Efficient Stille cross-coupling reaction catalyzed by the Pd(OAc) 2/Dabco catalytic system

Article abstract of DOI:10.1021/jo048066q

(Chemical Equation Presented) An efficient Pd(OAc)₂/Dabco- catalyzed Stille cross-coupling reaction procedure has been developed. In the presence of Pd(OAc)₂ and Dabco (triethylenediamine), various aryl halides including aryl iodides, aryl bromides, and activated aryl chlorides were coupled efficiently with organotin compounds to afford the corresponding biaryls, alkene, and alkynes in good to excellent yields. Furthermore, high TONs [turnover numbers, up to 980 000 TONs for the coupling reaction of 1-bromo-4-nitrobenzene and furan-2-yltributyltin] for the Stille cross-coupling reaction were observed.

Full text of DOI:10.1021/jo048066q

found that Dabco was a highly efficient ligand for the
palladium-catalyzed Suzuki-Miyaura cross-coupling re-
action resulting in high TONs (up to 950 000 TONs for
the reaction of PhI and p-chlorophenylboronic acid) (eq
1).7,8 Thus, we expected to extend the use of this type of
ligand to other palladium-catalyzed transformations.
Here, we report a stable, inexpensive, and efficient
Pd(OAc)2/Dabco catalytic system for the Stille reactions
of aryl halides with organotin compounds.
Efficient Stille Cross-Coupling Reaction
Catalyzed by the Pd(OAc)2/Dabco Catalytic
System
Jin-Heng Li,* Yun Liang, De-Ping Wang, Wen-Jie Liu,
Ye-Xiang Xie, and Du-Lin Yin
Key Laboratory of Chemical Biology & Traditional
Chinese Medicine Research, College of Chemistry and
Chemical Engineering, Hunan Normal University,
Changsha 410081, China
jhli@hunnu.edu.cn
Received October 31, 2004
To evaluate the efficiency of Pd(OAc)2/Dabco in the
Stille cross-coupling reaction, coupling of 4-bromoanisole
(1a) with phenyltributyltin (2a) was first tested, and the
An efficient Pd(OAc)2/Dabco-catalyzed Stille cross-coupling
reaction procedure has been developed. In the presence of
Pd(OAc)2 and Dabco (triethylenediamine), various aryl
halides including aryl iodides, aryl bromides, and activated
aryl chlorides were coupled efficiently with organotin com-
pounds to afford the corresponding biaryls, alkene, and
alkynes in good to excellent yields. Furthermore, high TONs
[turnover numbers, up to 980 000 TONs for the coupling
reaction of 1-bromo-4-nitrobenzene and furan-2-yltributyltin]
for the Stille cross-coupling reaction were observed.
(2) For recent representative papers on phosphine-palladium cata-
lysts, see: (a) Litter, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38,
2411. (b) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119. (c) Litter,
A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343 and
references therein. (d) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003,
125, 1696. (e) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718.
(f) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125,
14288. (g) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125,
15292. (h) Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 5079. (i) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077. (j)
Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7551. (k) Mee, S. P.
H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004, 43, 1132. (l)
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2004, 69, 220. (n) Ho¨genauer, K. Synlett 2001, 878. (o) Scrivanti, A.;
Matteoli, U.; Beghetto, V.; Antonaroli, S.; Crociani, B. Tetrahedron
2002, 58, 6881. (p) Kim, N.; Kwon, M. S.; Park, C. M.; Park, J.
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43, 895. (s) Ceccarelli, S.; Piarulli, U.; Gennari, C. J. Org. Chem. 2000,
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(3) For recent reviews and papers on N-heterocyclic carbene-
palladium catalysts, see: (a) Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1290. (b) Yong, B. S.; Nolan, S. P. Chemtracts: Org. Chem.
2003, 205. (c) Herrmann, W. A.; O¨ fele, K.; Preysing, D. v.; Schneider,
S. K. J. Organomet. Chem. 2003, 687, 229. (d) Grasa, G. A.; Nolan, S.
P. Org. Lett. 2001, 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, 69.
(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, 2095. (b) Alonso, D. A.;
Na´jera, C.; Pacheco, M. C. Org. Lett. 2000, 2, 1823. (c) Chouday, B.
