CA1232911A - Process for preparing 5,6-dihydroxyindole - Google Patents

Abstract

PROCESS FOR PREPARING 5.6-DIHYDROXYINDOLE

ABSTRACT OF THE DISCLOSURE

5,6-Dihydroxyindole is prepared by the catalytic reductive cyclization of 4,5-dihydroxy-2,.beta.-dinitrostyrene in a single step using hydrogen with a palladium, platinum or rhodium catalyst in a polar hydroxylic reaction system. No reaction byproducts or only a single reaction byproduct are produced. The 4,5-hydroxy-2-.beta.-dinitrostryrene intermediate can be produced by the chemoselective debenzylation of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene using trifluoroacetic acic. 5,6-Dihydroxyindole is a useful component in hair dye formulations and as an intermediate in the synthesis of melanin.

Description

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PROCESS FOR PREPARING 5, 6-DIllYDROXYINDOLE

BACKGROUND OF THE INVENTI ON

Field of the Invention This inventivn relates to a method for preparing 5,6-dihydroxyindole. More particularly, thi~ invention relates to a one step process for preparing 5,6-dihydroxyindole from 4,5 dihydroxy-2,B-dinitrostyrene in high yield~ and purity by a catalytic reductive cyclization in the pre~ence of hydrogen and a supported pall~dium,plstinum or rhodium catalyst. The invention ~lso relateF, to the preparation of the ~tarting 4,5-dihydroxy-2,~-dinitrostyrene reactant and the reaction intermediate~ therefor.

Di~cussion of the Prior ~rt 5,6-dihydroxyindole i~ a known intermediate in tbe preparation of melanin whic~ i~ an organic pigment useful 15~ in, for example, hair dye preparstions. Hair;~dyeiog composition snd methods using 5,6-dihydroxyindole or a derivative thereof ~re ~bown, for exampl2, in U.s. P~tent~ 2,934,396 and 3,194,734.
~The hydroxyindole~ are also known as anti-oxidant6, 8ee e.g. U.S. Patent 2,787,551, and ~ intermediute~ in the

2~ ~ production of amino acid~, alkaloids, tryptamines;,~ snd the like, ~ee~e.g. U.S. Patent 3,732,245.~ For ~bese vari~u~
utilities~, it is essential thut the~5,6-dihydroxyindole be available in hig~ purity and un~er ~stable condition~.
Therefore,~the 6ynthe8iu of indoles aDd hydroxyindoles 2~5 ~ ~hs~received much uttention, due to their broad ran8e of : ~ ;

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use~ and biol~gic~l applic~tions. ln p~rticul~r, extensive ~tudies have been made of the synthesi6 of 5,6-dihydr~xyindole and it6 subsequent polymerization to melanin. See, for example, Mason, H.S., J. Biol. Chem, 1948, Vol. 172, p.
83; Bu'Loc~, J.D. and Harley-Mason, J., 3. Chem. Soc. 1951, p. 703 and p. 2249; Cromartie, R.I.T. and Harley-Mason, J., J. Chem. Soc. 1953, p. ~00; Beer, R.J.S., et al, J.
Chem. Soc. 1948, p. 2223; Clemo, G.R. and Wei~s, J., J.
Chem. Soc. 1945, p. 702 snd p. 1795; Clemo, G.R. and Duxbury, F.K., J. Chem. Soc. 1952, p. 3464 and p. 3844; Benigni, J.D., et ~1, J. Heterocycl Compounds, 1965, Vol. 2, p. 387;
and Young, T.E., et al, J. Org. Chem. 1980, Vol. 45, p.
2901. The chemical reductive cyclization of 5-benzyl~xy-2, g-dinitrostyrene to 5-benzyloxyindole using powdered iron and organic acid i~ ~hown in Canadisn Patent 555,760. The reductive cyclization of ortho-nitro-~-aminostyrene to the corresponding indole~ by either chemical (e.g. Fe--CH3C02H) or catslytic (e.g. H2--Pd/C, organic ~olvent) reduction : i8 shown in U.S. patent 3,732,245. These ~yntheses, however, -~ 20 are unattractive either because of low yields or the res~lt~
; sre difficult to repr~duce on a large ~c~le.
The isomeric 4,5-dihydroxy-2,B-dinitrostyrene& are promisin~ intermediate~ in the 6ynthesis of 5,6-dihydroxyindole.
; Foe example, in the above cited article by Beer, et 81, ~ ~cetyl~tio~,chemicsl reductive cyclization (Fe--CH3C02H) ; and deacetyl~tion give ~bout 35% yield as ~hown in the following Scheme I.
~ . ~

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: ~
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: ~

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~Z3;Z9 ~ + CH3N2 KOH (alc) ~ ~ ~10 +
HO No2 2 (1~ (2) ~OH ~ N~ (CH CO) 2O
Ht)~ 2 :~ 2 CH3CO2Na;~

~3) (4) ~X; CH3 ; Ac~
AcO 2 `:: (5) (6) .
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However, ~his ~cheme, in addition to requiring the acetyla-tio~ and deacetylation 6tepfi to protect and then unblock the hydroxyl groups also requires a com~licated cyclization using elemental iron, Fe, and acetic acid. Still further, ~tringent purification i~ required to isolate the intermediate 5,6-diacetoxyindole (6) from the resulting black gum. 5,6-Dihydroxy-indole (7~ resulting from the deacetylation of 5,6-diacetoxyind~l is unstable under the reaction conditions (pH ~ 7), and anti-oxidant~ (e.g. Na2S2O4~ must be included. Accordingly, the product 5,6-dihydroxyindole ide-al~j is.not us.ed ~~Te:c$1y fer the production of melanin.
Other researcherx have shown the efficacy of AlX3--thiol and AlC13--dichloroethane systems in the cleavage of methylene-:: dioxy ethers. See, for example, M. Node, et al, J. Org. Chem.
19~0, Vol. 45, p. 4275; and M.A. Avery, et al, J. Org. Chem., 1980, Vol. 45, p. 2750, ~espectively. In the latter proeedure, which uses a ring opening method, 4,5-dihydroxy-2-nitro-benzaldehyde (1) is.synthesized from 6-nitropiperonal (9) ¦ < l ~ CHO
through 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde ~10), ~ :
:~ : Cl~H2 ~ CHO
: H ~ NO :

