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Structure of 2043-61-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sulfuric acid; benzyltriethylammonium bromide In 1,4-dioxane at 120℃; for 15 h;
That is, the palladium-supported crosslinked polymer (12.2 mg, 0.01 mmol), acetamide (59.1 mg, 1.0 mmol), BnEt3NBr (95.3 mg, 0.35 mmol) and cyclohexane carboxaldehyde (168 mg, 1.5 mmol) were mixed in a 0.05M sulfuric acid-dioxane solution (2 mL, 0.10 mmol). A reaction vessel was put in an autoclave, followed by stirring under a carbon monoxide atmosphere of 60 atm at 120°C for 15 hr. A reaction mixture was cooled to room temperature, followed by exhausting carbon monoxide and adding methanol (50 mL). After filtering to remove the catalyst, 2,6-xylenol that is an internal standard material was added to a filtrate, followed by analyzing by means of the HPLC to determine a yield (yield: 96percent). The leakage of palladium (Pd) from the catalyst was not at all observed in the fluorescent X-ray analysis (XRF). Furthermore, the reaction can isolate a targeted N-acyl-α-amino acid. That is, after the filtrate of the reaction was concentrated under reduced pressure, a residue was diluted with a saturated sodium hydrogen carbonate aqueous solution, followed by washing with chloroform and ethyl acetate. In the next place, after phosphoric acid was added to an aqueous phase to adjust the pH to 2, followed by extracting with ethyl acetate, organic phases were gathered, further followed by drying with anhydrous sodium sulfate. After the filtration, the solution was concentrated under reduced pressure and thereby a targeted N-acyl-α-amino acid was obtained (isolation yield: 100percent). On the other hand, a yield, when Et4NBr (35 mol percent) was used as a quaternary ammonium salt, was 72 percent and that when Bu4NBr (35 mol percent) was used was 98 percent. When acetonitrile was used as the solvent, though a very slight amount of palladium eluted off, the yield was quantitative. Similarly, various kinds of aldehyde compounds and amide compounds were reacted, and thereby N-acyl-α-amino acid could be synthesized with results below. [Show Image] [Table 1] entryR1 R2 yield (percent)b 1c-Hex Mequant (96)c,d 2c-Hex(CH2)4Me75c 3c-Hex Ph20c 4c-Hex NHMe20c,e 5PhCH2CH2 Me49c,f 6i-Pr Me 67 7t-Bu Me 55 8 Ph Me 78 9p-CF3C6H4 Me46g 10p-MeOC6H4 Me 38 11α-Naph Me58g 12β-Naph Me44ha Unless otherwise noted, the loading level of the palladium was 1.04 mmol/g. b Isolated yields. c Yield was determined by HPLC analysis. d The loading level of the palladium was 0.820 mmol/g. e The product was identified as 3. f The reaction mixture was stirred at rt for 6 h before introducing CO. g The loading level of the palladium was 0.629 mmol/g. h The reaction was performed for 24 h.
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 24, p. 4523 - 4526
[2] Patent: EP1731501, 2006, A1, . Location in patent: Page/Page column 10-11
[3] Chemistry - A European Journal, 1998, vol. 4, # 5, p. 935 - 941
[4] Bulletin of the Chemical Society of Japan, 2006, vol. 79, # 5, p. 806 - 809
[5] Synlett, 2006, # 17, p. 2795 - 2798
[6] Chemistry Letters, 2008, vol. 37, # 12, p. 1292 - 1293
[7] Journal of Organometallic Chemistry, 2004, vol. 689, # 23, p. 3806 - 3809
With boron trifluoride In tetrahydrofuran; dichloromethane at 5 - 20℃; for 4 h;
Example 5CyclosideidepreparationThe compoundII-3 (2.3 g, 5 mmol)(See, for example, Chemical Journal, 2006, 20 (5), 30-32) and dichloromethane (50 ml)A solution of 47percent boron trifluoride in tetrahydrofuran (0.2 ml) was added,Cyclohexylformaldehyde (III-3) (0.9 g) was added at 5 ° C,20 ° C for 4 hours, washed with water (10 ml × 3)The organic layer was dried and concentrated to give 2.48 g of ciclesonide ,Yield: 88percent,
96 % de
With perchloric acid In dichloromethane; acetonitrile at 0 - 5℃;
11β,16α,17α-trihydroxypregna-21-(2-methyl-1-oxopropoxy)1,4-diene-3,20-dione (100 gms) was charged in a mixture of dichloromethane (1.0 ltr.) and acetonitrile (1.0 ltr.) and cooled to 0° C. Perchloric acid (400 ml) was added to the reaction mass at 0 to 5° C. followed by cyclohexane carboxaldehyde (40 ml) and stirred at 0 to 5° C. for 4 to 5 hrs. After reaction completion, 10percent sodium bicarbonate solution (2.0 ltrs) was added under stiffing. The dichloromethane layer was separated and washed with water and dried using sodium sulphate. The solvent was concentrated under vacuum below 50° C. to residue. The residue was dissolved in methanol (300 ml) and stirred at 25 to 30° C. for 2 hrs. The product was filtered, recrystallized from methanol and dried under vacuum at 50° C. to give 90 gms. of (1) (Epimer Ratio R:S=98:2).
