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CAS No. : | 1620-98-0 | MDL No. : | MFCD00008826 |
Formula : | C15H22O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DOZRDZLFLOODMB-UHFFFAOYSA-N |
M.W : | 234.33 | Pubchem ID : | 73219 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | 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 |
---|---|---|
87% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: for 12 h; Reflux |
3,5-di-tert-butyl-4-methoxybenzaldehyde (1) At first, sodium hydride (NaH, 1.27 g, 53 mmol) is added slowly into a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 21 mmol) dissolved in dry tetrahydrofuran (THF, 22.5 ml) at 0° C. under nitrogen. The mixture is removed from the cooling bath and the reaction proceeds for 30 min. Then, processes including adding methyl iodide (CH3I, 5.2 ml, 84 mmol) dissolved in dry THF (9 ml) in the mixture, refluxing for 12 hr, quenching with methanol (MeOH) in the cooling bath, extracting with dichloromethane (CH2Cl2), concentrating, purifying by a column chromatography method (using ethyl acetate:hexane=1:7 as eluent) are sequentially performed. A yellow liquid product (1) is obtained (4.5 g, 87percent). 1H NMR (CDCl3, 400 MHz) δ 9.91 (s, 1H), 7.79 (s, 2H), 3.73 (s, 3H), 1.46 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bromine In <i>tert</i>-butyl alcohol at 25℃; for 1h; | |
93% | With N-Bromosuccinimide; dimethyl sulfoxide | |
85% | With iodine; potassium carbonate In methanol for 0.416667h; |
83% | With barium manganate In methanol for 7h; Ambient temperature; | |
81% | With oxygen; cobalt(II) acetate; sodium hydroxide In water; ethylene glycol at 50℃; for 12h; Green chemistry; chemoselective reaction; | 2.2. Typical procedure for the Co(OAc)2-catalyzed aerobic oxidation of 1 (Table 2 in the text) General procedure: Typical procedure: a mixture of substrate 1 (5.0 mmol), Co(OAc)2*4H2O (0.05 mmol, 12 mg) and NaOH (5.0 mmol, 0.2 g) in EG/H2O (5.0 mL/0.25 mL) was stirred with O2 (1.0 atm) being bubbled at 50 °C for 12 h. Hydrochloric acid (10.0 mL, 2 %) and chloroform (10.0 mL) were successively added to the reaction mixture. The chloroform phase was separated, and the aqueous phase was further extracted with chloroform (10.0 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by column chromatography on silica gel (eluents: .petroleum ether/ethyl acetate, 5/1) to provide the desired products 2. |
79% | With copper diacetate; ethylene glycol at 65℃; for 12h; Green chemistry; chemoselective reaction; | |
70% | With benzyltrimethylammonium tribromide In dichloromethane; water; <i>tert</i>-butyl alcohol for 10h; Ambient temperature; | |
68% | With sodium methylate In methanol; diethyl ether at 25℃; electrolysis; anode: glassy carbon plate; cathode: platinum foil; S.C.E.; 0.12 V; 0.1 M NaClO4; | |
32% | With palladium on activated charcoal; water; caesium carbonate In N,N-dimethyl acetamide at 110℃; for 48h; Inert atmosphere; Sealed tube; | |
10% | With oxygen; copper dichloride; acetone oxime In ethanol at 40℃; for 1.41667h; | |
With bromine; <i>tert</i>-butyl alcohol | ||
With bromine; acetic acid | ||
(i) CBrCl3, (irradiation), (ii) aq. EtOH; Multistep reaction; | ||
With oxygen In ethanol at 40℃; for 5h; Yield given; | ||
59 % Chromat. | With oxygen In acetic acid at 60℃; for 5h; | |
95 % Chromat. | With N-Bromosuccinimide In dimethyl sulfoxide at 120℃; for 0.166667h; | |
95 % Chromat. | With N-Bromosuccinimide In dimethyl sulfoxide at 120℃; for 0.166667h; | |
With hydrogen bromide In water; dimethyl sulfoxide | ||
Multi-step reaction with 2 steps 1: 80 percent / manganese triacetate / 3 h / 20 °C / conc. sulfuric acid presence, acetic acid presence 2: 10 percent / potassium dichromate, acetic acid / 3 h / Heating; other reagent: manganese triacetate, methanol | ||
Multi-step reaction with 3 steps 1: 90 percent / manganese triacetate / 3 h / 20 °C 3: 10 percent / potassium dichromate, acetic acid / 3 h / Heating; other reagent: manganese triacetate, methanol | ||
Multi-step reaction with 2 steps 1: 97 percent / benzyltrimethylammonium tribromide / CH2Cl2; H2O / 0.5 h / Ambient temperature 2: 90 percent / benzyltrimethylammonium tribromide / CH2Cl2; H2O / 1 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 73 percent Chromat. / cobalt(III) acetate / acetic acid / 15 h / 50 °C 2: 47 percent Chromat. / cobalt(III) acetate / acetic acid / 15 h / 50 °C | ||
440 gm. (71%) | With bromine In <i>tert</i>-butyl alcohol | 3,5-Di-t-butyl-4-hydroxy benzaldehyde 3,5-Di-t-butyl-4-hydroxy benzaldehyde In a 5 l., four-neck, round-bottom flask equipped with a thermometer, mechanical stirrer, dropping funnel and vent tube were placed 600 gm. of 2.6-di-t-butyl-p-cresol and 3600 ml. of t-butyl alcohol. To this stirred solution at 25°-35° C were added 908 gm. of Br2 over a period of ten hours. The resulting solid was separated by filtration, washed with hexane and dried. The yield was 440 gm. (71%) of aldehyde melting at 187°-189° C. |
440 gm. (71%) | With bromine In <i>tert</i>-butyl alcohol | 3,5-Di-t-butyl-4-hydroxy benzaldehyde 3,5-Di-t-butyl-4-hydroxy benzaldehyde In a 5 1., four-neck, round-bottom flask equipped with a thermometer, mechanical stirrer, dropping funnel and vent tube were placed 600 gm. of 2.6-di-t-butyl-p-cresol and 3600 ml. of t-butyl alcohol. To this stirred solution at 25°-35° C were added 908 gm. of Br2 over a period of ten hours. The resulting solid was separated by filtration, washed with hexane and dried. The yield was 440 gm. (71%) of aldehyde melting at 187°-189° C. |
100 %Spectr. | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In methanol at 20℃; for 24h; | |
With oxygen; sodium hydroxide In 2-methoxy-ethanol at 80℃; for 7h; chemoselective reaction; | 2.4. Oxidation of p-cresols General procedure: In a typical procedure, NaOH (5.4 g, 135 mmol) was first dissolvedwith 20 g EGME in a four-necked round-bottom flask, then 50 mmolsubstrate and 0.04 g catalyst (cobalt/substrate molar ratio, 0.4%) wereadded to the above solution. The flask was equipped with a condenser,a stirrer and an air-vent needle for continuous flow of 100 mL min-1 O2. The stirring speed was 600 rpm to minimize the effect of mass transfer (Fig. S1). The reaction temperature is 80 °C and the reaction time is 7 h. After the reaction, the CoOxCN was separated by an externalmagnet for reuse and the decanted reaction solution was dilutedwith water. A high performance liquid chromatography (HPLC)(Shimadzu LC-20AT) equipped with a UV detector connected to a C18reversal pillar (size: 250×4.6 mm) was used for product analysis. Amixture of methanol and water (volume ratio, 40:60) was used asmobile phase at a flow rate of 1.0 mL min-1. The column temperaturewas 40 °C and the UV detection wavelength was 230 nm. HPLC andhigh performance liquid chromatography-mass spectrum (HPLC-MS)were used to test the products and intermediates by comparison withstandard chemicals. The conversions (conv.) of p-cresols, yields (Yi) ofp-hydroxybenzaldehydes, selectivity (Si) of p-hydroxybenzaldehydesand turnover numbers (TONs) of catalysts are defined as followingequations: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium acetate In ethanol at 50 - 80℃; | 1 Example 1. Synthesis of tyrphostin 9 and related benzylidenemalonic acid derivatives A) 3 mole-g (703 g) of 4-hydroxy-3,5-di-tert-butylbenzaldehyde (99.1 % pure, purchased from Yongyi Chemicals Group Co., Ltd, Changzhou, Jiangsu, China) and 2.5 L anhydrous ethanol are charged into a 5 L reactor provided with mechanical stirring and fitted with a reflux condenser. B) 3 mole-g (198 g) of malonodinitrile (99.76% pure, purchased from Aceto Corporation, Port Washington, NY, USA) are quickly added to the reactor while stirring. C) 75 g of ammonium acetate (98.5% pure, purchased from Fermont, Monterrey) are quickly added while stirring. The color of the reaction mixture goes from beige to yellow and then to orange. D) The reactor is heated to reflux using a water bath. Reflux is first observed when the bath temperature reaches about 80 °C and is maintained during 1 hour. Complete solution is observed before reflux starts. E) The water bath is removed and the temperature is allowed to drop to 50°C. F) 1.5 L of water is added to the reaction mixture under brisk stirring. A precipitate appears. G) The reaction mixture is cooted to 0°C. H) The reaction mixture is filtered under reduced pressure using a Buchner funnel attached to a Kitasato flask. I) The filter cake is thoroughly washed with water. J) The wet filter cake is dried by heating in an oven at 60°C until constant weight is achieved. This procedure yields about 800 g (about 95% yield) of a light-yellow microcrystalline solid that melts at 141-142 "C (uncorrected), presents UV absorption maxima at 247 nm and 365 nm and has an Rf value of 0.65 (using benzene as eluant and Merck's TLC silica gel 60 F254 plastic-backed sheets), with only one spot being observed. The mixed melting point of this compound and authentic tyrphostin 9 (acquired from Cayman Chemical) was also 141-142 (uncorrected), and its spectroscopic and chromatographic properties were identical to those of the authentic product. This compound is stable, with a shelf life of over 1 year at 25-35°C; if necessary it may be recrystallized from ethanol. |
83% | In N,N-dimethyl-formamide for 10h; Heating; | |
75.7% | With piperidine In ethanol at 50 - 60℃; for 4h; |
50% | With piperidine In ethanol Heating; | |
With piperidine; benzene | ||
With piperidine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With perchloric acid; lead dioxide In water; acetone at 25℃; | |
With potassium hexacyanoferrate(III) | ||
With lead dioxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tetrahydroborate In ethanol at 20℃; | 2.General procedure for the preparation of 1a-d and 1f-1i General procedure: To a solution of 4-hydroxy or4-methoxybenzaldehyde derivatives (1.5 mmol) in anhydrous ethanol (8 mL) wasadded NaBH4 (6.0 mmol). The reaction mixture was stirred at room temperature until the TLC indicated the consumption of the starting material. An appropriate amount of water was added to the reaction, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine,dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was puried byash chromatography (petroleum ether/ethyl acetate 10:1 to 1:1) to give the products 1a-1d and 1i. 2,6-Di-tert-butyl-4-(hydroxymethyl)phenol (1a).1Compound 1a was prepared from3,5-di-tert-butyl-4-hydroxybenzaldehyde according to the general procedure. White solid, 95% yield. 1H NMR (300 MHz, CDCl3)δ 7.18 (s, 2H), 5.19 (s, 1H), 4.59 (d, J = 5.5 Hz, 2H), 1.46 (s, 18H). |
93% | With sodium tetrahydroborate; sodium hydrogencarbonate In ethanol at 0℃; for 2h; | 1 Synthesis of 3,5-di-tert-butyl-4-hydroxybenzyl alcohol Take 4 g of the above prepared3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.017 mol) was dissolved in 40 mL of absolute ethanol,1.7 g of NaHCO3 (0.02 mol) was added, and 0.77 g (0.02 mol)NaBH4 continued to react for 2 h, ending the reaction.Ether extraction, the organic phase was combined, washed and dried, and the solvent was removed under reduced pressure to give 3.7 g of a pale yellow solid,Yield 93%, m.p. 140-141 ° C (literature value 139-141 ° C). |
47% | With sodium hydroxide; sodium tetrahydroborate In methanol for 27h; Ambient temperature; |
45% | With sodium tetrahydroborate In methanol at 5℃; for 1.5h; | Synthesis of alcohols 6-10 (general procedure). General procedure: To a solution or a suspension of aldehyde 1-5 (1.0 mmol) in anhydrous MeOH(15 mL), NaBH4 (0.189 g, 5.0 mmol) was added at ~5 C (bath temperature) and the mixture was stirred for 1.5 h. After the reaction completion, the mixture was warmed to room temperature,treated with 2 M NaOH (12 mL), stirred 5 min, diluted with diethyl ether (30 mL), and stirring was continued for15 min. The organic layer was separated, washed with 2 M NaClto pH ~7.0, dried with anhydrous K2CO3, and co-evaporated with small amount of pentane. The product was collected by filtration and washed with petroleum ether. Compound 6 was additionally purified by silica gel column chromatography (elution with CHCl3). 4-Hydroxymethyl-2,6-di-tert-butylphenol (6). Colorless powder,m.p. 141-143 C (cf. Ref. 26: 140-145 C (MeOH)). Yield0.106 g (45%). Found (%): C, 76.49; H, 10.44. C15H24O2.Calculated (%): C, 76.23; H, 10.24. IR (KBr), /cm-1: 3568,3522 (OH); 2945, 2953, 2914, 2872, 1481, 1435 (CH3, CH2);1584 (C=C); 1204, 1113, 1013 (C-O); 881 (=C-H). 1H NMR spectral data are in agreement with those described previously.2613C NMR (CDCl3), : 30.26 (2 C(CH3)3); 34.34 (2 C(CH3)3);66.10 (CH2OH); 124.44 (C(3), C(5)); 131.62, 136.13 (C(2),C(4), C(6)); 153.52 (C(1)). |
With lithium aluminium tetrahydride; diethyl ether | ||
With sodium hydroxide; sodium tetrahydroborate | ||
With sodium tetrahydroborate In methanol | ||
Multi-step reaction with 2 steps 1: NaOH; KOH; H2O 2: LiAlH4; diethyl ether | ||
91 %Chromat. | With methylamine-borane In water at 20℃; for 0.5h; Green chemistry; chemoselective reaction; | General Procedure for the Hydrogenation of Carbonyl Compounds to Alcohols General procedure: A mixture of carbonyl compound (1 mmol) and MeAB (1 mmol) in neat water (2 mL) was stirred at room temperature for an appropriate time. The reaction was monitored by TLC and gas chromatography (GC). After completion, the reaction mixture was extracted with ethyl acetate (310 mL). Then, the organic extracts were concentrated by rotary evaporation, and the residue was purified by silica-gelcolumn chromatography (elution by using petroleum ether=ethyl acetate 5:1) to obtain the alcohol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In nitrobenzene for 5h; Reflux; Inert atmosphere; | |
