* 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.
Reference:
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 12, p. 1239 - 1241
2
[ 50889-29-7 ]
[ 25775-90-0 ]
Reference:
[1] Journal of Organic Chemistry, 1989, vol. 54, p. 3477 - 3478
3
[ 4224-70-8 ]
[ 603-35-0 ]
[ 50889-29-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
for 48 h; Heating / reflux
A solution of6-bromohexanoic acid (10.00 g, 51.27 mmol) and triphenyl phosphine (14.12 g, 53.83 mmol) in freshly distilled acetonitrile (50 mL) was vigorously stirred and refluxed for 48 hours. The solution was allowed to come to ambient temperature and the Wittig salt was precipitated upon scratching the inside wall of the glass reaction vessel with a spatula. The white solid product was collected, washed with ether and filtered to provide the title compound in 98percent yield (22.87 g): 1H NMR (400 MHz1 CD3OD) δ 1.62-1.72 (m, 6H), 2.29 (t, 2H), 3.40-3.47 (m, 2H), 7.76-7.91 (m, 15H)
97.5%
for 72 h; Reflux
Triphenylphosphine (20 mg, 0.076 mmol) and 6-bromohexanoic acid (14.8 mg, 0.076 mmol) were dissolved in dry toluene (0.2 mL). The reaction mixture was refluxed over 72 hours. The solution was concentrated. The residue was washed consecutively with benzene (3 x 1 mL), hexane (1 mL), and Et20 (2 x 1 mL). The crystalline white solid was dried to give the pure product (28 mg, 97.5 percent). 1H NMR (300 MHz, CDC13) δ 7.80-7.68 (m, 15H), 3.58 (bs, 2H), 2.34-2.32 (m,2H), 1.63-1.57 (m, 6H). EI-MS (m z): Calcd for C24H2602P+ 377.16; found 377.1
95%
for 20 h; Heating / reflux
A solution of 6-bromohexanoic acid (3.9 g, 20.0 mmol, 1 equiv) in anhydrous acetonitrile (16 mL) was treated with triphenylphosphine (6.3 g, 24.0 mmol, 1.2 equiv) and warmed at reflux for 20 h. The reaction mixture was concentrated and the crude product was purified by column chromatography (SiO2, 5.5 x 8 cm, 50-100percent EtOAc-hexanes gradient and then 5percent MeOH-CH2Cl2) to afford Sl (8.7 g, 19.0 mmol, 95percent) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.78-7.67 (m, 15H), 3.58 (m, 2H), 2.33 (m, 2H), 1.63 (m, 4H).
94%
for 48 h; Inert atmosphere; Reflux
General procedure: A mixture of ω-bromocarboxylic acid (1 equiv) and triphenylphosphine (1 equiv) in 300 mL of toluene was refluxed for 48 h under argon. The mixture was allowed to cool at room temperature and concentrated in vacuum. The residue was crystallized from various solvents to give the corresponding phosphonium salt.
91%
for 24 h; Reflux
Example 1 Synthesis of TPP-(CH2)5-COOH A mixture of 6-bromohexanoic acid (2.0 g, 10.3 mmol) and TPP (2.8 g, 10.8 mmol) was heated to reflux for 24 h in acetonitrile. The solvent was evaporated to dryness. The resulting residue was washed with hexane-diethyl ether (3*30 mL) followed by vacuum drying to afford a white solid as a pure product. Yield: 91percent (4 g). Melting point: 200-205° C.; 1H NMR (CDCl3): δ 9.3 (s, 1H), 7.6-7.8 (m, 15H), 3.5 (t, 2H), 2.3 (t, 2H), 1.6 (m, 6H). 13C NMR (CDCl3): δ 175, 135, 133.6, 130.6, 118.5, 34.2, 29.37, 23.9, 22.8, 22.29, 21.9. 31P NMR (CDCl3) 24.34. ppm. HRMS-ESI (m/z): [M-Br]+ calcd. for C24H26O2P+, 377.1665. found, 377.1629.
65%
for 24 h; Inert atmosphere; Reflux
Bromohexanoic acid (0.600 g, 3.076 mmol) and triphenylphosphine (0.968 g 3.691 mmol) were dissolved in 40 mL of acetonitrile.This reaction was refluxed for 24 h under a N2 environment. After 24 h, the solvent was evaporated to yield an oil, which was then precipitated with diethyl ether. The precipitate was filtered through a glass frit filter, and washed several times with diethyl ether to remove any impurities from the starting materials. The product was kept on vacuum for 1 h. Yield 0.760 g 65percent. 1H NMR (CDCl3, 400 MHz): δ 7.78 [m, 15H], 3.56 [m, 2H], 2.44 [m, 2H], 1.68 [m, 6H] ppm.
55%
for 20 - 24 h; Heating / reflux
A solution of 6-Bromohexanoic acid (3g, 0.0512 moles) and triphenylphosphine 4.8g, 0.018 moles) in dry acetonitrile (5OmL) was refluxed for 20-24 h and excess solvent was removed under reduced pressure to afford a color less oil which was triturated with dry benzene and wash in succession with dry benzene and ether (3 times each). During the washing procedure the material crystallized drying at reduced pressure afford Wittig salt as a white micro- crystalline powder (3.6g, 55percent yield).
55%
Reflux
A solution of 6-Bromohexanoic acid (3 g, 0.0512 moles) and triphenylphosphine 4.8 g, 0.018 moles) in dry acetonitrile (50 mL) was refluxed for 20-24 h and excess solvent was removed under reduced pressure to afford a color less oil which was triturated with dry benzene and wash in succession with dry benzene and ether (3 times each). During the washing procedure the material crystallized drying at reduced pressure afford Wittig salt as a white micro-crystalline powder (3.6 g, 55percent yield).
