Tuesday, February 2, 2016

An Adventure into Nickel Cross Coupling Chemistry!


Here’s a behind the scenes look at one of our newest papers in JACS that highlights some nickel chemistry that we have developed!  Phil has been interested for quite awhile now in transition metal cross-coupling methodology.  A few ideas with various metals have bounced around the group, but unfortunately nothing managed to stick.  Fortunately, Pep (commonly referred to as Dr. Pep around the lab) had a lot of previous experience working with transition metals, and within a few weeks of insanely hard work he got the first hit on a reaction that provided the basis for the new paper. Inspired by our lab’s previous work with Barton esters, Pep thought that maybe he could irradiate the Barton ester and trap the resulting alkyl radical – before it recombines with the thiopyridyl radical – with a preformed Ni-Ar complex, which could then reductively eliminate to give a new sp2-sp3 C-C bond.  The reaction not only worked but also gave a decent yield (~50%)!!! 



I was actually in Phil’s office that same day, talking about some other ideas for projects, when he looked at me and said, “There has been a breakthrough.” At this point I was lucky enough to join Pep on the project. I had some experience working with organozinc reagents and quickly realized that arylzinc coupling partners could react without destroying the starting material, so we began our optimization. I want to give a shout out to Paul Knochel and his group; we prepared our organozinc reagents using methods they’ve published that are user-friendly and easy to follow. At first we continued to irradiate the reactions during the early stages of optimization, but it didn’t take too long to realize that the reactions took place with essentially the same yield in the complete absence of light!

While we were getting serviceable yields of product using the Barton esters, they were somewhat impractical (even though we didn’t need light). They required quite a bit of care when preparing them (all flasks, separatory funnels, columns, column fractions, etc had to be shielded from light), and even with careful storage we found they would decompose, so felt like we were beating our heads against the wall trying to optimize the reaction. Because of the problems associated with the Barton esters, we switched other types of activating groups for the carboxylic acid; in particular, we looked at N-hydroxyphthalimide (NHPI) esters and found that they also worked! After a decent amount of the usual optimization screens (solvents, ligands, nickel sources, etc), we found that these NHPI-esters worked pretty well (92% with NiCl2•glyme and 93% with NiCl2•6H2O).  We also found that for some substrates, swapping out the NHPI ester for the more electron-withdrawn 4,5,6,7-tetrachloro-N-hydroxyphthalimide ester improved the yield; notably, the ortho-substituted anisole substrate 9 failed to give anything more than 10% yield of the desired product, whereas simply switching to the tetrachloro analogue provided a serviceable yield without any other change to the reaction conditions! 


While it’s nice being able to isolate these esters and just weigh them out and dump them into the reaction flask, a one-pot procedure to do both acid activation as well as the cross-coupling reaction could be useful for someone who wants the product as quickly as possible (time is money, right?).  We found that activated esters employed in peptide coupling such as HOAt and HOBt esters could be made in situ from HATU/HBTU and your favorite amine base like triethylamine, and then the cross-coupling could be run in the same reaction flask.  In some cases, such as the coupling of the 3-pyridyl zinc reagent, making the ester by this method actually gave a higher yield than either the NHPI or 4Cl-NHPI esters for substrate 31.

We found that this reaction scaled pretty well up to one gram and probably even larger scales if desired, and thanks to our collaborators Mike Schmidt and Martin Eastgate from Bristol-Myers Squibb, it seems that employing these esters on process scale is safe and viable. Pep and I also want to thank Tian, Shuhei, Jie, and Eddie for jumping on board and helping us to finish up the substrate table in about 2 days and Ryan for lending his expertise on Barton esters. It was great working with all of these guys!


One nice thing about this reaction is that it’s easy to run; it doesn’t require rigorous drying of glassware, and once you have a solution of your arylzinc reagent (many of which are commercially available or can be prepared in a straightforward manner (even one of our first-years managed to do it right on his first attempt J)), the reaction is just dump and stir at room temp overnight!  No fancy equipment is required, and you get to see some pretty cool colors!  Even though I’ve run this reaction probably close to 1000 times, seeing the color change from green/blue to orange is always exciting.  Just as a note, we recommend that you run this reaction with inhibitor-free THF, as we found using THF with BHT dramatically decreased the yield.

