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Topic: Tricky Buchwald N-arylation  (Read 6998 times)

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Offline asa029

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Tricky Buchwald N-arylation
« on: May 15, 2012, 03:37:12 AM »
Hello!

I'm trying to do a Buchwald N-arylation on a 4-substituted 1H imidazole. The group recently described a method in JACS (2012) where they used Pd(dba)3 and a modified XPhos-ligand in dry toluene/dioxane with K3PO4 as an additive. I followed their procedure, but only observed the product in very low yields (gc-ms). Does anyone have any idea what is going wrong? And does anyone know exactly HOW sensitive the reaction is to air and water?

Details: Toluene and Dioxane were destilled over Na with benzophenone (until purple). The catalyst and ligand kept in exicator, the phosphate dried in a heating cabinet for days and then kept in exicator. Reactions done under argon. Catalyst loading about 1-2%. I have replicated twice and found the same (low) conversions.

Offline g-bones

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Re: Tricky Buchwald N-arylation
« Reply #1 on: June 26, 2012, 08:31:24 PM »
try more catalyst.  are they this rigorous in terms of drying all of their reagents?

Offline asa029

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Re: Tricky Buchwald N-arylation
« Reply #2 on: June 27, 2012, 06:12:25 AM »
More catalyst was attempted, but did not yield any results.

They did dry all their reagents, as did I.


try more catalyst.  are they this rigorous in terms of drying all of their reagents?

Offline Doc Oc

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Re: Tricky Buchwald N-arylation
« Reply #3 on: June 27, 2012, 08:31:00 AM »
Caveat: I've never done a Buchwald-Hartwig amination.

I've seen so many different papers on this reaction it's mind-boggling.  It seems like every different reaction requires its own reaction conditions, and more importantly, optimization of the ligand used in it.  It may be worth exploring that if you have some others you can use.

Offline djt

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Re: Tricky Buchwald N-arylation
« Reply #4 on: June 27, 2012, 03:56:17 PM »
Hi asa029,

For some reason, I have yet to get to the bottom of, Pd2(dba)3 is one of the most unreliable catalysts when purchased from commercial suppliers. It always seems to work to some extent, but the catalytic activity varies so much from batch to batch.

See the following thread.

http://www.chemicalforums.com/index.php?topic=58910.msg211049#msg211049

I would try a different batch, which may mean purchasing a new sample. If you do this, phone the supplier and find out which batches they have in stock and request one which is different to the one you have now. If they supply the batch numbers you can usually look up the certificate of analysis online. Pick the one which seems the best.

Alternatively, if you have the chemicals and feel capable, try making your own. Let me know if you need me to dig out a reference.

I have some colleagues who won't use commercial sources and will only trust samples they have made themselves. In these cases, we test each batch we make (Pd2(dab)3 and others) against a standard reaction to make sure the batch is good.

In my opinion, these reactions and this catalyst isn't particularly sensitive to air or water and have had just as good results being lazy and weighing the catalyst out on the bench rather than in the glove box.

See if that helps and let us know. We can try narrowing down if your still having problems.

Also, what is your N substrate? Is it an aniline?

Good luck
djt

Offline asa029

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Re: Tricky Buchwald N-arylation
« Reply #5 on: June 28, 2012, 07:52:11 AM »
Hi asa029,

For some reason, I have yet to get to the bottom of, Pd2(dba)3 is one of the most unreliable catalysts when purchased from commercial suppliers. It always seems to work to some extent, but the catalytic activity varies so much from batch to batch.

See the following thread.

http://www.chemicalforums.com/index.php?topic=58910.msg211049#msg211049

I would try a different batch, which may mean purchasing a new sample. If you do this, phone the supplier and find out which batches they have in stock and request one which is different to the one you have now. If they supply the batch numbers you can usually look up the certificate of analysis online. Pick the one which seems the best.

Alternatively, if you have the chemicals and feel capable, try making your own. Let me know if you need me to dig out a reference.

I have some colleagues who won't use commercial sources and will only trust samples they have made themselves. In these cases, we test each batch we make (Pd2(dab)3 and others) against a standard reaction to make sure the batch is good.

In my opinion, these reactions and this catalyst isn't particularly sensitive to air or water and have had just as good results being lazy and weighing the catalyst out on the bench rather than in the glove box.

See if that helps and let us know. We can try narrowing down if your still having problems.

Also, what is your N substrate? Is it an aniline?

Good luck
djt

I was not aware that pd2(dba)3 was so unreliable. I have an old (but unopened sample), so it might just be bad. I usually work with other palladium catalysts that usually give reliable, reproducible results! I might need to make the catalyst myself. It should be pretty straight-forward.

The N-heterocycle is a substituted imidazole.

Offline g-bones

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Re: Tricky Buchwald N-arylation
« Reply #6 on: June 28, 2012, 06:37:07 PM »
Doc Oc is right, it seems like an endless amount of publication comes from the Buchwald group about special cases of C-N couplings.  I think this review might be quite useful to you. Its a step-by-step guide he published for C-N coupling.  Hope it helps :)

Chem. Sci., 2011,2, 27-50

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