Pd-tetrahydrosalan-type complexes as catalysts for sonogashira couplings in water: Efficient greening of the procedure

Article abstract of DOI:10.1002/cssc.201402147

New sulfonated tetrahydrosalen-type ligands and their water-soluble palladium(II) complexes have been synthesized. The palladium(II) complexes catalyze the Sonogashira coupling (23 examples) of various aryl halides (including chloroarenes) with terminal alkynes, with good to excellent conversions under mild conditions (80 °C, air, no Cu^I cocatalyst) in aqueous-organic mixtures and turnover frequencies of up to 2790 h ^-1. Under optimized reaction conditions to minimize environmental contamination, diphenylacetylenes can be isolated in 76-98 % yield. The aqueous catalyst solution can be recycled four times with decreasing activity; however, yields between 93 and 98 % can still be achieved with extended reaction times. Several water-insoluble products can be isolated in excellent yield by simple filtration and purification by washing with water; this method is used, for the first time, for this type of C - C coupling procedure.

Full text of DOI:10.1002/cssc.201402147

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DOI: 10.1002/cssc.201402147
Pd–Tetrahydrosalan-Type Complexes as Catalysts for
Sonogashira Couplings in Water: Efficient Greening of the
Procedure
Krisztina Voronova,*[a] Levente Homolya,[a] Antal Udvardy,[a] Attila C. Bꢀnyei,[a] and
Ferenc Joꢁ*[a, b]
New sulfonated tetrahydrosalen-type ligands and their water-
soluble palladium(II) complexes have been synthesized. The
palladium(II) complexes catalyze the Sonogashira coupling (23
examples) of various aryl halides (including chloroarenes) with
terminal alkynes, with good to excellent conversions under
mild conditions (808C, air, no CuI cocatalyst) in aqueous–organ-
ic mixtures and turnover frequencies of up to 2790 hÀ1. Under
optimized reaction conditions to minimize environmental con-
tamination, diphenylacetylenes can be isolated in 76–98%
yield. The aqueous catalyst solution can be recycled four times
with decreasing activity; however, yields between 93 and 98%
can still be achieved with extended reaction times. Several
water-insoluble products can be isolated in excellent yield by
simple filtration and purification by washing with water; this
method is used, for the first time, for this type of CÀC coupling
procedure.
Introduction
Cross-coupling reactions are of utmost importance in the
metal-catalyzed formation of carbon–carbon bonds. One of the
best methods for the formation of C(sp2)ÀC(sp) bonds is the
reaction of vinyl or aryl halides with alkynes.[1] The reaction has
been widely used for the synthesis of various complex organic
compounds, such as polymers,[2] liquid crystals,[3] compounds
of natural origin,[4] pharmaceuticals,[5] and many others.[1,6]
Originally, Sonogashira coupling was performed with relatively
high amounts of palladium(0)–tertiary phosphine catalysts and
with copper(I)-containing cocatalysts in the presence of base.[7]
Owing to the air sensitivity of the Pd0 catalyst and phosphine
ligands, the reaction had to be performed with the exclusion
of air; in addition, the copper(I)-based cocatalysts facilitated
the formation of unwanted butadiyne byproducts through
Glaser coupling.[8] In the last 30 years, many improvements
have been made in the reaction conditions: various new cata-
lysts have been introduced (some of them with less oxygen
sensitive N-donor ligands), copper-free variants of the reaction
have been developed, and various solvents have also been ap-
plied.[1,9]
The use of water is becoming more and more pronounced
in synthesis due to the favorable green properties of this sol-
vent. Water is nontoxic and nonflammable; this makes it at-
tractive compared with common organic solvents. In addition,
water is suitable for the construction of biphasic systems,[10] in
which a water-soluble catalyst can be recovered by phase sep-
aration once the reaction ends. Water-soluble catalysts have
been used for diverse reactions, such as hydrogenation,[11] hy-
droformylation,[12] and various cross-coupling reactions.[13] It is
important to mention that, despite the reactions being run in
water, in many cases, the products are isolated by extraction
with organic solvents, so the overall process cannot be regard-
ed as environmentally friendly. To overcome this deficiency, in
several new processes, the isolation of the products is ach-
ieved by filtration or decantation.[14]
[a] K. Voronova,+ L. Homolya, Dr. A. Udvardy, Dr. A. C. Bꢀnyei, Prof. F. Joꢁ
Department of Physical Chemistry
In aqueous organometallic catalysis the most widely used
catalysts are metal complexes of tertiary phosphines and N-
heterocyclic carbenes, although N- and/or O-donor ligands
may also play a crucial role. Less attention has been devoted
to the study of complexes with multidentate N,O-donor li-
gands, which includes the various N,N’-bis(salicylidene)ethyle-
nediamine (salen) ligands.
Complexes of salen[15] were mainly investigated in nonaqu-
eous solutions for catalysis of reactions such as oxidation,[16]
epoxidation,[17] opening of epoxide rings,[18] and hydrogena-
tion.[19] In aqueous solutions, salen complexes serve as catalysts
for oxidation[20] and coupling reactions,[21] but there are also
University of Debrecen, Egyetem tꢀr 1
H-4032 Debrecen (Hungary)
E-mail: voronova.krisztina@science.unideb.hu
[b] Prof. F. Joꢁ
MTA-DE Homogeneous Catalysis and
Reaction Mechanisms Research Group
P.O.B. 7, H-4010 Debrecen, (Hungary)
E-mail: joo.ferenc@science.unideb.hu
[+] Current address:
Department of Chemistry, University of the Pacific
3601 Pacific Avenue, Stockton, CA 95211 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201402147.
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examples for catalysis of kinetic resolution[22] and N-aryla-
tion.[23]
Herein, we report on the synthesis of new sulfonated tetra-
hydrosalen-type ligands (BuHSS (2), CyHSS (3); Scheme 1) ob-
tained by direct sulfonation of the corresponding tetrahydrosa-
lens. Palladium(II) complexes of these ligands (4–6) were then
used for the catalysis of Sonogashira coupling of aryl halides
with alkynes. With these new catalysts, the abovementioned
coupling reactions can be performed with high efficiency in
water and in the presence of air without a copper-based coca-
talyst and, in many cases, product isolation can be achieved by
simple filtration, which avoids the use of organic solvents. In
such a way, this carbon–carbon cross-coupling process largely
meets the requirements of green and sustainable chemistry.
