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CAS No. : | 1452-77-3 | MDL No. : | MFCD00023483 |
Formula : | C6H6N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IBBMAWULFFBRKK-UHFFFAOYSA-N |
M.W : | 122.12 | Pubchem ID : | 15070 |
Synonyms : |
2-Picolinamide;2-Pyridinecarboxamide;2-Carbamoylpyridine;Picolinoylamide
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.33 |
TPSA : | 55.98 Ų |
GI absorption : | High |
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) : | -6.94 cm/s |
Log Po/w (iLOGP) : | 1.14 |
Log Po/w (XLOGP3) : | 0.15 |
Log Po/w (WLOGP) : | 0.18 |
Log Po/w (MLOGP) : | -0.43 |
Log Po/w (SILICOS-IT) : | 0.52 |
Consensus Log Po/w : | 0.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.12 |
Solubility : | 9.29 mg/ml ; 0.076 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.88 |
Solubility : | 16.0 mg/ml ; 0.131 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.57 |
Solubility : | 3.3 mg/ml ; 0.027 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
81% | With MCM-41 mesoporous silica In ethanol; water at 80 - 90℃; for 9 h; Green chemistry | General procedure: In a typical reaction a solution of amide (1 mmol), rhodanine (1.2 mmol) and Morpholine (1.2 mmol) in EtOH/water (2 + 2 ml) were refluxed at 80-90 °C till completion using 40 mg of MCM-41 catalyst. The completion of the reaction was indicated by the disappearance of the starting material in thin layer chromatography. After completion of the reaction the solvent was evaporated in a rotary evaporator and the crude product was taken in dichloromethane and filtered to separate the products as filtrate from the catalyst (residue). Then the crude product was purified by silica gel column chromatography where the compound (5) came out from the column with 25percentEtOAc/75percent petroleum ether, but thioamide (4) came out with 65percentEtOAc/35percent petroleum ether making their separation easy. The thioamides (4) were characterized by IR, 1H NMR, 13C NMR, CHN and X-ray single crystal analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In ethanol; water at 60℃; for 8h; Inert atmosphere; | |
63% | With potassium carbonate In water at 20 - 40℃; for 16h; | |
With potassium carbonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With titanium silicate; dihydrogen peroxide In methanol at 60℃; for 24h; | |
84% | With oxygen; isobutyraldehyde In 1,2-dichloro-ethane at 30℃; for 18h; | |
With peracetic acid; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With manganese(IV) oxide; mesoporous silica In chlorobenzene for 5h; Heating; | |
99% | With cerium(IV) dioxide; water monomer at 30℃; for 12h; | |
99% | With manganese(IV) oxide In 1,4-dioxane at 140℃; for 1h; Inert atmosphere; |
99% | With cerium(IV) dioxide; water monomer at 30℃; for 12h; | |
99% | With manganese(IV) oxide; water monomer In isopropanol at 100℃; for 0.05h; | |
99.9% | With potassium hydroxide In water monomer; dimethyl sulfoxide at 60℃; for 8h; High pressure; Green chemistry; | |
99% | With [RuH(tBu-PNP(-))(CO)]; water monomer In <i>tert</i>-butyl alcohol at 20℃; for 24h; | |
98% | With dihydrogen peroxide; potassium carbonate In dimethyl sulfoxide for 0.0833333h; Ambient temperature; | |
98% | In water monomer at 100℃; for 2h; | |
98% | With water monomer; C33H28F3N5O3Ru(1+)*Cl(1-) at 60℃; for 0.666667h; Sonication; | 2.5 General Procedure for the Catalytic Hydration ofNitriles. General procedure: The corresponding nitrile (1.0mmol), water (5.0 mL)and the ruthenium(III) catalyst 5a (0.1 mol%) were introducedinto a flask and the reaction mixture was sonicated at 60 °C forthe indicated time. The course of the reaction was monitored byTLC analysis. Once the reaction finished, the hot mixture waspassed through a filter paper (to remove the catalyst), allowedto reach room temperature, and then kept in an ice bath for 2 h.This led to the crystallization of the corresponding primaryamide, which was separated, recrystallized from hot water,washed with n-hexane (3 5.0 mL) and vacuum-dried. Theidentity of the amides was assessed by comparison of theirNMR spectroscopic data with those reported in the literature. |
97% | With Acetaldehyde oxime; copper(II) oxide In water monomer for 2h; Reflux; | Experimental Procedures for Hydration of Various Nitriles General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 2-14 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give the corresponding amides. The commercially available amides were characterised by melting points, 2-amino-5-bromobenzamide (Table 2, entry 6) and 3,4-dichloropicolinamide (Table 2, entry 13) were characterised by NMR spectra and LC-MS. |
97% | With nickel oxide; Acetaldehyde oxime; water monomer for 2h; Reflux; chemoselective reaction; | |
97% | With water monomer at 120℃; for 24h; | 6 Example 6 Weigh 2.04 g of 2-pyridine cyanide and 0.05 g of ETS-10 into the reaction tube.Add 30mL of water, raise the temperature to 120 ° C, and check by TLC.The reaction was completed in 24 hours, and after cooling, it was centrifuged.The resulting solution was evaporated to give the product, 2-pyridinecarboxamide, 1.18 g.The yield was 97%, and the purity was 99.54% (gas chromatography detection). The solid obtained by centrifugation was used to repeat the reaction, and the reaction conditions and the amount of the raw materials were the same as above, and repeated 5 times.The yield is above 93%, and in the sixth reaction,The yield was 89%, and the purity was 99% or more. |
96% | With polystyrene-triethylenetetramine anchored ruthenium(II) complex; air In water monomer at 90℃; for 7h; Green chemistry; | |
96% | With mPMF-Ag0 nanocatalyst In water monomer at 90℃; for 7h; | |
95% | With N-ethyl-N-hydroxy-ethanamine; water monomer at 100℃; for 4h; | |
94% | With water monomer at 140℃; for 0.25h; Inert atmosphere; | |
94% | With natrium In ethanol at 20℃; for 24h; | 2.1 2-Pyridinecarboxyimidate 2.2.1 2-Pyridinecarboxyimidate Sodium metal (0.044 g, 1.91 mmol) was added to a solution of 2-cyanopyridine (2 g, 19.21 mmol) in EtOH (30 ml) and stirred at room temperature for 24 h. Glacial acetic acid (0.12 ml, 2.09 mmol) was then added to quench the reaction and the solvent removed under reduced pressure. The crude product was dissolved in CH2Cl2 (50 ml), washed with water (2 * 50 ml), brine (10% w/v, 50 ml) and dried over Na2SO4. After filtering, the solvent was removed under reduced pressure to give the product as a light brown oil. Yield = 2.71 g (94%). 1H NMR (400.1 MHz, CDCl3, 293 K) δ = 9.03 (1H, br s, NH), 8.53 (1H, d, 3JHH = 5.6 Hz, pyH), 7.78 (1H, d, 3JHH = 7.9 Hz, pyH), 7.70 (1H, dd, 3JHH = 7.7 and 5.6 Hz, pyH), 7.27 (1H, m, pyH), 4.36 (2H, q, 3JHH = 7.1 Hz, CH2), 1.37 (3H, t, 3JHH = 7.1 Hz, CH3) ppm. |
94% | With copper (I) iodide; nitromethane; Cs2CO3; 1,8-diazabicyclo[5.4.0]undec-7-ene In water monomer at 100℃; for 4h; | |
94% | With copper (I) iodide; Cs2CO3; 1,8-diazabicyclo[5.4.0]undec-7-ene In nitromethane; water monomer at 20 - 100℃; for 4h; | Synthesis of Picolinamide (5a).S1 To a nitromethane (0.1 mL) solution of picolinonitrile (4a) (30 mg, 0.288 mmol) were added H2O (1.0mL), DBU (88 mg, 0.576 mmol), copper (I) iodide (11 mg, 0.0576 mmol), cesium (I) carbonate (47mg, 0.144 mmol) at room temperature. The reaction mixture was heated at 100 °C for 4 h and thenpoured into water (50 mL). The organic layer was separated and the aqueous layer was extractedwith AcOEt. The combined organic layer was dried over MgSO4. The solvent was removed underreduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-nhexane(1:1) to give picolinamide (5a)S1 (33 mg, 94%) as pale yellow powders. |
93% | With (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)silver(I) chloride; water monomer at 50℃; for 8h; | 1.3. General procedure for the synthesis of amides 2a-2x: General procedure: Synthesis of benzamide (2a) : (0.03 mmol) of Ag(I)-NHC catalyst (3a) was added to 1 mL of H2O in 5 mL round bottom flask. To this 1 mmol of benzonitrile (1a) was added and the reaction mixture was stirred for 8 h at 50 °C. After the completion of reaction as monitored by TLC, the resulting mixture was filtered through a pad of celite and extracted with DCM (2 x 5 mL). The combined organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography using a gradient of hexane/ethyl acetate (1:1). The compound 2a (91%) was isolated as a white solid. Similar procedure was followed to synthesize other amides 2b-2x. |
92% | With NaY zeolite; water monomer for 24h; Heating; | |
90% | With water monomer at 120℃; for 10h; Green chemistry; | 2.4 Typical procedure for the Ni NPs/HT catalyzed hydration of nitriles to amides General procedure: Ni NPs/HT (0.05 g) is placed in a heavy-walled pressure tube, followed by the addition of water (4 ml) and benzonitrile (1 mmol), and the reaction mixture is vigorously stirred at 120 °C in an oil bath for the specified time in tables. The progress of the reaction in each case was monitored by TLC analysis. After completion of the reaction, the reaction mixture is extracted with ethyl acetate, after the extraction, the catalyst is removed by filtration, and the filtrate is cooled to 0 °C, and white crystals are precipitated from the filtrate. The crystalline product was obtained by simple filtration and dried in vacuo at room temperature to give analytically amide product. In cases where the product not precipitated out, the reaction mixture was extracted with ethyl acetate, subsequent purification by column chromatography on silica gel provided amide product. |
88% | With water monomer at 100℃; for 0.75h; Microwave irradiation; | |
88% | With chitosan-supported ruthenium catalyst (ChRu) In water monomer at 120℃; for 1h; Microwave irradiation; Sealed tube; | |
87% | With ((1,2-bis(diisopropylphosphino)ethane)NiH)2; water monomer at 100℃; for 72h; Inert atmosphere; | |
87% | With [Os(η6-p-cymene)(OH)(1,3-bis(2,6-diisopropylphenyl)imidazolylidene)](CF3SO3); water monomer; isopropanol; potassium hydroxide In para-xylene at 120℃; for 0.5h; Schlenk technique; Inert atmosphere; | |
87% | With Acetaldehyde oxime; sodium molybdate(VI) dihydrate In water monomer for 5h; Reflux; | Experimental Procedures for Hydration of Various Nitriles General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2 mmol), acetaldoxime (6 mmol), sodium molybdate (VI) dihydrate (0.2 mmol) and H2O (10 mL). The mixture was heated to reflux for 5-16 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethylacetate/n-hexane) to give the corresponding amide. |
87% | With C14H30ClN3PRh; water monomer at 100℃; for 2h; Inert atmosphere; Schlenk technique; | |
86% | Stage #1: 2-Cyanopyridine With Cs2CO3 In 2-pyrrolidinon at 130℃; for 2h; Sealed vessel; Stage #2: With methanol In 2-pyrrolidinon; dichloromethane at 20℃; Filtering through Celite pad; | General procedure for hydration of (hetero)aryl nitriles 1 General procedure: A flame-dried resealable 2-5 mL Pyrex reaction vessel was charged with the solid reactant(s): (hetero)aryl nitriles 1 (1.0 mmol) and Cs2CO3 (1.5 mmol). The reaction vessel was capped with a rubber septum, and pyrrolidinone (2 mL per mmol [0.5 M]) was added through the septum. The septum was replaced with a teflon screwcap. The reaction vessel was sealed and heated at 130 °C for 2 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with CH2Cl2/MeOH (7:3), and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product. |
85% | With potassium carbonate In ethanol; water monomer; toluene for 12h; Reflux; | 2 Example 2 2-chloro group [I than later (10 mmol, 1. 04 g), K2CO3 (0. 5 mmol, 69 mg) was dissolved in toluene / water / ethanol (V: V: V = 6: 2: after 1) mixed solvent, the reaction was refluxed for 12 hours, the reaction was stopped. after standing at room temperature, the solvent after the spin dry, and purified by silica gel column chromatography to give a white solid was isolated amination of 2- cool Night 1.04 g (yield rate: 85%); |
84% | With caesium hydroxide; water monomer; dimethyl sulfoxide at 30℃; for 24h; Schlenk technique; Green chemistry; | |
82% | With C34H38N6NiO2(2+)*2Cl(1-); water monomer In isopropanol at 70℃; for 6h; Schlenk technique; Inert atmosphere; | |
81% | With manganese(IV) oxide; mesoporous silica for 0.0666667h; microwave irradiation; | |
79% | With ammonium hydroxide; caesium hydroxide monohydrate at 100℃; for 1h; Schlenk technique; Sealed tube; | |
77% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold bis(trifluoromethanesulfonyl)imidate; water monomer In tetrahydrofuran at 140℃; for 6h; Microwave irradiation; | |
76% | With 3,4,5-trihydroxybenzoic acid; potassium hydroxide In ethanol; water monomer at 20℃; Green chemistry; | |
75% | With sodium perborate; water monomer In methanol at 50℃; | |
75% | With water monomer; [RuCl2(dmso)3(NH3)]PF6Cl at 60℃; for 24h; | |
