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Chemical Structure| 1066-54-2
Chemical Structure| 1066-54-2
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Product Details of [ 1066-54-2 ]

CAS No. :1066-54-2 MDL No. :MFCD00008569
Formula : C5H10Si Boiling Point : -
Linear Structure Formula :- InChI Key :CWMFRHBXRUITQE-UHFFFAOYSA-N
M.W : 98.22 Pubchem ID :66111
Synonyms :

Calculated chemistry of [ 1066-54-2 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.6
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.18
TPSA : 0.0 Ų

Pharmacokinetics

GI absorption : Low
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) : -5.24 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.25
Log Po/w (XLOGP3) : 2.34
Log Po/w (WLOGP) : 1.58
Log Po/w (MLOGP) : 2.08
Log Po/w (SILICOS-IT) : -0.18
Consensus Log Po/w : 1.61

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.92
Solubility : 1.17 mg/ml ; 0.0119 mol/l
Class : Very soluble
Log S (Ali) : -1.98
Solubility : 1.03 mg/ml ; 0.0105 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.15
Solubility : 7.02 mg/ml ; 0.0714 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.95

Safety of [ 1066-54-2 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P261-P305+P351+P338 UN#:1993
Hazard Statements:H225-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1066-54-2 ]

* 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.

  • Upstream synthesis route of [ 1066-54-2 ]
  • Downstream synthetic route of [ 1066-54-2 ]

