* 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, 2006, vol. 8, # 13, p. 2779 - 2782
[2] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6190 - 6199
2
[ 5159-41-1 ]
[ 4387-36-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 120℃; for 18 h;
The reaction was carried out using o-iodobenzyl alcohol (i.e., R1 in the formula (I) o) 1.0 mmol (234.0 mg)The procedure and procedure were the same as in Example 1, aqueous ammonia (1.6 mol / L) 5.0 mL, catalyst copper sulfate was used in an amount of 5 molpercent (8.0 mg)TEMPO is used in an amount of 8 molpercent (12.5 mg) at a reaction temperature of 120 ° C and a reaction time of 18 h. The crude product is purified by column chromatography(Petroleum ether: ethyl acetate = 10: 1) to give the pure title product at 206.1 mg yield of 90percent.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; ammonium acetate In water; acetonitrile at 20℃; for 4 h;
General procedure: To a solution of alcohol (1 mmol) in MeCN–H2O (9:1, 3 mL) were successively added TEMPO (7.8 mg,5 molpercent), NH4OAc (0.308 g, 4 equiv), and PhI(OAc)2 (0.708g, 2.2 equiv). The suspension was stirred at roomtemperature (progress of the reaction was monitored byTLC) for the reaction time indicated in Table 2. The resultantclear two-phase reaction mixture was concentrated, dilutedwith H2O and Et2O, and the organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography(PE–Et2O or PE–CH2Cl2) to give 2.
Reference：
[1] Patent: CN106866326, 2017, A, . Location in patent: Paragraph 0055; 0056; 0057; 0058; 0059
[2] ChemistryOpen, 2018, vol. 7, # 11, p. 885 - 889
[3] Synlett, 2014, vol. 25, # 9, p. 1275 - 1278
3
[ 5159-41-1 ]
[ 28272-96-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 32, p. 7245 - 7252
4
[ 5159-41-1 ]
[ 26260-02-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With silica gel; pyridinium chlorochromate In dichloromethane at 20℃; Inert atmosphere
PCC (415mg, 1.93mmol, 1.2equiv.) and celite (1.75g) were dried under vacuum in 2-neck-flask and then flushed with nitrogen. After suspension in 19.3mL of dry DCM, a solution of o-iodobenzyl alcohol (14) (390mg, 1.60mmol, 1.0equiv.) in dry DCM (5.33mL) was added drop wise at room temperature. The reaction mixture turns from red to brown and then black, and is stirred at ambient temperature overnight. After filtration through celite, the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (short column, eluent Hexanes/EtOAc=9/1), yielding 367mg (98percent) of aldehyde 15. (0055) Rf (Hexanes/EtOAc=9/1)=0.63; 1H NMR (400MHz, CDCl3) δ (ppm)=10.1 (1H, s, H-7), 7.97 (1H, dd, H-3, J=8.0, 1.0Hz), 7.87 (1H, dd, H-6, J=8.0, 1.8Hz), 7.42–7.48 (1H, m, H-4), 7.25–7.31 (1H, m, H-5); 13C NMR (101MHz, CDCl3) δ (ppm)=195.9 (C-7), 140.8 (C-4), 135.6 (C-3), 135.3 (C-1), 130.4 (C-5), 128.9 (C-6), 100.9 (C-2).
95%
With pyridinium chlorochromate In dichloromethane at 20℃; for 2 h;
2-Iodobenzaldehvde (19); A suspension of pyridinium chlorochromate (8.28 g, 38.4 mmol) and dry celite (5.00 g) in dry dichloromethane was stirred at room temperature for 15 min. 2-Iodobenzyl alcohol (3.03 g, 12.9 mmol) in dry dichloromethane (50 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 solid which was dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. The solution was concentrated to give 2- iodobenzaldehyde (19) as a pale yellow oil (2.87 g, 95percent). 1H nmr (400 MHz, CDC13): 87. 29 (Td, J 8. 0,1. 8 Hz, 1H) H4, H6; 7.46 (brt, J 8. 0 Hz, 1H) H5,7. 88 (dd, J8. 0,1. 8 Hz, 1H) H6; 7.95 (d, J 8.0 Hz, 1H) H3; 10.07 (s, 1H) CHO.
92%
With pyridinium chlorochromate In dichloromethane at 20℃;
2- iodo- benzyl alcohol ( 2 - iodobenzylalcohol ) ( 10 g , 42.73 mmol ) and dichloromethane ( Dichloromethane ) in 200 mLAfter mixing and put into a pyridine -chloro formate ( pyridium chlorochromate ) ( 10.13 g , 47 mmol ) was stirred at room temperature .After the reaction was completed the solvent was removed and column chromatography (ethyl acetate ( ethyl acetate ) : hexane ( hexane ) =1: 8) to perform , to give a yellow liquid The compound 23-2 ( 2 - iodobenzaldehyde ) ( 9.1g , 92percent)
92%
With pyridinium chlorochromate In dichloromethane at 20℃;
Synthesis of Intermediate 1-(2) (0183)10 g(42.73 mmol) of 2-iodobenzylalcohol was added to 200 mL of dichloromethane, 10.13 g (47 mmol) of pyridine chlorochromate (PCC) was added thereto, and was then stirred at room temperature. When the reaction was complete, the solvent was removed, and column chromatography (ethyl acetate: hexane=1:8) was used to obtain 9.1 g of Intermediate 1-(2) (2-iodobenzaldehyde) as a yellow liquid (yield: 92percent). (0184)1H NMR (300 MHz, CDCl3): δ (ppm) 10.09 (s, 1H), 7.94 (dd, J=15.0, 7.2 Hz, 2H), 7.48 (s, 1H), 7.30 (s, 1H) (0185) A molecular weight for C7H5IO: Cal. 231.9385 (0186) LR-Mass (EI+): 232.0, HR-Mass (EI+): 231.9393
91%
With manganese(IV) oxide In dichloromethaneReflux
Preparation Example 63: Synthesis of 2-iodobenzenealdehydeIn a flask, 2-iodobenzyl alcohol (4g, 17.09mmol) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide (Mn02, 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6g, yield 91percent).1H NMR(400MHz, CDCl3)57.30~7.99(m, 4H), 10.10(s, 1H)
91%
With manganese(IV) oxide In dichloromethaneReflux
Preparation Example 63 Synthesis of 2-iodobenzenealdehyde In a flask, 2-iodobenzyl alcohol (4 g, 17.09mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO2, 14.86 g, 170.92mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6 g, yield 91percent). 1H NMR(400 MHz, CDCl3)δ7.30~7.99(m, 4H), 10.10(s, 1H)
91%
With manganese(IV) oxide In dichloromethaneReflux
Preparation Example 63 Synthesis of 2-iodobenzenealdehyde In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO2, 14.86 g, 170.92 mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6 g, yield 91percent). 1H NMR (400 MHz, CDCl3) δ7.30~7.99 (m, 4H), 10.10 (s, 1H)
91%
With manganese(IV) oxide In dichloromethaneReflux
Preparation Example 63 Synthesis of 2-iodobenzenealdehyde In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO2, 14.86 g, 170.92 mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6 g, yield 91percent). 1H NMR (400 MHz, CDCl3) δ7.30˜7.99 (m, 4H), 10.10 (s, 1H)
91%
With manganese(IV) oxide In dichloromethaneReflux
In a flask, 2-iodobenzyl alcohol (4g, 17.09mmol) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide (Mn02, 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6g, yield 91percent). 1H NMR(400MHz, CDCl3)57.30~7.99(m, 4H), 10.10(s, 1H)
90%
With manganese(IV) oxide In dichloromethaneReflux
Preparation example 16: 2-Iodobenzenealdehyde In a flask, 2-.iodobenzyl alcohol (4g, 17.09mmo 1 ) was dissolved in dichloromethane (MC, 85ml), and then, manganese oxide ( M11O2 , 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under reflux. When the reaction was completed, the obtained reaction product was cooled to room temperature, and then, filtered and concentrated using celite, to obtain the title compound (3.6g, yield 75~90percent) . lH NMR (400MHz, CDC 13) δ 7.30~7.99(m, 4H), lO.HXs, 1H)
90%
With manganese(IV) oxide In dichloromethane at 20℃; for 30 h;
To a THF solution (16 mL) of commercially available o-iodobenzoicacid (4.15 g, 16.8 mmol) was added boran–dimethylsulfide complex (1.90 mL, 20.0 mmol) at 0°C. After stirring for 15 h at room temperature, phosphate buffer (pH 7) was added. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, o-iodobenzylalcohol (3.84 g, 98 percent) was obtained as a white solid and used for the next step without further purification. To a DCM suspension (33 mL) of manganese(IV) oxide (14.0 g, 161 mmol) was added the crude o-iodobenzylalcohol (3.77 g, 16.1 mmol). After stirring for 30 h at room temperature, the resulting suspension was filtrated through a small pad of celite using DCM as an eluent. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give o-iodobenzaldehyde (3.36 g,90percent) as pale yellow crystals.
