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There are many procedures out there for the production of N-methyl-amphetamines
(methamphetamines) from various starting materials, such as phenyl-2-propanone (P2P) or
ephedrine, but what if you already have an amphetamine (or phenethylamine) and wanted to
add a methyl group to the nitrogen atom? If you would use the first reaction that comes to
mind for the conversion, to alkylate the amphetamine with methyl iodide or dimethylsulfate,
you would be disappointed, as you would get a mixture of products, most important the N,N-
dimethyl-amphetamine (of very low activity), as once the amphetamine has been methylated to
methamphetamine, the molecule is much more succeptible to another alkylation, and thus the
dimethyl- amphetamine is formed much faster than the remaining amphetamine is alkylated to
methamphetamine. Actually, in the reaction mix you would find unreacted amphetamine, N-
methylamphetamine, N,N-dimethyl- amphetamine and even some of a quaternary N,N,N-
trimethylamphetammonium salt.

To avoid this happening, we must usually resort to indirect methods of introducing the methyl
group. One way is to react the amphetamine with formaldehyde (either as an aqueous solution,
or as paraformaldehyde) to get the amphetamine formaldehyde imine, which can then be
reduced to the N-methylamphetamine using a several different reducing agents, for example
Al/Hg or Pt/H2.

Amphetamine can also from an amide with formic acid, N-formylamphetamine, if boiled in a
Dean-Stark apparatus where the formed water in the reaction is continously removed, thus
driving the formation of the amide forward. The amide can then be reduced by for example
lithium aluminum hydride.

Another way is to react the amine with benzaldehyde to form an imine, which then can safely
be alkylated with methyl iodide or dimethyl sulfate, and after hydrolysis of the resulting
compound, N-Methylamphetamine is formed.
 „inally, it must be said that using exotic reagents like cesium salts, it might be possible to
directly mono-methylate amphetamine without too much overalkylating taking place. You get
an approximate 9:1 ratio of secondary amine to tertiary amine, while not perfect it is pretty
good for one step with no reduction necessary. The selectivity might be somewhat lower with
methylations than with the butylation described in the last synthesis of this document.

c 
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N-Methyl-amphetamines were prepared by the reaction of the corresponding

amphetamine with formaldehyde and reduction in the absence of acid. Thus, a mixture of
1 mole amphetamine freebase (136g) and 1 mole aqueous formaldehyde (81ml 37% or
75ml 40%) in 350 ml alcohol and an excess of aluminum amalgam was reduced for
several hours, water added, aluminum hydroxide filtered off, the solution acidified and
evaporated, and the freebase separated by means of alkali yielding phenyl-N-
methylisopropylamine, converted to the hydrochloride, mp 140°C. Similarly, 70g À-
amphetamine in alcohol with aluminum and 1 mole formaldehyde gave À-
methamphetamine, which was converted to the phosphate salt. 1-Phenyl-2-
aminopropanol similarly yielded ephedrine.


c 
c  
  


This procedure is for the methylation of 2-phenethylamine, but it can easily be adapted
for use with any amphetamine.

A solution of 30.25 g (0.25 mole) of 2-phenylethylamine and 7.5 g. (0.25 mole) of

paraformaldehyde (Note 1) in 50 ml of 95% ethanol was allowed to stand for a short
period (Note 2). Additional ethanol (100 ml), 15 g. (0.25 mole) of glacial acetic acid
(Note 3), and 0.5 g. of platinum oxide (Note 4) were added, and hydrogenation was
carried out at room temperature and 3 atm. When hydrogen absorption was complete,
the catalyst was removed, and the filtrate and washings concentrated to dryness. The
residue was treated with sodium hydroxide solution (Note 5), extracted with ether, dried
and distilled to give an 80-90% yield of N-methyl 2-phenethylamine (Note 6).

