10.1002/cmdc.201800233
ChemMedChem
FULL PAPER
2g: 1H NMR (CDCl3, 400 MHz) δ 7.44 (d, J = 2.0 Hz, 1H), 7.42 (dd, J =
2.0, 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.91
(dd, J = 2.8, 8.4 Hz, 1H), 6.89 (d, J = 11.6 Hz, 1H), 6.82 (d, J = 2.8 Hz,
1H), 6.81 (d, J = 11.6 Hz, 1H), 3.80 (s, 3H), 2.61-2.56 (m, 2H), 2.41-2.34
(m, 2H), 2.26 (s, 3H), 2.28-2.08 (m, 4H); 13C NMR (CDCl3, 125 MHz)
158.1, 138.2, 136.6, 135.5, 132.4, 132.3, 131.9, 131.0, 130.8, 130.6,
130.0, 129.9, 129.6, 119.9, 114.6, 112.6, 56.9, 55.3, 45.8, 29.8, 29.7;
HRMS (ESI+) Calcd. for C22H23BrNO [M + H]+: 396.0958. Found
396.0948
8.4 Hz, 1H), 6.76 (br, 1H), 6.66 (d, J = 12.0 Hz, 1H), 3.08-2.99 (m, 2H),
2.77-2.47 (m, 4H), 2.50 (s, 3H), 2.44-2.31 (m, 2H); 13C NMR (CD3OD,
125 MHz) δ 159.7, 140.4, 138.3, 137.8, 136.9, 133.9, 133.4, 131.6, 130.7,
130.1, 129.0, 128.8, 127.9, 115.8, 115.3, 56.36, 56.34, 43.9, 28.6, 28.4;
HRMS (ESI+) Calcd. for C21H21ClNO [M + H]+: 338.1306. Found
338.1297.
2n: 1 H NMR (CD3OD, 500 MHz) δ 7.37-7.34 (m, 2H), 7.27 (td, J = 1.0,
7.5 Hz, 1H), 7.19 (dd, J = 1.5, 7.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.90
(d, J = 12.0 Hz, 1H), 6.82 (dd, J = 2.0, 8.5 Hz, 1H), 6.82 (d, J = 12.0 Hz,
1H), 6.77 (d, J = 2.0 Hz, 1H), 2.57-2.50 (m, 2H), 3.11-3.09 (m, 2H), 2.70-
2.64 (m, 2H), 2.65 (s, 3H), 2.57-2.50 (m, 2H), 2.39-2.30 (m, 2H); 13C
NMR (CD3OD, 125 MHz) δ 158.3, 140.6, 138.7, 138.1, 136.8, 132.9,
132.1, 131.2, 131.0, 130.4, 129.9, 129.7, 128.6, 117.4, 116.2, 57.62,
57.59, 45.2, 29.80, 29.76; HRMS (ESI+) Calcd. for C21H22NO [M + H]+:
304.1696. Found 304.1702.
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2h: H NMR (CDCl3, 400 MHz) δ 7.36-7.30 (m, 4H), 7.26 (d, J = 1.6, 7.2
Hz, 1H), 7.18 (dd, J = 1.6, 7.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.94 (d, J
= 11.6 Hz, 1H), 6.84 (d, J = 11.6 Hz, 1H), 2.56-2.50 (m, 2H), 2.41-2.30
(m, 2H), 2.24 (s, 3H), 2.22-2.05 (m, 4H); 13C NMR (CDCl3, 125 MHz)
140.6, 138.6, 134.6, 133.7, 132.1, 131.6, 130.9, 129.8, 129.6, 129.2,
128.5, 128.2, 128.0, 126.5, 121.8, 57.00, 56.98, 45.9, 30.0; HRMS (ESI+)
Calcd. for C21H21BrN [M + H]+: 366.0852. Found 366.0859.
2o: 1 H NMR (CD3OD, 400 MHz) δ 7.40 (dd, J = 2.0, 8.4 Hz, 1H), 7.34 (d,
J = 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.85 (s,
2H), 6.83 (dd, J = 2.4, 8.0 Hz, 1H) , 6.75 (d, J = 2.4 Hz, 1H), 2.81-2.77 (m,
2H), 2.45-2.19 (m, 6H), 2.38 (s, 3H); 13C NMR (CD3OD, 125 MHz) δ
156.1, 140.5, 135.7, 133.8, 133.6, 132.7, 131.4, 130.2, 129.9, 129.7,
129.3, 129.1, 129.0, 121.2, 115.3, 113.9, 55.84, 55.80, 43.9, 28.52,
28.47; HRMS (ESI+) calcd. for C21H21BrNO [M + H]+: 382.0801. Found
382.0803.
