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CAS No. : | 874-87-3 | MDL No. : | MFCD00270118 |
Formula : | C8H9ClS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VWVZFHRDLPHBEG-UHFFFAOYSA-N |
M.W : | 172.68 | Pubchem ID : | 70128 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.93 |
TPSA : | 25.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.18 cm/s |
Log Po/w (iLOGP) : | 2.26 |
Log Po/w (XLOGP3) : | 3.06 |
Log Po/w (WLOGP) : | 3.0 |
Log Po/w (MLOGP) : | 3.53 |
Log Po/w (SILICOS-IT) : | 3.35 |
Consensus Log Po/w : | 3.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.15 |
Solubility : | 0.122 mg/ml ; 0.000707 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.26 |
Solubility : | 0.0954 mg/ml ; 0.000552 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.91 |
Solubility : | 0.0212 mg/ml ; 0.000123 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.4 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 1760 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dimethyl sulfoxide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With thionyl chloride In toluene at 20℃; for 0.5h; | |
95% | With thionyl chloride In tetrahydrofuran at 20℃; for 48h; | 26.a; 27.a EXAMPLE 26; 4, 6-BIS (4-FLUOROPHENYL)-2- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4- pyridine; EXAMPLE 27; 4, 6-BIS (4-FLUOROPHENYL)-1- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4- b] pyridine; A) 1-CHFOROMETHYL-4- (METHYLSULFANYL) BENZENE A solution OF THIONYL CHLORIDE (0. 2 ML, 3. 2 MMOL) IN THF (9 ML) WAS ADDED SLOWLY to 4- (METHYLSULFANYLPHENYL) METHANOL (0. 346G, 2. 2 MMOL) UNDER ARGON ATMOSPHERE. The MIXTURE WAS STIRRED AT ROOM TEMPERATURE FOR 2 DAYS. INE (9 ML) WAS ADDED and the phases were separated. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 0. 37 G OF THE DESIRED COMPOUND (YIELD : 95%). |
93% | With thionyl chloride In toluene at 80℃; for 2h; |
84.3% | With thionyl chloride In toluene at 20℃; | 4.2.1. 4-Methylthiobenzyl chloride (1) To a solution of 4-methylthiobenzyl alcohol (13.0 g, 84.2 mmol) in anhydrous toluene (150 mL) was added dropwise neat thionyl chloride (7.6 mL, 12.4 g, 104 mmol) at room temperature. The resultant pale yellow solution was stirred at room temperature for 30 min, and ice-cold brine (150 mL) was added. The organic phase was separated, washed with ice-cold brine (5 × 150 mL), dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure. The residue (14.0 g) was distilled in vacuum at 115 °C/2.5 mmHg to yield 1 (12.27 g, 84.3%) of viscous oil which crystallized easily in refrigerator. 1H NMR (300 MHz, CDCl3) ppm (δ): 7.20-7.35 (m, 4H), 4.56 (s, 2H), 2.49 (s, 3H). 13C NMR (75 MHz, CDCl3) ppm (δ): 139.3, 134.3, 129.2, 126.7, 46.1, 15.8. |
78% | With 1-pyrrolidinecarboxaldehyde; benzoyl chloride In 1,4-dioxane at 20 - 40℃; Sealed tube; | 4.7.1.1 Synthesis of 4-(Methylthio)benzyl chloride (254) General procedure: 3 ., 110 (4-Methylthio)benzyl alcohol (154, 308 mg, 2.00 mmol, 1.0 equiv), FPyr6 5Jjj (19.7 ilL, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (lmL) and BzCI (282 ilL,341 mg, 2.40 mmol, 1.2 equiv) were combined as described in general254 procedure II. Chromatographic purification of the crude material (430 mg,cony. 98%, 254/354 97:3) on silica gel (mass of crude material/Si02 1:12) with Et20/nPen 3:97furnished the chloride 254 (270 mg, 1.56 mmol, 78%) as a colorless oil. To load the crude productonto the column, it was dissolved in the eluent (0.5 mL).M (C8H9CIS) = 172.675 g/mol; HR-MS (Cl, [C8H9C135S]j calc. 172.0108 u found 172.0123 u. |
71.4% | With thionyl chloride In dichloromethane for 2h; Cooling with ice; | General procedure for the synthesis of 4-Methoxybenzyl chloride, 4-(methylthio)benzyl chloride, 4-phenoxybenzyl chloride, 2,4,6-trimethylbenzyl chloride, 2-methoxybenzyl chloride, 2,4-dimethylbenzyl chloride, 3,4-dimethylbenzyl chloride, 4-methylbenzyl chloride, 2-methylbenzyl chloride and 4-tert-butylbenzyl chloride General procedure: An appropriate benzyl alcohol was dissolved in CH2Cl2 (15 ml) and placed in an ice bath. After cooling (10 min) a solution of SOCl2 in CH2Cl2 was added dropwise and the reaction mixture was stirred under reduced pressure for 2 hours. The organic layer was washed with dilute Na2CO3 (3 × 20 ml) and water (3 × 20 ml), and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a substituted benzyl chloride. |
61.3% | With hydrogenchloride at 0℃; | |
57% | With thionyl chloride In tetrahydrofuran at 25℃; | |
54% | With thionyl chloride In dichloromethane at 20℃; for 2h; | 133.A To a solution of 4-(methylthio)benzyl alcohol (1 g, 6.48 mmol) in dry dichloromethane (2 mL) was added drop by drop thionyl chloride (0.2 mL) and the mixture stirred at room temperature for 2 hours and then condensed. The chloride was used without any further purification (0.6 g, 54 %). 1H NMR (400 MHz, CDCl3) δ ppm 2.49 (s, 3 H) 4.57 (s, 2 H) 7.22 - 7.28 (m, 2 H) 7.29 - 7.36 (m, 2 H). |
With thionyl chloride; chloroform | ||
With pyridine; thionyl chloride | ||
With pyridine; thionyl chloride In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene | 1.2 Step 2 Step 2 Preparation of (4-methylthiophenyl)chloromethane To a solution of 50.0 g (325 mMol) of 4-(methylthio)benzyl alcohol in 350 ml of toluene stirring at room temperature under nitrogen, was added 5 drops of pyridine, and then 28.4 ml (46.4 g, 390 mMol, 1.2 eqs) of thionyl chloride was added dropwise. After 3 hours, ice water was added and the mixture was stirred for 20 minutes. The mixture was transferred to a separatory funnel and shaken thoroughly. The organic layer separated and was dried over sodium sulfate, filtered, and evaporated. Distillation of the residue under reduced pressure gave (4-methylthiophenyl)chloromethane (50.54 g) as a colorless liquid: b.p. 89-95° C. (1 mm). | |
With thionyl chloride In dichloromethane | 57 EXAMPLE 57 7.71 g of (p-methylthio)benzyl alcohol were dissolved in 25 ml of dry methylene chloride. 4 ml of SOCl2 were added to this solution within 30 minutes, while cooling in an ice bath. After distilling the solvent and the excess reagent, the residue was filtered over silica gel with methylene chloride. After distillation, there were obtained 4.3 g of (p-methylthio)benzyl chloride, boiling point 92° C./0.05 Torr. | |
With pyridine; thionyl chloride In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene | 1.2 Step 2 Step 2 Preparation of (4-methylthiophenyl) chloromethane To a solution of 50.0 g (325 mMol) of 4-(methylthio)benzyl alcohol in 350 ml of toluene stirring at room temperature under nitrogen, was added 5 drops of pyridine, and then 28.4 ml (46.4 g, 390 mMol, 1.2 eqs) of thionyl chloride was added dropwise. After 3 hours, ice water was added and the mixture was stirred for 20 minutes. The mixture was transferred to a separatory funnel and shaken thoroughly. The organic layer separated and was dried over sodium sulfate, filtered, and evaporated. Distillation of the residue under reduced pressure gave (4-methylthiophenyl)chloromethane (50.54 g) as a colorless liquid: b.p. 89°-95° C. (1 mm). | |
