A Unified Strategy Towards N-Aryl Heterocycles
M.p. 141–143 °C. 1H NMR (500 MHz, CDCl3): δ = 8.68 (d, J = 121.5, 120.7, 119.5, 118.0, 117.9, 117.2, 116.7, 116.6, 115.1, 114.9,
8.2 Hz, 1 H), 8.46–8.44 (m, 1 H), 8.08 (d, J = 2.7 Hz, 1 H), 8.06
(s, 1 H), 7.93–7.89 (m, 1 H), 7.65 (dd, J = 8.4, 0.5 Hz, 1 H), 7.46–
7.44 (m, 1 H), 7.41 (d, J = 2.8 Hz, 1 H), 7.19 (ddd, J = 7.3, 4.8,
0.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 149.9, 148.6,
148.5, 146.7, 139.2, 128.8, 126.1, 125.4, 123.9, 120.9, 116.8, 116.6,
113.2, 110.3, 106.9 ppm. HRMS (ESI): calcd. for C15H10F3N4 [M
+ H]+ 303.0852; found 303.0855.
110.5, 110.4, 109.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5
(1.0), –60.8 (0.23) ppm. FTIR (neat, KBr): ν = 3019, 2927, 1732,
˜
1609, 1571, 1448, 1325, 1284, 1158, 756, 667 cm–1. HRMS (ESI):
calcd. for C19H12N4F3 [M + H]+ 353.1014; found 353.1025.
Note: The identity of 3ha2 was confirmed through a partial purifi-
cation of the above isomeric mixtures. The experimental data for
the pure compound 3ha2 is noted below.
Rf = 0.53 (20% ethyl acetate in hexanes); m.p. 121–124 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.87–8.82 (m, 1 H), 8.78 (d, J =
8.4 Hz, 1 H), 8.59 (d, J = 3.7 Hz, 1 H), 8.08 (s, 1 H), 7.97 (ddd, J
= 8.4, 7.4, 1.9 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.78 (td, J =
4.0, 1.6 Hz, 1 H), 7.58 (dd, J = 8.3, 0.8 Hz, 1 H), 7.46–7.39 (m, 2
H), 7.26 (td, J = 4.0, 0.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.8, 148.1, 146.6, 138.9, 134.0, 125.4, 124.6, 123.6,
123.4, 120.8, 118.1, 118.0, 117.2, 116.7, 116.6, 115.2, 110.5,
110.5 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 ppm.
3gb1 and 3gb2: Following the general procedure, the reaction was
carried out between 2-(1H–imidazol-1-yl)-5-(trifluoromethyl)anil-
ine (1g; 100 mg, 0.440 mmol, 1 equiv.) and 2-bromo-4-methylpyr-
idine (2b; 95 μL, 0.880 mmol, 2.0 equiv.). Column chromatography
on silica gel (6% ethyl acetate in hexanes) yielded 98 mg (70%) of
an inseparable mixture of the regioisomeric products 3gb1* and
3gb2 (0.7:1) as a white solid. Rf = 0.50 (20% ethyl acetate in hex-
1
anes); m.p. 126–129 °C. H NMR (400 MHz, CDCl3): δ = 9.22 (s,
1 H), 8.52 (s, 1 H), 8.52* (s, 0.7 H), 8.43 (d, J = 5.0 Hz, 1 H), 8.30*
(d, J = 5.0 Hz, 0.7 H), 8.09* (s, 0.7 H), 8.08 (s, 1 H), 7.68* (d, J =
8.3 Hz, 0.7 H), 7.62 (d, J = 8.3 Hz, 1 H), 7.57* (dd, J = 1.1 Hz,
0.7 H), 7.46 (d, J = 1.4 Hz, 1 H), 7.48–7.45* (m, 0.7 H), 7.41* (d,
J = 2.7 Hz, 0.7 H), 7.32 (d, J = 1.1 Hz, 1 H), 7.03 (d, J = 4.32 Hz,
1 H), 7.05–7.01* (m, 0.7 H), 2.53* (s, 2.1 H), 2.50 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 151.1, 151.0, 150.4, 148.7, 148.0,
