Two Cyclizations for the Price of One!

Desjardins, S.; Andrez, J.-C.; Canesi, S. A Stereoselective Oxidative Polycyclization Process Mediated by a Hypervalent Iodine Reagent Org. Lett. ASAP May 27th, 2011

After a long overdue break, I am finally back! Not much to report, all I can say is chemistry is going quite well in our lab. Between the 3+ projects I’ve got on my plate, I certainly do enough reactions to keep any organic chemist happy. In fact, this week I did my first Wittig reaction (outside the realm of undergraduate chemistry) for a new project I’ve been working on. As I always say, there really is nothing that can beat old organic chemistry. Old reactions simply just work and they are always cool. Like this one turned a neon yellowish color. The only problem is the dreaded triphenylphosphine oxide, a byproduct that is analogous to a bad case of acne. No matter what you try, it just keeps coming back (or in this case back into your “purified” product). I’ve tried countless times to get rid of the stuff in one swift blow but it’s nearly impossible. There are always those trace peaks in the aromatic region which make you want to smack you head against the NMR computer monitor. The only effective way I’ve found is vacuum distillation (if your compound is low boiling) or running a long column (praying that it doesn’t run with your material). Appel reactions and the Mitsunobu are just as bad. I know you can triturate out the oxide with a ether-hexanes mix, but honestly, it’s just a pain. But that’s enough of an aside for now, let’s hit the chemistry!
Some of the best carbocation work was done in the context of steroids and sterols. Initially, much of the focus of sterol synthesis was as a testing grounds for total synthesis. Two of the classics of total synthesis were Woodward’s and Robinson’s preparations of cholesterol. Robinson started from a dihydroxynapthelene while Woodward used a methoxy-hydroquinone derivative. Both routes essentially construct one ring at a time using the standard tools of their time (condensation chemistry, Diels-Alder, hydrogenation, Michael-addition etc.). It wasn’t until the mid 1970′s that a truly revolutionary methodology was developed by Johnson and coworkers for the simultaneous annulations of 3 of the 4 rings in a steroid system. Johnson was able to take a monocyclic trienyne system (which could be prepared in 5 steps from known materials) and utilize what I could call a carbocation collapse (or a series of electrophilic additions to alkenes) to construct a complex and diastereospecific intermediate relating to the synthesis of methylprogesterone. I find it just a beautiful piece of mechanistic work:

This pretty much kicked off the field of biomimetic syntheses, or syntheses which are inspired by the way natural products are constructed in biological systems. Often in such systems, there are a series of cascade reaction facilitated by proteins which produce an extraordinarily complex compound in near perfect diastereo-and even enantio-specificity. Often by determining how the organism does this, synthetic organic chemists can devise a similar or analogous cascade. And the field of biomimetic syntheses has just been constantly growing. Some of the best names, such as Baldwin or Trauner, have utilized biomimetics to access complex compounds such as terpenoids or alkaloids. In a similar strain, Canesi’s group is interested in using biomimetics, specifically those similar Johnson’s, to access complex materials from relatively simple (and less costly) starting materials. In this particular example he was interested if he could activate enyne-phenols to induce dearomatization and cyclization. This is somewhat unusual considering the electron-rich nature of phenols (which we would expect to serve as nucleophile rather than as electrophiles). However, a whole methodology for activation of phenols to produce phenoxonium ions has been developed by Kita and coworkers starting with their first report of phenolic oxidation in the late 1980s. Kita uses Lewis acidic hypervalent iodide to facilitate phenoxonium formation in situ. In the presence of a nucleophilic species, this undergoes a substitution reaction at the para position. If the nucleophile is already attached to the phenol, cyclization occurs.

Seeking to take advantage of this activation methodology, Canesi and coworkers thought they could induce decalin formation by simple having a terminal alkyne hanging off the ring. They theorized that, upon cation formation, the alkyne would attack in a form of electrophilic addition. However, if you think about it this could be reversible and potentially unfavorable due such a strained transition state. However, the authors argued that the strain would actually be beneficial, in that it would pump up the electrophilicity of the now vicinal carbocation leading to an increased likelihood of solvent capture. Now here is where I was shocked. The solvent they used, which is supposed ideal for this sort of reaction according to Kita, was hexafluoroisopropanol (HFIP). I’ve worked with the stuff and its a great solvent but one of the main reasons I use it is because its extremely non-nucleophilic but very polar. Hence I was surprised to find that their monocyclization not only worked but was contingent on HFIP attack of the carbocation!

