Promiscuous lipase catalyzed a new P–C bond formation: Green and efficient protocol for one-pot synthesis of α-aminophosphonates

Article abstract of DOI:10.1002/hc.21408

α-Aminophosphonates are valuable substructures with important biological and pharmacological properties. Lipase catalytic promiscuity is a new method in the organic synthesis for the preparation of α-aminophosphonates via multicomponent reaction in one pot. This efficient, simple, and eco-friendly method proceeds in the presence of immobilized Candida Antarctica lipase as catalyst under solvent-free conditions at room temperature. The new α-aminophosphonates are synthesized in high yields (up to 96%). Moreover, enzymatic-catalyzed P–C bond formation through a Kabachnik-Fields reaction was achieved for the first time.

Full text of DOI:10.1002/hc.21408

Received: 4 May 2017
DOI: 10.1002/hc.21408
Revised: 18 September 2017
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R E S E A R C H A R T I C L E
Promiscuous lipase catalyzed a new P–C bond formation:
Green and efficient protocol for one-pot synthesis of
α-aminophosphonates
Samia Guezane-Lakoud1
Martial Toffano2
Louisa Aribi-Zouioueche1
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1Ecocompatible Asymmetric Catalysis
Laboratory (LCAE), Badji Mokhtar
Annaba-University, Annaba, Algeria
Abstract
α-Aminophosphonates are valuable substructures with important biological and
pharmacological properties. Lipase catalytic promiscuity is a new method in the or-
ganic synthesis for the preparation of α-aminophosphonates via multicomponent re-
action in one pot. This efficient, simple, and eco-friendly method proceeds in the
presence of immobilized Candida Antarctica lipase as catalyst under solvent-free
conditions at room temperature. The new α-aminophosphonates are synthesized in
high yields (up to 96%). Moreover, enzymatic-catalyzed P–C bond formation through
a Kabachnik-Fields reaction was achieved for the first time.
2Equipe de Catalyse Moléculaire-ICMMO-
CNRS UMR8182 Bât 420, Université Paris-
Sud, Orsay, France
Correspondence
Louisa Aribi-Zouioueche, Ecocompatible
Asymmetric Catalysis Laboratory (LCAE)
Badji Mokhtar Annaba-University, Annaba,
Algeria.
Email: louisa.zouioueche@univ-annaba.dz
Funding information
Algerian Ministry of Higher Education and
Scientific Research (DGRSDT, FNR)
organometallic catalysts does not satisfy us with the objective
to develop biologically active compounds through a greener
1
INTRODUCTION
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The α-aminophosphonates are analogs of amino acids and as
such are of great interest in organic synthesis because of their
biological and pharmacological activities.[1] That is why the
synthesis of new aminophosphonates is underway to find an-
tibiotics,[2] enzymes inhibitors,[3] antileishmanial,[4] antifun-
gal,[5] or antitumoral compounds.[6] For example, compound
1 showed optimal antiproliferative activity to human tumor
cells from colon carcinoma and from malignant tumors of
the breast and urinary bladder,[7] compound 2 influenced
the antitumor activity,[8] and compound 3 showed moderate
activities on both cancerous cells and noncancerous cells[9]
(Figure 1).
The synthesis of α-aminophosphonates by multicompo-
nent condensation in one pot according to the Kabachnik-
Fields reaction[10] is widely described in the literature
with a variety of catalysts.[11] We have recently reported
NiSO4·6H2O as a new and efficient catalyst for the syn-
thesis of α-aminophosphonates.[12] However, the use of
process.
During the three last decades, enzymes have emerged as
a powerful catalytic tool for organic synthesis especially in
pharmaceutical processes since chirality is a key factor in the
efficacy of many drugs.[13] Biocatalysis has many benefits in
the context of green and sustainable chemistry as illustrated
in the synthesis of active pharmaceutical molecules.[14] The
high selectivity of hydrolases as biocatalysts strongly con-
tributes to their use of chiral chemicals synthesis which de-
mand is growing.[15] Lipases are the most used enzymes in
synthetic organic chemistry. They allow the development of
a practical and environmentally friendly alternative to tradi-
tional metallo- and organocatalysis.[16]
More recently, the use of lipases was extended to cata-
lytic promiscuity to promote new reactions.[17a] Enzymatic
promiscuity is the ability of an enzyme active site to cata-
lyze several different chemical transformations. This has
implications not only for fundamental understanding of mo-
lecular recognition and evolution of protein function over
time but also for the realm of biotechnology.[18] Exploiting
enzyme catalytic promiscuity provides new catalytic tools
Contract grant sponsor: Algerian Ministry of Education and Scientific
Research.
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Heteroatom Chemistry. 2017;e21408.
https://doi.org/10.1002/hc.21408
wileyonlinelibrary.com/journal/hc
© 2017 Wiley Periodicals, Inc.
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GUEZANE-LAKOUD Et AL.
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l
C
O
O
P
Et
Et
O
N
O
O
N
NH
NH
O
NH
O
P
N
P
Et
Et
O
Et
O
Et
O
Et
O
S
FIGURE 1 Several α-
aminophosphonates having biological
activities
1
3
2
especially for multicomponent reactions (MCRs). These one-
pot reactions allow the creation of several bonds in one step
with excellent chemical yields, reduction in reaction times
and waste, toward the access to biologically important com-
pounds.[19] Many reactions were successfully revisited, such
as the Mannich reaction,[20] Morita-Baylis-Hillman reac-
tion,[21] Knoevenagel reaction,[22] Henry reaction,[23] Michael
addition,[24] and aldolization reaction.[17e]
Lipases are a powerful tool to the organic chemist due
to their easy use and many advantages showing broad ver-
satility regarding their catalytic behavior.[25] In our group,
the biocatalyst was mostly used in enantioselective catal-
ysis[26] and for the first time, we envisaged lipases to give
access to α-aminophosphonates forming a P–C bond by en-
zymatic promiscuity. Numerous works have shown that li-
pases are efficient to catalyze in the kinetic resolution of the
hydroxyphosphonates.[27]
In the current work, we reported three-component
Kabachnik-Fields reaction (MCRs) carried out in “one
pot” in the presence of a lipase as catalyst to synthesize α-
aminophosphonates (Scheme 1).
