R.A. Heacock and O. Hutzinger- The Chemistry of the Aminochromes Part VIII: The Preparation and Properties of 4- and 7-Methyladrenochrome

8/3/2019 R.A. Heacock and O. Hutzinger- The Chemistry of the Aminochromes Part VIII: The Preparation and Properties of 4-

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THE CHEMISTRY OF THE AMINOCHROMES. PART VIIITHE PREPARATION AND PROPERTIES OF 4- AND 7-METHYLADRENOCHROME'

R. A. HEACOCK~N D 0 . HUT ZINGER^The Psychiatric Research Uni t , University Hospital , Saskatoon, Saskatchewan

Received April 15, 1965ABSTRACT

Two new catecholamines, 2- an d 5-methyladrenaline, have been prepared from 3-methyl-catechol and they gave 4- nd 7-methyladrenochrome, respectively, on oxidation. 7-Iodo-4-methyladrenochrome was obtained on oxidation of 2-methyladrenaline with potassium iodate ;however, an iodoaminochrorne could not be obtained in a similar manner from 5-methyl-adrenaline. T he expected 5,6-dihydroxyindole derivatives were obtained on reduction of theseaminochromes.I t has been known for many years th at t he oxidation of adrenaline with potassium

ioda te leads to th e forination of deep-violet products (1, 2). Th e compound responsiblefor the violet color was first isolated in 1937 by Richter and Blaschko who described it as3-hydroxy-2-iodo-l-methylindoline-5,6-quoi.e. 2-iodoadrenochrome) (3). However,i t has recently been shown tha t iodination actually occurs in the 7-position of t he adreno-chrome nucleus and it was further demonstrated that iodinatioil (and bromination)invariab ly occurs in the 7-position and not the 2-position in the aminochrome lnolecule (4).

As part of a research prograin into the chemistry of the aminochromes, that is beingcarried out in these laboratories, it was decided to prepare 2- and 5-inethyladrenaline (Iand I1 respectively) and t o investigate the effects of the methyl substitution of thearomatic ring on the oxidation of these hitherto unknown catecholamines with severaldifferent oxidizing agents .

I t was possible t o prepare I and I1 by procedures similar to tha t originally described byStolz for the preparation of adrenal ine (5). w-Chloro-3,4-dihydroxy-2-methylacetophenone(111) was prepared froin 3-inethylcatechol (IV) by a Friedel-Crafts condensa tion withchloracetyl chloride in th e presence of aluminium chloride in carbon disulfide solution.Methyla tion of the phenolic hydroxy groups of I11 gave w-chloro-3,4-dimethoxy-2-methylacetophenone (V), a compound that had previously been described in the literature(6), proving th at t he chloroacetyl residue had entered the aromat ic ring of IV in the posi-tion or tho to the inethyl group. T he n.m.r. spec trum of I11 in hexadeuteroacetone showedtwo well separated doublets centered a t 6 7.38 and 6 6.92 with a coupling cons tan t of ca.8.5 c.p.s., indicating th e presence of two ort ho aroma tic hydrogens in the molecule andconfirming th e position of the chloroacetyl residue. w-NIethylamino-3,4-dihydroxy-2-methylacetophenone (VI) was prepared by tr eating I11 with methanolic methylainine atroom temperatu re (cf. ref. 7). Treatment of I11 with sodium iodide in acetone gave 3,4-dihydroxy-w-iodo-2-lnethylacetophenone cf. ref. 6). Preliminary experiments indicatedthat there was no advantage in using the w-iodo derivative to prepare VI. 2-Methyl-adrenaline (I) was obtained in good yield by catalytic hydrogenation of VI. T he hydro-chloride of I was hygroscopic, b ut t he acid oxalate sal t of I was not an d was readilypurified by recrystallization from aqueous ethanol.

'T hi s investigation was supported by grants from the Department of N ational Health a?zd Welfare, Ottawarand the Saskatchewan Debartnzent of Public H ealth.Part VII .J . C h e n ~ .O'LC.n press: 1965.2Present address: Th e Atlantic Regional Laboratory, Th e National Research Coz~ncil , 411 Oxford St . , Hali fax,Nova Scotia.3Present address: The Department of Plant P athology, Th e University of C alifor nia, Davis, C alifor nia, U.S .A.Canadian Journa l of Chemist ry . Volume 43 (1965)

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Th e condensation of 3-n~ethy lcatechol IV) with chloroacetyl chloride in boiling benzene,in the presence of phosphorus oxychloride (i.e. using conditions similar t o those originallyemployed for synthesis of compounds of thi s type (cf. ref. 5, 8, 9) , gave a chloroacetylderivative of 3-methylcatechol, isomeric wit h, but different to, w-chloro-3,4-dihydroxy-2methylace tophenone (111), obtained by the conventional Friedel-Crafts procedure. Thi snew w-chloroacetophenone derivative was probably formed by a Fries rearrangement(cf. ref. 10) of an initially formed chloroacetyl ester of IV. In general thi s type of reactioncan be carried o ut by either isolating a suitab le ester of the catechol and subsequentlyrearranging it with either phosphorus oxychloride (9) or aluminium chloride ( l l ) , or bycarrying out the entire procedure, without the isolation of the intermediate ester, in thepresence of phosphorus oxychloride (9). In the present investigation, the latt er procedurewas employed. All attempt s to bring about a direct Fries-type rearrangement of pre-formed 2,3-di(chloroacetoxy)toluene VII ) were unsuccessful. The n.m.r. spectrum of t hesecond chloroacetophenone derivative in hexadeuteroacetone showed only a single peak(6 7.5), corresponding to two hydrogens, in the aromatic proton region, effectively rulingout one of the two alternative structures, i.e., w-chloro-2,3-dihydroxy-4-methylacetphenone, since the n.m.r. spec trum of thi s lat ter compound should indicate the presenceof two ortho aromatic protons. Therefore, the only possible str uctu re for th is chloro-actophenone derivative is w-chloro-3,4-dihydroxy-5-methylacetophenoneVIII). 3,4-Dihydroxy-w-methylamino-5-n~ethylacetophenone(IX) was prepared by treatment ofVI II with methanolic methylamine, and 5-methyladrenaline (11) was obtained by catalyticreduction of the aminoketone ( IX). Th e hydrochloride, sulfate, and oxalate of 5-methyl-adrenaline (11) were prepared but were too hygroscopic to purify completely; however, itwas possible to prepare a pure nonhygroscopic picrate of 11.4-Methyladrenochrome (X) was obtained as a deep-red crystalline solid on oxidation of2-methyladrenaline (I) with silver oxide in dr y methanol (cf. ref. 1 2) ; aqueous solutionsof X were readily obtained by oxidizing the base ( I) with potassium ferr icyanide, bufferedwith sodium bicarbonate (cf. ref. 13). A crystalline monosemicarbazone of X could beprepared by standard procedures. 7-Iodo-4-methyladrenochrome (XI) was readilyobtained as a violet-brown crystalline solid, when a n aqueous solution of I was oxidizedwith potassium iodate.5,6-Dihydroxy-l,4-dimethylindole XII) was obtained on reduction of $-methyl-adrenochrome (X) with ascorbic acid, and reduction of 7-iodo-4-methyladrenochrome ( XI )1~4th sodium borohydride gave 5,6-dihydroxy-7-iodo-1,4-dimethylindole XI II ); a11,ever, werettempts to reduce 7-iodo-4-methyIadrenochrome (X I) with ascorbic acid, how


