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[ CAS No. 619-72-7 ] {[proInfo.proName]}

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Product Citations

Product Citations

Jang, Mingyeong ; Lim, Taeho ; Park, Byoung Yong , et al. DOI: PubMed ID:

Abstract: In this study, we developed a metal-free and highly chemoselective method for the reduction of aromatic nitro compounds. This reduction was performed using tetrahydroxydiboron [B2(OH)4] as the reductant and 4,4'-bipyridine as the organocatalyst and could be completed within 5 min at room temperature. Under optimal conditions, nitroarenes with sensitive functional groups, such as vinyl, ethynyl, carbonyl, and halogen, were converted into the corresponding anilines with excellent selectivity while avoiding the undesirable reduction of the sensitive functional groups.

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Product Details of [ 619-72-7 ]

CAS No. :619-72-7 MDL No. :MFCD00007279
Formula : C7H4N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :NKJIFDNZPGLLSH-UHFFFAOYSA-N
M.W : 148.12 Pubchem ID :12090
Synonyms :

Calculated chemistry of [ 619-72-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 39.98
TPSA : 69.61 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) : -6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.14
Log Po/w (XLOGP3) : 1.19
Log Po/w (WLOGP) : 1.47
Log Po/w (MLOGP) : 0.26
Log Po/w (SILICOS-IT) : -0.36
Consensus Log Po/w : 0.74

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.85
Solubility : 2.11 mg/ml ; 0.0143 mol/l
Class : Very soluble
Log S (Ali) : -2.25
Solubility : 0.837 mg/ml ; 0.00565 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.84
Solubility : 2.12 mg/ml ; 0.0143 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.74

Safety of [ 619-72-7 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P264-P270-P271-P273-P280-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405-P501 UN#:3439
Hazard Statements:H300-H311+H331-H402 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 619-72-7 ]

* 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 [ 619-72-7 ]
  • Downstream synthetic route of [ 619-72-7 ]

