A simple protocol for the synthesis of α-substituted phosphonates

Article abstract of DOI:10.1080/10426507.2016.1167056

An efficient, easy-to-handle, and mild substitution reaction approach has been developed for the synthesis of phosphonate derivatives, which are very important in the field of industrial, agricultural, and medicinal chemistry. A large number of nucleophiles, including arylamines, alkylamines, heteroarylamines, primary amines and secondary amines, sulfides, and carbides were attempted to react with α-tosyloxyphosphonate 1. The reaction proceeded under catalyst-free and neat conditions and the corresponding phosphonates 2 were afforded in good yields.

Full text of DOI:10.1080/10426507.2016.1167056

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A SIMPLE PROTOCOL FOR THE SYNTHESIS OF
α–SUBSTITUTED PHOSPHONATES
Xing Wang, Yuan Cai, Jian Chen & Francis Verpoort
To cite this article: Xing Wang, Yuan Cai, Jian Chen & Francis Verpoort (2016): A SIMPLE
PROTOCOL FOR THE SYNTHESIS OF α–SUBSTITUTED PHOSPHONATES, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2016.1167056
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1167056
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A SIMPLE PROTOCOL FOR THE SYNTHESIS OF α--SUBSTITUTED PHOS-
PHONATES
Xing Wang,1,2 Yuan Cai,1,2 Jian Chen,1,2* Francis Verpoort1,2,3
*
1Department of Chemical Engineering, School of Chemistry, Chemical Engineering, and
Life Science, Wuhan University of Technology, Wuhan 430070, China.
2Laboratory of Organometallics, Catalysis and Ordered Materials, State Key Laboratory of
Advanced Technology for Materials Synthesis and Processing, Wuhan University of
Technology, Wuhan 430070, P.R. China.
3National Research Tomsk Polytechnic University. Tomsk, 634050, Russian Federation
We are grateful for the financial support from Specialized Research Fund for the Doctoral
Program of Higher Education (Grant No. 20120143120014) and Fundamental Research Funds
for the Central Universities (WUT: 2014-zy-219).
*Address correspondence to Prof. Jian Chen, Department of Chemical Engineering, School
of Chemistry, Chemical Engineering, and Life Science, Wuhan University of Technology, Wu-
han, China. E-mail: chenjian0501@163.com;
Abstract
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An efficient, easy-to-handle and mild substitution reaction approach has been developed for the
synthesis of phosphonate derivatives, which are very important in the field of industrial, agricul-
tural, and medicinal chemistry. A large number of nucleophiles, including arylamines, alkyla-
mines, heteroarylamines, primary amines and secondary amines, sulfides, and carbides were at-
tempted to react with α-tosyloxyphosphonate 1. The reaction proceeded under catalyst-free and
neat conditions and the corresponding phosphonates 2 were afforded in good yields.
Keywords
α-substituted phosphonate, p-toluenesulfonyl chloride, catalyst-free, substitution reac-
tion.
