PEG-400 promoted Pd(OAc)2/DABCO-catalyzed cross-coupling reactions in aqueous media

Article abstract of DOI:10.1016/j.tet.2005.09.138

PEG-400 [poly(ethylene glycol-400)] was found to improve the Pd(OAc) ₂/DABCO-catalyzed aqueous Suzuki-Miyaura and Stille cross-coupling reactions. In the presence of Pd(OAc)₂, DABCO, and PEG-400, a variety of aryl halides were coupled with arylboronic acids or organotin compounds efficiently to afford the corresponding cross-coupled products in moderate to excellent yields. The turnover numbers was up to 900,000 for the Suzuki-Miyaura reaction and up to 9800 for the Stille reaction. The catalyst system was also effective for Heck and Sonogashira cross-coupling reactions to some extent.

Full text of DOI:10.1016/j.tet.2005.09.138

Tetrahedron 62 (2006) 31–38
PEG-400 promoted Pd(OAc)2/DABCO-catalyzed cross-coupling
reactions in aqueous media
*
Jin-Heng Li, Xi-Chao Hu, Yun Liang and Ye-Xiang Xie
College of Chemistry and Chemical Engineering, Human Normal University, Changsha 410081, China
Received 1 July 2005; revised 28 September 2005; accepted 30 September 2005
Available online 24 October 2005
Abstract—PEG-400 [poly(ethylene glycol-400)] was found to improve the Pd(OAc)2/DABCO-catalyzed aqueous Suzuki–Miyaura and
Stille cross-coupling reactions. In the presence of Pd(OAc)2, DABCO, and PEG-400, a variety of aryl halides were coupled with arylboronic
acids or organotin compounds efficiently to afford the corresponding cross-coupled products in moderate to excellent yields. The turnover
numbers was up to 900,000 for the Suzuki–Miyaura reaction and up to 9800 for the Stille reaction. The catalyst system was also effective for
Heck and Sonogashira cross-coupling reactions to some extent.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the Pd(OAc)2/DABCO-mediated aqueous cross-coupling
reactions.7d,8 Indeed, we found that Pd(OAc)2/DABCO-
catalyzed Suzuki–Miyaura, Stille and Heck reactions
proceeded efficiently in aqueous media when PEG-400
was used as the phase-transfer catalyst, but the same
conditions were ineffective for the Sonogashira cross-
coupling reactions. Here we report the details of those
reactions (Eqs. 1–4 in Scheme 1).
Palladium-catalyzed cross-coupling reactions were one of
the most powerful tools for the formation of C–C bond in
organic synthesis.1–5 The recent development of highly
active palladium–ligand complexes has allowed chemists to
extend such protocol to less reactive but inexpensive and
readily available aryl chlorides.2 Cross-coupling reactions
are usually carried out in polar organic solvent under inert
and anhydrous conditions due to the instability of most
catalysts and coupling reagents. From an economic and
environmental standpoint, however, it is desirable to avoid
any use of hazardous and expensive organic solvents. To
satisfy these concerns, water or aqueous solution represents
a very attractive medium for organic reactions,6 and
considerable effort has been directed to the application of
water or aqueous solutions in cross coupling reactions.2–5
Very recently, we have demonstrated DABCO as an
efficient ligand for the palladium-catalyzed Suzuki–
Miyaura, Sonogashira and Stille cross-coupling reactions.7
However, water was not an effective solvent for the
Pd(OAc)2/DABCO-catalyzed Suzuki–Miyaura reaction.7a
In the earlier work, phase-transfer catalysts such as crown
esters and TBAB could significantly promote the cross-
coupling reaction.3–5 Moreover, our recent results also
showed that the use of PEG as medium would favor the
Suzuki–Miyaura reaction.7d Thus, we expected that
the addition of phase-transfer catalysts might help improve
2. Results and discussion
2.1. PEG-400 promoted Pd(OAc)2 and DABCO-cata-
lyzed aqueous Suzuki–Miyaura cross-coupling reaction
The effect of PEG on palladium-catalyzed aqueous Suzuki–
Miyaura cross-coupling reaction of p-bromoanisole (1a)
with phenylboronic acid (2a) was investigated, and the
results are summarized in Table 1. Initially, three phase-
transfer catalysts including PEG-400, 18-crown-6, and
TBAB were tested, and PEG-400 was the most effective
to improve the reaction (entries 1–4). Without the addition
of any phase-transfer catalysts, the treatment of 1a with 2a,
Pd(OAc)2 (2 mol%), DABCO (4 mol%), and KOH
(3 equiv) for 4 h using water as the medium afforded 87%
yield of the corresponding coupled product 3 (entry 1),
whereas the yield of 3 was increased to 100% when
20 mol% of PEG was added (entry 2). A series of bases,
such as KOH, NaOH, K3PO4, NaOAc, K2CO3, and Cs2CO3,
were then evaluated, where KOH produced the highest yield
(entries 2 and 5–9). A set of solvents including H2O,
acetone, toluene, DMF, ethanol, and MeCN were also
Keywords: PEG-400; Pd(OAc)2/DABCO; Cross-coupling reaction; Aryl
halide; Arylboronic acids; Organotin compounds.
Corresponding author. Tel.:C86 731 8872530; fax: C86 731 8872531;
e-mail: jhli@hunnu.edu.cn
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.138

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J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
Scheme 1.
As shown in Table 2, the Pd(OAc)2/DABCO/PEG/KOH
system was effective for coupling of various aryl halides
with arylboronic acids 2a–d in aqueous media. High yields
were still obtained for coupling of aryl iodides when Pd
loadings were decreased to 0.0001% (entries 5 and 6). In the
presence of 0.0001 mol% Pd, p-nitroiodobenzene (1b) was
coupled with 2a efficiently to give 90% yield of the
corresponding product 7 (entry 5). For the coupling of
deactivated aryl iodide 1c with 2a, 88% yield of the
corresponding product 3 was also isolated after 4 h in
the presence of 0.001 mol% Pd (entry 6). However, for the
coupling reaction of aryl bromides, the efficiency of
the Pd(OAc)2/DABCO/PEG/KOH system was decreased.
The suitable Pd loadings were 2–0.01 mol% (entries 1–3
and 7–18). For example, the coupling of bromide 1e with
arylboronic acids 2a and 2d, respectively, afforded good
yields of the corresponding products 8 and 9 in the presence
of 0.01 mol% Pd (entries 11 and 12). It is noteworthy that
the use of ethanol as co-solvent is essential to improve the
coupling reactions of aryl halides bearing electron-with-
drawing groups (entries 4, 5, 7–12, and 19–21). In the
absence of ethanol, low yields were observed for coupling
of halides 1b, 1d, 1e, 1i, and 1j, whereas moderate to good
yields were obtained when these reactions were employed in
ethanol–H2O (1/4). It is worth mentioning that the system
was effective for coupling of the activated aryl chlorides. In
the presence of 2 mol% of Pd(OAc)2, 4 mol% of DABCO,
and 20 mol% of PEG, moderate yields were obtained for the
reaction of 2a with activated aryl chlorides 1i and 1j,
respectively, in ethanol/water (entries 20 and 21). Attempts
to couple 2a with chlorides 1k and 1l, respectively, both
afforded low yields (entries 22 and 23).
Table 1. Palladium-catalyzed Suzuki–Miyaura cross-coupling reaction of
4-bromoanisole (1a) with phenylboronic acid (2a)a
Entry
Additive
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
0
PEG-400
KOH
KOH
18-Crown-6 KOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
87
100
90
91
84
48
79
89
91
65
Trace
Trace
TBAB
KOH
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
NaOH
K3PO4
NaOAc
K2CO3
Cs2CO3
KOH
KOH
KOH
KOH
KOH
9
H2O
10
11
12
13
14
15c
16d
17e
Acetone
Toluene
DMF
CH3CH2OH Trace
MeCN
H2O
H2O
Trace
87
100
79
KOH
KOH
KOH
H2O
a Under otherwise indicated, the reaction conditions were as follows: 1a
(0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (2 mol%), DABCO (4 mol%),
additive (20 mol%), base (3 equiv), and solvent (5 mL) at 80 8C under N2
for 4 h.
b Isolated yield.
c Without DABCO.
d Pd(OAc)2 (0.1 mol%) and DABCO (0.2 mol%) for 13 h.
e Pd(OAc)2 (0.01 mol%) and DABCO (0.02 mol%) for 15 h.
examined, and H2O gave the best results as solvent (entries
2 and 10–14). Only 65% yield of 3 was isolated with
acetone, the reported effective solvent (entry 10).7a Finally,
the effect of DABCO was evaluated, and the results
indicated that DABCO has a fundamental influence on the
reaction (entries 2 and 15). In the absence of DABCO, the
yield of 3 was reduced to 87% (entry 15). It is interesting to
note that the reaction can be carried out efficiently under
lower Pd loadings (entries 16 and 17). In the presence of
Pd(OAc)2 (0.1 mol%), DABCO (0.2 mol%), PEG
(20 mol%), KOH (3 equiv), and H2O (5 mL), coupling of
1a with 2a gave the desired product 3 in 100% yield (entries
16). Further decreasing the Pd loading to 0.01 mol% led to a
moderate yield (79% yield, TONsZ7900; entry 17)
Compared with Zhang’s results,8 both DABCO and PEG
play crucial roles in the reaction. In the presence of catalytic
amounts of DABCO and PEG, the loadings of Pd(OAc)2
might be reduced to 0.1–0.0001 mol% while high yields
were still obtained (Tables 1 and 2). However, 1 mol% of
Pd(OAc)2 and 175 mol% of PEG were required to improve
the reaction under DABCO-free conditions.8 In the presence
of 1 mol% of Pd(OAc)2, moderate yields were observed
when a catalytic amount of PEG-2000 was added. For
example, !60% yield was obtained in the presence of
50 mol% of PEG-2000.8 Similarly, without DABCO the
yield was decreased under our conditions (entry 15 in
Table 1). Furthermore, only a moderate yield was isolated

J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
Table 2. Palladium-catalyzed Suzuki–Miyaura coupling reaction in aqueous mediaa
33
Entry
1
ArX
ArB(OH)2
(2b)
Pd (mol%)
0.1
Time (h)
16
Yield (%)b
83 (4)
(1a)
2
0.1
16
16
24
24
15
22
22
14
36
76 (5)
(1a)
(1a)
(1b)
(1b)
(1c)
(1d)
(1d)
(1d)
(2c)
3
0.1
90 (6)
(2d)
4c,d
5e
6
0.001
0.0001
0.001
0.01
0.01
2
38 (7)
(2a)
(2a)
90 (7)
(2a)
(2a)
(2a)
(2a)
(2a)
88 (3)
7f
Trace (7)
29 (7)
8e
9e
10 g
93 (7)
0.01
Trace (8)
(1e)
(1e)
11e
(2a)
(2d)
0.01
0.01
11
26
93 (8)
80 (9)
12e
(1e)
(1f)
(1f)
(1g)
13
14
15
(2a)
(2b)
(2a)
0.1
0.1
0.1
13
13
10
96 (10)
93 (11)
84 (11)

34
J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
Table 2 (continued)
Entry
16 h
ArX
(1g)
(1g)
ArB(OH)2
Pd (mol%)
1
Time (h)
0.5
Yield (%)b
(2a)
65 (11)
17
18
(2b)
(2a)
0.1
0.1
10
18
80 (12)
57 (13)
(1h)
19ij
(2a)
2
24
Trace (7)
(1i)
(1i)
20ej
21ej
(2a)
(2a)
2
2
24
24
50 (7)
52 (8)
(1j)
(1k)
(1l)
22j
23j
(2a)
(2a)
2
2
22
24
35 (3)
24 (11)
a Under otherwise indicated, the reaction conditions were as follows: 1 (0.50 mmol), 2 (0.60 mmol), Pd(OAc)2–DABCO (1/2), PEG-400 (20 mol%), KOH
(3 equiv), and H2O (5 mL) under N2 at 80 8C.
b Isolated yield.
c Without DABCO.
d Compound 1b (O55%) was recovered.
e CH3CH2OH–2O (1/4; 5 mL).
f
Compound 1d (O90%) was recovered.
g Compound (O90%) 1e was recovered.
h 1 (1.0 mmol), 2 (1.50 mmol), Pd(OAc)2 (1 mol%), PEG-400 (3.5 g), Na2CO3 (2 equiv), and H2O (3 g) under N2 at 50 8C.
i
Compound 1i (O95%) was recovered.
At 120 8C.
j
Table 3. Palladium-catalyzed Stille coupling reaction in aqueous mediaa
Entry
1
ArX
(1a)
(1a)
(1a)
Time (h)
16
Yield (%)b
R0Sn(Bu)3
PhSn(n-Bu)3 (14a)
92 (3)
2c
(14a)
(14a)
26
26
71 (3)
40 (3)
3d

J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
35
Table 3 (continued)
Entry
4d
ArX
(1b)
(1c)
(1d)
(1d)
Time (h)
10
Yield (%)b
R0Sn(Bu)3
(14a)
98 (7)
5d
(14a)
(14a)
12
10
16
93 (3)
6
100 (7)
70 (15)
7
(14b)
(14c)
8
15
86 (16)
(1d)
(1d)
9
15
10
78 (17)
100 (8)
(14d)
(14a)
10
(1e)
(1f)
(1f)
(1g)
11
12
13
14
(14a)
(14b)
(14a)
(14a)
16
15
15
10
95 (10)
87 (18)
100 (11)
93 (13)
(1h)
(1i)
15
(14a)
24
11 (7)
a Under otherwise indicated, the reaction conditions were as follows: 1 (0.50 mmol), 14 (0.60 mmol), Pd(OAc)2 (2 mol%), DABCO (4 mol%), PEG-400
(20 mol%), KOH (3 equiv), and H2O (5 mL) at 80 8C under N2.
b Isolated yield.
c Pd(OAc)2 (0.1 mol%) and DABCO (0.2 mol%).
d Pd(OAc)2 (0.01 mol%) and DABCO (0.02 mol%).
when PEG-400 was used to replace PEG-2000 under
Zhang’s conditions (65% yield, entry 16 in Table 2).
efficiency of the Pd(OAc)2/DABCO/PEG/KOH system for
the reaction of the substrate 1a with PhSn(Bu)3 (14a) was
evaluated in water. In the presence of 2 mol% of Pd(OAc)2,
4 mol% of DABCO and 20 mol% of PEG, the coupling
reaction of bromide 1a with 14a proceeded smoothly to
afford 92% yield of the corresponding product 3 (entry 1).
The catalyst loadings was decreased to 0.1 mol% for
coupling of the substrate 1a resulting in a moderate yield
of 3 after prolonged stirring (entry 2). However, a low yield
2.2. PEG-400 promoted Pd(OAc)2 and DABCO-cata-
lyzed aqueous stille cross-coupling reaction
The Pd(OAc)2/DABCO/PEG/KOH system was further
extended to effect the Stille cross-coupling reaction, and
the results are summarized in Table 3. Initially, the

36
J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
Table 4. Palladium-catalyzed Heck coupling reaction in aqueous mediaa
Entry
1
ArX
(1a)
(1a)
(1a)
Olefine
Time (h)
36
Yield (%)b
10 (20)
(19a)
(19a)
2c
3d
4
36
17
4
55 (20)
78 (20)
98 (21)
98 (22)
90 (20)
90 (21)
94 (22)
87 (23)
(19a)
(19a)
(1b)
(1b)
(1c)
(1d)
(1d)
5
4
(19b)
(19a)
6
4
7
(19a)
15
15
15
8
(19b)
(19b)
9
(1e)
(1f)
(1g)
10
11
(19a)
(19a)
36
36
68 (24)
60 (25)
a Under otherwise indicated, the reaction conditions were as follows: 1 (0.50 mmol), 19 (0.60 mmol), Pd(OAc)2 (2 mol%), DABCO (4 mol%), PEG-400
(20 mol%), K2CO3 (3 equiv), and H2O (5 mL) at 80 8C under N2.
b Isolated yield.
c KOH (3 equiv) instead of K2CO3.
d TBAB (20 mol%) instead of PEG.
was isolated when the Pd loading was further reduced to
0.01 mol% (entry 3). Furthermore, the system was effective
for coupling of aryl iodides 1b and 1c providing excellent
yields in the presence of 0.01 mol% Pd (entries 4 and 5).
The results also indicated that other aryl bromides 1d–h
were treated with 14a–d, Pd(OAc)2 (2 mol%), DABCO
(4 mol%), PEG (20 mol%) and KOH (3 equiv) to afford the
corresponding products in moderate to good yields (entries
6–14). For example, coupling of bromide 1d with 14a–d,
respectively, gave the corresponding coupled products 7 and
15–17 in 100%, 70%, 86%, and 78% yields (entries 6–9).
Unfortunately, coupling of activated aryl chloride 1i with
14a was unsuccessful (entry 15).
2.3. The Pd(OAc)2/DABCO/PEG/KOH system for
aqueous Heck and Sonogashira cross-coupling reactions
As demonstrated in Table 4, the Pd(OAc)2/DABCO/PEG/