96 % de
With perchloric acid In dichloromethane; acetonitrile at 0 - 5℃;
11β,16α,17α-trihydroxypregna-21-(2-methyl-1-oxopropoxy)1,4-diene-3,20-dione (100 gms) was charged in a mixture of dichloromethane (1.0 ltr.) and acetonitrile (1.0 ltr.) and cooled to 0°C. Perchloric acid (400 ml) was added to the reaction mass at 0 to 5°C followed by cyclohexane carboxaldehyde (40 ml) and stirred at 0 to 5°C for 4 to 5 hrs. After reaction completion, 10percent sodium bicarbonate solution (2.0 ltrs) was added under stirring. The dichloromethane layer was separated and washed with water and dried using sodium sulphate. The solvent was concentrated under vacuum below 50 °C to residue. The residue was dissolved in methanol (300 ml) and stirred at 25 to 30 °C for 2 hrs. The product was filtered, recrystallized from methanol and dried under vacuum at 50°C to give 90 gms. of (1) (Epimer Ratio R:S= 98:2).
(S)-2-[(S)-2-{3-[1-(4-Fluoro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-6-yl]-ureido}-3-(4-methoxy-phenyl)-propionylamino]-5-guanidino-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
methyl 4-((6-amino-1H-indol-1-yl)methyl)benzoate[ No CAS ]
4-(6-{3-[(S)-1-[(S)-1-(Cyclohexylmethyl-carbamoyl)-4-guanidino-butylcarbamoyl]-2-(4-methoxy-phenyl)-ethyl]-ureido}-3-pyrrolidin-1-ylmethyl-indol-1-ylmethyl)-benzoic acid methyl ester[ No CAS ]
1-(4-trifluoromethoxy-benzyl)-1<i>H</i>-indol-6-ylamine[ No CAS ]
(S)-5-Guanidino-2-((S)-3-(4-methoxy-phenyl)-2-{3-[3-pyrrolidin-1-ylmethyl-1-(4-trifluoromethoxy-benzyl)-1H-indol-6-yl]-ureido}-propionylamino)-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
(S)-2-[(S)-2-{3-[1-(4-Fluoro-benzyl)-3-piperidin-1-ylmethyl-1H-indol-6-yl]-ureido}-3-(4-methoxy-phenyl)-propionylamino]-5-guanidino-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
1-(3-methyl-benzyl)-1<i>H</i>-indol-6-ylamine[ No CAS ]
(S)-5-Guanidino-2-((S)-3-(4-methoxy-phenyl)-2-{3-[1-(3-methyl-benzyl)-3-piperidin-1-ylmethyl-1H-indol-6-yl]-ureido}-propionylamino)-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
1-(4-trifluoromethoxy-benzyl)-1<i>H</i>-indol-6-ylamine[ No CAS ]
(S)-5-Guanidino-2-((S)-3-(4-methoxy-phenyl)-2-{3-[3-piperidin-1-ylmethyl-1-(4-trifluoromethoxy-benzyl)-1H-indol-6-yl]-ureido}-propionylamino)-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
(S)-2-[(S)-2-{3-[3-Diethylaminomethyl-1-(4-fluoro-benzyl)-1H-indol-6-yl]-ureido}-3-(4-methoxy-phenyl)-propionylamino]-5-guanidino-pentanoic acid cyclohexylmethyl-amide[ No CAS ]
EXAMPLE 2 (Z)-4-methoxy-5-(cyclohexylmethylene)-3-pyrrolin-2-one (IV, R2 =H, R3 =Me, R4 =cyclohexyl) 23.9 g of <strong>[69778-83-2]4-methoxy-3-pyrrolin-2-one</strong> (94.6 percent) in 1360 ml of 4 n sodium hydroxide solution and 27.5 g of cyclohexanecarbaldehyde (90 to 95 percent) in 330 ml of methanol were reacted as described in Example 1. Data for the product was: Yield: 39.8 g (96.1 percent) Melting point: 134° to 136° C., colorless crystals 1 H-NMR: delta=9.07 (br.s, 1H), 5.32 (d, 1H), 5.14 (d, 1H), 3.83 (s, 3H), 2.40 (m, 1H), 1.09-1.81 (m, 10H)
methyl (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane;
