[www.rhodium.ws] [] [Chemistry Archive]
 
 

MDMA via Tosyl Chloride Intermediate?

Synthesis of MDMA by Addition of Methylamine to
1-(3,4-Methylenedioxyphenyl)-2-Propanol Tosylate

HTML by Rhodium

Ollie-RSM

Has anyone ever heard of MDMA being produced by a Markonikov hydration of safrole and conversion of the alcohol to an alkyl tosylsulfonate (via rx with tosyl chloride) followed by SN2 amination with methylamine? This synthetic pathway would be very similar to the bromination/debromination pathway that is recently in vogue, and might be even simpler. Plus tosyl chloride is dirt cheap ($23 for 1kg).

Siegfried

I try this procedure alot and it was much better than normal alkyl-halide process because the tosylate (and brosylate or nosylate) don't give a lot of elimnation contrary to the alkyl-halide. I got the alkohol intermediate with oxymercuration of the allylbenzene and made the tosyaltion with tosylchloride/pyridine, then the SN2 in MeOH with a little THF for solubility purpose and RT. The yield and reaction time are:

The RT and polar solvent are very important because increase the temperatur favorise the elimination, decrease the polarity too. Anyway, this family of SN2 is favorised with polar protic solvent as MeOH (see the March). As I wrote under another topic, the tosylate are very good but there is even better leaving group they don't give any elimination and have better kinetics: the Triflate, but it's an expensive reagent.



For the tosylation of alkohol, the base is pyridine, because

For the hydratation of the alkene, acid medium is not good because the 1-aryl-2 propanol first formed is rapidly deshydrated to the stabilized isosafrole wich is hydrated to the 1-aryl-1-propanol. The result is:

The oxymercuration process give only the 1-aryl-2-propanol intermediate without rearrangement in about 20min with >95% yield but HgCl2 can not be used, sorry. Hg(OAc)2 or Hg(NO3)2 or Hg(ClO4)2 or Hg(CF3COO)2 can be used. You must use Hg2+ (mercuric) and not Hg+ ion (mercurous). You can make Hg(OAc)2 from HgCl2 + CH3COOH but you must purify it. Anyway Hg(OAc)2 can easily be purchased.

Tr-E-frog

Thank you for the informative post. What originally got me interested in this method was the fortuitous discovery of 'triflate' anhydride in reasonable quantity. Have you used this leaving group in this reaction? Would you mind posting the details of your procedure? Ultimately, I suspect that the cost of this reagent makes it impractical for any scale up but for a small scale high-yield experiment it may be interesting.

Ritter

I believe the only better leaving group than tosyl is methanesulphonate from mesyl chloride, of course. The methanesulphonly group will probably provide yields 10% or so better in SN2 substitution w/ anhydrous alcoholic methylamine or ethylamine soln. Methanesulphonyl chloride is a little more expensive than tosyl chloride however it is a liquid and therefor much simpler to handle than stinky irritating tosyl chloride.

On a side note safrol-2 mesylate reacted in 80% yield with excess benzylamine to make N-benzyl MDA which was easily hydrogenated at 30 lbs w/ five percent loading of 10%Pd/C catalyst to produce a total yield of 73% MDA from starting alkene. not too shabby! The methylenedioxyphenyl-2-propanol was generated from methylenedioxyphenylacetaldehyde w/ MeMgI grignard.

Siegfried

Ritter: the oxymercuration process is very simple and easy to carry: RT , >95% yield, 25min reaction time... The mesylate group is about the same than tosylate or nosylate or brosylate but the best known leaving group are triflate and nonaflate, tresylate is not so good it's about 400 times less reactiv than triflate but it is still about 100 time more reactive than tosylate and analogs... Conclusion: triflate is 4000 time more reactiv than tosylate and analogs (mesylate, brosylate, nosylate). For a good explanation of the leaving goup see the chemist bible: "Advanced organic chemistry - Jerry March" chapter: nucleophilic substitution.

Siegfried

The tosylation must be conducted in pure pyridine. 11 mmole tosylchlorid is added slowly ( t<30°C ) to a stirred solution of 10 mmole alkohol in 10 ml pyridine. When tosyl chloride is added, the mixture is stirred for 30-40 min RT. Then the mixture is poured in 100ml 2N HCl, then tosyl is purified . Yield over 95%.

Ritter

Just dug up some references for advancement of tosylate/mesylate esters as feasible, high yielding synthetic intermediates to our beloved honey in an aqueous environment.

