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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: kriggy on April 04, 2019, 08:55:33 AM

Title: protecting group help
Post by: kriggy on April 04, 2019, 08:55:33 AM

Hey guys, I need a bit help with protecting group choice. I need something that a) survives mild basic conditions (K3PO4, 40°C) b) survives acidic conditions (BINOL-phospohonic acid or equivalent at 65°C in toluene) c) is selective for oxygen compared to nitrogen (need to protect oxygen of aminobenzylalcohol but I think I can manage to do with protecting group swap if needed so this point is the least important).

I was trying TBDPS protection which kinda works well but it seems too bulky for the last reaction to proceed (https://onlinelibrary.wiley.com/doi/epdf/10.1002/anie.201802963, scheme 2, p6253) I was thinking using less bulky silyl but im not sure if it survives the reaction conditions (they are somehow acid labile). I have complete conversion of the starting material but only about 15% of the product and rest are some byproducts that I am unable to identify ATM.
I was thinking MOM, tbutyl or benzylether but im not sure about their stability to acidic-nonaquaeous conditions.

Title: Re: protecting group help
Post by: rolnor on April 04, 2019, 09:21:17 AM

If you can use benzyl it would be great, its stable to base and your acidic conditions. Deprotection by hydrogenolysis or TMSI. MOM and t-Butyl is more sensitive to acid.

Title: Re: protecting group help
Post by: kriggy on April 04, 2019, 09:38:23 AM

Is there a chance I can get it on the OH over the aniline? Probably not right?

Title: Re: protecting group help
Post by: rolnor on April 04, 2019, 10:58:34 AM

If you can do it acidic with benzyltrichloroacetimidate there is a chance but its a gamble.
You could try benzylbromide/NaH/DMF also, maybe the alkoxide is a better nuchleophile then ArNH2?
You can protect the amine with t-Boc and deprotect very easy with TFA.

Title: Re: protecting group help
Post by: kriggy on April 12, 2019, 02:29:46 AM

If you are interested in small update:
I havent solved the protection yet BUT I can use the unprotected aminobenzylamine in the coupling step and it works well. 70% HPLC purity, no trace of the O-arylated compoud. Which is great because I dont have to do some protecting group dance.

Also, the coupling with TBDPS protected aminobenzylalcohol failed - the TBDPS group got cleaved during the reaction (I think I left it too long, but since I can do it with the unprotected, it doesnt matter)

Title: Re: protecting group help
Post by: rolnor on April 12, 2019, 04:22:05 AM

Great!

Title: Re: protecting group help
Post by: wildfyr on April 12, 2019, 09:21:44 AM

Thanks for the update! Always great to hear people's successes. Too often we just hear a problem, and no results!