* 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 the American Chemical Society, 1999, vol. 121, # 41, p. 9550 - 9561
[2] Angewandte Chemie - International Edition, 1999, vol. 38, # 16, p. 2413 - 2416
6
[ 2856-63-5 ]
[ 224311-51-7 ]
[ 19853-10-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium fluoride In tetrahydrofuran
EXAMPLE 30 Synthesis of 2-cyanomethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboron dihydroxide (183 mg. 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 178 mg (92percent) of the title compound.
92%
With potassium fluoride In tetrahydrofuran
Example 30 Synthesis of 2-cyanomethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 178 mg (92percent) of the title compound.
Reference：
[1] Journal of the American Chemical Society, 1961, vol. 83, p. 1691 - 1697
8
[ 1058649-12-9 ]
[ 10442-39-4 ]
[ 2856-63-5 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 135 - 140℃; for 0.075 h; Microwave irradiation
General procedure: A mixture of MOM–ethers (1 mmol) [Bu4N][X](2 mmol) was added to [Hmim][NO3] (0.4 mmol) (and exposed to MWirradiation (All reactions were carried out at 135-140 oC with 170 Wapplied power). After completion of the reactions (monitored by TLC, eluent:n–hexane/ethyl acetate, 5:1), the mixture was extracted with Et2O(3×10 mL). The organic phase was dried over anhydrous Na2SO4and rotary evaporation afforded a residue, which was then passed through ashort pad of neutral alumina (n–hexane/ethyl acetate, 5:1, 75 mL) to obtain thehighly pure products. The spectral data were inaccordance with those reported in the literature:
With palladium diacetate; sodium carbonate; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 140℃; for 10 h; Inert atmosphere
General procedure: 0.06 mmol PPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tube under a dry nitrogen atmosphere. After the mixture was stirred at room temperature for about 5 min to give a homogeneous solution, 0.3 mmol K4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP were added under a dry nitrogen atmosphere. The reaction tube was sealed with a septum and placed in a constant-temperature oil bath set at 140(+/-5) °C to perform the reaction for 10 h. Once the reaction time was reached, the mixture was cooled to room temperature, then acetophenone was added as an internal standard. GC analysis of the mixture provided the yield of the product (note: in order to decrease the analysis error, the mixture after the reaction was not purified or concentrated). The cyanation product was purified by column chromatography and identified by 1H NMR, 13C NMR or GC-MS data.
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 44, p. 16352 - 16355
14
[ 773837-37-9 ]
[ 611-17-6 ]
[ 2856-63-5 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 21, p. 11609 - 11612
15
[ 143-33-9 ]
[ 611-19-8 ]
[ 2856-63-5 ]
Reference：
[1] Helvetica Chimica Acta, 2002, vol. 85, # 7, p. 2089 - 2104
[2] Tetrahedron, 1977, vol. 33, p. 581 - 588
[3] Australian Journal of Chemistry, 1970, vol. 23, p. 329 - 339
[4] Journal of the American Chemical Society, 1961, vol. 83, p. 1691 - 1697
16
[ 17849-38-6 ]
[ 2856-63-5 ]
Reference：
[1] Australian Journal of Chemistry, 1970, vol. 23, p. 329 - 339
17
[ 151-50-8 ]
[ 611-19-8 ]
[ 2856-63-5 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
[2] Bulletin de la Societe Chimique de France, 1966, p. 1956 - 1966
18
[ 7282-58-8 ]
[ 2856-63-5 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1251,1254
19
[ 139109-52-7 ]
[ 108-24-7 ]
[ 2856-63-5 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1251,1254
General procedure: Amberlyst A26 OH (0.11 g) was added to a suspension ofthe nitrile (1 mmol) in EtOH?H2O (0.5 mL). The reactionmixture was stirred at 50?60 °C, and the progress of thereaction was followed by TLC. After the completion ofreaction, the mixture was diluted with acetone or EtOAc andfiltered to remove the catalyst. The desired products wereisolated by evaporation of the EtOAc or addition of H2O and filtration of the precipitate.
2-(2-chlorophenyl)acetonitrile (3.000 g, 19.790 mmol) in N,N-dimethylformamide (20 mL) at 0 C and sodium hydride (0.950 g, 39.580 mmol) was added and stirred at the same temperature for 30 minutes. To the reaction mixture 1,3-dibromopropane (2.018 mL, 19.790 mmol) was added and further stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution 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, 12 g cartridge; ethyl acetate / hexane = 0% to 15%) and concentrated to give the desired title compound (1.470 g, 38.8%) as a colorless oil.
With sodium hydride; In toluene; mineral oil; at 80℃;Inert atmosphere;
[0455] Under argon, sodium hydride (21.8 g, 544 mmol, 60% in mineral oil) and diethyl carbonate (60 ml, 490 mmol) were added to a solution of (2-chlorophenyl)acetonitrile (75.0 g, 495 mmol) in toluene (2.0 l), and the mixture was stirred at 80C. overnight. After cooling to RT, 1 liter of 1 M hydrochloric acid was added, and the mixture was stirred for 5 min and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by flash column chromatography (silica gel, cyclohexane/ethyl acetate 10:1). The combined target fractions were concentrated and the residue was dried under reduced pressure. This gave 100 g (90% of theory) of the title compound. An alternative preparation method is described in Journal of the American Chemical Society 1965, 87 (5), 1115-112.
To a suspension of NaH (60% oil suspension, 7.37 g, 184.4 mmol) in DMF (110 mL), cooled by ice/water, was added a solution of the nitrile 35.237 (9.782 g, 64.52 mmol) in DMF (20 mL) over 20 min. Hydrogen evolved, and the reaction mixture turned yellow. After 30 min, a solution of the chloroamine 34 (14.88 g, 61.45 mmol) in DMF (15 mL) was added. After 15 min the cooling bath was removed, and the reaction mixture was heated to 75 C. (bath temperature) for 5.5 h. TLC indicated the complete consumption of both starting materials. The DMF was evaporated. Upon addition of water and ether (200 mL each) a solid separated, which was filtered off, washed thoroughly with ether and EtOAc, and dried, yielding 8.018 g (24.99 mmol, 41%) of Boc-29.237. The layers of the combined filtrte and washings were separated, and the aqueous layer was extracted with more ether (2x150 mL). The combined organic layers were washed with 5% HOAc, water, IN NaOH, water, and brine and dried over MgSO4. This solution was ltered through a pad of silica gel. Upon concentration a solid precipitated, which was ltered off, washed with ether and hexanes and dried, yielding 6.138 g (19.13 mmol, 31%) of Boc-29.237. The mother liquor was concentrated and the residue purified by column chroma-tography on silica gel, yielding 2.885 g (8.99 mmol, 15%) of Boc-29.237. The total yield was 17.04 g (53.12 mmol, 86%), mp 165-166 C. 2H NMR (CDC13, 200 MHz): 8=1.48 (s, 9H), 2.00 (brdt, J=4.2,13.0 Hz, 2H), 2.43-2.53 (m, 2H), 3.28 (brt, J=12.8 Hz, 2H), 4.28 (brd, J=13.2 Hz, 2H), 7.28-7.50 (m, 4H). C17H21C1N2O2 (320.82): calcd. C 63.65, H 6.60, Cl 11.05, N 8.73; found C 63.82, H 6.61, Cl 10.90, N 8.72.
