一種空間調控的2-氟吡啶鹽用于無催化劑、可見光介導的醇類脫氧反應：基于電子供體-受體復合物的機理研究

羥基基團在有機分子中的普遍性推動了多種醇類官能團轉化方法的發展。其中，脫氧反應是調節分子氧化態的重要手段，尤其在天然產物合成中具有重要意義。傳統方法（如）依賴有毒試劑（如三丁基錫氫化物）或金屬催化劑。近年來，可見光化學在“氧化還原輔助”策略中展現出潛力，但現有方法仍需光催化劑或金屬配合物。本研究提出一種無催化劑、基于EDA復合物的新策略。

將醇轉化為硫代酯類中間體，然后自由基斷裂得到醇的脫羥基產物的反應，稱為Barton-McCombie脫羥基反應。也被稱為Barton脫氧反應，是脫去醇羥基最有效的一種方法。此反應最早由Barton 和 McCombie在1975年報道。大位阻的仲醇和叔醇也可通過此方法得到脫羥基產物，但反應活性沒有伯醇高，反應活性順序：伯醇>仲醇>叔醇。經典的方法是將醇轉化為硫代酯衍生物，接著和Bu3SnH/AIBN在甲苯中回流反應。 YGNF，公眾號：有機合成

近期，Takeshi Nanjo等人報道了一種新型空間調控的2-氟-1-甲基吡啶鹽，通過無催化劑、可見光介導的脫氧反應，可將醇類轉化為相應的烷氧基吡啶中間體并生成脫氧產物。該反應的關鍵在于吡啶鹽3位引入大位阻的環己基，其通過強制C-O鍵處于垂直于吡啶環平面的構象，促進光激發下電子供體-受體（Electron Donor-Acceptor, EDA）復合物的形成，從而實現高效的C-O鍵斷裂。該方法適用于氨基酸衍生物、甾體及糖類等多種復雜分子的脫氧反應，并可擴展至C-C鍵偶聯反應【Org. Lett. 2025, DOI: 10.1021/acs.orglett.5c00266】。

【 DOI: 10.1021/acs.orglett.5c00266】

反應條件優化：

以1-Cbz-4-哌啶醇（1）為模型底物進行條件篩選，發現3位取代基對反應效率至關重要。未取代（2c）或甲基/苯基取代（2a、2d）的吡啶鹽產率低下（3-47%），而環己基取代的2e顯著提升產率至65%（440 nm LED），溶劑（THF）與胺（iPr?NEt）協同參與氫轉移（HAT）。

底物適用性：

氨基酸衍生物：手性氨基醇（5、6）脫氧保留立體構型，奎寧環（quinuclidine）添加劑提升產率。

甾體：表雄酮（7）和雄甾酮（8）的羥基脫氧需奎寧環輔助（產率提升至73-77%）。

糖類：半乳吡喃糖苷（9、10）的伯/仲羥基脫氧（產率70-83%），可放大至2 mmol規模。酮糖（11、12）、核糖（14）及核苷（15）成功脫氧，葡萄糖胺衍生物（16）產率62%。

對比實驗：傳統Ir光催化劑對底物16無效，表明此無催化劑體系的官能團兼容性更優。

機理研究：

烷氧基吡啶中間體與胺形成EDA復合物，可見光激發觸發單電子轉移（SET），生成吡啶自由基（C）并釋放烷基自由基。同位素標記（THF-d?）實驗證實THF作為氫供體（產物17氘代率82%），而iPr?NEt優先參與空間位阻較小的自由基HAT。

DFT計算與晶體學研究發現，3位環己基迫使C-O鍵垂直于吡啶環平面（φC1?C2?O3?C4 ≈ 100°），降低過渡態能壘（TS_Cy < TS_Me < TS_H）。X射線晶體結構（19a、19e）顯示取代基對中間體構象的調控作用。

烷氧基吡啶中間體（如3）與胺（如iPr?NEt）通過靜電相互作用形成電子供體-受體（EDA）復合物B。該復合物的HOMO（胺）-LUMO（吡啶鹽）能隙匹配可見光能量（440 nm），光照觸發單電子轉移（Single Electron Transfer, SET），生成吡啶自由基C并釋放烷基自由基（R·）， THF作為氫供體生成脫氧產物。

應用擴展：

以丙烯腈、丙烯酸乙酯為自由基受體進行C-C偶聯反應 ，一鍋法實現脫氧-偶聯（產物20-25，產率51-63%）。γ-萜品烯（γ-terpinene）作為HAT供體抑制副反應，驗證反應的多功能性。

