* 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] Phosphorus and Sulfur and the Related Elements, 1984, vol. 19, p. 113 - 130
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Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2002, # 10, p. 1070 - 1071
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[ 210240-20-3 ]
Reference：
[1] Patent: WO2013/149362, 2013, A1,
6
[ 1072-72-6 ]
[ 17396-35-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
With peracetic acid In water; ethyl acetate at 20℃;
EXAMPLE 22 2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile To a stirred solution of tetrahydrothiopyran-4-one (5.30 g, 43.1 mmol, Aldrich) in 50 mL of ethyl acetate was added dropwise 32percent peracetic acid (24 g, 110 mmol) at a rate to avoid reflux. After the addition, the mixture was cooled to room temperature and the solid filtered to give 1,1-dioxo-tetrahydro-thiopyran-4-one as a white solid (5.69 g, 89percent).
89%
With peracetic acid In acetic acid; ethyl acetate at 15 - 30℃; for 2 h;
Reference Example 52; tetrahydro-4H-thiopyran-4-one 1,1-dioxide; [Show Image] To a solution of tetrahydro-4H-thiopyran-4-one (2.65 g) in ethyl acetate (25 mL) was added peracetic acid (32percent acetic acid solution, 13 g) over 1 hr at room temperature. The reaction solution was stirred at the same temperature for 1 hr, and cooled to 0°C. The precipitate was collected by filtration, washed with ethyl acetate (cooled to 0°C in advance), and dried under reduced pressure to give the title compound (3.01 g, yield 89percent) as white crystals. 1H NMR (300 MHz, DMSO-d6) δ: 2.03-2.35 (4 H, m), 2.93-3.12 (2 H, m), 3.11-3.29 (2 H, m).
67%
With 3-chloro-benzenecarboperoxoic acid In ethyl acetate
A solution of m-chloroperbenzoic acid (1.859 g, 10. 8 mmol) in ethyl acetate (13 ml) was added dropwise to a solution of tetrahydrothiopyran-4-one (0.500 g, 4.30 mmol) in ethyl acetate (5 ml) at such a rate that no reflux was caused by heat generation. The resulting mixture was stirred overnight. The solution thus obtained was cooled on an ice bath and the solid precipitated was collected by filtration. The precipitate on a filter was washed with cold ethyl acetate and then dried under reduced pressure to obtain 1,1-dioxidetetrahydro-2H-thiopyran-4-one (0.430 g, 67percent).
55%
With dihydrogen peroxide In methanol; water at 20℃; for 33 h; Cooling with ice
To a solution of ketone 16 (0.50 g, 4.304 mmol) in methanol (40 mL) 30percent aqueous solution of hydrogen peroxide (1.67 g, 17.21 mmol) was slowly added dropwise with the cooling in ice bath for 1 hour (the temperature of reaction mixture should not exceed 20 FontWeight="Bold" FontSize="10" ). Stirring was continued in the ice bath for 8 hours and then 1 day at r.t. The solid of unknown by-products was filtered off. The filtrate was evaporated in vacuo to obtain of pure ketosulfone 9. Yield: 0.35 g (55percent), mp 172-175 FontWeight="Bold" FontSize="10" (163-170 FontWeight="Bold" FontSize="10" [5]), Rf 0.50 (ethyl acetate). 1NMR (500 MHz, DMSO-d6) δ3.51 (4, t, J= 6.5 Hz, H-2,6), 2.76 (4, t, J= 6.5 Hz, H-3,5). 13C NMR (125 MHz, DMSO-d6) δ203.24 (=O), 48.20(-2,6),37.89(-3,5).NMR spectra of the ketosulfone 9 were identical to those described.[5]
52%
With dihydrogen peroxide In acetic acid at 100℃; for 3 h;
Example 4; 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (4); To a solution of dihydro-2H-thiopyran-4(3H)-one 4.1 (1.50 g, 12.9 mmol) in acetic acid was added H2O2 (1.30 g, 38.7 mmol) under nitrogen, and the resulting mixture was heated to 100° C. for 3 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the acetic acid was evaporated under reduced pressure, and the resulting crude product was extracted with 10percent methanol in dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, and the solvent removed in vacuo to give compound 4.2 (1.0 g, 52percent).
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 6, p. 1665 - 1673
[2] Patent: US2007/129416, 2007, A1, . Location in patent: Page/Page column 19/1
[3] Patent: EP2261213, 2010, A1, . Location in patent: Page/Page column 60
[4] Journal of Organic Chemistry, 1998, vol. 63, # 24, p. 8952 - 8956
[5] European Journal of Medicinal Chemistry, 1999, vol. 34, # 2, p. 125 - 135
[6] Patent: EP1403255, 2004, A1, . Location in patent: Page 138
[7] Synthetic Communications, 2018, vol. 48, # 17, p. 2198 - 2205
[8] Patent: US2009/82423, 2009, A1, . Location in patent: Page/Page column 24
[9] Journal of the American Chemical Society, 1948, vol. 70, p. 1813,1816
[10] Patent: US2007/72847, 2007, A1, . Location in patent: Page/Page column 72
[11] Patent: US6884868, 2005, B1,
[12] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 92
[13] Patent: WO2010/101302, 2010, A1, . Location in patent: Page/Page column 134
[14] Magnetic Resonance in Chemistry, 2010, vol. 48, # 9, p. 718 - 726
[15] Research on Chemical Intermediates, 2017, vol. 43, # 12, p. 7291 - 7306
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[ 17396-35-9 ]
Yield
Reaction Conditions
Operation in experiment
73%
With oxone; sodium hydrogencarbonate In acetonitrile
1,1-Dioxotetrahydrothiopyran-4-one. To a solution of tetrahydrothiopyran-4-one (400 mg, 3.45 mmol) in acetonitrile (5 ml) was added aqueous Na2EDTA (3 ml, 0.0004 M). A mixture of oxone (6.30 g, 10.30 mmol) and sodium bicarbonate (2.70, 32 mmol) was added in small portions to the above solution over a period of 20 min. The slurry was stirred for another 1 h before being quenched with methylene chloride. The organic solvent was decanted and the solid residue was triturated with ethyl acetate (3*25 ml). The combined organic layers were dried over sodium sulfate and concentrated to give the desired ketone (0.37 g, 73percent) as a colorless solid. mp 170-172° C. (lit. 168-170° C.); 1H NMR (500 MHz, CDCl3) 2.99 (t, J=6.8 Hz, 4H), 3.39 (t, J=6.8 Hz, 4H). Ref: Yang, D.; Yip, Y.-C.; Jiao, G.-S.; Wong, M.-K. Design of Efficient Ketone Catalysts for Epoxidation by Using the Field Effect. J. Org. Chem, 1998, 63, 8952-8956.
Reference：
[1] Patent: US6486199, 2002, B1,
8
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[ 17396-36-0 ]
[ 17396-35-9 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2010, vol. 48, # 9, p. 718 - 726
[2] Organic Letters, 2015, vol. 17, # 20, p. 5100 - 5103
General procedure: Ni-Al alloy (200 mg) and cyclohexanone (35 μL, 0.34 mmol) were suspended in 28–30percent NH4OH (3 mL) and sonicated (Branson 1510MTH ultrasonic bath) for 2 h. After the completion of the reaction, the excess alloy and solid by-products were removed by filtration. The filtrate was extracted with EtOAc (2 × 2 mL). The organic extracts were combined and dried over anhyd Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography.
With sodium tetrahydroborate In methanol at 20℃; for 3 h; Cooling with ice
General procedure: To a mixture of ketosulfone 12 (40.10 g, 0.271 mol) in methanol (700 mL) was added sodium borohydride (15.36 g, 0.406 mol) of portionwise with stirring and cooling in ice bath during 1 hour (strongly exothermic reaction). The reaction mixture was then stirred during 2 hours at 20 FontWeight="Bold" FontSize="10" , evaporated in vacuo to solid residue, and mixture of saturated aqueous solution of sodium hydrogen carbonate (150 mL) and ethyl acetate (250 mL) was added (caution: product is soluble in water). After intensive shaking the layers were separated, and water layer was additionally extracted with ethyl acetate (4×250 mL). The combined organic layers were dried over sodium sulfate and solvent was evaporated in vacuo to solid residue.
89%
With sodium tetrahydroborate In methanol at 0 - 20℃;
To a 50 mL two-neck flask were added tetrahydro-2H-thiopyran-4-one (1.00 g, 8.61 mmol) and anhydrous methanol (20 mL), then sodium borohydride (330 mg, 8.61 mmol) was added at 0°C. The mixture was warmed to rt and stirred at rt overnight. After the reaction monitored by TLC was completed, the reaction mixture was concentrated in vacuo to remove the solvent, and to the residue was added water (30 mL). The resulting mixture was acidified with hydrochloric acid (1 mol/L) to adjust pH 5∼6, then extracted with EtOAc (30 mL*2). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give colorless oil (0.91 g, 89percent).
87%
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 14 h;
Referential Example 44: tetrahydrothiopyran-4-ol tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol (100 ml).. Under ice cooling, sodium borohydride (1.6 g, 42.3 mmol) was added and the resulting mixture was stirred at room temperature for 14 hours.. The residue obtained by concentrating the reaction mixture under reduced pressure was added with water (50 ml).. The resulting mixture was made weakly acidic with 1N hydrochloric acid, and then it was extracted with diethyl ether.. The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine.. The organic layer was dried over anhydrous magnesium sulfate.. After filtration, the filtrate was concentrated under reduced pressure, whereby the title compound (4.40 g, 37.2 mmol, 87percent) was obtained as a pale yellowish brown solid.1H-NMR (400 MHz, CDCl3) δ: 1.47(1H,br s), 1.64-1.80(2H,m), 2.10-2.24(2H,m), 2.55-2.70(2H,m), 2.73-2.88(2H,m), 3.60-3.75(1H,m). MS m/z: 119 (M++H).
87%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 14 h;
Tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol (100 ml). After sodium borohydride (1.6 g, 42.3 mmol) was added to the resulting solution under ice cooling, the resulting mixture was stirred at room temperature for 14 hours. Water (50 ml) was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The liquid property of the resulting mixture was then made weakly acidic with 1N hydrochloric acid, followed by extraction with diethyl ether. The extract was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (4.40 g, 37.2 mmol, 87percent) as a pale yellowish brown solid. 1H-NMR(400MHz, CDCl3) δ: 1.47(1H,brs), 1.64-1.80(2H,m), 2.10-2.24(2H,m), 2.55-2.70(2H,m), 2.73-2.88(2H,m), 3.60-3.75(1H,m). MSm/z: 119(M++H).
84%
With lithium aluminium tetrahydride In diethyl ether for 1.5 h; Reflux
LiAlH4 (1.13 g, 30 mmol) was suspended in anhydrous diethyl ether (200 mL). A solution of tetrahydrothiopyran-4-one (4, 5.28 g, 45 mmol) in anhydrous diethyl ether was added dropwise in 1 h. After the addition, the reaction mixture was heated at reflux temperature for 90 min and then stirred at room temperature overnight. The reaction mixture was subsequently placed in an ice-bath and carefully quenched with excess water. The aqueous phase was extracted with diethyl ether (2 × 100 mL), and the organic phase dried with MgSO4. The solvent was evaporated to give 4.45 g (38 mmol, 84percent) of 5. δH (CDCl3) 3.66 (m, 1H, CHOH), 2.78 (m, 2H, CH2S), 2.59 (m, 2H, CH2S), 2.17 (m, 2H, SCH2CH2), 1.73 (m, 2H, SCH2CH2), 1.45 (s, 1H, OH). δC (CDCl3) 68.2 (COH), 36.2 (SCC), 26.5 (SC).
83%
at 20℃;
Step 1 a Synthesis of 4-Bromo-3,5-dimethylphenol To a solution of dihydro-2H-thiopyran-4(3H)-one (530 mg, 4.56 mM) in methanol, NaBH4 (207 mg, 5.47 mM) was added. The reaction mixture was stirred at RT and quenched with saturated NH4CI. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated to obtain a crude product which was purified by column chromatography to afford the title compound tetrahydro-2H-thiopyran-4-ol (446 mg). Yield: 83 percent; H NMR(CDCI3, 300 MHz): δ 3.66 (s, 1 H), 2.76-2.57 (m, 4H), 2.16-2.14 (m, 2H), 1 .76-1 .59 (m, 2H); Ms: m/z 1 18 (M+).
51.9%
at 20℃; Cooling with ice
To an ice cold solution of tetrahydrothiopyran-4-one (10, 5 g, 0.043 mol) in methanol (40 mL), 5N sodium hydroxide solution (10 mL) solution was added slowly. Then sodium borohydride (0.488 g, 0.013 mol) was added portion wise. After addition, the reaction mixture was allowed to reach room temperature. After the reaction completion (~lh), the reaction mixture was poured in to water and extracted with dichloromethane. Combined organic layer was washed with saturated brine solution, dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude product was purified by column chromatography using 5percent> methanol in DCM to afford the pure product (4 g, 51.90percent). 1H-NMR (400 MHz, DMSO-d6): δ 4.69 (d, J = 4.24 Hz, 1H), 3.41-3.47 (m, 1H), 2.65-2.70 (m, 2H), 2.50-2.54 (m, 1H), 2.47 (d, J = 2.76 Hz, 1H), 2.00-2.02 (m, 2H), and 1.96-1.99 (m, 2H).
96%
With sodium borohydrid In tetrahydrofuran; ethanol
Example 94 Synthesis of 4-hydroxytetrahydrothiopyran To a mixed solution of 15.0 g (0.13 mol) of tetrahydrothiopyran-4-one in 100 ml of ethanol and 100 ml of tetrahydrofuran, 2.44 g (0.06 mol) of sodium borohydride was added at 0° C. and stirred at room temperature for 2 hours under an argon atmosphere. The solvent of the reaction solution was distilled off under vacuum, diluted with ethyl acetate (200 ml), and successively washed with water (100 ml) and saturated saline (100 ml), dried over anhydrous sodium sulfate and the solvent was distilled off under vacuum. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 14.6 g (96percent) of the above-identified compound, as a colorless crystal. IR(KBr)cm-1: 3282, 2929, 1428, 1338, 1271, 1058. MS(FAB) 119[M+1]+. 1H-NMR(CDCl3): δ 1.40(1H, d, J=4.4 Hz) 1.66-1.76(2H, m) 2.13-2.20(2H, m) 2.55-2.63(2H, m) 2.75-2.81(2 H, m) 3.63-3.69(1H, m).
Reference：
[1] Synthetic Communications, 2018, vol. 48, # 17, p. 2198 - 2205
[2] Chemistry - A European Journal, 2018, vol. 24, # 62, p. 16526 - 16531
[3] Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 9, p. 2739 - 2750
[4] Chemical Communications (Cambridge, United Kingdom), 2002, # 10, p. 1070 - 1071
[5] Patent: EP3342765, 2018, A1, . Location in patent: Paragraph 0337
[6] Patent: EP1466898, 2004, A1, . Location in patent: Page 192
[7] Patent: EP1640366, 2006, A1, . Location in patent: Page/Page column 23-24
[8] Journal of Molecular Structure, 2013, vol. 1036, p. 115 - 120
[9] Patent: WO2013/128378, 2013, A1, . Location in patent: Page/Page column 112; 113
[10] Patent: WO2018/178338, 2018, A1, . Location in patent: Page/Page column 133
[11] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 1268,1270
[12] Canadian Journal of Chemistry, 1981, vol. 59, p. 1574 - 1579
[13] Australian Journal of Chemistry, 2005, vol. 58, # 7, p. 531 - 534
[14] Patent: US4702763, 1987, A,
[15] Patent: EP534511, 1993, A1,
[16] Patent: US6331548, 2001, B1,
[17] Organic and Biomolecular Chemistry, 2012, vol. 10, # 36, p. 7321 - 7326
[18] Chemistry - A European Journal, 2014, vol. 20, # 46, p. 14959 - 14964
[19] Patent: WO2014/194242, 2014, A2, . Location in patent: Paragraph 00682-00683
[20] Patent: WO2015/135094, 2015, A1, . Location in patent: Page/Page column 64
[21] Patent: JP2015/27992, 2015, A, . Location in patent: Paragraph 0235
[22] Patent: JP5856508, 2016, B2, . Location in patent: Paragraph 0161
[23] Process Biochemistry, 2017, vol. 58, p. 137 - 144
[24] Organic Letters, 2018, vol. 20, # 14, p. 4290 - 4294
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[ 621-84-1 ]
[ 29683-23-6 ]
[ 402927-98-4 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 26, p. 4379 - 4382
13
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[ 2896-98-2 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With hydrogenchloride; sodium azide In water at 0 - 20℃; for 4 h; Stage #2: With sodium carbonate In water
To a mixture of tetrahydrothiopyran-4-one (5.14 g) and conc. hydrochloric acid (20 mL) was added sodium azide (4.31 g) under ice-cooling. The reaction mixture was stirred at room temperature for 4 hrs., and sodium carbonate was added. The mixture was diluted with iced water and extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1,4-thiazepan-5-one as crystals (3.62 g, yield 62percent). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121°C.
Reference：
[1] Patent: EP1486490, 2004, A1, . Location in patent: Page 46
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1960, p. 1904 - 1905[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1960, p. 2053 - 2054
[4] Patent: WO2006/56875, 2006, A1, . Location in patent: Page/Page column 22-23
[5] Patent: US2015/197493, 2015, A1,
[6] Patent: US2015/225355, 2015, A1,
[7] Patent: WO2017/15106, 2017, A1,
14
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[ 101184-85-4 ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium carbonate In hydrogenchloride; water
Preparation 34 1,4-Thiazepane To a stirred solution of tetrahydrothiopyran-4-one (4.74 g) in conc. HCl (20.7 mL) cooled to 0° C. is added portion-wise sodium azide (3.98 g, 61.2 mmol). After addition is complete, the reaction is stirred at room temperature for 4 h. Solid sodium carbonate is then added portion-wise until the solution was slightly alkaline (pH=9). Water is added during addition of sodium carbonate to dissolve the salt. The alkaline solution is diluted with CHCl3 (125 mL), and the phases are separated. The aqueous layer is extracted with CHCl3 (2*75 mL). The combined organic layers are dried (Na2SO4), filtered, and concentrated. The crude product is recrystallized from CH2Cl2/hexanes to afford 4.30 g (81percent) of 1,4-thiazepan-5-one as a white solid. Physical characteristics are as follows: Mp 114-116° C.; 1H NMR (300 MHz, CDCl3) δ6.41, 3.66, 2.96, 2.76.
