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From: "guest" <guest@webshack-cafe.com>
Newsgroups: alt.drugs.chemistry
Subject: MDMA from Eugenol
Date: 8 Nov 97 18:43:39 GMT
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Recently some posted an enquiry on Strike's database asking how Eugenol
could be used to make MDMA.
This response might be relevant to the guy in the UK who also wanted to
know what to use when no chemicals could be bought.
Some research is needed here - but everything should work.

MDMA from Eugenol

================
Someone was asking how this could be done.
What would happen if you heated eugenol with alkali to 200° C?
Protocatechuic Acid has been prepared from vanillin by heating vanillin at
240 C with KOH/NaOH. [I A Pearl, Org. Syn. Coll. Vol. 3, p 745] What could
you expect if you treated Eugenol to similar conditions? 2-allyl-catechol?
If this was methylenated it would give isosafrole.

MDMA from Eugenol

================
A more likely method. The following method is tedious - but has the virtue
of using no lab. chemicals only those obtained OTC from the
hardware/pharmacy/grocery shops]. Safrole is not used because I can't get
my hands on any. This method could also be used by other Safrole deprived
chemists such as those who live in the UK. I haven't yet tried it out.
But, it works in theory and if not all processes work in practice then you
should be able to substitute another process.
Many of the reactions below use Phase Transfer catalysts (PTCs). See the
Appendix 4.
Scale-up the processes below as appropriate.
MDMA from Eugenol - Outline.
============================
Eugenol is extracted from cloves or clove oil. Eugenol is refluxed with
HCl to give catechol-2-chloro-propane. This is easily converted to the
alcohol and then methylenated to give MD-P2Pol. The alcohol is oxidised to
ketone which is then reductively aminated with MeNH2 to give MDMA.
Extraction of Eugenol from cloves
==========================
see "Experimental Organic Chemistry"; Durst, Gokel, Durst, Gokel; McGraw
Hill; 1980; p. 467.
50 g of whole cloves (from a supermarket - you can buy cloves in Kg
quantities from Indian grocery stores) placed in a 500 ml rb. 3-necked
flask with 250 ml of water and several boiling sticks. Steam dist. for 50
to 75 min., with water volume kept constant at 250 ml. Distillate
transferred to a separating funnel, extd. with 2 x 50 ml CH2Cl2. Combined
CH2Cl2 portion then extd. with 3 x 50 ml 5% KOH soln. (heat is evolved).
Combined KOH portion washed with 25 ml CH2Cl2. Aq. layer transferred to a
600 ml beaker and slowly acidified with 5% HCl to a pH = 1 (tested using
indicator paper). Aq. layer extd. with 2 x 40 ml CH2Cl2, combined CH2Cl2
portions washed with 25 ml of water followed by 25 ml of half saturated
NaCl soln. The CH2Cl2 portion dried over anhydrous granular NaSO4,
decanted, CH2Cl2 removed on a steam bath. Pure, 98% Eugenol is obtained as
a pale yellow oil. [Scale-up as you see fit].
Phase transfer cleavage of phenolic ether
===============================
Using HBr & surfactant, Landini, Montanari, Rolla, Synthesis, 1978, 771
Mixt. 1 mol ArOMe, 560 ml, 5 mol 47% HBr, 50 g, 0.1 mol HPB
[hexadecyltributylphosphonium bromide], stirred & refluxed at 115 C, 5 h.
Organic layer separated, extracted yd 91% phenol.
Distn. residue was dissolved in hexane to recover 46 g, 92%, of pure
phosphonium bromide was Mp. 54-56 C. Note MeBr is not recovered as it is a
gas at room temp. MeBr is poisonous. Reaction rate is not effected by the
nature of the onium salt provided that it is completely soluble in the
organic phase. Eg. tetraoctylammonium bromide or trioctylmethylammonium
chloride can also be used as catalysts.
Alkyl-aryl Ether Cleavage Using HCl & surfactant
=====================================
B Jursic, J Chem. Research (S), 1989, 284-5.
Mixt. of 1 mol phenol ether, 50 mol (4 L) HCl (37% aq.) & 0.1 mol (36.4 g)
CTAB [cetyltrimethylammonium bromide] stirred under reflux for 36 h. Mixt.
diluted with 500 ml water & extd. with ether [DCM is OK substitute here].
Ether ext. dried over MgSO4 & dist. Products purified by distn. Yd: phenol
65%, MeCl is a poisonous gas. Note: HCl is used in concn. 20 to 50 molar
excess. 37% aq. HCl gives best results. Surfactant can be recouped.
Use of HBr rather than HCl gives higher yields.
[Note 2: the chloromethane produced is very volatile and quite poisonous -
but it can be dissolved in alcoholic ammonia solution and with react to
give methylamine - which is always useful to have].
