The Electrophilic Fluorination of Enol Esters Using SelectFluor: A Polar Two‐Electron Process

Abstract

The reactiono fe nol esters with SelectFluor is facile andl eads to the corresponding a-fluoroketones under mild conditions and, as ar esult, this route is commonly employed for the synthesis of medicinally importantc ompoundss uch as fluorinated steroids. However,d espite the use of this methodology in synthesis, the mechanism of this reactiona nd the influence of structureo nr eactivity are unclear.Arigorous mechanistic study of the fluorination of these substrates is presented,i nformed primarily by detailed and robust kinetic experiments. The resultso ft his study implicateapolar two-electron process via an oxygen-stabilised carbenium species, rather than as ingle-electron process involvingr adical intermediates. The structure-reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of a-fluoroketones.Scheme1.The fluorination of steroid structures via enol ester intermediates.[a] S.Scheme2.Literature studies that implicate two-electron or single-electron reaction mechanisms.Scheme14. Values of 1 for the three different Hammett studies conductedd uring thiswork.Scheme15. Proposed mechanisms for the hydrolysisof( a) 3 and (b) 8c after fluorination.

Pyridinium Salts as Redox‐Active Functional Group Transfer Reagents

“…[109] This inconsistency requires continued investigation on whether mechanisms are substrate-dependent, as it remains unclear in some studies using an frontier molecular orbital (FMO) approach if there is alow-lying LUMO on the fluorine atom of the N-fluoropyridinium or the p*o rbital of the pyridinium core. [110] Our recent results provide additional support that functional group transfer reagents are typically both highly polarized and strong oxidants can react through radical mechanisms.…”

Kinetics of Electrophilic Fluorination of Steroids and Epimerisation of Fluorosteroids

“…Fluorination of 17 was conducted using Selectfluor (Scheme1)t oo btain a mixture of a and b isomers of 6-fluoroprogesterone 21. [8] The fluorination proceeded cleanly,w ith 100 %c onversion as determined by 1 Ha nd 19 FNMR spectroscopy,a nd 96 %y ield of the a/b isomer mixture, where the a and b isomersw erep resent in a3 4:66 ratio. The isomer mixture was resolved using columnc hromatography to afford isolated yields of 19 % aisomer and4 6% b-isomer.T he structures of the isomers were assigned by X-ray crystallography (Scheme 2).…”

“…Closer inspection of 1 HNMR kinetic data for the fluorinations of progesterone enol acetate 17 with NFPy TfO À 9 and NFSI 8 showedc onstant a:b isomer ratios over the courses of the reactions. In order to furtheri nvestigate the potential for in situ epimerisation we explored whether 'spent' Selectfluor (ClCH 2 -DABCO + •BF 4 À )c ould play an acid/base catalysis role in this process.W hen 21-b was incubated with ClCH 2 -DABCO + •BF 4 À in MeCN-d 3 ,n of ormationo f21-a was observed by 19 FNMR spectroscopy over the course of 1 week.T op robe the possibility of protonated 'spent' Selectfluor catalysing in situ epimerisation,w ea ttempted to prepare as ample of this protonated species, although our efforts were unsuccessful (see Supporting Information Section 2.1.12). Thus, at present, we are unable to confirm that in situ epimerisation is in operation.…”

“…[36] We believe oxidation processes are likely to result in the formation of HF,w hich will be lost from the reaction mixture, thus leading to the loss of detectable 19 FNMR signals over the course of the reaction. When the reactionw as conducted in MeCN-d 3 with 1equiv of Selectfluor (with sonication to fully solubilise 25), small amountso f21-a and 21-b were detected by 1 Ha nd 19 FNMR spectroscopy,asw ell as traces of unidentified fluorinated products (NMR spectra are included in the Supporting Information Section2 .1.11). Progesterone enol acetate 17 was not detected;h owever,t he major product of the reaction was progesterone 13,which could have formed by oxidation of 25 to 17,followed by hydrolysis of the ester group to form 13.T he formation of 13 was confirmed by comparison of the spectra with an authentic sample of 13.…”

Pyridiniumsalze als redoxaktive Reagenzien zur Übertragung funktioneller Gruppen

“…In jedem Fall ist jedoch der Vorschlag eines Fluoroniumkations [F + ] nicht gerechtfertigt, da es sich um eine reaktivere Spezies als das bereits hochenergetische Fluorradikal handelt . Diese Inkonsistenz erfordert weitere Untersuchungen darüber, ob die Mechanismen substratabhängig sind, da es in einigen Studien unklar bleibt, ob in einem FMO‐Ansatz (FMO=frontier molecular orbital) ein niedrig liegendes LUMO auf dem Fluoratom von N ‐Fluorpyridinium liegt oder dem π* des Pyridiniumkerns entspricht . Die neuen Ergebnisse von Togni, Carreira et al.…”