With thionyl chloride In pyridine; hexane; dichloromethane | 14 1,1'-(Dithiodi-2,1-ethanediyl)bis{4-[4-methylthio)benzyl])piperazine} Example 14 1,1'-(Dithiodi-2,1-ethanediyl)bis{4-[4-methylthio)benzyl])piperazine} A solution of thionyl chloride (47.6 g) in methylene chloride is slowly added to a solution of 4-(methylthio)benzyl alcohol (50.0 g) in pyridine (37.2 g) such that the temperature never exceeds 25° C. After the addition is complete the mixture is stirred an additional 2 hours at room temperature, then washed with water, dried, and the solvents removed. The resulting red oil is mixed with hexane which is decanted and evaporated to give 49.6 g of 4-(methylthio)benzyl chloride as a yellow oil, suitable for use in the reaction described next below. | |
With thionyl chloride In dichloromethane for 2h; Heating / reflux; | ||
270 mg | With 1-pyrrolidinecarboxaldehyde; benzoyl chloride In tert-butyl methyl ether | |
550 mg | With thionyl chloride In dichloromethane for 1h; | 2.2.1 2.1 Synthesis of compound VI Compound V 550 mg (3.24 mmol) was dissolved in 20 ml of dry dichloromethane, 0.35 ml of SOCl2 (4.86 mmol) was slowly added dropwise thereto, and the reaction was completed after 1 h. Extract with saturated brine, dry over anhydrous sodium sulfate and concentrate. The compound colorless liquid 550mg, used directly in the next reaction. |
With 1-methylsulfinyl-2-methoxybenzene; benzoyl chloride In acetonitrile at 20℃; for 17h; Sealed tube; chemoselective reaction; | ||
17.A 2-Methyl-9-[[p-(methylthio)benzyl] oxy] -4H-pyrido[ 1,2-a]-4-one A. By following the procedure of Example 13B, but substituting 154.0 g of (p-methylthio)benzyl alcohol for the p-methoxybenzyl alcohol, there is obtained p-(methylthio)-benzyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With iodine; sodium acetate at 120℃; for 12h; | |
With hydrogenchloride; iodine; sodium acetate | 93 2-(4-Methylthiobenzyl)amino-5-fluoronitrobenzene EXAMPLE 93 2-(4-Methylthiobenzyl)amino-5-fluoronitrobenzene Formula (V): X1 =5-F, X2 =X3 =H, X4 =4-SCH3, A=phenyl 24.8 g of 2-amino-5-fluoronitrobenzene and 27.6 g of 4-methylthiobenzyl chloride are mixed and 14.4 g of anhydrous sodium acetate and 0.3 g of iodine are added. The mixture is heated at 120° C. for 12 hours, with stirring, and is then cooled, taken up with a dilute solution of hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with dilute hydrochloric acid and then with water, dried over magnesium sulfate and evaporated to dryness. The oil obtained crystallizes from isopropyl ether to give 23.8 g of 2-(4-methylthiobenzyl)amino-5-fluoronitrobenzene in the form of crystals melting at 117° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | for 2h; Heating; | |
80% | at 130℃; | 4.2.2. Diethyl 4-(methylthiobenzyl) phosphonate (2) To a triethyl phosphite (14.27 mL, 13.82 g, 83.2 mmol) which was heated at reflux, 4-methylthiobenzyl chloride (12.27 g, 71.06 mmol) was added dropwise with stirring, at such a rate that a gentle reflux was maintained. When the addition was completed, the reaction was refluxed for an additional 2 h. The mixture was cooled to 25 °C, and the product mixture was fractionally distilled under vacuum to yield 15.6 g (80%) of water clear, viscous liquid: bp 142-145 °C/0.025 mmHg; 1H NMR (300 MHz, CDCl3) ppm (δ): 1.27 (t, J = 7.2, 6H), 2.49 (s, 3H), 3.13 (d, J = 21.6, 3H), 4.04 (q, J = 7.6, 4H); 7.23 (s, 4H). |
In neat (no solvent) at 140℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate In tetrahydrofuran; ethanol for 6.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; sodium for 1h; Heating; | ||
0.95 g | With sodium hydride In tetrahydrofuran; mineral oil at 0 - 50℃; for 18.5h; | S-020.1 Step 1. Synthesis of diethyl 2-(4-(methylthio)benzyl)malonate Diethyl malonate (1.5 mL, 10 mmol) was added to a 0 °C mixture of 60% NaH (0.61 g, 15 mmol) and THF (30 mL). The mixture was stirred for 30 min at room temperature before being cooled to 0 °C and a mixture of (4-(chloromethyl)phenyl)(methyl)sulfane (1.8 g, 10 mmol) and THF (10 mL) was slowly added. The resulting mixture was stirred for 30 min at 0 °C, and 12h at room temperature, and 6 h at 50 °C. Aqueous KHSO4(0.5 M) was added, and the mixture was extracted by EtOAc (3x). The extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica chromatography (2-10% EtOAc in heptane) provided 0.95 g of diethyl 2-(4-(methylthio)benzyl)malonate. |
0.95 g | With sodium hydride In tetrahydrofuran; mineral oil at 0 - 50℃; for 18.5h; | S-020.1 Step 1. Synthesis of diethyl 2-(4-(methylthio)benzyl)malonate Diethyl malonate (1.5 mL, 10 mmol) was added to a 0 °C mixture of 60% NaH (0.61 g, 15 mmol) and THF (30 mL). The mixture was stirred for 30 min at room temperature before being cooled to 0 °C and a mixture of (4-(chloromethyl)phenyl)(methyl)sulfane (1.8 g, 10 mmol) and THF (10 mL) was slowly added. The resulting mixture was stirred for 30 min at 0 °C, and 12h at room temperature, and 6 h at 50 °C. Aqueous KHSO4(0.5 M) was added, and the mixture was extracted by EtOAc (3x). The extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica chromatography (2-10% EtOAc in heptane) provided 0.95 g of diethyl 2-(4-(methylthio)benzyl)malonate. |
0.95 g | With sodium hydride In tetrahydrofuran; mineral oil at 0 - 50℃; for 18.5h; | S-020.1 Step 1. Synthesis of diethyl 2-(4-(methylthio)benzyl)malonate Diethyl malonate (1.5 mL, 10 mmol) was added to a 0 °C mixture of 60% NaH (0.61 g, 15 mmol) and THF (30 mL). The mixture was stirred for 30 min at room temperature before being cooled to 0 °C and a mixture of (4-(chloromethyl)phenyl)(methyl)sulfane (1.8 g, 10 mmol) and THF (10 mL) was slowly added. The resulting mixture was stirred for 30 min at 0 °C, and 12h at room temperature, and 6 h at 50 °C. Aqueous KHSO4(0.5 M) was added, and the mixture was extracted by EtOAc (3x). The extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica chromatography (2-10% EtOAc in heptane) provided 0.95 g of diethyl 2-(4-(methylthio)benzyl)malonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: (S)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: 5-(2-(pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-benzyl-trimethylammonium hydroxide In methanol; N,N-dimethyl-formamide at 90℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 25% 2: 47% | With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 60℃; | 26.b; 27.b EXAMPLE 26; 4, 6-BIS (4-FLUOROPHENYL)-2- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4- pyridine; EXAMPLE 27; 4, 6-BIS (4-FLUOROPHENYL)-1- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4- b] pyridine; B) Title compounds In A VOLUMETRIC flask, 4, 6-BIS (4-FLUOROPHENYL)-5- (4-PYRIDYL)-1 H-PYRAZOLO [3, 4- B] PYRIDINE (0. 30 G, 78. 0 MMOL, OBTAINED IN EXAMPLE 1) AND DMF (3. 5 ML) WERE introduced under argon ATMOSPHERE. KOH (0. 06 G, 1. 1 MMOL) WAS ADDED FOLLOWED by A solution of 1-chloromethyl-4-(methylsulfanyl)benzene (0.15 g, 0.9 mmol, obtained in SECTION A) IN DMF (0. 