642
H.-P. Buchstaller, U. Anlauf
PAPER
2-Methyl-2-(4-methyl-2-nitrophenoxy)propionamide (7c)
From compound 6c (416 mg, 1.74 mmol), SOCl2 (1.6 mL), and tol-
uene (3 mL); reflux, 2 h; NH4OH (32%, 242 mL) in toluene (2 mL),
1 h; yield: 390 mg (94%); yellow oil (crystallized upon standing).
2-Methyl-1-[(4-methyl-2-nitrophenyl)amino]propan-2-ol (8c)
From compound 7c (100 mg, 0.42 mmol), borane/dimethyl sulfide
complex (120 mL, 1.26 mmol), and THF (1.5 mL); 65 °C, 1.5 h; pu-
rification: column chromatography (12 g silica gel, eluent: Et2O–
petroleum ether, 2:3); yield: 50 mg (53%); red oil.
2-Methyl-2-(5-methyl-2-nitrophenoxy)propionamide (7d)
From compound 6d (243 mg, 1.02 mmol), SOCl2 (0.92 mL), and
toluene (3 mL); reflux, 1.5 h; NH4OH (32%, 141 mL) in toluene (2
mL), 1 h; yield: 230 mg (95%); brown oil (crystallized upon stand-
ing).
1H NMR (250 MHz, DMSO-d6): d = 8.22 (t, 1 H, NH), 7.87 (d, 1 H,
3
4
4J = 2.1 Hz, 3¢-H), 7.37 (dd, 1 H, J = 8.8 Hz, J = 2.1 Hz, 5¢-H),
3
7.01 (d, 1 H, J = 8.8 Hz, 6¢-H), 4.78 (s, 1 H, OH), 3.23 (d, 2 H,
3J = 5.2 Hz, CH2), 2.22 (s, 3 H, CH3), 1.19 (s, 6 H, 2 CH3).
HRMS: m/z calcd for C11H16N2O3: 224.1161; found: 224.1159.
2-Methyl-2-(5-fluoro-2-nitrophenoxy)propionamide (7e)
From compound 6e (302 mg, 1.24 mmol), SOCl2 (1.13 mL), and
toluene (3 mL); reflux, 2 h; NH4OH (32%, 173 mL) in toluene (2
mL), 1 h; yield: 130 mg (43%); yellow oil.
2-Methyl-1-[(5-methyl-2-nitrophenyl)amino]propan-2-ol (8d)
From compound 7d (97 mg, 0.41 mmol), borane/dimethyl sulfide
complex (116 mL, 1.22 mmol), and THF (1.5 mL); 65 °C, 1.5 h; pu-
rification: column chromatography (12 g silica gel, eluent: Et2O–
petroleum ether, 2:3); yield: 20 mg (22%); yellow solid; mp 127 °C.
2-Methyl-2-(4-chloro-5-methyl-2-nitrophenoxy)propionamide
(7f)
From compound 6f (215 mg, 0.79 mmol), SOCl2 (0.71 mL), and tol-
uene (3 mL); reflux, 1.5 h; NH4OH (32%, 109 mL) in toluene (2
mL), 1 h; yield: 210 mg (98%); yellow oil (crystallized upon stand-
ing).
1H NMR (250 MHz, DMSO-d6): d = 8.34 (t, 1 H, NH), 7.96 (d, 1 H,
4J = 8.8 Hz, 3¢-H), 6.88 (d, 1 H, 6¢-H), 6.5 (dd, 1 H, 3J = 8.8 Hz, 4¢-
3
H), 4.81 (s, 1 H, OH), 3.24 (d, 2 H, J = 5 Hz, CH2), 2.3 (s, 3 H,
CH3), 1.21 (s, 6 H, 2 CH3).
HRMS: m/z calcd for C11H16N2O3: 224.1161; found: 224.1159.
2-Methyl-1-[(2-nitro-4-trifluoromethylphenyl)amino]propan-
2-ol (8a); Typical Procedures
2-Methyl-1-[(5-fluoro-2-nitrophenyl)amino]propan-2-ol (8e)
From compound 7e (100 mg, 0.41 mmol), borane/dimethyl sulfide
complex (117 mL, 1.24 mmol), and THF (1.5 mL); 65 °C, 1.5 h; pu-
rification: column chromatography (12 g silica gel, eluent: Et2O–
petroleum ether, 2:3); yield: 44 mg (47%); yellow solid; mp 101 °C.
1H NMR (250 MHz, DMSO-d6): d = 8.44 (t, 1 H, NH), 8.17 (dd, 1
H, 3J = 9.6 Hz, 4JH,F = 6.4 Hz, 3¢-H), 6.91 (dd, 1 H, 3JH,F = 12.4 Hz,
4J = 2.7 Hz, 6¢-H), 6.52 (m, 1 H, 4¢-H), 4.83 (s, 1 H, OH), 3.25 (d, 2
H, 3J = 5.3 Hz, CH2), 1.19 (s, 6 H, 2 CH3).
Method A; from 7a: To a solution of compound 7a (131 mg, 0.45
mmol) in THF (1.5 mL) was added borane/dimethyl sulfide com-
plex (127 mL, 1.34 mmol) at r.t. and the reaction mixture was stirred
for 1 h at 70 °C. The mixture was cooled to 0 °C and cautiously
treated with conc. aq HCl (pH 1–2). The mixture was rendered basic
with 2 M aq NaOH solution and extracted with EtOAc. The com-
bined organic layers were successively washed with H2O and brine,
dried (Na2SO4), and concentrated in vacuo. The crude product was
purified by column chromatography (12 g silica gel, eluent: Et2O–
petroleum ether, 2:3) to yield 8a (87 mg, 70%) as a yellow solid; mp
77 °C.
