Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: GinaTageldin on October 08, 2017, 01:47:20 PM
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Hi
I have Dichloro pyrimidine derivative and want to react it with different arylamines ? i tried the reaction in Dioxane/TEA and it didn't work. any suggestions???
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Mabey reflux in DMF with catalytic NaI?
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could i substitute NaI with KI?
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Yes
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Possibly, yes.
Which dichloropyrimidine are you trying to aminate, which aryl amine, and (if appropriate) which regioisomer? Usually these seem fairly facile in my experience
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Are you hoping to get the monoamine or diamine? Reflux in THF with between 1-2 equivalents of DMAP overnight has always been my go to with these substrates. You may get competing reactions depending on your substitution pattern however, so you might need to play with conditions and the way you perform the addition of A to B. Do you have anything in the 2-position?
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You could try a Buchwald coupling too?
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Possibly, yes.
Which dichloropyrimidine are you trying to aminate, which aryl amine, and (if appropriate) which regioisomer? Usually these seem fairly facile in my experience
4,6-dichloropyrimidin-2-amine,
substituted phenylene diamines
i think 4,6-dichloropyrimidin-2-amine has a plane of symmetry across the amino group so, attack on cl in both position is equivalent!!!!
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Are you hoping to get the monoamine or diamine? Reflux in THF with between 1-2 equivalents of DMAP overnight has always been my go to with these substrates. You may get competing reactions depending on your substitution pattern however, so you might need to play with conditions and the way you perform the addition of A to B. Do you have anything in the 2-position?
4,6-dichloropyrimidin-2-amine
yes position 2 is an amino group, i need only a monoamine
could you specify the condition using DMAP condition?
Thank you
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Yes
Thank you Sir
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You could try a Buchwald coupling too?
Actually, its conditions are not available in my lab.
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Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
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i think 4,6-dichloropyrimidin-2-amine has a plane of symmetry across the amino group so, attack on cl in both position is equivalent!!!!
That it does - hence why I was checking on your precise compound. 2,4-dichloropyrimidine for instance does not have this symmetry.
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Maybe procect the aminopyrimidine with a Boc-group or make the aminogroup into a azido-group via diazotation that after coupling can be reduced easily?
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Making the reaction dilute might also be an solution to avoiding self-reaction.
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Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
I do not see any point with pre-treating the amine with base, the amine does not form anion that could be a better nucleophile, at least not with a weak base like pyridine?
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Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
My problem is no reaction of this pyrimidine with the amine, i tried TEA.
Yesterday, i repeated the reaction in trifluoroacetic acid and dioxane and left it over night (refluxing). Today, dioxane was almost evaporated and a new spot appeared near the baseline of the TLC, actually i don't have any idea about what happened and i was wondering if this spot is my proposed compound or not since both amine and aminodichloropyrimidine always appeared at the middle or nearly top in the TLC.
i didn't have GCMS. it isn't applicable in my lab.
Does using acidic conditions (HCl, TFA) would be more promising than using pyridine. All the reported reactions in the literature used DIPEA. Is it essential??? to protect the other chloro from the reaction. or any basic or acidic media would proceed the rx.
Finally, does the amino group reactive to be reacted with phenyl isocyanates or thiocyanates (addition rx)??? To increase the M.wt of the compound and to aviod self-reaction (protection).
Thank you very much sir, i would learn from you as you worked with this compound before. and if you please could you show me any tricks for this compound (ratios of solvents used in TLC)?
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Maybe procect the aminopyrimidine with a Boc-group or make the aminogroup into a azido-group via diazotation that after coupling can be reduced easily?
It is very good idea. Thank you Sir.
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How did you perform the workup? It could just be salts on the baseline.
The DiPEA is just another base. I've found TEA not to be very effective, personally. I use DMAP or pyridine in my work.
Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
I do not see any point with pre-treating the amine with base, the amine does not form anion that could be a better nucleophile, at least not with a weak base like pyridine?
Sorry, I was half asleep when I wrote it. I didn't mean pre-treat, just to add a solution of the amine plus base to the pyrimidine.
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What I can suggest is to start with dichloro-nitro pyrimidine if its available and run the amination and then reduce to amino group. You will have more activated system for SnAr and you remove the risk of selfcondensation.
See for example
http://pubs.acs.org/doi/abs/10.1021/acscombsci.5b00071
Its different regioisomer and its solid phase chemistry but should work similarly. Problem might be that they are using excess of pyrimidine because it can be washed away while using solid phase chemistry. Im not sure if it can be extracted away into aq. phase. If that method is not working for you, PM me and I will ask them directly, friend of mine is in the group and I think they work more in solution chemistry so they might have procedure published somewhere as well
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What I can suggest is to start with dichloro-nitro pyrimidine if its available and run the amination and then reduce to amino group. You will have more activated system for SnAr and you remove the risk of selfcondensation.