In aqueous solutions, salen undergoes hydrolysis,[24] especial-
ly at higher temperatures. This is a clear disadvantage in catal-
ysis. The hydrogenation of salen yields tetrahydrosalen or salan
with much higher stability in aqueous systems. Complexes of
salan with palladium, chromium, aluminum, zirconium, hafni-
um, titanium, iron, and niobium have already been used as cat-
alysts of reactions such as oxidation[25] and polymerization.[26]
The solubility of salan and its complexes in water can be in-
creased by attaching sulfonate or phosphonate substituents to
the aromatic rings of the ligand.[24a,b,27]
Although there are several reports in the literature on aque-
ous–biphasic Sonogashira couplings,[28] the number of PdII cat-
alysts with N- or N,O-donor ligands is small. A relevant exam- Results and Discussion
ple is the PdII–salen-type complex containing triphenylphos-
Synthesis and characterization of sulfosalan-type ligands
phonium substituents used by Bakherad and co-workers.[21e]
This complex was an active catalyst in the reaction of aryl io-
dides and terminal alkynes under aerobic conditions in water
at 608C in the presence of sodium lauryl sulfate surfactant and
Cs2CO3. Relatively high catalyst loadings ([S]/[C]=[100]/[1])
were required to perform the coupling in good to excellent
yields in reaction times of 6–12 h. No reactions of aryl bro-
mides and chlorides were reported and recycling of the cata-
lyst was not tested. In another study, Wang and co-workers ac-
complished Sonogashira coupling promoted by a PdII–2,2’-di-
pyridylamine complex in the absence of copper under mild
conditions (water, 258C, 6 h, N2 atmosphere).[29] Aryl iodides
and terminal alkynes were coupled with good to excellent
yields by using triethylamine (TEA) as a base (39 examples).
Previously, we reported an improved synthesis of sulfonated
salan (sulfosalan, HSS, Scheme 1, 1) and its palladium(II) com-
plex (4). The latter showed high catalytic activity and good
chemical stability in the redox isomerization of allylic alcohols
in aqueous systems.[24a] Encouraged by these results, we ex-
tended our investigations to the synthesis of more salan-type
ligands with different bridging units between the two nitrogen
atoms.
and their PdII complexes
The synthesis of sulfonated tetrahydrosalen[24a] (sulfosalan, HSS
(1); Scheme 1) was adapted for the synthesis of BuHSS (2) and
CyHSS (3). Briefly, salicylaldehyde was treated with the appro-
priate diamine (ethylenediamine, 1,4-butylenediamine, or 1,2-
cyclohexyldiamine), the product diimines were reduced with
NaBH4, and the resulting amines were sulfonated in a mixture
of concentrated H2SO4 and fuming sulfuric acid (oleum). After
dilution of the sulfonation mixture and adjusting the pH to 5,
the zwitterionic forms of the free acid ligands (1–3; Scheme 1)
were obtained. These are sparingly soluble in water, in contrast
to the sodium salts, which are soluble. Ligands 1–3 were char-
1
acterized by H and 13C NMR spectroscopy, ESI-TOF mass spec-
trometry, and elemental analysis.
X-ray quality crystals of 2 were obtained by layering 2-prop-
anol on a solution of 2 prepared with 0.1m KOH. An ORTEP
view of 2 is shown in Figure 1. The bond lengths and angles
are in good agreement with those of similar molecules found
in the literature.[24,30a] The asymmetric unit contains half of the
molecule and shows C2 symmetry (Figure S16 in the Support-
ing Information). In the unit cell, there are four potassium
counterions for the two phenolate and two sulfonate
groups. All K+ ions are coordinated to seven oxygen
atoms with KÀO distances in the range of 2.78–
3.11 ꢃ. A search of the Cambridge Structural Databa-
se[30b] (CSD, Version 5.35, Update November 2013) in-
dicated that the C2ÀO2 distance of 1.299(8) ꢃ repre-
sented a deprotonated phenolic OH group; the crys-
tal was obtained from a strongly basic solution. Bond
length data also prove single bonds between N1 and
neighboring carbon atoms.
In the crystal lattice, BuHSS is positioned in parallel
layers between the inorganic layers composed of K+
and H2O (Figure S17 in the Supporting Information).
The solid-state structure of 2 represents a polymer
held together with electrostatic and van der Waals in-
teractions as well as hydrogen bonds. Similar layered
structures are found in crystals of the nickel–sulfosa-
len complex determined by Rogez et al.,[24c] and in
other compounds containing sulfonate groups, for
Scheme 1. Sulfosalan-type ligands HSS (1), BuHSS (2), and CyHSS (3) along with their PdII
complexes [Pd(HSS)] (4), [Pd(BuHSS)] (5), and [Pd(CyHSS)] (6).
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Table 1. Optimization of the amount of catalyst in the Sonogashira cou-
pling of iodobenzene and phenylacetylene.[a]
Entry
[Substrate]/[Pd(BuHSS)] Ratio
Yield[b]
[%]
TOF[c]
[hÀ1
]
1
2
3
4
5
6
7
100
500
67
60
42
31
27
19
10
134
600
840
1240
1620
1520
1000
1000
2000
3000
4000
5000
Figure 1. An ORTEP view of 2 at the 50% probability level; the numbering
scheme is also shown. Water molecules and potassium counterions are omit-
ted for clarity. Symmetry code (vii): Àx+1/2, Ày+1/2, Àz+1/2. Selected
bond lengths [ꢃ] and angles [8]: C2ÀO2 1.299(8), C5ÀS5 1.749(7), S5ÀO51
1.459(5), S5ÀO52 1.452(5), S5ÀO53 1.459(5), C11ÀN1 1.472(7), C12ÀN1
1.484(3); C1-C11-N1 114.2(5), C11-N1-C12 109.3(5), N1-C12-C13 110.7(5).
