Organic Solvent-Free, Pd(II)-Salan Complex-Catalyzed Synthesis of Biaryls via Suzuki-Miyaura Cross-Coupling in Water and Air

Article abstract of DOI:10.1021/acs.joc.8b02340

With use of a Pd(II)-sulfosalan complex as a water-soluble catalyst, we have developed an efficient synthesis of biaryls via Suzuki-Miyaura cross-coupling in water under aerobic conditions. The water-insoluble target molecules were isolated by simple filtration in analytical purity after washing with 0.01 M aqueous HCl (20 examples). In most cases, palladium contamination was below 5 ppm considered acceptable for active pharmaceutical ingredients. The established method is scalable, reproducible, and provides biaryl products in isolated yields up to 91%.

Full text of DOI:10.1021/acs.joc.8b02340

Subscriber access provided by Kaohsiung Medical University
Note
Organic solvent-free, Pd(II)-salan complex-catalyzed synthesis
of biaryls via Suzuki-Miyaura cross-coupling in water and air.
Szilvia Bunda, Antal Udvardy, Krisztina Voronova, and Ferenc Joo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 26, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 27
The Journal of Organic Chemistry
1
1
2
3
4
5
6
Organic solvent-free, Pd(II)-salan complex-catalyzed synthesis of biaryls
via Suzuki-Miyaura cross-coupling in water and air.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Szilvia Bunda,†* Antal Udvardy,† Krisztina Voronova,†‡ Ferenc Joó†§*
†University of Debrecen, Department of Physical Chemistry, P. O. Box 400, Debrecen, H-4002
Hungary
‡Present address: Department of Chemistry, University of Nevada, Reno, NV 89557-0216,
USA
§MTA-DE Redox and Homogeneous Catalytic Reaction Mechanisms Research Group, P. O.
Box 400, Debrecen, H-4002 Hungary
E-mail: bunda.szilvia@science.unideb.hu; joo.ferenc@science.unideb.hu
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 27
2
1
2
3
4
Abstract Graphic
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract
With use of a Pd(II)-sulfosalan complex as a water-soluble catalyst we have developed an
efficient synthesis of biaryls via Suzuki-Miyaura cross-coupling in water under aerobic
conditions. The water-insoluble target molecules were isolated by simple filtration in analytical
purity after washing with 0.01 M aqueous HCl (20 examples). In most cases, palladium
contamination was below 5 ppm considered acceptable for active pharmaceutical ingredients.
The established method is scalable, reproducible, and provides biaryl products in isolated yields
up to 91%.
ACS Paragon Plus Environment

Page 3 of 27
The Journal of Organic Chemistry
3
1
2
3
4
5
6
7
8
9
Water plays an increasingly important role in development of environment-friendly methods of
chemical synthesis.1-4 In addition to its other advantageous features, water is relatively cheap,
non-toxic and non-flammable so its use makes processes safer at reduced cost. Often the
reactions are carried out in aqueous-organic biphasic mixtures or in mixed aqueous-organic
homogeneous solutions. In other cases the chemical transformations can be performed in water,
however, workup is based on extraction with organic solvents. In order to achieve most of the
environmental benefits of an aqueous procedure, organic solvents should be avoided all along
the synthesis pathway. For homogeneously catalyzed reactions in aqueous media water-soluble
catalysts are required. Favorably, due to the exponential development of aqueous
organometallic catalysis hydrosoluble catalysts are now available for most kind of reactions,
including hydrogenation, hydroformylation, hydration, hydrocyanation, oxidation, C-C
couplings, and many others.1-4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Transition-metal complex catalyzed C-C cross-coupling reactions have utmost
importance in modern organic chemistry since they allow synthesis of complex molecules from
relatively simple starting materials.5-8 An important class of such reactions is the Suzuki-
Miyaura cross-coupling of aryl halides and organoboronic acids. Numerous efforts have been
made in order to apply water as solvent in this reaction, too, however, in most cases organic co-
solvents had to be used, furthermore, isolation and purification of products often required
organic solvents for extraction and column chromatography.9-16 The use of a water-soluble
Pd(II)-sulfonated triphenylphosphine complex to catalyze this process in aqueous reaction
medium was first studied by Casalnuovo and Calabrese in 1990.17 Main efforts of later research
were focused on application of various water-soluble Pd-tertiary phosphine,18-21
palladacycle,22, 23 and Pd-N-heterocyclic carbene24, 25 (Pd-NHC) complex catalysts in aqueous
solution, often with microwave irradiation.15 Procedures with ligandless Pd-catalysts
(nanoparticles) with high catalytic activities were also developed.26
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 27
4
1
2
3
4
5
6
7
8
9
Water-insolubility of several biaryls leads to precipitation/crystallization of the products
from aqueous reaction mixtures allowing isolation of target molecules by simple filtration.27, 28
This approach helped also in keeping Pd-contamination low, even down to ppb level.28 For
example, with use of palladacycle catalysts, Eppinger and co-workers synthesized a large group
of variously functionalized biaryls without the use of organic solvents.29, 30 Lipshutz et al.
applied various designer surfactants to facilitate Suzuki-Miyaura cross-couplings inside the
core of micelles that allowed to perform the synthesis in water.31-34 In several cases no organic
solvent was added to the reaction mixture or applied during workup and the analytically pure
products were isolated from the aqueous media by filtration.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Various metal complexes of Schiff-base ligands, including salens,
bis(salicylaldiminato)-1,2-ethanediamines, are widely used in coordination chemistry and
catalysis.35-41 However, it has been reported ion several cases that in aqueous solvents they are
degraded under catalytic conditions due to the hydrolytic instability of the C=N bond.38,42-44
Hydrogenation of salens gives rise to structurally more flexible and hydrolytically stable N,N’-
bis(2-hydroxybenzyl)alkylenediamines (salans) which, however, have been scarcely used as
ligands in homogeneous catalysis.42 Recently we have synthesized a series of Pd(II)-complexes
with various water-soluble salan ligands (obtained via sulfonation of the respective
tetrahydrosalens).45, 46 Here we report a procedure capitalizing on the outstanding catalytic
activity of a water-soluble Pd(II)-complex of N,N’-bis(2-hydroxy-5-sulfonatobenzyl)-1,4-
diaminobutane, Na2[Pd(BuHSS)] which allows performing Suzuki-Miyaura cross-couplings in
water under aerobic conditions (Scheme 1). We have also synthesized similar catalysts with
various bridges from 1,2-diamines derived from ethane, 1,2-diphenylethane, cyclohexane, and
benzene. These Pd(II)-salan type complexes catalyzed the reaction of phenylboronic acid and
bromobenzene with isolated yields between 13% and 93%; in the particular case of
ACS Paragon Plus Environment

Page 5 of 27
The Journal of Organic Chemistry
5
1
2
3
4
5
6
Na2[Pd(BuHSS)] with 82%; this catalyst was chosen for extensive scrutiny for its easy synthesis
and for affording high yields.
