* 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.
With hydrogenchloride In water; acetone for 2 h; Heating / reflux
To a solution of acetone (720 mL) was added 10 G (43.8 MMOL, 1 equiv) of ethyl 1, 4-dioxaspiro [4.5] dec-8-ylacetate followed by 1 N Hydrochloric acid (180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted twice with EtOAc (100 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated to yield 7.57 g (94percent) of a clear OIL. H-NMR (CDCI3-D) 8 4.16 (q, 2H), 2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H), 1.28 (t, 3H); TLC Rf = 0.32 (3: 7 EtOAc/Hex).
94%
With hydrogenchloride; water In acetone for 2 h; Heating / reflux
Step 3; Preparation of ethyl (4-oxocvclohexyl)acetate; This material was prepared by either of two methods described below. Method A; To a solution of 10 g (43.8 mmol, 1 equiv) of ethyl l,4-dioxaspiro[4.5]dec-8- ylacetate in acetone (720 mL) was added aqueous HCl (IN, 180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated to yield 7.57 g (94percent) of a clear oil. 1H-NMR (CDCl3-d) δ 4.16 (q, EPO <DP n="48"/>2H), 2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H), 1.28 (t, 3H); TLC Rf = 0.32 (3:7 EtOAc/Hex).
78.1%
With hydrogenchloride In water; acetonitrile at 20℃; for 2 h;
Step 1 : Synthesis of ethyl 2-(4-oxocyclohexyl)acetate. [00418] To a solution of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)acetate (from Step 1, Example 77, 4.71 g, 19.44 mmol) in acetonitrile (45 mL) was added 6N HCl aqueous solution (45 mL). The resulting mixtures was stirred at rt for 2 h and neutralized with solid NaHC03 to pH 8, extracted with EtOAc. The organic phase was washed with brine, dried over Na2S04. Filtration and evaporation to dryness gave the ketone product as colorless oil (2.97 g, 78.1percent).
75%
With hydrogenchloride In water at 70℃;
A solution of reagent KR-47 (5 g, 21 .9 mmol) in HCI (6N, 10 mL) was stirred at 70°C overnight, then concentrated to give the crude product which was purified by the column to obtained pure reagent KR-48 (3 g, 75percent) as white solid. ESI-MS (Mi-i): 185.2 calc. for C10H1603: 184.1.
73.4%
With hydrogenchloride In water; acetone for 2 h; Reflux
In a 10 liter reactor was taken ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate(67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1183 mL, 1183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extractedwith ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water andbrine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Thecrude material was purified through flash column chromatography, eluting with 0-20percentethyl acetate in petroleum ether to give Intermediate 1 64C (pale yellow liquid, 40 g, 217mmol, 73.4percent yield). GC-MS Anal. Calc’d for C,0H,603, 184.11 found [M] 184. T =10.03 mm (Method J).
73.4%
With hydrogenchloride In water; acetone for 2 h; Reflux
In a 10 liter reactor was taken Intermediate 154B (67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1 183 mL, 1 183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extracted with ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-20percent ethyl acetate in petroleum ether to give Intermediate 154C (pale yellow liquid, 40 g, 217 mmol, 73.4percent yield). GC- MS Anal. Calc'd for Ci0Hi6O3, 184.1 1 found [M+H]+ 184. Tr = 10.03 min (Method C).
73%
With hydrogenchloride In water; acetone for 2 h; Reflux
In a 10 liter reactor was taken Intermediate lB (67.5g. 296 mmol) in Acetone (5000 mL). To that FIC1 (1M) (1183 mL, 1183 mmol) was added and the reaction was heated to reflux for 2 hrs. After 2 hours, the reaction mixture was concentrated. The residue was then transferred to 10 liter separatory funnel and extracted with ethylacetate ( 3 x i000mi). The combined organic layers were washed with water (i000mi) and brine (l000mi), dried over sodium sulphate and concentrated in vacuo. The crude material was purified through silica gel flash column (750g coiunm using 0 to 20percent ethyl acetate in petether) to give Intermediate IC (40 g, 217 mmoi. 73percent). ‘HNMR (C1-TLOROFORM-d, 400 MHz) d: 4.15 (q, J=7.0 FIz. 2H), 2.35- 2.41 (m, 3H), 2.20-2.34 (in, 3H), 2.04-2.13 (m, 3H). 1.41-1.53 (m, 21-1), 1.24-1.30 (t. 31-1)
Reference：
[1] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 105-106
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 33, p. 5693 - 5697
[3] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 46-47
[4] Angewandte Chemie - International Edition, 2007, vol. 46, # 33, p. 6278 - 6283
[5] Tetrahedron, 1995, vol. 51, # 37, p. 10259 - 10280
[6] Patent: WO2014/89365, 2014, A1, . Location in patent: Paragraph 00418
[7] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 66
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[9] Patent: WO2016/73774, 2016, A2, . Location in patent: Paragraph 0416
[10] Patent: WO2016/73770, 2016, A1, . Location in patent: Paragraph 0471
[11] Patent: WO2018/39512, 2018, A1, . Location in patent: Paragraph 00190
[12] Patent: US5877199, 1999, A,
