[tomek]

I need to alkylate a secondary amine with chloroacetone. The problem is I'm really low on starting material and making it would cost me some time. Therefore I'm somewhat limited to a number of experiments I can carry out. I have it in a form of hydrochloride. So far any alkylation I have attempted involved freebase but this time I tried it on a hydrochloride (DMF, sodium carbonate, MW radiation, 100°C, 45 min) and it worked (MS confirmed the mass of the product) but after the workup the yield was rather low. So having only scarce amount of SM I want to avoid losses while freebasing it. I would appreciate if you could share any experience you might have on this matter or point me to relevant references.

[TheUnassuming]

I'm assuming you got complete conversion just low yield?  What else did you isolate/side reactions did you see?

Using base to insitu create the free amine shouldn't be an issue.  If anything I would have just started at rt and slowly started applying pressure (temp increase) to avoid any decomposition/side reactions.

[tomek]

I didn't get complete conversion despite extending reaction time three times than originally planned. I did MS after 15 min. and measured number of counts for the substrate and the product (I know it's quite rough but gives idea how reaction is progressing). And then repeated that two more times after 20 min and 10 min respectively. The ratio increased but I didn't want to carry out the reaction for longer - this is after all MW, they say it should be at speed of light . Anyway I'm thinking of using another base (like maybe NaH) do deprotonate the ammonium salt or even the freebase consequently as I feel the sodium carbonate might not be up for the job although people use it quite frequently. When it comes to isolating other stuff I didn't bother much with identifying what else was there. I blew out DMF and chromatographed the residue to get the product which was still contaminated with some colored stuff which drags through a TLC plate and coelutes (I know I should spend more time optimizing the separation but I am also low on time on that one).

[Babcock_Hall]

I am unsure of whether a strong base is a good idea.  The pK_a value of a C-H bond in an α-chloroketone is pretty low, maybe 17-18 or so.

[TheUnassuming]

Using straight MS isn't optimal by any means, can't do TLC? 
Carbonate is plenty strong enough to get your free amine and soak up the HCl formed by the reaction, ~2 equiv should be enough to cover any base needs.  Alkylation of the amine won't really be helped by NaH and will certainly cause problems with your alkylating agent as babcock_hall says.
You could add catalytic NaI to increase the rate though an insitu finkelstein reaction.  I would also add additional alkylating agent (maybe slower addition of aliquots over time), to see if it pushes the reaction to full conversion.
Also consider using something other than DMF.  DMF tends to decompose at elevated temperatures which can cause all sorts of problems/side reactions

[Dan]

So far any alkylation I have attempted involved freebase but this time I tried it on a hydrochloride (DMF, sodium carbonate, MW radiation, 100°C, 45 min) and it worked (MS confirmed the mass of the product) but after the workup the yield was rather low.

Did you previously perform exactly the same reaction with the freebase? If so, did it work?
How many equivalents of base did you add when using the hydrochloride?

When it comes to isolating other stuff I didn't bother much with identifying what else was there.

It's difficult to solve a problem if you don't know what the problem is. If you have not performed this exact reaction successfully with the freebase form, then there is no evidence that the problem is due to the fact you are using the HCl salt. Unless you didn't add enough carbonate, I doubt this is the root of the problem.

You could isolate the freebase by organic extraction from sat. Na₂CO₃ or ion exchange (if the freebase is too water soluble) and test that. However, if your remaining mass balance is very polar streaky material, this may suggest quaternary ammonium salts from amine overalkylation (which will not be avoided by using the freebase). Do you see any of that by MS (you should see it clearly using ESI +ve if it's there)?

I imagine you could try reductive amination of pyruvaldehyde instead of using an alkyl halide (which avoids the classic amine overalkylation side reaction).

[discodermolide]

So you are generating a free amine in the presence of a ketone!
And the product will be a free amine in the presence of a ketone?
These are not compatible functional groups. So I guess this might be where your losses are happening.
What else did the MS show? Also MS is not a quantitative method, in this case.
Try isolation of the product by making the HCl salt

[tomek]

Thanks for the suggestions.

 I used 2eq of sodium carbonate in my first attempt (one to freebase my amine and the other to sponge liberated HCl). I will try to freebase my compound first and then perform alkylation. I am aware of condensation between carbonyl and amine but I'm hoping alkylation in case of chloroacetone will be simply main reaction (I don't want to bother with protection/deprotection).

Would reductive amination of pyrulvaldehyde blew out the ketone as well as it is performed under reductive conditions?

I will try repeating this reaction using freebase of the amine. I'll let you know how it goes.

[BobfromNC]

I would go to potassium or cesium carbonate if you are getting low yields.   Sodium is not as soluble in DMF. 

[tomek]

Did the reaction again using the freebase instead of HCl salt. Ran it in dioxane with TEA at RT for 72h. Got 30% yield this time. I just needed it for spectra characterization but as it turned out the freebase of the product decomposed on air. Darnnnn.