[Monoamine]

]I have been reading much about protecting groups for amines, but it looks to me as if all the methods are designed for primary and secondary amines.

I have a compound containing an aromatic OH group which I hope to homologate via an ether synthesis (using EtBr). The problem however is that the compound in question also contains a tertiary amine, which means that the lone pair on the amine will likely also act as a nucleophile for the for the EtBr, and form a quaternary aminium ion.

One thing that might help is that after the aromatic OH group has been deprotonated, the remaining O^- will be a much better nucleophile than the amine lone pairs.

Nonetheless, I would feel much more comfortable if I could nonetheless protect the amine lone pair so that it won't be able to act as a nucleophile any more.

Are there any fundamental reasons why protective groups can only be applied to secondary and primary amines?

For instance, might to following approach work?

[Orcio_87]

If the amine is sufficient strong base, maybe adding CH₃-CH₂Br will be good enough?

In my opinion first reaction ([HNR₃]⁺ + CH₃-COCl) is rather unlikely.

[wildfyr]

I think the phenol will react much more quickly than the amine, especially under basic enough conditions to deprotonate the phenol. Its common enough for people to use tertiary amines as bases for all sorts of nucleophilic reactions without worrying about quaternary amine products. Typically to make quaternary amines from tertiary amines you have to do things like heat it vigorously (like 120C) for a long time, or use a halide scavenger like AgNO3 to drive it forward, since the reaction of the halide ion with the carbon alpha to the quaternary amine is also a favorable reaction. NO3 is a crappy nucleophile, and AgCl precipitates out.

I don't think the acylation reaction you drew would work. Under acidic conditions that amine has no lone pairs and would be an abysmal. nucleophile. Also, using strong base like aqueous NaOH to deprotonate the phenol probably also would deprotect your amine.

Give plain old Williamson ether conditions a try, finely ground K2CO3, alkyl halide, phenol, polar aprotic solvent.

[Monoamine]

I think the phenol will react much more quickly than the amine, especially under basic enough conditions to deprotonate the phenol. Its common enough for people to use tertiary amines as bases for all sorts of nucleophilic reactions without worrying about quaternary amine products. Typically to make quaternary amines from tertiary amines you have to do things like heat it vigorously (like 120C) for a long time, or use a halide scavenger like AgNO3 to drive it forward, since the reaction of the halide ion with the carbon alpha to the quaternary amine is also a favorable reaction. NO3 is a crappy nucleophile, and AgCl precipitates out.

I don't think the acylation reaction you drew would work. Under acidic conditions that amine has no lone pairs and would be an abysmal. nucleophile. Also, using strong base like aqueous NaOH to deprotonate the phenol probably also would deprotect your amine.

Give plain old Williamson ether conditions a try, finely ground K2CO3, alkyl halide, phenol, polar aprotic solvent.

Oh thanks for the tip regarding the high temperatures for forming quaternary amine ions! Good to know. And I think this can pretty much all be done at room temperature overall.

For the Williamson ether synthesis conditions, while K2CO3 be a strong enough base to deprotonate an aromatic OH? Also, during the deprotonation, won't the ammonium ion get deprotonated, leaving the lone pair exposed, and - in fact - sitting right on the other side of all the steric junk around the nitrogen, so it would be wide open to nucleophilic attack.

For the solvent I'm guessing just anhydrous acetone (Assuming the deprotonated compound is actually soluble in it), I guess I'm just trying to avoid something like DMSO because it has an annoyingly high boiling point and - for whatever reason - in always attracts swarms of flies into my workspace!

(Just as a side question since you mentioned K2CO3, I had some shipped to me and upon comparing how alkaline a solution of K2CO3 is compared to Na2CO3, I was shocked to see that K2CO3 was orders of magnitude more caustinc than the Na counterpart, so I just concluded that it must have been mislabeled... But is K2CO3 actually that much of a stronger base than Na2CO3? I usually look at K and Na as being more or less interchangeable)

[rolnor]

You dont need a protecting group for this, just use K2CO3/DMF or Cs2CO3/DMF + ethyl iodide Tertiary amines are not so easy to alkylated.

[kriggy]

You dont need a protecting group for this, just use K2CO3/DMF or Cs2CO3/DMF + ethyl iodide Tertiary amines are not so easy to alkylated.

 
Exactly

Also, in the OP scheme, the acylated tertiary amine wont survive the hydroxide treatment, very often combination of acyl chloride and tertiary base are used for acylation reactions via the acyl-ammonium intermediates.

[Orcio_87]

If this will be primary or secondary amine - does this reaction can be do in acidic environment ?

I mean - H⁺ blocks nitrogen atom, but -OH can still react with CH₃-CH₂Br.

But - in acidic conditions reaction is shifted towards CH₃-CH₂Br and R-OH rather than the ether and HBr, am I right ?

[wildfyr]

Huh... I never thought about K2CO3 being more caustic. I just pick it because its more soluble! But yes, also its a stronger base. Has to do with the tightness of the ionic bonding of potassium versus sodium and the anion I guess.

[hollytara]

I don't think your scheme will work - I am not aware of any stable, isolatable ammonium salts where one of the groups on N is acyl. 

You might consider the work of Jensen et al - she used 9-bromofluorene to prepare ammonium salts with various tertiary amines - the purpose was to make a photobase generator, as the stable fluorenyl cation would be liberated along with the tertiary amine on UV irradiation.  But it might also work as a photo-deprotectable group for tertiary amines. 

https://pubs.acs.org/doi/abs/10.1021/cm000767q

[wildfyr]

@hollytara , this person is worried about making the quaternary amine side product, not trying to make that species. All they want to do is Williamson ether the phenol with ethyl bromide