The synthesis of dialkoxyphosphorylcarboxamides

Article abstract of DOI:10.1080/10426500701807517

The synthesis of dialkoxyphosphorylcarboxamides, which is difficult to monitor by TLC, was investigated by ESI-MS and ESI-MSn. Their fragmentation pathways were rationalized and supported by tandem mass spectrometry. The characteristic ions in ESI-MS are

Full text of DOI:10.1080/10426500701807517

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Phosphorus, Sulfur, and Silicon
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The Synthesis of
Dialkoxyphosphorylcarboxamides
Yong Ye a b , Ping Li a , Xiao-lian Hu a , Zhi-yu Ju a
Yu-fen Zhao a b
&
a Department of Chemistry, Key Laboratory
of Chemical Biology and Organic Chemistry ,
Zhengzhou University , Zhengzhou, China
b Key Laboratory of Bioorganic Phosphorus Chemistry
& Chemical Biology (Ministry of Education) ,
Tsinghua University , Beijing, China
Published online: 20 Jun 2008.
To cite this article: Yong Ye , Ping Li , Xiao-lian Hu , Zhi-yu Ju & Yu-fen Zhao (2008)
The Synthesis of Dialkoxyphosphorylcarboxamides, Phosphorus, Sulfur, and Silicon and
the Related Elements, 183:2-3, 701-705, DOI: 10.1080/10426500701807517
To link to this article: http://dx.doi.org/10.1080/10426500701807517
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Phosphorus, Sulfur, and Silicon, 183:701–705, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701807517
The Synthesis of Dialkoxyphosphorylcarboxamides
Yong Ye,1,2 Ping Li,1 Xiao-lian Hu,1 Zhi-yu Ju,1
and Yu-fen Zhao1,2
1Department of Chemistry, Key Laboratory of Chemical Biology and
Organic Chemistry, Zhengzhou University, Zhengzhou, China
2Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology (Ministry of Education), Tsinghua University, Beijing China
The synthesis of dialkoxyphosphorylcarboxamides, which is difficult to moni-
tor by TLC, was investigated by ESI-MS and ESI-MSn. Their fragmentation
pathways were rationalized and supported by tandem mass spectrometry. The
characteristic ions in ESI-MS are useful for the structural determination of
phosphorylcarboxamides.
Keywords Dialkoxyphosphorylcarboxamides; ESI-MS; fragment pathways; synthesis
INTRODUCTION
Aminoalkylphosphonic acid has received considerable attention be-
cause of their biological activity.1−3 Several well-know reducing agents
reported could be applied to selective reduction of the amide group
of dialkoxyphosphorylcarboxamide, leading to aminoalkylphosphonic
acids.4,5 The dialkoxyphosphorylcarboxamides can be easily prepared
from dialkyl phosphites through treatment with acrylamide according
to known procedures.6 However, the ESI-MS fragmentation character-
istics of this type of compound has not been studied. Therefore, we
synthesized a series of dialkoxyphosphorylcarboxamides and investi-
gated their fragmentation processes. We found that ESI-MS/MSn is a
powerful tool for tracing the addition reaction.
The authors would like to thank the financial support from the National Natural
Science Foundation of China (No. 20602032 and 20572061).
Address correspondence to Yong Ye, Department of Chemistry, Key Laboratory of
Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450052,
China. E-mail: yeyong03@mail.nankai.edu.cn
701

702
Y. Ye et al.
APPARATUS AND REAGENTS
Acrylamide was from Beibo (Zhengzhou, China). Dialkyl phosphites
were synthesized as described previously.7−9 Mass spectra were ac-
quired in positive ion mode using a Bruker ESQUIRE-LCTM ion trap
spectrometer equipped with a gas nebulizer probe that was capable of
analyzing ions up to m/z 20000. Nitrogen was used as drying gas at a
flow rate of 4 L/min. The nebulizer pressure was 7 psi. The capillary
was typically held at 4 kV and the source temperature was maintained
at 300◦C. The instrument was operated at unit-mass resolution and
calibration of m/z was performed using a standard ES-tuning-mix. The
samples that were dissolved in methanol were ionized by ESI and con-
tinuously infused into the ESI chamber at a flow rate of 4 ul/min by a
Cole-Parmer 74900 syringe pump (Cole Parmer Instrument Company).
RESULTS AND DISCUSSION
The Synthesis of Dialkoxyphosphorylcarboxamides
As shown in Scheme 1, compounds 1 are the key intermediate for the
synthesis of the aminoalkylphosphonic acids and can be synthesized
from dialkyl phosphite with acrylamide. It is impossible to monitor
the reaction by TLC because there is no ultraviolet absorption for the
products. Fortunately, we found that this reaction can be monitored by
ESI-MS. After the reaction was complete (detected by ESI-MS) it was
allowed to cool to room temperature and then was filtered. The propi-
onamide was isolated by seeding the cooled solution and filtering off the
precipitated crystals.
SCHEME 1 The synthetic route of dialkoxyphosphorylcarboxamides.
A solution of freshly prepared sodiun alkyloxide in MeOH was added
slowly to a solution of acrylamide and dialkyl phosphite. When the
reaction mixture was stirred at room temperature for 5 min, the re-
action was checked by ESI-MS. The result showed that dialkyl phos-
phite but not the desired product was observed (Figure 1a), but not
the desired product. The peak at m/z 111 and m/z 133 in the ESI-MS
were identified as the dialkyl phosphite and its [M+Na]+. Consequently,