Hydrogen halide will add across the double bond to give a secondary alkyl
halide. This reaction requires a lower temperature than that for the
methoxy cleavage. PTC speeds up the addition of both HCl and HBr to allyl
benzene compounds. [Addition of hydrohalogen acid to alkenes: Landini &
Rolla, JOC 45, 3527, (1980).]
The two operations above (addition of halogen halide and cleavage of the
methoxy group) can be combined in one operation using the conditions for
the cleavage. Use of HBr will require less time, milder conditions and give
higher yields than HCl.
The 2-halo-propan-catechol will be prone to polymerisation under basic
conditions. Don't treat this with an alkali or you'll get a gooey mess.
You'll have to carefully separate it from the concentrated acid by
neutralising acid with bicarb., then extracting. Next, we need to close
that catechol with a m
dioxy bridge. The m
dioxy-bridge can't
be closed at this stage because of that 2-chloro-propane. The alkyl halide
has to be converted to something less reactive - an alcohol will do fine.
Convert the catechol-2-halo-propane to an isopropanol group.
==============================================
[H. A Zahalka, Y. Sasson, Synthesis 1986, 763.].
This is a two-stage process but can be done as a one-pot conversion by
first reacting the 2-chloro-propan-catechol with sodium formate and a PTC
and then hydrolysing the ester with dilute alkali. The isopropyl-catechol
produced is much more stable and can be methylenated.
Note - see App. 3 - prep. of formic acid.
The process of Methylenation.
======================
[I don't like any of the five methods mentioned in Strike's book]. This 6th
method is the best. It can be done entirely with OTC chemicals.
References:
=========
Jap patent. 84 046 949-B, To Takasago perfumery KK, 1984. 7 pages in
Japanese, abstract available in Jap pat. Abstracts - see appendix 1.
Brit. Pat spec. 1518064, Appl. No. 2653/77, Filed 21-1-77; Appl. No. 19735,
Filed 30-1-76 in Italy (IT), Complete Spec. published 19-7-78. (To Brichima
S.P.A. of Milan, Italy). This is also available in Italian and German. See
Appendix 2.
Z Yiuguing et al, Jilin Daxue Ziran Kexue Xuebao 2, 92, (1983) [aka Acta
Scientiarum Naturalium: in Chinese {any Chinese speakers out there who can
translate this please?}
"Williamson synthesis of ethers": B Jursic; Tetr. 44, 6677, (1988).]
Outline:
======
To your isopropyl-catechol add:
1) 1.5 mole equivalent of strong alkali [NaOH or KOH]
2) four mole equivalent of DCM [dichloromethane]
3) one-tenth mole equivalent of PTC [available from "hair conditioner" or
"fabric conditioner" or both]
4) a trace of iodine [1/100 mole equivalent will do] or an iodide.
[available OTC as "Tincture of iodine", or you can get iodine from seaweed
(if this sounds tedious - remember that I said no lab. chemicals were
needed). The iodine is needed to act as a promoter in this reaction.
5) Stir vigorously [750 rpm] at reflux for several hours. [The articles
above mentioned the use of pressure but I think they use pressure in order
to carry out the reaction at a temperature above that of the bp of DCM -
the reaction is faster at the higher temperatures].
Isolate and purify the MD-P2-Pol produced - this could be quite tedious. I
can think of no other method apart from fractional vacuum distillation.
Oxidise MD-P2-Pol to MD-P2P
This can be done using a reaction analogous to the "cold cat" method or ...
Alcohols can be oxidised to ketones with bleach [R. Stevens et al, J. Org.
Chem. 45, 2030, (1980); P. L. Anelli et al, JOC 52, 2559, (1987); J. R.
Mohrig et al, J. Chem. Educ. 62, 519, (1985); P. L. Anelli et al, J. Org.
Chem. 52, 2559, (1987)]
Oxidation of alcohols to carbonyl cpds. using bleach is quite easy. Liquid
bleach at about 5% concn., or higher, is neutralised to pH 8.4. [yes a pH
meter is essential - but a pocket $40 job will do]. A PTC in aq. soln. is
used to allow the OCl- anion to penetrate into the organic phase. The mole
ratio of bleach to alcohol is from 1.05 to 1.1. Swimming pool bleach may
also be used. There are some more recent papers that achieve higher yields
but require Br- and exotic PTCs. (60 - 85% yield, depending upon the
specific PTC and conditions).
The problem with using bleach is that the aromatic ring may also be
attacked to some extent. [but this is not likely to be a major problem]
The ketone is isolated and purified using the bisulfite addition method.
Methylamine [see prep. From Hexamine elsewhere] is added and the Schiff
base reduced using available methods [Al amalgam or electrolytic
reduction.] to MDMA.

