2-Fluoro-5-(1,2,2,2-tetrafluoro-ethyl)-benzonitrile 2-Fluoro-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzonitrile (1 g, 4.56 mmol) in DCM (5 mL) was treated with DAST (Aldrich, 1.12 mL, 9.13 mmol) at -78 ℃ for 2 hours. The reaction was quenched with saturated NaHCO₃ and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to give the crude material, purified by silica gel column (hexanes: ethyl acetate 4:1) to afford the title compound. Colorless solid, yield 1.01 g, 100%.

WO2011156554

Intermediate 35 (1 g, 3.1 mmol) was suspended in DCM (7.7 mL) and the reaction was cooled down to 0 °C. Then DAST (0.45 mL, 3.7 mmol) was added dropwise. After 20 min at 0 ℃ the reaction mixture was quenched with aqueous NaHCO₃ (sat. sol.), then extracted with DCM. The organic layers were separated, dried (Na₂SO₄), filtered and the solvents evaporated in vacuoto yield intermediate 36 which was used as such in the next reaction step. Yield 1 g, quant.

WO2011154431

To a solution of methyl 6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate (1.0 equiv.) in CH₂Cl₂(0.04 M) at -78 ℃ under Ar was added methylDAST (2.0 equiv.). After addition, the solution was stirred under Ar at -78 ℃ for 10 minutes and then the bath was removed. The reaction was allowed to warm up to rt and quenched by addition of NaHCO₃₍_sat_.). The solution was diluted with EtOAc, washed with NaHCO₃₍_sat_.), NaCl₍_sat_.), dried over MgSO₄, filtered, concentrated, purified by ISCO SiO₂chromatography (0-100 EtOAc/n-heptanes) to yield methyl 6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate. 100% yield.

WO2012120415

A solution of alcohol 51 (2.5 mg, 0.0052 mmol, 1.0 equiv) in CH₂Cl₂ (1.0 mL) at -78 ℃ was treated with DAST [(diethylamino)sulfur trifluoride] (1.3 μL, 0.010 mmol, ca. 2 equiv) and stirred at that temperature for 3 h. The reaction mixture was quenched by the addition of solid NaHCO₃ (30 mg), warmed to 25 ℃, concentrated, and purified by flash chromatography (silica gel, EtOAc:CH₂Cl₂:MeOH, 10:10:1). The desired sarcodictyin analog 52 (2.5 mg, 99% yield).

10.1021/ja9823870

Compound 2 (0.24 mmol) was dissolved in dry methylene chloride (3 mL) and to this solution, diethylaminosulfur trifluoride (DAST) (0.24 mmol) was added at -78 ℃ (dry ice/acetone) under nitrogen. The reaction was warmed to room temperature and stirred for 1 h. Progress of the reaction was monitored by TLC. The complete conversion of 2 into the desired product was achieved in 1 h. The reaction mixture was diluted with methylene chloride (10 mL), washed with brine and water, dried over Na₂SO₄, and concentrated to dryness under reduced pressure at 20 ℃ to obtain a crude reaction product. A silica gel flash column (n-hexane/ethyl acetate, 2:1, vol/vol. Yield: 98.5%, a colorless, viscous oily.

※本文より p 380

Compound 4 might have the inversion of an R- to S-configuration at C-12 to which the fluorine is bonded. Since stereochemistry was not studied, we preferred to show the bonding of fluorine at C-12 as a mixture of isomers (Scheme 1).

10.1007/s11745-006-1397-x

脱酸素的フッ素化 Deoxofluorination

・近年、複数の研究者の貢献により、安定で取扱い容易なフッ素化剤が多数開発された。

(求核的フッ素化剤, 求電子的フッ素化剤の両分野において）

合成の自由度は格段に向上したが、何だかんだ言って、DAST も使い勝手が良い。

　他のフッ素化剤と同様、DAST も一緒に準備しておくと便利。

・２級アルコールの場合は、一般的に立体反転を伴ってフッ素化が進行するが、

　隣接基関与の影響等により、生成物の位置選択性、

　立体選択性が影響を受ける場合もあるらしい。

　（場合によっては、ちょっと気を付けた方が良いのかも）

　計算化学に基づく研究例

　→ DASTを用いたフッ化物アニオンによるSN2反応に関する理論的研究 (2000)

