With thionyl chloride In dichloromethane at 20℃; for 30 h; Reflux
A solution of 3-iodobenzyi alcohol (600 mg, 2.56 mmol) in DCM (3ml) was treated with thionyl chloride (3 ml, 41.3 mmol) and stirred at ambient temperature for 18h, before addition of further thionyl chloride (1 ml, 13.7 mmol) and heating to reflux for 12h. The cooled solution was basified with 50percent NaOH, diluted with water and extracted with DCM, The combined organics were dried over MgS04, filtered and evaporated to afford a clear syrup which crystallises on standing to give 3-iodobenzyl chloride as a white solid (650mg, quant.).
Reference：
[1] Patent: WO2011/86085, 2011, A1, . Location in patent: Page/Page column 39-40
[2] Recueil des Travaux Chimiques des Pays-Bas, 1923, vol. 42, p. 522
[3] Patent: EP1386913, 2004, A1, . Location in patent: Page 94
[4] Patent: WO2017/72021, 2017, A1, . Location in patent: Page/Page column 76
2
[ 10026-13-8 ]
[ 57455-06-8 ]
[ 60076-09-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1923, vol. 42, p. 522
3
[ 696-41-3 ]
[ 57455-06-8 ]
[ 618-51-9 ]
Reference：
[1] Trans. roy. Soc. Canada, 1934, vol. <3> 28 III, p. 97,98
[2] Trans. roy. Soc. Canada, 1934, vol. <3> 28 III, p. 97,98
4
[ 57455-06-8 ]
[ 696-41-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With pyridinium chlorochromate In dichloromethane at 20℃; for 2 h;
3-Iodobenzaldehyde (12) A suspension of pyridinium chlorochromate (2.45 g, 11.4 mmol) and dry celite (-2. 00 g) in dry dichloromethane (20 ml) was stirred at room temperature for 15 min. 3-Iodobenzyl alcohol (11) (1.02 g, 4.35 mmol) in dry dichloromethane (5 ml) was added. The suspension was shielded from light and stirred at room temperature for 2 h after which it was diluted with ether, and filtered through celite. The cloudy brown filtrate was concentrated to a red- brown gummy paste which was re-dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. This gave a clear, colourless solution which was concentrated to give 3-iodobenzaldehyde (12) as a white solid (0.953 g, 95percent). 1H nmr (400 Mz, CDC13) : 67. 29 (t, J 7. 8 Hz, 1H) H5; 7.85 (brd, J 7. 8 Hz, 1H) H6; 7.96 (brd, J7. 8 Hz, 1H) H4; 8.21 (brs, 1H) H2; 9.93 (s, 1H) CHO.
80%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane; acetonitrile at 20℃; for 3 h; 4 A molecular sieves
A solution of 3-iodobenzyl alcohol (Aldrich, 4.72g, 20 mmol) in dichloromethane (50mL) and acetonitrile (5mL) was treated sequentially with 4 A molecular sieves powder (5g), tetra-n-propyl ammoniumperruthenate (0. 1 g) and N-methyl morpholine-N-oxide (2.34g, 40mmol). After stirring at ambient temperature for 3h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10percent ethyl acetate in hexane as the eluent to afford the title compound (3.7g, 80percent). It was used as such for the next step.
80%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane; acetonitrile at 20℃; for 3 h; Molecular sieve
3-Iodo-benzaldehyde; A solution of 3-iodobenzyl alcohol (Aldrich, 4.72g, 20 mmol) in dichloromethane (50mL) and acetonitrile (5mL) was treated sequentially with 4 A molecular sieves powder (5g), tetra-n-propyl ammoniumperruthenate (0. lg) and N- methyl morpholine-N-oxide (2.34g, 40mmol). After stirring at ambient temperature for 3h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10percent ethyl acetate in hexane as the eluent to afford the title compound (3.7g, 80percent). It was used as such for the next step
90 %Chromat.
