Halogens, Ethers and Dicarbonyls, Oh My!

Gururaja, G. N.; Mobin, S. M.; Namboothiri, I. N. N. Formation of Five-Membered Cyclic Orthoesters from Tribromides with

Participation of a Neighboring Carbonyl Group Euro. J. Org. Chem. Early View Feb. 23rd 2011

So as promised, I will be updating more often now. So far this week has built on the success that was last week. I’ve been getting a lot of, surprisingly, successful reactions. And in good yield too, upwards of 70%! Plus, my new method continues to gain steam as more and more substrates seem to work under my reaction conditions. The suspense is killing me too, but I will certainly have to wait to tell you for the time being :P. Professor Tilley looks like he’s going to give a talk on some of the work we’ve done thus far (hopefully) at the next ACS meeting in Denver in the Fall. I may consider going to that one despite my high aversion to flying :/. Also, I will soon hear from the NSF GFP. Last year, I got honorable mention. While this was awesome, I really hope this year I get the actual award. I put about two months of work into it and so much editing it started to give me a headache! Getting that award isn’t really about the money to me. It’s really just the prestige associated with being selected while competing on a national level. But that’s enough on the personal side, let’s get to the chemistry!

So I found this excellent article on my hiatus from blogging and I was attracted to it because of its unique but simple approach to the synthesis of previously unknown compounds. Moreover, it demonstrated the most important part of any organic synthesis: the workup. Some reactions work but if you cannot isolate the product, what’s the point? Purification is a biggie for me. If I plan on publishing something, I make damn sure that the compound I obtain is as pure as I can get it. And that’s one of the reasons I really enjoyed this article. They spent a good amount of effort on purification! Anyway the authors of this article (which is interesting dedicated to a legendary organic chemist, Ronald Breslow, who will be speaking at UConn in a few weeks) hoped to develop a novel method for the synthesis of orthoesters from relatively cheap starting materials. Moreover, they wanted to prepare synthetically valuable 2,2-dialkoxydihydrofuran which have limited known preparatory methods. I really liked flow of this article. The first thing the authors discuss is where this idea came from. It seems like it was off-shoot of some work that they were already doing with nitroalkenes. Essentially, they developed a selective method for the incorporation of methyltribromides or methylenedibromides using relatively simple Michael-like reactions:

Based on EPR data and some basic knowledge of the chemistry of organomagnesium compounds, Namboothiri and coworkers suggested that the magnesium-mediated reaction probably proceeded through a SET radical mechanism whereas the LDA conditions lead to an anionic mechanism. Either way, two equivalents of bromoform were required for successful Michael addition. From what it seems, they initially were just looking to expand the scope of their Mg-mediated reaction in this paper to include alpha, beta-unsaturated carbonyls. Seems like a logical step to me. That in it of itself could have been a short paper to Tet. Lett considering their high yields with a relatively broad scope. But the authors were quite clever here. They wanted to see what these sort of gamma-keto tribromides could be used for.
Their goal was to treat the tribromides with a basic ethanolic solution to see if they could transform the tribromidemethyl moiety into a carboxylic acid or ester functionality. However, they got more than they bargained for. By varying the workup of the crude reaction mixture, they found that they could either obtain a 2,2-dialkoxydihydrofuran (Neutral Workup) or a gamma-keto ester (Acidic Workup).
Namboothiri and coworkers, perceiving that the 2,2-dialkoxydihydrofuran was an intermediate in the formation of the gamma-keto ester, decided to optimize their conditions accordingly. They found that the optimal solvent for this reaction was a 1:1 mixture of EtOAc to EtOH as it homogenized the reaction mixture while providing excess ethanol. Upon optimization, they were able to conduct similar reactions on at least 7 other substrates. The only difficulty they encounter was when the aromatic rings in the tribromide were electron-withdrawing.

They then offered a particularly detailed mechanism accounting for the formation of the 2,2-dialkoxydihydrofuran under their conditions. The only issue I encountered is I was quite confused as to why an aromatic system would undergo room temperature addition of an alkoxide. My only guess is that it is such an electron-withdrawn (and highly delocalized) system, that addition by an anionic species has a low activation barrier. Plus the authors point out that it’s only stable under neutral workup conditions.

However, the authors didn’t stop there. They then optimized for the formation of the gamma-keto esters. The actual reaction conditions remained the same (solvent, time etc.) but the workup was adjusted. They found that they never obtained the lactone during this workup and that. by altering the alcoholic portion of the solvent, they could obtain a variety of esters and 2,2-dialkoxydihydrofuran. Moreover they found that they could take the 2,2-dialkoxydihydrofuran from their earlier optimization and hydrolyze them to give the gamma-keto esters in comparable yield. To put the nail in the coffin, they suggested a mechanism for this transformation:

This was a fine article by Namboothiri and co-workers and certainly worthy of EJOC (I even think they could of got a Org. Lett. out of it). I look forward to see more articles from their lab! I still have some more articles to review on the back burner, so stay turned! Ckellz…Signing off…


I Have Returned!!

