From Zero to Highly Strained in 45 Minutes!

Enantioselective Synthesis of 2-Arylbicyclo[1.1.0]butane Carboxylates Qin, C.; Davies, H. M. L. Org Lett. ASAP January 3rd, 2013

Happy New Year from New Reactions! 2013 brings another year of methodology blogging! It’s hard to believe that I started blogging two years ago this month. It most certainly has been one of my best decisions and I plan to continue doing it for a long time to come. After returning to lab this week, I have really begun cranking on some new projects in addition to finishing up two others. My hope would be to publish 3-4 research papers this year if possible. I just recently finished two review articles which should be published soon (one next month and one by the end of March). I’ll be sure to link them on NR once they are up. I am working closely with some of our undergrads as well (yes they do chemistry over winter break!) to hopefully get them on some papers. Additionally, we met with Professor Tilley yesterday as part of our collaboration with him (which is near completion!). I hope to send one of our excellent undergrads to work with him this summer.

Considering it has been little over a week since my last post (with a holiday there in between), I had a much smaller selection of new articles to choose from for this post. But in a way that was a good thing because I would have missed today’s article. While I do appreciate the need for chiral methodologies and high ees, they aren’t my cup of tea. I get excited for interesting, new transformations (especially those involving fluorine, but that’s beside the point). So I nearly skipped reading this new article from Davies at Emory because it started with “Enantioselective Synthesis of…”. However, the [1.1.0] managed to catch my attention. They are making bicyclobutanes! As you may already know, in addition to organofluorine chemistry, I loved strained systems. My undergrad research was focused on preparing bicyclobutanes so they always have a warm place in my heart. I was even more ecstatic when I found out that Davies cited my bicyclobutane paper!

For those of you who don’t know much about these systems, bicyclobutanes are some of the most strained systems known. The first bicyclobutyl system was prepared by Wiberg in 1959 via an anionic-ring closure:


Apparently they also were able to make the bromide tertiary and still perform the ring closure (although no synthesis of this bromide is given)


It wasn’t until a few years later (1963) that the unsubstituted system was prepared by Wiberg via a Wurtz coupling method:


Finally, others started to get into the business of these small strained bicyclics. In the early 70s, Sieja, at du Pont, became very interested in synthesizing strained ring systems. You may remember his name from my last post. He was the first one to synthesize cyclobutenone. Not only that, but in a two year span from 1971 to 1972 he synthesized cyclobutanone as well as several bicyclobutane derivatives (Cyano, phenyl/polysubsituted/unsubstituted). His approach was, like Wiberg’s, anionic in nature. One route was to generate a carbanion via a Grignard process and do an internal displacement:


The other route was more akin to Wiberg’s 1959 work in which an acidic proton would be deprotonated to induce ring closure. In fact it was an expansion of the lesser known work by Blanchard:


As far as I am aware, no additional work was done on preparing bicyclobutane or its derivatives until my article in 2011. Rather than using an anionic approaches, we investigated whether an cationic route could be used. Shiner showed that ring closure can be affected by 1,3 silyl elimination in the cyclohexyl manifold when the silyl group and the leaving group are in the ideal “cis” conformation. However, even in this ideal configuration, it is a minor product. We attempted a similar study in the cyclobutyl system. However reaching the desired sulfonate ester proved problematic as confirmed by Creary. We were able to pyrolzye it in situ to give low yield of the desired bicyclobutane. Unfortunately, this was by no means an efficient or effective method to synthesize the unsubstituted parent compound. Theorizing that the 1,3 elimination pathway could be enhanced by increasing electron demand at the cationic center, we installed a CF3 group at the -position. Isolation of the sulfonate ester was not only possible with this derivative but could be done in good yield. Solvolysis of this reactive species gave solely 1,3-silyl elimination, yielding the novel 1-(trifluoromethyl)bicyclo[1.1.0]butane. Similarly, the pentafluoroethyl derivative could be synthesized this way as well. The route I utilized is below:

Tilley 4

Now that you know how it was made previously, how did Davies accomplish the synthesis of several bicyclobutyl derivatives? Well Davies, who for a long period of time was at the University of Buffalo, focus on enantioselective reactions utilizing chiral rhodium or dirhodium catalysts. He uses the carbenoid intermediates produced by these catalysts to perform cyclization reactions. While not solely his focus, he has used these catalysts to affect enantioselective cyclopropanation with remarkable success:


Seeking to further expand the scope of his methodology and develop the one of the first (if not the first) enantioselective route to bicyclobutanes, Davies explored a new system for cyclopropanation. He postulated that by simply extending the chain and placing the alkene within the same molecule as the putative carbenoid, he could obtain a double ring closing reaction:


