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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Where Drugs Come From: The Numbers | Main | Peer Review's Problems »

November 4, 2010

Finally, An Alternative to Palladium. About Time.

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Posted by Derek

A reader sent this paper along the other day. Is it just me, or does it seem a bit odd to talk about how aryl coupling in these systems is traditionally done by (list of metal-catalyzed reactions), which unfortunately involve (list of toxic and/or expensive metals) under (list of rigorous conditions involving oxygen exclusion and protecting groups). . .and then propose as a shiny new alternative: three equivalents of aluminum chloride?

Not that there's anything particularly wrong with aluminum chloride. The workup is much nastier than with the metal-catalyzed couplings, though, and I'd think that the waste stream is also more hefty. And I'm willing to bet that a lot more structures can survive Suzuki coupling conditions than can survive scoops of aluminum chloride, too. But it certainly is a lot cheaper and simpler to set up.

Still, isn't this just more or less the aryl-Friedel-Crafts (Scholl) reaction? And haven't very similar couplings been reported before, many times? This new paper cites a few of these (but not that last one). Maybe it's just the whole "Now we can finally get rid of all that palladium" tone. . .

Comments (20) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. HK on November 4, 2010 10:18 PM writes...

You'd know best, does industry hate using Pd? I guess if we find a cheaper metal that does everything Pd does, that would be splendid, but what's the likelihood of that happening?

Make me eat my words, world!

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2. barry on November 5, 2010 8:22 AM writes...

Industry--at the Research stage--uses whatever works. Industry--on the Development side--are somewhat restricted. I've seen more trouble getting rid of Boron than of Palladium (see Sandoz's adventures in the HMGCoA reductase game for the best account).
In Research, Palladium is a real daily work-horse. On the Development/Manufacturing side it seems to get used in early steps (where there'll be multiple opportunities to purify it out) but rarely in a final step.

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3. Iridium on November 5, 2010 8:27 AM writes...

There have also been a lot of papers submitted/published recently in which the authors are simply 're-discovering' chemistry published >50-60 years ago simply because they didn't search the literature. My post-doc advisor would routinely get papers he would reject after a first read because: a) the authors were basically re-publishing something that was discovered a few decades earlier, didn't cite the original work, nor contributed anything new; or, b) incorrectly classified a new type of chemistry which in reality occurred through a mechanism other than that reported (they didn't have any evidence to support their mechanism or refute the previously published work) and had, again, been discovered many years earlier. With the existence of Sci-Finder and Bielstein one would think it is easier to search for prior art in your research area and not re-publish chemsitry originally reported in 1902 or publish pseudo-useless variants thereof. Granted, Sci-Finder seat and journal prices are starting to become a bit rediculous, but there really isn't an acceptable reason why papers like this should be popping up in the 'top teir' journals. Yes, aluminium chloride is a cheaper/easier alternative to the transition metal variants, but you don't gain that much in the end by using it simply because of all the time you'll spend trying to free your product from the aluminum.

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4. Will on November 5, 2010 8:50 AM writes...

not impressed - simply a FC acylation, that chloro purine is a well established electrophile...wake me up when they can do that "coupling" on a substrate that doesn't have a leaving group on it

something like this would be probably be more useful in bulk chemical preparation, rather than any kind of drug or fine chemical preparation. whether there is any demand for 1000's of kgs of aryl purines is another matter

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5. opsomath on November 5, 2010 8:59 AM writes...

"Orientating" is not a word.

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6. Brian on November 5, 2010 9:06 AM writes...

@1 The industry does not hate Pd, process chemists are using all the time. The problem with palladium is that if you put it into your synthesis, you have to be able to reduce the amount of palladium in your product before it gets to patients, in the pharma industry (typically

Derek, talking about alternatives to Pd, did you see the paper on TEMPO-assisted Sonogashira Type couplings on Aryl and Alkynyl Grignards ?

You can find it on my blog as the last entry.

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7. tuky tuky on November 5, 2010 9:18 AM writes...

Check out Baran´s recent work based on the Minisci´s radical process, using silver nitrate:

Direct C−H Arylation of Electron-Deficient Heterocycles with Arylboronic Acids
DOI: 10.1021/ja1066459

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8. jd on November 5, 2010 9:36 AM writes...