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[2] Analytical Chemistry, 2006, vol. 78, # 1, p. 71 - 81
[3] Journal of Organic Chemistry, 2004, vol. 69, # 14, p. 4615 - 4625
[4] Journal of Natural Products, 2001, vol. 64, # 11, p. 1426 - 1429
[5] Patent: WO2008/30532, 2008, A2, . Location in patent: Page/Page column 41
[6] Patent: WO2017/78623, 2017, A1, . Location in patent: Paragraph 0068
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 20, p. 2683 - 2687
[8] Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368
[9] Patent: WO2008/150492, 2008, A1, . Location in patent: Page/Page column 41
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[11] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 567 - 579
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4
[ 1191-25-9 ]
[ 50889-29-7 ]
Reference:
[1] Tetrahedron Asymmetry, 1998, vol. 9, # 8, p. 1345 - 1350
[2] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1342 - 1346
[3] Patent: CN106632474, 2017, A,
5
[ 502-44-3 ]
[ 6399-81-1 ]
[ 50889-29-7 ]
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 4, p. 685 - 696
6
[ 60633-18-3 ]
[ 50889-29-7 ]
Reference:
[1] Journal of Organic Chemistry, 1980, vol. 45, # 11, p. 2240 - 2243
7
[ 502-44-3 ]
[ 50889-29-7 ]
Reference:
[1] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1342 - 1346
A solution of6-bromohexanoic acid (10.00 g, 51.27 mmol) and triphenyl phosphine (14.12 g, 53.83 mmol) in freshly distilled acetonitrile (50 mL) was vigorously stirred and refluxed for 48 hours. The solution was allowed to come to ambient temperature and the Wittig salt was precipitated upon scratching the inside wall of the glass reaction vessel with a spatula. The white solid product was collected, washed with ether and filtered to provide the title compound in 98% yield (22.87 g): 1H NMR (400 MHz1 CD3OD) delta 1.62-1.72 (m, 6H), 2.29 (t, 2H), 3.40-3.47 (m, 2H), 7.76-7.91 (m, 15H)
97.5%
In toluene; for 72h;Reflux;
Triphenylphosphine (20 mg, 0.076 mmol) and 6-bromohexanoic acid (14.8 mg, 0.076 mmol) were dissolved in dry toluene (0.2 mL). The reaction mixture was refluxed over 72 hours. The solution was concentrated. The residue was washed consecutively with benzene (3 x 1 mL), hexane (1 mL), and Et20 (2 x 1 mL). The crystalline white solid was dried to give the pure product (28 mg, 97.5 %). 1H NMR (300 MHz, CDC13) delta 7.80-7.68 (m, 15H), 3.58 (bs, 2H), 2.34-2.32 (m,2H), 1.63-1.57 (m, 6H). EI-MS (m z): Calcd for C24H2602P+ 377.16; found 377.1
95%
In acetonitrile; for 20h;Heating / reflux;
A solution of 6-bromohexanoic acid (3.9 g, 20.0 mmol, 1 equiv) in anhydrous acetonitrile (16 mL) was treated with triphenylphosphine (6.3 g, 24.0 mmol, 1.2 equiv) and warmed at reflux for 20 h. The reaction mixture was concentrated and the crude product was purified by column chromatography (SiO2, 5.5 x 8 cm, 50-100% EtOAc-hexanes gradient and then 5% MeOH-CH2Cl2) to afford Sl (8.7 g, 19.0 mmol, 95%) as a white solid: 1H NMR (CDCl3, 400 MHz) delta 7.78-7.67 (m, 15H), 3.58 (m, 2H), 2.33 (m, 2H), 1.63 (m, 4H).
94%
In toluene; for 48h;Inert atmosphere; Reflux;
General procedure: A mixture of omega-bromocarboxylic acid (1 equiv) and triphenylphosphine (1 equiv) in 300 mL of toluene was refluxed for 48 h under argon. The mixture was allowed to cool at room temperature and concentrated in vacuum. The residue was crystallized from various solvents to give the corresponding phosphonium salt.
92%
In acetonitrile; for 48h;Inert atmosphere; Reflux;
General procedure: Triphenylphosphine (11.5 mmol) was added in a solution of bromoalkyl carboxylic acid (12mmol) in dry acetonitrile (20 mL) and the mixture was stirred at reflux under argon for 48 h. After cooling, the solvent was evaporated and the product precipitated out upon addition of ethyl acetate(or diethyl ether). Filtration and washing with the same solvent furnished pure products [38]. (5-Carboxypentyl)triphenylphosphonium bromide (2a). White powder (4.83 g, 92%). 1H NMR (200MHz, CDCl3) delta: 8.46 (bs, 1H, COOH), 7.91-7.57 (m, 15H, ArEta), 3.73-3.56 (m, 2H, CH2P), 2.41-2.33 (m,2H, CH2COOH), 1.67-1.55 (m, 6H, CH2). 13C NMR (50 MHz, CDCl3) delta: 176.09, 135.21 (d, J = 2.8 Hz,PPh3 para), 133.66 (d, J = 10.0 Hz, PPh3 ortho), 130.65 (d, J = 12.5 Hz, PPh3 meta), 118.11 (d, J = 86.0 Hz,PPh3 ipso), 34.25, 29.58 (d, J = 16.2 Hz, CH2CH2CH2P), 24.06, 22.56 (d, J = 51.0 Hz, CH2P), 21.99 (d, J =4.1 Hz, CH2CH2P). 31P NMR (81 MHz, CDCl3) delta: 25.23. ES-MS m/z for C24H26O2P [M]+: calcd. 377.2,found 377.2.
91%
In acetonitrile; for 24h;Reflux;
Example 1 Synthesis of TPP-(CH2)5-COOH A mixture of 6-bromohexanoic acid (2.0 g, 10.3 mmol) and TPP (2.8 g, 10.8 mmol) was heated to reflux for 24 h in acetonitrile. The solvent was evaporated to dryness. The resulting residue was washed with hexane-diethyl ether (3*30 mL) followed by vacuum drying to afford a white solid as a pure product. Yield: 91% (4 g). Melting point: 200-205 C.; 1H NMR (CDCl3): delta 9.3 (s, 1H), 7.6-7.8 (m, 15H), 3.5 (t, 2H), 2.3 (t, 2H), 1.6 (m, 6H). 13C NMR (CDCl3): delta 175, 135, 133.6, 130.6, 118.5, 34.2, 29.37, 23.9, 22.8, 22.29, 21.9. 31P NMR (CDCl3) 24.34. ppm. HRMS-ESI (m/z): [M-Br]+ calcd. for C24H26O2P+, 377.1665. found, 377.1629.
