Diene to Get Some Olefins

Jacobsen, M. J.; Funder, E. D.; Cramer, J. R.; Gothelf, K. V. β-Olefination of 2-Alkynoates Leading to
Trisubstituted 1,3-Dienes Org. Lett. ASAP June 7th, 2011

So after nearly two weeks of reaction after reaction after reaction, I finally found time to write another review. Chemistry in the Leadbeater lab has been going pretty well. Our collaboration with the Fenteany group is drawing to a close while our collaboration with Professor Tilley seems to get more interesting with each day. As for our own research, we have a couple of flow projects going (one of which is mine which is getting close to completion) so I’ll keep you updated on those as well. Also we’ve got a few undergrads in our lab this past week. One is a former student of mine from organic lab while the other is a rising senior from Bard College. Both have been extremely helpful in the lab and are really adding to the exciting research we are doing!
One of the more interesting issues that has come up in the past couple of weeks is the concept of buying or synthesizing a reagent. I’ve seen a couple of commentaries or suggestions (one from Alison Frontiers site, another from Transition States. But I guess how I view it really depends on the situation. The first thing I consider is how long will it take me to make the target intermediate? I’d say I’m one who will more often than not make a compound just because I really enjoy running reactions. However, there are only so many hours in a day and if it’s more than let’s say 4 steps, I would more likely opt to buy it (cost-permitting). I would caveat that with the following:

1. Are the steps long?
2. Can I get to the reagent or intermediate in a week (or the amount of time it would take for it to ship and be received)?
3. Does it involve any toxic, highly dangerous, or very expensive compounds to make?
4. *IMPORTANT* Do I have the reagents and/or equipment for every step involved (either in-house or via loaning from other labs)?
5. What’s my source of procedures for the synthesis? Are they quality journals with detailed procedures?
6. How necessary is this compound to my project?
7. *IMPORTANT* How expensive is the chemical? Can I get an adequate supply for a reasonable price?

Based on my responses to those questions, I generally have a feel for what I should do about this chemical. Sometimes you aren’t luck enough to be able to order a chemical and you have to just run the synthesis. I’d be curious to hear about some experiences (good/bad) from some of you all. For me, making some chemicals lately has really expanded my named reaction checklist. I mean in the past six months I’ve probably done at least ten new named reactions! I can’t say that all of them have been, well…successful, but at least I have the experience. But let’s talk olefins!
So this week I stumbled across a somewhat different article about a methodology useful in the synthesis of our highly conjugated friend, the diene. There are quite a few ways to prepare these compounds, from the classical Wittig reaction to the Julia Olefination to the newer enyne metathesis reactions. However despite the numerous ways they can be prepared, having another method for accessing these useful compounds is always beneficial. Building off of a paper by Xu and co-workers in 2009, Gothelf was interested if alkynyl esters (instead of those reactive unstable allenes) could be used to synthesize dienes via a phosphine-mediated pathway.

Before the article gets into the actual chemistry, however; it does what I would call a mini review on reactions of alkynyl esters activated by phosphines. There are some pretty interesting reactions already known, from furan/pyrrole formation to gamma addition. The reason they did this review because they wanted to show that their route would give yet another application for these species (and stress the “novel”-ness of it). What bothered me a little about this article is its stark similarity to Xu’s. They even optimized using the same initial substrate (o-chlorobenzylaldehyde), phosphine catalyst (triphenylphosphine) and solvent (DCM). However, unlike Xu’s allenes, this only gave 10% of the diene product. After screening time, temperature, solvent, and the substituents attached to the phosphine, they finally found the ideal conditions. The only phosphine that really worked well was 1,3,5-triaza-7-phospha-adamantane (PTA). They found that since they were operating at elevated temperatures (100 oC), extended reaction times lead to product degradation.
With their desired optimized conditions in hand, they then screened a variety of aldehydes with somewhat mixed results. No discernable trend can explain their results because both electron-rich and electron-poor substrates gave comparable yields. They then screened alkynyl esters showing that really only the one that they chose as a starting ester (where R1 in the first graphic = phenyl) gave acceptable yields.

Unlike Xu’s work, Gothelf’s article decided to investigate the utility of these dienes by performing a cyclization reactions. First, they did an interesting cyclization (by inserting an aldehyde as part of the ester moiety) to give a lactone. That alone great increases the usefulness of this method. They also took one of their diene and reacted it withN-methylmaleimide in a Diels-Alder reaction to give bicyclic system in the endoconformation.

To explain this somewhat unusual reaction, they borrowed some mechanistic ideas from Xu. First, the phosphine adds to the alkyne in a Michael-sense. Next a series of proton transfers occur, resulting in a phosphonium ylide. That ylide then reacts with the aldehyde via a Wittig-like reaction to give the desired diene. Overall quite a well done job by Gothelf and co-workers. That’s enough for this week, Ckellz…Signing off…


1 Comment

  1. It is known that phosphines catalyze reversible isomerisation of propiolic acid esters into the correspending allenic esters. I think Trost group was first to desribe this and they used 1,2,-bis-(diphenylphosphino)-ethane as a catalyst because PPh3 did not work too well. So I think someone in Jacobsen group saw the Xu group work and extended it to propiolate esters.

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