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[ CAS No. 623-03-0 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 623-03-0
Chemical Structure| 623-03-0
Chemical Structure| 623-03-0
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Product Details of [ 623-03-0 ]

CAS No. :623-03-0 MDL No. :MFCD00001813
Formula : C7H4ClN Boiling Point : -
Linear Structure Formula :- InChI Key :GJNGXPDXRVXSEH-UHFFFAOYSA-N
M.W : 137.57 Pubchem ID :12163
Synonyms :

Calculated chemistry of [ 623-03-0 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.17
TPSA : 23.79 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.39 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.79
Log Po/w (XLOGP3) : 2.47
Log Po/w (WLOGP) : 2.21
Log Po/w (MLOGP) : 2.05
Log Po/w (SILICOS-IT) : 2.46
Consensus Log Po/w : 2.2

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.74
Solubility : 0.249 mg/ml ; 0.00181 mol/l
Class : Soluble
Log S (Ali) : -2.61
Solubility : 0.335 mg/ml ; 0.00243 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.07
Solubility : 0.117 mg/ml ; 0.000853 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.38

Safety of [ 623-03-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H302+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 623-03-0 ]

* 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.

  • Upstream synthesis route of [ 623-03-0 ]
  • Downstream synthetic route of [ 623-03-0 ]

[ 623-03-0 ] Synthesis Path-Upstream   1~50

  • 1
  • [ 267877-39-4 ]
  • [ 623-03-0 ]
  • [ 62882-02-4 ]
  • [ 79965-68-7 ]
  • [ 140-53-4 ]
Reference: [1] Australian Journal of Chemistry, 1999, vol. 52, # 11, p. 1029 - 1033
  • 2
  • [ 623-03-0 ]
  • [ 16687-61-9 ]
YieldReaction ConditionsOperation in experiment
99% With sodium azide; ammonium cerium (IV) nitrate In N,N-dimethyl-formamide at 110℃; for 6 h; Inert atmosphere; Green chemistry General procedure: sodiumazide (1.5 mmol) was added to a magnetically stirred solution of nitrile 1a(1 mmol) in anhydrous DMF and the CAN (10 mmol percent) was added. The reactionmixture was constantly stirred for another 6 h at 110 C under nitrogenatmosphere. After the completion of reaction as seen by TLC, the reactionmixture was brought to room temperature and the solvent was evaporatedunder vacuum. The crude thus obtained, was dissolved in ethyl acetate (20 mL)and solution was washed with acidified water (4 M HCl, 15 mL) twice.Separated organic layer was washed with brine solution dried overanhydrous Na2SO4, and solvent was removed under high vacuum to obtaintetrazole 1b as a white crystalline solid in 97percent yield.
99% With sodium azide In N,N-dimethyl-formamide at 120℃; for 4 h; General procedure: Cu(II)-NaY (0.1 g) was added to a mixture of benzonitrile (0.206 g, 2.0 mmol) and sodium azide (0.169 g, 2.6 mmol) in DMF (5 mL) and mixture was stirred at 120 °C for 3 h. After completion of reaction (as monitored by TLC), the catalyst was centrifuged, washed with ethyl acetate and the centrifugate was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL) and stirred vigorously. The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water and concentrated to give the crude solid crystalline 5-phenyltetrazole. The product was characterizedby 1H NMR , 13C NMR and mass spectroscopic analysis.
97% With sodium azide In N,N-dimethyl-formamide at 90℃; for 3 h; General procedure: In a double-necked round bottom flask (100 mL) equippedwith a condenser was added a mixture consisting ofnitrile (0.005 mol), NaN3 (0.006 mol), and monodisperse Pt NPsVC in DMF (1.5 mL). The mixture washeated at reflux until TLC monitoring indicated no furtherimprovement in the conversion. The reaction mixture wasthen cooled to room temperature, vacuum-filtered usinga sintered-glass funnel and the residue was washed withethyl acetate (3×10 mL). The filtrate was treated with5 mL HCl (4 mol L−1 to reach pH= 3 and it was allowedto stir for 30 minutes. Subsequently, the organic layer wasseparated, dried over anhydrous Na2SO4 and evaporated.The crude product was purified by recrystallization and/orcolumn chromatography on silica gel eluted with propersolvents to get pure 5-Phenyl 1H-tetrazole.
96% With sodium azide In water at 100℃; for 2 h; Green chemistry General procedure: Benzonitrile (1 mmol, 0.103 g), sodium azide (1.1 mmol, 0.0759 g), and 2 mL water were taken in a reaction tube and stirred at room temperature to make homogeneous suspension, and then 20 wtpercent catalyst (ZnO–RGO) was added to the reaction mixture. The reaction mixture was heated to 100 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and centrifuged. The filtrate was treated with 5N HCl (10 mL) and then with ethyl acetate. The organic layer was separated, washed with deionized water, and then dried over anhydrous sodium sulfate and concentrated to give the crude solid crystalline 5-phenyl-1H-tetrazole. It was recrystallized from n-hexane, ethyl acetate, and the yield was about 0.143 g.
95% at 120℃; for 4 h; General procedure: A mixture of the required nitrile (1 mmol), sodium azide(1 mmol) and the catalyst MNP (0.05 g) was stirred at 120° C in PEG (1 mL) as solvent. After completion of the reaction, as indicated by TLC, the mixture was cooled to room temperature and diluted with 1:1 H2O:Ethyl acetate(10 mL) and then stirred at ambient temperature (10 min). The catalyst was removed by applying a magnetic field, and the decantate was treated with HCl (4 N, 10 mL). The organic layer was separated, washed with water, dried over sodium sulfate and concentrated to precipitate the crude crystalline solid. The pure tetrazoles were characterized bytheir spectroscopic data and melting points.
95% With sodium azide; aminosulfonic acid In N,N-dimethyl-formamide at 120℃; for 5 h; General procedure: A mixture of 4-nitrobenzonitrile (0.296 g, 2 mmol), sodium azide (0.195 g, 3 mmol), and sulfamic acid (0.0097 g, 0.1 mmol) was stirred at 120°C in DMF (5 mL) for the appropriate time (Table 2) until TLC (4:1 n-hexane:ethyl acetate) indicated no further progress in the conversion. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature, then 20 mL diethyl ether was added to the mixture and stirred for 10 minutes. The catalyst was separated by simple gravity filtration, washed with diethyl ether (2 £ 10 mL) and dried at 40°C for 30 min. The recovered catalyst wasused for three additional cycles and gave the tetrazole in 95, 85 and 75percent (with 4-nitrobenzonitrile). The filtrate was treated with ethyl acetate (30 mL) and 6 N HCl(20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 5-(4-nitrophenyl) tetrazole (0.363 g), 95percent yield.
