G Model
CCLET 3422 1–6
2
M.N. Joy et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
53
2. Experimental
2-(4-Nitrophenyl)-1H-Imidazo[4,5-b]pyrazine (4b): Mp: 99–
102 8C; 1H NMR (400 MHz, DMSO-d6):
7.92–7.94 (dd, 2H,
J1 = 1.96 Hz J2 = 8.44 Hz, ArH), 8.46–8.49 (dd, 2H,
J1 = 2.08 Hz, J2 = 8.56 Hz, ArH), 8.72 (d, 2H, J = 7.12 Hz, ArH),
12.73 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
123.1
(2 peaks), 129.6, 138.1, 145.8, 148.9, 149.7; LC-MS: Calcd. 241.2,
Observed 242.2; Analysis calcd. for C11H7N5O2: C, 54.77, H, 2.93, N,
29.03, found: C, 54.82, H, 2.91, N, 29.03.
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
d
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
All solvents and reagents were obtained from commercial
suppliers and used without any further purification. All the
reactions were carried out under inert argon atmosphere.
Analytical TLC was performed on pre-coated aluminum sheets
d
of silica (60 F254 nm) and visualized by short-wave UV light at
l
254. Melting points were determined on an EZ-Melt automated
melting point apparatus. 1H NMR spectra were recorded at
400 MHz using an internal deuterium lock. Chemical shifts were
2-(4-Fluorophenyl)-1H-Imidazo[4,5-b]pyrazine (4c): Mp: 91–
93 8C; 1H NMR (400 MHz, DMSO-d6):
d
7.35–7.39 (dd, 2H,
7.79–7.83 (dd, 2H,
J1 = 1.76 Hz, J2 = 8.24 Hz, ArH), 8.97 (s, 2H, ArH), 12.44 (br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6):
118.3, 124.0, 129.9, 131.5,
measured in
using an internal deuterium lock. LC-MS analyses were performed
using ESI/APCI, with an ATLANTIS C18 (50 mm  4.6 mm – 5 m)
column and flow rate of 1.2 mL/min. Microwave-assisted
d
(ppm). 13C NMR spectra were recorded at 100 MHz
J1 = 2.16 Hz, J2 = 8.04 Hz,
ArH),
m
d
a
131.7, 146.7, 149.9, 165.1; LC-MS: Calcd. 214.2, Observed 215.2;
Analysis calcd. for C11H7FN4: C, 61.68, H, 3.29, N, 26.16, found: C,
61.72, H, 3.26, N, 26.16.
synthesis was performed in a single mode Biotage Initiator
Microwave Synthesizer and temperature was monitored using
infrared. The microwave reaction was carried out in a 5 mL glass
vial and high absorption level was maintained. The conditions
were maintained till the completion of the reaction.
Methyl 4-(1H-imidazo[4,5-b]pyrazin-2-yl)benzoate (4d): Mp:
106–108 8C; 1H NMR (400 MHz, DMSO-d6):
d 3.96 (s, 3H, OCH3),
7.81–7.83 (dd, 2H, J1 = 2.44 Hz, J2 = 8.24 Hz, ArH), 8.26–8.29 (dd,
2H, J1 = 2.64 Hz, J2 = 8.76 Hz, ArH), 8.75 (d, 2H, J = 6.48 Hz, ArH),
12.44 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d 53.3, 122.9,
71
2.1. Procedure for the synthesis of intermediate 2
128.8, 132.1 (2 peaks), 136.2, 146.1, 148.8, 167.2; LC-MS: Calcd.
254.2, Observed 255.2; Analysis calcd. for C13H10N4O2: C, 61.41, H,
3.96, N, 22.04, found: C, 61.45, H, 3.95, N, 22.04.
72
73
74
75
76
77
78
79
80
81
To a solution of 2,3-diamino pyrazine 1, was added CDI in THF,
which was then heated at 80 8C for 4 h. The reaction completion
was monitored by TLC. The mixture was diluted with water and
extracted in ethyl acetate, dried in anhydrous sodium sulphate,
and distilled under reduced pressure. The crude product was
purified by column chromatography to procure the titled
compound in 92% yield. MP: 74–76 8C; 1H NMR (400 MHz,
4-(1H-Imidazo[4,5-b]pyrazin-2-yl)benzonitrile (4e): Mp: 96–
98 8C; 1H NMR (400 MHz, DMSO-d6):
d
7.73–7.80 (m, 4H, ArH),
8.84 (d, 2H, J = 7.28 Hz, ArH), 12.52 (br, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): 114.4, 117.1, 122.8, 129.7, 134.1, 136.4,
d
145.9, 149.2; LC-MS: Calcd. 221.2, Observed 222.2; Analysis calcd.
for C12H7N5: C, 65.15, H, 3.19, N, 31.66, found: C, 65.19, H, 3.16, N,
31.64.
DMSO-d6):
NMR (100 MHz, DMSO-d6):
Calculated 136.1, Observed 137.1.
d
6.84 (br, 2H, NH), 8.68 (d, 2H, J = 8.04 Hz, ArH); 13C
135.2, 143.7, 157.5, LC-MS:
d
4-(1H-Imidazo[4,5-b]pyrazin-2-yl)phenol (4f): Mp: 90–92 8C;
1H NMR (400 MHz, DMSO-d6):
J1 = 2.36 Hz, J2 = 8.16 Hz,
d
5.04 (s, 1H, OH), 7.01–7.04 (dd, 2H,
ArH), 7.47–7.49 (dd, 2H,
J1 = 2.28 Hz, J2 = 8.44 Hz, ArH), 8.77 (d, 2H, J = 7.44 Hz, ArH),
12.34 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
118.0
82
2.2. Procedure for the synthesis of intermediate 3
83
84
85
86
87
88
89
90
91
To a solution of intermediate 2 in dichloro ethane was added
POBr3 at 0 8C, and the reaction mixture was gradually warmed to
ambient temperature. The reaction mass was then heated at 80 8C
for 6 h. The reaction mixture was poured into crushed ice, basified
with NaHCO3, and extracted with DCM and distilled in reduced
pressure to render the titled compound in 76% yield. MP: 83–85 8C;
d
(2 peaks), 122.8 (2 peaks), 124.7, 130.1, 145.8, 149.1, 159.9; LC-MS:
Calcd. 212.2, Observed 213.2; Analysis calcd. for C11H8N4O: C,
62.26, H, 3.80, N, 26.40, found: C, 62.31, H, 3.78, N, 26.38.
