Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Sach on December 09, 2017, 05:18:43 PM
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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
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But you also have Cs2CO3 present? Is the pivalic acid in excess?
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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.
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But then the reaction mixture should be basic, not acidic? More likely then that the Cs2CO3 and trace H2O hydrolyzes the Cbz-group.
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The reaction mixture will be acidic as the reaction proceeds, liberating HBr though.
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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.
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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.
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Ok and my protecting group is sensitive to (strong) acids, so that could have removed the protecting group
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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.
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Yes I also had not expected the protecting group to be removed by pivalic acid.
But thank you very much
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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
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Do you mean hydrogenation, not halogenation? It could be basic hydrolysis if it happens in the begining before the Cs2CO3 is consumed.
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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?
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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
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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.
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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.
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Cbz should go off. The thiophene α position is extremely easy to modify, and there are multiple ways reported in the literature.
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I expect I can find the answer in the literature in less than an hour, this a fairly obvious protecting group to have to deal with. I really think you should check again yourself before wasting money, time and energy, albeit on an easy test reaxtion. I will look tomorrow when I can use a PC, but if it's easy to find I may shame you :)
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I spent some time searching, and I could not find an example of a direct arylation using Pd(0) in the presence of a tBoc group. However I found many examples using Pd(OAc)2 such as http://pubs.acs.org/doi/abs/10.1021/ja058141u, http://pubs.acs.org/doi/abs/10.1021/ja0605265 or http://pubs.rsc.org/en/content/articlelanding/2013/sc/c3sc50428j#!divAbstract. So, in light of that, my suggestion is to put another few hours into scifinder/google scholar seeing if you can find an answer, and if not, give the test reaction a shot.
P.S. A subtlety, all the examples I found with palladium acetate had boc protected alkyl amines, for whatever that is worth.
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I did find an example where SO2-ph is used as protecting group (see scheme 184 p214) using the same conditions while performing direct arylation reaction:
http://pubs.acs.org/doi/abs/10.1021/cr0509760
p-toluenesulfonyl chloride is is sometimes used as protecting group but this is the first time I have seen benzenesulfonyl chloride (SO2-ph) as protecting group. Is it possible that any one of those two could be used as protecting group?
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And thnx a lot for the help.
I have actually finished my research in the lab, now I have to look for possible reasons for obtained results while writing my thesis. So I won't be able to actually work with the protecting group I chose, but i still need to give an alternative protecting group (for people who would want to do similar research in the future).
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It could work, I think you remove it with Na/NH3? I think I have seen that, att least for the tosylgroup, the benzenesulphonylgroup should should be similar. Its i pity you have no more time in the lab, this is interesting chemistry.
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Yes I wanted more time as well but it was a relatively short project. So I am going to propose P-toluenesulfonyl chloride as alternative protecting group instead of benzyl carbamate. It is reasonable to propose this, right?
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Maybe there could happen something with the thiophene-ring if you deprotect with Na/NH3 and the DA can be slower because the Tos-NH- is less activating then Cbz-NH- but the tosylgroup is more stable to basic and acidic conditions.
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You can probably n hydrolyze tosyl with aqueous KOH. I don't know at all how thiophene would handle that
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The thiophene is aromatic and will not react with acid or base but the method using Na/liquidNH3 to remove tosylgroups is more of electron transfer or free radical type of reaction so the sulfur in the thiophene-ring can somehow react perhaps. If it is OK to not de-protect after DA this is of course no problem.
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I found this link, they use Li and naphtalene to cleave tosylamides, I think this is similar to Na/NH3.
http://www.organic-chemistry.org/protectivegroups/amino/toluenesulfonamides.htm
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I also saw that it is cleaved by Li and naphtalene. Can it be cleaved with using KOH like wildfyr said? Because thiophene can certainly withstand KOH.
If the organic linker is succesfully designed, a metal organic framework will be synthesized with it. The target is to deprotect it after the direct arylation but if that is not possible, the alternative is to deprotect is after the metal organic framework has been synthsized but that would be more difficult i imagine.
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You could use nosyl instead of tosyl and cleave it using thiol (mercaptoethanol or thiophenol AFAIK) at mild conditions. It smells but might be better than refluxing it with KOH or H2SO4
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Ok thnx