The reaction is carried out under most environmentally
benign reaction conditions due to their enzymatic promiscu-
ity at room temperature and without solvent. To the best of
our knowledge, the lipase catalytic promiscuity in the P-C
bond-forming reactions has not been reported yet.
are used, in which three are microbial lipases, Pseudomonas
cepacia lipase (PCL), Candida cylindracea lipase (CCL), and
Candida antarctica B lipase immobilized on acrylic resin
(CAL-B), and the fourth is animal lipase, Porcine pancreatic
lipase (PPL).
At first, all these lipases are used with a catalytic amount
based on the previous work from our laboratory: PCL (80 mg),
CCL (100 mg), CAL-B (100 mg), and PPL (100 mg). Four
different solvents hydrophobicity were studied. The reaction
is carried out at 25°C at different reaction times. The results
are reported in Table 1.
Several commercially available lipases were examined in
THF as solvent. For free lipases, PCL, CCL, and PPL, the
yield does not exceed 10% (Table 1, entries 1, 2, 3) despite
heating at 40°C for 24 hours in THF. Only the CAL-B is able
to promote the multicomponent reaction in one pot in THF
at 40°C (Table 1, entry 4), and the α-aminophosphonate 4a
is obtained in 75% yield. So, the optimum catalytic amount
is 50 mg of CAL-B (Table 1, entry 5), and using 100 mg of
CAL-B did not change the yield (Table 1, entry 4 vs entry 5).
The reduction in the catalytic amount of the CAL-B to 25 mg
caused a decrease in yield to 30% with better conditions reac-
tion (Table 1, entry 6 vs entry 5). Then, the study of the multi-
component reaction in various other solvents such as toluene,
diethyl ether, and methyl tert-butyl ether (MTBE) showed a
decrease in the yield in 4a compared to reaction in THF. We
obtained a 50% yield in toluene and MTBE (Table 1, entries
7, 8) and 35% yield in ether (entry 9), while in THF, the yield
is 75% (entry 5) under the same condition reactions. The de-
sired product was easily obtained by recrystallization from
hexane after a simple extraction.
2
RESULTS AND DISCUSSION
|
In our quest for developing a lipase-catalyzed MCRs proto-
col, we selected the reaction of benzaldehyde, aniline, and
diethylphosphite as model reaction. We studied several pa-
rameters to optimize the reaction conditions such as the lipase
nature, the solvent effect, and the reaction time. Four lipases
To our delight, the α-aminophosphonate 4a was obtained
in 94% yield exclusively under solvent-free conditions at
room temperature by catalytic promiscuity in the presence
of 50 mg of CAL-B (Table 1, entry 10). Furthermore, there
SCHEME 1 Lipase catalyzed the
α-aminophosphonates

GUEZANE-LAKOUD Et AL.
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TABLE 1 Optimization reaction of the
O
P
α-aminophosphonatesa,b,c
H
C O
NH2
H
N
Et
Et
O
O
O
HP
Lipase
+
Et
Et
O
O
+
Entry
Lipase (mg)
Solvent
T (°C)
Time (h)
Yield (%)c
1a
PCL (80)
THF
THF
THF
THF
THF
THF
PhMe
TBME
Et2O
None
None
None
None
None
None
None
40
40
40
40
40
40
40
40
40
25
25
40
25
25
25
25
24
24
24
24
24
24
24
24
24
24
24
24
2
10
10
10
75
75
30
50
50
35
94
NR
Traces
5
2a
CCL (100)
PPL (100)
CAL-B (100)
CAL-B (50)
CAL-B (25)
CAL-B (50)
CAL-B (50)
CAL-B (50)
CAL-B (50)
None
3a
4a
5a
6a
7a
8a
9a
10b
11b
12b
13b
14b
15b
16b
None
CAL-B (50)
CAL-B (50)
CAL-B (50)
CAL-B (50)
6
36
72
10
94
94
The bold values indicate the best condition found for this reaction.
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), and diethylphosphite (1.2 mmol) were stirred
with lipase from solvent (2 mL).
bReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), and diethylphosphite (1.2 mmol) were stirred
with lipase without solvent.
cYield of the pure product, purified by recrystallization from hexane.
is no reaction in the absence of lipase at 25°C and traces of
products appear at 40°C (Table 1, entries 11, 12).
The reaction time of the enzyme catalytic promiscuity
reaction was also studied. In less than 10 hours, the desired
product was obtained in low yield (<10%) (Table 1, entries
13, 14) while the yield did not increase after 24 hour (94%)
(Table 1, entries 10, 15 and 16).
Subsequently, the recycling of CAL-B was examined on
the model reaction. After completion of the reaction, the li-
pase was removed by filtration, recovered, and reused three
times. There is a decrease in catalytic performance for the 3rd
cycle (Figure 2).
To validate this new method of biocatalytic promiscuity
with CAL-B and to show the effectiveness of the MCRs re-
action, we applied the optimized reaction on a series of var-
iously substituted aldehydes with electron-withdrawing and
electron-donating groups associated with various aromatic
amines in order to access to α-aminophosphonates. The re-
sults are summarized in Table 2.
