An efficient Stille cross-coupling reaction catalyzed by Pd(OAc) 2/DAB-Cy catalytic system

Article abstract of DOI:10.1016/j.tet.2005.04.073

An efficient palladium-catalyzed Stille cross-coupling reaction has been developed. In the presence of 3 mol% of Pd(dba)₂ and 6 mol% of DAB-Cy (1,4-dicyclohexyl-diazabutadiene), various aryl halides (iodides and bromides) were coupled with organotin compounds to afford the corresponding biaryls and alkyne in good to excellent yields. Furthermore, high TONs [turnover numbers, TONs up to 950,000 for the reaction of 1-iodo-4-nitrobenzene and tributyl(phenyl)stannane] for the Stille cross-coupling reaction were observed.

Full text of DOI:10.1016/j.tet.2005.04.073

Tetrahedron 61 (2005) 7289–7293
An efficient Stille cross-coupling reaction catalyzed by
Pd(OAc) /DAB-Cy catalytic system
2
Jin-Heng Li, Yun Liang and Ye-Xiang Xie
*
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research, College of Chemistry and Chemical Engineering,
Hunan Normal University, Changsha 410081, China
Received 22 February 2005; revised 27 April 2005; accepted 30 April 2005
Available online 13 June 2005
Abstract—An efficient palladium-catalyzed Stille cross-coupling reaction has been developed. In the presence of 3 mol% of Pd(dba)
6
2
and
mol% of DAB-Cy (1,4-dicyclohexyl-diazabutadiene), various aryl halides (iodides and bromides) were coupled with organotin compounds
to afford the corresponding biaryls and alkyne in good to excellent yields. Furthermore, high TONs [turnover numbers, TONs up to 950,000
for the reaction of 1-iodo-4-nitrobenzene and tributyl(phenyl)stannane] for the Stille cross-coupling reaction were observed.
q 2005 Elsevier Ltd. All rights reserved.
3–5
remains an interesting area for organic chemists. Herein,
1. Introduction
we report a stable and efficient Pd(dba) /DAB-Cy (1,4-
2
The Stille cross-coupling reaction of organohalides with
organotin compounds has been proven to be a useful
synthetic method for carbon–carbon bond formation in
organic synthesis. Consequently, many effective palladium
catalytic systems have been developed for Stille cross-
dicyclohexyl diazabutadiene) catalytic system for the Stille
reactions of aryl halides with organotin compounds (Eq. 1).
1
–5
coupling reaction.
Generally, the combination of
palladium catalysts with various phosphine ligands results
(
1)
1
,2
in excellent yields and high efficiency.
However,
phosphine ligands and their palladium complexes are
often air-sensitive and are object to P–C bond degradation
at elevated temperature. Thus, the use of other supporting
6
2. Results and discussion
ligands for the Stille cross-coupling reaction emerged as an
3
–5
2.1. Palladium-catalyzed Stille cross-coupling of
4-bromoanisole with phenyltributyltin
attractive alternative to the phosphine ligands. Of these
phosphine-free supporting ligands, only one paper has
reported the use of diazabutadiene as the ligands combined
with Pd(0) [Pd(Ar-BIAN)(dmfu)] to catalyze Stille cross-
Initially, the efficiency of diazabutadienes as the ligands for
the palladium-catalyzed Stille cross-coupling reaction was
evaluated, and the results were summarized in Table 1. The
results showed that DAB-Cy (1,4-dicyclohexyl-diazabuta-
diene) was the most effective ligand for the coupling
reaction of 4-bromoanisole (1a) with phenyltributyltin (2a).
Without any ligands, only a 45% yield of the corresponding
cross-coupled product 3 was isolated in the presence of
5
coupling reaction. Compared with allyl halides and benzyl
bromide, however, Pd(Ar-BIAN)(dmfu) showed low
activity for the reaction of aromatic iodides. On the other
hand, it is desirable to employ low catalyst loadings for
pharmaceutical and industrial application. Although, many
of the reported catalytic systems are effective, few reports
employed the Stille reaction under !1 mol% loadings of
2
a,2c,2n–p,3a,3e–g
3 mol% of Pd(dba) and 3 equiv of KF (entry 1). Whereas,
2
palladium catalysts
(general 1 to 5 mol%
1
the yield of 3 was increased sharply to 93% when 6 mol% of
DAB-Cy was added (entry 3). An identical yield was
observed when the amount of DAB-Cy was further
increased to 12 mol% (entry 4). Other diazabutadienes as
the ligands were less effective than DAB-Cy (entries 3 and
Pd). For these reasons, the development of new and
efficient phosphine-free palladium catalytic systems
2
Keywords: Pd(dba) /DAB-Cy; Stille cross-coupling reaction; Aryl halide;
Organotin compound; Turnover number.
*
5–7). The results also demonstrated that Pd(OAc) was
2
inferior to Pd(dba) (entries 3 and 8). The use of n-Bu NF as
2
Corresponding author. Tel.: C86 731 8872530; fax: C86 731 8872531;
e-mail: jhli@hunnu.edu.cn
4
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.073

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J.-H. Li et al. / Tetrahedron 61 (2005) 7289–7293
a
Table 1. Palladium-catalyzed Stille cross-coupling reaction of 4-bromoanisole (1a) with phenyltributyltin (2a)
b
Entry
1
Pd
Ligand
—
Time (h)
Yield (%)
Pd(dba)
2
2
22
18
45
78
c
2
Pd(dba)
3
Pd(dba)
2
2
18
18
93
94
d
4
Pd(dba)
5
Pd(dba)
2
22
20
6
7
8
Pd(dba)
2
2
20
21
22
79
72
70
Pd(dba)
Pd(OAc)
2
e
9
Pd(dba)
2
18
32
a
Under otherwise indicated, the reaction conditions were as follows: 1a (0.30 mmol), 2a (0.40 mmol), Pd (3 mol%), ligand (6 mol%), KF (3 equiv), and
dioxane (5 mL) at 100 8C under N
Isolated yield.
Ligand (3 mol%).
2
.
b
c
d
e
Ligand (12 mol%).
4
n-Bu NF (3 equiv) instead of KF. The reaction was not clean, and some side products were observed.
the base was also investigated, the reaction was not clean
and resulted in a low isolated yield of 3 (entry 9).
afford 45% yield of 4 (entry 1 in Table 1; entries 11 and 12
in Table 2). A low yield was still observed from the reaction
of 1i with 2a under the same catalytic system (entry 14).
7
2.2. Palladium-catalyzed Stille cross-coupling of aryl
halides with organotins
2.3. Screening the catalytic efficiency of the palladium-
catalyzed Stille coupling reaction
As shown in Table 2, treatment of various aryl halides 1b–g
with organotin compounds 2a–d, respectively, afforded
good to excellent yields of the corresponding cross-coupled
products 3–11 in the presence of 3 mol% of Pd(dba)2,
As shown in Table 3, the catalytic efficacy of Pd(dba)2/
DAB-Cy was further evaluated. For coupling of aryl
bromides 1a and 1d with 2a, respectively, satisfied yields
could still be obtained after prolonged reaction time when
the catalyst loading was reduced to 0.1 mol% (entries 1 and
6
indicated that Pd(dba) /DAB-Cy was an efficient catalytic
mol% of DAB-Cy, and 3 equiv of KF. The results
2
7
). Further reduction of the catalyst, loading to 0.01 mol%
system for the Stille cross-coupling reactions. For example,
aryl iodide 1b was reacted with organotin compounds
including phenyltributyltin (2a), furan-2-yltributyltin (2b),
thiophen-2-yltributyltin (2c), and 2-phenylethynyltri-butyl-
tin (2d), respectively, to afford quantitative yields of the
corresponding desired products 4–7 in the presence of
Pd(dba)2 (3.0 mol%), DAB-Cy (6 mol%), and KF
led to a low yield (28%, TONsZ28,000, entry 2). For
coupling of aryl iodides 1b and 1c, the catalytic efficiency of
Pd(dba) /DAB-Cy was also excellent. For example, 1b was
2
coupled with 2a smoothly to afford 95% isolated yield for
4
0
8 h when the catalyst loading was decreased to
.0001 mol% (TONsZ950,000, entry 3).
(
3.0 equiv) (entries 1–4). Coupling of aryl bromides 1d–g
with organotin compounds 2a and 2b, respectively, was also
carried out smoothly and efficiently to afford the desired
cross-coupled products in moderate to good yields (entries
3. Conclusion
In summary, a stable and efficient Pd(dba) /DAB-Cy
2
6
for the reaction of aryl chlorides 1h and 1i with 2a,
respectively (entries 11 and 13). The use of n-Bu NF as the
4
base was further examined, the results showed that the
activated aryl chlorides 1h was coupled with 2a smoothly to
–10). The Pd(dba) /DAB-Cy/KF system was ineffective
catalytic system for the palladium-catalyzed Stille cross-
coupling reaction has been developed. In the presence of
Pd(dba)2 (3.0 mol%), DAB-Cy (6 mol%), and KF
(3.0 equiv), the reaction of aryl halides with organotin
compounds were carried out smoothly to afforded the
2

J.-H. Li et al. / Tetrahedron 61 (2005) 7289–7293
7291
a
Table 2. Palladium-catalyzed Stille coupling reaction in the presence of DAB-Cy
0
b
Entry
1
ArX
R Sn(n-Bu)
Time (h)
16
Yield (%)
3
PhSn(n-Bu)
3
(2a)
98 (4)
100 (5)
100 (6)
100 (7)
100 (3)
96 (4)
(
(
(
(
1b)
1b)
1b)
1b)
2
3
4
5
6
7
16
16
16
16
18
23
(2b)
(2c)
(2d)
PhSn(n-Bu)
PhSn(n-Bu)
PhSn(n-Bu)
3
3
3
(2a)
(2a)
(2a)
(1c)
(
1d)
70 (8)
(1e)
8
9
PhSn(n-Bu)
3
(2a)
(2a)
22
20
24
85 (9)
52 (10)
82 (11)
(
1f)
1f)
(2b)
(
1
0
PhSn(n-Bu)
3
(
1g)
11
12
13
14
PhSn(n-Bu)
PhSn(n-Bu)
PhSn(n-Bu)
PhSn(n-Bu)
3
3
3
3
(2a)
(2a)
(2a)
(2a)
24
24
24
24
Trace (4)
45 (4)
(
(
1h)
1h)
c
Trace (9)
22 (9)
(
1j)
c
(1j)
a
Under otherwise indicated, the reaction conditions were as follows: 1 (0.30 mmol), 2 (0.40 mmol), Pd(dba)
2
(3.0 mol%), DAB-Cy (6.0 mol%), KF (3 equiv),
2
and dioxane (5 mL) at 100 8C under N .
Isolated yield.
n-Bu NF (3 equiv) instead of KF.
4
b
c
a
Table 3. Screening the catalytic efficiency of the palladium-catalyzed Stille coupling reaction of 1 with 2
0
b
Entry
ArX
R Sn(n-Bu)
Pd (mol%)
Yield (%)
TON
3
1
2
3
4
5
6
7
1a
1a
1b
1b
1b
1c
1d
2a
2a
2a
2b
2b
2a
2a
0.1
65 (3)
28 (3)
95 (4)
96 (5)
90 (5)
90 (3)
73 (8)
650
0.001
0.0001
0.001
0.0001
0.0001
0.1
28,000
950,000
96,000
900,000
900,000
730
a
2
Under otherwise indicated, the reaction conditions were as follows: 1 (0.30 mmol), 2 (0.40 mmol), Pd(dba) /DAB-Cy (1:2), KF (3 equiv), and dioxane
(5 mL) at 100 8C under N for 48 h.
Isolated yield.
2
b