78%
In acetonitrile; for 16h;Inert atmosphere; Reflux;
Weigh 2.62g of triphenylphosphine (TPP, 10mmol) and 2.07g of 6-bromohexanoic acid (10.5mmol), dissolve in anhydrous acetonitrile, and then reflux for 16h under nitrogen protection and stirring, and determine the reflux by TLC detection The end of the reaction,Then, the reaction liquid obtained by the reflux reaction is placed in a rotary evaporator to spin-dry the solvent,The obtained solid was ground into a powder with a mortar,After washing with n-hexane for 2 to 3 times, it was filtered with suction to obtain 2.94g of white solid, namely intermediate 1.After calculation, the yield of intermediate 1 is 78%;
65%
In acetonitrile; for 24h;Inert atmosphere; Reflux;
Bromohexanoic acid (0.600 g, 3.076 mmol) and triphenylphosphine (0.968 g 3.691 mmol) were dissolved in 40 mL of acetonitrile.This reaction was refluxed for 24 h under a N2 environment. After 24 h, the solvent was evaporated to yield an oil, which was then precipitated with diethyl ether. The precipitate was filtered through a glass frit filter, and washed several times with diethyl ether to remove any impurities from the starting materials. The product was kept on vacuum for 1 h. Yield 0.760 g 65%. 1H NMR (CDCl3, 400 MHz): delta 7.78 [m, 15H], 3.56 [m, 2H], 2.44 [m, 2H], 1.68 [m, 6H] ppm.
55%
In acetonitrile; for 20 - 24h;Heating / reflux;
A solution of 6-Bromohexanoic acid (3g, 0.0512 moles) and triphenylphosphine 4.8g, 0.018 moles) in dry acetonitrile (5OmL) was refluxed for 20-24 h and excess solvent was removed under reduced pressure to afford a color less oil which was triturated with dry benzene and wash in succession with dry benzene and ether (3 times each). During the washing procedure the material crystallized drying at reduced pressure afford Wittig salt as a white micro- crystalline powder (3.6g, 55% yield).
55%
In acetonitrile;Reflux;
A solution of 6-Bromohexanoic acid (3 g, 0.0512 moles) and triphenylphosphine 4.8 g, 0.018 moles) in dry acetonitrile (50 mL) was refluxed for 20-24 h and excess solvent was removed under reduced pressure to afford a color less oil which was triturated with dry benzene and wash in succession with dry benzene and ether (3 times each). During the washing procedure the material crystallized drying at reduced pressure afford Wittig salt as a white micro-crystalline powder (3.6 g, 55% yield).
In toluene; for 3h;Reflux;
The present embodiment provides a process for the preparation of 6-brominated triphenylphosphonium orthohexanoic acid, which comprises the steps of: Hydrolysis reaction: 500ml bottle into the 220g caprolactam, 140g sodium hydroxide, heated to reflux reaction for 5 hours, the reaction completed, add 230 water diluted to get the hydrolyzate To the 1000ml bottle, add 353g hydrolyzate, drop 230g 30% industrial hydrochloric acid to adjust the pH to 4, pour out. Diazotization reaction: in 1000ml bottle by adding 150g water, 100g sodium nitrite, stirring dissolved, down to -5 C, at -5 C ~ 0 C dropping good pH hydrolyzate, 35min drop finished , Add drop at -5 C ~ 0 C for 5 hours, then add 42g 30% of industrial hydrochloric acid, heated to reflux 13min to starch potassium iodide test paper unchanged blue, pH = 1, down to 25 C, transferred to Separate the funnel, divide the water layer below, and separate the upper reservoir. Bromination reaction: Add 200 g of the upper layer to the 1000 ml bottle, 500 g of 48% hydrobromic acid, start stirring, add 94 g of concentrated sulfuric acid, raise the temperature to 70 C for 3.5 hours, drop to 45 , transfer to the separatory funnel, Out of the upper oil about 360g (by 50% content into the next step reaction). The lower layer of acid water was added to a 30% solution with a pH of 7% (96% of caustic soda). 4, 6-brominated triphenylphosphonium n-hexanoic acid synthesis: 1000ml bottle by adding 180g of the previous bromine oil, 370g toluene, 136g triphenyl phosphorus, temperature reflux reaction 3 hours, cooling and crude crude. efined: by the crude: methanol (m: m) = 1: 0.6 all dissolved, then add 5 times the crude amount of ethyl acetate, stir, add 13% times the crude activated carbon, filter, the filtrate plus 6 times In the crude amount of ethyl acetate will be finished all the finished product, filtered and dried finished product, the mother liquor washed away after the methanol off the water recovery of ethyl acetate.
In acetonitrile; for 16h;Inert atmosphere;
Triphenylphosphine (TPP) and 6-bromohexanoic acid were fed at a molar ratio of 1: 1.05, dissolved in anhydrous acetonitrile, reacted under nitrogen for 16h, and recrystallized to give TPP-COOH.
In acetonitrile; for 15h;Reflux;
General procedure: To a round-bottom flask was added 5a (5.0?mmol), P(Ph)3 (20.0?mmol) and dry MeCN (10.0?mL). The mixture was stirred vigorously and heated to reflux. After the refluxing was ceased (15?h), the solution was concentrated. The residue was rinsed consecutively with benzene (3?x?10?mL), hexanes (10?mL), and ether (2?x?10?mL). The crystalline white solid was dried to give 6a (1.8?g, 87%) [26] 6b-d were prepared according to the procedure described as 6a.
In acetonitrile; for 16h;Inert atmosphere; Reflux;
Weigh 2.62 g of triphenylphosphine (TPP, 10 mmol),6-bromohexanoic acid 2.07 g (10.5 mmol),Dissolved in anhydrous acetonitrile, protected with nitrogen and refluxed for 16 h. After recrystallization, it is pure.
