Catalyst free one-pot synthesis of α-aminophosphonates in aqueous ethyl lactate

Article abstract of DOI:10.1080/10426507.2018.1542395

An highly efficient and environmentally friendly process for the synthesis of α-aminophosphonates has been devised, through a one-pot three-component condensation of various aldehydes, amines and triethyl phosphate in water-ethyl lactate under ultrasonic

Full text of DOI:10.1080/10426507.2018.1542395

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Catalyst free one-pot synthesis of α-
aminophosphonates in aqueous ethyl lactate
Ge Gao, Meng-Nan Chen, Li-Ping Mo & Zhan-Hui Zhang
To cite this article: Ge Gao, Meng-Nan Chen, Li-Ping Mo & Zhan-Hui Zhang (2018): Catalyst
free one-pot synthesis of α-aminophosphonates in aqueous ethyl lactate, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1542395
To link to this article: https://doi.org/10.1080/10426507.2018.1542395
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1542395
Catalyst free one-pot synthesis of α-aminophosphonates in aqueous
ethyl lactate
Ge Gao, Meng-Nan Chen, Li-Ping Mo, and Zhan-Hui Zhang
National Demonstration Center for Experimental Chemistry Education, College of Chemistry and Material Science, Hebei Normal University,
Shijiazhuang, China
ABSTRACT
ARTICLE HISTORY
Received 4 July 2018
Accepted 26 October 2018
An highly efficient and environmentally friendly process for the synthesis of α-aminophosphonates
has been devised, through a one-pot three-component condensation of various aldehydes, amines
and triethyl phosphate in water-ethyl lactate under ultrasonic irradiation conditions at room tem-
perature. The expected products were obtained in high yield without the need for any add-
itional catalyst.
KEYWORDS
α-Aminophosphonates;
three-component reaction;
ethyl lactate; ultrasound
GRAPHICAL ABSTRACT
1. Introduction
Over the past few decades, with the increasing demand
for environmentally friendly, sustainable and efficient syn-
thesis strategies in green chemistry, catalyst-free, solvent-
mediated protocols for the preparation of organic com-
pounds has emerged as an important strategy due to their
simple workup, low cost, reduced pollution, and avoiding
the impact of catalysts on sensitive substrates.[18] In these
processes, some green solvents such as glycerol,[19] fluori-
nated alcohols,[20] water,[21] and deep eutectic solvent
(DES)[22–24] have often been utilized as solvent and catalyst
to promote organic chemical reactions. At the same time,
multi-component reactions (MCRs) allow the assembly of
simple precursors in a single synthesis operation without
isolation of the intermediates, producing products contain-
ing most of the atoms in the starting materials. MCRs have
been shown to be more powerful and superior than the
traditional stepwise approach due to their atomic economy,
energy efficiency, simplicity of operation, and generally
excellent productivity.[25] Therefore, the catalyst-free MCRs
have acquired new dimensions in various research works to
produce elaborate libraries of biological active compounds.
