[Sach]

Hi guys, I did the reaction that you can find in the attachment (direct arylation). You can also find the link to the article that I based my conditions on. After doing the reaction (after work up and column), I got the molecule you can also find in the attachment (according to H-nmr and infrared spectrum). It seems like the benzyl carbamate protecting group is removed and I am not sure why. Normally it is a stable protecting group and it doesn't get removed easily (although it is not stable at 100°C at pH 1 or lower). I was thinking that maybe it is removed by stirring at 100°C in the presence of pivalic acid. I don't really have another explanation. Any suggestions are welcome

article: http://pubs.acs.org/doi/abs/10.1021/jo8026565

Thank you in advance

[rolnor]

But you also have Cs2CO3 present? Is the pivalic acid in excess?

[Sach]

Yes, I do have Cs2CO3 and I used 2 equivalent of Cs2CO3.
40mol % of pivalic acid was used so it wasn't used in excess.

[rolnor]

But then the reaction mixture should be basic, not acidic? More likely then that the Cs2CO3 and trace H2O hydrolyzes the Cbz-group.

[rolnor]

The reaction mixture will be acidic as the reaction proceeds, liberating HBr though.

[Sach]

Ooh ok, so the protecting group could be removed by hydrolysis by the base (Cs2CO3) and traces of water. But I don't understand how the reaction mixture will become acidic as the reaction proceeds.

[rolnor]

The bromoatoms will form hydrogenbromide, this will react with the cesium carbonate untill it will be consumed, then you have pivalic acid remaining, this will make reaction mixture acidic. So the mixture will be basic in the beginning, then acidic.

[Sach]

Ok and my protecting group is sensitive to (strong) acids, so that could have removed the protecting group

[rolnor]

I am surprised by that, pivalic acid is not strong acid but somehow the Cbz-group is hydrolyzed and this is the only explanation I can think of.

[Sach]

Yes I also had not expected the protecting group to be removed by pivalic acid.
But thank you very much

[Sach]

Is it possible that the benzyl carbamate is cleaved under nucleophilic conditions because there is 2 eq of base (Cs2CO3) used during this reaction?

A very common deprotection method for benzyl carbamate is also halogenation in presence of Pd/C catalyst. During this reaction, Pd(OAc)2 is used, but could it be possible that in the course of the recation, Pd(OAC)2 is converted to Pd/C? And what could be the H2 source for halogenation?

I am kind of stuck here. Thank you in advance guys

[rolnor]

Do you mean hydrogenation, not halogenation? It could be basic hydrolysis if it happens in the begining before the Cs2CO3 is consumed.

[Sach]

Yes I meant hydrogenation. So the protecting group could be removed by hydrolysis? But wouldn't I need water for hydrolysis? Or are traces of water that organic solvent (dmac) contains enough?

[Sach]

I was thinking about an alternative protecting group. Could Boc be used as an alternative protecting group because it is more stable in basic conditions than benzyl chloroformate. I couldn't find experiment data where direct arylation is done with a protected amine. If anyone has an article in which they use direct arylation reaction succesfully with a protected amine, it would be a great help.

Thnx in advance

[wildfyr]

Why not use/make boc bromoaniline (moderately priced or easy to make) and do a test reaction? I bet it is somewhere in the literature though.