Journal of Medicinal Chemistry
Article
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compound 3a as a white solid (1.10 g, 91% over 2 steps). H NMR
(400 MHz, CDCl3, δ): 3.84 (s, 6H), 6.44 (s, 1H), 6.69 (s, 2H), 6.97−
7.01 (d, J = 16.24 Hz, 1H), 7.36−7.40 (m, 2H), 7.50−7.52 (d, J = 8.42
Hz, 1H), 7.55 (s, 1H). 13C NMR (100 MHz, CDCl3, δ): 55.51, 100.60,
105.11, 121.37, 124.27, 127.60, 130.27, 131.89, 132.43, 134.20, 134.41,
138.81, 161.12. ASAP−MS (m/z): [M + H]+ calcd for C16H14BrClO2,
352.9939; found, 352.9939.
as a white crystalline solid (0.022 g, 88%) with mp 186.0 °C. 1H NMR
(500 MHz, CD3OD, δ): 6.23 (s, 1H), 6.52 (s, 2H), 7.05−7.09 (d, J =
16.20 Hz, 1H), 7.41−7.45 (d, J = 16.23 Hz, 1H), 7.54−7.56 (d, J =
7.85 Hz, 1H), 7.63 (s, 1H), 7.75−7.76 (d, J = 7.81 Hz, 1H). 13C NMR
(125 MHz, CD3OD, δ): 103.77, 106.32, 124.88, 126.71, 133.26,
133.34, 133.90, 135.91, 137.59, 140.29, 159.89. HRMS−ESI (m/z):
[M − H]− calcd for C14H12BClO4, 288.0481; found, 288.0482.
3-[(1E)-2-(4-Bromophenyl)ethenyl]benzoic Acid Methyl Ester
(5a). Ethyl 3-(bromomethyl)benzoate (2.0 g, 8.7 mmol) was dissolved
in neat triethylphosphite (1.78 mL, 10.4 mmol) and heated to 150 °C
for 4 h. The reaction mixture was cooled to 0 °C and diluted with
DMF (87 mL). NaH (60% w/v in mineral oil, 0.69 g, 17.46 mmol)
was added to the resulting solution, and the reaction mixture stirred at
0 °C for 20 min. A solution of 4-bromobenzaldehyde (1.62 g, 8.73
mmol) in DMF (87 mL) was then added dropwise. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. The reaction mixture was then diluted with EtOAc (50 mL)
and washed with 10% w/v citric acid (20 mL), followed by brine (20
mL). The organic layer was separated, dried with Na2SO4(s), and
filtered. The solvent was removed under reduced pressure, and the
crude product was purified by flash column chromatography (10% v/v
EtOAc in hexanes) to afford the 5a as a white solid (1.75 g, 63% over 2
steps). 1H NMR (500 MHz, CD3OD, δ): 3.84 (s, 3H), 6.94−6.96 (d, J
= 8.70 Hz, 2H), 7.09−7.12 (d, J = 16.28, 1H), 7.20−7.25 (d, J = 16.41
Hz, 1H), 7.45−7.48 (t, J = 7.67, 1H), 7.53−7.55 (d, J = 8.62 Hz, 2H),
7.76−7.78 (d, J = 7.85 Hz, 1H), 7.88−7.90 (d, J = 7.72, 1H), 8.18 (s,
1H). 13C NMR (125 MHz, CD3OD, δ): 54.31, 113.73, 124.97, 126.93,
127.58, 127.80, 128.40, 129.13, 130.01, 138.21, 159.72, 168.62.
HRMS−ESI (m/z): M+• calcd for C16H13BrO2, 316.0094; found,
316.0081.
5-[(1E)-2-(2-Chloro-4-bromo)ethenyl]-1,3-benzenediol (3b).
Compound 3a (0.500 g, 1.42 mmol) was dissolved in DCM (14
mL), and the reaction mixture was cooled to 0 °C. A solution of 1.0 M
BBr3 (7.10 mmol) in DCM (7.1 mL) was then added dropwise at 0
°C. The reaction mixture was allowed to warm to room temperature
and stirred for 4 h. The reaction mixture was then poured carefully
into a separation funnel containing ice−water (∼10 mL) and extracted
with DCM (3 × 10 mL). The organic layers were combined and
washed with brine (15 mL), dried with Na2SO4(s), and filtered. The
solvent was removed under reduced pressure, and the crude product
was suspended in cold DCM (5 mL). The resulting precipitate was
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filtered to afford compound 3b as a white solid (0.335 g, 72%). H
NMR (500 MHz, CD3OD, δ): 6.23, (s, 1H), 6.51 (s, 2H), 7.03−7.07
(d, J = 16.23 Hz, 1H), 7.31−7.35 (d, J = 16.23 Hz, 1H), 7.45−7.47 (d,
J = 8.31 Hz, 1H), 7.60 (s, 1H), 7.67−7.69 (d, J = 8.47 Hz, 1H). 13C
NMR (125 MHz, CD3OD, δ): 103.79, 106.34, 124.89, 126.71, 133.26,
133.34, 133.90, 135.91, 137.59, 140.29, 159.89. HRMS−ESI (m/z):
[M − H]− calcd for C14H10BrClO2, 322.9480; found, 322.9480.
5-[(1E)-2-(2-Chloro-4-boronic acid pinacol ester)ethenyl]-1,3-
benzenediol (3c). Compound 3b (0.100 g, 0.308 mmol), KOAc
(0.088 g, 0.926 mmol), bis(pinacolato)diboron (0.235 g, 0.926 mmol),
and Pd(dppf)Cl2 (0.0225 g, 0.0308 mmol) were added to a flame-
dried Schlenk flask, which was then evacuated and backfilled with
N2(g). Dioxane (3.5 mL) was deoxygenated by sonication under high
vacuum and backfilled with N2(g). The deoxygenated dioxane was
then added by cannula into the reaction flask, and the reaction mixture
was heated to 80 °C and stirred overnight. The reaction mixture was
filtered, and the solvent was removed under reduced pressure. The
crude product was purified by flash column chromatography (2% v/v
CH3OH in DCM) to afford compound 3c as a white solid (0.080 g,
3-[(1E)-2-(4-Bromophenyl)ethenyl]benzoic Acid (5b). Compound
5a (1.5 g, 4.7 mmol) was dissolved in 3:1 THF/EtOH (47 mL). A
solution of 2 M NaOH (4.7 mL, 9.4 mmol) was added to the resulting
solution, and the reaction mixture was stirred overnight. The reaction
mixture was then diluted with EtOAc (20 mL) and washed with 10%
w/v citric acid (20 mL), followed by brine (20 mL). The organic layer
was separated, dried with Na2SO4(s), and filtered. The solvent was
removed under reduced pressure, and the crude product was purified
by flash column chromatography (20% v/v EtOAc in hexanes) to
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69%). H NMR (500 MHz, CD3OD, δ): 1.33 (s, 12H), 6.23 (s, 1H),
6.53 (s, 2H), 7.05−7.09 (d, J = 16.29 Hz, 1H), 7.40−7.44 (d, J = 16.28
Hz, 1H), 7.60−7.62 (d, J = 7.98 Hz, 1H), 7.70 (s, 1H), 7.72−7.74 (d, J
= 7.83 Hz, 1H). 13C NMR (125 MHz, CD3OD, δ): 25.18, 75.82,
85.42, 103.90, 106.42, 124.82, 126.88, 133.83, 133.90, 134.11, 136.74,
139.11, 140.17, 159.84. HRMS−ESI (m/z): [M − H]− calcd for
C20H22BClO4, 370.1263; found, 370.1263.
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afford compound 5b as a white solid (1.36 g, 96%). H NMR (500
MHz, DMSO, δ): 7.33−7.36 (d, J = 16.52 Hz, 1H), 7.40−7.43 (d, J =
16.44 Hz, 1H), 7.50−7.54 (t, J = 7.68 Hz, 1H), 7.58−7.60 (d, J = 8.64
Hz, 2H), 7.63−7.61 (d, J = 8.66 Hz, 2H), 7.84−7.88 (t, J = 8.63 Hz,
2H), 8.16 (s, 1H), 13.10 (s, 1H). 13C NMR (125 MHz, DMSO, δ):
121.27, 127.81, 128.68, 128.92, 129.00, 129.10, 129.51, 131.04, 132.09,
136.61, 137.66, 167.69. HRMS−ESI (m/z): M+• calcd for
C15H11BrO2, 301.9937; found, 301.9944.
