The Journal of Organic Chemistry
Article
(ESI-TOF) m/z [M + Na]+ calcd for C24H18N2O2F4SNa 497.0917,
found 497.0920.
Oxidation Products of N-(4-Fluoro-2-trifluoromethylphenyl)-
2-(4-oxo-6-phenyl-3,4-dihydro-2H-1,5-benzothiazepin-5-yl)-
acetamide (5): The Sulfoxide Isomers (8I, 8II) and Sulfone (9).
relation between two stereogenic elements at the sulfur atom and
axis. The sterically controlled reaction observed in the S-oxidation
of 1,5-benzothiazepin-4-one (5) was shown to be caused by the
remote stereogenic axis. Furthermore, using the enantiomerically
pure lactams, interconversion between the diastereomers was
unequivocally clarified to originate from rotation around the axis.
These results indicate that axial chirality plays an important role
in controlling the stereochemistry and chemical reactivity of
the 1,5-benzothiazepin-4-one nucleus. The stereochemistry of
S-oxides revealed in this study is also important for understanding
the metabolism of the biologically active sulfide derivatives. We
hope that this study will contribute to drug design of phar-
maceutically important 1,5-benzothiazepin-4-one molecules.
EXPERIMENTAL SECTION19
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2-Bromo-N-(4-fluoro-2-trifluoromethylphenyl)acetamide.
To a solution of bromoacetic acid (695 mg, 5.0 mmol) and 4-fluoro-2-
trifluoromethylaniline (690 mg, 3.85 mmol) in THF (25 mL) at 23 °C
under argon was added N,N′-dicyclohexylcarbodiimide (DCC) (1.34 g,
6.5 mmol) portionwise with stirring. After being stirred at 23 °C for 24 h,
the mixture was filtrated to remove N,N′-dicyclohexylurea. The filtrate
was concentrated, and ethyl acetate was added to the concentrate. The
mixture was washed successively with dilute HCl, H2O, saturated
NaHCO3, and H2O and dried. The solvent was evaporated, and the
residue was treated with diisopropyl ether to afford 2-bromo-N-(4-
fluoro-2-trifluoromethylphenyl)acetamide as colorless crystals (465 mg,
1.55 mmol, 40%): mp 105−107 °C; 1H NMR (600 MHz, CDCl3) δ 4.06
(s, 2H, CH2), 7.30 (1H, dt, J = 8.4, 2.8 Hz, H5), 7.37 (1H, dd, J = 8.4, 2.8
Hz, H3), 8.12 (1H, dd, J = 8.4, 4.8 Hz, H6), 8.51 (1H, br, NH); 13C
NMR (150 MHz, CDCl3) δ 29.1 (Br−C), 113.7 (dq, C3), 119.7 (d,
C5), 122.9 (dq, C2), 122.9 (q, CF3), 126.7 (d, C6), 130.5 (C1), 159.2
(d, C4), 163.9 (CO); IR (KBr) 3275, 1670, 1315, 1176, 1122 cm−1;
HRMS (ESI-TOF) m/z [M − H]− calcd for C9H6NOF4Br 297.9496,
found 297.9502.
To a solution of 5 (15.4 mg, 0.032 mmol) in CH2Cl2 (0.3 mL) at 23 °C
under argon was added dropwise a solution of meta-chloroperoxy-
benzoic acid (mCPBA) (9.0 mg, 0.034 mmol) in CH2Cl2 (0.24 mL).
After being stirred at 23 °C for 0.5 h, the mixture was treated with
saturated aq NaHCO3 and extracted with ethyl acetate. The extract was
washed with brine, dried, and concentrated. The concentrate was
purified by column chromatography (silica gel, ethyl acetate/hexane =
1:4) to afford sulfoxide (8) (14.4 mg, 91%) and sulfone (9) (6.8 mg,
4%). The sulfoxide (8) was separated by preparative HPLC using a
nonchiral column (YMC SIL-06) to give the diastereomers 8I and 8II in
a ratio of ≈5:1. See the Supporting Information for the HPLC
chromatogram. The oxidation at −78 °C gave similar results, affording 8
(89%) (8I/8II ≈ 5:1) and 9 (4%), although the reaction proceeded
slowly, taking approximately 3 h to complete. The product ratio of the
oxidation reaction was also confirmed by HPLC analysis using an aliquot
of the reaction mixture before work up.