74% | With [RuCl2(η3:η3-C10H16){PMe2(OH)}]; water monomer at 60℃; for 6h; Inert atmosphere; Schlenk technique; Sealed tube; | |
74% | With [RuCl2(η3:η3-2,7-dimethylocta-2,6-diene-1,8-diyl)(PMe2OH)] In water monomer at 60℃; for 6h; Inert atmosphere; Sealed tube; | |
72% | With [RuCl2(PTA)4]; water monomer at 100℃; for 24h; | |
72% | With [RuCl2(1,3,5-triaza-7-phosphaadamantane)4]; water monomer at 100℃; for 24h; Green chemistry; | 1.1j Example 1 The catalytic activity of 5 mol % [RuCl2(PTA)4] toward nitrile hydration was evaluated in aqueous solution at 100 ° C. with 1 mmol nitrile in a culture tube under air (Scheme 2). Under the conditions described here, RuCl3 (5 mol %) provided a 54% conversion of benzonitrile to benzamide in 24 hours. Benzonitrile hydration by 2 mol % RuCl3 was previously reported to yield 28% benzamide after 3 h at 130° C. No hydration was observed in the absence of a catalyst, or with PTA, [RuCl2(η6-toluene)]2, or [RuCl2(PPh3)3] as catalysts. Benzonitrile hydration by [RuCl2(PTA)4] did not occur at 50° C. and provided only 23% conversion after 24 h at 75° C. The hydration of benzonitrile catalyzed by [RuCl2(PTA)4] showed a >99% conversion to benzamide at 100° C. after 7 hours, in contrast to the inactive [RuCl2(PPh3)3], potentially demonstrating a cooperative effect of the nitrogen-containing PTA versus PPh3. For comparison, nitrile hydration catalyzed by 5 mol % [RuCl2(η6-arene)(PTA)] (η6-arene=benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene), showed >98% conversions in 4-9 h for aqueous benzonitrile hydration under N2 at 100° C. An in situ generated catalyst formed by the addition of RuCl3 hydrate with 6 equivalence of PTA provided results similar to the preformed complex RuCl2PTA4 (Table 1).The conversion of various nitriles (1a-1n) to the corresponding amides (2a-2n) was explored with results summarized in Table 1. All nitriles were efficiently converted to amides with 67-99% conversion in 7 hours and >99% conversions by 24 hours, with the exception of 2-cyanopyridine (1j, 81% after 24 h). After completion, the reaction was cooled to 0° C. and, in most cases, the product amides crystallized out as white needles and were easily isolated in 67-81% yield by decantation. Identity of the isolated amides (2a-2n) was confirmed by GC-MS and NMR spectroscopy. Substituted benzonitriles bearing electron-withdrawing groups (Table 1 above, entries 1g-1i) exhibited slightly more efficient conversions to amides than those with electron-donating groups (entries 1b-1f). Presumably, the presence of the electron-withdrawing group makes the nitrile carbon more susceptible to nucleophilic attack by an activated water molecule. As previously reported for ortho-substituted benzonitriles, o-tolunitrile exhibited lower conversion relative to m- and p-tolunitriles (Table 1, entries 1b-1d), which is attributed to steric hindrance of the o-tolunitriles. Hydration of 4-cyanobenzaldehyde led to 4-formylbenzamide in a 99% conversion in 7 h with an intact formyl moiety (entry 1i). The coordinating ability of the pyridyl functionality reduced catalytic activity as hydration of 2-cyanopyridine to picolinamide resulted in only 81% conversion after 24 h (entry 1j).[RuCl2(PTA)4] was also effective as a hydration catalyst for the less reactive aliphatic nitriles (Table 1, entries 1k-1m). 4-Methylbenzyl cyanide was transformed with 99% conversion in 7 hours (entry 1k) into the amide. Hydration of the sterically bulky pivalonitrile (1m) to pivalamide proceeded with a 99% conversion in 24 h although a modest conversion of 67% was observed after 7 h (entry 1m). The resistance of tertiary nitriles toward hydrolysis has been noted. The industrially important acrylonitrile was almost quantitatively converted into acrylamide in 7 hours without observation of polymerization or hydrolysis byproducts (Table 1, entry 1n). For all the nitrile hydrations studied, the corresponding amides were the only product observed (no carboxylic acids were detected by GC-MS). Thus, the catalytic conditions described here are compatible with ether (entry 1e), hydroxyl (entry 10, nitro (entry 1g), bromo (entry 1h), formyl (entry 1i), pyridyl (entry 1j), benzyl (entry 1k), alkyl (entries 1l-1m), and olefinic (entry 1n) functional groups, which establishes a wide synthetic scope. |
70% | With fac-[(CO)3Mn(iPr2P(CH2)2PiPr2)(triflato)]; water monomer In tetrahydrofuran at 100℃; for 18h; Glovebox; Inert atmosphere; Schlenk technique; | |
69% | With water extract of pomelo, peel at 150℃; for 1h; Sealed tube; Green chemistry; | 3.3. General Procedure for the Hydrolysis of Nitriles in WEPPA (Taking 1a as an Example General procedure: Benzonitrile 1a (103 mg, 1.0 mmol) and WEPPA (2.0 mL) were added into a 10-mL closed tubewith a stir bar. Then the reaction was stirred in a closed vessel synthesis reactor at 150 C for 0.5 h.After cooling to ambient temperature, the resulting precipitate was collected by filtration, washed withice water, and further dried in a vacuum drying oven. The filtrate was evaporated under reducedpressure. The resultant residue was purified by silica gel column chromatography (eluent: petroleumether (35-60 C)/EtOAc = 2:1 to 0:1, v/v). Finally, these two parts were combined to produce the desiredbenzamide 2a with a 94% yield. |
57% | With trans-RuCl<SUB>2</SUB>(1,3,5-triaza-7-phosphaadamantane)<SUB>4</SUB> In aq. phosphate buffer at 100℃; for 7h; Sealed tube; Green chemistry; | |
52% | With sodium hydroxide; poly(ethylene glycol)-400 for 0.0111111h; microwave irradiation; | |
36% | With [(η6-toluene)RuCl(κ2-(P,N)-(1,3,5-triaza-7-phosphaadamantan-6-yl)CPh2NHPh)]Cl; water monomer at 100℃; for 7h; | |
35% | With [(η6-toluene)RuCl2(κ1-1,3,5-triaza-7-phosphaadamantane-PiPr2)]; oxygen In water monomer at 100℃; for 24h; Sealed tube; Inert atmosphere; | 4.1.9. General procedure for catalytic nitrile hydration General procedure: A culture tube was charged with 1 mmol nitrile, 3 mL water, and 5 mol% ruthenium complex 7 or 8 sealed under air and heated to 100 C. In the case of the in situ generated catalyst a culture tube containing RuCl33H2O (0.05 mmol) or [(g6-toluene)RuCl(l-Cl)]2(0.05 mmol) was transferred to a dry box and 0.05 or 0.10 mmol phosphine was added along with 1.0 mmol nitrile and 3 mL degassed water. The culture tube was sealed, removed from the dry box, and stirred at 100 C. Small aliquots (50 lL) were taken at 7 and 24 h, extracted with CH2Cl2 (3 2 mL) and the % conversion measured by gas chromatography. Isolated yields were obtained by evaporation of solvent followed by column chromatography on silica gel with ethyl acetate as eluent. GC/MS and 1H NMR spectroscopic data of the product amides were compared to authentic samples. |
10% | With [Ru(OTf){η6:κ1(P)-PPh2-binaphthyl}{PPh2(OH)}][OTf] In water monomer at 100℃; for 24h; Inert atmosphere; Sealed tube; | |
With ammonia; water monomer at 30 - 75℃; for 2 - 6h; | 1 Example 1 A batch hydrolysis was designed to simulate the quench of gaseous reaction product from the preparation of 2-cyanopyridine prepared from 2-picoline reactor feed in the presence of air and ammonia over a catalyst. To a 100 mL glass tube reactor, 0.5 grams of 2-cyanopyridine, a magnetic stir bar, and 20 mL of an ammonia solution were added per Table 1. The tube was capped and heated at the temperatures and for the contact times indicated in Table 1. After each interval, the tube reactor was transferred to be cooled with a water bath and the tube's cap opened. After a gas chromatography sample of 2 μL of the solution was taken, the tube was recapped and heated for another interval of time. The simulated aqueous quench fluid included ammonia representing unreacted ammonia. The samples were analyzed for remaining 2-cyanopyridine. The balance of the remaining 2-cyanopyridine is viewed as theoretical hydrolysis of 2-cyanopyridine to the corresponding pyridine-2-carboxamide (2-picolinamide). Under these conditions, hydrolysis at reaction times longer than 4 hours leads to significant amounts of pyridine-2-carboxylic acid. TABLE 1 Quench Fluid - aqueous % of original % converted to 2-cyanopyridine pyridine-2- Temperature remaining carboxamide of QuenchNH3 content 2 4 6 2 4 6 Fluid - ° C. % wt hours hours hours hours hours hours 30 2 96 92 4 8 45 2 85 74 63 15 16 37 60 2 65 40 35 60 75 2 47 26 18 53 74 82 75 1 54 34 26 46 66 74 75 0.5 63 46 40 37 54 60 75 0.1 84 71 62 16 29 38 Table 1 demonstrates that the desired cyanopyridine product hydrolyzes in aqueous quench fluid to pyridinecarboxamide. | |
With α-picoline; ammonia; water monomer at 75 - 100℃; for 2 - 24h; | 2 Example 2 The batch hydrolysis simulation of Example 1 was repeated with a predominately non-aqueous quench fluid comprising 2-cyanopyridine in 2-picoline solution, water and ammonia in the respective weight percents indicated in Table 2. To a 100 mL glass tube reactor were added 6.25% 2-cyanopyridine in 2-picoline solution. Under these conditions, the predominately non-aqueous quench fluid was stirred at the temperatures for the contact times indicated in Table 2 below. Samples were analyzed at the indicated intervals for the hydrolyzed by-product pyridinecarboxamide. TABLE 2 Quench Fluid - 2-picoline % converted to Temperature of pyridinecarboxamide Quench Fluid -H2O contentNH3 content 2 4 8 24 ° C. % wt % wt hours hours hours hours 75 5 0.1 0 0 0 0 75 10 1 .14 .18 .22 .25 100 10 1 .11 .23 .3 .36 100 20 2 .33 .46 .7 1.22 6b 2-Cyanopyridine quenched in 2-picoline demonstrates a lower rate of hydrolysis to the undesired pyridine-2-carboxamide. Examples 1 and 2 demonstrate that a reduction in water content in quench fluid leads to a lower rate of hydrolysis. Example 2 also demonstrates that a predominately non-aqueous quench fluid substantially minimizes pyridinecarboxamide formation and pyridinecarboxylic acid formation and substantially improves cyanopyridine isolation yield. Example 2 also demonstrates that a predominately non-aqueous quench fluid substantially minimizes hydrolysis while the quench fluid is at elevated temperatures compared to aqueous quench fluid. | |
With nitrile hydratase from Rhodopseudomonas palustris CGA009 In dimethyl sulfoxide at 30℃; for 17h; aq. phosphate buffer; chemoselective reaction; | ||
10 %Chromat. | With C20H21Cl2OPRu; Triton X-114; water monomer at 100℃; for 24h; | |
With Eupergit C-supported recombinant Geobacillus pallidus RAPc8 nitrile hydratase; water monomer at 50℃; aq. phosphate buffer; Enzymatic reaction; | ||
96 %Chromat. | With ammonia; water monomer In 1,4-dioxane at 130℃; for 1h; Autoclave; Inert atmosphere; | |
With cerium(IV) dioxide; water monomer at 160℃; Inert atmosphere; | ||
91 %Chromat. | With water monomer In N,N-dimethyl-formamide at 89.84℃; for 48h; | |
98 %Chromat. | With water monomer at 140℃; for 3h; | |
With cerium(IV) dioxide; octanol; water monomer at 160℃; | ||
With magnesium phthalocyanine; water monomer at 100℃; | ||
> 99 %Chromat. | With manganese(IV) oxide; water monomer In 1,4-dioxane at 140℃; for 1h; Inert atmosphere; Autoclave; | |
With water monomer In isopropanol at 85 - 90℃; | 9 In a four neck round bottom flask fitted with thermo well, agitator and reflux condenser, 2-cyanopyridine (100 g), de-mineralized water (150 g) isopropyl alcohol (10 g) and chromium oxide - nickle oxide catalyst (1 g) prepared in Example 2 is charged. The mixture is heated up to 85-90 °C for 4-6 h. The completion of reaction is monitored by HPLC. After the completion of reaction the crude product is cooled and filtered to separate picolinamide from the catalyst bed. The catalyst bed is washed with de-mineralized water to make catalyst free from hydrolyzed mass of 2-cyanopyridine. The wet catalyst is recycled back for next batch of hydrolysis. The colorless mother liquor is concentrated and dried to get pure picolinamide. The recovered water layer containing 2-cyanopyridine and alcohol is recycled back for next hydrolysis batch. | |
With cerium(IV) dioxide; water monomer | ||
With water monomer; glacial acetic acid at 170℃; | ||
With cerium(IV) oxide; water monomer at 140℃; for 3h; Autoclave; | 2.5 The hydrolysis of 2-cyanopydine over CeO2 with a different morphology In a typical procedure for the hydrolysis of 2-cyanopyridine to 2-picolinamide, 0.1g 2-cyanopyridine, 3g H2O, and 0.03g CeO2 with different morphologies were added into the autoclave. The resulting mixture was vigorously stirred at 140°C. After the reaction, the mixture was extracted with CHCl3 three times. | |
