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We performed the one-pot preparation of bupropion in class where the bromination of the carbon adjacent to the carbonyl group was performed using DCM as solvent, and upon completion the solvent was switched to n-methyl-2-pyrrolidone and was then reacted with an amine. I know that the nucleophilic substitution won't occur in DCM, the reason for which was also explained here on this site, so what alternate solvent could be used that allow for both bromination and substitution to occur without a solvent switch, AND still allow this procedure to still be conducted within a single class session? I asked the professor, but he said that he would have to think about it and get back to me... yeah, I have a feeling I am being blown off.

I believe that water would work for the bromination as long as the mixture is kept acidic, but then that complicates things with the amine as it will need to be in its basic form, unless that doesn't matter because by the time you add the amine, the bromination has already taken place and you would just neutralize first. However, aren't these reactions very slow in aqueous conditions? I know that water lowers nucleophilicity, so would that explain the hindered reaction times?

What about acetonitrile? I know this can be used in bromination, as I have read procedures that claim increased selectivity for monobromination.

In the event that you are not familiar with the preparation I am referring to, I am providing a link to the ACS paper that we used as the basis of the experiment. http://pubs.acs.org/doi/abs/10.1021/ed077p1479

EDIT: There is also a follow up question regarding the usage of more than an equivalent of the amine during the substitution step as an acid scavenger. What is up with that? Why isn't the acid being formed in the substitution step being neutralized with an appropriate base that won't hydrolyze the bromoketone first? This just seem rudimentary to me, but I lack the encompassing understanding at this time. Is there a procedure I could reference as an example of what I just proposed?

Jeffrey Schultz
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As a general comment published procedures have been optimised. I don't have access to the paper you link so I don't know if the procedure is from process chemistry (where you expect a high degree of optimisation) or from med chem (where the priority is to get the compound out fast but there is still some optimisation).

But your questions are still valid. So I agree that doing the bromination - amination in one pot using the same solvent is a reasonable experiment to try and actually acetonitrile is a good choice. Why do you think acetonitrile is nucleophilic? it is not (unless you deprotonate it with a strong base). So it is very possible that the first researcher tried your approach initially and possibly found that the bromination was not very selective or the amination step was too slow, or low yielding and switched to the current procedure.

I also agree that you can use a base instead of excess of amine, for example an amine base like triethylamine or inorganic bases like $\ce{K2CO3}$ are standard in this case and this is what they would have used if they had to do the reaction with a different amine (as the nucleophile) of higher cost.

K_P
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  • You are absolutely right about acetonitrile. I had been cramming my head with strong base deprotonations that night and acetonitrile had been one of the substrates in the literature I had been reading. It somehow transferred to this question! Thank you for your response. I will take a look at this since my exam is over and post a follow up response if I have one after thinking about it. – Jeffrey Schultz May 02 '16 at 21:12
  • Acetonitrile is likely not used for student procedures as this since it is more expensive than DCM. That is my initial response, but since I was looking to increase my knowledge I will look into this from the perspective of acetonitrile. – Jeffrey Schultz May 02 '16 at 21:16