T3P-mediated one-pot synthesis of Bis(α-aminophosphonates)

Article abstract of DOI:10.1002/hc.21170

Two series of bis(α-aminophosphonates) were synthesized by one-pot three-component reactions using 4-phenylenediamine, an aldehyde (2 equiv) and a phosphite (2 equiv), or terephtalaldehyde, an amine (2 equiv), and a phosphite (2 equiv) together with propy

Full text of DOI:10.1002/hc.21170

Heteroatom Chemistry
Volume 00, Number 0, 2014
T3PꢀR -Mediated One-Pot Synthesis of
Bis(α-aminophosphonates)
1
1
Ma´tya´s Milen,1,2 Pe´ter Abra´nyi-Balogh, Re´ka Kangyal,
´
Andra´s Dancso´,2 Da´vid Frigyes,2 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2Egis Pharmaceuticals Plc., Chemical Research Division, 1475 Budapest, Hungary
Received 17 February 2014; revised 15 April 2014
peptide mimics [8], antibiotics [9], herbicides [10],
ABSTRACT: Two series of bis(α-aminophos-
plant growth regulators [11], haptens of catalytic an-
phonates) were synthesized by one-pot three-
tibodies [12], enzyme inhibitors [13], and antitumor
component reactions using 4-phenylenediamine, an
agents [14,15].
aldehyde (2 equiv) and a phosphite (2 equiv), or
Various methodologies for the preparation of
terephtalaldehyde, an amine (2 equiv), and a phos-
several α-aminophosphonates have been described
phite (2 equiv) together with propylphosphonic anhy-
in the literature [16–19]. However, one of the most
dride (T3PꢀR ) in both series as a coupling reagent. The
important pathways to α-aminophosphonates is the
bis(α-aminophosphonates) were obtained in moderate
three-component Kabachnik–Fields reaction of a
to excellent yields. The condensations take place un-
carbonyl compound, an amine, and a dialkyl phos-
der mild conditions and the isolation of the products
phite or trialkyl phosphite. This one-pot reaction is
ꢀC
is simple. 2014 Wiley Periodicals, Inc. Heteroatom
often catalysed by Brønsted or Lewis acids [20, 21].
In recent years, green variations have been devel-
oped based on microwave irradiation [22–24], ultra-
sound [25], and on the use of ionic liquids [26,27].
In our previous study, a simple and efficient
synthesis of α-aminophosphonates was developed
using propylphosphonic anhydride (T3PꢀR ) in an
equivalent quantity. This condensing agent was used
successfully in the presence of different functional
groups and the reaction time was only 5–10 min [28].
Calix[4]arene α-aminophosphonic acids form a
special group of the compounds discussed [29,30].
The bis(α-aminophosphonates) form in-
teresting new families of compounds. Bis(α-
aminophosphonates) may be regarded as mul-
tidentate ligands suitable for the extraction of
metals from solution. Furthermore, they can be
used as starting materials in the preparation
of P-macrocyclic or polymeric compounds [31].
Bis(phosphinoyl)amines are the products of the
bis Kabachnik–Fields reaction that after a double
Chem. 00:1–11, 2014; View this article online at wi-
leyonlinelibrary.com. DOI 10.1002/hc.21170
INTRODUCTION
Organophosphorus compounds are applied widely
in synthetic organic chemistry as building blocks,
reagents, solvents, catalysts, P-ligands in catalysts
and in other ways, as well as biologically active sub-
strates [1–3]. In the past decade, the synthesis and
biological evaluation of α-aminophosphonic acids
and their derivatives attracted considerable inter-
est, as they are the structural analogues of α-amino
acids. α-Aminophosphonic derivatives may show a
broad spectrum of biological activity [4–7], such as
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@mail.
bme.hu.
ꢀC
2014 Wiley Periodicals, Inc.
1

2
Milen et al.