The following is quoted from: J. Org. Chem. 53, 4081-84 (1988)

(R)-Tomoxetine Hydrochloride: A solution of phenyl-3-(2-methylphenoxy)-propyl methane sulfonate [the mesylate group is on the gamma carbon] (450mg, 1.45mmol) and methylamine (10ml, 40% in water) in THF (10ml) was heated to 65°C for 3h. After cooling, the solution was diluted with ether, washed w/ aq. sat. NaHCO3 soln. and brine, and dried with anhydrous K2CO3. After concentration a pale yellow oil was obtained which was dissolved in ether, bubbled w/ dry HCl gas [and you guys certainly know the rest] to produce a white ppt which was recrystallized w/ acetonitrile to yield title compound (400mg, 94%)

Thats amazing! Ninety-four freakin percent from an aqueous MeAmine soln!!! Try achieving that with a halogen leaving group on our favorite alkene by cooking the stinky shit up in a pipe bomb w/ alcoholic MeAmine. You can't, if you are lucky 50% will be . Halogens blow as leaving groups compared to sulfonate derivatives as proved by this paper. It is such an advantage to be able to use good 'ol fashioned aqueous MeAmine compared to homebrew anhydrous alcoholic amine solns! The only drawback noticed immediately is the large excess of MeAmine employed by the authors. This shouldn't present a huge problem because the excess amine cooked off during the heating process can be collected by bubbling through HCl. The 65°C rctn temp is the bp of THF so excess amine will be liberated out of the top of the reflux condensor on rctn pot. A slow stream of N2 can be admitted through a bubbler in the second neck of the rctn. flask forcing the methylamine gas to be expelled out the top of the condenser into a beaker of HCl. Simply evap off HCl to obtain your excess amine back as MeAmine hydrochloride.

There is one other procedure for producing alkyl-methylamines from an alkyl mesylate using the exact same protocol listed above with product isolated in 96% yield! This proves the procedures high yields are reproducible, however both examples listed are performed on primary alkyl mesylates. Since we are working with a secondary alkyl mesylate yields may suffer a bit from steric hindrance during the nucleophilic substitution by MeAmine. Well actually, let me restate that.. my chem theory is getting a little weak.. In most if not all nucleophilic substition reactions in the literature compounds with a leaving group always have higher yields in nucleophilic substition rctns than a complementary compnd w/ a secondary leaving group. Therefore the mesylate in our case may not produce the 90+% yields quoted in the literature but it sure will be much higher than that produced by any halogen.

Siegfried: Excellent work in this area. Was wondering if you'd be kind enough to post the physical properties of the tosylate. Simple experience has proved that most tosylates are solids, however you're the only one who knows for sure. A melting pt. would be very useful. Any recrystallization solvent of choice?

Was an attempt ever made at esterifying the propanol produced w/ H2SO4? As a side note any tertiary amine can be used in a similar manner as pyridine to scavenge protons in the esterification rctn. Triethylamine was the amine of choice in the quoted article. Yields of 85% were recognized after several wasteful recrystallizations.

On the subject of hydration of alkene to alcohol, oxymercuration is obviously the most simple method considering rctn. time and yield. However soluble mercury salts just plain suck. It sure would be nice if the H2SO4 thing worked. Another possible synthesis may be a PTC rctn. between aq. NaOH and halosafrole. This is a well documented rctn. however conditions will probably have to be closely monitored to minimize isoalkene formation.

Finally, to sum everything up this is a major breakthrough because of the reactivity of amines to sulfonic esters in aqueous environment. Similar reactions in the past have usually reacted alkyl halides as leaving groups and fickle-to-make alcoholic amine solns with long rctn times or high temperature pipebomb pressure vessels. Not very desirable when compared w/ a 3hr STP reflux. Reported yields are also very poor w/ halide exchange rctns. Comment?

Siegfried

RevDrone: the direct tosylation of the alkene won't work really good because the tosylate is not a good nucleophil . But you can try it , perhaps it will work , but your reaction medium must be anhydrous and without other nucleophile wich will compete. The theoritical mechanism of your proposition is a markownikow addition of tosluenesulfonic acid... First the proton attack the double bond of the alkene forming a crabocation , then the nucleophil (the tosylate part ) can attack the carbocation .

Others: For the physical properties of 1-phenyl- 2-tosyloxy-propane, it's a solid white transparent, insoluble in water, i don't have the melting point because i use a better procedure for purity control.

The pyridine must be used for tosylation because it give better yield than triethylamin because the complex intermediate between tosyl and pyridine is a greater electrophile.

The nucleophil substitution is conducted with an excess methylamine in water with THF in RT for some days ... You can increase the temp as described by Ritter . Aqueous MeNH2 is better than alkoholic solution because in this type of SN2 substitution: the more polar is the medium, the best the cinetic is and the more polar is the medium the best is the ratio substituion vs elimination .

For the 1-phenyl-2-propanol intermediate, acid condition of the normal Markownikov reaction give poor yield and a lot of elimination and rearrangement product ...

The other way from halosafrole and NaOH will give a lot of elimination, because it's the same mecanism than nucleophil substitution with MeNH2, and even poorer yield because NaOH is more basic than MeNH2... The reasons for predominant elimination with the 1-aryl-2-halo-propanes are:

So the best is oxymercuration, the mercury is really easily removed.