89%
With 1-hydroxy-1H-1,2,3-benziodoxathiole 1,3,3-trioxide; Oxone; cetyltrimethylammonim bromide In water at 20℃; for 2 h; Green chemistry
General procedure: The alcohol (2 mmol) was added to a solution of IBS (0.02 mmol, 0.01 eq), oxone (2.2 mmol, 1.1 equiv.) and 3 wtpercent CTAB solution (5 mL). The mixture was stirred at room temperature. The reaction was monitored by TLC. After completion, the solution was extracted with CH2Cl2 (3 × 10 mL). The combined organic phase was then filtered through a pad of silica gel and evaporated under vacuum to afford the desired product.
89%
at 100℃; for 18 h;
General procedure: In a 150 mL thick-walled pressure tube equipped with a magnetic stirrer,In an air atmosphere,To the system was added benzyl alcohol (i.e., R1 in formula (I) H) 1.0 mmol (108.1 mg)Ammonia (1.6 x 10-2 mol / L) 5.0 mL,5 molpercent (9.5 mg) of cuprous iodide,TEMPO 5 molpercent (7.8 mg),100 & lt; 0 & gt; C for 12 h,After the reaction is over,The reaction solution was cooled to room temperature,And extracted with ethyl acetate (3 x 5.0 mL). The organic layers were combined and concentrated in vacuo to remove ethyl acetate to give the crude product. The crude product was purified by column chromatography(Petroleum ether: ethyl acetate = 10: 1) to give the pure desired product.The yield of 97.6 mg was 92percent.
88%
With oxygen In N,N-dimethyl-formamide at 20℃; for 6 h; UV-irradiation
General procedure: A 25 mL round-bottomed flask was charged with alcohol (1 mmol),3D-RGO/ZnO (40 mg) and N,N-dimethyl formamide (5 mL). The resultant mixture was stirred under O2 with two white LED lamps (12W). After completion of the reaction, the 3D-RGO/ZnO catalyst was recycled by filtration and the organic phase of the filtrate was extracted with EtOAc, washed three times with water and dried over Na2SO4.The pure product was then isolated by silica chromatography using petroleum ether/EtOAc mixtures as the eluent.
85%
With iron(II) triflate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N-(4-methoxyphenyl)glycine; oxygen In tert-Amyl alcohol for 24 h; Reflux; Green chemistry
Equipped with a magnetic stirrer in round bottom flask methyl benzyl alcohol (12. 22g, 100. Ommol, namely formula The R1 is 4-methyl, R2 is hydrogen, X is carbon, η is 1, m is 0), ferric chloride (0. 81g, 5mmol), L- isoleucineAcid (1.31g, 10mmol), TEMP0 (1.56g, 10mmol), toluene 300. OmL was added , then the reaction with oxygen in the air bottleReplacement, stirred and reflux for 6h. After completion of reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate evaporated to give the crude product,The resultant crude product was purified by column chromatography, with n-hexane: Elution: (10 1 volume ratio) mixed liquid of ethyl acetate containing the desired collectionLabeled compound of the eluent, evaporation of the solvent and dried to give the product p-tolualdehyde 10. 93g, 91percent yield. The reactants adjacent iodobenzene methanol (2. 34g, 10. Ommol, i.e., of formula (I), R1 is iodo, R 2 isHydrogen, X is carbon, [eta] is 1, m is 0) is taken, experimental methods and procedures were the same as in Example 1, except that: ferrous trifluoromethanesulfonate(0 · 35g, 1. Ommol), 4- methoxyphenyl Glycine (0 · 18g, 1 · Ommol), TEMPO (0 · 16g, 1 · Ommol), tert-amyl alcohol 30. OmL, oxygen the reaction was stirred at reflux bottle of air displacement 24h. To give the final product 1. 97g, yield 85percent.
69%
With tert.-butylhydroperoxide; N,N'-ortho-phenylene-bis(salicylideneiminato) copper(II); sodium hydroxide In water; acetonitrile at 20℃;
General procedure: Alcohol (0.5 mmol), salophen copper (II) complex (2 molpercent), NaOH (0.6 equiv), and 70percent TBHP in water (1.1 equiv) were dissolved in acetonitrile (5 mL), and the homogeneous solution was stirred at room temperature in air overnight. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified over silica gel by column chromatography (10–25percent EtOAc in hexane).
65%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water at 25℃; for 24 h; Micellar solution
General procedure: A vial was charged with alcohol (1 mmol), IBX (1.2 mmol, 1.2 equiv) and 2 wt percent GMPGS-2000/H2O solution (5 mL). The mixture was stirred for 24 h at 25 °C and filtered. The solid was washed with CH2Cl2 and the filtrate was extracted with CH2Cl2 (3×10 mL). Then, the organic phase was combined and dried with anhydrous Na2SO4, evaporated to dryness. The crude product was purified was purified by column chromatography on silica gel eluted with (petroleum ether/EtOAc) to afford the desired product.
99.9 %Chromat.
With sodium bromate; acetic acid In water at 75℃; for 5 h;
In a 25 ml Kjeldahl flask equipped with a magnetic stirrer and a reflux condenser, 2.30 g (9.8 mmols) of o-iodobenzyl alcohol and 5 ml of (87 mmols) of acetic acid were charged and an aqueous solution prepared by dissolving 0.50 g (3.33 mmols) of sodium bromate in 3 ml of water was added dropwise over 2 hours under stirring. After the completion of dropwise addition, stirring was conducted at 75°C for 3 hours. With respect to the components in the reaction solution, an area ratio as determined by gas chromatography of the intended o-iodobenzaldehyde was 99.9percent or more. It was confirmed by GS-MS that a molecular ion peak is 232.