With water monomer at 79.84℃; for 24h; chemoselective reaction; | 4.4. Catalytic nitrile hydration in water General procedure: Catalyst (50.0 mg, 0.009 mmol of Pd) and substrate (0.50 mmol)were dissolved in water (milliQ-grade) and transferred into a pyrexvial. The obtained suspension was stirred at 353 K in air atmospherefor the desired time. Afterward, the obtained solution was cooled to273 K and extracted with diethyl ether (3 × 2.0 mL). To the unifiedorganic phases was added toluene (50.0 L) as internal standard.The obtained solution was objected to GC and GC-MS analysis. Thecatalyst was recovered after diethyl ether extraction by precipita-tion with iso-propanol, filtration and drying by vacuum at roomtemperature. The recovered catalyst was then used for recyclingexperiments. | |
With C40H45ClN3O2PRu In methanol; water monomer at 20℃; for 4h; Inert atmosphere; Schlenk technique; Green chemistry; | 4.7. General procedure for the hydration of nitriles to amides General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the [Ru-NHC] catalyst (0.5 mol%) and the reaction mixture was stirred at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of reaction the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified with authentic samples. | |
> 99 %Chromat. | With poly(amic acid) salt-stabilized silver nanoparticles; air In water monomer at 90℃; for 1h; | |
With [2,2]bipyridinyl; water monomer; palladium diacetate In 1,4-dioxane at 70℃; for 24h; Schlenk technique; Sealed tube; | General Procedure XI - Notable Substrate Exceptions General procedure: Some less successful substrates are tabulated below. To an oven dried Schlenk carousel tube containing the appropriate nitrile (1 mmol) was added palladium acetate (11 mg, 5 mol%), 2,2'-bipyridine, (7.8 mg, 5 mol%) and either water (2 mL, 0.5 M) or water/dioxane (1.4 mL/0.6 mL) as stated. The tube was then sealed and the reaction mixture heated at 70 °C for 24 hours. After being allowed to cool to room temperature, the reaction mixture was diluted with methanol (5 mL) and the solvent removed in vacuo on a rotary evaporator. 1,4-Dimethoxybenzene (46 mg, 1/3 mmol)) was used as an NMR standard and the crude reaction mixture was analysed by 1H NMR spectroscopy. | |
95 %Chromat. | Stage #1: 2-Cyanopyridine With dimethyl sulfoxide; sodium hydroxide In ethanol; water monomer at 25℃; for 0.0416667h; Flow reactor; Stage #2: With dihydrogen peroxide In ethanol; water monomer at 25℃; for 0.0694444h; Flow reactor; | 4.2. General procedure for the selective hydrolysis of nitriles in continuous flow General procedure: 0.6 mmol benzonitrile and 0.6 mmol DMSO were solved in 3 mL EtOH and pumped into inlet A, 50 μL 1 M NaOH (aq) solved in 1 mL EtOH and pumped into inlet B, 30% H2O2 (aq) was solved in 7 mL ethanol and pumped into inlet C (flow rate A: B: C = 1.54 μl/min:0.46 μl/min:0.3 μl/min for a 400s residence time). The whole system was maintained on 25 °C. The flow system was equilibrated for 30 min, then the product stream was quenched and collected in a glass vessel with saturated aqueous NaHSO3 in it for 2 h. After being filtered, 5.0 ml of this solution was injected to the HPLC instrument for analysis. The conversion of the reaction was determined by relative area percentage of nitriles and corresponding amides. Conversion = Area (benzamide)/[Area (benzamide) + Area (benzonitrile)]. |
With carbon dioxide; water monomer; aniline; isopropanol at 149.84℃; | ||
Stage #1: 2-Cyanopyridine With methanesulfonic acid; (η5-C5H5)Fe(η5-C5H4CH(CH(CH3)2)OH) In 1,2-dichloro-ethane at 20℃; for 24h; Stage #2: With ammonium hydroxide; water monomer In 1,2-dichloro-ethane Cooling with ice; | General procedure for the synthesis of rac-1-R-3,3-dimethyl-3,4-dihydroferroceno[c]pyridines 3 (GP). General procedure: The mixture of 1-ferrocenyl-2-methylpropan-1-ol (1) (645 mg, 2.5 mmol) and the nitrile 2 (2.5 or 3.0 mmol) in DCE(5 mL) was added dropwise with vigorous stirring to MsOH (1.30 mL, 20 mmol) at room temperature. The resulting mixture was then heated with stirring at 60 °C for the noted reaction time. After, the reaction mixture was cooled to roomtemperature, poured into a mixture of crushed ice (20 g) and 25% aq NH3 (6 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the crude mixture by silica gel column chromatography gave the desired product 3. rac-3,3-Dimethyl-1-phenyl-3,4-dihydroferroceno[c]pyridine(3a). The title compound was prepared according to GP (reaction time = 4 h) using benzonitrile 2a (309 mg, 309 µL, 3.0 mmol). Purification by silicagel column chromatography (petroleum ether/EtOAc15:1 followed by petroleum ether/TEA 100:1) gave 3a as a dark red oil which solidified on standing in a refrigerator (481 mg, 56% yield). | |
5.14 g | With manganese(IV) oxide; sodium hydroxide In water monomer; acetone at 70℃; for 3.5h; | Synthesis of 2-pyridinecarboxamide 2-Cyanopyridine(5.20 g, 0.050 mol), 32 mL of acetone, 32 mL of 5 % aqueous solution of NaOH and 4.35 g of MnO2 (0.050 mol) were added into reaction bottle and reacted for 3.5 h at 70 C with continuous stirring. The reactant was distilled under 60 C for removing the acetone and then filtrated to separate the remaining MnO2and its conversion product. The filtrate was cooled to ambient temperature for forming the crystal of 2-pyridinecarboxamide before filtration. The wet filter residue was dried at 60 C using vacuum drying oven and 5.14 g of 2-pyridinecarboxamide was obtained (Scheme-I) |
With phosphorylated silica catalyst at 240 - 400℃; | 1; 2 2-OP distillation residue in situ-catalytic cracking and vacuum distillation: zeolite or silica gel is immersed in a phosphoric acid aqueous solution with a mass concentration of 10% to 80% for 2 to 48 hours, and then the liquid phase is removed by filtration, and the obtained solid The material is burned in a muffle furnace at 300 ~ 800 for 2 to 12 hours, and then the solid material after high temperature burning is pulverized to obtain phosphorylated zeolite or phosphorylated silica gel; phosphorylated zeolite and / or phosphorylated Silica gel and 2-OP distillation residue are added to the cracking reactor at a mass ratio of 1 to 10:10 to 1000, and are held in place under the conditions of stirring and 240 to 400 temperature and a vacuum of 0.01 MPa to 0.1 MPa. Catalytic cracking and reduced pressure distillation, that is, a pyridine-2-formamide-containing reduced pressure distillation distillate is obtained in a yield of 60% to 90% relative to the mass of the 2-OP rectification residue. The distillate was cooled and crystallized to obtain crude pyridine-2-formamide. | |
44 %Chromat. | With [RuCl2(p-cymene)(P(Fur)3)] In water monomer at 80℃; for 24h; Green chemistry; | |
0.86 g | With water monomer; sodium hydroxide at 35 - 45℃; for 3h; | 1 Example 1 In a 40mL reaction flask, 29.3mg (0.08mmol, 0.01eq.) Of allyl palladium chloride dimer, 92.6mg (0.16mmol, 0.02eq.) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 10.1mL 1,4-dioxane, 1.26g (8mmol, 1.0eq.) 2-bromopyridine, 1.69g (4mmol, 0.5eq.) Potassium ferrocyanide trihydrate and Adjust and control the temperature of the reaction liquid 95-105 in 5.1mL water, and stir for 18 hours;After completion of the reaction, add sodium hydroxide aqueous solution [0.38g (9.6mmol, 1.2eq.) Sodium hydroxide dissolved in 5.1mL water], adjust and control the temperature of the reaction liquid 35-45 , stir for 3 hours, adjust with 6M hydrochloric acid aqueous solution pH to 7-8, distillation and concentration at 50 ° C under reduced pressure to obtain a yellow-green solid, which was separated by column chromatography (200-300 mesh silica gel) to obtain 0.86 g of pale yellow solid with a yield of 88.0%.The resulting product was subjected to high performance liquid chromatography, liquid chromatography / mass spectrometry and nuclear magnetic analysis. Analysis conditions: Agilent 1260 liquid chromatograph and ultraviolet detector, Eclipse Plus C18 (50 × 4.6mm, 1.8μm) chromatography column, mobile phase: A: 0.05% formic acid in water, B: 0.05% formic acid in acetonitrile. Equilibrated at 40mL, 1.5mL / min, detection wavelength 220nm. Nuclear Magnetic: Bruker 400MHz. |
With 5% Pd/CeO2 In water monomer at 140℃; for 18h; | 61 Example 61 Add 100mg Pd/CeO2 (mass percentage of Pd load: 5.0%, mass percentage of the entire catalytic material in the mixture: 1.7%), 60mg 2-cyanopyridine (mass percentage in the mixture: 1%) in 6g water, mix Uniform; reaction at 140°C for 18 hours, conversion of 2-cyanopyridine>99.0%, corresponding selectivity of 2-pyridinecarboxamide>99.0%. | |
With manganese(IV) oxide; iron(III) oxide; cobalt(II,III) oxide In tert-Amyl alcohol; water monomer at 80℃; for 24h; | 57 Example 57 To 6 g of tert-amyl alcohol were added 100 mg of ferric oxide, 100 mg of tricobalt tetraoxide and 100 mg of manganese dioxide (mass percentage in the mixture: 4.6%), 60 mg 2-cyanopyridine (mass percentage in the mixture: 0.91%), 200uL water (mass percentage in the mixture: 3.0%), mixed evenly; reacted at 80°C for 24 hours, the conversion rate of 2-cyanopyridine was 99.0%, and the selectivity of the corresponding 2-pyridinecarboxamide was 99.0%. | |
95 %Chromat. | With water monomer; C27H27ClIrNO at 80℃; for 6h; | |
With nitrile hydratase mutant βL48H at 30℃; for 0.166667h; Enzymatic reaction; | 2.4 Enzymatic assay General procedure: The specific activity of NHase was determined by the increase of the pyridine and pyrazine carboxamide product. The reaction mixture was the same as that reported in our previous study [17]. The reaction was carried out at 30°C for 10min. The amide concentration was analyzed by HPLC equipped with a HITACHI C18 reverse phase column (solvent: acetonitrile/water=1:2 (v/v)). The detection wavelength was set to 215nm. One unit (U) of NHase activity was defined as the amount of enzyme that produced 1μmol amide product per minute under the above assay conditions. | |
With 1,4,7-triaza-9-phosphatricyclo[5.3.2.1(4,9)]tridecane; water monomer; [Ru2(μ-Cl)3(1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane)6]Cl at 100℃; for 8h; Schlenk technique; Inert atmosphere; | ||
With cerium(IV) dioxide; water monomer at 140℃; | 4-8 Example 5: Hydration of Nitrile Catalyzed by CSR/CLR and Commercial CeO2 Catalyst without Cavitations Influence Catalytic activity studies were carried out in a double-necked glass-round bottom flask fitted with a water-cooled condenser and placed in a temperature-controlled oil bath. In a typical experiment, required quantities of 2-Cyanopyridine, water, and ceria supported PTC catalysts were taken in the reactor, and the reaction was conducted at temperature 140° C., up to 3h and 6 hr. The resulting mixture was extracted with dichloromethane (DCM-30 mL) and used for GC analysis. Initially, inventor have studied the hydration using ceria supported mixed metal oxide catalyst at temperature 140° C. by following reaction conditions:-2-CP:H2O molar ratio (1:1) where 2-cyanopyridine (2-CP) (5.2485 g, 50.41 mmol) and H2O (1.0 g, 55 mmol), two different ceria supported mixed metal oxides catalysts were used. CSR/CLR and pure ceria (commercial) (approx. -0.52 g, 3 mmol), the amount of the catalyst was 10 wt % with respect to 2-CP. This reaction mixture, along with catalyst, has been taken in a three-necked glass-round bottom flask fitted with a condenser and placed in a temperature-controlled oil bath at desired temperature. Reaction results are as shown in FIG. 12; these experimental results show that among ceria supported mixed metal oxides catalyst (CSR/CLR) and pure CeO2 (commercial), CSR catalyst is more active for the hydration than the CLR and pure CeO2 catalyst. (0120) The catalytic activity also studied for the residence time of 3h and 6h at 140° C. The results of the experiments demonstrate that the conversion shown by the CSR (Ce-Sm-Ru) catalyst is higher than the CLR (Ce-La-Ru) and pure CeO2 catalyst. The characterization data reveals that the CSR catalyst is having a higher surface area when compared to CLR catalyst (table-1) and reported commercial CeO2. Apart from this, CSR catalyst is also having an appropriate ratio of acidic to basic site. The other reason for the higher activity of the CSR catalyst can be substantiated with help of elemental mapping (FIG. 5a), which reveals the uniform dispersion of the elements over the catalyst surface and the formation of homogenous solid solution, which makes this catalyst superior to the other tested catalysts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Lawessons reagent; In toluene; at 85℃; for 64h; | A solution of pyridine-2-carboxamide (3.1 g, 25.4 mmol) in toluene (25 mL) was treated with Laweson's reagent (5.1 g, 12.6 mmol), heated at 85 C. for 64 hours, cooled to 25 C., and partitioned between ethyl acetate and water. The organic phase phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification. | |
With Lawessons reagent; In toluene; at 85℃; for 64h; | EXAMPLE 3H 2-pyridinecarbothioamide A solution of pyridine-2-carboxamide (3.1 g, 25.4 mmol) in toluene (25 mL) was treated with Laweson's reagent (5.1 g, 12.6 mmol), heated at 85 C. for 64 hours, cooled to 25 C., and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification. | |