・フッ素原子の導入は、以前のエントリーでも述べた通り、

　リガンドデザインにおいて極めて重要。

　リガンドの代謝ブロック、塩基性の減弱（hERG リスクの改善）、

　コンホメーションの操作等によく使われる。

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Bond formation

Horner-Wadsworth-Emmons (HWE) Reaction - 01

Trimethyl phosphonoacetate (78.6 mL, 485 mmol) was added to a 0 ℃ solution of 4-(4-hydroxyphenyl)cyclohexanone A-1 (76.9 g, 404 mmol) in tetrahydrofuran (3.0 L) in a flame-dried 5.0 L 3-neck round bottom flask equipped with mechanical stirrer and placed under an atmosphere of nitrogen. Sodium hydride (60% in mineral oil, 37.2 g) was added portionwise so that the internal temperature was maintained below 10 ℃. The reaction mixture was stirred at 0 ℃ for 20 minutes and slowly warmed to R.T. and stirred for additional 2.5 h. After disappearance of starting material on TLC (EtOAc:Hexanes 3:7), the reaction mixture was quenched with water (200 ml), then concentrated under reduced pressure to a volume of ca. 1.5 L and diluted with water (500 ml). The aqueous layer was extracted with ethyl acetate (3 x 800 mL). The combined extracts were dried with anhydrous sodium sulfate and magnesium sulfate, filtered, and concentrated to give methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene) acetate A-2. White solid, yield 110.0 g, 100%.

10.1021/ml400527n

To an ice-cooled solution of ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% oil suspension, 1.54 g, 38.5 mmol) and the mixturewas stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hrs. and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (7.07 g, yield 97%) as a colorless oil. Reference Example 38. tert-butyl (2E)-3-[4-(benzyloxy)phenyl]acrylate. The title compound was obtained as colorless crystals from 4-(benzyloxy)benzaldehyde and tert-butyl diethylphosphonoacetate according to a method similar to the method of Reference Example12 (yield 94%).

WO2005063729A1

A stirred ice-cold suspension of NaH (1.19 g, 24.8 mmol) in 50 mL of dry THF, maintained under a nitrogen atmosphere, was treated with diethyl (cyanomethyl)-phosphonate (4.39 g, 24.8 mmol, Aldrich). When the evolution of hydrogen was over (ca. 20 min), a solution of benzylated vanillin 13 (5.00 g, 20.7 mmol) in 15 mL of dry THF was added dropwise, and the resulting mixture was stirred at 0 ℃ for 1.5 h. The reaction mixture was then filtered through a pad of TLC-grade silica gel and washed several times with Et₂O. Evaporation of the solvents afforded 14 as a white solid, which was used without any further purification (5.47 g, quantitative yield).

10.1021/jo020010d

A solution of aldehyde 95 (4.02 g, 7.9 mmol) in THF (20 mL) was added at 0 ℃ to a stirred mixture of NaH (417 mg, 10.3 mmol) and phosphonate 96 (2.20 mL, 10.3 mmol) in THF (80 mL). The mixture was stirred for 1.5 h at rt, before sat. aq. NH₄Cl and Et₂O (each 100 mL) were added. The layers were separated, the aq. layer was extracted with Et₂O (3 x 80 mL), the combined organic solutions were washed with brine, dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (hexanes - EtOAc, 2 : 1) to yield amide 97 (4.32 g, 92%) as a colorless oil.

(2E,7E,5S,6S)-5-(tert-Butyldiphenylsilanyloxy)-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-octa-2,7-dienoic N-methoxy-N-methyl-amide (97), yield (4.32 g, 92%) .

