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Author Topic: Minimize pyrazine during sn2 of primary amine?  (Read 2704 times)

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goeatpaiste

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Minimize pyrazine during sn2 of primary amine?
« on: January 10, 2011, 07:41:40 AM »

During the addition of primary amine to alpha-brominated keto-alkane the yield is very poor due to cyclization (Gabriel type). I would like to avoid this without using a protecting group on the carbonyl if possible. I have increased the amount of solvent (DCM) todecrease interaction of the aminated product but there must be a better way that does not generate so much waste. I perform the reaction at around 15-18c with minimal stirring and the brominated substrate is added dropwise at around 1 drop per second into a mixture o DCM, triethylamine and methylamine hydrochloride with a 1.2:1 molar ratio of amine:substrate to increase sn2 character.

Yields so far of the alpha aminated product are under 10% with lots of color remaining in the nonpolar solvent during extraction into pH 1.5 distiller water. This suggests to me that the nonpolar pyrazine remain while small amounts of amine go over as a salt into the DI water.

I also now perform the reaction with minimal light. I hope this helps the yield. Any other ideas?

Thanks in advance
Stephen shaw
Advanced AgroChem
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goeatpaiste

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Re: Minimize pyrazine during sn2 of primary amine?
« Reply #1 on: January 10, 2011, 11:35:52 AM »

Hmm the methylamine with addition of triethylamine stays suspended in solution and perhaps does not react therefore minimizing product formation. I am going to try getting the methylamine into 5M sodium hydroxide and doing the reaction stoppered instead of at atmospheric pressure. This will prohibit the escape of methylamine gas. I hope this is the key...
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Doc Oc

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Re: Minimize pyrazine during sn2 of primary amine?
« Reply #2 on: January 10, 2011, 12:37:25 PM »

I haven't performed the specific reaction you're attempting, but I do know that in reductive aminations the amination is fairly rapid.  Carbonyls are excellent electrophiles, I don't think there's any way to avoid carbonyl protection for the reaction you want.  Is there any reason (aside from adding steps to your reaction) that you're trying to avoid carbonyl protection?
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goeatpaiste

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Re: Minimize pyrazine during sn2 of primary amine?
« Reply #3 on: January 10, 2011, 10:39:42 PM »

No there really isn't much reason to avoid protection othe than to keep cost and time of reaction low. I performed the reaction in a 1L roundbottom today with a rubber stopper as a safeguard in case of excess pressure and the addition of the brominated substrate/Dichloromethane went very well. I did notice that the dichloromethane in which the nucleophile (methylammonium hcl) was stirred there was a cloudiness which I am taking means the amine stayed in solution When converted to gas using 5M NaOH. I hope this is a good sign. Until I can get on an NMR or use of an IR there is no way I could tell if I am getting nonpolar pyrazines which stay in the DCM or unreacted substrate due to escape of methylammonium gas. I did realize that the lachrymatory characteristic of the brominated substrate continued through post processing, and given this is the limiting reagent, I am now quite certain it is escaother the gas. I have heard that pyrazines do play a large role in these types of reactions and still expect yield to be under 50% without using a large excess of solvent. I am considering a way to possibly evacuate the reaction flask with argon as I have heard the Gabriel type pyrazine synthesis rely in atmospheric oxygen. Another alternative is protection of the carbonyl. Well see tomorrow what kind of yield I get after the workup.

Thanks
Steve   
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ckellz

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Re: Minimize pyrazine during sn2 of primary amine?
« Reply #4 on: January 14, 2011, 02:48:28 PM »

Yeah i think you are onto something with the inert atmosphere. Kinda like the dihydropyridine synthesis you need an oxidant to get it to have full aromaticity. I also have a couple of suggestions: First, can you try running the reaction at a much cooler temperature. While this may hurt you in terms of solubility I think it will have the beneficial effect of slowing down imidation of the carbonyl. I think that the reaction with the bromide is substantially faster. Second, have you tried other bases besides TEA? Another possiblity is that the TEA isnt doing as good of a job picking up the the HBr. Could you possibly use an inorganic base like Na2CO3 where the excess acid would just end up giving off CO2. This would prevent activation of the carbonyl by H+. Just my thoughts...let me know how it goes!
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