70% | With ammonium acetate In ethanol at 75℃; for 10h; | Synthesis of 2-phenylbenzimidazoles 7-12 (general procedure). General procedure: A procedure similar to that described in the work21 was used. A mixture of o-phenylenediamine (0.053 g, 0.49 mmol), aldehyde 1-6 (0.51 mmol), and NH4OAc (0.038 g, 0.49 mmol) in anhydrous EtOH (15 mL) was stirred for 10 h at 75C. The reaction mixture was cooled to room temperature, the precipitate was collected by ltration, washed with EtOAc, and dried. An additional amount of the product was obtained after evaporation and precipitation from the mother liquor. Compounds 9, 10, and 12 were isolated by column chromatography (eluent PhH-MeOH (9), petroleum ether-EtOAc (10, 12)). |
44% | In ethanol at 20℃; for 168h; |
9% | In ethanol for 12h; Ambient temperature; | |
In nitrobenzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid In chloroform for 21h; Heating; | |
75% | With sulfuric acid In acetic acid for 51h; Ambient temperature; | |
51.5% | With piperidine In ethanol for 8h; Reflux; | 3.2. Chemistry General Procedure General procedure: In a round bottom flask 0.0068 mol 1,3-indandione and 0.0075 mol of the corresponding arylaldehyde were added and diluted in 30 mL of absolute ethanol using piperidine (0.06 mL) as catalyst. The mixture was heated reflux for approximately 8 h monitoring with TLC (petroleum ether/ethyl acetate, 7/3) for the completion of the reaction. The excess of the solvent was removed with rotary evaporator. The residue was ltered and puried either with recrystallization with EtOH 95or ethanol/water or with preparative TLC using CH3COOC2H5: petroleum ether (1:2). |
With piperidine In acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With piperidine; pyridine In benzene at 80℃; for 6h; | General Method for Synthesizing 7-12 General procedure: A mixture of aldehyde 1-6 (1 mmol) and malonic acid (2.5 mmol) in C6H6 (25 mL) was treated with Py (1 mL) and piperidine (0.1 mL), heated at 80°C for 6 h, cooled, treated with aqueous HCl (2 N), and extracted with Et2O. The organic extract was washed with H2O, dried over Na2SO4, and evaporated at reduced pressure. The product was precipitated from CHCl3-petroleum ether. |
48% | With piperidine; pyridine at 80℃; | |
27% | With piperidine; pyridine Reflux; | 4.2. General procedure for the synthesis of 3-heteroaryl-acrylic acids 1-4ii [26], [27], [28] and [29] General procedure: Title compounds were prepared, as illustrated in Scheme 1, by a Knoevenangel condensation of the suitable heteroarylaldehyde with malonic acid. Malonic acid (0.01 mol) was dissolved in 1.12 mL of pyridine and the heteroaldehyde (0.01 mol) and piperidine (0.01 mol) were added. The mixture was refluxed until the emission of CO2 stopped. Then the solution was poured into 2 N HCl and then on ice. The formed precipitate was collected by filtration and recrystallized from water or from 3:1 water/ethanol mixture. If no precipitate was formed an extraction with 3 × 100 mL CHCl3 or CH2Cl2 was made and the organic phase was collected, dried over MgSO4, and evaporated to dryness affording a residue that was recrystallized from aqueous ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; for 28h; Heating / reflux; | N Example N Synthesis of 4-(2-Methoxy)ethoxymethoxy-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (8 g, 33 mmol) in 1,2-dichloroethane (150 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. 2-Methoxyethoxymethyl (MEM) chloride (5.7 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then at reflux for 26 h until no more hydroxybenzaldehyde was detected by TLC (Rf=0.92 for product and 0.70 for starting material using 1:1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated (98% yield) as a brown oil. |
87% | Stage #1: 3,5-di-t-butyl-4-hydroxybenzaldehyde With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 2-Methoxyethoxymethyl chloride In tetrahydrofuran for 3h; Reflux; | |
72% | With N-ethyl-N,N-diisopropylamine In dichloromethane for 38h; Heating; |
With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane Heating; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane | 2 3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde EXAMPLE 2 3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH2 Cl2 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM-Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2 Cl2, washed with 1N HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2 Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol for 2h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: acetylacetone With boron trioxide In dichloromethane at 20℃; for 1h; Stage #2: With tri-sec-butylborate In dichloromethane for 0.0833333h; Stage #3: 3,5-di-t-butyl-4-hydroxybenzaldehyde With tri-sec-butylborate; water; acetic acid; N-butylamine more than 3 stages; | 1 EXAMPLE 1Preparation of (1E,6E)-1,7-Bis(3,5-di-tert-butyl-4-hydroxyphenyl)-1,6-heptadiene-3,5-dioneRepresentative of the Molecules of the Present InventionAcetylacetone (2.0 g, 0.02 mol) and boric oxide (0.98 g, 0.014 mol) are mixed in dry dichloromethane (30 mL) in a 100 mL round bottomed flask and stirred at room temperature for one hour under dry condition. Tri-sec-butylborate (9.2 g, 0.04 mol) is added to this mixture and stirred for 5 min. The aromatic aldehyde (1a-f) (0.04 mol) is dissolved in dry dimethylformamide/chloroform/dichloromethane or a mixture of these solvents (50-100 mL) in a three necked 250 mL round bottomed flask fitted with a mechanical agitator and calcium chloride drying tube. Tri-sec-butylborate (9.2 g, 0.04 mol) is added and stirred for 5 min. Acetylacetone-boric oxide complex prepared above is added and stirred for 10 min. n-Butylamine (0.3 g, 0.004 mol) dissolved in dichloromethane (3.0 mL) is dropped in over a period of 30 min and stirred at room temperature over night (24 h). This is poured into 100 mL of 5% aq. acetic acid at 50° C. and stirred for an hour. The precipitated crude curcuminoid is filtered, dried in vacuo and crystallized from isopropyl alcohol to get the pure curcuminoid.Properties of (1E,6E)-1,7-Bis(3,5-di-tert-butyl-4-hydroxyphenyl)-1,6-heptadiene-3,5-dione(1E,6E)-1,7-Bis(3,5-di-tert-butyl-4-hydroxyphenyl)-1,6-heptadiene-3,5-dione is a yellow powder (yield 66%), m.p. 192.0-196.0° C., 98% HPLC purity.1H NMR (CDCl3, 300 MHz): δ 1.467 (s, 36H), 5.533 (s, 2H, -OH), 5.870 (s, 1H), 6.495 (d, J=15.6 Hz, 2H), 7.405 (s, 4H), 7.623 (d, J=15.6 Hz, 2H).13C NMR (CDCl3, 75 MHz): δ 30.403, 34.604, 101.166, 121.347, 125.746, 126.640, 136.595, 141.617, 156.307, 183.665, 192.161.LC-MS: m/e 533 (M++1). |
45% | Stage #1: acetylacetone With boron trioxide; boric acid tributyl ester In N,N-dimethyl-formamide at 65℃; for 0.25h; Stage #2: 3,5-di-t-butyl-4-hydroxybenzaldehyde With 1,2,3,4-tetrahydroisoquinoline; acetic acid In N,N-dimethyl-formamide at 95℃; for 4h; Stage #3: With acetic acid In water; N,N-dimethyl-formamide at 70℃; for 1h; | |
