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Structure of 7686-77-3 * Storage: {[proInfo.prStorage]}
* 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] Organic Letters, 2015, vol. 17, # 4, p. 940 - 943
[2] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 451 - 452
[3] ChemMedChem, 2011, vol. 6, # 9, p. 1559 - 1565
2
[ 99-67-2 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2542 - 2553
3
[ 88326-51-6 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 451 - 452
[2] ChemMedChem, 2011, vol. 6, # 9, p. 1559 - 1565
[3] Organic Syntheses, 1998, vol. 75, p. 195 - 195
[4] Journal of Organic Chemistry, 1962, vol. 27, p. 2395 - 2398
[5] Journal of Organic Chemistry, 1984, vol. 49, # 5, p. 928 - 931
[6] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
[7] Organic Letters, 2006, vol. 8, # 26, p. 5947 - 5950
4
[ 7686-78-4 ]
[ 7686-77-3 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 3, p. 907 - 909
[2] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
5
[ 21622-00-4 ]
[ 7686-77-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
6
[ 124-38-9 ]
[ 1781-66-4 ]
[ 7686-77-3 ]
Reference：
[1] Tetrahedron, 1965, vol. 21, p. 25 - 30
[2] Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 383 - 389
7
[ 3195-24-2 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2542 - 2553
8
[ 4372-31-0 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2542 - 2553
9
[ 4492-41-5 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Organic Chemistry, 1969, vol. 34, # 4, p. 860 - 864
10
[ 14320-38-8 ]
[ 7686-77-3 ]
Reference：
[1] Journal of Organic Chemistry, 1969, vol. 34, # 4, p. 860 - 864
11
[ 67886-24-2 ]
[ 74-88-4 ]
[ 7686-77-3 ]
[ 6240-43-3 ]
[ 4541-43-9 ]
Reference：
[1] Synthesis, 1991, # 5, p. 395 - 398
12
[ 67-56-1 ]
[ 7686-77-3 ]
[ 58101-60-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 20℃; for 4 h;
To a solution of 1.1 (10 g, 89 mmol) in DCM (100 mL) at 0° C. under N2 atmosphere was added 1,1-carbonyldiimidazole (43 g, 267 mmol). The mixture was stirred at room temperature for 4 hours, then MeOH (100 mL) was added. The mixture was allowed to stir overnight. The solvent was evaporated at low temperature to afford 2 (11.2 g, 99percent).
Reference：
[1] Patent: US2007/254952, 2007, A1, . Location in patent: Page/Page column 35
[2] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 661 - 664
[3] ChemMedChem, 2011, vol. 6, # 9, p. 1559 - 1565
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 19, p. 5336 - 5339
13
[ 7686-77-3 ]
[ 74-88-4 ]
[ 58101-60-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 16 h;
To a solution of 3-cyclopentene-1-carboxylic acid (Org. Synth. 75, PL95-200, 1998) (31.5 g, 281 mmol) in anhydrous N, N-DIMETHYLFORMAMIDE (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 703 mmol), and iodomethane (35 mL, 563 mmol). The resulting mixture was stirred at room temperature for 16 hours, then poured into water (1 litre), and extracted with diethyl ether (3 x 400 mL). The combined diethyl ether layers were washed with water (3 x 500 mL), saturated NACL (200 mL), dried over MGS04, filtered and concentrated I71 VACUO, to give 34 g (96 percent) of crude product. H NMR (CDC13, 500 MHz) : 8 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J = 8.5 Hz, 1H), 2.63 (d, J = 8.3 Hz, 4 H).
96%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 16 h;
To a solution of 3-CYCLOPENTENE-1-CARBOXYLIC acid (Org. Synth. 75, PL95-200, 1998) (31.5 g, 281 mmol) in anhydrous N, N-DIMETHYLFORMAMIDE (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 710 MMOL), and iodomethane (35 mL, 560 mmol). The resulting mixture was stirred at room temperature for 16 h, then poured into water (1 L), and extracted with diethyl ether (3 x 400 mL). The combined diethyl ether layers were washed with water (3 x 500 mL), saturated NACI (200 ML), dried over MGS04, filtered and concentrated in vacuo, to give 34 g (96 percent). 'H NMR (CDCL3, 500 MHz) : 8 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J = 8.5 Hz, 1H), 2.63 (d, J = 8.3 Hz, 4 H).
96%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;
INTERMEDIATE 21; Step A; To a solution of 3-cyclopentene-1-carboxylic acid (Org. Synth. 75, p195-200, 1998) (31.5 g, 281 mmol) in anhydrous N,N-dimethylformamide (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 710 mmol), and iodomethane (35 mL, 560 mmol). The resulting mixture was stirred at room temperature for 16 h, then poured into water (1 L), and extracted with diethyl ether (3.x.400 mL). The combined diethyl ether layers were washed with water (3.x.500 mL), saturated NaCl (200 mL), dried over MgSO4, filtered and concentrated in vacuo, to give 34 g (96percent).1H NMR (CDCl3, 500 MHz): δ 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J=8.5 Hz, 1H), 2.63 (d, J=8.3 Hz, 4H).
Reference：
[1] Patent: WO2004/41777, 2004, A2, . Location in patent: Page 41-42
[2] Patent: WO2004/94371, 2004, A2, . Location in patent: Page 81-82
[3] Patent: US2008/81803, 2008, A1, . Location in patent: Page/Page column 35
[4] Chemical Communications, 2013, vol. 49, # 100, p. 11758 - 11760
With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 7 h;
(a) cyclopent-3-enylmethanol (0164) (0165) To a suspension of lithium aluminum hydride (0.5083 g, 13.37 mmol, 3eq) in dry 100 ml THF at −78° C., cyclopent-3-enecarboxylic acid (0.5000 g, 4.45 mmol) was added drop wise over 1 h. The mixture was stirred for 6 h, and then quenched with 15 ml 1M NaOH. Mixture was stirred for an additional 2 h, then concentrated and up taken in diethyl ether and dried over MgSO4 to afford clear liquid (3.79 mmol, MW 98.14 g/mol, 85percent).1H NMR (300 MHz, CDCl3): δ 2.12-2.16; (ttt 1H), 2.49-2.53; (dd, 2H), 3.57-3.58 (d, 3H, 5.14 Hz), 5.69; (s, 2H).
Reference：
[1] Tetrahedron, 2003, vol. 59, # 5, p. 671 - 676
[2] Journal of the American Chemical Society, 1982, vol. 104, p. 7105
[3] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 14, p. 2175 - 2178
[4] European Journal of Organic Chemistry, 2004, # 2, p. 289 - 303
[5] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 451 - 452
[6] Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 383 - 389
[7] Chemical Communications, 2013, vol. 49, # 100, p. 11758 - 11760
[8] Patent: US2016/206748, 2016, A1, . Location in patent: Paragraph 0164-0165
[9] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
[10] Canadian Journal of Chemistry, 1968, vol. 46, p. 3758 - 3762
[11] Journal of Organic Chemistry, 1969, vol. 34, # 4, p. 860 - 864
[12] Journal of Organic Chemistry, 1970, vol. 35, # 8, p. 2803 - 2806
[13] Tetrahedron: Asymmetry, 1994, vol. 5, # 3, p. 337 - 338
[14] Journal of the American Chemical Society, 1982, vol. 104, # 3, p. 907 - 909
[15] Organic Letters, 2006, vol. 8, # 26, p. 5947 - 5950
[16] Synlett, 2006, # 10, p. 1583 - 1585
[17] Organic Letters, 2008, vol. 10, # 2, p. 169 - 171
[18] Patent: WO2003/99795, 2003, A1, . Location in patent: Page 58
[19] Patent: WO2003/99289, 2003, A2, . Location in patent: Page 63
[20] Patent: WO2010/62415, 2010, A1, . Location in patent: Page/Page column 22
[21] Patent: EP2433926, 2012, A1, . Location in patent: Paragraph 0078; 0080
[22] Patent: WO2012/31307, 2012, A1, . Location in patent: Page/Page column 21
[23] Patent: WO2016/106623, 2016, A1, . Location in patent: Page/Page column 115
[24] Patent: WO2016/106624, 2016, A1, . Location in patent: Page/Page column 78-79
With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 7h;
(a) cyclopent-3-enylmethanol (0164) (0165) To a suspension of lithium aluminum hydride (0.5083 g, 13.37 mmol, 3eq) in dry 100 ml THF at -78 C., cyclopent-3-enecarboxylic acid (0.5000 g, 4.45 mmol) was added drop wise over 1 h. The mixture was stirred for 6 h, and then quenched with 15 ml 1M NaOH. Mixture was stirred for an additional 2 h, then concentrated and up taken in diethyl ether and dried over MgSO4 to afford clear liquid (3.79 mmol, MW 98.14 g/mol, 85%).1H NMR (300 MHz, CDCl3): delta 2.12-2.16; (ttt 1H), 2.49-2.53; (dd, 2H), 3.57-3.58 (d, 3H, 5.14 Hz), 5.69; (s, 2H).
