* 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] Journal of the Chemical Society, 1942, p. 103,107
2
[ 874-89-5 ]
[ 17201-43-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With phosphorus pentoxide; potassium bromide In acetonitrile at 20℃; for 1 h;
General procedure: To a mixture of alcohol (1 mmol) and KBr (1.5 mmol, 0.18 g) in acetonitrile (5 mL), P2O5 (1.5 mmol, 0.23 g) was added and the reaction was stirred at room temperature for the time specified in Table 3. After reaction completion (TLC or GC), the reaction mixture was filtered and the residue washed with ethyl acetate (3 × 8 mL). The combined organic layers were washed with water (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to afford the corresponding product. If necessary, further purification was performed by column chromatography.
With 1H-imidazole; tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In water at 80℃; for 17 h; Green chemistry
General procedure: To a mixture of benzyl alcohol (108 mg, 1.0 mmol) and TBHP(180 mg, 2.0 mmol) in water (3 ml), the catalyst TBAI (73.8 mg,0.2 mmol), imidazole (136 mg, 2.0 mmol), and MeOH (2 ml)were added, and the mixture was stirred at 80 °C for 8 h. Theprogress of the reaction was monitored by TLC. After completionof reaction, the reaction mixture was cooled to room temperature.Then MeOH was distilled out, and the organic productwas extracted with ethyl acetate (3 × 10 ml), repeatedly washedwith distilled water (4 × 5 ml) to remove the unreacted TBHP,dried with anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to afford methyl benzoate (112mg, yield 82percent).
Stage #1: With borane-THF; boron trifluoride diethyl etherate In tetrahydrofuran at 20 - 25℃; for 2 h; Stage #2: With water; sodium hydrogencarbonate In ethyl acetate
8A. 4-Hydroxymethyl-benzonitrile Boron trifluoride diethyl etherate (0.85 mL, 6.8 mmol) was added to a solution of 4-cyanobenzoic acid (1.0 g, 6.8 mmol) and THF (10 mL). At room temperature, borane-tetrahydrofuran complex (1.0 M, 13.6 mL) was added to the reaction mixture drop-wise with no observed exotherm. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The resulting residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.900 g, 95percent yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 4.65 (s, 2H), 7.38 (d, 2H), 7.53 (d, 2H).
With potassium carbonate In water at 80℃; for 10 h;
Into a 3000 mL four-necked flask, 138 g of potassium carbonate, 151.5 g of 4-chloromethylbenzonitrile, and 2300 g of water were placed.Heat to 80°C, react for 10 hours, sample for HPLC detection,It was confirmed that the hydrolysis reaction of 4-chloromethylbenzonitrile was complete. Dichloromethane extraction was performed in the hydrolysis reaction solution (800 mL each time, and extracted 3 times at room temperature).The extract was distilled to remove the extraction solvent to obtain 128 g of 4-cyanobenzyl alcohol with a purity of 96-98percent and a yield of 96.2percent.
Reference：
[1] Patent: CN107556214, 2018, A, . Location in patent: Paragraph 0031; 0032; 0035; 0038; 0041; 0044; 0047
[2] Journal of the Chemical Society, 1942, p. 103,107
[3] Journal of Organic Chemistry, 2015, vol. 80, # 4, p. 2310 - 2318
10
[ 105-07-7 ]
[ 874-89-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
With C48H43ClN2P2Ru; ammonium formate In water; toluene at 90℃; for 3.5 h; Schlenk technique
