* 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] Catalysis Science and Technology, 2015, vol. 5, # 4, p. 2406 - 2417
2
[ 24964-64-5 ]
[ 115-20-8 ]
[ 244621-31-6 ]
Reference：
[1] Patent: US6509335, 2003, B1,
3
[ 64-17-5 ]
[ 24964-64-5 ]
[ 2463-16-3 ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate In water at 20℃; for 5 h;
General procedure: A mixture of bromine chloride resin and K2CO3 in MeOH–H2O (8:2) 3 mL was placed in a round-bottom flask fitted with amagnetic stirrer. To this, the aldehyde (1 mmol, 1 equiv) was added dropwise, and the reaction mixture stirred at r.t. The progress of the reaction was monitored by TLC. After completionof the reaction the mixture was filtered, and the filtrate was extracted with Et2O. The ether layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, if required, over silicagel (60–120 mesh) using a mixture of PE and EtOAc (9:1) as eluent.
Reference：
[1] Synlett, 2016, vol. 27, # 9, p. 1344 - 1348
[2] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 2070 - 2072
4
[ 24964-64-5 ]
[ 1877-77-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With lithium aluminium tetrahydride In tetrahydrofuranHeating / reflux
Lithium aluminum hydride (1.0 M in THF, 29.9 mL, 29.9 mmol) was added slowly to a solution of 3-cyanobenzaldehyde (1.12 g, 9.25 mmol) in anhydrous THF (25.0 mL) at room temperature under argon and the mixture was stirred at reflux (overnight). The reaction mixture was cooled to room temperature and quenched by addition of ice and NaOH (aq. 3.0 N, 10.0 mL). The mixture was extracted with chloroform (3 x 80 mL) and the combined organic phase was washed with brine (2 x 20 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by silica gel column chromatography to yield [3- (hydroxymethyl)phenyl] amine as colorless oil (70percent yield). [1H NMR (CDCl3): δ 7.26-7.22 (m, IH), 7.21-7.19 (m, IH), 7.16-7.14 (m, IH), 7.12-7.09 (m, IH), 4.55 (d, 2H, J = 6.0 Hz), 3.71 (d, 2H, /= 8.0 Hz); 13C NMR (CDCl3): δ 142.7, 142.0, 128.6, 126.0, 125.5, 125.4, 64.4, 46.1; FAB-MS m/z 138.1 (MH+).] Reaction of this material according to general procedure G provided 23f in 38percent yield. 1H NMR (CDCl3): δ 7.22 (s, IH), 7.20-7.18 (m, 2H), 7.11-7.09 (m, IH), 6. 98 (d, IH, 7 = 8.4 Hz), 6.91 (d, IH, 7 = 8.4 Hz), 4.60 (s, 2H), 4.57 (s, 2H), 4.06 (s, 2H), 4.01 (d, 3H, 7 = 1.2 Hz), 3.80 (d, 3H, 7 = 1.2 Hz); 13C NMR (CDCl3): δ 166.8, 152.2, 147.2, 141.9, 137.1, 134.5, 128.8, 127.0, 126.6, 126.1, 124.7, 117.8, 116.5, 64.6, 62.4, 56.7, 48.5, 46.2; FAB-MS m/z 314.1 (MH+).
Reference：
[1] Chemistry Letters, 1987, p. 1113 - 1116
6
[ 24964-64-5 ]
[ 42287-97-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 437 - 450
[2] Die Pharmazie, 1973, vol. 28, # 11, p. 724 - 729
7
[ 141-82-2 ]
[ 24964-64-5 ]
[ 16642-93-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: at 100℃; for 4 h; Stage #2: With hydrogenchloride In water at 20℃;
General procedure: 3-Cyanobenzaldehyde (11a) or 4-cyanobenzaldehyde (11b) (15 mmol) and malonic acid (30 mmol) were dissolved in pyridine (30 mL). Piperidine (3.0 mmol) was added and the reaction was heated for 4 h at 100 °C. The reaction was cooled to room temperature and 5 M HCl (25 mL) was added slowly. The resulting white precipitate was collected by filtration, washed with water and dried to give (E)-3-cyanocinnamic acid (12a) or (E)-4-cyanocinnamic acid (12b) in yields of 81percent and 78percent, respectively.
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 5162 - 5174
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 1560
[3] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2021 - 2034
[4] Patent: WO2006/123725, 2006, A1, . Location in patent: Page/Page column 40
8
[ 24964-64-5 ]
[ 16642-93-6 ]
Reference：
[1] Patent: US4665189, 1987, A,
9
[ 24964-64-5 ]
[ 126534-87-0 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 18, p. 5690 - 5698
[2] RSC Advances, 2013, vol. 3, # 3, p. 895 - 899
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118
[2] New Journal of Chemistry, 2010, vol. 34, # 12, p. 2922 - 2931
12
[ 42967-27-1 ]
[ 24964-64-5 ]
[ 90389-96-1 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1985, # 2, p. 64 - 65
[2] Journal of the Chemical Society, Chemical Communications, 1985, # 2, p. 64 - 65
13
[ 24964-64-5 ]
[ 593-51-1 ]
[ 90389-96-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 16, p. 2527 - 2531
14
[ 24964-64-5 ]
[ 34231-22-6 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 15, p. 4786 - 4797
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 2, p. 251 - 259
[3] Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5438 - 5443
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S404 - S406
[5] Organic Mass Spectrometry, 1993, vol. 28, p. 67 - 70
[6] Journal of Catalysis, 2011, vol. 284, # 2, p. 176 - 183
15
[ 24964-64-5 ]
[ 226070-69-5 ]
Reference：
[1] Patent: WO2005/18557, 2005, A2,
16
[ 24964-64-5 ]
[ 550364-01-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4645 - 4648
17
[ 24964-64-5 ]
[ 775304-57-9 ]
Reference：
[1] Patent: US2017/362192, 2017, A1,
18
[ 24964-64-5 ]
[ 220364-34-1 ]
Reference：
[1] Patent: WO2005/18557, 2005, A2,
19
[ 109-01-3 ]
[ 24964-64-5 ]
[ 859850-90-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #2: With sodium carbonate In dichloromethane; water
Preparation 14: 1-[3-(4-WlethyI-piperazin-1-ylmethyl)-phenyI]-ethanone; STEP A; A mixture of 3-formyl-benzonitrile (1.5 g, 11.45 mmol), N-methyl piperazine (1.49 g, 14.9 mmol) and NaBH(OAc)3 (3.63 g, 17.18 mmol) in DCM (75 ml) and CH3COOH (0.851 ml, 14.9 mmol) was stirred overnight at room temperature, then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.5) to give 1.7 g of 3-(4- methyl-piperazin-1-ylmethyl)-benzonitrile. Y= 70percent
70%
Stage #1: With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #2: With sodium carbonate In dichloromethane; water
STEP A A mixture of 3-formyl-benzonitrile (1.5 g, 11.45 mmol), N-methyl piperazine (1.49 g, 14.9 mmol) and NaBH(OAc)3 (3.63 g, 17.18 mmol) in DCM (75 ml) and AcOH (0.851 ml, 14.9 mmol) was stirred at RT overnight and then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.5) to give 3-(4-methyl-piperazin-1-yl-methyl)-benzonitrile (1.7 g). Y=70percent
General procedure: 3-Cyanobenzaldehyde (11a) or 4-cyanobenzaldehyde (11b) (15 mmol) and malonic acid (30 mmol) were dissolved in pyridine (30 mL). Piperidine (3.0 mmol) was added and the reaction was heated for 4 h at 100 C. The reaction was cooled to room temperature and 5 M HCl (25 mL) was added slowly. The resulting white precipitate was collected by filtration, washed with water and dried to give (E)-3-cyanocinnamic acid (12a) or (E)-4-cyanocinnamic acid (12b) in yields of 81% and 78%, respectively.