3.6 g
With manganese(IV) oxide In dichloromethaneReflux
In a flask, 2-iodobenzyl alcohol (4g, 17.O9mmol) was dissolved in dichioromethane (MC, 85m1), and then, manganese oxide (Mn02, 14.86g, 170.92mmol) was added thereto. The obtained reaction product was stirred under reflux. When the reaction was completed, the obtained reaction product was cooled to room temperature, and then, filtered and concentrated using celite, to obtain the titlecompound (3.6g, yield 75r’9Opercent).1H NMR(400MHz, CDCI3)67.30”7.99(m, 4H), 10.10(s, 1H)
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5
[ 609-67-6 ]
[ 26260-02-6 ]
[ 5159-41-1 ]
Reference：
[1] European Journal of Organic Chemistry, 1998, # 4, p. 671 - 678
6
[ 88-67-5 ]
[ 5159-41-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 15 h;
To a THF solution (16 mL) of commercially available o-iodobenzoicacid (4.15 g, 16.8 mmol) was added boran–dimethylsulfide complex (1.90 mL, 20.0 mmol) at 0°C. After stirring for 15 h at room temperature, phosphate buffer (pH 7) was added. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, o-iodobenzylalcohol (3.84 g, 98 percent) was obtained as a white solid and used for the next step without further purification. To a DCM suspension (33 mL) of manganese(IV) oxide (14.0 g, 161 mmol) was added the crude o-iodobenzylalcohol (3.77 g, 16.1 mmol). After stirring for 30 h at room temperature, the resulting suspension was filtrated through a small pad of celite using DCM as an eluent. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give o-iodobenzaldehyde (3.36 g,90percent) as pale yellow crystals.
94%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 16 h; Inert atmosphere
To a solution of 2-iodobenzoic acid (5.3 g, 21 mmol) in tetrahydrofuran (43 mL) at 0 °C, was addedborane-dimethyl sulfide (2.2 mL, 24 mmol) dropwise over 20 minutes. The reaction mixture wasstirred vigorously at room temperature for 16 hours then quenched with methanol (1 mL) followed bya saturated aqueous solution of potassium carbonate (5 mL). The layers were separated and theaqueous layer extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washedwith water (10 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The crude product was recrystallised from hexanes affording(2-iodophenyl)methanol S1 (4.7 g, 94percent) as long white crystals; mp 90–92 °C (lit.,1 90–95 °C); Rf =0.82 (1:1 hexanes-ethyl acetate); δH (400 MHz; CDCl3) 7.82 (1H, d, J = 7.6 Hz, ArH), 7.46 (1H, dd, J= 7.6, 1.5 Hz, ArH), 7.40 (1H, t, J = 7.6 Hz, ArH), 7.00 (1H, dt, J = 7.6, 1.5 Hz, ArH), 4.68 (2H, d,J = 6.2 Hz, CH2), 2.00 (1H, t, J = 6.2 Hz, OH); The spectroscopic data were in agreement with thatreported in the literature.
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[2] Patent: CN105237342, 2016, A, . Location in patent: Paragraph 0023; 0027; 0040
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[ 99948-46-6 ]
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[3] Chinese Journal of Chemistry, 2012, vol. 30, # 5, p. 1189 - 1191
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[ 118-92-3 ]
[ 5159-41-1 ]
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[2] Organic Letters, 2015, vol. 17, # 17, p. 4180 - 4183
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[ 609-67-6 ]
[ 26260-02-6 ]
[ 5159-41-1 ]
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14
[ 62300-07-6 ]
[ 5159-41-1 ]
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15
[ 18698-96-9 ]
[ 5159-41-1 ]
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[1] Journal of Organic Chemistry, 1960, vol. 25, p. 424 - 428
16
[ 52470-94-7 ]
[ 5159-41-1 ]
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[1] Journal of Organic Chemistry, 1960, vol. 25, p. 424 - 428
17
[ 66370-75-0 ]
[ 5159-41-1 ]
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[1] Journal of Organic Chemistry, 1960, vol. 25, p. 424 - 428
18
[ 101290-83-9 ]
[ 5159-41-1 ]
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[1] Journal of Organic Chemistry, 1960, vol. 25, p. 424 - 428
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[ 40400-13-3 ]
[ 5159-41-1 ]
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[2] Journal of the Chemical Society, 1958, p. 1375,1378
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[ 26260-02-6 ]
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[ 5159-41-1 ]
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[ 80953-51-1 ]
[ 5159-41-1 ]
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22
[ 615-37-2 ]
[ 5159-41-1 ]
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[1] Journal of the Chemical Society, 1958, p. 1375,1378
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[ 116599-64-5 ]
[ 64-19-7 ]
[ 5159-41-1 ]
[ 7782-50-5 ]
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24
[ 5344-90-1 ]
[ 5159-41-1 ]
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25
[ 5159-41-1 ]
[ 40400-13-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 150℃; for 2 h;
To 2-iodobenzyl alcohol (0.94 g, 4.0 mmol) were added hydrobromic acid (48percent, 10 mL) and sulfuric acid (98percent, 2 mL). The resulted suspension was heated and stirred on an oil bath (150 °C) for 2 h. The reaction mixture was then cooled down to room temperature and extracted with CH2Cl2 (2 x 10 mL). The organic layer was dried over MgSO4, and concentrated to a residual, which was purified with flash column chromatography (SiO2, 0-20percent CH2Cl2/hexanes), affording 2-iodobenzyl bromide (8, 1.0 g, 84percent yield).
91%
With phosphorus tribromide In methanol; diethyl ether; hexane
Step A: Preparation of 1-(Bromomethyl)-2-iodobenzene To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91percent) of the title material of Step A as a solid, mp 55-57° C.
91%
With phosphorus tribromide In methanol; diethyl ether; hexane
Step A Preparation of 1-(Bromomethyl)-2-iodobenzene To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-water bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91percent) of the title material of Step A as a solid, mp 55°-57° C.
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[1] Tetrahedron, 2005, vol. 61, # 13, p. 3311 - 3324
[2] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5705 - 5713
[3] Helvetica Chimica Acta, 1995, vol. 78, p. 765 - 771
[4] Tetrahedron, 1993, vol. 49, # 20, p. 4439 - 4446
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[6] Journal of Organic Chemistry, 2000, vol. 65, # 20, p. 6398 - 6411
[7] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1648 - 1655
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3632 - 3638
[9] Collection of Czechoslovak Chemical Communications, 1972, vol. 37, p. 1734 - 1747
[10] Organic Letters, 2003, vol. 5, # 7, p. 1115 - 1117
[11] Patent: US5977149, 1999, A,
[12] Patent: US5747516, 1998, A,
[13] Journal of Organic Chemistry, 2010, vol. 75, # 24, p. 8410 - 8415
[14] Synthesis (Germany), 2013, vol. 45, # 4, p. 545 - 555
[15] Patent: US2014/248242, 2014, A1, . Location in patent: Paragraph 0348
[16] Tetrahedron, 2016, vol. 72, # 48, p. 7875 - 7887
[17] Organic Letters, 2018, vol. 20, # 11, p. 3310 - 3313
[18] Organic Letters, 2018, vol. 20, # 24, p. 7898 - 7901
26
[ 5159-41-1 ]
[ 40400-13-3 ]
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[1] Patent: EP728018, 2003, B1,
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[2] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5705 - 5713
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[2] Chemistry - A European Journal, 2017, vol. 23, # 60, p. 15046 - 15049
[3] Organic Letters, 2018, vol. 20, # 2, p. 345 - 348
[4] Journal of Organic Chemistry, 2018, vol. 83, # 13, p. 7250 - 7270
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 16h;
100%
With sodium tetrahydridoborate; iodine In tetrahydrofuran at 0 - 20℃;
100%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 25℃; for 16.1667h;
99%
With dimethylsulfide borane complex In tetrahydrofuran for 12h; Ambient temperature;
99%
With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 12h;
98%
With dimethylsulfide borane complex at 0 - 20℃; for 15h;
98%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 15h;
o-Iodobenzaldehyde
To a THF solution (16 mL) of commercially available o-iodobenzoicacid (4.15 g, 16.8 mmol) was added boran-dimethylsulfide complex (1.90 mL, 20.0 mmol) at 0°C. After stirring for 15 h at room temperature, phosphate buffer (pH 7) was added. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, o-iodobenzylalcohol (3.84 g, 98 %) was obtained as a white solid and used for the next step without further purification. To a DCM suspension (33 mL) of manganese(IV) oxide (14.0 g, 161 mmol) was added the crude o-iodobenzylalcohol (3.77 g, 16.1 mmol). After stirring for 30 h at room temperature, the resulting suspension was filtrated through a small pad of celite using DCM as an eluent. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to give o-iodobenzaldehyde (3.36 g,90%) as pale yellow crystals.