Transfer hydrogenation in a biphasic system with formate salts as hydride donor on aldehyde substrates The selected aldehyde (2.5 mmol), HCOONH4 (10 mmol, 0.63 g) and complex (e.g. 1 .25 μηιοΙ, 1 mg; S/C = 2000) are transferred into a 50 ml Schlenk tube. Then toluene (1 .2 ml) and water (5 ml) are sequentially added. The biphasic mixture is subjected to four vacuum-argon cycles under vigorous stirring and then put into an oil bath at 90°C for the desired time. The reaction is sampled by removing ~1 ml of the mixture, diethyl ether (4 ml) is added, the organic phase separated, dried over MgS04, filtered and the solvent gently removed under reduced pressure. The crude residue was dissolved with CDCI3 and analyzed by H-NMR. Alternatively, the dried organic fraction is filtered over a short silica pad and the conversion determined by GC analysis. Table 11. TH of aldehydes catalyzed by complexes 13-15 with HC02NH4 in toluene/H20 at 90°C Aldehyde Complex S/C Substrate NH4-formate Time Alcohol By- molar molar;equivalents (h) (percent) products (percentL_ 13 5000 0.5 1 ; 2 16 60 0 13 5000 0.5 1 ; 2 22 76 0 14 5000 0.5 1 ; 2 15 96 0 14 5000 0.5 1 ; 2 24 97 0 14 5000 1 .0 1 ; 2 15 86 0 14 5000 1.0 1; 2 24 95 0 14 5000 0.5 1; 4 15 96 0 14 5000 0.5 1; 4 24 96 0 14 5000 1.0 1; 4 15 96 0 14 5000 1.0 1; 4 24 96 0 14 20000 2.0 2; 4 24 94 0 14 20000 2.0 2; 4 48 96 0 15 5000 0.5 1; 2 16 96 0 15 10000 2.0 1; 2 20 86 0 15 20000 2.0 1; 2 40 96 0 14 2000 0.5 1; 2 10 97 0 14 20000 2.0 2; 4 24 62 0 14 20000 2.0 2; 4 48 72 0 14 2000 0.5 2; 4 10 >99 0 14 2000 0.5 1; 2 3.5 >99 0 14 2000 0.5 1; 1.5 9 57: 83 0 58: 17 14 2000 0.5 1; 2 10 57: 71 0 58: 21 0 14 2000 0.5 1;4 10 57: 0 58: 99 14 2000 0.5 1; 2 10 97 54:10 14 5000 2.0 2; 4 16 78 0 14 5000 2.0 2; 4 24 86 0 14 5000 2.0 2; 4 48 97 0 14 5000 2.0 4; 4 16 84 0 14 5000 2.0 4; 4 24 91 0 14 5000 2.0 4; 4 48 94 0 14 10000 0.5 1;2 24 38 0 14 10000 0.5 1;2 38 49 0 With complexes 13-15 the transfer hydrogenation of aldehydes with NH4-formate is an improvement compared to using 2-propanol as hydride donor and K2C03 as base (examples 28 and 29). The use of less complex (higher S/C ratio) is possible and less by-products are formed. It is important to note that no primary amines are produced by reductive amination of the aldehyde. Interestingly, the presence of the toluene solvent as co-solvent is not entirely required, as shown in the table below. Toluene was not added to the reactions carried out on a 2.5 mmol substrate scale. Table 12. TH of aldehydes catalyzed by complex 14 with HC02NH4in H20 at 90°C Aldehyde Complex S/C Substrate NH4-formate Time Alcohol By- molar molar;equivalents (h) (percent) products (percent) 13 5000 0.5 1; 2 16 60 13 5000 0.5 1; 2 22 76 14 2000 2.5 mmol 1; 2 2 50 14 2000 2.5 mmol 1; 2 4 76 14 2000 2.5 mmol 1; 2 7 97 14 5000 2.5 mmol 1; 2 14 53 14 5000 2.5 mmol 1; 4 24 97 14 5000 2.5 mmol 2; 4 24 90 45 14 5000 0.5 1; 2 15 96 14 5000 0.5 1; 2 24 97 14 5000 1.0 1; 2 15 86 14 5000 1.0 1; 2 24 95 14 5000 0.5 1; 4 15 96 14 5000 0.5 1; 4 24 96 14 5000 1.0 1; 4 15 96 14 5000 1.0 1; 4 24 96 14 20000 2.0 2; 4 24 94 14 20000 2.0 2; 4 48 96 0 15 5000 0.5 1; 2 16 96 0 15 10000 2.0 1; 2 20 86 0 15 20000 2.0 1; 2 40 96 0 14 2000 2.5 mmol 1; 2 14 33 6 14 2000 2.5 mmol 1; 2 16 61 0 14 2000 0.5 1; 2 10 97 0 46 14 2000 2.0 2;4 11 97 0 14 10000 2.0 2;4 24 24 0 14 20000 2.0 2; 4 24 62 0 14 20000 2.0 2; 4 48 72 0 14 5000 2.0 2; 4 15 96 0 47 >99, 14 2000 0.5 2; 4 10 0 48 65[bl 14 2000 0.5 1; 2 3.5 >99 0 55 14 2000 2.0 2;4 3.5 99, 65[bl 0 