Appendix 1: The Preparation of m

dioxy derivatives. [Abstract of
Jap. pat. 84 046 949-B]
=======================================================================
1 mole of a 1,2-dihydroxy aromatic derivative such as catechol,
4-methyl-catechol, 4-propylcatechol, etc., is reacted with DCM, (4 to 3
moles) in caustic alkali at 50 - 130° C using a quarternary ammonium or
phosphonium salt as a phase transfer catalyst and, optionally iodine, an
alkyl iodide or metal iodide as a promoter in an amount of 1/10 to 1/100
molar times based on the diphenol compound. The methylenedioxy compound
can easily be prepared in high yield.
[Note 3: the Bp. of DCM is 40 C so this implies higher than atmospheric
pressure is being used here].
[Note 4: the reaction can be carried out a temperatures as low as 30 C an
this will obviate the need for a pressurised container]
Details of PTC used; A quarternary ammonium or phosphonium salt. [eg,
tetramethyl ammonium, trimethyl-phenyl ammonium, tetramethyl phosphonium,
trimethyl-phenyl phosphonium etc.
[Note 5: Try using the quat. present in hair conditioner:
cetyltrimethyl-ammonium chloride - aka cetrimonium chloride].

Appendix 2: Process For Preparing Aromatic Methylenedioxy Compounds [Brit.

Pat. spec. 1518064]
===========================================================================
The invention relates to a process for preparing aromatic methylenedioxy
compounds by methylenation of ortho-diphenol compounds. eg, piperonal.
Many processes have already been proposed for preparing these compounds, in
particular by methylenation of ortho-diphenol compounds. However, all such
process have one or more of the following disadvantages:
a) costly methylenation agents are used, such as bromine and iodine
derivatives,
b) dilute aqueous solutions are used in order for the intramolecular
cyclisation process to prevail over intermolecular processes which lead to
the formation of dimers and polymers. Obviously when operating in dilute
conditions there are problems of low productivity and separation and
recovery of the mother liquors, which make the processes uneconomical.
c) dipolar aprotic solvents such as DMSO and DMF, are alternatively used,
under anhydrous conditions. In this case although good dioxymethylene
derivative yields and good reaction speeds are obtained, the consumption
and possibly the recovery cycle for costly solvents considerably affect
production costs.
The process of the invention avoids the above disadvantages. The process
comprises directly methylenating an ortho-diphenol compound of the general
formula (I):
[start non-proportional font]
---
// \
// \--R1
/\ //
HO \ //
/===
HO
[end non-proportional font]
in which R1 is an alkyl group having from 1 to 4 carbon atoms, an aldehyde
or carboxylic acid group, an alkoxy group having from 1 to 4 carbon atoms,
a halogen atom or a nitro group; by reaction with methylene dichloride in
concd. aqueous alkaline soln., in the presence of one or more of the
following quaternary ammonium salts as catalysts, at a temperature of from
30° C to 120° C, and preferably with fierce agitation.
The quaternary ammonium salts which may be used as catalysts have the
general formula (ii) N(R)4.Br in which the four R groups may be the same or
different, each an alkyl group having from 2 to 8 carbon atoms.
Note 6: the Japanese patent implies that other PTCs will also do.
{cut out removed - contains details of yet other, more exotic, PTCs that
can be used}
The preparation is carried out by subjecting a mixture of methylene
dichloride, a concentrated aqueous alkaline solution of the sodium salt of
the ortho-diphenol compound (I) and small quantities of the catalyst to
fierce agitation. Alternatively, NaOH and the ortho-diphenol compound (I),
each either in the solid form or in concentrated aqueous solution, may be
added at the same time or successively to a solution of the catalyst in
methylene dichloride.
As the reaction products form they are extracted by the methylene
dichloride, because of which at the end of reaction it is sufficient to
allow the organic layer to decant to obtain simple and rapid separation of
the reaction product from the starting compounds, which remain in the
aqueous layer. The methylene dichloride may first be distilled from the
organic phase and recycled, and then the methylenedioxy product may be
distilled off at high purity. The catalyst remains as a residue, and may be
recovered and recycled.
The quantity of methylene dichloride may vary between 1 to 5 moles per mole
of the ortho-diphenol compound (I). However it is better to operate with an
excess of methylene dichloride so as to work with a double phase and
extract the product into the organic phase.
The catalysts are preferably used in quantities of from 1 to 10 mole % with
respect to the ortho-diphenol compound (I), and may be recycled. NaOH is
preferably present in an amount between 30% and 150%, based on the mole
equivalent of the diphenol added. The concentration of the diphenol sodium
salt in the aqueous phase is advantageously maintained between 0.1% and 40%
by weight.
The reaction occurs between 30° C and 120° C, but maximum reaction speed is
obtained between 60° C and 90° C.
The following examples illustrate the invention.
Example 1
100 ml (1.56 moles) of methylene dichloride, 6.42 g (0.02 moles) of
tetrabutylammonium bromide and 200 ml of water were placed in an autoclave,
and a total of 15 g (0.1362 moles) of pyrocatechin and 15.9 g (0.3975
moles) of NaOH flakes were added in successive stages.
The reaction temperature was 70° C and the pressure rose to a maximum of
2.4 atmospheres gauge. The reaction finished in 3 hours.
After this time the organic phase was separated, the excess methylene
dichloride was distilled off and recycled, and 13.8 g of pure benzodioxole
was obtained by distillation, at a yield of 83%.
The tetrabutylammonium bromide remained as a distillation residue, to be
recovered and reused.
Example 2
The process was carried out exactly as described in Example 1, but using
hexadecyl-tributyl-phosphonium bromide instead of the tetrabutylammonium
bromide. 11.65 g of benzodioxole was obtained, at a yield of 70%.
Example 3
100 ml (1.56 moles) of methylene dichloride and 6.42 g (0.02 moles) of TBAB
[tetrabutylammonium bromide] were placed in an autoclave, and to this were
added with agitation at 800C a total of 24.8 g (0.2 moles) of 4
methyl-pyrocatechin and 24 g (0.6 moles) of NaOH flakes. The reaction was
continued for 5 hours. Proceeding as in eg, 1, 19.4 g of 1
methyl-3,4-MD-benzene was obtained, at a yield of 71.3%.
Example 4
100 ml of methylene dichloride, 6.42 g of tetrabutyl-ammonium, bromide and
200 ml of water were placed in an autoclave, and a total of 27.6 g (0.2
moles) of protocatechuic aldehyde and 24 g (0.6 moles) of NaOH in 30 ml of
water were added in stages at a temperature of 700C. The pressure increased
to a maximum of 2.4 atmospheres gauge, and the reaction was continued for 4
hours.
After this time the reaction mixture was cooled to ambient temperature, the
organic phase was separated and the excess methylene dichloride was
recovered by distillation. 21 g of high purity piperonal were isolated.
Yield 70%.

