Put A Ring On It…Or Two!

Halocycloalkenones as Diels−Alder Dienophiles. Applications to Generating Useful Structural PatternsRoss, A. G.; Townsend, S. D.; Danishefsky, S. J. J. Org. Chem. ASAP Nov. 14 2012

As promised, I have a review for today, the last one of 2012! I was all set to go trap shooting with my brand new shotgun with my best friend today but unfortunately mother nature had other plans. Since I’m all snowed in here, I figured there was no better time to do a review! Not much has changed in the few days since my last post with the exception of some new ChemSpider posts (Oxidation of CF3 Alcohols by an Oxoammonium Salt, Oxidation of a Propargyl Alcohol with an Oxoammonium Salt, and Synthesis of a CF3 Ketone via Trifluoromethylation of a Weinreb Amide). Go check them out! They are all based on our recently published work so I hope you enjoy them. After spending a good hour or so looking through my favorite journals and catching up on many excellent articles I missed, I decided to go with an easy pick by a legendary chemist, Samuel Danishefsky. While I’ve never had the formal pleasure of meeting Professor Danishefsky, I have seen his laboratory while I was down at Columbia. He certainly has a nice set-up down there. Moreover, as the director for the Bioorganic Chemistry Laboratory at Sloan-Kettering Cancer Research Institute, much of his work is directed towards targeted syntheses . In fact, my former graduate student adviser at Columbia (who came to my talk at the ACS conference in Philadelphia!) currently works as a NIH post-doc at Sloan under Professor Danishefsky. While much of Danishefsky’s work centers around total synthesis, he is no foreigner to methods development. I’ve said it before but I will say it again: the best way to figure out where methods are sorely needed is by conducting a targeted synthesis. It’s quite clear that Danishefsky knows this concept quite well. Danishefsky is most famous for his named diene which has seen widespread usage because of its highly regioselective additions in Diels-Alder reaction.

a) Typical Danishefsky’s Diene Diels-Alder Reaction b) Intermolecular Cyclobutenone Diels-Alder Reaction c) Intramolecular Cyclobutenone Diels-Alder Reaction

On a related note, Danishefsky has recently been exploring the Diels-Alder of chemistry of an interesting dienophile, cycloalkenones. Specifically, he has been focusing on cyclobutenones as coupling partners both in the inter– and intra-molecular sense. This new area of research the Danishefsky group is pursuing is part of a more general strategy to promote pattern recognition analysis (PRA). PRA provides an interesting alternative to Corey’s strategic bond-oriented retrosynthetic approach to total synthesis. PRA takes more of a building block approach and hence the key to PRA is having a diverse array of “templates”, or core motifs as he calls them, to build off of.

Danishefsky’s explorations in cyclobutenone chemistry have proven quite successful in diversifying the available templates. However, there is always room for improvement in any type of chemistry. Seeking to “enhance the synthetic value” of cyclobutenones, his attention turned to 2-halocycloalkenones. Having developed a reliable route to synthesize cyclobutenone, preparation of its 2-bromo derivative was quite easy. Treatment with molecular bromine followed by an E2 elimination affords the vinylic bromide in 67% overall yield.


As a side note, I was quite curious about cyclobutenone. Surprisingly, or maybe not surprisingly, it’s not all that stable and readily polymerize at room temperature. It can be stored neat at -78 oC for a very short period of time but apparently can be kept as a stock solution in deuterated chloroform for much longer. I was also surprised that it was not until 1971 that it was definitively synthesized by Sieja and, even after it was synthesized, the chemical community paid little attention to it. To me, being a classical physical organic chemist, I thought this was somewhat of a travesty considering the interesting properties such a strained molecule must have!
After preparing his model 2-halocyclobutenone system, Danishefsky then began his investigation of it ability to serve as a dienophile. He was delighted to find that using a variety of dienes he could obtain excellent yields of the corresponding bicyclic (or in one case tricyclic) adducts. Moreover, the reaction was diastereospecific, producing only a single pair of diastereomers. He was even able to produce a facile reaction with Dane’s diene.

a) Dane’s diene reacting with a dienophile under thermal conditions b) Dane’s diene reacting with a dienophile under Lewis acidic conditions c) Dane’s diene reacting with a 2-bromocyclobutenone