14 2000 0.5 1; 1.5 9 57: 83 0 56 58: 17 14 2000 0.5 1; 2 10 57: 71 0 58: 21 14 2000 0.5 1;4 10 57: 0 0 58: 99 14 2000 0.5 1; 2 10 97 54:10 14 5000 2.0 2; 4 16 78 54:6 14 5000 2.0 2; 4 24 86 0 52 14 5000 2.0 2; 4 48 97 54:12 14 5000 2.0 4; 4 16 84 0 14 5000 2.0 4; 4 24 92 54:5 14 5000 2.0 4; 4 48 94 54:7 14 10000 0.5 1 ; 2 24 38 14 10000 0.5 1 ; 2 38 49 59 14 10000 2.0 4; 4 20 98 0 60 14 10000 2.0 2; 4 24 65 0 60 14 10000 2.0 4; 4 24 97 0 61 14 5000 2.0 4;4 20 98, 88[bl 62 14 5000 2.0 2;4 8 95 63 14 2000 2.0 4;4 9 96, 79[bl Conversion and product content were determined by GC analysis or by -NMR spectroscopy. Isolated yield. On 2.5 mmol scale, reduction of benzaldehyde 45 (0.5 molar in toluene) at S/C =2000, 90°C and 4 equivalents of 2M aqueous Na-formate gave only traces of benzylalcohol after 14 hours. Use of 4 equivalents of (NEt3H)-formate improves the yield to 50 percent in 22 hours. Use of 5 equivalents of (NEt3H)-formate on frans-cinnamaldehyde 52 gives after 18 hours 80 percent of allylic alcohol 53 and 15 percent of saturated alcohol 54. NH4-formate is preferred over the other formate reagents.
96%
Stage #1: With chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium (II); phenylsilane In toluene for 20 h; Reflux Stage #2: With tetrabutyl ammonium fluoride In toluene at 20℃; for 0.5 h;
General procedure: To a solution of [CpRu(PPh3)2Cl] (1 molpercent) and solid aldehyde (1.0 mmol) in toluene (3 ml) was added PhSiH3 (1.2 mmol). The reaction mixture was stirred at reflux temperature under an air atmosphere (the reaction times are indicated in Table 4). Then, TBAF (1.0 mmol) was added and the reaction mixture was stirred at room temperature during 30 min. After evaporation, the reaction mixture was purified by silica gel column chromatography with ethyl acetate:n-hexane (1:3) to afford the corresponding alcohols.
94%
With potassium diisobutyl-tert-butoxyaluminum hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
General procedure: A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with dicarbonyl compound (1.0 mmol) and 10 mL THF. After cooling to 0°C, PDBBA (1.3 mmol) was added dropwise and stirred for 1h at same temperature. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel afforded the desired product.
93%
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; tris[3,5-bis(trifluoromethyl)phenyl]-borane In 1,4-dioxane at 25℃; for 12 h; Glovebox
General procedure: In a glovebox, aldehydes (0.25 mmol) and the Hantzsch ester 1 (95 mg, 0.38 mmol) were added to asolution of tris[3,5-bis(trifluoromethy)phenyl]borane (9) (8.1 mg, 12.5 μmol) in 1 mL of anhydrous1,4-dioxane. The reaction mixture was stirred at 25 or 100 C for 12 h. An internal standard (biphenylor mesitylene) was added to the reaction mixture and filtrated through a cotton plug. The resultingsolution was analyzed with gas chromatography.
92%
With sodium borohydrid In ethanol
Step A Preparation of 4-cyanobenzyl alcohol To a solution of 4-cyanobenzaldehyde (1.97 g, 15.0 mmol) in 50 mL of ethanol at room temperature was added sodium borohydride (0.57 g, 15.0 mmol). After 4 days, the solution was quenched with saturated ammonoum chloride solution, then poured into EtOAc, washed with sat, NaHCO3 soln. and brine, dried (Na2 SO4), filtered, and concentrated in vacuo to provide the product (1.82 g, 92percent yield) as a white waxy solid which was sufficiently pure for use in the next step without further purification.
