Water-soluble palladacycles containing hydroxymethyl groups: Synthesis, crystal structures and use as catalysts for amination and Suzuki coupling of reactions

Article abstract of DOI:10.1007/s11243-016-0036-5

Two water-soluble monophosphine [PPh₃ and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(Sphos)]-palladacycles containing hydroxymethyl groups 2-3 were prepared by cyclopalladation and chloride bridge-splitting reactions. The complexes were characterized by elemental analysis, ESI-MS and NMR. In addition, single-crystal X-ray analysis reveals that they have one-dimensional lamellar structures involving intermolecular hydrogen bonds and π-π interactions. The use of these palladacycles as catalysts for amination and Suzuki coupling of aryl chlorides in water was investigated. Complex 3 was found to be very efficient for these coupling reactions. Additionally, it was also successfully used in Suzuki coupling of (hydroxymethyl)phenylboronic acid for the synthesis of substituted 2-N-heterocyclic biarylmethanols.

Full text of DOI:10.1007/s11243-016-0036-5

Transition Met Chem (2016) 41:403–411
DOI 10.1007/s11243-016-0036-5
Water-soluble palladacycles containing hydroxymethyl groups:
synthesis, crystal structures and use as catalysts for amination
and Suzuki coupling of reactions
Xin Han1 Hong-Mei Li2 Chen Xu2,3 Zhi-Qiang Xiao1
•
•
•
•
Zhi-Qiang Wang2 Wei-Jun Fu2 Xin-Qi Hao1 Mao-Ping Song1
•
•
•
Received: 13 January 2016 / Accepted: 16 February 2016 / Published online: 29 February 2016
Ó Springer International Publishing Switzerland 2016
Abstract Two water-soluble monophosphine [PPh3 and
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl(Sphos)]-
palladacycles containing hydroxymethyl groups 2–3 were
prepared by cyclopalladation and chloride bridge-splitting
reactions. The complexes were characterized by elemental
analysis, ESI–MS and NMR. In addition, single-crystal
X-ray analysis reveals that they have one-dimensional
lamellar structures involving intermolecular hydrogen
bonds and p–p interactions. The use of these palladacycles
as catalysts for amination and Suzuki coupling of aryl
chlorides in water was investigated. Complex 3 was found
to be very efficient for these coupling reactions. Addi-
tionally, it was also successfully used in Suzuki coupling of
(hydroxymethyl)phenylboronic acid for the synthesis of
substituted 2-N-heterocyclic biarylmethanols.
Introduction
Palladium-catalyzed coupling reactions such as aminations
and Suzuki couplings have become extremely powerful
methods in organic synthesis for the formation of C–N or
C–C bonds [1–3]. Among various Pd catalysts, pallada-
cycles are one of the most efficient precatalysts for these
coupling reactions [4, 5]. Key to the success of such cou-
plings is the efficient generation of the active Pd(0)Ln
species (L = ligand) which participates in the catalytic
cycle [6, 7]. Many such systems have been reported,
including both phosphine and N-heterocyclic carbene
(NHC)–palladacycles [4, 8, 9]. Recent progress in this field
is focused on the use of water as a green solvent and on the
use of the inexpensive and readily accessible aryl chlorides
as starting materials. There are only a few examples of
palladacycles containing water-soluble groups such as –OH
or –SO3H being used in coupling reactions; furthermore,
the coupling of aryl chlorides in water has been little
reported [10–14].
In recent years, part of our research effort has focused
on the synthesis and application of palladacycles [15, 16].
Generally, phosphine or NHC–palladacycles are far more
active than the corresponding dimeric palladacycles. We
have also developed palladacycle-catalyzed Suzuki reac-
tion of aryl halides for the synthesis of substituted biaryl-
methanols in water [17, 18]. However, substrates are
limited to aryl bromides and chlorides containing water-
soluble hydroxymethyl groups. As a continuation of our
interest in palladacycle-catalyzed coupling reactions, we
prepared two water-soluble monophosphine-cyclopalla-
dated arylpyrazine complexes 2 and 3 (Scheme 1) and
examined their catalytic activities in water. Here, we report
that complex 3 is an effective catalyst for amination and
Suzuki coupling of aryl chlorides in water.