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HEACOCK AKD HUTZINGER: AMINOCHROMES. V I I I

unsuccessful. 5,G-Diacetoxy-l,4-dimethylindole XIV) and 5,6-diacetoxy-7-iodo-l,4-diinethylindole (XV) were obtained on acetylat ion of XI 1 and XI11 respectively.Deiodination of XV with zinc and acetic acid gave XIV.

Th e red color of aqueous solutions of 4-methyladrenochrome (X) was discharged byalkali, ~vi th he formation of pale-yellow solutions, exhibiting the typical intense yellon-green fluorescence associated with 5, 6- di hy dr o~ ~i nd ox yl ssee ref. 14 for references),indicating that the expected rearrangement of X to 4-n~eth~ladrenolutinad occurred.Treatme nt of an aminochrome with a n acetic anhydride - pyridine mixture usually leadsto the formation of a 3,5,6-triacetoxyindole derivat ive (cf. refs. 13, 15). However, solutionsof 7-iodo-4-inethyladrenochromeXI) in acetic anhydride - pyridine illixtures did notlose their violet color, even after they had s tood fo r several weeks a t rooill temperature orhad been heated a t 80' for 2 h, suggesting th at no reaction had occurred in this case.

'7-h~Iethyladrenochrome XVI ) was obtained as a d ark violet, allnost blaclc, crystallinesolid by the oxidation of 5-methyladrenaline (11) with potassium ferricyanide, in aqueoussolution; it could also be prepared, in relatively poor yield, by the oxidation of 11 by silveroxide in methanol. Th e properties of t he aillinochroine (XVI) are unusual in several res-pects. The low water-solubility of XVI is unusual for non-halogenated aminochromes;aqueous solutions of XVI are violet, and not red in color, showing visible absorptionmaxima a t 534 mp in water and a t 530 inp in methanol, i.e. at longer ~vavelengthshan areusual f or unhalogenated anlinochronles (cf. refs. 1 4,1 5,1 6).Th is shift of the visible absorp-tion maxiina towards longer wavelengths appears to be associated with 7-substitution.All known 7-halogenoaminochromes absorb in th e 530 inp region (cf. ref. 14). Two other7-111ethyl substituted an~inochroineshave been described; solutions of 7-methyldopa-chrome and 4,7-dimethylnorepinochrome were prepared by Cromartie and Harley-Mason,and were reported to be deep violet in color (17). It was no t possible to prepare an iododerivative of XVI by the oxidation of I1 with pota ssiun~ odate under a wide variety ofconditions; the iodine-free anlinochrome (XVI) was invariably obtained. I t would appear,therefore, th at when the 7-position of the anlinochrome nucleus is blocked the iodine atomwill not enter any of th e alter native free positions in the molecule.

Th e violet color of aqueous solutions of X VI was also discharged by alkal i; yellowfluorescent solutions, presumably containing the corresponding 5,G-dihydroxyindoxyl,were obtained. 5,G-Dihydroxy-l,7-dimethyindoleXVIII: R = H ) , was obtained on thereduction of 7-inethyladrenochron~e (XVI) by ascorbic acid; this 5,6-dihj~droxyindole


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C A N A D I A N JOURNAL OF CHEMISTRY. VOL. 43. 1965