95% at 120℃; for 2 h; General procedure: To a stirred mixture of sodium azide (1.2 mmol) in PEG-400(2 mL), a nitrile compound (1 mmol) and NiNP-PNF (200 mL) were added and heated at 120°C under atmospheric conditions.The reaction progress was monitored by TLC. Upon reaction completion, the mixture was allowed to cool to ambient temperature and then filtered and extracted with ethyl acetate. The organic layer was washed with 1N HCl, dried with anhydrous Na2SO4, and filtered to afford pure 5-substituted tetrazoles.
95% at 120℃; for 0.333333 h; Green chemistry General procedure: To a suspension of the catalyst (0.004 g) in PEG (2 mL), nitrile (1 mmol) and sodium azide (1.2 mmol) were added and the mixture was stirred vigorously at 120 °C for the required time (Table 6). After the reaction was completed (as monitored by TLC), the catalyst was separated with a magnet. HCl (4 N, 10 mL) was then added to the residue, and the tetrazole was extracted with ethyl acetate. The organic extract was washed with distilled water, dried over anhydrous Na2SO4 and then evaporated to give the desired tetrazole.
95% With sodium azide; C19H17N3O4(2-)*Cu(2+) In ethylene glycol at 120℃; for 3 h; General procedure: In 25mL round-bottomed flask, sodium azide (0.076g, 1.2mmol) and polymeric copper (II) complex (0.005g) were added to a solution of benzonitrile (0.103g, 1mmol) in ethylene glycol (3mL) with stirring at room temperature. The reaction temperature was raised up to 120°C for 3h. The reaction was monitored by TLC at regular intervals. After completion of the reaction, the reaction mixture was cooled to room temperature and treated with 10mL HCl (2N) and extracted with 10mL ethyl acetate. The resulted organic layers were separated and washed with 2×10mL distilled water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was then purified by column chromatography on silica gel (100–200 mesh) to afford the corresponding products.
94% With sodium azide In N,N-dimethyl-formamide at 110℃; for 2.5 h; Green chemistry General procedure: A mixtureof benzonitrile and sodium azide was added to 0.5g of 30molpercent CAN supportedHY-zeolite in DMF. Then the reaction mixture was stirred at 110 °C forspecified time. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction the catalyst was removed by simple filtration andthe filtrate was treated with 1N HCl solution followed by extraction with ethylacetate twice. The combined organic layer was finally washed with water anddried over anhydrous sodium sulfate and was evaporated under reduced pressure.The crude product was recrystallized from hot ethanol to obtain pure 5-phenyl-1H-tetrazole. The same procedure has beenfollowed for other tetrazole derivatives. All the synthesized compounds except 10& 11 (Table 4) are known compounds and their spectral dataand physical properties are identical with those reported in literature.
94% at 140℃; for 0.833333 h; Green chemistry General procedure: NaN3 (0.975 g, 15 mmol) was dissolved in DES (10 mL) at room temperature by stirring until a clear solution was formed. Then benzonitrile (10 mmol) was added. The reaction mixture was constantly stirred at 140 °C and monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into the cold water (10 mL). The solid was obtained and filtered. The obtained solid is taken into cold water (10 mL). Then it was acidified carefully to pH 5 with 5 M HCl. The organic material was extracted thrice with ethyl acetate; the resultant organic layer was washed with distilled water, dried over anhydrous sodium sulfate, and concentrated to give the crude solid crystalline 5-substituted 1H-tetrazole. The resulting product, although evident as a single compound by TLC, was purified by simple recrystallization from aqueous ethanol giving pure 5-substituted 1H-tetrazoles.
94% With sodium azide; <i>L</i>-proline In N,N-dimethyl-formamide at 110℃; Green chemistry General procedure: The mixture of organic nitrile (1 mmol), NaN3 (1.25 mmol) and L-proline (30 molpercent) in DMF (5mL) was stirred at 110 °C for 1-2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was allowed to cool to room temperature. Thecooled reaction mixture was poured in ice water (15 mL) with stirring. The resulting mixture wasacidified with dilute HCl under vigorous stirring. The solid product* was filtered under suction,washed with sufficient cold water till free of acid. The product was air dried to obtain the pureproduct.*In cases where solid product was not obtained after acidification, like benzyl cyanide andaliphatic nitriles, the acidified aqueous phase was extracted with ethyl acetate (2 X 20 mL), thecombined organic phase was washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to get the corresponding pure product.
93% With sodium azide In dimethyl sulfoxide at 85℃; for 12 h; General procedure: General procedure for the synthesis of Tetrazole. A mixture of benzonitrile (103 mg, 1 mmol), sodium azide (97.5 mg, 1.5 mmol), and 3 mL DMSO solvent was added in a 25 mL round bottomed flask. Further (50 mg, 23 mol percent, w/w) catalyst was added to the reaction mixture. The reaction mixture was heated to 85 °C for 12 h. After completion of the reaction (as monitored by TLC), the catalyst was separated by simple filtration, washed with diethyl ether and the filtrate was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL) and stirred vigorously. The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate and were evaporated under reduced pressure to give the product. The product was purified by the column chromatography. The structure was confirmed by spectral analysis (1H NMR, mass and elemental analysis).
93% With sodium azide In N,N-dimethyl-formamide at 110℃; for 4 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 molpercent) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110 °C temperature. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (2 × 20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product.
