* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Chemical Research, Miniprint, 1993, # 12, p. 3320 - 3338
[2] Journal of Chemical Research, Miniprint, 1993, # 12, p. 3320 - 3338
3
[ 98-53-3 ]
[ 98-52-2 ]
Yield
Reaction Conditions
Operation in experiment
100 %Chromat.
With potassium formate In water; N,N-dimethyl-formamide at 100℃; for 8 h; Inert atmosphere; Green chemistry
For a typical reduction, 2 mmol of the aldehyde substrate,0.504 g (6 mmol) potassium formate, 0.54 mL (30 mmol) water and5 mL (65 mmol) dimethylformamide (DMF) were added to a 25 mLround-bottom flask. After heating the reaction mixture to 100Cunder a flow of nitrogen, 100 mg of 1 wt.percent Ru/AlO(OH) (0.5 mol percentof Ru) was added. Samples were taken at regular intervals and ana-lyzed by gas chromatography (GC) and gas chromatography massspectrometry (GC–MS). For comparison, the direct hydrogenationof benzaldehyde using molecular H2at 0.5 MPa was carried out in a Parr autoclave at 100C. Due to their lower reactivity, the catalytictransfer hydrogenation of ketones was carried out using 200 mg of2 wt.percent Ru/AlO(OH). For recycling tests, the used catalyst was recov-ered by centrifugation, washed with water followed by ethanol anddried at room temperature before use
Reference：
[1] Journal of Organometallic Chemistry, 1980, vol. 195, # 1, p. 1 - 12
[2] Tetrahedron Letters, 2000, vol. 41, # 39, p. 7567 - 7570
[3] Tetrahedron Letters, 1981, vol. 22, p. 179 - 180
[4] Tetrahedron Letters, 1998, vol. 39, # 22, p. 3729 - 3732
[5] Patent: US6340775, 2002, B1, . Location in patent: Example 5
[6] Chemistry - A European Journal, 2018, vol. 24, # 62, p. 16526 - 16531
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[8] Tetrahedron Letters, 2006, vol. 47, # 1, p. 9 - 12
[9] Journal of Organic Chemistry, 1982, vol. 47, # 23, p. 4581 - 4583
[10] Liebigs Annalen, 1995, # 4, p. 677 - 684
[11] Angewandte Chemie, 1989, vol. 101, # 3, p. 329 - 330
[12] Chemistry Letters, 1991, # 2, p. 307 - 310
[13] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3943 - 3945
[14] Journal of Organic Chemistry, 1997, vol. 62, # 9, p. 3019 - 3020
[15] Helvetica Chimica Acta, 1984, vol. 67, # 3, p. 669 - 683
[16] Chemistry Letters, 1982, p. 261 - 264
[17] Chemical Communications, 2007, # 7, p. 760 - 762
[18] Journal of the Chemical Society, Chemical Communications, 1981, # 20, p. 1066 - 1067
[19] Tetrahedron Letters, 2000, vol. 41, # 29, p. 5543 - 5546
[20] Journal of Organic Chemistry, 1984, vol. 49, # 1, p. 166 - 168
[21] Journal of the Chemical Society, Chemical Communications, 1995, # 4, p. 465 - 466
[22] Journal of Organic Chemistry, 1984, vol. 49, # 1, p. 163 - 166
[23] Synthesis, 2005, # 15, p. 2619 - 2622
[24] Journal of Organic Chemistry, 1982, vol. 47, # 23, p. 4581 - 4583
[25] Chemistry Letters, 1980, p. 1239 - 1242
[26] Tetrahedron Letters, 1981, vol. 22, p. 179 - 180
[27] Journal of the American Chemical Society, 1987, vol. 109, # 3, p. 908 - 910
[28] Synthetic Communications, 1984, vol. 14, # 10, p. 955 - 960
[29] Journal of the American Chemical Society, 1984, vol. 106, # 22, p. 6709 - 6716
[30] Recueil des Travaux Chimiques des Pays-Bas, 1985, vol. 104, # 9, p. 217 - 219
[31] Journal of Organometallic Chemistry, 1982, vol. 240, # 4, p. 453 - 460
[32] Tetrahedron Letters, 1996, vol. 37, # 33, p. 5987 - 5988
[33] Tetrahedron Letters, 1981, vol. 22, p. 675 - 678
[34] Tetrahedron Letters, 1980, vol. 21, p. 3963 - 3964
[35] Journal of Organic Chemistry, 1980, vol. 45, # 13, p. 2724 - 2725
[36] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3412 - 3422
[37] Journal of the American Chemical Society, 1980, vol. 102, # 8, p. 2693 - 2698
[38] Journal of Organic Chemistry, 1993, vol. 58, # 11, p. 3046 - 3050
[39] Journal of the American Chemical Society, 1984, vol. 106, # 22, p. 6709 - 6716
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[41] Journal of Organic Chemistry, 1998, vol. 63, # 6, p. 1761 - 1766
[42] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1101 - 1107
[43] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2582 - 2589
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[45] Tetrahedron Letters, 2001, vol. 42, # 50, p. 8857 - 8859
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[48] Journal of Catalysis, 2003, vol. 215, # 2, p. 294 - 304
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[50] Patent: US5107038, 1992, A,
[51] Tetrahedron Letters, 2007, vol. 48, # 52, p. 9120 - 9123
[52] Synthetic Communications, 2010, vol. 40, # 8, p. 1187 - 1191
[53] Angewandte Chemie - International Edition, 2013, vol. 52, # 9, p. 2538 - 2542[54] Angew. Chem., 2013, vol. 125, # 9, p. 2598 - 2602,5
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[57] Organometallics, 2016, vol. 35, # 20, p. 3538 - 3545
4
[ 677-22-5 ]
[ 98-53-3 ]
[ 98-52-2 ]
[ 19437-29-7 ]
Reference：
[1] Journal of the American Chemical Society, 1989, vol. 111, # 12, p. 4392 - 4398
[2] Journal of the American Chemical Society, 1989, vol. 111, # 12, p. 4392 - 4398
5
[ 693-03-8 ]
[ 98-53-3 ]
[ 98-52-2 ]
[ 53188-79-7 ]
Reference：
[1] Journal of the American Chemical Society, 1989, vol. 111, # 12, p. 4392 - 4398
6
[ 3780-00-5 ]
[ 98-53-3 ]
[ 98-52-2 ]
Reference：
[1] Chemistry - A European Journal, 2004, vol. 10, # 21, p. 5493 - 5506
7
[ 111-90-0 ]
[ 98-53-3 ]
[ 98-52-2 ]
Reference：
[1] Patent: US5196601, 1993, A,
8
[ 67-56-1 ]
[ 98-53-3 ]
[ 98-52-2 ]
[ 944-19-4 ]
[ 57466-12-3 ]
Reference：
[1] Chemistry Letters, 1982, p. 261 - 264
9
[ 98-53-3 ]
[ 75-05-8 ]
[ 98-52-2 ]
[ 6555-57-3 ]
[ 6555-58-4 ]
[ 71750-16-8 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 28, p. 7175 - 7187
[2] Journal of Organic Chemistry, 1992, vol. 57, # 28, p. 7175 - 7187
10
[ 98-53-3 ]
[ 10347-88-3 ]
[ 98-52-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1993, # 12, p. 3320 - 3338
[2] Journal of Chemical Research, Miniprint, 1993, # 12, p. 3320 - 3338
11
[ 98-53-3 ]
[ 98-52-2 ]
Reference：
[1] Chemical Communications, 1997, # 20, p. 1989 - 1990
With pyridine; trichloroisocyanuric acid; In ethyl acetate; at 20℃; for 0.333333h;
General procedure: O.1 mole of 4-t-butylcyclohexanol (ACROS) was weighed and placed in a 50 mL Erlenmeyer flask with stir bar and 10 mL ethyl acetate (Fisher). 1.0 g trichloroisocyanuric acid (Leslie?s Swimming Pool Supplies) was weighed into a 30 mL beaker and dissolved in 10 mL ethyl acetate. 1.0 mL (0.12 mol) pyridine (Aldrich) was delivered to the alcohol mixture by pipet. The TCICA solution was transferred to a dropping funnel and added dropwise to the stirring alcohol solution. Following addition, stirring was continued for 20 minutes and the mixture was filtered. The filtrate was washed with 10 mL 1 M HCl, 10 mL 5% NaHCO3, and 5 mL saturated NaCl. The organic layer was dried over MgSO4, a GC sample removed, filtered and evaporated to dryness. Yield 1.50 g (100%), nmr attached.
96%
With oxygen; ascorbic acid; In toluene; at 60℃; for 45h;
EXAMPLE-7; Method for oxidation of 4-tertiary butyl cyclohexanol. Oxygen gas (25 ml min-1) was continuously bubbled through a solution of 4-tertiary butyl cyclohexanol (5 mmol), polystyrene supported [meso-(2,6-dichlorophenyl) porphinato] Iron (II) (corresponding to 0.056 mol % of metalloporphyrin) in toluene (25 ml). Ascorbic acid (15 mmol) was added to reaction mixture at intervals of 2 hours till maximum conversion of reactant to product was achieved). The reaction mixture was vigorously stirred at 60 C. and the progress of the reaction was monitored by TLC. After stirring the reaction mixture for 45 hrs, it was concentrated to half. Addition of equal volume of methanol precipitated the catalyst that was filtered and the filtrate was evaporated to dryness to give the product. The product was purified by column chromatography and characterized by physical constants and spectroscopic data (IR, 1H-NMR and mass spectra). Yield: 0.74 g (96%).
92%
General procedure: Firstly, GO (0.01 g) was added into water (3 mL) and the mixturecould generate the stable colloidal suspensions under a mild ultrasonictreatment. Afterwards, the alcohol (2 mmol) and (NH4)5H5[H2(WO4)6](0.03 mmol, M=1602) were added. The mixture was stirred for 15 min atroom temperature. Subsequently, hydrogen peroxide (30 wt%, 8 mmol)was added dropwise and the mixture was heated to 70C until thereaction was fully completed (monitored by TLC). After the reactioncompleted, GO could be readily separated from the mixtures bycentrifugation, and then ethyl acetate was added to the mixture to extract organic constituents. Finally, the organic extracts were concentratedunder reduced pressure and purified by column chromatography.