derivative oxidizes readily in ai r, and w as converted t o i ts more stab le diacetyl derivative( X V I I 1 : R = CH3CO).T h e n.m.r. spe ctra of the three 5,6-diacetoxyindole derivatives (in deuterochloroforinsolu t ion) described above ( i.e. XI V , XV, and X V II I: R = CHBCO) ar e fully compatiblewith the structures assigned to them on other grounds. The n.rn.r. spectrum of 5,6-diacetoxy-l,4-dimethylindole XIV ) exhibited a singlet peak a t 6 6.95, correspondingto th e arom atic hydrogen in the 7-position; the hydroge ns in the 2- and 3-positions of theindole nucleus in X IV gave rise to two d oublets centered a t 6 6.96 and 6 6.43 respectively,with a coupling constant of ca. 3 c.p.s. In the case of 5,6-diacetoxy-1,7-dimethylindol( X V I I I : R = COCHB), the 4-hydrogen was observed a s a singlet a t 6 7.19; the 2- and3-hydrogens gave rise to two dou blets centered a t 6 6.89 and 6 6.35 respectively with acoupling const ant of ca. 3 c.p.s. As would h ave been expected th e n.rn.r. spectr um of5,6-diacetoxy-7-iodo-1,4-dimethylindoleXV) only showed two doublets , due to the 2-and 3-hydrogens, centered a t 6 6.96 and 6 6.38 respectively, with a coupling constant ofca. 3 c.p.s. T he posit ions (6 values) of th e signals (and the coupling consta nts) du e to th evarious hydrogen a tom s in these substi tute d indole nuclei are quite compa tible with w hat\vould have been expected froin a consideration of the literature on the n.m.r. spectra ofindoles (cf. refs. 4, 18 , 19 ,20 ) .5 - i~ l e thy lad rena l ine11) has two positions ortho to the ethano lamine side chain a t whichintrainolecular cyclization might occur during am inochrome form ation. Howe ver, theoreti-cal considerations an d consideration of all repor ted am inoch rom e cyclizations suggestth at cyclization would occur a t the &posit ion (a fter the init ial oxidation of the cato-cholainine to an uncyclized o-quinone deriva tive). If the cyclization occurred in the a boveinanner a norinal aininochroine (i .e. 7-methyladrenoch rome ( XV I)) would result . How ever,if cyclization had take n place a t the 2-position in 11, an abnorinal alninochrome w ith theo-quinone functio n in the 6,7-position of t he indole ring systein would hav e resulted.T o show th at abnormal cycl ization had not occurred , the monosernicarbazone (XV II)obtained fro111 this aminochrome was treated with hot aqueous alkali, a procedure knownto remove the semicarbazide residue froil l adrenochroine monosemicarbazones (21).T h e n.1n.r. spectrum of t he degra dation prod uct dein onstra ted th at it wa s derived fro1117-methyladrenoch rome (X V I), since the degradation p roduct was clearly 6-methoxy-1,7-diluethylindole (XIX). If abnormal cyclization had occurred during the aininochromeformation from 11, the final product would have been 6-methoxy-1,5-dimethylindole(X X) . T he n.1n.r. spe ctra of t he degradation product (i .e. 6-methoxy-1,7-dimethylindol


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HEACOCK AND HUTZINGER: AMINOCHROMES. VIII 2539(XIX)) in carbon tetrachloride and deuterochloroform both clearly show the presenceof two aromatic hydrogens in an or tho relationship to each other. These aromatic hydrogenpeaks are observed as doublet s with a coupling cons tant of ca. 8.5 c.p.s. In th e alternativestructure (i.e.XX) the two hydrogens would be in a para relationship to each other andwould no t be expected t o show a coupling cons tant of this magnitude. Th e 6 valuesobtained are given in Table I.

T A B L E INuclear magnetic resonance spectral data for 6-methoxy-1,7-dimethyl indole*

Values o f 6Solv ent 4-H 5-H 2-H 3-H

*All peaks are doublets; the 6 values a re calculated from the observeddoublets.The coupling constants observed for the 4- and 5-hydrogens are -8.5c.p.s. and t hose for th e 2- and 3-hydrogens are -3.2 c.p.s.

E X P E R I M E N T A LUnless otherwise stated the infrared spectra were recorded on a Beckman IR-8 recording spectrophoto-me ter ; the ultraviolet and visible absorption spectra were recorded on a Un icam SP.800 recording spectro-photom eter and t he nuclear magn etic resonance spectra were recorded on either a Varian A-60 or HA -100instrumen t . Only th e more im portant peaks in the infrared and nuclear mag netic resonance spectra o f certaincomp ounds, which are relevant t o the discussion, are reported.T h e l ight petroleum used through out this invest igat ion was B.D.H. An alaR grade (b.p. 80-100") . Peroxide-free ether was invariably used t o minimize loses of readily oxidizable indole derivatives.

W-Chloro-3,4-dihydroxy-2-methylacetophenoneI I I )Powdered a nhydro us aluminium chloride (5 0 g) was added cautiously, with st irring, to a solution o f3-methylcatechol"25 g) and chloroacetyl chloride (20g) in carbon disul fide5 300 mi ) , a t lo0,with the rigorousexclusion of moisture. T h e resul ting suspension w as boi led, under ref lux, unt i l th e evolut ion o f hydrogenchloride had virtual ly ceased (c a. 45 m in) . Ice wa ter (1 000 mi ) and concentrated hydrochloric acid (50 m l)were added cau tiously t o the reaction mixture a f ter i t had been al lowed to cool to room tem perature.T h e crude product which separated out as an "of f -w hite" solid was removed b y f i l tration, washed wit h wate r,and on recrystallisation fr om wate r gave w-chloro-3,4-dihydroxy-2-methylacetophenoie24 g) in colorlessneedles, m.p. 17g0,r::!' 3 480; 3 340 ; 1 665 cm-1. T h e n.m.r. spe ctrum o f I11 in acetone-ds showed signals at6 7.38 (do uble t )an d 6 6.92 (double t ) ; = 8.5 c.p.s.Anal . Calcd. for CgHgC103: C , 53 .96; H , 4 .55; CI , 17 .22 . Fou nd: C , 54 .16; H, 4 .51; CI , 18 .08.w-Chloro-S,4-dinzethoxy-2-nte thylacetopheoe ( V )A solution of o-chloro-3,4-dihydroxyacetophenone1 g) and d imethy l su l fa te (1.25 g) in ace tone (30 m l )containing a nhydro us potassium carbonate (1.4 g) was st irred and boi led under ref lux for 8 h. Af t er this t im eth e suspension was poured into water (150 m i) , and the aq ueous react ion m ixture was cooled t o 5'. T h e crudecrystalline product was removed b y filtration, washed w ith wat er, and recrystallized from benz ene - ightpetroleum. It gave w-chloro-3,4-dimethoxy-2-methylacetophenonen colorless prisms (0.8 g) , m.p . 1 0l 0,undepressed on adm ixture with an authent ic sample, prepared by th e method of Hornbaker and Burger (6 ) .The se tw o samples of this compoun d also had identical infrared spectra.S,4-Dihydroxy-w-iodo-2-methylacetophenoneA solution containing o-chloro-3,4-dihydroxy-2-methylacetophe101e2 g) and sodium iodide (1.7 g)in acetone (250 m l) was stirred, at room tempera ture, for 30 min . Af te r this t im e th e solut ion was f i l tered,and t he f i l trate was evaporated to dryness. 3,4-Dihydroxy-w-iodo-2-methylacetophenone1.8 g) was obtainedin pale-yellow needles, m.p . 171-172O, o n recrystallization o f he residue from aqueo us ethanol.Anal . Calcd. for CsH9103: C , 37.01; H, 3.11. F ound: C , 37.17; H , 3.11.

