Benzyne Makes Life More Fun!

Łączkowski, K.; Penã, D.; Escudero, S.; Pérez, D.; Guitián, E.; García, D.; Agustín Cobas Highly Selective Insertion of Arynes into a C(sp)-O(sp3) σ Bond Org. Lett. ASAP February 3, 2011

So I’m back. Sorry I’ve hadn’t posted in over a week. Shame on me. But if you want you can blame the chemistry gods for smiling on me. My reactions are [finally] working and I should have my current project completed by the end of next week. Moreover, the paper regarding my undergraduate research got accepted…TO ORGANIC LETTERS! Needless to say, I am pleased. I’m currently working on the revisions for that as well as a few other projects. Not to mention, our group just got the Vapourtec R2+, an amazing new toy! Check out the announcement here. This device is possibly the most badass lab apparatus I have or will ever used. It is like our old Uniqsis Flowsyn on a triple overdose of anabolic steroids. You can pretty much program in reactions and it does the rest (and even sorts them via an automated collection device). It…OWNS. Anyway…on to the chemistry…
I can’t think of one molecule I love more than benzyne. I’ve already given a talk and written a paper on it but I still find myself in awe that it actually exists. I mean think about it, you are adding a triple bond in a very stable aromatic system. I know the p-orbitals end up resting perpendicular to the aromatic pi system and it has significant diradical character but still. It just looks unhappy and the fact that it’s so easy to form is remarkable. Moreover, its reactions are somewhat irregular. So if you put it all together (odd reactions, weird probably strained molecule, and a more physical organic chemistry feel to the research), you’ve basically put all my favorite aspects of organic chemistry . Not to mention the most common way to make benzyne (the Kobayashi protocol) involves a trimethylsilyl (TMS) group and uses fluoride-induced silyl elimination…This has Ckellz written all over it. So anytime I see the words aryne or benzyne in the title of an article, I immediately give it a once over. I was especially interested in this one because it was written by one of the most renowned benzyne groups aside from the Larock group.
The Penã/Guitián/Pérez has had a long standing interest in aryne chemistry. For a while, it seemed like it was a back and forth battle between their group and the Larock group. Fortunately for Penã and coworkers, Larock will be retiring soon so they will have the battlefield to themselves. Before I get started on the review, I just wanted to show you the typical (and cool!) way that benzyne is made from the commercially available o-trimethylsilylphenyl triflate.

It’s a pretty nifty reaction whose driving force relies on the fact that Si-F bonds are quite strong, OTf is a excellent leaving group, and the product of fluoride-induced silyl elimination, trimethylsilylfluoride, is a gas at room temperature. That particular reaction was discovered by the Kobayashi group in the late 1980s but really did not receive a lot of attention at the time. It wasn’t until the past decade or so did it become truly popular. Now it has become the springboard of aryne chemistry because it can reliably generate the aryne under relatively mild conditions.
Much has been going on with benzyne in terms of new reactions. The general theme is ability to use non-conventional reagents (as opposed to the normal dipolar molecules or to Diels Alder candidates) such as C-N or CO-Cl bonds to obtain disubstituted phenyl rings with the substituents in an ortho relationship. The utility of this sort of reaction is clear even to an undergrad straight out of Organic II: you can defy the normal directing effects of various substituents, simultaneously put two groups on a phenyl ring (reducing the number of steps in your synthesis), and finally you avoid the use of expensive metal catalysts. I’d say that sort of method is pretty impactful, wouldn’t you?
Following an observation by Stiles in 1962, Penã and coworkers investigated the possibility of using alkynyl ethers as a new non-conventional reagent to react with benzyne. Surprisingly, there are only a few of benzyne (or any aryne) inserting into a C-O bond. Therefore the authors set out to see if it was possible in other systems besides those reported. They chose the alkynyl ether system for two reasons. First, it would incorporate a, what I would call, protected phenol into the aromatic system. Second it would introduce an alkyne as a substituent on the ring. Currently, the only real viable way of doing the latter is performing a Sonogashira using expensive catalysts and fancy ligands.


Using unsubstituted benzyne and a model substrate, namely ethoxyacetylene (side note: this must be a pain to work with, since it boils so low and probably polymerizes if it is not in a solvent), they screened reactivity. It doesn’t seem like they did much in the way of optimization most likely due to the fact that their test reactions worked on the first try in 51% yield. That’s not terrible but also not amazing considering how that the benzyne precursor is somewhat expensive. The conditions, though, were extremely mild: Just dump the stuff together, let it sit for twelve hours and you have your product. Typical of benzyne papers, the author tested substituent effects on the aryne. The tested only a few substituents on the aryne such as -OMe, CH3, and polyaromatic or polycyclic systems (most likely because the benzyne precursors are somewhat difficult to prepare). Yields were reasonable but regioselectivity was substrate specific. The methoxy derivative gave only one regioisomers while the tolyl gave a one to one mixture of regioisomers. Interestingly they did not alter the ether what so ever. To me, that means it may only work with that particular ether but it is nonetheless interesting because you can do reactions with either the alkyne or the ethearl moiety to customize your system. The comparison study that they did next is what really sold me on this article. It (see below) wasn’t intended to do that but rather it was to prove the identity of one of the compounds they had prepared.

As you can see from the synthesis of this ortho-methoxy derivative, the authors can do what should take four steps in one. And in substantially better yield (54% using benzyne chemistry vs. 37% by employing a Sonogashira). Now here is where the paper really began to shine. The sought out to develop a mechanistic rationale for the reactivity that they were observing. I won’t bore you with the calculation details (which actually showed me the power of transition state modeling and the meticulous nature of the authors) but I will present to you what they believe is the likely mechanism. To me it’s a little odd but it does make sense with considering their observations :

Overall, a pretty good paper by Penã and coworkers. I truly look forward to more benzyne in the near future!

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