7
8
9
Scheme 1. Suzuki-Miyaura cross-coupling of arylboronic acids and aryl halides with
Na2[Pd(BuHSS)] catalyst
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cross-coupling of phenylboronic acids and aryl halides proceeded smoothly in air in the
presence of bases at 80 °C with 0.1 mol% catalyst. Cs2CO3 and Et3N promoted the reaction
with the same efficiency, however, for environmental reasons and to avoid contamination of
the products with any organics Cs2CO3 was used in the syntheses (Na2CO3 could be used, too,
but see Table 3). Aryl halides showed the expected reactivity with conversions (GC) in 1 h:
iodobenzene 100%, bromobenzene 71%, chlorobenzene 17%.
There has been an enduring interest in the activation of aryl chlorides in aqueous systems
under phosphine-free conditions. Shahnaz et al.36 recently reported a simple palladium Schiff-
base catalyst that produced good-to-excellent yields of Suzuki-Miyaura cross-cross-coupling
products using aryl chlorides in aqueous conditions. Note that employing our Pd(II)-salan
catalyst high conversion, 82%, was achieved with chlorobenzene, too, when the reaction time
was increased to 6 h. This results in a turnover number (TON) of 820, which is an order of
magnitude higher than that obtained by Shahnaz et al. (TON = 12-96) in the cross-coupling of
various aryl chlorides at 100 °C, underscoring the remarkable activity of Pd(II)-salan
complexes.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 27
6
1
2
3
4
5
6
7
8
9
Limited solubility of biaryls in water allowed to develop an efficient synthetic method
including a simple workup. Suzuki-Miyaura cross-couplings were performed in water as
solvent. After the desired time the reaction mixture was diluted with water, the solid product
was isolated by filtration, washed thoroughly with 0.01 M HCl and dried to constant weight.
The resulting compounds were characterized by their melting points, 1H and 13C NMR spectra.
Previously unreported solid-state structures of five biaryls were determined by single crystal
X-ray diffraction (see SI). For 20 examples, isolated yields and Pd-contents are shown in Table
1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 7 of 27
The Journal of Organic Chemistry
7
1
2
3
4
5
6
7
8
Table 1. Synthesis of biaryls with Suzuki-Miyaura cross-coupling of arylboronic acids
and aryl halides in water under aerobic conditions catalyzed by the water-soluble Pd(II)
complex Na2[Pd(BuHSS)].
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry/
Compound
No.
Isolated
yield,% (ppm)
Pd
Product
1a
2a
3a
4a
5b
6b
7b
82 (72j)
84
8
3
77
1
89
14
<1
1
78 (74j)
70
82
<1
8b
91
4
9c
10c
59
74
1
9
11c
90
2
12d
13d
14d
79 (82e, 89j)
70 (72e)
70
4
3
2
15d
16f
90 (89e)
21
4
92
17g
18g
79
91
1
3
19h
20i
78
90
n.d.
n.d.
Conditions: 5.0×10-7 mol Na2[Pd(BuHSS)], 5.0×10-4 mol
aryl halide, 7.5×10-4 mol boronic acid, 5.0×10-4 mol
Cs2CO3, 3 mL water, 80 °C, 2 h.
abromobenzene, 4-bromoacetophenone, 4-bromoanisole,
b
c
d4-nitro-1-iodobenzene, e4-nitro-1-bromobenzene, Pd-
content
n.d.,
f4-bromobenzoic
acid,
g5-bromo-
salicylaldehyde, h2-iodopyridine, i2-bromo-1,3-thiazole.
jAll quantities multiplied by 10, except V(H2O)=15 mL; 80
°C, a-g2 h, h,i4 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
8
1
2
3
4
5
6
7
8
9
Most biaryls were obtained in reactions of aryl bromides and/or aryl iodides; under conditions
of Table 1 they reacted equally well. In general, the use of aryl halides as well as of arylboronic
acids with either electron donating or electron withdrawing substituents resulted in high
conversions with only 0.1 mol% of the Na2[Pd(BuHSS)] catalyst. Due to the method of workup,
the isolated yields depend also on the aqueous solubility of the respective biaryl so they may
not reflect fine differences in reactivity. Organic solvents were not used at all, neither for the
cross-coupling reaction nor for workup, furthermore, the products were not recrystallized
before recording 1H and 13C NMR spectra (Supporting Information). It is of utmost importance,
that despite the simple method of isolation, Pd-content of the products was found very low, in
14 cases below the 5 ppm limit47 established for active pharmaceutical intermediates (API-s).
Accordingly, thorough washing with 0.01 M aqueous HCl is highly effective for removal of
palladium from the solid products. Only in cases of the 4-carboxy-1,1’-biphenyl (4) and 4-
carboxy-4’-nitro-1,1’-biphenyl (15) were >10 ppm Pd-contents determined. Although
formation of Pd-carboxylate complexes cannot be ruled out, 4 and 5 form water-insoluble
dimers with strong H-bonds and their relatively high Pd-content may be due to inclusion of
some of the reaction mixture during fast precipitation. The above synthesis can be scaled up
easily; three biaryls (1, 5, 12; Table 1) were synthesized starting with 5 mmol of the respective
aryl halides; quantities of other reactants were multiplied accordingly (but V(H2O) = 15 mL).
Small or no changes of the isolated yields (%) were observed (Table 1) so the synthesis proved
applicable for several gram quantities of target molecules. In general, in terms of catalytic
activity our findings are compare well to those obtained with similar N/O coordinated Pd
complexes with the additional benefit of no use of organic solvents.36-38, 40, 41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sodium tetraphenylborate and potassium phenyltrifluoroborate can serve as convenient
phenyl sources in Suzuki-Miyaura cross-couplings.26 Although their use limits the modularity
of such processes to syntheses of biaryls with (at least) one unsubstituted phenyl ring, the water-
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
9
1
2
3
4
5
6
7
8
9
solubility of Na[BPh4] and K[BPhF3] leads to high reaction rates with hydrosoluble catalysts
especially in cases (at temperatures) when the aryl halide is soluble in the aqueous reaction
mixture (Table 2). For example, with Na[BPh4] poorly water-soluble 4-bromoacetophenone
underwent only 5% conversion at room temperature while it reacted with 100% conversion at
80 °C. In contrast, 4-bromobenzoic acid afforded 4-carboxy-1,1’-biphenyl (4) with 100%
conversion in short reaction times both at 80 °C (15 min) and at room temperature (30 min).
Such high reaction rates demonstrate the efficiency of catalysis in purely aqueous reaction
mixtures under proper conditions. Again, the water-insoluble products could be obtained in
analytical purity after washing with 0.01 M HCl.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Phenylboronic acid, Na-tetraphenylborate and K-phenyltrifluoroborate as
phenyl-group donors in Suzuki-Miyaura cross-couplings catalyzed by Na2[Pd(BuHSS)] in
water
Conversion (%)
PhB(OH)2a Na[BPh4]b K[PhBF3]a
bromobenzene
4-bromoanisole
4-bromoacetophenone
4-bromobenzoic acid
4-nitro-1-
72
28
94
88
73
100
100
78
47
97
100
100
55
100
80
bromobenzene
4-iodotoluene
60
90
10
Conditions: 5.0×10-7 mol Na2[Pd(BuHSS)], 7.5×10-4 mol
phenylboronic acid/Na-tetraphenylborate/K-phenyltrifluoro-
borate, 5.0×10-4 mol aryl halide, 5.0×10-4 base (aCs2CO3,
bNa2CO3), 3 mL water, 80 °C, 1 h.
Table 3 shows the results of catalyst recycling experiments. At the end of each cycle the
undiluted reaction mixture was filtered carefully to collect as much of the aqueous phase as
possible, which was then supplied with new batches of 4-bromoacetophenone, phenylboronic
acid and base. At the end of each cycle the yield was determined according to the mass of the
isolated product. These results demonstrate that in the presence of Cs2CO3 the catalyst can be
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 27
10
1
2
3
4
5
6
7
8
9
recycled three times with no loss of activity. However, while the product biaryl precipitated
nicely in the first three cycles, there was no precipitation in the 4th cycle. After extraction of the
reaction mixture with CHCl3, gas chromatography showed only 45% conversion of the aryl
halide. When Na2CO3 was used as base, we observed a rapid loss of the catalyst’s activity from
cycle to cycle. Inorganic byproducts, such as bromide accumulate in the recycled catalyst
solution (concentration of Br- is 0.67 M at the end of the 4th cycle) and its complex formation
with Pd(II) may be responsible for catalyst deactivation. In summary, while originally both
Cs2CO3 and Na2CO3 are very effective as bases in the cross-coupling reaction, Na2[Pd(BuHSS)]
looses its activity much faster in Na2CO3 solutions than in the presence of Cs2CO3. In addition,
the precipitates from Na2CO3-containing reaction mixtures are more sticky and can be collected
by filtration with difficulties. Concerning the physical state of the catalyst during the reaction,
a drop of conversion from 95% to 76% was observed in the presence of Hg (cross-coupling of
4-bromoacetophenone with phenylboronic acid, conditions as in Table 1, except 1 h reaction
time). This may refer to participation of nanoparticles in catalysis, however, this question was
not investigated in detail.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Recycling of the Na2[Pd(BuHSS)] catalyst in Suzuki-Miyaura cross-coupling of
phenylboronic acid and 4-bromoacetophenone
Yield (%)
No. of cycles
Base: Cs2CO3
Base: Na2CO3
1
2
3
4
76
86
89
73a
15a
0a
81
45a
Conditions: 5.0×10-7 mol Na2[Pd(BuHSS)], 7.5×10-4 mol
phenylboronic acid, 5.0×10-4 mol 4-bromoacetophenone,
5.0×10-4 base, 3 mL water, 80 °C, 1 h each cycle. aNo biaryl
precipitates, conversions determined by GC.
ACS Paragon Plus Environment

Page 11 of 27
The Journal of Organic Chemistry
11
1
2
3
4
5
6
7
8
9
In conclusion, a green method was developed for synthesis of biaryls by Suzuki-
Miyaura cross-coupling of aryl halides and arylboronic acids in water in the presence of an
inorganic base (Cs2CO3). An easily available, highly active salan-type water-soluble catalyst,
Na2[Pd(BuHSS)] (BuHSS = N,N’-bis(2-hydroxy-5-sulfonatobenzyl)-1,4-diaminobutane) was
employed in 0.1 mol% and the various biaryls were isolated in high yields. No organic solvents
were used in synthesis or workup; the water-insoluble products were isolated from the reaction
mixture by simple filtration in high purity and –in most cases– with Pd-content below 5 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental part
Na2[Pd(BuHSS)] was synthesized as described in reference 45. All other reagents were
commercial products of Sigma-Aldrich and were used as received. Solvents were obtained from
Molar. Deionized water was used throughout. Melting points were determined on a Büchi
melting point apparatus Model B-540 and are uncorrected. Pd contents were determined with
use of an Agilent MP-AES spectrometer (biaryls were dissolved in aqua regia with the aid of
an MLS 1200 microwave digestion equipment).
1H- and 13C{1H} NMR spectra were recorded on a Bruker 360 MHz instrument at room
temperature and were referenced to tetramethylsilane (TMS), as well as to 1H or 13C resonances
of residual non-deuterated solvents in CH3OD, CDCl3 and dmso-d6 (99.9% isotopic purity,
1
13
Sigma-Aldrich), respectively (CH3OH: H NMR δ=3.34 ppm, C{1H} NMR δ=49.05 ppm;
1
1
CHCl3: H NMR δ=7.24 ppm, 13C{1H} NMR δ=77.23 ppm; dmso: H NMR δ=2.50 ppm,
13C{1H} NMR δ=39.51 ppm).
Single crystal X-Ray analyses were performed with the use of a Bruker D8 Venture system.
Conversions of aryl halides were determined by gas chromatography.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 27
12
1
2
3
4
5
6
Typical procedure of Suzuki-Miyaura cross-couplings: Synthesis of biphenyl in reaction of
iodobenzene and phenylboronic acid.
7
8
9
Bromobenzene (52 μL; 0.5 mmol), phenylboronic acid (92 mg; 0.75 mmol), and Cs2CO3 (163
mg, 0.5 mmol) were placed into a Schlenk tube or a screw cap vial. 300 μL of an aqueous
solution of Na2[Pd(BuHSS)] (1.7 mM; 0.51 μmol – synthesized according to reference 60) was
added followed by addition of 2.7 mL distilled water. The reaction vesssel was closed with a
septum and the reaction mixture was magnetically stirred at 80 °C (water bath) in air for 2
hours. After cooling to room temperature it was diluted with 15 mL water facilitating
precipitation of the product. The white solid was collected on a filter, washed thoroughly with
0.01 M aqueous HCl and dried in air to constant weight. Yield: 63 mg (82%), mp: 74-75 °C (lit.
mp: 69-73 °C).48
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The following products were obtained by the above general method with 0.5mmol aryl halide
(for reaction times and composition of the reaction mixtures see Table 1):
Biphenyl (1) from phenylboronic acid and bromobenzene: Yield 63 mg (82%), white solid,
mp: 74-75 °C, after recrystallization from CHCl3, mp: 70-71 °C (lit. mp: 69-73 °C).48
1H NMR (360 MHz, 298 K, CDCl3):  = 7.62 (d, 4H, JHH = 7.2 Hz), 7.46 (t, 4H, JHH = 7.3 Hz),
7.37 (t, 2H, JHH = 7.2 Hz) ppm. 13C{1H} NMR (90 MHz, 298 K, dmso-d6):  = 140.1, 128.8,
127.3, 126.5 ppm.
4-Methylbiphenyl (2) from p-tolylboronic acid and bromobenzene: Yield 71 mg (84%), white
solid, mp: 49-50 °C (lit. mp: 49-50 °C).49, 50
1H NMR (360 MHz, 298 K, CDCl3):  = 7.93-7.19 (m, 9H), 2.51 (s, 3H) ppm. 13C{1H} NMR
(90 MHz, 298 K, CDCl3): = 141.4, 138.6, 137.2, 129.7, 128.9, 127.2, 21.3 ppm.
