* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1985, vol. 131, p. 327 - 342
3
[ 4746-97-8 ]
[ 176251-49-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 10 - 25℃; for 12 h; Stage #2: With boron trifluoride diethyl etherate; hydrogen fluoride In triethylamine at 5 - 30℃; for 12 h;
In turn will 8, 8 - difluoro - 1, 4 - dioxo-spiro [4.5] decane and 8 - fluoro - 1, 4 - dioxo-spiro [4.5] decyl -7 - ene mixture (146 g, 1.0 μM, 1.0 eq) and catalyst boron trifluoride ether (142 g, 1.0 μM, 1.0 eq) in 1000 ml three-neck bottle in, keeping the temperature at 5 ± 5 °C dropping hydrogen fluoride under the conditions of the triethylamine solution (459.4 g, 3.0 μM, 3.0 eq), after the completion of the dropping, the reaction temperature is raised to 30 ± 5 °C reaction 12 hours; after the reaction, the reaction solution is poured into the water in the, layered water phase after dichloromethane is used for extraction three times (dichloromethane total consumption is 438 g × 3), combining all the organic phase, dried with anhydrous sodium sulfate and filtered, the resulting organic phase and the filtrate is concentrated under reduced pressure to obtain crude, the crude distillation, in 30 mm Hg pressure, receiving 70 - 72 °C fraction, to obtain 162 g, yield 91percent.The resulting product is subjected to gas chromatography (GC) detecting, in the GC map only 8,8-difluoro-1,4-dioxaspiro[4.5]decane peak, its purity is 99.3percent. By nuclear magnetic resonance spectroscopy (HNMR) detection for determining the structural formula thereof is 8,8-difluoro-1,4-dioxaspiro[4.5]decane .
73%
Stage #1: With morpholinosulfur trifluoride In dichloromethane at 0 - 20℃; for 72 h; Inert atmosphere Stage #2: With potassium permanganate In dichloromethane; water for 24 h;
Method B A solution of ketone 6 (4.40 g, 28.2 mmol) in dry CH2Cl2 (100 mL) was cooled to 0 °C under argon atmosphere. Morph-DAST (11.85 g, 67.7 mmol, 2.4 equiv) was added dropwise upon stirring. The reaction mixture was allowed to warm to a room temperature and was stirred for 72 h. A saturated solution of NaHCO3 in water (50 mL) was added and the reaction mixture was stirred for 10 min to quench the unreacted fluorinating agent. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*50 mL). Solution of KMnO4 (5.7 g, 36 mmol, 10 equiv) in water (100 mL) was added to the combined organic phase and the formed suspension was vigorously stirred for 24 h. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*100 mL). The combined organic phases were dried over Na2SO4, and evaporated under vacuum at 30 °C to provide pure compound 7 (3.65 g, 20.5 mmol, 73percent yield) as a colourless oil, which crystallized upon storage.
60%
With (diethylamino)sulfur trifluoride In dichloromethane; water
EXAMPLE 46 8,8-Difluoro-1,4-dioxa-spiro[4.5]decane 1,4-Dioxa-spiro[4.5]decan-8-one (9.0 g, 56 mmol) and (diethylamino)sulfur trifluoride (19 g, 112 mmol) are reacted in dichloromethane (180 ml) for 2 h at room temperature. The mixture is poured in water (300 ml), the layers are separated and the aqueous phase back-extracted twice with dichloromethane (50 ml). The combined organic phases are dried with magnesium sulfate and evaporated. Distillation under reduced pressure over a vigreux-column afforded the title compound as colorless liquid (6.0 g, 60percent), bp 65-72° C. at 13-14 mbar, MS: m/e=186 (M+), contaminated with ~30percent 8-Fluoro-1,4-dioxa-spiro[4.5]dec-7-ene, MS: m/e=158 (M+).
45%
With N-methyl-N-phenylaminodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere
General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene).
Reference：
[1] Patent: CN108299376, 2018, A, . Location in patent: Paragraph 0032-0039; 0046; 0054; 0059; 0064-0065; 0070; 0076
[2] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3401 - 3411
[3] Organic Letters, 2013, vol. 15, # 5, p. 1088 - 1091
[4] Tetrahedron, 2013, vol. 69, # 20, p. 4066 - 4075
[5] Patent: US2003/149036, 2003, A1,
[6] Journal of Fluorine Chemistry, 2013, vol. 153, p. 57 - 60
[7] Patent: US2006/293392, 2006, A1, . Location in patent: Page/Page column 51
[8] Patent: WO2008/7930, 2008, A1, . Location in patent: Page/Page column 28
[9] Patent: WO2009/48547, 2009, A1, . Location in patent: Page/Page column 40
[10] Patent: US2010/120783, 2010, A1, . Location in patent: Page/Page column 10
[11] Patent: WO2010/56022, 2010, A2, . Location in patent: Page/Page column 23
[12] Patent: EP2786986, 2014, A2, . Location in patent: Paragraph 0122-0124
[13] Patent: CN105985355, 2016, A, . Location in patent: Paragraph 0670; 0671; 0672; 0673
4
[ 4746-97-8 ]
[ 176251-49-3 ]
[ 142273-44-7 ]
Yield
Reaction Conditions
Operation in experiment
60%
With pyrrolidinodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere
General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene).
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 153, p. 57 - 60
[2] Organic Letters, 2009, vol. 11, # 21, p. 5050 - 5053
[3] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3401 - 3411
[4] Tetrahedron, 2013, vol. 69, # 20, p. 4066 - 4075
[5] Patent: CN107827721, 2018, A, . Location in patent: Paragraph 0100-0105
[6] Patent: CN108299376, 2018, A, . Location in patent: Paragraph 0032-0037; 0042-0044; 0049-0051; 0057; 0062; 0068
diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene, p-toluenesulfonic acid monohydrate; ethyl acetate; toluene;
1,4-Dioxaspiro[4.5]decan-8-one (40 g) and <strong>[6296-99-7]diethyl aminomethylenemalonate</strong> (47.94 g) are dissolved in 500 ml of toluene. p-Toluenesulfonic acid monohydrate (2.44 g) and 100 ml of toluene are then added and the mixture is refluxed for 3 days collecting water in a Dean-Stark trap. The resulting mixture is decanted and solvent is removed to leave on oil. This oil is flash chromatographed on 750 g silica gel using 9:1 CH2 Cl2, EtOAc as eluant to yield diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate as an oil.
Then <strong>[38573-88-5]2,3-difluorobromobenzene</strong> (T-10) (115.2 g) was dissolved in DryTHF (600 ml), and the resultant solution was cooled to -70°C. In a nitrogen atmosphere, n-BuLi (364 ml) was added dropwise, and agitation was carried out at -70°C for 2 hours. Then, a DryTHF solution of cyclohexanedione monoethylene ketal (T-3) (93.6 g) was slowly added dropwise at -70°C, and the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was dissolved in toluene (400 ml), p-TsOH (4.74 g) was added, and heating reflux was carried out for 4 hours while performing dehydration. After completion of the reaction, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was subjected to silica gel column chromatography (heptane:ethyl acetate = 20:1 in a volume ratio) and recrystallization (Solmix), and thus (T-11) was obtained as a colorless crystal (121.0 g, yield: 80percent).
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