40btain ed rom the Aldrich Chemical Co.5T wo other solvents: 1,2-dichloroethane and nitrometha ne, were tried i n place of the carbon disuljide, to reducethe danger of $re, since the carbon disz~ ljide ystem is very inflantnzable, but these alternate solvents gave unsat is-factory results.


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2540 CANADIAN JOURNAL OF CHEMISTRY. VOL. 43, 19653,4-Dihydroxy-2-methyl-w-methylaminoacetophenoneV I )w-Chloro-3,4-dihydroxy-2-methylacetophenone4 g) was added in port ions to a s t i rred, cooled mixture ofmethano l (5 ml) and a solut ion of m ethylamine (Matheso n Co.) in methanol (15 ml, saturated a t 5 ') ; s t i rr ingwas continued un ti l solut ion was complete (ca. 5 min). T he resul t ing brown solut ion was al lowed to s tan d a t5" for 2 h, during which time tan-colored prisms of 3,4-dihydroxy-2-methyl-w-methylaminoacetophenon(2.3 g), m.p. 218-222" (with decompo sition) sepa rated o ut, r,",":' 3 20 0 - 2 600; 1630 cm-I. I t was notpossible to purify this prod uct by re crystallization since it does not dissolve in most of the comm on solvents.Anal . Calcd. for CloHlaNOo: C, 61.52; H, 6.71; N, 7.18. Found : C, 60.81; H, 6.72; N, .17.The hydrochloride of 3,4-dihydroxy-2-methyl-w-methylaminoacetophenoneas prepared by s t i r r ing asuspension of th e base in ethano l with excess concentrated hydrochloric acid; the base dissolved a nd colorlessneedles of 3,4dihydroxy-2-methyl-o-methylaminoacetophenone ydrochloride, m.p. 256" (with decom-posi t ion), separated ou t af ter the solut ion had been st i rred a t room tem pera ture for a sh ort t ime (ca. 5-15min).Anal. Calcd. for CloHlrCINOa: C, 51.84; H, 6.12; N, 6.08; CI, 15.30. Found: C, 51.90; H, 5.95; N, .76;CI, 15.20.Treatment of a solution of w-chloro-3,4-dihydroxy-2-methylacetophenoe0.5 g) in ether (50 ml) withmethanolic methylamine (3 ml) for a few minutes a t room tem pera ture gave pale-yel low needles (0.3 g) ,m.p. 155'. Th is product, which is readily soluble in water an d ethanol , is prob ably a phenolic methy lam inesal t of w-chloro-3,4-dihydroxy-2-methylacetophenonecf. refs. 5,2 2) .Anal . Calcd. for CloHlrCIN03: C, 51.84; H , 6.12; Found: C, 52.04; H , 6.24.I -Me thy ladrenal ine ( I ) Hydrogen Oxalate ( i .e . 2-Methyl-a-methylaminomethylprotocatecltuyl Alcohol HydrogenOxalate)A suspension of 3,4-dihydroxy-2-methyl-o-methylaminoacetophenone5 g) , oxalic acid dihy drate (3. 25 g) ,an d 5% palladium-charcoal (3 g) in water (300 ml) a t 40' was shaken in an atmosph ere of hydrogen a tatmosph eric pressure for 30 h. After this t im e the reaction mixture was f i l tered, an d t he aqueous f i l t rateconcentrated i n vacuo (nitrogen "leak") to ca. 15m l; colorless prisms of 2-methy ladrenaline hy drogen ox alate(4.2 g) separated ou t af ter the co ncentrate had stood a t room temperature overnight . A small sample of theprod uct, purified for microanalysis by recrystallization from w ate r, had m.p. 181 " (with decomposition).Aual . Calcd . for ClzH17N07:CP 50.1 7;H ,5 .97 ;N,4 .88 . Foun d: C, 50.1 2;H , 6 .11;N, 4 .74.2- M e thy l adr e na li ne ( I ) F r e e B as e )A solu tion of 3,4-dihydroxy-2-methyl-o-methylaminoacetophenoneydrochloride ( 3 g) in water (220 ml) ,containing 5% pal ladium-charcoal (1 g) , was shaken in an atmosph ere of hydrogen a t atmospheric pressurefor 8 h. The catalyst was removed by f i l t rat ion and the clear f i l t rate was concentrated i n vaczto (nitrogen"leak") below 40" to ca. 1 5 ml. Solid potassium carb onate (2 g) was add ed to the st i rred solut ion; the crudebase (2.6 g) , which separated o ut af ter the react ion mixture ha d been al lowed to sta nd a t 5' for 1 h, wasremoved by f i l trat ion and was suff icient ly pure for the next ste p in the syn thesis of 4m ethyladrenoc hrome.A sam ple of 2-methy ladrenaline, purified for microanalysis by rec rystallization from a large volume of m eth-ano l, wa s obta ined in colorless prisms (m.p. 19G 192 " (with decom position)).Anal . Calcd. for CloHlaNOa: C, 60.89; H , 7.67; N, 7.10. F oun d: C , 60.85; H, 7.82; N, 6.82.4-Methyladrenochrome ( X ) cf . the Preparat ion of Ad ren ~ch rom e y the Method of Heacock e t al . (12 ))2-Methyladrenal ine (1 g) was suspended in absolute methanol (30 ml) , and 98% formic acid was addeddropwise, with st i rr ing, unt i l a clear solut ion was obtained. Freshly prepared si lver oxide was added inport ions to th e vigorously st i rred solut ion. After being st i rred, a t room temperature for 3 min, th e react ionmixture was f i l tered through a Dowex-1 (CI-) resin bed (cf. ref. 12). 4-Meth yladrenoc hrome (0.11 g) wasobtained in dark-red needles ( total ly decomposed without melt ing by 132")7 from the deep-red f i l t rateafter i t had been al lowed to stan d a t -20 for 4 h. A second crop (0.06 g) of crystal l ine 4-methyladrenochromewas obtained by addin g anhydrous ethe r (15 ml) to th e remaining f i l t rate and keeping the solut ion at -20'overnight, 222,312,4 90 mp; e:2OaOa 221,308 ,484 mp.Anal. Calcd. for CtoHl1N03: C, 62.16; H , 5.74; N, 7.25. Fo und : C, 62.12; H, 5.82; N, 7.01.4-Methyladrenochrome MonosemicarbazoneA solut ion of 2-methyladrenal ine hyd rochloride, prep ared by suspending 2-methy ladrenal ine (0.2 g) inwater (1.5 ml) and cautiously adding 2 N hydrochloric acid, with shaking, un t i l al l the sol id had dissolved,was oxidized with a solution of potass ium ferricyan ide (1.15 g) and sodium bicar bon ate (0.4 g) in water (3 ml).A deep-red solut ion of 4-methyladrenochrome formed rapidly an d considerable frothing occurred (due t o theevolut ion of carbon dioxide) . After this solut ion had been al lowed to stand a t room tem perat ure for 5 min, asolut ion containing semicarbazide hydrochloride (0.2 g) an d sodium ace tate (0.2 g) in wa ter (1.5 ml) wasadd ed; the react ion mixture, af ter being st i rred a t room tem perature for 10 min an d standing a t 5 ' for 5 h,