4 ML). THIS WAS HEATED TO 60 C OVERNIGHT. IT WAS ALLOWED to cool and concentrated. The residue was dissolved in a mixture of water and ETOAC. The two phases were separated. The organic phase was dried over NA2S04 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as ELUENT, TO AFFORD 0. 10 G OF 4, 6-BIS (4-FLUOROPHENYL)-2- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4-B] PYRIDINE (YIELD : 25%) AND 0. 19 G OF 4, 6-BIS (4- FLUOROPHENYL)-1- (4-METHYLSULFANYLBENZYL)-5- (4-PYRIDYL) PYRAZOLO [3, 4-B] PYRIDINE (YIELD : 47%). Example 26: 1H NMR (300 MHZ, CDCL3) No. (TMS): 2.50 (S, 3 H), 5. 60 (S, 2 H), 6. 84 (dd, Jo = 1.5 Hz, Jm = 4,5 Hz, 2 H), 6.92 (t, J = 8.8 Hz, 2 H), 7.00 (t, J = 8.7 Hz, 2 H), 7. 05 (M, 2 H), 7. 24-7. 37 (complex signal, 6 H), 7. 76 (S, 1 H), 8. 34 (DD, JO = 1. 5HZ, JM=4. 5HZ, 2H). Example 27 : 1H NMR (300 MHZ, CDCL3) No. (TMS): 2.49 (S, 3 H), 5.77 (S, 2 H), 6. 85 (dd, Jo = 1.6 Hz, Jm = 4.4 Hz, 2 H), 6.97 (t, J = 8.8 Hz, 2 H), 7.03 (t, J = 8. 7 HZ, 2 H), 7. 15 (M, 2 H), 7. 24-7. 33 (complex signal, 4 H), 7. 42 (D, J = 8. 1 HZ, 2 H), 7. 89 (S, 1 H), 8. 36 (DD, J = 1. 5 HZ, JM = 4. 5 HZ, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 2.2 To 0.15 g (0.5 mmol) of bicyclo[3.2.1]-lα,3, 8-triaza- spiro [4.5]dodecan-2, 4-dione-8-carboxylic acid tert-butyl ester were added successively 96 mg (0.56 mmol) of 4- methylthiobenzyl chloride, 70 mg (0.5 mmol) of potassium carbonate and 2.5 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then water was added and a white precipitated solid was collected by filtration. This crude material was back washed with water, hexanes and diethyl ether and dried under reduced pressure yielding 0.15 g (70%) of 3- (4-methylsulfanylbenzyl) - bicyclo [3.2.I]-Ia,3, 8-triaza-spiro[4.5] dodecan-2, 4-dione-8- carboxylic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, DMSO-d5) : δ [ppm] 8.77 (s, IH), 7.19 (d, 2H), 7.13 (d, 2H), 4.45 (s, 2H), 4.05 (s, 2H), 2.43 (s, 3H), EPO 2 . 15-2 . 05 (m, 2H) , 2 . 00-1 . 8 6 (m, 4H) , 1 . 61-1 . 50 (m, 2H) , 1 . 39 ( s , 9H ) . . |
70% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 1.2 To 0.15 g (0.5 mmol) of bicyclo[3.2.1] -lα,3,8-triaza- spiro[4.5]dodecan-2, 4-dione-8-carboxylic acid tert-butyl ester were added successively 96 mg (0.56 mmol) of 4- methylthiobenzyl chloride, 70 mg (0.5 mmol) of potassium carbonate and 2.5 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then water was added and a white precipitated solid was collected by filtration. This crude material was back washed with water, hexanes and diethyl ether and dried under reduced pressure yielding 0.15 g (70%) of 3- (4-methylsulfanylbenzyl) - bicyclo[3.2.1]-lα,3, 8-triaza-spiro[4.5]dodecan-2,4-dione-8- carboxylic acid tert-butyl ester as a white sol.id.1H NMR (400 MHz, DMSO-d5) : δ [ppm] 8.77 (s, IH), 7.19 (d, 2H), 7.13 (d, 2H), 4.45 (s, 2H), 4.05 (s, 2H), 2.43 (s, 3H), 2.15-2.05 (m, 2H), 2.00-1.86 (m, 4H), 1.61-1.50 (m, 2H), 1.39 (s, 9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g (68%) | With sodium acetate In tetrahydrofuran; ethanol; ethyl acetate | 1.II II) II) Compound according to the invention 5-(4-Fluorophenyl)-2-[(4-methylthio)benzylthio]-4-(4-pyridyl)imidazole 5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione (343 mg, 1.3 mmol), prepared by the process described above under I), was suspended in 12 ml of a 50% strength solution of ethanol in THF and treated with 123 mg (1.5 mmol) of sodium acetate. 258 mg (1.5 mmol) of (4-methylthio)benzyl chloride were introduced into this initial mixture. The reaction mixture was refluxed for 4 h with stirring. The mixture was filtered and the filtrate was concentrated. The residue was crystallized using ethyl acetate and the crystallizate was filtered off. Yield: 0.35 g (68%). 1H NMR ([D6]DMSO): δ(ppm) 8.46-8.43 (AA', 2H, 4-pyridyl), 7.67-7.05 (m, 11H, 4-F-phenyl), 4-CH3S-phenyl, 4-pyridyl, NHIm), 4.33 (s, 2H, -CH2-), 2.45 (s, 3H, -SCH3). IR (KBr) 1/λ=cm-1: 3429, 1606, 1579, 1504, 1424, 1226, 832. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; lithium hexamethyldisilazane In tetrahydrofuran; <i>N</i>-methyl-acetamide; dichloromethane; ethyl acetate; toluene | 1.3 Step 3 Step 3 Preparation of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethan-1-one To 321 ml of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (containing 321 mMol, 1.1 eqs) along with an additional 200 ml of dry tetrahydrofuran stirring at -70° C., was added dropwise a solution of 65.1 g (292 mMol) of (4-fluorophenyl)-2-trimethylsilyl-ethanenitrile from Step 1 in 100 ml of tetrahydrofuran. After stirring for 1 hour, a solution of 50.5 g (292 mMol, 1.0 eq) of (4-methylthiophenyl)chloromethane from Step 2 in 100 ml of tetrahydrofuran. The mixture was stirred overnight while warming to room temperature. To the mixture was then added 300 ml of 3N aqueous hydrochloric acid, and the resulting two phase mixture was stirred for 6 hours. The layers were separated, and the organic layer evaporated. The residue was taken up in 400 ml of dichloromethane, 250 ml of 2N aqueous sodium hydroxide was added, and the resulting two phase mixture was stirred rapidly overnight. The organic layer was separated and 100 ml of dimethylformamide were added. The solution was dried over sodium sulfate, filtered, and evaporated to give a yellow solid. Crystallization of the crude intermediate from ethyl acetate/toluene gave 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethan-1-one as white plates (25.8 g). Concentration of the filtrate followed by trituration of the residue gave an additional 15.7 g of white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate | S.15.1 (1) (1) Synthesis of 4-methylthiobenzyl chloride: To 200 ml of 1,2-dichloroethane was added 18.2 g of methylal, and 61.4 g of anhydrous aluminum chloride was dissolved in the solution under cooling with water. Then, 24.8 g of thioanisole was added dropwise to the mixture at room temperature and the mixture was stirred for 3 hours to effect reaction. The reaction mixture was poured into water, and concentrated hydrochloric acid was added to dissolve solids. Then, the mixture was extracted with benzene, and the extract was washed with water and with a dilute aqueous solution of sodium hydrogencarbonate and washed with water again. Then, the extract was dried over Na2 SO4, and evaporated to give 30.7 g of an oily residue. | |
