NBS bromination of 2,4-dimethoxyphenylethylamine

[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.

[Vaaguh]

From a bottle that was labeled as "ricuarte's 2,4-dimethoxyphenylethylamine HCl" there was 5 gram (23 mmol) dissolved into 35 ml GAA.



To this mixture was added 4,9 gram (28 mmol) NBS which caused the solution to turn deeply red.



After covering the RBF with foil and placing a stopper on the flask the whole was stirred for 30 minutes. The precipated crystaline mass was filtered off and washed twice with ethyl acetate, another wash with H2O caused the solids to dissolve, the pH was adjusted to > 11 and the organic layer was extracted with 3x 30 ml EtO2, after removal of the solvents the residual oil was dissolved in 20 ml IPA and the solution was neutralized with dry HCl in IPA. The solids that formed where washed once with EtO2 and filtered to provide a crop of white crystals weighing 5,38 gram.

[/

An attemp to recrystalize the solids from IPA/Toluene (10ml ipa:5ml Toluene / gram) did not dissolve all sollids, even the addition of more IPA caused the solution to stay turbid. After allowing the solution to slowly cool down to RT the whole was refrigerated overnight providing 4,86 gram of what is beleived 4-bromo-2,4-dimethoxyphenylethylamine HCl (71 %)  with a mp of 235-237°C, a marquis reagent test gave a a dark green spot.

[Captain_America]

...refrigerated overnight providing 4,86 gram of what is beleived 4-bromo-2,4-dimethoxyphenylethylamine HCl

Are you sure?    

interesting work btw..

[Vaaguh]

Are you sure?

There must have been mixed up a couple of 5's somewhere.

[Captain_America]

btw, what are you going to do with this compound? as I can see it can't yield anythig active w/o bost from MAOI.

Do you think that you can try this

Post 518568

(Kinetic: "Iodination of arenes with KI and H2O2", Chemistry Discourse) on the 2,4-dimethoxyphenylethylamine and report back?

[Vaaguh]

It was just a proof of concept.
More interesting substrates can be brominated in this friendly manner.

[edit (im seriously starting to go braindead with all those numbers) ]: Any idea what 5-iodo-2,4-dimethoxphenylethylamine would be like?

[Bandil]

Any idea what 4-iodo-2,4-dimethoxphenylethylamine would be like?

Non existant, as the 4 position only holds one substitutent hehe...

However 2,4-dimethoxy-5-iodo-PEA, might be another story (although very likely to be inactive...)

Regards
Bandil
*kiss kiss*  

[Captain_America]

2,4-dimethoxy-5-halo-amphetamines are active, META-DOB have according to Pihkal at a dosage of about 100 milligrams produced effects that were similar to those produced by MDA. Seem to bee some toxic sines involved. Vaaugh, are you going to taste this META-2CB? I don't think it will bee active. Look at TMPEA, 2C analog of TMA-2, it is inactive while TMA-2 is turbulantly active comound. So there is no reason to believe that META-2CB will bee active, it will bee even less active than TMPEA as META-DOB is less active than TMA-2. It is the same pattern/relationship. But in combination it might boost the effects of some other compound.

[Vaaguh]

Meta-2c-b won't be tasted by me for now. NBS is just a really attractive bromination agent compared to elemental bromine in these cases, especially since no additional catalyst is required and the reaction time is pretty short.