[ 1066-54-2 ] Synthesis Path-Upstream   1~111

  • 1
  • [ 75-15-0 ]
  • [ 1066-54-2 ]
  • [ 930-35-8 ]
Reference: [1] Synlett, 1997, vol. 1997, # 3, p. 319 - 321
  • 2
  • [ 3437-95-4 ]
  • [ 1066-54-2 ]
  • [ 4298-52-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 24, p. 8644 - 8645
[2] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3518 - 3521
  • 3
  • [ 872-31-1 ]
  • [ 1066-54-2 ]
  • [ 67237-53-0 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 9, p. 2133 - 2143
  • 4
  • [ 16110-09-1 ]
  • [ 151-21-3 ]
  • [ 109-89-7 ]
  • [ 1066-54-2 ]
  • [ 86873-60-1 ]
Reference: [1] Patent: US5380861, 1995, A,
  • 5
  • [ 50-01-1 ]
  • [ 100-07-2 ]
  • [ 1066-54-2 ]
  • [ 99844-02-7 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 19, p. 3451 - 3454
  • 6
  • [ 104830-06-0 ]
  • [ 1066-54-2 ]
  • [ 67346-74-1 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 3, p. 836 - 839
  • 7
  • [ 1122-96-9 ]
  • [ 1066-54-2 ]
  • [ 36057-44-0 ]
YieldReaction ConditionsOperation in experiment
76% With 4 A molecular sieve; N,N-Dimethylcarbamoyl chloride In dichloromethane at 0 - 20℃; 2-Cyano-4-methoxypyridine 153 [0310] To a solution of 4-methoxypyridine-N-oxide hydrate (1.25 g, 10 mmol) in DCM (mL) were added molecular sieves (4 A, 3 g, 300 mg/mmol) and the mixture was stirred overnight. The resulting suspension was then cooled at 0 °C and trimethylsilyl cyanide (1.6 mL, 12 mmol) and N, N- dimethyl carbamoyl chloride (1 mL, 10.5 mmol) were added successively. The reaction mixture was stirred at room temperature overnight. Finally, the mixture was filtered over celite and the filtrate was diluted with dichloromethane (80 mL) and an aqueous solution of potassium carbonate (1 M, 70 mL). The mixture was extracted at pH 10-12 with dichloromethane (3 x 80 mL). The combined organic phase was dried by filtration over anhydrous magnesium sulfate, and the filtrate was concentrated to afford 1.2 g of crude product. Separation by column chromatography using hexanes: acetone (95: 05 to 70: 30,5 percent gradient) gave 1.023 g (76 percent yield) of cyanopyridine 18 as a white solid; 1H NMR (acetone d6) 8 : 4. 01 (s, 3H, OCHs), 7. 27 (dd, 1H, J= 5.8 2.6 Hz), 7.55 (d, 1H, J= 2.6 Hz), 8. 54 (d, 1H, J = 5. 8 Hz).
Reference: [1] Patent: WO2005/66194, 2005, A1, . Location in patent: Page/Page column 180
  • 8
  • [ 1066-54-2 ]
  • [ 724442-38-0 ]
  • [ 4745-93-1 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 43, p. 8087 - 8090
  • 9
  • [ 4595-60-2 ]
  • [ 1066-54-2 ]
  • [ 37972-24-0 ]
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 7, p. 2185 - 2191
  • 10
  • [ 109-04-6 ]
  • [ 1066-54-2 ]
  • [ 1945-84-2 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3518 - 3521
  • 11
  • [ 124-38-9 ]
  • [ 1066-54-2 ]
  • [ 5683-31-8 ]
Reference: [1] Chemical Communications, 2014, vol. 50, # 10, p. 1195 - 1197
[2] New Journal of Chemistry, 2017, vol. 41, # 23, p. 14145 - 14151
[3] Dalton Transactions, 2015, vol. 44, # 48, p. 20874 - 20882
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2353 - 2360
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 24, p. 3351 - 3362
  • 12
  • [ 1066-54-2 ]
  • [ 6746-94-7 ]
  • [ 101911-12-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 38, p. 11485 - 11489[2] Angew. Chem., 2016, vol. 128, p. 11657 - 11661,5
  • 13
  • [ 1066-54-2 ]
  • [ 59376-64-6 ]
Reference: [1] Chinese Journal of Chemistry, 2018, vol. 36, # 10, p. 916 - 920
  • 14
  • [ 50-00-0 ]
  • [ 1066-54-2 ]
  • [ 5272-36-6 ]
Reference: [1] Chemistry - A European Journal, 2005, vol. 11, # 8, p. 2577 - 2590
[2] Chinese Journal of Chemistry, 2018, vol. 36, # 10, p. 916 - 920
[3] Tetrahedron Letters, 1999, vol. 40, # 43, p. 7605 - 7609
[4] Chemical Communications, 2006, # 39, p. 4113 - 4115
[5] Journal of the American Chemical Society, 2000, vol. 122, # 9, p. 1937 - 1944
[6] European Journal of Organic Chemistry, 2009, # 21, p. 3605 - 3612
  • 15
  • [ 68-12-2 ]
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
49%
Stage #1: With ethylmagnesium bromide In tetrahydrofuran at 10 - 20℃; Inert atmosphere
Stage #2: at -25 - 30℃;
Stage #3: With sulfuric acid; water In tetrahydrofuran; diethyl ether at 0℃;
d) Preparation of trimethylsilyl-propynalTrimethylsilylethyne (5.0 ml, 36.10 mmol) in THF (25.0 ml) was dropwsise added to a solution of EtMgBr in THF (IM, 44.0 ml, 44.0 mmol) at 10-150C under nitrogen. Once the addition finished, the mixture was stirred at room temperature for one hour and was added over a 30 min. period to an efficiently stirred mixture of DMF (10.0 ml, 123.0 mmol) in Et2O (20.0 ml) at -25°C. The white suspension was allowed to reach room temperature, stirred for one hour, heated at 300C for 15 minutes, and poured into H2SO4 5percent at 00C. The aqueous layer was extracted three times with Et2O, the combined organic layers were washed with a saturated aqueous solution of NH4Cl, dried over Na2SO4, and the solvents were carefully removed under vacuum to give a crude which was further purified by bulb to bulb distillation (20 mBar, room temperature) to afford the title compound (2.255 g) in 49percent yield. 1H NMR: 9.15 (s, IH), 0.25 (s, 9H). 13C NMR: 176.7, 103.0, 102.3, 0.88.
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 3, p. 401 - 404
[2] Angewandte Chemie - International Edition, 2008, vol. 47, # 6, p. 1130 - 1133
[3] Tetrahedron, 2002, vol. 58, # 12, p. 2415 - 2422
[4] Arkivoc, 2012, vol. 2012, # 7, p. 253 - 273
[5] Patent: WO2009/141781, 2009, A1, . Location in patent: Page/Page column 18
[6] Journal of Organic Chemistry, 1995, vol. 60, # 14, p. 4331 - 4338
[7] J. Gen. Chem. USSR (Engl. Transl.), 1966, vol. 36, p. 920 - 922[8] Zhurnal Obshchei Khimii, 1966, vol. 36, p. 907 - 909
[9] Tetrahedron, 1983, vol. 39, # 19, p. 3073 - 3082
[10] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 3, p. 398 - 404
[11] Synthesis, 2002, # 12, p. 1759 - 1774
[12] Journal of the American Chemical Society, 2013, vol. 135, # 36, p. 13502 - 13511
[13] Chemistry - A European Journal, 2014, vol. 20, # 50, p. 16694 - 16706
[14] Organometallics, 2018, vol. 37, # 9, p. 1346 - 1357
  • 16
  • [ 183718-76-5 ]
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium In hexane
Stage #2: at 0℃; for 8 h;
General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 °C). The reaction was stirred at 0 °C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92percent yields along with the by-product aldehyde.
Reference: [1] Tetrahedron, 2016, vol. 72, # 49, p. 8106 - 8116
  • 17
  • [ 104831-79-0 ]
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With n-butyllithium In hexane
Stage #2: at 0℃; for 8 h;
General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 °C). The reaction was stirred at 0 °C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92percent yields along with the by-product aldehyde.
Reference: [1] Tetrahedron, 2016, vol. 72, # 49, p. 8106 - 8116
  • 18
  • [ 10102-94-0 ]
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
84%
Stage #1: With n-butyllithium In hexane
Stage #2: at 0℃; for 8 h;
General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 °C). The reaction was stirred at 0 °C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92percent yields along with the by-product aldehyde.
Reference: [1] Tetrahedron, 2016, vol. 72, # 49, p. 8106 - 8116
  • 19
  • [ 19012-03-4 ]
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
38%
Stage #1: With n-butyllithium In hexane
Stage #2: at 0℃; for 8 h;
General procedure: To the ice-cold solution of aldehyde in THF was added, the solution of alkylmagnesium halide or alkyllithium in THF (1.3 eq., at 0 °C). The reaction was stirred at 0 °C for 1 h, diluted with saturated aq. NH4Cl (10 mL) and ethyl acetate (10 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), and dried over Na2SO4. Evaporation of the solvent and purification of the crude mixture by column chromatography (9:1, hexane: EtOAc) gave the corresponding bisindolylmethane derivatives (BIM) up to 92percent yields along with the by-product aldehyde.
Reference: [1] Tetrahedron, 2016, vol. 72, # 49, p. 8106 - 8116
  • 20
  • [ 1066-54-2 ]
  • [ 2975-46-4 ]
YieldReaction ConditionsOperation in experiment
28% With hydrogenchloride; n-butyllithium In diethyl ether; hexane; N,N-dimethyl-formamide Example 2
Ethynyltrimethylsilane (5.0 g, 50.9 mmol) was dissolved in dry diethyl ether (50 ml), 1.6 M n-butyllithium in hexane(35.0 ml, 56.0 mmol) was added dropwise at 0°C under argon atmosphere.
The mixture was stirred at the same temperature for 1h. DMF(3.72g, 50.9mmol) was dissolved in diethyl ether (20ml), and was added dropwise below 5°C for 30 min, then the mixture was stirred at room temperature for 2 h.
The reaction was quenched by the addition of 2N hydrochloric acid, and the mixture was extracted with diethyl ether.
The organic layer was washed with water, saturated sodium hydrogencarbonate solution, and brine in order, and dried over sodium sulfate.
Purification by distillation (40-45°C/15mmHg) gave 3-(trimethylsilyl)propiol aldehyde (28percent).
Colorless oil
1H-NMR (CDCl3) δ:0.27 (9H, s), 9.17 (1H, s).
Reference: [1] Patent: EP1145718, 2001, A1,
[2] Chemical Communications, 2006, # 4, p. 383 - 385
  • 21
  • [ 1066-54-2 ]
  • [ 109-94-4 ]
  • [ 2975-46-4 ]
Reference: [1] Synthesis, 1978, p. 307 - 309
  • 22
  • [ 503-30-0 ]
  • [ 1066-54-2 ]
  • [ 13224-84-5 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 4, p. 1291 - 1301
  • 23
  • [ 591-31-1 ]
  • [ 1066-54-2 ]
  • [ 768-70-7 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 3, p. 564 - 567
  • 24
  • [ 2398-37-0 ]
  • [ 1066-54-2 ]
  • [ 768-70-7 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6707 - 6712
  • 25
  • [ 766-85-8 ]
  • [ 1066-54-2 ]
  • [ 768-70-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 4, p. 415 - 420
  • 26
  • [ 1066-54-2 ]
  • [ 459-04-1 ]
  • [ 13101-83-2 ]
YieldReaction ConditionsOperation in experiment
69% With trifluoroacetic acid In hexane; dichloromethane; ethyl acetate Step 3
6-Fluoro-2-naphthol
A solution of 2-(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH2Cl2 was added to AlCl3 (7.73g;58 mmol) in CH2Cl2 at -20° C. over 30 min.
Trimethylsilyl acetylene (9.96g; 101.43 mmol) was added also over 30 min and stirred at -10° C. for 1h.
The mixture was poured in ice and extracted with EtOAc.
The organic phase was washed with water, NaHCO3 and brine.
After purification by gel silica chromatography (10percent EtOAc in hexane) 2.43 g (36percent) of 3-(trimethylsilyl)-6-chloro-2-naphthol was collected.
The desylilation was done with TFA in CH2Cl2 at rt overnight.
Purification by gel silica chromatography (10percent EtOAc in hexane) afforded the title compound in 69percent yield.
1H NMR (CDCl3) δ7.10-7.20 (3H, m), 7.37 (1H, dd) and 7.65 (2H, m).
Reference: [1] Patent: US6242493, 2001, B1,
  • 27
  • [ 591-17-3 ]
  • [ 1066-54-2 ]
  • [ 766-82-5 ]
Reference: [1] Patent: WO2012/45018, 2012, A1, . Location in patent: Page/Page column 52
  • 28
  • [ 626-39-1 ]
  • [ 1066-54-2 ]
  • [ 7567-63-7 ]
Reference: [1] Chemistry - A European Journal, 2009, vol. 15, # 44, p. 11985 - 11998
[2] Chemical Communications, 2016, vol. 52, # 81, p. 12032 - 12035
[3] Tetrahedron Letters, 2001, vol. 42, # 14, p. 2697 - 2699
  • 29
  • [ 108-37-2 ]
  • [ 1066-54-2 ]
  • [ 766-83-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6707 - 6712
  • 30
  • [ 591-18-4 ]
  • [ 1066-54-2 ]
  • [ 766-81-4 ]
Reference: [1] Patent: US2008/51395, 2008, A1, . Location in patent: Page/Page column 131
[2] Catalysis Communications, 2014, vol. 47, p. 40 - 44
  • 31
  • [ 768-92-3 ]
  • [ 1066-54-2 ]
  • [ 40430-66-8 ]
  • [ 82094-48-2 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 7, p. 1934 - 1937
  • 32
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  • [ 18163-47-8 ]
Reference: [1] Arkivoc, 2011, vol. 2011, # 3, p. 128 - 139
[2] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 6829 - 6839
[3] Journal of the Chemical Society, Chemical Communications, 1988, p. 909 - 910
[4] Tetrahedron Letters, 1991, vol. 32, # 19, p. 2169 - 2170
[5] Chemistry - A European Journal, 2009, vol. 15, # 2, p. 388 - 404
[6] Journal of Organic Chemistry, 2010, vol. 75, # 15, p. 5414 - 5416
[7] Synthesis, 1989, # 6, p. 461 - 463
[8] Synlett, 1999, # 8, p. 1227 - 1230
[9] Organic Letters, 2007, vol. 9, # 18, p. 3679 - 3682
[10] Organic Letters, 2008, vol. 10, # 5, p. 725 - 728
[11] Organic Letters, 2011, vol. 13, # 19, p. 5072 - 5075
  • 33
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  • [ 772-38-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6707 - 6712
  • 34
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  • [ 14235-81-5 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 5, p. 1752 - 1755
  • 35
  • [ 25309-64-2 ]
  • [ 7681-65-4 ]
  • [ 1066-54-2 ]
  • [ 40307-11-7 ]
Reference: [1] Patent: US2004/87789, 2004, A1,
  • 36
  • [ 610-97-9 ]
  • [ 1066-54-2 ]
  • [ 33577-99-0 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 17, p. 6255 - 6258
  • 37
  • [ 610-94-6 ]
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  • [ 33577-99-0 ]
Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 10, p. 5320 - 5328
  • 38
  • [ 3058-39-7 ]
  • [ 1066-54-2 ]
  • [ 3032-92-6 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 30, p. 6686 - 6695
  • 39
  • [ 583-55-1 ]
  • [ 1066-54-2 ]
  • [ 766-46-1 ]
Reference: [1] Angewandte Chemie, 1986, vol. 98, # 3, p. 268 - 270
[2] Catalysis Communications, 2014, vol. 47, p. 40 - 44
  • 40
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  • [ 1066-54-2 ]
  • [ 101597-25-5 ]
YieldReaction ConditionsOperation in experiment
57.6%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -10℃; for 4 h; Inert atmosphere
Stage #2: With sodium hydroxide In methanol at 0℃;
General procedure: To a solution of (trimethylsilyl)acetylene (4.5 g, 45 mmol) in anhydrous THF (150 mL) under nitrogen atmosphere was added slowly n-BuLi (1.6 M in hexane, 28.5 mL, 45 mmol) at -10°C and the solution stirred 1h at - 10°C. A solution of benzophenone (7.44 g, 40.8 mmol) in dry THF (75 mL) was then added at -10°C. After 3h stirring at -10°C, the temperature was raised to 0°C and a solution of NaOH (2.16 g, 54 mmol) in MeOH (40,8 mL) was added. After the solution was warmed to room temperature, the solution was neutralized to pH 7 with acetic acid and the resulting solution poured into water (546 mL). The organic layer was extracted with EA (3x105 mL). The combined organic layers were dried over MgSO4. The crude product was recristallized from EA/PE to give 7,5 g of 1c as a light yellow solid (88,4percent).
Reference: [1] European Journal of Organic Chemistry, 2003, # 7, p. 1220 - 1230
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 17, p. 4341 - 4345[3] Angew.Chem.Int.Ed., 2014, vol. 53, p. 4341 - 4345,5
[4] Tetrahedron, 2011, vol. 67, # 2, p. 401 - 407
[5] European Journal of Organic Chemistry, 2011, # 11, p. 2111 - 2119
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  • [ 38846-64-9 ]
Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6299 - 6302
[2] Synthesis, 2006, # 21, p. 3661 - 3669
[3] Chemical Communications, 2017, vol. 53, # 12, p. 2036 - 2039
  • 42
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  • [ 1066-54-2 ]
  • [ 72-33-3 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 23, p. 4068 - 4072
  • 43
  • [ 701-34-8 ]
  • [ 1066-54-2 ]
  • [ 1788-08-5 ]
Reference: [1] Patent: WO2006/71184, 2006, A1, . Location in patent: Page/Page column 15
  • 44
  • [ 589-87-7 ]
  • [ 1066-54-2 ]
  • [ 16116-78-2 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 20℃; for 0.0833333 h; Inert atmosphere
Stage #2: at 20℃; for 0.5 h; Inert atmosphere
In a two neck rbf containing TEA (200 ml) was added 1-Bromo-4-iodobenzene 5 (24.00 g, 84.83 mmol) at rt under nitrogen. Themixture was stirred for 5 min followed by addition ofethynyltrimethylsilane 2 (13.19 ml, 93.31 mmol), Pd(PPh3)2Cl2(2.98 g, 4.24 mmol) and CuI (1.62 g, 8.48 mmol). The reaction mixturewas stirred for 30 min at the same temperature. The reactionmixture was evaporated in vaccum to remove excess of TEA followedby addition of 1 N HCl until the pH reached to 1. The mixturewas then extracted with EtOAc/water. The organic layer waswashed with brine and dried over anhydrous MgSO4. The solventwas evaporated and the residue was purified by column chromatography(Hexane) to give the desired compound 6 (21.00 g)as a white solid; Yield = 98percent; 1H NMR (CDCl3, 500 MHz): d 7.19–7.06 (4H, m, ArAH), 0.00 (9H, s, ASi(CH3)3); 13C NMR (CDCl3,125 MHz): d 133.5, 131.6, 122.8, 122.3, 104.0, 95.7, 0.00.
96% at 20℃; for 1.5 h; Cooling with ice To an anhydrous triethylamine solution (30 mL), 4-iodo-bromobenzene(2.0 g, 7.07 mmol) was dissolved at room temperature.This solution was cooled in an ice bath, and Pd(PPh3)4 (0.20 g,0.18 mmol) and CuI (34.28 mg, 0.18 mmol) were added. Cold trimethylsilylacetylene solution (1.1 mL, 0.76 g, 7.78 mmol) wasthen added in a dropwise manner. The mixture was stirred in anice bath for 1.5 h, and then saturated NH4Cl aqueous solution(30 mL) was added. The product was extracted with CH2Cl2(3 50 mL), and the organic phases were combined and dried overNa2SO4. Purification by chromatography on silica gel gave a whitesolid (1.73 g, 6.82 mmol, 96percent yield). 1H NMR (CDCl3): d 7.45–7.41(m, 2H), 7.33–7.30 (m, 2H), 0.25 (s, 9H).
95% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 25℃; for 1.5 h; A mixture of 4-iodobromobenzene (2.01 g, 7.10 mmol), trimethylsilylacetylene (1.2 mL, 8.67 mmol), PdCl2(PPh3)2 (52 mg, 0.074 mmol), and CuI (15 mg, 0.079 mmol), NEt3 (5 mL) in THF (20 mL) was stirred at 25 °C. After stirring for 1.5 h, to the mixture was added aqueous 2 M HCl, and extracted with EtOAc (3 times). The organic phase was sequentially washed with brine, aqueous sat.NaHCO3, and brine, and dried with MgSO4. After concentration, the residue was purified with silicagel column chromatography (hexane to hexane/EtOAc = 8/2) to afford 4-(trimethylsilylethynyl)bromobenzene as colorless solids (1.71 g, 95percent). mp 56-59 °C (colorless plates); Rf: 0.65 (hexane); 1H NMR (CDCl3, 400 MHz): 0.06 (s, 9H), 7.13 (d, 2H, J = 8.5 Hz), 7.24 (d, 2H, J = 8.5 Hz); 13C NMR (CDCl3, 100 MHz):  -0.1, 95.6, 103.8, 122.1, 122.7, 131.5, 133.4; IR (KBr): vmax 2956, 2898, 2285, 2157, 1895, 1645, 1580, 1484, 1412, 1392, 1311, 1246, 1209, 1110, 1094, 1070, 1009, 844, 822 cm-1; HRMS (DART): [M+H]+ calcd for C11H13BrSi, 253.00481; found, 252.99518.
95% at 48℃; for 2 h; To a mixture of 1-bromo-4-iodobenzene(1) (3.0 g, 10.06 mmol), dichlorobis(triphenylphosphine)palladium (II) (28 mg, 0.04 mmol),and copper iodide (18 mg, 0.09 mmol) in triethylamine (30 ml) was added trimethylsilylacetylene(1.7 ml, 11.94 mmol), and stirred at 48C for 2 hours. Solvent was evaporatedunder reduced pressure, and the residue was chromatographed on silica gel with hexaneto give 2 (2.42 g, 95percent) in a white solid. 1H NMR (CDCl3, 400 MHz): δ = 0.25 (s, 9H),7.30(d, 2H), 7.40 (d, 2H). Anal. Calcd for C11H13BrSi: C, 52.17percent; H, 5.17percent. Found: C,52.29percent; H, 5.08percent
95% at 0℃; for 3 h; Inert atmosphere 10.0 g of 1-bromo-4-iodobenzene, 400 mg of Pd (OAc) 2, 170 mg of CuI and 250 mg of PPh3 were placed in a 500 mL flask and an argon atmosphere was made. This mixture was diluted with 28.6 g of dry TEA. The mixture was bubbled with argon to remove oxygen and the temperature was lowered to 0 & lt; 0 & gt; C. 4.16 g of (trimethylsilyl) acetylene slowly putThe reaction mixture was stirred for 3 hours. The reaction was quenched with aqueous NH4Cl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. 8.50 g of [(4-Bromophenyl) ethynyl] (trimethyl) silane was obtained through column chromatography (SiO2, Hexanes: EtOAc = 15: 1)
93% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 18 h; Inert atmosphere Compound 76.1. ((4-Bromophenyl)ethynyl)trimethylsiIane. Into a 100-mL three neck round-bottom flask, which was maintained with an inert atmosphere of nitrogen, was placed a solution of l -bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA(9: l) (30 mL). PdCl2(PPh3)2 (50 mg, 0.07 mmol), Cul (13.4 mg, 0.07 mmol), and ethynyltrimethylsilane (748 \xL, 5.29 mmol) were added and the mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield the title compound as a light yellow solid (0.83 g, 93percent
93% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 18 h; Inert atmosphere Compound 76.1. ((4-Bromophenyl)ethynyl)trimethylsilane.
Into a 100-mL three neck round-bottom flask, which was maintained with an inert atmosphere of nitrogen, was placed a solution of 1 -bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA(9: l) (30 mL). PdCl2(PPh3)2 (50 mg, 0.07 mmol), Cul (13.4 mg, 0.07 mmol), and ethynyltrimethylsilane (748 μ, 5.29 mmol) were added and the mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield the title compound as a light yellow solid (0.83 g, 93percent).
87% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 3 h; Inert atmosphere 1-bromo-4-iodobenzene (200.0 g, 704.8 mmol), (1,1 ‘-bis(diphenylphosphine)ferrocene)dichloropalladium(D) (25.8 g, 35.4 mmol), copper iodide (4.04 g, 21.2 mmol),triethylamine (295.6 ml, 2120 mmol), and tetrahydrofuran(1700 mE) were put in a 3 E round-bottomed flask under anitrogen atmosphere. Then, trimethyl silylacetylene (107.6 ml, 776.6 mmol) was added thereto in a dropwise fashion, and the mixture was stirred at room temperature for 3 hours. The reactant was filtered, and a solvent therein was removed. The resultant was purified through column chromatography to obtain an intermediate 1-11 (155.3 g, a yield:87percent).
71.5% at 0℃; for 5 h; Inert atmosphere 1-Bromo-4-iodobenzene (1a, 300 mg, 1.06 mmol),Pd(PPh34 (61.2 mg, 0.053 mmol), and CuI (20 mg,0.11 mmol) were dissolved in 10 mL of triethylamine and trimethylsilyl acetylene (1b, 176 mL, 1.27 mmol) was added slowly at 0° C. Then, reaction mixture was stirred under N2 atmosphere for 5 h and trimethylamine was distilled off under vacuo. The residue obtained was taken up in ethyl acetate and washed with distilledwater and brine. The organic layer was next driedover anhydrous MgSO4 and evaporated in vacuo togive the crude product. Then the crude product was purified by flash column chromatography on silica gel to give ((4-bromophenyl)ethynyl)trimethylsilane (1) as awhite solid (192 mg, 71.5percent).11 1H NMR (400 MHz,CDCl3: 7.40 (d, 8.4 Hz, 2H), 7.30 (d, 8.4 Hz, 2H),0.24 (s, 0.22 Hz, 9H).