Appendix 3: Formic Acid [64-18-6]; CHOOH

==================================
Formic acid is available as "Descalite" kettle scale remover in UK. Concn.
54%.
Formate is a product of the Cannizzaro reaction of formaldehyde.
From glycerol & oxalic acid. [Mann & Saunders, Practical Organic Chemistry,
3rd. ed. page 84; Chattaway, Prepn. of Allyl Alcohol, J. Chem. Soc., 107,
p. 407 (1915); Thorpe's Dictionary of Applied Chemistry].
From: UpYours Pigs. "The Complete Book of Ecstasy, 2nd ed." Mix an equal
amount of glycerine and oxalic acid and place in a flask. Heat this mixture
at 75-90° C. Continue heating until no more CO2 bubbles out. Fresh oxalic
acid is added and the process continued. When enough acid is made, distil
it over using the proper apparatus and raising the temp. with an oil bath.
90% formic acid is collected. Alternatively, place the mixture in a
distillation apparatus with a vacuum connection. Read the temperature with
the thermometer placed into the mixture. Heat the mixture to ~ 90° C, while
under reduced pressure. As the reaction proceeds the formic acid will
distil over. This takes about 4 to 5 hours for 500 g of glycerine and 500 g
of oxalic acid. [If you really are going to do this then lookup the Mann &
Saunders method first]
Anhydrous formic acid: [I L Finar - Organic Chemistry, vol. 1, 6th ed.]
Butyl formate added to aq. soln. 70-77% formic acid followed by distn.
First fraction is an azeotrope of ester and water. Then xs. ester is
removed from formic acid by fractionation.

Appendix 4: Phase Transfer Catalysts. Aka quats. PTC.

==========================================
PTCs are available as OTC chemicals in a variety of household products such
as fabric softeners, hair conditioners, bactericides. They are present as
quarternary ammonium salts (quats) and are referred to as cationic
surfactants. They may not be explicitly named on the package.
The use of quats as phase transfer catalysts (PTC) is a useful modern
development. Quats are most useful in allowing anions to transfer into the
organic phase. They speed up many reactions, increase yields and, most
importantly, allow reactions to proceed that otherwise would not. The need
for costly and dangerous organic solvents is often dispensed with. For the
last word on PTCs see the most wonderful "Phase Transfer Catalysis" by C.
M. Starks, C. L. Liotta and M. Halpern, Chapman & Hall, 1994. You can buy
them from chemical companies but the household varieties will make-do for
many reactions. The PTCs can be recovered and used again. All reactions
using PTC to mix the aqueous and organic phases must be done with vigorous
stirring - at least 600 rpm.
Hair conditioners use one long chain alkyl group and 3 methyl groupings in
the quat. Fabric conditioners use two long chain alkyl groups in the
quats. see The Handbook of Surfactants (p248) and The Handbook of
Industrial Surfactants.
Quaternary ammonium salts.
======================
Hydrophobes: generally 2 or 3 of the alkyl groups are methyl.
Hair conditioners are alkyl (C12 -C18), trimethyl or dialkyl, dimethyl
types.
Usually: Me3NR; where R = C14
Solubility: Quat with one long hydrophobe is sol. in water, insol. in
mineral oil, white spirit & perchloro-ethylene.
Fabric conditioners (for dryer sheets) consist of the methosulphate salt of
dialkyl type (C16 - C18) dimethyl type of quat. Fabric conditioners for
liq. softeners to be added to laundry during rinse cycle have
dialkyl,dimethyl quat in combination with more soluble salt such as a)
unsaturated. dialkyl, dimethyl quat, b) amido-imdazolium salt, or c)
diamido alkoxylated quat.
Usually: Me2N+R2 R = C14
Solubility: Quat with two hydrophobes is dispersible in water and sol. in
organic solvents.
pH - stable to pH changes.
moderate foaming, poor wetting, good emulsifiers, poor to moderate
detergency.
Quat with only one long alkyl (C12 -C18) or two shorter alkyl (C8 - C10)
are primarily anti-microbial active substances. Eg. Detol: Benzalkonium
Chloride; mouthwash: Cetyl pyridium Cl
Benzalkonium chloride [PhCH2.N(Me)2.R] + Cl- (R is C8 - C18) is a biocide.
Cetrimide BP is [RN(Me)3]+ Br- where R is mix of C12 - C16 mainly C14.

[non-proportional font]
Typical composition of European fabric conditioners:
Substance %
------------------------------------------------------------------
DA DA AC 1- 9
imidazolinium methyl sulphate 40 - 50
methyl bis alkyl amidothyl -2-hydroxy ethyl AMS none
alcohol ethers 0 - 3
fluorescent whitening agent 0 - 0.2
preservative 0.1 - 0.5
alkyl benzyl dimethyl AC 0 - 1.5
dye, fragrance +
water balance
Textiles conditioners are mainly dimethyl, dialkyl A C.
Solubility:
R solubility (water) use
---------------------------------------------------------
C8 very sol. mild germicide
C10 sol. strong germicide
C12 poor weak germicide
C14 low antistatic
C16-18 practically insol. softener
[end non-proportional font]

Appendix 5 - Phenyl acetones by electrolytic oxidation.