With dihydrogen peroxide In water; acetonitrile for 4 h; Reflux
General procedure: In a 25 mL round-bottomed flask equipped with a reflux condenser, a mixture of 1 g PWM/SiO2(M = Cr, Mn, Fe, Co, Ni, and Cu)catalyst containing 0.03 mmol POM, 3 mL acetonitrile and 1 mmol of alcohol was added. Then 1 mL of H2O2 30percent was added and the mixture was refluxed for 2 h with stirring. The progress of the reaction was monitored by GC equipped with a flame ionization detector and a silica pack column. At the end of reaction, the catalyst was filtered out and 10 mL NaHCO3 10percent was added. The organic phase extracted with chloroform and dried. Flash chromatography on a short column of silica gel with ethyl acetate:n-hexane as eluent gave pure products.
Reference：
[1] Advanced Synthesis and Catalysis, 2004, vol. 346, # 7, p. 767 - 776
[2] Patent: WO2005/82894, 2005, A1, . Location in patent: Page/Page column 41-42
[3] Bulletin of the Chemical Society of Ethiopia, 2013, vol. 27, # 1, p. 131 - 136
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 20, p. 3047 - 3052
[5] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[6] European Journal of Organic Chemistry, 2008, # 19, p. 3328 - 3334
[7] Synthetic Communications, 1988, vol. 18, # 1, p. 69 - 76
[8] Patent: WO2005/58301, 2005, A1, . Location in patent: Page/Page column 78
[9] Patent: WO2005/58798, 2005, A2, . Location in patent: Page/Page column 49
[10] Journal of the American Chemical Society, 2018, vol. 140, # 28, p. 8652 - 8656
[11] Chemistry - A European Journal, 2002, vol. 8, # 9, p. 2005 - 2010
[12] Advanced Synthesis and Catalysis, 2003, vol. 345, # 12, p. 1341 - 1352
[13] Tetrahedron, 1994, vol. 50, # 28, p. 8301 - 8316
[14] International Journal of Chemical Kinetics, 1997, vol. 29, # 1, p. 9 - 16
[15] Journal of Chemical Research, Miniprint, 1998, # 9, p. 2251 - 2272
[16] Journal of the American Chemical Society, 1999, vol. 121, # 39, p. 9073 - 9087
[17] Journal of Chemical Research, 2004, # 9, p. 581 - 584
[18] Journal of the Chemical Society. Perkin Transactions 2, 2002, # 6, p. 1151 - 1157
[19] Advanced Synthesis and Catalysis, 2003, vol. 345, # 4, p. 497 - 505
[20] Patent: US2006/111394, 2006, A1, . Location in patent: Page/Page column 14-15
[21] Tetrahedron, 2009, vol. 65, # 34, p. 6805 - 6809
[22] E-Journal of Chemistry, 2011, vol. 8, # 1, p. 264 - 268
[23] Journal of Molecular Catalysis A: Chemical, 2014, vol. 392, p. 8 - 15
[24] Journal of the Iranian Chemical Society, 2016, vol. 13, # 8, p. 1463 - 1470
[25] Angewandte Chemie - International Edition, 2018, vol. 57, # 33, p. 10535 - 10539[26] Angew. Chem., 2018, vol. 130, # 33, p. 10695 - 10699,5
5
[ 67-56-1 ]
[ 57455-06-8 ]
[ 618-91-7 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10776 - 10782
6
[ 201230-82-2 ]
[ 57455-06-8 ]
[ 52010-98-7 ]
[ 100-51-6 ]
Reference：
[1] Journal of the American Chemical Society, 1983, vol. 105, # 24, p. 7175 - 7176
[2] Journal of the American Chemical Society, 1986, vol. 108, p. 452
With thionyl chloride; In dichloromethane; at 20℃; for 30h;Reflux;
A solution of 3-iodobenzyi alcohol (600 mg, 2.56 mmol) in DCM (3ml) was treated with thionyl chloride (3 ml, 41.3 mmol) and stirred at ambient temperature for 18h, before addition of further thionyl chloride (1 ml, 13.7 mmol) and heating to reflux for 12h. The cooled solution was basified with 50% NaOH, diluted with water and extracted with DCM, The combined organics were dried over MgS04, filtered and evaporated to afford a clear syrup which crystallises on standing to give 3-iodobenzyl chloride as a white solid (650mg, quant.).
With thionyl chloride; In toluene; at 60 - 90℃; for 4h;
Reference example 15-1 Preparation for dimethyl (3-iodobenzyl)malonate To a solution of m-iodobenzylalcohol (5.0g, 21.4mmol) in toluene (60ml) was added thionyl chloride (5.5g, 46.2mmol), and the mixture was stirred for 2 hours at 60C. Additional thionyl chloride (3.5g, 29.4mmol) was added thereto and the mixture was further stirred for 2 hours at 90C. The reaction mixture was concentrated under reduced pressure to give a mixture of m-iodobenzyl chloride. To a solution of dimethyl malonate (2.3g, 17.4mmol) in methanol (20ml) was added sodium methoxide/methanol (28%, 3.3g, 17.4mmol), and the mixture was stirred for 2 hours at 60 C. Thereto was added the mixture of m-iodobenzyl chloride in tetrahydrofuran (50ml) at 60C and the mixture was stirred for 2 hours at 60C and for 90 hours at room temperature. The solvent was removed and the residue was diluted with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=8:1?2:1) to give the subject compound (0.98g, 16%).1H NMR (CDCl3, 400 MHz) delta 7.54 - 7.58 (m, 2 H), 7.17 (brd, 1 H, J = 7.9 Hz), 7.02 (brt, 1 H, J = 7.9 Hz), 3.71 (s, 6 H), 3.63 (t, 1 H, J = 7.8 Hz), 3.15 (d, 2 H, J = 7.8 Hz).
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 2h;
Methanesulfonylchloride (868 pL, 10.7 mmol) is added to a stirred solution of 3-lodo- benzyl alcohol (2.5 g, 11.2 mmol) and triethylamine (3.7 ml, 26.7 mmol) dissolved in dry DCM and the reaction mixture is stirred at room temperature for 2 hours. Water is added, the organic layer is separated and concentrated under reduced pressure toobtain the crude title compound (yield 2.5 g).GO (Method 9): tR = 7.91 mm; Mass spectrum (Eli-): mlz = 252 [M]
With borane tetrahydrofuran In tetrahydrofuran at 25℃; for 20h;
83%
With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
54%
Stage #1: 3-Iodobenzoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -8℃; for 0.5h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 10 - 20℃; for 22h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
1
3-Iodobenzvl alcohol (11) Ethyl chloroformate (1.02 g, 11.1 mmol) in dry tetrahydrofuran (5 ml) was added slowly over 10 min to a stirred solution of 3-iodobenzoic acid (1.98 g, 7.98 mmol) and triethylamine (0.500 g, 11.6 mmol) in dry tetrahydrofuran at-8° (ice/salt/water bath). The yellow mixture soon became cloudy. It was shielded from light and stirred at-8° for 0.5 h, after which it was filtered to remove the triethylammonium chloride precipitate. The filtrate was added slowly to a suspension of sodium borohydride (0.795 g, 21.1 mmol) in water (30 ml) in a three necked flask, equipped with a thermometer, and connected to nitrogen, making sure that the temperature of the mixture is kept below 10° during the addition. Gas evolution (carbon dioxide) was observed. After the addition was completed, the mixture was stirred, shielded from light, at room temperature for 22 h under nitrogen. The resultant cloudy mixture was acidified with aqueous hydrochloric acid (10%) to pH- 1. The layers were separated, and the aqueous layer was extracted with ether (x 3). The combined ether extract and tetrahydrofuran layer was washed with aqueous sodium hydroxide (x 1, 10%) and then with water (x 1). Drying with magnesium sulphate, and concentration gave 3-iodobenzyl alcohol (11) a pale yellow oil (1.02 g, 54%). IH nmr (400 MHz, CDC13) : 64. 66 (s, 2H) CH2 ; 7.10 (brt, J 7. 7 Hz, 1H) H5; 7.32 (brd, J 7.7 Hz, 1H) H6,7. 63 (brd, J 7. 7 Hz, 1H) H4; 7.74 (brs, 1H) H2.
With lithium aluminium tetrahydride; diethyl ether
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 2h;
3-Iodobenzaldehyde (12) A suspension of pyridinium chlorochromate (2.45 g, 11.4 mmol) and dry celite (-2. 00 g) in dry dichloromethane (20 ml) was stirred at room temperature for 15 min. 3-Iodobenzyl alcohol (11) (1.02 g, 4.35 mmol) in dry dichloromethane (5 ml) was added. The suspension was shielded from light and stirred at room temperature for 2 h after which it was diluted with ether, and filtered through celite. The cloudy brown filtrate was concentrated to a red- brown gummy paste which was re-dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. This gave a clear, colourless solution which was concentrated to give 3-iodobenzaldehyde (12) as a white solid (0.953 g, 95%). 1H nmr (400 Mz, CDC13) : 67. 29 (t, J 7. 8 Hz, 1H) H5; 7.85 (brd, J 7. 8 Hz, 1H) H6; 7.96 (brd, J7. 8 Hz, 1H) H4; 8.21 (brs, 1H) H2; 9.93 (s, 1H) CHO.
80%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 20℃; for 3h;4 A molecular sieves;
A solution of 3-iodobenzyl alcohol (Aldrich, 4.72g, 20 mmol) in dichloromethane (50mL) and acetonitrile (5mL) was treated sequentially with 4 A molecular sieves powder (5g), tetra-n-propyl ammoniumperruthenate (0. 1 g) and N-methyl morpholine-N-oxide (2.34g, 40mmol). After stirring at ambient temperature for 3h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10% ethyl acetate in hexane as the eluent to afford the title compound (3.7g, 80%). It was used as such for the next step.
80%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 20℃; for 3h;Molecular sieve;
3-Iodo-benzaldehyde; A solution of 3-iodobenzyl alcohol (Aldrich, 4.72g, 20 mmol) in dichloromethane (50mL) and acetonitrile (5mL) was treated sequentially with 4 A molecular sieves powder (5g), tetra-n-propyl ammoniumperruthenate (0. lg) and N- methyl morpholine-N-oxide (2.34g, 40mmol). After stirring at ambient temperature for 3h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10% ethyl acetate in hexane as the eluent to afford the title compound (3.7g, 80%). It was used as such for the next step
To a solution of oxalyl chloride (8.72 ml, 99.33 mmol) in anhydrous methylene chloride (240 ml) at -78 C. was added anhydrous dimethyl sulfoxide (14.12 ml, 199 mmol). After stirring for 15 minutes, 3-iodobenzyl alcohol was dissolved in 50 ml anhydrous methylene chloride and added dropwise to the chilled solution via syringe over four minutes. After 30 minutes, triethylamine (41.04 ml, 295 mmol) was added and stirred at -78 C. for one hour before being warmed to 0 C. After one hour, the reaction was poured into water (1 L) and the layers separated. The aqueous layer was extracted with diethyl ether (4×150 ml) and the combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography (SiO2, 300 g, 2:8 ethyl acetate/hexanes) yielded the product as an oil (26.83 g): 1H NMR (CDCl3, 300 MHz) delta 9.92 (s, 1H), 8.21 (s, 1H), 7.95 (d, 1H, J=7.0 Hz), 7.85 (d, 1H, J=7.5 Hz), 7.29 (t, 1H, J=8 Hz).
90%Chromat.
With dihydrogen peroxide; In water; acetonitrile; for 4h;Reflux;
General procedure: In a 25 mL round-bottomed flask equipped with a reflux condenser, a mixture of 1 g PWM/SiO2(M = Cr, Mn, Fe, Co, Ni, and Cu)catalyst containing 0.03 mmol POM, 3 mL acetonitrile and 1 mmol of alcohol was added. Then 1 mL of H2O2 30% was added and the mixture was refluxed for 2 h with stirring. The progress of the reaction was monitored by GC equipped with a flame ionization detector and a silica pack column. At the end of reaction, the catalyst was filtered out and 10 mL NaHCO3 10% was added. The organic phase extracted with chloroform and dried. Flash chromatography on a short column of silica gel with ethyl acetate:n-hexane as eluent gave pure products.
With dihydrogen peroxide; In water; acetonitrile; at 85℃; for 5.15h;
The typical procedure is the following: 3 mL CH3CN,0.01 mmol catalyst, and 1 mmol Benzyl alcohol were added to round-bottomed flask equipped with a reflux condenser.Then, 1 mmol aqueous H2O2 was dropwise added with in 5 min under stirring. The reaction time was counted after the addition of aqueous H2O2, and the reaction mixture was sampled periodically. The typical reaction temperature is 85 C, and reaction time is 3-7 h. The progress was monitored by TLC (EtOAc/n-hexane, 1/5). After completionof the reaction, the catalyst was separated from the product by filtration and the liquid was analyzed by a gas chromatograph.
With triethylamine In dichloromethane at 0℃; for 0.5h;
84%
Stage #1: 3-iodobenzylalcohol With triethylamine In tetrahydrofuran at 0℃;
Stage #2: methanesulfonyl chloride In tetrahydrofuran at 0 - 20℃;
General procedure for the preparation of benzyl mesylates
General procedure: To a flask that was charged with the benzyl alcohol (10 mmol), triethylamine (20 mmol) in THF (25 mL) cooled at 0 °C, was added mesyl chloride (20 mmol) in THF (50 mL) over half an hour. Then the mixture was allowed to stir at room temperature for about 20-30 min. Cold water was added to the mixture, then the mixture was extracted with diethyl ether (125 mLx1). Triethylamine (5 mol) was added into the crude product solution to remove the unreacted mesyl chloride. Then the solution was washed with saturated aqueous NaHCO3 (10 mL), cold water (25 mL) and brine (25 mL). The solution was dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the benzyl mesylate products, which are used in the coupling reaction without further purification.
80%
With triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere;
With triethylamine In tetrahydrofuran at 5℃; for 16h; Inert atmosphere;
Stage #1: 5-((trimethylsilyl)ethynyl)nicotinonitrile With tetrabutyl ammonium fluoride; triethylamine In tetrahydrofuran for 0.0833333h;
Stage #2: 3-iodobenzylalcohol With zinc dibromide In tetrahydrofuran at 55℃; for 2h;
197
Add a 1 M solution oftetrabutylammonium fluoride in THF (3. 33 mL, 3. 33 mmol) to a solution of 5-trimethylsilanylethynyl-nicotinonikile, (prepared as described in PREPARATION 3), (0. 801g, 4. 00 mmol), in tetrahydrofuran (8. 3 mL) and triethylamine (3. 34 mL). After 5 min add zinc (II) bromide (1. 56 g, 5. 99 mmol), 3-iodobenzyl alcohol (0. 42 mL, 3. 33 mmol), and tetrakis (triphenylphosphine) palladium (0) (269 mg, 0. 233 mmol). Heat to 55 °C for 2 h, cool to room temperature, and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 80 : 20 to 60 : 40 (1 : 1 hexanes : dichloromethane) : ethyl acetate, to give the title compound as a yellow crystalline solid (380 mg, 49%). 1HNMR (400 MHz, DMSO-d6) 6 4. 49 (d, J=5. 7 Hz, 2H), 5. 27 (t, J=5. 7 Hz, 1H), 7. 37- 7. 45 (m, 3H), 7. 52-7. 53 (m, 1H), 8. 53 (t, 1H, J=2. 0 Hz), 8. 98-8. 99 (m, 2H) ; MS (ES) : m/z= 235. 0 [M+H] +.
1
5-(3-{(1 R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-propyl)-thiophene-2-carboxylic acid isopropyl ester. The title compound was prepared from the corresponding acid using the standard procedure described in U.S. patent application Ser. No. 11/009,298, filed on Dec. 10, 2004 (now U.S. Pat. 7,091,231 issued Aug. 15, 2006). (E)-3-(3-Hydroxymethyl-phenyl)-acrylic acid methyl ester (2-3). The procedure described in Reich, S. H. et.al. J.Med.Chem. 2000, 43, 1670 was followed. Pd(OAc)2 (8.2 mg, 0.037 mmol) and triethylamine (0.360 mL, 2.58 mmol) were added to a solution of 3-iodobenzyl alcohol 2-1 (0.27 mL, 2.13 mmol) and methyl acrylate 2-2 (0.220 mL, 2.44 mmol) in CH3CN (4.5 mL). The reaction vessel was sealed with a Teflon screw-cap and was heated at 100° C. for 5 h. At this time, the reaction was allowed to cool to room temperature and the tube was charged with 0.22 mL more of methyl acrylate, 11.7 mg Pd(OAc)2 and 0.360 mL triethylamine. The reaction was heated at 100° C. overnight and then 10 mL saturated ammonium chloride solution was added. The resulting mixture was extracted with dichloromethane (3*40 mL) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (30% ethyl acetate/hexanes) gave 395 mg (97%) of 2-3. 3-(3-Hydroxymethyl-phenyl)-propionic acid methyl ester (2-4).
97%
With triethylamine In acetonitrile at 100℃;
2.a
The procedure described in Reich, S. H. etal. J. Med. Chem. 2000, 43, 1670 was followed. Pd(OAc)2 (8.2 mg, 0.037 mmol) and triethylamine (0.360 mL, 2.58 mmol) were added to a solution of 3-iodobenzyl alcohol 15 (0.27 mL, 2.13 mmol) and methyl acrylate 16 (0.220 mL, 2.44 mmol) in CH3CN (4.5 mL). The reaction vessel was sealed with a Teflon screw-cap and was heated at 100° C. for 5 h. At this time, the reaction was allowed to cool to room temperature and the tube was charged with 0.22 mL more of methyl acrylate, 11.7 mg Pd(OAc)2 and 0.360 mL triethylamine. The reaction was heated at 100° C. overnight and then 10 mL saturated ammonium chloride solution was added. The resulting mixture was extracted with dichloromethane (3*40 mL) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (30% ethyl acetate/hexanes) gave 395 mg (97%) of compound 17.
97%
With triethylamine In acetonitrile at 100℃;
1
5-(3-{(1R,2S,3R,5R)-5-ChIoro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-ρhenyl]-cyclopentyI}-propyI)-thiophene-2τ 1 carboxylic acid isopropyl ester.; The title compound was prepared from the corresponding acid using the standard procedure described. (E)-3-(3-Hydroxymethyl-phenyl)-acrylic acid methyl ester (19-3). The procedure described hi Reich, S.H. et.al. J.Med.Chem. 2000, 43, 1670 was followed. Pd(OAc)2 (8.2 mg, 0.037 mmol) and triethylamine (0.360 mL, 2.58 mmol) were added to a solution of 3-iodobenzyl alcohol 19-1 (0.27 mL, 2.13 mmol) and methyl acrylate 19-2 (0.220 mL, 2.44 mmol) in CH3CN (4.5 mL). The reaction vessel was sealed with a Teflon screw-cap and was heated at 100 °C for 5 h. At this time, the reaction was allowed to cool to room temperature and the tube was charged with 0.22 mL more of methyl acrylate, 11.7 mg Pd(OAc)2 and 0.360 mL triethylamine. The reaction was heated at 100 °C overnight and then 10 mL saturated ammonium chloride solution was added. The resulting mixture was extracted with dichloromethane (3 x 40 mL) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (30 % ethyl acetate/hexanes) gave 395 mg (97%) of 19-3.
With potassium fluoride; potassium carbonate In N,N-dimethyl-formamide at 175℃; for 6h;
46
Example 46; 5-Cyano-1-(3-imidazol-1-yl-benzyl)-1H-indole-2-carboxylic acid (3-hydroxy- 2,2dimethylpropyl)amide3-lodobenzylalcohol (5.17g, 21.0mmol), imidazole (1.73g, 25.2mmol), potassium carbonate (3.78g, 27.3mmol), copper (0) powder (275mg, 4.33mmol) and potassium fluoride (260mg, 4.44mmol) in DMF (30ml) were refluxed at 175°C for 6 h. The reaction was filtered, the solid washed with DCM and washing and filtrate concentrated. Purification by silica chromatography using DCM followed by DCM:MeOH (15:1 then 10:1) yielded (3-imidazol-1-yl-phenyl)-methanol as an orange oil (3.17g, 72%).