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INTRODUCTION
α-Aminophosphonate, α-phosphoryl sulfide, and related derivatives have caught consider-
able attention on account of their structural and biological analogy to α-amino acids.1 These
phosphonates are very important in the fields of industrial, agricultural, and medicinal chemistry
since they can be used as enzyme inhibitors,2 antibacterial agent,3 herbicide,4 antiviral agent,5
antitumor agent.6
Specifically, a number of methods for the synthesis of α-aminophosphonate have been re-
ported during past two decades. Among these, the conventional Kabachnik--Fields
three-component reaction or Pudovik reaction is predominantly employed, and mostly catalyzed
by an inorganic Lewis acid, such as BF3•Et2O,7 Mg(ClO4)2,8 Al(OTf)3,9 AlCl3,10 InCl3,11
In(OTf)3,12 SnCl4,13 BiCl3,14 TiO2,15 TiCl4,16 FeCl3,17 CuI,18 CuCl2,19 Yb(OTf)3,20 YbCl3,21 CeCl3
•7H2O,22 ZrOCl2•8H2O and ZrO(ClO4)2•6H2O.23 Besides, organic compounds or organometal-
lic complexes are also important, such as tetramethylguanidine,24 trimethylchlorosilane,25
p-toluenesulfonic acid,26 acetic acid,27 trifluoromethanesulfonic acid,28 cupreine-derived cata-
lyst,29 and tetra(tert-butyl) phthalocyanine aluminum chloride,30 and zirconocene
bis(perfluorobutanesulfonate).31 Next to these homogeneous catalysts, recyclable immobilized or
solid acid catalysts appeared more attractive recently, such as SbCl3/Al2O3,32 NaHSO4/SiO2,33
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polyacrylic acid/SiO2,34 Al(phthalocyanine) complex/SiO2,35 BF3/SiO2,36 amberlyst 15,37
H2Ti3O7 nanotubes,38 graphene oxide,39 and L-cysteine functionalized magnetic nanoparticles
(LCMNP).40 Moreover, another type of reusable catalyst so called ionic liquids were also applied
and demonstrated interesting results.41
In addition to the C‒P bond formation strategy through the hydrophosphorylation of
imines, alternative methods were available to produce α-aminophosphonates. For example, C−C
bond formation through addition reaction42 or C−H bond formation through catalytic hydrogena-
tion of enamido phosphonate43 were also fairly useful mainly for the synthesis of asymmetric
α-aminophosphonates. Another representative approach is direct formation of C-N bond through
nucleophilic substitution reaction of a nucleophilic zincate and O-acylhydroxylamine in the
presence of copper catalyst (Scheme 1).44 Similarly, a simple protocol where the electrophilic
α-tosyloxyphosphonate 1 reacts with amine to generate an α-aminophosphonate without metal
catalyst seems more attractive and convenient (Scheme 1). Moreover, a changeable nucleophile
would render this route extremely versatile. Actually, this strategy has produced numerous useful
α-substituted phosphonates 2, such as azidobenzylphosphonates45, α-sulfanylphosphonates46 and
bisphosphonates47. However, reactions of 1 with amine, aryl sulfide or carbide have not been re-
ported yet. Consequently, in this paper we report the systematic study of this synthetic route to
obtain α-substituted phosphonates.
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RESULTS AND DISCUSSION
In view of the strong electron‒withdrawing ability of the phosphonate group in 1a,
p-tosyloxyl as leaving group (LG) was chosen to promote the process of the substitution reac-
tion.48 Optimized reaction conditions were explored through the reaction of 1a and aniline as
model substrate. The obtained results are given in Table 1. Reflux of 1a and aniline (1:1.2) was
carried out in different solvents including dichloromethane, ethyl acetate, tetrahydrofuran, ace-
tonitrile, toluene, methanol, ethanol, and DMF (Table 1, entries 1-8). Unfortunately, the per-
centage yield of 2a was rather low (< 25%), which is presumably due to the strong C‒OTs bond
in 1a even with p-tosyloxyl as the leaving group. The solvent-free approach (35%) evidenced to
be better reaction conditions compared with reactions carried out in solvent (Table 1, entry 9).
The results clearly indicate that 80°C was the most suitable reaction temperature under sol-
vent-free conditions, since the yield did not increase and by-product appeared when the reaction
was performed at higher temperature (Table 1, entries 11-14). Surprisingly, the influence of mo-
lar ratio on the yield of 2a was highly important. The yield increased about 12% when one more
equivalent of aniline was added (Table 1, entries 15-20). The optimum stoichiometric ratio of 1a
and aniline was 1:5, and higher dosage did not give higher conversion. The apparent growth may
come from the catalytic action of aniline, which facilitated the deprotonation step of protonated
2a and eventually enhanced the reaction rate (Scheme 2). To verify this hypothesis, one experi-
ment was conducted by adding 1.2 equivalent K2CO3 to the mixture (Table 1, entry 10). Unex-
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pectedly, the substitution reaction did not result in a substantial higher yield compared to entry 9
(Table 1, entry 10). Hence, the assumption that an excess of amine act as catalyst was incorrect,
therefore an equilibrium-controlled reaction is more tenable.
