An improved procedure for the synthesis of aryl phosphonates by palladium-catalysed cross-coupling of aryl halides and diethyl phosphite in polyethylene glycol

Article abstract of DOI:10.3184/174751913X13686082295417

A general and greener protocol for the synthesis of aryl phosphonates by the cross-coupling of aryl halides and diethyl phosphite using tetrakis(triphenylphosphine)palladiume/triethylamine/polyethylene glycol 600 [Pd(PPh3)4/ Et3N/PEG 600] as an efficient catalytic system has been developed. This procedure also avoids hazardous solvents and is therefore an eco-friendly alternative to the existing methods.

Full text of DOI:10.3184/174751913X13686082295417

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 359
JUNE, 359–361
An improved procedure for the synthesis of aryl phosphonates by
palladium-catalysed cross-coupling of aryl halides and diethyl phosphite
in polyethylene glycol
Ping Wanga,b, Jie Lub and Zhan-Hui Zhangb*
aDepartment of Chemical and Environmental Engineering, Hebei Chemical & Pharmaceutical VocationalTechnology College,
Shijiazhuang 050026, P. R. China
bCollege of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, P. R. China
A general and greener protocol for the synthesis of aryl phosphonates by the cross-coupling of aryl halides and
diethyl phosphite using tetrakis(triphenylphosphine)palladiume/triethylamine/polyethylene glycol 600 [Pd(PPh3)4/
Et3N/PEG 600] as an efficient catalytic system has been developed. This procedure also avoids hazardous solvents
and is therefore an eco-friendly alternative to the existing methods.
Keywords: Hirao reaction, aryl phosphonates, polyethylene glycol
Aryl phosphonates and their derivatives have received atten-
tion recently because of their wide range of applications in
polymers, medicinal chemistry, catalysis and photoelectric
materials.1 Phosphonates play an important role in organome-
tallic catalysis2 and organocatalysis.3 Various approaches to
the synthesis of aryl phosphonates have been explored over
the past few years.4–7 The transition-metal-catalysed Hirao
reaction8 is one of most widely-used methods for the synthesis
of arylphosphonates. Some improved procedures by the
cross-coupling of aryl halides,9–12 triflates,13 tosylates,14 boronic
acids15–16 imidazolylsulfonates17 and azoles18 with dialkyl
phosphites have also been developed to construct C(sp2)–P
bonds. Although these methods are suitable for certain synthe-
ses, some of these procedures have one or more disadvantages
such as the use of volatile and hazardous organic solvents,
the requirement for expensive ligands and a microwave oven.
Thus, the development of a more practical and economical
procedure for the preparation of these compounds is still highly
desirable.
The use of polyethylene glycol as a reaction medium has
gained considerable interest in organic synthesis due to its
many advantages from environmental, economical, and safety
standpoints. It is noncorrosive, nonvolatile, stable, non-toxic,
inexpensive, biologically acceptable and eco-friendly, and
allows many useful organic transformations to be performed
under mild reaction conditions.19–25 In continuation of our
research program for the development of environmentally
benign methodologies,26–32 we now report the synthesis of aryl
phosphonates by cross-coupling of aryl halides and diethyl
phosphite in PEG 600 (Scheme 1).
did not proceed smoothly in the absence of the catalyst and
only a trace of the product was formed. To identify the best
medium for the reaction, we also performed the model reaction
with different solvents such as THF, DMF, 1,4-dioxan, EtOH,
MeCN, CH2Cl2, toluene and PEG 600. PEG 600 was found to
be the best reaction medium. Further examination of the condi-
tions indicated that Et3N was the optimal base. Other organic
and inorganic bases were poorer at promoting this cross-
coupling of the model substrates. The influence of the reaction
temperature was also optimised. Increasing or reducing the
reaction temperature from 130 °C led to a lower yield of 3a.
We then examined the reaction of representative aryl halides
and diethyl phosphite under these optimised reaction condi-
tions (5 mol% Pd(PPh3)4, Et3N, PEG 600, 130 °C). The reaction
proceeded efficiently with aryl iodides and gave the corre-
sponding aryl phosphonates in high to excellent yields without
the formation of any by-products (Table 2, entries 1–3). This
method was found to be equally effective for conversion
of aryl bromides with electron-withdrawing and electron-
donating groups. Aryl halides having electron-withdrawing
groups gave higher yields compared to those containing
electron-donating groups. Steric hindrance had a negative
influence on the reaction. The corresponding products were
obtained in slightly lower yield and required longer reaction
times when the substituent groups was present in the ortho
position of the benzene ring. More importantly, aryl chlorides
were successfully employed to afford the desired product with
moderate to high yields. This procedure was also compatible
with the presence of a variety of functional groups such
as ester, ketone, aldehyde, nitro, dialkylamine, amides, and
hydroxy in the substrates.
In order to achieve a practical protocol for the synthesis of
aryl phosphonates, the effect of a number of parameters such
as catalysts, bases, and solvents were screened for a model
reaction employing N-(3-iodobenzyl)acetamide and diethyl
phosphonate. The results are shown in Table 1. Among various
catalysts it was found that Pd(PPh3)4 was the most effective.
A concentration of 5 mol% was sufficient to complete the
reaction with maximum yield (Table 1, entry 4). The reaction
In summary, we have successfully developed a convenient
protocol for the synthesis of aryl phosphonates by the cross-
coupling of aryl halides and diethyl phosphite using a catalytic
system that employs Pd(PPh3)4 along with triethylamine as
the base in PEG 600. The operational simplicity, and the use
of commercially available Pd(PPh3)4 with no need for any
other ligands, and the wide range of substrates make this
approach a useful as an alternative to the existing synthetic
methodologies.
Experimental
All chemicals were purchased and used without further purification.
Melting points were determined on an X-4 apparatus and are
uncorrected. IR spectra were recorded using a Bruker-TENSOR 27
spectrophotometer. NMR spectra were taken with a Bruker DRX-500
spectrometer at 500 MHz (1H), 125 MHz (13C) and 201 MHz (31P)
using CDCl3 as the solvent with TMS as internal standard. Elemental
analyses were obtained on a Vario EL III CHNOS elemental analyser.
Scheme 1 Palladium-catalysed synthesis of aryl
phosphonates in PEG 600.
* Correspondent. E-mail: zhanhui@126.com

