An efficient protocol for copper-free palladium-catalyzed Sonogashira cross-coupling in aqueous media at low temperatures

Article abstract of DOI:10.1016/j.tetlet.2011.09.031

A thorough study on copper-free Sonogashira cross-couplings in water was carried out using the palla-dacycle, [{Pd(μ-Cl){K²-P,C-P(iPr) ₂(OC₆H₃-2-Ph)}}₂] as pre-catalyst with different bases and palladium concentrations. The highly active pre-catalyst imparts good to near quantitative yields using a concentration of 0.25 mol % at 40 °C. This broadly applicable protocol exhibits high tolerance of functional groups and substitution patterns.

Full text of DOI:10.1016/j.tetlet.2011.09.031

Tetrahedron Letters 52 (2011) 6355–6358
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient protocol for copper-free palladium-catalyzed Sonogashira
cross-coupling in aqueous media at low temperatures
⇑
Alexander N. Marziale, Johannes Schlüter, Jörg Eppinger
Biological & Organometallic Catalysis (BOC) Laboratories, KAUST Catalysis Center (KCC), 4700 King Abdullah University of Science and Technology, Thuwal 23955 6900, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2011
Revised 29 August 2011
Accepted 7 September 2011
Available online 10 September 2011
A thorough study on copper-free Sonogashira cross-couplings in water was carried out using the palla-
dacycle, [{Pd(l-Cl){j
2-P,C-P(iPr)2(OC6H3-2-Ph)}}2] as pre-catalyst with different bases and palladium
concentrations. The highly active pre-catalyst imparts good to near quantitative yields using a concentra-
tion of 0.25 mol % at 40 °C. This broadly applicable protocol exhibits high tolerance of functional groups
and substitution patterns.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Palladacycle
Sonogashira
Sustainability
Palladium-catalyzed cross-coupling reactions represent one of
the most powerful tools in organic synthesis.1 The Nobel Prize in
chemistry, which was awarded to Suzuki, Heck and Negishi in
2010, underlines their importance. Heck, Suzuki2 and Sonogashira
cross-coupling reactions are highly tolerant to moisture and sev-
eral protocols were reported using aqueous media.3 Compared to
organic solvents, water is particularly advantageous as a reaction
medium since it is cheap, widely available, non-toxic, and non-
flammable.4 Moreover its high polarity facilitates straightforward
product isolation by extraction or even filtration5 due to the forma-
tion of a lipophilic layer of coupling products. Hence, research on
the application of water as a benign and sustainable alternative
to organic solvents has become a highly active field, addressing
upcoming requirements in synthesis and catalysis.6 Sonogashira
coupling of aryl halides with alkynes7 provides a versatile method
to generate a broad variety of organic compounds, such as hetero-
cycles,8 pharmaceuticals,7 and natural products.9 Nevertheless,
many Sonogashira protocols suffer from high palladium loadings,10
elevated reaction temperatures,11 and the addition of a copper co-
catalyst. Typically, under aqueous conditions, addition of either a
phase-transfer catalyst12 or surfactants13 is required. Among re-
cent developments improving the original Sonogashira protocol,
the use of pure water and elimination of copper as a co-catalyst
are the most important in terms of environmental sustainability
and selectivity.14 The copper co-catalyst is particularly problematic
in the presence of oxidizing agents or air, since it is prone to induce
Glaser-type homocoupling reactions.15 Improved aqueous
protocols and catalysts were reported by Plenio16 and Djakov-
itch.17 Coupling of heterocyclic chloro arenes in water/iso-propanol
mixtures was achieved at elevated temperatures using 0.25 mol %
of a sulfonated N-heterocyclic Pd carbene complex.16c An impor-
tant innovation is the application of heterogeneous catalysts,18
combining a copper-free coupling procedure and the use of water19
as the reaction medium with the typical advantages of heteroge-
neous catalytic systems such as catalyst separation, recycling,
and reuse.17,20 Nevertheless, examples that offer a truly sustainable
and versatile approach for the Sonogashira reaction remain
scarce.21
We recently reported an environmentally friendly reaction pro-
tocol for aqueous Suzuki–Miyaura cross-coupling catalysis under
air at room temperature with no organic co-solvents or other addi-
tives needed.5 The Bedford-type22 palladacycle 2 is a highly active
catalyst for the Suzuki cross-coupling in water. It is easily obtained
by the reaction of 2-phenylphenol with diisopropyl-chlorophos-
phine and subsequent palladation of the resulting phosphinite
ligand 1 (Scheme 1). We here report a protocol based on the use
of catalyst 1 optimized for the requirements of the Sonogashira
Scheme 1. Reagents and conditions: (i) Et3N, ClPiPr2, toluene, reflux, 16 h. (ii) PdCl2,
toluene, reflux, 16 h.