In order to examine the scope and the limitation of this method, different nucleophiles
were combined with 1a under optimal conditions, and the obtained data are disclosed in Table 2.
It is obvious that the reaction using substituted aniline bearing an electron-withdrawing group
displayed higher yields of the desired products 2 (Table 2, entries 1-3). We conjectured that the
relative advantageous deprotonation step after substitution should be responsible for this phe-
nomenon (Scheme 2). Moreover, with the increase of the steric hindrance of the aniline the over-
all reaction rate decreased dramatically (Table 2, entries 4-8), which is in accordance with the
characteristics of a bimolecular nucleophilic substitution (SN2) reaction. Nevertheless, five
equivalent n-butylamine (Table 2, entry 9) did not react smoothly with 1a unless a large exces-
sive of amine was added. Heteroarylamines were also tested to examine the application scope of
this method, such as 2-benzothiazolamine, 2-aminopyridine and pyrrole, but unfortunately unfa-
vorable results were obtained. Interestingly, sodium thiophenolate (1.2 equiv, table 2, entry 10)
can react with 1a easily at room temperature in THF, which is attributed to its strong nucleo-
philic ability. Other nucleophiles were investigated, such as potassium phthalimide,
(EtOOC)2CHNa+ and Me3SiC≡CLi+, but the desired products were not obtained presumably
due to the weak nucleophilicity or strong basicity.
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Several α-tosyloxyphosphonates 1 were prepared to verify this statement. When
iso-butyraldehyde was employed as raw material, it is reasonable that the substitution tendency
between aniline and 1b was much lower than that of benzyl-type p-TsOCHPh[PO(OEt)2] 1a
(Table 3, entry 1). When different substituted benzaldehydes were used, including electron‒
donating and electron‒withdrawing group on benzene ring, 70-85% yield of 2 was achieved (Ta-
ble 3, entries 2-6).
The structure of 2p was confirmed by single crystal X-ray diffraction as shown in Figure 1.
The most important structural feature is the existence of two N1-H…O3 hydrogen bonds
[H-bond length: 2.303 Å; H-bond angle: 137.4(2)°] between two secondary amine molecules. A
similar configuration was also described by Kapoor32 in which 3 possesses a N--H…O distance
of 2.053 Å and a N--H…O angle of 168.1(2)°. The formative H-bonded dimer stabilizes these
compounds, increases their melting point and render them solid at ambient conditions. Although
other H-acceptors (F1, O1 and O2) are present in 2p, they are not used for H-bond formation.
For α-aminophosphonates 2h and 2i with tertiary amine moiety, intermolecular H-bonds are not
formed and as a consequence they exist as liquids. X-ray data collection parameters are present-
ed in Table S 1 (Supplemental Materials) and bond lengths and angles in Tables S 2 and S 3.
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CONCLUSION
In conclusion, a simple protocol to synthesize α-substituted phosphonates via a substitution
reaction of 1 and different nucleophiles was developed. The versatile procedure benefits from
numerous nucleophilic reagents and avoids the use of sensitive metal compounds and harsh reac-
tion conditions. The nucleophilicity and dosage of the nucleophiles are highly important for the
reaction outcome. Sodium thiophenolate can react with 1a smoothly in favorable proceeding
conditions with 86% yield. Further application of this method toward the synthesis of biologi-
cally active molecules is in progress in our group.
EXPERIMENTAL
All chemicals and solvents were purchased from Aladdin and Sinopharm Chemical Reagent Co.,
Ltd, and were directly used for the synthesis. All reactions were carried out in sealed vial, and no
special precautions were taken. 1H-NMR, 13C-NMR, 31P-NMR, and 19F-NMR were recorded on
a Bruker Avance HD III 500NMR spectrometer in CDCl3 using TMS as internal standard.
Chemical shifts were reported in parts per million (ppm). Coupling constants (J) were reported in
Hz and refer to apparent peak multiplicity. IR spectra were recorded on Bruker-Vertex 80V
Vacuum infrared spectrometer. The Supplemental Materials contains complete characterization
data for the products and sample 1H, 13C and 31P NMR spectra are presented in Figures S 1 -- S
69. CCDC 1448386 contains the supplementary crystallographic data for this paper. These data
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can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge, B2 1EZ, UK; fax +44 1223 336033;
or deposit@ccdc.cam.ac.uk).
General Procedure for Synthesis of 1：A solution of aldehyde (10 mmol), diethyl
phosphite (10 mmol), and triethylamine (7 mL) in DCM (20 mL) was stirred at room tempera-
ture for 4 h. Subsequently, p-toluenesulfonyl chloride (12 mmol) was added, and the mixture was
stirred continuously at room temperature overnight. Saturated NH4Cl solution was added, and the
crude product was extracted by DCM (310 mL), washed with brine, and dried over anhydrous
Na2SO4. The volatiles were removed in vacuo to offer a yellowish-brown crude product, which
was purified by column chromatography using silica gel, producing the desired product (78-93%
yield).
General Procedure for Synthesis of 2: Nucleophiles (10.0 mmol) and 1 (2.0 mmol) were
stirred in an oil bath at 80°C for 6-48 h (detection using TLC). The reaction mixture was
separated directly on silica gel column, providing the corresponding product (56-90% yield).
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Table 1 Effects of solvent, temperature and stoichiometric ratio on the reaction of 1a and anilin-
ea.
Molar
ratio
Temperature
[°C]
Yield
[%]c
En-
try
Yield
[%]c
Solventb
Entry
1
2
DCM
EA
< 5
< 5
8
11
12
13
14
15
16
17
18
19
20
1:1.2
1:1.2
1:1.2
1:1.2
1:2
60
70
90
100
80
80
80
80
80
80
15
21
35
34
40
53
65
77
77
76
3
THF
4
CH3CN
Toluene
MeOH
EtOH
DMF
Sol-
9
5
13
14
19
23
35
37
6
1:3
7
1:4
8
1:5
9
1:6
10
Sol-
1:7
aReaction conditions: 1a (1.0 mmol), PhNH2 (1.2 mmol), 6 h under reflux. b5 ml solvent. cIso-
lated yield. dReaction temperature: 80°C. e1.2 equivalent K2CO3 was added.
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Table 2 Synthesis of α-substituted phosphonates 2 from 1a.a
En-
try
Nucleophiles
t/h
Yield
[%]b
Refer-
ence
2
2b
1
2
6
6
85
80
[49]
[50]
2c
2d
2e
2f
3
4
6
90
60
[11]
[51]
10
5
48
67
-
2g
2h
6
7
48
9
60
56
-
[17]
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8
9
6
70
73
-
2j
9c
[52]
2k
10d
3
86
[53]
aReaction conditions: 1a (2.0 mmol), nucleophiles (10.0 mmol) under neat conditions at 80°C.
bIsolated yield. c5 ml n-butylamine was added. d1.2 equivalent sodium thiophenolate and 5 ml
THF was added, room temperature.
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Table 3 Synthesis of α-aminophosphonates 2 by using aniline as nucleophile.a
En-
try
Nucleophiles
t/h
Yield[% Refer-
2
b
]
ence
1b
1c
2l
1
2
3
12
8
<5
80
76
[52]
2m
[15a]
[54]
1d
2n
10
2o
2p
1e
4
9
78
-
5c
6
6
85
70
-
1e
1f
2q
12
[15a]
aReaction conditions: 1 (2.0 mmol), aniline (10.0 mmol) under neat conditions at 80°C. bIsolated
yield. c3-fluoroaniline was used as nucleophile.
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Figure 1 ORTEP diagram and the labeling of atoms for the crystal structure of
α-aminophosphonate 2p (left). H-bonds between phosphonate oxygen (O3) and the hydrogen
attached to nitrogen (N1) (right).
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Scheme 1 Synthetic route to α-substituted phosphonates 2 through nucleophilic substitution re-
action.
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Scheme 2 Substitution and deprotonation steps during formation of α-substituted phosphonates
2.
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