F. Zhou, L. Zhang and Ji-cheng Shi
Journal of Catalysis 402 (2021) 238–243
ingly, 1g was obtained in 93% yield using our catalyst only at even
0.1 mol% loading at 100 °C within 3 h. This result indicates that the
terphenyl-type phosphine TXPhos is much better than the biaryl-
type phosphine XPhos as a supporting ligand in palladium-
catalysed C-N coupling reactions. Considering that the difference
in structure between TXPhos and XPhos is only that TXPhos bears
one additional 2,4,6-triisopropylphenyl group next to the PCy2 unit
compared to XPhos, this findings strongly support the feasibility of
our hypotheses. The more challenging substrate combinations of 2-
chloroanisole with ethyl 2-aminobenzoate, 2-aminoacetophenone,
2-aminobenzonitrile, and 2-nitroaniline were successfully coupled
by 0.5 mol% of our catalyst in conjunction with K2CO3 as base in
tBuOH, and 1h, 1i, 1j and 1k were isolated in 77–96% yields, of
which the latter three cases have not been studied before.
For coupling both electron-rich partners, the palladium catalyst
supported by TXPhos is highly effective. The survey of base and sol-
vent revealed that a range of bases such as NaOPh, Na2CO3, K2CO3,
Cs2CO3, K3PO4, NaOMe, NaOtBu, and LHMDS in the solvents tBuOH,
toluene, dioxane, and THF are suitable conditions for the coupling
of 3-chloroanisole with 4-aminoanisole (Fig. 2B). The weak bases
as NaOAc and KOAc in conjunction with our catalyst system pro-
moted the reaction, despite its relatively low efficiency. With Cs2-
CO3 as the base, a catalyst loading of 0.05 mol% can make the
reaction as efficient as that with NaOtBu for 2a in nearly quantita-
tive yields (Table 1). Even using K2CO3 as the base, the electron-
rich partners containing one or two ortho-substituents could be
coupled by our catalyst at a loading of 0.1–0.5 mol% in excellent
yields (2c and 2f).
The coupling reaction of chloroarenes containing electron-
withdrawing groups, recognized as a class of activated substrates,
with electron-rich anilines is usually prone to proceed, but some
complex situations can arise when these electron-withdrawing
groups exist in the ortho position. Catalytic data for this type of
substrate combination are listed in Table 1. With 0.05 mol% of
the palladium/TXPhos system and 1.2 equivalents of K2CO3, the
coupling product 3a, an intermediate for an antioxidant used in
rubber, could be produced from 4-chloronitrobenzene and aniline
in 98% yield under much milder conditions compared to those used
in industry. However, when replacing 4-chloronitrobenzene with
2-chloronitrobenzene as the substrate, even the loading of catalyst
increased to 0.5 mol%, and only 31% of 3b was produced when
using K2CO3 as the base. Therefore, a survey of the base was carried
out for this type of coupling reaction (Fig. 2C). Strong bases such as
NaOMe, NaOtBu, and LHMDS indeed promoted coupling, but a
large quantity of side products were produced because of the intol-
erance of the nitro group to these strong bases. Na2CO3, Cs2CO3 and
K3PO4 were even worse choices than K2CO3 as the base for the
reaction. Surprisingly, the weak bases KOAc and NaOPh were the
good choice for the reaction, and 86–87% of 3b was isolated. The
electron-rich substrates such as 4-methoxyaniline and 2-
methoxy-4-methylaniline were amenable to coupling with 2-
nitrochlorobenzene, and 95% and 82% of 3c and 3h were isolated
using KOAc and NaOAc as the base, respectively. Notably, when
using NaOPh as the base, no phenyl (2-nitrophenyl) ether was
observed in the reaction mixtures using electron-neutral and
electron-rich chloroarenes as substrates. Likewise, K2CO3 was not
suitable for the two couplings.
all of which are considered to be electron-withdrawing groups.