EtO
EtO
P
OEt
Ar1
O
P
O
OEt
OEt
OEt
EtO
HN
OEt
Ar1
2 equiv
26°C, t
HN
HN
P
NH2
T3P®
O
Method I
2 equiv
+
Ar1
H
EtOAc, CH2Cl2
Method II
2 equiv
P
OEt
O
NH2
O
OEt
Ar1
P
NH2
3a–h
1
2a–h
H
OEt
4a–h
2 equiv
SCHEME 1 The bis Kabachnik-Fields reaction of 1,4-phenylenediamine, aromatic aldehydes and triethyl phosphite or diethyl
phosphite.
deoxygenation can be converted to ring platinum
complexes, useful as catalysts in hydroformyla-
tions [32, 33]. Bis(α-aminophosphonates) were
synthesized from Schiff bases [34–37] and stere-
oselective approaches were also studied [38–41].
At the same time, not too many efficient meth-
ods are known for the one-pot preparation of
bis(α-aminophosphonates) by the condensation of
aldehydes, amines, and diethyl or triethyl phos-
phite [21,42–45]. Rezaei et al. reported the iron(III)
chloride catalyzed preparation of biologically active
bis(α-aminophosphonates) in excellent yields [31].
Moreover, the prepared indole-containing bis(α-
aminophosphonates) had a high-to-moderate cyto-
toxic activity [31]. Peptidic analogues were also syn-
thesized as potential receptors for biomolecules [46],
or possible inhibitors of the meso-DAP synthetase
[47].
stead of triethyl phosphite (Scheme 1, method II).
In this case, the reaction time was 4 h and prod-
uct 4a was obtained in a yield of 87%. Attempt-
ing the condensation of 1,4-phenylenediamine and
2 equiv of benzaldehyde in the absence of the T3PꢀR
reagent, the reaction was reluctant and the main
component was the monoaminophosphonate (3a).
At 26°C, the consumption of the diamine required
24 h according to LC-MS. Using triethyl phosphite or
diethyl phosphite, after 24 h, the ratio of the mono-
product (3a) and the bisproduct (4a) was 92%–8%
and 86%–14%, respectively, that, after 48 h, was
changed to 82%–18% and 79%–21%, respectively.
Next, the reaction was extended using 4-substituted
aromatic aldehydes and phosphites under the same
conditions. The completion of the reaction re-
quired 3–9 h to afford the corresponding bis(α-
aminophosphonates) (4b–h) in 64%–87% yields
(Table 1).
The reactions were monitored by HPLC-MS and
we found that the Kabachnik–Fields reactions took
place through the monoaminophosphonates (3a–h)
as the intermediates. In the reaction mixtures ana-
lyzed, no other intermediate was detected. The start-
ing materials disappeared shortly after the beginning
of the reaction, but in most cases, the 100% conver-
sion could not be attained even after 1 day (Table 2).
It was observed that the reaction of 2b with triethyl
phosphite (method I) was faster than its reaction
with diethyl phosphite (method II). Already in the
5th min, the ratio of 3b and 4b was 79:21 (method
I) against 93:7 (method II), and the 80% conver-
sion of 4b was reached after 5 h (method I) against
6 h (method II). This observation verifies that un-
der these conditions, triethyl phosphite is more re-
active in the Kabachnik–Fields reaction than diethyl
phosphite.
As a continuation of our work, we now applied
the T3PꢀR protocol to the one-pot preparation of
bis(α-aminophosphonates).
