Suzuki cross-coupling in aqueous media

Article abstract of DOI:10.1039/c5gc00794a

We report a simple and efficient procedure for the ligand-free as well as ligand-assisted Suzuki reaction in both pure water and aqueous media. The cross-coupling reactions proceed successfully using phenylboronic acid or potassium phenyltrifluoroborate as a nucleophilic coupling partner. The method can be effectively applied to both activated and deactivated aryl halides yielding quantitative conversions. The catalytic activity of couplings performed in pure water increases when utilizing supramolecular additives, but decreases under standard phase-transfer conditions. Finally, the palladium loading is reducible from 3.0 mol% to 0.4 mol% without any loss of conversion.

Full text of DOI:10.1039/c5gc00794a

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Journal Name
Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Suzuki Cross-Coupling in Aqueous Media
Ina Hoffmann, Bettina Blumenröder, Silvia Thumann, Sabine Dommer and Jürgen Schatz*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
We report a simple and efficient procedure for the ligand-free as well as ligand-assisted Suzuki reaction
in both pure water and aqueous media. The cross-coupling reactions proceed successfully using
phenylboronic acid or potassium phenyltrifluoroborate as nucleophilic coupling partner. The method can
be effectively applied to both activated and deactivated aryl halides yielding quantitative conversions.
The catalytic activity of couplings performed in pure water increases utilizing supramolecular additives,
however, decreases under standard phase-transfer conditions. Finally, the palladium loading is reducible
from 3.0 mol% to 0.4 mol% without the loss of conversion.
1
0
compounds, which efficiently stabilize palladium nanoparticles
Introduction
(NP), showed to be an effective and recoverable catalytic system
for the Suzuki cross-coupling reaction in aqueous media as well
as pure water.
Another possibility to improve the efficiency of the Suzuki
catalysis in water is the employment of hydrophilic ligands. The
3 4
modification of the pre-built catalyst Pd(PPh ) has been
The palladium-catalyzed Suzuki cross-coupling reaction between
organoboron compounds and organic halides is one of the most
powerful tools for forming carbon-carbon bonds, particularly for
the synthesis of biaryls.1,2 Owing to the fact that the aryl-aryl
structure motif is an important building block in organic
chemistry, the Suzuki reaction is widely applied in academic
research as well as in industrial synthesis of fine chemicals and
1
7,18
5
5
6
6
7
7
8
0
5
0
5
0
5
0
1
2
2
3
3
4
4
5
0
5
0
5
0
5
frequently studied. However, despite their large application
range, ligands including phosphines are often moisture and air
9
sensitive, toxic, and hard to separate from the organic products.
3
highly complex pharmaceuticals. The wide application of the
Alternatively, electron-rich N-heterocyclic carbenes (NHC) have
established as effective ligands for Suzuki cross-coupling
reaction results from the broad functional group tolerance, the
commercially availability and low toxicity of the organoborons,
mild reaction conditions, ease of handling of products and by-
products, and the possibility of using water as solvent or co-
19–25
reactions.
The catalytically active species is either formed in-
4
,26–31
situ from a NHC precursor, a palladium source, and a base
or pre-built palladium-NHC complexes
3
2,33
are utilized to
4
,5
solvent.
catalyze the cross-coupling reaction.Nevertheless, the interest in
The utilization of water as suitable reaction medium has received
increasing attention over the last decades. In comparison with
organic solvents that are commonly used in the palladium-
catalyzed Suzuki cross-coupling reaction, water is not
inflammable, cheap, non-toxic, and abundant.6,7 Besides,
inorganic reagents, which are often highly soluble in water, can
phosphine-free and moreover ligand-free cross-coupling reactions
10,11,34–37
has grown over the past decade.
Ligand-free catalysts
allow the reaction to occur in aqueous and aerobic media as well
as under mild reaction conditions. Indeed, successful
a
conversion of sterically hindered, or the less reactive aryl
chlorides, is still a problem that is frequently studied.
8
be easily separated from the organic product. Indeed, a clear
In general, boronic acids or esters are used in the Suzuki cross-
coupling reaction. However, tetra-coordinated organoborates
gained increased popularity due to their ready availability and
drawback of the aqueous catalysis is the disposal of contaminated
wastewater, which can in turn be decimated by the reduction of
the catalyst loading or the recycling of the catalyst. However, an
efficient Suzuki catalysis in aqueous media is often restricted due
to limited substrate solubility or the decreased stability of the
catalyst in water. Therefore, phase-transfer reagents are employed
to solubilize the non-polar substrates and increase their
concentration in the reaction medium. In order to enhance the
catalytic activity, additives like inverse phase-transfer catalysts
5
,38–42
ease of handling.
Especially organotrifluoroborates offer
substantial benefits. They are air and moisture stable and can be
5
,43
easily prepared and purified,
however the use as substrates in
Suzuki reactions is only marginally exploited.
Herein, we report our recent results including ligand-free Suzuki
cross-coupling reactions in aqueous media and within this context
the utilization of potassium phenyltrifluoroborate as alternative
coupling partner. The efficiency of the catalysis in pure water
should be improved by utilizing imidazolium salts as NHC ligand
precursors, phase-transfer catalysts, and sulfocalix[n]arenes as
both solubilizing and mass transfer agents. In addition,
optimization studies were carried out, containing pH fine tuning
(
PTC,
tetrabutylammonium bromide (TBAB), sodium dodecyl sulfate
SDS))have already been successfully utilized.9–12 Latter can also
serve as protective agents stabilizing colloidal palladium
e.g.,
calix[n]arenes)
or
surfactants
(e.g.,
(
1
3–16
suspensions.
In this context, water-soluble PEG-tagged
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and the reduction of the catalyst loading revealing the Suzuki
coupling to be successful reducing the palladium loading from
Table 1 Average conversions of ligand-free Suzuki cross-couplings of
phenylboronic acid with aryl halides 1-15 in different solvents
a
55
3
.0 mol% down to 0.4 mol%.
Results and Discussion
5
Ligand-free Suzuki Cross-Coupling Reactions
At the outset, the ligand-free catalytic system consisting of
palladium acetate and potassium carbonate was tested for its
scope and limitations. Therefore, the nucleophilic phenylboronic
acid as well as potassium phenyltrifluoroborate was coupled with
a variety of differently functionalized aryl halides, screening both
activated aryl halides containing electron-withdrawing
substituents and deactivated aryl halides containing electron-
donating substituents (cf. table 1 and 2). Aside from electronic
characteristics, the effect of steric hindrance and different halogen
substituents was investigated. The substrate screenings were
carried out under aerobic conditions in diverse solvents, which
were 1,4-dioxane, water, 1,4-dioxane/water (1:1), and
ethanol/water (1:1).
From the data compiled in table 1 and 2 one can deduce a couple
of general trends that are valid for different solvents as well as for
both organoboron nucleophiles. Firstly, the less expensive, but
unreactive chlorobenzene derivatives 5 and 12 did not show an
efficient Suzuki coupling under this reaction conditions. As
expected, the reaction rate of the cross-couplings with the
acetophenones bearing Cl 5, Br 1, or I 4 in para position
increased strongly in the sequence Cl << Br, I. A certain
distinction of the reactivity between 4’-bromo- and 4’-
iodoacetophenone could not be stated. Secondly, the activated
bromoacetophenones 1-3 as well as the deactivated
bromotoluenes 9-11 and bromoanisoles 13-15 showed
conversions dependent on the position of their substituents. The
higher the steric hindrance, the lower was the conversion. This
dependency was also mirrored in the low conversions of the
extremely sterically hindered 2-bromomesitylene 8. Thirdly, the
substrate screenings with phenylboronic acid as organoboron
coupling partner resulted in overall higher conversions compared
to the couplings with potassium phenyltrifluoroborate. Last, but
not least, the catalytic activity of the Suzuki cross-couplings
increased with respect to the reaction media in the sequence 1,4-
dioxane < water < 1,4-dioxane/water (1:1) < ethanol/water (1:1).
A closer look at the cross-coupling reactions with phenylboronic
acid reveals notable distinctions of the conversions between
different reaction media (Table 1). The couplings in pure water
resulted in good yields with respect to the activity and steric
demand of the aryl halides. It is notable that the result of the
conversion of 3-bromoanisole 14b (61%) falls completely out of
alignment being more sterically hindered, but yielding nearly
twice the conversion of 4-bromoanisole 13b (36%). The highest
conversions were received by the activated electrophiles 4’-
bromoacetophenone 1b (82%), 4-bromo-1-nitrobenzene 6b
b
Conversion [%]
Entry
ArX
c)
d)
a)
2
b) H O
Dioxane/H
2
O EtOH/H
2
O
Dioxane
1
1
2
2
3
3
4
4
5
0
5
0
5
0
5
0
5
0
(1:1)
(1:1)
c
1
2
63, 69
82
63
> 99 (97)
98
44
0
72
93 (78)
26 (29)
3
28
15
4
5
n.d.
0
78
3
> 99 (98)
99
9
3
6
7
79
83
85
> 99 (74)
> 99 (71)
89
n.d.
> 99
8
9
0
3
14
30
20
15
0
88
86
74
0
> 99
88
93
0
> 99 (78)
> 99 (95)
> 99 (87)
0
1
1
1
1
1
0
1
2
3
4
0
(83%), and ethyl 4-bromobenzoate 7b (85%) as well as the
deactivated aryl bromides 4- 9b and 3-bromotoluene 10b (88%
and 86%).
0
36
61
70
66
86 (98)
> 99 (60)
n.d.
2
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Table 2 Average conversions of ligand-free Suzuki cross-couplings of
potassium phenyltrifluoroborate with aryl halides 1-15 in different
solvents
1
5
n.d.
23
24
89 (83)
a
a
Reaction conditions: phenylboronic acid (1.50 mmol), aryl halide (1.00
mmol), Pd(OAc) (3.0 mol%), K CO (4.88 mmol), solvent (3 mL),
solvent/H O (4 mL), 15 h, 40 °C. Conversions determined by H-NMR,
2
2
3
1
2
b
average values of 3-5 single measurements, general deviation ≤ 7%.
Isolated yields in parentheses. With IMes×HCl (6.0 mol%).
c
5
The replacement of water with 1,4-dioxane led to overall lower
conversion values. Although the substrate solubility is decreased
in water, the base potassium carbonate is, compared to the
suspension in 1,4-dioxane, completely dissolved in water, which
might contribute to the rate enhancement. The addition of the
ligand IMes×HCl (Figure 1) to the coupling of 4’-
bromoacetophenone 1a increased the conversion from 63% to
Conversion [%]
Entry
ArX
c)
Dioxane/H
(1:1)
d)
O EtOH/H
(1:1)
a)
b) H
2
O
2
2
O
Dioxane
1
1
2
2
3
3
4
4
5
5
0
5
0
5
0
5
0
5
0
5
b
6
9%.
1
2
0, 10
82
19
78
48
96
47
The utilization of a solvent mixture of 1,4-dioxane/water at a
ratio of 1:1 resulted in high to excellent yields. The combination
of the beneficial effect of water and the dissolution of the
substrates by 1,4-dioxane increased the efficiency of the Suzuki
couplings. The cross-coupling reactions with 4’-bromo- 1c and
0
0
4
’-iodoacetophenone 4c, 4-bromo-1-nitrobenzene 6c, ethyl 4-
bromobenzoate 7c, and 4-bromotoluene 9c now all yielded
quantitative conversions (> 99%). Most noticeable is the doubling
of the conversion of 4-bromoanisole 13c increasing from 36% in
neat water to 70%. Besides, the conversions of the deactivated
bromoanisoles 13c-15c decreased with higher steric hindrance
from 70%, over 66% to 24%. The activated bromoacetophenones
3
18
19
13
4
5
n.d.
0
58
6
84
6
98
15
1
c-3c showed the same conversion dependence with regard to the
steric disturbance of their substituents ranging from > 99%, over
2%, to 15%. Even the highly sterically hindered 2-
7
bromomesitylene 8c displayed a conversion increase from 3% in
pure water to 14%. The bromotoluenes 9c-11c exhibited excellent
conversion values ranging from 88% to > 99%, however, not
maintaining the conversion dependency on the steric demand of
their substituents.
6
7
0
61
29
78
52
72
53
The application of the more environmentally benign solvent
mixture ethanol/water (1:1) revealed superior conversions for
most of the aryl halides. A special rate enhancement could be
assigned to the coupling of 3-bromoanisole 14d, now resulting in
a quantitative conversion (> 99%), and 2-bromoanisole 15d
showing a nearly fourfold increase in conversion from 23% in
pure water to 89%. Especially the high conversions of all three
deactivated bromotoluenes 9d-11d (> 99%) raised the question
n.d.
8
9
0
0
24
16
0
0
19
16
8
90
86
88
6
> 99
> 99
> 99
0
1
about the quality of the conversion values determined by H-
NMR spectroscopy. There is a chance that one compound, either
the substrate (aryl halide), or the product (biaryl), is preferentially
extracted from the ethanol/water mixture, i.e., the preferential
extraction of the biaryl would result in a higher conversion than it
really is. For this purpose, extraction blank tests for both
ethanol/water (1:1) and 1,4-dioxane/water (1:1) were carried out,
which ruled out such a possibility. Additionally, the isolated
yields (Table 1 in parentheses) were in good agreement with the
conversion values, which underline their quality.
In conclusion, one can state, that the catalytic activity of the
Suzuki cross-couplings with phenylboronic acid increases with
the examined reaction media in the order 1,4-dioxane < water <
1,4-dioxane/water (1:1) < ethanol/water (1:1).
1
1
1
1
0
1
2
3
0
0
0
0
11
69
73
68
86
14
n.d.
94
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(98%). Only the activated ethyl 4-bromobenzoate 7d broke ranks
1
5
n.d.
16
21
69
keeping the moderate conversion of 53% and thus being half the
conversion of the reaction with phenylboronic acid (> 99%).
Here, too, the catalytic activity increases with respect to the
reaction media in the order 1,4-dioxane << water < 1,4-
dioxane/water (1:1) < ethanol/water (1:1).
a
Reaction conditions: potassium phenyltrifluoroborate (1.50 mmol), aryl
halide (1.00 mmol), Pd(OAc) (3.0 mol%), K CO (4.88 mmol), solvent
3 mL), solvent/H O (4 mL), 15 h, 40 °C. Conversions determined by H-
60
2
2
3
1
(
2
NMR, average values of 3-5 single measurements, general deviation ≤
7%. With IMes×HCl (6.0 mol%).
b
Ligand-assisted Suzuki Cross-Coupling Reactions
5
The substrate screenings with potassium phenyltrifluoroborate as
nucleophile resulted in overall lower conversion values demoting
the advantages of using the boron-containing salt as alternative
The ligand-free Suzuki cross-couplings in pure water presented
1
coupling partner (Table 2). In addition, H-NMR experiments
1
1
2
2
3
3
4
4
5
5
0
5
0
5
0
5
0
5
0
5
showed that potassium phenyltrifluoroborate partly converted to
phenylboronic acid in aqueous solution anyway, thus, raising the
question which nucleophile ultimately reacts with the
electrophilic aryl halide in a Suzuki cross-coupling.
However, when choosing water as reaction medium, the best
conversion was achieved by the coupling with 4’-
bromoacetophenone 1b (82%). The conversions of the
bromoacetophenones further decreased in dependence of the
steric hindrance of the acetyl group from 19% 2b to 18% 3b. The
other activated aryl halides bearing substituents in para position
only gave low to modest conversions ranging from 29% (ethyl 4-
bromobenzoate 7b) to 58% (4’-iodoacetophenone 4b) and 61%
6
5
Fig. 1 Utilized imidazolium salts for the in situ preparation of N-
heterocyclic carbene ligands
(
4-bromo-1-nitrobenzene 6b). The bromotoluenes 9b-11b
before, resulted in moderate to high conversions, thus, leaving
room for improvement. One possibility to enhance the catalytic
activity is the utilization of imidazolium salts. These imidazolium
salts can be simply added to a Suzuki cross-coupling reaction in
displayed a decrease in conversion analog to the substitution
pattern ranging from 19% over 16% to 8%. Most notable is the
modest conversion of 69% resulting from the coupling with 3-
bromoanisole 14b, which is six times larger than the conversion
emerging from the reaction with the less sterically hindered 4-
bromoanisole 13b (11%).