85%
With glucose dehydrogenase; D-glucose; Bacteroides fragilis ATCC 25285 7α-hydroxysteroid dehydrogenase; NAD In dimethyl sulfoxide at 30℃; for 25 h; aq. phosphate buffer; Enzymatic reaction
General procedure: The reaction procedure was as follows: glucose (18 mg), glucose dehydrogenase (0.35 U), NAD (2 mg), 7α-hydroxysteroid dehydrogenase (1.1 U) and benzaldehyde (0.02 mmol, dissolved in 10 μL of DMSO) were mixed in 1 mL of potassium phosphate buffer (100 mM, pH 7.0). The mixture was shaken for 12 h at 30 °C, and was then extracted with methyl tert-butyl ether (800 μL). The organic extract was dried over anhydrous sodium sulfate and subjected to HPLC analysis to measure the conversion. The products were identified by comparison with authentic samples in HPLC analysis.
82%
With sodium tetrahydroborate In methanol at 0℃; for 1.5 h;
To a solution of 4-formyl-benzonitrile (1.51 g, 11.5 mmoL) in MeOH(15 mL)was added NaBH4 (0.51 g, 13.4 mmoL) at 0 °C. Then the mixture was stirred at this temperature for 1.5 hrs. The reaction was quenched with H20 (7.5 mL) and the resulting mixture was concentrated to remove most of the MeOH. Then the residue was poured into H20 (20 mL) and extracted with EtOAc (30 nJ*2) The combined EtOAc extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated to give 4-hydroxymethyl-benzonitrile (1.26 g, yield: 82percent) as colorless oil.
81%
Stage #1: With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 50℃; for 2 h; Stage #2: With methanol; sodium hydroxide In tetrahydrofuran; water at 60℃; for 24 h;
General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50–55 °C until there was no aldehyde left (monitored by TLC and GC–MS). The reaction was then quenched byMeOH (2mL) and a 10percent aqueous solution of NaOH (5 mL) with vigorous stirring at 60 °C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5–10percent ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information.
10 %Chromat.
With formaldehyd; tricarbonyl(η4-1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-one)iron; water; sodium carbonate In dimethyl sulfoxide at 120℃; for 24 h; Inert atmosphere; Sealed tube
General procedure: Knölker iron complex 2a (3 mol percent,12.6 mg), paraformaldehyde (300 mg, 10 mmol), and Na2CO3 (106 mg, 1 mmol,1.0 equiv) and a stirring bar were charged in a pressure tube and flushed withargon. DMSO (1.0 mL), degassed water (1.0 mL), and benzaldehyde (1 mmol)were added under an argon atmosphere to the pressure tube with a syringe.The pressure tube was placed in oil and heated at 120 C for 24 h, then cooledto room temperature. The reaction mixture was neutralized with HCl (1M) andstirred for 30 min. After extraction with EtOAc for 3 times, the combinedorganic layers were dried over MgSO4. The crude product was purified bycolumn chromatography (Heptane/EtOAc: 70:30). The reaction was cooled toroom temperature and hexadecane (100 lL) was added as a GC internalstandard.
990.0 mg
With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 0.25 h; Cooling with ice; Inert atmosphere
Sodium borohydride (289.0 mg, 7.6 mmol) and Dowex 50 (1.4 g) were addedsuccessively to a solution of 4-cyanobenzaldehyde 27 (1.0 g, 7.6 mmol) in THF (20 mL) at icebath temperature under argon atmosphere. The reaction mixture was stirred at room temperaturefor 15 minutes and quenched with water. The layers were separated; aqueous layer was extractedwith DCM (2 × 30 mL). The combined organic layer was dried (MgSO4) and concentrated to getdesired product as a colorless solid. Yield: 990.0 mg, quant.
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11
[ 119072-55-8 ]
[ 18282-51-4 ]
[ 874-89-5 ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper (II) trifluoroacetate hydrate; palladium diacetate In dimethyl sulfoxide at 130℃; for 6 h; Sealed tube; Inert atmosphere
General procedure: Aryl iodide (0.7 mmol, 1 equiv), tert-butyl isocyanide (2.1 mmol, 237 μL, 3 equiv), Pd(OAc)2 (0.035 mmol, 8 mg, 5 mol percent), Cu(TFA)2*xH2O (1.4 mmol, 405 mg, 2 equiv) and DMSO (2.5 mL) were added to a 15 mL sealed tube, and stirred at 130 °C for 4-12 h under nitrogen. After completion of the reaction indicated by TLC, the mixture was extracted with Et2O (510 mL). The combined organic phases was dried over Na2SO4, and concentrated under vacuum. Then the residue was purified by column chromatography on silica gel using petroleum ether (30-60 °C)/Et2O as eluant to provide the pure target product.