EXAMPLE 64-(hvdroxymethyl)cyclopentane-l ,2-diyl dinitrateStep A: cyclopent-3-en-l~ymiethanol; A 2.0 M tetrahydrofuran solution of lithium aluminium hydride (11.2 mL, 22.5 mmol) was added dropwise to a tetrahydrofuran solution (45 mL) of 3-cyclopentene-l-carboxylic acid(2.33 mL, 22.5 mmol). The reaction mixture was stirred at room temperature for 16 hours.Water was added, and the solution was extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CHCl3) delta 2.04- 2.11 (m, 2H),2.20 (br s, IH), 2.43-2.49 (m, 3H)5 3.51 (d, J- 5.3 Hz, 2H), 5.64 (s, 2H).
A. Cyclopent-3-enyl-methanol 3.66g of LAH was suspended in 100 mL of THF and 10.49 g of cyclopent-3-enecarboxylic acid dissolved in 40 mL of THF was added dropwise. The mixture was kept at reflux for 2 h, cooled to rt and slowly water and 10% sulfuric acid were added. The mixture obtained was extracted with diethylether and the organic phase dried and carefully evaporated using a cold water bath. 10 g of Example 3 Step A product (still contains THF) was obtained as colorless liquid. 1H-NMR (200 MHz, CDC13, delta, ppm, characteristic signals): 1.73 (s, 1H), 2.10 (m, 2H), 2.50 (m, 3H), 3.49 (d, 2H, J=16Hz), 5.66 (s, 2H). TLC: toluene/EtOAc = 3:1, Rf = 0.35.
3.66g of LAH was suspended in 100 mL of THF and to the suspension obtained 10.49 g of cyclopent-3-enecarboxylic acid dissolved in 40 mL of THF was added dropwise. The mixture obtained was kept at reflux for 2 h, cooled to rt and slowly water and 10% sulfuric acid were added. The mixture obtained was extracted with diethylether, the organic phase obtained was dried and solvent was carefully evaporated using a cold water bath. 10 g of Example 3, Step A product (still contains THF) was obtained in the form of a colorless liquid.1 H-NMR (200 MHz, CDC13, delta, ppm, characteristic signals): 1.73 (s, 1H), 2.10 (m, 2H), 2.50 (m, 3H), 3.49 (d, 2H, J=16Hz), 5.66 (s, 2H). TLC: toluene/EtOAc = 3: 1, Rf = 0.35.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a suspension of LiAlH4(6.77 g, 178 mmol) in dry THF (100 mL) , was added cyclopent-3-enecarboxylic acid (5.0 g, 44.6 mmol) dropwise at 0 . After that, the temperature of the mixture was warmed to room temperature and stirred for 3 hours. A solution of NaOH (10 mL) in 10 mL of H2O was then added slowly and the mixture was stirred for 1 hour. After filtration, the filtrate was concentrated under vacuum to give cyclopent-3-en-1-ylmethanol which was used in next step without further purification.1H NMR (400MHz, DMSO-d6) 5.64 (s, 2H) , 4.54 (t, J5.3 Hz, 1H) , 3.26 (t, J5.5 Hz, 2H) , 2.38 -2.27 (m, 3H) , 2.09 -1.98 (m, 2H) ppm.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a suspension of LiAlH4 (6.77 g, 178 mmol) in dry THF (100 mL) , was added cyclopent-3-enecarboxylic acid (5.0 g, 44.6 mmol) dropwise at 0 . After that, the temperature of the mixture was warmed to room temperature and stirred for 3 hours. A solution NaOH (10 mL) in 10 mL of H2O was then added slowly and the mixture was stirred for 1 hour. After filtration, the filtrate was concentrated under vacuum to give cyclopent-3-en-1-ylmethanol which was used in next step without further purification. 1H NMR (400MHz, DMSO-d6) delta 5.64 (s, 2H) , 4.54 (t, J5.3 Hz, 1H) , 3.26 (t, J5.5 Hz, 2H) , 2.38 -2.27 (m, 3H) , 2.09 -1.98 (m, 2H) ppm.
With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 0.5h;
Example B Method B: Procedure for preparation of [4-CYCLOPENT-3-ENYLMETHYL-1,] 3-dihydro- imidazole-2-thione (Compound 18) OH H LiAIH4 H OH N DIBAL PPh3, DEAD H Intermediate B1 Intermediate B2 Intermediate B3 Intermediate B4 H 1) TosMIC N 1) PhOC (S) CI N 2) NH3, MEOH I' NH NaHC03, H20 NH nu 2) NEt3 Intermediate B5 Compound 18 A solution [OF 3-CYCLOPENTENE-1-CARBOXYLIC] acid (Intermediate [BL,] available from Aldrich, 2 g, 17.8 mmol) in ether (100 mL) was treated with LiAlH4 (19 [ML,] 1M in ether) at [0 C] for 30 min. The reaction mixture was quenched by addition of Rochelle's salt solution. The mixture was extracted with 50% Et2O : hexanes (3 x 50 mL). The extracts were dried over [MGS04,] filtered and evaporated to dryness. The material' (Intermediate B2) was used directly in the next step. A solution of triphenylphosphine (10.3 g, 39 mmol) in THF (50 mL) at [0 C] was treated with diethyl [AZODICARBOXYLATE] (DEAD) (6 mL) and the mixture was allowed to stir for about 5 min. A solution of cyclopent-3-enyl-methanol (Intermediate B2,1. 8 g, 18.3 mmol) and acetone cynaohydrin (3.4 mL, [38] mmol) in THF (50 [ML)] was added via syringe over 5 min. The mixture was allowed to stir at 0 ['C FOR] 40 min. The ice bath was removed and stirring was continued for 17h. The mixture was quenched with water and extracted with ether. The ether layer was dried over MgS04 and the mixture was carefully freed of solvent. The residue was purified by chromatography with 10 % ether : pentane to give cyclopent-3-enyl-acetonitrile (Intermediate B3) [1.] 16 g (60%) over two steps. A solution of (diisobutyl aluminum hydride (DIBAL) (7 mL, 1M in cyclohexane) was added to cyclopent-3-enyl-acetonitrile (Intermediate B3,520 mg, 4.9 mmol) [AT-70 C.] After 30 min, the mixture was quenched with Rochelle's salt solution. The aqueous phase was extracted with ether (3 x 20 mL) and the combined organic layers were dried over [MGS04,] filtered and evaporated to dryness. The crude aldehyde (Intermediate B4) (-0. 5 g) was employed in the next step. Formation of [4-CYCLOPENT-3-ENYLMETHYL-1,] 3-dihydro-imidazole-2-thione (Compound 18) was completed by employing the same procedure, without formation of the fumarate, as described in Example A, and indicated above in the reaction scheme. [1II NMR (500 MHZ, DMSO-D6 W/TMS) 6] 11.8 (s, 1H) 11.6 (s, 1H) 6.56 (s, 1H) 5.65 (s, 2H) 2.50-2. 35 (m, 5H), 1.98-1. 94 (m, 2H).
To a solution of 1.1 (10 g, 89 mmol) in DCM (100 mL) at 0 C. under N2 atmosphere was added 1,1-carbonyldiimidazole (43 g, 267 mmol). The mixture was stirred at room temperature for 4 hours, then MeOH (100 mL) was added. The mixture was allowed to stir overnight. The solvent was evaporated at low temperature to afford 2 (11.2 g, 99%).
80%
With sulfuric acid; at 0 - 80℃; for 6h;
A stirred solution of cyclopent-3-ene-l-carboxylic acid (250 g, 2.23 mol) in MeOH (2.0 L) at 0 C, was charged with H2S04 (10 mL) dropwise and the reaction mixture was heated at 80 C for 6 h. When TLC analysis showed complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (2.0 L). The organic layer was washed with saturated aqueous NaHC03 (2 L) and brine (2 L). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford title compound (225 g, 80%) as a colorless oil. 1H NMR (400MHz, CDC13): delta 5.67(s, 2H), 3.68 (s, 3H), 3.07-3.15 (m, 1H), 2.61-2.66 (m, 4H).
