Carbon Monoxide, What the Heck Just Happened???

Ye, S.; Wu, J. Org. Lett. ASAP Oct 20th 2011

With work coming back to a (slightly) more regular pace, I now actually have to blog on a more regular even (gasp) weekly basis! Not all too much new to report this week. We are pretty much at a standstill with all our pending publications. Even our research has been, at best, coming along slowly. I did manage to have some late-day success Friday synthesizing a particularly hard compound to make. While the yield wasn’t the best, I’m going to retry it and scale it up because it is somewhat critical to our project with Dr. Tilley. Meanwhile, I’ve come up with a couple of new ideas to try, in addition to searching for a molecule to synthesize (and developing an appropriate synthesis). Mike has been doing the same. We also have the exciting (and somewhat daunting) task of designing an undergraduate advanced organic chemistry lab. The goal of this course is to give the undergrads the tools necessary to begin conducting research and prepare them for graduate school. We want to teach how to run flash columns (and learn other more advanced forms of purification), get them to perform some more complicated reactions (and we are open to suggestions!) as well as teaching them how to write scientifically. Moreover, it’s useful for us in that we will be learning how to design a course (and for someone looking at academia like me, such a skill is quite useful). I still haven’t decided where exactly I’ll end up (industry or academia) but I will likely carry out a post-doc after I complete my Ph.D. at UConn. I’ve even had a few thoughts as to where I would like to go for my post-doc. But that’s a ways off; I still have my thesis, classes, teaching and all sorts of other things to get done first. On an unrelated note, I’d like to mention I’ve added quite a number of links (thanks to a very useful post on BRSM) I hope you find them as useful as I and some of my lab mates have! And now, on to the lit!

This weeks article is from, surprise surprise, Org. Lett. As promised the focus of this article isn’t fluorine. Rather, we have some useful and mechanistically interesting palladium chemistry developed by the Wu group. The article begins with a discussion of the history of palladium chemistry, in particular with respect to carbonylation. If you don’t already know, carbon monoxide is a very useful material for the functionalization of aryl halides under mild conditions. I’ve in fact conducted such reactions and, for the most part, they are pretty reliable. With the recent rise in popularity of gem-dihaloolefins in the literature, it was simply a matter of time before these substrates were explored for carbonylation procedures. In fact, Wu had just recently explored it for use in Suzuki coupling reactions (forming indenes). Not surprisingly, indenes are quite useful in material science and chemical biology, so more routes to access these sorts of structures is beneficial. Instead of simply continuing on with their Suzuki work, Wu and co-workers attempted to prepare functionalized indenes (e.g. 1-methylene-1H-indene-2-carboxylates) via carbonylation. They theorized that 1,2 disubstituted aryl systems (in which one substituent was a gem-dihaloolefin and the other was some sort of cross coupling partner such as another point of unsaturation) could undergo a tandem Heck-carbonylation reaction.

Starting with (E)-methyl 3-(2-(2,2-dibromovinyl)phenyl)acrylate (which is surprisingly easy to prepare), Wu and co-workers conducted an extensive optimization study, ultimately finding that the ideal solvent was toluene, and most effective catalyst was palladium(II) acetate with PPh3 added in as a ligand. As one would expect, the carbonylated intermediate was trapped with an alcohol (in their optimization study, n-butanol). They found that the ideal base was in fact KHCO3.

Once optimized, they then screened pretty much every alcohol under the sun, from trifluoroethanol to naphthol (to me this didn’t prove all too much, just that you could make different esters, but it did get them more substrates). They then switched over to the more important variable, the gem-dibromoolefin. Initially, they had little to no luck until they realized that 4 angstrom molecular sieves were a necessary additive in order to achieve adequate yields. Unfortunately this limited them to phenols (likely due to competitive dehydration reactions). Therefore, they used 3-methylphenol as their “alcohol” source. With these modifications in place, Wu and co-workers decided to switch the substitution pattern on the ring up a bit (both EWGs and EDGs were tolerated under their conditions). Next, they changed the substituent on the other olefin. While changing it to a ketone or phenyl ring proved unamendable to their reaction, esters modifications and nitriles were well- tolerated. Overall the yields on the reactions that worked were good and they provided a reasonable mechanism.