After establishing that this reaction works, they decided to screen substrates. They found that substitution at the ortho position with halogens, benzyl, and alkyl groups all were tolerated under their conditions. In fact, the more substituted the phenol core, the better the reaction seemed to go. The authors argued this had to do with oxidation at these positions if they were open. Hoping to increase the scope of their new cyclization, the authors investigated the possibility of extending their methodology to bicyclization.

This seemed analogous to much of Johnson’s work with steroids. Interestingly they found this particular reaction to be highly diastereospecific. However, it was highly dependent on the geometry of the double bond in the starting material. Initially they started with a mixture of (E) and (Z) isomers in a 2:1 ratio. This was reflected in the products in that they got a 1:2 mixture of diastereomers. Hence they developed a route to prepare the (Z) precursor selectively. They found that upon treatment of this isomer to their reaction conditions, they obtained a single diastereomer proving that the reaction was diastereomerspecific.

Overall, I really enjoyed this article. It was more bio-organic than I usual read but if it involves cations chances are I’m in. And this work was extremely well done and thorough. Congratulations Canesi and co-workers!

Sometimes you just need to heat it…

Deb, I; Coiro; D. J.; Seidel, D. Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyproline Chem. Comm. Advance Article April 18th, 2011

Honestly, there is nothing worse than being in a chemistry lab when you have a bad cold. You are constantly sneezing and coughing, you can’t get anything done, and you simply feel miserable. Not to mention the acetone fumes from cleaning make you cough even more. Needless to say this represented my experience in lab last week. I went to a concert Sunday (which I have some video from here and I must have picked up something cause I woke up the next morning quite ill. Not only that but I really needed to get more done last week than I did. I’m a lot better physically now, but I’m rushing to get things done. Tomorrow I have some flow stuff, a vac distill, a column, and a new reaction to test out, and two other reactions to carry out….yeah…but at least the chemistry itself is working. I think the thing that kills the most time is cleaning. I spend at least 5 hrs a week cleaning glassware (or more depending on how bad it gets). Not that I mind it because there’s nothing more beautiful (besides maybe clean white crystals from a recrystallization) than spotless glassware. And if I really can’t get it clean, the magic of the glass-eating base bath will take care of it. In terms of chemistry though (and not cleaning) things progress well. I hope to be done with our collaboration with Fenteany’s group in two weeks at maximum. I also came up with a new reaction based on a recent JOC article which could lead to a new project (hopefully). Otherwise our collaboration with Professor Tilley is going pretty well too. I plan on beginning to writing it up sometime this week to get an idea of what needs to be done and where the article will go. I’m thinking Org. Lett. but possibly J. Org Chem. considering all the information we will be putting in it.
I know I’ve been getting quite a few views lately (which makes me really excited!!!). I came up with an interesting idea the other night. If you want me to review an article or a topic etc. in organic chemistry I’d be all for it. So just send me a message either by leaving a comment or by e-mailing me at . And now, chemistry time….

So as you all may know, I’m a big fan of Dan Seidel’s work at Rutger’s. His work is pretty simple, but it’s usually elegantly presented and has good applications. And as I always say, the best kind of chemistry is simple. Seidel’s group has done quite a bit of work with C-H bond activation and redox isomerizations. Lately, he is very much interested in the formation of azomethine ylides in situ from relatively cheap materials such as pyrollidines and utilize them to form some complicated, difficult to synthesize materials. His other area of interest is in thiourea catalysis, but since this the former topic is the one involved in this paper, I’ll leave it to you to read more about this project and Seidel here.

