* 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] Chemische Berichte, 1933, vol. 66, p. 1209
2
[ 4341-76-8 ]
[ 4344-87-0 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 330[2] Chem.Abstr., 1938, p. 5377
3
[ 4341-76-8 ]
[ 2999-46-4 ]
[ 5448-16-8 ]
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 31, p. 5481 - 5484
[2] Journal of the American Chemical Society, 2005, vol. 127, # 25, p. 9260 - 9266
4
[ 4341-76-8 ]
[ 626-34-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1906, vol. 345, p. 96[2] Justus Liebigs Annalen der Chemie, 1923, vol. 433, p. 52,56, 58
[3] Justus Liebigs Annalen der Chemie, 1906, vol. 345, p. 96[4] Justus Liebigs Annalen der Chemie, 1923, vol. 433, p. 52,56, 58
5
[ 4341-76-8 ]
[ 7664-41-7 ]
[ 626-34-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1906, vol. 345, p. 96[2] Justus Liebigs Annalen der Chemie, 1923, vol. 433, p. 52,56, 58
6
[ 4341-76-8 ]
[ 626-34-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1906, vol. 345, p. 96[2] Justus Liebigs Annalen der Chemie, 1923, vol. 433, p. 52,56, 58
7
[ 4341-76-8 ]
[ 60-34-4 ]
[ 5203-77-0 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 48, # 1, p. 123 - 131
Reference：
[1] Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 4, p. 503 - 506
22
[ 5982-65-0 ]
[ 4341-76-8 ]
Reference：
[1] Journal of Organic Chemistry, 1971, vol. 36, p. 2836 - 2838
23
[ 30318-90-2 ]
[ 4341-76-8 ]
Reference：
[1] Journal of Organic Chemistry, 1971, vol. 36, p. 2836 - 2838
24
[ 623-47-2 ]
[ 74-88-4 ]
[ 4341-76-8 ]
[ 74460-85-8 ]
[ 74460-84-7 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[2] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[3] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[4] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[5] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[6] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
25
[ 72568-47-9 ]
[ 4341-76-8 ]
[ 709-79-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3401 - 3405
26
[ 146857-35-4 ]
[ 4341-76-8 ]
[ 146857-41-2 ]
[ 146857-44-5 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1992, vol. 28, # 2.1, p. 256 - 262[2] Zhurnal Organicheskoi Khimii, 1992, vol. 28, # 2, p. 317 - 324
27
[ 590-93-2 ]
[ 4341-76-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1968, p. 2994 - 3000
28
[ 623-47-2 ]
[ 74-88-4 ]
[ 4341-76-8 ]
[ 5717-41-9 ]
[ 74460-85-8 ]
[ 74460-84-7 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[2] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
29
[ 141-97-9 ]
[ 2526-64-9 ]
[ 4341-76-8 ]
Reference：
[1] Proceedings of the Chemical Society, London, 1961, p. 302
Step c: 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (9.8 g, 44percent) which was obtained as an off white solid. MS: m/e=250.1 [M+H]+.
44%
With triethylamine In diethyl ether at 0 - 20℃;
To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0 °C followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (9.8 g, 44percent) which was obtained as an off white solid. MS: m/e = 250.1 [M+H]+.
Step c: 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester: To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0 °C followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (9.8 g, 44percent) which was obtained as an off white solid. MS: m/e = 250.1 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
Example 31 Synthesis of tert-Butyl(2-methylpyrazolo[1,5-a]pyridin-3-yl)carbamate (CE298) Step 1: 1-Aminopyridinium iodide (10 g), ethyl but-2-ynoate (6.05 g), potassium carbonate (7.45 g) were mixed in anhydrous DMF (50 mL). The reaction mixture was stirred at ambient temperature for 3 days. A mixture of water (100 mL), ethyl acetate (100 mL) and hexane (100 mL) was added and the product was collected by filtration. The filter cake was washed with a mixture of ethyl acetate:hexane=1:1, affording 6.4 g of ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (70% yield).