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J.-H. Li et al. / Tetrahedron 61 (2005) 7289–7293
corresponding biaryls and alkyne in good to excellent yields
maximum TONs up to 950,000 for the reaction of 1-iodo-4-
nitrobenzene and phenyltributyltin). Currently, further
efforts to extend the application of these ligands and this
protocol in organic synthesis are underway in our
laboratory.
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(
2
002, 41, 4176. (h) Hassan, J.; S e´ vignon, M.; Gozzi, C.;
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4
. Experimental
2
4
.1. General methods
1
13
2
001, 3, 119. (c) Litter, A. F.; Schwarz, L.; Fu, G. C. J. Am.
H and C NMR spectra were recorded on an INOVA-400
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with CDCl as the solvent. All reagents were directly used
Chem. Soc. 2002, 6343 and references cited therein. (d) Kim,
Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696. (e) Menzel,
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S.; Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125,
(
3
as obtained commercially. All the products 3–11 are
known.
8
–12
1
4288. (g) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003,
25, 15292. (h) Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem.,
1
4.2. Typical experimental procedure for the palladium-
catalyzed Stille cross-coupling reaction
Int. Ed. 2003, 42, 5079. (i) Wolf, C.; Lerebours, R. J. Org.
Chem. 2003, 68, 7077. (j) Wolf, C.; Lerebours, R. J. Org.
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A mixture of aryl halide 1 (0.30 mmol), organotin 2
(0.40 mmol), Pd(dba)2 (3.0 mol%), DAB-Cy (6 mol%),
KF (3 equiv), and dioxane (5 mL) was added to a sealed
tube. Then the mixture was stirred at 100 8C under N for
2
desired time until complete consumption of starting material
as judged by TLC. After the mixture was filtered and
evaporated, the residue was purified by flash column
chromatography (hexane or hexane/ethyl acetate) to afford
3
3
–11.
4
.3. Typical experimental procedure for 0.0001 mol% of
Pd and 0.0002 mol% of DAB-Cy-catalyzed Stille cross-
coupling reaction of 1-iodo-4-nitrobenzene (1b) and
phenyltributyltin (2a) (entry 3 in Table 3)
¨
Ofele, K.; Preysing, D. v.; Schneider, S. K. J. Organomet.
Chem. 2003, 687, 229. (d) Grasa, G. A.; Nolan, S. P. Org. Lett.
2
001, 3, 119. (e) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee,
H. M.; Yang, C.; Nolan, S. P. J. Organomet. Chem. 2002, 653,
9.
First, Pd(dba)2 (4.5 mg, 0.02 mmol) was dissolved in
200 mL of dioxane, and DAB-Cy (4.5 mg, 0.04 mmol)
was also dissolved in another 200 mL of dioxane. Then 3 mL
of Pd(dba) dioxane solution and 6 mL of DAB-Cy dioxane
2
solution were added to a mixture of 1-iodo-4-nitrobenzene
6
4
. For recent representative papers on other phosphine-free
ligand-palladium catalysts, see: (a) Albisson, D. A.; Bedford,
R. B.; Lawrence, S. E.; Scully, P. N. Chem. Commun. 1998,
2
095. (b) Alonso, D. A.; N a´ jera, C.; Pacheco, M. C. Org. Lett.
000, 2, 1823. (c) Chouday, B. M.; Madhi, S.; Chowdari, N. S.;
(
(
1b) (0.30 mmol), phenyltributyltin (2a) (0.40 mmol), KF
3 equiv), and dioxane (5 mL) in a sealed tube (by syringe).
2
Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124,
4127. (d) Davis, J. L.; Dhawan, R.; Arndtsen, B. A. Angew.
The mixture was stirred at 100 8C under N2 for 48 h
determined by TLC. After the mixture was filtered and
evaporated, the residue was purified by flash column
chromatography (hexane/ethyl acetate) to afford 95%
yield of 4 (TONs: 950,000).
1
Chem., Int. Ed. 2004, 43, 590. (e) Amatore, C.; Bahsoun,
A. A.; Jutand, A.; Meyer, G.; Ntepe, A. N.; Ricard, L. J. Am.
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2
Acknowledgements
706.
5
6
. For a representative paper on diazabutadiene-palladium
catalysts [Pd(Ar-BIAN)(dmfu)] for the Stille cross-coupling
reactions, see: van Asselt, R.; Elsevier, C. J. Tetrahedron
We thank the National Natural Science Foundation of China
No. 20202002) for the financial support.
(
1
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7. The reaction was not clean, and some side products were
1

J.-H. Li et al. / Tetrahedron 61 (2005) 7289–7293
7293
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1 13
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