Developments in the SimmonsϪSmith Mediated-Epoxidation Reaction
FULL PAPER
Hz, PyH), 7.72 (1 H, m, PyH), 8.00 (1 H, m, PyH), 8.65 (1 H, m, (0.62 g, 4.0 mmol), sodium hydride (97 mg, 4.0 mmol) and the par-
PyH). 13C NMR (63 MHz, CDCl3): δ ϭ 10.7 (q), 22.5 (q), 26.1 (q), ent mesylate 13 (700 mg, 1.34 mmol) in THF (14 mL) followed by
46.3 (s), 69.8 (t), 74.9 (d), 123.8 (d), 125.4 (d), 136.4 (d), 146.5 (s), purification by flash chromatography [gradient elution, CH2Cl2 to
149.6 (d), 163.3 (s). MS (EI); m/z (%): 236 (18) [Mϩ], 148 (90), 89 CH2Cl2/MeOH (99:1, v/v)] afforded the desired sulfide as a yellow
(100). C12H16N2OS [Mϩ]: calcd. 236.0983; found 236.0973.
foam (0.45 g, 53%), [α]2D3 ϭ Ϫ92 (c ϭ 1 in CHCl3). Rf ϭ 0.45
˜
(CH2Cl2/MeOH, 98:2). IR: νmax ϭ 1663 (CϭN), 1510 (NO2), 1338
(؊)-[(4S,5S)-4,5-Dihydro-2-{[(4S,5S)-4,5-dihydro-4-{[(methyl-
sulfonyl)oxy]methyl}-5-phenyl-1,3-oxazol-2-yl]methyl}-5-phenyl-1,3-
oxazol-4-yl]methyl Methanesulfonate (13): A stirred solution of (Ϫ)-
(4S,4ЈS,5S,5ЈS)-bis(4,5-dihydro-4-hydroxymethyl-5-phenyl-
dioxazol-2-yl)methane[20] (7.36 g, 20.1 mmol) in CH2Cl2 (125 mL)
under argon was cooled to 0 °C and treated with triethylamine
(12.3 mL, 88.5 mmol). Methanesulfonyl chloride (3.43 mL,
44.3 mmol) was added dropwise and the mixture was stirred for 20
min and then allowed to warm to room temperature. After 3 h, the
reaction mixture was washed with saturated aqueous NaHCO3 (2
ϫ 150 mL) and brine (150 mL), and then dried (Na2SO4). Concen-
tration under reduced pressure afforded the product as a white
foam (10.1 g, 96%), [α]2D3 Ϫ75 (c ϭ 1.04 in EtOH). Rf ϭ 0.5
cmϪ1 (NO2). 1H NMR (250 MHz, CDCl3): δ ϭ 3.17 (2 H, dd, J ϭ
13.1 and 7.6 Hz, 2 CHHЈS), 3.45 (2 H, dd, J ϭ 13.1 and 5.2 Hz, 2
CHHЈS), 3.55 [2 H, s, CH2C(O)ϭN], 4.29 (2 H, m, CHN), 5.33 (2
H, d, J ϭ 6.7 Hz, PhCH), 7.25Ϫ7.34 (14 H, m, ArH), 8.04 (4 H,
m, ArH). 13C NMR (63 MHz, CDCl3): δ ϭ 28.5 (t), 37.0 (2 t), 73.6
(2 d), 86.2 (2 d), 123.9 (4 d), 125.9 (4 d), 127.0 (4 d), 128.7 (2 d),
128.8 (4 d), 139.1 (2 s), 145.4 (2 s), 145.7 (2 s), 162.5 (2 s). MS
(FAB); m/z (%): 641 (52) [MHϩ], 472 (10), 154 (96), 136 (100).
C33H29N4O6S2 [MHϩ]: calcd. 641.1529; found 641.1565.
