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…



  1. I the proposed mechanism for forming 2,2,-diethoxy-2,3-dihydrofuranes is not right. First, I worked with esters and amides of 5-bromofuroic acid – they are not very electrophilic, I think the room temperature addition of alkoxide does not happen. More importantly, the dibromo-substituted ienolate intermediate (third from the left) would haave difficulty to cyclize to dihydrofurane because the electronic requrements for endo-ring closure would have the enolate to approach from somewhere above or below the plane of the Br2C=C moiety, and this obviously cannot happen.

    I think a more plausible mechaism is a plain SN2 displacement of Br with enolate derived from the starting trobromocompound.

    Maybe the base-promoted elimination of bromide from the tribromide also happens but as a side-pathway that does not produce diydrofuran products (maybe that would explain the trouble with electron-deficient aryl substituents)

    • Yeah I had a hard time believing the part about addition to furan. If that were the case I would expect that you could just add ethoxide to furan and get the same sort or furanyl ethers and get the same sort of intermidates (I found no precedent for such addition on reaxys). So yes I would agree with you that their proposed mechanism is most likely incorrect. and yes according to baldwins rules just a cyclization is very much disfavored. I also buy your mechanism, now are you saying it would be an internal SN2 to give a cyclopropyl intermediate (in which case you would have a enolexo exo trig, a favored reaction by baldwins rules) or are you talking about a intermolecular reaction. Since I feel the intramolecular mechanism is much more likely, how to you figure you get the dihydrofurans? Do you think you add to the alkoxide to that cyclopropyl structure? They also propose (in the SI) that the y-keto esters can be formed in the absence of participation by the carbonyl group to give the orthoester (aka triethoxy compound on CBr3 carbon). I feel that pathway is much more likely. But I still don’t have a good grasp as for an alternative to get to the dihydrofurans.

      • i did not mean cyclorpoane formation – I imagined direct O-alkylation of the enolate with CBr3 moiety

  2. Oh gotcha, yeah i could see that, and then just do alkoxide substitution at that carbon (maybe via assistance the oxygen like during substitution at the anomeric carbon in sugars)….Yeah I think that mechanism sits better with me cause you don’t invoke a furan intermediate.

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