* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydroxylamine hydrochloride In methanol; water at 20℃; for 18 h; Irradiation
General procedure: A round bottom flask was charged with a mixture of benzaldehyde 1(1.0 mmol), NH2OH.HCl 2 (1.5 mmol), Cog-C3N4 (20 mg) in H2O/MeOH (1:1, 5 mL) and stirred under the visible light condition at roomtemperature for 14–20 h. After completion of the reaction (monitored by TLC), the catalyst was filtered and added EtOAc (10 mL). Remaining organic layer was washed with brine (2×5 mL) and distilled water(1×10 mL) and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to afford the crude residue, which was further purified by flash chromatography, EtOAc/n-hexane: 10:90 to obtain the analytically pure product 3
86%
With hydroxylamine hydrochloride; zinc trifluoromethanesulfonate In toluene at 100℃; for 24 h;
General procedure for the synthesis of nitriles: A pressure tube was charged with an appropriate amount of Zn(OTf)2 (0.036 mmol, 5.0 mol percent), the corresponding aldehyde (0.72 mmol) and hydroxylamine hydrochloride (1.2 equiv, 0.86 mmol). After the addition of toluene (2.0 mL) the reaction mixture was stirred in a preheated oil bath at 100 °C for 24 h. The mixture was cooled in an ice bath and biphenyl (internal standard) was added. The solution was diluted with dichloromethane and an aliquot was taken for GC-analysis (30 m Rxi-5 ms column, 40-300 °C). The solvent was carefully removed and the residue was purified by column chromatography (n-hexane/ethyl acetate). The analytical properties of the corresponding nitriles are in agreement with the literature.
Reference：
[1] Organic Letters, 2017, vol. 19, # 11, p. 3005 - 3008
[2] Catalysis Communications, 2019, p. 76 - 81
[3] Journal of Polymer Science, Part A: Polymer Chemistry, 2014, vol. 52, # 8, p. 1055 - 1058
[4] Tetrahedron Letters, 2012, vol. 53, # 7, p. 882 - 885
[5] Chemical Communications, 2013, vol. 49, # 54, p. 6030 - 6032
[6] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3349 - 3354
[7] Organic and Biomolecular Chemistry, 2015, vol. 13, # 39, p. 9948 - 9952
2
[ 71637-34-8 ]
[ 1641-09-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With ammonium hydroxide; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N-Phenylglycine; sodium hydroxide In methanol at 50℃; for 24 h; Cooling with ice
General procedure: Benzyl alcohol was added in a 2L round-bottomed flask (108.02g, 1000mmol, i.e., of formula (I) wherein R is H, X = C, n = 1, m = 0),cuprous iodide (9.50g, 50mmol) , of N- phenylglycine (7.51g, 50mmol), TEMPO ( 7.80g, 50mmol),sodium carbonate (10.60g, 100mmol), aqueous ammonia (300mL, 25 ~ 28percent) ,800mL methanol, under ice-cooling, with the oxygen round bottom flask was evacuated of air ventilation 3 times, and then the system was stirred at 50 at 12h, after completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure and dried to give the product benzonitrile 95.79g, yield 93percent. The reactants used is 2-thiophene methanol (57.12g, 500mmol, i.e., of formula (I) wherein R is H, X = S, n = 0, m = 0), experimental methods and procedures were the same as in Example 1, except that: cuprous iodide (4.76g, 25mmol), N- phenylglycine (3.79g, 25mmol), TEMPO ( 3.91g, 25mmol), sodium hydroxide (2.03g, 50mmol), aqueous ammonia (60mL, 25 ~ 28percent), methanol 160mL, stirred at at 50 24h, to give the final product 49.05g, yield 90percent.