(؊)-(4R,4ЈR,5S,5ЈS)-Bis[4,5-dihydro-4-(2-pyridinylthiomethyl)-5-
phenyldioxazol-2-yl]methane (16): Treatment of 2-mercaptopyridine
(0.23 g, 2.0 mmol), sodium hydride (48 mg, 2.0 mmol), and mesyl-
ate 13 (0.35 g, 0.67 mmol) in THF (7 mL), followed by purification
by flash chromatography [gradient elution, CH2Cl2 to CH2Cl2/
MeOH (98:2, v/v)] afforded the desired sulfide as a colourless oil
(0.28 g, 75%), [α]2D3 ϭ Ϫ39 (c ϭ 1 in CHCl3); Rf ϭ 0.45 (CH2Cl2/
˜
(CH2Cl2/MeOH, 95:5). IR: νmax ϭ 1666 (CϭN), 1354 (OSO2), 1175
cmϪ1 (OSO2). 1H NMR (250 MHz, CDCl3): δ ϭ 2.99 (6 H, s,
SO2CH3), 3.58 [2 H, s, CH2C(O)ϭN], 4.31 (2 H, m, CHN), 4.39
(4 H, AB part of ABX system, 2 CHHЈOS), 5.40 (2 H, d, J ϭ 6.7
Hz, PhCH), 7.26Ϫ7.38 (10 H, m, ArH). 13C NMR (63 MHz,
CDCl3): δ ϭ 28.5 (t), 37.4 (2 q), 69.3 (2 t), 73.5 (2 d), 83.4 (2 d),
125.8 (4 d), 128.8 (2 d), 128.9 (4 d), 138.9 (2 s), 163.2 (2 s). MS
(FAB); m/z (%): 523 (100) [MHϩ]. C23H27N2O8S2 [MHϩ]: calcd.
523.1209; found 523.1211.
MeOH, 95:5). IR: νmax ϭ 1664 (CϭN), 1578 (CϭC), 1414 cmϪ1
.
˜
1H NMR (250 MHz, CDCl3): δH ϭ 3.44 (2 H, dd, J ϭ 13.7 and
6.7 Hz, 2CHHЈS), 3.61 [2 H, s, CH2C(O)ϭN], 3.77 (2 H, dd, J ϭ
13.7 and 4.9 Hz, 2 CHHЈS), 4.38 (2 H, m, CHN), 5.39 (2 H, d,
J ϭ 6.7 Hz, PhCH), 6.96 (2 H, ddd, J ϭ 7.3, 4.9 and 1.2 Hz, PyH),
7.18 (2 H, m, PyH), 7.24Ϫ7.35 (10 H, m, ArH), 7.44 (2 H, m,
PyH), 8.38 (2 H, ddd, J ϭ 4.9, 1.8 and 0.9 Hz, PyH). 13C NMR
(63 MHz, CDCl3): δ ϭ 28.6 (t), 34.0 (2 t), 74.4 (2 d), 85.5 (2 d),
119.5 (2 d), 122.3 (2 d), 125.7 (4 d), 128.0 (2 d), 128.5 (4 d), 135.8
(2 d), 140.1 (2 s), 149.2 (2 d), 157.7 (2 s), 162.1 (2 s). MS (FAB);
m/z (%): 553 (100) [MHϩ], 124 (33). C31H29N4O2S2 [MHϩ]: calcd.
553.1732; found 553.1752.
Standard Procedure for the Preparation of Bis(oxazoline)-Based Sul-
fides: A solution of thiol (2.0 mmol) in THF (1.5 mL) was added
dropwise at Ϫ78 °C under argon to a stirred suspension of sodium
hydride (2.0 mmol) in THF (3.5 mL). The mixture was stirred for
10 min and then allowed to warm to room temperature. After 2 h,
the reaction mixture was again cooled to Ϫ78 °C and treated with
a solution of the mesylate 13 (0.67 mmol) in THF (2 mL). The
mixture was allowed to warm to ambient temperature and stirred
for 16 h, and then quenched with H2O (7 mL). Products were ex-
tracted into ethyl acetate (35 mL), washed with KOH (2 , 2 ϫ
35 mL), H2O (35 mL), and brine (2 ϫ 35 mL), and then dried
(Na2SO4). Concentration under reduced pressure afforded the
crude sulfide, which was purified by flash chromatography.
