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CAS No. : | 51673-84-8 | MDL No. : | MFCD00134410 |
Formula : | C4H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OGFKTAMJLKHRAZ-UHFFFAOYSA-N |
M.W : | 104.10 | Pubchem ID : | 162650 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 23.71 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.23 cm/s |
Log Po/w (iLOGP) : | 1.32 |
Log Po/w (XLOGP3) : | -0.41 |
Log Po/w (WLOGP) : | -0.2 |
Log Po/w (MLOGP) : | -0.8 |
Log Po/w (SILICOS-IT) : | -0.04 |
Consensus Log Po/w : | -0.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.03 |
Solubility : | 97.3 mg/ml ; 0.935 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.13 |
Solubility : | 140.0 mg/ml ; 1.34 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.06 |
Solubility : | 90.7 mg/ml ; 0.871 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.48 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
84% | Stage #1: With ammonium acetate In methanol; water at 20℃; for 16 h; Stage #2: With hydrogenchloride In water at 80℃; for 0.5 h; Stage #3: With sodium hydroxide In water |
A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60percent solution in water, 232 mL, 1.54 mol) in methanol (1.1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1.1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCl solution (1.1 L) and heated at 80° C. for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84percent) as a light brown solid. LC-MS: m/z=173.0 (MH+), tR=0.66 min, method C |
84% | Stage #1: With ammonium acetate In methanol; water at 20℃; for 16 h; Stage #2: With hydrogenchloride In water at 80℃; for 0.5 h; Stage #3: With sodium hydroxide In water |
A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60percent solution in water, 232 mL, 1 .54 mol) in methanol (1 .1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1 .1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCI solution (1 .1 L) and heated at 80°C for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84percent) as a light brown solid. LC-MS: m/z = 173.0 (MH+), tR = 0.66 min. |
84% | Stage #1: With ammonium acetate In methanol; water at 20℃; for 16 h; Stage #2: With hydrogenchloride In methanol; water at 80℃; for 0.5 h; Stage #3: With sodium hydroxide In water |
4-Phenyl-1 H-imidazole-2-carbaldehyde A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60percent solution in water, 232 ml_, 1.54 mol) in methanol (1.1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1.1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCI solution (1.1 L) and heated at 800C for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84percent) as a light brown solid. LC-MS: m/z = 173.0 (MH+), tR = 0.66 min, method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
350 mg | With ruthenium trichloride In dichloromethane; acetonitrile at 20℃; for 0.5 h; | To a suspension of NaIO4 (3 g, 14 mmol) supported on silica (10 g) in DCM (30 mL) was added alkene 9 (355 mg, 2 mmol) previously diluted in DCM (20 mL). The mixture was stirred for 30 min at room temperature before being filtered. The solid residue was washed twice with DCM (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum very carefully (20 oC, 300 mmHg) due to the high volatility of aldehyde 10. The residue was a clear liquid (350 mg, 85percent crude) used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ = 9.47 (d, J = 1.5 Hz, 1H, 1-H), 4.50 (d, J = 1.5 Hz, 1H, 2-H), 3.46 (s, 6H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 199.2 (1-C), 122.3 (2-C), 54.6 (3-C) ppm. |
29 g | at -10℃; for 10 h; Inert atmosphere | In a 1000mL reaction flask with mechanical stirring and a thermometer was added 1,1,4,4-tetramethoxy-2-butene compound 70g and 500mL dimethylsulfide. Place in -10 deg.C conditions, the replacement of the bottle after the air into nitrogen, to a closed reaction system was slowly injected ozone 30g, to control the reaction temperature was maintained at -10 deg.C, reaction 10h after completion of the reaction raw materials, warmed to room temperature, the solvent was evaporated to give the compound 1,1-dimethoxy acetaldehyde 29g. |
32 g | at -10℃; for 10 h; Inert atmosphere | In 1000 mL of a reaction flask equipped with a mechanical stirrer and a thermometerCompound 1,1,4,4-tetramethoxy-2-butene (70 g) and methyl sulfide (500 mL)Placed at -10 ° C,Replace the bottle after the air into the nitrogen,To the closed reaction system slowly into the ozone 30g,Control the reaction temperature at -10 ° C,After 10 hours of reaction, the reaction reaction was complete and the temperature was raised to room temperature. After the solvent was distilled off, the compound 1,1-dimethoxyacetaldehyde (32 g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | at 90 - 100℃; for 4 - 8 h; | In eine beheizbare 1m-Kolonne (Durchmesser 29mm) mit Drahtgeflechteinsaetzen wurde am Kopf eine waessrige Glyoxal-Loesung (40 Gew.-percent), die mit einer kleinen Menge einer Loesung von p-Toluolsulfonsaeure in Methanol versetzt wurde, ueber eine Pumpe eindosiert. Gleichzeitig wurde am untersten Boden der Kolonne gasfoermiges Methanol eingespeist. Am Kopf der Kolonne wurde ein Destillat-Gemisch aus Wasser und Methanol aufgefangen, am Sumpfablauf wurde ein Gemisch aus 1,1,2,2-Tetramethoxyethan, 2,2-Dimethoxyacetaldehyd und Methanol aufgefangen. Das Kopfdestillat, bestehend aus Wasser und Methanol, wurde an einer weiteren Kolonne aufdestilliert, wobei das Methanol zurueckgefuehrt, wieder verdampft und in den untersten Eintritt der Kolonne eingespeist wurde. Die Rueckgewinnung des Methanols kann ebenfalls an der Reaktionskolonne geschehen, wenn oberhalb der Dosierstelle der Glyoxal-Loesung noch eine weiter Kolonne, die ueber einen Seitenabzug verfuegt, eingesetzt wird. Das ablaufende Gemisch bestehend aus 1,1,2,2-Tetramethoxyethan (TME), 2,2-Dimethoxyacetaldehyd und Methanol wurde ebenfalls an einer weiteren Kolonne destillativ aufgearbeitet, wobei die leichtersiedenden Komponenten Methanol und 2,2-Dimethoxyacetaldehyd in den Prozess zurueckgefuehrt wurden. Methanol wurde wiederum verdampft und am Boden der Kolonne eingespeist, 2,2-Dimethoxyacetaldehyd konnte der waessrigen Glyoxal-Loesung zugegeben und mit dieser am Kopf der Kolonne eingespeist werden. Die Glyoxal- und Methanol-Dosierung wurde so gewaehlt, dass Verhaeltnisse von Glyoxal zu Methanol von 1 mol : 4 mol bis zu 1 mol : 18 mol vorlagen. Die Kolonne wurde entweder unbeheizt gefahren oder bis zu einer Temperatur von 160 °C beheizt. Die folgende Tabelle gibt die Ergebnisse unterschiedlicher Fahrweisen wieder: [] NrVerhaeltnis Glyoxal : MeOH [mol : mol]Temp. [°C]Dosierung Glyoxal [mol/h]Reaktionszeit [h]Ausbeute TME [g (percent)]11 : 4900,178112(55percent)21 : 8900,178138(68percent)31 : 121000,464226 (82 percent)41 : 12900,258276 (92 percent)51 : 181000,178161 (79percent)61 : 18900,178169(83percent) |
10% | for 11 h; Heating / reflux | In einem 4-1-Vierhalskolben mit Tropftrichter, Ruehrer und einer Kolonne, bei der Destillat ueber Kopf und ueber einen Seitenabzug entnommen werden konnte, wurden 100 g Methanol, 1 269 g (8,74 mol) einer 40 percentigen waessrigen Glyoxal-Loesung und 70 g p-Toluolsulfonsaeure vorgelegt. Aus diesem Ansatz wurde derart ein Gemisch aus Wasser und Methanol abdestilliert, dass ueber den Seitenabzug der Kolonne Wasser und Methanol und ueber Kopf reines Methanol entnommen wurde, welches dem Sumpf wieder zugefuehrt wurde. Die ueber den Seitenabzug entfernte Methanolmenge wurde per Gaschromatographie bestimmt und im Sumpf durch frisches Methanol ersetzt. Nach einer Reaktionszeit von 11 Stunden liess sich im Sumpf die Bildung eines Gemisches bestehend aus 12,1 percent 1,1,2,2-Tetramethoxyethan, 2,2-Dimethoxyacetaldehyd, Wasser, Methanol und einiger hochsiedender Komponenten nachweisen. Aus diesem Gemisch liessen sich destillativ 126 g 1,1,2,2-Tetramethoxyethan isolieren (0,84mol, 10 percent). |
10% | With toluene-4-sulfonic acid In water at 90 - 100℃; for 4 - 8 h; | [0037] An aqueous glyoxal solution (40percent by weight) which had been admixed with a small amount of a solution of p-toluenesulfonic acid in methanol was metered using a pump into the top of a heatable 1 m column (diameter 29 mm) with wire braid inserts. At the same time, gaseous methanol was fed in at the lowermost tray of the column. At the top of the column, a distillate mixture of water and methanol was collected, and a mixture of 1,1,2,2-tetramethoxyethane, 2,2-dimethoxyacetaldehyde and methanol was collected at the bottom discharge. The top distillate consisting of water and methanol was distilled in a further column, and the methanol was recycled, reevaporated and fed into the lowermost inlet of the column. The methanol can likewise be recovered in the reaction column when a further column which had a stream above the metering point of the glyoxal solution is used. The effluent mixture consisting of 1,1,2,2-tetramethoxyethane (TME), 2,2-dimethoxyacetaldehyde and methanol was likewise worked up by distillation in a further column, and the lower-boiling components methanol and 2,2-dimethoxyacetaldehyde were recycled into the process. Methanol was again evaporated and and fed in at the bottom of the column, and 2,2-dimethoxyacetaldehyde could be added to the aqueous glyoxal solution and fed in with it at the top of the column. The glyoxal and methanol were metered in at such a rate that the mole ratios of glyoxal to methanol present were from 1:4 mol up to 1:18. The column was either operated unheated or heated up to a temperature of 160° C.[0038] The apparatus described under Example 1 was operated in such a way that 174 g of a mixture which consisted of 1.16 mol of glyoxal, 0.04 mol of 2,2-dimethoxyacetaldehyde, a small amount of p-toluenesulfonic acid and also of methanol and water were metered in at the top of the column. At the same time, gaseous methanol was introduced at the bottom of the column. The column was heated. On completion of metering, the bottom effluent was neutralized and worked up by means of vacuum distillation. 162 g (1.08 mol, 90percent based on glyoxal and 2,2-dimethoxyacetaldehyde) of 1,1,2,2-tetramethoxyethane were isolated.[0042] A 4 L four-neck flask equipped with dropping funnel, stirrer and a column in which the distillate could be removed via the top and via a sidestream was initially charged with 100 g of methanol, 1269 g (8.74 mol) of a 40percent aqueous glyoxal solution and 70 g of p-toluenesulfonic acid. A mixture of water and methanol was distilled out of this mixture in such a way that water and methanol were withdrawn via the sidestream of the column and pure methanol was withdrawn overhead and fed back to the bottom. The amount of methanol withdrawn via the sidestream was determined by gas chromatography and replaced at the bottom by fresh methanol. After a reaction time of 11 hours, the formation of a mixture in the bottom consisting of 12.1percent of 1,1,2,2-tetramethoxyethane, 2,2-dimethoxyacetaldehyde, water, methanol and some high-boiling components could be detected. It was possible to isolate 126 g of 1,1,2,2-tetramethoxyethane (0.84 mol, 10percent) from this mixture by distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | for 4 h; | [0041] A 40percent aqueous glyoxal solution was metered at a rate of 0.17 mol/h into the top of a heatable 1 m column (diameter 29 mm) filled with spheres of diameter 5 mm of the catalyst KA-3 (Sud-Chemie). At the same time, gaseous methanol was metered in at the bottom of the column. During the entire reaction, the apparatus was operated under nitrogen as a protective gas. The column was heated. A mixture of water and methanol was collected at the top of the column. The bottom effluent of the column consisted of a mixture of 1,1,2,2-tetramethoxyethane, 2,2-dimethoxyacetaldehyde, methyl 2-hydroxyacetate, 2-hydroxyacetic acid and methanol. The apparatus was operated for 4 hours, and the bottom effluent was analyzed by gas chromatography. According to the analysis, there were 11 g (0.07 mol, 11percent) of 1,1,2,2-tetramethoxyethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 760.051 Torr; for 16h; | Glyoxyl dimethyl acetal (1.27 g, 12.2 mmol, 2.2 eq) was added to 3- trifluoromethoxyaniline (1.00 g, 5.7 mmol, 1.0 eq) in EtOH (15 ml). Palladium on charcoal (10% w/w; 0.20 g) was added and the reaction was placed under hydrogen (1 atmosphere). The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was taken up in brine (20 ml) and the product was extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide (1) as a yellow oil (1.43 g, 4.9 mmol, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In n-heptane; at 60℃; for 15h; | To a stiiTed solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 fiL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1 .0 mL, 4.2 mmol). The solution was stiiTed for 15 h at 60C. After the reaction was cooled, water was added and the mixture was extracted with CH2C1 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (is)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, > 100%). The procedure was adapted from Tetrahedron 2002, 2533 |
In n-heptane; water; at 60℃; for 15h; | Step (a): To a stirred solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 muL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1.0 mL, 4.2 mmol). The solution was stirred for 15 h at 60 C. After the reaction was cooled, water was added and the mixture was extracted with CH2Cl2 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, >100%). The procedure was adapted from Tetrahedron 2002, 2533. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With palladium 10% on activated carbon; hydrogen; triethylamine; In methanol; water; at 20℃; for 16h; | A methanolic solution containing L-leucine methyl ester hydrochloride (6.9 g, 38 mmol), aqueous 60% dimethoxy acetaldehyde (5.7 mL, 6.59 g, 38 mmol), triethylamine (5.3 mL, 3.84 g, 38 mmol) and 10% Pd/C (552 mg) was stirred under a H2 atmosphere and at room temperature for 16 h. The reaction mixture was then filtered over celite and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, EtOAc/petr. et. 1:2 + 1? Et3N) affording the title compound as a yellow oil (4.90 g, 55% yield). [alpha]D24 -22.9 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3) delta 4.43 (dd, J = 6.2, 4.8 Hz, 1 H), 3.70 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 3.30 (m, 1H), 2.73 (dd, J = 11.7, 6.2 Hz, 1H), 2.56 (dd, J = 11.7, 4.7 Hz, 1H), 1.71 (m, 2H), 1.46 (m, 2H), 0.89 (d, J = 4.4 Hz, 3H), 0.87 (d, J = 4.4 Hz, 3H). 13C NMR (200 MHz, CDCl3) delta 175.8 (s), 103.8 (d), 60.0 (d), 54.2 (q), 53.3 (q), 52.0 (q), 49.5 (t), 42.8 (t), 25.4 (d), 22.5 (q), 22.2 (q). ESI-MS: (m/z) 233.2 [M++H, 23], 202.3 [100], 158.2 [43]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium cyanoborohydride; In methanol; tert-butyl methyl ether; at 3.5 - 20℃; | Method A: Reductive amination with sodium cyanoborohydrideTo a mixture ofp-TSA salt 1-13 (50 g; 0.118 mol), MeOH (300 mL), and glyoxal-1,1-dimethyl acetal (45 wt % in MTBE; 40 g; 0.165 mol) was slowly added a solution of NaBH3CN (9.35 g; 0.141 mol; 95 %) in MeOH (50 mL). The rate of addition was such that thetemperature never exceeded 3.5C (over 50 mm). The reaction mixture was allowed to warm up to ambient temperature. After reaction completion (4-5 hours, final batch temperature was 16C), ice was placed around the flask and aqueous NaHCO3 (14.8 g in 200 mL of H20) solution was added slowly. The mixture was concentrated to 420 mL. Additional H20 (200 mL) and EtOAc (500 mL) were added. The aqueous layer was separated and extracted with EtOAc (500mL). The organic layers were combined, dried over MgSO4, and concentrated to approximately100 mL. The resulting solution was passed through a small silica gel pad followed by additional300 mL of EtOAc. The fractions containing 1-14 were combined and concentrated in vacuo togive 46.2 g of product 1-14 (46.2 g; 90.4 wt %; 92%) as an oil. This compound was used for thenext step without further purification. An authentic sample was prepared by silica gel columnchromatography.?H NIVIR (400 MHz; CDC13): oe 8.08 (d, J= 2.4 Hz, 1H), 7.61 (dd, J= 8.4 and 2.4 Hz, 1H), 6.73(d, J 8.4 Hz, 1H), 4.41 (t, J 5.6 Hz, 1H), 4.00 (dd, J= 8.2 and 6.0 Hz, 1H), 3.93 (s, 3H), 3.35(s, 3H), 3.31 (s, 3H), 2.67 (dd, J= 15.3 and 8.2 Hz, 1H), 2.60 (dd, J 12.0 and 5.6 Hz, 1H), 2.51(dd, J= 12.0 and 5.6 Hz, 1H), 2.49 (dd, J= 15.3 and 6.0 Hz, 1H), and 1.40 (s, 9H);?3CNIVIR(101 IVIHz, CDC13): oe 170.6, 163.8, 145.9, 137.4, 130.4, 110.9, 103.5, 80.9, 56.9,53.71, 53.68, 53.4, 48.6, 43.8, and 28.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 4h; | 4,4-Dimethoxy-but-2-enoic acid ethyl ester (0037) Add potassium carbonate (16.5 g, 120 mmol) to a solution of dimethoxy acetaldehyde (60% wt. in water) (15 mL, 100 mmol) and triethyl phosphonoacetate (20 mL, 100 mmol) in 210 mL tetrahydrofuran and 30 mL water. Stir the mixture at room temperature for 4 hours. Pour the reaction mixture into diethyl ether (200 mL) and wash with saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a yellow oil (15.8 g, 90%). 1H-NMR(300 MHz, CDCl3): delta 6.77 (dd, J= 15.9,4.0 Hz, 1H), 6.13 (dd, J= 15.9, 1.4 Hz, 1H), 4.95 (dd, J= 4.0, 1.4 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.34 (s, 6H), 1.30 (t, J= 7.1 Hz, 3H). |
With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 4h; | Preparation 156; Alternate Synthesis of 2- (imidazo [1, 2-a] pyridin-3-yl) acetamide; Ethyl 4,4-dimethoxy-but-2-enoate; Dissolve <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (97g, 0.635 mol, 60% in water) and triethylphosphonoacetate (142 g, 0.633 mmol) in 7: 1 tetrahydrofuran: water. Add potassium carbonate (100g, 0.723 mole) and stir for 4 hours at room temperature. Pour the reaction into ethyl acetate (500 ml) and wash with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Concentrate under reduced pressure to provide the desired compound as a clear oil. H-NMR (400 MHz, DMSO-d6) : 8 6.6 (dd, 1H), 6.1 (d, 1H), 4.95 (dd, 1H), 4.13 (q, 2H), 1.2 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogen; triethylamine;palladium 10% on activated carbon; In methanol; water; at 20℃; for 18h;Product distribution / selectivity; | EXAMPLE 26. Synthesis of methyl (3S)-4-(9/-/-fluoren-9-ylmethoxycarbonyl)-2,3- dihydro-[1 ,4]oxazin-3-carboxylate [structure Villa where X = CO, R1 = H, R2 = COOMe, R3 = (9H-fluoren-9-yl)methoxy-].; L-serine methylester hydrochloride (1.00 g, 6.47 mmol) is dissolved in MeOH (20 ml_), and triethylamine (902 mul_, 6.47 mmol), aqueous 60% <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (1.1 1 g, 6.47 mmol) and 10% Pd/C (90 mg) are successively added, and the resulting mixture is left stirring at room temperature for 18 h. The suspension is filtered over Celite and the solvent is evaporated. Then, the crude is evaporated by flash chromatography (CH2CI2-MeOH 12:1 , Rf 0.43), thus giving compound Il (where X = <n="40"/>bond, R1 = H, R2 = COOMe, R3 = H, R4 = H, R7 = CH3, R8 = H) as a colourless oil (1.31 g, 98%). [CC]24D -28.5 (c = 1.0, CH2CI2). 1H NMR (400 MHz, CDCI3) delta = 4.44 (t, J = 4.5 Hz, 1 H), 3.77 (dd, J = 1 1.2, 4.5 Hz, 1 H), 3.74 (s, 3H), 3.59 (dd, J= 12.5, 8.0 Hz, 1 H), 3.40 (t, J = 4.5 Hz, 1 H), 3.36 (s, 6H), 2.84 (dd, J = 12.5, 4.5 Hz, 1 H), 2.65 (dd, J = 12.5, 4.5 Hz, 1 H), 2.39 (br, 1 H). 13C NMR (50 MHz, CDCI3) delta = 173.1 (s), 103.5 (d), 62.7 (d), 62.5 (t), 53.9 (q), 53.1 (q), 52.0 (q), 49.1 (t). MS m/z 207 (M+, 26), 149 (13), 133 (18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a Parr bottle was charged Raney Nickel (10.1 g), water (40.0 g), tetrahydrofuran (166.3 g), ethanol (32.0 g) and acetic acid (2.5 g). A solution of 2,3-dichloro-5-nitropyridine (40.0 g) in tetrahydrofuran (40.1 g) was added to the Parr bottle in four portions and the mixture was hydrogenated at 40 psi and 35 C. for about 1 hour after each addition. The reaction mixture was cooled to room temperature, and then glyoxal-1,2-dimethyl acetal (47.2 g of 50 wt % aqueous), tetrahydrofuran (35.6 g) and water (80.4 g) were added and the mixture was hydrogenated at 40 psi and 50 C. for about 12 hours. The reaction was cooled to room temperature and then filtered through a bed of Hy-Flo. The pH of the filtrate was adjusted to 7 with 5% aqueous phosphoric acid, and then the mixture was concentrated. Isopropyl acetate (79 g) was added, this was concentrated, and then more isopropyl acetate (485 g) was added. After warming to 50 C. to dissolve the solids, the solution was washed with 5% aqueous phosphoric acid (3×215 g) and then washed with 20% aqueous sodium chloride solution (231 g). The organic solution was concentrated to about 78 mL and heptane (124 g) was added. After heating to 83 C. to dissolve everything, the solution was slowly cooled to room temperature. More heptane (124 g) was added and then the suspension was cooled to 5 C. After filtering, the wetcake was washed with cold heptane/isopropyl acetate and then dried in the vacuum oven. 1H NMR (400 MHz/CDCl3) delta 7.71 (d, J=2.7 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 4.53 (t, J=5.2 Hz, 1H),4.05 (s, br, 1H), 3.42 (s, 6H), 3.22 (d, J=5.21 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 16 iV-[2-(Diethylamino)ethyl]-iV-(2-[2-(4-hydroxy-2-oxo-2,3-dihydro-l,3- benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(l-naphthyI)ethoxy]propanamide dihydrobromide.a) iV-(2,2-Dimethoxyethyl)-LambdaVV-diethyl-ethane-l,2-diamine. EPO <DP n="80"/>A solution of N,N-diethyl-ethylenediamine (15Og) in methanol (50OmL) was treated dropwise rapidly with glyoxal dimethylacetal (60wt% soln. in water, 225 g) at 10-15C. After the addition was complete the solution was warmed to 150C, then to 220C and left at this temperature for 16hr. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15g) and hydrogenated at 6 bar until reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5L), affording 196.2g of the sub-titled compound. 1H NMR (300MHz, CDCl3): 4.48 (t, IH), 3.39 (s, 6H), 2.75 (d, 2H), 2.69 (t, 2H), 2.57-2.48 (m, 6H), 1.01 (ts, 6H). | ||
