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Structure of 2739-97-1 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 24, p. 10186 - 10189
3
[ 5451-39-8 ]
[ 2739-97-1 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 5, p. 1627 - 1631
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 5752,5756
4
[ 109-04-6 ]
[ 75-05-8 ]
[ 2739-97-1 ]
Reference：
[1] Synlett, 2000, # 10, p. 1488 - 1490
5
[ 109-04-6 ]
[ 928664-98-6 ]
[ 2739-97-1 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951
6
[ 117504-08-2 ]
[ 2739-97-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 6, p. 1513 - 1517
7
[ 109-09-1 ]
[ 75-05-8 ]
[ 2739-97-1 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 24, p. 10186 - 10189
8
[ 2706-56-1 ]
[ 2739-97-1 ]
Reference：
[1] Synlett, 2004, # 12, p. 2180 - 2184
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2392 - 2399
11
[ 55401-97-3 ]
[ 2739-97-1 ]
Reference：
[1] Journal of the Chemical Society [Section] A: Inorganic, Physical, Theoretical, [2] Journal of the Chemical Society [Section] A: Inorganic, Physical, Theoretical, 1968, p. 923 - 929
[3] , Gmelin Handbook: Co: Org.Verb.1, 1.1.3.1.1.2, page 58 - 65,
With sodium ethanolate In tetrahydrofuran at 10℃; for 16 h;
[507] To a solution of 2-(2-pyridyl)acetonitrile (2,00 g, 16,93 mmol, 1.83 mL, 1 ,00 eg) in THF (5 mL) was added EtONa (3.46 g, 50.79 mmol, 3.00 eg) and formyl chloride (2.18 g, 33.86 mmol, 2.00 eg). The reaction mixture was stirred at 10 °C for 16 h. TLC (ethyl acetate) indicated -40percent of SM remained and one major new spot formed. The reaction mixture was diluted with water (50 mL), and adjusted to pH=5 with sat. aq. KHSO4 solution. Then the resulting mixture was extracted with ethyl acetate (50 mL χ 3). The organic layers were combined, dried over anhydrous NazSC , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (5- 50percent ethyl acetate/petroleum ether) to afford 3-oxo-2-(2-pyridyl)butanenitrile (780 mg, 4.87 mmol, 29percent yield) as a yellow solid. LC-MS (ESI): m/z 161.0 { .M 1 I s ' .
With sodium hydride In DMF (N,N-dimethyl-formamide); oil at 0 - 60℃; for 5.63333 h;
Sodium hydride (60percent in mineral oil, 2.04g, 51mmol) was added portion wise over 8 minutes to a stirring solution of 2-pyridineacetonitrile (1. 8ml, 17mmol) and N- (tert-butyloxycarbonyl) bis (2-chloroethyl) amine in anhydrous DMF (50ml) at 0OC. The reaction was then heated at 60°C for 5 1/2hours. The reaction was cooled and extracted into ethyl acetate (4 x 150ml), and washed with water (3 x 200ml). The organic layer was then dried over anhydrous MgSO.cents., filtered and evaporated in vacuo to give a red/black oil. This was absorbed onto silica and purified by column chromatography using 20percent ethyl acetate in isohexane to give ter-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate as an orange solid (2.13g, 44percent). 1H NMR 8 (ppm) 360MHz (CDC13): 1.48 (9 H, s), 2.04-2. 08 (2 H, m), 2.17-2. 25 (2 H, m), 3.15-3. 28 (2 H, m), 4.20-4. 35 (2 H, m), 7.25-7. 29 (1 H, m), 7.61 (1 H, d, J = 8Hz), 7.73-7. 78 (1 H, m), 8. 61 (1 H, dd, J = 0.7, 3.9Hz). MSp m/z for MH+ = 287 (- 56).
Reference：
[1] Patent: WO2005/51390, 2005, A1, . Location in patent: Page/Page column 28
[2] Bioorganic and medicinal chemistry letters, 2000, vol. 10, # 15, p. 1625 - 1628
[3] Patent: US5635510, 1997, A,
[4] Patent: US5824690, 1998, A,
1. Preparation of l-methyl-4-(pyridin-2-yl)piperidine-4-carbonitrile <n="57"/>[00183] A solution of 2-pyridyl acetonitrile (1.Og, 8.54 mmol) in DMSO (8 mL) was treated with sodium hydride (1.195g, 29.88 mmol) portionwise. The resulting brown suspension was stirred at 23C for 30 minutes. 2-Chloro-N-(2-chloroethyl)-N- methylethanamine (1.81g, 9.39 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65C overnight. The reaction was then diluted with IN hydrochloric acid and washed with ethyl acetate (2x). The aqueous phase was basified with IN sodium hydroxide and extracted with ethyl acetate (3x). The combined extracts were washed with water (5x) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified on Biotage silica gel column (1% to 10% (methanol +1% ammonia) in dichloromethane) to give the desired product as an oil (0.583g, 34%). 1H nuMR (400 MHz, CDCl3) delta ppm: 2.14- 2.25 (2H, m), 2.30-2.38 (2H, m), 2.40 (3H, s), 2.51 (td, J=12.25 and 2.27 Hz), 2.99 (2H, d, J=12.13 Hz), 7.25-7.36 (IH, m), 7.56 (IH, d, J=8.08 Hz), 7.75 (IH, td, J=LIl and 1.77 Hz), 8.64 (IH, d, J=4.80 Hz). LC/MS (M+H)+: 202. HPLC ret. time (Condition E): 1.025 min.
General procedure: Appropriate starting arylacetonitrile (1 eq.) was added to a stirredsuspension of KOH (5 eq.) in DMSO (200 mL per 1 mol of KOH). Themixture was brought to 60 C. Bromopyridine (1.5 eq.) was then addeddropwise, at 60-70 C, followed by further stirring at this temperaturefor 4 h. The reaction mixture was cooled and poured onto water(500 mL) and the resulting cloudy solution was extracted with AcOEt(2 × 150 mL), washed with water (100 mL) and brine (100 mL). Theorganic extract was dried over anhydrous MgSO4, filtered and concentratedunder reduced pressure. The residue was dissolved in AcOH(100 mL) and concentrated H2SO4 (35 mL). The solution was heated at100 C until TLC showed complete reaction (1-3 h). The solution wascooled and poured onto excess of ice-25% aqueous ammonia. The resultingmixture was extracted with CH2Cl2 (3 × 75 mL). The combinedorganic extracts were washed with water (2 × 75 mL), brine (75 mL),dried over anhydrous Na2SO4, filtered and evaporated. The title compoundswere purified by recrystallization or by FC.
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; In water;
EXAMPLE 3 Synthesis of alpha, 2-pyridinyl-2,8-bis (trifluoromethyl)-4-quinolineacetonitrile of Formula (5) 4-chloro-2, 8-bis (trifluoromethyl)quinoline (3), (0.0385 mole, 11.52 g), 2-pyridyl acetonitrile 4 (0.0423 mole, 5.0 g) NaOH (20N, aq. 9.63 ml, 0.192 moles), (THF) (35 ml) and benzyltriethylammonium chloride (0.26 g, 3 mole %), were reacted as described in Example-1. After consumption of compound (3), the reaction mixture was cooled to 0-5 C. and neutralized by ortho-phosphoric acid (85% aq., 4.5 ml). THF was distilled off, water (30 ml) added and extracted with toluene (50 ml*5). All extracts were combined and solvent distilled off. The crude product was crystallized from toluene/hexane. Yield=14.52 gm (99%).
Step 1. 3,3-Bis(methylthio)-2-(pyridin-2-yl)acrylonitrile Sodium hydride (370 mg, 15.42 mmol) and CS2 (710 mg, 9.34 mmol) was added to a solution of 2-(pyridin-2-yl)acetonitrile (1 g, 8.46 mmol) in DMF (15 mL) at 0 C. After stirring for 5 hours at room temperature, MeI (3.6 g, 25.35 mmol) was added. After 1 hour, the reaction was quenched by water (40 mL), extracted with dichloromethane (3*50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a residue, which was purified by a silica gel column chromatography with 5% ethyl acetate in petroleum ether to afford 3,3-bis(methylthio)-2-(pyridin-2-yl)acrylonitrile as a yellow solid (31.4 g, 74%). LC/MS (ES, m/z): [M+H]+ 223.0. 1H-NMR (300 MHz, CDCl3) delta 8.67-8.69 (m, 1H), 7.74-7.80 (m, 1H), 7.64-7.67 (m, 1H), 7.23-7.28 (m, 1H), 2.65 (s, 3H), 2.42 (s, 3H)
EXAMPLES; Preparation of 2H-1-Benzopyran-2-one, 3-(2-pyridinyl (3-(2-pydinyl)coumarin or pcm): o-hydoxycarbonylbenzene (40 mmol) and 2-pyridylacetonitrile (40 mmol) were added to an aqueous solution of NaOH (0.05 N, 200 ml). The mixture was vigorously stirred at 90 C. for 3.5 hours. After cooling the solid was filtered, washed with cold water and dried. The crude compound was purified by crystallization from ethanol. yield: 92%. MS: m/z calcd 223; found 224 [M+1].
A mixture of 2-(pyridin-2-yl)acetonitrile (15.0 g, 0.127 mol), DMF-DMA (30 mL, 0.229 mol) andmethanol (36 mL) was stirred at 30 C for 24 h. The solvent was evaporated, moderate methanol andethyl acetate was added in. The solution was concentrated under a reduced pressure to remove excessDMF-DMA completely. The residue was poured into petroleum ether (100 mL) and stirred for 6 h.The suspension was separated by filtration and washed with ether to give compound 10 as a dark redsolid (18.3 g, 83.2%). MS (ESI) m/z: 174.0 [M + H+].
With triethylamine; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;Microwave irradiation;
General procedure: A solution of aryl acetonitrile 2 (50 mg), and triethylamine (1.1 equiv.) in dimethylformamide dimethyl acetal (0.5 mL, 3.76 mmol) was heated in a microwave reactor at 120 C for 20 minutes. The mixture was cooled to RT, and solvents were then evaporated. To the resulting crude product 3 was added hydrazine mono-hydrobromide (3.0 equiv.), 200 proof EtOH (1.0 mL), and H2O (0.3 mL). The mixture was heated in a microwave reactor at 120 C for 20 minutes. The mixture was cooled to RT and concentrated in vacuo. The resulting residue was subjected to liquid-liquid extraction using saturated NaHCO3 (aq) and CH2Cl2. The organic layer was collected, dried over anhydrous MgSO4, filtered and removed under vacuum to afford 4.The resulting crude product 4 and 2-arylsubstitutedmalondialdehydes or 1,1,3,3tetramethoxypropane (1.0 equiv.) were dissolved in glacial AcOH (1.0 mL) and 200 proof EtOH (1.5 mL). The mixture was heated in a microwave reactor at 120 C for 20 minutes. After cooling on ice, the precipitate was collected on a fine scintered-glass frit and washed with icecold EtOH (2 x 1.0 mL). The resulting crystals 5-32 were dried and collected.
With sodium hydride; In DMF (N,N-dimethyl-formamide); oil; at 0 - 60℃; for 5.63333h;
Sodium hydride (60% in mineral oil, 2.04g, 51mmol) was added portion wise over 8 minutes to a stirring solution of 2-pyridineacetonitrile (1. 8ml, 17mmol) and N- (tert-butyloxycarbonyl) bis (2-chloroethyl) amine in anhydrous DMF (50ml) at 0OC. The reaction was then heated at 60C for 5 1/2hours. The reaction was cooled and extracted into ethyl acetate (4 x 150ml), and washed with water (3 x 200ml). The organic layer was then dried over anhydrous MgSO¢, filtered and evaporated in vacuo to give a red/black oil. This was absorbed onto silica and purified by column chromatography using 20% ethyl acetate in isohexane to give ter-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate as an orange solid (2.13g, 44%). 1H NMR 8 (ppm) 360MHz (CDC13): 1.48 (9 H, s), 2.04-2. 08 (2 H, m), 2.17-2. 25 (2 H, m), 3.15-3. 28 (2 H, m), 4.20-4. 35 (2 H, m), 7.25-7. 29 (1 H, m), 7.61 (1 H, d, J = 8Hz), 7.73-7. 78 (1 H, m), 8. 61 (1 H, dd, J = 0.7, 3.9Hz). MSp m/z for MH+ = 287 (- 56).
33.1 Synthesis of 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-2-yl)-piperidine Prepare by the method of example 30.2 using 2-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol). Purify to give the title compound.
33.1 Synthesis of 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-2-yl)-piperidine Prepare by the method of example 30.2 using 2-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol). Purify to give the title compound.
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In nitromethane; water; at 20 - 100℃; for 3h;
To a nitromethane (0.1 mL) solution of 2-(pyridin-2-yl)acetonitrile (4k) (30 mg, 0.254 mmol) wereadded H2O (1.0 mL), DBU (77 mg, 0.508 mmol), copper (I) iodide (9.6 mg, 0.508 mmol), cesium (I)carbonate (41 mg, 0.127 mmol) at room temperature. The reaction mixture was heated at 100 C for1 h and then poured into water (50 mL). The organic layer was separated and the aqueous layer wasextracted with CHCl3. The combined organic layer was dried over MgSO4. The solvent wasremoved under reduced pressure. The residue was purified by preparative TLC on silica gel elutingwith CHCl3-MeOH (20:1) to give 2-(pyridin-2-yl)acetamide (5k)S1 (15 mg, 43%) as pale yellowpowders.mp 111-113 C,
[(5-phenyl-1<i>H</i>-pyrazol-3-yl)-hydrazono]-pyridin-2-yl-acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: 3(5)-phenylpyrazol-5(3)-amine With hydrogenchloride; sodium nitrite In water at 0 - 5℃;
Stage #2: pyridine-2-acetonitrile With sodium acetate In water at 0 - 5℃;
With hydroxylamine hydrochloride; sodium; In methanol;
D. 1-(4-Methylpiperazin-1-yl)-7-(3-(pyrid-2-ylmethyl)-1,2,4-oxadiaz-5-ylnaphthalene Sodium (0.183 g, 7.96 mmol), hydroxylamine hydrochloride (0.570 g, 8.20 mmol), and (2-pyridyl)acetonitrile (0.375 g, 3.17 mmol) and methanol (5 mL) were used to prepare (2-pyridyl)acetamidoxime (0.55 g, >100%) as described above.
100%
With hydroxylamine hydrochloride; sodium; In methanol;
D. 1-(4-Methylpiperazin-1-yl)-7-(3-(pyrid-2-ylmethyl)-1,2,4-oxadiaz-5-yl)naphthalene Sodium (0.183 g, 7.96 mmol), hydroxylamine hydrochloride (0.570 g, 8.20 mmol), and (2-pyridyl)acetonitrile (0.375 g, 3.17 mmol) and methanol (5 mL) were used to prepare (2-pyridyl)acetamidoxime (0.55 g, >100%) as described above.
(Z)-3-(4-fluorophenyl)-2-(pyridin-2-yl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium ethanolate; In ethanol; at 25℃; for 0.5h;
3- (4-Fluoro-phenyl)-2-pyridin-2-yl-acrylonitrile To a solution of 4-fluorobenzaldehyde (52.5 g, 423 mmol) in EtOH (200 mL) at 25 C was added pyridin-2-yl-acetonitrile (50.0 g, 423 mmol) and NaOEt (151 g of 21% solution, 466 mmol). The reaction was stirred at 25 C for 0.5 hr during which time a light brown precipitate developed. The solid was isolated by filtration and washed with EtOH (75 mL). The product was then dried under vacuum to afford 3- (4-fluoro- phenyl)-2-pyridin-2-yl-acrylonitrile (87 g, 92%) which was used without further purification: MS (APCI) : Sz 225.3 (M+H); H-NMR (CDC13) o 8.62 (d, 1 H), 8.40 (s, I H), 8.06-8. 01 (m, 2 H), 7.92-7. 88 (m, 1 H), 7.80-7. 78 (d, 1 H), 7.41-7. 33 (m, 3 H).
2-imino-3-(2'-pyridyl)-4,5,5-trimethyl-2,5-dihydrofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
~ 100%
With sodium ethanolate; In ethanol; for 0.133333h;Microwave irradiation;
A mixture of 3- hydroxy-3-methylbutan-2-one (3 mmol, 306 mg), 2-pyridylacetonitrile (3 mmol, 355 mg) and sodium ethoxide (0.3 mmol), prepared from sodium (0.3 mmol, 6.9 mg), in ethanol (0.3 mL) was irradiated under focused microwave at 20 W for 8 minutes. Solvent was removed by rotary evaporation and the residue was purified via a flash chromatography on silica gel with a gradient eluent of dichloromethane to 1 % ethanol in dichloromethane to afford 606 mg of product as a brown oil at almost quantitative YIELD. 1H NMR (CDCL3) 6 8.63-8. 67 (m, 1H), 7.71-7. 75 (m, 2H), 7.18-7. 26 (m, 1H), 2.14 (s, 3H), 1.47 (S, 6H).