I haven't tried the triflates, but they have faster kinetics and less abilility to give elimination... But the tosylate give already much less elimination than the halides, so your only gain is the kinetics. The procedure was used to prepare Methamphetamine but it will surely work for MDMA and it will be the same process .

Cyrax

It seems that it would be more convenient to use a mesylate instead of a tosylate. If one has to make a choice between pyridine and triethylamine, one would take the TEA, right? Just compare the following procedures:

Synthesis of 2-(2-thienyl)ethanol methanesulfonate

2-(2-thienyl)ethanol (100 g, 0.78 mole) in 1000 mL DCM was stirred with 1.5 eq. triethylamine (120 g, 1.18 mole) at ice bath temperature. Then 1.3 eq. methanesulfonyl chloride (120 g, 1 mole) was added dropwise to control the exotherm. After 6 hours at room temperature the mixture is washed with water (2 x 200 mL), aq. sodium bicarbonate (2 x 100 mL), dried over anhydrous magnesium sulfate and the solvent is evaporated to give the crude mesylate (144 g, 92%) as a yellow range oil. GC analysis showed 97% purity. The mesylate was used immediately and is stable for extended periods if storred in the refrigerator.

Synthesis of 2-(2-thienyl)ethanol toluenesulfonate

To an ice cold solution of 2-(2-thienyl)ethanol (4.22 g, 0.033 mol) in dry pyridine (6 mL) was added in portions solid p-toluenesulfonyl chloride (6.90 g, 0.036 mol). The resultant mixture was stirred 2 hours at ice bath temperature, then poured into crushed ice/water (ca. 100 mL). Concentrated hydrochloric acid was added until the mixture was acidic. The acidic solution was extracted with several portions of diethyl ether. The combined ether extracts were washed with water and saturated sodium chloride solution, then dried. Subsequent evaporation of the ether afforded a quantitative yield of crude 2-(2-thienyl)ethyl tosylate which was used with no further purification.

Rhodium

Is there a measurement of "lability" one can use when discussing tosylate vs. mesylate? I was under the impression mesylates underwent elimination so easily you had to keep the ester cold at all times, or else you'd wind up with alkene.

The procedures above uses TEA/MsCl and Pyr/TsCl, but why not use TEA/TsCl? There is probably a reason, but as I don't know about it, I would be very glad for a little elaboration on the topic.

Cyrax

Rhodium: I see your reason for concern - esters of sulfonic acids also undergo elimination by treatment with a base (or by heating). It seems that we have to find the reaction conditions that favour nucleophilic substitution and minimalize the extent of alkene formation.

My impression is that you don't have to worry much about steric hinderance. Take a look at this:

A mixture of 5.7g (0.03 mol) 3-methyl-N-phenyl-4-piperidineamine HCl and phenyl-2-propanol mesylate (7g, 0.033 mol) in i-BuCOMe (300 mL) was stirred and refluxed for 48 hours. The mixture was allowed to cool and extracted with H2O, the organic phase dried (MgSO4), and the solvent removed in vacuo. The residue was crystallized as the HCl salt from i-Pr2O - i-PrOH to give 3-methyl-1-(1-methyl-2-phenylethyl)-N-phenyl-4-piperidineamine dihydrochloride (10.5 g, 92%).

It seems that the steric hinderance and the heating didn't cause elimination.

As a side note: bis(tetra-n-butylammonium)oxalate is the reagent of choice for inducing tosylates to undergo elimination rather than substitution.

The procedures above uses TEA/MsCl and Pyr/TsCl, but why not use TEA/TsCl? There is probably a reason, but as I don't know about it, I would be very glad for a little elaboration on the topic.

I know that they use pyridine as a catalyst to make the ester between an alcohol and an acyl chloride. Pyridine catalysis involves the initial formation of an acyl pyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, and the acylpyridinium ion reacts more rapidly with the alcohol than the acyl chloride. Furthermore, the piperidine captures the HCl that is formed during the reaction.

I don't know this for sure, so don't shoot me if I am wrong, but I guess that it would be the same thing for the tosyl chloride. Tosyl chloride is an (inorganic) acid chloride after all. First pyridine reacts with the p-toluenesulfonyl chloride, and then the alcohol reacts with the tosylpyridinium ion. Since pyridine is used as solvent, there is more than enough of that nasty stuff to capture the liberated HCl.

Rhodium

Here is a very good procedure for the preparation of mesylate esters from alcohols, using 1.1 equivalents of methanesulfonyl chloride (CH3SO2Cl), 1.5 equivalents of triethylamine in chilled (0°C) dichloromethane solution. The entire procedure can be performed in under one hour, and consistently gives yields between 85-95%.

