In situ formation of N,O-bidentate ligand via the hydrogen bond for highly efficient Suzuki reaction of aryl chlorides

Article abstract of DOI:10.1039/b925144h

A highly efficient protocol for the Pd(OAc)₂-catalyzed aerobic Suzuki reaction of aryl chlorides is reported, which is proposed to be promoted by the N,O-bidentate ligand formed in situ via the hydrogen bond of solvents.

Full text of DOI:10.1039/b925144h

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In situ formation of N,O-bidentate ligand via the hydrogen bond
for highly efficient Suzuki reaction of aryl chloridesw
Weibo Yang, Chun Liu* and Jieshan Qiu
Received (in Cambridge, UK) 1st December 2009, Accepted 3rd February 2010
First published as an Advance Article on the web 23rd February 2010
DOI: 10.1039/b925144h
A highly efficient protocol for the Pd(OAc)2-catalyzed aerobic
Suzuki reaction of aryl chlorides is reported, which is proposed
to be promoted by the N,O-bidentate ligand formed in situ via
the hydrogen bond of solvents.
(Table 1, entry 5). The reaction performed in EtOH/N,N-
dimethylformamide (DMF) delivered the product in 97%
yield after 20 min (Table 1, entry 4), far more efficient than
that catalyzed by macroporous polystyrene supported bulky
NHC–Pd catalyst in DMF–H2O at 100 1C for 24 h.7 A little of
the cross-coupling product was obtained when a portion of
water was added into the EtOH/DMA system (Table 1, entry 6).
As one of the main interaction patterns between molecules, the
hydrogen bond plays an important role in materials science1
and biological systems.2 This weak interaction has also been
used very often in asymmetric catalysis via various hydrogen
bonding interactions,3 such as catalyst to substrate, substrate
to substrate, ligand to metal and so on. To the best of our
knowledge, however, the influence of the hydrogen bond
generated between the molecules of solvents on the reactivity
of a catalytic reaction has not been taken into account. For
example, although the hydrogen bonding complexes between
ethanol (EtOH) and N,N-dimethylacetamide (DMA) have
attracted attention,4 its application to catalysis has not been
reported. In this paper, we demonstrate a fast and efficient
protocol for the Pd(OAc)2-catalyzed Suzuki reaction of aryl
chlorides under ligand-free and aerobic conditions, which was
strongly mediated by the combination of the organic solvents.
This process is a previously uninvestigated example of where
this type of weak hydrogen bond has been shown to influence
the reactivity of the Suzuki reaction.
Only
a trace amount of product was obtained when
EtOH–toluene, EtOH/n-decane or DMA/toluene were used
(Table 1, entries 7, 8 and 11). The results in Table 1 show
clearly that the combination of organic solvents has a
significant impact on the activation of aryl chlorides for the
Pd(OAc)2-catalyzed ligand-free Suzuki reaction. Only the
solvent systems, in which the hydrogen bond complexes form
between alcohol and amide, could promote the Suzuki reaction.
Among them the EtOH/DMA system provides the highest
reactivity with a TOF up to 2376 hÀ1 (Table 1, entry 3).
With the optimized conditions at hand, we further explored
the generality of the coupling reaction between 4-chloronitro-
benzene with a variety of arylboronic acids using 0.5 mol%
Pd(OAc)2 in EtOH/DMA. The results are shown in Table 2.
Both electron-rich and electron-poor arylboronic acids
proceeded smoothly. The cross-coupling reaction between
4-chloronitrobenzene and p-tolylboronic acid could be conducted
in 99% yield after 5 min. Electron-poor 4-fluorophenyl
boronic acid resulted in the expected product in 98% yield
Generally, solvent plays an important role in chemical
processes, which has also been observed in the palladium-
catalyzed Suzuki reaction under both ligand-promoted5 and
ligand-free6 conditions. Our initial studies about the effect of
solvents on the Suzuki coupling of aryl chlorides were
performed using a model reaction of 4-chloronitrobenzene
with phenylboronic acid with 0.5 mol% Pd(OAc)2 in the
absence of additives at 80 1C under air. The results are
summarized in Table 1. Both of the polar protic solvent
ethanol and the polar aprotic solvent DMA gave the
corresponding product 4-nitrobiphenyl in rather low yields,
respectively (Table 1, entries 1 and 2). It is noteworthy that the
choice of EtOH/DMA was crucial, and the desired cross-
coupling product with 99% isolated yield was provided in 5
min (Table 1, entry 3). However, the mixed solvents of DMA
with isopropanol or glycol reduced the reactivity of the
reaction obviously, respectively (Table 1, entries 9 and 10).
