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CDCl3) δ: 8.21 (1H, d, J = 8.8 Hz, 2 × ArH), 7.50 (1H, d, J = 8.8 Hz,
2 × ArH), 6.86 (1H, s, ArH), 4.05 (3H, s, OCH3), 4.02 (3H, s,
OCH3), 3.91 (3H, s, OCH3). 13C (100 MHz, CDCl3) δ: 151.7, 149.0,
138.8, 135.5, 135.3, 132.5, 126.8, 123.4, 99.2, 61.5, 57.0, 56.2. IR (thin
film) νmax 3002 (w), 2931 (w), 2847 (w), 1610 (m), 1567 (s), 1384
(s), 1238 (s), 1098 (s), 913 (s), 826 (s), 777 (s) cm−1. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C12H13BrNO3 298.0073 and 300.0053,
found 298.0070 and 300.0047. Mp: 149−150 °C (recrystallized from
CH2Cl2).
C44H42F3N3O9Na 836.2771, found 836.2736. Mp: 190−195 °C
(recrystallized from CH2Cl2).
( )-Methyl 5-Amino-4-(2-hydroxy-3,4-dimethoxyphenyl)-6-
(6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)-3-methylpico-
linate (45). Palladium (10 wt.% on carbon, 0.007 g) was added to a
solution of quinoline-5,8-dione 39 (0.020 g, 0.034 mmol) in
methanol/EtOAc (3:1 by volume, 13.5 mL total). The reaction
mixture was degassed in vacuo, placed under an atmosphere of H2 (g),
and stirred in the dark at rt for 12 h. The mixture was filtered through
a pad of Celite eluting with EtOAc (10 mL), and the combined
organic layers were concentrated in vacuo. The crude product was
purified by column chromatography (1:1 PE/EtOAc, Rf 0.28) to afford
General Procedure for the Asymmetric Suzuki−Miyaura
Reaction. A solution of the palladium source (0.008 mmol) and
ligand (0.010 mmol) in dioxane (0.1 mL) was stirred at rt for 30 min.
A solution of aryl boronate ester 28 (0.049 mmol) and pyridine 37
(0.032 mmol) in dioxane (0.22 mL) was subsequently added. The
reaction mixture was degassed and refilled with argon five times, and
then a solution of sodium carbonate (1.0 M, 0.10 mL) was added. The
mixture was degassed and refilled with argon five times again and then
heated at the designated temperature for 24 h. The mixture was
allowed to cool to rt, diluted with EtOAc (1.0 mL), and washed with
brine (1.0 mL). The organic phase was dried over Na2SO4, filtered,
and concentrated in vacuo. The crude product was purified by column
chromatography (2:1 PE:EtOAc, Rf 0.32) to afford 38 as a yellow
solid. A sample obtained using phosphino hydrazone ligand 41 that
1
debenzylated 45 as a dark red/brown solid (0.017 g, 97%). H (200
MHz, CDCl3) δ: 9.04 (1H, d, J = 8.4 Hz, Ar-H), 8.50 (1H, d, J = 8.4
Hz, Ar-H), 6.82 (1H, d, J = 8.7 Hz, Ar-H), 6.67 (1H, d, J = 8.6 Hz, Ar-
H), 6.29 (1H, s, Ar-H), 5.89 (1H, br s, OH), 3.99 (6H, s, OCH3), 3.96
(3H, s, OCH3), 3.95 (3H, s, OCH3), 2.34 (3H, s, CH3). 13C (126
MHz, CDCl3) δ: 182.8, 179.4, 167.0, 163.1, 160.5, 152.7, 147.0, 146.2,
145.6, 138.0, 136.3, 135.7, 134.4, 132.9, 130.7, 125.7, 125.4, 125.1,
113.7, 109.9, 105.1, 61.2, 56.6, 56.0, 55.2, 17.4. IR (thin film) νmax
:
3467 (br), 3249 (br), 2953 (w), 1707 (s), 1687 (s), 1656 (m), 1610
(s), 1586 (s), 1460 (m), 1296 (s), 1243 (s), 1088 (s) cm−1. HRMS
(ESI-TOF) m/z: [M + Na]+ Ccalcd for C26H23N3O8Na 528.1377,
found 528.1355. Mp: 113−114 °C (recrystallized from CH2Cl2).