RESULTS AND DISCUSSION
Synthesis of Bis(α-aminophosphonate)
Derivatives (4a–h) by the Reaction of
1,4-Phenylenediamine with Aromatic Aldehydes
and Triethyl Phosphite or Diethyl Phosphite
First, the three-component reaction of 1,4-
phenylenediamine (1), 2 equiv of benzaldehyde
(2a), and 2 equiv of triethyl phosphite was inves-
tigated in the presence of propylphosphonic an-
hydride (T3PꢀR ). According to our earlier study,
equimolar T3PꢀR (in this case 2 equiv) had to be
added to the reaction mixture [28] (Scheme 1,
method I). The reaction was performed in ethylac-
etate/dichloromethane at 26°C and completed after a
time of 3 h to provide tetraethyl {benzene-1,4-diylbis
[imino(phenylmethanediyl)]}bis(phosphonate) (4a)
in a yield of 80%. The bis(α-aminophosphonate)
(4a) was also prepared using diethyl phosphite in-
The reaction of 4-methylbenzaldehyde (2b)
and 4-chlorobenzaldehyde (2e) was also compared
(Table 3). It can be seen that the conversion of 2e
to 4e is faster than that of 2b to 4b. After 5 min,
the ratio of 3e:4e was 68:32 whereas that of 3b:4b
Heteroatom Chemistry DOI 10.1002/hc

T3PꢀR -Mediated One-Pot Synthesis of Bis(α-aminophosphonates)
3
TABLE 1 Details for the Preparation of Bis(α-aminophosphonates) 4a–h Starting from 4-Phenylenediamine
Entry
Ar1
Product
P-Reagent
Time (h)
Yield (%)
Diastereomer Ratio (A/B)
δP (CDCl3)
1
2
3
4
5
6
7
8
Ph
4a
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
3
4
5
6
9
9
8
8
3
6
9
9
3
6
6
6
80
87
73
78
78
80
74
68
72
70
70
85
72
85
64
66
59:41a
52:48a
51:49a
52:48a
51:49a
51:49a
61:39c
54:46c
52:48a
23.4b
4-MeC6H4
4-MeOOCC6H4
4-FC6H4
4b
4c
4d
4e
4f
22.3b
22.3b
23.02
22.98
22.7b
9
4-ClC6H4
10
11
12
13
14
15
16
54:46a
d
4-BrC6H4
22.5b
21.4b
23.6b
4-O2NC6H4
4-MeOC6H4
4g
4h
53:47a
53:47a
51:49a
51:49a
(EtO)2P(O)H
aAccording to 1H NMR spectral data (HN C6H4 NH).
bBroad signal.
cAccording to 31P NMR shifts.
d Could not be determined from NMR spectral data.
TABLE 2 Measured Time–Conversion Values for the Reac-
tion 2b→4b
Synthesis of Bis(α-aminophosphonate)
Derivatives (8a–i) by the Reaction of
Terephthalaldehyde with Aromatic Amines and
Triethyl Phosphite or Diethyl Phosphite
Method I
Method II
Time
3b
4b
3b
4b
Then, the reaction of terephthalaldehyde (6) was
studied with aniline (5a) and with various mono-
substituted aniline derivatives (5b–i) under the same
conditions applied above (Scheme 2). The reactions
took place at 26°C and resulted in the formation of
the corresponding bis(α-aminophosphonates) (8a–
i) in shorter reaction times (1.5–5 h), as compared
to the earlier series of reactions. The results of the
T3PꢀR -promoted condensations are summarized in
Table 4. One can see that the yields were above 69%;
only 4-fluorobenzaldehyde was obtained in a consid-
erably lower yield (Table 4, entries 7 and 8).
0.1 min
5 min
60 min
3.5 h
5 h
100
79
49
38
21
17
0
21
51
62
79
83
100
93
66
46
33
18
0
7
34
54
67
82
6 h
TABLE 3 Measured Time–Conversion Values for the Reac-
tions 2b→4b and 2e→4e
Method I
On the contrary to the reactions of 4-
phenylenediamine, in this case an imine interme-
diate 7 could be detected by HPLC-MS. In this reac-
tion, the starting material also disappeared shortly
after the beginning, and the reaction took place
faster than in the case of the diamine (Table 5).
The 20:80% ratio of intermediate 7a and bis(α-
aminophosphonate) 8a was reached after 5 min
(method III), and after 160 min, all of the interme-
diate 7a disappeared.
Time
3b
4b
3e
4e
0.1 min
5 min
60 min
3.5 h
5 h
100
79
49
38
21
17
0
21
51
62
79
83
100
68
39
20
18
13
0
32
61
80
82
87
6 h
In the blind probe reaction with terephthalde-
hyde (6) and 2 equiv of aniline (5a) (carried out
without the T3PꢀR condensing agent), no bisprod-
uct 8a was formed using triethyl phosphite as the
P-reagent. After 24 h, the reaction mixture com-
prised 80% of the monoimine of bisaldehyde 6,
is less (79:21). A conversion of 80% was reached
after 3.5 h against 5 h. This can be explained
with the higher electron-withdrawing effect of the
chlorine atom that makes the aldehyde more sen-
sible to the nucleophilic attack of the aniline
derivative.