5-[(1E)-2-(2-Chloro-4-hydroxyphenyl)ethenyl]-1,3-benzenediol
(3). Compound 3 was derived from the oxidation of compound 3c by
an aryl N-oxide in one step as described previously.75 Here, compound
3c (0.020 g, 0.053 mmol) was dissolved in DCM (0.6 mL). N,N-
Dimethyl-p-toluidine-N-oxide (0.012 g, 0.081 mmol) was added to the
resulting solution, and the reaction mixture was stirred for 1 h. The
solvent was removed under reduced pressure, and the crude product
was purified by flash column chromatography (15% v/v EtOAc in
hexanes) to afford compound 3 as a pale-yellow solid (0.010 g, 70%)
with mp >400 °C. 1H NMR (500 MHz, CD3OD, δ): 6.18−6.19 (t, J =
2.15 Hz, 1H), 6.47 (s, 2H), 6.74−6.76 (d, J = 8.66 Hz, 1H), 6.82 (s,
1H), 6.82−6.85 (d, J = 14.57 Hz, 1H), 7.31−7.34 (d, J = 16.16 Hz,
1H), 7.58−7.59 (d, J = 8.64 Hz, 1H). 13C NMR (125 MHz, CD3OD,
δ): 103.10, 105.96, 115.92, 117.03, 124.95, 127.75, 128.32, 129.78,
134.77, 140.91, 159.08, 159.77. HRMS−ESI (m/z): [M − H]− calcd
for C14H11ClO3, 261.0324; found, 261.0325.
5-[(1E)-2-(2-Chloro-4-boronic acid)ethenyl]-1,3-benzenediol (4).
Compound 3c (0.050 g, 0.134 mmol) was dissolved in 4:1 THF/H2O
(1.3 mL). NaIO4 (0.143 g, 0.670 mmol) was added to the resulting
solution, followed by 1.0 M HCl (33 μL, 0.033 mmol). The reaction
mixture was then stirred overnight. The reaction mixture was diluted
with H2O (1.0 mL) and extracted with EtOAc (3 × 2 mL). The
organic layers were combined and washed with brine (6 mL), dried
with Na2SO4(s), and filtered. The solvent was removed under reduced
pressure, and the crude mixture was purified by flash column
chromatography (4% v/v CH3OH in DCM) to afford compound 4
3-[(1E)-2-(4-Boronic acid pinacol ester)ethenyl]benzoic Acid (5c).
Compound 5b (1.0 g, 3.3 mmol), KOAc (0.971 g, 9.9 mmol),
bis(pinacolato)diboron (2.5 g, 9.9 mmol), and Pd(dppf)Cl2 (0.24 g,
0.33 mmol) were added to a flame-dried Schlenk flask, which was then
evacuated and backfilled with N2(g). Dioxane (33 mL) was
deoxygenated by sonication under high vacuum and backfilled with
N2(g). The deoxygenated dioxane was then added by cannula into the
reaction flask, and the reaction mixture was stirred overnight at 80 °C.
The reaction mixture was filtered, and the solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (20% v/v EtOAc in hexanes) to afford compound 5c
as a white solid (0.850 g, 73%). 1H NMR (500 MHz, CDCl3, δ): 1.36,
(s, 12H), 7.22 (s, 2H), 7.46−7.50 (t, J = 7.44 Hz, 1H), 7.54−7.55 (d, J
= 7.72 Hz, 1H), 7.76−7.77 (d, J = 8.12 Hz, 2H), 7.81−7.83 (d, J =
8.10 Hz, 2H), 8.00−8.01 (d, J = 8.11 Hz, 1H), 8.27−8.28 (d, J = 7.72
Hz, 1H), 8.28 (s, 1H). 13C NMR (125 MHz, CDCl3, δ): 24.90, 83.87,
125.97, 128.19, 128.32, 128.94, 129.28, 129.70, 130.06, 131.67, 135.23,
137.70, 139.50. HRMS−ESI (m/z): [M + NH4]+ calcd for C21H23BO4,
367.2064; found, 367.2062.
3-[(1E)-2-(4-Hydroxyphenyl)ethenyl]benzoic Acid (5). Compound
5c (0.050 g, 0.142 mmol) was dissolved in DCM (1.4 mL). N,N-
Dimethyl-p-toluidine-N-oxide (0.032 g, 0.213 mmol) was added to the
resulting solution, and the reaction mixture was allowed to stir for 1 h.
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J. Med. Chem. XXXX, XXX, XXX−XXX