55%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
00727] (i) Production of ethyl 2-methylpyrazolo[l,5-a]pyridine-3-carboxylate [00728] To a suspension of <strong>[6295-87-0]1-aminopyridinium iodide</strong> (125 g, 0.56 mmol) in N,N-dimethylformamide (1.2 L) were added ethyl 2-butynoate (54.0 g, 0.48 mmol) and potassium carbonate (79 g, 0.56 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water (500 mL), ethyl acetate (500 mL) and hexane (500 mL), and the precipitated solid was collected by filtration, and washed with water (500 mL). The filtrate was extracted with a mixed solvent (1.5 L x 2) of ethyl acetate/hexane (1: 1) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The residue obtained by concentration of the filtrate and the solid collected by filtration in the above were combined, washed with diethyl ether (25 mL) and hexane (25 mL) and dried to give the title compound (36.0 g, 37%) as a white solid. The washing solution was concentrated, and the obtained residue was washed with diethyl ether (10 mL) and hexane (10 mL) and dried to give a second crop (11.0 g, 11%) of the title compound as a white solid. The washing solution of the second crop was concentrated, and the obtained residue was purified using a pad (elution solvent: ethyl acetate/hexane=l/l) with silica gel and activated carbon in 2 layers, washed with diethyl ether (5.0 mL) and hexane (5.0 mL) and dried to give a third crop (6.5 g, 7%) of the title compound as a white solid (total yield 55%).[00729] 1H-NMR (DMSOd6, 300 MHz) delta 1.35 (3H, t, J = 7.2 Hz), 2.57 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 7.09 (IH, dt, J = 1.5, 6.9 Hz), 7.49 - 7.61 (IH, m), 8.00 (IH, td, J = 1.3 Hz), 8.75 (IH, td, J = 1.0, 6.9 Hz).
55%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
Preparation of intermediate EA Ethyl-2-butynoate (CAS [4341-76-8], 6.2 mL, 54.0 mmol) was added to a solution of <strong>[6295-87-0]1-aminopyridinium iodide</strong> (CAS [6295-37-0], 10 g, 45 mmol) and potassium carbonate (7.5 g, 54 mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature for 72 h. The mixture was evaporated to dryness and the residue was solubilized in EtOAc and washed with brine (3x). The organic layer was dried over 10 MgSC , filtered and evaporated to dryness to give 5.1 g of intermediate EA as a brown solid (55%).
With sodium azide;copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; dimethyl sulfoxide; at 20 - 100℃;
Intermediate 11 : Ethyl 5-methyl-1-(6-methyl-3-pyridinyl)-1 H-1 ,2,3-triazole-4- carboxylate; To a mixture of <strong>[695-17-0]5-iodo-2-methylpyridine</strong> (160 mg, 0.731 mmol) and ethyl 2-butynoate (0.085 ml, 0.731 mmol) in water/DMSO (0.2ml/2ml) was added at room temperature L-proline (16.82 mg, 0.146 mmol), sodium carbonate (15.49 mg, 0.146 mmol), sodium azide (57.0 mg, 0.877 mmol), sodium l-ascorbate (14.47 mg, 0.073 mmol) <n="34"/>and copper(ll) sulfate pentahydrate (9.12 mg, 0.037 mmol) (in this order) and the mixture was heated at 65C overnight. Monitoring by LC/MS revealed starting material to be present and so the temperature was increased to 100 degrees and the mixture was heated overnight at lOOdegC. The mixture was then quenched with aqueous ammonia (1 ml) and EtOAc (20ml) and water (20 ml) were added. The two phases were separated, and the aqueous phase was extracted with EtOAc (3 x 30 ml). The organic phases were combined and washed with water/brine (50ml) repeatedly. The organic phases were dried over sodium sulfate, filtered and the solvent was evaporated to afford a crude product that was purified by MDAP to give the title compound (6.7%) MH+=247.