[13] Patent: US2006/264489, 2006, A1, . Location in patent: Page/Page column 78
[14] Patent: WO2010/103429, 2010, A1, . Location in patent: Page/Page column 34
[15] Patent: WO2011/146371, 2011, A1, . Location in patent: Page/Page column 25
2
[ 62141-22-4 ]
[ 58012-34-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hypochlorite In acetic acid at 30℃;
Method B; Ethyl (4-hydroxyphenyl)acetate (5Og, 277 mmol) was dissolved in 150 niL of ethanol in a Parr bottle with Rh/Al2O3 (1.00 g, 5 wtpercent, Aldrich Lot:07727AB). The suspension was hydrogenated on a Parr shaker at 60 psi. After 48 h, starting material was still present, so additional Rh/ Al2O3 (4.00 g) was added. The suspension was hydrogenated for another 8 h, at which time a sample analyzed by 1H NMR indicated the reaction was complete. The reaction mixture was filtered through Celite.(R). and rinsed with ethanol (450 mL). The reaction mixture was concentrated to afford a clear colorless oil (55.0 g, quantitative).The resulting ethyl (4-hydroxycyclohexyl)acetate (45.0 g, 240 mmol) was dissolved in AcOH (160 mL) and slowly treated with NaOCl (171 mL, 10-13percent available chlorine, -1.7 M, -290 mmol) to maintain the temperature below 30 °C. Brine (500 mL) was added to the solution and the aqueous layer was extracted withEtOAc (3X500 mL). The organic layers were combined, washed with brine (500 mL), concentrated to an oil and chased with heptane. 1H NMR indicated ~1 equivalent of AcOH. The oil was redissolved in EtOAc (500 mL), washed with sat. NaHCO3 (2X250 mL) and brine (200 mL). The organic layer was collected, dried (Na2SO4), filtered, and concentrated to yield 40.7 g (92percent) of a clear colorless oil. 1HNMR (DMSO-d6) 64.05 (q, 2H), 2.39 (dt, 2H), 2.30 (d, 2H), 2.19-2.14 (m, 3H), 1.96-1.90 (m, 2H), 1.39 (dq, 2H), 1.18 (t, 3H). GCMS (EI) RT = 9.3 min, [M]+ = 184.
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 3 h;
The compound 223d (4.6 g) was dissolved in CH2Cl2 (10 ml) and treated with diethylaminosulfur trifluoride (DAST, 5 ml) at room temperature for 3 hours. The reaction mixture was poured into ice/water (30 ml) and extracted with CH2Cl2. The extract was washed with satd. aqueous NaHCO3, brine, dried over Na2SO4 and concentrated to afford 223e as brown oil (3.2 g, 62percent).
0.4 g
With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 20℃; for 16 h;
To a solution ofethyl 2-(4-oxocyclohexyl)acetate(0.4 g) inDCM(5 mL) was addedDeoxo-Fluor®(0.881 mL) andEtOH(0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution ofethyl 2-(4,4-difluorocyclohexyl) acetateinTHF/MeOH(2 mL) was added 1NNaOH(1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield2-(4,4-difluorocyclohexyl)acetic acidas ayellowsolid.1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
With hydrogenchloride; In water; acetone; for 2h;Heating / reflux;
To a solution of acetone (720 mL) was added 10 G (43.8 MMOL, 1 equiv) of ethyl 1, 4-dioxaspiro [4.5] dec-8-ylacetate followed by 1 N Hydrochloric acid (180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted twice with EtOAc (100 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated to yield 7.57 g (94%) of a clear OIL. H-NMR (CDCI3-D) 8 4.16 (q, 2H), 2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H), 1.28 (t, 3H); TLC Rf = 0.32 (3: 7 EtOAc/Hex).
94%
With hydrogenchloride; water; In acetone; for 2h;Heating / reflux;Product distribution / selectivity;
Step 3; Preparation of ethyl (4-oxocvclohexyl)acetate; This material was prepared by either of two methods described below. Method A; To a solution of 10 g (43.8 mmol, 1 equiv) of ethyl l,4-dioxaspiro[4.5]dec-8- ylacetate in acetone (720 mL) was added aqueous HCl (IN, 180 mL) The reaction was heated at reflux for 2 h. Upon cooling the solution was diluted with EtOAc (100 mL) and washed with water (100 mL). The water layer was back extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated to yield 7.57 g (94%) of a clear oil. 1H-NMR (CDCl3-d) delta 4.16 (q, EPO <DP n="48"/>2H), 2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H), 1.28 (t, 3H); TLC Rf = 0.32 (3:7 EtOAc/Hex).
78.1%
With hydrogenchloride; In water; acetonitrile; at 20℃; for 2h;
Step 1 : Synthesis of ethyl 2-(4-oxocyclohexyl)acetate. [00418] To a solution of ethyl 2-(l,4-dioxaspiro[4.5]decan-8-yl)acetate (from Step 1, Example 77, 4.71 g, 19.44 mmol) in acetonitrile (45 mL) was added 6N HCl aqueous solution (45 mL). The resulting mixtures was stirred at rt for 2 h and neutralized with solid NaHC03 to pH 8, extracted with EtOAc. The organic phase was washed with brine, dried over Na2S04. Filtration and evaporation to dryness gave the ketone product as colorless oil (2.97 g, 78.1%).
75%
With hydrogenchloride; In water; at 70℃;
A solution of reagent KR-47 (5 g, 21 .9 mmol) in HCI (6N, 10 mL) was stirred at 70C overnight, then concentrated to give the crude product which was purified by the column to obtained pure reagent KR-48 (3 g, 75%) as white solid. ESI-MS (Mi-i): 185.2 calc. for C10H1603: 184.1.