Notes:

1.m Originally about 20 ml of 37% formaldehyde solution was added (0.25 mole). In
view of the reported danger of dimethylation of primary amines when formaldehyde
is used, it appeared safer to use paraformaldehyde, since an exact amount could be
weighed.
2.m When the aldehyde and base were mixed, the solution became warm. The solution
was allowed to stand for 0.25-0.5 hr. for complete reaction. In some cases the
mixture was allowed to stand overnight, but this gave no improvement in yield after
reduction. When no heat developed in the reaction of aldehyde and amine, the
mixture was warmed slightly and allowed to stand before reduction. When low
boiling components are to be mixed, it is best to cool the solution of amine while the
aldehyde is added to prevent loss of amine or aldehyde from the exothermic
reaction. After standing, the mixture can then be hydrogenated. Hydrogen uptake
was usually complete within 2 hr or less.
3.m The reaction rate in this reduction was slower in the absence of acetic acid. Other
acids should also be satisfactory as long a they do not cause reversal of the
formation of imine. Strong acids should not be used with rhodium because they act
as inhibitors of its activity. Many reductive alkylations were carried out successfully
with platinum or palladium in the absence of acid. When reduction was too slow,
interruption for addition of the required amount of acid did speed hydrogen uptake.
4.m Palladium on carbon was not used in this experiment, but 5 g of 5% rhodium on
carbon did prove satisfactory. „reifelder states there is little doubt that 5 g of 5%
 palladium on carbon or an equal amount of 5% platinum on carbon would work as
they had in other reductive alkylations.
5.m When acid is not used, addition of alkali and extraction of base are unnecessary.
6.m A reaction such as this is actually a reduction of the imine 3
3, a very useful
procedure that may be used in alkylations with other aldehydes.

c  
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A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8

mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no
further H2O was generated (about 20 h was sufficient, and 1.4 mL H2O was collected).
Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in 100 mL
CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally once again with
dilute acid. The solvent was removed under vacuum giving 7.7 g of an amber oil that, on
standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine. An alternate
process for the synthesis of this amide involved holding at reflux for 16 h a solution of
10g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles
yielded an oil that set up to white crystals, weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL anhydrous TH„

was added dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL
anhydrous TH„ under an inert atmosphere. The reaction mixture was held at reflux for 4
days. After being brought to room temperature, the excess hydride was destroyed with
7.4 mL H2O in an equal volume of TH„, followed by 7.4 mL of 15% NaOH and then
another 22 mL H2O. The solids were removed by filtration, and the filter cake washed
with additional TH„. The combined filtrate and washes were stripped of solvent under
vacuum, and the residue dissolved in 200 mL CH2Cl2. This solution was extracted with
3x100 mL dilute HCl, and these extracts pooled and made basic with 25% NaOH.
Extraction with 3x75 mL CH2Cl2 removed the product, and the pooled extracts were
stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white residue
which was distilled at 100-110°C at 0.4 mm/Hg to give 5.0 g of a colorless oil. This was
dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the addition of
sufficient anhydrous Et2O to produce a lasting turbidity. On continued stirring, there was
the deposition of fine white crystals of 3,4-methylenedioxy-N-methylamphetamine
hydrochloride (MDMA) which were removed by filtration, washed with Et2O, and air dried,
giving a final weight of 4.8 g.


 
 c



p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by

stirring with conc. aq NaOH, was treated with 100 ml of benzene (toluene could be
substituted) and 70 g (0.66 mole) of benzaldehyde. A mildly exothermic reaction began
at once. The mixt was heated under reflux until no more H2O was present in the
condensate (ca. 1 hr), then, without cooling, an attached Dean-Stark trap was removed
and a soln of 82 g (0.65 mole) of Me2SO45 in 200 ml of benzene (toluene could be
substituted) was added through the condenser at such a rate as to maintain reflux (15
min). The 2-phase mixt was heated for 90 min on the steam bath, cooled slightly,
treated with 200 ml of H2O, and heated for an addn 20 min. After cooling in ice, the
aqueous layer was washed twice with Et2O to remove unreacted benzaldehyde and made
strongly basic with 50% aq NaOH. Two Et2O exts of the basic aqueous phase were added
to the amine layer which separated, and the resulting solution was evacuated at the
aspirator for 30 min, leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine.
This material was dissolved in 500 ml of 20% abs EtOH-Et2O and treated with 50 ml of
conc HCl with swirling and cooling to yield the white, cryst hydrochloride, which was
washed thoroughly with ice-cold 20% EtOH-Et2O and dried, mp 185.5-186.5°C. The yield
was 83 g (77%).
c    c  c



Selective N-alkylation of primary amines was developed using cesium hydroxide to prepare
various secondary amines efficiently. A cesium base not only promoted monoalkylations of
primary amines but also suppressed overalkylations. Various amines and alkyl bromides were
examined, and the preliminary results demonstrated this methodology was highly
chemoselective, favoring mono-N-alkylation over dialkylation. In particular, use of amino acid
derivatives afforded the desired secondary amines exclusively.

