An Efficient Method for Synthesis of 4-(Phosphonomethyl)benzene Derivatives under Solvent-Free Conditions

Article abstract of DOI:10.1081/SCC-120028632

A simple, efficient and general method has been developed for synthesis of 4-(phosphonomethyl)benzene derivatives through one-pot reaction of phosphoric acid, 4-substitute benzyl chlorides and hexamethyldisilazane under solvent-free conditions and the following hydrolysis in 2M NH₄OH.

Full text of DOI:10.1081/SCC-120028632

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An Efficient Method for Synthesis of
4‐(Phosphonomethyl)benzene Derivatives Under
Solvent‐Free Conditions
Ting Yang a , Changxue Lin a , Hua Fu a , Yuyang Jiang a & Yufen Zhao a
a Key Laboratory of Bioorganic Phosphorus Chemistry, Ministry of Education, Department
of Chemistry, School of Life Sciences and Engineering , Tsinghua University , Beijing,
100084, P.R. China
Published online: 21 Aug 2006.
To cite this article: Ting Yang , Changxue Lin , Hua Fu , Yuyang Jiang & Yufen Zhao (2004) An Efficient Method for
Synthesis of 4‐(Phosphonomethyl)benzene Derivatives Under Solvent‐Free Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:6, 1017-1022, DOI: 10.1081/
SCC-120028632
To link to this article: http://dx.doi.org/10.1081/SCC-120028632
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1017–1022, 2004
An Efficient Method for Synthesis of
4-(Phosphonomethyl)benzene Derivatives
Under Solvent-Free Conditions
*
Ting Yang, Changxue Lin, Hua Fu, Yuyang Jiang,
and Yufen Zhao
Key Laboratory of Bioorganic Phosphorus Chemistry, Ministry of
Education, Department of Chemistry, School of Life Sciences and
Engineering, Tsinghua University, Beijing, P.R. China
ABSTRACT
A simple, efficient and general method has been developed for synthesis
of 4-(phosphonomethyl)benzene derivatives through one-pot reaction of
phosphoric acid, 4-substitute benzyl chlorides and hexamethyldisilazane
under solvent-free conditions and the following hydrolysis in 2M
NH4OH.
Key Words: Phosphorus-carbon bond; Arbuzov reaction; Phosphoric
acid.
*
Correspondence: Hua Fu, Key Laboratory of Bioorganic Phosphorus Chemistry,
Ministry of Education, Department of Chemistry, School of Life Sciences and
Engineering, Tsinghua University, Beijing 100084, P.R. China; E-mail: fuhua@mail.
tsinghua.edu.cn.
1017
DOI: 10.1081/SCC-120028632
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Yang et al.
INTRODUCTION
Although phosphorus compounds containing the phosphorus-carbon bond
are not particularly abundant in nature, their diverse biological activity, has for
a long time attracted considerable synthetic and pharmacological interest.[1]
Nonhydrolyzable O-phosphotyrosine analogs for use in peptide synthesis have
been of great interest over the last more than ten years. This interest stems
from their broad utility in studying various cellular signal transduction
pathways. For example, generation of such mimetics and incorporation into
suitable peptides would afford systems that could bind to a Src-homology 2
(SH2) domain and potentially prevent interaction with receptor tyrosine
kinase molecules. Thus signaling events that can induce changes in cell shape,
mobility, or adhesiveness leading to a variety of diseases such as cancer[2] may
be modulated.
Much of the interest in nonhydrolyzable phosphotyrosine mimics has
centered around phosphonic acids such as (phosphonomethyl)phenylalanine
(Pmp) 1 (Sch. 1). In this procedure, the phosphorus-carbon bond is the key
point. And many potential phosphotyrosine mimics for the Lck SH2 domain
have phosphorus-carbon bond. There are many papers reporting the synthesis
of phosphorus-carbon bond. The authors used different phosphorus reagents as
donates, such as phosphoramidite/tetrazole,[3] red phosphorus[4] and trialkyl
phosphate.[1,5] Among these, the Michaelies–Arbuzov rearrangement, also
knows as the Arbuzov reaction, is a very versatile way to create a phosphorus-
carbon bond from a trialkyl phosphate and an alkyl halide. However, all used
phosphorus chemicals should firstly be synthesized or purchased, and products
obtained through Arbuzov reaction are hydrolyzed to phosphonates under
special conditions for a long time.[5]
In this paper, we reported a new and efficient one-pot method to
synthesize 4-(phosphonomethyl)benzene derivatives through one-pot reaction
of phosphoric acid.
Scheme 1. Structure of (phosphonomethyl)phenylalanine (Pmp).

