Author Topic: MDMA via Tosyl Chloride Intermediate?  (Read 15626 times)

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Ollie-RSM

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MDMA via Tosyl Chloride Intermediate?
« on: July 20, 1999, 06:06:00 PM »
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).

I'm away from school for the summer so I don't have access to CAS, hence no citations. Just throwing the idea out.

ORSM


Tr-E-frog

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #1 on: July 24, 1999, 01:28:00 AM »
ORSM,

Funny you should mention this...I've been wondering a about it for a little while. I can't say that I've seen any discussion on the bulletin board, but hopefully we can get one going.

Drone, Rhodium, anybody out there thought about this???  Is the methylenedioxy ring going to be stable under such circumstances or is this idea dead in the water?

Many thanx,

treefrog.


Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #2 on: July 24, 1999, 08:53:00 PM »
Hi ,
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 ofr solubility purpose and RT . the yield and reaction time are :
>95%,20min,RT for oxymercuration
>95%,45min,RT for tosylation
50-60%,5d,RT for SN2 with MeNH2-MeOH
The RT and polar solvent are very miportant 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 cinetic : the Triflate , but it's an expensive reagent .

Ollie-RSM

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #3 on: July 26, 1999, 07:02:00 PM »
Siegfried, it's good to hear of your success! Did you add any base during tosylation to suck up the HCl produced? Just curious.

Also, is mercuric acetate available anywhere but chemical houses? Could you make it by combining HgCl and sodium acetate, perhaps? Personally, I would be tempted to use acid-catylized hydrolysis and just distill the alcohol off of from any side products...although I'm not sure how well this would work.

ORSM 


Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #4 on: July 26, 1999, 09:01:00 AM »
For the tosylation of alkohol , the base is pyridine , because :
1) it take the HCl
2) very important : it form a complex with tosyl chloride which make the attack by the alkohol on the sulfur more easily .
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 :
1) very poor yield in 1-aryl-2-propanol
2) mixture of 1-aryl-2-propanol and 1-aryl-2- propanol which are not easy to separate ( must use distillation ) .
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 
HgAc2 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 HgAc2 from HgCl2+CH3COOH but you must purify it .
Anyway HgAc2 can easily be purchased .
I will probably send the total procedure in HTML format with all the detail and mechanism to Rhodium's site soon .

Tr-E-frog

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #5 on: July 27, 1999, 02:43:00 AM »
Sigfried,

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.

I look forward to you write-up at Rhodium's site.

treefrog.


Ritter

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #6 on: July 27, 1999, 11:29:00 AM »
I believe the only better leaving group than tosly 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 2 proponal was generated from methylenedioxyphenylacetaldehyde w/ MeMgI
grignard.


Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #7 on: July 27, 1999, 10:30:00 PM »
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 time less reactiv than triflate but it is still about 100 time more reactiv 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 .

Ollie-RSM

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #8 on: July 27, 1999, 10:52:00 PM »
Is there any other solvent besides pyridine or other amines that could be used in the tosylation? Even with a hood the stench gets everywhere....the first time I used pyridine, I almost vomited. 

ORSM


Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #9 on: July 28, 1999, 10:54:00 PM »
No , the tosylation is 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 tosylcl 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

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #10 on: July 29, 1999, 02:00:00 AM »
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:
Journal of Organic Chemistry 1988, 53, 4081-4

(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?



Tr-E-frog

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #11 on: July 29, 1999, 02:28:00 AM »
Ritter:

Great post, thanks for going to the trouble of finding relevant refs!

Sigfried:

What can you tell us about use of triflates/tosylates in this reaction (physical properties & some basi info on conditions and/or refs)?

Ollie:

I'm glad you got people talking about this one...

-treefrog.


ReFlux

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #12 on: July 30, 1999, 05:15:00 AM »
Siegfried, could you please post the full details of your safrole->MD-P2Pol->tosyl->amine reactions using Hg(OAc)2 and tosyl chloride.

Thanks!

-ReFlux


rev drone

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #13 on: August 01, 1999, 04:59:00 AM »
Say, what about direct addition of tosylate across the alkene, a la the variations of HX? Such a reaction would follow the same mechanism (though I'm guessing it may need a catalytic push somehow.) I'm sure there has to be a procedure out there for this. Any ideas? If "tosylosafrole" is as great an intermediate as y'all are saying, this would be amazing.