A combination of EtOH with 1,4-dioxane also gave a low yield
Table 1 Effect of solvent on Pd(OAc)2-catalyzed cross-coupling of
4-chloronitrobenzene with phenylboronic acida
Entry
Solvent (4 mL)
Time/min
Yield (%)b
1
2
3
4
5
6
7
8
EtOH
DMA
5
5
5
7
5
99
97
23
11
Trace
Trace
70
32
Trace
EtOH/DMA
EtOH–DMF
EtOH/Dioxane
EtOH/DMA/H2O
EtOH/Toluene
EtOH/n-Decane
i-PrOH/DMA
Glycol/DMA
Toluene/DMA
20
20
20
20
20
20
20
20
9
10
11
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Zhongshan Road 158, 116012, Dalian, China.
E-mail: chunliu70@yahoo.com; Fax: +86 411 39893854;
Tel: +86 411 39893854
w Electronic supplementary information (ESI) available: Experimental
details and characterization of cross-coupling products. See DOI:
10.1039/b925144h
a
Reaction conditions: 4-chloronitrobenzene (0.5 mmol), phenyl
boronic acids (0.75 mmol), K2CO3 (1 mmol), Pd(OAc)2 (0.5 mol%),
solvent A/solvent B (1 : 1; for entry 6, 1 : 1 : 1; volume ratio), 80 1C, in
b
air. The reaction was monitored by TLC. Isolated yield.
ꢀc
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Table 2 Suzuki reaction of 4-chloronitrobenzene with arylboronic
acidsa
Table 3 EtOH/DMA-Pd(OAc)2-catalyzed Suzuki cross-coupling of
aryl chlorides with arylboronic acidsa
Time/ Yield
min (%)b
Entry Ar–Cl
1
Product
Time/ Yield
(%)b
Entry Ar–B(OH)2
Product
min
8
98
96
46
77c
1
2
3
5
99
60
5
89c
99
2
3
4
10
60
60
4
8
97
5
6
7
20
30
30
10
98
92
94
98
5
6
7
8
45
30
60
40
90
91
88
97
8
a
Reaction conditions: 4-chloronitrobenzene (0.5 mmol), aryl boronic
acid (0.75 mmol), K2CO3 (1 mmol), Pd(OAc)2 (0.5 mol%), EtOH/
9
60
60
41
51
b
c
DMA (2 : 2 mL), 80 1C. Isolated yield. Pd(OAc)2 (0.05 mol%). The
reaction was monitored by TLC.
10
for 10 min (Table 2, entry 8). In addition, ortho-substituted
arylboronic acids, such as o-tolylboronic acid and 2-methoxy-
phenylboronic acid were also successfully employed in the
reactions with 4-chloronitrobenzene (Table 2, entries 5 and 7).
Even reducing the Pd(OAc)2 loading down to 0.05 mol%, an
89% yield of 4-nitrobiphenyl was still reached in 1 h (Table 2,
entry 2).