With Lawessons reagent; In toluene; at 85℃; for 48h; | Example 273A; ethyl 2- (2-pyridinyl)-1, 3-thiazole-4-carboxylate; 2-Picolinamide (3.1 g, 25.4 mmol) was dissolved in toluene (25 mL) and treated with Lawesson's Reagent (5.1 g, 0.5 equivalents). The reaction was heated to 85C and stirred for 48 hrs. The reaction was quenched with water and extracted and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed by evaporation. This material was dissolved in ethanol (50 mL) and treated with ethyl bromopyruvate (3 mL, about 1 equivalent) and powdered 3A molecular sieves (10 g). The reaction was refluxed for 16 hrs. The reaction was then filtered and the solvent was removed by evaporation. The material was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate, washed with brine, and dried over magnesium sulfate. The reaction was filtered and the solvents were removed by evaporation. This material was purified using dichloromethane: ethyl acetate (3: 1) to give 1. 98 g of the title compound (33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonia at 210 - 380℃; for 0.00166667h; | 1; 2; 3; 4; 5 Example 2 The fixed bed is heated to 370-380 ° C, and the absorption circulation pump is turned on to control the air flow rate of 360L / h.Subsequently, ammonia was introduced into the reactor to control the ammonia gas flow rate of 36 L / h.After that, 2-pyridylcarboxamide is fed into the system, and the flow rate of 2-pyridylcarboxamide is controlled to 20g / h.The feed temperature is controlled at 210-220 ° C and the residence time is 6s. The reaction gas is condensed.Control the stratified residence time of 6 minutes; 2-cyanopyridine product is obtained after rectification,The conversion of raw materials was 99%, and the yield of 2-cyanopyridine was 89%. |
88% | With ethyl phosphodichloridite; 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 1h; | |
87% | With dioxouranium(VI) nitrate hexahydrate; N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide In 1,2-dimethoxyethane at 100℃; for 24h; |
79% | With diphenylsilane; FeH(PMe<SUB>3</SUB>)<SUB>2</SUB>(SiPh(NCH<SUB>2</SUB>PPh<SUB>2</SUB>)<SUB>2</SUB>C<SUB>6</SUB>H<SUB>4</SUB>) In tetrahydrofuran at 70℃; for 24h; Schlenk technique; Inert atmosphere; | |
73% | With Triethoxysilane; o-Ph<SUB>2</SUB>P(C<SUB>6</SUB>H<SUB>4</SUB>)Si(Me)<SUB>2</SUB>Fe(H)(PMe<SUB>3</SUB>)<SUB>3</SUB> In tetrahydrofuran at 60℃; for 24h; Schlenk technique; | |
70% | With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 60℃; for 24h; Inert atmosphere; | 2.2. General procedure for the dehydration of amides to nitriles General procedure: To a 25ml Schlenk tube containing a solution of 1 in 2ml of THF was added amide (1.0 mmol) and (EtO)3SiH (0.50 g, 3.0 mmol). The reaction mixture was stirred at 60 °C until there was no amide left (monitored by TLC and GC-MS). The product was purified according to literature procedures by Beller [27]. |
70% | With lead (II) acetate In dichloromethane for 12h; Reflux; | |
67% | With Triethoxysilane; [(2,5-F2C6H2-CH=N-C10H6)Co(III)(H)(PMe3)2] In tetrahydrofuran at 60℃; for 24h; Schlenk technique; | 2.2 General procedure for the dehydration of amides to nitriles General procedure: To a 25 mL Schlenk tube containing a solution of 2 in 2 mL of THF was added amide (1.0 mmol) and (EtO)3SiH (0.50 g, 3.0 mmol). The reaction mixture was stirred at 60 °C until there was no amide left (monitored by TLC and GC-MS). The product was purified according to literature procedures by Beller |
64% | With Triethoxysilane; C43H50FeP4Si; anhydrous zinc bromide In tetrahydrofuran at 40℃; for 30h; Schlenk technique; | |
58% | With methylcerium dichloride at -78 - 0℃; for 1h; | |
With sodium oxide; mesoporous silica In 1,3,5-trimethyl-benzene at 164.84℃; | ||
23.6 %Chromat. | With K2CO3 on silylated silica gel In 1,3,5-trimethyl-benzene at 180℃; for 10h; Inert atmosphere; Molecular sieve; Green chemistry; | Activity tests 0.1 g of catalyst, 0.122 g (1 mmol) of 2-picolinamide and 20 mL of mesitylene as solvent were put together into the Soxhlet reactor equipped with a reflux condenser. 4A molecular sieve which was calcined at 350 °C for 8 h under air atmosphere to remove physical adsorbed water was placed into the upper part ofthe Soxhlet reactor. The reactor was purged with Ar and then heated at 180 °C under azeotropic reflux for removing water from the mixture while stirring constantly. After the reaction, when the reactor was cooled to room temperature, 10 mL of ethanol was added to the reactor to solve the unreacted 2-picolinamide, and n-propanol was added as an internal standard. The product 2-cyanopyridine was analyzed by using a gas chromatograph (Agilent 4890 D). 2-Cyanopyridine was the only product observed in our work, meaning the selectivity was nearly 100%. |
33.5 g | With Cs2O/SiO2 In diphenylether at 95 - 229℃; for 8h; | |
With sodium oxide-silicon dioxide In 1,3,5-trimethyl-benzene at 165℃; for 400h; | 1 Comparative Examples 1 Through 17 In the meantime, in comparative examples 1 through 17, a solvent containing none of the four specific solvent compounds was used. In comparative examples 10, 14 and 16, the dehydration reaction was performed in substantially the same manner as in example 4. In the other comparative examples, the dehydration reaction was performed in substantially the same manner as in example 1. As a result, 2-cyanopyridine was produced from 2-picolinamide (see Table 4). (0153) In comparative example 1 with a significantly longer reaction time of 400 hours, an aromatic nitrile compound was generated at a high yield, and the generation of pyridine as a by-product was suppressed. However, the dehydration reaction requiring such a long reaction time is not suitable to practical use. In comparative examples 2 and thereafter with a reaction time of 24 hours (only in comparative example 10, the reaction time was 12 hours), the nitrile yield was significantly lower, and the generation amount of pyridine with respect to the generation amount of the nitrile compound (2-cyanopyridine) was larger, than in examples 1 through 6 having a reaction amount of 24 hours or significantly shorter than 24 hours. (0154) The results in examples 1 through 12 and comparative examples 1 through 17 are shown in Tables 1 through 4 below. | |
10 %Chromat. | With molybdenum oxide on silica In 1,3,5-trimethyl-benzene at 164.84℃; for 120h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 2-Picolinic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h; | 4.2.9 4.2. Typical procedure for the primary amidation of 3-phenylpropanoic acid 1a with NH4Cl General procedure: To a colorless solution of 75mg (0.50mmol) of 3-phenylpropanoic acid 1a in 10mL of THF were added at 0°C 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) was added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 72mg (96% yield) of 3-phenylpropanamide 2a. 4.2.9 Picolinamide 2i 59 mg (97%); colorless solid; mp: 95-97 °C; 1H NMR (400 MHz, CDCl3): δ 5.55 (br, 1H, NHA), 7.44-7.48, 7.85-7.89, 8.20-8.23, 8.57-8.59 (m, m, m, m, 1H, 2H, 1H, 1H, pyridyl, NHB); 13C NMR (100 MHz, CDCl3): δ 122.4, 126.5, 137.3, 148.3, 149.6, 167.0; IR (KBr, vmax/cm-1) = 3417 (CONH), 3182 (CONH), 1662 (CON); HRMS (ESI-TOF): Calcd for C6H6N2ONa (M+Na)+: 145.0372, found: 145.0370. |
86% | With magnesium(II) nitrate hexahydrate; urea In octane at 120℃; for 24h; | |
68.8% | With ammonium carbonate; ortho-tungstic acid; zinc(II) oxide In N,N,N,N,N,N-hexamethylphosphoric triamide at 140℃; for 8h; | 8 Example 8 In the reactor, add 12.3g, 0.1mol pyridine-2-carboxylic acid, add 38.4g, 0.4mol ammonium carbonate, 0.8g, 10mmol zinc oxide, 1.25g, 5mmol tungstic acid, 200ml HMPA, heat to 140 degrees, stir React for 8 hours. Filtration with suction and rotary evaporation under reduced pressure to remove the solvent to obtain 13.7 g of crude pyridine-2-carboxamide as a pale yellow product. The crude product was recrystallized by heating and refluxing with 30 ml of ethanol to obtain 8.4 g of white crystals with a yield of 68.8%. |
56% | With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | |
With ammonia; dicyclohexyl-carbodiimide | ||
Multi-step reaction with 2 steps 1: 2.8 g / thionyl chloride / 40 h / Ambient temperature 2: concd. aqueous ammonia / H2O / 1 h | ||
Multi-step reaction with 2 steps 1: SOCl2 / 1 h / Heating 2: 25percent NH4OH | ||
With ammonium hydroxide; 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 5 h / 0 - 20 °C / Inert atmosphere; Sealed tube 2: ammonia / chloroform / 5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; water; In ethanol; at 20℃; for 15h; | To a solution of pyridine-2-carboxamide (1.2 eq, 3.4 mmol, 0.41 g) in H2O (1.4 ml) and NaOH (1.5 eq, 4.3 mmol, 0.17 g), is added a solution of <strong>[6283-81-4]3-oxo-3-pyridin-3-yl-propionic acid ethyl ester</strong> (1eq, 2.85 mmol, 0.55 g) in EtOH (1.7 ml) at room temperature. The reaction is left to stir for 15 hours. The reaction solvent was removed under reduced pressure to give a solid residue. The crude product is purified by flash chromatography (DCM / MeOH 100:0 to 0:100) to afford 6-pyridin-3-yl-2-pyridin-2-yl-3H-pyrimidin-4-one as a white solid; MH+= 251 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In N,N-dimethyl-formamide at 20℃; for 10h; | |
64% | With tetrabutyl ammonium fluoride; copper diacetate In 1,4-dioxane; N,N-dimethyl-formamide at 20 - 25℃; for 10h; | Vinylation of Amides 1-8 [14] (General Method) General procedure: A 1 M solution of TBAF (2 ml, 2 mmol) in dioxane was added to a solution of aryl(hetaryl)carboxamide (1 mmol), copper(II) acetate (1 mmol) and vinyltrimethoxysilane (2 mmol) in the appropriate solvent. The reaction mixture was stirred at 20-25 °C. After evaporating the solvent in vacuum, pure compound was obtained by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 48h; | General procedure for conversion of aldehydes to primary amides General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO-H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data. |
93% | With [Ru(L1)Cl(CO)(PPh3)2]; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 12h; Inert atmosphere; Reflux; | 2.4 Representative procedure for the rearrangement of aldehydes to amides General procedure: Conversion of aldehydes to amides was carried out using the procedure described in the literature [34]. Under nitrogen atmosphere, the corresponding aldehyde (1mmol), NH2OH·HCl (1mmol), NaHCO3 (1mmol), toluene (3mL) and ruthenium(II) catalyst 1 (0.01mmol) were introduced into a RB flask, and the reaction mixture was stirred at 120°C in an oil bath for 12h. After the completion of reaction, 2-3mL of MeOH was added to the reaction mixture. The catalyst and NaHCO3 which settled down the flask was removed by filtration through Celite. The filtrate has been dried and the crude product was purified by the use of column chromatography (MeOH/CH2Cl2). Finally, the isolated amide was characterized by the aid of 1H NMR. |
89% | With hydroxylamine hydrochloride; C21H27ClIrNO; sodium hydrogencarbonate In water at 50℃; for 6h; |
86% | With hydroxylamine hydrochloride In water at 120℃; for 7h; Reflux; | |
85% | With hydroxylamine hydrochloride; C27H27ClIrNO; sodium hydrogencarbonate In dimethyl sulfoxide at 50℃; for 6h; | |
75% | With ammonia; water at 120℃; Autoclave; | |
73% | With hydroxylamine hydrochloride; C30H30ClNO2Ru; sodium hydrogencarbonate In acetonitrile for 7h; Reflux; Inert atmosphere; | 4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: The reaction mixture containing complex catalyst 2 (1 mol%),the aldehyde (1 mmol), NH2OHHCl (1 mmol) and NaHCO3(1 mmol) in 5 mL of acetonitrile was refluxed for the time specifiedunder an N2 atmosphere. Then, the resulting was cooled to roomtemperature and the solvent was evaporated. The residue obtainedwas dissolved in CH2Cl2 and the solvent was removed. The crudeproduct was then purified using silica gel chromatography usingCHCl3/MeOH as an eluent. |
72% | Stage #1: pyridine-2-carbaldehyde With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 100℃; Stage #2: With palladium diacetate In water; dimethyl sulfoxide at 100℃; for 20h; chemoselective reaction; | |
72% | With hydroxylamine In water at 110℃; for 12h; | 2.4. General procedure for the synthesis of amides from aldehydes General procedure: Aldehyde (1 mmol), hydroxylamine (1 mmol), polymer supported-Cu (II) catalyst (30 mg-10 mg) and solvent (2 m/L) were added in a 10 mL round bottom flask and the reaction mixture was stirred at 110 °C. The progress of the reaction was by TLC. The crude product obtained was purified by column chromatography with ethyl acetate:hexane as 1:5 eluent system. |
