K. Keerthi Krishnan et al. / Journal of Catalysis 372 (2019) 266–271
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phenyl boronic acid 2a gave the desired cross-coupled product 3a
in 92% yield (Scheme 1). The structure of the product was estab-
lished by analyzing NMR and mass spectrometric methods. All
the spectral data were in good agreement with the reported values
6.
We first examined the effect of other zinc sources in this reac-
tion and observed that Et2Zn possesses good catalytic ability in this
coupling strategy. Anhydrous ZnCl2 gave traces of the desired pro-
duct while other Zn salts were catalytically inactive under this
reaction condition and the results are shown in Table 1.
revealed that THF offered the best result of the desired product
3a in 92% yield (Table 2, entry 1). Comparatively better yields of
the products were obtained when polar aprotic solvents like CH3-
CN and 1,4-dioxane were used (entries 8, 9). Moderate yield was
obtained when DME was used as the solvent (entry 10). Other
polar aprotic solvents like DMF and DMSO were found to be less
effective for this coupling reaction (entries 13, 14). No product
was observed when toluene was used as the solvent (entry 15).
The polar protic solvents like EtOH gave moderate result (entry
11), whereas MeOH gave only low conversion (entry 12). Further,
we increased the reaction temperature to 130ꢀC which resulted
in the formation of debrominatively coupled product as the major
along with traces of the desired cross-coupled product (entry 16).
Later, we decreased the boronic acid equivalents to 2 and 1.5,
which showed decrease in yields to 52% and 46% respectively
(entries 17, 18). Decreasing the base loading resulted in lower yield
of 3a (entry 19). The decrease of reaction time to 24 h also afforded
a low yield of the product (entry 20) Absence of either catalyst or
ligand and absence of both catalyst and ligand resulted in traces of
the required product (Table 2, entries 21–23). When the reaction
was conducted in the absence of N2 atmosphere, trace amount of
the desired product was obtained (Table 2, entry 24).
Finally, we checked the effect of the amount of catalyst loading
in the present coupling reaction. We conducted the reaction either
by decreasing or increasing the metal–ligand ratio and arrived at a
conclusion that 15 mol% of Et2Zn and 30 mol% of DMEDA gave the
excellent result (Table 3, entry 4). Further increase or decrease of
metal-ligand ratio resulted in decreasing the yield of the product
3a (Table 3, entry 1–3 and 5). Overall the optimum condition for
the desired zinc-catalyzed cross-coupling reaction was found to
be 15 mol% of Et2Zn, 30 mol% of DMEDA and 4 equivalents of
K3PO4 at 80ꢀC in THF solvent to obtain 96% of the desired product
3a (Table 3, entry 4).
The efficiency of cross-coupling reaction mainly depends on the
choice of ligand, and therefore we studied the effect of some easily
available bidentate N-N, N-O and O-O ligands for this reaction
using 1a and 2a as the model substrates and catalytically active
Et2Zn as the metal source in the presence of K3PO4 as the base in
THF solvent at 80ꢀC under inert condition (Scheme 2). Surprisingly,
the bidentate N-N ligand, N,N-dimethyl ethylenediamine (DMEDA)
(La) gave excellent results. This may be due to the good complexing
ability of this ligand with Et2Zn [10] under the reaction conditions.
Other bidentate N-N ligands like ethylene diamine (Lb), 1,10-
phenanthroline (Lc) and trans-1,2-diaminocyclohexane (Ld) were
not effective for this reaction. The use of N-O ligands also gave
the product, but with moderate yields (Le, Lf). Bidentate O-O
ligands such as ethylene glycol (Lg) and trans-1,2-cyclohexane diol
(Lh) gave lower amount of the products. Thus, we fixed our optimal
ligand as DMEDA (La) and carried out further optimization studies
in detail (Table 2).
We tried the reaction using different inorganic bases like phos-
phate, hydroxide, butoxide, carbonate, hydride as well as one
organic base, triethyl amine (Table 2, entries 1–7). Among these
we could observe that the inorganic phosphate base, K3PO4 showed
the optimal result in which the desired cross-coupled product was
generated in 92% yield (entry 1). The butoxide and triethyl amine
bases were not effective for this reaction (entries 2, 7). The base
KOH gave moderate yield of 52% of the product (entry 4). Other
bases such as Cs2CO3, K2CO3 and NaH afforded low yields of the
products (entries 3, 5, 6).With K3PO4 as the optimal base, we stud-
ied the effect of different solvents using this protocol, which
Finally, in order to ensure the absence of other metal contami-
nants in Et2Zn, we analyzed the metal impurities in the sample by
Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-
OES), which showed that other trace metals were absent in our
sample (Table 4).
Scheme 1. Preliminary experiment on Zn(II)-catalyzed cross-coupling reaction of 1-bromotolylacetylene with phenyl boronicacid. (aReaction conditions: 1-bromotoly-
lacetylene (1 equiv.), Phenylboronic acid (3 equiv.), K3PO4 (4 equiv.), Et2Zn (20 mol%), DMEDA (40 mol%), THF (3 mL), 80ꢀC, 48 h, under nitrogen atmosphere.)
Table 1
Screening of different zinc sources in the Zn-catalyzed cross-coupling reaction of 1-bromotolylacetylene with phenylboronic acida.
Entry
Zn catalyst
Yield 3a (%)b
1
2
3
4
5
Zn(OAc)2
Anhydrous ZnCl2
Zn(SO4)2
Zn(CO3)2
Et2Zn
ndc
traces
nd
nd
92
a
Reaction conditions: 1-bromotolylacetylene (1 equiv.), phenylboronic acid (3 equiv.), K3PO4 (4 equiv.), Et2Zn (20 mol%), DMEDA (40 mol%), THF (3 mL), 80ꢀC, 48 h, under
nitrogen atmosphere;
b
Isolated yield.
nd = Not detected.
c
Keerthi Krishnan