=========================================
Process for 3,4-dimethoxyphenyl-acetone preparation. European Patent
Application 0247526, Filed: 02.12.87; to LARK S.p.a. Milan.
A process for preparing 3,4-dimethoxyphenylacetone is disclosed, which
consists in electrolytically epoxidating isoeugenol-methylether in a
mixture consisting of water and of a dipolar aprotic solvent, in the
presence of Br- ions, and in isomerizing the so-obtained epoxide, in an
inert organic solvent, in the presence of catalytic amounts of lithium
salts, by means of a heating at temperatures comprised within the range of
from 50° C up to the solvent refluxing temperatures.
The present invention relates to a process for the preparation of
3,4-dimethoxyphenylacetone by means of the electrochemical epoxidation of
isoeugenol-methylether and subsequent catalytic isomerization of the
so-obtained epoxide.
3,4-dimethoxyphenyl acetone is a useful intermediate for the synthesis of
Methyldopa, (-methyl-(-(3,4-dihydroxyphenyl)-alanine, an important
antihypertensive agent (U.S. Pat. 2,868,818).
State Of The Prior Art
------------------------------
The preparation of 3,4-dimethoxyphenylacetone by means of the oxidation of
isoeugenol-methylether by organic peracids (performic acid or peracetic
acid), to yield an intermediate diol which is subsequently converted into a
ketone by acidic hydrolysis is known (C.A. 82, 72640, 1975; and C.A. 69,
106243, 1968).
Such methods show however the drawback of requiring the use or organic
peracids, the dangerousness of which is known.
Furthermore, the preparation is known of 3,4-dimethoxyphenylacetone by
starting from veratraldehyde via the Darzens reaction (C.A. 101, 152292,
1984), or by starting from 3,4-dimethoxyphenylacetic acid by condensation
with acetic anhydride and ketene (C.A. 102, 24290, 1985).
Such methods, however, do not result economically valid, and they are
difficulty accomplishable on an industrial basis, mainly due to the high
cost and the not easy availability of the starting products.
Purpose of the present invention is preparing 3,4-dimethoxyphenylacetone by
means of a simple, cheap, highly selective and high-yield process, which
can be easily accomplished on an industrial scale by using non-dangerous
reactants and low-cost, easily available starting products.
It has been found now that the above purpose, and still other purposes, are
achieved by means of a process which comprises the electrochemical
epoxidation of isoeugenol-methylether and the subsequent catalytic
isomerization of the obtained epoxide into 3,4-dimethoxyphenylacetone.
Description Of The Invention
Therefore, the object of the present invention is a process for preparing
3,4-dimethoxyphenylacetone, characterised in that:
(a) isoeugenol-methylether, having the formula: 3,4-(MeO)2.C6H3.CH=CH.Me I
is submitted to an electrolysis in a not-partitioned electrochemical cell,
in a medium comprising a dipolar aprotic solvent and an aqueous solution
containing an alkali metal bromide or an alkali-earth metal bromide or a
quaternary ammonium bromide, in such an amount as to have at least 0.6 mol
of Br- ions per water litre, with graphite anodes or anodes constituted by
titanium, coated with oxides of precious metals of the VIII group or with
mixed oxides thereof with valve metals selected from Ti, Nb, Ta and Zr, and
that: (b) the epoxide II having the formula:
[begin non-proportional font]
MeO //\
\ // \
\// \ O
| || / \
| || / \
| ||---CH---CH--Me
/\\ /
/ \\ /
MeO \\/
[end non-proportional font]
isolated from the reaction mixture resulting from (a) step is submitted to
an isomerization, in an inert organic solvent and in the presence of
catalytic amounts of a lithium salt selected from lithium iodide, bromide
and perchlorate, by being heated at temperatures comprised within the range
of from 50° C to the solvent refluxing temperature, to produce a methyl
ketone III.
The electrolysis reaction (a), leading to the formation of the epoxide, can
be carried out both batch-wise and continuously, at temperatures comprised
within the range of from 0° C to 50° C, preferably of from 10° C to 30° C,
with current intensities higher than 100 A/m2 being used, and with the
reaction mixture being kept stirred, by a stirring of mechanical type, or
obtained by exploiting the turbulence as generated by the gases formed
during the electrochemical reaction.
As the dipolar aprotic solvents, e.g., acetonitrile, dimethylformamide,
dimethylsulphoxide, sulpholane, N-methylpyrrolidone and dimethylacetamide,
preferably acetonitrile and dimethylformamide, can be used.
Generally, a volume ratio of the dipolar aprotic solvent to water comprised
within the range of from 1:1 to 10:1 and a concentration of
isoeugenol-methylether (I) in the mixture constituted by the solvent and
water higher than 10 g/L is used.
In order to be able to obtain high selectivities and high yields of epoxide
(II), it was found in particular that using is necessary, in the
electrolysis reaction (a), both a high concentration of Br- ions, higher
than 0.6 mol/water litre, up to the concentration corresponding to the
maximum solubility in H2O of the used bromide, and anodes constituted by
graphite or titanium coated with oxides of precious metals of the VIII
Group of the Periodic System, e.g., with Ru oxides or with mixed oxides of
the same metals with such valve metals as Ti, Zr, Nb and Ta. In fact, the