I’ll confess that I was unfamiliar with Dane’s diene until reading this paper. According to Danishefsky, Dane’s diene doesn’t undergo Diels-Alder chemistry all too easily. When it does it gives two distinct products depending on the conditions. If Lewis acid catalysis is used the “meta” product is obtained while the “ortho” product is produced under thermal conditions:

Using 2-bromocyclobutenone, strictly the “meta” product was obtained in excellent yield. Additionally, the reaction was complete in only two hours at room temperature! During the course of the reaction, the double bond undergoes an unusual migration to become tetrasubstituted. No explanation for how this migration occurred is given, though my guess is that the isomerization reaction is low enough in energy (and produces the more thermodynamically stable alkene) that it can occurs spontaneously.


Danishefsky then moved on to assess the reactivity of larger 2-halocycloalkenones. He found that unlike their non-halogenated analogues, 2-bromocyclopentenone and 2-bromocyclohexenone reacted quite readily and gave good to excellent yield of their corresponding Diels-Alder adducts. Treatment of these adducts with sodium hydroxide in MeCN gave, at least to me, the most synthetically interesting products. These adducts underwent a quasi-Favorskii ring contraction (one of my favorite named reactions) to yield cyclopropane-containing products:


Danishefsky totes this as an alternative way to access the theoretical product of the Diels-Alder reaction between a cyclopropenyl carboxylic acid and a diene. Interestingly, one of the compounds examined does not undergo a ring contraction but rather gives the α-hydroxy substitution product … with retention of stereochemistry! Even more unusually is that treatment with methoxide produces an analogous result, the α-methoxy substitution product. Now I’m going to do something I normally don’t do here at New Reactions: put my own two cents in about an unusual finding in an article. I’m going suggest a mechanism that’s consistent with the observed data but…WARNING: I have no proof for this mechanism and some of it may be heretical. My hope is that we can maybe get a bit of discussion going out of it:


So what do you think? What are your thoughts on this peculiar product?

Well I hope you enjoyed this review and I recommend you take a look at the article yourself. Hats off to Danishefsky and co-workers for an excellent, well-written, and thorough article. I look forward to more work on these 2-halocycloalkenones! Ckellz…Signing off…


Back by popular demand…New Reactions Returns!

Dear Friends,

It has been a long seven months since my last post and for that I must apologize. You see life has a funny way of getting very complicated very fast. Let me give you a summary of the events that occurred in my world over the past few months.

1. Near the end of October, my father passed away after a two and a half year battle with lung cancer (non-smoker, living only 58 years). I’ve been spending a lot of time with my mom trying to help her out as best I can.

2. Our group (myself included) have published several articles regarding the construction of trifluoromethylketones (TFMKs). Below are schemes with the associated references:

a) A Weinreb amide approach to the synthesis of trifluoromethylketones Rudzinski, D. M.; Kelly C. B.;
Leadbeater, N. E. Chem. Commun. 2012, 48, 9610
B) Oxidation of α-Trifluoromethyl Alcohols Using a Recyclable Oxoammonium Salt Kelly, C. B;
Mercadante, M. A.; Hamlin, T. A.; Fletcher, M. H.; Leadbeater, N. E. J. Org. Chem., 2012, 77, 8131

3. We are in the process of wrapping up our work with Professor Tilley as well as some other small projects to be published in the near future 🙂

4. I successfully submitted and defended my general exam. I am now a Ph.D. candidate!

5. Dr. G. K. S. Prakash visited UConn as part of the PLU-sponsored seminar series. He gave an excellent talk and I was so happy to meet one of the leaders in organofluorine chemistry!! A lot of planning went into his visit.

6. In the little time that I have had I’ve published several chemspider articles…and only a mere week ago I received an email informing me that I had won a chemspider lab coat for my posts LINK

7. We are currently working on a collaboration with Vapourtec for a educational series flow unit.

8. Our group attended the ACS national meeting in Philadelphia in August. There we meet up with one of our former undergraduate student and had an amazing time!