While I did like this article, I felt it wasn’t all that impactful. I was displeased with the fact that more of their substrates were simple alcohol swaps. However, the transformation (tandem heck-carbonylation) was very cool in itself so congratulations to the Wu group for a pretty good article. That’s all for this week. Ckellz…Signing off…

One Of These Halogens (Is Not Like The Other)

John, J. P.; Colby, D. A. J. Org. Chem. ASAP October 13, 2011

What’s one way to relax after a somewhat stressful week in lab? Some good ol’ fashion blogging! That and a bit of sleep, food, range time (Yes, I am in fact an avid shooter), and pumpkin picking. As promised, I plan on delivering more updates. So let’s start with lab. While this week was somewhat overwhelming for me, all in all, the deity of organic chemistry must have been smiling on me. We have once again resumed out collaboration with Dr. Tilley, and things are going exceeding well. We were finally able to isolate a few key compounds, which were necessary to continue the project. Isolating these compounds (sorry I can’t be more descriptive) is unbelievable difficult, but we were able to obtain about 4.5 grams of them each! We owe this to a little luck and using very pure reagents. We found out really quickly early on that the reaction is very sensitive to impurities. Hence, me and Mike spent a good deal of time purifying our starting materials as well as the reagents going into the mix.
Our other projects are also coming to fruition. Barring any unforeseen problems, our next paper should be submitted shortly (we are just tying up a few loose ends). We’ve had some mixed results with a continuous flow project we’ve been working on (a project that seems to have many highs and lows unfortunately). I’ve also begun thinking a bit about the future and I have a few projects in mind, one of which may be more synthetically driven (and by that I mean I would like to attempt small molecule synthesis, possibly using methods developed by our lab). I think Mike is also is looking into doing the same (though with a different target molecule in mind).
I really have gained some valuable skills in the past few months: becoming pro at columns, developing much more concise and elaborate synthetic skills, and enhancing my skills as a scientific writer. While grad school isn’t the most exciting job (and yes I do say it’s a job) on the planet, it sure as hell is fun, challenging, and at the end of the day, I really couldn’t envision myself doing anything else right now. As for non-research related events, I successfully presented a few syntheses of the Welwitindolinones alkaloids to my synthesis class (the Wood, Baran, and Garg syntheses). I seriously love presenting. It’s a rush of adrenaline right before I start, but once I get into it, I’m very relaxed (and almost on autopilot). Plus, it time to talk about one of my favorite items to discuss: organic chemistry. Speaking of which, let’s get on with the organic!
So this week’s article comes from JOC and its more organofluorine chemistry (Sorry, I promise next time I’ll pick a fluorine-free article but this one was too good to pass up). So if you have been following me for a while, you clearly know why organofluorine chemistry is so popular right now: new ways of getting fluorine into synthetic targets is very appealing to Med Chem. And if you read my last post, you know that the introduction of the CF2 group is currently very difficult to do. The Colby group has recently become interested in tackling this problem. Not long ago they introduced an extraordinary strategy for the rapid formation of alpha, alpha difluoroenolates:

It appears as if Colby stumbled upon some findings by Ogden in the 1960s regarding the decomposition of hexafluoroacetone. Ogden found that, in the presence of metal hydroxides, hexafluoroacetone underwent a fragmentation to yield trifluormethylacetate and CF3-. Colby reasoned that a similar fragmentation could be achieved in 1,1,1-trifluoro-2,4-dione systems to yield trifluormethylacetate as well as the corresponding difluoroenolate. Colby and his group therefore set out to first prepared some 1,1,1-trifluoro-2,4-diones via trifluoroacetylation of various methyl ketones followed by alpha difluorination with Selectfluor. They then used conditions that can best describe as (very roughly) Krapcho-like (lithium salt to induce fragmentation). With conditions to facilitate trifluoroacetate-release in hand, he was successfully able to induce an Aldol between the other fragment, the difluoroenolate, and an aldehyde additive. Unfortunately, they really didn’t give a mechanistic rationale for why it worked, but it worked well (great yields, reactions completing in 3 minutes at room temp).