147.7, 133.9, 132.3, 127.1, 126.6, 126.3, 122.2, 121.6, 119.5, 119.5,
117.0, 116.6, 115.2, 115.1, 114.5, 113.6, 110.6, 110.2, 106.9, 106.7,
21.6 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 (0.7), –60.8
3hc1 and 3hc2: Following the general procedure, the reaction was
carried out between 2-(1H-benzo[d]imidazol-1-yl)-5-(trifluorome-
thyl)aniline (1h; 50 mg, 0.180 mmol, 1 equiv.) and 2-bromo-6-meth-
ylpyridine (2c; 50 μL, 0.451 mmol, 2.5 equiv.). Column chromatog-
raphy on silica gel (9% ethyl acetate in hexanes) yielded 55 mg
(82%) of an inseparable mixture of the regioisomeric products
3hc1* and 3hc2 (0.9:1) as a white solid. Rf = 0.53 (20% ethyl acetate
in hexanes); m.p. 132–135 °C. 1H NMR (400 MHz, CDCl3): δ =
9.26* (s, 0.9 H), 8.89–8.87* (dd, J = 4.7, 0.9 Hz, 0.9 H), 8.56 (d, J
= 8.2 Hz, 1 H), 8.09 (s, 1 H), 7.90–7.79* (m, 3.6 H), 7.90–7.79 (m,
4 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.45–
7.40* (m, 1.8 H), 7.45–7.40 (m, 1 H), 7.35* (t, J = 7.6 Hz, 0.9 H),
7.11* (dd, J = 7.4, 1.8 Hz, 0.9 H), 7.11 (dd, J = 7.4, 1.8 Hz, 1 H),
2.68* (s, 2.7 H), 2.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 157.5, 157.5, 152.5, 151.7, 150.1, 150.0, 147.0, 146.6, 139.3,
139.2, 134.1, 133.8, 129.5, 127.9, 127.4, 125.8, 125.5, 125.4, 124.5,
124.0, 123.3, 121.5, 120.3, 120.3, 120.2, 119.6, 117.9, 117.9, 117.3,
116.6, 116.6, 114.8, 114.8, 112.0, 111.7, 110.5, 110.5, 110.4, 110.0,
24.4, 24.3 ppm. 19F NMR (376 MHz, CDCl3): δ = –60.5 (1.0),
(1.0) ppm. FTIR (neat, KBr): ν = 2927, 2852, 2104, 1644, 1609,
˜
1571, 1448, 1325, 1158, 1118, 755, 668 cm–1. HRMS (ESI): calcd.
for C16H12N4F3 [M + H]+ 317.1014; found 317.1027.
3gc1: Following the general procedure, the reaction was carried out
between
2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
(1g;
100 mg, 0.440 mmol, 1 equiv.) and 2-bromo-6-methylpyridine (2c;
95 μL, 0.880 mmol, 2.0 equiv.). Column chromatography on silica
gel (7% ethyl acetate in hexanes) yielded 71 mg (51%) of the title
compound 3gc1 as a white solid. Rf = 0.50 (20% ethyl acetate in
1
hexanes); m.p. 136–139 °C. H NMR (400 MHz, CDCl3): δ = 9.30
–61.0 (0.93) ppm. FTIR (neat, KBr): ν = 3020, 1729, 1640, 1556,
˜
(s, 1 H), 8.50 (d, J = 8.2 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.63
(d, J = 8.2 Hz, 1 H), 7.57 (dd, J = 8.2, 0.9 Hz, 1 H), 7.46 (d, J =
0.9 Hz, 1 H), 7.30 (s, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 2.65 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.4, 150.3, 139.1,
133.8, 132.2, 127.1, 123.2, 119.7, 119.4, 119.4, 115.2, 115.1, 110.9,
1457, 1324, 1215, 758, 669 cm–1. HRMS (ESI): calcd. for
C20H14N3F3 [M + H]+ 367.1171; found 367.1186.
Benzimidazokinetins 5 and 6: Following the general procedure, the
reaction was carried out between kinetin-derived azole 4 (100 mg,
0.326 mmol, 1 equiv.) and 2-bromopyridine (2a; 100 μL,
0.816 mmol, 2.5 equiv.). Column chromatography on silica gel
yielded 126 mg (85%) of 5 and 6 (0.4:1) as a viscous liquid. Rf =
110.6, 106.9, 24.3 ppm. 19F NMR (376 MHz, CDCl3):
δ =
–61.1 ppm. FTIR (neat, KBr): ν = 2927, 2852, 2102, 1730, 1597,
˜
1577, 1456, 1123, 770, 669 cm–1. HRMS (ESI): calcd. for
C16H12N4F3 [M + H]+ 317.1014; found 317.1005.
1
0.30 (50% ethyl acetate in hexanes). H NMR (400 MHz, CDCl3):
δ = 8.90–8.87 (m, 1 H), 8.63 (s, 1 H), 8.55–8.51 (m, 2 H), 8.38 (d,
J = 8.4 Hz, 1 H), 8.12–8.10 (m, 1 H), 7.76–7.35 (m, 2 H), 7.44–
7.35 (m, 3 H), 7.31–7.30 (m, 1 H), 7.18–7.14 (m, 2 H), 6.26–6.23
(m, 2 H), 5.84 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
155.8, 152.4, 152.3, 150.9, 150.0, 148.4, 147.9, 147.7, 141.7, 138.6,
138.2, 137.0, 134.3, 125.1, 124.5, 124.4, 123.5, 120.8, 120.2, 117.3,
3ha1 and 3ha2: Following the general procedure, the reaction was
carried out between 2-(1H-benzo[d]imidazol-1-yl)-5-(trifluorome-
thyl)aniline (1h; 50 mg, 0.180 mmol, 1 equiv.) and 2-bromopyridine
(2a; 40 μL, 0.451 mmol, 2.5 equiv.). Column chromatography on
silica gel (9% ethyl acetate in hexanes) yielded 46 mg (73%) of an
inseparable mixture of the regioisomeric products 3ha1* and 3ha2
(0.2:1) as a white solid. Rf = 0.53 (20% ethyl acetate in hexanes);
m.p. 107–110 °C. H NMR (400 MHz, CDCl3): δ = 9 ppm. 17* (s,
0.2 H), 8.82* (d, J = 8.3 Hz, 0.2 H), 8.81 (dd, J = 9.0, 2.5 Hz, 1
H), 8.75 (d, J = 8.3 Hz, 1 H), 8.62–7.89* (m, 0.2 H), 8.57 (d, J =
114.4, 112.4, 110.3, 108.0, 45.5 ppm. FTIR (neat, KBr): ν = 3414,
˜
3066, 1644, 1442, 1025, 773 cm–1. HRMS (ESI): calcd. for
C26H19N8O [M + H]+ 459.1676; found 459.1675.
1
General Procedure for the Synthesis of N-Aryl Heterocycles: The
4.0 Hz, 1 H), 8.05 (s, 1 H), 7.96–7.93* (m, 0.2 H), 7.95 (td, J = 8.7, starting amine 1 (100 mg, 1 equiv.) and aryl bromide (2 equiv.) were
1.7 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.79–7.76* (m, 0.4 H), 7.73
(dd, J = 5.3, 2.1 Hz, 1 H), 7.65* (d, J = 8.2 Hz, 0.2 H), 7.55 (d, J
added to an oven-dried screw-cap reaction tube charged with a
magnetic stirring bar, Cu(OAc)2·H2O (20 mol-%), 1,10-phen-
= 8.2 Hz, 1 H), 7.42–7.38* (m, 0.2 H), 7.41–7.36 (m, 2 H), 7.32* anthroline monohydrate (30 mol-%), tBuONa (3 equiv.) and TBAI
(t, J = 8.3 Hz, 0.2 H), 7.24 (dd, J = 7.5, 2.6 Hz, 1 H), 7.25–7.22* (1 equiv.) in dry DMF at room temp. Then the reaction mixture
(m, 0.4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.3, 150.8, was closed with a screw cap and the mixture was stirred at 130 °C
148.1, 146.5, 138.9, 138.8, 133.9, 129.4, 125.3, 124.5, 124.0, 123.4,
for 17 h. It was then cooled to room temperature, water (5 mL) was
Eur. J. Org. Chem. 2014, 5986–5997
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5995