Among the cesium bases examined, cesium hydroxide monohydrate, in general, gave the
highest yields and selectivities although cesium carbonate also worked well, depending on
substrates. To confirm the possible cesium effect, defined by the enhanced reactivities in the
presence of cesium salts, comparative studies between cesium bases and other bases were
performed, demonstrating that cesium hydroxide was superior to other alkali bases tried with
the regard to the observed chemoselectivities. Other alkali hydroxides produced moderate
yields of the desired product along with a considerable amount of the tertiary amine, whereas
cesium hydroxide allowed for a greater selectivity of 9:1 in preference for the monoalkylation
product. It was apparent that an unprecedented "cesium effect" in N-alkylation was observed as
seen in O-alkylation. Interestingly, the next comparative study implied that the cesium base not
only promoted N-alkylation of primary amines, but also inhibited the formation of tertiary
amines. According to our experiments, the intended alkylation of a secondary amine (N-butyl-
phenethylamine) was very sluggish under our conditions, affording the tertiary amine (N,N-
dibutyl-phenethylamine) in only 10% yield, whereas 72% of N,N-dibutyl-phenethylamine was
obtained along with the recovery of 25% of N-butyl-phenethylamine in absence of cesium
hydroxide after the same duration. Under our cesium base promoted N-alkylation conditions,
primary and secondary amines exhibited opposing reactivities, suggesting that the
improvement of chemoselectivity would stem mainly from the retarded overalkylation or
reversal of normally observed alkylation rates.
aepresentative Experimental Procedure

To activated powdered 4 Å molecular sieves (500 mg) in anhydrous N,N-

dimethylformamide (8.3 mL), was added cesium hydroxide monohydrate (280 mg, 1.7
mmol), and then the white suspension was vigorously stirred for 10 min. After
phenethylamine (0.21 mL, 1.7 mmol) was added and followed by additional 30 min of
stirring, 1-bromobutane (0.21 mL, 2.0 mmol) was added into the white suspension. The
reaction was stirred for 20 h, filtered to remove the molecular sieves and undissolved
inorganic salts, and rinsed several times with EtOAc. After the filtrate was concentrated
to a nominal volume by blowing air, the residue was taken up in 1 N NaOH, and
extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. „lash column
chromatography (EtOAc-EtOH, 9:1 v/v) afforded the secondary amine, N-butyl
phenethylamine (260 mg, 1.5 mmol; 89%) as a colorless oil as well as tertiary amine,
N,N-dibutyl phenethylamine (40 mg, 0.17 mmol; 10%) as a pale yellow oil.





1.m reil et al., 
    3 , erman Pat. 871,155 (1953); CA
52:20055e.
2.m „reifelder, uatalytic Hydrogenation in Organic Synthesis: Procedures and
uommentary, 98-101.
3.m Alexander Shulgin, Pihkal #109 (MDMA)
4.m Edgar „. riefer, . Med. uhem. 15(2), 214 (1972)
5.m . . Lucier, A. D. Harris, and P. S. rorosec, Org. Syn., 44, 72 (1964)
 6.m Org. Lett. 1(12), 1893-1896 (1999)
7.m Patent -O 50377

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1.m the thickness/type of the aluminum

2.m the consistency (i.e. flat, ground, etc.)
3.m the amount of HgCl2 used in relation to the amount of aluminum
4.m the addition rate of the MeNO2/MDP-2-P
5.m the size of the reaction vessel in relation to the scale of the reaction
6.m the ability to effectively stir the reaction
7.m the coldness of the water through the reflux condenser (yes, even that!)



 

 


 
 

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dm 27.5g Reynolds Wrap Heavy Duty aluminum foil

dm 25g MDP-2-P
dm 20 mL MeNO2 of 99+% purity
 dm 750 mL MeOH + 50 mL more for addition funnel + additional small amounts that will be
needed later to thin the mixture
dm 400mg HgCl2
dm 2-liter 2-neck flat bottom flask
dm reflux condenser (400mm preferable)
dm 250mL or 500mL addition or separatory funnel
dm cooling setup (bucket, water pump, tubing, 1 bag ice)

 

1.m Weigh 27.5g of Reynolds Wrap Heavy Duty aluminum foil (NOTE: it HAS to be Reynolds and it
must be the heavy duty stuff) and then tear it by hand or cut it with scissors into small
rectangles approximately 1" by .75". Settle down with this task with a good CD or TV show
because it is tedious and will take about 30-40 minutes.