⇑
Corresponding author. Tel.: +966 2 808 2414.
E-mail address: jorg.eppinger@kaust.edu.sa (J. Eppinger).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.031

6356
A. N. Marziale et al. / Tetrahedron Letters 52 (2011) 6355–6358
Table 2
reaction, targeting lower palladium loadings and elimination of the
copper co-catalyst using water as the reaction medium.
Effect of catalyst loading on substrate conversiona
Preliminary experiments showed that the protocol we reported
recently was not directly applicable to the Sonogashira reaction.
Adapting the model reaction used to optimize the Suzuki coupling
protocol, phenylacetylene and iodophenol were chosen as the test
substrates and reacted in the presence of 0.5 mol % of palladacycle
2. When the coupling reaction was carried out in either neat water
with 2.5–10 equiv of sodium carbonate as base or in a buffered
aqueous solution at pH 11 (NaHCO3/NaOH, c = 1.0 M) only negligi-
ble conversion was observed (Table 1, entries 1 and 7). Hence, we
investigated the effects of different reaction parameters on the cat-
alytic activity in order to optimize the protocol for Sonogashira
coupling. The strong influence of the base on catalytic activities
in cross-coupling reactions is well documented.23 Hence, we
focused first on identifying a suitable base. Six different bases were
screened at varying concentrations (Table 1).
Entry
R
Catalyst loading (mol %)
0.01
0.025
0.05
0.10
0.25
0.5
1.0
Yield (%)
1
2
3
H
OH
CH3
17
0
0
22
44
31
84
51
74
93
69
77
99
75
87
99
81
89
99
93
96
a
Reagents and conditions: 1.0 equiv aryl halide, 1.0 equiv acetylene, 2 ml H2O,
10 equiv Et3N, reaction time 6 h, yields were determined by GC analysis.
We found that the coupling reaction was highly dependent on
the nature of the base. Good yields were only obtained with
5–10 equiv of triethylamine (Table 1, entry 5). All the other bases
gave only little or no detectable conversion. We subsequently
investigated the influence of the catalyst concentration on sub-
strate conversion for different aryl iodides. Catalyst loadings of pal-
ladacycle 2 ranged from 0.01 to 1.0 mol % with 10 equiv of Et3N as
the base (Table 2).
In general, electron-rich iodophenols are challenging substrates,
under the conditions applied. Therefore screening was extended to
less deactivated substrates. For iodobenzene, excellent conversion
was obtained with catalyst loadings as low as 0.1 mol % (Table 2,
entry 1), while for the reaction of p-tolyl iodide with phenylacety-
lene near-to-quantitative conversion was reached at a catalyst
loading of 0.25 mol % (Table 2, entry 3). Copper as a co-catalyst
had no beneficial influence on the catalyst performance in water.
In the presence of catalytic (1.0 mol %) amounts of CuI, Glaser-cou-
pling products were formed (21% GC yield), while for stoichiome-
tric CuI addition (1.0 equiv) dialkynes were the only products
detected (Table 1, entry 6). In order to optimize the reaction times,
product formation was monitored for the conversion of phenyl io-
dide and phenylacetylene (Fig. 1). A yield of 80% was reached after
25 min, while after 1 h a yield of 91% was obtained reaching near
quantitative yield after 3 h.
Figure 1. Yield of 1,2-diphenylacetylene as a function of time using 0.5 mol % of
pre-catalyst 2 in H2O at 40 °C (average of three runs, error bars indicate standard
deviation).
under Sonogashira conditions require exclusion of oxygen. Hence,
the catalytic tests were performed under an inert atmosphere. In
total sixteen aryl halides (iodides and bromides) and four different
acetylenes were tested. Overall 19 different Sonogashira coupling
products covering a variety of substitution patterns and function-
alities were produced in good to excellent yields.24 The protocol
is well suited for the reaction of electron-rich and electron-defi-
cient aryl halides with aromatic acetylenes. Tolerated functional-
ities include aldehydes, halides, trifluoromethyl, nitro and
hydroxy groups. Sterically demanding substrates such as o-phe-
nyliodobenzene (Table 3, entry 5) also underwent cross-coupling.
