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The Journal of Organic Chemistry
dried over magnesium sulfate and the solvent is evaporated in
vacuo. The resulting colorless oil (26.7 g, 117 mmol, 86%) is di-
rectly used for the synthesis of 1b, without further purification.
19.2 Hz), 78.1 (d, JFC = 5.3 Hz), 26.4. The analytical data corre-
sponds with literature data.13 chiral HPLC: Chiralpak® OJ-H (n-
hexane:2-propanol = 95:5, 0.8 mL min-1, 30 °C, 10 MPa, 210 nm,
tR = 50.8 min.45
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2,2-dimethyl-3-phenyl-2H-1,4-benzoxazine (1b) (according to
ref.43). 2-aminophenole (3.00 g, 27.6 mmol) and potassium car-
bonate (3.80 g, 27.5 mmol) are added to acetone (100 mL). The
suspension is stirred for 3 h at room temperature. Potassium car-
bonate (6.00 g, 41.5 mmol) and 2-bromo-2-methyl-1-phenylpro-
pan-1-one (synthesis is described above) (4.60 ml, 27.6 mmol) are
added and the mixture is stirred under refluxing for 6 h. The solid
is filtered off, washed with acetone and the solvent evaporated in
vacuo. Cold, distilled water (200 mL) and diethylether (300 mL)
are added to the residue, phases are separated, the organic phase is
washed with HCl (1.5 M) and distilled water. The organic phase is
dried over magnesium sulfate and the solvent is evaporated in
vacuo. 1b (530 mg, 2.5 mmol, 9%) is obtained after flash column
chromatography (20-70% ethyl acetate in cyclohexane) as colorless
solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.59 (dd, J = 7.0, 2.8
Hz, 2H), 7.42 (m, 4H), 7.17 (td, J = 7.7, 1.5 Hz, 1H), 7.00 (td, J =
7.7, 1.5 Hz, 1H), 6.90 (dd, J = 8.0, 1.3 Hz, 1H), 1.59 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3) δ (ppm): 167.5, 145.9, 137.8,
133.6, 129.7, 129.0, 128.5, 127.9, 127.5, 122.0, 116.5, 74.7, 25.6.
MS (ESI) m/z calculated for C16H15NO [M+H]+: 238.1, found:
238.1. The analytical data corresponds with literature data.43 chiral
SFC-HPLC: Chiralpak® OJ-H (supercritical CO2:EtOH (Et2NH) =
90:10 (0.01), 1 mL min-1, 20 °C, 10 MPa, 210 nm, tR = 24.3 min.
Synthesis of rac-3,4-dihydro-2H-1,4-benzoxazines 2a-d as ref-
erence compounds.
3-phenyl-3,4-dihydro-2H-benzoxazine (2a). 1a (300 mg, 1.43
mmol) is dissolved in dichloromethane (5 mL). Hantzsch Ester
(507 mg, 2.00 mmol) and diphenylphosphate (18.0 mg, 0.07 mmol)
are added and the mixture is stirred for 24 h at 40 °C under argon
atmosphere. The solvent is evaporated in vacuo. 2a (266 mg, 1.26
mmol, 88%) is obtained after flash-column chromatography (1-
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1
10% ethyl acetate in cyclohexane) as colorless oil. H NMR (500
MHz, CDCl3) δ (ppm): 7.43–7.33 (m, 5H), 6.87–6.80 (m, 2H), 6.70
(ddd, J = 17.5, 7.7, 1.6 Hz, 2H), 4.52 (dd, J = 8.6, 3.0 Hz, 1H), 4.29
(dd, J = 10.6, 3.0 Hz, 1H), 4.01 (dd, J = 10.7, 8.6 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ (ppm): 142.9, 138.5, 133.3, 128.2,
127.7, 126.6, 120.9, 118.3, 116.0, 114.8, 70.4, 53.6. MS (ESI) m/z
calculated for C14H14NO [M+H]+: 212.1, found: 212.0. The analyt-
ical data corresponds with literature data.18 chiral SFC-HPLC:
Chiralpak® OJ-H (supercritical CO2:EtOH (Et2NH) = 85:15
(0.015), 1 mL min-1, 20 °C, 10 MPa, 210 nm, tR (S) = 28.7 min, tR
(R) = 30.6 min.