2.m With a coffee grinder, "grind" these pieces of foil for durations of about 10 seconds. „ill the
coffee grinder only loosely (about two thirds full - don't stuff it! That will adversely change the
consistency of the ground foil). It will probably take about 4 to 5 "loads" in your grinder to do
the whole 25g of foil, depending on the size of your grinder. (In actuality, the foil does not get
"ground," but rather, each individual piece just gets compacted and compressed. If it is
compressed too heavily, the inner surfaces of the foil nuggets may be rendered inaccessible to
the Hg/MeOH solution, changing the timing of the amalgamation and maybe even causing an
incomplete or failed reaction.) When properly done, the foil should be in gnarled little nuggets
about the size of sunflower seeds (shell included) and should NOT look super-tight and small.

3.m Place a 3" stirbar in your 2L flat bottom flask and onto your stirplate. Add the foil nuggets to
the flask and then proceed to set up your glass, support and clamps so that the reflux
condenser and addition/sep funnel are securely affixed and your flask is well-centered on the
stirplate (this will be critical when you begin to attempt stirring!). Also, prepare your cooling,
i.e. attach the inflow and outflow tubes to the reflux condenser.

4.m Carefully add the 400mg HgCl2 to 750mL MeOH to a tightly sealable bottle and shake to
dissolve all HgCl2. Set this solution aside.

5.m Combine the 25g MDP-2-P, 20mL MeNO2, and 50mL MeOH and pour them into the
addition/sep funnel. Rinse your beaker (or whatever you used) with a tiny bit of additional
MeOH to get the residual ketone and add it to this MDP-2-P/MeNO2/MeOH solution.

6.m Very slowly and carefully (w/gloves, glasses, long sleeves and a Hail Mary if you're Catholic),
using a large funnel, pour the HgCl2/MeOH solution from step 4 down the condenser.

7.m Turn the stirring on full blast for a 5-second burst to intimately mix the solution and the foil. If
you have prepared the foil as described above, it will easily stir. Give it a few more 5-second
stirs over the next few minutes. I believe that doing this really helps facilitate the
amalgamation process that is about to occur.

8.m After about 5 minutes or so, you will begin to see bubbles popping up on the surface of the
MeOH solution. At first they will be tiny, like champagne bubbles. Then after a few minutes
you will see them joined by larger bubbles closer to the size of those seen in boiling water. It
is around this same time that the appearance of the aluminum will change from its normal
shiny silver color and start to take on a dull gray look, accompanied by a gray cloudy look that
begins forming in the MeOH. This is the magic moment when you want to begin dripping in
your MDP-2-P/MeNO2/MeOH mixture. Set a drip rate of approximately 1 drop per second at
this point and no faster. You can speed it up a bit later to accelerate the reaction if desired.
9.m Place about 3 lbs ice into your bucket. When you can feel exothermic warmth begin by feeling
the outside of the flask, quickly add about 2.5 liters water to the bucket (or an appropriate
amount to make very ice-heavy ice water) and plug in the pump.

10.mWhile monitoring the growing intensity of the bubbling amalgamation, turn on/off the stirring
intermittently as you did earlier. This time it is to assure distribution of the added
ketone/nitromethane in the reaction flask but also because the amalgamation seems to gain
its vital momentum more effectively if given some significant blocks of time (meaning about
30 sec at a time) in between "stirring bursts." When the reaction is clearly starting to get
vigorous and hot, crank the stirring to 10 and leave it on.


   




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11.mAs the reaction progresses only a few minutes after the addition was started, you will observe
that the aluminum is breaking up fairly rapidly. This is good, as long as you have the
ketone/nitro mixture dripping in at a good rate of about 1drop per second. But be careful with
the addition rate at this point, as a rate that is much faster than this could easily send the
reaction into overdrive (not good). Your reflux should be unnervingly vigorous as the
amalgamation really starts to pick up speed, with the MeOH literally pouring down out of the
condenser. I know it's hard to believe, but this is what you want, this is good. I'm telling you,
LOTS of trial and error came before this writeup. Trust me. You will also see sludge already
starting to settle at the bottom and forming a ring on the glass around the top surface of the
spinning mess. The consistency will get thicker by the minute. Add more ice to your bucket as
needed.

