B
Synlett
G. Shen et al.
Letter
desired product could not be detected (Table 1, entry 1).
There were also no reaction using DMF, DMSO, 1,4-dioxane,
or n-PrCN as solvents (Table 1, entries 2–5). Interestingly,
we used N,N′-dimethylethane-1,2-diamine (1b, 1.0 mL) as
reaction substrate and solvent to repeat the reaction, the
product 1,2,3,4-tetrahydroquinoxaline (1c) was got in 35%
yield (Table 1, entry 6). It was found that the reaction tem-
perature affected the product yield significantly. The prod-
uct yield was improved to 52% with the increasing of the re-
action temperature to 110 °C (Table 1, entry 7). Higher tem-
perature (120 °C) did not improve the reaction yield further
Table 1 Optimization of the Reaction Conditionsa
I
N
N
copper catalyst
NH HN
base
I
1
a
1b
1c
Entry Copper catalyst
Base
Solvent
Temp Yield
b
(
°C)
(%)
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuO
K
K
K
2
2
2
CO
CO
CO
3
3
3
toluene
DMF
100
100
100
100
100
100
110
120
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
0
0
0
(
(
Table 1, entry 8). KOH and DBU were also explored as bases
Table 1, entries 9 and 10), and DBU was found to be the
DMSO
best. But the low yield was got in the absence of base (Table
, entry 11). From the atom-economy point of view, the in-
K2CO3
n-PrCN
1,4-dioxane
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
toluene
DMEDA
0
1
K
K
K
K
2
2
2
2
CO
CO
CO
CO
3
3
3
3
0
fluence of the amount of DMEDA on the reaction was also
examined (Table 1, entries 12–15). The results showed that
two equivalents of DMEDA provided the best yield (Table 1,
entry 14). Different copper catalysts were also tested, and
CuI was the best choice (Table 1, entries 16–18). With other
ligands to repeat the reaction, the yields did not change ob-
viously (Table 1, entries 19–21). An excess amount of
DMEDA (2.5 equiv) was also applied in toluene to repeat the
reaction, and the product was isolated in 4% yield (Table 1,
entry 22). Without CuI, the reaction could not proceed (Ta-
ble 1, entry 23). Thus, the optimized reaction conditions in-
volved using CuI (10 mol%) as the catalyst, DBU (2.0 equiv)
as the base, DMEDA (2.0 equiv) as dually aminating reagent
and solvent, and conducting the reaction at 110 °C under
nitrogen for 24 hours.
35
52
50
56
75
25c
60d
70e
78f
75g
72
60
11
77
70
KOH
DBU
–
1
0
1
2
3
4
1
1
1
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
15
16
17
18
19
With the optimal conditions established, we tried to ex-
pand the scope of substrates. The substituted 1,2-diiodo-
benzenes a bearing both electron-donating groups (4-Me,
CuI/1,10-phenanthroline
20
21
22
CuI/N,N-dimethylglycine
4
4
-i-Pr and 4-t-Bu) and electron-withdrawing groups (4-F,
-F C, 4-F CO, and 3,5-Cl) were able to couple with DMEDA
CuI/Ph3P
72
3
3
CuI
–
4g
(
1b) in moderate yields (Table 2, entries 2–8). When N,N′-
23
0f
diethylethane-1,2-diamine (DEEDA, 2b) was used to run
the reaction, the yield obviously decreased to 21% (Table 2,
entry 9). No product was detected when N,N′-diisopropy-
lethane-1,2-diamine (3b) was used (Table 2, entry 10). 1,8-
Diiodonaphthalene 9a could also reacted with DMEDA (1b)
or DEEDA (2b) to get the corresponding seven-membered
heterocyclic products (Table 2, entries 11 and 12). From the
results we concluded that the yields were affected more ob-
viously by the steric hindrance of N,N′-disubstituted eth-
ane-1,2-diamines b than the electronic effect of 1,2-dihalo-
benzenes a. The optimal conditions were also suitable for
the substrates 1-bromo-2-iodobenzene (10a) and 1,2-di-
bromobenzene (11a), but the yields were not high (Table 2,
entries 13 and 14). N,N′-Diphenylethane-1,2-diamine was
also used to repeat the reaction, and no product was detect-
ed (Table 2, entry 15).
a
Reaction conditions: CuI (0.05 mmol), 1,2-diiodobenzene (0.5 mmol),
DMEDA (0.5 mmol), base (1.0 mmol), and solvent (1.0 mL) under N atmo-
2
sphere for 24 h.
b
Isolated yield after flash chromatography based on 1,2-diiodobenzene
(
1a).
c
No base was used.
d
e
f
Conditions: 0.5 mmol (1.0 equiv) DMEDA was used.
Conditions: 0.75 mmol (1.5 equiv) DMEDA was used.
Conditions: 1.0 mmol (2.0 equiv) DMEDA was used.
Conditions: 1.25 mmol (2.5 equiv) DMEDA was used.
g
In summary, an efficient ‘ligand- and solvent-free’
method for the synthesis of quinoxaline derivatives via cop-
per(I)-catalyzed cross-coupling process has been devel-
9
oped. A variety of 1,4-disubstituted 1,2,3,4-tetrahydroqui-
noxalines and 1,4-disubstituted 1,2,3,4-tetrahydronaph-
tho[1,8-ef][1,4]diazepines, which might be potentially
applicable in the pharmaceutical, dyes, and biochemical ar-
eas, were conveniently synthesized in moderate yields.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E