To a suspension of <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (4.228 g, 9.245 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 18.5 mL, 18.5 mmol, 2 eq.) at 0 C. The solution was stirred for 30 min at 0 C. A solution of benzaldehyde (0.94 mL, 9.245 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidied with 3 M hydrochloric acid to pH = 1, then extracted three times with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel with a mixture of hexanes and ethyl acetate to give 1.242 g of product (66%) as a colorless oil and a 2:1 mixture of isomers.
7-(4-methoxyphenyl)-6-Heptenoic acid, 19dTo a suspension of <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (3.968 g, 8.676 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.4 mL, 17.4 mmol, 2 eq.) at 0 C. The solution was stirred for 30 min at 0 C. A solution of p-anisaldehyde (1.05 mL, 8.676 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The aqueous layer was washed three times with ether. The water layer was then acidied with 3 M hydrochloric acid to pH = 1 and extracted three times with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel with a mixture of hexanes and ethyl acetate to give 1.317 g of product (65%) as a light brown solid and a 2:1 mixture of isomers.
With potassium tert-butylate; In tetrahydrofuran; at -78 - 0℃; for 17h;
A solution of 4-((Z)-hex-l- enyl)benzaldehyde (S17, 400 mg, 2.13 mmol) and BrPh3P(CH2)5CO2H (2.40 g, 5.25 mmol, 2.4 equiv) in anhydrous THF (10 mL) at -78 C was treated with a suspension of t-BuOK (1.4 equiv) in anhydrous THF (8 mL). After 1 h, the reaction mixture was allowed to warm at 0 C and was stirred for 16 h. The reaction was quenched with the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. Chromatography (SiO2, 25^0% EtOAc-hexanes) afforded the diene (480 mg, 1.68 mmol, 79%).
To a solution of <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (0.57 g, 1.2 mmol, 1.2 eq.) in tetrahydrofuran (6 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 2.5 ml, 2.5 mmol, 2.5 eq.) at 0 C. The solution was stirred for 30 min, then cooled to -78 C. A solution of o-anisaldehyde (0.14 g, 1.0 mmol, 1 eq.) in tetrahydrofuran (3 mL) was then added dropwise. The reaction was allowed to warm to rt overnight. Water and ether were added. The water layer was separated and acidied with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.20 g of product (82%) as a colorless oil.
To a solution of <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (0.58 g, 1.3 mmol, 1.2 eq.) in tetrahydrofuran (6 ml) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 2.5 ml, 2.5 mmol, 2.3 eq.) at 0 C. The solution was stirred for 30 min, then cooled to -78 C. M-anisaldehyde (0.13 ml, 1.1 mmol, 1 eq.) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidied with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.23 g of product (92%) as a colorless oil.
A mixture of NaH, 60% (0.026 mol, free from mineral oil) in DMSO, dry (15 ml) was heated to 65 C AND the mixture was stirred for 1.5 hour (until the generation of H. 2 stopped), then the suspension (dark green) was cooled to 15 C and a solution of 5- carboxypentyltriphenylphosponium bromide (0.013 mol) in DMSO (10 ml) was added dropwise. The resulting solution (red) was stirred at RT for 10 min. and a solution of 4-bromo-2-nitro-benzaldehyde (0.013 mol; ; 4-Bromo-2- NITROBENZALDEHYDE) in DMSO, dry (8 ml) was added rapidly. The solution (dark brown) was stirred for 105 min. and quenched with H20/Et20 (25/75, 100 ML). THE Et2O-layer was removed and the aqueous layer was extracted 2 times with ethylacetate, then acidified (pH: 1-2) with HC1 (37 %) and extracted again with ethylacetate. The organic layer was separated, dried (MGS04), FILTERED off and the solvent was evaporated, yielding intermediate 56.
Step 2. Wittig reaction of 8 to give 9Potassium bis(trimethylsilyl)amide (0.5 M in PhMe, 1.92 mL, 0.96 mmol) was added to a solution of aldehyde 8 (86 mg, 0.35 mmol) in THF (2 mL) at rt. After 15 min at rt, the reaction mixture was cooled to - 55 C for 10 min before a solution of 5- carboxypentyltriphenylphosphonium bromide (207 mg, 0.45 mmol) was added via cannula. After 10 min at - 55 C, the reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3 x 15 mL). Combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography (5% MeOH/CH2Cl2) afforded 10.5 mg (9%) of desired alkene 9.
9%
Step 2. Wittig Reaction of 8 to Give 9Potassium bis(trimethylsilyl)amide (0.5 M in PhMe, 1.92 mL, 0.96 mmol) was added to a solution of aldehyde 8 (86 mg, 0.35 mmol) in THF (2 mL) at rt. After 15 min at rt, the reaction mixture was cooled to -55 C. for 10 min before a solution of 5-carboxypentyltriphenylphosphonium bromide (207 mg, 0.45 mmol) was added via cannula. After 10 min at -55 C., the reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). Combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography (5% MeOH/CH2Cl2) afforded 10.5 mg (9%) of desired alkene 9.
R.1 REFERENCE EXAMPLE 1
REFERENCE EXAMPLE 1 To dimethylsulfoxide (40 ml) was added dropwise sodium hydride (1.0 g), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, to which was added 5-carboxypentyltriphenyl phosphonium bromide (9.5 g, 21 mmole), and the mixture was stirred for 5 minutes. To the reaction mixture was added a tetrahydrofuran solution (10 ml) of 3.7 g (0.02 mole) of 3-benzoylpyridine. The mixture was stirred for 30 minutes at room temperature, followed by addition of water (100 ml), which was subjected to extraction twice with ethylacetate (50 ml). The aqueous layers were combined and adjusted to pH 6 with 2N HCl, which was subjected to extraction with ethyl acetate. The organic layers were combined and washed with water and dried (magnesium sulfate). The solvent was then evaporated and the residue was subjected to a silica-gel chromatography using ethanol-ethyl acetate (1:5) as the eluent to yield (E)+(Z)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (A-3, I-4 in Table 10) (4.5 g 79%).