2-p-Tolyl-1H-imidazo[4,5-b]pyrazine (4 g): Mp: 88–90 8C; 1H
NMR (400 MHz, DMSO-d6):
J1 = 2.36 Hz, J2 = 8.28 Hz,
d
2.67 (s, 3H, CH3), 7.32–7.34 (dd, 2H,
1H NMR (400 MHz, DMSO-d6):
d 9.05 (d, 2H, J = 7.76 Hz, ArH); 12.6
ArH), 7.65–7.68 (dd, 2H,
(br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d 123.9, 138.3, 146.7;
J1 = 1.96 Hz, J2 = 8.36 Hz, ArH), 8.92 (d, 2H, J = 7.08 Hz, ArH),
12.12 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
26.7, 123.7,
LC-MS: Calculated 198.0, Observed 199.0.
d
129.4, 129.8, 131.8, 140.7, 146.9, 149.7; LC-MS: Calcd. 210.2,
Observed 211.2; Analysis calcd. for C12H10N4: C, 68.56, H, 4.79, N,
26.65, found: C, 68.61, H, 4.77, N, 26.62.
92
2.3. General procedure for the coupling reaction
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
To a solution of 2-bromo imidazopyrazine intermediate 3
(1 equiv.) in DME-H2O (4:1), were added boronic acid (1.5 equiv.),
CsF (3 equiv.), and (A-taphos)2PdCl2 (10 mol%), and the solution
was purged with argon and stirred at room temperature for
10 min. The reaction solution was then placed in the microwave
and heated for 20–30 min at 100 8C. When TLC and LC-MS showed
full consumption of starting materials, the reaction mixture was
filtered and diluted with ethyl acetate. The ethyl acetate layer was
extracted, washed in water, washed in brine, dried over
anhydrous sodium sulfate, and distilled in vacuum to get the
crude material. The crude product was purified by column
chromatography and eluted in varying polarities to obtain the
substituted diaryls 4a-n.
2-Phenyl-1H-Imidazo[4,5-b]pyrazine (4a): Mp: 85–87 8C; 1H
NMR (400 MHz, DMSO-d6):
ArH), 12.32 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
129.7, 131.2, 131.7, 133.1, 146.6, 149.8; LC-MS: Calcd. 196.2,
Observed 197.2; Analysis calcd. for C11H8N4: C, 67.34, H, 4.11, N,
28.55, found: C, 67.38, H, 4.08, N, 28.53.
2-(4-Methoxyphenyl)-1H-imidazo[4,5-b]pyrazine (4 h): Mp:
98–100 8C; 1H NMR (400 MHz, DMSO-d6):
d 3.81 (s, 3H, OCH3),
7.09–7.13 (dd, 2H, J1 = 2.44 Hz, J2 = 8.36 Hz, ArH), 7.51–7.53 (dd,
2H, J1 = 1.96 Hz, J2 = 8.48 Hz, ArH), 8.84 (d, 2H, J = 7.56 Hz, ArH),
12.46 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d 57.1, 116.1
(2 peaks), 123.2 (3 peaks), 129.8, 146.0, 148.9, 162.1; LC-MS: Calcd.
226.2, Observed 227.2; Analysis calcd. for C12H10N4O: C, 63.71, H,
4.46, N, 24.76, found: C, 63.75, H, 4.44, N, 24.75.
3-(1H-Imidazo[4,5-b]pyrazin-2-yl)-N,N-dimethylbenzenamine
(4i): Mp: 109–111 8C; 1H NMR (400 MHz, DMSO-d6):
d 3.12 (s, 6H,
CH3), 6.85–7.04 (m, 4H, ArH), 7.45–7.48 (dd, 2H,
J1 = 2.44 Hz, J2 = 8.36 Hz, ArH), 8.96 (s, 2H, ArH), 12.64 (br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6):
d 42.6, 114.5, 116.7, 119.1,
123.8, 132.4, 133.9, 146.6, 149.8, 152.4; LC-MS: Calcd. 239.3,
Observed 240.3; Analysis calcd. for C13H13N5: C, 65.25, H, 5.48, N,
29.27, found: C, 65.28, H, 5.47, N, 29.24.
d
7.64–7.86 (m, 5H, ArH), 8.94 (s, 2H,
123.9,
d
2-(Pyridine-3-yl)-1H-Imidazo[4,5-b]pyrazine (4j): Mp: 86–
88 8C; 1H NMR (400 MHz, DMSO-d6):
d
7.62 (dd, 1H,
J1 = 2.36 Hz, J2 = 8.48 Hz, ArH), 8.04 (d, 1H, J = 6.36 Hz, ArH),
Please cite this article in press as: M.N. Joy, et al., A facile access for the synthesis of some C-2 substituted imidazopyrazines by utilizing
the palladium catalyzed Suzuki cross-coupling reaction under microwave irradiation, Chin. Chem. Lett. (2015), http://dx.doi.org/