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M. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1742–1747
(b) 2,5-Dichloro-2,5-dimethylhexane (1): Concentrated HCl (400 mL) was added
212 C (lit.2 210–211 °C). 1H NMR (DMSO-d6): d 13.65 (br s, 1H), 8.00 (t,
J = 7.5 Hz, 1H), 7.86 (dd, J = 8.0, 1.0 Hz, 1H), 7.77 (dd, J = 11.5, 1.0 Hz, 1H), 3.89
(s, 3H).
(j) Methyl 4-(chlorocarbonyl)-2-fluorobenzoate (9): A suspension of compound 8
(3.0 g, 15.2 mmol) in thionyl chloride (30 mL, 411 mmol) was stirred and
heated to reflux for 4 h. Excess thionyl chloride was removed in vacuo, the
residual was dissolved in benzene (10 mL) and evaporated to dryness three
times to remove residual thionyl chloride. The crude product was dried under
vacuum to afford 9 as a white solid (3.18 g, 97%), which was used directly for
next step.
(k) Methyl 2-nitro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-
carbonyl)benzoate (10): To a 250 mL round-bottomed flask fitted with water
condenser were added compound 2 (6.0 g, 29.7 mmol), compound 4 (7.57 g,
31.16 mmol) and CH2Cl2 (60 mL). To this vigorously stirred solution, aluminum
chloride (11.64 g, 87.3 mmol) was added slowly in portionwise which resulted
in rapid evolution of gaseous hydrochloride acid. The reaction mixture was
stirred at RT for 5 min followed by refluxing for an additional 30 min to give a
red solution. After the mixture was poured into ice and acidified with 2 N HCl
aqueous solution (55 mL), it was extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography with hexanes/EtOAc (from 50:3 to 50:5) to afford 10 as a
pale yellow solid (10.7 g, 88%), mp 115–116 °C (lit.2 115–116 °C). 1H NMR
(CDCl3): d 8.33 (d, J = 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.83 (d, J = 8.0,
1.0 Hz, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 3.97 (s, 3H), 2.38 (s, 3H), 1.70 (s, 4H), 1.32
(s, 6H), 1.21 (s, 6H).
to 2,5-dimethyl-2,5-hexanediol (50.0 g, 432 mmol) dropwise with gentle
swirling. The diol flakes gradually dissolved and a white precipitate formed
simultaneously. The reaction mixture was stirred at room temperature (RT) for
2 h; the white precipitate was filtered off and was washed with water until pH
ꢀ7 followed by cold EtOH. The solid was dried under vacuum to afford 1 as a
white solid (42.5 g, 68%), mp 63–65 C (lit.2 63–65.8 C, lit.19 63–65 °C). 1H NMR
(CDCl3): d 1.95 (s, 4H), 1.60 (s, 12H).
(c) 1,1,4,4,6-Pentamethyl-1,2,3,4-tetrahydronaphthalene (2): To
a 1000 mL
round-bottomed flask fitted with water condenser were added compound 1
(30.0 g, 165 mmol), toluene (35.1 mL, 330 mmol) and CH2Cl2 (150 mL). To this
vigorously stirred solution was added aluminum chloride (1.92 g, 1.4 mmol)
slowly in portionwise, which resulted in rapid evolution of gaseous
hydrochloride acid. The reaction mixture was stirred at RT for 30 min
followed by additional aluminum chloride (400 mg). After the reaction
mixture was stirred and heated to reflux for 15 min, it was cooled in an ice
bath and quenched with 20% HCl aqueous solution (150 mL). The mixture was
extracted with hexanes; the combined organic layers were washed with water
and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by column chromatography with hexanes to
afford 2 as a white solid (28.3 g, 85%), mp 34–35 °C (lit.2 34–36 °C). 1H NMR
(CDCl3): d 7.40 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 2.49 (s,
3H), 1.87 (s, 4H), 1.48(s, 6H), 1.47 (s, 6H).
(d) 4-(Methoxycarbonyl)-3-nitrobenzoic acid (3): To
a stirred solution of
dimethyl-2-nitroterephthalate (24.0 g, 100.4 mmol) in dioxane (200 mL) was
added 1 N NaOH aqueous solution (100 mL) dropwise. The reaction mixture
was stirred at RT overnight, water (200 mL) was added and the yellow solution
was washed with diethyl ether (200 mL) twice. The aqueous layer was acidified
with 1 N HCl aqueous solution (120 mL) until pH ꢀ1, it was extracted with
EtOAc. The combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The crude product was recrystallized in
water to afford 3 as a white solid (11.6 g, 51%), mp 177–179 °C (lit.2 177–
179 °C). 1H NMR (DMSO-d6): d 13.9 (br s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.34 (dd,
J = 8.0, 1.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H).