A solution of N,N-diethyl-ethylenediamine (15Og) in methanol (50OmL) was treated dropwise rapidly with glyoxal dimethylacetal (60wt% soln. in water, 225g) at 10-15C. After the addition was complete the solution was warmed to 150C, then to 220C and left at this temperature for 16hr. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15g) and hydrogenated at 6 bar until reaction was io complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5L), affording 196.2g of the sub-titled compound.1U NMR (300MHz, CDCl3): delta 4.48 (t, IH), 3.39 (s, 6H), 2.75 (d, 2H), 2.69 (t, 2H), 2.57- I5 2.48 (m, 6H), 1.01 (ts, 6H). | ||
A solution of N,N-diethyl-ethylenediamine (150 g) in methanol (500 mL) was treated dropwise rapidly with glyoxal dimethylacetal (60wt% soln. in water, 225 g) at 10-15C. After the addition was complete the solution was warmed to 150C, then to 220C and left at this temperature for 16 hours. The reaction mixture was treated with 5% palladium on carbon (Jolinson-Matthey type 38H paste, 15 g) and hydrogenated at 6 bar until the <n="34"/>reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5 L), affording 196.2 g of the subtitled compound.1H NMR (CDCl3): 4.48 (t, IH), 3.39 (s, 6H), 2.75 (d, 2H), 2.69 (t, 2H), 2.57-2.48 (m, 6H), 1.01 (ts, 6H). |
solution of N,N-diethyl-ethylenediamine (150 g) in methanol (500 mL) was treated dropwise rapidly with glyoxal dimethylacetal (60wt% soln. in water, 225 g) at 10-150C. After the addition was complete the solution was warmed to 150C, then to 220C and left at this temperature for 16 hours. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15 g) and hydrogenated at 6 bar until the reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5 L), affording 196.2 g of the subtitled compound.1H NMR (CDCl3): 4.48 (t, IH), 3.39 (s, 6H), 2.75 (d, 2H), 2.69 (t, 2H), 2.57-2.48 (m, 6H), 1.01 (ts, 6H). | ||
A solution of N,N-diethyl-ethylenediamine (150 g) in methanol (500 mL) was treated dropwise rapidly with glyoxal dimethylacetal (60wt% soln. in water, 225 g) at 10-150C. After the addition was complete the solution was warmed to 150C, then to 220C and left at this temperature for 16 hours. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15 g) and hydrogenated at 6 bar until the reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5 L), affording 196.2 g of the sub- titled compound.1H NMR (CDCl3): 4.48 (t, IH), 3.39 (s, 6H), 2.75 (d, 2H), 2.69 (t, 2H), 2.57-2.48 (m, 6H), 1.01 (ts, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 57; (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid-1-[(4-chloro-phenyl)-amide]-2-[(2-methyl-4-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (mixture of isomers) (a) N-methyl-N-(4-nitrophenylmethyl)-2,2-dimethoxy-ethylamineA mixture of 1.56 g N-methyl-N-(4-nitrobenzyl)amine in 40 ml THF is combined with 2.85 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in tert.-butylmethylether. Then 24 mg of p-TsOHx H2O and 1.12 ml glacial acetic acid are added and the mixture is stirred for 2 h. Then 1.81 g of sodium cyanoborohydride are added batchwise and the mixture is stirred for another 2 h. 5 ml of water are added to the mixture, then it is evaporated down to approx. 30% of the volume, the residue is combined with water and extracted 3× with EtOAc. The combined organic phases are dried with Na2SO4, concentrated and the crude product is purified by chromatography (Alox; petroleum ether/EtOAc 8/2->7/3).Rt value: 2.2 min (Method D)Mass spectrum: (M+H)+=255 |
Yield | Reaction Conditions | Operation in experiment |
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Step i) N-(252-Dimethoxyethyl)cyclohexanamineTo a solution of cyclohexylamine (4.34 g, 5 mL) in methanol (10 mL) was added glyoxal 1,1 -dimethyl acetal (7.58 g, 6.57 mL). The reaction was stirred at ambient temperature for 18 h. After this time 5% palladium on charcoal (Johnson Mattey 38H paste; 0.5 g) was added to the mixture and the reaction hydrogenated under 4 atm pressure OfH2 for 24 h. The reaction mixture was filtered and the filtrates concentrated in vacuo to give the subtitled compound as a pale-coloured oil (7.85 g).1H NMR (299.946 MHz, CDCl3) delta 4.46 (t, J = 5.6 Hz, IH), 3.38 (s, 6H), 2.75 (d, J = 5.6 Hz, 2H), 2.40 (tt, J = 10.4, 3.7 Hz5 IH), 1.91 - 1.83 (m, 2H), 1.76 - 1.69 (m, 2H), 1.65 - 1.58 (m, IH), 1.38 - 1.00 (m, 6H) | ||
A mixture of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (3.00 g, 50.4 mmol) and cyclohexanamine (5.00 g, 50.4 mmol) in methanol (50 ml) was stirred at room temperature for 16 hours to give a yellow solution. Pd/C (0.537 g, 5.04 mmol) was added. The mixture was hydrogenated for 24 hours at 2 bar. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (8.0 g, 42.7 mmol, 85% yield) as an oil, which was used further without purification. |
Yield | Reaction Conditions | Operation in experiment |
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52% | With water; sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 20℃; for 16h; | PREPARATION 11; Preparation of 2-(3-(2,2-diniethoxyethyl)-3-(4-fluorophenethyl)ureido)-4-niethyl-7V- (pyridin-3-ylniethyl)thiazole-5-carboxamide; <n="100"/>A. To a solution of 4-fluorophenethylamine (2.00 mL, 15.0 mmol) and dimethoxyacetaldehyde (60% solution in water, 2.53 mL, 16.83 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (4.28 g, 20.20 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (3 chi 100 mL) and the combined organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford jV-(4-fluorophenethyl)-2,2-dimethoxyethanamine as a colorless oil in 52% yield ( 1.78 g): 1H NMR (300 MHz, CDCl3) delta 7.14-7.10 (m, 2H), 6.97-6.91 (m, 2H), 4.43-4.40 (m, IH), 3.35 (s, 6H), 2.89-2.81 (m, 2H), 2.76-2.71 (m, 4H); MS (ES+) m/z 228.2 (M +1 ). |
Yield | Reaction Conditions | Operation in experiment |
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99% | With hydrogen;palladium 10% on activated carbon; In methanol; water; at 20℃; | EXAMPLE 19. Synthesis of methyl (2R,3S)-6-methoxy-2-methyl-morpholine-3- carboxylate [structure VIIIb where X = bond, R1 = CH3, R2 = COOMe, R3 = H, R5 = OMe]; L-Thr(OTBDMS)-OMe (3.70 g, 14.9 mmol) (corresponding to compound IV where Ri = CH3, R2 = COOMe, R8 = TBDMS) was dissolved in MeOH (45 ml_), then 60% aqueous solution of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (2.59 g, 14.9 mmol) (corresponding to structure III where R7 = CH3) and 10% Pd/C (329 mg) were successively added, and the resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. Then, the suspension was filtered on Celite and MeOH was removed under reduced pressure. The resulting mixture was partitioned between water and Et2O. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield compound Il (where X = bond, Ri = CH3, R2 = COOMe, R3 = H, R7 = CH3, R8 = TBDMS) as a colourless oil (4.95 g, 99%). [alpha]25D -1 1.4 (c = 1.1 , CH2CI2). 1H NMR (400 MHz, CDCI3) delta 4.53 (t, J = 5.2 Hz, 1 H), 4.18 (quintet, J = 5.3 Hz, 1 H), 3.73 (s, 3 H), 3.37 (s, 6 H), 2.94 (dd, J = 12.2, 5.8 Hz, 1 H), 2.73 (dd, J = 12.2, 5.0 Hz, 1 H). 13C NMR (50 MHz, CDCI3) delta 171.9 (s), 102.9 (d), 69.1 (d), 66.8 (d), 54.4 (q), 53.6 (q), 52.0 (q), 48.9 (t), 25.7 (q, 3 C), 20.8 (q), 17.9 (S), -4.2 (q), -5.1 (q). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 48h; | General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
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> 90% | Example 6 Synthesis of N-(2,2-dimethoxyethyl)-3-fluoro-4-morpholinoaniline (IX; R=R1=R3=H; R2=F; R7=CH3) A solution of methyl 2-(3-fluoro-4-morpholinophenylamino)acetate (3 g, 15.289 mmol), of formula (VI), in EtOH (61 ml), under N2 atmosphere, is added with a <strong>[51673-84-8]dimethoxyacetaldehyde</strong> aqueous solution 60% weight/weight (3.068 ml, 20.33 mmol) and the mixture is left under stirring for about 2 hours. After that, 300 mg of Pd/C are added and the mixture is kept under H2 atmosphere at atmospheric pressure. After approximately 12 hours the reaction is completed, the catalyst is filtered through Celite, the residue is washed with ethanol and ethyl acetate, the solvent mixture is evaporated off under reduced pressure, the crude is taken up with ethyl acetate and the organic phase is washed 3 times with H2O. The combined organic phases are dried over Na2SO4 and evaporated under reduced pressure. The resulting product is recrystallized from hexane in a yield higher than 90%. 1H NMR (400 MHz, CDCl3) ppm 7.04-6.76 (bm, 1H), 6.46-6.34 (m, 2H), 4.56 (t, J= 5.5 Hz, 1H), 3.98-3.79 (m, 5H), 3.43 (s, 6H), 3.21 (d, J = 5.5 Hz, 2H), 3.07-2.95 (bm, 4H). | |
90% | EXAMPLE 6 Synthesis of N-(2,2-dimethoxyethyl)-3-fluoro-4-morpholinoaniline (IX; R=R1=R3=H; R2=F; R7=CH3) A solution of methyl 2-(3-fluoro-4-morpholinophenylamino)acetate (3 g, 15.289 mmol), of formula (VI), in EtOH (61 ml), under N2 atmosphere, is added with a <strong>[51673-84-8]dimethoxyacetaldehyde</strong> aqueous solution 60% weight/weight (3.068 ml, 20.33 mmol) and the mixture is left under stirring for about 2 hours. After that, 300 mg of Pd/C are added and the mixture is kept under H2 atmosphere at atmospheric pressure. After approximately 12 hours the reaction is completed, the catalyst is filtered through Celite, the residue is washed with ethanol and ethyl acetate, the solvent mixture is evaporated off under reduced pressure, the crude is taken up with ethyl acetate and the organic phase is washed 3 times with H2O. The combined organic phases are dried over Na2SO4 and evaporated under reduced pressure. The resulting product is recrystallized from hexane in a yield higher than 90%. 1H NMR (400 MHz, CDCl3) ppm 7.04-6.76 (bm, 1H), 6.46-6.34 (m, 2H), 4.56 (t, J=5.5 Hz, 1H), 3.98-3.79 (m, 5H), 3.43 (s, 6H), 3.21 (d, J=5.5 Hz, 2H), 3.07-2.95 (bm, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60% solution in water, 232 mL, 1.54 mol) in methanol (1.1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1.1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCl solution (1.1 L) and heated at 80 C. for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84%) as a light brown solid. LC-MS: m/z=173.0 (MH+), tR=0.66 min, method C | |
84% | A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60% solution in water, 232 mL, 1 .54 mol) in methanol (1 .1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1 .1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCI solution (1 .1 L) and heated at 80C for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84%) as a light brown solid. LC-MS: m/z = 173.0 (MH+), tR = 0.66 min. | |