[ 619-72-7 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 619-72-7 ]
  • [ 46047-18-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7392 - 7416
[2] Patent: WO2012/135641, 2012, A2,
  • 2
  • [ 619-72-7 ]
  • [ 3704-41-4 ]
Reference: [1] Chemistry - An Asian Journal, 2013, vol. 8, # 7, p. 1408 - 1411
  • 3
  • [ 619-72-7 ]
  • [ 16687-60-8 ]
YieldReaction ConditionsOperation in experiment
100% 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.
99% 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
98% at 120℃; for 24 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.
96% 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.
96% With sodium azide; silver(I) triflimide In toluene at 85℃; for 2.5 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.
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%
Stage #1: With sodium azide; tris(pentafluorophenyl)borate In N,N-dimethyl-formamide at 120℃; for 6 h;
Stage #2: With hydrogenchloride In water; ethyl acetate; N,N-dimethyl-formamide for 0.25 h;
General procedure: B(C6F5)3 (67.3 mg, 0.13 mmol, 5 mol percent) was added to a stirred solution of 3,4-dichlorobenzaldehyde (172 mg, 1 mmol) and NaN3 (97.5 mg, 1.5 mmol) in DMF (5 mL) and was heated at 120 °C. After completion of reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and was added 5 mL of cold water followed by 10 mL of 2 N HCl and 10 mL of ethyl acetate. The resulting mixture was stirred vigorously for 15 min. The organic layer was separated and aqueous layer was again extracted with ethyl acetate (3 × 15 mL). The combined organic layer was washed with water and dried over anhydrous sodium sulfate and was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, EtOAc/hexane 9:1) to obtain pure 5-(3,4-dichlorophenyl)-1H-tetrazole. The known compounds were characterized and confirmed by comparison of their spectral data and physical properties with reported literature.
95% 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.
95% With bismuth(III) chloride; sodium azide In water; isopropyl alcohol at 160℃; for 1 h; Microwave irradiation General procedure: 2-Furonitrile 1m (186 mg, 2 mmol), NaN3 (260 mg, 4 mmol), BiCl3 (126 mg, 0.4 mmol), and 8 mL of a 3:1 isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel, which was then capped. The microwave vessel was then placed in a Milestone Start Synth microwave reactor. The reaction was magnetically stirred and heated for 1 h at 150°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 was hed with ethyl acetate (2×15 mL). The aqueous sodium bicarbonate layer was cooled with ice and acidified to a pH of 2 or less with concentrated hydrochloric acid, which was added dropwise. The precipitate formed was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried with anhydrous sodium sulfate and decanted into a tared round-bottom flask. The organic layer was concentrated under reduced pressure by rotary evaporation at 40°C and then under high vacuum. The tetrazole product was recrystallized from ethyl acetate and hexane.
95% With sodium azide; aminosulfonic acid In N,N-dimethyl-formamide at 120℃; for 5 h; 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. Recrystallization from aqueous ethanol gave the pure product as a white powder, mp. 215-218°C, lit.43 219-220°C. IR (KBr): 3421, 3023, 2978, 2779, 2439, 1644, 1520, 1340,854 cm1. 1H NMR (90 MHz, DMSO-d6): d 13.47 (bs, 1H), 8.07–7.07 (m, 4H). Anal.Calcd. for C7H5N5O2: C, 43.98, H, 2.62, N, 36.64. Found: C, 44.16, H, 2.91, N, 37.02
95% With sodium azide; acetic acid; urea In water; N,N-dimethyl-formamide at 60 - 110℃; for 9 h; General procedure: The procedure for the synthesis of the tetrazole 2a is representative. A mixture of sodium azide (0.39 g 0.0060 mol), urea (0.36 g, 0.0060 mol) and water (2.5 mL) was taken in a round–bottom flask and stirred at 60 °C for 1 h. Charged benzonitrile 1a (0.5 g 0.0048 mol), acetic acid(0.5 mL) and DMF (2.5mL) at 60 °C and heat to 110°C stirred for 8 h. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to room temperature and diluted the reaction mass with water (2.5 mL)and ethyl acetate (5.0 mL) at 25-35 °C. Add 5N aqueous hydrochloric acid (2.5 mL) at 25-35 °C. Stirred for 20- 30 min, the resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (2.5 mL). The combined organic layer was washed with 40 percent aq.NaCl solution (2.5 mL) and dried over anhydrous Na2SO4 and concentrated to give a crude product, which was isolated using chilled water after 3-4 h maintenance, and eventually filtered off to give 0.67 g (95percent) of an off-white solid.
94% With lithium tetraazidoborate; ammonium acetate In methanol; N,N-dimethyl-formamide at 80℃; for 6 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.
94% at 120℃; for 1 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.
93%
Stage #1: With sodium azide; zinc dibromide In 1-methyl-pyrrolidin-2-one; water at 190℃; for 0.333333 h; Stainless steel syringe
Stage #2: With hydrogenchloride In 1-methyl-pyrrolidin-2-one; water
In order to expand the scope of this flow method, a variety of nitriles were subjected to the optimized conditions in the entry 6 (Table 1), and the results are summarized in Tables 3 and 4 {Method A). For substrates 2 and 3, where no electron- donating or electron- withdrawing group was present on the aromatic ring, or substrate 4 where the nitrile was rendered electron poor by the presence of electron- withdrawing group at the para position, the reactions proceeded to 100percent conversions without the formation of any side product. Similarly, meta tolunitrile (5) and the hetero aromatic substrates (6-8) also showed excellent conversions. Electron rich nitriles 10 and 10 reacted to give moderate but clean conversions to the corresponding tetrazoles. The biphenyl nitriles 9, 13 and 14 also proved to be good substrates for this reaction regardless of position of the phenolic hydroxy group on the second aromatic ring.Notably, chiral nitrile 15 provided 15a, a derivative of which (no CBZ group) has found utility as an organocatalyst, in > 99percent ee and 92percent yield based on conversion. To test if an increase in the 3/4 can drive the reaction of moderately yielding substrates to completion, the model substrate 1 was reacted at a 3/4 of 30 min (Table 4). There was no significant change in the conversion observed; instead a small amount of hydrolysis product la was formed. However, significant improvement in the reaction rate was observed by doubling the concentration of the reaction (0.4 M). For nitrile 1, the conversion increased from 65percent to 81percent (3/4 = 30 min), while similar improvement in conversions were observed for substrates 11 and 13-15 when the reaction concentration was doubled.As this continuous flow method has the advantage of using high temperatures in a safe manner, it was determined that the presence of a catalyst (e.g., ZnBr2) was not essential for all reactions carried out at these temperatures. To test this, the flow process was repeated with selected substrates without the use of ZnBr2 (Tables 3 and 4, Method B). The non- substituted benzo- and napthonitrile substrates (2 and 3), electron poor nitrile (4), and the heterocyclic substrates (6, 7 and 8), all showed excellent conversions to corresponding tetrazoles in the absence of ZnBr2. The conversions were found to decrease moderately in case of biphenyl substrates 9, 13 and 14 indicating decrease in the reaction rate of these substrates in the absence of ZnBr2. Similar decrease in conversion was observed for the electron rich substrates (1 and 12), but it was noted that there was no side product observed in the absence of ZnBr2 even at 30 min of residence time. This shows that ZnBr2 may be promoting the competing side reaction. Thus, the use of ZnBr2 may be useful for enhancing the conversion of the electron-rich nitriles, but can also lead to formation of side product. In many, if not all instances, reactions without ZnBr2 can give clean conversions. To demonstrate the scale-up capabilities of this, the synthesis of 3a was carried out using aUniqsis FlowSyn continuous flow reactor. FlowSyn is an integrated continuous flow reactor system that uses a pair of high pressure pumps to deliver reagent solutions through a 'T'-mixer into the electrically heated flow coil or column reactors. The homogenous solution of reagents ([3] = 1M; [NaN3] = 1.05 M) in NMP:H20 (7:3) was pumped using a single pump through a coiled PFA tubing reactor (volume of heated zone ~ 6.9 mL) with a flow rate of 0.35 mL/min (tr = 20 min) at 190 °C (see Example 2). The flow process was run continuously for 2.5 h to obtain 9.7 g of 3a in 96 percent yield. This corresponds to a product output of 4.85 g/h or 116 g/day for the tetrazole 3a.Overall, the method performed is a safer alternative for currently used methods to synthesize 5-substituted tetrazoles as the hazards due to accumulation and condensation of HN3 are greatly minimized. Only uses a slight excess of NaN3 (1.05 equiv) was used, and hence the production of azide waste is minimal. The method is highly efficient and clean, and works for a wide range of substrates. In case of substrates where the reaction does not go to completion, the remaining NaN3 in the reaction can be quenched by introducing streams of sodium nitrite and sulfuric acid after the reaction is complete. The incorporation of this quenching procedure increases the overall safety of the process. Therefore, given the widespread applications of tetrazoles in chemical andpharmaceutical industry, this method can serve as a safe and highly efficient alternative for synthesis of tetrazoles.EXAMPLE 2This example provides additional experimental details and data in connection with Example 1.General protocol for continuous flow synthesis of tetrazoles (Method A):Sodium azide (68 mg, 1.05 mmol) was added to a solution of zinc bromide (111 mg, 0.5 mmol) in 0.5 mL water. To this solution was added the nitrile substrate (1 mmol) dissolved in 4.5 mL of N-methylpyrrolidone (NMP) and the resulting clear solution was filled in a 10 mL stainless steel syringe (Harvard Apparatus, High Pressure stainless steel syringe with 1/16 inch SWAGELOK.(R).), which was then charged to a syringe pump (Harvard PHD 2000) (see FIG. 3A and 3B). The syringe was connected to a 41 cm tubular coiled reactor (Upchurch Scientific PFA tubing; 1/16 x 0.03 in.) with the help of SWAGELOK.(R). fittings (stainless steel front ferrule, stainless steel back ferrule and 316 stainless steel nut for 1/16 in.). The tubular reactor was coiled in such a way that 26.4 cm (constituting an internal volume of 120 \\L) of the middle portion of the tubing was dipped in the oil bath (heating source). A 250 psi back pressure regulator (Upchurch Scientific) was installed at the distal end of this tubing followed by short outlet tubing. The reaction mixture was pumped through the tubular reactor at a rate of 6 μ/ιηη, and the temperature of the oil bath was set to 190 °C. This resulted in a 20 min residence time for reaction mixture in the part of tubing immersed in the oil bath. After the reactor reached equilibrium (flowing approximately 3 full-reactor volumes), 1 mL of output was collected and diluted with 10 mL of water. The solution was acidified to pH 1 using 3 N HC1 and stirred vigorously. Note: for the heterocyclic substrates 10, 11 and 12, the reaction was basified and stirred vigorously until a white precipitate (zinc hydroxide) was observed. The precipitate was filtered and the pH of the filtrate was adjusted to 6.5. The resulting precipitate was extracted with ethyl acetate, and the organic layer concentrated to yield the product. A white precipitate appeared which was extracted into non-aqueous layer using 10 mL of ethyl acetate. The organic layer was separated and concentrated to yield a crude product. This crude product was taken in 20 mL of 0.25 N sodium hydroxide solution and stirred vigorously until a white precipitate of zinc hydroxide was observed. The resulting precipitate was filtered and the filtrate was acidified to pH 1 using 3 N HC1. The tetrazole product precipitated upon stirring, which was then filtered, washed with 10 mL of 3 N HC1, and dried to obtain a pure product.The parts used to assemble the apparatus shown in FIG. 3B include at least the following: PHD 22/2000 Remote Syringe Pump from Harvard Apparatus (syringe rack high pressure); PFA tubing (1/16 x 0.03 inch) from Upchurch Scientific;SWAGELOK.(R). fitting from Upchurch.(R). Scientific (Stainless Steel Nut for 1/16 inch; Stainless Steel Front Ferrule; Stainless Steel Back Ferrule); 250 psi Back Pressure Regulator from Upchurch Scientific (or alternatively, a 100 psi PEEK.(TM). back pressure regulator); Flat Bottom Fitting from Upchurch Scientific; Nut (PEEK.(TM).); Flangeless Ferrule (TEFZEL.(R).); High Pressure 8 mL Stainless Steel Syringe with 1/16 inchSWAGELOK ; 5/16 Wrenches (2); Aluminium or any other flexible wire; Glass Vials; Oil Bath with High Temperature Oil and a Magnetic Stirrer -1
93% at 120℃; for 12 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.
93% 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.
92% With sodium azide; triethylamine hydrochloride In toluene at 100℃; 5-(4-Nitrophenyl)-l-tetrazole (10a, Fig. 8): A solution of 4-nitrobenzonitrile (1.100 g, 7.4 mmol), a 3 (1.32 g, 20 mmol) and triethylamine hydrochloride (2.73 g, 20 mmol) in toluene (20 ml) were heated at 100 C overnight, (formation of two phases was observed). Water (50 ml) was added and the phases were separated. The aqueous phase was acidified with concentrated HC1 (pH= 5-6) the solid that precipitated was filtered and washed with water. The product was dried under vacuum to give pure 10a (1.30 g, 92percent) as a yellow-white compound. XH NMR (400 MHz, DMSO-d6) δ 8.40 (d, J= 8.8 Hz, 2H), 8.26 (d, J= 8.8 Hz, 2H). LC-MS (ESI-) m/z 190.04 (M-H)"; HRMS (ESI-) m/z calculated for C7H5N5O2 (M-H)" 190.0371 , found 190.0367.
92% With sodium azide; ammonium acetate In N,N-dimethyl-formamide at 70℃; for 1 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.
92% 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
91% With sodium azide In N,N-dimethyl-formamide at 90℃; for 1.5 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.
90% at 105℃; for 20 h; Sealed tube; Green chemistry General procedure: A screw capped vial was charged with nitrile (2 mmol), NaN3(2.4 mmol, 1.2 equiv.) and tetrabutylammonium bromide (2.4 mmol,1.2 equiv.). The resulting mixture was stirred at 105 °C and monitoredby TLC. After completion of the reaction, the reaction mixture wascooled to room temperature and dissolved with water (5 mL). Then, theaqueous solution was acidified with 1M HCl to pH = 3. If a precipitatewas formed, the suspension was filtered and the filter cake was washedwith water to afford the pure product. Otherwise, the aqueous solutionwas extracted with EtOAc (3 × 4 mL). The organic phase was washedwith 1M HCl (3 × 4 mL), dried with anhydrous Na2SO4, filtered andevaporated under vacuum to afford the pure product.