With sodium tetrahydroborate; In methanol; at 20℃; for 3h;Cooling with ice;
General procedure: To a mixture of ketosulfone 12 (40.10 g, 0.271 mol) in methanol (700 mL) was added sodium borohydride (15.36 g, 0.406 mol) of portionwise with stirring and cooling in ice bath during 1 hour (strongly exothermic reaction). The reaction mixture was then stirred during 2 hours at 20 FontWeight="Bold" FontSize="10" , evaporated in vacuo to solid residue, and mixture of saturated aqueous solution of sodium hydrogen carbonate (150 mL) and ethyl acetate (250 mL) was added (caution: product is soluble in water). After intensive shaking the layers were separated, and water layer was additionally extracted with ethyl acetate (4×250 mL). The combined organic layers were dried over sodium sulfate and solvent was evaporated in vacuo to solid residue.
89%
With sodium tetrahydroborate; In methanol; at 0 - 20℃;
To a 50 mL two-neck flask were added tetrahydro-2H-thiopyran-4-one (1.00 g, 8.61 mmol) and anhydrous methanol (20 mL), then sodium borohydride (330 mg, 8.61 mmol) was added at 0C. The mixture was warmed to rt and stirred at rt overnight. After the reaction monitored by TLC was completed, the reaction mixture was concentrated in vacuo to remove the solvent, and to the residue was added water (30 mL). The resulting mixture was acidified with hydrochloric acid (1 mol/L) to adjust pH 5?6, then extracted with EtOAc (30 mL*2). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give colorless oil (0.91 g, 89%).
87%
Referential Example 44: tetrahydrothiopyran-4-ol tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol (100 ml).. Under ice cooling, sodium borohydride (1.6 g, 42.3 mmol) was added and the resulting mixture was stirred at room temperature for 14 hours.. The residue obtained by concentrating the reaction mixture under reduced pressure was added with water (50 ml).. The resulting mixture was made weakly acidic with 1N hydrochloric acid, and then it was extracted with diethyl ether.. The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine.. The organic layer was dried over anhydrous magnesium sulfate.. After filtration, the filtrate was concentrated under reduced pressure, whereby the title compound (4.40 g, 37.2 mmol, 87%) was obtained as a pale yellowish brown solid.1H-NMR (400 MHz, CDCl3) delta: 1.47(1H,br s), 1.64-1.80(2H,m), 2.10-2.24(2H,m), 2.55-2.70(2H,m), 2.73-2.88(2H,m), 3.60-3.75(1H,m). MS m/z: 119 (M++H).
87%
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 14h;
Tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol (100 ml). After sodium borohydride (1.6 g, 42.3 mmol) was added to the resulting solution under ice cooling, the resulting mixture was stirred at room temperature for 14 hours. Water (50 ml) was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The liquid property of the resulting mixture was then made weakly acidic with 1N hydrochloric acid, followed by extraction with diethyl ether. The extract was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (4.40 g, 37.2 mmol, 87%) as a pale yellowish brown solid. 1H-NMR(400MHz, CDCl3) delta: 1.47(1H,brs), 1.64-1.80(2H,m), 2.10-2.24(2H,m), 2.55-2.70(2H,m), 2.73-2.88(2H,m), 3.60-3.75(1H,m). MSm/z: 119(M++H).
84%
With lithium aluminium tetrahydride; In diethyl ether; for 1.5h;Reflux;
LiAlH4 (1.13 g, 30 mmol) was suspended in anhydrous diethyl ether (200 mL). A solution of tetrahydrothiopyran-4-one (4, 5.28 g, 45 mmol) in anhydrous diethyl ether was added dropwise in 1 h. After the addition, the reaction mixture was heated at reflux temperature for 90 min and then stirred at room temperature overnight. The reaction mixture was subsequently placed in an ice-bath and carefully quenched with excess water. The aqueous phase was extracted with diethyl ether (2 × 100 mL), and the organic phase dried with MgSO4. The solvent was evaporated to give 4.45 g (38 mmol, 84%) of 5. deltaH (CDCl3) 3.66 (m, 1H, CHOH), 2.78 (m, 2H, CH2S), 2.59 (m, 2H, CH2S), 2.17 (m, 2H, SCH2CH2), 1.73 (m, 2H, SCH2CH2), 1.45 (s, 1H, OH). deltaC (CDCl3) 68.2 (COH), 36.2 (SCC), 26.5 (SC).
83%
With methanol; sodium tetrahydroborate; at 20℃;
Step 1 a Synthesis of 4-Bromo-3,5-dimethylphenol To a solution of dihydro-2H-thiopyran-4(3H)-one (530 mg, 4.56 mM) in methanol, NaBH4 (207 mg, 5.47 mM) was added. The reaction mixture was stirred at RT and quenched with saturated NH4CI. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated to obtain a crude product which was purified by column chromatography to afford the title compound tetrahydro-2H-thiopyran-4-ol (446 mg). Yield: 83 %; H NMR(CDCI3, 300 MHz): delta 3.66 (s, 1 H), 2.76-2.57 (m, 4H), 2.16-2.14 (m, 2H), 1 .76-1 .59 (m, 2H); Ms: m/z 1 18 (M+).
51.9%
With methanol; sodium tetrahydroborate; sodium hydroxide; at 20℃;Cooling with ice;
To an ice cold solution of tetrahydrothiopyran-4-one (10, 5 g, 0.043 mol) in methanol (40 mL), 5N sodium hydroxide solution (10 mL) solution was added slowly. Then sodium borohydride (0.488 g, 0.013 mol) was added portion wise. After addition, the reaction mixture was allowed to reach room temperature. After the reaction completion (~lh), the reaction mixture was poured in to water and extracted with dichloromethane. Combined organic layer was washed with saturated brine solution, dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude product was purified by column chromatography using 5%> methanol in DCM to afford the pure product (4 g, 51.90%). 1H-NMR (400 MHz, DMSO-d6): delta 4.69 (d, J = 4.24 Hz, 1H), 3.41-3.47 (m, 1H), 2.65-2.70 (m, 2H), 2.50-2.54 (m, 1H), 2.47 (d, J = 2.76 Hz, 1H), 2.00-2.02 (m, 2H), and 1.96-1.99 (m, 2H).
With sodium borohydrid; In 1,4-dioxane; dioxane-water; chloroform;
Step 1: Tetrahydro-4H-thiopyran-4-ol To a stirred solution of 0.8 g (0.021 mole) of sodium borohydride in 30 mL of 1:1 dioxane-water was added a solution of 5.0 g (0.043 mole) of tetrahydro-4H-thiopyran-4-one in 20 mL of dioxane, and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give a residue which was dissolved in chloroform and washed with water. Concentration of the chloroform solution gave 4.5 g of product as an oil which solidified upon standing.
With sodium tetrahydroborate; In ethanol;
EXAMPLE 8 Preparation of 4-Hydroxytetrahydrothiopyran Tetrahydrothiopyran-4-one, 2.0 g, was dissolved in 20 mL of absolute ethanol and added to a stirred suspension of NaBH4 1.3 g in 20 mL of absolute ethanol at 0oC. After stirring for 15 minutes, the resulting mixture was acidified with 10% aqueous citric acid to pH 6. Evaporation of the solvents provided a residue which was extracted with ethyl acetate (2x20 mL). Evaporation of the solvent yields the title compound as a white solid.
14.6 g (96%)
With sodium borohydrid; In tetrahydrofuran; ethanol;
Example 94 Synthesis of 4-hydroxytetrahydrothiopyran To a mixed solution of 15.0 g (0.13 mol) of tetrahydrothiopyran-4-one in 100 ml of ethanol and 100 ml of tetrahydrofuran, 2.44 g (0.06 mol) of sodium borohydride was added at 0 C. and stirred at room temperature for 2 hours under an argon atmosphere. The solvent of the reaction solution was distilled off under vacuum, diluted with ethyl acetate (200 ml), and successively washed with water (100 ml) and saturated saline (100 ml), dried over anhydrous sodium sulfate and the solvent was distilled off under vacuum. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 14.6 g (96%) of the above-identified compound, as a colorless crystal. IR(KBr)cm-1: 3282, 2929, 1428, 1338, 1271, 1058. MS(FAB) 119[M+1]+. 1H-NMR(CDCl3): delta 1.40(1H, d, J=4.4 Hz) 1.66-1.76(2H, m) 2.13-2.20(2H, m) 2.55-2.63(2H, m) 2.75-2.81(2 H, m) 3.63-3.69(1H, m).
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
[00683] Synthesis of compound 117.2. To a solution of thian-4-one (1.0 g, 8.61 mmol, 1.00 equiv) in methanol (10 mL) was added NaBH4 (655 mg, 17.31 mmol, 2.00 equiv) portionwise with stirring at 0 C and the reaction was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum and the residue was diluted with H20, extracted with 3 x 30 mL of dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum to give 0.95 g (crude) of compound 117.2 as a white solid.
With methanol; sodium tetrahydroborate; at 10℃; for 1h;
Tetrahydro-2H-thiopyran-4-ol To the reaction mixture of dihydro-2H-thiopyran-4(3H)-one (2.0 g, 16.92 mmol) in MeOH (20 mL) was added NaBH4 (1.95 g, 51.64 mmol) at 0 C. The reaction mixture was stirred at 10 C for 1 hour. The reaction was quenched with saturated NH4C1 (20 mL), extracted with EtOAc (20 mL x 3). Combined organic layers were dried over Na2S04, filtered and concentrated to give the desired crude product as colourless oil.
With sodium tetrahydroborate; In water; acetonitrile; at 23℃; for 2h;
Compound was added 25.2 parts of acetonitrile 75.6 parts ofthe formula (I-7-a), and stirred for 1 hour at 23 C.. The resulting mixturewas cooled to 0 C., after dropwise 4.10 parts of sodium borohydride and amixture of ion-exchange water 20.51 parts over a period of 1 hour, were added50.4 parts of acetonitrile, additionally, the mixture was stirred for 1 hour at0 . To the resulting reaction mass, after addition of 1N hydrochloricacid 108.45 parts of concentrated, added to 200 parts of chloroform and35 parts of ion-exchanged water and stirred for 30 min at 23 C., the organiclayer was removed by liquid separation. This operation was repeated four times.The recovered organic layer was filtered and concentrated the filtrate to givethe compound 24.11 parts of the formula (I-7-b)
Compound represented by the formula (I1-a) 2.00 parts and 10parts of acetonitrile were added and stirred for 2 hours at 23 C. Theresulting mixture was cooled to 0 C, and a mixture of 0.33 parts of sodiumborohydride and deionized water 4.88 parts was added dropwise over 10 minutes, andfurther stirred for 3 hours at 0 C. To the resulting reaction mass, 1Nhydrochloric acid 8.61 parts was added, concentrated, and 40 parts ofchloroform and 100 parts of ion-exchanged water were added and stirred for 30min at 23 C, and the organic layer was removed by liquid separation. Thisoperation was repeated four times. The recovered organic layer was filtered andthe filtrate was concentrated to give 1.37 parts of the salt represented by theformula (I1-b).
With culture of M. racemosus (SCR21); at 26℃; for 96h;Microbiological reaction;
General procedure: Fungal strains were cultured as detailed in Standard Growth Conditions. After 6days, cyclohexanone (10mM) was added, and the reaction was carried out at 26C in an orbital shaker at 180rpm for 4days. After removing the cells by filtration, the supernatants were extracted using ethyl acetate or diethyl ether. The organic layers were analyzed by GC.
With hydroxylamine hydrochloride; sodium acetate In ethanol for 6h; Heating / reflux;
6.1 Step 1; 4-aminotetrahydrothiopyran
A suspension mixture of 5 g (0.043 mole) of tetrahydrothiopyran-4-one 16, 29.26 g (0.215 mole) of sodium acetate trihydrate and 14.9 g (0.215 mole) of hydroxylamine hydrochloride in 200 mL of ethanol was heated to reflux for six hours until reaction was completed. The reaction mixture was cooled and ethanol was removed under reduced pressure. The residue was diluted with 400 mL of ice water and was extracted with ethyl acetate, 3x150 mL. The organic solution was washed with brine, dried and filtered. The filtrate was concentrated under reduced pressure affording 5.6 g (quantitative yield) of the thianone oxime 17 (white solid).
99%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 4h; Heating / reflux;
1d.a
Example Id: Preparation of tetrahydro-2H-thiopyran-4-amineStep a: Tetrahydro-4H-thiopyran-4-one (15 gm, 0.129 mole), hydroxylamine hydrochloride (15.27 gm, 0.219 mole) and sodium acetate trihydrate (30 gm, 0.219 mole) were taken together in a mixture of water (150 ml) and ethanol (60 ml). The reaction mixture was re fluxed for about 4 hours. The solvent was evaporated under reduced pressure. Solid compound, which separated out, was filtered and dried under vacuum.Yield: 15 gm (99 %)
99%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 4h; Heating / reflux;
1d.a
Step a: Tetrahydro-4H-thiopyran-4-one (15 gm, 0.129 mole), hydroxylamine hydrochloride (15.27 gm, 0.219 mole) and sodium acetate trihydrate (30 gm, 0.219 mole) were taken together in a mixture of water (150 ml) and ethanol (60 ml). The reaction mixture was re fluxed for about 4 hours. The solvent was evaporated under reduced pressure. Solid compound, which separated out, was filtered and dried under vacuum.Yield: 15 gm (99 %)
99%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 13h; Reflux;
34
Reference Example 34; tetrahydro-4H-thiopyran-4-one oxime; [Show Image] Tetrahydro-4H-thiopyran-4-one (50.0 g), sodium acetate (176.5 g) and hydroxyamine hydrochloride (149.5 g) were suspended in a mixed solvent of ethanol (1000 mL) and water (70 mL), and the suspension was heated under reflux for 13 hr. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted three times with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (55.8 g, yield 99%) as pale-yellow crystals. 1H NMR (300 MHz, CDCl3) δ: 2.52-2.60 (2 H, m), 2.70-2.84 (4 H, m), 2.84-2.91 (2 H, m), 7.65 (1 H, br. s.).
96%
With hydroxylamine hydrochloride; sodium acetate In ethanol at 20℃; for 2h;
12.1
To a solution of 4-tetrahydrothiopyranone (2.32 g) in ethanol (100 mL) was added sodium acetate (3.28 g) and hydroxylarnine hydrochloride (1.81 g) at room temperature and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate and an aqueous sodium hydrogencarbonate solution. After stirring, the mixture was extracted with ethyl acetate and the organic layer was washed with a brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain 4-tetrahydrothiopyrane oxime (2.53 g, yield: 96 %) as a colorless solid. MS(APCI)m/z; 132 [M+H]+
93%
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 20℃; for 2h;
I
To a solution of compound 1-1 (87.4 g, 0.75 mol) in EtOH (610 mL) at r.t. was added a solution of NH2OH.HCl (104.5 g, 1.5 mol) and NaOH (60 g, 1.5 mol) in H20 (218 mL). The mixture was stirred at r.t. for 2 firs. EtOH was removed in vaccum and the mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuum to give compound 1-2 (91.4 g, 93%). 1H NMR (CDC13, 400 MHz): δ 9.33 (s, 1H), 2.87 - 2.85 (m, 2H), 2.78 - 2.75 (m, 2H), 2.73 - 2.70 (m, 2H), 2.56 - 2.53 (m, 2H).
90%
oximation;
89.2%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 25℃; for 1h;
1.36.1 1.36.1 Preparation of Compound 2
A mixture of Compound I (1.0 g, 8.6 mmol) and NH2OH.HCl (3.0 g, 43 mmol), AcONa (2.1 g, 25.8 mmol) in EtOH/H2O (20 mL/20 mL) was stirred at 25° C. for 1 hour. Then the mixture was extracted with EA (150 mL×3), the organic layer was dried over Na2SO4, and concentrated to give compound 2 (1.0 g, 89.2%).
79%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 4h; Reflux;
1.1 Step 1: Synthesis of Dihydro-2H-thiopyran-4(3H)-one oxime (la-i)
To a solution of dihydro-2H-thiopyran-4(3H)-one (10 g, 0.086 mol) and hydroxylamine hydrochloride (10.4 g, 0.15 mol) in H20 (100 mL) and ethanol (40 mL) was added sodium acetate (13.1 g, 0.16 mol). The mixture was refluxed for 4h, the organic solvent was removed in vacuum and the residue was cooled in an ice bath, 8.92 g solid was obtained in 79% yield by filtration. ‘H-NMR (400 MHz, CDC13) 5: 2.88 (m, 2H), 2.80 (m, 2H), 2.74 (m, 2H), 2.57 (m, 2H).
67%
With hydroxylamine hydrochloride; sodium acetate In ethanol
XXXVIII.1 Dihydro-2H-thiopyran-4(3H)-one oxime
Dihydro-2H-thiopyran-4(3H)-one oxime To a solution of dihydro-2H-thiopyran-4(3H)-one (9.0 g, 77.46 mmol) in ethanol (600 mL) was added NH2OH.HCl (27.0 g, 258.22 mmol) and NaOAc (51.0 g, 619.71 mmol). The mixture was stirred overnight. The mixture was concentrated in vacuo to remove ethanol. The residue was washed by H20 (550 mL), and extracted into EtOAc (3 x 300 mL). The combined organic layer was dried over Na2S04, and concentrated in vacuo to give dihydro- 2H-thiopyran-4(3H)-one oxime (6.8 g, 67%): 1H NMR (400 MHz, CDC13) δ 4.11-2.51 (m, 6H), 2.08-1.90 (m, 2H).
66%
With hydroxylamine hydrochloride; sodium acetate In ethanol at 20℃;
55 Reference Example 55
To a mixture of tetrahydrothiopyran-4-one (5.0 g), hydroxylamine hydrochloride (15 g) and ethanol (400 mL) was added sodium acetate (29.3 g) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C, and the precipitated crystals were collected by filtration and washed with water at 0°C to give tetrahydrothiopyran-4-one oxime as crystals. Recrystallization from petroleum ether gave white prism crystals. (2.36 g, yield 66%). melting point: 85-86°C.