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-016-0036-5) contains supplementary
material, which is available to authorized users.
& Chen Xu
xubohan@163.com
& Xin-Qi Hao
xqhao@zzu.edu.cn
1
College of Chemistry and Molecular Engineering,
Zhengzhou University, Zhengzhou 450052, Henan, China
2
College of Chemistry and Chemical Engineering, Luoyang
Normal University, Luoyang 471022, Henan, China
3
College of Food and Pharmacy, Luoyang Normal University,
Luoyang 471022, Henan, China
123

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Transition Met Chem (2016) 41:403–411
OH
OH
2 L= PPh3
L
L
Pd Cl
2
Pd
Cy2P
MeO
3 L=
Cl
N
OMe
N
(Sphos)
N
N
1
Scheme 1 Synthesis of complexes 2 and 3
General procedure for Buchwald–Hartwig
amination
Experimental
All chemicals were commercially available expect for 4-(2-
pyrazinyl)phenylmethanol [19] and its palladacyclic dimer
1 [20] which were prepared according to the published
procedures. Elemental analyses were determined with a
Carlo Erba 1160 Elemental Analyzer. Mass spectra were
In a Schlenk tube, a mixture of the required amount of
catalyst, plus the aryl chloride (1.0 mmol), amine
t
(1.2 mmol), KOH (3.0 mmol) and BuOH (4 mmol) in
water (3.0 mL) was evacuated and charged with nitrogen.
The reaction mixture was then heated at 100 °C for 12 h.
After cooling, the mixture was extracted three times with
CH2Cl2. The combined organic layers were washed with
water, dried and evaporated to dryness. The products were
isolated by flash chromatography on silica gel using a
mixture of CH2Cl2/ethyl acetate (5/1) as eluent and char-
acterized by comparison of data with those in the literature
[15, 21].
1
measured on an LC-MSD-Trap-XCT instrument. H NMR
and 13C NMR spectra were recorded on a Bruker DPX-400
spectrometer (400 and 100 MHz, respectively) in CDCl3
with TMS as an internal standard.
Synthesis of complexes 2 and 3
A solution of dimer 1 (0.1 mmol) and PPh3 or Sphos
(0.2 mmol) in acetone (10 mL) was stirred at room tem-
perature for 30 min. The product was separated by passing
through a short silica gel column with CH2Cl2 as eluent.
Complex 2: Yield 82 %. Anal. Calcd. for C29H24ClN2-
OPPd: C, 59.1; H, 4.1; N, 4.8. Found: C, 59.5; H, 3.8; N,
5.0 %. MS–ESI? [m/z]: 553.1 (M–Cl)?. 1H NMR
General procedure for Suzuki coupling
In a Schlenk tube, a mixture of the required amount of
catalyst, plus the aryl chloride (1.0 mmol), aryl boronic
acid (1.5 mmol) and the selected base (2.0 mmol) in water
was evacuated and charged with nitrogen. The reaction
mixture was heated at 100 °C for 12 h. After cooling, the
mixture was extracted with CH2Cl2 and the extract was
evaporated. The resulting residue was purified by flash
chromatography on silica gel using a mixture of CH2Cl2/
ethyl acetate (5/1) as eluent. The known products 5, 6a [17,
18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26]
were characterized by comparison of data with those in the
literature. The products 6d, 6f and 7b–h were new com-
1
(400 MHz, CDCl3): H NMR (400 MHz, CDCl3): d 9.27
(s, 1H), 8.89 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 1.6 Hz,
1H), 8.12 (d, J = 8.0 Hz, 1H), 7.73–7.80 (m, 8H),
7.39–7.43 (m, 9H), 4.81 (s, 2H), 2.13 (br, 1H). 13C NMR
(100 MHz, CDCl3): d 158.3, 141.2, 139.1, 138.4, 134.7,
132.5, 131.8, 130.3, 130.7, 128.9, 123.6, 119.1, 104.4,
103.2, 65.1. Complex 3: Yield 90 %. Anal. Calcd. for
C37H44ClN2O3PPd: C, 60.3; H, 6.0; N, 3.8. Found: C, 60.6;
H, 5.8; N, 4.1 %. MS–ESI? [m/z]: 701.2 (M–Cl)?. 1H
NMR (400 MHz, CDCl3): d 9.32 (s, 1H), 8.91 (d,
J = 1.6 Hz, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.14 (d,
J = 8.0 Hz, 1H), 7.85 (m, 1H), 7.79 (s, 1H), 7.19–7.25 (m,
3H), 6.53–6.68 (m, 4H), 4.83 (s, 2H), 3.46 (s, 6H), 2.72 (m,
2H), 1.36–1.69 (m, 20H). 13C NMR (100 MHz, CDCl3): d
166.2, 158.6, 146.5, 145.4, 143.7, 141.8, 139.4, 139.2,
135.9, 135.7, 134.7, 132.1, 131.3, 129.5, 129.1, 125.3,
124.1, 119.5, 109.7, 109.5, 104.6, 103.6, 65.3, 55.2, 32.5,
29.1, 27.8, 26.6.