[a] Reaction conditions: iodobenzene (5ꢄ10À4 mol), phenylacetylene
(7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol), water (3 mL), 30 min, 808C,
air. [b] Yield determined by GC on the basis of the amount of starting io-
dobenzene. [c] TOF: turnover frequency, which is defined as (mol of prod-
uct)ꢄ[(mol of catalyst)ꢄh]À1
.
instance, in the crystal of meta-monosulfonated triphenylphos-
phine (mtppms).[31]
but steady progress until completion in 4 h (Figure S13 in the
Supporting Information). Under the conditions outlined in
Table 1 entry 5, the reaction was also attempted in the pres-
ence of CuI with [Cu]/[Pd]=2. Strong inhibition by copper(I)
was observed and instead of 27% yield only 0.5% diphenyla-
cetylene was obtained together with 1% 1,4-diphenyl-1,3-bu-
tadiyne. Such an effect of CuI was observed previously by
Schoenebeck et al.[32a] and by Gelman and Buchwald.[32b]
In the 40–1208C range, the yield of diphenylacetylene
showed a strong temperature dependence (Table 2). With [S]/
[C]=3000, the maximum TOF of 2190 hÀ1 was observed at
1208C. It is gratifying that the reaction also proceeded—albeit
slowly—at low temperatures (e.g., at 408C, Table 2, entry 1);
this is an important condition in reactions of heat sensitive
compounds.
The palladium–sulfosalan complexes 4–6 were obtained by
stirring an aqueous solution of ammonium tetrachloropalla-
date and the respective sulfosalan sodium salt at 608C for
10 h. The yellow, air-stable products could be precipitated by
the addition of absolute ethanol. The complexes are soluble in
water and their aqueous solutions can be stored for months
with no sign of decomposition or loss of catalytic activity.
1
These compounds were characterized by elemental analysis, H
and 13C NMR spectroscopy, and ESI-MS spectrometry (see the
Experimental Section and Supporting Information). The ob-
tained data are in agreement with the structures shown in
Scheme 1.
Catalytic activity of water-soluble PdII–tetrahydrosalen com-
plexes in Sonogashira coupling
Table 2. Sonogashira coupling of iodobenzene and phenylacetylene as
a function of temperature.[a]
The new PdII–sulfosalan complexes were studied as catalysts
for biphasic Sonogashira coupling in the presence of a base.
The catalyst was dissolved in water and the organic phase was
comprised of the substrate, product, and water-immiscible
base (if any). Table S2 in the Supporting Information shows re-
sults for the effect of various inorganic and organic bases (en-
tries 1–14) on the yield of Sonogashira coupling of phenylace-
tylene and iodobenzene catalyzed by [Pd(BuHSS)]. The highest
conversion was achieved with TEA (74%; Table S2 in the Sup-
porting Information, entry 14) with an optimum TEA to sub-
strate (iodobenzene) ratio of four (Table S2 in the Supporting
Information, entries 14–19).
Entry
T [8C]
Yield [%][b]
1
2
3
4
5
6
40
40
60
80
100
120
14
58[c]
40
51
63
73
[a] Reaction conditions: [Pd(BuHSS)] (1.67ꢄ10À7 mol), iodobenzene (5ꢄ
10À4 mol; substrate), phenylacetylene (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ
10À3 mol), water (3 mL), 60 min, air. [b] Yield determined by GC on the
basis of the amount of starting iodobenzene. [c] 10 h.
As expected, decreasing the catalyst concentration in the
aqueous phase (i.e., increasing the [substrate]/[catalyst] ratio)
led to a decrease in the yield of diphenylacetylene (Table 1);
however, high turnover frequencies were obtained, even at [S]/
[C]=5000. The TOF changed according to a maximum curve
and the highest TOF observed was 1620 hÀ1 at [S]/[C]=3000
(Table 1, entry 5). Under these conditions, the reaction pro-
ceeded rapidly to about 70% conversion followed by lower
With the aim of increasing the solubility of the organic com-
ponents in water, the reaction was also run in the presence of
tetrahydrofuran (THF) as a cosolvent. Small amounts of THF
did not change the conversion; however, at water/THF=2/
1 a significant decrease in yield was observed (Figure S14 in
the Supporting Information).
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Table 3. Recycling of the catalyst in the Sonogashira coupling of iodo-
benzene and phenylacetylene.[a]
Table 5. Sonogashira coupling of aryl iodides and phenylacetylene.[a]
Entry
Product
Yield [%][b]
Entry
Number of cycles
Yield [%][b]
TON[c]
1
2
3
4
5
51
35
34
87
93
1
2
3
4
1
2
3
4
51
27
20
11
1530
2340
2940
3270
[a] Reaction conditions: [Pd(BuHSS)] (1.67ꢄ10À7 mol), iodobenzene (5ꢄ
10À4 mol), phenylacetylene (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol),
water (3 mL), 60 min, 808C, air. [b] Yield determined by GC on the basis
of the amount of starting iodobenzene. [c] TON: turnover number, de-
fined as (mol of product)/(mol of catalyst).
6
7
37
11
Recycling of the [Pd(BuHSS)]-containing aqueous phase in
biphasic Sonogashira coupling was also studied (Table 3). Al-
though the yields decreased steadily, the catalyst was still
active in the 4th cycle with a TOF=330 hÀ1. The drop in activi-
ty may be due to accumulation of inorganic halide ([Et3NH]I) in
the catalyst-containing aqueous phase, similar to the effect of
NaCl on [Pd(HSS)]-catalyzed redox isomerization of allylic alco-
hols.[24a]
8
42[c]
9
6
10
36[c]
11
44
[Pd(HSS)], [Pd(BuHSS)], and [Pd(CyHSS)] showed comparable
activities, of which [Pd(CyHSS)] is the most effective catalyst
(Table 4). Nevertheless, the TOF values did not differ signifi-
cantly (1380–1650 hÀ1).
[a] Reaction conditions: [Pd(BuHSS)] (1.67ꢄ10À7 mol), aryl iodide (5ꢄ
10À4 mol), phenylacetylene (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol),
water (3 mL), 60 min, 808C, air. [b] Yield determined by GC on the basis
of the amount of starting aryl iodide. [c] 6 h.