The conduction of the substrate-screening in pure 1,4-dioxane
brought about no conversions at all emphasizing the higher
catalytic activity in water despite poorer solubility of the
substrates. The addition of the ligand IMes×HCl to the cross-
coupling reaction with 4’-bromoacetophenone 1a resulted in a
conversion increase from 0% to 10%.
The application of the solvent mixture 1,4-dioxane/water (1:1)
resulted in higher conversions than in pure water. Owing to the
former results that the substrate screening in neat 1,4-dioxane
provided absolutely no conversion, it seems that now 1,4-dioxane
facilitates to dissolve the substrates, but water significantly
contributes to an efficient cross-coupling, which is, amongst other
things, achieved by the completely dissolution of the base. The
most significant rate enhancements were achieved by the three
deactivated bromotoluenes 9c-11c gaining conversions in the
range of 86% to 90% as well as by 4-bromoanisole 13c yielding a
sevenfold higher conversion (73%). Besides, the activated aryl
halides 3’-bromoacetophenone 2c, 4’-iodoacetophenone 4c, 1-
bromo-4-nitrobenzene 6c, and ethyl 4-bromobenzoate 7c
underwent an increase in conversion by 24% on average.
The replacement of 1,4-dioxane with ethanol in the one-to-one
mixture with water led to overall superior conversions. The
deactivated bromotoluenes 9d-11d converted quantitatively and
even the also less electrophilic bromoanisoles 13d-15d yielded
conversions in the range of 69% to 94%. Furthermore, an almost
quantitative conversion was achieved by the reaction with
activated 4’-bromo- 1d (96%) and 4’-iodoacetophenone 4d
7
7
8
8
9
9
0
5
0
5
0
5
4
order to form N-heterocyclic carbene ligands in situ. The
generated palladium complex carries two substantial benefits. On
the one hand, NHC ligands are strong σ-donors, hence increasing
the electron density on the palladium and accelerating the
oxidative addition of the catalyst to the electrophilic aryl halide.
On the other hand, bulky NHC ligands destabilize the
transmetallated complex, therefore facilitating the reductive
elimination.
Within this study the imidazolium salts (Figure 1) 1,3-bis(2-
(diisopropylamino)ethyl)-1H-imidazol-3-ium
Pr) NEt) IM]Cl) and 1-dodecyl-3-methylimidazolium chloride
[C12MIM]Cl) were tested for their capability to improve the
chloride
([((i-
2
2
(
catalytic activity in pure water (Table 3). Latter does not only
serve as NHC ligand, but is also able to solubilize lipophilic
substrates, increase their concentration in water, and, thus,
enhance the cross-coupling reaction. The amphiphilic
imidazolium salt [C12MIM]Cl is structurally closely related to the
surfactant SDS, which has been frequently used to promote cross-
coupling reactions.
Initially, substrate screenings with both phenylboronic acid and
potassium phenyltrifluoroborate were carried out utilizing
[C12MIM]Cl as ligand precursor. Besides, the imidazolium salt
was applied in two different concentrations 0.6 mol% and 6.0
mol%, respectively. Table 3 shows three distinct trends only
including a few exceptions. Firstly, the ligand-assisted Suzuki
cross-couplings did result in higher conversions than the
couplings without a ligand precursor. The conversions increased
with the ligand concentration, i.e., the higher the concentration,
the higher the conversions. Secondly, the more cost-efficient aryl
1
00 chlorides 5 and 12 could still not be successfully converted.
4
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Green Chemistry
Table 3 Ligand-assisted Suzuki cross-couplings of both phenylboronic
acid and potassium phenyltrifluoroborate with aryl halides 1-15 and 1-
dodecyl-3-methylimidazolium chloride as ligand precursor in pure water
phenyltrifluoroborate remained lower compared to the couplings
with phenylboronic acid.
Taking a closer look at the substrate screenings with
a
1
2
2
3
3
5
0
5
0
5
phenylboronic acid, some conversions clearly stand out. Most
noticeable is the quantitative conversion of ethyl 4-
bromobenzoate 7b and 7c, 3-bromo- 10b and 10c, and 2-
bromotoluene 11b and 11c for both ligand concentrations. By
contrast, 4-bromotoluene 9c only converted quantitatively when
the ligand concentration was 6.0 mol%. The deactivated
bromoanisoles 13-15 showed a steadily rate enhancement with
b
higher [C MIM]Cl concentration revealing an overall increase of
Conversion [%]
a) Ligand-free b) [L] = 0.6 mol% c) [L] = 6.0 mol%
12
Entry
ArX
conversion by 25% on average. Although not converting
quantitatively, the most significant difference between the
conversion of the ligand-free Suzuki coupling and the reaction
with 6.0 mol% [C MIM]Cl was yielded by 3’-bromo- 2c (63%
8
2
93
97
1
2
(82)
(91)
(89)
1
2
→
96%) and 2’-bromoacetophenone 3c (28% → 79%).
6
3
85
96
The conversions of the cross-couplings with potassium
phenyltrifluoroborate were not similarly high, but for many of the
aryl bromides a larger rate enhancement could be realized
regarding the conversion difference between the reaction without
and with 6.0 mol% imidazolium salt. This difference was most
significant for the reaction of deactivated bromotoluenes (9-11)
causing an increase of 82% on average. A likewise high
enhancement was obtained by some activated aryl bromides, now
yielding conversions from 56% (2’-bromoacetophenone (3c)),
over 85% (ethyl 4-bromobenzoate (7c)), to 88% (3’-
bromoacetophenone (2c)). However, modest conversion
(19)
(39)
(88)
2
8
20
79
3
(18)
(17)
(56)
7
8
79
85
4
5
(58)
(62)
(78)
3
5
10
(6)
(7)
(6)
8
91
88
6
7
40 improvements were gained by deactivated 4-bromoanisole (13c)
(61)
(93)
(84)
(
(
11% → 41%) as well as activated 4’-iodoacetophenone (4c)
58% → 78%) and 4-bromo-1-nitrobenzene (6c) (61% → 84%),
8
5
> 99
(83)
> 99
(85)
(
29)
whereby latter yielded a higher conversion of 93% (6b) using
only 0.6 mol% ligand precursor.
The capability of the second imidazolium salt [((i-
3
7
14
8
9
4
5
(0)
(6)
(18)
Pr)
pure water was tested by the coupling of phenylboronic acid with
-bromotoluene as well as 4-bromoanisole (Table 3). This
imidazolium salt does not feature the same surfactant
2 2
NEt) IM]Cl (6.0 mol%) to enhance the catalytic activity in
c
8
8
83
> 99, > 99
(97)
(
19)
(45)
4
8
6
> 99
(40)
> 99
(93)
1
1
0
1
(
16)
50 characteristics, but definitively accelerates the reductive
elimination step regarding its bulky substituents. The conversions
of both Suzuki cross-couplings did not much differ from the
results of the reactions with [C12MIM]Cl of the same
concentration. 4-Bromotoluene 9c converted quantitatively and 4-
55 bromoanisole 13c gained a conversion increase from 36%
without ligand precursor to 59%.
7
4
> 99
(29)
> 99
(98)
(8)
0
0
0
(0)
c
1
1
1
2
3
4
(0)
(0)
d
3
6
54
62, 59 , 59
(41)
(
11)
(27)
In conclusion, it can be noted that the catalytic activity of the
Suzuki cross-coupling in neat water as environmentally benign
solvent, is efficiently promoted utilizing the imidazolium salts
6
1
66
87
(69)
(80)
(82)
6
0
2 2
[C12MIM]Cl as well as [((i-Pr) NEt) IM]Cl as ligand precursors.