Preparation 2-4) To a dry ice-acetone bath cooled solution of diisopropylamine (4.84 g) in tetrahydrofuran (100 ml) was added a 1.61M solution of n-butyl lithium in n-hexane (24.8 ml) and the mixture was stirred for 30 minutes at the same temperature. Methyl (2-benzyloxyphenyl)acetate (5.12 g) was added and the mixture was stirred at -70 C. for 30 minutes and allowed to warm to 0 C. Cyclohexanecarbaldehyde (2.24 g) was added and the solution was stirred for 30 minutes. The reaction mixture was quenched by 1N aqueous hydrochloric acid solution (80 ml), washed with aqueous sodium bicarbonate solution and brine, dried, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluding with 20% diethyl ether in hexane) to afford less polar isomer of methyl (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomer A) (394 mg) and more polar isomer of methyl (2RS,3RS)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomer B) (2.67 g). isomer A: NMR (CDCl3, delta): 0.9-1.95 (11H, m), 2.46 (1H, d, J=4.3 Hz), 3.63 (3H, s), 3.97-4.05 (1H, m), 4.57 (1H, d, J=5.7 Hz), 5.06 (1H, d, J=11.8 Hz), 5.13 (1H, d, J=11.8 Hz), 6.94-7.01 (2H, m), 7.16-7.53 (7H, m). isomer B: NMR (CDCl3, delta): 0.85-1.90 (11H, m), 3.16 (1H, d, J=5.8 Hz), 3.64 (3H, s), 3.93-3.99 (1H, m), 4.32 (1H, d, J=7.9 Hz), 5.05 (1H, d, J=11.8 Hz), 5.10 (1H, d, J=11.8 Hz), 6.90-6.98 (2H, m), 7.19-7.42 (7H, m)
To a solution of <strong>[579474-47-8](2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester</strong> (22.63 mg, 0.10 mmol, 1.0 equiv; Intermediate A) in MeOH (1.0 mL) was added cyclohexanecarbaldehyde (16.83 mg, 18.05 mul, 0.15 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (4-chloro-2-methyl-phenoxy)-acetic acid (20.06 mg, 0.10 mmol, 1.0 equiv; [CAS RN 94-74-6]) and cyclohexyl isocyanide (10.92 mg, 12.27 mul, 0.10 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 38.7 mg (50%) of the title compound. MS (ISP): 512.3 [M+H]+.
To 2-(4-Aminomethyl-piperidin-l-yl)-ethanol (0.5 mmol) in tetrahydrofuran (2 mL) at room temperature are added cyclohexylmethylaldehyde (0.6 mmol)) and anhydrous magnesium sulfate (60 mg). After stirring for 1.5h at room temperature, sodium borohydride (0.5 mmol) is added and the mixture is then stirred for a further 2h. Water (3 mL) is added to the mixture and stirring resumed for 10 min. Additional water is added (1 mL) and the mixture is extracted with dichloromethane (10 mL x 3). After being dried over anhydrous magnesium sulfate the solvent is removed under reduced pressure to give the crude product. This material is used in subsequent steps without requiring further purification. [00349] The amine obtained in the previous step (0.26mmol) is added to a solution of 5-chloro-l- methyl-3-tert-Butyl-l,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (0.13mmol) in t- BuOH (0.5 mL). The reaction is heated in a sealed tube to 1000C for 24h. On complete reaction (monitored by LCMS), the mixture is allowed to cool to room temperature and the solvent is removed under reduced pressure. The final compound is then isolated by preparative HPLC.[00350] Preparative HPLC: Waters XBridge Prep C18 5mum ODB 19mm ID x 100mm L. The method uses MeCN/H2O 35-60% gradients. H2O contains 0.1% Trifluoroacetic acid (TFA)..