Synthesis of Dialkoxyphosphorylcarboxamides
703
FIGURE 1 ESI-MS spectra of the components in the synthesis of compound
1a. (a) Spectrum of the reaction in 5 min; (b) MS analysis of the reaction in
40 min; and (c) reaction in 60 min.
we added a solution of sodiun alkyloxide in MeOH to the reaction
mixture, which was warmed to 70◦C and continuously stirred for
40 min. Then, the reaction was checked by ESI-MS. The resulting
mixture showed quite a difficult pattern of spots on the TLC plate.
In contrast, the reactants peak at m/z 111 was observed with quite
low intensity from ESI-MS analysis, while a new peak at m/z 204 ap-
peared in the spectrum, suggesting that the formation of the product
had occurred, but in low yield (Figure 1b). Therefore, reaction time
was prolonged 20 min, and the reactant was completely consumed
(Figure 1c).
ESI MS/MSn of Dialkoxyphosphoryl-carboxamides
ESI mass spectra for 1a–d showed both [M+H]+, [M+Na]+, and
[2M+Na]+ ions, which were studied via multistage tandem mass
spectrometry. It was found that all gave the [2M+Na]+ ion as the
base peak. Positive ion ESI-MS/MS of [M+Na] of 1a–d are shown in
Table I.
The mass spectral fragment pathways of compound 1c are discussed
as a typical example (shown in Scheme 2). The other compounds dis-
played similar fragment pattterns to 1c in ESI-MS. [M+Na]+ of 1c first
gave the fragment ion at m/z 218 through the C3H6 extrusion pathway.
Second, the fragmentation of m/z 218 gave peaks at m/z 176 by losing

704
Y. Ye et al.
TABLE I MS and MSn Spectra of Compound 1
Cationized (Na+) Ion
Comp. Precursor Fragment ions (relative, intensities)
1a
1b
204(69)
232(100)
204(12)
260(100)
218(29)
288(32)
232(53)
187(30) 168(100)
204(34) 187(3) 158(56)
187(12) 176(3) 158(100)
218(46) 201(9) 176(4) 158(71)
201(9) 176(4) 158(100)
232(70) 215(5) 176(9) 158(100)
215(5) 176(6) 158(100)
1c
1d
NH3
Na+
OH
O
Na
O
P
H2
C
CH2
C
C O
n-Pro P
HCH2CCO
HO
C
C NH2
H
-17
H
HO
m/z 201
Na
Na
O
O
O
P
-42
O
CH3CH2CH2O
CH3CH2CH2O
HO
CH2 C NH2
P
CH2 C NH2
CH2
m/z 260
CH3CH2CH2O
CH2
C3H6
m/z 218
-42
Na
Na
O
O
O
O
C3H6
8
1
-
CH2
C NH2
P
CH2
C NH2
HO
HO
P
O
CH2
CH2
m/z 158
H2O
m/z 176
SCHEME 2 Fragment pathway proposed for the compound 1c cationized (Na+)
ion.
another C3H6 group. The m/z 176 fragment ion could generate the m/z
158 fragment ion by the losing water pathway.
CONCLUSIONS
The synthesis of dialkoxyphosphorylcarboxamides were investigated by
ESI-MS and ESI-MSn. Consequently, the reaction could be monitored
successfully. The fragmentation pathways of those compounds were ra-
tionalized and supported by tandem mass spectrometry. These charac-
teristic ions in ESI-MS are useful for the structural determination of
phosphorylcarboxamides containing.

Synthesis of Dialkoxyphosphorylcarboxamides
705
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