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CAS No. : | 1660-04-4 | MDL No. : | MFCD00074739 |
Formula : | C12H18O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DACIGVIOAFXPHW-UHFFFAOYSA-N |
M.W : | 178.27 | Pubchem ID : | 123126 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.92 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 53.4 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.59 cm/s |
Log Po/w (iLOGP) : | 2.31 |
Log Po/w (XLOGP3) : | 2.53 |
Log Po/w (WLOGP) : | 2.79 |
Log Po/w (MLOGP) : | 2.88 |
Log Po/w (SILICOS-IT) : | 2.94 |
Consensus Log Po/w : | 2.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.47 |
Solubility : | 0.6 mg/ml ; 0.00336 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.54 |
Solubility : | 0.52 mg/ml ; 0.00292 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.28 |
Solubility : | 0.936 mg/ml ; 0.00525 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.87 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
85% | With N-Bromosuccinimide In methanol; Petroleum ether at 59.84℃; for 2 h; | 1-Adamantyl methyl ketone was refluxed with N-bromo succinimide and petroleum ether in methanol at 333 K for two hours. The resultant 1-adamantyl bromomethyl ketone (1) precipitate was filtered and recrystallized with ethanol. After that, 1-adamantyl bromomethyl ketone (1) (0.51 g, 0.002 mol) was reacted with the corresponding carboxylic acid (0.003 mol) with the presence of potassium carbonate in DMF (8 mL) and stirred at room temperature for about 3 h. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction completed, the reaction mixture was poured into ice-cooled water and kept stirring for 10 min. The solid obtained was filtered out, washed successively with distilled water and recrystallized from acetone after it dried [20]. All targeted compounds were synthesized in good yield and high purity. Suitable single-crystal specimens were obtained from various types of solvents, as described below. The chemical structures were characterized by using FTIR and NMR spectroscopies. The crystal structures for all compounds except 2m and 2q were determined by single-crystal X-ray diffraction analysis. |
78% | at 20℃; for 4 h; Cooling with ice | [359] To an ice- cooling solution of 1-(adamantan-1-yl)ethanone (1.78 g, 10.0 mmol) in THF (30 mL) was added Br2 (1.70 g, 10.7 mmol, dissolved in 5 mL THF). The resultedmixture was stirred at room temperature for 4h, and then the reaction was quenched by addition of saturated sodium thiosulfate solution (20 mL), extracted with dichloromethane (100 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to afford compound 19.1(2.0 g, yield: 78percent) as a yellow solid. |
70% | at 160℃; for 4 h; Sealed tube; Inert atmosphere | General procedure: The reactions were carried out in glass ampoules (20 mL) or in a pressure microreactor of stainless steel (17 mL). The results of parallel experiments were identical. Into the microreactor (ampoule) in an argon atmosphere was charged 0.3 mmol of Fe(acac)3, 10 mmol of initial adamantane, 10 mmol of CBr4, and 150 mmol of CH2Br2. The reactor was hermetically closed (the ampoule was sealed) and heated while stirring. On the completion of the reaction the reactor (ampoule) was cooled to room temperature, opened, the solvent was distilled off, the residue was crystallized from hexane or ethanol. Yields are given in respect to converted adamantane (adamantine derivatives) (GLC procedure, internal reference decene; correction factor for adamantane 1.09, for bromoadamantane 1.53). The structure of compounds obtained was proved by comparison with known samples and published data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | Stage #1: for 0.25 h; Stage #2: at 0 - 80℃; for 11.5 h; |
Equipped with a mechanical stirrer, reflux condenser, constant pressure dropping funnel,Thermometer 250mL four-necked flask was added concentrated sulfuric acid 100mL, with stirring,15 g (84.1 mmol) of 1-adamantane methyl ketone (R = CH3)After the addition was maintained for 15 minutes, ice water bath control 0 , and then within 30 minutes with a constant pressure dropping funnel slowly dropping mixed acid solution (fuming nitric acid 16ml (0.34mol) + concentrated sulfuric acid 16ml)Insulation 1h, naturally heated to 80 reaction 10h, the reaction was completed,The reaction solution was slowly poured into 200mL ice water, stirring while pouring, white solid precipitation, filtration was precipitated,A small amount of washing cake,Dried in vacuo to give a white powdery solid 14.9g, content 98percent, yield 79.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; acetic acid for 3h; Irradiation; Inert atmosphere; | Reduction of α-Haloketones 2; General Procedure General procedure: Into a flask charged with the respective α-haloketone 2 (1 mmol) and ethidine (Hantzsch's ester, 1a; 1.2 mmol), was added the solvent as per Tables 2-4 (2.5 mL). The flask was then attached to a balloon filled with N2 and irradiated with 3 W blue LED at a distance of 5 cm. The workup was followed when TLC showed that ethidine or the haloketone was consumed. When AcOH was used as the solvent, the reaction was worked up as follows: the reaction mixture was partitioned between EtOAc (40 mL) and H2O (10 mL), then the organic phase was washed with sat. aq NaHCO3 (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). After concentration under reduced pressure, the residue was subjected to flash chromatography for purification eluting with petroleum ether (PE) and CH2Cl2. When aprotic polar solvents were used, the reaction mixture was diluted with EtOAc (40 mL) and the organic layer was washed with H2O (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). When volatile solvents were used, the mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography for purification. |
With water; lithium diisopropyl amide 1.) THF/ether, -78 deg C, 10 min, 2.) THF/ether, room temperature; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In diethyl ether at 25℃; for 4h; | |
91% | In diethyl ether for 24h; Heating; | |
91% | In diethyl ether; hexane at -5 - 20℃; |
In diethyl ether at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.8% | With sodium ethanolate In ethanol | 66.A A. A. 1-(1-Adamantyl)-3-(4-fluorophenyl)-2-propen-1-one A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and 1-adamantyl methyl ketone (10.00 g, 56.10 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out of solution. After stirring at room temperature for 48 hours, the mixture was cooled to -10° C. and the precipitate was collected by filtration. The solid was washed with cold ethanol, dried in vacuo and recrystallized from hexane. The title compound was obtained as an off-white solid (9.20 g, 57.8%). m.p. 126°-127° C. Rf 0.55 (25% EtOAc/hexane), UV Analysis for C19 H21 FO: Calc'd C, 80.25; H, 7.44; F, 6.68 Found C, 79.43; H, 7.54; F, 6.94 |
With sodium ethanolate In ethanol for 15h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ethanol; sodium hydride In tert-butyl methyl ether at 20℃; | Sodium Enolate 6 Sodium hydride (60% dispersion, 0.84 g, 21 mmol) was suspended in MTBE (15 mL). EtOH (0.1 mL) was added slowly with gas evolution atr.t. Next, a solution of ethyl formate (1.37 g, 18.5 mmol) and 1-acetyl-adamantane (4) (2.99 g, 16.8 mmol) in MTBE (5.0 mL) was addeddropwise over 2 h. The resulting yellow slurry was diluted with MTBE(5 mL) and the suspension was stirred overnight at r.t. The mixture was filtered, and the yellow residue was washed multiple times withn-pentane. After drying in vacuo, the product was obtained as a paleyellow solid (3.2 g, 83%). No NMR data were obtained because of theinsolubility of the product. The product was used without further pu-rification.IR (ATR): 2892, 2850, 1698, 1586, 1446, 1360, 1224, 774 cm -1 .HRMS (ESI): m/z [M-Na] - calcd for C13H17O2 : 205.1234; found:205.1233. |
82% | With ethanol; sodium | |
82% | With ethanol; sodium In diethyl ether for 12h; |
With sodium 1.) ether, 2.) ethanol; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydroxylamine hydrochloride In pyridine at 80℃; for 2h; | |
97% | With pyridine; hydroxylamine hydrochloride In ethanol at 100℃; for 2h; | 1 Preparation of 1-adamantane methyl ketone oxime In the reaction bottle,Add 1.9 g of hydroxylamine hydrochloride,10 mL of pyridine and 10 mL of absolute ethanol,Heated to 100 ° C,The solution is homogeneous,Add 1.42g adamantyl methyl ketone,Reflux for 2h,Distilling solids,10mL deionized water wash,filter,dry,To obtain 1-adamantane methyl ketone oxime 1.57g,Yield 97%; |
97% | With pyridine; hydroxylamine hydrochloride In ethanol at 100℃; for 2h; Green chemistry; | 1-3 Preparation of 1-adamantyl methyl ketone oxime: In the reaction flask, 1.9 g of hydroxylamine hydrochloride, 10 mL of pyridine and 10 mL of absolute ethanol were added, and the mixture was heated to 100 ° C, the solution was homogeneous, and 1.42 g of adamantane methyl ketone was added, and refluxed for 2 hours and the solid was distilled off, 10 mL of deionized water was washed, filtered, and dried to give 1-adamantane methyl ketone oxime 1.57 g, yield 97% |
97% | With pyridine; hydroxylamine hydrochloride at 100℃; for 2h; | 1.1.c; 2.1.c; 3.1.c; 4.1.c; 1-3 c. 1-adamantane methyl ketone oxime preparation: In the reaction flask, adding hydroxylamine hydrochloride 1.9g,10 mL of pyridine and 10 mL of absolute ethanol, heated to 100 ° C, the solution is homogeneous.1.42 g of adamantyl methyl ketone was added, refluxed for 2 h, and distilled to obtain a solid.10mL deionized water washing, filtration, and drying, to obtain 1-adamantane methyl ketone oxime 1.57g, yield 97%; |
97% | With pyridine; hydroxylamine hydrochloride In ethanol at 100℃; for 2h; Green chemistry; | 1 1-adamantane methyl ketone oxime preparation In the reaction flask, 1.9 g of hydroxylamine hydrochloride, 10 mL of pyridine and 10 mL of absolute ethanol were added, and the mixture was heated to 100 °C. The solution was homogeneous, and 1.42 g of adamantane methyl ketone was added and refluxed for 2 h. The solid was distilled off, washed with 10 mL of deionized water, filtered, and dried to give 1-adamantane methyl ketone oxime 1.57 g, yield 97% |
97% | With pyridine; hydroxylamine hydrochloride In ethanol at 100℃; for 2h; | 1-3 Preparation of 1-adamantane methyl ketone oxime: In the reaction flask, 1.9 g of hydroxylamine hydrochloride, 10 mL of pyridine and 10 mL of absolute ethanol were added, and the mixture was heated to 100 ° C. The solution was homogeneous. 1.42 g of adamantane methyl ketone was added, refluxed for 2 h, and the solid was distilled off, and 10 mL of deionized water was washed. , filtration, drying, to obtain 1-adamantane methyl ketone oxime 1.57g, yield 97%; |
95.6% | With hydroxylamine hydrochloride; sodium acetate In water for 10h; Heating; | |
95% | With hydroxylamine hydrochloride; sodium carbonate In ethanol; water Heating; | |
With hydroxylamine | ||
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 100℃; | ||
15.9 g | With pyridine; hydroxylamine hydrochloride In ethanol at 100℃; for 2h; | 1-3 Example 2 In the reaction flask, add 0.3 mol of hydroxylamine hydrochloride, 85 mL of pyridine and 85 mL of absolute ethanol, heat to 100 ° C, the solution is homogeneous, add 1-adamantane methyl ketone 0.08 mol, reflux for 2 h, and distillate to obtain solid matter 1- Adamantyl methyl ketone oxime, 80 mL of water, filtered, and dried to give a crude product of 1-adamantane methyl ketone oxime 15.4 g, yield: 98%, mpl 80-182 °C. |
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h; | ||
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h; | ||
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tetrahydroborate In ethanol at 20℃; for 29h; Cooling with ice; | 4.3 General procedure for preparation of racemic alcohols (4a, 7a) NaBH4 (0.60g, 15.8mmol) was added to a stirred solution of 1-acetyladamantane (1.62g, 9.09mmol) in dry ethanol (20mL) for 5h. The exotherm was controlled by an ice bath. The suspension was stirred at room temperature for 24h, monitored by TLC. After the reaction was quenched by an addition of water (20mL), ethanol was removed under vacuum and the residue was extracted with ethyl acetate (3×30mL). The combined organic phases were washed with brine (20mL), dried over MgSO4 and then filtered. The organic solvent was evaporated under reduced pressure; and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 3:1) to give 7a (1.56g, 8.7mmol, 95% yield). The 1H NMR spectra of the obtained rac-alcohol 4a31 and 7a32 was in agreement with those reported value. |
