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CAS No. : | 123-39-7 | MDL No. : | MFCD00003280 |
Formula : | C2H5NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ATHHXGZTWNVVOU-UHFFFAOYSA-N |
M.W : | 59.07 | Pubchem ID : | 31254 |
Synonyms : |
|
Num. heavy atoms : | 4 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 15.12 |
TPSA : | 29.1 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.35 cm/s |
Log Po/w (iLOGP) : | 0.82 |
Log Po/w (XLOGP3) : | -0.97 |
Log Po/w (WLOGP) : | -0.64 |
Log Po/w (MLOGP) : | -0.49 |
Log Po/w (SILICOS-IT) : | -0.5 |
Consensus Log Po/w : | -0.36 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.47 |
Solubility : | 175.0 mg/ml ; 2.96 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.84 |
Solubility : | 413.0 mg/ml ; 6.99 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.09 |
Solubility : | 48.0 mg/ml ; 0.813 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: With tetrabutyl ammonium fluoride In acetonitrile at 20℃; for 3 h; Inert atmosphere Stage #2: at 20℃; |
General procedure: To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate 1 (53 μL, 0.20 mmol) and 1-formylpiperidine 4, N,N-dibenzylformamide 6, or N-methylformamide 8 (2.0 mmol) in CH3CN (1.4 mL) was added TBAF (1.0 M solution in CH3CN, 0.60 mL, 0.60 mmol) under argon atmosphere at room temperature. After being stirred at the same temperature for 3 h, H2O (0.1 mL) was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt/hexane=1/20 to 1/8 with 2percent CH2Cl2) afforded the products 2, 5, 7, and 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tert.-butylhydroperoxide; 1,10-Phenanthroline; copper diacetate In decane at 20℃; for 2 h; Molecular sieve; Inert atmosphere | General procedure: In a reaction vessel Cu(OAc)2 (20 molpercent), 1,10-phenanthroline (20 molpercent) was dissolved with 2 mL of formamide source. The reaction mixture stirred for 5 minutes and added the phenol (1) substrates. To the above reaction mixture, TBHP (5-6 M in decane solution) was added dropwise, with stirring over a period of 5 min. Then the reaction temperature was increased to 80 °C and stirred for eight hours. After cooling to room temperature, the reaction mixture was directly subjected to purification with column chromatography on silica gel using 5-10percent ethyl acetate and hexane mixture to afford the required product (3). Care should be taken while doing the product separation by column chromatography. We have observed that in some cases both the starting materials and products are very close, in which TLC’s have to be monitored by both UV and iodine. A slightly modified procedure was adopted for N-methylformamide reactions, in which the reactions were performed at room temperature for two hours. The crude products were directly subjected to column chromatography on silica gel to afford the required product (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.34% | at 95 - 180℃; | The reaction bottle adding 2, 4 - dimethyl aniline (121 g, 1 µM), N - methyl formamide (214 g, 1.45 µM), the original carboxylic acid triethyl ester (44.2 g, 0 . 75 µM), zinc chloride catalyst (1.36 g, 0.1 µM), 2, 4 - dimethyl aniline hydrochloride salt catalyst (3.1 g, 0.2 µM), temperature reaction, when the mixture temperature reaches 95 - 96 °C when, begin to boil off ethanol (due to the reaction of the materials change, boil off ethanol initial temperature rise about 18 °C), when the 135 °C begins to boil off ethyl formate and alcohol mixture, has been slowly rising temperature to 180 °C, temperature control reaction 3 - 7 the H, then -0.07 mpa pressure reducing reaction 2 h, HPLC monitoring the reaction to the completion of the reaction, cooling to room temperature, adding isopropyl alcohol 200 ml stirring 1 h, filtration, solid 40 °C decompression drying 5 - 8 hours to obtain bis-amidine 128 g, yield 87.34percent, purity 99.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 150℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hydroxide | |
89% | Stage #1: 2-bromo-pyridine; N-Methylformamide With tripotassium phosphate tribasic; copper (I) iodide; 1,10-phenanthroline monohydrate In toluene for 12h; Reflux; Stage #2: With potassium carbonate In methanol for 4h; Reflux; | 3.3.5. N-Methylpyridin-2-amine (3a) Scale: 0.1 mol. To a 500 mL, one-necked, round-bottomed flask equipped with a refluxcondenser and a magnetic stirring bar, were added 1,10-phenanthroline monohydrate(396 mg, 2.0 mmol), copper iodide (381 mg, 2 mmol), potassium phosphate (42.5 g, 0.2 mol),N-methylformamide (6.5 g, 0.11 mol), 2-bromopyridine (15.8 g, 0.1 mol), and toluene(125 mL). The mixture was stirred vigorously while the flask was flushed with nitrogen for15 min. The mixture was then heated at reflux with stirring for 12 h. After cooling to rt, thetoluene was removed on a rotary evaporator. Potassium carbonate (1 equiv., 13.8 g) andmethanol (125 mL) were added; then, the mixture was heated at reflux with stirring for 4 h.The methanol was removed on a rotary evaporator. Ethyl acetate (75 mL), 15% ammoniumhydroxide (75 mL), and water (75 mL) were added to the flask. The mixture was vigorouslystirred at rt for 20 min and then transferred to a 500 mL separatory funnel. The aqueouslayer was extracted with ethyl acetate (3 25 mL). The combined organic extracts werewashed with 25 mL portions of 15% Na2CO3, 50% brine, and brine, and then dried overK2CO3. Filtration through Celite and solvent removal in vacuo provided the crude productas a yellow oil (10.6 g), which was purified by vacuum distillation to give 9.4 g (89%) of 3aas a clear oil, bp 93-96 C (28 mmHg), lit. bp 100-102 C (18 mmHg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium chloride for 24h; Heating; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetraphosphorus decasulfide In diethyl ether at 0 - 20℃; for 3h; | General procedure for the thionations with P4S10 (Method A). General procedure: To a cooled (0-5 C) solution of appropriate amide (1.0 mmol) in diethyl ether (3.0 mL) was added tetraphosporus decasulfide (0.25 mmol) in small portions. The reaction mixture was allowed warm to ambient temperature and stirred. After the completion, the reaction mixture was filtered and concentrated under vacuum. To the resulting mixture was added silica gel, concentrated in vacuum and purified by silica gel column chromatography using hexane/ethyl acetate as eluent to give compounds 2a-e. |
61% | With diphosphorus pentasulfide In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 100% 2: 21.5% 3: 23.6% 4: 44.5% | With trimethylsilyl formate at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 80.2% 2: 13.1% 3: 41.5% 4: 45.2% | With N-Methylformamide; triethyl(methylamino)silane at 20℃; for 0.0333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; | |
98% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(I) thiophene-2-carboxylate; caesium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 12h; | |
75% | With caesium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 15h; | |
95% | With potassium phosphate; copper(l) iodide; dimethylaminoacetic acid In N,N-dimethyl-formamide at 110℃; for 24h; Schlenk technique; Inert atmosphere; | 3.3. General Procedure for the Coupling of Aryl Bromides with Amides Using Copper/N,N-DimethylglycineCatalytic System General procedure: A Schlenk tube was charged with amide (1.2 mmol), aryl halide (1 mmol), CuI (0.05 or 0.1 mmol), N,N-dimethylglycine (0.1 or 0.2 mmol), and potassium carbonate (2 mmol). The tube was evacuated and backfilled with argon at room temperature. DMF (0.5 mL) was added under argon via syringe. The Schlenk tube was immersed in a preheated oil bath and the reaction mixture was stirred for the specified time at the indicated temperature. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 to 1:2 ethyl acetate/petroleum ether) to give the the desired N-aryl amides. |