2i: 1 H NMR (CDCl3, 400 MHz) δ 7.45 (br, 1H), 7.42 (d, J = 2.0, 8.4 Hz,
1H), 7.35-7.31 (m, 2H), 7.26-7.24 (m, 1H), 7.18 (brd, J = 7.6 Hz, 1H),
7.06 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 6.81 (d, J = 12.0 Hz,
1H), 2.54-2.50 (m, 2H), 2.37-2.30 (m, 2H), 2.23 (s, 3H), 2.19-2.14 (m,
2H), 2.10-2.05 (m, 2H); 13C NMR (CDCl3, 125 MHz)
139.0, 137.9,
136.7, 136.0, 134.5, 132.4, 132.3, 130.7, 130.6, 130.1, 129.5, 128.5,
128.4, 128.1, 126.5, 119.9, 57.13, 57.11, 46.0, 30.2; HRMS (ESI+) calcd.
for C21H21BrN [M + H]+: 366.0852. Found 366.0845.
2p: 1 H NMR (DMSO-d6, 500 MHz) δ 9.52 (s, 1H), 7.63 (d, J = 2.0 Hz,
1H), 7.55 (d, J = 2.0, 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (d, J =
8.5 Hz, 1H), 6.93 (d, J = 12.0 Hz, 1H) , 6.91 (d, J = 12.0 Hz, 1H), 6.84
(dd, J = 2.5, 8.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 2H), 2.48-2.40 (m, 2H),
2.30-2.23 (m, 2H), 2.14 (s, 3H), 2.06-1.97 (m, 4H); 13C NMR (DMSO-d6,
125 MHz) δ 156.2, 137.3, 136.7, 135.5, 134.9, 132.1, 130.6, 130.4, 129.7,
129.4, 129.0, 128.9, 119.8, 115.5, 114.1, 55.4, 55.3, 43.1, 27.7; HRMS
(ESI+) Calcd. for C21H21BrNO [M + H]+: 382.0801. Found 382.0791.
Preparation of compound 2j: A solution of compound 2a (50 mg, 0.16
mmol) in dichloromethane (2 ml) was cooled to -78°C under an argon
atmosphere, and a 1.0 M solution of boron tribromide in dichloromethane
(0.78 ml, 0.78 mmol) was added to it. The reaction mixture was stirred for
2 h at room temperature, then poured into ice-water, and extracted with
dichloromethane. The organic phase was dried over sodium sulfate, and
the solvent was removed in vacuo. The residue was purified by silica gel
column chromatography (dichloromethane : methanol = 8 : 1) to afford 2j
1
(45 mg, 0.15 mmol, y. 92%) as a white solid. H NMR (CD3OD, 500 MHz)
Preparation of 13a: Sodium carbonate (20 mg, 0.19 mmol) and
potassium hexacyanoferrate(II) trihydrate (18 mg, 0.041 mmol) were
ground to a fine powder, placed in pressure tube, and dried in vacuo at
δ 7.41-7.31 (m, 3H), 7.25 (d, J = 8.5 Hz, 1H), 7.24 (brd, J = 7.5 Hz, 1H),
6.89 (d, J = 11.5 Hz, 1H), 6.82 (d, J = 11.5 Hz, 1H), 6.79 (dd, J = 2.0, 8.5
Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 3.31-3.25 (m, 2H), 2.88 (br, 2H), 2.80 (s,
3H), 2.70-2.56 (m, 2H), 2.51-2.37 (m, 2H); 13C NMR (CD3OD, 125 MHz)
δ 160.0, 141.3, 139.6, 139.2, 137.2, 132.6, 132.0, 130.3, 130.2, 130.1,
129.71, 129.68, 128.9, 128.94, 128.88, 116.2, 115.9, 57.31, 57.28, 44.7,
29.4, 29.3; HRMS (ESI+) Calcd. for C21H22NO [M + H]+: 304.1696. Found
304.1685.
