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F. Tibiletti et al. / Tetrahedron 66 (2010) 1280–1288
8.92 (s, 1H), 8.85 (s, 1H), 8.62 (d, J¼5.4 Hz, 1H), 7.97 (d, J¼5.4 Hz,
of 2-chloro-4-ethynylpyrimidine (139 mg, 1.0 mmol) in toluene
(12 mL) and the reaction mixture was heated at 80 ꢀC for 7 h. After
the complete conversion of the nitrosoarene, the reaction mixture
was cooled to rt, and the solvent was removed in vacuo to give
a dark solid. Separation of the crude material by chromatography
on silica gel (CH2Cl2–MeOH¼98:2) afforded 3-(2-chloropyrimidin-
4-yl)-7-methyl-1H-indole (135 mg, 55% yield) as a dark-brown
13
1H), 7.72–7.69 ppm (m, 2H). C NMR (100 MHz, DMSO-d6, 25 ꢀC,
TMS) d: 165.0, 163.6, 159.2, 134.6, 132.0, 127.1, 125.7, 121.1, 120.2,
114.0, 111.0, 107.3, 104.0 ppm. MS (CI): m/z 255 [Mþ1]. IR (KBr,
n):
2924, 2224, 1615, 1592, 1532, 1371, 809 cmꢁ1. Elemental analyses
for C13H7ClN4: calcd (%) C 61.31, H 2.77, N 22.00; found (%) C 60.99,
H 2.53, N 22.13.
1
solid, mp 193–195 ꢀC (dec). H NMR (400 MHz, DMSO-d6, 25 ꢀC,
4.1.21. 3-(2-Chloropyrimidin-4-yl)-7-nitro-1H-indole (5e). 2-Nitro-
nitrosobenzene (152 mg, 1.0 mmol) was added to a solution of
2-chloro-4-ethynylpyrimidine (139 mg, 1.0 mmol) in toluene
(10 mL) and the reaction mixture was heated at 80 ꢀC for 6 h. After
the complete conversion of the nitrosoarene, the reaction mixture
was cooled to rt and the solvent was removed in vacuo to give
a black solid. Separation of the crude material on silica gel (Hexane–
EtOAc¼30:70) afforded 3-(2-chloropyrimidin-4-yl)-7-nitro-1H-in-
dole (104 mg, 38% yield) as an orange solid, mp 205 ꢀC. 1H NMR
TMS)
d
: 12.08 (s, 1H), 8.50 (d, J¼5.5 Hz, 1H), 8.49 (d, J¼3.1 Hz, 1H),
8.24 (d, J¼8.0 Hz, 1H), 7.92 (d, J¼5.5 Hz, 1H), 7.12 (t, J¼8.0 Hz, 1H),
7.02 (d, J¼8.0 Hz, 1H), 2.48 ppm (s, 3H). 13C NMR (100 MHz, DMSO-
d6, 25 ꢀC, TMS)
d: 165.1, 160.3, 158.5, 136.8, 130.9, 124.7, 123.3, 121.6,
121.5, 119.2, 114.6, 112.3, 16.7 ppm. MS (CI): m/z 246, 244 [Mþ1]. IR
(KBr,
n
): 2925, 1574, 1341, 1133, 787 cmꢁ1. Elemental analyses for
C13H10ClN3: calcd (%) C 64.07, H 4.14, N 17.24; found (%) C 64.23, H
4.08, N 17.15.
(400 MHz, CDCl3, 25 ꢀC, TMS)
d
: 10.41 (br, 1H), 8.98 (d, J¼8.0 Hz,
4.1.25. 4-Bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (5i) and 6-
bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (5j). 3-Bromo-nitro-
sobenzene (186 mg, 1.0 mmol) was added to
1H), 8.50 (d, J¼5.4 Hz, 1H), 8.29 (d, J¼8.0 Hz, 1H), 8.18 (d, J¼2.8 Hz,
1H), 7.55 (d, J¼5.4 Hz, 1H), 7.45–7.43 ppm (m, 1H). 13C NMR
a solution of
(100 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 165.1, 160.3, 158.6, 137.3, 129.0,
2-chloro-4-ethynylpyrimidine (139 mg,1.0 mmol) in toluene (10 mL)
and the solutionwas heated at 80 ꢀC for 7 h. After 2 h, precipitation of
a solid byproduct was observed. After the complete conversion of the
nitrosoarene, the solid was removed by filtration, and the washings
rotary evaporated to afford a dark-brown solid. Separation of the
crude material on silica gel (Hexane–AcOEt¼40:60) afforded
4-bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (60 mg, 19% yield)
as a brown solid and 6-bromo-3-(2-chloropyrimidin-4-yl)-1H-indole
(62 mg, 20% yield) as a brown solid.