90% | With potassium phosphate; copper(l) iodide; rac-diaminocyclohexane In 1,4-dioxane Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 23h; | |
95% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 23h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 23h; | |
99% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane; dodecane at 110℃; for 23h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 23h; | |
98% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane; dodecane at 110℃; for 23h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With palladium diacetate; XPhos; phenylboronic acid In <i>tert</i>-butyl alcohol at 110℃; for 20h; | |
76 mg (93%) | In hexane | N-(3,5-dimethylphenyl)-N-methylformamide N-(3,5-dimethylphenyl)-N-methylformamide Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with N-methylformamide (45 mg, 0.75 mmol) with the reaction time of 20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 76 mg (93%) of the title compound as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 180℃; for 4h; | Method 16-Hvdroxy-3-methylquinazolin-4(3H)-one; 2-Amino-5-hydroxybenzoic acid (2.00 g, 0.0131 mol) was reacted with N- methylformamide (5 ml) at 180 C for 4 hours. The reaction was quenched with H2O and the resulting precipitate was collected by vacuum filtration to give 1.84 g (80%) of a brown solid; m/z 177. |
74% | With pyrrolidine; In acetonitrile; at 160℃; for 10h; | <strong>[394-31-0]2-amino-5-hydroxybenzoic acid</strong> (0.1 mol) and N-methylformamide were reacted at 160C for 10 hours. After thereaction was completed, ice water was used to terminate the reaction. Extraction with ethyl acetate was conducted.The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation underreduced pressure. The residue was applied to column chromatography (eluent: petroleum ether : ethyl acetate =1:1)to give 13g of brown solid. Yield: 74%.MS (ESI) m/z 176.1([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3% | Stage #1: 4-Chloropyridine; N-Methylformamide With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 20 - 60℃; for 21h; light protection; Stage #2: With sodium hydroxide In water | A.20.1 Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO4.7H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1 h then was heated slowly over 4 h at 45° C. When bubbling subsided, the reaction was heated at 60° C. for 16 h. The opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3*500 ml) and the organic layers were washed separately with a saturated NaCl solution (3*150 mL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluding with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): δ 8.44 (d, 1H, J=5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J=2.4, 5.4 Hz, ClCHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
5.3% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 20 - 60℃; for 21h; | A.A2.1a Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O, 17 mL) followed by FeSO4.7H2O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; 1H NMR (CDCl3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1H); CI-MS m/z 171 ((M+H)+). |
5.3% | With sulfuric acid; dihydrogen peroxide at 20 - 60℃; for 21h; | A.A20.1 A. General Methods for Synthesis of Substituted Anilines. A20. Formation of 2-(N-methylcarbamoyl)pyridines via the Menisci reaction Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO47H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1h then was heated slowly over 4 h at 45 °C. When bubbling subsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was diluted with H2O (700 mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCl solution (3 x 150 mlL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc /20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): d 8.44 (d, 1 H, J = 5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J = 2.4, 5.4 Hz, ClCHCN), 3.04 (d, 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
5.3% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 20 - 60℃; for 21h; | B.B10.1 B10. Formation of 2-(N-methylcarbamoyl)pyridines Via the Menisci Reaction; Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine; (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO4.7H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1 h then was heated slowly over 4 h at 45° C. When bubbling subsided, the reaction was heated at 60° C. for 16 h. The opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3×500 mL) and the organic layers were washed separately with a saturated NaCl solution (3×150 mL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): δ 8.44 (d, 1H, J=5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J=2.4, 5.4 Hz, ClCHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
5.3% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 20 - 60℃; for 21h; | A.A.10 Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO4.7H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1 h then was heated slowly over 4 h at 45° C. When bubbling subsided, the reaction was heated at 60° C. for 16 h. The opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3*500 mL) and the organic layers were washed separately with a saturated NaCl solution (3*150 mL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluding with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc./50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): δd 8.44 (d, 1H, J=5.1 Hz, CHN), 8.21 (s, 1H, CHC CO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J=2.4, 5.4 Hz, ClCHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
5.3% | With ferrous(II) sulfate heptahydrate; sulfuric acid; dihydrogen peroxide In water at 20 - 45℃; Inert atmosphere; Darkness; | B10.1 Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO4.7H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1 h then was heated slowly over 4 h at 45° C. When bubbling subsided, the reaction was heated at 60° C. for 16 h. The opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3*500 mL) and the organic layers were washed separately with a saturated NaCl solution (3*150 mlL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): d 8.44 (d, 1H, J=5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J=2.4, 5.4 Hz, ClCHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
5.3% | With sulfuric acid; dihydrogen peroxide In water at 20 - 60℃; for 16.75h; | B.B10.1 (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H2SO4 (3.55 mL) (exotherm). To this was added H2O2 (17 mL, 30% wt in H2O) followed by FeSO4·7H2O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for 1h then was heated slowly over 4 h at 45 °C. When bubbling subsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCl solution (3 x 150 mlL. The combined organics were dried (MgSO4) and filtered through a pad of silica gel eluding with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS; 1H NMR (CDCl3): d 8.44 (d, 1 H, J = 5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd. 1H, J = 2.4, 5.4 Hz. ClCHCN), 3.04 (d. 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With sulfuric acid; dihydrogen peroxide In water at 6 - 22℃; for 0.5h; | H.1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6°C with an ice bath. Iron (II) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (II) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22°C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (1L, 2 x 500 mL). The combined organic extracts were washed with water (2 x 500 mL), 5% aqueous sodium bicarbonate (3 x 100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, 1H), 8.3 (m, 1H), 8.0 (dd, 1H), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