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YieldReaction ConditionsOperation in experiment
93%
Stage #1: With n-butyllithium In tetrahydrofuran at -20℃; for 0.5 h; Inert atmosphere
Stage #2: at -20℃; for 1 h; Inert atmosphere
Stage #3: With potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 0.5 h;
The mixture of 1 and 1x prepared as previous procedure from 19-hydroxyandrost-4-ene-3,17-dione in two steps and 80percent overall yield. The mixture of 1 and 1x prepared as previous procedure from 19-hydroxyandrost-4-ene-3,17-dione in two steps and 80percent overall yield. Under the inert atmosphere, the solution of 1-mix (2.04 g, 6.0 mmol), tricyclopentyl orthoformate (8.04 g, 30 mmol) and TfOH (552 ul, 6.0 mmol) in cyclopentanol (60 mL) was stirred at 100 °C for 2 h. The reaction was quenched with saturated NaHCO3. The organic solvent was removed under reduced pressure and the residual was diluted with ethyl acetate and washed with brine. The organic phase was dried over Na2SO4, concentrated under reduced pressure, and chromatographed on silica gel to give 2b-mix as a white solid (1.63 g). Under inert atmosphere, Raney Ni (1.6 g) was washed with dry THF for several times. The solution of 2b-mix (1.63 g) in dry THF (180 mL) was added to Raney Ni. The suspension was stirred at room temperature and monitored with HPLC. After the reaction finished (1.5 h), the suspension was filtered. The filtrate was concentrated and chromatographed on silica gel to give estrone 3-cyclopentyl ether (2b) as a white solid (1.62 g, 79percent overall yield). Under inert atmosphere, n-BuLi (1.2 mL, 3.0 mmol, 2.5 N) was added to a solution of ethynyltrimethylsilane (424 ul, 3.0 mmol) in THF (2 mL) at -20 °C. After 0.5 h, a solution of ketone 2b (338 mg, 1.0 mmol) in THF (4 mL) was added into the solution of lithium acetylene at -20 °C. After 1 h, the mixture was added with methanol (6 mL) and KOH (224 mg, 4 mmol) and stirred for 0.5 h at room temperature and quenched with 2N-hydrochloric acid. The organic solvent was removed under reduced pressure and the residual was diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over Na2SO4, concentrated under reduced pressure, and chromatographed on silica gel to give quinestrol as a white solid (340 mg, 93percent). Mp 94-96 °C; [α]D23.4=+11.3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.6 Hz, 1H), 6.68 (dd, J=8.5, 2.3 Hz, 1H), 6.61 (d, J=2.7 Hz 1H), 4.74-4.70 (m, 1H), 2.91-2.79 (m, 2H), 2.61 (s, 1H), 0.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.9, 137.8, 132.0, 126.2, 115.5, 112.9, 87.5, 79.9, 79.0, 74.0, 49.4, 47.1, 43.5, 39.4, 38.9, 32.9, 32.7, 29.8, 27.3, 26.3, 24.0, 22.8, 12.7; HRMS (ESI) calcd for C25H33O2 [M+H]+: 365.2402, found 365.2472.
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  • 52
  • [ 75-03-6 ]
  • [ 1066-54-2 ]
  • [ 62108-37-6 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 2.16667 h;
Stage #2: With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #3: at -78 - 20℃;
A 3 L three-necked round bottom flask was charged with (trimethylsilyl)acetylene (116 g, 1.19 mol) and dry THF (400 mL). The solution was cooled to -78 °C. To this solution, butyllithium in hexane (2.5 M, 500 mL, 1.25 mol) was added dropwise over 2 hours. The resulting mixture was warmed to 0 °C for 10 minutes and then re-cooled to -78 °C. HMPA (234 g, 1.31 mol) was added, and the mixture was stirred at -78 °C for 30 minutes. To this solution, iodoethane (200 g, 1.28 mol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4x600 mL) and then brine (2x500 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. Hexane and THF were distilled off at 751 10 °C. But-1-yn-1-yltrimethylsilane was distilled between 125135 °C affording 91 g of a colorless liquid (6 1percent). 1H NMR (400 MHz, DMSO-d6) ö 2.20 (q, 2H),1.05 (t, 3H), 0.11 (s, 9H); 13C NMR (100 MHz, CDCl3): ö 108.8, 83.3, 13.7, 13.4, 0.0.
61%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 2.16667 h;
Stage #2: With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #3: at 20℃;
Intermediate 1But-l-yn- -yltrimethylsilane[00372] A 3 L three-necked round bottom flask was charged with (trimethylsilyl)acetylene (116 g, 1.19 mol) and dry THF (400 mL). The solution was cooled to -78 °C. To this solution, butyllithium in hexane (2.5 M, 500 mL, 1.25 mol) was added dropwise over 2 hours. The resulting mixture was warmed to 0 °C for 10 minutes and then re-cooled to -78 °C. HMPA (234 g, 1.31 mol) was added, and the mixture was stirred at -78°C for 30 minutes. To this solution, iodoethane (200 g, 1.28 mol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4x600 mL) and then brine (2x500 mL). The organic layer was dried over sodium sulfate and filtered. Hexane and THF were distilled off at 75—110 °C. But-l-yn-l-yltrimethylsilane was distilled between 125 to 135 °C affording 91 g of a colorless liquid (61percent). 1H NMR (400 MHz, DMSO-de) δ 2.20 (q, 2H), 1.05 (t, 3H), 0.11 (s, 9H).
61%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 2.16667 h;
Stage #2: With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #3: at -78 - 20℃; for 16 h;
Step-1.1: Synthesis of but-l-yn-l-yltrimethylsilane: To a stirred solution of (trimethylsilyl)acetylene (116 g, 1.19 mol) in dry THF (400 mL) was added rc-BuLi (2.5M in THF, 500 mL) at -78 °C over 2 h. The resulting mixture was warmed to 0 °C for 10 min. The reaction mixture was again cooled to -78 °C, HMPA (234 g, 1.13 mol) was added to the above mixture and stirred at -78 °C for 30 min. To the above reaction mixture iodoethane (200 g, 1.28 mol) was added and the resulting mixture was stirred at room temperature for 16 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (1000 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product but-l-yn-l-yltrimethylsilane was distilled between 125-135 °C to afford the desired product (91 g, 61 percent) as a colourless liquid.
61%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 2.16667 h;
Stage #2: With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at 23℃; for 16.5 h;
10204] To a stirred solution of (trimethylsilyl)acetylene (ii6 g, i.i9 mol) in dry THF (400 mE) was added n-l3uEi (2.5M in THF, 500 mE) at —78° C. over 2 h. The resulting mixture was warmed to 0° C. for iO mm. The reaction mixture was again cooled to —78° C., HMPA (234 g, i.i3 mol) was added to the above mixture and stirred at —78° C. for 30 mm. To the above reaction mixture iodoethane (200 g, i .28 mol) was added and the resulting mixture was stirred at room temperature for i 6 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (i000 mE). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product but-i -yn-i - yltrimethylsilane was distilled between i25-i35° C. to afford the title compound of Ex. i Step-2 (9i g, 6ipercent) as acolourless liquid.

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  • [ 1066-54-2 ]
  • [ 86521-05-3 ]
YieldReaction ConditionsOperation in experiment
95% at 20℃; To a solution of 2-brompyridine (4.74 g, 0.030 mol), CuI (0.14 g, 0-74 mmol), and Pd(PPh3)2Cl2 (0.52 g, 0,74 mmol) in 100 ml of diisopropylamine was added (trimetliylsilyl)aceτylene (3.0 g, 0.030 mol). The mixture was stirred at room temperature overnight under nitrogen atmosphere. After removal of the solvent under reduce pressure, the residue was purified by reduced pressure distillation to offer 5.0 g (yield 95percent) of pure compound 1 of 2-(triinethylsilyl)pyridine.
93% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 120℃; for 0.0833333 h; Microwave irradiation; Sealed tube; Inert atmosphere General procedure: A sealed 10mL glass tube containing substrate 1a–1s (1.5mmol), trimethylsilylacetylene (1.5mmol), triethylamine (7.5mmol), Pd(PPh3)2Cl2 (5molpercent), CuI (10molpercent), and acetonitrile (1mL) was placed in the cavity of a microwave reactor and irradiated for 2–10min, at 120°C and power 150W. After cooling to room temperature by an N2-flow, the tube was removed from the rotor. The reaction mixture was combined with dichloromethane (30mL) and water (30mL). The organic layer was separated and washed with water (2×30mL), dried over sodium sulfate, and concentrated. Purification by column chromatography, eluting with petroleum ether gave 1-aryl-2-(trimethylsilyl)acetylenes (2a–2s) as coloured oils or solids. All the products 2a–2s were characterized by 1H NMR and EI-MS. (See Supporting Information file for characterization data of 1H NMR and EI-MS spectrum.)
81% at 20℃; Inert atmosphere To a solution of 2-bromopyridine (1800 mg, 11.4 mmol) in 30 mL of degassed Et3N was added successively CuI 217 mg, 1.14 mmol), trimethylsilyl acetylene (1227 mg, 12.5 mmol) and bis(triphenylphosphine) palladium dichloride (417mg, 0.57mmol). The mixture was then degassed for 20min under N2 atmosphere and stirred at rt overnight. The reaction mixture was filtered and 60 mL of H2O was added into the black filtrate. After stirring for 10 min, the solution was extracted with EtOAc (3*30 mL). The organic layer was washed with brine (2x30 mL) and dried over anhydrous Na2SO4, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give 2-((trimethylsilyl)ethynyl)pyridine (1.6g, 81percent yield).
78% at 20℃; for 72 h; Inert atmosphere Intermediate 252-((Trimethylsilyl)ethynyl)pyridine. A flask was charged with 2- bromopyridine (1.21 mL, 12.66 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.97 mL, 13.92 mmol) and the reaction was purged 15 min longer. To this was added copper(I) iodide (0.121 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). Reaction stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5percent- > 15percent EtO Ac/Hex) gave 1.73 g (78percent) as a dark oil. XH-NMR (CDC13, 500 MHz) δ 8.58 (m, IH), 7.66 (ddd, J=7.9, 7.9, 1.8, IH), 7.47 (m, IH), 7.24 (ddd, J=7.6, 4.9, 1.2, IH), 0.29 (s, 9H). C-NMR (CDCI3, 126 MHz) δ 150.1, 143.2, 136.1, 127.4, 123.1, 103.8, 94.9, -0.2. Mass spec: 176.14 (MH)+.
71.5% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine In tetrahydrofuran at 45℃; Inert atmosphere General procedure: Cross coupling of bromopyridines was completed using a modified experiment from Shin et. al.1 To a flame dried 250 mL Round Bottom flask under nitrogen and equipped with a stir bar, 60mL of degassed anhydrous tetrahydrofuran (THF) and 60 mL of degassed diisopropylamine were added, followed by dibromopyridine (12.6 mmol) to make a concentration of 0.1 M(bromopyridine in THF:iPr2NH). Copper (I) iodide, 480 mg, (2.5 mmol, 20 mol percent) was addedand the solution turned yellow/green. Stirring was set to high (~600 rpm) and 4.5 mL ofethynyltrimethylsilane (31.5 mmol, 1.25 equiv per bromine) was added dropwise over 4-5 min.prior to the addition of 900 mg of bis(triphenylphosphine)palladium(II) dichloride (1.3 mmol, 10mol percent). The flask was lowered into a 45 °C oil bath and monitored by TLC. The solution turns black over time. The mixture was run through a silica gel plug with 1:1 EtOAc:hexanes, and concentrated under reduced pressure.