12.mAt this point you can sort of control the reaction rate by slowing down or speeding up the
addition rate a bit. Of course the reaction is already barreling along, so you won't want to
speed it up much. The concept here is that you want the addition of the ketone/nitromethane
to be paced neck-and-neck, as it were, with the breakdown of the foil as it amalgamates and
gets turned into sludge. In other words, you have to watch those two things and sort of adjust
the addition so that they proceed at approximately the same rate. It's tricky, and imprecise,
but with a little experience and intuition you'll get the hang of it. Sure, you could be lazy and
just leave the addition at a steady 1 drop/second the whole time, but if the amalgamation
peters out way before your addition is finished, and you find yourself adding your beautiful
ketone to impotent sludge, don't cry to me. The addition should take about 40-45 minutes in
total, and as it's finishing, the state of the aluminum should be about 95% broken down. In
fact the reaction should by now (~45 minutes after addition was started) look like a really
thick, steely-gray chowder with only minor small slivers of undissolved aluminum visible if any
at all. You will probably even need to add an extra 20-30mL of MeOH down the condenser at
this point (or before) to help it keep stirring effectively. This is no problem.

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A.m the reflux has slowed to almost no reflux at all

B.m if you stop the stirring you do not see any small bubbles anymore
C.m no "uneaten" aluminum is visible and the solution is a thick, uniform gray soup,

 


 
   



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13.mIf you chose to apply external heat, turn it off at 30 minutes before the targeted finish time.
Otherwise you will have to wait an extra 30 minutes for it to cool for the next steps.

14.mWhen finish time has arrived, dismantle your setup, set aside your reaction flask, and make
750 mL 35% NaOH solution (750 mL H2O + 262.5g NaOH) and let it cool to room temp or
below (safety glasses!).

15.mInto a separatory funnel no smaller than 2000mL capacity, pour your nice gray reaction
mixture, being very careful to keep the stirbar from falling into the sep funnel and
breaking it (that would be ugly). If your mixture is really thick, you may need to add small
amounts of MeOH to thin it to a pourable consistency. This is perfectly fine. Wash the final
residue out of the reaction flask with a few mLs of MeOH and add it to the funnel also.

16.mSlowly pour the NaOH solution into the sep funnel (gloves and glasses! no excuses!). That's
right, don't dump it in wholesale. Basifying should be a gentle process. If you bully those
molecules they may decide they're being disrespected and choose not to cooperate. Adding
the NaOH will cause the mixture to warm up a bit as the very last bits of the aluminum are
dissolved, which is fine. Swirl it a couple times and give it about 10 minutes to cool down to
something closer to ambient temperature. That yummy stinky methylamine smell tells you
that the reaction was successful.

17.mWhen the mixture in the sep funnel has cooled down, extract it once with 400mL toluene
followed by once with 100mL toluene. These are the critical moments for your yield now, so
you be sure to shake long and hard (at least 3 min) during these extractions (I don't have to
tell you to vent do I?!). The toluene/product layer will of course be on top since toluene floats
on water. Also, be sure to give the separations ample time to happen (at least 15 min); it is
easy to tell when it's okay to separate because the interface of small toluene bubbles finally
resolves and you have a nice clean line between the layers. If you like, do as Mr. A does and
finish off with a final small extraction of 50-60 mL toluene just to get the last of the stuff.


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 18.mIf you haven't already, drain the garbage layer out of your sep funnel into a storage bottle or
something, and wash the garbage residue out your sep funnel with water.

19.mWash the toluene/product 4 times (or more) in your sep funnel with 400 or 500mL H2O and a
final time with 500mL of a saturated NaCl solution to remove any traces of solvated HgCl2.

20.mDry your toluene/product solution with 30g of your favorite drying agent (MgSO4
recommended) in an acetone-cleaned, heat-dried bottle for no less than 30 minutes (Mr. A is
superstitious so he lets it sit for an hour). Shake it a few times during this period.

21.m„ilter the solution and gas it with that good ol' HCl bubbler setup. Be smart and use just
enough muriatic (31% HCl) to wet the salt but not enough to make any puddles, and put a
wad of drying agent wrapped in tissue paper in line somehow between the reaction flask and
the tube leading to your pipette end. Weep with joy as a bumper crop of white precipitate
crashes out of solution.

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