With NaH; In tetrahydrofuran; methanol; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 4 4-(2-Chlorophenyl)-4-cyano-N-(1,1-dimethylethoxycarbonyl)piperidine A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60 C. (7 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2 O (2*50 ml), and saturated aqueous NaCl (50 ml), dried (Na2 SO4) and concentrated in vacuo. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a white solid. 1 H NMR (CD3 OD, 400 MHz) d 7.53 (m, 2H), d 7.41 (m, 2H), 4.28 (br dd, 2H, J=13.4 Hz), 3.26 (m, 2H), 2.52 (dd, 2H, J=2.2, 11.2 Hz), 2.03 (dt, 2H, J=4.0, 9.2 Hz), 2.03 (s, 9H).
Sodium hydride (60% dispersion in mineral oil, 1.28 g, 45 mmol) was suspended in DMF (20 mL) and cooled in an ice bath under a nitrogen atmosphere. (2-Chloro-phenyl)- acetonitrile (1.77 g, 11.7 mmol) in DMF (5 mL) was added slowly, and the mixture stirred for 2 hours. Bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol) in DMF (5 mL) was then added and the mixture heated to 75C for 6 hours. The solvent was removed by evaporation under vacuum and the residue dissolved in ethyl acetate (50 mL), washed with water, then brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by silica chromatography eluting with a mixture of ethyl acetate and hexane. The fractions containing the desired products were combined and the solvent removed by evaporation to give the title compund as an orange gum (1.1 g). LCMS m/z 321.0 [M+H]+. R.T. = 4.76 min (Analytical Method 4).
2-benzylsulfanyl-6-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidin-7-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; potassium carbonate; at 110℃; for 3h;
A mixture of 5 g (20.4 mmol) of aldehyde 7, 3.71 g (24.4 mmol) of 2-chlorobenzylcyanide and 18 g (130 mmol) of potassium carbonate in 50 mL of DMPU was heated in a 110 C. oil bath for 3 hours until the reaction was completed. The mixture was poured into 600 ml of water and extracted with 300 mL of ethyl acetate. The organic solvent was washed with water (3x250mL), diluted with 200 mL of hexanes, washed with brine, dried (MgSO4), and filtered through a short plug of silica. The solvent was removed in vacuo. Residual solid was stirred in 50 mL of ethyl acetate for 30 minutes. The solid was filtered off and washed with small amount of ethyl acetate, recovering 2.23 g of the aminopyridopyrimidine 8. The filtrate was concentrated and the residue was purified by column chromatography with silica eluting with 50% ethyl acetate in hexanes, isolating an additional 0.62 g of 2-benzylsulfanyl-6-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidin-7-ylamine 8 (total yield: 37%).
With hydrogen sulfide; In pyridine; at 0℃; for 1h;
(a) 1-Amino-2-(2-chlorophenyl)ethane-1-thione. To a 100-mL round-bottomed flask was added 2-chlorobenzyl cyanide (4.53 g, 30 mmol, Aldrich), pyridine (30 mL, Aldrich) and trimethyl amine (12 mL, 90 mmol, Aldrich). Hydrogen sulfide (Aldrich) was bubbled through the reaction solution at 0 C. for 1 h. After the reaction mixture was stirred at room temperature overnight, nitrogen was bubbled through the reaction solution for 15 min at room temperature. Solvent was removed in vacuo. The residue was diluted in 100 mL of EtOAc, and washed with 2% aqueous HCl (50 mL) and brine (100 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title product as a crude yellow solid. MS (ESI, pos. ion) m/z: 186 (M+1); MS (ESI, neg. ion) m/z: 184 (M-1).
N,N-Dimethylformamide-dimethylacetal (9.06 mL; 64.3 mMol) and 2-chlorobenzylcyanide (1.95 g; 12.86 mMol) is heated under stirring to 100 C. under an atmosphere of Argon. After cooling to rt, the mixture is concentrated under reduced pressure and purified by and chromatography (silica gel, 120 g RediSep, ISCO Sg-100, eluting with EtOAc/hexanes 1:1) to obtain the title compound as yellow thick oil (2.44 g, 11.8 mmol; 92%); MS(ESI+):m/z=207 (M+H)+; TLC (EtOAc/hexanes 1:1) Rf=0.38.
92%
at 100℃;
Stage 77.1: (Z)-2-(2-Chloro-phenyl)-3-dimethylamino-acrylonitrile N,N-Dimethylformamide-dimethylacetal (9.06 mL; 64.3 mMol) and 2-chlorobenzylcyanide (1.95 g; 12.86 mMol) is heated under stirring to 100 C. under an atmosphere of Argon. After cooling to rt, the mixture is concentrated under reduced pressure and purified by and chromatography (silica gel, 120 g RediSep, ISCO Sg-100, eluding with EtOAc/hexanes 1:1) to obtain the title compound as yellow thick oil (2.44 g, 11.8 mmol; 92%); MS(ESI+):m/z=207 (M+H)+; TLC (EtOAc/hexanes 1:1) Rf=0.38.
3-(ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; sodium t-butanolate; In 1,2-dimethoxyethane;
Example 6 3-(ETHOXY-HYDROXY-METHYLENE)-3H-INDENE-1-CARBONITRILE, SODIUM SALT A solution of tricyclohexylphosphine (204 mg, 0.720 mmol) in ethylene glycol dimethyl ether (10 mL) under nitrogen was charged with palladium (II) acetate (148 mg, 0.660 mmol). The reaction was stirred at room temperature until the solution was homogenous (approx. 25 minutes), cooled to 0 C. and charged with sodium tert-butoxide (1.63g, 16.6 mmol). After 10 minutes a solution of 2-chlorophenylacetonitrile (1.00 g, 6.60 mmol) and ethyl-3-transethoxyacrylate (953 muL, 6.60 mmol) in ethylene glycol dimethyl ether (10 ml) was added dropwise over 5 minutes. Upon complete addition, the reaction was warmed to room temperature and then heated to 85 C. for 22 hours. The reaction was cooled to room temperature then diluted with methyl tert-butyl ether (30 mL) and poured into aqueous potassium dihydrogenphosphate (0.25 M, 40 mL), pH=7. The aqueous layer was separated then saturated by addition of solid sodium chloride and extracted with ethyl acetate (1*50 mL). The organic layer was separated and washed with aqueous saturated sodium chloride (2*30 mL), dried over sodium sulfate, filtered and concentrated in vacuo affording 3-(ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt, as a light orange oil (1.06 g, 5.0 mmol, 75 %). For physical data see Example 5 above.