(؊)-(4R,4ЈR,5S,5ЈS)-Bis[4-(tert-butylthiomethyl)-4,5-dihydro-5-
phenyldioxazol-2-yl]methane (17): Treatment of 2-methyl-2-pro-
panethiol (518 mg, 5.75 mmol), sodium hydride (138 mg,
5.75 mmol), and the parent mesylate 13 (1.0 g, 1.9 mmol) in THF
(20 mL) following the order of addition shown above, gave the de-
sired sulfide as a colourless oil (926 mg, 95%), [α]2D0 ϭ Ϫ58 (c ϭ
˜
0.65 in CHCl3). Rf ϭ 0.4 (CH2Cl2/MeOH, 95:5). IR: νmax ϭ 1665
(؉)-(4R,4ЈR,5S,5ЈS)-Bis[4,5-dihydro-4-[4-(methoxy)phenyl]-
thiomethyl-5-phenyldioxazol-2-yl]methane (14): Treatment of 4-me-
thoxybenzenethiol (806 mg, 5.75 mmol), sodium hydride (138 mg,
5.75 mmol) and the parent mesylate 13 (1.0 g, 1.9 mmol) as above,
in THF (20 mL), followed by purification by flash chromatography
[gradient elution, CH2Cl2 to CH2Cl2/MeOH (99:1, v/v)] afforded
the desired sulfide as a colourless oil (1.07 g, 91%), [α]2D3 ϭ ϩ64
(CϭN), 1390 [C(CH3)3], 1364 cmϪ1 [C(CH3)3]. 1H NMR
(250 MHz, CDCl3): δ ϭ 1.32 [18 H, s, C(CH3)3], 2.67 (2 H, dd,
J ϭ 11.9 and 9.2 Hz, 2 CHHЈS), 2.99 (2 H, dd, J ϭ 11.9 and 4.7
Hz, 2 CHHЈS), 3.58 [2 H, s, CH2C(O)ϭN], 4.18 (2 H, m, CHN),
5.34 (2 H, d, J ϭ 6.1 Hz, PhCH), 7.26Ϫ7.37 (10 H, m, ArH). 13C
NMR (63 MHz, CDCl3): δ ϭ 28.7 (t), 30.9 (6 q), 33.6 (2 t), 42.4
(2 s), 74.7 (2 d), 86.1 (2 d), 125.9 (4 d), 128.2 (2 d), 128.6 (4 d),
140.2 (2 s), 161.8 (2 s). MS (FAB); m/z (%): 511 (100) [MHϩ], 407
(33). C29H39N2O2S2 [MHϩ]: calcd. 511.2453; found 511.2430.
˜
(c ϭ 1 in CHCl3). Rf ϭ 0.5 (CH2Cl2/MeOH, 95:5). IR: νmax ϭ 2835
1
(CϪH), 1666 (CϭN), 1246 (CϪO), 1031 cmϪ1 (CϪO). H NMR
(250 MHz, CDCl3): δ ϭ 2.85 (2 H, dd, J ϭ 13.4 and 9.2 Hz, 2
CHHЈS), 3.32 (2 H, dd, J ϭ 13.4 and 4.3 Hz, 2 CHHЈS), 3.52 [2
H, s, CH2C(O)ϭN], 3.74 (6 H, s, OCH3), 4.13 (2 H, m, CHN), 5.36
(2 H, d, J ϭ 6.4 Hz, PhCH), 6.72 (4 H, m, ArH), 7.17 (4 H, m,
ArH), 7.25Ϫ7.34 (10 H, m, ArH). 13C NMR (63 MHz, CDCl3):
δ ϭ 28.5 (t), 40.7 (2 t), 55.0 (2 q), 73.7 (2 d), 86.1 (2 d), 114.4 (4
d), 124.6 (2 s), 126.0 (4 d), 128.1 (2 d), 128.4 (4 d), 133.4 (4 d),
139.8 (2 s), 158.9 (2 s), 161.9 (2 s). MS (FAB); m/z (%): 611 (100)
[MHϩ], 471 (9), 457 (6). C35H35N2O4S2 [MHϩ]: calcd. 611.2038;
found 611.2028.
Standard Procedure for the Simmons؊Smith-Based Aziridination
(Table 5): Diethylzinc (1.1 solution in toluene, 1.0 mL) was added
to a stirred solution of imine (1.0 mmol), chloroiodomethane
(0.15 mL, 2.0 mmol), and chiral sulfide (2.0 mmol) in CH2Cl2
(5 mL) at room temperature under a positive pressure of argon.
After 16 h, the reaction mixture was quenched with saturated aque-
ous NH4Cl (5 mL) and the reaction products were extracted into
CH2Cl2 (3 ϫ 10 mL). The combined organic extracts were washed
with triethanolamine (2 , 2 ϫ 10 mL) and brine (10 mL), dried
(؊)-(4R,4ЈR,5S,5ЈS)-Bis{4,5-dihydro-4-[4-(nitrophenyl)thiomethyl]- (Na2SO4), and concentrated under reduced pressure to afford the
5-phenyldioxazol-2-yl}methane (15): Treatment of p-nitrothiophenol
crude aziridine, which was purified by flash chromatography.
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