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CAS No. : | 607-81-8 | MDL No. : | MFCD00009166 |
Formula : | C14H18O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ICZLTZWATFXDLP-UHFFFAOYSA-N |
M.W : | 250.29 | Pubchem ID : | 69090 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 67.63 |
TPSA : | 52.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.87 cm/s |
Log Po/w (iLOGP) : | 2.79 |
Log Po/w (XLOGP3) : | 2.76 |
Log Po/w (WLOGP) : | 1.97 |
Log Po/w (MLOGP) : | 2.39 |
Log Po/w (SILICOS-IT) : | 2.86 |
Consensus Log Po/w : | 2.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.85 |
Solubility : | 0.354 mg/ml ; 0.00141 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.52 |
Solubility : | 0.0756 mg/ml ; 0.000302 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.82 |
Solubility : | 0.0381 mg/ml ; 0.000152 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.92 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In ethanol at 65℃; for 8h; | General procedure to prepare substituent diethyl malonate 2 General procedure: Nano-K2CO3 (0.65mol, 0.90g), diethyl malonate solution (0.5mol, 80.1g), and benzylic halide 1 (1.1mol) in absolute ethanol (250ml) were added into a round-bottomed flask equipped with a water-cooled reflux condenser and a thermometer. The mixture was heated to 65°C on oil bath and stirred for 8h. The reaction was monitored by TLC. The mixture was filtered, and the solvents were removed in vacuo. The residue obtained was added into an equal volume of the mixture of water and ice, and the organic layer was separated. Water layer was extracted with ethyl acetate (4×30ml), mixed with organic the layer, and dried over MgSO4. Concentration under reduced pressure followed by column chromatography over silica gel produced the title compound 2. |
89.3% | With potassium carbonate In ethanol; water at 65℃; for 8h; regioselective reaction; | |
81% | With potassium carbonate In toluene at 80℃; for 5h; |
72% | With tetrabutylammomium bromide; potassium carbonate for 0.0333333h; Irradiation; | |
72% | With potassium carbonate; 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate at 120 - 130℃; for 5h; | |
72% | With sodium ethanolate In ethanol at 20℃; | |
64% | Stage #1: benzyl chloride With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: diethyl malonate With sodium hydride In tetrahydrofuran; mineral oil for 12h; Inert atmosphere; | |
With ethanol; sodium | ||
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide 1.) 0 deg C, 30 min, 2.) r.t., 12 h; | ||
With sodium ethanolate In ethanol | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; | ||
With sodium ethanolate | ||
With sodium methylate In ethanol; water | R.1 Production of 2-benzylmalonic acid diethyl ester REFERENCE EXAMPLE 1 Production of 2-benzylmalonic acid diethyl ester In 200 ml of ethanol, 16.2 g of sodium methoxide were dissolved. Into this solution, 49.5 g of diethyl malonate were dropped and gently refluxed. 37.98 g of benzyl chloride were dropped into the mixture over one hour and the mixture was refluxed for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and water was added to the residue. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride. After removing the solvent under reduced pressure, followed by purification with distillation, 50 g of 2-benzylmalonic acid diethyl ester were obtained. | |
Stage #1: diethyl malonate With sodium methylate In ethanol Heating / reflux; Stage #2: benzyl chloride for 3h; Heating / reflux; | 1 REFERENCE EXAMPLE 1 Production of 2-benzylmalonic Acid Diethyl Ester REFERENCE EXAMPLE 1 Production of 2-benzylmalonic Acid Diethyl Ester In 200 ml of ethanol, 16.2 g of sodium methoxide were dissolved.. Into this solution, 49.5 g of diethyl malonate were dropped and gently refluxed. 37.98 g of benzyl chloride were dropped into the mixture over one hour and the mixture was refluxed for 2 hours.. After the reaction was completed, the solvent was removed under reduced pressure, and water was added to the residue.. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride.. After removing the solvent under reduced pressure, followed by purification with distillation, 50 g of 2-benzylmalonic acid diethyl ester were obtained. | |
With sodium ethanolate In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium ethanolate In ethanol at 40℃; for 4h; | 1.I A mixture of diethyl benzylmalonate (100 g, 0.4 mol), ethyl chloroacetate (53.8 g, 0.44 mol) and sodium ethoxide (30 g, 0.44 mol) in absolute ethanol (500 ml) was stirred at 40° C. for 4 h under argon. The solvent was removed under reduced pressure to yield a residue, which was dissolved in ethyl acetate (1 L). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the title compound as a light yellow oil (130 g, 96% yield), which was used in the next step without further purification. 1H-NMR (CDCl3) δ 7.02-7.27 (m, 5H), 4.13-4.24 (m, 6H), 3.38 (s, 2H), 2.84 (s, 2H), 1.23-1.30 (m, 9H). |
With sodium ethanolate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 5h; | |
99% | With Hantzsch ester; titanium tetrachloride In tetrahydrofuran; dichloromethane at 20℃; for 1h; regioselective reaction; | |
95% | With hydrogen In toluene at 80℃; for 24h; Autoclave; |
95% | With hydrogen In toluene at 80℃; for 24h; | 1 Catalysis Studies for Hydrogenation of Alkylidene Malonate Compounds frustrated Lewis pairs show remarkable reactivity toward the activation of molecular . However, the frustrated Lewis pair-promoted catalytic hydrogenation of electron-poor unsaturated compounds still presents a significant challenge. In view of the interesting catalytic performance of MtL-101(Cr)-LP in the above imine reduction reactions, MtL-101(Cr)-LP was used to achieve the catalytic hydrogenation of alkylidene malonates, which is one important kind of electron-poor unsaturated compound, directly using gas. Alkylidene malonate compounds with different substituted groups were used to investigate the catalytic performance of the heterogeneous MIL- 101(Cr)-LP. As presented in Table 3, the reaction yields catalyzed by MIL-101(Cr)-LP from related alkylidene malonate compounds are 95% for diethyl 2-benzylidenemalonate (Entry 1), 84% for diethyl 2-(2-methylpropylidene)malonate (Entry 2), 83% for diethyl 2- hexylidenemalonate (Entry 3), and 88% for diethyl 2-(cyclohexylmethylene) malonate (Entry 4). For comparison, the yields are 92%, 79%, 81%, and 79% when catalyzed by 10 mol % homogeneous frustrated Lewis pair catalyst, respectively. The comparison of the yields of these products indicates the MIL-101 (Cr)-LP can be used as a porous frustrated Lewis pair catalyst and exhibits excellent catalytic performance in the frustrated Lewis pair-promoted hydrogenation. |
92% | With 1,4-diaza-bicyclo[2.2.2]octane; tris(pentafluorophenyl)borate; hydrogen In toluene at 80℃; for 24h; Autoclave; Inert atmosphere; | |
89% | With CuF(PPh3)3*2MeOH; bis[2-(diphenylphosphino)phenyl] ether In toluene at 25℃; for 8h; Inert atmosphere; chemoselective reaction; | |
87% | With indium(III) chloride; sodium tetrahydroborate In acetonitrile at 20℃; for 6h; | |
87% | With indium(III) chloride; sodium tetrahydroborate In acetonitrile at 28 - 30℃; for 6h; | |
86% | With bis-triphenylphosphine-palladium(II) chloride; Triethoxysilane; (Z)-N,N-diisopropyl-2-styrylbenzamide In tetrahydrofuran at 65℃; for 24h; Inert atmosphere; chemoselective reaction; | |
83% | With 2-(Aminomethyl)pyridine; bromopentacarbonylmanganese(I); potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 120℃; for 12h; Autoclave; chemoselective reaction; | 4.3. Representative procedure for the catalytic hydrogenation reactions General procedure: A 4 ml glass vial was sequentially charged with solid [Mn(CO)5Br](0.015 0.030 mmol), the substrate (0.5 mmol), 2-picolylamine(0.015 0.030 mmol), and a magnetic stirring bar. The reaction componentswere then dissolved in THF (2 ml) or 1,4-dioxane (2 ml)whereupon the resulting yellow solution was then gently stirred(200 rpm) for a period of 5 min. Whilst stirring, the glass vial was sealed with the septum cap. Hereafter, solid t-BuOK (0.015 0.030 mmol) was added to the reaction mixture upon which the reaction vessel was again sealed with a septum cap which was then penetrated with a needle.Notably, the base addition was carried out without stirring. After that,the glass vial was placed in a drilled aluminum liner which was promptly transferred into the 300 ml autoclave. Once tightly sealed, the latter was purged five times with H2 (20 bar per cycle) before being pressurized to the desired value. The autoclave was then placed on a pre-heated stirring plate and heated up to the required reaction temperature. On completion of the hydrogenation reaction, the autoclave was allowed to reach room temperature. Afterwards, the remaining gas was slowlyreleased upon which the reaction mixture was degassed through brieflystirring on air. Finally, n-dodecane (12 mg) or n-hexadecane (20 mg)were added and an aliquot of 30 μl was taken from the solution, mixedwith acetone (1 ml) whereupon the resulting solution was analyzed byGC. |
82.3% | With magnesium(II) perchlorate; 1-Benzyl-1,4-dihydronicotinamide In methanol; acetonitrile at 16℃; for 6.5h; | |
82.3% | With magnesium(II) perchlorate; 1-Benzyl-1,4-dihydronicotinamide In methanol; acetonitrile for 6.5h; Heating; | |
82% | With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; triethylsilane In dichloromethane at 150℃; for 0.5h; Microwave irradiation; chemoselective reaction; | |
81.5% | With Hantzsch ester (PyH2) In pyridine; methanol for 8h; Irradiation; 1-benzyl-1,4-dihydronicotinamide (BNAH), magnesium perchlorate, acetonitrile, methanol, 6.5h, reflux; | |
81.5% | With Hantzsch ester (PyH2) In pyridine; methanol for 8h; Irradiation; 1-benzyl-1,4-dihydronicotinamide (BNAH), magnesium perchlorate, acetonitrile, methanol, 6.5h, reflux; | |
70% | With crosslinked polystirene anion exchange resin in BH4- form In 1,4-dioxane for 10h; Ambient temperature; | |
With diethyl ether; nickel Hydrogenation; | ||
With diethyl ether; aluminium amalgam; water | ||
With ethanol; nickel Hydrogenation; | ||
With sodium cyanoborohydride In ethanol | ||
With hydrogen | ||
With 2,3-dihydro-2-phenyl-1H-benzoimidazole Heating; | ||
> 95 %Spectr. | With C18H9BF6*C4H8O; hydrogen In dichloromethane-d2 at -196.16 - 25℃; for 12h; Inert atmosphere; Schlenk technique; Glovebox; | |
With 1,4-diaza-bicyclo[2.2.2]octane; tris(2,4,6-trifluorophenyl)borane triethylphosphine oxide at 50℃; for 24h; Inert atmosphere; | ||
72 %Spectr. | With cyclohexa-1,4-diene; [IPrGaCl2][SbF6] In 1,2-dichloro-ethane at 80℃; for 16h; Inert atmosphere; chemoselective reaction; | |
100 %Chromat. | With tris(pentafluorophenyl)borate; hydrogen In toluene at 80℃; for 6h; Autoclave; | |
With nicotinamide adenine dinucleotide phosphate; Bacillus subtilis enzyme YqiG In aq. phosphate buffer; N,N-dimethyl-formamide at 30℃; for 1h; Enzymatic reaction; | ||
90 %Spectr. | With (S,S)-N,N′-bis(1-phenylethyl)benzamidinate; hydrogen; tris(2,6-difluorophenyl)borane triethylphosphine oxide In benzene-d6 at 90℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tert-butyl methyl ether; sodium ethanolate In ethanol at 40℃; for 1h; | |
With 1,4-dioxane; N-benzyl-trimethylammonium hydroxide | ||
With N-benzyl-trimethylammonium hydroxide In 1,4-dioxane at 60℃; |
With ammonia |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium aluminium tetrahydride In diethyl ether | |
99% | With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol | |
98% | With lithium aluminium tetrahydride In diethyl ether at 20℃; for 3h; |
98% | With sodium tetrahydroborate; bromine In 1,2-dimethoxyethane at 0 - 20℃; for 15h; | |
