MDMA from MDA w/ NaBH3CN?

[pyBOP]

If one were to take some MDA and mix it with 1 equivilent of paraformaldehyde in a methanolic solution followed by the addition of NaBH3CN as the reducing agent, would one anticipate MDMA with negligible amounts of N,N-dimethyl MDMA?

dread out

[Rhodium]

You would likely get a mixture of MDA, MDMA and N,N-dimethyl-MDA that way.

[Ritter]

There are references on our Chiefs page which state methamphetamine can be made in high yield from amphetamine and either paraformaldehyde or 37% aq. formaldehyde via catalytic hydrogenation so I see no reason why NaBH3CN would not react similarly.  Just make sure to use only 1 or even slightly less than 1 molar equiv. of formaldehyde and be sure to keep the rxn. mixture as dilute as possible (use a high volume of solvent).

[Barium]

to 1 mol MDA free base in 250 ml refluxing toluene is added 0,98 mol paraformaldehyde in portions of 0.1-0.2 mol, allow the the water to boil off between each addition. Cool the mixture to room temperature and add 250 ml MeOH and finally 1-1.5 mol NaBH4 in portions. By doing it this way there should be very little N,N-dimethylation occurring. Just a guess.

I do also remember Freifelder wrote that when N-methylating a primary amine with paraformaldehyde and H2/Pd-C there was very little N,N-dimethylation and the yield was in the 90% range.
Catalytic hydrogenation freak

[pyBOP]

MDA (4 mmol) & paraformaldehyde (4 mmol) were stirred, under argon, in a solution of methanol (60 mL)^{1 for 10 min.  NaBH3CN (4 mmol)}2 was then added and the mixture placed back under argon.

^{1 To keep conditions dilute as suggested above.}
2 I know this is an overkill...

it's so good to be back      

respect due to all...

[Rhodium]

Methylation of primary amines using NaBH3CN/Paraformaldehyde

To a solution of primary amine 21 (219 mg, 0.5 mmol) in acetic acid (5 mL) were added paraformaldehyde (45 mg, 1.5 mmol) and sodium cyanoborohydride (314 mg, 1.5 mmol). The mixture was vigorously stirred at 40°C. At 8-h intervals (four times), paraformaldehyde (45 mg, 1.5 mmol), and sodium cyanoborohydride (314 mg, 1.5 mmol) were stepwise added to the mixture. The product was then worked up in the usual manner and purified by flash chromatography to give the dimethylated product 23 (208 mg, 95%).

The addition of 10 eqv. paraformaldehyde and 5 eqv. NaBH3CN at once and stirring the mixture at room temp for 48h gave 100% yield of di- and monomethylated products, in a 1:1 ratio.

Reference: J. Org. Chem. 61, 4412-4422 (1996)

[pyBOP]

Such large excesses of paraformaldehyde and NaBH3CN still give a 1:1 ratio? 

Is the second imine formation easier than the first?
Is the monomethylated, secondary amine bore basic than the primary amine? 

10% MeOH:DCM gets the spot to move on TLC but it streaks?  Add a few drops of AcOH to stop the streaking?  Ahhhhh, columns.  Gotta love 'em!!!

[pyBOP]

Using 20% MeOH/DCM, one can see 4 spots on TLC.  One faint spot at the top (tertiary), 2 which streak in the middle having RF values of about 5 and 3 and one at baseline.  One of the spots in the middle is the primary amine and either the other middle spot or the one at baseline is the secondary, N-methyl amine.  What could the other spot be... the imine?  That would most likely be reduced as fast as it forms, correct?  

Rxn was checked by litmus and was basic, reacidified to pH 6-7 with conc. HCl to get things moving again.  I and I think that this rxn went as Rhod said above.

excuse me while I light this spiff...

[Rhodium]

Cesium Effect: High Chemoselectivity in Direct N-Alkylation of Amines

A novel method for the mono-N-alkylation of primary amines, diamines, and polyamines was developed using cesium bases in order to prepare secondary amines efficiently. A cesium base not only promoted alkylation of primary amines but also suppressed overalkylations of the produced secondary amines. Various amines, alkyl bromides, and alkyl sulfonates were examined, and the results demonstrated this methodology was highly chemoselective to favor mono-N-alkylation over dialkylation.

Reference:

J. Org. Chem. 67, 674-683 (2002)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/amine.alkylation.cesium-effect.pdf)

[pyBOP]

9:1 ratio of monomethylated to dimethylated is pretty good, but you still have that 10% dimethyl amine and then you have methyl bromide.  Running a column over 10% MeOH gets messy so SWINM decided to reflux 2.0g in 10mL ethyl formate.  Will follow up with LAH reduction. 

Next time... convert nitropropene to ketone.  Much easier.  Must reduced iron be used?  Shulgin just mentions regular ol' iron. 
excuse me while I light this spiff...

[moo]

I have understood that the yields were higher with electrolytic iron than ordinary iron powder, but you could also check out this thread:

Post 320730

(Barium: "Another  easy route to P-2-P´s", Novel Discourse).

[madprosr]

pyBOP, you mean Fe/HCl reduction of the nitropropene?
Rhodium posted a 75% yielding Steel/AcOH reduction for tmp2np.
if you don't like the yields with Fe, try it out on mdp2np for us, m'kay?

[Rhodium]

I don't think I have ever reccommended boiling 2,4,5-trimethoxyphenyl-2-nitropropene in any acid.

The Fe/AcOH reduction I was talking about is from

Pihkal #100

(http://www.erowid.org/library/books_online/pihkal/pihkal109.shtml)

An alternate synthesis of 3,4-methylenedioxyphenylacetone starts originally from piperonal. A suspension of 32 g electrolytic iron in 140 mL glacial acetic acid was gradually warmed on the steam bath. When quite hot but not yet with any white salts apparent, there was added, a bit at a time, a solution of 10.0 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see the synthesis of MDA for the preparation of this nitrostyrene intermediate from piperonal and nitroethane). This addition was conducted at a rate that permitted a vigorous reaction free from excessive frothing. The orange color of the reaction mixture became very reddish with the formation of white salts and a dark crust. After the addition was complete, the heating was continued for an additional 1.5 h during which time the body of the reaction mixture became quite white with the product appeared as a black oil climbing the sides of the beaker. This mixture was added to 2 L H2O, extracted with 3x100 mL CH2Cl2, and the pooled extracts washed with several portions of dilute NaOH. After the removal of the solvent under vacuum, the residue was distilled at reduced pressure (see above) to provide 8.0 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil.