Pd(PPh3)4-PEG 400 catalyzed protocol for the atom-efficient stille cross-coupling reaction of organotin with aryl bromides

Article abstract of DOI:10.1021/jo9005206

(Chemical Equation Presented) Aryl bromides (4 equiv) were coupled efficiently with organotin (1 equiv) in an atom-efficient way using the tetra(triphenylphosphine)palladium/polyethylene glycol 400 (Pd(PPh ₃)₄/PEG 400) catalytic syst

Full text of DOI:10.1021/jo9005206

pubs.acs.org/joc
are important structural substructures in numerous natural
Pd(PPh3)4-PEG 400 Catalyzed Protocol for the
Atom-Efficient Stille Cross-Coupling Reaction of
Organotin with Aryl Bromides
products, polymers, agrochemicals, and pharmaceutical med-
iates.4 During the past decades, numerous efforts have been made
to develop an efficient catalyst protocol for Stille cross-coupling
reactions.5 However, most of these reactions were carried out in
organic solvents under inert and anhydrous conditions due to the
instability of most catalysts and coupling reagents.
Wen-Jun Zhou,† Ke-Hu Wang,† and Jin-Xian Wang*,†,‡
†Institute of Chemistry, Department of Chemistry,
Northwest Normal University, 967 An Ning Road (E.),
Lanzhou 730070, P. R. China, and ‡State Key Laboratory of
Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
The advantage of tetraphenyltin is that it can react with
4 equiv of electrophilic reagents.6 Despite this obvious
advantage, only a few reactions involving tetraphenyltin
for C-C bond formation have been reported.7-9 Further-
more, almost all of these reactions suffer from drawbacks
such as atom inefficiency, long reaction times, and harsh
reaction conditions. In our recent investigations, luckily, we
found that tetraphenyltin can react with 4 equiv of aryl
bromides in the Stille cross-coupling reaction, which has
attracted our attention as a viable atom-efficient organome-
tallic coupling partner for C-C bond formations. Hence, to
expand the scope and reactivity of tetraphenyltin, the devel-
opment of new and efficient catalytic protocols is in demand.
As environmentally friendly “green” synthesis is becoming
more and more important, it is desirable to avoid any use of
hazardous and expensive organic solvents. To satisfy these
concerns, polyethylene glycol (PEG) represents a very at-
tractive medium for organic reactions.10 PEG as an envir-
onmentally benign protocol proved to have many appli-
cations, particularly in coupling,11 oxidation,12 substitution,13
wangjx@nwnu.edu.cn
Received March 9, 2009
Aryl bromides (4 equiv) were coupled efficiently with
organotin (1 equiv) in an atom-efficient way using the
tetra(triphenylphosphine)palladium/polyethylene glycol
400 (Pd(PPh3)4/PEG 400) catalytic system in the presence
of sodium acetate (NaOAc) as base at 100 °C, providing
excellent yields of the corresponding functionalized bi-
aryls in short reaction times.
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The cross-coupling reactions of organometallic reagents with
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and triflates, has proven to be one of the most important,
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bonds.2 This coupling reaction has been widely applied in organic
synthesis,3 especially in the synthesis of biaryls compounds, which
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DOI: 10.1021/jo9005206
r
Published on Web 06/24/2009
J. Org. Chem. 2009, 74, 5599–5602 5599
2009 American Chemical Society