M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2002, 124, 14127. (d) Davis, J. L.; Dhawan, R.; Arndtsen,
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J. Inorg. Chem. 2004, 2706.
The palladium-catalyzed Stille cross-coupling reaction
represents one of the most important transformations in
constructing the carbon-carbon bonds in organic syn-
thesis. For this reason, a number of effective palladium
catalytic systems have been developed for the Stille cross-
coupling reaction.1-5 Generally, the combination of pal-
ladium catalysts with various phosphine ligands results
in excellent yields and high efficiency.1,2 However, most
of the phosphine ligands are air-sensitive and expensive,
which places significant limits on their synthetic applica-
tions.6 On the other hand, it is desirable to be able to
employ low catalyst loadings particularly for pharma-
ceutical and industrial application. Although many of the
reported catalytic systems are effective, few reports
employed the Stille reaction under <1 mol % loadings of
palladium catalysts2a,c,n-p,3a,e-g (normal 1-5 mol % Pd).1
Thus, the development of new and efficient phosphine-
free palladium catalytic systems remains a potentially
promising area for organic chemists.3-5 Very recently, we
(1) For reviews, see: (a) Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508. (b) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-
coupling Reactions; Wiley-VCH: Weinheim, 1998. (c) Shirakawa, E.;
Hiyama, T. J. Organomet. Chem. 1999, 576, 169. (d) Miyaura, N. Cross-
Coupling Reaction; Springer: Berlin, 2002. (e) Hegedus, L. S. In
Oranometallics in Synthesis; Schlosser, M., Ed.; J. Wiley & Sons:
Chichester, 2002; p 1123. (f) Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002. (g) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(h) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359. (i) Espinet, P.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2004, 43, 4704.
(5) For a representative paper on diazabutadiene-palladium cata-
lysts [Pd(Ar-BIAN)], see: van Asselt, R.; Elsevier, C. J. Tetrahedron
1994, 50, 323.
(6) (a) Pignolet, L. H., Ed. Homogeneous Catalysis with Metal
Phosphine Complexes; Plenum: New York, 1983. (b) Parshall, G. W.;
Ittel, S. Homogeneous Catalysis; J. Wiley and Sons: New York, 1992.
(7) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809.
(8) For other papers on amine-palladium catalysts for the Suzuki
cross-coupling reaction, see: (a) Tao, B.; Boykin, D. W. Tetrahedron
Lett. 2003, 44, 7993. (b) Tao, B.; Boykin, D. W. J. Org. Chem. 2004,
69, 4330.
10.1021/jo048066q CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/25/2005
2832
J. Org. Chem. 2005, 70, 2832-2834

TABLE 1. Palladium-Catalyzed Stille Coupling
Reaction of 1a with 2aa
TABLE 2. Stille Coupling Reactions of Aryl Halides (1)
with 2a Catalyzed by the Pd(OAc)2/Dabco Catalytic
Systema
entry
ligand
base
solvent
yield (%)b
1
2
0
KF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
48
84
82
26
36
14
72
10
15
27
57
41
6
Dabco
KF
3c
4
Dabco
KF
(i-Pr)2NEt
(c-hexyl)2NMe
TMEDA
HMTA
KF
5
KF
6
KF
7
KF
8d
9
(-)-spartein e
Dabco
KF
KF
10
11
12e
13
14
15
Dabco
KF
DMF
Dabco
KF
acetone
dioxane
dioxane
dioxane
dioxane
Dabco
Bu4NF
Cs2CO3
K2CO3
Et3N
Dabco
Dabco
5
Dabco
20
a Unless otherwise indicated, the reaction conditions were as
follows: 1a (0.5 mmol), 2a (0.55 mmol), Pd(OAc)2 (3 mol %), ligand
(6 mol %), base (3 equiv), and solvent (5 mL) at 100 °C for 16 h.