9. In a need to find some relaxation, I’ve been playing quite a bit of airsoft and making videos of the games. Here’s a link to one: LINK

10. I’ve applied for a summer internship at Boehringer Ingelheim to work as a research assistant at their Ridgefield, CT plant. There is a good chance I will get to work there this summer! 🙂

So as you can see, life essentially wanted all of my time. Anytime I tried to sit down and write a post I was interrupted and, rather than putting out poor posts, I decided to let the waters calm a bit. This week, I have taken time off to be with my mom on this first Christmas without my father. It has been rough for us but we’ve managed to make it a decent Christmas. Now that my house is quiet and I have far less to do than over the past seven months, I finally can sit down and just read the literature and return to posting. Rather than doing a new article, I figured I could go through our two articles that we published and then in my next post begin again fresh. So…what did we do?

In the first of the articles is the work I did with DiAndra on a one-pot route to TFMKs. The idea for this project came to me one day after reading a review on TMS-CF3. The review stated that to date, TMS-CF3 had not been used constructive manner for an acyl substitution reaction with amides. I was kind of surprised to find this because of the several successful reports of ester displacement. However, at the same time, it kind of made sense. Even if the nitrogen species was displaced, it would likely add right back into the electrophilic CF3 ketone. Thinking to basic organic chemistry, I pondered whether Weinreb amides (which have been immensely useful in constructing ketones via with Grignard reagents) would be suitable candidates as leaving group. In more general terms, I wanted to see if any amide, even a reactive one, could be used to construct TFMKs directly.

So DiAndra and myself began exploring the feasibility of this reaction. We hit immediate success with the simplest system, a phenyl Weinreb amide. By GCMS analysis we found that we had complete conversion to the TFMK. However, conversions are always deceptive and apparently the heat of the injector decomposed an unbeknownst to us intermediate When we attempted isolation by our traditional method we obtained very little TFMK. Thinking that our low yield was due to the volatility of this compound, we switched to a p-t-butyl phenyl system. Again, after workup we obtained low yield. Examining the crude reaction mixture by NMR revealed the presence of a silylated intermediate. However, as we monitored the stability of this species in THF, we found that it would slowly revert back to the starting material. Fortunately if cleaved rapidly, we could obtain substantially more CF3 ketone product. Still, yield was lacking. I then suggested that rather than go for the TFMK, let’s optimize the reaction for the silylated intermediate. Sure enough we found that, using toluene as the solvent and CsF as the fluoride source to initiate the trifluoromethylation process, we could obtain near quantitative conversion and excellent yield of the silylated intermediate. Yes, we could in fact isolate the intermediate!!


We then focused on cleavage conditions. This took a bit a work and I’ll spare you all the details. We found that heating the reaction mixture to 50 oC in the presence of TBAF in THF and H2O we could successfully convert the silylated intermediate to the TFMK product in good yield (81% for the p-t-butyl). With this two-step, one pot protocol hammered out, we moved on to a substrate screen. We found that this reaction had a reasonably broad scope, with some exceptions. Ortho-substituted arenes and straight chain systems with significant alpha branching failed to convert to the desired intermediate. Beta branching was less of a problem but did lead to lower yields. We attempted this to a steric requirement by the reaction rather than an electronic rational. My current theory is that there is a necessary chelation of TMS-CF3 by the amide Weinreb amide which is decomposed by the addition of fluoride. In some substrates, either the chelation is too poor or the activation energy for complex formation is too high and hence trifluoromethylation cannot occur.


We also explored α,β-unsaturated Weinreb amides. Here another complication arose. While we could successfully convert to the silylated intermediate quite easily, we obtained low isolated yield of the TFMK product. This time we analyzed the crude cleavage mixture and found that in addition to the desired α,β-unsaturated TFMK we found another TFMK ketone product. This new product was the result of the Michael addition of the displaced N,O-dimethylhydroxylamine anion into the highly electrophilic alkene of the desired α,β-unsaturated TFMK. Luckily, this unwanted byproduct could be removed by column chromatography. And that’s about it. What I loved most about this reaction is the scalability. One of my biggest pet peeves is when papers publish reactions done on 0.1 mmol scale. To me that’s not practical other than to maybe a chemist performing a total synthesis. This reaction has been performed anywhere from 10 mmol to 60 mmol and could likely be performed on the hundreds of mmol scale. Additionally, we have recently made some modifications that have improved yields and reaction times which will be published in chemspider in the coming week or so.