實驗操作：

A round bottom flask was charged with a stir bar, 3-bromo-2-fluropyridine S5 (1.76 g, 10.0 mmol,1.0 equiv.), cyclohex-1-en-1-ylboronic acid S6 (1.39 g, 11.0 mmol, 1.1 equiv.), PdCl2(dppf)?CH2Cl2 (408 mg, 0.500 mmol, 0.05 equiv.), and Na2CO3 (4.26 g, 40.2 mmol, 4.0 equiv.), equipped with a balloon, and evacuated and backfilled with Ar gas (repeated three times). To the mixture were added 1,4-dioxane (70 mL) and H2O (30 mL) and the mixture was heated to 80 °C. After stirring overnight, the mixture was cooled to room temperature, concentrated under reduced pressure to remove 1,4-dioxane, diluted with water, and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative medium pressure liquid chromatography (Q-PACK SI50, 120 mL, 0% →10% EtOAc/hexane) to afford 3-(cyclohex-1-en-1-yl)-2-fluoropyridine S7 (1.65 g, 9.31 mmol, 93%yield) as a colorless oil. A round bottom flask was charged with a stir bar, the pyridine S7 (1.50 g, 8.46 mmol, 1.0 equiv.), and Pd/C (10%, 90 mg, 0.085 mmol, 1 mol%), equipped with a balloon, evacuated and refilled with H2 gas. To the mixture was added EtOH (40 mL). After stirring at room temperature overnight, the mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude residue was purified by preparative medium pressure liquid chromatography (QPACK SI50, 120 mL, 0% → 10% EtOAc/hexane) to afford 3-cyclohexyl-2-fluoropyridine S8 (1.25g, 6.97 mmol, 82% yield) as a colorless oil.

A round bottom flask was charged with a stir bar, 3-cyclohexyl-2-fluoropyridine S8 (359 mg, 2.00 mmol, 1.0 equiv.), and CH2Cl2 (10 mL). To the mixture was MeOTf (263 μL, 2.40 mmol, 1.2 equiv.) and the flask was flowed with Ar gas and capped. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure and the resulting precipitate was washed withhexane (50 mL×5) to afford the pyridinium salt 2e (521 mg, 1.88 mmol, 94% yield) as a white solid.

General Procedure for Reduction of Alcohols (GP2): A borosilicate glass tube with a screw cap was charged with a stir bar, alcohol (0.100 mmol, 1.0 equiv.), and pyridinium salt 2e (41.2 mg, 0.120 mmol, 1.2 equiv.) and carried into a glove box. To the mixture were added THF (2.0 mL) and iPr2NEt (51.0 μL, 0.300 mmol, 3.0 equiv.), and the tube was capped and carried out of the glove box. After stirring for 2 hours at room temperature, the mixturewas placed on a photoreactorS2 equipped with two LED lamps (4 cm from tube) and a fan (Yamazen YCS-C188). After stirring for 16 hours under 440 nm LEDs irradiation (the temperature of the reaction mixture is usually 45–55 °C), the volatiles were removed under reduced pressure. The crude residue was purified by flash column chromatography (BW-300 SiO2) or preparative TLC to afford the deoxygenated product.

Reduction of 10 without Glove Box: A borosilicated glass tube with a three-way stopcock was charged with a stir bar, methyl 2,3,6-tri-Obenzoyl-α-D-galactopyranoside 10 (50.6 mg, 0.0999 mmol, 1.0 equiv.), and pyridinium salt 2e (41.2 mg, 0.120 mmol, 1.2 equiv.), equipped with a gas bag, and evacuated and backfilled with Ar gas (repeated three times). To the mixture were added THF (2.0 mL) and iPr2NEt (51.0 μL, 0.300 mmol, 3.0 equiv.) by a syringe. After stirring for 2 hours at room temperature, the mixture was placed on a photoreactor equipped with two 440 nm LED lamps (4 cm from tube) and a fan (Yamazen YCSC188) as shown in Figure S2. After stirring for 16 hours under 440 nm LEDs irradiation, the volatiles were removed under reduced pressure. The crude residue was purified by flash column chromatography (BW-300 SiO2, 20 mL, 20% EtOAc/hexane) to afford the deoxygenated product 17 as a white solid.

本研究開發了一種基于空間調控吡啶鹽2e的無催化劑脫氧策略，其通過EDA復合物機制實現醇類的高效功能化。該方法的底物廣譜性（涵蓋氨基酸、甾體、糖類）及可擴展的C-C偶聯能力，為復雜分子合成提供了新工具。進一步機理研究及合成應用正在進行中。