~in 87.9% reported yield basPd on 6-nitropiperonal.
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~ ~ -4- ~

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Although a one-step demethylenation of 6-nitropiperonal with AlCl3--ClCH2CH2Cl seems viable, the desired product (1) is isolated in higher yield through the intermsdiary (10). 4,5-dihydroxy-2-nitrobenzaldehyde (1) can then be converted to 4,5-dihydroxy-2,B-dinitrostyrene (2~ by known procedures, such as shown by Beer, et al.
However, it has been found that the dechloromethylation of Avery, et al cannot be effectively utilized for amounts of starting material in excess of about 1 gram.
Alternate routes to (E)-4,5-dihydroxy-2,B-dinitrostyrene are also known. Thus, condensation of

3,4-dialkoxybenzaldehyde with CH3NO2, followed by nitration, gives the corresponding 4,5-dialkoxy-2,B-dinitrostyrene. However, standard ether cleavage with hydrogen halides is not useful, since hydrohalo-genation occurs. It was necessary, therefore, to develop a mild method for removal of the protecting groups. Although trifluoroacetic acid (CF3CO2H) has been reported as a debenzylation reagent (March, ~.P.
and Goodman, L., J. Org. Chem. 1965, Vol. 30, pp.
2491-2) the authors do not elucidate on the general theory or scope of the debenzylation reaction or on its advantages. For example, it has now been found that -~ other groups in the molecule can increase the rate of ~ebenzylation, but these groups are not necessary for the success of the reaction. It has also now been found that CF3CO2H is 100% selective and does not affect other functional groups in this molecule. Based on this discovery, a mild and selective method for unblocking ~ 30 the hydroxyl protecting benzyl groups has now been ; ~ ~ developed using trifluoroacetic acid as the selective debenzylation agent. According to this reaction, the benzyl groups of 4,5-dibenzyloxy-2,B-dinitrostyrene are removed without reduction of the nitro ~: :

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groups or ~ddition to styrene double bond ~ would occur w~th norm~l ether elesvsge reagent~ (e.g. H2--Pd/C, hydrogen h~lides, and H~S04). Accordingly, ~ highly effective ~nd nove~ mean~ h~ been developed to prepsre the 4,S-dihydroxy-2, ~-dinitrostyrene compound used a6 the reactant for formin~
the object 5,6-dihydroxyindole by the ~elective debenzyl~tion of 4,5-dibenzyloxy-2,~-dinitrostyrene with trifluoroacetic scid.
Previously, catalytic cyclization of 4,5-dihydroxy-2,g-dinitrostyrene ~14) was unknown, although several methods are known for the corresponding dialkoxy and diaryloxy deriv~-tive~. See, for example, the above mentioned article by J.D. Benigni, et al and C.F. Heubner, et ~1, J. Amer. Chem.
Soc. 1953, Vol. 75, pp. 5887-5890. However, these procedures which involve refluxing CH3C02H--Fe and 10% Pd/C--H~ in organic solvent~, e.g. a mixtur~ of ethyl acetate, ~cetic ~cid, and ethanol, are not u~eful for cyclization of 4,5-dihydroxy-¦ 2,~-dinitro6tyrene (14). Under the typical H2 pressure : range of from 40 to 55 pounds per squ~re inch (psi) the 20 ~ ~cyciiz~tion of 4,5-dihydroxy-2,B-dinitrostyrene gives only a ~mall ~mo~nt of 5,6-dihydroxyindole whicb is contamin~ted:
wlth mflny by-products.

SUMMARY OF l'HE INVENTI ON .
;It i~, therefsre, sn object of the present ;nvention to provide B direct route or preparing 5,6-dihydroxyindole from 4,5-dihydroxy-2,~-dinitrostyrene which minimize~ or totally elimin~tes formation of any by-products.

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It is another object of this invention to provide a process for preparing 5,6-dihydroxyindole which is stable under the reaction conditions and which can be easily recovered.
A still further object of this invention is to provide a simple process for preparing 5,6-dihydroxy-indole from 4,5-dibenzyloxy-2,B-dinitrostyrene by first selectively debenzylating the latter to form 4,5-dihydroxy-2,B-dinitrostyrene using trifluoroacetic acid and, thereafter, catalytically reducing the dinitrostyrene compound to 5,6-dihydroxyindole in the presence of hydrogen and a palladium, platinum or rhodium catalyst in a suitable reaction medium.
Still yet another object of this invention is to provide a more efficient process for preparing

4,5-dihydroxy-2 nitrobenzaldehyde, which can then be easily converted into 4,5-dihydroxy-2,B-dinitrostyrene, by ring-opening 6-nitropiperonal with AlCl3 and dichloroethane to produce 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde in yields in excess of 93%
followed by ether cleavage to produce 4,5-dihydroxy-2-nitrobenzaldehyde.
These and other objects of the invention which will be more readily apparent from the following detailed description can be accomplished by a process for preparing 5,6-dihydroxy-indole H0 ~ N
by subjecting 4,5-dihydroxy-2,B dinitrostyrene H0 ~ CHzCH-N02 ~` .
r~