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  • 58
  • [ 1066-54-2 ]
  • [ 54048-10-1 ]
YieldReaction ConditionsOperation in experiment
2.1 g
Stage #1: With n-hexyllithium In tetrahydrofuran; n-heptane at -5℃; for 0.5 h;
Stage #2: for 15 h;
To a solution of hexillithium (65 mL) in heptane (100 mL) cooled at -5°C, a solution oftrimethylsilyl acetylene (26 mL) in 100 ml of a mixture of THF/heptanes 1/3 was slowlyadded. The reaction mixture was stirred at -5°C for 30 mm, then a solution of compound 4(10 g) in 100 mL of THF/heptanes 1:1 was added and the mixture stirred for 15h further. Water (200 mL) was added to quench the excess of lithium reagent and the organic phase concentrated under vacuum. The residue (containing 90percent ofcompound 5 and 10percent of compound 4) was dissolved in 50 mL of methanol, 0.5 mL of HCI were added and stirred 1 h at 20°C, followed by addition of 3 mL of NaOH 50percent and stirring for 1 h further. The solvent was evaporated under reduced pressure, the residue dissolved in 100 mL of DCM. It was washed first with a solution of glacial acetic acid 3percent and then with a solution of NaHCO3 7percent. The crude obtained was dissolved in 30mL of acetone, concentrated to a volume of 12 mL and 12 mol of IPA were added with further reduction of the volume of 50percent. The operation was repeated twice. The suspension was cooled in an ice bath and the solid filtered, washed with 4 mL of cold IPA and dried at 40°C under vacuum, to yield 2.1 g of Etonogestrel.
Reference: [1] Patent: WO2017/149091, 2017, A1, . Location in patent: Page/Page column 33
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  • [ 51934-41-9 ]
  • [ 1066-54-2 ]
  • [ 10602-03-6 ]
Reference: [1] Chemistry Letters, 2013, vol. 42, # 10, p. 1308 - 1310
[2] Patent: CN104151174, 2016, B, . Location in patent: Paragraph 0011; 0020; 0021
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  • [ 7681-65-4 ]
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  • [ 10602-03-6 ]
Reference: [1] Patent: US2002/120006, 2002, A1,
[2] Patent: US6624154, 2003, B1,
  • 61
  • [ 16932-44-8 ]
  • [ 1066-54-2 ]
  • [ 126829-31-0 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With copper(l) iodide; diisopropylamine In toluene at 20 - 60℃; for 49 h; Inert atmosphere
Stage #2: With methanol; sodium hydroxide In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Example 15; 1 ) Me3SiCCH,9I (93percent)[0125] 2,6-Dimethoxyphenylacetylene (91). To a stirred, degassed solution of 2-iodo-l ,3- dimethoxybenzene (13.2 g, 50 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (702 mg, 1 mmol), triphenylphospine (524 mg, 2 mmol), and copper(I) iodide (288 mg, 1.5 mmol) in 3 : 1 (v/v) toluene : diisopropylamine (200 mL) under argon is addedtrimethylsilylacetylene (8.0 mL, 57 mmol). The resulting mixture is stirred under argon at room temperature for lh, followed by 48 hour at 60°C, during which period a heavy precipitate attributed to iPr2NHHI is formed. Contents are passed on a Si02 plug with ethyl acetate as eluent. Volatiles are evaporated under reduced pressure, and the contents are passed on a short Si02 column with 95 :5 to 90: 10 pentane : ethyl acetate (v/v) as the eluent to afford the crude TMS-protected alkyne as an off-white solid that is directly carried to the next step without further purification. The solid is dissolved in THF (90 mL) and the solution is degassed by bubbling argon gas through for ca. 30 min. To the stirred mixture is added by a solution of sodium hydroxide (6 g) in methanol (30 mL). The reaction mixture is stirred at room temperature for lh, before pouring of the contents in saturated aqueous NaCl. After extration with diethyl ether and evaporation of the volatiles, the crude alkyne is purified by passage through a short Si02 column using 1 : 1 dichloromethane : pentane (v/v) as the eluent to afford alkyne 91 as a beige solid (7.55 g, 93percent over 2 steps). 1H-NMR (CDC13, 300 MHz): δ = 7.25 (t, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 3.89 (s, 6H), 3.57 (s, 1H). 13C-NMR (CDC13, 75 MHz): δ =161.9, 130.2, 103.2, 99.9, 85.3, 76.3, 55.9. Characterization data for 91 are consistent with literature values (See Wayland, B. B.; Sherry, A. E.; Poszmic, G.; Bunn, A. G. J. Am. Chem. Soc. 1992, 1 14, 1673-1681).
Reference: [1] Patent: WO2011/139704, 2011, A2, . Location in patent: Page/Page column 41
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  • [ 1066-54-2 ]
  • [ 79887-09-5 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 57, p. 15303 - 15308
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  • [ 1066-54-2 ]
  • [ 134856-58-9 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 7, p. 1623 - 1633
[2] Journal of Organic Chemistry, 1999, vol. 64, # 6, p. 1968 - 1971
[3] Chemistry - A European Journal, 2013, vol. 19, # 48, p. 16240 - 16247
[4] European Journal of Organic Chemistry, 2006, # 14, p. 3087 - 3096
[5] Organic Letters, 2007, vol. 9, # 5, p. 737 - 740
[6] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2569 - 2574
[7] Journal of the American Chemical Society, 2013, vol. 135, # 4, p. 1264 - 1267
[8] Chemical Communications, 2016, vol. 52, # 90, p. 13237 - 13240
[9] Angewandte Chemie - International Edition, 2017, vol. 56, # 49, p. 15649 - 15653[10] Angew. Chem., 2017, vol. 129, p. 15855 - 15859,5
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[2] Journal of Molecular Structure, 2009, vol. 938, # 1-3, p. 245 - 253
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[2] European Journal of Organic Chemistry, 2012, # 3, p. 529 - 538
  • 66
  • [ 1122-91-4 ]
  • [ 1066-54-2 ]
  • [ 63697-96-1 ]
YieldReaction ConditionsOperation in experiment
85.1%
Stage #1: With triethylamine In tetrahydrofuran for 0.75 h; Inert atmosphere
Stage #2: With copper(l) iodide; triphenylphosphine hydrochloride In tetrahydrofuran for 10 h; Inert atmosphere
Stage #3: With potassium carbonate In methanol at 20℃; for 5 h;
15.0 mmol (2.78 g) of p-bromobenzaldehyde was dissolved in 95 ml of a tetrahydrofuran and triethylamine mixed solution (1: 1 by volume) and placed in a 250 ml single-necked flask,The cells were ventilated for 45 minutes and then 18.0 mmol (1.76 g)Of trimethylsilylacetylene. Adding 97.2 mg of triphenylphosphonium dichloride,46.5mg cuprous iodide. Under argon, the reaction was carried out for 10 hours.After the reaction was stopped, the solvent was removed by distillation under reduced pressure and purified by silica gel column chromatography (developing solvent: dichloromethane: petroleum ether 1: 4), steamed and dried in vacuo to give 2.19 g of a white solid in 72.3percent yield.B: A solution of 8.0 mmol (1.62 g) of a product was dissolved in 30 mlMethanol and 60 ml of tetrahydrofuran, placed in a 250 ml single-necked round bottom flask,Then add anhydrous potassium carbonate,And the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure,Silica gel column (developing solvent for petroleum ether and dichloromethane 1: 1 mixed solvent) crude purification;Dried in vacuo to give 0.88 g of a white solid in 85.1percent
Reference: [1] Patent: CN106588789, 2017, A, . Location in patent: Paragraph 0047-0049
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[4] Polyhedron, 2015, vol. 86, p. 10 - 16
[5] Patent: CN107987094, 2018, A, . Location in patent: Paragraph 0038; 0039
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  • [ 59247-47-1 ]
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  • [ 111291-97-5 ]
Reference: [1] Patent: US4818819, 1989, A,
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  • [ 111291-97-5 ]
Reference: [1] Patent: US4818819, 1989, A,
  • 69
  • [ 540-38-5 ]
  • [ 1066-54-2 ]
  • [ 88075-18-7 ]
YieldReaction ConditionsOperation in experiment
100% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine In toluene at 20℃; for 24 h; Inert atmosphere 4-Iodophenol 9 (2 g, 9.09 mmol, 1 eq) were dissolved in 20 mL of dry toluene. To the resulting solution PdCl2(PPh3)2 (191.4 mg,0.27 mmol, 0.03 eq), copper (I) iodide (172.8 mg, 0.909 mmol, 0.1 eq), N,N-diisopropylethylamine (1.58 mL, 9.09 mmol, 1 eq) and trimethylsilylacetylene (1.28 mL, 9.09 mmol, 1 eq) were subsequently added. The reaction was stirred at room temperature for 24 h. Evaporation of the solvent, and the residue was purified by column chromatography (EtOAc/hexane = 1:10) to afford 10 (1.73 g, quant.) as a brown oil. 1H-NMR (CDCl3, 500 MHz) δ 7.37 (2H, d, J= 8.8 Hz, Ar-H), 6.76 (2H, d, J = 8.8 Hz, Ar-H), 4.92 (1H,brs, Ar-OH), 0.24 (9H, s, -Si(CH3)3). 13C-NMR (CDCl3, 75MHz) δ 155.76, 133.69, 115.49, 115.31, 105.02, 92.50, 0.05.
100% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N,N-diethylnmethylamine In N,N-dimethyl-formamide at 60℃; for 0.333333 h; Microwave irradiation; Inert atmosphere 4-Iodophenol (2) (440 mg, 2.0 mmol) and trimethylsilylacetylene(0.42 mL, 3.0 mmol) were dissolved in 10 mL ofdiethylmethylamine and 10 mL of dimethylformamide,and then, 60 mg (0.30 mmol) of CuI and 70 mg (0.10 mmol)of PdCl2(PPh3)2 were added. The solution was stirred in amicrowave reactor at 60 °C for 20 min (100 W) under N2atmosphere. The solvent was evaporated, and the residuewas dispersed in 20 mL aqueous 2 M HCl and extractedwith diethyl ether (3 × 20 mL). The combined organic layers were dried over Na2SO4, the solvent was evaporated,and the residue purified with FCC (isohexane-ethylacetate 3:1) to give 380 mg (100 percent) of 4 as a brown oil.– 1H NMR (400 MHz, CDCl3): δ = 0.23 (s, 9 H, 3 CH3), 6.76(d, J = 8.8 Hz, 2 H, aromat. CH), 7.34 (d, J = 8.8 Hz, 2 H,aromat. CH). – 13C NMR (125 MHz, CDCl3): δ = 0.19 (3 CH3),92.12 (quat. C), 105.39 (quat. C), 114.98 (quat. C), 115.48(2 aromat. CH), 133.51 (2 aromat. CH), 156.44 (quat. C).These data are in accordance with those published inRef. [12]. – GC-MS (EI): m/z (percent) = 190 (23) [M]+, 175 (100).– HRMS: m/z = 190.0814 (calcd. 190.0815 for C11H14O2Si,[M]+). – IR (KBr): ν (cm−1) = 3322, 2959, 2155, 1662, 1607,1508, 1437, 1251, 1230, 1167, 1100, 867, 840.
80% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 25℃; for 24 h; A mixture of 4-iodophenol (3.08 g, 14.0 mmol), trimethylsilylacetylene (2.1 mL, 15.2 mmol), PdCl2(PPh3)2 (31 mg, 0.044 mmol), and CuI (4.9 mg, 0.026 mmol), NEt3 (10 mL) in THF (20 mL) was stirred at 25 °C. After stirring for 1 day, to the mixture was added aqueous 2 M HCl, and extracted with EtOAc (3 times). The organic phase was sequentially washed with brine, aqueous sat.NaHCO3, and brine, and dried with MgSO4. After concentration, the residue was purified with silicagel column chromatography (hexane to hexane/EtOAc = 8/2) to afford 4-(trimethylsilylethynyl)phenol as colorless amorphous solids (2.12 g, 80percent). mp 41-42 °C (colorless amorphous solids, recrystallized from hexane); Rf: 0.40 (hexane/EtOAc = 4/1); 1H NMR (CDCl3, 400 MHz):  ;0.24 (s, 9H), 5.23 (s, 1H), 6.76 (d, 2H, J = 8.8 Hz), 7.36 (d, 2H, J = 8.8 Hz); 13C NMR (CDCl3, 100 MHz):  0.0, 92.5, 105.0, 115.3, 115.5, 133.7, 155.8; IR (KBr): vmax 3745, 3334, 2958, 2898, 2158, 1886, 1606, 1508, 1437, 1358, 1252, 1209, 1168, 1101, 866, 839 cm-1; HRMS (DART): M+ calcd for C11H14OSi, 190.08139; found, 190.08161
79% at 80℃; for 24.5 h; Inert atmosphere To a refluxingsuspension of iodophenol (2.5 g, 1.0 mmol), copper acetate monohydrate (1.35 g,1.07 mmol), and palladium chloride (1.8 g, 1.07 mmol) in triethylamine (10 mL) in an inertatmosphere was added dropwise trimethylsilylacetylene (1.36 g, 1.20 mmol) over 30 min.The reaction mixture was further refluxed at 80C for 24 h under nitrogen atmosphereand monitored by TLC for completion of reaction. The mixture was cooled and filteredto remove the solids. The volatile solvents were evaporated under reduced pressure, andthe resulting crude light brown colored viscous oil was extracted into ether, washed withsaturated potassium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated.The silylated product was purified by column chromatography on silica gel with3percent ethyl acetate in hexane as eluent. Yield = 1.58 g (79percent).
68% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; A suspension of 4-iodophenol (3.00 g, 13.64 mmol), ethynyltrimethylsilane (2.27 mL, 16.36 mmol), copper (_) iodide (130 mg, 0.68 mmol), bis(triphenylphosphine)palladium(II) dichloride (479 mg, 0.68 mmol), TEA (5.70 ml, 40.91 mmol) were stirred in THF (23 mL) at ambient temperature for overnight. The reaction solvent was evaporated under reduced pressure, and the residue was purified by column chromatography with hexane/ethyl acetate (2/1, v/v) to obtain the compound 52 (1.76 g, 68percent yield): 1H NMR (400 MHz, CDCl3) _ 7.33 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 5.82 (bs, 1H), 0.23 (s, 9H); 13C NMR (100 MHz, CDCl3) _ 155.8, 133.8, 115.6, 115.4, 105.6, 92.9, 0.1.
40.5%
Stage #1: With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran for 0.333333 h; Inert atmosphere
Stage #2: for 21 h; Reflux
Compound 1 was obtained as shown in Scheme I shown below.That is, p-iodophenyl (9.90 g, 45.0 mmol), copper (I) iodide (CuI (I)) (0.358 g, 1.8 mmol)Bis (triphenylphosphine) palladium (II) dichloride (PdCl 2 (PPh 3) 2) (0.640 g, 0.90 mmol)Was substituted with deaerated argon (Ar), then tetrahydrofuran (THF) (112.5 mL) and triethylamine (Et 3 N) (7.5 mL) were added and the mixture was stirred for 20 minutes. Thereafter, trimethylsilylacetylene (TMSA) (6.35 mL, 45.0 mmol) was added and the mixture was shaken for 21 hoursFollowed by stirring (refluxing). After completion of the reaction, the solvent was distilled off, diethyl ether was added to the residue, and the obtained organic layer was washed with pure water and dried with anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the solvent was distilled off to obtain a brown viscous residue.The obtained residue was dissolved in benzene (20 mL), heated to 60 ° C., and ethylenediamine (4 mL) was added and the mixture was stirred for 20 minutes. The precipitate was filtered off and the filtrate taken out was washed with 0.5 M aqueous hydrochloric acidWashed with the solution and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off, The solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: ethylacetone / hexane = 1/4)Compound 1 (3.47 g, yield: 40.5percent) was obtained as a brown solid. Identification of Compound 1 was carried out by 1 H-NMR spectrum. Incidentally, 1 H-NMRPector was measured after dissolving Compound 1 in deuterochloroform without tetramethylsilane (TMS).

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YieldReaction ConditionsOperation in experiment
87% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 4 h; Inert atmosphere General procedure: Toa solution of 2-iodoarenes 1 (1 mmol)in dry THF/Et3N (2:1, 10 mL) were added Pd(PPh3)2Cl2(0.025 mmol) and CuI (0.05 mmol) under argon atmosphere. Trimethylsilyl acetylene2 (1.3 mmol) was then added dropwiseand the resulting mixture was stirred at room temperature for 4 h (TLC). Thereaction mixture was concentrated under reduced pressure and the residue waspurified by silica gel (100–200 mesh) column chromatography using diethyl etherin petroleum ether (4–10percent) to afford the pure2-((trimethylsilyl)ethynyl)arenes3 in good to excellent yields (Table1).
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YieldReaction ConditionsOperation in experiment
100% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran at 20℃; Inert atmosphere To a solution of 4-bromobenzaldehyde 7 (3.70 g, 20.0 mmol), CuI (380 mg, 2.00 mmol) and Pd(PPh3)4 (924 mg, 800 mol) in THF (60 mL) were added Et3N (11.2 mL, 80.3 mmol) and trimethylsilylacetylene (4.24 mL, 30.0 mmol). The reaction mixture was stirred at room temperature under Ar overnight and filtered, and the solids were washed with EtOAc (30 mL). The filtrate and EtOAc washing were combined and concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, petroleum benzine ramping to petroleum benzine:EtOAc = 98:2) to give 4-((trimethylsilyl)ethynyl)benzaldehyde as a pale brown solid (4.04 g, 100percent). RF (petroleum benzine:EtOAc = 4:1) 0.87. m.p. 6667 °C (lit. [7] m.p. 70 °C). IR νmax/cm-1 2960, 2899, 2832, 2733, 2159, 1702, 1600, 1563, 1412, 1384, 1303, 1251, 1205, 1165, 862, 842. 1H NMR (300 MHz, CDCl3) δ 0.19 (s, 9H, Si(CH3)3), 7.47 (d, 2H, J 8.1, Ph-H), 7.68 (d, 2H, J 7.8, Ph-H), 9.87 (s, 1H, CHO). 13C NMR(75 MHz, CDCl3) δ 0.3, 98.8, 103.8, 129.1, 129.3, 132.3, 135.5, 191.0 (four carbon signals overlapping or obscured). MS (GC-EI) 187.1 ([MCH3]+, 100percent), 202.0 (M+, 8percent). The spectroscopic data were in agreement with those in the literature. [7]
100%
Stage #1: for 0.0833333 h; Sealed tube; Sonication
Stage #2: for 3 h; Sealed tube
General procedure: In a tightly sealed tube (septa system),aryl halides (5.5 mmol) and 5percent nanocatalyst Pd/Cu, PPh3 (17 mg) were suspended in drytriethylamine (10 mL). The mixture was placed in an ultrasound bath and sonicated for 5 min.Then, the acetylene compound (5.6 mmol) was added and the mixture was stirred for 3 h. Themixture was cooled to room temperature and the catalyst was centrifuged, filtered and washedwith ethyl acetate (3 x 10 mL). The filtrate was washed three times with deionized water (3 x 15mL) and then dried over magnesium sulfate, filtered and concentrated under reduced pressureto give the product.
99% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 40℃; for 2 h; p-bromobenzaldehyde (1.85 g, 10 mmol) was dissolved in 15 mL of anhydrous THF and trimethylsilylacetylene was added.(1.47 g, 15 mmol), bistriphenylphosphine dichloropalladium (70 mg, 0.1 mmol), cuprous iodide (38 mg, 0.2 mmol), and 5 ml triethylamine.Reaction at 40 °C for 2 h. Spin-dry the THF, and column-purify with PE and DCM (2:1 by volume) to obtain 2.0 g of compound 4 as a white solid. The yield is 99percent.
98.6% for 2 h; Heating / reflux Example 4Part A: Synthesis of 4- [(TrimethylsilyDethynyll benzaldehydeA deaerated solution of 24.5 g (132 mmol) of 4-bromobenzaldehyde and 1.00 g of triphenylphosphine in 300 ml of anhydrous triethylamine was treated with 20.0 g (204 mmol) of ethynyltrimethylsilane and then 0.3 g of palladium(II)acetate under argon. The mixture was heated at reflux for 2 h, cooled and filtered to give 24.Og (100 percent) of triethylamine hydrobromide. The filtrate was concentrated to an oil which solidified into long needles. The crude material was dissolved in hexane and filtered through silica gel to give 26.3 g (130 mmol, 98.6 percent) of 4-[(trimethylsilyl)ethynyl]benzaldehyde. The material was used in the next step without any further purification. 1H-NMR (CDCl3, 400 MHz): δ[ppm] = 0.21(s, 9 H), 7.60 (q, 4 H, J = 7.0 Hz), 9.85 (s, 1 H)
96.1% With triphenylphosphine In triethylamine for 2 h; Heating / reflux To a solution of 4-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (80 mL) under Angon, were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol). The final mixture was heated to reflux for 2 hours, and then it was cooled down to room temperature and filtrated. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) and recrystallized from cold cyclohexane to give 10.5 g (96.1percent yield) of 4-(trimethylsilylethynyl)benzaldehyde; MS m/e 187.2 (M+); 1H-NMR (CDCl3) ? ppm: 0.27 (s, 9H, SiMe3), 7.60 (d, 2H, ArH, J=8.1 Hz), 7.82 (d, 2H, ArH, J=8.1 Hz), 10.00 (s, 1H, CHO)].
96% With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride In tetrahydrofuran for 2 h; Reflux To a stirred mixture of 3 (4.61 g, 24.9 mmol), CuI (193 mg,1.01 mmol, 0.041 equiv.), PdCl2 (93 mg, 0.52 mmol, 0.021 equiv.),and PPh3 (405 mg, 1.54 mmol, 0.062 equiv.) in 25 mL of THF was addedEt3N (5.2 mL, 37.3 mmol, 1.5 equiv.)and trimethylsilylacetylene(6 mL, 42.5 mmol, 1.7 equiv.). The mixture was stirred for 2 hours at refluxtemperature, then poured into water and extracted with CHCl3. TheCHCl3 layer was washed with brine, dried over Na2SO4,and filtered. The filtrate was evaporated, and silica gel flash column chromatography(n-hexane to n-hexane/AcOEt = 20/1) of the residue gave 4.82 g (96percent) of 4 as a brown solid: 1H NMR(CDCl3 500 MHz, δ; ppm) 10.00 (1H, s), 7.82 (2H, dd, J = 6.7 Hz, 1.8 Hz), 7.61 (2H, d, J = 8.2 Hz), 0.27 (9H, s).
92% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 40℃; Inert atmosphere Trimethylsilylacetylene (5mL, 4.03g, 41.0mmol) was added to a solution of 4-bromobenzaldehyde (5.00g, 27.0mmol), Pd(PPh3)2Cl2 (50mg, 0.07mmol), and CuI (25mg, 0.13mmol) in distilled THF (40mL) under argon. Then, triethylamine (6.5mL) was added and the reaction mixture was heated at 40°C overnight. The solvent was evaporated under reduced pressure. The obtained residue was extracted in DCM, washed in water, dried with MgSO4, and then taken into dryness. The solid was then purified by column chromatography on silica gel using a mixture of heptane/DCM (1:1) as eluent. The compound 9 was obtained as a pale yellow solid to yield 5.04g (92percent). 1H NMR (400MHz, CDCl3, δ in ppm): 10.01 (s, 1H, CHO), 7.83 (d, 2H, Hphenyl, 3JHH=7.6Hz), 7.62 (d, 2H, Hphenyl, 3JHH=7.2Hz), 0.29 (s, 9H, (CH3)3Si).
89% for 6 h; Reflux A deaerated solution of 4-bromobenzaldehyde (3, 4.87 g, 25 mmol),triphenylphosphine (0.33 g, 1.25 mmol), PdCl2 (45 mg, 0.25 mmol), and Cu(OAc)2 (48 mg, 0.25 mmol) inanhydrous triethylamine (60 mL) was treated with trimethylsilylacetylene (5.5 mL, 38 mmol). The mixture wasbrought to reflux for 6 h. After cooling, the precipitated triethylamine hydrobromide was filtered off, and thesolvent was evaporated. The crude material was purified by silica gel column chromatography (silica gel 120 g,hexanes/ethyl acetate = 90/10), affording 4-((trimethylsilyl)ethynyl)benzaldehyde (4.49 g, 89percent yield) as a yellowsolid. 4-((Trimethylsilyl)ethynyl)benzaldehyde (4.05 g, 20 mmol) was treated with K2CO3 (2.28 mg, 2 mol) inMeOH (24 mL) at room temperature for 24 h. The solvent was removed in vacuo. The crude material was purifiedby silica gel column chromatography (silica gel 120 g, hexanes/ethyl acetate = 90/10), affording 4-ethynylbenzaldehyde (5; 2.20 g, 85percent yield) as a yellow solid.
88% With copper(l) iodide; N-cyclohexyl-cyclohexanamine In tetrahydrofuran at 30℃; for 17 h; [Example A-18] Synthesis of 4-[(trimethylsilyl)ethynyl]benzaldehyde from 4-bromobenzaldehyde and trimethylsilylacetylene (Synthesis in which tri-tert-butylphosphonium tetraphenylborate was handled in air) A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 9 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.157 g (0.3 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30°C for 30 minutes. 0.925 g (5 mmol) of 4-bromobenzaldehyde and 0.589 g (6 mmol) of trimethylsilylacetylene were added, followed by stirring at 30°C for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.893 g of 4-[(trimethylsilyl)ethynyl]benzaldehyde (yield: 88 molpercent based on 4-bromobenzaldehyde). The identification of the product was made by 1H-NMR and 13C-NMR. (1) 1H-NMR spectrum (δ in CDCl3) 0.26 ppm (s, 9H, H3C) 7.59 ppm (d, J=8.1 Hz, 2H, ring proton) 7.81 ppm (d, J=8.1 Hz, 2H, ring proton) 9.99 ppm (s, 1H, HC) (2) 13C-NMR spectrum (δ in CDCl3) -0.2, 99.0, 103.8, 129.3, 129.4, 132.5, 135.6, 191.4 ppm
88% With copper(l) iodide; N-cyclohexyl-cyclohexanamine In tetrahydrofuran at 30℃; for 17 h; In argon atmosphere [Comparative Example 33] Synthesis of 4-[(trimethylsilyl)ethynyl]benzaldehyde from 4-bromobenzaldehyde and trimethylsilylacetylene (Synthesis in which tri-tert-butylphosphine was handled in argon) The procedures in Example A-18 or B-36 were repeated except that 0.157 g (0.3 mmol) of tri-tert-butylphosphonium tetraphenylborate of Example A-18 or 0.174 g (0.3 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate of Example B-36 was replaced with 0.061 g (0.3 mmol) of tri-tert-butylphosphine, and except that the procedures were carried out in a glove box in which an argon atmosphere was strictly maintained. Consequently, 0.894 g of 4-[(trimethylsilyl)ethynyl]benzaldehyde was obtained (yield: 88 molpercent based on 4-bromobenzaldehyde). The identification of the product was made by 1H-NMR and 13C-NMR, and the results were in agreement with those of Example A-18 or B-36.
88% With copper(l) iodide; N-cyclohexyl-cyclohexanamine In tetrahydrofuran at 30℃; for 17 h; [Example B-36] [Similar to Example A-18] Synthesis of 4-[(trimethylsilyl)ethynyl]benzaldehyde from 4-bromobenzaldehyde and trimethylsilylacetylene (Synthesis in which tri-tert-butylphosphonium tetra-para-tolylborate was handled in air) A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 9 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.174 g (0.3 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30°C for 30 minutes. 0.925 g (5 mmol) of 4-bromobenzaldehyde and 0.589 g (6 mmol) of trimethylsilylacetylene were added, followed by stirring at 30°C for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.890 g of 4-[(trimethylsilyl)ethynyl]benzaldehyde (yield: 88 molpercent based on 4-bromobenzaldehyde). The identification of the product was made by 1H-NMR and 13C-NMR. (1) 1H-NMR spectrum (δ in CDCl3) 0.26 ppm (s, 9H, H3C) 7.59 ppm (d, J=8.1 Hz, 2H, ring proton) 7.81 ppm (d, J=8.1 Hz, 2H, ring proton) 9.99 ppm (s, 1H, HC) (2) 13C-NMR spectrum (δ in CDCl3) -0.2, 99.0, 103.8, 129.3, 129.4, 132.5, 135.6, 191.4 ppm
85% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 24 h; To a mixture of PdCl2(PPh3)2 (175 mg, 0.3 mmol) andCuI (190 mg, 1.0 mmol) in THF (30 mL), 4-bromobenzaldehyde (1.85 g, 10 mmol), trimethylsilyl acetylene(1.12 mL, 12 mmol), and NEt3 (10 mL) were added.The resulted mixture was stirred for 24 h at room temperature.The solvent was removed and 30 mL CH2Cl2 wasadded. The mixture was washed with water (3 30 mL). Theorganic phase was dried with MgSO4 and the solvent wasremoved by rotary evaporation. Purification by columnchromatography (Silica gel, CH2Cl2/hexane 1:2) gave 4-(2-(trimethylsilyl)ethynyl) -benzaldehyde derivative as whitesolid (yield 85percent).To a stirred solution of 4-(2-(trimethylsilyl)ethynyl) benzaldehyde(5 mmol) in CH3OH (30 mL), K2CO3 (69 mg, 0.5mmol) was added. The mixture was stirred for 24 h at roomtemperature, and the solvent was removed. The residue wasdiluted with 30 mL Et2O and washed with water (3 30mL). The organic phase was dried over MgSO4 and the solventwas removed by rotary evaporation. Purification by aflash colum chromatography (Silica gel, Et2O) provide 5 aswhite solid (546 mg, yield 84percent).1H NMR (400 MHz, CDCl3)
81% With triethylamine In tetrahydrofuran at 25 - 30℃; for 3 - 20.5 h; Example 1; Synthesis of 4-trimethylsilanylethynyl-benzaldehyde (2); 4-Bromobenzaldehyde (1) (185 g, 1.0 mole) was dissolved in THF (1 L) followed by addition of copper (I) iodide (7.6 g, 0.04 mol), dicholobis(triphenylphospine) palladium (II) (14.02 g, 0.02 mol) and triethylamine (151.5 g, 1.5 mol). Ethynyltrimethylsilane (109.1 g, 1.11 mol) was added from addition funnel as a solution in THF (0.2 L). The reaction was stirred at 30° C. for 30 min and then at 25° C. for 20 hours. Analysis by HPLC indicated the completion of the reaction. THF was removed and the residue was treated with hexane (1.8 L). The solid was removed by filtration and the filter cake washed with hexane (0.3 L). The combined hexane solution was washed with water (2.x.0.5 L). Hexane was removed in a rotovap. The residue was dissolved in EtOH (0.5 L) at 50° C. The solution was then slowly cooled to 16° C. and was stirred for 30 minutes. Product started to crystallize. The mixture was further cooled to 5° C. 1:1 of EtOH/H2O (0.24 L) was added slowly. The mixture was stirred at 5° C. for 30 minutes. Solid was collected by filtration, washed with 4:1 of EtOH/H2O (0.2 L) and dried to provide 137.0 g of product. The mother liquor was concentrated to dryness. The residue was partitioned between hexane (0.5 L) and brine (0.25 L). Hexane layer was separated and concentrated to dryness. The residue was crystallized from hexane (40 ml) and further recrystallized from 4:1 of EtOH/H2O (0.1 L) to provide second crop of aldehyde 2 (27.0 g). The combined yield for aldehyde 2 was 81percent. 1H NMR (300 MHz, CDCl3) δ 0.081(s, 9H), 7.41(d, 2H, J=8.1 Hz), 7.63(d, 2H, J=8.4 Hz), 9.81 (s, 1H).
80% at 20℃; Inert atmosphere; sealed tube; Reflux B. 4-ethynylbenzaldehyde; A degassed solution of 4-bromobezaldehyde (6.0 g, 32.4 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) in 60 mL of anhydrous triethylamine was added ethynyltrimethylsilane (26.7 mL, 48.6 mmol) followed by palladium (II) acetate (0.072 g, 0.32 mmol) at room temperature under argon atmosphere. The reaction mixture was heated at reflux for 2 h in sealed tube. The reaction mass was cooled to room temperature and the precipitated solid was filtered. The filtrate was concentrated to provide crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) by using 1percent ethyl acetate in pet-ether as mobile phase to provide 4- ((trimethylsilyl)ethynyl)benzaldehyde (5.2 g, 80percent). This compound was taken up in methanol (100 mL), to which potassium carbonate (0.341 g, 2.47 mmol) was added at room temperature. The reaction mass was stirred for 2 h. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (50 mL). The organic solution was washed with water (50 mL), brine solution (25 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to get 4-ethynylbenzaldehyde as light brown solid (3.0 g, 94percent).LC-MS: [M+H]+ 131.2 Mass: calculated for C9H6O, 130.15IH NMR (400 MHz, δ ppm, CDC13): δ 10.02 (s, IH), 7.85 (d, 2H), 7.65 (d, 2H), 3.29 (s, IH)
80% Reflux To a solution of 4-bromobenzaldehyde (10.0 g, 54.04 mmol) in diisopropylamine (600 mL) were added bistriphenylphosphine palladium (II) chloride (380 mg, 0.54 mmol) and Cul (205 mg, 1.08 mmol). The reaction mixture was degassed for 20 min. Then the reaction mixture was cooled to ice temperature and trimethyl silylacetalide (11.2 mL, 81.06 mmol) was added drop wise at same temperature for 30 min and it was refluxed over a period of 3 h. Diisopropylamine was evaporated under reduced pressure and the residue was diluted with ethyl acetate (1000 mL). The ethyl acetate layer was washed with IN Hydrochloric acid (2X100 mL), saturated sodium bicarbonate (1X100 mL) and water (2X 200 mL). Organic layer was dried over sodium sulphate and it was evaporated under reduced pressure to obtain crude product. The crude product was further purified by column chromatography to give 4-Trimethylsilanylethynyl-benzaldehyde as a colorless solid (8.5 g, 80 percent).
80% at 0℃; for 3.5 h; Reflux To a solution of 4-bromobenzaldehyde (10.0 g, 54.04 mmol) in diisopropylamine (600 mL) were added bistriphenylphosphine palladium (II) chloride (380 mg, 0.54 mmol) and CuI (205 mg, 1.08 mmol).
The reaction mixture was degassed for 20 min.
Then the reaction mixture was cooled to ice temperature and trimethyl silylacetalide (11.2 mL, 81.06 mmol) was added drop wise at same temperature for 30 min and it was refluxed over a period of 3 h.
Diisopropylamine was evaporated under reduced pressure and the residue was diluted with ethyl acetate (1000 mL).
The ethyl acetate layer was washed with 1N Hydrochloric acid (2*100 mL), saturated sodium bicarbonate (1*100 mL) and water (2*200 mL).
Organic layer was dried over sodium sulphate and it was evaporated under reduced pressure to obtain crude product.
The crude product was further purified by column chromatography to give 4-Trimethylsilanylethynyl-benzaldehyde as a colorless solid (8.5 g, 80percent).
74% at 40℃; Trimethylsilylacetylene (19.4 mL, 135.9 mmol) was added to a mixture of 4-bromobenzaldehyde (5.0 g, 27.18 mmol), Pd(PPh3)2Cl2 (950 mg, 1.36 mmol) and CuI (520 mg, 2.72 mmol) in Et3N (60 mL). The mixture was stirred overnight at 40 °C. After cooling to room temperature, the resulting   ammonium salt was filtered off, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography with petroleum ether as eluent to afford 4-((trimethylsilyl)ethynyl)benzaldehyde as a yellow powder after removal of the solvent (4.0 g, 74percent). 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 0.27 (s, 9H).
70% at 0 - 20℃; for 3.5 h; Reflux A solution of 548 4-bromobenzaldehyde (10 g, 54.64 mmol) in 549 diisopropyl amine (500 mL) was charged with 550 bis(triphenylphosphine)palladium(II) dichloride (380 mg, 0.546 mmol) and 314 copper iodide (205 mg, 1.09 mmol) and degassed for 20 min. The reaction mixture was cooled to 0° C. and followed by dropwise addition of 551 trimethyl silyl acetylene (11.2 mL, 81.06 mmol) for a period of 30 min. The reaction mixture was allowed to attain room temperature and further refluxed for 3 h. The reaction mixture was cooled to room temperature and HBr salt formed was filtered. The filtrate was concentrated in vacuo, diluted with ethyl acetate and washed with 1N HCl solution followed by saturated 125 sodium bicarbonate and water. The separated organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo resulting in the crude 545 compound which was purified by column chromatography on silica gel eluting with 0-5percent ethyl acetate in n-hexane to afford 7.7 g, 70percent yield, of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3) δ=10.00 (s, 1H), 7.82 (d, J=8.31 Hz, 2H), 7.60 (d, J=7.83 Hz, 2H), 0.27 (s, 9H); MS (ES+): m/z=244.16 [M+H]+; LCMS: tR=3.58 min.
1.2 g With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran at 18 - 25℃; Inert atmosphere A suspension of 4-bromobenzaldehyde (1 g, 5mmol), Pd(PPh3 ) 4 (0.23 g, 0.2 mmol). Cui (95 mg, 0.5mmol), triethylamine (2.02 g, 20 mmol) and ethynyltrimethylsilane(0.79 g, 8 mmol) in THF (20 mL) under a N2atmosphere was stirred at RT overnight. The mixture wasfiltered and the filtrate was concentrated. The residue waspurified by silica-gel colunm chromatography to give 1.2 gof 4-((trimethylsilyl)ethynyl)benzaldehyde as a light brownsolid.