EXAMPLE 19 Preparation of 2-Chlorophenyl-(2-pyrimidinyl)acetonitrile A mixture of 2-chlorobenzyl cyanide (4.50 g, 0.297 mol), potassium carbonate (6.84 g, 0.0495 mol) and dimethylformamide is stirred 30 minutes at 100 C. and treated dropwise with a solution of 2-chloropyrimidine (2.30 g, 0.0201 mol) in dimethylformamide. The resultant mixture is stirred overnight at 100 C. and treated with additional 2-chlorobenzyl cyanide (1.54 g, 0.0102 mol). The mixture is stirred several more hours at 100 C., cooled and diluted with water. The mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant brown oil is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a brown oil (3.25 g, 70.8%) which is identified by NMR spectral analysis.
16 1-(2-Chlorophenyl)-cyclopropane-carbonitrile
1-(2-Chlorophenyl)-cyclopropane-carbonitrile A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of 1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride [55-65% in oil] at room temperature. It is stirred for several hours and carefully added to water. After extraction with ethyl acetate and filtration by silica gel, the desired product is obtained: 13.1 g MS (ei): M(+)=177
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
EXAMPLE 30 Synthesis of 2-cyanomethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboron dihydroxide (183 mg. 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 178 mg (92percent) of the title compound.
178 mg (92%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
Example 30 Synthesis of 2-cyanomethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 178 mg (92percent) of the title compound.
With sodium hydroxide; In n-heptane; water; toluene;
Preparation of (+-)-alpha-(2-Chlorophenyl)-1-piperidinebutanenitrile (Step 1) STR7 To a reaction vessel under a nitrogen atmosphere was charged 756.6 kg of sodium hydroxide solution (50% w/w), 220.6 kg of 1-(2-chloroethyl)piperidine, monohydrochloride, 199.0 kg of 2-chlorobenzeneacetonitrile, and 4.2 kg of methyltributylammonium chloride (75% w/w in water). The reaction mixture was heated to 40 C. and was stirred for 6 hours and then heated to 60 C. for 6 hours. When the reaction was complete as indicated by GC, the reaction mixture was cooled to 25 C. The reaction mixture was diluted with 996 L of water and 396 L of toluene and stirred for 1 hour. After separation of the layers, the organic phase was extracted with 789 L of hydrochloric acid, 2N. The acidic extract was washed twice with 151 L of toluene at 50 C., basified with 136.9 kg of sodium hydroxide solution (50% w/w) to a pH>12 and extracted twice with a total of 1,103 L of heptane (or mixed heptanes). The combined organic phase was washed with 100 L of water and filtered through a layer of powdered cellulose. The solvent was removed by distillation under reduced pressure to give 310.2 kg (86.36% pure by HPLC Method A, 77.6% yield) of an oil which was (+-)-alpha-(2-chlorophenyl)-1-piperidine-butanenitrile (B).
104.5 kg (90.0%)
With sodium hydroxide; In n-heptane; water; toluene;
EXAMPLE 3 Preparation of alpha-(2-Chlorophenyl)-1-piperidinebutane nitrile STR15 A reaction vessel under a nitrogen atmosphere containing 74.0 kg of 1-(2-chloroethyl)piperidine, monohydrochloride at 10 C. was charged with 255.4 kg of sodium hydroxide solution (50% w/w). The reaction was warmed to 30 to 35 C. and 67.0 kg of 2-chlorobenzeneacetonitrile and 1.4 kg of methyltributylammonium chloride (75% w/w in water) were added. The reaction was stirred at 40 C. for 6 h and then heated to 60 C. for at least 6 h. When the reaction was completed as indicated by gas chromatographic analysis, the reaction mixture was cooled to 25 C. The reaction mixture was diluted with 335 L of water and 134 L of toluene and stirred for 30 min. After separation of the layers, the organic phase was extracted with 275 L of hydrochloric acid (2N). The acidic extract was washed twice with 50 L of toluene, basified with 30 L of sodium hydroxide solution (50% w/w) to a pH>12 and extracted twice with a total of 368 L of heptane. The combined organic phase was washed with 50 L of water and filtered through a layer of diatomaceous earth. The filtrate was dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 104.5 kg (90.0%) of the title product alpha-(2-chlorophenyl)-1-piperidinebutanenitrile as an oil. Analysis calcd for C15 H19 ClN2: C,68.56; H,7.29; Cl,13.49; N,10.66. Found: C,69.64; H,7.53; Cl,12.45; N,9.75.
In sodium hydroxide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate
2.a Methyl α-[2-(1'-ortho-chlorophenyl)-cyclopropylcarbonyloxymethylphenyl]-β-methoxyacrylate STR11
(a) A mixture of 30.0 g (200 millimoles) of 2-chlorobenzyl cyanide and 80.0 g (426 millimoles) of bromoethane are slowly added dropwise to a solution of 40.0 g of triethylbutylammonium chloride in 200 ml of 30% strength sodium hydroxide solution. The mixture is stirred for 2 hours at 80° C., allowed to cool, hydrolyzed with 500 ml of ice water and extracted with diethyl ether. The organic phase is washed with ammonium chloride solution and water, dried over MgSO4 and evaporated down. The oil obtained is purified by distillation (97° C., 0.4 mbar). 20.0 g (56%) of 1-(2'-chlorophenyl)-cyclopropylnitrile are obtained as a colorless liquid.
With tetramethyl ammoniumhydroxide; In tetrahydrofuran; water; for 0.2h;
A 330 muL sample of tetramethylammonium hydroxide (40% in water) was added with stirring to a solution of 750 mg (4.95 mmol) of 2-chlorophenylacetonitrile and 1.86 mL of 37% formaldehyde in 9 mL of tetrahydrofuran. The reaction was quenched at 12 min by acidification with 3 N HCl and diluted with ethyl acetate and water. The organic phase was washed with water, saturated salt solution, then stripped to an oil. This was flash chromatographed on 15 g of silica gel eluding with 5?90% ethanol in hexane. Fractions containing product were stripped to yield 622 mg (69%) of the alcohol as a colorless oil, Rf 0.14 (silica gel, ethyl acetate:hexane 1:4)
(1) Preparation of (+-) alpha-Chloro-2-(2-chlorophenyl) acetonitrile The same reaction conditions as described in step (1) for example 8 except that bromination was instead by slow purging with chlorine (80g) for 6 h. The crude product (172g, 92.5% yield) was distillated to afford (159g, 85.5% yield) of qualified target product.