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to catalytic reductive cyclization with hydrogen in the presence of a palladium, platinum or rhodium catalyst in a suitable reaction medium to produce the object

5,6-dihydroxy-indole. According to this invention, the object 5,6~dihydroxy-indols can b~ obtained at a yield of 95 to 100% based on the starting 4,5-dihydroxy-2,B-dinitrostyrene without any by-products, i.e. 95 to 100%
conversion at 100% selectivity. Only a single by-product is observed when a mixture of distilled water and acetic acid is used as the reaction medium.
In a further aspect of the invention, the 4,5-dihydroxy-2,B dinitrostyrene reactant is obtained by the debenzylation of 4,5-dibenzyloxy-2,B-dinitrostyrene with trifluoroacetic acid.
In an alternative aspect of the invention, the 4,5-dihydroxy-2,B-dinitrostyrene reactant is obtained from 4,5-dihydroxy-2-nitrobenzaldehyde which in turn is prepared from 6-nitropiperonal by a two-step dimethylenation and ether cleavage reaction using aluminum trichloride and dichloro-alkane solvent in the ; first step and hydrohalide in the second step, and then converting the resulting 4,5-dihydroxy-2-nitroben~aldehyde into 4,5-dihydroxy-2,B-dinitrostyrene with CH3N02~
DETAILED DESCRIPTION OF THE
INVENTION AND PREFERRED EMBODIMENTS
In the conventional method of preparing 5,6-dihydroxyindole from 4,5-d~ihydroxy-2,B-dinitrostyrene three reactions are required:
; 30 acetylation; chemical reductive cyclization; and deacetylation; such as shown in Scheme I, above.
However, as noted by Beer, et al this method furnishes ; only a moderate _ _ .

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yield of 5,6-dihydroxyindole. Moreover, 5 6-dihydroxyindole is unstable under the conditions of the chemical reduction reaction.
The present invention provides an alternative one step or direct route from 4,5-dihydroxy-2,B-dinitrostyrene to 5,6-dihydroxyindole using a catalytic reductive cyclization in a suitable reaction medium.
The overall reaction scheme starting with the commercially available 3,4-dibenzyloxybenzaldehyde (ll) is shown ln the following Scheme II:

SCHEME II

PhCH20 ~, ~CH3N02 ~H3C02NH4PhCH20~ CH=C~-N2 PhCH20 ~J
(11) PhCHzO (12 HN03 PhCH20 ~ CH=CH-N02CF3C02H

CH3~02H ~
PhCH20 NOz (133 HO ~ CH=CH-N02 HO
Pd, Pt or R~ HO
HO NO~ H
(14) ~7) Ph ~ ~

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The condensation reaction of (11) to (12) with CH3N02 is carried out at atmospheric pressure in a solution of CH3C02NH4 in acetic acid preferably at reflux, although the reaction will proceed at lower temperatures. 3,4-dibenzyloxy-B-nitrostyrene (12) is only slightly soluble at ambient temper~ture in the reaction medium and the precipitate can be recovered by filtration.
After recovery of 3,4-dibenzyloxy-B-nitrostyrene (12), this compound is nitrated according to known procedures with fuming HNO3 to produce 4,5-dibenzyloxy-2,B-dinitrostyrene (13). The synthesis of 3,4-dibenzyloxy-B-nitrostyrene (12) and 4,5-dibenzyloxy-2,B-dinitrostyrene (13) is described in greater detail by Benigni and Minnis, J. Heterocycl.
Compounds, 1965, Vol. 2, p. 387, et seq. The latter compound is then subjected to novel debenzylation reaction with refluxing trifluoroacetic acid. The debenzylation reaction preferably should be carried out in an inert non-oxidizing atmosphere, for example, in N2 gas, argon, etc. The reaction is preferably carried out under reflux conditions and at atmospheric pressure, although the reaction will proceed at ambient temperature conditions. Since trifluoroacetic acid is liquid under the reaction conditions and is a good solvent for (13), no additional solvent or diluent is required, and preferably trifluoroacetic acid is the only reaction solvent, since it is removed easily at the end of the reaction by distillation. The amounts of 4,5-dibenzyloxy-2,B-dinitrostyrene and CF3COOH are not particularly critical so long as sufficient CF3COOH is ; present to remove both benzyl groups, and dissolve the ,~ ~

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reactant6 snd products. Generally, therefore, at le~t 2, preferably from 37 to 50 equiv~lents of CF3COOH are presen~
per mole of 4,5-dibenzyloxy-2,~-dinitrostyrene, for example, ~ 7:1 (v/w) ratio of CF3COOH:4,5-dibenzyloxy-2,e-dini~rostyrene.
Suitable reaction times are generally in the range of from about 30 minute~ to about 10 hour~, preferably from sbout 1 hour to abou~ ~ hour~.
After the debenzylation reaction, the product 4,5-~ihydroxy-2,B-dinitrostyrene (14) is recovered at substanti~lly complete purity. Thi~ is easily accomplished by washing the solid reaction product mixture, after cooling to room temperature and filtering with, for example, diethyl ether, followed by recrystallization in aqueou~ ethanol, or preferably by distilling off excess CF3COOH and recrystallizing from H2O, u~ing a filter-aid (e.g. Celite* Hy-flo* etc.) to remove the black gum, which is presumably benzyltrifluoroaceta~e.
The obtained product i~ ~ bright yellow powder and consist~
primarily or entirely of the more stable (E) or trans i~omer:

¦¦ no~c=c/ (14-E) At this point, rather than proceeding with the conven-tion~l -three-step chemical reductive cyclizstion of 4,5-: dihydroxy-~,~-dinitrostyrene thi~ compound i~ directly convertedto the o~ject 5,6-dihydroxyindole ~7) by cat~lytic reductive cyclizstion using hydrogen and & reductive cycli~ation catalyst in a suitable reaction medium. It wa~ quite surprising to find that the catalytic reductive cyclization would proceed almost quantitAtively in view of the f~ct that when the reaction of (14) gor (14-E3) i~ carried ous in most organ~c 601vents a complex mixture of product~ i~ produced from which only very little or none of 5~6-dihydroxyindole (7 * trade~arks lZ~2~
can be reciDvered. However, when, for ex8mple, 8n ~queou6 reaction medium is used~6 the reaetion medium the conYer~iion from ~14) to (7) iB qu~ntit~tive, slthi3ugh the isol~ted yield6 of (7~ tend to be generally lower, eO~. aboue 50%
or ~igher, bec~u~e 5,6-dihydroxyindole i8 unistable ~n ~ir.
In term~ of the ~t~rting 3,4-dibenzyloxybenz~ldehyde ~
iæolated yielidi~ of 5,6-dihydroxyindole ~re in the r~nge of about 35% or higher.
As the suitable reaction medium any medium which ls liquid under the resction conditions and in which cycli~ation will occur and in which 5,6~dihydroxyindole slone or 5,6-dihydroxyindole and only one or a few m;nor cont~minsnt6 ii~ produced or from which pure 5,6-dihydroxyindole can be i~olated, can be u~ed.
In particul~r, polsr, hydroxyl group coritsining .
siDlvent~ sucb as water, lower a1kano1ç, lower ~liphatic .carboxylic scidi~ and mixture~ thereof sre e6pecially ~uit~ble ~6 th~ re~ction medium. Example of the lower ~lkanols ~re methanol, ethanol, i~opropanol, n-butanol, etc. Ex~mples of the lower ~liph~itic carboxylic ~cid~ are acetic ~cid, propionic acid, etc. These polar ~iDlvents c~n be used indivi- :du~lly or in mixtures of two or more ~t any proportioni~ .
; in whic~ they are mutually soluble under the re~ction conditions : Genierally, percent and ra~e of conver6ion to the ~ 25 object 5,6-dihydroxy;ndole increa~ie ~s the solvent polsrity : : i~ increai~ied. When, for eXBmple, is~propanol i8 u~ed a~
ehe æolvent or as t~e major solvent component, the 5,6-dihydroxy : indole isol~ted from the ~olvent require~ more purific~tlon than when methanol, ethanol, water or acetic acid ~8 u~ed ~ the ~olvent or ~ the major ~olvent component.

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ln view of the econ~my ~nd efficiency of the reacti~n, the preferred reflction med~um i6 an ~queous re~ction medium.
The ~queou~ re~ction medium prefer~bly con~t~
of di~tllled w~ter. When di~t~lled water ~lone i~ u~ed the re~ceion medium there i6 no byproduct formation, i.e. 6electivity to 5,6-dihydroxyindole is 100%. A minor amount of ~ co~olven~ 6uch a~ lower sliphatic c~rboxylic ~cid, e.g. ~cetic ~cid or ethanol, etc~, c~n be present ~n the ~queou6 reaction mediu~. When the amount of the cosolvent doe6 not exceed about 50%, preferably up to 30%, especially preferably up to about 10% by weight of the total aque~u6 reaction medium only ~ ~ingle byproduct, which i~ believed to be 5,6-dihydroxyind~line, i~ observed. Generally, ~n ~mount of cosolvent which i~ equim~lar to the amount of the 4,5-dihydroxy-2,~-dinitrostyrene (14) can be used.
The catalytic reductive cycliz~tioo i~ performed under ~ hydrogen ~tm~sp~ere of, for example, sb~ut 40 to 60 p~i, prefer~bly ~bout 40 to 55 psi, most prefer8bly about 50 p~i. The re~ction can proceed at ro~m temperature or ~lightly elevated temper~ture~, for ex~mple, up to about 50~.
A~ the reductive cyclization cataly~t a platinum-group met~l selected from palladium ~Pd), plstinum (Pt) or r~odium (Rh) c~n be u~ed ~lone or ~6 ~ mixture. P~lladium, slone or with one of he other two metal~ is preferred. Surpri~ingly, however, other platinum-group metals, ~uch 8~ ruthenum ~nd iridium whcih ~re ~l~o known ~ reductive hydrogen8tion C~t~ly~tB are not effecti~e in tbe cat~lytie reductiv~ cycliza-tion rP~ction of ehi~ invention.

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The platinum-group metal catalyst is used in the form supported on a solid carrier. Examples of the solid carrier include carbon, e.g. activated carbon, alumina, silica, diatomaceous earth, silicon carbide, pumice, zeolite, molecular sieve, etc. ~arbon and alumina are the preferred solid carriers, and palladium on carbon (Pd/C) which is readily commercially available from a number of sources is especially preferred.
The platinum-group metal supported catalyst can be prepared by any suitable technique. For example, it can be formed by impregnating a solid carrier with an aqueous solution of a water-soluble salt of the platinum-group metal or a mixture of such salts when a mixed platinum-group metal catalyst is used. Examples o~ the salt of the platinum-group metal include nitrates, sulfates, phosphates, halides, acetates, oxalates, benzoates, chloro complex salts and amine complex salts of the above-exemplified metals. The impregnated solid carrier is then contacted with an alkali, and the alkali-treated product is then contacted with a reducing agent in the liquid phase (e.g. using such reducing agents as hydrazine, formaldehyde, sodium formate and formic acid) or in the gaseous phase (e.g.
using such reducing agents as hydrogen, carbon monoxide and ammonia).
Generally, the amount of supported platinum-group metal can range from about 1 to about 25%, preferably from about 3 to 15%, by weight, based on the weight of carbon. The ratio, by weight, of the catalyst to ; 4,5-dihydroxy-2,B-dinitrostyrene can be selected depending on such factors as the amount of supported Pt-group metal, the hydrogen pressure reaction medium, reaction temperature, and the like. Generally, however, in terms of a 10% Pd/C the weight ratio of catalyst to 4,5-dihydroxy-2,B-dinitrostyrene will range from about 1:0.05 to about 1:100, pref~rably, from about ; ~ 0.1 to .