( )-Methyl 5-Amino-4-(2-(benzyloxy)-3,4-dimethoxyphen-
yl)-6-(6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)-3-meth-
ylpicolinate (39). Example of an attempted nitration of quinoline 38:
Silver(II) oxide (0.016 g, 0.128 mmol) and nitric acid (35% aq, 0.04
mL) were added to a solution of quinoline (0.020 g, 0.032 mmol) in
acetonitrile/water (4:1 by volume, 0.20 mL in total). The reaction
mixture was allowed to stir at rt for 16 h, water was then added, and
the mixture was extracted with ethyl acetate (3 × 5.0 mL). The
combined organic layers were washed with satd aq NaHCO3 and ,
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (1:1 PE/
EtOAc, Rf 0.52) to afford p-quinoline-5,8-dione 39 as a dark red
crystalline solid (0.013 g, 68%). 1H (200 MHz, CDCl3) δ: 9.02 (1H, d,
J = 8.5 Hz, Ar-H), 8.49 (1H, d, J = 8.5 Hz, Ar-H), 7.13−7.07 (3H, m,
Ar-H), 7.02−6.98 (2H, m, Ar-H), 6.87 (1H, d, J = 8.7 Hz, Ar-H), 6.82
(1H, d, J = 8.7 Hz, Ar-H), 6.28 (1H, s, Ar-H), 4.96 (1H, d, J = 11.2 Hz,
OCH2Ph), 4.89 (1H, d, J = 11.2 Hz, OCH2Ph), 3.99 (3H, s, OCH3),
3.96 (3H, s, OCH3), 3.94 (6H, s, OCH3), 2.24 (3H, s, CH3). 13C (62.5
MHz, CDCl3) δ: 182.7, 179.3, 166.9, 163.0, 160.4, 154.3, 150.5, 146.2,
145.5, 143.4, 137.8, 137.1, 135.5, 134.3, 133.9, 130.4, 128.1 (2 × C),
127.9 (2 × C), 127.8, 125.4, 125.3, 124.8, 121.3, 109.8, 108.6, 75.1,
61.1, 56.6, 56.1, 52.2, 17.6. Mp: 242−246 °C (recrystallized from
CH2Cl2) (lit.19 mp 242−243 °C). These data were in accordance with
the literature values.17
afforded product with 30% ee (by chiral HPLC analysis) gave [α]D25
51.5 (c = 0.29, CHCl3).
+
Methyl 5-Amino-4-(2-(benzyloxy)-3,4-dimethoxyphenyl)-3-
methyl-6-(5,6,8-trimethoxyquinolin-2-yl)picolinate (38). 1H
(200 MHz, CDCl3) δ: 8.88 (1H, d, J = 9.1 Hz, Ar-H), 8.49 (1H, d,
J = 9.1 Hz, Ar-H), 7.12−7.10 (3H, m, Ar-H), 7.05−7.01 (2H, m, Ar-
H), 6.88 (2H, s, Ar-H), 6.83 (1H, s, Ar-H), 4.93 (1H, d, J = 11.0 Hz,
OCH2Ph), 4.86 (1H, d, J = 11.0 Hz, OCH2Ph), 4.04 (3H, s, OCH3),
4.01 (6H, s, 2 × OCH3), 3.97 (6H, s, 2 × OCH3), 3.95 (3H, s,
OCH3), 2.29 (3H, s, CH3). 13C (62.5 MHz, CDCl3) δ: 167.2, 155.7,
154.1, 152.1, 150.7, 148.7, 145.2, 143.4, 137.1, 136.6, 135.8, 134.4,
133.1, 133.0, 132.7, 130.0, 128.1 (2 × C), 128.0 (2 × C), 127.7, 125.1,
123.0, 122.1, 120.9, 108.4, 98.3, 75.2, 61.6, 61.1, 57.2, 56.1 (2 × C),
52.1, 17.5. Mp 209−210 °C (recrystallized from CH2Cl2). These data
were in accordance with the literature values.17
(S)-(5-Amino-4-(2-(benzyloxy)-3,4-dimethoxyphenyl)-3-
methyl-6-(5,6,8-trimethoxyquinolin-2-yl)pyridin-2-yl)methyl
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (52). A solution
of LiAlH4 (1.0 M, 0.062 mL) was added to a solution of racemic 38
(0.013 g, 0.021 mmol) in THF (0.20 mL) at −30 °C. The mixture was
warmed to rt and stirred for 4 h. A saturated aqueous solution of
Na2SO4 was added until excess LiAlH4 was quenched, and solid
Na2SO4 had precipitated. The solution was then filtered and
concentrated in vacuo. The crude product 42 was used without
further purification. DMAP (0.011 g, 0.086 mmol) and (R)-(−)-α-
methoxy-α-(trifluoromethyl)phenylacetyl chloride (0.013 mL, 0.069
mmol) were added to a solution of 42 (0.0079 g, 0.013 mmol) in
dichloromethane (0.13 mL). The reaction was stirred at rt for 16 h or
until TLC indicated consumption of the starting material. The reaction
was filtered through a small silica plug and then purified by column
chromatography (gradient PE to 2:1 PE/EtOAc, Rf 0.30 in 2:1) to
(
)-Methyl 5-Amino-4-(2-(benzyloxy)-5-bromo-3,4-dime-
thoxyphenyl)-6-(7-bromo-6-methoxy-5,8-dioxo-5,8-dihydro-
quinolin-2-yl)-3-methylpicolinate (50) and ( )-Methyl 5-
Amino-4-(2-(benzyloxy)-5-bromo-3,4-dimethoxyphenyl)-6-(6-
methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)-3-methylpicoli-
nate (49). Example bromination with 1.1 equiv of brominating
reagent: Bromine (19 μL, 0.037 mmol) was added to a solution of
quinoline-5,8-dione 39 (0.020 g, 0.034 mmol) in chloroform (1.1 mL)
in the dark at rt The resulting reaction mixture was stirred for 8 h.