Gw-Ch10ro-3,4-diAydr~xy-2-methylacetopltenoneould be extracted w ith ether from aqueo us solutions o f the yellowproduct which had been made alkal ine with sodiu m hydroxide .7T he decomposi t ion points of al l the aminochromes and aminochrome se~nicarbazonesdescribed i n this paperwere measitred on a Leitz hot-stage instru men t.


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HEACOCK AND HUTZINGER: AMINOCHROMES. VIII 2 5 4 1deposi ted d ark redd ish-o range crysta ls of the cru de semicarbazone. 4 -Methy ladrenoch rome m onosemi-carba zone (0.125 g) was obtained in deep-orange needles (totally decomposed witho ut melting by 248 ') onrecrystallization of the crud e produ ct from a pyridine-water (1 .1) mixture.Anal. Calcd . for CllH14N.,03: C, 52.79; H , 5.64; N , 22 .39 . Fou nd : C , 52 .95 ; H , 5 .72 ;N, 22.44.7-Iodo-4-methyladrenochro~ne X I )Potass ium iodate (1.7 g ) was added , a t room te mpe ratu re wi th s t i r r ing , to an aqueou s so lu t ion of 2 -m ethy l-ad renal ine hydroch lo ride (p repared by cau t iously add in g 2N hydrochloric acid to a suspension of 2-me thyl-ad renal ine (1 g ) in water (350 ml) un t i l a c lear so lu t ion was ob tained) . Th e reaction m ix tu re was s t i r red fo r3 h a t 5"; durin g this time deep -violet needles of 7-iodo-4-methyladrenochrome (1.1 g ) separated ou t ( to ta l lydecomposed wi thou t mel t ing by ca . 110) ,A% 2 3 4 , 3 1 4 , 5 3 4 m p ; 2 3 4 , 3 0 9 , 5 3 0 m p .A na l. Ca lc d. f or C ~ O H ~ O I N O ~ :, 37 .64 ; H , 3 .16 ; I , 39 .78 ; N, 4 .38. Foun d : C , 37 .74 ; H, 3 .15 ; I , 39.85 ; N,4.45.6,6-Dilzydroxy-1,4-dimethylindoleX I I )Ascorb ic acid was added in por t ions to a v igorously s t i r red two-phase system, consis t ing of a n aqueousso lu t ion of 4 -m ethy lad renochrome (p repared as descr ibed abov e by th e ox idat ion of 2 -m ethy lad renal ine(0 .3 g ) wi th po tass ium ferr icyan ide) and ethe r (20 ml) , un t i l the red co lo r of the aqueo us phase ha d d is-ap p ea red . T h e e th e r l ay e r w as sep a ra t ed an d th e aq u eo u s p h ase w as ex t r ac t ed w i th a fu r th e r q u an t i t yof e ther . Dry benzene (10 ml) was added to th e combined , d r ied (NaZS04) e ther so lu tions , and t he resu l t ingso lu tion was concen trated t o ca . 5 ml in vacuo (n i t rogen " leak"); co lo r less p risms of 5 ,6 -d ihy dro xy- l ,4d imethy lindo le (0 .11 g ) , m.p . 14&141, were ob tained by the add i t ion o f a smal l qua n t i ty o f n -he p tane to t hewarm concen trated benzene so lu t ion .Anal . Calcd . fo r Ci oH iiN 0~ : , 67 .78 ; H, 6 .26 ; N, 7 .91 . Found : C , 67 .56 ; H, 6 .25 ; N, 7 .87 .5,6-Diacetoxy-1,4-dimetltylindoleX I V )A mix tu re o f d r y pyr id ine (2 ml) a i ld acet ic anhy dride (2rill) was adde d to a d r ied e thereal so lut ion of5,6-dihydroxy-1,4-dimethylindoleprepared by the method descr ibed above) . The l igh t-b rown so lu t ion ,ob tained a f ter removal of t he e th er in vaczlo , was a l lowed to s t and overn igh t a t room temp eratu re a ndthen poured in to an ice-water mix tu re . Th e crude d iacetate , th at sep arated o u t , af fo rded co lor less need les o f5,6-diacetoxy-l,4-dimethylindole0.22 g) , m.p . 135-136O, on recry stallizatio n fro m benzen e- ight petroleum.Anal. Calcd. for C14HlbN04: C, 64.37; H , 5 .79; N, 5 .36. Fo und : C, 64.47; H , 5 .82; N, 5 .52.6,6-Diltydroxy-7-iodo-l,4-dimethylindoleX I I I )Sodium borohydride was ad ded cau t iously to a v igorously s t i r red two-phase system, consis t ing o f a sus-pension of 7-iodo-4-methyladrenochrome (0 .5 g) in water (20 ml) and ether (20 ml), until the violet color ofth e am in o ch ro m e h ad b een to t a l ly d i sch a rg ed . T h e e th e r l ay e r w as sep a ra t ed an d th e aq u eo u s p h ase w asex tracted wi th a fu r ther quan t i ty of e ther . Dry benzene (10 ml) was adde d to the combined , d r ied ( Na ~S 04 )ether ex tr acts and th e resu l t ing so lu t ion was conc en trated t o ca . 5 ml in vacuo (n i t rogen " leak") ; co lo r lessprism s of 5,6-dihydroxy-7-iodo-1,4-dimethylindole0 .19 g ) were ob tained b y th e add i t ion of a smal l quan t i tyof n -hep tane to the warm co ncen trated benzene so lu tion . Th is substance d id no t mel t , bu t tu rned b lacksomewhere between 140 and 180, depend ing on t he ra te o f heat ing .Anal. Calcd. for CioHi01NOz: C, 39.62; H , 3 .33 ; N, 4 .62 ; I , 41 .87 . Fo und : C , 39 .65; H , 3 .24 ; N , 4 .55 ;I, 42.04.6,6-Diacetoxy-7-iodo-l,4-dimethylindoleX V )A mix tu re o f d ry pyr id ine (2 ml) an d acet ic a i ihydr ide (2 ml) was adde d to a d r ied e thereal so lu tion o f5,6-dihydroxy-7-iodo-1,4-dimethylindole,nd th e react ion mix tu re was worked up a s descr ibed above.Colorless prisms of 5,6-diacetoxy-7-iodo-1,4dimethylindole0.22 g), m.p. 192-193", were obtai ned on re-crystalliz ation of th e crud e product from berizene- ight petroleum. T he n.m.r. spectru m of this substance indeu teroch lo ro fo rm showed two doub lets cen tered a t6 6 .96 an d 6 6.38 (J= 3.2).Anal . Calcd . fo r C14H141N 04: , 43 .43 ; H , 3 .65 ;I, 32.79; N, 3.62. Found: C, 43.26; H, 3 .72; I, 32.37; N ,--Deio dinati on of 5,6-Diacetoxy-7-iodo-l,4-dimethylindoleX V )Zinc powder (0 .8 g) was adde d in portions t o a solution of5,6-diacetoxy-7-iodo-1,4-dimethylindolen glacialacet ic acid (5 ml) . Th e suspension was bo i led under reflux , wi th s t i r r ing , fo r 5 min a nd f i l tered , and t he res idualzinc was washed wi th a smal l quan t i ty o f ho t g lacial acet ic acid . Crushed ice was added to the combinedf i l t ra te and wash ings and the resu l t ing aqueous p roduct was ex tracted several t imes wi th e ther . T he combinedethe r ex tracts were washed wi th aq ueous sod ium b icarbonate un t i l f ree of acet ic acid and f inal ly w i th water .Dry benzene (5 ml) was added to th e d r ied (NaZS04) e ther so lu t ion and th e vo lume of th e so lu t ion wa sreduced to ca . 3 ml. 5,6-Diacetoxy-1,4-dimethylindole32 mg) , iden t ical in a l l respects wi th the samp leprepared by th e method descr ibed above, was ob tained on the add i t ion o f a smal l qua n t i ty of l igh t pet ro leumto th e concen trated benzene so lu t ion .


