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[ CAS No. 124931-12-0 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 124931-12-0
Chemical Structure| 124931-12-0
Chemical Structure| 124931-12-0
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Product Details of [ 124931-12-0 ]

CAS No. :124931-12-0 MDL No. :MFCD00134233
Formula : C8H18NO5P Boiling Point : -
Linear Structure Formula :- InChI Key :WYLRYBDGIILFIR-UHFFFAOYSA-N
M.W : 239.21 Pubchem ID :2773719
Synonyms :

Safety of [ 124931-12-0 ]

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:

Application In Synthesis of [ 124931-12-0 ]

* 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.

  • Downstream synthetic route of [ 124931-12-0 ]

[ 124931-12-0 ] Synthesis Path-Downstream   1~95

  • 1
  • [ 26489-02-1 ]
  • [ 124931-12-0 ]
  • [ 141868-91-9 ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature;
50% With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere;
  • 2
  • [ 124931-12-0 ]
  • [ 432-25-7 ]
  • [ 141208-06-2 ]
YieldReaction ConditionsOperation in experiment
71% With n-butyllithium In tetrahydrofuran; hexane for 24h; Ambient temperature;
With sodium hydride In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
1.43 g Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,6,6-trimethylcyclohex-1-enecarbaldehyde In 1,4-dioxane at 100℃; for 16h; Inert atmosphere;
  • 3
  • [ 124931-12-0 ]
  • [ 150943-17-2 ]
  • [ 153474-56-7 ]
  • [ 150943-18-3 ]
YieldReaction ConditionsOperation in experiment
1: 73% 2: 4.6% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: (2R)-1-(tert-butyloxycarbonyl)-2-((tert-butyldiphenylsilyl)oxymethyl)-3-azetidinone In tetrahydrofuran at 20℃; for 14h;
1: 67% 2: 7.7% In methanol at -78 - 20℃; for 25h;
With sodium hydride In tetrahydrofuran at 0℃; Yield given. Yields of byproduct given;
  • 4
  • [ 124931-12-0 ]
  • [ 108-94-1 ]
  • [ 124931-20-0 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature;
With n-butyllithium 1.) THF, -78 deg C, 2.) 0 deg C, 1 h; Yield given. Multistep reaction;
  • 5
  • [ 124931-12-0 ]
  • [ 100-52-7 ]
  • N-methoxy-N-methylcinnamamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: benzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
91% With sodium hydride In diethyl ether for 1h; 0 deg C to room temperature;
  • 6
  • [ 67442-07-3 ]
  • [ 122-52-1 ]
  • [ 124931-12-0 ]
YieldReaction ConditionsOperation in experiment
78% at 100℃; for 18h; A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (2.48 g,17.7 mmol) and triethyl phosphite (3.00 mL, 17.7 mmol) was heated to 100 °C for 18 h. The crude product was purified by flash column chromatography (0?2percent MeOH in CH2Cl2) to give 1 as a colorless oil; yield: 3.31 g (13.8 mmol; 78percent); Rf = 0.42 (2percent MeOH in CH2Cl2); HPLC purity (method b): >95percent (210 nm), >95percent (254 nm). IR (ATR): 2985, 2940, 2908, 1659, 1381, 1253, 1050, 1020, 998, 961 cm?1. 1H NMR (400 MHz, CDCl3): delta = 4.26?4.07 (m, 4 H, 2 × OCH2CH3), 3.76(s, 3 H, OCH3), 3.20 (s, 3 H, NCH3), 3.15 (d, J = 22.1 Hz, 2 H, 1-H), 1.33(td, J = 7.1, 0.6 Hz, 6 H, 2 × OCH2CH3). 13C NMR (101 MHz, CDCl3): delta = 166.2 (C-2), 62.7 (2 × OCH2CH3), 61.6(OCH3), 32.3 (NCH3), 30.9 (C-1), 16.5 (2 × OCH2CH3). HRMS (ESI): m/z [M + H]+ calcd for C8H19NO5P+: 240.0995; found: 240.0996.
  • 7
  • [ 124931-12-0 ]
  • [ 121660-37-5 ]
  • [ 141750-56-3 ]
  • 8
  • [ 124931-12-0 ]
  • [ 33603-83-7 ]
  • [ 180779-72-0 ]
YieldReaction ConditionsOperation in experiment
80% With potassium <i>tert</i>-butylate
80% With potassium <i>tert</i>-butylate In tetrahydrofuran 1.) 0 deg C, 30 min, 2.) -78 deg C, 1 h;
  • 9
  • [ 762-04-9 ]
  • [ 67442-07-3 ]
  • [ 124931-12-0 ]
  • 10
  • [ 124931-12-0 ]
  • [ 193337-38-1 ]
  • [ 193337-41-6 ]
YieldReaction ConditionsOperation in experiment
85% With n-butyllithium In tetrahydrofuran at 0℃;
  • 11
  • [ 124931-12-0 ]
  • [ 555-16-8 ]
  • [ 253122-46-2 ]
YieldReaction ConditionsOperation in experiment
98% With sodium methylate In tetrahydrofuran at 20℃; for 0.333333h;
  • 12
  • [ 124931-12-0 ]
  • [ 123-11-5 ]
  • [ 243665-13-6 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
97% With sodium methylate In tetrahydrofuran at 20℃; for 0.333333h;
93% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere;
66% With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere;

  • 13
  • [ 124931-12-0 ]
  • (2R)-2-benzyloxycarbonylamino-3-(4-methoxybenzylsulfanyl)-succinic acid 1-methyl ester 4-tert-butyl ester [ No CAS ]
  • (2R,3R,4E)-3-benzyloxycarbonylamino-2-[4-methoxybenzylsulfanyl]-5-[N-methyl-N-methoxy carbamoyl]pent-4-enoic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: (2R)-2-benzyloxycarbonylamino-3-(4-methoxybenzylsulfanyl)-succinic acid 1-methyl ester 4-tert-butyl ester With diisobutylaluminium hydride In tetrahydrofuran; hexane; toluene at -78 - 20℃;
  • 14
  • [ 124931-12-0 ]
  • [ 23637-56-1 ]