(e) Methyl 4-(chlorocarbonyl)-2-nitrobenzoate (4): A suspension of compound 3
(10.0 g, 44.4 mmol) in thionyl chloride (100 mL, 1.37 mol) was stirred and
heated to reflux for 4 h. Excess thionyl chloride was removed in vacuo, the
residual was dissolved in benzene (30 mL) and evaporated to dryness three
times to remove residual thionyl chloride. The crude product was dried under
vacuum to afford 4 as a pale yellow solid (10.6 g, 98%), which was used directly
for next step.
(f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of 2-
fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in
acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the
reaction mixture was heated to reflux overnight, the solvent was removed in
vacuo. The residual was diluted with EtOAc, washed with water and brine,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography with hexanes/EtOAc (6:1) to
afford 5 as a white solid (1.73 g, 79%), mp 51–53 °C. 1H NMR (CDCl3): d 7.83 (t,
J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,
3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoic
acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric
acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the
solvent was removed in vacuo. The residual was diluted with EtOAc, washed
with saturated NaHCO3 aqueous solution and brine, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The crude product was purified by
column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid
(6.88 g, 90%). Analytical data were same as above.
(l) Methyl 2-fluoro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-
carbonyl)benzoate (11): To a 100 mL round-bottomed flask fitted with water
condenser were compound
2 (2.03 g, 10.1 mmol), compound 9 (2.0 g,
9.3 mmol) and CH2Cl2 (25 mL). To this vigorously stirred solution, aluminum
chloride (3.03 g, 22.7 mmol) was added slowly in portionwise which resulted
in rapid evolution of gaseous hydrochloride acid. The reaction mixture was
stirred at RT for 5 min followed by refluxing for an additional 30 min to give a
red solution. After the mixture was poured into ice and acidified with 2 N HCl
aqueous solution (15 mL), it was extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography with hexanes/EtOAc (25:2) to afford 11 as a white solid
(2.99 g, 84%), mp 105–107 °C (lit.2 105–106 °C). 1H NMR (CDCl3): d 8.01 (t,
J = 7.5 Hz, 1H), 7.60 (dd, J = 8.0, 1.5 Hz, 1H), 7.57 (dd, J = 10.5, 1.0 Hz, 1H), 7.26
(s, 1H), 7.22 (s, 1H), 3.97 (s, 3H), 2.35 (s, 3H), 1.70 (s, 4H), 1.32 (s, 6H), 1.21 (s,
6H).
(m) Methyl 2-nitro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)vinyl)benzoate (12): To
a suspension of methyltriphenylphosphonium
bromide (3.0 g, 8.4 mmol) in THF (5 mL) was added a 2.5 M solution of n-
butyl lithium in hexanes (4.5 mL, 3.72 mmol). The red solution was stirred at
RT for 30 min to give
triphenylphosphonium methylide solution was added to
a
triphenylphosphonium methylide solution. The
solution of
a
compound 10 (2.24 g, 5.46 mmol) in THF (10 mL) dropwise. After the
reaction mixture was stirred at RT for 5 h, it was pour into ice water and
extracted with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography with hexanes/EtOAc (10:1)
followed by preparative TLC plates with hexanes/EtOAc (4:1) to afford 12 as a
pale yellow solid (147 mg, 7%). 1H NMR (CDCl3): d 7.77 (d, J = 2.0 Hz, 1H), 7.69
(d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.10 (s, 1H), 7.09 (s, 1H), 5.88 (s,
1H), 5.43 (s, 1H), 1.96 (s, 3H), 1.70 (s, 4H), 1.31 (s, 6H), 1.27 (s, 6H).
(n) Methyl 2-fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-
(g) Methyl 4-(dibromomethyl)-2-fluorobenzoate (6): To a stirred solution of
yl)vinyl)benzoate (13): To a suspension of methyltriphenylphosphonium
compound
5
(7.5 g, 44.6 mmol) in CCl4 (60 mL) was added NBS (19.1 g,
bromide (1.0 g, 2.8 mmol) in THF (2 mL) was added a 2.5 M solution of n-
107.1 mmol), followed by benzoylperoxide (721 mg, 2.23 mmol). After the
reaction mixture was heated to reflux for 36 h, it was cooled to RT. The solid
was filtered off and washed with CCl4. The combined filtrates were
concentrated in vacuo to afford the crude product 6, which was dried under
vacuum and used directly for next step.