Heteroatom Chemistry DOI 10.1002/hc

4
Milen et al.
EtO
EtO
Ar2
HN
Ar2
O
P
OEt
O
P
OEt
OEt
OEt
OEt
HN
P
O
O
2 equiv
26°C, t
T3P®
Method III
2 equiv
Ar2NH2
2 equiv
+
EtOAc, CH2Cl2
Method IV
OEt
OEt
O
OEt
N
Ar2
HN
Ar2
P
O
P
6
5a–i
H
OEt
2 equiv
7a–i
8a–i
SCHEME 2 The bis Kabachnik-Fields reaction of aromatic amines, terephthaldehyde and triethyl phosphite or diethyl phos-
phite.
TABLE 4 Details for the Preparation of Bis(α-aminophosphonates) 8a–i Starting from Terephtalaldehyde
Entry
Ar2
Product
P-Reagent
Time (h)
Yield (%)
Diastereomer Ratio (A/B)
δP (CDCl3)
1
2
3
4
5
6
7
8
Ph
8a
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
2
92
95
80
91
81
82
54
46
86
84
89
91
69
70
75
72
72
77
55:45a
53:47a
58:42c
62:38c
52:48d
51:49d
51:49a
52:48a
55:45c
51:49c
51:49a
56:44a
55:45c
56:46d
52:48d
57:43d
52:48d
54:46c
22.9b
1.5
1.5
2.5
2.5
4.5
4.5
2
1.5
4
3.5
2.5
1.5
3
4-MeC6H4
4-EtOOCC6H4
4-FC6H4
8b
8c
8d
8e
8f
23.09
23.03
22.1b
22.8b
9
4-BrC6H4
22.49
22.43
22.3b
10
11
12
13
14
15
16
17
18
4-O2NC6H4
4-MeOC6H4
2-MeSC6H4
3-F3CC6H4
8g
8h
8i
23.13
23.08
22.5b
(EtO)2P(O)H
(EtO)3P
(EtO)2P(O)H
(EtO)3P
3
5
3
2.5
22.36
22.25
(EtO)2P(O)H
aAccording to 13C NMR spectral data [HN CH(Ar) P].
bBroad signal.
cAccording to 31P NMR shifts.
d According to 1H NMR spectral data (HC C6H4 CH).
TABLE 5 Measured Time–Conversion Values for the Reac-
tion 5a→7a
8a appeared in 5% that was accompanied by 74%
of the monoimine, 14% of the monoaminophospho-
nate, and 7% of unidentified components. On the
basis of the above experiments, the role of the T3PꢀR
reagent to enhance the condensation is unambigu-
ous.
After all, 17 bis(α-aminophosphonates) were
synthesized. Compounds 4a, 4b, 4e, 4f, 4h, 8a,
8b, and 8d–g have been known from the litera-
ture [48–52], whereas 4c, 4d, 4g, 8c, 8h, and 8i are
new. In all cases, similar results were obtained with
triethyl phosphite and diethyl phosphite. The struc-
tures of products 4a–h and 8a–i were confirmed by
31P, 13C, and 1H NMR, as well as IR and mass spec-
tral data.
Method III
Time (min)
7a
8a
0.1
1
5
70
130
160
40
37
22
12
7
60
63
78
88
93
0
100
13% of the monoaminophosphonate formed from
5a, 6, and triethyl phosphite, and 7% of unidenti-
fied components. This ratio did not change signif-
icantly after 48 h. In the similar reaction with di-
ethyl phosphite, after 24 h, 89% of monoimine, 10%
of monoaminophosphonate, and 1% of unidentified
components were formed. After 48 h, the bisproduct
The products were obtained as a mixture of a
racemate and the mezo form in a comparable quan-
tity. In most cases, the ratio of the diastereomers
could be determined from the NMR spectra. The di-
astereomers could not be separated by HPLC.
Heteroatom Chemistry DOI 10.1002/hc

T3PꢀR -Mediated One-Pot Synthesis of Bis(α-aminophosphonates)
5
Y
CHO + H2N
OH
Z
HO
Q
O
HO
Q
12
OH
..