Using a simple model system, they explored Rh2(TPA)4 based on some reports by Fox indicating that this type of transformation would require a bulky rhodium species. However, rather than obtaining a bicyclobutane, a cyclohexene and a diene was instead isolated:


Davies argued that these product could result from two possible pathways. The first pathway involves no bicyclobutyl intermediates:


The second invokes the formation of bicyclobutyl derivatives. However, under the reaction conditions these strained systems further undergo reactions with the rhodium catalyst:


Both mechanisms are quite plausible. Later exploratory studies found that the bicyclobutanes could be obtained using Rh2(TPA)4 if ultra-low catalyst loadings were used in addition to short reaction times. However, both the cyclohexene and the diene were still being formed. Switching to Rh2(OAc)4, which is only slightly soluble in their reaction solvent (DCM), they were able to substantially improve selectivity towards bicyclobutane formation. Apparently this rhodium species does not catalyze the rearrangement to the diene/cyclohexene as readily and hence by using even shorter reaction times, strictly the bicyclobutane can be isolated. This catalyst gave excellent diastereoselectivity but no enantioselectivity.


Since Davies is interested in asymmetric transforms, chiral dirhodium catalysts were explored to facilitate an enantioselective cyclization. After some careful study, Rh2(R-BTPCP)4 was found to be the optimal catalyst. Using this catalyst, 9 bicylobutyl derivatives were prepared in moderate to excellent e.r. Davies did not forget about his cyclohexenes however. Using high loadings of Rh2(TPA)4 and longer reaction times, he showed that a variety of highly substituted cyclohexenes could be prepared.


Finally, with bicyclobutanes in hand, Davies sough to address the mechanistic question of which of the two pathways is operative. Using Rh2(TPA)4, at short reaction times (40 minutes), he showed that a mix of products could be obtained (diene/cyclohexene/bicyclobutane). By allowing the reaction mixture to stir for 12 hours, the remaining bicyclobutane starting material was completely converted into the expected products (mostly into the cyclohexene). He then proceeded to expose a previously isolated bicyclobutane to the same reaction conditions. After 40 minutes, a mixture of the diene/cyclohexene/bicyclobutane was obtained and after 12 hours no more bicyclobutane was detected. Rather it completely converted to the cyclohexene. However, since the ratios between the 40 minute two trials were drastically different, Davies concluded that both mechanism were occurring. He did state that, based on the ratios, direct conversion of the starting material to the cyclohexene is faster than decomposition of the product (which is in line with the necessity for short reaction times).

Well this certainly was an excellent article by Davies and I hope you all enjoyed it. It’s not too often you see a new route to bicyclobutanes, not to mention an enantioselective one! Hats off to the Davies group for an excellent job! That’s it for this week, Ckellz…signing off…

New Blogs

After reading a previous post on BRSM, I too have added some new chem blogs to the list of links —–>, Hope you enjoy them, as I certainly did!

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…

And suddenly fluorine…all of it!

Methyl 2,2-Difluoro-2-(fluorosulfonyl)acetate, a Difluorocarbene Reagent with Reactivity Comparable to That of Trimethylsilyl 2,2-Difluoro-2-(fluorosulfonyl)acetate (TFDA) Eusterwiemann, S.; Martinez, H.; Dolbier, W. R., Jr. JOC ASAP May 21, 2012.

Direct Electrophilic N-Trifluoromethylation of Azoles by a Hypervalent Iodine Reagent Niedermann, K.; Früh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A. Angew. Chem. Int. Ed. Early View May 22, 2012

