MDMA from Eugenol

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.