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  • 78
  • [ 3375-31-3 ]
  • [ 1122-91-4 ]
  • [ 1066-54-2 ]
  • [ 77123-57-0 ]
YieldReaction ConditionsOperation in experiment
96.1% With triphenylphosphine In triethylamine 4-Ethynylbenzaldehyde (13):
To a solution of 4-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (80 mL) under argon were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol).
The final mixture was heated to reflux for 2 hours, and was then cooled to room temperature and filtered.
The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) and recrystallized from cold cyclohexane to give 10.5 g (96.1percent yield) of 4-(trimethylsilylethynyl)benzaldehyde [MS m/e 187.2 (M+); 1H-NMR (CDCl3) δ ppm: 0.27 (s, 9H, SiMe3), 7.60 (d, 2H, ArH, J=8.1 Hz), 7.82 (d, 2H, ArH, J=8.1 Hz), 10.00 (s, 1H, CHO)].
96.1% With triphenylphosphine In triethylamine 4-Ethynylbenzaldehyde (13):
To a solution of 4-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (80 mL) under argon were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol).
The final mixture was heated to reflux for 2 hours, and was then cooled to room temperature and filtered.
The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) and recrystallized from cold cyclohexane to give 10.5 g (96.1percent yield) of 4-(trimethylsilylethynyl)benzaldehyde [MS m/e 187.2 (M+); 1H-NMR (CDCl3) δ ppm: 0.27 (s, 9H, SiMe3), 7.60 (d, 2H, ArH, J=8.1 Hz), 7.82 (d, 2H, ArH, J=8.1 Hz), 10.00 (s, 1H, CHO)].
Reference: [1] Patent: US2004/106592, 2004, A1,
[2] Patent: US2004/116385, 2004, A1,
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  • [ 77123-57-0 ]
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  • 80
  • [ 223463-13-6 ]
  • [ 1066-54-2 ]
  • [ 111770-86-6 ]
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  • 81
  • [ 15862-19-8 ]
  • [ 1066-54-2 ]
  • [ 162318-34-5 ]
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  • [ 19578-68-8 ]
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Reference: [1] Patent: WO2005/775, 2005, A2, . Location in patent: Page 41-43
  • 83
  • [ 19798-81-3 ]
  • [ 1066-54-2 ]
  • [ 173314-98-2 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With copper(l) iodide; triethylamine In benzene at 50℃; for 7 h; Inert atmosphere
Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at -20 - 0℃;
Preparation 96-Ethynylpyridin-2-amine[00164]A mixture of 6-bromopyridin-2-amine (25.90 g, 150 mmol), ethynyltrimethylsilane (22.10 g, 225 mmol), PdCI2[PPh3]2 (3.50 g, 5 mmol), Cul (2.90 g, 15 mmol), TEA (70 ml_), and benzene (150 ml_) is stirred for 7 h at 50 °C under argon atmosphere, cooled down to r.t. and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide a product mixture of 6- ((trimethylsilyl)ethynyl)pyridin-2-amine and 6-ethynylpyridin-2-amine. The obtained mixture is dissolved in THF (150 ml_), and 1 M solution of TBAF in THF (150 ml_) is added dropwise at -20 °C. The mixture is stirred at 0 °C for 20 min, diluted with water and extracted with DCM. The organic layer is dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (1 1.90 g, 67percent, for two steps) as grey solid.
Reference: [1] Patent: WO2012/52451, 2012, A1, . Location in patent: Page/Page column 53
  • 84
  • [ 24424-99-5 ]
  • [ 591-19-5 ]
  • [ 1066-54-2 ]
  • [ 185619-66-3 ]
Reference: [1] New Journal of Chemistry, 2017, vol. 41, # 22, p. 13391 - 13398
  • 85
  • [ 875305-49-0 ]
  • [ 1066-54-2 ]
  • [ 169674-57-1 ]
YieldReaction ConditionsOperation in experiment
85% at 0 - 20℃; for 1.5 h; Heating / reflux 10 g (68.7 mmol) of 4-chloro-3-fluoro-phenylamine were dissolved in 38 ml dichloro-methane and treated with a solution of 6.82 g (72.1 mmol) of sodium bicarbonate in water (110 ml). At RT 8 ml (103 mmol) of methyl chloroformate were added dropwise over a period of 25 min (temperature rise from 22 to 28° C.). After stirring for 1.5 h at RT, the reaction mixture was diluted with dichloromethane (100 ml). After phase separation, the organic layer was washed with brine (45 ml), dried with magnesium sulfate, filtered and diluted with hexane (140 ml). The dichloromethane was then removed in vacuo and the resulting suspension filtered leading to 13 g (4-chloro-3-fluoro-phenyl)-carbamic acid methyl ester as a white powder (92percent). MS (El) 203.1 (M)+.5.34 g (26.2 mmol) of (4-chloro-3-fluoro-phenyl)-carbamic acid methyl ester were dissolved in acetonitrile (50 ml) and treated with 6.49 g (28.85 mmol) of N-iodosuccinimide and 0.23 ml (2.62 mmol) of trifluoromethanesulfonic acid under nitrogen and stirred at RT for 3 hours. The reaction mixture was then poured into 50 ml of saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were then washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 8.2 g of (4-chloro-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester (95percent) as a dark blue powder. MS (EI) 328.9 (M)+.153 mg (0.22 mmol) of Pd(PPh3)2Cl2 and 42 mg (0.22 mmol) of CuI were dissolved in 40 ml of triethylamine under argon and the mixture was heated to reflux for 20 min. The reaction mixture was then cooled to 0° C. and 7.2 g (21 mmol) of (4-chloro-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester were added. After 10 min stirring at RT, 3.45 ml (24.9 mmol) of ethynyltrimethylsilane were added dropwise (exothermic, temperature rise from 18 to 33° C.) and the reaction mixture was stirred for one hour at RT. The mixture was then poured into 180 ml of aqueous 1N HCl and ice and extracted with ethyl acetate. The organic extracts were then washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining crude material (ca 21 mmol) was dissolved in THF (200 ml) and treated with 43.3 ml (43.3 mmol) of tetrabutylammonium fluoride (1M in THF) at RT. After 5 min stirring at RT, the reaction mixture was refluxed for one hour under argon. The reaction mixture was then cooled to RT and concentrated in vacuo. The resulting oil was treated with water (55 ml), stirred for 10 min and finally extracted with ethyl acetate. The combined organic layers were sequentially washed with 1M HCl (50 ml), saturated sodium bicarbonate (50 ml), brine (50 ml) and finally dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was suspended in hexane (200 ml) and-the mixture was heated to reflux, then cooled to 5° C. and the solid was collected by filtration leading to 3.15 g of 5-chloro-6-fluoro-1H-indole as a light brown solid (85percent). MS (EI) 169.1 (M)+.35 ml of THF were cooled to -75° C. and 19.05 ml (30.5 mmol) of a 1.6M solution of n-butyllithium in hexane were added under argon. Then a solution of 2.35 g (13.7 mmol) of 5-chloro-6-fluoro-1H-indole in THF (9 ml) was added dropwise (temperature kept between -70 and -75° C.) over 15 min. After 5 additional min of stirring at this temperature a solution of 3.7 g of potassium tert-butylate in THF (15 ml) was added over period of 10 min (temperature kept between -70 and -75° C.). The resulting brown solution was then stirred for 2 hours at the same temperature and treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min and water (30 ml) was added to the reaction mixture. After separation of the organic layer, the aqueous layer was extracted with ether and treated with concentrated HCl to adjust the pH to 1. The resulting suspension was then filtered and the solid was washed with water and dried in high vacuo. The remaining residue was suspended in 10 ml of hexane/ether 9:1 and stirred for 15 min, filtered off, washed with 5 ml of the same solvent mixture and was dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75percent). MS: 212.2 (M-H)-
Reference: [1] Patent: US2007/185113, 2007, A1, . Location in patent: Page/Page column 16
  • 86
  • [ 4595-59-9 ]
  • [ 1066-54-2 ]
  • [ 216309-28-3 ]
YieldReaction ConditionsOperation in experiment
85% With copper(l) iodide; diisopropylamine In toluene at 60℃; for 3 h; Example 3 N-((1R,2R)-2-Hydroxy-cyclohexyl)-6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinamidea) 5-Trimethylsilanylethynyl-pyrimidine; Tetrakis(triphenylphosphine)palladium(O) (727 mg, 0.6 mmol) was added to a stirred, degassed suspension of 5-bromopyrimidine (5.0 g, 31.4 mmol) and copper(I)iodide (120 mg, 0.6 mmol) in toluene and diisopropylamine (1:1, 200 ml) under nitrogen. The reaction mixture was heated to 60° C., trimethylsilylacetylene (4.89 ml, 34.6 mmol) was added and the reaction mixture was stirred for 3 hours at 60° C.. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (200 ml) and washed with saturated aqueous ammonium chloride solution (3.x.100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (5percent ethyl acetate/heptane) to give 5-trimethylsilanylethynyl-pyrimidine as a pale brown solid, 4.71 g (85percent yield). LC at 215 nm; Rt 2.07: 88percent, m/z (ES+): 177 (M+H).
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  • [ 29289-13-2 ]
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  • [ 215589-37-0 ]
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[2] Chemistry - A European Journal, 2015, vol. 21, # 20, p. 7413 - 7416
  • 88
  • [ 873-75-6 ]
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
YieldReaction ConditionsOperation in experiment
66% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tri-tert-butyl phosphine In triethylamine at 130℃; for 4 h; Inert atmosphere; Microwave irradiation To a solution of (4-bromophenyl) methanol (935mg, 5mmol) in dry TEA was added Pd (PPh3) 2Cl2 (175mg, 0.25mmol) , CuI (48mg, 0.25mmol) and P (t-Bu) 3 (51mg, 0.25mmol) under N2 atmosphere. The reaction mixture was stirred for 5mins, followed by addition of ethynyltrimethylsilane (980mg, 10mmol) dropwise. The reaction mixture was then microwaved at 130 for 4hrs. The reaction mixture was cooled to room temperature, filtered over celite. Solvents were removed from the filtrate in vacuo, then the residue was extracted by EtOAc/H2O 3 times. The organic layer was combined, washed with brine, dried over Na2SO4 and further pufrified by silica gel column chromatography (PE/EA4/1) to give 670mg of (4- ( (trimethylsilyl) ethynyl) phenyl) methanol as a brown oil (66) .[0633]To a solution of (4- ( (trimethylsilyl) ethynyl) phenyl) methanol (250mg, 1.23mmol) in THF was added TBAF (500mg, 2.45mmol) in portions at 0. The reaction mixture was stirred at 0 to room temperature for 3hrs. Solvents were removed from the mixture in vacuo, and the residue was extracted by EtOAc/H2O 3 times. The organic layer was combined, washed with brine, dried over Na2SO4 and further pufrified by silica gel column chromatography (PE/EA4/1) to give 170mg of (4-ethynylphenyl) methanol as a brown oil (100) . 1H NMR (400Hz, CDCl3) δ7.45-7.49 (m, 2H) , 7.21-7.26 (m, 2H) , 4.69 (s, 1H) , 4.65 (s, 2H) .
1.274 g With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diethylamine; triphenylphosphine In N,N-dimethyl-formamideMicrowave irradiation; Heating; Inert atmosphere A solution of 4-Bromobenzyl alcohol (1.276 g, 6.82 mmol), Ethynyltrimethylsilane (1.061 ml, 7.51 mmol), PdCl2(PPh3)2 (24 mg, 0.034 mmol), Copper iodide (52 mg, 0.273 mmol), Triphenylphosphine (358 mg, 1.365 mmol), Diethylamine (10.70 ml, 102 mmol) in 2 ml of dry DMF (dimethylformamide) was heated under argon in a microwave oven at 150° C. for 30 min. The mixture was filtered. The filtrate was acidified with 1 M HCl and extracted 3 times with ether. The combined organic layers were washed with bicarbonate and water, dried over MgSO4 and concentrated to afford 3 (1.274 g, 6.23 mmol, 91percent yield) as a brown solid.
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[8] Patent: US9758545, 2017, B2, . Location in patent: Page/Page column 19; 20; 26
  • 89
  • [ 18282-51-4 ]
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
YieldReaction ConditionsOperation in experiment
100% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; A suspension of (4-iodophenyl)methanol (3.00 g, 13.64 mmol), ethynyltrimethylsilane (2.13 mL, 15.38 mmol), copper (_) iodide (122 mg, 0.64 mmol), bis(triphenylphosphine)palladium(II) dichloride (450 mg, 0.64 mmol), TEA (5.36 ml, 38.46 mmol) were stirred in THF (22 mL) at ambient temperature for overnight. The reaction solvent was evaporated under reduced pressure, and the residue was purified by column chromatography with hexane/ethyl acetate (20/1, v/v) to obtain the compound 53 (2.66 g, quant. yield): 1H NMR (400 MHz, CDCl3) _ 7.44 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.63 (s, 2H), 2.17 (bs, 1H), 0.25 (s, 9H); 13C NMR (100 MHz, CDCl3) _ 141.3, 132.2, 126.7, 122.4, 105.0, 94.3, 64.9, 0.1.
Reference: [1] Patent: WO2018/160967, 2018, A1, . Location in patent: Page/Page column 86
[2] Journal of the American Chemical Society, 2015, vol. 137, # 45, p. 14319 - 14328
  • 90
  • [ 873-75-6 ]
  • [ 109-89-7 ]
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
Reference: [1] Patent: US2013/266644, 2013, A1, . Location in patent: Page/Page column
  • 91
  • [ 1122-91-4 ]
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
Reference: [1] Patent: WO2008/31157, 2008, A1,
  • 92
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
Reference: [1] Patent: EP2610243, 2013, A2,
  • 93
  • [ 51934-41-9 ]
  • [ 1066-54-2 ]
  • [ 275386-60-2 ]
Reference: [1] Chirality, 2015, vol. 27, # 8, p. 454 - 458
  • 94
  • [ 61676-62-8 ]
  • [ 1066-54-2 ]
  • [ 159087-46-4 ]
YieldReaction ConditionsOperation in experiment
88% With C15H14N4; caesium carbonate; triphenylphosphine; silver(I) chloride In N,N-dimethyl-formamide at 50℃; for 24 h; Inert atmosphere; Schlenk technique General procedure: A mixture of 1 (0.5 mmol), B(OiPr)pin (0.75 mmol), PPh3+L1+AgCl (1 mol percent), and Cs2CO3 (1.1 mmol) in DMF (5 mL) was stirred at 50°C under Ar atmosphere for 24 h. The reaction mixture was acidified by 1 M solution of hydrochloric acid in an ice water bath, and the aqueous phase was extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding products.
65%
Stage #1: With n-butyllithium In diethyl ether; hexane at -30 - 0℃; for 1.5 h; Inert atmosphere
Stage #2: at -50℃; Inert atmosphere
Stage #3: With hydrogenchloride In diethyl ether at -50 - -10℃; for 1.5 h; Inert atmosphere
To a solution of trimethylsilyl acetylene (200 g, 2.04 mol, 1 equiv) in diethylether (4 L) at −30 °C under argon in a 10 L jacketed vessel was added nBuLi (1.8 mol in hexanes, 1.14 L, 2.04 mol, 1 equiv) by cautious dropwise addition (internal reaction temperature rose to ≤−21 °C) and the reaction mixture was allowed to stir at this temperature for 1 h prior to warming to 0 °C. After 30 min the reaction mixture was cooled to −50 °C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 g, 2.04 mol, 1 equiv) was added dropwise and the reaction mixture was stirred overnight. To the white precipitate was added ethereal 2 N HCl (1.33 L, 2.65 mol, 1.3 equiv) and the reaction was warmed to −10 °C and stirred for 1.5 h, filtered through Celite, concentrated in vacuo and allowed to recrystallise in the refrigerator, yielding   trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane 1a as a white crystalline solid (299 g, 65percent, obtained by four successive recrystallisations from the mother liquor). Mp 91–93 °C; 1H NMR (250 MHz, CDCl3) δ: 0.00 (9H, s), 1.09 (12H, s); 13C NMR (62 MHz, CDCl3) δ: −0.5, 24.6, 84.4, 111.3. All data in accordance with literature.21