------------------
-the good reverend drone


Ollie-RSM

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #14 on: August 02, 1999, 08:24:00 PM »
That's an interesting idea, drone. I'm not sure that tosylation could occur via acid  attack of the double bond like bromination occurs, though. I believe the sulfur in the tosyl group is somewhat cationic in character, and would therefore have a hard time attacking a carbocation.

ORSM


Siegfried

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1-phenyl-2-tosyloxy-propane
« Reply #15 on: August 02, 1999, 11:17:00 PM »
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-tosylate -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 electrophil .
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 markownikow 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 reason of predominant elimination with the 1-aryl-2-halid-propyl are :
1. elimination product is stabilised by resonnance ( isosafrole ,(cis,trans)methyl styrene )
2. stabilised carbocation with a cyclopropyl phenyl intermediate .
So the best is oxymercuration , the mercury is really easily removed .

I don't try the triflates but it have a greater cinetic and less abilility to give elimination ... But the tosylate give allready much less elimination than halid , so your only gain is the cinetic .

I will post the total synthesis , with mecanism , theoritical discussion etc... in about 1 month to the Rhodium site and an HTML version of my synthesis of Fentanyl ( with some precisions + mecanism + theoritical discussion ) .
The procedure was trying for Methamphetamine but it will surely work for MDMA and it will be the same process .


ReFlux

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #16 on: August 03, 1999, 01:43:00 AM »
Siegfried- I'd like to thank you once again for elucidating this unique, interesting and overlooked pathway to X!  I look forward with anticipation for your detailed HTML on the subject, however if at all possible, could I trouble you to email me just the basic reaction details and protocol?  My email is sprucegeese@hotmail.com  and I would greatly appreciate it as I am ready to start dreaming about this reaction right away!  PS: any help I can offer you on direct-aminomercuration (I've done quite a bit of research on it) I  would be more than happy to offer.

Thanks!

-ReFlux


rev drone

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #17 on: August 03, 1999, 05:40:00 AM »
Siegfried,

The addition of tosylate across to an olefin admittedly is something I haven't seen, but I suspect it isn't unknown. Perhaps by adding something to coordinate and weaken the double bond, the reaction could be catalyzed? I'll look into it.

As for the mechanism epxlaination: thanks, though I'm well-aware of electron pushing going on here. I've sort of done this chemistry stuff before. 

------------------
-the good reverend drone


Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #18 on: August 03, 1999, 11:22:00 PM »
Reflux : if you have experience with direct amino-mercuration ( i mean direct - not the MeCN or phosphoramidate process ) , i'm very interressed by your experience because i tried it and don't have any result !!
I used MeNH2 in MeOH , THF and HgAc2 , a amino-mercurial complex was formed and it was a poor nucleophil and the MeOH added instead MeNH2 , i made an analyse and found 1-phenyl-2-methoxy-propane .... 
So i tried an amine alone ( piperidine ) , THF and HgAc2 for test purpose ... It worked but required a long reaction time ( a week ) whereas oxymercuration with water need onyl some minutes !! In addition i found a non negligeable part of 1-phenyl-2-propanol acetate meaning the acetate ion was enough nucleophile to compete the amino-mercuial complex ..
This reaction was RT and i read that 60°C are required for destroying the amino-mercurial complex ? I did not try other Hg2+ salt as CF3COO- or nitrate or perchlorate ?
So i am very interressed by your self experience .
I will send you soon a mail with the process for MDMA via oxymercuration and tosylation .

RevDrone : yes i agree with you but the problem in my sense is the poor nucleophilicity of tosylate for the attack of the carbocation . But it's theoritical possible


Tr-E-frog

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #19 on: August 04, 1999, 02:08:00 AM »
Sigfried or Rev. Drone:

I have been hypothetically toying with this idea for a month or two now but have a couple of questions for which March has no suitable answers (I am currently with out good library access).  If one went a slightly different route for example, because one was skittish about buying sass. oil...and had a supply of 4-bromo-1,2-methylenedioxybenzene and wished to react it with propylene oxide to get MDP-2-Pol, the immidiate product is MDP-2-PoMgBr which would be converted to the Pol compound with acid.  Question:  Could one react directly with 'triflic' anhydride (I suspect the oxygen is sufficiently nucleophilic, but have not seen any examples of this in the literature or would it be necessary to destroy the Grignard w/ H30+, extract and then react with the anhydride)?  I like this idea because it decreases the number of extractions/distillations required for the labor intensive nature of synthesis from catechol. 

I think that on a cost and time basis the use of the tosyl chloride (or other analog) with MDP-2-Pol is a substantial improvment and hope that we can get some real investigation going!!!

-the frog-