Moar Oxidation! MOAR!

Eddy, N. A.; Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E.; Fenteany G. Access to Dienophilic Ene-Triketone Synthons by Oxidation of Diketones with an Oxoammonium Salt Org. Lett. ASAP December 29, 2011

So that moment that you all have been waiting for (well lets be real, mostly the moment I have been waiting for) has arrived. I can finally share with you the project we worked on with Dr. Fenteany’s group this past year. After our group became interested in green oxidations using, surprise surprise, Bobbitt’s salt, we found that a graduate student upstairs had discovered something very unique. If 2,2 dimethyl-1,3-cyclohexadione was exposed to Bobbitt’s salt for an extended period, very little of the α-oxidation product was obtained. The student, Nick Eddy, was really interested in obtaining this another project he was working.

However, he noticed that another unusual product was obtained because some of the starting material had been consumed. After careful NMR analysis, he determined that the product was in fact an overly oxidized derivative of his starting material, an ene-triketone. Now at that point, it was fundamentally interesting but was it useful? After doing a bit of reading, he soon found out that the compound he has prepared normally took four steps to make and at 15% overall yield. No other ene-triketone had been reported in the literature, likely because of the difficulty of their synthesis. After talking with us about it, we agreed that if we could optimize the reaction to give a high yield of the ene-triketone and turn this into a project, it would likely be of high interest to the organic community. So we spent some time optimizing the reaction, ultimately finding that reaction only occurred at slightly elevated temperatures in highly polar solvents (DMF, MeCN). Moreover, it required a large loading of salt (3.8 equiv)! On a large scale, this meant greater than 60 grams of salt. So we became experts at preparing Bobbitt’s salt (which, as I’ve said, is very easy).
We also found that the quality of the salt needed to the be the highest it possibly could be. It needed to be absolutely free from impurities and water (as did the solvent). We needed to not only recrystallize the salt from boiling water but also rigorously dry it using not a desiccator but with a Abderhalden over KOH and ethanol! This boosted our yield from 20-30% using the normal powder version of the salt to 60-80% using the highly purified salt. With that accomplished, we then prepared a range of 2,2 disubstituted cyclohexadiones. Now you may wonder why it was necessary to block that 2 position (in between the two ketones). That is to prevent enolization at that position (very stable enol) and oxidation to give the 1,2,3 triketone which has been reported. Therefore we tried a variety of substituents with mixed results. Most of the ones we tried worked (and the syntheses of these substrates were amazingly fun)! We also got some meaningful mechanistic information out of the substrates we tried. The following two results:


told us that the driving force of the reaction was that first ene-like reaction and sterics (which was said to be, in their system, disfavorable by the AZADO article I just reviewed) and subsequent oxidation to the triketone. From there, the triketone immediately enolizes and reacts again. Since there is a acid proton in the vicinity, it eliminates to generate the olefin of the ene-triketone. We need for excess salt, heating, and the polarity of the solvent all make sense with the mechanism (stabilizing enol form, 3 oxidations, steric repulsion). The mechanism is by far the best part of the article to me so here it is in all its glory:

At that point we could have stopped and submitted the work. But we weren’t satisfied with just the oxidation, we wanted to see what sort of reactions we could do with the ene-triketones (being the only people to have access to them at that time). We decided that an excellent application would be as dienophiles in Diels-Alder reactions. That olefin is very electron-withdrawn and therefore would likely react in a shot. And, as predicted it did at room temperature! We found that most of our ene-triketones reacted quite well with fair to excellent endo : exo ratios. The sheer complexity of the molecules were generating was what really impressed me though. Well I really hope you go take a look at our article for more details and enjoy it! It certainly made my day yesterday! Ckellz…Signing Off…

December 30, 2011
Categories: My Publications . . Author: ckellz . Comments: 3 Comments

What the Heck is an AZADO?


Hayashi, M.; Shibuya, M.; Iwabuchi, Y. Oxidative Conversion of Silyl Enol Ethers to α,β-Unsaturated Ketones Employing Oxoammonium Salts Org. Lett. ASAP December 19, 2011

