[Babcock_Hall]

We are interested in making alpha-pyridinium ketones as possible enzyme inhibitors.  We recently set up a reaction between 2-chloro-3',4'-dihydroxyacetophenone (commercially available) with pyridine.  The reaction seems to be proceeding slowly at room temperature (there is a small amount of KI as a catalyst if I recall correctly); therefore, we let it run 10 days before filtering it.  More recently we set up an exchange reaction between 2-chloro-3',4'-dihydroxyacetophenone and NaI in acetone.  The reaction quickly turned brown.  After three days we see two spots with similar Rf values by TLC.

We hope to react pyridine derivatives bearing one or two carboxylic acid groups with various halomethylketones, including aryl halomethylketones.  The only synthesis we found in the literature with the chloromethylketone above and nicotinic acid had a temperature of 160 and a reported yield of less than 10%; ordinarily I try to follow the literature, but I think that maybe we should come up with a better synthesis than that one.  I think that the chloromethylketone above may be too unreactive for some or all of our intended pyridine derivatives.  In doing a brief survey of the synthesis of various alpha-pyridinium ketones, it seems that many are made from bromoketones.  BTW, some alpha-pyridinium ketones are made as precursors in the Krohnke pyridine synthesis.  However, the Krohnke synthesis uses simple pyridine, and we hope to use nicotinic acid and related compounds.

My first question is whether we should attempt to convert 2-chloro-3',4'-dihydroxyacetophenone (or other chloromethylketones we may purchase in the future) into an iodomethylketone or a bromomethyl ketone.  I am a little bit worried that iodomethylketones will decompose, but I don’t have much related experience.  I am aware of at least one protocol for chlorine-to-bromine exchanges (it uses bromoethane and two other reagents) but I have never done one; therefore, my second question is whether or not anyone has a favorite protocol.

I am happy to provide references for any syntheses we found and our rationale for choosing our targets.

[Babcock_Hall]

Based upon a preliminary examination of the H-1 spectrum, the reaction between our chloromethylketone and pyridine looks to have been successful.

[wildfyr]

It can get messy, but you can force these quaternization reactions with AgNO3. The silver halide will precipitate out, driving the reaction forward. NO3 is too terrible a nucleophile to kick the pyridine off the alpha carbon, but the chloride can do the reverse reaction if its hanging around.

One other note, are you sure you dont want to do a silyl ether protection on the phenols? Anything with that catechol configuration of a diphenol is begging for all sorts of side reactions and coordination chemistry. Im certain it will coordinate silver if you try my trick.