97% | With lithium aluminium tetrahydride In tetrahydrofuran for 72h; Reflux; | |
97% | With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 72h; Inert atmosphere; Reflux; | |
85% | With lithium aluminium tetrahydride | |
85% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
84% | With lithium aluminium tetrahydride In diethyl ether at 0℃; for 24h; | |
84% | Stage #1: diethyl 2-benzylmalonate With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol at 20 - 30℃; for 1.5h; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol; water at 20 - 30℃; | |
78% | With lithium aluminium tetrahydride In diethyl ether for 1h; Ambient temperature; | |
77% | With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; Cooling with ice; | 2-benzylpropane-1,3-diol (S5) Et2O (70 mL) was slowly added to the flask on ice bath injected LAH (2.23 g, 60 mmol). To this stirred mixture at0 °C was slowly added 2-benzylmalonic acid diethyl ester as a solution of Et2O (20 mL). After stirred overnight atroom temperature, the reaction mixture was cooled to 0 °C and quenched with H2O (2 mL), 2N-NaOH aqueoussolution (2 mL) and then H2O (6 mL). The residue was filtered on celite pad and washed with EtOAc. The filtratewas washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was through a short pad of silicagel (EtOAc as a eluent) to afford S5 (2.55 g, 77%) as a white solid. The spectral data is in agreement with the datapreviously reported.7 |
76% | With lithium aluminium tetrahydride In diethyl ether at 20℃; | |
72% | With lithium aluminium tetrahydride In diethyl ether for 2.5h; Ambient temperature; | |
71% | Stage #1: diethyl 2-benzylmalonate With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 24.25h; Stage #2: With water In diethyl ether at 0℃; | |
70% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; | 46 To a stirred solution of LAH (600 mg, 15 mmol) in THF (4 mL) at 0 °C were added dropwise a solution of diethyl benzylmalonate (940 μL, 4 mmol) in THF (4 mL). The mixture was then refluxed overnight. The excess of LAH was quenched with wet Na2SO4. The solid was eliminated and the filtrate evaporated to give 2-benzyl-propane-1,3-diol. Yield 70%. tR,LCMS = 1.93 min, Purity 98%; MS (ESI+): m/z = 167 (M+H)+. |
66% | With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 2h; Inert atmosphere; | |
63% | With lithium aluminium tetrahydride In tetrahydrofuran for 20h; Heating; | |
60% | With lithium aluminium tetrahydride In diethyl ether for 3.5h; Heating; | |
60% | With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether Ambient temperature; | |
60% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; Schlenk technique; | |
54% | Stage #1: diethyl 2-benzylmalonate With sodium tetrahydroborate; bromine In 1,2-dimethoxyethane at -20 - 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In 1,2-dimethoxyethane | 7 Example 7 Synthesis of Compound 2-6: 1′,1′″-(2-Benzylpropane-1,3-diyl)bis(1-(2-isopropylphenyl)-[4,4′-bipyridine]-1,1′-diium) tetrakis(tetrafluoroborate) Bromine (11.26 g, 70 mmol) was added dropwise to a suspension of NaBH4 (6.08 g, 160 mmol) in 1,2-dimethoxyethane (70 mL) under N2 with stirring at -20° C. After the addition the mixture was stirred at 0° C. for 2 h, cooled to -5° C. and diethyl 2-benzylmalonate (8 g, 32 mmol) was added. The mixture was allowed to warm to room temperature overnight, cautiously poured onto HCl (1 M, 100 mL) and EtOAc (100 mL) with rapid stirring at 5° C. The aqueous phase was separated and extracted with EtOAc (100 mL). The combined organic phases were washed with Na2CO3 (2×100 mL), water (100 mL), dried (Na2SO4) and the solvent removed under reduced pressure. The residue was filtered through silica using EtOAc (40-100% in hexanes) as eluent. The third band (Rf=0.05; 40% EtOAc in hexanes) was collected and the solvent removed under reduced pressure to give 2-Benzylpropane-1,3-diol (2.87 g, 54%) as a colourless oil which solidified on standing. (0111) δH (400 MHz, CDCl3) 7.10-7.4 (5H, m), 3.83 (2H, dd, J=4, 11 Hz), 3.69 (2H, dd, J=7, 11 Hz), 2.64 (2H, d, J=7 Hz), 2.35 (2H, bs), 2.02-2.16 (1H, m). (0112) δC (100 MHz, CDCl3) 139.85, 129.01, 128.48, 126.17, 65.64, 43.84. |
32% | With indium(III) chloride; sodium tetrahydroborate In acetonitrile for 42h; Heating; | |
With methanol; copper oxide-chromium oxide at 150 - 160℃; Hydrogenation; | ||
With lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In diethyl ether Heating; | ||
With lithium aluminium tetrahydride In tetrahydrofuran | ||
With lithium aluminium tetrahydride In tetrahydrofuran Heating; | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 4h; Ambient temperature; | ||
With lithium aluminium tetrahydride In diethyl ether | ||
With lithium aluminium tetrahydride | ||
With sodium borohydrid; acetic acid; lithium chloride In tetrahydrofuran; ethanol; water; ethyl acetate | 45.a (2R)-2-benzyl-3-hydroxypropionic acid (a) 5 g of diethyl benzylmalonate was dissolved in a mixture of 120 ml of ethanol and 80 ml of THF, and 3.8 g of sodium borohydride and 4.3 g of lithium chloride were added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours. Then, 5.8 ml of acetic acid was added thereto, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue. The ethyl acetate layer was separated, washed with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.5 g of 2-benzyl-1,3-propanediol as colorless solid. Rf value: 0.17(n-hexane/ethyl acetate=1/1) | |
6.94 g (90%) | With hydrogenchloride In tetrahydrofuran; water | 1.1 N-Boc-5-Amino-2-benzyl-3-pentenoic Acid (10) 1. Preparation of 2-benzyl-1,3-propanediol (2). To a stirred solution of 3.80 g (100 mmol) of lithium aluminum hydride in 200 ml of tetrahydrofuran at 0° C. was added dropwise a solution of 11.61 g (46.4 mmol) of diethyl benzylmalonate in 100 ml of tetrahydrofuran. After being stirred at 0° C. for 3 hours, the reaction mixture was quenched by cautious dropwise addition of 50 ml of 1N hydrochloric acid followed by 100 ml of water. The mixture was extracted with ethyl acetate. The extracts were dried and concentrated to afford 6.94 g (90%) of a white crystalline solid; 1 H NMR (CDCl3) δ 1.97 (m, 1H), 2.45 (s, 2H), 2.82 (s, 2H), 3.55 (m, 2H), 3.70 (m, 2H), 7.05 (m, 3H), 7.18 (m, 2H). |
In diethyl ether | 15 EXAMPLE 15 The 9-oxo-bis(tetrahydropyranyl)ether used as the starting material was prepared as follows:- Diethyl benzylmalonate (100g.) was added dropwise to a stirred suspension of lithium aluminimum hydride (12g.) in anhydrous diethyl ether (300ml.) at 0° C. under argon. The reaction mixture was then stirred overnight at room temperature and worked up by the conventional procedure, described in J. Org. Chem. 1953, 18, 1190. Evaporation of the ether solution gave 2-benzylpropane-1,3-diol. | |
Stage #1: diethyl 2-benzylmalonate With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Stage #2: With hydrogenchloride In water | 4 REFERENCE EXAMPLE 4 Production of 2-benzyl-1,3-propanediol 7.59 g of lithium aluminum hydride were suspended in 100 ml of tetrahydrofuran. Into this suspension, 70 ml of tetrahydrofuran solution containing 25.0 g of 2-benzylmalonic acid diethyl ester which was obtained in Reference example 1 were dropped under ice cooling, and then stirred for 1 hour under ice cooling and for 3 hours at room temperature. To this reaction solution, 200 ml of a 2N hydrogen chloride solution were added, then a tetrahydrofuran layer and a water layer were separated. To the water layer, ethyl acetate was added and the ethyl acetate layer was recovered. The obtained tetrahydrofuran layer and the ethyl acetate layer were mixed. After washing this mixture with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, the mixture was dried with sodium sulfate anhydride. After the solvent was removed under reduced pressure, 13.7 g of colorless and solid 2-benzyl-1,3-propanediol were re-crystallized from ethyl acetate-hexane. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.002.11 (m, 1H), 2.32 (br s, 2H), 2.64 (d, J=7.8 Hz, 2H), 3.67 (dd, J1=6.8 Hz, J2=10.5 Hz, 2H), 3.81 (dd, J1=3.9 Hz, J2=10.5 Hz, 2H), 7.127.34 (m, 5H). | |
With lithium aluminium tetrahydride In tetrahydrofuran Cooling; Reflux; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3h; | 31.1 Step 1: 2-benzylpropane-1,3-diol (262-2) To a solution of LAH (6 g, 160 mmol) in THF (200 mL) was added Compound 7A-1 (10 g, 40 mmol) in THF (40 mL) at 0°C. The mixture was stirred at 20°C for 3 hrs. LCMS showed the reaction completed and desired mass was detected. The reaction mixture was quenched by addition 6 mL H2O, 6 ml10% NaOH, 18mL H2O at 0°C, and then filtered and concentrated in vacuum to give Compound 7A-2 (10 g, crude) as a white solid. M+H+=167.1 (LCMS);1H NMR (400MHz, CHCl3-d) d = 7.38 - 7.29 (m, 2H), 7.26 - 7.20 (m, 3H), 3.86 (dd, J=3.8, 10.6 Hz, 2H), 3.77 - 3.68 (m, 2H), 2.68 (d, J=7.6 Hz, 2H), 2.18 - 2.04 (m, 1H). | |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 18h; | ||
With lithium aluminium tetrahydride In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid at -10℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ethanol; potassium hydroxide; at 20℃; for 3h; | To a 100-mL eggplant-shaped flask, 9 mL of an ethanol solution of potassium hydroxide (337 mg, 6 mmol, 1 eq) and benzylmalonic acid diethyl ester (1.5 g, 6 mmol, 1 eq) were added. The mixture was stirred at room temperature for 3 hours. The reaction was followed by TLC (SiO2/CHCl3 : MeOH = 10 : 1) and completed when the production of the compound of interest was confirmed. The solvents were distilled off under reduced pressure using a vacuum pump. The residue was dissolved in a 5% aqueous sodium bicarbonate solution (100 mL) . The aqueous layer was washed with ethyl acetate (100 mL, twice) . Then, the pH was adjusted to acidic pH (up to 1.0) with a 1 N aqueous hydrochloric acid solution. After extraction with ethyl acetate (100 mL, three times), the organic layer was washed with a 1 N aqueous hydrochloric acid solution (100 mL, once) and then dried over anhydrous magnesium sulfate. Insoluble matter was filtered off. Then, the solvents were distilled off under reduced pressure. The residue was vacuum-dried to obtain a white solid. Identification was conducted by 1H-NMR. Experimental Results> White Solid Yield : 1 . 28 g ( 96% ) |
~ 95% | a. Preparation of ethyl (phenylmethyl)propanedioic acid To a solution of diethyl benzylmalonate (20.0g, 80 mmol) in ethanol (500 mL) was added potassium hydroxide (4.7 g, 84 mmol) as pellets. The mixture was stirred at room temperature for 24 h, and concentrated to dryness in vacuo. The residue was dissolved in water (300 mL), transferred to a separatory funnel, and washed with ether (2*150 mL). The aqueous solution was acidified to pH~2 by adding conc. HCl, and extracted with ether (2*400 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo, yielding the title compound as an oil residue (16.9 g, 95%) which was used without further purification. | |
95% | To a solution of diethyl benzylmalonate (20.0 g, 80 mmol) in ethanol (500 mL) was added potassium hydroxide (4.7 g, 84 mmol) as pellets. The mixture was stirred at room temperature for 24 h, and concentrated to dryness in vacuo. The residue was dissolved in water (300 mL), transferred to a separatory funnel, and washed with ether (2*150 mL). The aqueous solution was acidified to pH~2 by adding conc. HCl, and extracted with ether (2*400 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo, yielding the title compound as an oil residue (16.9 g, 95%) which was used without further purification. |