54%
With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water at 0 - 20℃; for 2h;
18.1
Step 1 : To a solution of 18a (2.96g, 25.5mmol) in 23mL of ethanol was added NH2OH.HC1 (3.64g, 51mmol). The mixture was cooled to O 0C in ice bath and was added a solution of NaOH (2.08g) in 8mL of H2O. With the addition of NaOH solution, precipitate was formed. The reaction mixture was warmed to r.t. and stirred for an additional 2h, evaporated to remove ethanol. The aqueous solution was extracted with ether. The ether layer was washed with water and brine, dried over anhydrous Na2SO4. The organic layer was evaporated to dryness and the residue was recrystallized from hexane/ether to give compound 18b (1.8 Ig, 54%).
54%
With sodium hydroxide; hydroxylamine hydrochloride In water at 0 - 20℃; for 2h;
18.1
Example 18 Preparation of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1,1-dioxo-hexahydro-thiopyran-4-yl)-amide Preparation of 1,1-Dioxo-hexahydro-thiopyran-4-ylamine Step 1: To a solution of 18a (2.96 g, 25.5 mmol) in 23 mL of ethanol was added NH2OH.HCl (3.64 g, 51 mmol). The mixture was cooled to 0° C. in ice bath and was added a solution of NaOH (2.08g) in 8 mL of H2O. With the addition of NaOH solution, precipitate was formed. The reaction mixture was warmed to r.t. and stirred for an additional 2 h, evaporated to remove ethanol. The aqueous solution was extracted with ether. The ether layer was washed with water and brine, dried over anhydrous Na2SO4. The organic layer was evaporated to dryness and the residue was recrystallized from hexane/ether to give compound 18b (1.81 g, 54%).
With hydroxylamine
With hydroxylamine hydrochloride; sodium acetate In ethanol for 3h; Heating;
With hydroxylamine In pyridine
With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water
2.A Step A
Step A 4-Oximino-tetrahydrothiopyran To a stirring solution of solution of tetrahydrothiopyran-4-one (4.9 g, 42.1 mmol) and hydroxylamine hydrochloride (5.9 g, 84 mmol) in 35 mL of ethanol at 0° C. was added a solution of sodium hydroxide (3.38 g, 84.5 mmol) dissolved in 13 mL water. The reaction mixture was warmed to room temperature and stirred for an additional 2 h. The ethanol was removed in vacuo and the aqueous solution extracted with ether (2*250 mL). The etheral layer was washed with with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give crude oxime which was recrystallized from hexane/ether to give 4.66 g of 4-oximino-tetrahydrothiopyran. 1 H NMR (500 MHz, CDCl3): δ9.43 (brs, 1H), 2.86 (m, 2H), 2.78(m, 2H), 2.73 (m, 2H), 2.56 (m, 2H). 13 C NMR (125 MHz, CDCl3): δ158.24, 33.94, 29.75, 28.38, 26.78.
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 56h; Heating / reflux;
Anhydrous sodium acetate (16.25g, 18.86mmol) and hydroxylamine hydrochloride (7.72g, 10.66mmol) were added to a solution of 4-oxothiane (10.02g, 8.2mmol) in ethanol (100ml) and water (100ml). The reaction mixture was stirred and heated at reflux for 56 hrs. The cooled reaction mixture was diluted with water (200ml) and extracted with ether (2x150ml). The combined organic extracts were washed with brine (100ml), dried (hydrophobic frit) and evaporated to dryness to give the title compound as a colourless solid (12.8g). MH+132, rt= 1.56 mins
4.66 g
With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water at 0 - 20℃; for 2h;
With hydroxylamine hydrochloride; potassium carbonate In ethanol for 1h; Heating / reflux;
15.1
4-Oxothiane (2.32 g, 20.0 mmol) was dissolved in ethanol, and hydroxylamine hydrochloride (2.78 g, 40.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) were added thereto, and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction system to extract the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was dissolved in pyridine (20 mL), and p-toluene sulfonic acid chloride (6.46 g, 24.0 mmol) was added thereto at -20°C, and the mixture was stirred at - 20°C for 1 hour. Water and ethyl acetate were added to the reaction system to extract the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was dissolved in ethanol, and an ethanol solution of 4 mol/L potassium ethoxide (15.7 mL, 40.0 mmol) was added thereto at 0°C, and the mixture was stirred for 1 hour. After the mixture was stirred at 50°C for an additional 1 hour, water and ethyl acetate were added to the reaction system to extract the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate), whereby 3-amino-4,4-diethoxythiopyrane (2.31 g, 56%) was obtained. 1H NMR (CDCl3, δ ppm): 1.19 (t, J = 7.1 Hz, 6H), 1.85-1.98 (m, 2H), 2.28-2.37 (m, 1H), 2.50-2.57 (m, 1H), 2.69-2.84 (m, 1H), 3.14-3.28 (m, 2H), 3.42 (q, J = 7.1 Hz, 4H)
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 25℃; for 1h;
I.1.36.1 1.36.1 Preparation of Compound 2
A mixture of Compound 1 (1.0 g, 8.6 mmol) and NH2OH.HCl (3.0 g, 43 mmol), AcONa (2.1 g, 25.8 mmol) in EtOH/H2O (20 mL/20 mL) was stirred at 25° C. for 1 hour. Then the mixture was extracted with EA (150 mL×3), the organic layer was dried over Na2SO4, and concentrated to give compound 2 (1.0 g, 89.2%).
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 56h; Heating / reflux;
Anhydrous sodium acetate (16.25g, 18.86mmol) and hydroxylamine hydrochloride (7.72g, 10.66mmol) were added to a solution of 4-oxothiane (10.02g, 8.2mmol) in ethanol (100ml) and water (100ml). The reaction mixture was stirred and heated at reflux for 56 h. The cooled reaction mixture was diluted with water (200ml) and extracted with ether (2x150ml). The combined organic extracts were washed with brine (100ml), dried (hydrophobic frit) and evaporated to dryness to give the title compound as a colourless solid (12.8g). MH+= 132, rt = 1.56 min
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 56h; Reflux;
4
Description 4 (D4);Tetrahydro-4H-thiopyran-4-one oxime; Anhydrous sodium acetate (16.25g, 18.86mmol) and hydroxylamine hydrochloride (7.72g, 10.66mmol) were added to a solution of 4-oxothiane (10.02g, 8.2mmol) in ethanol (100ml) and water (100ml). The reaction mixture was stirred and heated at reflux for 56 hrs. The cooled reaction mixture was diluted with water (200ml) and extracted with ether(2x150ml). The combined organic extracts were washed with brine (100ml), dried(hydrophobic frit) and evaporated to dryness to give the title compound as a colourless solid (12.8g).LCMS (Method A): MH+ 132 seen at retention time: 1.56 mins.
With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol at 0℃;
With peracetic acid; In water; ethyl acetate; at 20℃;
EXAMPLE 22 2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine-1-carbonyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile To a stirred solution of tetrahydrothiopyran-4-one (5.30 g, 43.1 mmol, Aldrich) in 50 mL of ethyl acetate was added dropwise 32% peracetic acid (24 g, 110 mmol) at a rate to avoid reflux. After the addition, the mixture was cooled to room temperature and the solid filtered to give 1,1-dioxo-tetrahydro-thiopyran-4-one as a white solid (5.69 g, 89%).
89%
With peracetic acid; In acetic acid; ethyl acetate; at 15 - 30℃; for 2h;
Reference Example 52; tetrahydro-4H-thiopyran-4-one 1,1-dioxide; [Show Image] To a solution of tetrahydro-4H-thiopyran-4-one (2.65 g) in ethyl acetate (25 mL) was added peracetic acid (32% acetic acid solution, 13 g) over 1 hr at room temperature. The reaction solution was stirred at the same temperature for 1 hr, and cooled to 0C. The precipitate was collected by filtration, washed with ethyl acetate (cooled to 0C in advance), and dried under reduced pressure to give the title compound (3.01 g, yield 89%) as white crystals. 1H NMR (300 MHz, DMSO-d6) delta: 2.03-2.35 (4 H, m), 2.93-3.12 (2 H, m), 3.11-3.29 (2 H, m).
67%
With 3-chloro-benzenecarboperoxoic acid; In ethyl acetate;
A solution of m-chloroperbenzoic acid (1.859 g, 10. 8 mmol) in ethyl acetate (13 ml) was added dropwise to a solution of tetrahydrothiopyran-4-one (0.500 g, 4.30 mmol) in ethyl acetate (5 ml) at such a rate that no reflux was caused by heat generation. The resulting mixture was stirred overnight. The solution thus obtained was cooled on an ice bath and the solid precipitated was collected by filtration. The precipitate on a filter was washed with cold ethyl acetate and then dried under reduced pressure to obtain 1,1-dioxidetetrahydro-2H-thiopyran-4-one (0.430 g, 67%).
55%
With dihydrogen peroxide; In methanol; water; at 20℃; for 33h;Cooling with ice;
To a solution of ketone 16 (0.50 g, 4.304 mmol) in methanol (40 mL) 30% aqueous solution of hydrogen peroxide (1.67 g, 17.21 mmol) was slowly added dropwise with the cooling in ice bath for 1 hour (the temperature of reaction mixture should not exceed 20 FontWeight="Bold" FontSize="10" ). Stirring was continued in the ice bath for 8 hours and then 1 day at r.t. The solid of unknown by-products was filtered off. The filtrate was evaporated in vacuo to obtain of pure ketosulfone 9. Yield: 0.35 g (55%), mp 172-175 FontWeight="Bold" FontSize="10" (163-170 FontWeight="Bold" FontSize="10" [5]), Rf 0.50 (ethyl acetate). 1NMR (500 MHz, DMSO-d6) delta3.51 (4, t, J= 6.5 Hz, H-2,6), 2.76 (4, t, J= 6.5 Hz, H-3,5). 13C NMR (125 MHz, DMSO-d6) delta203.24 (=O), 48.20(-2,6),37.89(-3,5).NMR spectra of the ketosulfone 9 were identical to those described.[5]
52%
With dihydrogen peroxide; In acetic acid; at 100℃; for 3h;
Example 4; 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (4); To a solution of dihydro-2H-thiopyran-4(3H)-one 4.1 (1.50 g, 12.9 mmol) in acetic acid was added H2O2 (1.30 g, 38.7 mmol) under nitrogen, and the resulting mixture was heated to 100 C. for 3 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the acetic acid was evaporated under reduced pressure, and the resulting crude product was extracted with 10% methanol in dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, and the solvent removed in vacuo to give compound 4.2 (1.0 g, 52%).
With peracetic acid; acetic acid; In ethyl acetate; at 50 - 55℃;
A4a) 1,1-dioxo-tetrahydro-1lambda6-thiopyran-4-one A solution of 5.3 g (45.6 mmol) tetrahydrothiopyran-4-one in 50 mL EtOAc was heated to 50 C. At this temperature, 18.6 mL (110 mmol) peracetic acid solution (39% in AcOH) were slowly added dropwise, while the temperature was kept between 50-55 C. using an ice bath. After the addition had ended the reaction mixture was cooled to RT, during which time a precipitate was formed. This was suction filtered and dried. The product was reacted further without purification. Yield: 6.70 g (99% of theory, purity 80%) EI-MS: (M)+=148 Rf=0.50 (silica gel, EtOAc)
With m-chloroperoxybenzoic acid; In dichloromethane; water; ethyl acetate;
PREPARATION 130 To a solution of tetrahydrothiopyran-4-one (1.0 g) in dichloromethane (20 ml) was added 3-chloroperoxybenzoic acid (4.16 g, purity 80%) under ice-cooling with stirring. The mixture was stirred at the same temperature for 20 minutes and then stirred at ambient temperature for 1 hour. The resulting precipitates were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate. (50 ml) and water (20 ml) and adjusted to pH 2 with 1N-hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed in turn with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was dissolved in a mixture of dichloromethane (100 ml) and methanol (20 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give 1,1-dioxotetrahydrothiopyran-4-one (1.18 g). NMR (CD3CD, delta): 2.20 (4H, t, J=6.05 Hz), 2.90-3.20 (4H, m).
With oxone; edetate disodium; sodium hydrogencarbonate; In acetonitrile; at 20℃; for 2.5h;
To a solution of tetrahydrothiopyran-4-one (400 mg) stirring in acetonitrile (5 ml) and Na2.EDTA (0.0004 M aq, 3 ml) was added potassium peroxymonosulphate (Oxone, 6.34 g) and NaHCO3 (2.69 g) in several aliquots over 30 minutes. The reaction mixture was stirred at room temperature for a further 2 hours, then diluted with water (40 ml), extracted into dichloromethane, and dried (MgSO4) to give 1,1-dioxo-tetrahydro-thiopyran-4-one (330 mg) as a white solid. To this compound (75 mg) stirring in anhydrous 1,2-dichloroethane (6 ml) was added 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-yl methyl methylamine (150 mg, as previously prepared from 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-carbaldehyde and methylamine under reductive amination conditions), followed by glacial acetic acid (31 mul) and sodium triacetoxy borohydride (138 mg). The reaction mixture was stirred for 24 hours at room temperature, and the product isolated by extraction into dichloromethane, followed by purification by flash chromatography to give (2-chloro-4-morpholin-4-yl-thienopyrimidine-6-ylmethyl)-(1,1-dioxo-hexahydro-thiopyran-4-yl)-methyl-amine (115 mg) as a yellow solid, which was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole, to give, after flash silica purification the title compound (38 mg) as a white solid. 1H NMR 400 MHz DMSO 13.18 (bs, 1H); 8.87 (s, 1H); 8.21 (d, 1H, J=7.2 Hz); 7.65 (d, 1H, J=8.2 Hz) 7.45 (m, 2H); 3.98 (m, 6H) 3.82 (m, 4H); 3.26-3.06 (m, CH2×2) 2.91 (m, 1H); 2.28 (s, 3H); 2.04 (m, CH2×2) M/S ESI (m+1)=513.1
With Oxone; edetate disodium; sodium hydrogencarbonate; In acetonitrile; for 1.33333h;
To a stirred solution of tetrahydrothiopyran-4-one (0.400 g, 3.40 mmol) in acetonitrile (4.5 mL) was added Na2EDTA (3 mL, 0.0004 M in water). Solid NaHCO3 (2.70 g, 32.0 mmol) and OXONE (trade name, 6.30 g, 10.3 mmol) were combined separately and this dry mixture was added to the reaction mixture over 30 min. Then, the reaction was allowed to stir for 50 min. The mixture was diluted with dichloromethane (80 mL) and the white inorganic material was removed by filtration. The filtrate was dried over magnesium sulfate and concentrated to give the title compound (0.326 g, 64%) as a white solid:1H NMR (300 MHz, CDCl3) delta 2.97-3.01 (4H, m) , 3.36-3.41 (4H, m) .
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; ethyl acetate; at 5℃; for 0.5h;
General procedure: A solution of m-CPBA (3.0 mmol) in AcOEt (5 mL) was added to the solution of1a-5a (1.0 mmol) in dichloromethane (DCM) (20 mL) dropwise at 5 C and stirredfor 30 min at this temperature. The resulting solution was diluted with 30 mL ofDCM, washed with 3 9 10 mL of saturated solution of Na2CO3, dried overanhydrous Na2SO4, and concentrated under vacuum to give S,S-dioxides 1c-5c inexcellent yields as white solids (Table 2).
With bismuth (III) nitrate pentahydrate In methanol for 20h; Heating; Inert atmosphere;
88%
With bismuth (III) nitrate pentahydrate In methanol for 1.25h; Reflux;
85%
With bismuth (III) nitrate pentahydrate In methanol for 2h; Reflux;
85%
With bismuth (III) nitrate pentahydrate In methanol for 2h; Reflux;
a a) General procedure for the preparation of l,2,4,9-tetrahydro-3-thia-9-azafluorenes
a) General procedure for the preparation of l,2,4,9-tetrahydro-3-thia-9-azafluorenes 5To a solution of phenyl hydrazine hydrochloride 3 (12 mmol) and tetrahydrothiopyran-4-one 4 (12 mmol) in methanol (50 mL) was added Bi(N03)3-5H20 (2.4 mmol). After being stirred for 2 h under reflux, the reaction mixture was poured into water (100 mL), and bismuth nitrate was removed trough filtration. The crude product was extracted with ethyl acetate (100 mL), washed with saturated NaHC03(100 mL), brine (100 mL) and dried over anhydrous MgS04. Filtration of the drying agent and removal of the solvent in vacuo afforded the crude thioether 5, which was purified by means of recrystallization from ethanol to provide pure l,2,4,9-tetrahydro-3-thia-9-azafluorene 5 (10.2 mmol, 85%).
With hydrogenchloride In ethanol Heating;
With bismuth (III) nitrate pentahydrate In methanol for 3.5h; Reflux;
To a mixture of tetrahydrothiopyran-4-one (5.14 g) and conc. hydrochloric acid (20 mL) was added sodium azide (4.31 g) under ice-cooling. The reaction mixture was stirred at room temperature for 4 hrs., and sodium carbonate was added. The mixture was diluted with iced water and extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1,4-thiazepan-5-one as crystals (3.62 g, yield 62%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121C.
(Ref: J. Org. Chem. 1960, 25, 1953-1956.) To a stirred solution of tetrahydrothiopyran-4-one 1 (10 g, 86 mmol) in cone. HCl (43 mL) cooled to 0 0C is added sodium azide (8.4 g, 129 mmol) portionwise over 30-60 min, (note: gas evolution). When the addition is complete the reaction mixture is stirred at RT for 4 h.The mixture is cooled to 0 0C and solid Na2CO3 is added portionwise (note: gas evolution), plus water to dissolve the salts, until the solution is alkaline ~pH 9. The alkaline solution is diluted with DCM (200 mL), the phases are seperated and the aqueous layer is extracted with DCM (3 x 100 mL). The combined organic layers are EPO <DP n="24"/>dried over MgSOphi filtered and concentrated to a low volume (-20 mL), petroleum ether is added and the solid is collected by filtration and dried to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO) delta 7.52 (s, IH), 3.39 (m, 2H), 2.63 (m, 2H), 2.58 (m, 4H); MS-APCI (m/z+-) 131.9 (M+H).