With sodium ethanolate; sodium; In ethanol; dichloromethane;
2-Imino-3-(2'-pyridyl)-4,5,5-trimethyl-2,5-dihydrofuran. A mixture of 3-hydroxy-3-methylbutan-2-one (3 mmol, 306 mg), 2-pyridylacetonitrile (3 mmol, 355 mg) and sodium ethoxide (0.3 mmol), prepared from sodium (0.3 mmol, 6.9 mg), in ethanol (0.3 mL) was irradiated under focused microwave at 20 W for 8 minutes. Solvent was removed by rotary evaporation and the residue was purified via a flash chromatography on silica gel with a gradient eluent of dichloromethane to 1% ethanol in dichloromethane to afford 606 mg of product as a brown oil at almost quantitative yield. 1H NMR (CDCl3) delta 8.63-8.67 (m, 1H), 7.71-7.75 (m, 2H), 7.18-7.26 (m, 1H), 2.14 (s, 3H), 1.47 (s, 6H).
3-[1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(pyridin-2-yl)prop-2-enenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.5%
With sodium; In ethanol;
EXAMPLE 43 3-[1,2-Dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(2-pyridyl)prop-2-enenitrile Formula (I): X=Z2 =H, Y=O, Z1 =4--OCH3, R=2-pyridyl 2.8 g of [1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]carboxaldehyde are suspended in 90 ml of ethanol with 1.2 ml of 2-pyridylacetonitrile (1.1 eq). A solution of 0.023 g of sodium in 10 ml of ethanol (0.1 eq) is then added. The pale yellow suspension obtained is stirred for 24 h and gradually becomes bright yellow. The precipitate formed is filtered off and washed with ethanol and then ether to give 3.4 g of 3-[1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(2-pyridyl)prop-2-enenitrile in the form of an orange-yellow solid melting at 251 C. Yield 89.5%.
89.5%
With sodium; In ethanol;
EXAMPLE 83 3-[1,2-Dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(2-pyridyl)prop-2-enenitrile Formula (I): X=H; Y=O; R2 =4-OCH3 -phenyl; R=3-pyridyl; R1 =CN 2.8 g of [1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]carboxaldehyde are suspended in 90 ml of ethanol with 1.2 ml of 2-pyridylaceto-nitrile (1.1 eq). A solution of 0.023 g of sodium in 10 ml of ethanol (0.1 eq) is then added. The pale yellow suspension obtained is stirred for 24 h and gradually becomes bright yellow. The precipitate formed is filtered off and washed with ethanol and then ether to give 3.4 g of 3-[1,2-dihydro-1-(4-methoxy-phenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(2-pyridyl)prop-2 -enenitrile in the form of an orange-yellow solid melting at 251 C. Yield 89.5%. The following derivatives of formula (I) are prepared by this method:
6-Pyridin-2-yl-pyrido[2,3-d]pyrimidine-2,7-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 111 6-Pyridin-2-yl-pyrido[2,3-d]pyrimidine-2,7-diamine The procedure of Example 1 was followed to react 0.84 mL of 2-pyridylacetonitrile and 1.0 g of <strong>[20781-06-0]2,4-diamino-5-pyrimidinecarboxaldehyde</strong> to afford the title compound, mp 312-321 C. Analysis calculated for C12 H10 N6.0.07 H2 O: C, 60.18; H, 4.27; N, 35.09. Found: C, 60.46; H, 4.34; N, 34.70.
1-benzyl-4-cyano-4-(pyridin-2-yl)-piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide;
Preparation 9 Synthesis of 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide Combine 2-pyridylacetonitrile (5.9 g, 50 mmol), N-benzyl-N,N-bis-(2-chloroethyl)amine hydrochloride (13.4 g, 50 mmol), and hexadecyltributyphosphonium bromide (1.3 g, 2.5 mmol) and a 50% aqueous sodium hydroxide solution (75 mL). Heat to 100 C. After 1 hour, cool the reaction mixture to ambient temperature and repeatedly extract with diethyl ether. Extract the combined organic layers twice with an aqueous 10% hydrochloric acid solution (350 mL). combine the aqueous layers and neutralize with an aqueous 50% sodium hydroxide solution. Again extract three times with diethyl ether, combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give 1-benzyl-4-cyano-4-(pyridin-2-yl)-piperidine: Rf =0.56 (silica gel, 9/1 dichloromethane/methanol). Elemental Analysis calculated for C18 H19 N3: C, 77.95; H, 6.90; N, 15.15. Found: C, 78.20; H, 6.97; N, 15.04.
With sodium hydride; In diethyl ether; dimethyl sulfoxide; mineral oil; at 15 - 20℃; for 25h;Inert atmosphere;
To a solution of NaH (60% dispersion in mineral oil, 800 mg, 20 mmol) in DMSO (10 mL) at 15 C under N2 was added a solution of 2-(pyridin-2-yl)acetonitrile (1.18 g, 10 mmol) and 1,5-dibromopentane (2.3 g, 10 mmol) in Et20 (80 mL) and DMSO (2 mL) dropwise over 1 h. The mixture was allowed to warm to RT and stirred for 24 h. The reaction was carefully quenched by dropwise addition of isopropanol (5 mL) followed by water (10 mL). The mixture was stirred for 10 min, then extracted with EtOAc (200 mL) and the organic layer was washed with water, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.86 g, 100%) as a brown oil. LCMS-C: Rt 1.87 min, m/z 187.0 [M+H]+.
74%
With sodium hydride; In diethyl ether; dimethyl sulfoxide; mineral oil; at 15 - 20℃; for 25h;Inert atmosphere;
General procedure: To a stirred suspension of NaH (60% dispersed in oil) (0.14 g, 3.4 mmol) in DMSO (20 mL) under nitrogen at 15 C, a solution of the appropriate acetonitrile (1.8 mmol) and 1,5-dibromopentane (0.41 g, 1.8 mmol) in Et2O (4 mL) and DMSO (1 mL) was added dropwise over 1 h. The mixture was allowed to warm to room temperature and stirred for an additional 24 h under nitrogen. The reaction mixture was carefully quenched by the addition dropwise of isopropanol (5 mL), followed by H2O (5 mL) 10 min later. The mixture was diluted with AcOEt and washed with H2O. The aqueous layer was re-extracted with AcOEt, and the two organic layers were combined, dried (Na2SO4), and concentrated in vacuo. The crude residue was chromatographed (n-hexane/AcOEt, 4:1, as eluent) to give the desired compound as a colorless oil.
72%
In water; dimethyl sulfoxide; ethyl acetate; isopropyl alcohol;
Step 1 To a stirred suspension of sodium hydride (60% dispersed in oil) (4 g, 0.1 m) in DMSO (70 mL) under nitrogen at 15 C. was added dropwise a solution of 2-pyridyl acetonitrile (6 g, 51 mmol) and 1,5-dibromopentane (6.81 mL, 51 mmol) in ether (40 mL) and DMSO (10 mL) over 1 hour. The mixture was allowed to warm to room temperature and stirred for a further 24 hours under nitrogen. The reaction mixture was carefully quenched by the addition dropwise of isopropanol (10 mL), followed by water (100 mL) 10 minutes later. The reaction solution was taken up in EtOAc and washed with water. The aqueous layer was re-extracted with EtOAc, and the two organic layers were combined, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica with a gradient of heptane to 9:1 heptane/EtOAc to give 1-cyano-1-(2-pyridyl)cyclohexane (6.77 g, 72%). 1H NMR (CDCl3): delta 1.77-2.17 (10H, 2*m, cyclohexyl), 7.20-7.27 (1H, m, pyridyl H), 7.60-7.62 (1H, m, pyridyl H), 7.70-7.73 (1H, m, pyridyl H), 8.4-8.42 (1H, m, pyridyl H).
To a suspension of 1,1 equivalent of sodium hydride 0,1 M in tetrahydrofuran (THF) was added dropwise a solution of one equivalent of 2-pyridylacetonitrile 0.1 M in THF. The mixture is stirred for 30 minutes and then cooled to 0C by an ice bath, A solution of one equivalent of 2,4-dichioropyrimidine I M in dimethylformamide (DMF) was added dropwise and the reaction mixture is stirred overnight at room temperature. Thereaction mixture is partially evaporated, diluted with water and returned to pH 7 with concentrated HC1. The solution is extracted with ethyl acetate, the organic phase is dried and evaporated to give an orange solid (halogenated intermediate) which was used without further purification. The halogenated intermediate is obtained with a yield of 55%.
