Radical hydrodifluoromethylation of unsaturated C-C bonds via an electroreductively triggered two-pronged approach

Abstract

Due to its superior ability in controlling pharmaceutical activity, the installation of difluoromethyl (CF₂H) functionality into organic molecules has been an area of intensive research. In this context, difluoromethylation of C-C π bonds mediated by a CF₂H radical have been pursued as a central strategy to grant access to difluoromethylated hydrocarbons. However, early precedents necessitate the generation of oxidative chemical species that can limit the generality and utility of the reaction. We report here the successful implementation of radical hydrodifluoromethylation of unsaturated C-C bonds via an electroreductively triggered two-pronged approach. Preliminary mechanistic investigations suggest that the key distinction of the present strategy originates from the reconciliation of multiple redox processes under highly reducing electrochemical conditions. The reaction conditions can be chosen based on the electronic properties of the alkenes of interest, highlighting the hydrodifluoromethylation of both unactivated and activated alkenes. Notably, the reaction delivers geminal (bis)difluoromethylated products from alkynes in a single step by consecutive hydrodifluoromethylation, granting access to an underutilized 1,1,3,3-tetrafluoropropan-2-yl functional group. The late-stage hydrodifluoromethylation of densely functionalized pharmaceutical agents is also presented.

Fig. 1. Radical hydrodifluoromethylation of unsaturated C–C bonds.

A Precedent examples of difluoromethylation under oxidizing conditions. B Reductive photocatalysis for radical difluoromethylation. C A two-pronged electroreductive hydrodifluoromethylation.

Fig. 2. Proposed mechanism.

A cathodic reduction of (A) would furnish a CF₂H radical (B), which would afford carbon-centered radical (D) upon addition into alkene substrate (C). The radical (D) would be reduced into corresponding carbanion (E) when the reduction potential of (D) is on par with (A) (path A). A subsequent protonation with water would furnish hydrodifluoromethylation product (F). Alternatively, a carbon-centered radical (D) would directly perform hydrogen-atom transfer (HAT) to form (F) in the presence of a hydrogen atom donor, when E_red(D/E) is too negative to be reduced on the cathode (path B).

Fig. 3. Reaction parameter optimization.

Yields determined by ¹H NMR using CH₂Br₂ as an internal standard (isolated yields in parenthesis). The voltaic profile of each electrode during electrolysis of entry 1 is shown (inset box). The sacrificial Zn anode operates at the anticipated onset potential for Zn oxidation (blue line, E_onset = ca. −0.5 V vs Fc/Fc⁺). The initial cathodic potential (E_cathode = −1.8 V) is in accordance with the onset potential for reduction of 2 (red line). Under the given cathodic potential, a simultaneous reduction of benzylic radical intermediate 4 into corresponding carbanion 5 is also conceivable.

Fig. 4. Preliminary mechanistic investigation.

A A significant amount of deuterium incorporation was observed upon employment of D₂O in under optimized reaction conditions (Eq. 1). The reaction with piperidine-d₁₁ result in low deuterium incorporation (Eq. 2). B Vinyl cyclopropane 6a with higher ring opening rate constant (k_Ph = ~10⁸s⁻¹) underwent rupture of the three-membered ring (8a), while the cyclopropyl ring in 6b (k_H = ~10⁵s⁻¹) remained intact after electrolysis.

Fig. 5. Substrate scope of conjugated alkenes^a.

^a9 (0.2 mmol), 2 (0.4 mmol), H₂O (2.0 mmol), LiClO₄ (0.8 mmol) in MeCN/piperidine (6.0 mL, 40:1) at 50 °C. ^b9 (0.2 mmol), 2-py (0.6 mmol), LiClO₄ (0.8 mmol) and H₂O (1.0 mL) in MeCN/Et₃N (14/1, 4.0 mL) at 22 °C. ^cYield was measured by ¹H NMR spectroscopy with CH₂Br₂ as an internal standard. Isolated yields are reported unless otherwise noted.

Fig. 6. Substrate scope of aliphatic and electron-rich alkenes^a.

^a11 (0.2 mmol), 2-py (0.6 mmol), TBA·PF₆ (0.8 mmol) and H₂O (1.0 mL) in MeCN/Et₃N (14/1, 4.0 mL) at 22 °C. Isolated yields are reported unless otherwise noted.

Fig. 7. Double hydrodifluoromethylation of alkynes^a.

^a15 (0.2 mmol), 2-py (0.6 mmol), LiClO₄ (0.8 mmol) and H₂O (1.0 mL) in MeCN/Et₃N (14/1, 4.0 mL) at 50 °C. Isolated yields are reported unless otherwise noted.

Fig. 8. Synthesis of CF₂H analogues of ibuprofen.

The requisite starting material 20 was prepared in three steps from 2-(4-hydroxyphenyl)propanoic acid (17). The desired hydrodifluoromethylation was proceeded under the standard conditions (21). Hydrolysis of 21 led to the formation of difluoromethyl analogue of Ibuprofen (22) in 28% overall yield (5 steps). The developed double hydrodifluoromethylation protocol allowed conversion of alkyne 25 into corresponding geminal bis-difluoromethylation product 26. Upon treatment of 26 with base under aqueous conditions, a bis-difluoromethyl analogue of Ibuprofen (27) was obtained.