98%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
General procedure for the acid reduction.
To a stirred solution of 2-iodobenzoic acid (Sigma-Aldrich S.r.l., 17675) (3 g, 12.09 mmol) in dry THF (40 mL) under N2 atmosphere cooled to 0 °C, borane dimethyl sulfide complex (Sigma-Aldrich S.r.l., 199825) (3.44 mL, 36.29 mmol) was added dropwise. The mixture was allowed to gently warm at room temperature and stirred for 12h. Water and K2CO3 were carefully added, then the mixture was stirred for 30 min. The mixture was extracted with EtOAc (50 mL) and washed twice with NaOH IN (30 mL) and with Brine (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure, to give pure 2-iodobenzyl alcohol 19f as a white solid. Yield: 98 %. 1H-NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 8 Hz, 1H), 4.66 (s, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 139.0, 136.7, 128.9, 128.3, 126.5, 95.4, 64.5 ppm.
98%
Stage #1: 2-Iodobenzoic acid With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;
Stage #2: With lithium hydroxide monohydrate; potassium carbonate for 0.5h;
97%
With borane-THF In tetrahydrofuran at 0℃;
96%
With borane-THF In tetrahydrofuran at 0 - 20℃;
96%
With Trimethyl borate; dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;
94%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere;
(2-iodophenyl)methanol
To a solution of 2-iodobenzoic acid (5.3 g, 21 mmol) in tetrahydrofuran (43 mL) at 0 °C, was addedborane-dimethyl sulfide (2.2 mL, 24 mmol) dropwise over 20 minutes. The reaction mixture wasstirred vigorously at room temperature for 16 hours then quenched with methanol (1 mL) followed bya saturated aqueous solution of potassium carbonate (5 mL). The layers were separated and theaqueous layer extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washedwith water (10 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The crude product was recrystallised from hexanes affording(2-iodophenyl)methanol S1 (4.7 g, 94%) as long white crystals; mp 90-92 °C (lit.,1 90-95 °C); Rf =0.82 (1:1 hexanes-ethyl acetate); δH (400 MHz; CDCl3) 7.82 (1H, d, J = 7.6 Hz, ArH), 7.46 (1H, dd, J= 7.6, 1.5 Hz, ArH), 7.40 (1H, t, J = 7.6 Hz, ArH), 7.00 (1H, dt, J = 7.6, 1.5 Hz, ArH), 4.68 (2H, d,J = 6.2 Hz, CH2), 2.00 (1H, t, J = 6.2 Hz, OH); The spectroscopic data were in agreement with thatreported in the literature.
89%
Stage #1: 2-Iodobenzoic acid With sodium tetrahydridoborate In tetrahydrofuran for 0.5h; Inert atmosphere; Cooling;
Stage #2: With boron trifluoride diethyl ether complex In tetrahydrofuran at 20℃; for 3.5h; Inert atmosphere;
85%
With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 8h;
85%
Stage #1: 2-Iodobenzoic acid With 1,3,5-trichloro-2,4,6-triazine; potassium carbonate; triphenylphosphine In neat (no solvent) for 0.0833333h; Green chemistry;
Stage #2: With sodium tetrahydridoborate In neat (no solvent) for 0.0833333h; Green chemistry;
85%
With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere;
84%
With phenylsilane; C34H30CoO6; potassium mirror In tetrahydrofuran at 20℃; for 20h; Inert atmosphere; Schlenk technique; Glovebox;
84%
With borane-THF In tetrahydrofuran at 0 - 23℃; for 15h; Inert atmosphere;
73%
With 4-methyl-morpholine; phenylsilane; Zinc acetate In 2-methyltetrahydrofuran at 80℃; for 16h; Inert atmosphere;
(i) NaBH4, THF, (ii) BF3-Et2O, (iii) aq. HCl; Multistep reaction;
With sodium tetrahydridoborate; methyl chloroformate
With dimethylsulfide borane complex In tetrahydrofuran at 0℃;
Multi-step reaction with 2 steps
1: 67 percent / SOCl2, DMF / 2 h / Heating
2: tert-butyl alcohol, LiAlH4 / bis-(2-methoxy-ethyl) ether / -78 - 20 °C
With borane-THF at 20℃; for 6h;
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 20℃;
With borane-THF In tetrahydrofuran at 0℃; for 5h; Inert atmosphere;
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 20℃;
With borane-THF at 0 - 20℃; for 5h; Inert atmosphere;
With sodium tetrahydridoborate; iodine In tetrahydrofuran at 0℃; for 12h; Heating;
Stage #1: 2-Iodobenzoic acid With sodium tetrahydridoborate; iodine In tetrahydrofuran for 0.5h; Cooling with ice;
Stage #2: In tetrahydrofuran for 12h; Reflux;
With sodium tetrahydridoborate; iodine In tetrahydrofuran at 0 - 70℃; for 12h;
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 20℃; for 16.5h; Inert atmosphere; Schlenk technique;
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 72h;
100%
With N-ethyl-N,N-diisopropylamine In toluene at 60℃; for 1.66667h;
17
Example 17: Carbonylation of 2-iodobenzyl alcohol to form 3H-isobenzofuran-l-one using compound 2IIIA as a catalyst; 2-iodobenzyl alcohol (0.5g, 2.14mmol),ethyldiisopropylamine (0.74ml, 4.58mmol),triphenylphosphine (28.04mg, O.llmmol), toluene (20cm3)and compound 2IIIA (10.14mg, 0.0107 mmol) were added toglass reactor. Carbon monoxide was introduced via asinter to produce a stream of fine bubbles. The reactorwas placed in a water bath heated to 60°C. The mixturewas allowed to carbonylate for 100 minutes at thistemperature. During the course of the reaction, thecolour of the solution changed from virtually colourless to deep purple. After the reaction time, the mixture wasallowed to cool to room temperature, and analysed byG.C.M.S. 2-iodobenzyl alcohol had been completelyconsumed, to give 3H-isobenzofuran-l-one quantitatively.