Table 4. Sonogashira coupling of iodobenzene and phenylacetylene with
PdII–tetrahydrosalen complexes.[a]
entry 11) also gave somewhat lower yields relative to the reac-
tion of iodobenzene. Under the applied mild conditions, even
2-iodopyridine could be coupled with phenylacetylene. In the
standard reaction time of 1 h the yield was only 6% (Table 5,
entry 9); however, after 6 h we obtained 36% yield of the cou-
pled product. Although for electronic reasons 2-iodopyridine is
expected to react faster than iodobenzene, this low reactivity
may reflect the effect of nitrogen coordination to palladium. A
similar decrease in conversion was also observed in the case of
pentafluoroiodobenzene (Table 5, entries 7 and 8).
Entry
Catalyst
Yield [%][b]
TOF [hÀ1
]
1
2
3
[Pd(HSS)]
[Pd(BuHSS)]
[Pd(CyHSS)]
46
51
55
1380
1530
1650
[a] Reaction conditions: catalyst (1.67ꢄ10À7 mol), iodobenzene (5ꢄ
10À4 mol), phenylacetylene (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol),
water (3 mL), 60 min, 808C, air. [b] Yield determined by GC on the basis
of the amount of starting iodobenzene.
Various terminal alkynes were coupled with iodobenzene
(Table 6). 4-Ethynyltoluene was less reactive than phenylacety-
lene, whereas 4-ethynylanisole and 1-bromoethynylbenzene
gave higher conversions under the same conditions (Table 6,
entry 3 versus entries 2 and 4). When iodobenzene was cou-
pled with the water-soluble propargyl alcohol, only 8% conver-
sion was obtained in 1 h; however, the catalyst was not pois-
oned and had not decomposed because in 6 h the conversion
attained 60% (Table 6, entries 7 and 8). Similarly, 4-ethynylpyri-
dine reacted slowly but steadily (3% conversion in 1 h versus
15% in 6 h; Table 6, entries 5 and 6).
The scope of the reaction was studied under optimized con-
ditions of the coupling of phenylacetylene and aryl iodides
with various substituents (Table 5). Aryl iodides with electron-
withdrawing substituents showed higher reactivity, for exam-
ple, 1-iodo-4-nitrobenzene and 1-bromo-4-iodobenzene gave
excellent yields (Table 5, entries 4 and 5) and in case of the
bromo derivative the TOF reached 2790 hÀ1. However, multiply
substituted iodobenzenes, such as 2,4-difluoroiodobenzene or
iodopentafluorobenzene, reacted less efficiently (Table 5, en-
tries 6 and 7). Iodoaromatics with electron-donating substitu-
ents, such as 4-iodoanisole (Table 5, entry 2) and iodoaniline
(Table 5, entry 3), showed diminished reactivity and the cou-
pling of 1-iodonaphtalene with phenylacetylene (Table 5,
Bromo- and chloroaryl derivatives are usually less reactive
than the corresponding iodo compounds. To determine the ac-
tivity of water-soluble PdII–salan complexes in a biphasic reac-
tion of such substrates, the coupling of various bromo- and
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sole and 1-bromonaphtalene showed lower reactivity than that
of bromobenzene (Table 7, entries 3 and 7 versus entry 1). To
achieve substantial conversion of chloroarenes, the amount of
catalyst had to be increased to 1 mol%; under such conditions
chlorobenzene was coupled with phenylacetylene with 22%
conversion, whereas 1,2-dichlorobenzene reacted with 69%
conversion (Table 7, entries 8 and 9).
Table 6. Sonogashira coupling of iodobenzene and terminal alkynes.[a]
Entry
Product
Yield [%][b]
1
2
3
4
5
51
60
25
59
3
The data obtained so far do not allow solid conclusions to
be drawn on the reaction mechanism with the new PdII–sulfo-
salan catalysts. The generally accepted mechanistic scheme[1c]
cannot be simply applied to this system. The substituent ef-
fects are in accordance with an initial oxidative addition of the
ArÀX substrate onto the catalyst. Because the initial form of
the catalysts involves PdII ion reduction to Pd0, which is likely
to be brought about by TEA or the alkyne substrates in reac-
tion mixtures when inorganic bases, such as KOH, are used.
Furthermore, in the coordinatively saturated catalysts, for ex-
ample, in [Pd(HSS)] at least one free coordination site has to
be created by decoordination of one of the phenolate oxygen
atoms. Our earlier DFT calculations on the reaction of [Pd(HSS)]
and H2 showed that such phenolate decoordination was feasi-
ble.[24a]
6
7
8
15[c]
8
60[c]
[a] Reaction conditions: [Pd(BuHSS)] (1.67ꢄ10À7 mol), iodobenzene (5ꢄ
10À4 mol), terminal alkyne (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol),
water (3 mL), 60 min, 808C, air. [b] Yield determined by GC on the basis
of the amount of starting iodobenzene. [c] 6 h.
It is also known that in several cases palladium-containing
catalysts degrade under the conditions of CÀC coupling reac-
tions, which are catalyzed by palladium nanoparticles (Pd NPs)
formed in such degradation processes. Furthermore, ripening
of Pd NPs may decrease their activity over longer reaction
times; this could rationalize the drop in catalyst activity in our
recycling experiments, too. During the reactions, we did not
observe the formation of precipitates or any other sign of par-
ticle formation, and there was no baseline increase in the UV/
Vis spectra of the catalyst-containing aqueous phase. To gain
more information on possible NP catalysis in our systems, we
performed a standard mercury test and performed dynamic
light scattering (DLS) measurements. When the standard reac-
tion of iodobenzene and phenylacetylene was performed in
the presence of mercury, conversion to diphenylacetylene
dropped from 51 to 36%. In contrast, DLS measurements on
the resulting aqueous and organic phases did not show the
presence of NPs. Nevertheless, based on these observations,
the formation of NPs and their participation in catalysis cannot
be excluded. Clearly, further work is needed to gain an insight
into the reaction mechanism of Sonogashira coupling with
PdII–sulfosalan catalysts, including the establishment of the
true nature of the catalyst (molecular vs. NP).