  • (+/-)-N-methoxy-N-methyl-2-(2t-benzoyl-3c-phenylcycloprop-1r-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With methyllithium In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3,6-diphenyl-3,6-dihydro-1,2-dioxine In tetrahydrofuran for 3h; Further stages.;
  • 15
  • [ 124931-12-0 ]
  • [ 53646-91-6 ]
  • trans-(+/-)-N-methoxy-N-methyl-2-(2-benzoylcyclopropyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With methyllithium In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3-phenyl-3,6-dihydro-1,2-dioxine In tetrahydrofuran for 3h; Further stages.;
  • 16
  • [ 124931-12-0 ]
  • [ 445306-60-5 ]
  • [ 445306-61-6 ]
YieldReaction ConditionsOperation in experiment
92% With sodium hydride In tetrahydrofuran at 20℃;
92% With sodium hydride In tetrahydrofuran at 20℃; for 1.5h;
  • 17
  • [ 124931-12-0 ]
  • (2S,4RS)-5-(tert-butyldimethylsilyloxy)-2-methyl-4-(trimethoxymethylphenyl)pentanal [ No CAS ]
  • [ 478303-49-0 ]
  • (4S,6S)-7-(tert-butyldimethylsilyloxy)-4-methyl-6-(trimethoxymethylphenyl)hept-2-enoic acid methoxymethylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 57% 2: 35% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: (2S,4RS)-5-(tert-butyldimethylsilyloxy)-2-methyl-4-(trimethoxymethylphenyl)pentanal In tetrahydrofuran at 20℃; for 2.5h;
  • 18
  • [ 124931-12-0 ]
  • [ 111865-84-0 ]
  • [ 526217-80-1 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 5h;
  • 19
  • [ 124931-12-0 ]
  • C28H44O10 [ No CAS ]
  • C32H51NO11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.171 g Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: C28H44O10 In tetrahydrofuran at 20℃; for 0.5h;
  • 20
  • [ 124931-12-0 ]
  • [ 623151-46-2 ]
  • [ 623151-47-3 ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.16667h; Stage #2: (5Z,7E)-(3R,4R)-4-(tert-butyldimethylsilanyloxy)-10-(tert-butyldiphenylsilanyloxy)-3-methyldeca-5,7-dienal In tetrahydrofuran at 20℃; for 1.16667h;
  • 21
  • [ 862893-91-2 ]
  • [ 124931-12-0 ]
  • [ 862893-92-3 ]
YieldReaction ConditionsOperation in experiment
77% With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 2h;
  • 22
  • [ 863407-41-4 ]
  • [ 124931-12-0 ]
  • [ 863407-46-9 ]
YieldReaction ConditionsOperation in experiment
48% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [6-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃;
  • 23
  • [ 863407-42-5 ]
  • [ 124931-12-0 ]
  • [ 863407-47-0 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [4-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃;
  • 24
  • [ 863407-40-3 ]
  • [ 124931-12-0 ]
  • [ 863407-45-8 ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: [7-fluoro-1-(4-toluenesulfonyl)indol-3-yl]carboxaldehyde In tetrahydrofuran at 0℃;
  • 25
  • [ 468718-26-5 ]
  • [ 124931-12-0 ]
  • [ 468718-27-6 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-6-carbonitrile In tetrahydrofuran at 0℃;
  • 26
  • [ 863407-39-0 ]
  • [ 124931-12-0 ]
  • [ 863407-44-7 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-4-carbonitrile In tetrahydrofuran at 0℃;
  • 27
  • [ 468717-73-9 ]
  • [ 124931-12-0 ]
  • [ 468717-74-0 ]
YieldReaction ConditionsOperation in experiment
91% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: 3-formyl-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile In tetrahydrofuran at 0℃; for 1h;
  • 28
  • [ 863407-38-9 ]
  • [ 124931-12-0 ]
  • [ 863407-43-6 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-formyl-1-(4-toluenesulfonyl)-1H-indole-7-carbonitrile In tetrahydrofuran at 0℃;
  • 29
  • [ 124931-12-0 ]
  • [ 217489-00-4 ]
  • [ 468717-78-4 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 5-fluoro-1-(p-tolylsulfonyl)indole-3-carboxaldehyde In tetrahydrofuran at 0℃;
88% In tetrahydrofuran 2 Trans-1-(N,N-dimethylaminomethyl)-2-[5-fluoroindol-3-yl]cyclopropane A solution of diethyl (N-methoxy-N-methylcarbamoylmethyl) phosphonate (5.64 ml, 6.54 g, 27.4 mmol) in anhydrous tetrahydrofuran (25 ml) was added to a stirred suspension of oil free sodium hydride (1.05 g, 27.4 mmol) in anhydrous tetrahydrofuran (350 ml) maintained at 0° C. The reaction was warmed to room temperature and was stirred for 2 h. After cooling to 0° C., [5-fluoro-1-(p-toluenesulfonyl)indol-3-yl]carboxaldehyde (7.24 g, 22.8 mmol) was added. The resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched with aqueous hydrochloric acid (0.1 N) and poured into water (150 ml). After being made acidic with hydrochloric acid (1.0 N), the aqueous portion was extracted with ethyl acetate (3*100 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate to afford a total of 8.03 g (88% yield) of (E)-[5-fluoro-1-(p-toluenesulfonyl)indol-3-yl]-N-methoxy-N-methylacrylamide as a white solid: mp 199-200° C. (dec.); 1H NMR (400 MHz, DMSO-d6) 8.56 (1 H, s), 7.99 (1 H, m), 7.93 (2 H, d, J=8.4 Hz), 7.68 (2 H, m), 7.42 (2 H, d, J=8.1 Hz), 7.28 (1 H, t, J=9.2 Hz), 7.12 (1 H, d, J=16 Hz), 3.77 (3 H, s), 3.22 (3 H, s), 2.33 (3 H, s); MS m/e 403 (M+H)+. Anal. Calcd. For C20H19FN2O4S: C, 59.69; H, 4.75; N 6.96. Found: C, 59.60; H, 4.70; N, 6.86.
  • 30
  • [ 124931-12-0 ]
  • [ 1489-69-6 ]
  • [ 141580-89-4 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: Cyclopropanecarboxaldehyde In tetrahydrofuran at 20℃; for 2h; Further stages.;
79% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: Cyclopropanecarboxaldehyde In tetrahydrofuran at 20℃; for 4h;
  • 31
  • [ 20780-76-1 ]
  • [ 124931-12-0 ]
  • (E)-2-(5-iodo-2-oxoindolin-3-ylidene)-N-methoxy-N-methylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 18h;
  • 32
  • [ 124931-12-0 ]
  • [ 689258-07-9 ]
YieldReaction ConditionsOperation in experiment
With NaH In tetrahydrofuran 63.3 (2-{2,3-Difluoro-4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}cyclopropyl)acetic acid Trifluoroacetate. Step 3: (2E)-3-(2,3-Difluoro-4-methoxyphenyl)-N-methoxy-N-methylprop-2-enamide. Diethyl (N-methoxy-N-methylcarbamoylmethyl)-phosphonate (4.8 g) was added to a suspension of 95% NaH (550 mg) in THF (40 mL) under nitrogen atmosphere. The mixture was stirred at an ambient temperature for 10 minutes, and was treated with the product of step 2 (3.44 grams). The mixture was stirred at room temperature for 1 hour and was quenched with water (10 mL). The mixture was concentrated in vacuoo afforded an oily residue. The residue was extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated to yield 3.2 grams of the title compound as white solid. 1H-NMR(CDCl3): 7.72 (d, 1H), 7.22(m, 1H), 7.15(d, 1H), 6.75(m,1H), 3.92(s, 3H), 3.78(s, 3H), 3.3(s, 3H).
  • 33
  • [ 124931-12-0 ]
  • [ 225786-18-5 ]
  • C12H21NO4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
13.4 g Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; Stage #2: (S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)ethanal In tetrahydrofuran at 0 - 20℃; Further stages.;
13.4 g Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 24℃; Inert atmosphere; Stage #2: (S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)ethanal In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere;
  • 34
  • [ 124931-12-0 ]
  • [ 939795-56-9 ]
  • (2E,4S,5S,6S)-N-methyl-N-methoxy-7-(tert-butyldimethylsilyloxy)-4,6-dimethyl-5-hydroxy-hept-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75h;
86% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: (2R,3R,4S)-5-(tert-butyldimethylsilyloxy)-2,4-dimethyl-3-hydroxy-pentanal In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere;
  • 35
  • [ 124931-12-0 ]
  • [ 6188-43-8 ]
  • C12H13N3O2 [ No CAS ]
  • 36
  • [ 5381-20-4 ]
  • [ 124931-12-0 ]
  • [ 468718-37-8 ]
  • 37
  • [ 124931-12-0 ]
  • [ 209256-42-8 ]
  • [ 209256-81-5 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 18h; Diethyl (N-methoxy-N-methyl-carbamoylmethyl) phosphonate (4.0 g, 16.7 mmol) was added dropwise to a suspension of sodium hydride (671 mg, 60% dispersion in mineral oil, 16.7 mmol) in THF (75 mL) at 0C. A solution of <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carboxaldehyde</strong> (3.0 g, 15.2 mmol) in THF (25 mL) was added dropwise. The resulting suspension was allowed to warm to room temperature. After 18 h, water (60 mL) was added and the solution was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over K2CO3, and concentrated to give a pale red oil, 3.5 g (100%).
  • 38
  • [ 124931-12-0 ]
  • [ 101125-34-2 ]
  • [ 375846-19-8 ]
YieldReaction ConditionsOperation in experiment
With sodium In tetrahydrofuran; water; pentane 12 (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide EXAMPLE 12 (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide 0.465 g (10.65 mmol) of sodium hydride (55%) are introduced into a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 10 ml of THF, rendered absolute using sodium, are added, and 1.84 g (7.46 mmol) of diethyl (N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml of THF are slowly added dropwise so that the temperature does not exceed 30° C. 1 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 10 ml of THF is then added dropwise and the clear, slightly yellow solution is stirred overnight. The reaction mixture is poured into 100 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate=2:1) and crystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
  • 39
  • [ 871094-94-9 ]
  • [ 124931-12-0 ]
  • [ 917483-65-9 ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.75h; Stage #2: (1R,2R,3aS,6aS)-2-(tert-butyldimethylsilyloxy)-5-(5-(4-methoxybenzyloxy)pentyl)-1,2,3,3a,6,6a-hexahydropentalene-1-carbaldehyde In tetrahydrofuran at 20℃; Further stages.;
  • 40
  • [ 124931-12-0 ]
  • [ 22062-53-9 ]
  • [ 1019841-01-0 ]
  • 41
  • [ 124931-12-0 ]
  • [ 104501-60-2 ]
  • [ 1012041-69-8 ]
YieldReaction ConditionsOperation in experiment
44% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With lithium hydroxide; 4 A molecular sieve In tetrahydrofuran at 40℃; for 0.333333h; Stage #2: 2-tert-butyldimethylsilyloxypropanal In tetrahydrofuran at 0 - 20℃; Stage #3: With hydrogenchloride In isopropyl alcohol at 20℃; Further stages.;
  • 42
  • [ 124931-12-0 ]
  • [ 104-87-0 ]
  • [ 141750-54-1 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydride In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
80% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere;
  • 43
  • [ 124931-12-0 ]
  • [ 104-88-1 ]
  • [ 771557-40-5 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 4-chlorobenzaldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere;
74% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-chlorobenzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 44
  • [ 124931-12-0 ]
  • [ 529-20-4 ]
  • [ 1019840-98-2 ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: 2-methylphenyl aldehyde In tetrahydrofuran at -10 - 20℃; Inert atmosphere;
  • 45
  • [ 124931-12-0 ]
  • [ 220861-39-2 ]
