Just ran across a new blog this morning by the Sussex Drug Discovery group over in the UK. It’s a bit more med chem oriented but it looks promising and will likely have a lot of useful information so go take a look!
Link:
http://sussexdrugdiscovery.wordpress.com/
New Blog!
In Soviet Russia, Catalyst Reacts You!
Kuznetsov, A.; Gevorgyan, V. General and Practical One-Pot Synthesis of Dihydrobenzosiloles from Styrenes Org. Lett. ASAP January 24, 2012
No I’m not dead! Sorry it’s been so long since my last post but I have finally returned to New Reactions after a very very busy 4 weeks. But what a 4 weeks it’s been. So a quick update on the happenings in the Leadbeater lab starting with some bad news. We unfortunately did not get our flow paper into Organic Letters and have subsequently resubmitted to a more appropriate journal, Org. Proc. Res. Dev. where we believe it should get in. But really, that’s about it in terms of bad news. DiAndra and myself continue to make progress with the project we are working on (and its allowed me to get into all sorts of chemistry from making benzofuran to bromination of thiophenes). I’ve never worked with heterocycles as much as I have recent and I have greatly enjoyed it. We are a little behind where I would hope we would be but the reactions are progressing quite well and based on some recent findings, I think this one might be better suited in Organic Letters! As for other projects, we are in the midst of substrate screen for our collaboration with Dr. Tilley and it has been extremely successful! We hope to have that out by the middle of this year. I really am very excited to get that work out and a few other projects we have been working on that are near completion.
Last week was the start of the semester for UConn students meaning the the course that Mike is TAing (Adv. Org. Chem. Lab) has begun. I assisted him in preparing some of the labs as well as giving a joint lecture yesterday on ChemDraw. I think the students will really enjoy the reactions we have in store for them this semester (a RCM, a Sonogashira, Suzuki, Click, and Paal-Knorr to name a few)! I’m also giving a seminar next month on some of the work I’ve done thus far at UConn. I’m also looking into going to the ACS meeting in Philly in the fall to present there as well (hopefully with a bit more accomplished 
). I do find it weird sometimes that I used to be so scared of public speaking but now I really enjoy it. I actually look forward to talks. I still get nervous right before the talk of course, but as soon as I get past that first slide, things just slip into autopilot. Plus I genuinely love just talking chemistry! And with that, let’s get to it.
I’ve had the chance to read a number of articles since my last post (many of them quite excellent) and I’d like to share with you a few that stood out to me as cool/interesting/useful:
o-Iodoxybenzoic Acid, and Dimethyl Sulfoxide: describes a convenient and very effective way to make highly reactive ketoaldehydes in situ and trap them as quinoxalines. What I like about this is the shear number of examples done by the authors and the potentially variable approach that can be used by simply switching the phenylene diamine or varying the starting aldehyde.
This week’s article comes from, you guessed it, Org. Lett. Its by a Dr. Vladimir Gevorgyan at the University of Illinois at Chicago, whose work I have been following for some time (this being the second article of his I will be featuring). Gevorgyan does chemistry that is near and dear to me, namely small ring synthesis, organosilyl work, C-H bond functionalization, and heterocycle synthesis. He’s sort of a jack of all trades when it comes to his chemistry, but he publishes very good work (in only the top named journals). In this new article, he focuses on a new (or arguably a very recently discovered) class of organosilyl compounds: dihydrobenzosiloles. Prior to the release of this article, no effective synthetic method was available to access these compounds. One example was given by Hartwig in a 2005 paper, but synthesis of these compounds was not the main focus (hence the article gives only one example under very harsh conditions). Dibenzosiloles and biarylbenzosiloles are far better known in the literature.
Seeking a route to these compounds, Gevorgyan decided to use a two-stage approach to their synthesis. The first step with be β-hydrosilylation of a styrene derivative using diphenylsilane as their hydrosilylation source. That would give the desired phenethyldiphenylsilane compound. With that in hand, a dehydrogenative cyclization could then be used to obtain the elusive dihydrobenzosilole. However, like most things in chemistry, nothing is as easy in practice as it is in theory. Their first step was, simply put, known put somewhat impractical. Hydrosilylation of stryenes using diphenylsilane was known using some late transition metals (gold, rhodium etc.) but none were inexpensive and easy. Hydrosilylation of simple olefins was known using much more affordable nickel based catalysts but it was unknown whether these systems were compatible with stryenes. So rather than finding a new route, Gevorgyan explored some nickel catalysts to mediate the desired hydrosilylation. He ultimately found that NiBr2(PPh3)2 worked best after screen a plethora of nickel catalyst. With the hydrosilylation problem addressed, Gevorgyan turned to the cyclization step. Using a bit of inspiration from some previous findings he was able to use a general method for silylating aromatics to induce his cyclization. Better yet, he found this two step process could be conducted in a single flask in excellent overall yield!
After screening a variety of styrene derivatives, he found that only meta styrene substrates proved problematic. They lead to regiochemical isomers (whose ratio was influenced by sterics). m-fluorostyrene was the worst offender of this giving a 2:1 regiochemical ratio. Gevorgyan then investigated α-phenyl and α-methyl stryenes to see if the alkene substitution patterned played any role and in fact it did. These substrates were far more difficult to hydrosilylate and hence the addition of a LA catalyst was necessary. By adding B(C6F5)3, 3-methylbenzosilole and 3-phenyldehydrobenzosilole could successfully be accessed.
Gevorgyan finally got to my favorite part of discovering new reactions: mechanism proposal. After some study, he was able to determine that electron-withdrawing groups on the styrene accelerated the reaction dramatically. Moreover, kinetic isotope studies showed that the second cyclization step was likely the rate-determining step. Bearing this information in mind, the following mechanism was proposed (and its cool!):
Finally all good methods papers end with an application. Gevorgyan used his dihydrobenzosiloles to not only synthesize benzosiloles by DDQ oxidation but also to access dihydrobenzofuran derivatives by peroxide oxidation of the silyl moiety followed by Mitsunobu-mediated cyclization.
Overall I found this to be a excellent article by Gevorgyan and co-workers. Dihydrobenzosiloles are very unusual and interesting compounds (though I’m a bit biased since I came from Dr. Tilley’s group and therefore I love silicon-related molecules). I look forward to future articles from the Gevorgyan group. That’s all for now…Ckellz…signing off…
2011 No More!
HAPPY NEW YEARS!!!! Thank you all for making this year a wonderful year of blogging for me and I hope you continue to visit in 2012!
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…
