Rates of Reactions of Polymer-Bound Radicals
A R T I C L E S
in benzene (10.6 mL, 0.01 M) and a solution of Bu3SnH (34 µL, 0.126
mmol) and AIBN (5.2 mg, 0.3 equiv) in benzene (10.0 mL) were each
degassed for 30 min by slow bubbling of deoxygenated nitrogen at
room temperature. The degassed benzene solution of Bu3SnH and AIBN
was added dropwise to the refluxing benzene solution of 3 over 6 h by
syringe pump under nitrogen atmosphere at 80 °C. Heating was
continued for 1 h, and the reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The residue was
dissolved in THF (2.0 mL), and aqueous KF (2.0 mL) was added. After
2 h, the mixture was concentrated and filtered through a short silica
gel pad. The crude product was purified by silica gel column
chromatography to afford the 1:1 cis/trans mixture of cyclized product
(1.86 g, 10.45 mmol) and benzoyl peroxide (482 mg, 1.99 mmol) in
anhydrous CCl4 (3 mL) at room temperature. The reaction mixture was
refluxed for 10 h at 80 °C under nitrogen atmosphere, cooled to room
temperature, and extracted with CH2Cl2 (10 mL × 3), aqueous NaHCO3
(5 mL), and H2O (10 mL × 3). The organic layer was dried (MgSO4),
concentrated under reduced pressure, and the residue was subjected to
column chromatography to afford an inseparable mixture of 13 and 14
1
(2.36 g, 77%, 1:8.5). H NMR (300 MHz, CDCl3): δ 3.94 (3H, s),
4.61 (2H, s), 7.54 (1H, d, J ) 8.0 Hz), 7.96 (1H, d, J ) 8.0 Hz), 8.25
(1H, s). 13C NMR (75 MHz, CDCl3): δ 32.2, 52.5, 124.3, 128.9, 131.1,
131.7, 134.4, 141.7, 165.2. IR (CH2Cl2): 3055.95, 1725. LRMS: m/z
308, 277, 227, 89. HRMS (ESI) calcd for C9H8O2Br2 305.8891, found
305.8879.
1
5 (18.4 mg, 76%). H NMR (300 MHz, CDCl3): δ 0.81-0.84 (1.5H,
d, J ) 7.1 Hz), 0.92-0.94 (1.5H, d, J ) 7.0 Hz), 1.20-1.65 (14H, m),
2.05-2.10 (2H, m), 3.60-3.91 (5H, m). 13C NMR (125 MHz,
CDCl3): δ 15.7, 20.3, 21.1, 22.1, 23.3, 23.6, 30.1, 30.2, 30.4, 33.1,
33.2, 35.3, 36.3, 40.6, 49.9, 50.0, 51.6, 51.7, 62.6, 62.8, 177.9, 178.6.
IR (neat): 3439, 2936, 1725.9. LRMS: m/z 228, 196, 156, 95. HRMS
(ESI) calcd for C13H24O3 228.1725, found 228.1731.
2-(3-Bromo-4-bromomethylbenzyloxy)tetrahydropyran (15). LAH
(284 mg, 7.47 mmol) was added to the above product mixture (2.30 g,
7.47 mmol) in anhydrous ether (20 mL) at 0 °C, and the suspension
was vigorously stirred for 30 min at 0 °C. The mixture was diluted
with ether (10 mL) and extracted with aqueous 10% HCl (10 mL) and
ether (20 mL × 3). After drying (MgSO4) and evaporation of the
solvents, a white solid was obtained. To the crude white solid were
added anhydrous CH2Cl2 (10 mL), DHP (680 µL, 7.47 mmol), and a
catalytic amount of TsOH (47 mg) at 0 °C. After 30 min at 0 °C, the
mixture was extracted with CH2Cl2 (10 mL × 3), aqueous NaHCO3 (5
mL), and H2O (10 mL × 3) and dried. The residue obtained after
evaporation of solvents was purified with column chromatography to
Solution-Phase Kinetic Experiments with 3. Bromide 3 (61.5 mg,
0.20 mmol) and AIBN (16.4 mg) were added into a 100 mL volumetric
flask. This was purged with dried nitrogen gas for 10 min at room
temperature. To make a 0.002 M solution, about 100 mL of degassed
toluene was added to the volumetric flask. A suitable volume of the
mixture (8 mL, first trial; 10 mL, second trial) was added to five tubes,
and a different amount of Bu3SnH was added to each of the five tubes
to obtain the concentrations listed in Table 1. The tubes were sealed
and heated for 8 h at 80 °C, cooled, and concentrated under reduced
pressure. The residue was dissolved in THF (3.0 mL), and aqueous
KF (2.0 mL) was added. After 2 h, each mixture was concentrated and
filtered through a short silica gel pad. The crude products were purified
by flash column chromatography to give mixtures of 4 and 5 (84-
87%). The ratio of 4 and 5 was analyzed with GC, as shown in Table
1.
