tryptic
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Reductive methylation of amines
Hi
I've got some benzylamine I'd like to methylate..
Here is one journal ref:
>>
Formalin (35%, 35 mmol) was added with stirring to a solution of holafébrine (primary amine) 3 mmol in methanol (10 ml) and the solution was refluxed
for 30 min. After cooling, 400 mg NaBH4 was added slowly. After 1 h the reaction was evaporated and the mixture was extracted with CH2Cl2. Evaporation
yields 85% iréhine (dimethyl-holafébrine).
<<
Is the reflux step done in order to depolymerize the formaldehyde so that it doesn't react with the NaBH4 so quickly or why is it necessary..?
Here is another journal ref.
>>A mixture of primary amine [i.e. tryptamine] (5 mmol) or secondary amine (10 mmol), ZnCl2 (20 mmol) and paraformaldehyde (20 mmol) in 25 ml
CH2Cl2 was stirred at RT for 1h under dry atmosphere. NaBH4 20 mmol was then added and the resulting mixture was stirred for 9 h (secondary amines) or
12h (primary amines). The reaction mixture was then quenched by addition of aqueous ammonia (40 ml, 2 N), stirred for 10 min. and the organic layer
was separated. The aqueous part was extracted with CH2Cl2(1x25 ml) and the combined organic extracts were concentrated in vacuo after drying over
anhydrous Na2CO3. The product from primary amines were purified by distillation, crystallization or flash chromatography. The secondary amines
afforded the pure tertiary amines without any chromatographic separation.<<
In this reaction, how important is the "dry atmosphere" part? Is it achievable in kitchen chemistry conditions? Can you substitute DCM
solvent with ethyl acetate or perhaps methanol? Would the presence of ammonium chloride disturb this reaction somehow..?
Thanks for possible replies
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Strange
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While I'm not absolutely sure, I guess the dry atmosphere is necessary to prevent breakdown of the ZnCl2. Also NaBH4 can give you lower yields if
it has too much water to play with. You achive this dry atmosphere by
1. distilling your solvent over some sort of drying agent or sometimes it's enough to stir them with dry Na2SO4 overnight
2. Heating your glassware with a hotgun or baking the stuff before use
3. Attach a drying tube to the opening of your setup
So it's definitly achievable in the kitchen.
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tryptic
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Thanks!
I read some more references and apparently the reflux step isn't really necessary in the first synthesis, it's more important to add both
formalin and NaBH4 really slowly. That's good. Refluxing methanol would have been some genuinely mad science...
[Edited on 4-8-2004 by tryptic]
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unionised
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"Refluxing methanol would have been some genuinely mad science...
"
Why?
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tryptic
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Well alright, maybe not..It's just that I'm not a very experienced chemist, and methanol vapors are flammable and poisonous..
It's true that with proper equipment and sufficient skill it probably wouldn't be dangerous at all, but I don't quite feel up to it
just yet..
I guess it'd be safe in my apartment if I set up the equipment with a pipe that dumps all the vapors outside or most of them..
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If_6_was_9
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Have you seen this?
https://www.the-hive.ws/forum/showflat.pl?Cat=&Number=50...
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tryptic
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No, but I was aware of those cyanoborohydride - based methods..Here is another interesting page BTW
https://www.the-hive.ws/forum/showflat.pl?Cat=&Number=43...
I guess it could still be useful to heat the formalin before the methylation process, because apparently the formalin can be polymerized to some
extent and using polymerized formalin could lead to the formation of unwanted beta-carboline cycles..
I guess I could depolymerize the formalin in a pressure cooker.
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If_6_was_9
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This looks interesting:
https://www.the-hive.ws/forum/showflat.pl?Cat=&Number=49...
If the amine free base is used the methylated amine will be in the form of the oxalate which is converted to the free base using a strong base (ie.
CaO or NaOH) according to the article.
[Edited on 12-8-2004 by If_6_was_9]
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