2-chloro-5-methyl-α-2(1H)-pyridinylidene-4-pyrimidineacetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
To a suspension of LiH (404mg, 50. 79MMOL) in anhydrous THF (lOmL), was added dropwise a solution of 2-pyridylacetonitrile (3g, 25.39mmol) in anhydrous THF (LOML). The reaction mixture was stirred at zero degree for 1 hour. A solution of 2, 4-dichloro-5- methyl-pyrimidine (4. 55G, 27.93mmol), dissolved in anhydrous THF (SML), was added dropwise at zero degree. The reaction mixture was stirred and heated to reflux for 14 hours. The reaction mixture was allowed to warm to r. t. and water was added (20mL). THF was evaporated under vacuum and a solution of 1N HCl (20mL) was added. The precipitate was filtered and washed with water (LOML) and cycloHexanes (LOML) to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4- pyrimidineacetonitrile, 2-CHLORO-5-METHYL-ALPHA-2 (LH)-PYRIDINYLIDENE was isolated. (5. 5G, 90%).
86%
To a suspension of NaH (1.3g, of NaH in a 60% dispersion oil, 32. 5MMOL, 4eq) in anhydrous DMF (lOmL), was added dropwise at room temperature a solution of 2- pyridylacetonitrile (960mg, 8.12 mmol, leq) in anhydrous DMF (lOmL). The reaction mixture was stirred at room temperature for 1 hour. A solution of 2, 4-dichloro-5-methyl- pyrimidine (1.32g, 8.12mmo, leq), dissolved in anhydrous DMF (5ML), was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The mixture is hydrolysed with water (LML) and acidified with 1. 6mL of LOM HCI. The solvents were evaporated under vacuum. The residue was extracted with ethyl acetate. The organic layer was dried over MgS04 and evaporated to dryness. The residue was purified by column chromatography with 50: 50 (EtOAc: CHEX). The fractions evaporated to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2 (1H)-PYRIDINYLIDENE was isolated. (1.7g, 86%). 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2 (1H)-PYRIDINYLIDENE-: IH NMR (300 MHz, DMSO); 2.34 (s, 3H), 3.31 (s, 1H), 6.94 (t, 1H), 7.41 (d, 1H), 7. 84-7. 97 (m, 2H), 8.25 (d, 1H), 15.19 (brs, 1h). MS (ESI+) 245, (ESI-) 243.
3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) is added to a dry 250-ml round-bottom flask under N2 followed by THF (50 mL) and pyridin-2-yl-acetonitrile (800 mg, 7.68 mmol). The reaction is degassed for 30 min. NaHMDS (1.0 M, 14.13 mL, 14.13 mmol) is added and the reaction is stirred overnight. The reaction mixture is transferred to a beaker and air stirred vigorously for several hours. The reaction mixture is quenched with saturated sodium bicarbonate solution. The organics are extracted with dichloromethane. The combined organic layers are washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified via flash chromatography on silica gel (0-20percent methanol in CH2Cl2) to afford the title compound (616 mg, 44percent). 1H NMR (400 MHz, DMSO-d6) delta=8.68 (m, 1H), 8.26 (m, 1H), 8.16 (m, 1H), 7.76 (m, 1H), 2.45 (s, 3H), 2.21 (s, 3H).
Stage #1: p-chloroaniline hydrochloride With sodium nitrite In water Cooling;
Stage #2: pyridine-2-acetonitrile With sodium acetate In ethanol; water at 20℃; Cooling;
With sodium hydride; In diethyl ether; dimethyl sulfoxide; mineral oil; at 15 - 20℃; for 25h;Inert atmosphere;
To a solution of NaH (60% dispersion in mineral oil, 800 mg, 20 mmol) in DMSO (10 mL) at 15 C under N2was added a solution of 2-(pyridin-2-yl)acetonitrile (1.18 g, 10 mmol) and 1,4-dibromobutane (2.16 g, 10 mmol) in Et20 (10 mL) and DMSO (2 mL) dropwise over 1 h. The mixture was then allowed to warm to RT and stirred for 24 h. The reaction was carefully quenched by dropwise addition of isopropanol (5 mL) followed by water (10 mL). The mixture was stirred for 10 min, then extracted with EtOAc (200 mL) and the organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (1.72 g, 100%) as a brown oil. LCMS-C: Rt 1.11 min, m/z 173.0 [M+H]+.
82%
With sodium hydride; In diethyl ether; dimethyl sulfoxide; at 0 - 20℃; for 4.5h;
To a suspension of sodium hydride (60%) (0.745 g, 18.644 mmol) in dimethyl sulfoxide (10 mL) was dropwise added a mixture of pyridin-2-yl-acetonitrile (429) (1 g, 8.475 mmol) and 1,4-dibromo-butane (1.831 g, 8.475 mmol) dissolved in dimethyl sulfoxide-ether (10 mL, 1:1) at 0 C. and the reaction mixture was stirred for 30 min at the same temperature and then stirred at room temperature for 4 h. After completion of the reaction (monitored by silica TLC, Rf=0.4, in 10% ethyl acetate/ hexane) the mixture was quenched with HCl (1 N, 10 mL). The reaction mixture was diluted water (20 mL) and extracted with ethyl acetate (2×50 mL) combined extracts were washed with water (20 mL) and brine (2×20 mL). The organic phase was thereafter dried and concentrated in vacuo to get a crude mass which was purified by combi-flash to get 1-pyridin-2-yl-cyclopentanecarbonitrile (430) (1.2 g, 82%) as a color less liquid. [1515] LC-MS: 173.0 (M+H)
General procedure: a well stirred solution of the base aromatic amine (0.1 mol) in 2 N hydrochloric acid (125 mL) was cooled in an ice-salt bath and diazotized with 1 N sodium nitrite solution (100 mL). The mixture was then tested for complete diazotization using starch iodide paper which gives a weak blue test. If the mixture does not give the test, more sodium nitrite was added dropwise until a positive test is obtained and the color is stable for few minutes. If, on the other hand, strong test for nitrite is obtained, a few drops of a dilute solution of the base hydrochloride are added until the nitrite test is nearly negative. The above cold diazonium solution was added slowly to a well stirred solution to cyanomethyl pyridine (0.1 mol) in ethanol (150 mL) containing 10% sodium acetate solution (50 mL) and the mixture was cooled in an ice-salt bath. After the addition of the diazonium salt solution, the reaction was tested for coupling reaction. A drop of the reaction mixture was placed on a filter paper and the colorless ring surrounding the spot dye was treated with a drop of an alkaline solution of a reactive coupler, such as a sodium salt of 3-hydroxy-2-naphthanilide. If unreacted diazonium salt is present, a dye is formed. The presence of unreacted coupler can be determined in a similar manner using a diazonium salt solution to test the colorless ring. After the coupling reaction was complete, the reaction mixture was stirred for 15 min at room temperature to coagulate the dye particles. The crude product was filtered, dried and recrystallized from ethanol to give N-arylpicolino and/or isonicotinohydrazonyl cyanide derivatives 2a-d and 4a-f (Table 2).
General procedure: a well stirred solution of the base aromatic amine (0.1 mol) in 2 N hydrochloric acid (125 mL) was cooled in an ice-salt bath and diazotized with 1 N sodium nitrite solution (100 mL). The mixture was then tested for complete diazotization using starch iodide paper which gives a weak blue test. If the mixture does not give the test, more sodium nitrite was added dropwise until a positive test is obtained and the color is stable for few minutes. If, on the other hand, strong test for nitrite is obtained, a few drops of a dilute solution of the base hydrochloride are added until the nitrite test is nearly negative. The above cold diazonium solution was added slowly to a well stirred solution to cyanomethyl pyridine (0.1 mol) in ethanol (150 mL) containing 10% sodium acetate solution (50 mL) and the mixture was cooled in an ice-salt bath. After the addition of the diazonium salt solution, the reaction was tested for coupling reaction. A drop of the reaction mixture was placed on a filter paper and the colorless ring surrounding the spot dye was treated with a drop of an alkaline solution of a reactive coupler, such as a sodium salt of 3-hydroxy-2-naphthanilide. If unreacted diazonium salt is present, a dye is formed. The presence of unreacted coupler can be determined in a similar manner using a diazonium salt solution to test the colorless ring. After the coupling reaction was complete, the reaction mixture was stirred for 15 min at room temperature to coagulate the dye particles. The crude product was filtered, dried and recrystallized from ethanol to give N-arylpicolino and/or isonicotinohydrazonyl cyanide derivatives 2a-d and 4a-f (Table 2).