chloroarenes with phenylacetylene was studied with the [Pd-
(BuHSS)] catalyst. The reactions run smoothly at 808C and no
formation of any byproducts was observed. The results are
presented in Table 7. At a [S]/[C]=500 ratio, bromoarenes gave
good to excellent yields, although over a longer reaction time
(20 h). Dibromobenzenes were particularly reactive (Table 7, en-
tries 4–6) with conversions in the 85–89% range. 4-Bromoani-
Table 7. Sonogashira coupling of aryl halides and phenylacetylene.[a]
Entry
Aryl halide
Product
Yield [%][b]
1
2
3
64
66
46
4
86
5
6
89
85
Copper-free Sonogashira coupling in the presence of air
with no need for organic bases and solvents: Towards
a green procedure
7
16
8[c]
9[c]
22
69
In aqueous-phase organometallic catalysis, products are usually
isolated by extraction with organic solvents. This is a fast and
effective method in the case of small-scale reactions for deter-
mining reaction parameters (reaction kinetics, activity and se-
lectivity of the catalyst, etc.). However, to eliminate pollution of
the environment, it is of paramount importance to devise
methods for product isolation with no need to use toxic or-
[a] Reaction conditions: [Pd(BuHSS)] (1ꢄ10À6 mol), aryl halide (5ꢄ
10À4 mol), phenylacetylene (7.5ꢄ10À4 mol, 1.5 equiv), TEA (2ꢄ10À3 mol),
water (3 mL), 20 h, 808C, air. [b] Yield determined by GC on the basis of
the amount of starting aryl halide. [c] 5ꢄ10À6 mol [Pd(BuHSS)].
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ganic solvents. In the following, we describe a possible solu-
tion of this problem, which, to the best of our knowledge, has
not been applied before for Sonogashira couplings.
Table 8. Sonogashira coupling of aryl iodides and terminal alkynes in
water.[a]
Sonogashira coupling procedures characteristically involve
a 10–100% excess of the alkyne to achieve high reaction rates
together with full conversion of the aryl halide. Additionally,
when a CuI cocatalyst is used, the formation of butadiyne de-
rivatives often leads to substantial substrate loss. As a conse-
quence, the coupled product should be purified by chroma-
tography or other techniques.
Entry Product
Reaction time
[h][b]
Isolated yield
[%]
1
2
4
12
12
12
8
97
98
3
97
To overcome these difficulties, we first checked the effect of
using equimolar amounts of aryl halide and alkyne (Table S4 in
the Supporting Information). In the coupling of phenylacety-
lene with iodobenzene, the yield obtained in 1 h decreased
from 58 to 35% when the [alkyne]/[aryl halide] ratio decreased
from 2/1 to 1/1. Encouraged by the finding that no side prod-
ucts were formed, in the rest of the studies we used longer re-
action times (unoptimized) to achieve 100% conversion (as de-
termined by GC).
4
99
5
88
6
12
12
8
95
7
93
8
97
9
8
76[c]
90[c]
In most cases, the water-insoluble products precipitated
from the aqueous reaction mixture. Upon cooling, the prod-
ucts solidified and could be isolated by simple filtration. Thor-
ough washings with cold water yielded analytically pure prod-
10
12
11
12
12
12
88[c]
85[c]
1
ucts, the identity and purity of which were checked by H and
13C NMR spectroscopy and GC, respectively.
89[c]
96[c]
91[c]
Table 8 shows the yields of diphenylacetylene derivatives ob-
tained by the above method in Sonogashira couplings of sev-
eral aryl iodides and terminal alkynes with the [Pd(BuHSS)] cat-
alyst. This simple method, which led to full conversion of the
starting compounds (applied in 1/1 ratio) and did not require
extraction by an organic solvent for product isolation, led to
the products being isolated in excellent yields.
13
14
15
12
12
12
[a] Reaction conditions: [Pd(BuHSS)] (3.34ꢄ10À7 mol), aryl iodide (1ꢄ
10À3 mol), terminal alkyne (1ꢄ10À3 mol, 1 equiv), TEA (4ꢄ10À3 mol), water
(3 mL), 808C, air. [b] Reaction times are not optimized. [c] 1.00ꢄ10À6 mol
[Pd(BuHSS)].
Replacement of TEA by a less harmful base was also
deemed necessary for a greener procedure. For this purpose
KOH was chosen because, of the inorganic bases, it was the
most effective (Table S2 in the Supporting Information). How-
ever, in this case, the coupling reaction was not complete,
even when using a higher catalyst loading (1 mol%) and a reac-
tion time of 24 h. Additionally, the products stuck to the mag-
netic stirrer bar so strongly that they could only be removed
by dissolution in organic solvents. These difficulties could be
overcome simply by adding a surfactant, sodium dodecylsul-
fate (SDS), to the reaction mixture. The reactions became fast
enough to achieve 100% conversion (as determined by GC) in
24 h, and the products could be easily collected by filtration.
Table 9 shows the excellent yields of diphenylacetylene deriva-
tives obtained by this method. It should be added, however,
that thorough washings with cold water were needed to
remove the surfactant from the products.
Table 9. Sonogashira coupling of aryl iodides and terminal alkynes in
water.[a]
Entry
Product
Isolated yield [%][b]
1
2
3
4
5
6
90
98
91
93
95
93
The aqueous catalyst solutions obtained upon filtering out
the products were recycled for further reactions. To achieve
high conversions in the preparative-scale processes, we ap-
plied longer reaction times from run to run. In such a way, the
product was isolated in 93–98% yield, as exemplified by the
coupling of 1-iodo-4-nitrobenzene and phenylacetylene
(Table 10). Furthermore, the overall TON of the catalyst reached
8640 by the end of the 3rd cycle.
[a] Reaction conditions: [Pd(BuHSS)] (1ꢄ10À5 mol), aryl iodide (1ꢄ
10À3 mol), terminal alkyne (1ꢄ10À3 mol, 1 equiv), KOH (4ꢄ10À3 mol), SDS
(5ꢄ10À6 mol), water (3 mL), 24 h, 808C, air. [b] Reaction times are not op-
timized.
