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NBS bromination of 2,4-dimethoxyphenylethylamine

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Vaaguh:
Would the brominating of 2,4-dimethoxyphenylethylamine freebase using 1-1,2 molar equivalent NBS as described in post Post 71830 (missing) (Rhodium: "2C-B and 2C-C with N-halosuccinimide", Methods Discourse) work as it is?.

The post Post 506068 (moo: "NBS works because it liberates Br2 when ...", Newbee Forum) describing the bromination mechanism of NBS stating that "NBS works because it liberates Br2 when reacting with HBr, which itself is usually liberated when a substrate is brominated by Br2, thus keeping the concentration of free elemental bromine low in the reaction mixture."

If this would bee true isnt it possible that the H-Br reacts with the freebase amine which would probably lower the yields when using only a 1-1,2 molar NBS equivalent?

Or does the bromination with NBS proceed as described in post Post 478637 (Nicodem: "NBS generates bromine radicals that will ...", Chemistry Discourse) stating "NBS generates bromine radicals that will potentialy substitute any easily abstractable hydrogen."

Which if correct and using CH3CN as solvent should only brominate the aromatic ring.

Vaaguh:
To a stirred solution of 55 mmol 2,4-dimethoxyphenylethylamine freebase in 100 ml CH3CN there was in 6 portions added 66 mmol NBS. The orange reaction mixture turned from blue/green to deep red within seconds, after stirring at RT for 4 hours the CH3CN was removed under vacuum, the remaining red oil was dissolved in warm dilute acetic acid and washed with ether, this caused a lot of tar to fall out of the solution, after adjusting the pH to >11 the now even dirtier looking solution was extracted with ether and the organic phase washed twice with H2O and once with sodium sulfite. The now yellowish ether phase was dried over MgSO4 and gassed with HCl. No significant crystals could be obtained (perhaps 5 mg) :(

Would bromination of an activated aromatic ring using NBS/CH3CN perhaps require a catalyst like perchloric acid or simply longer reaction times (say 24 hours) ?

Bandil:
Any reason you chose acetonitrile as the solvent? AFAIK one of the reason for running the reaction in acetic acid is that the amine gets protonated in a protic solvent. This way its less reactive towards N-bromination.

I could imagine you'd got quite an amount of N-bromo-xxx-PEA in your mixture. From empirical knowledge N-brominated amines tends to cause emulsions like hell and will be somewhat removed in an acid base extraction.

So try using GAA as the solvent! Don't know how NBS behaves in GAA though.

Regards
Bandil

Vaaguh:
The reason why acetonitrile was used is because it is beleived that it causes a substantial increase in the rate of the ionic process hoping that ring bromination would be greatly favored. Indeed the amine is most likeley attacked.

GAA might not be a bad idea at all or perhaps the hydrochloride salt dissolved in hot/refluxing acetonitrile.

Vaaguh:
N-Bromosuccinimide in Acetonitrile: A Mild and Regiospecific Nuclear Brominating Reagent for Methoxybenzenes and Naphthalenes

M. Carmen Carreiio,* Jose L. Garcia Ruano,* Gemama Sanz, Miguel A. Toledo, and Antonio Urbano

Departamento de Quimica Orgcinica G I ) , Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain

J. Org. Chem. 1995,60, 5328-5331

In this paper, we describe the high regioselectivity achieved in the ring bromination of several methoxy derivatives of benzene and naphthalene with NBS in CCl4 and the substantial increase in reactivity observed using acetonitrile as solvent. We also report on the exclusive aromatic ring bromination of several methyl anisoles with NBS in CH3CN, which strongly contrasts with the predominant benzylic brominationg observed for the same substrates in CCl4.

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