After a long hiatus, I have finally returned to the world of chemistry blogging. These past two months have been some of the busiest of my graduate career thus far. After my tetrahedrane guest post on BRSM, I really stepped-up my chemistry game trying to finish up the three project that I am currently involved in. Two of these three should be ready for submission very soon and the remaining one should be complete by summer’s end (at least that’s my expectation right now). We manage to get another publication, a flow paper in OPRD in April. It was more technically oriented so it fit better in OPRD than in a more organic journal like Org. Lett. With the semester ending, I am finally officially done with class for the rest of my life (at least for required class, I presume I will take classes of my own volition in the near future *cough* pistol permit safety class *cough*). With this complete, I will have even more time to do research in the fall. Speaking of the fall, rumor has it we may have an exciting speaker coming to UConn to give a talk next semester, Dr. G. K. S. Prakash! I would be very happy to get a chance to talk with the guy whose lab helped develop one of the most powerful trifluoromethylating reagents known, TMS-CF3. Speaking of TMS-CF3, I’ve put up a bunch of procedures (including one using TMS-CF3) up on Chem Spider Synthetic Pages (Paal-Knorr Pyrrole, KBH4 Reduction, [2+2] Cyclobutanone Synthesis, Finkelstein TMS-CF3) so go check them out!
The graduate student conference in Buffalo, the CGSS, went quite well. The Leadbeater group all had great posters and presentations. It was my first time to Buffalo and I ended up really liking it there. We all meet some cool people (including DiAndra’s former boss at Niagara University, Dr. Ronney Priefer) and saw some excellent presentations (especially by one of the key note speakers, Corey Stephenson from BU). I’m really looking forward to our next conference, the ACS meeting in Philly in August. All of the talks and posters submitted by our group have been approved so we will all be going.
With the end of classes and the beginning of the summer, I’ve had far more time for research. Its also nice to get out of work feeling like I accomplished light AND its not pitch black out. We have several students in our lab for the summer, one from CCSU, one from UConn, and a Stonehill Student that was sent by Dr. Tilley. They all seem excited to start doing research but they all require a bit of training. Everyone in the lab has been pitching in to get them trained up. Unfortunately though, while gaining some people, we are also losing DiAndra. She is off to Boehringer Ingelheim (BI) for the next part of her Master’s in synthetic organic chemistry. Her internship at BI could possible lead to a job there. I hope she really enjoys it there and I know she will own. She won’t be all that far away either…the BI research plant is in Ridgefield Connecticut and after she’s done there she will return in the fall to finish her thesis and defend. Considering that I have no experience with industry, I am currently looking into the possibility of getting an internship there for the summer of my third year. BI and UConn have a great relationship and many students have done that sort of thing in the past. An internship like that may swing me towards industry or academia but I think you’ve heard enough about my life now though :P, let’s get to the chemistry.

While I wasn’t blogging, I was still trying to keep up with the latest literature. However, to keep things current, I found a number of good articles in past few weeks that have been interesting and have had great chemistry in them:

  • Intramolecular σ-Bond Metathesis Between Carbon- Carbon and Silicon- Silicon Bonds from the
    Murakami Group details a interesting strained-ring expansion strategy to access silaindanes (see my previous post about another awesome method to access this sort of motif)
  • Palladium-Catalyzed Substitution and Cross-Coupling of Benzylic Fluorides by Brown and Gouverneur detailing a remarkable C-F bond-breaking method (a transformation which is not very common, although benzylic fluorides are somewhat reactive). This article was also featured on Synthetic Remarks!
  • Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides from the Renaud group which demonstrates how a radical cleavage of a C-I bond mediated by Et3B and O2 in the presence of an alkenyl azide can induce cyclization.
  • Today’s special double feature, however, will be two rather different ways of introducing fluorine into organic molecules. The first is very reminiscent of two articles I’ve reviewed in the past (link 1, link 2) The author? None other than William R. Dolbier, Jr., one of the premier organofluorine chemists. Dolbier has put out a continuous stream of articles within the past year or so dealing with strained fluorinated small ring systems. In a sort of response, Prakash and some former students of his developed a method to form difluorocarbene from TMS-CF3 via TBAT and/or NaI. Dolbier’s “reagent” or the one he tend to employ/market is TFDA or trimethylsilyl fluorosulfonyldifluoroacetate. One detail that didn’t really surprise me with Prakash’s method was that electron-deficient alkenes were a no-go. Difluorocarbene generated by this method (which is likely not a “naked” carbene) is simply not reactive enough to give successful cyclization. As Dolbier notes, the only reagent capable of getting a truly naked carbene is in fact TFDA because all of the byproducts are gaseous under atmospheric conditions. However, TFDA isn’t the most friendly reagent: it has a short shelf life (because of its instability), moisture-sensitive (meaning rigorously dried solvents are required) and its very expensive (meaning if you waste it, your PI will be displeased to say the least). Therefore, to mitigate these drawbacks but still promote this system as a viable and practical difluorocarbene source
    In that vein, Dolbier and his group looked into an analogous compound, Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, MDFA. They hoped to exploit it in a similar manner to TFDA by a demethylation strategy:

    The fluoride byproduct, which would likely interfere with free carbene formation, can be trapped with TMS-Cl. Initial runs using this system did in fact give promising results. However, high temperatures and minimal solvent were necessary. As Dolbier notes, this temperature requirement is very similar to both Prakash’s method and the TFDA method. Solvent, while minimal, needed to be somewhat good at dissociating the KI (used as the I- source). Hence a mixture of dioxane and diglyme was chosen. This was also advantageous because it provided a good thermal cushion. It was later found that 2 equiv of MDFA was required as compared to the substrate. After the tedious process of optimization was accomplished, Dolbier demonstrated that this system, while somewhat harsh, enable difficult-to-react alkenes to undergo cyclopropanation in good yield. In fact, it was later revealed that a much less Lewis-acidic trapping agent hexamethyldisiloxane could be used as an alternative trapping agent, though this required extended reaction times.