2,2-dimethyl-3,4-dihydro-3-phenyl-2H-1,4-benzoxazine (2b)
(according to ref.44). 1b (50.0 mg, 0.24 mmol) is diluted in
THF/H2O (1:1, 10 mL), sodiumhypophosphite-monohydrate
(76.0 mg, 0.70 mmol) and palladium on activated carbon (10%
w/w, 10.0 mg) are added and the mixture is stirred for 24 h at room
temperature. The suspension is filtered and washed with THF/H2O
(1:1). The filtrate is diluted with dH2O, extracted with diethylether,
the organic phase is dried over magnesium sulfate and the solvent
is evaporated in vacuo. 2b (34.0 mg, 0.14 mmol, 59%) is obtained
after flash-column chromatography as brownish oil. 1H NMR (500
MHz, CDCl3) δ (ppm): 7.43 (m, 2H), 7.34 (m, 3H), 6.84 (dd, J =
7.9, 1.3 Hz, 1H), 6.80 (td, J = 7.6, 1.4 Hz, 1H), 6.71 (td, J = 7.6,
1.5 Hz, 1H), 6.65 (dd, J = 7.7, 1.5 Hz, 1H), 4.21 (s, 1H), 3.99 (s,
1H), 1.31 (s, 3H), 1.17 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ (ppm): 142.6, 140.1, 133.3, 128.5, 128.4, 128.2, 121.1, 119.1,
117.1, 114.8, 62.8, 26.4, 20.5. MS (ESI) m/z calculated for:
C16H17NO [M+H]+: 240.1, found: 240.0. The analytical data corre-
sponds with literature data.44 chiral SFC-HPLC: Chiralpak® OJ-
H (supercritical CO2:EtOH (Et2NH) = 90:10 (0.01), 1 mL min-1,
20 °C, 10 MPa, 210 nm, tR (S) = 30.0 min, tR (R) = 40.3 min.
1-(2,3-difluoro-6-nitrophenoxy)propan-2-one (according to
ref.45). 2,3-difluoro-6-nitrophenole (2.12 g, 12.1 mmol) is dis-
solved in toluene (4 mL). Chloracetone (1.94 mL, 24.2 mmol), po-
tassium bromide (173 mg, 1.45 mmol), sodium bicarbonate (1.12
g, 13.3 mmol) and tributylmethylammoniumchloride (75% w/w in
dH2O, 0.26 mmol) are added and the mixture is stirred for 6 h at
65 °C. Chloracetone (0.49 mL, 6.04 mmol) is added and the mix-
ture is stirred for 18 h at 65 °C. Distilled water (4 mL) is added and
the pH is adjusted to 6.5-7. The phases are separated, the organic
phase is mixed with sodium chloride solution (5%, 8 mL) and
stirred for 10 min at 55-60 °C. The phases are separated, the organic
phase is dried over magnesium sulfate and the solvent is evaporated
in vacuo. 1-(2,3-Difluoro-6-nitrophenoxy)propan-2-one (2.53 g,
10.9 mmol, 91%) is obtained as yellow solid. 1H NMR (500 MHz,
CDCl3) δ (ppm): 7.73 (ddd, J = 9.4 Hz, JFH = 5.2, 2.4 Hz, 1H),
7.07–7.03 (m, 1H), 4.80 (d, JFH = 1.3 Hz, 2H), 2.31 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ (ppm): 203.0, 154.1 (dd,
JFC = 259.6, 11.5 Hz), 144.7 (dd, JFC = 252.9, 14.5 Hz), 142.6 (dd,
JFC = 10.9, 2.9 Hz), 140.0, 120.8 (dd, JFC = 9.0, 4.0 Hz), 111.8 (d,
JFC = 19.2 Hz), 78.2 (d, JFC = 5.3 Hz), 26.5. MS (ESI) m/z calcu-