95% | With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 1h; Inert atmosphere; | |
94% | Stage #1: 1-acetyladamantane With n-butyllithium; iron(II) acetate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In tetrahydrofuran; hexane at 65℃; Inert atmosphere; Stage #2: With sodium hydroxide In tetrahydrofuran; methanol; hexane; water at 20℃; for 3h; Inert atmosphere; |
92% | Stage #1: 1-acetyladamantane With n-butyllithium; 1-(2-hydroxyethyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate; iron(II) acetate In tetrahydrofuran at 65℃; for 2h; Inert atmosphere; Stage #2: With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 2h; Inert atmosphere; | |
With lithium aluminium tetrahydride | ||
With sodium hydroxide; sodium tetrahydroborate In isopropyl alcohol for 3h; Heating; | ||
85 % Spectr. | With dibutylstannane In toluene at 25℃; for 3h; | |
With sodium tetrahydroborate | ||
0.50 g | With lithium aluminium tetrahydride | |
With sodium tetrahydroborate | ||
With sodium hydroxide; sodium borohydrid In methanol; water | 23 EXAMPLE 23 EXAMPLE 23 Powdery sodium borohydride (4.8 g) was added slowly over 30 minutes to a mixture of 45.0 g of 1-acetyladamantane, 100 ml of methanol, and 20 ml of 0.1 N sodium hydroxide on a water bath. The resultant mixture was further stirred for 30 minutes, was neutralized with a 1 N hydrochloric acid aqueous solution, and 200 ml of water was added to the mixture. The obtained crystals were filtrated, was washed with water and was dried in vacuo to give 45.0 g of 1-(1-hydroxyethyl)adamantane. | |
With lithium aluminium tetrahydride Inert atmosphere; | General remarks General procedure: All reactions were carried out using Schlenk techniques. Proline derived ligands 3a-3c and 3e-k were prepared from Boc-L-proline and the corresponding commercially available amines, as described in the literature[i]. [RuCl2 (p-cymene)]2 and (1R,2S)-(+)-cis-1-amino-indanol 3d were purchased. Racemic alcohols 2a-m were prepared by LiAlH4 reductions of the corresponding ketone. Other reagents are commercially available. Products were purified by preparative thin layer chromatography using plates prepared from silica gel. Bruker AM 250 spectrometer, operating at 250 MHz for 1H, and at 62.5 MHz for 13C, was used for the NMR spectra which are referenced to the solvent as internal standard. Infrared spectra were recorded in CHCl3 solution using CaF2 cells on a Perkin-Elmer 1000 FT-IR spectrometer. HRMS were measured with a Thermo-Finnigan-Mat 95 spectrometer. Optical rotations were determined using a Perkin-Elmer 241 Polarimeter at room temperature using a cell of 1 dm length and l = 589 nm. Data are reported as follows: [a]D20 (concentration in g/100 mL, solvent). Reactions were monitored by gas chromatography analysis on apparatus Fisons 8000 equipped with column β-P1. Enantiomeric excesses of alcohols were determined by gas chromatograph analysis on Fisons 9000 apparatus equipped with Chiraldex β-PM column. For the separation of the enantiomers of the mixture of alcohols 2a-g, the program was as follows: oven temperature was maintained at 50°C during 30 min, then heated to 100°C (5°C/min) maintained at 100°C during 65 min, then heated to 120°C (5°C/min) and maintained at 120°C during 100 min. | |
With sodium tetrahydroborate In methanol at 0℃; | ||
Stage #1: 1-acetyladamantane With diphenylsilane; C43H60ClCuN3PSi2; sodium t-butanolate at 20℃; Stage #2: With hydrogenchloride In methanol | ||
With sodium tetrahydroborate In ethanol for 1h; | 2.5 (5) Preparation of rimantadine Add 4g in 50mL three-necked flask adamantane methyl ketone, 10ml of ethanol and 4.4g of sodium borohydride, the reaction was stirred for 1h, 12mL of hydrochloric acid was slowly added dropwise Ph is adjusted to 2.5, filtered to obtain a solid.The solid was dissolved in ethanol was added dropwise at 0 ammonia 20mL conditions, the reaction 0.5h, the reaction was heated to 40 1h, extracted with ethyl acetate, the extract was removed by rotary evaporation of ethyl acetate, to give 3.78g of white crystals, rimantadine is the desired product in a yield of 94.1%. | |
With C50H54IrO3P2(1+)*F6P(1-); isopropyl alcohol; potassium hydroxide at 80℃; for 24h; Schlenk technique; Inert atmosphere; | Screening of substrates General procedure: A general procedure was applied depending on the physical state of the substrate, as follows: a. For solid ketones: The catalyst (3, 9µmol) and the ketone (1.85mmol) were added to a Schlenk flask. Air was purged by three vacuum/gas (N2) cycles. Degassed iPrOH (3.3mL) was added, followed by base from a freshly prepared stock solution of KOH in iPrOH (90µmol, 200µL from stock solution 0.45mol/L). A reflux condenser was connected to the Schlenk and the system was heated to 80°C in an oil bath. After the reaction time (24h) the heating was stopped and the yield was determined by 1H NMR. b. For liquid ketones: The catalyst (3, 9µmol) was added to a Schlenk flask. Air was purged by three vacuum/gas (N2) cycles. Then, the ketone (1.85mmol), iPrOH (3.3mL), and KOH (90µmol, 200µL from stock iPrOH solution 0.45mol/L) were added with a syringe. A reflux condenser was connected to the Schlenk and the system was heated to 80°C in an oil bath. After the reaction time (24h) the heating was stopped and the yield was determined by 1H NMR | |
With sodium tetrahydroborate; calcium chloride In methanol at 0 - 20℃; | ||
36 %Chromat. | With C18H21BrMnN3O3; potassium <i>tert</i>-butylate; isopropyl alcohol at 40℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; | |
98% | With 2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 20℃; optical yield given as %ee; enantioselective reaction; | |
95% | With Candida magnoliae carbonyl reductase; D-glucose dehydrogenase; NADPH In water; dimethyl sulfoxide at 20℃; |
94% | With (-)-(3aS)-1,1-dimethoxy-3,3-diphenyl-hexahydro-1H-pyrrolo[1,2-c][1,3,2]oxazaborol-7-ium-1-uide; dimethylsulfide borane complex In tetrahydrofuran at 20℃; enantioselective reaction; | |
With lithium aluminium tetrahydride In diethyl ether for 2h; Ambient temperature; Yield given; | ||
Multi-step reaction with 2 steps 1: chiral t-butyl(methyl)phosphine-based rhodium complex / tetrahydrofuran / 30 h / -20 °C 2: HCl / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 2 steps 1: chiral t-butyl(methyl)phosphine-based rhodium complex / tetrahydrofuran / 72 h / -40 °C 2: HCl / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 2 steps 1: AgBF4 / (S)-[RhBr(nbd)(oxazolinyl-carbene)] / CH2Cl2 / 10 h / -60 °C 2: K2CO3 / methanol / 4 h / 20 °C | ||
Multi-step reaction with 2 steps 1: Rh(III)-NHC complex / tetrahydrofuran / 24 h / 15 °C 2: 96 percent / aq. HCl / 0.5 h / 20 °C | ||
> 99 % ee | With C17H38BFeNOP2; hydrogen In ethanol at 30℃; for 6h; Autoclave; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With C48H54CoN2O4 In tetrahydrofuran; methanol at -20℃; for 24.33h; Inert atmosphere; enantioselective reaction; | Procedure for Reusable Catalytic System in Reduction of1-Adamantyl Methyl Ketone (3). General procedure: Under a nitrogen atmosphere, NaBH4 (18.9 mg, 0.50mmol) and MeOH (121 L, 3.0mmol) in 3.9mL of THF was stirred at 20 °C for 2 h. To a solution of cobalt complex 1 (19.5 mg, 25 mol, 10mol%) or recovered complex 2, 1-adamantyl methyl ketone (3) (44.6mg, 0.25mmol) and 1,1,1-trichloroethane (7.5 L, 75 mol,30 mol%) in THF (2.5 mL) was added the prepared borohydride mixture at 20 °C over 20min. After stirring for 24 h at 20 °C, the reaction was quenched with 1.5mL of cooled aqueous THF. To the solution was added water and AcOEt, extracted 3 times with AcOEt, then washed with brine. Thecombined organic layers were dried over Na2SO4 and thesolvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography pressurized by nitrogen with an eluent (AcOEt/hexane = 1/15) to affordthe corresponding alcohol 4. After elimination of the yellow colored fractions with an eluent (AcOEt/Et2O = 1/12), thered-colored fractions were collected with an eluent (AcOEt/Et2O = 4/1). The collected red-colored fractions evaporatedunder reduced pressure (Do not evaporate completely underhigh vacuum. When the red-colored fractions were driedcompletely to obtain the recycled catalyst, the enantiomeric excesses decreased). The secondary alcohol 4 was followed byesterification with 1-naphthoyl chloride for HPLC analysis.5 |
With diphenylsilane; potassium carbonate 1.) THF, -40 deg C, 48 h, 2.) MeOH; Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts; | ||
With phosphate buffer In ethanol at 30℃; for 360h; Rhodotorula rubra; Yield given. Yields of byproduct given. Title compound not separated from byproducts; |
With (-)-C5Me5FeC10H10N; bis(2-methylphenyl)silane In tetrahydrofuran at 0℃; Title compound not separated from byproducts; | ||
Stage #1: 1-acetyladamantane With silver tetrafluoroborate; (S)-Rh(nbd)Br[MesNC3H2N-C3H3NO(t-Bu)]; PhSiH2 In dichloromethane at -60℃; for 10h; Stage #2: With potassium carbonate In methanol; dichloromethane at 20℃; for 4h; Title compound not separated from byproducts; | ||
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 20℃; for 24h; Title compound not separated from byproducts; | ||
With potassium hydroxide; isopropyl alcohol at 28℃; for 2h; +; Title compound not separated from byproducts.; | ||
With diethoxymethylane; Fe(tetraphenyl-carBPI)(OAc) In tetrahydrofuran at 40℃; for 40h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With (p-cymene)ruthenium(II) chloride; water; sodium formate; (2S)-N-phenylpyrrolidine-2-carboxamide at 30℃; for 48h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | General procedure for catalytic reductions: General procedure: In a Schlenk tube, dichloro-p-cymene ruthenium dimer (15.5 mg, 0.025 mmol) and ligand (0.05 mmol) were dissolved in water (4 mL) at 30°C and stirred during 1h. Sodium formate (0.68 mg, 10 mmol) and substrate (1 mmol) were then added. The reaction mixture was maintained at 30°C until total reduction of the ketone (monitored by GC). Alcohol was extracted with pentane (3x10 mL), dried over MgSO4 and evaporated under reduced pressure. The product was purified by thin layer chromatography with petroleum ether/ethyl acetate mixture, and spectral data compared with the literature[ii]. Enantiomeric excesses were determined by GC on chiral column. | |
With methanol; sodium tetrahydroborate; Co((OC(CH3)C(COC6H2(CH3)3)CHNCHC6H2(CH3)3)2); 1,1,1-trichloroethane In tetrahydrofuran at -20 - 0℃; for 24.3333h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With methanol; sodium tetrahydroborate; 1,1,1-trichloroethane; (1S,2S)-N,N'-bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-1,2-bis(2,4,6-trimethylphenyl)ethylenediaminatocobalt(II) In tetrahydrofuran at -20 - 0℃; for 16.3333h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With methanol; sodium tetrahydroborate; 1,1,1-trichloroethane; C50H56ClCoN2O4 In tetrahydrofuran at -20℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
Stage #1: 1-acetyladamantane With diethoxymethylane; C36H31FeN3O3 In toluene at -78 - 20℃; for 6h; Schlenk technique; Inert atmosphere; Stage #2: With potassium carbonate In methanol at 20℃; for 1h; Schlenk technique; Inert atmosphere; Overall yield = 23 %; Optical yield = 15 %ee; enantioselective reaction; | ||
81 % ee | With silver tetrafluoroborate; diphenylsilane; C33H43ClN3ORh In dichloromethane at 40℃; for 24h; Glovebox; Sealed tube; Overall yield = 81 percent; Overall yield = 72.1 mg; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuryl dichloride at 80℃; | 13 Example 13: Synthesis of 2,2-Dichloro-1-(1-adamantane)-1-ethanone IIm To a 25 mL two-necked flask connected with a drying tube and a reflux condenser, 1-(1-adamantane)ethanone Im (1.0 mmol) and sulfonyl chloride (3.0 mmol) were added.The reaction mixture was heated to 80°C and stirred for 4-8 hours, and TLC was used to continuously monitor the reaction during the reaction.When the reaction is complete, it is put into a rotary evaporator to remove excess sulfonyl chloride under reduced pressure, and finally directly subjected to silica gel column chromatography (using ethyl acetate-hexane as the eluent) to separate, to obtain 2,2-dichloro-1-(1-Adamantane)-1-ethanone IIm is a white solid with a yield of 95%. |