With C21H35BrMnN2O2P; hydrogen; potassium hydride In toluene at 100℃; for 60 h;
Hydrogenation of 1 mmol of hexyl hexanoate under 20 bar at 100°C in toluene, resulted in 99percent yield of hexanol (Entry 1). Under the same conditions ethyl butyrate was hydrogenated to give 98percent yield of butanol and 91 percent yield of ethanol after 50 hours (Entry 2). When the reaction was performed at shorter reaction time (22 hours, Entry 2bis), small amounts of ethyl acetate and butyl butanoate were also formed, attributed to a transesterification reaction with the formed ethanol and butanol. Cyclohexylmethyl acetate gave 99percent yield of cyclohexylmethanol and 60percent yield of ethanol (Entry 3), and no transesterification products were observed. Hydrogenation of the secondary aliphatic ester heptan-2-yl acetate resulted in 98percent yield of heptane-2-ol and 57percent yield of ethanol (Entry 4). Ethyl 3-phenylpropanoate was smoothly hydrogenated, rendering 99percent yield of 3-phenylpropan-l-ol and 70percent yield of ethanol after 21 hours (Entry 5). Similarly, ethyl 3- phenylpropanoate gave 99percent yield of phenyknethanol and 74percent yield of butanol after 22 hours (Entry 6). In order to get full hydrogenation of benzyl benzoate longer reaction time was needed (43 hours, 99percent yield benzyl alcohol, Entry 7). Similarly, methyl benzoate gave 96percent yield of benzyl alcohol and 63 percent of methanol after 50 hours (Entry 8). ε-Caprolactone was smoothly and quantitatively hydrogenated to 1 ,6-hexanediol (99percent yield, Entry 9). The activated benzyl trifluoroacetate gave 99percent yield of benzyl alcohol and 78percent of 2,2,2- trifluoroethanol (Entry 10), and no secondary products where observed. Gratifyingly, allyl trifluoroacetate gave 97percent yield of 2,2,2-trifluoroethanol and 96percent of allyl alcohol (Entry 1 1), showing high chemoselectivity to ester hydrogenation over C=C hydrogenation. Hydrogenation of ethyl 4-isocyano-benzoate required an increase of precatalyst loading to 3percent, probably due to competing nitrile coordination, and resulted in 61 percent yield of (4-isocyanophenyl)methanol and 66percent yield of ethanol, with no hydrogenation of the nitrile group detected (Entry 12).
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[4] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2785 - 2788
[5] Chemical and Pharmaceutical Bulletin, 1976, vol. 24, # 5, p. 1059 - 1063
[6] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
14
[ 873-75-6 ]
[ 143-33-9 ]
[ 874-89-5 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 10, p. 2890 - 2891
15
[ 10406-25-4 ]
[ 874-89-5 ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium carbonate; dimethyl sulfoxide; trifluoroacetic acid; sodium nitrite In water
Example 1 p-Cyanobenzylamine (26.2 g), sodium nitrite (20.8 g), and dimethyl sulfoxide (200 ml) were mixed, and the mixture was vigorously stirred at room temperature (about 20 to 30° C.). Trifluoroacetic acid (45.6 g) was added dropwise to the mixture over a one hour period. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. The reaction mixture was analyzed by use of high performance liquid chromatography, to thereby obtain proportions (on the mol basis) of predominant reaction products: p-cyanobenzyl alcohol:p-cyanobenzaldehyde:p-cyanobenzoic acid=72:18:10. Dimethyl sulfoxide was removed through distillation under vacuum, and water (300 ml) was added to the residue. Sodium carbonate was added to the thus-formed solution, to thereby adjust pH to 8. The resultant aqueous solution was subjected to extraction with toluene (300 ml*2). Toluene was removed through distillation under reduced pressure, and the resultant solution was subsequently distilled under vacuum, to thereby obtain 16.2 g of p-cyanobenzyl alcohol (bp. 175-178° C./1.5 kPa) (yield 61percent). The purity of the product was 98percent.