51%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 2 h; Inert atmosphere
To a solution of compound 19 (3 g, 30.5 mmol, 1.0 eq) in ethyl ether (30 mL) was added a solution of n-BuLi (2.5 M in hexane, 12.8 mL, 1.05 eq) dropwise at -78 °C over a period of 5 min under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 h, then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.7 g, 30.5 mmol, 1.0 eq) in TH F (8 mL) was added dropwise. After stirring for 2 h at -78 °C, the mixture was poured into cooled sat. aq. NH4CI (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with saturated brine (3 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was dissolved in petroleum ether (30 mL) and cooled to -60 °C. The resulting precipitate was collected by filtration and dried under vacuum to afford compound 20 (3.5 g, .15.6 mmol, 51percent yield) as white solid: H N R (300 MHz, CDCI3) 60.21 (s, 9H) 1.30 (s, 12H).
Reference: [1] Tetrahedron, 2014, vol. 70, # 35, p. 5815 - 5819
[2] Tetrahedron, 2013, vol. 69, # 5, p. 1546 - 1552
[3] Patent: WO2016/97870, 2016, A1, . Location in patent: Page/Page column 0174
[4] Patent: WO2013/52394, 2013, A1, . Location in patent: Paragraph 00253
[5] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11637 - 11645
[6] Patent: WO2015/104653, 2015, A1, . Location in patent: Page/Page column 52
[7] Patent: US2016/368906, 2016, A1, . Location in patent: Paragraph 0213
  • 95
  • [ 25015-63-8 ]
  • [ 1066-54-2 ]
  • [ 159087-46-4 ]
Reference: [1] Chemical Science, 2016, vol. 8, # 1, p. 165 - 168
[2] Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3560 - 3566
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 19, p. 3649 - 3654
[4] Chemical Science, 2015, vol. 6, # 11, p. 6572 - 6582
  • 96
  • [ 25015-63-8 ]
  • [ 1066-54-2 ]
  • [ 159087-46-4 ]
Reference: [1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 19, p. 3649 - 3654
  • 97
  • [ 1066-54-2 ]
  • [ 159087-46-4 ]
Reference: [1] Chemical Science, 2015, vol. 6, # 11, p. 6572 - 6582
  • 98
  • [ 36809-26-4 ]
  • [ 1066-54-2 ]
  • [ 205877-26-5 ]
Reference: [1] Advanced Functional Materials, 2014, vol. 24, # 46, p. 7257 - 7271
[2] European Journal of Organic Chemistry, 2009, # 32, p. 5587 - 5593
[3] Journal of Materials Chemistry, 2012, vol. 22, # 33, p. 16781 - 16790
  • 99
  • [ 38257-52-2 ]
  • [ 1066-54-2 ]
  • [ 205877-26-5 ]
Reference: [1] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 370, p. 207 - 210
[2] Dyes and Pigments, 2017, vol. 140, p. 203 - 211
  • 100
  • [ 1066-54-2 ]
  • [ 183677-71-6 ]
  • [ 183677-72-7 ]
  • [ 630127-51-4 ]
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 14, p. 2331 - 2335
  • 101
  • [ 5122-99-6 ]
  • [ 1066-54-2 ]
  • [ 630127-51-4 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 27, p. 8465 - 8469
  • 102
  • [ 924892-34-2 ]
  • [ 1066-54-2 ]
  • [ 910467-59-3 ]
Reference: [1] Beilstein Journal of Organic Chemistry, 2009, vol. 5,
  • 103
  • [ 157942-12-6 ]
  • [ 1066-54-2 ]
  • [ 478169-68-5 ]
YieldReaction ConditionsOperation in experiment
91% With copper(l) iodide; triethylamine In tetrahydrofuran at 50℃; for 4 h; Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. Triethylamine (8.14 mL, 58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2.x.40 mL), dried (MgSO4) and concentrated to a brown oily-solid (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0947 (M+H)+.
91% With triethanolamine; copper(I) iodide In tetrahydrofuran; hexane; chloroform; ethyl acetate Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h.
The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2*40 mL), dried over anhydrous MgSO4 and concentrated to a brown paste (8.31 g).
The crude material is chromatographed over a standard 90 g Biotage column, eluding with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L).
The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H1: 249.0947, found 249.0947.
91% With triethanolamine; copper(I) iodide In tetrahydrofuran; hexane; chloroform; ethyl acetate Methyl-3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h.
The mixture is diluted with CHCl3 (60 mL), washed with 5percent HCl (2*40 mL), dried over MgSO4 and concentrated to a brown oily-solid (8.31 g).
The crude material is chromatographed over a standard 90 g Biotage column, eluding with 10percent EtOAc/hexane (1 L) followed by 15percent EtOAc/hexane (1 L).
The appropriate fractions are combined and concentrated to afford 4.22 g (91percent) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3Si+H: 249.0947, found 249.0947 (M+H)+.
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4425 - 4436
[2] Patent: US2003/232853, 2003, A1, . Location in patent: Page 38
[3] Patent: US2003/73707, 2003, A1,
[4] Patent: US2003/105089, 2003, A1,
  • 104
  • [ 307503-19-1 ]
  • [ 1066-54-2 ]
  • [ 943320-53-4 ]
YieldReaction ConditionsOperation in experiment
72% With copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; triethylamine In acetonitrile for 3 h; Inert atmosphere; Reflux In a 500 mL three-necked flask,Under nitrogen protection conditions,3-iodoimidazo [1,2-a] pyridine (10.0 g, 41.0 mmol)PdCl2 (pph3) 2 (0.6 g, 0.8 mmol),CuI (0.2 g, 0.8 mmol) was successively added to anhydrous acetonitrile (200 mL)Then Et3N (12.4 g, 122.9 mmol)And trimethylsilylacetylene (12.1 g, 122.9 mmol)Reflux reaction 3h. Reaction is completed, suction filter,The filtrate was evaporated under reduced pressure,The residue was dissolved in methanol (150 mL)Anhydrous potassium carbonate (22.7 g, 163.9 mmol) was added at room temperature for 30 min,Filter, the filtrate vacuum distillation solvent was crude,The crude product was subjected to silica gel column (mobile phase: PE: EA = 20: 1) to give 4.2 g of 3-acetimidazo [1,2-a] pyridine as a white solid in 72percent yield.
Reference: [1] Patent: CN107163042, 2017, A, . Location in patent: Paragraph 0023; 0024; 0025; 0034; 0035; 0036; 0045; 0046
  • 105
  • [ 4926-47-0 ]
  • [ 1066-54-2 ]
  • [ 943320-53-4 ]
Reference: [1] Patent: WO2013/162727, 2013, A1, . Location in patent: Page/Page column 59
[2] Patent: WO2014/145022, 2014, A1, . Location in patent: Page/Page column 49
  • 106
  • [ 24241-18-7 ]
  • [ 1066-54-2 ]
  • [ 875781-41-2 ]
YieldReaction ConditionsOperation in experiment
94% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at -5 - 0℃; for 1.5 h; Inert atmosphere To a solution of 3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (24 mL)were added triethylamine (3.3 mL, 24 mmol), cuprous iodide (151 mg, 0.79 mmol) andPd(PPh3hCh (561 mg, 0.79 mmol). The mixture was cooled to -5 oc under nitrogen protection,then trimethylsilylacetylene (1.07 mL, 7.50 mmol) was dropwised slowly into the mixture. Afterthe addition, the mixture was warmed to 0 oc and stirred for 1.5 h. The mixture was concentratedin vacuo to remove the solvent and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 511) to give the title compound as black oil (42 mg, 94 percent).MS (ESI, pos. ion) m/z: 272.00 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 8.04 (s, lH), 5.14 (s, 2H), 0.30 (s, 9H).
84.4% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 1.16667 h; Inert atmosphere; Cooling with ice Ice bath,3,5-dibromopyrazine-2-amine (16.30 g, 64.50 mmol), cuprous iodide (2.45 g, 12.90 mmol)Tetraphenylphenylphosphine palladium (3.70 g, 3.20 mmol)And N, N-dimethylformamide (80 mL) was placed in a single-necked flask,Under N2, triethylamine (44.8 mL, 321 mmol) was added,Trimethylsilylacetylene (8.7 mL, 61.3 mmol) was slowly added dropwise over 10 min,After the dropwise addition, the mixture was stirred at room temperature for 1 h. Filtered, washed with dichloromethane (100 mL) and the filtrate was concentrated, The concentrate was subjected to column chromatography (eluent: PE / EtOAc (v / v) = 20/1) to give 14.70 g of a white solid, yield:84.4percent.
75% With triethylamine In N,N-dimethyl-formamide at 20℃; Step 1 : 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(Trimethylsilyl)acetylene (1.845 g, 2.655 niL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (5 g, 19.77 mmol), triethylamine (10.00 g, 13.77 mL, 98.85 mmol), Copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4(1.142 g, 0.9885 mmol) in DMF (25.00 mL) and the resulting solution stirred at ambient temperature for 30 minutes. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organics washed with water, dried (MgSO4) and concentrated in vacuo. The mixture was purified on silica gel by flash column chromatography (0-15percent EtO Ac/Petrol) to afford the product as a yellow solid (3.99g, 75percent Yield). IH NMR (400.0 MHz, DMSO) d 0.30 (s, 9H), 8.06 (s, IH) ppm; MS (ES+) 271.82
75% With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; [00195] Step 1 : (Trimethylsilyl)acetylene (1.9 g, 2.7 niL, 18.8 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (5.0 g, 19.8 mmol), triethylamine (10.0 g, 13.8 mL, 98.9 mmol), copper (I) iodide (452 mg, 2.37 mmol) and Pd(PPh3)4 (1.14 g, 0.99 mmol) in DMF (25 mL) and the resulting solution stirred at room temperature for 30 min. The reaction was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted further with ethyl acetate and the combined organics washed with water, dried over MgS04, and concentrated in vacuo. The mixture was purified via silica gelchromatography (0-15percent ethyl acetate/hexanes) to afford 5-bromo-3-((trimethylsilyl) ethynyl)pyrazin-2-amine as a yellow solid (3.99g, 75percent yield). 3/4 NMR (400 MHz, DMSO- d6) δ 0.30 (s, 9H), 8.06 (s, 1H); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL)Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). XH NMR (400.0 MHz, DMSO) ? 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; [00178] (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL)Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). IH NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (compound i) (5 g, 19.77 mmol) in DMF (25 mL). Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtOAc/Petroleum ether to give the product as a yellow solid (3.99 g, 75percent Yield). 1H NMR (400.0 MHz, DMSO) ? 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82.
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; 5-Bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine 2 [00178] (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL) Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). 1H NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
71% With triethylamine In N,N-dimethyl-formamide at 120℃; for 0.5 h; Step 1: Synthesis of 5-Bromo-3-trimethylsilanylethynyl-pyrazm-2-yIamine.[0282] To a solution of 3,5-Dibromo-pyrazin-2-ylamine (3.00 g, 11.86 mmol) in DMF(35 ml) was added triethylamine (16 ml), then tetraldstriphenylphine palladium (0) (685 mg,0.59 mmol) and copper(i) iodide (271 mg, 1.42 mmol) were added sequentially. Finallytrimethylsilylacetylene (2.0 ml, 14.3 mmol) was added dropwise. The reaction mixture wasstirred at 120 °C for 30 minutes and then directly adsorbed onto silica gel. Purification byflash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the titlecompound (2.30g, 71percent yield) as yellow oil. MS: m/z 270.0/272.0 [MH+].
70% With copper(l) iodide; triethylamine In tetrahydrofuran at 0 - 10℃; for 7 h; To a solution of 3,5-dibromopyrazin-2-amine (40.0 g, 158 mmol), TEA (66.1 mL, 475 mmol), and copper(I) iodide (0.301 g, 1.58 mmol) in THF (1172 ml) was added PdCl2(PPh3)2 (1.11 g, 1.58 mmol). The reaction mixture was cooled at about 0° C. and a solution of (trimethylsilyl)acetylene (20.8 mL, 150 mmol) in THF (146 mL) was added drop-wise. The reaction mixture was stirred at about 0-10° C. for about 7 h and then concentrated under reduced pressure. The dark brown residue was dissolved in DCM (600 mL) and filtered through a Celite.(R). pad (3 cm in height.x.9 cm in diameter) while eluting with DCM (300 mL). The filtrate was washed with water (2.x.500 mL) and brine (500 mL), dried over anhydrous MgSO4, filtered through a Florisil.(R). pad (1 cm in height by 9 cm in diameter) while washing with DCM/MeOH (9:1, 200 mL), and concentrated under reduced pressure to give a brown solid. The solid was triturated and sonicated with warm petroleum ether (b.p. 30-60° C., 250 mL), cooled and collected, washing with petroleum ether (b.p. 30-60° C.; 2.x.100 mL), and dried in a vacuum oven at about 70° C. to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (34.6 g, 70percent): LC/MS (Table 2, Method d) Rt=1.59 min; MS m/z: 272 (M+H)+.
47% With copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 1200C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). 1H NMR (CDCl3, 300 MHz): δ 8.04 (s, IH), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H) +, calc. 269.
47% With copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere Preparation of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (Intermediate AQ) [0313] To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)- palladium(O) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120°C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). 1H NMR (CDC13, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H) +, calc. 269.
47% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere Making reference to Scheme 5, to a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120°C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). XH NMR (CDC13, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H)+, calc. 269
17% With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 120℃; for 0.5 h; To a solution of intermediate I-82 (10 g, 40 mmol, 1.0 eq) in DMF (115 mL) was added neat triethylamine (53 mL), Pd(PPh3)4 (2.3 g, 2.0 mmol, 0.05 eq) and CuI (0.90 g, 4.7 mmol, 0.12 eq) followed by drop wise addition of ethynyltrimethylsilane (6.7 mL, 48 mmol, 1.2 eq) and the reaction mixture was stirred for 30 minutes at 120° C. The crude reaction mixture was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate I-83 (3.0 g, 17percent) as yellow oil. MS (ESI): m/z 271 (M+H+).
20 g With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In acetonitrile at 0 - 20℃; for 1.75 h; Inert atmosphere Step 1 A 500 ml three necked round bottom flask was charged with 3,5-dibromopyrazine-2- amine (25.0 g, 0.0988 mole) which was dissolved in acetonitrile (250 ml). The reaction mixture was cooled to 0 ° C and triethylamine (50.0 g, 0.4941 mole), copper (1) iodide (2.26 g, 0.0119 mole), and Pd (PPh3)4 (5.7 g, 0.0049 mole) were added under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0 °C followed by slow addition of trimethylsilylacetylene (10.7g, 0.1089 mole) over 15 min at the same temperature. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 90 min. The reaction mixture was diluted by ethyl acetate and filtered. The filtrate was collected and washed with water. Layers were separated and aqueous layer was re-extracted by ethyl acetate. Combined organic layer was dried over Na2S04, filtered and concentrated to afford crude product which was purified using column purification to afford 20.0 g of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine.

