Microwave-assisted synthesis of α-hydroxybenzylphosphonates and -benzylphosphine oxides

Article abstract of DOI:10.1002/hc.20649

A series of α-hydroxy-benzylphosphonates and -benzylphosphine oxides was synthesized by the Na₂CO₃-catalyzed microwave-assisted addition of dialkyl phosphites and dipenylphosphine oxide to P-substituted benzaldehydes. The solventless reaction provided the products in short reaction times and in 71-88% yield.

Full text of DOI:10.1002/hc.20649

Heteroatom Chemistry
Volume 22, Number 1, 2011
Microwave-Assisted Synthesis of α-Hydroxy-
benzylphosphonates and -benzylphosphine
Oxides
Gyo¨rgy Keglevich,1 Viola Ro´za To´th,1 and La´szo´ Drahos2
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary
2Hungarian Academy of Sciences, Chemical Research Center, H-1525 Budapest, Hungary
Received 22 July 2010; revised 22 September 2010
[12], brought a kind of breakthrough, but the reac-
ABSTRACT: A series of α-hydroxy-benzylphosph-
tion times were variable (10 min to 3 days).
onates and -benzylphosphine oxides was synthesized
To the best of our knowledge, only in one article
by the Na2CO3-catalyzed microwave-assisted addition
was the effect of microwave (MW) irradiation stud-
of dialkyl phosphites and dipenylphosphine oxide to
ied on the addition of diethyl phosphite to aldehydes
P-substituted benzaldehydes. The solventless reaction
[12]. However, no temperatures were reported and
provided the products in short reaction times and
the experiments cannot be reproduced, as the reac-
ꢀ
C
in 71–88% yield.
2010 Wiley Periodicals, Inc. Het-
tions were performed in a kitchen MW equipment
[12]. We wished to elaborate a generally usable MW-
assisted and solventless method for the synthesis
of α-hydroxyphosphonates and α-hydroxyphosphine
oxides under controlled MW conditions.
eroatom Chem 22:15–17, 2011; View this article online
at wileyonlinelibrary.com. DOI 10.1002/hc.20649
INTRODUCTION
α-Hydroxyphosphonates are of significant biological
and pharmaceutical interest [1]. They can be pre-
pared by thermal noncatalyzed addition [2,3] and
base or acid-catalyzed addition [2,4,5]. The main
drawbacks of these procedures are the relatively
long reaction times or the need to apply solvents.
The solventless reaction using alumina [6,7], mag-
nesia [8], or other solids, such as cesium fluoride
[9], potassium fluoride [9], phosphates [10], sodium-
modified hydroxyapatite [11], and sodium carbonate
RESULTS AND DISCUSSION
First of all benzaldehyde was reacted with diethyl
phosphite under solventless and MW conditions. Af-
ter 3.5 h irradiation, α-hydroxy-benzylphosphonate
1a was obtained in 80% yield (Table 1, entry 1). It
was found that in the presence of Na2CO3 as the cata-
lyst, the addition reaction was faster. Increasing the
quantity of the catalyst from 5% to 75%, the reac-
tion time decreased from 45 min to 20 min (Table 1,
entries 2–5) (Scheme 1).
The following experiments applying P-
substituted benzaldehydes and diethyl or dimethyl
phosphite, as well as diphenylphosphine oxide were
carried out in the presence of 75% of Na2CO3, in
most cases for 20 min (Scheme 2).
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant numbers: OTKA K067679 and K83118.
c
ꢀ
2010 Wiley Periodicals, Inc.
15

