Li et al.
There are problems associated with the use of an aqueous
solvent. These include solubility of substrates and stability of
the metal catalysts in water. Although the application of phase-
transfer catalysts10,8e and water-soluble phosphine ligands11 has
been developed, most of these systems require harsh conditions.
Also, fewer catalytic systems could perform the cross-coupling
reaction of aryl bromides or aryl chlorides at room temperature.
In previous studies,12 we found that tetramethylguanidine
(TMG) was a highly efficient ligand for the palladium-catalyzed
Heck reaction. Its use resulted in high turnover numbers (TONs)
(up to 106 TONs for the reaction of iodobenzene and butyl
acrylate). Furthermore, the Brønsted guanidine acid-base ionic
liquids could act as ligand, base, and solvent in the Heck
reaction. This offered the advantages of high activities and
reusability in this environmentally benign process (eq 1).
coupling reactions. We are especially interested in the possibility
of using these types of ligands for room temperature Suzuki
cross-coupling reactions in aqueous solvent under air conditions.
Results and Discussion
Screening of the Ligands. The synthesis of tetraalkyl-
guanidines (TAGs) and pentaalkylguanidines (PAGs) was
according to literature methods,13 and the structure of TAGs
and PAGs is outlined in Figure 1. The chemical structure and
elemental composition of the guanidines were confirmed by
1
elemental analysis and H NMR spectroscopies (see the Sup-
porting Information). To examine the efficiency of Pd(OAc)2/
guanidine as a catalyst in the Suzuki cross-coupling reaction, a
model coupling reaction of 4-bromoanisole with phenylboronic
acid was initially tested. The results are summarized in Table
1. These data show that these guanidines are effective ligands
for the palladium-catalyzed Suzuki reaction. In the absence of
ligands, only a 42% yield of the cross-coupling product was
isolated in the presence of 1.5 mol % of Pd(OAc)2 and 3 equiv
of K2CO3 in CH3CN at 80 °C (entry 1). The yield of the product
increased sharply upon addition of guanidine (entries 2-10).
Among the guanidines investigated, TAGs showed moderate
efficiency, which gave the coupling product in 74-83% yield
(entries 2-6). PAGs were found to be the best ligands, which
gave the coupling product in nearly quantitative yield (entries
7-10). To further evaluate the influence of the steric bulk of
the guanidine ligands, the coupling reaction of the less active
chlorobenzene with phenylboronic acid, in the presence of 2.0
mol % of Pd(OAc)2 and 3 equiv of K2CO3 in CH3CN at 80 °C,
was also tested. The results are summarized in Table 2. 1,1,3,3-
Tetramethylguanidine (1a) displayed less efficiency, giving the
coupling product in 12% yield. The more bulky PAGs were
found to be better ligands. 1,1,3,3-Tetramethyl-2-n-butylguani-
dine (1f) afforded the product in 31% yield. The more bulky
1,1,3,3-tetramethyl-2-sec-butylguanidine (1g) was found to be
the best ligand, giving the product in 45% yield in 10 h.
However, the more bulky guanidine, 1,1,3,3-tetramethyl-2-tert-
butylguanidine (1h), furnished the product in a lower yield
Although there are high activities obtained in the guanidine/
Pd-catalyzed Heck reaction, a high reaction temperature (140
°C) was still required to afford high yield of the product. From
these promising results, we endeavored to examine the efficiency
of these types of ligands on palladium-catalyzed Suzuki cross-
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