54%
With potassium phosphate; copper(l) iodide In N,N-dimethyl-formamide at 35 - 40℃; for 40h; Inert atmosphere; chemoselective reaction;
With potassium phosphate; copper(l) iodide; trans-1,2-cyclohexanediamine In 1,4-dioxane at 95℃; for 6.5h; Inert atmosphere;
3-Iodobenzyl alcohol (104.4 mg, 0.54 mmol) and 4-phenyl-lH-indole (128.9 mg, 0.551 mmol) were dissolved in 1,4- dioxane (1.0 mL). To this solution was added freshly ground potassium phosphate tribasic (230.4 mg, 1.09 mmol), racemic trans- 1 ,2-diaminocyclohexane (0.015 mL, 9.5 mg, 0.083 mmol) and copper (I) iodide (7.5 mg, 0.039 mmol). [see Antilla, J.C.; Klapars, A.;Buchwald, S.L.J. Am. Chem. Soc. 2002, 124, 11684. Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L. J. Am. Chem. Soc. 2001, 123, 7727] The solution was degassed for 5 minutes by bubbling nitrogen gas directly into the solution using a syringe needle. The vial was capped and stirred at 95 °C for 6.5 hours. The reaction turned a deep aqua blue during bubbling with nitrogen and then a pale purple after 5 minutes of heating. The reaction was poured into water (20 mL), extracted with 1 : 1 ethyl acetate -petroleum ether (30 mL), the organic layer was washed with water (15 mL) and brine (10 mL), concentrated, and purified by chromatography (12 g silica gel, 0% to 40% ethyl acetate -petroleum ether) to afford [3- (4-phenyl-lH-indol-l-yl)phenyl]methanol (104.8 mg, 65% yield) as a white crystalline solid; R/0.22 (20% ethyl acetate-petroleum ether); 1H NMR (400 MHz, CDC13) δ 7.71 (d, J = 7.5 Hz, 2H), 7.55-7.44 (m, 6H), 7.40-7.35 (m, 3H), 7.29 (t, J= 7.8 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 6.84 (d, J= 3.1 Hz, 1H), 4.79 (s, 2H), 1.85 (s, 1H) ppm; LRMS (ESI) m/z[M+H]+ = 300.41.
65%
With potassium phosphate; copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine In 1,4-dioxane at 100℃; for 24h; Inert atmosphere;
2.9 1.2.5. Procedure F: Copper catalyzed Indole coupling to aryl halide
General procedure: To a solution of indole derivative (1.0 equivalence) and aryl halide (1.2 equivalence) in 1, 4-Dioxane or Toluene (1.0 M), was added freshly ground potassium phosphate tribasic (2.2 equivalence), copper (I) iodide (0.07 equivalence) and racemic trans-N,N’-dimethylcyclohexane-1,2-diamine (0.15 equivalence). The suspension was degassed for 5 minutes by bubbling nitrogen gas directly into the solution using syringe needle. The reaction vessel was closed tightly and stirred at 100 oC for overnight or until the completion of reaction as judged by TLC. The reaction mixture was filtered through a pad of celite, poured into water (25 mL) and extracted with ethyl acetate (3 x 25 mL), the organic layer was washed with water (20 mL), dried over Na2SO4 and finally concentrated and purified by column chromatography.
With palladium diacetate; sodium carbonate; In water; N,N-dimethyl-formamide; at 55℃; for 1.5h;
1M ofaqueous Na2CO3 (34 mL) solution was added to3-iodo-benzyl alcohol 13 (2.72g, 11.6mmol) and 3- (methoxycarbonyl) phenylboronic acid (14) (2.009, 11.1 mmol) and DMF (7 mL ) solution of Pd (OAc)2 (56.2ng, 0.250 mmol) and was heated at 55 C for 1.5 hours. Thereaction solution was diluted with chloroform and filtered. Then the chloroformlayer was separated, and after washed with water and brine, it was dried overanhydrous sodium sulfate. Furthermore, it was vacuum concentrated, and purifiedby silica gel flash column (eluent 0-80% ethyl acetate / n-hexane) to obtain 3.85g of compound 15 as a pale brown oil.
With potassium carbonate; In acetone; for 6h;Reflux;
General procedure: <strong>[3470-50-6]6-Hydroxy-1-tetralone</strong> (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;
General procedure: A vial was charged with 5-bromopyrimidine (1.58 g, 10.0 mmol, 1.00 equiv), (3- hydroxyphenyl)boronic acid (2.07 g, 15.0 mmol, 1.50 equiv), 1,1'- bis(diphenylphosphino)ferrocenepalladiumdichloride (0.731 g, 1.00 mmol, 0.10 equiv), potassium carbonate (4.14 g, 30.0 mmol, 3.00 equiv), ethylene glycol dimethyl ether (16 mL) and water (4 mL). The resulting solution was stirred overnight at 80 C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (1/1) to provide 1.27 g (74% yield) of 3-(pyrimidin-5-yl)phenol as a yellow solid. LCMS (ESI, m/z): 173 [M+H]+.
With tetrabutylammomium bromide; potassium acetate; palladium diacetate; tris-(o-tolyl)phosphine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 4h;Schlenk technique; Inert atmosphere;
General procedure: Cross-coupling of 1a with Bi(p-tolyl) 3 : An oven-dried Schlenk tube was charged with (2-iodophenyl)methanol (1a) (0.75 mmol, 3 equiv.), Bi(p-tolyl) 3 (0.25 mmol, 1 equiv.), Pd(OAc) 2 (0.025 mmol, 0.1 equiv.), P(o-tolyl) 3 (0.1 mmol, 0.4 equiv.), KOAc(1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.) and NMP (3 mL) under a N 2atmosphere. The mixture was stirred in an oil bath at 110 C for 4 h. The contents were quenched with water (10 mL) at rt and extracted with ethylacetate (30 mL). The organic extract was washed with brine and dried usingMgSO 4 . The organic solvent was removed under reduced pressure to obtain thecrude product. It was puried by silica gel chromatography using hexane/ethylacetate as eluent. The product 2a was obtained in 74% yield. The spectralcharacterization data for all the products is given in the Supporting information.
With bis(triphenylphosphine)carbonylmonohydrate ruthenium dichloride at 150℃; for 5h; Inert atmosphere; Schlenk technique; Sealed tube;
98%
With bis(triphenylphosphine)carbonylmonohydrate ruthenium dichloride In toluene at 140℃; for 6h;
19 Example 19: Synthesis of 4-(3-iodobenzyl)thiomorpholine
Dissolve 3-iodobenzyl alcohol (0.702g, 3mmol) and thiomorpholine (0.103g, 1mmol) in 1mL of toluene, and combine with 0.01mmol (7.4mg) of bis(triphenylphosphine) carbonyl monohydrate dichloride Ruthenium is added to the pressure tube together, and reacted at 140°C for 6 hours.The obtained reaction solution was cooled to room temperature, desolvated, and purified by rapid preparative liquid chromatography (the volume ratio of ethyl acetate: petroleum ether was 5:100), the eluent containing the target compound was collected, and the reaction mixture was evaporated under reduced pressure to obtain 0.313g formula Compound shown in 3,The yield is 98%, and the liquid phase purity is 99%.
98%
With bis(triphenylphosphine)carbonylmonohydrate ruthenium dichloride In toluene at 140℃; for 6h;
19 Example 19: Synthesis of 4-(3-iodobenzyl)thiomorpholine
Dissolve 3-iodobenzyl alcohol (0.702g, 3mmol) and thiomorpholine (0.103g, 1mmol) in 1mL of toluene, and combine with 0.01mmol (7.4mg) of bis(triphenylphosphine) carbonyl monohydrate dichloride Ruthenium is added to the pressure tube together, and reacted at 140°C for 6 hours. The obtained reaction solution was cooled to room temperature, desolventized, and purified by rapid preparative liquid chromatography (the volume ratio of ethyl acetate: petroleum ether was 5:100), the eluent containing the target compound was collected, and the eluate was evaporated under reduced pressure to obtain 0.313g formula The compound shown in 3 has a yield of 98% and a liquid phase purity of 99%.
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