With sodium azide;copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; dimethyl sulfoxide; at 20 - 65℃;
Intermediate 7: Ethyl 1-(3,4-difluorophenyl)-5-methyl-1H-1 ,2,3-triazole-4-carboxylate; To a mixture of 1 ,2-difluoro-4-iodobenzene (1 g, 4.17 mmol) and ethyl 2-butynoate (0.484 ml_, 4.17 mmol) in water (0.444 ml)/DMS0 (4 ml) at room temperature were added L-proline (0.096 g, 0.833 mmol), sodium carbonate (0.088 g, 0.833 mmol), sodium azide (0.325 g, 5.00 mmol), sodium l-ascorbate (0.083 g, 0.417 mmol) and copper(ll) sulfate pentahydrate (0.052 g, 0.208 mmol) (in this order) and the mixture was heated at 65 0C overnight. On cooling to room temperature, the mixture was quenched with aqueous ammonia (1 ml) and EtOAc (20ml) and water (20 ml) were added. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 30 ml). The organic phases were combined and washed with water/brine (50ml) repeatedly. The organic phases were dried over sodium sulfate, filtered and the solvent was evaporated to afford a crude product that was purified by MDAP to afford the title compound (23.9%); MH+=267.9; 1HNMR (DMSO, 400 MHz): 1.34 (3H t), 4.36 (2H, q), 7.57 (1 H m), 7.76 (1 H m), 7.94 (1 H m).
With sodium azide;copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; dimethyl sulfoxide; at 20 - 65℃;
Intermediate 4: Ethyl 1-(3,5-difluorophenyl)-5-methyl-1/-/-1 ,2,3-triazole-4-carboxylate; To a mixture of 1 ,3-difluoro-5-iodobenzene (0.2 g, 0.833 mmol) and ethyl 2- butynoate (0.097 ml, 0.833 mmol) in water/DMSO (0.22ml/2ml) at room temperature was added L-proline (0.019 g, 0.167 mmol), sodium carbonate (0.018 g, 0.167 mmol), sodium azide (0.065 g, 1.000 mmol), sodium l-ascorbate (0.017 g, 0.083 mmol) and copper(ll) sulfate pentahydrate (10.40 mg, 0.042 mmol) (in this order) and the mixture was heated at 65C overnight. Monitoring by LC/MS revealed starting material to be present and so the temperature was increased to 100 degrees and the mixture was heated overnight at lOOdegC. On cooling to room temperature, the mixture was quenched with aqueous ammonia (1 ml) and EtOAc (20ml) and water <n="29"/>(20 ml) were added. The two phases were separated, and the aqueous phase was extracted with EtOAc (3x 30 ml). All organic phases were combined and washed with water/brine (50ml) repeatedly. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give a crude product that was purified by MDAP to afford the title compound (14.9%); MH+=267.9.
With sodium azide;copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; dimethyl sulfoxide; at 20 - 65℃;
Intermediate 5: Ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1 H-1 ,2,3-triazole-4- carboxylate; To a mixture of <strong>[156150-67-3]2-chloro-1-fluoro-4-iodobenzene</strong> (0.5 g, 1.950 mmol) and ethyl 2- butynoate (0.227 ml, 1.950 mmol) in water/DMSO (0.22ml/2ml) at room temperature was added L-proline (0.045 g, 0.390 mmol), sodium carbonate (0.041 g, 0.390 mmol), sodium azide (0.152 g, 2.340 mmol), sodium l-ascorbate (0.039 g, 0.195 mmol) and copper(ll) sulfate pentahydrate (0.024 g, 0.097 mmol) (in this order) and the mixture was heated at 65 0C overnight. On cooling to room temperature, the mixture was quenched with aqueous ammonia (1 ml) and EtOAc (20ml) and water (20 ml) were added. The two phases were separated, and the aqueous phase was extracted with EtOAc (3 x 30 ml). All organic phases were combined and washed with water/brine (50ml) repeatedly. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to afford a crude product that was purified by MDAP to afford the title compound (6.5%); MH+=284.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux;
Example 67 (S)-2-[4-(2-Chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide To a stirred mixture of <strong>[2040-90-6]2-chloro-6-fluoro-phenol</strong> (2.92 g, 20.0 mmol) and ethyl-2-butynoate (4.37 g, 38.90 mmol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.04 g, 20.0 mmol) slowly. After addition was complete the mixture was stirred at reflux for 4 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10percent aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 120 g, 0percent to 20percent ethyl acetate/hexanes) to afford, (E)-3-(2-chloro-6-fluoro-phenoxy)-but-2-enoic acid ethyl ester (3.70 g, 71percent) as a colorless oil: 1H-NMR (300 MHz, CDCl3) delta ppm 1.14-1.30 (m, 3H), 2.55 (s, 3H), 3.94-4.25 (m, 2H), 4.81 (br. s., 1H), 7.02-7.21 (m, 3H).
