Over the past few years our laboratory has become interested in the radical
functionalization of heterocycles. This started with arylboronic acids as radical precursors but recently
developed into alkylsulfinate chemistry. The latest addition to our list of commercialized reagents is sodium difluoroethanesulfinate (DFES-Na), a difluoroethylating agent.
According to Sigma-Aldrich, DFES-Na sold out of stock within 1 week of being listed, and due to the incredible demand, they are targeting multi-kilo quantities. Metric tons of DFES-Na will likely be needed in the next 10 years. This is, of course, exciting news for us but we would also like this blog post to be exciting for you as well. So, we have put up another video. This one is about Qianghui (first author of the paper describing DFES-Na) running a difluoroethylation reaction and hopefully after watching this video, you will be running your own difluoroethylation, too!
1) Zn(II) importance - did you recognize it due to the Zn-reduction chemistry originally used to prepare sulfinates from sulfochlorides? What other Lewis acids did you examine - for example did you look at FeCl3.hexahydrate? What is the actual role of the Lewis acid - does it activate the sulfinate or does it activate tBuOOH?
ReplyDelete2) Did you look into other mild sources of tBuO(.) radical, i.e. BocOOBoc?
We have demonstrated that usually zinc sulfinate are more reactive than corresponding sodium salt(see our nature paper). The original idea for adding ZnCl2 to DFES-Na system aimed at generating zinc salt in situ for we have difficulty in getting the pure DFES-Zn. The exact role of Zn is not very clear right now, so we are conducting further research including testing some other lewis acids as you mentioned on understanding the process.
ReplyDeleteAs to your second question, we did try some other oxidant like cumene hydroperoxide and H2O2, but TBHP( aq solution) is the best. We didn't try the reagent you mentioned, but we will take into consideration, thanks.
BocOOBoc is made from Boc2O (2 eq.) and H2O2 + KOH in aqueous THF. It is a solid peroxide that has lower temperature of fragmentation than most organic peroxides; I used it as a radical initiator for telomerization of CCl4 with diketene. BocOOBoc might be shock sensitive but I did not have any problems handling it in multigram quantity. http://orgprepdaily.wordpress.com/2006/09/page/4/
ReplyDeleteThank you for your recommendation and introduction of the special reagent. Our sulfinate radical process will generate strong acid. Whether this reagent is stable or not towards acidic condition?
ReplyDeleteBocOOBoc is stable in water but not in a strong anhydrous acid like TFA. I expect that in a bi-phasic water+DCM system with few equivalents of acid it should be fine, especially at 0C. But this peroxide decomposes right above room temperature and is probably shock sensitive so when I made it I evaporated the react mixture from a cold bath and stored the product it in a freezer.
ReplyDeleteBy the way, it is not my reagent - BocOOBoc was introduced as a radical probe for clean production of tBuO(.) at ambient temperature for kinetic studies but it was in some old obscure paper, and they used a different Boc-ylation agent (Boc-ON if I remember correctly), their workup was more involved and their yield was poor - I think it was all done before Boc2O became commercially available.
You are highly appreciated for sharing your valued research experience. I think it may be safer to use BocOOBoc as an initiator for our radical chemistry by syringe pumping the stock solution of it.
ReplyDeleteI agree about the slow addition of BocOOBoc solution - I did that when I was using it as radical initiator: http://orgprepdaily.wordpress.com/2006/10/page/4/ (its the procedure at the bottom of the page).
DeleteAnd thank you for having patience with commenters like me who make unsolicited suggestion about your work (the practical usefulness of which is manifest; the medicinal chemists working on kinase projects are going to love your methodology).