The Journal of Organic Chemistry
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Rf = 0.14) to afford 8 as a yellow oil (275 mg, 276 μmol, 73%). IR
CDCl3): δ 151.6, 151.0, 150.5, 137.3, 137.1, 130.0, 129.2, 129.1, 128.9,
128.7, 128.6, 128.2, 127.1, 127.0, 123.1, 115.2, 114.0, 113.5, 99.0, 79.5,
79.4, 79.2, 72.0−71.9, 71.2−71.1, 70.8−70.6, 65.3, 59.2−59.1. HRMS
(MALDI): m/z [M]+ calcd for C146H242O58 2923.5987, found
2923.6151.
(cm−1): 2919, 2857, 1682, 1588, 1463, 1390, 1350, 1298, 1253, 1200,
1
1097, 937, 849, 742. H NMR (300 MHz, CDCl3): δ 10.37 (s, 1H),
7.69 (s, 1H), 7.37 (s, 1H), 4.51 (quin, J = 5.0 Hz, 2H), 3.76−3.71 (m,
8H), 3.67−3.60 (m, 40H), 3.55−3.52 (m, 8H), 3.37 (s, 12H). 13C
NMR (150 MHz, CDCl3): δ 189.5, 155.9, 152.7, 128.5, 127.0, 111.8,
97.8, 80.3, 79.9, 72.0, 71.3, 71.2, 70.8−70.6, 59.2. HRMS (ESI): m/z
[M + Na]+ calcd for C41H73IO19Na 1019.3688, found 1019.3687; m/z
[M + K]+ calcd for C41H73IO19K 1035.3428, found 1035.3416.
2-(2,5-Bis(2,5,8,11,15,18,21,24-octaoxapentacosan-13-
yloxy)-4-iodophenyl)-1,3-dioxolane (9). To a solution of 8 (300
mg, 1.30 mmol, 1.00 equiv) and triethyl orthoformate (153 μL, 1.43
mmol, 1.10 equiv) in ethylene glycol (1 mL) was added
tetrabutylammonium tribromide (5.55 mg, 13.0 μmol, 0.01 equiv).
The reaction mixture was stirred at room temperature for 72 h. The
reaction mixture was purified directly by column chromatography
(silica gel, petroleum ether/dichloromethane/ethyl acetate/methanol
= 5:3:1:0.6, Rf = 0.12) to yield 9 as a yellow oil (152 mg, 555 μmol,
43%). IR (cm−1): 2870, 1473, 1391, 1350, 1292, 1251, 1198, 1098,
4,4′-{[2,5-Bis(2,5,8,11,15,18,21,24-octaoxapentacosan-13-
yloxy)benzene-1,4-diyl]bis[(E)ethene-2,1-diylbenzene-4,1-diyl-
(E)ethene-2,1-diyl]}bis[2,5-bis(2,5,8,11,15,18,21,24-octaoxa-
pentacosan-13-yloxy)benzaldehyde] (13). Compound 12 (129
mg, 44.1 μmol, 1.00 equiv) was dissolved in acetone/water = 3:1 (12
mL acetone + 4 mL water), and a catalytic amount of p-
toluenesulfonic acid was added. The solution was stirred at room
temperature overnight. The reaction was quenched by addition of a
saturated aqueous solution of NaHCO3 (5 mL) and dichloromethane
(10 mL). The layers were separated, and the aqueous layer was
extracted with dichloromethane (4 × 20 mL). The combined organic
extracts were washed with brine and dried over MgSO4, and the
solvents were evaporated to yield 13 as a dark yellow oil (102 mg, 40.0
μmol, 82%). IR (cm−1): 2867, 2361, 1675, 1592, 1481, 1418, 1349,
1288, 1251, 1197, 1098, 965, 849, 719. 1H NMR (300 MHz, CDCl3):
δ 10.40 (s, 2H), 7.55−7.47 (m, 14H), 7.42 (s, 2H), 7.35 (s, 2H), 7.19
(d, J = 16.4 Hz, 2H), 7.09 (d, J = 16.4 Hz, 2H), 4.66 (quin, J = 5.0 Hz,
2H), 4.57 (quin, J = 4.8 Hz, 4H), 3.80−3.76 (m, 24H), 3.69−3.57 (m,
120H), 3.53−3.48 (m, 24H), 3.36−3.34 (m, 36H). 13C NMR (150
MHz, CDCl3): δ 189.4, 156.1, 151.0, 150.7, 138.0, 136.5, 135.9, 132.0,
128.9, 128.5, 127.5, 127.1, 126.1, 123.5, 122.5, 114.0, 113.8, 79.7, 79.5,
78.9, 72.0, 72.0, 71.2−71.1, 70.8−70.6, 59.2, 59.2. HRMS (MALDI):
m/z [M + H]+ calcd for C142H235O56 2836.5541, found 2836.5610.
2-(4-Vinylphenyl)-1,3-dioxolane (15). The reaction was per-
formed in a 100 mL round-bottomed flask equipped with a Dean−
Stark distilling receiver. A solution of 4-ethenylbenzaldehyde (2.60 g,
19.7 mmol, 1.00 equiv), ethylene glycol (8.54 mL, 197 mmol, 10.0
equiv), and a catalytic amount of p-toluenesulfonic acid in toluene (60
mL) was refluxed (140 °C) for 6 h. Then the reaction mixture was
quenched with a saturated aqueous solution of NaHCO3 (40 mL).
The phases were separated, and the aqueous layer was extracted with
dichloromethane (3 × 50 mL). The combined organic layers were
washed with brine (60 mL) and dried over MgSO4, and the solvents
were removed in vacuo. Purification of the crude product by column
chromatography (silica gel, petroleum ether/ethyl acetate = 15:2, Rf =
0.21) yielded 15 as a colorless oil (2.73 g, 15.5 mmol, 79%). 1H NMR
(300 MHz, CDCl3): δ 7.47−7.41 (m, 4H), 6.73 (dd, J = 17.6 Hz, 10.9
Hz, 1H), 5.82 (s, 1H), 5.77 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.9 Hz,
1H), 4.16−4.01 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 138.6, 137.5,
136.6, 126.8, 126.3, 114.6, 103.7, 65.4. HRMS (EI): m/z [M]+ calcd
for C11H12O2 176.0837, found 176.0838.
1
941, 849, 761. H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.14 (s,
1H), 6.04 (s, 1H), 4.45 (quin, J = 5.0 Hz, 1H), 4.38 (quin, J = 5.0 Hz,
1H), 4.11−3.95 (m, 4H), 3.75−3.62 (m,48H), 3.54−3.52 (m, 8H),
3.37 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 152.5, 152.0, 129.3,
127.3, 113.7, 98.9, 89.2, 80.1, 80.0, 72.1, 71.3, 71.2, 70.8−70.7, 65.3,
59.2. HRMS (ESI): m/z [M + Na]+ calcd for C43H77IO20Na
1063.3951, found 1063.3949; m/z [M + K]+ calcd for C43H77IO20K
1079.3690, found 1079.3683.
13-[2,5-Bis{(E)-2-[4-iodo-2,5-bis(2,5,8,11,15,18,21,24-octaox-
a p e n t a c o s a n - 1 3 - y l o x y ) p h e n y l ] e t h e n y l } - 4 -
(2,5,8,11,15,18,21,24-octaoxapentacosan-13-yloxy)phenoxy]-
2,5,8,11,15,18,21,24-octaoxapentacosane (11). Bisphosphonate
10 (200 mg, 175 μmol, 1.00 equiv) was dissolved in dry THF (5 mL).
The solution was cooled to 0 °C, and KOtBu (45.0 mg, 402 μmol, 2.30
equiv) was added. The mixture was stirred at 0 °C for 10 min before
aldehyde 8 (366 mg, 175 mmol, 2.10 equiv) was added. The reaction
mixture was allowed to reach room temperature and stirred for 3 d.
The reaction was quenched by addition of a saturated NH4Cl solution
(20 mL). The layers were separated, and the aqueous layer was
extracted with DCM (5 × 20 mL). The combined organic extracts
were washed with brine and dried over MgSO4, and the solvents were
removed by rotary evaporation. Purification by column chromato-
graphy (silica gel, petroleum ether/dichloromethane/ethyl acetate/
methanol = 5:3:1:1.5, Rf = 0.33) afforded a mixture of E- and Z-
isomers of 11 (328 mg, 116 μmol, 66%), which was used in the next
step without further purification. HRMS (MALDI): m/z [M + H]+
calcd for C124H221O54I2 2828.2637, found 2828.2752.
