Synthesis of Dipyrido[1,2-a:2′,3′-d]imidazole
118.5, 116.3, 111.8; HRMS (ESI) for C10H7N3 [M + H]+ calcd
lecular amination (Table 5, entries 1 and 3). The remarkable
temperature-selective behavior with 2b and 2e can be rational-
ized via a temperature-dependent oxidative addition on the
intermediates 3b and 3e. To the best of our knowledge, reaction
product control in palladium-catalyzed aminations by altering
the reaction temperature is hitherto unprecedented. In contrast,
amination of 1 with 2-aminopyridine (2a) and 2-aminopyrazine
(2d) at 140 °C almost exclusively gave the corresponding
intermediates 3a and 3d (Table 4, entries 2 and 11). Only trace
amounts of the respective tricyclic compounds 4a and 4d were
isolated. Consequently, to obtain 4a and 4d at 140 °C, an
orthogonal tandem Pd- and Cu-catalyzed process is required.
170.0718, found 170.0711.
Pyrido[2′,3′:4,5]imidazo[1,2-a]quinoline (4b). The general
procedure was followed using 2-aminoquinoline (2b) (1.80 mmol,
0.259 g) as amidine: yield 0.290 g (88%); white solid; mp 207
1
°C; H NMR (400 MHz, CDCl3) 8.82 (1H, d, J ) 4.6 Hz, H2),
8.66 (1H, d, J ) 8.2 Hz, H4), 8.46 (1H, d, J ) 8.6 Hz, H6), 7.89
(1H, dd, J ) 7.7, 1.4 Hz, H9), 7.80 (1H, td, J ) 8.6, 1.4 Hz, H7),
7.79 (1H, d, J ) 9.4 Hz, H10), 7.73 (1H, d, J ) 9.4 Hz, H11), 7.54
(1H, t, J ) 7.7 Hz, H8), 7.42 (1H, dd, J ) 8.2, 4.6 Hz, H3); 13C
NMR (100 MHz, CDCl3) 156.7, 149.8, 147.2, 135.6, 132.5, 130.3,
130.2, 124.9, 123.5, 121.9, 118.0, 117.4, 115.2; HRMS (ESI) for
C14H10N3 [M + H]+ calcd 220.0875, found 220.0873.
In summary, we have developed a regioselective orthogonal
tandem-catalyzed amination based on a chemoselective oxidative
addition, in which a Pd-catalyzed intermolecular amination and
a Cu-catalyzed intramolecular amination occur consecutively.
In addition, a hitherto unprecedented process control (regiose-
lective intermolecular or auto-tandem inter- and intramolecular
Pd-catalyzed amination) in Buchwald-Hartwig reactions by a
simple alteration of the reaction temperature is also presented.
The developed method gives access to unknown polycyclic aza
heteroaromatic skeletons with potential antitumor properties in
a simple and straightforward way.22
Pyrido[3′,2′:4,5]imidazo[2,3-a]isoquinoline (4c). The general
procedure was followed using 1-aminoisoquinoline (2c) (1.80 mmol,
0.259 g) as amidine. The reaction mixture was heated for 30 h:
yield 0.284 g (86%); white solid; mp >250 °C (decomp); 1H NMR
(400 MHz, CDCl3) 8.93 (1H, m, H8 or H11), 8.78 (1H, dd, J ) 4.7,
1.4 Hz, H2), 8.15 (1H, d, J ) 7.2 Hz, H6), 8.13 (1H, dd, J ) 8.1,
1.4 Hz, H4), 7.78-7.71 (3H, m, H11 or H8, H9 and H10), 7.33 (1H,
dd, J ) 8.1, 4.7 Hz, H3), 7.15 (1H, d, J ) 7.2 Hz, H7); 13C NMR
(100 MHz, CDCl3) 156.3, 148.9, 147.5, 131.8, 130.9, 128.7, 127.3,
126.1, 123.5, 122.7, 121.35, 118.0, 116.9, 112.4; HRMS (ESI) for
C14H10N3 [M + H]+ calcd 220.0875, found 220.0869.
Pyrido[2′,3′:4,5]imidazo[1,2-a]pyrazine (4d). The general pro-
cedure was followed using aminopyrazine (2d) (1.80 mmol, 0.171
1
Experimental Section
g) as amidine: yield 0.109 g (44%); white solid; mp 229 °C; H
NMR (400 MHz, CDCl3) 9.43 (1H, d, J ) 1.5 Hz, H9), 9.00 (1H,
dd, J ) 4.5, 1.5 Hz, H7), 8.38 (1H, dd, J ) 4.6, 1.5 Hz, H2), 8.34
(1H, dd, J ) 8.2, 1.5 Hz, H4), 8.09 (1H, d, J ) 4.5 Hz, H6), 7.47
(1H, dd, J ) 8.2, 4.6 Hz, H3); 13C NMR (100 MHz, CDCl3) 155.4,
150.9, 146.2, 142.7, 128.2, 120.3, 119.9, 118.1, 118.1; HRMS (ESI)
for C10H6N4 [M + H]+ calcd 171.0671, found 171.0663.
General Procedure for the Synthesis of Dipyrido[1,2-a:2′,3′-
d]imidazole and Its Benzo and Aza Analogues via an Orthogonal
Tandem Intermolecular Pd-Catalyzed and Intramolecular Cu-
Catalyzed Amination. A round-bottom flask of 50 mL was charged
with Pd2(dba)3 (0.030 mmol, 0.028 g, 2.0 mol %), XANTPHOS
(0.066 mmol, 0.038 g, 4.4 mol %), and DME (5 mL). The obtained
mixture was flushed with N2 for 10 min under magnetic stirring.