General procedure: a well stirred solution of the base aromatic amine (0.1 mol) in 2 N hydrochloric acid (125 mL) was cooled in an ice-salt bath and diazotized with 1 N sodium nitrite solution (100 mL). The mixture was then tested for complete diazotization using starch iodide paper which gives a weak blue test. If the mixture does not give the test, more sodium nitrite was added dropwise until a positive test is obtained and the color is stable for few minutes. If, on the other hand, strong test for nitrite is obtained, a few drops of a dilute solution of the base hydrochloride are added until the nitrite test is nearly negative. The above cold diazonium solution was added slowly to a well stirred solution to cyanomethyl pyridine (0.1 mol) in ethanol (150 mL) containing 10% sodium acetate solution (50 mL) and the mixture was cooled in an ice-salt bath. After the addition of the diazonium salt solution, the reaction was tested for coupling reaction. A drop of the reaction mixture was placed on a filter paper and the colorless ring surrounding the spot dye was treated with a drop of an alkaline solution of a reactive coupler, such as a sodium salt of 3-hydroxy-2-naphthanilide. If unreacted diazonium salt is present, a dye is formed. The presence of unreacted coupler can be determined in a similar manner using a diazonium salt solution to test the colorless ring. After the coupling reaction was complete, the reaction mixture was stirred for 15 min at room temperature to coagulate the dye particles. The crude product was filtered, dried and recrystallized from ethanol to give N-arylpicolino and/or isonicotinohydrazonyl cyanide derivatives 2a-d and 4a-f (Table 2).
2-(N-butyl-1,8-naphthalimide)-2-(pyridin-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.3%
With sodium hydride; In toluene; at 25 - 30℃; for 3h;Inert atmosphere;
In 100ml three bottles,Adding 25 ml of organic solvent 1, i.e., toluene,0.50 g (3.70 mmol) of R2 substituted acetonitrile, i.e., <strong>[2739-97-1]pyridine-2-acetonitrile</strong>And 0.72 g (17.92 mmol) of base catalyst NaH (60 w%),Nitrogen replacement three times,Stir at room temperature,Then, N-n-butyl-4-bromo-1,8-naphthalimide (1.10 g, 3.32 mmol)With 25 ml of organic solvent 1, i.e., toluene,After the drop,The control temperature is 25-30 C,Stirring speed of 500r / min for 3h,The reaction was tracked with TLC plate to complete reaction;
Stage #1: ethyl O-(2-mesitylenesulfonyl)acetohydroxamate With perchloric acid In 1,4-dioxane; water at 0℃; for 0.5h;
Stage #2: pyridine-2-acetonitrile In dichloromethane at 20℃; for 1h;
Stage #3: With potassium carbonate In methanol at 0 - 20℃; for 2h;
With potassium acetate; silver carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: A mixture of phenylacetylene 1a(1 equiv.), ethyl-2-pyridylacetate 2a(2 equiv.), Ag2CO3 (2 equiv.), and KOAc (2 equiv.) in DMF was stirred at 110 C for 12 h. The completion of the reaction was monitored by TLC, the mixture was quenched with diluted hydrochloride (3 mL, 2M), and the reaction mixture was filtered with sintered funnel and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate 3 times. The organic layers were combined, and dried over sodium sulfate. The pure product was obtained by column chromatography on silica gel to afford 3a in 86% yield.
3-(4-methoxyphenyl)indolizine-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium acetate; silver carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: A mixture of phenylacetylene 1a(1 equiv.), ethyl-2-pyridylacetate 2a(2 equiv.), Ag2CO3 (2 equiv.), and KOAc (2 equiv.) in DMF was stirred at 110 C for 12 h. The completion of the reaction was monitored by TLC, the mixture was quenched with diluted hydrochloride (3 mL, 2M), and the reaction mixture was filtered with sintered funnel and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate 3 times. The organic layers were combined, and dried over sodium sulfate. The pure product was obtained by column chromatography on silica gel to afford 3a in 86% yield.
With potassium acetate; silver carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: A mixture of phenylacetylene 1a(1 equiv.), ethyl-2-pyridylacetate 2a(2 equiv.), Ag2CO3 (2 equiv.), and KOAc (2 equiv.) in DMF was stirred at 110 C for 12 h. The completion of the reaction was monitored by TLC, the mixture was quenched with diluted hydrochloride (3 mL, 2M), and the reaction mixture was filtered with sintered funnel and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate 3 times. The organic layers were combined, and dried over sodium sulfate. The pure product was obtained by column chromatography on silica gel to afford 3a in 86% yield.
With potassium acetate; silver carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: A mixture of phenylacetylene 1a(1 equiv.), ethyl-2-pyridylacetate 2a(2 equiv.), Ag2CO3 (2 equiv.), and KOAc (2 equiv.) in DMF was stirred at 110 C for 12 h. The completion of the reaction was monitored by TLC, the mixture was quenched with diluted hydrochloride (3 mL, 2M), and the reaction mixture was filtered with sintered funnel and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate 3 times. The organic layers were combined, and dried over sodium sulfate. The pure product was obtained by column chromatography on silica gel to afford 3a in 86% yield.
3-(thiophen-3-yl)indolizine-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium acetate; silver carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: A mixture of phenylacetylene 1a(1 equiv.), ethyl-2-pyridylacetate 2a(2 equiv.), Ag2CO3 (2 equiv.), and KOAc (2 equiv.) in DMF was stirred at 110 C for 12 h. The completion of the reaction was monitored by TLC, the mixture was quenched with diluted hydrochloride (3 mL, 2M), and the reaction mixture was filtered with sintered funnel and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate 3 times. The organic layers were combined, and dried over sodium sulfate. The pure product was obtained by column chromatography on silica gel to afford 3a in 86% yield.
2-(N-butyl-3-nitro-1,8-naphthalimide)-2-(pyridin-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
To a 50 mL three-necked flask was added 10 mL of anhydrous tetrahydrofuran and sodium hydroxide (0.16 g, 4.0 mmol) at room temperature,Pyridine-2-acetonitrile (0.07 g, 0.56 mmol) was added under nitrogen atmosphere,0.5h after the increaseTo a solution of the resulting N-butyl-4-bromo-3-nitro-1,8-naphthalimide (0.15 g, 0.4 mmol)To replace the reaction 2h,After the reaction was quenched with saturated brine, 50 mL of dilute hydrochloric acid was added to the acid,The resulting solution was extracted with ethyl acetate and separated on a silica gel column,A black solid powder was obtained in 63% yield.
3-(4-methoxyphenyl)indolizine-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper diacetate; In dimethyl sulfoxide; at 80℃; for 12h;
General procedure: The reaction mixture of terminal alkenes 1 (0.5 mmol), 2-alkylazaarenes 2 (0.5mmol), Cu(OAc)2 (20 mol%), and DMSO (2mL) in a 10 mL round-bottom flask was stirred at 80 C for 12 h.Upon completion, the reaction mixture was diluted with H2O(30 mL) and extracted with EtOAc (3 × 30 mL). The combinedorganic layers were washed with brine, dried over anhydrousNa2SO4, and filtered. The solvent was removed under vacuum.The residue was purified by flash column chromatography toafford indolizines 3.
With copper diacetate; In dimethyl sulfoxide; at 80℃; for 12h;
General procedure: The reaction mixture of terminal alkenes 1 (0.5 mmol), 2-alkylazaarenes 2 (0.5mmol), Cu(OAc)2 (20 mol%), and DMSO (2mL) in a 10 mL round-bottom flask was stirred at 80 C for 12 h.Upon completion, the reaction mixture was diluted with H2O(30 mL) and extracted with EtOAc (3 × 30 mL). The combinedorganic layers were washed with brine, dried over anhydrousNa2SO4, and filtered. The solvent was removed under vacuum.The residue was purified by flash column chromatography toafford indolizines 3.
ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68 g
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
KOBut (57.Og, 508.4mmol) was added to a solution 2-Pyridine acetonitrile (50.Og, 423.72mmol) and ethyl acrylate (89.Og, 889.8mmol) in THF (500mL) at 0 C and stirred for16h at RT. The reaction mixture was quenched with sat NH4CI solution and extracted withethyl acetate (2X500mL). The combined organic layer was washed with brine, dried overNa2504 and distilled under reduced pressure to afford 68.Og (60%; crude) of Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as brown color liquid
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0 C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
68 g
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (0206) KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0 C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
With potassium tert-butylate; In tetrahydrofuran; at 0 - 23℃; for 16h;
[0151] KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0C and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4C1 and extracted with EtOAc (2x500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
With potassium tert-butylate; In tetrahydrofuran; at 0 - 23℃; for 16h;
Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (0207) KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0 C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 16h;
KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0 C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
Example 7 Intermediate Compound G of Scheme 1 (0171) (0172) Intermediate compound G (Formula 8) was made by first adding 2-pyridineacetonitrile (18 mg; 0.15 mmol) to a suspension of of NaH (6 mg; 0.15 mmol) in toluene/DMF mixture (2:1; 1 mL). After stirring at ambient temperature for about 30 min, a solution of intermediate compound F (Formula 7) (25 mg; 0.07 mmol) in toluene/DMF mixture (2:1; 1 mL) was added and the reaction mixture was stirred at about 20 h. The reaction mixture was then diluted with ethylacetate (15 mL) and water (15 mL). The organic phase was separated, washed with water (3×10 mL), dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with EtOAc/PE (50:50) to provide intermediate compound G (Formula 8), which was a dark orange solid (25 mg; 83% yield). RF=0.45 (PE-EA 1:1). 1H NMR (300 MHz, CDCl3): delta 6.05 (s, 1H); 7.32 (dd, 1H); 7.47 (d, 1H); 7.79 (m, 2H); 8.13 (s, 1H); 8.21 (d, 1H); 8.44 (d, 1H); 8.60 (d, 1H). 19F NMR (125 MHz, CDCl3): delta -61.2 (s, 3F, CF3); 51.2 (d, 4F, SF5); 75.5 (p, 1F, SF5).
(E)-3-(3,4-dihydroxy-5-nitrophenyl)-2-(pyridin-2-yl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With ammonium acetate; In methanol;Reflux;
] A solution of 2-(pyridin-2-yl)acetonitrile (142 mg, 1.2 mmol), <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> (182 mg, 1 mmol) and NH4OAc (462 mg, 6 mmol) in MeOH (10 mL) was heated to reflux for overnight. LCMS showed no <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> left. The reaction mixture was cooled to room temperature. The solid was filtered and washed by MeOH and H20. The solid was re-dissolved in MeOH (5 mL). 5 mL of iN aqueous HC1 was added to adjust pH 34. The desired product was obtained by filter as a bright solid (56 mg, 20o). ?H NMR (400 MFIz, DMSO) 8.57 (m,, 1H), 8.12 (s, 1H), 7.92 (d, J= 2.2 Hz, 1H),7.84 (td, J 7.8, 1.8 Hz, 1H), 7.70 (d, J 8.1 Hz, 1H), 7.56 (d, J= 2.4 Hz, 1H), 7.3 1-7.25 (m, 1H). MS [MFT] calcd for C,4H9N304 284.0, found 284.0.
3-(3,4-dimethoxy-5-nitrophenyl)-3-oxo-2-(pyridin-2-yl)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Under a nitrogen atmosphere, NaH (60% w/w, 176 mg, 4.4 mmol) was added to solution of 2-(pyridin- 2-yl)acetonitrile (236 mg, 2.0 mmol) in anhydrous THF (10 mL) at -5C. The resulting suspension was stirred at-S C for 15 mm and the solution of 3,4- dimethoxy-5-nitrobenzoyl chloride (500 mg, 2.2 mmol) in THF (5 mL) was added over 10 mm and stirred for an additional 1 hour at -5 C. The reaction mixture was warmed to 0C, quenched by the addition of 1N.HC1 solution (4 mL) and stirred for 10 mm at room temperature. The mixture was extracted with ethyl acetate (25 mL X 2). The combined organic layers were dried with anhydrous sodium sulfate and concentrated in vacuo to give the desired product (425 mg, 64%). MS [MH]calcd for C16H14N305 328.09, found 328.1.
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%.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.0h;
2-(pyridin-2-yl)acetonitrile (5.000 g, 42.323 mmol) and sodium hydride (2.234 g, 93.110 mmol) was dissolved in N,N-dimethylformamide (100 mL) at 0 C and 1,3-dibromopropane (8.545 g, 42.323 mmol) was added at same temperature and stirred for 1 h, then after further stirring at room temperature for 17 hours, Water (10 mL) was added to the reaction mixture at 0 C, and the reaction was terminated by stirring for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 5% to 40%) and concentrated to give the title compound (0.891 g, 11.4%) as a pale yellow oil.
With [carbonylchlorohydrido{bis[2-(diphenylphosphinomethyl)ethyl]amino}ethylamino] ruthenium(II); potassium <i>tert</i>-butylate In toluene at 135℃; for 4h; Inert atmosphere;
With hydroxylamine; In ethanol; at 20℃;Sonication;
General procedure: The mixture of nitrile 1 (1 mmol) and hydroxylamine solution 50% (2 mmol) in ethanol (15 mL) was irradiated with ultrasound for 20-50 min. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with water (10 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated to afford the pure amidoxime.
(2Z,2'Z)-3,3'-((hexylazanediyl)bis(4,1-phenylene))bis(2-(pyridin-2-yl)acrylonitrile)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With piperidine; In toluene; at 120℃; for 2h;
General procedure: Compound-3a or 3b or 3c (0.0006 mol) was dissolved in 20 mLof toluene. To this 2- acetonitrile pyridine (0.0013 mol) and piperidine(0.0013 mol) was added and the reaction mixture was stirredapproximately at 120 C for 2 h. After completion of the reaction,the mixture was diluted with water extracted with DCM. The crudeproduct was purified by column chromatography using ethyl acetateand hexane as a mobile phase. DPA-PA-1: Yield: 75%; 1H NMR (400 MHz, CDCl3, deltappm): 8.54(d, 2H, pyridyl CH2), 8.31 (s, 2H, cyano-vinylene H), 7.89 (d, 4H,diphenylamine H), 7.64 (m, 4H, pyridine H), 7.15 (m, 2H, pyridineH), 7.06 (d, 4H, diphenylamine H), 3.75 (t, 2H, N-CH2), 1.97 (m, 2H,N-CH2CH2-), 1.64-1.20 (m, 6H, -CH2), 0.83 (t, 3H, CH3). 13C NMR(100 MHz, CDCl3, deltappm): 151.53, 149.52, 148.75, 148.46, 144.12, 137.22, 131.77, 126.83, 122.92, 120.75, 120.67 (aromatic C), 118.46,106.77 (vinylene C), 52.28 (-N-CH2-), 31.50, 27.54, 26.62, 22.60,14.03 (hexyl C). HRMS-ESI (m/z) calculated for C34H31N5[M - H]+ = 509.2579, found = 509.2575.
(2Z,2'Z)-3,3'-((dodecylazanediyl)bis(4,1-phenylene))bis(2-(pyridin-2-yl)acrylonitrile)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With piperidine; In toluene; at 120℃; for 2h;
General procedure: Compound-3a or 3b or 3c (0.0006 mol) was dissolved in 20 mLof toluene. To this 2- acetonitrile pyridine (0.0013 mol) and piperidine(0.0013 mol) was added and the reaction mixture was stirredapproximately at 120 C for 2 h. After completion of the reaction,the mixture was diluted with water extracted with DCM. The crudeproduct was purified by column chromatography using ethyl acetateand hexane as a mobile phase.
(2Z,2'Z)-3,3'-((allylazanediyl)bis(4,1-phenylene))bis(2-(pyridin-2-yl)acrylonitrile)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With piperidine; In toluene; at 120℃; for 2h;
General procedure: Compound-3a or 3b or 3c (0.0006 mol) was dissolved in 20 mLof toluene. To this 2- acetonitrile pyridine (0.0013 mol) and piperidine(0.0013 mol) was added and the reaction mixture was stirredapproximately at 120 C for 2 h. After completion of the reaction,the mixture was diluted with water extracted with DCM. The crudeproduct was purified by column chromatography using ethyl acetateand hexane as a mobile phase.
diphenyl(vinyl)sulfonium trifluoromethanesulfonate[ No CAS ]
1-(pyridin-2-yl)cyclopropanecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 21℃; for 12h;
General procedure: To a 5 mL Schlenk tube were added aryl / heteroaryl acetonitriles 1 (1.0 mmol, 1.0 equiv.), vinyl diphenylsulfonium triflate (434.4 mg, 1.2 mmol, 1.2 equiv.), and DMSO (5 mL). The mixture was stirred at room temperature for 2 min and to the mixture DBU (456 mg, 3 mmol, 3.0 equiv.) was added. The mixture was stirred for 12 hours at room temperature, and then to the mixture was added saturated ammonium chloride solution (25 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with H2O (2 x 30 mL), dried with anhydrous sodium sulfate. After concentration, product 2 was purified using silica gel column chromatography using an appropriate eluent.
Weigh out metallic sodium (52 mg, 1.3 eq.) accurately and add it to absolute ethanol (10 mL) at 0C.Stir until complete conversion of the metal sodium, then add 2-pyridineacetonitrile (225.1 mg, 1.1 eq.),After stirring at room temperature for 5 minutes, Intermediate 2a (300 mg, 1.0 eq) was added and stirring was continued at room temperature overnight.After the reaction was completed, the pH of the reaction solution was adjusted to 6-8 with a 1N hydrochloric acid solution, extracted three times with dichloromethane, and the dichloromethane layer was washed once with saturated brine. After drying, the solvent was distilled off under reduced pressure.The resulting solid was purified by column chromatography to give an orange solid 278 mg, yield 65.1%
2-(pyridin-2-yl)-2-(tetrahydro-2-furanyliden)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine; In 1,4-dioxane; at 0 - 70℃; for 1.5h;
General procedure: To a suspension of hetarylacetonitriles 2a-2h (10 mmol) in25 cm3 of anhydrous dioxane 3.45 cm3 of triethylamine(25 mmol) was added. The reaction mixture was cooled to0-5 C and 1.4 cm3 of 4-chlorobutyric chloride(12.5 mmol) in 5 cm3 of anhydrous dioxane was addeddropwise with stirring. The reaction mixture was stirred for30 min at room temperature and then heated at 50-70 Cfor 1 h (with TLC monitoring). Then, the solvent wasevaporated in vacuo. For compounds 1a-1f the residue wasdiluted with 50 cm3 of water and the precipitated productwas filtered off, washed with water, dried, and recrystallizedfrom appropriate solvent. For compounds 1g and 1h,the residue was diluted with 100 cm3 of water and extracted with DCM (2 9 50 cm3). The combined extractswere washed with brine, dried over Na2SO4, and evaporatedin vacuo. The residue was purified by silica gelcolumn chromatography using a mixture of CHCl3-MeOHto yield the oily product.
1-hydroxy-2-(2-pyridyl)ethane-1,1-diphosphonic acid monosodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Aqueous methanesulfonicacid (85%, 432.5 mL) was added to 2-pyridylacetonitrile(10.0 g, 0.085 mol), and the mixture washeated at 98-100C for 8 h. After cooling to 65C,PCl3 (39.6 g, 0.288 mol) was added over a period of25 min. After stirring for 5 h at 65-70C, the mixturewas cooled to 30C, and precooled water (1000 mL)was added very slowly over a period of 30 min. Then,the mixture was heated to 98C and stirred at this temperaturefor 15 h. After cooling to 50C, pH 4.3 wasadjusted with 30% NaOH solution, and methanol(1500 mL) was added. After stirring for 2 h at 5-10C,the product was collected by filtration and dried.HPEDP (yield 71 ± 4%) was obtained in the form ofhemipentahydrate as a white solid.
3-benzyl-2-phenylindolizine-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,6-bis(diphenylphosphanyl)dibenzofuran; In N,N-dimethyl-formamide; at 120℃; for 16h;Inert atmosphere;
General procedure: Ethyl 2-(pyridin-2-yl)acetate (1a, 0.4 mmol), 1,3-diphenylprop-2-yn-1-yl methyl carbonate (2a, 0.2 mmol),Pd2(dba)3 (0.01 mmol), DBFphos (0.02 mmol), K2CO3 (0.4 mmol)were mixed under N2 atmosphere in DMF (2 mL). The reactiontube was heated in an oil bath at 120 C for 16 h. After completionof the reaction, the reaction mixture was extracted withEtOAc (3 × 15 mL), and the solvent was removed under reducedpressure. The remaining crude product was then purifiedthrough column chromatography using silica gel (EtOAc-petroleumether = 1:5) to afford 3a as a white solid in 65% yield. 1HNMR (500 MHz, CDCl3): delta = 8.24 (dd, J = 9.2, 1.3 Hz, 1 H), 7.53 (d,J = 7.0 Hz, 1 H), 7.23-7.32 (m, 5 H), 7.15 (t, J = 7.3 Hz, 2 H), 7.10(t, J = 7.2 Hz, 1 H), 6.93- 6.99 (m, 3 H), 6.54 (td, J = 6.8, 1.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2 H), 4.08 (s, 2 H), 1.06 (t, J = 7.1 Hz, 3 H).13C NMR (125 MHz, CDCl3): delta = 165.2, 137.5, 136.2, 135.4, 131.5,130.5, 128.9, 127.8, 127.7, 127.1, 126.7, 123.4, 122.2, 121.4,120.2, 112.6, 102.0, 59.3, 30.2, 14.3. HRMS (ESI): m/z [M + H]+calcd for C24H22NO2 : 356.1645; found 356.1642
5-bromo-2-butyl-7-(trifluoromethyl)-1H-benzo[de]-isoquinoline-1,3(2H)-dione[ No CAS ]
2-(8-bromo-2-butyl-1,3-dioxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-4-yl)-2-(pyridin-2-yl)-acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
General procedure: To a solution of NaH (60%, 0.24 g, 6.00 mmol) in 10 mL of CH3CN was added aryl acetonitrile (1.10 mmol) under N2 atmosphere at room temperature, and stirred for 30 min. Then, compound 1 (0.40 g,1.00 mmol) was added into the mixture. The mixture was stirred at room temperature for another 4 h and quenched with saturated citric acid.The solution was extracted with ethyl acetate (20 mL x 3), and the organic layer was dried over anhydrous sodium sulfate, concentrated,and purified by column chromatography to give 3.
49.6%
0.16 g (1.41 mmol) of <strong>[2739-97-1]pyridine-2-acetonitrile</strong> and 0.28 g (7.0 mmol) were added to a 50 ml three-necked flask.The base catalyst NaH (60w%) and tetrahydrofuran 25ml were replaced three times with nitrogen.After stirring at room temperature for 30 min, 0.5 g (1.25 mmol) obtained in Example 2 was added.4-trifluoromethyl-6-bromo-1,8-naphthalimide compound, N-n-butyl-4-trifluoromethyl-6-bromo-1,8-naphthalimide continued to react at room temperature for 3 h,The reaction process was followed by TLC dot plate until the reaction was complete; After completion of the reaction, the pH of the reaction mixture was adjusted to 1-2 with a saturated citric acid solution, and then extracted with ethyl acetate.The obtained organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and then separated by silica gel column chromatography.The eluent used in the separation process is a mixture of petroleum ether (boiling range: 60-90 C): ethyl acetate in a volume ratio of 15:1.The peak of the stage of Rf = 0.6 (the ratio of petroleum ether: ethyl acetate was 3:1) was collected, and finally 0.32 g of a pale green crystal product was obtained with a yield of 49.6%.
4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
General procedure: An oven-dried screw cap test tube was charged with a magnetic stir bar, Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), and K2CO3 (0.4mmol). The tube was then evacuated and backfilled with argon.The evacuated/backfill sequence was repeated two additional times. Under a counter-flow of argon, DMF (1 mL), iodoarene(1a, 0.2 mmol), and methyl propiolate (2a, 0.3 mmol) were added. The tube was placed in a preheated oil bath at 80 C, andthe mixture was stirred vigorously for 10 min. Then the screwcap was opened and 2-pyridyl ethyl ester (3a, 0.2 mmol) wasadded in air at 80 C. The mixture was allowed to react for another 8 h at 80 C in air atmosphere. After the reaction was finished, water (5 mL) was added, and the solution wasextracted with ethyl acetate (3 × 5 mL), the combined extractwas dried with anhydrous MgSO4. Solvent was removed, andthe residue was separated by column chromatography (petroleumether/ethyl acetate, 2:1) to give 4a (50 mg, 86%) as ayellow solid.
3-[[(tert-butyldimethylsilyl)oxy]methyl]-5-(2-hydroxyethyl)benzaldehyde[ No CAS ]
3-(3-[[(tert-butyldimethylsilyl)oxy]methyl]-5-(2-hydroxyethyl)phenyl)-2-(pyridin-2-yl)prop-2-enenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With ammonium acetate; In methanol; at 60℃; for 0.5h;
Into a 50-mL round-bottom flask, was placed 3-[[(tert-butyldimethylsilyl)oxy] methyl] -5 -(2-hydroxy ethyl)benzaldehyde (270 mg, 0.92 mmol, 1.00 eq.), 2-(pyridin-2-yl)acetonitrile (108.4 mg, 0.92 mmol, 1.00 eq.), CFLCOONFL (353.6 mg, 4.59 mmol, 5.00 eq.), methanol (4 mL). The resulting solution was stirred for 30 min at 60C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was separated by PREP-TLC with ethyl acetate/petroleum ether (1:1). This resulted in 240 mg (66%) of 3-(3-[[(tert-butyldimethylsilyl)oxy]methyl]-5-(2- hydroxyethyl)phenyl)-2-(pyridin-2-yl)prop-2-enenitrile as yellow oil.