(1) Preparation of (+-) alpha-Bromo-2-(2-chlorophenyl)acetonitrile 2-(2-Chlorophenyl) acetonitrile (151.5 g, 1 mol)was heated to 110C in a three-necked flask, keep the temperature, bromine (176 g, 1.1 mol) was added dropwise over a period of 3 h and the mixture was reacted with constant stirring for another 3 h. The reaction mixture was cooled to below 30C and water (400mL) was added and stirring continued for another 5 minutes to remove HBr and stand aside. The organic layer was separated and washed with small amount of 5% sodium bisulfite for 15 minutes with stirring. The organic layer was again separated and washed with water to near pH 7, and the brown oily product was obtained (225g, 96% yield); bp: 107-110C/15mmHg. IR (cm-1): 2969, 2253, 1589, 1472, 1445, 1194, 1051, 765, 725, 646; 1H-NMR (300 MHz, CDCl3): 7.83 (1 H, m), 7.38-7.45(4 H, m), 5.87 (1 H, s). The crude product was used directly for the next step.
96%
With bromine; at 110℃; for 6h;
2-(2-Chlorophenyl) acetonitrile (151.5 g, 1 mol) was heated to 110 C. in a three-necked flask, keep the temperature, bromine (176 g, 1.1 mol) was added dropwise over a period of 3 h and the mixture was reacted with constant stirring for another 3 h. The reaction mixture was cooled to below 30 C. and water (400 mL) was added and stirring continued for another 5 minutes to remove HBr and stand aside. The organic layer was separated and washed with small amount of 5% sodium bisulfite for 15 minutes with stirring. The organic layer was again separated and washed with water to near pH 7, and the brown oily product was obtained (225 g, 96% yield); bp: 107-110 C./15 mmHg. IR (cm-1): 2969, 2253, 1589, 1472, 1445, 1194, 1051, 765, 725, 646; 1H-NMR (300 MHz, CDCl3): 7.83 (1 H, m), 7.38-7.45(4 H, m), 5.87 (1 H, s). The crude product was used directly for the next step.
86%
With bromine; at 105 - 110℃; for 6h;
[00165) Bromine 76 g: 1.1 moi) was added over a period of 3 h to 2-{2- chlorophenyf)acetOflitri.e 1 (151.5 g, 1 mol) with stirring at 105-1 10 C and was reacted for another 3 h. Then butyl acetate (250 raL) and sodium bi sul ate ( 1 1.4 g, 0. ? 1 mol) were added at 30 C, After 15 min stirring, the mixture was filtered, washed with water, and dried over anhydrous sodium sulfate. Removal of the soivent was done in vacuum to afford 2 (200 g, 86%); mp: 1 10 C /I S mroHg; IHNMR (300 MHz, CDC13); £7.83 (1 B, m), 7.38-7.45(4 H, m), 5.87 ( I H, s).
86%
With bromine; at 105 - 110℃; for 6h;
bromine(176 g, 1.1 mol) was added over a period of 3 h to 2~(2- chloTX)phenv )acetonitirile 1 (151 ,5 g, i mol) with stirring at 105-1 10 C and was reacted for another 3 li . Then butyl acetate (250 mL) and sodium bi sulfate (1 1.4 g, 0.1 1 mol ) were added at 30 C. After 1 5 rain stirring, the mixture was filtered, washed with water, and dried over anhydrous sodium sulfate. Removal of the sol vent was done in vacuum to afford 2 (200 g, 86%): mp: 1 10 C /15 mmHg; 1HNMR (300 MHz, CDCl3):delta 7.83 (1 H, m), 7.38-7.45(4 H,m), 5.87 (1 H, s).
86%
With bromine; at 105 - 110℃; for 6h;
Step -I : Synthesis of Compound 2: 6 h. 88% [0095] Bromine{176 g, 1.1 moi.) was added over a period of 3 h to 2-(2- chiorophen i)acetonitriie 1 (151.5 g, 1 mol) with stirring at 105-110 nC and was reacted for another 3 h. Then butyl acetate (250 mL) and sodium bisulfate (1 1 ,4 g, 0.11 mol ) were added at 30 C. After 15 min stirring, the mixture was filtered, washed with water, and dried over anhydrous sodium sulfate. Removal of the solvent was done in vacuum to afford 2 (200 g, 86%): mp: 1 10 C /15 mmHg; 1 HNMR (300 MHz, CDC13):
86%
With bromine; for 6h;
Bromine (176 g, 1.1 mol) was added over a period of 3 h to 2-(2-chlorophenyl)acetonitrile 1 (151.5 g, 1 mol) with stirring at 105-110 C. and was reacted for another 3 h. Then butyl acetate (250 mL) and sodium bisulfate (11.4 g, 0.11 mol) were added at 30 C. After 15 min stifling, the mixture was filtered, washed with water, and dried over anhydrous sodium sulfate. Removal of the solvent was done in vacuum to afford 2 (200 g, 86%): mp: 110 C./15 mmHg; 1HNMR (300 MHz, CDCl3): delta7.83 (1H, m), 7.38-7.45 (4H, m), 5.87 (1H, s).
EXAMPLE 22; N-({1-[(2-Bromophenyl)methyl]-2-[(2-chlorophenyl)methyl]-4-hydroxy-6-oxo-1,6-dihydro-5-pyrimidinyl}carbonyl)glycine; 22a) N-[(2-Bromophenyl)methyl]-2-(2-chlorophenyl)ethanimidamide hydrochloride; Trimethylaluminum (8.7 mL of a 2 molar solution in toluene) was added to a stirred suspension of 2-bromobenzylamine hydrochloride (3.86 g, 17.34 mmoles) in toluene (25 mL). The mixture was stirred for 2 hours, during which time the reaction produced an exotherm, cleared, and then formed a precipitate. A solution of 2-chlorobenzylcyanide (2.63 g, 17.34 mmoles) in toluene (25 mL) was added and the mixture was heated at 80 C. for 2 hours. The mixture was cooled; some silica gel and chloroform (100 mL) were added then stirred for 5 minutes. The mixture was filtered and washed through with chloroform (100 mL0 and methanol (200 mL). The filtrate was evaporated to a semi-solid that was triturated with diethyl ether to give the title compound (4.1 g, 63%) 1H NMR (400 MHz, DMSO-d6) delta ppm 8.91 (br. s., 2 H), 7.66 (dd, J=7.58, 1.52 Hz, 2 H), 7.41-7.49 (m, 4 H), 7.28-7.34 (m, 2 H), 4.62 (s, 2 H), 4.09 (s, 2 H).