However, very few catalyst systems can handle those coupling
partners, especially when both of these coupling partners contain
one of these substituents in the ortho position. In fact, BINAP and
XantPhos have become the most frequently used ligands for these
types of C-N coupling reactions [13]; that the bidentate ligands can
prevent the coordination of these substituents on the substrates to
the palladium centre should be the reason why they have evolved
as supporting ligands [26,27]. However, 5–10 mol% of catalyst
loading is usually necessitated even for bromoarene partners
[34]; in fact, there are no reported examples of the coupling of both
chloroarene and aniline bearing the abovementioned functional
groups in the ortho position. A breakthrough in the aspect has been
achieved along with the innovation of the terphenyl phosphine
TXPhos. Catalytic data obtained from the TXPhos-based palladium
catalyst system for the couplings of electron-deficient partners are
listed in Table 1.
A survey of the base and solvent for the coupling of ethyl 2-
chlorobenzoate with 2-nitroaniline to produce 4v was carried out
with 0.5 mol% of the palladium/TXPhos system, and the results
are depicted in Fig. 2D. The base and solvent combinations
NaOPh/tBuOH, Cs2CO3/tBuOH and K2CO3/tBuOH were found to be
good conditions to realize a clean reaction and afford 4v in 83–
94% yields. The combinations NaOtBu/dioxane and NaOtBu/toluene
also produced 4v in 86–91% yields but with 4–7% of unidentified
side products, and significant side products appeared in the combi-
nations NaOtBu/tBuOH, NaOMe/tBuOH and LHMDS/THF. Unex-
pectedly, the conditions K3PO4/ tBuOH also created large
amounts of side products. For this coupling, the weak bases NaOAc
and KOAc in tBuOH were effective as well, and 4v was produced in
appreciable yields of 64–68%.
While seeking drugs to treat malaria, the chemists in Merck
reported the synthesis of an intermediate 4a through the reaction
of 4-trifluoromethyliodobenzene and 4-trifluoromethylaniline, and
10 mol% loading of a catalyst derived from XPhos was employed
[35]. To our delight, at a lower temperature of 100 °C with 1.2
equivalents of K2CO3 in tBuOH, 0.05 mol% of our catalyst promoted
the coupling of 4-trifluoromethylchlorobenzene to afford 4a in 98%
yield. Consistent with the finding during the preparation of 1e, the
employment of NaOtBu as base did not produce any of the product
4a.
When both the nucleophilic and electrophilic components con-
taining an ester, acetyl, nitrile, or CF3 functional group and only one
was in the ortho position, using only 0.05–0.1 mol% of the TXPhos-
based catalyst in conjunction with K2CO3 as base, 4c, 4d, 4e, 4f, 4g,
4i and 4j were produced in 89–98% isolated yields. Notably, the
catalyst based on the easily activated palladacycle and the ligand
BrettPhos, which is recognized as the most suitable biaryl phos-
phine for palladium-catalysed arylation of primary anilines,
required a 1 mol% loading, 20 times that of our catalyst, to produce
4j in 95% yield at the higher temperature of 110 °C [20]. These data
demonstrate again that the design of TXPhos is very successful.
The TXPhos-based palladium catalyst at 0.5 mol% loading in
conjunction with K2CO3, Cs2CO3, NaOPh or KOAc as base has
unprecedentedly realized the coupling of ethyl 2-aminobenzoate,
2-acetylaniline, 2-aminobenzonitrile and even 2-nitroaniline with
ethyl
2-chlorobenzoate,
2-acetylchloro-benzene,
2-
With K2CO3 used as the base in tBuOH, the coupling of
chloroarenes containing ester, acetyl, and nitrile functional groups,
including in the ortho position, could be promoted with a range of
anilines containing one or two ortho-methyl and ortho-methoxy
substituents, and 3d, 3e, 3f, 3g, 3i, and 3j were obtained in good
to excellent yields.
In a typical synthetic application for biologically active mole-
cules, both the nucleophilic and electrophilic components may
contain functional groups such as ester, acetyl, nitrile, and nitro,
chlorobenzonitrile and 2-trifluorochlorobenzene; 4m, 4o, 4p, 4r,
4s, 4t, 4v, 4w and 4x were isolated in 91–98% yields, except for
4l, which was isolated in 64% yield. The product 4z, with three
ortho-substituents, including an ester and a nitrile group, can be
prepared with 0.5 mol% of our catalyst. The power of the
TXPhos-based catalyst can be further highlighted by comparing it
with the BINAP-based catalyst, the most commonly used catalyst
system for highly functionalized partners: 5 mol% of the BINAP-
based catalyst was loaded to couple ethyl 2-bromobenzoate with
241