91.3%
Example 6 In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer, <strong>[98-52-2]4-tert-butylcyclohexanol</strong> (15.6 g, 0.10 mol), dimethyl sulfoxide (117.2 g, 1.50 mol) and toluene (40 g) were added, and the resulting reaction solution was stirred at a temperature of 20 to 23 C. To this reaction solution, pyridine (7.9 g, 0.10 mol) was added dropwise, followed by dichloroacetic acid (6.4 g, 0.05 mol). The resulting mixture was maintained at a temperature of 25 C. or lower and was stirred for 10 minutes. After stirring, Carbodilite V-03 (manufactured by Nisshinbo Chemical Inc., 431.1 g/mol) (86.2 g, 0.20 mol) was added dropwise to the reaction liquid, while the reaction liquid was maintained at 25 C. or below. After the dropwise addition, the reaction liquid was stirred for 5 hours at 23 to 25 C., and the reaction was terminated with a 1.0% aqueous solution of acetic acid (16 g). After the reaction was terminated, a urea compound precipitated from the reaction liquid was separated by filtration. The filtrate was partitioned to remove the aqueous phase, and then the organic phase was washed with an aqueous sodium chloride solution.The resulting organic layer was treated such that the solvent was removed under reduced pressure, and the residue was distilled under reduced pressure. Thus, 4-tert-butylcyclohexanone (bp: 88 to 90 C./1.06 kPa, 14.1 g, 0.09 mol) was obtained (yield 91.3%). The ketone compound thus obtained was confirmed by using NMR, mass spectrometry and IR spectroscopy.
87%
With 2-azatricyclo[3.3.1.13,7]dec-2-yloxidanyl; sodium hypochlorite pentahydrate; sodium hydrogencarbonate; potassium bromide; In water; for 0.5h;Milling;
General procedure: NaOCl·5H2O (247 mg 1.5 mmol), NaHCO3 (185 mg, 2.2 mmol), and KBr (3.6mg, 0.03 mmol, 3 mol %) were placed in an Ertalyte jar (15 mL, 41.2 g) equippedwith six zirconia balls (5 mm ). The jar was ball-milled at 1800 rpm for 1 min.Following this initial grinding period, secondary alcohol 11a-19a (1.0 mmol),and 2-aza-adamantane-N-oxyl (AZADO, 1.6 mg, 0.01 mmol, 1 mol %), wereadded and the reaction mixture was milled at 30 Hz for further 30 minutes. Theprogress of the reaction was monitored by TLC (heptane/AcOEt 9:1, v/v) andGC-MS analysis of an aliquot of the crude. The milling was stopped, Na2SO3(189 mg, 1.5 mmol) added to the jar. Then, milling was continued at 30 Hz forfurther 3 minutes. AcOEt (2 × 1.5 mL) was added into the jar and the crude wastransferred to a round-bottomed flask together with silica gel (350 mg). Thecombined organic layers were concentrated in vacuo. The resulting residue waspurified through a short column on silica gel with ethyl acetate/hexane 1:9 (v/v)as the eluent to yield the target ketones 11b-19b
With triethylamine In methanol at 20℃; for 0.166667h;
5. General procedure for the synthesis of dimethyl acetals catalyzed by ATRT
General procedure: ATRT (99 mg, 1 mol%) was added to a mixture of undecanal (1a) (1.70 g, 10 mmol) and methyl orthoformate (2.12 g, 20 mmol) in dry MeOH (40 mL). The mixture was stirred at room temperature for 20 min. The mixture was filtered and the precipitate was washed with methanol. One drop of Et3N was added to the filterate and the solution was evaporated under reduced pressure. The residue was purified by column chromatography with hexane-acetone (20 : 1) containing one drop of Et3N on silica gelto give acetal 1c (2.07 g, 96%).
With toluene-4-sulfonic acid In methanol
With toluene-4-sulfonic acid In methanol Heating;
With toluene-4-sulfonic acid In methanol at 20℃; for 24h;
With toluene-4-sulfonic acid In methanol at 20℃; for 24h;
With toluene-4-sulfonic acid In methanol at 20℃; for 2h; Molecular sieve;
Benzaldehyde dimethyl acetal4a)
General procedure: To a stirred suspension of benzaldehyde (4.25 g, 40 mmol), trimethyl orthoformate (6.37 g, 60 mmol) and MS 3A in MeOH (8.0 mL), p-toluenesulfonic acid monohydrate (0.080 g, 0.40 mmol) in MeOH (4.0 mL) was slowly added and stirred at room temperature for 2 h. After the reaction was completed, Et2O and sat. NaHCO3 aq. were added. The organic layer was separated and the aqueous layer was extracted with Et2O three times. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the crude product was distilled under reduced pressure (70 °C/10 mmHg) to give benzaldehyde dimethyl acetal as a colorless oil (5.3 g, 87%).
With Amberlyst 15 In dichloromethane at 45℃; for 0.5h;
2.b
b) (R = t-Bu); 4-tert-butyl-cyclohexanone (25 g, 162 mmol) was added to a 250 mL 3 neck round bottom flask with stirring, Trimethyl orthoformate (25 g),50 grams of dichloromethane and Amberlyst-15. The reaction was stirred under heating to 45 deg C 30 minutes.then, The reaction mixture was transferred to a separatory funnel, The organic layer was shaken with 5% aqueous sodium bicarbonate solution, And then shake with salt water. Separating the organic layer, Dried over MgSO4, And evaporated under reduced pressure to afford 1,1'-dimethoxy-4-tert-butyl-cyclohexane as a pale yellow liquid. The product 1,1'-dimethoxy-4-tert-butyl-cyclohexane was confirmed by NMR> 99% purity.
With oxygen; trifluoroacetic acid; sodium nitrite; at 0 - 20℃; for 5.25h;Product distribution / selectivity;
An operation was conducted in the same manner as in Example 2 except that cyclohexanol was replaced by an alicyclic secondary alcohol compound or an alicyclic ketone compound, both shown in Table 2 as a raw material compound. The results are shown in Table 2.
With nano titania supported sulfonic acid In neat (no solvent) at 90℃; for 0.5h; Green chemistry;
General procedure for the synthesis of α,α'-bis(substituted-benzylidene)cycloalkanones
General procedure: A mixture of cycloalkanone (1 mmol), aromatic aldehyde (2 mmol) and 0.20 mmol (0.032 g) n-TSA was stirred at 90 °C under solvent-free conditions for an appropriate time. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, eluted with hot ethanol (5 mL) and was centrifuged to filter the catalyst. The title compounds were obtained in their yellowish crystalline forms by recrystallization of ethanol solution.
87%
With sodium hydroxide In ethanol; water at 0 - 20℃;
76%
With hydrogenchloride at 20℃; for 16h;
70%
With N-benzyl-trimethylammonium hydroxide In methanol for 4h; Heating;
With nano titania supported sulfonic acid In neat (no solvent) at 90℃; for 0.416667h; Green chemistry;
General procedure for the synthesis of α,α'-bis(substituted-benzylidene)cycloalkanones
General procedure: A mixture of cycloalkanone (1 mmol), aromatic aldehyde (2 mmol) and 0.20 mmol (0.032 g) n-TSA was stirred at 90 °C under solvent-free conditions for an appropriate time. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, eluted with hot ethanol (5 mL) and was centrifuged to filter the catalyst. The title compounds were obtained in their yellowish crystalline forms by recrystallization of ethanol solution.
85%
With hydrogenchloride at 20℃; for 16h;
80%
With N-benzyl-trimethylammonium hydroxide In methanol for 4h; Heating;
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h;
99%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃; for 0.5h;
Stage #2: 4-tercbutyl-cyclohexanone In acetonitrile at 0 - 20℃;
94%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h;
Stage #2: 4-tercbutyl-cyclohexanone In tetrahydrofuran; mineral oil at 20℃; for 2h;
1.1 Step 1,4-tert-butyl-cyclohexane subunit synthesis of acetic acid ethyl ester
Sodium hydride (commercial content 60%) 14.74g (0.37mol) suspended in 500 ml of dry tetrahydrofuran, the reaction of the cold trap and the system lower the temperature to 0 °C, the phosphoryl acetic acid triethyl ester 76.6 ml (0.386mol) dropping to the above-mentioned reaction system and in the 0 °C reaction stirring 15 minutes, the 4-tert-butyl cyclohexanone 54g (0.35mol) dissolved in 100 ml of tetrahydrofuran, in 0 °C to the dripping in the above-mentioned reaction system, the reaction system after dropping the temperature to room temperature, the reaction to stir at room temperature for 2 hours, then using 500 ml water quenching reaction, concentrating under reduced pressure to remove a part of tetrahydrofuran, then using 300 ml × 2 methyl tert-butyl ether extraction the aqueous phase, the organic phase after the merger 200 ml × 3 saturated salt water washing, drying the organic phase obtained after concentrating 73.8g the oil 4-tert-butyl-cyclohexane subunit ethyl acetate (yield 94%, purity 96.6%), does not pass through the after-treatment, directly used for the next step.
91%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 4-tercbutyl-cyclohexanone In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
86%
With rubidium hydroxide In benzene at 20℃; for 165h;
With sodium hydride In 1,2-dimethoxyethane
With sodium hydride In N,N-dimethyl-formamide 1) 20 deg C, 1 h, 2) 90 deg C to 100 deg C, 8 h; Yield given;
With (1R,2R)-1,2-diphenyl-1,2-dimethoxyethane; lithium diisopropyl amide In toluene
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃;
Stage #2: 4-tercbutyl-cyclohexanone In acetonitrile at 0℃; for 72h;
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃; for 0.5h;
Stage #2: 4-tercbutyl-cyclohexanone In acetonitrile at 20℃;
With toluene-4-sulfonic acid In toluene for 8h; Reflux; Dean-Stark;
Synthesis of spirans 7-23 (General method).