14-hydroxy-7-methyltetradec-6-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran
14 Example 14
Example 14 The procedure of Example 14 was performed analogously to the procedure of Example 3. 45.7 g (0.1 mol) of (5-carboxypentyl)triphenylphosphonium bromide were placed in 200 ml of tetrahydrofuran and 25 g (0.22 ol) of potassium t-butylate in 100 l of tetrahydrofuran were added dropwise at 0° C. Then, 15.8 g (0.1 mol) of 9-hydroxy2-nonanone were added. After stirring for 30 minutes and usual work up, 28.5 g of crude 14-hydroxy-7-methyltetradec-6-enoic acid were obtained.
A solution of sodium hydride (60%, 0.364g, 0.0152 moles) in dry THF (5 ml.) was added to a stirred suspension of Wittig salt 5-12 (0.95g, 0.002 moles) in dry THF (10 ml.) at 0 0C under N2 atmosphere. The mixture was stirred for 30 min. Then a solution of aldehyde 5-11 (0.5g, 0.0019 moles) was added. The reaction was kept under stirring for 36h. After the completion of reaction, water was added and the solvent was removed under reduced pressure. The aqueous solution was washed with ethyl acetate and acidified to pH 2 with 5% HCL and extracted with ethyl acetate. The combined organic extract was washed with saturated brine, dried over anhydrous Na2SO4 and evaporated. The oil obtained was purified by flash column chromatography (Hexane: Ethyl acetate -75:25) to afford the Wittig product 5-13 (0.2g, 35% yield).1HNMR (CDCI3): delta 1.49 (3H, s), 1.51 (3H, s), 1.40-1.49 (4H, m), 1.55-1.95 (4H, m), 2.22-2.48 (3H, m), 3.70-3.75 (1 H, m), 3.80 (3H, s), 4.05-4.15 (1 H, m), 5.12-5.42 (2H, m), 5.35 (1 H,d, J =2.30 Hz), 6.75-6.80 (1 H, d), 6.92-6.99 (1 H, t), 7.21- 7.25 (1 H, m), 7.40 -7.47 (1 H, d).LC/MS: Purity 91 % and MW: 385 (M + Na).
Potassium bis(trimethylsilyl)amide (0.5 M in PhMe, 1.92 mL, 0.96 mmol) was added to a solution of aldehyde 12 (86 mg, 0.35 mmol) in THF (2 mL) at rt. After 15 min at rt, the reaction mixture was cooled to -55 C. for 10 min before a solution of 5-carboxypentyltriphenylphosphonium bromide (207 mg, 0.45 mmol) was added via cannula. After 10 min at -55 C., the reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). Combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography (5% MeOH/CH2Cl2) afforded 10.5 mg (9%) of desired alkene 13.
General procedure: To a stirring suspension of phosphonium salts (5a-e) (1 equiv) in THF (250 mL) was added slowly 40% solution of sodium hexamethyldisilylamide (2 equiv) THF at room temperature in argon and stirring continued for 2 h. Aldehyde (1 equiv) was dissolved in THF (25 mL) and introduced drop wise. The mixture was stirred for further 3 h and then poured into 150 mL of water to get a clear solution. The resulting solution was concentrated in vacuum and the residue was extracted with diethyl ether (3 x 250 mL). The aqueous layer was acidified with 10% HCl and extracted with ether (3 x 200 mL). The organic layer obtained from the aqueous extract was dried and concentrated to afford the corresponding unsaturated carboxylic acids (6a-m).
General procedure: To a stirring suspension of phosphonium salts (5a-e) (1 equiv) in THF (250 mL) was added slowly 40% solution of sodium hexamethyldisilylamide (2 equiv) THF at room temperature in argon and stirring continued for 2 h. Aldehyde (1 equiv) was dissolved in THF (25 mL) and introduced drop wise. The mixture was stirred for further 3 h and then poured into 150 mL of water to get a clear solution. The resulting solution was concentrated in vacuum and the residue was extracted with diethyl ether (3 x 250 mL). The aqueous layer was acidified with 10% HCl and extracted with ether (3 x 200 mL). The organic layer obtained from the aqueous extract was dried and concentrated to afford the corresponding unsaturated carboxylic acids (6a-m).
General procedure: To a stirring suspension of phosphonium salts (5a-e) (1 equiv) in THF (250 mL) was added slowly 40% solution of sodium hexamethyldisilylamide (2 equiv) THF at room temperature in argon and stirring continued for 2 h. Aldehyde (1 equiv) was dissolved in THF (25 mL) and introduced drop wise. The mixture was stirred for further 3 h and then poured into 150 mL of water to get a clear solution. The resulting solution was concentrated in vacuum and the residue was extracted with diethyl ether (3 x 250 mL). The aqueous layer was acidified with 10% HCl and extracted with ether (3 x 200 mL). The organic layer obtained from the aqueous extract was dried and concentrated to afford the corresponding unsaturated carboxylic acids (6a-m).
General procedure: To a stirring suspension of phosphonium salts (5a-e) (1 equiv) in THF (250 mL) was added slowly 40% solution of sodium hexamethyldisilylamide (2 equiv) THF at room temperature in argon and stirring continued for 2 h. Aldehyde (1 equiv) was dissolved in THF (25 mL) and introduced drop wise. The mixture was stirred for further 3 h and then poured into 150 mL of water to get a clear solution. The resulting solution was concentrated in vacuum and the residue was extracted with diethyl ether (3 x 250 mL). The aqueous layer was acidified with 10% HCl and extracted with ether (3 x 200 mL). The organic layer obtained from the aqueous extract was dried and concentrated to afford the corresponding unsaturated carboxylic acids (6a-m).