Reference: [1] Patent: WO2018/108125, 2018, A1, . Location in patent: Paragraph 00586
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[4] Patent: CN106432246, 2017, A, . Location in patent: Paragraph 0540; 0541; 0542
[5] Patent: WO2010/54398, 2010, A1, . Location in patent: Page/Page column 150-151
[6] Patent: WO2011/143426, 2011, A1, . Location in patent: Page/Page column 69
[7] Patent: WO2013/49722, 2013, A1, . Location in patent: Paragraph 00209
[8] Patent: WO2013/49720, 2013, A1, . Location in patent: Paragraph 00178
[9] Patent: WO2013/49726, 2013, A2, . Location in patent: Paragraph 00162
[10] Patent: WO2013/49719, 2013, A1, . Location in patent: Paragraph 00178
[11] Patent: US2014/107093, 2014, A1, . Location in patent: Page/Page column
[12] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 102
[13] Patent: US2009/312338, 2009, A1, . Location in patent: Page/Page column 61
[14] Patent: WO2010/68483, 2010, A2, . Location in patent: Page/Page column 66-67
[15] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 65-66
[16] Patent: WO2014/85795, 2014, A1, . Location in patent: Paragraph 0280
[17] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 114
[18] Patent: WO2012/158785, 2012, A1, . Location in patent: Page/Page column 89-90
[19] Patent: WO2014/81732, 2014, A1, . Location in patent: Page/Page column 31-32
[20] Patent: US2015/118229, 2015, A1, . Location in patent: Paragraph 0183
[21] Patent: WO2015/162459, 2015, A1, . Location in patent: Page/Page column 327; 328
[22] Drugs of the Future, 2018, vol. 43, # 10, p. 731 - 743
  • 107
  • [ 289039-83-4 ]
  • [ 1066-54-2 ]
  • [ 860624-89-1 ]
Reference: [1] Patent: WO2016/87975, 2016, A1, . Location in patent: Page/Page column 26 27
  • 108
  • [ 1066-54-2 ]
  • [ 52727-57-8 ]
  • [ 860624-90-4 ]
YieldReaction ConditionsOperation in experiment
11.3%
Stage #1: at 20℃; for 17 h; Inert atmosphere
Stage #2: at 20℃; for 1.5 h; Inert atmosphere
463.5 mg of methyl 5-bromoanthranilate was placed in an argon atmosphere and dissolved in 2 mL of acetic acid. 499.5 mg of N-iodosuccinimide was added thereto, and the mixture was stirred at room temperature for 17 hours. The reaction solution was added dropwise to a saturated aqueous sodium hydrogen carbonate solution (5 mL) to neutralize acetic acid. This was extracted with ethyl acetate, and the ethyl acetate phase obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure.The obtained material was placed in an argon atmosphere and dissolved in 6.6 mL of triethylamine. 74.2 mg of bis (triphenylphosphine) palladium (II) dichloride, 22.3 mg of copper (I) iodide and 0.34 mL of trimethylsilylacetylene were added thereto, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was diluted with dichloromethane, washed sequentially with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The obtained substance dissolved in 9 mL of N-methyl-2-pyrrolidone was added dropwise to a mother liquor in which 512.3 mg of potassium tert-butoxide was changed to 0 ° C. under an argon atmosphere and 7 mL of N-methyl-2-pyrrolidone was added , Stirred for 1 hour, and then stirred at room temperature for 90 minutes. The reaction solution was again brought to 0 ° C., 32 mL of water was added, and the temperature was returned to room temperature. The diethyl ether phase extracted with diethyl ether was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, And the solvent was distilled off. The residue was dissolved in methanol, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using 10percent ethyl acetate / hexane as a developing solvent, and the solvent was distilled off .62.5 mg of the obtained substance was placed under an argon atmosphere, 2 N sodium hydroxide 2.4 mL and 2.4 mL ethanol were added and the temperature was adjusted to 40 ° C. and stirred for 2 hours. The reaction solution was brought to room temperature, the pH was made acidic using 3 N hydrochloric acid, sodium chloride was added until saturation, and the ethyl acetate phase eluted with ethyl acetate was dried with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was suspended in diethyl ether, the brown solids in the insoluble matter was removed, and the remaining insoluble matter was washed with warm hexane. The solvent was distilled off, dissolved in ethyl acetate, activated charcoal was added to adsorb impurities, and the activated carbon was removed by filtration. The residue obtained by distilling off the solvent was dissolved in diethyl ether, the insoluble matter was removed by filtration, and the solvent was distilled off. As a result, 54.2 mg (yield 11.3percent) of a compound was obtained.
Reference: [1] Patent: JP2018/52865, 2018, A, . Location in patent: Paragraph 0039
  • 109
  • [ 59142-68-6 ]
  • [ 1066-54-2 ]
  • [ 749874-24-6 ]
Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6299 - 6302
[2] Chemical Communications, 2017, vol. 53, # 12, p. 2036 - 2039
  • 110
  • [ 13472-79-2 ]
  • [ 1066-54-2 ]
  • [ 1064706-78-0 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 36, p. 8522 - 8529
  • 111
  • [ 84249-14-9 ]
  • [ 1066-54-2 ]
  • [ 1094679-27-2 ]
YieldReaction ConditionsOperation in experiment
33% With bis(benzonitrile)palladium(II) dichloride; caesium carbonate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl-formamide at 50℃; for 2 h; Compound 2 (400 mg, 2.31 mmol), trimethylsilylacetylene (0.38 ml, 2.77 mmol), cesium carbonate (39.1 mg, 0.12 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene (69.4 mg , 0.12 mmol) and was dissolved bis (benzonitrile) palladium (II) dichloride (46.0 mg, a 0.12 mmol) in DMF (5 ml). Further added triethylamine (2 ml) to this was stirred for 2 hours at 50 in an oil bath. After completion of the reaction, THF and (3 ml) and tetrabutylammonium fluoride (2.77 ml) was added and the solvent was concentrated under reduced pressure, and allowed to react for 30 minutes at room temperature. The solvent was evaporated, adsorbed resulting residue was applied to a silica gel column,Methanol - was eluted with a mixed solvent of chloroform (1:50) to give Compound 5a (90.1 mg, 33percent).
Reference: [1] Patent: JP2015/221769, 2015, A, . Location in patent: Paragraph 0031; 0033
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[ 1066-54-2 ]

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Chemical Structure| 14630-40-1

[ 14630-40-1 ]

Bis(trimethylsilyl)acetylene

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