51%
With sulfuric acid; sodium nitrite In water; toluene
Example 3 p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt percent aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51percent). The purity of the product was 98percent.
Reference：
[1] Research on Chemical Intermediates, 2013, vol. 39, # 1, p. 205 - 220
[2] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0067; 0068
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 13, p. 2790 - 2796
43
[ 105-07-7 ]
[ 619-65-8 ]
[ 874-89-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1981, vol. 30, # 3, p. 459 - 466[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1981, # 3, p. 617 - 624
[3] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 12, p. 2633 - 2635
[4] Tetrahedron Letters, 1983, vol. 24, # 9, p. 851 - 854
[5] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2207 - 2211
(4-Aminomethyl-phenyl)-methanol hydrochloride salt 4-Hydroxymethyl-benzonitrile (2.0 g, 15 mol) was reduced using Raney nickel (0. 5g) and hydrogen (50 psi) in MeOH: NH3 (100ml) for 20 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford (4-aminomethyl-phenyl)-methanol hydrochloride salt (2.01 g, 98percent) as a white solid of sufficient purity for use without further purification: MS (APCI+) : m/z 138.3 (M+H); H-NMR (DMSO-d6) 8 7.20 (s, 4 H), 5.04 (s, 2 H), 4.42 (s, 2 H), 3.83 (s, 1 H), 2.45 (s, 2 H).
29%
With lithium aluminium tetrahydride In diethyl ether at 0℃; for 3.25 h; Reflux
Example 99 N-((4-(hydroxymethyl)phenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamide hydrochloride (57MBT72D) To a stirred suspension of LiAlH4 (285 mg, 7.52 mmol) in diethylether (10 mL) at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2Cl2 (20 mL). Extraction with additional CH2Cl2 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15percent MeOH in CH2Cl2) gave 152 mg (29percent) of 4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. Rf=0.51 (30percent MeOH in CH2Cl2+3.5percent NH4OH).
29%
Stage #1: With lithium aluminium tetrahydride In diethyl ether at 0℃; for 3.25 h; Heating / reflux Stage #2: With sodium hydroxide In diethyl ether; water at 20℃;
To a stirred suspension of LiAlHU (285 mg, 7.52 mmol) in diethylether (10 mL)at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t, the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2Cl2 (20 mL). Extraction with additional CH2Cl2 (20 mL) and n- butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0- 15percent MeOH in CH2Cl2) gave 152 mg (29percent)of 4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. Rf=0.51 (30percent MeOH in CH2Cl2 +3.5percent NH4 OH).
Reference：
[1] Patent: WO2005/56004, 2005, A1, . Location in patent: Page/Page column 154-155
[2] ACS Catalysis, 2018, vol. 8, # 10, p. 9125 - 9130
[3] Journal of Organic Chemistry, 1998, vol. 63, # 22, p. 7663 - 7669
[4] Patent: US2015/259291, 2015, A1, . Location in patent: Paragraph 0612
[5] Patent: WO2007/124136, 2007, A1, . Location in patent: Page/Page column 130
[6] Organic Mass Spectrometry, 1990, vol. 25, # 12, p. 649 - 654
[7] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3187 - 3200
[8] Chemical Communications, 2010, vol. 46, # 7, p. 1073 - 1075
[9] Journal of Medicinal Chemistry, 2009, vol. 52, # 1, p. 33 - 47
[10] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8140 - 8151
67
[ 105-07-7 ]
[ 228546-60-9 ]
[ 589-18-4 ]
[ 874-89-5 ]
[ 39895-56-2 ]
Reference：
[1] Chemical Communications, 2005, # 1, p. 40 - 42
68
[ 874-89-5 ]
[ 123986-64-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 1, p. 33 - 47
[2] Patent: US9096856, 2015, B2,
69
[ 874-89-5 ]
[ 187283-17-6 ]
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[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3187 - 3200
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 1, p. 33 - 47
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8140 - 8151
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; at 75℃; for 6h;
General procedure: To a round-bottom flask equipped with a stir bar was added 7a-e (1.0 eq), hydroxylamine hydrochloride (2.0 eq), NaHCO3 (4.0 eq), and methanol (5.0mL/mmol). The reaction was refluxed and stirred in a pre-heated 75C oil-bath for 6h. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with methanol. The filtrate was concentrated in vacuo without further purification
70%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; at 75℃; for 6h;
General procedure: Intermediates 6a-g (shown below) were synthesized from 5a-g using the following general procedure (labeled as ?a? on FIG. 1). To a round-bottom flask equipped with a stir bar was added 5a-g (1.0 eq), hydroxylamine hydrochloride (2.0 eq), NaHCO3 (4.0 eq), and methanol (5.0 mL/mmol). The reaction was refluxed and stirred in a pre-heated 75 C. oil-bath for 6 h. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with methanol. The filtrate was concentrated in vacuo without further purification. Example 8 Synthesis of 41 (E)-N?-hydroxy-4-(hydroxymethyl)benzimidamide (6a) (0154) The synthesis follows the general procedure described in Example 7. Yield: 70%, MP: 217-219 C. 1H NMR (400 MHz, DMSO-d6) delta =7.88-7.78 (m, 4H), 5.93 (s, 2H).