A solution of sodium hydride (60%, 0.364 g, 0.0152 moles) in dry THF (5 mL) was added to a stirred suspension of Wittig salt 8 5-12 (0.95 g, 0.002 moles) in dry THF (10 mL) at 0 C. under N2 atmosphere. The mixture was stirred for 30 min. Then a solution of aldehyde 7 5-11 (0.5 g, 0.0019 moles) was added. The reaction was kept under stirring for 36 h. After the completion of reaction, water was added and the solvent was removed under reduced pressure. The aqueous solution was washed with ethyl acetate and acidified to pH 2 with 5% HCL and extracted with ethyl acetate. The combined organic extract was washed with saturated brine, dried over anhydrous Na2SO4 and evaporated. The oil obtained was purified by flash column chromatography (Hexane:Ethyl acetate -75:25) to afford the Wittig product 9 5-13 (0.2 g, 35% yield). 1H-NMR (CDCl3): delta 1.49 (3H, s), 1.51 (3H, s), 1.40-1.49 (4H, m), 1.55-1.95 (4H, m), 2.22-2.48 (3H, m), 3.70-3.75 (1H, m), 3.80 (3H, s), 4.05-4.15 (1H, m), 5.12-5.42 (2H, m), 5.35 (1H,d, J=2.30), 6.75-6.80 (1H, d), 6.92-6.99 (1H, t), 7.21-7.25 (1H, m), 7.40 -7.47 (1H, d). LC/MS: Purity 91% and mass: 385 (M+Na).
7-(2,4-dimethoxyphenyl)hept-6-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
To a solution of <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (0.57 g, 1.2 mmol, 1.1 eq.) in tetrahydrofuran (6 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 2.5 ml, 2.5 mmol, 2.4 eq.) at 0 C. The solution was stirred for 30 min, then cooled to -78 C. A solution of 2,4-dimethoxybenzaldehyde (0.175 g, 1.05 mmol, 1 eq.) in tetrahydrofuran (2 mL) was then added dropwise. The reaction was allowed to warm to room temperature overnight. Water and ether were added. The water layer was separated and acidied with 1 M hydrochloric acid to pH = 1, then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (2:1 ether:hexanes) to give 0.220 g of product (79%) as an oily solid.
An oven dried flask is charged under argon atmosphere with <strong>[50889-29-7]triphenyl-6-hexanoic acid phosphonium bromide</strong> (90 mg, 0.195 mmol) and 5 mE anhydrous THE Potassium t-butoxide (1 M solution in THF, 0.39 mE, 0.39 mmol) is added at 00 C. and the solution is stirred for 30 minutes to give a bright orange colot Compound 3 (81 mg, 0.065 mmol, dissolved in 1 mE anhydrous THF) is added to the reaction drop-wise and stirring is continued at room temperature over night. The reaction is quenched with sat. NH4C1 solution and is extracted with EtOAc. The extract is washed with brine and dried over Na2504. The solvent is removed in vacuum and the crude product is purified over silica gel (toluene/acetone 3:1).
Synthesis of carboxylic acids used for the synthesis of Table 1 Molecules 8 _:To a solution of the phosphonium bromide [50889-29-7] (1.2 eq.) in dry THF (0.3 M) was added KHMDS (Potassiumhexamethyldisilazane - 2.4 eq.) at ambient temperature. After stirring for 30 minutes at the same temperature, a solution of iso-butyraldehyde (1 eq.) in dry THF (0.3 M) was added drop wise. The mixture was stirred for 3 hours, quenched with water (0.3 M) and extracted with Et20. The resulting water layer was acidified with a HC1 aqueous solution (10%) till pH 2 was obtained. This mixture was extracted with Et20 and the extracts were dried over MgS04and concentrated under reduced pressure. The resulting oil was purified using a quick filtration over silica gel by eluting with a petroleum ether - Et20 mixture (1-1). Concentration under reduced pressure resulted in the compound as a slightly yellow oil. (89% yield)
(6-((4-azidophenyl)amino)-6-oxohexyl)triphenylphosphonium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.7%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
[0069] Synthesis of TPP-Az ((6-((4-azidophenyl)amino)-6- oxohexyl)triphenylphosphonium bromide): <strong>[50889-29-7](5-carboxypentyl)triphenylphosphonium bromide</strong> (10 mg, 0.026 mmol), 4-azidobenzenaminium chloride (4.5 mg, 0.026 mmol), and HBTU (20 mg, 0.052 mmol) were dissolved in a mixture of solvents (dry DMF (0.05 mL) and DCM (0.1 mL). To the reaction mixture, 7 of DIE A was added and the reaction mixture was stirred overnight at room temperature. Solvent was evaporated and the crude was purified by column chromatography (EA: Hexane = 1: 2). Product was obtained as white solid (9.9 mg, 77.7 %). 1H NMR (DMSO-d6, 300 MHz): 7.83-7.70 (m, 15H), 7.63 (d, j= 9Hz, 2H), 7.07 (d, j= 9 Hz, 2H), 3.62 (bs, 2H), 2.30-2.25 (m, 2H), 1.61-1.54 (m, 6H). 13C NMR (75 MHz, DMSO-d6) 5 171.29, 136.94, 135.23, 133.99, 130.67, 120.85, 119.72, 119.47, 118.33, 36.14, 31.13, 24.64, 18.43, 17.08. HRMS: m/z calculated for C3oH3oN4OP+ 493.2152, found (0138) 493.2153 .
