The Journal of Organic Chemistry
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potassium permanganate. E. Merck silica gel (60, particle size 0.043−
0.063 mm) was used for flash column chromatography. Preparative
thin-layer chromatography (PTLC) separations were carried out on
0.25 or 0.5 mm E. Merck silica gel plates (60F-254). NMR spectra
were recorded on 600, 500, and 400 MHz instruments and calibrated
using residual undeuterated solvent as an internal reference (CHCl3 at
8.39 (dd, J = 6.7, 2.3 Hz, 1 H), 8.03 (dd, J = 8.3, 1.7 Hz, 1 H), 7.39−
7.28 (m, 3 H), 6.84 (d, J = 1.7 Hz, 2 H), 6.78 (ddd, J = 8.0, 1.8, 0.8 Hz,
2 H), 6.65 (d, J = 8.0 Hz, 2 H), 5.78 (dd, J = 9.2, 1.5 Hz, 4 H), 4.04
(td, J = 8.0, 3.3 Hz, 1 H), 3.97−3.87 (m, 2 H), 3.37 (q, J = 11.2 Hz, 1
H), 2.65 (dtd, J = 9.9, 7.8, 3.3 Hz, 1 H); 13C NMR (CDCl3, 101 MHz)
δ 169.0, 147.9, 147.5, 145.9, 138.3, 136.2, 134.5, 134.3, 127.8, 127.3,
121.4, 121.1, 120.1, 116.5, 108.0, 107.8, 100.7, 54.8, 38.9, 30.7.
N-(Quinolin-8-yl)-2,4-bis(3,4,5-trimethoxyphenyl)cyclo-
butane-1-carboxamide (32). This compound was prepared
analogously to 31, only employing 3,4,5-trimethoxyiodobenzene
(195 mg), and purified by silica gel chromatography (2/2/3 to 2/2/
1 DCM/Et2O/hexanes) to give 32 (118.2 mg, 96%) as a pale yellow
foam: Rf = 0.2 (silica gel, 1/1 hexanes/EtOAc); HRMS (m/z) calcd
for C32H34N2O7 ([M + H]+) 559.2444, found 559.2444; IR (film) νmax
1
7.26 ppm for H NMR and 77.16 ppm for 13C NMR). The following
abbreviations (or combinations thereof) are used to explain the
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
b, broad. High-resolution mass spectra (HRMS) were recorded on an
LC/MSD TOF time-of-flight mass spectrometer by electrospray
ionization time-of-flight reflectron experiments. IR spectra were
recorded on a FTIR spectrometer. Melting points were recorded on
a melting point apparatus and are uncorrected.
1
br 3349, 2937, 1686, 1587, 1520, 1236, 1123, 1006, 826 cm−1; H
N-(Quinolin-8-yl)cyclobutanecarboxamide (28). Cyclobutane-
carbonyl chloride (2.47 g, 20.8 mmol, 1 equiv) in DCM (50 mL) was
added dropwise to a vigorously stirred biphasic solution of 8-
aminoquinoline (3.00 g, 20.8 mmol) in DCM/saturated aqueous
sodium bicarbonate (50 mL/100 mL) at room temperature. The
reaction mixture was stirred for 3 h, and the layers were separated,
extracted with DCM (2 × 50 mL), washed with brine, and dried over
sodium sulfate. After filtration and concentration, the product was
filtered through a silica plug (3% Et2O in DCM) to give 28 (4.58 g,
97%) as a colorless oil that slowly crystallizes upon standing: white
crystalline solid (53−54 °C): Rf = 0.45 (silica gel, 3/1 hexanes/
EtOAc); HRMS (m/z) calcd for C14H14N2O ([M + H]+) 227.1184,
found 227.1188; IR (film) νmax 3351, 2942, 1680, 1521, 1484, 1323,
790 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.73 (br s, 1 H), 8.80 (dd, J
= 7.6, 1.4 Hz, 1 H), 8.75 (dd, J = 4.2, 1.7 Hz, 1 H), 8.09 (dd, J = 8.3,
1.7 Hz, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.43 (dd, J = 8.3, 1.4 Hz, 1 H),
7.38 (dd, J = 8.2, 4.2 Hz, 1 H), 3.37 (p, J = 8.5 Hz, 1 H), 2.54−2.41
(m, 2 H), 2.35−2.19 (m, 2 H), 2.09−1.99 (m, 1 H), 1.99−1.89 (m, 1
H); 13C NMR (CDCl3, 126 MHz) δ 173.7, 148.1, 138.4, 136.3, 134.6,
127.9, 127.4, 121.5, 121.3, 116.3, 41.4, 25.5, 18.2.