Stage #1: 3-pyridinecarboxaldehyde With lithium perchlorate; N,N-diethyl-1,1,1-trimethylsilanamine In diethyl ether at 20℃; for 0.166667h;
Stage #2: Tetrahydrothiopyran-4-one In diethyl ether at 20℃; for 2h;
94%
With triethylamine; lithium bromide In dichloromethane
81%
With magnesium bromide ethyl etherate; triethylamine In methanol at 20℃; for 2.5h;
77%
With hydrogenchloride; acetic acid at 25 - 30℃;
4.2. Synthesis of curcumin analogs
General procedure: A total of 61 curcumin analogs were synthesized as previously described with modification [35]. A mixture of the appropriate aldehyde (0.01 mol) and the ketone (0.005 mol) was dissolved in glacial acetic acid saturated with anhydrous hydrogen chloride and heated in a water bath at 25-30 °C for 2 h. After standing for 2d, the mixture was treated with cold water and filtered. The solid obtained was then washed and dried. The crude product was recrystallized from appropriate solvents (methanol or ethanol). Fourteen of the compounds studied were synthesized and characterized earlier in our laboratory [35]. The compounds described in Ref. [35] and their labeling in Ref. [35] are given in parenthesis in Table 1. Prior synthesis of additional curcumin-related compounds described in the literature are indicated below by providing appropriate references.
Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide at 20℃; for 1h;
Stage #2: Tetrahydrothiopyran-4-one In dimethyl sulfoxide at 20℃; for 14h;
118 1-oxa-6-thiaspiro[2.5]octane
Under a nitrogen atmosphere at room temperature, to a suspension of trimethylsulfoxonium iodide (37.1 g, 165.1 mmol) in dimethylsulfoxide (120 mL) was slowly added sodium hydride (60% in oil, 6.10 g, 152.4 mmol) and the mixture was stirred for 1 hr. A solution of tetrahydro-4H-thiopyran-4-one (14.8 g, 127.0 mmol) in dimethylsulfoxide (60 mL) was added dropwise over 20 min. The reaction solution was further stirred at room temperature for 14 hr, diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was stood at room temperature and the obtained crystals were washed with a small amount of hexane and dried to give the title compound (8.22 g, yield 50%) as colorless needle crystals. 1H NMR (CDCl3) δ: 1.69-1.82(2H, m), 1.93-2.09 (2H, m), 2.56-2.73(4H, m), 2.85-3.01(2H, m).
Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide; mineral oil for 1h;
Stage #2: Tetrahydrothiopyran-4-one In dimethyl sulfoxide; mineral oil for 12h;
1-Oxa-6-thiaspiro[2.5]octane
1-Oxa-6-thiaspiro[2.5]octane To a suspension of trimethylsulfoxonium iodide (2 g) in dimethylsulfoxide (15 mL) is added portionwise NaH (820 mg of a 60% dispersion in mineral oil). The mixture is stirred for 1 hour and a solution of dihydro-2H-thiopyran-4(3H)-one (2 g) in dimethylsulfoxide (2 mL) is added dropwise. The mixture is stirred for 12 hours, diluted with ethylacetate and washed twice with water and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 742 mg; LC (method 7): tR=0.64 min; Mass spectrum (ESI+): m/z=131 [M+H]+.
742 mg
Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide; mineral oil for 1h;
Stage #2: Tetrahydrothiopyran-4-one In mineral oil for 12h;
1 -Oxa-6-thiaspiro[2.51octane
To a suspension of thmethylsulfoxoniunn iodide (2 g) in dimethylsulfoxide (15 mL) is added portionwise NaH (820 mg of a 60% dispersion in mineral oil). The mixture is stirred for 1 hour and a solution of dihydro-2H-thiopyran-4(3H)-one (2 g) in dimethylsulfoxide (2 mL) is added dropwise. The mixture is stirred for 1 2 hours, diluted with ethylacetate and washed twice with water and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 742 mg; LC (method 7): tR = 0.64 min; Mass spectrum (ESI+): m/z = 131 [M+H]+.
With 1,4-diaza-bicyclo[2.2.2]octane In water at 20℃; for 0.0666667h; Green chemistry;
Typical procedure for Knoevenagel condensation
General procedure: A mixture of 1a (232 mg, 2.0 mmol) and 2a (132 mg, 2.0 mmol) in H2O (0.5 mL) and DABCO (224 mg, 2.0mmol) was stirred at room temperature for 3 min until TLC showed complete disappearance of the starting materials. The mixture was extracted by EtOAc (5 mL) and the organic layer was washed with saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 . Product 3aa was obtained by evaporation of the volatile portion of the organic layer and was puried by recrystallization from EtOAc/hexane mixture. Product 3aa was obtained in 80% yield (262 mg). The product was identied based on its physical and spectral characteristics. The remaining compounds 3ab-3db were synthesized in a similar manner.
39%
With ammonium acetate In toluene at 150℃; for 48h;
6.a (a) Ethyl 2-cyano-2-(tetrahydrothiopyran-4-ylidene)acetate (C15)
(a) Ethyl 2-cyano-2-(tetrahydrothiopyran-4-ylidene)acetate (C15) Tetrahydrothiopyran-4-one (C14)(520 mg, 4.5 mmol), ethyl cyanoacetate (C5)(1.4 ml, 1.48 g, 13.1 mmol), ammonium acetate (50 mg, 0.65 mmol) and toluene (50 mL) were heated to 150°C using a dean-stark trap. 1H NMR after 24 h indicated that no reaction had occurred so a spatula of ammonium acetate (approx. 200 mg) was added to the reaction mixture and additional toluene (50 mL) was added to replace evaporative losses. The reaction mixture was then heated at 150°C for a further 24h. The mixture was then concentrated to give a yellow oil. Purification by silica column chromatography (gradient elution: 10% EtOAc in hexane - 15% EtOAc in hexane) resulted in the desired compound as a clear oil (355 mg, 39%). 1H NMR (500 MHz, CDCI3) δ 4.26 (q, 2H, J = 7.2 Hz), 3.32-3.30 (m, 2H), 3.00-2.98 (m, 2H), 2.90-2.87 (m, 2H), 2.83-2.81 (m, 2H), 1.33 (t, 3H, J = 7.2 Hz). 13C NMR (125 MHz, CDCI3) δ 175.5, 161.5, 1 14.8, 104.3, 62.1 , 38.2, 33.4, 31.0, 30.8, 14.0.
With ammonium acetate; acetic acid In toluene Heating;
With sodium periodate In methanol; water at 20℃; for 6h;
98%
With aluminum(III) nitrate nonahydrate; water; silica gel; citric acid; potassium bromide In dichloromethane at 20℃; for 0.916667h;
98%
With ammonium nitrate; ammonium bromide In dichloromethane at 20℃; for 0.583333h; chemoselective reaction;
98%
With air; poly-(2,4,6-tri(9H-carbazole-9-yl)-1,3,5-triazine) In methanol at 20℃; for 8h; Irradiation;
92%
With aluminum(III) nitrate nonahydrate; sulfuric acid; silica gel; silica gel; sodium bromide In dichloromethane; water at 20℃; for 0.416667h; chemoselective reaction;
92%
With dihydrogen peroxide In water; acetonitrile at 20℃; for 0.25h;
2.4 Oxidation of benzyl phenyl sulfide to benzyl phenyl sulfoxide
General procedure: A mixture of benzyl phenyl sulfide (1 g, 5.0 mmol), silica vanadic acid (5 mg, 0.039 mmol of V) and H2O2 30% (6 mmol) in CH3CN (3 mL) was stirred for 10 min. After completion of the reaction, solvent was evaporated and the product was extracted with ether (2× 10 mL), dried with anhydrous Na2SO4, filtered and evaporated to afford the crude sulfoxide product. Finally, the product was purified by column chromatography using ethyl acetate/hexane (1.5:8.5) as eluent to give benzyl phenyl sulfoxide as a white solid in 93% yield.
89%
With sodium bromite; "wet" H(1+)-exchanged zeolite F-9 In dichloromethane for 0.5h; Ambient temperature;
85%
With aluminum oxide; [bis(acetoxy)iodo]benzene for 0.025h; Irradiation;
83%
With iron(III) nitrate impregnated on montmorillonite clay In neat (no solvent) for 60h; Irradiation;
82%
With urea-hydrogen peroxide In acetone at 20℃; for 2h;
73%
With 1,1'-(ethane-1,2-diyl)dipyridinium bistribromide In dichloromethane; water at 20℃; for 0.333333h; chemoselective reaction;
66%
With aluminum oxide; sodium chlorite; [N,N'-bis(salicylidene)-1,2-ethanediaminato]Mn(III) chloride In dichloromethane at 20℃; for 0.116667h;
42%
With sodium periodate In methanol; water
40.1
To a stirred solution of tetrahydrothiopyran-4-one (0.500 g, 4.30 mmol) in 15:1 methanol/water (10 mL) was added sodium periodate (0.962 g, 4.50 mmol). The mixture was allowed to stir overnight. Then, the reaction was diluted with ethyl acetate (50 mL) and the white solid was filtered off. The filtrate was concentrated several times with ethyl acetate to give the title compound (0.241 g, 42%) as a white solid:1H NMR (300 MHz, DMSO-d6) δ 1.75-1.80 (2H, m) , 2.01-2.11 (2H, m) , 2.68-2.82 (4H, m) .
With sodium periodate In water at 0℃;
With 3-chloro-benzenecarboperoxoic acid
9.1 g
With sodium periodate In methanol; water for 6h; Ambient temperature;
94 % Chromat.
With aluminum oxide; sodium chlorite In acetone at 20℃; for 0.25h;
75 %Chromat.
With dihydrogen peroxide; pyridinium p-toluenesulfonate In water at 20℃; for 75h;
General procedure for the synthesis of sulfoxides 2a-o
General procedure: To a 0.25 M water(3.0 mL) solution of PPTS I (2.5 mol %) and sulfide 1a, H2O2 (35% v/v in water1.1 equiv) was added. The resulting mixture was stirred at room temperatureand followed by GC-MS until completion (2a/3a ratio 98:2, 95% conversion).The reaction mixture was filtered and extracted with CH2Cl2. The combinedorganic phase was dried on Na2SO4 and concentrated under reduced pressure.Pure sulfoxide 2a was obtained by flash column chromatography (silica gel,70:30 hexane/EtOAc) in 87% yield. 1H NMR (500 MHz, CDCl3) d: 7.66-7.63 (m,2H), 7.54-7.50 (m, 3 H), 2.72 (s, 3H); 13C NMR (125 MHz, CDCl3) d: 145.8,131.0, 129.3, 123.5, 44.0.17a
With sodium periodate In methanol; water
With iodosylbenzene; 2C22H18N2O6(4-)*2Mn(3+)*2Cl(1-)*2NO3(1-)*3H2O*6C3H7NO*2Gd(3+) In acetonitrile at 20℃; for 16h;
With oxygen In methanol at 20℃; for 18h; Irradiation;
With 3-chloro-benzenecarboperoxoic acid In dichloromethane; ethyl acetate at 5℃; for 0.5h;
General procedure for the synthesis of thiopyran-S-oxides 1b-5b
General procedure: A solution of m-CPBA (1.0 mmol) in AcOEt (2 mL) was added to the solution of1a-5a (1.0 mmol) in dichloromethane (DCM) (10 mL) dropwise at 5 C and stirredfor 30 min at this temperature. The resulting solution was diluted with 20 mL ofDCM, washed with 3 * 10 mL of saturated solution of Na2CO3, dried overanhydrous Na2SO4, and concentrated under vacuum to give S-oxides 1b-5b inexcellent yields as white solids (Table 1).
With sulfur; triethylamine In water at 20℃; for 4h;
83%
With morpholine; sulfur In ethanol at 45℃; for 1h;
82.3%
With morpholine; sulfur In ethanol at 50℃; for 1h;
71%
With morpholine; sulfur In ethanol at 50℃; for 16h;
70%
With sulfur; diethylamine In ethanol at 50℃; for 1h;
68%
With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 16h;
Preparation [OF 45B] from 44b
To ethyl cyanoacetate (226 mg, 2 mmol) and sulfur (76 mg) in DMF (2 mL), triethylamine (0.25 mL) is added under stirring. To this solution tetrahydrothiopyran- 4-one (44b, 232 mg, 2 mmol) is added. The mixture is stirred at room temperature for 16 hours and it is poured into water (20 mL), which is extracted with diethyl ether (20 mL). The ethereal solution is dried with sodium sulfate and concentrated. The residue is triturated with hexanes (10 mL) and the precipitate is collected to give a yellow solid (0.33 g, 68% yield). Physical characteristics: MS (ES+) for [NILZ] 244 [(M+H) .]
With sulfur In ethanol
With sulfur; triethylamine In N,N-dimethyl-formamide
With morpholine; sulfur In ethanol at 50℃;
With morpholine; sulfur In ethanol Reflux;
Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylic acid ethyl ester [AA-3]
Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylic acid ethyl ester [AA-3]To a mixture of tetrahydro-thiopyran-4-one, cyano-acetic acid ethyl ester and elemental sulphur in ethanol was added morpholine. The reaction was reflux overnight. The mixture was left to cool down and a precipitate appeared. The solid was recovered by filtration and to give the title compound as a yellow solid. LCMS method: 3, RT: 5.78 min, MI: 244 [M+l].
Multi-step reaction with 2 steps
1: 1,4-diaza-bicyclo[2.2.2]octane / water / 0.07 h / 20 °C / Green chemistry
2: 1,4-diaza-bicyclo[2.2.2]octane; sulfur / water / 4 h / 20 °C
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 30℃;
29
Reference Example 29; tetrahydro-2H-thiopyran-4-carbonitrile; [Show Image] Tetrahydro-4H-thiopyran-4-one (10.00 g) and p-toluenesulfonylmethyl isocyanide (18.49 g) were dissolved in DME (400 mL). A solution of potassium tert-butoxide (19.32 g) in tert-butanol (150 mL) was added thereto at 0°C, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with diethyl ether, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine (twice), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate] to give the title compound (10.93 g, yield 100%) as a brown transparent oil. 1H NMR (300 MHz, CDCl3) δ: 2.03-2.22 (4 H, m), 2.52-2.65 (2 H, m), 2.77-2.93 (3 H, m).
100%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 20℃; for 3h;
29a; 29b Tetrahydro-2H-thiopyran-4-carbonitrile
To a solution of dihydro-2H-thiopyran-4(3H)-one (10.0 g, 86.2 mmol) and tosylmethyl isocyanide (18.68 g, 94.82 mmol) in 1,2-dimethoxyethane (250 mL) was added a solution of t-BuOK (19.31 g, 172.4 mmol) in 1:1 t-BuOH/1,2-dimethoxyethane (200 mL). The mixture was stirred at RT for 3 h, then diluted with EtOAc and washed with 5% aq. NaHCO3, dried over Na2SO4, and concentrated under reduced pressure to give the title compound as a brown oil (10.93 g, 100%). MS (ES+): C6H9NS requires: 127, found: 128 [M+H]+.
93%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 20℃; for 3h;
13 Example 13: Synthesis [OF 6- (4-BENZYLOXY-PHENYL)-7- (TETRAHYDRO-THIOPYRAN-4-YL)-3- (IH-] tetrazol-5-yl) -pyrazolo [1, 5-a] pyrimidine
According to a modification of a literature procedure (Helv. Chim. Acta 1997, [80,] 1528) to an ice cold solution of 2.0 g (17.2 mmol) of tetrahydro-thiopyran-4-one, and 3.69 g (18.9 mmol) [OF 1-ISOCYANOMETHANESULFONYL-4-METHYL-BENZENE] in 100 mL of 1,2- dimethoxyethane (DME) was added 34.4 mL (34.4 mmol) [OF POTASSIUM T-BUTOXIDE (1] M solution in t-butanol), and the resulting mixture was stirred at rt for 3 h. The reaction mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give 2.05 g (93% yield) of desired [TETRAHYDRO-THIOPYRAN-4-] [CARBONITRILE] as indicated by 1H NMR. A solution of 1.97 g (15.5 mmol) [OF TETRAHYDRO-THIOPYRAN-4-CARBONITRILE] in 5 mL of ethanol (EtOH) was added to a solution of 6.2 g (155 mmol) of sodium hydroxide (NaOH) in 30 mL of EtOH and 15 mL of water, and the resulting mixture was heated at reflux for 4 h. The reaction mixture was cooled in an ice bath, acidified with concentrated hydrochloric acid to pH=2, and then concentrated to give a precipitate which was filtered to afford 1.36 g (60%) of desired [TETRAHYDRO-THIOPYRAN-4-CARBOXYLIC ACID] as a brown crystalline solid as indicated by [H NMR.] To an ice cold solution of [1.] [36 G] (9.32 mmol) tetrahydro-thiopyran-4-carboxylic acid in 25 [ML] of dichloromethane (DCM) was added [DROPWISE 1. 1 ML (12.] 6 mmol) of oxalyl chloride, and the resulting mixture was stirred at [0 C FOR 2 H. THEN 2, UL OF DIMETHYLFORMAMIDE] (DMF cat) was [ADDED, AND THE REACTION MIXTURE WAS STIRRED AT RT FOR 2 H, AND CONCENTRATED TO GIVE] [1.] 43 g [93%)] [OF DESIRED TETRAHYDRO-THIOPYRAN-4-CARBONYL] chloride as a brown oil as indicated by 1H NMR. The product was used without any further purification in the next step toward the preparation of 6-(4-Benzyloxy-phenyl)-7-(tetrahydro-thiopyran-4-yl)-3-(1H-tetrazol-5-yl)- pyrazolo[1,5-a]pyrimidine (below,entry 375)
85%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol for 3h; Ambient temperature;
50.7%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 20℃; for 3h;
2
A cold (ice water bath) solution of tetrahydro-2H-thiopyran-4-one (3.57 g, 30.7 mmol) and tosylmethylisocyanide (6.61 g, 33.8 mmol) in DME (125 ml) was treated with a suspension of potassium t-butoxide (6.93 g, 61.8 mmoles) in t-butyl alcohol (100 ml). The reaction mixture was stirred at room temperature for 3 hours, and then diluted with ether (250 ml). The mixture was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by short path distillation under high vacuum to give nitrile 1 as colorless oil (1.98 g, 50.7%). A solution of nitrile 1 (1.0 g, 7.9 mmoles) in ethanol (15 ml) was cooled in an ice bath. Hydrogen chloride gas was bubbled into the solution until saturation. The reaction mixture was then stirred at room temperature for 2 hours. Water (5 ml) was added and stirring was continued at room temperature for 2.5 hours, at 60° C. for 4 hours, and finely at room temperature for 12 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to afford ester 2 (539 mg, 40%). A solution of ester 2 (539 mg, 3.1 mmoles) and hydrazine monohydrate (3 ml, 61.9 mmoles) in MeOH (1 ml) was heated in a microwave oven at 160° C. for 10 min. Concentration of the reaction mixture under reduced pressure afforded hydrazide 3 (481 mg, 97%). A solution of 3 (481 mg, 3 mmoles) in acetone (2 ml) was heated in a microwave oven at 120° C. for 20 min. The acetone was removed under vacuum and the residue was dissolved in TFA (8 ml) and treated with triethylsilane (0.874 ml, 5.47 mmol) at 60° C., for 18 hours. The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product (302 mg, 55%).