With maleic anhydride; 2,2'-biquinoline; Dimethylphenylsilane; nickel(II) acetate tetrahydrate; In tetrahydrofuran; at 100℃; for 12h;Schlenk technique; Inert atmosphere;
Add 3-cyanobenzoic acid (74mg, 0.50mmol) to a dry 10mL Schlenk reaction tube, then add L8 (64mg, 0.25mmol), Ni (OAc) 2.4H2O (37mg, 0.15mmol) in sequence, and argon Under protectionTHF (3.0 mL), maleic anhydride (294 mg, 3 mmol) and HSiMe2Ph (150 muL, 1 mmol) were added, and reacted at 100 C. for 12 h. After the reaction is completed, extract,The solvent was removed under reduced pressure, and column chromatography (petroleum ether / tetrahydrofuran = 15/1, volume ratio) gave the target product H. Experimental data of this compound: Crystalline Powder, isolated yield 63%
With [Ir(2,2':6',2'?-terpyridine)(1,10-phenanthroline)Cl](PF6)2; sodium formate; In ethanol; water; at 100℃; for 0.333333h;Microwave irradiation;
General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid.
98%
With sodium tetrahydroborate; In tetrahydrofuran; methanol;
To an ice-cold solution of 3-cyanobenzaldehyde (5. 0 g, 38 mmol) in 1: 1 MEOH/THF (90 ML) was added NaBH4 (1.6 g, 42 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with brine, and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous layer was extracted with Et2O (3 x 100 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which was used in the next step without further purification or characterization.
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 2h;
3-Hydroxymethyl-benzonitrile was prepared as follows: To 3- cyanobenzaldehyde in dry MeOH at O0C was added NaBH4 and the reaction stirred at room temperature for 2hours. The mixture was quenched with 50:50 H2O:sat. aq.NaHCO3 then extracted into MeOH-EtOAc to yield 3-hydroxymethyl-benzonitrile.
With hydrogen; In methanol; water; at 79.84℃; under 30003.0 Torr; for 4h;
Unless specified otherwise, all hydrogenation reactions were carried out at 353 K in small glass vials placed inside a 200-mL autoclave with vigorous magnetic stirring (P900 RPM). Conversions and selectivities were measured by 1H NMR and gas chromatographic techniques. All hydrogenated products were initially identified by using authentic commercial samples of the expected products. The recycling experiments with 1 and 2 were carried out at 353 K under 50 and 40 bar H2 pressure, respectively, with a substrate-to-Ru molar ratio of 283 and 625 in 5 mL of methanol and water, respectively. Recycling experiments with 2 covering five successive batches were also carried out with styrene as the substrate, with a styrene-to-Ru molar ratio of 625 in 5 mL of methanol. Catalyst 1 was filtered off, washed several times with methanol, and used for the second batch. For the reaction with 2, the product was separated from the aqueous solution by ethyl acetate extraction(2 x 10 mL). The aqueous solution of 2 was then reused. A few recycling experiments were also carried out, where 2 was precipitated from the water solution by the addition of acetone and reused. The results obtained by both these methods of catalyst recovery were comparable.
With methanol; sodium tetrahydroborate; for 1h;Cooling with ice;
General procedure: To a solution of compound 7a (1.06 g, 10 mmol) in methanol(10 mL) was added NaBH4 (0.57 g, 15 mmol). After stirring for 1 hwhile cooled with an ice-water bath, methanol was evaporatedand the residue was dissolved in EtOAc (100 mL). The organic layerwas washed with water (3 100 mL) and brine (3 100 mL), anddried over MgSO4 overnight. EtOAc was evaporated to give 8a ascolorless oil (2.01 g, yield: 94%). ESI-MS m/z 109.4 [M+H]+. The crude product was used directly in the next reaction without furtherpurification. Compounds 8b-8u, 8aa-8ff, 10v-10w, 17a-17b and 22a-22hwere prepared using the same procedure described above
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; rac-Ala-OH; iron(II) bromide; In 1,4-dioxane; for 12h;Reflux; Green chemistry;
Equipped with a magnetic stirrer in round bottom flask methyl benzyl alcohol (12. 22g, 100. Ommol, namely formula The R1 is 4-methyl, R2 is hydrogen, X is carbon, eta is 1, m is 0), ferric chloride (0. 81g, 5mmol), L- isoleucineAcid (1.31g, 10mmol), TEMP0 (1.56g, 10mmol), toluene 300. OmL was added , then the reaction with oxygen in the air bottleReplacement, stirred and reflux for 6h. After completion of reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate evaporated to give the crude product,The resultant crude product was purified by column chromatography, with n-hexane: Elution: (10 1 volume ratio) mixed liquid of ethyl acetate containing the desired collectionLabeled compound of the eluent, evaporation of the solvent and dried to give the product p-tolualdehyde 10. 93g, 91%.Reactants used were 3-cyano-benzyl alcohol (1.33g, 10. Ommol, i.e., of formula (I), R1 is cyano, R2Is hydrogen, X is carbon, [eta] is l, m is 0 is taken, experimental methods and procedures were the same as in Example 1, except that: ferrous bromide (0. llg,0. 5mmol), DL- alaine propionic acid (0 · 09g, lmmol), TEMPO (0 · 16g, lmmol), dioxane 30. OmL, the reaction with oxygenAfter stirring at reflux of air displacement should bottle 12h. To give the final product 1. 17g, yield 89%.
88%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium carbonate; N-Phenylglycine; copper(ll) bromide; In water; for 2h;Reflux; Schlenk technique;
General procedure: A mixture of p-methylbenzyl alcohol (1.0 mmol), N-phenylglycine(0.0076 g, 0.05 mmol), CuBr2 (0.0112 g, 0.05 mmol),Na2CO3 (0.1060 g, 1.0 mmol), TEMPO (0.0078 g, 0.05 mmol),H2O (3.0 mL) were added to a 100 mL Schlenk tube, which wasvigorously stirred in air under reflux for 0.5 h. After the reaction,the product was extracted with CH2Cl2 (3 × 2.0 mL). Thecombined organic phase was washed with H2O (3.0 mL) anddried over anhydrous MgSO4. After concentration undervacuum, the residue was purified by column chromatography toafford p-methylbenzaldehyde.Isolated yield: 0.1080 g (90%).
69%
With indium(III) triflate; chloroamine-T; In acetonitrile; for 3h;Reflux; Inert atmosphere;
General procedure: The starting 1-(paratolyl)ethanol (1 mmol), chloramine-T (1 mmol), and In(OTf)3(0.3 mmol) were dissolved in CH3CN (10 mL) in a 100 mLflask equipped with a magnetic stirrer and a reflux condenser.The reaction mixture was heated at reflux for 3 h under anArgon atmosphere and was monitored for completion by TLC.After the reaction mixture was cooled to room temperature,the solvent was removed via rotary evaporation. The residueof the reaction mixture was separated through flash columnchromatography on silica gel. The obtained product was confirmed by spectroscopy.
With toluene-4-sulfonic acid; In benzene; for 18h;Heating / reflux;
EXAMPLE 19 5-chloro-2-(3-formylbenzyl)-isothiazol-3-one (Cpd 59) 3-cyanobenzaldehyde Compound 19a (10.00 grams, 76.3 mmol), p-toluenesulfonic acid (2.0 grams), ethylene glycol (18 mL) and benzene (100 mL) were added to a 200 mL round bottom flask equipped with a Dean-Stark trap. The reaction mixture was stirred at reflux for 18 hrs before being concentrated in vacuo. EtOAc (200 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate, then water. The organic layer was dried (sodium sulfate) and evaporated to give 3-[1,3]dioxolan-2-yl-benzonitrile Compound 19b (12.43 g, 93%) as an oil. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.50 (t, 1H), 5.83 (s, 1H), 4.10 (m, 4H).
With toluene-4-sulfonic acid; In toluene;Heating / reflux;
To a solution of 3-formyl-benzonitrile (2 g, 15.25 mmol, 1 eq) in dry toluene (30 mL), paratoluenesulfonic acid (262 mg, 1.5 mmol, 0.1 eq) and ethylene glycol (12.8 mL, 228 mmol, 15 eq) were added and the mixture was heated to reflux in a Dean-Stark apparatus overnight. The toluene was concentrated and the reaction mixture purified by flash chromatography (EtOAc/cHex) to afford the title compound as a colorless liquid (2000 mg, <n="172"/>74%). 1H NMR: (CDCI3, 300 MHz) δ 7.78 (m, 1 H), 7.69 (m, 1 H), 7.64 (m, 1 H), 7.48 (t, J=7.7 Hz, 1 H), 5.81 (s, 1 H), 4.08 (m, 4H). HPLC (Method A) Rt: 2.45 min (purity: 92.1%).
Reference example 1 3-Cyanocinnamaldehyde To a solution of 3-cyanobenzaldehyde (4.5 g) in toluene (200 ml) was added <strong>[2136-75-6](triphenylphosphoranylidene)acetaldehyde</strong> (13.6 g), and the resulting mixture was stirred at 70C for 4 hours and then evaporated in vacuo.. The residue obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent.. The crude product obtained was recrystallized from a mixture of toluene and hexane to afford the title compound (3.09 g, yield: 57 %) as pale yellowish needle crystals. 1H NMR (500MHz, CDCl3) delta ppm: 6.76 (1H, dd, J=16.0, 7.5), 7.46 (1H, d, J=16.0), 7.58 (1H, t, J=8.0), 7.73 (1H, d, J=8.0), 7.80 (1H, d, J=8.0), 7.84 (1H, s), 9.75 (1H, d, J=7.5).
3-(1-methyl-3,5-dioxo-3,4,5,6,8,9-hexahydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridin-4-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 53 3-(1-methyl-3,5-dioxo-3,4,5,6,8,9-hexahydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridin-4-yl)benzonitrile The product from Example 45A (0.085 g, 0.75 mmol), 3-cyanobenzaldehyde (0.14 g, 0.75 mmol) and <strong>[61363-56-2]2H-pyran-3,5(4H,6H)-dione</strong> (0.085 g, 0.75 mmol) were heated in 2 mL of ethanol for 2 days. The resulting mixture was allowed to cool to ambient temperature and filtered to provide the title compound as the filter cake (0.09 g). 1H NMR (300 MHz, DMSO-d6) delta 3.28 (s, 3H), 4.05 (s, 2H), 4.59 (q, 2H), 4.81 (s, 1H), 7.5 (t, 1H), 7.6 (m, 1H), 7.62 (m, 1H), 7.64 (d,1H), 10.8 (s, 1H); MS (ESI) m/z 322 (MH)-; Anal. Calcd for C17H13N3O40.0.25H2O: C, 62.48;H, 3.86; N, 12.86. Found: C, 62.55;H, 4.07; N, 12.61.
3-(6,6-dimethyl-3,4,5,6-tetrahydrobenzo[7,8]chromeno[5,6-d]imidazol-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; acetic acid; at 70℃;
General procedure: To a solution of beta-lapachone (1.1 mmol) in acetic acid (6 mL), the desired aldehyde (2.5 mmol) was added, and the mixture was heated to 70 C; at this point, ammonium acetate (16.5 mmol) was slowly added, and reflux was maintained for a determined time. All the reactions were monitored by thin layer chromatography. At the end of the reaction, after addition into water, the precipitate was purified by column chromatography using as eluent a mixture of hexane/ethyl acetate, with a gradient of increasing polarity, as previously described.16
With Ru/Al2O3; hydrogen; In methanol; water; at 79.84℃; under 30003.0 Torr; for 4h;
Unless specified otherwise, all hydrogenation reactions were carried out at 353 K in small glass vials placed inside a 200-mL autoclave with vigorous magnetic stirring (P900 RPM). Conversions and selectivities were measured by 1H NMR and gas chromatographic techniques. All hydrogenated products were initially identified by using authentic commercial samples of the expected products. The recycling experiments with 1 and 2 were carried out at 353 K under 50 and 40 bar H2 pressure, respectively, with a substrate-to-Ru molar ratio of 283 and 625 in 5 mL of methanol and water, respectively. Recycling experiments with 2 covering five successive batches were also carried out with styrene as the substrate, with a styrene-to-Ru molar ratio of 625 in 5 mL of methanol. Catalyst 1 was filtered off, washed several times with methanol, and used for the second batch. For the reaction with 2, the product was separated from the aqueous solution by ethyl acetate extraction(2 x 10 mL). The aqueous solution of 2 was then reused. A few recycling experiments were also carried out, where 2 was precipitated from the water solution by the addition of acetone and reused. The results obtained by both these methods of catalyst recovery were comparable.
With lithium aluminium tetrahydride;
Conversion of 3-bromobenzaldehyde (14-1 ) to the nitrile was accomplished through nucleophilic aromatic substitution with copper(l) cyanide. Subsequent reduction of both the carbonyl and nitrile with lithium aluminum hydride (LAH) provided the amino alcohol after appropriate work-up, which was then protected with Fmoc using standard conditions (Method 1 W, Example 1A). The corresponding Boc derivative is accessed by substituting B0C2O and K2CO3 in the last step of the scheme.
3-{hydroxy-[3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-methyl}-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; In tetrahydrofuran; at -78℃; for 0.5h;
To a solution of <strong>[197007-87-7](4-bromo-pyridin-3-yl)-methanol</strong> (53 mg 0.2 mmol) in THF (2 ml_) at -78C was added dropwise 2.5 M n-butyllithium (0.24 mL, 0.6 mmol). After 15 min a solution of 3-cyanobenzaldehyde (79 mg) in THF (0.5 ml) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and the residue purified by flash chromatography to yield 3-{hydroxy-[3-(hydroxy-phenyl-methyl)-pyridin-4- yl]-methyl}-benzonitrile as white crystals.LCMS: 2.250 min, m/z: 317 (M + 1).
3-[hydroxy-(3-hydroxymethyl-pyridin-4-yl)-methyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; In tetrahydrofuran; at -78℃; for 0.5h;
To a solution of <strong>[197007-87-7](4-bromo-pyridin-3-yl)-methanol</strong> (20 mg, 0.11 mmol) inTHF (1 ml_) at -78C was added dropwise 2. 5M ?-butyllithium (0.22 ml_). After 15 min, a solution of 3-cyanobenzaldehyde (69 mg) in THF (0.5 ml_) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4-yl)- methyl]-benzonitrile as a white solid.
With n-butyllithium; In tetrahydrofuran; at -78℃; for 0.5h;
To a solution of <strong>[197007-87-7](4-bromo-pyridin-3-yl)-methanol</strong> (20 mg, 0.11 mmol) inTHF (1 mL) at -78C was added dropwise 2. 5M n-butyllithium (0.22 mL). After 15 min, a solution of 3-cyanobenzaldehyde (69 mg) in THF (0.5 mL) was added. The reaction mixture was stirred for 15 min, then quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4-y|)- methyl]-benzonitrile as a white solid.
2-Amino-3-cyano-4-(3-cyano-phenyl)-4H-indolo[7,6-b]pyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
EXAMPLE 53 2-Amino-3-cyano-4-(3-cyano-phenyl)-4H-indolo[7,6-b]pyran The title compound was prepared from <strong>[2380-84-9]7-hydroxyindole</strong> and 3-cyanobenzaldehyde by a procedure similar to that described in Example 46 in 35% yield. 1H NMR (CDCl3): 8.43 (brs, 1H), 7.55-7.51 (m, 2H), 7.47-7.40 (m, 2H), 7.33 (dd, J=0.9, 8.1 Hz, 1H), 7.28-7.25 (m, 1H), 6.61-6.55 (m, 2H), 4.92 (s, 1H), 4.73 (brs, 2H).
tert-butyl 2-methoxycarbonyl-3-(3-cyanophenyl)-acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With hydrogenchloride; In hexane; ethyl acetate; toluene;
A. Preparation of tert-butyl 2-methoxycarbonyl-3-(3-cyanophenyl)-acrylate. To a solution of 3-cyanobenzaldehyde (0.700 g, 5.34 mmol) and t-butyl methyl malonate (0.845 mL, 5.00 mmol) in toluene (40 mL), piperidine (0.500 mL, 5.06 mmol) was added. The mixture was heated to reflux overnight. Dean-Stark apparatus was used to remove generated water. Ethyl acetate (50 mL) and 0.5 N HCl (50 mL) were added. Organic phase was separated, washed with saturated aq. NaHCO3, dried over Na2SO4, concentrated in vacuo to give an oil. The oil was dry-packed onto a silica gel column, eluted with hexane first, then with 5percent to 10percent EtOAc in hexane gradually to give the desired product as a mixture of E and Z isomers (0.44 g) (yield: 31percent). 1H NMR (CDCl3) 7.78-7.57 (m, 3H), 7.57-7.43 (m, 1H), 3.88 (s, 3H, minor isomer), 3.85 (s, 3H, major isomer), 1.53 (br. s, 9H).
(E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In acetic anhydride;
b) In analogy to example 12b), from <strong>[6622-92-0]2,4-dimethyl-6-hydroxypyrimidine</strong> (1.1 g, 8.86 mmol) and 3-cyanobenzaldehyde (1.16 g, 8.86 mmol) in acetic anhydride there was obtained (E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (1.56 g, 74%) as a yellow solid. EI mass spectrum, m/e: 237 (M calculated for C14H11N3O: 237).
EXAMPLE 29 5-(3-cyanophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione A mixture of <strong>[61363-56-2]tetrahydro<strong>[61363-56-2]pyran-3,5-dione</strong></strong> (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) (0.27 g, 2.4 mmol), 3-cyanobenzaldehyde (0.54 g, 2.9 mmol) and the product from Example 11C (0.27 g, 2.4 mmol) in ethanol (3 mL) was heated to 80 C. for 60 hours, cooled and concentrated. The residue was purified by chromatography on silica gel (5% methanol in methylene chloride) to provide a product which was dissolved in 1:5 methanol/methylene chloride, filtered, concentrated on a steam bath to remove the methylene chloride and allowed to stand at ambient temperature for 16 hours. The resulting solid was collected by filtration, washed with methanol and dried to provide the title compound (0.062 g). mp>260; MS (ESI(+)) m/z 323 (M+H)+; MS (ESI(-)) m/z 321 (M-H)-; 1H NMR (DMSO-d6) delta 4.05 (s, 4H), 4.51 (AB q, 4H), 4.99 (s, 1H), 7.48 (m, 1H), 7.54-7.64 (m, 2H), 10.12 (bs, 1H); Anal. Calcd for C18H14N2O4: C, 67.08; H, 4.38; N, 8.69. Found: C, 66.76; H, 4.67; N, 8.56.
(a) 3-Cyanocinnamic acid 3-Cyanobenzaldehyde was reacted with malonic acid by the method described in Example 2(a) to give the title product, m.p. ca 240 C.
EXAMPLE 29 5-(3-cyanophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione A mixture of <strong>[61363-56-2]tetrahydro<strong>[61363-56-2]pyran-3,5-dione</strong></strong> (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) (0.27 g, 2.4 mmol), 3-cyanobenzaldehyde (0.54 g, 2.9 mmol) and the product from Example 11C (0.27 g, 2.4 mmol) in ethanol (3 mL) was heated to 80 C. for 60 hours, cooled and concentrated. The residue was purified by chromatography on silica gel (5% methanol in methylene chloride) to provide a product which was dissolved in 1:5 methanol/methylene chloride, filtered, concentrated on a steam bath to remove the methylene chloride and allowed to stand at ambient temperature for 16 hours. The resulting solid was collected by filtration, washed with methanol and dried to provide the title compound (0.062 g). mp>260; MS (ESI(+)) m/z 323 (M+H)+; MS (ESI(-)) m/z 321 (M-H)-; 1H NMR (DMSO-d6) delta 4.05 (s, 4H), 4.51 (AB q, 4H), 4.99 (s, 1H), 7.48 (m, 1H), 7.54-7.64 (m, 2H), 10.12 (bs, 1H); Anal. Calcd for C18H14N2O4: C, 67.08; H, 4.38; N, 8.69. Found: C, 66.76; H, 4.67; N, 8.56.
3-(3-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 229 3-(3-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-cyanobenzaldehyde as starting materials, which are commercially available from Aldrich; m.p. 172-174 C.
A solution of 3-cyanobenzylaldehyde (1.0 g) and N-cyclohexyl-1,3-propane-diamine (2.4 g) in CH3OH (150 mL) was heated to 60 C. for 18 hours. After cooling to room temperature, NaBH4 (1.5 g) was slowly added to the above solution. The mixture was stirred for another 30 minutes. The mixture was then concentrated, quenched with NH4Cl (aq), and extracted with CH2Cl2. The organic layers were combined, dried with anhydrous MgSO4, and concentrated to give a residue. The residue was purified by chromatography on silica gel (EtOAc/Et3N=7/3) to afford Intermediate 201-I (1.6 g) in a 80% yield. A solution of Intermediate 201-I (1.6 g) and Boc2O (3.5 g) in CH2Cl2 (160 ml) was stirred at 25 C. for 15 hours and then concentrated. The resultant residue was purified by chromatography on silica gel (EtOAc/Hexane=1/1) to afford Intermediate 201-II as a yellow oil (2.36 g) in a 85% yield. A solution of Intermediate 201-II and LiAlH4 (2.3 g) in THF (230 mL) was stirred at 0 C. for 4 hours. After Na2SO4110H2O was added, the solution was stirred at room temperature for 0.5 hour. The solution was then filtered through a celite pad. The filtrate was dried over anhydrous MgSO4 and concentrated to give a residue. The residue was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 201-III (1.1 g) in a 50% yield. Diisopropylethylamine (1.1 mL) was added to a solution of 2,4-dichloro-6-aminopiperidine (0.41 g) and Intermediate 201-III (1.1 g) in 1-pentanol (10 mL). The reaction mixture was stirred overnight at 120 C. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (EtOAc/Hexane=3/7) to afford 201-IV (1.0 g) in a 65% yield. To a solution of Intermediate 201-IV (1.0 g) in 1-pentanol (1 mL) was added N1-hydroxyethoxyethyl piperazine (0.25 g). After the solution was stirred at 120 C. for 8 hours, it was concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/MeOH=4/1) to afford Intermediate 201-V (730 mg) in a 60% yield. A solution of 20% TFA/CH2Cl2 (5 mL) was added to a solution of Intermediate 201-V (0.73 g) in CH2Cl2 (2 mL). The reaction mixture was stirred for 5 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Compound 201 (434 mg) in a 85% yield. Compound 201 was then treated with 1 M HCl (4 mL) in CH2Cl2 (2 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of compound 201. CI-MS (M++1): 541.3.