89% | With potassium hydroxide; In ethanol; at 20℃; for 72h; | Malonate 1a (7.5 g, 30.0 mmol) was added to a solution of KOH (1.68 g, 30.0 mmol) in 45 mL of EtOH at room temperature and the solution was stirred for 72 h. For the work-up the solvent was evaporated and the resulting residue was dissolved in NaHCO3 5% (20 mL) and washed with ethyl acetate (15 mL). The aqueous layer was acidified and extracted with ethyl acetate (3*15 mL). The combined organic layers were dried over Na2SO4, filtered, and solvent evaporated to give monoacid 2a as a colorless oil (89%). Monoacid 2a was obtained as a chromatographically pure compound and no further purification was required. Its spectroscopic behavior was consisted with reported data. 2-(Ethoxycarbonyl)-3-phenylpropionic acid (2a). Colorless oil, 89% yield. 1H NMR (300 MHz, CDCl3) δ 10.84 (br s, 1H), 7.32-7.28 (m, 5H), 4.18 (q, J=7.1 Hz, 2H), 3.72 (t, J=7.7 Hz, 1H), 3.25 (d, J=7.7 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 168.8, 137.5, 128.9, 128.7, 126.9, 61.9, 53.7, 34.6, 13.9; IR (cm-1): 1716. |
87% | With potassium hydroxide; In ethanol; at 20℃; for 24h; | To a solution of diethyl benzylmalonate (6.0 g, 24 mmol) in EtOH (150 mL) was added KOH (1.4 g, 25 mmol) as pellets. The mixture was stirred at RT for 24 h and then the solvent was concentrated under reduced pressure. The residue was dissolved in H2O, transferred to a separatory funnel and washed twice with Et2O. The aqueous phase was acidified by using conc. HCl to pH = 1 and extracted with Et2O twice. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-benzyl-3-ethoxy-3-oxopropanoic acid as a colorless oil (4.7 g, 87% yield). |
74% | To a solution of 2-benzylmalonic acid diethyl ester 2.5 g (10 mmol) in EtOH (10 mL) was added 1N KOH in EtOH (8.5 mL). The solution was stirred for 1 h at room temperature. The solvent was removed under reduced pressure, and the resulting liquid dissolved in 5% NaHCO3 (30 mL), washed with EtOAc (3×10 mL), and back extracted with 5% NaHCO3 (50 mL). The combined NaHCO3 solutions were acidified to pH=3 with 1N HCl and extracted with EtOAc. The organic layer was washed with H2O, dried with Na2SO4. The solvent was removed under reduced pressure to give final product as oil, 1.4 g (74%).1H NMR (DMSO-d6) δ 7.17-7.25 (m, 5H), 4.02 (q, J=7.2 Hz, 2H), 3.67 (t, J=7.2 Hz, 1H), 3.04 (dd, J=7.2, J=8.8 Hz, 2H), 1.06 (t, J=7.2 Hz, 3H).MS (ESI) (C12H14O4) ([M+H]+: found m/z, 223.4; calcd, 223.2.Anal. Calcd for C12H14O4: C, 64.85; H, 6.35; O, 28.80; Found: C, H, N. | |
69% | With water; potassium hydroxide; at 18 - 25℃; for 2h; | General procedure: In a manner similar to 19, a RBF equipped with a stirring bar was charged with themalonate derivative 3 (1.0 equiv) and the solvent (c = 0.5 M, V mL). A 5 M aqueous solution of KOH (1.0 equiv) was added with asyringe and the reaction mixture was stirred at rt for 2 h. Then, the mixture was concentrated, diluted with water (V mL), and the mresulting aqueous layer was washed with Et2O (3*V/4 mL), acidified to pH 1 by the addition of 1 M aq HCl, saturated with NaCl, and extracted with EA (3*V/4 mL). The combined organic layers were dried (Na2SO4) and evaporated to afford the expected product 4. |
With potassium hydroxide; In ethanol; | STR3 Step 1 Preparation of benzylmalonic acid monoethyl ester. Benzylmalonic acid diethyl ester (10 g, 40 mmol) in 25 mL of ethanol is cooled to 0 C. Potassium hydroxide (2.5 g, 40 mmol) dissolved in 25 mL of ethanol is added dropwise over 50 minutes. The cooling bath is removed and the mixture is stirred for one additional hour. The volume of solvent is reduced by evaporation in vacuo, and the residual solution is poured into aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The aqueous phase is acidified with aqueous 10% HCl and extracted twice with ethyl acetate. The organic phase is dried with a brine extraction, filtered from anhydrous sodium sulfate, and concentrated in vacuo, yielding 8.08 g of the title compound as a colorless oil. | |
With potassium hydroxide; In ethanol; | (a) Monoethyl benzylmalonate Diethyl benzylmalonate (89.5 g) was dissolved in absolute ethanol (230 ml) and a cold solution of KOH (22.06 g) in absolute ethanol (230 ml) added with stirring over a period of 1 hour. Stirring was continued at ambient temperature overnight. The mixture was concentrated in vacuo to an oil (63 g) | |
With potassium hydroxide; In ethanol; | Step 1 Preparation of benzylmalonic acid monoethyl ester. Benzylmalonic acid diethyl ester (10 g, 40 mmol) in 25 mL of ethanol is cooled to 0 C. Potassium hydroxide (2.5 g, 40 mmol) dissolved in 25 mL of ethanol is added dropwise over 50 minutes. The cooling bath is removed and the mixture is stirred for one additional hour. The volume of solvent is reduced by evaporation in vacuo, and the residual solution is poured into aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The aqueous phase is acidified with aqueous 10% HCl and extracted twice with ethyl acetate. The organic phase is dried with a brine extraction, filtered from anhydrous sodium sulfate, and concentrated in vacuo, yielding 8.08 g of the title compound as a colorless oil. | |
(1) monoethyl benzylmalonate To a solution of diethyl benzylmalonate (27.1 g) in ethanol (70 mL) was added a solution of potassium hydroxide (6.1 g) in ethanol (70 mL), and the mixture was stirred at room temperature for 18 hr. After concentration under reduced pressure, water (300 ml) and ether (100 mL) were added to extract the mixture. The aqueous layer was adjusted to pH = 1-2 by the addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL*2). The organic layer was washed with saturated brine and concentrated under reduced pressure to give the title compound (19.3 g) as an oil. 1H-NMR(300MHz, DMSO-d6)δ1.08(3H, t, J = 7.2Hz), 3.05(2H, dd, J = 9.3, 4.8Hz), 3.67-3.72(1H, m), 4.04(2H, q, J = 7.2Hz), 7.17-7.30(5H, m), 12.94(1H, brs). | ||
With ethanol; potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.85h; | To a stirred solution of diethyl benzylmalonate (5 g, 19.98 mmol) in 20 mL of ethanol at 0C was added a solution of KOH (1.121 g, 19.98 mmol) in 15 mL of ethanol slowly over 15 mm. It was allowed to warm to rt and stirred for 16 h. It was concentrated and the residue was partitioned between water (2x100 mL) and diethyl ether (100 mL). The aqueous layer was separated and acidified by addtion of 4 M HC1 to pH = 3. It was extracted with ethyl acetate (3x200 mL). Thecombined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (mle): 223.09 [M + H]. | |
With potassium hydroxide; In ethanol; at 20℃; for 19h; | General procedure: Solution of KOH (560 mg, 10.0 mmol in a case of 8a-d) in ethanol (95 %, 10 mL) was added dropwiseduring 1 h to a solution of the corresponding diethyl malonate S1 (10.0 mmol) in ethanol (95 %, 10 mL). The resulting mixture was stirred at rt for 18 h. Solution was concentrated to 3 mL under reduced pressure in a rotary evaporator at rt. The residue was dissolved in water (20 mL) and washed with Et2O (3 × 15 mL). The aqueous solution was cooled in an ice bath saturated with NaCl and Et2O (15 mL) was added. This mixture was carefully acidified with 6M HCl under stirring, organic layer was collected, and aqueous solution was additionally extracted with Et2O (2 × 15 mL). The combined ether extracts were washed with saturated aqueous NaCl and dried over Na2SO4. The ether was removed under reduced pressure in a rotary evaporator at rt to give the desired malonic acid half ester 8. The latter was used in the synthesis of pyrrolidines without an additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With lead(IV) acetate; zinc dibromide In acetonitrile at 20℃; for 18h; | |
79% | Stage #1: diethyl 2-benzylmalonate With bromine In diethyl ether at 20℃; for 4h; Stage #2: for 4h; | |
With bromine; dibenzoyl peroxide Irradiation; |
Stage #1: diethyl 2-benzylmalonate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iodine; aluminium In acetonitrile at 80℃; for 18h; | |
87% | With water; sodium hydroxide In methanol at 70℃; for 1h; | General procedure 2 (GP2) - saponification: General procedure: A RBF equipped with a stirring bar was charged with malonate 3 (1.0 equiv) and MeOH(c = 2 M). After addition of a 6 M aqueous solution of NaOH (5.0 equiv), the reaction mixture was stirred at 70 °C for 1 h. The resulting mixture was then acidified to pH 1 with 1 M aq HCl, and extracted twice with EA (20 mL). The combined organic layers were dried(Na2SO4) and evaporated to afford the expected product 9. |
85% | With sodium hydroxide In methanol; water at 20℃; Inert atmosphere; |
41% | Stage #1: diethyl 2-benzylmalonate With potassium hydroxide In ethanol; water at 90℃; for 6h; Stage #2: With hydrogenchloride In water | |
With potassium hydroxide | ||
With potassium hydroxide | ||
With potassium hydroxide In methanol | ||
With potassium hydroxide In ethanol at 0 - 20℃; for 4h; | ||
With sodium hydroxide In methanol; dichloromethane at 20℃; for 2h; | ||
Alkaline hydrolysis; | ||
With potassium hydroxide | ||
With water; potassium hydroxide In ethanol at 20℃; for 10h; | ||
With water; potassium hydroxide at 20℃; for 48h; | ||
With sodium hydroxide In water for 2h; Reflux; | Procedures and characterization of 3-(2-methylenehexanoyl)oxazolidin-2-one and 3-(2-benzylacryloyl)oxazolidin-2-one General procedure: Substituted malonate (30 mmol) was added to a solution of NaOH (2 M, 40 mL) and the resulting mixture was refluxed for 2 h with vigorous stirring. After completion of reaction, resulting mixture was extracted with n-hexane. The aqueous phase was acidified to pH 1 with HCl. The resulting aqueous layer was then extracted with EtOAc (2 times).The mixture was concentrated in vacuo and purified over silica gel by column chromatography afford the corresponding diacid. The diacid was further transferred to α-substituted Nacryloyloxazolidinones by known procedure reported in literature. | |
187 mg | With water; sodium hydroxide for 5h; Reflux; | 4.8 2-Methylene-3-phenylpropionic acid (19) To a suspension of the above crude 17 in water (10mL) was added solid NaOH (100.0mg, 2.50mmol) followed by refluxing with stirring for 5h. The reaction mixture was adjusted to ca. pH 1 with concn. aqueous HCl and was then extracted with EtOAc (20mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in hexane) to give 2-benzylmalonic acid (18, 187.0mg, 93% for 2 steps) as a yellow oil. Rf=0.30 (50% EtOAc in hexane); 1H NMR (400MHz, DMSO-d6) δ 7.30-7.18 (m, 5H), 3.56 (t, J=7.6Hz, 1H), 3.04 (d, J=7.2Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 170.6, 138.8, 128.9 (×2), 128.4 (×2), 126.5, 53.4, 34.4. |
With water; sodium hydroxide at 70℃; for 2h; | i Synthesis of Intermediate A Synthesis of Intermediate A (0433) 9.0 g (84.0 mmol) of benzylamine and 100 mL of toluene were put into a flask and cooled to 0° C., and 10.0 g (84.0 mmol) of phenyl isocyanate was added dropwise thereto over 10 minutes. After dropwise addition, the solution was stirred for 30 minutes, heated to 40° C., and then stirred for 2 hours, and the obtained solution was named solution (A). Meanwhile, 27.3 g (109.2 mmol) of diethyl benzyl malonate was put into a flask, and 200 mL of a 2 M aqueous NaOH solution was added dropwise thereto over 20 minutes. After dropwise addition, the solution as heated to 70° C., stirred for 2 hours, and cooled to 0° C., and 40 mL, of concentrated hydrochloric acid was added dropwise thereto over 30 minutes. After dropwise addition, 86 g of NaCl and 200 mL of ethyl acetate were added to the reaction solution, the resulting solution was stirred for 1 hour at 40° C., and then an organic layer was concentrated. The organic layer and 61.5 g (602.2 mmol) of acetic anhydride were added to the solution (A) obtained as above, and the resulting solution was stirred for 2 hours at 75° C. After the reaction, the reaction solution was concentrated under reduced pressure, 100 mL, of methanol and 0.1 mL of concentrated hydrochloric acid were added thereto, and the resulting solution was heated under reflux for 2 hours. Then, methanol was distilled away, and 100 mL of toluene and 84 mL of a 1 M aqueous NaOH solution were added to the resultant at 25° C., followed by stirring for 1 hour at 25° C. The aqueous layer was cooled to 0° C., and 80 mL of 3 M hydrochloric acid was added dropwise thereto over 30 minutes. As a result, a crystalline product was precipitated. The product was further stirred for 1 hour at 10° C., and the precipitated crystal was subjected to suction filtration and washed once with cooled aqueous methanol (methanol/water=1/3) and dried, thereby obtaining 30.9 g (80.4 mmol) of an intermediate A with an yield of 96% and a purity of 97.89%. | |