    While this article was short and many of the yields are solely by NMR, I still really enjoyed this article because of the complexity of the transformation. There’s a lot going on in the reaction flask so I’m kind of surprised how well the reaction does in fact work.

    In a sort of up-and-coming field, we have article featuring electrophilic trifluoromethylation. The two leading reagents have kind of set the standard for electrophilic trifluoromethylation. Togni’s reagent(s), which uses a Dess-Martin-like hypervalent iodine architecture, is commercially available (though it is expensive) and have become quite popular even though they are less than 10 years old. The other older reagent system, whose popularity is increasing, is those based off of Umemoto reagent. These are O-(trifluoromethyl)dibenzofuranium, (Trifluoromethyl)dibenzothio-, seleno- and telluro-phenium salts. They rely on the principle of attaching the CF3 group to a formally positive heteroatom to make it electrophilic. I personally am a fan of the Togni system mostly because I like hypervalent iodine. How often do you see a halogen with that many bonds to it that has some synthetic utility? With the exception of the Dess-Martin reagent itself and a few other chlorine examples, there pretty much are none. In this latest paper, Togni at ETH Zürich reports on a method to trifluoromethylate azoles using his 2nd generation reagent. As you probably know by now from reading the various post on my blog, adding fluorine into a molecule (whether it be via a CF3 group or a simple fluorine atom) is pretty popular in medicinal chemistry. Not only does it (usually) increase the ability of a molecule to penetrate cellular membranes but it can serve as a bioisostere. Bioisosterism is the capacity of substituent with similar sizes or shapes to be interchanged with others without substantially altering biological behavior, i.e. binding affinity.

    Many drugs have exploited this principle and Togni acknowledges this by citing the powerful antibacterial agent norfloxacin and Ciprofloxacin as an examples. The paper Togni cites, by Asahina of Kyorin Pharmaceutical Co., states that the N-CF3 compound is comparable to that of a simple methyl group with respect to the antibacterial properties and on par with the with activity of norfloxacin for most species of bacteria.

    With that in mind, this paper is kind of a follow up work which I really like. Basically Togni’s group observed the formation of a N-CF3 triazole compound attempting to make trifluoromethyl imines from azoles by way of a Ritter-type reaction. While only a side product, knowing that there were limited methods for accessing this class of compounds, Togni decided to optimize the reaction to yield this as the major product.

    Now here’s another interesting part about this article: the discussion of the results from their study (yields, how they characterized their products by some fancy 19F-NMR techniques) came before their optimization of reaction conditions. I think this was something that a reviewer may have wanted them to add in after the fact but its quite extensive. Much of the focus was on solvent, temperature, Lewis acid catalyst choice, and concentration. In fact they did a good deal of reaction monitoring to assist in some finer details of the conditions (i.e. silylating the nitrogen just prior to conducting the reaction rather than storing it and adding LiNTf2 into the mix as a “less Lewis acidic fluoride scavenger”. Overall, work was done quite thoroughly and didn’t leave me with much in the way of questions, which is something I love see.

    Well that’s it for this post. I will hopefully be posting again soon about some more interesting methods now that my schedule is somewhat less hectic! Hats off to the Togni and Dolbier group for some excellent work!! Ckellz…Signing off…

    A Treat!

    Special new post coming soon…keep an eye on :P

    UPDATE New guest post on BRSM Blog: Unnatural Products 4: Tetrahedrane

    What’s that smell?!?

    Synthesis of Sulfur-Containing Heterocycles through Oxidative Carbon–Hydrogen Bond Functionalization Cui, Y.; Floreancig, P. E. Org. Lett. ASAP March 15, 2012.

