P-arylation of aryl halides by an environmentally compatible method

Article abstract of DOI:10.1139/cjc-2017-0364

In this paper, palladium-DABCO complex supported on magnetic nanoparticles was successfully used as a new magnetically recoverable heterogeneous catalyst for the synthesis of arylphosphonates via P-arylation of different types of aryl halides (aryl iodides/bromides/chlorides and benzene boronic acid/sulfonate), with phosphite esters (triethyl/triphenyl/tri-iso-propyl/diethyl/diphenyl/di-iso-propyl phosphite) in neat water without using any additive. The heterogeneous catalyst was easily isolated from the reaction mixture by an external magnet and reused five times without significant degradation in its activity.

Full text of DOI:10.1139/cjc-2017-0364

Page 1 of 16
P-Arylation of aryl halides by an environmentally compatible method
*
Sara Sobhani , Zahra Vahidi
Department of Chemistry, College of Sciences, University of Birjand, Birjand, Iran
E-mail: ssobhani@birjand.ac.ir; sobhanisara@yahoo.com; Fax: +98 56 32202065; Tel: +98
56 32202065

Page 2 of 16
Abstract
In this paper, palladium-DABCO complex supported on magnetic nanoparticles was
successfully used as a new magnetically recoverable heterogeneous catalyst for the synthesis
of arylphosphonates via P-arylation of different types of aryl halides (aryl
iodides/bromides/chlorides and benzene boronic acid/sulfonate), with phosphite esters
(triethyl/triphenyl/tri-iso-propyl/diethyl/diphenyl/di-iso-propyl phosphite) in neat water
without using any additive. The heterogeneous catalyst was easily isolated from the reaction
mixture by an external magnet and reused five times without significant degradation in its
activity.
Keywords: Arylphosphonates. Hirao reaction. Heterogeneous catalyst. Magnetic
nanoparticles. Palladium

Page 3 of 16
Introduction
Arylphosphonates are valuable compounds in a variety of fields, especially as intermediates in
1
organic synthesis, in the preparation of biologically active materials, and in designing fuel
2
3
cell membranes and materials with special optical properties. The widespread use of
arylphosphonates in material sciences and biological chemistry caused a demand for
improved protocols for P-arylation. The transition metal catalyzed cross-coupling reaction
between aryl and vinyl bromides and diethylphosphite is the first and the most widely-used
4
methods for the synthesis of arylphosphonates (Hirao reaction). This classic method has
,5
6 7,8
been significantly modified and improved in terms of type of the catalyst, palladium
9
source, and reaction conditions
10,11
to meet the requirements of contemporary synthetic
organic demands. Although the reported methods are suitable for certain syntheses, some of
these procedures have one or more disadvantages such as the use of volatile and hazardous
12,13,14
organic solvents,
15,16
17,18
the requirement for expensive ligands
and a microwave oven,
and severe problems related to the separation, recovery, and instability of the homogeneous
catalysts. Thus, effort to elaborate greener variations of Hirao reaction for the preparation of
arylphosphonates is highly desirable.
One way to have a greener process in organic synthesis is minimize the amount of waste
formed by immobilization of homogeneous catalysts on an insoluble support.
Heterogenization of homogeneous catalysts would simplify removal and reuse of the catalyst.
Various solid supports such as metal oxides, zeolites, mesoporous and amorphous silica,
carbon material and polymers have been used for heterogenization of homogeneous catalysts.
Among the solid supports, magnetic nanoparticles (MNPs) serve as an attractive platform for
catalyst immobilization because of their magnetic nature, which allows facile recovery and
recycling of the catalyst and eliminates the requirement of catalyst filtration after completion