72% | With hydroxylamine In water at 110℃; for 12h; | 2.4. General procedure for the synthesis of amides from aldehydes General procedure: Aldehyde (1 mmol), hydroxyl amine (1 mmol), polymer supported-Cu (II) catalyst (30 mg-10 mg) and solvent (2 m/L) were added in a 10 mL round bottom flask and the reaction mixture was stirred at110 °C. The progress of the reaction was by TLC. The crude product obtained was purified by column chromatography with ethyl acetate:hexane as 1:5 eluent system. |
72% | With C29H29ClN2ORu; hydroxylamine hydrochloride; sodium hydrogencarbonate In acetonitrile at 78℃; for 5h; Inert atmosphere; | 4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: To an oven-dried round-bottom flask equipped with magneticstirring bar was added complex (1) (1 mol%), the aldehyde(1 mmol), NH2OHHCl (1 mmol) and NaHCO3 (1 mmol) and themixture was placed under an atmosphere of N2. Dry and degassedMeCN (2 mL) was added and the reaction mixture was refluxed forthe time specified under an N2 atmosphere. The reaction wascooled to room temperature and the solvent evaporated. The residuewas dissolved in CH2Cl2, filtered and the solvent removed. Thecrude product was then purified using silica gel chromatography(CHCl3/MeOH) giving the amides in high isolated yields. Characterizationdetails for each amide are given in the supporting informationS16-S20. |
70% | With hydroxylamine hydrochloride; C59H50ClN2OP2Ru; sodium hydrogencarbonate In acetonitrile for 5h; Inert atmosphere; Reflux; | 2.4. General procedure for the conversion of aldehyde to amide General procedure: The reaction vessel was equipped with magnetic stirring bar, complex catalyst(1 mol%), aldehyde (1 mmol), NH2OHHCl(1 mmol) and NaHCO3 (1 mmol) was taken and the mixture was placed under an atmosphere of N2. Dry and degassed acetonitrile(3 mL) was added and the reaction mixture was refluxed for 5 h.The reaction mixture was then cooled to room temperature and the solvent was evaporated. The residue was dissolved in CH2Cl2,filtered and the solvent was removed. The amide was then purified using column chromatography, which gives the amide in high isolated yield. The products were confirmed by1H NMR spectra. |
39% | With tert.-butylhydroperoxide; tetraethylammonium iodide; ammonium bicarbonate In 1,2-dichloro-ethane at 70℃; for 22h; | |
25% | With tert.-butylhydroperoxide; titanium superoxide; saccharin In 1,4-dioxane; hexane at 90℃; for 1h; Green chemistry; | |
94 %Chromat. | With ammonia; water; oxygen In 1,4-dioxane at 130℃; for 1h; Autoclave; | |
94 %Chromat. | With ammonium hydroxide; cryptomelane; oxygen In 1,4-dioxane at 130℃; for 1h; Autoclave; Green chemistry; | |
With C33H27ClN3OPRu; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 20 - 110℃; for 8.25h; Inert atmosphere; Schlenk technique; | 2.7 Representative procedure for ruthenium-catalyzedaldehydes to amides conversion General procedure: The reaction vessel was charged with aldehyde (1mmol), NH2OH·HCl (1 mmol), NaHCO3 (1 mmol),[Ru-NHC] catalyst (0.5 mol %) and the mixture wasplaced under an atmosphere of N2. About 2 mL of dryand degassed toluene was added and the mixture wasstirred for 15 min at room temperature followed byreflux for 8 h. On completion of the reaction, 2-3 mLmethanol was added to the mixture followed by filtrationthrough Celite to remove the catalyst and NaHCO3.The crude product was then purified by column chromatography(MeOH/CH2Cl2, 1:1) using silica (200-400 mesh) as solid phase provided the amide in goodyield. The resultant amide solution was subjected to GCanalysis and the product was identified in comparisonwith authentic samples | |
84 %Chromat. | Stage #1: pyridine-2-carbaldehyde With hydroxylamine hydrochloride; sodium hydrogencarbonate In water Stage #2: In water at 100℃; for 10h; | |
95 %Chromat. | With C23H27Cl2N3Rh(1+)*C24H20B(1-); hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 110℃; for 2h; Inert atmosphere; Schlenk technique; | 4.3. General procedure for the catalytic transformation of aldehydeto amide General procedure: Compound 3 (0.002 mmol), the aldehyde (1 mmol), NH2OHHCl(1 mmol) and NaHCO3 (1 mmol) were introduced in a dried schlenktube and purged with N2. Then, to the mixture, dried and degassedtoluene (2 ml) was added and the mixture was stirred for about10 min at room temperature, before the solution was refluxed understirring for 2 h. The mixture was cooled and the products wereextracted with methanol and dichloromethane before beingfiltered through celite to remove the remaining catalyst andNaHCO3. The crude amide was purified using column chromatography,and dried under vacuum. |
96 %Chromat. | With hydroxylamine hydrochloride; C27H26Cl2NORh; sodium hydrogencarbonate In water at 39.84℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; Schlenk tube; | 2 Synthesis of Cp*RhCl(2-picolinamide) complex (Rh-1) Example 2 Synthesis of Cp*RhCl(2-picolinamide) complex (Rh-1) 150 mg (0.243 mmol) of [Cp*RhCl2]2 (MW: 618.08) and 59 mg (0.485 mmol) of 2-picolinamide (MW: 122.12) were introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. 5 mL of dehydrated methylene chloride and 71 μL (0.509 mmol) of triethylamine (MW: 101.19) were added and the mixture was stirred at room temperature for 1 hr. Then 10 mL of methylene chloride was added, the resulting solution was washed twice with a small amount of water, and solvent in the organic layer was distilled away, and it was dried under reduced pressure to give 164 mg of orange powder crystal (86% isolated yield). 1H-NMR (400 MHz, CDCl3, δ/ppm): 1.72 (s, 15H), 5.45 (brs, 1H), 7.48-7.55 (m, 1H), 7.88-7.96 (m, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H) 13C-NMR (100 MHz, CDCl3, δ/ppm): 9.1, 94.0, 94.1, 125.6, 126.9, 138.8, 149.8, 155.6, 155.7, 170.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; Schlenk tube; | Example 6; Synthesis of Cp*IrCl(2-picolinamide) complex (Ir-1); 100 mg (0.126 mmol) of [Cp*IrCl2]2 (MW: 796.67) and 30.7 mg (0.251 mmol) of 2-picolinamide (MW: 122.12) were introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. 4 mL of dehydrated methylene chloride and 35 muL (0.25 mmol) of triethylamine (MW: 101.19) were added and the mixture was stirred at room temperature for 1 hr. Then 10 mL of methylene chloride was added, the resulting solution was washed twice with a small amount of water, and solvent in the organic layer was distilled away, then it was dried under reduced pressure to give 103 mg of orange powder crystal (85% isolated yield).1H-NMR (400 MHz, CDCl3, delta/ppm): 1.73 (s, 15H), 6.02 (brs, 1H), 7.47 (ddd, J=7.3, 5.5, 0.9 Hz, 1H), 7.92 (ddd, J=7.8, 7.3, 1.4 Hz, 1H), 8.08 (dd, J=7.8, 0.9 Hz, 1H), 8.56 (dd, J=5.0, 1.4 Hz, 1H)13C-NMR (100 MHz, CDCl3, delta/ppm): 9.0, 86.0, 126.0, 127.4, 138.7, 150.1, 154.5, 172.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 150℃; for 1h; | 56.A The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (500 mg, 1.8 mmol) and pyridine 2-carboxamide (551 mg, 4.51 mmol) was heated to 150° C. for 1 hour. Then the reaction mixture was cooled, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice, and the combined organic layers were washed with water and brine, dried over MgSO4. After concentration, the solid residue was dissolved in methanol and subject to mass-directed HPLC purification to give 21 mg of 2-{4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine. LCMS: m/z 301.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tert.-butylhydroperoxide; ammonia; oxygen In water monomer; N,N-dimethyl-formamide at 80℃; for 5h; Green chemistry; | |
70% | With tert.-butylhydroperoxide; ammonium hydroxide In water monomer at 100℃; for 16h; | |
95 %Chromat. | With ammonia; water monomer; oxygen In 1,4-dioxane at 130℃; for 1h; Autoclave; |
95 %Chromat. | With ammonium hydroxide; cryptomelane; oxygen In 1,4-dioxane at 130℃; for 1h; Autoclave; Green chemistry; | |
77 %Chromat. | With ammonium acetate; oxygen In tert-Amyl alcohol at 130℃; for 18h; Autoclave; | |
With oxygen; urea In acetonitrile at 120℃; for 6h; Autoclave; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With C31H29Br2N3Ru; potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 70℃; for 24h; | |
88% | With potassium <i>tert</i>-butylate; C36H24N2O12Ru3 In <i>tert</i>-butyl alcohol for 10h; Reflux; | |
75% | With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In water at 85℃; for 8h; Green chemistry; | General procedure for the allylic/benzylic oxidation and oxidation of benzylamines General procedure: Water (1.0 mL), substrate (1 mmol), TBAI (0.25 equiv.) and TBHP (5 equiv.) were added to a 20-mL test tube and the mixture was stirred at 85 °C for 8 h. After completion of the reaction, ethyl acetate (5 mL) was added for quenching. The aqueous layer was extracted with ethyl acetate (3 * 10 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product mixture was purified by flash column chromatography (EtOAc/Hexanes gradient). |
72% | With tetra(n-butyl)ammonium hydroxide In water at 70℃; for 12h; Green chemistry; | |
71% | With (carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II); potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 70℃; for 12h; | |
61% | With tert.-butylhydroperoxide; zinc dibromide In pyridine; water at 80℃; for 16h; | |
57% | With fluorenone imine; oxygen In toluene for 12h; Reflux; | |
65 %Chromat. | With ammonia In 1,4-dioxane; water at 130℃; for 3h; Autoclave; | |
With manganese(IV) oxide; oxygen In dichloromethane at 180℃; for 24h; | 37 Example 37 300 mg of manganese dioxide was added to 6 g of dichloromethane.60 mg 2-aminomethylpyridine (mass concentration in the mixture: 1%),Mix well; charge 2MPa oxygen, react at 180 °C for 24 hours,2-aminomethylpyridine conversion rate of 88.5%, correspondingThe selectivity of 2-pyridinecarboxamide was 97.1%. | |
70.9 %Chromat. | With oxygen In tert-Amyl alcohol; water at 130℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sulfuric acid In N,N-dimethyl-formamide at 100℃; for 0.05h; Microwave irradiation; | 4.2. Typical procedure for the synthesis of N-acylation of amide derivatives General procedure: Amide derivatives (1.0 mmol), acid anhydrides (3.0 mmol), and 2 drops of concd H2SO4 were placed in a 50 mL round bottom flask equipped with a reflux condenser. The reaction flask was microwave irradiated (50 W, 100 °C) for 3 min with stirring. After the reaction, the solution was extracted with ethyl acetate (2×10 mL), and the combined organic layer was washed with 5% aq NaHCO3 (2×10 mL), and brine (20 mL), dried over anhydrous MgSO4, and evaporated to provide the crude material. The crude material was purified by flash column chromatography using various hexane/ethyl acetate eluent systems to afford the desired products 1a-22a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Fe3+ exchanged montmorillonite K-10 In neat (no solvent) at 140℃; for 30h; Inert atmosphere; | General procedure: A typical procedure for transamidation of benzamide with n-octylamineis as follows. Fe-mont (121.4mg, 1.0 mol% Fe-mont with respect to benzamide) was added to the mixture of benzamide (1.0 mmol), n-octylamine (1.1 mmol) in a reaction vessel equipped with a condenser under N2. The resulting mixture was vigorously stirred at 140 °C. The reaction mixture was analyzed by GC.Conversion and yield of the products were determined based on benzamide and n-octyl benzamide using dodecane as an internal standard. After completion of the reaction, acetone (2 g) was added to the mixture, and then the Fe-mont catalyst was separated by centrifugation. The crude product was isolated by column chromatography and the resulting product was identified by GCMS, 1H-NMR and 13C-NMR analyses. |
84% | With cerium(IV) oxide at 160℃; for 24h; Inert atmosphere; Neat (no solvent); | |
With cerium(IV) oxide; water at 160℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hexafluorophosphate; aluminium(III) triflate In nitromethane at 50℃; for 2h; Microwave irradiation; | |
81% | With 3-tetradecyl-1-(4-sulfobutyl)imidazolium trifluoromethanesulfonate In 1,4-dioxane at 120℃; for 24h; | |
