[SKX]

Hey guys!

As Part of my master thesis I am supposed to synthesize several Pyridin-(Pincol-) Boronic-acid-esters. The synthesis of them was quite straightforward, but some time ago I ran into a few Problems and I thought I might be able to crowd-source this problem, with the hope that someone, who has experience on the topic will read my post.

My compounds are almost all oils, so recrystallization does not seem to be an option. I tried to distill my compounds, but they seem to be too heavy, or the vacuum too bad, or the Kugelrohr-apparatus not sufficiently airtight. Depending on your point of view. But still, distillation is still my best bet, if I can get the pressure down sufficiently. The Compounds are quite pure (>90%) but for coming coupling experiments they are supposed to be as pure as possible.

Up to a few days ago I thought that a flash column is out of the question, since with standard-eluent-mixtures I was not able to produce proper, TLCs that do not smear all the way. Then I found a Paper[1] I which they try to saturate the silica with Boric acid to improve the separation. According to the authors this does not necessarily work for Pyridin-Boronic acids. Of course I tried it anyways, and was disappointed. Does anyone know solvent systems where chromatography might still be possible? I thought about reverse phase, but that is probably too expensive.

Is anybody experienced on the topic and would like to share that knowledge? I find it odd, that the whole world is Suzuki-coupling, but there apparently are no standard purification Methods, when distillation and recrystallization are not an option. Or am I just not finding them?
Well, thank you for reading this post, I would be really happy for any kind of answer.
Best regards

Skx

PS.: It might be possible to purify small amounts via Prep-HPLC, but I am to produce >1g, so this might be difficult (yet not completely impossible).

[1] Chem. Lett. 2012, 41, 972-973.

[Dan]

Note that in the paper you cited they show that a pyridineboronic ester does not respond favourably to boric acid doping.

This sounds like quite a tricky problem. The boric acid doping is probably incompatible with the basic pyridyl group. I guess the problem here is that streaking can be induced by both basic or acidic groups. Usually doping with a base (commonly triethylamine) reduces base-induced streaking, and doping with an acid (like boric acid) reduces acid-induced streaking. However, your compounds contain both a basic N and a Lewis acidic B.

If you are going to go down the chromatography route, you could fiddle with eluents. What have you tried? Even seemingly minor changes, like using hexane/acetone instead of hexane/EtOAc can vastly improve bad TLC profiles. I suspect that in many cases this is to do with problems with product crystallinity (which is not your issue), but experimentation in this respect can give very nice results - just yesterday I found the fairly exotic combination of toluene/acetonitrile to completely clean up nasty trailing (seen with hexane/EtOAc) of an organometallic Rh complex on silica gel.

I normally try the following solvent combinations:

Weak solvents: hexane, toluene, chloroform, DCM
Strong solvents: chloroform, DCM, Ether, ethyl acetate, acetone, acetonitrile*, IPA, methanol*

*immiscible with hexane

Another possibility I might be tempted to check in this case is pyridine doping. Triethylamine is probably too basic a dopant for compatibility with the boronic ester, whereas pyridine might mediate any streaking attributable to the pyridyl motif in your product. The problem here is that (if it works) you really don't want to be performing column chromatography with pyridine if you can avoid it, especially on large scale.

Do you know what your impurities are? Perhaps they can be selectively degraded and removed.

[Babcock_Hall]

I did a search here with my search term as "boronate ester."  I found some threads that might or might not be useful.  Here is one:  http://www.chemicalforums.com/index.php?topic=57646.msg207493#msg207493

[opsomath]

Are they really oils, or are they just impure? I made two aromatic pinacol boronate esters in grad school and they were pretty white crystals.

[MOTOBALL]

See     http://sussexdrugdiscovery.wordpress.com/tag/pinacol-boronate-ester/

for a discussion about a paper by Wang, where Py-Bpin synthesis is described and purified by recrystallization (you will have to check original Wang paper to find solvents).

The instability of these aromatic amine type compds. to silica gel chromatography is noted.

I think that distillation is still the way to go; your dept. must have good rotary pumps to enable a sufficiently low vacuum; suggest you might try to distil a small sample onto a cold finger to obtain seed crystals.