73.4%
With hydrogenchloride; In water; acetone; for 2h;Reflux;
In a 10 liter reactor was taken ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate(67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1183 mL, 1183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extractedwith ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water andbrine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Thecrude material was purified through flash column chromatography, eluting with 0-20%ethyl acetate in petroleum ether to give Intermediate 1 64C (pale yellow liquid, 40 g, 217mmol, 73.4% yield). GC-MS Anal. Calc?d for C,0H,603, 184.11 found [M] 184. T =10.03 mm (Method J).
73.4%
With hydrogenchloride; In water; acetone; for 2h;Reflux;
In a 10 liter reactor was taken Intermediate 154B (67.5 g, 296 mmol) in acetone (5000 mL). To the reaction mixture was added 1 M HC1 solution (1 183 mL, 1 183 mmol) and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated to remove acetone. The residue was extracted with ethyl acetate (3 x 1000 mL). Combined organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-20% ethyl acetate in petroleum ether to give Intermediate 154C (pale yellow liquid, 40 g, 217 mmol, 73.4% yield). GC- MS Anal. Calc'd for Ci0Hi6O3, 184.1 1 found [M+H]+ 184. Tr = 10.03 min (Method C).
73%
With hydrogenchloride; In water; acetone; for 2h;Reflux;
In a 10 liter reactor was taken Intermediate lB (67.5g. 296 mmol) in Acetone (5000 mL). To that FIC1 (1M) (1183 mL, 1183 mmol) was added and the reaction was heated to reflux for 2 hrs. After 2 hours, the reaction mixture was concentrated. The residue was then transferred to 10 liter separatory funnel and extracted with ethylacetate ( 3 x i000mi). The combined organic layers were washed with water (i000mi) and brine (l000mi), dried over sodium sulphate and concentrated in vacuo. The crude material was purified through silica gel flash column (750g coiunm using 0 to 20% ethyl acetate in petether) to give Intermediate IC (40 g, 217 mmoi. 73%). ?HNMR (C1-TLOROFORM-d, 400 MHz) d: 4.15 (q, J=7.0 FIz. 2H), 2.35- 2.41 (m, 3H), 2.20-2.34 (in, 3H), 2.04-2.13 (m, 3H). 1.41-1.53 (m, 21-1), 1.24-1.30 (t. 31-1)
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; In acetone;
EXAMPLE 59 Ethyl 4-oxocyclohexylacetate 50 ml of a 1N aqueous solution of hydrochloric acid was added to a solution of 5.0 g of ethyl 4-oxocyclohexylacetate ethylene acetal, as obtained in Example 58, in 50 ml of acetone. The reaction mixture was stirred for 10 minutes at room temperature, neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and then concentrated by evaporation under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 100 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 3.9 g of the title compound as an oil.
With formic acid; at 70℃; for 1h;
The compound 223c (7 g) was dissolved in formic acid (50 ml) and heated at 70 C. for 1 h. The solution was concentrated and the residue was taken up in EtOAc and washed with satd. aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel to afford 223d (5 g).
With phosphoric acid; In water; acetone; for 16h;Reflux;
(1 ,4-Dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester (Preparation 6, 2 g), acetone (125 ml_), phosphoric acid (5.0 ml_) and water (25.0 ml_) were refluxed overnight (approximately 16 h). The reaction mixture was cooled to room temperature and concentrated to a minimal volume in vacuo. The residue was taken up in 50% Heptane/Et2O (100 ml_) and washed with water (2x50 ml_), and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (1.4 g). 1H NMR (400 MHz, CDCI3) delta ppm 1.25 (t, J=IA 2 Hz, 3H), 1.36 - 1.54 (m, 2H), 2.01 - 2.13 (m, 2H), 2.22 - 2.31 (m, 3H), 2.32 - 2.41 (m, 4H), 4.13 (q, J=7.22 Hz, 2H).
With formic acid; In water; at 20℃;
Step C : ethyl (4-oxocyclohexyl)acetate; To a solution of ethyl l,4-dioxaspiro[4.5]dec-8-ylacetate (13.01 g, 57.0 mmol) in formic acid (90 ml) was added water (1.54 g, 86.0 mmol). After stirring at rt overnight, formic acid was removed by reduced pressure. The mixture was partitioned between CH2CI2 (300 ml) and water (300 ml). The organic layer was washed with brine, dried over NaS04, and concentrated to provide the title compound.
10 g
With hydrogenchloride; In water; acetone; at 20℃;
To a solution of Methyl 2-(4-(1 ,3-dioxalane)cyclohexyl)acetate (17.5 g, 76.4 mmol) in acetone, was added 1 N HCI (160 ml_, 160 mmol) dropwise. After the reaction mixture was stirred at room temperature overnight, water and EtOAc were added and the layers were separated. The organics were washed sequentially with water and brine, and dried over Na2S04. Filtration and concentration in vacuum gave a crude product, which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the title compound (10 g, 72% yield). (ESI) m/z calcd for C10H16O3: 184.1 1 . Found: 185.34 (M+1 )+.
ethyl [(2E)-2-({1-[4-(trifluoromethyl)phenyl]butyl}imino)cyclohexyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; for 16h;Heating / reflux;
Step 1 Ethyl 2-cyclohexanoneacetate (0.34 ml, 1.92 mmol) was added to a solution of Intermediate 1 (418 mg, 1.92 mmol) in toluene (10 ml) in a flask fitted with Dean- Stark apparatus. The reaction was heated to reflux under N2 for 16 h, then allowed to cool to room temperature. The resulting solution of ethyl [(2E)-2-({1-[4- (trifluoromethyl)phenyl]butyl}imino)cyclohexyl]acetate in toluene was used directly in the next step.