81% | With [BsTdmim]OTf In 1,4-dioxane at 120℃; for 3h; | 73 Embodiment 73 Embodiment 73Under 120 °C , the pyridineamide (0.75mmol, 91.5 mg) (E) - 1,3-diphenyl-2-propen-1-ol (0.5mmol, 105.0 mg) and [BsTdmim]OTf (10mol %, 27.5 mg) 1,4-dioxane 2.0 ml is placed in a dry reaction flask, magnetic stirring reaction for 3h. After the completion of the reaction separation was done using column chromatography (by silica gel column, eluent: petroleum ether/ethyl acetate = 5/1), to obtain white solid (E)-N-(1,3-diphenylallyl)pyridineamide 27.2 mg, yield is 81% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With caesium carbonate In toluene at 140℃; for 2h; Microwave irradiation; | 6.1 Example 6-1 : Preparation of N-{3-[4-(cyclopropylcarbamoyl)phenyl]-8-[(2- methylpropyl)amino]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-2-carboxamide To a solution of 100 mg (0.23 mmol) 4-{6-bromo-8-[(2- methylpropyl)amino]imidazo[1 ,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide in 2 mL toluene were added 88 mg (0.7 mmol) pyridine-2-carboxamide, 76 mg (0.23 mmol) caesium carbonate, 8.4 mg (0.01 mmol) 1 E,4E)-1 , 5-diphenylpenta-1 ,4-dien-3-one - palladium (3:2) and 10.8 mg (0.02 mmol) (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the mixture was heated at 140 C for 2 h in a microwave tube. The mixture was filtered and purified by HPLC to yield 32 mg (28 %) of the title compound. UPLC-MS: RT = 1 .32 min; m/z (ES+) 470.5 [MhT]; required MW = 469.5. 1H-NMR (300 MHz, d6-DMSO): δ = 9.88 (1 H, s), 8.76 (1 H, s), 8.73 (1 H, d), 8.56 (1 H, d), 8.13 - 8.04 (2H, m), 7.99 (2H, d), 7.88 (1 H, t), 7.76 (1 H, s), 7.72 (1 H, d), 7.69 (1 H, m), 3.31 (2H, t), 2.87 (1 H, m), 2.06 (1 H, m), 0.92 (2H, d), 0.69 (2H, m), 0.55 (2H, m) ppm |
28% | With tris(dibenzylideneacetone)dipalladium (0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 140℃; for 2h; Microwave irradiation; | 6.1 Preparation of N-{3-[4-(cyclopropylcarbamoyl)phenyl]-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-6-yl}pyridine-2-carboxamide To a solution of 100 mg (0.23 mmol) 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide in 2 mL toluene were added 88 mg (0.7 mmol) pyridine-2-carboxamide, 76 mg (0.23 mmol) caesium carbonate, 8.4 mg (0.01 mmol) 1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) and 10.8 mg (0.02 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and the mixture was heated at 140° C. for 2 h in a microwave tube. The mixture was filtered and purified by HPLC to yield 32 mg (28%) of the title compound. UPLC-MS: RT=1.32 min; m/z (ES+) 470.5 [MH+]; required MW=469.5. 1H-NMR (300 MHz, d6-DMSO): δ=9.88 (1H, s), 8.76 (1H, s), 8.73 (1H, d), 8.56 (1H, d), 8.13-8.04 (2H, m), 7.99 (2H, d), 7.88 (1H, t), 7.76 (1H, s), 7.72 (1H, d), 7.69 (1H, m), 3.31 (2H, t), 2.87 (1H, m), 2.06 (1H, m), 0.92 (2H, d), 0.69 (2H, m), 0.55 (2H, m) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With nanosized zeolite beta In neat (no solvent) at 135℃; for 24h; | |
96% | With graphene oxide In neat (no solvent) at 130℃; for 15h; Sealed tube; | |
86% | With zirconocene dichloride In cyclohexane at 80℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,4-di-tert-butyl-1,4-diazabutadiene; In tetrahydrofuran; at 20℃; for 15h;Schlenk technique; Inert atmosphere; | TPA=N-C(O)-2-NC5H4 (N,N-IM) (1) TPA (0.157 g, 1.0 mmol) and picolinamide (0.122 g, 1.0 mmol) were placed in a Schlenk flask under nitrogen. Dry, degassed THF tetrahydrofuran (15 mL) was added and to this solution, tBuDAD N,N-bis(tert-butyl)1,4-diazabutadiene (0.230 g, 1.0 mmol) in dry and degassed THF (4 mL) was added dropwise at 0 C. The reaction was left stirring at RT for 15 h. After this period, the yellow reaction mixture was colourless with some white precipitate. The solvent was reduced in vacuo to a minimum (< 2 mL) and Et2O (10 mL) was added, giving a white solid that was filtered and dried in vacuo. Yield: 0.254 g (93%). Anal. Calcd for C12H16N5OP (277.11): C, 51.98; H, 5.82; N, 25.26. Found: C, 51.76; H, 5.79; N, 25.24. MS (ESI+) [m/z]: 278.12 [M]+. 31P{1H} NMR: δ - 29.4 (s, CDCl3), - 31.4 (s, DMSO-d6), - 24.8 (s, D2O). 1H NMR (CDCl3): δ 8.68 (1H, d, 3JHH 4 Hz, NCH), 8.10 (1H, d, 3JHH 8 Hz, C(O)CCH), 7.75 (1H, t, 3JHH 8 Hz, C(O)CCHCH), 7.37 (1H, t, 3JHH 7 Hz, NCHCH), 4.35 (6H, d, 2JPH 8 Hz, PCH2N), 4.42 (AB system, 6H, NCH2N). 13C{1H} NMR (CDCl3): δ 177.7 (s, C═O), 152.0 (s, C(O)C(N)(CH)), 149.1 (s, NCH), 136.7 (s, C(O)CCHCH), 125.4 (s, NCHCH), 123.5 (s, C(O)CCH), 72.8 (d, JPC 9 Hz, NCH2N), 52.7 (d, JPC 46 Hz, PCH2N). IR (cm- 1): ν 1582 (C═O), 1360 (P═N). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With MCM-41 mesoporous silica; In ethanol; water; at 80 - 90℃; for 9h;Green chemistry; | General procedure: In a typical reaction a solution of amide (1 mmol), rhodanine (1.2 mmol) and Morpholine (1.2 mmol) in EtOH/water (2 + 2 ml) were refluxed at 80-90 C till completion using 40 mg of MCM-41 catalyst. The completion of the reaction was indicated by the disappearance of the starting material in thin layer chromatography. After completion of the reaction the solvent was evaporated in a rotary evaporator and the crude product was taken in dichloromethane and filtered to separate the products as filtrate from the catalyst (residue). Then the crude product was purified by silica gel column chromatography where the compound (5) came out from the column with 25%EtOAc/75% petroleum ether, but thioamide (4) came out with 65%EtOAc/35% petroleum ether making their separation easy. The thioamides (4) were characterized by IR, 1H NMR, 13C NMR, CHN and X-ray single crystal analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1,4-diaza-bicyclo[2.2.2]octane; N-methoxylamine hydrochloride; sodium iodide; palladium dichloride In acetonitrile at 90℃; for 8h; Autoclave; Inert atmosphere; | Aminocarbonylation of Aryl and Heteroaryl Iodides;General Procedure General procedure: To an autoclave (100 mL capacity), were added an arylhalide (1 mmol), methoxylamine hydrochloride (1.2 equiv),DABCO (2 equiv), PdCl2 (10 mol%), NaI (0.2 mmol) and MeCN (15 mL), under an inert atm. The autoclave was flushed three times with CO and then pressurized to 5 atm of CO. The mixture was stirred with a mechanical stirrer (550rpm) at 90 °C for 8 h. The reactor was cooled to r.t., degassed carefully, opened and the reaction mixture removed. The reactor vessel was washed with EtOAc (2 × 5 mL) to remove residual product. The mixture was filtered and the filtrate washed with brine (2 × 4 mL), dried over Na2SO4, filtered and the solvent evaporated under vacuum. Purification of the residue was carried out by column chromatography (silicagel, 100-200 mesh, PE-EtOAc) to afford the corresponding product in good to excellent yield. |
72% | With 1,4-diaza-bicyclo[2.2.2]octane; palladium 10% on activated carbon; ammonium carbamate; potassium iodide In acetonitrile at 90℃; for 8h; Autoclave; Green chemistry; | |
> 99 %Chromat. | With dichloro bis(acetonitrile) palladium(II); ammonium bicarbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In acetonitrile at 120℃; for 3h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 50℃; for 24h; Inert atmosphere; Darkness; | 1.XI XI) 2-carbamoyl-1-{3-[7,8-dimethyl-2,4-dioxo-10-butyl-4,10-dihydro-2H-benzo[g]pteridin-3-yl]propyl}pyridinium iodide (73) XI) 2-carbamoyl-1-{3-[7,8-dimethyl-2,4-dioxo-10-butyl-4,10-dihydro-2H-benzo[g]pteridin-3-yl]propyl}pyridinium iodide (73) 3-(10-Butyl-7,8-dimethyl-2,4-dioxo-4,10-dihydro-2H-benzo[g]pteridin-3-yl)propyl iodide (80) (0.51 g, 1.05 mmol) was stirred with nicotinamide (146 mg, 1.2 mmol) and NaHCO3 (0.1 g, 1.2 mmol) in DMF (10 mL) in a nitrogen atmosphere in the dark at 50° C. for 24 h. The solvent was drawn off under reduced pressure and the residue was purified by preparative thin-layer chromatography (CHCl3/MeOH 6:1). 276 mg of orange solid (0.47 mmol, 46% of theory) were obtained. 1H NMR (300 MHz, DMSO): δ [ppm]=0.91 (t, 3H), 1.43 (m, 2H), 1.72 (m, 2H), 2.31 (m, 2H), 2.41 (s, 3H), 2.58 (s, 3H), 4.02 (m, 2H), 4.63 (m, 2H), 4.71 (m, 2H), 5.31 (s, 2H), 7.86 (s, 1H), 7.95 (m, 1H), 8.18 (s, 1H), 8.51 (s, 1H), 8.94 (d, J=5.6 Hz, 1H), 9.23 (d, J=5.6 Hz, 1H), 9.52 (m, 1H); -MS (ESI-MS, H2O/MeOH+0.1% TFA): m/z (%)=461.1 (100, (M+)); -MW=461.55+126.90 -MF=C25H29N6O3I |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonia; oxygen at 200℃; for 0.5h; Autoclave; | 1.2; 5.2 (2) Preparation of 2-pyridinecarboxamide: Weigh 0.1g porous carbon material, 0.5g 2-picoline, 0.5g ammonia, add it to the autoclave, blow in oxygen for 3 times, and fill with oxygen to 0.1 MPa. The temperature was raised to 200° C., and the reaction was carried out for 0.5 hours; after the reaction was completed, it was cooled to room temperature; the reaction solution was analyzed by gas chromatography, and the yield of 2-picolinamide was 87%. |
55% | With tert.-butylhydroperoxide; iron(III) chloride hexahydrate; tetrabutylammonium iodide; ammonium hydroxide In water at 80℃; for 18h; Sealed tube; | |
48% | With ammonium acetate; oxygen; copper(I) bromide In 1,4-dioxane at 130℃; for 24h; Sealed tube; |
89 %Chromat. | With oxygen; urea In water at 140℃; for 4h; Autoclave; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In methanol at 20℃; for 1h; | [Cu(HL)2(H2O)2]Cl2 (1) 10mL solution of CuCl2·6H2O (1 mmol, 0.24 g) in methanol was added dropwiseto a methanolic solution (25 mL) of pyridine 2-carboxamide(HL,2 mmol, 0.23 g) with stirring at room temperature.The stirring was continued for 1 h, during whichtime a light blue compound was separated out. The productwas filtered off and recrystallized from methanol.Yield 0.35 g (85%). Anal. Calcd. for C12H16CuCl2N4O4:C, 34.92; H, 3.99; N, 13.36. Found: C, 34.75; H, 3.89;N, 13.51. FT-IR (KBr, /cm.1) 3448(s), 3269(s, br),3078(s,br),1666(s),1568(s),1438(s),1309(w),1278(w),1126(m), 1033(m), 783(m), 761(m), 657(m), 503(m).UV-Vis (in MeOH) [max, nm (/M.1 cm.1)]: 756 (86). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In chloroform; at 60.0℃; for 16.0h; | 2.2.2 Bn-Pyox (1a) 2-Pyridinecarboxyimidate (0.523 g, 3.48 mmol) and l-phenylalaninol (0.527 g, 3.48 mmol) in CHCl3 (15 ml) were heated at 60 C for 16 h. The organic solution was washed with water (2 * 30 ml), brine (10% w/v, 30 ml) and dried over Na2SO4. After filtering, the solvent was removed under reduced pressure to give the product as an off-white solid. Yield = 0.739 g (89%). 1H NMR (400.1 MHz, CDCl3, 293 K) δ = 8.62 (1H, d, 3JHH = 5.9 Hz, pyH), 7.97 (1H, d, 3JHH = 7.9 Hz, pyH), 7.60 (1H, dd, 3JHH = 7.9 and 5.9 Hz, pyH), 7.30 (1H, m, pyH), 7.26-7.06 (5H, m, PhH), 4.58 (1H, m, CHBn), 4.36 (1H, app. t, app. JHH = 9.0 Hz, CHHO), 4.13 (1H, app. t, app. JHH = 8.1 Hz, CHHO), 3.32 (1H, dd, 2JHH = 13.2 Hz, 3JHH = 5.1 Hz, CHHPh), 2.56 (1H, dd, 2JHH = 13.0 Hz, 3JHH = 5.2 Hz, CHHPh) ppm. ES-MS: m/z (%) = 239.13 (100) [Bn-Pyox+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In chloroform at 60℃; for 16h; | 3 Ph-Pyox (1b) 2.2.3 Ph-Pyox (1b) Prepared similarly from 2-pyridinecarboxyimidate (0.508 g, 3.38 mmol) and d-phenylglycinol (0.464 g, 3.38 mmol). Yield = 0.728 (96%). 1H NMR (400.1 MHz, CDCl3, 293 K) δ = 8.67 (1H, d, 3JHH = 6.0 Hz, pyH), 8.08 (1H, d, 3JHH = 7.9 Hz, pyH), 7.71 (1H, app. t, 3JHH = 7.9 Hz, pyH), 7.36 (1H, m, pyH), 7.30-7.18 (5H, m, PhH), 5.38 (1H, app. t, app. 3JHH = 8.6 Hz, CHPh), 4.81 (1H, app. t, app. JHH = 8.6 Hz, CHHO), 4.30 (1H, app. t, app. JHH = 8.5 Hz, CHHO) ppm. ES-MS: m/z (%) = 225.10 (100) [Ph-Pyox+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In chloroform at 60℃; for 16h; | 4 iPr-Pyox (1c) 2.2.4 iPr-Pyox (1c) Prepared similarly from 2-pyridinecarboxyimidate (0.524 g, 3.49 mmol) and l-valinol (0.360 g, 3.49 mmol). Yield = 0.604 g (91%). 1H NMR (400.1 MHz, CDCl3, 293 K) δ = 8.65 (1H, d, 3JHH = 5.8 Hz, pyH), 8.03 (1H, d, 3JHH = 7.9 Hz, pyH), 7.72 (1H, app. t, 3JHH = 7.8 Hz, pyH), 7.33 (1H, m, pyH), 4.46 (1H, app. t, 3JHH = 8.0 Hz, CHiPr), 4.18-4.04 (2H, m, CH2O), 1.85 {1H, sept, 3JHH = 6.8 Hz, CH(CH3)2}, 1.00 {3H, d, 3JHH = 6.8 Hz, CH(CH3)(CH3)}, 0.89 (3H, d, 3JHH = 6.8 Hz, CH(CH3)(CH3)} ppm. ES-MS: m/z (%) = 191.12 (100) [iPr-Pyox+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: <i>N</i>-methyl-acetamide With oxalyl dichloride In dichloromethane at 0℃; for 0.5h; Stage #2: pyridine-2-carboxylic acid amide In dichloromethane at 20℃; for 3h; | 4.2. Synthesis of L1 (4,5-dimethy-2-(pyridine-2-yl)imidazole) The synthetic routes of the ligand L1 are illustrated inScheme S1 [16]. 1 ml oxalylchloride (10 mmol) was added dropwiseto a CH2Cl2 solution (100 ml) with 1.5 g N-methylacetamide(20 mmol) at 0 C under heavy gas evolution. After stirred for about30 min, 2-pyridine carboxamide (2.74 g, 10 mmol) was added. Theobtained mixture was stirred for 3 h at rt, and the volatiles wereremoved under reduced pressure. The residue was dissolved inan aqueous solution of NaHCO3 (60 ml) and refluxed for a further2 h at 100 C. The water phase was extracted three times withCHCl3. The organic phase was concentrated and re-crystallizedfrom MeOH gave the ligand L1. Yield: 1.14 g, ca. 78%. M.p. 116-118 C. Elemental analysis (%) for L (C10H11N3): Calc.: C, 69.34; H,6.40; N, 24.25; found: C, 69.27; H, 6.44; N, 24.19%. IR (KBr,cm1): 3048, 2980, 2180, 1750, 1560, 1562, 1533, 1482, 1340,1269, 1235, 1120, 1040, 1015, 987, 960, 798, 747, 721. 1H NMRd: 2.67-2.75 (d, 6H), 7.36 (m, H), 7.85 (m, 1H), 8.38 (d, 1H), 8.59(d, 1H), 13.00 (s, 1H). 13C NMR d: 12.6, 43.5, 124.5, 125.6, 131.6,137.2, 143.4, 149.2, 155.1, 165.9. |