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about 1:20. However, at ratios of catalyst:4,5-dihydroxy-2,B-dinitrostyrene of less than about 1:30, the reaction time can be in excess of about 10 hours, and additional complications may occur. Therefore, the pre~erred minimum ratio of catalyst to reactant is in the range of about 1:20 to about 1:30. On the other hand, there is no problem when the catalyst is present in great excess so long as the reaction is not run long enough to allow over-reduction to 5,6 dihydroxy-indoline (e.g. more than about 30 to 60 minutes). Of course, too great an amount of catalyst is generally economically impractical. Therefore, the most preferred weight ratio of catalyst to reactant is in the range o~
from ahout 1:0.1 to about 1:30, especially preferably 15 from about 1:0.5 to 1:20, again in terms of a 10% Pd/C
catalyst. Within these ratios it will be understood that, at least at the beginning of the reaction, the starting material 4,5-dihydroxy-2,B-dinitrostyrene should be soluble in the reaction medium.
At the completion of the reaction, which will generally require from about 30 minutes to about 3 hours, preferably from about 45 minutes to about 2 hours, the reaction system may be acidified to a pH of about 5 or less, preferably about 4.5, by the addition of acekic a¢id. The reaction mixture is then extracted, ; preferably after filtration, with ether or dichloromethane one or more times, under a nitrogen gas atmosphere, to recover the product 5,6-dihydroxyindole.
According to a particular feature of the invention, the isolated yield of 5,6-dihydroxyindole can be further increase by carrying out the isolation of the product 5,6-dihydroxyindole by adding to the acetic acid mixture a compound which will protect the hydroxy groups to give the product compound `

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~ ~ 3~in 8 form which ~ m~re 6t~ble in sir. For exsmple, addition of ~cetic ~nhydride to the filtered mixture gives 5,6-di~cetoxy-indole ~n hesting. It ~6 ~160 possible to form the bor~te e~ter / ~ 0 ~

by ~ddition of boric ~cid to the acetic ~cid re~ction mixture.
.Gener~lly, ~ny protecting group which i~ 6table to acetic ncid can be added to the filtered reaction mixture to ~ive the protected 5,6-dihydroxyindole.
As a fitill fur~her ~lternative, the filtered mixture may be used directly for hair dyeing, melanin formation, : ~r other reaction~ in which 5,6-dihydroxyindole is used : in an ~queou~ medium.
In ~n alternative emb~diment, the 4,5-dihydroxy-2,B-dinitro~tyrene reactant;c~n be prepared by reaction of 4,5-dihydroxy-2-nitrobenzaldehyde with CH3NO2 under subst~nti~lly the same conditions a~ shown by Beer, et al (~ee Scheme I~
to produce a mixture of (Z)-4,5-dihydroxy-2,B-dinitro~tyrene : (2) with 1-(4',5'-dihydroxy-2'-nitrophenyl)-2-nitroethanol (3) and/or (4). The (Z) (or Ci6~ i~omer can be ~eparated fr~m t~e product mixture by column chromatography (dry ~ilic~
gel) with 2:1 hexane~:~ichloromethane or other ~uit~ble : : eluent~. Alternatively, the mixture of (2) ~nd (3~ ~nd/or (4) : containing the (Z)-i~omer can be converted int~ the more ~:~ 25 ~table (E)-i~omcr by recrystallization of the mixture from : aqueou~ eth~nol.
. It i6 ~ particular feature of thi~ invention that : in the prep~r~tion of 4,5-dihydroxy-2-nitr~benz~ldehyde (1) the convers;on of 6-nitropiper~nal (9) to 5-chloromethoxy-: :
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4-hydroxy-2-nitrobenzaldehyde (lo) from whi~h the chloromethoxy group is cleaved to produce (1), i5 produced in high yields, regardless of the amount o~ the starting material.
According to this feature of the invention,

6-nitro-piperonal is converted to (10) by cleavage of the methylene-dioxy group using AlC13 which has an affinity for ether oxygens. The use of the AlC13-dichloroethane (ClCH2CH2Cl~ system for cleavage of methylenedioxy ether is shown by Avery, et al.
However, according to Avery, et al high temperature (25C) and lony reaction time (2 hours) are used, and under these excessive conditions the yields of (10) are reduced, especially at amounts o~ the starting material in excess of about 1 gram.
According to this invention, the yields of (10) are maximized by maintaining the reaction temperature at loC or less, especially from -5C to 10C, for a reaction time of about 75 minutes, or less, especially from about 40 to 75 minut s. Thus, according to experiments by the inventor when the procedure of Avery, et al [KI, THF, 6N HCl, reflux] are reproduced for more than 1 gram of starting material, the yields of : product become unacceptable, i.e. on a scale of 1 to 5 grams, an oil, from which 50 to 60% of pure 4,5-dihydroxy-2-nitrobenzaldehyde (1) is isolated, results, and the yield falls to approximately 20% as the amount of starting material is increased to about 25 grams.
: 30 In the methylenedioxy cleavage, any dichloro(lower)alkane can be used as the solvent, : especially dichloromethane and dichloroethane, : especially pre~erably dichloroethane. The yields of . 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10~ using ` 35 AlC13-ClCH2CH2Cl under the above specified reaction -:, ," .: . -:

~3~

conditions typically range from 93 to 97%, a~ter recrystallization, regardless of tha amount of starting material.
Standard ether cleavage procedures convert (10) to (1). Presumably, electron withdrawal by the chlorine of the chloromethyl group and the P-N02 group makes ether cleavage particularly easy. Cleavage with either 6N HCl or 48% HBr, under mild conditions, gives (1~ in high yield (80-100%). HBr cleavage is faster, and there is le~s by-product formation. Stirring (10) with 48% HBr, at ambient temperature (23C), affords (1) in 100~
yieldO The formation of (1) starting from piperonal (8) is shown in the following Scheme III.
SCHEME III

0 ~ CH~ HN03 0 ~ CH0 AlC13 < ~ ~ ;<o ,~ ClC~,~%
(8) (9~

ClCH2 ~ CH0 HBr ~ H0 ~ CH0 H0 No2 H0 No2 (10) (1) The chloromethyl group may also be removed with pyridine--AlC13, although in lower yield. Dry pyridine is added to a cooled (0C) mixture of (10), AlC13 and methylene chloride in a 1~ 4.4 molar ratio. When addition is complete, the reaction is warmed to 47~C
for 18 hours. After acidification with dilute HCl, 4,5-dihydroxy-2-nitrobenzaldehyde is extracted from the reaction mixture with ether. Dechloromethylation '~
' ,~ :

:`

; ~ ' , lZ32911 i~ not ~ high yield proce6s without ~olation of (10), i.e.
~ddition of pyridine or AlC13 and pyridine to the AlC13--dichloroethane mixture used to open the methylenedioxy ring doe~ not effect dechloromet~ylstion to an scceptable degree under these condition~.
The invention will now be illustrated by w~y of the f~llowing example~ in which all parts and percentage~
sre on a weight ba~i~, unles~ otherwi~e indicated.
In the following example~, melting poin~ were taken on ~ Thoma~-Hoover capillary melting p~int ~pparatu~, and are uncorrected. lNHMR spectra were obtained on a Perkin-Elmer R12B NMR spectrometer, with tetramethylsilane as the internal tandard. Mas~ 6pectra were obtained on ~ Finnigan 40~0/GC/MS/D
Sy6tem. IR spectra were taken on ~ Perkin-Elmer 137 infr~red ; 15 ~pectrophotometer. Mieroanaly~e~ were dvne by Micro-Analy~i6, P.O. Box 5800, Wilmington, Del~ware.

~ 3,4-Dibenzyloxy-B-nitrostyrene (12~
; A mixture of 79.5 ~ ~1.25 mol) of 3,4-dibenzyloxybenzal-~ehyde (11) (available from Aldrich Chemicsl Co.), 47 g CH3C~2NH4, 47 g CH3N02, and 400 ml CH3C02H i~ refluxed for two hour~. The mixture i~ cooled to 23C to precipitat~
the product. The yellow ~olid i6 i~olated by filtr~tion, wa~hed with et~anol, ~nd air dried. Recryst~lliz~tion from ~; 25 CH3C02~-- C2HsOH gives 67.2 g (74.5%~ of (12): mp 118-ll9~C.
''~
~: . -19-' :~L;2329~

~E)-4,5-Dibenzyloxy-2,~dinitrostyrene (131 3,4-Dibenzyloxy-B-nitrostyrene (12) (67.2 g; 0.1~6 mol) is dispersed in 1.5 L CH3C02H. HN03(d 1.42) is added until the temperature reaches 40~C. The mixture is cooled to 20~C, and the remainder of the 375 mL HN03 is added without further cooling. After stirring at 23C for three hours, the reaction mixture is poured onto 2 kg of ice, and filtered. The yellow powder is washed well with H2O. Recrystalliæation from CH3CO2H
af~ords 70.3 g (93%) of (13) as yellow needles, mp 162-164C.

(E)-4,5-dihydroxy-2-B-dinitrostyrene (14-E) A mixture of 72 g (0.177 mol) of 4,5-dibenzyloxy-2,B-dinitrostyrene (13) is refluxed in 500 ml trifluoroacetic acid (CF3C02H), under N2, for three hours. The cooled reaction mixture is filtered, and the solid is washed with diethyl ether. An insoluble brown solid remains. The ether is removed at reduced pressure, and the solid is recrystallized from aqueous ethanol yielding 40 g of a bright yellow powder, the majority of which is identified as (14-E): mp 169-170C;
mass spectrum, m/e 226 (M+), 180, 165, 150, 134, 124, 110, 97, 38, 76, 68; lHNMR (d6-Me2CO) ~8.47(d, J=13.2 Hz,lH), ~7.9(d,J=13.2 Hz,lH), ~7.62(s,1H), 7.19(s,1H).
Alternatively, after the reaction is complete, excess CF3C02H is removed by distillation and the solid is recrystallized from H2O using a filter-aid, such as Celite or Hy-flo, to remove the brown, gummy solid which is a by-product of the reaction~

~`
:.

;,. . . .