Happy holidays to all my readers!!! I hope that the holidays treated you all well. Thankfully, I have the week off this week which has allowed me to catch up on much of the writing I have put off. As I mentioned in my last article, our work with Dr. Fenteany’s group was accepted into Org. Lett. and (should) be up on the ASAPs this week. We received the proofs on Friday of last week and they were resubmitted on Christmas Day with very minimal corrections. I plan on doing a special post on it when it comes out so check back over the next few days. As for chemistry in the Leadbeater lab, nothing really new to report. The lab has the week off for the holidays allowing all of us to recoup and get ready for a very busy January. In the meantime, I have been working on prepping DiAndra’s work for submission to JOC. I’m still debating personally on whether it belongs there or Org. Lett. Either way it’s shaping up to be a phenomenal paper worthy (in my opinion) of both journals. In other news, one of our methods papers is just about complete and should be in by mid-January. I’m really excited about that one as it relates quite closely to the work DiAndra has been doing and gives a good feel for the sort of chemistry we’ve become interested in the Leadbeater lab. Our flow paper has (FINALLY) been submitted to Org. Lett. and, as far as I know, it is already out for review. So with all our hard work coming to fruition, 2012 is looking to be an excellent year in terms of publications. I hope to have at least 10 publications before I graduate from UConn (hopefully allowing me to graduate in less than 5 years). So far, that looks to be a very real possibility!
Not that I enjoy politics, but I can’t help but comment on the UCLA incident and the current criminal charges being filed against Professor Patrick Harran. For those who do not know what I am talking about see the summary here and the latest news here. I think what’s happening to him is appalling and not justice but revenge for an act he didn’t have much responsibility for. Do I feel bad for Sheri Sangji, the research assistant who died from the burns she received? Absolutely, no one deserves the suffering she endured from the fire. However, that does not mean the PI is responsible. Much of the fault is in fact her own. She was wearing inappropriate lab attire, minimal eye protection, and working with a extraordinarily dangerous reagent that she had little familiarity with by herself. She was also using a syringe size that no experienced chemist would use for the particular reagent she was dealing with (t-BuLi). For those who haven’t worked with t-BuLi, it’s one of the few reagent that puts me a little on edge. It ignites in a beautiful but frightening purple flame on contact with air and is stored in pentane, adding to its volatile nature. So if a bottle were accidentally exposed to air, the bottle would explode into flames and that’s exactly what happened with Sangji. However, I don’t believe that Harran deserves to have his life destroyed (4.5 years in prison and basically he will have no chance of returning to chemistry) for an incident he is, at most, minimally responsible for. Some fines against the university are understandable but not jail time for the PI. What do you all think?
Now on to some lighter, more academic news, a new review! I had another tough time again this week choosing an article. Here’s a few of the runner ups (which are they themselves very interesting and good chemistry!):
1. CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic Oxidative Synthesis of 2-Substituted Quinazolines and 4H-3,1-Benzoxazines Yu, W. et al JOC ASAP December 14, 2011
2. A phosphine-free Pd catalyst for the selective double carbonylation of aryl iodides Castillón, S. et al Chem. Commun. Advanced Articles
3.[1,4]Dithiepino[2,3-b]furans from Oxiranecarbaldimines and Lithiated 1,3-Dithiane: A Series of Rearrangement Reactions in One Pot Würthwein, E.-U. et al EJOC Early View
4.Reaction of InCl3 with Various Reducing Agents: InCl3–NaBH4-Mediated Reduction of Aromatic and Aliphatic Nitriles to Primary Amines JOC ASAP


However, for the sake of a bit of foreshadowing (HINT!) of my own article and to stick with the theme of oxoammonium salts, I decided to go with an article detailing the oxidation of silyl-enol ethers to their corresponding α,β-unsaturated ketones. I had never heard of 2-azaadamantane N-oxyl (AZADO) before nor it’s the oxoammonium salt derived from it. In fact there are quite a few of these oxyl radicals derived ridged ring systems (9-azabicyclo-[3.3.1]nonane N-oxyl ABNO being another). According to this article, these bicyclic oxoammonium salts are far more effective oxidant than our friend TEMPO-BF4,a salt very similar to Bobbitt’s salt. However, if you dig a little bit, you soon realize that synthesizing AZADO is far more difficult than TEMPO-BF4 (9 steps to get to AZADO (of ten total) and only two (of three total) to get to TEMPO). I smiled a little bit when I saw the sheer number of references to Bobbitt on the first page alone. The first few paragraphs simply outline the advantages of oxoammonium salts and their use so I won’t bore you with that. The author’s goal of this article was to provide an alternative (possibly greener and safer) approach to performing α,β-dehydrogenation of ketones.

