Klute
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Monomethylation of primary amines: N-methyl-2-phenethylamine
Introduction:
After trying a few different methods, I have found what I beleive is the best way of preparing secondary N-methyl amines from primary amines without
any tertiary amine formation, or quaternary ammonium salts.
I have tried in the past: alkylation of sulfonamides or formamides followed by hydrolysis, formation of the formamide and reduction by LiAlH4,
alkyaltion by trimethylphosphate, all where tedious or yield mixtures of products.
The procedure I followed is from J. Med. Chem, (2)15, 214 (1972) link, simialr to Org. Syn. 5, 758 (1973)
The benzaldimine is formed condensing benzaldehyde with the primary amine, using a Dean stark to remove the formed water. The prepared aldimine is
then methylated, forming a quaternary iminium salt. this salt is then hydrolyzed, liberating the N-methylated amine salt and benzaldehyde. No over
methylation can occur as long as all the methylating agent is consumed before hydrolysis. I used methyl tosylate and dimethyl sulfate as methylating
agents, both with great success, albeit DMS takes much less time to complete the reaction.
Experiemental:
Preparation of N-methyl-2-phenethylamine
Step 1: N-benzylidenephenethylamine
In a 250mL 4-neck RBF equipped with a Dean Stark trap and a condenser, a thermometer and magnetic stirring is charged 12.6mL (100mmol)
2-phenethylamine, followed by 30mL toluene. 12.6mL (125mmol) of benzaldehyde are then added. After a minute there is a exothermic reaction, and the
initially limpid solution turns turbid as water is formed. The mixture is heated to reflux until no more water is collected int he trap (1H30). 1.8mL
(100mmol) of water are collected, hence total conversion to the aldimine. The flask is cooled down in the water bath.
Step 2: N-benzylidene-N-methylphenethylammonium tosylate or methylsulfate
The Dean Stark trap is removed and replaced by a condenser. A solution of 19.5g (105 mmol) of methyl tosylate (Or equimolar amount of
dimethylsulfate) in 20mL toluene is added dropwise. Once the addition is complete, the flask is gently heated to reflux.
After a few minutes with DMS (an hour with MeOTs) a dark orange oil seperates out. Upon cooling this oil cristallizes. Heating is continued for h
with DMS, overnight with MeOTs.
Step 3: N-methylphenethylamine
25mL of water are then added, and the mixture heated to 80°C for 30min. the oil is dissolved in the aqueous layer. The flask is cooled to room
temperature, and its contents transfered to a seperating funnel. The top organic layer is seperated, and washed with 25mL water. The combined aqueous
are washed with 3*25mL DCm, which removes most of the yellow color.The oragnics are backwashed with 2*25mL water, and the combined aqueous are
basified with conc. KOH. A slightly yellow oil with a strong amine odor seperates. It is extracted with 3*25mL DCM, the extracts washed with brine,
dried and evaporated. The crude amine contains traces of impurity by TLC (4:1 AcOEt:MeOH + Et3N), and can be purified by distillation.
A alternative is to directly steam distill the amine from the basified aqueous layer. This amine is very volatil with steam, and only 100mL distillate
will carry over all the colorless amine, pur by TLC.
A hinsberg (tosyl chloride in aq. NaOH) test is negative for either primary or tertiary amines.
The yields have been routinely over 95%, both with MeOTs and DMS.
This procedure is very efficient and can be adapted to a variety of priamry amines. You can put that CsCO3 away!
[Edited on 19-7-2009 by Klute]
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turd
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Thanks a lot!
That's so much more home-chemistry friendly than the classic method (amide + LAH).
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Klute
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Yes! Much less tedious reaction conditions, and better yields! I wonder why this method isn't more popular in the litterature...
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Ullmann
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Good work Klute!
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Barium
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Klute, have you tried to monoalkylate 2-PEA with a equimolar amount of paraformaldehyde, using toluene and a Dean-Stark to form the imine, and then
reducing it with sodium borohydride?
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Klute
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No, but i did try using hydrogen gas and Pd/C with sluggish results... the imine forms very quickly, the reaction is exothermic. Have a look in the
mono-methylation thread for the experimental data.
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jon
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well have you cosidered the cesium promoted/mediated mono n-alkylation of primary amines?
or evena method where formaldehydeis condensed onto the amine and reduced insitu ina sodium phoshate bufered solution?
this is much easier to do.
it's similar to the steve TM reduction where zinc catalyses a hydride transfer in the reduction of the imine thenapo4 is there to buffer the formic
acid produced.
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Klute
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Cesium carbonate is pretty expensive and none-recyclable.. It's a good method for a few mmols of a specific amine, but not a preparative option.
I'm sceptical the zinc method would produce only monomethylamines. Even with one eq of paraformaldehyde you get some dimethylamine using the Pd/C
method. In a more acidic envinronement, I think the secondary imine would form even quickier.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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jon
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perhaps you are right but formaldimes are pretty stable entities and they tend to form at wider ph ranges.
also i recall that cth's tend to be favored in basic enviroments,
water has to split into ions for it to undergo insertion into the carbon centre of the formaldehyde.
i imagine the situation is more complex but i remember the analogy of the different formate salts and the more electropositive the cation the formate
ion was bound to the more readly transfer hydrogenation procedds
[Edited on 4-9-2009 by jon]
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aliced25
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How about 3/4A sieves to remove the water and vanillian as the benzaldehyde? Should work no?
From a Knight of the Realm: "Animated movies are not just for kids, they're also for adults who do a lot of drugs." Sir Paul McCartney
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Satan
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How to proceed if we would like to introduce to our primary amine both benzyl and methyl groups? N-benzylidene-N-methyl-2-phenylethylammonium tosylate
is easly separated crystalline solid, stable when kept under dry conditions.
Dose anyone have experience in hydrogenation of such spiecies?
My thoughts are sodium borohydride or PtO<sub>2</sub> under H<sub>2</sub>.
Pt on activated carbon would be reusable and easly separated for recovery, maybe someone can share experience in preparing this catalyst from
chloroplatinic acid?
http://www.sciencemadness.org/talk/files.php?pid=95371&a...
In this pdf author states that in his experience Pt would not catalyze hydrogenolysis of N-benzyl group. Monomethylation of phenylethylamine is also
discussed.
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