2,2′-([2,5-Bis(2,5,8,11,15,18,21,24-octaoxapentacosan-13-
yloxy)benzene-1,4-diyl]bis{(E)ethene-2,1-diylbenzene-4,1-diyl-
(E)ethene-2,1-diyl[2,5-bis(2,5,8,11,15,18,21,24-octaoxapenta-
cosan-13-yloxy)benzene-4,1-diyl]})bis(1,3-dioxolane) (12). The
reaction was performed in a heat-gun-dried 25 mL Schlenk tube under
a nitrogen atmosphere. Compounds 2 (100 mg, 91.0 μmol, 1.00
equiv) and 9 (208 mg, 200 μmol, 2.20 equiv) were dissolved in dry
DMF (4 mL). Pd(OAc)2 (2.00 mg, 9.10 μmol, 0.10 equiv), tris(o-
tolyl)phosphine (11 mg, 36.4 μmol, 0.40 equiv), and triethylamine
(0.5 mL) were added. The mixture was stirred at 105 °C for 72 h.
After the reaction mixture was cooled to room temperature, it was
poured into 50 mL of water to give a brown suspension that was
extracted with dichloromethane (5 × 50 mL) until the aqueous layer
was colorless. The combined organic layers were washed with brine
and dried over MgSO4. The solvents were removed under reduced
pressure. The brown residue was purified by column chromatography
(silica gel, petroleum ether/dichloromethane/ethyl acetate/methanol
= 5:3:1:1.5, Rf = 0.22) to give 12 as a highly viscous yellow oil (149
mg, 50.9 μmol, 56%). IR (cm−1): 2868, 1609, 1489, 1455, 1416, 1350,
1251, 1196, 1099, 962, 849, 734, 530. 1H NMR (300 MHz, CDCl3): δ
7.52−7.50 (m, 10H), 7.46 (d, J = 5.8 Hz, 2H), 7.32 (d, J = 2.5 Hz,
4H), 7.21 (s, 2H), 7.10−7.03 (m, 4H), 6.11 (s, 2H), 4.57−4.48 (m,
6H), 4.15−3.96 (m, 8H), 3.80−3.75 (m, 24H), 3.69−3.57 (m, 120H),
3.53−3.48 (m, 24H), 3.35−3.33 (m, 36H). 13C NMR (150 MHz,
4,4′-{[2,5-Bis(2,5,8,11,15,18,21,24-octaoxapentacosan-13-
yloxy)benzene-1,4-diyl]bis[(E)ethene-2,1-diyl[2,5-bis-
(2,5,8,11,15,18,21,24-octaoxapentacosan-13-yloxy)benzene-
4,1-diyl](E)ethene-2,1-diyl]}dibenzaldehyde (16). The reaction
was performed in a heat-gun-dried 25 mL Schlenk tube under a
nitrogen atmosphere. Compounds 11 (200 mg, 71.0 μmol, 1.00 equiv)
and 15 (27.4 mg, 156 μmol, 2.20 equiv) were dissolved in dry DMF (5
mL). Pd(OAc)2 (1.59 mg, 7.07 μmol, 0.10 equiv), tris(o-tolyl)-
phosphine (8.61 mg, 28.3 μmol, 0.40 equiv), and triethylamine (0.5
mL) were added. The mixture was stirred at 125 °C for 48 h. After the
reaction mixture was cooled to room temperature, it was poured into
50 mL of water to give a yellow suspension that was extracted with
dichloromethane (5 × 50 mL) until the aqueous layer was colorless.
The combined organic layers were washed with brine and dried over
MgSO4.
Deprotection. The crude product (149 mg, 50.9 μmol, 1.00 equiv)
was then dissolved in toluene (5 mL), and a catalytic amount of iodine
was added. The mixture was refluxed for 6 h and then quenched with a
saturated aqueous solution of NaSO3. The layers were separated, and
the aqueous layer was extracted with dichloromethane (4 × 10 mL).
The combined organic extracts were dried over MgSO4, and the
solvents were evaporated. Column chromatography (silica gel,
petroleum ether/dichloromethane/ethyl acetate/methanol =
5:3:1:1.5, Rf = 0.32) afforded 16 as a bright yellow oil (122 mg,
K
dx.doi.org/10.1021/jo501129d | J. Org. Chem. XXXX, XXX, XXX−XXX