1a) 76 g (4-hydroxy-cyclohexyl-)acetic acid ethyl ester produced by catalytic hydrogenation from 4-hydroxyphenyl acetic acid ethyl ester (Raney-Ni/H2/160° C./200 bar/72 h/ethanol) is dissolved in 130 ml methylene chloride and admixed with 20.6 g Dess-Martin periodinan. The reaction solution is subsequently stirred for 30 h at room temperature. Afterwards the precipitated precipitate is filtered, the methylene chloride solution is washed successively with saturated sodium thiosulfate solution and water and dried over sodium sulfate. After removing the solvent 16.5 g (4-oxocyclohexyl)-acetic acid ethyl ester is obtained as a colourless oil. 1H-NMR (DMSO-d6):delta=4.05 ppm (q, 2H); 2.48-2.25 (m, 8 lines, 3H); 2.15 (m, 3H); 1.92 (m, 2H); 1.90 (sextet, 2H), 1.15 (t, 3H).
(4-ethoxycarbonylmethyl-cyclohexylidene)-acetic acid tert.-butyl ester[ No CAS ]
[ 58012-34-3 ]
[ 86302-43-4 ]
(4-ethoxycarbonylmethyl-cyclohexyl)-acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid;carbon palladium; In tetrahydrofuran; dichloromethane; toluene;
1b) A solution of 3.6 g (4-oxo-cyclohexyl)-acetic acid ethyl ester and 8 g (tert.-butoxycarbonylmethylene)-triphenylphosphorane (Aldrich GmbH and Co. KG) in 100 ml toluene is heated for 40 hours under reflux. Subsequently the toluene is removed in a vacuum and the product is purified by column chromatography (ethyl acetate/isohexane 1/10). The (4-ethoxycarbonylmethyl-cyclohexylidene)-acetic acid tert.-butyl ester (2.7 g) obtained in this way is dissolved in 40 ml tetrahydrofuran, admixed with 300 mg 10 percent palladium/carbon and hydrogenated for 20 hours at normal pressure and room temperature. Afterwards the catalyst is removed by filtration, the tetrahydrofuran is removed on a rotary evaporator and the residue (2.8 g) is taken up in 5 ml methylene chloride. After addition of 5 ml trifluoroacetic acid the reaction solution is stirred for 2 h at room temperature and evaporated to dryness. 2.7 g (4-ethoxycarbonylmethyl-cyclohexyl)-acetic acid is obtained in this way. FAB: 228, 1H-NMR (CDCl3):delta= 7.70 ppm (broad s, 1H); 4.15 (q, 2H); 2.20 (d, 2H); 2.17 (d, 2H); 1.75 (m, 5H); 1.60 (m, 1H); 1.40 (m, 1H); 1.25 (t, 3H); 1.05 (m, 3H).
EXAMPLE 60 Ethyl (1,2,3,4-tetrahydrocarbazol-3-yl)acetate Following a procedure and using relative proportions of starting materials similar to those described in Example 48, but using ethyl 4-oxocyclohexylacetate, as obtained in Example 59, as starting material, the title compound was obtained in a yield of 90percent, melting at 122°-123° C. Nuclear Magnetic Resonance Spectrum (CDCl3, 270 MHz), delta ppm: 1.29 (3H, triplet, J=7.1 Hz); 1.6-1.8 (1H, multiplet); 2.0-2.2 (1H, multiplet); 2.3-2.5 (4H, multiplet); 2.7-3.0 (3H, multiplet); 4.18 (2H, quartet, J=7.1 Hz); 7.07 (1H, triplet, J=7.0 Hz); 7.12 (1H, triplet, J=7.0 Hz); 7.27 (1H, doublet, J=7.0 Hz); 7.44 (1H, doublet, J=7.0 Hz): 7.70 (1H, broad singlet).
With morpholine; sulphur; In ethanol; at 20℃; for 72h;
Step 4; Preparation of ethyl 2-amino-6-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahvdro-l- benzothiophene-3 -carboxylate; Ethyl (4-oxocyclohexyl)acetate (40.7 g, 221 mmol) was dissolved in ethanol (450 mL). Ethyl cyanoacetate (25.0 g, 221 mmol), morpholine (19.2 g, 221 mmol), and sulfur (7.08 g, 221 mmol) were added to the reaction flask in that order. The reaction was stirred at room temperature for 3 days, during which time the suspension turned EPO <DP n="49"/>into a clear solution. The reaction mixture was concentrated on a rotavap to -20percent of the original volume. The solution was diluted with EtOAc (IL), washed once with dilute brine (500 mL water:50 mL sat. brine), then with sat. brine (100 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to obtain a viscous light brown oil (69.9 g, quantitative). 1H NMR (CDCl3-d) delta 5.96 (s, 2H),4.25 (q, 2H), 4.15 (q, 2H), 2.87 (m, 1H), 2.65 (m, 2H), 2.32 (m, 4H), 1.91 (m, 1H), 1.46 (m, 1H), 1.34 (t, 3H) ), 1.28 (t, 3H); LCMS RT = 3.17 min, [M+H]+ = 312.0.
