Better get out your name reaction book — this is a mouthful….and dig back to your Berichte der deutschen chemischen Gesellschaft to find examples of some of the earliest examples of metal mediated couple reactions (loved that I got to goof off in German a bit — it’s the only other language I can speak in the house with an echo since the other three speak a little Tagolog.

Anyway — the scheme below depicts the Glaser Cu(I) homocoupling reaction

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Glaser coupling of 1869

If we add a nice coordinating base like TMEDA to the copper and do the entire step in the presence of the oxidant (keeping the sequence catalytic to the metal), we have the Glaser-Hay coupling. One of the nicest features of this reaction is that it is extremely resilient to functionality and takes place in a number of solvents.

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Glaser-Hay — Examples for Synthesis 2010, 3461

No let’s mix in the pot — macrocylization and microwave and see what kind of meal we make. Over the next few blog inserts I will stick to some of these macromolecules out of interest in what people have been recently improving.

Macrocyclizations are a wild lot; there’s all sorts of things that can go wrong from the get go — and some nifty techniques to orchestrate the right pieces to come into play. Included in the list of challenges: competing oligomerization, lack of ability to increase the scale because the dilutions necessary to produce product and the general need for heat to promote the ring closure……whereas, increased temperature would normally get me jazzed to run it in a microwave, often times the slow addition techniques often found in these preps present an obstacle to the technology.

Shawn Collins at the University of Montreal was able to develop a way around high dilution and low-yielding conventional procedures through a phase separation strategy (he was able to utilize a two-phase system that could handle heat and shuttle the desired product away from undesired reactions and starting materials — this group chose PEG400/MeOH but mentions that other phase separations are viable). Inserted below is the strategy on a first shot comparison using phase separation vs. traditional thermal heating under high dilution (Figure 1/Scheme 1).

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Since this was a side-by-side, the goal was to look for the phase separation to work — so the yield needed to be better (11 vs. 73% and a 150x factor on dilution) — WOW! OK so now the stage is set — can the 2 day reaction be improved upon with the aid of microwave heating. Taking the same 16-membered ring formation some optimization provided a path for microwave’s benefits.

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Optimization of the ligand and improvement in time

There is a lot to be said for cutting the time down to 6/12 hr from 2 days, but the group marked forward with larger rings sizes and shortened time studies to make a number of exiting molecules featuring the 1,3-diyne moiety within the marcocycle…and the table illustrates it nicely.

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I cant take you away from reading the article so I will leave you to read through the studies on concentration compared with conventional heating….quite incredible actually to see the differences….and it really goes back to my thinking about the things that are in play in different reactions — keeps me excited that people are pushing the boundaries of accepted reaction techniques and practices.

Enjoy the read — and as a note, on Shawn’s website, he lists a number of his strategies — and kind enough to provide copies on request. Kudos, Shawn. Vive Shawn, je vous dois un verre!

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