From the text:
The original scale-up conditions for the fluorination reaction involved treatment of 5 with 1.5−1.8 equiv of Deoxo-Fluor (27) at −78 °C in methylene chloride or THF to furnish 2. While the ratio of diastereomers (2:3) was ∼8:1, the need to use, and subsequently quench, an excess of Deoxo-Fluor, coupled with the need for cryogenic equipment prompted us to explore alternative conditions. Several deoxofluorination conditions were evaluated for the conversion of tertiary alcohol 5 to the free-base form of API, 2. These included not only other fluorinating reagents but also involved attempts to render the Deoxo-Fluor amenable to scale-up in noncryogenic vessels.The authors explore their results, which I've partially summarized with the altered graphic below. (I've not used any of the other reagents other than Deoxo-Fluor, so I don't have experience with them.) It's interesting that both DFI and TFFH suffer from an inability to purge the urea byproduct, even after aqueous wash and isolation of product.
Credit: Hawkins et al., Org. Process Res. Dev. |
A pretty cool paper, I think.
[1] Hawkins, J.M.; Dubé, P.; Maloney, M.T.;Wei, L.; Ewing, M.; Chesnut, S.M.; Denette, J.R.; Lillie, B.M.; Vaidyanathan, R. "Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition." Org. Process Res. Dev., Article ASAP DOI: 10.1021/op300093j
Deoxyfluor is nasty on scale because of the huge quench and the corrosive properties - it even makes the plastic storage containers brittle so old large container of it is a hazard. I wonder why they did not try the new hotness, Aryl-SF3 with o,o,p-substituents. There was a paper in JACS few years ago that described these reagents as being air/misture stable crystalline solids prepared without use of F2, HF or SF4 - if I remember correctly the reagent was obtained on good scale by oxidizing the aryl thiol with Cl2 in the presence of KF. I think this could be a great alternative for scale up.
ReplyDeleteFluolead? http://dx.doi.org/10.1021/ja106343h
ReplyDeleteAlso need to cautious. More often than not the reaction runs away liberating Nasty HF
ReplyDeletePasupathy