General procedure: A mixtureof the corresponding salicylamide 1-6 (0.010 mol), ketone(0.012 mol), and p-TsOH·H2O (0.03 mol) in PhMe (45 ml)was refluxed for 8 h with continuous removal of water witha Dean-Stark trap. Then solvent was evaporated to drynessunder reduced pressure, the solid residue was washed with5% aqueous NaOH solution and filtered off.Spiro[1,3-benzoxazine-2,1'-cycloheptan]-4(3H)-one (7).Yield 2.10 g (91%)
With 5% active carbon-supported ruthenium In ethanol at 78℃; for 14h;
2 Example 2: Preparation of methylene malononitrile compounds (III-2)The reaction formula is as follows:
To the reaction flask, add 7.713g (50mmol) of p-tert-butylcyclohexanone (I-2), 0.5g (Ru molar amount is (I-2) 5 ‰) Ru / C catalyst,3.303g (50mmol) of malononitrile II and 80mL of ethanol were stirred at 78 ° C for 14h. The following operations were the same as in Example 1.Finally, 9.892 g of liquid product was obtained, the yield was 97.8%, and the purity of GC-MS was 99.0%.
95%
With Sn-MCM-41 In toluene at 100℃; for 3h;
88%
With ((S)-N-(2-aminoethyl)pyrrolidine-2-carboxylate) functionalized polyacrylonitrile fiber In water at 30℃; for 2h; Green chemistry;
83%
82%
With ammonium acetate In hexane; acetic acid
82%
With ammonium acetate; acetic acid In benzene for 3h; Heating;
82%
With 3-amino propanoic acid In water Heating;
79%
With ammonium acetate; acetic acid In benzene at 130℃; Dean-Stark;
With sodium hydroxide; hydroxylamine hydrochloride at 20℃; for 0.666667h; grinding;
88%
With hydroxylamine hydrochloride; sodium acetate In methanol; water at 60℃;
88.28%
With pyridine; hydroxylamine hydrochloride In ethanol Reflux;
General procedure for ketone oximation
General procedure: 50 mL of ethanol, 5 mL of pyridine, 6.50 mmol ketone and 60 mmol hydroxylamine hydrochloride were added into a 100 mL round-bottom flask. The reaction was monitored with thin layer chromatography. After the complete reaction of the substrates, 300 mL of distilled water was added to the mixture. The beaker was placed in the refrigerator to accelerate product crystallization. The crystals were filtered under reduced pressure. The crude product was sufficiently pure for use in the next stage of the reaction and microbiological assays.
87%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water 1.) steam bath, 1-5 h, 2.) room temp.;
84%
With hydroxylamine hydrochloride In ethanol for 0.666667h;
27%
With hydroxylamine hydrochloride; sodium hydroxide at 20℃; for 0.833333h; Milling;
With hydroxylamine hydrochloride
With hydroxylamine hydrochloride
With hydroxylamine hydrochloride; sodium acetate In ethanol at 80℃; for 1h;
With pyridine; hydroxylamine hydrochloride In ethanol for 5h; Reflux;
With hydroxylamine hydrochloride; sodium acetate In methanol; water at 20℃; for 1h;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 100℃; Irradiation;
Stage #1: 4-tercbutyl-cyclohexanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: With methyl chlorosulfate In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Overall yield = 100 %; Overall yield = 189 mg;
α-chlorination of ketones
General procedure: To a solution of diisopropylamine (170 µL, 1.2 eq.) in dry THF (2 mL) in a flame dried round bottom flask under argon at 0 °C was added n-butyllithium (690 µL, 1.6 M in hexanes, 1.1 eq.), and the reaction mixture was stirred at this temperature for 15 minutes. It was then cooled to -78 °C and a solution of ketone (1) (1 mmol) in THF (2 mL) slowly added. Stirring at -78 °C was continued for a further 30 minutes and methyl chlorosulfate (100 µL, 1.1 eq.) was then added. After stirring at -78 °C for 30 minutes, the reaction was quenched with an aqueous saturated ammonium chloride solution (5 mL). The mixture was then extracted with dichloromethane (3 x 5 mL), the combined organic phases were dried with anhydrous magnesium sulfate and the solvent evaporated under vacuum affording the desired α-chloroketone 2.
With chlorine
With chlorine In acetic acid
With chlorine Yields of byproduct given. Title compound not separated from byproducts;
With p-toluenesulfonyl chloride; lithium diisopropyl amide In tetrahydrofuran -78 deg C to room t., 1 h; Yield given; Yields of byproduct given;
With silica gel; copper(II) nitrate In tetrachloromethane for 0.416667h; Ambient temperature;
95%
With zirconium sulphenyl phosphonate; Glyoxilic acid at 60℃; for 0.5h;
85%
With aluminium trichloride; 1-benzyl-1-aza-4-azoniabicyclo<2.2.2>octane periodate at 20℃; for 0.5h;
85%
With dipotassium peroxodisulfate; 1-n-butyl-3-methylimidazolim bromide at 60 - 70℃; for 0.333333h;
81%
With water; 2,3-dicyano-5,6-dichloro-p-benzoquinone In acetonitrile for 1.5h; Ambient temperature;
71%
With p-benzoquinone; sodium iodide In water; acetonitrile at 100℃; for 19h;
4.3.1 Representative procedure for deprotection of 1,3-dithianes (Table 2, entry 3)
General procedure: A mixture of 2-(2-methoxyphenyl)-1,3-dithiane (1c) (0.11 g, 0.50mmol), 1,4-benzoquinone (64.8 mg, 0.60 mmol), and NaI (0.70 mg, 0.005 mmol) in MeCN (2mL) and H2O (0.2mL) was stirred at 100°C for 24 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent: hexane/AcOEt=15/1) to give 2-methoxybenzaldehyde (2c, 66.5mg, 98%) as colorless oil.
(2E,6E)-4-tert-butyl-2,6-bis(4-chlorobenzylidene)cyclohexanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With nano titania supported sulfonic acid In neat (no solvent) at 90℃; for 0.333333h; Green chemistry;
General procedure for the synthesis of α,α'-bis(substituted-benzylidene)cycloalkanones
General procedure: A mixture of cycloalkanone (1 mmol), aromatic aldehyde (2 mmol) and 0.20 mmol (0.032 g) n-TSA was stirred at 90 °C under solvent-free conditions for an appropriate time. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, eluted with hot ethanol (5 mL) and was centrifuged to filter the catalyst. The title compounds were obtained in their yellowish crystalline forms by recrystallization of ethanol solution.
82%
With sodium hydroxide In ethanol; water at 0 - 20℃;
With trichloroacetic acid at 100℃; for 0.0833333h;
96%
With 1,3-bis(3-sulfopropyl)-1H-imidazol-3-ium hydrogensulfate In water at 100℃; for 1h;
95%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 100℃; for 0.166667h; Microwave irradiation; Sealed vessel;
1. Typical procedure for a T3P mediated Fischer indole synthesis
General procedure: T3P (50% in EtOAc) (0.55-0.68 mmol) was added to a mixture of hydrazine (59 mg, 0.55 mmol) and ketone/aldehyde (0.55 mmol) in a microwave vial. The reaction volume was then made up to 0.5 mL with EtOAc and the vessel was sealed under air. The mixture was heated under microwave irradiation (Biotage Initiator) at 100-150 °C for 5-15 min. The solvent was evaporated under reduced pressure and the oily residue was purified by filtration through a plug of silica gel (eluent: isohexane/EtOAc, 8:2) to yield the desired indole or tetrahydrocarbazole. When the reaction was conducted on a 5 mmol scale the product (3a) was purified by precipitation from acetone/water.
94%
With liquid 1-butyl-3-methylimidazolium hydrosulfate at 70℃; for 1h;
(6-bromo-3-tert-butyl-1,2,3,4-tetrahydro-carbazol-9-yl)-furan2-yl-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: 4-bromophenylhydrazine hydrochloride With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃;
Stage #2: 2-furancarbonyl chloride With pyridine at 80℃;
Stage #3: 4-tercbutyl-cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
89%
Stage #1: 4-bromophenylhydrazine hydrochloride With aldehyde resin; triethylamine In dichloromethane at 45℃;
Stage #2: 2-furancarbonyl chloride With pyridine at 80℃;
Stage #3: 4-tercbutyl-cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃;
EXAMPLE 5A 4-tert-butyl-1-cyclohexen-1-yl trifluoromethanesulfonate A -78 C. solution of 4-tert-butylcyclohexanone (1.54 g, 10 mmol) and N-phenyl(trifluoromethanesulfonamide) (3.75 g, 10.5 mmol) in THF (20 mmol) was treated with 1M NaHMDS in THF (11 mL), warmed to room temperature, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% ethyl acetate/hexanes to provide the desired product.
In tetrahydrofuran; diethyl ether; ethyl acetate;
Example 5A 4-tert-butyl-1-cyclohexen-1-yl trifluoromethanesulfonate A -78 C. solution of 4-tert-butylcyclohexanone (1.54 g, 10 mmol) and N-phenyl(trifluoromethanesulfonamide) (3.75 g, 10.5 mmol) in THF (20 mmol) was treated with 1M NaHMDS in THF (11 mL), warmed to room temperature, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1% ethyl acetate/hexanes to provide the desired product.
With mesitylenesulfonylhydroxylamine In acetonitrile at 20 - 70℃; for 6h;
General procedure for the preparation of amides from ketones
General procedure: To a round bottom flask, equipped with a magnetic stirring bar, was added ketone 1 (0.5 mmol, 1.0 equiv.) and acetonitrile (2 mL) at room temperature. To this stirred solution, freshly prepared O-(Mesitylsulfonyl)hydroxylamine 2 (2.0 equiv.) was added. The reaction mixture was stirred for the specified duration and temperature. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with a saturated aqueous NaHCO3 solution (3 x 5 mL). The combined organic layer was washed with brine solution and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to get the crude product. The reaction that required elevated temperature was stirred first at room temperature for 2 hours after addition of MSH and then heated at 70 °C for the specified time.
85%
With caesium hydroxide monohydrate; copper(II) bis(trifluoromethanesulfonate); hydroxylamine-o-sulphonic acid In dichloromethane; 2,2,2-trifluoroethanol at 20℃; for 14h;
Amides from Ketones
General procedure: To a stirred solution of Cu(OTf)2 (0.05 mmol, 10 mol%) in TFE/CH2Cl2 (1:4, 2-3 mL) were added ketone (0.5 mmol, 1.0 equiv), HOSA (2.0 equiv), and CsOH·H2O (2.0 equiv) at rt. The reaction mixture was maintained at the temperature and for the time indicated in Scheme 2. After completion, the mixture was diluted with CH2Cl2 (10 mL) and washed with sat. aq Na2CO3 (3 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried (anhyd Na2SO4). The crude product obtained after removal of all volatiles in vacuo was purified by SiO2 (100-200 mesh) chromatography using EtOAc/hexane as eluent.