93% With sodium azide; Acetate de N,N-dimethylamino-4 pyridinium In neat (no solvent) at 100℃; for 2 h; General procedure: To a round-bottomed flask containing 4-(N,N-dimethylamino)pyridiniumacetate (0.15 mmol, 0.02 g) at 100 C, 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.06 g) were added and the mixture was stirred. After1 h, the reaction was complete. The mixture was cooled and washed with coldEtOH (2 5 mL), each time it was permitted to stir for 1 h. Filtration followed bydrying of the precipitate gave the corresponding pure tetrazole
93% With sodium azide; silver(I) triflimide In toluene at 85℃; for 3 h; General procedure: A mixture of the appropriate nitrile (1 mmol), NaN3 (1.5 mmol),toluene (2 mL) and AgNTf2 (5 molpercent) was placed in a round bottomed flask and heated at 85 oC. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled and treated with ethyl acetate (15 mL) and 1M HCl (15 mL)and stirred vigorously. The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water and concentrated to give the pure tetrazole. All the products are known compounds and the spectral data and melting points were identical to those reported in the literature. The disappearance of one strong and sharp absorption band (CN stretching band), and the appearance of an NH stretching band in the IR spectra, were characteristic of the formation of 5-substituted 1H-tetrazoles.
93% at 100℃; for 2 h; General procedure: In a roundbottom flask in 100°C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white In a roundbottom flask in 100°C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white
93% With sodium azide; copper(II) nitrate trihydrate In N,N-dimethyl-formamide at 120℃; for 16 h; General procedure: Cu(NO3)2·3H2O (0.10 mmol), the appropriate nitrile 1 (1.0 mmol), NaN3(2.0 mmol) and DMF (1 mL) were added to a 50 mL round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred in an oil bath at 120 °C for 16 h. After cooling to room temperature, the reaction was acidified HCl (3 M, pH 1.0). Ethyl acetate (~30 mL) wasadded, and stirring was continued until no solid was present. The organic layer was separated, and the aqueous layer was extracted with ethylacetate twice. The combined organic layers were washed with saturatedbrine, and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, EtOAc-PE) to afford the product 2.
92% With Nano TiO2/SO42- In N,N-dimethyl-formamide for 2 h; Green chemistry General procedure: In a round-bottom flask, benzonitrile (1 mmol), sodiumazide (1 mmol), and nano TiO2/SO42 (0.2 g) were charged.Then the reaction mixture was stirred in distilleddimethylformamide (1 mL) at 120 8C. The progress ofthe reaction was followed by TLC (75:25 ethyl acetate:n-hexane). After completion of the reaction, the catalystwas separated by centrifugation, washed with doublydistilled water and acetone, and the centrifugate wastreated with 5 N HCl (20 mL) under vigorous stirring. Theaqueous solution finally obtained was extracted twice with ethyl acetate. The combined organic phase was washedwith water and concentrated to precipitate the crudecrystalline solid. All products were characterized by NMR,IR, mass spectra, and CHN analysis and the data for theknown compounds were found to be identical with theliterature. The complete spectroscopic data are describedin the supporting information. Yield: 92percent. White solid. M.p. 262–263 8C (lit. [11] 261–263 8C) 1H-NMR (250 MHz; DMSO-d6): d 8.04 (d, 2H,J = 8.52 Hz, Ar–H), 7.62 (d, 2H, J = 8.52 Hz, Ar–H), 4.15 (brs,1H,–NH); 13C-NMR (62.9 MHz, DMSO-d6): d 154.8, 135.8,129.4, 128.6, 123.1; IR (KBr): n = 3419, 2927, 2816, 2723,1602, 1457, 1437, 1383, 1350, 1161, 1095, 1055, 875,765 cm1.
91% With sodium azide In N,N-dimethyl-formamide at 90℃; for 8 h; Inert atmosphere General procedure: 5-Benzyl-1H-tetrazole (2a). To a DMF solution of benzyl cyanide (1a, 100 mg, 0.85 mmol) and NaN3(67 mg, 1.02 mmol, 1.2 eq) was added OSU-6 (15 mg, 15 wtpercent relative to 1a). The reaction mixturewas heated at 90 °C (oil bath temperature 95–100 °C) for 4 h at which time TLC indicated the reactionwas complete. The crude reaction mixture was filtered to remove the catalyst, and the filtrate was added to water and extracted with EtOAc (3 x 15 mL). The combined extracts were washed with H2O (3 x 15 mL) and saturated aq. NaCl (1 x 15 mL), dried (MgSO4), filtered, and concentrated under vacuum to give 2a (129 mg, 94percent).
91% at 120℃; for 10 h; Green chemistry General procedure: In a round-bottomed flask, a mixture of nitrile (1 mmol) and sodium azide (1.2 mmol) in the presence of 40 mg of Fe3O4*SBTU*Ni(II) was stirred at 120 °C in PEG for an appropriate time (monitored by TLC). Then, the reaction mixture was cooled down to room temperature. After magnetic separation of catalyst, HCl (4 N, 10 mL) was added to the filtrate and the product extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with water several times, dried with anhydrous Na2SO4 and concentrated to give the crude solid crystalline product.
90% With sodium azide; ammonium acetate In N,N-dimethyl-formamide at 70℃; for 2.5 h; General procedure: The [AMWCNTs-O–Cu(II)–PhTPY] heterogeneous catalyst was subjected to 5 successive reuses under the reaction conditions: For each reaction, nitrile (1.0mmol), NaN3 (1.3mmol) and NH4OAc (1.0mmol) were mixed and stirred in DMF (1mL) in the presence of 4mol-percent of [AMWCNTs-O–Cu(II)–PhTPY] at 70°C in an uncapped vial. After the completion of the reaction, as monitored by TLC using n-hexane/ethyl acetate, the mixture was diluted by H2O (5mL), then the mixture was vacuum-filtered onto a sintered-glass funnel, and the residue was consecutively washed with ethyl acetate (30mL), water (5mL). The heterogeneous catalyst was recharged for another reaction run. The combined supernatant and organic washings were extracted with ethyl acetate (3×10mL), the combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum, followed by purification on silica gel using hexane/ethyl acetate as the eluent afforded the pure products.
90% With lithium tetraazidoborate; ammonium acetate In methanol; N,N-dimethyl-formamide at 100℃; for 8 h; General procedure: NH4OAc (15 mg) was added to a mixture of benzonitrile(103 mg, 1 mmol) and LiB(N3)4(93 mg, 0.5 mmol) in DMF/MeOH (9/1) solution (5 mL) and stirred the mixture was at 100 oC for 8 h. After completion of reaction (monitored by TLC),the mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with 1 M HCl, dried over anhydrous Na2SO4, and concentrated. An aqueous solution of NaOH (1 M) was added to the residue, and the mixture was stirred for 30 min at room temperature. The resulting solution was washed with ethyl acetate, and then 2 M HCl was added until the pH value of the water layer became 1~2. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were washed with 1M HCl.The organic layer was dried over anhydrous Na2SO4 and concentrated to furnish pure 5-phenyl-1-H-tetrazole 1b as a white solid (125 mg) in 86percent yield.
