Note: Descriptions are shown in the official language in which they were submitted.
~.Z3~9~
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
: ~ ;
: ~
~ :
~ 232~ 1~
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.
~ . ~
-2-
-
~ ~ :
: ~
: : :: : ` : :
: ~
:;: :
~Z3;Z9
SCHEME 1
~ + CH3N2 KOH (alc) ~ ~ ~10 +
HO No2 2
(1~ (2)
~OH ~ N~ (CH CO) 2O
Ht)~ 2 :~ 2 CH3CO2Na;~
HO N02 HD ND2
~3) (4)
~X; CH3 ; Ac~
AcO 2
`:: (5) (6)
.
`~
~ ~ (73
; :
;:
~ :
: ~
~ -3-
: ~ '
~, .
~'~ 3~
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.
: ~ ~
~ ~ -4- ~
:
; ~
:: :
~23~9~
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
~: :
.
:: ~ : "
, ~,: , . , . : . . ,
~ Z 3'~9 ~
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.
-6-
.-
: ~ :: :
: : ~
.
~;~3~9~
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
H0 ~ N
by subjecting 4,5-dihydroxy-2,B dinitrostyrene
H0 ~ CHzCH-N02
HO N2
~` .
r~
`:
; .
1~3;~9~
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 _ _
.
,
,.
;
'
~;~3~
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 ~ ~
~'
. .
: ~ ; .
:~; , ` " .
, -
~1 23;~
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
,~ ~
.
. . ~ ~ .
:
.:
' , ' .' : , ' ~, .
.
~ 2 3~ 9~ ~
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.
~ 2 3~
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.
-13-
~3;Z 9~
14
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
.
:~Z3;~9~
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
`
:;
-
, .
,:
~ ~ 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-
: :
`~ ~ -16-
~Z329:~
17
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~
18
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.
EXAMPLE 1
~ 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~
EXANPLE 2
~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.
EXAMPLE 3
(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
EXAMPLE 4
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
EXAMPLE 6
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).
EXAMPLE 7
_
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.
I -23-
~3~29~
24
EXAMPLE 8
(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~-
:~ : ~