Page 4 of 16
19-24
of the reaction.
Moreover, MNPs have unique physical properties including high surface
2
5,26
area, surface modification ability and excellent thermal and chemical stability.
In recent
years, application of magnetically recoverable heterogeneous catalysts for different organic
reactions such as reductions, oxidations, couplings, and multicomponent reactions has
2
7,28
become increasingly popular and attracted considerable practical attention.
In contrast to
the considerable success achieved in the field of magnetically separable nanocatalysts, the use
of these kinds of catalysts for P-arylation remains unexplored.
Another approach to a green process is the replacement of volatile organic solvents by an
environmentally benign reaction media such as water. Water is cheap, readily available, non-
toxic, safe, non-flammable and sustainable. Apart from the economic and environmental
benefits, water also exhibits unique physical and chemical activity that leads to unique
selectivity compared with organic solvents. To the best of our knowledge, there are a few
29-32
reports for the synthesis of arylphosphonates via P-arylation in water.
The reported
methods mainly suffer from requiring inert atmosphere, microwave irradiation, high
temperature, and tedious work-up procedures leading to copious amount of toxic wastes or
using unstable dialkyl phosphites in water and therefore require an additive.
To benefit the valuable applications of MNPs and the unique properties of water as an
environmentally benign reaction media, and in continue of our recent works on the
3
3-41
development of new heterogeneous catalysts,
diazabicyclo[2.2.2]octane) complex supported on γ-Fe
DABCO-γ-Fe O ) as a new heterogeneous catalyst for the synthesis of arylphosphonates in
herein, we report palladium-DABCO (1,4-
2
O
3
magnetic nanoparticles (Pd-
2
3
neat water without using any additive.

Page 5 of 16
Experimental
2
.1. General procedure for the synthesis of arylphosphonates catalyzed by Pd-DABCO-
γ-Fe in neat water
Pd-DABCO-γ-Fe (2.5-3.6 mg, 0.07 or 0.1 mol%) was added to a stirring mixture of aryl
halide (1 mmol), phosphite ester (2 mmol) and Et N (4 mmol) in water and heated at 100 ˚C.
2
O
3
2
O
3
3
Progress of the reaction was monitored by TLC. After an appropriate time (Table 2), the
reaction mixture was cooled to room temperature. The catalyst was separated using an
external magnet, washed several times with ethyl acetate, dried and reused for a new run. The
organic compound was extracted with ethyl acetate (3 × 10 mL) from aqueous layer and dried
2 4
over anhydrous Na SO , filtered and concentrated in vacuum. The crude organic mixture was
then purified by silica gel column chromatography using n-hexane/ethyl acetate (3/1) as
eluent to obtain the desired product (Table 2).
Results and discussion
The designed Pd catalyst denoted as Pd-DABCO-γ-Fe
2
O
3
were readily prepared via a 4-step
procedure following our previously reported route (Scheme 1): (1) synthesis of γ-Fe NPs
by a chemical co-precipitation technique of ferric and ferrous ions in alkali solution; (2)
functionalization of γ-Fe with 3-chloropropyl trimethoxysilane; (3) condensation of
chloro-functionalized γ-Fe O with DABCO and (4) complexation of DABCO functionalized
3
3
2
O
3
2
O
3
2
3
2 3 2
γ-Fe O with Pd(OAc) in dry acetone.
Scheme 1

Page 6 of 16
2 3
The catalytic activity of Pd-DABCO-γ-Fe O was studied in the P-arylation reaction. At first,
coupling reaction of iodobenzene (1 mmol) and triethylphosphite (2 mmol) in the presence of
˚
(0.07 mol%) at 100 C as a test model was investigated for optimizing
Pd-DABCO-γ-Fe
2
O
3
reaction parameters such as the base, solvent and amount of the catalyst (Table 1). Among the
examined bases, Et N showed the best results for this reaction in terms of reaction time and
yield (Entries 1-4). A trace amount of the desired cross-coupling product was obtained after
4 h in the absence of a base (Entry 5). Study of the model reaction in different solvents such
as, H O, DMF, toluene, EtOH, THF and under solvent-free conditions showed that the solvent
had a crucial role in this coupling reaction. Water was found to be the best reaction medium
Entry 3). The yield of the product in a similar reaction at 80 °C was decreased to 57% (Entry
3
2
2
(
1
1). Coupling reactions did not take place in the absence of the catalyst even after 24 h (Entry
2). Only 43% of the product was achieved by decreasing the amount of the catalyst to 0.03%
1
(Entry 13). When the reaction was carried out in the presence of lower amount of
triethylphosphite, the yield of the desired product was decreased (Entry 14).
Table 1
On having the optimized reaction conditions (Table 1, Entry 3), the scope of the present
catalytic system for the P-arylation of a range of aryl halides was extended. As shown in
Table 2, the reaction of aryl iodide with various phosphite esters furnished the corresponding
arylphosphonates in good to excellent yields without using any additive (Entries 1-6). The
2 3
coupling of 4-iodoanisole with triethylphosphite using 0.1 mol% of Pd-DABCO-γ-Fe O
proceeded in 94% yield in 2.5 h (Entry 7). Moreover, bromobenzene and aryl bromides
bearing the electron donating and electron withdrawing groups at the para position were
reacted with triethylphosphite in 82-97% yields in 3-8 h (Entries 9-11 and 13). The
methodology was also tolerant of sensitive functional groups such as carbonyls and styrene
(Entries 14,15 and 23). Moreover, 1-chloro-4-iodobenzene and 1-bromo-4-chlorobenzene

