Light-driven Deoxyfluorination of Alcohols with Seletfluor

Deoxyfluorination remains amongst the most frequently used method for preparing alkyl fluoro compounds.¹ The reaction typically involves activation of a leaving group followed by S_N2 (but occasionally S_N1) reaction with fluoride ion. This is usually accompanied with significant elimination side-reactions and can frequently be low yielding. The original deoxyfluorination reagents such as DAST (diethylaminosulfur-trifluoride) and Dexofluor (Bis(2-methoxyethyl)aminosulfur trifluoride) are toxic and difficult to handle, particularly at scale, leading to the development of flow chemistry processes and use of microreactors.² That said, these reagents have had a significant impact on the access to alkyl fluoro compounds, with a notable increase in fluorine-containing clinical candidates and drugs appearing in the 1970’s and 80’s once these reagents gained traction in the synthetic community.³ DAST was reported by chemists at Dupont in 1975 as a bench stable alternative to SF_4.⁴

Improvements in handleability and safety with the introduction of PhenoFluor, AlkylFluor and reagents such as PyFluor and XtalFluor have partially addressed some of these issues,⁵ however their remains considerable scope for improvement- particularly transposition of tertiary alcohol substrates.

Mechanistically this should be achievable by switching pathways. Formation of a radical at a tertiary carbon should be facile and the radical intermediate a good nucleophile to trap with an electrophilic fluorine source. This gives an orthogonal approach to the reaction of an activated leaving group with a poorly nucleophilic fluoride ion. Generation of a radical intermediate of this type is perfectly suited for visible light photoredox, leveraging low-temperature activation and mild reaction conditions.

Not Surprisingly the MacMillan group have just published a very nice paper on photoredox-catalyzed deoxyfluorination of activated alcohols with everybody’s favourite fluorine source- the commercially available, inexpensive, stable reagent Selectfluor (Tetrahedron 2019, 75, 4222-4227).⁶ Generation of the alkyl radical from the corresponding alcohol was achieved by conversion to the oxalate half-ester and double decarboxylation- methodology developed through a collaboration between the MacMillan and Overman groups (Scheme 1).⁷

A proposed mechanism is outlined in Scheme 2. Upon exposure to visible light the heteroleptic (mixed ligand) complex (Ir[df(CF₃)ppy]₂(dtbbpy)PF₆) forms a long-lived excited state species. Reduction of selectfluor (to initiate the catalytic cycle) generates an Ir(IV) oxidant via a single electron transfer (SET) process. Reaction of this species with the activated alcohol results in loss of CO₂, generation of an alkyl radical and return of the catalyst to its ground state.

Fluorine atom transfer to the alkyl radical gives the fluoroalkane product and a radical cation that re-oxidizes the triplet excited iridium catalyst to the Ir(IV) species, cycling the process. ⁸ Photochemical quenching experiments using the Stern-Volmer procedure showed that selectfluor is able to oxidise the excited state Ir(III) species Ir(Iv) adding weight to the proposed mechanism.

Optimization (utilizing the oxalate derived from 2-decanol) revealed the best reaction conditions were using 1mol% of photocatalyst (Ir[dF(OMe)ppy]2(dtbbpy)PF6) , Na₂HPO₄ as base in acetone/water with a 34W blue LED lamp (Scheme 3).⁹  A range of secondary and tertiary alcohols could be converted to their corresponding fluorides in good yield (67-80% isolated yield). Protected amines, esters and amides were stable to the reaction conditions, however for tertiary alcohols higher yields were observed with a lower power carbon filament lamp and less Selectfluor reagent.

Deoxyfluorination of a range of natural product alcohols and sterically hindered bridge structures, including steroids, proceeded in good yields with good selectivity.

Its good to see a new twist on the deoxyfluorination reaction, complimentary to traditional nucleophilic S_N2 processes, providing access to tertiary alkyl fluorides under mild conditions with a reagent that most people are familiar with. 

Organofluorine Chemistry: Synthesis, Applications, Sources and Sustainability

Organofluorine compounds are frequently encountered in the pharmaceutical, agrochemical and fine chemical industries. Often the selective introduction of a fluorine atom or functional group into a molecule can be challenging, particularly at scale, with chemists often designing synthetic routes in which fluorine is introduced through strategic sourcing of raw materials rather than synthetically.

Scientific Update offer a new two-day course that aims to provide an overview of fluorination technology and synthetic methods- both traditional and state of the art- highlighting industrial application. Detailed case studies are used to provide context and workshops enable delegates to familiarize themselves with the chemistry described. For more information contact me at [email protected]

References:

1. Recent Developments in the Deoxyfluorination of Alcohols and Phenols: New Reagents, Mechanistic Insights, and Applications: W. Hu et al, Synthesis 2017, 49, 4917.
2. The use of diethylaminosulfur-trifluoride (DAST) for fluorination in a continuous flow microreactor: S. Ley et al, Synlett 2008, 14, 2111-2114; Aminosulfurtrifluorides: relative thermal stability: W. Middleton et al, J. Fluorine Chem. 1989, 42, 137-143
3. Archived Webinar, J. Studley, Scientific Update, April 2019 https://www.scientificupdate.com/webinar_events/fluorine-synthetic-methods-for-selective-introduction-into-small-molecule-drugs/20190424/
4. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis: J. Hu et al, Chem. Rev. 2015,  115, 765-825.
5. Late-stage deoxyfluorination of alcohols with PhenoFluor: T. Titter et al, J. Am. Chem. Soc. 2013, 135, 2470-2473; AlkylFluor: deoxyfluorination of alcohols: N. Goldberg et al, Org. Lett. 2016, 18, 6102-6104; PyFluor: A low-cost, stable, and selective deoxyfluorination reagent: A. Doyle et al, J. Am. Chem. Soc.2015, 137, 9571-9574; XtalFluor-E: A useful and versatile reagent in organic transformations: M. Heravi et al, J. Fluorine Chem. 2019, 225, 11-20.
6. Selectfluor reagent F-TEDA-BF4 in action: tamed fluorine at your service R. Banks, J. Fluorine Chem. 1998, 87, 1-17; Recent advances in the application of Selectfluor F-TEDA-BF₄as a versatile mediator or catalyst in organic synthesis: S. Stavber Molecules 2011, 16, 6432-6464.
7. Oxalates as Activating Groups for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling: MacMillan and Overmann et al, J. Am. Chem. Soc. 2015, 137, 11270-11273.
8. Fluorine Transfer to Alkyl Radicals: G. Sammis et al, J. Am. Chem. Soc. 2012, 134, 4026-4029.
9. The oxalate half ester was prepared using oxalyl chloride then water and was used without further purification.
10. Lisa M. JarvisC&EN 2019, 97  https://cen.acs.org/pharmaceuticals/drug-development/new-drugs-2018/97/i3. Fluorine-containing small molecules: Vitrakvi, Lorbrena, Xofluza, Talzenna, Vizimpro, Pifeltro, Xerava, Orlissa, Krintafel, Tibsovo, Tpoxx, Mektovi, Akynzeo, Tavalisse, Erleada, Symdeko and Biktarvy.