16 Keglevich, To´th, and Drahos
MW
110°C, t
(1a–e/2a–e) and α-hydroxy-benzylphosphine oxides
(3a–e) in 71–88% yields. The products that are well
known from earlier literature were identified by
31P NMR chemical shifts, mass spectroscopy, and
melting points (Table 2).
OH
O
PhCHO + (EtO)2P(O)H
Ph CH P(OEt)2
Na2CO3
no solvent
1a
SCHEME 1
Our method is an environment friendly pro-
cedure for the addition of dialkyl phosphites and
diphenylphosphine oxide to substituted benzaldehy-
des and may be of general value for the reaction of
>P(O)H species with carbonyl derivatives.
In conclusion, ten α-hydroxy-benzylphos-
phonates and five α-hydroxy-benzylphosphine
oxides were prepared by the MW-assisted addition
of dialkyl phosphites and diphenylphosphine oxide
to benzaldehydes in the presence of Na2CO3, under
solventless conditions. The yields are between 71%
and 88%.
MW
110°C, 20 min
O
OH
CH PY1
O
+
CHO
Y12P
H
Y2
Y2
2
Na2CO3 (0.75 equiv.)
no solvent
Y1
OEt
OMe
Ph
Y2
1
2
3
a
b
c
d
e
H
OMe
Me
NO2
Cl
SCHEME 2
TABLE 1 Effect of Na2CO3 Catalyst on the Outcome of the
Addition of Diethyl Phosphite to Benzaldehyde at 110◦C un-
der Solventless MW Conditions
Na2CO3 (equiv)
t (min)
Yield (%)
Entry
EXPERIMENTAL
General
–
240
45
45
30
20
46
84
89
86
85
1
2
3
4
5
0.05
0.25
0.5
The 31P NMR spectra were obtained on a Bruker
DRX-500 spectrometer operating at 202.4 MHz.
Chemical shifts are downfield relative to 85% H3PO4.
Mass spectrometry was performed on a ZAB-2SEQ
instrument. The reactions were carried out in a
300W CEM Discover focused microwave reactor un-
der isotermic conditions applying 50 W.
0.75
The additions took place smoothly and crystal-
lization of the crude products from acetone–pentane
afforded
the
α-hydroxy-benzylphosphonates
TABLE 2 Yields and Characterization of α-Hydroxy-benzylphosphonates 1, 2, and 3
Yield (%)
δ
31P
δPlit.
MS
mp (◦C)
mplit. (◦C)
Entry
1a
2a
3a
1b
85
87
88
82
21.5
23.9
32.7
21.5
22.0 [13]
24.3 [14]
33.2 [15]
20.9 [17]
245.1 (M + H)
216.9 (M + H)
309.3 (M + H)
275 (M + H)
74–75
74–76 [13]
102 [14]
173–175 [16]
116 [17]
120–121.5 [8]
72 [7]
72 [19]
155 [20]
160–162 [21]
94–95 [8]
92–93 [23]
98 [7]
152.5–155 [21]
89 [17]
90–91 [24]
93–94 [25]
133 [25]
186.5–188.5 [27]
191.5–193 [21]
67–68 [8]
72–73 [28]
68 [7]
181.5–183 [21]
188 [29]
1
2
3
4
101–102
173–175
121–122
2b
3b
84
78
23.4
31.1
23.8 [18]
–
245 (M – H)
73–74
5
6
339 (M + H)
160–162
1c
2c
87
62
21.7
24.0
22.0 [22]
23.8 [18]
276.3 (M + NH4)
231 (M + H)
96–97
92–93
7
8
3c
1d
80
86
31.8
19.9
–
323 (M + H)
155–156
90–92
9a
18.9 [17]
290.1 (M + H)
10b
2d
3d
71
80
21.9
31.1
21.8 [18]
–
262.2 (M + H)
354.3 (M + H)
130–132
189–91
11
12
1e
84
21.9
18.7 [8]
354.4 (M + H)
68–70
13
14
2e
3e
72
79
22.1
33.1
–
–
273.0 (M + Na)
343.2 (M + H)
68–70
183
15a
a110◦C, 0.5 h, 0.75 equiv of Na2CO3.
b150◦C, 1 h, 0.75 equiv of Na2CO3.
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Synthesis of α-Hydroxy-Benzylphosphonates and -Benzylphosphine Oxides 17
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nitrobenzaldehyde 0.38 g, p-chlorbenzaldehyde 0.35
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tals (except for 1d and 2d, which were orange crys-
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General Procedure for the Preparation of
α-Hydroxy-benzylphosphine Oxides (3a−e)
A mixture of 0.50 mmol of aromatic aldehyde
(benzaldehyde 0.05 mL, p-methoxybenzaldehyde
0.06 mL, p-methylbenzaldehyde 0.24 mL, p-
nitrobenzaldehyde 0.08 g, p-chlorbenzaldehyde 0.28
g) and 0.10 g (0.50 mmol) of diphenylphosphine ox-
ide and 0.04 g (0.38 mmol) of Na2CO3 was heated
at 110◦C in a vial (open vessel) in a CEM Discover
Microwave reactor for 20 min (except for 3c and 3e,
when the reactions time was 30 min). The work-up
procedure was similar as described above for prod-
ucts 1a–e/2a–e to give products 3a–e as white crys-
tals (except for 3d, which was orange crystals; see
Table 1).
ACKNOWLEDGMENTS
This work is connected to the scientific program of
the “Development of quality-oriented and harmo-
nized R+D+I strategy and functional model at BME”
project. This project is supported by the New Hun-
´
gary Development Plan (Project ID TAMOP-4.2.1/B-
09/1/KMR-2010–0002).
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Heteroatom Chemistry DOI 10.1002/hc