4226 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Barker et al.
(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) (0.5
M in toluene, 5.6 mL, 2.8 mmol), the mixture was allowed to come
to room temperature and stirred for 2 h, and then ether (10 mL)
was added. The reaction was quenched by the cautious addition of
2 M NaOH solution, filtered, and dried over MgSO4. Volatiles were
removed in vacuo to give an orange oil (1.6 g). Purification by
Biotage eluting with DCM gave 0.3 g (61%) of the methylene
filtered off, and the organic layer of the filtrate was separated. The
aqueous layer was extracted with EtOAc, and the combined organic
solutions were dried and evaporated to a brown oil. Purification
by silica SPE eluting with DCM, chloroform, ether, and EtOAc
gave 24 mg of 22 (75%) as a yellow solid. LC/MS: tR ) 3.04
min; MH+ ) 462, MH- ) 460. 1H NMR (CD3OD, 400 MHz): δ
8.26-8.18 (m, 2 H), 8.13 (dd, J ) 8.5, 2.0 Hz, 1 H), 6.68 (t, J )
7.5 Hz, 1 H), 6.59 (d, J ) 7.5 Hz, 1 H), 6.44 (d, J ) 8.0 Hz, 1 H),
2.94 (m, 1 H), 2.62 (dd, J ) 15.0, 5.0 Hz, 1 H), 2.56-2.45 (m, 5
H), 2.37 (m, 1 H), 2.06 (dd, J ) 15.0, 8.0 Hz, 1 H), 2.05-1.88 (m,
2 H), 1.86-1.75 (m, 2 H). HRMS for C23H23F3N3O4 (MH+): calcd
462.1641, found 462.1633.
1
compound as a yellow oil. H NMR (CDCl3, 400 MHz): δ 7.34
(m, 1H), 7.19 (m, 1H), 6.77 (d, J ) 5.7 Hz, 1H), 5.54 (s, 1H), 5.03
(s, 1H), 3.86 (s, 3H), 2.85 (m, 2H), 2.52 (m, 2H), 1.93 (m, 2H).
The methylene compound (143 mg, 0.82 mmol) and 12 (312
mg, 0.98 mmol) were mixed together in a flask and then placed
into a preheated (200°C) oil bath for 10 min and cooled to room
temperature. Purification on a 10-g Si SPE cartridge eluting with
2-[(5-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-
trifluoro-2-hydroxy-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-
propanamide (23a-23f) was prepared from 5-bromotetralone
similarly to 17 utilizing the Wittig reagent. LC/MS (diastereomer
1, 23a): tR ) 3.78 min, (diastereomer 2, 23b) tR ) 3.85 min; MH+
) 525, 527, MH- ) 523, 525 (both peaks). 23a: 1H NMR (CDCl3,
400 MHz): δ 8.96 (s, 1 H), 8.37 (d, J ) 8.5 Hz, 1 H), 8.29 (d, J
) 2.0 Hz, 1 H), 7.77 (dd, J ) 8.5, 2.0 Hz, 1 H), 7.33 (d, J ) 7.5
Hz, 1 H), 7.17 (d, J ) 7.5 Hz, 1 H), 6.91 (t, J ) 7.5 Hz, 1 H), 3.09
(m, 1 H), 2.85 (m, 1 H), 2.75-2.65 (m, 2 H), 2.62 (s, 3 H), 2.26
(dd, J ) 15.0, 8.0 Hz, 1 H), 1.96-1.84 (m, 4 H). HRMS for C23H21-
BrF3N2O4 (MH+): calcd 525.0367, found 525.0640. 23b: 1H NMR
(CDCl3, 400 MHz): δ 9.16 (s, 1 H), 8.40-8.36 (m, 2 H), 7.87
(dd, J ) 8.5, 2.0 Hz, 1 H), 7.41 (d, J ) 7.0 Hz, 1 H), 7.17 (d, J )
7.5 Hz, 1 H), 7.01 (t, 7.5 Hz, 1 H), 3.20 (m, 1 H), 2.85-2.68 (m,
2 H), 2.71 (d, J ) 9.5 Hz, 1 H), 2.64 (s, 3 H), 2.24 (dd, J ) 15.1,
3.5 Hz, 1 H), 1.86 (s, 1 H), 1.77 (s, 1 H), 1.68 (t, J ) 4.3 Hz, 2 H).
HRMS for C23H21BrF3N2O4 (MH+): calcd 525.0637, found 525.0634.