We are very excited about extending this work to new reactions: sp3-sp3 C-C bond formation, alternative transition metal catalysis, construction of quaternary centers, enantioselective reactions, and applications in total synthesis only represent a small portion of the myriad of directions we plan to take this chemistry.

If you’re curious about what it’s actually like to run this reaction and want to try it for yourself, we’ve included a step-by-step pictorial guide in the Supporting Information section that details the entire process of the reaction.  We’ve tried to be as specific as possible, but if you have any questions, please feel free to email me (jedwards@scripps.edu) or Pep (cornella@scripps.edu)!

Thanks for reading!





Thanks for being supportive all these days at the back of the fumehood!

30 comments:

  1. The substrate table and manuscript only discusses use of, and generation of, secondary alkyl radicals in this coupling reaction. Can you comment on the use of either primary or tertiary radicals as intermediates? Did you see any radical rearrangement happening, such as in example 21 from Table 1 (the indane)? Thank you!

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    1. Hey LL Cool Chris,

      Thanks for the comment! For this initial publication we were most interested in optimizing around secondary carboxylic acids. We hope to optimize for both primary and tertiary carboxylic acids in the (near) future; we have obtained the desired product in these reactions but the conditions are far from optimized. Tertiary in particular will likely be a big challenge because these substrates are typically difficult in cross coupling chemistry.

      As far as radical rearrangement happening, we didn't observe this other than the cyclopropane ring-opening experiment (substrate 35 in Fig. 3 of the manuscript).

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    2. it would be lovely if you could do this aryl decarboxylative coupling on some inexpensive derivate of aspartic or glutamic acid, on the sidechain free carboxyl, to get to phenylalanine/homophenylalanine analogs while keeping the original sterocenter intact

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    3. Someone has to try this once we get some free time. That would be a nice list of substrates in a table.

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    4. I think Boc protected alpha benzyl esters of Asp, Glu would be reasonable, (they are both very cheap from ChemImpex)

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  2. I wanted to ask you if you have any thoughts on the stoechiometry, why 3 equivs of aryl zinc are optimal. Also, with in situ HATU activation, you are producing 1 equiv of NEt3.HPF6, isn't this going to quench 1 equiv of the aryl zinc?

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    1. Hi Milkshake,

      For some substrates less aryl zinc (1.5 - 2 equiv) works very well, but 3 equiv worked well in all cases, so these conditions were the most general for all substrates. I think with additional optimization the equivalents of aryl zinc can likely be reduced.

      Regarding the HATU activation, some of the aryl zinc reagent is definitely quenched; if we used only 1 equiv of aryl zinc reagent in reactions with HATU activation, the yield is pretty low (< 10%).

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    2. Jacob, hi,

      thank you for your kind reply. Two things: Please have you tried low aryl zinc stoechiometry (1.5 eq.) under vacuum, or with Ar sparge? (I realize THF would be lost from reaction mix but presumably DMF would stay; your system generates CO2, maybe that is what is killing 1 eq. of ArZnX). And since you have such a nice new system for making secondary radicals - have you tried to intercept them with propellane, to see if it would insert?

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    3. We never tried running the reaction under vacuum or with an Ar sparge. I never saw any carboxylation products suggesting that the aryl zinc reagent was reacting with CO2.

      In regards to the propellane idea, we haven't tried this but you could imagine some pretty interesting products from this type of reaction! We'll have to add it to the to-do list.

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    4. ...who knows how the zinc dies. By the way, 4A powdered sieves that Aldrich sells already preactivated have pores big enough for CO2 to fit. Unfortunately they would also probably gobble up Li(+), exchanging it for Na(+). But they don't upset Pd(II) coordinated to pyridine ligands so it might be worth trying just to dump in some sieves powder, to see if there is any improvement.
      Best luck with your project, it really is interesting methodology, as it's always the case with papers from your group.

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    5. I like the idea and will definitely keep it in mind for this project and related ones!

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    6. This comment has been removed by the author.

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  3. I didn't realize you guys were posting any more till Chemjobber linked you! Something in the RSS feed isn't working, at least for me. Anyone else have this problem?

    I also enjoy your email address, Jacob. Heard of the cheesy Irish band, Jedward?

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    1. Well, I hadn't. Maybe some of their music will have to make the lab playlist.

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    2. Me too - my RSS feed wasn't updated either

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  4. Hey guys, what happened to your RSS feeds? They seem to be stuck in June 2015.