The three-component condensation reaction in one pot
was carried out among a series of various aromatic aldehyde,
different aromatic amines and diethylphosphite with 50 mg
94
90
Yield (%)
60
100
80
60
40
20
0
1
2
3
Number of Reuse
FIGURE 2 Reusing of the CAL-B catalyst
of CAL-B without solvent for 24 hours at room temperature.
The α-aminophosphonates are obtained in 40%-96% yield
depending on the structures of the aldehyde and the amine.
We also confirmed the activity of the CAL-B after the reac-
tion described and verified that the lipase is not deactivated
under the reaction conditions.
Use of aniline with benzaldehyde, 1-naphtaldehyde,
and 4-nitrobenzaldehyde leads, respectively, to the

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GUEZANE-LAKOUD Et AL.
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TABLE 2 Lipase-catalyzed synthesis of a series α-aminophosphonatesa,b
O
P
O
H
C O
NH2
H
N
t
OE
Et
O
HP
CALB (50mg)
+
Et
Et
O
O
+
rt, solvent-free
24h
R'
R
R'
R
1
2
3
4
α-aminophosphonates 4(a-o) (yield %)
O
P
O
O
H
N
O
Et
O
H
N
H
N
Et
O
Et
O
P
O
P
O
Et
Et
Et
N
O2
4a, 94
%
4b, 95
%
4c, 60
%
O
H
N
O
O
P
O
Et
O
P
O
H
H
Et
O
Et
O
N
N
P
O
Et
Et
Et
O
4f, 94%
4e, 90%
4d, 40%
(Continues)

GUEZANE-LAKOUD Et AL.
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TABLE 2 (Continued)
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), and diethylphosphite (1.2 mmol), CAL-B (50 mg), room temperature, 24 h.
bYield of the pure product, purified by recrystallization from hexane.
α-aminophosphonates 4a, 4b, and 4c with 60%-95% yield.
Similarly in the presence of toluidine with the above se-
ries of aromatic aldehydes, the α-aminophosphonates
4f, 4g, and 4h are obtained in 65%-96% yield. The use of
4-biphenylbenzaldehyde with aniline and toluidine gives
moderate yields of the α-aminophosphonates 4d (40%) and
4i (45%), respectively. The presence of the phenyl in posi-
tion 4 probably hinders the coordination with the natural ac-
tive site of the lipase. This phenomenon is reduced with the
compound 4n. This suggests a probably different enzymatic
SCHEME 2 Proposed mechanism of
CAL-B-catalyzed Kabachnik-Fields reaction

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GUEZANE-LAKOUD Et AL.
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activation mode in the presence of diazo group. Indeed,
the use of 4-phenylazoaniline and 3-phenoxybenzaldehyde
leads to original α-aminophosphonates structures 4e, 4j, 4k,
4l, 4n, and 4o with excellent yields in the range 72%-92%.
This indicates that the effectiveness of the catalytic promis-
cuity CAL-B is provided by aromatic aldehydes substituted
electron-donating groups. In the case of 4-nitrobenzaldehyde
with phenylazoaniline, the MCRs show only traces of com-
pound 4m. The absence of reactivity in this case is probably
due to the combined effects of the geometry of the molecules
with a sterically hindered group associated with the presence
of the electron-withdrawing group, which impedes the ap-
proach of the active site.
It is interesting to note that all α-aminophosphonates ob-
tained are racemic, and no asymmetric induction is induced
by CAL-B. The majority of papers on enzymatic promis-
cuity for carbon–carbon bond-forming reactions that yield
chiral products report low or no enantioselectivities despite
the fact that enzymes provide a natural chiral environment
for asymmetric catalysis.[17f,28] However, the synthesis of α-
aminophosphonates is carried out under conditions of MCRs
by catalysis with a lipase under solvent-free condition which
is a synthetic route including biocatalysis, MCRs, neat reac-
tion, the biocatalyst reuse, simple purification without column
chromatography, the criteria for a green chemistry process.[29]
Based on the generally accepted chemically catalyzed
mechanism of the Kabachnik-Fields reaction[12,30] and the
literature regarding enzymatic promiscuity to form carbon–
carbon bonds,[17a,c,f] a mechanism was suggested for the C–P
bond formation starting the interaction with lipase active site
of CAL-B (Scheme 2).
The active site of CAL-B contains the catalytic triad,
Ser105-His224-Asp187 common to all serine hydrolases.
The top pocket is the “oxyanion hole.” It is a spatial arrange-
ment of three hydrogen-bond donors, one from the side chain
of Thr40 and two from the backbone amides of Thr40 and
Gln106.[31] When the CAL-B catalyzes promiscuous C–C
bond formation reactions, the “oxyanion hole” is utilized for
negative charge stabilization. It seems that in these reactions,
the nucleophilic serine takes no role, and acid-base transfer
is thought to be mediated by His 224 in conjunction with
Asp187.[32] In this case, the C–P bond is formed by enzy-
matic proximity by direct CAL-B-catalyzed three-component
reaction between benzaldehyde, amine, and diethylphosphite.
The formation of the imine is supposed to be the first
step of the reaction. The influence of the order of addition
of the three components in “one pot” with lipase has been
investigated. The multicomponent reaction is carried out in
three different protocols: (i) Benzaldehyde, aniline, and CAL-B
were mixed together for a few minutes, and then, diethyl-
phosphite was added; (ii) benzaldehyde, diethylphosphite,
and CAL-B were mixed together for a few minutes, and then,
aniline was added; (iii) aniline, diethylphosphite, and CAL-B
were mixed during a few minutes, and then, benzaldehyde
was added. It is observed that only the reaction carried out
according to the first order was effective and afforded the
α-aminophosphonates with an excellent yield (94%). In the
case of the two other procedures, the reaction did not proceed.