With sulfuric acid; nitric acid; In dichloromethane; at 0 - 20℃; for 0.833333h;
To a solution of 2-chloro-phenyl-acetonitrile (15. 0g, 99.0 mmol) in the dichloromethane (50 mL) and H2S04 (40 mL) is slowly added a mixture of H2SO4 (14 mL) and HN03 (5.5 mL) at 0C. The reaction mixture is stirred at 0C for 20 minutes, warmed to room temperature for 30 minutes and then concentrated to remove organic solvent. The solution is poured into a beaker containing ice-water (4-00 mL) to give a crystalline precipitate, which is collected by vacuum filtration and washed with water to give the title intermediate (13.4 g, 69.0%).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -20 - 20℃;Inert atmosphere;
General procedure: A solution of 14a-c (2 mmol), appropriate aryl acetonitrile (3 mmol) and anhydrous DMF (30 mL) was stirred for 0.5 h at -20 C. Then NaH (0.14 g, 3.5 mmol; 60% dispersion in mineral oil) was added portionwise at -20 C under Ar. The mixture was stirred at RT for 48-72 h under Ar, and then stirred under air for another 36-72 h at RT. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layers were dried by Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel; EtOAc/petroleum ether, 1:6 to 1:4) gave 16a-z.
With sodium hydride; In N,N-dimethyl-formamide; at -20 - 20℃;Inert atmosphere;
General procedure: To dried DMF (30.0 mL) was added the intermediate 7 (2.00 mmol) and the halogenated phenylacetonitrile (a, R = 2-Cl, 755 mg; b, 4-Br, 975 mg; 5.00 mmol). The reaction mixture was cooled down to -20 C within an ethanol cooling bath. NaH (60.0%, 184 mg, 4.60 mmol) was added under nitrogen atmosphere and was continued with stirring for 1 h. The reaction mixture was raised to r.t. for 24-72 h with the monitoring by TLC. The intermediate 8 (8a or 8b) was then obtained without further purifications. The reaction mixture was then kept for another 24-72 h without N2 protection until the TLC analysis showed the disappearance of compound 8. The reaction mixture was then poured into water (300 mL) and acidified with HCl to pH = 7. The obtained mixture was extracted with ethyl acetate (150 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated to give the solid, which was recrystallized with acetonitrile to afford the important intermediate 9a or 9b, with a yield of 24-65%, respectively.
With 1-methyl-3H-imidazolium nitrate; at 135 - 140℃; for 0.075h;Microwave irradiation;
General procedure: A mixture of MOM-ethers (1 mmol) [Bu4N][X](2 mmol) was added to [Hmim][NO3] (0.4 mmol) (and exposed to MWirradiation (All reactions were carried out at 135-140 oC with 170 Wapplied power). After completion of the reactions (monitored by TLC, eluent:n-hexane/ethyl acetate, 5:1), the mixture was extracted with Et2O(3×10 mL). The organic phase was dried over anhydrous Na2SO4and rotary evaporation afforded a residue, which was then passed through ashort pad of neutral alumina (n-hexane/ethyl acetate, 5:1, 75 mL) to obtain thehighly pure products. The spectral data were inaccordance with those reported in the literature:
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -20 - 20℃;Inert atmosphere;
General procedure: A solution of 14a-c (2 mmol), appropriate aryl acetonitrile (3 mmol) and anhydrous DMF (30 mL) was stirred for 0.5 h at -20 C. Then NaH (0.14 g, 3.5 mmol; 60% dispersion in mineral oil) was added portionwise at -20 C under Ar. The mixture was stirred at RT for 48-72 h under Ar, and then stirred under air for another 36-72 h at RT. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layers were dried by Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel; EtOAc/petroleum ether, 1:6 to 1:4) gave 16a-z.
4-(4-chloro-6-methyl-pyrimidin-2-ylamino)-benzonitrile[ No CAS ]
[ 2856-63-5 ]
[ 1232185-97-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -20 - 20℃;Inert atmosphere;
General procedure: A solution of 14a-c (2 mmol), appropriate aryl acetonitrile (3 mmol) and anhydrous DMF (30 mL) was stirred for 0.5 h at -20 C. Then NaH (0.14 g, 3.5 mmol; 60% dispersion in mineral oil) was added portionwise at -20 C under Ar. The mixture was stirred at RT for 48-72 h under Ar, and then stirred under air for another 36-72 h at RT. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layers were dried by Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel; EtOAc/petroleum ether, 1:6 to 1:4) gave 16a-z.
With palladium diacetate; sodium carbonate; triphenylphosphine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 10h;Inert atmosphere;
General procedure: 0.06 mmol PPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tube under a dry nitrogen atmosphere. After the mixture was stirred at room temperature for about 5 min to give a homogeneous solution, 0.3 mmol K4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP were added under a dry nitrogen atmosphere. The reaction tube was sealed with a septum and placed in a constant-temperature oil bath set at 140(+/-5) C to perform the reaction for 10 h. Once the reaction time was reached, the mixture was cooled to room temperature, then acetophenone was added as an internal standard. GC analysis of the mixture provided the yield of the product (note: in order to decrease the analysis error, the mixture after the reaction was not purified or concentrated). The cyanation product was purified by column chromatography and identified by 1H NMR, 13C NMR or GC-MS data.
Multi-step reaction with 6 steps
1.1: bromine / neat (no solvent) / 6 h / 105 - 110 °C / Green chemistry
2.1: sodium hydrogencarbonate / methanol / 3 h / Reflux; Green chemistry
3.1: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / water; butan-1-ol / 12 h / Reflux; Green chemistry
4.1: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / methanol; water / 0.5 h / 10 - 40 °C / Reflux; Green chemistry
4.2: 12 h / 40 °C / Green chemistry
5.1: (R)-10-camphorsulfonic acid / water; toluene / 49 h / 20 - 50 °C / Green chemistry
6.1: sulfuric acid / 12 h / 0 °C / Green chemistry
Multi-step reaction with 7 steps
1.1: bromine / neat (no solvent) / 6 h / 105 - 110 °C / Green chemistry
2.1: sodium hydrogencarbonate / methanol / 3 h / Reflux; Green chemistry
3.1: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / methanol; water / 12 h / Reflux; Green chemistry
4.1: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / methanol; water / 12 h / Reflux; Green chemistry
5.1: N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide / methanol; water / 0.5 h / 10 - 40 °C / Reflux; Green chemistry
5.2: 12 h / 40 °C / Green chemistry
6.1: (R)-10-camphorsulfonic acid / water; toluene / 49 h / 20 - 50 °C / Green chemistry
7.1: sulfuric acid / 12 h / 0 °C / Green chemistry
With hydrogenchloride; sodium azide; triethylamine; In toluene; at 110℃;
General procedure: Nitriles (1 mmol) were added to a solution of NaN3 (3 mmol), PhMe (50 mL), and Et3N.HCl (3 mmol) in around-bottomed flask. The reaction mixture was stirred at 110 C. After completion of the reaction (as indicated byTLC), the product was cooled and extracted with water. Next, 36% HCl was added dropwise to the aqueous layer to precipitate the tetrazoles. After filtration, the solid wasdried under reduced pressure and recrystallized fromEtOAc/Et2O to yield the 5-substituted-1-H-tetrazoles.
