Ether Aryl Sulfonic Acid Esters with Improved Antimalarial/Anticancer Activities
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d, CH2O), 5.30 (1H, d, CH2=C), 5.40 (1H, d, CH2=C), 6.00 (1H, m,
CH=C), 6.89 (2H, d, ArH), 7.16 (2H, d, ArH). δC (68 MHz, CDCl3,
Me4Si) 37.0, 69.2, 115.8, 118.0, 123.1, 132.8, 142.8, 157.5. m/z 228
(20%, M+•), 149 (64), 41 (100).
(6H, s, CH3Ar, CH3S), 6.88 (2H, d, J 8.9, ArH), 7.10 (2H, d, J 8.9,
ArH), 7.27 (2H, d, J 8.4, ArH), 7.69 (2H, d, J 8.4, ArH). δC (68 MHz,
CDCl3, Me4Si) 16.0, 21.7, 122.9, 127.4, 128.6, 129.8, 132.3, 137.7,
145.4, 147.1. m/z 294 (18%, M+•), 139 (100%), 91 (11).
B. The methanesulfonate allyl ether (180 mg, 0.79 mmol) was dis-
solved in chloroform (25 mL), and the reaction mixture cooled with
an ice/water bath. m-Chloroperoxybenzoic acid (50%, 266 mg) was
added in small portions. The reaction mixture was stirred at ambient
temperature for 18 days.
Sulfonate 12
Sodium metal (58 mg, 2.5 mmol) was dissolved in allyl alcohol
(35 mL), and the ditoluenesulfonate ester of hydroquinone[3] (1.0 g,
2.4 mmol) was added. The reaction mixture was refluxed for 23 h.
Allyl alcohol (25 mL) was distilled from the reaction mixture.
Chloroform (125 mL) was added to the residue and the resultant
mixture was extracted with 2.5% w/v sodium hydroxide solution
(3 × 75 mL). The aqueous layer was acidified and back-extracted to
give p-toluenesulfonoxyphenol (242 mg, 42%). The organic layer was
dried (MgSO4), filtered, and the solvent evaporated to furnish crude
product. The crude product was chromatographed on silica gel (40 g),
employing 1/1 chloroform/light petroleum (40 mL fractions) for elu-
tion. Fractions 12–23 were combined and concentrated to afford clean
p-toluenesulfonoxyphenyl allyl ether 12 (247 mg, 0.812 mmol, 38%),
mp 56.6–57.2◦C. (Found: C 63.3, H 5.1%. C16H16O4S requires C 63.1,
H 5.3%.) νmax/cm−1 1369, 1157. δH (270 MHz, CDCl3, Me4Si) 2.42
(3H, s, CH3Ar), 4.45 (2H, dt, J 5.3, 1.6, CH2O), 5.25 (1H, dq, J 10.5,
1.3, C=CH2), 5.40 (1H, dq, J 17.1, 1.6, C=CH2), 5.98 (1H, m, CH=C),
6.77 (2H, d, J 9.1, ArH), 6.83 (2H, d, J 9.1, ArH), 7.29 (2H, d, J 8.6,
ArH), 7.65 (2H, d, J 8.6, ArH). δC (68 MHz, CDCl3, Me4Si) 21.7, 69.2,
115.3, 118.0, 123.4, 128.6, 129.7, 132.43, 132.89, 143.2, 145.3, 157.2.
m/z 304 (29%, M+•), 155 (32), 149 (100), 91 (69), 41 (54).
Chloroform (150 mL) was added and the resultant mixture washed
with 2.5% w/v sodium hydroxide (100 mL). The organic layer was
dried (MgSO4), filtered, and the solvent evaporated. The residue was
chromatographed on silica gel (20 g) employing chloroform for elution
(10 mL fractions). Fractions 26–40 were combined and concentrated
to furnish the epoxysulfone 8 (56 mg, 0.23 mmol, 29%), mp 76.7–
78.6◦C. (Found: C 49.7, H 5.2%. C10H12O5S requires C 49.2, H 5.0%.)
