Pd(OAc)2-catalyzed synthesis of benzyl phenyl ether derivatives with H2O2 as an oxidant in neat water

Article abstract of DOI:10.1016/j.catcom.2018.10.026

A new protocol for Pd(OAc)₂-catalyzed reactions of different benzyl bromides and various arylboronic acids has been developed to form functionalized benzyl phenyl ethers. This method represents the first instance where arylboronic acid is used as a reaction substrate for benzyl phenyl ether synthesis with H₂O₂ as the green oxidant under atmospheric oxygen and pure H₂O as an environmental friendly solvent without the requirement for phosphine- and N-based ligands, remarkable functional group tolerance, and considerable yield.

Full text of DOI:10.1016/j.catcom.2018.10.026

Accepted Manuscript
Pd(OAc)2-catalyzed synthesis of benzyl phenyl ether derivatives
with H2O2 as an oxidant in neat water
Qian-Qian Chen, Hui-Xian Zhang, Jian-Xin Yang
PII:
DOI:
Reference:
S1566-7367(18)30557-0
doi:10.1016/j.catcom.2018.10.026
CATCOM 5537
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Catalysis Communications
Received date:
Revised date:
Accepted date:
28 July 2018
24 October 2018
25 October 2018
Please cite this article as: Qian-Qian Chen, Hui-Xian Zhang, Jian-Xin Yang ,
Pd(OAc)2-catalyzed synthesis of benzyl phenyl ether derivatives with H2O2 as an oxidant
in neat water. Catcom (2018), doi:10.1016/j.catcom.2018.10.026
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ACCEPTED MANUSCRIPT
Pd(OAc)2-catalyzed synthesis of benzyl phenyl ether
derivatives with H2O2 as an oxidant in neat water
Qian-Qian Chen, Hui-Xian Zhang, Jian-Xin Yang*
Hainan Provincial Fine Chemical Engineering Research Center, Key Laboratory of
Green Catalysis and Reaction Engineering of Haikou, College of Chemistry and
Chemical Engineering, Hainan University, Haikou 570228, PR China
Abstract
A new protocol for Pd(OAc)2-catalyzed reactions of different benzyl bromides
and various arylboronic acids has been developed to form functionalized benzyl
phenyl ethers. This method represents the first instance where arylboronic acid is used
as a reaction substrate for benzyl phenyl ether synthesis with H2O2 as the green
oxidant under atmospheric oxygen and pure H2O as an environmental friendly solvent
without the requirement for phosphine- and N-based ligands, remarkable functional
group tolerance, and considerable yield.
Keywords: Pd(OAc)2 catalyst, arylboronic acid, benzyl phenyl ethers, H2O2, H2O
1. Introduction
Benzyl phenyl ethers are important building blocks in pharmaceuticals, as well
as in biologically active compounds. Benzyl phenyl ether diamidines with
trypanocidal activity [1], benzyl phenyl ether diamidine derivatives with antiprotozoal
activity [2], benzyloxybenzaldehyde derivatives with anticancer activity [3], and
benzyloxyacetophenone derivatives as inhibitors of monoamine oxidase B [4] are
highly in demand for various synthetic approaches toward benzyl phenyl ether
derivatives.
*Corresponding author.
E-mail address: yangjxmail@hainu.edu.cn (J. Yang).

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The most conventional approach to synthesize benzyl phenyl ether derivatives is
phenol benzylation, which was first reported by McKillop by using dichloromethane
as a solvent in 1974 [5]. Various synthetic strategies have been developed for the
efficient synthesis of benzyl phenyl ether derivatives. These synthetic strategies
include the use of crown ethers [6], phase-transfer catalysis [7-8], ionic liquids [9], etc.
[10]. However, the use of high temperature and strong base as well as toxic, volatile,
and flammable organic solvent significantly decreases the appeal of these strategies.
In C-O ether bond formation, Pd- or Cu-catalyzed etherifications of alcohols or
phenols with organometalloid reagents, such as organo-Bi [11], -Sn [12], and -B
[13-15], have received considerable attention. The advantages of organoboron
reagents, such as low toxicity, tolerance toward various functional groups, availability,
inert properties toward H2O and oxygen [16], and the synthesis of benzyl phenyl ether
derivatives from the catalytic coupling of organoboron compounds with benzyl
alcohols, have been reported by Batey [17]. This reaction is limited by the fact that
10% of Cu(OAc)2 and 20% of ligand are required, and dichloromethane is used as a
solvent (Scheme 1). Consequently, the development of economical, accessible, and
low catalytic amount of ligand-free Pd(II) catalytic systems for the synthesis of benzyl
phenyl ethers is urgently needed. Water is also the leading candidate in the synthesis
of benzyl phenyl ether derivatives because of its low cost, nonflammability,
nontoxicity, and low environmental concerns [18]. Herein, we report the first
Pd(OAc)2-catalyzed reaction that uses benzyl halides as coupling partners by using
arylboronic acids as the aryl source and H2O2 as the green oxidant for the synthesis of
benzyl phenyl ethers under atmospheric oxygen in pure H2O (Scheme 2). Although
this new protocol is less cost effective than the well-established phenol benzylation
with benzyl halides, benzyl alcohol coupling with aryl halide, and the

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Chan-Lam-Evans coupling of benzyl alcohol and arylboronic acid for benzyl phenyl
ether synthesis, the current system represents a novel alternative to the existing
methodologies and can be useful for the synthetic literature.
Batey’s work[17]:
Scheme 1
Our work:
Scheme 2
2. Results and discussion
2.1 Optimization of the reaction conditions
4-Cyanobenzylbenzyl bromide and phenylboronic acid were first examined as
standard substrates in the presence of a catalytic amount of Pd(OAc)2 by using H2O2
(30% aq.) as the oxidant under atmospheric oxygen in pure H2O. After stirring for 10
h in 80 °C oil bath, a yield of 85% 4-(phenoxymethyl)benzonitrile was obtained with
1 mol% Pd(OAc)2 and 0.2 mL of H2O2 (Table 1, Entry 2). Then, the effect of the
amount of H2O2 on the reaction was examined. Increasing the amount of H2O2 from
0.1 mL to 0.3 mL (Table 1, Entries 1-3) decreased the yield, along with
4-(phenoxymethyl)benzonitrile. Small amounts of the corresponding phenol,
4-cyanobenzyl alcohol, 4-cyanobenzaldehyde, biphenyl, and 4-benzylbenzonitrile
were detected by GC-MS. Changing the amount of Pd(OAc)2 to 1.2 mol% showed
insignificant effect on yield (Table 1, Entry 5). For the further optimization of the
reaction conditions with certain amounts of Pd(OAc)2 and H2O2 fixed at 1 mol% and
0.1 mL, respectively, survey on the role of bases for this reaction showed that NaOH
was the most suitable base (Table 1, Entry 1). KOH and Cs2CO3 were also the

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appropriate choices and resulted in 83% and 85% yields, respectively (Table 1,
Entries 6-7). Other bases, such as Na2CO3, K2CO3, and NEt3, only obtained yield of
the desired product ranging from 57% to 69% (Table 1, Entries 8-10). Decreasing the
reaction temperature to 25 °C decreased the yield to 43%, and increasing the
temperature to 100 °C showed insignificant effect on yield (Table 1, Entries 11-13).
Prolonging the reaction time from 5 h to 15 h (Table 1, Entries 14-15) resulted in the
highest yield of the desired product for 10 h (Table 1, Entry 1).
Table 1
Optimization of the reaction conditionsa
Entry H2O2 Base
(mL) (0.8 mmol) (mol%) (oC)
Pd(OAc) Temperature Time Yieldb
(h)
10
10
10
10
10
10
10
10
10
10
10
10
10
5
(%)
89
85
56
71
90
83
85
69
57
64
43
78
87
78
87
1
0.1
0.2
0.3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
1.0
1.0
1.0
0.5
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
80
80
80
80
80
80
80
80
80
80
25
60
100
80
80
2
3
4
5
6
7
8
Cs2CO3
NEt3
9
Na2CO3
K2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
10
11
12
13
14
15
15
aReaction conditions: 0.5 mmol of 4-cyanobenzylbenzyl bromide, 0.6
mmol of phenylboronic acid, 3.0 mL of H2O, air.
bIsolated yield.
2.2 Scope and limitations of substrates
In order to clarify the scope and limitations of this reaction, we conducted a
series of reactions of different benzyl bromides and various arylboronic acids under
optimized conditions. As shown in Table 2, the substituted arylboronic acids

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examined bearing electron-donating or -withdrawing groups on either ortho-, metra-,
or para-position and reacted readily with 4-cyanobenzylbenzyl bromide to obtain
considerable yield of the corresponding benzyl phenyl ethers. (Table 2, Entries 2-10),
Ortho-substituted arylboronic acids increased the effectivity of the reaction with the
isolated yield of 74% because steric hindrance prevented the self-coupling of
arylboronic acid identified by GC-MS (Table 2, Entry 3). Then, the substituted benzyl
bromides were investigated. Compared with the reactions of benzyl bromides with
minimal electron-withdrawing or -donating groups, such as fluro and methyl group
with 4-flurophenylboronic acid (Table 2, Entries 13-14), benzyl bromides with strong
electron-withdrawing or -donating groups, such as cyano and methoxy group, were
the suitable substrates to obtain high yields (Table 2, Entry 8). When arylboronic acid
with sensitive functional group, such as thioether group, reacted with
4-cyanobenzylbenzyl bromide under oxidation condition, the yield of the desired
product also increased up to 83% (Entry 15).
Table 2
Pd(OAc)2-catalyzed synthesis of benzyl phenyl ether derivatives: Substrate scopea
Benzyl
bromides
Entry
1
Arylboronic acids
Products
Yieldb
89
Br
Br
Br
B(OH)2
NC
NC
NC
H3CO
B(OH)2
2
3
72
74
OCH3
B(OH)2

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Br
B(OH)2
4
5
74
71
NC
NC
HO
Br
B(OH)2
Br
Br
Cl
F
B(OH)2
B(OH)2
B(OH)2
6
7
8
80
83
85
NC
NC
NC
Br
Br
F
Br
Br
9
82
NC
NC
F
B(OH)2
NC
B(OH)2
10
11
92
85
Br
Br
O
B(OH)2
B(OH)2
OCH3
H3CO
12
13
14
15
81
68
66
83
O
Br
F
F
B(OH)2
B(OH)2
H3C
Br
F
Br
NC
aReaction conditions: conducted with 0.5 mmol of benzyl bromide, 0.6 mmol of
arylboronic acid, 1 mol% Pd(OAc)2, 0.1 mL of H2O2, 0.8 mmol of NaOH, 3.0 mL
of H2O at 80 °C in the air for 10 h.

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b Isolated yield.
A plausible mechanism is envisioned with the aid of previous reports in the
literature (Scheme 3). Initially, Pd(OAc)2 Awas followed by a transmetalation of the
benzyl group from benzyl bromide to palladium to form intermediate B [19].
Research work by Prakash shows that H2O2 equivalents are found to be much safer,
convenient, and efficient reagent systems for the ipso-hydroxylation of arylboronic
acids to the corresponding phenols in high yields at a faster rate [20]. Then, Pd(II)
intermediate C is produced by the reaction of phenol with intermediate B. Reductive
elimination ensues to form the products and Pd(0) species, which is then oxidized by
H2O2 to regenerate the palladium(II) to complete the catalytic cycle.
Scheme 3
3. Experimental
Benzyl bromides, arylboronic acids, and Pd(OAc)2 were obtained commercially
1
from Alfa Aesar and used without further purification. H and 13C NMR were
recorded on a Bruker Avance III (400 MHz) spectrometer by using tetramethylsilane
as the internal standard and CDCl3 as the solvent. All benzyl bromide and arylboronic
acid reactions were conducted in air. A reaction tube was charged with 0.5 mmol of
benzyl bromide, 0.6 mmol of arylboronic acid, 0.005 mmol of Pd(OAc)2, 0.8 mmol of
NaOH, and 3 mL of H2O. This mixture was added with 0.1 mL of H2O2 (30%),,and

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then the mixture was stirred at 80 °C in the air for 10 h and cooled to room
temperature. Then, saturated NH4Cl was added, and the resulting mixture was
extracted with AcOEt (3 × 10 mL). The combined organic layers were dried with
Na2SO4. The solution was filtered and evaporated in a vacuum, and the residue was
purified through flash chromatography (hexane/AcOEt) to obtain the product.
4. Conclusions
We have developed a new and efficient reaction of benzyl bromides and
arylboronic acids to generate benzyl phenyl ether derivatives by using ligand-free
Pd(OAc)2 as the catalyst and H2O2 as the oxidant. The reaction was completed
smoothly, and we obtained considerable yields of the corresponding substituted
benzyl phenyl ethers. Remarkable advantages of this protocol include the use of H2O2
as the green oxidant under atmospheric oxygen and pure H2O as an environmental
friendly solvent without the need for phosphine- and N-based ligands and remarkable
functional group tolerance. The described reactions of benzyl bromides and
arylboronic acids should be efficient and indicate substantial improvement to the
known synthesis methods for benzyl phenyl ethers because of these advantages.
Further detailed investigations on this reaction mechanism and synthetic applications
are ongoing in our laboratory.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (no.
51663009).
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Graphical abstract

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Highlights:
1. A new protocol for Pd(OAc)2-catalyzed synthesis of benzyl phenyl
ethers.
2. H2O2 as the green oxidant.
3. Pure H2O as an environmentally friendly solvent.
4. Without the requirement for phosphine- and N-based ligands.
5. Remarkable functional group tolerance and considerable yield.