80°C overnight.
methylpyrrolidone (1.5 ml),
A
solution of 2i (70 mg, 0.19 mmol) in N-
3.8 mM solution of 1,1'-
a
bis(diphenylphosphino)ferrocene in N-methylpyrrolidone (0.1 ml, 0.38
μmol) and a 1.9 mM solution of palladium acetate in N-methylpyrrolidone
(0.1 ml, 0.19 μmol) were then added to it. The atmosphere in the
pressure tube was replaced with argon, and the tube was sealed. The
contents were heated with stirring at 120°C for 19 h, then cooled to room
temperature, poured into water, and extracted with dichloromethane. The
organic phase was dried over sodium sulfate, and the solvent was
removed in vacuo. The residue was purified by silica gel column
chromatography (dichloromethane : methanol = 10 : 1) to afford 13a (34
mg, 0.11 mmol, y. 57%) as a brown solid. 1H NMR (CDCl3, 500 MHz) δ
7.60 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 1.5, 8.0 Hz, 1H), 7.39-7.26 (m, 4H),
7.19 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 11.5 Hz, 1H), 6.86 (d, J = 11.5 Hz,
1H), 2.54-2.52 (m, 2H), 2.39-2.30 (m, 2H), 2.24 (s, 3H), 2.20-2.04 (m,
4H); 13C NMR (CDCl3, 125 MHz) 143.7, 138.7, 137.4, 136.1, 134.7,
133.6, 132.5, 132.3, 131.0, 129.8, 129.1, 129.0, 128.9, 127.2, 119.2,
110.5, 57.3, 46.3, 30.5, 30.4; HRMS (ESI+) Calcd. for C22H21N2 [M + H]+:
313.1699. Found 313.1708.
2k – 2p were similarly prepared from corresponding compounds 2.
Those analytical data were given below.
2k: 1 H NMR (CD3OD, 400 MHz) δ 7.37 (dd, J = 2.0, 8.0 Hz, 1H), 7.28 (d,
J = 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.86 (d,
J = 11.6 Hz, 1H), 6.80 (d, J = 2.8, 8.4 Hz 1H), 6.71 (d, J = 11.6 Hz, 1H),
6.68 (d, J = 2.8 Hz, 1H), 3.01 (br, 2H), 2.70 (br, 2H), 2.51 (s, 3H), 2.51-
2.38 (m, 4H); 13C NMR (CD3OD, 125 MHz) δ 158.0, 138.9, 134.8, 134.2,
131.2, 130.1, 129.8, 129.5, 129.4, 126.61, 126.57, 121.0, 114.1, 113.9,
55.4, 55.3, 43.2, 27.9, 27.7; HRMS (ESI+) Calcd. for C21H21BrNO [M +
H]+: 382.0801. Found 382.0806.
2l: 1H-NMR (CDCl3, 500 MHz) δ 7.44 (d, J = 1.5 Hz, 1H), 7.38 (brd, J =
8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.97 (brd, J = 8.5 Hz, 1H), 6.88 (d,
J = 12.0 Hz, 1H), 6.75 (brd, J = 8.5 Hz, 1H), 6.67 (d, J = 12.0 Hz, 1H),
6.62 (d, J = 2.0 Hz, 1H), 2.79-2.71 (m, 2H), 2.57-2.25 (m, 4H), 2.24 (s,
3H), 2.01-1.93 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.8, 140.0,
137.3, 136.8, 133.9, 133.6, 132.2, 130.9, 130.4, 130.3, 130.1, 127.2,
126.9, 120.3, 115.1, 115.0, 56.4, 45.8, 30.1, 29.3; HRMS (ESI+) Calcd.
for C21H21BrNO [M+H]+: 382.0801. Found 382.0790.
Preparation of compound 13b: A flame-dried flask fitted with a
magnetic stirring bar was charged with 13a (30 mg, 0.10 mmol),
potassium tert-butoxide (32 mg, 0.30 mmol) and tert-butanol (3 ml). The
reaction mixture was stirred at room temperature for 21 h under an argon
atmosphere. After addition of water, the aqueous phase was extracted
with dichloromethane. The organic phase was dried over sodium sulfate,
and the solvent was removed in in vacuo. The residue was purified by
silica gel column chromatography (dichloromethane : methanol = 5 : 1) to
afford 13b (15 mg, 0.045 mmol, y. 46%) as a white powder. 1H NMR
(CD3OD, 500 MHz) δ 7.91 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 2.0, 8.0 Hz,
2m: 1H-NMR (CDCl3, 400 MHz) δ 7.21-7.17 (m, 2H), 7.14, (dd, J = 2.0,
8.0 Hz), 6.91-6.88 (m, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.82 (dd, J = 2.4,
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