Late-Stage Deoxyfluorination of Alcohols with PhenoFluor^™

Abstract

An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting selectivity in substrates with multiple alcohols is given.

The selective modification of natural products and drug-like molecules can rapidly generate new pharmaceutical candidates with potentially improved pharmacological profiles.¹ Late-stage fluorination² is particularly promising in this regard because incorporation of fluorine into molecules can increase their metabolic stability, bioavailability, and blood brain barrier penetration.³ But late-stage fluorination is challenging and, to the best of our knowledge, no general late-stage aliphatic fluorination method is currently available. Here we report the first functional group tolerant aliphatic deoxyfluorination reaction of complex primary, secondary, and tertiary alcohols. Deoxyfluorination of structurally simple alcohols is known, and several reagents for deoxyfluorination have been described.^4,5 However, current deoxyfluorination methods are commonly characterized by limited functional group tolerance, side reactions such as elimination, and instability or explosion of the reagents upon heating.^4c,5a,6 The method presented herein employs commercially available PhenoFluor (1), a crystalline, non-explosive solid that does not suffer from competing side reactions to the extent that other deoxyfluorination reagents do. The conceptual advantage of PhenoFluor, beyond its better safety profile, is manifested in its chemoselectivity which results in the ability to selectively and predictably introduce fluorine also into complex small molecules with several hydroxyl groups, which has not been shown with other reagents.

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PhenoFluor (1) was originally developed for deoxyfluorination of phenols,⁷ and we found that appropriate modification of the reaction conditions allows deoxyfluorination of aliphatic alcohols. Deoxyfluorination of alcohols can be accomplished with several commercially available reagents, such as DAST^5a and Deoxo-fluor,^5b but is normally not compatible with a variety of functional groups, and is often plagued by elimination or other side reactions.^5a,6 Table 1 shows the utility of PhenoFluor compared to other commercially available deoxyfluorination reagents, and illustrates that PhenoFluor gives access to fluorinated molecules that are practically inaccessible by deoxyfluorination with other reagents. Fmoc-serine methyl ester was selected as a simple but challenging test substrate for evaluation. The β-hydroxy ester moiety of Fmoc-serine methyl ester is prone to formal elimination of water when the hydroxyl group is converted into a leaving group, and the carbamate group can form the corresponding aziridine by intramolecular cyclization subsequent to alcohol activation, both of which were observed with the conventional reagents shown in Table 1. Evaluation of each reagent was performed in toluene, dioxane, and under optimized conditions previously reported for each reagent.^5a–e Fluoroserine 2 was obtained at best in 11% yield with conventional deoxyfluorination reagents, but could be obtained in up to 80% yield with PhenoFluor.

Table 1.

Comparison of PhenoFluor with other commercially available deoxyfluorinating reagents.^a

^aYields were determined by ¹⁹F-NMR using 1-fluoro-3-nitrobenzene as internal standard.

^bBest yield obtained from reactions run in toluene, dioxane and under optimized reaction conditions previously reported for each reagent (see SI for details).

Deoxyfluorination of aliphatic alcohols with PhenoFluor can be carried out at room temperature, enabling fluorination of temperature-sensitive substrates. For example, for everolimus⁸ (see 15) or oligomycin A (see 17), fluorination was performed at room temperature to avoid decomposition (Table 2). The addition of Hünig’s base is beneficial to shorten the reaction time, and KF was found to reduce side products resulting from elimination, but is not generally required for the reaction to proceed. The formation of reaction products resulting from elimination could also be reduced by increasing the reaction temperature from 23 °C to 80 °C when toluene is used as solvent. For example, while deoxyfluorination proceeds at 23 °C, deoxyfluorination of testosterone (see 3) and epi-androsterone (see 13) was performed at 80 °C because elimination was found to be the main side reaction for epi-androsterone and testosterone at 23 °C. Appropriate reaction solvents in addition to toluene are dioxane and CH₂Cl₂, depending on the solubility of the alcohol substrate. Chiral secondary alcohols can typically be deoxyfluorinated with inversion without observed epimerization or elimination. In addition, secondary allylic alcohols afforded allylic fluorides consistent with an S_N2 mechanism, and only small amounts, if any, of allylic fluorides consistent with an S_N2′ mechanism. Ketones and especially aldehydes are challenging substrates for deoxyfluorination reactions because they are often converted to the corresponding gem-difluorides,^4a yet, PhenoFluor can tolerate carbonyl functional groups (see e.g. 3, 6, 13).

Table 2.

Late-Stage Deoxyfluorination of Alcohols with PhenoFluor.

^aParent compound refers to the name of the natural product/pharmaceutical used as starting material or to the name of the natural product/pharmaceutical from which the starting material is derived.

^bIsolated yields of single compound.

^cNo KF was used.

^d16% of the corresponding primary allylic fluoride was isolated.

^eDeoxyfluorination with retention was observed.

Complex molecules, such as several of those depicted in Table 2, frequently contain more than one carbinol. Typically, PhenoFluor can discriminate between different carbinols and afford a single fluorinated analog in synthetically useful selectivity; for example, 71% of the fluorinated oligomycin A analog 16 was isolated, despite the presence of five hydroxyl groups in oligomycin A (18, Figure 1). We have observed several trends that enable prediction of the fluorination site in the presence of several hydroxyl groups: 1) Primary alcohols are selectively deoxyfluorinated in the presence of secondary and tertiary alcohols. 2) Secondary alcohols react significantly slower or not at all when they are β, β′ -dibranched, unless the secondary alcohol is allylic. 3) Tertiary alcohols do not react, unless they are allylic. 4) Based on previous observations,⁷ hydroxyl groups engaged in hydrogen bonding are not reactive. For the substrates evaluated, these four guidelines were suitable to correctly predict reactivity and selectivity for deoxyfluorination.

Figure 1.

Rationale for the site-selective deoxyfluorination of oligomycin A (18).

PhenoFluor distinguishes itself from other deoxyfluorination reagents such as DAST primarily through its better safety profile and higher chemoselectivity. The chemoselectivity of PhenoFluor enables access to complex fluorinated molecules; other de-oxofluorination reagents do not discriminate well between reactive functional groups. For example, DAST affords several (at least five) more fluorinated analogs upon reaction with 18, which results from indiscriminate reaction of DAST with secondary alcohols, including β, β′-substituted carbinols. The source of the differentiated chemoselectivity of PhenoFluor is not yet understood, but likely is more complex than could be rationalized simply based on its larger size compared to the other deoxyfluorination reagents. We have observed that unanticipated hydrogen bonding between the hydrogen atoms of the imidazoline ring of PhenoFluor with bifluoride is important for reactivity.⁷ The better safety profile is another benefit of PhenoFluor. Several conventional reagents are unstable toward heat or even explosive. An exotherm of only 0.15 kcal·g⁻¹ at 213 °C was observed by differential scanning calorimetry (DSC) when PhenoFluor was heated until its decomposition temperature of 213 °C.

In conclusion, we have developed a general method for the selective, predictable, direct deoxyfluorination of complex alcohols. The substrate scope and functional group tolerance surpasses those of any aliphatic fluorination reaction reported to date. One drawback of PhenoFluor is its molecular mass of 427 g·M⁻¹, which makes it a convenient reagent for sub-gram and gram scale, but a wasteful reagent for larger scale reactions. We are currently investigating the potential of extending the reported method to late-stage ¹⁸F-radiolabeling⁹ for positron emission tomography (PET) applications.