Page 7 of 16
selectively furnished diethyl 4-chlorophenylphosphonate as the only product in 96 and 92%
yields, respectively (Entries 8 and 12). Under the present reaction conditions, the coupling
reaction of 1,4-diiodo and 1,4-dibromobenzene with triethylphosphite worked well to afford
diethyl 4-iodophenylphosphonate and diethyl 4-bromophenylphosphonate in 92 and 94%
yields, respectively (Entries 16 and 17). Both halogens in 1,4-diiodo and 1,4-dibromobenzene
were replaced by twice amount of phosphite ester under the present reaction conditions
(Entries 18 and 19). More importantly, the coupling reaction of aryl chlorides with
triethylphosphite proceeded well in the presence of this catalytic system (Entries 20-22). This
method was also applicable for some other aryl halides such as aryl tosylate, benzene boronic
acid and vinyl bromide (Entries 24-26).
Table 2
The stability, durability, and reusability of the heterogeneous catalysts are important.
2 3
Therefore, the recycling performance of Pd-DABCO-γ-Fe O was studied in the P-arylation
reaction of aryl iodide in water. Once the reaction was completed in the first run, the catalyst
was recovered by an external magnet, followed by washing with ethyl acetate and dried under
vacuum. The catalyst was carefully reused for a subsequent five cycles and resulted in 98, 98,
96, 92 and 83% yields of the desired product, respectively.
To determine whether the Pd catalyst is truly heterogeneous in nature in our catalytic system,
a hot filtration test was performed. To do this, the solid catalyst was removed from the
reaction mixture by an external magnet after the phosphonation of aryl iodide had run for 0.5
h (conversion 35%). The remaining solution was continually stirred at 100 ˚C. After 2 h, the
analysis of the catalyst-free reaction showed no change in the progress of the reaction.
As a final point, in order to show the merit of the present method for the synthesis of
arylphosphonates, we have compared our results with those reported in the literature for the
synthesis of these important scaffolds in water (Table 3). These results indicate well the

Page 8 of 16
superior activity of Pd-DABCO-γ-Fe
catalyst loading and higher TON (mol of the product/mol of the catalyst) and TOF
TON/reaction time in h). Using a magnetically recyclable heterogeneous catalyst which
works in pure water without requiring any additive [SDS (sodium dodecyl sulphate), TBAB
tetrabutylammonium bromide), Zn, iso-propanol] or activation by microwave irradiation are
the other advantageous of the present method. It is worth to mention that Pd-DABCO-γ-Fe
2 3
O than those of other promoters especially for low
(
(
2
O
3
showed a high activity for C-P bond formation, when different phosphite esters (triphenyl/ tri-
iso-propyl/ diethyl/ diphenyl/di-iso-propyl phosphite) were used in the reaction (Table 3,
entry 1). Similar phosphite esters did not react with aryl halides in the presence of our
previously reported catalyst (Pd-imino-Py-γ-Fe
2 3
O ) (Table 3, entry 2).
Table 3
Conclusion
In summary, we have successfully developed a new convenient protocol for the
synthesis of aryl phosphonates by the P-arylation of aryl halides (aryliodides/
bromides/chlorides and benzene boronic acid/sulfonate) with different types of phosphite
esters (triethyl/ triphenyl/ tri-iso-propyl/ diethyl/ diphenyl/di-iso-propyl phosphite) in neat
2 3
water using Pd-DABCO-γ-Fe O as a magnetically recyclable heterogeneous catalyst.
Because of the utilization of (a) water as solvent without requiring any additive or activator,
and (b) a small amount of a simply recyclable heterogeneous catalyst, this method is an
environmentally friendly and sustainable reaction for carbon-phosphorus coupling.
Acknowledgements. Financial support of this project by University of Birjand Research
Council is appreciated
.