With sodium hypochlorite; In acetic acid; at 30℃;Product distribution / selectivity;
Method B; Ethyl (4-hydroxyphenyl)acetate (5Og, 277 mmol) was dissolved in 150 niL of ethanol in a Parr bottle with Rh/Al2O3 (1.00 g, 5 wtpercent, Aldrich Lot:07727AB). The suspension was hydrogenated on a Parr shaker at 60 psi. After 48 h, starting material was still present, so additional Rh/ Al2O3 (4.00 g) was added. The suspension was hydrogenated for another 8 h, at which time a sample analyzed by 1H NMR indicated the reaction was complete. The reaction mixture was filtered through Celite.(R). and rinsed with ethanol (450 mL). The reaction mixture was concentrated to afford a clear colorless oil (55.0 g, quantitative).The resulting ethyl (4-hydroxycyclohexyl)acetate (45.0 g, 240 mmol) was dissolved in AcOH (160 mL) and slowly treated with NaOCl (171 mL, 10-13percent available chlorine, -1.7 M, -290 mmol) to maintain the temperature below 30 °C. Brine (500 mL) was added to the solution and the aqueous layer was extracted withEtOAc (3X500 mL). The organic layers were combined, washed with brine (500 mL), concentrated to an oil and chased with heptane. 1H NMR indicated ~1 equivalent of AcOH. The oil was redissolved in EtOAc (500 mL), washed with sat. NaHCO3 (2X250 mL) and brine (200 mL). The organic layer was collected, dried (Na2SO4), filtered, and concentrated to yield 40.7 g (92percent) of a clear colorless oil. 1HNMR (DMSO-d6) 64.05 (q, 2H), 2.39 (dt, 2H), 2.30 (d, 2H), 2.19-2.14 (m, 3H), 1.96-1.90 (m, 2H), 1.39 (dq, 2H), 1.18 (t, 3H). GCMS (EI) RT = 9.3 min, [M]+ = 184.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 3h;
The compound 223d (4.6 g) was dissolved in CH2Cl2 (10 ml) and treated with diethylaminosulfur trifluoride (DAST, 5 ml) at room temperature for 3 hours. The reaction mixture was poured into ice/water (30 ml) and extracted with CH2Cl2. The extract was washed with satd. aqueous NaHCO3, brine, dried over Na2SO4 and concentrated to afford 223e as brown oil (3.2 g, 62percent).
A mixture of [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 g) and boron trifluoride diethyl etherate (0.1 ml_) in toluene (15 ml_) at 0 0C was allowed to stand for 1.3 h with occasional stirring. A solution of (4-Oxo- cyclohexyl)-acetic acid ethyl ester (Preparation 7, 1.38 g) in toluene (10 ml_) was added. The reaction mixture was stirred at 50 0C for 1 day. The mixture was then cooled to 0 0C and the mixture was added to 50 ml_ of 5 N NaOH and 100 ml_ of Et2O/Heptane (1 :1 ) at 0 ° C. After stirring for 30 min, the phases were separated. The organic layer was washed with 100 ml_ of water, 1 N HCI, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product. 1H NMR (400 MHz, CDCI3) delta ppm 1.18 - 1.40 (m, 6H), 1.62 - 1.93 (m, 4H), 1.98 - 2.14 (m, 2H), 2.19 - 2.30 (m, 2H), 4.12 (q, J=7.03 Hz, 2 H).
With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 16h;
Cap N-1: 2-(4,4-difluorocyclohexyl)acetic acid To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
0.4 g
With ethanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 16h;
To a solution of<strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong>(0.4 g) inDCM(5 mL) was addedDeoxo-Fluor®(0.881 mL) andEtOH(0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution ofethyl 2-(4,4-difluorocyclohexyl) acetateinTHF/MeOH(2 mL) was added 1NNaOH(1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield2-(4,4-difluorocyclohexyl)acetic acidas ayellowsolid.1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In ethanol; dichloromethane; at 20℃; for 16h;
To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. aHC03 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2S04, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl) acetate in THF/MeOH (2 mL) was added IN NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with IN HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2S04, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-i) ppm 12.13 (1 H, br. s.), 2.06 - 2.28 (3 H, m), 1.92 - 2.03 (1 H, m), 1.72 - 1.91 (4 H, m), 1.31 - 1.48 (1 H, m), 1.10 - 1.31 (2 H, m).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 72h;
[B is(2-methoxyethyl)amino] sulfur trifluoride (Deoxofluor.(R)., 7.5 g, 34.8 mmol) was added to a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> [Alonso F., et. al. Tetrahedron, 1995, 57, 10259-10280] (2.0 g, 10.9 mmol) in dichloromethane (20 mL). The mixture was stirred for 3 days at room temperature and quenched with sat. NaHCO3 (20 mL) and extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were dried (MgSO4) and evaporated. The residue was purified with flash chromatography to give the title compound.
EXAMPLE 4 Preparation of 3-bromo-4-oxocyclohexaneacetic acid ethyl ester 74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 l. three-necked flask, provided with a thermometer, nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10° by means of a dry ice-acetone bath, and 64.0 g. of bromine was added dropwise over a period of 30-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then two times with 125 ml. of cold saturated sodium bicarbonate solution followed by 100 ml. of water. The combined aqueous solutions were extracted twice with 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g.
