一种酚羟基三氟甲基化的方法

chem 有机方法 3.5K+ 0

文献(DOI: 10.1021/acs.joc.9b02717)报道了一种由酚类化合物合成芳基三氟甲醚的方法,即:酚与咪唑甲硫羰基硫醇盐生成芳基黄原酸酯,进而与氟化试剂生成芳基三氟甲醚。该方法与传统方法相比,操作简单,条件相对温和,底物适用范围广等。

一种酚羟基三氟甲基化的方法  第1张


底物普适性考察
一种酚羟基三氟甲基化的方法  第2张

aStandardcondition of xanthate formation; 1 (2.0 mmol), 6 (2.0 mmol), TEA(2.0 mmol), ACN (10 mL), 0 °C, 1 h. bCondition A; 2 (0.5mmol), XtalFluor-E (2.5 mmol), TCCA (0.5 mmol), H2O (0.5 mmol), and (CH2Cl)2 (10 mL), 80 °C. cCondition B; (0.5 mmol), XtalFluor-E (1.5 mmol), NFSI (1.5 mmol), and (CH2Cl)2(10 mL), 80 °C. dNMR yields determined by 19F NMR using PhCF3as an internal standard were reported in the parentheses. eReagent 7 was used instead of 6. fReagent 5 (1.5equiv.), Cs2CO3 (2.0 equiv.), and DMF (0.1 M) were used instead of the standard conditions. gSelectfluor (0.5 mmol,1.0 equiv.) was added. hSelectfluor (1.0 mmol, 2.0 equiv.)was added


芳基黄原酸酯2的制备
Reagent 6 or 7 (2.00 mmol, 1.0 eq.) was added to a solution of the phenol 1a~1w (2.00 mmol, 1.0 eq), TEA (330 µL,2.2 mmol, 1.1 eq.), and ACN (10 mL) at 0 °C. After stirring at 0 °C for 1 h,the mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with EA (2 x 20 mL). The combined organic extracts were dried over Na2SO4,filtered, and concentrated. The residue was purified by silica gel column chromatography or recrystallization to give xanthates 2a~2w.

2f的制备:Cesium carbonate (1.30 g, 4.00 mmol, 2.0 eq) was added to asingle-necked flask, dried by heat gun under vacuum, cooled, and filled backwith nitrogen. 2,4-di-t-butyl-phenol 1f (413 mg, 2.00 mmol, 1.0 eq) and DMF (20 mL) were added to the flask.The resulting mixture was cooled to 0 °C, added benzotriazole reagent 5 (628 mg, 3.00 mmol, 1.5 equiv.). After stirring for 3 h at 0 °C, the mixture was treated with saturated aqueous NaHCO3, extracted with hexane (20 mL x 3). The combined organic extractswere dried over Na2SO4, filtered, and concentrated. The residue was purified by silicagel column chromatography (EA/Hexane 0:100) to give the product as a white solid(587 mg, 99%)