With p-toluenesulfonic acid monohydrate; In ethylene glycol; toluene;
Reference Example 8 A mixture of 3-cyanobenzaldehyde (9.81 g), ethylene glycol (9.31 g), p-toluenesulfonic acid monohydrate (0.07 g) and toluene (200 ml) was heated under reflux for 15 hrs., while removing generated water with a Dean-Stark trap. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine; dried over anhydrous magnesium sulfate, and concentrated to give 3-(1,3-dioxolan-2-yl)benzonitrile (13.1 g, yield 100%) as a colorless oil. NMR (CDCl3) δ: 4.01-4.17 (4H, m), 5.83 (1H, s), 4.50 (1H, t, J = 7.6 Hz), 7.63-7.74 (2H, m), 7.80 (1H, t, J = 1.6 Hz).
With sodium methylate; acetic acid; In methanol; water;
a. 3-(4-Oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A) A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30 C. over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml), the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2*50 ml) and dissolved in water (1800 ml). The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2*200 ml) and dried in vacuo to give 3-(1,3-dioxoindan-2-yl)benzonitrile (83.2 g) as a dark red solid, m.pt. 179-182 C., m/z (M+H)+ 248, which was used without further purification.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -10 - 20℃;
A mixture of 12.4 g of <strong>[21406-61-1]pentyltriphenylphosphonium bromide</strong> and 30 ml of DMF was stirred at -10C or lower. Thereafter, 1.06 g of 60% sodium hydride (in oil) was added to the mixture, and a mixture solution of 2.62 g of 3-cyanobenzaldehyde and 5 ml of DMF was further added thereto. The obtained mixture was stirred at a room temperature over a day and a night. After, water was added to the reaction mixture, it was then extracted with ethyl acetate. The obtained organic layer was successively washed with diluted hydrochloric acid, water and a saturated saline solution, and it was then dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was subjected to silica gel chromatography, so as to obtain 3 -(1 -hexenyl)benzonitrile.
With 3-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl-1-(2,4,6-trimethylphenyl)-1H-imidazol-3-ium iodine salt; caesium carbonate; In toluene; at 60℃; for 3h;
Weigh accurately 0.1mol of 3-cyanobenzaldehyde,Add to 500mL round bottom flask, then add 0.5mol ethanol,0.005mol 3- (7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl-1- (2,4,6-trimethyl) phenyl-1H-imidazole -3-ium iodide,0.05mol cesium carbonate, 150mL toluene,Put on an air balloon and stir at 60 C for 3h.After the reaction, the reaction solution was cooled to room temperature.Extracted to neutrality with saturated brine, concentrated under reduced pressure,Column chromatography gave ethyl 3-cyanobenzoate,The yield was 98%.
95%
With C22H29N2O(1+)*I(1-); caesium carbonate; In toluene; at 60℃; for 3h;
General procedure: A three-neck flask was charged with aldehyde 7a-7p(1.0mmol), camphor-based imidazolium salts (5mol%),Cs2CO3(163mg, 0.5mmol), alcohol (5mmol) and 10ml oftoluene in an air atmosphere, then the mixture was stirred for3h at 60C. The reaction mixture was extracted with diethylether (3 × 30ml), concentrated under reduced pressure andthe residue was purified by flash column chromatography onsilica gel (PE (petroleum ether):EA (ethyl acetate) = 20:1)to give the desired product. All products were identified by1H and 13C NMR and in accord with literatures [42-52] (forspectra see Supplementary Data).
65%
With potassium carbonate; In water; at 20℃; for 5h;
General procedure: A mixture of bromine chloride resin and K2CO3 in MeOH-H2O (8:2) 3 mL was placed in a round-bottom flask fitted with amagnetic stirrer. To this, the aldehyde (1 mmol, 1 equiv) was added dropwise, and the reaction mixture stirred at r.t. The progress of the reaction was monitored by TLC. After completionof the reaction the mixture was filtered, and the filtrate was extracted with Et2O. The ether layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, if required, over silicagel (60-120 mesh) using a mixture of PE and EtOAc (9:1) as eluent.
General procedure: In a 14-ml vial, the substituted acetophenone (1.25 mmol) and lithium hydroxide monohydrate (0.251 mmol) were dissolved in ethanol (5 mL) and the mixture was stirred at RT for 10 min followed by addition of substituted benzaldehyde (1.272 mmol). The reaction mixture was then stirred at RT and monitored by TLC using 25% ethyl acetate/hexanes as the solvent system. The reaction was quenched after 2 hr by pouring into 50 ml of stirring ice cold water. If the product precipitated out after quenching with cold water, it was filtered off and crystallized with hot ethanol. In some examples, a sticky mass was observed in the aqueous solution after quenching. In those cases, the product was extracted by ethyl acetate (3 x 50 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexanes as the solvent system in increasing order of polarity. Chalcones 1a- 1j, 2a- 2j, 3a- 3j, 4a- 4j, 5a- 5j, 6a-e, 6g-h, 6i, 7a-h, 7j, 8a, 9a, 9d-e, 9i, 10a-b, 10d-e, 10h-j have been reported earlier in the literature.1-32 To the best of our knowledge, there is no literature available for rest of the chalcones. The characterization data of these chalcone derivatives i.e. 1H, 13C NMR, LC-MS-TOF and purity analysis are given in subsequent sections.