νmax/cm−1 1376, 1153. δH (270 MHz, CDCl3, Me4Si) 2.75 (1H, dd, J
2.7, 4.8, epoxy CH2), 2.90 (1H, dd, J 4.8, 4.6, epoxy CH2), 3.09 (3H, s,
CH3SO3), 3.34 (1H, m, epoxy CH), 3.92 (1H, dd, J 5.9, 11.0, CH2O),
4.22 (1H, dd, J 2.9, 11.0, CH2O), 6.92 (2H, d, J 6.8, ArH), 7.20 (2H, d,
J 6.8, ArH). δC (68 MHz, CDCl3, Me4Si) 37.1, 44.6, 50.0, 69.3, 115.7,
123.2, 143.0, 157.4. m/z 244 (26%, M+•), 165 (63), 57 (100).
Disulfonate 9
4-Toluenesulfonoxyphenol[3] (493 mg, 1.9 mmol) was dissolved in
1/4 water/acetone (5 mL), and sodium hydroxide (108 mg, 2.7 mmol)
in water (0.5 mL) added. The reaction mixture was vigorously stirred.
Methanesulfonyl chloride (0.29 g, 2.5 mmol) was added dropwise. The
reaction mixture became homogeneous and was stirred at ambient
temperature for 3 days.
Chloroform (100 mL) was added and the resultant mixture extracted
with 2.5% w/v sodium hydroxide (2 × 50 mL).Acidification and extrac-
tion of the aqueous layer furnished unchanged tosylate phenol (219 mg,
44%). The organic layer was dried (MgSO4), filtered, and concentrated
to give the disulfonate 9 (243 mg, 0.71 mmol, 38%), mp 96.3–96.4◦C.
νmax/cm−1 1367, 1150. δH (270 MHz, CDCl3, Me4Si) 2.44 (3H, s,
CH3Ar), 3.13 (3H, s, CH3SO3), 7.04 (2H, d, J 8.9, ArH), 7.20 (2H,
d, J 8.9, ArH), 7.33 (2H, d, J 8.4, ArH), 7.70 (2H, d, J 8.4, ArH). δC
(68 MHz, CDCl3, Me4Si) 21.8, 37.6, 123.3, 124.0, 128.5, 129.9, 132.1,
145.8, 147.4, 148.2. m/z 155 (81%), 91 (100), 79 (25).
Sulfonate 13
Sodium metal (44 mg, 1.9 mmol) was dissolved in methanol (2 mL),
and p-toluenesulfonoxyphenol[3] (0.5 g, 1.9 mmol) in methanol
(1.5 mL) was added. Benzyl chloride (0.24 g, 1.9 mmol) in methanol
(0.5 mL) was added and the resultant reaction mixture was stirred at
ambient temperature for 24 h.
Chloroform (50 mL) was added and the resultant mixture was
extracted with 2.5% w/v sodium hydroxide (2 × 50 mL). The aque-
ous layer was acidified and back-extracted to afford unchanged tosylate
phenol (0.233 g, 47%). The organic layer was dried (MgSO4), filtered,
and the solvent evaporated. The residue was recrystallized (methanol)
to furnish tosylate benzyl ether 13[9] (138 mg, 0.39 mmol, 21%), mp
143.5–144.4◦C. νmax/cm−1 1375, 1172. δH (270 MHz, CDCl3, Me4Si)
2.43 (3H, s, CH3Ar), 4.99 (2H, s, OCH2Ar), 6.81 (2H, d, J 8.0, ArH),
6.88 (2H, d, J 8.0, ArH), 7.3 (7H, m, Ph and ArH), 7.65 (2H, d, J 8.1,
ArH). δC (68 MHz, CDCl3, Me4Si) 21.7, 70.4, 115.5, 123.4, 127.5,
128.21, 128.65, 128.70, 129.7, 132.4, 136.5, 143.3, 145.2, 157.4. m/z
91 (100%), 65 (12).