35%
With formic acid; hydroxylamine-o-sulphonic acid at 0 - 100℃; for 16h; Inert atmosphere;
0.42 g
With hydroxylamine; anhydrous Sodium acetate In diethyl ether; water monomer for 2h; Heating;
Multi-step reaction with 2 steps
1: hydroxyamino hydrochloride; anhydrous Sodium acetate / ethanol / 1 h / 80 °C
2: thionyl chloride / 1,4-dioxane / 0.5 h / 20 °C
Multi-step reaction with 2 steps
1: pyridine; hydroxyamino hydrochloride / ethanol / Reflux
2: sodium hydroxide; p-toluenesulfonyl chloride / water monomer; tetrahydrofuran / 24 h / -10 - 20 °C
With palladium on activated charcoal In toluene at 118 - 154℃; for 11.5h; Autoclave;
1.2.2.1-1.2.2.2; 2.2.21-2.2.2.2; 3.2.2.1-3.2.2.2 Substep 2.1
Add 0.5g of palladium-carbon catalyst into a 500mL round-bottom flask, add 250mL of toluene, heat up to 118°C and reflux for 3.5 hours to remove water from the palladium-carbon; Then transfer to a 500mL autoclave, add 106g of p-tert-butylphenol, and hydrogenate at 154°C and 0.8MPa for 8 hours; when the reaction is over, cool to 25°C, filter and remove the palladium-carbon catalyst to obtain the organic phase . Among them, the organic phase contains toluene, p-tert-butyl cyclohexanol, p-tert-butyl cyclohexanone and incompletely reacted p-tert-butyl phenol. Substep 2.2, For the organic phase, first use a water-circulating vacuum pump at a temperature of 45-55°C and a pressure of -0.092MPa to distill off the solvent toluene for 1 hour, and then use a rotary vane mechanical pump to distill with a 280mm packed column at 20mmHg. The by-product p-tert-butylcyclohexanol was recovered at ~113°C (2.2 hours basically completed), and then p-tert-butylcyclohexanone was recovered at 115-117°C for 1.8 hours, 99.0g of p-tert-butylcyclohexanone was recovered, and the content was 98.9%. The yield was 90.5%.
88.5%
With borax; 5%-palladium/activated carbon; hydrogen In water; methyl cyclohexane at 100℃; for 5h; Autoclave;
1 Example 1 Synthesis of 4-tert-butylcyclohexanone
The autoclave was charged with 0.5 g of borax,Water 3.5 g and 5% palladium / carbon catalyst 3 g,After mixing evenly,120 g of p-tert-butylphenol (0.8 mol)And 150 mL of methylcyclohexane,The exhaust inside the kettle,Hydrogen to about 5 atmospheres,Stirring heated to 100 ° C reaction until no hydrogen absorption,About 5h. cool down,Filtration catalyst, atmospheric pressure solvent,The product was distilled under reduced pressure,Yield 88.5%Which contains 4 - tert - butyl cyclohexanone 96.4%Containing cis 4-tert-butylcyclohexanol 1.7%.
80%
With C33H49ClNRh; hydrogen In 2,2,2-trifluoroethanol; water at 70℃; for 24h; Autoclave;
Multi-step reaction with 2 steps
1: nickel / 160 °C / Hydrogenation
2: CrO3
With hydrogen; palladium In water at 100℃; for 8h; Sealed;
With potassium tetrachloropalladate(II); dodecatungstophosphoric acid hydrate; hydrogen In water at 100℃; for 20h;
With 3% Pd/C; hydrogen at 160℃; for 1.3h;
16 Preparation of 4-tert-butylcyclohexanone
Example 16 Preparation of 4-tert-butylcyclohexanone 300 g of tert-butylphenol were dissolved in 125 g of 4-methylpentan-2-ol and hydrogenated at 160° C./6 bar of hydrogen over 1.7 g of a Pd/C catalyst treated with basic magnesium carbonate and sodium carbonate. The hydrogenation time was 1.3 h. The reaction mixture contained 93% of 4-tert-butylcyclohexanone.
With sodium formate In water at 120℃; for 24h; Sealed tube; chemoselective reaction;
With hydrogen In water at 80℃; for 8h;
With hydrogen In water at 75℃; for 6h;
With hydrogen In dichloromethane; water at 100℃; for 20h; Autoclave;
2.3 Hydrogenation of phenol
General procedure: A typical procedure for the hydrogenation of phenol was as follows: phenol (47mg, 0.5mmol), Pd/TiN (2.5-5 mol%) and H2O (2mL), CH2Cl2 (1mL), were placed into a 50mL stainless steel autoclave. The reactor system was purged with N2 three times followed by H2 three times. The autoclave was pressurized with 0.2MPa of H2. The reaction mixture was stirred vigorously at the desired reaction temperature. After a prescribed reaction time, the autoclave was cooled to room temperature and the residue gas was released. The catalyst was removed from the liquid by filtration, and then the organic phase was extracted. The conversion and selectivity were determined by a GC 112A equipped with a FID detector and an SE-54 column (30m×0.25mm×0.25μm film thickness).
With hydrogen In cyclohexane at 25℃; for 10h;
With hydrogen In water at 80℃;
85 %Spectr.
With palladium 10% on activated carbon In tetrahydrofuran; water at 80℃; for 18h;
With hydrogen In dichloromethane at 100℃; for 3h;
2.2 Hydrogenation Reaction
General procedure: The hydrogenation reaction was carried out in the stainless steel reactor equipped with a magnetic stirrer. Amounts of phenol, Pd/C-HPA and solvent were added into the reactor. The reactor was ushed with 0.2MPa H2 for five times to remove air and 1.0MPa H2 was introduced. Then the mixture was heated to a desired temperature and reacted for a certain time. After the reaction was nished, the reactor was cooled to room temperature and depressurized. The reaction mixture was centrifuged to separate the catalysts and got the product mixture. The separated catalysts were directly used in the recycle experiments. The sample of the upper layer were characterized qualitatively with HP6890/5973 GC/MS equipped with an HP-5MS column, 30m × 0.25mm × 0.25μm, and its quantitative analysis were determined by GC using HP6890 GC equipped with an HP-5 column, 30m × 0.32mm × 0.25μm. The contents of the reactants and products were directly showed by the system of GC chemstation according to the area of each chromatograph peak. The conversion of phenol was dened as Conv.%, which was the wt% of phenol consumed in the reaction. The selectivity of one product was calculated by Sel.% = Wp/Wall × 100, where Wp was the mass of one product, and Wall was the total mass of all products, including cyclohexanone and cyclohexanol. All the experiments were repeated for five times to conrm the results eectiveness.
With hydrogen In ethanol at 100℃; for 6h; Autoclave;
With 1,3-bis(3-sulfopropyl)-1H-imidazol-3-ium trifluoromethanesulfonate In water at 100℃; for 0.25h; Microwave irradiation; Green chemistry;
3 4.3 Representative procedure for the one-pot Fischer indole synthesis
General procedure: Cyclohexanone (0.91 g, 10.0 mmol) was mixed with [(HSO3- p)2im][CF3SO3] (0.5 mmol) in water (15 mL), and phenylhydrazine hydrochloride (1.44 g, 10.0 mmol) was added. The mixture was then stirred at 100 8C for about 15 min under microwave irradiation. Reaction progress was monitored by GC-MS. After completion, the reaction mixture was cooled to room temperature, and 1,2,3,4-tetrahydrocarbazole was obtained by filtration. The remaining mixture of [(HSO3-p)2im][CF3SO3]/H2O was reused directly.
64%
With silica gel at 20℃; for 6h; Milling;
General Procedure: Mechanochemical Fischer Indolisation
General procedure: The phenylhydrazine salt, cyclohexanone and silica were added to a stainless-steel jar (12 mL)containing 29 balls (5 mm). The rotation speed of the planetary disk was set at 600 rpm and the reaction mixture ball-milled for the time specified. Rotation intervals (typically 5 min) were applied to ensure efficient mixing. At the conclusion of the reaction, the resulting solid was suspended in ethyl acetate and Na2SO4 was added. The mixture was filtered and the filtrate concentrated under reduced pressure to give a crude product that was purified by flash chromatography on silica gel eluting with the solvent(s) stated.
55%
In acetic acid at 20 - 70℃;
1.1
Phenyl hydrazine hydrochloride (3Og, 0.28mol), tert-butyl cyclohexanone (42.79g, 0.28mol) and acetic acid (60OmL) were added to a round bottom flask, equipped with a nitrogen line and condenser. The reagents were stirred at room temperature for 30 mins and then warmed to 300C. After 20 mins, the heating was increased to 350C and held at this temperature. After 30mins, the heating was increased to 4O0C for a further 6 hours and then warmed to 7O0C overnight. The reaction mixture was allowed to cool to room temperature and then toluene was added. The organic phase was washed with water, NaHCO3 and finally water. The solvent was evaporated and the product recrystallized from hexane. Yielding 24.29g (~55% yield) of desired material.