10.1021/jo026743f

■ Z選択的な条件

通常の HWE 反応は、E選択的に反応が進行する。

一方で、特殊なホスホン酸ジエステルを用いると、

Z選択的に反応が進行するようになる。

・Still-Gennari法（10.1016/S0040-4039(00)85909-2）

To a solution of (CF₃CH₂O)₂P(O)CH₂CO₂Me (4.09 mL, 19.3 mmol) and 18-crown-6 (17.0 g, 64.3 mmol) in anhydrous THF (100 mL) at -78 ℃ was added KHMDS (0.5 M in toluene, 38.5 mL, 19.3 mmol) dropwise. After stirring for 20 min at the same temperature, a solution of aldehyde 15 (3.83 g, 12.8 mmol) in anhydrous THF (140 mL) was added dropwise via cannula. Thereaction was allowed to warm to 0 ℃ over 3 hrs and quenched with sat. NH₄Cl (250 mL). The resulting solution was extracted with EtOAc (350 mL) and the organic layer was washed with H₂O, brine, dried (Na₂SO₄) and concentrated. Purification by silica-gel chromatography (hexane/EtOAc, 1/1) provided Z-enolate 7 (4.32 g, 95%) as a yellow oil.

10.1021/ol061267r

・安藤法 (10.1021/jo970057c)

(PhO)₂P(O)CH₂CO₂Et (260 mg, 0.810 mmol) was added to a suspension of NaH (60% in oil) (35.1 mg, 0.878 mmol) in THF (5 mL) with stirring at 0 ℃ and the stirring was continued at this temperature for 15 min. Then, a solution of the (E)-aldehyde (150 mg, 0.675 mmol) in THF (1 mL) was added to the mixture and the whole was stirred at rt for 1 h. The reaction was quenched with saturated NH₄Cl and the mixture was extracted with EtOAc. The extract was washed with brine prior to drying and solvent evaporation. The residue was chromatographed on silica gel with hexane.EtOAc (1:1) to give 1b (159 mg, 80%) and (2E)-isomer of 1b (20.9 mg, 10%) each as a yellow oil. Ethyl (2Z,6E)-7-[(R)-(p-Tolylsulfinyl)]-2,6-heptadienoate (1b), yield (159 mg, 80%).

10.1021/jo0492923

■ ルイス酸による活性化

ルイス酸を系中に共存させると、

ルイス酸がホスホン酸ジエステルの酸素原子に配位し、

活性プロトンがさらに活性化される。

その結果、比較的弱い塩基でも、脱プロトン化が生じるようになる。

・Roush-正宗法

A solution of aldehyde 5 (0.25g, 0.65 mmol), LiCl (0.03 g, 1.21 mmol), trimethylphosphonoacetate (0.11 mL, 0.71 mmol) and DBU (0.19 mL, 1.21 mmol) in CH₃CN (10 mL) was stirred under a N₂ atmosphere at RT for 2 h. The reaction mixture was partitioned between 2 M HCl (15 mL) and EtOAc (20 mL). The organic layer was separated, washed with sat. NaHCO₃ (15 mL), brine (15 mL), dried (Na₂SO₄) and the volatiles were removed in vacuo to give a crude ester 6. Yield 0.31g, 99%.

WO2012003414

・亜鉛による活性化

Phosphonate (0.10 g, 0.52 mmol, 1 equiv) was added along with anhyd THF (1.5 mL) to a flask containing Zn(OTf)₂ (2.2 equiv, 0.42 g, 1.2 mmol). TMEDA (0.09 mL, 0.63 mmol) was added. DBU (0.31 mL, 4 equiv, 6.3 mmol) was added followed by aldehyde (1.1 equiv, 0.58 mmol). The reaction mixture was stirred at 25 ℃ for 12 h under argon. The reaction was quenched with 1 N HCl (5 mL) and extracted with CH₂Cl₂ (4 × 15 mL). The organic phases were combined and dried over Na₂SO₄. Solvent was removed in vacuo to yield crude carboxylic acid. A known quantity of mesitylene was added to the crude material. Crude yields were quantified by ¹H NMR via comparison of the most upfield olefinic proton signal vs. the aromatic mesitylene signal.

10.1055/s-2006-950292

ホーナー・ワズワース・エモンス反応 Horner-Wadsworth-Emmons (HWE) Reaction

・「ホスフィンオキシドの除去問題」を回避できる。

　そういう意味で、Wittig 反応より後処理や精製が楽。

・様々なホスホン酸ジエステルが市販されているが、

　自前で作る必要がある場合は、Michaelis-Arbuzov 反応により合成する。

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