(h) Methyl 2-fluoro-4-formylbenzoate (7): To a stirred and preheated solution
(50 °C) of compound 6 (44.6 mmol) in EtOH (125 mL) was added silver nitrate
(15.9 g, 93.7 mmol) in warm water (22 mL) dropwise at 50 °C. Upon addition of
butyl lithium in hexanes (1.5 mL, 3.72 mmol). The red solution was stirred at
RT for 30 min to give
triphenylphosphoniu methylide solution was added to
a
triphenylphosphoniu methylide solution. The
solution of
a
compound 11 (694 mg, 1.82 mmol) in THF (3 mL) dropwise. After the
reaction mixture was stirred at RT for 1 h, it was pour into ice water and
extracted with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by preparative TLC plates with hexanes/EtOAc (97:3) to
afford 13 as a white solid (130 mg, 19%), mp 131–133 °C (lit.2 130–132 C). 1H
NMR (CDCl3): d 7.86 (t, J = 8.0 Hz, 1H), 7.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.10 (s, 1H),
7.08 (s, 1H), 7.01 (dd, J = 12.5, 1.5 Hz, 1H), 5.82 (s, 1H), 5.35 (s, 1H), 3.92 (s, 3H),
1.95 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.27 (s, 6H).
(o) 2-Nitro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)vinyl)benzoic acid (14): To a stirred solution of compound 12 (100 mg,
0.25 mmol) in MeOH (3 mL) was added 5 N KOH aqueous solution (0.12 mL,
0.61 mmol). After the reaction mixture was stirred and heated to reflux for 2 h,
it was cooled and acidified with 2 N HCl aqueous solution, and extracted with
EtOAc. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was
triturated with cold hexanes, and filtered. The solid was washed with small
amount of cold hexanes to afford 14 as a pale yellow solid (89.1 mg, 92%), mp
210–212 °C (lit.2 212–214 °C). 1H NMR (CDCl3): d 7.85 (d, J = 8.5 Hz, 1H), 7.70
(d, J = 1.0 Hz, 1H), 7.52 (dd, J = 8.0, 1.5 Hz, 1H), 7.11 (s, 1H), 7.10 (s, 1H), 5.91(s,
1H), 5.46 (s, 1H), 1.97 (s, 3H), 1.70 (s, 4H), 1.31 (s, 6H), 1.27 (s, 6H). LC–MS (ESI,
m/z): calcd for C24H31N2O4 ([M+NH4]+) 411.2, found 411.0; calcd for C24H26NO4
([MÀH]À) 392.2, found 392.0.
the silver nitrate solution,
a green precipitate formed. After the reaction
mixture was stirred at 50 °C for 1 h, it was cooled to RT and the green
precipitate was filtered off. The filtrate was concentrated in vacuo, and
extracted with EtOAc. The combined layers were washed with water and brine,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography with hexanes/EtOAc (from
12:1 to 8:1) to afford 7 as a white solid (4.67 g, 53%), mp 75–76 C. 1H NMR
(CDCl3): d 10.05 (d, J = 1.5 Hz, 1H), 8.11 (t, J = 7.5 Hz, 1H), 7.73 (dd, J = 8.0,
1.5 Hz, 1H), 7.65 (dd, J = 10.0, 1.5 Hz, 1H), 3.98(s, 3H).
(i) 3-Fluoro-4-(methoxycarbonyl)benzoic acid (8): To
a stirred solution of
compound 7 (4.37 g, 24.0 mmol) and sulfamic acid (2.56 g, 26.4 mmol) in
acetonitrile (30 mL) and water (15 mL) was added a solution of 80% NaClO2
(2.9 g, 15.6 mmol) in water (15 mL) dropwise. After the reaction mixture was
stirred at RT for 2 h, it was poured into saturated Na2SO3 solution (35 mL) and
1 N HCl aqueous solution (70 mL), and extracted with EtOAc. The combined
layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The crude product was washed with small amount of
hexanes/EtOAc (5:1) solution to afford 8 as a white solid (4.06 g, 85%), mp 211–
Wang, Min