1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000][ No CAS ]
[ 50889-29-7 ]
C156H287N2O55P2(1+)*H3N[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Accurately weighed 20.0mg 5_ carboxypentyl triphenyl phosphonium bromide dissolved in 0.5mL chloroform,Magnetic stirring makes 5_ carboxypentyl triphenyl phosphonium bromide fully dissolved,Then 29.5 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) was added,17.5 mg of N-hydroxysuccinimide (NHS) and 0.05 mL of triethylamine,After 4 hours at room temperature,Then add 25Omg amino-modified distearoyl phosphatidylethanolamine polyethylene glycol derivatives, hereinafter referred to as DSPE-PEG-NH2),Magnetic stir,The reaction was carried out at room temperature for 24 hours, Until the reaction is completed,The mixed solution was transferred to a rotary flask,At 37 C under the rotation evaporated to dryness,The sample was then dissolved in 2 mL of triple distilled water and placed in a 2 KDa dialysis bag for three days after dialysis. The solution was removed, lyophilized, weighed and sealed to obtain a lipophilic cationic copolymer
(10R)-10-methyl-18-(tetrahydro-2H-pyran-2-yloxy)octadec-6-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
(5-Carboxypentyl)triphenylphosphonium bromide (18.3 g, 40.2 mmol) was dissolved in 3:1 dry 119 toluene/dry 120 DMSO (200 ml). The solution was cooled to 0 C. and 21 lithium bis(trimethylsilyl)amide (1.06 M in 6 THF, 79.4 ml, 84.2 mmol) was slowly added maintaining a temperature of less than 0.3 C. The resultant bright red orange solution was warmed to ambient temperature over 3 hours and stirred at ambient temperature for a further 1 hour. The solution was cooled to -15 C. and 116 (4R)-4-methyl-12-(tetrahydro-2H-pyran-2-yloxy)dodecanal (5.7 g, 19.1 mmol) was added as a solution in dry toluene (15 ml); the temperature was seen to rise on this addition. The solution was allowed to slowly return to ambient temperature and stirred overnight. A saturated aqueous solution of 7 NH4Cl (200 ml) was added and the mixture extracted with ethyl acetate (4×100 ml). The combined organic phases were washed with brine (100 ml), dried, filtered and evaporated. Column chromatography (petrol/ethyl acetate, 5:2) gave 121 (10R)-10-methyl-18-(tetrahydro-2H-pyran-2-yloxy)octadec-6-enoic acid (3.85 g, 9.72 mmol, 51%) as a colourless oil.
2,2-dichloro-1-(4'-hydroxy-3'-nitro-[1,1'-biphenyl]-4-yl)ethan-1-one[ No CAS ]
[ 50889-29-7 ]
(6-((4'-(2,2-dichloroacetyl)-3-nitro-[1,1'-biphenyl]-4-yl)oxy)-6-oxohexyl)triphenylphosphonium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
General procedure: To a round-bottom flask was added 1b (0.25mmol), 6a (0.2mmol) and DCC (0.246mmol). The flask was flushed with nitrogen, and then anhydrous DCM (6mL) was added. The reaction was stirred at room temperature for one day. Then was filtered and concentrated, and purified by silica gel chromatography to afford compound 1c in 70% yield [27].
[(3R,4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]-1-[(R)-2-methyl-Sar]-3-cyclosporin[ No CAS ]
[ 50889-29-7 ]
C69H121N11O15[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
An oven dried flask is charged under argon atmosphere with <strong>[50889-29-7]triphenyl-6-hexanoic acid phosphonium bromide</strong> (90 mg, 0.195 mmol) and 5 mL anhydrous THF. Potassium t-butoxide (1 M solution in THF, 0.39 mL, 0.39 mmol) is added at 0 C and the solution is stirred for 30 minutes to give a bright orange color. Compound 3 (81 mg, 0.065 mmol, dissolved in 1 mL anhydrous THF) is added to the reaction drop-wise and stirring is continued at room temperature overnight. The reaction is quenched with sat. H4CI solution and is extracted with EtOAc. The extract is washed with brine and dried over Na2S04. The solvent is removed in vacuum and the crude product is purified over silica gel (toluene/acetone 3: 1).
(0675) [00268] An oven dried flask is charged under argon atmosphere with <strong>[50889-29-7]triphenyl-6-hexanoic acid phosphonium bromide</strong> (90 mg, 0.195 mmol) and 5 mL anhydrous THF. Potassium t-butoxide (1 M solution in THF, 0.39 mL, 0.39 mmol) is added at 0 C and the solution is stirred for 30 minutes to give a bright orange color. Compound 3 (81 mg, 0.065 mmol, dissolved in 1 mL anhydrous THF) is added to the reaction drop-wise and stirring is continued at room temperature overnight. The reaction is quenched with sat. NH4C1 solution and is extracted with EtOAc. The extract is washed with brine and dried over Na2S04. The solvent is removed in vacuum and the crude product is purified over silica gel (toluene/acetone 3: 1).
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In ethanol; at 50℃;
Example 2 Synthesis of TPP-Tris-(OH)3 TPP-(CH2)5-COOH (0.50 g, 1.1 mmol), Tris (0.15 g, 1.2 mmol), and EEDQ (0.32 g, 1.3 mmol) were dissolved in ethanol. This mixture was stirred at 50 C. for 12 h followed by drying under vacuum. The crude mixture was recrystallized 3-4 times using ethanol/CH2Cl2/diethyl ether to give a white solid of TPP-Tris-(OH)3 in 86% yield (0.52 g). Melting point: 115-120 C.; 1H NMR (CDCl3): 7.7 (m, 15H), 3.7 (s, 6H), 3.5 (t, 2H), 2.4 (t, 2H), 1.7 (m, 6H) ppm. 13C NMR (CDCl3): delta 175.6, 135.2, 133.6, 130.6, 118.4, 113.2, 64.1, 62.3, 36.2, 29.3, 24.9, 22.5, 21.5 ppm. 31P NMR (CDCl3) 24.28 ppm. HRMS-ESI (m/z): [M-Br]+ calcd. for C28H35NO4P+, 480.2298. found, 480.2243.
(1R,2S,5S)-2-benzyloxy-5-n-hexylcyclopentane-1-carbaldehyde[ No CAS ]
[ 50889-29-7 ]
(E)-7-((1S,2S,5S)-2-(benzyloxy)-5-n-hexylcyclopentyl)hept-6-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
5-Carboxybutyltriphenylphosphonium bromide (2.75 g, 6 mmol) was placed in a reaction flask.Anhydrous tetrahydrofuran (40 mL) was added.LiHMDS (11 mL, 1 M in THF, 11 mmol) was added under ice bath.The reaction was stirred for 0.5 hours and then lowered to -78 C.To the obtained blood red solution was added a solution of (1R,2S,5S)-2-benzyloxy-5-n-hexylcyclopentane-1-carbaldehyde 6 (1.15 g, 4.0 mmol) in water THF (4 mL).After the addition was completed, the mixture was allowed to react to room temperature for 12 hours.1M hydrochloric acid solution after completion of the reactionQuenched,Extracted with ethyl acetate,Combine the organic phase,Wash with saturated sodium chloride solution.Dry over anhydrous magnesium sulfate,After desolvation,By silica gel column chromatography (petroleum ether: acetone = 5:1), 1.23 g of colorless liquid was obtained.The yield was 80%.