1
pounds and characterized by elemental analysis, MS, H
and 13C NMR.
4-(6-Methoxy-2-pyridinyl)phenylmethanol 6d. Anal.
Calcd. for C13H13NO2: C, 72.5; H, 6.1; N, 6.5. Found: C,
72.9; H, 5.8; N, 6.7 %. MS–ESI? [m/z]: 216.1 (M ? H)?.
1H NMR (400 MHz, CDCl3): d 8.07 (d, J = 6.4 Hz, 2H),
7.65 (t, J = 6.0 Hz, 1H), 7.47 (d, J = 6.0 Hz, 2H), 7.36 (d,
J = 6.0 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 4.77 (s, 2H),
4.06 (s, 3H), 1.88 (br, 1H). 13C NMR (100 MHz, CDCl3):
123

Transition Met Chem (2016) 41:403–411
405
163.7, 154.3, 141.5, 139.2, 138.5, 127.2, 126.9, 112.8,
109.3, 65.1, 53.3.
2-(2-Pyrazinyl)phenylmethanol 7g. Anal. Calcd. for
C11H10N2O: C, 70.9; H, 5.4; N, 15.0. Found: C, 71.3; H,
5.2; N, 15.3 %. MS–ESI? [m/z]: 187.1 (M ? H)?. 1H
NMR (400 MHz, CDCl3): d 9.97 (d, J = 1.0 Hz, 1H), 8.56
(d, J = 1.0 Hz, 2H), 7.62 (d, J = 6.4 Hz, 1H), 7.56 (d,
J = 6.0 Hz, 1H), 7.50–7.53 (m, 2H), 5.25 (br, 1H), 4.51 (s,
2H). 13C NMR (100 MHz, CDCl3): 154.4, 145.2, 143.2,
142.4, 140.7, 136.3, 131.6, 130.3, 129.7, 128.1, 127.6,
64.3.
4-(5-Acetyl-2-pyridinyl)phenylmethanol 6f. Anal. Calcd.
for C14H13NO2: C, 74.0; H, 5.8; N, 6.2. Found: C, 74.3; H,
1
5.5; N, 6.6 %. MS–ESI? [m/z]: 228.1 (M ? H)?. H NMR
(400 MHz, CDCl3): d 9.22 (d, J = 1.2 Hz, 1H), 8.30 (d,
J = 6.4 Hz, 1H), 8.05 (d, J = 6.4 Hz, 2H), 7.85 (d,
J = 6.8 Hz, 1H), 7.50 (d, J = 6.4 Hz, 2H), 4.79 (s, 2H),
2.68 (s, 3H), 2.29 (br, 1H). 13C NMR (100 MHz, CDCl3):
196.6, 160.7, 150.1, 143.1, 137.3, 136.5, 130.6, 127.6, 127.3,
120.2, 64.8, 26.8.
2-(2-Pyrimidinyl)phenylmethanol 7h. Anal. Calcd. for
C11H10N2O: C, 70.9; H, 5.4; N, 15.0. Found: C, 71.2; H,
5.1; N, 15.3 %. MS–ESI? [m/z]: 187.1 (M ? H)?. 1H
NMR (400 MHz, CDCl3): d 8.90 (d, J = 4.0 Hz, 2H),
8.20–8.23 (m, 1H), 7.50–7.53 (m, 3H), 7.32–7.35 (m, 1H),
5.92 (br, 1H), 4.62 (s, 2H). 13C NMR (100 MHz, CDCl3):
156.1, 157.1, 140.7, 137.5, 131.5, 131.3, 130.9, 128.3,
119.0, 64.8.
2-(5-Methyl-2-pyridinyl)phenylmethanol 7b. Anal. Calcd.
for C13H13NO: C, 78.4; H, 6.6; N, 7.0. Found: C, 78.8; H, 6.3;
N, 7.2 %. MS–ESI? [m/z]: 200.1 (M ? H)?. 1H NMR
(400 MHz, CDCl3): d 8.48 (s, 1H), 7.66 (d, J = 6.0 Hz, 1H),
7.42–7.53 (m, 5H), 6.52 (br, 1H), 4.48 (s, 2H), 2.42 (s, 3H).
13C NMR (100 MHz, CDCl3): 156.4, 148.4, 140.3, 139.9,
138.2, 131.9, 131.1, 129.9, 128.1, 123.7, 121.7, 64.7, 18.2.
2-(6-Methyl-2-pyridinyl)phenylmethanol 7c. Anal. Calcd.
for C13H13NO: C, 78.4; H, 6.6; N, 7.0. Found: C, 78.7; H,
Crystal structure determination
1
6.2; N, 7.3 %. MS–ESI? [m/z]: 200.1 (M ? H)?. H NMR
Crystallographic data for complexes 2 and 3 were collected
on an Xcalibur Eos Gemini diffractometer with Cu–Ka
(400 MHz, CDCl3): d 7.76 (t, J = 6.0 Hz, 1H), 7.55–7.59
(m, 1H), 7.51–7.54 (m, 1H), 7.44–7.49 (m, 3H), 7.21 (d,
J = 6.4 Hz, 1H), 6.64 (br, 1H), 4.49 (s, 2H), 2.65 (s, 3H).
13C NMR (100 MHz, CDCl3): 158.6, 157.0, 140.4, 140.2,
137.7, 131.1, 130.1, 129.2, 128.1, 121.9, 120.8, 64.7, 24.3.
2-(6-Methoxy-2-pyridinyl)phenylmethanol 7d. Anal.
Calcd. for C13H13NO2: C, 72.5; H, 6.1; N, 6.5. Found: C,
72.8; H, 5.9; N, 6.9 %. MS–ESI? [m/z]: 216.1 (M ? H)?.
1H NMR (400 MHz, CDCl3): d 7.73 (t, J = 6.4 Hz, 1H),
7.50–7.52 (m, 2H), 7.42–7.48 (m, 2H), 7.15 (d,
J = 6.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.44 (br, 1H),
4.55 (s, 2H), 4.00 (s, 3H). 13C NMR (100 MHz, CDCl3):
163.3, 157.4, 139.9, 139.8, 139.7, 130.6, 130.4, 129.2,
128.2, 117.1, 109.7, 64.5, 53.8.
˚
radiation (k = 0.71073 A) at ambient temperature. The
data were corrected for Lorentz-polarization factors as well
as for absorption. Structures were solved by direct methods
and refined by full-matrix least-squares methods on F2 with
the SHELXL-97 program [27]. The hydroxymethyl group
in 2 was disordered over two positions with occupancies of
0.567(7):0.433(7); it is also refined isotropically. Crystal
data, as well as details of data collection and refinements,
are summarized in Table 1. The CCDC deposition numbers
are 14,44,953 and 14,44,954 for 2 and 3, respectively.
These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/datarequest/cif.
2-(5-Trifluoromethyl-2-pyridinyl)phenylmethanol 7e.
Anal. Calcd. for C13H10F3NO: C, 61.7; H, 4.0; N, 5.5.