These observations strengthen the initial formation of an
imine in the presence of lipase by coordination. In the absence
of lipase, the imine was not formed in the reaction conditions.
In this case, the imine is formed rapidly between aromatic
benzaldehyde and aromatic amines in coordination with
“oxyanion hole” (carbonyl pocket). The lipase active site is
activated by a relay of hydrogen bond with histidine, aspar-
tate, and oxygen of aromatic aldehyde which promotes the
attack of the aromatic amine and the corresponding imine
formation, followed by a nucleophilic attack of the phosphite,
which leads to the formation of the P–C bond and the desired
α-aminophosphonates.
3
CONCLUSION
|
An efficient and simple method for the synthesis of α-
aminophosphonates derivatives via Kabachnik-Fields reac-
tion catalyzed by CAL-B is reported for the first time. After
optimization of reaction conditions, all the products could
be obtained in high yields (from 45% to 95%). The multi-
component reaction in one pot, aromatic aldehydes, aromatic
amines, and diethylphosphite, was achieved in the presence
of CAL-B (50 mg) at room temperature under solvent-free
conditions. Easy purification and the absence of column
chromatography are the highlights of the process. The lipase
was easily recovered and reused. New α-aminophosphonates
4e, 4j, 4k, 4l, 4n, and 4o have been prepared. This new syn-
thetic route incorporates several green chemistry principles,
atom economy, biocatalyst, environmental friendliness, and
simple operational process. This work significantly expands
the utility of CAL-B for important carbon–phosphorus bond-
forming reactions. These results are starting point for more
applications of biocatalysts in organic synthesis.
4
EXPERIMENTAL SECTION
General information
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4.1
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All starting materials and reagents used in this study were
obtained commercially from Aldrich and Acros and were
used without purification. Various commercially available
lipases were screened: lipase from Porcine pancreas type II
(PPL; LA = 100-500 U/mg), Candida Cylindracea lipase
(CCL, LA = 3.85 U/mg), Pseudomonas Cepacia lipase (PCL;
LA > 30 000 U/mg),andtheCandidaantarcticalipasefraction
B immobilized on acrylic resin (CAL-B; LA > 10 000 U/mg).
All reactions were monitored by thin-layer chromatography

GUEZANE-LAKOUD Et AL.
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(TLC) carried out on 0.25-mm Merck silica gel plates (60F-
254) using ultraviolet light (254 nm) as the visualizing agent
and KMnO4 solution as developing agents. H NMR and
7.89-7.44 (m, 6H, ArH), 7.05-7.02 (dd, 2H, J = 8.5, 7.4 Hz,
ArH), 6.68-6.63 (dd, 1H, J = 10.6, 4.1 Hz, ArH), 6.57-6.53
(m, 2H, ArH), 5.60 (d, 1H, JHP = 24.1 Hz, CHP), 5.10 (s,
1H, NH), 4.25-4.13 (m, 2H, OCH2–CH3), 3.75-3.72 (m,
1H, –OCH2–CH3), 3.25-3.15 (m, 1H, –OCH2–CH3), 1.33
(t, 3H, J = 7.00 Hz, –OCH2–CH3), 0.70 (t, 3H, J = 7.1 Hz,
–OCH2–CH3). 13C NMR (63 MHz, CDCl3, 25°C): δ 13C
NMR (63 MHz, CDCl3): δ 146.11 (d, J = 13.9 Hz), 133.81,
131.63 (d, J = 8.0 Hz), 129.09 (d, J = 10.6 Hz), 128.44,
126.25, 126.05, 125.65, 125.37 (d, J = 5.8 Hz), 122.94,
118.26, 113.57, 63.26 (dd, J2CP = 12.4, 6.8 Hz), 52.67,
1
13C NMR spectra were recorded with Bruker spectrometers
(300 MHz and 250 MHz for 1H, 75 MHz and 63 MHz for 13C
and 101 MHz and 121 MHz for 31P). Chemical shifts were
reported downfield from CDCl3 (δ = 7.26 ppm). For 13C
NMR, chemical shifts were reported in the scale relative to
the solvent of CDCl3 (δ = 77 ppm) used as internal reference.
Coupling constants (J) are given in hertz. Following abbrevia-
tions classify the multiplicity: s = singlet, d = doublet, t = tri-
plet, q = quartet, m = multiplet, br = broad signal. Melting
points were measured using Büchi Melting Point B-545. Mass
spectra were recorded with a MicrOTOF-Q Bruker spectrom-
eter using electrospray ionization (ESI) analysis.
50.25, 16.45 (d, J3CP = 6.2 Hz), 15.75 (d, J3CP = 5.7 Hz). 31
P
NMR (101 MHz, CDCl3, 25°C): δ 22.98 ppm. HRMS (ESI)
m/z calcd for C21H24NO3P [M + Na+]: 392.1401; Found
392.1386.
4.2.3
|
Diethyl [4-nitrophenyl(phenylamino)
4.2
General procedure for synthesis of α-
|
aminophosphonates 4a-4o
methyl]phosphonate (4c)[11,12]
1
To the reaction mixture containing aromatic aldehyde 1
(100 mg, 1 mmol), aromatic amine (93 mg, 1 mmol), and
diethylphosphite (165 mg, 1.2 mmol), a CAL-B (50 mg) was
added. It was stirred for an appropriate time at room tempera-
ture for 24 hours. After the reaction proceeded to comple-
tion, the enzyme was removed by filtration. The filtrate was
washed by water (10 mL) and extracted with dichlorometh-
ane (10 mL ×2). The organic phases were combined and
evaporated in vacuum. The crude product was purified by
recrystallization in hexane. Complete experimental data have
been provided (NMR spectra and HRMS).
Yield: 94%, as a yellow crystalline solid; mp 89.2°C. H
NMR (250 MHz, CDCl3, 25°C): δ 8.22-8.19 (m, 2H, ArH),
7.69-7.64 (dd, 2H, JHP = 8.80, 2.3 Hz, ArH), 7. 15-7. 09 (m,
2H, ArH), 6.77-6.71 (t, 2H, J = 7.4 Hz, ArH), 6.59-6.52 (m,
2H, ArH), 4.92-4.81 (d, 1H, JHP = 25.2 Hz, CHP), 4.19-4.10
(m, 2H, OCH2–CH3), 4.09-4.02 (m, 1H, –OCH2–CH3), 3.
99-3. 95 (m, 1H, –OCH2–CH3), 1.30 (t, 3H, J = 7.00 Hz,
–OCH2–CH3), 1.19 (t, 3H, J = 7.1 Hz, –OCH2–CH3).
13C NMR (63 MHz, CDCl3, 25°C): δ 13C NMR (63 MHz,
CDCl3): δ 147.59, 145.63 (d, J = 14.2 Hz), 144.04 (d,
J = 2.5 Hz), 129.34, 128.63 (d, J = 4.9 Hz), 123.75, 119.10,
113.79, 63.60 (dd, J2= 17.1, 6.9 Hz), 57.20, 54.84, 16.30 (dd,
J3CP = 10.3, 5.5 Hz). 31P NMR (101 MHz, CDCl3, 25°C):
δ 21.31 ppm. HRMS (ESI) m/z calcd for C17H21N2O5P
[M + Na+]: 387.1094; Found 387.1080.
4.2.1
|
Diethyl [phenyl(phenylamino)methyl]
phosphonate (4a)[11,12]
1
Yield: 94%, as a white crystalline solid; mp 88°C. H NMR
(250 MHz, CDCl3, 25°C): δ 7.52-7.29 (m, 6H, ArH), 7.16-7.10
(t, 1H, J = 7.9 Hz, ArH), 6.75-6.69 (t, 1H, J = 7.3 Hz, ArH),
6.64-6.61 (m, 2H, ArH), 4.84-4.75 (d, 1H, JHP = 24.3 Hz,
CHP), 4.18-4.10 (2H, m, –OCH2–CH3), 4.01-3.76 (2H, m,
–OCH2–CH3), 3.74-3.63 (1H, m, –OCH2 CH3), 1.31 (t, 3H,
J = 7.1 Hz, –OCH2–CH3), 1.14 (t, 3H, J = 7.1 Hz, –OCH2–
CH3). 13C NMR (63 MHz, CDCl3, 25°C): δ 146.33 (d,
J = 14.5 Hz); 136.00, 129.29, 128.74, 128.71, 128.00, 127.03,
118.40, 113.87, 63.27 (d, J2CP = 6.9 Hz), 57.29, 54.90,
16.46 (d, J3CP = 15.1), 16.37 (d, J3CP = 5.6 Hz). 31P NMR
(101 MHz, CDCl3, 25°C): δ 22.46 ppm. HRMS (ESI) m/z
calcd for C17H23NO3P [M + H+]: 320.1408; Found 320.1410.
4.2.4
Diethyl [4-biphenyl(phenylamino)
|
methyl]phosphonate (4d)[12]
1
Yield: 94%, as a white crystalline solid; mp 158°C. H
NMR (300 MHz, CDCl3): δ 7.64-7.53 (m, 6H, ArH), 7.45
(t, J = 7.4 Hz, 2H, ArH), 7.36 (t, J = 6.7 Hz, 1H, ArH),
7.15 (t, J = 7.9 Hz, 2H, ArH), 6.74 (t, J = 7.3 Hz, 1H,
ArH), 6.66 (d, J = 8.1 Hz, 2H, ArH), 4.89 (d, J = 7.5 Hz,
1H, HCP), 4.80 (d, J = 7.7 Hz, 1H, NH), 4.27-4.09 (m,
2H, –OCH2–CH3), 4.01-3.80 (m, 1H, –OCH2–CH3),
3.78-3.96 (m, 1H, –OCH2–CH3), 1.33 (t, J = 7.1 Hz,
3H, –OCH2–CH3), 1.18 (t, J = 7.1 Hz, 3H, OCH2–CH3).
13C NMR (75 MHz, CDCl3): δ 146.26 (d, J = 21.3 Hz),
140.70 (d, J = 6.8 Hz), 134.92, 129.22, 128.78, 128.72,
128.23 (d, J = 5.4 Hz), 127.35 (d, J = 2.9 Hz), 127.29,
127.02, 118.48, 113.88, 63.35 (d, J2CP = 7.0 Hz), 56.81,
54.82, 16.47 (d, J3CP = 5.8 Hz), 16.25 (d, J3CP = 6.1 Hz).
31P NMR (121 MHz, CDCl3, 25°C): δ 22.58 ppm. HRMS
4.2.2
|
Diethyl [1-naphtyl(phenylamino)
methyl]phosphonate (4b)[11,12]
Yield: 95%, as a white crystalline solid; mp 123°C. 1H NMR
(250 MHz, CDCl3, 25°C): δ 8.26 (d, 1H, JHP = 8.3 Hz, ArH),

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|
(ESI) m/z calcd for C23H26NO3P [M + Na+]: 418.1550;
Found 418.1542.