Li, H; Li, W.; Liu, W.; He, Z.; Li, Z. An Efficient and General Iron-Catalyzed C-C Bond Activation with 1,3-Dicarbonyl Units as a Leaving Groups Ang. Chem. Int. Ed. Vol 50 pg 2975-2978, March 21st, 2011

 Wow. Seems like the last time I posted was in the Stone Age. But I’m back after way too long. I’ve been unbelievably busy lately between teaching, classes, and research. But a lot of exciting things going on in the lab. Our collaboration with Professor Tilley is going quite well. We are close to knocking off two substrates and we have an addition few more to make. I also managed to come up with a brand new methodology!!! I’m really excited about that one. I can’t reveal the details (yet!) but this one is pretty big. And I also have a lot of new toys coming in to help me out with some of the synthetic work that I’ve been doing. I’m gonna be getting a brand spanking new manifold which I am extremely excited about and some more equipment to use in and around the lab. But I haven’t forgot to keep up with the literature. I’ve been keeping a list of articles that I definitely wanted to review and this one is one of them.

Just like benzyne and the trifluoromethyl group, I love carbocation-based methodologies. I love them partially because of my gamma-silyl routes but also because cations are remarkably difficult to control. So, if a group is able to successfully utilize carbocations to affect a particular transformation, I think that shows the capabilities of the group. It may not be the most AMAZING chemistry, but it is certainly commendable. And that’s why I really loved this article. Not only did they control cations, but they essentially developed a new leaving group (one that I wouldn’t have thought to try). (Fan Boy alert!!!) That’s kind of why I really loved Lambert’s use of cyclopentadiene as a leaving group

So the article starts out by listing some of the common leaving groups (Sulfonic esters, halogens, etc.) and traditional substitution reactions rely on C-X bond dissociation in order for the incoming nucleophile, Y, to form a C-Y bond. They also mention that in recent years researchers have been looking into alternatives to leaving groups and have been looking at compounds with high strain or that are semi-stable carbanions (such as the oldest of these, CN-). Now here’s where they got me hooked. They weren’t looking for this reaction, they discovered it by accident doing other work. And they came right out and said that. But being remarkable efficient scientists, Li’s group pursued the chemistry. When working with structures of type 1 they found that in the presence of FeCl3 (catalytic amounts too!) and 2, they obtained both 3 and 4.

The only explanation they could come up with led them to an unprecedented reaction: The 1,3 diketone was acting as a leaving group and proceeded through C-C heterolytic bond cleavage. They immediately turned their attention to screening general reaction conditions, ultimately finding that 1 was in fact the best diketone for this sort of cleavage. They attributed this to the high stability of the forming anion (don’t worry a mechanism will come!).


After determining which diketone was the best substrate, they performed a little Friedel-Crafts chemistry. A variety of aryl compounds underwent electrophilic aromatic substitution (EAS) reactions with diphenyl cation including indoles, phenols, furans, and thiophanes. Not really any unusual occurrences there. We all know cations react with aromatics and indeed their compounds were the thermodynamic products expected from EAS chemistry.

They then began changing their cationic piece. Using 5 a model aromatic, they were able to substitute a variety of diaryl, monoaryl, and allylic compounds (again all chosen because of cationic stability and limited rearrangement). Interestingly, when comparing their cation to cations normally formed via removal of benzylic hydroxyl groups by iron (III) chloride, they found that their methodology was less prone to alkylation of heteroatoms (i.e. alkylation the indole nitrogen rather than EAS)

They next tried alkenes and alkynes. Note surprisingly these compounds underwent electrophilic substitution followed by a EAS step for form very nice indane (alkene) and indene (alkyne) products. If performed at room temperature, they obtained the acyclic alkene products, whereas heating preferred the indane/ene products.

Here’s were I had a huge question. They noted that trans-stibene and cis stibene had a disparity in reactivity. That, to me, is unusual because I would expect that since there these two are iso-electronic, there would be no difference between the two. Hence, its possible that their iron may have trace amounts of palladium in their FeCl3 (or some other transition metal) and some sort of organometallic reaction is actually taking place. I have a hard time accepting my own argument just based on the plethora of examples they have which, if this as all C-H bond activation, would be remarkable coincidental and highly unusual. Therefore, despite some concerns, I still think that their proposed mechanism is correct:

Overall, this was an excellent article by Li and co-workers so hats off! Even though the conditions are somewhat harsh, as a novel methodology this is certainly at par. I hope to be posting more soon so stay tuned! Ckellz…Signing off…

New Chem Blogs added

Check out the links section for some new chemistry blogs. Just add: Chemfun (which has some pretty awesome links including their “named rules and effects” section which did a better job at explaining the Zimmerman Traxler model than anywhere else I’ve); Synthetic Remarks (which has some very awesome and very humorous posts); Transition States (a blogsphere hosted by C&EN with the focus on “the transition from undergrad researcher to grad student, and all that goes along with it”, with contributions from some fellow bloggers like ChiralJones).