With dmap; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃; for 12h;
Weighing 0.199 g (0.8 mmol) of p-hydroxybenzaldehyde nitroxide, 0.469 g (1.2 mmol) of 5-carboxypentylphosphonium bromide, and 0.25 g (1.2 mmol) of N,N'-dicyclohexylcarbodiimide. Then, 0.015 g (0.12 mmol) of 4-dimethylaminopyridine was dissolved in 30 mL of acetonitrile, stirred, and reacted at room temperature for 12 hours, and then filtered, and the filtrate was evaporated. TLC detection, column chromatography to obtain pure product.
With dmap; dicyclohexyl-carbodiimide; In acetonitrile; at 20℃; for 12h;
0.237 g (0.8 mmol) of vanillin nitroxide, 0.469 g (1.2 mmol) of 5-carboxypentylphosphonium bromide, 0.25 g (1.2 mmol) of N,N'-dicyclohexylcarbodiimide, 4 - dimethylaminopyridine 0.015 g (0.12 mmol) was dissolved in 30 mL of acetonitrile, stirred, and allowed to react at room temperature for 12 h, then filtered, filtered, and the solvent was evaporated. TLC detection, column chromatography to obtain pure product.
General procedure: The general procedure and characterization of 3 are also presented in ref. 17 of the text: To an ice-cold suspension of 2a (432 mg, 1.01 mmol, 2 equiv) in THF (5 mL) was added NaHMDS (1.0 M in THF, 1.0 mL, 1.0 mmol, 2 equiv). The mixture was stirred at 0 C for 1 h and the resulting reddish-orange mixture was cooled to-95 ~ -90 C (abbreviated as -90 C) (realized by making a slushy mixture of hexane and liquid N2). A solutionof aldehyde 1 (67 mg, 0.50 mmol, 1 equiv) in THF (1.5 mL) was added to the mixture dropwise. After 1 h, the mixture was warmed to 0 C over 2 h before addition of saturated NH4Cl. The resulting mixture was extracted with Et2O three times. The combined extracts were dried over MgSO4 and concentrated to afford a residue, which was purified by chromatography on silica gel (hexane/EtOAc) to give olefin 3 (66 mg, 63%):
With triphenylphosphine; In toluene; at 120℃; for 17h;
In a 100?mL triple-necked round-bottom flask 5.01?g (19.1?mmol, 1.0 eq.) 6-bromohexanoic acid and 6.71?g (19.61 mmol, 1.0 eq.) triphenylphosphine were dissolved in 30?mL dry toluene. The reaction mixture was heated to 120? C and stirred for 17?h. After cooling to room temperature, the product was collected by filtration and washed with toluene (2?*?20?mL) and Et2O (2?*?20?mL) before drying under reduced pressure. 11 was obtained as colorless powder in quantitative yield. m.p.?=?201-205?C; 1H NMR (300.36?MHz; CDCl3) delta?=?9.12 (s, 1H), 7.74 (m, 15H), 3.60 (s, 2H), 2.34 (s, 2H), 1.64 (s, 6H); 13C NMR (75.53?MHz; CDCl3) delta?=?175.9, 135.1, 133.7, 133.6, 130.7, 130.5, 34.27, 29.6, 24.0, 21.9, 22.2.
In a 250?mL twin-necked round-bottom flask 3.00?g (6.57?mmol, 1.0 eq.) 11 and 1.53?g (13.89?mmol, 2.0 eq.) KOtBu were dissolved in 80?mL dry THF and cooled to 0?C using an ice bath. The reaction mixture turned bright red while the compounds were dissolved. A solution of 720?muL (7.89?mmol, 1.2 eq.) isobutyraldehyde in 5?mL dry THF was slowly added to the cooled reaction mixture, which turned white immediately. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 12?h. The reaction mixture was quenched by addition of 80?mL?H2O at 0?C. After acidification to pH 2, the reaction mixture was extracted with EtOAc (3?*?80?mL) and the combined organic layers were washed with brine (1?*?100?mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure. Purification via flash chromatography (125 g silica gel, cyclohexane/EtOAc = 4/1 + 0.5% glacial acetic acid, fraction size: 70 mL) gave 12 as a colorless oil (0.99?g, 88%). 1H NMR (300.36?MHz; CDCl3) delta?=?10.51 (s, 1H), 5.30 (m, 2H), 2.57 (q, 3JHH?=?13.6, 6.8?Hz, 1H), 2.36 (t, 3JHH?=?7.4?Hz, 2H), 2.03 (m, 3JHH?=?7.08?Hz, 2H), 1.65 (m, 2H), 1.40 (m, 2H), 0.95 (d, 3JHH?=?6.1?Hz, 6H) 13C NMR (75.53?MHz; CDCl3) delta?=?180.3, 138.2, 126.7, 34.1, 29.4, 27.0, 26.6, 24.4, 23.3.
With dmap; dicyclohexyl-carbodiimide; In acetonitrile; at 20 - 35℃; for 12h;
0.199g (0.8mmol) of the intermediate 4 obtained in step 4, 0.469 g (1.2 mmol) of the intermediate obtained in step 1, 1, 0.25 g (1.2 mmol) of N,N?-dicyclohexylcarbodiimide and 0.015 g (0.12 mmol) of 4-dimethylaminopyridine dissolved in 30 mL acetonitrile and stir, then react at room temperature 20 C~ 35 C for 12h, determine the end point of the reaction by TLC detection; filter the product system obtained by the reaction to obtain a filtrate, and spin the filtrate to a solvent to obtain a crude product. Purified by column chromatography (eluent was prepared from ethyl acetate, petroleum ether and ethanol according to the volume ratio of 8: 1: 5) to obtain 0.341g of dark blue solid, TPP-L-NIT-1 after calculation, the yield of TPP-L-NIT-1 is 70%;