Cyclohexanecarboxaldehyde (145muL, 1.2mmol) and Boc-aminoethylpiperazine (229mg, 1mmol) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114mul_, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (278mul, 2mmol) and indole-3-glyoxylyl chloride (414mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml). The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product, 4-(2- {cyclohexylmethyl-[2-(1H-indol-3-yl)-2-oxo-acetyl]-amino}-ethyl)-piperazine-1- carboxylic acid tert-butyl ester 84, as a brown oil which was carried through to the next step without further purification
Cyclohexanecarboxaldehyde (145muL, 1.2mmol) and Boc-aminoethylpiperazine (229mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114muL, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (278mul, 2mmol) and indole-3-glyoxylyl chloride (414mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml). The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product, 4-(2- {cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-ethyl)-piperazine-1- carboxylic acid tert-butyl ester 84, as a brown oil which was carried through to the next step without further purification.
Cyclohexanecarboxaldehyde (145mul, 1.2mmol) and H-LyS-(BoC)-O1Bu. HCI (302mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with NaHCO3 (saturated, 20ml) and extracted with DCM (3 x 10ml), The combined organics were dried over Na2SO4, and concentrated in vacuo to yield a brown oil which was dissolved in DCM (10ml) before the addition of triethylamine (560mul, 2mmol) and indole-3-glyoxylyl chloride (415mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml) and extracted with EtOAc (3 x 20ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil. TFA (1 ml) was added to the brown oil in DCM (5ml) and the reaction was stirred at room temperature for 16hr. The solvent was removed in vacuo and purification by preparative HPLC yielded the product, (S)-6-amino-2-{cyclohexylmethyl-[2-(1 H- indol-3-yl)-2-oxo-acetyl]-amino}-hexanoic acid 95, as an off-white solid (72.5mg, 18% yield over 3 steps).
Cyclohexanecarboxaldehyde (145mui, 1.2mmol) and H-Lys-(Boc)-O'Bu.HCI (302mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with NaHCO3 (saturated, 20ml) and extracted with DCM (3 x 10ml). The combined organics were dried over Na2SO4, and concentrated in vacuo to yield a brown oil which was dissolved in DCM (10ml) before the addition of triethylamine (560mul, 2mmol) and indole-3-glyoxylyl chloride (415mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml) and extracted with EtOAc (3 x 20ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil. TFA (1ml) was added to the brown oil in DCM (5ml) and the reaction was stirred at room temperature for 16hr. The solvent was removed in vacuo and purification by preparative HPLC yielded the product, (S)-6-amino-2-{cyclohexylmethyl-[2-(1 H- indol-3-yl)~2-oxo-acetyl]-amino}-hexanoic acid 95, as an off-white solid (72.5mg, 18% yield over 3 steps).
With hydrogen;dicobalt octacarbonyl; dichlorotricarbonylruthenium(II) dimer; cetyltrimethylammonium chloride; In toluene; at 140℃; for 15h;Product distribution / selectivity;
Example 1 [Hydroformylation of cyclohexene using a catalyst system composed of a ruthenium compound, a cobalt compound and a chloride salt] At room temperature, a stainless steel-made pressurized reactor having an inner volume of 50 ml was charged with 0.05 mmol of Ru2(CO)6Cl4 as a ruthenium compound, 0.05 mmol of CO2(CO)8 as a cobalt compound, 2.5 mmol of hexadecyltrimethylammonium chloride as a halide salt, 10.0 mmol of cyclohexene as a raw material organic compound and 10.0 mL of toluene as a solvent, followed by stirring to cause them to be dissolved. Then, carbon dioxide and hydrogen were introduced such that the partial pressure each of these gases became 4 MPa, and the resultant was retained at 140C for 15 hours. Thereafter, the reactor was cooled to room temperature, and the remaining organic phase was extracted by releasing pressure. The extracted organic phase was examined by gas chromatography. The conversion ratio of cyclohexene was 54%. As hydroformylated products, cyclohexane carboaldehyde was formed in a yield of 20%, cyclohexane methanol was formed in a yield of 20%, and cyclohexane methanol was formed in a yield of 24%. Cyclohexane was formed as a hydrogenated product in a yield of 2%.
