Thursday, May 21, 2015

Formal Olefin Hydroamination With Nitroarenes


Our latest work in the field of iron chemistry came out today in Science. First we would like to present a graph (shown below) on how this newly developed chemistry could simplify the synthesis of some biologically active intermediates: starting from the same starting material, this reaction only took one step and 1 hour to get the desired product, while the traditional route required 3 steps and 29 hours in order to get the same product. Taking all the estimated cost (materials and labor, for 1.5 g product) into account, this chemistry would start from 30¢ of iron catalyst, and save the total cost by ca. $1388 (1.2 oz of gold). In essence, this is the modern equivalent of the Alchemist’s dream of turning iron into gold.

Unlike our previous two papers in this area, which focused on the formation of C–C bonds, this time we developed a method for the construction of C–N bonds, more specifically, a reaction for the synthesis of highly hindered secondary aryl amines. Since all the scientific details are described in this research article, this blog post will serve to give our readers the background of this project.

First, how we discovered this reaction is a story on its own. During an ongoing project regarding new applications of iron-mediated bond formation, an unexpected product was isolated in 17% yield (scheme below). After full characterization, it was clear that it was a secondary aryl amine derived from a formal hydroamination process between the olefin and nitroarene. At that time, I didn’t fully realize the importance of this product and the transformation that had occurred, so I only reported this “unexpected” result to Phil after TWO weeks. But in 10 seconds, he replied: “Wait! Wait! This reaction is interesting!” In another 1 min, Phil was able to convince me (which he is naturally good at) of the high novelty of this discovery, and from then on, this new approach of hydroamination was developed.

Second, the mechanism of this reaction is indeed complicated. Even though we had performed a series of control reactions, we are still not quite sure what actually happens in the reaction. For this reason, we decided to move the mechanism proposal from the main text into the SI (detailed discussion on mechanism there). But in general, we propose that the nitrosoarene is the reactive intermediate, and the unique effectiveness of the iron catalyst plays a key role: it reduces the nitroarene to the nitrosoarene, and the olefin to the alkyl radical; then, these two reactive species combine with each other without over-reduction by the iron catalyst to give a fully reduced aniline or an olefin hydrogenation product. Notably, the cobalt and manganese catalysts completely failed in this reaction, since they were shown to be unable to reduce the nitroarene to the nitrosoarene (a convincing TLC plate is shown in the SI, Fig. S2). 

Third, in the paper, we presented over 100 examples to show the broad scope and generality of this reaction, which seems to be an unusually large number for a methodology paper. But in fact, this project only took 6 months from beginning to end due to some great teamwork. On the one hand, with the fantastic teammates (Eddie, Jin, Tian and Julian) at Scripps, we managed to build up the substrate scope, synthetic applications, as well as limitations very quickly and efficiently; on the other hand, through working with industry (BMS & Kemxtree), this chemistry was field-tested immediately by different research organizations. In late February of this year, our lab published our views regarding academia–industry symbiosis. Indeed, this project is another good example for the collaboration between academia and industry. As you could see in the main text and the SI, the examples provided by BMS (marked in blue in the SI) exemplified its utility in medicinal, process, and radiochemical settings, and the decagram-scale results provided by Kemxtree (also marked in blue in the SI) showed its feasibility in large-scale settings. 

Lastly, it is our lab’s publication tradition to show the limitations of the methodology being developed, in order to give the readers a better understanding of the reaction. Some of the limitations for the hydroamination are shown in Fig. 5 of main text, and here we provide more examples. The contents below may be helpful for those who decide to give this reaction a try for similar substrates.

18 comments:

  1. FAQ section of the SI should include "What happens when reaction is run in Fireball?"

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  3. Great work, people! Being honest and showing the limitations of your methodology is quite useful. Hopefully it prompts others to start doing the same...

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  4. 1. Have you looked at alkyl azides with your system (as an alternative to nitroalkanes)?
    2. Have you tried Ru(acac)3 as a catalyst?

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    1. Thanks for the questions. Hope these answers would help you.
      1) We didn't look at using alkyl azide as a nitrogen source in our system. Actually, Carreira has published a lot of great work in this area, including Mn or Co catalyzed hydrohydrazination and hydroazidation of olefin using azodicarboxylates (Angew, 2004, 4099 and JACS, 2004, 5676) and tosyl azide (JACS, 2005, 8294 and JACS, 2006, 11693);
      2) We didn't try Ru(acac)3 as the catalyst, since it's not a common catalyst for the hydrofunctionalization of olefin. The most used catalysts in this area are Fe, Co, and Mn-based catalysts.

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  5. Let me congratulate you for nice piece of work !

    How long did it take to complete the project and how many people were working on it ?

    What are the average working hours in Baran lab, especially for a PhD student ?

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    1. I average about ~100 hours a week. Just kidding—we're not robots. The grad students here are pretty self-motivated, and as such, Phil doesn't prescribe working hours or vacation limits. He told me that he "learned many years ago that placing rules on already driven people doesn't work. The lab is results driven. It just so happens that students that spend more time in the lab get more results.” As a whole, I'd say the grad students average between 10 and 12 hours a day.