95% | With sulfuryl dichloride In neat (no solvent) at 80℃; for 4h; | General procedure for dichlorination of ketones. General procedure: To a 25 mL two necked flask equipped with a condenser and a drying tube was added ketone (5.0 mmol) and sulfuryl chloride (15.0 mmol). The reaction mixture was then stirred at 80 °C. After completion of the reaction (monitored by TLC), the organic mixture was concentrated under reduced pressure to remove the excess amount of sulfuryl chloride, and separated by silica-gel column chromatography using ethyl acetate-hexane as eluent in increasing polarity to yield the desired product. |
With chlorine In acetic acid at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | In benzene for 2h; | 2.4 (4) Preparation of adamantane methyl ketone 50mL three-necked flask was added 4g (CH3)2CdCu, added to the flask drop benzene solution step of adamantane chloride, 2h dropwise.The reaction mixture was poured into cold water to give a pale yellow compound, filtered, 100 drying 5h adamantane methyl ketone to give the product 3.60g, yield 75.3%. |
58.3% | In diethyl ether for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-Bromosuccinimide In methanol; Petroleum ether at 59.84℃; for 2h; | 3.1. Synthesis 1-Adamantyl methyl ketone was refluxed with N-bromo succinimide and petroleum ether in methanol at 333 K for two hours. The resultant 1-adamantyl bromomethyl ketone (1) precipitate was filtered and recrystallized with ethanol. After that, 1-adamantyl bromomethyl ketone (1) (0.51 g, 0.002 mol) was reacted with the corresponding carboxylic acid (0.003 mol) with the presence of potassium carbonate in DMF (8 mL) and stirred at room temperature for about 3 h. The reaction progress was monitored by thin layer chromatography (TLC). After the reaction completed, the reaction mixture was poured into ice-cooled water and kept stirring for 10 min. The solid obtained was filtered out, washed successively with distilled water and recrystallized from acetone after it dried [20]. All targeted compounds were synthesized in good yield and high purity. Suitable single-crystal specimens were obtained from various types of solvents, as described below. The chemical structures were characterized by using FTIR and NMR spectroscopies. The crystal structures for all compounds except 2m and 2q were determined by single-crystal X-ray diffraction analysis. |
78% | With bromine at 20℃; for 4h; Cooling with ice; | [358] Intermediate 10: synthesis of 1-(adamantan-1-yl)-2-bromoethanone (19.1) [359] To an ice- cooling solution of 1-(adamantan-1-yl)ethanone (1.78 g, 10.0 mmol) in THF (30 mL) was added Br2 (1.70 g, 10.7 mmol, dissolved in 5 mL THF). The resultedmixture was stirred at room temperature for 4h, and then the reaction was quenched by addition of saturated sodium thiosulfate solution (20 mL), extracted with dichloromethane (100 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to afford compound 19.1(2.0 g, yield: 78%) as a yellow solid. |
70% | With iron(III)-acetylacetonate; carbon tetrabromide at 160℃; for 4h; Sealed tube; Inert atmosphere; | General procedure General procedure: The reactions were carried out in glass ampoules (20 mL) or in a pressure microreactor of stainless steel (17 mL). The results of parallel experiments were identical. Into the microreactor (ampoule) in an argon atmosphere was charged 0.3 mmol of Fe(acac)3, 10 mmol of initial adamantane, 10 mmol of CBr4, and 150 mmol of CH2Br2. The reactor was hermetically closed (the ampoule was sealed) and heated while stirring. On the completion of the reaction the reactor (ampoule) was cooled to room temperature, opened, the solvent was distilled off, the residue was crystallized from hexane or ethanol. Yields are given in respect to converted adamantane (adamantine derivatives) (GLC procedure, internal reference decene; correction factor for adamantane 1.09, for bromoadamantane 1.53). The structure of compounds obtained was proved by comparison with known samples and published data. |
With aluminum tri-bromide; bromine | ||
With N-Bromosuccinimide; toluene-4-sulfonic acid at 80℃; for 0.166667h; | ||
With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With n-butyllithium; diisopropylamine In tetrahydrofuran | 18.a a a trans-1-(1-Adamantyl)-3-(4-pyridyl)-2-propen-1-one The method essentially followed that described in Example 17a but using 4-pyridinecarboxaldehyde (0.48 ml, 5.0 mmol) in THF (6 ml), diisopropylamine in THF (20 ml), butyllithium (3.13 g, 5.0 mmol) and 1-adamantyl methyl ketone (0.48 ml, 5.0 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:100:1, gave the title compound (881 mg, 66%), which crystallized from hexane, m.p. 128°-129° C., IR νmax 1690 cm-1; 1 H-NMR (CDCl3) δ1.72-1.89 (12H, adamantyl CH2) 2.12 (3H, s, adamantyl CH), 7.36 (1H, d, J 15.6 Hz, COCHCH), 7.56 (1H, d, J 15.6 Hz, COCHCH), 7.71 (2H, d, J 5.5 Hz, Py 3-H and 5-H), 8.71 (2H, d, J 5.5 Hz, Py 2-H and 6-H); MS m/z 267 (M+). Anal. Calcd: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.96; H, 8.13; N, 5.04 %. |
54% | With sodium hydroxide In methanol; ethanol at 40 - 60℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide In methanol Inert atmosphere; | 38 To a solution of adamantan-1-yl methyl ketone (256 mg, 2.0 mmol) in methanol (10 mL) was added pyridine-3-carbaldehyde (214 mg, 2.0 mmol), followed by NaOH (200 mg, 5.0 mmol). The mixture was stirred under nitrogen overnight, neutralized with IN HCl and diluted with water. The solid was collected, washed with water and dried oin vacuo. Purification with flash column (DCM-ethyl acetate; gradient elution) yielded the title compound as yellow solid (330 mg, 62 %). mp 107-108.5 °C; TLC single spot at Rf 0.50 (30 % EtOAc/DCM); 1H NMR (270 MHz, CDCl3) δ 1.69-1.80 (6H, m, 3 x CH2), 1.87 (6H, d, J= 2.7 Hz, 3 x CH2), 2.08 (3H, br, 3 x CH), 7.24 (IH, d, J= 15.7 Hz, CH), 7.31 (IH, dd, J= 8.0, 5.0 Hz, ArH), 7.62 (IH, d, J= 15.7 Hz, CH), 7.86 (IH, dt, J= 8.0, 1.9 Hz, ArH), 8.58 (IH, dd, J= 4.6, 1.8 Hz, ArH) and 8.77 (IH, d, J= 2.2 Hz, ArH); LC/MS (ESI) m/z 268 (M'+H); tr = 1.31 min (>99 %) in 5 % water-methanol; HRMS (ESI) calcd. for Ci8H22NO (M++..) 268.1701, found 268.1699; HPLC tr = 3.17 min (>99 %) in 10% water-acetonitrile. |
61% | With sodium hydroxide In methanol; ethanol at 60℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 1-acetyladamantane With (((1S,2S)-2-t-BuS-c-hexyloxy)PPh2)-(2,5-norbornadiene)RhOTf; 1-naphthylphenylsilane In tetrahydrofuran at -20℃; for 12h; Stage #2: With methanol In tetrahydrofuran at 20℃; for 0.5h; | |
99% | With C44H47N2O3PRuS3(2+)*2BF4(1-); potassium <i>tert</i>-butylate; hydrogen; dimethyl sulfoxide In methanol at 25℃; for 24h; Autoclave; enantioselective reaction; | |
98% | With [dichloro((S)-2,2'-bis(di-4-tolylphosphino)-1,1'-binaphthyl)(α-picolylamino)ruthenium(II)]; potassium <i>tert</i>-butylate; hydrogen In ethanol at 25℃; for 5h; |
84% | With trimethylaluminum; C42H42O2; isopropyl alcohol In pentane at -10℃; for 24h; Molecular sieve; enantioselective reaction; | |
81% | Stage #1: 1-acetyladamantane With C32H41CrN3O2Si; C7H14O4Si In toluene at -40 - 20℃; for 2h; Stage #2: With potassium carbonate In methanol for 1h; enantioselective reaction; | |
78% | Stage #1: 1-acetyladamantane With diphenylsilane In tetrahydrofuran at -40℃; for 10h; Stage #2: With methanol; potassium carbonate In tetrahydrofuran at 20℃; for 4h; | |
Multi-step reaction with 2 steps 1: AgBF4 / (S)-[RhBr(nbd)(oxazolinyl-carbene)] / CH2Cl2 / 10 h / -60 °C 2: K2CO3 / methanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With water In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | |
With water; oxygen In N,N-dimethyl-formamide at 100℃; | ||
94 %Chromat. | With tert.-butylhydroperoxide; silver hexafluoroantimonate; dodecane; [Pd(Quinox)Cl2] In dichloromethane for 1.25h; |
94 %Chromat. | With tert.-butylhydroperoxide In dichloromethane for 0.25h; | An additional adamantane alkene substrate was tested. To a small 1.5 mL vial was weighed AgSbF6 (3.9 mg, 0.01 mmol) and Pd(Quinox)Cl2 (1.1 mg, 0.003 mmol). The solvent CH2Cl2 (64 μL) and a stirbar were added to the vial and the mixture was stirred for 10 min. TBHP (86 μL) was added to the flask and stirred for an additional 10 min. A solution of 1-ethenyladamantane (9.7 mg, 0.05 mmol) and dodecane (-1 mg as an internal standard for GC analysis) was made in CH2Cl2 (380 μL). An amount of 350 μL of the standard solution was used to add substrate to the reaction mixture while the remaining solution was used as an initial timepoint. A timepoint taken after 15 min indicated complete consumption of the starting material and a GC yield of 94% (measured relative to the internal standard and corrected for response factor). After 1 h the reaction mixture was worked up in the standard way and the product was isolated to confirm that the product was indeed the methyl ketone. Each of 1H NMR, 13C NMR, and GC-MS analysis all indicate exclusive formation of the methyl ketone in accordance with the published NMR data, with no aldehyde product observed. Further, dodecane was observed in the NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With boron trifluoride diethyl etherate In chloroform at 0 - 20℃; for 5.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium ethanolate In ethanol at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-acetyladamantane; oxalic acid diethyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran; water; ethyl acetate Stage #3: With hydroxylamine hydrochloride In ethanol at 20℃; | 8 To a solution of potassium t-butoxide (6.92g) in THF(90mL) were added oxalic acid diethyl ester (9.14mL) and 1-adamantylmethylketone (10g) in THF(30mL). After termination of this reaction, cooled 1N HCl soln-EtOAc was added to the mixture and partitioned between water and EtOAc and extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo. To a solution of the residue in EtOH(150mL) was added hydroxylamine hydrochloride(8.58g) under N2 atmosphere and the resulting solution was stirred at room temp.. The reaction mixture was refluxed, then cooled to room temp. and the volatile was removed under reduced pressure. Sat. NaHCO3 soln. and EtOAc were added to the residue and the aqueous layer was extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 23 (13.4mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; Reflux; | |
55% | In tetrahydrofuran Heating; | |
Stage #1: 1-acetyladamantane With cerium(III) trichloride In tetrahydrofuran at 20℃; Stage #2: ethenylmagnesium bromide In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide at 20℃; Stage #2: 1-acetyladamantane In dimethyl sulfoxide at 130℃; for 12h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | As an adamantane compound as a starting material, acetyladamantane 1 was used, and the acetyl group of acetyladamantane was changed to alkyneadamantane 2 by the procedure shown in (Chemical Formula 12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With methyllithium In diethyl ether at -5 - 20℃; for 1h; Inert atmosphere; | 1-(Adamantan-1-yl)ethanone 25.3 1-Adamantanecarboxylic acid (7.20 g, 40.0 mmol) was dissolved in 40 mL of diethyl ether under argon. The mixture was maintained at approximately -5 °C with a NaCl-ice bath while methyllithium (1.6M in diethyl ether, 52.5 mL, 84.0 mmol) was added dropwise with vigorous stirring. After complete addition, the cooling bath was removed and the slurry was allowed to stir for one hour at room temperature. The reaction was quenched and diluted by the addition of water and extracted with diethyl ether. The combined organic extracts were dried with MgSO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (10% ethyl acetate / 90%hexanes) to yield 5.70 g (80%) of ketone 25 as a white solid. |
Multi-step reaction with 2 steps 1: 89 percent / SOCl2 / toluene / 8 h / 70 °C 2: 89 percent / LiCl; CuCl; AlCl3 / tetrahydrofuran / 0.17 h / 10 °C | ||
Multi-step reaction with 2 steps 1: SOCl2 2: CuCl / diethyl ether |