84% | 4-Phenyl-1 H-imidazole-2-carbaldehyde A solution of phenylglyoxal monohydrate (102 g, 0.67 mol) and glyoxal dimethyl acetal (60% solution in water, 232 ml_, 1.54 mol) in methanol (1.1 L) was treated with a solution of ammonium acetate 8202 g, 2.61 mol) in methanol (1.1 L) and the resulting solution stirred at RT for 16 h. The volatiles were removed in vacuo and the residue slurried in 2N HCI solution (1.1 L) and heated at 800C for 30 min. The cooled solution was extracted with EtOAc (200 mL) and the separated aqueous layer was basified to pH 9 with 9N NaOH solution. The solids were filtered, washed with water and dried in vacuo to yield the title compound (97.2 g, 84%) as a light brown solid. LC-MS: m/z = 173.0 (MH+), tR = 0.66 min, method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 9; N-(2,2-Dimethoxyethyl)cyclopentanamine <n="45"/> To a stirred solution of cyclopentanamine (5 g) in methanol (20 rnL) was added 2,2- <strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% in water (8.86 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of palladium on carbon (10%, 200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)cyclopentanamine (9.44 g) as a oil.1H NMR (400 MHz, CDCl3) delta 4.47 (t, J = 5.6 Hz, IH), 3.39 (s, 6H), 3.05 (quintet, J = 6.8 Hz, IH), 2.72 (d, J = 5.4 Hz, 2H), 1.89 - 1.80 (m, 2H), 1.73 - 1.62 (m, 2H), 1.58 - 1.48 (m, 2H), 1.36 - 1.27 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
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Preparation 6; N-(2,2-Dimethoxyethyl)cycloheptanamineMeC To a stirred solution of cycloheptanamine (8.62 g) in methanol (20 mL) was added 2,2- <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (11.49 mL) and the mixture stirred at room temperature for 5 h. Palladium on carbon 10% (1 g) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated under vacuum to give N-(2,2- dimethoxyethyl)cycloheptanamine as an oil (15.26 g).1H NMR (300 MHz, CDCl3) delta 4.47 (t, J = 5.6 Hz, IH), 3.39 (s, 6H), 2.73 (d, J = 5.6 Hz, 2H), 2.67 - 2.55 (m, IH), 1.90 - 1.25 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium on activated charcoal; In methanol; water; at 25℃; under 3750.38 Torr; for 3h; | Preparation 11; N-(2,2-Dimethoxyethyl)-3-methylbutan- 1 -amine A solution of 3-methylbutan-l-amine (1.33 niL) and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (1.73 niL) in MeOH (10 mL) was added to palladium on carbon (0.366 g) in water (0.5 mL) at 25C. The mixture of was hydrogenated under 5 bar at 25C for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3-methylbutan-l- amine (1.8 g) as a liquid.1H NMR (300 MHz, CDCl3) delta 4.47 (t, J = 5.5 Hz, IH), 3.39 (s, 6H), 2.74 (d, J = 5.6 Hz, 2H), 2.65 - 2.59 (m, 2H), 1.62 (septet, J = 6.7 Hz, IH), 1.44 - 1.33 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium on activated charcoal; In methanol; water; at 25℃; under 3750.38 Torr; for 3h; | Preparation 12; N-(2,2-Dimethoxyethyl)-3,3-dimethylbutan-l -amine A solution of 3,3 -dimethylbutan-1 -amine (1.33 mL) and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (1.5 mL) in MeOH (10 mL) was added to palladium on carbon (0.316 g) in water (0.5 mL) at 25C. The mixture of was hydrogenated under 5 bar at 25C for 3 h. The reaction mixture <n="47"/>was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3,3- dimethylbutan-1 -amine (1.85 g) as a liquid.1H NMR (300 MHz, CDCl3) delta 4.47 (t, J = 5.6 Hz, IH), 3.40 (s, 6H), 2.75 (d, J = 5.8 Hz, 2H), 2.65 - 2.57 (m, 2H), 1.45 - 1.35 (m, 2H), 0.90 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium on activated charcoal; In methanol; water; at 25℃; under 3750.38 Torr; for 24h; | Preparation 4; (R)-N-(2,2-Dimethoxyethyl)-3-methylbutan-2-amine A solution of (R)-3-methylbutan-2-amine (10.50 g) and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (18.18 mL) in methanol (50 mL) was added to palladium on carbon (3 g) in water (3.0 mL) at 25C. The mixture was hydrogenated under 5 bar at 25C for 24 h. The reaction mixture was filtered through Celite and concentrated under vacuum to afford (R)-N-(2,2- dimethoxyethyl)-3-methylbutan-2-amine as a colourless liquid (16.40 g).1H NMR (300 MHz, CDCl3) delta 4.47 (t, J = 5.6 Hz, IH), 3.39 (s, 6H), 2.77 (dd, J = 11.9, 5.4 Hz, IH), 2.66 (dd, J = 11.9, 6.0 Hz, IH), 2.44 (qd, J = 6.4, 5.1 Hz, IH), 1.75 - 1.63 (m, IH), 0.96 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Intermediate 35(2,2-Dimethoxy-ethyl)-((R)-l-meth l-pentyl)-amineA steel reaction vessel was charged with as solution of (R)-l-methyl-pentylamine (10 g, 98.8 mmol) and dimethoxy-acetaldehyde (60wt% aqueous; 19.5 g, 187.8 mmol) in MeOH (20 mL) and the contents stirred at RT for 18 h. The reaction mixture was purged with Argon and 10% palladium on carbon (1 g) was added and the mixture hydrogenated at 60 psi for 24 h at RT. The reaction mixture was filtered through Celite and concentrated in vacuo then purified on an SCX-2 cartridge (eluting with MeOH, then 2 M NH3 in MeOH) to give the title compound as a colourless oil (18.6 g, 98%>). NMR (300 MHz, CDC13): 4.47 (t, 1H, J = 5.6 Hz), 3.39 (s, 6H), 2.80-2.64 (m, 2H), 2.64-2.55 (m, 1H), 1.66 (br s, 1H), 1.54-1.39 (m, 1H), 1.37-1.21 (m, 5H), 1.04 (d, 3H, J = 6.3 Hz), 0.90 (t, 3H, J = 6.8 Hz). | |
Preparation 13; (R)-N-(2,2-Dimethoxyethyl)hexan-2-amine 2,2-Dimethoxyacetaldehyde (7.54 mL) was added to a solution of (R)-hexan-2-amine (5.06 g) in methanol (20 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of 10% palladium on carbon (200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h, then filtered and concentrated in vacuo to afford the sub- titled compound as a colourless liquid (9.22 g).1H NMR (400 MHz, CDCl3) delta 4.46 (t, J = 5.5 Hz, IH), 3.39 (s, 6H), 2.72 (ddd, J = 31.1, 11.9, 5.6 Hz, 2H), 2.60 (sextet, J = 6.0 Hz, IH), 1.36 - 1.24 (m, 6H), 1.04 (d, J = 6.2 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | E) ((S)-3-Benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-amine; To a solution of (S)-3-benzyloxy-1-methoxymethyl-propylamine (1.34 g, 6.40 mmol) in methanol (25 mL) were added <strong>[51673-84-8]dimethoxyacetaldehyde</strong> solution (45% in tert-butyl methyl ether, 1.81 mL, 7.04 mmol), magnesium sulfate (6.94 g, 57.6 mmol), acetic acid (1.54 g, 25.6 mmol), and sodium cyanoborohydride (551 mg, 8.32 mmol), then after 4 h the reaction mixture was cooled to 0 C. and treated with another portion of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> solution (45% in tert-butyl methyl ether, 0.22 mL, 0.96 mmol). The ice bath was removed, then after 2 h the reaction was stopped by careful addition of sat. aq. sodium hydrogencarbonate solution. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate, the organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol 19:1) furnished the title compound (1.60 g, 84%). Light yellow liquid, MS (ISP)=298.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sodium cyanoborohydride; magnesium sulfate; acetic acid; In methanol; at 0℃; | A) (2,2-Dimethoxy-ethyl)-(3-piperidin-1-yl-propyl)-amine; To a solution of 1-piperidinepropylamine (3.00 g, 21.1 mmol) in MeOH (60 mL) were added dimethoxyacetaldehyde (45% solution in TBME, 6.5 mL, 25 mmol) magnesium sulfate (22.8 g, 190 mmol), AcOH (5.07 g, 84.4 mmol), and sodium cyanoborohydride (1.99 g, 31.6 mmol) at 0 C. The ice bath was removed, then after 18 h the reaction mixture was partitioned between sat. aq. sodium hyrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (2.08 mg, 43%). Colorless liquid, 231.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; sodium cyanoborohydride; In tetrahydrofuran; methanol; water; at 20℃; | Step A: lambdar-(lH'-benzimidazol-2-ylmethyl)-2J2-dimeth.oxyethanamine To a MeOH 15OmL suspension of 1 -(I H-benzimidazol-2 -yl)methanamine dihydrochlori.de (4. Og, 18.2ramol) were added dimethoxyacetaldehyde (1.89g, 18.2mmol, 60wt.% solution, in water), sodium acetate (7.45g, 91mmol) and sodium cyanoborohydride (9.09mL, 9.09mmol, 1.0 M TetaF solution). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and reconstituted in DCM (15OmL). The resulting suspension was filtered. The filtrate was concentrated and chromatographed on silica gel with a gradient solvent mixture (5% MeOeta-DCM to 15% MeOeta-DCM over 15 CV) to give the title compound as oil (3.Ig). LC/MS: m/z 205(M+-OMe). 1H-NMR (CDCl3 , 500MHz) delta 3.02 (d, 1H), 3.36 (s, 6H), 4.40 (s, 2H), 4.52 (t, 1H)3 7.28-7.32 (m, 2H), 7.58-7.62 (m, 2H), 8.78-8.92 (br.s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With methanol; sodium cyanoborohydride; magnesium sulfate; In tert-butyl methyl ether; at 0℃; | A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester; To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were added at 0 C. dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+. |
80% | With methanol; sodium cyanoborohydride; magnesium sulfate; In tert-butyl methyl ether; at 0℃; for 16h; | Intermediate 1 (S)-2-[Benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in MeOH (100 mL) were added at 0C <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (5.50 g, 80%>). Light yellow liquid, MS (ISP) = 192.2 (M+H)+. |
80% | To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in MeOH (100 mL) were added at 0 C. <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+. |
80% | With sodium cyanoborohydride; magnesium sulfate; In methanol; tert-butyl methyl ether; at 0℃; for 16h; | To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were aded at 0C dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful adition of sat. aq. sodium hydrogencarbonate solution at 0C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgS04), filtered, and evaporated to afford the titled compound (5.50 g, 80%). Light yellow liquid, MS (ISP) = 192.2 (M+H)+. |
80% | With sodium cyanoborohydride; magnesium sulfate; In methanol; tert-butyl methyl ether; at 0℃; for 16h; | A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were added at 0 C. dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the titled compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In water; at 20℃; for 12h; | To a solution of hydroxylamine, hydrochloric acid (2.0 g, 28.8 mmol) in water (20 mL) was added a solution of NaHCO3 (3.87 g, 46.1 mmol) in water (20 mL) at 20 C, then a solution of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (5 g, 28.8 mmol) in 2-methoxy-2-methylpropane (30 mL) was added at 20 C, and the resulting solution was stirred for 12 hours at 20 C. The mixture was extracted with ethyl acetate (2 × 100 mL), and the combined organic fractions was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.5 g, 26.4, 92% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.71 (s, 1H), 7.37 (d, J=5.26 Hz, 1H), 4.86 (d, J=5.26 Hz, 1H), 3.37-3.44 (m, 6H). |
92% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In tert-butyl methyl ether; water; at 20℃; for 12h; | To a solution of hydroxylamine, hydrochloric acid (2.0 g, 28.8 mmol) in water (20 mL) was added a solution of NaHC( (3.87 g, 46.1 mmol) in water (20 mL) at 20 C, then a solution of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (5 g, 28.8 mmol) in 2-methoxy-2-methylpropane (30 mL) was added at 20 C, and the resulting solution was stirred for 12 hours at 20 C. The mixture was extracted with ethyl acetate (2 x 100 mL), and the combined organic fractions was dried over anhydrous Na2SO/t, filtered and concentrated under reduced pressure to give the title compound (3.5 g, 26.4, 92% yield). JH NMR (400 MHz, CDC13) delta ppm 8.71 (s, 1H), 7.37 (d, J=5.26 Hz, 1H), 4.86 (d, J=5.26 Hz, 1H), 3.37-3.44 (m, 6H). |
With hydroxylamine hydrochloride; sodium methylate; In methanol; tert-butyl methyl ether; at 10 - 20℃; | 6.608 g of hydroxylamine hydrochloride (95.10 mmol) dissolved in 110 ml of methanol are added dropwise to 22.7 ml of a 25% strength methanolic sodium methoxide solution (95.10 mmol) at 10 C. The reaction mixture is stirred at 10 C. for 1 h, and the resulting precipitate is filtered off and washed with a little methanol. The combined filtrates are mixed with 20 g (86.5 mmol) of a 45% strength solution of glyoxal 1,1-dimethyl acetal in tert-butyl methyl ether and stirred at room temperature for 16 h. For working up, 50 ml of water are added, the methanol is removed in a rotary evaporator, and the residue is extracted four times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in a rotary evaporator. Drying under a high vacuum results in 6.19 g of an oily residue which is employed without further purification for the subsequent reaction.The resulting residue is dissolved in 50 ml of DMF and, at room temperature, 7.772 g of N-chloro-succinimide (58.20 mmol) are added in portions. After the reaction starts, an ice/acetone cooling mixture is used for cooling in such a way that the temperature of the reaction mixture does not exceed +40 C. After the temperature of the mixture has returned to room temperature, the cooling bath is removed and stirring is continued for 2 h. For working up, 300 ml of cold water (approx. 5 C.) are added, and the mixture is extracted three times with tert-butyl methyl ether. The combined organic phases are washed twice with water, dried over sodium sulfate and concentrated in a rotary evaporator. The residue after drying is dissolved in 10 ml of ethyl acetate, and cyclohexane is slowly added (about 40 ml) until crystallization of the product starts. To complete the crystallization, the mixture is stored at 5 C. for 16 h. The resulting precipitate is filtered off and dried under high vacuum. 3.26 g (41% of theory) of the title compound are obtained.1H-NMR (400 MHz, CDCl3): delta=3.44 (s, 6H), 4.89 (s, 1H), 7.86 (s, 1H).MS (EI): m/z (rel. Int. %)=75 (100) [M-78]+, 122 (48) [M-OCH3]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In tetrahydrofuran; diethyl ether; water; | 4,4-Dimethoxy-but-2-enoic acid ethyl ester Add potassium carbonate (16.5 g, 120 mmol) to a solution of dimethoxy acetaldehyde (60% wt. in water) (15 mL, 100 mmol) and triethyl phosphonoacetate (20 mL, 100 mmol) in 210 mL tetrahydrofuran and 30 mL water. Stir the mixture at room temperature for 4 hours. Pour the reaction mixture into diethyl ether (200 mL) and wash with saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a yellow oil (15.8 g, 90%). 1H-NMR (300 MHz, CDCl3): delta 6.77 (dd, J=15.9, 4.0 Hz, 1H), 6.13 (dd, J=15.9, 1.4 Hz, 1H), 4.95 (dd, J=4.0, 1.4 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.34 (s, 6H), 1.30 (t, J=7.1 Hz, 3H). |
79% | Intermediate 46 (E)-4,4-Dimethoxy-but-2-enoic acid ethyl ester; To a suspension of potassium carbonate (5.0 g, 35.79 mmol) in cyclohexane (120 mL) was added triethyl phosphonoacetate (7.20 mL, 35.79 mmol) and the mixture was stirred vigorously for 5 minutes. Glyoxal dimethyl acetal (3.6 mL; 23.86 mmol; 60% wt in water) was added and the mixture was heated at 850C overnight. Removal in vacuo of the solvent left a yellow oily slurry that was purified on silica by flash column chromatography by column chromatography to give 3.3 g of the title product (E)-4,4-dimethoxy-but-2-enoic acid ethyl ester as a transparent oil. (Yield: 79%). <n="141"/>1H-NMR (300 MHz, CDCl3): delta 6.74 (1H, dd, J = 15.9, 4.0 Hz), 6.11 (1 H, dd, J = 15.9, 1.4 Hz), 4.93 (1 H, s), 4.19 (2H, q, J = 7.1 Hz)1 3.31 (6H, S)1 1.27 (3H1 t, J = 7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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99% | With piperidine; In acetonitrile; at 60℃; for 18h; | Example 12; l-(4-(5-(4-(Difluoromethyl)-3-phenylisoxazol-5-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylic acid, 2,2,2-trifluoroacetic acid salt; 12-A. (E)-Methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate; [00200] A mixture of methyl 2-(phenylsulfinyl)acetate (1 g, 5.04 mmol), 2,2- <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (3.15 ml, 10.09 mmol) and piperidine (0.999 ml, 10.09 mmol) in acetonitrile (20 ml) was heated to 600C for 18 hr. After cooling to rt, the volatiles were removed in vacuo and the residue was chromatographed on a 5 x 12 cm silica gel column, eluting with a 0-40%EtO Ac/Hex gradient. The pure fractions were concentrated to afford (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (1.42 g, 4.99 mmol, 99 % yield) as a light yellow oil. HPLC retention time = 1.23 minutes (PHENOMENEX Luna 4.6 x 30 mm S-5 ODS column) eluting with 10- 90% aqueous methanol + 0.1% TFA over a 2 minute gradient. MS:(M+Na)= 307.06. 1H NMR (500 MHz, chloroform-d) delta ppm 3.40 (s, 3H), 3.41 (s, 3H), 3.69 (s, 3H), 5.71 (d, J= 7.2 Hz, IH), 7.07 (d, J= 6.6 Hz, IH), 7.48 (m, 3H), 7.66 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | (33a) 2-(Dimethoxymethyl)-4-(trifluoromethyl)-1H-imidazole Sodium acetate (1.33 g, 16.2 mmol) was added to a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.0 g, 7.41 mmol) in water (10 ml), and the mixture was heated under reflux for 40 minutes. Following cooling to room temperature, <strong>[51673-84-8]dimethoxyacetaldehyde</strong>/60% aqueous solution (1.3 ml, 8.64 mmol), 28% aqueous ammonia solution (2 ml) and methanol (4 ml) were added, and the mixture was stirred for 19 hours. The reaction solution was extracted with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain 1.41 g of the title compound as a pale yellow oily substance (90%). 1H NMR spectrum (400 MHz, CDCl3) delta ppm: 3.41 (6H, s), 5.49 (1H, s), 7.36 (1H, s), 9.60 (1H, br s). | |
89.7% | Following Scheme A, to a stirred solution of compound a (10 g, 37.31 mmol) inwater (50 mL), was added sodium acetate (6.12 g, 74.62 mmol), and the solution was stirredat 100C for 40 mm. To this solution, 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (4.26 g, 41.04 mmol) in MeOH (20 mL) and NH4OH (10 mL) were added at rt and the resulting reaction mixture was stirred at rt for 12 h. The progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous Na2 SO4 and concentrated under reduced pressure resulting in a crude compound which was purified by column chromatography to afford the compound b (7 g, 89.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogen;5% Pd(II)/C(eggshell); In methanol; at 50℃; under 3750.38 Torr; for 3.5h; | Example 4: Preparation of decylaminoethanal dimethylacetal III[000116] A mixture of glyoxal 1,1 -dimethylacetal (18.6 g, 107 mmol), decylamine (15.0 g, 95.4 mmol) and 5% Pd/C (0.15 g) in methanol (100 ml) was hydrogenated at 50C/5 bar for 3.5 h. The reaction mixture was then filtered through diatomaceous earth, and the apparatus and the filter cake were washed with MeOH (50 ml). The combined filtrate was evaporated under reduced pressure with two codistillations with toluene at 500C (90.6 mmol, Yield: 95%, purity: 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | g) N-(2,2-Dimethoxyethyl)butan-1-amine To a solution of butan-1-amine (limiting reagent) in EtOH (5 volumes) was added 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (60%) in water (1 molar equivalent) and the mixture was stirred at room temp for 4 days. A slurry of 5% palladium on carbon (0.01 molar equivalent) in EtOH (1 volume) was added and the mixture was hydrogenated at 3 bar pressure for 20 hours. The mixture was filtered through a glass fibre filter paper, washed with EtOH (2*3 volumes) and the mother liquor was carefully concentrated to leave a cloudy brown oil. This oil was dissolved in DCM (15 volumes), dried (Na2SO4), filtered and carefully concentrated in vacuo to leave an orange oil. Yield: 101% of theoretical. 1H NMR (400 MHz, CDCl3) delta 4.48 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 2.74 (d, J=5.6 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 1.48 (quintet, J=7.2 Hz, 2H), 1.31 (sextet, J=7.2 Hz, 2H) and 0.92 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogen; sodium hydrogencarbonate;palladium 10% on activated carbon; In methanol; for 4h; | A) (S)-4-(2,2-Dimethoxy-ethylamino)-3-hydroxy-butyric acid methyl ester A solution of 2.50 g (14.7 mmol) of (S)-4-amino-3-hydroxy-butyric acid methyl ester; HCl (intermediate 24) in 18 ml of methanol was treated with 6.19 g (73.7 mmol) of natriumhydrogencarbonat, 2.2 ml (14.7 mmol) of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (in H2O 60%), 0.250 g of Pd/C (10%) and was stirred over H2-atmosphere for 4 h. After filtration, the solution was evaporated, dissolved in toluene, evaporated under reduced pressure (2*) to yield 3.781 g (70%) of the titled compound as yellow oil. MS: 222.13 (MH+). |