General procedure: To a solution of beta-lapachone (1.1 mmol) in acetic acid (6 mL), the desired aldehyde (2.5 mmol) was added, and the mixture was heated to 70 C; at this point, ammonium acetate (16.5 mmol) was slowly added, and reflux was maintained for a determined time. All the reactions were monitored by thin layer chromatography. At the end of the reaction, after addition into water, the precipitate was purified by column chromatography using as eluent a mixture of hexane/ethyl acetate, with a gradient of increasing polarity, as previously described.16
With morpholin-4-ium hydrogen sulphate; 1-butyl-3-methylimidazolium Tetrafluoroborate; for 48h;Sealed tube; Heating;
To 20ml reactor followed by addition of a solvent [Bmim] BF4(2 ml), 2,6- lutidine (1 mmol), inter-cyano benzaldehyde (0.5 mol), the catalyst [Hnhm] HSO4(0.5 mmol), sealed reactor, 100 for 48 hours.After the reaction system was cooled with diethyl ether (2 ml) and extracted 6 times, the combined organic phases, the organic phase was dried over anhydrous magnesium sulfate, the organic phase by rotary evaporation to give the crude product.The crude product with petroleum ether: ethyl acetate = 3: 1 (v / v) as eluent and silica gel as the adsorption phase column chromatography, to obtain a solid productC2, Yield 80%. Since the catalyst and a solvent used for the reaction can be recycled after extraction system vacuum dried at 40 degrees Celsius for one hour, then sequentially added <strong>[108-48-5]2,6-lutidine</strong> (1 mmol), inter-cyano benzaldehyde (0.5 mol ), sealed heating 48 hours, the product was isolatedC2Yield 81%.And so, the catalyst cycle times can still use 8 to 80% yield of the productC2Yield not significantly reduced, indicating that the catalyst for this reaction can be recycled, greatly reducing the cost of the experiment, reducing waste emissions and environmental pollution. NMR data:1the H NMR (400 MHz, CDCl3, TMS) delta 7.60 -7.47 (m, 5H), 7.03 (d,J= 7.6 Hz, 1H), 6.86 (d,J=7.6Hz,1H),5.16(dd,J=3.2,8.8Hz,1H),2.96-3.08(m,2H),2.53(s,3H);13CNMR(400MHz,CDCl3TMS) delta158.8, 157.5, 149.7, 137.5, 132.2, 126.6, 121.7, 120.7, 119.0, 110.9, 72.7, 44.6, 24.3
78%
With H2O4P(1-)*C4H7N2(1+); In 1,4-dioxane; water; at 100℃; for 24h;Schlenk technique; Sealed tube;
General procedure: A 25 mL Schlenk tube equipped with a magneticstirring bar was charged with<strong>[108-48-5]2,6-lutidine</strong> (0.75 mmol, 3equiv.), p-nitro-benzaldehyde(0.25 mmol), dioxane/water(1:1, 1ml) and [Hmim][H2PO4](1equiv.).The tube was sealed and heated at 100 for 24h. Aftercompletion of the reaction, the resulting solution was extracted with ether (3×10 ml). The organic layer was dried with anhydrous Na2SO4,and concentrated under vacuum. The residue was chromatographed on a silica gelcolumn eluted with a mixture of petroleum ether and ethyl acetate (1:1) to givepure products (92%).
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 9h;Inert atmosphere;
General procedure: To a 10 mL glass tube aryl halide (1 mmol), K4FeCN6(0.6 mmol,220 mg), K2CO3(1.5 mmol, 207 mg), catalyst (10 mg), and 2 mL DMFwere added and mixture was stirred for appropriate reaction timeat 120C under argon atmosphere. The progress of the reactionwas monitored by GC analysis. After completion of the reaction,reaction mixture was washed with 5 mL water and crude productwas isolated using dichloromethane (5× 1 mL). Organic extractswere combined together, evaporated and purified by flash chro-matography using hexane/EtOAc to give the desired aryl cyanideproducts.
92%Chromat.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 9h;Inert atmosphere;
General procedure: To a 10 mL glass tube aryl halide (1 mmol), K4FeCN6(0.6 mmol,220 mg), K2CO3(1.5 mmol, 207 mg), catalyst (10 mg), and 2 mL DMFwere added and mixture was stirred for appropriate reaction timeat 120C under argon atmosphere. The progress of the reactionwas monitored by GC analysis. After completion of the reaction,reaction mixture was washed with 5 mL water and crude productwas isolated using dichloromethane (5× 1 mL). Organic extractswere combined together, evaporated and purified by flash chro-matography using hexane/EtOAc to give the desired aryl cyanideproducts.
4-[(3-cyanophenyl)methyl]amino}-N,N-dimethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 2h;
To a solution of 4-Amino-N,N-dimethylbenzamide (50 mg, 0.30 mmol) in DCM (20 mL) was added 3-cyanobenzaldehyde (42 mg, 0.32 mmol), followed by triacetoxyborohydride (322 mg). Mixture was stirred at rt for 1 hour. A further25mg of aldehyde was added and stirring continued at RT for a further hour. The mixture was concentrated in vacuo then partitioned between EtOAc and saturated sodium bicarbonate solution. Organic phase was separated and washed with water, dried (magnesium sulphate) then concentrated in vacuo to give a clear oil which was triturated with ethanol/hexane mixture to afford 4-[(3-cyanophenyl)methyl]amino}-N,N-dimethylbenzamide as a colourless solid (68 mg, 80%). LC/MS (method A): RT = 2.07 min; m/z = 280 [M+H]. Total run time 3.75 mins.
ethyl 6-amino-5-cyano-4-(3-cyanophenyl)-2-ethoxy-3-fluoro-2-methyl-2,3-dihydro-4H-pyran-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium hydroxide; at 20℃; for 8h;
General procedure: A mixture of ethyl 2-fluoroacetoacetate 1 (148.0 mg, 1.0 mmol),malononitrile 2 (66.0 mg, 1.0 mmol), and benzaldehydes 3a (106.0 mg, 1.0 mmol), NaOH (20.0 mg, 0.5 mmol) was stirred in 10 mL EtOH for 8 h at room temperature. After the completion of the reaction (monitored by TLC), the solvent was evaporated unde rreduced pressure and the residue was purified by chromatography on a silica column using petroleum ether-ethyl acetate (4/1, v/v) as eluent to afford the final product 4a, 261.1 mg, 75% yield.