11
12
60
60
60
40
89
90
13
a
Reaction conditions: aryl chloride (0.5 mmol), aryl boronic acid
(0.75 mmol), K2CO3 (1 mmol), EtOH/DMA (2 : 2 mL), Pd(OAc)2
(1 mol%; for entries 1 and 2, 0.5 mol%; for entries 9, 10 and 11,
The effectiveness of the Pd(OAc)2-EtOH/DMA system was
further extended to various aryl chlorides with arylboronic
acids. As shown in Table 3, functional groups such as NO2,
CN, CF3, CH3, F, OCH3 and COCH3 were compatible in this
catalytic system. The aryl chlorides bearing electron-with-
drawing groups (e.g., NO2, CN, CF3, COCH3) favored the
coupling reaction with arylboronic acids, affording the
corresponding biaryls in high yields. Steric hinderance due to
the ortho substituents on the aryl chlorides affected the
reaction progress. Thus, only a 46% yield of 2-nitrobiphenyl
was obtained after 1 h from the reaction of 2-chloronitrobenzene
with phenylboronic acid (Table 3, entry 3). To our delight, the
addition of 1.0 equiv of tetrabutyl-ammonium bromide
(TBAB) increased the yield from 46% to 77% in the coupling
of 2-chloronitrobenzene with phenylboronic acid (Table 3,
entries 3 and 4). Moreover, the catalytic system is not only
suitable for the electron-deficient aryl chlorides, but also for
electron-rich aryl chlorides. A moderate yield was obtained in
b
c
2 mol%), 80 1C. Isolated yield. TBAB 0.5 mmol. The reaction was
monitored by TLC.
the coupling reaction between 3-chloroanisole and 4-tolyl-
boronic acid (Table 3, entry 10).
To understand the mechanism of the Pd(OAc)2-catalyzed
Suzuki reaction in EtOH/DMA, the effect of the volume ratio
of EtOH to DMA on the model reaction of 4-chloronitrobenzene
with phenylboronic acid was further investigated. The results
are illustrated in Table 4. The catalytic system afforded
4-nitrobiphenyl in a 47% yield after 1 h using a volume ratio
of EtOH/DMA as 3 : 5 (Table 4, entry 4; 1 : 1 in molar ratio).
Increasing the volume ratio of EtOH/DMA resulted in a
positive effect on the reactivity (Table 4, entries 1–3). As
expected, decreasing the volume ratio of EtOH/DMA resulted
in a negative effect (Table 4, entries 5 and 6). These results
ꢀc
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Table 4 Effect of solvent on Pd(OAc)2-catalyzed cross-coupling of
4-chloronitrobenzene with phenylboronic acida
formed, in which the EtOH-DMA hydrogen bond complex
plays a role as a N,O-bidentate ligand formed in situ. The
active (I) undergoes oxidative addition with Ar–Cl to give (II).
The superfluous ethanol could also act as a promotor for
reducing the bond energy of Cl to (III) via a hydrogen bond
and accelerate the transmetallation step to form (IV) according
to the literature reports.8
Entry
EtOH/DMA (4 mL)
Time/min
Yield (%)b
In conclusion, we have developed a fast and highly efficient
protocol for the Pd(OAc)2-catalyzed Suzuki reaction of aryl
chlorides with arylboronic acids via a simple combination of
two common organic solvents under aerobic and ligand-free
conditions. The results prompted us to suppose that the key to
the efficient Suzuki reaction could be the N,O-bidentate ligand
formed in situ via the hydrogen bond between alcohol and
amide. Efforts to improve the cross-coupling efficiency for
electron-neutral and -rich aryl chlorides and application to
other cross-coupling reactions are currently in progress.
We thank the financial support from State Key Laboratory
of Fine Chemicals (KF0801), Science Research Foundation of
DUT, Graduate Student Education Reform Fund of DUT,
the National Natural Science Foundation of China (20725619,
20836002, 20976024), and the Innovative Research Team in
University (IRT0711).
1
2
3
4
5
6
2/1
3/1
2/2
3/5
1/2
1/3
60
60
60
60
60
60
52
55
61
47
30
14
a
Reaction conditions: 4-chloronitrobenzene (0.5 mmol), phenyl
boronic acids (0.75 mmol), NaOMe (1 mmol), Pd(OAc)2 (0.5 mol%),
EtOH/DMA in volume ratio, 25 1C, in air. The reaction was
b
monitored by TLC. Isolated yield.
Notes and references
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Scheme 1 Proposed mechanism.
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reveal that the hydrogen bond complexes between EtOH and
DMA are responsible for the reactivity of the Suzuki reaction.
Based on the results in Table 1 and Table 4, we propose that
the mechanism of the reaction could be shown as in Scheme 1.
The Pd(II) is first reduced to Pd(0) under the Suzuki reaction
conditions, then a six-membered palladium intermediate (I) is
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2659–2661 | 2661