Found: C, 61.9; H, 3.7; N, 5.3 %. MS–ESI? [m/z]: 254.1
(M ? H)?. 1H NMR (400 MHz, CDCl3): d 8.85 (d,
J = 4.0 Hz, 1H), 7.87 (s, 1H), 7.48–7.58 (m, 5H), 5.66 (br,
1H), 4.50 (s, 2H). 13C NMR (100 MHz, CDCl3): 160.6,
149.3, 140.3, 139.5, 139.7, 138.5, 131.5, 130.1, 128.5,
126.9, 123.8, 121.6, 119.6, 117.8, 64.4.
Results and discussion
Synthesis and structures of complexes 2 and 3
The water-soluble palladacycles 2 and 3 were easily pre-
pared via the bridge-splitting reactions of dimer 1 with
PPh3 or Sphos (Scheme 1). They were characterized by
elemental analysis, MS, 1H and 13C NMR. The NMR
spectra of these complexes are consistent with the proposed
structures. In the mass spectra of 2–3, the most intense
peak was attributed to [M–Cl]. In addition, the structures of
both complexes have been determined by X-ray single-
crystal diffraction.
2-(5-Acetyl-2-pyridinyl)phenylmethanol 7f. Calcd. for
C14H13NO2: C, 74.0; H, 5.8; N, 6.2. Found: C, 74.4; H, 5.6;
N, 6.5 %. MS–ESI? [m/z]: 228.1 (M ? H)?. 1H NMR
(400 MHz, CDCl3): d 9.21 (d, J = 1.2 Hz, 1H), 8.40 (d,
J = 6.4 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.59 (d,
J = 6.0 Hz, 1H), 7.53 (d, J = 6.0 Hz, 1H), 7.43–7.51 (m,
2H), 5.90 (br, 1H), 4.50 (s, 2H), 2.71 (s, 3H). 13C NMR
(100 MHz, CDCl3): 196.0, 162.9, 148.6, 140.5, 138.8,
137.0, 131.5, 130.6, 130.3, 130.2, 128.4, 123.8, 64.5, 26.8.
Both palladacycles adopt a trans-geometry in the solid
state. The molecules are shown in Figs. 1 and 2. The Pd
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Transition Met Chem (2016) 41:403–411
Table 1 Crystallographic data
for complexes 2 and 3
Empirical formula
C29H24ClN2OPPd 2
C37H44ClN2O3PPd 3
Fw
589.32
737.56
Monoclinic
P21/n
Crystal system
Space group
Triclinic
P-1
˚
a (A)
10.1923(6)
10.5975(6)
13.6470(7)
87.800(4)
68.259(5)
66.385(6)
1244.39(14)
2
9.5974(4)
19.3574(8)
18.9165(7)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
100.308(4)
90
3
˚
Volume (A )
3457.6(2)
4
Z
Dc (g/cm3)
1.573
1.417
GOF
1.037
1.025
F(000)
596.0
1528.0
14,404
7051
Reflections
9004
Independent reflections
Final R indices [I [ 2 sigma(I)]
R indices (all data)
4441
R1 = 0.0356, wR2 = 0.0928
R1 = 0.0418, wR2 = 0.0966
R1 = 0.0428, wR2 = 0.0860
R1 = 0.0665, wR2 = 0.0957
atom in each complex is in a slightly distorted square-
planar environment, being coordinated by a Cl atom, the P
atom and the C and N atoms of the arylpyrazine ligand.
˚
The Pd–N (2.101(3) A) and Pd–P (2.2953(9) A) bond
˚
lengths of 3 are similar to those of related Sphos-pallada-
˚
˚
cycles (2.124(3)–2.126(4) A and 2.2786(9)–2.2848(12) A)
[20, 28, 29], while they are longer than those of the PPh3-
˚
palladacycle 2 (2.091(3) A and 2.2531(9) A) possibly due
˚
to the steric bulk of the Sphos ligand. The crystal of 2
˚
shows intermolecular C–HÁÁÁCl (ClÁÁÁH = 2.828 A) and C–
˚
HÁÁÁN (NÁÁÁH = 2.711 A) hydrogen bonds. In addition,
there are also intermolecular p–p interactions with ca.