b Isolated yield. c Dabco (12 mol %). d 26 h. e The reaction was not
clean, and some side products were observed.
results are summarized in Table 1. The results showed
that Dabco was an effective ligand for the palladium-
catalyzed Stille reaction. Without any ligands, only a 48%
yield of the corresponding cross-coupled product 3 was
isolated in the presence of 3 mol % of Pd(OAc)2 and 3
equiv of KF (entry 1), whereas the yield of 3 was
increased sharply to 84% when 6 mol % of Dabco was
added (entry 2). An identical yield was obtained by even
further increasing the loadings of Dabco to 12 mol %
(entry 3). Other tertiary amines as the ligands were less
effective than Dabco (entries 2 and 4-8). A series of
solvents including dioxane, DCE (1,2-dichloroetane),
DMF, and acetone were then examined; the highest yield
was observed in dioxane (entries 2 and 9-11). Several
bases were also investigated, and KF gave the best
results (entries 2 and 12-15).
As demonstrated in Table 2, the Pd(OAc)2/Dabco
catalytic system is remarkably active and tolerant of a
range of functionalities. The results showed that coupling
of the organotin 2a with a number of aryl halides,
including aryl iodides (1b and 1c), aryl bromides (1d-
g), and activated aryl chlorides (1h and 1i), was carried
out smoothly and efficiently to afford good to excellent
yields of the corresponding coupled products 3-7 with
extremely high TONs in the presence of Pd(OAc)2, Dabco,
and base. By treatment of aryl iodides (1b and 1c),
activated aryl bromides (1d and 1e), and activated aryl
chlorides (1h) with 2a, respectively, the loadings of the
catalyst could be decreased to 0.0001 mol %, and desir-
able yields could still be obtained after prolonged heating
(entries 5, 8, 11, 13, and 20, TONs up to 960 000),
whereas for coupling of deactivated aryl bromides 1a and
1g, the results indicated that the catalytic efficiency
decreased to some extent (entries 1, 2, and 15-17). For
example, treatment of 1a with 2a afforded good yield of
the corresponding product 3 for 24 h when the catalyst
loadings were decreased to 0.001 mol % (75% yield, TONs
) 75 000, entry 1). However, further decreasing the
a Unless otherwise indicated, the reaction conditions were as
follows: 1 (0.5 mmol), 2a (0.55 mmol), Pd(OAc)2/Dabco (1:2),
additive (3 equiv), and dioxane (5 mL) at 100 °C. b Isolated yield.
c The reaction was not clean, and some side products were
observed. d No reaction was observed.
catalyst loadings to 0.0001 mol % led to a low yield (27%
yield, TONs ) 270 000, entry 2).
The results also indicated that the additives affected
the reaction (entries 3, 4, 6, 7, 9, 10, 15, and 16 in Table
2). Generally, Bu4NF is more effective than KF.1,2 For
the present reaction, however, the efficacy of Bu4NF and
KF depended on aryl halides. By treatment of substrates
1c and 1e-i with 2a, Pd(OAc)2, and 6 mol % of Dabco (6
mol %), respectively, Bu4NF as the additive provided
higher yields of the desired cross-coupled products than
did KF (entries 6, 7, and 12-22), whereas KF gave much
higher yields for coupling of aryl halides bearing oxygen-
contained groups 1a, 1b, and 1d, respectively (entries 2
and 12 in Table 1; entries 3, 4, 9, and 10 in Table 2). It
is noteworthy that all halides 1a, 1b, and 1d were
consumed completely, respectively, when Bu4NF was
J. Org. Chem, Vol. 70, No. 7, 2005 2833

TABLE 3. Palladium-Catalyzed Stille Coupling
Reactions of Aryl Bromides (1) with 2b-e Using Dabco
as the Liganda
(entries 1, 4, 6, and 9). For coupling of aryl bromide 1f
with 2b and 2e, respectively, excellent yields were also
obtained (entries 10 and 11). The results also demon-
strated that aryl bromide 1e was a suitable substrate at
the loading of 0.0001 mol % of Pd (entries 3, 5, and 8).