Their first attempts to utilize AZADO for this transformation were met with mixed results. They tried using a cyclohexyl derivative to accomplish oxidation and got a mixture of the desired α,β-unsaturated ketone as well as the α-aminooxy ketone. As with most good reactions, their was the minor product and therefore the authors needed to find a way to turn the side reaction into the major reaction. By switching to lower temperatures (-78 oC) and using a tert-butyldimethyl silyl enol ether instead of the trimethylsilyl, they were able to obtain a 93:7 ratio of the dehydrogenated product to the α-aminooxy product. They compared salts too, finding that their original candidate, AZADO, was the reagent of choice for this oxidation.
Next they did a comparison of counter-ions: BF4-, PF6-, ClO4-, SbF6-, Cl-, NO3-. They found that the less nucleophilic counter-ions (BF4-, PF6-, ClO4-, SbF6-) gave very similar ratios of dehydrogenation to addition of the α-aminooxy group with BF4- being the most selective. Cl- and NO3 gave far worse ratios. No explanation was given for this so I’d be very interested as to why there is a counter-ion effect.
What I liked most about this article was the detail they went into in their experiments. Rather than immediately jumping to substrate screening, they focused on isolating a transient intermediate species in their oxidation. It turns out that an intermediate (before queching the reaction with saturated bicarbonate) is a mixed acetal. This gave the authors a unique insight into the reaction mechanism. They proposed the following:

Also they used the same rational to explain why the TEMPO derived salt gave far more of the α-aminooxy product:

After giving a plausible mechanism for their transformation, they then explored the scope. They found their reaction to be quite broad. Moreover they found their reaction proceeded stereoselectively in that acyclic species gave only the less sterically demanding E-isomer. Finally they noted that AZADOH (the reduction product of the spent oxidant) was recovered and re-oxidized quite easily, suggesting that their method was “recyclable” in oxidant.
Overall this was a short but very practical article demonstrating the versatility of these salts for transformations other than simple carbinol oxidation. Hats off to Iwabuchi and co-workers for an excellent investigation and a useful method! Be on the lookout for another post within the next couple of days! Ckellz…Signing off…

December 29, 2011
Categories: Reviews . . Author: ckellz . Comments: 2 Comments

Husky Pride


Qui, J.; Pradhan, P.P.; Blanck, N. B.; Bobbitt, J. M.; Bailey, W. F. Org. Lett. ASAP December 8, 2011

Nothing makes me want to blog more than good news. And frankly, I’ve hit the jackpot with good news lately. First off, I am extraordinary happy to be done with my teaching responsibilities, final projects for my classes, and finals in general. Less time for studying equates to more time for lab work! Secondly, I’m am happy to report that our collaborative work with the Fenteany group has been accepted to Organic Letters pending minor revisions (I’ll be giving a hint of what the article is about at the end of this post). Needless to say, getting another publication in one of the best organic journals out there made my day. Next, we just finished a flow project which, in theory, should also be submitted by the end of the week (likely to the same journal). DiAndra’s project, which I have spent an increasing amount of time on lately, has continued to give us excellent results and my estimate is that it will be done (and submitted) by the middle of January. I’ve made some progress with a few avenues I’ve been exploring as well (though due to the amount of work I’ve had, progress is slow to say the least).
As part of the requirements at UConn, students are required to take a graduate seminar course in which speakers from other institutions are brought in to present on their work. This past week was a somewhat special occasion as the speaker was Dr. Brian Stoltz from Cal-Tech and he gave one of the best talks I’ve heard in some time. His talk detailed a recently methodology developed in his lab for the synthesis of enantioselective decarboxylative alkylation reactions of cyclohexyl rings.