  • C15H29NO3Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 23℃; 2 To the solution of the ester prepared in the precedent procedure (5.85 g, 20.4 mmol) in CH2CI2 (100 mL) under nitrogen atmosphere, DIBAL (24.5 mL, IM in toluene, 1.2 equiv.) was added at -78 0C and the reaction was kept stirring at the same temperature for half an hour. Then saturated tartrate salt solution (100 mL) was added to the reaction and stirred for 2 hrs until the system turned clear. The two phases were separated and extracted by CH2CI2 (100 mL x 2), washed by brine, dried over Na2SO4. After removal of the solvent, the residue (4.33 g) obtained was used for the next step without further purification. To the solution of the aldehyde (4.33 g) in CH2Cl2 (100 mL) was added Wittig reagent (7.33g, 20.2 mmol, 1.0 equiv.) at 23 0C. The reaction was stirred overnight. After removal of the solvent under reduced vacuum, the residue underwent flash chromatography (PE/EA = 20: 1, then 10/1, 3/1) afforded the desired compound (4.25 g) in the yield of 71 % for the two steps. 1H (CDCI3, 400 MHz, 25 0C) δ 6.89-6.96 (dt, IH); 6.41 (d, IH); 5.77-5.85 (m, IH); 5.18 (dd, IH); 5.05 (dd, IH); 4.23 (dd, IH); 3.67 (s, 3H); 3.22 (s, 3H); 2.42 (dd, 2H); 0.88 (s, 9H); 0.03 (d, 6H).13C (CDCl3, 400 MHz, 25 0C) δ 166.6, 143.5, 140.6, 120.9, 114.3, 72.7, 61.6, 41.4, 32.3, 25.8, 18.2, -4.5, -4.9.
  • 46
  • [ 124931-12-0 ]
  • [ 256417-11-5 ]
  • [ 689258-07-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2,3-difluoro-4-methoxy-benzaldehyde In tetrahydrofuran at 20℃; for 1h; 63.3 Diethyl (N-methoxy-N-methylcarbamoylmethyl)-phosphonate (4.8 g) was added to a suspension of 95% NaH (550 mg) in THF (40 mL) under nitrogen atmosphere. The mixture was stirred at an ambient temperature for 10 minutes, and was treated with the product of step 2 (3.44 grams). The mixture was stirred at room temperature for 1 hour and was quenched with water (10 mL). The mixture was concentrated in vacuoo afforded an oily residue. The residue was extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated to yield 3.2 grams of the title compound as white solid. 1HNMR(CDCl3): 7.72 (d, 1H), 7.22(m, 1H), 7.15(d, 1H), 6.75(m,1H), 3.92(s, 3H), 3.78(s, 3H), 3.3(s, 3H).
  • 47
  • [ 1173891-73-0 ]
  • [ 124931-12-0 ]
  • [ 1007313-82-7 ]
YieldReaction ConditionsOperation in experiment
80% With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 23℃; for 0.75h; Inert atmosphere;
  • 48
  • [ 124931-12-0 ]
  • [ 667419-29-6 ]
  • [ 1204185-43-2 ]
YieldReaction ConditionsOperation in experiment
91% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Stage #2: 7-(4-methoxyphenylmethoxy)heptanal In tetrahydrofuran; mineral oil at 20℃; for 1h; Inert atmosphere;
  • 49
  • [ 112-45-8 ]
  • [ 124931-12-0 ]
  • [ 1222465-49-7 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Stage #2: 10-Undecenal In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h;
  • 50
  • [ 124931-12-0 ]
  • [ 144681-67-4 ]
  • C15H31NO3Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With barium(II) hydroxide In tetrahydrofuran at 20℃; for 0.666667h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropionaldehyde In tetrahydrofuran; water at 20℃; for 24h; Inert atmosphere;
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropionaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃;
  • 51
  • [ 124931-12-0 ]
  • [ 122606-77-3 ]
  • [ 1222190-46-6 ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: (R)-4-hydroxy-1-undecene With ozone In dichloromethane at -78℃; for 0.0833333h; Stage #2: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In dichloromethane; acetonitrile at 20℃; for 18h;
  • 52
  • [ 3095-95-2 ]
  • [ 6638-79-5 ]
  • [ 124931-12-0 ]
YieldReaction ConditionsOperation in experiment
77% With (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 12h;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h;
  • 53
  • [ 124931-12-0 ]
  • [ 133271-07-5 ]
  • [ 1374348-48-7 ]
YieldReaction ConditionsOperation in experiment
491 mg Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 0℃; for 0.333333h; Stage #2: C11H12O2 In acetonitrile at 20℃; for 4h; (S,2E,6E)-5-hydroxy-N-methoxy-N-methyl-7-phenylhepta-2,6-dienamide (21). To a stirred solution of 10 (1 g, 2.61 mmol) in dry THF (20 mL) was added asolution of DIBAL-H in toluene (4.4 mL, 7.83 mmol, 25% solution in toluene) at -78 oC, and allowed to stir for 30 min at same temperature. Then the reaction was quenched by adding saturated sodiumpotassiumtartarate solution (10 mL). The resultant mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and evaporated. The resulting crude product 390 mg was employed in next step without further purification. To a stirred solution of (OEt)2P(O)CH2C(O)NMe(OMe) (794 mg, 3.32 mmol) in CH3CN (15 ml) was added LiCl (140 mg, 3.32 mmol) and DBU (0.494 ml, 3.32 mmol) at 0 oC and the mixture was stirred for 20 minutes and the aldehyde (390 mg, 2.215 mmol ) in CH2Cl2 (5 mL) was added dropwise at 0 oC and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, evaporated under reduced pressure and purified by column chromatography (60-120 silica gel) using EtOAc/hexane (40%) as an eluent to afford 21 (491 mg, 78%) as yellow liquid. Rf = 0.5 (60% EtOAc/hexane). IR (neat) υmax : 3405, 2931, 1659, 1618, 1448, 1387, 970 cm-1; 1H NMR (500 MHz, CDCl3) : δ 7.32-7.13 (m, 5H), 6.92 (dt, J = 15.0, 7.0 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.44 (d, J = 15.0 Hz, 1H), 6.17 (dd, J = 15.0, 6.0 Hz, 1H), 4.38 (q, J = 13.0, 6.0 Hz, 1H), 3.58 (s, 3H), 3.15 (s, 3H), 2.50 (m, 2H); 13C NMR (75 MHz, CDCl3) : δ 166.5, 143.1, 136.4, 131.2, 130.4, 128.4, 127.6, 126.4, 121.4, 71.3, 61.6, 40.5, 32.2; Mass (ESI-MS) m/z : 284 [M + Na]+; HRMS (ESI) : Calcd. for C15H19NO3Na 284.1262, found 284.1280.