With sodium hydroxide In methanol; dichloromethane | ||
With lithium hydroxide In methanol; water at 25℃; for 2h; | ||
With potassium hydroxide In ethanol at 0 - 20℃; for 24h; | General procedure for the synthesis of acrylic acids of type 3 General procedure: Sodium (1.0 equiv) is slowly added and dissolved in abs. ethanol (1.4mL/mmol). Then, diethyl malonate (1.0 equiv) is added dropwise and the resulting mixture is stirred during 30 min at room temperature. Then, the respective bromide is added dropwise at room temperature and the resulting mixture is refluxed during 24 h. After removal of volatiles, H2O is added and extractions with Et2O (×3) are performed. The combined organic layers are dried with Na2SO4 and evaporated to afford the crude product which is assumed to contain only the target monoalkylated diethyl ester of type 6. The residue is dissolved in EtOH (0.5 mL/mmol of 6) and cooled at 0°C. At the same temperature, a solution of KOH (2.0 equiv) in EtOH (1.5 mL/mmol of 6) is slowly added. The mixture is stirred at rt and the progress of the reaction is followed by TLC, until diethylester 6 is fully consumed (if needed, up to 1.0 equiv of KOH is gradually added). Typically, reaction time is 24h. The mixture is concentrated and the residue is diluted H2O and Et2O. The aqueous phase is separated, washed with Et2O (×2), acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford diacid of type 7. The latter is dissolved/suspended to ΑcOEt (1.8 mL/mmol of 7) and Et2NH (1.2 equiv) is added slowly at 0 °C. The temperature is raised at rt, ΗCHO (1.4 equiv) is added and the mixture is refluxed for 4 h. Then, the mixture is concentrated, treated with aq. NaHCO3 5% and washed with Et2O (×3). The aqueous phase is acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford acrylic acid of type 3 inadequately pure form to be used in the P-Michael reaction without further purification. | |
With water; sodium hydroxide In ethanol at 120℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium etoxide In ethanol for 2h; Heating; | |
88% | With (3S,4S)-1-benzyl-3,4-pyrrolidin-diol-onium iodide; potassium carbonate In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
80% | With aluminum(III) oxide; potassium-t-butoxide for 6h; |
80% | With zinc powder In N,N-dimethyl-formamide at 60℃; for 6h; Inert atmosphere; | |
76% | Stage #1: malonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 2h; Inert atmosphere; | General procedure 1 (GP1) General procedure: alkylation: A RBF equipped with a stirring bar was charged with NaH 60% (1.0 equiv) and purged withargon. DMF (V mL) was added and the RBF was cooled to 0 °C (ice/water bath). Malonate 1 (1.1 equiv) was added dropwise with asyringe and the mixture was stirred for 15 min. The alkyl halide 2 (1.0 equiv) was then added dropwise with a syringe. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Then, the resulting mixture was poured in sat aq NH4Cl (3 V)and the resulting solution was extracted with Et2O (3 × 2 V). The combined organic layers were washed with water (10 V) and brine (5V), dried (Na2SO4), and evaporated. Purification by FC afforded the expected product 3. |
72% | Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran Inert atmosphere; Reflux; | |
67% | Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | |
65% | Stage #1: malonic acid diethyl ester With N-hexadecyl-N,N,N-trimethylammonium bromide; potassium carbonate In water monomer at 20℃; for 0.25h; Green chemistry; Stage #2: benzyl bromide In water monomer at 60℃; for 16h; Green chemistry; regioselective reaction; | |
64% | With potassium carbonate In acetonitrile for 17h; Reflux; | |
63% | In tetrahydrofuran for 24h; Heating; | |
61% | Stage #1: malonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.75h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 20h; Inert atmosphere; | |
With potassium carbonate In toluene at 80℃; for 1h; Yield given; | ||
With sodium hydride 1) THF, rt, 2) reflux, 24 h; Multistep reaction; | ||
With potassium etoxide In ethanol Heating; | ||
With sodium hydride 1.) THF, r.t., 60 min; 2.) THF, 70 deg C, 2 h; Yield given. Multistep reaction; | ||
With potassium etoxide 1.) EtOH, 50 deg C, 1 h, 2.) EtOH, 50 deg C, 6 h; Multistep reaction; | ||
Stage #1: malonic acid diethyl ester With natrium In ethanol Stage #2: benzyl bromide In ethanol Heating; | ||
With potassium etoxide In ethanol for 8h; Heating; | ||
With potassium etoxide In ethanol | ||
Stage #1: malonic acid diethyl ester With potassium etoxide In ethanol at 20℃; Stage #2: benzyl bromide In ethanol Reflux; | ||
Stage #1: malonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20 - 25℃; Inert atmosphere; | ||
With N,N,N-tributyl-1-butanaminium iodide; potassium carbonate In acetonitrile for 10h; Reflux; | 4.8 2-Methylene-3-phenylpropionic acid (19) A solution of diethyl malonate (16) (200.0mg, 1.25mmol), K2CO3 (345.0 mg, 2.50 mmol), tetrabutylammonium iodide (23.0 mg, 0.06 mmol), and benzyl bromide (178μL, 1.50mmol) in MeCN (13mL) was stirred under refluxing for 10h. The reaction was quenched with aqueous 10% HCl and the reaction mixture was extracted with EtOAc (30mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a crude product of 17. | |
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Schlenk technique; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran for 1h; Reflux; Schlenk technique; Inert atmosphere; | ||
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran; paraffin oil at 0 - 20℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran; paraffin oil at 20℃; for 3h; | ||
Stage #1: malonic acid diethyl ester With natrium In ethanol at 20℃; for 0.5h; Stage #2: benzyl bromide In ethanol for 24h; Reflux; | General procedure for the synthesis of acrylic acids of type 3 General procedure: Sodium (1.0 equiv) is slowly added and dissolved in abs. ethanol (1.4mL/mmol). Then, diethyl malonate (1.0 equiv) is added dropwise and the resulting mixture is stirred during 30 min at room temperature. Then, the respective bromide is added dropwise at room temperature and the resulting mixture is refluxed during 24 h. After removal of volatiles, H2O is added and extractions with Et2O (×3) are performed. The combined organic layers are dried with Na2SO4 and evaporated to afford the crude product which is assumed to contain only the target monoalkylated diethyl ester of type 6. The residue is dissolved in EtOH (0.5 mL/mmol of 6) and cooled at 0°C. At the same temperature, a solution of KOH (2.0 equiv) in EtOH (1.5 mL/mmol of 6) is slowly added. The mixture is stirred at rt and the progress of the reaction is followed by TLC, until diethylester 6 is fully consumed (if needed, up to 1.0 equiv of KOH is gradually added). Typically, reaction time is 24h. The mixture is concentrated and the residue is diluted H2O and Et2O. The aqueous phase is separated, washed with Et2O (×2), acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford diacid of type 7. The latter is dissolved/suspended to ΑcOEt (1.8 mL/mmol of 7) and Et2NH (1.2 equiv) is added slowly at 0 °C. The temperature is raised at rt, ΗCHO (1.4 equiv) is added and the mixture is refluxed for 4 h. Then, the mixture is concentrated, treated with aq. NaHCO3 5% and washed with Et2O (×3). The aqueous phase is acidified with HCl 2M to pH ~1 and extracted with AcOEt (×3). The combined organic layers are dried over Na2SO4 and evaporated to afford acrylic acid of type 3 inadequately pure form to be used in the P-Michael reaction without further purification. | |
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: benzyl bromide at 0 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 8.9% 2: 4.7% 3: 13.2% | With cetyltrimethylammonim bromide; sodium carbonate In water; acetonitrile for 24h; Ambient temperature; | |
1: 48.8 % Chromat. 2: 23.0 % Chromat. 3: 28.2 % Chromat. | With cetyltrimethylammonim bromide; sodium carbonate In water; acetonitrile for 24h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With stearic acid at 200℃; for 4h; | |
92% | In water; N,N-dimethyl-formamide at 160℃; for 0.333333h; microwave irradiation; | |
87% | With water; sodium chloride In dimethyl sulfoxide at 160 - 165℃; for 9h; |
87% | With lithium sulfate In water at 210℃; for 0.5h; Microwave irradiation; Green chemistry; | |
65% | With N-benzyl-trimethylammonium hydroxide In dimethyl sulfoxide at 80℃; for 3h; | |
Multi-step reaction with 2 steps 1: porcine liver acetone powder (PLAP), 2N aq. NaOH / H2O / 7 h / 20 °C / pH 7.2 2: 87 percent / 160 - 200 °C / 1 Torr | ||
Multi-step reaction with 2 steps 1: potassium hydroxide / ethanol / 72 h / 20 °C 2: 1H-imidazole / neat (no solvent) / 0.07 h / 69 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tributylphosphine; 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione In benzene for 24h; Ambient temperature; | |
56% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In benzene 1) 0 deg C, 10 min, 2) RT, 24 h; | |
99 %Chromat. | In trifluorotoluene at 180℃; for 2h; Inert atmosphere; Autoclave; | 2.2.2. Catalyzed α-monoalkylation of malonate diester with benzyl alcohol A mixture of benzyl alcohol (1 mmol), diethylmalonate (3 mmol), 0.0998 g of Pd-MgO (Pd: 0.0075 mmol), trifluorotoluene (1 ml), and n-dodecane (20 μl) as internal standard were placed into an autoclave. The resulting mixture was vigorously stirred at 180 °C (or 100 °C) under nitrogen. The reaction was monitored by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: With 2,4,5-trichloropyridazin-3(2H)-one In tetrahydrofuran at 0℃; for 0.5h; | |
98% | With lead(IV) acetate; aluminium trichloride In acetonitrile at 20℃; for 7h; | |
95% | With manganese triacetate; lithium chloride In acetic acid for 1h; Heating; |
Stage #1: diethyl 2-benzylmalonate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In N,N-dimethyl-formamide at 0 - 14℃; for 3.33333h; | |
69% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; | 2.38b diethyl 2-benzyl-2-methylmalonate Anhydrous DMF (20.0 mL) and diethyl 2-benzylmalonate (1.5 g, 6 mmol) were placed in an oven-dried, N2-flushed, 100 mL round-bottom flask and cooled to 0° C. in an ice bath. NaH (263 mg, 6.5 mmol), and iodomethane (548 ul, 6 mmol) were added and the reaction mixture was allowed to warm to room temperature. The reaction medium was stirred vigorously at room temperature for 2 hr, quenched with water (20 mL) and extracted with DCM (3×25 mL). The combined organic phase was washed with brine, dried over MgSO4, and solvents were evaporated. The residue was purified by flash chromatography using a 12 g Silicycle column and EtOAc/Hexanes as eluant to obtain the pure product (1.1 g, 69%) as a clear colorless oil. MS 265 (MH+). H1-NMR is consistent with the structure. |
With sodium hydride 1.) THF, 2.) THF, 1 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium perchlorate; fluorosulphonic acid; sodium hydride In tetrahydrofuran | |