The Day Has Finally Come!

Kelly, C.B.; Colthart, A. M.; Constant, B. D.; Corning, S. R.; Dubois, L. N. E.; Genovese, J. T.; Radziewicz, J. L.; Sletten, E. M.; Whitaker, K. R.; Tilley, L. J. Enabling the Synthesis of Perfluoroalkyl Bicyclobutanes via 1,3 γ-Silyl Elimination Org, Lett. ASAP March 2, 2011

So its out. On the ASAPs. AWESOME. After about 4-5 years of work and hours upon hours of writing and revising, our article is finally out in one of the most presigious organic chemistry journals out there (and my favorite in fact). Now time to give ya a brief summary of 4+ years of work in a few paragraphs. So the orginal goal of my project was to just explore gamma-silyl interactions in the cyclobutyl system. If you know the beta silyl effect, you kinda have a good idea of what the gamma effect does. The gamma-silyl effect, which really is just a form of long range neighboring group participation (NGP). Think of it like a acetate group performing anchimeric assistance. Below is the accepted mechanism for this sort of interaction, potentially yielding cyclopropanes upon elimination.

V.J. Shiner, Dr. Tilley‘s former PI, did a lot of work with this effect and found that he could affect gamma silyl elimination of gamma silyl cyclohexyl brosylates. He noted an interesting trend :i f the relationship was “W” or the gamma silyl group was in a cis relationship (B, green arrow) to the leaving group, he observed that cyclopropyl products formed in addition to rearrangement products and substitution. However if the relationship was trans, no cyclopropyl products were observed and only elimination and substitution without retention occurred (A, Red arrow). Shiner explained it as percaudal participation of the silyl back lobe with the forming cation (see below). However, cyclopropanation was only a minor product, giving at most 20% conversion to the small ring system.

I began work on this project in the summer of  ’07. My orginal goal was the preparation of bicyclobutane via 1,3 gamma silyl elimination  to form the brigehead bond. Now that’s truly a feat if you considered a cationic approach (which is much more difficult to control) has never been used to form just a bond in the cyclobutyl system and the amount of strain that would be introduced by forming such a bond. After getting to the desired gamma-silyl cyclobutanol, I attempted to put on leaving groups with mixed success. Any sort of reactive leaving group (i.e. tosylate, mesylate etc.) readily decomposed on workup. Other reactive groups like the iodide was stable but when solvolyzed gave only subsitution or rearrangment to give beta silyl elimination  It seemed that we wouldn’t be able to get our methodology to work in this sysyem. However, since we found that the tosylate was stable in solution, we attempted to pyrolysize it and collect the vapor coming off of the reaction. We were pleased to find that bicyclobutane did form, but only in 2.5% yield.

Going off of work by Gassman regarding NGP and electron-deficient cations (or destabilized cations if you will), I then investigated what would happen is we placed a electron-withdrawing group (EWG) at the cationic center. In theory, it should dramatically increase NGP causing the silicon to be much more electrophilic. The electrophilic Si should be readily eliminated at that point. So simply (if you can call two years of simply) modified my method to introduce a CF3 group and then tosylated it.  In December of 2009 I solvolyzed it to give a new bicyclobutane! Moreover as the only product of solvolysis showing the power of the EWG in enhancing gamma silyl participation. It took some time but in april of 2010 I finally isolated and purified the CF3-Bicyclo. When your compound boils at 28 oC, distillation becomes a real issue and forget columns or conventional techniques. However, I couldn’t get it more than 60% pure. Hence I turned my attention to writing up what I did while Professor Tilley focused on the purification. That summer after I graduated, Professor Tilley had his students synthesized the pentafluoroethyl derivative and, by using a 60/40 mixture of H2O to trifluoroethanol, he was able to successfully distill off the CF3 bicyclo in 97% purity. I’d say that was key to the success of our article. We also established a small collaberation with UC Berkely via a former Stonehill student, Ellen Sletten. One of the instruments at UC Berkley could do whats called a HOESY. We were able to determing the relative stereochemistry of the major isomer after trifluoromethylation. This gave us insight into the mechanism. It showed us that the cis isomer was indeed the one undergoing solvolysis, while the minor trans isomer failed to react. Annnnd thats enough for now. I hope you enjoy the article!!! Ckellz…signing off.