  • 54
  • [ 866324-09-6 ]
  • [ 124931-12-0 ]
  • [ 1384193-05-8 ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride In acetonitrile at 20℃; for 0.333333h; Inert atmosphere; Stage #2: (3R,5R,6E)-3,5--butyl(dimethyl)silyl]oxy}-7-phenylhept-6-enal In dichloromethane; acetonitrile at 20℃; for 1h; Inert atmosphere;
  • 55
  • [ 124931-12-0 ]
  • 3-(tert-butyldimethylsilyloxy)-20-((oxomethyl)methylene)pregn-5-ene [ No CAS ]
  • [ 1384735-81-2 ]
  • [ 1384736-29-1 ]
YieldReaction ConditionsOperation in experiment
1: 75% 2: 24% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)-20-((oxomethyl)methylene)pregn-5-ene In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; 4.2.1. (20E,23E)-N-Methoxy-N-methyl-24-(3β-(tert-butyldimethylsilyloxy)-chola-5,20(22),23-triene)carboxamide and [(20E,23E)-17] and (20Z,23E)-N-methoxy-N-methyl-24-(3β-(tert-butyldimethylsilyloxy)-chola-5,20(22),23-triene)carboxamide [(20Z,23E)-17] NaH (60% dispersion in mineral oil, 190 mg, 4.75 mmol) was added portion-wise to a solution of diethyl 2-(methoxy(methyl)amino)-2-oxoethylphosphonate30 (16) (1.030 g, 4.31 mmol) in anhydrous THF (15 mL) stirring under a N2 atmosphere at 0 °C. The mixture was stirred for a further 10 min following the completion of effervescence of H2 then a solution of isomeric aldehydes (20E)-15 and (20Z)-15 (∼75%:25%, 912 mg, 2.00 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. Saturated aqueous NH4Cl solution (10 mL) was added to quench the reaction and the aqueous and organic layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extract was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 100% CH2Cl2 to 2% EtOAc in CH2Cl2) to afford the major unsaturated Weinreb amide (20E,23E)-17 (810 mg, 1.49 mmol, 75%) and the minor isomer (20Z,23E)-17 (261 mg, 0.48 mmol, 24%; total 99% yield) as white solids.
  • 56
  • [ 124931-12-0 ]
  • [ 1416466-41-5 ]
  • C27H39NO4Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With sodium hydride In tetrahydrofuran at -78 - -40℃; for 1h; Inert atmosphere;
  • 57
  • [ 124931-12-0 ]
  • C39H53FN4O10 [ No CAS ]
  • C43H60FN5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H53FN4O10 In tetrahydrofuran at 20℃; for 2h; 13 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (91 mg, 0.368 mmol) in THF (5.0 mL) was added NaH (2.8 mg, 0.1 104 mmol) in anhydrous THF (0.2 mL) at 0 °C with stirring. The solution was then stirred at 20°C until it became clear. Then 23-3 (70 mg, 0.092 mmol) was added to the clear solution and the mixture stirred at 20 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with brine and dried over Na2S04, filtered and reduced in vacuo. The residue was purified by preparative HPLC to obtained 23 as a white solid.
  • 58
  • [ 124931-12-0 ]
  • C39H52F2N4O10 [ No CAS ]
  • C43H57F2N5O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H52F2N4O10 In tetrahydrofuran at 20℃; for 2h; 20 xample 20 - preparation of compound 30 xample 20 - preparation of compound 30 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (37 mg, 0.155 mmol) in THF (1.0 mL) was added NaH (2.3 mg, 0.0575 mmol) in anhydrous THF (0.2 mL) at 0 °C with stirring. The solution was then stirred at 20 °C until it became clear. Then 28-3 (30 mg, 0.0387 mmol) was added to the clear solution and the mixture stirred at 20 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine and dried over Na2S04, filtered, evaporated. The residue was purified by preparative HPLC to obtained 30 as a white solid.
  • 59
  • [ 124931-12-0 ]
  • C39H53FN4O10 [ No CAS ]
  • C43H60FN5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; 13 Example 13 Preparation of Compound 23 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (91 mg, 0.368 mmol) in THF (5.0 mL) was added NaH (2.8 mg, 0.1104 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 23-3 (70 mg, 0.092 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with brine and dried over Na2SO4, filtered and reduced in vacuo. The residue was purified by preparative HPLC to obtained 23 as a white solid.