In the past I've used AlCl3 for promoting C-N bond formation with heteroaryl chlorides in a reaction that would be analogous to Buchwald-Hartwig coupling. I don't have access to my notebooks anymore, but I remember that it was important to have a certain ratio between DCE and a cosolvent (either methanol or DMF I can't remember, although DMF makes sense if it was perhaps a vilsmeir reagent played some role in the reaction) in order for the reaction to work at its best. Don't ask me for the mechanism. :-)

Anyhow, the workup was worse than Pd coupling, but the reaction was more reliable, and often the products cleaner. Our group came up with this approach after a long futile search for the right ligand to use for a particular desired coupling so I'd say this type of chemistry has utility in medchem.

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9. Reopen on November 5, 2010 10:14 AM writes...

These days doing a Friedel Crafts reaction can even land you a paper in Science followed by one in Angew. Chem.!

Just ask Matt Gaunt - the great white hope of Cambridge.

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10. HK on November 5, 2010 11:12 AM writes...

@Brian - what about for cost purposes? Does process avoid using Pd on account of it necessitating thorough purification or to cut costs? Which one's more important?

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11. Brian on November 5, 2010 12:02 PM writes...

@10 If there was some way to avoid using Pd, I think chemists would. As far as I know, there isn't a better solution. Palladium chemistry will always be used unless there are better alternatives. I don't think I said process chemists avoid using palladium, palladium is used in many processes. Because there is toxicity associated with residual palladium, the process chemist must be aware of its presence and work on trying to reduce it. The steps that one takes to reduce the palladium add to the time of research taken, the time of delivery of the complete process and the cost of the final drug product. I have been talking in terms of pharmaceuticals. If you wanted to talk about other industries, as long as it isn't consumed, you might be fine.

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12. Ron on November 5, 2010 3:34 PM writes...

Do process chemists recover spent Pd catalysts in large scale syntheses?

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13. milkshake on November 5, 2010 3:57 PM writes...

palladium is actually a lot less toxic than nickel salts. But it is classified as heavy metal and detetectable down to ppb levels.

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14. Brian on November 5, 2010 3:58 PM writes...

@12 Ron, they recover spent Pd catalysts whenever. Often, the process chemist is the last step before a reaction gets scaled for manufacturing. If the palladium level is above 5 ppm in the final drug product, it has to be reworked. I have been on the receiving side of raw drug product as well, if it fails for having too much Pd or other heavy metals, it won't be used in manufacture. No pharmaceutical chemist wants to see the hard work they have done not be used in the drug product. The levels of Pd can be less on manufacturing scale than in the lab, but it is always a concern.

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15. Brian on November 5, 2010 4:49 PM writes...

@14 Brian: I understand that pharmaceutical chemists want to remove trace Pd residues from the product - that's not what I was asking. What I meant to ask was whether the Pd catalysts that are used are typically recovered and recycled in large-scale syntheses (since Pd used on a large scale can become costly very quickly)

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16. Brian on November 5, 2010 5:26 PM writes...

@15 Sorry about that, for a second, I thought my eyes were playing tricks on me. You used to be Ron, right ? Yes. Johnson Matthey offers that service to recover trace Pd residues from waste streams. As far as I know, the pharma company itself doesn't do that. Of course, the palladium costs lots of money and there is some desire to recover the spent palladium.

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17. processchemist on November 6, 2010 3:06 AM writes...

@14 & 16

In manufacturing for homogeneous catalysts there's no recycle. For palladium complexes there are no usual "rent-like" contracts from catalyst suppliers: you buy the catalyst, you give back the waste (liquid and solid)for metal recovery - and this is the reason why some groups work on suzuki like couplings catalyzed by supported catalysts (mostly Pd/C). By the way, there's a conflict of interest between catalyst manufacturers and users: while the interest of users is for eterogeneous catalysts with high activity/high turnover, the interest of suppliers is to sell as much precious metal is possible with the higher added value (some math about prices of palladium complexes and price of palladium metal can show how much is charged by suppliers/manufacturers).

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18. Sili on November 6, 2010 12:19 PM writes...

"What has been will be again,
what has been done will be done again;
there is nothing new under the sun."

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19. QED, OED on November 10, 2010 8:44 AM writes...

@opsomath #5

"Orientating" is a word, at least in the English I speak.
http://dictionary.cambridge.org/dictionary/british/orientate_1#orientate_1__3

It may not be a word in the American you speak, however. Bad luck old chap, what?

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20. Saad on March 11, 2012 1:25 AM writes...

Can palladium catalyst be recovered in electrolytic plating of plastics, where it is used for surface activation of non-conductive ABS polymer.. Really need sum expert opinion.. Or if there is sum alternate to palladium chloride for this purpose???

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