Compound 23a was separated into its enantiomers using a 25
cm Chiralcel OD-H column eluting with 15% EtOH in heptane
with a flow rate of 15 mL/min. Compound 23c (enantiomer 1)
eluted around 10.6 min and 23d (enantiomer 2) around 16.0 min.
Analytical chiral HPLC (25 × 0.46 cm Chiralcel OD-H column,
15% EtOH in heptane eluting at 1 mL/min): 11.41 min (enantiomer
1) and 17.83 min (enantiomer 2). LC/MS: tR ) 3.78 min; MH+ )
525, 527, MH- ) 523, 525 (both peaks). Compound 23b was
separated into its enantiomers using a 25 cm Chiralpak AD column
eluting with 15% IPA in heptane with a flow rate of 15 mL/min.
Compound 23e (enantiomer 1) eluted around 12.6 min and 23f
(enantiomer 2) around 15.7 min. Analytical chiral HPLC (25 ×
0.46 cm Chiralpak AD column, 15% IPA in heptane eluting at 1
mL/min): 9.55 min (enantiomer 1) and 11.80 min (enantiomer 2).
LC/MS: tR ) 3.85 min; MH+ ) 525, 527, MH- ) 523, 525 (both
peaks).
1-Methyl-1,2,3,4-tetrahydronaphthalen-1-ol (31). Cerium chlo-
ride (25 g) was suspended in anhydrous THF (100 mL) at 5 °C
and then stirred for 1.5 h under nitrogen. The mixture was cooled
to -70 °C and methyllithium (64 mL of a 1.6 M solution in Et2O)
was added over 15 min. When addition was complete, the mixture
was stirred for 30 min then a solution of R-tetralone (9.85 g) in
THF (50 mL) was added over 30 min and stirring at -65 °C was
continued for 2 h. The ice bath was removed and the mixture was
stirred at room temperature overnight, quenched with 5% acetic
acid (100 mL), filtered through Celite, and extracted with EtOAc
(400 mL). The aqueous layer was further extracted with EtOAc (2
× 100 mL), and the combined extracts were washed with water
(1×) and brine (2×), dried over magnesium sulfate, and evaporated
in vacuo to a brown solid (10.32 g). Flash chromatography using
cyclohexane:EtOAc 20:1 gave the product 31 as a white solid (5
g). 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J ) 7.5 Hz, 1H), 7.16-
7.07 (m, 2H), 6.90 (d, J ) 7.5 Hz, 1H), 2.78-2.64 (m, 2H), 1.89-
1.69 (m, 5H), 1.48 (s, 3H). LC/MS: tR ) 3.62 min; MH+ ) 163.
TLC: SiO2, 18:2 cyclohexane:EtOAc, Rf ) 0.22.
1
4% MeCN/DCM gave 301 mg (77%) of the coupled product. H
NMR (CDCl3, 400 MHz): δ 8.27 (d, J ) 9.0 Hz, 1H), 8.10 (s,
1H), 7.50 (m, 1H), 7.08 (t, J ) 7.05 Hz, 1H), 6.90 (d, J ) 7.05
Hz, 1H), 6.67 (d, J ) 7.05 Hz, 1H), 6.15 (m, 1H), 3.73 (s, 3H),
3.62 (d, J ) 15.1 Hz, 1H), 3.12 (d, J ) 15.1 Hz, 1H), 2.58 (m,
2H), 2.55 (s, 3H), 2.22 (m, 2H). LC/MS: tR ) 3.38 min; MH-
473.
