOTT,J. W. 0. B. DALY. B. WITKOP. J. Am. Chern. Soc. 85.1825 and
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Acknowledgment
T h e technical assistance o f M r s .

B. D. Scott o f