Full Papers
cross-coupling has been little explored.[22] The synthetic use of
boronic acids is becoming more common in coupling reactions
as they are more stable, less toxic, and greener[23] than aryl hal-
ides. Boronic acids have a broad substrate scope, however,
their utility in MOF-catalyzed coupling reactions is very limit-
ed.[24] Therefore, in the present study, we aim to utilize
If the same reaction was performed under identical condi-
tions using Cu(tpa)-MOF as the catalyst, the reaction proceed-
ed smoothly with a good conversion. To choose the optimum
solvent for the N-arylation of 2, various nonpolar and polar sol-
vents, dioxane, acetonitrile (ACN), dichloromethane (DCM),
EtOH, MeOH, DMF, DMSO, and water, were investigated, and
nonpolar and aprotic polar solvents resulted in poor yields or
no reaction. Protic polar solvents, MeOH, EtOH, and water,
favor the arylation to give good to excellent yields, however,
the high nucleophilicity of MeOH disturbs the framework of
Cu(tpa)-MOF, which decomposes during the course of the
reaction.
a
simple copper terephthalate MOF[25] (Cu(tpa)-MOF) as
a ligand-free, sustainable catalyst for the facile and benign syn-
thesis of N-arylimidazoles. The exposed apical Cu2+ coordina-
tion sites, high surface area, and large pore volume of Cu(tpa)-
MOF will be expected to catalyze the N-arylation of imidazole
using arylboronic acids as electrophiles. Except for very few re-
ports[24c,26] on the application of Cu(tpa)-MOF in organic syn-
thesis, to the best of our knowledge this is the first report of
Cu(tpa)-MOF as a catalyst for the synthesis of N-arylimidazoles
by CÀN cross-coupling.
The same phenomenon was noted if water was used as the
solvent, and the catalyst became pasty and stuck to the reac-
tion vessel. In EtOH, the reactions went to completion with
a very good yield of 99% with a minimum catalyst loading
(Table 1, entry 10). Consequently, EtOH was chosen as the reac-
tion medium for this coupling reaction and it does not influ-
ence Cu(tpa)-MOF negatively. A survey of solvent section
guides[23,27] showed that EtOH is a greener solvent than MeOH,
and industrial companies, such as Pfizer, Astra Zeneca, GCI-PR,
and GSK, rank EtOH as a green solvent for medicinal chemis-
try[27] in terms of health, safety, and environmental scores.
Although other catalytic systems employ MeOH[14b,c,h–j] as the
medium for N-arylation, the present Cu(tpa)-MOF catalyst in
EtOH offers a green methodology to synthesize N-arylimida-
zole by CÀN cross-coupling. However, the catalyst was sensi-
tive to water, and a notable decrease in the yield was observed
if an aqueous mixture of solvents was used. The catalyst was
highly specific towards N-arylation, and no other homocou-
pling or conversion of the CÀB bond into a CÀO bond was
found with any protic polar solvents, which was observed in
previous studies under identical conditions.[24c,28] The reaction
was highly time dependent, and shorter reaction times result
in moderate conversions (Table 1, entry 10), whereas reaction
times of 12 h afford an excellent yield of 99% without any by-
products. The reaction is insensitive to the temperature as it
proceeds smoothly at room temperature, and an increase in
temperature does not affect the yield. Among the bases
screened, the soluble organic base TEA showed the best result
in EtOH, and catalyst was inactive in the absence of base. The
catalyst loading plays a significant role in the maximization of
the yield, and an increase in the catalyst loading results in
a rapid enhancement of the yield. Finally, optimization showed
that 7.6 mol% catalyst was enough (Figure 2) to obtain a good
conversion with the minimum Cu loading (0.06 mmol).
Results and Discussion
To optimize the reaction conditions for the N-arylation of imi-
dazole using Cu(tpa)-MOF as a catalyst, a model reaction was
performed to screen various parameters such as the catalyst,
solvent, time, temperature, base, and catalyst loading using
imidazole (2) with phenylboronic acid (1a), and the results are
listed in Table 1. Without catalyst, the treatment of 2 with 1a
using triethylamine (TEA) as a base and EtOH as the solvent re-
sulted in no reaction.
Table 1. Optimization of the Cu(tpa)-MOF-catalyzed N-arylation of imida-
zole.[a]
Entry Solvent
Base
Yield [%][b]
[c]
1
2
3
4
5
6
7
8
EtOH
Dioxane
ACN
DCM
DMF
DMSO
MeOH
Water
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
–
–
–
trace
–
–
99[d]
47[e]
9
MeOH/water TEA
76[f]
10
11
12
13
14
15
16
17
18
EtOH
EtOH
EtOH/water
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
TEA
TEA
TEA
–
51,[g] 70,[h] 99,[i] 99[j]
98,[k] 98[l]
60,[f] 98[m]
Although Cu(tpa)-MOF catalyzes the N-arylation with a mini-
mum Cu loading, to understand the role of framework Cu, vari-
ous Cu sources, namely, Cu(NO3)2·3H2O, Cu(OAc)2·H2O,
CuSO4·5H2O, Cu(BF4)2·H2O, CuCl, CuCl2·2H2O, and CuCO3, were
screened using TEA in EtOH without any ligands (Table 2). All
invariably worked but afforded moderate yields with stoichio-
metric amounts of the catalysts. In addition, to prove the com-
petence of the catalytic activity of Cu in Cu(tpa)-MOF, N-aryla-
tion was performed using various MOFs, such as Cu(bpy)-
(H2O)(BF4)2(bpy) (bpy=bipyridine), Cu(btc) (btc = benzene-
1,3,5-tricarboxylic acid), MIL-53(Fe), Fe(btc), and IRMOF-3,
–
74
73
40
94
35
Na2CO3
K2CO3
Cs2CO3
N,N-diisopropylethylamine
pyridine
[a] Reaction conditions: 1a (1 equiv.),
2 (1.2 equiv.), Cu(tpa)-MOF
(7.6 mol%), base (1.2 equiv.), solvent 3.0 mL, RT, 12 h. [b] Isolated yield.
[c] Without catalyst. [d] MOF decomposed. [e] MOF becomes pasty.
[f] MeOH/water and EtOH/water ratios are 1:9. Yields in [g] 4 h, [h] 8 h,
[i] 12 h, and [j] 24 h. Yields at [k] 60 and [l] 708C. [m] EtOH/water ratio is
9:1.
&
ChemCatChem 2016, 8, 1 – 9
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