2
Q. Zhou et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Cu powder/MI-Catalyzed Coupling Reaction of Aryl halides with Amines in water.a,b
Fig. 1. Schematic Diagram Depicting the Procedure for the Discovery of
Myo-inositol.
Results and discussion
To initiate our studies, we treated bromobenzene with piperi-
dine (5.0 equiv) in the presence of 20 mol% Cu-catalyst and MI at
100 °C in a hydrothermal reactor without any inert gas protection
(Table 1). Amination product 3a was obtained in 38% yield under
aqueous condition, using copper powder as catalyst (entries 1–4).
Interestingly, performing Cu-catalytic amination reaction in dry
DMSO, 3a was not observed (entry 1), suggesting that water was
essential. Only trace 3a was detected without MI, indicating that
MI played an important role to promote Cu catalytic capability.
Then, attempts to reduce the amounts of amine by using inorganic
base and TBAB were successful, which exclusively promoted the
conversion of amination product 3a (90%, entry 5). In addition,
lowering the loading of copper powder to 10% delivered 3a with
quantitative yield (entry 6). The use of other base in place of
Cs2CO3 led to lower yield, with Cs2CO3 proving to be optimal in
terms of yield (entries 8–10). In endeavors to improve the reaction,
we turned our attention to different PTCs to favor the formation of
coupling product in water. Incorporation of TBAB, PEG-400,
18-crown-6 or TBAHS into reaction led to obviously different
results, and TBAHS was beneficial and furnished 3a in 94% isolated
yield. In comparison to MI, the lead tridentate ligand L1 expressed
the weaker effect on the transformation (entry 14). Thus, we
hypothesized that preferred conformation of three hydroxyls was
contributed to facilitate the amination.
a
Standard condition: aryl bromides (1.0 mmol), amines (1.5 mmol), 10 mol% Cu
powder, 20 mol% MI, 20 mol% TBAHS, Cs2CO3 (2.2 mmol), H2O (2.0 mL), 100 °C,
unless noted otherwise.
b
Isolated yield.
Cs2CO3 (3.0 mmol).
Bromobenzene (1.0 mmol), tryptamine (1.0 mmol).
Bromobenzene (2.0 mmol), tryptamine (1.0 mmol).
c
With optimized conditions in hand, we set out to evaluate the
scope of aryl halides and amines that would participate in this
d
e
f
40% aqueous methylamine (10.0 mmol).
Table 1
Identification of Reaction Conditions.a
transformation, as shown in Table 2. Gratifyingly, Cu powder/
MI-catalyzed CAN coupling reaction of aryl halides with amines
gave desired compounds in good to excellent yield (76–97%),
which was more potential comparably to results reported in liter-
atures [8d]. Substrates bearing electron-withdrawing groups (3e)
coupled with better yield than electron-donating substituent
(3c). The better solubility of the amine in water, it seemed to be
delivered the amination product in higher yield (3q vs 3r). In addi-
tion, electron deficient aryl chlorides furnished the target products
in excellent yields (3l–n, 3s), and the presence of carboxyl sub-
stituents on the aromatic ring also facilitated the coupling reaction,
presumably due to helping to increase water solubility. In spite of
an often relatively difficult synthesis and instable property,
aminothiophenes have been widely compared to anilines due to
their exceptional electronic properties [11]. Through this catalytic
system, o-iodothiophene could be smoothly converted to aminoth-
iophene 3d in 90% yield. Moreover, with regard to the sterically
hindered acyclic secondary amines, target compounds (e.g. 3k,
80% yield) could be readily acquired in our case. Interestingly,
when the bifunctional compound tryptamine was reacted as sub-
strate, the different results were appeared by changing the loading
of bromobenzene. The primary amine preferentially coupled with
bromobenzene (1 equiv) giving 3o in 84% yield; however, the
bis-arylation product 3p was obtained in 91% yield when 2.0 equiv
bromobenzene was used. Accordingly, we proposed that coupling
Entry
Cu (mol%)
Base
PTC (20 mol%)
Yield (%)b
1c
2c
3c
4c
5
6
7
8
9
10
11
12
13
14f
Cu (20)
CuI (20)
Cu2O (20)
CuSO4 (20)
Cu (20)
Cu (10)
Cu (5)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
–
–
–
–
–
–
–
–
38/0d/tracee
19
28
0
90
87
65
80
trace
86
44
67
94
65
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4Á3H2O
KOH
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
PEG-400
18-Crown-6
TBAHS
TBAHS
a
Standard condition: 1a (1.0 mmol), 2a (1.5 mmol), 10 mol% Cu powder, 20 mol%
MI, 20 mol% PTC, base (2.2 mmol), H2O (2.0 mL), 100 °C, 8 h, and the reaction was
run in a hydrothermal reactor, unless noted otherwise.
b
Isolated yield.
1a (1.0 mmol), 2a (5.0 mmol), 20 mol% Cu catalyst.
Dry DMSO as solvent.
Absence of MI.
c
d
e
f
L1 was used as ligand instead of MI.
Please cite this article as: Q. Zhou, F. Du, Y. Chen et al., ‘‘On Water” promoted N-arylation reactions using Cu (0)/myo-inositol catalytic system, Tetrahedron