26%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 20℃; for 3h; Inert atmosphere;
Tetrahydro-2H-thiopyran-4-carbonitrile (S4)
A mixtureof tetrahydro-4H-thiopyran-4-one (S3) (3.00 g, 25.8 mmol) and toluenesulfonylmethyl isocyanide (TosMIC, 5.55 g, 28.4 mmol) in dimethoxyethane (105 mL) was cooled to 0 °C and a solution of t-BuOK (5.79 g, 51.6 mmol) in t-BuOH (52 mL) was added to the reaction mixture in a dropwise manner. The mixture was then allowed to warm to room temperature and stirred for 3 h before dilution with Et2O. The organic layer was washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated. The residue was purified by column chromatography (AcOEt/hexane = 1/10 to 1/4) to afford tetrahydro-2H-thiopyran-4-carbonitrile (S4) (836 mg, 6.57 mmol, 26%) as a yellow oil.1H-NMR (400 MHz, CDCl3) δ: 2.89-2.79 (m, 3H), 2.60 (dd,J = 7.2, 3.9 Hz, 1H), 2.56 (dd, J = 7.7, 3.4 Hz, 1H), 2.19-2.05 (m, 4H). 13C-NMR (100 MHz, CDCl3) δ: 121.1, 30.0, 27.8, 25.8. IR (neat, cm-1): 2917, 2240, 1712, 1431. MS m/z: 127 ([M]+), 127 (100%). HRMS (EI): Calcd for C6H9NS 127.0456, found: 127.0467.
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 20℃; for 3h;
68
A cold (ice water bath) solution of tetrahydro-4H-thiopyran-4-one (5 g, 43 mmol) and tosylmethylisocyanide (9.24 g, 47.3 mmol) in DME (200 ml) was treated with a suspension of potassium tert-butoxide (9.66 g, 86 mmoles) in tert-butyl alcohol (200 ml). The reaction mixture was stirred at room temperature for 3 hours, and then diluted with ether. The mixture was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by short path distillation under high vacuum to give the nitrile as colorless oil (3.06 g). A portion of this material (2 g, 15.7 mmol) was dissolved in 1M borane/THF (80 ml, 80 mmol) and stirred at room temperature for 48 h. Excess borane was quenched by adding methanol (room temperature, 1 h), and the mixture was concentrated to dryness. The residue was dissolved in 4N HCl/dioxane, stirred at room temperature for 1 h and then concentrated under reduced pressure. The solid residue was triturated with ether and collected by suction filtration. A suspension of this material (2.35 g, 14 mmol) in THF (100 ml) was treated with 1N NaOH (14 ml, 14 mmol) at room temperature for 1/2 h. The THF was removed by distillation and the aqueous solution was saturated with NaCl then extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with acetic acid (0.48 ml, 8.5 mmol) to provide, after drying in a vacuum oven, 2-(tetrahydro-thiopyran-4-yl)-methylammonium acetate (1.30 g).
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 20℃; for 3h;
II.A
II: Toluene-4-sulfonic acid 1 ,1-dioxo-hexahvdro-1-thiopyran-4-ylmethyl ester intermediate Step A: Tetrahvdro-thiopyran-4-carbonitrile A mixture of tetrahydro-thiopyran-4-one (75 g, 646 mmol) and toluenesulfonyl- methyl isocyanide (138.6 g, 710 mmol) in dimethoxyethane (2.5 L) was cooled to 0 °C and a solution of potassium tert-butoxide (145 g, 1.29 mol) in tert-butanol (1.3 L) added dropwise. The mixture was then allowed to warm to room temperature and stirred for 3 h before dilution with diethylether (3 L), washing with sat'd sodium bicarbonate (2 x 1.5 L) and drying over magnesium sulfate. Removal of the solvent in vacuo gave tetrahydro-thiopyran-4-carbonitrile as a pale brown oil (88.3 g, 646 mmol).
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 20℃; for 3h;
1.13
A mixture of compound dihydro-2H-thiopyran-4(3H)-one (0.75 g, 6.46 mmol) and TosMIC (0.138 g, 7.11 mmol) in DME (25 mL) was cooled to 0° C. and a solution of potassium tert-butoxide (0.145 g, 12.9 mmol) in tert-butanol (13 mL) added dropwise. The mixture was then allowed to warm to room temperature and stirred for 3 h before dilution with DCM, washing with Sat. sodium bicarbonate and dried over Na2SO4. Removal of the solvent in vacuo to afford the compound tetrahydro-2H-thiopyran-4-carbonitrile (1 g, crude) as pale brown oil. (0456) 1H-NMR (CDCl3/400 MHz): δ 7.98-7.94 (m, 1H), 7.44-7.43 (d, J=1.6 Hz, 1H), 7.37-7.34 (m, 1H).
With ethanol; potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 0℃; for 12h;
1.1 g
With potassium <i>tert</i>-butylate In tetrahydrofuran; 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 20℃; for 3h; Inert atmosphere; Cooling with ice;
69.69.1 69.1 Tetrahydrothiopyran-4-carbonitrile
69.1 Tetrahydrothiopyran-4-carbonitrile A 150 mL single-necked flask was charged with potassium tert-butoxide (3.33 g), and anhydrous tetrahydrofuran (20 mL) and tert-butanol (10 mL) were added at the same time. Under nitrogen protection, a solution of tetrahydrothiopyran-4-one (1.5 g) and p-toluenesulfonylmethyl isocyanide (3.0 g) in ethylene glycol dimethyl ether (30 mL) were added dropwise under a condition of an ice bath. After the completion of the addition, the mixture was reacted at room temperature for 3 h. A sample was taken, and the spots of the raw materials disappeared and the reaction was complete as monitored by TLC. Methyl tert-butyl ether (200 mL) was added to the reaction system. The resulting mixture was washed twice with saturated sodium bicarbonate solution (50 mL * 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography, so as to obtain 1.1 g of tetrahydrothiopyran-4-carbonitrile.
10.1 Step 1:Preparation of tert-butyl 2-(tetrahydro-4H-thiopyran-4-ylidene)hydrazine-1-carboxylate
3.3 g of tetrahydro-4H-thiopyran-4-one (28.40 mmol) was dissolved in 60 ml of hexane, and 4.13 g of tert-butyl carbazite (31.24 mmol) was added, followed by stirring under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 6.5 g of the title compound (28.40 mmol) in 100% yield. Rf = 0.15 (hexane:ethyl acetate = 3:1, v/v) 1H NMR (500 MHz, DMSO-d6) δ 9.67 (br s, 1H), 2.73-2.76 (m, 2H), 2.65-2.68 (m, 2H), 2.60-2.63 (m, 2H), 2.47-2.50 (m, 2H), 1.43 (s, 9H)
100%
With sodium hydroxide In hexane for 3h; Reflux;
19.1 Step 1: Preparation of tert-butyl 2-(tetrahydro-4H-thiopyran-4-ylidene)hydrazine-1-carboxylate
3.3 g of tetrahydro-4H-thiopyran-4-one (28.40 mmol) was dissolved in 60 ml of hexane, and 4.13 g of tert-butyl carbazate (31.24 mmol) was added, followed by stirring under reflux for 3 hours. After completion of the reaction, the resultant was concentrated under reduced pressure to give 6.5 g of the title compound (28.40 mmol) in 100% yield.Rf= 0.15 (hexane: ethyl acetate = 3:1, v/v) 1H NMR (500 MHz, DMSO-d6) δ 9.67 (br s, 1H), 2.73-2.76 (m, 2H), 2.65-2.68 (m, 2H), 2.60-2.63 (m, 2H), 2.47-2.50 (m, 2H), 1.43 (s, 9H)
In methanol at 20℃; for 4h;
174
A mixture of tetrahydro-4H-thiopyran-4-one (5.0 g), tert-butyl carbazate (6.82 g) and methanol (50 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. The obtained white solid was extracted with diisopropyl ether to give the title compound (9.6 g) as crystals.1H-NMR (300 MHz, CDCl3) δ: 1.51 (9H, s), 2.56-2.63 (2H, m), 2.69-2.79 (4H, m), 2.80-2.88 (2H, m).
In methanol
16.1 Step 1: tert-butyl ((tetrahydro-4H-thiopyran-4-ylidene)amino)glycinate
To a stirred solution of tetrahydro-4H-thiopyran-4-one (5 g, 43.09 mmol) in methanol (50 mL), tert- butyl hydrazinecarboxylate (6.20 g, 46.97 mmol) was added at RT and the reaction mixture was stirred overnight at same temperature. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under vacuum. To the resulting mixture, water (5 mL) was added and was extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2S04 and concentrated under vacuum. The resulting crude material was used in the next step as such without any further purification. Yield: 96% (9.5 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1 H), 2.75 (t, J = 8.1 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 7.4 Hz, 2H), 1.43 (s, 9H). LCMS: (Method A) 175.1 (M-t-Bu+H), Rt. 2.1 min, 35.3% (Max).
With toluene-4-sulfonic acid; In ethyl acetate; toluene;
(a) To a solution of 15 g of 4H-tetrahydrothiopyran-4-one in 500 mL of toluene, 25 g of <strong>[6296-99-7]diethyl aminomethylenemalonate</strong> and 0.8 of p-toluenesulfonic acid are added. The resultant mixture is refluxed for 48 hours with a water separator under nitrogen atmosphere, then evaporated to dryness. The dried residue is purified by flash chromatography on a silica gel column, using toluene and 5percent ethyl acetate in toluene as eluents to obtain the desired product, diethyl N-(2H-5,6-dihydrothiopyran-4-yl)aminomethylenemalonate.
With toluene-4-sulfonic acid; In ethyl acetate; toluene;
(a) To a solution of 15 g of 4H-tetrahydrothiopyran-4-one in 500 mL of toluene, 25 g of <strong>[6296-99-7]diethyl aminomethylenemalonate</strong> and 0.8 g of p-toluenesulfonic acid are added. The resultant mixture is refluxed for 48 hours with a water separator under nitrogen atmosphere, then evaporated to dryness. The dried residue is purified by flash chromatography on a silica gel column, using toluene and 5percent ethyl acetate in toluene as eluents to obtain the desired product, diethyl N-(2H-5,6-dihydrothiopyran-4-yl)-aminomethylenemalonate.
With toluene-4-sulfonic acid; In ethyl acetate; toluene;
(a) To a solution of 15 g of 4H-tetrahydrothiopyran-4-one in 500 mL of toluene, 25 g of <strong>[6296-99-7]diethyl aminomethylenemalonate</strong> and 0.8 g of p-toluenesulfonic acid are added. The resultant mixture is refluxed for 48 hours with a water separator under nitrogen atmosphere, then evaporated to dryness. The dried residue is purified by flash chromatography on a silica gel column, using toluene and 5percent ethyl acetate in toluene as eluents to obtain the desired product, diethyl N-(2H-5,6-dihydrothiopyran-4-yl)aminomethylenemalonate.
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
96%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃;
123.1 Example 123; 2-[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide; Step 1
Ethyltetrahydro-4H-thiopyran-4-ylideneacetate was prepared from tetrahydro thiopyran-4-one (10.0 g 86 mmol) and diethylphosphonoethylacetate (21.2 g, 95 mmol) in DMF/ K2CO3 at 80 °C. Colorless oil, Yield. 15.4 g, (96%), MS: 187 (M+H)+
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 20℃; for 1.33333h; Inert atmosphere;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
With sodium hydride Inert atmosphere;
1 Step 1 Preparation of ethyl 2-(dihydro- -thiopyran-4(3H)-ylidene)acetate
Step 1 Preparation of ethyl 2-(dihydro- -thiopyran-4(3H)-ylidene)acetate The title intermediate was prepared in accordance with that reported by Lammek, Derdowska and Rekowski in Polish Journal of Chemistry 64, 351 (1990).
5-(Pyridine-2-carbonyl)-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole-8-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: pyridine-2-carbonyl chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
(4-(dimethylamino)phenyl)-(6-methoxy-1,4-dihydro-2H-3-thia-9-aza-fluoren-9-yl)-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-(dimethylamino)benzoyl chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
47%
Stage #1: 4-methoxyphenylhydrazine hydrochloride With aldehyde resin; triethylamine In dichloromethane at 45℃;
Stage #2: 4-(dimethylamino)benzoyl chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
5-(Furan-2-carbonyl)-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole-8-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 2-furancarbonyl chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
9-(4-chloro-benzoyl)-1,2,4,9-tetrahydro-3-thia-9-aza-fluorene-6-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
5-(Biphenyl-4-carbonyl)-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole-8-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.5%
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃;
Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
3-[(1′-hydroxy-1′-(3″-bromophenyl))methyl]-tetrahydrothiopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: Tetrahydrothiopyran-4-one With (R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamide; acetic acid In dichloromethane at -20℃; for 0.5h;
Stage #2: m-bromobenzoic aldehyde In dichloromethane at -20℃; for 30h; stereoselective reaction;
3-[(1′-Hydroxy-1′-(3″-bromophenyl)methyl]-tetrahydrothiopyran-4-one6b 6i (Table 5, entry 9)
General procedure: A mixture of catalyst 1e (10mg, 0.025mmol), HOAc (1.5mg, 0.025mmol) and ketone (1.25mmol) in DCM (0.5mL) was stirred at -20°C for 30min. Next, the aldehyde (0.25mmol) was added and the reaction mixture was stirred at -20°C. The reaction was monitored by TLC, then quenched with 3mL of saturated NH4Cl solution, extracted with ethyl acetate (3×5mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure. Purification by flash chromatography afforded the corresponding products. Yield: 87% (65.5mg), [α]D20=+19.2 (c 0.5, CHCl3). The ee was determined by HPLC (Chiralpak AS-H column, hexane/i-PrOH 90:10, flow rate 1.0mL/min, λ=254nm, tR (major)=22.8min, tR (minor)=35.2min). Data for the major anti isomer: 1H NMR (300MHz, CDCl3): δ=7.50 (t, J=7.7Hz, 1H), 7.43 (d, J=6.8Hz, 1H), 7.23-7.19 (m, 2H), 4.90 (d, J=10.5Hz, 1H), 3.51 (d, J=3.0Hz, 1H), 3.01-2.91 (m, 3H), 2.83-2.71 (m, 2H), 2.61-2.57 (m, 1H), 2.53-2.48 (m, 1H) ppm. 13C NMR (75MHz, CDCl3): δ=212.3, 143.3, 132.1, 130.8, 130.6, 126.3, 123.5, 74.0, 60.2, 45.3, 33.5, 31.5ppm.
69%
With <i>L</i>-proline In water; N,N-dimethyl-formamide at 20℃; for 96h;
(2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)-(4-chlorophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) at 65℃; for 2h;
5.a a) Preparation of 12
To 4-chlorobenzoylacetonitrile (2,3. 6 g, 20 mmol) and sulfur (0.65 g) in DMF (6 mL), triethylamine (2.0 mL) is added under stirring. To this solution tetrahydrothiopyran-4-one (11,2. 32 g, 20 mmol) is added dropwise. The mixture is heated to [65°C] for 2 hours and it is poured into water (60 mL), which is extracted with diethyl ether (50 mL). The ethereal solution is dried with sodium sulfate and concentrated to give the desired compound as a brown solid (5.07 g, 82% yield). Physical characteristics: MS [(ES+)] for m/z [310.]
(S)-3-((R)-hydroxy-(4-nitrophenyl)methyl)tetrahydrothiopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With (S)-2-amino-N-(pyrene-1-yl)-3,3 dimethylbutanamide In water at 20℃; for 48h; Inert atmosphere; stereoselective reaction;
4.3. General procedure for the asymmetric crossed aldol reaction of aromatic aldehydes with acyclic or cyclic ketones
General procedure: To a solution of catalysts 4a-f (0.125 mmol, 25 mol%) in H2O (0.5 mL) was added cyclohexanones (5.0 mmol) and the aldehydes (0.5 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for an appropriate time until the reaction was completed, as monitored by TLC. Afterward, the mixture was extracted with DCM (3 5 mL), and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under a reduced pressure. The residue was purified by flash column chromatography on SiO2 (n-hexane/CH3CO2Et 4:1) to afford the corresponding aldol products [6].
95%
With C29H39N3O3S In chloroform at 20℃; for 62h; optical yield given as %ee; enantioselective reaction;
92%
With (1S)-2-benzyl-3-phenyl-1-(pyridin-2-yl)propan-1-amine; 2,4-dinitrobenzenesulfonic acid In water at 45℃; for 16h; enantioselective reaction;
92%
Stage #1: Tetrahydrothiopyran-4-one With (R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamide; acetic acid In dichloromethane at -20℃; for 0.5h;
Stage #2: 4-nitrobenzaldehdye In dichloromethane at -20℃; for 18h; stereoselective reaction;
3-[(1′-Hydroxy-1′-(4″-nitrophenyl))methyl]-tetrahydrothiopyran-4-one1b 6c (Table 5, entry 3)
General procedure: A mixture of catalyst 1e (10mg, 0.025mmol), HOAc (1.5mg, 0.025mmol) and ketone (1.25mmol) in DCM (0.5mL) was stirred at -20°C for 30min. Next, the aldehyde (0.25mmol) was added and the reaction mixture was stirred at -20°C. The reaction was monitored by TLC, then quenched with 3mL of saturated NH4Cl solution, extracted with ethyl acetate (3×5mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure. Purification by flash chromatography afforded the corresponding products. Yield: 92% (61.5mg), [α]D20=+17.6 (c 0.5, CHCl3). The ee was determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 85:15, flow rate 1.0mL/min, λ=254nm, tR (minor)=27.5min, tR (major)=48.8min). Data for the major anti isomer: 1H NMR (300MHz, CDCl3): δ=8.24 (d, J=6.5Hz, 2H), 7.55 (d, J=6.5Hz, 2H), 5.04 (d, J=6.0Hz, 1H), 3.70 (br s, 1H), 3.05-2.94 (m, 3H), 2.88-2.75 (m, 2H), 2.71-2.65 (m, 1H), 2.54-2.49 (m, 1H) ppm. 13C NMR (75MHz, CDCl3): δ=211.4, 147.8, 147.6, 127.8, 123.9, 73.2, 59.5, 44.8, 32.87, 30.9ppm.