~2 3 5,6-Dihydroxyindole (7) (E)-4,5-Dihydroxy-2,~ dinitro~tyrene l14) (1 g;
0.00044 mol) i~ disper6ed in 50 ml di~tllled H20 in ~ Parr bottle, ~nd 0.1 g 10% Pd/C i~ sdded. The reaction mixture i~ shaken ~n a Parr hydrogenator at 50 p8i H2 for 45 min~teE.
CH3C02H is added to brin~ the pH to 4.5, and the re~ction ~ixture i~ extr~cted with 4 x 50 ml diethyl ether or dichloro-methane, in a nitrogen atmosphere. The combined ether extract~
are dried over Na2S04, then filtered. The ether i~ removed at reduced pressure, without heating. 5,~-Dihydroxyindole i6 obtained in 50% yield (0.33 ~): mp 140~C (dec~.
When Pd on ~lumina, Pt on carbon, Pt on slumina, Rh on carbon or Rh on slumina is u6ed ~ the cataly~t in pl~ce of the Pd/C cat~ly6t similar results are obt~ined.
Simil~rly, methanol, et~anol, i~opropanol, ~cetic ~cid or mixture~ thereof can be used to replace part or all of the di6tilled water with~ut adver~ely sffecting the re~lt6.
However, when rutheni~ e;ther in the form of ruthens~um on powdered carbon or as RuC12~C02)(Ph3P)2(13.4V/oRu) is used ; in pl~ce of the lOD/D Pd/C catsly~t, little Qr no 5,6-dihydroxy-lndole i~ produced in 2 to 3 hour~

~: XAMPLE 5 5-Chloromethoxy-4-hydroxy-~-nitrobenzaldehyde ~10) AlC13 (6 g) ~nd dry dichloroet~ane (15 ~1~ ~re ~dded ~:~ to 5 three-neck round bottom flask, which ha~ been purged : . wieh N2, and the di~persion is cooled ~o -5~. A ~olution of 6-nitropiperon~l (3 g; 0.0154 mol) (avsil~ble from Aldrich Chemic~l Co.) in 12 ~1 dry dichlcr~e~hane ~ added ~o t~e . di~per6ion, i~ one pDrtion ~ while the temper~ture and M2 .~ ~ . -21-2 3Z~ ~

~tmo6phere are maintained. The resction mixture i~ stirred for 1.25 hour~, ~nd 100 ml H20 ~0) iæ ~dded. The emulsion is stirred for 15 minute~, then extracted with 3 x 100 ml ethyl acetste. The combined organics ~re w~shed with saturated NsCl, then dried over Na2S04. After filtration, the ethyl acetBte is removed ~t reduced pressure. Recryst~llization fro~ byl etate give~ 3.45 R (97%) of (10): mp 160-161'C.

~ \ i ~ -22-, ~ , :
.

~ Z ~2 4,5-Dihydroxy-2-nitrvbenæaldehyde (1) 5-Chloromethoxy-4-hydroxy-2-nitrobenz~ldehyde (10) (3 g;
0.013 mol) ~ ~tirred at 23VC with lS ml 48% HBr for tw~ day~.
The precipitate i5 removed by filtration, and washed well with H20, giving 2.2 g (93%) of 4,5-dihydroxy-2-nitrobenzaldehyde (1).
The remainder of the product i~ isolated by ether extraction of the filtrate. Drying the combined ether extracts over Na2S04, . filtering, and removing the ether at reduced pressure, gives the remaining 0.17 g ~7%) of (1~: mp 201-203CC; mass spectrum, m/e 183 (M+); lHNMR (d6-Me2CO) ~10.59 ~br s,2H), ~10.2(s,lH), ~7.6(~,1H), ~7.3(s,1H).

_ 4,5-Dihydroxy-2-nitrobenzaldehyde (1) lS To a stirred, coole~ (O~C) disper6ion of 1.52 g (0.00658 mol) of 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10), 1 g AlC13, and 10 ml dry dichloroethane, 2.4 ml of dry pyr~dine are added. During addition, the reaction mixture i5 protected from atmospheric m~isture, and the temperature is kept bel~w 35C. When addition is complete, the temperature is raised to : 47C, and maintained for 18 hours. 6N HCl is added, keeping ~ . the temperature at 30-35DC, until the mixture is acidic to : Congo Red indicator paper~ The acidic solution i~ extracted with diethyl ether, and the combined ether extract~ are dried o~er Na2S0~;. After fil~ration, the ether ~s removed at reduced : pres~ure, giving 0.82 g ~68%) of (1): mp 201-202~C.

~3~29~

(Z)-4,5-dihydroxy-2,B-dini rostyrene (2~
A solution of 1.61 g KOH, 2.3 ml H2O and 23 ml 95%
C2H5OH is added dropwise to a mixture of 2.3 g (0.0126 mol) of 4,5-dihydroxy-2-nitrobenzaldehyde (1~, 1.4 g CH3NO2, and 23 ml 95% C2H5OH at 0C. The dispersion i5 stirred at 0C for 30 hours, then poured into 50 g H2O
~0C) and acidified with cold (0C) 6N HCl. The mixture is extracted with 3 x 100 ml cold (015C) diethyl ether, and the combined ether extracts are washed with cold (ooc) NaHSO3. The organic are dried over Na2SO4. After filtration, the ether is removed at reduced pressure, without heating. The light y~llow powder (2.97 g) is a 1:1 mixture of 1-~4',5'-dihydroxy- 2'-nitrophenyl)-2-nitroethanol and (Z)-4,5-dihydroxy-2,B-dinitrostyrene (2). It is uncertain which of the enantiomeric alcohols, (3) or (4~, is present, or whether the product contains a mixture of both. (Z)-4,5-dihydroxy-2,B-dinitrostyrene (2) is separated from the product mixture by column chromatography (dry silica gel) with 2:1 hexanes:dichloromethane: mp 158C; mass spectrum, m/e 226 (M+); 1HNMR (d6-Me2CO) ~7.62 (s,lH), ~7.19(s,1H), ~5.95~d,J-4 H~,lH), ~5.81 (d,J-4 Hz,lH).
After chromatography, 1.48 g ~49%) of the alcohol 25 fraction (3 and/or 4) are isolated: mp 147-149C; mass spectrum, m/e-244 (M+), 226, 227, 180, 153, 136, 123, 108, 97, 88, 79, 69; lHNMR (d6-DMS03 ~7.62(s,1H), ~7.19(s,lH), S4.66(m,3H), ~4.2(s,lH); Anal. Calcd. for C8H8N2O7: C, 39.34; H, 3.28; N, 11.48; 0, 45.90.
30 Found: C, 39.32; H, 3.67; N, 11.43; 0, 45.77.