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.5 h / 25 °C 1.2: 2 h / 25 °C 2.1: tetrahydrofuran / 10 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: thionyl chloride / 4 h / Reflux 2.1: sodium / Petroleum ether / 20 °C 2.2: 20 °C 2.3: 6 h / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 1 h / 80 °C 2: benzene / 2 h | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C 2: trimethylantimony / acetonitrile | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C / Green chemistry 2: cesium formate / benzene / Inert atmosphere; Green chemistry | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C 2: cesium formate / benzene / 5 h / 100 °C | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C / Green chemistry 2: cesium formate / benzene / 5 h / 100 °C / Green chemistry | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C 2: cesium formate / benzene / 5 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-Bromosuccinimide In n-heptane at 80℃; for 3h; | 1 Comparative example 1 25.0 g (0.1 mol) of 2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one, 19.6 g (0.11 mol) of N-bromosuccinimide and 240 g of heptane were placed in a 500 ml egg-plant type flask equipped with a reflux condenser, and while the mixture was in a slurry state, the temperature was increased to the reaction temperature, 80°C under stirring. When the mixture was stirred at 80°C for about 1 hour, the reaction solution became brown. As a result of analyzing the reaction solution immediately before it became brown, it was found that the reaction solution contained 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one corresponding to 3% of the raw materials and adamantyl methyl ketone corresponding to 4% of the raw materials. When the reaction solution was further stirred for 2 hours, it became transparent. After the reaction solution was cooled in an ice bath, it was filtered to remove succinimide. As a result of analyzing the reaction solution, it was found that the reaction solution contained only 3.6 g of 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one (yield: 11 %) and that 82% of the raw materials was decomposed into adamantyl methyl ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In di-isopropyl ether at -10 - 20℃; for 3h; | 5 Comparative example 5 16.5 g (0.05 mol) of 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one was placed in a 500 ml egg-plant type flask, and 200 g of isopropyl ether was added thereto and dissolved therein. While cooling with a refrigerant of -10°C, 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 g of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.7 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 14%) and that 80% of the raw materials was decomposed into adamantyl methyl ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In di-isopropyl ether at 0 - 20℃; for 3h; | 8 Comparative example 8 A mixture obtained by dissolving 16.4 g of 5-bromomethyl-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one in 80 ml of isopropyl ether was placed in a flask equipped with an agitator, a thermometer, a condenser and a dropping funnel. While cooling in an ice bath, 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 ml of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.8 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 15%) and that 81 % of the raw materials was decomposed into adamantyl methyl ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In ethanol at 20℃; Alkaline conditions; | I; 1 1-Adamantyl methyl ketone 41 reacted readily, at ambient temperature, with a variety of substituted benzaldehydes 42 in alkaline ethanol to afford the corresponding chalcone like compounds 43(a-l) in good yields. Compounds synthesized by this method are shown in Table 1. These compounds were synthesized, purified and fully characterized by NMR, GC-MS, and Elemental Analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydroxide In ethanol | III; 4 A series of chalcone-like compounds 47 with modification in the A and C ring was synthesized. Het is used to represent the heterocyclic group. The reaction was carried out via aldol condensation of 1-adamantyl methyl ketone 41 and the heterocyclic aldehyde 46 to afford the desire product 47 as shown in (eq 4). The percent yield and melting point for these compounds 47 are presented in Table 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In ethanol at 20℃; Alkaline conditions; | II; 3 A series of chalcone-like compounds 45 with modification in the A and B regions was prepared by based-catalyzed Aldol condensation of 1-adamantyl methyl ketone 41, with substituted cinnamaldehydes 44 in alkaline ethanol at ambient temperature to give the corresponding chalcone-like compounds 45 (eq. 3). The percent yield and melting points for these compounds 45 are presented in Table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane | 17.a a a trans-1-(1-Adamantyl)-3-(3-pyridyl)-2-propen-1-one To a stirred solution of diisopropylamine (1.54 ml, 11 mmol) in THF (40 ml) at 0° C. was added butyllithium (1.6M; 6.25 ml, 10.0 mmol) in hexane, followed after 5 minutes by 1-adamantyl methyl ketone (1.96 g, 11.0 mmol). After stirring for 30 minutes at 0° C. the resulting solution of the lithium enolate of 1-adamantyl methyl ketone was then added to a stirred solution of 3-pyridinecarboxaldehyde (0.94 ml, 10.0 mmol) in THF (12 ml) at room temperature. After 3 hours the mixture was partitioned between diethyl ether and water, and the ether layers were concentrated. Chromatography, on elution with petrol-ether-triethylamine, 100:50:1 afforded the product as a solid (1.87 g, 70%), which crystallized from hexane, m.p. 98°-101° C.; IR νmax 1679 cm-1; 1 H-NMR (CDCl3) δ1.65-1.84 (12H, m, adamantyl CH2), 2.10 (3H, s, adamantyl CH), 7.27 (1H, d, J 15.8 Hz, COCHCH), 7.38 (1H, m, Py 5-H), 7.68 (1H, d, J 15.8 Hz, COCHCH), 7.93 (1H, m, Py 4-H), 8.55 (1H, m, Py 6-H), 8.81 (1H, m, Py 2-H); MS m/z 267 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane, p-toluenesulfonyl chloride; hexane | 15 (+)-(S)-1-(1-Adamantyl)-3-(4-pyridyl)butan-1-one EXAMPLE 15 (+)-(S)-1-(1-Adamantyl)-3-(4-pyridyl)butan-1-one The method followed that described in Example 9 but using (-)-(S)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (765 mg, 18%), which crystallized from hexane. m.p. 46°-48° C.; [α]D +6.8° (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane, p-toluenesulfonyl chloride; hexane; | EXAMPLE 16 (-)-(R)-1-(1-Adamantyl)-3-(4-pyridyl)butan-1-one The method followed that described in Example 9 but using (+)-(R)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (722 mg, 17%), which crystallized from hexane, m.p. 48-49 C.; [alpha]D -6.6 (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium permanganate; potassium hydroxide In water at 90℃; | |
47% | With potassium permanganate; N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide at 60 - 80℃; for 14.5h; | |
Stage #1: 1-acetyladamantane With sodium hydroxide; potassium permanganate In water at 27 - 55℃; for 24.5 - 25.5h; Stage #2: In water Acidic aqueous solution; | 1; 2 Example 1. 30 g of 1-acetyladamantane was added to solution of 6.8 g of NaOH in 500 mL of water. The temperature of the suspension was increased to 40-50° C. and 80 g of potassium permanganate was added during a period of 1.5 h. The obtained mixture was stirred at 50-55° C. for 6 h and thereafter at room temperature 27° C. for 17 h followed by separation of the formed manganese dioxide precipitate by means of filtration. After the filtrate work-up that included acidification of filtrate, extractions with organic solvent and concentration of the combined organic phases, 28 g of partly crystallized material was obtained. Recrystallization of the material gave 13.6 g of the target 3-hydroxyadamantaneglyoxylic acid (1) as white crystalline solid with the purity 92.1% according to GC analysis of the corresponding methyl ester. EXAMPLE 2 1.7 mL of NaOH 30% solution in water was diluted with 500 mL of water and 60 g of 1-acetyladamantane was added to that solution. Temperature of the suspension was increased to 35-40° C. and 144 g of potassium permanganate was added to the suspension during 0.5 h. The mixture was stirred at 35-40° C. for 25 h followed by manganese dioxide precipitate filtration. The filtrate work-up procedure consisting of acidification, extractions with organic solvent and concentration of the combined organic phases which resulted in 25.2 g of the target 3-hydroxyadamantaneglyoxylic acid (1) with purity 85.7% according to GC analysis of the corresponding methyl ester. |
Stage #1: 1-acetyladamantane With pyridine; potassium hydroxide; potassium permanganate In water at 20 - 60℃; for 66h; Stage #2: In water Acidic aqueous solution; | 5 3.0 g 1-acetyladamantane was suspended in 40 mL of water. 4.0 mL of pyridine and 1.1 g of KOH was added and temperature of obtained suspension was increased to 55° C. Then 8.6 g of potassium permanganate was added gradually during 3 h at 55-60° C. and stirring was continued for an additional 3 h. The mixture was then allowed to stay 60 h at room temperature. Then, manganese dioxide precipitate was filtered out and the filtrate was acidified and extracted. Concentration of the extract gave 3.7 g of partly crystallized material containing mainly 3-hydroxyadamantaneglyoxylic acid (1). | |
Stage #1: 1-acetyladamantane With sodium hydroxide; potassium permanganate In water at 20 - 52℃; for 8h; Stage #2: In water Acidic aqueous solution; | 3 3.0 mL of NaOH 30% solutions in water was diluted with 120 mL of water. The solution was heated to 50° C. and 0.36 g of tetrabutylammonium bromide was added to the solution. Now 10 g of 1-acetyladamantane was added while stirring, followed by addition of 24.8 g of potassium permanganate during 4 h at 50-52° C. Stirring was continued for additional 4 h. The mixture was allowed to stay at room temperature for overnight and then manganese dioxide precipitate was filtered out. The filtrate work-up included acidification of filtrate, extraction and partial concentration of the combined organic phase. To the concentrated solution 10 mL of organic solvent was added and the mixture was kept at room temperature overnight. The formed crystals were filtered out, washed with solvent and dried to yield 4.7 g of the target 3-hydroxyadamantaneglyoxylic acid (1) with purity 96.4% according to GC analysis of the corresponding methyl ester. | |
Stage #1: 1-acetyladamantane With sodium hydroxide; potassium permanganate In water; <i>tert</i>-butyl alcohol at 50 - 65℃; for 35h; Stage #2: In water Acidic aqueous solution; | 4 10 g of 1-acetyladamantane was dissolved in a mixture of 55 mL of t-BuOH and 35 mL of water at 50° C. Then 1.0 mL of NaOH 30% water solution was added and temperature of the obtained solution was increased to 55-60° C. Then 35.5 g of potassium permanganate was added gradually during 5 h period at the temperature 55-65° C. Stirring was continued for 30 h at the same temperature 55-65° C. The mixture was then allowed to cool down to room temperature and manganese dioxide precipitate was filtered out. Now t-BuOH was evaporated from filtrate, the filtrate was acidified and extracted. Concentration of the extract gave 9.7 g of half solid residue containing 34.9% of 3-hydroxyadamantaneglyoxylic acid (1) and 58.1% of adamantaneglyoxylic acid according to GC analysis of the corresponding methyl esters. These compounds were separated in due course. | |
With sodium hydroxide; potassium permanganate In water at 27 - 55℃; for 24.5 - 25.5h; | 1; 2 30 g of 1-acetyladamantane was added to solution of 6.8 g of NaOH in 500 mL of water. The temperature of the suspension was increased to 40-50 °C and 80 g of potassium permanganate was added during a period of 1.5 h. The obtained mixture was stirred at 50-55 °C for 6 h and thereafter at room temperature 27 0C for 17 h followed by separation of the formed manganese dioxide precipitate by means of filtration. After the filtrate work-up that included acidification of filtrate, extractions with organic solvent and concentration of the combined organic phases, 28 g of partly crystallized material was obtained. Recrystallization of the material gave 13.6 g of the target 3-hydroxyadamantaneglyoxylic acid (1) as white crystalline solid with the purity 92.1% according to GC analysis of the corresponding methyl ester.; Example 2; 1.7 mL of NaOH 30% solution in water was diluted with 500 mL of water and 60 g of 1-acetyladamantane was added to that solution. Temperature of the suspension was increased to 35-40 °C and 144 g of potassium permanganate was added to the suspension during 0.5 h. The mixture was stirred at 35-40 °C for 25 h followed by manganese dioxide precipitate filtration. The filtrate work-up procedure consisting of acidification, extractions with organic solvent and concentration of the combined organic phases which resulted in 25.2 g of the target 3-hydroxyadamantaneglyoxylic acid (1) with purity 85.7% according to GC analysis of the corresponding methyl ester. | |