See for example
http://pubs.acs.org/doi/abs/10.1021/acscombsci.5b00071
Its different regioisomer and its solid phase chemistry but should work similarly. Problem might be that they are using excess of pyrimidine because it can be washed away while using solid phase chemistry. Im not sure if it can be extracted away into aq. phase. If that method is not working for you, PM me and I will ask them directly, friend of mine is in the group and I think they work more in solution chemistry so they might have procedure published somewhere as well
Nice idea with the nitro pyrimidine.
I find a lot of the time you can remove the starting pyrimidines pretty easily with trituration or recrystallisation. Their solubility in organic solvents can change a lot once you start building onto them. YMMV.
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How did you perform the workup? It could just be salts on the baseline.
The DiPEA is just another base. I've found TEA not to be very effective, personally. I use DMAP or pyridine in my work.
Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
I do not see any point with pre-treating the amine with base, the amine does not form anion that could be a better nucleophile, at least not with a weak base like pyridine?
Sorry, I was half asleep when I wrote it. I didn't mean pre-treat, just to add a solution of the amine plus base to the pyrimidine.
What is the probably formed salt ?
Procedure
Add both amine and pyrimidine in dioxane and 1 equivalent of TEA and reflux overnight
Or i performed the rx in trifluoro acetic acid/ dioxane overnight refluxed but the spot was at the baseline and not soluble in water
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What I can suggest is to start with dichloro-nitro pyrimidine if its available and run the amination and then reduce to amino group. You will have more activated system for SnAr and you remove the risk of selfcondensation.
See for example
http://pubs.acs.org/doi/abs/10.1021/acscombsci.5b00071
Its different regioisomer and its solid phase chemistry but should work similarly. Problem might be that they are using excess of pyrimidine because it can be washed away while using solid phase chemistry. Im not sure if it can be extracted away into aq. phase. If that method is not working for you, PM me and I will ask them directly, friend of mine is in the group and I think they work more in solution chemistry so they might have procedure published somewhere as well
Thank you Sir
But both starting material and the method aren't applicable in my lab. I suggest to reflux 2-amino-4,6-dichloropyrimidine in NaOH, after substitution of one of the Cl atom to OH. 2-amino-4-hyroxy-6-chloropyrimidine wouldn't have symmetry, or probably formed regioisomer after rx with amines, also i would protect the amino group from self-condensation by a simple addition rx with isothiocyanates 1st then rx sNAr of amines on Cl, after this rx in POCl3 to substitute OH at 4-position?? Is it applicable or not and the addition rx on amino group would be easy or need specific condition????
Thanks again
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I dont understand what do you mean. You can easily try it with you the nitropyrimidine of the correct substitution. It could work easily in solution, but you might run a collumn or something after that. I dont realy think that converting one of the chlorines into OH and then back is good way to go.
I could see the problem with commercial availability.
btw you dont have to call me sir, Im not that old and Im even less accomplished. Just call me by my forum name :)
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I dont understand what do you mean. You can easily try it with you the nitropyrimidine of the correct substitution. It could work easily in solution, but you might run a collumn or something after that. I dont realy think that converting one of the chlorines into OH and then back is good way to go.
I could see the problem with commercial availability.
btw you dont have to call me sir, Im not that old and Im even less accomplished. Just call me by my forum name :)
Yes, there is a problem with chemicals and time consumed to import it to my country and even with column chromatography.
OK Kriggy :) :) :)
Thanks again
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I think that if you get one chlorine substituted by amine, the reactivity of the pyrimidine will decrease a lot, the amine being strongly electron-donating. I dont understand why you use acidic conditions, this will turn the amine to a amine-salt, a very weak nucleophile?
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How did you perform the workup? It could just be salts on the baseline.
The DiPEA is just another base. I've found TEA not to be very effective, personally. I use DMAP or pyridine in my work.
Ah. I have worked with that compound before. It's a bit of an oddity out of the 2-amino pyrimidines I've dealt with to be honest. I always had way more issues with it. Your biggest problem is going to be reaction of the pyrimidine with itself and generally over amination. Not going to be an easy thing to do I'm afraid.
Order of addition, temp, base strength and reaction time will be absolutely crucial. Pre-treat your amine (not the pyrimidine) with base (1 eq exactly) - I would use pyridine. Then add it in slowly to a solution of your pyrimidine in THF at room temp. You might struggle with TLC'ing it to monitor progress, so I would use GCMS if you can. You only need a short run (I'd use something that goes up to 230oC with a max run time of 12 minutes). I wouldn't let the reaction go longer than 2 hours to start with.
I do not see any point with pre-treating the amine with base, the amine does not form anion that could be a better nucleophile, at least not with a weak base like pyridine?
Sorry, I was half asleep when I wrote it. I didn't mean pre-treat, just to add a solution of the amine plus base to the pyrimidine.
How you use DMAP in your work???