Stage #1: Dimethyl 3-cyclopentene-1,1-dicarboxylate With water; potassium hydroxide In ethanol at 45℃; for 14h; Inert atmosphere;
Stage #2: at 180℃; for 1h; Inert atmosphere;
Multi-step reaction with 2 steps
1: 45percent KOH / aq. ethanol / 15 h / Heating
2: 100 percent / 1 h / 185 - 195 °C
Multi-step reaction with 2 steps
1: water; potassium hydroxide / ethanol / 1 h / Reflux
2: 1 h / 180 °C / Neat (no solvent)
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;
To a solution of 3-cyclopentene-1-carboxylic acid (Org. Synth. 75, PL95-200, 1998) (31.5 g, 281 mmol) in anhydrous N, N-DIMETHYLFORMAMIDE (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 703 mmol), and iodomethane (35 mL, 563 mmol). The resulting mixture was stirred at room temperature for 16 hours, then poured into water (1 litre), and extracted with diethyl ether (3 x 400 mL). The combined diethyl ether layers were washed with water (3 x 500 mL), saturated NACL (200 mL), dried over MGS04, filtered and concentrated I71 VACUO, to give 34 g (96 %) of crude product. H NMR (CDC13, 500 MHz) : 8 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J = 8.5 Hz, 1H), 2.63 (d, J = 8.3 Hz, 4 H).
96%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;
To a solution of 3-CYCLOPENTENE-1-CARBOXYLIC acid (Org. Synth. 75, PL95-200, 1998) (31.5 g, 281 mmol) in anhydrous N, N-DIMETHYLFORMAMIDE (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 710 MMOL), and iodomethane (35 mL, 560 mmol). The resulting mixture was stirred at room temperature for 16 h, then poured into water (1 L), and extracted with diethyl ether (3 x 400 mL). The combined diethyl ether layers were washed with water (3 x 500 mL), saturated NACI (200 ML), dried over MGS04, filtered and concentrated in vacuo, to give 34 g (96 %). 'H NMR (CDCL3, 500 MHz) : 8 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J = 8.5 Hz, 1H), 2.63 (d, J = 8.3 Hz, 4 H).
96%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
INTERMEDIATE 21; Step A; To a solution of 3-cyclopentene-1-carboxylic acid (Org. Synth. 75, p195-200, 1998) (31.5 g, 281 mmol) in anhydrous N,N-dimethylformamide (300 mL), under an atmosphere of nitrogen, was added potassium carbonate (97 g, 710 mmol), and iodomethane (35 mL, 560 mmol). The resulting mixture was stirred at room temperature for 16 h, then poured into water (1 L), and extracted with diethyl ether (3×400 mL). The combined diethyl ether layers were washed with water (3×500 mL), saturated NaCl (200 mL), dried over MgSO4, filtered and concentrated in vacuo, to give 34 g (96%).1H NMR (CDCl3, 500 MHz): delta 5.64 (s, 2H), 3.68 (s, 3H), 3.11 (quintet, J=8.5 Hz, 1H), 2.63 (d, J=8.3 Hz, 4H).
With diphenylphosphoranyl azide; triethylamine;copper(I) chloride; In dichloromethane; tert-butyl alcohol;
a tert-Butyl N-(3-cyclopenten-1-yl)carbamate To a solution of 3-cyclopentene-1-carboxylic acid (J.-P. Depres and A. E. Greene, J. Org. Chem. 1984, 49:928-931; 29.71 g, 0.261 mole), triethylamine (36.4 mL) in t-butanol (1 L) was added diphenylphosphoryl azide, Aldrich, 97%, 74.0 g, 0.261 mmole). The solution was maintained at 60-- C. for 4 hours. Cuprous chloride (1.3 g) was added and stirring continued at ambient temperature for 18 hours. Volatiles were evaporated and the residue was dissolved in methylene chloride (1250 mL) and washed with 10 % aqueous sodium carbonate (2*250 mL) and dried (magnesium sulfate). Volatiles were evaporated and the residue was chromatographed on a silica gel column. Title compound was eluted with chloroform as white crystals, from hexanes (22.63 g, 47%), m.p. 68-70 C. Anal. Calcd for C10 H17 NO2: C, 65.54 H, 9.35; N, 7.64. Found: C, 65.53; H, 9.40; N, 7.59. b) (+-)-(1alpha, 2beta, 4alpha)-4-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol
4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With LiAlH4; diisobutylaluminium hydride; triphenylphosphine; In tetrahydrofuran; cyclohexane; acetone;