P(OEt)3
(EtO)3P
CH
13
Y
CH NH
Z
Y
CH
10
N Z
(EtO)2P
O
CH2CH3
Y
N
Z
– H2O
T3P®
9
Y
CH NH Z
T3P®
14
– HO
Q
15
OEt
OH
Q
HO
Q
12
OH
(EtO)2P
O
O
P
O
P
O
P
O
Q =
O
O
Y
CH NH Z
Y
CH NH Z
Pr
Pr
Pr
16
11
SCHEME 3 Mechanism for the T3PꢀR -Mediated Kabachnik-Fields reactions utilizing triethyl phosphite as the P-reagent.
spectrometer (400, 100, and 162 MHz for 1H, 13C
NMR, and 31P NMR spectra, respectively; Bruker
BioSpin GmbH, Rheinstetten, Germany). CDCl3 was
used as solvent. Tetramethylsilane and 85% H3PO4
were used as internal (1H, 13C) and external (31P)
standards, respectively. Chemical shifts (δ) and cou-
pling constants (J) are given in parts per million
(ppm) and hertz (Hz), respectively.
The FT-IR spectra of KBr pellets or neat sam-
ples were recorded with a Bruker Alpha spectrome-
ter. Mass spectra were recorded on a Bruker Maxis
Impact Q-TOF spectrometer coupled to a Dionex Ul-
tiMate 3000 RRLC (Rapid Resolutions Liquid Chro-
matograph) system. The chromatographic column
used was a Waters Acquity BEH C18 column with
dimensions of 2.1 × 50 mm. 5 min gradient elution
was used at a flow rate of 0.5 mL/min [initial: 10%
acetonitrile, 0.01 M ammonium acetate; 5 min: 90%
acetonitrile, 0.01 M ammonium acetate]. Accurate
mass measurements were locked internally against
the peak at m/z = 556.2771 of leucine enkephaline.
The reactions were followed by analytical thin-layer
chromatography on silica gel 60 PF254 and LC-MS
chromatography.
In accord with our earlier suggestion [28], the
role of the T3PꢀR reagent in the Kabachnik–Fields
reaction may be the following. The reaction of the
aldehyde (in general Y–CHO) with the amine (in gen-
eral H2N–Z) results in imine 10 either via adduct 9
or via intermediate 11 formed from adduct (9) by the
reaction with T3PꢀR . In both cases, P,Pꢁ,Pꢁꢁ-tripropyl
triphosphonic acid (12) is the by-product. Then, the
imine (10) is attacked by triethyl phosphite to afford
zwitterionic intermediate 13 that is protonated by
the triposphonic acid (12). The phosphonium salt
(14) so formed then undergoes an Arbuzov reaction
to give the α-aminophosphonate (16) together with
HO P(O)Pr
(Scheme 3).
O
P(O)Pr
O
P(O)Pr OEt
(15)
In summary, we have elaborated a simple and
practical method for the one-pot synthesis of bis(α-
aminophosphonates) through the three-component
reaction of the corresponding aldehyde, amine,
and phosphite compound. The two series of bis(α-
aminophosphonates), 4a–h, and 8a–i were synthe-
sized from 1,4-phenylenediamine (1) and tereph-
talaldehyde (6), respectively. The reactions were
promoted by the use of propylphosphonic anhydride
(T3PꢀR ). The rate of the reactions was monitored
and we observed two different kinds of intermedi-
ates in the two series of reactions. The methods de-
scribed by us allow the preparation of various bis(α-
aminophosphonates) in moderate to excellent yields
under mild conditions.