芳基三氟甲醚3的制备


condition A:A 20 mL vial wascharged with xanthate 2 (0.5 mmol, 1.0 eq.), TCCA (116 mg, 0.5 mmol,1.0 eq.), and XtalFluor-E (573 mg, 2.5 mmol, 5.0 equiv.) in air. Then,anhydrous dichloroethane (5 or 10 mL) and water (9.0 mg, 0.5 mmol, 1.0 equiv.)were added to the vial. (*One equivalent of water was weighed into a pipet, and the water was transferred to the flask by forced air.) The resulting mixture was stirred at 80 °C for the reported reaction time. After cooling to RT, the mixture was quenched with saturated aqueousNaHCO3(5 mL), stirred for 30 min, and filtered through a pad of Celite. The filtrate was extracted with EA (2 x 10 mL). Activated charcoal powder (ca. 1 g) andsilica gel (ca. 1 g) were added to the combined organic layer (Note: Charcoalhelps to remoce brown by products derived from XtalFluor-E). After stirring for1 min, the mixture was filtered with Celite and washed with EA. The filtratewas concentrated and purified by silica gel column chromatography to give ArOCF3.
condition B:A 20 mL vial was charged with xanthates 2 (0.5 mmol, 1.0 equiv.), NFSI (473 mg, 1.5 mmol,3.0 equiv.), and XtalFluor-E (343 mg, 1.5 mmol, 3.0 equiv.) under air. Then,anhydrous dichloroethane (2 or 5 mL) was added to the vial. The resulting mixture was stirred at 80 °C for desired reaction time. After cooling to RT, the mixture was quenched with saturated aqueous NaHCO3 (5 mL), stirredfor 30 min, and filtered through a pad of Celite. The filtrate was extractedwith EA (2 x 10 mL). Activated carbon powder (ca. 1 g) and silica gel (ca. 1 g)were added to the combined organic layer. After stirring for 1 min, the mixturewas filtered with Celite and washed with EA. The filtrate was concentrated and purified by silica gel column chromatography to give ArOCF3.



反应所用部分试剂

XtalFluor-Ecas号: 63517-29-3
TCCAcas号: 87-90-1
NFSIcas号: 133745-75-2


反应可能存在的机理

一种酚羟基三氟甲基化的方法  第3张


咪唑甲硫羰基硫醇盐6 and 7的制备

的制备:A 250 mL single-neck-shield flask equipped with stir bar and septum was purged with nitrogen. Methylthio(thiocarbonyl)imidazole 4 (7.09 g, 44.9 mmol,1.0 eq.) in benzene (120 mL) wastransferred to the flask via cannula. Iodomethane (28 mL, 450 mmol, 10 equiv.)was added to the mixture. The septum was replaced with a screw cap quickly. The resulting mixture was warmed to 80 °C with an oil bath. While stirring for 3 h,an orange precipitate formed. The precipitate was filtered, washed with anhydrous benzene (100 mL), and dried under high vacuum to give 6.44 g ofimidazolium reagent 6 (48%).

的制备:

一种酚羟基三氟甲基化的方法  第4张

(参考文献:DOI: 10.1055/s-1997-1019)

的制备:A 250 mL single-neck-shield flask equipped with a stir bar and septum was purged with nitrogen. N-Methylthio(thiocarbonyl)- benzimidazole (9.00 g, 43.2 mmol, 1.0 eq) in ACN (90 mL) was transferred to the flask via cannula.Iodomethane (22 mL, 350 mmol, 8.0 eq) was added to the mixture. The septum was replaced with a screw cap quickly. The resulting mixture was warmed to 80 °C with an oil bath. While stirring for 4.5 h, a bright orange precipitate was generated. The precipitate was filtered, washed with EA/Hexane 3:1 (100 mL),and dried under high vacuum to give 10.9 g of benzimidazolium reagent 7 (72%) as a yellowish orange solid

N-Methylthio(thiocarbonyl)-benzimidazole的制备:A solution of benzimidazole (100 mg, 0.85 mmol) in THF (1 mL) was added to a stirred suspension of NaH (26 mg, 1.1 mmol) in THF (1 mL). After 5min, CS2 (61 μL, 1.02 mmol) and MeI (80 μL, 1.27 mmol) were added to the reaction mixture at RT, which was further stirred for 20 min;the reaction mixture was diluted with ice-cold water and extracted with EA. The combined organic extract was concentrated under reduced pressure to yield aresidue that was separated by FCC (SiO2; EA/hexane, 1:4, v/v) to yield N-Methylthio(thiocarbonyl)- benzimidazole ( 126 mg, 0.61 mmol) as a yellow solid in 72% yield.(参考文献:doi.org/10.1021/jf302038a)


参考文献

DOI: 10.1021/acs.joc.9b02717
DOI: 10.1055/s-1997-1019
doi.org/10.1021/jf302038a


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