With boric acid tributyl ester; N-butylamine Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 3,5-di-tert-butyl-4-methoxybenzaldehyde (1) At first, sodium hydride (NaH, 1.27 g, 53 mmol) is added slowly into a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 21 mmol) dissolved in dry tetrahydrofuran (THF, 22.5 ml) at 0 C. under nitrogen. The mixture is removed from the cooling bath and the reaction proceeds for 30 min. Then, processes including adding methyl iodide (CH3I, 5.2 ml, 84 mmol) dissolved in dry THF (9 ml) in the mixture, refluxing for 12 hr, quenching with methanol (MeOH) in the cooling bath, extracting with dichloromethane (CH2Cl2), concentrating, purifying by a column chromatography method (using ethyl acetate:hexane=1:7 as eluent) are sequentially performed. A yellow liquid product (1) is obtained (4.5 g, 87%). 1H NMR (CDCl3, 400 MHz) delta 9.91 (s, 1H), 7.79 (s, 2H), 3.73 (s, 3H), 1.46 (s, 18H). | |
45% | A stirring mixture of 3,5-di-tert-butyl-4-hydroxy-benzaldehyde (2 g, 8.53 mmol, 1 eq) in anhydrous THF (25 mL) was treated with NaH (853 mg, 21.34 mmol, 60%, 2.5 eq) at 0C under an argon atmosphere. The resulting mixture was stirred at 25 C for 30 min and then treated with Mel (7.7 g, 54.25 mmol, 3.38 mL, 6.36 eq) by dropwise addition. The resulting mixture was stirred at 85 C for 16 hr. The excess reagents were quenched by slow addition of brine (50 mL) and then extracted with Ethyl acetate (50 mL*3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (S1O2, Petroleum ether to Petroleum ether/Ethyl acetate=l0:l). The title compound (955 mg, 3.85 mmol, 45% yield) was obtained as yellow oil. 1 H NMR (CDCL, 400MHz) d = 9.91 (s, 1H), 7.79 (s, 2H), 3.73 (s, 3H), 1.45 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; for 18h; Heating / reflux; | M Example M Synthesis of 4-Methoxymethoxy-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (10 g, 40 mmol) in 1,2-dichloroethane (200 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. Chloromethoxymethyl ether (3.77 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then refluxed for 16 h until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.70 for starting material using 1:1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated in 100% yield as a brown oil. Spectroscopic data were as follows: 1H NMR (DMSO-d6, 270 MHz): δ=9.89 (1H, s, aldehyde CHO), 7.80 (2H, s, phenyl H), 4.92 (2H, s, CH3), 3.64 (3H, s, CH3), 1.46 (18H, s, 6 CH3). 13C NMR (DMSO-d6, 270 MHz): δ=192.11, 160.11, 145.77, 131.65, 128.55, 100.98, 57.66, 35.99 and 30.16. |
22% | Stage #1: chloromethyl methyl ether; 3,5-di-t-butyl-4-hydroxybenzaldehyde With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 19h; Stage #2: With hydrogenchloride In dichloromethane; water | |
With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane Heating; |
Yield | Reaction Conditions | Operation in experiment |
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35% | piperidine; In ethanol; for 12h;Heating / reflux; | To a solution of the appropriate carbonylcompound I (1 mmole) in ethanol 4 MI, the appropriate SULFONYLCOMPOUND 11 (1MMOLE) and a catalytic amount of piperidine (0.1 mmole) was added. The reaction mixture was heated at reflux for 12 hours. The products III were iso- lated either by, Step A: cooling filtration and crystallisation or Step B: cooling, separation of the compound with water, and crystallisation with an organic solvent or Step C: Aquae's work up followed by column chromatography; The title compound was prepared from 3, 5-DI-TERT-BUTYL-4-HYDROXYBENZALDEHYDE and methanesulfonylacetonitrile in 35 % yield. H NMR (CDCI3) : No. 1.47 (s, 18 H) 3.18 (s, 3 H) 6.03 (s, 1 H) 7.86 (s, 2 H) 8.04 (s, 1 H); HPLC-MS (Method A): m/z = 358 (M+Na); Rt = 4.79 min. |
35% | Step A: The title compound was prepared from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and methanesulfonylacetonitrile in 35% yield. 1H NMR (CDCl3): delta 1.47 (s, 18 H) 3.18 (s, 3 H) 6.03 (s, 1 H) 7.86 (s, 2 H) 8.04 (s, 1 H); HPLC-MS (Method A): m/z=358 (M+Na); Rt=4.79 min. |
Yield | Reaction Conditions | Operation in experiment |
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96% | With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 2.25h; | H Example H Synthesis of 4-(Ethylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DMF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid. Spectroscopic data were as follows: 1H NMR (DMSO-d6, 270 MHz): δ=9.96 (1H, s, aldehyde CHO), 8.04 (1H, t, carbamate NH), 7.83 (2H, s, phenyl H), 3.09 (2H, m, ethyl CH2), 1.34 (18H, s, 6 CH3), 1.07 (3H, t, ethyl CH3). 13C NMR (DMSO-d6, 270 MHz): δ=193.4, 155.1, 154.2, 145.0, 133.3, 127.8, 35.9, 31.4, 30.5. |
96% | With triethylamine In ethyl acetate; N,N-dimethyl-formamide | H Synthesis of 4-(Ethylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde Example H Synthesis of 4-(Ethylaminocarbonyloxy)-3,5-di-tert-butylbenzaldehyde To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DMF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC(Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid. Spectroscopic data were as follows: 1H NMR (DMSO-d6, 270 MHz): δ=9.96 (1H, s, aldehyde CHO), 8.04 (1H, t, carbamate NH), 7.83 (2H, s, phenyl H), 3.09 (2H, m, ethyl CH2), 1.34 (18H, s, 6CH3), 1.07 (3H, t, ethyl CH3). 13C NMR (DMSO-d6, 270 MHz): δ=193.4, 155.1, 154.2, 145.0, 133.3, 127.8, 35.9, 31.4, 30.5. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium hydroxide; sodium cyanoborohydride; In 1,4-dioxane; methanol; ethanol; water; ethyl acetate; | Step e: 1,19-Bis[(3,5-di-t-butyl-4-hydroxyphenyl)methyl]-1,6,14,19-tetraazanonadecane, tetrahydrochloride Dissolve 1,6,14,19-tetraazanonadecane (1.35 g, 0.005 mol) in methanol (distilled from Mg) (50 mL) and add 3,5-di-t-butyl-4-hydroxybenzadehyde (2.34 g, 0.01 mol), sodium cyanoborohydride (0.62 g, 0.010 mol) and 1 drop of 1% bromocresol green in ethanol. Maintain the pH of the reaction with 1N hydrochloric acid in methanol until the indicator no longer changes. Evaporate the solvent in vacuo and partition the residue between 1N sodium hydroxide (50 mL) and ethyl acetate (100 mL). Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo give the crude product. Dissolve the crude 1,19-bis[(3,5-di-t-butyl-4-hydroxyphenyl)methyl]-1,6,14,19-tetraazanonadecane (3.54 g, 5 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of di-t-butyl dicarbonate (4.8 g, 22 mmol) at 10 C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3X), dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give 1,19-bis[(3,5-di-t-butyl-4-hydroxyphenyl)methyl]-1,6,14,19-tetra(t-butyloxycarbonyl)-1,6,14,19-tetraazanonadecane. |
Yield | Reaction Conditions | Operation in experiment |