Moving on to the next article, we have a more traditional approach to TFMK construction via the oxidation of their corresponding carbinols. Not surprisingly, we attempting to do so via our favorite oxidizing agent in the Leadbeater lab, Bobbitt’s salt. To date no reports of oxidation of these difficult-to-oxidize carbinols via an oxoammonium salt have been reported. TEMPO-based methods have been reported but these protocols use aqueous media in their reaction conditions. While this is not normally a problem for traditional ketones, trifluoromethylketones have the nasty habit of hydrating in aqueous systems, particularly in basic conditions (and TEMPO oxidations are conducted under alkaline conditions). The only reliable method for oxidizing these carbinols that is currently known is the use of Dess-Martin periodinane. While I LOVE DMP, it is insanely expensive and making it in-house is…difficult…to say the least. Therefore, we set out to attempt to use Bobbitt’s salt to oxidize these alcohols. However, using the traditional conditions (DCM, SiO2, Oxidant) no reaction occurred. The putative hydride transfer from the α-carbon was likely too high in energy because of the resulting destabilized “electron-deficient” carbocation.


After some discussion with Dr. Bobbitt, we attempted to use the newer, basic conditions for our oxidation. According to Bailey and Bobbitt, the presence of a base dramatically alters the reaction mechanism. The change in reactivity results from a tightly bound ion pairing between the now formally deprotonated alcohol and the salt. This enables a more facile hydride transfer. Note that by “formally deprotonated”, I mean that there is a much greater percentage of the alkoxide in solution than under neutral/slightly acidic conditions. The bases we use, pyridyl bases, can most certainly not deprotonate the alkoxide irreversibly. We were pleased to find that under basic conditions, we could obtain quantitative conversion to the desired ketone and isolated yield. We found that as we increased the basicity of the base, the rate of the reaction increased (e.g. 2,4,6 collidine reacted faster than 2,6 lutidine) However, for in an effort to balance ease of purification with timely oxidation, we chose 2,6 lutidine over pyridine and 2,4,6 collidine.

Once we had optimal conditions, we move on to oxidizing a variety of carbinols. Aryl substituted, alkenyl, and propargyl CF3 carbinols all oxidized easily and in good yield. However, under our original conditions aliphatic CF3 alcohols failed to oxidize. To circumvent this problem, we chose to use 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) as the base to formally deprotonate these alcohols. This resulted in a rapid, mildly exothermic reaction and smoothly converted the aliphatic species to TFMKs. Due to degradation of the base by the oxidant, not only was more salt required for complete conversion but more extensive purification was needed (e.g. vacuum distillation). Therefore, while it can be done with these compounds, this method likely isn’t the optimal way to oxidize CF3 alcohols lacking a neighboring sp or sp2 center.

To further demonstrate the power of our method, we found that we could selectively oxidze alcohols by simply adjusting the conditions. We conducted the following:


By taking advantage of the fact that the oxidant will not react with CF3 carbinols unless under basic conditions, we can selectively oxidize the non-CF3 alcohol. We can then oxidize the CF3 alcohol using our optimal conditions. Now I know what you are going to ask, what happens if you oxidize the diol under basic conditions? Unfortunately there is no selectivity; you get a mix of oxidation products.

Finally we conducted a simple rate study to get a idea of the relative rate of oxidation. We used the convenient method of Mullet and Nodding to obtain kinetic data. From there we used one of our aryl systems as our base line for the rate of oxidation. We found that the more extensive the conjugation, the fast the rate. Interestingly this was not the only factor. The propargyl CF3 system we studied oxidized extraordinarily fast (120 times faster!) indicating to us that a steric component to the oxidation was present as well. Therefore, we suggested that, in addition to cation stability, the combined electronic repulsion by the highly electron-rich CF3 group and the steric repulsion by any β-substituent contribute significantly to oxidant/alcohol complexation and hence successful oxidation. Again what I like most about our method is it’s scalability. You can perform these oxidations on any size scale. Moreover they are colorimetric. Prior to addition of the pyridyl base, the reaction will be bright yellow from the oxoammonium salt. After the base is added the reaction will transition from yellow to orange to finally deep blood red. This red color typically indicates reaction completion. Finally, you can recover the spent oxidation and reuse it to make more salt!

Well that’s it for this post. I really hoped you enjoyed the update and the work we have done over the past few months. I have to say I am very proud of what our group has accomplished so far and more is yet to come! I plan on posting much more frequently now so keep a look out for an upcoming post! Ckellz…Signing off…