Zhou et al.
JOCNote
TABLE 1. Optimized Conditions via the Coupling of Bromobenzene
with Tetraphenyltina
presence of different bases in PEG-400 revealed that NaOAc
as a suitable base provided the highest yield (Table 1, entry
10). Further study with varying NaOAc equivalents revealed
that 3.0 equiv of base is necessary to obtain a high yield of the
coupled product (Table 1, entries 11-14). Finally, the effect
of temperature was also evaluated, and the results indicated
that 100 °C was the appropriate temperature for the atom-
efficient Stille cross-coupling reaction (Table 1, entries 10,
15-20). It is interesting to note that the reaction can be
carried out efficiently under higher Pd loading in a short
reaction time (entry 21).
Strikingly, the Stille reaction carried out in the presence of
NaOAc in PEG-400 with Pd(PPh3)4 catalyst at 100 °C
provided the highest conversion (Table 1, entry 10). Further-
more, the atom-efficient reaction of tetraphenyltin in
which all four phenyls were efficiently coupled with 4 equiv
of their electrophilic coupling partner was thoroughly
established.
Thus, we investigated the Stille cross-coupling reaction of
tetraphenyltin with a variety of electronically diverse aryl
bromides (Table 2). The reactivity and substrate scope
provided by the aryl bromides under the present conditions
are excellent, giving good to high yields of the cross-coupled
products, and biphenyl was obtained as byproduct. As
shown in Table 2, all of the reactions of electron-withdraw-
ing aryl bromides occurred efficiently with tetraphenyltin
(Table 2, entries 1-17). We can discern that chloro, nitro,
cyano, and acetyl substituents at the meta or para positions
of the aromatic ring did not exert a strong influence upon the
Stille cross-coupling reaction (Table 2, entries 2, 3, 5, 6, 8, 9,
11, 12, and 14-17), except for the ortho position of the
aromatic ring, which gave the product of in lower yield
(Table 2, entries 4, 7, 10, and 13). Furthermore, 1-bromo-
naphthalene and 2-bromonaphthalene were remarkable,
furnishing the corresponding coupling products in excellent
yields (Table 2, entries 18 and 19). Amazingly, heterocyclic
bromides also provided the cross-coupling products in high
yields, except for 3-bromopyridine where a moderate yield
was observed (Table 2, entries 20-23). A possible problem
for 3-bromopyridine is that the pyridine nitrogen coordi-
nates to Pd strongly and slows the turnovers. Further study
revealed that the Stille cross-coupling reactions of electron-
rich functional groups such as methyl and methoxyl groups
in aryl bromides at the para position furnished moderate
yields of the desired products of 48% and 50% (Table 2,
entries 24 and 25), respectively.
entry
base (mmol)
T (°C)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
K2CO3 (3.0)
Na2CO3 (3.0)
K3PO4 (3.0)
KF/Al2O3 (3.0)
NaHCO3 (3.0)
KF (3.0)
KOH (3.0)
NaOH (3.0)
Et3N (3.0)
NaOAc (3.0)
NaOAc (4.0)
NaOAc (3.5)
NaOAc (2.5)
NaOAc (2.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
56
52
66
66
72
70
83
78
20
97
96
95
95
90
89
93
96
92
91
92
97c
90
95
105
110
120
100
aReaction conditions: bromobenzene (1.0 mmol), Ph4Sn (0.28 mmol),
PEG 400 (3 mL), base, Pd(PPh3)4 (0.005 mmol), stirring for at an
appropriate temperature. bIsolated yield based on bromobenzene.
c0.01 mmol Pd(PPh3)4 was used.
addition,14 and reduction reactions15 and so on.16 To the best
of our knowledge, the atom-efficient Stille cross-coupling
reaction catalyzed by palladium catalyst in PEG 400 has not
been reported thus far. In continuation of our interest on the
transition-metal-catalyzedorganictransformations,17 wenow
report a new and novel palladium-catalyzed protocol for
the atom-efficient cross-coupling of tetraphenyltin with aryl
bromides in PEG-400.
In order to explore an atom-economic reaction in PEG-
400, we screened the Stille cross-coupling reaction of bromo-
benzene as a representative example reacting with tetra-
phenyltin using Pd(PPh3)4 catalyst by optimizing the
conditions in terms of bases, reaction time, and tempera-
tures. As shown in Table 1, it was found that K2CO3,
Na2CO3, K3PO4, and KF/Al2O3 (mol ratio of 1:1) were
ineffective in providing the desired coupled product (Table 1,
entries 1-4). A comparative reactivity study of bases in the
reaction showed that NaHCO3, KF, KOH, and NaOH
proved to be more effective for this coupling (Table 1, entries
5-8). When Et3N was used as base, 20% of biphenyl was
obtained (Table 1, entry 9). The reaction carried out in the
We next examined the Stille cross-coupling reaction of
tetra-n-butyltin with electronically diverse aryl bromides; the
results are summarized in Table 3. We find out that carbox-
aldehyde, acetyl, nitro, and cyano substituents at the para
position of the aromatic ring give the desired products in
moderate yields (Table 3, entries 1-4). When 3-bromoben-
zonitrile was used, a lower yield was obtained even after
prolonged reaction times (Table 3, entry 5).
(14) (a) Kumar, R.; Chaudhary, P.; Nimesh, S.; Chandra, R. Green
Chem. 2006, 8, 356–358. (b) Andrews, P. C.; Peatt, A. C.; Raston, C. L.
Green Chem. 2004, 6, 119–122.
(15) (a) Walter, L. Nature 2003, 423, 930–931. (b) Cole-Hamilton, D. J.
Science 2003, 299, 1702–1706. (c) Wang, W.; Lu, S.; Yang, P.; Han, X.; Zhou,
Y. J. Am. Chem. Soc. 2003, 125, 10536–10537.
To evaluate the activity of the Pd catalyst, we also
investigated the influence of simple catalyst on the repre-
sentative reaction under the applied conditions (Table 1,
entry 10), and the results are summarized in Table 3. It can
be gathered that Ni and Co pieces were not efficient for the
cross-coupling reaction even after a prolonged stirring
time (Table 3, entries 1-3). Both reactions catalyzed by
PdCl2 and Pd/C provided moderate yields of biphenyl
(16) (a) Sun, J.; Yan, C. Synth. Commun. 2002, 32, 1735–1739. (b)
Neumann, R.; Sasson, Y. J. Org. Chem. 1984, 49, 3448–3451.
(17) (a) Bai, L.; Wang, J. -X. Adv. Synth. Catal. 2008, 350, 315–320. (b)
Bai, L.; Wang, J. -X.; Zhang, Y. Green Chem. 2003, 5, 615–617. (c) Bai, L.;
Zhang, Y.; Wang, J. -X. QSAR Comb. Sci. 2004, 23, 857–882. (d) Wang,
J. -X.; Fu, Y.; Hu, Y. Angew. Chem., Int. Ed. 2002, 41, 2757–2760. (e) Wang,
J. -X.; Wang, K.; Zhao, L.; Li, H.; Fu, Y; Hu, Y. Adv. Synth. Catal. 2006,
348, 1262–1270.
5600 J. Org. Chem. Vol. 74, No. 15, 2009

Zhou et al.
JOCNote
TABLE 2. Pd-Catalyzed Cross Coupling of Aryl Bromides (1) with Tetraphenyltin (2)a
aReaction conditions: 1 (1.0 mmol), 2 (0.28 mmol), PEG 400 (3 mL), NaOAc (3.0 mmol), Pd(PPh3)4 (0.005 mmol), stirring at 100 °C for an
appropriate time.
TABLE 3. Pd-Catalyzed Cross Coupling of Aryl Bromides with Tetra-
(Table 4, entries 4 and 5). When PdCl2(PPh3)2 was used,
the cross-coupling reaction proceed smoothly, and satis-
n-butyltina
factory yields was obtained (Table 4, entry 6). It can be
seen that Pd(PPh3)4 was the most effective catalyst for the
atom-efficient Stille cross-coupling reaction (Table 4,
entry 7). The control reaction carried out without catalyst
delivered no cross-coupling product, indicating that
the catalyst is necessary to the cross-coupling reaction
(Table 4, entry 8).
To conclude, in the present study we reported a palladium-
catalyzed protocol for the Stille cross-coupling reaction of
organotin with aryl bromides using the catalytic system
employs Pd(PPh3)4 along with NaOAc as base in PEG-400
media. It is noteworthy that the present protocol is highly
efficient as 4 equiv of aryl bromides reacted with 1 equiv
of tetraphenyltin cleanly to provide high yield of the
cross-coupling products in short reaction time. This process
has significant features: (i) atom-efficient coupling under
mild conditions in environmentally friendly media in air,
aReaction conditions: aryl bromides (1.0 mmol), tetra-n-butyltin
(0.30 mmol), PEG 400 (3 mL), NaOAc (3.0 mmol), Pd(PPh3)4
(0.01 mmol), stirring at 100 °C for an appropriate time.
J. Org. Chem. Vol. 74, No. 15, 2009 5601

Zhou et al.
JOCNote
TABLE 4. Comparative Experiments with Simple Catalysts on the
followed by tetraphenyltin (0.28 mmol) or tetra-n-butyltin
(0.30 mmol), NaOAc (3.0 mmol), Pd (PPh3)4 (0.005 mmol),
and PEG 400 (3 mL). Then the mixture was stirred at 100 °C
for an appropriate time. After being cooled to room tempera-
ture, the mixture was directly extracted with diethyl ether (5Â
10 mL). The upper layers were decanted, combined, and washed
with water and brine. PEG 400 was recovered by a short flash
column chromatography and reused several times. The organic
phase was then dried over anhydrous MgSO4 and concentrated
under vacuo, and the crude product was purified by flash
column chromatography to provide the corresponding product.
Representative Reactiona
entry
catalyst
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
Nano Ni
Ni(PPh3)2Cl2
Co(PPh3)3Cl
PdCl2
24
24
24
2
2
1
0
0
0
63
44
94
98
0
Pd/C
Pd(PPh3)2Cl2
Pd(PPh3)4
none
1
24
aReaction conditions: bromobenzene (1.0 mmol), Ph4Sn (0.28 mmol),
PEG 400 (3 mL), NaOAc (3.0 mmol), catalyst (0.01 mmol), stirring at
100 °C for an appropriate time. bIsolated yield based on bromobenzene.
Acknowledgment. This work was supported by the Natur-
al Science Foundation of China (Grant Nos. 20272047 and
20572086), the Gansu Natural Science Foundation of China
(0308RJZA-100), and the Key Laboratory of Eco-Environ-
ment-Related Polymer Material (Northwest Normal Univer-
sity), Ministry of the Education of China.
(ii) short reaction time, (iii) easy isolation of the product, and
(iv) broad substrate scopes. Further research is in progress in
our laboratory to utilize these catalytic systems in wide
synthetic applications.
Supporting Information Available: Experimental details,
Experimental Section
1
characterization data, H NMR and 13C NMR spectra for all
Typical Procedure for the Stille Cross-Coupling Reactions.
A glass flask was charged with aryl bromides (1.0 mmol)
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
5602 J. Org. Chem. Vol. 74, No. 15, 2009