97%
With triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; palladium dichloride In toluene at 80℃; for 4h;
94%
With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; hydrazine In tetrahydrofuran; 1,4-dioxane at 100℃; Flow reactor;
94%
With water; potassium carbonate In acetonitrile at 100℃; for 0.0161111h;
Flow Hydroxycarbonylation of Iodobenzene (5a); TypicalProcedure
General procedure: A 25 mM solution of iodobenzene (5a) and K2CO3 (2 equiv) in H2O/CH3CN (2:1) was pumped at a flow rate of 1.0 mL/min(contact time: 58 s) through a Phoenix flow reactor systemequipped with two cartridges of 4 (total 500 mg; 0.084 mmolPd). Flow hydroxycarbonylation with CO gas introduced from agas module (10 mL/min) was conducted at 100 °C and a systempressure of 5 bar. The resulting solution was collected for 50min (50 mL) and the solvent was removed by evaporation. 2 Naq HCl (10 mL) was added and the resulting solid was collectedby filtration, washed with H2O (3 × 10 mL), and dried undervacuum to give benzoic acid (9a) as a white solid without anyfurther purification.Yield: 125 mg (82%); mp 122 °C; 1H NMR(400 MHz, DMSO-d6): δ = 12.96 (br s, 1 H, COOH), 7.93 (d, J = 7.2Hz, 2 H, PhH-2 and PhH-6), 7.62 (t, J = 7.2 Hz, 1 H, PhH-4), 7.49 (t, J =7.2 Hz, 2 H, PhH-3 and PhH-5); 13C NMR (101 MHz, DMSO-d6): δ = 167.32 (COOH), 132.87 (Ph), 130.76 (Ph), 129.26 (Ph),128.57 (Ph); ESI-TOF-MS (neg.): m/z = 121 [M - H]-.
91%
With triethylamine In acetonitrile at 250℃; for 16h; Autoclave;
Typical procedure for the reaction of 2-iodobenzyl alcohols with carbon monoxide under thermal conditions
A magnetic stirring bar, 2-iodobenzyl alcohol (1a, 116.0 mg, 0.5 mmol), NEt3 (251.6 mg, 2.5 mmol), and MeCN (10 mL) were placed in a stainless steel autoclave equipped with an inserted Pyrex glass liner. The autoclave was closed, purged three times with carbon monoxide, pressurized with 65 atm of CO and then heated at 250 °C by salt bath with stirring for 16 h. After the reaction, excess CO was discharged at room temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (hexane/EtOAc = 3/1) to give 2a (60.4 mg, 91%) as a white solid.
89%
With palladium 10% on activated carbon; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; Inert atmosphere;
85%
With triethylamine In toluene at 100℃; for 4h;
5000 % Turnov.
With triethylamine In carbon dioxide; N,N-dimethyl-formamide at 130℃; for 18h;
With indium In N,N-dimethyl-formamide for 13h; Heating;
56%
With copper(I) thiophene-2-carboxylate; copper In dimethyl sulfoxide at 65℃;
4.2 General procedure for the modified Cu(0)-Cu(I)-mediated Ullmann biaryl coupling
General procedure: (0013) A mixture of aryl halide (1 equiv), Cu(0) powder (10 equiv), and CuTC (2 equiv) in DMSO (0.2 mL/mmol of aryl halide) was stirred at 65-70 °C for 15-72 h. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by preparative TLC (EtOAc/hexanes) to furnish the desired product.
With 1-methyl-pyrrolidin-2-one; copper(I) thiophene-2-carboxylate at 70℃; for 24h; Yield given;
Stage #1: [2-(5,6-dihydro-4H-pyranyl)]dimethylsilanol With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃;
Stage #2: 2-iodobenzyl alcohol With bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 20℃; for 0.333333h;
5-(2-(hydroxymethyl)phenyl)pent-4-yn-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine at 20℃; Schlenk technique; Inert atmosphere;
92%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine at 20℃; Schlenk technique; Inert atmosphere;
91%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;
General procedure for Sonogashira cross-coupling
General procedure: A dried two-neck flask was charged with (2-iodophenyl)methanol 4 (1 eq), the appropriate alkyne (1 eq),(PPh3)2PdCl2 (0.05 eq) and CuI (0.10 eq) under an N2-atmosphere. Dry, de-gassed THF was then added,followed by Et3N (2 eq). The solution was stirred at room temperature for 16h. The reaction mixture wasfiltered through celite and added EtOAc. The organic phase was washed twice with sat. NH4Cl solution,followed by brine. After drying over anhydrous Na2SO4 and filtration, silica gel was added to the crude productsolution, followed by drying in vacuo. Purification by column chromatography (pentane:EtOAc) yielded thefinal products.
{2-[(3-bromo-5-methylpyridin-2-yl)amine]phenyl}methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.0%
With potassium carbonate;copper(l) iodide; ethanolamine; In methoxybenzene; at 20 - 130℃; for 7.16667h;
Under a nitrogen atmosphere, 2-amino-3-bromo-5- methylpyridine (1.50 g, 8.02 mmol), 2-iodobenzyl alcohol (1.88 g, 8.02 mmol), copper (I) iodide (153 mg, 0.80 mmol), ethanol amine (98 mg, 1.60 mmol), potassium carbonate (2.22 g, 16.04 mmol) and anisole (22.5 ml) were mixed, and the mixture was stirred at room temperature for 10 minutes. The mixture was heated and stirred at 130C for 7 hours. The reaction solution was cooled to room temperature, and water (22.5 ml) was added <n="164"/>thereto. The mixture was concentrated under reduced pressure. To the concentrate, ethyl acetate (30 ml), water (10 ml) and activated carbon Shirasagi A were added, and the mixture was filtered. The organic layer was separated, washed with water (10 ml) and concentrated under reduced pressure. Methanol (1 ml) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration, and dried at room temperature under reduced pressure, to yield the title compound (470 mg) (yield 20.0%) . 1H-NMR (DMSO-d6, TMS, 300 MHz) delta (ppm) : 2.24 (3H, s) ,2.49 (IH, br), 4.72 (2H, d, J = 5.3 Hz), 7.06 (IH, t, J = 7.4 Hz), 7.30-7.37 (2H, m) , 7.63 (IH, d, J = 1.7 Hz), 7.82-8.00 (3H, m) .High resolution mass spectrometry (Ci3Hi3BrN2O) Theoretical value : 292 . 0211 [M+]Measured value : 292 . 0208 [M+]Melting point : 129 . 3 to 131 . 8C
20%
With copper(l) iodide; potassium carbonate; ethanolamine; at 130℃;Inert atmosphere;
General procedure: Under N2 atmosphere, to a solution of copper iodide (204 mg, 0.11 mmol, 10 mol %) and ethanolamine (131 mg, 0.22 mmol, 20 mol %) in anisole (30 mL) was added aryl iodides (6) (10.7 mmol), 3-bromo-5-methyl-pyridin-2-ylamine (5) (10.7 mmol) and potassium carbonate (2.2 g, 16.0 mmol, 1.5 equiv), and the mixture was stirred at 130 C for 4-18 h. After cooling to room temperature, water (30 mL) was added to the mixture. The mixture was concentrated in vacuo and ethyl acetate (50 mL) was added to the residue. The organic layer was washed with water (20 mL) and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography to give the title compound.