90% With sodium azide; copper(l) chloride In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and copper(I) chloride (4 mole percent) in DMF (2 mL) was stirred at 120 °C for the appropriate time period. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled and treated with 5 mL of HCl (4 mol L−1) and 10 mL of ethyl acetate, successively. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product thus obtained was recrystallised from acetic acid to afford pure 5-substituted 1H-tetrazoles.
90% With sodium azide; activated Fuller’s earth In dimethyl sulfoxide at 120℃; for 1.5 h; Green chemistry General procedure: To a DMSO (3 ml) solution of nitrile (1 mmol), and sodium azide (1.5 mmol), was added catalyst (10 wt percent). The reaction mixture was stirred to 120 0C in an oil bath. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered to separate the catalyst. The filtrate was quenched with water (30 ml), acidified with 5N HCl (20 ml) to precipitate the product, extracted with ethyl acetate (2 X 20 ml). The combined organic layers were washed with water, dried over sodium sulphate and evaporated under reduced pressure to give the product.
90% at 90℃; for 0.5 h; Green chemistry General procedure: A mixture of benzonitriles (2a-p) (0.009 mol), sodium azide (0.009 mol) was dissolved in DIPEAc (5 ml) and allowed to stirr for 30 min at 80° FontWeight="Bold" FontSize="10" C. After completion of the reaction (monitored by thin-layer chromatography, TLC), the reaction mixture was cooled to room temperature and poured on crushed ice. To it 5N HCl (10 mL) was added and stirred vigorously. Otained solid products was filtered and crystallized from ethanol. The synthesized compounds were confirmed by Melting points, IR, 1H and 13C NMR which were in good agreement with those reported in the literature.
90% With sodium azide; (1,10-phenanthroline)bis(triphenylphosphine)copper(I) nitrate In water; isopropyl alcohol at 65℃; for 0.25 h; Inert atmosphere; Microwave irradiation; Green chemistry General procedure: In a round-bottomed flask, a mixture of organic nitrile 1 (1.0 equiv) and NaN3 (1.5 equiv) was added to 5 ml solution of H2O-IPA (1:1) containing 10 molpercent [Cu(phen)(PPh3)2]NO3 as catalyst under N2 atmosphere. The reaction mixture was irradiated under microwave heating at 245 W for 15–25 min at 65°C. Reaction progress was monitored by thin-layer chromatography (TLC). After reaction completion, the mixture was filtered to remove the catalyst. The filtrate was acidified with 5 N HCl (20 ml) to neutralize the product, extracted with ethyl acetate (2 9 10 ml). The combined organic layer was dried over anhydrous MgSO4. The combined filtrate was subjected to evaporation to obtain the crude compound, which was purified over silica gel column (60–120 mesh) using 50 percent ethyl acetate in hexane as eluent to obtain corresponding 5-substituted 1H-tetrazoles 2 as product.
89% With sodium azide; copper(II) ferrite In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), catalyst (40 molpercent) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 °C temperature for 12 h. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product. refText
89% With sodium azide; scandium tris(trifluoromethanesulfonate) In water; isopropyl alcohol at 160℃; for 1 h; Microwave irradiation; Sealed tube General procedure: Synthesis of 5-(4-chlorophenyl)-1H-tetrazole (2c) was achieved as follows: 4-chlorobenzonitrile 1c (274 mg, 2 mmol), NaN3 (260 mg, 4 mmol), Sc(OTf)3(197 mg, 0.4 mmol), and 8mL of a 3:1 isopropanol=water mixture were added to a30-mL Pyrex microwave vessel and capped. The microwave vessel was then placedin a Milestone Start Synth microwave reactor. The reaction was magnetically stirredand heated for 1 h at 160 C. The reaction was monitored by thin-layer chromatography(TLC) using an ether=hexane mixture (typically 50=50) for development.The reaction mixture was then diluted with saturated aqueous sodium bicarbonate(20 mL) and washed with ethyl acetate (215mL). The aqueous sodium bicarbonatelayer was cooled with ice and acidified to a pH of 2 or less with concentratedhydrochloric acid, which was added dropwise. The precipitate formed was extractedwith ethyl acetate (315 mL). The combined organic layers were dried with anhydroussodium sulfate and decanted into a tared round-bottom flask. The organiclayer was concentrated under reduced pressure by rotary evaporation at 40 C andthen under high vacuum. The tetrazole product was recrystallized from ethyl acetateand hexane. All reagents mentioned were not unpurified.NMR spectra were acquired on a spectrometer at 300MHz for 1H and 75MHzfor 13C acquisitions. All 1H NMR spectra were taken in dimethylsulfoxide (DMSOd6)using DMSO as a standard at 2.52 ppm. All 13C NMR spectra were taken inDMSO-d6 using DMSO as a standard at 40.5 ppm. An IR spectrum was obtainedusing a Fourier transform infrared (FTIR) spectrophotometer. A melting point wasalso obtained for the solid products. 5-(4-Chlorophenyl)-1H-tetrazole (2c) is a whitesolid. IR (KBr, thin film) vmax (cm1): 3385 (br), 1645 (m), 1634 (m); 1H NMR(DMSO-d6, d): 11.60 (s, br, 1H), 8.07 (d, J8.28 Hz, 2H), 7.70 (d, J8.25 Hz,2H); 13C NMR (DMSO-d6, d): 155.8 (br), 136.9, 130.6, 129.7, 124.1; mp 250251 C.
89% With sodium azide In N,N-dimethyl-formamide at 120℃; for 1.5 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol),catalyst (25 mg), and DMF (3 mL) was taken in a 5 mLround bottomed flask and heated at 120C. After completionof the reaction (observed on TLC) the reactionmixture was cooled to r.t. and separated from catalyst bycentrifugation. The solvent was removed under reducedpressure. The residue was dissolved in water (5 mL) andacidified with HCl (37percent). The precipitation was filteredand crystallized in a mixture of water and ethanol. Furtherpurification with column chromatography was notnecessary.