use of low concentrations of Br- ions and of common Pt anode leads to the
formation of substantial amounts of by-products, mainly constituted by
dimerization products. The high concentration of bromides in the reaction
mixture, besides favouring the yield of epoxide, renders easier the end
separation of the epoxide from the organic reaction phase and allows
furthermore high current efficiencies to be achieved.
The reaction (b) of isomerization of epoxide (II) to ketone (III), in the
presence of catalytic amounts of a lithium salt, takes place with high
yields and in a regioselective way. Generally, amounts of lithium salt
comprised within the range of from 0.05 to 0.4 mol per mol of epoxide (II),
and concentrations of epoxide in the organic solvent comprised within the
range of from 5 to 50 g/100 ml of solvent are used.
As the inert organic solvents, e.g., acetonitrile and (C1-C4)-alkyl
acetates, preferably ethyl acetate, can be used. The duration of the
isomerization reaction can range from 2 up to 10 hours, according to the
adopted experimental parameters.
According to a practical operating way, to a not-partitioned
electrochemical cell the aqueous solution of alkali-metal bromide is
charged, and to it the organic solution of olefin (I) is added; then, with
the temperature being kept at a prefixed value comprised within the range
of from 10° C to 30° C, a current amount comprised within the range of from
2 to 2.6 Faradays per olefin mole is passed, until the starting olefin has
disappeared.
After the reaction has been completed, the epoxide (II) is separated from
the aqueous phase containing the alkali-metal bromides.
The so-obtained epoxide is dissolved in the organic solvent selected for
the subsequent isomerization step, e.g., in an alkyl acetate, to it a
catalytic amount of lithium salt is added and the reaction mass is heated
at the reflux temperature for the necessary time for isomerization to be
completed.
The lithium salt is then separated from the organic phase by means of
aqueous washes, or by the addition of a suitable non-solvent and subsequent
filtration.
The ketone (III) is finally obtained by evaporating its organic solution to
dryness, and shows, at a chromatographic analysis, a purity of (90%.
Then, if necessary, a further purification thereof may be performed by
means of the common techniques, e.g., of distillation, liquid
chromatography.
Some non-limitative examples are now supplied to the purpose of
illustrating the invention.
Example 1.
6.27 g of NaBr is dissolved in 25 ml of H2O and 125 ml of CH3CN, the
mixture is then strongly stirred by means of magnetic stirring, and to it
3.76 g of isoeugenol-methylether (I) is then added.
The obtained mixture is then electrolysed in a 250-ml not-partitioned
electrochemical cell, with a constant current of 850 mA, with two graphite
anodes with a total surface of about 17 cm2, and a central stainless-steel
cathode having a surface of about 25 cm2 being used, with a distance
between electrodes of about 1 cm. 5,200 Coulombs are passed, with the
reaction mixture being kept at a temperature of 20° C.
From the reaction mixture, discharged from the electrochemical cell, two
phases, i.e., the aqueous phase, containing Br- ions, and the organic
phase, containing acetonitrile and the reaction product, are separated.
From the organic phase acetonitrile is evaporated off under reduced
pressure, and to the resulting reaction product 40 ml of ethyl acetate is
added.
The gas-chromatographic analysis of the organic phase shows the presence of
epoxide (II) with a >90% purity.
The reaction mixture in ethyl acetate is then transferred to a 100-ml
reactor, purged under a nitrogen atmosphere, 340 mg of LiI is added, and
the whole mass is then heated, with mechanical stirring, on an oil bath, up
to ethyl acetate reflux temperature. The heating is continued for 5 hours,
until the disappearance of the epoxide (II), as evidenced by the thin-layer
chromatography.
The reaction product is cooled to room temperature, is washed with 10 ml of
H2O to the purpose of removing lithium iodide and is then dehydrated over
Na2SO4.
3.57 g is obtained of dimethoxy-phenylacetone (III), as determined by
gas-chromatographic analysis with an inner standard of
4,4'-dimethoxybenzophenone. The yield of ketone (III) relative to the
olefin (I) used as the starting material is of 87.1%.
Example 2
Example 1 is repeated in exactly the same way, with the exception that in
the isomerization step 250 mg of LiBr instead of 340 mg of LiI is used, and
that the reaction time results to be of 10 hours, instead of 5 hours. In
this way, a yield of ketone (III) of 86% relatively to the olefin (I) used
as the starting material is obtained.
Example 3
To a 250-ml not-partitioned electrochemical cell, 125 ml of CH3CN, 25 ml of
H2O, 6.47 g of NaBr and 2.78 g of isoeugenol-methylether (I) is added. The
mixture is electrolysed at a constant current of 350 mA, with a titanium
anode coated with a mixed Ru-Ti oxide (50:50 by weight), with a total
surface of about 7 cm2, and a central stainless-steel cathode having a
surface of about 15 cm2 being used, with a distance between electrodes of
about 1 cm. Through the cell 4,000 Coulombs are passed, with the reaction
mixture being kept at the temperature of 20° C.
The reaction mixture is then processed according to such modalities as
reported in Example 1, until the solution of the reaction product in ethyl