(d, J = 19.7 Hz), 129.70, 129.00, 128.40, 127.50, 126.22,
125.64, 125.35 (d, J = 6.0 Hz), 123.00, 113.67, 20.33, 16.49
(d, J = 5.9 Hz), 15.79 (d, J = 5.9 Hz). 31P NMR (121 MHz,
CDCl3, 25°C): δ 23.07 ppm. HRMS (ESI) m/z calcd for
C22H26NO3P [M + Na+]: 406.1555; Found 406.1542.
4.2.5
Diethyl [3-phenoxy(phenylamino)
|
methyl]phosphonate (4e)
Yield: 94%, as a white crystalline solid; mp 127°C. 1H NMR
(300 MHz, CDCl3): δ 7.37-7.26 (m, 4H, ArH), 7.24 (m, 4H,
ArH), 6.94 (t, J = 8.5 Hz, 3H, ArH), 6.74 (t, J = 7.3 Hz,
1H, ArH), 6.60 (d, J = 8.3 Hz, 2H, ArH), 4.85-4.68 (m, 2H,
HCP + NH), 4.23-4.07 (m, 2H, –OCH2–CH3), 4.08-3.94
(m, 1H, –OCH2–CH3), 3.88-3.71 (m, 1H, –OCH2–CH3),
1.30 (t, J = 7.0 Hz, 3H, –OCH2–CH3), 1.18 (t, J = 7.1 Hz,
3H, –OCH2–CH3). 13C NMR (75 MHz, CDCl3): δ 157.17
(d, J = 22.5 Hz), 146.15 (d, J = 14.7 Hz), 138.12, 129.90,
129.72, 129.17, 123.26, 122.72 (d, J = 5.0 Hz), 118.47 (dd,
J = 20.2, 14.8 Hz), 113.96, 63.31 (d, J2CP = 10.6 Hz), 56.92,
4.2.8
|
Diethyl [4-nitrophenyl(p-tolylamino)
methyl]phosphonate (4h)[12]
1
Yield: 94%, as a yellow crystalline solid; mp 158°C. H
NMR (300 MHz, CDCl3, 25°C): δ 8.21 (d, J = 8.5 Hz,
2H, ArH), 7.67 (dd, J = 8.8, 2.3 Hz, 2H, ArH), 6.94 (d,
2H, J = 8.3 Hz, ArH), 6.46 (d, J = 8.4 Hz, 2H, ArH),
4.85 (d, J = 25.1 Hz, 2H, HCP+NH), 4.20-4.02 (m, 3H,
–OCH2–CH3), 3.94-3.86 (m, 1H, –OCH2–CH3), 2.35 (s,
3H, CH3-Ph), 1.32 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 1.21
(t, 3H, J = 7.1 Hz, –OCH2–CH3). 13C NMR (75 MHz,
CDCl3, 25°C): δ 147.54, 144.20, 143.25 (d, J = 14.8 Hz),
129.86, 128.65 (d, J = 4.8 Hz), 128.62, 123.74, 113.93,
63.58 (dd, J2CP = 23.8, 6.9 Hz), 57.26, 55.29, 20.36, 16.45
(d, J3CP = 12.6 Hz), 16.30 (d, J3CP = 5.8 Hz). 31P NMR
(121 MHz, CDCl3, 25°C): δ 20.94 ppm. HRMS (ESI)
m/z calcd for C18H24N2O5P [M + H+]: 379.1412; Found
379.1417.
54.93, 16.43 (d, J3CP = 5.5 Hz), 16.24 (d, J3CP = 5.9 Hz). 31
P
NMR (101 MHz, CDCl3, 25°C): δ 22.26 ppm. HRMS (ESI)
m/z calcd for C23H26NO4P [M + Na+]: 434.1491; Found
434.1491.
4.2.6
|
Diethyl [phenyl(p-tolylamino)methyl]
phosphonate (4f)[12]
Yield: 94% as a white crystalline solid; mp 120°C. 1H NMR
(300 MHz, CDCl3, 25°C): δ 7.49-7.47 (m, 2H, ArH), 7.37-
7.27 (m, 3H, ArH), 6.93 (d, J = 8.3 Hz, 2H, ArH), 6.53
(d, 2H, J = 8.4 Hz, ArH), 4.76 (d, J = 24.2 Hz, 2H, HCP
and NH), 4.17-4.10 (m, 2H, –OCH2–CH3), 4.00-3.92 (m,
1H, –OCH2–CH3), 3.74-3.66 (m, 1H, –OCH2–CH3), 2.20
(s, 3H, CH3-Ph), 1.30 (t, 3H, J = 7.1 Hz, –OCH2–CH3),
1.13 (t, 3H, J = 7.1 Hz, –OCH2–CH3). 13C NMR (75 MHz,
CDCl3, 25°C): δ 13C NMR (63 MHz, CDCl3) δ 143.95 (d,
J = 15.1 Hz), 135.98, 129.62, 128.50, 127.81 (d, J = 4.7 Hz),
127.58, 113.96, 64.83-61.51 (m), 57.54, 55.15, 20.31, 16.27
(dd, J3CP = 15.2, 5.7 Hz). 31P NMR (101 MHz, CDCl3,
25°C): δ 21.48 ppm. HRMS (ESI) m/z calcd for C18H24NO3P
[M + Na+]: 356.1397; Found 356.1386.
4.2.9
|
Diethyl [4-biphenyl(p-tolylamino)
methyl]phosphonate (4i)[12]
Yield: 94%, as a white crystalline solid; mp 140°C. 1H NMR
(300 MHz, CDCl3, 25°C) : δ 7.42-7.59 (m, 6H, ArH), 7.26-
7.39 (m, 3H, ArH), 6.93 (d, 2H, J = 8.2 Hz, ArH), 6.55 (d,
2H, J = 8.4 Hz, ArH), 4.79 (d, 1H, J = 24.3 Hz, HCP), 4.10-
4.18 (m, 2H, OCH2–CH3), 3.84-4.01 (m, 1H, –OCH2–CH3),
3.71-3.81 (m, 1H, –OCH2–CH3), 2.19 (s, 3H, CH3-Ph), 1.30
(t, 3H, J = 7.1 Hz, –OCH2–CH3), 1.15 (t, 3H, J = 7.0 Hz,
–OCH2–CH3). 13C NMR (75 MHz, CDCl3, 25°C): δ
143.82, 140.59, 129.67, 128.70, 128.20 (d, J = 5.5 Hz),
127.66, 127.24 (d, J = 2.7 Hz), 126.96, 113.98, 63.31 (t,
J = 7.0 Hz), 57.28, 54.87, 20.33, 16.38 (d, J3CP = 14.0 Hz),
16.16 (d, J3CP = 5.5 Hz) 31P NMR (121 MHz, CDCl3, 25°C):
δ 22.71 ppm. HRMS (ESI) m/z calcd for C24H29NO3P
[M + H+]: 410.1876; Found 410.1879.
4.2.7
|
Diethyl [1-naphtyl(p-tolylamino)
methyl]phosphonate (4g)[11]
Yield: 94%, as a white crystalline solid; mp 145°C. 1H NMR
(300 MHz, CDCl3, 25°C): δ 8.27 (d, 1H, JHP = 8.5 Hz, ArH),
7.91 (d, 1H, J = 7.9 Hz ArH), 7.80-7.77 (m, 2H, ArH), 7. 63-
7. 48 (m, 2H, ArH), 7.45 (t, 1H, J = 7.7 Hz, ArH), 6.67 (d, 2H,
J = 8.48 Hz, ArH), 6.48 (d, 2H, J = 8.4 Hz, ArH), 4.64 (d,
1H, JHP = 24.0 Hz, HCP), 4.23-4.15 (m, 2H, –OCH2–CH3),
3.77-3.73 (m, 1H, –OCH2–CH3), 3. 28-3.17 (m, 1H, –OCH2–
CH3), 2.16 (s, 3H, CH3-Ph), 1.34 (t, 3H, J = 7.1 Hz, –OCH2–
CH3), 0.75 (t, 3H, J = 7.1 Hz, –OCH2–CH3). 13C NMR
(75 MHz, CDCl3) δ 143.83 (d, J = 24.8 Hz), 133.81, 131.68
4.2.10
Diethyl [3-phenoxy(p-tolylamino)
|
methyl]phosphonate (4j)
Yield: 94%, as a white crystalline solid; mp 128.5°C. 1H NMR
(300 MHz, CDCl3): δ 7.29 (m, 4H), 7.17-7.05 (m, 2H, ArH),
6.95 (dd, J = 10.7, 4.6 Hz, 4H, ArH), 6.51 (d, J = 8.5 Hz, 2H,
ArH), 4.73 (d, J = 24.4 Hz, 1H, HCP), 4.21-4.11 (m, 2H, –
OCH2–CH3), 4.07-3.95 (m, 1H, –OCH2–CH3), 3.80-3.76 (m,
1H, –OCH2–CH3), 2.22 (s, 3H, ArCH3), 1.30 (t, J = 7.1 Hz,
1H, –OCH2–CH3), 1.18 (t, J = 7.1 Hz, 1H, –OCH2–CH3).

GUEZANE-LAKOUD Et AL.
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|
13C NMR (63 MHz, CDCl3): δ 157.19 (d, J = 15.9 Hz),
143.82 (d, J = 15.1 Hz), 138.04, 129.88, 129.69, 123.23,
122.73 (d, J = 5.2 Hz), 118.74, 118.55, 114.10, 63.29 (t,
J = 7.7 Hz), 57.40, 55.01, 20.36, 16.43 (d, J3CP = 5.6 Hz),
16.24 (d, J3CP = 5.7 Hz). 31P NMR: (121 MHz, CDCl3,
25°C): δ 22.38 ppm. HRMS (ESI) m/z calcd for C23H26NO4P
[M + Na+]: 448.1648; Found 448.1640.
J = 24.2, 7.8 Hz, 1H), 4.22-4.14 (m, 2H, –OCH2–CH3),
4.12-4.00 (m, 1H, –OCH2–CH3), 3.85-3.77 (m, 1H, –
OCH2–CH3), 1.33 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 1.20
(t, 3H, J = 7.1 Hz, –OCH2–CH3). 13C NMR (75 MHz,
CDCl3): δ 157.55, 156.88, 152.98, 148.94 (d, J = 13.7 Hz),
145.54, 137.55, 130.09, 129.81, 128.99, 124.94, 123.45,
122.63 (d, J = 4.7 Hz), 122.35, 118.87, 118.44, 118.28 (d,
J = 5.3 Hz), 113.64, 63.52 (dd, J = 11.4, 6.9 Hz), 56.60,
54.60, 16.48 (d, J = 5.7 Hz), 16.29 (d, J = 5.6 Hz). 31P
NMR (121 MHz, CDCl3, 25°C): δ 21.65 ppm. HRMS
(ESI) m/z calcd for C29H30N3O3P [M + Na+]: 522.1911;
Found 522. 1916.
4.2.11
Diethyl [phenyl(p-phenylazoaniline)
|
methyl]phosphonate (4k)
Yield: 94%, as a grown crystalline solid; mp 114.5°C.