With pyridine; potassium hydroxide; potassium permanganate In water at 20 - 60℃; for 66h; | 5 3.0 g 1-acetyladamantane was suspended in 40 mL of water. 4.0 mL of pyridine and 1.1 g of KOH was added and temperature of obtained suspension was increased to 55 0C. Then 8.6 g of potassium permanganate was added gradually during 3 h at 55-60 0C and stirring was continued for an additional 3 h. The mixture was then allowed to stay 60 h at room temperature. Then, manganese dioxide precipitate was filtered out and the filtrate was acidified and extracted. Concentration of the extract gave 3.7 g of partly crystallized material containing mainly 3-hydroxyadamantaneglyoxylic acid (1). | |
With sodium hydroxide; potassium permanganate; tetrabutylammomium bromide In water at 50 - 52℃; for 8h; | 3 3.0 ml_ of NaOH 30% solutions in water was diluted with 120 mL of water. The solution was heated to 50 0C and 0.36 g of tetrabutylammonium bromide was added to the solution. Now 10 g of 1-acetyiadamantane was added while stirring, followed by addition of 24.8 g of potassium permanganate during 4 h at 50-52 °C. Stirring was continued for additional 4 h. The mixture was allowed to stay at room temperature for overnight and then manganese dioxide precipitate was filtered out. The filtrate work-up included acidification of filtrate, extraction and partial concentration of the combined organic phase. To the concentrated solution 10 mL of organic solvent was added and the mixture was kept at room temperature overnight. The formed crystals were filtered out, washed with solvent and dried to yield 4.7 g of the target 3-hydroxyadamantaneglyoxylic acid (1) with purity 96.4% according to GC analysis of the corresponding methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium cyanoborohydride In benzene | 22 1-[1'-(Adamant-1"-yl)ethyl]-2-methylhydrazine hydrochloride EXAMPLE 22 1-[1'-(Adamant-1"-yl)ethyl]-2-methylhydrazine hydrochloride A solution of 1.8 g (10 mmol) of acetyladamantane and 600 mg (13 mmol) of methylhydrazine was refluxed in 150 ml of benzene with continuous removal of water via a Dean-Stark Apparatus. After 21/2 hours the reaction was cooled the volatiles removed in vacuo leaving 1.7 g oil which was reduced with 800 mg of sodium cyanoborohydride according to the procedure of Example 1. Treatment of the resulting ether solution with hydrogen chloride gave 900 mg of the title compound (37% yield). mp 239°-241° (d), (acetone) nmr (CDCl3 /TFA) δ1.3 (d, 3H) Anal calcd for C13 H25 N2 Cl: C, 63.75; H, 10.30; N, 11.44; Cl, 14.49; Found: C, 63.71; H, 10.60; N, 11.29; Cl, 14.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With acetic acid | 7.1 (1) (1) Hydroxylation A mixture of 1-acetyladamantane (10 mmols), NHPI (2 mmols), acetylacetonatocobalt (Co(AA)2) (0.1 mmol) and acetic acid (25 ml) was stirred in an oxygen atmosphere at 75°C for 6 hours, whereby 1-hydroxy-3-acetyladamantane was obtained (yield 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 80% 2: 0.8 g | With potassium permanganate; potassium hydroxide In water at 50 - 80℃; for 12h; | 2-(3-Hydroxy-1-adamantyl)-2-oxoethanoic acid (4) A solution of ketone 3 (15.7 g, 88 mmol) in water (180 mL) was treated with KOH(4.9 g, 88 mmol). The reaction mixture was heated to 50 °C, then KMnO4 (41.7 g, 264 mmol) was added and the internal temperaturewas kept below 80 °C. After the completion of the addition, the reaction mixture was vigorously stirred for 12 h at 80 °C. At this point HPLC assay indicated the disappearance of the starting material. The reaction mixture was filtered, the aqueous layer was acidified with 12N HCl topH = 1 and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to obtain a residue (17.7 g), The residue was recrystallised from water (17 mL) to give the desired 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid 4 (15.8 g,704 mmol) as colourless needles, yield 80%. M.p. 164-165 °C [lit.5162-164 °C]. IR (cm-1) 3399, 2933, 2861, 1712, 1689. 1H NMR (500 MHz,DMSO) δ 14.39 (s, 0H), 4.75 (s, 1H), 2.18 (s, 2H), 1.67 (s, 3H), 1.54 (d,J = 25.9 Hz, 3H). ESI-MS m/z: 225.1 (M + 1)+. 2-(1-Adamantyl)-2-oxoethanoic acid (4a): The mother liquor of 4 from the crystallisation was extracted with EtOAc (3 × 10 mL), dried with MgSO4, and concentrated to give a residue of 4a (0.8 g,3.84 mmol) as alight yellow solid, M.p. 100.5-103 °C [lit.12 102-104 °C]. IR (cm-1) 2906,2887, 1720. 1H NMR (500 MHz, CDCl3) δ 7.47 (brs, 1H), 2.09 (s, 3H),2.02, 2.01 (2 s, 6H), 1.78-1.71 (m, 6H). ESI-MS m/z: 209.1 (M + 1)+ |
With sodium hydroxide; potassium permanganate In water; <i>tert</i>-butyl alcohol at 50 - 65℃; for 35h; | 4 10 g of 1-acetyladamantane was dissolved in a mixture of 55 mL of f-BuOH and 35 mL of water at 50 0C. Then 1.0 mL of NaOH 30% water solution was added and temperature of the obtained solution was increased to 55-60 °C. Then 35.5 g of potassium permanganate was added gradually during 5 h period at the temperature 55-65°C. Stirring was continued for 30 h at the same temperature 55- 65 0C. The mixture was then allowed to cool down to room temperature and manganese dioxide precipitate was filtered out. Now £-BuOH was evaporated from filtrate, the filtrate was acidified and extracted. Concentration of the extract gave 9.7 g of half solid residue containing 34.9% of 3-hydroxyadamantaneglyoxylic acid (1) and 58.1 % of adamantaneglyoxylic acid according to GC analysis of the corresponding methyl esters. These compounds were separated in due course. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium hydroxide In ethanol; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: methyl adamantane-1-carboxylate With sodium hydride In dimethyl sulfoxide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: 1-acetyladamantane In dimethyl sulfoxide at 60℃; for 4h; | 10 Synthesis intermediate (463-c): Repeat vacuuming and filling with nitrogen three times in a dry 250mL bottle, place sodium hydride (20g, 5eq), add DMSO (150mL), then add 1-adamantane carboxylate (27.32g, 1eq), stir at room temperature for 40 minutes ,Then slowly add 1-adamantan ketone (22.3g, 0.7eq), and heat to 60°C for 4 hours to complete the reaction.Then slowly add 1000 mL of ice water to quench the remaining sodium hydrogen, then add 1000 mL of petroleum ether for extraction, and concentrate to obtain a reddish brown liquid. After distillation, a white intermediate (463-c) is obtained with a yield of 69%. |
67% | With sodium hydride In tetrahydrofuran; mineral oil for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium permanganate; N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water; <i>tert</i>-butyl alcohol at 40 - 45℃; for 3h; | Preparation of 2-(1-adamantyl)-2-oxoacetic acid (3): NaOH (2.0 g, 0.05 mol), t-butanol (30 mL) and TEBAC (0.5g) were added at room temperature to a suspension of 2 (8.9g, 0.05 mol) in 100 mL H2O, and the mixture was heated to 40-45°C. Then potassium permanganate (15.8 g, 0.1 mol)was added within one hour, and the reaction was stirred foran additional two hours at 40°C. The mixture was quenchedwith 10% Na2SO3 (10 mL) and filtered off while hot, and thefilter cake and reaction flask were rinsed with 20 mL hotwater. The filtrate was adjusted to pH=1 by concentratedhydrochloric acid and a large amount of white solid formed immediately. The white solid was filtered off and dried to afford 3. (Yield 9.90 g, 95%); mp 98-101°C (102-104 °C[14]); IR (KBr, cm-1): 2906, 2887, 2848, 2675, 2557, 1717;ESI-MS, (m/z): 207[M-H]-; 1H NMR (300 MHz, MeOH-d4),: 2.05 (s, 3H), 1.92-1.74 (m, 12H). |
93% | With pyridine; potassium permanganate; potassium hydroxide In water at 60℃; for 3h; | 1.0 Example 1Step 0, Preparation of educt; Pyridine (3 Eq., 40.8 mL, 0.51 mol) and KOH (1.2 Eq., 13.2 g, 0.20 mol) were added at room temperature to a suspension of ADMK (1 Eq., 30 g, 0.17 mol) in 500 mL H20 and the mixture was warmed to 60 °C. KMn04 (2 Eq., 53.7 g, 0.34 mol) was added in three portions under ice cooling, so that the temperature of the reaction did not exceed 60 °C, and the mixture was stirred for 3 h at this temperature. The mixture was filtered off while hot, and the remaining solid was washed with 300 mL hot H20. After cooling, the aqueous phase was extracted with EtOAc (2 x 150 mL). The aqueous phase was then acidified (pH < 1) and extracted again with EtOAc (3 x 250 mL). The combined organic phases were washed with brine, dried over Na2S04 and the solvent removed in vacuo. Yield: 33 g (93 %). NMR: (δ, 1H, 300 MHz, DMSO-d6): 1.99 - 1.97 (m, 3H, Ad), 1.81 - 1.80 (m, 6H, Ad), 1.67 - 1.66 (m, 6H, Ad). |
88% | With pyridine; potassium permanganate; potassium hydroxide In water at 60℃; for 3h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; for 3.16667h; Inert atmosphere; Stage #2: 1-acetyladamantane In tetrahydrofuran at 0 - 20℃; for 72h; Inert atmosphere; | |
69% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: 1-acetyladamantane In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | |
53% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-acetyladamantane In tetrahydrofuran; hexane at 20℃; for 18h; |
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: 1-acetyladamantane at 0 - 20℃; for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In tetrahydrofuran at 70℃; for 18h; Inert atmosphere; regioselective reaction; | |
70% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In tetrahydrofuran at 70℃; for 18h; Inert atmosphere; Sealed tube; | |
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In tetrahydrofuran at 70℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With sulfuric acid; acetic acid In water Reflux; | 1.5; 2.5 Step 5: Add glacial acetic acid (50 mL), water (30 mL) and concentrated sulfuric acid (3 mL) to the residue and heat to reflux until no more carbon dioxide gas emerges, cool, and pour into ice water (300 g). Yellow compound 4, filtered and dried to give 12.35 g, mp 53.5-55 ° C, from1-adamantanic acid to1-adamantane methyl ketoneThe total synthesis yield was 75.2%. |