acetate is obtained; to such solution, 337 mg of LiI is added.
The mixture is then refluxed (at ethyl acetate refluxing temperature) for 5
hours, and the process is continued as described in Example 1, until 2.795
g is obtained of ketone (III), with a yield of 92.2% relatively to the
olefin (I) used as the starting material.
Example 4
To a 250-ml not-partitioned electrochemical cell, 125 ml of CH3CN, 25 ml of
H2O, 6.40 g of NaBr and 2.675 g of isoeugenol-methylether (I) is added.
The mixture, kept at 20° C, is electrolysed, with the same constant current
density and the same set of electrodes as of Example 1 being used, through
the cell 3,625 Coulombs, equalling 2.5 Faradays/mol, being passed. The
reaction mixture is then transferred to a rotary evaporator, for CH3CN to
be stripped under vacuum. The resulting reaction product is then extracted
three times with 30 ml of ethyl acetate, and is then dried over Na2SO4.
The organic extract, concentrated to a volume of 25 ml, and with 160 mg of
added LiI, is refluxed (at ethyl acetate refluxing temperature) for 6
hours.
The process is continued as described in Example 1, and 2.54 g is obtained
of ketone (III), with a yield of 86.5% relatively to the olefin (I) used as
the starting material.
Example 5
To a 250-ml not-partitioned electrochemical cell, 135 ml of CH3CN, 15 ml of
H2O, 6.20 g of NaBr and 2.82 g of olefin (I) is added.
The mixture, kept at 20° C, is electrolysed by using the same electrodes as
of Example 1, but with a constant current density of 1.7 A being used,
until through the cell 4,000 Coulombs have been passed. The reaction
mixture is then processed as described in Example 4.
2.56 g is obtained of ketone (III), with a yield of 83.2%, as computed
relatively to the olefin (I) used as the starting material.
Examples 6-9
To a 250-ml not-partitioned electrochemical cell, 100 ml of DMF, 50 ml of
H2O, 6.72 g of NaBr and 4.25 g of isoeugenol-methylether (I) is charged.
The mixture is then electrolysed under the same conditions, and by using
the same set of electrodes as used in Example 1, with a total of 5,670
Coulombs being passed.
At reaction end, the mixture is discharged, to it 250 ml is added of 20%
aqueous NaCl solution, and it is then extracted four times with 50 ml of
ethyl acetate. The extract is washed twice with 50 ml of 20% aqueous NaCl
solution, and is then dried.
The organic extract is concentrated to a volume of 100 ml by the solvent
being evaporated off.
On three aliquots, of 20 ml each, of said extract, the isomerization
reactions are carried out at the ethyl acetate reflux temperature, by using
the same lithium salts and reaction times as shown in Table 1.
From the fourth aliquot of 20 ml of above said extract, ethyl acetate is
evaporated off and replaced with the same amount of acetonitrile.
The isomerization of the reaction product is then carried out at
acetonitrile refluxing temperature, with the lithium salt and the reaction
time being used as shown in Table 1.
In Table 1 also the conversions and the yields of ketone (III), as computed
relatively to olefin (I) used as the starting material, are reported for
each example.
Table 1
Lithium Salt
Eg. Solvent Type mg Time Con % Yield %
6 Ethyl Acetate LiI 180 6 h 100 91.4
7 Ethyl Acetate LiBr 140 10 h 100 87.7
8 Ethyl Acetate LiClO4 160 10 h 60 45.8
9 Aceto-nitrile LiI 185 6 h 100 77.1
Claims
1. Process for preparing 3,4-dimethoxyphenylacetone, characterised in that:
(a) isoeugenol-methylether is submitted to an electrolysis in a
not-partitioned electrochemical cell, in a medium comprising a dipolar
aprotic solvent and an aqueous solution containing an alkali metal bromide
or an alkali-earth metal bromide or a quaternary ammonium bromide, in such
an amount as to have at least 0.6 mol of Br- ions per water litre, with
graphite anodes or anodes constituted by titanium, coated with oxides of
precious metals of the VIII group or with mixed oxides thereof with valve
metals selected from Ti, Nb, Ta and Zr.
and that: (b) the epoxide isolated from the reaction mixture resulting from
(a) step is submitted to an isomerization, in an inert organic solvent and
in the presence of catalytic amounts of a lithium salt selected from
lithium iodide, bromide and perchlorate, by being heated at temperatures
comprised within the range of from 50° C to the solvent refluxing
temperature.
2. Process according to claim 1, characterised in that the electrolysis is
carried out at temperatures comprised within the range of from 0° C to 50°
C, using a current density higher than 100 A/m2
3. Process according to one or both of the claims 1-2, characterised in
that the ratio by volume of the dipolar aprotic solvent to water is
comprised within the range of from 1:1 to 10:1 and that the concentration
of isoeugenol-methylether in the mixture constituted by the dipolar aprotic
solvent and water is higher than 10
4. Process according to claim 3, wherein the dipolar aprotic solvent is
selected from acetonitrile and dimethylformamide.
5. Process according to one or more of the claims 1-4, wherein in (b)
isomerization reaction an amount of lithium salt comprised within th range
of from 0.05 to 0.4 mol/mol of epoxide (II), and a concentration of epoxide
in the inert organic solvent comprised within the range of from 5 to 50
g/100 ml of solvent is used.
6. Process according to claim 5, characterised in that the inert organic
solvent is selected from acetonitrile and ethyl acetate.