Disulfonate 10
Triethylamine (1.1 g, 10.8 mmol) and hydroquinone (0.6 g,
5.4 mmol)weredissolvedindrypyridine(75 mL), andtheresultantsolu-
tion cooled with an ice/water bath. 1-Hexanesulfonyl chloride (1.96 g,
10.7 mmol) was added in small portions. The reaction mixture was
stirred at ambient temperature for 7 days.
Chloroform (150 mL) was added and the resultant mixture extracted
with 5% HCl (100 mL portions) until the aqueous pH remained
acidic. The organic layer was dried (MgSO4), filtered, and the residue
was recrystallized (methanol) to furnish the disulfonate 10 (0.75 g,
1.85 mmol, 34%), mp 79.0–79.1◦C. νmax/cm−1 1363, 1191, 1154. δH
(270 MHz, CDCl3, Me4Si) 0.89 (6H, t, CH3C), 1.31 (8H, m, CH2CH2),
1.47 (4H, quin, CH2CH2), 1.97 (4H, quin, CH2CH2), 3.24 (4H, t,
CH2SO2), 7.30 (4H, s, ArH). δC (68 MHz, CDCl3, Me4Si) 13.9, 22.3,
23.4, 27.8, 31.1, 50.8, 123.6, 147.3. m/z 258 (17%), 110 (100), 109 (96).
Sulfonate 14
Triethylamine (0.83 g, 8.2 mmol) and 4-methoxyphenol (1.0 g,
8.1 mmol) were dissolved in dry pyridine (50 mL). Phenylmethanesul-
fonylchloride(1.53 g, 8.0 mmol)wasaddedinsmallportionsover5 min.
The reaction mixture was stirred at ambient temperature for 4 days.
Chloroform (200 mL) was added and the resultant mixture washed
with 2.5% hydrochloric acid (100 mL aliquots) until the aqueous pH
remained acidic. The organic layer was dried (MgSO4), filtered, and the
solvent evaporated. The crude product was recrystallized (methanol)
to afford p-methoxyphenyl benzylsulfonate 14[10] (0.76 g, 2.7 mmol,
34%), mp 92.0–94.5◦C. νmax/cm−1 1369, 1150. δH (270 MHz, CDCl3,
Me4Si) 3.77 (3H, s, CH3O), 4.47 (2H, s, ArCH2SO3), 6.85 (2H, d, J
9.2, ArH), 7.03 (2H, d, J 9.2, ArH), 7.42 (5H, m, ArH). δC (68 MHz,
CDCl3, Me4Si) 55.7, 56.5, 114.8, 123.1, 127.4, 129.06, 129.31, 130.9,
142.6, 158.3. m/z 278 (2%, M+•), 214 (11), 123 (17), 91 (100).
Sulfonate 11
4-Thiomethylphenol (0.54 g, 3.8 mmol) and dry triethylamine (0.4 g,
3.9 mmol) were dissolved in dry pyridine (25 mL). The reaction mixture
was cooled with an ice/water bath. The reaction mixture was stirred at
ambient temperature for 3 days.
Chloroform (250 mL) was added and the resultant mixture extracted
with 5% hydrochloric acid (100 mL aliquots) until the aqueous pH
remained acidic. The organic layer was dried (MgSO4), filtered, and
the solvent evaporated. The residue was recrystallized (methanol) to
give clean sulfide tosylate 11 (535 mg, 1.82 mmol, 47%), mp 77.3–
79.8◦C. νmax/cm−1 1375, 1157. δH (270 MHz, CDCl3, Me4Si) 2.43
Sulfonate 15
p-Cresol (0.51 g, 4.7 mmol) and triethylamine (0.47 g, 4.7 mmol)
were added to dry pyridine (50 mL). 4-Methoxybenzenesulfonyl chlo-
ride (0.96 g, 4.6 mmol) was added over 15 min. The reaction mixture
was stirred at room temperature for 13 days.