* 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 N-iodo-succinimide; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In 1,2-dichloro-ethane; toluene at 85℃; for 14 h;
General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products.
36%
With iodine; Selectfluor In methanol at 50℃; for 21 h;
A mixture of p-anisaldehyde (1.00 g, 7.34 mmol), iodine (932 mg, 3.67 mmol) and selectfluor (1.56 g, 4.40 mmol) in 75 mL of methanol was heated at 50 °C for 21 h. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a brown residue. The residue was purified by column chromatography, eluting with 20-40percent gradient EtOAc in hexanes, to give 690 mg (36percent) of 3-iodo-4-methoxybenzaldehyde as a yellow solid; MS 263.1 (M+H).
Reference：
[1] European Journal of Organic Chemistry, 2000, # 8, p. 1527 - 1533
[2] European Journal of Organic Chemistry, 2012, # 30, p. 5935 - 5942,8
[3] Synthesis, 2010, # 16, p. 2776 - 2786
[4] Organic letters, 2003, vol. 5, # 4, p. 415 - 418
[5] Tetrahedron Letters, 1997, vol. 38, # 35, p. 6305 - 6306
[6] Synlett, 2014, vol. 25, # 3, p. 399 - 402
[7] Synthetic Communications, 2007, vol. 37, # 21, p. 3855 - 3860
[8] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1205 - 1217
[9] Organic Letters, 2018, vol. 20, # 23, p. 7726 - 7730
[10] Journal of Organic Chemistry, 2006, vol. 71, # 3, p. 1027 - 1032
[11] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6731 - 6734
[12] Patent: WO2009/76602, 2009, A1, . Location in patent: Page/Page column 124
[13] Journal of the Chemical Society, 1956, p. 1417,1418, 1421
[14] Journal fuer Praktische Chemie (Leipzig), 1899, vol. <2> 59, p. 143
[15] Tetrahedron Letters, 2004, vol. 45, # 43, p. 8083 - 8085
[16] Patent: WO2006/82245, 2006, A1, . Location in patent: Page/Page column 156
[17] Patent: US2005/65066, 2005, A1, . Location in patent: Page/Page column 69
[18] Patent: WO2004/80480, 2004, A1, . Location in patent: Page/Page column 150
[19] Patent: WO2006/5683, 2006, A1, . Location in patent: Page/Page column 151
[20] Patent: US2003/229120, 2003, A1, . Location in patent: Page 52
2
[ 105-13-5 ]
[ 2314-37-6 ]
[ 123-11-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With iodic acid In N,N-dimethyl-formamide at 60℃; for 2 h; Inert atmosphere
General procedure: To a solution of p-bromobenzyl alcohol I-1 (187 mg, 1.0 mmol) in DMF (2.0 mL) was added HIO3 (194 mg, 1.1 mmol). The mixture was stirred at 60 °C for 2 h under an Ar atmosphere. After the reaction, the reaction mixture was poured into aq Na2S2O3, and extracted with a mixture of Et2O: hexane=1:1 (3*10 mL). The organic layer was dried over Na2SO4. After being filtration and removal of the solvent under reduced pressure, the residue was purified by flash short column chromatography on silica gel (EtOAc-hexane, 1:4) to give p-bromobenzaldehyde II-1 in 95percent yield.
71%
With iodic acid In N,N-dimethyl-formamide at 20 - 60℃; for 2 h; Inert atmosphere
General procedure: 4-Bromobenzyl alcohol (187 mg, 1.0 mmol)Was dissolved in 2.0 mL of DMF solvent,This was mixed with iodic acid (194 mg, 1.1 mmol).The mixture was stirred for 2 hours at room temperature to 60 ° C. in an Ar atmosphere.To the reaction mixture was added aqueous sodium thiosulfate solution and extracted with diethyl ether: hexane = 1: 1 (3 × 10 mL).The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give 4-bromobenzaldehyde as a final product (yield 91percent). The same treatment was carried out except that the primary alcohol or secondary alcohol was used instead of 4-bromobenzyl alcohol used in Example 1 based on the following general formula (1) to obtain a carbonyl compound shown in Table 1 Were obtained in yields shown in Table 1, respectively.
Reference：
[1] Tetrahedron, 2016, vol. 72, # 44, p. 6948 - 6954
[2] Patent: JP2018/2680, 2018, A, . Location in patent: Paragraph 0032-0035
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane for 24h;
97%
With sulfuric acid; potassium 4-iodylbenzenesulfonate; iodine; acetic acid In water monomer; acetonitrile at 65℃; for 12h;
96%
With iodine; iodic acid; acetic acid In ethanol; water monomer for 3h; Reflux;
91%
With sodium (meta)periodate; sulfuric acid; iodine; acetic acid In water monomer at 90℃;
1 Synthesis of intermediate g
Take 4-methoxybenzaldehyde (6.8g, 50mmol), elemental iodine(6.3g, 25mmol), sodium periodate(2.7g, 12.5mmol) dissolved in acetic acid-water mixture (2:1,500mL)After slowly adding sulfuric acid (10 mL), react at 90°C overnight. cold However, the reaction solution was poured into 5 times the amount of ice water, and an appropriate amount of sodium bisulfite was added until the purple color disappeared and precipitation occurred. Suction filtration, filter cake It was washed with water and dried in vacuum to obtain a white solid with a yield of 91%.