Reference：
[1] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
[2] Patent: CN105294646, 2016, A, . Location in patent: Paragraph 0041; 0064; 0065
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3349 - 3354
3
[ 18895-10-8 ]
[ 1641-09-4 ]
Yield
Reaction Conditions
Operation in experiment
42%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 60℃; for 1.5 h; Inert atmosphere
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 191 - 209
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
Reference：
[1] European Journal of Organic Chemistry, 2008, # 20, p. 3524 - 3528
[2] Chemistry - A European Journal, 2012, vol. 18, # 10, p. 2978 - 2986
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 19, p. 5433 - 5437[2] Angew. Chem., 2018, vol. 130, # 19, p. 5531 - 5535,5
38
[ 88-13-1 ]
[ 1641-09-4 ]
Reference：
[1] Patent: CN104557357, 2018, B,
39
[ 1641-09-4 ]
[ 27757-86-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
With C25H19N3ORuS; potassium <i>tert</i>-butylate In iso-butanol at 120℃; for 0.5 h; Inert atmosphere
General procedure: A flask (25 mL) containing ruthenium(II) complex (1 Mpercent) and 2-butanol (5 mL) was stirredfor 5 min under an argon atmosphere at room temperature. Afterwards, KOtBu(0.05 mM) was added and the mixture was stirred for another 5 min. Then, the nitrile(0.5 mM) was added and placed on a hot plate at 120 °C for 30 min. After completion ofthe reaction, the catalyst was removed from the reaction mixture by addition of petroleumether followed by filtration and subsequent neutralization with 1 M HCl. The ether layerwas filtered through a short path of silica gel by column chromatography. To the filtrate,hexadecane was added as a standard and the yield was determined by GC.
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 109 - 116
[2] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4991 - 5002
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14653 - 14657[4] Angew. Chem., 2016, vol. 128, # 47, p. 14873 - 14877,5
[5] Journal of Coordination Chemistry, 2015, vol. 68, # 2, p. 321 - 334
[6] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9491 - 9494
[7] Chemistry - A European Journal, 2013, vol. 19, # 14, p. 4437 - 4440
40
[ 1641-09-4 ]
[ 1108712-56-6 ]
Yield
Reaction Conditions
Operation in experiment
36.5%
With N-chloro-succinimide In acetic acidReflux
Synthesis of Intermediate 1Molecul t: 143.6[00394] In a 3-neck 100 mL round-bottomed flask, 3-Cyanothiophene (5.0 g, 1 eq.) was dissolved in Acetic acid (50 mL, 10 Vol.) and Added N-chloro succinamide (6.73 g, 1.1 eq.). Reaction mixture was stirred at reflux temperature for 2-3 h. Reaction completion was monitored on TLC using ethyl acetate: n-hexane (1 :9) as mobile phase. Reaction mixture was brought to room temperature and poured into ice-water slurry (250 mL) and neutralized with sodium bicarbonate solution. Compound was extracted in the EtOAc (100 mL x 3). Organic layer was washed with brine solution (100 mL X 2) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 5.0 g of crude compound. Compound was purified by flash chromatography using ethyl acetate and Hexane to afford 2.4 g pure compound. Yield (36.5 percent). Mass/LCMS: 177.0' NMR : Confirmed.