79.2% | Stage #1: N-Methylformamide; isonicotinic acid ethylester With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 6 - 22℃; for 0.5h; Stage #2: With sodium citrate In water | H.1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6°C with an ice bath. Iron (IT) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (H) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22°C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (IL, 2 x 500 mL). The combined organic extracts were washed with water (2 x 500 mL), 5% aqueous sodium bicarbonate (3 x 100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, IH), 8.3 (m, IH), 8.0 (dd, IH), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
79.2% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 6 - 22℃; for 0.5h; | H.1 Step 1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6° C. with an ice bath. Iron (II) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (II) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22° C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (1L, 2×500 mL). The combined organic extracts were washed with water (2×500 mL), 5% aqueous sodium bicarbonate (3×100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, 1H), 8.3 (m, 1H), 8.0 (dd, 1H), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
58.64% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate at 5 - 15℃; | The commercially available ethyl isonicotinate 1 (5.00g, 33.08mmol) was dissolved in N-methylformamide (20mL), and cold 98% H2SO4 (3.24g, 33.08mmol) was added drop wise and the temperature was kept below 5°C. After the addition of H2SO4, 30% H2O2 and a saturated solution of FeSO4 were added to the reaction mixture at 10-15°C [9] until compound 1 disappeared. After extraction, washing, recrystallization, the pure compound 2 (4.04g, 19.40mmol, 58.64%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: N-Methylformamide; 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate In 1,4-dioxane at 110℃; for 14h; Stage #2: With lithium hydroxide In tetrahydrofuran; 1,4-dioxane; water at 45℃; for 3h; | 102 3- [5- (4-Acetylamino-phenyl)-1-p-tolyl-1 H-pyrazol-3-yl]-2-m-tolyl-propionic acid. To a solution [OF 3- [5- (4-BROMO-PHENYL)-1-P-TOLYL-1H-PYRAZOL-3-YL]-2-M-TOLYL-] propionic acid ethyl ester (Example 77, Step C; 100 mg, 0.2 [MMOL)] in dioxane (0.6 mL) was added Cul (3 mg, 0.02 mmol, 10 [MOL%), (1R, 2R)-N,-DIMETHYL-] cyclohexane-1, 2-diamine (0.003 mL, 0.02 mmol, 10 [MOL%),] [K2CO3] (55 mg, 0.40 mmol, 2.0 equiv) and N-methylformamide (15 mg, 0.26 mmol, 1.3 equiv). The mixture was stirred at 110 [°C] for 14 h, and then cooled to [45 °C] prior to the addition of a solution of [LIOH] (28 mg, 1.2 mmol, 3 equiv) in 2: 1 [THF/H20] (1 mL). After 3 h at 45 [°C,] the reaction mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (50 mg, 50 %). HPLC: Rt= 3.62 (Method A). MS [(ESI)] : mass calculated for [C28H27N303,] 453.21 ; [M/ZFOUND,] 454.3 [M+H] +.'H NMR (500 MHz, [CDCIS)] : 7.43-7. 39 [{M,] 3H), 7.25-7. 17 (m, 3H), 7.10-7. 06 (m, 6H), 6.24 (s, [1H),] 4.09 (dd, J= 10.0, 5.2 Hz, [1H),] 3.53 (dd, J = 15. 0,10. 0 Hz, 1H), 3.13-3. 09 (dd, J= 15.0, 5.2 Hz, 1H), 2.34 (s, 6H), 2.16 (S, 3H). |
50% | Stage #1: N-Methylformamide; 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate In 1,4-dioxane at 110℃; for 14h; Stage #2: With lithium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 45℃; for 3h; | 102 To a solution of 3-i'5-(4-bromo-phenyl)-1 -p-tolyl-1 H-pyrazol-3-yl]-2-/n-tolyl-propionic acid ethyl ester (Example 77, Step C; 100 mg, 0.2 mmol) in dioxane(0.6 ml) was added Cu. (3 mg, 0.02 mmol, 10 mol%), (1R,2R)-NtN- dimethyl-cyclohexane-1,2-diamine (0.003 ml, 0.02 mmol, 10 mol%), K2CO3 (55 mg,0.40 mmol, 2.0 equiv) and A/-methylformamide (15 mg, 0.26 mmol, 1.3 equiv).10 The mixture was stirred at 110 °C for 14 h, and then cooled to 45 °C prior tothe addition of a solution of LiOH (28 mg, 1.2 mmol, 3 equiv) in 2:1 THF/H2O (1ml). After 3 h at 45 °C, the reaction mixture was purified by preparativereversed-phase HPLC (acetonitrile/water) to afford the title compound (50 mg,50%). HPLC: Rt= 3.62 (Method A). MS (ESI): mass calculated for15 C28H27N3O3, 453.21; m/z found, 454.3 [M+Hf. 1H NMR (500 MHz, CDCI3):7.43-7.39 (m, 3H), 7.25-7.17 (m, 3H), 7.10-7.06 (m, 6H), 6.24 (s, 1H), 4.09 (dd, J= 10.0, 5.2 Hz, 1H), 3.53 (dd, J= 15.0, 10.0 Hz, 1H), 3.13-3.09 (dd, J= 15.0, 5.2 Hz, 1H), 2.34 (s, 6H), 2.16 (S, 3H). ; |
50% | Stage #1: N-Methylformamide; 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester With potassium carbonate In 1,4-dioxane at 110℃; for 14h; Stage #2: With lithium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 45℃; for 3h; | 102 3-[5-(4-Acetylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid 3-[5-(4-Acetylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid To a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 77, Step C; 100 mg, 0.2 mmol) in dioxane (0.6 mL) was added CuI (3 mg, 0.02 mmol, 10 mol %), (1R,2R)-N,N'-dimethyl-cyclohexane-1,2-diamine (0.003 mL, 0.02 mmol, 10 mol %), K2CO3 (55 mg, 0.40 mmol, 2.0 equiv) and N-methylformamide (15 mg, 0.26 mmol, 1.3 equiv). The mixture was stirred at 110° C. for 14 h, and then cooled to 45° C. prior to the addition of a solution of LiOH (28 mg, 1.2 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the reaction mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (50 mg, 50%). HPLC: Rt=3.62 (Method A). MS (ESI): mass calculated for C28H27N3O3, 453.21; m/z found, 454.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.43-7.39 (m, 3H), 7.25-7.17 (m, 3H), 7.10-7.06 (m, 6H), 6.24 (s, 1H), 4.09 (dd, J=10.0, 5.2 Hz, 1H), 3.53 (dd, J=15.0, 10.0 Hz, 1H), 3.13-3.09 (dd, J=15.0, 5.2 Hz, 1H), 2.34 (s, 6H), 2.16 (S, 3H). The compounds of Examples 103 and 104 were made according to the synthetic methods outlined in Example 102 and Scheme L. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium methylate In N,N-dimethyl-formamide at 120℃; for 4h; | 91 Example 91; 1-(3"Methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methylamide:; A solution of 1-(3-methanesulfonyIamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazo.in-6-yI)-1H-imidazole-4-carboxylic acid methyl ester (800 mg, 1.79 mmol) and N-methylformamide (0.357 ml, 6 mmol) in 5 ml of dimethylformamide is heated to 120°C and sodium methylate (100 mg, 1.79 mmol) is added under stirring. After two hours at 120 °C another 100 mg of sodium methylate is added and stirring at 120°C continued for additional two hours. After cooling to room temperature the solution is evaporated in vacuo and the residue chromatographed to give 560 mg (1.25 mmol, 70%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methylamide, m.p. 292 - 295 °C, ES-MS: m/z447 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: N-Methylformamide; 5-Bromo-2-aminobenzoic acid at 180℃; for 12h; Stage #2: With water | 104 2-Amino-5-bromobenzoic acid (5.00 g, 0.023 mol) was reacted with iV- methylformamide (40 ml) at 180 0C for 12 h. The reaction was quenched with H2O and the resulting precipitate was collected by vacuum filtration to give 5.26 g (95%) of a yellow- white solid; m/z 240. |
95% | In N,N-dimethyl-formamide at 180℃; for 12h; | 1 Method 1 6-Bromo-3-methylquinazolin-4(3H)-one 2-Amino-5-bromobenzoic acid (5.00 g, 0.023 mol) was reacted with N-methylformamide (40 ml) at 180° C. for 12 h. The reaction was quenched with H2O and the resulting precipitate was collected by vacuum filtration to give 5.26 g (95%) of a yellow-white solid; m/z 240. |
95% | at 180℃; for 12h; | 3 Method 3; 6-Bromo-3-methylquinazorm-4(3H)-one; 2-Amino-5-bromobenzoic acid (5.00 g, 0.023 mol) was reacted with N- methylformamide (40 ml) at 180 0C for 12 h. The reaction was quenched with H2O and the 5 resulting precipitate was collected by vacuum filtration to give 5.26 g (95%) of a yellow- white solid; m/z 240. |
63% | for 6.5h; Sealed tube; Reflux; | 12.1 Preparation 12: 3-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinazolin- 4(3H)-one; Step 1 : 6-bromo-3-methylαuinazolin-4(3H)-one; A mixture of 2-amino-5-bromobenzoic acid (250 g, 1.25 mol) and N-methylformamide (1.3 L) was refluxed in a steel bomb reactor for 6.5 h and cooled to room temperature. The mixture was poured over crushed ice, stirred for 2 h and filtered to give 6-bromo-3- methylquinazolin-4(3H)-one (180 g, 63%) as a brown solid. 1 H NMR (500 MHz, METHANOL-O4) δ ppm 3.36 (1 H, m), 3.58 (3 H, s), 7.58 (1 H, d, J=8.5 Hz), 7.90 (1 H, dd, J=8.7, 2.3 Hz), 8.30 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 150℃; for 20h; | |