  • 60
  • [ 124931-12-0 ]
  • C39H52F2N4O10 [ No CAS ]
  • C43H59F2N5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; 20 Example 20 Preparation of Compound 30 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (37 mg, 0.155 mmol) in THF (1.0 mL) was added NaH (2.3 mg, 0.0575 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 28-3 (30 mg, 0.0387 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, evaporated. The residue was purified by preparative HPLC to obtained 30 as a white solid
  • 61
  • [ 124931-12-0 ]
  • C15H30O4Si [ No CAS ]
  • C19H37NO5Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: C15H30O4Si In tetrahydrofuran; mineral oil at 20℃; for 3h; Inert atmosphere; To a solution of phosphate 19 (23.9 g, 100.1 mmol) in THF (130 mL) was slowly added NaH (4.17g, 95.6 mmol, 55% dispersion in mineral oil) at 0 C, and the mixture was stirredfor 1 h. To this was added a solution of aldehyde 18 (27.5 g, 91.0 mmol) in THF (100 mL), and the mixture was stirredfor 3 h at room temperature. A saturated aqueous NH4Cl solution wasadded, and the mixture was separated. The aqueous layer was extracted with ethylacetate, and the combined organic layers were washed with brine, dried overanhydrous MgSO4, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate/hexane)to afford amide 20 (32.6 g, 92%) as acolorless oil: IR (neat) νmax 2970,2891, 1664, 1634, 1462, 1381, 1161, 1105, 1068, 1037, 928, 683 cm-1;1H NMR (500 MHz, CDCl3)δ 6.77 (d, J = 16.0 Hz, 1H), 6.60 (d,J = 16.0 Hz, 1H), 4.94 (d, J = 6.3 Hz, 1H), 4.71 (d, J = 6.3 Hz, 1H), 4.01 (d, J = 11.5 Hz, 2H), 3.94 (s, 2H),3.70-3.67 (m, 5H, involving a singlet at 3.69), 3.25 (s, 3H), 1.16-1.05 (m,21H); 13C NMR (125 MHz, CDCl3) δ 145.83,119.88, 93.97, 70.34, 64.18, 61.69, 42.15, 17.97, 11.88 (2C missing); HRMS (FI+) calcd for C19H37NO5Si [M]+: 387.2441, found: 387.2431.
  • 62
  • [ 142-83-6 ]
  • [ 124931-12-0 ]
  • (2E,4E,6E)-N-methoxy-N-methyl-octa-2,4,6-trienamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.08333h; Inert atmosphere; Darkness; Stage #2: trans,trans-2,4-Hexadienal In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Darkness;
  • 63
  • [ 16326-86-6 ]
  • [ 124931-12-0 ]
  • (2E,4E,6E,8E)-N-methoxy-N-methyl-deca-2,4,6,8-tetraenamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.08333h; Inert atmosphere; Darkness; Stage #2: (2E,4E,6E)-2,4,6-octatrienal In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Darkness;
  • 64
  • [ 887267-04-1 ]
  • [ 124931-12-0 ]
  • (E)-3-(3,6-difluoro-2-methoxyphenyl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In diethyl ether; mineral oil at 0℃; for 0.5h; Stage #2: 3,6-difluoro-2-methoxybenzaldehyde In diethyl ether; mineral oil at 0 - 20℃; for 18h; AN.AN1 Step AN1. A 60 % dispersion of sodium hydride in mineral oil (0.906 g, 37.8 mmol) was added to a chilled 0 °C solution of diethyl (2-(methoxy(methyl)amino)-2- oxoethyl)phosphonate (7.64 g, 32.0 mmol) in diethyl ether (250 mL). After 30 minutes, 3,6-difluoro-2-methoxybenzaldehyde (5.0 g, 29.0 mmol) was slowly added. The resulting mixture was allowed to warm to rt and stir for 18 h. The reaction was quenched with IN HC1 (10 mL), then poured into water. The aqueous layer was made acidic with IN HC1 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product mixture was purified by silica-gel column chromatography (0-50% EtOAc/hexanes) to afford (E)-3-(3,6-difluoro-2-methoxyphenyl)-N-methoxy- N-methylacrylamide (4.96 g, 66 % yield). LC-MS (M+H)+ 258.1.
  • 65
  • [ 124931-12-0 ]
  • [ 74-88-4 ]
  • [1-(methoxy-methyl-carbamoyl)-ethyl]-phosphonic acid diethylester [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h; Diethyl 1-mehtyl-(N-methoxy-N-methylcarbamoylmethyl)phosphonate (S5) A solution of S49 (1.08 g, 4.53 mmol) in THF (2.0 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 217.6 mg, 5.44 mmol) in THF (6.5 mL) at 0 °C. After the reaction mixture was stirred for 30 min, methyl iodide (0.85 mL, 13.7 mmol) was added dropwise to the reaction mixture at 0 °C. The mixture was stirred 0 °C to room temperature for 18 h and quenched with sat. NH4Cl, and extracted with CH2Cl2. The combined organic layer was washed with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was distilled by bulb to bulb distillation to give S510 (770.3 mg,72%) as a colorless oil. 1H NMR (500 MHz, CDCl3) 4.18-4.12 (m, 4H), 3.77 (s, 3H), 3.73-3.62 (m, 1H), 3.23 (bs, 3H), 1.43 (dd, J = 18.4, 7.2 Hz, 3H), 1.34 (t, J = 7.1 Hz, 6H).