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Synthesis of 4-(Phosphonomethyl)benzene Derivatives
1019
Scheme 2. Synthetic route of 4-(phosphonomethyl)benzene derivatives.
RESULT AND DISCUSSION
4-(Phosphonomethyl)benzene derivatives were prepared as shown in
Sch. 2. 4-Substitute benzyl chlorides, 1.1 equiv. of phosphoric acid and 1.9
equiv. of hexamethyldisilazane were mixed and refluxed under nitrogen
atmosphere for 3–12 hrs, and the corresponding phosphonate esters were
obtained. 31P NMR of resulting solution showed high reaction yields as shown
in Table 1. Excess of HMDS was evaporated by rotary distillation, and the
residue can be quickly and quantitatively hydrolyzed into our target products
2–6 in 2M NH4OH.
The reaction progress was determined by 31P NMR. The resulting
solution immediately showed the peak at 212 ppm corresponding to
di(trimethylsilyl) H-phosphate after 1.9 equiv. of hexamethyldisilazane was
added to 1.1 equiv. of phosphoric acid under nitrogen atmosphere, and then
the solution was refluxed, di(trimethylsilyl) H-phosphate quantitatively
transferred into tricoordinated phosphorus P(OTMS)3 at 31P NMR 115 ppm
Table 1. Synthesis of 4-(phosphonomethyl)benzene derivatives.
Reaction time
(hr)
Reaction yieldb
(%)
Isolation yield
(%)
Products
X
31P NMRa
2
3
4
5
6
CH3
H
9
4
21.7
21.4
20.8
19.5
19.2
93
97
46
56
59
58
62
Cl
12
3
100
95
CN
NO2
3
70
a31P NMR are relative to 85% H3PO4 (d ¼ 0.0 ppm), and D2O is used as solvent.
bReaction yields were determined by 31P NMR.

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Yang et al.
within 2 hr. Subsequently, addition of 4-substitute benzyl chloride yielded
4-(di(trimethylsilyl)phosphonomethyl)benzene derivative at 31P NMR
6–10 ppm, and its hydrolysis in 2M NH4OH led to target product at 31P
NMR 19–21 ppm. The results indicated the reaction mechanism as follows:
phosphoric acid (H3PO3) was firstly changed into P(OTMS)3 by hexamethyl-
disilazane (HMDS), and Arbuzov reaction of P(OTMS)3 with benzyl
chlorides gave phosphonate esters. As we know, tris(trimethylsilyl) phosphite
(P(OTMS)3) is a very versatile reagent to form the phophorus-carbon bond.[6]
Tris(trimethylsilyl) group played important roles during the whole process,
and it acted as a protecting group before Arbuzov reaction and a leaving group
during hydrolysis.
Five compounds (2–6) were synthesized as shown in Table 1. From this
table, we can see that reaction time changes with different substituting groups
(X) at the para-site of benzene cycle. The reaction of P(OSiMe3)3 with
4-substitute benzyl chlorides began with nucleophilic attack of the phosphorus
atom on the carbon atom of methylene (CH2), and the mechanism is supported
by the rates of 4-substitute benzyl chlorides with P(OSiMe3)3. The methylene
carbon atoms of benzyl chlorides with electron-withdrawing group are more
electrophilic and reactive, so the corresponding reactions can complete in
shorter time. In the contrary, when X was electron-donating group, the
reaction time became longer.
In summary, one-pot reaction of phosphoric acid, 4-substitute benzyl
chloride and HMDS could produce high-yield phosphonates under mild and
solvent-free conditions. The method by using cheap H3PO3 and HMDS as
donate of phosphorus reagent is simple and efficient for synthesis of
4-(phosphonomethyl)benzene derivatives, and can generally be applied to
synthesis of other biologically active phosphonates.
EXPERIMENTAL
All reactions were monitored by 31P NMR. The reaction yields of
products were obtained according to the integral area of target products and
1
side products in 31P NMR. H NMR and 13C NMR spectra were recorded
(internal standard tetramethylsilane) on Bruker AM 500 type spectrometer
using CDCl3 as the solvent. 31P NMR spectra were taken on Bruker AC 200
1
spectrometer at 81 MHz under H decoupled conditions. 31P NMR chemical
shifts were reported in ppm downfield (þ) or upfield (2) from external 85%
H3PO4 as reference. Mass spectra were obtained using a Bruker Esquire ion-
trap mass spectrometer in negative ion mode.