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43% | In chloroform; toluene; | EXAMPLE 6 (compound 49) Diethyl alpha-(3.,5-di-tert-butyl-4-hydroxyphenyl)-N-methyl-N-(3-picolyl) aminomethylphosphonate STR11 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (5.0 g, 21.4 mmol) was added at room temperature to a solution of N-methyl-3-picolylamine (2.6 g, 21.6 mmol) and diethyl phosphite (3.0 g, 21.6 mmol) in 20 ml toluene. The reaction mixture was stirred at room temperature for 2 h then refluxed for 15 min. After the evaporation of toluene, the residue was column chromatographed using 95/5 CHCl3 /MeOH as eluent. An amount of 4.4 g of title compound was isolated, yield =43%. IR (film): 3640 cm-1: OH, 1480: C=N, pyridine, 1430: tert-Bu, 1240: P=O, 1040: P--O--C. NMR (CDCl3): delta=8.52, 7.77 and 7.27 (3 m, 4H): aromatic H, 3-picolyl 7.25 (d, JP-H =2 Hz, 2H): aromatic H, 3,5-di-t-butyl-4-hydroxyphenyl 5.29 (s, 1H): OH 4.20, 3.90 and 3.70 (3 m, 4H): P--O--CH2 --CH3 3.90 (d, JP-H =23.5 Hz, 1H): CH--PO3 Et2 3.90 and 3.37 (2d, J=13.5 Hz, 2H): N(CH3)--CH2 --Py 2.42 (s, 3H): N(CH3)--CH2 --Py 1.45 (s, 18H): tert-Bu 1.37 and 0.99 (2t, J=7 Hz, 6H): P--O--CH2 --CH3 MS: m/e=477: M+ +1,339: M+ --PO3 Et2 |
Yield | Reaction Conditions | Operation in experiment |
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22% | In methanol; | EXAMPLE 1 Synthesis of (4R)-2-(3,5-di-tert-butyl-4hydroxyphenyl)-4-thiazolidine carboxylic acid A mixture of cysteine (Aldrich, 2.0 g, 17.1 mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (Aldrich, 4.0 g, 17.1 mmol) in methanol (100 mL) was warmed at reflux for 2.25 h. The reaction mixture was cooled to ambient temperature and the solid that formed upon cooling was collected by filtration. The solid was washed with methanol and recrystallized from a mixture of ethanol/ethyl acetate. Recrystallization from ethanol gave 1.3 g (22% yield) of (4R)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-thiazolidine carboxylic acid as an off white solid, m.p. 163-165 C. Elemental Analysis Calculated for C18 H27 NO3 S. Calculated: C, 64.05; H, 8.06; N, 4.15. Found: C, 64.18; H, 8.08; N, 4.09. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; dichloromethane; water; | (d) 0.48 g of <strong>[83279-44-1]1-<strong>[83279-44-1]aminoimidazole hydrochloride</strong></strong> are suspended in 30 ml of ethanol, whereupon 0.93 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde is added. The suspension is stirred at room temperature for 3 hours, whereby there results a clear solution which is evaporated in a vacuum. The residue is taken up in 15 ml of water, neutralized (pH=7) with ice-cold saturated sodium bicarbonate solution and extracted rapidly three times with 30 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated in a vacuum. By sublimation of the residue (160/12 Torr), there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole of m.p. 171-174. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.8 g (38%) | With sodium acetate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid; | EXAMPLE 1 5-[[3,5-Bis(1,1,-dimethylethyl)-4-hydroxyphenyl]methylene]-2-imino-4-thiazolidinone, (Z)- A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (9.4 g, 0.04 mole), <strong>[556-90-1]pseudothiohydantoin</strong> (4.7 g, 0.0405 mole), sodium acetate (8.3 g, 0.1 mole), and glacial acetic acid (200 mL) is stirred and heated at reflux for 21 hours. The cooled mixture is added to ice-water and the precipitated solid is filtered and washed with water. The solid residue is dissolved in ether and washed successively with water, aqueous sodium bicarbonate solution, and water. The extract is dried and the solvent is removed to give 9.4 g of a residue. The crude product is recrystallized from methanol-ethyl acetate to give 3.8 g (38%) of 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-imino-4-thiazolidinone, (Z)-, mp 277-279 C. Anal. for C18 H24 N2 O2 S: Calcd: C, 65.03; H, 7.28; N, 8.43; S, 9.64. Found: C, 64.90; H, 7.30; N, 8.21; S, 9.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With trichlorophosphate In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20 - 70℃; for 2h; | 1 Synthesis of 3,5-di-tert-butyl-4-hydroxybenzaldehyde 2.42 mL of POCl3 (0.026 mol) was added to 2.01 mL of DMF (0.026 mol) at 0 & lt;Stir to give a white solid which was added to 20 mL1,2-dichloroethaneDissolved in solution A. Take 4.12g2,6-di-tert-butylphenol (0.02 mol)Dissolved in 20mL1,2-dichloroethane to give solution B.Solution B was added dropwise to solution A at room temperature,The reaction was refluxed at 70 ° C for 2 h,After completion of the reaction, the saturated Na2CO3 solution was added to the reaction solution and neutralized to produce no gas,And then refluxed at 80 ° C for 40 min,Liquid, organic phase washed,Na2CO3 saturated solution was washed and dried.The organic phase was removed by distillation under reduced pressure, and the resulting pale brown flaky solid was 4.48 g, yield 96%Melting point 185-189 ° C (literature value 186-190 ° C) |
With ammonium acetate In formaldehyd; acetic acid | 20 EXAMPLE 20 EXAMPLE 20 A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 200 ml of glacial acetic acid, and 61.7 g (0.8 mole) of ammonium acetate. To the stirred mixture there were slowly added 97 g of 37% formalin (1.2 moles of formaldehyde) and 20.6 g (0.1 mole) of 2,6-ditert.-butylphenol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (107°-9°) for 6 hours. After cooling to ambient temperature, the mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 15.8 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 184°-86° (67.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Step A: The title compound was prepared from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and propane-2-sulphonylacetonitrile in 34% yield 1H NMR (DMSO-d6): delta ppm 1.32 (d, J=6.78 Hz, 6 H) 1.41 (s, 18 H) 3.56 (m, 1 H) 7.98 (s, 2 H) 8.16 (s, 1 H) 8.41 (s, 1 H); HPLC-MS (Method A): m/z=464 (M+1); Rt=5.0 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Example 79 (General Procedure (F)) 2-(3,5-Bis-Trifluoromethyl-Phenyl)-3-(3,5-Di-Tert-Butyl-4-Hydroxy-Phenyl)-Acrylonitrile. The title compound was prepared from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 3,5-bis-trifluoromethyl-phenylacetonitrile in 20% yield 1H NMR (DMSO-d6): ppm 1.51 (m, 18 H) 5.78 (s, 1 H) 7.57 (s, 1 H) 7.85 (s, 1 H) 7.86 (s, 2 H) 8.07 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With hydrogenchloride; In methanol; for 120.0h;Heating / reflux; | To a well stirred solution of 3, 5-di-te7 » t-butyl-4-hydroxy-benzaldehyde (100 g, 0.41 mol) and N-tert-butyl hydroxylamine (65.0 g, 0.73 mol) in methanol (2.0 L) was added 10 drops of conc. HCl and the mixture was refluxed for 5 days. The mixture was concentrated to dryness and the residue was dissolved in 700 mL of ethyl acetate and left in a refrigerator overnight where upon the product crystallized out. The crystalline product was filtered and vacuum dried to obtain 116.95 g (93. 