With dmap; potassium carbonate In tetrahydrofuran at 25 - 85℃;
98
acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide A mixture of 5,6,7,8-tetrahydro-naphthalen-1-ol (3.00 g, 20.24 mmol) and ethyl-2-butynoate (13.62 g, 121.46 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (3.10 g, 22.43 mmol) and 4-dimethylaminopyridine (0.26 g, 2.12 mmol). The reaction was then heated at 85° C. overnight. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and was washed with water (1*100 mL) and a saturated aqueous sodium chloride solution (1*100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The material was taken up in ethyl acetate and absorbed onto silica gel. Purification by Analogix flash chromatography (115 g, 1-10% ethyl acetate/hexanes) afforded 3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (3.82 g, 72%) as a light yellow oil: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.1 Hz, 3H), 1.61-1.77 (m, 4H), 2.44 (s, 3H), 2.46 (br. s., 2H), 2.76 (br. s., 2H), 3.98 (q, J=7.1 Hz, 2H), 4.57 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 130℃; for 2h;
Example 33 (S)-3-Cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide To a stirred mixture of <strong>[10288-36-5]2,3-dihydro-1,4-benzodioxin-5-ol</strong> (1.00 g, 6.58 mmol) and ethyl-2-butynoate (1.48 g, 13.16 mmol) in tetrahydrofuran (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.00 g, 6.58 mmol). After addition was complete the mixture was stirred at 130 C. for 2 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue redissolved in dichloromethane and washed with 2N aqueous hydrochloric acid, 5% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 50% ethyl acetate/hexanes) to afford, 3-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-but-2-enoic acid ethyl ester (750 mg, 43%) as a colorless oil: LR-ES-MS m/z calculated for C14H16O5 [M]+ 264, observed [M+H]+ 265.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 25 - 130℃;
Example 97 (S)-2-[4-(3-Chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide A mixture of <strong>[2613-22-1]3-chloro-2-fluoro-phenol</strong> (1.31 g, 8.93 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130 C. for 2 h. At this time, the reaction was cooled to 25 C. and was stirred at 25 C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1*100 mL), a 1N aqueous sodium hydroxide solution (1*100 mL) and a saturated aqueous sodium chloride solution (1*100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 61%) as a white solid: HR-ES-MS m/z calculated for C12H12O3FCl [M+H]+ 259.0532, observed 259.0531; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.14 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.03 (q, J=7.1 Hz, 2H), 4.76 (s, 1H), 7.27-7.39 (m, 2H), 7.50-7.61 (m, 1H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 25 - 130℃;
Example 103 (S)-2-[4-(2-Fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide A mixture of <strong>[63762-79-8]2-fluoro-5-methyl-phenol</strong> (0.97 mL, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130 C. for 4 h. At this time, the reaction was cooled to 25 C. and was stirred at 25 C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1*100 mL), a 0.5N aqueous sodium hydroxide solution (1*100 mL) and a saturated aqueous sodium chloride solution (1*100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded 3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.12 g, 52%) as a clear oil: HR-ES-MS m/z calculated for C13H15O3F [M+H]+ 239.1078, observed 239.1078; 1H NMR (300 MHz, DMSO-d6) delta ppm 1.12 (t, J=7.0 Hz, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.69 (s, 1H), 7.01-7.19 (m, 2H), 7.30 (dd, J=10.7, 8.3 Hz, 1H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran Reflux;
72 (S)-2-[4-(3-Chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide
Example 72 (S)-2-[4-(3-Chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide To a stirred mixture of 3-chloro-2,6-difluoro-phenol (4.60 g, 28.0 mmol) and ethyl-2-butynoate (6.30 g, 56.0 mmol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene slowly (4.30 g, 28.0 mmol). After addition was complete the mixture was stirred at reflux for 4 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed with 1N aqueous hydrochloric acid, 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 20% ethyl acetate/hexanes) to afford, (E)-3-(3-chloro-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (6.44 g, 84%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.0 Hz, 3H), 2.54 (s, 3H), 4.13 (q, J=7.0 Hz, 2H), 4.90 (s, 1H), 6.98 (td, J=9.2, 2.1 Hz, 1H), 7.15-7.33 (m, 1H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 130℃; for 2h;Product distribution / selectivity;