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  6. Very nice work!

    I have a small question: in supporting information (page S23) it is written "(Note: For products with extremely low or high polarity, 5% Et3N is added to the eluent to avoid mass loss during column chromatography.)". This advise is specific to amine and amine-like compounds only correct? (and not to organic compounds with extremly high-or low polarity).

    Cheers

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    1. Thanks! For column chromatography, E3N is often added to neutralize the silica gel column, which is a useful technique for most high polarity compounds (not only amine compounds).

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  7. Hi, cant acces the article atm so forgive a question that might be answered by reading the article:
    did you try it on dinitro compounds? forming something like N,N´-alkylated phenylenediamies or maybe ring closing forming some partialy reduced pyrazine?
    ps: sorry for possible double posting, internet troubles :/

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    1. Thanks! That's a good question! We thought about trying the dinitro compounds in this reaction before, but never give it a try. It's possible that N,N'-alkylated phenylenediamines product could be formed starting from dinitro compound. But for ring closure to form the pyrazine-like product (starting from diene as olefin part), the only issue is that for intramolecular reaction, the alkyl radical addition to O (not N) of nitroso compound might happen first, which would give an olefin hydration product instead of amine product. For a intramolecular example, please see compound S14 to S15 in SI (page 13).

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    2. Thanks for answer :)
      I was thinking more something like this
      http://i.imgur.com/aoaD7eo.png
      (I can already see some possible problems with this but what the hell...)

      BTW your paper(s) are very detailed, I hope more chemists will take you as an example (aparatus photos? seriously? :D )

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  8. Maybe this scheme would be helpful to your question: http://imgur.com/Bo4H7fJ
    Even though the six-membered ring transition state (from pathway via attacking on N, left) might be preferred to the seven-membered ring (shown on the right), we could not completely rule out the possibility of the right pathway (to form the undesired hydration product). Or maybe the second amination reaction occurs intermolecularly instead of intramolecularly, to give the dimer product. Anyway, this is a great question and worth a try. Thanks!

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  9. I had a few mechanism related questions:

    1) In going from S17 to S6 (NO• to NOH) this is effectively the delivery of H•. Assuming this also applies for the transformation from S1 to S2 (nitroarene to nitrosoarene), would this result in the loss of OH•? Or, does the addition of H• to S1 occur twice to result in the loss of H2O instead?
    2) Have you performed any EPR or radical-trapping experiments to identify radical intermediates (and preclude an ionic pathway)?
    3) For S14 you see exclusively O-addition to the nitroso rather than N-addition, is this due to the stability of the 6-membered ring intermediate - driven by the fact this is an intramolecular reaction?
    4) Following on, have you seen any other selective or preferential O-addition?

    Congrats on the paper and great work by everyone in the Baran lab!

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    1. Thanks for these great questions. We don’t have clear answers to some of them, but here is what we think:
      1) You are right that from nitroarene to nitrosoarene, it actually needs the addition of H. to nitroarene two times, to afford the nitrosoarene via the loss of H2O. Due to the complicated mechanism in this reaction, we didn’t draw every detail (proton transfers and loss of water) in the scheme. The scheme just showed one arrow from Fe-H to nitroarene S1, which didn’t mean it occur only once. Alternatively, it’s also possible that this reduction process (from nitro to nitroso) occurs via ionic pathway, instead of the radical pathway. We don’t have clear evidence which one is right.
      2) We didn’t do any EPR or radical-trapping experiments to trap the radical for this reaction. But in our two previous papers in this area (JACS, 2014, 136, 1304 and Nature, 2014, 516, 343), we did do some control experiments to show it’s a radical mechanism.
      3) That’s the only intramolecular example we have, and its selectivity may be due to the stability of 6-membered ring, as you mentioned. But the N vs O-addition is case dependent. As you could see in example S13 (in SI), the product from N-addition was also isolated. So for most intermolecular examples, if the O-addition is preferred to occur first, its addition to the nitroso compound would give the N-centered radical species, which would be trapped again by the tertiary alkyl radical to form the bis-alkylated product. In this regard, you could still get your desired amination product after Zn-HCl reduction (in this case, after the first step (1 h, that is before Zn-HCl reduction) you may find on the LC-MS that the bis-alkylated product is the major product). But for intramolecular reactions, if the O-addition is preferred to occur first, the only product you could get is the Mukaiyama hydration product, not the amination product.
      We also tried to control the reaction to favor the N-addition first, which would directly give the desired amination product, but found it’s extremely difficult to control. In the end we chose to the two-step one-pot procedure to increase the yield.
      4) This intramolecular example is the only example we saw the preference of O-addition. For other intermolecular examples, due to the formation of the N,O-bisalkylated product, we can’t tell the selectivity of N vs O-addition just from the final product distribution.
      Thanks again for your great questions and your interest.

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  10. does this protocol also works for hydroamination of alkyne

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  11. We tried this idea but it afforded a mixture of products. The major products are the same as those from hydroamination of alkene, i.e., the saturated alkyl aryl amine and its corresponding N,O-bisalkylated product.

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