J.-H. Li et al. / Tetrahedron 62 (2006) 31–38
37
Scheme 2.
KOH system was less effective for the Heck and
Sonogashira cross-coupling reactions. In the presence of
Pd(OAc)2 (2 mol%), DABCO (4 mol%), PEG (20 mol%),
and KOH (3 equiv), a low yield of the desired product 20
was isolated for the reaction of bromide 1a with styrene 19
(entry 1 in Table 4). It is interesting to note that the yield of
20 was enhanced to 55% when K2CO3 was used as the base
(entry 2). As indicated in the earlier report,5a TBAB might
be a better promoter for the Heck reaction. Indeed, in the
presence of Pd(OAc)2 (2 mol%), DABCO (4 mol%), TBAB
(20 mol%), and K2CO3 (3 equiv), the yield of 20 was
increased to 78% (entry 3). However, our interesting is
extended PEG as the additive to improve the cross-coupling
reactions. Thus, treatment of a number of aryl iodides and
activated aryl bromides with olefins were tested in the
presence of Pd(OAc)2 (2 mol%), DABCO (4 mol%), PEG
(20 mol%), and K2CO3 (3 equiv), and moderate to excellent
yields of the desired products were obtained (entries 4–11).
For example, the reaction of bromide (1d) with 19a or 19b
gave the corresponding (E)-olefins 21 and 22 in 90% and
94% yields, respectively (entries 7 and 8).
4. Experimental
4.1. Typical experimental procedure for the PEG
promoted Pd(OAc)2/DABCO-catalyzed cross-coupling
reactions in aqueous media
A mixture of 1 (0.50 mmol), 2 (14, 19 or 26, 0.60 mmol),
Pd(OAc)2 (the indicated amount), DABCO (the indicated
amount), PEG-400 (20 mol%), KOH (3 equiv), and H2O
(5 mL) was stirred under N2 at 80–120 8C until complete
consumption of starting material as monitored by TLC and
GC analysis. After the mixture was filtered and evaporated,
the residue was purified by flash column chromatography
(hexane or hexane/ethyl acetate) to afford the desired
coupled products 3–13, 15–18, 20–25, 27, and 28, which are
all known compounds.2–5,7
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20202002) and Hunan Provincial Natural Science
Foundation of China (No. 05JJ1002) for financial support.
The Sonogashira cross-coupling reaction of 1-iodo-4-
nitrobenzene (1b) with phenylacetylene (26) gave 80%
yield of the corresponding product 27 in the presence of
Pd(OAc)2 (2 mol%), DABCO (4 mol%), PEG (20 mol%),
and KOH (3 equiv) (run 1 in Scheme 2). However, only
35% yield of the corresponding alkyne 28 was isolated after
24 h when the reaction of p-iodoanisole (1c) with alkyne 26
was conducted (run 2). Other bases including K2CO3,
Cs2CO3, Et3N, and NaOAc were also evaluated but only
resulted in low yield. Rather low yields were obtained for
the Sonogashira cross-coupling products due to the
formation of red oils, by-products which were also observed
in our previous results.9
References and notes
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Catalyzed Cross-coupling Reactions; Wiley-VCH: Weinheim,
1998. (b) Miyaura, N. Cross-Coupling Reaction; Springer:
Berlin, 2002. (c) Negishi, E., Ed.; Handbook of Organo-
palladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002; Vol. 1. (d) Herrmann, W. A.
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3. Conclusion
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reactions in aqueous media promoted by PEG-400 has been
developed. In the presence of Pd(OAc)2, DABCO, and PEG,
coupling of a variety of aryl halides with arylboronic acids
or organotin compounds was carried out efficiently in
aqueous media to afford the corresponding cross-coupled
products in moderate to excellent yields and high TONs.
The TONs is up to 900,000 for the Suzuki–Miyaura reaction
and up to 9800 for the Stille reaction. Moreover, the present
reaction conditions were also effective for the Heck and
Sonogashira cross-coupling reactions to some extent.

38
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8. Very recently, Zhang and co-workers also reported that the
Pd(OAc)2-catalyzed Suzuki–Miyaura reaction preformed
smoothly in PEG-2000/H2O under ligand-free conditions. The
results showed that both the quantity and the type of PEG
affected the reaction. However, high loadings of PEG-2000
(175 mol%) and Pd(OAc)2 (S1 mol%) were required. We also
tested PEG-400 instead of PEG-2000 under Zhang’s conditions,
only 65% yield was observed when p-bromotoluene was reacted
with phenylboronic acid (entry 16 in Table 2). See: Liu, L.;
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1
9. We could not confirm the construction of the red oils by H
NMR, 13C NMR and MS spectra. See: (a) Li, J.-H.; Jiang,
H.-F.; Chen, M.-C. J. Org. Chem. 2001, 66, 3627–3629. (b) Li,
J.-H.; Xie, Y.-X. Chin. J. Chem. 2004, 22, 1432–1435. (c) Li,
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5. For selected papers on aqueous other cross-coupling reaction,
see: (a) Jeffery, T. Tetrahedron 1996, 52, 10113. (b) Genet,