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Single-crystal X-ray structure determinations
Table 10. Recycling of the catalyst in the Sonogashira coupling of 1-
iodo-4-nitrobenzene and phenylacetylene.[a]
A colorless prism crystal (0.35 mmꢄ0.3 mmꢄ0.15 mm) of 2 was
mounted on top of a glass capillary by using epoxy glue. Diffrac-
tion intensity data collection was performed at 293(2) K on
a Bruker-Nonius MACH3 diffractometer equipped with a point de-
tector using graphite-monochromated MoKa radiation (l=
0.71073 ꢃ). The structure was solved by using the SIR-92 pro-
gram[33] and refined by a full-matrix least-squares method on F2,
with all non-hydrogen atoms refined with anisotropic thermal pa-
rameters by using the SHELXL-97 package.[34] Publication material
was prepared with the WINGX-suite.[35] Hydrogen atoms were lo-
cated geometrically and refined in the rigid mode, except water
hydrogen atoms, which could be found in the difference electron
density map. The distance between the hydrogen and oxygen
atoms had to be restrained in the final stage of the refinement of
the orientation of water molecules; hence the description of the
hydrogen-bond web is uncertain. The remaining electron density
peak represented an alternative position of one of the water hy-
drogen atoms and checkcif resulted in a few B and C level errors
because of the uncertain positioning of water protons.
Number of cycles
Reaction time [h][b]
Isolated yield [%]
TON [hÀ1
]
1
2
3
4
12
36
97
93
98
2910
5700
8640
[a] Reaction conditions: [Pd(BuHSS)] (3.34ꢄ10À7 mol), 1-iodo-4-nitroben-
zene (1ꢄ10À3 mol), phenylacetylene (1ꢄ10À3 mol, 1 equiv), TEA (4ꢄ
10À3 mol), water (3 mL), 808C, air. [b] Reaction times are not optimized.
Conclusions
We reported the synthesis of sulfonated tetrahydrosalen-type
ligands (sulfosalans, 1–3) and their palladium(II) complexes (4–
6). The syntheses are straightforward and yield stable ligands
and palladium(II) complexes that can be stored in aqueous so-
lution in the presence of air for months with no apparent sign
of decomposition. Complexes 4–6 showed excellent catalytic
activity in the Sonogashira coupling of aryl halides and termi-
nal alkynes in aqueous–organic biphasic systems. The hydro-
philic nature of 4–6 allowed us to run the reactions in biphasic
mixtures of water-insoluble reactants and aqueous solutions of
the catalysts; this allowed elimination of the use of organic sol-
vents.
Crystallographic and experimental details are summarized in
Table S1 in the Supporting Information. CCDC 989166 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Preparation of sulfosalans 1–3
Ligands were prepared as previously described for the preparation
of HSS.[24a] Accordingly, salen-type compounds were first obtained
through the condensation reaction of salicylaldehyde and the cor-
responding diamine; these were then reduced with NaBH4. The re-
sulting amines were sulfonated in fuming sulfuric acid. Adjusting
the acidity of the sulfonation mixtures to pH 5 led to the precipita-
tion of disulfonated salan-type ligands as the free acids in their
zwitterionic forms.
Based on these findings, we devised a simple preparative-
scale method for the synthesis of diphenylacetylene derivatives
by Sonogashira coupling. Because the reaction did not require
a copper(I) cocatalyst, no formation of butadiyne byproducts
was observed. With equimolar quantities of the aryl halide and
terminal alkyne, 100% conversion could be achieved with suffi-
ciently long reaction times (4–24 h) and did not leave unreact-
ed substrates (as opposed to reactions run in excess of alkyne).
Insolubility in water of the coupled products allowed their
simple isolation by filtration and purification by washing with
water. TEA could be replaced with KOH; however, in this case,
a micelle-forming agent, SDS, was required to speed up the re-
action and facilitate filtration of the products. Altogether, the
procedure befits several principles of green chemistry.
N,N’-Bis(salicylidene)-1,2-ethylenediamine: Yield: 10.12 g, 74%
(38 mmol); 1H NMR (360 MHz, [D6]DMSO, 258C): d=3.96 (s, 4H;
-CH2-CH2-), 6.90 (q, 3J(H,H)=7.9 Hz, 4H; CHarom), 7.35 (t, 3J(H,H)=
3
7.5 Hz, 2H; CHarom), 7.46 (d, J(H,H)=7.5 Hz, 2H; CHarom), 8.62 ppm
(s, 2H; CH=N).
N,N’-Bis(2-hydroxybenzyl)-1,2-ethylenediamine: Yield: 10.14 g,
98% (37 mmol); 1H NMR (360 MHz, [D6]DMSO, 258C): d=3.38 (s,
4H; -CH2-CH2-), 4.14 (s, 4H; CH2-NH), 6.87 (t, 3J(H,H)=7.0 Hz, 2H;
CHarom), 7.02 (d, 3J(H,H)=7.8 Hz, 2H; CHarom), 7.21 (t, 3J(H,H)=
7.6 Hz, 2H; CHarom), 7.46 ppm (d, 3J(H,H)=6.7 Hz, 2H; CHarom).
1
HSS (1): Yield: 135 mg, 97% (0.23 mmol); H NMR (360 MHz, D2O,
3
258C): d=2.67 (s, 4H; -CH2CH2-), 3.58 (s, 4H; CH2-NH), 6.52 (d, J=
8.6 Hz, 2H; CHarom), 7.36 (dd, 3J1 =8.6 Hz, 4J2 =2.1 Hz, 2H; CHarom),
3
7.41 ppm (d, J=2.1 Hz, 2H; CHarom); 13C NMR (90 MHz, D2O, 258C):
Experimental Section
d=168.7, 127.7, 126.8, 126.3, 126.2, 118.4, 48.7, 47.3 ppm; ESI-MS:
m/z calcd for C16H16Na2N2O8S2Pd: 431.059 [MÀ2Na+H]1À; found:
431.064 (for the correct isotope distribution, see Figure S2 in the
Supporting Information); elemental analysis calcd (%) for
C16H18Na2N2O8S2·2H2O (512.38): C 37.51, H 4.33, N 5.47, S 12.52;
found: C 37.55, H 4.68, N 5.48, S 13.23.