Water (5.0 mL) was added, and the aqueous layer was extracted with
dichloromethane (3 × 5.0 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo to afford a
mixture of starting material 39, monobrominated quinone 49, and
1
afford 52 as a red solid (0.0087 mg, 48%). H (400 MHz, CDCl3) δ:
8.80 (1H, d, J = 9.2 Hz, Ar-H), 8.42 (1H, d, J = 9.2 Hz, Ar-H), 7.58−
7.54 (2H, m, Ph), 7.33−7.29 (3H, m, Ph), 7.08−6.93 (5H, m, Mosher
Ph), 6.87 (2H, s, Ar-H), 6.83 (1H, s, Ar-H), 5.65−5.57 (1H, m,
CH2OC(O)), 5.48−5.41 (1H, m, CH2OC(O)), 4.93−4.86 (1H, m,
CH2Ph), 4.80−4.77 (1H, m, CH2Ph), 4.04 (3H, s, OCH3), 4.00 (3H,
s, OCH3), 3.96 (6H, s, OCH3), 3.94 (3H, s, OCH3), 3.52 (3H, s,
Mosher OCH3), 1.92 (3H, s, CH3). 13C (126 MHz, toluene-d8) δ:
166.6 (2 × C), 156.9, 154.5 (2 × C), 152.5, 151.5, 151.4, 148.9, 144.3
(q, CF3), 139.5, 139.4, 134.2, 133.7, 133.6, 133.5, 133.3 (2 × C),
133.2, 129.9, 123.5, 123.1 (2 × C), 121.2, 108.8, 99.8, 69.2, 68.9, 60.9,
60.7, 57.2, 55.6, 55.4, 14.4. δF (472 MHz, toluene-d8): 71.73, 71.76. IR
(thin film) νmax: 3460 (w), 3321 (w), 2930 (m), 2850 (m), 1746 (m),
1625 (m), 1600 (m), 1581 (m), 1490 (m), 1465 (m), 1422 (w), 1358
(m), 1228.21 (br m), 1169 (w), 1098 (s), 1069 (w), 1001 (w), 921
(w), 719 (w) cm−1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
dibromo-quinone 50 in a 2:1:2 ratio (by analysis of the H NMR
spectrum of the crude material, quantitative recovery). The
brominated compounds were unstable to silica, but small quantities
of purified dibromo 50 (2:1 PE/EtOAc, Rf 0.70) and monobromo 49
(2:1 PE/EtOAc, Rf 0.50) could be obtained following silica gel
chromatography, the data for which follows:
Dibromo 50. 1H (500 MHz, CDCl3) δ: 9.05 (1H, d, J = 8.5 Hz, Ar-
H), 8.46 (1H, d, J = 8.5 Hz, Ar-H), 7.14−7.11 (3H, m, Ar-H), 7.10
(1H, s, Ar-H), 7.01−6.99 (2H, m, Ar-H), 4.95 (1H, d, J = 11.3 Hz,
OCH2Ph), 4.88 (1H, d, J = 11.3 Hz, OCH2Ph), 4.37 (3H, s, OCH3),
K
dx.doi.org/10.1021/jo402388f | J. Org. Chem. XXXX, XXX, XXX−XXX