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the reaction medium. In this sense, it is interesting to highlight
in drug synthesis. Therefore, we decided to verify the concen-
tration of palladium in the crude isolated product of a model
the compatibility of Pd(OAc) @COF-300 with the aqueous
2
medium and this could allow for further development of envi-
ronmentally friendly methodologies employing this palladium
catalyst.
reaction using a substrate with NH group to potentially in-
2
crease the possibility of coordination to the Pd in the product
(Table 1, entry 10). Analysis by inductively coupled plasma
mass spectrometry (ICP–MS) gave a value of 85 ppb, much
smaller than the maximum of 10000 ppb fixed for orally ad-
In a subsequent step, the reaction conditions were fixed and
a number of varying substrates with different reactivity were
evaluated. The compilation of the results is shown in Table 1.
The results clearly demonstrate the efficiency and versatility of
the new catalyst.
[
8]
ministered drugs. This result is in line with the findings of the
previous test where leaching was not observed.
To evaluate the recyclability of Pd(OAc) @COF300, the reac-
2
Palladium loadings as low as 0.1 mol% were found to effi-
ciently catalyze the reaction. In general, nearly quantitatively
yields were observed for X=Br or I, and Ar=phenyl or naph-
thyl. The turnover numbers (TON) and frequencies (TOF) were
determined and range from very good to excellent (entries 1–
tion between bromobenzene and phenylboronic acid was
used as a model. Deactivation was not observed until the fifth
cycle, demonstrating the robustness of the catalyst (for details
see the Supporting Information). X-ray photoelectron spectros-
copy (XPS) analysis of the catalyst after the first cycle revealed
0
1
2, 31–41). Heteroaromatic boronic acids and aryl halides gave
that Pd is the predominant catalytic species (Figure 5a), dem-
II
moderated to good yields, which could also be enhanced by
an increased reaction time (entries 13–30). These are interest-
ing results as heterocyclic moieties are presented in a range of
natural products, drugs, and new drug candidates. Crude prod-
ucts are obtained in relatively high purity, as shown by GC–MS
analysis (see the Supporting Information).
onstrating that reduction of Pd occurs in the reaction
medium. Powder XRD analysis for the same sample indicates
that crystallinity is maintained. Additionally, the lack of peaks
0
of metallic palladium indicates that Pd is present either as
small crystallites or are not aggregated at all (Figure 5b).
Pd/C for the same reaction was reported to afford 55% yield
of products using the double of catalyst loading (0.2 mol% Pd)
[
9]
in 10 h of reaction. Comparison with other heterogeneous
[
4,5]
catalysts
reveals very good performance of the
Pd(OAc) @COF300.
2
Aryl
chlorides
also
react
under
catalysis
by
Pd(OAc) @COF300, but with low conversions (approximately
2
2
0%), smaller than those for the corresponding aryl bromides
and iodides (Supporting Information, Table S3). This result is re-
lated to the low reactivity of aryl chlorides in Suzuki–Miyaura
cross-coupling reactions. However, improvements were ob-
tained by increasing the reaction time.
To confirm the heterogeneous nature of the catalyst, a typical
test for catalyst leaching was carried out. Briefly,
Pd(OAc) @COF-300 and K CO were mixed in methanol and
2
2
3
H O. The solution was heated to 708C, with magnetic stirring,
2
for 60 min. After that, it was hot-filtered into another round-
bottom flask. The substrates (Table 1, entry 1) were added to
the filtrate and the reaction was heated to 708C, with magnet-
ic stirring, for 60 min. GC/MS analysis revealed the absence of
the product, suggesting that, if Pd is present in solution, the
amounts are insufficient to promote a significant level of catal-
ysis. In another test, using p-bromoacetophenone and phenyl-
boronic acid as substrates, under the optimized reactions con-
ditions, the catalyst was filtered off from the hot reaction mix-
ture after 2 min. However, analysis of the filtered solution indi-
cated a 100% conversion of p-bromoacetophenone in the
cross-coupled product. To stop the reaction before it is com-
pleted, 3-bromophenol, which is a less reactive substrate, was
used. The catalyst was filtered off from the hot reaction mix-
ture after one minute and the analysis of the filtered solution
indicated 80% conversion. The filtered solution was left stirring
at 708C and after one hour no extra conversion was observed.
The concentration of metals in drug products is a great con-
cern for the pharmaceutical industry if metal catalysis is used
Figure 5. Characterization of Pd(OAc)
spectrum of Pd(OAc) @COF-300 in the 3d region showing characteristic
peaks at 337.1 eV (3d5/2) and 342.3 eV (3d3/2), relative to Pd , and 334.9 eV
2
@COF-300 after the first cycle. a) XPS
2
II
0
(
3d5/2) and 340.2 eV (3d3/2), relative to Pd . b) Powder XRD profile of
0
Pd(OAc)
absence of peaks, for (111) and (200) planes of Pd nanoparticles at 40.08
and 46.58 respectively, in the PXRD profile of Pd(OAc) @COF-300 after the
first cycle, indicates that, besides formation of Pd , it could not be detected
by XRD analysis, because the size of the formed nanoparticles would be
close to the XRD detection limit (5–15 nm range, depending on the instru-
2
@COF-300 after the first cycle and powder XRD profile of Pd . The
2
0
[10]
ment and acquisition conditions).
ChemCatChem 2016, 8, 743 – 750
746
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