˚
3.813 and 3.676 A face–face separations, which link the
molecules into a 1D lamellar structure (Fig. 3). Like 2,
complex 3 also has a one-dimensional lamellar structure
˚
involving different O–HÁÁÁCl (ClÁÁÁH = 2.390 A) hydrogen
bonds and p–p interactions between the neighboring ben-
˚
zene and pyrazine rings (the interplane distance is 3.669 A)
(Fig. 4). However, no obvious C–HÁÁÁN hydrogen bonds
can be found in 3.
Fig. 1 Molecular structure of complex 2. H atoms are omitted for
˚
clarity. Selected bond lengths (A) and angles (°) are as follows:
Pd(1)–C(5) 2.021(4), Pd(1)–P(1) 2.2531(9), Pd(1)–N(1) 2.091(3),
Pd(1)–Cl(1) 2.3690(11), and C(5)–Pd(1)–N(1) 81.10(15), C(5)–
Pd(1)–P(1) 94.63(11), N(1)–Pd(1)–Cl(1) 91.11(108), P(1)–Pd(1)–
Cl(1) 93.09(4)
Buchwald–Hartwig amination reactions
The palladium-catalyzed coupling of amines with aryl
halides, commonly referred to as Buchwald–Hartwig
amination [2, 30, 31], is usually carried out in an organic
solvent in the presence of a strong base such as tBuOK. We
have found that phosphane–palladacycles are very efficient
for the amination of aryl chlorides in water [21]. Consid-
ering that complexes 2 and 3 are water-soluble phosphane–
palladacycles by virtue of hydroxymethyl groups, we were
interested to see whether catalytic activity was observed in
amination (Scheme 2). Based on our previous experiments
[21], we chose the coupling of o-chlorotoluene with p-
toluidine to evaluate the effectiveness of these palladacy-
cles with a catalytic loading of 0.5 mol% and shortening
123

Transition Met Chem (2016) 41:403–411
407
chloroanisole afforded the desired products 4d–h in
excellent yields. It is noteworthy that the present catalytic
system also showed high efficiency for the coupling of
aliphatic or secondary amines. Electron-deficient aryl
chlorides such as 4-chloroacetophenone and 3-chloroni-
trobenzene could be coupled very efficiently with a cat-
alytic loading as low as 0.2 mol%. Even the very sterically
hindered 2-chloromxylene yielded the corresponding ary-
lamines 4k–n in good yields.
Suzuki coupling reactions
Biarylalcohols are important building blocks for the con-
struction of biologically active compounds [22, 32, 33]. We
have previously reported aqueous-phase catalysis of Suzuki
coupling of aryl bromides and chlorides containing water-
soluble hydroxymethyl groups by palladacycles [17, 18].
To develop a general and efficient catalyst system for the
synthesis of substituted biarylmethanols, the Suzuki cou-
plings of common aryl chlorides were studied in water.