To a stirred mixture of <strong>[72232-49-6]2-chloro-3-methoxyphenol</strong> (1.00 g, 6.31 mmol) and ethyl-2-butynoate (1.42 g, 12.62 mmol) in tetrahydrofuran (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (960 mg, 6.31 mmol). After addition was complete the mixture was stirred at 130 C. for 2 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue redissolved in dichloromethane and washed with 2N aqueous hydrochloric acid, 5% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 50% ethyl acetate/hexanes) to afford, 3-(2-chloro-3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 58%) as a colorless oil: LR-ES-MS m/z calculated for C13H15ClO4 [M]+ 270, observed [M+H]+ 271.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux;
Example 81 (S)-2-[4-(2-Ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide Hydrochloride To a stirred mixture of 2-ethoxy-phenol (10.3g, 74.5 mmol) and ethyl-2-butynoate (16.80 g, 149.0 mmol) in tetrahydrofuran (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene slowly (16.80 g, 149.0 mmol). After addition was complete the mixture was stirred at reflux for 4 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was taken up in diethyl ether and washed with 1N aqueous hydrochloric acid, 10% aqueous sodium hydroxide solution, saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 20% ethyl acetate/hexanes) to afford, (E)-3-(2-ethoxy-phenoxy)-but-2-enoic acid ethyl ester (8.57 g, 46%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta ppm 1.22 (t, J=7.1 Hz, 3H), 1.37 (t, J=6.9 Hz, 3H), 2.51 (s, 3H), 3.95-4.19 (m, 4H), 4.83 (s, 1H), 6.88-7.08 (m, 3H), 7.09-7.24 (m, 1H).
001018] (ii) Production of ethyl 5-(benzyloxy)-2-methylpyrazolo[l,5-a]pyridine-3-carboxylate [001019] To a solution of ethyl (lE)-N-{ [(2,4,6-trimethylphenyl)sulfonyl]oxy}ethanimidate (11 g, 37 mmol) in 1,2-dimethoxyethane (15 mL) was slowly added dropwise perchloric acid (5 mL) under ice- cooling. The mixture was stirred for 0.5 hr under ice-cooling, and water (20 mL) was added. Water (10 mL) was further added, and the mixture was stirred. The resulting precipitate was collected by filtration and washed with water. The obtained white solid was dissolved in ethyl acetate. The aqueous layer was separated and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the obtained solution was added dropwise to a solution of <strong>[49826-70-2]4-(benzyloxy)pyridine</strong> (5.6 g, 30 mmol) produced above in ethyl acetate (30 mL) under ice-cooling. After stirring at room temperature for 1 day, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to MPI09-013Pl RNWOM PCT FILING the obtained residue. The separated oil was washed with ethyl acetate/diethyl ether and diethyl ether, and concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.0 g, 36 mmol) and ethyl 2-butynoate (3.4 g, 30 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90?50/50), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (1.5 g, 16%) as a colorless solid.[001020] 1H-NMR (DMSO-d6, 300 MHz) delta 1.33 (3H, t, J = 7.0 Hz), 2.50 (3H, s), 4.26 (2H, q, J = 7.0 Hz), 5.26 (2H, s), 6.82 (IH, dd, J = 2.8, 7.6 Hz), 7.32 - 7.47 (4H, m), 7.47 - 7.54 (2H, m), 8.61 (IH, d, J = 7.6 Hz).
Step c: 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester: To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0 C followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (9.8 g, 44%) which was obtained as an off white solid. MS: m/e = 250.1 [M+H]+.
Step c: 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0 C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (9.8 g, 44%) which was obtained as an off white solid. MS: m/e=250.1 [M+H]+.
44%
With triethylamine; In diethyl ether; at 0 - 20℃;
To a solution of (E)- and/or (Z)-N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0 C followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (9.8 g, 44%) which was obtained as an off white solid. MS: m/e = 250.1 [M+H]+.
With mercury(II) diacetate In ethanol at 20℃; for 0.5h; regioselective reaction;
General One-Pot Procedure for the Preparation of Ethyl 5-Methyl-1,3-diaryl-1H-pyrazole-4-carboxylates 6
General procedure: Phenyl hydrazine (0.119 g, 1.00 mmol, 1.1 equiv) was added to a stirred solution of benzaldehyde (0.106 g, 1.00 mmol) in EtOH (5 mL). After stirring at room temperature for 15 min, the benzaldehyde phenyl hydrazone was formed (based on thin-layer chromatographic, TLC, analysis). Hg(OAc)2 (0.478 g, 1.5 mmol, 1.5 equiv) in 5 ml EtOH and ethyl but-2-ynoate (0.224 g, 2.00 mmol, 2.0 equiv) were added simultaneously to the reaction mixture from two separate droppers. The contents were then allowed to stir at room temperature for 30 min (1.0 h total). On completion of the reaction, the reaction mixture was extracted with ethyl acetate (3X5 mL). The combined organic layer was washed with 1 M KBr solution (to remove mercury salts) and with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The crude product was purified by column chromatography (n-hexane/EtOAc 95/05) to give two fractions. On evaporation, 6a was obtained as a white solid (0.277 g, 96%) and 8a as an off-white solid (0.057 g, 2%).
7-tert-butyl 5-ethyl 6-methylpyrrolo[1,2-b]pyridazine-5,7-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.2%
With potassium carbonate In dimethyl sulfoxide at 30℃; for 8h; Inert atmosphere;
22.1 Step 1: Synthesis of 7-tert-butyl 5-ethyl 6-methylpyrrolo[l,2-b]pyridazine- 5 7-dicarboxylate
To a solution of pyridazine (2.0 g, 25.0 mmol) in dimethyl sulfoxide (100.0 mL) was added ethyl but-2-ynoate (2.8 g, 25.0 mmol), tert-butyl 2-bromoacetate (4.87 g, 25.0 mmol) and potassium carbonate (6.9 g, 50.0 mmol). The resulting solution was stirred at 30 °C under N2 for 8 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed by brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 12: 1) to afford 7-tert-butyl 5-ethyl 6-methylpyrrolo[l,2-b]pyridazine- 5,7-dicarboxylate (620.0 mg, 8.2%) as a light yellow solid.
5-trifluoromethyl-2-methylpyrazolo[1,5-a]pyridin-3-carboxylate ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45.44%
2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (1.63g, 7.56mmol) was dissolved in anhydrous DCM (25mL) under ice-cooling. To this was slowly added dropwise <strong>[3796-24-5]4-<strong>[3796-24-5]trifluoromethylpyridine</strong></strong> (1.11g, 7.56mmol) in dry DCM (25mL) solution. After stirring at room temperature for 2h, the solvent was spin-dried under reduced pressure. 20mL anhydrous DMF (20mL), 2-butynoic acid ethyl ester (0.84g, 7.56mmol), and anhydrous K2CO3 (2.1g15.12mmol) were added and was stirred overnight at room temperature. TLC was used to determine reaction completion. Large amount of water was added. Extracted three times with ethyl acetate. The organic phase was collected and washed with brine three times. Purification by column chromatography gave 5-trifluoromethyl-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate ethyl ester, solid 0.94g (45.44%).
(Z)-ethyl 3-(4-methyl-1H-pyrazol-1-yl)but-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With gold(I) chloride; In 1,2-dichloro-ethane; for 16h;Inert atmosphere; Reflux;
General procedure: To a 100 mL round-bottomed flask was addedpyrazole (438 mg, 6.43 mmol, 1.5 equiv), gold(I) chloride (9.97 mg,0.043 mmol, 1 mol %), and ethyl 2-butynoate (0.5 ml, 4.29 mmol, 1.0 equiv)in ClCH2CH2Cl (12 ml) to give a very light yellow solution (with a little solid).The mixture was heated at 90 C under nitrogen for 15 h (LCMS indicated 82%conversion with 5% other isomers: entry 16). Most of the solvent wasevaporated under reduced pressure and the crude residue was directlysubject to flash silica gel column chromatography purification up to 50%EtOAc in hexane to afford 545 mg (70%) of 3a as a colorless oil.
1-acetyl-3,5-dimethyl-2-oxo-7-trifluoromethyl-1,2-dihydrobenzo[cd]indole-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With dichloro[1,3-di(ethoxycarbonyl)-2,4,5-trimethylcyclopentadienyl]rhodium(III) dimer; copper(II) acetate monohydrate; silver(I) triflimide In dichloromethane; acetone at 20℃; for 72h; Sealed tube;
1-acetyl-3,5-dimethyl-2-oxo-1,2-dihydrobenzo[cd]indole-4-carboxylic acid ethyl ester[ No CAS ]
ethyl 7-acetoxy-1-acetyl-3,5-dimethyl-2-oxo-1,2-dihydrobenzo[cd]indole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 38%
2: 23%
With dichloro[1,3-di(ethoxycarbonyl)-2,4,5-trimethylcyclopentadienyl]rhodium(III) dimer; copper(II) acetate monohydrate; silver(I) triflimide In dichloromethane; acetone at 20℃; for 72h; Sealed tube;
With silver trifluoromethane sulfate In chlorobenzene at 120℃; for 24h; regioselective reaction;
C. General procedure for the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones
General procedure: A mixture of 2-aminopyridine (0.1mmol), alkynoate (0.1mmol) and AgSO3CF3 (30mol%) in chlorobenzene (0.8mL) was stirred at 120°C for 24h. After the reaction was finished, water (5mL) was added and the solution was extracted with ethyl acetate (3×5mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
(E)-ethyl 3-methyl-5-(naphthalen-2-yl)pent-2-en-4-ynoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: Ethyl 2-butynoate With palladium diacetate; tris(2,6-dimethoxyphenyl)phosphine In benzene at 20℃; Inert atmosphere;
Stage #2: 2-ethynylnaphthalene In benzene Inert atmosphere;
(E)-ethyl 3-methyl-5-(naphthalen-2-yl)pent-2-en-4-ynoate (8h)
General procedure: In a two neck rbf was stirred a mixture of Pd(OAc)2 (275 mg,1.22 mmol) and TDMPP (540 mg, 1.22 mmol) in benzene (30 ml)for 15 min at rt under nitrogen. To this mixture was added ethyl-2-butynoate 7 (2.84 ml, 24.48 mmol) and the resulting mixturewas further stirred for 10 min at rt. Next, ethynylbenzene 4a(2.50 g, 24.48 mmol) was added to this solution and the mixturewas stirred for 5-10 min until reaction was completed. Theworkup of reaction was performed by evaporating the solvent invacuum followed by column chromatography (Hexane:EtOAc = 100:1) to give the desired compound 8a (2.62 g);
(E)-ethyl 5-(4'-chlorobiphenyl-4-yl)-3-methylpent-2-en-4-ynoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: Ethyl 2-butynoate With palladium diacetate; tris(2,6-dimethoxyphenyl)phosphine In benzene at 20℃; Inert atmosphere;
Stage #2: 4-chloro-4'-ethynylbiphenyl In benzene Inert atmosphere;
(E)-ethyl 5-(4'-chlorobiphenyl-4-yl)-3-methylpent-2-en-4-ynoate (8j)
General procedure: In a two neck rbf was stirred a mixture of Pd(OAc)2 (275 mg,1.22 mmol) and TDMPP (540 mg, 1.22 mmol) in benzene (30 ml)for 15 min at rt under nitrogen. To this mixture was added ethyl-2-butynoate 7 (2.84 ml, 24.48 mmol) and the resulting mixturewas further stirred for 10 min at rt. Next, ethynylbenzene 4a(2.50 g, 24.48 mmol) was added to this solution and the mixturewas stirred for 5-10 min until reaction was completed. Theworkup of reaction was performed by evaporating the solvent invacuum followed by column chromatography (Hexane:EtOAc = 100:1) to give the desired compound 8a (2.62 g);
(E)-ethyl 3-methyl-5-(3-nitrophenyl)pent-2-en-4-ynoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
Stage #1: Ethyl 2-butynoate With palladium diacetate; tris(2,6-dimethoxyphenyl)phosphine In benzene at 20℃; Inert atmosphere;
Stage #2: 3-nitrophenylacetylene In benzene Inert atmosphere;
(E)-ethyl 3-methyl-5-(3-nitrophenyl)pent-2-en-4-ynoate (8e)
General procedure: In a two neck rbf was stirred a mixture of Pd(OAc)2 (275 mg,1.22 mmol) and TDMPP (540 mg, 1.22 mmol) in benzene (30 ml)for 15 min at rt under nitrogen. To this mixture was added ethyl-2-butynoate 7 (2.84 ml, 24.48 mmol) and the resulting mixturewas further stirred for 10 min at rt. Next, ethynylbenzene 4a(2.50 g, 24.48 mmol) was added to this solution and the mixturewas stirred for 5-10 min until reaction was completed. Theworkup of reaction was performed by evaporating the solvent invacuum followed by column chromatography (Hexane:EtOAc = 100:1) to give the desired compound 8a (2.62 g);
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 36h; regioselective reaction;
General procedure to make 3:
General procedure: To a stirred solution of pseudouridine (1.0mmol) in DMF (10.0 mL) at room temp., DBU (1.0 mmol) was added and the mixture was stirred for 15 mins. After 15 min. propiolate (0.8 mmol) was added to the reaction mixture and stirred for 4 h. Another portion of propiolate (0.5 mmol) was added to the reaction mixture and was further stirred at room temp. for the time specified in Table 2. Then, the reaction mixture was evaporated under rotary evaporator to give crude reaction mixture. The crude reaction mixture was purified by reverse phase column chromatography using Biotage instrument (Column: KP-C18-HS 120 g; Flow rate: 50.0 mL; Mobile phase A: Water; Mobile phase B: Acetonitrile; Gradient: 0 - 100% B). The fractions containing the pure product were evaporated and dried to give a white colored powder 3.
ethyl 2-methyl-6-oxo-1-propyl-1,6-dihydropyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With Oxone; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; potassium acetate In 1,4-dioxane at 110℃; for 30h; Inert atmosphere; regioselective reaction;
With silver trifluoromethanesulfonate In N,N-dimethyl-formamide at 100℃; for 4h; Inert atmosphere;
General procedure for the heterogeneous Au(I)-catalyzed synthesis of quinolines
General procedure: To a solution of 2-aminoaryl carbonyl 1 (0.5 mmol), MCM-41-PPh3-AuCl (128 mg, 0.05 mmol), AgOTf (12.9 mg, 0.05 mmol) in DMF (5 mL) was added internal alkyne 2 (0.75 mmol) under Ar. The reaction mixture was stirred at 100°C for 4 h (TLC monitored). The resulting mixture was then diluted with ethyl acetate (20 mL) and filtered. The gold catalyst was washed with NH3·H2O (2 × 5 mL), distilled water (5 mL), and acetone (2 × 5 mL) and reused in the next run. The filtrate was washed with water (2 × 10 mL) and brine (2 × 10 mL), and the organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 15/1) to afford the desired product 3.
With piperidine; toluene-4-sulfonic acid In acetonitrile at 75℃; for 24h;
A general procedure for the synthesis of coumarin derivatives
General procedure: To a solution of salicylaldehyde (0.5 mmol, 1.0 equiv.) and p-toluenesulfonic acidmonohydrate (0.05 mmol, 0.1 equiv.) in acetonitrile (1.0 mL) was added alkynoic ester (0.6 mmol,1.2 equiv.) and piperidine (0.1 mmol, 0.2 equiv.). The reaction was stirred at 75 for 24 hours.The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, anddried over anhydrous Na2SO4. The solvent was removed in vacuo. The crude product was purifiedby flash column chromatography to give the desired product.
3-acetyl-6,8-bis(1,1-dimethylethyl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With piperidine; toluene-4-sulfonic acid In acetonitrile at 75℃; for 72h;
A general procedure for the synthesis of coumarin derivatives
General procedure: To a solution of salicylaldehyde (0.5 mmol, 1.0 equiv.) and p-toluenesulfonic acidmonohydrate (0.05 mmol, 0.1 equiv.) in acetonitrile (1.0 mL) was added alkynoic ester (0.6 mmol,1.2 equiv.) and piperidine (0.1 mmol, 0.2 equiv.). The reaction was stirred at 75 for 24 hours.The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, anddried over anhydrous Na2SO4. The solvent was removed in vacuo. The crude product was purifiedby flash column chromatography to give the desired product.
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