Proline is a very interesting and very useful molecule. It’s very good for Diels-Alder reactions as a catalyst (particularly the methyl ester which for me worked like a charm). It’s also good at catalyzing aldol additions. It does so by forming the iminium species which tautomerizes to the enamine. However, Seidel likes to take advantage of the iminium tautomer for the formation of azomethine ylides. A while back, he published an article that I really liked where he took proline and benzaldehyde and a nucleophile (in their screening case, 2-naphthol) and did a three component reaction to give a highly substituted pyrrolidine:

He used a variety of “nucleophiles” to do the same including alkynes, indoles and nitro alkanes. All that’s really happening is the azomethine ylide is forming and the highly electrophilic iminium moiety (which rearranges to be inside the ring) is reacting with electron rich pi systems. Now you may be like, well who cares? Well this was a sort of precursor work to this next article and it also accessed difficult to synthesize compounds using relatively inexpensive materials.

So this follows suit on the theme of use simple starting materials to access complex products. The article starts out by describing the use of pyrroles in medicinal, material, and natural product chemistry. While there are a million ways to make them, being able to make theme relatively fast and in a cost effective manner would be useful. Hence Seidel’s group was interested in making this idea a reality.

They took some inspiration from an article by Tunge and coworkers (which caught my eye a while back). Tunge used 3-pyrrolines to make N-alkyl pyrroles. The problem I had (and apparently so did Seidel’s group) with this article is that 3-pyrrolines ain’t the cheapest compound to use. Moreover, as Seidel mentions, they have the annoying tendency to oxidize to pyrrole over time if exposed to atmospheric oxygen. So what Seidel thought to do was use 4-hydroxy proline as a surrogate for 3-pyrroline. Basically what he hoped to have happen mechanistically was as follows:

Note that the key is that dehydration step. That allows you to get at pyrroles. Initially though, this reaction failed hard. It seemed that they tried conventional approaches (refluxing in various solvents) but that simply didn’t give them much in the way of conversion. Switching over to microwave heating with the addition of a silicon carbide heating element, they reached temperatures of 240-250 oC. That’s pretty damn hot, especially since they are using toluene as the solvent which can be a pain to heat in the microwave. They found that it was necessary to have 20% mol of benzoic acid in there to catalyze enamine formation. Not surprisingly, the reaction was very fast (<15 min). And they found the scope was quite wide, in that a variety of aldehydes and even ketones could be used with moderate to good yields!
And that’s about it! Short, simple and to the point. I really enjoyed this article and look forward to more azomethine ylide chemistry by Seidel’s group!

I React With a Little Help From My Friends…

Accurso, A. A.; Cho, S.-H.; Amin, A.; Potapov, V. A.; Amosova, S. V.; Finn, M.G. Thia-, Aza-, and Selena[3.3.1]bicyclononane Dichlorides: Rates vs Internal Nucleophile in Anchimeric Assistance J. Org. Chem. ASAP May 5th, 2011

Another week in the lab, another round of owning chemistry. This week was quite good for me. Things with our collaboration with Dr. Fenteany’s lab have taken an unexpected (but very good!!!) turn. I cannot wait to finish that project and get it out there so I can tell/show you what I’m talking about. Not only is it a good conceptual project, but it also has been a learning experience for me and some of my labmates. I’ve had to do substantially more recrystallizations and columns than I have in the whole of my career as an undergrad. Moreover, I’ve gotten to do reactions I had never done before, like a Friedel-Crafts acylation! And in return, Fenteany’s group is way ahead of schedule on this project thanks to our help so it really has been beneficial to both groups. As for our work with Professor Tilley, we have most of the substrates at the final stage (only three more need some work) and then we can start writing up the manuscript! So my goal is to have at least two additional (if not more) Org. Lett. publications by the end of this year. And now that classes are finalllllllllllly done and I no longer have to teach, I will have a lot of time to investigate some of my own ideas as well. So overall, life in the Leadbeater lab is good. And I’m happy to say New Reactions has been getting quite popular. I’ve been averaging 100 hits a day and I am now linked on many other famous chemistry blogs. So thank you very much for visiting and reading!!! And now, its chemistry time!

So as you all probably know, I love carbocations. I just find them fascinating and, thus far in organic chemistry, there are few examples where they can readily be controlled. One of the few times they can be is when you have a local (internal) nucleophile which can participate in anchimeric assistance (another term I am intimately familiar with :P). It’s no surprise then that this article grabbed my attention, despite its lack of methodology nature. It’s pretty basic chemistry, but that’s really the kind I like mostly because that is where the best discoveries occur.