87%
With selectfluor; iodine In acetonitrile at 20℃; for 12h;
85%
With iodine; 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In acetonitrile at 22℃; for 10h;
85%
With N-iodo-succinimide; Au(PPh<SUB>3</SUB>)NTf<SUB>2</SUB> In 1,2-dichloro-ethane; toluene at 85℃; for 14h;
General Procedure:
General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products.
83%
With iodine; acetic acid; periodic acid In water monomer Heating;
79%
With Iodine monochloride; acetic acid In dichloromethane at 60 - 80℃; for 24h;
78%
With Iodine monochloride In acetic acid at 140℃;
76%
With Iodine monochloride; acetic acid at 140℃; for 4h;
70%
With iodine; 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol at 50℃; for 21h;
53%
With iodine; (2,2,2-trifluoroacetyl)oxysilver at 20℃;
36%
With iodine; 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol at 50℃; for 21h;
A mixture of p-anisaldehyde (1.00 g, 7.34 mmol), iodine (932 mg, 3.67 mmol) and selectfluor (1.56 g, 4.40 mmol) in 75 mL of methanol was heated at 50 °C for 21 h. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a brown residue. The residue was purified by column chromatography, eluting with 20-40% gradient EtOAc in hexanes, to give 690 mg (36%) of 3-iodo-4-methoxybenzaldehyde as a yellow solid; MS 263.1 (M+H).
With ethanol; sulfuric acid; iodine; mercuric (II) oxide
With iodine; iodic acid at 100℃;
With Iodine monochloride In acetic acid at 60℃;
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane at 20℃;
172
4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 ml_). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3 x 20 ml_) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde.Mp 104-107 0C; HPLC-MS (Method A): m/z:263 (M+1 ); Rt = 3.56 min.;1H NMR (CDCI3): δH = 8.80 (s,1 H), 8.31 (d,1 H), 7.85 (dd,1 H) 6.92 (d,1 H), 3.99 (s, 3H).
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane at 20℃;
Preparation of the Starting Material, 3-iodo-4-methoxybenzaldehyde
Preparation of the Starting Material, 3-iodo-4-methoxybenzaldehyde 4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3*20 mL) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde. Mp 104-107° C.; HPLC-MS (Method A): m/z:263 (M+1); Rt=3.56 min.;1H NMR (CDCl3): δH=8.80 (s, 1H), 8.31 (d, 1H), 7.85 (dd, 1H) 6.92 (d, 1H), 3.99 (s, 3H).
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane at 20℃;
4-Methoxybenzaldehyde (0.5 g, 3.67 MMOL) and silver TRIFLUOROACETATE (0.92 g, 4.19 MMOL) were mixed in dichloromethane (25 mL). Iodine (1.19 G, 4.7 MMOL) was added in small por- tions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3 x 20 mL) followed by drying with MgS04 and evaporation in vacuo afforded 0.94 G of 3-IODO-4-METHOXYBENZALDEHYDE. Mp 104-107 °C ; HPLC-MS (Method A): m/z: 263 (M+1); Rt = 3.56 min.;'H NMR (CI3) : AH = 8.80 (s, 1H), 8.31 (d, 1H), 7.85 (DD, 1H) 6.92 (d, 1 H), 3.99 (s, 3H).
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane at 20℃;
172
4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small por¬ tions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3 x 20 mL) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybeϖzaldehydβ.Mp 104-107 0C; HPLC-MS (Method A): m/z:263 (M+1); Rt = 3.56 min.;*H NMR (CDCl3): δH = 8.80 (s,1H), 8.31 (d,1H), 7.85 (dd.1H) 6.92 (d,1H). 3.99 (s, 3H).
With iodine; (2,2,2-trifluoroacetyl)oxysilver In dichloromethane at 20℃;
150 Preparation of the starting material, 3-iodo-4-methoxybenzaldehyde:
4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3*20 mL) followed by drying with MgSO4 and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde. Mp 104-107° C.; HPLC-MS (Method A): m/z: 263 (M+1); Rt=3.56 min.; 1H NMR (CDCl3): δH=8.80 (s,1H), 8.31 (d,1H), 7.85 (dd,1H) 6.92 (d,1H), 3.99 (s, 3H).