The transformation relies on the principle of stereoablation: the reaction destroys a stereocenter as part of the reaction mechanism and, in the ensuing chiral transformation, a highly enantio-enriched product is obtained. In the reaction discussed by Stoltz, which was modified Tsuji–Trost allylation, a methyl-substituted cyclohexyl beta-keto ester (the ester being an allyl ester) would be decarboxylated in a Trost-like manner yielding an enolate. Since enolate formation is independent of the stereochemistry of the starting material, a enatioselective recombination of the freed allyl group with the enolate is possible. In the presence of the proper ligand, high e.e.s for one enantiomer can be obtained from a completely racemic starting material. After his seminar, we had time to talk with him in person and I showed him a bit of the work we have been doing in the Leadbeater Lab. He seemed to like it and over all he was a very interesting and down to earth person to talk to.
Continuing with the trend of good news (and on to a review), there have been many good articles the past couple of weeks so choosing one for this post was quite hard. The runners up include:
1. A Suzuki cross coupling with 1-iodo-2,2,2-trifluoroethane to effect 2,2,2-trifluoroethylation of arenes in Ang. Chem.
2.Using a relatively under explored element, bismuth, for very unusual transformation (under the framework of “Carbobismuthination“) involving alkynes and silyl enol ethers. This paper was also in Ang. Chem..
3. Using lithium trimethoxy(trifluorovinyl)borate for the preparation of trifluorostyrene derivatives via a Suzuki cross coupling with arenes.This paper was also in Ang. Chem..
4. Converting Acids to Amides in one shot using trimethylaluminum in Org. Lett.
5. A SeO2/BF3 based method for the synthesis of triarylethanones from aromatic ketones and arenes in J. Org. Chem.
All of these articles are excellent and if you get a chance, certainly check them out! As for this week though, we have a home town pick, an article published by Dr. James Bobbitt (a emeritus professor here at UConn) and Dr. William Bailey. Dr. Bailey’s primary interest is in organolithiums, however in recent years he has worked quite closely with Dr. Bobbitt on studying oxoammonium salts for the oxidations of various species. Specifically, the oxoammonium salt of study by Bailey and Bobbitt is 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate, affectionately dubbed “Bobbitt’s Salt” due to the vast amount of work done by Dr. Bobbitt involving this salt. I cannot more highly recommend it as a oxidant of choice. It will selectively take primary alcohols to aldehydes with a extraordinarily simple workup (filter through a plug of silica). Moreover, oxidations are colorimetric; the reaction mixture will start off yellow and, when complete, turn milky white. While currently a UConn specialty, many members of the department have been spreading the word about the salt (especially since it’s very easy to prepare!). However, until now, oxidations with Bobbitt’s salt were somewhat limited in that they could only effectively be used to make aldehydes. In this new article, Bailey and Bobbitt detail a method for using the oxoammonium salt for the preparation of carboxylic acids.

The article begins by details the general use, advantage, and some previously established trends in reactivity. Early on they essentially revise and expand up some trends observed in their previous articles. Based on relative rate studies and computation work (done in collaboration with Dr. Kenneth Wiberg at Yale), Bobbitt and Bailey suggest that the mechanism is involves a formal hydride transfer from the carbinol to the oxoammonium salt. They found that the rate of oxidation is proportional the ability of substrates to accomidate positive charge at the carbinol carbon. With these tenets in mind, we can easily understand why oxidization of benzyl carbinols proceed quite fast (especially with electron rich arenes).

After this brief digression, the authors begin to describe their new methodology, namely the oxidation of primary alcohols to carboxylic acids. The conditions are relatively simple: 2-2.2 equiv of Bobbitt’s salt and the alcohol to be oxidized in a MeCN:H20 (9:1) solvent system. As with the oxidation of alcohols in DCM to aldehydes, this reaction is also colorimetric (doing from a orange-brown to a yellow-orange.
To demonstrate the versatility of their oxidation, a wide range of primary alcohols were oxidized. The authors also note a peculiar trend when examining the reactivity of these various substrates. Aliphatic alcohols seemingly oxidized the fastest while benzyl alcohols are very sluggish. This is in stark contrast to oxidations conduct in DCM to obtain aldehydes. In the latter case, benzyl alcohols react in mere hours rather than the former case in which it make take days to obtain the acid. Not only do the author’s give an explanation for this change in reactivity, they also exploit it. To better explain the change, a mechanism is necessary:

The authors argue that the rate determining step is hydration of the intermediate aldehyde. This is in line with previous work (and a previous post by myself) using TPAP. They further support this finding by conducting a relative rate study, finding that electron-deficient arenes (p-nitro) react many times fast than electron-rich arenes (p-methoxy). Hydrate formation is typically a function of the electrophilicity of the carbonyl carbon of the aldehyde, hence this finding makes sense. Bobbitt and Bailey then exploit this by working with a mixed aliphatic/benzyl diol system. They first show that the benzyl alcohol can be selectively oxidized over the aliphatic alcohol using the classic DCM conditions to the corresponding aldehyde. They then oxidize the aliphatic alcohol to the aldehyde. Treatment under their new conditions affords sole oxidation of the aliphatic aldehyde to the corresponding acid, thus proving the selective nature of their oxidant.

This was excellent work done by Bailey and Bobbitt, though I cannot say I’m not a little biased :P. I recently needed to oxidize a propargylic alcohol to the corresponding acid and I am happy to report that, using the conditions developed by the authors, I was able to obtain it in excellent yield. Overall this is a very practical and useful paper!
Now, as promised, a preview for our work with Dr. Fenteany’s group:

We were able to take diones to the ene-triketones all in one pot! As soon as it’s out I will share the rest of the story!

December 15, 2011
Categories: Reviews . . Author: ckellz . Comments: 8 Comments