General Procedure for the Synthesis of
Bis(α-aminophosphonates) (4a–h)
To the stirred mixture of 1,4-phenylenediamine (0.22
g, 2.0 mmol) and aldehyde (4.0 mmol, benzaldehyde:
0.41 mL, 4-methylbenzaldehyde: 0.47 mL, methyl 4-
formylbenzoate: 0.66 g, 4-fluorobenzaldehyde:
0.43 mL, 4-chlorobenzaldehyde: 0.56 g, 4-
bromobenzaldehyde: 0.74 g, 4-nitrobenzaldehyde:
0.60 g, 4-methoxybenzaldehyde: 0.49 mL) in EtOAc
(4 mL) and CH2Cl2 (4 mL), T3PꢀR (2.4 mL, 4.0 mmol,
Aldrich 50% solution in EtOAc) was added. After
5 min, triethyl phosphite (0.70 mL, 4.0 mmol) or di-
ethyl phosphite (0.52 mL, 4.0 mmol) was added and
the mixture was stirred at 26°C. After completion of
the reaction (3–9 h), the mixture was diluted with
EXPERIMENTAL
General
Commercially available reagents were purchased
from Sigma-Aldrich and used without further pu-
1
rification. H NMR, 13C NMR, and 31P NMR spec-
tra were recorded with a Varian Unity Inova 500
spectrometer (500 and 125 MHz for 1H and 13C
NMR spectra, respectively; Agilent Technologies
Inc., Santa Clara, CA) or with a Bruker Avance III
Heteroatom Chemistry DOI 10.1002/hc

6
Milen et al.
CH2Cl2 (15 mL) and washed with 10% NaHCO3
solution (15 mL). The organic phase was dried
(MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography on silica gel
(Merck 107736 Silica gel 60H, CH2Cl2–MeOH) to
afford products 4a–h as a mixture of two isomers
(A and B).
2H, CH), 4.32 (s, 2H, NH), 4.10–4.03 (m, 4H, CH2),
3.94–3.88 (m, 4H, CH2), 3.70–3.67 (m, 6H, CH3), 2.29
(s, 6H, CH3), 1.24 (t, J = 7.1, 6H, CH3), 1.10 (t, J =
1
7.0, 6H, CH3) {lit.: H NMR (400 MHz, DMSO): δ
7.29 (d, J = 8.0, 4H, ArH), 7.04 (d, J = 7.6, 4H,
ArH), 6.45 (d, J = 6.4, 4H, ArH), 5.45–5.41 (m, 2H,
2NH), 4.72 (2d, J = 10.4, 2H, 2P CH), 4.01–3.96
(m, 4H, 2CH2), 3.83–3.76 (m, 2H, CH2), 3.70–3.60
(m, 2H, CH2), 2.20 (s, 6H, 2CH3), 1.14 (t, J = 7.0,
6H, 2CH3), 1.01 (t, J = 6.8, 6H, 2CH3) [49]}; IR
(KBr): ν 3311, 2984, 1515, 1234, 1021 cm−1; HRMS
calcd. for C30H43N2O6P2 [M + H]+ 589.2596; found
589.2590.
OEt
EtO
O
2'
1'
O
3'
OEt EtO
P
P
2
4'
1
R
HN
NH
R
4a-h
Dimethyl 4,4ꢁ-(benzene-1,4-diylbis{imino[(dieth-
Tetraethyl
{benzene-1,4-diylbis[imino(phenyl-
0.90
methanediyl)]}bis(phosphonate)(4a). Yield:
oxyphosphoryl)methanediyl]})dibenzoate
(4c).
g (80%, method I), 0.98 g (87%, method II);
white crystals; mp 196–198°C; 31P NMR (CDCl3,
162 MHz): δ 23.4 (lit.: δ 23.5 [48]); 13C NMR (CDCl3,
125 MHz): δ 139.2 (d, J = 15.6, C(1ꢁ)[A]), 139.0
(d, J = 15.1, C(1ꢁ)[B]), 136.24 (d, J = 2.4, C(1)[A]),
136.21 (d, J = 2.5, C(1)[B]), 128.4 (d, J = 2.4,
C(3ꢁ)[A, B]), 127.85 (d, J = 5.9, C(2ꢁ)[B]), 127.83
(d, J = 5.3, C(2ꢁ)[A]), 127.7 (d, J = 3.4, C(4ꢁ)[A,
B]), 115.45 (C(2)[A]), 115.40 (C(2)[B]), 63.2 (d,
J = 6.8, CH2[A, B]), 63.0 (d, J = 6.3, CH2[A, B]),
57.1 (d, J = 149.9, PCH[A]), 57.0 (d, J = 150.4,
PCH[B]), 16.4 (d, J = 5.4, CH3[A, B]), 16.1 (d, J =
5.9, CH3[A, B]); 1H NMR (500 MHz, CDCl3): δ
7.42–7.38 (m, 4H, ArH), 7.30–7.26 (m, 4H, ArH),
7.24–7.21 (m, 2H, ArH), 6.401 (s, 4H, HC(2)[A]),
6.395 (s, 4H, HC(2)[B]), 4.59 (d, J = 23.8, 2H,
CH), 4.37 (bs, 2H, NH), 4.09–4.03 (m, 2H, CH2),
3.93–3.88 (m, 2H, CH2), 3.68–3.64 (m, 2H, CH2),
1.24 (t, J = 7.1, 6H, CH3), 1.08 (t, J = 7.1, 6H, CH3);
IR (KBr): ν 3299, 1514, 1231, 968, 698 cm−1; HRMS
calcd. for C28H39N2O6P2 [M + H]+ 561.2283; found
561.2260.