The article starts out by jumping right into the chemistry. It talks about how, back in the late 60s, Corey, Weil, and Lautenschlaeger all investigated the synthesis of 9-thiabicyclo[3.3.1]dichloride by the addition of SCl2 to 1,5 cyclooctadiene (COD). Apparently, it adds just as a traditional electrophile would (think Br2 addition to double bonds) but since there are two olefin moieties, it reacts twice. Interestingly, this reactions fails to work with smaller cyclic dienes (e.g. 1,4 cyclohexadiene) unless performed at very low concentrations (likely due to competing polymerization) but works perfectly with COD. Now here is why the authors were interested in this molecule (which they colloquially dubbed a WCL electrophile): many early workers noted that this halogenated heterocycle could be easily substituted. However, no one followed up on it (i.e. scope, kinetics etc.). It was more of a “hey we can synthesize these!” sort of deal. The goals for the authors were then as follows: First, use it as a substrate to test anchimeric assistance (which should be at its maximum due the proper and restricted conformation of WCL electrophiles; Second, develop this substrate as a “click” substrate where it can be easily added to a larger molecule like that of azides to alkynes; Third, continue their investigation into the reactivity and kinetics of WCL electrophiles.

Not wanting to limit their scope, the authors prepared several derivatives of 9-thiabicyclo[3.3.1]dichloride. They prepared fresh SeX2 by combining Br2 or SO2Cl2 with elemental selenium (aka awesome!) and reacted it with 1,5 COD in a similar manner to the analogous sulfur reaction. To prepare their nitrogen substrates, they chose a slightly more elaborate route. First they epoxidized COD to give the cis-diepoxide via a rhenium catalyst and hydrogen peroxide. They followed it up with a nitrogen-meditated double ring opening reaction to give the diol. The hydroxyl groups were then converted to chlorides either via MsCl and DMAP or thionyl chloride.

The next step was to explore the reactivity of their newly constructed WCL electrophiles. To perform kinetic studies, they used benzyl amine as the incoming nucleophile and observed the conversion by NMR in acetonitrile. Not surprisingly, the order of reactivity turned out to be: Se > N-Alkyl > S > N-Alkynyl > N-Pheny. What I found funny was the results of when they utilized the selenium substrate. Not only did it react so fast it was not observable, but the product could not be isolated as it was unstable. It decomposed readily on silica and on storage at low temperatures! By altering the solvent to THF, they were able to slow down the reactions substantially. This was due to the fact that THF is many times less polar than MeCN. Now there was the first tip off that this reaction’s rate-determining step was first-order (or carbocation-like/SN1-like). If the reaction was SN2 like, we should have seen a slight rate acceleration by switching to a less polar solvent. Since they were able to slow down the rate, they were able to determine the kinetics of the selenium derivative. It turns out that, in THF, the order of the rates is relatively the same (with the exception that N-alkynyl > S).

The authors then checked into the reactivity of these WCL electrophiles. They tested five nucleophiles of various strength with the benzyl amine derivative as the model WCL electrophile (chosen as its easily observed by UV-Vis). While the rates were greatly accelerated due to the aqueous nature required for these reactions, the nature of the nucleophile had little to no effect on the rate of the reaction. Hence the authors concluded that the mechanisms must be proceeding through a carbocationic intermediate. They propose the following as the mechanism:

Therefore the authors were able to show quantitatively, as the first documented case, the relative donating abilities of Se, S, and N in providing anchimeric assistance. I always love these sorts of articles. They are always to the point and very definitive. I mean how can you argue with rate data? Congratulations to Finn and coworkers on an excellent and thorough job!