90%
With (S)-N-{(R)-1-[3-(3,5-bis(trifluoromethyl)phenyl)ureido]-2-phenylethyl}pyrrolidine-2-carboxamide; 4-nitro-benzoic acid In toluene at -20℃; for 72h; enantioselective reaction;
4.3. General procedure for the aldol reaction
General procedure: To a stirred solution of catalyst (0.014 mmol) in toluene (1.0 mL), 4-nitrobenzoic acid (2.3 mg, 0.014 mmol) was added. The reaction mixture was cooled to -20 °C. The aldehyde (0.140 mmol) was added, followed by the ketone (1.40 mmol). The reaction mixture was left stirring at -20 °C for 24-120 h. The solvent was evaporated and the crude product was purified using column chromatography eluting with the appropriate mixture of petroleum ether (40-60 °C)/EtOAc to afford the desired product.
86%
With (S)-di-tert-butyl 2-{3-[(1S,2S)-1,2-diphenyl-2-[(S)-(pyrrolidine-2-carboxamido)]ethyl]thioureido}succinate; 4-nitro-benzoic acid In toluene at -20℃; for 48h; optical yield given as %ee; enantioselective reaction;
83%
Stage #1: Tetrahydrothiopyran-4-one With (S)-N-(1,3-dioxoisoindolin-2-yl)pyrrolidine-2-carboxamide In water at 20℃; for 0.166667h;
Stage #2: 4-nitrobenzaldehdye In water for 18h; enantioselective reaction;
General procedure for the aldol reaction of ketones to aldehydes
General procedure: To a mixture of catalyst 1 (15 mol %) and cyclohexanone(4 mmol) was added H2O (5 mol %) and stirred for 10 min. at roomtemperature. Next, the aldehyde (1 mmol) was added to theresulting mixture and stirred for an appropriate time (Table 3) atroom temperature. After completion of the reaction (monitoredby TLC), the mixture was purified by silica-gel column chromatography chromatographyto afford the desired product. The relative and absoluteconfigurations of the products were determined by comparisonof the 1H NMR, 13C NMR, and specific rotation values with thosereported in the literature
82%
In dichloromethane at -15℃;
82%
Stage #1: Tetrahydrothiopyran-4-one With silver hexafluoroantimonate; (S)-2-amino-3-methyl-N-(6-pivalamidopyridin-2-yl)butanamide; copper dichloride In tetrahydrofuran at 20℃; for 4h;
Stage #2: 4-nitrobenzaldehdye In tetrahydrofuran at 20℃; optical yield given as %ee; enantioselective reaction;
64%
Stage #1: Tetrahydrothiopyran-4-one With (S)-N-[2-(4-methylbenzamido)ethyl]pyrrolidine-2-carboxamide; acetic acid In ethanol; water at 0℃; for 0.25h;
Stage #2: 4-nitrobenzaldehdye In ethanol; water at 1℃; for 72h; optical yield given as %ee; enantioselective reaction;
60%
With formic acid In chloroform; water at 20℃; for 48h; optical yield given as %ee; stereoselective reaction;
41%
Stage #1: Tetrahydrothiopyran-4-one With (S)-N-(2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]-2-yl)pyrrolidine-2-carboxamide; trifluoroacetic acid In water at 20℃; for 0.5h;
Stage #2: 4-nitrobenzaldehdye In water at 20℃; for 72h; stereoselective reaction;
Typical procedure for enantioselective aldol reaction in water
General procedure: A mixture of catalyst 5a1 (4.3 mg, 0.01 mmol) and ketone (0.1 mmol) in 0.5 mL of water was stirredfor 30 min at room temperature. The corresponding aldehyde (0.1 mmol) was added and the mixturewas stirred for 12-54 h. The mixture was extracted with CH2Cl2 (5 mL × 2). The organic layers weredried over anhydrous Na2SO4 and concentrated in vacuo. The aldol product was obtained throughflash chromatography on silica gel (petroleum / ethyl acetate = 4 / 1). The dr and ee values weredetermined by chiral HPLC analysis.
at 20℃; for 168h;
With (4R)-4-((5-(4-(1-butylpentyl)pyridinium-1-yl)pentanoyl)oxy)-L-proline hexafluorophosphate In water at 20℃; for 20h; enantioselective reaction;
Stage #1: tetrahydro-4H-thiopyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at 20℃; for 4h;
14 2-(3,6-Dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
To a solution of 1.3 ml (9.0 mmol) diisoproylamine in 5 ml dry THF were added 5.7 ml (9.0 mmol) of a 1.6 M solution of n-butyllithium in hexanes at -78° C. After completed addition the mixture was allowed to warm to 0° C. To this solution was added dropwise a solution of 1.0 g (8.6 mmol) tetrahydro-4H-thiopyranone in 5 ml THF at -78° C. After 30 min a solution of 3.1 g (8.8 mmol) N-phenyl-bis(trifluoromethanesulfonimid) in 8 ml THF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 4 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography to give 2.1 g (98%) trifluoro-methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester.
85%
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
69%
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -70℃; for 0.333333h;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -70 - 20℃;
11 REFERENCE EXAMPLE 11; 2,3dihydro-4-trifluoromethylsulfonyloxy-(6H)-thiopyran
To a stirred solution of tetrahydrothiopyran-4-one (5.8 g, 50 mmol) in tetrahydrofuran (50 ml) at -70° C. under argon was added LDA (1.92M in THF) (26 ml, 50 mmol). The solution was stirred for 20 minutes, then a solution of N-phenyl-bis(trifluoromethane-sulfonimide) (17.85 g, 50 mmol) in THF (30 ml) was slowly added. The solution was stirred overnight with warming to ambient temperature. The solution was evaporated to dryness and purified by alumina MPLC (using a mixture of 3% ethyl acetate/hexane as eluant) to afford the title product. Yield=8.5 g (69%). NMR (250 MHz, CDCl3) δ: 2.60 (m, 2H), 2.85 (m, 2H), 3.30 (m, 2H), 5.95 (m, 1H).
65%
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;
The synthesis of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate
To a solution of LDA (6.5 mL, 13 mmol, 1.5 eq, 2M in THF) in THF (10 mL) at -78 °C under N2was added dihydro-2H-thiopyran-4(3H)-one (1 g, 8.62 mmol) in THF (10 mL) dropwise over 20 minutes and stirred at -78 °C for 20 minutes. To the solution was added N- phenylbis(trifluoromethanesulfonimide) (3.39 g, 9.5 mmol, 1.1 eq) and allowed to warm to rt and stirred for 16 h. The reaction was diluted with diethyl ether (80 mL), washed with NaOH (1M, 20 mL), water (30 mL), and brine (30 mL), dried (Na2SO4) and concentrated in vacuo. The crude was purified by column chromatography (EtOAc/Petroleum ether 1/20) to give the title compound (1.4 g, yield 65%).1H NMR (400 MHz, CDCl3) : 6.01-5.98 (m, 1H), 3.30-3.28 (m, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.64-2.59 (m, 2H).
65%
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 2.08333h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at 20℃; Inert atmosphere;
61%
With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 16h;
55%
Stage #1: tetrahydro-4H-thiopyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran at -78℃; for 3h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 0℃; for 16h; Inert atmosphere;
II.3.11.4
Diiopropylamine (0.70 ml, 4.7 mmol, 1.1 equiv) was diluted in 15 ml THF and cooled to -78 °C. A solution of 2.5 M nbutyllithium (0.50 ml, 4.7 mmol, 1.1 equiv) in hexanes was added dropwise at -78 °C. The reaction mixture was stirred for 30 min. After the reaction time, an 80 mM solution of tetrahydro-4H-thiopyran-4-one (0.50 g, 4.3 mmol, 1 equiv) was added dropwise and the reaction mixture was allowed to stir for an additional 3 h at -78 °C. After the reaction time a 90 mM solution of N-phenyl- bis(trifluoromethanesulfonimide) (1.7 g, 4.7 mmol, 1.1 equiv) was added dropwise. The reaction was gradually warmed to 0 °C with stirring for 16 h. The reaction was quenched with the slow addition of water and extracted three times with diethyl ether. The organic layers were combined and washed with water, brine, dried ( a2SC>4) , filtered, then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (10% ethyl acetate/hexanes) to afford 3.62 as a yellow oil (590 mg, 55% yield). Spectral data correspond to that reported.28 NMR (400 MHz, CDCI3): δ 6.01 (app. s, 1 H), 3,31 - 3.29 (m, 2 H), 2.88 - 2.85 (m, 2 H), 2.64 - 2.60 (m, 2 H).
38%
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78 - 20℃; for 0.5h;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 0.5h;
35.a
A solution of tetrahydro-thiopyran-4-one (1.00 g, 8.61 mmol) in 10 ml of THF was added to a solution of LDA (2.0 M, 4.52 ml, 9.04 mmol) in 20 ml of THF at- 78 °C under Ar. The mixture was warmed to RT and stirred for 0.5 h, then cooled to - 78 "C again. A solution of iV-phenyltrifluoromethanesulfonimide (3.42 g, 9.47 mmol) in 10 ml of THF was added. The resulting mixture was warmed to RT and stirred for 0.5 h under Ar. Treated with 200 ml of EtOAc, the mixture was washed with H2O (3 x 50 mL), brine (50 roL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (hexane-3 % EtOAc/hexane) gave 810 mg (38 %) of the title compound as a colorless oil. 1H- NMR (CDCl3; 400 MHz): δ 6.01 (m, IH), 3.30 (m, 2H), 2.86 (dd, 2H, J = 5.7, 5.7 Hz), 2.58-2.64 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C6H7F3O3S2, 249.0 (M+H), found 249.3.
With lithium dipropan-2-ylazanide In tetrahydrofuran
Stage #1: tetrahydro-4H-thiopyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.416667h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at 20℃; for 18h;
To a stirred solution of diisopropylamine (4.86 ml, 3.45 g, 34.1 mmol) in anhydrous THF (48.0 ml) at 0°C under nitrogen was added a solution of 2.5M n-butyllithium in hexanes (13.63 ml, 34.1 mmol), dropwise, over 5 minutes. The mixture was cooled to -78° and a solution of dihydro-2H- thiopyran-4(3H)-one (3.77 g, 32.4 mmol) in anhydrous THF (36.0 ml) was added dropwise over 10 minutes. After stirring at -78°C for 15 minutes, 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (12.75 g, 35.7 mmol) was added as a solid in 5 portions over 10 minutes. The dry-ice bath was removed and the mixture was allowed to stir at room temperature for 18 hours. Then the mixture was diluted with diethyl ether (200 ml), washed with aqueous IN NaOH (150 ml), washed with brine (100 ml), then dried over sodium sulfate. The organic layer was concentrated under reduced pressure and dried under high vacuum for 18 hours to provide the title compound as a red oil. XH NMR (400 MHz, CDC13) δ: 5.95 (d, J = 8.0 Hz, 1 H), 3.26 (m, 2 H), 2.82 (m, 2 H), 2.57 (m, 2 H).
Stage #1: tetrahydro-4H-thiopyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.416667h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at -78 - 20℃; for 18h;
3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate
To a stirred solution of diisopropylamine (4.86 ml, 3.45 g, 34.1 mmol) in anhydrous THF (48.0 ml) at 0° C. under nitrogen was added a solution of 2.5M n-butyllithium in hexanes (13.63 ml, 34.1 mmol), dropwise, over 5 minutes. The mixture was cooled to -78° and a solution of dihydro-2H-thiopyran-4(3H)-one (3.77 g, 32.4 mmol) in anhydrous THF (36.0 ml) was added dropwise over 10 minutes. After stirring at -78° C. for 15 minutes, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (12.75 g, 35.7 mmol) was added as a solid in 5 portions over 10 minutes. The dry-ice bath was removed and the mixture was allowed to stir at room temperature for 18 hours. The mixture was diluted with diethyl ether (200 ml), washed with aqueous 1N NaOH (150 ml), washed with brine (100 ml), then dried over sodium sulfate. The organic layer was concentrated under reduced pressure and dried under high vacuum for 18 hours to provide the title compound as a red oil. 1H NMR (400 MHz, CDCl3) δ: 5.95 (d, J=8.0 Hz, 1H), 3.26 (m, 2H), 2.82 (m, 2H), 2.57 (m, 2H).
2.5 g
Stage #1: tetrahydro-4H-thiopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78 - 20℃; for 0.5h; Inert atmosphere;
Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 2℃; for 0.5h; Inert atmosphere;
I.1 Step 1: Preparation of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (Intermediate 9-a):
[0232] To a solution of LDA (8.5 mL,17.0 mmol,1.10 equiv) in THF (20 mL) at -78°C was added a solution of thian-4-one (1.8 g,15.493 mmol,1 equiv) in THF (5mL) dropwise over a period of lOmin under argon atmosphere. After stirring at r.t. for 0.5 h under argon atmosphere, the mixture at -78 °C was added a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (6.09 g,17.047 mmol,1.10 equiv) in THF(10 mL) dropwise over a period of lOmin. The resulting mixture was stirred at r.t. for 0.5 h under argon atmosphere, quenched with water (100 mL) at 0 °C and extracted with EtOAc (200mL) twice. The combined organic layers were washed twice with brine (lOOmL), dried over anhydrous NaiSCL, concentrated under reduced pressure, purified by silica gel column chromatography, eluted with PE/EtOAc (99:1) to afford 2.5 g of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate as a yellow oil. LRMS (ES) m/z 249[M+H]
3,4-dihydro-1H-thiopyrano[4,3-b]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With Poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylic acid) In neat (no solvent) at 110℃; for 0.666667h; Green chemistry;
General Procedure for the Synthesis of Quinolines
General procedure: To mixture of a-methylene carbonyl compounds (1.2 mmol) and o-aminoaryl ketones oraldehydes (1 mmol) was added cross-linked poly(AMPS-co-AA) (0.06 g) [for solid substrates0.1 ml of ethanol was added] and the mixture was heated on an oil bath at 110Cfor the time show in Table 2. Upon completion of the reaction as indicated by TLC (hexane:ethyl acetate, 8:2), the appropriate amounts of hot EtOH (96%, 5 ml) was added andthe mixture stirred for 10 min. After separation of the catalyst by filtration, the filtratewas concentrated in vacuum to remove the ethanol. The residue was washed with coldwater and crystallized from hot ethanol (3 ml) to afford the pure products characterizedby comparison between their mp, IR and NMR data with those of authentic samples.
82%
With sodium ethanolate In ethanol for 2h; Heating;
6,9-dihydro-7H-1,3-dioxa-8-thia-5-aza-cyclopenta[b]anthracene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium ethanolate In ethanol for 2h; Heating;
92%
With Poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylic acid) In neat (no solvent) at 110℃; for 0.666667h; Green chemistry;
General Procedure for the Synthesis of Quinolines
General procedure: To mixture of a-methylene carbonyl compounds (1.2 mmol) and o-aminoaryl ketones oraldehydes (1 mmol) was added cross-linked poly(AMPS-co-AA) (0.06 g) [for solid substrates0.1 ml of ethanol was added] and the mixture was heated on an oil bath at 110Cfor the time show in Table 2. Upon completion of the reaction as indicated by TLC (hexane:ethyl acetate, 8:2), the appropriate amounts of hot EtOH (96%, 5 ml) was added andthe mixture stirred for 10 min. After separation of the catalyst by filtration, the filtratewas concentrated in vacuum to remove the ethanol. The residue was washed with coldwater and crystallized from hot ethanol (3 ml) to afford the pure products characterizedby comparison between their mp, IR and NMR data with those of authentic samples.
With sulfur; triethylamine; In DMF (N,N-dimethyl-formamide); for 16h;
To <strong>[21667-62-9]3-chlorobenzoylacetonitrile</strong> (24,360 mg, 2 mmol) and sulfur (76 mg) in [DUT] [(4] mL), triethylamine (0. [25ML)] is added under stirring. To this solution [TETRAHYDROTHIOPYRAN-4-ONE] (11,232 mg, 2 mmol) is added dropwise. The mixture is stirred for 16 hours and it is poured into water (30 [ML),] which is extracted with diethyl ether (30 mL). The ethereal solution is dried with sodium sulfate and concentrated to give the desired compound as an orange solid (373 mg, [78%).] Physical characteristics: MS [(ES+)] for [M/Z] 294,296 (M + H).
Stage 13a: 4-(3-hydroxypiperidino)-tetrahydro-4H-thiopyran-4-carbonitrile <strong>[64051-79-2]3-hydroxy-piperidine hydrochloride</strong> (6.5 g, 47.3 mmoles) in 30 ml of water is introduced into a 100 ml two-necked flask. Potassium cyanide (1.85 g, 35.5 mmoles) is added and tetrahydro-4H-thiopyran-4-one (2.7 g, 23.6 mmoles) is introduced dropwise. The pH of the medium is adjusted to 11 with a few drops of soda (10%). After 24 hours under agitation at ambient temperature, extraction with ether (3*80 ml) is carried out, the combined organic phases are washed with water (100 ml), dried over Na2SO4, filtered and concentrated to dryness. In this way, a colourless oil is obtained (3.9 g, 17.2 mmoles). NMR 13C: 117.87 (CN); 66.25 (Cbeta); 59.19 (C4); 53.20; 45.96 (Calpha'); 33.94 (C3-C5); 31.79 (Cgamma); 22.70 (C2-C6); 21.90 ((Cbeta').
With oxone; sodium hydrogencarbonate; In acetonitrile;
1,1-Dioxotetrahydrothiopyran-4-one. To a solution of tetrahydrothiopyran-4-one (400 mg, 3.45 mmol) in acetonitrile (5 ml) was added aqueous Na2EDTA (3 ml, 0.0004 M). A mixture of oxone (6.30 g, 10.30 mmol) and sodium bicarbonate (2.70, 32 mmol) was added in small portions to the above solution over a period of 20 min. The slurry was stirred for another 1 h before being quenched with methylene chloride. The organic solvent was decanted and the solid residue was triturated with ethyl acetate (3*25 ml). The combined organic layers were dried over sodium sulfate and concentrated to give the desired ketone (0.37 g, 73%) as a colorless solid. mp 170-172 C. (lit. 168-170 C.); 1H NMR (500 MHz, CDCl3) 2.99 (t, J=6.8 Hz, 4H), 3.39 (t, J=6.8 Hz, 4H). Ref: Yang, D.; Yip, Y.-C.; Jiao, G.-S.; Wong, M.-K. Design of Efficient Ketone Catalysts for Epoxidation by Using the Field Effect. J. Org. Chem, 1998, 63, 8952-8956.
