July 20, 2019, 01:46:14 AM
Forum Rules: Read This Before Posting


Topic: selective mono-methylation of primary amines  (Read 16772 times)

0 Members and 1 Guest are viewing this topic.

Offline lavoisier

  • Chemist
  • Full Member
  • *
  • Posts: 155
  • Mole Snacks: +17/-3
  • Gender: Male
  • El sueño de la razón produce monstruos
selective mono-methylation of primary amines
« on: February 26, 2007, 02:45:23 PM »
Does anyone know straightforward methods to mono-methylate primary amines with good selectivity over dimethylation?

The ones I know are rather costly and time-consuming (e.g. making the ethylcarbamate and reducing it with LiAlH4; making the trifluoroacetamide, deprotonating it and alkylating it with MeI, then deprotecting the nitrogen; and the like...).
And I was told that all reductive amination methods generate some dimethylated stuff...

Offline java

  • Regular Member
  • ***
  • Posts: 45
  • Mole Snacks: +2/-3
  • Gender: Male
  • I'm a person!
Re: selective mono-methylation of primary amines
« Reply #1 on: February 26, 2007, 09:31:25 PM »
It's better to die on your feet, than live on your knees.Emiliano Zapata..."Prefiero morir de pie que vivir siempre arrodillado."

Offline lavoisier

  • Chemist
  • Full Member
  • *
  • Posts: 155
  • Mole Snacks: +17/-3
  • Gender: Male
  • El sueño de la razón produce monstruos
Re: selective mono-methylation of primary amines
« Reply #2 on: February 28, 2007, 01:09:05 PM »
Yes, I read it, but I need to MONO methylate primary amines. Your post refers to the conversion of primary and secondary amines into the corresponding tertiary amines.

Offline java

  • Regular Member
  • ***
  • Posts: 45
  • Mole Snacks: +2/-3
  • Gender: Male
  • I'm a person!
Re: selective mono-methylation of primary amines
« Reply #3 on: February 28, 2007, 07:30:45 PM »
I doubt you understood, since it specifies mono methylation.....java

Quote
....Primary and secondary amines are N-methylated by a mixture of paraformaldehyde and oxalic acid dihydrate in good to excellent yields. The reaction proceeds without involvement of organic solvents and toxic formalin. Reaction temperatures of 100 C are required for the decomposition of oxalic acid
into the intermediate formic acid which acts as the actual reductant. The reaction conditions have been optimized, and the mechanism has been elucidated by means of deuteration experiments.
It's better to die on your feet, than live on your knees.Emiliano Zapata..."Prefiero morir de pie que vivir siempre arrodillado."

Offline lavoisier

  • Chemist
  • Full Member
  • *
  • Posts: 155
  • Mole Snacks: +17/-3
  • Gender: Male
  • El sueño de la razón produce monstruos
Re: selective mono-methylation of primary amines
« Reply #4 on: March 02, 2007, 01:33:24 PM »
Quote
Summary
Simple aliphatic amines are smoothly methylated to the corresponding tertiary amines by warming in formic acid solution with formaldehyde.Dibenzylamine, under these conditions, is mainly converted into methyldibenzylamine, but at the same time yields some benzaldehyde and a more volatile base (probably dimethylbenzylamine).
Tetra-alkyl-diaminomethanes,o n warming with formic acid, are converted into equimolar quantities of the corresponding dialkylamine and methyldialkylamine. Hexamethylenetetramine reacts with warm formic
acid yielding mainly ammonia and trimethylamine, with smaller amounts of mono- and dimethylamines; only three-quarters of the methylene carbon reappears as methyl in the final mixture.
Only about two-thirds of the anticipated amount of carbon dioxide, calculated on the assumption that the formic acid is the sole hydrogen donor, is obtained in these reactions; apparently some of the formaldehyde also contributes hydrogen.
Amino acids react with formaldehyde in warm formic or acetic acid with detachment of some of the nitrogen in the form of volatile bases. Dimethyl derivatives were isolated from the reaction in formic acid with glycine, P-aminopropionic acid, a-aminoisobutyric acid and a-amino-aphenylbutyric acid. Other amino acids yielded breakdown and condensation of various degrees of complexity. Benzaldehyde was
isolated from a-aminophenylacetic acid, propiophenone from a-amino-aphenylbutyric acid, and a-(4-phenyl-2,3-diketopyrrolidyl)-/3-phenylpropionic acid from phenylalanine. Mechanisms by which these products may be formed are suggested.

Now, I can be as thick as you like, but from the summary above here it looks like an NH2 group is generally converted into NMe2 under these conditions.
If you could please highlight the sentence where 'it specifies mono methylation', I would appreciate it.

I will get hold of the paper anyway, just to make sure.

Offline Custos

  • Full Member
  • ****
  • Posts: 217
  • Mole Snacks: +32/-0
  • Gender: Male
Re: selective mono-methylation of primary amines
« Reply #5 on: April 16, 2007, 08:40:17 PM »
You could try this method. Reaction of your primary amine with hydroxymethylbenzotraizole (HMBt, which is dirt cheap) leads to an adduct. This is actually a type of Mannich reaction - where the three components are formally formaldehyde, benzotriazole (precondensed as HMBt) and your primary amine. By controlling stoichiomentry you can stop it easily at one addition.

The reaction conditions, from memory, is to mix HMBt and the primary amine in benzene with a trace of pTSOH, driving off the water with a Dean-Stark trap, or molecular sieves for small reactions. The adduct that forms can be recrystallised to purity. The the benzotriazole can be easily removed by borohydride in say methanol.

See: J. CHEM. SOC. PERKIN TRANS. I 1987, 805
The Chemistry of N-Substituted Benzotriazoles. Part 4.' A Novel and Versatile
Method for the Mono-N-alkylation of Aromatic and Heteroaromatic Amines
Alan R. Katritzky, Stanislaw Rachwal, and Bogumila Rachwal

Sponsored Links