    It’s been far too long since my last post but I feel its just that time of year. I’ve noticed that posts have slowed at other blogs I follow as well (and around this time last year my posts were down). March and April seem to be very busy for chemists. For me, the lack of free time can be attributed to a number of factors. Since I’m a TA I’ve been seeing a lot more students because of mid-term preparation. Next, I plan on attending two conferences (one of which I’ve mentioned, the CGSS in Buffalo, the other being the ACS meeting in Philly in August) which required abstracts. Lastly, we are coming to a close on a couple of projects meaning we need to prepare supporting information, tighten up manuscripts, and start sending stuff out. Plus, our walk-on 300 MHz NMR went down for all of this past week and the week before. If one NMR goes down, it really becomes a headache with only two to bear the load of both the chemistry department and the school of pharmacy. Add to the mix that I have not encountered any really grabbing papers lately and you can see why posts are down. So what’s been going on in the Leadbeater lab since my last post? Well, as I mentioned, I sent my abstract in for the ACS meeting in Philly. I will be presenting (if I get accepted) on the work we’ve done with Professor Tilley (which I will also do at the CGSS). We finished writing the last two labs for the organic lab course. We are having them do a hydrogenation and a LiAlD4 reduction of ethyl cinnamate to show them not only that you can do reductions selectively but to give them exposure to working with gases as well as working with deuterated compounds. In other news, since projects have been winding down, I’ve been trying to come up with some more (mostly ones related to oxoammonium salt chemistry) and I’ve had some luck so far and I think I might be close to something good…maybe :). We hope to have our collaborative work with Dr. Tilley done by June and hence much of my focus (and Mike’s) has been on that. Our most recently flow paper has been accepted to OPRD pending revisions, so I spent a little time working on those as well recently. Now that you know pretty much my whole life for the past few weeks :P let’s get to the lit.!
    This week’s article comes from Floreancig group at the University of Pittsburgh and it involves (as you might have guessed) organosulfur chemistry. The Floreancig is a typical organic group (doing both total synthesis and methodology development). They specialize in oxidative C-C and C-H bond activation for novel transformations. DDQ, or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, is their reagent of choice for facilitating this sort of activation. Until recently, Floreancig has exploited these oxidative activations for the chemoselective preparation of oxygen containing heterocycles such as pyranones. The general idea can be seen below:

    The concept is based on oxocarbenium trapping of a carbocation, preventing rearrangement and allowing control over its reactivity. Building on this methodology, Floreancig speculated that the same could be done with a thiocarbenium ion. However, this was not a totally unexplored field. Thiocarbenium ions are popular intermediates such as in Pummer rearrangements, and cyliczations exploiting this ion have been investigated. However, they always had this pesky habit of ending with the sulfur outside the ring rather than a part of it. In more technical terms, the exo product predominates rather than the endo product. The endo product, however, would be far more useful as a way to access sulfur-containing heterocycles. Since a thia-prins reaction is virtually unknown (very few examples), the Floreancig group decided to explore the possibility of extending their existing cyclization conditions for the preparation of thiopyrans.

    They immediately hit success with the thio-analog to their oxygen substrates. It cyclized in stereocontrolled fashion giving the endo product. However, they hit a minor snag. The product was liable to further oxidation and hence underwent a dehydrogenation to give a dihydrothiopyranone instead of a tetrahydropyranone. While the over-oxidation product was formed in a mere 4% yield, it proved bothersome, Additionally, the fact that the yields of the cyclized product were only moderate (around 50-60%) lead them to decided to explore different systems for cyclization, namely vinyl sulfides instead of allylic sulfides. The reason for the switch was simple: mechanistic studies performed by their lab indicated that vinyl and allyl sulfides both oxidize to give the same thiocarbenium ion, but the vinyl species oxidizes significantly faster.

    By using these new systems, their reaction times were shortened to 5 minutes and saw improved yield with excellent diastereoselectivity. Best of all, the reaction proceeded without the formation of the unwanted over-oxidation product. With that success, they then explored different means of conducting their cyclization. While they initially started with an acetate-protected enol, they quickly expanded to enol carbamates because of the ease in which their geometry can be controlled (regiochemistry wise too). They then explored what I think is the most interesting part of the paper: allyl silanes as internal nucleophiles (cause I love silicon and carbocations :) ).

    They found that silicon serve as a excellent surrogate for the enol acetate and vinyl carbamates but found some interesting peculiarities. First, (Z)-allyl silanes gave a far lower diastereoselectivity their (E) counterparts. Moreover, the geometry of the intermediate thiocarbenium ion also plays an important role! They speculated that there were a few transition states that would lead to their diastereomeric mixture. However, while they could explain why (E)-allyl silanes gave a better degree diastereocontrol, they could give no conclusive explanation why the geometry of the intermediate thiocarbenium played a huge role.

    Overall, while sulfur isn’t really my cup of tea, I really enjoyed this article. What can be better than carbocations, cyclizations, and silicon right? I hope you enjoy this article as much as I did and hats off to the Floreancig group for a job well done! That’s it for this week…Ckellz…Signing off…


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