78% | Stage #1: <i>N</i>-methyl-acetamide With oxalyl dichloride In dichloromethane at 0℃; Stage #2: pyridine-2-carboxylic acid amide In dichloromethane at 20℃; for 3h; | Synthesis of L2 (4,5-dimethy-2-(pyridine-2-yl)imidazole) The synthetic routes of the ligand L2 are illustrated in Scheme 1 [28]. 1ml oxalylchloride (10mmol) was added dropwise to a CH2Cl2 solution (100ml) with 1.5gN-methylacetamide (20mmol) at 0°C under heavy gas evolution. After stirred for about 30min, 2-pyridine carboxamide (2.74g, 10mmol) was added. The obtained mixture was stirred for 3h at rt, and the volatiles were removed under reduced pressure. The residue was dissolved in an aqueous solution of NaHCO3 (60ml) and refluxed for a further 2h at 100°C. The water phase was extracted three times with CHCl3. The organic phase was concentrated and re-crystallized from MeOH gave the ligand L2. Yield: 1.14g, ca. 78%. Elemental analysis (%) for L2 (C10H11N3): Calc.: C, 69.34; H, 6.40; N, 24.25; found: C, 69.27; H, 6.44; N, 24.19%. IR (KBr, cm1): 3048, 2980, 2180, 1750, 1560, 1562, 1533, 1482, 1340, 1269, 1235, 1120, 1040, 1015, 987, 960, 798, 747, 721. 1H NMR d: 2.67-2.75 (d, 6H), 7.36 (m, H), 7.85 (m, 1H), 8.38 (d, 1H), 8.59 (d, 1H), 13.00 (s, 1H). 13C NMR d: 12.6, 43.5, 124.5, 125.6, 131.6, 137.2, 143.4, 149.2, 155.1, 165.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydrogencarbonate at 190℃; for 48h; Autoclave; High pressure; | (UO2)(OH)(Pic) (1) General procedure: Uranyl nitrate (1.0 mL, 0.5 M), picolinamide(2.0 mL, 0.5 M), NaHCO3 (0.5 mL, 0.25 M) solutions and 5.0 mLdeionized (DI) water were added in a 120 mL Teflon container,sealed in a stainless steel pressure Parr vessel and left in a 190 Coven for 48 h. A yellow crystalline product of 1 was formed afterslow cooling (5 C/h) to room temperature in a light yellow solution(pHf = 4.0) with 70% yield (72 mg) based on U content. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dipotassium peroxodisulfate; oxygen; sodium formate; silver nitrate In water at 80℃; for 4h; 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 |
94% | With dipotassium peroxodisulfate; oxygen; sodium acetate; silver nitrate In water at 80℃; for 4h; Green chemistry; | 1 Example 1 Compound 1: Under oxygen atmosphere, to a 25 ml reaction flask are sequentially added silver nitrate (0.1mmol), pyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 ml) and water (0.4 ml). The mixture at 80 °C react for 4h. Cooling to room temperature, reducing pressure and evaporating the solvent column chromatography separation to obtain the product, yield 94%. |
79% | With dipotassium peroxodisulfate at 70℃; for 12h; regioselective reaction; | General experimental procedure for the synthesis Primary 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), formamide 2a (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 3aa as a white crystalline solid (122 mg, 79% yield) Picolinamide (3aa): m.p.: 109-111 °C. IR (neat) cm-1: 3417, 3169,1659, 1584, 1389. 1H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.90 - 7.82 (m, 2H), 7.45 - 7.41(m, 1H), 6.38 (s, 1H). 13C NMR (100 MHz, CDCl 3 ) δ 167.2, 149.6, 148.4, 137.5, 126.6, 122.5. HRMS (ESI TOF) m/z calcd for C 6 H 6 N 2 O [M + H]+ 123.0558, found 123.0564. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: pyridine-2-carboxylic acid amide; Dimethyl-p-toluidine With Cl4Fe(1-)*C24H30N3(1+) In ethyl acetate for 0.25h; Stage #2: With tert.-butylhydroperoxide In water; ethyl acetate at 40℃; for 8h; | Typical procedure of amidation reaction General procedure: A 15 mL round-bottom flask was charged with a stirring bar, 2.0 mL ethyl acetate, N,N-dimethylaniline derivative (0.9 mmol), amide (0.5 mmol) and complex 2 (27.9 mg, 0.05 mmol) were added. After stirring 15 min, TBHP (0.75 mmol, 108 mL) was added without extrusion of the air. The mixture was stirred for 8 h at 40 oC. After cooling to room temperature, 10 mL ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using ethyl acetate/pet ether (60-90 oC) as eluent to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium persulfate; ammonium cerium (IV) nitrate In water at 110℃; for 12h; Schlenk technique; Sealed tube; | 16 Example sixteen In a Schlenk tube was charged with 2 successively pyridine carboxamide (0.5mmol), sodium persulfate (2mmol), ceric ammonium nitrate (0.025mmol), N, N- dimethylacetamide (2mmol), was added 1ml of deionized water, and then the system was sealed and heated in an oil bath at 110 deg.] C for about 12 hours, after the reaction was cooled and extracted with ethyl acetate (15ml × 3), and concentrated by a simple column chromatography (eluent petroleum ether: ethyl acetate = 2: 1) to giveMethylene-bis-2-pyridyl formamide, yield of 78% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With [4,4′-bipyridine]-1,1′-diium tricyanomethanide at 75℃; for 0.416667h; Green chemistry; | 2.4. General procedure for the synthesis of amido or aminoalkyl naphtholderivatives General procedure: [4,4′-BPyH][C(CN)3]2} (1 mol%; 0.0034 g) as a green mild catalyst was added to a mixture of aromatic aldehydes (1 mmol), β-naphthol(0.144 g, 1 mmol) and amide or amine derivatives (1 mmol) in around bottom flask, and the subsequent mixture was first stirred magnetically under solvent-free condition at 75 °C. After completion of the reaction, as identified by TLC n-hexane/ethyl acetate (5:3), ethyl acetate(10 mL)was added to a reaction mixture, stirred and refluxed for 5 min,and then was washed with water (10 mL) and decanted to separate catalyst from the reaction mixture (the reaction mixture was soluble in hot ethyl acetate and NMS catalyst was soluble in water). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol/water (10:1). In this study, bifunctional NMS catalyst were recycled and reused for five experimental errors with a minor loss of its catalytic activity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With [4,4′-bipyridine]-1,1′-diium tricyanomethanide at 75℃; for 0.333333h; Green chemistry; | 2.4. General procedure for the synthesis of amido or aminoalkyl naphtholderivatives General procedure: [4,4′-BPyH][C(CN)3]2} (1 mol%; 0.0034 g) as a green mild catalyst was added to a mixture of aromatic aldehydes (1 mmol), β-naphthol(0.144 g, 1 mmol) and amide or amine derivatives (1 mmol) in around bottom flask, and the subsequent mixture was first stirred magnetically under solvent-free condition at 75 °C. After completion of the reaction, as identified by TLC n-hexane/ethyl acetate (5:3), ethyl acetate(10 mL)was added to a reaction mixture, stirred and refluxed for 5 min,and then was washed with water (10 mL) and decanted to separate catalyst from the reaction mixture (the reaction mixture was soluble in hot ethyl acetate and NMS catalyst was soluble in water). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol/water (10:1). In this study, bifunctional NMS catalyst were recycled and reused for five experimental errors with a minor loss of its catalytic activity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With [4,4′-bipyridine]-1,1′-diium tricyanomethanide at 75℃; for 0.25h; Green chemistry; | 2.4. General procedure for the synthesis of amido or aminoalkyl naphtholderivatives General procedure: [4,4′-BPyH][C(CN)3]2} (1 mol%; 0.0034 g) as a green mild catalyst was added to a mixture of aromatic aldehydes (1 mmol), β-naphthol(0.144 g, 1 mmol) and amide or amine derivatives (1 mmol) in around bottom flask, and the subsequent mixture was first stirred magnetically under solvent-free condition at 75 °C. After completion of the reaction, as identified by TLC n-hexane/ethyl acetate (5:3), ethyl acetate(10 mL)was added to a reaction mixture, stirred and refluxed for 5 min,and then was washed with water (10 mL) and decanted to separate catalyst from the reaction mixture (the reaction mixture was soluble in hot ethyl acetate and NMS catalyst was soluble in water). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol/water (10:1). In this study, bifunctional NMS catalyst were recycled and reused for five experimental errors with a minor loss of its catalytic activity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cerium(IV) oxide at 150℃; for 2h; | 2.3 Reaction procedure and product analysis Catalytic reactions were conducted in a 100mLstainless-steel Parr pressure reactor. In a typical reaction,3.2 g of methanol (100 mmol), 5.2 g of 2-CP(50 mmol) and 0.1 g of ceria catalyst were taken in thereactor which was then pressurized with CO2 to 5MPa.The temperature of the reactor was raised to a specificvalue (120-160°C) and the reaction was conducted fora known period of time (1-6 h) while stirring at a speedof 600 rpm. At the end of the reaction, the reactor wascooled to 25C and the unreacted CO2 was vented out.Then, 30mL of ethanol and 0.2 g of nonan-1-ol wereadded to the liquid portion as a solvent and internalstandard, respectively. Further, the mixture was stirredfor 10 min to dissolve the solid 2-picolinamide (2-PA)completely in the liquid portion. The catalyst was separatedout of the liquid portion by centrifugation followedby filtration. The liquid product was analyzedand quantified with a Varian 3400 gas chromatograph(GC) equipped with a flame ionization detector and CPSIL5CBcolumn (60m long and 0.32mm i.d.). Standardmixtures of methanol, DMC, 2-CP, 2-PA, 2-methylpicolinate (2-MP) and methyl carbamate (MC) wereprepared, calibration plots were drawn and responsefactors of the reactants and products were determined.These were then used in quantifying the products. Thefollowing are the formulae used to describe conversionand product selectivity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium phosphate; t-BuBrettPhos; [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate In <i>tert</i>-butyl alcohol at 110℃; Inert atmosphere; | 23A Tert-butyl 4-{2-oxo-10-[(pyridin-2-ylcarbonyl)amino]-l,2-dihydropyrimido[l,2-b]indazol-4-yl} piperidine-1 -carboxylate A mixture of ieri-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (200 mg, 0.45 mmol), pyridine-2-carboxamide (137 mg, 1.12 mmol), tripotassium phosphate (133 mg, 0.63 mmol), [(2-di-ieri-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l,r- biphenyl)-2-(2 '-amino- l,l'-biphenyl)]palladium(II) methanesulfonate (= tBuBrettPhos Pd G3) (23 mg, 0.027 mmol), 2-(di-ieri-butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-l,l '-biphenyl (= tBuBrettPhos) (13 mg, 0.027 mmol) was added to a flask and flushed with argon before being suspended in 2 ml of ieri-butanol. Argon was bubbled for lmin more through the suspension, which was then stirred overnight at 110 °C. After cooling to RT, the mixture was filtered and purified by preparative HPLC (gradient acetonitrile/water with 0.1 % trifluoroacetic acid). Evaporation of the combined product fractions yielded the title compound (134 mg, 61 % of theory). LC-MS (Method 2): Rt = 3.60 min, MS (ESINeg): m/z = 487 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.2 mmol | With cerium(IV) oxide; at 119.84 - 599.84℃; under 7500.75 Torr; for 12h;Autoclave; | Cerium oxide (impurity concentration 0.02% or less) was calcined at 873 K in an air atmosphere for 3 hours to obtain a powdery solid catalyst. Therefore, a magnetic stirrer, the above solid catalyst (1 mmol), methanol (100 mmol) and 2-cyanopyridine (20 mmol) were introduced into a 190 ml autoclave (reactor), and air in the autoclave was purged three times with about 5 g of CO 2 , A predetermined amount of CO 2 was introduced and pressurized. The autoclave was heated while being stirred up to 363 K with a band heater and a hot stirrer, and the time at which the temperature reached the target temperature was taken as the reaction start time. After reacting at 363 K for 2 hours, the autoclave was cooled with water, cooled down to room temperature, depressurized, 2-propanol as an internal standard was added, the product was collected and analyzed by GC (gas chromatography). In this way, by changing the introduction amount of CO 2 and the reaction pressure, Test No. 1 shown in Table 1 was conducted. We conducted experiments 1 to 9.From the above results, it was confirmed that dimethyl carbonate (DMC) production amount was large at 1 ~ 2 MPa under relatively low pressure, and it was obtained with high yield. The amount of by-product 2-picolinamide produced is almost the same as that of DMC, and other by-products are No. 2. It was not detected at all in the experiments 1 to 9. Also, No. As shown in 9, when the reaction pressure became too high, the amount of DMC produced decreased greatly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With ammonium iodide; oxygen; copper; In dimethyl sulfoxide; acetonitrile; at 100℃;Sealed tube; | In the reaction vessel was added 50mol% Cu, the reaction tube was evacuated, filled with oxygen, in an oxygen atmosphere was added 0.2mmol 2-pyridine acetonitrile, 0.2mmol ammonium iodide,1 ml of acetonitrile and 1 ml of dimethylsulfoxide, the reaction vessel