2,4-Diphenyl-N-(quinolin-8-yl)cyclobutane-1-carboxamide
(29). 28 (226 mg, 1.00 mmol), Pd(OAc)2 (2.25 mg, 0.01 mmol, 0.01
equiv), silver acetate (500 mg, 3.0 mmol, 3 equiv), and iodobenzene
(334 μL, 3.0 mmol, 3 equiv) were placed in a sealed tube, and toluene
(3.3 mL) was added under ambient conditions. The tube was sealed
and placed in an 80 °C oil bath for 24 h. The reaction mixture was
cooled to room temperature, diluted with DCM (5 mL), filtered
through a pad of Celite, and concentrated. The resulting yellow solid
was purified by silica gel chromatography (10−20% EtOAc in
hexanes) to give 29 (368 mg, 97%) as a white crystalline solid
(137−138 °C): Rf = 0.4 (silica gel, 3/1 hexanes/EtOAc); HRMS (m/
z) calcd for C26H22N2O ([M + H]+) 379.1810, found 379.1809; IR
(film) νmax br 3354, 3025, 1686, 1518, 1483, 1322, 1159, 695 cm−1; 1H
NMR (500 MHz, CDCl3): δ 9.55 (s, 1 H), 8.73 (dd, J = 4.2, 1.7 Hz, 1
H), 8.33 (dd, J = 7.3, 1.7 Hz, 1 H), 8.01 (dd, J = 8.3, 1.7 Hz, 1 H), 7.39
(d, J = 7.3 Hz, 4 H), 7.35 (dd, J = 8.2, 4.2 Hz, 1 H), 7.32−7.27 (m, 2
H), 7.25 (t, J = 7.8 Hz, 4 H), 7.13−7.09 (m, 2 H), 4.19 (td, J = 8.2, 3.2
Hz, 1 H), 4.10 (dt, J = 11.7, 8.2 Hz, 2 H), 3.60 (td, J = 11.3, 10.1 Hz, 1
H), 2.77 (dtd, J = 10.1, 7.9, 3.2 Hz, 1 H); 13C NMR (CDCl3, 126
MHz) δ 168.9, 147.8, 140.7, 138.2, 136.1, 134.2, 128.1, 127.7, 127.2,
127.0, 126.1, 121.3, 121.0, 116.4, 54.6, 39.1, 29.9.
NMR (500 MHz, CDCl3) δ 9.56 (s, 1 H), 8.67 (dd, J = 4.3, 1.7 Hz, 1
H), 8.41 (dd, J = 7.4, 1.6 Hz, 1 H), 8.04 (dd, J = 8.3, 1.7 Hz, 1 H),
7.39−7.28 (m, 3 H), 6.51 (s, 4 H), 4.12 (td, J = 8.1, 3.2 Hz, 1 H), 3.96
(dt, J = 11.2, 8.0 Hz, 2 H), 3.69 (s, 12 H), 3.64 (s, 6 H), 3.36 (q, J =
11.1 Hz, 1 H), 2.75 (dtd, J = 9.7, 7.9, 3.2 Hz, 1 H); 13C NMR (CDCl3,
126 MHz) δ 169.1, 152.9, 147.8, 138.1, 136.5, 136.3, 136.2, 134.1,
127.7, 127.2, 121.4, 121.2, 116.3, 103.8, 60.6, 55.9, 54.3, 39.1, 31.1.
N-(Quinolin-8-yl)-2,4-bis(1-tosyl-1H-indol-3-yl)cyclobutane-
1-carboxamide (33). This compound was prepared analogously to
31, only employing N-tosyl-3-iodoindole56 (263 mg), and purified by
silica gel chromatography (1/1/3 to 3/3/4 DCM/Et2O/hexanes) to
give 33 (156.1 mg, 92%) as light yellow crystals. Crystals suitable for
X-ray diffraction were obtained from EtOAc: pale yellow crystals
(185−187 °C); Rf = 0.1 (silica gel, 3/1 hexanes/EtOAc); HRMS (m/
z) calcd for C44H36N4O5S2 ([M + H]+) 765.2205, found 765.2198; IR
(film) νmax br 3346, 2940, 1680, 1520, 1362, 1170, 1124, 736 cm−1; 1H
NMR (400 MHz, CDCl3) δ 9.57 (s, 1 H), 8.70 (dd, J = 4.3, 1.7 Hz, 1
H), 8.47 (dd, J = 7.1, 2.0 Hz, 1 H), 8.05 (dd, J = 8.3, 1.7 Hz, 1 H),
7.84−7.77 (m, 2 H), 7.73 (s, 2 H), 7.58−7.54 (m, 2 H), 7.52 (d, J =
8.4 Hz, 4 H), 7.44−7.33 (m, 3 H), 7.22−7.11 (m, 4 H), 6.82 (d, J =
8.0 Hz, 4 H), 4.28−4.10 (m, 3 H), 3.61−3.48 (m, 1 H), 2.99−2.87 (m,
1 H), 2.13 (s, 6 H); 13C NMR (CDCl3, 101 MHz) δ 168.7, 148.2,
144.2, 138.1, 136.0, 135.2, 134.9, 134.2, 130.6, 129.6, 127.7, 127.1,
126.6, 125.0, 124.4, 123.0, 121.6, 121.4, 121.1, 119.3, 116.2, 113.6,
53.8, 33.1, 31.9, 21.4.
