Sciencemadness Discussion Board

Question about amine protection for Grignard reaction

Monoamine - 26-3-2022 at 00:27

Imagine you need to form a Grignard reagent from a molecule containing both a halogen (from which we want to form a Grignard reagent) as well as an primary or secondary amine:
Screen Shot 2022-03-26 at 1.25.45 AM.png - 37kB

How do we prevent the amine protons from ruining the reaction?

After researching this question a bit, it seems that one should be able to protect the amine so that there are no acidic protons to mess up the Grignard formation. Unfortunately most options are out, since they contain carbonyls. A benzamide protecting group would work, but it has the drawback of being rather difficult to deprotect and takes a very long time (done with HCl and H2 I believe...).

Could another possibility be a sulfonyl or Tosylate protecting group? I read a claim that this is not stable against grignard reactions, but I don't see why it wouldn't work. Does Magnesium or the formed Grignard reagent react with Tosylates or sodium ammonium sulfate?
(I did however come across this paper where they did use a tosylate to protect an amine for a Grignard reaction

Is anyone aware of any other Grignard-stable protecting groups?

Finally, could one simply deprotonate the amine with E.g sodium or lithium (or their hydrides)


Wuts, P.G. and Greene, T.W., 2006. Greene's protective groups in organic synthesis. John Wiley & Sons.

Chinta, B.S. and Baire, B., 2016. Reactivity of indole-3-alkoxides in the absence of acids: Rapid synthesis of homo-bisindolylmethanes. Tetrahedron, 72(49), pp.8106-8116.

[Edited on 26-3-2022 by Monoamine]

timescale - 26-3-2022 at 11:37

Benzyl groups contain no carbonyls and are removable by hydrogenolysis. Tosylates might work, I'm not sure.

clearly_not_atara - 27-3-2022 at 05:41

If it's a secondary amine, consider using a triazene with benzenediazonium. IIRC these are stable to Grignard conditions.

For a primary amine the situation is difficult. You can form a pyrrole easily but cleavage will require vigorous hydrolysis. Benzyl groups can be added but require strong hydrogenation to remove. You can form a 1,3,5-triazane (think trioxane) adduct with formaldehyde in some cases but the solubility of the trimer may be a problem and formaldehyde is reactive with other moieties. The best option will depend on the substrate.

Monoamine - 4-4-2022 at 08:18

All nice tip! Than you folks. I'll give it a try. :)