Example B Method B: Procedure for Preparation of 4-cyclopent-3-enylmethyl-1,3-dihydroimidazole-2-thione (Compound 18) A solution of 3-cyclopentene-1-carboxylic acid (Intermediate B1, available from Aldrich, 2 g, 17.8 mmol) in ether (100 mL) was treated with LiAlH4 (19 mL, 1M in ether) at 0 C. for 30 min. The reaction mixture was quenched by addition of Rochelle's salt solution. The mixture was extracted with 50% Et2O:hexanes (3*50 mL). The extracts were dried over MgSO4, filtered and evaporated to dryness. The material (Intermediate B2) was used directly in the next step. A solution of triphenylphosphine (10.3 g, 39 mmol) in THF (50 mL) at 0 C. was treated with diethyl azodicarboxylate (DEAD) (6 mL) and the mixture was allowed to stir for about 5 min. A solution of cyclopent-3-enyl-methanol (Intermediate B2, 1.8 g, 18.3 mmol) and acetone cynaohydrin (3.4 mL, 38 mmol) in THF (50 mL) was added via syringe over 5 min. The mixture was allowed to stir at 0 C. for 40 min. The ice bath was removed and stirring was continued for 17 h. The mixture was quenched with water and extracted with ether. The ether layer was dried over MgSO4 and the mixture was carefully freed of solvent. The residue was purified by chromatography with 10% ether:pentane to give cyclopent-3-enyl-acetonitrile (Intermediate B3) 1.16 g (60%) over two steps. A solution of (diisobutyl aluminum hydride (DIBAL) (7 mL, 1M in cyclohexane) was added to cyclopent-3-enyl-acetonitrile (Intermediate B3, 520 mg, 4.9 mmol) at -70 C. After 30 min, the mixture was quenched with Rochelle's salt solution. The aqueous phase was extracted with ether (3*20 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude aldehyde (Intermediate B4) (~0.5 g) was employed in the next step. Formation of 4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 18) was completed by employing the same procedure, without formation of the fumarate, as described in Example A, and indicated above in the reaction scheme. 1H NMR (500 MHz, DMSO-d6 w/TMS) delta 11.8 (s, 1H) 11.6 (s, 1H) 6.56 (s, 1H) 5.65 (s, 2H) 2.50-2.35 (m, 51), 1.98-1.94 (m, 21).
4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With LiAlH4; diisobutylaluminium hydride; triphenylphosphine; In tetrahydrofuran; cyclohexane; acetone;
Example B Method B: Procedure for Preparation of 4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 18) A solution of 3-cyclopentene-1-carboxylic acid (Intermediate B1, available from Aldrich, 2 g, 17.8 mmol) in ether (100 mL) was treated with LiAlH4 (19 mL, 1M in ether) at 0 C. for 30 min. The reaction mixture was quenched by addition of Rochelle's salt solution. The mixture was extracted with 50% Et2O:hexanes (3*50 mL). The extracts were dried over MgSO4, filtered and evaporated to dryness. The material (Intermediate B2) was used directly in the next step. A solution of triphenylphosphine (10.3 g, 39 mmol) in THF (50 mL) at 0 C. was treated with diethyl azodicarboxylate (DEAD) (6 mL) and the mixture was allowed to stir for about 5 min. A solution of cyclopent-3-enyl-methanol (Intermediate B2, 1.8 g, 18.3 mmol) and acetone cynaohydrin (3.4 mL, 38 mmol) in THF (50 mL) was added via syringe over 5 min. The mixture was allowed to stir at 0 C. for 40 min. The ice bath was removed and stirring was continued for 17 h. The mixture was quenched with water and extracted with ether. The ether layer was dried over MgSO4 and the mixture was carefully freed of solvent. The residue was purified by chromatography with 10% ether:pentane to give cyclopent-3-enyl-acetonitrile (Intermediate B3) 1.16 g (60%) over two steps. A solution of (diisobutyl aluminum hydride (DIBAL) (7 mL, 1M in cyclohexane) was added to cyclopent-3-enyl-acetonitrile (Intermediate B3, 520 mg, 4.9 mmol) at -70 C. After 30 min, the mixture was quenched with Rochelle's salt solution. The aqueous phase was extracted with ether (3*20 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude aldehyde (Intermediate B4) (0.5 g) was employed in the next step. Formation of 4-cyclopent-3-enylmethyl-1,3-dihydro-imidazole-2-thione (Compound 18) was completed by employing the same procedure, without formation of the fumarate, as described in Example A, and indicated above in the reaction scheme. 1H NMR (500 MHz, DMSO-d6 w/TMS) delta 11.8 (s, 1H) 11.6 (s, 1H) 6.56 (s, 1H) 5.65 (s, 2H) 2.50-2.35 (m, 5H), 1.98-1.94 (m, 2H).
