[kriggy]

Im thinking about running grignard reaction like this one:



The point is to make the compound more soluble in water to facilitate next steps. I could run the reaction on the final derivative but I have only low amounts of it and the last step has rather bad yield so I was thinking about running the derivatization sooner than on the final compound.

Obviously, I will need at least 4 eq. of grignard reagent because i have two protons that can disociate and destroy the regagent. I could start with deprotonating using something like NaH but Im not sure if its stong enough base for that (probably yes) what I am not sure is if the grignard will reacti with the amide and lactam moyety, I would guess since both the nitrogens will be deprotonated I will be safe (I wouldnt mind if the acetyl would be cleaved in the process because it is next step anyway).
Also, arent there different methods to do this transformation that would tolerate the free amine? Am I missing something guys?

Thanks

[TheUnassuming]

I think you are right that the acetamide will probably be safe because it will be deprotonated and the same for the lactam.  The only thing I can think that might happen is the addition into the imine sort of moiety.  The electronics of it aren't strongly in favor of the addition in that manner, especially once you deprotonate the lactam, but it still is an ok electrophile.   
Could you convert to the acids at an earlier stage?

[kriggy]

Well, my starting compound is acetylated isatin and 4,5-dichloro-1,2-diamino benzene that react together to form the starting material in the sceme a I posted so I guess It could be done but the free amines would cause trouble. I would prefer to do the derivatization as late as possible to save steps but unless I am able to purify the final compound to get reasonable amounts (its about 80% of it in the mixture but Im isolating about half of it) of it its no-go.

[kriggy]

hm guess Im bit screwed, I did some literature search and I didnt find single example of Ar-Cl  Ar-MgX exchange (unless using metalic Mg). The good thing is that it can tolerate the free amino group which is cool since the derivatization can be done one step later. Anyway, anyone seen halogen - MgX exchange on aryl chlorides? Im gonna try anyway but I would rather have some literature to have some idea how to do that. It seems that every reaction is using aryl iodides or bromides (that are not available for me atm)

[zoork34]

Is there any chance you could accidentally make the benzyne with this reaction?  Would be interested to see how it turns out. 

[kriggy]

Well I have no idea could happen. There is also an option for me to run kumada coupling that should work with the chlorines but that would only allow for different substituents (Et, iPr ... ) Anyway I´tell you what happened when I run it 

[TheUnassuming]

With chlorides and converting at least to the mono-grignard you shouldn't get benzyne formation.   I've used 1-2 dibromobenzenes to make ortho-functionalized bromobenzenes and only ran into benzyne formation when I tried lithium-halogen exchange instead of going to the grignard with iPMgCl. 
I'd bet if you push it, you should get at least one to make the grignard.  I don't know how easy it is to get 1-2 phenyl grignards to form but I would think it will be much harder and I have no idea how stable it will be.
Do you think your compound would stand up to oxonolysis?  You could do a sonogashira to make the di-alkyne and hit it with oxzone to make the di-carboxyl compound.   

[kriggy]

Well I dont know if it holds the ozone, but I think it could hold. I was talking to my supervisor today so we set bit different direction of the project for now.
Its kinda weird because we started with a goal to synthesise set of derivatives and try to explore mechanism of the last step and now I ended with developing the reaction on different substrates. It somehow worked today for the first time so cant wait for NMR to see if the compound is realy what we wanted..

I wanted to do kumada coupling on those chlorines but it seems that there will not be enough time for that because I have to have my thesis complete in may

[TheUnassuming]

Well hopefully it worked! 

Congratulations, you are almost there!  I'm in much the same boat, though with a fall deadline.  There is always so much more you could/want to do, but never enough time! 

[kriggy]

Haha almost
It turns out that I dint make the product I wanted but something else It seems that my compound dimerized in the process, lost some functional groups and got the double bond reduced