4%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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45% | With copper(II) sulfate In tetrahydrofuran at 20℃; for 168h; | IV To a solution of tiacumicin B (0.53 g, 0.5 mmole) in dry THF (10 ml) was added 3,5-tert-dibutyl-4-hydroxybenzaldehyde (117 mg, 0.5 mmole), p-toluenesulfonic acid (catalytic amount 10 mg), and anhydrous CuSO4 (1 g). The solution was stirred at room temperature for several days. After the seventh day, solvent was removed and the crude product was purified on a column. 7:3 hexane/ethyl acetate was used to remove un-reacted benzaldehyde and the major product isolated using 1:1 hexane/EA. After purification, 173 mg (45% yield) of product was isolated. 13C-NMR chemical shift assignment for TB8 is summarized in Table 4.TABLE 4 Chemical shift of Chemical shift Tiacumicin B in reference No. of carbon (ppm) (ppm)* 23 11.3 11.3 24 13.9 13.9 19 14.5 14.6 21 15.4 15.4 25 17.0 17.5 6' 18.1 18.1 7 18.7 18.2 3'''' 19.1 19.1 4'''' 19.5 19.5 9''' 20.3 20.2 8''' 26.4 26.5 22 26.9 26.9 16 28.3 28.4 6 28.7 28.7 2'''' 35.4 35.4 6 37.3 37.3 10 42.5 42.5 2'-OCH3 62.2 62.2 20 63.9 63.9 18 68.2 68.3 3 70.5 70.5 2' 71.6 71.6 7 72.7 72.8 3' 73.2 73.2 2 73.5 73.5 5 74.5 74.5 4 75.9 75.9 4' 76.9 76.8 17 78.6 78.6 5' 82.4 82.5 11 94.3 94.3 1 97.2 97.1 1' 102.2 102.2 4''' 108.7 108.9 2''' 112.8 110.7 6''' 114.8 115.7 9 124.5 124.6 2 125.6 125.6 15 126.9 126.8 4 128.5 128.5 13 134.6 134.6 14 136.3 136.3 12 137.0 136.9 8 137.0 137.0 7''' 141.8 141.9 5 143.7 143.7 3 146.2 146.3 3''' or 5''' 153.8 155.4 3''' or 5''' 154.5 155.8 1 169.1 169.1 1''' 169.7 170.1 1'''' 178.4 178.4 |
Yield | Reaction Conditions | Operation in experiment |
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<strong>[3511-32-8]5-methyl-furan-3-one</strong> (2, 5.0 g g, 0.051 mol) was dissolved in dichloromethane (50 mL) and taken in a 3-necked 500 mL round bottomed flask fitted with a mechanical agitator and calcium chloride guard tube. 3,5-di-tert-butyl-4-hydroxybenzaldehyde hemihydrate (3e, 12.0 g, 0.049 mol) dissolved in dichloromethane (100 mL) was added. The mixture was cooled to 0-5 C. with stirring. Tri-sec-butyl borate (11.7 g, 0.051 mol) was added and stirred for 2 h. n-Butyl amine (6 drops) was added and the reaction mixture allowed to warm to room temp. on its own with stirring and stirred at room temp. overnight. The dark yellow color solution was poured into 5% aq. acetic acid solution (120 mL) preheated to 60 C. with stirring. This was stirred for 30 min., and then allowed to settle down. The dichloromethane layer was isolated and concentrated under reduced pressure to get yellow color solid. This was chromatographed on silica gel column (36×4 cm) using 10% ethyl acetate in hexane as eluent. A yellow color solid (0.5 g, Rf 0.94 on silica gel TLC in 60% ethyl acetate in hexane) was isolated and characterized as 2-(3,5-di-tert-butyl-4-hydroxybenzylidene)-<strong>[3511-32-8]5-methyl-furan-3-one</strong> (4e), m.p. 155.1-157.5 C.;1H NMR (CDCl3, 300 MHz): delta 1.465 (s, 18H), 2.384 (d, J=0.9 Hz, 3H), 5.597 (s, 1H, -OH), 5.711 (br q, 1H), 6.699 (s, 1H), 7.683 (s, 2H).13C NMR (CDCl3, 75 MHz): delta 16.054, 30.092, 34.337, 106.097, 113.904, 123.463, 129.174, 136.424, 145.286, 155.923, 179.660, 188.244.MS: m/e 315 (M++1);and an off-white color solid (0.5 g, Rf 0.75 on silica gel TLC in 60% ethyl acetate in hexane) was isolated and characterized as 2-[Bis-(3-keto-5-methylfuranyl)]-3,5-di-tert-butyl-4-hydroxyphenylmethane(5), m.p. 178.3-180.6 C.;1H NMR (CDCl3, 300 MHz): delta 1.396 (s, 18H), 2.145 (s, 6H), 3.469 (t, J=5.7 Hz, 6.3 Hz, 1H), 5.141 (s, 1H), 5.202 (d, J=6.3 Hz, 1H), 5.203 (d, J=6.0 Hz, 1H), 5.285 (s, 1H), 5.288 (s, 1H), 6.994 (s, 2H).13C NMR (CDCl3, 75 MHz): delta 16.845, 30.326, 34.241, 47.817, 84.031, 105.084, 123.741, 125.603, 135.052, 153.240, 190.296, 203.257.MS: m/e 413 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
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86.9% | Stage #1: 1-(N-morpholino)cyclopent-1-ene; 3,5-di-t-butyl-4-hydroxybenzaldehyde In benzene for 20h; Reflux; Stage #2: With hydrogenchloride; water In benzene at 20℃; for 2h; | 20.A Example 20; Preparation of 2-methylene-5-[3,5-di(t-butyl)-4-hydroxybenzylidene]-cyclopentanone; Step A: Preparation of 2-(3,5-di(t-butyl)-benzylidene)cyclopentanone With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 3,5-di(t-butyl)-benzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 86.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide In ethanol at 20℃; for 0.5h; | 20 (2E,6E)-2-(3,5-Dimethoxybenzylidene)-6-(4-(methylsulfonyl)benzylidene)cyclohexanone (I19) 4.2.20 (2E,6E)-2-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-6-(3,5-dimethoxybenzylidene)cyclohexanone (I20) Mp: 148.2-149.9 °C. Yield: 82%; 1H NMR δ (ppm): 7.79 (s, 1H, =CH), 7.70 (s, 1H, =CH), 7.37 (s, 2H, ArH), 6.60 (s, 2H, ArH), 6.45 (s, 1H, ArH), 5.48 (s, 1H, OH), 3.82 (s, 6H, OCH3), 2.903 (m, 4H, CH2), 1.80 (quint, 2H, J = 5.8 Hz, CH2), 1.46 (s, 18H, CH3). 13C NMR δ (ppm): 190.493, 160.829, 155.078, 139.015, 138.272, 137.232, 136.481, 136.151, 133.471, 128.514, 127.638, 108.539, 100.878, 55.704, 34.704, 30.539, 28.925, 28.785, 23.435. HR-MS: Calcd For C30H38O4 [M+H]+: 463.2843, Found: 463.2829. |
With sodium hydroxide In ethanol at 20℃; for 0.5h; | 5.2. General procedure for the preparation of compounds General procedure: Cyclohexanone or cyclopentane (0.11 mmol) and morpholine (0.12 mmol) were dissolved in benzene (20 ml). The mixture was heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give compound 2 or 5 (0.043 mmol). Next, compound 2 (0.043 mmol), 3,5-dimethoxy benzaldehyde (0.033 mmol) were dissolved in benzene (20 ml), and the mixture was heated under reflux for 8 h. After cooling to room temperature, 20 ml HCl(6 mg/L) was added dropwise, and the resulting solution was stirred at rt for 2 h. The reaction mixture was partitioned between H2O (20 mL) and benzene (20 ml). The organic layers were combined, dried with MgSO4, filtered and then concentrated under reduced pressure. The residue was recrystallized from toluene to give theintermediates 3 or 6. Various substitute benzaldehydes (1.22 mmol) and 3 or 6 (1.22 mmol) were dissolved in 10% NaOH ethanol solution (10 ml), and stirring at rt for 30 min. Then water (50 ml) was added, the product extraction was carried out with EtOAc. The organic layer was dried over Na2SO4, and after solvent evaporation the residue was purified by flash column chromatography (silicagel 60, 35-70 mesh) using CHCl3 as the eluent to give compounds 4a-4j and 7a-7l. |
Yield | Reaction Conditions | Operation in experiment |
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89% | In neat (no solvent) at 90℃; for 0.0333333h; Green chemistry; | General procedure for the synthesis of bis(2-tetrahydrobenzofuranyl)alkanes (3a-3r) General procedure: An intimate mixture of the 3-methyl-6,7-dihydrobenzofuran-4(5H)-one derivative (1, 1.0 mmol),aldehyde (2, 0.5 mmol) and H2SO4•SiO2 (30% weight ratio to 1) was vigorously stirred for 2 minat ca. 90 C. After completion of the reaction, the mixture was diluted with EtOH (2 × 5 mL). After filtrating off the solid catalyst, the filtrate was concentrated to afford crude product, which was further purified by flash column chromatography to yield 3a-3r (eluent: EtOAc/petroleumether 1:4 v/v). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; ethyl acetate; | 3,5-di-tert-butyl-4-methoxybenzaldehyde (1) At first, sodium hydride (NaH, 1.27 g, 53 mmol) is added slowly into a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 21 mmol) dissolved in dry tetrahydrofuran (THF, 22.5 ml) at 0 C. under nitrogen. The mixture is removed from the cooling bath and the reaction proceeds for 30 min. Then, processes including adding methyl iodide (CH3I, 5.2 ml, 84 mmol) dissolved in dry THF (9 ml) in the mixture, refluxing for 12 hr, quenching with methanol (MeOH) in the cooling bath, extracting with dichloromethane (CH2Cl2), concentrating, purifying by a column chromatography method (using ethyl acetate:hexane=1:7 as eluent) are sequentially performed. A yellow liquid product (1) is obtained (4.5 g, 87%). 1H NMR (CDCl3, 400 MHz) delta 9.91 (s, 1H), 7.79 (s, 2H), 3.73 (s, 3H), 1.46 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene for 5h; Reflux; Dean-Stark; | 1.a [Reaction (a): Synthesis of Compound (1 c)] First, 0.1 mole equivalents ofp-toluenesulfonic acid was added to a solution obtained by dissolving 1.90 g (0.01 mol) of a compound (1 a) and 2.34 g (0.01 mol) of a compound (lb) in 50 mE of toluene, and the resulting solution was refluxed for 5 hours with removal of water using a reaction tube equipped with a Dean-Stark trap. Afier a reaction in the reaction tube was complete, extraction into an organic layer was performed with addition of water, and the organic layer was dried. Subsequently, the toluene was evaporated under reduced pressure to give a compound (lc) in the form of an oil. The compound (lc) in the form of an oil was used in the reaction (b) without being refined. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With titanium tetrachloride; 4-methylmorpholine N-oxide In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere; | 2.3.7. Tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenylidene-1,1-bisphosphonate (10) To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde 9 (469 mg,2.0 mmol) in dry THF (4 mL) was added TiCl4 (0.658 mL, 6.0 mmol),tetraisopropyl methylenediphosphonate (0.910 mL, 2.8 mmol), and Nmethylmorpholine(1.25 mL, 11.4 mmol) at 0 °C under argon atmosphere.After stirring for 4 h at room temperature, saturated aqueousNH4Cl was added, and THF was removed under reduced pressure. Theresidue was extracted with EtOAc, and the organic layer was washedwith brine, dried over Na2SO4, and concentrated under reduced pressure.The crude product was purified by flash column chromatographyon silica gel (EtOAc /Hexane = 4:1) to afford the title compound 10(831.5 mg, 1.483 mmol, 74%) as a pale yellow solid. The spectra obtainedwere consistent with those in the previous report.39 1H NMR(500 MHz, CDCl3) δ 8.20 (dd, J=48.1, 30.4 Hz, 1H), 7.77 (s, 2H), 5.60(s, 1H), 4.83-4.74 (m, 2H), 4.72-4.63 (m, 2H), 1.44 (s, 18H), 1.39 (d,J = 5.7 Hz, 6H), 1.35 (d, J = 6.3 Hz, 6H), 1.22 (d, J = 5.7 Hz, 6H),1.16 (d, J = 5.7 Hz, 6H). 13C-NMR (CDCl3, 125 MHz, δ): 161.29,156.84, 135.58 (2C), 130.26 (2C), 125.92 (dd, J = 21.6, 8.4 Hz),117.30 (t, J = 169.1 Hz), 71.25 (d, J = 6.0 Hz, 2C), 71.13 (d,J = 6.0 Hz, 2C), 34.69 (s, 2C), 30.43 (s, 6C), 24.17-24.27 (m, 6C),23.76 (d, J = 6.0 Hz, 2C). |
55% | With 4-methyl-morpholine; titanium tetrachloride In tetrahydrofuran; tetrachloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | 3.3. General Procedure for the Synthesis of 4-(Substituted benzylideneamino)-3-(3,5-di-tert-butyl-4-hydroxybenzyl thio)methyl)-1H-1,2,4-triazole-5(4H)-thiones 4-10 General procedure: Compound 3 (0.63 mmol, 0.24 g) in DMF (5 mL) was added the appropriate aldehyde (0.63 mmol).A little bit of PTSA was added as a catalyst and the reaction mixture was stirred under nitrogen gasat room temperature for 3 h. The mixture was poured into ice-water (250 mL) with stirring for 3 h.The precipitated solid was filtered off, washed with water to remove the acid catalyst and solvent,dried under vacuum and recrystallized from appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetic acid In methanol at 70℃; for 6h; chemoselective reaction; | General procedure for the synthesis of 3 General procedure: A mixture of aryl substituted 2-aminothiazole (5mmol, 2 equiv.), aldehyde (2.5mmol, 1 equiv.) and acetic acid (2ml, 20mol%) in CH3OH (10ml) at 70°C was refluxed for 6h. After completion of the reaction, it was monitored in TLC and then the reaction mixture was poured into the water. The formed precipitates were filtered by simple filtration and washed with water to obtain the crude product. The crude product was recrystalized by using absolute ethanol to get pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium acetate In acetic acid at 90℃; for 4h; | Synthesis of 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (3) In a typical run, a mixture of 2-thiobarbituric acid (5) (5.0 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (4) (5.0 mmol) and anhydroussodium acetate (5 mmol) in 10 ml of glacial acetic acid as solvent andwas stirred at 90 C for 4 h. The reaction mixture was poured out inwater and acidified to pH = 5; the precipitate formed was filtered offunder vacuum and dried. The crude product was solubilised in 3 ml ofDMF and poured out in (H2O/AcOH = 9:1) to 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (3) (1260 mg, 70%) as a yellow solid, M.P. = 198 C, Rf =0.48 (hexane:ethyl acetate, 70:30): 1H-NMR (500.13 MHz) CDCl3 : 8.42(1H, s, H-1’), 7.72 (2H, s, H-2 and 6) 5.84 (1H, s, -OH), 1.48 (18H, s, H-7and 8); MS: [M+H]+ m/z of 361.1642; purity >98%. |