N-(Quinolin-8-yl)-2,4-di((E)-styryl)cyclobutane-1-carboxa-
mide (34). 28 (46 mg, 0.20 mmol), Pd(OAc)2 (4.6 mg, 0.02 mmol,
0.10 equiv), silver acetate (100 mg, 0.60 mmol, 3 equiv), and
iodostyrene (138 mg, 0.60 mmol, 3 equiv) were placed in a sealed
tube, and toluene (1 mL) was added under ambient conditions. The
tube was sealed and placed in an 80 °C oil bath for 12 h. The reaction
mixture was cooled to room temperature, diluted with DCM (2 mL),
filtered through a pad of Celite, and concentrated. The resulting
orange solid was purified by silica gel chromatography (10% EtOAc in
hexanes) to give 34 (66.2 mg, 77%) as pale yellow needles (128−129
°C): Rf = 0.45 (silica gel, 3/1 hexanes/EtOAc); HRMS (m/z) calcd
for C30H26N2O ([M + H]+) 431.2123, found 431.2125; IR (film) νmax
br 3349, 2934, 1677, 1519, 1483, 1322, 968, 748, 692 cm−1; 1H NMR
(400 MHz, CDCl3) δ 9.76 (s, 1 H), 8.87 (dd, J = 7.6, 1.4 Hz, 1 H),
8.61 (dd, J = 4.2, 1.7 Hz, 1 H), 8.07 (dd, J = 8.3, 1.7 Hz, 1 H), 7.52 (t,
J = 7.9 Hz, 1 H), 7.45 (dd, J = 8.3, 1.4 Hz, 1 H), 7.38−7.31 (m, 5 H),
7.27−7.21 (m, 4 H), 7.19−7.12 (m, 2 H), 6.69 (dd, J = 15.8, 8.3 Hz, 2
H), 6.52 (d, J = 15.9 Hz, 2 H), 3.75 (td, J = 8.3, 3.0 Hz, 1 H), 3.48
(dqd, J = 10.4, 8.2, 0.9 Hz, 2 H), 2.87 (q, J = 10.6 Hz, 1 H), 2.53 (dtd,
J = 10.9, 8.1, 2.9 Hz, 1 H); 13C NMR (CDCl3, 101 MHz) δ 170.3,
148.0, 138.5, 137.5, 136.3, 134.5, 131.2, 130.2, 128.4, 127.9, 127.4,
127.1, 126.4, 121.5, 121.5, 116.7, 53.2, 38.6, 34.0.
2,4-Bis(benzo[d][1,3]dioxol-5-yl)-N-(quinolin-8-yl)cyclo-
butane-1-carboxamide (31). 28 (50 mg, 0.221 mmol), Pd(OAc)2
(2.5 mg, 0.011 mmol, 0.05 equiv), silver acetate (111 mg, 0.66 mmol,
3 equiv), and 3,4-methylenedioxyiodobenzene (164 mg, 0.66 mmol, 3
equiv) were placed in a sealed tube and toluene (740 μL) was added
under ambient conditions. The tube was sealed and placed into an 80
°C oil bath for 5 h. The reaction mixture was cooled to room
temperature, diluted with DCM (2 mL), filtered through a pad of
Celite, and concentrated. The resulting orange solid was purified by
silica gel chromatography (1/1/4 to 1/1/3 DCM/Et2O/hexanes) to
give 31 (96.5 mg, 98%) as a white crystalline solid (182−183 °C): Rf =
0.2 (silica gel, 3/1 hexanes/EtOAc); HRMS (m/z) calcd for
C28H23N2O5 ([M + H]+) 467.1607, found 467.1607; IR (film) νmax
Dimethyl 5,5′-(2-(Quinolin-8-ylcarbamoyl)cyclobutane-1,3-
diyl)-(2E,2′E,4E,4′E)-bis(4-methylpenta-2,4-dienoate) (35). 28
(90 mg, 0.40 mmol), Pd(OAc)2 (8.9 mg, 0.04 mmol, 0.10 equiv),
silver acetate (199 mg, 1.20 mmol, 3 equiv) and vinyl iodide57 (301
mg, 1.20 mmol, 3 equiv) were placed in a sealed tube, and toluene
(1.32 mL) was added under ambient conditions. The tube was sealed
and placed in an 80 °C oil bath for 12 h. The reaction mixture was
cooled to room temperature, diluted with DCM (3 mL), filtered
1
br 3351, 2889, 1683, 1519, 1483, 1236, 1035, 931 cm−1; H NMR
(400 MHz, CDCl3) δ 9.50 (s, 1 H), 8.72 (dd, J = 4.2, 1.7 Hz, 1 H),
2444
dx.doi.org/10.1021/jo4027148 | J. Org. Chem. 2014, 79, 2430−2452