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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: Twitter: Dereklowe

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June 19, 2012

A New Reaction Discovery Platform

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Posted by Derek

Those of you who are fans of high-throughput reaction discovery have another paper to check out - and those who aren't have another reason to grit your teeth. (Previous examples here, here, and here). The authors, a collaboration between the Bellomo lab at Penn and the Merck process group at Rahway, have gotten the reaction screen size down to 20 microliters with 1 mg of compound, which allows you to go through 96-well plates pretty rapidly.

Their test bed was a pyrimidone synthesis reaction. They screened 475 reaction conditions (95 different additives/catalysts in 5 different solvents). Each of them got one hour at 60 C to show what it could do, and the entire analysis was completed in one day. A phenantholine/copper bromide catalyst in dioxane showed the best results from that run, so it was taken to a separate series of experiments, to see how low the loading could go, what similar solvents might work out, how low they could push the reaction temperature, and so on. As it turned out, 2-methyl THF at RT overnight with 5% catalyst gave an 84% yield, which already represented a significant improvement over the known conditions (which used no catalyst at 140 C).

Moving to different substrates, they found that these conditions gave product each time, but in varying yields. A further catalyst screen, with 112 phosphine ligands, gave another set of conditions that could also be applied to the diverse substrates. A re-screen of solvents together with the best phosphine gave (along with the initial optimization conditions) high-yielding reactions for each of the new substrates. There was no set of one-size-fits-all conditions, though, which certainly fits with organic synthesis as I know it.

With these in hand, they did some work on the mechanism. It appears that the copper is participating in a single-electron transfer reaction, but further details aren't clear. It's not the sort of thing that you would have been able to think your way to on a blackboard, which (to me) is the whole point of doing chemistry this way. As the authors put it:

We envision that similar, generally useful platform tools will soon become more widely available, thus dramatically impacting chemistry development and enabling increased access to chemical diversity and lower-cost synthesis. Most importantly, we believe that such platforms will lead to the discovery of new and potentially useful chemical reactivity and reaction mechanisms.

Exactly. We should be finding easier ways to make compounds, and new ways to make compounds we've never been able to prepare. I think that searching for them in this way is an efficient way to do that, and will also open up new areas of research as we stumble across things we never realized were even there. If there's a downside here, I'm not seeing it.

Comments (17) + TrackBacks (0) | Category: Chemical News


1. NorthwesternChemist on June 19, 2012 10:12 AM writes...

I've heard of 2-methylTHF being used before in process chemistry, is it quite common? Here in academia I've never run into it.

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2. Morten G on June 19, 2012 10:40 AM writes...

Some nice, simple, non-biological catalysts that would mimic the hacking and slashing in a human liver might be useful.

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3. cynical1 on June 19, 2012 11:09 AM writes...

Yeah, everyone has 95 additives/catalysts and then 112 phosphine ligands laying around. I think you're ignoring the significant financial investment in chemicals to run this type of study. Not everyone works at Merck and has access to their sort of chemical inventory. That, for me, is the downside.

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4. David Formerly Known as a Chemist on June 19, 2012 11:31 AM writes...

This isn't new. In fact the entire concept of this "combinatorial" (ach! that word!) approach was patented back in the 1990s. See US patents 6,044,212 and 6,175,816. I believe that Symyx tried to commercialize hardware and services based on automated reaction optimization methodology back in the same time period, if my brain recalls correctly.

The owners of those patents should go and sue the pants off Merck for infringement!

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5. Isomurmur on June 19, 2012 11:32 AM writes...


its common

in academia we rarely use isopropyl acetate or MTBE either. great solvents though.

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6. fng on June 19, 2012 11:52 AM writes...

what is the ref. for this paper?

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7. Legacy Merck Guy on June 19, 2012 11:54 AM writes...

I work in Rahway and our catalysis group is awesome. This is a larger scale of what they have been doing for us for years for all sorts of metal mediated reactions. They have kits that can test various caralysts/ligands/bases whatever to screen many combinations in a very short amount of time. It has been extremely useful because as Derek points out, there is no one-size-fits-all and they have developed a great way to find the right size for what you need considering the number of permutations there can be. We all know that Scifinder/Reaxys can give you a good lead, but many times, it doesn't work that well for your particular substrate and this is a great way to quickly ascertain a good way (or even a way at all in some cases I've had). However, cynical is quite right, unless you work here it can be difficult to access the ligands, etc. because some aren't commercial and have been made in-house. It is still a useful approach that has given my personally some great results if you have the resources.

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8. processchemist on June 19, 2012 12:28 PM writes...


Yes, 2-meTHF is a great substitution for THF in process chemistry (and I use it routinely in the lab too). It's an asymmetrical ether, and you must be aware of it when using lithium alkyls or grignard reagents.

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9. anon the II on June 19, 2012 12:43 PM writes...

I've never used 2-meTHF in the lab. I'd think that it might not be such a good solvent for a lab where solvents can be set in the back of a storage cabinet and forgotten. Wouldn't it be a greater peroxide risk, like di-isopropyl ether? I suspect it would be less of a problem in a process lab where people routinely worry about things going boom.

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10. Troggy on June 19, 2012 12:53 PM writes...

2-meTHF smells nicer too! (kinda minty)

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11. processchemist on June 19, 2012 12:58 PM writes...


Honestly I never experienced problems with diisopropyl ether (properly managed). I can't say the same for diethyl ether (used in many labs without much worries).

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12. antiaromatic on June 19, 2012 9:49 PM writes...

Well, there is one thing that is certainly a downside for this type of reaction development. It assumes that you know what you are looking for, but if you don't, and you are just looking to develop new types of reactivity, you have a new bottleneck, and that's analysis of the reaction products. We're still not at a stage where automated structural assignment is routine. Maybe this is a good reason to push the automated structural assignment field, although with 1 mg screens, unless the reaction is pretty clean, it would be non-trivial to get full characterization for assignments.

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13. RB Woodweird on June 20, 2012 8:39 AM writes...

So you are saying that I could have gotten my doctoral work done in seven days instead of seven years?

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14. 2MeTHFan on June 20, 2012 1:08 PM writes...

2-MeTHF offers many advantages. For one, it is much less miscible with water which means you can work-up the reaction directly in the reaction solvent regardless of pH. Also, amine-HCl salts which otherwise remain in aqueous layers with EtOAc can sometimes be extracted in the 2-MeTHF layer.

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15. Anonymous on June 20, 2012 6:06 PM writes...

The Automation/Catalysis group system is great, but yes, your organization must have the vast infrastructure to do this sort of thing. Unfortunately, too many chemists get a "hit' from the excellent screening in this group, but then walk away as if the reaction is a done deal. These "hits" should be treated as leads for further mechanistic insight work and development, not the end of the problem.

Alas, too often chemists just don't have the time or energy to do the mechanistic work any more. People (FTEs) are shuffled from project to project, with time constraints. No ownership = no lasting interest. "I used what the Auto/Cat group got in the screen, and I won't be on the project for much longer, so why bother understanding it?"

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16. Iridium on June 21, 2012 1:34 AM writes...

"High-Throughput Screening"
"Rapid Catalyst Identification"
That are rational and correct titles......BORING!

they should have called it something like:

Miraculous Incredibly Clever Discovery.... MICD!

They would have published in Nature rather than Angewandte.

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17. CombiKing on June 21, 2012 1:32 PM writes...

...David Formerly Known as a Chemist...

Too bad those patents are now too old and the freedom to operate is upon us. We all can benefit from the approach/tool.
No making lawyers fat and happy over this one.

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