1
afford 15 (2.01 g, 74%). H NMR (300 MHz, CDCl3): δ 1.46-1.91
(6H, m), 3.51-3.62 (1H, m), 3.85-3.96 (1H, m), 4.47 (1H, d, J )
12.6 Hz), 4.61 (2H, s), 4.71 (1H, m), 4.76 (1H, d, J ) 12.6 Hz), 7.29
(1H, d, J ) 7.8 Hz), 7.43 (1H, d, J ) 7.8 Hz), 7.60 (1H, s). 13C NMR
(75 MHz, CDCl3): δ 19.4, 25.5, 30.6, 33.4, 62.3, 67.6, 98.1, 124.6,
127.2, 131.3, 132.4, 136.1, 141.1. IR (neat): 3050.9, 2955.3, 1605.9,
1036.9. LRMS: m/z 363, 346, 283, 263, 182, 85. HRMS (ESI) calcd
for C13H16O2Br2 363.9497, found 363.9507.
2-[3-Bromo-4-(3-phenylpropoxymethyl)benzyloxy]tetrahydropy-
ran (16). 60% NaH in mineral oil (435 mg, 10.88 mmol) was added
to a solution of 3-phenyl-1-propanol (1.48 g, 10.88 mmol) in anhydrous
DMF (10 mL) at 0 °C under nitrogen. After 1 h at room temperature,
15 (1.98 mg, 5.44 mmol) was added, and the mixture was stirred for
10 h at room temperature. The final mixture was poured into brine (10
mL), extracted with aqueous NH4Cl and ether (10 mL × 3), and dried
with MgSO4. The residue obtained after evaporation of solvents was
subjected to flash chromatography to give 16 (1.67 g, 73%). 1H NMR
(300 MHz, CDCl3): δ 1.54-1.95 (6H, m), 1.96-2.01 (2H, m), 2.76
(2H, t, J ) 7.4 Hz), 3.53-3.59 (3H, m), 3.88-3.92 (1H, m), 4.48 (1H,
d, J ) 12.3 Hz), 4.57 (2H, s), 4.70-4.72 (1H, m), 4.76 (1H, d, J )
12.3 Hz), 7.17-7.33 (6H, m), 7.46 (1H, d, J ) 7.8 Hz), 7.58 (1H, s).
13C NMR (75 MHz, CDCl3): δ 19.4, 25.6, 30.7, 31.5, 32.5, 62.3, 67.9,
70.1, 72.1, 97.9, 122.8, 125.9, 126.9, 128.5, 128.6, 129.1, 131.8, 137.2,
139.6, 142.1. IR (neat): 3021.9, 2945.9, 1608, 1563, 1037. LRMS:
m/z 318, 289, 105. HRMS (ESI) calcd for (M-THPOH) C17H17OBr
318.0442, found 318.0431.
Resin-Bound Cyclization Substrate 8. To a mixture of Ellman resin
(0.98 mmol/g, 495.5 mg) and TsOH (434.7 mg, 4.7 equiv) in anhydrous
CH2Cl2 (2.0 mL) was added 3 (871.3 mg, 5.8 equiv) at 0 °C. After
being shook for 3 days, the resin was washed with CH2Cl2 (10 mL ×
3), acetone (10 mL × 3), and anhydrous CH2Cl2 (10 mL × 3) and
dried under high vacuum for 5 h to afford 8 (625.4 mg, loading level
) 87%, 0.68 mmol/g).