Initially, the coupling of o-chlorotoluene with 4-(hydrox-
ymethyl)phenylboronic acid was investigated with various
bases plus 0.2 mol% of complex 3 at 100 °C for 12 h. The
results are summarized in Table 2. Cs2CO3 was found to be
the most effective base; K3PO4Á3H2O and K2CO3 also gave
good yields (entries 2–4). The relative activities of several
catalyst systems for the model reaction were then investi-
gated. The dimer 1 as well as complex 2 and Pd(OAc)2/
Sphos were almost inactive under the same conditions
Fig. 2 Molecular structure of complex 3. H atoms are omitted for
˚
clarity. Selected bond lengths (A) and angles (°): Pd(1)–C(6)
2.024(3), Pd(1)–P(1) 2.2953(9), Pd(1)–N(1) 2.101(3), Pd(1)–Cl(1)
2.3993(9), and C(6)–Pd(1)–N(1) 80.65(11), C(6)–Pd(1)–P(1)
100.36(9), N(1)–Pd(1)–Cl(1) 91.09(7), P(1)–Pd(1)–Cl(1) 89.26(3)
the reaction time from 24 to 12 h. The palladacycle 3 was
found to be slightly more active than the related phos-
phane–palladacycle (yield of 4a is 87 %) [21], producing
the product 4a in a 96 % yield. However, complex 2 was
inactive. Similar to the result with o-chlorotoluene, o-
Fig. 3 One-dimensional lamellar structure of complex 2 formed by C–HÁÁÁCl(N) hydrogen bonds and p–p interactions. Non-hydrogen bonding
H atoms are omitted for clarity
123

408
Transition Met Chem (2016) 41:403–411
Fig. 4 One-dimensional lamellar structure of complex 3 formed by O–HÁÁÁCl hydrogen bonds and p–p interactions. Non-hydrogen bonding H
atoms are omitted for clarity
R
R1
R
R1
Cat, KOH
Water, tBuOH
+ H2N
Cl
NH
4a-na
OCH3
NH
NH
N
NH
4a, 96%; 4a,b 0%
4b, 94%
4c, 91%
4d, 93%
OCH3
OCH3
OCH3
OCH3
NH
NH
4h, 90%
NH
N
O
N
4e, 97%
4f, 92%
4g, 95%
NH
O2N
O
NH
NH
4i,c 85%
4j,c 82%
4k, 81%
4l, 86%
NH
NH
OCH3
4m, 87%
4n, 73%
Scheme 2 Amination of various aryl chlorides catalyzed by palladacycles. Reaction conditions: aryl chlorides (1.0 mmol), amine (1.2 mmol), 3
(0.5 mol %), KOH (3.0 mmol), tBuOH (4.0 mmol), H2O (3 mL), 100 °C, 12 h. aIsolated yield. bCatalyst 2 (0.5 mol %). cCatalyst 3 (0.2 mol %)
123

Transition Met Chem (2016) 41:403–411
409
Table 2 Optimization of reaction conditions for the coupling of o-chlorotoluene with 4-(hydroxymethyl)phenylboronic acid
Cat
Base, H2O
(HO)2B
Cl
+
OH
OH
5a
Entry
Base
Solvent
Catalyst (mol%)
Yield (%)a
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
3(0.2)
52
78
90
81
46
0
3(0.2)
Cs2CO3
K3PO4Á3H2O
KOAc
3(0.2)
3(0.2)
3(0.2)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1(0.1)
2(0.2)
0
Pd(OAc)2/Sphos (0.2/0.3)
1/Sphos (0.1/0.3)
Trace
75
Reaction conditions: o-chlorotoluene (1.0 mmol), 4-HOCH2-PhB(OH)2 (1.5 mmol), base (2.0 mmol), H2O (3 mL), 100 °C, 12 h
a
Isolated yield
Cat 3
CS2CO3, H2O
(HO)2B
Cl
+
OH
OH
R
R
5b-ma
H3CO
OH
OH
OH
OH
OH
5a,b 88%
5b, 97%
5c, 95%
OCH3
5d, 93%
HO
O
O2N
OH
OH
5e, 99%
5f, 99%
HO
5g, 89%; 5g,b 89%
5h, 91%
HO
HO
HO
HO
O
H3CO
OCH3
5i, 90%
5j, 88%
5k, 94%
5l, 85%
5m, 83%
Scheme 3 Coupling of aryl chlorides with (hydroxymethyl)phenylboronic acids catalyzed by 3. Reaction conditions: aryl chlorides (1.0 mmol),
HOCH2-PhB(OH)2 (1.5 mmol), 3 (0.2 mol %), Cs2CO3 (2.0 mmol), H2O (3 mL), 100 °C, 12 h. aIsolated yield. bUsing 4-chlorophenylmethanol
(entries 6–8). However, 1/Sphos generated the product 5a
in a 75 % yield, suggesting that the dimer 1 can act as a
good palladium source for Suzuki coupling in water (entry
9).
conditions. We then studied the reaction of 2-(hydrox-
ymethyl)phenylboronic acid. The yields were slightly
lower than those of the corresponding 4-substituted boronic
acid, presumably due to steric factors, but still were very
respectable. Reactions with ortho-aryl chlorides also pro-
ceeded efficiently to form the products 5l and 5m in good
yields.