ACS Paragon Plus Environment

Page 13 of 27
The Journal of Organic Chemistry
13
1
2
3
4
5
6
7
8
4-Methoxybiphenyl (3) from 4-methoxyphenylboronic acid and bromobenzene: Yield 71 mg
(77%), white solid, mp: 91-92 °C (lit. mp: 91-92 °C).50
9
1H NMR (360 MHz, 298 K, CDCl3):  = 7.51- 7.60 (m, 4H), 7.43 (t, 2H, JHH = 7.8 Hz), 7.31
(t, 1H, JHH = 7.0 Hz), 6.99 (d, 2H, JHH = 8.7 Hz), 3.85 (s, 3H) ppm. 13C{1H} NMR (90 MHz,
298 K, CDCl3):  =159.3, 141.0, 133.9, 128.9, 128.3, 126.9, 126.8, 114.3, 55.5 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methoxybiphenyl (3) from phenylboronic acid and 4-bromoanisole: Yield 68 mg (74%),
white solid, mp: 91-92 °C (lit. mp: 91-92 °C).50
1H NMR (360 MHz, 298 K, CDCl3):  = 7.50-7.68 (m, 4H), 7.41 (t, 2H, JHH = 7.8 Hz,, 7.29 (t,
1H, JHH = 7.0 Hz), 6.97 (d, 2H, JHH = 8.5 Hz), 3.84 (s, 3H) ppm. 13C{1H}NMR (90 MHz, 298
K, CDCl3):  = 159.3, 141.0, 133.9, 128.9, 128.3, 126.9, 126.8, 114.3, 55.5 ppm.
4-Carboxybiphenyl (4) from 4-carboxyphenylboronic acid and bromobenzene: Yield 88 mg
(89%), white solid, mp: 228-230 °C (lit. mp: 228-230 °C).51
1H NMR (360 MHz, 298 K, dmso-d6):  = 12.97, 8.02 (d, J HH= 7.8 Hz, 2H), 7.80 (d, JHH = 7.8
Hz, 2H), 7.72 (d, JHH= 8.1 Hz, 2H), 7.55-7.46 (m, 2H), 7.45-7.34 (m, 1H) ppm. 13C{1H} NMR
(90 MHz, dmso-d6): = 167.1, 144.3, 139.0, 129.9, 129.6, 129.1, 128.3, 127.0, 126.8 ppm.
4-Carboxybiphenyl (4) from phenylboronic acid and 4-bromobenzoic acid: Yield 83 mg
(85%), white solid, mp: 228-230 °C (lit. mp: 228-230 °C).51
1H NMR (360 MHz, 298 K, dmso-d6):  = 12.96 (s), 8.02 (d, JHH = 7.8 Hz, 2H), 7.79 (d, JHH
=
13
7.6 Hz, 2H), 7.73 (d, JHH = 8.0 Hz, 2H), 7.56-7.46 (m, 2H), 7.46-7.34 (m,1H) ppm. C{1H}
NMR (90 MHz, dmso-d6):  =167.3, 144.4, 139.1, 130.1, 129.7, 129.2, 128.4, 127.1, 126.9
ppm.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 27
14
1
2
3
4
5
6
7
8
4-Acetylbiphenyl (5) from phenylboronic acid and 4-bromoacetophenone: Yield 76 mg (78%),
white solid, mp: 127-128 °C (lit. mp: 126-128 °C).52
9
1H NMR (360 MHz, 298 K, CDCl3):  = 8.02 (d, JHH = 8.3 Hz, 2 H), 7.67 (d, JHH = 8.0 Hz, 2
H), 7.61 (d, JHH = 7.5 Hz, 2H), 7.53-7,34 (m, 3H), 2.63 (s, 3H) ppm. 13C{1H} NMR (90 MHz,
298 K, CDCl3):  = 198.0, 146.1, 140.2, 136.2, 129.2 (d), 128.5, 127.5 (d), 26.69 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methyl-4’-Acetylbiphenyl (6) from p-tolylboronic acid and 4-bromoacetophenone: Yield 74
mg (70%), white solid, mp: 127-128 °C (lit. mp: 126-128 °C).52
1H NMR (360 MHz, 298 K, CDCl3):  = 8.03 (d, JHH = 8.5 Hz, 2H), 7.68 (d, JHH = 7.8 Hz, 2H),
7.54 (d, JHH = 7.7 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 2.64 (s, 3H), 2.41 (s, 3H) ppm.
13C{1H} NMR (90 MHz, 298 K, CDCl3):  = 197.9, 145.9, 138.4. 137.2, 135.8, 129.9, 129,1
127.3, 127.2, 26.8, 21.4 ppm.
4-Methoxy-4’-Acetylbiphenyl (7) from 4-methoxyphenylboronic acid and 4-
bromoacetophenone: Yield 93 mg (82%), white solid, mp: 161-162 °C (lit. mp: 156.5-157.0
°C53 and 156-158 °C54).
1H NMR (360 MHz, 298 K, CDCl3):  = 7.98 (d, JHH = 8.9 Hz, 2H), 7.61 (d, JHH = 8.8 Hz, 2H),
7.55 (d, JHH = 8.9 Hz, 2H), 6.97 (d, JHH = 8.8 Hz, 2H), 3.83 (s, 3H), 2.60 (s, 3H) ppm. 13C{1H}
NMR (90 MHz, 298 K, CDCl3):  = 197.9, 160.1, 145.5, 135.4, 132.3, 129.1, 128.5, 126.7,
114.6, 55.5, 26.8 ppm.
4-Carboxy-4’-Acetylbiphenyl (8) from 4-carboxyphenylboronic acid and 4-
bromoacetophenone: Yield 109 mg (91%), white solid, mp >300 °C (lit. mp: 309-310 °C).20
ACS Paragon Plus Environment

Page 15 of 27
The Journal of Organic Chemistry
15
1
2
3
4
1H NMR (360 MHz, 298 K, dmso-d6):  = 12.86 (bs), 8.16-7.99 (m, 4H), 7.96-7.81 (m, 4H),
5
6
13
2.62 (s, 3H) ppm. C{1H} NMR (90 MHz, 298 K, dmso-d6):  = 197.5, 167.0, 143.3, 142.9,
7
8
9
136.2, 130.5, 130.0, 128.9, 127.2, 127.1, 26.8 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methyl-4′-Methoxybiphenyl (9) from p-tolylboronic acid and 4-bromoanisole:: Yield 58
mg (59%), white solid, mp: 112-113 °C; (lit. mp 111-112 °C).50
1H NMR (360 MHz, 298 K, CDCl3) = 7.60-7.40 (md, 4H), 7.33-7.11 (md, 2H), 6.98 (md,
JHH = 8.7 Hz, 2H), 3.86 (s, 3H), 2.40 (s, 3H) ppm. 13C{1H} NMR (90 MHz, 298 K, CDCl3): =
159.0, 138.0, 136.4, 133.8, 129.5, 128.0, 126.7, 114.2, 55.4, 21.1 ppm.