  • 66
  • [ 2385-77-5 ]
  • [ 124931-12-0 ]
  • (R,E)-N-methoxy-N,5,9-trimethyldeca-2,8-dienamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere;
  • 67
  • [ 5949-05-3 ]
  • [ 124931-12-0 ]
  • (S,E)-N-methoxy-N,5,9-trimethyldeca-2,8-dienamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With sodium hydride In tetrahydrofuran at -78 - 20℃; for 17h; Inert atmosphere;
  • 72
  • [ 867-13-0 ]
  • [ 6638-79-5 ]
  • [ 124931-12-0 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydroxide In water at 80℃; for 5h; Inert atmosphere; Stage #2: With 1,1'-carbonyldiimidazole In dichloromethane Inert atmosphere; Stage #3: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; for 16h; Inert atmosphere;
62% Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydroxide at 80℃; for 5h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16h; Inert atmosphere;
62% Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydroxide In ethanol at 20℃; for 5h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16h;
22 g Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydroxide In ethanol at 20℃; for 5h; Schlenk technique; Inert atmosphere; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16h; Schlenk technique; Inert atmosphere;

  • 73
  • [ 124931-12-0 ]
  • C39H54N4O10 [ No CAS ]
  • C43H61N5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With sodium hydride In tetrahydrofuran at -3 - 20℃; for 0.5h; Inert atmosphere; 4 Example 4
Synthesis of 10 Example 4Synthesis of 10To a suspension of NaH (0.974 mg, 0.041 mmol) in anhydrous THF (1.0 ml) was added dropwise a solution of diethyl 2-(methoxy(methyl)amino)-2-oxoethylphosphonate (25.8 mg, 0.108 mmol) in anhydrous THF (0.2 ml) under N2 atmosphere at -3° C. with stirring. The solution was then stirred at room temperature until it became clear. A solution of 8 (20 mg, 0.027 mmol) in anhydrous THF (0.2 ml) was added dropwise to the clear solution and the mixture stirred at room temperature for 30 min. The mixture was quenched with water and the THF was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with brine then dried. The solvent was removed under reduced pressure to yield a residue of 14 mg. The crude compound (dissolved in acetone) was loaded on TLC plate (1 mm, 20*20 cm) and developed with acetone/petroleum ether=3:2. The target band (visualized by UV) was collected and mixed with acetone, then filtered through a pad of silica gel (2-3 cm height, pre-rinsed with acetone to remove impurities). The filtration was concentrated under vacuo. Finally, adding acetonitrile and water to the obtained sample, the solution was freeze-dried to give the desired product as white solid powder (8.2 mg, 37%). LC-MS: 824 [M+1]+. See FIG. 2 for 1H NMR.
  • 74
  • [ 124931-12-0 ]
  • C39H53FN4O10 [ No CAS ]
  • C43H60FN5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H53FN4O10 In tetrahydrofuran at 20℃; for 2h; 13 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (91 mg, 0.368 mmol) in THF (5.0 mL) was added NaH (2.8 mg, 0.1104 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 23-3 (70 mg, 0.092 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with brine and dried over Na2SO4, filtered and reduced in vacuo. The residue was purified by preparative HPLC to obtained 23 as a white solid.
  • 75
  • [ 124931-12-0 ]
  • C39H52F2N4O10 [ No CAS ]
  • C43H59F2N5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: C39H52F2N4O10 In tetrahydrofuran at 20℃; for 2h; 20 Preparation of Compound 30 To a solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (37 mg, 0.155 mmol) in THF (1.0 mL) was added NaH (2.3 mg, 0.0575 mmol) in anhydrous THF (0.2 mL) at 0° C. with stirring. The solution was then stirred at 20° C. until it became clear. Then 28-3 (30 mg, 0.0387 mmol) was added to the clear solution and the mixture stirred at 20° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, evaporated. The residue was purified by preparative HPLC to obtained 30 as a white solid.
  • 76
  • [ 124931-12-0 ]
  • [ 34246-57-6 ]
  • (E)-3-(3-isopropylphenyl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With sodium hydride In tetrahydrofuran at -78 - 20℃; for 16h;
70% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere; Stage #2: 3-isopropylbenzaldehyde In tetrahydrofuran; mineral oil at -78 - 20℃; Inert atmosphere;
  • 77
  • [ 124931-12-0 ]
  • [ 79099-07-3 ]
  • [ 502609-76-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1.5h; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran at -78 - 20℃; for 16h; 301 Example 301 (General Procedure V) To a cooled (0°C) solution of potassium tert-butoxide (3.55 g, 31.6 mmol, 1.05 equiv) in tetrahydrofuran (50 mL) was added 2-diethoxyphosphoryl-N-methoxy-N-methyl-acetamide (7.92 g, 33.1 mmol). The reaction mixture was allowed to warm to room temperture over 30 mins then stuffed for an additional 1 h at room temperature. The mixture was cooled to -78°C and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6 g, 30.1 mmol) in tetrahydrofuran (50 mL) was added. The mixture was allowed to slowly warm to room temperature and allowed to stir for 16 h. Water (250 mL) wasadded and the mixture extracted with isopropyl acetate (3 x 100 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl 4- [2- [methoxy(methyl)amino] -2- oxo-ethylidene]piperidine-1-carboxylate as a white solid that was used in the next step without further purification.
  • 78
  • [ 124931-12-0 ]
  • [ 2987-06-6 ]
  • 2-(4-benzyloxycyclohexylidene)-N-methoxy-N-methyl-acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1.5h; Stage #2: 4-(benzyloxy)cyclohexanone In tetrahydrofuran at -78 - 20℃; for 16h; 302 Example 302 (General Procedure X) To a cooled (0°C) solution of potassium tert-butoxide (4.6 g, 41 mmol) in tetrahydrofuran (50 mL) was added 2-diethoxyphosphoryl-N-methoxy-N-methyl-acetamide (10 g, 43 mmol). The mixture was allowed to warm to room temperature over30 mins and stirred for an additional 1 h. The mixture was cooled to -78°C, and a solutionof 4-benzyloxycyclohexanone (7.9 g, 39 mmol, 1.0 equiv) tetrahydrofuran (50 mL) wasadded. The mixture was allowed to slowly warm to room temperature and was stirred for16 h. The mixture was diluted with water (250 mL) and extracted with isopropyl acetate(3 x 100 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 70% isopropyl acetate in heptane. The appropriate fractions were combined and concentrated under reduced pressure to afford 10 g (89%) of 2-(4-benzyloxycyclohexylidene)-N-methoxy-N-methyl-acetamide as a colorless oil.