90% With sodium azide; copper(l) chloride In N,N-dimethyl-formamide at 120℃; for 8 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; <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.
90% at 120℃; for 0.333333 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.
89% 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.
88% With sodium azide; activated Fuller’s earth In dimethyl sulfoxide at 120℃; for 3 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.
87% With sodium azide In methanol; N,N-dimethyl-formamide at 20 - 100℃; for 7 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]+.
87% 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.
86% 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.
84% 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).
84% With sodium azide In N,N-dimethyl-formamide at 90℃; for 12 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).
80% With sodium azide; zinc(II) chloride In propan-1-ol at 95℃; for 1 h; General procedure: NaN3 (11.6 mmol) and ZnCl2 (9.7 mmol) were added to a solution of the appropriate nitrile (9.7 mmol) in n-PrOH or n-BuOH (25mL). The temperatures, reaction times and solvents are listed in Table4. Vigorous stirring was essential.
80% With sodium azide In N,N-dimethyl-formamide at 120℃; for 0.5 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.
80% at 120℃; for 8.5 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.
77% With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In water at 85℃; for 10 h; Green chemistry General procedure: General Procedure for Preparation of Tetrazoles in Water(Method II). TBAHS (0.25 mmol) was added to a mixture of nitrile (1 mmol), sodium azide (1.5 mmol), and 2 mL H2O in around-bottomed flask. The reaction mixture was heated to 85 °C. After completion of the reaction (as monitored by TLC), the crude reaction mixture was transferred into a separatory funnel, to which was added 1 N HCl (15 mL) extracted by ethylacetate (EtOAc, 10 mL × 5). The combined organic layers were washed with H2O and dried over anhydrous sodium sulfate, and were evaporated under reduced pressure to give pure 5-substituted-1H-tetrazole.
77% 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.
56% With sodium azide; tributyltin chloride In toluene for 18 h; Reflux Part A:
Synthesis of 4-tetrazoyl nitrobenzene.
4-Nitrobenzonitrile (2g, 13.5 mmol), sodium azide (0.92 g, 14 mmol), and tributyltin chloride (3.8 mL, 14 mmol) were combined in toluene (30 mL) and heated to reflux 18h.
The reaction mixture was extracted with excess 1N NaOH.
The aqueous layer was cooled, acidified with con.
HCl, and the precipitated solid was filtered off and dried in vacuo.
The aqueous layer was extracted with ethyl acetate, combined with the solid and dried (MgS04) to afford 1.4 g (56percent). 1H-NMR(DMSO-d6)δ: 8.48 (d, j=8.79Hz, 2H), 8.34 (d, j=8.79Hz, 2H) ppm; MS (ES-) 190.0 (M-H).
53% With sodium azide; ammonium chloride In N,N-dimethyl-formamide for 20 h; Reflux A mixture of 4-nitrobenzonitrile (7.4 g, 0.05 mol) in DMF (120 mL), sodium azide (5.2 g, 0.08 mol) and NH4Cl (4.28 g, 0.08 mol) were refluxed for 20 h, yellow precipitate of ligand H(4-nptz) was then filtered off after cooling and dried under vacuum with a yield of 53percent. Anal. (wtpercent) Calc. for C7H5N5O2: C, 43.98; H, 2.64; N, 36.64. Found: C, 43.97; H, 2.64; N, 36.65percent. IR (KBr, cm-1): 3207 (m), 3102 (m), 1605 (m), 1552 (m), 1515 (s), 1339 (s), 1109 (w), 1065 (m), 998 (w), 861 (m), 774 (w), 729 (m), 498 (m).
32% With sodium azide; triethylamine hydrochloride In toluene at 110℃; General procedure: A mixture of the corresponding nitrile (50 mmol), NaN3 (65 mmol) and Et3N·HCl (150 mmol) in toluene (100 mL) was stirred at 110 °C for17–30 h (TLC monitoring). After cooling to r.t., the mixture was extracted with H2O (100 mL) and the aqueous phase was acidified with aq 36percent HCl. The solid formed was filtered, washed with H2O (3 × 10mL), and dried under reduced pressure to give the corresponding product 2a–e

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YieldReaction ConditionsOperation in experiment
90%
Stage #1: With C46H178O41Si42; titanium(IV)isopropoxide In toluene at 60℃; for 9 h; Inert atmosphere
Stage #2: With hydrogenchloride; water In toluene at 20℃; Inert atmosphere
General procedure: To a nitrogen purged screw-caped vial containing 1a (1.0 g, 5.1 mmol, 1.0 equiv) in 6.0 mL of toluene were added TMDS (900 μL, 5.1 mmol, 1.0 equiv) or PMHS (610 μL, 10.2 mmol, 2.0 equiv) and Ti(Oi-Pr)4 (1.5 mL, 5.1 mmol, 1.0 equiv) at rt. The mixture was then heated at 60 °C for 24 h (the colorless solution turned into black and the conversion of the substrate can be followed up by TLC and/or 1H NMR). After cooling to rt, the clear solution was acidified using aqueous 1 M HCl (7.7 mL, 1.5 equiv) and the crude mixture was concentrated under reduced pressure. The resulting solid was filtered, washed with pentane (3*50 mL), and dissolved in ethanol. The filtrate was finally concentrated under reduced pressure affording the amine 2a as a hydrochloride salt.
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