Solid-Phase Kinetic Experiments with 8. A suitable amount of
Bu3SnH (42-134 µL) was added to a mixture of 8 (50-52 mg) and
AIBN (about 3 mg, 0.5 equiv) in degassed toluene (3.2 mL for 5-10
equiv experiments, and 16.6 mL for 15 and 20 equiv experiments).
After being heated for 20 h at 80 °C with gentle stirring, the mixtures
were cooled to room temperature and washed with CH2Cl2 (10 mL ×
3), hexane (10 mL × 3), and anhydrous CH2Cl2 (10 mL × 3). The
resin-bound product was detached with TsOH (10 mg) for 10 h at room
temperature to give mixtures of 4 and 5 (93-98%). The ratio of 4 and
5 was analyzed by GC, and the results are shown in Table 2.
3-Bromo-4-methylbenzoic Acid Methyl Ester (13). 3-Bromo-4-
methylbenzoic acid 12 (2.51 g, 11.63 mmol) was dissolved in MeOH
(10 mL), 5 drops of H2SO4 were added, and the mixture was heated to
60 °C for 10 h. The solvent was removed, and the residue was diluted
with Et2O and water and extracted with diethyl ether. The brown oil
obtained after concentration was purified with silica gel column
chromatography to give 13 (2.29 g, 86%). 1H NMR (300 MHz,
CDCl3): δ 2.46 (3H, s), 3.91 (3H, s), 7.30 (1H, d, J ) 7.9 Hz), 7.87
(1H, d, J ) 7.8 Hz), 8.20 (1H, s). 13C NMR (75 MHz, CDCl3): 23.2.
52.2, 124.7, 128.3, 129.4, 130.7, 133.4, 143.3, 165.8. IR (neat): 3063.9,
1725. LRMS: m/z 230, 228, 197, 89. HRMS (ESI) calcd for C9H9O2-
Br 227.9786, found 227.9786.
2-[3-Iodo-4-(3-phenylpropoxymethyl)benzyloxy]tetrahydropy-
ran (17). First, 1.6 N BuLi in hexane (4.56 mL, 7.30 mmol) was added
to a solution of 16 (1.53 g, 3.65 mmol) in anhydrous THF (10 mL) at
-78 °C under nitrogen. After 1 h, a solution of 1,2-diiodoethane (2.06
g, 7.31 mmol) in THF (3 mL) was added. The mixture was allowed to
warm slowly to room temperature (1 h), poured into 5% Na2SO3 (10
mL), and extracted with ether (10 mL × 3). The organic layer was
dried with MgSO4, and the residue obtained after removal of solvents
was subjected to column chromatography to provide 17 (1.28 g, 75%).
δ 1.55-1.91 (6H, m), 1.96-2.01 (2H, m), 2.77 (2H, t, J ) 7.4 Hz),
3.53-3.60 (3H, m), 3.88-3.94 (1H, m), 4.46 (1H, d, J ) 12.4 Hz),
4.48 (2H, s), 4.69-4.70 (1H, m), 4.74 (1H, d, J ) 12.4 Hz), 7.17-
7.43 (7H, m), 7.85 (1H, s). 13C NMR (75 MHz, CDCl3): δ 19.4, 25.5,
30.6, 31.4, 32.5, 62.2, 67.6, 70.1, 76.4, 97.8, 125.8, 127.7, 128.4, 128.6,
138.4, 139.6, 140.0, 142.0. IR (neat): 3058, 3025, 2945, 2855, 1602.
3-Bromo-4-bromomethylbenzoic Acid Methyl Ester (14). A
solution of 3-bromo-4-methylbenzoic acid methyl ester 13 (2.28 mg,
9.95 mmol) in anhydrous CCl4 (2 mL) was added to a solution of NBS
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J. AM. CHEM. SOC. VOL. 124, NO. 50, 2002 14999