With sodium tetrahydroborate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; oxygen; caesium carbonate In dichloromethane at 40℃; for 40h; Irradiation;
Synthesis of Compound IIIB; 2-Iodobenzyl alcohol (0.5g, 2.14 mmol) was dissolved intoluene (20cm3) , and added dropwise to a stirredsuspension of tetrakis(triphenylphosphine)palladium(O)(2.47g, 2.14 mmol) in toluene (80cm3). The suspension wasdegassed and purged with N2. The mixture was stirred atroom temperature for 12 hours. Approximately one thirdof the solvent was removed in vacua and replaced with30ml petroleum ether. The mixture was refrigerated toaid crystallisation. The resultant precipitate wasfiltered under nitrogen and washed with diethyl ether (3x 20cm3) and dried in vacua to give compound IIIB as ayellowish solid (1.13g, 61%), this was thenrecrystallised from dichloromethane and petroleum etherto give yellow crystals. (Found: C, 55.32; H, 4.07%.C43H37lOP2Pd.dichloromethane requires C, 55.60; H, 4.14%);NMR assignments made by NOE, DEPT, 8H [CDC13] 0.00 (t, 2JH-8, H-7a,7b = 6.91 HZ 1H, H-8), 4.18 (d, 2JH-7a,7b - H-8, =6.91Hz 2H, H-7), 6.40-6.48 (m, 2H, H-3, H-4), 6.62 (t, J=7.35 Hz, 1H, H-2 or 5), 7.05-7.08 (m, 1H, H-2 or 5),7.21-7.25 (m, 12H PPh3) , 7.30-7.38 (m, 6H PPh3) , 7.40-7.48(m, 12H, PPh3); 8C [CDC13] 68.19, (C-7), 123.53 (C-2 or 3or 4 or 5), 125.72 (C-2 or 3 or 4 or 5), 127.91 (C- 10 or11), 128.38 (C-2 or 3 or 4 or 5), 130.00 (C-12), 131.77 (C-9), 134.04 (C-2 or 3 or 4 or 5), 134.85 (C-10 or 11),144.19 (C-l or 6), 158.37 (C-l or 6); 5P [CDC13] 6 =23.75, (s); m/z Electrospray 737.2 (M - I = 127)C43H37lOP2Pd requires 865.
With C22H24Cl2N6O2Pd2; potassium carbonate; In ethanol; water; for 4h;Reflux;Catalytic behavior;
General procedure: In a 10 mL glass tube containing a Teflon-coated stir bar was placed p-bromobenzaldehyde 2e (0.05 g, 0.27 mmol, 1 equiv), phenylboronic acid 1a (0.05 g, 0.40 mmol, 1.5 equiv), 2M K2CO3 (0.33 mL, 0.67 mmol, 2.5 equiv), 4-AAP-Pd(II) (0.28 mg, 0.3 mol % Pd) and EtOH (2 mL). The mixture was stirred at reflux for 4 h. After cooling, the mixture was diluted with ether Et2O (5 mL), washed with sat. aq. NaHCO3 (3 mL), brine (3 mL) and dried over Na2SO4. Evaporation of the solvent and purification of the residue over a silica gel column (Hex: AcOEt 90:10), furnished the biphenyl 3q.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere;
4.4. General procedure A: Sonogashira coupling
General procedure: A 50-mL round-bottom flask equipped with a magnetic stir bar was charged with an aryl iodide (3.57 mmol, 1.1 equiv), ethynyl MIDA boronate (3.24 mmol, 1.0 equiv), CuI (9 mol %), PdCl2(PPh3)2 (5 mol %), and placed under nitrogen atmosphere. Then, anhydrous DMF (15 mL) and Et3N (1.4 mL) were introduced via syringe, and the reaction mixture was allowed to stir for 6-7 h at room temperature, after which the mixture was poured into a separatory funnel containing deionized water. Extraction with ethyl acetate (3×25 mL) was carried out, and the combined organic extracts were concentrated in vacuo to give a crude residue. The crude product was subsequently loaded onto a silica gel column and purified by flash column chromatography (on this scale, 2-3 rounds of column chromatography was typically required for complete purification) to afford the desired compound.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120 - 160℃; for 0.416667h;microwave;
To a mixture of (2-iodophenyl)methanol [5159-41-1] (1.50 g, 6.41 mmol), 1 H-1 ,2,3-triazole (0.797 g, 11.54 mmol), trans-N, N'-dimethylcyclohexane-l ^-diamine [68737-65-5] (0.091 g, 0.641 mmol) and Cs2C03 (3.76 g, 1 1.54 mmol) in DMF (15 mL), Cul (0.61 g, 3.20 mmol) was added and the reaction mixture was stirred for 20 min at 120C and 15 min at 160C in the microwave. The reaction mixture was cooled to rt and filtered to remove the solids. The filtrate was concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (1.46 g, 64%). [1H NMR (400 MHz, DMSO-cfe) USD ppm 8.10 (s, 2 H), 7.74 (d, J=7.53 Hz, 1 H), 7.61 (dd, J=8.03, 1.25 Hz, 1 H), 7.52 (td, J=7.53, 1.25 Hz, 1 H), 7.44 (m, 1 H), 5.26 (t, J=5.40 Hz, 1 H), 4.59 (d, J=5.02 Hz, 2 H); LCMS RtA = 0.68, [M+H]+ = 176.1].
64%
With caesium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In N,N-dimethyl-formamide; at 120 - 160℃; for 0.583333h;Microwave irradiation;
Building block B2, L16, B23-B26: 2-(2-(bromomethyl)phenyl)-2H-<strong>[288-36-8]1,2,3-triazole</strong> a) (2-(2H-1,2,3-triazol-2-yl)phenyl)methanol; To a mixture of (2-iodophenyl)methanol (1.50 g, 6.41 mmol), 1H-<strong>[288-36-8]1,2,3-triazole</strong> (0.797 g, 11.54 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.091 g, 0.641 mmol) and Cs2CO3 (3.76 g, 11.54 mmol) in DMF (15 mL), CuI (0.61 g, 3.20 mmol) was added and the reaction mixture was stirred for 20 min at 120 C. and 15 min at 160 C. in the microwave. The reaction mixture was cooled to rt and filtered to remove the solids. The filtrate was concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (1.46 g, 64%). [1H NMR (400 MHz, DMSO-d6) delta ppm 8.10 (s, 2H), 7.74 (d, J=7.53 Hz, 1H), 7.61 (dd, J=8.03, 1.25 Hz, 1H), 7.52 (td, J=7.53, 1.25 Hz, 1H), 7.44 (m, 1H), 5.26 (t, J=5.40 Hz, 1H), 4.59 (d, J=5.02 Hz, 2H); LCMS RtA=0.68, [M+H]+=176.1].
64%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120 - 160℃; for 0.583333h;Microwave irradiation;
a) (2-(2H-1.2.3-triazol-2-yl)phenyl)methanolTo a mixture of (2-iodophenyl)methanol (1 .50 g, 6.41 mmol), 1H-<strong>[288-36-8]1,2,3-triazole</strong> (0.797 g, 11.54 mmol), frarts-N,N'-dimethylcyclohexane-1 ,2-diamine (0.091 g, 0.641 mmol) andCs2C03 (3.76 g, 11.54 mmol) in DMF (15 mL), Cul (0.61 g, 3.20 mmol) was added and the reaction mixture was stirred for 20 min at 120C and 15 min at 160C in the microwave. The reaction mixture was cooled to rt and filtered to remove the solids. The filtrate wasconcentrated under reduced pressure. The residue was purified by flash-columnchromatography over silicagel (eluent: gradient 10%- 100% ethyl acetate/heptane) to yield the title compound (1.46 g, 64%). [1H NMR (400 MHz, DMSO-d6) delta ppm 8.10 (s, 2 H), 7.74 (d, J=7.53 Hz, 1 H), 7.61 (dd, 8.03, 1.25 Hz, 1 H), 7.52 (td, J=7.53, 1.25 Hz, 1 H), 7.44 (m, 1 H), 5.26 (t, J=5.40 Hz, 1 H), 4.59 (d, J=5.02 Hz, 2 H); LCMS RtA = 0.68, [M+Hf = 176.1].