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2542 CANADIAN J OURNAL OF CHEMISTRY. VOL. 43. 19651,s-Di(chloroaceto.vy)tolueneV I I )A mixtu re of 3-methylcatechol (2 g) and chloroacetyl chloride (6 g) was heated in an oil bat h a t 12&130,under anhydrous conditions, until hydrogen chloride evolution had ceased (i.e. ca. 90 min). The reactionmixture was poured into water (100 ml) and the product was stirred, a t room temperature, for 30 min. T hesolid which precipitated afte r th e aqueou s produc t ha d been stored at 5O overnight gave colorless needles of2,3-di(chloroacetoxy)toluene (3.8 g), 1n.p. 64", on repeated recrystallization from aqueous ethanol, u$174 5, l 770 cm-I.Anal. Calcd. for Cl~HloClzOd:C, 47.68; H , 3.63; CI, 25.59. Fou nd: C, 47.64; H , 3.81; Cl, 25.51.w-Chloro-S,4-dihydroxy-5-methylacetoplzenoneV I 1 )A mixture of 3-methylcat echol (54 g), chloroacetic acid (47.3 g), pure phosphorus oxychlorides (28 g),and dr y benzene was boiled, under reflux, in a nitrogen atmosphere, for 31 h. Carbon tetrachloride (150 ml)was added and the reaction mixture allowed to st and overnight a t 5 The crude w-chloro-3,4-dihydroxy-methylacetophenone (24 g), m.p. 178", which separated as a pale-pink solid, was sufficiently pur e for use inthe next stage of t he synthesi s and was used directly, after washing with wat er and carbon tetrachloride.A sample was purified for analysis by recrystallizatioil from water and had m.p. 180, u ~ ~ ~ " '490, 3 290,16 70 an-'. Th e n.1n.r. sp ectru m of this subst ance in acetone-dt showed a single singlet peal< (6 7.5) in thearoma tic hydrogen region.Anal. Calcd. for CgH9C1O3:C, 53.96; H , 4.55; CI, 17.72. Found : C, 53.87; H, 4.29; CI, 17.85.5,4-Dilzydroxy-w-iodo-6-nzetlzylacetophenone3,4-Dihydroxy-w-iodo-5-methylacetophenonepale-yellow needles, 1n.p. 177") was prepared froin thecorresponding chloro compound by a procedure identical t o tha t described above for the preparat ion of t heanalogous 2-n~et hylacetoph enone erivative.Anal. Calcd. for C9Hg103: C, 37.01; H, 3.11. Found: C, 37.25; H, 3.38.S , 4 - D i h y d r o x y - 5 - m e l h y l - w - m e t h y l a m i ~ z o a ~ e n eI X )A mixture of methanol (5 ml) an d a solution of methylamine in methanol (15 inl, satu rat ed at 5O) wasadded a t 0' to solid 3,4-dihydroxy-5-methyl-w-chloroacetophenone5 g), and the resulting suspension wasshaken in a tight ly stoppered Aask for 6 min. Excess methylamine and the solvent was then removed i n vaczio,below 90"; the brownish solid residue was tri tura ted with etha nol (30 ml) and afforded ta n prisms of 3,4-dihydroxy-5-methyl-w-methylaminoacetophenone (2.1 g), m.p. 203-205". Th e product, after filtration andwashing with ethanol, was su f ciently pure for t he next stage in th e synthesis. A sample of IX was purifiedfor analysis by recrystallization from a large volume of methanol an d was obtained in light tan-coloredprisms (m.p. 205-206" (with decomposition)).Anal. Calcd. for CI OH I~ NO ~:, 61.52; H, 6.71; N, 7.18. Fou nd: C, 61.23; H, 6.87; N, 7.09.3,4-Dihydroxy-5-methyl-w-methylaminoacetophenone ydrochloride (colorless needles; m.p. 235", withdecomposition) was prepared from the base in an analorrous manner to t ha t described above for the preDara-. .tion o ft he 2-methyl derivative.Anal. Calcd. for ClaH14CIN03: C , 51.84; H , 6.12; N, 6.08: CI, 15.30. Found: C, 51.86; H , 5.87; N, .94;CI, 15.56.Treatment of w-chloro-3,4-dihydroxy-5-methylacetophe101eith methanolic methylamine in ether, in amanne r similar to th at described abov e for the analogous 3-methyl compound, gave pale-yellow needles(m.p. 80"). The microanalytical values for carbon and hydrogen are not incompatible with this substancebeing a methylamine salt of w-chloro-3,4-dihydroxy-5-methylcetophenone (cf. refs. 5, 22 ).Anal. Calcd. for CIO HI. ~CI NO~ :, 51.84;H , 6.12. Fou nd: C, 52.19, H , 6.30.6-Methyladrenal ine ( i .e . 5-Methyl-a-methylamino~nethylprotocatechz~yll cohol (11) )A solution of 3,4-dihydroxy-5-methyl-w-methylaminoacetopheone ydrochloride (2.4 g) in water (200 ml),containing 5% palladium-charcoal (1 g), was shaken in an atmosphere of hydrogen a t atmospheric pressurefor 5 h. After this time the catalyst was removed by filtration and the clear filtrate was concentrated in vacuo(nitrogen "leak"), below 40, to ca. 12 ml; solid potassium carbonate (1.5 g) was added, with sti rring, and thecrude base separated out, after t he solution had been allowed to stan d a t 5' for 1 h. Th e product obtained inthis mann er was pure enough for oxidation dire ctly t o the corresponding aminochrome. A sample of 5-methyl-adrenaline was purified for microanalysis by recrystallization from a large volume of methanol a nd wasobtained a s colorless prisms, m.p. 195-197" (with decomposition).