2
3
23
46
1
5
Phase-Transfer Catalysis
(16)
(15)
(27)
We next examined the reaction behaviour of the Suzuki cross-
couplings with potassium phenyltrifluoroborate under phase-
transfer conditions in comparison to the afore studied reaction in
65 pure aqueous media (Table 4). For our test reactions we kept the
reaction protocol in principle, but added TBAB as standard PTC
and 18-crown-6 to capture the potassium counter ion, which
should facilitate the dissociation of the ion pair by shielding the
positive charge and therefore enhancing the catalytic activity.
a
Reaction conditions: phenylboronic acid (1.50 mmol), aryl halide (1.00
mmol), Pd(OAc) (3.0 mol%), [C12MIM]Cl (0.6, 6.0 mol%), K CO (4.88
mmol), H O (3 mL), 15 h, 40 °C. Conversions of couplings with
potassium phenyltrifluoroborate in parentheses. Conversion of coupling
5
2
2
3
b
2
c
d
with [((i-Pr)
volume of H
2
2
NEt) IM]Cl (6.0 mol%) as ligand precursor. Twofold
2
O (6 mL).
1
0
The same applied to the reaction with the highly sterically
hindered 2-bromomesitylene 8. Thirdly, the conversions of the
cross-couplings with the alternative organoboron potassium 70 We then screened the catalysis for different substrates and
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5

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Page 6 of 13
solvents. The results follow the same trends observed in the
Suzuki couplings without PTC, see table 4 right column. The
bromoacetophenones provided yields decreasing with higher
their cavities through non-covalent interactions.12 Additionally,
sulfocalix[n]arenes, especially when alkylated at the lower rim,
possess surface activities and can therefore serve as amphiphilic
steric influence from 79% 1 over 9% 4 to 6% 5. The activated 4- 35 mass transfer agents helping the lipophilic substrates through
5
bromo-1-nitrobenzene 6 revealed a conversion of 52%, whereas
the deactivated 4-bromotoluene 7 converted with a yield of 10%.
bulk water.
8
In a first experiment, octylated sulfocalix[8]arene (SC8C ) was
By changing the solvent from CH
decrease of conversion about 24%. Finally, we replaced the
2
Cl
2
to toluene 3 we observed a
added to the ligand-free Suzuki cross-couplings of 4-
bromotoluene with phenylboronic acid as well as potassium
borate with phenylboronic acid and tested the coupling with the 40 phenyltrifluoroborate in pure water (Table 5). The small
1
0
activated 4’-bromoacetophenone
conversion of only 44%.
2
in CH
2
Cl
2
,
yielding
a
concentration of 0.5 mol% of the macrocycle was sufficient to
promote both reactions. Phenylboronic acid and 4-
1
bromotoluene reacted quantitatively, whereas the coupling with
Table 4 Phase-transfer catalysis of ligand-free Suzuki cross-coupling
between potassium phenyltrifluoroborate and different aryl halides
a
b
Entry
ArX
Conversion [%]
Conversion [%]
82
c
d
1
, 2, 3
79, 44 , 55
45
Fig. 2 General structure of utilized sulfocalix[n]arenes
the organoborate 2 yielded an about fivefold higher conversion
compared to the reaction without additive (19% → 86%).
4
5
9
6
19
18
Table 5 Ligand-free Suzuki cross-couplings of both phenylboronic acid
and potassium phenyltrifluoroborate with 4-bromotoluene using SC8C
8
in
a
50
pure water
6
7
52
10
61
19
b
Entry
M
Conversion [%]
Conversion [%]
1
2
B(OH)
2
> 99
86
88
19
3
BF K
a
a
Reaction conditions: organoboron (1.50 mmol), 4-bromotoluene (1.00
mmol), Pd(OAc) (3.0 mol%), K CO (4.88 mmol), SC8C (0.5 mol%),
O (3 mL), 15 h, 40 °C. Without SC8C
Reaction conditions: potassium phenyltrifluoroborate (1.50 mmol), aryl
halide (1.00 mmol), Pd(OAc) (3.0 mol%), 18-crown-6 (10.0 mol%),
TBAB (10.0 mol%), K CO (4.88 mmol), H O/DCM (3 mL/3 mL), 15 h,
0 °C. Without PTC in pure water. With phenylboronic acid as
2
2
3
8
1
5
2
b
H
2
8
.
2
3
2
b
c
3
While the catalytic activity of the ligand-free cross-coupling
could be readily facilitated by SC8C , the question arised how the
combination of a supramolecular additive and a N-heterocyclic
carbene precursor would affect the catalysis. Therefore, different
sulfocalix[n]arenes were added to the ligand-assisted cross-
coupling reaction between phenylboronic acid and deactivated 4-
bromoanisole with [((i-Pr) NEt) IM]Cl serving as ligand
2 2
precursor. Table 6 shows that the conversion increased from left
to right for alkylated sulfocalix[n]arenes. More precisely, the
addition of SC4C 1b, SC4C 2b, and SC8C 4b, respectively,
3 8 8
resulted in overall higher conversion values as compared to the
conversion of 36% a of the ligand-free coupling without additive.
However, these results could be exceeded by the blank ligand-
assisted Suzuki reaction (59%) c. Finally, the combination of
supramolecular additive and ligand yielded the highest
d
organoboron, without 18-crown-6. With toluene as co-solvent.
5
6
6
5
0
5
8
All in all the conversions under phase-transfer conditions using
TBAB or 18-crown-6 are lower than similar reactions in water
without added phase-transfer catalysts. Therefore, in this specific
case this methodology is not ecologically justified taking the
additional waste stemming from the PTC into account.
2
0
Suzuki Cross-Coupling Reactions Using Supramolecular
Additives
2
5
Another possibility to facilitate the Suzuki cross-coupling
reaction in pure water is the utilization of sulfocalix[n]arenes
(
additives are effective solubilizing agents. Owing to the sulfonate
groups at the upper rim, they are water soluble themselves and
can solubilize the nonpolar substrates by encapsulating them in
SC[n] Figure 2). On the one hand, these supramolecular
3
0
conversions, whereas the utilization of SC4C
8
2d rendered the
6
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Page 7 of 13
Green Chemistry
largest rate enhancement (66%). Looking at the results of the
1
00
cross-couplings with SC4OH the opposite is the case, i.e. the
ligand-free coupling yielded a higher conversion (64%) 3b than
the ligand-assisted reaction (58%) 3d.
8
6
4
2
0
0
0
0
0
5
Table 6 Ligand-assisted Suzuki cross-couplings of phenylboronic acid
with 4-bromoanisole using sulfocalix[n]arenes as additive and 1,3-bis(2-
(
diisopropylamino)ethyl)-1H-imidazol-3-ium choride as ligand precursor
a
in pure water
0
5
10
pH
45
Fig. 3 Conversion dependence on the pH value
Table 7 Examination of the conversion dependence on the pH value using
Conversion [%]
the ligand-free Suzuki cross-coupling between potassium
Entry
SC[n]
b
c
d
a
a)
b)
c)
d)
phenyltrifluoroborate and 1-bromo-4-nitrobenzene in pure water
1
2
3
4
SC4C
SC4C
SC4OH
SC8C
3
8
56
58
64
52
61
66
58
3
6
59
8
n.d.
a
Reaction conditions: phenylboronic acid (1.50 mmol), 4-bromoanisole
(1.00 mmol), Pd(OAc) (3.0 mol%), K CO (4.88 mmol), SC8C (0.5
mol%), [((i-Pr) NEt) IM]Cl (6.0 mol%), H O (3 mL), 15 h, 40 °C.
1
0
2
2
3
8
b
2
2
2
b
c
d
Entry
K
2
CO
3
[mmol]
pH
Conversion [%]
Ligand-free coupling without SC[n]. Ligand-free coupling. Coupling
without SC[n].
-
3
1
2
3
4
5
2.90  10
0.36
4.88
12.1
21.7
4.5
6
32
67
6
10.5
11.6
12.3
12.9
These initial reactions showed that all sulfocalix[n]arenes were
able to promote the Suzuki cross-coupling, whereat the influence
of different additives was rather low. 0.5 mol% of the calixarenes
were sufficient to achieve an average conversion increase of 22%,
while the addition to a ligand-assisted Suzuki cross-coupling
reaction yielded a conversion increase of 26% on average.
1
5
0
a
50
Reaction conditions: potassium phenyltrifluoroborate (1.50 mmol), 4-
bromo1-nitrobenzene (1.00 mmol), Pd(OAc) (3.0 mol%), K CO , H O (3
mL), 15 h, 40 °C. pH value of K
2
2
3
2
b
2
CO
3
2 2
and Pd(OAc) dissolved in H O.
Reduction of the Catalyst Loading
2
0
Optimization Studies
If a specific synthetic transformation is more sustainable just by
using water as solvent is an ongoing issue, because the disposal
of contaminated wastewater has to be taken into consideration,
Conversion Dependence on pH Value
5
5
With the substrate screenings in hand, we were further interested
in optimizing the Suzuki reaction towards water as suitable
reaction medium. Various reaction parameters, including
6
but is often neglected in the discussion. A clear way to improve
the ecology of a catalysis is the reduction of the catalyst loading.
We studied this by means of the ligand-free Suzuki cross-
coupling reaction between phenylboronic acid and 4’-
bromoacetophenone in pure water (Table 8, Figure 4). The
2
2
3
3
4
5
0
5
0
variation of the base, have already been investigated. Owing to
the fact, that any base forms hydroxide ions in aqueous media, it
is rather interesting to know what effect the pH adjustment has on
the catalytic activity. Therefore, we chose the coupling of
potassium phenyltrifluoroborate with 4-bromo-1-nitrobenzene as
test reaction (Table 7). The reaction conditions were kept
constant except for the variation of K CO concentration. The
2 3
conversions resulted in a Gaussian-like progression (Figure 3)
with increasing pH and a maximum conversion of 67% at which
6
6
7
7
0
5
0
5
application of the initial Pd(OAc)
in an average conversion of 82% with a standard deviation of ±
%. At first, the catalyst loading was reduced from 3.0 mol% to
1.0 mol% 1-5 in 0.5 mol% steps. Owing to the fact that the
coupling with 1.0 mol% Pd(OAc) 5 yielded a greater conversion
85%) than the initial one, further reductions from 1.0 mol% to
2
loading of 3.0 mol% 1 resulted
1
2
(
the K
2 3
CO equivalents (4.88 mmol) 3 according to literature were
0
.5 mol% 5-10 were carried out in steps of 0.1 mol%. The
10 afforded a conversion of
4
4
-3
employed. For very small hydroxide concentrations (2.90  10
utilization of 0.5 mol% Pd(OAc)
2
mmol) 1, less activated organoboron was produced, which is
required during the transmetallation step, causing an extremely
low conversion of 6%. Using an amount of base near its maximal
solubility (21.7 mmol) 5, the reactants did not convert at all. A
possible reason for this is the inhibition of the formation of the
catalytically active zerovalent palladium species due to a ligand
exchange of acetate with hydroxide ions in the first place. In
summary, the optimal pH for an effective coupling is already
found by this study.
82%, thus the remaining reductions down to 0.05 mol% 11-19
were chosen in steps of 0.05 mol% to guarantee a thorough
investigation. The Suzuki cross-coupling reaction with an ultra-
low catalyst loading of 0.05 mol% 19 still resulted in a moderate
conversion of 74%. However, the last time the conversion was
greater or equal than the initial one, was achieved by using 0.4
2
mol% Pd(OAc) 12 (83%).
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Page 8 of 13
3
3
0
,05100
2,5
100
0
,1
90
2
9
8
0
0
8
7
6
5
0
0
0
0
0
,15
,2
,25
,3
1,5
1
0,25
2,5
0
70
60
0
0,9
0,8
0,7
50
0
0
,5
2
0
,35
0
,4
0,6
0
,45
0,5
1
1,5
Fig. 4 Spider chart of the reduction of the Pd(OAc)
2
loading using the
ligand-free Suzuki reaction between phenylboronic acid and 4’-
2
bromoacetophenone. Abscissa (circumference): Pd(OAc) loading
Fig. 5 Spider chart of the reduction of the Pd(OAc)
ligand-assisted Suzuki reaction between phenylboronic acid and 4’-
2
loading using the
5
[mol%]; ordinates: conversion [%]
Table 8 Reduction of the Pd(OAc)
reaction between phenylboronic acid and 4’-bromoacetophenone
2
loading using the ligand-free Suzuki
30
2
bromoacetophenone. Abscissa (circumference): Pd(OAc) loading
a
[mol%]; ordinates: conversion [%]
Table 9 Reduction of the Pd(OAc)
Suzuki reaction between phenylboronic acid and 4’-bromoacetophenone
2
loading using the ligand-assisted
a
Pd(OAc)
2
Pd(OAc)
[mol%]
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
2
Entry
Conv. [%]
Entry
Conv. [%]
[
mol%]
1
2
3
4
5
6
7
8
9
3.0
2.5
2.0
1.5
1.0
0.9
0.8
0.7
82 ± 1
84
81
83
85
80
82
85
83
11
12
13
14
15
16
17
18
19
82
83
75
79
79
73
78
69
74
Entry
Pd(OAc)
2
[mol%]
Conversion [%]
1
2
3
4
5
6
7
3.0
2.5
2.0
1.5
1.0
0.5
0.25
97
100
96
98
88
88
85
0.6
0.05
1
0
0.5
82
a
a
Reaction conditions: phenylboronic acid (1.50 mmol), 4’-
bromoacetophenone (1.00 mmol), Pd(OAc) (3.0 → 0.25 mol%),
12MIM]Cl (6.0 mol%), K CO (4.88 mmol), H O (3 mL), 15 h, 40 °C.
Reaction conditions: phenylboronic acid (1.50 mmol), 4’-
35
2
2 2 3
bromoacetophenone (1.00 mmol), Pd(OAc) (3.0 → 0.05 mol%), K CO
(4.88 mmol), H
[
C
2
3
2
1
0
2
O (3 mL), 15 h, 40 °C.
In conclusion, though working with extremely low catalyst
loadings, which also made high demands on the weighing scale,
the conversion values clearly displayed stability for both test
For comparison, the reduction of the Pd(OAc)
2
loading was also
carried out by means of the ligand-assisted Suzuki cross-coupling
between phenylboronic acid and 4’-bromoacetophenone in pure
water, whereat [C12MIM]Cl served as ligand precursor (Table 9,
Figure 5). The initial conversion of 97%, achieved by the
4
0
series. In comparison, for the ligand-free coupling the Pd(OAc)
2
loading could be reduced from 3.0 mol% to 0.4 mol% without the
loss of conversion, whereas for the ligand-assisted coupling the
limit was reached at a catalyst loading of 1.5 mol%. However, the
application of 0.5 mol% catalyst to the ligand-assisted Suzuki
coupling still resulted in a higher conversion (88%) than any
yielded by the ligand-free coupling, thus raising the question if a
greater catalyst loading plus an ancillary additive can be accepted
for a higher conversion.
1
2
2
5
0
5
2
application of 3.0 mol% Pd(OAc) 1 was already higher than the
conversion yielded by the ligand-free coupling (82 ± 1%). Here
also, the catalyst loading was at first reduced in 0.5 mol% steps
from 3.0 mol% to 0.5 mol% 1-6. However, this time the limit
when the conversion was for the last time higher than the initial
45
one, was already reached by applying 1.5 mol% Pd(OAc)
98%), which prompted us not to thoroughly examine further
reduction of the catalyst loading below 1.0 mol%. The utilization
of 1.0 mol% 5 and 0.5 mol% 6 Pd(OAc) resulted in a conversion
2
4
(
Conclusions
2
decrease of 10%. Finally, the Suzuki cross-coupling with 0.25
mol% catalyst 7 yielded a conversion of 85%.
50
In conclusion, we have shown that an efficient, broadly
applicable and moreover sustainable Suzuki catalysis in pure
water is possible with a palladium loading of 0.4 mol% and
without the need for a ligand or any organic co-solvent. Besides,
the easy to handle and air-stable potassium phenyltrifluoroborate
8
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Green Chemistry
can be effectively employed for the ligand-free Suzuki cross- 55 phenyltrifluoroborate (276 mg, 1.50 mmol), respectively, were
coupling in aqueous media, however, not realizing the
conversions achieved by analog couplings with phenylboronic
acid as nucleophile. The simple reaction protocol had been
successfully applicable to a range of activated as well as
added. The sample was stirred for 15 h at 40 °C. The reaction
mixture was cooled down to rt. After adding CDCl (2 × 600 µL),
3
the mixture was centrifuged. 600 µL of the organic phase were
1
5
0
5
extracted with a pasteur-pipette and used for H-NMR analysis.
2
deactivated aryl halides. The catalytic activity of the Suzuki 60 Ligand-assisted Suzuki Cross-Coupling in H O
cross-coupling in pure water was increased by applying NHC
ligand precursors and/or supramolecular sulfocalix[n]arenes as
iPTC. The modification of the reaction conditions by means of
standard phase transfer catalysis, respectively, has proven to be
not more effective than the reaction in pure aqueous solution.
Furthermore, pH adjustment experiments have outlined the
optimal base concentration. Finally, the palladium loading of a
ligand-free Suzuki-coupling in pure water was successfully
reduced more than sevenfold without the loss of conversion,
while the catalyst loading of the analog ligand-assisted reaction
was halved yielding nearly quantitative conversion.
K
2
CO
mmol, 3.00 mol%) and an imidazolium salt were dissolved in
O (3 mL) and stirred for 30 min at 40 °C. At first the aryl
3 2
(675 mg, 4.88 mmol, 4.9 eq), Pd(OAc) (6.74 mg, 0.03
H
2
halide (1.00 mmol) and subsequently phenylboronic acid (183
mg, 1.50 mmol) or potassium phenyltrifluoroborate (276 mg,
1
6
5
1
.50 mmol), respectively, were added. The sample was stirred for
15 h at 40 °C. The reaction mixture was cooled down to rt. After
adding CDCl (2 × 600 µL), the mixture was centrifuged. 600 µL
3
1
of the organic phase were extracted with a pasteur-pipette and
1
70
used for H-NMR analysis.
Ligand-assisted Suzuki Cross-Coupling in
Additives
H
2
O
with
K
2
CO
3 2
(675 mg, 4.88 mmol, 4.9 eq), Pd(OAc) (6.74 mg, 0.03
Acknowledgment
mmol, 3.00 mol%) and 1,3-bis(2-(diisopropylamino)ethyl)-1H-
Generous support of the “Solar Technologies go Hybrid” 75 imidazol-3-ium chloride (6.00 mol%, 60.0 mmol, 21.5 mg) were
2
0
(SolTech) initiative initiated by the Government of Bavaria is
gratefully acknowledged.
dissolved in H
sulfocalixa[n]arene (0.50 mol%, 5.00 µmol), then the aryl halide
1.00 mmol) and subsequently phenylboronic acid (183 mg, 1.50
2
O (3 mL) and stirred for 30 min at 40 °C. At first a
(
Experimental section
mmol) or potassium phenyltrifluoroborate (276 mg, 1.50 mmol),
respectively, were added. The sample was stirred for 15 h at 40
80
General
°C. The reaction mixture was cooled down to rt. After adding
Chemicals were purchased from commercial sources and used
without further purification. Potassium phenyltrifluoroborate,
CDCl (2 × 600 µL), the mixture was centrifuged. 600 µL of the
3
2
3
3
5
0
5
organic phase were extracted with a pasteur-pipette and used for
1
IMes×HCl,
[((i-Pr)
2
NEt)
2
IM]Cl,
and
alkylated
H-NMR analysis.
4
4
sulfocalix[n]arenes were prepared according to the published 85 Ligand-free Suzuki Cross-Coupling in Dioxane
K CO (675 mg, 4.88 mmol) and a 0.05 M solution of Pd(OAc)
2
4
3–47 1
procedure.
H-NMR spectra were recorded on a Bruker
2
3
(600 L, 3.00 mol%) in dioxane were dissolved in dioxane (2.40
Avance 400 operating at 400.13 MHz. Chemical shifts  are
indicated in parts per million (ppm) with respect to the internal
standard TMS ( = 0 ppm). The conversions of the Suzuki
mL) and stirred for 30 min at 40 °C. At first the aryl halide (1.00
mmol) and subsequently potassium phenyltrifluoroborate (276
couplings were determined by comparing the integrated proton 90 mg, 1.50 mmol) or phenylboronic acid (183 mg, 1.50 mmol),
respectively, were added. The sample was stirred for 15 h at 40
signals of product and starting material. Blind extraction tests of
biaryls and aryl halides verified the correlation of yields with
°
C. After cooling down to rt, an aliquot of 300 L was filled up
1
1
with CDCl to 600 L and used for H-NMR analysis.
Ligand-assisted Suzuki Cross-Coupling in Dioxane
product/starting material ratios. The H-NMR spectra were
calibrated on TMS in CDCl
3
4
4
3
.
95
K
2
CO
3
(675 mg, 4.88 mmol), the IMes×HCl ligand precursor
Suzuki Cross-Coupling Reaction Protocols
(6.00 mol%), and a 0.05 M solution of Pd(OAc)
2
(600 L, 3.00
Ligand-free Suzuki Cross-Coupling in H
CO (675 mg, 4.88 mmol) and Pd(OAc)
3.00 mol%) were dissolved in H
2
O
mol%) in dioxane were dissolved in dioxane (2.40 mL) and
stirred for 30 min at 100 °C. At first 4’-bromoacetophenone (0.20
g, 1.00 mmol) and subsequently potassium phenyltrifluoroborate
K
2
3
2
(6.73 mg, 0.03 mmol,
4
0
2
O (3 mL) and stirred for 30 min
at 40 °C. After cooling down to room temperature (rt), the aryl 100 (276 mg, 1.50 mmol) or phenylboronic acid (183 mg, 1.50
halide
phenyltrifluoroborate (276 mg, 1.50 mmol) or phenylboronic acid
183 mg, 1.50 mmol), respectively, were added. The sample was
stirred for 15 h at 40 °C. The reaction mixture was cooled down
to rt. After adding CDCl (2 × 600 L), the mixture was
(1.00
mmol)
and
subsequently
potassium
mmol), respectively, were added. The sample was stirred for 15 h
at 40 °C. After cooling down to rt, an aliquot of 300 L was filled
1
(
up with CDCl
3
to 600 L and used for H-NMR analysis.
Ligand-free Suzuki Cross-Coupling in Dioxane/H
CO (675 mg, 4.88 mmol) and a 0.05 M solution of Pd(OAc)
600 L, 3.00 mol%) in dioxane were dissolved in H O (1 mL)
2
O (1:1)
4
5
105
K
2
3
2
3
(
2
centrifuged. 600 L of the organic phase were extracted with a
1
and stirred for 10 min at 40 °C. At first the aryl halide (1.00
mmol) and subsequently potassium phenyltrifluoroborate (276
mg, 1.50 mmol) or phenylboronic acid (183 mg, 1.50 mmol),
pasteur-pipette and used for H-NMR analysis.
Ligand-free Suzuki Cross-Coupling in H
CO (675 mg, 4.88 mmol, 4.9 eq) and Pd(OAc)
.03 mmol, 3.00 mol%) were dissolved in H
for 30 min at 40 °C. At first, a sulfocalixa[n]arene (0.50 mol%,
.00 µmol), then the aryl halide (1.00 mmol) and subsequently
2
O with Additives
5
0
K
2
3
2
(6.74 mg,
0
2
O (3 mL) and stirred 110 respectively, were added. After another addition of H
and dioxane (1.40 mL), the sample was stirred for 15 h at 40 °C.
The reaction mixture was cooled down to rt. After adding CDCl
(2 × 600 L), the mixture was centrifuged. 600 L of the organic
2
O (1 mL)
5
3
phenylboronic acid (183 mg, 1.50 mmol) or potassium
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Page 10 of 13
1
phase were extracted with a pasteur-pipette and used for H-NMR 60 Elution with Cyclohexane/EtOAc (9:1) afforded 98% of a
4
8
1
analysis.
colourless solid; mp 119-120 °C (Lit.: 116-117 °C); H-NMR
Ligand-free Suzuki Cross-Coupling in Ethanol/H
2
O (1:1)
(400.13 MHz, CDCl , 298 K):  = 8.03 (d, J = 8.7 Hz, 2H), 7.68
3
K
2
CO
3
(675 mg, 4.88 mmol) and Pd(OAc)
2
(6.73 mg, 0.03 mmol,
(
d, J = 8.5 Hz, 2H), 7.63 (d, J = 6.9 Hz, 2H), 7.47 (t, J = 7.3 Hz,
5
3.00 mol%) were dissolved in H
2
O (2 mL) and stirred for 30 min
13
2
H), 7.40 (t, J = 7.3 Hz, 1H), 2.63 (s, 3H) ppm; C-NMR (100.62
at 40 °C. At first ethanol (2 mL), then the aryl halide (1.00
mmol) and subsequently potassium phenyltrifluoroborate (276
mg, 1.50 mmol) or phenylboronic acid (183 mg, 1.50 mmol),
respectively, were added. The sample was stirred for 15 h at 40
°C. The reaction mixture was cooled down to rt. After adding
65
3
MHz, CDCl , 298 K):  = 197.94, 145.97, 140.07, 136.05,
129.15, 129.11, 128.43, 127.47, 127.42, 26.86 ppm.
4-Nitrobiphenyl (6c)
Elution with Cyclohexane/EtOAc (4:1) afforded 74% of a light
4
9
1
1
0
brown solid; mp 108-109 °C (Lit.: 114-115 °C); H-NMR
, 298 K):  = 8.31 (d, J = 8.9 Hz, 2H), 7.74
CDCl
3
(2 × 600 L), the mixture was centrifuged. 600 L of the 70 (400.13 MHz, CDCl
3
organic phase were extracted with a pasteur-pipette and used for
H-NMR analysis.
(d, J = 8.9 Hz, 2H), 7.63 (d, J = 6.9 Hz, 2H), 7.50 (t, J = 7.2 Hz,
2H), 7.43 (t, J = 7.4 Hz, 1H) ppm; C-NMR (100.62 MHz,
1
13
PTC; General Procedure
CDCl , 298 K):  = 147.79, 147.25, 138.92, 129.33, 129.10,
3
1
5
K
2
CO
3
(675 mg, 4.88 mmol) and Pd(OAc)
2
(6.73 mg, 0.03 mmol,
1
27.96, 127.55, 124.27 ppm.
3
.00 mol%) were dissolved in H
2
O (1 mL) and an organic solvent 75 Ethyl biphenyl 4-carboxylate (7c)
(
(
(
2 mL) and stirred for 15 min at 40 °C. At first, the aryl halide
1.00 mmol) and subsequently potassium phenyltrifluoroborate
276 mg, 1.50 mmol) or phenylboronic acid (183 mg, 1.50
Elution with Cyclohexane/EtOAc (9:1) afforded 71% of a white
5
0
1
solid; mp 49-50 °C (Lit.: 48-49 °C); H-NMR (400.13 MHz,
CDCl , 298 K):  = 8.11 (d, J = 8.5 Hz, 2H), 7.67-7.59 (m, 4H),
7.46 (t, J = 7.3 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 4.40 (q, J = 7.1
3
2
0
mmol), respectively, and the phase-transfer catalyst (0.10 mmol,
0.0 mol%) were added. After another addition of H O (2 mL) 80 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H) ppm; C-NMR (100.62 MHz,
and the organic solvent (1 mL), the sample was stirred for 15 h at CDCl , 298 K):  = 166.70, 145.71, 140.25, 130.25, 129.45,
0 °C. The reaction mixture was cooled down to rt. After adding
CDCl (2 × 600 L), the mixture was centrifuged. 600 L of the
1
3
1
2
3
3
129.10, 128.29, 127.46, 127.19, 61.15, 14.55 ppm.
2,4,6-Trimethylbiphenyl (8d)
Elution with Cyclohexane/EtOAc (98:2) and Kugelrohr
3
2
5
organic phase were extracted with a pasteur-pipette and used for
1
H-NMR analysis.
85 distillation could not afford the pure biaryl.
4
-Phenyltoluene (9d)
Preparative Catalysis
Elution with Cyclohexane/EtOAc (4:1) afforded 78% of a
4
9
1
General Procedure
The reaction was set according to the catalysis protocols for the
colourless crystalline solid; mp 44.3 °C (Lit.: 47-48 °C); H-
NMR (400.13 MHz, CDCl , 298 K):  = 7.57 (d, J = 7.4 Hz, 2H),
3
3
0
respective solvent and aryl halide (1.00 mmol) with 90 7.48 (d, J = 8.3 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4
1
3
phenylboronic acid (183 mg, 1.50 mmol) as organoboron
coupling partner. After heating at 40 °C for 15 h the sample was
Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H) ppm; C-NMR
(100.62 MHz, CDCl , 298 K):  = 141.37, 138.57, 137.21,
129.69, 128.92, 127.20, 127.18, 21.30 ppm.
-Phenyltoluene (10d)
Purification over celite afforded 95% of a yellow oil; H-NMR
400.13 MHz, CDCl , 298 K):  = 7.55 (d, J = 6.8 Hz, 2H), 7.41-
7.34 (m, 4H), 7.28 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H),
3
cooled down to rt, centrifuged and extracted with CHCl
3
(3-4 ×
3
6
00 µL). The organic phase was purified over celite or flash
1
95
3
5
column chromatography on silica gel. The product was
concentrated and dried in high vacuum.
Characterization
(
3
1
3
4
’-Phenylacetophenone (1c)
2.37 (s, 3H) ppm; C-NMR (100.62 MHz, CDCl
3
, 298 K):  =
Purification over celite afforded 97% of a colourless solid; mp
141.58, 141.46, 138.53, 128.90, 128.87, 128.21, 128.20, 127.39,
4
8
1
4
0
115-116 °C (Lit.: 116-117 °C); H-NMR (400.13 MHz, CDCl
3
,
100 127.37, 124.49, 21.76 ppm.
2
7
98 K):  = 8.02 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H),
.61 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.3
2-Phenyltoluene (11d)
Elution with Cyclohexane/EtOAc (4:1) afforded 87% of a yellow
1
3
1
Hz, 1H), 2.62 (s, 3H) ppm; C-NMR (100.62 MHz, CDCl
3
, 298
oil; H-NMR (400.13 MHz, CDCl
3
, 298 K):  = 7.40-7.33 (m,
K):  = 197.97, 145.96, 140.05, 136.03, 129.14, 129.10, 128.42,
127.45, 127.40, 26.83 ppm.
2H), 7.32-7.26 (m, 3H), 7.25-7.18 (m, 4H), 2.25 (s, 3H) ppm;
105 C-NMR (100.62 MHz, CDCl , 298 K):  = 142.18, 142.15,
3
1
3
4
5
5
5
0
5
3
’-Phenylacetophenone (2d)
135.55, 130.51, 130.00, 129.40, 128.27, 127.45, 126.97, 125.96,
20.67 ppm.
4-Phenylanisole (13d)
Elution with Cyclohexane/EtOAc (4:1) afforded 78% of a yellow
oil; H-NMR (400.13 MHz, CDCl
7
1
3
, 298 K):  = 8.18 (s, 1H),
.94 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.0
Elution with Cyclohexane/EtOAc (4:1) afforded 98% of a
4
9
1
Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, 110 colourless solid; mp 81-83 °C (Lit.: 92-94 °C); H-NMR
1
3
J = 7.4 Hz, 1H), 2.66 (s, 3H) ppm; C-NMR (100.62 MHz,
CDCl , 298 K):  = 198.30, 141.95, 140.40, 137.86, 131.96,
29.26, 129.14, 128.02, 127.41, 127.40, 127.18, 26.98 ppm.
’-Phenylacetophenone (3d)
(400.13 MHz, CDCl
3
, 298 K):  = 7.57-7.51 (m, 4H), 7.41 (t, J =
3
7.7 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 9.0, 2H), 3.85
1
3
1
2
(s, 3H) ppm; C-NMR (100.62 MHz, CDCl
3
, 298 K):  =
159.36, 141.05, 134.01, 128.93, 128.38, 126.96, 126.87, 114.41,
Elution with Cyclohexane/EtOAc (98:2) afforded 29% of a 115 55.56 ppm.
yellow oil. The product could not be separated from the aryl
bromide. The yield was determined by setting the conversion
against weight.
3-Phenylanisole (14d)
Elution with Cyclohexane/EtOAc (98:2) afforded 60% of a light
1
yellow oil; H-NMR (400.13 MHz, CDCl
3
, 298 K):  = 7.56 (d, J
4
’-Phenylacetophenone (4c)
1
0
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C5GC00794A
Page 11 of 13
Green Chemistry
=
6.8 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.27-7.34 (m, 2H), 7.15
10 N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973–2976.
1
1
D. Saha, K. Chattopadhyay and B. C. Ranu, Tetrahedron Lett., 2009,
0, 1003–1006.
(d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.80 (s,
5
1
3
3
1
H) ppm; C-NMR (100.62 MHz, CDCl
42.92, 141.26, 129.92, 128.90, 127.57, 127.35, 119.83, 113.07,
3
, 298 K):  = 160.13,
1
2
M. Baur, M. Frank, J. Schatz and F. Schildbach, Tetrahedron, 2001,
57, 6985–6991.
6
7
7
8
5
0
5
0
5
112.83, 55.38 ppm.
-Phenylanisole (15d)
13 A. Roucoux, J. Schulz and H. Patin, Chem. Rev., 2002, 102, 3757–
2
3778.
1
4
M. T. Reetz and E. Westermann, Angew. Chem. Int. Ed., 2000, 39,
165–168.
Elution with Cyclohexane/EtOAc (98:2) afforded 83% of a light
yellow oil; H-NMR (400.13 MHz, CDCl
=
1
3
, 298 K):  = 7.52 (d, J
15 M. Moreno-Mañas and R. Pleixats, Acc. Chem. Res., 2003, 36, 638–
43.
8.3 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.33-7.29 (m, 3H), 7.03 (t,
6
1
3
1
0
J = 7.3 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H) ppm; C-
NMR (100.62 MHz, CDCl , 298 K):  = 156.66, 138.74, 131.09,
30.92, 129.74, 128.80, 128.17, 127.10, 121.02, 111.42, 55.73
ppm.
16 D. Astruc, F. Lu and J. R. Aranzaes, Angew. Chem. Int. Ed., 2005,
44, 7852–7872.
3
1
1
1
7
8
9
N. Mejías, R. Pleixats, A. Shafir, M. Medio-Simón and G. Asensio,
Eur. J. Org. Chem., 2010, 5090–5099.
N. Mejías, A. Serra-Muns, R. Pleixats, A. Shafir and M. Tristany,
Dalt. Trans., 2009, 7748–7755.
1
-Dodecyl-3-methylimidazolium Chloride51
1
N. M. Scott and S. P. Nolan, Eur. J. Inorg. Chem., 2005, 1815–1828.
1
2
2
3
3
5
0
5
0
5
1-Methyl imidazole (4.78 mL, 60.0 mmol) and 1-chlorododecane
18.4 mL, 78.0 mmol) were refluxed at 70 °C for three days.
20 H.-W. Wanzlick and E. Schikora, Angew. Chem., 1960, 72, 494.
21 D. Bourissou, O. Guerret, F. P. GabbaÏ and G. Bertrand, Chem. Rev.,
(
2
000, 100, 39–91.
After cooling down to rt, the upper layer was discarded. The ionic
liquid was dissolved in water and washed with EtOAc (30 mL).
Once the solvent was evaporated, the obtained solid was again
2
2
2
3
M. Regitz, Angew. Chem. Int. Ed., 1996, 35, 725–728.
W. A. Herrmann and K. Christian, Angew. Chem. Int. Ed., 1997, 36,
2162–2187.
washed with EtOAc (4 × 20 mL) and redissolved in CH
2
Cl
2
.
85 24 M. C. Perry and K. Burgess, Tetrahedron: Asymmetry, 2003, 14,
51–961.
9
After evaporating the solvent of, the light yellowish solid was
dried in high vacuum. 5.94 g (20.7 mmol, 35%); light yellowish
solid; mp 50 °C; IR (ATR): 휈̃ (cm-1) = 3083 (m, Aryl, νC-H),
2
2
5
6
W. Kirmse, Angew. Chem. Int. Ed., 2010, 49, 8798–8801.
T. Brendgen, M. Frank and J. Schatz, Eur. J. Org. Chem., 2006,
2
378–2383.
3
050 (m, Aryl, νC-H), 2950 (w, -CH
2850 (m, -CH -, νC-H), 1571 (m, Aryl, νC=C), 1472 (m, -CH
CH -, δC-H), 1426 (w, -CH -, -CH , δC-H), 1383 (w, -CH
59 (m, Aryl, νC-H), 800 (m, Aryl, νC-H), 714 (m, -CH
further absorption bands: 3459 (m), 3409 (m), 1636 (m), 1176 (s),
63 (w), 622 (s), 506 (br), 476 (s); 1H-NMR (400.13 MHz,
CDCl , 298 K): δ = 10.45 (s, 1H), 7.50 (t, J = 1.5 Hz, 1H), 7.32 (t,
J = 1.6 Hz, 1H), 4.25 (t, J = 7.4 Hz, 2H), 4.06 (s, 3H), 1.83 (qu, J
2
-, νC-H), 2915 (s, -CH -, νC-H), 90 27 M. Frank, G. Maas and J. Schatz, Eur. J. Org. Chem., 2004, 607–
2
-, -
613.
2
2
2
2
8
9
C. Zhang, J. Huang, M. L. Trudell and S. P. Nolan, J. Org. Chem.,
3
2
3
3
, δsC-H),
1
999, 64, 3804–3805.
8
2
-, ρC-H);
N. Hadei, E. A. B. Kantchev, C. J. O’Brien and M. G. Organ, Org.
Lett., 2005, 7, 1991–1994.
95
6
30 A. Fürstner and A. Leitner, Synlett, 2001, 290–292.
3
3
3
1
2
3
T. Fahlbusch, M. Frank, J. Schatz and D. T. Schühle, J. Org. Chem.,
006, 71, 1688–1691.
C. W. K. Gstöttmayr, V. P. W. Böhm, E. Herdtweck, M. Grosche and
W. A. Herrmann, Angew. Chem. Int. Ed., 2002, 41, 1363–1365.
H. Lebel, M. K. Janes, A. B. Charette and S. P. Nolan, J. Am. Chem.
Soc., 2004, 126, 5046–5047.
3
2
=
7.3 Hz, 2H), 1.26-1.18 (m, 18H), 0.81 (t, J = 6.9 Hz, 3H) ppm;
C-NMR (100.62 MHz, CDCl3, 298 K): δ = 138.17, 123.65,
1
1
1
1
1
1
1
00
1
3
1
21.81, 50.24, 36.75, 32.00, 30.44, 29.70, 29.61, 29.49, 29.43,
+
34 C. Liu, Q. Ni, P. Hu and J. Qiu, Org. Biomol. Chem., 2011, 9, 1054–
29.12, 26.39, 22.78, 14.23 ppm; MS (EI): calc. for C16
H
31
N
2
:
+
1060.
2
51.25, found: m/z = 251 [M ].
05 35 B. P. Bandgar, S. V. Bettigeri and J. Phopase, Tetrahedron Lett.,
004, 45, 6959–6962.
36 D. N. Korolev and N. A. Bumagin, Tetrahedron Lett., 2006, 47,
225–4229.
2
Notes and references
4
a
Friedrich-Alexander University Erlangen-Nürnberg, Department of
Organic Chemistry I, Henkestraße 42, 91054 Erlangen, Germany.
Fax: +49 9131 85 24707; Tel: +49 9131 85 25766; E-mail:
juergen.schatz@fau.de
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This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C5GC00794A
Green Chemistry
Page 12 of 13
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| Journal Name, [year], [vol], 00–00
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Green Chemistry
View Article Online
DOI: 10.1039/C5GC00794A
Efficient and general applicable ligand-less and ligand-supported Suzuki coupling reactions in pure water
under aerobic conditions