N-(4-Fluoro-2-trifluoromethylphenyl)-2-(4-oxo-6-phenyl-
3,4-dihydro-2H-1,5-benzothiazepin-5-yl)acetamide (5).8b
Major Sulfoxide (8I): Colorless crystals; mp 220−221 °C; 1H NMR
(600 MHz, CDCl3) δ 2.76 (1H, ddd, J = 12.0, 7.2, 1.4 Hz, H3b), 2.93
(1H, ddd, J = 11.5, 8.9, 1.4 Hz, H2a), 2.98 (1H, ddd, J = 12.0, 10.8, 8.9
Hz, H3a), 4.14 (1H, ddd, J = 11.5, 10.8, 7.2 Hz, H2b), 3.22 (1H, d, J =
14.9 Hz, −CH2CO−), 4.28 (1H, d, J = 14.9 Hz, −CH2CO−), 7.21 (1H,
dt, J = 8.4, 2.7 Hz, H5″), 7.3 (1H, m, H3″), 7.30 (2H, d, J = 7.6 Hz, H2′,
H6′), 7.42 (1H, t, J = 7.6 Hz, H4′), 7.46 (2H, t, J = 7.6 Hz, H3′, H5′),
7.62 (1H, dd, J = 7.6, 1.4 Hz, H7), 7.71 (1H, t, J = 7.6 Hz, H8), 7.90 (1H,
dd, J = 8.4, 4.8 Hz, H6″), 7.92 (1H, dd, J = 7.6, 1.4 Hz, H9), 8.26 (1H, br,
NH); 13C NMR (150 MHz, CDCl3) δ 29.8, 52.9, 54.7, 113.5 (d), 119.6
(d), 123.8, 127.2 (d), 128.2 (2 × C), 128.9, 129.5 (2 × C), 129.7, 134.4,
134.6, 136.7, 137.1, 138.9, 158.9 (d), 165.5, 171.0 (signals due to C2″−
CF3 were not determined); IR (KBr) 3161, 1686, 1321, 1175, 1132,
1049, 1036 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C24H18N2O3F4SNa 513.0866, found 513.0868.
To a solution of 2,3-dihydro-6-phenyl-1,5-benzothiazepin-4(5H)-one8a
(120 mg, 0.47 mmol) in DMF (1.0 mL) at 0 °C under argon was added
sodium hydride (60% in oil) (20 mg, 0.5 mmol). The mixture was stirred
at 23 °C for 30 min, cooled to 0 °C, and treated with 2-bromo-N-(4-
fluoro-2-trifluoromethylphenyl)acetamide (120 mg, 0.4 mmol). After
being stirred at 23 °C for 20 h, the mixture was treated with H2O and
extracted with ethyl acetate. The extract was washed with brine, dried,
and concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, ethyl acetate/hexane = 1/2) to afford 5 as colorless
crystals (87 mg, 39%): mp 113−115 °C; 1H NMR (600 MHz, CDCl3) δ
2.85−2.90 (2H, m, H3a, H3b), 3.30 (1H, d, J = 16.3 Hz, −CH2CO−),
3.37 (1H, ddd, J = 11.7, 11.1, 8.1 Hz, H2b), 3.48 (1H, ddd, J = 11.7, 5.9,
2.9 Hz, H2a), 4.25 (1H, d, J = 16.3 Hz, −CH2CO−), 7.20 (1H, dt, J =
8.4, 2.8 Hz, H5″), 7.32 (1H, dd, J = 8.4, 2.8 Hz, H3″), 7.35 (2H, d, J = 7.6
Hz, H2′, H6′), 7.41 (1H, dt, J = 7.6, 1.4 Hz, H4′), 7.42 (1H, t, J = 7.6 Hz,
H8), 7.46 (2H, t, J = 7.6 Hz, H3′, H5′), 7.51 (1H, dd, J = 7.6, 1.4 Hz,
H7), 7.58 (1H, dd, J = 8.4, 4.8 Hz, H6″), 7.69 (1H, dd, J = 7.6, 1.4 Hz,
H9), 9.19 (1H, br, NH); 13C NMR (150 MHz, CDCl3) δ 33.5, 33.9,
53.3, 113.6 (d), 119.4 (d), 122.6 (q), 125.8 (dd), 128.1 (2 × C), 128.6,
128.8, 129.1, 129.4 (2 × C), 130.4 (d), 130.5, 133.4, 135.0, 137.8, 138.0,
142.8, 159.7 (d), 167.3, 173.0; IR (KBr) 3277, 1681 cm−1; HRMS
1
Minor Sulfoxide (8II): Colorless crystals; mp 224−225 °C; H
NMR (600 MHz, CDCl3) δ 2.85−2.90 (2H, m, H3a, H3b), 3.47 (1H,
ddd, J = 14.8, 6.0, 2.9 Hz, H2a), 3.65 (1H, ddd, J = 14.8, 10.5, 7.4 Hz,
H2b), 3.36 (1H, d, J = 16.6 Hz, −CH2CO−), 4.25 (1H, d, J = 16.6 Hz,
−CH2CO−), 7.16 (1H, dt, J = 8.4, 2.8 Hz, H5″), 7.27 (1H, dd, J = 8.4,
2.8 Hz, H3″), 7.3 (1H, m, H6″), 7.32 (2H, d, J = 7.6 Hz, H2′, H6′), 7.44
(1H, t, J = 7.6 Hz, H4′), 7.49 (2H, t, J = 7.6 Hz, H3′, H5′), 7.55 (1H, t,
J = 7.6 Hz, H8), 7.63 (1H, dd, J = 7.6, 1.4 Hz, H7), 7.71 (1H, dd, J = 7.6,
1.4 Hz, H9), 10.20 (1H, br, NH); 13C NMR (150 MHz, CDCl3) δ 31.0,
52.9, 53.6, 113.7 (d), 119.3 (d), 128.1 (2 × C), 128.2, 129,0 129.1, 129.7
(2 × C), 132.1 (d), 134.4, 134.6, 137.3, 137.4, 139.6, 139.8, 160.3 (d),
167.7, 173.0 (signals due to C2″−CF3 were not determined); IR (KBr)
3127, 1679, 1319, 1167, 1137, 1048, 1023 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C24H18N2O3F4SNa 513.0866, found 513.0863.
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dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX