Effective Pd-nanoparticle (PdNP)-catalyzed negishi coupling involving alkylzinc reagents at room temperature

Article abstract of DOI:10.1021/ol8007342

(Chemical Equation Presented) Pd(OAc)₂ is an efficient catalyst precursor for Negishi coupling in the presence of Bu₄NBr. Secondary and primary alkylzinc reagents with β-H and arylzinc reagents all reacted with aryl iodides at temper

Full text of DOI:10.1021/ol8007342

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2661-2664
Effective Pd-Nanoparticle (PdNP)-
Catalyzed Negishi Coupling Involving
Alkylzinc Reagents at Room Temperature
Jing Liu,†,‡ Yi Deng,‡ Haibo Wang, Hua Zhang,‡ Ganxiang Yu,‡ Bingbin Wu,‡
Heng Zhang,‡ Qiang Li,‡,§ Todd B. Marder,*,§ Zhen Yang,*,† and Aiwen Lei*,‡
College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing 100871,
People’s Republic of China, College of Chemistry and Molecular Sciences, Wuhan
UniVersity, Wuhan, Hubei 430072, People’s Republic of China, and Department of
Chemistry, Durham UniVersity, South Road, Durham DH1 3LE, United Kingdom
aiwenlei@whu.edu.cn
Received April 1, 2008
ABSTRACT
Pd(OAc)2 is an efficient catalyst precursor for Negishi coupling in the presence of Bu4NBr. Secondary and primary alkylzinc reagents with ꢀ-H
and arylzinc reagents all reacted with aryl iodides at temperatures as low as -20 °C, giving moderate to good yields. One example of coupling
between alkynylzinc reagents and aryl iodides was tested and the yield was good. Preliminary kinetic studies indicated that the process
involved PdNPs as the active catalytic species.
Negishi coupling, one of the most efficient methods to construct
carbon-carbon bonds, was first developed in 1977.1,2 From
then on, extensive investigations have been carried out to
extend the scope and application of the method. Reactions
involving alkenyl-, aryl-, and alkynylzinc reagents and in
some cases alkylzinc reagents3 have been achieved with high
yields and good functional group tolerance. Recently, by
employing sterically hindered and/or electronically rich
ligands, some efficient processes involving Csp3-coupling
were developed.4–14 In addition, employing olefin-type
ligands with Pd and Ni was proven by Knochel et al.15–19 to
be an effective manner to facilitate Csp3-related couplings.
During the past two decades, there have been increasing
amounts of literature about nanoparticles (NPs) of transition
metals which could catalyze reactions efficiently with low
loadings.20–23 Stabilizers of NPs are often used to prevent
them from further agglomeration and precipitation from the
reaction system, and meanwhile allow the reactants to access
their surfaces. Among the stabilizers, commercially available
and inexpensive tetraalkylamonium halides are common.24–27
Pincer-Pd complexes, palladacyles, and ligand free Pd
precursors such as Pd(OAc)2 and Pd/C have been investigated
or proposed to form PdNPs by reduction or thermal
decomposition followed by aggregation, mostly in Heck,
Suzuki, and Sonogashira reactions.23,28–52 To the best of our
† Peking University.
‡ Wuhan University.
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§ Durham University.
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10.1021/ol8007342 CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

knowledge, there have been few reports about application
of PdNPs in the Negishi reaction. Ligand-free Pd(OAc)2-
catalyzed Negishi couplings under homeopathic conditions
from 25 to 100 °C to prepare biaryls were reported once.53
Fu et al. had demonstrated an elegant example of Negishi
couplings between alkyl electrophiles and organozirconium
reagents under “ligandless” conditions in 2004.54 Recently,
we discovered that ligand-free Pd(OAc)2 could efficiently
promote Negishi reactions of alkyl-, aryl-, and alkynylzinc
reagents. Herein, we communicate our results.
Table 1. PdNP-Catalyzed Negishi Coupling of Aryl Iodides
with Primary Alkylzinc Reagentsa
When the reaction of ethyl 2-iodobenzoate 1a with n-
dodecylzinc chloride 2a was monitored by in situ IR, we
surprisingly found that the reaction proceeded quickly and
produced ethyl 2-dodecylbenzoate 3a in high yield using
Pd(OAc)2 as a catalyst precursor and a stoichimetric amount
of Bu4NBr as an additive. Pd(OAc)2 (0.5 mol %) promoted
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a Reaction conditions: aryl iodide (1 mmol), alkylzinc reagent (2 mmol),
Pd(OAc)2 (0.005 mmol), Bu4NBr (1 mmol) at rt. b Isolated yield.
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the reaction to completion in 32 s at 25 °C, and gave 92% yield
(see Figure 1 in the Supporting Information). Importantly,
alkylzinc reagents with ꢀ-H tend to undergo ꢀ-H elimination
to give dehalogenated byproducts in many cases, but in our
system, only 8% of ethyl benzoate (determined by GC) was
detected.
Without further optimization, the substrate scope of the
reaction involving aryl iodides and primaryl alkylzinc reagents
was examined. At 25 °C, 0.5 mol % of Pd(OAc)2 promoted
the Csp3-Csp2 coupling smoothly. Ethyl 2-iodobenzoate 1a
reacted with primary alkylzinc chlorides in excellent yields
(Table 1, entries 1-4). Ethyl 4-iodobenzoate 1b gave moderate
yield (Table 1, entry 5). However, the reaction involving the
electron-rich electrophile 2-iodoanisole 1d was unsatisfactory
(Table 1, entry 7).
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When secondary cyclohexylzinc chloride 2i was utilized
as the nucleophile, coupling with 1a proceeded smoothly in
98% yield (Table 2, entry 4). The reaction of sec-butylzinc
chloride 2f and 1a produced the desired product in 96%
isolated yield, yet the selectivity (ratio of ethyl 2-sec-
butylbenzoate and ethyl 2-butylbenzoate) was poor (Table
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Table 2. PdNP-Catalyzed Negishi Coupling of Aryl Iodides
Table 3. PdNP-Catalyzed Negishi Coupling of Aryl Iodides
with Secondary Alkylzinc Reagentsa
with Arylzinc Reagentsa
a Reaction conditions: aryl iodide (1 mmol), alkylzinc reagent (2 mmol),
Pd(OAc)2 (0.005 mmol), Bu4NBr (1 mmol) at rt. b Isolated yield. c The
data in parentheses are ratios of isomerized to unisomerized product,
determined by GC. For example, the ratio between ethyl sec-butylbenzoate
and ethyl n-butylbenzoate was 53:47 (entry1).
a Reaction conditions: aryl iodide (1 mmol), arylzinc reagent (2 mmol),
Pd(OAc)2 (0.005 mmol), Bu4NBr (1 mmol) at rt. b Isolated yield.
of the reactions between ethyl 2-iodobenzoate 1a and CyZnCl
2i in the presence of 0.5 mol % of Pd(OAc)2 using in situ
IR. The conversion of 1a at 25 °C reached 60% after only
30 s, and 100% after 2 min (Figure 1, black line). A similar
kinetic plot was obtained at a reaction temperature of 0 °C
(Figure 1, red line). Surprisingly, the reaction proceeded
smoothly even at -20 °C, and reached 100% conversion of
1a after 30 min with 97% GC yield (Figure 1, blue line).
2, entry 1) as a result of ꢀ-H elimination/alkene reinsertion
preceding reductive elimination. However, under otherwise
identical conditions, (s-Bu)2Zn 2g gave 95% product along
with improved selectivity (Table 2, entry 1 vs entry 2).
Similar results were obtained when (iPr)2Zn 2h was em-
ployed as the nucleophile (Table 2, entry 3). The reaction
of 1a with Cy2Zn 2j gave a satifactory yield, while a
moderate yield was obtained when ethyl 4-iodobenzoate 1b
was used as the electrophile.
For reactions between aryl iodides and arylzinc reagents,
both electron-deficient and electron-rich aryl iodides were
suitable substrates, and arylzinc reagents with ortho substituents
also gave excellent yields (Table 3, entries 2, 3, and 5).
When the reaction of phenylethynylzinc chloride 2p with
ethyl 4-iodobenzoate 1b was tested, no product was detected
at 25 °C. Raising the temperature to 60 °C improved the
yield to 96% (eq 1). Currently, there are not enough data to
rationalize the reactivity differences between alkynylzinc
reagents and arylzinc or alkylzinc nucleophiles.
Figure 1. Conversion of 1a vs time curve for the reaction of 1a
[0.33 M] with 2i [0.65 M], with 0.5 mol % Pd(OAc)2 as the catalyst
precursor in the presence of 1 equiv of Bu4NBr monitored by in
situ IR at different temperatures.
To gain some preliminary understanding of this Pd(OAc)2-
catalyzed Negishi coupling, we further followed the progress
At -20 °C, the rate increased during the first 15 min and
a sigmoidal curve throughout the reaction was observed. To
probe whether Pd(NPs) were involved in the transformation
above, a quantitative ligand poisoning experiment, shown to
be an effective method to establish the presence of NPs in the
reaction system,55 was conducted. PPh3 (0.5 equiv) [vs
Pd(OAc)2)] was added to the reaction system with [Pd(OAc)2]
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Figure 2. Conversion of 1a vs time curve for the reaction of 1a
[0.33 M] with 2i [0.65 M], with 2 mol % of Pd(OAc)2 as the catalyst
precursor in the presence of 1 equiv of Bu4NBr monitored by in
situ IR at rt. Black line: 1 mol % PPh3 was present.
Figure 3. Rate vs Pd loading curve for reactions of 1c [0.16 M]
and 2i [0.29 M] with different concentrations of Pd(OAc)2 in the
presence of 1 equiv of Bu4NBr monitored by in situ IR at -20 °C.
) 1.45 mM, [CyZnCl] ) 0.65 M in 3 mL of THF, and the
mixture was stirred for 5 min. After that, 0.92 mmol of 1a was
added to initiate the reaction. The reaction rate was much slower
than the control without PPh3 (Figure 2), the convesion was
less than 10% after 8 min, and only 4% cross-coupled product
together with 6% ethyl benzoate was detected by GC. The
results strongly supported PdNPs as being the active catalytic
species.
Generally, PdNPs are proposed to form by aggregation of
naked Pd(0) reduced from soluble Pd(II) species. The process
usually involves multipile naked Pd(0) interactions, and the
amount of active Pd on the surface of the PdNPs is not first
order in the concentration of the original Pd(II) complex. As a
result, the rate of the reaction catalyzed by PdNPs is not first
order in the concentration of the catalyst precursor, while in
homogeneous catalytic systems, the reaction rate is usually first
order in catalyst concentration.36,51,56–58 Kinetic studies of the
reaction between 1c and 2i, carried out with [1a] ) 0.16 M,
[2i] ) 0.29 M, [Bu4NBr] ) 0.16 M, and [Pd(OAc)2] )
0.08-8 mM (0.05-5 mol %) at -20 °C, indicated that the
rate was not first order in [Pd(OAc)2] (Figure 3), further
supporting the notion that this system is heterogeneous rather
than homogeneous. Indeed, the reaction with 5 mol % of
Pd(OAc)2 was only 1.7-fold faster than the one with 1 mol
% of Pd(OAc)2 (Figure 3). Though further lowering the
catalyst loading reduced the reaction rate, the reaction was
still fast even with only 0.05 mol % of Pd(OAc)2.
of the two reactions monitored by in situ IR were obviously
different (see Figure 2 in the Supporting Information). With
1 equiv of Bu4NBr, the reaction rate decreased when the
conversion reached ca. 72%, while the reaction rate decreased
from ca. 44% conversion without Bu4NBr. Moreover, the
maxmium reaction rate with Bu4NBr was around 3 times
faster than that without Bu4NBr. The differences indicated
that the Pd catalyst in the reaction system without Bu4NBr
was more prone to aggregate and lose reactivity. In addition,
we examined the reaction of 1a with 2i using Pd(OAc)2
loadings of 0.1, 0.01, and even 0.001 mol % at room
temperature in the absence of Bu4NBr. Although reproduc-
ibility of conversion vs time varied somewhat over 3 runs
at each concentration, reproducible isolated yields of 92%,
91%, and 94% were obtained at 0.01 mol % loading, and
up to 82% with 0.001 mol % loading. The key point to note
is that with this combination of reagents, only a few percent
of the hydrodehalogenated side product was observed in any
case.
In conclusion, Pd(OAc)2 is an efficient catalyst for Negishi
coupling. Secondary and primary alkylzinc reagents with ꢀ-H
were suitable nucleophiles to react with aryl iodides, and the
yields of the Csp2-Csp3 coupling were moderate to excellent.
In addition, the protocol has also been successfully applied in
Csp2-Csp2 and Csp-Csp2 couplings. Preliminary kinetic results
indicated that the process involved PdNPs as the active catalytic
species, and the reaction was very efficient even with only 0.05
mol % of Pd(OAc)2 in the presence of Bu4NBr or 0.01 mol %
of Pd(OAc)2 in the absence of Bu4NBr at room temperature.
Bu4NBr has been used as an additive in many “ligand free”
palladium catalytic systems, and was speculated to stablize
the PdNPs from further aggregation.59 To test the effect of
Bu4NBr in our system, we compared the reactions of methyl
2-iodobenzoate 1c with CyZnCl 2i in the presence of 0.5
mol % of Pd(OAc)2 at -20 °C with or without Bu4NBr.
Though the yields were almost the same, the kinetic profiles
Acknowledgment. This work was supported by National
Natural Science Foundation of China (20772093, 20502020)
and the startup fund from Wuhan University. Q.L. thanks the
China Scholarship Council for a Fellowship to work at Durham
University. We are very grateful to Dr. Ian Fairlamb (York
University) for helpful discussions.
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Supporting Information Available: General procedure
for the Negishi couplings, in situ IR, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
.
.
.
(59) A halide anion effect could be another reason for the accelerating
effect of Bu4NBr.
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