88% at 120℃; for 1.83333 h; General procedure: In order to the synthesis of 5-substituted tetrazoles, 0.005g of SBA-15(at)serine(at)Pd was added to a mixture of nitrile (1mmol) and sodium azide (1.2mmol) under stirring conditions at 120°C in PEG, and the completion of the reaction progress was monitored by TLC with n-hexane-ethylacetate (4:1). Then, the catalyst was separated by simple filtration after completion of reaction. Finally, HCl (4N, 10mL) added to the filtrate and then the resultant organic layers were extract with ethyl acetate and washed with distilled water in order to give corresponding tetrazole.
84% With sodium azide In N,N-dimethyl-formamide at 120℃; for 6 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and catalyst (0.02 g, contains 0.4 molpercent of Cu(II)) in DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 °C. The progress of the reaction was followed by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (3×20 mL). The catalyst was removed by using magnetic field or filtration and then the resulting solution was washed with 1N HCl, dried over anhydrous Na2SO4 and then was evaporated. The crude products were obtained in excellent yields. All products were characterized by 1H, 13C NMR, FT-IR, and melting point which were in agreement with literature. We have reported the spectral data of some aromatic and heteroaromatic synthesized compounds
84% With sodium azide In methanol; N,N-dimethyl-formamide at 20 - 100℃; for 8 h; General procedure: A mixture of benzonitrile (1 mmol), sodium azide (2 mmol), Ln(OTf)3-SiO2 (2008 mg) and DMF/MeOH (4:1, 5 mL) in a pressure vial was initially stirred at room temperature. After 30 min, the temperature of the reaction mixture was raised to 100 °C and stirred for another 7 h. After consumption of 1a (as indicated by TLC), the catalyst was separated by filtration and the filtrate was treated with ethyl acetate (15 mL). The organic layer was washed with 4 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layer was washed with water (2 × 10 mL), dried over anhydrous sodium sulfate and concentrated to afford white crystalline solid.5-Phenyl-1H-tetrazole(3a)IR (KBr, cm−1): 3331, 2907, 2850, 2611, 1607, 1485, 1433, 1050, 828, 742. 1H NMR (300 MHz, CDCl3): 8.04–8.007 (m, 1H), 7.611–7.574 (m, 2H). 13C NMR (75 MHz, CDCl3): 156.03, 131.19, 129.08, 126.805, 123.924. MS: m/z = 146 [M]+.
82% With indium(III) chloride; sodium azide In water; isopropyl alcohol at 160℃; Microwave irradiation General procedure: Synthesis of 4-acetylbenzotetrazole (2c). 4-Acetylbenzonitrile 3c (290 mg, 2 mmol), NaN3 (260 mg, 4 mmol), InCl3(89 mg, 0.4 mmol), and 8 mL of a 3:1 isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel and capped. The microwave vessel was then placed in a Milestone Start Synth microwave reactor. The reaction was magnetically stirred and heated for 1 hour at 160 oC. The pressure in the vessels was not determined. The reaction was monitored by TLC using an ether/hexane mixture (typically50/50) for development. After cooling, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20mL) and washed with ethyl acetate (2 x 15 mL). The aqueous sodium bicarbonate layer was cooled to 0 oC and acidified to a pH of 2 or less with concentrated hydrochloric acid,which was added drop-wise. The precipitate formed was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and decanted into a tared round bottom flask. The organic layer was concentrated under reduced pressure. The tetrazole product was recrystallized from ethyl acetate and hexane. All reagents mentioned above were used unpurified
80% With sodium azide; silver nitrate In N,N-dimethyl-formamide at 20 - 120℃; for 5 h; General procedure: Sodiumazide (0.378 g, 0.046 mmol) was added to a solution of AgNO3 (5 mg, 10 mmol)in DMF (5 ml) and reaction mixture was stirred for 5 min, to this stirredsolution benzonitrile 1a (0.4 ml, 0.033 mmol) was added dropwise over theperiod of 1 min at room temperature and stirring continued for 10 min at thesame temperature and then heated at 120 C for 5 h. After consumption of 1a,the reaction mixture was cooled to room temperature and chilled by addingcrushed ice into the reaction mixture followed by addition of 2 N HCl tillreaction mixture reached the pH 2. The reaction mixture was then extractedwith ethyl acetate. The organic layer was dried with anhydrous Na2SO4, andconcentrated to obtain tetrazole 2a in 83percent yield as an off white solid (268 mg).
80% With sodium azide In N,N-dimethyl-formamide at 120℃; for 16 h; General procedure: In a round-bottom flask, 0.2 g benzonitrile (2 mmol) and0.4 g sodium azide (6 mmol), were added to 10 mL DMF.To this mixture, 20 mg of functionalized KIT-6 was addedand the reaction mixture was refluxed. The progress ofreaction was monitored by TLC (75:25 ethyl acetate/nhexane).After completion of the reaction, the reactionmixture was cooled and filtered. The solid materials werewashed three times with acetone and then with the water.The catalyst was collected and dried to activation for nextrun. The product was obtained by acidification of solutionwith hydrochloric acid (5 mL, 6 M). The precipitate wasfiltered and recrystallized from a water/ethanol mixture toget pure product as a white powder, yield: 88percent.
77% With sodium azide; lead(II) chloride In N,N-dimethyl-formamide at 120℃; for 8 h; Inert atmosphere General procedure: Benzonitrile (103 mg, 1 mmol) and sodium azide (97.5 mg, 1.5 mmol) were dissolved in 2 ml of dry DMF in a 25 ml round bottom flask. PbCl2 (27.8 mg, 0.1 mmol, 10 mol percent) was added to the reaction mixture and stirred at 120 °C for 8 h under nitrogen. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and 10 ml of ice water was added followed by addition of 3 N HCl until the reaction mixture became strongly acidic (pH 2-3). The reaction mixture was extracted three times with 20 ml ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous sodium sulfate, and was evaporated under reduced pressure to give a white solid product of 5-phenyl 1H-tetrazole with 81percent yield.