With bromine;
EXAMPLE 1 Preparation of 3-bromo-4-oxocyclohexylacetic acid ethyl ester To a solution of 16 g. of 4-oxocyclohexylacetic acid ethyl ester in 200 ml. of ether, stirred and cooled to -10° C., were added 4.48 ml. of bromine, dropwise. After one-half hour, the ether solution was washed successively with two 100 ml. portions of water, one 100 ml. portion of saturated sodium bicarbonate, and three 100 ml. portions of water. The aqueous layers were extracted with two 100 ml. portions of ether. The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated at reduced pressure to give 23 g. of 3-bromo-4-oxocyclohexylacetic acid ethyl ester as a pale yellow oil.
With 2,6-di-tert-butyl-4-methylpyridine; In dichloromethane; at 20℃;
Intermediate 43-8: Ethyl 2-f4-ftrifluoromethylsulfonyloxy)cvclohex-3-enyl)acetateTriflouromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was added portionwise to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in DCM (250 mL). A solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (10.88 g, 59.05 mmol, CAS 58012-34-3) in DCM (100 mL) was then added dropwise and the reaction mixture was allowed to stir open to air and at room temperature overnight. The reaction mixture was washed with water, saturated Na2CO3, saturated brine, dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 <n="134"/>to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (16.05 g, 86 %) as a yellow oil.1H NMR (300 MHz, CDCl3) delta 1.22 - 1.29 (3H, m), 1.39 - 1.51 (IH, m), 1.76 - 1.85 (2H, m), 2.07 - 2.23 (4H, m), 2.29 (2H, d), 4.09 - 4.18 (2H, m), 4.96 (IH, s).
76%
With 2,6-di-tert-butyl-4-methylpyridine; In dichloromethane; at 20℃;Inert atmosphere;
A 2 liter 4 neck flask was charged with 2,6-di-tert-butyl-4-methylpyridine (84 g,407 mmol) in dichloromethane (500 mL) under nitrogen. Tf20 (55.0 mL, 326 mmol) wasadded dropwise. Then a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (50 g, 271 mmol) in dichloromethane (500 mL) was added slowly. After completion of the addition, the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with 1000 mL of dichioromethane and washed with water and sodium carbonate solution and then water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-10% ethyl acetate in petroleum ether to give Intermediate 1 64D (pale yellow oil, 65 g, 206mmol, 76% yield). GC-MS Anal. Calc?d for C,,H,5F305S, 316.06 found [M] 317. T =10.16 mm (Method J).
76%
With 2,6-di-tert-butyl-4-methylpyridine; In dichloromethane; at 20℃;Inert atmosphere;
In a 2 liter 4 neck flask was taken 2,6-di-tert-butyl-4-methylpyridine (84 g, 407 mmol) in dichloromethane (500 mL) under nitrogen. Triflic anhydride (55.0 mL, 326 mmol) was added dropwise. Then a solution of Intermediate 154C (50 g, 271 mmol) in dichloromethane (500 mL) was added slowly. After completion of addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1000 mL of dichloromethane and washed with water and sodium carbonate solution and then water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0- 10% ethyl acetate in petroleum ether to give Intermediate 154D (pale yellow oil, 65 g, 206 mmol, 76% yield). GC-MS Anal. Calc'd for CnHi5F305S, 316.06 found [M+H]+ 317. Tr = 10.16 min (Method C).
76%
With 2,6-di-tert-butyl-4-methylpyridine; In dichloromethane; at 20℃;Inert atmosphere;
In a 2 ltr 4 neck was taken 2.6-di-tert-butyi-4-mcthyipyridinc (84 g, 407 rnmoi) in dichloromethane (500 mL) under nitrogen. To that triflic anhydride (55.0 mL, 326 mrnoi) was added drop wise. Then ethyl Intermediate IC (So g, 271 mrnoi) in dichioromethane (50() mL) was added slowly. After completion of addition, stirred at room temperature overnight. After stirring overnight, the reaction mixture was diluted with i000mi of dichioromcthane and washed with water (SOOrnl) followed by sodium carbonaie (500m1) and then waler once again (500m1). The combined organic extracts were dried over sodium sulphate, filtered, and concentrated. The crude material was purified through flash silica gel column chromatography (750g column using 0 to 10% ethyl acetate in pet ether) to give Intermediate ID (65 g, 206 mmol, 76 %). Pure fractions were concentrated. ?1-1 NMR (CHLOROFORM-d, 400 M[Iz) & 5.73 (dt, J:::49, 2.3 Hz, 11-1), 4.15 (q, J:::7.2 1-lz, 2Ff), 2.28-2.52 (m, 5H), 2.07-2.2 1 (in, IH), 1.89-2.00 (m, 2FI). 1.54 (dt, J:::6.O, 3.5 Hz, 1H), 1.25-1.30 (t, 3H)
76%
With 2,6-di-tert-butyl-4-methylpyridine; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
The compound 2,6-di-tert-butyl-4-methylpyridine (4.1 g, 20 mmol) was dissolved in dichloromethane (15 ml), then <strong>[58012-34-3]ethyl 2-(4-carbonylcyclohexyl)acetate</strong> 1a (1.80 g, 18 mmol) and trifluoromethanesulfonic anhydride (5.4 g, 19 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 24 hours under an argon atmosphere and filtered. The solvent was removed under reduced pressure.After the organic phases were combined, they were washed with cold 1N hydrochloric acid (50 ml) and brine (50 ml) and dried over anhydrous sodium carbonate.After filtration again, the solvent was evaporated under reduced pressure to give ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate 1b (3.0 g, Colorless oil), Yield: 76%.