Stage #1: 3-thiophenecarbonitrile With calcium hydride; tiolacetic acid at 80℃; for 1h;
Stage #2: With water In ethyl acetate at 20℃;
84%
With hydrogenchloride; O,S-diethyl-dithiophosphoric acid In ethyl acetate Ambient temperature;
82%
With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 130℃; for 2.5h;
The general procedure of preparing all thioamides
General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 °C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
With pyridine; diammonium sulfide; triethylamine In water at 50℃;
Stage #1: With trimethylaluminum; ammonium chloride In hexane; toluene at 0 - 20℃; for 1.5h;
Stage #2: 3-thiophenecarbonitrile In hexane; toluene at 80℃;
Stage #3: With methanol In hexane; toluene at 0 - 20℃;
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In diethyl ether at 20℃; for 1h;
29
EXAMPLE 29; Mono borylation of 3-Cyanothiophene; In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar, was charged with 2,2'-bis[(4S)-4-benzyl-2-oxazoline]0 (9.6 mg, 0.03 mmol, 3 mol %). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand. [(Ir(OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) was weighed in a test tube. HBPin (145 μL, 128 mg, 1 mmol, 1 equiv) and ether (1 mL) were added to the [Ir(OMe)(COD)]2 containing test tube. The resulting solution was transferred to the 20 mL scintillation vial. Additional ether (1 mL) was used to wash the test tube and the washings were transferred to the scintillation vial. 3-cyanothiophene (182 μL, 218 mg, 2.00 mmol, 2.00 equiv) was then added to the scintillation vial and the reaction mixture was stirred at room temperature for 1 h. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford a mixture of borylated isomers (37% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiophene and 63% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiophene). (Note: 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiophene has been prepared by other methods (Christophersen, C. et al., J. Org. Chem. 2003, 68, 9513-9516 and Blackaby, W. P. et al. PCT Int. Appl. WO 2002076983), but never isolated. 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiphene; 1H NMR (CDCl3, 500 MHz): δ 8.13 (d, J=1.2 Hz, 1 H), 7.74 (d, J=1.2 Hz, 1 H), 1.31 (br s, 12 H, CH3 of BPin). 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiphene; 1H NMR (CDCl3, 500 MHz): δ 7.62 (d, J=4.9 Hz, 1 H), 7.37 (d, J=4.9 Hz, 1 H), 1.34 (br s, 12 H, CH3 of BPin).
In diethyl ether at 20℃; for 1h;
30
EXAMPLE 30; The procedure in Example 29 was followed using 2,2'-bis(2-oxazoline) in place 2,2'-bis[(4S)-4-benzyl-2-oxazoline]. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford a mixture of borylated isomers (14% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiphene and 86% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiphene). The effects of ligand on the regioselectivity for the mono borylation of 3-cyanothiophene is shown below.
In diethyl ether at 20℃; for 1h;
30
EXAMPLE 30; The procedure in Example 29 was followed using 2,2'-bis(2-oxazoline) in place 2,2'-bis[(4S)-4-benzyl-2-oxazoline]. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford a mixture of borylated isomers (14% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiphene and 86% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiphene). The effects of ligand on the regioselectivity for the mono borylation of 3-cyanothiophene is shown below.
With 4,4'-di(tert-butyl)-2,2'-dipyridyl In hexane at 20℃; for 1h; Title compound not separated from byproducts.;
Stage #1: 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer In tetrahydrofuran at 20℃; Glovebox; Inert atmosphere;
Stage #2: With bis(2-pyridyl)methane In tetrahydrofuran at 20℃; Glovebox; Inert atmosphere;
Stage #3: 3-thiophenecarbonitrile In tetrahydrofuran at 20℃; for 24h; Glovebox; Inert atmosphere; Overall yield = 74 percent; regioselective reaction;
With C25H19N3ORuS; potassium tert-butylate; In iso-butanol; at 120℃; for 0.5h;Inert atmosphere;
General procedure: A flask (25 mL) containing ruthenium(II) complex (1 M%) and 2-butanol (5 mL) was stirredfor 5 min under an argon atmosphere at room temperature. Afterwards, KOtBu(0.05 mM) was added and the mixture was stirred for another 5 min. Then, the nitrile(0.5 mM) was added and placed on a hot plate at 120 C for 30 min. After completion ofthe reaction, the catalyst was removed from the reaction mixture by addition of petroleumether followed by filtration and subsequent neutralization with 1 M HCl. The ether layerwas filtered through a short path of silica gel by column chromatography. To the filtrate,hexadecane was added as a standard and the yield was determined by GC.
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 6h; Reflux;
Preparation of amidoximes 1a-o
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL).
