Need more sulfur? Add a dash of DABSO!

Woolven, H.; González-Rodríguez, C.; Marco, I.; Thompson, A.L.; Willis, M.C. Org. Lett. ASAP August 25, 2011

I’m alive! And I finally have power back. However most of Connecticut still is without power thanks to our lovely encounter with Irene. My girlfriend and I actually ended up going to back to my house in NY and rode out the hurricane there. Was it scary? Not at all, it was more of an annoyance with intermittent power. However, for those who were traveling, Irene really took a toll. NY airports were completely closed as were many other major ones. Professor Tilley, who gave an excellent talk at the ACS conference today, managed to fly out to Denver with minimal delays. He presented some of the stuff we’ve been working on as part of our collaboration. Speaking of collaborations, our paper with Dr. Fenteany’s group should be submitted shortly after some delay. I’ll be sure to keep you updated on that as well. As for my own projects, I continue to wrap up the project that was assigned to our undergrads. We had to expand it a bit but I feel like this is going to be an amazing paper. I’ve already been writing it up and, next to my work as an undergrad, it’s been the most enjoyable piece of work I’ve had to write. Moreover, the project itself has allowed me to do all sorts of reactions that I never done before and for someone who loves doing reactions like I do it’s like Christmas. I did my first Sonogashira coupling and it was a great success! I did a few more lithium-halogen exchanges, as well as some silyl protections. Each day I feel more and more like a hardcore organic chemist! I even submitted two of my best procedures to ChemSpider and I’ll be submitting more over the next couple of days. I’ll be sure to put up links to them.
Now that Irene is gone (finally), what better way to celebrate having power back than with a little chemistry? This week’s article comes again from Org. Lett. and really caught my attention due to the name. I love when new reagents are developed (mostly because it is a rare occurrence). This one looks to be very promising. In some ways it reminds me of another useful reagent, Selectfluor®. Selectfluor® is an excellent source of electrophilic fluorine and can be used in a variety of reactions, such as α-fluorination of carbonyl compounds. DABSO, on the other hand, promises to be a source of “SO2” without having to use it in a gaseous state. In fact, SO2 is very toxic and a pain to work with. Unfortunately, the synthesis of many sulfur-based compounds relies on SO2 gas as a sulfur source. For example, the synthesis of many sulfones and sulfinates hinge on SO2. Moreover, SO2 gas is useful for a number of reactions including cheletropic additions and the synthesis of aromatic sulfonyl chlorides. So having a less toxic and easy to work with source of SO2 would be quite attractive

When SO2 is reacted with an amine a charge-transfer complex is formed. Now what is that you may ask? According to Wiki, these complexes occur when “a fraction of electronic charge is transferred between two molecular entities. The resulting electrostatic attraction provides a stabilizing force for the molecular complex.” They usually occur more in inorganic chemistry hence why I’m not all too familiar with it. With this knowledge in mind, the authors therefore decided to react DABCO with SO2 gas to see if a stable complex resulted. And it in fact did. It is air-stable and can be stored on the bench-top indefinitely. But can it serve as a SO2 surrogate?

Apparently the Willis group had already published on DABSO. In the presence of a palladium catalyst and hydrazine compounds, they were able to effect aminosulfonylation by using DABSO as a SO2 source. This was an unprecedented transformation and gave excellent yields starting from simple aryl iodides. However, after this article they wanted to test the limits of DABSO’s abilities. The authors decided to investigate whether DABSO could be used in more traditional SO2 reactions. The first reaction they attempted was based off some work done by the Barrett group. Barrett was able to take aryl Grignard reagents and hit them with SO2 gas. He followed that up with treatment with sulfuryl chloride and a secondary to give sulfonamides in excellent yields. Willis and his group followed up on that by replacing SO2 with DABSO and report that it served as a comparable source of SO2 as the gas itself. In fact they even went beyond the scope that Barrett originally investigated by adding primary amines and alkyl Grignards to the mix.

Next Willis examined another interesting reaction involving SO2. Rudkevich and his group reported that treatment of anilines with I2 in acetonitrile at 0 oC in the presence of pyridine and SO2 gas yielded symmetrical diarylsulfamides. However roughly 100 equivalents of SO2 was needed to obtain acceptable yields. Capitalizing on this, Willis and his group were able to use only 2 stiochiometric equivalents of DABSO to obtain similar results under identical conditions.

Lastly, to show the breadth of the scope of DABSO, Willis investigated whether it could be used in a cheletropic additionreaction. Interestingly, heating in a sealed tube with just DABSO and a diene afforded the sulfolene product in excellent yield. I think Willis definitely proved his case that DABSO is a perfect SO2 sources whose application has yet to fully be explored. However, its certainly looking like this will be a reagent for any chemist looking to engage in sulfur work. Hats off to Willis and his group for an excellent paper! That’s all for now, Ckellz…signing off…


Strained Systems Make a Comeback!