Notably, bromo arenes were also accepted as substrates, delivering
moderate yields when 1 mol % of catalyst was used (Table 3, en-
tries 1, 2, and 6). The reduced reactivity of aryl bromides allowed
the selective coupling of p-bromophenylacetylene with iodo are-
nes. Following the previously published protocol for the Suzuki
coupling in water two Sonogashira products were isolated by sim-
ple filtration in good to excellent yields and high purity (Table 3,
entries 4 and 17). Isolation of four more products was straightfor-
ward using extraction with ethyl acetate and subsequent recrystal-
lization from hexanes. The general applicability of the simplified
isolation process was hampered by the formation of an oily prod-
uct phase in water. Presumably the large amount of triethylamine
required for catalytic activity dissolved in the organic product and
prevented crystallization of the solid from the aqueous phase. In
two cases, aryl iodides could not be converted in satisfying yields
(Table 3, entries 11 and 13), which may be attributed to the forma-
tion of a lipophilic phase in water resulting in phase-transfer
limitation of the reaction kinetics. Correspondingly, the yields
The scope of the optimized reaction conditions was explored for
a variety of substrates (Table 3). The new protocol underlines the
potential of palladacycle 2 as a catalyst for cross-coupling reac-
tions, since a range of substitution patterns and functional groups
was tolerated. Unlike for Suzuki coupling, reproducible results
Table 1
Base screen for the Sonogashira coupling of iodophenol and phenylacetylene in
watera
Entry
Base
Yield (%)
5.0 equiv
2.5 equiv
10.0 equiv
1
2
3
4
5
6
7
Na2CO3
Cs2CO3
NaOH
KOH
2
1
0
0
27
0
3
1
1
6
0
71
11
2
0
9
0
Et3N
81/58b/<1c
23
(iPr)2NEt
Na2CO3/NaOH (1.0 M)
a
Reagents and conditions: 1.0 equiv aryl halide, 1.0 equiv acetylene, 2 mL H2O
[2] = 0.5 mol %, reaction time 6 h, yields were determined by GC analysis.
b
1.0 mol % of CuI was added.
1.0 equiv of CuI was added.
c

A. N. Marziale et al. / Tetrahedron Letters 52 (2011) 6355–6358
6357
Table 3
for the reaction of iodophenol and m-chlorophenylacetylene, could
be increased from 42% to 95% (Table 3, entry 11).
Sonogashira cross-coupling productsa
In conclusion, we have developed a sustainable protocol for the
Sonogashira reaction in pure water at mild temperatures without
copper or other additives. Surprisingly, addition of copper favored
the formation of Glaser-coupling products over Sonogashira cross-
coupling. The scope of the protocol covers a variety of different
substrates and tolerates several functionalities. Notably, some of
the coupling products can be easily isolated in excellent purity
without tedious work-up by filtration or column chromatography.
Moreover it has been shown that limitations, which occur for some
substrates, can be overcome by the addition of dimethylsulfoxide
to the reaction mixture.
c
Entry
Productb
R0
Yield (GC-yield)/%
H2O, X = I
Various conditionse,f,g
R
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
98 (99)
82 (87)
75 (87)
94d (99)
81 (84)
94 (95)
91 (96)
83 (89)
84 (87)
93 (96)
36 (42)
79 (86)
78 (79)
82 (86)
86 (94)
90 (97)
88d (92)
84 (89)
89 (91)
(67)g
4-CH3
4-OH
4-NO2
2-Ph
2-Cl
(96)e/(48)g
(93)e
(99)e
(99)e
(34)g
4-Cl
3,5-(CF3)2
4-CH3
3-F
H
(95)e
9
4-C(O)H
4-C(O)H
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Br
4-Br
4-Br
4-Br
Acknowledgment
10
11
12
13
14
15
16
17
18
19
H
4-CH3
3-F
(95)e/(94)f
(93)f
We are grateful to KAUST (baseline funding J.E., graduate fel-
lowship for A.N.M.) for funding of this project.
(93)e/(96)f
2-Cl
2,4-F2
4-CH3
4-Cl
2-CH3
2-F
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.031.
a
Reagents and conditions: 1.0 equiv aryl iodide, 1.0 equiv. acetylene, 2 ml water,
[2] = 0.25 mol %, reaction time 4 h, argon atmosphere.