With sodium hydrogencarbonate | S.29.1 (1) (1) Synthesis of 4-methylthiobenzyl chloride: To 200 ml of 1,2-dichloroethane was added 18.2 g of methylal, and 61.5 g of anhydrous aluminum chloride was dissolved in the solution under cooling with water. Then, 24.8 g of thioanisole was added dropwise to the mixture at room temperature and the mixture was stirred for 3 hours to effect reaction. The reaction mixture was poured into water, and concentrated hydrochloric acid was added to dissolve solids. Then, the mixture was extracted with benzene, and the extract was washed with water and with a dilute aqueous solution of sodium hydrogencarbonate and washed with water again. Then, the extract was dried over Na2 SO4, and evaporated to give 30.7 g of an oily residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropylamine In tetrahydrofuran | 19.1 Step 1 Step 1 2-Methyl-3-(4-methylthiobenzyl)-1-indanone To a cooled solution (-70° C.) of LDA (1M) in THF (37 mL) was added dropwise a solution of 2-methyl-1-indanone (J.A.C.S. Vol. 98, 8119-8124 (1976)) (2.5 g, 17 mmol) in THF (20 mL). The resulting dark red solution was stirred at room temperature for 3 hours, then cooled to -20° C. and a solution of 4-methylthiobenzyl chloride (3.1 g, 18 mmol) in THF (15 mL) was added slowly. The addition completed, the reaction mixture was stirred at -20° C. for 30 minutes before being quenched with 3N aqueous HCl (50 mL) and brine (50 mL). The product was extracted with ether, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel eluding with a 1:5 mixture of ethyl acetate-hexane to afford the pure title compound as an oil. | |
With diisopropylamine In tetrahydrofuran | 19.1 Step 1 Step 1 2-Methyl-3-(4-methylthiobenzyl)-1-indanone To a cooled solution (-70° C.) of LDA (1 M) in THF (37 mL) was added dropwise a solution of 2-methyl-1-indanone (J.A.C.S. Vol. 98, 8119-8124 (1976)) (2.5 g, 17 mmol) in THF (20 mL). The resulting dark red solution was stirred at room temperature for 3 hours, then cooled to -20° C. and a solution for 4-methylthiobenzyl chloride (3.1 g, 18 mmol) in THF (15 mL) was added slowly. The addition completed, the reaction mixture was stirred at -20° C. for 30 minutes before being quenched with 3N aqueous HCl (50 mL) and brine (50 mL). The product was extracted with ether, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel eluding with a 1:5 mixture of ethyl acetate-hexane to afford the pure title compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethanol; water | 14 1,1'-(Dithiodi-2,1-ethanediyl)bis{4-[4-methylthio)benzyl])piperazine} A mixture of 4-(methylthio)benzyl chloride (28.6 g), 1-(2-hydroxyethyl)piperazine (21.6 g), triethylamine (16.8 g), and ethanol (250 ml) is stirred at room temperature for 5 hours. The ethanol is then removed in vacuo and water added to the residue. The product is extracted with ether, dried, and the ether evaporated to give 31.6 g of 1-(2-hydroxyethyl)-4-[4-(methylthio)benzyl] piperazine as an orange oil, suitable for use in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane | 2 p-Methylthiobenzyl chloride EXAMPLE 2 p-Methylthiobenzyl chloride A solution of 24.8 g. (0.20 mole) of thioanisole in 180 ml. of ethylene dichloride was cooled to -5°C in an ice-methanol bath. 48 Ml. (83.6 g., 0.44 mole) of titanium tetrachloride was added dropwise over 15 minutes while maintaining the temperature at 0°-5°C. Another 10 ml. of ethylene dichloride was employed to wash forward the last quantities of titanium tetrachloride. The solution was cooled to -5°C again and 16.8 g. (0.22 mole) of methylal was added over 15 minutes while holding the temperature at 0-5°C. The reaction was stirred for 24 hours at 0-5°C and was quenched in 250 g. of ice. The organic layer was separated and the aqueous layer was extracted with 2 * 100 ml. of ethylene dichloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo at 50°-60°C to give 31.6 g. of crude product. Quantitative vpc analysis showed the product to contain a 64% yield of p-methylthiobenzyl chloride and a 5% yield of the ortho isomer. Similarly when an equivalent amount of ortho-methylthiotoluene is used in place of thioanisole, there is obtained 3-methyl-4-methylthiobenzyl chloride. Similarly when an equivalent amount of stannic chloride, zirconium oxychloride, hafnium tetrachloride, boron trichloride, ferric chloride or antimony chloride is used in place of titanium tetrachloride in the above example, the desired product is obtained. Similarly when diethoxymethane, di-n-propyloxymethane or dibenzyloxymethane is used in place of dimethoxymethane in the above procedure, the desired product is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sulfuric acid; magnesium; In water; toluene; | EXAMPLE 12 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-indene Twenty-five grams (1.04 moles) of magnesium turnings were placed in a dried flask under N2 with 400 ml. of ether. Ten ml. of 0.05 molar p-methylthiobenzyl magnesium chloride in ether is added and the mixture is warmed to 30C. About 2-3% of 39.7 g. (0.23 moles) of p-methylthiobenzyl chloride in 75 ml. of toluene is added. After 3-5 minutes of stirring an exotherm to 32-33C occurs signifying initiation of the reaction. After aging for 5 minutes, the rest of the benzyl chloride is added dropwise over 90 minutes. The reaction is aged for 30 minutes with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g., 0.199 mole) is added dropwise over 45 minutes. After aging for 30 minutes, the milky supernatant mixture is decanted from the magnesium. The flask and residual magnesium are rinsed with toluene. The reaction is then quenched by the addition of 120 ml. of 3N sulfuric acid. The lower layer is discarded. To the organic layer is added 80 ml. of 1:10 concentrated sulfuric acid, acetic acid and the two-phase mixture, stirred vigorously for one hour and water (100 ml.) is added. The bottom layer is discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final water wash the organic layer is concentrated to give 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene. Similarly, when p-methylsulfinylbenzyl chloride is used in place of p-methylthiobenzyl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; acetic acid; In water; benzene; | EXAMPLE 20 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-indene 13.44 Grams (0.56 mole) of magnesium turnings are placed in a dried flask under N2 with 125 ml. of ether and a crystal of iodine. Six ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether is added. After 3 to 5 minutes of stirring the iodine color disappears and the reaction begins. After aging for 5 minutes, the rest of the benzyl chloride is added dropwise over 45 minutes. It is rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 Grams (0.128 mole) of <strong>[41201-58-5]5-fluoro-2-methyl-1-indanone</strong> dissolved in 50 ml. of ether is added dropwise over 30 minutes. After aging for 1 hour, the milky supernatent mixture is decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium are rinsed into the acid solution with 4 * 50 ml. of benzene. Two hundred ml. of water are added, the layers are separated and the organic layer is washed with 5 * 200 ml. water. It is stripped to dryness after drying over Na2 SO4. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene, melting point 58-59C. | |