77% | With titanium(IV) isopropylate; N-fluorobis(methanesulfonyl)imide In dichloromethane for 12h; Inert atmosphere; Reflux; | |
With 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere; |
With sodium hydride; Selectfluor In tetrahydrofuran at 20℃; Inert atmosphere; | ||
With sodium hydride; Selectfluor In tetrahydrofuran at 20℃; | ||
Stage #1: diethyl 2-benzylmalonate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With Selectfluor In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With iodine; sodium acetate In tetrahydrofuran; water at 35℃; for 3h; Irradiation; Green chemistry; | |
94% | With 10% Pd on charcoal; oxygen; sodium ethanolate In ethanol at 20℃; for 24h; | |
90% | Stage #1: diethyl 2-benzylmalonate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: With (+)-camphorsulfonyl)oxazoridine 2a In tetrahydrofuran at -78℃; for 0.333333h; |
71% | With cesium fluoride In N,N-dimethyl-formamide at 40℃; for 72h; | The mixture of diethyl α-benzylmalonate (41g, 164mmol) and CsF (49.8g) in 90mL of DMF was heated at 40°C with vigorous air bubbling for 3days. The resulting mixture was diluted with ethyl acetate (800mL) and washed with water (1L×3). The organic layer was concentrated and then purified by biotage (5-20% ethyl acetate in hexanes) to give the diethyl α-benzyl α-hydroxy malonate (31g, 117mmol, 71%) as a colorless oil. 1H NMR (300MHz, CDCl3) δ: 7.22-7.26 (m, 5H), 4.23 (q, J=7.2Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J=7.2Hz, 6H). To diethyl α-benzyl α-hydroxy malonate (6.3g, 24mmol) in 50mL of EtOH (anhydrous) was added KOH (1.5g). The mixture was stirred at rt over night. After removing the solvent in vacuo, the residue was taken up with 100mL of ethyl acetate and 150mL of water. The organic layer was removed. To the aqueous layer containing the potassium salt of the desired product was added 0.2N HCl until pH=2. The mixture was extracted with 200mL ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to give the acid (2.6g, 11mmol, 46%) as a colorless oil. The racemic acid was then purified by chiral SFC (OJ-H, 4.6×100mm, 5% MeOH/0.1% TFA/CO2, 2.5mL/min, 100bar) to give (2R)-2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid as a single enantiomer (1.0g, the first eluting peak). The assignment of the absolute configuration is based on vibrational circular dichroism (details in supporting information). LC/MS 261.1 (M+23). To a mixture of (2R)-2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (112mg, 0.47mmol), 3,5-dimethoxybenzylamine (86mg, 0.51mmol) and HATU (197mg, 0.52mmol) was added DMF (4mL) and Hünig base (67mg, 0.52mmol). The mixture was stirred at rt for 2h. To the mixture was added ethyl acetate and water. The organic layer was washed with water twice, and dried with magnesium sulfate. After removal of the solvent, the residue was purified by biotage (10-30% ethyl acetate in hexanes) to give ethyl (2R)-2-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxy-3-oxopropanoate (132mg, 0.34mmol, 72%) as a colorless oil. To a mixture of ethyl (2R)-2-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxy-3-oxopropanoate (40mg, 0.10mmol) and isocyanate 11 (80mg, 0.54mmol) in 4mL of THF was added NaOH (solid, 50mg) at rt. The mixture was under vigorous stirring for overnight. Filtered, and washed with ethyl acetate. The filtrate was concentrated, taken up by DMSO, and purified by Gilson (30-100% acetonitrile/water/0.05% TFA) to give 1g (28mg, 0.057mmol, 57%) as a white solid. LC/MS 489.0 (M+1). 1H NMR (300MHz, CDCl3) δ: 7.20-7.29 (m, 8H), 7.01 (d, J=7.0Hz, 2H), 6.80 (t, J=5.5Hz, 1H), 6.42 (t, J=2.0Hz, 1H), 6.35 (d, J=2.0Hz, 2H), 5.06 (q, J=7.0Hz, 1H), 4.44 (dd, J=5.5, 14.5Hz, 1H), 4.36 (dd, J=5.5, 15.0Hz, 1H), 3.79 (s, 6H), 3.65 (d, J=14.0Hz, 1H), 3.40 (d, J=14.5Hz, 1H), 1.54 (d, J=7.0Hz, 3H). |
71% | With cesium fluoride In N,N-dimethyl-formamide at 40℃; for 72h; | |
71% | With cesium fluoride In N,N-dimethyl-formamide at 40℃; for 72h; | |
99 % Spectr. | With air; cesium fluoride In N,N-dimethyl-formamide at 20℃; for 31h; | |
99 % Spectr. | With air; cesium fluoride In N,N-dimethyl-formamide at 20℃; for 31h; | |
With oxygen; cesium fluoride In N,N-dimethyl-formamide at 40℃; for 72h; | 1.A Step A: Diethyl benzyl(hydroxy)propanedioate EXAMPLE 1 (5i?)-Benzyl-N-(3 ,5 -dimethoxybenzyl)-2,4-dioxo-3 - [( 1 R)- 1 -phenylethyl] -1,3 -oxazolidine-5- carboxamide (Compound 1) Step A: Diethyl benzyl(hydroxy)propanedioate A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40 °C with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (1 L x 3). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDC13) δ: 7.22-7.26 (m, 5H), 4.23 (q, J= 7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J = 7.2 Hz, 6H). | |
With cesium fluoride In N,N-dimethyl-formamide for 72h; | 1.A Step A: Diethyl benzyl(hvdroxy)propanedioate A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40 °C with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (1 L x 3). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDC13) δ: 7.22-7.26 (m, 5H), 4.23 (q, J= 7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J = 7.2 Hz, 6H). | |
With cesium fluoride In N,N-dimethyl-formamide at 40℃; for 72h; | Step A: Diethyl benzyl(hydroxy)propanedioate A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40 °C with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (3 x 1L). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDCI3) δ:7.22-7.26 (m, 5H), 4.23 (q, J= 7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J = 7.2 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-(9-borabicyclo[3.3.1]nonanyl)butyldiphenylphosphine; palladium diacetate In 1,4-dioxane for 2h; Inert atmosphere; Reflux; | |
80% | With triethyl borane; sodium hydride; triphenylphosphine In tetrahydrofuran; hexane at 25℃; for 27h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 4-(9-borabicyclo[3.3.1]nonanyl)butyldiphenylphosphine; palladium diacetate In 1,4-dioxane for 5h; Inert atmosphere; Reflux; | |
80% | With triethyl borane; sodium hydride; triphenylphosphine In tetrahydrofuran; hexane at 25℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium ethanolate In ethanol at 60℃; | |
Stage #1: formamidine acetic acid With sodium ethanolate In ethanol at 0℃; Stage #2: diethyl 2-benzylmalonate In ethanol at 20℃; | ||
Stage #1: formamidine acetic acid With sodium methylate In methanol; ethanol at 0℃; for 1h; Stage #2: diethyl 2-benzylmalonate In methanol; ethanol at 0 - 20℃; for 25h; Heating / reflux; Stage #3: With hydrogenchloride In methanol; ethanol; water at 0℃; | 7.1 To a suspension of formamidine acetate (46g, 0. 44mol) and ethanol (300ml), 28% methanol solution of sodium methoxide (250g, 1.3 mol) was added under ice cooling and, after stirring the mixture for 1 hour under continuous ice cooling diethyl benzylmalonate (100g, 0. 4mol) was added thereto. After stirring the mixture for 2 hours under ice cooling and for 19 hours at room temperature and then refluxed for 4 hours. After finishing the reaction, the precipitation, formed by adding concentrated hydrochloric acid (130g) under ice cooling, was filtered, washed with ethanol and then with diethyl ether, and dried in a desiccator to obtain 5-benzyl-lH-purimi- dine-4,6-dione (145g) which was used in the next reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium ethanolate In ethanol at 40℃; | |
Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; | ||
Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With sulfuric acid; potassium carbonate; sodium nitrite In ethanol; water at 10℃; for 5h; | |
90% | With ethyl nitrite; sodium ethanolate In ethanol at -15℃; for 12h; Cooling; | General procedure to prepare ethyl 2-alkyloxyimine-3-arylpropionate 4 General procedure: Diethyl or dimethyl arylmethylmalonate (0.1mol) was added into a 250ml reaction flask equipped with a mechanical stirrer, reflux condenser with drying tube, and dropping funnel. After cooling to -15°C, ethyl nitrite (0.105mol) was added into the reaction solution. Subsequently, EtONa/EtOH solution (0.1mol) was slowly added dropwise under mechanical stirring, and the mixture was refrigerated for 12h. The solution was concentrated, and the residue obtained was added into equal volume of water. The pH of the mixture was adjusted to 6 with diluted hydrochloric acid, extracted with ethyl acetate (4×50ml), and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude product 3A-E was obtained without purification (yield>90%). |
With ethyl nitrite; sodium ethanolate In ethanol at 0℃; |
With ethyl nitrite; sodium ethanolate In ethanol at -15℃; for 12h; Cooling; | ||
With sodium ethanolate; isopentyl nitrite In ethanol at 0℃; for 2h; Molecular sieve; | Step 3, preparation of α-hydroxyimino esters 2. General procedure: The crudesubstituted malonate (0.0422 mol) was dissolved in ethanol (60 mL, dried over 4 Å molecularsieve) and cooled to 0 °C. A 21% solution of sodium ethoxide in ethanol was added (18.4mL, 0.0493 mol) followed by a slow addition of isoamyl nitrite (6.2 mL, 0.046 mol). This wasstirred at 0 °C for two hours, made slightly acid by the addition of 1 N hydrochloric acid anddiluted in water (200 mL). The solution was extracted with ethyl acetate, the organic layerwas washed with water, brine, dried over magnesium sulfate and concentrated to dryness toyield the crude -hydroxyimino esters 2 which were further purified as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With piperidine; benzoic acid In benzene for 18h; Heating / reflux; | 1 2-benzyl diethyl malonate (VIII-a) Add benzaldehyde 21.2g (0.2mol), diethyl malonate 32g (0.2mol), piperidine 1.2ml, benzoic acid 0.6g, and benzene 60ml into 250ml eggplant-shaped flask, increase temperature until intensive reflux occurs, use water separator to separate water, and react for 18h; vacuum evaporate to remove benzene, extract with chloroform-water, wash the organic layer sequentially with water, 1mol/l hydrochloric acid, and saturated sodium hydrogen carbonate solution, and dry with anhydrous sodium sulfate overnight. Filter, and vacuum evaporate to remove solvent to give orange oil component VIII-a 42.5g, with yield of 80%, which is directly used for next step of reaction (the pure ester can be obtained by distillation, b.p. 140-142°/4mm). |
70% | Stage #1: benzaldehyde; diethyl malonate With water; triethylamine; <i>L</i>-proline at 25℃; for 24h; Stage #2: With carbon monoxide; rhodium(III) chloride trihydrate; water; triethylamine In acetonitrile at 25℃; for 48h; | |
5% | With 2,6-dimethyl-1,4-dihydropyrimidine-3,5-dicarboxylic acid diethyl ester; <i>L</i>-proline In ethanol at 25℃; |
Multi-step reaction with 2 steps 1: piperidine / benzene / 16 h / Molecular sieve; Reflux 2: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; triethylsilane / dichloromethane / 0.5 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 100 percent / KOH / ethanol / 5 h / Ambient temperature 2: 61 percent / NaH / tetrahydrofuran / Heating | ||
With potassium hydroxide In ethanol | 78.a (a) (a) α-Benzylacrylic acid, ethyl ester Diethyl benzylmalonate (25 g., 0.10 mole) in ethanol (65 ml.) at 0° in an argon atmosphere was treated dropwise with potassium hydroxide (5.6 g., 1.0 eq.) in ethanol (65 ml.) over a 15 minute period. After stirring for 72 hours at 25° the ethanol was stripped and the residue was acidified with concentrated hydrochloric acid (10 ml.). The resulting white oil was extracted into ethyl acetate then washed with brine, dried (MgSO4), and evaporated to give 24 g. of clear liquid ethyl benzylmalonic acid. Tlc (hexane:ethyl acetate; 3:1) major spot at Rf =0.1. The ethyl benzylmalonic acid (24 g., 0.10 mole), paraformaldehyde (2.5 g., 0.1 mole), pyridine (18 ml.), and piperidine (1.0 ml., 0.1 eq.) were refluxed for 1.5 hours; gas evolution was observed. The reaction mixture was diluted with ether and then washed with water, 1N hydrochloric acid, water, brine, dried (MgSO4), and evaporated to give a residue (23 g.). Distillation of the residue gives 13.5 g. of α-benzylacrylic acid, ethyl ester as a clear liquid at head temperature 70°-75° (0.1 mm Hg.). Tlc (hexane:ethyl acetate; 4:1) one spot at Rf =0.7. | |