With copper(l) iodide; caesium carbonate In acetonitrile at 100℃; for 36h; Inert atmosphere; diastereoselective reaction;
2.1. General procedure for the synthesis of benzoxazine and 1,3-oxazine derivatives
General procedure: An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, CuI (0.1 mmol, 20 mol %), Cs2CO3 (0.5 mmol, 100 mol %), and o-halophenylmethanol and/or (Z)-3-iodo-3-phenylprop-2-en-1-ol (0.5 mmol). The tube was evacuated and backfilled with N2 (this procedure was repeated three times). Carbodiimide (0.75 mmol) was added via syringe under a counter flow of N2. Then under a counter flow of N2, MeCN (2.0 mL) was added by syringe. The reaction mixture was sealed and stirred for 24 h at 100 °C. Then another part of carbodiimide (0.25 mmol) was added and stirred for 12 h at 100 °C. The reaction was monitored by TLC. After the starting material was consumed completely, the resulting suspension was cooled to room temperature and filtered through a pad of filter paper with the help of 30 mL of ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography on silica gel to give the pure product (AcOEt/petroleum ether v/v=1/10).
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; ammonium hydroxide; copper(II) sulfate; at 120℃; for 18h;
The reaction was carried out using o-iodobenzyl alcohol (i.e., R1 in the formula (I) o) 1.0 mmol (234.0 mg)The procedure and procedure were the same as in Example 1, aqueous ammonia (1.6 mol / L) 5.0 mL, catalyst copper sulfate was used in an amount of 5 mol% (8.0 mg)TEMPO is used in an amount of 8 mol% (12.5 mg) at a reaction temperature of 120 C and a reaction time of 18 h. The crude product is purified by column chromatography(Petroleum ether: ethyl acetate = 10: 1) to give the pure title product at 206.1 mg yield of 90%.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; ammonium acetate; In water; acetonitrile; at 20℃; for 4h;
General procedure: To a solution of alcohol (1 mmol) in MeCN-H2O (9:1, 3 mL) were successively added TEMPO (7.8 mg,5 mol%), NH4OAc (0.308 g, 4 equiv), and PhI(OAc)2 (0.708g, 2.2 equiv). The suspension was stirred at roomtemperature (progress of the reaction was monitored byTLC) for the reaction time indicated in Table 2. The resultantclear two-phase reaction mixture was concentrated, dilutedwith H2O and Et2O, and the organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography(PE-Et2O or PE-CH2Cl2) to give 2.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; boron trifluoride diethyl etherate; iodosylbenzene In dichloromethane at 20℃; for 0.5h;
General procedure:
General procedure: To the stirred mixture of methoxybenzene (2.0 mmol) and benzylalcohol (1.0 mmol) in DCM (5 mL) were added PhIO (1.2 equiv), TEMPO (0.13 equiv) with BF3.OEt2 (2.0 equiv). The reaction mixture was stirred 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, NaHCO3 (3 equiv) was added to the reaction mixture and concentrated in vacuo. The crude product was directly poured into silica gel column chromatography (100-200 mesh) using ethyl acetate: hexane (03:97 to 10:90) as eluent to afford corresponding triarylmethane products. The all obtained products were characterized by 1H NMR, 13C NMR, Mass, HRMS and IR spectral data.
methyl 2-(2-iodobenzyloxysulfonyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
General procedure: To a suspension of NaH (60% dispersion in oil, 297 mg) in THF (7 mL), was added a solution of o-iodobenzyl alcohol (1,4 g, 6.0 mmol) in THF (12 mL). Effervescence occurred and the mixture was stirred at room temperature for 20 min. A solution of the arylsulfonyl chloride (9.0 mmol) in THF (10 mL) was added and the mixture stirred for 24 h. Water (30 mL) was added and the mixture extracted with ether (3 x 25 mL), dried (MgSO4) and the solvent evaporated. The residue was purified by column chromatography or crystallisation.
ethyl 4-((2-(hydroxymethyl)phenyl)ethynyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 2h;Inert atmosphere; Schlenk technique;
General procedure: To a mixture of the 2-iodobenzyl alcohol (1.16 g, 5.0 mmol) inDMF (30 mL) were added PdCl2(PPh3)2 (0.70 g, 0.10 mmol), and CuI (0.19 g, 0.10 mmol) under nitrogen. After the reaction mixturewas stirred for 5 min at room temperature, N,N-diisopropylamine(2.02 g, 4.0 equiv) was added by a syringe. The reaction mixturewas then heated at 70 C. A solution of the alkynes (1.2 equiv)in DMF (5 mL) was added dropwise over 10 min, and the mixturewas allowed to stir at 70 C for 2 h. After cooling, the reactionmixture was washed with saturated aq NH4Cl and water, andthen extracted with EtOAc (325 mL). The combinedorganic extracts were dried over MgSO4 and concentrated undervacuum to give the crude product, which was purified by columnchromatography on silica gel using 9:1 to 4:1 hexane/EtOAc aseluent
With copper(l) iodide; palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere; Microwave irradiation;
General procedure: To a solution of aryl halide (0.5 mmol, 1 equiv.) and alkyne acid (1-1.5 mmol, 2-3 equiv.) in DMF (3 mL), was added copper (I) iodide (0.025 mmol, 0.05 equiv.), palladium (II) acetate (0.05 mmol, 0.1 equiv.), triphenylphosphine (0.05 mmol, 0.1 equiv.) and triethylamine (1 mmol, 2 equiv.) under argon atmosphere. The mixture was heated at 50 C for 2 hours by microwave irradiation. Treatment and purification: After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (3 * 10 mL). The combined organic phases were washed with brine (2 * 20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (100:0 to 90:10) as eluent.
(±)-N-(2-iodobenzylidene)-p-toluenesulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium carbonate; <i>L</i>-proline In toluene at 60℃; for 12h; Molecular sieve; Green chemistry;
With iron(III) chloride; TEMPOL; L-valine; oxygen In toluene at 60℃; for 24h; Molecular sieve; Schlenk technique;
(d) General procedures for synthesis of the N-sulfinylimines
General procedure: The preparation of these N-sulfinylimines was performed with 0.4 mmol (±)-sulfinamide and the 1.5 equimolar amount corresponding aromatic alcohol, L-valine(0.04 mmol), FeCl3 (0.04 mmol), 4-OH-TEMPO (0.08 mmol), toluene (2.5 mL), 4ÅMS (0.7000 g) were added to a 100 mL schlenk tube. Then the resulting mixture wasvigorously stirred under O2 at 60 °C for 24 h. After the reaction, the residue wasfiltered off, and the solvent was removed under vacuum to give the crude product,which was purified by column chromatography on silica gel to give the pure product.