75% With sodium azide; ammonium chloride In N,N-dimethyl-formamide for 24 h; Reflux General procedure: In a typical procedure, 5-aryl-1H-tetrazoles (1–24) were synthesized by adding aryl nitriles (1 eq.), sodium azide (1.2 eq.), and ammonium chloride (1 eq.) in solvent, the mixture was refluxed for 24 h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, 2.5 mL of 2M NaOH was added and the solution was stirred for half an hour. The reaction mixture was concentrated on reduced pressure, and dissolved in water. 3M HCl was added to the reaction mixture until precipitates formed. The precipitates were filtered and washed with distilled water. The yields of title compounds were found to be moderate to high.
74% With sodium azide In N,N-dimethyl-formamide for 24 h; Sealed tube; Green chemistry General procedure: The benzonitrile derivatives (2 mmol), sodium azide (3.2 mmol), and DMF (2 mL) were mixed in a sealed tube, then 30 mg of catalyst MSS-SO3H (or catalyst MSS-SO3Zn) was added into the tube, which was heated for 24 h under 140 C. After 24 hours’ reaction,the catalyst was separated by magnetic force, and the solution was poured into water.The liquid was acidified to pH 1, then ethyl acetate was added to extract the tetrazoles. Carefully evaporating the solvent under reduced pressure, we got the isolated tetrazoles. A sample for characterization was purified on a flash silica column.

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YieldReaction ConditionsOperation in experiment
90% 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.
86% With sodium tetrahydroborate; iron(III) oxide In methanol at 40℃; for 0.666667 h; Sonication General procedure: To the solution of substrate (10 mmol) in dry methanol (25 mL), Fe3O4 nanoparticles (50 mg) were added and the solution was sonicated for 10 min and then vigorously stirred at 40 °C. Sodium borohydride (30 mmol) was added in small lots cautiously while stirring the solution for 30 min and the progress of the reaction was monitored by thin layer chromatography (TLC). After the completion of reaction, the catalyst was separated by using external magnet and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and then separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography over silica gel (100–200 mesh) using ethyl acetate-hexane mixture (varying concentration) as the eluent. All products were analyzed by IR and NMR spectra which were in good agreement with the reported values [5, 10].
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[8] Tetrahedron, 1992, vol. 48, # 21, p. 4301 - 4312
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[14] Chemistry - A European Journal, 2013, vol. 19, # 14, p. 4437 - 4440
[15] Patent: US8563753, 2013, B2, . Location in patent: Page/Page column 17; 18; 19; 20
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YieldReaction ConditionsOperation in experiment
90% With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 12.1667 h; General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
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[2] Synthesis, 2009, # 15, p. 2517 - 2522
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YieldReaction ConditionsOperation in experiment
51% With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; Inert atmosphere To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent) and Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanochlorbenzene (138 mg, 1.0mmol), pyrazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under an atmosphere of argon gas. The reaction was carried out at 120 °C for 72 hours until the starting reaction was complete (the reaction was complete by TLC). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)pyrazole as a pale yellow oil in a yield of 51percent.
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[5] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0316-0327
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium t-butanolate In tetrahydrofuran; toluene at 90℃; for 8 h;
Stage #2: With hydrogenchloride In water
Stage #3: With sodium hydroxide In water
Example 6 4-Cyanochlorobenzene (13.8 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in a mixture of 120 ml of toluene and 80 ml of tetrahydrofuran, and degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2,4,6-triisopropylphenyl)phenyl]dicyclohexylphosphine (95 mg, 0.2 mmol) and (dibenzylideneacetone)palladium (40 mg, 0.05 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 90° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 17.8 g (95 mmol, 95percent of theory) of N-(4-cyanophenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.
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  • [ 100-47-0 ]
  • [ 34334-28-6 ]
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 27, p. 4807 - 4810
  • 17
  • [ 109-01-3 ]
  • [ 623-03-0 ]
  • [ 34334-28-6 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 44, p. 12829 - 12842
  • 18
  • [ 61713-85-7 ]
  • [ 623-03-0 ]
  • [ 790-41-0 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 12, p. 2019 - 2022
  • 19
  • [ 267877-39-4 ]
  • [ 623-03-0 ]
  • [ 62882-02-4 ]
  • [ 79965-68-7 ]
  • [ 140-53-4 ]
Reference: [1] Australian Journal of Chemistry, 1999, vol. 52, # 11, p. 1029 - 1033
  • 20
  • [ 267877-39-4 ]
  • [ 623-03-0 ]
  • [ 79965-68-7 ]
  • [ 539-03-7 ]
  • [ 140-53-4 ]
Reference: [1] Australian Journal of Chemistry, 1999, vol. 52, # 11, p. 1029 - 1033
  • 21
  • [ 123-75-1 ]
  • [ 623-03-0 ]
  • [ 10282-30-1 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In neat (no solvent) at 120℃; for 24 h; General procedure: In a conical flask (10 mL) a mixture of aryl halide (1 mmol),amine (3 mmol), K2CO3 (2 mmol), and Pd-PFMN catalyst (0.06 g, 1.2 molpercent) was stirred for 24 h. Afterward, themixture was cooled down to room temperature and the catalystwas magnetically separated from the reaction mixtureand washed with diethyl ether (2 × 10 mL) followed bydeionized and oxygen-free water (2 × 10 mL). The reusedcatalyst was dried for the next run. The aqueous phase wasextracted with diethyl ether (2 × 10 mL) and the combinedorganic phases were dried over Na2SO4. The products werepurified by column chromatography (hexane/ethyl acetate)to obtain the desired purity.
83% With bis{1,1’-diphenyl-3,3’-methylenediimidazoline-2,2’-diylidene}nickel(II) dibromide; potassium <i>tert</i>-butylate In 1,4-dioxane at 90℃; for 4 h; Inert atmosphere; Schlenk technique General procedure: Under an N2 atmosphere, KOtBu (1.3 mmol), complex 1 (1 mol percent), dioxane (2 ml), amines (1.3 mmol) and aryl chlorides (1.0 mmol) were successively added into a Schlenk tube. The mixture was stirred vigorously at 90 °C for 4 h. Then the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: PE/EA = 15:1) to give the pure products. The reported yields are the average of two runs.
33% at 100℃; for 24 h; closed vessel To commercially available 4-chlorobenzonitrile 17 (5 g, 36 mmol) 12 ml of pyrrolidine were added and the reaction was heated at 100°C for 24 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1 / Petroleum ether 9 as eluant gave 1.68 g of a pale yellow solid. Yield = 33percent 'HNMR (DMSO, 200 MHz) δ 1.96 (4H, m), 3.28 (4H, m), 6.58 (2H, d, J = 9 Hz), 7.51 (2H, d, J = 9 Hz)
33% at 100℃; for 24 h; Sealed vessel Example 15: 1-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea (scheme 1) Preparation of 4-(pyrrolidin-1-yl)benzonitrile 181 (scheme 9) To commercially available 4-chlorobenzonitrile (5 g, 36 mmol) 12 ml of pyrrolidine were added and the reaction was heated at 100°C for 24 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1 / Petroleum ether 9 as eluant gave 1.68 g of a pale yellow solid. Yield = 33percent 1HNMR (DMSO, 200 MHz) δ 1.96 (4H, m), 3.28 (4H, m), 6.58 (2H, d, J = 9 Hz), 7.51 (2H, d, J = 9 Hz)

Reference: [1] Journal of the Iranian Chemical Society, 2015, vol. 12, # 11, p. 2057 - 2064
[2] Journal of Organometallic Chemistry, 2017, vol. 831, p. 1 - 10
[3] Journal of the American Chemical Society, 2015, vol. 137, # 37, p. 11942 - 11945
[4] Tetrahedron Letters, 2003, vol. 44, # 10, p. 2217 - 2220
[5] Tetrahedron, 2008, vol. 64, # 23, p. 5604 - 5619
[6] Journal of Organic Chemistry, 2002, vol. 67, # 9, p. 3029 - 3036
[7] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 2, p. 217 - 222
[8] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 1, p. 42 - 49
[9] Chemistry Letters, 1987, p. 1187 - 1190
[10] Patent: WO2011/120604, 2011, A1, . Location in patent: Page/Page column 44; 134
[11] Patent: EP2377850, 2011, A1, . Location in patent: Page/Page column 17
  • 22
  • [ 623-03-0 ]
  • [ 90-11-9 ]
  • [ 1413355-67-5 ]
  • [ 22034-43-1 ]
  • [ 57103-17-0 ]
Reference: [1] Science, 2012, vol. 338, # 6107, p. 647 - 651
  • 23
  • [ 623-03-0 ]
  • [ 939-80-0 ]
YieldReaction ConditionsOperation in experiment
75.47% With nitronium tetrafluoborate In acetonitrile at 0 - 20℃; for 20 h; In dry acetonitrile (40 ml) was dissolved 4-chlorobenzonitrile (4g, 29.2 mmol), and nitronium tetrafluoroborate (7.7g, 58.39 mmol) was added therto at 0 °C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into cold water. The white solid precipitated out was collected by filtration, and the filterate was washed with water and dried. The compound (4.0g, 75.47percent) thus obtained was used for next step without purification.
Reference: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1252 - 1257
[2] Patent: WO2014/24056, 2014, A1, . Location in patent: Page/Page column 40
[3] MedChemComm, 2017, vol. 8, # 10, p. 2003 - 2011
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 1110 - 1116
[5] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 36
[6] Journal of the Chemical Society, 1927, p. 1117
[7] Journal of the Chemical Society, 1934, p. 1672,1676
[8] Journal of the American Chemical Society, 1961, vol. 83, p. 4564 - 4571
[9] Journal of the American Chemical Society, 1962, vol. 84, p. 1026 - 1032
[10] RSC Advances, 2016, vol. 6, # 27, p. 23038 - 23047
  • 24
  • [ 623-03-0 ]
  • [ 7697-37-2 ]
  • [ 939-80-0 ]
Reference: [1] Journal of the Chemical Society, 1927, p. 1117
  • 25
  • [ 623-03-0 ]
  • [ 57381-49-4 ]
Reference: [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11890 - 11894[2] Angew. Chem., 2014, vol. 126, # 44, p. 12084 - 12088,5
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 13, p. 4041 - 4045[4] Angew. Chem.,
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2473 - 2477[6] Angew. Chem., 2017, vol. 129, p. 2513 - 2517,5
  • 26
  • [ 623-03-0 ]
  • [ 948549-53-9 ]
  • [ 57381-49-4 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 7, p. 741 - 744
  • 27
  • [ 623-03-0 ]
  • [ 146328-82-7 ]
  • [ 62433-26-5 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 8, p. 2437 - 2440
  • 28
  • [ 623-03-0 ]
  • [ 63139-21-9 ]
  • [ 58743-75-2 ]
Reference: [1] Helvetica Chimica Acta, 2015, vol. 98, # 6, p. 805 - 818
  • 29
  • [ 623-03-0 ]
  • [ 6148-64-7 ]
  • [ 1528-41-2 ]
YieldReaction ConditionsOperation in experiment
47% With dmap; bis(η3-allyl-μ-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 140℃; for 20 h; Inert atmosphere General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 °C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
Reference: [1] Tetrahedron, 2012, vol. 68, # 9, p. 2113 - 2120
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474
  • 30
  • [ 623-03-0 ]
  • [ 105-53-3 ]
  • [ 1528-41-2 ]
Reference: [1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 9, p. 1565 - 1574
  • 31
  • [ 623-03-0 ]
  • [ 76-05-1 ]
  • [ 1735-54-2 ]
  • [ 320-41-2 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
  • 32
  • [ 623-03-0 ]
  • [ 30131-16-9 ]
Reference: [1] Patent: CN103588638, 2016, B,
[2] Patent: CN103588638, 2016, B,
[3] Patent: CN103588638, 2016, B,
  • 33
  • [ 623-03-0 ]
  • [ 6574-99-8 ]
Reference: [1] Patent: CN105732427, 2016, A, . Location in patent: Paragraph 0056; 0057; 0058; 0059; 0060
  • 34
  • [ 623-03-0 ]
  • [ 53312-79-1 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 27, p. 23038 - 23047
  • 35
  • [ 623-03-0 ]
  • [ 1314538-55-0 ]
  • [ 66389-80-8 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 15, p. 3956 - 3959
  • 36
  • [ 623-03-0 ]
  • [ 76-05-1 ]
  • [ 1735-54-2 ]
  • [ 320-41-2 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
  • 37
  • [ 623-03-0 ]
  • [ 14401-51-5 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 4 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; isopropyl alcohol at 0℃;
Into a 50 mL dry reaction flask charged with 1 M LiHMDS in THF (22 mmol), p- chlorobenzonitrile (2.76 g, 20.0 mmol) in 2 mL of THF is added, and the reaction mixture is kept stirring at RT for 4 h, at which point 5-6 N HCI (in/PrOH, 15 mL) is added. The crude reaction mixture is kept at 0 0C overnight.The precipitated product is filtered, washed with diethyl ether to yield 3.5 g(93percent) of the compound of formula 2b as a white solid, m.p. 238 0C (lit m.p. 243-245 0C) (E. Ragona, D. L. Nelson, M. Mares-Guis, J. Amer. Chem. Soc. EPO <DP n="74"/>1975, 97, 6844-6848). - IR (KBr): nu(tilde) = 3239 crrf1, 3054, 1678, 1460, 1401 , 1036, 715. - 1H NMR (250 MHz, [D6]DMSO): δ = 7.60-7.77 (m, 2 H), 7.85-7.97 (m, 2 H), 8.4 (br. s, 3 H, NH). - 13C NMR (62.9 MHz, [D6]DMSO), δ = 126.79 (Cquat), 129.36 (+), 130.57 (+), 139.1 (Cquat), 165.1 (NCN).