References and notes
b
R originates from the aryl halide, R0 from the acetylene substrate.
c
Isolation by extraction (ethyl acetate) and flash chromatography (hexanes/ethyl
1. (a) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: New York, 1998; (b) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-
Coupling Reactions, second ed; Weinheim: Wiley-VCH, 2004; (c) Beller, M.;
Bolm, C. Metals for Organic Synthesis, second ed; Weinheim: Wiley-VCH, 2004;
(d) Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840.
acetate mixtures).
d
Isolation by filtration.
50% DMSO added.
[2] = 1.0 mol %.
e
f
g
The corresponding aryl bromide was coupled using 1.0 mol % of 2.
2. Li, C.-J. Chem. Rev. 2005, 105, 3095.
3. (a) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 4324; (b)
DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. J. Org. Chem. 2004, 69, 7919; (c)
Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173; (d) Mio,
M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.;
Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199; (e) Bumagin, N. A.;
Sukhomlinova, L. I.; Luzikova, E. V.; Tolstaya, T. P.; Beletskaya, I. P. Tetrahedron
Lett. 1996, 37, 897.
Table 4
Solvent screen for the Sonogashira cross-couplinga
4. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; Wiley-VCH: New
York, 1997; (b) Grieco, A. Organic Synthesis in Water; Academic Press:
Dordrecht, The Netherlands, 1997; (c) Cornils, B.; Herrmann, W. A. Aqueous-
Phase Organometallic Catalysis; Wiley-VCH: Weinheim, 2004; (d) Shaughnessy,
K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9, 585.
5. (a) Marziale, A. N.; Faul, S. H.; Reiner, T.; Schneider, S.; Eppinger, J. Green Chem.
2010, 12, 35; (b) Marziale, A. N.; Jantke, D.; Faul, S. H.; Reiner, T.; Herdtweck, E.;
Eppinger, J. Green Chem. 2010, 13, 169.
6. (a) Horváth, I. T. Green Chem. 2008, 10, 1024; (b) Li, C.-J. Acc. Chem. Res. 2002, 35,
533; (c) Lipshutz, B. H.; Ghorai, S. Aldrichim. Acta 2008, 41, 59; (d) Alonso, F.;
Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64, 3047; (e) Sheldon, A. R. Green
Chem. 2005, 7, 267; (f) Liu, S.; Xiao, J. J. Mol. Catal. A: Chem. 2007, 270, 1.
7. (a) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874; (b) Negishi, E.; Anastasia,
L. Chem. Rev. 2003, 103, 1979.
8. Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929.
9. (a) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew. Chem., Int. Ed. 2001, 40,
603; (b) Toyota, M.; Komori, C.; Ihara, M. J. Org. Chem. 2000, 65, 7110.
10. (a) Suzuka, T.; Okada, Y.; Ooshiro, K.; Uozumi, Y. Tetrahedron 2010, 66, 1064;
(b) Suzuka, T.; Kimura, K.; Nagamine, T. Polymers 2011, 3, 621.
Rank
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
H2O/DMSO
H2O/toluene
H2O
H2O/MeCN
H2O/NMP
H2O/acetone
H2O/THF
H2O/DMF
94
85
81
79
77
74
72
60
47
29
H2O/1,4-dioxane
H2O/MeOH
a
Reagents and conditions: 1.0 equiv aryl halide, 1.0 equiv acetylene, 1 ml H2O,
1 ml organic solvent, 10 equiv Et3N, reaction time 6 h, argon atmosphere, yields
were determined by GC analysis. NMP = N-methylpyrrolidine.
11. Guan, J. T.; Weng, T. Q.; Guang-Ao, Y.; Liu, S. H. Tetrahedron Lett. 2007, 48, 7129.
12. Dawood, K. M.; Solodenko, W.; Kirschning, A. Arkivoc 2007, 104.
13. Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10, 3793.
14. (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290; (b) Soheili, A.;
Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5,
4191; (c) Gholap, A. R.; Venkatesan, K.; Pasricha, R.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J. Org. Chem. 2005, 70, 4869; (d) Yi, C. Y.; Hua, R. M. J. Org.
Chem. 2006, 71, 2535; (e) Komáromi, A.; László, T.; Novák, Z. Tetrahedron Lett.
2008, 49, 7294; (f) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Hashemi, M.
Tetrahedron Lett. 2009, 50, 1557.
increased to nearly quantitative conversion for higher catalyst
loadings. Phase-transfer limitations can be overcome by the addi-
tion of organic co-solvents homogenizing the reaction mixture.
Therefore we tested the influence of organic co-solvents on the cat-
alytic activity of ten different 1:1 water/solvent mixtures (Table 4).