14.7 g | With sulfuric acid; acetic acid In water at 100℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-acetyladamantane; Cyclopropylamine With acetic acid In methanol for 5h; Molecular sieve; Reflux; Stage #2: With sodium cyanoborohydride In methanol at 0℃; for 2h; Reflux; | 1.1 preparation of N-[1 -(adamantan-1 -yl)ethyl]cyclopropanamine hydrochloride To a solution of 640 mg (1 1 .2 mmol) of cyclopropylamine in 10 mL of methanol is added 1 g of 3 A molecular sieves followed by a slow addition of 673 mg (1 1 .2 mmol) of acetic acid and 1 g (5.6 mmol) of 1 -(adamantan-1 -yl)ethanone. The reaction mixture is stirred for 5 hours at reflux. The reaction mixture is then cooled to 0 °C and 528 mg (8.4 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hours at reflux then left overnight at ambient temperature. The reaction mixture is filtered over a cake of diatomaceous earth and the cake is washed twice by 50 mL of methanol. The combined methanolic extracts are concentrated under vacuum. The residu is dissolved in 50 mL of ethyl acetate and the organic solution is washed twice by 100 mL of a 1 N solution of sodium hydroxide followed by water and dried over magnesium sulfate. Vacuum concentration gives a yellow oil which is dissolved in 5 mL of diethyl ether. Addition of 2 mL of a 4 N solution of HCI in dioxan and filtration, yields 702 mg (57% yield) of the hydrochloride salt of N-[1 -(adamantan-1 -yl)ethyl]cyclopropanamine as a white solid (M+H = 256). logP = 5.82 (for the free base). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In tetrahydrofuran at 10 - 20℃; Inert atmosphere; | Adamantan-1-yl-ethan-1-one (3) A dry three-necked flask equippedwith a magnetic stirrer bar and a N2 balloon was charged with CH3MgCl(34.8 mL, 100 mol, 3 M in THF), and then a solution of the aboveWeinreb amide 2 (21.2 g, 95 mmol) in THF (100 mL) was added at 10 °C.The resulting mixture was allowed to warm to room temperature and stirred for 10 h. Then the reaction mixture was poured into ice HCl (2M,50 mL). The organic layer was separated, and the aqueous phase was extracted with dichloromethane (3 × 45 mL). The combined organiclayers were dried over MgSO4, filtered and the solvent was removed in vacuo to give the white solid 15.7 g (88 mol, 93%). M.p. 53.5-55 °C[lit.12. 52-53 °C]. IR (cm-1) 2897, 2854, 1683, 1430, 1019, 605. 1H NMR(500 MHz, CDCl3) δ 2.00 (s, 3H), 1.95 (s, 3H), 1.71 (s, 6H), 1.62 (d,J = 12.1 Hz, 6H). ESI-MS m/z: 179.1 (M + 1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonium nitrate; sulfuric acid; iodine In water; acetonitrile at 60℃; regioselective reaction; | General procedure for the aerobic oxidative iodination of methyl ketones and aromatic compounds: General procedure: A 10 mL glass flask equipped with a magnetic stir bar wascharged with a methyl ketone (1 mmol) and dissolved in MeCN (2 mL). To thethermostated solution NH4NO3 (10-25 mol %), I2 (50 mol %) and H2SO4(aqueous 96% solution, 10-20 mol %) were added and the flask was furtherequipped with a balloon filled with air (1 L) and magnetically stirred at 60 C.The consumption of starting material was monitored by TLC. After completionof the reaction, the mixture was cooled to room temperature, diluted withEtOAc (10 mL), and insoluble material identified as ammonium sulfate wasfiltered off. The filtrate neutralized with NaHCO3 (aqueous 10% solution, 2 mL)and Na2S2O3 (aqueous 10% solution, 2 mL) and phase was separated. The waterphase was washed with EtOAc additionally two times (2 5 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent distilled underreduced pressure. The crude product obtained was analyzed by 1H NMR. Finallythe crude product was purified using column chromatography (SiO2, n-hexane/CH2Cl2 elution) and preparative thin layer chromatography to afford purematerial, which was compared to authentic samples. Detailed data, concerningcatalyst loading, reaction times, yields of pure products and their spectroscopicand other identification data are given in SI in the chapter Characterization dataof isolated final products. Characterization, for example, 1-(9H-fluoren-2-yl)-2-iodoethanone (2i): 1-(9H-Fluoren-2-yl)ethanone (1 mmol, 208.3 mg), NH4NO3(0.15 mmol, 12 mg), I2 (0.50 mmol, 126.7 mg), H2SO4 (aqueous 96% solution,0.10 mmol, 5.56 lL), 2 mL MeCN, balloon filled with 1 L of air, 60 C, 20 h were used; crystallization from acetone; yield: 187.2 mg (55%) yellow solid, mp 163-164 C. 1H NMR (303 MHz, CDCl3+two drops of DMSO, 25 C, TMS): d (ppm) 3.92 (s,2H), 4.41 (s, 2H), 7.32-7.44 (m, 2H), 7.54-7.59 (m, 1H), 7.77-7.84 (m, 2H), 7.96-8.02(m, 1H), 8.13 (s, 1H); 13C NMR (76.2MHz, CDCl3+two drops of DMSO, 25 C): d(ppm) 2.3, 36.6, 119.6, 120.7, 125.0, 125.3, 126.9, 128.1, 128.1, 131.5, 139.9, 143.2,144.3, 146.8, 192.4;MS (ESI):m/z 335 ((M+H)+, 100%);HR-MS (ESI):m/z = 334.9925,calcd for C15H12IO: 334.9933; Anal. calcd for C15H11IO: C, 53.92; H, 3.32; found: C,54.39; H, 3.05. 3-(2-Iodoacetyl)-2H-chromen-2-one (2o): 3-Acetyl-2H-chromen-2-one (1 mmol, 188.2mg), NH4NO3 (0.20 mmol, 16 mg), I2 (0.50 mmol, 126.7mg),H2SO4 (aqueous 96% solution, 0.1 mmol, 5.56 lL), 2mLMeCN, balloon filledwith 1 Lof air, 60 C, 23 h were used; column chromatography (SiO2, CH2Cl2); yield:182.2mg (58%), yellow solid; mp 135-138 C. 1H NMR (303.0 MHz, CDCl3, 25C,TMS): d (ppm) 4.68 (s, 2H), 7.34-7.46 (m, 2H), 7.64-7.76 (m, 2H), 8.66 (s, 1H); 13CNMR (76.2MHz, CDCl3, 25 C): d (ppm) 6.8, 116.7, 118.1, 121.4, 125.1, 130.2, 134.9,149.5, 155.3, 158.6, 190.1; MS (ESI): m/z 314.9 ((M+H)+, 100%); HR-MS (ESI): m/z = 314.9523, calcd for C11H8IO3: 314.9518. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With acetic acid In ethanol for 4h; Reflux; | General procedure for conventional synthesis of the hydrazones (compounds 4, 27, 29,35{38) derived from (2S)-4-(methylsulfanyl)-2-[[(4-methylphenyl)-sulfonyl]amino]butanoicacid hydrazide (2) General procedure: Since the synthesis of compounds 4, 27, 29, and 35-38 was not achieved by microwave-assisted method, theconventional synthesis method consisting of reuxing equimolar amounts of hydrazide and selected aldehyde or ketone derivative in ethanol in the presence of a few drops of glacial acetic acid was performed. Thin layer chromatography (silica gel F254 (Merck), mobile phase; chloroform:methanol:glacial acetic acid 93:5:2 v/v/v,25C) was used to monitor the progress of the reaction and the reaction time for isolating sufficiently pure product was 4 h. The crude products were filtered and recrystallized from the appropriate solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium hydroxide semihydrate In dimethyl sulfoxide at 70℃; for 1h; High pressure; Autoclave; stereoselective reaction; | 2 Typical procedure for synthesis of bicyclooctanes 2c-i General procedure: A suspension of ketone 1c-i (20mmol) and powdered KOH·0.5 H2O (1.30g, 20mmol) in DMSO (100mL) was placed into a 0.25L Paar reactor. The latter was fed with acetylene under pressure (initial pressure at ambient temperature was ∼12atm) and then decompressed to atmospheric pressure to remove air. The reactor was fed with acetylene again and heated (70°C) for 1h. The reaction mixture, after cooling to room temperature, was diluted with cool (7-10°C) water (100mL) and extracted with Et2O (20mL×5). The combined organic extract was washed with H2O (20mL×3) and dried (K2CO3). The Et2O was evaporated under reduced pressure. The crude product was purified by column chromatography (SiO2, benzene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sulfuric acid; water at 140 - 145℃; for 5h; | 1-Acetyladamantane (6) To a water-sulfuric acid mixture (1 : 1, 10 mL), 3-(1-adamantyl)-3-oxopropanenitrile (3a) (1.25 g, 7 mL) was added. The reaction mixture was heated at 140-145 °C for 5 h, and extracted with benzene. Steam distillation, filtration of the product from water layer, and drying afforded compound 6 in the yield of 0.6 g (55%), m.p. 53-54 °C (cf. Ref. 18: m.p. 54 °C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | With sulfuric acid; acetic acid In water at 60℃; for 19h; | 11 Synthesis Example -11 in air, 1-adamantyl methyl ketone (5.00g, 28.0mol), and 4-bromo benzaldehyde (5.19g, 28.0mol) was dissolved in acetic acid (50 mL), was added dropwise concentrated sulfuric acid (7.5mL, 140mol), and the mixture was stirred for 19 hours at 60 .After stirring, water was added to 100 mL, and filtered off the precipitated solid.The resulting solid is washed with water (200 mL), the desired product 1- (1-adamantyl) -3- (4-bromophenyl) -propenone as a yellow solid (yield 8.54 g, yield: 88.2 %) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium ethanolate; In tetrahydrofuran; ethanol; at 20℃; | [402] To a solution of compound 1.1 (500 mg, 1.2 mmol) and 1-(adamantan-1-yl) ethanone (235 mg, 1.3 mmol) in a mixed solvent of ethanol (5 mL) and THF (5 mL) was added sodium ethoxide (122 mg, 1.8 mmol). The resulted mixture was stirred at room temperature for overnight, then the mixture was added water (30 mL), and extracted with ethyl acetate (60 mLx2). Then the combined organic phase was washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate= 2:1) to afford compound 1.2 (400 mg, yield: 62%) as a white solid.[403] m/z: [M+H] 575 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 33% 2: 22% | Stage #1: 1-acetyladamantane With N-hydroxyphthalimide; oxygen; acetic acid; cobalt acetylacetonate at 75℃; for 6h; Stage #2: 2-fluoro-6-[1-(triphenylmethyl)-1H-imidazol-4-yl]benzaldehyde With sodium ethanolate In tetrahydrofuran; ethanol at 20℃; for 0.5h; Stage #3: With acetic acid In methanol at 60℃; for 1.5h; | 15 Example 15. Preparations of (1s, 3r, 5R, 7S) -3- (2- (6-fluoro-5H-imidazo [5, 1-a] isoindol-5-yl) -1-hydroxyethyl) adamantan-1-ol (Compound 15d) and 1- ( (3r, 5r, 7r) -adamantan-1-yl) -2- (6-fluoro-5H-imidazo [5, 1-a] isoindol-5-yl) ethanol (Compound 15e) A mixture of 10b (200 mg, 1.124 mmol) , 2-hydroxyisoindoline-1, 3-dione (73 mg, 0.449 mmol) , Bis (acetylacetonato) cobalt (58 mg, 0.225 mmol) in HOAc (5 mL) was stirred under O2atmosphere at 75 for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) , and the mixture was filtered. The filtrate was concentrated in vacuo to afford a crude mixture of 10b and 14b (140 mg) as slight yellow oil, which was used to the next step without further purification.[0254]To a stirred mixture of compound 15a (97 mg, 0.224 mmol) and compounds 14b and 10b (43 mg, 0.224 mmol) in anhydrous THF (10 mL) was added dropwise a solution of EtONa (21in EtOH, 94 mg, 0.291 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to dryness under reduced pressure, the residue was diluted with NH4Cl solution and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was dissolved in MeOH (15 mL) . To this solution was added HOAc (3 mL) , and the reaction mixture was stirred at 60 for 1.5 h. The mixture was concentrated in vacuo to give a residue, which was dissolved in NaHCO3saturated solution and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (EtOAc) to afford compound 15b (27 mg, 33yield) , MS Found: 367.2 [M+H]+ and 15c (18 mg, 22yield) as a white solid, MS Found: 351.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | To a stirred mixture of compound 10a (97 mg, 0.234 mmol) and compound 10b (42 mg, 0.234 mmol) in anhydrous THF (10 mL) was added dropwise a solution of EtONa (21in EtOH, 98 mg, 0.304 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, and concentrated to dryness under reduced pressure. The residue was diluted with NH4Cl solution (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was dissolved in MeOH (8 mL) . To this solution was added HOAc (2 mL) , and the reaction mixture was stirred at 90 for 3 h. The mixture was concentrated in vacuo to give a residue, which was diluted with NaHCO3saturated solution (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (CH2Cl2: MeOH 50 : 1) to afford compound 10c (62 mg, 79yield) as a grey solid. MS 333.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55%; 31% | A mixture of 10b (210 mg, 1.180 mmol) , 2-hydroxyisoindoline-1, 3-dione (38 mg, 0.233 mmol) , Bis (acetylacetonato) cobalt (30 mg, 0.117 mmol) in HOAc (5 mL) was stirred under oxygen atmosphere at 75 for 6 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (10 mL) and the insoluble solid was filtered off. The filtrate was concentrated in vacuo to afford a crude mixture of 14b and 14c (160 mg) as slight brown oil, which was used for the next step without further purification. To a stirred mixture of compound 10a (150 mg, 0.362 mmol) and compounds 14b and 14c (70 mg, 0.362 mmol) in anhydrous THF (10mL) was added dropwise a solution of EtONa (21in EtOH, 152mg, 0.471mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. After the mixture was concentrated to dryness under reduced pressure, the residue was diluted with NH4Cl solution (10mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was dissolved in MeOH (8 mL) . To this solution was added HOAc (2 mL) , and the reaction mixture was stirred at 60 for 2 h. The mixture was concentrated in vacuo to give a residue, which was diluted with NaHCO3saturated solution (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (EtOAc) to afford compound 14d (70 mg, 55yield) , MS 349.2 [M+H]+, and 14e (40 mg, 31yield) as a light yellow solid, MS Found 365.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-acetyladamantane With tetrabutylammomium bromide; sodium hydroxide In water; ethylene glycol at 40 - 190℃; for 12h; Autoclave; Stage #2: With hydrogenchloride In water; ethylene glycol | 2 (2) Preparation of amantadine hydrochloride; (1) 225 g of sodium hydroxide was added to 500 g of water,Further, 1. 5 g of tetrabutylammonium bromide was added,Pour it into 5L highPressureKettle,Then, 2250 ml of ethylene glycol was poured into the autoclave.250 g of 1-acetyladamantane was added under stirring. Stirring to dissolve most.The autoclave was gradually warmed to 190 ° C. from 190 ° C to start the time, the reaction stopped after 12 hours of heating,Continue stirring, the temperature dropped to 40 ° C so that deflated, remove the reaction solution;(3) adding 650 ml of 36% hydrochloric acid to the reaction solution,Adjusting the pH of the reaction solution to 4, distilling ethylene glycol under reduced pressure,The heat conduction oil is heated and decompressed by vacuum oil chestnut.A sodium hydroxide caustic water with the mass fraction of 0.25% was pumped into the autoclave(Including 100 g of water and 25 g of NaOH)Stirring rotation; then pumped into 500ml of butyl acetate, 60 ° C heating rotation; reaction solution clarified after cooling, into the spherical reactor,And the aqueous layer was extracted with 250 ml of butyl acetate,Stirring and separating to obtain a butyl acetate layer; two butyl acetate,And then with 300g of water to stir, the water layer separated. Butyl acetate was added 500 g of water,Stirring and then add the pH value of 4 hydrochloric acid, stirring 40 minutes, separated from the water layer,The aqueous layer was distilled under reduced pressure to give amantadine hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; for 16h; | |
52% | With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | (Adamant-1-yl)vinyl trifluoromethanesulfonate Following a reported procedure,5 to a solution of 1-adamantyl methyl ketone(3.57 g, 20.0 mmol) in anhydrous DCM (60 mL) at 0 °C under N2 was added2,6-di-tert-butyl-4-methylpyridine (4.66 g, 22.7 mmol) and trifluoromethanesulfonicanhydride (4.04 mL, 24.0 mmol). The reaction mixture was warmedup to room temperature, stirred for 16 h and concentrated under reduced pressure. Pentane wasadded and the solid pyridinium triflate was filtered off and washed with pentane. The combinedpentane layers were washed with ice-cold aqueous HCl (1 M), water and brine, dried over MgSO4,filtered and concentrated under reduced pressure to give the crude product, which was purified bycolumn chromatography (eluent: petroleum ether) to yield the title compound as a colourless oil(3.21 g, 52%). Spectroscopic data for this compound is in accordance with the literature. |
Stage #1: 1-acetyladamantane With 2-chloropyridine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | An oven-dried 100 ml round-bottomed flask equipped with a magnetic stir bar was charged with <strong>[131211-27-3]di-1-adamantylphosphine</strong> (2.35 g, 7.77 mmol, 1.0 equiv) and 1-adamantylacetate (1.66 g, 8.54 mmol, 1.1 equiv) in the glove box. dichioromethane (40 ml) was added to dissolvethe entire solid. The flask was capped with a rubber septum, and taken out of the glove box. Me3SiOTf (1.69 ml, 9.32 mmol, 1.2 equiv) was added by syringe and the reaction mixture was stirred at room temperature for 24 h. Triethylamine(5 .4 ml, 39 mmol, 5.0 equiv)was then added and the reaction was stirred for an additional 0.5 h at room temperature. The neutralized PAd3 subsequently precipitated from solution and was isolated by simple filtration on a disposablefilter funnel followed by rinsing with ethanol (50 ml). After aspiration for 0.5 h, 2.2 g (63 %) of1 obtained as a pure white powder. Although a solution of PAd3 is prone to oxidation under air,material in the solid state can be stored on the bench top for at least three months without substantial decomposition. Note that slow decompose in chlorinated solvent (dichioromethane, chloroform) was observed even under an inert atmosphere, but the compound appears stable in solutions of THF, benzene and toluene under N2.?H NMR (501 MHz, CD2CI2) 6 2.13 (br, 18H), 1.84 (br, 9H), 1.74- 1.58 (m, 18H).?3C NMR (126 MHz, CD2C12) 6 42.68 (br), 41.10 (d, J= 34.3 Hz), 37.0 , 29.5 (d, J= 7.2 Hz). 31p NMR (121 MHz, C6D6) 6 59.35.HRMS (ESI) mlz calculated for C30H46P0 (M+17)453.3286, found 453.3289. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sulfur; acetic acid In N,N-dimethyl-formamide at 150℃; for 16h; Sealed tube; regioselective reaction; | |
17% | With nicotinic acid; sulfur In N,N-dimethyl acetamide at 150℃; for 20h; | 21 Example 21 Step 1: Indole compounds (see Table 1 for specific substances), ene (alkyne, ketone) compounds (see Table 1 for specific substances)And the sulfur powder is added to the reaction vessel, and the solution of the Bronst acid (see the specific substance in Table 1) is added to the reaction vessel or(See Table 1 for specific substances) and organic solvents (see Table 1 for specific substances);Step 2: The reaction vessel was heated uniformly (as in an oil bath) to the temperatures described in Table 1, indole compounds, ene(Alkyne, ketone) compounds and sulfur powder in a solvent, and the time described in Table 1;[0091] Step 3: Purification step[Table 1] In the Examples 1-46, indole compounds, ene (alkyne, ketone) compounds, Bronsted acids, indole compoundsThe molar ratio, reaction temperature and reaction time of the compound, the ene (alkyne, ketone) compound, the sulfur powder and the Brnster acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | Equipped with a mechanical stirrer, reflux condenser, constant pressure dropping funnel,Thermometer 250mL four-necked flask was added concentrated sulfuric acid 100mL, with stirring,15 g (84.1 mmol) of 1-adamantane methyl ketone (R = CH3)After the addition was maintained for 15 minutes, ice water bath control 0 , and then within 30 minutes with a constant pressure dropping funnel slowly dropping mixed acid solution (fuming nitric acid 16ml (0.34mol) + concentrated sulfuric acid 16ml)Insulation 1h, naturally heated to 80 reaction 10h, the reaction was completed,The reaction solution was slowly poured into 200mL ice water, stirring while pouring, white solid precipitation, filtration was precipitated,A small amount of washing cake,Dried in vacuo to give a white powdery solid 14.9g, content 98percent, yield 79.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 4-phenylnaphthalene-1,2-dione; acetic acid In acetonitrile at 23℃; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With ammonium acetate; acetic acid In benzene for 10h; Reflux; Dean-Stark; | 1 General procedure for the synthesis of compounds 12 and 13 The mixture of adamant-1-ylmethyl ketone (11) (20mmol), malonodinitrile (20mmol), ammonium acetate (2.4mmol), acetic acid (8.3mmol) and 100ml of benzene was heated at reflux with Dean-Stark adapter. After all water was separated, which required approx.10 h., the solvent was removed on rotary evaporator and the residue was recrystallized from ethanol to give 2-(1-((adamant-1-yl)ethylidene)malononitrile (12).The mixture of 12 (6.64 mmol),4-(dimethoxymethyl)morfoline [93] (13.3 mmol), acetic anhydride(1.3 mmol) and 5ml of toluene was heated at reflux for 5 h. Aftercooling to r.t. the solventwas removed on rotary evaporator and theresidue recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 140℃; for 2.5h; | 17 The reaction method for synthesizing boric acid ester of 1-adamantanone with pinacol borane without catalyst and solvent is as follows: In the glove box, 1-amantane ketone 0.5 mmol and pinacol borane 1 mmol were sequentially added to the nuclear magnetic tube, and then removed from the glove box, reacted at 140 ° C for 2.5 h, and the nuclear magnetic property was measured, and the yield was calculated to be 99%. |
99 %Spectr. | In neat (no solvent) at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
With C30H32N2S4Zn In hexadeuterobenzene at 20℃; for 0.166667h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; water In 1,4-dioxane Inert atmosphere; Schlenk technique; Reflux; | ||
With selenium(IV) oxide In 1,4-dioxane; water at 100℃; Inert atmosphere; | ||
With selenium(IV) oxide In 1,4-dioxane; water at 95℃; Inert atmosphere; Schlenk technique; |
With selenium(IV) oxide In 1,4-dioxane; water at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trimethylantimony In acetonitrile | 1 Preparation of adamantyl methyl ketone 0.23g (CH3)3Sb was added to the three-necked flask.0.02g nickel formate,Then, a solution of adamantyl chloride in acetonitrile was added dropwise at 0.25 mL/min.Adamantyl chloride is reacted with (CH3)3Sb to form adamantane methyl ketone,After the reaction is completed, the reaction solution is poured into ice water to obtain a pale yellow compound.Then filter,Dry at 100 ° C for 5 h,Light yellow precipitated adamantyl methyl ketone 1.95g,The yield is 90%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With cesium formate In benzene Inert atmosphere; Green chemistry; | 1-3 Preparation of adamantyl methyl ketone: 0.10 g of trimethylaluminum, 0.01 g of cesium formate was added to a three-necked flask, and then a solution of adamantylcarbonyl chloride in benzene was added dropwise at 0.25 mL/min to react adamantylcarbonyl chloride with trimethylaluminum to form adamantyl methyl ketone, After the reaction is completed, the reaction solution is poured into ice water to obtain a pale yellow compound, which is then filtered and dried at 100 ° C for 5 h. light yellow precipitated adamantane methyl ketone 1.95g, the yield is 90%; The chlorine atom in the formyl chloride and the oxygen atom in the C=O double bond have strong electron-withdrawing ability and are negatively charged, while the carbon atom connected to the chlorine atom and the oxygen atom is positively charged, and is easily compatible with trimethylaluminum. The carbon cation or free radical combines to form a methyl ketone group. Because of the high activity of trimethylaluminum, the reaction is extremely difficult to control. The combination of cesium formate and trimethylaluminum can be combined with benzene solution. And then form a methyl ketone group, thereby slowing down the intensity of the reaction, making the reaction system environment mild, easy to control, and the occurrence of by-products is reduced, and the reaction yield is improved. |
90% | With cesium formate In benzene at 100℃; for 5h; | 1.1.b; 2.1.b; 3.1.b; 4.1.b; 1-3 b. Preparation of adamantane methyl ketone: 0.10 g of trimethylaluminum, 0.01 g of cesium formate was added to a three-necked flask, and then a solution of adamantyl chloride in benzene was added dropwise at 0.25 mL/min.Adamantyl chloride is reacted with trimethylaluminum to form adamantane methyl ketone,After the reaction was completed, the reaction liquid was poured into ice water to obtain a pale yellow compound, which was then filtered and dried at 100 ° C for 5 h to obtain a pale yellow precipitated adamantane methyl ketone 1.95 g, yield 90%;The chlorine atom in the formyl chloride and the oxygen atom in the C=O double bond have strong electron-withdrawing ability.Negatively charged, and the carbon atom connected to the chlorine atom and the oxygen atom is positively charged and easily combines with carbon cation or radical in trimethylaluminum.Produces a methyl ketone group, which is extremely active due to its high activity.The reaction is extremely difficult to control, and the combination of cesium formate and trimethylaluminum,With the benzene solution, the complex can be formed first, and then the methyl ketone group is formed.Thereby slowing down the reaction and making the reaction system environment mild.Easy to control, while reducing the occurrence of by-products and increasing the reaction yield; |
90% | With cesium formate In benzene at 100℃; for 5h; | 1-3 Preparation of adamantyl methyl ketone: 0.10 g of trimethylaluminum, 0.01 g of cesium formate was added to a three-necked flask, and then a solution of adamantyl chloride in benzene was added dropwise at 0.25 mL/min to make adamantyl chloride and trimethylaluminum. The reaction is carried out to form adamantane methyl ketone. After the reaction is completed, the reaction solution is poured into ice water to obtain a pale yellow compound, which is then filtered and dried at 100 ° C for 5 h to obtain a light yellow precipitated adamantane methyl ketone of 1.95 g in a yield of 90%; The chlorine atom in the formyl chloride and the oxygen atom in the C=O double bond have strong electron-withdrawing ability and are negatively charged, while the carbon atom connected to the chlorine atom and the oxygen atom is positively charged, and is easily compatible with trimethylaluminum. The carbon cation or free radical combines to form a methyl ketone group. Because of the high activity of trimethylaluminum, the reaction is extremely difficult to control. The combination of cesium formate and trimethylaluminum can be combined with benzene solution. And then form a methyl ketone group, thereby slowing down the intensity of the reaction, making the reaction system environment mild, easy to control, while reducing the occurrence of by-products and increasing the reaction yield; |