Anal. Calcd. for C~OH LI NO ~:, 60.89;H , 7.67; N , 7.10. Found: C, 60.89; H, 7.84; N , 6.93.5-Methylad renaline picrate was prepared by addi ng a solution of picric acid (0.1 g) in dr y benzene (8 ml)to a stirred suspension of the base (0.1 g) in ethanol (1 ml). The solid dissolved a nd dark-yellow needles of thesCommercial phosphorus oxychloride wa s purified by the procedure described by Ott (9), i .e. b y washing asolution of the imp zire product i n clzloroform with ice water; removing the solvent in vacuo and fractional distillationof the product. T he fraction boiling in the range 105-106" wa s collected and used directly. T he direct use of thecommercial product, which contains phosphorus pentachloride and phosphorzls trichloride, leads lo extensive tarformation and low yields of product .


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HEACOCK AND HUTZINGER: AMINOCHROMES. VI I I 2543crude picrate were obtained after t he solution had stood a t 5' for 3 h. 5-Methyladre naline picra te (0.12 g)m.p. 183O, was obtained in yellow needles on recrystal lization of t he cru de produc t from a benzene-alcohol(9:l) mixture.Anal. Calcd. for CltjH18N4010: C, 45.07; H, 4.26; N , 13.14. Found: C , 45.07; H, 4.32; K, 3.08.7-iMethyladrenoclzrome ( X V I )5-Methylad renaline (0.6 g) was suspended in water (5 ml) and 2 N hydrochloric acid was added cautiously,with stirring, until a clear solution was obtained. A solution containing potassiu~ n erricyanide (3.5 g) an dsodium bicarbonate (1.2 g) in water (10 ml) was added, with stirring; the solution became deep violet incolor and vigorous effervescence occurred. 7-Methyladrenochrome (0.18 g) (totally decomposed withoutmelting by 105') was obtained in deep violet (almost black) needles after the reaction mixture ha d beenallowed to stand a t 5' for 1 h, 232,305,53 4 mp;Anal. Calcd. for CloH11NOa: C, 62.16; H, 5.74 ; N, 7.25. F ound: C, 62.60; H, 5.72; N, .92.Attempted Preparation of aft Iodo-7-ntethyladrenochromeAn aqueous solution of 5-methyladrenal ine hydrochloride (prepared from 0.3 g of t he base) was trea tedwith potassium iodate (0.5 g), at pH 7.2 (the pH of the solution was adjusted t o 7.2 by the cautious additionof solid sod iu ~n arbonate), in an identical manner t o that described above for th e preparation of 7-iodo-4-methyladrenochrome. A deep-violet solutioll, having ultraviolet and visible spectral characteristics identicalto those of 7-methy ladrenochrome was obtained. T he spect rum of t he solution was not affected by prolongedreaction time (i.e. ca. 2 h), or by th e addition of a further qua nti ty of potassium iodate (0.5 g).