' .

;:

, : ~' .

~29~1 .

~XAMPLE 9 ~E)-4,5-dihydroxy-2,~-dinitrost~rene (14-E~
The mixture of product~ containing (2) and t3~ snd/or (4) obtained rom Example 8 i6 transformed intv (14~E~ by warming 2 g of the mixture with 0.5 g CH3C02Na and 15 ml (CH3C0)20 at 70C
for one hour. The mixture is poured onto 50 g of ~ce and stirred for one hour. The dispersion is filtered, and the solid is ~ashed well with H20. The solid thus obtained is refluxed ln 50 ml 95% ethanol for two hours. Removing the solvent at reduced pressure affords a bright yellow solid, which is identical ~o the sample prepared in Example 3: mp 169-170C.

-2~-:~ : ~

Claims (20)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing 5,6-dihydroxyindole in high yield and purity which comprises subjecting 4,5-dihydroxy-2,.beta.-dinitrostyrene to catalytic reductive cyclization with hydrogen in the presence of a platinum group metal catalyst in a liquid reaction medium to produce 5,6-dihydroxyindole.

2. The method of claim 1 wherein the platinum group metal is palladium, platinum, rhodium or a mixture thereof.

3. The method of claim 2 wherein the platinum group metal is supported on a solid carrier.

4. The method of claim 1 wherein the catalyst comprises palladium, platinum or rhodium supported on a solid carbon or alumina catalyst support.

5. The method of claim 1 wherein the catalyst comprises palladium on carbon.

6. The method of claim 2 wherein the liquid reaction medium is a polar hydroxyl group containing solvent or a mixture of two or more polar hydroxylic group containing solvents.

7. The method of claim 6 wherein the liquid reaction medium is selected from the group consisting of water, methanol ethanol, isopropanol, acetic acid and mixtures thereof.

8. The method of claim 6 wherein the liquid reaction medium is an aqueous reaction medium.

9. The method of claim 8 wherein the aqueous reaction medium consists essentially of distilled water.

10. The method of claim 8 wherein the aqueous system consists essentially of a major amount of water and a minor amount of acetic acid.

11. The method of claim 2 which further comprises recovering the product 5,6-dihydroxyindole by the steps of separating the platinum group metal catalyst, acidifying the reaction mixture and separating the solvent from the product 5,6-dihydroxyindole.

12. The method of claim 11 wherein the reaction mixture is acidified with acetic acid.

13. The method of claim 12 wherein the step of separating the solvent comprises extracting the 5,6-dihydroxy with ether or dichloromethane.

14. The method of claim 12 which further comprises adding a compound capable of protecting the hydroxy groups of the 5,6-dihydroxyindole to the acidified reaction mixture and recovering the hydroxy group protected 5,6-dihydroxyindole.

15. A method for preparing 5,6-dihydroxyindole which comprises producing 4,5-dihydroxy-2,.beta.-dinitrostyrene by reacting 4,5-dibenzyloxy-2,.beta.-dinitrostyrene with trifluoro-acetic acid in an inert atmosphere to form 4,5-dihydroxy-2,.beta.-dinitrostyrene and subjecting 4,5-dihydroxy-2,.beta.-dinitrostyrene to catalytic reductive cyclization with hydrogen in the presence of a supported palladium, platinum or rhodium metal catalyst in an aqueous reaction medium to produce 5,6-dihydroxyindole.

16. The method of claim 15 wherein the catalyst comprises a palladium on carbon or palladium on alumina catalyst containing about 10%, by weight, of the catalyst of palladium.

17. A method for preparing 5,6-dihydroxyindole which comprises the steps of:
(a) reacting 6-nitropiperonal with AlCl3 in dichloro-ethane at a temperature of from about -5°C to about 10°C
for a reaction time of up to about 75 minutes to produce 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde;
(b) subjecting the 5-chloromethoxy-4-hydroxy-2-nitro-benzaldehyde from step (a) to ether cleavage with HBr or HNO3 to produce 4,5-dihydroxy-2-nitrobenzaldehyde;
(c) reacting the 4,5-dihydroxy-2-nitrobenzaldehyde from step (b) with CH3NO2 to produce 4,5-dihydroxy-2,.beta.-dinitro-styrene; and (d) subjecting the 4,5-dihydroxy-2,.beta.-dinitrostyrene to catalytic reductive cyclization with hydrogen in the presence of a platinum-group catalyst in a polar liquid reaction medium to produce 5,6-dihydroxyindole.

18. The method of claim 17 wherein the platinum-group catalyst is palladium, platinum or rhodium and is supported on a powdery solid.

19. The method of claim 18 wherein the catalyst is palladium or carbon.

20. The method of claim 18 wherein the liquid reaction medium is selected from the group consisting of water, acetic acid, methanol, ethanol, isopropanol and mixtures thereof.