1.95 g | With cesium formate In benzene at 100℃; for 5h; Green chemistry; | 1 Preparation of adamantane methyl ketone 0.10 g of trimethylaluminum, 0.01 g of cesium formate was added to a three-necked flask, and then asolution of adamantyl chloride in benzene was added dropwiseat0.25 mL/min to make adamantyl chloride and trimethylaluminum. The reaction is carried out to form adamantane methylketone. After the reaction is completed, the reaction solution is poured into ice water to obtain a pale yellow compound, which is then filtered and dried at 100 °C for 5 h to obtain a light yellow precipitated adamantane methyl ketone of 1.95 g in a yield of 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With quinuclidin-3-yl benzenesulfonate; [Ir(2-(2,4-difluorophenyl)-4-(trifluoromethyl)pyridine)2(5,5'-bis(trifluoromethyl)-2,2'-bipyridine)]PF6 In water; 1,2-dichloro-ethane at 38℃; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium tris(acetoxy)borohydride In dichloromethane at 30℃; for 12h; | 2 A6. To a stirring solution of benzylamine (10.0 mmol) inDCM (20 mL) was added l-(adamantan-l-yl)ethan-l-one (10.0 mmol) and NaBH(OAc)3(15 mmol) at room temperature. The reaction mixture was heated at 30 °C for 12 hours. After being cooled to room temperature and concentrated, the residue was purified using HPLC. Yield: 28%. Yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 68 %Chromat. 2: 51% | Stage #1: di-isopropyl azodicarboxylate; 1-acetyladamantane With cerium(IV) trifluoromethanesulfonate; trimethylsilyl cyanide; 9,10-diphenylanthracene; tetrabutyl-ammonium chloride; titanium tetrachloride In acetonitrile at 0 - 50℃; for 60h; Inert atmosphere; Irradiation; Glovebox; Stage #2: butan-1-ol With triethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere; Glovebox; | 4.3 General procedure for selective C-C bond cleavage of medium-size cyclicand linear ketones: General procedure: A 8-mL vial was charged with 2-phenylcyclohexanone (35 mg, 0.2 mmol, 1.0equiv.), DIAD (48 μL, 0.24 mmol, 1.2 equiv.), DPA (3.3 mg, 10 μmol, 0.05 equiv.),Ce(OTf)4 (2.9 mg, 4 μmol, 0.02 equiv.), n-Bu4NCl (5.5 mg, 20 μmol, 0.1 equiv.) inglovebox, then the vial was sealed with a poly-tetrafluoroethylene-lined cap before CH3CN (1 mL), PhCF3 (1 mL) was added. TiCl4 (0.1 mL, 0.2 M in CH3CN, 0.1 equiv.)and TMSCN (76 μL, 0.6 mmol, 3 equiv.) was added at 0 °C. The reaction mixture wasdegassed by Argon sparging for 2 min at 0 °C, then irradiated with a 100 W blue LEDlamp (at approximately 4 cm away from the light source, light intensity 0.16 Wcm-2,the reaction temperature was measured to be 50 °C). After the ketone was consumed,the reaction mixture was cooled to room temperature before anhydrous methanol (4mL) and Et3N (42 μL, 0.3 mmol, 1.5 equiv.) was added. The solution was stirred foranother 2h before concentrated in vacuo. Purification by flash chromatography onsilica gel (20% acetone in hexanes) provided the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With air In 1,4-dioxane at 20 - 60℃; for 24h; | DETAILED DESCRIPTION 21: Methyl ketone is 1-adamantanone dd 1 mmol of 1-adamantanone to the reaction flask and dissolve it in 1,4-dioxane (1 mL). Under stirring at room temperature, add 528 μL of tert-butyl nitrite dropwise, and then raise the temperature to 60 ° C. The reaction was carried out under an air atmosphere for 24 hours. After the reaction, the organic solvent was removed by a rotary evaporator, and purified by column chromatography or recrystallization to obtain 159 mg of the furoxan product. The reaction yield was 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 85% 2: 7% | With nitric acid In neat (no solvent) at -5℃; for 1h; | General procedure for the oxidation of compounds 1, 3-5, 7-9, and 13 with fuming nitric acid. General procedure: Compound 1, 3-5, 7-9, or 13, 0.01 mol, was added in portions to 98% nitric acid. The mixture was kept under the conditions indicated in Table 2 and poured onto crushed ice. Compounds 3, 21, and 2 were extracted with diethyl ether (3×10 mL), the combined extracts were washed with a 10% solution of sodium hydroxide and with water until neutral washings, dried over sodium sulfate, and evaporated. Compounds 23-26 and 30 precipitated and were filtered off, washed with water until neutral washings, and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With nitric acid; acetic anhydride at 10℃; for 2h; | General procedure for the oxidation of compounds 1-4 and 6-17 in the system HNO3-Ac2O. General procedure: Compound 1-4 or 6-17, 0.01 mol, was added to a mixture of 98% nitric acid and acetic anhydride. The mixture was kept under the conditions indicated in Table 1 and poured onto crushed ice. Compounds 18-21 and 31-34 were extracted with diethyl ether (3×10 mL), the combined extracts were washed witha solution of sodium hydrogen carbonate and water until neutral washings, dried over sodium sulfate, and evaporated. Compounds 23-30 precipitated and were filtered off, washed with water until neutral washings, and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With nitric acid In neat (no solvent) at 20℃; for 3h; | General procedure for the oxidation of compounds 1, 3-5, 7-9, and 13 with fuming nitric acid. General procedure: Compound 1, 3-5, 7-9, or 13, 0.01 mol, was added in portions to 98% nitric acid. The mixture was kept under the conditions indicated in Table 2 and poured onto crushed ice. Compounds 3, 21, and 2 were extracted with diethyl ether (3×10 mL), the combined extracts were washed with a 10% solution of sodium hydroxide and with water until neutral washings, dried over sodium sulfate, and evaporated. Compounds 23-26 and 30 precipitated and were filtered off, washed with water until neutral washings, and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine hydrate; acetic acid In ethanol at 85℃; for 6h; | 2.3.1. Preparation of the adamantyl methyl hydrazone ligand, L1 1-Adamantyl methyl ketone (0.150 g, 0.841 mmol) was dissolved in30 mL of ethanol, followed by the addition of hydrazine monohydrate(0.0862 g, 2.61 mmol) and four drops of acetic acid. This solution wasrefluxed at 85 C for 6 h. After 6 h, the solvent was removed using arotary evaporator and a white powder was obtained. The white powder(L1) was dried under vacuum for 6 h. Yield: 0.166 g, 100%. Meltingpoint: 81-83 C (Literature: 74-76 C [15]). FT-IR (max/ cm 1): 3366(N-H), 1625 (C- -N). 1H NMR (400 Hz, CDCl3) , ppm: 1.61-1.79 (br m,15H, Ha-c), 1.99 (br s, 3H, Hf), 4.31 (br s, 2H, Hg). 13C{1H} NMR (101MHz, CDCl3) , ppm: 9.2 (Cf), 28.3 (Cc), 36.9 (Ca), 39.8 (Cb), 40.2 (Cd),158.3 (Ce). Elemental Analysis, Calculated % for C12H10N2: C 74.95, H10.48, N 14.37. Found %: C 75.12, H 10.57, N 14.22. |
With hydrazine hydrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In ethanol at 20℃; for 24h; Alkaline conditions; | (2E)-3-(3-Hydroxy-4-methoxyphenyl) adamantane-1-prop-2-en-1-one (8). Sodium hydroxide (0.029 g, 0.728 mmol) was added with stirring to a solution of 1-adamant-1-yl ethanone (0.1 g, 0.56 mmol) in ethanol (5 mL). 3-Hydroxy-4-methoxybenzaldehyde (0.085 g, 0.56 mmol) was added to the mixture, and the reaction mixture was stirred at ~20 °C for 24 h. The solvent was evaporated under reduced pressure. The residue was chromatographed. Ethyl acetate-petroleum ether (40-70 ,gradient 1 : 7-1 : 5) served as the eluent for chromatography. The yield was 0.088 g (50%), white crystals, m.p. 142 . 1 NMR (CDCl3), δ: 1.72-1.81 (m, 6 H, HAd); 1.88 (d, 6 H, HAd,J = 2.8 Hz); 2.09 (m, 3 H, HAd); 3.94 (s, 3 H, OCH3); 5.67(m, 1 H, OH); 6.84 (d, 1 H, J = 8.2 Hz); 7.03 (d, 1 H, CH=CH-C(O), J = 15.5 Hz); 7.06 (dd, 1 H, J = 2.0 Hz, J = 8.2 Hz); 7.23(d, 1 H, J = 2.0 Hz); 7.59 (d, 1 H, CH=CH-C(O), J = 15.5Hz). 13 NMR (CDCl3), δ: 28.0, 36.6, 38.2, 45.4 (C(1)Ad); 56.0(OCH3); 110.4, 112.7 (OCH2O); 118.6, 122.5 (CH=CHC(O));128.7, 142.6 (CH=CHC(O)); 145.7, 148.4, 203.9 (C=O).Found (%): C, 76.82; H, 7.71. C20H24O3. Calculated (%):C, 76.89; H, 7.74. |
Yield | Reaction Conditions | Operation in experiment |
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83% | With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; regioselective reaction; | 14 Example 14 Intoa 25mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI2) in tetrahydrofuran (0.100mol/L) 7.50mL, compound 1n 53.5mg (0.300mmol), heavy water 150mg (7.50mmol) ).The reaction mixture was stirred at room temperature for 15 min, after which air was passed through to quench the reaction.Ethyl acetate and 1M hydrochloric acid solution were added for extraction, the organic phase was dried and concentrated, and 45.1 mg of the target compound 2n was separated by column chromatography with a yield of 83% and a deuteration rate of 98%. |
83% | With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; chemoselective reaction; | 3.2 General Procedure for the Reductive Deuteration of Ketones by SmI2-D2O General procedure: To a solution of samarium (II) iodide (0.100 M in THF; 7.50 mL, 0.750 mmol, 2.50 equiv),was added deuterium oxide (150 mg, 7.50 mmol, 25.0 equiv). A characteristic burgundy redcolor of SmI2-D2O complex was observed. A solution of ketones (0.300 mmol, 1.00 equiv) inTHF (1.0 mL) was then added under Ar at room temperature and stirred vigorously. After 15min, excess SmI2 was oxidized by bubbling air through the reaction mixture. The reactionmixture was diluted with EtOAc (10 mL) and HCl (5 mL, 1.0 M, aq). The aqueous layer wasextracted with EtOAc (3 × 10 mL), organic layers were combined, washed with Na2S2O3 (2 ×5 mL, sat., aq), dried over Na2SO4, filtered and concentrated. The crude product was purifiedby flash chromatography (silica, 10-50% EtOAc/Hexane). The sample was analyzed by 1HNMR (CDCl3, 300 MHz) to obtain the deuterium incorporation. |
Yield | Reaction Conditions | Operation in experiment |
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54% | Stage #1: 1-acetyladamantane With potassium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: With triethyl borane In tetrahydrofuran at 15 - 20℃; for 0.5h; Inert atmosphere; Stage #3: allyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | General Procedure 2 (GP2) - Preparation of Alkenes 1d, 1g, 1j, 1l, 1m and 1p General procedure: Beginning from the corresponding ketone, alkenes were first synthesized following modifiedWittig conditions. A solution of R-phosphonium bromide (2.0 equiv) was chilled to 0 °C in THF(0.5M). n-BuLi (1.2 eq) was then added slowly and the solution was allowed to warm to roomtemperature over the course of 15 minutes prior to addition of the corresponding ketone (1.0equiv). The reaction was allowed to stir overnight or until complete by TLC. Upon completion, silica gel was added to the reaction flask and the mixture was concentrated until suitable for dryloading into a Biotage column. The alkene was then purified via Biotage Isolera using 0 - 30%EtOAc:Hex as the running gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: berberine chloride With potassium hydroxide In water for 0.666667h; Stage #2: 1-acetyladamantane In water for 0.333333h; | Synthesis of 8-substituted berberines 10-34 (General method). General procedure: KOH (2 g) was added to a solution of berberinehydrochloride (1) (372 mg, 1.0 mmol) in EtOH or MeOH(25 ml) and H2O (15 ml), and the resulting mixture wasvigorously stirred for 40 min. Then, a solution of thecorresponding nucleophile (3 mmol) in EtOH or MeOH 10 ml) was added, and stirring was continued for another20 min. Next, the solution was poured into chilled H2O(250 ml). The formed precipitate was filtered off, washedon filter with warm H2O, and recrystallized from a H2O-MeOH, 1:1 mixture. |
Tags: 1660-04-4 synthesis path| 1660-04-4 SDS| 1660-04-4 COA| 1660-04-4 purity| 1660-04-4 application| 1660-04-4 NMR| 1660-04-4 COA| 1660-04-4 structure
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