General procedure: Step 1: To an 8-mL culture tube with stir bar was added lithium chloride (1.1 equiv) and the flask was flame-dried under vacuum and cooled under an atmosphere of N2. THF (1.0 M) was added, followed by the appropriate nitrile (1.0 equiv). While stirring, methylmagnesium bromide (1.1 equiv of a solution in Et2O) was added dropwise at r.t., and the solutionwas stirred at r.t. for 30 min under an atmosphere of N2. A 1.1M stock solution of dimethylmanononitrile (DMMN) or dibenzylmalononitrile (DBMN) inTHF was prepared and added at r.t. (1.1 equiv of a 1.1M solution inTHF, reaction volume 0.50M with respect to nitrile starting material). The reaction was stirred at 80 C for 6 h under an atmosphere of N2. Step 2: The reaction was cooled to r.t. and DMF was added to bring the reaction solvent to a 1:1 THF/DMF ratio (0.25Mof a 1:1 THF/DMF mixture with respect to nitrile starting material). The desired electrophile (1.2 equiv) was added in a single portion. Ifthe electrophile was a solid, it was added with the DMF as a 0.60Mstock solution. The reaction was stirred at 80 C for 16 h, or until complete conversion was achieved as judged by TLC. The reaction was cooled to r.t., opened to air, quenched with 1M aq. HCl, and extracted with EtOAc (3). The organic fractions were combined,dried over MgSO4, and concentrated. The crude residue was purified by flash column chromatography to yield the desired malononitrile.
With hydrogenchloride; In methanol; water; at 70 - 72℃; for 5h;
To a 500 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser.Add 50 grams of methanol, 80 grams of water, 11.8 grams (0.1 moles) of <strong>[2739-97-1]pyridine-2-acetonitrile</strong>,5.0 g (0.17 mol) of paraformaldehyde,10.0 g (0.11 mol) of aniline,0.2 g of 30% hydrochloric acid, stirring at 70 to 72 C for 5 hours,Cool to 20 ~ 25 C, extract 3 times with dichloromethane,50 grams of dichloromethane each time, combined with dichloromethane phase,10.0 g of 5% aqueous sodium hydrogencarbonate solution was washed once, and the solvent was distilled off.Obtained 22.1 g of a pale yellow viscous liquid, 3-anilino-2-(pyridin-2-yl)propionitrile (II1),The yield was 99.1%, and the gas phase purity was 99.8%.
With sodium hydroxide; In ethanol; at 20℃; for 1h;Inert atmosphere;
1) In a 250 mL round bottom flask,1 g (2.13 mmol) of 2,5-diphenylamine-1,4-dicarbaldehyde benzene,504.28 mg (4.26 mmol) of 2-pyridineacetonitrileAnd 37.804mL of absolute ethanol,Get a mixed solution; 2) 1.32 g (33.08 mmol) of sodium hydroxide is dissolved in 37.8 mL of absolute ethanol,Obtain a sodium hydroxide-ethanol solution; 3) Using a constant pressure dropping funnel,Add the sodium hydroxide-ethanol solution to the mixture dropwise under the protection of nitrogen,The reaction was stirred at room temperature for 1 hour.After cooling to room temperature and filtering, the obtained solid was washed with water and ethanol alternately three times, and after drying, it was recrystallized from dichloromethane and ethanol.Suction filtration gave orange-red crystal compound 2,78.2% yield;
With DBN; In 1,4-dioxane; at 70℃; for 4.0h;Inert atmosphere; Sealed tube;
In a 10 mL dry sealed reaction tube, add <strong>[114078-88-5]5-bromo-1,2,3-triazine</strong> 1a (15.9 mg, 0.10 mmol), DBN (37.3 mg, 0.30 mmol) in sequenceAnd 2-acetonitrile pyridine 6b (23.6 mg, 0.20 mmol). After nitrogen substitution three times, the solvent 1,4-dioxane (1.0 mL) was added, and the sealed reaction tube was placed at 70 C. for 4 h. The reaction was monitored by TLC. After the reaction was completed, it was extracted with dichloromethane (3 * 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the target product 27c. For the single crystal structure, see FIG. 1.
With potassium <i>tert</i>-butylate; palladium diacetate; nixantphos In 1,4-dioxane at 60℃; for 10h; Inert atmosphere; Sealed tube;
General procedure for direct α-arylation of 2-pyridylacetonitrile derivatives with aryl bromides
General procedure: 5 mol% Pd(OAc)2 /7.5 mol% Nixantphos, anhydrous 1,4-dioxane (3.0 mL) were added to a dried 10 mL reaction vial equipped with a stir bar, the mixture was stirred at 45 under an argon atmosphere for 1h to be a dark brown solution. 2-pyridylacetonitrile derivatives (1.0 mmol), aryl bromides (1.5 mmol) and t-BuOK (2.0 mmol) were added to a dried 10 mL reaction vial equipped with a stir bar. A stock solution of Pd(OAc)2/Nixantphos in 1 mL of dried 1,4-dioxane was taken up by syringe and added to the reaction vial. The reaction vial filled with argon was then sealed with a septum. The reaction mixture was stirred for10 h at 60 °C, quenched with two drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of MgSO4 and silica. The pad was rinsed with additional ethyl acetate, and the solution was concentrated in vacuo. The crude material was loaded onto a silica gel column and purified by flash chromatography.
With potassium <i>tert</i>-butylate; palladium diacetate; nixantphos In 1,4-dioxane at 60℃; for 10h; Inert atmosphere; Sealed tube;
General procedure for direct α-arylation of 2-pyridylacetonitrile derivatives with aryl bromides
General procedure: 5 mol% Pd(OAc)2 /7.5 mol% Nixantphos, anhydrous 1,4-dioxane (3.0 mL) were added to a dried 10 mL reaction vial equipped with a stir bar, the mixture was stirred at 45 under an argon atmosphere for 1h to be a dark brown solution. 2-pyridylacetonitrile derivatives (1.0 mmol), aryl bromides (1.5 mmol) and t-BuOK (2.0 mmol) were added to a dried 10 mL reaction vial equipped with a stir bar. A stock solution of Pd(OAc)2/Nixantphos in 1 mL of dried 1,4-dioxane was taken up by syringe and added to the reaction vial. The reaction vial filled with argon was then sealed with a septum. The reaction mixture was stirred for10 h at 60 °C, quenched with two drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of MgSO4 and silica. The pad was rinsed with additional ethyl acetate, and the solution was concentrated in vacuo. The crude material was loaded onto a silica gel column and purified by flash chromatography.
With potassium tert-butylate; palladium diacetate; nixantphos; In 1,4-dioxane; at 60℃; for 10.0h;Inert atmosphere; Sealed tube;
General procedure: 5 mol% Pd(OAc)2 /7.5 mol% Nixantphos, anhydrous 1,4-dioxane (3.0 mL) were added to a dried 10 mL reaction vial equipped with a stir bar, the mixture was stirred at 45 under an argon atmosphere for 1h to be a dark brown solution. 2-pyridylacetonitrile derivatives (1.0 mmol), aryl bromides (1.5 mmol) and t-BuOK (2.0 mmol) were added to a dried 10 mL reaction vial equipped with a stir bar. A stock solution of Pd(OAc)2/Nixantphos in 1 mL of dried 1,4-dioxane was taken up by syringe and added to the reaction vial. The reaction vial filled with argon was then sealed with a septum. The reaction mixture was stirred for10 h at 60 C, quenched with two drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of MgSO4 and silica. The pad was rinsed with additional ethyl acetate, and the solution was concentrated in vacuo. The crude material was loaded onto a silica gel column and purified by flash chromatography.
(Z)-2-(pyridin-2-yl)-3-(2,4,5-trimethoxyphenyl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium hydroxide In methanol at 58℃; for 18h;
The general method used to obtain the compounds (I, III, IV and V)
General procedure: An amount of 2,4,5-TMB (5.0 mmol) dissolved in (6 ml) of methanol were added 5.0 mmol of the acetonitrilederivative (PhAcN or 2-, 3- 4-PyAcN) in a ball flask, The reaction mixture temperature wasraised to reflux and KOH as catalyst was added. The resume of the reaction conditions isshown in Table S1. At the beginning of the reactions, the mixtures acquired differentappearances as brown yellow, a darker color, orange color. After the reaction mixture timebecame dense up until the precipitate formation. The precipitates were filtered under vacuumto obtain the powders, which are washed several times with distilled water. The products IIVwere purified by double recrystallization from methanol obtaining a yellows powderswith melting points and yields that are resume in the Table S1.
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