General procedure: [Using Mg turnings]: A solution of p-bromotoluene (1112 mg, 6.5 mmol) in dry THF (4 mL) was added dropwise to Mg turnings (182 mg 7.5 mmol) in THF (6 mL) at room temperature and then, the mixture was stirred at room temperature for 1 h. A solution of p-chlorobenzaldehyde (703 mg, 5.0 mmol) in THF (5 mL) was added to the mixture at 0 C and the obtained mixture was stirred at room temperature for 2 h. Then, DIH (1520 mg, 4.0 mmol), K2CO3 (1451 mg, 10.5 mmol), and t-BuOH (15 mL) were added and the obtained mixture was stirred for 20 h at refluxing conditions. The reaction mixture was quenched with satd aq Na2SO3 (10 mL) and was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine and dried over Na2SO4. Purification by short column chromatography (silica gel; hexane/CHCl3=1:1) yielded p-chlorophenyl p-tolyl ketone (934 mg, 81%).
General procedure: In a flame dried Schlenk tube, (Sa,R)-L1 (11.4 mg, 0.03 mmol) was dissolved in anhydrous Et2O (2.5 mL) and Ti(i-PrO)4 (366 muL, 4 equiv, 1.2 mmol) was added to the solution at 0 C. After 5 min, R3Al (1.5 equiv, 0.45 mmol) was added followed by the addition of the corresponding aldehyde (0.3 mmol). The reaction mixture was stirred at 0 C for 1 h (in the case of Me3Al) or 3 h (for the rest of organoaluminum reagents) and then quenched with 2 mL of H2O and 2 mL of HCl 2 M. The crude product was extracted with EtOAc (3 × 5 mL) and the combined organic layers were neutralized with aq satd NaHCO3, dried over MgSO4, and concentrated in vacuo. The crude product was purified by distillation or chromatography on silica gel to give the desired alcohol 2, whose data were in agreement with those previously reported in the literature.6c
General procedure: Ammonium salt 6 (1 equiv.) was suspended in dry THF (0.05 M) andstirred at 40 °C. t-BuOK (4 equiv.) was added and the mixture was stirred vigorously. After 10 minutes 2 equiv. of aldehyde 2 were added and the mixture was stirred for 3 hours at 40 °C. The reaction was then quenched by addition of a half-saturated NaCl solution. After phase separation, the aqueous phase was extracted three times with DCM and the combined organic phases were dried with Na2SO4 and evaporated to dryness. Purification by columnchromatography (gradient of heptanes and EtOAc) gave the corresponding epoxides in the reported yields as a mixture of diastereomers.
With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 24h;
A mixture of ethyl 3-oxobutanoate (0.4 g, 3 mmol), cyclohexanecarbaldehyde (0.34 g, 3 mmol), 1,3-thiazole-2-carboximidamide HCl salt (0.49 g, 3 mmol) and KOAc (0.59 g, 6 mmol) in CF3CH2OH (10 mL) was stirred for 24 hours at 90 C. After being cooled, it was partitioned (EtO Ac-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (0.35 g, 34%). ESIMS m/z = 334.1 [M+H]+.
(6-chloro-1H-indazol-4-yl)(cyclohexyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[885519-03-9]4-bromo-6-chloro-1H-indazole</strong> (78, 0.37 g, 1.62 mmol) in THF (6 ml) was added sodium hydride (60% dispersion in mineral oil, 0.08 g, 2.12 mmol). The mixture was allowed to stir at room temperature for 30 min and then was cooled to -78 C. Then, 2.5 M n- butyllithium in hexane (0.65 ml) was added dropwise over 5 min period. The mixture was allowed to stir at -78 C for 30 min followed by the addition of cyclohexanecarbaldehyde (0.08 g, 0.67 mmol). The reaction mixture was allowed to stir for 1h at -78C and then for 20 min while warming to room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate and water. The organic phase was washed with brine (3x), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography to provide product (P-0173). [M+H+]+ = 265.0.
