[herrhansen]

Hello.

I have this Di Boc protected bromo amino pyridine (see attached mechanism). I want to do a metal-halogen exchange using iPrMgCl and react this with methylchloroformate to yield the methyl ester. My compound is dissolved in THF and the grignard reagent added dropwise (1,2 eq.) @ 0 C. After around 45 min., my spot has gone up instead of down on my TLC plate. Normally it goes the other way around, as I quench it, giving it a proton. Since it gets more hydrophobic on TLC I guess that I made an isopropyl amide on one of my BOC groups (according to literature; amidation through carbamates). This correlates to my TLC analysis as I loose one oxygen then and it goes up. Because of time problems I did not isolate this product :-(

But now the really strange thing comes in. After all the starting compound has reacted, the electrophille is added. This gives one spot, much longer down the TLC plate. When I isolated the spot it turned out that the BOC and amide group is gone, and the electrophile have been attacked by the amine to yield a methyl carbamate. The bromine is unaffected. The last structure is validated by LC-MS, H-NMR and C-NMR, but I cant see how the amide + BOC can de deprotected by an electrophile. Maybe some intramolecular reactions? I Have never heard about deprotection of an pivatoyl group by a electrophile. I still have the MgCl as lewis acid, maybe it could do something on the other BOC group, but I am rather confused.
Any information regarding the mechanism, articles about this subject or ideas is more than welcome.
Thanks in advance.

[zeropoint]

You might want to change protecting groups. You can use a phthalate to di-protect the amine and then remove it with NaBH4/AcOH (easy to find on scifinder) or hydrazine if you want to be a bit rough with it.

Only other thing that I can suggest to use a lower temp for the addition of your grignard, say -78C

Good luck

[OC pro]

You should use (n) or maybe even better (tert) BuLi @ -78°C. That will do the job. Strange observation with iPrMgCl, especially when I think about the fact that diboc amines are somehow safe. But I don´t like Knochel metalation anyways so I am not surprised it didn´t work out for you  . Maybe a lower temperature will help as zeropoint pointed out already.

[herrhansen]

Thanks alot for your answers.

I have tried n-BuLi, but it resulted in alot of sidereactions. MeLi gave first the metal halogen Exchange, but the the formed MeBr was attacked ortho to the amine, because of ortho lithiation from the boc group. Maybe slower addition or dilution could be the answer to this. With tert BuLi it resulted in my wanted product, but one of the boc groups fell off. Maybe the formed LiBr from the metal halogen Exchange Can work A's an Lewis acid, deproteting my boc group? Thanks for your answers again.

[herrhansen]

But I think it is Strange that the ortho lithiation is seen, when there is a halogen present. According to litterature the ortho lithiation should be minimized, by having a halogen present too.

And thanks regarding the phathalate protecting group, but i am afraid too of ortho lithiation in that PG, maybe benzyl protection could dó the trick? Thanks