Page 9 of 16
Supplementary data
Supplementary data containing the elemental analysis of the products related to this
article is provided.
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Page 12 of 16
Table 1 Pꢀarylation of aryl iodide with triethylphosphite catalyzed by PdꢀDABCOꢀγꢀFe O
2
3
under different reaction conditions
O
I
P(OEt)2
PdꢀDABCOꢀγꢀFe O3
2
+
P(OEt)3
Base
a
Entry
Catalyst (mol%)
0.07
Solvent
Time (h)
Isolated Yield (%)
1
2
3
4
K CO
H O
2
4
84
93
98
92
Trace
64
53
52
29
63
57
ꢀ
2
3
2
0.07
KOH
H O
2
0.07
Et N
3
H O
2
1
0.07
(isoꢀPr) N
H O
2
5
3
b
5
0.07
ꢀ
H O
2
24
6
6
7
8
9
0.07
Et N
3
DMF
toluene
EtOH
THF
ꢀ
0.07
Et N
3
3
0.07
Et N
3
3
0.07
Et N
3
3
1
0
0.07
Et N
3
4
c
1
1
2
0.07
Et N
3
H O
2
4
d
1
1
ꢀ
Et N
3
H O
2
24
2
1
3
e
0.03
Et N
3
H O
2
43
86
4
0.07
Et N
3
H O
2
2
a
Reaction conditions: iodobenzene (1 mmol), triethylphosphite (2 mmol, except for entry 14), base (4 mmol, except
for entry 5), PdꢀDABCOꢀγꢀFe O (except for entry 12), 100 ˚C (except for entry 11).
2
3
b
No base.
c
Temperature = 80 ˚C.
d
No catalyst.
e
Triethylphosphite (1.5 mmol).

Page 13 of 16
Table 2 Pꢀarylation of various aryl halides with different phosphite esters catalyzed by Pdꢀ
DABCOꢀγꢀFe O
2
3
O
PdꢀDABCOꢀγꢀFe O
(0.07 or 0.1 mol%)
2
3
P(OR2)2
P(OR2)3
or
X
R1
R1
+
2
o
HP(O)(OR ) Et N, 100 C, H O
2
3
2
Entry
Aryl halide
C H I
Phosphite ester
P(OEt)3
Time (h)
Isolated Yield (%)
Ref.
32
1
2
1
4
98
82
6
5
HP(O)(OEt)
P(OPh)3
32
C H I
2
6
5
3
4
5
6
C H I
5
6
83
76
96
77
94
96
97
91
83
92
82
52
67
92
94
74
74
96
94
81
51
72
51
73
42
42
32
32
6
5
C H I
HP(O)(OPh)2
P(OꢀisoꢀPr)3
HP(O)(OꢀisoꢀPr)2
P(OEt)3
6
5
C H I
4
6
5
C H I
2
6
5
b
7
4ꢀMeOC H I
2.5
2
6
4
32
32
32
32
32
32
32
42
43
42
32
4
8
4ꢀClC H I
P(OEt)3
6
4
b
9
C H Br
P(OEt)3
3
6
5
b
1
0
4ꢀMeOC H Br
P(OEt)3
8
6
4
1
1
2
3
4
5
6
4ꢀMeC H Br
P(OEt)3
6
6
4
1
1
1
1
1
4ꢀClC H Br
P(OEt)3
5
6
4
4ꢀNO C H Br
P(OEt)3
4
2
6
4
4ꢀCH COC H Br
P(OEt)3
7
3
6
4
4ꢀCH =CHC H Br
P(OEt)3
3
2
6
4
4ꢀIC H I
P(OEt)3
4
6
4
b
1
7
8
9
4ꢀBrC H Br
P(OEt)3
3
6
4
c
c
1
1
4ꢀIC H I
P(OEt)3
13
15
5
6
4
4ꢀBrC H Br
P(OEt)3
6
4
4
2
0
C H Cl
P(OEt)3
6
5
32
32
32
42
32
32
32
2
2
2
1
2
3
4ꢀMeC H Cl
P(OEt)3
6
6
4
4ꢀO NC H Cl
P(OEt)3
5
2
6
4
4ꢀH CCOC H Cl
P(OEt)3
8
3
6
4
b
2
4
5
C H OTs
P(OEt)3
8
6
5
b
2
C H B(OH)
2
P(OEt)3
6
6
5
2
6
C H CH=CHBr
P(OEt)3
7
6
5
a
Reaction conditions: aryl halide (1 mmol), phosphite ester (2 mmol, except for entries 18 and 19), Et N (4 mmol,
3
except for entries 18 and 19), PdꢀDABCOꢀγꢀFe O (0.07 mol%, except for entries 7,9,10, 17, 24 and 25), 100 ˚C.
2
3
b
0
.1 mol% PdꢀDABCOꢀγꢀFe O .
2 3
c
Triethylphosphite (4 mmol), Et N (8 mmol).
3