69.2% | In ethanol; water at 20℃; for 16h; | 1.1-14 synthesis of compounds 1a to 1z Ethanol (4-8 mL) and H2O (4-8 mL) Various aldehydes (1.52-1.97 mmol) and thiobarbituric acid (0.9-1. 1.1 eq.) In toluene was heated to room temperature or 80°C. A precipitate was formed during the heating reaction. The precipitate was filtered through reduced pressure volatilization of ethanol, and the precipitate was filtered without volatilization of the ethanol under reduced pressure. Taking into account the physical properties of the residual aldehyde derivative and thiobarbituric acid after the reaction, the filtered solid was washed with ethanol and / or methylene chloride and water to give the above compound. According to the above synthesis method, in a solvent of ethanol (4-8 mL) and H2O (4-8 mL) A suspension of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (1.52-1.97 mmol) and thiobarbituric acid (0.9-1.1 eq.) Was stirred at room temperature For 16 hours to obtain an orange solid compound 1n in a yield of 69.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 8% 2: 2% 3: 0.76% | Stage #1: pyrrole; 4-methoxy-benzaldehyde; 3,5-di-t-butyl-4-hydroxybenzaldehyde With propionic acid for 1h; Reflux; Stage #2: at 20℃; for 120h; | Mixed aldehyde condensation of pyrrole, aldehyde 2, and4methoxybenzaldehyde (8). A solution of 3,5ditertbutyl4hydroxybenzaldehyde 2 (0.20 g, 0.85 mmol), 4methoxybenzaldehyde 8 (0.41 mL, 3.37 mmol), and pyrrole (0.29 mL,4.22 mmol) in propionic acid (10 mL) was added to the refluxing propionic acid (7 mL). The mixture was refluxed for 1 h,cooled down, and kept in air for 5 days. The reaction mixturewas diluted with chloroform and washed with water until neutral. The organic layer was dried with anhydrous Na2SO4 andconcentrated in vacuo. According to TLC and mass spectrometry, the residue is a mixture of porphyrins 9, 11, 13, and 15.The residue was washed with hexane and separated by columnchromatography as described above using the column loadedwith Al2O3 and SiO2 (elution with tetrachloromethane-acetone).Purification gives 0.014 g (2%) of the target product 11, 0.02 g(8%) of porphyrin 9, 0.006 g (0.76%) of porphyrin 13, and0.005 g of the mixture of 13 and 15.5(3,5Ditertbutyl4hydroxyphenyl)10,15,20tris(4methoxyphenyl)porphyrin (11). Violet fine crystalline powder.Rf 0.57 (Sorbfil, tetrachloromethane-acetone, 80 : 1). 1H NMR(CDCl3), δ : -2.67 (br.s, 2 H, NH); 1.68 (s, 18 H, C(5)ArC(CH3)3); 4.14 (s, 9 H, C(10,15,20) ArOCH3); 5.59(s, 1 H, OH); 7.33 (d, 6 H, C(10,15,20) ArH(3,5), J = 8.2 Hz);8.09 (br.s, 2 H, C(5) ArH(2,6)); 8.17 (d, 6 H, C(10,15,20)ArH(2,6), J = 8.2 Hz); 8.90 (br.s, 6 H, H(12,13,17,18)); 8.91(d, 2 H, H(2,8), J = 4.6 Hz); 8.95 (d, 2 H, H(3,7), J = 4.6 Hz).13C NMR (CDCl3), δ : 30.69 (C(5) ArC(CH3)3)); 34.59 (C(5)ArC(CH3)3); 55.61 (C(10,15,20) ArOCH3); 112.20(C(10,15,20) ArC(3,5)); 119.45 and 119.61 (C(meso)); 129.66-131.80 (C( α , β )); 132.12 (C(5) ArC(2,6)); 134.05 (C(10,15,20)ArC(4)); 134.83 (C(5) ArC(4)); 135.58 (C(10,15,20) ArC(2,6));153.61 (C(5) ArC(1)); 159.40 (C(10,15,20) ArC(1)). UV (CHCl3),λ max/nm (I (%)): 651 (1), 593 (1), 557 (3), 519 (4), 424 (100).MS (ESI), m/z 833.5 [MH]+. IR (KBr), ν/ cm-1: 3630 (OH); 3316 (NH); 2835 (CH3); 2957, 1607 (C=C); 1508, 1468, 1437,1246, 1177, 1034, 972, 802, 735. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid In ethanol; toluene; Petroleum ether for 7.08h; Reflux; | 2,6-Di-tert-butyl-4-[(quinolin-5-ylimino)methyl]phenol (3). 3,5-Di-tert-butyl-4-hydroxybenzaldehyde hemihydrate (1.12 g, 5 mmol) and several crystals of p-toluenesulfonic acid were added to a solution of 5-aminoquinoline (0.72 g, 5 mmol) in ethanol (30 mL). The mixture was refluxed for 1 h, the solvent was removed in vacuo to one-third of the initial volume, toluene (15 mL) was added to the residue, and the mixture was refluxed for 6 h. Then petroleum ether (3×5 mL, 15 mL in total) was added, the mixture was refluxed for 5 min, and the insoluble residue was filtered off . The solution was cooled to 5 °C, and the orange crystals that formed were washed with petroleum ether and dried in vacuo (8 Torr). The yield was 1.41 g (79%). M.p. 197 °C. IR, ν/cm-1: 3621 (OH free); 3029; 2870 (CH); 1620 (C=N); 1569; 1467; 1427; 1211. 1H NMR, δ: 1.55 (s, 18 H, But); 5.74 (s, 1 H, OH); 7.12 (d, 1 H, quinol, 3JHH = 8.1 Hz); 7.41-7.45(m, 1 H, quinol); 7.71 (t, 1 H, quinol, 3JHH = 8.0 Hz); 7.89 (s, 2 H,CH arom.); 7.97 (d, 1 H, quinol, 3JHH = 8.0 Hz); 8.50 (s, 1 H,CH=N); 8.74 (d, 1 H, quinol, 3JHH = 8.6 Hz); 8.96 (dd, 1 H, quinol, J = 4.0 Hz, J = 2.5 Hz). 13C NMR, δ: 30.2 (C(CH3)3);34.5 (C(CH3)3); 113.1 (CH quinol); 120.6 (CH quinol); 124.3; 126.4 (CH quinol); 126.5 (2 C); 127.8; 129.6 (CH quinol); 132.8 (CH quinol); 136.6 (2 C); 148.6; 149.9; 150.7 (CH quinol); 157.5; 161.7 (C=N). Found (%): C, 79.76; H, 7.67; N, 7.64. C24H28N20. Calculated (%): C, 79.96; H, 7.83; N, 7.77. UV (CHCl3), λmax/nm (ε): 246 (20029); 296,5 (9301); 342 (11394). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In ethanol at 90℃; | General procedure for the synthesisof semicarbazones (7a-j and 7a′-j′) General procedure: 0.65 mmol of substituted semicarbazides (5a-j) and an equimolar quantity of aldehyde were taken into round-bottle flask with approximately 10 mL of ethanol. Then the mixture was stirred at 90 °C for 4-5 h in the presence catalytic amountof HCl (1.6 mmol) until the disappearance of the starting materials spot in the thin-layer chromatography. Afterward, the reaction mixture was allowed to warm to ambient temperature, stirred for around half an hour. The expected semicarbazones started the formation of solid precipitate during ambient temperature stirring in some of the reactions. The precipitate was filtered and washed with hexane for several times. Then the resultant products were dried and either recrystallized from hexane or column chromatography. However, the reaction in which no precipitates were found, the reaction mixture was concentrated and purified by column chromatography on silica gel with hexane/EtOAc mixture as the eluent. All characterization data have been included into supporting files. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1,3,5-triscyano-2,4,6-tris(N-carbazolyl)benzene; water-d2; sodium carbonate; triisopropylsilanethiol In ethyl acetate at 20℃; for 36h; Inert atmosphere; Sealed tube; Irradiation; | General procedure for the formyl-selective deuteration of aldehydes General procedure: To a 10 mL glass vial was added 4CzIPN (11.8 mg, 0.015 mmol, 5 mol %), aldehyde (0.3 mmol, 1.0 equiv), thiol 5a (22.8 mg, 0.12 mmol, 40 mol %), Na2CO3 (12.7 mg, 0.12 mmol, 40 mol %), and EA/D2O (1:1, v/v; 3.0 mL). The reaction mixture was degassed by bubbling with Ar for 15 s with an outlet needle and the vial was sealed with PTFE cap. The mixture was then stirred rapidly and irradiated with a 36 W Blue LED (approximately 2 cm away from the light source) at room temperature for 36 h. The reaction mixture was diluted with 10 mL of aqueous 1 M NaHCO3 solution, and extracted with DCM (3x20 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel using the indicated solvent system afforded the desired product. |
Tags: 1620-98-0 synthesis path| 1620-98-0 SDS| 1620-98-0 COA| 1620-98-0 purity| 1620-98-0 application| 1620-98-0 NMR| 1620-98-0 COA| 1620-98-0 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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