Meanwhile, a pressure tube of 80 mL was charged with CuI (0.15
mmol, 0.028 g, 10 mol %), 2,3-dibromopyridine (1) (1.5 mmol,
0.355 g), amidine (2) (1.8 mmol), and cesium carbonate (6.0 mmol,
1.955 g). To this mixture was added the preformed Pd catalyst under
a N2 flow. The flask of 50 mL was subsequently rinsed with 2 ×
5 mL of DME. Then, the resulting mixture was flushed with N2
for 5 min, sealed, and heated (internal temperature: 140 °C, oil
bath temperature: 160 °C) under vigorous magnetic stirring for 24
h. After cooling the reaction mixture to room temperature, 20 mL
of dichloromethane was added and the suspension was filtered over
a glass filter. The filter was rinsed (a) with dichloromethane (130
mL) for components 4a-4c or (b) with 7 N NH3 in MeOH (200
mL) and dichloromethane (130 mL) for components 4d and 4e.
The filtrate was evaporated under reduced pressure, and the residue
was purified by flash column chromatography on silica gel using
dichloromethane/methanol (97:3) as the eluent.
Pyrido[2′,3′:4,5]imidazo[1,2-b]pyridazine (4e). The general
procedure was followed using 4.0 mol % Pd2(dba)3, 8.8 mol %
XANTPHOS, and 3-aminopyridazine (2e) (1.80 mmol, 0.171 g)
as amidine. The reaction mixture was heated for 30 h: yield 0.193
1
g (76%); white solid; mp 159 °C; H NMR (400 MHz, CDCl3)
8.90 (1H, dd, J ) 4.6, 1.4 Hz, H2), 8.49 (1H, dd, J ) 8.1, 1.6 Hz,
H4), 8.47 (1H, dd, J ) 4,5, 1.6 Hz, H7), 8.17 (1H, dd, J ) 9.4, 1.6
Hz, H9), 7.44 (1H, dd, J ) 8.1, 4.6 Hz, H3), 7.36 (1H, dd, J ) 9.4,
4.5 Hz, H8); 13C NMR (100 MHz, CDCl3) 154.6, 149.8, 144.1,
142.1, 126.8, 123.1, 122.5, 120.4, 118.2; HRMS (ESI) for C10H6N4
[M + H]+ calcd 171.0671, found 171.0664.
General Procedure for the Synthesis of Dipyrido[1,2-a:2′,3′-
d]imidazole and Its Benzo and Aza Analogues via an Auto-
Tandem Inter- and Intramolecular Pd-Catalyzed Amination.
A round-bottom flask of 50 mL was charged with Pd2(dba)3 (0.030
mmol, 0.028 g, 2.0 mol %), XANTPHOS (9,9-dimethyl-4,5-bis-
(diphenylphosphanyl)-9H-xanthene) (0.066 mmol, 0.038 g, 4.4 mol
%), and DME (5 mL). The obtained mixture was flushed with N2
for 10 min under magnetic stirring. Meanwhile, a pressure tube of
80 mL was charged with 2,3-dibromopyridine (1) (1.5 mmol, 0.355
g), amidine (2) (1.8 mmol), and cesium carbonate (6.0 mmol, 1.955
g). To this mixture was added the preformed Pd catalyst under a
N2 flow. The flask of 50 mL was subsequently rinsed with 2 × 5
mL of DME. Then, the resulting mixture was flushed with N2 for
5 min, sealed, and heated (internal temperature: 140 °C, oil bath
temperature: 160 °C) under vigorous magnetic stirring for 24 h.
After cooling the reaction mixture to room temperature, 20 mL of
dichloromethane was added and the suspension was filtered over a
glass filter. The filter was rinsed (a) with dichloromethane (130
mL) for components 4a-4c or (b) with 7 N NH3 in MeOH (200
mL) and dichloromethane (130 mL) for components 4d and 4e.
The filtrate was evaporated under reduced pressure, and the residue
was purified by flash column chromatography on silica gel using
dichloromethane/methanol (97:3) as the eluent.
Dipyrido[1,2-a:2′,3′-d]imidazole (4a). The general procedure
was followed using 2-aminopyridine (2a) (1.80 mmol, 0.169 g) as
1
amidine: yield 0.205 g (80%); white solid; mp 197 °C; H NMR
(400 MHz, CDCl3) 8.82 (1H, dd, J ) 4.7, 1.4 Hz, H2), 8.54 (1H,
d, J ) 6.7 Hz, H6), 8.27 (1H, dd, J ) 8.1, 1.4 Hz, H4), 7.83 (1H,
d, J ) 9.3 Hz, H9), 7.54 (1H, dd, J ) 9.3, 6.7 Hz, H8), 7.30 (1H,
dd, J ) 8.1, 4.7 Hz, H3), 6.97 (1H, t, J ) 6.7 Hz, H7); 13C NMR
(100 MHz, CDCl3) 155.9, 149.6, 148.9, 131.2, 126.1, 121.4, 119.2,
(22) Only the dipyrido[1,2-a:2′,3′-d]imidazole skeleton and some sub-
stituted analogues are known: (a) Chezal, J. M.; Moreau, E.; Chavignon,
O.; Gaumet, V.; Me´tin, J.; Blache, Y.; Diez, A.; Fradera, X.; Luque, J.;
Teulade, J. C. Tetrahedron 2002, 58, 295. (b) Baklanov, M. V.; Frolov, A.
N. Zh. Org. Khim. 1991, 27, 638.
(23) Trace amounts (<5%) of dipyrido[1,2-a:3′,2′-d]imidazole and its
benzo and aza analogues were also isolated. These regioisomers are
presumably formed via tandem C-3 intermolecular and C-2 intramolecular
metal-catalyzed amination.
J. Org. Chem, Vol. 71, No. 1, 2006 263