was sealed, reacted at 100 C,After the reaction was completed, it was washed with water, extracted with ethyl acetate, dried and concentrated by evaporation under reduced pressure to remove the solvent. The crude product was separated by column chromatography to give the desired product in a yield of 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.1% | Stage #1: pyridine-2-carboxylic acid amide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 120℃; for 2h; Stage #2: With hydrazine hydrate; acetic acid In water at 90℃; for 2h; | 2 5.4.4. General procedure for preparation of triazole intermediates(19a-19f) General procedure: A mixture of different amides A1-A6 (8.1 mmol) and DMF-DMA(10 mL, 0.08 mol) was stirred at 120 C for 2 h.The mixture was concentrated under reduced pressure to afford white solid, which was dissolved in HOAc (10 mL), and then 80% hydrazine hydrate(0.61 g, 9.8 mmol) was drop-wise to the solution. The mixture was stirred at 90 C for 2 h. The solvent was removed in vacuo and the mixture was added in ether at 0 C for 30 min. The precipitate was filtered and dried under reduced pressure to afford 19a-19f as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With hydrogenchloride; iron(III) nitrate hexahydrate In tetrahydrofuran; water at 70℃; | 12 Synthesis of Phenyl 2 - Picolinate In the equipped with 30 µM % of Fe (NO3 )3 · 6H2 O catalyst in the reaction tube, adding 0.2mmol2 - pyridine carboxamide, 80 µM % hydrochloric acid, 2 ml solvent tetrahydrofuran, 0.2mmol phenol, in 70 °C lower reaction, after the reaction water or saturated salt solution washing, then chloroform extraction, drying, concentrated distilled under reduced pressure to remove the solvent, the crude product by column chromatography separation, the object product is obtained: yield 57%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With cesiumhydroxide monohydrate; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With cesiumhydroxide monohydrate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; stereoselective reaction; | Cesium Hydroxide-Mediated Hydroamidation of Internal Aryl Alkynes with Amides General procedure: The reaction of diphenylacetylene (1a) with picolinamide (2a) is representative (Table 2, entry1): In a glovebox filled with nitrogen, diphenylacetylene (1a; 45 mg, 0.25 mmol), 2-picolinamide (2a;31 mg, 0.25 mmol), and CsOH•OH2 (42 mg, 0.25 mmol) were placed in a 2-mL microwave vessel(Biotage). The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl sulfoxide(DMSO, 1.0 mL) was sequentially injected via a syringe. The mixture was stirred for 24 h at 120 °C.The resulting mixture was then quenched with water. The mixture was extracted with ethyl acetatethree times, and the combined organic layer was dried over anhydrous Na2SO4. After concentrationunder reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v) afforded (Z)-N-(1,2-diphenylvinyl)picolinamide (3aa; 50 mg, 0.17 mmol) in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In water at 20℃; | 2.3.1. General procedure for preparation of coordination polymers General procedure: A warm water solution of picolinamide (0.24 g; 2 mmol in 25mL) was added dropwise with stirring to an aqueous solution of cadmium salt (10 mL; 2 mmol). The resultant clear solution was then left at room temperature allowing slow evaporation until X-ray quality crystals were formed. The crystals were filtered off, washed with small portions of cold water and dried in air. 2.3.1.1. Preparation of [CdCl2(pia)]n, (1). Used: CdCl2 (0.36 g, 2mmol). Yield: 0.46 g, 75%. IR (DRS, m, cm1): 3430 (s), 3343 (s),3330 (m), 3257 (m), 3214(w), 1665 (vs), 1611 (m), 1584 (s), 1573(s), 1482 (w), 1483 (w-m), 1414 (s), 1306 (m), 1271 (w-m), 1218(w), 1176 (w), 1163 (w), 1116 (w), 1017 (m), 821 (w), 772 (w),758 (m), 706 (m), 668 (w), 654 (m), 639 (w-m), 613 (w), 551 (m),493 (w). Anal. Calc. for C6H6CdCl2N2O: C, 23.59; H, 1.98; N, 9.17;Found: C, 23.59, H, 1.71; N, 8.78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In water at 20℃; | 2.3.1. General procedure for preparation of coordination polymers General procedure: A warm water solution of picolinamide (0.24 g; 2 mmol in 25mL) was added dropwise with stirring to an aqueous solution of cadmium salt (10 mL; 2 mmol). The resultant clear solution was then left at room temperature allowing slow evaporation until X-ray quality crystals were formed. The crystals were filtered off, washed with small portions of cold water and dried in air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In water at 20℃; | 2.3.3.1. Preparation of [Cd(SO4)(H2O)3(pia)]2H2O (4). An aqueous solution of picolinamide (0.24 g; 2 mmol in 5 mL) was slowly added to the aqueous solution of cadmium (II) sulphate monohydrate(0.22 g, 2 mmol in 5 mL). The resultant clear solution was leftat room temperature to evaporate. After few weeks, colourless single crystals suitable for X-ray diffraction formed. The crystals were filtered off, washed with small portions of deionized water and dried in desiccator. Yield: 0.35 g (83%). IR (DRS, m, cm1): 615(m), 640 (m), 653 (m), 754 (w), 825 (w), 844 (w), 979 (s), 1020(s), 1060 (s), 1072 (s), 1105 (s), 1141 (s), 1271 (w), 1425 (s), 1573(s), 1593 (m), 1626 (m), 1672 (vs), 2278 (w), 2328 (w), 3109 (s),3196 (s), 3398 (s). Anal. Calc. for C6H16CdN2O10S: C, 17.13; H,3.83; N, 6.66; Found: C, 16.85, H, 3.44; N, 6.46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With copper(l) iodide; potassium phosphate tribasic trihydrate; ethylenediamine In 1,4-dioxane at 60℃; for 48h; Inert atmosphere; | A1 Example A1: Preparation of Compound A1 Under nitrogen protection,(S)-(1-phenyl-2-(2-iodophenyl)-4-benzyl-4,5-dihydro)-1H-imidazole(0.4438 g, 1.01 mmol, 1.0 equiv)With 2-pyridinecarboxamide (0.1461 g, 1.20 mmol, 1.2 equiv)In 5.0 mL dioxane,CuI (0.0191 g, 0.1 mmol, 10 mol%),Ethylenediamine (0.0120g, 0.2mmol, 20mol%),Potassium phosphate trihydrate (0.5326 g, 2.0 mmol, 2.0 equiv),60 °C reaction for 48 hours,Petroleum ether: ethyl acetate = 3:1 column,Obtain 0.2509 g (0.58 mmol, yield 58%)Compound A1 containing imidazole pyridineamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.9 mmol; 0.5 mmol | With cerium monoxide; at 149.84℃; under 7500.75 Torr; for 24h; | In addition, 2-propanol (CH 3 CH (OH) CH 3) was used as a raw material alcohol.Amines and derivatives thereof, 2-propanol, cerium oxide,The amount of 2-CNPy mixed was 5 mmol of amine and its derivative,75 mmol of 2-propanol, cerium oxide (2 mmol of Examples 2-1 to 2-6: 1 mmol of Example 2-7) and 10 mmol of 2-CNPy,The pressure of carbon dioxide was 1 MPa. The reaction temperature was 423 K, the reaction time was 48 hours for Examples 2-1 to 2-6, and 24 hours for Example 2-7. Otherwise, the carbamic acid ester was produced in the same manner as in Examples 1-1 to 1-7. For each example, conversion, selectivity, carbonate as by-product and production amount of 2-PA were measured. Conversion and selectivity are values calculated based on amines and their derivatives. The obtained results are shown in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 10 mL methanolic solution of pyridine-2-carboxamide (0.3663 g, 3 mmol) and 10 mL methanolic solution of 4,4'-dimethoxy-2,2'-bipyridine (0.2162 g, 1 mmol) was stirred at room temperature for half an hour. Solution of EuCl3 was prepared by dissolving 1 mmol (0.2583 g) of EuCl3 in 10 mL of methanol and this solution was added to the ligands solution drop by drop with continuous stirring. The pH of resulting solution was maintained between 6 and 7. The reaction mixture was refluxed at 70 °C for 4 h. After refluxing for 4 h, the solution was cooled to room temperature and left as such overnight. Complex C1 was obtained as white precipitate which was filtered off, washed with methanol nd then dried under vacuum. The synthesis of complexes C2-C4 were done by adopting the same method as given above. Complex C2 was obtained from 3 mmol PCAO (0.3663 g), 1 mmol DMBP (0.2162 g) and1 mmol EuCl3 (0.2583 g), complex C3 was obtained from 3 mmol PDCA(0.4473 g), 1 mmol DMBP (0.2162 g) and 1 mmol EuCl3 (0.2583 g) and complex C4 was obtained from 3 mmol PM (0.3 mL), 1 mmol DMBP(0.2162 g) and 1 mmol EuCl3 (0.2583 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; triethylamine; N,N`-dimethylethylenediamine In toluene at 35 - 100℃; for 20h; | 1.5-4.4 Example 4 Preparation of substrate C 1. Dissolve 40g of compound A in 400ml of toluene under stirring conditions at 35°C,To the toluene solution of compound A, add 26.8 g of compound B, add 44.42 g of TEA and 38.66 g of DMEDA, degas for 20 min, add 20.92 g of CuI, and degas for 10 min. 2. Heat to 100°C and stir to react for 20h, then cool to 35°C to terminate the reaction. 3. The reaction mixture obtained in step 2 was made up to 200 ml with ethyl acetate, and 4 g of diatomaceous earth was added to filter, and the diatomaceous earth was washed twice with ethyl acetate, 100 ml each time.The washed ethyl acetate and the filtrate were combined, the total organic layer was washed with 200 ml of water, and the washed organic layer was evaporated and dried under reduced pressure at 50° C. to obtain a crude product. 4. Dissolve the crude product obtained in step 3 with 160ml ethyl acetate, crystallize at room temperature, filter, and evaporate the crystals to dryness under reduced pressure at 50°C.The purity of the product (substrate C) detected by HPLC was 99.1%, and the yield was 85.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | 3.5. General Procedure for the Preparation of Compounds (2), (5-25) General procedure: To a solution of the appropriate carboxamide compound (1.06 mmol, 1.5 equiv.) in dry DMF (3mL) at 0 °C under N2, 60% sodium hydride in oil (25.5 mg, 1.06 mmol, 1.5 equiv) were added portionwise. The resulting mixture were added dropwise to a solution of 4-chloro-2-(trichloromethyl)quinazoline (4) (200 mg, 0.71 mmol, 1.0 equiv.) in dry DMF (2 mL) at 0 °C under N2.The reaction was stirred overnight at rt. Then, the excess of NaH was hydrolyzed with ice. Thereaction mixture was extracted with EtOAc and washed three times with brine. The organic layerwas dried with Na2SO4, filtered, and evaporated. The crude product was purified by silica gel columnchromatography and recrystallized from appropriate solvent to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In water at 20℃; | 2.4.1. General procedure for preparation Cd complexes General procedure: A warm aqueous solution of picolinamide was added to anaqueous solution of cadmium salt. The resultant clear solutionwas then left at room temperature allowing slow evaporation.The products were filtered off, washed with small portions of coldwater and dried in air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 25 - 80℃; for 48h; Inert atmosphere; | 1 Step 1 - Methyl 2-[4-(benzyloxymethyl)cyclohexyl]-6-(pyridine-2-carbonylamino)-1,3- benzothiazole- 5-carboxylate To a solution of methyl 2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5- carboxylate (1.00 g, 2.11 mmol, synthesized via Steps 1-3 of Intermediate BAW) and pyridine-2- carboxamide (283 mg, 2.32 mmol, CAS 1452-77-3) in dioxane (10 mL) was added Cs2CO3 (1.37 g, 4.22 mmol), Xantphos (243 mg, 421 umol) and Pd2(dba)3 (193 mg, 210 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 48 hours under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20: 1 to 3: 1) to give the title compound (750 mg, 55% yield) as yellow solid. LC-MS (ESI+) m/z 516.1 (M+H)+. |
55% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 25 - 80℃; for 48h; Inert atmosphere; | Step 1 - Methyl 2-14-(benzyloxymethyl)cvclohexyll-6-(r)yridine-2-carbonylamino)-1.3- benzothiazole- 5-carboxylate To a solution of methyl 2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-l,3-benzothiazole- 5-carboxylate (1.00 g, 2.11 mmol, synthesized via Steps 1-3 of Intermediate BAW) and pyridine-2 - carboxamide (283 mg, 2.32 mmol, CAS 1452-77-3) in dioxane (10 mL) was added CS2CO3 (1.37 g, 4.22 mmol), Xantphos (243 mg, 421 umol) and Pd2(dba)3 (193 mg, 210 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 48 hours under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 20: 1 to 3: 1) to give the title compound (750 mg, 55% yield) as yellow solid. LC-MS (ESL) m/z 516.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With [bis(acetoxy)iodo]benzene In acetonitrile at 80℃; for 4h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With [bis(acetoxy)iodo]benzene In acetonitrile at 80℃; for 4h; Sealed tube; |
Tags: 1452-77-3 synthesis path| 1452-77-3 SDS| 1452-77-3 COA| 1452-77-3 purity| 1452-77-3 application| 1452-77-3 NMR| 1452-77-3 COA| 1452-77-3 structure
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H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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