45% | Stage #1: N-Methylformamide; 4-aminoisophthalic acid at 180℃; for 4h; Stage #2: With hydrogenchloride In water | 6 4-Aminoisophthalic acid (1.00 g, 5.52 mmol) was reacted with N-methylformamide (15 ml) at 180 °C for 4 hours. The reaction was quenched with H2O and extracted with EtOAc. The aqueous layer was acidified with 10% HC1 and the resulting precipitate was collected by vacuum filtration to give 504 mg (45%) of a yellow-white solid; m/z 205. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium phosphate In <i>tert</i>-butyl alcohol at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; at 100℃; for 22h; | a) N- (3-Fluoro-5 [(trimethylsilvOethvnyliphenvU -N-methylformamide l,3-Dibromo-5-fluorobenzene (1.0 g, 3.9 mmol), N-methylformamide (286 mg, 4.3 mmol), CuI (37 mg, 0.2 mmol), N, N' -dimethyl ethylenediamine (0.042 mL, 0.39 mmol) andK2CO3 (1.08 g, 7.8 mmol) in toluene (10 mL) were heated in a sealed tube at +100 0C for 22 h. The slurry was filtered through a silica plug that was washed with EtOAc, the solvents were removed by evaporation and the residual material was purified by flash chromatography on 70 g of silica gel using a gradient of 0% EtOAc to 40% EtO Ac/heptane. (3-Bromo-5-fluorophenyl)methylformamide was obtained as a colourless oil that slowly crystallised (260 mg, 28%).GC-MS m/z: 231/233 1:1 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | for 4h; Reflux; neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trichlorophosphate; at 50 - 60℃;Inert atmosphere; Microwave irradiation; | General procedure: The reliable procedure involved the treatment of N-1-phenyl-5-aminopyrazoles (1a-e, 1.0 equiv) with catalytic amount of POCl3 (?3 equiv) with N-methylformamide (2 mL) at 50-60 C with 100 W of microwave energy within 20-30 min. When the reaction was completed, the reaction mixture was concentrated, added to saturate sodium bicarbonate (15 mL), and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding N-(1H-pyrazol-5-yl)formamidines 3a-e in 76-97% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: N-Methylformamide; trityl chloride With zinc(II) chloride In acetonitrile at 20℃; for 0.0833333h; Stage #2: With triethylamine In acetonitrile at 20℃; for 0.0833333h; | Method A. General procedure of ZnCl2 assisted tritylations General procedure: The substrate (1.0 mmol) was introduced into a solution of TrCl (1.0 mmol) and ZnCl2 (1.0 mmol) in acetonitrile (6.0 mL) and the mixture was kept under magnetic stirring at room temperature for 5 minutes. Then, a solution of TEA (1.0 mmol) in the same solvent (2.0 mL) was added during 5 minutes. After quenching with aqueous 5% citric acid buffer at pH = 5-6 (10.0 mL) and stirring for other 5 minutes, the organic solvent was evaporated under reduced pressure and the resulting suspension extracted with diethyl ether or dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trichlorophosphate for 2h; Inert atmosphere; | |
94% | Stage #1: N-Methylformamide; edaravone With trichlorophosphate at 50 - 60℃; Inert atmosphere; Stage #2: With water; sodium hydrogencarbonate | Standard Procedure for the preparation of 4-formylpyrazolone products (2a-2g), amination products (3a, 4a-4g and 5a-5g) and dipyrazolylmethane products (6a-6f) General procedure: The reliable procedure involved the treatment of pyrazolones (1a-1g, 1.0 equivalent) with catalytic amount of POCl3 (~3 equivalent) with various of amide (2 mL) including formamide, N-methylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), piperidine-1-carbaldehyde, and pyrrolidine-1-carbaldehyde in CH2Cl2 solution (2 mL) at 50-60 °C within 0.5-1 h. When the reaction was completed, the reaction mixture was concentrated, added to saturate sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding 4-formylpyrazolone products 2a-2g, amination products 3a, 4a-4g and 5a-5g, dipyrazolylmethane products 6a-6f were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: N-Methylformamide; 1,3-diphenyl-5-oxo-4,5-dihydro-1H-pyrazole With trichlorophosphate at 50 - 60℃; Inert atmosphere; Stage #2: With water; sodium hydrogencarbonate | Standard Procedure for the preparation of 4-formylpyrazolone products (2a-2g), amination products (3a, 4a-4g and 5a-5g) and dipyrazolylmethane products (6a-6f) General procedure: The reliable procedure involved the treatment of pyrazolones (1a-1g, 1.0 equivalent) with catalytic amount of POCl3 (~3 equivalent) with various of amide (2 mL) including formamide, N-methylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), piperidine-1-carbaldehyde, and pyrrolidine-1-carbaldehyde in CH2Cl2 solution (2 mL) at 50-60 °C within 0.5-1 h. When the reaction was completed, the reaction mixture was concentrated, added to saturate sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding 4-formylpyrazolone products 2a-2g, amination products 3a, 4a-4g and 5a-5g, dipyrazolylmethane products 6a-6f were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In water at 0 - 130℃; for 36h; Autoclave; | |
With Ru/ceria catalyst In methanol at 150℃; for 24h; | ||
With sodium methylate In methanol at 60℃; for 5.5h; Autoclave; | 5-8; 2 This embodiment is a method for synthesizing N-methylformamide, and the synthesis method comprises the following steps: (a) Putting methylamine and a 25% by weight sodium methoxide-methanol solution into the autoclave, turning on the stirrer, stirring at 200 PRM, heating to 60 ° C, then introducing carbon monoxide to a pressure of 3 MPa, and controlling The temperature is kept at 60 ° C for 5.5 h, and after the reaction is completed, the reaction liquid is subjected to atmospheric distillation and vacuum distillation to obtain N-monosubstituted alkylformamide;Wherein, in the vacuum distillation process, the temperature of the column is 105-115 ° C, the temperature at the top of the column is 63-70 ° C, the pressure is -0.087 MPa, and the controlled reflux ratio is 1:1;Atmospheric distillation temperature is 178-185 ° C;The molar ratio of methylamine to sodium methoxide in sodium methoxide-methanol solution was 10.65:0.063. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,10-Phenanthroline; copper(I) thiophene-2-carboxylate; caesium carbonate In 2,4-dichlorophenoxyacetic acid dimethylamine at 45℃; for 18h; Inert atmosphere; | 4.2.12. N-((1E,4R,5S,7E,9S,10S,11S,12S,13S)-12-((tert-Butyldimethylsilyl)oxy)-6-hydroxy-4,10-dimethoxy-5,9,11,13-tetramethylpentadeca-1,7,14-trien-1-yl)-N-methylformamide (19) N-Methyl formamide (0.2 mL), Cs2CO3 (49 mg, 0.15 mmol), CuTC (19 mg, 0.1 mmol), 1,10-phenanthroline (36 mg, 0.2 mmol) were placed in a flame-dried 10 mL Schlenk tube with a stir bar. A solution of vinyl iodide 17 (58 mg, 0.098 mmol) in 1 mL of anhydrous DMA was added and the system was degassed under vacuum until gas evolution ceased. The mixture was heated to 45 °C for 18 h. The reaction was then diluted with Et2O and pH 7 buffer. The organic layer was separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Purification of the crude product by column chromatography (1:4 hexanes/EtOAc) provided the product 19 (37 mg, 72%) as a colorless oil. This compound contains two isomers (alcohol epimers, deriving from 17) and there are two rotamers for each isomer. The product was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.33-8.01 (1H), 7.21-6.45 (1H), 5.90-5.59 (2H), 5.50-5.32 (1H), 5.19-4.91 (3H), 4.29 (s, 1H), 3.86 (1H), 3.49-3.44 (3H), 3.41-3.37 (3H), 3.31-3.22 (1H), 3.07-3.00 (3H), 3.00-2.81 (2H), 2.55-2.39 (2H), 2.33-2.17 (2H), 1.88-1.78 (1H), 1.73-1.65 (1H), 1.12 (3H), 1.02-0.95 (3H), 0.93-0.88 (9H), 0.88-0.81 (3H), 0.80-0.74 (3H), 0.10-0.04 (6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With trichlorophosphate at 50 - 60℃; Inert atmosphere; Microwave irradiation; | 1 Standard procedure for the preparation of N-(1H-pyrazol-5-yl)formamidines 3a-e General procedure: The reliable procedure involved the treatment of N-1-phenyl-5-aminopyrazoles (1a-e, 1.0 equiv) with catalytic amount of POCl3 (∼3 equiv) with N-methylformamide (2 mL) at 50-60 °C with 100 W of microwave energy within 20-30 min. When the reaction was completed, the reaction mixture was concentrated, added to saturate sodium bicarbonate (15 mL), and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding N-(1H-pyrazol-5-yl)formamidines 3a-e in 76-97% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: N-Methylformamide; 2-Fluoroaniline With p-toluenesulfonyl chloride at 20℃; for 3h; Stage #2: With sodium hydroxide In water at 10℃; | 1 Example 1: Synthesis of /V'-(2-fluorophenyl)-λ/-methylformamidine (1) To λ/-methyl formamide solvent (11 ml), 2-fluoroaniline (1.11 g, 10mmol) was add ed and p-toluene sulfonylchloride (2.38g, 12.5mmol) was slowly added thereto at room t emperature followed by stirring for three hours. After confirming the completion of the reaction by TLC, the reaction mixture was poured over ice water and pH of the aqueous solution was adjusted to a basic value by adding an aqueous solution of 1ON sodium h ydroxide while maintaining the temperature of the mixture at 10°C or less. The resultin g reaction solution was extracted three times with ethyl acetate. Thus-obtained organi c layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. Further, the mixture that had been obtained by distillation of the filtrate under r educed pressure was purified by a column chromatography (development solvent: n-he xane/ethyl acetate = 1/1), yielding the yellow-colored liquid compound 1 (1.06g, 70.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With formaldehyd In ethanol at 80℃; | |
50% | With formaldehyd In ethanol at 65℃; Microwave irradiation; | 4.e N- methyl formamideUsing a double loop microwave nitrification When using a N- methyl formamide with an amine source, deep microwave quality - was created substituted amines in good yield. As it can be seen in scheme e, and p- tolyl propynyl phenylpropionyl olsan olsan made the pajil amine 4a and 4b in the deep by 50% and 46% yield. Switching from the two methylene paraformaldehyde was identified using the D2CO experiment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium iodide In dimethyl sulfoxide at 20℃; Electrochemical reaction; | Typical procedure for the transformation of ketones with formamides to amides General procedure: In a typical experiment, DMSO (8 mL), ketones (1 mmol), formamides (5 mmol) and NaI (4 mmol)were added to the undivided cell. The electrosynthesis was carried out in the undivided cell fitted with a Ni sheet cathode (2 cm × 2.5 cm× 0.02 cm) and a graphite rod anode at a constant current (50 mA) at room temperature under magnetic stirring. The electrolysis was ended when ketone had been completely consumed(monitored by GC-MS). After the electrolysis, the electrolyte solution was decolorized with Na2S2O3, and then washed with distilled water (50 mL) and extracted with ethyl acetate (10 mL × 3). The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel using petroleum ether-ethyl acetate(5:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride In water at 130℃; for 2h; Sealed tube; Green chemistry; | Experimental procedure (EP-1) for N-formylation of amines General procedure: To a mixture of aromatic or hetero aromatic amine 1 (1.0 eq) and amide 2 (4.0 eq), HCl (2.0 Vol) and water (5.0 Vol) was added. The mixture was stirred in 20.0-ml sealed vial under atmospheric air at 130 °C for 2.0 hrs. After bringing the mixture to room temperature, 10mL water was added and the mixture was extracted with ethyl acetate (3_20 mL). The combined organic layers were dried with anhydrous Na2SO4. Under vacuum, the solvent was evaporated, and the crude product was purified using column chromatography (silica gel, EtOAc/Hexane) in order to obtain a pure product. |
80% | With 1-(3-sulfopropyl)pyridinium phosphotungstate In neat (no solvent) at 120℃; for 1.33333h; Microwave irradiation; | |
54% | at 150℃; for 24h; Sealed tube; Green chemistry; |
50% | With 1,2,3-Benzotriazole In neat (no solvent) at 150℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | for 0.5h; | General procedure: A mixture of equal molar 1,2-H2BDC-Cl4 (91.2 mg, 0.3 mmol), Mn(OAc)24H2O (73.5 mg, 0.3 mmol) was dissolved in the MF/H2O mixed solvents (v/v, 1:1, 12 mL) with stirring for ca. 30 min. The resulting solution was filtered and left to stand at room temperature. Colorless block crystals of 1 suitable for X-ray single-crystal diffraction were obtained by slow evaporation of the solvents after three weeks in about 70% yield based on 1,2-H2BDC-Cl4. Anal. Calc. for C12H14Cl4MnN2O8 (1): C, 28.21; H, 2.76 ;N, 5.48. Found: C, 28.37; H, 2.79; N, 5.36%. IR (cm1): 3266 br, 3091 m, 2946 m, 2926 m, 1656 s, 1602 vs 1529 s, 1426 s, 1396 s, 1372 s, 1342 s, 1269 m, 1205 m, 1156 w, 1128 w, 932 w, 913 m,831 w, 780 m, 655 s, 616 m, 572 m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tert.-butylhydroperoxide; 1,10-Phenanthroline; copper diacetate; In decane; at 20℃; for 2h;Molecular sieve; Inert atmosphere; | General procedure: In a reaction vessel Cu(OAc)2 (20 mol%), 1,10-phenanthroline (20 mol%) was dissolved with 2 mL of formamide source. The reaction mixture stirred for 5 minutes and added the phenol (1) substrates. To the above reaction mixture, TBHP (5-6 M in decane solution) was added dropwise, with stirring over a period of 5 min. Then the reaction temperature was increased to 80 C and stirred for eight hours. After cooling to room temperature, the reaction mixture was directly subjected to purification with column chromatography on silica gel using 5-10% ethyl acetate and hexane mixture to afford the required product (3). Care should be taken while doing the product separation by column chromatography. We have observed that in some cases both the starting materials and products are very close, in which TLC?s have to be monitored by both UV and iodine. A slightly modified procedure was adopted for N-methylformamide reactions, in which the reactions were performed at room temperature for two hours. The crude products were directly subjected to column chromatography on silica gel to afford the required product (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tert.-butylhydroperoxide; 1,10-Phenanthroline; copper diacetate In decane at 20℃; for 2h; Molecular sieve; Inert atmosphere; | General Procedure for the Synthesis of Phenyl Carbamates General procedure: In a reaction vessel Cu(OAc)2 (20 mol%), 1,10-phenanthroline (20 mol%) was dissolved with 2 mL of formamide source. The reaction mixture stirred for 5 minutes and added the phenol (1) substrates. To the above reaction mixture, TBHP (5-6 M in decane solution) was added dropwise, with stirring over a period of 5 min. Then the reaction temperature was increased to 80 °C and stirred for eight hours. After cooling to room temperature, the reaction mixture was directly subjected to purification with column chromatography on silica gel using 5-10% ethyl acetate and hexane mixture to afford the required product (3). Care should be taken while doing the product separation by column chromatography. We have observed that in some cases both the starting materials and products are very close, in which TLC’s have to be monitored by both UV and iodine. A slightly modified procedure was adopted for N-methylformamide reactions, in which the reactions were performed at room temperature for two hours. The crude products were directly subjected to column chromatography on silica gel to afford the required product (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tert.