48%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; for 12h;Heating / reflux;
8B. N-Hydroxy-4-hydroxymethyl-benzamidine Hydroxylamine hydrochloride (5.17 g, 75.0 mmol) and sodium bicarbonate (12.6 g, 150 mmol) were added to a solution of 4-hydroxymethyl-benzonitrile (5.0 g, 37.5 mmol) and methanol (65.0 mL). The reaction was heated to reflux for 12 hours. The reaction mixture was cooled to room temperature and the resulting slurry was filtered. The filtrate was concentrated in vacuo to give of the title compound (6.0 g, 48% yield) as an oily solid. 1H NMR (400 MHz, CD3OD) 4.60 (s, 2H), 7.36 (d, 2H), 7.59 (d, 2H).
With Oxone; In water; acetonitrile; for 13h;Reflux;
General procedure: To 16 mL of acetonitrile/water (1:1 v/v) mixture was added 0.5-1.2 mmol of the starting compound. The contents were heated at reflux with introduction of oxone (cf. entries for each case) incrementally over the entire duration of the reaction. For secondary benzyl halides, the reactions were run at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of the reaction, the reaction mixture was cooled to room temperature and the organic matter was extracted with ethyl acetate. The combined organic extract was dried over anhyd Na2SO4 and concentrated in vacuo. Short pad silica gel column chromatography of the residue led to isolation of the pure product.
93%
With diethylene glycol dimethyl ether; at 70℃; for 0.5h;Sonication;
In a 10 mL round bottom flask, 0.66 g of 4-cyanobenzyl alcohol and 2 g of diethylene glycol dimethyl ether were sequentially added.The resulting mixture was subjected to ultrasonic irradiation at 40 kHz/30 W/70 C for 30 minutes in an ultrasonic reaction apparatus. The diethylene glycol dimethyl ether was removed under reduced pressure, and recrystallized to give 0.68 g of 4-cyanobenzoic acid, yield 93%.
86.4%
With oxovanadium(IV) sulfate; sodium tungstate (VI) dihydrate; dihydrogen peroxide; methyl tri-n-octyl ammonium hydrogen sulfate; sodium chloride; In water; at 90℃;
4-cyanobenzyl alcohol 128 g, Methyltrioctylammonium hydrogen sulfate6.2 g, sodium tungstate dihydrate 4.6 g,Vanadyl sulfate4g, sodium chloride 4g, water 500g, placed in a four-mouth bottle, the oil bath is heated, so that the temperature rises to 90 C,400 g of 30% hydrogen peroxide water was added dropwise to the kettle. Sampling for HPLC detection when 4-cyanobenzyl alcohol disappearsAt the end of the reaction, the reaction time was a total of 6 h. The reaction mixture was filtered while hot, and 138 g of a crude product was obtained with a purity of 85%.Dichloromethane was added and recrystallized to obtain 127 g of a product having a purity of 98.6% and an overall yield of 86.4%.
76%
With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen; In 1,2-dichloro-ethane; at 25℃; for 48h;Schlenk technique;
General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid. Yields of 57% of 2a and 38% of benzaldehyde (3a)15 were observed by NMR analysisof the crude product using CH2Br2 as an internal standard and by comparison with spectra reported in the literature.
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