With BF3.OEt2; diethylaminosulfur trifluoride In dichloromethane
20.a (a)
(a) Fluorination with DAST A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2 Cl2 (10.0 mL) was added to diethylaminosulfur trifluoride (483 mg, 3.0 mmol) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2 SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 67% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
67%
With BF3.OEt2; diethylaminosulfur trifluoride In dichloromethane
20.a (a)
(a) Fluorination with DAST A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2Cl2 (10.0 mL) was added to diethylaminosulfur trifluoride (483 mg, 3.0 mmol) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 67% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
20.b (b)
A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2 Cl2 (10.0 mL) was added to N-ethyl-N-phenylaminosulfur trifluoride (627 mg, 3.0 mmol) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 99% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
99%
With BF3.OEt2 In dichloromethane
20.b (b)
A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2Cl2 (10.0 mL) was added to N-ethyl-N-phenylaminosulfur trifluoride (627 mg, 3.0 mmol) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 99% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4.5]decane[ No CAS ]
[ 7646-78-8 ]
[ 98-53-3 ]
[ 3132-64-7 ]
8-tert-Butyl-2-(perhydroisoquinolinomethyl)-1,4-dioxaspiro[4.5]decane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; potassium carbonate; In dichloromethane; water; acetonitrile;
PREPARATION EXAMPLE 1 8-tert-Butyl-2-(perhydroisoquinolinomethyl)-1,4-dioxaspiro[4,5]decane (compound No. 1.1) 10 g (34 mmol) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane, 5.2 g (37.4 mmol) of <strong>[2744-08-3]perhydroisoquinoline</strong> (isomer mixture) and 4.7 g (34 mmol) of potassium carbonate in 100 ml of acetonitrile were refluxed for 16 hours. The solvent was distilled off under reduced pressure, the resulting residue was taken up with dilute 5% strength NaOH and methyl tert-butyl ether, and the organic phase was washed twice with water, dried over Na2 SO4 and evaporated down under reduced pressure. Fractionation of the crude product under reduced pressure gave 4.9 g of compound 1.1 (bp. 170 C., 0.5 mbar). Preparation of the starting compound STR8 30.15 g (120 mmol) of tin(IV) chloride were added dropwise to 115.5 g (750 mmol) of 4-tert-butylcyclohexanone in 700 ml of absolute dichloromethane at 5 C., followed by the dropwise addition of 205.5 g (1.5 mol) of epibromohydrin STR9 in 370 ml of absolute dichloromethane in the course of 5 hours. The mixture was stirred overnight at room temperature (20 C.), hydrolyzed with a solution of 42 g of KOH in 180 ml of water while cooling, and worked up in a conventional manner. Distillation of the crude product (279 g) under reduced pressure gave 169 g (77.5%) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane of boiling point 110 C./0.2 mbar.
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; C45H38FeNO2P; lithium tert-butoxide In ethanol; isopropyl alcohol at 20℃; Inert atmosphere; Glovebox;
16; 21 Example 16 Preparation of cis-4-tert-butylcyclohexyl acetate by selective hydrogenation of 4-tert-butylcyclohexanone using Ir-L1-(S,R)-f-ambinol catalyst
In an argon glove box, the ligands L1-(S,R)-f-ambinol (7.5mg, 0.0105mmol) and [Ir(COD)Cl]2 (3.4mg, 0.005mmol) were added to a 2mL vial Inside, it was dissolved in iPrOH (1 mL) and stirred at room temperature for 2 h. The raw material 4-tert-butylcyclohexanone (1 mmol) was put into a 4 mL hydrogenation bottle. Then, add 0.1 mL of the in-situ complexed catalyst solution and 1.6 mg of tBuOLi solid powder to the hydrogenation flask, and finally add 1 mL of EtOH to dissolve the reactants, and then put the reaction flask into the hydrogenation kettle, replace the kettle with hydrogen for three times and then fill it. Add 5bar H2 and react at room temperature for 12h. After the reaction is completed, the hydrogen is released carefully, the solvent is spin-dried under reduced pressure, and purified by silica gel column to obtain the hydrogenated product 4-tert-butylcyclohexanol, a white solid powder, >99% conversion, >99% yield, cis/trans>20:1.
20%
With manganese; water; 2,4,6-collidine hydrochloride In tetrahydrofuran at 20℃;
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 20℃; for 6h;
2
Example 2: General procedure for catalytic hydrogenation of ketones and aldehydes; In a typical catalytic hydrogenation procedure, a weighed amount of the respective ruthenium catalyst and KO1Bu were added to a solution of the substrate in 2-propanol under hydrogen gas. The pressure was adjusted to the desired value and the reaction progress was monitored using TLC or NMR. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The alcohols were purified by filtering a hexane solution of the crude product through a pad of silica, then removing the hexane under reduced pressure. The conversion and purity of the alcohol products was assessed using NMR. Discussion The ruthenium aminophosphine complexes RuCI2(Ph2PCH2CH2NH2)2(1) and RuCI2(R-binap)(Ph2PCH2CH2NH2) (2) were prepared as previously described.7 Table 1 shows the hydrogenation of ketones using the ruthenium- aminophosphine complex, RuCl2(/-Pr2PCH2CH2NH2)2 (3), to prove its efficacy as a catalyst for hydrogenation.Table 2 shows the hydrogenation of 4-tert-butylcyclohexanone using catalysts (1), (2) and (3) (see Figure 2) in the presence of a base. Catalyst (3) shows a cis:trans selectivity of 96:4 for the production of cis-4-tert- butylcyclohexanol.The results show that the ruthenium-aminophosphine complexes of the present disclosure represent a very effective class of catalysts for hydrogenation of 4-tert-butyl cyclohexanone. The ketone was readily converted to the alcohol using each of the complexes (1 , 2 and 3) as catalyst in the presence of base. Good selectivity was obtained for the desired cis-4- tert-butyl cyclohexanol, in particular with catalyst 3.
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 20 - 50℃; for 2 - 24h;
2; 3
Example 2: General procedure for catalytic hydrogenation of ketones and aldehydes; In a typical catalytic hydrogenation procedure, a weighed amount of the respective ruthenium catalyst and KO1Bu were added to a solution of the substrate in 2-propanol under hydrogen gas. The pressure was adjusted to the desired value and the reaction progress was monitored using TLC or NMR. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The alcohols were purified by filtering a hexane solution of the crude product through a pad of silica, then removing the hexane under reduced pressure. The conversion and purity of the alcohol products was assessed using NMR. Discussion The ruthenium aminophosphine complexes RuCI2(Ph2PCH2CH2NH2)2(1) and RuCI2(R-binap)(Ph2PCH2CH2NH2) (2) were prepared as previously described.7 Table 1 shows the hydrogenation of ketones using the ruthenium- aminophosphine complex, RuCl2(/-Pr2PCH2CH2NH2)2 (3), to prove its efficacy as a catalyst for hydrogenation.Table 2 shows the hydrogenation of 4-tert-butylcyclohexanone using catalysts (1), (2) and (3) (see Figure 2) in the presence of a base. Catalyst (3) shows a cis:trans selectivity of 96:4 for the production of cis-4-tert- butylcyclohexanol.The results show that the ruthenium-aminophosphine complexes of the present disclosure represent a very effective class of catalysts for hydrogenation of 4-tert-butyl cyclohexanone. The ketone was readily converted to the alcohol using each of the complexes (1 , 2 and 3) as catalyst in the presence of base. Good selectivity was obtained for the desired cis-4- tert-butyl cyclohexanol, in particular with catalyst 3.; Example 3: Catalytic Hydrogenation of 4-tert-butylcyclohexanone with RuCI2(i-; (a) Substrate:Catalyst Ratio of 10, 000: 1A weighed amount of the catalyst (3.2 mg, 0.0065 mmol) and KO'Bu (100 mg) were added to a solution of the substrate (10.0 g, 65 mmol) in 2-propanol in a 100 ml Parr pressure reactor under a flow of argon. The mixture was degassed with argon and then with hydrogen. It was finally pressurized to 10 atm. of hydrogen and stirred at the desired temperature. Yields are based on the amount of substrate and are shown in Table 3.(b) Substrate:Catalyst Ratio of 100,000:1A weighed amount of the catalyst (5 mg) was dissolved in 10.0 ml of 2- propanol. An aliquot of 1.0 ml of the diluted catalyst solution (0.5 mg of catalyst, 0.001 mmol) and KO1Bu (150 mg) were added to a solution of the substrate (15.6 g, 101 mmol) in 2-propanol in a 100 ml Parr pressure reactor under a flow of argon. The mixture was de-gassed with argon and then with hydrogen. It was finally pressurized to 10 atm. of hydrogen and stirred at the desired temperature. Yields are based on the amount of substrate and are shown in Table 3.(c) Substrate:Catalyst Ratio of 500,000:1 A weighed amount of the catalyst (5 mg) was dissolved in 10.0 ml of 2- propanol. An aliquot of 1.0 ml of this catalyst solution was further diluted to 10.0 ml with 2-propanol. An aliquot of 2.0 ml of the dilute catalyst solution (0.1 mg, 0.0002 mmol) and KO1Bu (150 mg) were added to a solution of the substrate (15.6 g, 101 mmol) in 2-propanol in a 100 ml Parr pressure reactor under a flow of argon. The mixture was de-gassed with argon and then with hydrogen. It was finally pressurized to 10 atm. of hydrogen and stirred at the desired temperature. Yields are based on the amount of substrate. (d) Substrate:Catalyst Ratio of 1,000,000:1 A weighed amount of the catalyst (5 mg) was dissolved in 10.0 ml of 2- propanol. An aliquot of 1.0 ml of this catalyst solution was further diluted to 10.0 ml with 2-propanol. An aliquot of 1.0 ml of the dilute catalyst solution (0.05 mg, 0.0001 mmol) and KO1Bu (150 mg) were added to a solution of the substrate (15.6 g, 101 mmol) in 2-propanol in a 100 ml Parr pressure reactor under a flow of argon. The mixture was de-gassed with argon and then with hydrogen. It was finally pressurized to 10 atm. of hydrogen and stirred at the desired temperature. Yields are based on the amount of substrate. Discussion Table 3 shows the hydrogenation of 4-tert-butylcyclohexanone using catalyst (3) in varying substrate: catalyst ratios, in the presence of a base. Catalyst (3) shows a cis:trans selectivity of at least 95:5 for the production of cis-4-tert- butylcyclohexanol, and 100% conversion for the 10,000/100,000/500,000:1 ratios of substrate:catalyst.
With trans-{RuCl2(1,3-bis(diphenylphosphino)propane)2}; potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 25℃; for 3h; optical yield given as %de; stereoselective reaction;
at 45℃; for 22h;
With (2,6-dichlorophenyl)bis(2,3,5,6-tetrafluorophenyl)borane; hydrogen In 1,4-dioxane at 50℃; for 112h;
With Zrβ-F-100 In isopropyl alcohol at 82℃; for 6h; stereoselective reaction;
With dihydrogen peroxide In water; acetonitrile at 20℃; for 0.166667h; Green chemistry;
Synthesis of 1,2,4,5-tetraoxanes; general procedure
General procedure: To a mixture of carbonyl compound (1 mmol) and HPA/NaY (0.01 g) in CH3CN (3 mL), gem-dihydroperoxide (1 mmol) was added and the mixture stirred at room temperature for the appropriate time (Table 5). After completion of the reaction, as monitored by TLC, the catalyst was separated by centrifuge and the solvent was evaporated under reduced pressure. The residue was purified by silica-packed column chromatography (hexane-EtOAc) to afford pure 1,2,4,5-tetraoxanes (Table 5, 71-92% yields). All of the products were characterised on the basis of IR, 1H NMR and 13C NMR spectral analysis, elemental analysis and by their melting points.