With that impressive work behind them, Colby and his group set out exploit their newly developed trifluoroacetate-release strategy by synthesizing alpha-halo difluoromethyl ketones (which aren’t at all easy to make). All Colby really needed to do was find the appropriate electrophilic source of each halogen and couple it with his lithium-salt induced trifluoroacetate-release strategy. While that may seem trivial, it wasn’t as easy as one may think. First they attempted bromination using Br2. While this simple approach worked, excess base was required (which they attributed to acidic impurities in the Br2). They then opted for NBS, a logical Br+ source. However this failed to react whatsoever. Finally, they switched back to utilizing Selectfluor to generate electrophilic bromine from LiBr (a modification pioneered by Shreeve . This proved provide a reliable source of electrophilic bromine without requiring excess base.

Next they targeted iodination. Attempting to capitalize on Selectfluor-mediated halogenation, they initially tried using lithium iodide (serving both as their lithium salt and as their iodine source) in the presence of Selectfluor. However, due to the fact that no sufficiently electrophilic iodine was present, self-coupling reactions occurred. Colby then made a slight tweet to his conditions: add I2 and exchange LiI with LiBr. That managed to do the trick and they were able to isolate alpha iododifluoroketones in excellent yields (though these species decomposed rapidly over times upon storage). With this in mind, they decided to demonstrate the power of their iodination method by synthesizing one of these ketones in situ followed by an immediate copper coupling to an alkene. Coupling proceed well and had the advantage of not having to isolate the somewhat sensitive iodoketone

Finally, to wrap things up, chlorination was examined. Unlike iodination and bromination, molecular chlorine was not examined due to its hazardous nature (a good call in my opinion). Instead, Colby opted straight for NCS/LiCl. Lucky this proved perfect for chlorination (though ketones with alpha hydrogen atoms were over chlorinated).
I really enjoyed this article quite a bit. While it may not have been as impact as Colby’s previous work, it certainly was interesting and very well done. I still am really curious on the exact mechanism of the trifluoroacetate-release, because it’s so unusual! Anyway, that’s all for now. Ckellz…Signing off…

The New Kid on the Block: The Difluoromethyl Group

(1) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii H. Org. Lett. ASAP Sept. 28th 2011
(2) Zhao, Y.; Huang, W.; Zheng, J.; Hu J. Org. Lett., 2011, 13 ,5342.

I have returned! Yes, I am in fact alive and well. I have not succumb to a lab accident (*knock on wood*) nor have I given up on blogging (or chemistry for that matter). These past few weeks I’ve been insanely busy. Between school work and lab work (more so the latter) I’ve barely had time to do just about anything. I did manage to put up a ChemSpider page for a Sonogashira procedure that I enjoyed (it worked like a charm!). So besides that what else have I been up to? Well first I have most of our next article written and the supporting information (which is in fact the more tedious and longer part of prepping a publication) is complete. I couldn’t have done it in a timely manner without the help of my lab mate Mike. I just need my boss to review it and it will be submitted very shortly. So far the people that I have shown it to with our department have liked it! With that project completed, we will be returning to our collaborative work with Dr. Tilley as well as continuing a few other projects we are currently involved in (though the latter projects have been giving us some trouble lately :/) . Our paper with the Fenteany lab did not get into the journal we initially tried for and it’s currently being formatted for another journal so I will keep you apprised on its status. I really hope it gets out there soon so I can share with you what it’s about!

Other than that I’ve been trying to keep up with the literature and with other blogs. I really enjoyed BRSM post on Woodward’s synthesis of Erythromycin A (which clearly showed how much of a genius Woodward was). I actually watched his lecture on the synthesis thanks to the link at the end of the blog post to U. of Minn. page hosting the video. I also enjoyed Synthetic Remark’s post on stirring a reaction mixture. I’ve had many conversations with colleagues on that issue and while I don’t think it’s necessary to stir a reaction mixture (unless its biphasic mixture). However, I still toss in a stir bar just out of habit (a flask with a reaction mixture just sitting there looks weird to me). And now, onto something I haven’t in too long, a review!