HRMS: m/z calcd for C10H13FN2O3: 228.0910; found: 228.0913.
2-Methyl-1-[(4-chloro-5-methyl-2-nitrophenyl)amino]propan-
2-ol (8f)
From compound 7f (110 mg, 0.40 mmol), borane/dimethyl sulfide
complex (115 mL, 1.21 mmol), and THF (1.5 mL); 65 °C, 1.5 h; pu-
rification: column chromatography (12 g silica gel, eluent: Et2O–
petroleum ether, 2:3); yield: 49 mg (47%); yellow solid; mp 123 °C.
1H NMR (250 MHz, DMSO-d6): d = 8.3 (t, 1 H, NH), 8.03 (s, 1 H,
3¢-H), 7.13 (s, 1 H, 6¢-H), 4.83 (s, 1 H, OH), 3.27 (d, 2 H, 3J = 5.2
Hz, CH2), 2.33 (s, 3 H, CH3), 1.2 (s, 6 H, 2 CH3).
1H NMR (500 MHz, DMSO-d6): d = 8.59 (t, 1 H, NH), 8.32 (d, 1 H,
4J = 2.3 Hz, 3¢-H), 7.77 (dd, 1 H, 3J = 9.3 Hz, 4J = 2.3 Hz, 5¢-H), 7.3
(d, 1 H, 3J = 9.3 Hz, 6¢-H), 4.88 (s, 1 H, OH), 3.34 (d, 2 H, 3J = 5.3
Hz, CH2), 1.21 (s, 6 H, 2 CH3).
HRMS: m/z calcd for C11H13F3N2O3: 278.0878; found: 278.0872.
Method B; from 3a: To a solution of compound 3a (35 mg, 0.12
mmol) in THF (1.5 mL) was added borane/dimethyl sulfide com-
plex (35 mL, 0.36 mmol) and the reaction mixture was stirred for 1
h at 60 °C. The mixture was cooled and cautiously treated with
conc. aq HCl (pH 1–2). The mixture was rendered basic with 2 M
aq NaOH solution and extracted with EtOAc. The combined organ-
ic layers were successively washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The crude product was puri-
fied by column chromatography (12 g silica gel, eluent: Et2O–petro-
leum ether, 2:8) to yield 8a (20 mg, 60%) as a yellow oil
(crystallized upon standing).
HRMS: m/z calcd for C11H15ClN2O3: 258.0771; found: 258.0767.
4-Hydroxy-2,2-dimethyl-6-trifluoromethyl-4H-1,4-benzoxazin-
3-one (9)
Method A: To a solution of 7a (300 mg, 1.03 mmol) in EtOH (3 mL)
was added SnCl2·2H2O (1.16 g, 5.13 mmol) and the reaction mix-
ture was stirred for 1 h at 70 °C. The mixture was cooled, rendered
basic with sat. aq NaHCO3 solution and the precipitate was filtered
off and washed with EtOH and EtOAc. The filtrate was concentrat-
ed in vacuo and extracted with EtOAc. The organic layer was suc-
cessively washed with H2O and brine, dried (Na2SO4), and
concentrated in vacuo to give 9 (226 mg, 84%) as a pale-brown sol-
id; mp 130 °C.
2-Methyl-1-[(2-nitrophenyl)amino]propan-2-ol (8b)
From compound 7b (100 mg, 0.45 mmol), borane/dimethyl sulfide
complex (127 mL, 1.34 mmol), and THF (1.5 mL); 70 °C, 1 h; puri-
fication: column chromatography (12 g silica gel, eluent: Et2O–pe-
troleum ether, 2:3); yield: 34 mg (36%); yellow solid; mp 81.5 °C.
1H NMR (250 MHz, DMSO-d6): d = 8.31 (t, 1 H, NH), 8.06 (dd, 1
H, 3J = 8.6 Hz, 4J = 1.6 Hz, 3¢-H), 7.52 (m, 1 H, 5¢-H), 7.07 (d, 1 H,
3J = 8.7 Hz, 6¢-H), 6.67 (m, 1 H, 4¢-H), 4.81 (s, 1 H, OH), 3.25 (d, 2
H, 3J = 5.2 Hz, CH2), 1.21 (s, 6 H, 2 CH3).
1H NMR (250 MHz, DMSO-d6): d = 11.07 (s, 1 H, OH), 7.45–7.35
(m, 2 H, 5-H, 7-H), 7.18 (d, 1 H, 8-H), 1.49 (s, 6 H, 2 CH3).
Method B: Compound 7a (200 mg, 0.68 mmol) was hydrogenated
at r.t. overnight using Pd/C in THF (10 mL). The mixture was fil-
tered through Kieselguhr and rinsed with THF, and the filtrate was
subsequently evaporated. The residue was purified by column chro-
matography (12 g silica gel, eluent: petroleum ether–EtOAc, 9:1);
yield: 125 mg (70%).
HRMS: m/z calcd for C10H14N2O3: 210.1004; found: 210.1004.
Synthesis 2005, No. 4, 639–643 © Thieme Stuttgart · New York