In subsequent experiments, the coupling of a variety of
aryl chlorides with (hydroxymethyl)phenylboronic acids
was investigated (Scheme 3). Both electron-poor and
electron-rich aryl chlorides reacted with 4-(hydrox-
ymethyl)phenylboronic acid to provide the products 5b–
g in excellent yields under the optimized reaction
The scope of the Suzuki reaction was further investi-
gated by varying the arylboronic acid. The couplings of
4-chlorophenylmethanol with 2-methylphenylboronic acid
123

410
Transition Met Chem (2016) 41:403–411
R
R
Cat 3
Cs2CO3, H2O
Cl
(HO)2B
+
OH
OH
N
N
6a-ha
OH
OH
N
OH
N
OH
OH
H3CO
N
N
6a, 93%
6b, 91%
6c, 89%
6d, 86%
6h, 90%
N
N
N
O
F3C
OH
OH
OH
N
N
N
6e, 96%
6f, 97%
6g, 94%
Scheme 4 Coupling of N-heteroaryl chlorides with 4-(hydroxymethyl)phenylboronic acid catalyzed by 3. Reaction conditions: N-heteroaryl
a
chlorides (1.0 mmol), 4-HOCH2-PhB(OH)2 (1.5 mmol), 3 (0.2 mol %), Cs2CO3 (2.0 mmol), H2O (3 mL), 100 °C, 12 h. Isolated yield
HO
N
HO
R
R
Cat 3
Cs2CO3, H2O
Cl
(HO)2B
+
N
7a-ha
HO
HO
HO
N
HO
N
N
H3CO
N
7a, 90%
7b, 87%
7c, 85%
7d, 81%
HO
HO
HO
HO
N
N
O
F3C
N
N
N
N
7e, 91%
7f, 93%
7g, 86%
7h, 83%
Scheme 5 Coupling of N-heteroaryl chlorides with 2-(hydroxymethyl)phenylboronic acid catalyzed by 3. Reaction conditions: N-heteroaryl
a
chlorides (1.0 mmol), 2-HOCH2-PhB(OH)2 (1.5 mmol), 3 (0.2 mol %), Cs2CO3 (2.0 mmol), H2O (3 mL), 100 °C, 12 h. Isolated yield
and 2-methoxy-phenylboronic acid afforded the products
5a and 5g in good yields under the same conditions
(Scheme 3). Suzuki coupling of heteroarylboronic acids is
an important method for the synthesis of biologically active
compounds [34, 35]. However, 2-pyridine-derived boronic
acids are a particularly difficult class of substrate for the
Suzuki reaction [36, 37]. Therefore, the coupling of 2-N-
heteroaryl chlorides with arylboronic acids provides a
valuable synthesis of the corresponding 2-N-heterocyclic
biarylmethanols. In the present study, we investigated the
Suzuki coupling of a variety of 2-N-heteroaryl chlorides
with (hydroxymethyl)-phenylboronic acids. As expected,
the catalyst was very effective for the coupling of 2-N-
heteroaryl chlorides with 4-(hydroxymethyl)phenylboronic
acid, giving the products 6a–h in excellent yields
(Scheme 4). This protocol was also found to proceed suc-
cessfully with 2-(hydroxymethyl)phenylboronic acid, again
furnishing good yields (Scheme 5).
Conclusion
Two water-soluble PPh3 and Sphos-palladacycles containing
hydroxymethyl groups have been synthesized and character-
ized. Complex 3 proved to be an efficient catalyst for both
amination and Suzuki coupling reactions of aryl chlorides in
water. Hence, this work provides a practical methodology for
the synthesis of arylamines and substituted biarylmethanols.
Acknowledgments We are grateful to the Innovation Scientists and
Technicians Troop Construction Projects of Henan Province
(154100510015), the tackle key problem of science and technology
Project of Henan Province (162102210125) and the Science Foundation
of Henan Education Department (14A150049 and 15B150008).
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