-butylhydroperoxide; 1,10-Phenanthroline; copper diacetate; In decane; at 20.0℃; for 2.0h;Molecular sieve; Inert atmosphere; | General procedure: In a reaction vessel Cu(OAc)2 (20 mol%), 1,10-phenanthroline (20 mol%) was dissolved with 2 mL of formamide source. The reaction mixture stirred for 5 minutes and added the phenol (1) substrates. To the above reaction mixture, TBHP (5-6 M in decane solution) was added dropwise, with stirring over a period of 5 min. Then the reaction temperature was increased to 80 C and stirred for eight hours. After cooling to room temperature, the reaction mixture was directly subjected to purification with column chromatography on silica gel using 5-10% ethyl acetate and hexane mixture to afford the required product (3). Care should be taken while doing the product separation by column chromatography. We have observed that in some cases both the starting materials and products are very close, in which TLC?s have to be monitored by both UV and iodine. A slightly modified procedure was adopted for N-methylformamide reactions, in which the reactions were performed at room temperature for two hours. The crude products were directly subjected to column chromatography on silica gel to afford the required product (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tert.-butylhydroperoxide; 4,7-dimethoxy-1,10-phenanthroline; iron(II) bromide In decane at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis General procedure: In a reaction vessel, 2ml of formamide was added to the phenol substrate and the solutionwas stirring over a period of 1 minute. On stirred add 5 mmol% of Iron (II)Bromide, and 5 mmol% 4,7-Dimethoxy- 1,10 phenanthroline to the above reaction mixture,then slowly add 3 mmol of TBHP (Oxidant) at room temperature. Then, raise thetemperature up to 60 C and allow the stirring for 4 hours under an inert atmosphere inpresence of molecular sieves. After completion of reaction time, the solvent wasremoved under reduced pressure or directly proceeded for the conventional work upwith ethyl acetate, water mixture. The organic layer was separated and dried overanhydrous Na2SO4. Removal of the solvent under reduced pressure afforded the crudeproduct, which was purified by column chromatography on silica gel using hexane andethyl acetate (8:2) mixture to afford the required product (3). TLC’s have to be monitoredby both UV and iodine |
20% | With tert.-butylhydroperoxide; 1,10-Phenanthroline; copper diacetate In decane at 20℃; for 2h; | General Procedure for the Synthesis of Phenyl Carbamates General procedure: In a reaction vessel Cu(OAc)2 (20 mol%), 1,10-phenanthroline (20 mol%) was dissolved with 2 mL of formamide source. The reaction mixture stirred for 5 minutes and added the phenol (1) substrates. To the above reaction mixture, TBHP (5-6 M in decane solution) was added dropwise, with stirring over a period of 5 min. Then the reaction temperature was increased to 80 °C and stirred for eight hours. After cooling to room temperature, the reaction mixture was directly subjected to purification with column chromatography on silica gel using 5-10% ethyl acetate and hexane mixture to afford the required product (3). Care should be taken while doing the product separation by column chromatography. We have observed that in some cases both the starting materials and products are very close, in which TLC’s have to be monitored by both UV and iodine. A slightly modified procedure was adopted for N-methylformamide reactions, in which the reactions were performed at room temperature for two hours. The crude products were directly subjected to column chromatography on silica gel to afford the required product (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 70% | In water; for 0.5h; | General procedure: A mixture of equal molar 1,2-H2BDC-Cl4 (91.2 mg, 0.3 mmol), Mn(OAc)24H2O (73.5 mg, 0.3 mmol) was dissolved in the MF/H2O mixed solvents (v/v, 1:1, 12 mL) with stirring for ca. 30 min. The resulting solution was filtered and left to stand at room temperature. Colorless block crystals of 1 suitable for X-ray single-crystal diffraction were obtained by slow evaporation of the solvents after three weeks in about 70% yield based on 1,2-H2BDC-Cl4. Anal. Calc. for C12H14Cl4MnN2O8 (1): C, 28.21; H, 2.76;N, 5.48. Found: C, 28.37; H, 2.79; N, 5.36%. IR (cm1): 3266 br,3091 m, 2946 m, 2926 m, 1656 s, 1602 vs 1529 s, 1426 s, 1396 s,1372 s, 1342 s, 1269 m, 1205 m, 1156 w, 1128 w, 932 w, 913 m,831 w, 780 m, 655 s, 616 m, 572 m. |
70% | In water; for 0.5h; | A mixture of equal molar 1,2-H2BDC-Cl4 (91.2 mg, 0.3 mmol),Mn(OAc)24H2O (73.5 mg, 0.3 mmol) was dissolved in the MF/H2O mixed solvents (v/v, 1:1, 12 mL) with stirring for ca. 30 min.The resulting solution was filtered and left to stand at roomtemperature. Colorless block crystals of 1 suitable for X-ray single-crystal diffraction were obtained by slow evaporation of thesolvents after three weeks in about 70% yield based on 1,2-H2BDC-Cl4. Anal. Calc. for C12H14Cl4MnN2O8 (1): C, 28.21; H, 2.76;N, 5.48. Found: C, 28.37; H, 2.79; N, 5.36%. IR (cm1): 3266 br,3091 m, 2946 m, 2926 m, 1656 s, 1602 vs 1529 s, 1426 s, 1396 s,1372 s, 1342 s, 1269 m, 1205 m, 1156 w, 1128 w, 932 w, 913 m,831 w, 780 m, 655 s, 616 m, 572 m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With [2,2]bipyridinyl; boron trifluoride diethyl etherate; oxygen; palladium diacetate; Trimethylacetic acid In toluene at 120℃; for 24h; | General procedure for the synthesis of product 3 General procedure: Under molecular oxygen atmosphere, to a mixture of Pd(OAc)2 (1.3 mg, 0.006 mmol) and bpy (0.9 mg, 0.006 mmol), toluene (2.0 mL) was added. Then aniline (0.2 mmol), amide (2.0 mmol), PivOH (40.9 mg, 0.4 mmol), and BF3Et2O (42.6 mg, 0.3 mmol) were added to the mixture. The mixture was heated to 120 C and it stirred at 120 C for 24 h. After completion, the mixture was cooled to room temperature and diluted with ethyl acetate. Washed withaq NaHCO3, water, and aq NaCl. Dried over MgSO4 and filtered. Aftere vaporation of the solvent, the residue was purified by preparative thin-layer chromatography on silica gel with PE/EtOAc (1/1) as aneluent to give the product 3. |
78% | With 1-(3-sulfopropyl)pyridinium phosphotungstate In neat (no solvent) at 120℃; for 1.33333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | at 90℃; for 48h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 24h; Inert atmosphere; | O,O,O,O-Tetra(trimethylsilyl)dimethylaminomethylenediphosphonate(Vc). General procedure: Trimethylsilyl triflate(3 mL) was added upon stirring to a solution of 15 g oftris(trimethylsilyl)phosphite and 1.5 g of DMF in 8 mL of methylene chloride. The mixture was incubated at 20° during 24 h, and then the solvent was evaporated.3 mL of hexane was added to the residue. After cooling to 5°, the solvent was decanted. White crystals were kept in vacuum at 0.5 mmHg. Yield 8.8 g(87%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(l) iodide; dimethylaminoacetic acid; potassium carbonate In N,N-dimethyl-formamide at 110℃; for 24h; Schlenk technique; Inert atmosphere; | 3.3. General Procedure for the Coupling of Aryl Bromides with Amides Using Copper/N,N-DimethylglycineCatalytic System General procedure: A Schlenk tube was charged with amide (1.2 mmol), aryl halide (1 mmol), CuI (0.05 or 0.1 mmol), N,N-dimethylglycine (0.1 or 0.2 mmol), and potassium carbonate (2 mmol). The tube was evacuated and backfilled with argon at room temperature. DMF (0.5 mL) was added under argon via syringe. The Schlenk tube was immersed in a preheated oil bath and the reaction mixture was stirred for the specified time at the indicated temperature. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 to 1:2 ethyl acetate/petroleum ether) to give the the desired N-aryl amides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In N,N-dimethyl-formamide at 90℃; for 72h; High pressure; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In toluene; at 110℃; for 24h;Inert atmosphere; Sealed tube; | General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane In toluene at 110℃; for 24h; Inert atmosphere; Sealed tube; | General procedure for indole synthesis by Cu-catalyzed amidation reaction. General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 °C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In toluene; at 110℃; for 24.0h;Inert atmosphere; Sealed tube; | General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane In toluene at 110℃; for 24h; Inert atmosphere; Sealed tube; | General procedure for indole synthesis by Cu-catalyzed amidation reaction. General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 °C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane In toluene at 110℃; for 24h; Inert atmosphere; Sealed tube; | General procedure for indole synthesis by Cu-catalyzed amidation reaction. General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 °C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dipotassium peroxodisulfate; oxygen; sodium formate; silver nitrate In water at 80℃; for 5h; Schlenk technique; regioselective reaction; | general procedure for Ag-catalyzed carbamoylation General procedure: A 25 mL Schlenk flask was charged with AgNO3 (17.2 mg, 20 mol% Ag), K2S2O8(408 mg, 1.5 mmol), and HCOONa (129 mg, 1.0 mmol) before standard cycles of evacuation and back-filling with dry and pure oxygen (three times). Corresponding pyridine 1 (0.5 mmol), formamide 2 (2 mL), and H2O (0.4 mL) were added successively. The mixture was stirred at 80 °C for the indicated time (monitored byTLC). At the end of the reaction, the reaction mixture was cooled to room temperature, poured into a saturated aqueous NaCl solution (15 mL), and extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, and the volatile components were evaporated in a rotary evaporator. The residue was purified by flash column chromatography on silica gel to afford the corresponding product 3 |
75% | With dipotassium peroxodisulfate at 70℃; for 12h; regioselective reaction; | General experimental procedure for the synthesis Secondary carboxamides: General procedure: In an oven dried glass tube containing a mixture of pyridine 1a (100 mg, 1.26 mmol), and potassium persulphate (683 mg, 2.53 mmol), N-methylformamide 2b (2 mL) was added and the reaction mixture was heated at 70 °C. Upon the completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution (5 mL) was added and the crude product was extracted in ethyl acetate (3 X 5 mL). The crude product was purified by column chromatography to furnish compound 3ab as yellow oil (129 mg, 75% yield). N-methylpicolinamide (3ab): IR (neat) cm-1: 3402, 3149, 1645, 1389, 1H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J = 4.6 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 8.03 (s, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H), 7.38 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 3.00 (d, J = 5.2 Hz, 3H). 13C NMR (100 MHz, , CDCl 3 ) δ 165.1, 150.0, 148.1, 137.4, 126.1, 122.2, 26.2. HRMS (ESI TOF) m/z calcd for C 7 H 8 N 2 O [M + H]+ , 137.0715 found 137.0721. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With 1,4-diaza-bicyclo[2.2.2]octane; bis(n-butylcyclopentadienyl)zirconium dichloride; 5,10,15,20-tetraphenyl-21H,23H-porphine; copper trifluoromethanesulfonate In 1,4-dioxane at 70℃; for 10h; | 1 Example 1 At room temperature,To the appropriate amount of organic solvent (for the volume ratio of 1: 2 1,4-dioxane and polyethylene glycol 200 (PEG-200)Of the mixture)100 mmol of the compound of the above formula (I)120 mmol of the compound of the above formula (II)8 mmol of catalyst bis (n-butylCyclopentadienyl) zirconium dichloride,10 mmol of 1,4- diazabicyclo [2.2.2] octane (DABCO) and 15 mmol of an auxiliaries (for3.75 mmol of a mixture of tetraphenylporphyrin and 11.25 mmol of copper trifluoromethanesulfonate (Cu (OTf) 2)),The temperature was then raised to 70 ° C with stirring,And the reaction was stirred at that temperature for 10 hours;After completion of the reaction,The reaction solution was filtered while hot,Adjust the pH of the filtrate to neutral,And then fully shaken with deionized water,Then add petroleum ether extraction 2-3 times,The organic phases were combined,Concentrated under reduced pressure,The resulting residue was subjected to silica gel flash column chromatography,To bodyThe ratio of 1: 3 mixture of acetone and chloroform for washing,To give the compound of the above formula (III) in a yield of 97.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | With 1,4-diaza-bicyclo[2.2.2]octane; bis(n-butylcyclopentadienyl)zirconium dichloride; 5,10,15,20-tetraphenyl-21H,23H-porphine; copper trifluoromethanesulfonate In 1,4-dioxane at 90℃; for 7h; | 2 Example 2 To a suitable amount of organic solvent (1: 2 by volume of 1,4-dioxane and polyethylene glycol 200 (PEG-200) at room temperature,), 100 mmol of the compound of the above formula (I), 180 mmol of the compound of the formula (II), 4 mmol of the catalyst bis (n-butylZirconium dichloride, 20 mmol of 1,4- diazabicyclo [2.2.2] octane (DABCO) and 8 mmol of1.6 mmol of tetraphenylporphyrin and 6.4 mmol of copper trifluoromethanesulfonate (Cu (OTf) 2)) was added, and then the temperature was raised to 90 ° C with stirringC, and the reaction was stirred at this temperature for 7 hours;After completion of the reaction, the reaction solution was filtered while hot, the pH of the filtrate was adjusted to neutral, and the solution was sufficiently shaken with deionized water, Then add petroleum ether extract 2-3 times, combine the organic phase, vacuum concentration, the resulting residue over silica gel flash column chromatography, the body1: 3 ratio of acetone to chloroform to give the compound of the above formula (III) in a yield of 97.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | With 1,4-diaza-bicyclo[2.2.2]octane; bis(n-butylcyclopentadienyl)zirconium dichloride; 5,10,15,20-tetraphenyl-21H,23H-porphine; copper trifluoromethanesulfonate In 1,4-dioxane at 80℃; for 9h; | 3 Example 3 To a suitable amount of organic solvent (1: 2 by volume of 1,4-dioxane and polyethylene glycol 200 (PEG-200) at room temperature,), 100 mmol of the compound of the above formula (I), 150 mmol of the compound of the formula (II), 6 mmol of the catalyst bis (n-butylZirconium dichloride, 15 mmol of 1,4- diazabicyclo [2.2.2] octane (DABCO) and 12 mmol of2.7 mmol of tetraphenylporphyrin and 9.3 mmol of copper trifluoromethanesulfonate (Cu (OTf) 2)) was added and the mixture was heated to 80Deg.] C, and the reaction was stirred at this temperature for 9 hours;After completion of the reaction, the reaction solution was filtered while hot, the pH of the filtrate was adjusted to neutral, and the solution was sufficiently shaken with deionized water, Then add petroleum ether extract 2-3 times, combine the organic phase, vacuum concentration, the resulting residue over silica gel flash column chromatography, the body1: 3 ratio of acetone to chloroform to give the compound of the above formula (III) in a yield of 97.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dipotassium peroxodisulfate at 70℃; for 12h; | General experimental procedure for the synthesis Secondary carboxamides: General procedure: In an oven dried glass tube containing a mixture of pyridine 1a (100 mg, 1.26 mmol), and potassium persulphate (683 mg, 2.53 mmol), N-methylformamide 2b (2 mL) was added and the reaction mixture was heated at 70 °C. Upon the completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution (5 mL) was added and the crude product was extracted in ethyl acetate (3 X 5 mL). The crude product was purified by column chromatography to furnish compound 3ab as yellow oil (129 mg, 75% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrafluoroboric acid In water for 72h; Autoclave; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With cobalt(II) acetate at 150℃; for 3h; Inert atmosphere; | Control trial groups 1 to 25 Tetrahydroisoquinoline (0.2 mmol), a catalyst, and an acylation reagent (1.0 mL) were added to a 10 mL reaction vessel, protected by argon gas, and the reaction was heated. The product wasquantitatively analyzedby1H NMR; each control group was specifically The reaction conditions are shown in Table 1 |