Those Damn Rearrangements…

Burkhard, J. A.; Tchitchanov, B. H.; Carreira, E. M. Cascade Formation of Isoxazoles: Facile Base-Mediated Rearrangement of Substituted Oxetanes Angew. Chem., Int. Ed. Early View April 28th, 2011

There’s not much I love more (besides my girlfriend…awww….) than a week of chemistry ownage. That really summarizes this week for me. I actually made a count of how many reactions (I did 14), which is roughly 3 a day. I’d call that pretty good considering I had not only teaching to do (and grading) but also going to classes and I was even out for a day because of car troubles! So all and all it was a good week. I even went in for 12 hours Saturday to make up for my missed day. I really enjoy lab on weekends. Its very quiet and peaceful and I can get a lot done. Speaking of getting stuff done, my work with Dr. Fenteany’s group is roughly halfway done! And my work with Professor Tilley is also nearing completion. I can’t believe it! I also got a bunch of new ideas this week that I’ve been dying to try. So my luck continues! I also wanted to send out a special thank you to all my readers. Since I started blogging in January, I already have over 8000 hits! So thanks for reading my reviews! Speaking of which, let’s get to this week’s article!

Until recently, when I was compiling information about impact factors for various journals to be put into our lab’s “organic chemistry bible”, I didn’t realize how high of an impact Angewandte Chemie had. It ranks higher than JACS. Interestingly, however, there is far more organic chemistry published in Angewandte than in its ACS competitor. I don’t know what to make of that. Are more significant findings in organic being sent to Angewandte as compared to JACS? Or is JACS biased against organic chemistry since there are two other sister journals it can be sent to? Who knows. But that’s aside from the point, we are here to talk organic not politics!

This week’s review comes out of some work done by Dr. Erick Carreira at the Laboratory for Organic Chemistry at ETH Zurich. For some time, Carreria’s group has been interested in the development of synthetic methods towards the synthesis of novel heterocyclic compounds. Considering his group is mostly in the business of natural product synthesis, it’s no surprise they often need to be a bit creative and develop some new methodologies. So this particular article starts out by detailing the use and methods to synthesize isoxazoles. Unfortunately, most current methods are harsh and low yielding. Hence, Carreira’s group looked into their own method for synthesis of these sorts of motifs (specifically 3-subsituted isoxazoles-4-carbaldehydes) but not so initially. They were really interested in the product of the Henry reaction of 3-oxetanone and (2-nitroethyl)benzene:

They believed that these moieties could serve as good oxetane donors. When added to larger molecular scaffolds via conjugate addition, oxetanes can modify properties of the scaffold to make it more effective as a drug. Hence their methodology would be highly attractive since the starting material, 3-oxetanone, is commercially available. I wouldn’t tote that fact though. It’s absurdly expensive (5 g is $780 from Synthonix or 0.5 g for $65 from Aldrich) and polymerizes over time. Despite this, the authors hoped to test the feasibility of using this substrate as an oxetene source by performing a 1,4 Michael addition with an amines. The authors chose two representative amines, benzylamine and dibenzylamine. The results they got were quite surprising:

While the primary amine worked as expected, the secondary amine gave an unusual rearrangement to give 3-benzyl isoxazole-4-carbaldehyde. To rationalize this result the authors invoked steric arguments citing that 1,4 addition of dibenzylamine results in a benzyl-benzyl or a benzyl-2x CH2 interaction (depending on the approach). 1,4 addition with benzyl amine give no such interactions (only a benzyl-nitro interaction). They give a nice Newman projection, which explain it visually far better than I can in words. As always, when you find something interesting and unusual in chemistry, pursue it! And that’s exactly what the authors did. Since they only got 48% conversion, the authors therefore decided to optimize the reaction by first examining the base. They found that of the bases examined (and many worked!), tertiary amines worked best, with diisopropylethylamine (DIPEA) being the most superior of these. They found that reaction could be performed as a cascade one-pot reaction by simply adding DIPEA to the crude reaction mixture and stirring for 12 hours (giving 82% yield of the desired isoxazole).

The authors found that this reaction was not limited to just (2-nitroethyl)benzene (otherwise they probably wouldn’t be publishing in a journal with an impact factor of near 12 :P). A variety of nitro compounds, from alkyl to pyridyl, could be used with little determent to the yield. But how are they forming these isoxazoles? Well, after conducting some careful NMR studies, they found that it occurs via the following pathway:

Overall this was some excellent work by Carreira and co-workers! I look forward to reading more from their lab because they seem to do some interesting (and highly strained :P) chemistry. That’s all for this week, Ckellz…Signing off…


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