71%
Stage #1: With hydrogenchloride In ethanol; chloroform at -78 - 20℃;
Stage #2: With ammonium carbonate In ethanol at 20℃; for 72 h;
Hydrogen chloride gas was passed through a solution of   4-chlorobenzonitrile (9b, 25.0 g) in   chloroform (350 mL) and   ethanol (100 mL) at −78 °C for 0.5 h. Then the solution was warmed up to room temperature, and stirred at room temperature overnight. The solution was evaporated in vacuo, and the resulting residue was dissolved with ethanol (500 mL). To the solution was added   ammonium carbonate (90.0 g), and the reaction mixture was stirred at room temperature for 3 days. To the mixture was added   water (300 mL), and ethanol was removed by concentration in vacuo. The resulting solid was collected by filtration, washed with water and dried in vacuo to give   12b (25.4 g, 71percent) as a white solid: 1H NMR (DMSO-d6) δ 2.60–4.80 (2H, br), 7.53 (2H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.50–9.50 (2H, br); FAB-MS m/z 155, 157 [(M+H)+].
Reference: [1] European Journal of Organic Chemistry, 2006, # 12, p. 2753 - 2765
[2] Patent: WO2006/94604, 2006, A1, . Location in patent: Page/Page column 62; 63; 72; 73
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246
[4] Journal of the American Chemical Society, 1985, vol. 107, # 9, p. 2743 - 2748
[5] Patent: US6218538, 2001, B1,
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 17, p. 3614 - 3621
[7] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 29 - 43
[8] Tetrahedron Letters, 2018, vol. 59, # 4, p. 361 - 364
  • 38
  • [ 623-03-0 ]
  • [ 84459-33-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2473 - 2477[2] Angew. Chem., 2017, vol. 129, p. 2513 - 2517,5
  • 39
  • [ 623-03-0 ]
  • [ 201230-82-2 ]
  • [ 6638-79-5 ]
  • [ 116332-64-0 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 21, p. 4843 - 4846
[2] Journal of Organic Chemistry, 2008, vol. 73, # 18, p. 7102 - 7107
  • 40
  • [ 623-03-0 ]
  • [ 126747-14-6 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
  • 41
  • [ 110-91-8 ]
  • [ 623-03-0 ]
  • [ 204078-31-9 ]
  • [ 10282-31-2 ]
Reference: [1] Tetrahedron, 2009, vol. 65, # 6, p. 1180 - 1187
  • 42
  • [ 623-03-0 ]
  • [ 220991-20-8 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586
  • 43
  • [ 623-03-0 ]
  • [ 109384-19-2 ]
  • [ 333954-86-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 2229 - 2238
  • 44
  • [ 623-03-0 ]
  • [ 118753-70-1 ]
  • [ 218451-34-4 ]
YieldReaction ConditionsOperation in experiment
41% With sodium hydride In N,N-dimethyl-formamide at 60℃; Cooling with ice; Inert atmosphere Example 39A2tert-butyl 4-(4-chlorophenyl)-4-cyanopiperidine- 1 -carboxylate To a mixture of Example 39A1 (3.5 g, 14.5 mmol) and 4-Chloro-benzonitrile (2.0 g, 13.2 mmol) in DMF (50 ml) was added NaH (2.1 g, 43.5 mmol) in portions with ice- bath under nitrogen atmosphere. After addition, the mixture was heated to 60 °C and stirred overnight. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica column to afford Example 39A2 (1.8 g, 41percent) as a white solid.
Reference: [1] Patent: WO2013/10453, 2013, A1, . Location in patent: Page/Page column 126
  • 45
  • [ 623-03-0 ]
  • [ 114365-04-7 ]
Reference: [1] Patent: WO2011/120604, 2011, A1,
[2] Patent: EP2377850, 2011, A1,
  • 46
  • [ 623-03-0 ]
  • [ 142994-09-0 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
  • 47
  • [ 623-03-0 ]
  • [ 942199-56-6 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 27, p. 23038 - 23047
  • 48
  • [ 623-03-0 ]
  • [ 948549-53-9 ]
YieldReaction ConditionsOperation in experiment
70% at 20℃; for 7 h; Add 4-chlorobenzonitrile 5g (3.63mmol) into 100mL 70percent sulfuric acid, stirring, slowly add potassium bromate 6.5g (5.98mmol), after 3 hours adding, the reaction at room temperature again 4 hours stirred, filtering, drying to obtain white solid 5.5g, GC tested content 98percent, yield 70percent.
Reference: [1] Patent: CN103524456, 2016, B, . Location in patent: Paragraph 0053; 0055; 0057-0059
  • 49
  • [ 623-03-0 ]
  • [ 948549-53-9 ]
  • [ 57381-49-4 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 7, p. 741 - 744
  • 50
  • [ 623-03-0 ]
  • [ 1373156-28-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2843 - 2849
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