Stage #1: benzaldehyde With palladium 10% on activated carbon; sodium carbonate In isopropyl alcohol at 110℃; for 24h; Inert atmosphere;
Stage #2: 2-iodobenzyl alcohol With triphenylphosphine In 1-methyl-pyrrolidin-2-one; isopropyl alcohol at 100℃; for 24h; Inert atmosphere;
1.2 Example 1
General procedure: Type of aldehyde as carbon monoxide source:In the following reaction formulas, the aldehyde (Aldehyde) listed in Table 1 was used and the yield of the ester compound was examined. The yields are also shown in Table 1.Specific reactions were carried out as follows. First, a test tube was prepared, to which aldehyde (0.25 mmol), 10% Pd / C ([K-type catalyst] (palladium content: 10 wt%, specific surface area value: 1,100 m 2 / g) Manufactured by Chemcat Corporation)),Na 2 CO 3, iPrOH were put in and substituted with N 2 and stirred at 110 ° C. and 600 rpm for 24 hours.2-iodobenzyl alcohol, PPh 3 NMP solution was added using a 1 mL syringe and a needle [24 G 1 (0.55 × 30 mm)] and further stirred at 100 ° C. for 24 hours.After a total of 48 hours, the reaction solution was filtered using Kiriyama funnel (1 μm). The recovered catalyst on the funnel was ethyl acetate (5 mL),This was washed successively with distilled water (5 mL), methanol (5 mL), distilled water (5 mL) and methanol (5 mL), and dried under a reduced pressure for 2 days with a desiccator.The filtered organic layer was washed four times with 15 mL of distilled water, dried with magnesium sulfate, and concentrated under reduced pressure with an evaporator.CDCl 3 (ca 0.6 mL) and 1,4-dioxane as an internal standard were added to the obtained residue, and the yield was calculated from 1 H NMR.The weight of the recovered catalyst was 135 mg (usage amount: 26.6 mg × 4 = 106 mg,> 99%). The reaction was carried out in the same manner also in the following Examples.
Stage #1: benzaldehyde With palladium 10% on activated carbon; sodium carbonate In isopropyl alcohol at 120℃; for 24h; Inert atmosphere;
Stage #2: 2-iodobenzyl alcohol With triphenylphosphine In 1-methyl-pyrrolidin-2-one at 100℃; for 24h; Inert atmosphere;
With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In ethanol; at 80℃; for 0.75h;Inert atmosphere;
General procedure: A glass vial equipped with a magnetic stir bar and fitted with a Teflon screw cap was charged with BBA (90 mg, 1.0 mmol), KOAc (98 mg, 1.0 mmol) and the aryl halide (0.50 mmol). To this vessel was added EtOH (2.5 mL) and the reaction media was degassed with Argon for 5 minutes. XPhos Pd G2 (79 mg, 10 mol%) was then added, and the solution was stirred (750 rpm) and heated at 80C until full conversion was observed. The reaction media was filtered over celite and the crude filtrate was purified using Teledyne Isco Combiflash device (silica gel column chromatography 15 mum) and Hept:DCM (90:10 to 0:100) as solvent.
Stage #1: 3-phenyl-propenal With palladium 10% on activated carbon; sodium carbonate In isopropyl alcohol at 110℃; for 24h; Inert atmosphere;
Stage #2: 2-iodobenzyl alcohol With triphenylphosphine In 1-methyl-pyrrolidin-2-one; isopropyl alcohol at 100℃; for 24h; Inert atmosphere;
1.1 Example 1
General procedure: Type of aldehyde as carbon monoxide source:In the following reaction formulas, the aldehyde (Aldehyde) listed in Table 1 was used and the yield of the ester compound was examined. The yields are also shown in Table 1.Specific reactions were carried out as follows. First, a test tube was prepared, to which aldehyde (0.25 mmol), 10% Pd / C ([K-type catalyst] (palladium content: 10 wt%, specific surface area value: 1,100 m 2 / g) Manufactured by Chemcat Corporation)),Na 2 CO 3, iPrOH were put in and substituted with N 2 and stirred at 110 ° C. and 600 rpm for 24 hours.2-iodobenzyl alcohol, PPh 3 NMP solution was added using a 1 mL syringe and a needle [24 G 1 (0.55 × 30 mm)] and further stirred at 100 ° C. for 24 hours.After a total of 48 hours, the reaction solution was filtered using Kiriyama funnel (1 μm). The recovered catalyst on the funnel was ethyl acetate (5 mL),This was washed successively with distilled water (5 mL), methanol (5 mL), distilled water (5 mL) and methanol (5 mL), and dried under a reduced pressure for 2 days with a desiccator.The filtered organic layer was washed four times with 15 mL of distilled water, dried with magnesium sulfate, and concentrated under reduced pressure with an evaporator.CDCl 3 (ca 0.6 mL) and 1,4-dioxane as an internal standard were added to the obtained residue, and the yield was calculated from 1 H NMR.The weight of the recovered catalyst was 135 mg (usage amount: 26.6 mg × 4 = 106 mg,> 99%). The reaction was carried out in the same manner also in the following Examples.
Stage #1: 4-methoxycinnamaldehyde With palladium 10% on activated carbon; sodium carbonate In isopropyl alcohol at 120℃; for 6h; Inert atmosphere;
Stage #2: With iodobenzene; tetra-(n-butyl)ammonium iodide In 1-methyl-pyrrolidin-2-one at 120℃; for 18h; Inert atmosphere;
Stage #3: 2-iodobenzyl alcohol With palladium; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; Inert atmosphere;
10.43 Systems that react simultaneously in multiple containers:
General procedure: In the following reaction formulas, the reaction vessel shown in FIG. 1 was used and the yields were examined and listed in Table 10.The amount of the substrate of tube 1 (Tube 1) to the substrate of tube 2 (Tube 2) is 1.5 equivalents.The pipe 1 and the pipe 2 are connected, and the carbon monoxide generated in the pipe 1 comes and goes in the connecting portion, and the pipe 2 can also use carbon monoxide.
Stage #1: 3-(4-nitrophenyl)-2-propenal With palladium 10% on activated carbon; sodium carbonate In isopropyl alcohol at 120℃; for 6h; Inert atmosphere;
Stage #2: With iodobenzene; tetra-(n-butyl)ammonium iodide In 1-methyl-pyrrolidin-2-one at 120℃; for 18h; Inert atmosphere;
Stage #3: 2-iodobenzyl alcohol With palladium 10% on activated carbon; sodium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; Inert atmosphere;
10.44 Systems that react simultaneously in multiple containers:
General procedure: In the following reaction formulas, the reaction vessel shown in FIG. 1 was used and the yields were examined and listed in Table 10.The amount of the substrate of tube 1 (Tube 1) to the substrate of tube 2 (Tube 2) is 1.5 equivalents.The pipe 1 and the pipe 2 are connected, and the carbon monoxide generated in the pipe 1 comes and goes in the connecting portion, and the pipe 2 can also use carbon monoxide.
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 6Cu(2+)*54H2O*6Ni(2+)*6C13H10N2O6(4-) In toluene at 110℃;
General procedure for the synthesis of cinnamates or cinnamamides
General procedure: 0.7mmol of the corresponding cyclopropenone were inserted in a glass vialwith either Cu(OAc)2 (1-2 mol%) or NiCuMOF (10 mol%), toluene (0.5M final dilution respect to the cyclopropenone reactant) and the correspondingalcohol or amine (0.35 mmol). The solution was left overnightat 100 C and at the end was quenched with water (5 ml). Then, themixture was extracted with EtOAc (3 × 5 ml) and the organic layerswere washed with water (5 ml) and brine (5 ml). Afterwards, the organicphase was dried over MgSO4, filtered and concentrated under vacuum.The resulting mixture was purified by either thin-layer chromatography(TLC) or flash chromatography with the appropriate AcOEt/n-hexanesmixture.
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