360 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Effect of reaction parameters on the synthesis of diethyl (3-(acetamidomethyl)phenyl)phosphonate (3a)a
Entry
Catalyst
Solvent
Base
Temperature /°C
Time/h
Yield/%b
1
2
CuI
PEG 600
PEG 600
PEG 600
PEG 600
THF
Et3N
Et3N
130
130
45
17
40
15
20
19
20
23
27
26
25
22
22
21
22
22
23
23
21
23
45
15
15
15
15
15
15
60
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
no
3
Et3N
130
62
4
Et3N
130
95
5
Et3N
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
130
35
6
DMF
Et3N
74
7
1,4-dioxane
EtOH
Et3N
25
8
Et3N
39
9
MeCN
CH2Cl2
Et3N
56
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24
25
26
Et3N
68
toluene
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
Et3N
45
Na2CO3
K2CO3
NaF
60
130
15
130
Trace
25
NaOAc
KOAc
KOH
NaOH
NaHCO3
DMAP
Et3N
130
130
15
130
10
130
13
130
16
130
5
130
Trace
71
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Et3N
130
Et3N
130
95
Et3N
110
73
Et3N
120
80
Et3N
140
85
a Reaction conditions: N-(3-iodobenzyl)acetamide (1 mmol), diethyl phosphite (1.5 mmol), base (4.0 mmol), catalyst (0.05 mmol),
solvent (5 mL).
b Isolated yields.
c Reaction was performed using 2 mol % catalyst.
d Reaction was performed using 10 mol % catalyst.
Table 2 Synthesis of aryl phosphonates
Entry
Aryl halide
Product
Time/h
Yield/%a
M.p./°C
1
2
3-CH3CONHCH2C6H4I
2-CH3OOCC6H4I
3-CH3COOC6H4I
C6H5Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3k
3l
3m
3n
3o
3p
15
16
15
15
16
16
20
18
18
20
15
15
15
20
25
25
21
21
20
23
20
20
20
25
25
21
95
86
93
83
65
81
76
78
80
78
83
85
90
85
72
82
88
61
70
68
73
70
72
60
65
79
Oil
Oil33
3
Oil33
4
Oil14
5
2-CH3C6H4Br
4-CH3C6H4Br
3-OHC6H4Br
Oil14
6
Oil14
7
68–70 (67–69)34
8
4-OHC6H4Br
95–96 (93–94)34
9
3-NH2C6H4Br
4-NH2C6H4Br
3-NO2C6H4Br
4-NO2C6H4Br
4-AcC6H4Br
49–50 (47–50)34
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
117–118 (115–119)34
Oil34
Oil34
Oil15
4-CH3OOCC6H4Br
2-BrC6H4CHO
3-BrC6H4CHO
4-BrC6H4CHO
4-CH3CONHC6H4Cl
4-CNC6H4Cl
3-NO2C6H4Cl
4-NO2C6H4Cl
4-AcC6H4Cl
4-CH3OOCC6H4Cl
2-ClC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
Oil14
Oil35
Oil36
Oil33
Oil8
32–33 (30–32)8
Oil12
Oil12
Oil15
Oil14
Oil35
Oil36
Oil33
a Isolated yields.

JOURNAL OF CHEMICAL RESEARCH 2013 361
9
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Synthesis of aryl phosphonates; typical procedure
A mixture of N-(3-iodobenzyl)acetamide (1 mmol), diethyl phosphite
(1.5 mmol), triethylamine (4.0 mmol), and Pd(PPh3)4 (0.05 mmol) in
PEG 600 (5 mL) was stirred in an oil bath at 130 °C for an appropriate
time under the nitrogen. The progress of the reaction was followed by
TLC. After the completion of the reaction, the resulting mixture was
cooled to room temperature and extracted with diethyl ether (10 mL).
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Na2SO4. The solvent was removed in vacuo, and the crude reaction
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diethyl (3-(acetamidomethyl)phenyl)phosphonate (3a): Oil; IR (KBr):
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CH3), 4.02–4.14 (m, 4H), 4.44 (d, J = 5.5 Hz, 2H), 6.23 (br s, 1H),
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= 10.6 Hz), 131.8 (d, 4Jc-p = 3.1 Hz), 139.4 (d, 2Jc-p = 14.5 Hz), 170.6 ppm;
31P NMR (201 MHz, CDCl3): 18.9 ppm; Anal. Calcd.for C13H20NO4P:
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Received 19 February 2013; accepted 21 March 2013
Paper 1301799 doi: 10.3184/174751913X13686082295417
Published online: 12 June 2013
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