2-(2-(3-cyanobenzylidene)hydrazino)-6-fluorobenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
With potassium carbonate; In water; at 20℃; for 1h;
General procedure: A mixture of bromine chloride resin and K2CO3 in MeOH?H2O (8:2) 3 mL was placed in a round-bottom flask fitted with amagnetic stirrer. To this, the aldehyde (1 mmol, 1 equiv) was added dropwise, and the reaction mixture stirred at r.t. The progress of the reaction was monitored by TLC. After completionof the reaction the mixture was filtered, and the filtrate was extracted with Et2O. The ether layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, if required, over silicagel (60?120 mesh) using a mixture of PE and EtOAc (9:1) as eluent.
3-(2,2-difluoro-1-hydroxyethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With caesium carbonate; In dimethyl amine; at -10℃;Glovebox;
In a glove box, Cs2CO3 (0.6 mmol) and 3-cyanobenzaldehyde (0.2 mmol) were weighed into a 25 mL reaction tube and DMA (1 mL) was added to the reaction tube. The bromodifluoromethylphosphonium salt (0.6 mmol) was weighed and dissolved in DMA (2 mL) and aspirated into a syringe. It was stirred at -10 , simultaneously with a syringe pump at rate of 0.5mL h / DMA solution of bromine difluoromethyl phosphonium salt injected into the reactor tube.After the injection, the reaction is over. The solution in the reaction tube was transferred to a separatory funnel, 15 mL of water was added, extracted three times with dichloromethane (10 mL x 3), and the organic phases were combined and washed three times with water (10 mL x 3). The final obtained organic phase was dried over anhydrous sodium sulfate, and the solid was filtered off, the solvent removed by rotary evaporation, on a silica gel column with n-pentane and ethyl acetate as eluent, to give the final isolated product difluoromethyl, yield 91%, purity> 99.9% (nuclear magnetic purity).
2-amino-6-chloro-4-(3-cyanophenyl)-4H-benzo[h]chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
3-Cyanobenzaldehyde (131 mg, 1.0 mmol) and malononitrile (70 mg, 1.0 mmol) were dissolved in MeCN (3 mL) and three drops of Et3N were added. The reaction mixture was stirred at room temperature for 30 min. 4-Chloro-1-naphthol (178 mg, 1.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The formed precipitate was collected, washed with MeCN and n-hexane and dried in vacuum. Yield: 217 mg (0.61 mmol, 61%); colorless solid of m.p. 248-249 C;
With triphenylphosphine; In 1-methyl-pyrrolidin-2-one; at 100℃;Sealed tube; Inert atmosphere;
General procedure: An oven-dried 3-neck round-bottomed ask equipped with amagnetic stir bar was charged with aryl aldehyde (1.0 equiv.) andtriphenylphosphine (1.2 or 1.5 equiv.). The system was sealed withthree PFTE septa, and subsequently evacuated and backlled withN2 three times. Dry NMP was added via syringe transfer (PTFE sy-ringe with oven-dried stainless-steel needle), and the system wasimmersed in a preheated 100C oil bath. Once no solid reagentsremained (approximately 2 min of heating), potassium bromodi-uoroacetate (1.5 or 1.8 equiv.) was added portionwise over 0.5 h,with the rate of addition controlling the evolution of CO2 gas. Onceall of the potassium bromodiuoroacetate was added, the solutionwas allowed to stir for 0.5e1 h. Upon completion, the reaction wascooled to room temperature and then quenched with H2O. Subse-quently, Et2O was added to the reaction, and the mixture waswashed with H2O (ve times), and the aqueous layer was back-extracted with Et2O (two times). The combined organic layerswere dried over Na2SO4 and concentrated. The crude material wasdry-packed onto silica gel and then eluted through a plug of silicagel with EtOAc:hexanes (1:1) to remove triphenylphosphine oxide.Subsequently, H2O2 (30% in H2O) was added to the mother liquorand allowed to react for 30 min to oxidize the residual triphenyl-phosphine. The organic layer was washed with H2O (three times),dried over Na2SO4, concentrated, and subjected to normal phaseash chromatography using EtOAc and hexanes.
5,7-dichloro-2-[2-(3-cyanophenyl)vinyl]quinolin-8-yl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With acetic acid; at 130℃;Inert atmosphere;
General procedure: The appropriate quinoline derivative(2.5 mmol) in acetic anhydride with 80% acetic acid was thoroughlymixed with one equivalent aldehyde and heated in an inert gasatmosphere (N2) for 18e22 h at 130 C. Then, the mixture wasevaporated to dryness and a solid was crystallized from ethanol, methanol or ethyl acetate
3-[(2-chlorothiazol-5-yl)-hydroxymethyl]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.8%
2 -Chlorothiazole (1 g, 8.36 mmol) was dissolved in THF (12 mL) and cooled to -78C. To this was added dropwise n-butyl lithium in hexanes (2.5 M, 3.68 mL) and the mixture was stirred for lh at -78 C. 3-Formylbenzonitrile (987 mg, 7.53 mmol) in THF (4 mL) was then added, and after 5 minutes at -78C the mixture was slowly warmed to RT and quenched by sat. NH4Cl(aq). The mixture was diluted with water, then extracted with EtOAc. The organic phase was washed with brine before being dried over MgSCri, filtered and evaporated under reduced pressure. Purification by CombiFlash provided 3-[(2- chlorothiazol-5-yl)-hydroxy-methyl]benzonitrile (1.40 g, 5.58 mmol, 66.8%).
N'-(3-cyanobenzylidene)-3-aminopyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
for 0.183333h;Microwave irradiation;
General procedure: Second step consists of condensation of <strong>[6761-52-0]3-aminopyrazine-2-carbohydrazide</strong> (0.5 gm, 0.003 mol) with aromatic aldehydes (0.5 gm, 0.008 mol) using microwaveirradiation (8 - 10 min, 350 W). After cooling and filtration,the product was recrystallized using ethanol [6, 9] (Fig. 1).
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