67%
With 2,6-dimethylpyridine; In dichloromethane; at 20℃;
At 0C, to a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (10 g, 54.3 mmol) and trifluoromethanesulfonic anhydride (18.4 g, 65.2 mmol) in dichloromethane, was added 2,6-dimethylpyridine (12.5 ml_, 108.6 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. Then this was partitioned between aq. NH4CI and EtOAc and the layers were separated. The organics were washed sequentially with water and brine, and dried over Na2S04. Filtration and concentration in vacuum gave a crude product, which was purified by flash chromatography to afford the title compound (11.5 g, 67% yield). (ESI) m/z calcd for C11H15F3O5S: 316.06. Found: 317.19 (M+1 )+.
With methanol; sodium tetrahydroborate; at 20℃; for 13h;
To a solution of ethyl (2-(4-oxocyclohexyl)acetate (See References in General Procedure A for preparation) (1.0 g, 5.4 mmol) in methanol (40 mL) at rt was added NaBH4 (0.60 g, 16 mmol). The resulting solution was stirred open to air for 13 h, after which it was diluted with CH2C12 (60 mL), washed with 1 M HC1 (3 x 30 mL), dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to afford Intermediate 31A as a 1 :3 mixture of cis and trans isomers, as a clear colorless oil (1.0 g, 99percent yield).
99%
With sodium tetrahydroborate; In methanol; at 20℃; for 13h;
To a solution of ethyl (2-(4-oxocyclohexane)acetate (1.0 g, 5.4 mmol) in methanol (40 mL) at rt was added NaBH4(0.60 g, 16 mmol). The resulting solution was stirred open to air for 13 h, after which it was diluted with CH2C12(60 mL), washed with 1 M HCl (3 x 30 mL), dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to afford the desired product as a 1 :3 mixture of diastereomers, clear, colorless oil (1.0 g, 99percent yield)
92%
With sodium tetrahydroborate; ethanol; In ethanol; at 0℃; for 2h;Inert atmosphere;
To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (5.00 g, 26.6 mmol) in ethanol (50mL) was added slowly sodium tetrahydroborate (2.10 g, 55.5 mmol) at 0 °C undernitrogen atmosphere. After stirred at 0 °C under nitrogen atmosphere for 2 hours, the reaction was quenched with saturated ammonium chloride aqueous solution (150 mL) at 0 °C, then concentrated at room temperature under reduced pressure to give a residue, which was dissolved in water (100 mL) and extracted with ethyl acetate (150 mL) forthree times. The combined organic layers were washed with brine (100 mL), dried over Na2SO4() and filtered. The filtrate was concentrated under reduced pressure to afford the title compound Intermediate 22a (4.80 g, 95 percent purity from ?H NIVIR, 92 percent yield) as colorless oil. ?H NIVIR (300 1VIHz, CDC13) 4.15 -4.07 (m, 2H), 4.00-3.92 (m, 0.3H), 3.59 - 3.48 (m, 0.7H), 2.24 -2.08 (m, 2H), 1.98 - 1.40 (m, 7H), 1.35 - 0.96 (m,6H).
With methanol; sodium tetrahydroborate; at 0℃; for 2h;
Step D : ethyl (4-hydroxycyclohexyl)acetate; To a solution of <strong>[58012-34-3]ethyl (4-oxocyclohexyl)acetate</strong> (10.5 g, 57.0 mmol) in methanol (100 ml) at 0 °C was added NaBHU (3.23 g, 86.0 mmol) in several portions. The mixture was stirred at 0 °C for 2 h and then it was concentrated. The residue was partitioned between ether (300 ml) and water (300 ml). The organic layer was separated, washed with brine, dried over NaS04, and concentrated. The residue was purified by flash chromatography using 0 to 50percent EtOAc hexane gradient, affording the title compound.
General procedure: To asolution of keto ester (0.200 mmol, 1.0 eq) and PEt3 (0.18 mL of20percent in toluene, 0.244 mmol, 1.2 eq) in CH2Cl2 (0.50 mL, 0.4 M) was added TMSOTf (43 muL, 0.238 mmol, 1.2 eq) dropwise atrt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and DIBAL-H (0.58 mL of 1.03 M in hexane,0.597 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M inTHF)). To the mixture were added saturated aqueous NaHCO3 solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt,the mixture was extracted several times with EtOAc (50 mL).The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.
With titanium(IV) tetraethanolate; triethylamine; In dichloromethane; for 4h;
Step 3: Synthesis of ethyl 2-[4-[2-(methanesulfonamido)ethylamino]cyclohexyl]acetate. [00318] To a mixture of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (736mg, 4 mmol) and N-(2- aminoethyl)methanesulfonamide; 2,2,2-trifluoroacetic acid salt (1.26 g, 5 mmol) in dichloromethane (6 mL) was added triethylamine (690 mu, 5 mmol) followed by Titanium (IV) ethoxide (420 mu, 2 mmol, technical grade). The resulting cloudy mixture was stirred for 4 hours then concentrated under reduced pressure. The residue was taken up in methanol (6 mL). This mixture was cooled to -78°C. To the resulting mixture was added sodium borohydride (187mg, 4.8 mmol). On complete addition, the cold bath was allowed to expire and stirring continued for 15.5 hours. The resulting mixture was concentrated under reduced pressure to give a thick paste. This residue was taken up in dichloromethane (40 mL). To this mixture was added Na2C03 (5.5 mL, saturated aqueous solution). The resulting mixture was stirred for 5 minutes. To this mixture was added celite (1.8g). This mixture was stirred for 5 minutes then filtered through a pad of celite. The filtrate is washed with saturated aqueous Na2C03, dried over magnesium sulfate and concentrated to give the title compound as a 6: 1 mixture of trans: cis isomers. This material was used without further purification.
Step 2: Synthesis of ethyl 2-(4-methylenecyclohexyl)acetate. [00419] To a cooled (0°C) suspension of methyl triphenylphosphonium bromide (8.58 g, 23.5 mmol) in THF (60 mL) was added KOtBu (3.17 g, 28.3 mmol) in portions under N2. The reaction was slowly warmed to rt and stirred for 1 h. The resulting mixture was cooled to 0°C and added a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (2.9 g, 15.7 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h and at 50°C overnight. After cooling to RT, the reaction was quenched by addition of saturated NH4C1, extracted with EtOAc, washed with brine, dried over Na2S04. Purification by flash column chromatography (eluent: 20percent EtOAc in hexanes) gave the product as colorless oil (2.11 g, 73.7percent).
60%
To a solution of methyl triphenyl phosphonium bromide (2.74 g, 8.2 mmol) inTHE was added n-BuLi (3.4 mL, 2.5 M, 8.2 mmol) at -70°C. The mixture solution was stirred at 0 °C for 2 hrs. Then a solution of reagent KR-48 (1 g, 30 mmol) in THE was added to the solution at -70°C. The mixture solution was stirred at r.t overnight. The mixture was quenched with aqueous NH4CI and extracted with EtOAc, the organic layer was washed with brine, driedover anhydrous Na2504, concentrated to give the crude product which was purified by the column to give the reagent R-23c (0.5 g, 60 percent yield) as a white solid. calc. for C11H1802: 182.1.
To a solution of commercially available <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (SI-17) (1.0 g,5.43 mmol) in anhydrous THF (30 mL) was added LiHMDS (5.7 mL, 1.0 M in THF, 5.70mmol) at -78 C and the mixture was stirred for 1 hour. Then, PhN(SO2CF3)2 (2.04 g, 5.70mmol) in THF (20 mL) was added under N2 protection. After addition, the mixture wasstirred at room temperature overnight. Then, the reaction was quenched with aqueousKHSO4 and extracted with MTBE. The organic layer was washed with 1.0 M aqueousNaOH, aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered and concentratedto give Int. 8 (1.50 g, 87%) as a yellow oil. ESI-MS m/z 317 [M+H]+ calc. forC11H15F3O5S. 1H NMR (CDCl3, 400 MHz): delta 5.66 (s, 1H, C=CH), 4.12-4.05 (m, 2H, OCH2-CH3), 2.35-2.23 (m, 5H, cyclohexene and cyclohexene-CH2-CO), 2.21-2.03 (m, 1H,cyclohexene), 1.90-1.83 (m, 2H, cyclohexene), 1.49-1.42 (m, 1H, cyclohexene), 1.23-1.18(m, 3H, O-CH2-CH3).
35%
Step 1. Ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-l-yl)acetate. To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.50 g, 2.71 mmol) in tetrahydrofuran (2.71 mL) was slowly added a solution of lithium bis(trimethylsilyl)amide in THF (4.07 mL, 1.00 M, 4.07 mmol). The reaction was cooled to -40C then stirred for 1 h then a solution of /V-phenyl- bis(trifluoromethanesulfonimide) (1.16 g, 3.26 mmol) in tetrahydrofuran (0.90 mL) was added dropwise at -40C. The reaction was allowed to warm up to room temperature and stirred for an additional 3 h. The reaction mixture was quenched with sat. NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to give the crude product. The crude oil was purified via flash chromatography 0- 30% EtOAc/Heptanes to obtain the title compound as a colorless oil (300 mg, 35%). 'H NMR (400 MHz, CDCb) d 5.77 - 5.56 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.50 - 2.39 (m, 1H), 2.33 (td, J = 2.6, 5.0 Hz, 2H), 2.29 (d, J = 7.1 Hz, 2H), 2.18 - 2.04 (m, 1H), 2.01 - 1.85 (m, 2H), 1.60 - 1.45 (m, 1H), 1.25 (t, / = 7.2 Hz, 3H). [M+H] = 317.1.
To a solution of commercially available <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (1 .0 g, 5.43 mmol) in anhydrous THE (30 mL) was added LHMDS (5.7 mL, 1 .0 M in THE, 5.70 mmol) at -78C, then the mixture was stirred at the sametemperature for ihr, compound PhN(SO2CE3)2 (2.04 g, 5.70 mmol) in THE (20 mL) was added under N2 protection. After addition, the mixture was stirred at room temperature overnight until TLC showed the starting material was consumed completely, the mixture was quenched with aqueous KHSO4, extracted with MTBE, the organic layer was washed with 1 .0 M aqueousNaOH, aqueous NH4CI, brine, dried over anhydrous Na2SO4, concentrated to give the crude reagent R-27b (1 .50 g, 87%) as a yellow oil. ESI-MS (Mi-i):317 calc. for C11H1SE3OSS: 316.0.
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