Materials and methods
All reagents were obtained commercially and used as received.
1
The H and 13C NMR spectra of samples were recorded on a Bruker
Avance 360 MHz spectrometer. Coupling constants are reported in
Hz. ESI mass spectra were recorded on a Bruker micrOTOFQ ESI-
TOF mass spectrometer. Reaction mixtures in the Sonogashira cou-
pling were analyzed by GC (Agilent 7890A gas chromatograph;
HP-5 30 mꢄ0.32 mmꢄ0.25 mm; FID; carrier gas nitrogen) and
1H NMR spectroscopy. Elemental analysis was performed on an Ele-
mentar varioMicro cube instrument (CHNS). DLS measurements
were made on a Malvern Zetasizer Nano ZS instrument.
N,N’-Bis(salicylidene)-1,4-butylenediamine: Yield: 13.90 g, 92%
(47 mmol); 1H NMR (360 MHz, [D6]DMSO, 258C): d=1.73 (s, 4H;
-CH2-CH2-), 3.66 (s, 4H; -N-CH2-), 6.90 (t, 3J(H,H)=8.3 Hz, 4H;
3
3
CHarom), 7.35 (t, J(H,H)=7.7 Hz, 2H; CHarom) 7.44 (d, J(H,H)=7.9 Hz,
2H; CHarom), 8.58 ppm (s, 2H; CH=N).
N,N’-Bis(2-hydroxybenzyl)-1,4-butylenediamine: Yield: 4.44 g,
87% (15 mmol); 1H NMR (360 MHz, [D6]DMSO, 258C): d=1.75 (s,
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4H; -CH2-CH2-), 2.92 (s, 4H; CH2-NH), 4.07 (s, 4H; CH2-NH), 6.86 (t,
3J(H,H)=7.5 Hz, 2H; CHarom), 7.00 (d, 3J(H,H)=8.1 Hz, 2H; CHarom),
7.26 (t, 3J(H,H)=7.9 Hz, 2H; CHarom), 7.43 ppm (d, 3J(H,H)=7.5 Hz,
2H; CHarom).
calcd (%) for C18H20Na2N2O8S2Pd·3H2O (662.84): C 32.62, H 3.95, N
4.23, S 9.68; found: C 32.78, H 3.80, N 4.18, S 9.76.
[Pd(CyHSS)] (6): Yield: 135 mg, 89% (0.21 mmol); 1H NMR
(360 MHz, D2O, 258C): d=1.12 (m, 4H; CHring), 1.65 (m, 2H; CHring),
2.39–2.71 (m, 4H; CHring), 3.63 (m, 2H; CH2-NH), 4.00 (m, 2H; CH2-
NH), 5.55 (m, 2H; CHarom), 6.83 (m, 2H; CHarom), 7.47 ppm (m, 4H;
CHarom); 13C NMR (90 MHz, D2O, 258C): d=157.6, 134.3, 128.1, 127.8,
115.9, 50.2, 45.7, 24.1 ppm; ESI-MS: m/z calcd for
C20H22Na2N2O8S2Pd: 293.990 [MÀ2Na]2À; found: 293.990 (for the
correct isotope distribution, see Figure S12 in the Supporting Infor-
mation); elemental analysis calcd (%) for C20H22Na2N2O8S2Pd·6H2O
(742.94): C 32.33, H 4.61, N 3.77, S 8.63; found: C 32.08, H 4.51, N
3.84, S 8.60.
BuHSS (2): Yield: 905 mg, 59% (1.97 mmol); 1H NMR (360 MHz,
D2O, 258C): d=1.49 (s, 4H; -CH2CH2-), 2.56 (s, 4H; -CH2-NH), 3.60 (s,
3
3
4H; CH2-NH), 6.55 (d, J=8.5 Hz, 2H; CHarom), 7.40 (dd, J1 =8.6 Hz,
4J2 =2.2 Hz, 2H; CHarom), 7.44 ppm (s, 2H; CHarom); 13C NMR (90 MHz,
D2O, 258C): d=168.8, 127.9, 126.3, 126.2, 118.4, 48.8, 48.0,
26.6 ppm; ESI-MS: m/z calcd for C18H22Na2N2O8S2: 459.090
[MÀ2Na+H]À; found: 459.087 (for the correct isotope distribution,
see Figure S6 in the Supporting Information); elemental analysis
calcd (%) for C18H24N2O8S2·H2O (478.46): C 45.19, H 5.48, N 5.86, S
13.40; found: C 45.46, H 5.33, N 6.17, S 13.39.
N,N’-Bis(salicylidene)-1,2-cyclohexanediamine: Yield: 15.48 g,
94% (48 mmol); H NMR (360 MHz, [D6]DMSO, 258C): d=1.48–1.93
(m, 10H; CHring), 6.87 (m, 4H; CHarom), 7.36 (m, 4H; CHarom), 8.50 (s,
1H; CH=N), 8.59 ppm (s, 1H; CH=N).
1
General procedure for the Sonogashira cross-coupling reac-
tion
The coupling reactions were performed under air in a 25 mL flask
equipped with a rubber septum. The reaction mixture was pre-
pared by mixing aryl halide (0.5 mmol), terminal alkyne (0.5–
0.75 mmol), base (0.5–3.0 mmol), a solution of the catalyst in water
(0.1ꢄ10À3–5.0ꢄ10À3 mmol Pd), and water (total volume of solvent
3 mL). The reaction vessel was immersed into a thermostated bath
(40–808C) and the mixture was stirred for 15–210 min. At room
temperature, the products were extracted with chloroform (1 mL),
dried over MgSO4, and subjected to gas chromatography. In the re-
cycling experiments, after extraction the catalyst-containing aque-
ous phase was used in the next run.