10-amino-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide;Zinc chloride; In water;
EXAMPLE 6 9-Amino-2-thia-1,2,3,4-tetrahydroacridine Anthranilonitrile (2.6 g, 21.5 mmole), tetrahydrothiopyran-4-one (5.0 g, 43 mmole) and zinc chloride (2.54 g, 21.5 mmole) were combined and heated to 120 C. for 20 minutes. The reaction mixture was cooled and the solid residue was filtered using ethyl ether (100 ml). The resulting orange solid (5.2 g) was placed in a beaker containing a saturated solution of <strong>[60-00-4]EDTA</strong> (ethylene diamine tetracetic acid) in water (125 ml) and the pH was adjusted to 13 with the help of 12% NaOH. The aqueous phase was then extracted with methylene chloride (4*50 ml) which was washed with water (2*70 ml) and dried (MgSO4). Removal of methylene chloride under vacuum afforded a yellow paste (2.0 g) which was triturated with ether and filtered to afford a light yellow solid (1.36 g, 29%, m.p. 205 C. dec.). 1 H-NMR (CDCl3, 300 MHz, delta): 2H, 5, 3.0 ppm (J=6.0 Hz); 2H, t, 3.35 ppm (J=6.0 Hz); 2H, s, 3.72 ppm; 2H, bs, 4.69 ppm; 1H, t, 7.4 (J=8.0 Hz); 1H, t, 7.6 (J=8.0 Hz); 1H, d, 7.69 (J=8.0 Hz); 1H, d, 7.88 (J=8.0 Hz). HRMS: Calculated--216.0719; Found--216.0688. TLC: (TLC plate pretreated with 2% triethylamine in hexane; eluant:5% methanol in methylenechloride) Rf =0.23.
With N,N-Dimethyltrimethylsilylamine; magnesium bromide ethyl etherate at 20℃; for 3h; Inert atmosphere; neat (no solvent);
80%
With N,N-Dimethyltrimethylsilylamine; iron oxide In neat (no solvent) at 20℃; for 4h; Green chemistry;
Synthesis of α,β-Unsaturated Heterocyclic and Cyclic Ketones: General Procedure
General procedure: A mixture of an aldehyde (4 mmol), an amine (2 mmol), and nanosized magnetite (7 mol% with respect to aldehyde) was stirred at room temperature. An appropriate ketone (4 mmol) was then added almost immediately to the mixture. The progress of reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, magnetite was removed easily by dropping a bar magnet to the reaction vessel. The product was isolated and purified by column chromatography using hexane-ethyl acetate (30:70) as solvent system (Table 2).
48.5%
With potassium hydroxide In water at 20 - 65℃; for 26h;
12
EXAMPLE 12; (7Z)-[1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-1,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazol-3-yl]-piperidin-1-yl-methanone (Cpd 55); Aqueous KOH (0.3 g in 250 mL water) was added to 4-fluoro-benzaldehyde Compound 12a (4.82 g, 38.9 mmol) and tetrahydro-4H-thiopyran-4-one Compound 1a (4.5 g, 38.8 mmol), and the mixture was heated to about 65° C. for 24 hrs, then cooled to r.t. and stirred for 2 hrs. The mixture was acidified to pH 7 with 1.0N HCl (2 mL) and diluted with EtOAc (200 mL). The organic layer was separated, washed with brine and dried with anhydrous Na2SO4, then filtered and concentrated to provide a crude product, which was purified by silica gel column (eluted with 8% EtOAc in hexane) to give 3-(4-fluoro-benzylidene)-tetrahydro-4H-thiopyran-4-one Compound 12b (4.8 g, 48.5%) as a white solid.
10-amino-3,4-dihydro-7-methyl-1H-thiopyrano[4,3-b]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In nitrobenzene;
EXAMPLE 5 10-amino-3,4-dihydro-7-methyl-1H-thiopyrano[4,3-b]quinoline A mixture of 4-methylanthranilonitrile (4.46 g) and freshly fused zinc (6.8 g) in 20 ml of nitrobenzene was heated at 50 C. for 1 hour. To this was added tetrahydrothiopyran-4-one (5.1 g) and the mixture was heated to 130 C. for 1.5 hours. After cooling, the zinc complex was filtered, rinsed with ethyl ether and partitioned between 2-butanone (MEK) and NH4 OH. The aqueous phase was extracted with MEK and the organics were washed with water and dried (saturated NaCl, MgSO4). This was concentrated to give 4.76 g of an off-white powder, m.p. 239-245 C. d., which was recrystallized from ethyl acetate to give 2.95 g of an off-white powder, m.p. 243-246 C. d.
10-amino-3,4-dihydro-7-trifluoromethyl-1H-thiopyrano[4,3-b]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Zinc chloride; In nitrobenzene;
EXAMPLE 7 10-amino-3,4-dihydro-7-trifluoromethyl-1H-thiopyrano[4,3-b]quinoline To a solution of <strong>[1483-54-1]4-trifluoromethyl anthranilonitrile</strong> (12.2 g) in 50 ml of nitrobenzene was added freshly fused and pulverized zinc chloride (13.4 g). This was stirred at 50 C. for 1.5 hours after which was added tetrahydrothiopyran-4-one (9.9 g). The reaction mixture was stirred at 130 C. for 2 hours and allowed to cool, and the resulting complex was filtered and rinsed with ethyl ether. The solid was partitioned between 2-butanone (MEK) and NH4 OH and the aqueous phase was extracted with MEK (2x). The organics were washed with water, dried (saturated NaCl, MgSO4) and concentrated to give 10.2 g of a yellow powder m.p. 253-259 C. d. A 3.7 g portion was recrystallized from methanol/water to give 3.0 g of an off-white powder, m.p. 258-262 C. d.
With sodium carbonate; In hydrogenchloride; water;
Preparation 34 1,4-Thiazepane To a stirred solution of tetrahydrothiopyran-4-one (4.74 g) in conc. HCl (20.7 mL) cooled to 0 C. is added portion-wise sodium azide (3.98 g, 61.2 mmol). After addition is complete, the reaction is stirred at room temperature for 4 h. Solid sodium carbonate is then added portion-wise until the solution was slightly alkaline (pH=9). Water is added during addition of sodium carbonate to dissolve the salt. The alkaline solution is diluted with CHCl3 (125 mL), and the phases are separated. The aqueous layer is extracted with CHCl3 (2*75 mL). The combined organic layers are dried (Na2SO4), filtered, and concentrated. The crude product is recrystallized from CH2Cl2/hexanes to afford 4.30 g (81%) of 1,4-thiazepan-5-one as a white solid. Physical characteristics are as follows: Mp 114-116 C.; 1H NMR (300 MHz, CDCl3) delta6.41, 3.66, 2.96, 2.76.
A solution of 4-bromo-N-Boc aniline (6.0 g, 22.1 mmol) in THF (100 ml) at -78 0C under nitrogen was added n-butyllithium (1.6 M in hexane, 34.4 ml, 55 mmol) dropwise over 20 min. The resulting yellow solution was stirred at -78 0C for 30 min and was then treated with a solution of tetrahydrothiopyran-4-one (2.82 g, 24.3 mmol) in THF (25 mi_). The reaction mixture was stirred for 4 hrs, during which the reaction temperature was allowed to rise to 0 0C. The eraction was quenched with saturated aqueous ammonium chloride (25 ml). The mixture was then diluted with water (25 ml) and Et2O (25 ml). The layers were separated, and the organic phase was washed with brine (10 ml), dried over Na2SO4, and concentrated in vacuo. The residue was flushed through a plug of silica gel with EtOAc: Heptane (1:1) to afford tert-butyl 4-(4-hydroxy-tetrahydro-2H-thiopyran-4-yl)phenylcarbamate (6.2 gram, 92%) as a white solid. 1H NMR (400 MHz1 d-CDCI3) delta 7.30 - 7.41 (m, 4 H) 6.44 (br. s., 1 H) 3.13 - 3.24 (m, 2 H) 2.41 - 2.50 (m, 2 H) 2.09 - 2.19 (m, 2 H) 1.95 - 2.03 (m, 2 H) 1.50 (s, 9 H)
3-[(1′-hydroxy-1′-(4″-cyanophenyl))methyl]-tetrahydrothiopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: Tetrahydrothiopyran-4-one With (R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamide; acetic acid In dichloromethane at -20℃; for 0.5h;
Stage #2: 4-cyanobenzaldehyde In dichloromethane at -20℃; for 18h; stereoselective reaction;
3-[(1′-Hydroxy-1′-(4″-cyanophenyl))methyl]-tetrahydrothiopyran-4-one1b 6d (Table 5, entry 4,)
General procedure: A mixture of catalyst 1e (10mg, 0.025mmol), HOAc (1.5mg, 0.025mmol) and ketone (1.25mmol) in DCM (0.5mL) was stirred at -20°C for 30min. Next, the aldehyde (0.25mmol) was added and the reaction mixture was stirred at -20°C. The reaction was monitored by TLC, then quenched with 3mL of saturated NH4Cl solution, extracted with ethyl acetate (3×5mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure. Purification by flash chromatography afforded the corresponding products. Yield: 95% (58.7mg), [α]D20=+14.2 (c 0.5, CHCl3). The ee was determined by HPLC (Chiralpak OD-H column, hexane/i-PrOH 92:8, flow rate 1.0mL/min, λ=254nm, tR (major)=45.6min). Data for the major anti isomer: 1H NMR (300MHz, CDCl3): δ=7.68 (d, J=8.1Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 5.00 (dd, J=3.8, 3.8Hz, 1H), 3.63 (d, J=3.9Hz, 1H), 3.03-2.96 (m, 3H), 2.88-2.75 (m, 2H), 2.68-2.60 (m, 1H), 2.53-2.48 (m, 1H) ppm. 13C NMR (75MHz, CDCl3): δ=211.3, 145.7, 132.4, 127.7, 118.5, 112.1, 73.4, 59.4, 44.7, 32.8, 30.8ppm.
86%
Stage #1: Tetrahydrothiopyran-4-one With silver hexafluoroantimonate; (S)-2-amino-3-methyl-N-(6-pivalamidopyridin-2-yl)butanamide; copper dichloride In tetrahydrofuran at 20℃; for 4h;
Stage #2: 4-cyanobenzaldehyde In tetrahydrofuran at 20℃; optical yield given as %ee; enantioselective reaction;
3-[(1′-hydroxy-1′-(2″-nitrophenyl))methyl]-tetrahydrothiopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With C29H39N3O3S In chloroform at 20℃; for 60h; optical yield given as %ee; enantioselective reaction;
92%
Stage #1: Tetrahydrothiopyran-4-one With (R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamide; acetic acid In dichloromethane at -20℃; for 0.5h;
Stage #2: 2-nitro-benzaldehyde In dichloromethane at -20℃; for 18h; stereoselective reaction;
3-[(1′-Hydroxy-1′-(2″-nitrophenyl))methyl]-tetrahydrothiopyran-4-one1b 6a (Table 5, entry 1)
General procedure: A mixture of catalyst 1e (10mg, 0.025mmol), HOAc (1.5mg, 0.025mmol) and ketone (1.25mmol) in DCM (0.5mL) was stirred at -20°C for 30min. Next, the aldehyde (0.25mmol) was added and the reaction mixture was stirred at -20°C. The reaction was monitored by TLC, then quenched with 3mL of saturated NH4Cl solution, extracted with ethyl acetate (3×5mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure. Purification by flash chromatography afforded the corresponding products. Yield: 92% (61.5mg), [α]D20=+35.8 (c 1.0, CHCl3). The ee was determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10, flow rate 1.0mL/min, λ=254nm, tR (minor)=34.6min, tR (major)=42.3min). Data for the major anti isomer: 1H NMR (300MHz, CDCl3): δ=7.92 (d, J=8.1Hz, 1H), 7.79 (d, J=7.5Hz, 1H), 7.68 (t, J=7.5Hz, 1H), 7.47 (t, J=7.5Hz, 1H), 5.56 (d, J=6.6Hz, 1H), 3.85-3.68 (m, 1H), 3.21-3.14 (m, 1H), 3.08-2.93 (m, 3H), 2.87-2.73 (m, 2H), 2.65-2.61 (m, 1H) ppm. 13C NMR (300MHz, CDCl3): δ=211.9, 148.6, 136.2, 133.7 129.3, 128.9, 124.7, 69.3, 60.1, 45.6, 32.9, 30.6ppm.
89%
With benzyl 3,4,6-tri-O-benzyl-2-deoxy-2-(L-prolylamino)-α-D-glucopyranoside In dichloromethane at 0℃; for 48h; optical yield given as %ee; enantioselective reaction;
89%
With benzyl 3,4,6-tri-O-benzyl-2-deoxy-2-(L-prolylamino)-α-D-glucopyranoside at 0℃; for 48h; enantioselective reaction;
76%
Stage #1: Tetrahydrothiopyran-4-one With silver hexafluoroantimonate; (S)-2-amino-3-methyl-N-(6-pivalamidopyridin-2-yl)butanamide; copper dichloride In tetrahydrofuran at 20℃; for 4h;
Stage #2: 2-nitro-benzaldehyde In tetrahydrofuran at 20℃; optical yield given as %ee; enantioselective reaction;
With lithium diisopropyl amide In tetrahydrofuran at -50 - 20℃;
26.c
c) 4-(Methoxymethylene)tetrahvdro-2H-thiopyran A slurry of (methoxymethyl)triphenylphosphonium chloride (266 g, 770 mmol) and THF (400 mL) was cooled to - 50 0C. LDA (390 mL, 0.78 mol, 2M in THF) was added slowly and the temperature was kept below -20 0C. After 15 min, tetrahydrothiopyran-4-one dissolved in THF (250 mL) was added slowly at -40 0C. After 15 min, the reaction mixture was allowed to reach RT and was then stirred overnight. The mixture was cooled to 3 0C and the precipitate was filtered off, the filtrate was evaporated and the crude residue purified by distillation, (B.p. 90 -105 0C, 14 mbar) to yield the title compound (68 g,73%).1H NMR (400MHz, CDCl3) δ 5.82 (s, IH), 3.54 (s, 3H), 2.63 - 2.58 (m, 4H), 2.56 - 2.50 (m, 2H), 2.30 - 2.26 (m, 2H); GC-MS: m/z 144 [M+].
50%
Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -50 - -20℃; for 0.25h;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; n-heptane; ethylbenzene at -40 - 20℃;
1b Preparation of 4-(methoxymethylene)-3,4,5,6-tetrahydro-2H-thiopyran
A mixture of (methoxymethyl)triphenylphosphonium chloride (885 g, 2.58 mol, 1.50 eq.) in THF (1300 mL) was cooled to -50°C and LDA (1 .29 L of a 2 M solution in THF/Heptane/ Ethylbenzene, 2.58 mol, 1.50 eq.) was added dropwise keeping the temperature below -20°C. After 15 min at -20°C the deep red reaction mixture was cooled to -40°C and a solution of tetrahydrothiopyran-4-one (200 g, 1 .72 mol, 1 .00 eq) in THF (1000 mL) was added dropwise. After 15 min at -40°C the mixture was allowed to reach rt and was stirred overnight. The reaction mixture was filtered, concentrated in vacuo and filtered again. The obtained filtrate was purified by distillation (B.p. 60°C, 0.02 mbar) to give the title compound (125 g, 50%). 1H-NMR (300MHz, CDCI3): Shift [ppm] = 2.27 - 2.30 (m, 2H), 2.52 - 2.55 (m, 2H), 2.59 - 2.62 (m, 4H), 3.55 (s, 3H), 5.82 (s, 1 H). UPLC-MS (ESI+): [M + H]+ = 145.
50%
Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -50 - -20℃; for 0.25h;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; n-heptane; ethylbenzene at -40℃; for 0.25h;
A.1.1 Preparation of 4-(methoxymethylene)-3,4,5,6-tetrahydro-2H-thiopyran
A mixture of (methoxymethyl)triphenylphosphonium chloride (885 g, 2.58 mol, 1.50 eq.) inTHF (1300 mL) was cooled to -50°C and LDA (1 .29 L of a 2 M solution in THF/Heptane/Ethylbenzene, 2.58 mol, 1.50 eq.) was added dropwise keeping the temperature below -20 °C.After 15 min at -20 °C the deep red reaction mixture was cooled to -40 °C and a solution oftetrahydrothiopyran-4-one (200 g, 1 .72 mol, 1 .00 eq) in THF (1000 mL) was added dropwise. After 15 mm at -40°C the mixture was allowed to reach rt and was stirred overnight. The reaction mixture was filtered, concentrated in vacuo and filtered again. The obtained filtrate was purified by distillation (B.p. 60°C, 0.02 mbar) to give the title compound (125 g, 50%). 1H-NMR (300MHz, CDCl3): Shift [ppm] = 2.27 - 2.30 (m, 2H), 2.52 - 2.55 (m, 2H), 2.59 -2.62 (m, 4H), 3.55 (s, 3H), 5.82 (s, 1H). UPLC-MS (ESI+): [M + H]+ = 145.
50%
Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -20℃; for 0.25h;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; n-heptane; ethylbenzene at -40 - 20℃;
125 g
Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -50 - -20℃; for 0.25h;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; n-heptane; ethylbenzene at -40 - 20℃;
A.1.1b Step 1 b Wittig reaction Preparation of 4-(methoxymethylene)-3,4,5, 6-tetrahydro-2 H-thiopyran
A mixture of (methoxymethy)triphenylphosphonium chloride (885 g, 2.58 mol, 1.50 eq.) in THF (1300 mL) was cooled to -50°C and LDA (1.29 L of a 2 M solution in THF/Heptane/ Ethylbenzene, 2.58 mol, 1.50 eq.) was added dropwise keeping the temperature below -20°C . After 15 min at -20°C the deep red reaction mixture was cooled to -40°C and a solution of tetrahydrothiopyran-4-one (200 g, 1.72 mol, 1.00 eq) in THF (1000 mL) was added dropwise. After 15 min at -40°C the mixture was allowed to re ach rt and was stirred overnight. The reaction mixture was filtered, concentrated in vacuo and filtered again. The obtained filtrate was purified by distillation (B.p. 60°C 0.02 mbar) to give the title compound (125 g, 50%). 1H-NMR (300MHz, CDCl3): Shift [ppm] = 2.27 - 2.30 (m, 2H), 2.52 - 2.55 (m, 2H), 2.59 - 2.62 (m, 4H), 3.55 (s, 3H), 5.82 (s, 1 H). UPLC-MS (ESI+): [M +H]+ = 145
Stage #1: (methoxymethyl)triphenylphosphonium chloride With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; hexane at 0℃; for 0.333333h; Inert atmosphere;
To a mixture of <strong>[5177-27-5]2,4-dichloropyrimidin-5-amine</strong> (1.58 g, 9.63 mmol) and dihydro-2H-thiopyran-4(3H)-one (1.45 g, 12.5 mmol) in dichloromethane (50 ml) at 0 C. was added dropwise a 1 M solution of titanium tetrachloride (10.6 ml, 10.6 mmol) in dichloromethane. After the reaction mixture was stirred at room temperature for 2 h, sodium cyanoborohydride (1.91 g, 28.9 mmol) was added in single portion and the reaction mixture was stirred at room temperature for 16 hours. After the reaction mixture was diluted with dichloromethane, the reaction mixture was poured carefully into iced-saturated NaHCO3 solution. EtOAc was added and then the insoluble materials were filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated NaCl, dried with Na2SO4 and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 3:1) to afford 2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg, 3.27 mmol, 34% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.59-1.76 (m, 2H) 2.07-2.20 (m, 2H) 2.58-2.69 (m, 2H) 2.70-2.85 (m, 2H) 3.42-3.57 (m, 1H) 5.78 (d, J=8.84 Hz, 1H) 8.25 (s, 1H). MS [M+H] 264.
(3Z)-3-[(4-nitrophenyl)methylene]-4H-tetrahydrothiapyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N,N-Dimethyltrimethylsilylamine; magnesium bromide ethyl etherate at 20℃; for 3h; Inert atmosphere; neat (no solvent);
72%
With N,N-Dimethyltrimethylsilylamine; iron oxide In neat (no solvent) at 20℃; for 4h; Green chemistry;
Synthesis of α,β-Unsaturated Heterocyclic and Cyclic Ketones: General Procedure
General procedure: A mixture of an aldehyde (4 mmol), an amine (2 mmol), and nanosized magnetite (7 mol% with respect to aldehyde) was stirred at room temperature. An appropriate ketone (4 mmol) was then added almost immediately to the mixture. The progress of reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, magnetite was removed easily by dropping a bar magnet to the reaction vessel. The product was isolated and purified by column chromatography using hexane-ethyl acetate (30:70) as solvent system (Table 2).
Stage #1: Tetrahydrothiopyran-4-one; 4-nitrobenzaldehdye With magnesium sulfate heptahydrate; sodium hydroxide In water at 25℃; for 20h;
Stage #2: With hydrogenchloride In ethanol for 1h; Reflux;
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.283333h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.266667h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.25h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.216667h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.266667h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 140℃; for 0.233333h; Microwave irradiation; regiospecific reaction;
General procedure for the synthesis of polysubstituted fused pyrimidines 4 under microwave irradiation
General procedure: In a 10-mL reaction vial, aromatic aldehyde 1 (2 mmol), tetrahydrothiopyran-4-one or trahydropyran-4-one 2 (1 mmol), t-BuOK (2.0 mmol), t-BuOH (2.0 mL) were mixed and stirred at room temperature for 10 min. Subsequently aryl amidine 3 (1.1 mmol) was added into the mixture and then capped. The mixture was irradiated for a given time at 140 °C. Upon completion as shown by TLC monitoring, the reaction mixture was cooled to room temperature and neutralized by protonic acids and then diluted with cold water. The solid product was filtered, washed with water and acetone, and subsequently dried and then recrystallized from acetone to give the pure product.
The title compound can also be prepared according to the following procedure: TMSOTf (1.4 ml_, 7.7 mmol) was added dropwise to a solution of tetrahydro-4H-thiopyran- 4-one (0.88 g, 7.6 mmol) in DCM (80 ml.) in the presence of molecular sieves at 0 0C (bath temp). A solution of ethyl 5-bromo-1 /-/-indole-7-carboxylate (2 g, 7.4 mmol). in DCM (20 ml.) was added and the reaction was stirred for 15 min. Triethylsilane (2 ml_, 12.5 mmol) was added and the reaction was allowed to warm to room temperature overnight. Saturated aqueous Na2CO3 was added, the layers separated and the aqueous layer extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was washed with MeOH and dried in a vacuum oven, giving 2.07 g (76%) of the title compound.
8,9-diamino-10-oxo-3-thia-9-azaspiro[5.5]undec-7-ene-7,11-dicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With piperidine; hydrazine hydrate In ethanol at 25 - 30℃; for 0.583333h; Sonication;
3.2. General Procedure for the Synthesis of 1,6-Diamino-2-oxo-1,2,3,4-Tetrahydro-Pyridine-3,5-Dicarbonitrile Derivatives 5
General procedure: A 100 mL flask was charged with ketone 1 (1 mmol), malononitrile 2 (1 mmol), ethyl cyanoacetate 3 (1 mmol), hydrazine hydrate 4 (1 mmol) and piperidine (10 mol%, 0.1 mmol) in ethanol (10 mL). The mixture was sonicated in the water bath of an ultrasonic cleaner at 25-30 °C. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to remove the solvent. The residue was quenched with water and then filtered. The crude products were purified by recrystallization from ethanol to afford the pure products 5.
2-(tetrahydro-4H-thiopyran-4-ylidene)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: diethyl 1-cyanomethylphosphonate With sodium hydride In tetrahydrofuran; mineral oil for 0.25h; Cooling with ice;
Stage #2: Tetrahydrothiopyran-4-one In tetrahydrofuran; mineral oil at 0 - 5℃; for 2h;
3 2-(tetrahydro-4/H/-thiopyran-4-ylidine) acetonitrile (5b)
To an ice cold stirred solution of diethyl cyanomethylphosphonate (109.7 g, 0.6197 mol,1.2 eq.) in dry THF (600 mL), sodium hydride (60% in mineral oil, 32.0 g, 0.672 mol,1.3 eq) was added, portion wise. The reaction mixture was stirred for 15 minutes and then tetrahydro-4H -thiopyran-4-one (60.0 g, 0.5164 mol,1.0 eq) was added slowly as a solution in dry THF (120 mL, 2.0 volumes). Stirring was continued for another 2h at the same temperature (0°C - 5°C). After confirming the completion of reaction by TLC, the reaction was quenched by the slow addition of ice cold water. Then reaction mixture was extracted with DCM (600 mL), the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography to afford 2-(tetrahydro-4H -thi opy ran-4-y 1 i di ne)acetoni tri 1 e (5b) as a white solid (50 g, 86.0%.). 'H NMR results are shown in Table 3.
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h;
1-(2-amino-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With piperidine; octasulfur; In methanol; at 55 - 65℃; for 24h;
General procedure: 3-Acetyl-2-aminothiophene Derivatives; General Procedure Carbonyl compound (0.025 mol) was added to freshly prepared cya-noacetone (0.03 mol) in either MeOH or EtOH (40 mL). Sublimed sul-fur S8 (0.03 mol) and piperidine (0.03 mol) were added and the mix-ture was stirred and heated to 55-65 C for 24 h. Ice was then addedand the formed precipitate was filtered under vacuum and washedwith water. The obtained solid was crystallised from a suitable sol-vent, with the exception of 4g and 4j, which were collected directlywithout further purification.
2-amino-5,7-dihydro-N-phenyl-4H-thieno[2,3-c]thiopyran-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With sulfur; barium aluminate; In ethanol; water; at 80℃; for 18h;Green chemistry;
General procedure: A mixture of tetrahydrothiopyran-4-one (1 mmol), 2-cyano-Nphenylacetamide (1 mmol), sulfur powder (1.5 mmol) and barium aluminate nanopowder (0.025 g) in EtOH (90% v/v) wasreuxed (80C) for the appropriate time. The progress of thereaction was monitored by TLC (Table 1). After completion ofthe reaction, the reaction mixture was dissolved in hot ethanol.Simple fltration removed the catalyst. The solvent was concentrated, and recrystallization purifed the crude products fromEtOH.
Stage #1: Tetrahydrothiopyran-4-one; t-butoxycarbonylhydrazine With acetic acid In dichloromethane for 2h;
Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃; for 12h;
1.1 Step 1: Synthesis of tert-butyl 2- (tetrahydro-2H-thiopyran-4-yl) hydrazin-1-carboxylic acid
Tetrahydro-4H-thiopyran-4-one (5.0g, 0.043mol, 1.0eq),Tert-Butyl hydrazinecarboxylate (5.68g, 0.043mol, 1.0eq) was dissolved in DCM,Add acetic acid (3.87g, 0.065mol, 1.5eq) and stir for 2h.The temperature was lowered to 0 ° C, and STAB (18.2 g, 0.086 mol, 2.0 eq) was slowly added, and the temperature was naturally raised to room temperature and stirred for 12 h.TLC monitoring showed the reaction was complete. Saturated NaCO3 solution (100 mL) and DCM (100 mL) were added.Separated, dried the organic phase, concentrated,The crude product was purified by silica gel column chromatography (PE: EA = 20: 1-10: 1) to obtain the product (8.67 g, yield: 86.8%).
Multi-step reaction with 2 steps
1: methanol / 4 h / 20 °C
2: sodium cyanoborohydride; acetic acid / water / 2 h / 20 °C
Multi-step reaction with 2 steps
1: hexane / 3 h / Reflux
2: sodium tris(acetoxy)borohydride / tetrahydrofuran / 15 h / 20 °C
Multi-step reaction with 2 steps
1: sodium hydroxide / hexane / 3 h / Reflux
2: sodium tris(acetoxy)borohydride / tetrahydrofuran / 15 h / 20 °C
tert-butyl 4-((tetrahydro-2H-thiopyran-4-yl)amino)phenethylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.7%
A mixture of dihydro-2//-thiopyran-4(3//)-onc (0.488 g, 4.2 mmol), tert- butyl 4- aminophenethylcarbamate (0.5 g, 2.1 mmol) and ZnCh (0.859 g, 6.3 mmol) in methanol (10 mL) was stirred at room temperature overnight. After this time NaBHiCN (0.66 g, 10.5 mmol) was added and the mixture was heated at 40 C for 4 h. After it was cooled to room temperature, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by column chromatography to afford the title compound as light-yellow solid (0.401 g, 56.7% yield). NMR (500 MHz, DMSO-r/d) d: 6.87 (d, J= 8.3 Hz, 2H), 6.79 (t, J = 5.3 Hz, 1H), 6.50 (d, J= 8.4 Hz, 2H), 5.31 (d, .7= 8.6 Hz, 1H), 3.26 - 3.19 (m, 1H), 3.03 (dd, J= 14.6, 6.3 Hz, 2H), 2.68 (dd, J= 9.6, 3.4 Hz, 4H), 2.52 (d, J= 9.6 Hz, 2H), 2.20 - 2.09 (m, 2H), 1.47 (ddd, J= 13.4, 9.7, 4.7 Hz, 2H), 1.37 (s, 9H).
6H,8H-thiopyrano[4,3-b:4,5-b‘]dichromene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With tetrachlorosilane In ethanol at 20℃; Inert atmosphere;
1. Synthesis
General procedure: Briefly, a mixture of the ketone (0.01 mol), the required substituted salicylaldehyde (0.02 mol), and SiCl4 (silicon tetrachloride, 0.03 mol) in absolute ethanol (20 ml) were stirred under nitrogen atmosphere at room temperature. The completion of the reaction was indicated by formation of solid (whitish in color) in the reaction vessel. Post completion, the contents were poured into ice to quench the unreacted SiCl4 and stirred for around 15 minutes. The solid obtained was filtered followed by washing with water. The solid was then dried and recrystallized from distilled chloroform. In case there was formation of a colored solid in the reaction vessel, the work-up procedure was followed as mentioned above till filtration. After filtering, the colored solid obtained was then suspended in diethyl ether (20 mL) to which 20 mL of aqueous ammonia was added. The suspension was shaken vigorously and the ether layer was separated. The aqueous layer was extracted 2 more times with diethyl ether. The ether layers were concentrated, dried over anhydrous Na2SO4. Evaporation of ether yielded a crude solid which was then recrystallized from distilled acetone or chloroform.
Multi-step reaction with 2 steps
1: hydrogenchloride
2: ammonium hydroxide / water
ethyl (2S,3'R)-2-(p-methoxyphenylamino)-2-(4'-oxotetrahydrothiopyran-3'-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: N-(4-methoxy)phenylglycine ethyl ester With tris(bipyridine)ruthenium(II) dichloride hexahydrate; copper(II) acetate monohydrate In acetonitrile at 20℃; for 2h; Irradiation;
Stage #2: Tetrahydrothiopyran-4-one With (R)-N-(pyrrolidin-3-yl)trifluoromethanesulfonamide In acetonitrile stereoselective reaction;
3'-methyl-1'-phenyl-4'-(p-tolyl)-2,3,4',5,6,7'-hexahydrospiro[pyrazolo[3,4-b]pyridine-6,4'-thiopyran]-5',5'(1'H)-dicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With acetic acid In ethanol at 80℃; for 3h; Sealed tube;
4.1. Typical procedure for the preparation of 3'-methyl-1',4'-diphenyl-4',7'-dihydrospiro[cyclohexane-1,6'-pyrazolo[3,4-b]pyridine]-5',5'(1'H)-dicarbonitrile (4a)
General procedure: The mixture of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1a, 0.5 mmol), 2-benzylidenemalononitrile (2a, 0.5 mmol), cyclohexanone (3a, 0.5 mmol), and acetic acid (0.05 mmol) was submitted in 3.0 mL ethanol and stirred at 80 °C for about 4 h. After completion of the reaction as detected by TLC, the reaction was cooled to room temperature and a great deal of suspension was formed. After the solid being filtered, the product 4a was collected without further purification (175 mg, yield 86%, mp: 287-288 °C).
With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; regioselective reaction;
19 Example 19
Intoa 25mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI2) in tetrahydrofuran (0.100mol/L) 7.50mL, compound 1s 34.9mg (0.300mmol), heavy water 150mg (7.50mmol) ).The reaction mixture was stirred at room temperature for 15 min, after which air was passed through to quench the reaction.Ethyl acetate and 1M hydrochloric acid solution were added for extraction, the organic phase was dried and concentrated, and 35.0 mg of the target compound 2s was obtained by column chromatography with a yield of 98% and a deuteration rate of 98%.
98%
With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; chemoselective reaction;
3.2 General Procedure for the Reductive Deuteration of Ketones by SmI2-D2O
General procedure: To a solution of samarium (II) iodide (0.100 M in THF; 7.50 mL, 0.750 mmol, 2.50 equiv),was added deuterium oxide (150 mg, 7.50 mmol, 25.0 equiv). A characteristic burgundy redcolor of SmI2-D2O complex was observed. A solution of ketones (0.300 mmol, 1.00 equiv) inTHF (1.0 mL) was then added under Ar at room temperature and stirred vigorously. After 15min, excess SmI2 was oxidized by bubbling air through the reaction mixture. The reactionmixture was diluted with EtOAc (10 mL) and HCl (5 mL, 1.0 M, aq). The aqueous layer wasextracted with EtOAc (3 × 10 mL), organic layers were combined, washed with Na2S2O3 (2 ×5 mL, sat., aq), dried over Na2SO4, filtered and concentrated. The crude product was purifiedby flash chromatography (silica, 10-50% EtOAc/Hexane). The sample was analyzed by 1HNMR (CDCl3, 300 MHz) to obtain the deuterium incorporation.
With magnesium(II) sulfate; toluene-4-sulfonic acid; In 1,4-dioxane; toluene; at 110℃;Inert atmosphere;
General procedure: To a solution of <strong>[5428-40-0]4-bromo-2-hydroxybenzamide</strong> 9a (2.8 g, 13 mmol), tetrahydro-4H-pyran-4-one(2.6 mL, 26 mmol) and p-toluenesulfonic acid monohydrate (494 mg, 2.6 mmol) in 1,4-dioxaneand toluene (60 + 100 mL), magnesium sulfate (4.68 g, 38.87 mmol) was added. The mixture wasrefluxed overnight at which point LC-MS showed 80% conversion. More tetrahydro-4H-pyran-4-one (1.2 mL, 12 mmol), p-toluenesulfonic acid monohydrate (120 mg, 0.24 mmol) were added andthe mixture was refluxed for 6 h. The solid was filtered off and the filtrate was concentrated underreduced pressure. EtOAc (300 mL) was added, and the organic phase was washed by saturatedNaHCO3 and brine. The organic phase was dried over MgSO4. The MgSO4 solid was removed,and the filtrate was concentrated to result compound 9b (3.26 g, yield 84%) as pale solid.
With magnesium(II) sulfate; toluene-4-sulfonic acid; In 1,4-dioxane; toluene; at 110℃;Inert atmosphere;
General procedure: To a solution of <strong>[5428-40-0]4-bromo-2-hydroxybenzamide</strong> 9a (2.8 g, 13 mmol), tetrahydro-4H-pyran-4-one(2.6 mL, 26 mmol) and p-toluenesulfonic acid monohydrate (494 mg, 2.6 mmol) in 1,4-dioxaneand toluene (60 + 100 mL), magnesium sulfate (4.68 g, 38.87 mmol) was added. The mixture wasrefluxed overnight at which point LC-MS showed 80% conversion. More tetrahydro-4H-pyran-4-one (1.2 mL, 12 mmol), p-toluenesulfonic acid monohydrate (120 mg, 0.24 mmol) were added andthe mixture was refluxed for 6 h. The solid was filtered off and the filtrate was concentrated underreduced pressure. EtOAc (300 mL) was added, and the organic phase was washed by saturatedNaHCO3 and brine. The organic phase was dried over MgSO4. The MgSO4 solid was removed,and the filtrate was concentrated to result compound 9b (3.26 g, yield 84%) as pale solid.
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