For example, 98% yield of 8 was still isolated after 40 h
when coupling of 1e with 2b was carried out in the
presence of 0.0001 mol % of Pd, 0.0002 mol % of Dabco,
and 3 equiv of Bu4NF (TONs ) 980 000, entry 3).
In summary, we have developed an efficient Pd(OAc)2/
Dabco-ctalyzed Stille cross-coupling protocol for synthe-
sizing various biaryls, alkene, and alkynes in good to
excellent yields (maximum TONs up to 980 000 for the
Stille cross-coupling reaction of 1-bromo-4-nitrobenzene
and furan-2-yltributyltin). We also found that the efficacy
of Bu4NF and KF depended on aryl halides. Currently,
further efforts to extend the application of these ligands
and this protocol in organic synthesis are underway in
our laboratory.
Experimental Section
(1) Typical Experimental Procedure for the Palladium-
Catalyzed Stille Cross-Coupling Reaction. A mixture of aryl
halide 1 (0.5 mmol), organotin 2 (0.55 mmol), Pd(OAc)2 (3 mol
%), Dabco (6 mol %), the indicated base (3 equiv), and dioxane
(5 mL) was added to a sealed tube. The mixture was then stirred
at 100 °C for the 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 3-13.
(2) Typical Experimental Procedure for 0.0001 mol %
of Pd and 0.0002 mol % of Dabco-Catalyzed Stille Cross-
Coupling Reaction of 1-Bromo-4-nitrobenzene (1e) and
Furan-2-yltributyltin (2b) (Entry 3 in Table 3). First,
Pd(OAc)2 (4.5 mg, 0.02 mmol) was dissolved in 200 mL of
dioxane, and Dabco (4.5 mg, 0.04 mmol) was also dissolved in
another 200 mL of dioxane. Next, 5 µL of Pd(OAc)2 dioxane
solution and 5 µL of Dabco dioxane solution were added to a
mixture of 1-bromo-4-nitrobenzene (1e) (0.5 mmol), furan-2-
yltributyltin (2b) (0.55 mmol), Bu4NF (3 equiv), and dioxane (5
mL) in a sealed tube, respectively (by syringe). The mixture was
stirred at 100 °C for 40 h as determined by TLC. After the
mixture was filtered and evaporated, the residue was purified
by flash column chromatography (hexane) to afford 98% yield
of 8 (TONs: 980 000).
a Unless otherwise indicated, the reaction conditions were as
follows: 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2/Dabco (1:2), Bu4NF
(3 equiv), and dioxane (5 mL) at 100 °C. b Isolated yield.
used as the additive (entry 12 in Table 1; entries 3 and
9 in Table 2).9 For the coupling reactions of another aryl
halide bearing an oxygen-contained group 1i with 2a,
however, good yield was observed in the presence of
Bu4NF (81%, entry 21). Unactivated aryl chlorides 1j and
1k were found to be unreactive under the present
reaction conditions (entries 22 and 23).
The scope of the Pd(OAc)2/Dabco catalytic system was
further extended to the coupling reactions of aryl bro-
mides 1e and 1f with other organotin reagents including
furan-2-yltributyltin (2b), thiophen-2-yltributyltin (2c),
vinyltributyltin (2d), and 2-phenylethynyltributyltin (2e),
respectively, and the results are summarized in Table 3.
In the presence of 3 mol % of Pd(OAc)2, 6 mol % of Dabco,
and 3 equiv of Bu4NF, activated aryl bromide 1e coupled
efficiently with 2b-e, respectively, to afford the corre-
sponding desired products 8-11 in quantitative yields
Acknowledgment. We thank the National Natural
Science Foundation of China (No. 20202002), Depart-
ment of Education of Hunan Province (No. 02C211), and
Hunan Normal University for financial support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all products 3-13. This material
is available free of charge via the Internet at http://pubs.acs.org.
(9) The reaction was not clean, and some side products were
observed. Structures of the side products could not be determined by
1H NMR and 13C NMR spectra.
JO048066Q
2834 J. Org. Chem., Vol. 70, No. 7, 2005