[AlphaScent]

Hey All!  Been a while.  Posting something that I am trying to think may work here.  Having trouble finding something cheap enough - also pick apart the idea too.

Need to deprotonate an aniline (pKa ~ 1, EWG para) in the presence of a protonate amine (amino acid) where an amide bond has been formed with the amine meta to the EW.

The SM is a 1,2-aminobenzene with a strong EWG in the 4-position.  I want so a second amidation using a proton as the protecting group for the amino acid amine.

Let me know your thoughts! 

Cheers!

[AlphaScent]

I should add that pyridine and dimethylaniline are possible choices but their stink and toxicity are awful to handle on >10 KG scale.

Triethylamine (TEA) and other tertiary amines (4-methylmorpholine) are too basic. 

I was thinking possibly like dipotassium hydrogenphosphate but that pKa is ~ 7.  That may be too basic too and lead to a mixture.

Appreciate any thoughts!

[rolnor]

 If you have the aromatic amino group with pKa 1 it can be a very weak nucleophile, even too weak to give a reaction with an acid chloride. To use a phosphate seems hard, your acid chloride would react with water very fast, and you need water to dissolve the phosphate? It is no problem if you add just 1eqv. base, then you would deprotonate only the aromatic amino group. Triethyl amine is cheap. Mix the aromatic amine with base first in a solvent in the cold, then slowly add the acid chloride.

[AlphaScent]

Rolnor,

The K₂HPO₄ would be done under phase transfer conditions most likely as you are 100% correct - this cannot have water around.

TEA is a cheap base but what is actually cheaper is 4-methylmorpholine.  Why? No idea.

Below is the current method with uses Gabriel conditions to protect the amine and then free it.  A lot of problems for going to a pilot scale.  The hydrazine hydrate step is something I would never do in a 100L reactor unless it was absolutely necessary.  The safety costs alone make this route prohibitively expensive.  Also atom economy is terrible from a green chem perspective.

Adding a base, like TEA or 4-Memorpholine, would work to deprotonate the aniline proton (pKa 1) selectively.  Since the customer has shown this to work already I think it would go.  Again it may need a little push.  A second equivalent of base is going to be needed to abstract the proton and push the reaction to completion during the amide formation.  This is where it may get dicey as something too basic would deprotonate the amine (pKa ~10) and the acid chloride would react there forming an amide in the wrong spot (regioisomer issues).

As much as I dont like using it I think DMA (dimethylaniline) is going to have to be used here because the pKa (Pka ~ 5) is right and it is cheap.  Toxic but cheap.

Food for thought.  Thanks for letting me bounce this around.

[rolnor]

There is a good reason why they use the protecting group strategy. The amino acid chloride is very reactive and would react even with the moist solvent you get when using phase transfer conditions, I think. I am afraid that your aromatic amino group is very unreactive, the scheme you suggest will be problematic. Are you trying to save money this way? Or do you want to avoid hydrazine hydrate? Can you tell us what the EWG is?

[AlphaScent]

Rolnor,

I cannot tell you the the EWG, unfortunately : (.  Lets just say it is QUITE electron withdrawing ; ) - hence the pKa of 1 on the para amine.

There are other protecting groups used in the literature - FMoc being one.  The choice here is to both save money and not use hydrazine hydrate.  Hydrazine hydrate is not used in pilot plants unless it is absolutely necessary.  Safety is the paramount reason here.  Also it would remove a protection and deprotection step from the synthesis.  Time and money.

Below is a ref from Organic Letters showing that this can be done.  I acknowledge the low yield and absence of an electron with drawing group here - but this ref and the clients current ability to form the amide leads me to believe that this can be done.  Will be tricky but order of addition, solubility, ect.. will all be crucial.

With the respect to the phthalimide protecting group - you think this particular acid chloride is more reactive, due to electron withdrawing nature of it beta to the acid chloride, or just stating the reactivity of acid chlorides in general?

One of the issues I do worry about too is intramolecular cyclization to the benzoimidazole - this is also known in the literature.  See OL 1,8, 1999, p 1157 and refs.

Phase transfer can be done without a solvent that has water.  I have used them to bring salts into organic phase successfully.  We have also been able to add benzoyl chloride to a mixture resorcinol (treatment with aq. NaOH (50%) first) and an organic solvent to form the ester in high yields and purity (95%, 97% respectfully).  Was shocked at how well it worked.  And granted the nucleophile was a phenoxide - far cry reactivity wise from what we are dealing with here.

I 100% agree with you that the reactivity of the amine is the sticking point.  Maybe an excess of acyl chloirde (cheap) may help. 

Will have to see when (if haha) I do the work. 

And the issue is always money - client wants this, sales guy wants that - and then its plopped in your lap to "make it happen" ; )

[rolnor]

Benzoyl chloride is less reactive than the acyl chloride you will use, this explains why it does not react with water. I understand your situation and if you believe in this, you just have to try. I would start with 1eqv of TEA just to see if it works at all, if it looks OK, test the cheaper alternatives. The reference you show is a diamino aromat without EWG so it's fairly reactive.

[AlphaScent]

Think you right.  IF we get the go ahead Ill let you know how it goes.

Appreciate it!

Cheers!

[rolnor]

Good Luck!

[AlphaScent]

Got the go ahead - start next week : )

I will keep you apprised as to how this goes!

Thanks again!

[rolnor]

Great!

[Meter]

Why wouldn't a carbonate work here?

[rolnor]

its not soluble in organic solvents?

[Meter]

its not soluble in organic solvents?

It can still work on the phase interface. Takes a lot of time, but yes, solubility is a good reason to look in other directions.

[MagnificentElectrophile]

Maybe I'm writing this too late but...
Are 2,6-Lutidine(Dimethylpyridine) or 3,5-Lutidine not options due to some reason? These are much less toxic compared to pyridine or 4-DMAP(Dimethylaminopyridine). 2,6-Lutidine is sterically hindered to form pyridinium intermediate hence has lower reactivity but 3,5-Lutidine is not. I often substitute 3,5-Lutidine for pyridine when doing esterification with acyl chlorides and it works just fine. Although Lutidines are much more expensive than pyridine, I guess it won't be huge problem if not being used as solvent.