

(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…

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October 2, 2011

Categories: Reviews . . Author: ckellz

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