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I am trying to protect a second degree amino group by doing acetylation and although I did find workup mechanism in DCM, water and NaOH using acetyl chloride, its a custy reaction scheme because Acetyl chloride with water just doesn't feel right to me.

So what I do is that I make a hydrochloride salt of the secondary amine and dissolve it in water and DCM layer and under vigorous stirring, I add some Acetyl Chloride and NaOH simultaneously. But Acetyl Chloride and water is a not too compatible mixture so I am looking for an alternative pathway.

If anyone has ever performed such a reaction in a non-aqueous solution, I'd appreciate the help you can provide with solvents and conditions for the same. In the meanwhile, I am trying to do it with some basic tertiary amine based solvents like NMP, disubstituted piperazine etc. I appreciate any inputs on this

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A standard procedure from my lab uses acetyl chloride and pyridine in DCM.

Dissolve your substrate amine and 1.1 eq of pyridine in DCM. Stir under nitrogen and cool in an ice bath. Add dropwise a solution of 1.05 eq acetyl chloride in DCM. Monitor by TLC and leave it until no starting amine is detected (Ninhydrin visualisation is useful here). If the reaction is slow adding a few mgs of DMAP should speed it up.

Wash the organic phase with dilute acid then dilute base, a third wash with aq CuSO4 will remove the last traces of pyridine. Dry, filter and evaporate.

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  • $\begingroup$ Hi sorry its late my system got fried. I got some questions. 1 Can I use Triethylamine instead of pyridine because both are tertiary amines and Triethylamine is lot easier to source for me than Pyridine and someday I'll have to scale this and pyridine is frowned on in the industry and 2 My amine is in its hydrochloride salt form. Should I free base it first or just add 2.2 eq of Triethylamine in order to freebase the secondary amine in situ? I really want to avoid an ether extraction again due to scale up issues. Thanks! $\endgroup$ Aug 3, 2022 at 16:51
  • $\begingroup$ Pyridine works better as it forms pyridinium acetate as an active intermediate, otherwise you can use 2.2eq TEA. You may need to run it dilute as TEA.HCl has limited solubility in DCM. A few mgs of DMAP can replace the catalytic effect of pyridine. $\endgroup$
    – Waylander
    Aug 3, 2022 at 20:09
  • $\begingroup$ So elevated temperature and longer reaction time with dilute DCM (I'll use like 100ml for 10 g) should help achieve results with TEA and I'll add 1-2% DMAP as catalyst. Am I going in the right direction? $\endgroup$ Aug 4, 2022 at 12:14
  • $\begingroup$ I don't think you need elevated temperature initially unless tlc shows the reaction is not proceeding. I would use more DCM, maybe 250ml $\endgroup$
    – Waylander
    Aug 4, 2022 at 12:35

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