With sodium azide; silver; In N,N-dimethyl-formamide; at 120℃; for 8h;
General procedure: Briefly, AgNPs (20 mol%) was added to the reaction mixture ofthe solution of benzonitrile (0.206 g, 2 mmol) in DMF (3 ml) andsodium azide (0.195 g, 3 mmol) with stirring for 8 h at 120C. Thereaction was monitored by TLC and solvent removed in vacuoon completion of reaction. The crude product was then dilutedby ice cooled water and centrifuged. The pH of the solution wasadjusted to 2-3 by addition of 6 N HCl and extracted with ethyl-acetate. The resultant organic layer was separated and aqueous layer was extracted again with ethylacetate (3 × 20 mL). The com-bined organic layer was concentrated in vacuo to yield the crudewhite crystalline solid 5-phenyltetrazole in 82-93% yield. The crudetetrazole was then recrystallized by mixture of solvents (50% ethylacetate in hexane) and subsequently characterized by1HNMR,13CNMR, IR and crystallography.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
General procedure: General: To a solution of phenylacetonitrile 1 (1.0 eq) in methyl formate (10 eq), THF was added. In anhydrous condition, solution of NaH (1.25 eq) in THF was added dropwise to the reaction mixture at 0 C and the resulting mixture was stirred at room temperature overnight. After the reaction, the mixture was quenched with H2O, and several drops of 1 N HCl were added until the pH of the solution is lowered to 4 to 5. Then the mixture was extracted with methylene chloride and dried with MgSO4. After filtration and evaporation, the resulting solution was concentrated under vacuum to give the product 2 as yellowish oil in 72%-100% yields.
5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde[ No CAS ]
[ 2856-63-5 ]
(Z)-3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-2-(2-chlorophenyl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
To a solution of 2-(2-chlorophenyl)acetonitrile (728 mg, 4.8 mmol) in DMF (20 mL) was added t-BuOK (539 mg, 4.8 mmol). The resulted mixture was degassed and charged with nitrogen for three times, and stirred at 50 C for 15 minutes. Then a solution of 5-bromo-l- (phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.461 g, 4.0 mmol) in DMF (40 mL) was added dropwise over 2 hours. The mixture was stirred at 50 C overnight, then quenched with water (1 mL), and concentrated in vacuo. The residue was redissolved in EtOH (80 mL) and NaOH aqueous solution (40 mL, 10%). The resulted mixture was refluxed for 2 hours, then cooled to rt, and concentrated in vacuo. The residue was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (430 mg, 25%). MS (ESI, pos. ion) m/z: 358.0 (M+l). 1H NMR (400 MHz, DMSO-de): delta 12.82 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 3.0 Hz, 1H), 8.42 (d, J= 2.1 Hz, 1H), 7.95 (s, 1H), 7.67-7.58 (m, 2H), 7.51-7.46 (m, 2H).
2-(2-butyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)-2-(2-chlorophenyl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: Anhydrous THF (25 mL) solution of 2a (0.40 g, 3.42 mmol) was stirred for 1 h at r.t., then N-butyl-4-bromo-1,8-naphthalimide(1, 1.00 g, 3.02 mmol) was added. After completion, the reaction mixture was quenched with HCl (15%) until pH 2-3. The organic fraction was extracted with EtOAc (3 × 20 mL), dried over anhydrous Na2SO4, and filtered. Volatile fractions were removed under reduced pressure, and the residual material was purified by flash column chromatography on silica gel (PE-EtOAc, 25:1) to provide 3a as a pink solid 0.80 g (72% yield).
4-(methylamino)-2-(methylthio)pyrimidine-5-carbonyl fluoride[ No CAS ]
7-amino-6-(2-chlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-5(8H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
A solution of 2-(2-chlorophenyl)acetonitrile (34 mg, 0.22 mmol) in anhydrous DMF (1 mL) was cooled to 0 C followed by the addition of sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol) . The resulting mixture was stirred at RT for10 mm before re-cooling to 0 C. To the suspension was added dropwise a solution of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbonyl fluoride (45 mg, 0.22 mmol) in anhydrous DMF (0.5 mL), the mixture was allowed to warm to RT and stirred for 60 mm. Additional sodiumhydride, 60% in mineral oil (9 mg, 0.22 mmol) was added and the mixture stirred at RT for a further 60 mm. Further sodium hydride, 60% in mineral oil (9 mg, 0.22 mmol) was added and the mixture stirred at RT for 60 mm. The reaction mixture was diluted with water (8 mL) andextracted into ethyl acetate (3 x 5 mL) . The combined organic phases were washed with 1:1 water/brine (3 x 5 mL), dried over Na2504, filtered, and concentrated to dryness under reduced pressure to give the title compound (23 mg, 31%) as a beige solid. ?H NMR (500 MHz, DMSO-d6)6 8.94 (s, 1H), 7.54 (t, 1H), 7.38 (t, 2H), 7.25 (t, 1H),6.53 (br s, 2H), 3.78 (s, 3H), 2.62 (s, 3H) . LCMS (Method A) : = 0.83 mi m/z = 333/335 [M+H].
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ad; Yield: 40.5 mg (84%); fluorescent yellow solid; mp 193.7-194.6 C.
9-chloroindolo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ae; Yield: 49.5 mg (90%); fluorescent yellow solid; mp 208.5-209.6 C.
9-bromoindolo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3af; Yield: 59.2 mg (93%); fluorescent yellow solid; mp 205.6-207.1 C.
9-methylindolo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ag; Yield: 50.8 mg (99%); fluorescent yellow solid; mp 199.4-201.1 C.
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ah; Yield: 18.7 mg (48%); tan solid; mp 182.3-183.6 C.
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 °C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60?90 °C)?EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60?90°C)?EtOAc, 10:1 to 30:1] to give 3ai; Yield: 19.9 mg (41percent); tan solid; mp 251.7?252.8 °C.
9-methylbenzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
10-methylbenzo[4,5]imidazo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3aj; Yield: 16.2 mg (32%); tan oil; 1.1:1 mixture of inseparable isomers(ratio by 1H NMR analysis).
3-methylimidazo[1,5-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3am; Yield: 27.9 mg (67%); tan solid; mp 191.3-192.0 C.
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3aa; yield: 32.9 mg (86%); tan yellowsolid; mp 155.6-156.3 C.
1-methylpyrrolo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ab; Yield: 38.2 mg (93%); fluorescent yellow solid; mp 154.2-155.7 C.