Only for the addition of DMSO and toluene there was an increase
in the coupling yield (Table 4, entries 1 and 2) observed, while
yields were decreased significantly when acetone, THF, DMF, meth-
anol, and 1,4-dioxane were used as co-solvents. Using 0.25 mol % of
pre-catalyst 2, addition of 50% DMSO generally increased the yields
for Sonogashira coupling products that could not already be ob-
tained in very good yields from pure water. For example, the yield
15. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.
16. (a) Fleckenstein, C. A.; Plenio, H. Green Chem. 2008, 10, 563; (b) Fleckenstein, C.
A.; Plenio, H. Chem. Eur. J. 2007, 13, 2701; (c) Roy, S.; Plenio, H. Adv. Synth. Catal.
2010, 352, 1014.
17. (a) Rollet, P.; Kleist, W.; Dufaud, V.; Djakovitch, L. J. Mol. Catal. A: Chem. 2005,
241, 39; (b) Rollet, P.; Djakovitch, L. Adv. Synth. Catal. 2004, 346, 1782; (c)
Rollet, P.; Djakovitch, L. Tetrahedron Lett. 2004, 45, 1367; (d) Gruber, M.;
Chouzier, S.; Koehler, K.; Djakovitch, L. Appl. Catal., A 2004, 265, 161.

6358
A. N. Marziale et al. / Tetrahedron Letters 52 (2011) 6355–6358
18. Djakovitch, L.; Köhler, K.; de Vries, J. G. In Nanoparticles and Catalysis; Astruc, D.,
Ed.; Wiley-VCH: Weinheim, 2008; pp 303–348.
M. B. Dalton Trans. 2003, 4164; (e) Bedford, R. B.; Blake, M. E. Adv. Synth. Catal.
2003, 345, 1107.
19. (a) Islam, S. M.; Mondal, P.; Singha Roy, A.; Mondal, S.; Hossain, D.
Tetrahedron Lett. 2010, 51, 2067; (b) He, Y.; Cai, C. J. Organomet. Chem. 2011,
696, 2689; (c) Kim, J.-H.; Lee, D.-H.; Jun, B.-H.; Lee, Y.-S. Tetrahedron Lett.
2007, 48, 7079.
20. (a) Jin, M.-J.; Lee, D.-H. Angew. Chem., Int. Ed. 2010, 49, 1119; (b) Lamblin, M.;
Nassar-Hardy, L.; Hierso, J.-C.; Fouquet, E.; Felpin, F.-X. Adv. Synth. Catal. 2010,
352, 33; (c) Banerjee, S.; Khatri, H.; Balasanthiran, V.; Koodali, R. T.; Sereda, G.
Tetrahedron 2011, 67, 5717; (d) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
21. Guan, J. T.; Weng, T. Q.; Yu, G.-A.; Liu, S. H. Tetrahedron Lett. 2007, 48, 7129–
7133.
23. Ogo, S.; Takebe, Y.; Uehara, K.; Yamazaki, T.; Nakai, H.; Watanabe, Y.;
Fukuzumi, S. Organometallics 2006, 25, 331.
24. Typical procedure: 0.01 ml of a catalyst stock solution (0.05 mol Lꢀ1) containing
palladacycle 2 (20.0 mg, 2.35 mmol) in 0.47 ml of CH2Cl2 was placed in a
Schlenk tube. The solvent was removed in vacuo and 0.2 mmol (1.0 equiv) of
the appropriate aryl halide, 0.273 ml (2.0 mmol, 10.0 equiv) Et3N, and 2 ml
deoxygenated H2O were added. The mixture was stirred vigorously for 15 min
at 40 °C. Subsequently, 0.2 mmol (1.0 equiv) of the respective aryl alkyne was
added. The reaction mixture was stirred for 4 h at 40 °C. Subsequently, 10% HCl
(3 ml) and EtOAc (4 ml) were added. The layers were separated and the solvent
was removed in vacuo. The residue was purified by flash chromatography
using either hexane or hexane/EtOAc 10:1 as eluent to yield the pure product.
GC yields are referenced to mesitylene as the internal standard; for sample
preparation see Supplementary data.
22. (a) Bedford, R. B.; Welch, S. L. Chem. Commun. 2001, 129; (b) Bedford, R. B.;
Hazelwood (née Welch), S. L.; Limmert, M. E. Chem. Commun. 2002, 2610; (c)
Bedford, R. B.; Cazin, C. S. J.; Hazelwood (née Welch), S. L. Angew. Chem., Int. Ed.
2002, 41, 4120; (d) Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse,