[JeffG]

Hello again.

I have this para bromo methoxy benzene. I have planned to make a metal halogen exchange with n-or tert Buli and then use this lithiated anion to attack ethyl 4-bromobutyrate to get the ester, but I am not sure whatever this reaction is possible or gives comparable yields.

It is common to use other electrophiles like ethyl chloroformate, but will it work with this alkyl halide?

Thanks alot in advance

Best

Jeff

[movies]

I think you will primarily get addition to the ester, not the alkyl halide.

[Doc Oc]

That particular ester would also be susceptible to E2 elimination.

[JeffG]

Thank you very much for the quick answers.

If I am using Tert Buli I dont think that addition to the ester should be a problem?

But If I start to make the halogen metal exchange at -78 C and then add the electrophile, would I then get elimination from the alkyl halide?

Thanks in advance.

Best Jeff

[JeffG]

I forgot to say that I have found a reference, using alkyl halides as electrophiles, they just dont have the ester motif and uses n-buli for the dehalogenation. Yields are reported up to 60 % (can link to the article if anyone is interested). Normally I dont see any addition to the chloromethyl formate if this is used as the electrophille, even though I can´t explain my bad yields. Maybe problems getting the dehalogenation, as the aromat is activated by either metoxy or amine groups, but because of this bad yield (30-40 %) I will not be able to fully elucidate that no addition to the ester takes place.

Wish everyone a good night.

[Doc Oc]

Because the alkyl halide is primary and it's a bromide (one of the better-er leaving groups) I think E2 is still a consideration even at reduced temperature.  I would try it at a small scale first before using up valuable starting material.

[movies]

I would be worried about your aryllithium species adding to the ester.  By the time you add the bromoester the BuLi should be gone.  You might be able to minimize the addition to the ester by changing to a t-Bu-ester instead of ethyl, but even then it might not be enough.

Like J-bone said, you will probably just have to try it and see, but don't commit much material at this point.

[JeffG]

Thanks for the good answers.

It is of course a good consideration about the addition to the ester, as it is more activated, but compared to the bromine as leaving group, would´nt it it choose the alkyl halide which is not reversible as the addition to the ester? Or maybe I am wrong. But of course the tert ester would be better yes.

I think I will try. Am going to write whatever happens. Maybe someone could use it, in their work.

Thanks

Best

Jeff

[OC pro]

Lithiated benzene plus ethyl chloroformate normally delivers ester in high yield.
Have you carefully analyzed the lithiation? Was it complete before you added the chloro formate? You can check it by taking a small aliquot and quench it with water and ethyl acetate giving you the completely dehalogenated methoxybenzene (TLC analysis or GC analysis should also work). If bromo benzene is gone than you have complete addition.
Have you measured internal temperature? So if I were you I would have carefully dropped in the chloro formate so that internal temp will not rise above ca -70°C to avoid side reactions.

30 - 40% bad yield  ? It is something to start with. But I understand that academics (especially supervisors) always want yields beyond 90% which is far from being reality in industry.