[0432] To a solution of 4-bromo-6-chloro-lH-indazole (78, 0.37 g, 1.62 mmol) in THF (6 ml) was added sodium hydride (60% dispersion in mineral oil, 0.08 g, 2.12 mmol). The mixture was allowed to stir at room temperature for 30 min and then was cooled to -78 C. Then, 2.5 M n- butyllithium in hexane (0.65 ml) was added dropwise over 5 min period. The mixture was allowed to stir at -78 C for 30 min followed by the addition of cyclohexanecarbaldehyde (0.08 g, 0.67 mmol). The reaction mixture was allowed to stir for lh at -78C and then for 20 min while warming to room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate and water. The organic phase was washed with brine (3x), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting crude material was purified by silica gel column chromatography to provide product (P-0173). [M+H+]+ = 265.0.
tert-butyl 1-(4-(methoxycarbonyl)benzyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
General procedure: To a solution of cyclohexanecarboxyaldehyde 6a (0.224 mL, 1.85 mmol) in acetic acid (6 mL) phenylhydrazine (7) was added (0.182 mL, 1.85 mmol) and the reaction mixture was then heated to 80 °C for 2 h. Then methyl 4-formylbenzoate 8a (0.359 g, 1.85 mmol) in 1,2-DCE (6 mL) was added at 0 °C and after 15 min NaBH(OAc)3 (0.943 g, 4.25 mmol) was added portionwise. Reaction mixture was stirred at 25 °C for 12 h. Solvents were removed under reduced pressure, residue was diluted with 10 mL of EtOAc and washed with a saturated solution of Na2CO3. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc/n-hexane 1:20) afforded the title compound as a yellow oil (yield 16percent).
(−)-dimethyl 2-(cyclohexyl((4-(dimethoxymethyl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; In para-xylene; at 50℃; for 60h;
General procedure: Reactions were performed with 0.30 mmol of<strong>[165807-05-6]4-(dimethoxymethyl)pyrimidin-2-amine</strong> (1a), 0.30 mmol of aldehyde 2, 0.30 mmol of malonate 3 in 3.0mL of p-xylene in the presence of 20 molpercent catalyst A1 or A5 at 50 °C and stirred for 48?60 h. Aftercompletion of the reaction (as observed by TLC), the crude product was purified by preparative TLC(GF254 silica gel: hexane/EtOAc = 5/1), which yielded the target product
(+)-dimethyl 2-(cyclohexyl((4-(dimethoxymethyl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With quinine thiourea; In para-xylene; at 50℃; for 60h;
General procedure: Reactions were performed with 0.30 mmol of<strong>[165807-05-6]4-(dimethoxymethyl)pyrimidin-2-amine</strong> (1a), 0.30 mmol of aldehyde 2, 0.30 mmol of malonate 3 in 3.0mL of p-xylene in the presence of 20 molpercent catalyst A1 or A5 at 50 °C and stirred for 48?60 h. Aftercompletion of the reaction (as observed by TLC), the crude product was purified by preparative TLC(GF254 silica gel: hexane/EtOAc = 5/1), which yielded the target product
(-)-diethyl 2-(cyclohexyl((4-(dimethoxymethyl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; In para-xylene; at 50℃; for 60h;
General procedure: Reactions were performed with 0.30 mmol of<strong>[165807-05-6]4-(dimethoxymethyl)pyrimidin-2-amine</strong> (1a), 0.30 mmol of aldehyde 2, 0.30 mmol of malonate 3 in 3.0mL of p-xylene in the presence of 20 molpercent catalyst A1 or A5 at 50 °C and stirred for 48?60 h. Aftercompletion of the reaction (as observed by TLC), the crude product was purified by preparative TLC(GF254 silica gel: hexane/EtOAc = 5/1), which yielded the target product
(+)-diethyl 2-(cyclohexyl((4-(dimethoxymethyl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With quinine thiourea; In para-xylene; at 50℃; for 60h;
General procedure: Reactions were performed with 0.30 mmol of<strong>[165807-05-6]4-(dimethoxymethyl)pyrimidin-2-amine</strong> (1a), 0.30 mmol of aldehyde 2, 0.30 mmol of malonate 3 in 3.0mL of p-xylene in the presence of 20 molpercent catalyst A1 or A5 at 50 °C and stirred for 48?60 h. Aftercompletion of the reaction (as observed by TLC), the crude product was purified by preparative TLC(GF254 silica gel: hexane/EtOAc = 5/1), which yielded the target product
(+)-dimethyl (cyclohexyl-2-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(-)-dimethyl (cyclohexyl-2-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With quinine; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
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