Page 14 of 16
Table 3 Comparison of the present method with those reported in water as reaction media.
O
X
P(OR)2
P(OR)3
Or
HP(OR)2
Entry Phosphite ester
X
Catalyst (mol%) Conditions
Time Yield TON TOF
Ref.
this
ꢀ
1
(
h)
(%)
(h )
1
P(OEt)3,
I, Br, Cl
OTs,
PdꢀDABCOꢀγꢀ
Fe O [0.07 or
H O, Et N,
1ꢀ15 51ꢀ98 510ꢀ
85ꢀ
2
3
HP(O)(OEt)2,
P(OPh)3,
100 °C
1400 1400
work
2
3
B(OH)2
0.1]
HP(O)(Ph)2, P(Oꢀ
isoꢀPr)3,
HP(O)(OꢀisoꢀPr)2
P(OEt)3
2
3
4
I, Br, Cl
OTs,
PdꢀiminoꢀPyꢀγꢀ
Fe O [0.1]
H O, Et N,
1ꢀ15 57ꢀ98 570ꢀ
38ꢀ
34
2
3
100 °C
980
980
2
3
B(OH)2
I, Br, Cl
HP(O)Ph2
Pd/C [1]
H O, K CO
3,
1
18ꢀ87 18ꢀ
87
18ꢀ87 30
2
2
Microwave,
80 °C
1
HP(O)(Oꢀiso-Pr)2, I, Br, Cl
Palladacycle
H O, TBAB, 16
2
53ꢀ99 53ꢀ
35ꢀ99 99
35ꢀ
3.3ꢀ
6.1
31
a
HP(O)(Ph)2
(II) [1]
KF, reflux,
isoꢀPrOH,
N2
2.1ꢀ
6.1
HP(O)(Oꢀiso-Pr)2
65ꢀ99 99
Palladacycle
b
(
I)/XꢀPhos [1]
65ꢀ
4.0ꢀ
6.1
9
9
5
6
HP(O)(Ph)2,
P(OEt)3
I, Br
NiCl .6H O [10
H O, Zn,
15
75ꢀ97 3.7ꢀ
9.7
0.1ꢀ
0.6
29
35
2
2
2
and 20]
2,2'ꢀ
and
24
bipyridine,
7
0 °C
I, Br, Cl,
OTs,
Pdꢀ2ꢀATPꢀγꢀ
Fe O [0.1]
H O, SDS,
2
1.5ꢀ
15
48ꢀ97 480ꢀ
970
32ꢀ
100 °C
646.6
2
3
B(OH)2

Page 15 of 16
7
P(OEt)3
I, Br, Cl
PdCl [4.4]
H O, TBAB, 1.5ꢀ6 65ꢀ99 14.7ꢀ 1.7ꢀ15 32
2
2
P(Oꢀiso-Pr)3
nꢀPr N, 100
22.5
3
°C
a
Cyclopalladated ferrocenylimine.
b
2
ꢀ(Dicyclohexylphosphanyl)ꢀ2,4,6ꢀtriꢀisoꢀpropylꢀ1,1ꢀbiphenyl.
c
TON = mol of the product/mol of the catalyst.
TOF = TON/reaction time in h.
d

Page 16 of 16
Scheme 1 Synthesis of Pd-DABCO-γ-Fe O
2
3