4-Methoxy-4′-Methoxybiphenyl (10) from 4-methoxyphenylboronic acid and 4-
bromoanisole: Yield 78 mg (74%), white solid, mp: 186-187 °C (lit. mp: 180-182 °C).55
1H NMR (360 MHz, 298 K, CDCl3):  = 7.5 (d, JHH = 8.8 Hz, 4H), 6.98 (d, JHH = 8.8 Hz,
4H), 3.86 (s, 6H) ppm. 13C{1H} NMR (90 MHz, 298 K, CDCl3)  = 158.9, 133.7, 127.9, 114.4,
55.5 ppm.
4-Carboxy-4′-Methoxybiphenyl (11) from 4-carboxyphenylboronic acid and 4-bromoanisole:
Yield 96 mg (90%), white solid, mp: 250-253 °C (lit. mp: 250.0-251.7 °C).56
1H NMR (360 MHz, 298 K, dmso-d6):  = 8.04-7.94 (m, 2H), 7.81-7.63 (m, 4H), 7.15-6.96 (m,
13
2 H), 3.81 (s, 3 H) ppm. C{1H} NMR (90 MHz, 298 K, dmso-d6):  =167.2, 159.6, 143.9,
131.2, 129.9, 128.8, 128.1, 126.1, 114.5, 55.2 ppm.
4-Carboxy-4′-Methoxybiphenyl (11) from 4-methoxyphenylboronic acid and 4-
bromobenzoic acid: Yield 95 mg (89%), white solid, mp: 250-253 °C (lit mp: 250.0-251.7 °C).56
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 27
16
1
2
3
4
1H NMR (360 MHz, 298 K, dmso-d6):  = 8.04-7.94 (m, 2H), 7.81-7.63 (m, 4H), 7.15-6.96 (m,
5
6
13
2H), 3.81 (s, 3H) ppm. C{1H} NMR (90 MHz, 298 K, dmso-d6):  =167.2, 159.6, 143.9,
7
8
9
131.2, 129.9, 128.8, 128.1, 126.1, 114.5, 55.2 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Nitrobiphenyl (12) from phenylboronic acid and 4-nitro-1-iodobenzene: Yield 79 mg (79%),
light yellow solid, mp: 118-119 °C. (lit. mp: 114.5-115.0 °C).53
1H NMR (360 MHz, 298 K, CDCl3):  = 8.26 (d, J HH= 8.4 Hz, 2H), 7.70 (d, J
= 8.6 Hz,
HH
13
2H), 7.61 (d, J
= 7.0 Hz, 2H), 7.53–7.38 (m, 3H) ppm. C{1H} NMR (90 MHz, 298 K,
HH
CDCl3)  = 147.8, 147.3, 138.9, 129.3, 129.1, 127.9, 127.6, 124.3 ppm.
4-Methyl-4’-Nitrobiphenyl (13) from p-tolylboronic acid and 4-nitro-1-iodobenzene: Yield
75 mg (70%), yellow solid, mp: 142-143 °C (lit. mp: 142.5-143.0 °C).53
1H NMR (360 MHz, 298 K, CDCl3):  = 8.28 (d, JHH = 8.3 Hz, 2H), 7.72 (d, JHH = 8.8 Hz, 2H),
13
7.54 (d, JHH = 7.9 Hz, 2H), 7.32 (d, JHH = 8.8 Hz, 2H), 2.44 (s, 3H) ppm. C{1H}NMR (90
MHz, 298 K, CDCl3):  = 147.6, 146.9, 139.2, 135.9, 130.0, 127.4(d), 124.2, 21.3 ppm.
4-Methoxy-4’-Nitrobiphenyl (14) from 4-methoxyphenylboronic acid and 4-nitro-1-
iodobenzene: Yield 81 mg (70%), yellow solid, mp: 104-105 °C (lit. mp: 104-105 °C).57
1H NMR (360 MHz, 298 K, CDCl3):  = 8.25 (d, JHH= 8.8 Hz, 2 H), 7.67 (d, JHH = 8.8 Hz, 2H),
13
7.58 (d, JHH = 8.8 Hz, 2H), 7.00 (d, JHH = 9.0 Hz, 2H), 3.86 (s, 3H) ppm. C{1H} NMR (90
MHz, 298 K, CDCl3): = 160.7, 147.3, 146.8, 131.4, 128.9, 127.4, 124.4, 114.9, 55.7 ppm.
4-Carboxy-4’-Nitrobiphenyl (15) from 4-carboxyphenylboronic acid and 4-nitro-1-
iodobenzene: Yield 110 mg (90%), yellow solid, mp: >300 °C (lit. mp: 340 °C). 58, 59
ACS Paragon Plus Environment

Page 17 of 27
The Journal of Organic Chemistry
17
1
2
3
4
1H NMR (360 MHz, 298 K, dmso-d6):  = 13.27(s), 8.32 (d, JHH=8.0, 2H), 8.15-7.96 (dd, JHH
5
6
13
= 8.0, 4H) 7.89 (d, JHH=7.5, 2H) ppm. C{1H} NMR (90 MHz, 298 K, dmso-d6)  = 167.1,
7
8
9
147.1, 145.6, 141.2, 132.4, 130.0, 128.2, 127.3, 124.1 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4,4'-Dicarboxybiphenyl (16) from 4-carboxyphenylboronic acid and 4-bromobenzoic acid:
Yield 111 mg (92%), white solid, mp >300 °C (lit. mp: 309-310 °C).20
1H NMR (360 MHz, 298 K, dmso-d6):  = 13.03 (2H), 8.05 (d, JHH = 6.9 Hz, 4H), 7.86 (d,
13
JHH = 7.3 Hz, 4H) ppm. C{1H} NMR (90 MHz, 298 K, dmso-d6) = 167.5, 143.6, 130.8,
130.5, 107.6 ppm.
4-Hydroxy-3-formylbiphenyl (17) from phenylboronic acid and 5-bromosalicylaldehyde:
Yield 79 mg (79%), yellow solid, mp: 107-108 °C (lit. mp: 95-97 °C)60
1H NMR (360 MHz, 298 K, dmso-d6)  = 10.87 (s, 1H,), 10.32 (s, 1H), 7.97-7.88 (m, 1H), 7.88-
7.76 (m, 1H) 7.67-7.54 (m, 2H), 7.52-7.38 (bt, 2H), 7.37-7.26 (m, 1H), 7.10 (d, J = 9.0 Hz, 1H)
ppm. 13C{1H} NMR (90 MHz, dmso-d6): δ = 191.7, 160.3, 138.9, 134.6, 131.5, 129.0, 127.1,
127.0, 126.1, 122.5, 118.0 ppm.
3'-Formyl-4'-hydroxy[1,1'-biphenyl]-4-carboxylic acid (18)61 from 4-carboxyphenylboronic
acid and 5-bromosalicylaldehyde: Yield 111 mg (91%), yellow solid, mp >300 °C (mp not
available in reference 61).
1H NMR (360 MHz, 298 K, dmso-d6) = 12.03 (br), 10.27 (s, 1H), 8.04-7.89 (m, 3H), 7.88-
13
7.82 (m, 1H), 7.75-7.65 (m, 2H), 7.09-7.06 (m, 1H) ppm. C{1H} NMR (90 MHz, 298 K,
dmso-d6) = 191.3, 167.2, 161.0, 143.2, 142.9, 134.7, 130.1, 130.0, 127.1, 126.0, 122.6, 118.2
ppm.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 27
18
1
2
3
4
5
6
7
8
9
4-(Pyridin-2-yl)benzoic acid (19)62 from 4-carboxyphenylboronic acid and 2-iodopyridine:
Yield 72 mg (78%), white solid, mp: 230-232 °C (lit. mp: 238-240 °C) 63. 1H NMR (360 MHz,
298 K, dmso-d6):  = 13.03 (s, 1H), 8.69-8.79 (m, 1H), 8.17-8.37 (m, 2H), 8.02-8.15 (m, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.85-8.00 (q, 2H), 7.38-7.49 (m, 1H) ppm. 13C{1H} NMR (90 MHz, 298 K, CH3OD): = 169.4,
157.5, 150.3, 144.3, 139.4, 134.5, 132.6, 131.3, 129.7, 128.2, 124.6, 123.2 ppm.
4-(1,3-Thiazol-2-yl)benzoic acid (20)64 from 4-carboxyphenylboronic acid and 2-
bromothiazole: Yield 92 mg (90%), white solid, mp: 230-231 °C (lit. mp: 235-237 °C)65. 1H
NMR (360 MHz, 298 K, dmso-d6):  = 12.94 (s, 1H), 8.11-8.44 (m, 2H), 7.77-8.08 (m, 4H)
ppm. 13C{1H} NMR (90 MHz, 298 K, dmso-d6): = 167.3, 141.6, 133.9, 133.3, 131.8, 128.1,
127.9 ppm.
ACS Paragon Plus Environment

Page 19 of 27
The Journal of Organic Chemistry
19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
13
1H and C NMR spectra of biaryls 1-20; CIF files and X-ray structures of compounds 8, 11,
15, 17, 18.
Acknowledgement
The research was supported by the EU and co-financed by the European Regional Development
Fund under the projects GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004.
Thanks are due to Dr. Edina Baranyai and Mr. Sándor Harangi for Pd-content determinations
and to Dr. Mihály Herczeg for his help in determination of melting points.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 27
20
1
2
3
4
References and endnotes
5
6
7
8
(1) Shaughnessy, K. H. Hydrophilic Ligands and Their Application in Aqueous-Phase Metal-
Catalyzed Reactions. Chem. Rev. 2009, 109, 643–710.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) Joó, F. Aqueous Organometallic Catalysis (Catalysis by Metal Complexes Vol. 23);
Kluwer:Dordrecht, 2001.
(3) Li, C.-J. Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond
Formations:ꢀ A Decade Update. Chem. Rev. 2005, 105, 3095–3166.
(4) Dixneuf, P. H, Cadierno,V., Eds. Metal-Catalyzed Reactions in Water, Wiley-VCH:
Weinheim, 2013.
(5) Molnár, Á., Ed. Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future
Developments, Wiley-VCH:Weinheim, 2013.
(6) Miyaura, N. Metal‐Catalyzed Cross‐Coupling Reactions of Organoboron Compounds with
Organic Halides. In Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed., de Meijere, A.;
Diderich, F., Eds. Wiley-VCH:Weinheim, 2004, pp. 41–123.
(7) Nishihara, Y., Ed. Applied Cross-Coupling Reactions, Springer:Berlin, 2013.
(8) de Vries. J. D. Palladium-Catalysed Coupling Reactions; In Organometallics as Catalysts
in the Fine Chemical Industry-Top. Organomet. Chem; Beller, M.; Blaser, H.-U., Eds. 2012,
pp. 1–34.
(9) Alonso, D. A.; Nájera, C. Water in Organic Synthesis. In Science of Synthesis; Kobayashi,
S., Ed. Thieme, Stuttgart, 2012, pp. 535–578.
(10) Mori, Y.; Kobayashi, S. Water in Organic Synthesis. In Science of Synthesis; Kobayashi,
S., Ed. Thieme:Stuttgart, 2012; pp. 831–854.
(11) Moore, J. N.; Laskay, N. M.; Duque, K. S.; Kelley, S. P.; Rogers, R.D.; Shaughnessy, K.
H. Synthesis of 4-Sulfonatobenzylphosphines and Their Application in Aqueous-Phase
Palladium-Catalyzed Cross-Coupling. J. Organometal. Chem. 2015, 777, 16–24.
ACS Paragon Plus Environment

Page 21 of 27
The Journal of Organic Chemistry
21
1
2
3
4
5
6
7
8
(12) Roy, S.; Plenio, H. Sulfonated N‐Heterocyclic Carbenes for Pd‐Catalyzed Sonogashira
and Suzuki–Miyaura Coupling in Aqueous Solvents. Adv. Synth. Catal. 2010, 352, 1014–
1022.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13) Alonso, F.; Beletskaya, I. P.; Yus, M. Non-Conventional Methodologies for Transition-
Metal Catalysed Carbon–Carbon Coupling: A Critical Overview. Part 2: The Suzuki
Reaction. Tetrahedron 2008, 64, 3047–3101.
(14) Chatterjee, A.; Ward, T. R. Recent Advances in the Palladium Catalyzed Suzuki–
Miyaura Cross-Coupling Reaction in Water. Catal. Lett. 2016, 146, 820–840.
(15) Arvela, R. K.; Leadbeater, N. E.; Mack, T. L.; Kormos, C. M. Microwave-Promoted
Suzuki Coupling Reactions with Organotrifluoroborates in Water Using Ultra-Low Catalyst
Loadings. Tetrahedron Lett. 2006, 47, 217–220.
(16) Shaughnessy, K. H. Greener Approaches to Cross-Coupling. In New Trends in Cross-
Coupling: Theory and Applications; Colacot, T., Ed. The Royal Society of Chemistry, 2015;
pp. 645–696.
(17) Casalnuovo, A. L.; Calabrese, J. C. Palladium-Catalyzed Alkylations in Aqueous Media.
J. Am. Chem. Soc. 1990, 112, 4324–4330.
(18) Ueda, M.; Nishimura, M.; Miyaura, N. A Palladium-Catalyzed Biaryl Coupling of
Arylboronic Acids in Aqueous Media Using a Gluconamide-Substituted Triphenylphosphine
(GLCAphos) Ligand. Synlett 2000, 2000, 856–858.
(19) Anderson, K. W.; Buchwald, S. L. A New Minimal Surface and the Structure of
Mesoporous Silicas. Angew. Chem. 2005, 117, 3307–3312; Angew. Chem. Int. Ed. 2005, 44
(21), 3243–3248.
(20) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. Aqueous-Phase, Palladium-
Catalyzed Cross-Coupling of Aryl Bromides under Mild Conditions, Using Water-Soluble,
Sterically Demanding Alkylphosphines. J. Org. Chem. 2004, 69, 7919–7927.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 27
22
1
2
3
4
5
6
7
8
(21) Beller, M.; Krauter, J. G. E.; Zapf, A.; Bogdanovic, S. Carbohydrate-substituted
Phosphines as New Ligands for Two-Phase Catalysis – Synthesis and Application. Catal.
Today 1999, 48, 279–290.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) Huang, R.; Shaughnessy, K. H. Water-Soluble Palladacycles as Precursors to Highly
Recyclable Catalysts for the Suzuki Coupling of Aryl Bromides in Aqueous Solvents.
Organometallics 2006, 25, 4105–4112.
(23) Li, H.; Wu, Y. Water‐Soluble 2‐Arylnaphthoxazole‐Derived Palladium (II) Complexes
as Phosphine‐Free Catalysts for the Suzuki Reaction in Aqueous Solvent. Appl. Organometal.
Chem. 2008, 22, 233–236.
(24) Godoy, F.; Segarra, C.; Poyatos, M.; Perís, E. Palladium Catalysts with Sulfonate-
Functionalized-NHC Ligands for Suzuki−Miyaura Cross-Coupling Reactions in Water.
Organometallics 2011, 30, 684–688.
(25) Levin, E.; Ivry, E.; Diesendruck, C. E.; Lemcoff, N. G. Water in N-Heterocyclic
Carbene-Assisted Catalysis. Chem. Rev. 2015, 115, 4607–4692.
(26) Bumagin, N. A.; Bykov, V. V. Ligandless Palladium Catalyzed Reactions of Arylboronic
Acids and Sodium Tetraphenylborate with Aryl Halides in Aqueous Media. Tetrahedron
1997, 53, 14437–14450.
(27) Polshettiwar, V.; Varma, R. S. Nanoparticle‐Supported and Magnetically Recoverable
Ruthenium Hydroxide Catalyst: Efficient Hydration of Nitriles to Amides in Aqueous
Medium. Chem. Eur. J. 2009, 15, 1582–1586.
(28) Bhilare, S.; Gayakhe, V.; Ardhapure, A. V.; Sanghvi, Y. S.; Schulzke, C.; Borozdina, Y.;
Kapdi, A. R. Novel Water-Soluble Phosphatriazenes: Versatile Ligands for Suzuki–Miyaura,
Sonogashira and Heck Reactions of Nucleosides. RSC Adv. 2016, 6, 83820–83830.
ACS Paragon Plus Environment

Page 23 of 27
The Journal of Organic Chemistry
23
1
2
3
4
5
6
7
8
(29) Marziale, A. N.; Faul, S. H.; Reiner, T.; Schneider, S.; Eppinger, J. Facile Palladium
Catalyzed Suzuki–Miyaura Coupling in Air and Water at Ambient Temperature. Green.
Chem. 2010, 12, 35–38.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(30) Marziale, A. N.; Jantke, D.; Faul, S. H.; Reiner, T.; Herdtweck, E.; Eppinger, J. An
Efficient Protocol for the Palladium-Catalysed Suzuki–Miyaura Cross-Coupling. Green.
Chem. 2011, 13, 169–177.
(31) Isley, N. A.; Wang, Y.; Gallou, F.; Handa, S.; Aue, D. H.; Lipshutz, B. H. A Micellar
Catalysis Strategy for Suzuki–Miyaura Cross-Couplings of 2-Pyridyl MIDA Boronates: No
Copper, in Water, Very Mild Conditions. ACS Catal. 2017, 7, 8331–8337.
(32) Lipshutz, B. H.; Ghorai, S. Transitioning Organic Synthesis from Organic Solvents to
Water. What's your E Factor? Green Chem. 2014, 16, 3660–3679.
(33) Handa, S.; Smith, J. D.; Hageman, M. S.; Gonzalez, M.; Lipshutz, B. H. Synergistic and
Selective Copper/ppm Pd-Catalyzed Suzuki–Miyaura Couplings: In Water, Mild Conditions,
with Recycling. ACS Catal. 2016, 6, 8179–8183.
(34) Landstrom, E. B.; Handa, S.; Aue, D. H.; Gallou, F.; Lipshutz, B. H. EvanPhos: a Ligand
for ppm Level Pd-Catalyzed Suzuki–Miyaura Couplings in either Organic Solvent or Water.
Green Chem. 2018, 20, 3436–3443.
(35) Das, P.; Linert, W. Schiff Base-Derived Homogeneous and Heterogeneous Palladium
Catalysts for the Suzuki–Miyaura Reaction. Coord. Chem. Rev. 2016, 311, 1–23.
(36) Shahnaz, N.; Puzari, A.; Paul, B.; Das, P. Activation of Aryl Chlorides in Water for
Suzuki Coupling with a Hydrophilic Salen-Pd(II) Catalyst. Catal. Commun. 2016, 86, 55–58.
(37) Borhade, S. R.; Waghmode, S. B. Phosphine-Free Pd–Salen Complexes as Efficient and
Inexpensive Catalysts for Heck and Suzuki Reactions under Aerobic Conditions. Tetrahedron
Lett. 2008, 49, 3423–3429.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
24
1
2
3
4
5
6
7
8
(38) Liu, P.; Feng, X.-J.; He, R. Salen and Half-Salen Palladium(II) Complexes: Synthesis,
Characterization and Catalytic Activity toward Suzuki–Miyaura Reaction. Tetrahedron 2010,
66, 631–636.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(39) Henrici-Olivé, G.; Olivé, S. A Palladium(II) Complex as Hydrogenase Model. Angew.
Chem, 1974, 13, 549–550.
(40) Dewan, A. A Highly Efficient and Inexpensive Palladium-Salen Complex for Room
Temperature Suzuki-Miyaura Reaction. Bull. Korean Chem. Soc. 2014, 35, 1855–1858.
(41) Liu, Y.-S.; Gu, N.-N.; Liu, P.; Ma, X.-W.; Liu, Y.; Xie, J.-W.; Dai, B. Water-Soluble
Salen–Pd Complex as an Efficient Catalyst for Suzuki–Miyaura Reaction of Sterically
Hindered Substrates in Pure Water. Tetrahedron 2015, 71, 7985–7989.
(42) Correia, I.; Costa Pessoa, J.; Veiros, L. F.; Jakusch, T.; Dornyei, A.; Kiss, T.; Castro, M.
M. C. A.; Geraldes, C. F. G. C.; Avecilla, K. Vanadium(IV and V) Complexes of Schiff Bases
and Reduced Schiff Bases Derived from the Reaction of Aromatic o‐Hydroxyaldehydes and
Diamines: Synthesis, Characterisation and Solution Studies. Eur. J. Inorg. Chem. 2005, 2005,
732–744.
(43) Sippola, V. O.; Krause, A. O. I. Oxidation Activity and Stability of Homogeneous
Cobalt-Sulphosalen Catalyst: Studies with a Phenolic and a Non-Phenolic Lignin Model
Compound in Aqueous Alkaline Medium. J. Mol. Catal. A: Chem. 2003, 194, 89–97.
(44) Sukanya, D.; Evans, M. R.; Zeller, M.; Natarajan, K. Hydrolytic Cleavage of Schiff
Bases by [RuCl2(DMSO)4]. Polyhedron 2007, 26, 4314–4320.
(45) Voronova, K.; Purgel, M.; Udvardy, A.; Bényei, A. C.; Kathó, Á.; Joó,F. Hydrogenation
and Redox Isomerization of Allylic Alcohols Catalyzed by a New Water-Soluble Pd–
tetrahydrosalen Complex. Organometallics 2013, 32, 4391–4401.
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
25
1
2
3
4
5
6
7
8
(46) Voronova, K.; Homolya, L.; Udvardy. A.; Bényei, A. C.; Joó, F. Pd-Tetrahydrosalan‐
Type Complexes as Catalysts for Sonogashira Couplings in Water: Efficient Greening of the
Procedure. ChemSusChem 2014, 7, 2230–2239.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(47) Garrett, C. E.; Prasad, K. The Art of Meeting Palladium Specifications in Active
Pharmaceutical Ingredients Produced by Pd‐Catalyzed Reactions. Adv. Synth. Catal. 2004,
346, 889–900.
(48) Demir, A. S.; Findik, H.; Saygili, N.; Subasi, N.T. Manganese(III) Acetate-Mediated
Synthesis of Biaryls under Microwave Irradiation. Tetrahedron 2010, 66, 1308–1312.
(49) Nandurkar, N. S.; Bhanage, B. M. Palladium bis(2,2,6,6-Tetramethyl-3,5-
heptanedionate) Catalyzed Suzuki, Heck, Sonogashira, and Cyanation Reactions. Tetrahedron
2008, 64, 3655–3660.
(50) Wang, L.; Wang, Z.-X. Efficient Cross-Coupling of Aryl Chlorides with Arylzinc
Reagents Catalyzed by Amido Pincer Complexes of Nickel. Org. Lett. 2007, 9, 4335–4338.
(51) Du, Z.; Zhou, W.; Wang, F.; Wang, J.-X. In Situ Generation of Palladium Nanoparticles:
Ligand-Free Palladium Catalyzed Ultrafast Suzuki–Miyaura Cross-Coupling Reaction in
Aqueous Phase at Room Temperature. Tetrahedron 2011, 67, 4914–4918.
(52) Sasmita, M.; Suresh, D.; Maravanji, S. B.; Joel, M. T. Phosphine Free Diamino-diol
Based Palladium Catalysts and Their Application in Suzuki–Miyaura Cross-Coupling
Reactions. J. Organometal. Chem. 2009, 694, 2114–2121.
(53) Hoshiya, N.; Shimoda, M.; Yoshikawa, H.; Yamashita, Y.; Shuto, S.; Arisawa, M. Sulfur
Modification of Au via Treatment with Piranha Solution Provides Low-Pd Releasing and
Recyclable Pd Material, SAPd. J. Am. Chem. Soc. 2010, 132, 7270–7272.
(54) Mutule, I.; Suna, E. Arylzinc Species by Microwave Assisted Grignard Formation–
Transmetallation Sequence: Application in the Negishi Coupling. Tetrahedron 2005, 61,
11168–11176.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
26
1
2
3
4
5
6
7
8
(55) Hsu, M.-H.; Hsu, C.-M.; Wang, J.-C.; Sun, C.-H. Air-Stable Pd(II) Catalysts with
Cryptand-22 Ligand for Convenient and Efficient Suzuki Cross-Coupling Reactions.
Tetrahedron 2008, 64, 4268–4274.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(56) Prastaro, A.; Ceci, P;. Chiancone, E.; Boffi, A.; Cirilli, R.; Colone, M.; Fabrizi, G.;
Stringaro, A.; Cacchi, S. Suzuki-Miyaura Cross-Coupling Catalyzed by Protein-Stabilized
Palladium Nanoparticles under Aerobic Conditions in Water: Application to a One-Pot
Chemoenzymatic Enantioselective Synthesis of Chiral Biaryl Alcohols. Green Chem. 2009,
11, 1929–1932.
(57) Maddali, R. L. N.; Deepak, J. N.; Banerjee, D. A New Palladium Catalyzed Protocol for
Atom-Efficient Cross-Coupling Reactions of Triarylbismuths with Aryl Halides and Triflates.
Tetrahedron 2008, 64, 5762–5772.
(58) Basford, F. R. 297. Derivatives of 4-Cyclohexyldiphenyl. Part III. J. Chem. Soc.1937,
1440–1443.
(59) Harley-Mason, J.; Mann, F. G. 260. Quaterphenyl. Part I. Some Dihydroxy-Derivatives.
J. Chem. Soc. 1940, 1379–1385.
(60) Bhatt, S.; Nayak, S. K. Reductive Deoxygenation of Ortho-Hydroxyaromatic Aldehydes
to 1,2-bis(Hydroxyaryl)ethanes: Application to the Synthesis of Ethylene Bridged Calixarene-
Analogous Metacyclophanes. Tetrahedron Lett. 2009, 50, 5823–5826.
(61) Patterson, J. B; Lonergan, D. G. Aromatic Aldehyde Derivatives as IRE-1α Inhibitors
and their Preparation and Use in the Treatment of Diseases, PCT Int. Appl. WO 2008154484
A1, December 18, 2008; C. A. 150:55806.
(62) Gong, Y.; Pauls, H. W. A Convenient Synthesis of Heteroaryl Benzoic Acids via Suzuki
Reaction. Synlett 2000, 829-831.
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
27
1
2
3
4
5
6
7
8
(63) Dong, J.; Pan, X.; Wang, J.; Su, P.; Zhang, L.; Wei, F.; Zhang, J. Synthesis and
Biological Evaluation of Novel Aromatic-Heterocyclic Biphenyls as Potent Anti-Leukemia
Agents. Eur. J. Med. Chem. 2015, 101, 780-789.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(64) Staderini, S.; Tuci, G.; Luconi, L.; Müller, P.; Kaskel, S.; Eychmüller, A.; Eichler, F.;
Giambastiani, G.; Rossin, A. Zinc Coordination Polymers Containing Isomeric Forms of p-
(Thiazolyl)benzoic Acid: Blue-Emitting Materials with a Solvatochromic Response to Water.
Eur. J. Inorg. Chem. 2017, 42, 4909-4918.
(65) Sum, P. E.; How, D. B.; Sabatini, J. J.; Xiang, J. S.; Iper, M.; Feyfant, E. Preparation of
Glutamate Derivatives as Aggrecanase Inhibitors, PCT Int. Appl. WO 2007/008994 A2; C. A.
146:163390.
ACS Paragon Plus Environment