81%
With rhenium(VII) oxide In dichloromethane at 20℃; for 0.5h;
70%
With phosphomolybdic acid In dichloromethane at 20℃;
2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With morpholine; sulfur In ethanol at 70℃; for 12h; Inert atmosphere;
2-Amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (8c)
To a suspension of 2-cyanoacetamide (3.0g, 35.7mmol), 4-tert-butylcyclohexanone (5.8mL, 35.7mmol), and morpholine (7.1mL, 71.4mmol) in EtOH (60.0mL) was added sulfur (1.1g, 35.7mmol) at room temperature. The reaction mixture was stirred at 70°C for 12h. The reaction mixture was cooled to room temperature, diluted with EtOAc and quenched with H2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in CH2Cl2 and collected by adding Et2O. The resulting solid was collected to afford 8c (5.2g, 69%) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 6.91 (s, 1H), 6.48 (brs, 1H), 2.66 (m, 1H), 2.59 (m, 1H), 2.44 (m, 1H), 2.23 (m, 1H), 1.91 (m, 1H), 1.39 (m, 1H), 1.17 (m, 2H), 0.89 (s, 9H); 13C NMR (100MHz, DMSO-d6) δ 167.87, 159.34, 129.94, 116.08, 107.08, 44.55, 32.14, 27.10, 26.99, 25.62, 24.18; LRMS (ESI) m/z 247 [M+ H]+. HRMS (ESI) m/z calculated for C13H21N2OS+ [M+ H] +: 253.13. Found: 253.1505.
28%
With morpholine; sulfur In ethanol at 120℃; for 0.25h; Microwave irradiation; Sealed tube;
2-Amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide
Butylcyclohexanone (500 mg, 3.24 mmol), 2-cyanoacetamide (409 mg, 4.86 mmol, 1.5 equiv), sulfur (104 mg, 3.24, 1.0 equiv) and morpholine (282 mg, 4.86 mmol, 1.5 equiv) were combined in ethanol (3 mL) in a microwave vial and sealed. The reaction was heated at 120° C for 15 minutes under microwave irradiation then cooled to rt. The solvent was removed in vacuo and the resulting residue purified by medium pressure silica gel chromatography to afford the thiophene product as a light yellow solid (227 mg, 0.90 mmol, 28% yield). Rf = 0.48 (10% MeOH in CH2Cl2); mp = 223-226 °C; 1H NMR (401 MHz, DMSO-d6) δ 0.87 (s, 9H), 1.16 (dq, J = 5.2, 12.1 Hz, 1H), 1.34-1.41 (m, 1H), 1.90 (dd, J = 2.5, 12.4 Hz, 1H), 2.22 (t, J = 14.8 Hz, 1H), 2.41-2.58 (m, 2H), 2.66 (dd, J = 4.9, 16.0 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 24.6, 26.1, 27.4, 27.6, 32.6, 45.0, 107.5, 116.5, 130.4, 159.8, 168.3; IR 3304, 2952, 1628, 1556 cm-1; HRMS calcd. for C13H21N2OS [M + H]+ 253.1369, found 253.1358.
With ammonium cerium (IV) nitrate In methanol at 20℃; for 1h;
88%
With 1-butyl-3-methylimidazolium hydrogen sulfate at 70℃; for 3h; neat (no solvent);
87%
With (Bu4N)2S2O8 In neat (no solvent) at 20℃; for 1h;
Ethyl-2-methyl-4-phenylquinoline-3-carboxylate (3a) (typical procedure)
General procedure: A mixture of o-aminobenzophenone (1.97 g, 10 mmol), ethyl acetoacetate (1.30 g, 10 mmol), and (Bu4N)2S2O8, (0.108 g, 25 mol%) was stirred at ambient temperature under solvent-free conditions for the appropriate time (Table 1) until starting material could no longer be detected by TLC (petroleum ether/EtOAc, 9:1). After completion of the reaction, the mixture was diluted with ethyl acetate (30 mL), washed with water (15 mL), dried (Na2SO4), and concentrated. The residue was purified by silica-gel column chromatography (10% ethyl acetate in hexane) to afford the pure product 3a as a pale yellow solid (2.76 g, 95%).
86%
With Nafion NR50 In ethanol at 200℃; for 1h; Microwave irradiation;
Quinoline Derivatives 1, 5, and 6; General Procedure
General procedure: A mixture of 2-aminobenzophenone 2 (1.0 mmol), ketone 3 or 4 (1.1 mmol), and Nafion NR50 (20 mol%) in ethanol (10 mL) was loaded into a dried 35 mL microwave vial at 25 °C. The mixture was subjected to microwave irradiation and stirred at 200 °C for 1 h. Consumption of the starting materials was confirmed by TLC. The mixture was cooled to 25 °C and then transferred to a 100 mL round-bottom flask; the solvent was concentrated under reduced pressure to afford crude product. The solid crude product was recrystallized (hexane-EtOAc, 5:1 to 2:1). The oily or gummy crude product was purified by column chromatography (silica gel, hexanes-EtOAc, 4:1 to 1:1). This afforded products 1a-ac, 5a-k, and 6a-p.
82%
With sulfuric acid-modified polyethylene glycol 6000 at 130℃; for 0.15h; Microwave irradiation; Neat (no solvent);
With Cs2CO3 In 1,4-dioxane; toluene regioselective reaction;
83%
Stage #1: 4-tercbutyl-cyclohexanone With pyridine In dichloromethane for 0.333333h; Cooling with ice;
Stage #2: trifluoromethylsulfonic anhydride In dichloromethane for 6.5h; Cooling with ice; Reflux;
2.1-2.5 A preparation method of enol trifluoromethanesulfonate, including the following quality materials:
1-tert-butyl-4cyclohexanone, 3.08g, 0.02mol, the structural formula is as follows: Tf2O, 7.90g, 0.028mol; Pyridine, 1.90g, 0.024mol; Dichloromethane, 30mL; The molar ratio of raw materials: 1-tert-butyl-4 cyclohexanone: Tf2O: pyridine=1:1.4:1.2. The synthesis steps are: (1) Under ice bath conditions, completely dissolve 3.08g of 0.02mol 1-tert-butyl-4cyclohexanone in 30mL of dichloromethane, then add 0.024mol of pyridine, and fully stir for 20 minutes; (2) Slowly add 0.02mol of trifluoromethanesulfonic anhydride dropwise to the solution, and continue to keep stirring in an ice bath for 30 minutes (the solution will gradually become viscous at this time), Then remove the ice bath, slowly warm up to room temperature, and stir at room temperature until the mixed solution can flow fully. (3) The mixture is heated to reflux, and after refluxing for 4 hours, 0.004 mol of trifluoromethanesulfonic anhydride is added to the reaction, and refluxing is continued for 1 hour. Then add 0.004 mol of trifluoromethanesulfonic anhydride to the reaction, continue to reflux for 1 hour, then detect the result of the reaction with a thin layer chromatography silica gel plate, and stop the reaction after the ketone raw material has reacted. The product was tested with thin-layer chromatography silica gel plate, the developing solvent was petroleum ether, Rf=0.7. (4) After the reaction, the reaction was quenched with distilled water, and then saturated sodium bicarbonate solution was added dropwise until no obvious gas was released. (5) The reaction was extracted with 3×20 mL of dichloromethane, the organic layer was collected, and the organic solvent was removed by rotary distillation to obtain a crude product. Purification by thin-layer chromatography on a silica gel column gave the final solid product 4.75 g of 4-tert-butylcyclohexenol trifluoromethanesulfonate, with a yield of 83%.
81%
Stage #1: 4-tercbutyl-cyclohexanone With 2-chloropyridine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere;
Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;
80%
With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; for 16h;
77%
Stage #1: trifluoromethylsulfonic anhydride; 4-tercbutyl-cyclohexanone With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃;
Stage #2: In n-Pentane for 0.5h; Reflux;
4-tert-Butylcyclohex-1-enyl trifluoromethanesulfonate (7)
Following the published procedure,8 a cold (0 °C), stirred solution of 4-tert-butylcyclohexanone (1.50 g, 9.72 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2.26 g, 13.3 mmol) in CH2Cl2 (75 mL) was treated with Tf2O (1.8 mL, 10.7 mmol) via syringe. The reaction mixture was allowed to warm to rt over 8-12 h at which time the reaction solvent was removed and pentane (75 mL) was added. The reaction mixture was refluxed for 30 min, cooled and the resulting precipitate removed by filtration and washed with pentane (5x20 mL). The filtrate was washed with 10% HCl (2x50 mL), 10% NaOH (50 mL), brine and dried (MgSO4). Filtration, concentration of the filtrate in vacuo followed by bulb to bulb distillation gave compound 7 (2.14 g, 77%) as a colourless oil: bp 50-55 °C / 0.05 mm Hg (Lit.8 bp 75-80 °C / 0.5 mm Hg).
51%
With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 20℃; Cooling with ice;
1.1
Example 1; 8-tert-Butyl-6,7,8,9-tetrahydro-5H-pyrido[4,3-b]indole Trifluoromethanesulfonic acid 4-tert-butyl-cyclohex-1 -enyl esterTo an ice-cooled solution of 4-tert-butylcyclohexanone (17.0 g, 1 10.5 mmol) and 2,6- di-tert-butyl-4-methylpyridine (26.63 g, 129.7 mmol) in DCM (575 ml), was added dropwise trifluoromethanesulfonic anhydride (37.6 g, 133.3 mmol). After completion of the addition, the mixture was stirred and allowed to warm up to room temperature overnight. The resulting white precipitate was filtered off and washed with a small amount of heptane. The solution was washed with 1 N HCI (aq), 1 N NaOH (aq) and brine, respectively. The organic phase was concentrated and subjected to chromatography (silica gel, eluting with 100% heptane), to afford trifluoromethanesulfonic acid 4-tert-butyl-cyclohex-1 -enyl ester as a clear oil (16.23 g, 51 %).
With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; for 10h; Inert atmosphere;
With anhydrous sodium carbonate In dichloromethane at 20℃; for 24h;
Stage #1: 4-tercbutyl-cyclohexanone With 2-chloropyridine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere;
Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at 0 - 20℃; Inert atmosphere;
8-tert-butyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrido[4,3-b]indole trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1%
Stage #1: 4-amino-3-chloro-5-iodopyridine; 4-tercbutyl-cyclohexanone With potassium <i>tert</i>-butylate; magnesium sulfate; acetic acid In N,N-dimethyl acetamide at 140℃; Inert atmosphere;
Stage #2: trifluoroacetic acid In water; acetonitrile
6
Example 6; 8-tert-Butyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrido[4, 3-b]indoleA suspension of 3-chloro-4-amino-5-iodopyridine (2.0 g, 7.87 mmol), 4-tert- butylcyclohexanone (3.64 g, 23.6 mmol), potassium tert-butoxide (1 .148 g, 10.23 mmol), MgSO4 (0.474 g, 3.94 mmol) and acetic acid (0.708 g, 1 1 .8 mmol) in DMA (25 ml) was bubbled with N2 before Pd(OAc)2 (88 mg, 0.393 mmol) was added. The mixture was heated overnight at 140°C. The reaction mixture was partitioned with H2O/EtOAc (100 ml/100 ml). The aqueous phase was extracted with EtOAc (100 ml x 5). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was subjected to preparative HPLC (ds, eluting with CH3CN in H2O with 0.1 % TFA). The title compound was obtained as a TFA salt (38mg, 1 %).
With tetrakis(acetonitrile)palladium(II) tetrafluoroborate; [bis(acetoxy)iodo]benzene; p-benzoquinone In dimethyl sulfoxide at 35℃; for 24h;
1: 72%
2: 18%
Stage #1: 4-tercbutyl-cyclohexanone With bis(2,2,6,6-tetramethyl-1-piperidyl)zinc In toluene at 0℃; for 0.166667h; Inert atmosphere;
Stage #2: With bis(η3-allyl-μ-chloropalladium(II)); allyl diethyl phosphate In toluene at 0 - 120℃; for 2h; Inert atmosphere; Sealed tube;
1: 37.7%
2: 15.7%
With oxygen; palladium diacetate; scandium tris(trifluoromethanesulfonate) In acetonitrile at 79.84℃; for 24h;
General procedure for indoline dehydrogenation reaction by Pd(OAc)2 with Zn(OTf)2
Pd(OAc)2 (1.12 mg, 0.005 mmol), Zn(OTf)2 (3.63 mg, 0.01 mmol) were dissolved in 5 mL acetonitrile in a glass tube, after stirring for 10 min, indoline (60 mg, 0.5 mmol) were added. The glass tube was equipped with a reflux condenser. Next, the reaction solution was magnetically stirred at 353K in oil bath for 6 h with O2 balloon. The product analysis was performed by GC using the internal standard method. Control experiments including using Pd(OAc)2, or Zn(OTf)2 alone were carried out in parallel.
1: 34 %Chromat.
2: 56 %Chromat.
With palladium(II) trifluoroacetate; oxygen; dimethyl sulfoxide at 80℃; for 12h;
1: 91 %Chromat.
2: 8 %Chromat.
With palladium(II) trifluoroacetate; oxygen; acetic acid; dimethyl sulfoxide at 80℃; for 12h;
In tetrahydrofuran at -78℃; for 2h; Inert atmosphere;
4.3 Organocatalytic enantioselective deprotonation of prochiral cyclohexanones 4.3.1 General procedure II
General procedure: To a solution of cyclohexanone 2a-f (0.25mmol) and QN+1, 4-MeOC6H4O- (0.0125mmol, 7mg) in THF (0.25mL) at -78°C was added BSA (0.375mmol, 92μL) as a solution in THF (0.25mL). The reaction mixture was stirred at the same temperature for 2h. The conversion was measured by GC-FID. Next, 100μL of a saturated solution of NaHCO3 was added at -78°C. The reaction mixture was dried over Na2SO4, filtered and concentrated. The crude product 3a-f was purified on silica gel by using petroleum ether/Et2O (95:5) as eluent and then subjected to GC-FID analysis using chiral column in order to determine the enantiomeric excess.
With trimethylsilylazide In methanol at 20℃; for 24h; stereoselective reaction;
2 5b: N'-((1RS,4RS)-4-tert-Butyl-1-(1-tert-butyl-1H-tetrazol-5-yl)cyclohexyl)thiophene-2-carbohydrazide
General procedure: To a solution of hydrazide 1 (1mmol), ketone 2 (1mmol), isocyanide 3 (1.2mmol) and trimethylsilyl azide 4 (1mmol) in 8mL MeOH was added. The mixture was stirred for 24h at ambient temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 1:3), the solvent was removed under vacuum, and the residue was precipitated by addition of 3mL of EtOH and 1mL of H2O. The precipitate was filtered off and then crystallized from ethanol. Yield (222 mg, 55%) as a white solid; mp 242-244 °C; Rf (33% EtOAc/Hexane) 0.25; νmax (KBr) 3283, 3116, 2954, 1634, 1473 cm-1; δH (300 MHz, CDCl3) 0.91 (s, 9H, Ht-Bu), 1.08-1.72 (m, 5H, HCyclohexyl), 1.89 (s, 9H, Ht-Bu), 1.99-2.10 (m, 2H, HCyclohexyl), 2.46-2.50 (m, 2H, HCyclohexyl), 5.95 (br s, 1H, NH), 6.99 (br s, 1H, HThienyl), 7.45 (d, 1H, J 4.5 Hz, HThienyl), 7.66 (br s, 1H, HThienyl), 8.82 (br s, 1H, NH); δC (75 MHz, CDCl3) 21.9, 27.5, 31.1, 32.4, 33.9, 46.9, 59.8, 65.1, 127.6, 128.1, 129.9, 137.1, 160.0, 160.2. HRMS (ESI): [M+H]+ found 405.24318 C20H33N6OS requires 405.24320, [M+Na]+ found 427.22514 C20H32N6NaOS requires 427.22516.
tert-butyl ((R)-1-(2-((1S,4S)-4-tert-butyl-1-(1-cyclohexyl-1H-tetrazol-5-yl)cyclohexyl)hydrazinyl)-1-oxo-3-phenylpropan-2-yl)carbamate[ No CAS ]
C31H49N7O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With trimethylsilylazide; In methanol; at 20℃; for 24.0h;
General procedure: To a solution of hydrazide 1 (1mmol), ketone 2 (1mmol), isocyanide 3 (1.2mmol) and trimethylsilyl azide 4 (1mmol) in 8mL MeOH was added. The mixture was stirred for 24h at ambient temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 1:3), the solvent was removed under vacuum, and the residue was precipitated by addition of 3mL of EtOH and 1mL of H2O. The precipitate was filtered off and then crystallized from ethanol. Yield (369 mg, 65%) as a white solid; mp 188-189 C; Rf (33% EtOAc/Hexane) 0.36; numax (KBr), 3350, 3293, 3096, 2965, 1719, 1680, 1504 cm-1; deltaH (300 MHz, CDCl3) 0.91 (s, 9H, Ht-Bu), 1.00-2.09 (m, 19H, Hcyclohexyl), 1.32 (s, 9H, Ht-Bu), 3.00 (m, 2H, CH2), 4.16-4.24 (m, 1H, CHN), 4.88-4.90 (m, 1H, CH), 5.28 (d, 1H, J 7.0 Hz, NH), 7.10-7.30 (m, 6H, HAr, NH), 7.53 (br s, 1H, NH); deltaC (75 MHz, CDCl3) 21.6, 21.8, 24.9, 25.6, 27.4, 28.1, 31.7, 32.4, 32.6, 33.4, 33.5, 46.9, 58.1, 59.3, 80.4, 127.0, 128.6, 129.1, 136.2, 157.0, 170.0; HRMS (ESI): [M+H]+ found 568.39664 C31H50N7O3 requires 568.39658; [M+Na]+ found 590.37859 C31H49N7NaO3 requires 590.37854.
(2S,4S)-4-(tert-butyl)-2-((R)-1-hydroxy-2,2-dimethoxyethyl)-cyclohexanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 48h;
General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product.
With zinc(II) oxide In water at 20℃; for 1.08333h; Green chemistry;
General procedure for the preparation of nitrones 4a-h and 5a-f
General procedure: DAG (0.12 g, 1 mmol), aldehyde (1.2 mmol) or ketones (1.2 mmol) and ZnO NPs(0.034 g, 0.2 mmol) were added to a solution of water (3 mL), and the mixture was stirred at room temperature for an appropriate time. The progress of the reaction was monitored by thin layer chromatography (TLC; ethyl acetate/n-hexane 7:3). The precipitated solid was filtered, dried, washed with petroleum ether to remove any residual starting material and then recrystallized from methanol to afford the pure product. The catalyst could be recovered after evaporation of the aqueous layer, then reused in subsequent reactions without any significant loss of activity. The products were identified by physical data (mp) by comparison with those reported in the literatures.
Stage #1: 2-thienylhydrazide; isatoic anhydride In neat (no solvent) at 120℃; for 0.25h; Green chemistry;
Stage #2: 4-tercbutyl-cyclohexanone With propyl sulfonic acid functionalized SBA-15 In neat (no solvent) at 120℃; for 0.25h; Green chemistry;
General procedure for the synthesisof spiroquinazolinones (4a-j)
General procedure: Synthesis of spiroquinazolinones 4a-j was accomplishedthrough one-pot three-component reaction of isatoic anhydride1, hydrazides 2a-c, and ketones 3a-f. Isatoic anhydride(1 mmol), hydrazide derivatives (1 mmol) was heatedfor 15 min under solvent-free conditions at 120 °C. Then,ketone (1.2 mmol) and SBA-Pr-SO3H (0.02 g) were addedto the mixture. The stirred mixture was heated under solventfreecondition at 120 °C for 15 min (Table 1, entry 2). Aftercompletion of the reaction, the mixture was dissolved in hotEtOH to remove the heterogeneous catalyst. After a simple filtration,cold water was added slowly to obtain pure precipitateof the product. Then, the obtained precipitate was filtered. Thecatalyst was washed subsequently with hot EtOH, diluted acidsolution, distilled water and then acetone, dried under vacuumand re-used for several times without significant loss of activity.The spectral data of new compounds are given below:
1-{2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl}ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With piperidine; octasulfur; In methanol; at 55 - 65℃; for 24h;
General procedure: 3-Acetyl-2-aminothiophene Derivatives; General Procedure Carbonyl compound (0.025 mol) was added to freshly prepared cya-noacetone (0.03 mol) in either MeOH or EtOH (40 mL). Sublimed sul-fur S8 (0.03 mol) and piperidine (0.03 mol) were added and the mix-ture was stirred and heated to 55-65 C for 24 h. Ice was then addedand the formed precipitate was filtered under vacuum and washedwith water. The obtained solid was crystallised from a suitable sol-vent, with the exception of 4g and 4j, which were collected directlywithout further purification.
