[herrhansen]

Hi again. I tried to carry out a metal halogen exchange on an aminopyridine. I can see from ordinary H-NMR that the metal halogen exchange occurs, but I get one extra methyl group incorporated. So now I dont know which of the positions it is incorporated in or in which step. From normal pyridine, 2,4 nucleophilic attack is common, but from the metal halogen exchange I also get MeBr out, which is an excellent methylating agent. This would then be able to methylate ortho to the chelating group, if this get methylated? I have attached the two mechanisms.

Thanks everybody.

[MissPhosgene]

Do you really make the pyridine dianion?

My guess is that you are methylating at the three position. An easy way to see which one is correct is to compare 1HNMR of SM and product.

How many equivalents of MeLi do you add? Decreasing could probably help a lot.

[herrhansen]

Hi.

Thanks for your reply. I have made many trials. I used between 1.2 - 3 eq. The excess was to convert all the starting material according to TLC.

On NMR it looks like I have ortho directed methylation. But for this to happen I have to have some MeBr in the solution as well. So I assume that the metal halogen exchange have occured to form the MeBr. I actually guess I have a mixture of my wanted product and my starting material methylated ortho to the amine in almost a 50/50 ratio, as the methyl tops are almost equally in height. So you are probably right that I havent formed the di anion, but just got a mixture of methylated starting material and wanted product. Probably because of too fast addition of MeLi. Was this the case you also suspected?

Again thanks alot for replying.

[MissPhosgene]

Was the starting material which got lithiated ortho to the di-Boc-N debrominated?

[herrhansen]

I dont know. I did not try to quench it with water to see if I got an extra proton. The problem was that I could not see anything wrong on TLC, so I just quenched with my electrophile. This gave me almost one spot positioned longer down and away from the starting material on TLC. (This also means that my plan with methylated starting material also do not hold, as this would be positioned in the top of the TLC plate (1:4 EtOAc/heptane). I also guess it would be wrong to assume that MeLi rather would ortho lithiate, than participate in the metal halogen exchange?

So my problem is that I got 2 methyl groups in the NMR integrating for the same (ArCH3)2 and 2 Ar protons integrating for the same 1 H each and one COOCH3 top integrating for 3H. So even in combinations I cant see how it is possible. The two Ar methyl groups are positioned VERY close and almost looks like a doublet.

Thanks again.

[MissPhosgene]

Is there any way you could scan 1HNMR spectra of the SM and products and post them here?

[orgopete]

I can appreciate the challenge of metal halogen exchange and the possibility of a directed metalation. There are several possible solutions. First, avoid the formation of methyl bromide by changing to another exchange agent, butyllithium or t-butyllithium.

However, neither will improve the directed metalation (which I don't think should be the problem, did your reaction turn red?). You should be able to tell whether the ortho pyridine hydrogen is present in the NMR fairly easily.

[g-bones]

chichibauben type chemistry with methyl lithium?

http://en.wikipedia.org/wiki/Chichibabin_reaction

[herrhansen]

Hello.

Currently I have no scanner. So unfortuantly I am not able to scan the spectres. But thanks for the replies.

Orgopete: I have done the synthesis using tert-BuLi and this worked, but gave only fair yields. I dont know if it helps to use 2 eq. of the other organometallics too and thereby quench the butyl bromide? The reaction did turn red actually. Is this a known problem? The reason why I supect ortho lithiation is; On one of my fractions from column I found 2-methyl groups with almost the same shift instead of one methyl group from the starting product, and the one proton is missing. In another fraction I also have these two methyl groups shifts, but also 2 protons, which I cant explaine. (It should not be possible according to available positions). I dont know what have happened in this reaction, but on TLC it gave two spots with almost the same RF value (which I expect to be the di methylated and the methylated methyl ester). I also found some references where they have used ortho lithiation directed by BOC to in planned synthesis (I can link to them if needed?).

G-bones: I have thought about the chichibauben type, but this is done on normal pyridine, which are very electron deficient and primary gets attacked at the 2-and 4-position. Doing the reaction on an aminopyridine will somehow be different I guess, due to the activating amine.

Thanks for the replies.

[OC pro]

What means fair yield?

[herrhansen]

Sorry a definition taken from wiki. 45 %.

[OC pro]

That doesn´t sound too bad. 45% yield of pure, isolated product is good enough to proceed. How many steps will follow?

[orgopete]

herrhansen: I believe the effectiveness of t-butyl lithium is that as a tertiary bromide, it cannot readily alkylate any anions formed, unlike methyl bromide. t-butyl bromide w/ t-butyl lithium give lithium bromide, butane, and butene, I think and that is a reason it is used with halogen exchange reactions.

We formed some metallated pyridine dianions. We found that after formation of the monoanion, the red color was one of the best indicators for out butyllithium. It was a lot better than any of the commercial indicators because it was much deeper in color and a really sharp endpoint. I am convinced you are seeing deprotonation of your pyridine.

[MissPhosgene]

Orgopete:  Just out of curiosity, how do you know it was the dianion? I have been wondering about this since the original post in this topic was made. NMR?

 

[orgopete]

Oops, sorry, don't know that. Mine was a dianion. He listed a dianion, which made sense, but given that the correct product was not conclusively identified, I really don't know what occurred.