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  5. Hi guys,

    Have you always used the Knochel-type arylzinc reagents (lithium chloride adducts)? Obviously, there are a lot of arylzinc bromides that are commercially available, did these also work in this type of reaction?

    Thanks!

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    1. Good question! The first hit for showing that we could successfully transmetallate an organozinc reagent and have the desired reaction occur was actually performed with an old bottle of PhMgBr and some pretty wet zinc chloride. After this we started preparing them according to Knochel's procedure because it was straight forward and gave us consistent results. We actually didn't try any of the commercial aryl zinc bromides, but I would imagine that they work.

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  6. an immodest proposal: please have you tried to improve the aryl zinc economy by adding a dummy non-transferable ligand, to form a higher-order zincate , maybe an extra equivalent of Knochel-Hauser base, or sodium-DMSO anion?

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    1. We haven't tried that - and I don't have a good excuse not to do so, considering I have a bottle of Knochel's base on my bench...

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  7. Hi!

    Very interesting methodology, but I have a few questions:
    Did you try using another solvent instead of DMF? Actually, I'll be more specific: did you try MeCN? I've worked with C. Gosmini, and have done a lot of ArZnBr using catalytic CoBr2 and Zn in MeCN (see JACS 2003,125, 3867 or better yet Tet Lett 2003, 44, 6417), and I wonder if that methodology could be used to prepare the arylzinc for the cross-coupling.
    Also, does the reaction work with AlkylZnX.LiCl?

    Cheers, and keep up the good work!

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    1. Hi Martin,

      We did try MeCN in place of DMF, and this resulted in much lower yields. However, we always were using a MeCN/THF mixture since we prepared the organozinc reagent in THF, so maybe if we prepared the organozinc reagent in MeCN and also ran the reaction with just MeCN (no THF) this could work. I'm not so sure how stable the activated esters will be towards zinc, however, so I think excess zinc might need to be filtered off before running the reaction.

      In regards to the second question, we are definitely interested in trying to expand the scope to this type of reactivity!

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    2. Hi Jacob,

      thanks for the answer! Filtering the excess zinc from the mixture shouldn't be too much of a problem: I've done it hundreds of times (literally!), either on celite (a bit bothersome, but OK), through a filtering canula (works perfectly), or through syringe filters (ok on small scales).

      Anyway, very cool chemistry, and I look forward to any other project you might have on this kind of stuff!

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    3. Yeah, for the scale we run I think a syringe filter should be adequate. If I get some free-time I'll try a reaction and let you know!

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  8. hey edward,myself raju
    that was a realy nice work, good breakthrough in ni chemistry,
    i have a two question, in these reaction you have ever tried the reaction with only one solvent like either THF or DMF.
    I didn't gate the idea behind the using 3(eq) of Zn catalyst


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    1. Hi Raju,

      We tried the reaction in just THF - this resulted in lower yields typically by about 20%. We never ran the reaction in just DMF because it was most convenient for us to make the organozinc species in THF, and since the reaction worked fine with this mixture of solvents, we didn't try to pump off the THF and just run the reaction with DMF.

      We use 3 equivalents of aryl zinc species because this resulted in the best yields for all substrates. In some cases we still got good yields with less aryl zinc. In particular, when we used HATU we needed a lot of aryl zinc because about 1 equiv was always quenched by the triethylammonium salt byproducts of HATU/triethylamine.

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    2. it means that 2eq are the responsible for the reaction.
      its really nice work.

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  9. Please have you seen this paper from MacMillan-Gregg Fu collaboration? pubs.acs.org/doi/pdf/10.1021/jacs.5b13211

    Their system is pretty similar on nickel (and the bisoxazolidine ligand) and they are getting ees around 90% with photocatalytic decarboxylation of N-Boc aminoacids. If you could combine the scalability and very low cost of your system with the good ee induction that they are getting... (Blue LEDs and iridium-based photocatalysts are like a mother in law - helpful, but life is easier when there is none)

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    1. Hi Milkshake,

      I've definitely seen this paper, and we are very interested in trying something like this...

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  10. I have been trying to set up my amateur lab for quite some time now, and I'm finding finances a bit difficult to come by. Any donation of any size would be greatly appreciated by a learning chemist in need.

    https://fundanything.com/en/campaigns/heating-mantle-for-home-education?col=-68710

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