  • 79
  • [ 124931-12-0 ]
  • [ 128461-65-4 ]
  • (E)-N-methoxy-5-((4-methoxybenzyl)oxy)-N-methylpent-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; paraffin oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3-(p-methoxybenzyloxy)propanal In tetrahydrofuran; paraffin oil at 0 - 20℃; Inert atmosphere;
85% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; paraffin oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3-(p-methoxybenzyloxy)propanal In tetrahydrofuran; paraffin oil at 0℃; Inert atmosphere;
  • 80
  • [ 124931-12-0 ]
  • C14H25NO5 [ No CAS ]
  • C18H32N2O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.583333h; Stage #2: C14H25NO5 In tetrahydrofuran at 0 - 20℃; for 15h;
  • 81
  • [ 124931-12-0 ]
  • [ 135-02-4 ]
  • [ 1422176-88-2 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: ortho-anisaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 82
  • [ 1121-60-4 ]
  • [ 124931-12-0 ]
  • (E)-N-methoxy-N-methyl-3-(pyridin-2-yl)acrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: pyridine-2-carbaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 83
  • [ 872-85-5 ]
  • [ 124931-12-0 ]
  • [ 372183-81-8 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: pyridine-4-carbaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 84
  • [ 98-03-3 ]
  • [ 124931-12-0 ]
  • [ 134197-97-0 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: thiophene-2-carbaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 85
  • [ 124931-12-0 ]
  • [ 105-07-7 ]
  • [ 1429057-73-7 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-cyanobenzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 86
  • [ 124931-12-0 ]
  • [ 7468-67-9 ]
  • [ 1220889-33-7 ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: o-formylbenzonitrile In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 87
  • [ 124931-12-0 ]
  • [ 24964-64-5 ]
  • (E)-3-(3-cyanophenyl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3-Cyanobenzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 88
  • [ 124931-12-0 ]
  • [ 89-98-5 ]
  • [ 701913-98-6 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 2-chloro-benzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 89
  • [ 124931-12-0 ]
  • [ 6287-38-3 ]
  • (E)-3-(3,4-dichlorophenyl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3,4-dichlorobenzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 90
  • [ 124931-12-0 ]
  • [ 86-81-7 ]
  • [ 1082730-34-4 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 3,4,5-trimethoxy-benzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 91
  • [ 124931-12-0 ]
  • [ 100-10-7 ]
  • (E)-3-[4-(dimethylamino)phenyl]-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 4-dimethylamino-benzaldehyde In tetrahydrofuran at -78 - 20℃; HWE Reaction; General Procedure A General procedure: Diethyl 2-[methoxy(methyl)amino]-2-oxoethylphosphonate (1; 1.2 equiv) was dissolved in anhyd THF and NaH (1.2 equiv) was added portionwise at r.t. until gas evolution ceased. The mixture was then cooled to -78 °C and the appropriate benzaldehyde derivative (1 equiv) dissolved in anhyd THF was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to r.t. and stirred overnight. H2O (10 mL) was added, the layers were separated, and the organic layer was washed with sat. aq NaHCO3 (2 × 10 mL). The combined aqueous phases were extracted with EtOAc (3 × 15 mL). The combined organic phases were then washed with brine (2 × 10 mL) ,dried (MgSO4), and concentrated in vacuo. If necessary, the crude product was purified by flash column chromatography (FCC) using the indicated eluent.
  • 92
  • [ 5949-05-3 ]
  • [ 124931-12-0 ]
  • [ 216220-55-2 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydride In tetrahydrofuran at -78 - 20℃; Schlenk technique; Inert atmosphere;
  • 93
  • [ 124931-12-0 ]
  • [ 3218-36-8 ]
  • (E)-3-([1,1'-biphenyl]-4-yl)-N-methoxy-N-methylacrylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere; Stage #2: 4-Phenylbenzaldehyde In tetrahydrofuran; mineral oil at -78 - 20℃; Inert atmosphere;
  • 94
  • [ 5381-20-4 ]
  • [ 124931-12-0 ]
  • [ 468718-37-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In tetrahydrofuran; EXAMPLE 167 (2-Benzo[b]thiophen-3-yl-cyclopropylmethyl)-dimethyl-amine Diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate (6.13 g, 25.6 mmol) was added dropwise via syringe to a stirred suspension of sodium hydride (1.02 g, 25.6 mmol) in anhydrous THF (75 ml) at 0 C. The reaction was warmed to room temperature and was stirred for 1 h. After cooling to 0 C., benzo[b]thiophene-3-carbaldehyde (3.78 g, 23.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hr. The reaction was quenched with 100 mL aqueous HCl (0.1 N) and extracted with ethyl acetate (250 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo and triturated with hexane to give (E)-3-benzo[b]thiophen-3-yl-N-methoxy-N-methyl-acrylamide (5.38 g, 93%) as a yellow solid. 1H NMR (500 MHz, CDCl3) 8.06-8.01 (2 H, 2 superimposed d, J=8.24, 15.87 Hz), 7.89 (1 H, d, J=7.94 Hz), 7.78 (1 H, s), 7.47 (1 H, t, J=7.93 Hz), 7.41 (1 H, t, J=8.24 Hz), 7.13 (1 H, d, J=15.87 Hz), 3.79 (3 H, s), 3.34 (3 H, s); MS m/e 248.07 (M+H)+.
  • 95
  • [ 124931-12-0 ]
  • [ 100-52-7 ]
  • [ 896464-49-6 ]
YieldReaction ConditionsOperation in experiment
96% With potassium hydroxide In ethanol at 20℃; Inert atmosphere;
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