So we are once again back to Org. Lett. but as a change of pace I will be doing two separate articles covering a relatively under-explored field: difluoromethylation. The first, more recent article details the difluoromethylation of arenes. Unlike their trifluoromethyl relative, difluoromethyl arenes are relatively understudied. However, they are quite useful especially as candidates for drugs. Currently, the main method used to prepare difluoromethyl arenes is treatment of the corresponding aldehyde with DAST or SF4. While this is a viable method, other methods are needed (for instance what if your molecule doesn’t have an aldehyde functionality?). So Amii and coworkers set out to see copper mediated coupling of CF2H would be possibly. However, it was already know that, unlike CF3-, CF2H- complexes with copper are thermally unstable. Therefore, Amii and co-wokers adjusted their strategy and focused on first forming a -CF2R bond, then converting CF2R into CF2H. The perfect way to do this is to stabilize the CF2 anion by placing it alpha to a carbonyl (in Amii’s case, alpha to an ester). To simplify and enable better control of conditions, they decided to use alpha silyl esters with the general formula R3SiCF2COO2ET.

The silyl group could be easily removed by treatment with a fluoride source to give the alpha anion. In the presence of catalytic amounts of CuI this anion will undergo metalation to form an organocopper species with will then do an oxidation addition followed by a reductive elimination to form the aryl difluoroethylacetate and regenerate copper iodide. Initially, the authors used a TMS group as their silyl substituent but switched to a trimethylsilyl (TES) moiety due to improved yields using this species. Ultimately, they found that DME worked best as a solvent (which could be due to some sort of solvent stabilization via chelation in my opinion).

While coupling the difluoroethylacetate moiety to the arene was an accomplishment, they next needed to remove that ester functionality. The easiest way to do that is a hydrolysis followed by a decarboxylation. Hydrolysis proved relatively easy; the reaction proceeded readily at room temperature in alkaline aqueous methanol. The crude carboxylic acid acid intermediate was then taken up in the appropriate solvent (NMP or DMF) containing a fluoride base (KF or CsF) and heated to reflux to induce decarboxylation. It should be noted that the only arenes that seemed to decarboxylate easily were electron-deficient arenes. Electron-rich arenes did not undergo decarboxylation. Overall, I enjoyed the Amii article, but I felt that the application was somewhat limited (mostly because of the high temperatures required for successful decarboxylation and restriction placed on the types of arenes that compatible).

Our next article is a tad bit older but I feel is somewhat more impactful. As you probably known, TMS-CF3 is the reagent of choice for the introduction of a CF3 moiety into organic compounds. You can do coupling reactions with it or nucleophilic addition of CF3- to electrophilic regions (notably to carbonyls). However, it stands to reason that if we were to simply remove a fluorine and replace it with a hydrogen, we would have ourselves a CF2H- source. A while back Prakash (a hero of mine) developed TMS-CF2H in addition to other difluoromethylsilyl reagents. However, neither Prakash nor Fuchikami, who reported on PhMe2SiCF2H, had much luck difluoromethylating aldehydes or ketones. Fuchikami did get some to work, but only under harsh conditions. Since those reports in the mid to late 1990s no attempts were made to use TMS-CF2H as a CF2H- surrogate.

That’s where Hu and co-workers come in. They have developed a very effective methodology for using this reagent for difluoromethylation. Initially, they confirmed Fuchikami’s findings that KF alone could not do a very good job initializing the reaction. They quickly turned to CsF, TBAT, and t-BuOK as initiators and achieved success in difluoromethylting p-anisaldehyde. Solvent was critical to reaction success. DMF proved ideal whereas the typical solvent for trifluoromethylation (THF) gave little to no difluoromethylation with fluoride initiators. However, THF could be used as the solvent if t-BuOK was employed. As expected with fluoride initiators, a second cleavage step was required to desilylate the silyl ether to reveal the difluoromethylcarbinol.

After this brief optimization study, they began testing substrates, finding that most aldehydes gave good to excellent yields. However, ketones gave low yields, likely due to decreased electrophilicity. They therefore switched over to the t-BuOK/THF conditions (at -78 oC) and found that non-enolizable ketones could be difluoromethylated easily. However, enolizable ketones failed to react, likely because t-BuOK induced side reactions (Aldol). Despite this limitation, Hu pressed on, targeting N-tert-butylsulfinimines. This class of substrates has been successful trifluoromethylated with the Prakash-Ruppert reagent. Hu met equal success here as well, achieving reasonable to excellent yields and diastereoselectivity (though somewhat lower than analogous trifluoromethylations). I really enjoyed this article, particularly because it was even dedicated to Prakash himself for his achievements in fluorine chemistry. Well that’s it for now, Now that things are slowing down a tad I promise to post more reviews! Ckellz…Signing off…