4-(2-(4-tert-butylcyclohexyl)-1,2-dihydro-4-oxoquinazolin-3(4H)-yl)-3-(4-chlorophenyl)butanoic acid[ No CAS ]
C28H35ClN2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propyl sulfonic acid-functionalized SBA-15; In neat (no solvent); at 110℃; for 2h;
General procedure: To the mixture of isatoic anhydride (160 mg, 1 mmol),gabapentin or baclofen (1 mmol), and aromatic aldehyde(1 mmol), SBA-Pr-SO3H (0.02 g) was added, and then itwas stirred at 110 C for an appropriate period of time.After completion of the reaction, the mixture of productswas dissolved in hot EtOH to remove the heterogeneouscatalyst. Then, the solvent was evaporated and extractedusing EtOAc and then washed with water. Some productscontained a mixture of two diastereoisomers. Further purificationwas done using crystallization in water/EtOH (1:4).
17.7 g of a mixture of 4-tert-butylcyclohexylacetonitrile and 4-tert-butylcyclohexenylacetonitrile obtained in Example 4,Styrene 350mg,Toluene 80mL was added to a four-necked flask,Nitrogen for 5min,6.0 g of a 10% palladium / carbon catalyst was added,Under normal pressure reflux reaction 24h,While slowly passing nitrogen.After completion of dehydrogenation, the catalyst was filtered off and the catalyst was filtered off. The solvent was distilled off under reduced pressure and the residue was recrystallized to give p-tert-butylbenzeneacetonitrile in a yield of 95% and 98.6%.
4-tert-butylcyclohexanone (5-chloropyridin-2-yl)hydrazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In ethanol; for 0.5h;Reflux;
General procedure: A solution of the appropriateketone (4.0 mmol) in ethanol (7 ml) was added to asolution of hydrazine 1 (0.574 g, 4.0 mmol) in ethanol(5 ml), and the mixture was refluxed for 30 min. Thesolvent was removed by distillation until constant mass,producing the corresponding hydrazone 5a-p. Theobtained reaction residue was treated with polyphosphoricacid (5 g),12 stirred and heated to 160 (beginning of anexothermic reaction), and maintained at 160-180 untilthe foaming stopped (~5 min). After cooling to ~40, thereaction mixture was suspended in water (30 ml), cooled to0-5C, and adjusted with aqueous 25% NH3 solution to pH9-10. The precipitate that formed was filtered off, washedwith ice water (2×5 ml), methanol (1 ml, cooled to 0),and air-dried, then recrystallized. In the case if oilseparated the reaction mixture was extracted with CH2Cl2(3×20 ml), the extract was dried over anhydrous Na2SO4and evaporated to dryness. The obtained residue wasrecrystallized from methanol or ethyl acetate.
3,6-di-tert-butyl-2,3,4,9-tetrahydro-1H-carbazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride; In ethanol; water; for 5h;Reflux;
9-(2-dicyclohexylphosphonophenyl) -3,6-di-tert-butyl-9H-carbazole as shown,The preparation of 9- (2-dicyclohexylphosphonophenyl) -3,6-di-tert-butyl-9H-carbazole is:In a 250 ml round bottom flask,10.0 g of <strong>[36600-66-5]4-tert-butylphenylhydrazine hydrochloride</strong> (60 mmol) was added,Then 8.48 g of 4-tert-butylcyclohexanone (66 mmol) was added,Add 100 ml of ethanol,And then slowly add 5 ml of hydrochloric acid,The mixture was stirred for 5 hours under reflux,After the reaction is completely returned to room temperature,After crystallization, water was collected and washed with water to obtain 14.4 g of 3,6-di-tert-butyl-2,3,4,9-tetrahydro-1H-carbazole,Decompress all the solution,Yield 85percent, can be directly into the next step reaction.
N-(4-(t-butyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl) cyclohexyl)-2-(phenyl ethynyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: 2-phenylethynylaniline; 4-tercbutyl-cyclohexanone In methanol at 20℃; for 2h;
Stage #2: Cyclohexyl isocyanide With trimethylsilylazide In methanol for 24h;
General Procedure for the Synthesis of Compounds 5a-i
General procedure: 2-(Phenylethynyl)aniline in MeOH (5 ml) and cyclohexanone (1mmol) were stirred at room temperature for 2 h, then the requisiteisocyanide (1 mmol) and trimethylsilyl azide were added.The mixture was stirred for 24 h until the reaction was completed.Then, the desired product was either filtered off as awhite solid filtered for 5a-e (ketone derivatives) or purifiedusing column chromatography on silica gel (n-hexane/EtOAc,9:1) for 5f-i (aldehyde derivatives). The yields were in the rangeof 75-92%.
6-bromo-4'-tert-butylspiro[1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With toluene-4-sulfonic acid; In toluene; for 8h;Reflux; Dean-Stark;
General procedure: A mixtureof the corresponding salicylamide 1-6 (0.010 mol), ketone(0.012 mol), and p-TsOH·H2O (0.03 mol) in PhMe (45 ml)was refluxed for 8 h with continuous removal of water witha Dean-Stark trap. Then solvent was evaporated to drynessunder reduced pressure, the solid residue was washed with5% aqueous NaOH solution and filtered off.Spiro[1,3-benzoxazine-2,1'-cycloheptan]-4(3H)-one (7).Yield 2.10 g (91%)
General procedure: 3-oxo-3-phenylpropanenitrile (2.96 g, 20.4 mmol) and pentan-3-one(2.14 mL, 20.4 mmol) were put into 100 mL round bottom flask, then50 mL ethyl alcohol chloride as solvent and 1 mL morpholine used ascatalyst for the reaction were added. The reaction mixture was stirred atroom temperature for 15 mins. Then sulphur (0.85 g, 26.6 mmol) wasadded to above mixture. The reaction mixture was heated at 60 C for12 h. The organic solvent was evaporated and the residue dissolved inethyl acetate and purified with silica gel column chromatography(product eluted at 10% [v/v] ethyl acetate/petroleum ether) to afford(2-amino-4-ethyl-5-methylthiophen-3-yl)(phenyl) methanone(1a) as ayellow crystal.
General procedure: 3-oxo-3-phenylpropanenitrile (2.96 g, 20.4 mmol) and pentan-3-one(2.14 mL, 20.4 mmol) were put into 100 mL round bottom flask, then50 mL ethyl alcohol chloride as solvent and 1 mL morpholine used ascatalyst for the reaction were added. The reaction mixture was stirred atroom temperature for 15 mins. Then sulphur (0.85 g, 26.6 mmol) wasadded to above mixture. The reaction mixture was heated at 60 C for12 h. The organic solvent was evaporated and the residue dissolved inethyl acetate and purified with silica gel column chromatography(product eluted at 10% [v/v] ethyl acetate/petroleum ether) to afford(2-amino-4-ethyl-5-methylthiophen-3-yl)(phenyl) methanone(1a) as ayellow crystal.
General procedure: 3-oxo-3-phenylpropanenitrile (2.96 g, 20.4 mmol) and pentan-3-one(2.14 mL, 20.4 mmol) were put into 100 mL round bottom flask, then50 mL ethyl alcohol chloride as solvent and 1 mL morpholine used ascatalyst for the reaction were added. The reaction mixture was stirred atroom temperature for 15 mins. Then sulphur (0.85 g, 26.6 mmol) wasadded to above mixture. The reaction mixture was heated at 60 C for12 h. The organic solvent was evaporated and the residue dissolved inethyl acetate and purified with silica gel column chromatography(product eluted at 10% [v/v] ethyl acetate/petroleum ether) to afford(2-amino-4-ethyl-5-methylthiophen-3-yl)(phenyl) methanone(1a) as ayellow crystal.
(2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: 3-oxo-3-phenylpropanenitrile (2.96 g, 20.4 mmol) and pentan-3-one(2.14 mL, 20.4 mmol) were put into 100 mL round bottom flask, then50 mL ethyl alcohol chloride as solvent and 1 mL morpholine used ascatalyst for the reaction were added. The reaction mixture was stirred atroom temperature for 15 mins. Then sulphur (0.85 g, 26.6 mmol) wasadded to above mixture. The reaction mixture was heated at 60 C for12 h. The organic solvent was evaporated and the residue dissolved inethyl acetate and purified with silica gel column chromatography(product eluted at 10% [v/v] ethyl acetate/petroleum ether) to afford(2-amino-4-ethyl-5-methylthiophen-3-yl)(phenyl) methanone(1a) as ayellow crystal.
Stage #1: N-(4-methoxy)phenylglycine ethyl ester With tris(bipyridine)ruthenium(II) dichloride hexahydrate; copper(II) acetate monohydrate In acetonitrile at 20℃; for 2h; Irradiation;
Stage #2: 4-tercbutyl-cyclohexanone With (R)-N-(pyrrolidin-3-yl)trifluoromethanesulfonamide In acetonitrile stereoselective reaction;
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; (R)-(-)-4, 12-Bis(bis (3,5-trifluoromethylphenyl)phosphino)-[2,2]-para-cyclophane; hydrogen; iodine In toluene at 65℃; for 22h; Autoclave;
General Procedure 2: Catalysed Reductive Amination using F24Phanephos
General procedure: The product was synthesised following general procedure 2 using 4-tert-butylcyclohexanone (77.1 mg, 0.5 mmol), iodine (0.8 mol%) and no acid additive. Purification yielded a white solid which was a chemically pure mixture of diastereomers (103 mg, 0.49 mmol, 98%, 98% dr). dr was determined by NMR. This compound has been synthesised previously by a different method and our data is in agreement with the literature.[7]
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