95% | With cobalt(II) diacetate tetrahydrate at 150℃; for 3h; Sealed tube; Inert atmosphere; | |
93% | With manganese(II) chloride tetrahydrate at 150℃; for 10h; Sealed tube; Microwave irradiation; Inert atmosphere; | N-Substituted Formamides 2; General Procedure General procedure: A solution of amine (0.2 mmol) and MnCl2·4H2O (5.9 mg, 15 mol%) in DMF (1.0 mL) was stirred in a sealed microwave reaction tube under an atmosphere of argon at 150 °C for 10 h. The mixture was cooled to r.t., and water (10 mL) was added; the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (anhyd Na2SO4), the solvent was evaporated under vacuum, and the crude product was purified by preparative TLC (silica gel, petroleum ether/EtOAc) to obtain the pure product. |
89% | With graphene oxide at 150℃; for 18h; Sealed tube; | 15 Tetrahydroisoquinoline (0.2 mmol), a catalyst, and an acylation reagent (1.0 mL) were added to a 10 mL reaction vessel, protected by argon gas, and the reaction was heated. The product was quantitatively analyzed by 1H NMR; the specific reaction of each control group was performed. The conditions are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulphur; tripotassium phosphate tribasic at 115℃; for 20h; Sealed tube; | |
72% | With sulphur; lithium carbonate In neat (no solvent) at 120℃; for 20h; Inert atmosphere; | 3.3. General procedure for synthesis aryl thioamides General procedure: A mixture of alkynes 1a-c (1 mmol), sulfur 2 (9.6 mmol), amides 3a-e (1.5 mL) and Li 2 CO 3 (0.37 mmol, 0.028 g) in the pres- ence of Fe 3-x Ti x O 4 -SiO 2 TrpBu 3 + I --Co(II) (0.1 g) was magnetically stirred at 120 °C under air for the desired reaction time monitored by TLC (n-hexane/EtOAC eluent, 5:1). After completion of the reac- tion, the catalyst separated by an external magnet. Purification of the product was accomplished by washing with methanol to give the products 4a-c . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With manganese(II) chloride tetrahydrate; at 150℃; for 10h;Inert atmosphere; Sealed tube; | General procedure: Phenethylamine (0.2 mmol),catalyst,Carboxamides (1.0 mL) were addedIn a 10 mL reaction vessel,Argon protection,Heating reaction,The product was quantitatively analyzed by 1H NMR;The specific reaction conditions for each control group are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | With sodium hydride In N,N-dimethyl-formamide at 100℃; for 3h; | 1.3; 2.3; 3.3; 4.3 (3) Preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine Add 125 g of DMF to a 1 L four-necked flask, lower the temperature to 10 ° C, add 5.1 g (0.21 mol) of sodium hydride, stir to dissolve,Add 12.4 g (0.21 mol) of N-methylformamide and 50.2 g (0.2 mol) of 2,5-dibromo-3-methylpyridine, raise the temperature to 100 ° C, and hold the reaction for 3 hours.Reduce the temperature to 20-40 , add 250g of water, adjust the pH to 1,130g with 30% hydrochloric acid to extract impurities, separate the lower aqueous layer, and adjust the pH of the aqueous layer to 9.5-10.5 with 30% liquid alkali.Extract with 200 g of isopropyl acetate, wash the upper organic layer with 0.5% dilute hydrochloric acid to pH 7-8, remove the lower aqueous layer, and distill the isopropyl acetate to dryness under reduced pressure.Distill isopropyl acetate under reduced pressure at a temperature of 45-50 ° C and a degree of vacuum of -0.1 to -0.09 MPa; add 120 g of n-hexane to reduce the temperature to 0-10 ° C and crystallize to obtain flaky crystals.After drying at 80 ° C, 33.8 g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine was obtained with a yield of 84.2% and an HPLC content of 99.7%.The benzoic acid content was not detected, and the N- (3-bromo-5-methylpyridin-2yl) -N-methylbenzamide was 0.05%, and the remaining single impurities were less than 0.2%. |
70.4% | Stage #1: N-Methylformamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20 - 80℃; for 1.5h; Stage #2: 2,5-dibromo-3-methylpyridine In N,N-dimethyl-formamide for 2h; | 1.1 step one:At room temperature,Potassium tert-butoxide (80.5 g, 0.66 mol) and N-methylformamide (42.4 g, 0.72 mol) were sequentially added to 300 ml of N,N-dimethylformamide, and the mixture was heated to 80 ° C for 1.5 h.2,6-Dibromo-3-methylpyridine (100 g, 0.40 mol) was added and the reaction was continued for 2 h.The system was cooled to room temperature, then poured into 1.5 L of ice water, adjusted to pH = 2 with concentrated hydrochloric acid, and extracted three times with ethyl acetate (250 ml × 3), the aqueous phase was separated, and the aqueous solution was adjusted to pH 10-11.The organic phase was extracted three times with ethyl acetate (3 ml) (3 ml).The crystal was allowed to stand still, and after filtration and drying, 56.3 g of needle crystals were obtained, yield: 70.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tert.-butylhydroperoxide In ethyl acetate at 110℃; for 12h; Schlenk technique; | 25 Example 25 Reaction with N-methylformamide To a Schlenk bottle were added a 1,6-enyne compound (39.8 mg, 0.2 mmol) represented by Formula 1a, N-methylformamide (0.5 mL) represented by Formula 2m, and tert-butanol peroxide (TBHP, 108.0). mg, 1.2 mmol), and then the reaction was stirred in an air atmosphere at 110 ° C. The reaction progress was monitored by TLC until the raw materials disappeared (reaction time was 12 hours). After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain the target product I-13 (68% yield); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sulphur; lithium carbonate In neat (no solvent) at 120℃; for 17h; Inert atmosphere; | 3.3. General procedure for synthesis aryl thioamides General procedure: A mixture of alkynes 1a-c (1 mmol), sulfur 2 (9.6 mmol), amides 3a-e (1.5 mL) and Li 2 CO 3 (0.37 mmol, 0.028 g) in the pres- ence of Fe 3-x Ti x O 4 -SiO 2 TrpBu 3 + I --Co(II) (0.1 g) was magnetically stirred at 120 °C under air for the desired reaction time monitored by TLC (n-hexane/EtOAC eluent, 5:1). After completion of the reac- tion, the catalyst separated by an external magnet. Purification of the product was accomplished by washing with methanol to give the products 4a-c . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper (I) iodide; 1,10-phenanthroline monohydrate; potassium carbonate In tert-Amyl alcohol; toluene for 8h; Reflux; | 3.2.3. N-Methyl-N-(pyridin-2-yl)formamide (1) Scale: 0.1 mol. To a 500 mL, one-necked, round-bottomed flask equipped with areflux condenser and a magnetic stirring bar, 1,10-phenanthroline monohydrate (396 mg,2.0 mmol), copper iodide (381 mg, 2.0 mmol), potassium carbonate (27.6 g, 0.2 mol), potassiumphosphate (2.12 g, 10 mmol), N-methylformamide (5.84 mL, 0.1 mol), 2-bromopyridine(9.54 mL, 0.1 mol), and toluene (125 mL) were added. The mixture was stirred vigorouslywhile the flask was flushed with nitrogen for 15 min. The mixture was then heated atreux with stirring for 12 h. After cooling to rt, 100 mL of ethyl acetate was added, and themixture was stirred at rt for 15 min. The mixture was vacuum-filtered through Celite withan ethyl acetate wash (2 75 mL). The filtrate was concentrated on a rotary evaporatorto provide the crude compound as a yellow oil (13.5 g), which was purified by vacuumdistillation to give 11.5 g (85%) of 1 as a clear oil, bp 95-100 C (1.0 mmHg), lit. bp 71-72 C(0.005 torr) |
Tags: 123-39-7 synthesis path| 123-39-7 SDS| 123-39-7 COA| 123-39-7 purity| 123-39-7 application| 123-39-7 NMR| 123-39-7 COA| 123-39-7 structure
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