Author Topic: MDMA via Tosyl Chloride Intermediate?  (Read 6528 times)

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Siegfried

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #20 on: August 04, 1999, 11:19:00 PM »
Yes Frog , the alcoolat formed during the addition of Grignard to propylene oxid is much more nucleophile than alkohol ... So it will surely work with anhydrid or tosylchlorid but i think this is better to do just the work-up plus a little purification ( extraction-wash-dry , you don't need vacuum distillation for the next step ) , because if the great nucleophile alcoolat directly react with the great electrophil anhydrid or tosyl chlorid the reaction will surely be very exothermic and hard to control .

Tr-E-frog

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #21 on: August 05, 1999, 01:44:00 AM »
Sigfried:

Thanks for the info, I had suspected a highly exothermic reaction (necessitating a small scale and adequate cooling) but if you think a quick wash process is desirable, it will be taken under advisement.  Do you have the Guo & Sharpless paper that Ritter quoted?  They prepare the mesylate in high yield by dropwise addition of mesylchloride  to ice cold (-10C) THF containing the precursor alcohol with triethylamine (about 1.5-to-1 molar excess).  That's why I liked the ease of avoiding wash/extract steps.  What is the relative solubility of MDP-2-Pol in water and THF.  In other words, what solvents did you use to wash and extract it prior to tosylation?  In addition, the choice of pyridine vs. triethylamine is not so important when using the more reactive triflates, is it?  Thanks!

Ollie:  you're awefully silent lately, what's up?

Reflux:  any progress yet?
 
treefrog.


ReFlux

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Re: MDMA via Tosyl Chloride Intermediate?
« Reply #22 on: August 05, 1999, 03:33:00 AM »
I've been able to obtain modest results from direct intermolecular aminomercuration w/ Hg(NO3)2 & 40% Aq. MeNH2 in THF but problems always occur in the reduction which tends to favor elimination / side products.  I've recently found a paper that describes NaBH4 reduction of the organo-mercurial intermediate using a PTC in DCM which addresses these issues.

-ReFlux


Cyrax

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Tosylate and friends
« Reply #23 on: July 24, 2002, 03:13:00 PM »
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

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Is there a measurement of "labileness" one can ...
« Reply #24 on: July 24, 2002, 03:55:00 PM »
Is there a measurement of "labileness" 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

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Rhodium, I see your reason for concern: esters of ...
« Reply #25 on: July 24, 2002, 05:15:00 PM »
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 with this reaction. 
Take a look at this:
A mixture of 5.7 g (0.03 mol) 3-methyl-N-phenyl-4-piperidineamine HCl and phenyl-2-propanol methanesulfonate (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 & 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 (anorganic) 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

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1-Phenyl-2-alkyl Tosylates: Elimination Tendency
« Reply #26 on: November 03, 2004, 03:26:00 AM »
Eliminations from 1-Phenyl-2-alkyl Tosylates Promoted by MeONa in MeOH. Steric Effects in Alkene-forming Elimination.
Bong Rae Cho and Man So Han

J. Chem. Soc. Perkin Trans. 2, 105-108 (1993)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/phenyl-2-propanol.tosylate.pdf)

Abstract
Reactions of PhCH2CH(OTs)R [R = Me- (1), Et- (2), i-Pr- (3), s-Bu- (4), t-Bu- (5)] with MeONa in MeOH have been studied. The reactions produce both conjugated and unconjugated alkenes. The yields of the conjugated alkenes are nearly the same for 1-4, while the E/Z ratios depend strongly upon the ?-alkyl group. The rates of eliminations forming the conjugated E alkenes are decreased by a bulkier alkyl group as indicated by the relative rate of 1, 0.8, 0.7, 0.6, 0.2 for 1, 2, 3, 4, 5, respectively. On the other hand, the relative rates for the formation of the unconjugated alkenes are 1, 1.7, 2.8, 1.9 for 1, 2, 3, 4, respectively, indicating that the rate increases with the double bond stabilizing ability of the alkyl groups and decreases with their steric effect. From these results, the relative steric effect of the ?- and ?-alkyl groups in alkene-forming elimination is assessed.