N,N’-Bis(2-hydroxybenzyl)-1,2-cyclohexanediamine: Yield: 5.12 g,
1
83% (15 mmol); H NMR (360 MHz, [D6]DMSO, 258C): d=1.23–1.76
3
(m, 10H; CHring), 4.08 (s, 4H; CH2-NH), 6.85 (t, J(H,H)=7.0 Hz, 2H;
CHarom), 7.01 (d, 3J(H,H)=6.6 Hz, 2H; CHarom), 7.22 (t, 3J(H,H)=
7.5 Hz, 2H; CHarom), 7.45 ppm (d, 3J(H,H)=7.0 Hz, 2H; CHarom).
CyHSS (3): Yield: 480 mg, 32% (0.99 mmol); 1H NMR (360 MHz,
D2O, 258C): d=1.06 (m, 4H; CHring), 1.50 (m, 2H; CHring), 1.83 (m,
3
2H; CHring), 2.28 (m, 2H; CHring), 3.55 (m, 4H; CH2-NH), 6.45 (d, J=
8.4 Hz, 2H; CHarom), 7.32 (d, 3J=8.7 Hz, 2H; CHarom), 7.37 ppm (s,
2H; CHarom); 13C NMR (90 MHz, D2O, 258C): d=169.1, 128.0, 127.1,
126.3, 126.1, 118.5, 118.4, 46.5 ppm; ESI-MS: m/z calcd for
C20H24Na2N2O8S2: 485.105 [MÀ2Na+H]À; found: 455.105 (for the
correct isotope distribution, see Figure S10 in the Supporting Infor-
mation); elemental analysis calcd (%) for C20H24Na2N2O8S2·5H2O
(620.54): C 38.71, H 5.52, N 4.51, S 10.34; found: C 38.88, H 5.59, N
4.43, S 10.66.
General procedure for the preparation of Sonogashira cou-
pling products without organic solvents
The coupling reactions were performed under air in a 25 mL flask
equipped with a rubber septum. The reaction mixture was pre-
pared by mixing aryl halide (1 mmol), terminal alkyne (1 mmol),
TEA or KOH (4 mmol), a solution of the catalyst in water (3.34ꢄ
10À4-–1.00ꢄ10À2 mmol Pd), and water (total volume of solvent
3 mL). When KOH was used as a base, SDS (5ꢄ10À3 mmol) was
also added. The reaction mixture was stirred for 4–24 h at 808C
then cooled to 48C before the product was filtered. After washing
the residue several times with deionized water, the analytically
pure product was obtained.
Preparation of Pd–sulfosalans 4–6
Complexes were prepared as previously described[24a] for the prep-
aration of [Pd(HSS)] by stirring equimolar amounts of (NH4)2[PdCl4]
and the corresponding ligand in an aqueous solution at pH 7.5 (ad-
justed with NaOH) for 10 h at 608C followed by precipitation with
ethanol.
1
[Pd(HSS)] (4): Yield: 135 mg, 97% (0.23 mmol); H NMR (360 MHz,
D2O, 258C): d=2.78 (d, 3J(H,H)=8.0 Hz, 2H; -CH2CH2-), 2.94 (d,
3
3J(H,H)=8.0 Hz, 2H; -CH2CH2-), 3.46 (d, J(H,H)=13.0 Hz, 2H; CH2-
Acknowledgements
NH), 4.15 (d, 3J(H,H)=13.2 Hz, 2H; CH2-NH), 6.81 (d, 3J(H,H)=
8.9 Hz, 2H; CHarom), 7.41 (s, 2H; CHarom), 7.45 ppm (d, 3J(H,H)=
9.2 Hz, 2H; CHarom); 13C NMR (90 MHz, D2O, 258C): d=165.1, 129.2,
128.1, 127.6, 123.6, 118.9, 53.2, 53.0 ppm; ESI-MS: m/z calcd for
C16H16Na2N2O8S2Pd: 266.970 [MÀ2Na]2À; found: 266.967 (for the
correct isotope distribution, see Figure S4 in the Supporting Infor-
mation); elemental analysis calcd (%) for C16H16Na2N2O8S2Pd·10H2O
(778.83): C 24.68, H 4.92, N 3.60, S 8.23; found: C 24.68, H 4.55, N
3.65, S 8.60.
The work was supported by the National Research Fund of Hun-
gary (OTKA 101372) and by the grant TꢂMOP-4.2.2A-11/1/KONV-
2012–0043 (ENVIKUT) co-financed by the European Union and
the European Social Fund. We are grateful to Dr. Attila Kiss for el-
emental analyses and to Dr. Lajos Nagy for ESI-MS measure-
ments.
[Pd(BuHSS)] (5): Yield: 140 mg, 96% (0.23 mmol); 1H NMR
(360 MHz, D2O, 258C): d=1.61 (m, 2H; -CH2CH2-), 2.27 (m, 4H; CH2-
Keywords: biphasic catalysis
·
cross-coupling
·
green
chemistry · homogeneous catalysis · palladium
2
NH), 2.45 (m, 2H; -CH2CH2-), 3.33 (d, J=13.6 Hz, 2H; CH2-NH), 4.13
2
3
(d, J=13.6 Hz, 2H; CH2-NH), 6.85 (d, J=8.3 Hz, 2H; CHarom), 7.44
(s, 2H; CHarom), 7.52 ppm (d, 3J=7.9 Hz, 2H; CHarom); 13C NMR
(90 MHz, D2O, 258C): d=164.6, 129.7, 128.0, 123.2, 118.4, 51.6, 51.5,
25.3 ppm; ESI-MS: m/z calcd for C18H20Na2N2O8S2Pd: 280.986
[MÀ2Na]2À; found: 280.984 (for the correct isotope distribution,
see Figure S8 in the Supporting Information); elemental analysis
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Received: March 6, 2014
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K. Voronova,* L. Homolya, A. Udvardy,
A. C. Bꢀnyei, F. Joꢁ*
&& – &&
Pd–Tetrahydrosalan-Type Complexes
as Catalysts for Sonogashira Couplings
in Water: Efficient Greening of the
Procedure
Exclusive partnership: Water-soluble
sulfonated tetrahydrosalen complexes
of palladium(II) efficiently catalyze the
Sonogashira coupling of aryl halides
and terminal alkynes in aqueous–organ-
ic biphasic mixtures under mild condi-
tions. Instead of extraction with organic
solvents, several of the products can be
isolated in high purity by simple filtra-
tion.
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 11
&11
&
ÞÞ
These are not the final page numbers!