α-Amino phosphonates have been the focus in recent
years because of their structural analogy to the correspond-
ing α-amino acids as well as heterocyclic phosphonates. As a
result of continuous efforts, utilization of α-amino phospho-
nates is expanding into many new channels. They have
been found to exhibit a vital role in industrial, biological,
synthetic organic chemistry and medicinal chemistry.[26]
In the organic synthesis process, the reaction medium plays a
vital role in promoting the contact between the reactants and
even changing the progress of the reaction. Therefore, the search
for new green reaction solvents with unique properties and func-
tions is still important in current green organic synthesis
research. In recent years, biomass-derived ethyl lactate (EL) has
attracted widespread attention as a new type of a green and eco-
nomically viable alternative to traditional solvents. It has favor-
able characteristics such as stability, non-corrosiveness and good
solubility in water and organic compounds.[1] Due to its low tox-
icity, EL has been approved by FDA (Food and Drug
Administration) and EFSA (European Food Safety Authority) for
use as a food and pharmaceutical additive.[2] EL can be produced
by fermentation of renewable carbohydrate feedstocks derived
from corn and soybeans.[3] Moreover, ethyl lactate is soluble in
paraffin oil, which actually leads to the formation of some van
der Waals interactions. Therefore, this ester provides different
solvent properties that may cover a large number of solutes.[4] It
has been demonstrated to be a good extractive solvent for various
food and bioactive compounds such as caffeine,[5] amino acids,[6]
polyphenols[7] and carotenoid.[8] In addition, EL has also applied
as a green reaction medium in some useful organic reactions[9] to
prepare some important compounds such as 1,4-benzothia-
zines,[10] spirooxindole-pyran derivatives,[11] polyfunctionalized
alkenes,[12] bis(Indolyl)methanes,[13] 4(3H)-quinazolinones,[14]
quinoxalines,[15] enaminones[16] and 2-pyrazoline derivatives.[17]
CONTACT Zhan-Hui Zhang
zhanhui@126.com
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
G. GAO ET AL.
Scheme 1. Synthesis of α-aminophosphonates.
Therefore, the development of an efficient and convenient irradiation (USI) on the reaction. It was found that although
method to α-amino phosphonates is of great significance
and highly desirable. The three-component reaction involv-
ing amine, aldehyde and dialkyl phosphonate or triethyl
phosphate is a simple and straightforward method for the
synthesis of α-aminophosphonates. This transformation pro-
ceeds via an in situ imine formation, followed by phospha-
Mannich reaction between phosphite nucleophile and imine
electrophile to form an N–C–P bond. Usually, this reaction
was carried out in the presence of various catalysts, such as
aqueous formic acid,[27] zinc di(L-prolinate),[28] NbCl5,[29]
CeCl3·7H2O,[30] HfCl2,[31] BF3·OEt2,[32] SbCl3/Al2O3,[33] gold
complex,[34] ceric ammonium nitrate,[35] dehydroascorbic
acid capped magnetite (DHAA-Fe3O4),[36] nano-magnetic
sulfated zirconia (Fe3O4@ZrO2/SO42-),[37] phosphomolybdic
acid,[38] dodecatungstophosphoric acid (DTP/SiO2),[39] xan-
than sulfuric acid,[40] sulfated polyborate,[41] propylphos-
phonic anhydride(T3P®),[42] or TiO2.[43] Although these
methods have demonstrated their efficiency in α-amino
phosphonates, they are also suffer from some drawbacks
such as long reaction times, poor yields, the need for stoi-
chiometric catalysts, harsh reaction conditions with the use
of acids, the use of toxic solvents and high reaction tempera-
tures. Moreover, the water formed during imine formation
decomposes or deactivates those humidity-sensitive Lewis
acids or Brønsted acids. Therefore, the development of a
milder, convenient and environmentally benign approach to
overcome these shortcomings is still under investigation.
With our ongoing interest toward the development of
new environmentally friendly synthetic methodologies,[44–48]
herein, we wished to develop a convenient, ultrasound
assisted catalyst free synthesis of α-aminophosphonates via
the condensation of aldehydes, amines, and triethyl phos-
phate using water-ethyl lactate as the reaction medium
(Scheme 1).
the reaction time was extended to 90 min at room tempera-
ture, the reaction could not achieve complete conversion
without USI (Table 1, entry 23). Upon increasing the tem-
perature (30 °C, 60 °C, 80 °C and 100 °C) in the absence of
ultrasound irradiation, product 4a was obtained in yields of
87%, 88%, 90% and 93%, respectively (Table 1, entries
24–27). Therefore, it clearly shows that USI accelerates the
reaction as compared with the results obtained under heat-
ing conditions.
To demonstrate the practicability and reliability of the
developed process, we conducted the model reaction on a
large scale under similar conditions. The reaction of benzal-
dehyde, (100 mmol), aniline (100 mmol), and triethyl phos-
phate (100 mmol) successfully worked to afford the product
4a in an excellent yield (Table 1, entry 28).
With the optimized conditions established, the scope and
generality of this novel strategy were evaluated by reacting
varieties of aldehydes, amines, and triethyl phosphate in
aqueous ethyl lactate under ultrasonic irradiation. As illus-
trated in Table 2, benzaldehyde with different substituents
was explored and it was found that the benzaldehyde bear-
ing both electron rich and deficient group are well tolerated
Table 1. Optimization of reaction conditionsa.
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
no
EtOAc
DMF
CH2Cl2
CHCl3
PEG 400
THF
EtOH
H2O
EtOH/H2O (1:1)
MeOH
CH3CN
EL
EL/H2O (9:1)
EL/H2O (8:1)
EL/H2O (4:1)
EL/H2O (2:1)
EL/H2O (1:1)
EL/H2O (1:2)
EL/H2O (1:3)
EL/H2O (1:5)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
EL/H2O (3:2)
90
90
90
90
90
90
90
90
90
90
90
90
30
30
30
30
30
30
30
30
30
30
90
90
90
90
90
30
30
trace
35
40
48
50
51
55
57
42
49
58
59
75
77
80
84
91
86
80
75
65
95
75
80
87
88
90
93
93
9
10
11
12
13
14
15
16
2. Results and discussion
In our preliminary examination, benzaldehyde, aniline, and 17
triethyl phosphate were chosen as the model substrates to
18
19
20
21
22
23
optimize the reaction conditions and the results were col-
lected in Table 1. At room temperature, some solvents were
examined under ultrasound irradiation, and it is observed
that the reaction formed only low yield in ethyl acetate,
DMF, H2O, CH2Cl2, CHCl3, PEG 400, THF, MeOH, EtOH,
and CH3CN. It is interesting to note that reaction resulted
in 75% in the EL (Table 1, entry 13). Inspired by these
results, we further optimized the conditions by varying the
different ratios of EL/H2O. The results show clearly that EL/
H2O (3:2) was the most efficient in producing the expected
product 4a with the highest yield (Table 1, entry 22). At the
same time, we also investigated the effect of ultrasound
23c
24c,d
25c,e
26c,f
27g
28h
aThe reaction was performed with benzaldehyde (1.0 mmol), aniline
(1.0 mmol) and triethyl phosphate (1.0 mmol) in 3 ml solvent at room tem-
perature under ultrasonic irradiation. bIsolated yield. cWithout sonication.
d30 °C. e60 °C. f80 °C. g100 °C. hThe reaction was carried out in
100 mmol scales.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Table 2. Ultrasound-assisted synthesis of α-aminophosphonates in EL/H2O.
Entry
Aldehydes
C6H5CHO
3-OMeC6H4CHO
4-OMeC6H4CHO
4-MeC6H4CHO
4-FC6H4CHO
2-ClC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
4-NO2C6H4CHO
2-Furaldehyde
Cyclohexanecarboxaldehyde
C6H5CHO
R2
Product Time (min)
Yield (%)a
mp (oC)
1
2
3
4
5
6
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
40
41
40
40
19
25
25
20
22
29
40
47
44
40
24
25
25
45
40
46
45
40
25
25
95
92
94
89
95
94
94
95
94
94
89
79
92
94
94
94
94
89
94
94
94
90
94
95
90–91[40]
102–104[35]
102–104[40]
64–65[40]
84–85[42]
88–89[40]
89–91[40]
59–60[40]
96–98[34]
96–97[40]
51–52[40]
oil[40]
7
8
9
C6H5
C6H5
C6H5
4g
4h
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
C6H5
C6H5
C6H5
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
3-MeC6H4
4-MeC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
4-NO2C6H4
4-OMeC6H4
3-MeC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
125–129[32]
116–118[40]
122–124[32]
112–114[40]
111–114[32]
144–145[40]
118[43]
C6H5CHO
C6H5CHO
C6H5CHO
C6H5CHO
C6H5CHO
4-OMeC6H4CHO
4-OMeC6H4CHO
4-OMeC6H4CHO
4-MeC6H4CHO
3-ClC6H4CHO
4-BrC6H4CHO
86[43]
109–110[49,50]
90–91[33]
85–86[50]
111–112[33]
aIsolated yield.
to furnish corresponding products in high to excellent 250 W. Melting points were determined on X-5 apparatus and
yields. Generally, the electronic properties of substrates had
no pronounced effects on the yields. In addition, the steric
influence of the substituents of benzaldehyde was not obvi-
ous. Notably, the treatment of heteroaromatic carbaldehydes
such as 2-furaldehyde with aniline and triethyl phosphate
also proceeded smoothly and gave the desired product 4k in
89% yield. It is also important to note that the reactions
were efficient for aliphatic aldehydes such as cyclohexanecar-
boxaldehyde (entry 12) under similar reaction conditions.
Additionally, aniline bearing electron-donating and electron-
withdrawing groups on the benzene ring proceeded
smoothly and offered the respective products in high yield.
Strongly electron-poor aromatic amines such as 4-nitroani-
line also worked well in this reaction, leading to the desired
product in high yield (Table 2, entry 18). These results
demonstrate that this protocol provided an efficient,
facile and practical method for the synthesis of α-
aminophosphonates.
were uncorrected. The IR spectra were obtained with KBr
power-pressed pellets in the range of 400–4000 cm−1 using a
1
Thermo Fisher is 50 spectrometer. The H NMR and 13C
NMR spectra were recorded on a Bruker AV III-500 or
Zhongke Niujin AS 400 spectrometer using TMS as internal
standard. The mass spectra were performed on a 3200 Qtrap
instrument with an ESI source. The Supplemental Materials
contains sample spectroscopic characterization data including
1H and 13C NMR spectra for products 4 (Figures S1–S80).
4. General procedure for synthesis of α-
aminophosphonates
Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phos-
phate (1.0 mmol) were put into a 25 ml round-bottomed
flask in ethyl lactate/water (3:2, 3 ml). The reaction flask was
located in the ultrasonic bath and irradiated at room tem-
perature for the appropriate time. After completion of the
reaction as indicated by TLC, the mixture was extracted
with ethyl acetate (10 ml ×3). The combined organic phase
In conclusion, we have developed a convenient and prac-
tical approach for synthesis of α-aminophosphonates via
one-pot three-component reaction in water-ethyl lactate
under ultrasound irradiation conditions at room tempera- was dried over anhydrous Na2SO4 and the solvent was
ture. This reaction allows broad functional group compati-
bility, mild and neutral reaction conditions, easy product
separation and purification, avoidance of toxic solvents,
catalyst free, and operational simplicity. The further use of
aqueous ethyl lactate in the preparation of other heterocyclic
organic compounds is currently underway in our laboratory.
removed under reduced pressure. The residue was then sub-
jected to preparative TLC to give pure product by using
mixed ethyl acetate and petroleum ether as an eluent.
Disclosure statement
No potential conflict of interest was reported by the authors.
3. Experimental
Funding
The chemicals used were obtained from commercial sources
and were used as received without purification. Ultrasound
irradiation was performed in KH5200V ultrasonic cleaner
We are grateful for the financial support from the Science and
Technology Research Foundation of Hebei Normal University
with a 40 KHz processing frequency and a normal power of (L2018Z06), the Natural Science Foundation of Hebei Province

4
G. GAO ET AL.
(B2015205182) and the National Natural Science Foundation of
China (21272053).
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of 1,2-Diketones and Quinoxalines in Sustainable Medium.
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ORCID
Zhan-Hui Zhang
http://orcid.org/0000-0002-1082-5773
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