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…


  1. Practicality of these reagents: The azaadamantane is too hard to make to serve as a starting material for a stoechiometric reagent. Perhaps you can justify it as a catalyst if it shows significant advantage over TEMPO.

    Homotropane (used for ABNO) is accessible from homotropinone (Robinson tropane synthesis, a product of ammonia, glutaraldehyde and acetondicarboxylic acid) but the keto removal by Wold-Kishner is unpleasant on scale, I have done it and its sucked.

    If anyone is interested, there is a chiral bicyclic iminium product obtained simply by Ritter reaction of (+)-limonene with acetonitrile and acid. And better still, (-)-beta-pinene as a starting material gives the opposite enantiomer of the same iminium product. I think this could be fast and dirt cheap way to make optically active versions of Bobbitt reagent and TEMPO:

    See this review, page 302, compound formula number 164, in Natural Product Reports (1989):

    Click to access Limonene.pdf

    • Oh yes I think you can certainly justify its synthesis (AZADO) so long as it has some sort of advantage over TEMPO (perhaps unique reactivity or accelerated oxidations). Its synthesis however is wayyyy too long to be practical. I was wondering how ABNO is made and yeah I figured it wasn’t fun. Anything more complicated than TEMPO/Bobbitt’s seems to be far less useful. I do like that idea of the chiral oxidant. It looks relatively easy to prep and the fact that its chiral is attractive. I know Dr. Bobbitt worked on a chiral oxidant at one point. I’ll have to ask him about what he found!

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