* 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 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
2
[ 58101-60-3 ]
[ 25125-21-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 18 h;
To a solution of 2 (8.6 g, 68 mmol) in THF (40.0 mL) at 0° C. was added LAH (54 mL, 1M solution in THF) under N2 atmosphere. The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was quenched with water and NaOH (10 w/t percent). The mixture was filtered through celite and solvent was removed to give compound 3 (6.6 g, 100percent).
95%
With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; Inert atmosphere
To a suspension of lithium aluminum hydride (15.2g, 0.40 mol) in anhydrous ether (1 L) at 0°C under nitrogen, was added the solution of methyl cyclopent-3-enecarboxylate (50 g, 0.40 mol) in ether (300 mL) dropwise over 5 hrs. The suspension was stirred at room temperature overnight. TLC indicated the completion of the reaction. The reaction was re-cooled to 0°C. Saturated solution of Na2S04 (32 mL) was added dropwise to quench the reaction. After the addition was complete, the mixture was stirred for another 3 hrs and was filtered through a pad of celite. Evaporation of solvent afforded cyclopent-3-enylmethanol 146-2 (37.3 g, 95 percent) as a colorless liquid.
Stage #1: With lithium aluminium tetrahydride; sodium hydroxide In tetrahydrofuran at -78℃; for 4 h; Inert atmosphere Stage #2: With sodium hydroxide In water at 0 - 20℃;
To a cold (—78° C.) solution of 703 (7 g, 50 mmol) in dry THF (150 mE) was added EiA1H4 (1 M soln in THF, 25 mE, 25 mmol), and the reaction solution was stirred at —78° C.under argon for 4 h. Then the reaction solution was allowed towarm to 0° C., and 2.5 mE of water, 2.5 mE of 15percent NaOH,and 7.5 mE of water were added sequentially. Afier warming to tt., the precipitates were filtered through a celite, and the celite was washed with hot EtOAc. The combined filtrateswere washed with 0.1 N NaOH, and brine, dried (MgSO4),filtered, concentrated and dried in vacuo to give 4.294 g(84percent) of 704 as a pale yellow liquid. ‘H NMR (400 MHz, CDC13) ö 5.68 (s, 2H, 2CH=CH), 3.57 (d, J=6.0 Hz, 2H, CH2OH), 2.54-2.48 (m, 3H, CH+CH2), 2.15-2.10 (m, 2H, CH2).
Reference：
[1] Organic Letters, 2006, vol. 8, # 26, p. 5947 - 5950
[2] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
[3] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 451 - 452
5
[ 35357-77-8 ]
[ 25125-21-7 ]
Reference：
[1] Synlett, 2005, # 5, p. 765 - 768
6
[ 7686-78-4 ]
[ 25125-21-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
[2] Journal of the American Chemical Society, 1982, vol. 104, # 3, p. 907 - 909
7
[ 84646-68-4 ]
[ 25125-21-7 ]
Reference：
[1] Synlett, 2005, # 5, p. 765 - 768
[2] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 451 - 452
8
[ 1781-66-4 ]
[ 25125-21-7 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 383 - 389
9
[ 21622-00-4 ]
[ 25125-21-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 9, p. 2784 - 2794
10
[ 18325-74-1 ]
[ 25125-21-7 ]
Reference：
[1] Patent: US9180138, 2015, B2,
11
[ 3195-24-2 ]
[ 25125-21-7 ]
Reference：
[1] Patent: US9180138, 2015, B2,
12
[ 14320-38-8 ]
[ 25125-21-7 ]
Reference：
[1] Journal of Organic Chemistry, 1969, vol. 34, # 4, p. 860 - 864
13
[ 4492-41-5 ]
[ 25125-21-7 ]
Reference：
[1] Journal of Organic Chemistry, 1969, vol. 34, # 4, p. 860 - 864
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).
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