1,3-dimethylpyrrolo[1,2-a]quinoline-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium phosphate; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60-90 C)-EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60-90C)-EtOAc, 10:1 to 30:1] to give 3ac; Yield: 43.0 mg (98%); fluorescent yellow solid; mp 168.1-168.6 C.
1-(1-chlorocyclopropyl)formic acid isopropyl ester[ No CAS ]
C12H9Cl2NO[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium amide; In 5,5-dimethyl-1,3-cyclohexadiene; at 100 - 105℃; for 5h;
0.5 moles of sodium amide dissolved in xylene,In the case of stirring,Heated to 100 ~ 105 ,A mixture of 2-chlorobenzonitrile (0.5 mol) and isopropyl chlorocarbamate (0.5 mol) was added dropwise,1 hour drop finished,And then incubated at 100 to 105 C for 4 hours,Then cooled to 0 to 5 degrees,Add 300 ml of water,Adjust pH to 5 to 6 with 5% sulfuric acidAt 5 to 10 C,Stir for 30 minutes,Separate water,To obtain a xylene solution of an alphabeta-ketonitrile compound,Adding 70% sulfuric acid 350ml,Heating up to reflux,Stirring for 18 hours,Cooling the water layer to separate,The xylene layer was used in 100 ml of water,5% aqueous sodium carbonate solution,After washing with 100 ml of water,Vacuum distillation of xylene,To give 95.2 g of 2-chlorobenzyl- (1-chlorocyclopropyl) ketone as an oil,The content of gas analysis was 92.4%.
1-(1-chlorocyclopropyl)formic acid ethyl ester[ No CAS ]
C12H9Cl2NO[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium ethanolate; In ethanol; at 80℃; for 4h;
0.5 mol sodium ethoxide into 100 ml of anhydrous ethanol,In the case of stirring, the mixture was heated to 80 C,A solution of 2-chlorobenzonitrile (0.45 mol)With 1-chlorocyclopropanecarboxylate (0.45 mol)1 hour dripping, and then heat for 3 hours,Cooling to 0 ~ 5 ,Add 300 ml of water and 200 ml of toluene,Then add 5% hydrochloric acid to adjust the pH to 5 ~ 6,At 5 to 10 C,Stir for 30 minutes,Separate water,To obtain a toluene solution of an alphabeta-ketonitrile compound,Add 60% sulfuric acid 400ml,Heating up to reflux,Stirring for 20 hours,Cooling the water layer to separate,Toluene layers were used in 100 ml of water,5% aqueous sodium carbonate solution, 100 ml of water,Evaporated toluene,To give 92.6 g of 2-chlorobenzyl- (1-chlorocyclopropyl) ketone as an oil,The content of gas analysis was 91.2%.
With bis(8-hydroxyquinolato)copper(II); sodium hydroxide; at 105 - 115℃; under 3375.34 - 3600.36 Torr; for 5h;
1L pressure kettle,76 g (0.5 mol) of o-chlorobenzeneacetonitrile was added,800 g (2 mol) of 10% sodium hydroxide,17.6 g (0.05 mol) of 8-hydroxyquinoline copper,After joining,Closing the kettle to 105 ~ 115 , keep the kettle pressure at 0.45 ~0.48MPaG, to maintain the reaction temperature between 105 ~ 115 , the reaction 5h, the detection of raw materials is completed, the reactor cooling, The pH of the reaction solution was adjusted to between 7 and 8 with 36% hydrochloric acid, and the catalyst was recovered by filtration. The mother liquor was adjusted to pH 13 with 30% NaOH~ 14,A bright red liquid was obtained, which was treated with sodium salt of o-hydroxyphenylacetate and 759 g of weighing solution. The yield of o-hydroxyphenylacetic acid was 9.5% and the yield was 95.0%.
6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde[ No CAS ]
(Z)-2-(2-chlorophenyl)-3-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium methylate; In methanol; for 1.5h;Reflux;
General procedure: To a stirred solution of MeONa in MeOH (5%,1.5 mL) was added 3a (ca. 122 mg, 0.5 mmol, 1 eq), immediatelyfollowed by cyano derivative (1.1 eq) at room temperature. Thereaction mixture was heated under reflux for 1.5 h. After coolingfor 1 h in ice bath, the solid was filtered and washed with a minimumof cold MeOH. If not pure, crude product was purified by columnchromatography on silica gel with CH2Cl2/MeOH: 99:1?90:10 as eluent.
With 5% active carbon-supported ruthenium; potassium carbonate; In 1,2-dichloro-benzene; at 155℃; for 35h;
Under an air atmosphere, 0.075 g (5% by weight of Ru (1-1) was added) Ru/C catalyst, 15 mmol K2C03 into the reaction flask, and then 50 mL of o-dichlorobenzene was added, and then 1.516 was stirred. g (10 mmol) o-chlorophenylacetonitrile (1_7) was added to the reaction flask, the temperature was maintained at about 155 C, and the reaction was stirred for 35 hours. The following operation was the same as in Example 1, and finally the dicyanidine represented by the formula (Pi-7) was obtained. The base di-chlorostyrene compound was 1.212 mg, the yield was 81%, and the GC-MS purity was 99.0%.
With copper(II) bis(trifluoromethanesulfonate); at 80℃; for 2h;
The reaction flask was charged sequentially Compound 1a (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316 muL), Cu(OTf)2 (0.01 mmol, 3.6 mg) and compound 2p (1515.9 mg). The system is then heated in air at 80 C for about 2 hours. Quenched with saturated sodium sulfite solution, extract with ethyl acetate (10 mL × 3), remove the solvent with a rotary evaporator, silica gel adsorption, The product 5o was obtained by simple column chromatography with a yield of 68%.
With 1,4-diaza-bicyclo[2.2.2]octane; In N,N-dimethyl-formamide; at 70℃; for 12h;Schlenk technique; Inert atmosphere;
The unsubstituted quinazoline N,N-1,3-dipolar compound A (0.2 mmol), o-chlorophenylacetonitrile (0.4 mmol) and DABCO (1.0 equiv) were placed in 25 mL of dried Schlenk tube. The solvent DMF (2 mL) was added under a nitrogen atmosphere at room temperature, and the reaction was stirred at 70 C for 12 hours until the reaction starting material was completely reacted (TLC tracking reaction). After the reaction was completed, the reaction solution was cooled to room temperature. The solvent was removed on a rotary evaporator. After concentrating the reaction mixture, it was purified by silica gel column chromatography using petroleum ether/ethyl acetate (EA:PE=1:3) as eluent to give 2-amino-3- (2-chlorophenyl) quinoline 4a, white solid, yield 78%.Mp: 111-112C.