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Synthesis of 4-(Phosphonomethyl)benzene Derivatives
1021
General Procedure for Synthesis of
4-(Phosphonomethyl)benzene Derivatives
Benzyl chloride (2.4 mmol, 250 mg), phosphoric acid (2.6 mmol, 214 mg)
and NH(SiMe3)2 (4.5 mmol, 1 mL) were refluxed under nitrogen atmosphere
for 4 hours, and the resulting solution was cooled. Excess of HMDS was
removed by rotary evaporation, and the residue was hydrolyzed in 2M
ammonia at room temperature for about 10 min. The solvent was removed in
vacuum, the crude product obtained was purified by recrystallization in water
and acetone.
Ammonium (4-methyl-benzyl)phosphonate (compound 2). 31P NMR
(81 MHz, D2O): 21.7 ppm; 1H NMR (500 MHz, D2O): 7.18–7.14 ppm
2
(m, 4H), 2.93 ppm (d, JP-H ¼ 20.5 Hz, 2H), 2.27 ppm (s, 3H); 13C NMR
(125 MHz, D2O): 135.51 ppm (s, Ph para), 131.51 ppm (d, 2JP-C ¼ 8.88 Hz, Ph
3
ipso), 128.94 ppm (d, JP-C ¼ 5.63 Hz, Ph ortho), 128.49 ppm (s, Ph meta),
1
35.72 ppm (d, JP-C ¼ 127.75 Hz, CH2), 19.04 ppm (s, CH3); Negative ion
ESI–MS: [M-2NH3-H]2 m/z 185.
Ammonium benzylphosphonate (compound 3). 31P NMR (81 MHz,
D2O): 21.4 ppm; 1H NMR (500 MHz, D2O): 7.34–7.23 ppm (m, 5H),
2
2.99 ppm (d, JP-H ¼ 21.0 Hz, 2H); 13C NMR (125 MHz, D2O): 134.72 ppm
2
3
(d, JP-C ¼ 8.88 Hz, Ph ipso), 128.95 ppm (d, JP-C ¼ 5.63 Hz, Ph ortho),
1
127.91 ppm (s, Ph meta), 125.53 ppm (s, Ph para), 35.24 ppm (d, JP-
¼ 127.00 Hz, CH2); Negative ion ESI–MS: [M-2NH3-H]2 m/171.
C
Ammonium (4-chloro-benzyl)phosphonate (compound 4). 31P NMR
(81 MHz, D2O): 20.8 ppm; 1H NMR (500 MHz, D2O): 7.18–7.16 ppm
(m, 4H), 2.95 ppm (d, JP-H ¼ 20.0 Hz, 2H); 13C NMR (125 MHz, D2O):
2
2
135.48 ppm (s, Ph para), 131.58 ppm (d, JP-C ¼ 8.75 Hz, Ph ipso),
3
128.94 ppm (d, JP-C ¼ 5.62 Hz, Ph ortho), 128.48 ppm (s, Ph meta),
1
35.25 ppm (d, JP-C ¼ 127.63 Hz, CH2); Negative ion ESI–MS: [M-2NH3-
H]2 m/z 205, 207.
Ammonium (4-cyano-benzyl)phosphonate (compound 5). 31P NMR
(81 MHz, D2O): 19.5 ppm; 1H NMR (500 MHz, D2O): 7.67 ppm (d, JH-
3
¼ 7.5 Hz, 2H, Ph meta), 7.41 ppm (dd, 3JH-H ¼ 7.5 Hz, 4JH-H ¼ 2.0 Hz, 2H,
H
Ph ortho), 3.08 ppm (d, JP-H ¼ 21.0 Hz, 2H); 13C NMR (125 MHz, D2O):
2
2
3
141.23 ppm (d, JP-C ¼ 8.88 Hz, Ph ipso), 129.64 ppm (d, JP-C ¼ 5.5 Hz, Ph
ortho), 131.83 ppm (s, Ph meta), 119.48 ppm (s, Ph para), 107.90 ppm (s, CN),
1
35.90 ppm (d, JP-C ¼ 124.88 Hz, CH2); Negative ion ESI–MS: [M-2NH3-
H]2 m/z 196.
Ammonium (4-nitro-benzyl)phosphonate (compound 6). 31P NMR
(81 MHz, D2O): 19.2 ppm; 1H NMR (500 MHz, D2O): 8.13 ppm (d, JH-
3
¼ 8.0 Hz, 2H, Ph meta), 7.45 ppm (dd, 3JH-H ¼ 8.0 Hz, 4JH-H ¼ 2.5 Hz, 2H,
H
Ph ortho), 3.13 ppm (d, JP-H ¼ 21.5 Hz, 2H); 13C NMR (125 MHz, D2O):
2

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Yang et al.
2
145.39 ppm (s, Ph para), 143.48 ppm (d, JP-C ¼ 8.75 Hz, Ph ipso),
3
129.76 ppm (d, JP-C ¼ 5.50 Hz, Ph ortho), 123.05 ppm (s, Ph meta),
1
35.72 ppm (d, JP-C ¼ 124.50 Hz, CH2); Negative ion ESI–MS: [M-2NH3-
H]2 m/z 216.
ACKNOWLEDGMENTS
The authors would like to thank the financial support from the Excellent
Dissertation Foundation by the Chinese Ministry of Education (No. 200222).
REFERENCES
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microwave assisted Arbuzov rearrangement on the solid surface. Synth.
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3. Tholey, A.; Hoffmann, R. Solid-phase synthesis of tyrosyl H-phosphono-
peptides and methylphosphonopeptides. J. Pept. Sci. 1997, 3, 186–192.
4. Albouy, D.; Etemad-Moghadam, G.; Koenig, M. Phosphorylating power of
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5. Charles, F.S.; Scott, A.B.; Malloy, E.; Demarest, K.; Minor, L.;
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therein.
Received in Japan July 3, 2003

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