Example 1 Preparation of ethyl-3-cyclopentene-1-carboxylate (5) A solution of 3-cyclopentene-1-carboxylic acid (500 g, 4.45 mole) in ethanol (500 mL) was stirred at 5-10 C. Then thionyl chloride (257.59 g, 2.16 mole) was added in a drop wise manner for 1 hr. After complete addition was over, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into the water (1000 mL) and extracted with ethyl acetate (2*250 mL). The ethyl acetate layer was washed with 10% sodium carbonate solution (500 mL), with water (2*500 mL) and concentrated to give ethyl-3-cyclopentene-1-carboxylate (5). Yield: 558 g, 89.42%.
84%
With thionyl chloride; at 5 - 20℃; for 0.5h;
[00208] To a solution of 3-cyclopentene-1-carboxylic acid (200 g, 1.79 mol) in ethanol (2 L) was added thionyl chloride (106 g, 0.892 mol) dropwise at 5-10C. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was poured into water and then extracted with EtOAc (2 L). The organic layer was washed with 10% aqueous sodium carbonate, dried over anhydrous Na2SO4 and concentrated to afford ethyl cyclopent-3-ene-1-carboxylate (210 g, 84% yield) as a pale yellow oil.
54%
With thionyl chloride; at 0 - 20℃;
To a stirred solution of cyclopent- 3-enecarboxylic acid (10 g, 89.3 mmol) in anhydrous ethanol (30 mL) was added sulfurous dichloride (15.9 g, 134 mmol) at 0 C. The reaction mixture was stirred at roomtemperature overnight and then concentrated. The residue was poured into water. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel columnchromatography (2.5 % ethyl acetate in petroleum ether) to give the desired product (6.7 g, 47.9 mmol, yield = 54%) as a yellow oil which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ ppm 5.66 (s, 2H), 4.18-4.10 (m, 2H), 3.16- 3.05(m, 1H), 2.66 (s, 2H), 2.63 (s, 2H), 1.29-1.24 (t, J=9.4, 3H).
A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0 C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0 C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0 C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 muL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0 C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic).
With potassium tert-butylate; isopropyl alcohol; In 2-methyltetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
General procedure: To a solution of methyl/ethyl ester (1.0 equiv) in 20 mL 2-MeTHF under N2 was added IPA (0.2 equiv),CH3CN (1.0 equiv), followed by KOt-Bu (1.0 equiv). The reaction mixture was stirred at room temperaturefor an hour under N2 atmosphere, then dosed-up with an additional 1.0 mol equiv of CH3CN and KOt-Bu,respectively. The reaction mixture was stirred for another hour, quenched with 200 mL of saturated NH4Cl solution and the layers separated. The aqueous layer was extracted with 200 mL DCM. The combinedorganic layer was dried over Na2SO4, filtered and the solvents removed in vacuo by roto-evaporation. Theresulting residue was purified by SiO2 gel column chromatography using EtOAc/hexane mixtures as mobilephases.
With water; lithium hydroxide; In tetrahydrofuran; at 25℃; for 15h;
To a solution of methyl 1-methylcyclopent-3-ene-1-carboxylate (50 g, 396 mmol) in THF:H2O (500 mL:125 mL) at 25 C. was added LiOH (19 g, 793 mmol). After 15 h, the reaction mixture was extracted with EtOAc. The aqueous layer was then acidified to pH=3 with 1N HCl and extracted with EtOAc (3*1 L). The combined organic extracts were combined, dried (Na2SO4) and filtered. The filtrate was concentrated to afford 40 g (90%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 5.68 (s, 2H), 3.29-3.03 (m, 1H), 2.82-2.53 (m, 4H).
With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Schlenk technique; Inert atmosphere;
8
Replace the gas environment in the Shrek tube with a nitrogen environment, add 3-cyclopentenecarboxylic acid 0.25 mmol, palladium acetate 0.00125 mmol, methylene chloride 0.5 mL, add pinacol borane 0.275 mmol under stirring, and react at room temperature for 12 h After the completion of the reaction, the reaction liquid obtained was subjected to column chromatography, and the target product obtained with a yield of> 99% was a colorless liquid.
99%
With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction;
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