Bunker, K. D.; Sach, N. W.; Huang, Q.; Richardson, P.F. Scalable Synthesis of 1-Bicyclo[1.1.1]pentylamine via a Hydrohydrazination Reaction Org. Lett. ASAP August 11th, 2011

Have you ever noticed that projects generally work better when you are under pressure? Well, maybe this isn’t true for all people but I have recently found this to be true for myself. With the departure of our undergrads last week and the beginning of classes (and teaching) in only two weeks, I have found myself putting in much longer days than usual in order to get through my to do lists and (hopefully) get another publication out before the end of the month. Currently, my focus has been on wrapping up (and in some cases re-doing) a project I assigned to two of our undergrads. The project was a great success in terms of the chemistry, but in order to be publishable, some work needed to be done by the pros 😛 (me and my lab-mate, Mike). I’m currently halfway through writing the manuscript and so far it’s looking very pretty promising. I’m going to aim for Org. Lett. as the target journal for this work. Once that’s finally done, and we wrap up another, more process chemistry related project (again by the end of the month), I will get back (finally) to working on our collaborative work with Dr. Tilley. And after that, who knows? I am excited though for the upcoming semester. Not only will I likely be TAing for an organic chemistry course, I will also be assisting Mike in designing an advanced organic chemistry course to be given in the spring of next year. Mike and I hope to impart on the students the basic skills needed by every organic chemist in a research lab (e.g. flash column chromatography, vacuum distillation, designing a synthesis of a target compound from a more practical perspective than those seen in organic texts, and performing advanced reactions which you will no doubt need to do during your graduate career such as a cross coupling or Weinreb ketone synthesis). Additionally, many of our undergrads who were with us this summer will be returning this fall so I am excited to work with them again as well. I can’t wait for the end of the month and hopefully soon I can share with you all what I’ve been up to! And now…on to some awesome chemistry!
I’ve certainly been on a Organic Letters kick lately. This latest article comes from a rather surprising source considering the content of the article: the La Jolla Laboratories of Pfizer Worldwide R&D. What immediately attracted me to this article, despite it being somewhat of a targeted synthesis, was the starting material depicted in the graphical abstract. [1.1.1] Propellanes are not your run-of-the-mill sython and considering the fond place I have in my heart for strained systems, I couldn’t pass this one up.

The article begins by outlining that one of the up and coming strategies for medicinal chemistry is gaining “access to novel chemical space”. One area that is somewhat underdeveloped in this regard is small molecules with rather unusual structures, such as bicyclopentanes (and in my opinion, bicyclobutanes). In particular, Bunker and his colleagues at Pfizer were interest in bicyclo[1.1.1]pentylamine. Why you might ask? Well, many recent medicinally-active structures feature the bicyclo[1.1.1]pentylamine moiety. The article gives two examples, one being a new quinolone-based antibiotic and the other is a heat-shock protein inhibitor.

Bicyclo[1.1.1]pentylamine is a known, but fairly challenging molecule to synthesize (especially on a large scale). A well-known and quite remarkable chemist, Dr. Kenneth Wiberg (whom I consider the king of strained systems) was the first to prepare it back in the beginning of the 70s.

Starting from a compound also first prepared by his lab, Wiberg took bicyclo[1.1.1]pentane and performed the arduous task of derivitizing it (which proved surprisingly more difficult than one would expect). However, he ultimately found that bicyclo[1.1.1]pentane was prone to free-radical reactions and by treating this bicyclic system with oxalyl chloride while being irradiated with ultraviolet light, the acid chloride derivative could be obtained. Subsequent hydrolysis with water followed by treatment with sodium azide in acidic conditions (Schmidt Conditions) gave the bicyclic amine, albeit in low overall yield. Moreover, it involved reactions that are unamendable for scale-up (e.g. the Schmidt reaction involves the formation of hydrazoic acid, a highly toxic and potentially explosive material).

More recently, Toops and co-workers have attempted synthesis of this bicyclic amine via organostannanes. Again this method also involves toxic materials and low overall yields which cannot be used to produce the large quantities need by Pfizer. Seeking the most practical way to synthesize bicyclo[1.1.1]pentylamine, Bunker and co-workers decided to start with the strained [1.1.1] Propellane and carry it to the iodo azide like the Timberlake group did. This iodo azide is attractive since all you need to do is remove the iodide and reduce the azide to an amine.

While Timberlake was unable to do reduce his iodo azide, Bunker and his group managed to do this by using hydrogen gas and Pd(OH)2 on carbon under acidic conditions. However, just like many of the groups before them, they obtained unacceptably low yield. Upon doing some digging, Bunker determined that just like bicyclo[1.1.1]pentane, [1.1.1] propellanes are prone to free-radical functionalization. With this information in hand, they decided to take some chemistry developed Carreira and co-workers involving transition-metal mediated free radical hydrohydrazination (say that five times fast!).

Starting from [1.1.1] propellane yet again, which was be prepared via a modification of the Wiberg method from the dibromocyclopropane, Bunker and co-workers performed a hydrohydrazination using tris(dipivaloylmethanto)manganese and DBAD. This gave the Boc- protected hydrazine which was de-protected simply using HCl to give the hydrazine salt. Hydrogenation using PtO2 in methanol yielded the HCl salt of bicyclo[1.1.1]pentylamine in 62% overall yield! Moreover the authors were able to scale up the reaction to yield 100 grams of bicyclo[1.1.1]pentylamine! And the best is yet to come according to the last line of the article so I await more from Pfizer regarding other strained systems. I thoroughly enjoyed this article and hope you do to! Ckellz…Signing off…

Check out this fun game….

So this morning one of my undergrads reminded me about a NMR spectra game I play every once and a while (which I think is really cool and fun) and I figured I’d share it with you all. Check it out and see how well you can do!