With magnesium; acetic acid; In water; benzene; | EXAMPLE 7 5-Fluoro-2-methyl-1-(p-methylthiobenzyl)-indene 13.44 G. (0.56 mole) of magnesium turnings were placed in a dried flask under N2 with 125 ml. of ether and a crystal of iodine. 6 Ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether was added. After 3 to 5 minutes of stirring, the iodine color disappeared and the reaction began. After aging for 5 minutes, the rest of the benzyl chloride was added dropwise over 45 minutes. It was rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 G. (0.128 mole) of <strong>[41201-58-5]5-fluoro-2-methyl-1-indanone</strong> dissolved in 50 ml. of ether was added dropwise over 30 minutes. After aging for 1 hour, the milky supernatent mixture was decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium were rinsed into the acid solution with 4 * 50 ml. of benzene. 200 Ml. of water were added, the layers were separated and the organic layer was washed with 5 * 200 ml. water. It was stripped to dryness after drying over Na2 SO4. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene, melting point 58-59C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sulfuric acid; iodine; magnesium; In water; toluene; | (A) 6-fluoro-2-methyl-3-(p-methylthiobenzyl)indene Twenty-five grams (1.04 mol) of magnesium turnings, a crystal of iodine, and 2 ml of p-methylthiobenzyl chloride were stirred in 400 ml of anhydrous ether under nitrogen at reflux until Grignard formation commenced. A total of 39.7 g (0.23 mol, including the initial 2 ml) of p-methylthiobenzyl chloride was added dropwise so as to maintain a gentle reflux. Refluxing was continued for 15 min. A 25-30% solution of <strong>[41201-58-5]5-fluoro-2-methyl-1-indanone</strong> in toluene was added dropwise over 50 min at 25-35C. Over 15 minutes, the reaction mixture was quenched with 120 ml of 3 N sulfuric acid at 30-35C. The aqueous layer was discarded and the organic layer was stirred vigorously for 1 hour with 80 ml of 1:10 concentrated sulfuric acetic acid. This was washed with 2 X 100 ml of water, 200 ml of 2 N sodium hydroxide and again with water. The organic layer was concentrated under vacuum to yield 6-fluoro-2-methyl-3-(p-methylthiobenzyl)indene as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In ethanol; water | V.1.1 Step 1 Step 1 A mixture of 8.0 g (0.08 mol) of pentane-2,4-dione, 14.5 g (0.08 mol) of 4-methylthio-benzyl chloride, 12 g of potassium carbonate and 100 ml of ethanol is heated under reflux for 15 hours. After cooling, the mixture is diluted to about three times the original volume using approximately identical amounts by volume of water and methylene chloride, the organic phase is separated off after vigorous shaking, dried with sodium sulphate and filtered. The filtrate is concentrated using water pump vacuum and the residue is distilled using oil pump vacuum. This gives 8.2 g (60% of theory) of 1-(4-methylthio-phenyl)-butan-3-one of boiling point 105° C. (at 2 mbar). | |
With potassium carbonate In ethanol; water | V.2.1 Step 1 Step 1 A mixture of 8.0 g (0.08 mol) of pentane-2,4-dione, 14.5 g (0.08 mol) of 4-methylthio-benzyl chloride, 12 g of potassium carbonate and 100 ml of ethanol is heated under reflux for 15 hours. After cooling, the mixture is diluted to about three times the original volume using approximately identical amounts by volume of water and methylene chloride, the organic phase is separated off after vigorous shaking, dried with sodium sulphate and filtered. The filtrate is concentrated using water pump vacuum and the residue is distilled using oil pump vacuum. This gives 8.2 g (60% of theory) of 1-(4-methylthio-phenyl)-butan-3-one of boiling point 105° C. (at 2 mbar). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine In tetrahydrofuran; ethyl acetate | 41.2 Step 2 Step 2 1-(4-fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-ethanone To a 78° C. solution of the cyanohydrin (70 mmol., 15.6 g) in THF (70 mL) was added LDA (75 mmol., 94 mL of a 0.8 M THF solution prepared from 2.1 M n-BuLi and diisopropyl amine in THF in the usual manner) dropwise and the mixture was stirred 1 hour at this temperature. Then 4-(methylthio)benzyl chloride (100 mmol., 17 g) as a THF (50 mL) solution was added and the mixture was stirred at c.a. 0° C. for 16 hours. The mixture was then cooled to -5° C. and a 1M THF solution of n-Bu4N+F- (100 mmol., 100 mL) was added dropwise. After 1.5 hour the mixture was poured on water and the pH adjusted to c.a. 9, then it was extracted with ethyl acetate (3*). The combined extracts were washed with brine, dried with magnesium sulfate and the solvents were removed in vacuo. The residue was swished in ethyl acetate and hexanes (1:25) to give a nearly pure ketone (17.9 g). 1H NMR, CD3COCD3, (δ, ppm):8.15 (2H, dd), 7.15-7.35 (6H, m), 4.45 (2H, s), 2.45 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH In N,N-dimethyl-formamide; mineral oil | 29.2 Step 2 Step 2 Dimethyl 2-(4-(diethoxymethyl)benzyl)-2-(4-(methylthio) benzyl)malonate To a solution of the product from Step 1 (1.42 g, 4.4 mmol) in DMF (14 mL) at 0° C. was added NaH (131 mg, 80% in mineral oil). After 1 h. 4-(methylthio)benzyl chloride (0.64 mL, 4.4 mmol) was added and the mixture was stirred a further 2 h at 0° C. Following a standard aqueous/Et2O work-up, the crude was purified by flash column (1:20 EtOAc/toluene) to give a colorless oil (1.92 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trimethylsilyl cyanide; 4-fluorobenzaldehyde With zinc(II) iodide In dichloromethane at 20℃; for 20h; Stage #2: With lithium diisopropyl amide In tetrahydrofuran; hexanes at -60 - -55℃; for 0.5h; Stage #3: 1-(chloromethyl)-4-methylthiobenzene With methanol; sulfuric acid; water more than 3 stages; | 6 Reference Example 6; (4-Methylthiobenzyl)-(4-FLUOROPHENYL)-KETONE To [10 ML] of sieve-dried DCM containing anhydrous zinc iodide [(50MG)] was added 4- fluorobenzaldehyde (630mg, 0. [54ML,] 5mmol). To this stirred mixture, at room temperature and under argon, was added trimethylsilyl cyanide (520mg, 0. [7ML,] 5. [25MMOL)] and the reaction was stirred overnight (-20 hours). The solvent was evaporated in vacuo and the residue was treated with anhydrous ether [(15ML)] and a little magnesium sulphate. The solution was filtered and the solvent removed [INVACUO] to give the cyanohydrin as an orange oil [(1.] 14g). Lithium diisopropylamide was made from n-butyl lithium (2. 5M in hexanes, 2. [1ML,] 5.25mmol) and diisopropylamine [(500MG,] 0. [69ML,] [5MMOL)] in THF [(5ML)] [AT-40°C.] The reaction was then cooled to-60°C and the cyanohydrin in THF [(5ML)] was added, under argon, at such a rate as to keep the temperature [BELOW-55°C.] After this addition the reaction was stirred for 30mins and then 4-methylthiobenzyl chloride [(900MG,] 5. [25MMOL)] was added in THF (2. 5ml). The cooling bath was removed and the reaction stood at room temperature overnight. To the reaction was added saturated ammonium chloride solution (13ml) and ether [(25ML).] The organic phase was separated, washed with saturated ammonium chloride solution, dried [(MGS04)] and the solvent was removed in vacuo to give an orange oil (1.78g). The oil was taken up in methanol (7ml) and treated with 2M sulphuric acid [(LOML),] the oil precipitated and so acetone (20ml) was added to give a clear solution. This stood at room temperature overnight. The pH was adjusted to 7.5 with 2M sodium hydroxide solution and the solution was concentrated invacuo. To the residue was added water and this was extracted with DCM (2x 30ml). The combined extracts were washed with brine and evaporated to give a sticky solid (1.3g). This was purified by MPLC (1: 5 EtOAc: hexane) to give an off-white flaky solid (930mg). NMR (DMSO-d6; [400MHZ)] : 2.40 (s, 3H), 4.30 (s, 2H), 7.20 (s, 4H), 7.35 [(TT,] 2H), 8.10 (m, 2H); m/z 260. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With magnesium In tetrahydrofuran; toluene for 3 - 4h; Stage #2: N-methoxy-N-methyl-6-methylnicotinamide In toluene at -20℃; for 1.5h; | |
