[apilkington]

So I'm coming across some issues in my research and thought I would throw this question out there. Are there any reactions for the addition of chloroacetyl chloride to a pyridine derivative. Specifically for (4-methoxypyridin-3-yl)methyl acetate and/or pyridin-3-ylmethyl acetate. My issue seems to be that the carbo-cation generated during the reaction is going to add to the lone pair of the nitrogen instead of the ring structure. Right now I'm thinking about using a protecting group such as Tosylamide (Ts-NR2) but I'm not finding anyone that has done such a thing. I don't feel the protecting group will be stable under the conditions. Any help on this or if someone could point me in the right direction I would very much appreciate it.

RXN conditions: (4-methoxypyridin-3-yl)methyl acetate in dry DCM, dropwise addition of chloroacetyl chloride @ 20°C  followed by addition of aluminum chloride in several portions. Reflux for 16 hrs then poured into ice water. Extracted with DCM and the typical work-up procedure from there... The idea is that adding a protecting group Ts-NR2 I can keep my reaction conditions virtually the same as they are above here.

[discodermolide]

Have a look at page 23 in the following.
http://faculty.kfupm.edu.sa/CHEM/ajhamdan/CHEM202/CHAPTER%2019.pdf

[orgopete]

Friedel-Crafts acylation is not going to work. Pyridine is like an electron deficient aromatic ring and electron deficient aromatic rings fail in F.C. acylation reactions.

I would rethink your synthesis. It may be easier to introduce your carbomethoxy group.

[apilkington]

I did look at introducing the methoxy group later but that becomes problematic down the line. I think I figured out how to do this and I would like to bounce the thought off you guys. First of all though the nitrogen is very deactivating the methoxy group is activating. In addition to this I can convert the pyridine into a pyridine-N-oxide with treatment of hydrogen peroxide and acetic acid. While the resonance is not as favorable as I want it to be (haven't worked it out for my whole structure just the N-oxide) addition to the C-5 position is possible and the formation is stable. My concern is that in removing the oxide I treat with PCl3, and the lewis acid I'm using for the addition is AlCl3. I don't know a whole lot about phosphorus chem and my inorganic is not as good as it should be. So could you guys tell me if this seems feasible or is the AlCl3 gonna remove my oxide and leave me where I was. If so do you have suggestion for other reagents to use for the addition. 

[discodermolide]

I did look at introducing the methoxy group later but that becomes problematic down the line. I think I figured out how to do this and I would like to bounce the thought off you guys. First of all though the nitrogen is very deactivating the methoxy group is activating. In addition to this I can convert the pyridine into a pyridine-N-oxide with treatment of hydrogen peroxide and acetic acid. While the resonance is not as favorable as I want it to be (haven't worked it out for my whole structure just the N-oxide) addition to the C-5 position is possible and the formation is stable. My concern is that in removing the oxide I treat with PCl3, and the lewis acid I'm using for the addition is AlCl3. I don't know a whole lot about phosphorus chem and my inorganic is not as good as it should be. So could you guys tell me if this seems feasible or is the AlCl3 gonna remove my oxide and leave me where I was. If so do you have suggestion for other reagents to use for the addition. 

The Lewis acid will attack the N-oxide and you will be back where you started, with the pyridine.