With boron tribromide; In dichloromethane; at 0 - 20℃; for 24h;
Approximately 1 g of 3-iodo-4-methoxybenzaldehyde was added to 100 mL of anhydrous dichloromethane and stirred at 0 C. 0.405 mL of boron tribromide was added dropwise to the solution and was allowed to warm to room temperature over a period of 24 hours. Approximately 40 mL of water was then added to the solution to quench the reaction. The aqueous and organic layers were then separated and the aqueous layer was extracted with two 100 mL washings of ethyl acetate. The ethyl acetate layers were collected and combined with the organic layer from the initial separation. The combined organic layer was washed with 100 mL of water and 100 mL of brine and was then dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Thin layer chromatography was then applied to the crude product to determine the conditions for optimal separation by silica gel flash column chromatography. A mobile phase composition of 80% hexanes and 20% ethyl acetate provided the best separation of product from starting material. Fractions collected from the column which contained the product compound were combined and concentrated under vacuum. The final yield of purified product was approximately 46%. FIG. 3 and FIG. 4 show the respective proton NMR spectrum and MALDI MS of the synthesized 4-hydroxy-3-iodobenzaldehyde. 1H NMR (400 MHz, CDCl3) delta 9.81 (s, 1H), 8.22 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 5.84 (s, 1H). MALDI MS (M+H+) m/z 248.238.
3-(1-adamantylethynyl)-4-methoxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.4%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; for 10h;Reflux; Inert atmosphere;
[Synthesis of Compound F] [0185] Under the argon atmosphere, <strong>[40430-66-8]1-ethynyladamantane</strong> (192 mg, 1.20 mmol, commercially available product) was added at room temperature to a triethylamine (Et3N) (2 mL) solution of 3-iodo-4-methoxybenzaldehyde (262 mg, 1.00 mmol, commercially available product), dichlorobistriphenylphosphinepalladium ((Ph3P)2PdCl2) (35.1 mg, 50.0 mumol, commercially available product) and copper iodide (CuI) (5.7 mg, 30 mumol, commercially available product), and the mixture was heated to reflux for 10 hours. Water was added thereto and the mixture was extracted three times by use of ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1), thereby obtaining 3-(1-adamantylethynyl)-4-methoxybenzaldehyde (Compound F) (172 mg, 584 mumol, 58.4%) as a brown solid. [0186] mp 86-87 C. [0187] TLC Rf 0.35 (n-hexane/ethyl acetate=5/1) [0188] 1H NMR (CDCl3, 500 MHz) delta 1.72 (brs, 6H, adamantyl), 1.98 (brs, 9H, adamantyl), 3.93 (s, 3H, OCH3), 6.93 (d, J=8.5 Hz, 1H, aromatic), 7.75 (dd, J=2.0, 8.5 Hz, 1H, aromatic), 7.88 (d, J=2.0 Hz, 1H, aromatic), 9.83 (s, 1H, CHO) [0189] 13C NMR (CDCl3, 126 MHz) delta 27.9, 30.3, 36.3, 42.7, 56.2, 74.0, 104.0, 110.5, 114.2, 129.4, 130.8, 135.5, 164.3, 190.4 [0190] IR (cm-1) 814, 1138, 1271, 1501, 1684, 2359, 2849, 2903
N-(3-iodo-4-methoxybenzyl)-4-((2-methylpiperidin-1-yl)sulfonyl)aniline trifluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-((2-methylpiperidin-1-yl)sulfonyl)aniline; 3-iodo-4-methoxybenzaldehyde With N-ethyl-N,N-diisopropylamine In ethanol for 18h; Reflux;
Stage #2: With sodium tetrahydroborate; ethanol for 4h;
Stage #3: trifluoroacetic acid
1 Method C
General procedure: Sulfonamide formation by reaction with sulfonyl chloride intermediate, acetamide hydrolysis, and reaction between resulting amine and aromatic acid chloride
4-methoxy-3-((triphenylsilyl)ethynyl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.5%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine In tetrahydrofuran at 70℃; for 1.5h; Inert atmosphere; Sealed tube;
4.4.2. Sonogashira coupling reaction (procedure A)
General procedure: Synthesis of 3-((dimethylphenylsilyl)ethynyl)-4-methoxybenzaldehyde (S2) is shown as a representative. To a 20 mL cappedvial equipped with a magnetic stirrer bar were added 3-iodo-4-methoxybenzaldehyde (300 mg, 1.14 mmol, 1 equiv), PdCl2(PPh3)2(40.0mg, 57.0 mmol, 0.05 equiv), CuI (22.1mg, 0.116mmol, 0.1 equiv),PPh3 (30.9mg, 0.118mmol, 0.1 equiv),THF (2.9mL), Et3N(2.9mL), andethynyl(dimethyl)(phenyl)silane (222 mg, 1.38 mmol, 1.2 equiv),sequentially. The mixture was stirred for 90 min at 70 C and thencooled to room temperature. After dilution with Et2O (ca. 9 mL), themixturewas filtered through a pad of Celite 545, and the filtratewasconcentrated under reduced pressure. The residue was purified bysilica-gel column chromatography to afford S2 (311 mg, 1.06 mmol, 92.2%) as a brown oil.
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