82%
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 6h; Reflux;
3 General procedure (GP 1): preparation of amidoximes (10 a-e)
General procedure: To a stirred suspension of nitrile (30 mmol) and hydroxylaminehydrochloride (3.13 g, 45 mmol) in EtOH (50 mL) a NaHCO3 (3.78 g,45 mmol)was added. The reaction mixturewas stirred under refluxfor 6 h. After the reaction had completed, the reaction mixture wasconcentrated under reduced pressure, and the residue was dilutedwith cold water (80 mL). The resulting precipitate was filtered off,washed with cold water (20 mL) and dried in air at roomtemperature.4.2.3. N'-Hydroxypicolinimidamide (10a) [35]Yield 3.54 g (86%); White solid; m.p. 117-118 °C. 1H NMR(400 MHz, DMSO) δ ppm 9.90 (s, 1H), 8.57 (d, J 4.8 Hz, 1H), 7.86 (d,J 7.9 Hz, 1H), 7.82 (t, J 8.1 Hz, 1H), 7.40 (t, J 6.6 Hz, 1H), 5.80(br.s, 2H).
82%
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 6h; Reflux;
Preparation of amidoximes 1a-o. General procedure [1].
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL).
82%
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 6h; Reflux;
51%
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer Reflux;
With hydroxyamino hydrochloride; triethylamine In methanol at 50℃;
With hydroxyamino hydrochloride In ethanol for 8h; Reflux;
With hydroxyamino hydrochloride; potassium carbonate In ethanol at 85℃;
With hydroxyamino hydrochloride; sodium hydroxide In water monomer for 3h;
With hydroxyamino hydrochloride; triethylamine In ethanol at 20 - 70℃; for 22h; Sealed tube;
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In methanol Reflux;
With hydroxylamine In ethanol; water monomer at 70℃; for 12h;
Synthesis of Intermediate 1Molecul t: 143.6[00394] In a 3-neck 100 mL round-bottomed flask, 3-Cyanothiophene (5.0 g, 1 eq.) was dissolved in Acetic acid (50 mL, 10 Vol.) and Added N-chloro succinamide (6.73 g, 1.1 eq.). Reaction mixture was stirred at reflux temperature for 2-3 h. Reaction completion was monitored on TLC using ethyl acetate: n-hexane (1 :9) as mobile phase. Reaction mixture was brought to room temperature and poured into ice-water slurry (250 mL) and neutralized with sodium bicarbonate solution. Compound was extracted in the EtOAc (100 mL x 3). Organic layer was washed with brine solution (100 mL X 2) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 5.0 g of crude compound. Compound was purified by flash chromatography using ethyl acetate and Hexane to afford 2.4 g pure compound. Yield (36.5 %). Mass/LCMS: 177.0' NMR : Confirmed.
With trifluorormethanesulfonic acid; O-benzenesulfonyl-acetohydroxamic acid ethyl ester In dichloromethane at 23℃; for 24h; Inert atmosphere;
89%
With hydroxyamino hydrochloride In methanol; water monomer at 20℃; for 18h; Irradiation;
3.1. General method for the synthesis of nitrile 3
General procedure: A round bottom flask was charged with a mixture of benzaldehyde 1(1.0 mmol), NH2OH.HCl 2 (1.5 mmol), Cog-C3N4 (20 mg) in H2O/MeOH (1:1, 5 mL) and stirred under the visible light condition at roomtemperature for 14-20 h. After completion of the reaction (monitored by TLC), the catalyst was filtered and added EtOAc (10 mL). Remaining organic layer was washed with brine (2×5 mL) and distilled water(1×10 mL) and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to afford the crude residue, which was further purified by flash chromatography, EtOAc/n-hexane: 10:90 to obtain the analytically pure product 3
88%
With ammonium hydroxide; iodine
86%
With hydroxyamino hydrochloride; Zinc di(trifluoromethanesulphonate) In toluene at 100℃; for 24h;
General procedure for the synthesis of nitriles: A pressure tube was charged with an appropriate amount of Zn(OTf)2 (0.036 mmol, 5.0 mol %), the corresponding aldehyde (0.72 mmol) and hydroxylamine hydrochloride (1.2 equiv, 0.86 mmol). After the addition of toluene (2.0 mL) the reaction mixture was stirred in a preheated oil bath at 100 °C for 24 h. The mixture was cooled in an ice bath and biphenyl (internal standard) was added. The solution was diluted with dichloromethane and an aliquot was taken for GC-analysis (30 m Rxi-5 ms column, 40-300 °C). The solvent was carefully removed and the residue was purified by column chromatography (n-hexane/ethyl acetate). The analytical properties of the corresponding nitriles are in agreement with the literature.
76%
With [2,2]bipyridinyl; 4-sulfantooxy-2,2,6,6-tetramethylpiperidinyloxy; ammonia; copper(II) bis(trifluoromethanesulfonate); sodium hydroxide In water monomer; acetonitrile at 40℃; for 16h;
60%
With ammonia; oxygen; copper(II) nitrate In water monomer; dimethyl sulfoxide at 80℃; for 5h;
70 %Chromat.
With oxygen; phenylacetonitrile; acetonitrile; copper chloride (I) In N,N-dimethyl acetamide at 130℃; for 24h; Schlenk technique;
With ammonium hydroxide; iodine In tetrahydrofuran at 20℃;
With ammonia; oxygen In tert-Amyl alcohol; water at 100℃; for 5h; Autoclave; High pressure;
95.4%
With ammonium hydroxide; manganese sesquioxide; oxygen at 130℃; for 48h; Autoclave;
2.2. Catalytic evaluation
General procedure: The ammoxidation of alcohols and hydration of nitrileswere performed in a high-pressure steel autoclave reactorequipped with a PTFE bottle, magnetic stirrer (900 rpm), andan explosion-proof pressure sensor. For the ammoxidation ofalcohols, the as-prepared catalyst, aqueous ammonia(28%-30% NH3), and alcohols were added into a certainamount of t-amyl alcohol solvent in the reactor, then the autoclavewas sealed and purged with oxygen for two times to excludethe inside air. For the hydration of nitrile, the as-preparedcatalyst, nitrile, and water were added into a certain amount oft-amyl alcohol solvent in the reactor, then the autoclave wassealed and purged with N2 for two times to exclude the insideair. After that, the reactor was quickly heated to the desiredtemperature (the reaction temperature was measured by athermocouple in the autoclave) in an oil bath. After a desiredreaction time, the reactor was placed in an ice bath to quenchthe reaction. After separation of the solid catalyst by centrifugation,the liquid was analyzed with a Shimadzu GC-2014 gaschromatograph equipped with a flame ionization detector(FID) and an Agilent HP-6890 gas chromatograph-mass spectrometer,with ethylbenzene, bromobenzene, hexadecane, orbiphenyl used as internal standards. The gas-phase products,such as CO and CO2, were analyzed with a Fu Li-9790 gaschromatograph equipped with a thermal conductivity detector(TCD). Notably, no CO and CO2 signals were observed in TCDand total carbon balances were always >90.0% in this work.Safety Note: The high-pressure oxygen has been extensivelyused in the aerobic oxidations [21,22], and the reaction systemsin this work were out of the explosion limits of the reactants.For example, the explosion limit of benzyl alcohol is1.3%-13.0% in oxygen, and the concentration of benzyl alcoholin the gaseous phase in this work is in a 0-0.4% region, whichis out of the explosion limits. Furthermore, the fire and staticelectricity are not allowed to access the internal reactor forsafety reasons. In the kinetics study, the average reaction rateswere calculated from the moles of substrate converted pergram of catalyst in one hour (mmol gcat-1 h-1), with the conversionof substrate controlled to be lower than 20.0%.
91%
With ammonia; oxygen In 1,4-dioxane for 3h; Reflux;
90%
With ammonium hydroxide; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N-Phenylglycine; sodium hydroxide In methanol at 50℃; for 24h; Cooling with ice;
13
General procedure: Benzyl alcohol was added in a 2L round-bottomed flask (108.02g, 1000mmol, i.e., of formula (I) wherein R is H, X = C, n = 1, m = 0),cuprous iodide (9.50g, 50mmol) , of N- phenylglycine (7.51g, 50mmol), TEMPO ( 7.80g, 50mmol),sodium carbonate (10.60g, 100mmol), aqueous ammonia (300mL, 25 ~ 28%) ,800mL methanol, under ice-cooling, with the oxygen round bottom flask was evacuated of air ventilation 3 times, and then the system was stirred at 50 at 12h, after completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure and dried to give the product benzonitrile 95.79g, yield 93%. The reactants used is 2-thiophene methanol (57.12g, 500mmol, i.e., of formula (I) wherein R is H, X = S, n = 0, m = 0), experimental methods and procedures were the same as in Example 1, except that: cuprous iodide (4.76g, 25mmol), N- phenylglycine (3.79g, 25mmol), TEMPO ( 3.91g, 25mmol), sodium hydroxide (2.03g, 50mmol), aqueous ammonia (60mL, 25 ~ 28%), methanol 160mL, stirred at at 50 24h, to give the final product 49.05g, yield 90%.
83%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; ammonia; oxygen; copper(II) nitrate In water; dimethyl sulfoxide at 80℃; for 5h;
Stage #1: 3-thiophenecarbonitrile; 3-Hydroxypropionitrile With zinc trifluoromethanesulfonate; hydrazine In 1,4-dioxane at 70℃; for 40h; Inert atmosphere;
Stage #2: With hydrogenchloride; sodium nitrite In 1,4-dioxane; water Inert atmosphere; Cooling with ice;
35%
Stage #1: 3-thiophenecarbonitrile; 3-Hydroxypropionitrile With zinc trifluoromethanesulfonate; hydrazine In 1,4-dioxane at 70℃; for 40h; Inert atmosphere;
Stage #2: With hydrogenchloride; sodium nitrite In 1,4-dioxane
7 Example 7 Synthesis of 3-(thiophen-3-yl)-6-hydroxyethyl-s-tetrazine Tzf
Example 7 Synthesis of 3-(thiophen-3-yl)-6-hydroxyethyl-s-tetrazine Tzf To a 50 mL flask equipped with a stir bar, Zn(OTf)2 (363 mg, 1.0 mmol), 3-hydroxy-propionitrile (430 mg, 6 mmol), 3-Thiophenecarbonitrile (238 mg, 2 mmol), and anhydrous hydrazine (1.5 mL, 50 mmol), dioxane (1 mL) were added. The reaction was protected with a shield. Under N2 gas, the mixture was stirred in an oil bath at 70° C. for 40 hours. Sodium nitrite (20.0 mmol, 1.4 g) in 20 mL of ice water was slowly added to the solution, followed by slow addition of 1M HCl during which the solution turned bright red in color and gas evolved. Addition of 1M HCl continued until gas evolution ceased and the pH value was 3. The solution was extracted with EtOAc (50 mL*3), the combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica column (Hexanes:EtOAc=1.5:1) to afford 147 mg product Tzf as a pink solid, with a yield of 35%. 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J=3.0, 1.2 Hz, 1H), 7.99 (dd, J=5.1, 1.2 Hz, 1H), 7.49 (dd, J=5.1, 3.0 Hz, 1H), 4.26 (t, J=5.9 Hz, 2H), 3.57 (t, J=5.9 Hz, 2H), 3.39-2.70 (br, 1H). 13C NMR (126 MHz, CDCl3) δ 167.54, 161.89, 134.37, 130.12, 127.44, 126.26, 59.90, 37.40. HRMS [M+H]+m/z calcd. for [C8H9N4OS]+ 209.02492, found 209.0493.