General Procedure

To an approximately 0.2M solution of the alcohol in DCM17 solution containing a 50% molar excess of triethylamine, kept at between 0°C and -10°C, was added a 10% excess of methanesulfonyl chloride (mesyl chloride) over a period of 5-10 minutes18. Stirring for an additional 10-15 minutes completed the reaction. The reaction mixture was transferred to a separatory funnel with the aid of more DCM. The mix was first extracted with ice water, followed by cold 10% HCl acid, sat. sodium bicarbonate, sat. brine. Drying the DCM solution followed by solvent removal gave the product19, which was pure enough for most uses, including solvolysis.

  1. Both cyclohexane and pentane may also be used as solvent. The choice is based solely on the solubility of the starting alcohol.
  2. Mesyl Chloride was redistilled; triethylamine was refluxed over phthalic anhydride, distilled, and then taken redistilled from KOH pellets; DCM was taken from a freshly opened bottle of AR grade. Anhydrous reaction conditions were maintained.
  3. The more reactive the product mesylate, the more slowly the mesyl chloride was added and the lower the temperature. For very reactive systems, the glassware used in the work-up was prechilled to 0°C. With large scale (~1.0mol) the excess of triethylamine may be reduced to 20%.
Reference:
Synthesis of Methanesulfonate Esters (Mesylates) From Alcohols
R. K. Crossland and K. L. Servis
J. Org. Chem. 35(9), 3195-3196 (1970)

Another very promising method, suitable for both mesylation and tosylation, is excerpted below. As a substitute for pyridine, catalytic trimethylamine hydrochloride (0.1-1 eqv) and triethylamine (1.5-2 eqv) is used, with dichloromethane as the solvent. Yields are good, and the reaction times are reasonable.

Practical and Efficient Methods for Sulfonylation of Alcohols Using Ts(Ms)Cl/Et3N and
Catalytic Me3N·HCl as Combined Base: Promising Alternative to Traditional Pyridine

Yoshihiro Yoshida, Yoshiko Sakakura, Naoya Aso, Shin Okada, and Yoo Tanabe
Tetrahedron 55, 2183-2192 (1999)

Abstract
Several alcohols were smoothly and practically tosylated by two methods A and B. Method A uses the TsCl/Et3N (1.5-2.5 equiv)/cat. Me3N·HCl (0.1-1.0 equiv) reagent. Compared with the traditional Py-solvent method, the method A has merits of its much higher reaction rate, operational simplicity, economy in the use of the amine, and circumvention of the undesirable side reaction from R-OTs to R-Cl. Method B uses TsCl/KOH [or Ca(OH)2]/cat. Et3N (0.1 equiv)/cat. Me3N·HCl (0.1 equiv) as the reagent, which will be suited for praclical and large scale production for primary alcohols. On both methods A and B, a clear joint action of Et3N and Me3N·HCl catalysts was observed. 1H-NMR measurements support the proposed mechanism of the catalytic cycle. Related methanesulfonylation using Et3N and cat. Me3N·HCl in toluene solvent also successfully proceeded, wherein the clear joint action was also observed.


Experimental

General procedure of Method A

TsCl (1.2-1.5 mmol) in solvent (1.0 ml) was added to a stirred solution of an alcohol (1.0 mmol), Et3N (1.5-2.5 mmol) and Me3N·HCl (0.1 or 1.0 mmol) in solvent (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h. To decompose an excess TsCl, N,N-dimethylethylenediamine (ca. 130 mg) was added to the mixture, which was stirred for 10 min. (This procedure is not always necessary, if TsCl is easily separated off by column chromatography). Water was added to the mixture, which was extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The obtained crude product was purified by silica-gel column chromatography (hexane/ether = 30→10:1) to give the desired tosylate.

General procedure of Method B

TsCl (1.5 mmol) in solvent (1.0 ml) was added to a stirred suspension of an alcohol (1.0 mmol), inorganic base (1.5-3.0 mmol), Et3N (10 mg, 0.1 mmol) and Me3N·HCl (10 mg, 0.1 mmol) in solvent (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h and at room temp. for 3-5 h. Aqueous 1M HCl was added to the mixture, which was extracted with EtOAc. A similar work up and purification of Method A gave the desired tosylate.

Note: Pellet KOH was refluxed in toluene for 30 min to change into dispersion, which was used. High granules Ca(OH)2 was used.

Mesylation of alcohols using MsCl/Et3N and cat. Me3N·HCl

MsCl (172 mg, 1.5 mmol) in toluene (0.5 ml) was added to a stirred solution of an alcohol (1.0 mmol), Et3N (1.5 or 2.0 mmol), and Me3N·HCl (0.1 or 1.0 mmol) in toluene (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h. A similar workup and purification by silica-gel column chromatography (hexane/EtOAc = 5:1) gave the desired mesylate.