1H NMR (250 MHz, CDCl3, 25°C): δ 7.82-7.75 (m, 4H,
ArH), 7.50-7.26 (m, 8H, ArH), 6.68 (d, J = 8.9 Hz, 2H,
ArH), 5.32 (s, J = 24.7, 1H, NH), 4.85 (d, J = 24.1 Hz,
1H, CH), 4.19-4.12 (m, 2H, –OCH2–CH3), 4.10-3.89 (m,
1H, –OCH2–CH3), 3.70-3.60 (m, 1H, –OCH2–CH3), 1.32
(t, 3H, J = 7.1 Hz, –OCH2–CH3), 1.12 (t, 3H, J = 7.1 Hz, –
OCH2–CH3). 13C NMR (63 MHz, CDCl3) δ 158.29, 152.96,
148.97 (d, J = 19.8 Hz), 145.47, 135.28, 129.74, 128.92,
128.75, 128.21, 127.79 (d, J = 5.3 Hz), 124.92, 122.29,
63.54 (d, J2CP = 7.1 Hz), 63.29 (d, J2CP = 6.9 Hz), 56.99,
54.59, 16.41 (d, J3CP = 6.0 Hz), 16.15 (d, J3CP = 5.1 Hz).
31P NMR (121 MHz, CDCl3, 25°C): δ 22.05 ppm. HRMS
(ESI) m/z calcd for C23H26N3O3P [M + H+]: 424.1785;
Found 424.1784.
4.2.14
Diethyl [3-phenoxy(p-
|
phenylazoaniline)methyl] phosphonate (4o)
Yield: 94%, as a yellow oil. 1H NMR (300 MHz, CDCl3): δ
7.85-7.71 (m, 4H, ArH), 7.51-7.35 (m, 3H, ArH), 7.34-7.19
(m, 4H, ArH), 7.15-7.00 (m, 2H, ArH), 6.98-6.90 (m, 3H,
ArH), 6.66 (d, J = 7.0 Hz, 2H, ArH), 5.30-5.21 (m, 1H, NH),
4.82 (dd, J = 24.2, 7.8 Hz, 1H, HCP), 4.23-4.06 (m, 2H, –
OCH2–CH3), 4.02-3.95 (m, 1H, –OCH2–CH3), 3.85-3.70 (m,
1H, –OCH2–CH3), 1.30 (t, J = 7.0 Hz, 3H, –OCH2–CH3),
1.17 (t, J = 7.0 Hz, 3H, –OCH2–CH3). 13C NMR (75 MHz,
CDCl3): δ 157.59, 156.87, 152.98, 148.86 (d, J = 18.2 Hz),
145.57, 137.50, 130.09, 129.80, 128.98, 124.93, 123.43,
123.28,122.61(d,J = 5.3 Hz),122.35,118.87,118.44,118.22
(d, J = 9.6 Hz), 113.64, 63.52 (dd, J = 12.4, 7.0 Hz), 56.62,
4.2.12
Diethyl [naphtyl(p-
|
54.62, 16.47 (d, J3CP = 5.9 Hz), 16.28 (d, J3CP = 5.8 Hz). 31
P
phenylazoaniline)methyl]phosphonate (4l)
NMR (121 MHz, CDCl3, 25°C): δ 21.93 ppm. HRMS (ESI)
m/z calcd for C29H30N3O4P [M + H+]: 516. 2027; Found
516.2046.
Yield:94%, asagrowncrystallinesolid;mp131.5°C.1HNMR
(250 MHz, CDCl3, 25°C): δ 8.26 (d, J = 8.4 Hz, 1H, ArH),
7.80-7.69 (m, 9H, ArH), 7.49-7.26 (m, 4H, ArH), 6.64 (d,
J = 8.9 Hz, 2H, ArH), 5.73 (d, J = 23.8 Hz, 1H, CH), 4. 27-
4.16 (m, 2H, –OCH2–CH3), 3.76-3.72 (m, 1H, OCH2–CH3),
3.24-3.14 (m, 1H, OCH2–CH3), 1.35 (t, 3H, J = 7.1 Hz, –
OCH2–CH3), 0.73 (t, 3H, J = 7.0 Hz, OCH2–CH3). 13C NMR
(63 MHz, CDCl3): δ 152.91, 148.87 (d, J = 13.2 Hz), 145.28,
133.84, 131.18 (d, J = 24.2 Hz), 129.67, 129.11, 128.99
(d, J = 15.6 Hz), 126.49, 125.82, 125.59, 124.97, 122.73,
122.25, 113.32, 63.64 (d, J = 6.9 Hz), 63.25 (d, J = 7.2 Hz),
52.57, 50.15, 16.47 (d, J = 5.2 Hz), 15.74 (d, J = 5.6 Hz). 31P
NMR (101 MHz, CDCl3, 25°C): δ 21.91 ppm. HRMS (ESI)
m/z calcd for C27H28N3O3P [M + Na+]: 496.1749; Found
496.1760.
ACKNOWLEDGMENTS
The Algerian Ministry of Higher Education and Scientific
Research (DGRSDT, FNR) is gratefully acknowledged for
financial support of this work. The technical support pro-
vided by Emilie KOLODZIEJ is highly appreciated. Dr.
Mounia MERABET-KHELASSI is thanked for her helpful
in many ways.
ORCID
Louisa Aribi-Zouioueche
http://orcid.org/0000-0002-2619-7206
4.2.13
Diethyl [4-biphenyl(p-
|
phenylazoaniline)methyl] phosphonate (4n)
1
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SUPPORTING INFORMATION
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How to cite this article: Guezane-Lakoud S, Toffano M,
Aribi-Zouioueche L. Promiscuous lipase catalyzed a new
P–C bond formation: Green and efficient protocol for
one-pot synthesis of α-aminophosphonates. Heteroatom
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