With zinc trifluoromethanesulfonate; hydrazine hydrate at 70℃; Schlenk technique; Inert atmosphere;
bis(2-phenoxyethyl) 3,3'-(3-cyanothiophene-2,4-diyl)(2E,2'E)-diacrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With silver hexafluoroantimonate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; copper(II) acetate monohydrate In acetic acid; 1,2-dichloro-ethane at 120℃; for 16h; Inert atmosphere; regioselective reaction;
4-methoxy-2-(thiophen-3-yl)-4,5-dihydrooxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With trifluorormethanesulfonic acid In 1,2-dichloro-ethane at 20℃; for 24h;
4-Alkoxy-2-oxazolines; General Procedure
General procedure: To a solution of the appropriate nitrile (0.31 mmol) in anhyd DCE (1 mL) was added TfOH (44 μL, 0.49 mmol) and GADA (47 μL, 0.46 mmol). After stirring at r.t. for 24 h, the reaction mixture was poured into H2O and adjusted to pH 8 with sat. aq NaHCO3, which was then extracted with CH2Cl2 (3 ×). The organic layers were combined and washed with H2O and brine, dried over anhyd Na2SO4, and concentrated in vacuo to give the product. The crude product was purified by a silica gel column (PE/EtOAc = 10:1-3:1, v/v), unless stated otherwise. The significant loss of product was due to the difficulty in isolation.
With 2,3,6,7-tetramethoxy-9(10H)-anthracenone; caesium carbonate In dimethyl sulfoxide at 25℃; for 18h; Irradiation; Sealed tube; regioselective reaction;
General Procedure for the Carboxylation of Hetero(arenes) and Styrenes- GP2a
General procedure: To a dry flat-bottomed crimp vial (5 mL) equipped with stirring bar, was added the arene (if solid)(0.1 mmol) and 2,3,6,7-tetramethoxyanthracen-9(10H)-one (6.3 mg, 0.02 mmol, 20 mol %). Cs2CO3 (98 mg,3 equiv.) was quickly added and the vial was sealed with a Supelco aluminium crimp seal with septum(PTFE/butyl). The vial was then evacuated and refilled with CO2 (5×) via syringe needle. The reactionmixture was dissolved in DMSO (1 mL, dry and degassed by bubbling with N2) and the arene (0.1 mmol) (ifliquid) was added via syringe. The vial was sealed with two layers of Parafilm and then had gaseous CO2added via a Luer Lock Monoject (20 ccm) syringe, into the head space. The vial was then irradiated fromthe bottom side with blue LED light and a constant reaction temperature (25°C) was maintained byemploying a water-cooling circuit connected to a thermostat. After 18 hrs of reaction time the pressure wasreleased. For product isolation, the reaction mixtures of 4 reactions run in parallel were combined andtransferred with water and Et2O into a separating funnel. The ether layer was extracted with water (3×) andthe combined aqueous layers were acidified with aq. HCl (2M) to adjust to an acidic pH. The aqueous layerwas extracted with EtOAc (3×) and the combined EtOAc layers were dried over Na2SO4, filtered andconcentrated in vacuo. The crude material was purified by silica flash column chromatography usingmixtures of hexanes and ethyl acetate with 0.5% HOAc (v/v) as eluents.
With 1,3-bis-(diphenylphosphino)propane; nickel(II) bromide; sodium tertiary butoxide In toluene at 150℃; for 12h; Inert atmosphere; Schlenk technique;
9 Example 9
Under nitrogen protection, 0.4 mmol (84 mg) 3-iodothiothiophene,NiBr2(1equiv, 87.4 mg), sodium tert-butanol (1equiv, 38.4 mg), phosphine ligand dppp (20 mol%, 33 mg) were added to a 25 mL Schlenk tube, 2 mL toluene was added as a solvent, followed by 0.6 mmol (49.9 mg) tert-butyroisonitrile. Next, the reaction was placed in a 150 °C oil bath and stirred for 12 hours. After the end of the reaction, the reaction liquid was cooled to room temperature, the reaction solution was diluted with 2mL of ethyl acetate, and then 500mg of silica gel was added to the reaction solution, mixed and rotated to evaporate, using n-hexane: ether = 20:1 by silica gel column for elution, and the target product was obtained after vacuum pressure concentration to obtain a pure product of 27mg, with a yield of 62%.
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