)
A mixture of the coupled product (100 mg, 0.21 mmol), tosyl
hydrazide (78 mg, 0.42 mmol), and NMP (7 drops) was heated at
150 °C for 16 min, during which time further quantities (78 mg)
of tosyl hydrazide were added every 4 min. The mixture was cooled
and applied directly to a Si SPE cartridge eluted with DCM and
1-3% MeCN/DCM mixtures. The appropriate fractions were
combined and evaporated to give a yellow foam that was subjected
to mass-directed autopreparation to give 12.4 mg (25%) of 17
(diastereomer 1) and 16.7 mg (33%) of diastereomer 2. LC/MS:
tR ) 3.56 min (diastereomer 1) and 3.61 min (diastereomer 2); both
1
peaks MH+ ) 477, MH- ) 475. H NMR (CD3OD, 400 MHz):
δ 8.29-8.26 (m, 2H), 8.16 (m, 1 H), 6.89 (t, J ) 7.5 Hz, 1 H),
6.79 (d, J ) 7.5 Hz, 1 H), 6.58 (d, J ) 7.5 Hz, 1 H), 3.73 (s, 3H),
2.99 (m, 1 H), 2.72-2.61 (m, 2 H), 2.55 (s, 3 H), 2.50 (m, 1H),
2.08 (dd, J ) 15, 8.5, Hz 1 H), 2.00 (m, 1 H), 1.92-1.72 (m, 3 H).
HRMS for C24H24F3N2O5 (MH+): calcd 477.1637, found 477.1628.
3,3,3-Trifluoro-2-hydroxy-N-(4-methyl-1-oxo-1H-2,3-benzox-
azin-6-yl)-2-[(5-nitro-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-
propanamide (24). To a suspension of methyltriphenylphospho-
nium bromide (4.4 g, 12.5 mmol) in THF (50 mL) at -45 °C was
added a solution of BuLi (1.6 M in hexanes, 7.3 mL, 11.7 mmol).
The resulting dark red suspension was stirred at -45 °C for 1 h
and then a solution of 5-nitrotetralone25 (1.5 g, 7.8 mmol) in THF
(25 mL) was added over 5 min. The reaction mixture was allowed
to come to room temperature and then poured slowly onto water.
The aqueous mixture was extracted with cyclohexane, and the
combined extracts were dried and evaporated in vacuo. Purification
of the residue via Biotage eluting with 2.5% EtOAc/cyclohexane
1
gave 970 mg (66%) of the Wittig product. H NMR (CDCl3, 400
MHz): δ 7.88 (d, J ) 7 Hz, 1H), 7.72 (d, J ) 7 Hz, 1H), 7.29 (t,
J ) 7 Hz, 1H), 5.51 (s, 1H), 5.12 (s, 1H), 3.02 (t, J ) 7 Hz, 2H),
2.63 (m, 2H), 1.9 (m, 2H).
Further reaction of the Wittig product was similar to that
described for 17 to give a mixture of diastereomers. Mass-directed
autopreparation separated diastereomer 1 (24) as a yellow gum.
1H NMR (CDCl3, 400 MHz): δ 9.25 (s, 1 H), 8.38 (d, J ) 8.5 Hz,
1 H), 8.33 (d, J ) 2.0 Hz, 1 H), 7.79 (dd, J ) 8.5, 2.0 Hz, 1 H),
7.60 (d, J ) 8.0 Hz, 1 H), 7.53 (d, J ) 7.5 Hz, 1 H), 7.21 (t, J )
8.0 Hz, 1 H), 5.38 (br s, 1 H), 3.12 (m, 1 H), 3.02-2.87 (m, 2 H),
2.70 (dd, J ) 14.5, 3.5 Hz, 1 H), 2.62 (s, 3 H), 2.21 (dd, J ) 14.5,
9.0 Hz, 1 H), 2.03-1.78 (m, 4 H). LC/MS: tR ) 3.5 min; MH+
)
492, MH- ) 490. HRMS for C23H21F3N3O6 (MH+): calcd
492.1382, found 492.1378.
2-[(5-Amino-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-
trifluoro-2-hydroxy-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-
propanamide (22). A mixture of 24 (33 mg, 0.07 mmol), tin(II)
chloride (90 mg, 0.4 mmol), and THF (1 mL) was heated at 60 °C
for 45 min and then allowed to stir at room temperature overnight.
The reaction mixture was diluted with EtOAc and the pH was taken
to 6 using sodium bicarbonate solution. Precipitated solids were
Methyl 3-(1-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-oxo-
propanoate (32). To 31 (0.73 g) and methyl 2-(trimethylsiloxy)-
acrylate26 (1.8 g) in CHCl3 (250 mL) at -60 °C was added tin
tetrachloride (1 M in DCM) (3.4 mL) dropwise over 30 s. After 5
min the reaction was quenched with brine (50 mL) and the organic
layer separated, dried (MgSO4), and concentrated in vacuo. This