70% | With hydrogen; sodium hydrogencarbonate;palladium 10% on activated carbon; In methanol; water; for 4h; | A solution of 2.50 g (14.7 mmol) of (S)-4-amino-3-hydroxy-butyric acid methyl ester; HC1 (intermediate 24) in 18 ml of methanol was treated with 6.19 g (73.7 mmol) of natriumhydrogencarbonat, 2.2 ml (14.7 mmol) of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (in H20 60%), 0.250 g of Pd/C (10%) and was stirred over H2-atmosphere for 4h. After filtration, the solution was evaporated, dissolved in toluene, evaporated under reduced pressure (2x) to yield 3.781 g (70%) of the titled compound as yellow oil. MS: 222.13 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 23℃; for 14.5h; | 00408] (2R,6S)-2,6-Bis(dirnethoxyrnethvn-5-methylidene- l ,3-dioxan-4-one. 1 ,4- Diazabicyclo[2.2.2]octane (275 mg, 2.45 mmol, 0.15 equiv) was added to a solution of 2,2- dimethoxyacetaldehyde (5.10 g, 49.0 mmol, 3.0 equiv) and sulfonyl imide (4.40 g, 16.3 mmol, 1 equiv) in dichloromethane (26 mL) at 23 °C. After 2.5 h, a second portion of 1 ,4- diazabicyclo[2.2.2]octane (275 mg, 2.45 mmol, 0.15 equiv) was added. After 12.5 h, the reaction mixture was concentrated. The residue was purified by flash-columnchromatography (30% ethyl acetate-hexanes initially, grading to 50% ethyl acetate-hexanes) to provide (2R,6S)-2,6-bis(dimethoxymethyl)-5-methylidene- l ,3-dioxan-4-one (the product was obtained as a single diastereomer; the stereochemistry at C2 is inconsequential and is assigned tentatively as 5; see Drewes, S. E.; Emslie, N. D.; Karodia, N.; Khan, A. A. Chem. Ber. 1990, 123, 1447-1448) contaminated with -20% of the sultam auxiliary (total mass: 3.90 g). The bulk of the product was transformed as outlined in the following paragraph, without additional purification. Independently, an analytically pure sample of the product was obtained by further flash-column chromatography (30% ethyl acetate-hexanes initially, grading to 50% ethyl acetate-hexanes) and was characterized by NMR, 13C NMR, IR, andHRMS. TLC: (30% acetone-hexanes) R = 0.40 (KMn04); NMR (500 MHz, CDC13) δ: 6.49 (m, 1 H), 5.91 (dd, 1 H, 7 = 2.0, 1 .0 Hz), 5.17 (d, 1 H, J = 4.5 Hz), 4.70 (m, l H), 4.40 (d, 1 H, J = 4.5 Hz), 4.38 (d, 1 H, J = 5.0 Hz), 3.51 (s, 3H), 3.51 (s, 3H), 3.48 (s, 3H), 3.45 (s, 3H); , 3C NMR ( 125 MHz, CDCI3) δ: 163.6, 131.8, 129.2, 104.7, 102.6, 98.1 , 77.7, 57.0, 55.9, 55.7, 54.9; FTIR (neat), cm-1 : 2944 (w), 2838 (w), 1746 (s), 1 192 (s), 1074 (s); HRMS (ESI): Calcd for (Cn Hi807+Na)+ 285.0945, found 285.0946. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | The 4(R)-benzyl propionyl oxazolidinone 101 (16 g, 68.6 mmol) was dissolved in anhydrous DCM (343 ml). To this solution was added di-nbutylboron triflate (75 ml, 75 mmol) and triethylamine (TEA) (9.72 g, 96 mmol) slowly at -78 C. The reaction mixture was then warmed to 0 C. and stirred at that temperature for 1 hour then cooled back to -78 C. A DCM solution (1.0 M) of 1,1-dimethoxy acetaldehyde (100 ml, 100 mmol) was added to the reaction mixture slowly at -78 C. then the resulting solution was slowly warmed to 0 C. over 1 hour and stirred for 1 hour at that temperature. The reaction was then quenched with 100 ml solution of methanol and phosphate buffer (1:3 ratio) at 0 C., followed by addition of 100 ml solution of 30% H2O2 and methanol (1:2 ratio). The reaction was then stirred for 10 minutes at 0 C. Diluted with 200 ml DCM, washed with cold water (2×100 ml). Organic layer was separated and dried over anhydrous Na2SO4, then concentrated down to dryness under reduced pressure. Flash column chromatography using 40% EtOAc in hexane gave aldol product 102 as white solid (20.9 g, 90% yield). [alpha]25D=-51.5 (c=0.01, CHCl3); IR numax (neat)/cm-1 3485, 2937, 1778, 1696, 1386; 1H NMR (500 MHz, CDCl3) delta 7.35-7.25 (m, 3H), 7.21 (d, J=7.0 Hz, 2H), 4.72-4.65 (m, 1H), 4.33 (d, J=6.0 Hz, 1H), 4.23-4.15 (m, 2H), 4.05-3.96 (m, 1H), 3.42 (s, 3H), 3.38 (s, 3H), 3.26 (dd, J=13.5, 3.5 Hz, 1H), 2.78 (dd, J=13.5, 10 Hz, 1H), 2.68-2.60 (bs, 1H), 1.32 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) delta 176.1, 153.2, 135.4, 129.6 (2), 129.1 (2), 127.5, 104.9, 71.4, 66.3, 55.4, 54.9, 54.4, 39.2, 38.1, 12.8; m/z (ESIMS) found: 360.2 (M+Na)+. calc'd: 360.2. | |
73% | To a 1 L flask was added a 60% aq. solution of 2,2- <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (250 g, 1441 mmol) and benzene (300 mL). The mixture was refluxed and water was removed by a Dean-Stark trap. 130 mL of water was removed over 3 h. After cooling under nitrogen, the benzene solution was transferred to a clean 1 L flask with 4 A mol. sieves and diluted with anhydrous CH2C12 (300 mL) to obtain a 14.6 weight % solution of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong>. 1H NMR (400 MHz, CDC13) delta 9.49 (d, J=1.3 Hz, 1H), 4.50 (d, J=1.5 Hz, 1H), 3.48 (s, 6H). (R)-4-Benzyl-3- propionyloxazolidin-2-one (10.0 g, 42.9 mmol) was dissolved in anhydrous CH2CI2 (50.0 mL) in a dry 3 -neck 500 mL flask. The solution was cooled to below -20 C. A I M solution of TiCl4 in CH2CI2 (45.0 mL, 45.0 mmol) was added slowly. After the addition, the reaction mixture was warmed to 0 C. Once the internal temperature reached 0 C, the reaction mixture was recooled to -20 C. TMEDA (9.70 mL, 64.3 mmol) was added slowly. DIPEA (7.49 mL, 42.9 mmol) was added slowly. The reaction mixture was warmed to 0 C for 5-10 min. The dark red solution was recooled to below -40 C. A cold 14.6 weight % solution of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (45.6 mL, 72.9 mmol) was added via addition funnel as a stream. After the addition, the internal temperature was raised to 0 C and then carefully to 15 C. The reaction mixture was recooled to -20 C and quenched with sat. aq. NH4CI (150 mL) and then stirred at rt for 30 min. Most of the clear CH2CI2 phase separated out. The remaining solution with yellow sticky precipitates was filtered though a CELITE pad. The filtrate was extracted with CH2CI2. The (0572) CH2C12 phases were combined, washed with sat. aq. NH4C1 (2 x 50 mL) and brine, dried (MgS04), and concentrated. Hexane (400 mL) was added and the reaction mixture was stirred for 30 min. The product crystallized out. The solid was filtered and then dissolved in a minimal amount of CH2CI2 (~30 mL). Hexane (400 mL) was added while stirring to recrystallize the product. The solid was filtered to obtain 1Z (10.5 g, 31.1 mmol, 73% yield) as a white solid. LC-MS Anal. Calc'd for Ci7H23N06: 337.37, found [M-MeOH+H] 306.1. 1H NMR (400 MHz, CDC13) delta 7.36 - 7.30 (m, 2H), 7.30 - 7.27 (m, 1H), 7.23 - 7.18 (m, 2H), 4.74 - 4.63 (m, 1H), 4.33 (d, J=6.0 Hz, 1H), 4.23 - 4.14 (m, 2H), 4.07 - 3.95 (m, 2H), 3.42 (s, 3H), 3.38 (s, 3H), 3.27 (dd, J=13.4, 3.1 Hz, 1H), 2.78 (dd, J=13.3, 9.5 Hz, 1H), 2.55 (d, J=3.5 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ammonium acetate; In methanol; tert-butyl methyl ether; water; at 20℃; for 4h; | To a stirred solution of 8 (13.50 g, 50.70 mmol) in a mixtureof tert-butyl methyl ether (80 mL) and MeOH (40 mL) were added 60% 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> in H2O (17.7 mL, 101.40 mmol) and NH4OAc (9.77 g, 126.75 mmol).The mixture was stirred at room temperature for 4 h, and the solvent was removed under reduced pressure. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (2 × 50 mL). The combined CH2Cl2 solution was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using CH2Cl2/MeOH (20:1) as eluent to give the titled compound as a white solid. Yield 83%. |
78% | A stirred solution of 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (6.00 g, 22.49 mmol) in tert-butyl methyl ether (120 mL) was treated with glyoxal dimethyl acetal (60 wt. % solution in water, 7.8 mL, 44.98 mmol). NH4OAc (4.33 g, 56.2 mmol) in MeOH (60 mL) was added to it, and the resulting mixture was stirred at room temperature for 3 h. The pH of the reaction was adjusted to 8 with saturated aqueous NaHCO3 solution. The reaction mixture was extracted with CHCl3 (2×150 mL), and the CHCl3 solution was washed with water (100 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 as eluent to give the titled compound (6.13 g, 78%) as a light yellow foam. 1H NMR (400 MHz, CDCl3): delta 10.54 (br s, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 7.82 (dd, 1H, J=9.2, 1.6 Hz), 7.77 (dd, 1H, J=9.2, 0.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.23 (d, 1H, J=7.6 Hz), 7.04 (d, 1 H, J=8.0 Hz), 5.57 (s, 1H), 3.48 (s, 6H), 2.58 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: dimethoxyacetaldehyde; acrylcamphorsultam With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 23℃; for 16h; Stage #2: methanol With triethylamine at 23℃; for 0.5h; Stage #3: t-butyldimethylsiyl triflate With N-ethyl-N,N-diisopropylamine enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen;palladium 10% on activated carbon; In ethanol; water; at 20℃; under 760.051 Torr; for 12h; | EXAMPLE 3N-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N'-(2,2-dimethoxyethyl)-N-methylpropane-1,3-diamine1 g (3.7 mmoles) of N-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropane-1,3-diamine is dissolved in 20 mL of ethanol. 520 mg (0.45 mL) of a 60% solution of glyoxal 1,1-dimethyl acetal in water and then 100 mg of Pd/C 10% are added. The reaction mixture is hydrogenated at atmospheric pressure and ambient temperature for 12 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. 1.2 g of expected product are obtained in the form of an oil.Yield=90%IR: nu=1207, 1508, 834 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With titanium(IV) tetrabutoxide; triethylsilyl chloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrogen;palladium 10% on activated carbon; In ethanol; water; under 760.051 Torr; for 31h;Inert atmosphere; | Step 1. (2,2-Dimethoxyethyl)-(4-trifluoromethoxyphenyl) amine. To a stirred solution of 4-trifluoromethoxyaniline (1 mL, 7.46 mmol) and glyoxaldehyde dimethyl acetal (60% v/v in water; 8.95 mmol, 1.6 mL) in EtOH (37 mL) was added 10% Pd/C (300 mg). The mixture was evacuated and flushed with nitrogen three times. Hydrogen was then added in a balloon apparatus and the mixture was stirred under 1 atm of hydrogen for 31 h. The mixture was filtered through a pad of Celite and the pad was washed with EtOH (25 mL). The ethanol was removed under reduced pressure and the residue was diluted with CH2Cl2 (30 mL). The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated to give (2,2-dimethoxyethyl)-(4-trifluoromethoxyphenyl) amine (1.7 g, 86%): 1H NMR (400 MHz, CDCl3) delta 7.04 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H), 4.56 (t, J = 5.4 Hz, IH), 3.92 (br s, IH), 3.51 (d, J= 5.4 Hz, 2H), 3.42 (s, 6H); EIMS m/z 265 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With methanesulfonic acid; In tetrahydrofuran; at 40℃; | General procedure: A mixture of compound 9 (2.00 g, 7.58 mmol), ethyl 2-oxoacetate (1.16 g, 11.4 mmol) and methanesulfonic acid(73 mg, 0.76 mmol) in THF (25 mL) was stirred at 40 oC for 2hours. After the reaction was completed,the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30mLx3). The organic layer was washed withbrine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by columnchromatography (Petroleum ether:EtOAc= 15:1) to afford desired product of compound 10b (1.2 g, yield: 84%).For NMR, see Table 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