62% | With magnesium; ethylene dibromide In tetrahydrofuran; toluene at 36℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: zinc(II) chloride With lithium chloride at 320 - 450℃; for 0.166667h; Inert atmosphere; Schlenk technique; Stage #2: 1-(chloromethyl)-4-methylthiobenzene With magnesium In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Schlenk technique; | |
With magnesium; lithium chloride In tetrahydrofuran ligand, Mg, LiCl, and ZnCl2 (1:2.5:1.25:1.1 molar ratio) for 1.5 h at 25°C; | ||
Stage #1: zinc(II) chloride With magnesium; lithium chloride In tetrahydrofuran for 0.0833333h; Inert atmosphere; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In tetrahydrofuran for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With magnesium; lithium chloride; zinc(II) chloride In tetrahydrofuran at 25℃; for 1.5h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran at 25℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; tetrabutylammomium bromide In 1,2-dichloro-ethane at -40 - 25℃; Inert atmosphere; | ||
With sodium azide In ethanol Reflux; | 18.4 (4) Preparation of substituents: Add 5.0 mmol of p-methylthiobenzyl chloride, 0.65 g of NaN3, and 5 mL of absolute ethanol to a 50 mL round-bottomed flask, heat and reflux under stirring, and follow the reaction by TLC; after the reaction is completed, remove by rotary evaporation. After the ethanol was extracted with EA for 2-3 times, the organic layers were combined, and the organic layers were washed 3 times with saturated NaCl solution. After the EA was removed by rotary evaporation, the remaining material was subjected to silica gel column chromatography using petroleum ether as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl 8-[(4-methylpiperidin-1-yl)carbonyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In N,N-dimethyl-formamide at 20℃; for 2h; | 133.B 60% NaH (74 mg, 1.85 mmol) was added in one portion to a suspension of tert-butyl 8-[(4-methylpiperidin-1-yl)carbonyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate (200 mg, 0.50 mmol) in DMF (7 mL) at room temperature under nitrogen. The mixture was stirred for 30 min, 1-(chloromethyl)-4-(methylthio )benzene (100 mg, 0.58 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water dried over sodium sulfate. Removal of solvent gave the crude product. MS (M+l): 534.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(chloromethyl)-4-methylthiobenzene With potassium hydroxide In toluene for 0.166667h; Stage #2: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With Tris(3,6-dioxaheptyl)amine In toluene for 18h; Heating / reflux; | 210 Example 210:4-[2-(4-Methylsulfanylbenzyloxy)ethyl]piperidine-l -carboxylic acid tert-butyl esterPowdered KOH (449 mg, 8 mmol) was suspended in anhydrous toluene (20 mL) and (4- methylthio)benzyl chloride (345 mg, 2 mmol) added in one portion. After stirring for 10 min, 4- (2-hydroxyethyl)piperidine-l -carboxylic acid tert-butyl ester (688 mg, 3 mmol) was added followed by tris[2-(2-methoxyethoxy)ethyl]amine (64 μL, 200 μmol) and the resulting mixture heated under gentle reflux for 18 h. The mixture was cooled, diluted with toluene and washed with water (30 mL). The aqueous phase was extracted with toluene (2 x 20 mL) and the combined organics washed with brine (30 mL), dried (MgSO4) and evaporated to afford the title compound: RT = 4.47 min; mlz (ES+) = 366.2 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With indium(III) chloride; chloro-trimethyl-silane; aluminium In tetrahydrofuran at 25℃; for 3h; Inert atmosphere; Stage #2: With zinc diacetate In tetrahydrofuran at 25℃; for 0.333333h; Inert atmosphere; Stage #3: rac-3-bromocyclohexene With copper(I) cyanide di(lithium chloride) In tetrahydrofuran at -30℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
134 mg | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With lithium manganese chloride; magnesium In tetrahydrofuran at 0℃; for 1.5h; Schlenk technique; Inert atmosphere; Stage #2: 2-formylbenzo[b]furan In tetrahydrofuran at 0 - 25℃; Schlenk technique; Inert atmosphere; Stage #3: With ammonium chloride In tetrahydrofuran; water Schlenk technique; Inert atmosphere; | General procedure: A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with magnesium (175 mg, 2.40 equiv), followed by dry THF (1 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.75 mL, 1.25 equiv; 1.0 M in THF). The mixture was cooled to 0 °C, the benzyl chloride (3.0 mmol, 1.0 equiv) was added at once and the reaction was maintained at 0 °C still complete conversion of the starting material was observed (reaction of aliquots with iodine followed by GC analysis). When the insertion reaction was complete, the solution of benzyl manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another Schlenk-flask, dry and argon flushed, before being titrated against iodine. A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with the electrophile (1.0 equiv), followed by dry THF. The benzyl manganese chloride solution (1.05-1.10 equiv) was added dropwise at 0 °C and the reaction mixture was slowly warmed up to 25 °C and stirred overnight. Sat. aq. NH4Cl (4 mL) and water (2 mL) were added and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and filtered. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
127 mg | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With lithium manganese chloride; magnesium In tetrahydrofuran at 0℃; for 1.5h; Schlenk technique; Inert atmosphere; Stage #2: 4-methoxy-benzoyl chloride In tetrahydrofuran at 0 - 25℃; Schlenk technique; Inert atmosphere; | General procedure: A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with magnesium (175 mg, 2.40 equiv), followed by dry THF (1 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.75 mL, 1.25 equiv; 1.0 M in THF). The mixture was cooled to 0 °C, the benzyl chloride (3.0 mmol, 1.0 equiv) was added at once and the reaction was maintained at 0 °C still complete conversion of the starting material was observed (reaction of aliquots with iodine followed by GC analysis). When the insertion reaction was complete, the solution of benzyl manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another Schlenk-flask, dry and argon flushed, before being titrated against iodine. A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with the electrophile (1.0 equiv), followed by dry THF. The benzyl manganese chloride solution (1.05-1.10 equiv) was added dropwise at 0 °C and the reaction mixture was slowly warmed up to 25 °C and stirred overnight. Sat. aq. NH4Cl (4 mL) and water (2 mL) were added and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and filtered. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