125.4, 122.7, 121.6, 121.4, 114.6, 112.4, 111.8 ppm. MS (CI): m/z 277,
275 [Mþ1], 247, 245. IR (KBr,
n): 2964, 1637, 1583, 1383, 1262,
801 cmꢁ1. Elemental analyses for C12H7ClN4O2: calcd (%) C 52.48, H
2.57, N 20.40; found (%) C 52.56, H 2.48, N 20.33.
4.1.22. 3-(2-Chloropyrimidin-4-yl)-7-(trifluoromethyl)-1H-indole
(5f). 2-(Trifluoromethyl)-nitrosobenzene (175 mg, 1.0 mmol) was
added to a solution of 2-chloro-4-ethynylpyrimidine (139 mg,
1.0 mmol) in toluene (10 mL) and the reaction mixture was heated
at 80 ꢀC for 6 h. After the complete conversion of the nitrosoarene,
the reaction mixture was cooled to rt and the solvent was removed
in vacuo to give a dark solid. Separation of the crude material on
silica gel (Hexane–EtOAc¼30:70) afforded 3-(2-chloropyrimidin-4-
yl)-7-(trifluoromethyl)-1H-indole (89 mg, 30% yield) as an orange
4.1.26. 4-Bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (5i). 1H NMR
(400 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 12.39 (s, 1H), 8.93 (d, J¼5.1 Hz,
1H), 7.99 (d, J¼5.1 Hz, 1H), 7.11–7.08 (m, 2H), 7.06 (dd, J3¼6.9 Hz,
J4¼2.0 Hz, 1H), 5.68 ppm (s, 1H). 13C NMR (100 MHz, DMSO-d6,
25 ꢀC, TMS): 168.8, 161.4, 159.8, 153.9, 133.6, 129.6, 128.3, 119.1,
118.2, 116.0, 96.2, 85.3 ppm. MS (CI): m/z 308 [Mþ1], 310, 312. IR
solid, mp 194 ꢀC. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 12.23
(s,1H), 8.84 (d, J¼7.8 Hz,1H), 8.83 (s,1H), 8.60 (d, J¼5.4 Hz,1H), 7.97
(KBr, n
): 2960, 2924, 1567, 1383, 1342, 795 cmꢁ1. Elemental analyses
(d, J¼5.4 Hz, 1H), 7.68 (d, J¼7.8 Hz, 1H), 7.40 ppm (t, J¼7.8 Hz, 1H).
for C12H7BrClN3: calcd (%) C 46.71, H 2.29, N 13.62; found (%) C
46.85, H 2.21, N 13.72. Brown solid, mp 208–209 ꢀC (dec).
13C NMR (100 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 163.8, 160.2, 159.1,
131.9, 129.2, 126.6, 125.0, 123.6, 122.3, 121.6, 120.9, 115.2, 107.5 ppm.
MS (CI): m/z 300, 298 [Mþ1]. IR (KBr,
n
): 2924, 2856, 1633, 1584,
4.1.27. 6-Bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (5j). 1H NMR
1382, 1293, 801 cmꢁ1. Elemental analyses for C13H7ClF3N3: calcd (%)
C 52.46, H 2.37, N 14.12; found (%) C 52.42, H 2.45, N 14.16.
(400 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 12.18 (s, 1H), 8.55 (d, J¼5.5 Hz,
1H), 8.53 (d, J¼3.0 Hz, 1H), 8.35 (d, J¼8.6 Hz, 1H), 7.91 (d, J¼5.5 Hz,
1H), 7.69 (d, J¼1.6 Hz, 1H), 7.37 ppm (dd, J3¼8.6 Hz, J4¼1.6 Hz, 1H).
13C NMR (100 MHz, DMSO-d6, 25 ꢀC, TMS): 164.6, 160.3, 158.9,
138.1, 131.9, 124.3, 124.0, 123.3, 115.4, 115.0, 114.7, 112.0 ppm. MS
4.1.23. 3-(2-Chloropyrimidin-4-yl)-1H-indole-5-carboxylic acid
(5g). 4-Nitrosobenzoic acid (151 mg, 1.0 mmol) was suspended in
dioxane (10 mL) and heated until the solid was completely dis-
solved, then 2-chloro-4-ethynylpyrimidine (139 mg, 1.0 mmol) was
added and the mixture was heated at reflux for 7.5 h. After the
complete conversion of the nitrosoarene, the reaction mixture was
cooled to rt and the solvent removed in vacuo to give an orange
solid. Separation of the crude material on silica gel (CH2Cl2–MeOH)
afforded 3-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylic acid
(147 mg, 54% yield) as an orange solid, mp 253–255 ꢀC (dec). 1H
(CI): m/z 308 [Mþ1], 310, 312. IR (KBr,
n): 2957, 2924, 2854, 1573,
1383, 1344, 798 cmꢁ1. Elemental analyses for C12H7BrClN3: calcd
(%) C 46.71, H 2.29, N 13.62; found (%) C 46.88, H 2.17, N 13.66.
Brown solid, mp 197–199 ꢀC (dec).
4.1.28. 3-(2-Chloropyrimidin-4-yl)-5-methoxy-1H-indole
(5k). 4-Methoxynitrosobenzene (137 mg, 1.0 mmol) was added to
a solution of 2-chloro-4-ethynylpyrimidine (139 mg, 1.0 mmol) in
toluene (12 mL) and the solution was heated at 80 ꢀC for 48 h. The
reaction mixture was cooled to rt and the solvent was removed in
vacuo to give a dark red-brown solid. After separation of the crude
material on silica gel (CH2Cl2–MeOH¼98:2) unreacted nitrosoarene
(64% conversion) and 3-(2-chloropyrimidin-4-yl)-5-methoxy-1H-
indole (39 mg, 23% yield) as a red-brown solid were collected. Red-
brown solid, mp 222–223 ꢀC. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC,
NMR (400 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 12.96 (br, 1H), 12.25
(s, 1H), 9.15 (dd, J4¼1.6 Hz, J5¼0.8 Hz, 1H), 8.81 (s, 1H), 8.57
(dd, J3¼5.4 Hz, J4¼0.8 Hz, 1H), 7.91 (d, J¼5.4 Hz, 1H), 7.89 (dd,
J3¼8.6 Hz, J4¼1.6 Hz, 1H), 7.58 ppm (d, J¼8.6 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 167.9, 164.1, 160.3, 158.9, 136.3,
131.2, 124.7, 124.4, 124.2, 121.1, 114.8, 109.2, 107.8 ppm. MS (CI): m/z
276, 274 [Mþ1]. IR (KBr,
n): 3448, 2855, 1686, 1578, 1460, 1422,
1384, 1290, 1082, 744 cmꢁ1. Elemental analyses for C13H8ClN3O2:
calcd (%) C 57.05, H 2.95, N 15.35; found (%) C 56.94, H 3.10, N 15.22.
TMS)
d
: 11.96 (s, 1H), 8.49 (d, J¼5.5 Hz, 1H), 8.43 (d, J¼2.7 Hz, 1H),
7.93 (d, J¼2.5 Hz, 1H), 7.86 (d, J¼5.5 Hz, 1H), 7.39 (d, J¼8.8 Hz, 1H),
6.88 (dd, J3¼8.8 Hz, J4¼2.5 Hz, 1H), 3.81 ppm (s, 3H). 13C NMR
4.1.24. 3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole
(100 MHz, DMSO-d6, 25 ꢀC, TMS)
d: 164.8, 160.0, 158.2, 154.8, 132.0,
(5h). 2-Nitrosotoluene (121 mg, 1.0 mmol) was added to a solution
131.1, 125.4, 114.1, 112.8, 112.0, 111.3, 103.7, 55.0 ppm. MS (CI): m/z