228.5 mg | With diphenyl hydrogen phosphate; 3,5-diethyl 1,4-dihydropyridine-3,5-dicarboxylate In dichloromethane at 15℃; for 9.5h; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 52h; | General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 48h; | General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 96h; | General procedure: To a mixture of the 2,2-dimethoxyacetaldehyde 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-dimethoxyacetaldehyde was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 32h; | General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-[(1S)-2'-[[(4-methylphenyl)sulfonyl]amino][1,1'-binaphthalen]-2-yl]-2-pyrrolidinecarboxamide; In water; at 25℃; for 50h; | General procedure: To a mixture of the 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Methylamine hydrochloride (4.05 g, 1.05 equiv.) in DCM (60 mL) was cooled to 0C, then K2C03 (5.53 g, 1 equiv.) was added over 5 minutes. Reaction was stirred at 0C for a further 10 minutes then 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (6.04 mL, 40 mmol) was added and the reaction was stirred vigorously at 0C. After 5 minutes at 0C, the reaction was allowed to warm to room temperature. After 15 minutes at room temperature, DCM was decanted off, solid was extracted with DCM (2 x 15 mL). Combined DCM fractions were dried (Na2S04), filtered, and evaporated to give product which was used without further purification (4.10 g, 87%). | |
With potassium carbonate; In dichloromethane; at 0 - 20℃; for 0.333333h; | Procedure for synthesis of 2,2-dimethoxy-N-methyl-ethanimine (Step 1) - - Methylamine hydrochloride (4.05 g, 1.05 equiv.) in DCM (60 imL) was cooled to 0C, then K2C03 (5.53 g, 1 equiv.) was added over 5 minutes. Reaction was stirred at 0C for a further 10 minutes then 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (6.04 mL, 40 mmol) was added and the reaction was stirred vigorously at 0C. After 5 minutes at 0C, the reaction was allowed to warm to room temperature. After 15 minutes at room temperature, DCM was decanted off, solid was extracted with DCM (2 x 15 mL). Combined DCM fractions were dried (Na2S04), filtered, and evaporated to give product which was used without further purification (4.10 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness;Catalytic behavior; | General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness;Catalytic behavior; | General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness; | General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness;Catalytic behavior; | General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness;Catalytic behavior; | General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With ammonium acetate; In methanol; tert-butyl methyl ether; water; at 20℃; | General procedure: In a 250-mL round-bottomed flask, were placed 15a, 15b, or15c (2.65 g, 9.32 mmol), NH4OAc (180 g, 23.30 mmol), 60% 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong>in H2O (3.2 mL, 18.64 mmol), tert-butyl methyl ether (20 mL), and MeOH (10 mL). The mixture wasstirred at room temperature for 4-6 h, and the solvent was removed under reducedpressure. The residue was cooled to 0 oC and neutralized withsaturated NaHCO3 solution. The mixture was extracted with CH2Cl2(2 × 70 mL), and the combined extracts were dried over anhydrous Na2SO4,filtered, and then evaporated to dryness under reduced pressure. The residue waspurified by MPLC on silica gel using CH2Cl2/MeOH (20:1)as eluent to afford the titled compounds as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With ammonium acetate; In methanol; tert-butyl methyl ether; water; at 20℃; | General procedure: In a 250-mL round-bottomed flask, were placed 15a, 15b, or15c (2.65 g, 9.32 mmol), NH4OAc (180 g, 23.30 mmol), 60% 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong>in H2O (3.2 mL, 18.64 mmol), tert-butyl methyl ether (20 mL), and MeOH (10 mL). The mixture wasstirred at room temperature for 4-6 h, and the solvent was removed under reducedpressure. The residue was cooled to 0 oC and neutralized withsaturated NaHCO3 solution. The mixture was extracted with CH2Cl2(2 × 70 mL), and the combined extracts were dried over anhydrous Na2SO4,filtered, and then evaporated to dryness under reduced pressure. The residue waspurified by MPLC on silica gel using CH2Cl2/MeOH (20:1)as eluent to afford the titled compounds as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Step 1: K2CO3 (7.90 g, 57.1 mmol) was added to a stirred solution of 18 (8.00 g, 31.7 mmol) in cyclohexane (50 mL) and the resultant suspension was stirred at 60 C for 2 h. 2,2-Dimethoxyacetaldehyde 19 (60% in H2O, 12 mL, 69.3 mmol) was added, and the resultant mixture was stirred at 60 C for 16 h, then allowed to cool to rt before satd aq NH4Cl (50 mL) was added. The aqueous layer was extracted with Et2O (3x50 mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (50 mL), H2O (50 mL) and brine (50 mL), then dried and concentrated in vacuo to give 20 in >99:1 d.r. [(E):(Z)]. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 20:1) gave 20 as a colourless oil (7.00 g, 96%, >99:1 d.r. [(E):(Z)]);32 deltaH (400 MHz, CDCl3) 1.49 (9H, s, CMe3), 3.34 (6H, s, CH(OMe)2), 4.92 (1H, dd, J 4.3,1.3, C(4)H), 6.06 (1H, dd, J 15.9, 1.3, C(2)H), 6.67 (1H, dd, J 15.9, 4.3, C(3)H). Step 2: p-Toluensulfonic acid monohydrate (1.98 g, 10.4 mmol) was added to a stirred solution of 20 (18.1 g, 89.6 mmol, >99:1 d.r. [(E):(Z)]) in a 1:1 mixture of H2O and acetone (400 mL). The resultant mixture was heated at reflux for 1.5 h, then satd aq NaHCO3 (100 mL) was added. The aqueous layer was extracted with Et2O (3150 mL) and the combined organic extracts were washed with brine (100 mL), then dried and concentrated in vacuo to give 21 in>99:1 d.r. [(E):(Z)]. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 20:1) gave 21 as a colourless oil (14.0 g, 86%, >99:1 d.r. [(E):(Z)]);32 deltaH (400 MHz, CDCl3) 1.51 (9H, s, CMe3), 6.65 (1H, d, J 15.9, C(2)H), 6.88 (1H, dd, J 15.9, 7.8, C(3)H),9.73 (1H, d, J 7.8, C(4)H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | NaBH(OAc)3 (3.3 g, 15 mmol) was added to a stirring solutionof benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL,12 mmol) in CHCl3 (60 mL) and the mixture was stirred atroom temperature (rt) for one hour (h). 2,2-Dimethoxyacetaldehyde (30 mmol) was then introduced into the reaction mixturefollowed by NaBH(OAc)3 (3.3 g, 15.0 mmol) and the resultantmixture was stirred at rt for further 8 h. The mixture was thenquenched with saturated aqueous solution of K2CO3 (60 mL)and the aqueous (aq) layer was extracted with CHCl3(2 × 30 mL). The combined organic layers were dried withMgSO4, filtered and evaporated to give the crude compound 9aas a pale yellow oil (3.87 g).N-Benzyl-N-(2,2-dimethoxyethyl)aniline (9a). The crudecompound was purified by column chromatography (eluent:from 0-30% EtOAc in pet. ether) to give 9a as a colorless oil(2.92 g, 99%) which showed: 1H NMR (500 MHz, CDCl3) delta3.41 (s, 6H, OCH3), 3.58 (d, J = 5.1 Hz, 2H, NCH2CH), 4.63 (t,J = 5.1 Hz, 1H, CH(OR)2), 4.67 (s, 2H, CH2Ar), 6.70 (tt, J =0.9, 7.4 Hz, 1H, ArH), 6.74 (dd, J = 0.9, 8.9 Hz, 2H, ArH),7.16-7.25 (5H, m, ArH), 7.27-7.34 (m, 2H, ArH) ppm;13C NMR (126 MHz, CDCl3) delta 53.9 (CH2CH), 54.6 (CH3),54.9 (ArCH2), 103.5 (CH(OR)2), 112.3 (ArCH), 116.7 (ArCH),126.6 (ArCH), 126.8 (ArCH), 128.7 (ArCH), 129.4 (ArCH),138.9 (ArCCH2) and 148.7 (ArCN) ppm; LC-MS (ES+) tR 1.81 min (87%), m/z 226.0 (M + H)+; HRMS (ES+): (M + H)+calcd. for C17H22NO2, 272.1645; found, 272.1651. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: NaBH(OAc)3 (3.3 g, 15 mmol) was added to a stirring solutionof benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL,12 mmol) in CHCl3 (60 mL) and the mixture was stirred atroom temperature (rt) for one hour (h). 2,2-Dimethoxyacetaldehyde (30 mmol) was then introduced into the reaction mixturefollowed by NaBH(OAc)3 (3.3 g, 15.0 mmol) and the resultantmixture was stirred at rt for further 8 h. The mixture was thenquenched with saturated aqueous solution of K2CO3 (60 mL)and the aqueous (aq) layer was extracted with CHCl3(2 × 30 mL). The combined organic layers were dried withMgSO4, filtered and evaporated to give the crude compound 9aas a pale yellow oil (3.87 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.9 g | With palladium 10% on activated carbon; hydrogen; In ethanol; at 20.0℃; under 760.051 Torr; for 16.0h; | A mixture of <strong>[106877-20-7]3-methoxy-4-(trifluoromethyl)aniline</strong> [CAS 106877-20-71(25 g, 130.7 mmol), glyoxal-dimethylacetal [CAS 51673-84-81(39.3 mL, 261 .571 mmol) andPd/C (10%) (2.8 g, 2.62 mmol) in EtOH (250 mL) was hydrogenated under atmospheric pressure of H2 at room temperature for 16 h. The mixture was filtered through a pad of celite. The filter cake was washed with EtOH and the combined filtrates were concentrated under reduced pressure. The residue was taken up with EtOAc. The organic layer was washed with water, dried over Mg504, filtered and the solvent was evaporated to give N-(2,2-dimethoxyethyl)-3-methoxy-4- (trifluoromethyl)aniline 2a (39.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a suspension of N-4-aminophenylmorpholine-3-one (2) (960 mg; 5 mmol) in dry CH2Cl2 (20 mL) and 4 A molecular sieves (0.5 g) was added the solution of <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (60%) in water (1.13 mL, 7.5 mmol). The mixture was stirred at room temperature for 2 hours. Then, solid NaBH(OAc)3 (1.59 g; 7.5 mmol) was added portionwise during 20 min and the slurry was stirred for 1 hour at room temperature. Afterwards, the mixture was filtered through a plug of Celite and washed with CH2Cl2 (30 mL). The filtrate was evaporated under reduced pressure and the crude product 3 was purified by column chromatography (SiO2; acetone/hexanes/TEA 2/1/0.001, Rf 0.47).1 Yield: 1.32 g (94%); mp: 99-101 C; 1H NMR (CDCl3; 400 MHz): delta 7.09 (m, 2H), 6.65 (m, 2H), 4.56 (t, J = 4.4 Hz, 1H), 4.32 (s, 2H), 4.00 (m, 2H), 3.95 (br, 1H), 3.69 (m, 2H), 3.41 (s, 6H), 3.24 (d, J = 4.4 Hz, 2H); 13C NMR (CDCl3; 100 MHz): delta 167.1, 147.2, 131.6, 127.0, 113.6, 102.5, 68.8, 64.4, 54.1, 50.4, 45.5; FT-IR (ATR, cm-1): 3343, 3054, 2951, 2910, 2857, 2834, 1741, 1639, 1608, 1525, 1478, 1342, 1323, 1121 (100%), 1043, 995, 915, 831, 544; HR-MALDI-MS (DHB): m/z calcd. for C14H21N2O4 ([M+H]+) 281.15014, found 281.15024 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trifluoroacetic acid In dichloromethane for 1h; | |