152 mg | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With lithium manganese chloride; magnesium In tetrahydrofuran at 0℃; for 1.5h; Schlenk technique; Inert atmosphere; Stage #2: 1-bromo-3,4,5-trimethoxybenzene With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In tetrahydrofuran at 0 - 25℃; Schlenk technique; Inert atmosphere; | General procedure: A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with magnesium (175 mg, 2.40 equiv), followed by dry THF (1 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.75 mL, 1.25 equiv; 1.0 M in THF). The mixture was cooled to 0 °C, the benzyl chloride (3.0 mmol, 1.0 equiv) was added at once and the reaction was maintained at 0 °C still complete conversion of the starting material was observed (reaction of aliquots with iodine followed by GC analysis). When the insertion reaction was complete, the solution of benzyl manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another Schlenk-flask, dry and argon flushed, before being titrated against iodine. A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum was charged with the electrophile (1.0 equiv), followed by dry THF. The benzyl manganese chloride solution (1.05-1.10 equiv) was added dropwise at 0 °C and the reaction mixture was slowly warmed up to 25 °C and stirred overnight. Sat. aq. NH4Cl (4 mL) and water (2 mL) were added and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and filtered. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With iron(III)-acetylacetonate; phenylmagnesium bromide; 1,2-bis-(diphenylphosphino)ethane In tetrahydrofuran at 65℃; for 0.166667h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate In acetonitrile at 60℃; for 2h; | Intermediate 1 B1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole Intermediate 1 B1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole 150 mg (1.06 mmol) 3,5-dimethyl-4-nitro-1H-pyrazole (CAS-No. 14531 -55-6) was dissolved in 5 mL acetonitrile and 158 μL ( 1.28 mmol) 1 -(bromomethyl)-4-fluorobenzene and 416 mg (1.28 mmol) cesium carbonate were added. The suspension was stirred at 60° C for 2 h. Afterwards the reaction mixture was filtered, the filtrate was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 259 mg (1.04 mmol, 98%) of the desired title compound after drying. 1 H NMR (400 MHz, CDCl3): δ (ppm) = 2.55 (s, 3 H), 2.58 (s, 3 H), 5.23 (s, 2 H), 7.05 (m, 2 H), 7.13 - 7.19 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzyldicarbonylcyclopentadienyliron(II); sodium t-butanolate In dibutyl ether at 25℃; for 16h; Inert atmosphere; UV-irradiation; Glovebox; Overall yield = 20%Spectr.; | General procedure for catalytic reactions General procedure: In a nitrogen filled glovebox, catalyst (∼10mg) was dissolved in solvent (1mL). Base, benzyl chloride, and styrene were added to the solution according the stoichiometry described in the data tables or in the text, and then the reaction solution was quantitatively transferred to either a J-Young NMR tube or an airtight NMR tube with screw cap seal. The NMR tube was taken out of the glovebox and placed approximately 0.75 inches away from the condenser of a 450W mercury arc UV lamp. After 16h, the NMR tube was transferred back into the glovebox, and the reaction mixture was filtered through a small plug of silica gel. Multiple aliquots of diethyl ether were used to wash the silica gel plug. Volatiles were removed under vacuum until an oil or solid remained. This residue was dissolved in CDCl3, and mesitylene was added as an internal standard. Yields and isomeric ratios were determined by integrating the 1H NMR resonance for the benzylic protons of the product(s) relative to the internal standard. In the 1H NMR spectra shown as Supplementary Data for the product mixtures, the chemical shifts and integral values for the benzylic protons and the internal standard peaks are shown. Yields are reported as averages of three independent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 1-(chloromethyl)-4-methylthiobenzene With tetra-(n-butyl)ammonium iodide In acetonitrile at 50℃; for 10h; Inert atmosphere; Stage #2: potassium thioacetate In dichloromethane at 20℃; for 6h; Inert atmosphere; | 2 Example 2 Synthesis of SS- (4-methylthiobenzyl) acetyl dithioester: Under a nitrogen atmosphere,Was added to the flask TolSO2SNa (5mmol, 1.051g, 1equiv.),Methylthio benzyl chloride (6mmol, 1.036g, 1.2equiv.), TBAI (0.25mmol, 92.4mg, 5mol%) and MeCN (20mL),The reaction system was reacted at 50 for 10 h,Adding silica gel,After removal of the solvent under reduced pressure,Column chromatography to obtain thiosulfonate compound.The resulting thiosulfonate compound (3 mmol, 1 equiv, 972 mg), KSAc (3.9 mmol, 1.3 equiv, 445 mg) and DCM (20 mL) were added to the flask,The reaction system was reacted at room temperature for 6 hours. After the TLC detection reaction was completed, the solvent was removed under reduced pressure,Column chromatography gave product 2b (689 mg, 94%).(Eluent polarity: PE: EA 50: 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With magnesium In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Schlenk technique; | Benzylic Manganese Chlorides 1a-i; General Procedure (GP1) General procedure: A dry and argon-flushed Schlenk tube, equipped with a magnetic stirring bar and a rubber septum, was charged with Mg turnings (0.18 g, 7.20 mmol, 2.40 equiv), followed by freshly distilled THF (3.0 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.80 mL, 3.80 mmol,1.25 equiv, 1.0 M in THF). The mixture was cooled to 0 °C, the corresponding benzylic chloride (3.0 mmol, 1.00 equiv) was added at once and maintained at 0 °C until a complete conversion of starting material was observed. The completion of the metalation was monitored by GC analysis of hydrolyzed and iodolyzed aliquots. When the oxidative insertion was complete, the solution of benzylic manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another predried and argon-flushed Schlenk tube, before titrating with an iodine solution in THF. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: C13H23NO5 With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In N,N-dimethyl-formamide; mineral oil for 1h; | 2.2.2 2.2 Synthesis of compound VII Compound IV 100 mg (0.366 mmol) was dissolved in 5 ml of N, N-dimethylformamide. At 0 ° C, 16 mg of NaH (0.403 mmol) was slowly added in an amount of 60%. After 5 min, compound VI 126 mg (0.732 mmol) was added. After reaction for 1h, the system was slowly quenched with water, washed with water, washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. Petroleum ether / ethyl acetate = 5/1 column chromatography gave 140 mg of compound VII as a pale yellow oily liquid in 93% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With racemic methyl phenyl sulfoxide In acetonitrile at 20℃; for 17.5h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium azide In water at 20℃; for 5h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 20℃; for 2h; | 4.2.4 (4) 1 mol of the thio-squaric acid dye (IV2b) was placed in a dry acetonitrile solvent, and 4-methylthiobenzyl chloride (2.5 mol) was added thereto, followed by stirring at room temperature for 2 hours. After cooling to room temperature, the solvent was separated by column chromatography to give the desired dye (IV7a) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 % de | Stage #1: 5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one oxime With potassium hydroxide In water; dimethyl sulfoxide at 20℃; for 0.333333h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In water; dimethyl sulfoxide at 20℃; for 24h; Overall yield = 0.076 g; | 2.1.6. General Procedure for Preparation of the Benzyloximes 8a-d General procedure: To a solution of oxime (6) (0.058 g, 0.25 mmol) in DMSO:H2O (8:2, 3 mL) at room temperature, was added KOH (0.056 g, 1 mmol). After 20 minutes, the respective benzyl halide was added (0.30 mmol). The reaction was stirred for 24 h and then the solvent was removed to give the residue which was purified by column chromatography on silica gel (80:20 hexane/EtOAc) to provide the compounds 8a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium iodide In acetone at 25℃; for 16h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl acetoacetate With sodium hydride In 1,2-dimethoxyethane; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In 1,2-dimethoxyethane; mineral oil for 12h; Reflux; | 5.1.1. 5-Methyl-4-[4-(methylsulfanyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one (2a) NaH (161mg, 4.03mmol, 60% oil dispersion), under ice cooling, was added to a solution of ethyl 3-oxobutanoate (0.50g, 3.84mmol) in 1,2-dimethoxyethane (5mL), and the mixture was stirred for 5min. 4-(Methylsulfanyl)benzyl chloride (663mg, 3.84mmol) was added, and the mixture was refluxed for 12h. After cooling to room temperature, saturated NH4Cl aq. was added, and the resulting mixture was extracted with EtOAc. The extract was washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo to give crude ethyl 2-[4-(methylsulfanyl)benzyl]-3-oxobutanoate. This material was dissolved in toluene (5mL), and hydrazine monohydrate (192mg, 3.84mmol) was added. The reaction mixture was stirred at 90°C for 10h and then cooled to room temperature. The precipitate was filtered off, washed with toluene and water and dried in vacuo to give 2a (350mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ: 2.00 (3H, s), 2.42 (3H, s), 3.50 (2H, s), 7.07-7.18 (4H, m), 8.80-11.6 (2H, br); MS m/z: 235 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl propanoylacetate With sodium hydride In 1,2-dimethoxyethane; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In 1,2-dimethoxyethane; mineral oil for 12h; Reflux; | 5.1.1. 5-Methyl-4-[4-(methylsulfanyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one (2a) General procedure: NaH (161mg, 4.03mmol, 60% oil dispersion), under ice cooling, was added to a solution of ethyl 3-oxobutanoate (0.50g, 3.84mmol) in 1,2-dimethoxyethane (5mL), and the mixture was stirred for 5min. 4-(Methylsulfanyl)benzyl chloride (663mg, 3.84mmol) was added, and the mixture was refluxed for 12h. After cooling to room temperature, saturated NH4Cl aq. was added, and the resulting mixture was extracted with EtOAc. The extract was washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo to give crude ethyl 2-[4-(methylsulfanyl)benzyl]-3-oxobutanoate. This material was dissolved in toluene (5mL), and hydrazine monohydrate (192mg, 3.84mmol) was added. The reaction mixture was stirred at 90°C for 10h and then cooled to room temperature. The precipitate was filtered off, washed with toluene and water and dried in vacuo to give 2a (350mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ: 2.00 (3H, s), 2.42 (3H, s), 3.50 (2H, s), 7.07-7.18 (4H, m), 8.80-11.6 (2H, br); MS m/z: 235 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sodium hydride In 1,2-dimethoxyethane; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-(chloromethyl)-4-methylthiobenzene In 1,2-dimethoxyethane; mineral oil for 12h; Reflux; | 5.1.1. 5-Methyl-4-[4-(methylsulfanyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one (2a) General procedure: NaH (161mg, 4.03mmol, 60% oil dispersion), under ice cooling, was added to a solution of ethyl 3-oxobutanoate (0.50g, 3.84mmol) in 1,2-dimethoxyethane (5mL), and the mixture was stirred for 5min. 4-(Methylsulfanyl)benzyl chloride (663mg, 3.84mmol) was added, and the mixture was refluxed for 12h. After cooling to room temperature, saturated NH4Cl aq. was added, and the resulting mixture was extracted with EtOAc. The extract was washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo to give crude ethyl 2-[4-(methylsulfanyl)benzyl]-3-oxobutanoate. This material was dissolved in toluene (5mL), and hydrazine monohydrate (192mg, 3.84mmol) was added. The reaction mixture was stirred at 90°C for 10h and then cooled to room temperature. The precipitate was filtered off, washed with toluene and water and dried in vacuo to give 2a (350mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ: 2.00 (3H, s), 2.42 (3H, s), 3.50 (2H, s), 7.07-7.18 (4H, m), 8.80-11.6 (2H, br); MS m/z: 235 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In 1,4-dioxane at 110℃; for 20h; Autoclave; | General procedure for the heterogeneous Pd-catalyzed carbonylative cyclization of benzyl chlorides and salicylic aldehydes General procedure: Into a 15 ml vial fitted with a magnetic stirring bar, a small cannula, and a septum was added SBA-15-P,P-PdCl2 (0.02 mmol). After this vial being purged with Ar, benzyl chloride (1.1 mmol), salicylic aldehyde (1 mmol), Et3N (2 mmol), and dry dioxane (2 ml) were added into the vial by syringes. Then the vial was diverted to an autoclave (300 mL) under an atmosphere of argon. After the autoclave was flushed with carbon monoxide gas for three times, the pressure of CO gas was adjusted to 10 bar, and the resulting mixture was stirred at 110 °C for 20 h. Upon the autoclave being cooled to room temperature, the pressure of CO was cautiously released. Ethyl acetate (10 ml) was added to the reaction mixture, and the palladium catalyst was separated by filtration of the resulting mixture, followed by washing with deionized water (2 × 6 ml) and ethanol (2 × 6 ml). After being dried at 90 °C in vacuo for 2 h, the recovered Pd catalyst was directly employed in the next run. The resultant filtrate was then washed with water (2 × 8 ml), dried over anhydrous Na2SO4, and evaporated under vacuum. The resulting residue was purified by a flash column chromatography on silica gel (light petroleum ether-ethyl acetate) to deliver the expected coumarin 3. |
Tags: 874-87-3 synthesis path| 874-87-3 SDS| 874-87-3 COA| 874-87-3 purity| 874-87-3 application| 874-87-3 NMR| 874-87-3 COA| 874-87-3 structure
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