[Uberbane]

Hi all,

I've done a reaction twice now using the same conditions, and observed the desired product mass by UPLC-MS on both occasions, but by the end of the workup procedure (or column, in the second case) I only observed a single peak whose mass corresponded to the dehalogenated byproduct. Did SciFinder/Reaxys searches for similar reactions but couldn't come up with anything, so turning to you good people. It's pretty clear I'll need to explore other conditions to obtain the desired product, but I'm really baffled as to why I'm seeing dehalogenation.

The general procedure I'm following from a patent is dissolving the oxime in methanol/water (2:1), adding Zinc dust (2 eq.) and cooling to 0C and adding formic acid (same amount as water by volume) portionwise, continuing to stir at 0C for a few hours then allowing to warm to room temp. I generally need to add 1-2 additional eq. of Zinc to no longer observe starting material. Then dilute with EtOAc, extract a few times with water, and concentrate acidic aq. layers in vacuo to recover the product and use during the next step without further purification.

In the patent for the next step their yield is 30-40% for the bromo compound, while the same reaction using the des-bromo pyridine results in 80-90% yield, so I'm convinced that in their hands they experience the same dehalogenation, however, I'm baffled about the mechanism. Any pointers or empirical experience would be greatly appreciated.

Thanks!

[wildfyr]

I have no clue, but I'd like to thank you for posing a fascinating question for our chemists here to chew on.

[hypervalent_iodine]

I have seen this before with other metals, maybe zinc as well. I think one paper proposed a radical mechanism? I'll have to check.

A few papers:
https://www.journal.csj.jp/doi/10.1246/bcsj.58.2709
https://onlinelibrary.wiley.com/doi/abs/10.1002/jccs.200800089
https://pubs.acs.org/doi/abs/10.1021/jo00867a004
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267473/

I haven't looked through these, but the second and third mention mechanistic aspects.

[rolnor]

Have you considered other reducing agents?

[OrganicDan96]

try making the O-methyl oxime and reduce with Borane THF.

maybe you get oxidative addition to the zinc?

[pgk]

A possible reaction mechanism can be based on pyridine protonation by the formic acid, which leads to the formation of 4-bromopyridinium and which is transformed to dihydropyridin- 4 [1H] -ylidledenebromonium by conjugation. Bromonium (bromine cation) is now bonded with the 4-carbon via a double bond and thus, the compound is debrominated by a reaction mechanism that is similar to the one of the Clemmensen reduction.

[Uberbane]

Thanks for all of the responses!

@hypervalent_iodine, I came across papers which describe it occurring with zinc as well, but most if not all described it for alkyl halides as opposed to aryl halides, so they didn't seem applicable mechanistically in this case.

@rolnor & @OrganicDan96, unfortunately functional groups to the right of what I've drawn limit what reducing agents I can consider, and for that reason I wouldn't be able to use Borane THF.

@pgk, thanks, that seems like a pretty feasible mechanism.


In order to circumvent the dehalogenation, I'm going to substitute the bromine for desired functional groups from the beginning, and then carry out the same sequence of reactions, which should work fine.

[hypervalent_iodine]

Thanks for all of the responses!

@hypervalent_iodine, I came across papers which describe it occurring with zinc as well, but most if not all described it for alkyl halides as opposed to aryl halides, so they didn't seem applicable mechanistically in this case.

@rolnor & @OrganicDan96, unfortunately functional groups to the right of what I've drawn limit what reducing agents I can consider, and for that reason I wouldn't be able to use Borane THF.

@pgk, thanks, that seems like a pretty feasible mechanism.


In order to circumvent the dehalogenation, I'm going to substitute the bromine for desired functional groups from the beginning, and then carry out the same sequence of reactions, which should work fine.

I think most of the papers I linked were regarding aryl halides.