4-amino-5-(2-chlorophenyl)-1,3-diazaspiro[5.5]undec-3-ene-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium methylate; In methanol; for 4h;Reflux;
General procedure: In a 25 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser, a mixture of cyclic ketone(1 mmol), nitrile compound (1 mmol) and thiourea (114 mg,1.5 mmol) was dissolved in MeOH and a solution of NaOMe in MeOH (2 M, 2 mL, 4 mmol) was added dropwise with good stirring during 2 min. After that, the reaction mixture was stirred and heated under reflux condition for 4 h.The progress of reaction was monitored by TLC, using an EtOAc:n-hexane (5:1) mixture as the eluent. After completion of the reaction (100% conversion of nitrile compound), saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting precipitate was filtered with suction. Recrystallization of the crude products from a mixture of methanol:acetonitrile (1:2) afforded pure compounds as white or off-white powders in moderate to high yields (43-91%).
Stage #1: 2-Chlorophenylacetonitrile With sodium ethanolate In tetrahydrofuran at 10℃; for 0.5h;
Stage #2: methyl cyclopropylcarboxylate In tetrahydrofuran for 4h;
Stage #3: With hydrogenchloride In water; toluene for 2h;
1-13
O-chlorophenylacetonitrile (0.48 mol) was sequentially added to a three-neck reaction flask.Strong base (0.6 mol) and solvent A 200 mL,After stirring at 10 ° C for 30 min, methyl cyclopropylcarboxylate (0.40 mol) was added, and the mixture was stirred for 4 h. The reaction was terminated by TLC, and the pH was adjusted to 2 with acid.At the same time, add 100ml of water and 100ml of solvent B, and stir for 2 hours.The organic phase was separated to obtain a toluene solution of the α,β-ketonitrile compound, and 400 mL of an acid was added.The temperature was raised to 110 ° C, and the mixture was stirred for 14 hours to carry out a hydrolysis reaction.TLC detects the end of the reaction, and the water layer is separated by cooling, and the toluene is used in sequence.Wash with saturated sodium bicarbonate solution and water, and remove toluene by distillation under reduced pressure.Obtained the oil 2-(2-chlorophenyl)-1-cyclopropylethanone, weighed, calculated yield,GC analysis of content, weighing, calculation of yield, GC analysis content.
(+/-)-tert-butyl 4-(2-chlorophenyl)-4-cyanobutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.20 g
[0579] To a solution of (2-chlorophenyl)acetonitrile (5.00 g, 33.0 mmol) in THF (46 ml) under argon was added gradually while stirring, at -78C., a 2 M solution of LDA in THF (25 ml, 49 mmol). The mixture was allowed to come to 0C. and, after 15 min, cooled back down again to -78C. Subsequently, tert-butyl 3-bromopropanoate (8.28 g, 39.6 mmol) was slowly added dropwise thereto at -78C. while stirring. Stirring of the mixture was continued overnight, in the course of which the cooling bath (dry ice/acetone) was allowed to come gradually to RT. Subsequently, water was added gradually to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (Method 19). The combined target fractions were concentrated and the residue was dried under reduced pressure. This gave 5.20 g (75% purity, 42% of theory) of the title compound. [0580] LC-MS (Method 1): Rt=2.22 min; MS (ESIpos): m/z=280 [M+H]+
With lithium diisopropyl amide;
Example 13A (+/-)-tert-Butyl 4-(2-chlorophenyl)-4-cyanobutanoate (Racemate) To a solution of (2-chlorophenyl)acetonitrile (5.00 g, 33.0 mmol) in THF (46 ml) under argon was added gradually while stirring, at -78 C., a 2 M solution of LDA in THF (25 ml, 49 mmol). The mixture was allowed to come to 0 C. and, after 15 min, cooled back down again to -78 C. Subsequently, tert-butyl 3-bromopropanoate (8.28 g, 39.6 mmol) was slowly added dropwise thereto at -78 C. while stirring. Stirring of the mixture was continued overnight, in the course of which the cooling bath (dry ice/acetone) was allowed to come gradually to RT. Subsequently, water was added gradually to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (Method 8). The combined target fractions were concentrated and the residue was dried under reduced pressure. 5.20 g (75% purity, 42% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=2.22 min; MS (ESIpos): m/z=280 [M+H]+
(+/-)-tert-butyl 5-(2-chlorophenyl)-5-cyanopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
[0665] To a solution of (2-chlorophenyl)acetonitrile (2.12 g, 14.0 mmol) in THF (20 ml) under argon was added gradually while stirring, at -78C., a 2 M solution of LDA in THF (8.4 ml, 17 mmol). The mixture was allowed to come to 0C. and, after 15 min, cooled back down again to -78C. Subsequently, a solution of tert-butyl 4-bromobutanoate (3.75 g, 16.8 mmol) in THF (10 ml) was slowly added dropwise thereto at -78C. while stirring. Stirring of the mixture was continued overnight, in the course of which the cooling bath (dry ice/acetone) was allowed to come gradually to RT. Subsequently, water and ethyl acetate (70 ml of each) were gradually added at about 0C. to the mixture, which was agitated. After phase separation, the aqueous phase was extracted once with ethyl acetate (70 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was taken up in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap-Cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7?7:3, Isolera One). The combined target fractions were concentrated and the residue was dried under reduced pressure. This gave 2.70 g (96% purity, 63% of theory) of the title compound. [0666] LC-MS (Method 1): Rt=2.31 min; MS (ESIpos): m/z=294 [M+H]+ [0667] 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 7.62-7.50 (m, 2H), 7.49-7.37 (m, 2H), 4.49 (dd, 1H), 2.28 (td, 2H), 1.99-1.78 (m, 2H), 1.72-1.51 (m, 2H), 1.38 (s, H).
(+/-)-tert-butyl 3-(2-chlorophenyl)-3-cyanopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
[0483] To a solution of (2-chlorophenyl)acetonitrile (5.00 g, 33.0 mmol) in THF (50 ml) under argon was added gradually while stirring, at -78C., a 2 M solution of LDA in THF (25 ml, 49 mmol). The mixture was allowed to come to 0C. and, after 15 min, cooled back down again to -78C. Subsequently, tert-butyl bromoacetate (5.8 ml, 40 mmol) was slowly added dropwise with stirring. The cooling bath was removed and, with stirring, the mixture was allowed to warm to RT overnight. Subsequently, water was added gradually to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [column: Kinetix C18, 5 mum, 10021.2 mm; flow rate: 30 ml/min; detection: 210 nm; injection volume: 0.4 ml; mobile phase: 50% water/45% acetonitrile/5% formic acid (1% in water)?5% water/90% acetonitrile/5% formic acid (1% in water), run time: 6.0 min]. This gave 6.98 g (purity 100%, 78% of theory) of the title compound. [0484] LC-MS (Method 1): Rt=2.10 min; MS (ESIpos): m/z=266 [M+H]+
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