94% | With trifluoroacetic acid In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium acetate; In methanol; tert-butyl methyl ether; at 20℃; for 18h; | Dione iv (2.0 g, 7.8 mmol) is dissolved in methyl /-butyl ether (40 mL) and dry methanol (20 mL). 2,2-dimethoxy acetaldehyde (1.7 g, 9.6 mmol) and ammonium acetate (60%, 1.5 g, 12 mmol) are added. The reaction is stirred at room temperature for 18 hours, then cooled to 10 C. The pH is adjusted to pH 8-9 via addition of aqueous sodium carbonate. The resultant mixture is extracted into chloroform (3 x 50 mL). The organic layer is washed with water and dried over sodium sulfate before removal of the residual solvent. The resultant brown 011 is dissolved in methyl /-butyl ether (15 mL) and the solvent is removed. Hexanes (2 x 20 mL) are added, and the solvent is decanted to give v in 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: To a solution of compound 8 (150 mg, 1.17 mmol) in dry CH2Cl2 (10 ml) at -35 C were added a solution of TiCl4 (0.19 ml, 1.75 mmol) and tributylamine (0.83 ml, 3.5 mmol) in CH2Cl2 (2 ml each). After stirring the resulting solution for 30 minutes at same temperature, 1 ml solution of 2,2-dimethoxy acetaldehye (5.85 mmol) in CH2Cl2 (extracted from 60% aqueous solution) was added and the reaction mixture was allowed to attain room temperature. Once the reaction was complete (confirmed by TLC), water (15 ml) was added to quench the reaction. Workup was done with CH2Cl2 (3 x 15 ml) and after washing the organic portion with brine (25 ml), it was dried over sodium sulphate (2 g). Solvent was removed under reduced pressure and the resulting crude reaction mixture was subjected to column chromatography with ethyl acetate/hexane (3:97). The product was obtained as a colorless liquid in 67% yield (104 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonium acetate; In methanol; tert-butyl methyl ether; water; at 50℃; for 2h; | General procedure: To a solution of compound 11 or 17 (3.18 mmol) in MeOH (17 mL) at room temperature, NH4OAc (27.98 mmol), 60% 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> in H2O (22.38 mmol) and tert-butyl methyl ether (48 mL) were added. The reaction mixture was heated to 50 C and stirred for 2 h. The mixture was cooled to room temperature, and then the solvent was removed by reduced pressure. The residue was cooled to 0 C and neutralized with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate (2 25 mL) and the combined extracts were washed with water (15 mL) and brine (15 mL), dried over anhydrous MgSO4, filtered, and then evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride and MeOH (70:1) as eluent to give the titled compounds 12 or 18 as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of l-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2-(6-methylpyridin-2- yl)ethane-l,2-dione (CAS 356560-84-4; 2.7 g, 10.1 mmol) in a 2: 1 mixture of tert-butyl methyl ether and methanol (25 mL) were added 60% 2,2-dimethoxyacetaldehyde in H20 (3.5 mL, 20 mmol) and NH4OAc (1.95 g, 25.2 mmol). The mixture was stirred at room temperature for 5h before the solvent was removed. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaHC03 solution and extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na2S04, filtered, and evaporated. The residue was purified on silica gel (ISCO gold, 40g; 0% to 20% CH2Cl2/MeOH over 15 minutes) to give the desired imidazole product which dissolved in 1 N HC1 (20 mL) and heated at 70C for 4h. The reaction mixture was allowed to cool to 0C and then it was neutralized with saturated aqueous NaHCO, solution. The precipitate was collected and washed with water (20 mL) and ether (40 mL) to give the desired product Int 1. la as a yellow-brown solid. 1H NMR (DMSO-d6) d 10.0 (dd, J=L6, 0.8 Hz, 1H), 9.56 (s, 1H), 8.42 (s, 1H), 8.27 (dd, J=9.2, l.6Hz, 1H), 7.82 (br d, J = 0.8 Hz, 1H), 7.72 (dd, J = 9.2, 0.8Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 2.46 (s, 3H). LCMS (M+H) = 305.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With ammonium acetate; In water; at 40℃; for 1h; | In turn, alpha, alpha-dihydroxyphenyl ethyl ketone 15.2g,76g of water, 34.7g of 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> 60% aqueous solution, 29.6g of ammonium acetate were added with a thermometer,Three-necked round bottom flask with reflux condenser and stirring device;Warm to 40 C with stirring, stir the reaction,TLC monitors the reaction,The raw material alpha, alpha-dihydroxyphenyl ethyl ketone disappeared to end the reaction (about 5h); 76g of water was added at 40 C and stirred for 1h, a large amount of solid was formed,Filter to obtain crude product;The above filtered solid was beaten with 50g of warm water at 40 C for 1h,filter,Dried product2- (dimethoxymethyl) -5-phenyl-1H-imidazole 20.0g,The yield was 94.9% and the content was 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Example 1 (0290) (0291) Glycine methyl ester (13) (20.0 g, 0.159 mol) was added at room temperature to a reaction vessel with 100 mL of MeOH. The reaction mixture was mixed until all the glycine methyl ester had dissolved. After mixing, Et3N (22.2 mL, 0.159 mol) and 2,2-dimethyloxoacetaldehyde (14) (27.8 mL, 0.159 mmol) were added to the reaction vessel at room temperature. Under N2, Pd/C was transferred to a reaction vessel. An additional 20 mL of MeOH was added. The reaction vessel was kept under H? (25 bar) for 10-12 hours and the reaction was monitored via TLC. After complete consumption of starting materials, the reaction mixture was filtered through celite to remove the Pd/C. The celite cake was washed with MeOH (200 mL). The reaction mixture was then transferred to a round-bottom flask (RBF) and the methanol was removed under reduced pressure. The mixture was transferred to a separatory funnel and extracted five times with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Extraction of the material yielded 23 as a pale-yellow material (26.2 g, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tert.-butylhydroperoxide; oxygen; toluene-4-sulfonic acid In 1,4-dioxane at 60℃; for 2h; | Typical procedure for the synthesis of N-phenylformamide derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.6 mmol) was mixed with 2a (0.3 mmol), PTSA (20 mol %) in 1,4-dioxane (1.0 mL) under O2 atmosphere. The mixture was then stirred at 60 oC for 2 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 10/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With toluene-4-sulfonic acid In chloroform at 60℃; for 8h; Inert atmosphere; | Typical procedure for the synthesis of 2, 2'-(phenylazanediyl)diacetate derivative. General procedure: The reactions were conducted in a 10 mL V-type flask equipped with triangle magnetic stirring. In a typical reaction, 1a (0.3 mmol) was mixed with 2a (0.6 mmol), PTSA (20 mol %) in chloroform (1.5 mL) under N2. The mixture was then stirred at 60 oC for 8 h. After reaction, the product was obtained by isolation with silica column chromatography (eluting solution: petroleum ether/ ethyl acetate = 20/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 40℃; for 72h; | 7.1; 8.1 Step (1): take 19.8 g (150 mmol) of phenyl vinyl ketone and 16.8 g (150 mmol) of DABCO into a 1000 mL round-bottomed flask containing 200 mL of dichloromethane, stir at room temperature until the solid is completely dissolved, add to the mixed solution 17.3 g of 2,2-dimethoxyacetaldehyde aqueous solution (60 wt %, 100 mmol) was added, and the mixture was stirred and reacted at 40° C. for 72 hours.After the completion of the reaction, the organic layer was separated by a separating funnel, washed 3 times with 0.1M aqueous hydrochloric acid solution, 300 mL each time, and the organic layer solution was concentrated after separation, and then separated by silica column chromatography (with ethyl acetate/petroleum ether volume ratio 1:10 as eluent) yielded 17.7 g of product Morita-Baylis-Hillman alcohol (75% yield) |
75% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane; lithium hydroxide monohydrate at 40℃; for 72h; | 7.1; 8.1 Step (1): take 19.8 g (150 mmol) of phenyl vinyl ketone and 16.8 g (150 mmol) of DABCO into a 1000 mL round-bottomed flask containing 200 mL of dichloromethane, stir at room temperature until the solid is completely dissolved, add to the mixed solution 17.3 g of 2,2-dimethoxyacetaldehyde aqueous solution (60 wt %, 100 mmol) was added, and the mixture was stirred and reacted at 40° C. for 72 hours.After the completion of the reaction, the organic layer was separated by a separating funnel, washed 3 times with 0.1M aqueous hydrochloric acid solution, 300 mL each time, and the organic layer solution was concentrated after separation, and then separated by silica column chromatography (with ethyl acetate/petroleum ether volume ratio 1:10 as eluent) yielded 17.7 g of product Morita-Baylis-Hillman alcohol (75% yield) |
With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane; lithium hydroxide monohydrate at 20 - 40℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane; lithium hydroxide monohydrate at 20 - 40℃; for 48h; | |
77% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane; lithium hydroxide monohydrate at 40℃; for 72h; | 1.1; 2.1; 3.1; 4.1 Example 1 Preparation of benzyl 1-p-methylphenylpyrrole-3-carboxylate based on 2,2-dimethoxyacetaldehyde derivatized Morita-Baylis-Hillman acetate, comprising the following steps: Step (1) Take 24.3 g (150 mmol) of benzyl acrylate and 16.8 g (150 mmol) of triethylenediamine (DABCO) into a 1000 mL round-bottomed flask containing 200 mL of dichloromethane, stir at room temperature until the solid is completely dissolved, and add to the flask. 17.3 g of 2,2-dimethoxyacetaldehyde aqueous solution (60 wt %, 100 mmol) was added to the mixed solution, and the mixed solution was stirred at 40° C. for 72 hours.After the completion of the reaction, the organic layer was separated by a separating funnel, washed 3 times with 0.1M aqueous hydrochloric acid solution, 300 mL each time, and the organic layer solution was concentrated after separation, and then separated by silica column chromatography (with ethyl acetate/petroleum ether volume ratio 1:10 as eluent) to give 20.7 product Morita-Baylis-Hillman alcohol (77% yield). |
77% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane; lithium hydroxide monohydrate at 40℃; for 72h; | 1.1; 2.1; 3.1; 4.1 Example 1 Preparation of benzyl 1-p-methylphenylpyrrole-3-carboxylate based on 2,2-dimethoxyacetaldehyde derivatized Morita-Baylis-Hillman acetate, comprising the following steps: Step (1) Take 24.3 g (150 mmol) of benzyl acrylate and 16.8 g (150 mmol) of triethylenediamine (DABCO) into a 1000 mL round-bottomed flask containing 200 mL of dichloromethane, stir at room temperature until the solid is completely dissolved, and add to the flask. 17.3 g of 2,2-dimethoxyacetaldehyde aqueous solution (60 wt %, 100 mmol) was added to the mixed solution, and the mixed solution was stirred at 40° C. for 72 hours.After the completion of the reaction, the organic layer was separated by a separating funnel, washed 3 times with 0.1M aqueous hydrochloric acid solution, 300 mL each time, and the organic layer solution was concentrated after separation, and then separated by silica column chromatography (with ethyl acetate/petroleum ether volume ratio 1:10 as eluent) to give 20.7 product Morita-Baylis-Hillman alcohol (77% yield). |
Tags: 51673-84-8 synthesis path| 51673-84-8 SDS| 51673-84-8 COA| 51673-84-8 purity| 51673-84-8 application| 51673-84-8 NMR| 51673-84-8 COA| 51673-84-8 structure
[ 18370-95-1 ]
Methyl 2,2,2-trimethoxyacetate
Similarity: 0.63
[ 18370-95-1 ]
Methyl 2,2,2-trimethoxyacetate
Similarity: 0.63
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