7-RiIethyladrenochrome monose~nicarbazo~~e0.21 g) (tot ally decomposed with out melting by 245') wasobtained, when a solution of semicarbazide hydrochloride (0.2 g) and sodium a cetat e (0.2 g) in water (3 ml)was added to a solution of 5-methy ladrenaline hydrochloride tha t had been oxidized with potass iu~nodate.Th e sample of 7-methyladrenoc hrome monosemicarbazone, obtained in this manner, was identical to theproduct prepared by th e method described below.7-d&ethyladren oc/zrome Monosenlicarbazo?ze ( X V I I )X solution of 7-methyladrenochrome, prepared by t he oxidation of all aqueous solution of 5-methyl-adrenaline hydrochloride (from 1 g of base) with potassium ferricyanide, was trea ted with a solution of semi-carbazide hydrochloride and sodium acetate in the manner described above for the analogous 4-methylderivative. 7-Methyladrenochrome monosemicarbazone (0.95 g) (totally decomposed without melting by24.5') was obtained in wine-red needles on recrystallizatio ll of the crude prod uct from a pyridine-water(1 1) mixture.Anal. Calcd. for C~IHI.IN.IO~:, 52.79; H, 5.64; N, 22.39. Found: C, 52.62; H, 5.61; N, 22.22.

5,6-Dihydroxy-l,7-dinzelhylindoleX V I I I : R = H )Ascorbic acid wasadd ed in portions, with stirring, t o a two-phase system consisting of ether and an aqueoussolutio~lf 7-methyladrenochron1e, prepared by the potassium ferricyanide oxidation of 5-methyladrena line(0.6 g) by t he method described above, until the deep-violet color of t he solution had disappeared. Th e ethe rlayer was removed an d the aqueous phase was extracted with a further quant ity of ether . Dry benzene (10 ml)\\;as added to th e combined, dried (Na?SOr) ethereal extracts, an d the resulting solution concentrated toca. 5 ml. Colorless prisms of 5,6-dihydroxy-l,7-dimethylindole0.15 g) were obtained 011 addition of a smallqua nt ity of n-heptane t o the warm benzene solution. The product could be further purified (m.p. 155") by highvacuum sublimation at 160 (bath temperature) a t 0.2 mm.Anal. Calcd. for CIOH IIN OI: , 67.78; H,6.26; N, 7.91. Foun d: C , 67.64; H , 6.32; N, .87.5,6-Diacetosy-l,7-dimethylindoleX V I I I : R = C O C H 3 )

-4 ~ni xtu re f d ry pyridine (3 ml) and acetic anhydride (3 ml) was added to a dry ethereal solution of5,6-dihydroxy-1,7-dimethyli~ldole,repared by the method described above. The ether was removed inoaczro, and t he concentrated reaction mixture was poured into all ice-water mixture, afte r it had been allowedto st and overnight at room temperatu re. Recrystallization of t he crude product from benzene - ightpetroleum gave 5,6-diacetoxy-1,7-dimethylindole0.35 g) in small colorless prisms, m.p. 137-135'..Anal. Calcd. for CI ~ H ~ S N O ~ :, 64.37; H, 5.79; N, 5.36. Fou nd: C, 64.01; H, 5.68; N , 5.21.6-ilfetlzosy-l,7-dintethylindoleX I X ) : Prepared by the Alkal ine Degradat ion of 7- i l&et l~yladrenochromeVIono-

senzicarbazone and Sz~bseque?~t- i l&ethylat ion (c f . re f . d l )Solid potassium hydroxide (2 g) was added, with stirring, in a nitrogen atmosphere, to a suspension of7-methyla drenochrome monosemicarbazone (0.5 g) in water (20 ml) a t DO0, the resulting deep red-brownsolution was boiled (in an atmosphere of nitrogen) until effervescence had ceased (ca. 2-5 min). Th etemperature of t he solution was then reduced to ca. 50' by th e addition of crushed ice; dimethyl sulfate(2.5 ml) was added dropwise and the reaction mixture was cautiously heated to 80, and maintained a t thistemperature for 5 minutes. The resulting solution was cooled to room temperature and extracted severaltimes with ether. T he combined ex trac ts were washed with N potassium hydroxide solution, dried (Na?S 04),and evaporated to dryness. Th e crude product was purified by recrystallization from light petroleum and


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2544 CANADIAN JOURNAL OF CHEMISTRY. VOL 43 . 1965gave 6-methoxy-1,7-dimethylindolen colorless prisms (0.19 g) ; m.p. 93': 224, 275, 292 (sh), 304(sh) mp. Th e significant n.m.r. peaks are given in Table I.Anal. Calcd. for C1IHlrNO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.55; H, 7.31; N, 7.98.

ACKNOWLEDGMENTSThe authors wish to express their thanks to Dr. K. McCallum of the Univers ity of

Saskatchewan for the use of the Varian A-60 nuclear magnetic resonance spectrometer.Th e authors are also grateful to Dr. R . G. Micetich of R. & L. Molecular Research Ltd.,Edmonton, Albert a, and to Dr. R. Greenhalgh and his colleagues in the Defence Chemical,Biological and Radiation Laboratories, Ottawa, Ontario, for assistance in obtaining someof the n.m.r. spectra and to the lat ter group for some useful comments on t he interpreta-tion of t he spectra.

REFERENCES1. S. FRANKELnd R. ALLERS. Biochem. Z. 18,40 (1909).2. L. KRAUS. Biochem. Z. 22,131 (1909).3. D. ICHTERnd H. BLASCHKO.J. Chem. Soc. 601 (1937).4. R. A. HEACOCK,. HUTZINGER,. D. SCOTT. . W. DALY, nd B. WITKOP. J. Am. Chem. Soc. 85,1825(1963).5 . F. STO& Ber. 37,4149 (1904).6. E. HORNBAKERnd A. BURGER. J. Am. Chem. Soc. 77,5314 (1955).7. F. K i j ~ znd C. HORNING.Ger. Patent No. 682,394 (September 28th, 1939); Chem. Abstr. 36, 3011(1942).8. S. K. ZEKZGOVSKY.. Russ. Chem. Soc. 25,154 (1893); J . Chem. Soc. 66, Abstr. I , 73 (1894).9. E. OTT. Ber. 59,1068 (1926).10. A. H. BLATT. Chem. Rev. 27,413 (1940); Org. Reactions, 1 ,343 (1942).

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Documents

R.A. Heacock and O. Hutzinger- The Chemistry of the Aminochromes Part VIII: The Preparation and Properties of 4- and 7-Methyladrenochrome