lated for C9H7F2NO4Na [M+Na]+: 254.1, found: 254.0. The analyt-
ical data corresponds with literature data.45
7,8-difluoro-3-methyl-3,4-dihydro-2H-benzoxazine (2c) (ac-
cording to ref.45). 1-(2,3-Difluoro-6-nitrophenoxy)propan-2-one
(1.85 g, 8.00 mol) is dissolved in methanol (200 mL) and palladium
on activated carbon (800 mg, 7.52 mmol 10%wt) is added. The
mixture is stirred under hydrogen atmosphere (20 bar) in a high-
pressure autoclave for 6 h at room temperature. The suspension is
filtered, washed with diethylether and the solvent is evaporated in
vacuo. 2c (1.36 g, 7.35 mmol, 92%) is obtained as colorless oil after
flash-column chromatography (100% ethyl acetate). 1H NMR (500
MHz, CDCl3) δ (ppm): 6.55 (ddd, J = 10.0 Hz, JFH = 9.0, 7.8 Hz,
1H), 6.25 (ddd, J = 9.0 Hz, JFH = 4.7, 2.3 Hz, 1H), 4.28 (dd,
J = 10.5, 2.8 Hz, 1H), 3.78 (dd, J = 10.4, 8.2 Hz, 1H), 3.61 (s, 1H),
3.53–3.47 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ (ppm): 144.6 (dd, JFC = 236.9, 10.8 Hz), 140.8 (dd,
JFC = 244.2, 15.7 Hz), 133.4 (dd, JFC = 10.6, 2.8 Hz), 131.1 (t,
JFC = 2.5 Hz), 108.6 (dd, JFC = 7.4, 3.8 Hz), 107.9 (d, JFC = 18.3 Hz),
71.1, 45.0, 17.6. MS (ESI) m/z calculated for C9H10F2NO [M+H]+:
186.06, found: 186.0. The analytical data corresponds with litera-
ture data.45 chiral HPLC: Chiralpak® OJ-H (n-hexane:2-propanol
= 95:5, 0.8 mL min-1, 30 °C, 10 MPa, 210 nm, tR (R) = 24.5 min, tR
(S) = 26.3 min.45
7,8-difluoro-3-methyl-2H-benzoxazine (1c) (according to
ref.44). 1-(2,3-Difluoro-6-nitrophenoxy)propan-2-one (synthesis
described above) (540 mg, 2.33 mmol) is diluted in THF/H2O (1:1,
20 mL), sodiumhypophosphite-monohydrate (1.36 g, 12.8 mmol)
and palladium on activated carbon (10 wt%, 30.9 mg, 0.29 mol) are
added and the mixture is stirred for 15 min at room temperature.
The suspension is filtered and washed with THF/H2O (1:1). The
filtrate is diluted with dH2O, extracted with diethylether, the or-
ganic phase is dried over magnesium sulfate and the solvent is
evaporated in vacuo. 1c (194 mg, 1.32 mmol, 57%) is obtained after
flash-column chromatography (5-40% ethyl acetate in cyclohex-
1
ane) as brownish oil. H NMR (500 MHz, CDCl3) δ (ppm): 7.67
(ddd, J = 9.4 Hz, JFH = 5.2, 2.4 Hz, 1H), 6.99 (ddd, J = 9.3 Hz,
JFH = 8.7, 7.2 Hz, 1H), 4.80 (d, JFH = 1.3 Hz, 2H), 2.32 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ (ppm): 202.9, 154.0 (dd, JFC
=259.6, 11.5 Hz), 144.7 (dd, JFC =252.9, 14.5 Hz), 142.5 (dd, JFC
10.9, 2.9 Hz), 139.9, 120.7 (dd, JFC = 9.0, 4.0 Hz), 111.7 (d, JFC
=
=
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