Stage #1: diethyl 2-benzylmalonate With potassium hydroxide In ethanol at 20℃; for 12h; Stage #2: With piperidine; formaldehyd In pyridine Heating / reflux; | 2 To a solution of diethyl benzylmalonate (23.3 ml, 100 mmol) in ethanol (64 ml), was added dropwise a solution of KOH (5.6 g, 100 mmol) in ethanol (64 ml) and the resulting mixture was stirred for 12 h at rt. The solution was partially evaporated and the residue dissolved in water (10 ml). Conc. HCl was added at 0° C. and the solution extracted several times with ether. The combined organic layers were dried over MgSO4, filtered and evaporated. Pyridine (18 ml), piperidine (1 ml, 10 mmol) and paraformaldehyde (2.5 g, 83 mmol) were added to the residue and heated under reflux until the gas evolution ceased. After cooling to rt the reaction mixture was diluted with water (300 ml) and extracted several times with pentane. The combined organic layers were washed with 1 N HCl, water, sat. bicarbonate, water and brine, dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate). 1H-NMR (300 MHz, CDCl3) 7.34-7.21 (m, 5H), 6.25 (d, 1H), 5.47 (d, 1H), 4.17 (q, 2H), 3.66 (s, 2H), 1.28 (t, 3H) |
Multi-step reaction with 2 steps 1: potassium hydroxide / water / 18 - 25 °C 2: morpholine / toluene / 4 h / Reflux; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: benzyl bromide; diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 17h; Stage #2: With ammonium chloride In water | Synthesis of (PhCH2)2C(CO2Et)2 (2,2-bis(ethylcarboxylate)-1,3-diphenylpropane. To a solution of PhCH2CH(CO2Et)2 (74.1 g, 0.30 mol) in tetrahydrofuran (THF) (150 mL) at 0 C under an inert atmosphere (N2 or Ar) was added portionwise with stirring NaH (60 % suspension in mineral oil, 13.6 g, 0.34 mol). After a clear solution was obtained (ca. 1 h), 58.2 g (0.34 mol) of benzyl bromide in 50 mL of THF was added dropwise in 1 h. Afterwards, the reaction mixture was allowed to reach room temperature, stirred for ca. 15 h and then hydrolyzed with an aqueous solution of NH4Cl (16 g in 200 mL of water) to give two phases. The organic phase was separated and set aside. The aqueous layer was washed three times with ethyl ether. After the washings were poured into the organic phase, the resulting solution was treated with sodium sulfate to remove water and pumped to dryness. The oily residue was distilled under reduced pressure to give 91 g of (PhCH2)2C(CO2Et)2 (93% yield); b.p.: 190 C (0.1 torr). 1H NMR (CDCl3, 20 C, 200.13 MHz): d 7.4-7.1 (m, 10 H, Ph), 4.12 (q, 4 H, J(HH) = 7.2 Hz, CH2CH3), 3.24 (s, 4 H, CH2Ph), 1.17 (t, 6 H, J(HH) = 7.2 Hz, CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; formaldehyd; In methanol; ethanol; water; | (a) 2-Benzyl-acrylic Acid Diethyl benzylmalonate (100 g, 400 mmol) was dissolved in ethanol (300 mL) and treated with a solution of potassium hydroxide (134.4 g, 2.4 mol) in water (500 mL). The mixture was heated under reflux for 5 hours and then allowed to cool. Ethanol was removed under reduced pressure and the remaining aqueous solution cooled in ice and acidified to pH1 with concentrated HCl. The product was extracted with ethyl acetate (3*200 mL). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield benzylmalonic acid as a white crystalline solid. The solid was taken-up in ethanol (250 mL) and treated portionwise with piperidine (33 g, 397 mmol) followed by an aqueous solution of formaldehyde (37%, 150 mL) which resulted in formation of a white precipitate. The reaction mixture was heated and treated with methanol (50 mL) to give a homogeneous solution. Following dissolution the reaction mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH1 with 1 M HCl and the product extracted with ethyl acetate (3*150 mL). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 2-benzyl-acrylic acid as a colourless oil which crystallized on standing (45 g, 75%). 1H-NMR; δ (CDCl3), 7.32-7.17 (5H, m), 6.36 (1H, s), 5.54 (1H, d, J=1.3 Hz), 3.61 (2H, s). | |
With potassium hydroxide; formaldehyd; In methanol; ethanol; water; | Step A 2-Benzyl-acrylic Acid Diethyl benzylmalonate (100 g, 400 mmol) was dissolved in ethanol (300 mL) and treated with a solution of potassium hydroxide (134.4 g, 2.4 mol) in water (500 mL). The mixture was heated under reflux for 5 hours and then allowed to cool. Ethanol was removed under reduced pressure and the remaining aqueous solution cooled in ice and acidified to pH 1 with concentrated HCl. The product was extracted with ethyl acetate (3*200 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield benzylmalonic acid as a white crystalline solid. The solid was taken-up in ethanol (250 mL) and treated portionwise with piperidine (33 g, 397 mmol) followed by an aqueous solution of formaldehyde (37%, 150 mL) which resulted in formation of a white precipitate. The reaction mixture was heated and treated with methanol (50 mL) to give a homogeneous solution. Following dissolution the reaction mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH 1 with 1 M HCl and the product extracted with ethyl acetate (3*150 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 2-benzyl-acrylic acid as a colorless oil which crystallized on standing (45 g, 75%). 1H-NMR; δ (CDCl3), 7.32-7.17 (5 H, m), 6.36 (1 H, s), 5.54 (1 H, d, J=1.3 Hz), 3.61 (2 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; toluene; | Ethyl 2-carboxy-3-phenylpropionate is prepared by stirring a solution of diethyl 2-benzylmalonate and potassium hydroxide in ethanol under argon at room temperature for 12 days and then purifying by removing the solvent under vacuum, dissolving the reside in water, washing the aqueous layer with aqueous hydrochloric acid and with ether. A solution of this half-acid half-ester in toluene is added to a refluxing solution of 2-n-butyl-1-(4-carboethoxy-2-chlorobenzyl)imidazole-5-aldehyde and piperidine in toluene. Twice at 1 hour intervals an additional amounts of the half-acid, half-ester is added, and the solution is then refluxed for 17 hours. Evaporation of the toluene and chromatography of the residue over silica gel using 2:3 ethyl acetate-hexane for elution gives the diester of the title product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; potassium hydroxide; paraformaldehyde In hydrogenchloride; ethanol; hexane; water | 11.a Step 11(a): Step 11(a): Preparation of α-benzylacrylic acid ethyl ester A mixture of 4.0 g of KOH in 50 ml of ethanol was added at room temperature to 20 g of benzylmalonic acid diethyl ester in 40 ml of ethanol. The mixture was stirred overnight at room temperature, then concentrated by evaporation, thereafter 7.1 ml of water was added and then the mixture was acidified in an ice bath with 6.3 ml of concentrated hydrochloric acid. Partitioning between water and ether was carried out, the organic phase was dried and the ether was distilled off. Then, 12.9 ml of pyridine, 0.61 g of piperidine and 1.78 g of paraformaldehyde were added to the residue. The mixture was heated in an oil bath (130°) for 90 minutes, cooled, 220 ml of water was added and extraction was carried out 3 times with 75 ml of n-hexane. The combined organic phases were washed alternatively with water, 1N HCl, water, saturated NaHCO3 solution and brine. The solution was dried (MgSO4) and evaporated to give the title compound as colorless oil (26 g, 85% yield). 1 H NMR: 300 MHz spectrum consistent with proposed structure. |
85% | With pyridine; potassium hydroxide; paraformaldehyde In hydrogenchloride; ethanol; hexane; water | a Step (a) Step (a) Preparation of α-benzylacrylic acid ethyl ester: A mixture of 8.5 g of KOH in 100 ml of ethanol was added at room temperature to 40 g of benzylmalonic acid diethyl ester in 80 ml of ethanol. The mixture was stirred overnight at room temperature, then concentrated by evaporation, thereafter 14 ml of water was added and then the mixture was acidified in an ice bath with 12.6 ml of concentrated hydrochloric acid. Partitioning between water and ether was carried out, the organic phase was dried and the ether was distilled off. Then, 26 ml of pyridine, 1.22 g of piperidine and 3.56 g of paraformaldehyde were added to the residue. The mixture was heated in an oil bath (130°) for 90 minutes, cooled, 440 ml of water was added and extraction was carried out 3 times with 150 ml of n-hexane. The combined organic phases were washed alternatively with water, 1N HCl, water, saturated NaHCO3 solution and brine. The solution was dried (MgSO4) and evaporated to give the title compound as colorless oil (26 g, 85% yield) 1 H NMR: 300 MHz spectrum consistent with proposed structure. |
85% | With pyridine; potassium hydroxide; paraformaldehyde In hydrogenchloride; ethanol; water | 8 Step 8: Step 8: Preparation of ethyl α-methylenebenzenepropanoate A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at room temperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80 mL) and the solution was stirred at room temperature overnight, then concentrated by evaporation. Water (14 mL) was added and then the mixture was acidified in an ice bath with concentrated hydrochloric acid (12.6 mL). The mixture was partitioned between water and ether; the organic phase was separated, dried and the ether was evaporated. The residue was treated with pyridine (26 mL), piperidine (1.22 g) and paraformaldehyde (3.56 g). The mixture was heated in an oil bath (130°) for 90 minutes, then cooled, and water (440 mL) was added. The mixture was extracted 3 times with n-hexane (150 mL). The combined organic phases were washed successively with water, 1N HCl, water, saturated NaHCO3 solution and brine. The organic solution was dried (MgSO4) and evaporated to give the title compound as colorless oil (26 g, 85 % yield). 1 H NMR: 300MHz spectrum consistent with proposed structure. |
With pyridine; potassium hydroxide; paraformaldehyde In hydrogenchloride; ethanol; hexane; water | 1.1 (1) (1) α-benzylacrylic acid ethyl ester: 4.0 g of KOH in 50 ml of ethanol are added at room temperature to 20 g of benzylmalonic acid diethyl ester in 40 ml of ethanol and the whole is stirred overnight at room temperature, concentrated by evaporation, 7.1 ml of water are added and the whole is acidified in an ice bath with 6.3 ml of concentrated hydrochloric acid. Partitioning between water and ether is carried out, and the organic phase is dried and the ether is distilled off. 12.9 ml of pyridine, 0.61 g of piperidine and 1.78 g of paraformaldehyde are added to the residue. The mixture is heated in an oil bath (130°) for 90 minutes, cooled, 220 ml of water are added and extraction is carried out 3 times with 75 ml of n-hexane. The combined organic phases are washed with water, 1N HCl, water, saturated NaHCO3 solution and brine. The title compound is obtained by distillation. 1 H-NMR (DMSO-d6): 1.2 ppm (t, 3 H); 3.6 (d, 2H); 4.1 (q, 2H); 5.6 (m, 1H); 6.15 (m, 1H); 7.25 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; sodium hydroxide; ethyl acetate n-hexane; ethanol; 2-Nonanone; water | R.11 gamma-Oxo-alpha-(phenylmethyl)-3-(trifluoromethyl)benzenebutanoic acid REFERENCE EXAMPLE 11 gamma-Oxo-alpha-(phenylmethyl)-3-(trifluoromethyl)benzenebutanoic acid A sample of 1.714 g of sodium hydride (60% in oil) is washed with hexane under argon. To the solid sodium hydride is added 65 ml of dry tetrahydrofuran. To the mixture cooled to 0° C. is added dropwise 10.72 g of diethyl benzylmalonate. The mixture is stirred for 15 minutes and a solution of 11.44 g of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone in 15 ml of tetrahydrofuran added dropwise. The ice bath is removed and the mixture stirred at room temperature overnight. The mixture is filtered and the filtrate concentrated under vacuum. The residue (19.3 g) is chromatographed by HPLC over silica gel on a Waters-Prep 500A instrument with hexane-ethyl acetate (10:1) as solvent to give 7.35 g of yellow oil. To the preceding compound (7.35 g) stirring in 30 ml of ethanol and 15 ml of water, while being cooled in an ice bath, is added slowly in several portions, 3.36 g of sodium hydroxide pellets. After 15 minutes, the ice bath is removed and the mixture is refluxed for 4 hours. The mixture is concentrated and the aqueous residue diluted with 35 ml of water, extracted with 20 ml of ether, and acidified with 6N hydrochloric acid (20 ml). The mixture is extracted with three 25 ml portions of dichloromethane, the extract dried (Na2 SO4) and the solvent removed to give a yellow solid. The solid is dissolved in 45 ml of hexane-acetone (8:1) and the solution chilled to give 5.16 g of [2-oxo-2[3-(trifluoromethyl)phenyl]ethyl](phenylmethyl)propanedioic acid as white crystals, m.p. 145°-147° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 71% 2: 27% | With N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride; triphenylphosphine In toluene at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In ethanol; water at 65 - 75℃; for 18h; | 1 Add 20ml aqueous solution of compound VIII-a 50g (0.2025mol) and KCN 14g (0.215mol), and 500ml ethanol into 1L three-necked flask, increase temperature to 65-75 , react for 18h while stirring. Cool to 15 after reaction, filter to remove KHCO3, wash the filter cake with 20ml ethanol and combine it with the filtrate. Carefully acidify with diluted hydrochloric acid 5ml, vacuum concentrate to semi-solid state. Cool, extract with ethyl ether-water, dry the organic layer with anhydrous calcium chloride, filter, and vacuum evaporate to remove solvent to give red oil component IX-a 27g, with yield of 66%, which is directly used for next step od reaction. (the pure ester can be obtained by distillation, b.p. 161-164°/8mm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 2-amidinopyridinehydrochloride (25g, O. lmol) and ethanol, 28% methanol solution of sodium methoxide (60g, 0. 31 mol) was added under ice cooling and, after stirring the mixture for 15 minutes under continuous ice cooling, diethyl benzylmalonate (100g, 0. 4mol) was added thereto. After stirring the mixture for 1.5 hours under ice cooling and for 1 hour at room temperature, it was refluxed for 4 hours. After finishing the reaction, the precipitation, formed by adding concentrated hydrochloric acid (32g) under ice cooling, was filtered, washed with ethanol and then with diethyl ether, and dried in a desiccator to obtain 5-benzyl-2-pyridin-2-yl-lH-pyrimidine-4, 6-dione hydrochloride (38.7g) which was used in the next reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tetra-(n-butyl)ammonium iodide In water; acetonitrile for 6h; Reflux; | 4.4 Large-scale synthesis of diethyl benzyl(tert-butylperoxy)malonate 2d (Table 2) To a solution of diethyl benzylmalonate 1d (2.50g, 10.1mmol) in acetonitrile (50mL), 70% t-BuOOH (3.86g, 30.0mmol) was added. The mixture was heated to reflux, and then Bu4NI (0.74g, 2.00mmol) was added. The solution was refluxed for 6h. The solvent was removed under water aspirator pressure. The suspension that formed was diluted with diethyl ether (100mL), and the precipitate was filtered using silica gel. The solvent was removed under water aspirator pressure. Product 2d was isolated by chromatography on silica gel, eluting with PE-EtOAc (10/1). Yield of 2d is (2.77g, 8.20mmol, 81%). |
67% | With copper(II) perchlorate hexahydrate In water; acetonitrile at 79 - 81℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 69% 2: 7 %Chromat. | In trifluorotoluene at 100℃; Inert atmosphere; Autoclave; | 2.2.2. Catalyzed α-monoalkylation of malonate diester with benzyl alcohol A mixture of benzyl alcohol (1 mmol), diethylmalonate (3 mmol), 0.0998 g of Pd-MgO (Pd: 0.0075 mmol), trifluorotoluene (1 ml), and n-dodecane (20 μl) as internal standard were placed into an autoclave. The resulting mixture was vigorously stirred at 180 °C (or 100 °C) under nitrogen. The reaction was monitored by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.75h; Inert atmosphere; Stage #2: 1-bromo-6-benzyloxyhexane In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h; Inert atmosphere; | |
92% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.75h; Inert atmosphere; Stage #2: 1-bromo-6-benzyloxyhexane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 24h; Inert atmosphere; | 13 Synthesis 13Diethyl 2-benzyl-2-(6-(benzyloxy)hexyl)malonate Synthesis 13Diethyl 2-benzyl-2-(6-(benzyloxy)hexyl)malonate (13)To a solution of diethyl 2-benzylmalonate (97%, 1 .9 mL, 7.8 mmol, 1 eq) in dry DMF (15 mL), sodium hydride (60% dispersion in mineral oil, 387 mg, 9.7 mmol, 1 .2 eq) was added at 0°C. The suspension was stirred under nitrogen atmosphere at 0°C for 45 minutes. Then ((6-bromohexyloxy)methyl)benzene (97%, 2.0 mL, 8.6 mmol, 1 .1 eq) was added. The solution was stirred at room temperature under nitrogen atmosphere for 24 hours. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with small portions of diethyl ether. The collected organic phases were dried over anhydrous Na2S04, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (n-Hex/EtOAc 9:1 ) to give 3.165 g of 13 (92%) as a pale yellow oil.Rf = 0.31 (n-Hex/EtOAc 9:1 ). 1 H NMR (400 MHz, CDCI3) δ 7.30 - 7.08 (m, 8H), 7.01 - 6.96 (m, 2H), 4.42 (s, 2H), 4.14 - 4.04 (m, 4H), 3.37 (t, J = 6.6 Hz, 2H), 3.15 (s, 2H), 1 .73 - 1 .64 (m, 2H), 1 .55 - 1 .48 (m, 2H), 1.34 - 1.19 (m, 6H), 1.15 (t, J = 7.1 Hz, 6H);13C NMR (100 MHz, CDCI3) δ 171 .6, 138.9, 136.6, 130.1 , 128.6, 128.5, 127.9, 127.8, 127.1 , 73.2, 70.6, 61.4, 59.1 , 38.3, 32.0, 30.0, 29.9, 26.3, 24.4, 14.4; ESI MS m/z: calcd. for C27H3705 [/W+H]+ 441.3, C27H36Na05 [/W+Na]+ 463.2, found: 441 .2, 463.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 23℃; for 18h; | 33 Example 33 Preparation of 2-(methylthiomethyl)-3-phenylpropanoic acid Preparation of diethyl 2-benzyl-2-(methylthiomethyl)malonate Chloromethyl methyl sulfide (1.4 mL, 17 mmol, 1.0 equiv) and 60% sodium hydride in mineral oil (750 mg, 19 mmol, 1.1 equiv) were sequentially added to a stirred solution of diethyl 2-benzylmalonate (4.0 mL, 17 mmol, 1.0 equiv) in N,N-dimethylformamide (34 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 18 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (150 mL) and extracted with diethyl ether (4*70 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford a yellow oil (5.3 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.13-7.30 (m, 5H), 4.22 (q, J=7 Hz, 4H), 3.36 (s, 2H), 2.94 (s, 2H), 2.11 (s, 3H), 1.27 (t, J=7 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: guanidine hydrochloride; diethyl 2-benzylmalonate With sodium In ethanol at 20℃; for 4h; Inert atmosphere; Stage #2: In ethanol for 1h; Inert atmosphere; Reflux; | General procedure for the preparation of 5-substituted2-amino-4,6-dihydroxypyrimidines A2-A11 General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200-300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water. |
91% | With sodium In ethanol Inert atmosphere; | General procedure for the preparation of 5-substituted2-amino-4,6-dihydroxypyrimidines A2-A11 General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200-300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.9% | Stage #1: ethyl 3-amino-5-methylhex-2-enoate; diethyl 2-benzylmalonate In neat (no solvent) at 220℃; for 0.75h; Stage #2: With sodium hydroxide at 160℃; for 1h; Microwave irradiation; | General procedure: The following substituted pyridones were prepared according to the above method using corresponding 2-substituted malonates and ethyl 3-amino-4-substituted but-2-enoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With cesium acetate; copper(II) bis(trifluoromethanesulfonate); triethylamine In 1,2-dichloro-ethane at 35℃; for 48h; Glovebox; Inert atmosphere; | |
57% | With cesium acetate; copper(II) bis(trifluoromethanesulfonate); triethylamine In 1,2-dichloro-ethane at 35℃; for 48h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) chloride; sodium sulfite In nitromethane at 65℃; for 35h; | 3 Example 3 In the case where a stirrer, thermometer, the reaction vessel of the dropping funnel, 4.6 moles of malonic acid diethyl ester (2) were added, 0.13 mol of cuprous chloride, mass fraction of 90% sodium sulfite solution 13.6mol, nitromethane 310ml, the stirring speed was controlled at 160 rpm, the solution temperature was raised to 65C, was added benzylamine (3) 5.3mol, 35h was complete the reaction, to precipitate a solid, filter, the filter cake was washed with a potassium nitrate solution, mass fraction of 85% cyclohexane washing, 0.98 kPa vacuum distillation, a fraction of 90 - 95 ° C was collected, in the mass fraction of 95% acetonitrile recrystallization, to give 954.5 g of crystals of benzylmalonic acid diethyl ester in 83% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | at 200℃; for 0.5h;Microwave irradiation; | General procedure: General procedure for the synthesis of benzothiazolopyrimidones 3-Benzyl-2-hydroxy-8-methoxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one (1); 3-benzyl-8-chloro-2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one (2); and 3-benzyl-2-hydroxy-4-oxo-4H-benzo[4,5]thiazolo[3,2-a] pyrimidine-8-carbonitrile were synthesized following a method similar to that described. 20 Briefly, 1 equivalent (eq.) of either 2-amino-6-methoxybenzothiazole (Aldrich, 162590) (for 1), 2-amino-6-chlorobenzothiazole (Aldrich, 136085) (for 2), or <strong>[19759-66-1]2-aminobenzothiazole-6-carbonitrile</strong> (AstaTech, Inc. 25305) (for the 8-carbonitrile derivative) was combined with 1.5eq. diethyl benzylmalonate (Aldrich, 135542) and heated to 200C on a Biotage Initiator Microwave Synthesizer for 30min. After cooling to room temperature, the reaction mixture was added to ethyl acetate and filtered. The resulting precipitate was solubilized in boiling ethanol, allowed to cool to room temperature, and recrystallized at -20C overnight. All molecules reported herein were analyzed for purity and identity using a Waters QToF LC-MS and Bruker Ascend 500 NMR instrument, and displayed purities greater than 95%. Compounds were stored at -80C, as single-use stocks, at 10-40mM in DMSO. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; for 4h;Reflux; | General procedure: To a stirred solution of 2-methyl-2-thiopseudourea sulfate (8.35 g, 60 mmol) in ethanol 120 mL was added 1,3-dicarbonyl derivatives (50 mmol) and sodium hydroxide (2.4 g, 60mmol) at room temperature, and then heated at refluxed for 4 h. After this time, the reaction mixture was cooled to room temperature, the residue was precipitated and filtered, yielding compounds 3 as white solid. The solid was dried in vacuum and used directly to react with POCl3 (40 mL) in the presence of NEt3 (5.05 g, 50 mmol) heated at reflux for 3 h. The solvent was evaporated under reduced pressure, the residue was dissolved in 100 mL ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure. The desired products 4-chloro-2-(methylthio)pyrimidines 4a-4f were obtained by recrystallization from the mixed solvent of EtOAc-petroleum ether. Yields, melting points and spectroscopic data for selected 2-(methylsulfonyl)pyrimidines are listed as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With C32H46N4O3S In toluene at 4℃; for 168h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: diethylzinc; diethyl benzalmalonate In hexane; dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: With copper(l) chloride In hexane; dichloromethane at 20℃; Inert atmosphere; | 4.2.1 General procedure for the reaction of diethylzinc with substrates 5a and 5b General procedure: Dialkylzinc (2, 4 or 8 equiv) was added under argon, at room-temperature, to a solution of 5 (1 equiv, 0.2M), in the presence or in the absence of additive (BF3·OEt2, TMSCl) in non-degassed dichloromethane. The mixture was stirred for 30minat room temperature and quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica pad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 1-Bromo-2-chloroethane In tetrahydrofuran; mineral oil for 24h; Reflux; | Diethyl 2-benzyl-2-(2-chloroethyl)malonate (22) To a suspended solution of sodium hydride (1.06 g, 60% dispersion inmineral oil, 1.3 equiv, 26.5 mmol) in THF (6.8 mL, 0.3 M) was added benzyl malonate (5.1 g, 1 equiv, 20.4 mmol). The reaction mixture was stirred for 30 min at room temperature and then 1-bromo-2-chloroethane (17.0 mL, 10 equiv, 204 mmol) was added. The reaction mixture was heated to reflux and stirred for 24 h. The reaction was quenched with H2O and extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using agradient of 5-10% ethyl acetate in hexanes to give a colorless oil (2.4 g, 38% yield). 1H NMR (600 MHz, CDCl3) d 7.33-7.23 (m, 3H),7.15-7.09 (m, 2H), 3.63-3.56 (m, 2H), 3.29 (s, 2H), 2.34-2.19 (m,2H), 1.29 (t, J 7.1 Hz, 6H). 13C NMR (151 MHz, CDCl3) d 170.41, 135.37, 129.90, 128.48, 127.25, 77.27, 77.06, 76.85, 61.67, 57.89, 40.09, 39.35, 35.73, 14.02. HRMS (APCI) Exact mass calculated for C16H22ClO4 [M+H], 313.1207. Found 313.1191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diethyl 2-benzylmalonate With sodium ethanolate In ethanol for 0.5h; Inert atmosphere; Reflux; Stage #2: amyl iodide In ethanol Inert atmosphere; Reflux; | Diethyl 2-benzyl-2-pentylmalonate 3e Na (0.552 g, 24.0 mmol) was added gradually to dry EtOH (15 mL), and the mixture was stirred for 30 min under argon atmosphere to prepare sodium ethoxide. A solution of diethyl benzylmalonate (5.003g, 19.99 mmol) in dry EtOH (8 mL) was added dropwise to the sodium ethoxide, and the mixture was stirred for 30 min under gentle reflux to prepare enolate. A solution of 1-iodopentane (4.949 g, 24.99 mmol) in dry EtOH (6 mL) was added dropwise to the enolate, and the mixture was gently refluxed overnight. The ethanol was removed by distillation, and aqueous HCl (1 mol L-1, 20 mL) was added to the residue at 0 C. The mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), saturated aqueous Na2S2O3 (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford (±)-3e (5.826 g, 91%) as a colorless oil. IR (neat): 1037, 1732 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.88 (3H, t, J = 6.8 Hz), 1.24 (3H, app t, J = 7.2), 1.26-1.34 (6H, m), 1.74-1.78 (2H, m), 3.23 (2H, s), 4.15 (1H, dq, J = 7.2, J = 10.8), 4.20 (1H, dq, J = 7.2, J = 10.8), 7.06-7.27 (5H, m); 13C NMR (100 MHz, CDCl3): δ 13.97, 14.06, 22.39, 23.76, 31.64, 31.94, 37.95, 58.85, 61.11, 126.85, 128,21, 129,87, 136.37, 171.41; MS (EI): m/z 320 (M+); HRMS: Calcd for C19H28O4 320.1988, Found 320.1988. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: diethyl 2-benzylmalonate With sodium ethanolate In ethanol for 0.5h; Inert atmosphere; Reflux; Stage #2: 1-Iodohexane In ethanol Inert atmosphere; Reflux; | Diethyl 2-benzyl-2-pentylmalonate 3e General procedure: Na (0.552 g, 24.0 mmol) was added gradually to dry EtOH (15 mL), and the mixture was stirred for 30 min under argon atmosphere to prepare sodium ethoxide. A solution of diethyl benzylmalonate (5.003g, 19.99 mmol) in dry EtOH (8 mL) was added dropwise to the sodium ethoxide, and the mixture was stirred for 30 min under gentle reflux to prepare enolate. A solution of 1-iodopentane (4.949 g, 24.99 mmol) in dry EtOH (6 mL) was added dropwise to the enolate, and the mixture was gently refluxed overnight. The ethanol was removed by distillation, and aqueous HCl (1 mol L-1, 20 mL) was added to the residue at 0 C. The mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), saturated aqueous Na2S2O3 (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford (±)-3e (5.826 g, 91%) as a colorless oil. IR (neat): 1037, 1732 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.88 (3H, t, J = 6.8 Hz), 1.24 (3H, app t, J = 7.2), 1.26-1.34 (6H, m), 1.74-1.78 (2H, m), 3.23 (2H, s), 4.15 (1H, dq, J = 7.2, J = 10.8), 4.20 (1H, dq, J = 7.2, J = 10.8), 7.06-7.27 (5H, m); 13C NMR (100 MHz, CDCl3): δ 13.97, 14.06, 22.39, 23.76, 31.64, 31.94, 37.95, 58.85, 61.11, 126.85, 128,21, 129,87, 136.37, 171.41; MS (EI): m/z 320 (M+); HRMS: Calcd for C19H28O4 320.1988, Found 320.1988. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: diethyl 2-benzylmalonate With sodium ethanolate In ethanol for 0.5h; Inert atmosphere; Reflux; Stage #2: 1-Iodoheptane In ethanol Inert atmosphere; Reflux; | Diethyl 2-benzyl-2-pentylmalonate 3e General procedure: Na (0.552 g, 24.0 mmol) was added gradually to dry EtOH (15 mL), and the mixture was stirred for 30 min under argon atmosphere to prepare sodium ethoxide. A solution of diethyl benzylmalonate (5.003g, 19.99 mmol) in dry EtOH (8 mL) was added dropwise to the sodium ethoxide, and the mixture was stirred for 30 min under gentle reflux to prepare enolate. A solution of 1-iodopentane (4.949 g, 24.99 mmol) in dry EtOH (6 mL) was added dropwise to the enolate, and the mixture was gently refluxed overnight. The ethanol was removed by distillation, and aqueous HCl (1 mol L-1, 20 mL) was added to the residue at 0 C. The mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), saturated aqueous Na2S2O3 (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (hexane/EtOAc = 10/1) to afford (±)-3e (5.826 g, 91%) as a colorless oil. IR (neat): 1037, 1732 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.88 (3H, t, J = 6.8 Hz), 1.24 (3H, app t, J = 7.2), 1.26-1.34 (6H, m), 1.74-1.78 (2H, m), 3.23 (2H, s), 4.15 (1H, dq, J = 7.2, J = 10.8), 4.20 (1H, dq, J = 7.2, J = 10.8), 7.06-7.27 (5H, m); 13C NMR (100 MHz, CDCl3): δ 13.97, 14.06, 22.39, 23.76, 31.64, 31.94, 37.95, 58.85, 61.11, 126.85, 128,21, 129,87, 136.37, 171.41; MS (EI): m/z 320 (M+); HRMS: Calcd for C19H28O4 320.1988, Found 320.1988. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 2-Picolinic acid; bis[dichloro(pentamethylcyclopentadienyl)ruthenium(III)]; caesium carbonate In acetonitrile at 60℃; for 18h; Inert atmosphere; stereospecific reaction; | 3. General procedure for the ruthenium-catalyzed stereospecific benzylic alkylation of the optically active benzyl esters with malonate nucleophiles General procedure: (S)-1-(Naphthalen-2-yl)ethyl 2,3,4,5,6-pentafluorobenzoate ((S)-1a) (0.25 mmol, 91.7 mg, >99% ee), [Cp*RuCl2]2 (3.8 mg, 0.00625 mmol, 0.025 equiv), picolinic acid (L1) (1.5 mg, 0.0125 mmol, 0.05 equiv), Cs2CO3 (89.6 mg, 0.275 mmol, 1.1 equiv) were charged into a screw cap vial. The resulting mixture was carefully evacuated and refilled with N2 five times. After the addition of CH3CN (1 mL) and diethyl methylmalonate (2a) (47 μL, 0.275 mmol, 1.1 equiv), the resulting yellow suspension was stirred at 60 °C for 18 h. The reaction was allowed to cool to room temperature and quenched with water (1 mL). The resulting aqueous phase was extracted with EtOAc (3 mL1). The organic phase was washed with brine and dried over MgSO4. After removal of the solvent, the resulting crude mixture was purified by silica gel column chromatography (Hexane/EtOAc = 95/5, 92/8, 9/1) and preparative thin-layer chromatography (Toluene/EtOAc = 9/1) to give (S)-diethyl 2-methyl-2-(1-(naphthalen-2-yl)ethyl)malonate ((S)-3aa)3 as a pale yellow oil (63.5 mg, 0.193 mmol, 77% yield, 99% ee, 99% es). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran for 0.5h; Stage #2: bis(di-O,O-isopropyl phosphinothioyl)diselenide With iodine In tetrahydrofuran | Method BReaction between sodium salts of C-H acids 1 and diselenide 2 with a subsequent addition of iodine in THF. General procedure: Diethyl 2-(diisopropoxyphosphinothioyl)seleno-2-ethylmalonate(3e). To a suspension of 60% NaH (0.054 g, 1.35 mmol) in THF (5 ml) diethyl 2-ethylmalonate 1e (0.24 g, 1.25 mmol) was added with stirring. After evolution of hydrogencompletely ceased (ca. 0.5 h) bis(disopropoxyphosphinothioyl) diselenide 2 (0.26 g,0.5 mmol) was added in one portion at room temperature. After diselenide 2 dissolution,a THF iodine solution (0.134 g, 0.52 mmol, 1.05 eq, 2 ml) was added dropwise for15 min. Next the reaction mixture was poured onto water-ethyl acetate mixture (1:2 v/v) and both layers were separated. The organic phase was washed with 5% Na2S2O3solution, water and dried over MgSO4. Evaporation of the solvent left an oily residuewhich was purified on silica gel column. n-Hexane-EtOAc (14:1) solvent system wasused to afford 0.36 g (80%) chromatographically pure 3e as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-((1,1,2,2-tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide In tetrahydrofuran; mineral oil at 20℃; for 0.25h; Inert atmosphere; | 3 Diethyl 2-benzyl-2-((1,1,2,2-tetrafluoroethyl)thio)malonate (13a): Protocol A: using reagent 3a A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with NaH (60% in mineral oil, 9 mg, 0.23 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.5 mL of anhydrous THF were added using a syringe followed by diethyl 2-benzylmalonate (35.5 µl, 0.15 mmol, 1.0 eq.) and the mixture is stirred at room temperature for 15 minutes. Then, reagent 3a (118 mg, 0.38 mmol, 1.7 eq.) was quickly added to the flask and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was diluted with Et2O, washed with NH4Cl (saturated) and dried over MgSO4. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a colorless oil (51 mg, 88% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: diethyl 2-benzylmalonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.25h; Inert atmosphere; Stage #2: N-(methylsulfonyl)-N-((perfluoroethyl)thio)methanesulfonamide In tetrahydrofuran; mineral oil at 20℃; for 0.25h; Inert atmosphere; | 3 Protocol B: using reagent 6a An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with NaH (60% in mineral oil, 3 mg, 0.075 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 0.5 mL of anhydrous THF were added using a syringe followed by diethyl 2-benzylmalonate (11.8 µl, 0.05 mmol, 1.0 eq.) and the mixture is stirred at room temperature for 15 minutes. Then, reagent 6a (26 mg, 0.085 mmol, 1.7 eq.) was quickly added to the flask and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was diluted with Et2O, washed with NH4Cl (saturated) and dried over MgSO4. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a colorless oil (47 mg, 81% yield).1H NMR (CDCl3, 400 MHz) δ in ppm: 7.30-7.18 (m, 5H), 5.80 (tt, J = 53.7, 3.5 Hz, 1H), 4.29-4.15 (m, 4H), 3.64 (s, 2H), 1.23 (t, J = 7.1 Hz, 6H).;19F NMR (CDCl3, 376.5 MHz) δ in ppm: - 88.79 (td, J = 8.9, 3.5 Hz, 2F), -132.48 (dt, J = 53.7, 8.9 Hz, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tripotassium phosphate tribasic In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Schlenk technique; |
Tags: 607-81-8 synthesis path| 607-81-8 SDS| 607-81-8 COA| 607-81-8 purity| 607-81-8 application| 607-81-8 NMR| 607-81-8 COA| 607-81-8 structure
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. |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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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 |
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