Yield: 1.06 g (78%, method I), 1.08 g (80%, method
II); white crystals; mp 200–202°C; 31P NMR (CDCl3,
162 MHz): δ 22.3; 13C NMR (CDCl3, 125 MHz):
δ 166.8 (C O [A, B]), 141.8 (d, J = 3.1, C(4ꢁ)[A,
B]), 139.0 (d, J = 15.1, C(1ꢁ)[A]), 138.9 (d, J =
15.1, C(1ꢁ)[B]), 129.7 (d, J = 2.4, C(1)[A]), 129.6
(d, J = 3.5, C(1)[B]), 127.9 (C(3ꢁ)[A, B]), 127.84
(d, J = 2.4, C(2ꢁ)[A]), 127.81 (d, J = 2.4, C(2ꢁ)[B]),
115.43 (C(2)[A]), 115.40 (C(2)[B]), 63.4 (d, J = 6.9,
CH2[A, B]), 63.2 (d, J = 6.8, CH2[A, B]), 57.6 (d,
J = 148.4, PCH[A]), 56.5 (d, J = 149.9, PCH[B]),
16.3 (d, J = 5.9, CH3[A, B]), 16.1 (d, J = 5.9, CH3[A,
B]); 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, J =
7.0, 4H, ArH), 7.50–7.47 (m, 4H, ArH), 6.36 (s, 4H,
HC(2)[A]), 6.35 (s, 4H, HC(2)[B]), 4.67–4.61 (m,
2H, CH), 4.42–4.40 (m, 2H, NH), 4.10–4.04 (m, 4H,
CH2), 3.96–3.91 (m, 6H, OCH3), 3.88 (d, J = 3.2,
2H, CH2), 3.76–3.73 (m, 2H, CH2), 1.24 (t, J = 7.0,
6H, CH3), 1.11 (t, J = 7.0, 6H, CH3); IR (KBr): ν
3302, 2984, 1723, 1516, 1291, 1022 cm−1. HRMS
calcd. for C32H43N2O10P2 [M + H]+ 677.2393; found
677.2397.
Tetraethyl (benzene-1,4-diylbis{imino[(4-methyl-
phenyl)methanediyl]})bis(phosphonate) (4b). Yield:
0.86 g (73%, method I), 0.92 g (78%, method II);
white crystals; mp 168–170°C; 31P NMR (CDCl3,
162 MHz): δ 22.3; 13C NMR (CDCl3, 100 MHz): δ
139.2 (d, J = 15.6, C(1ꢁ)[A]), 139.1 (d, J = 16.1,
C(1ꢁ)[B]), 137.3 (d, J = 3.4, C(1)[A, B]), 133.09 (d,
J = 2.9, C(2ꢁ)[A]), 133.07 (d, J = 3.4, C(2ꢁ)[B]), 129.2
(d, J = 2.4, C(3ꢁ)[A, B]), 127.7 (d, J = 5.4, C(4ꢁ)[A,
B]), 115.4 (d, J = 4.9, C(2)[A, B]), 63.1 (d, J = 7.3,
CH2[A, B]), 63.0 (d, J = 6.8, CH2[A, B]), 56.8 (d, J =
150.9, PCH[A]), 56.6 (d, J = 151.2, PCH[B]), 16.4
(d, J = 5.4, CH3[A, B]), 16.2 (d, J = 5.4, CH3[A,
B]); 1H NMR (400 MHz, CDCl3): δ 7.28–7.26 (m,
4H, ArH), 7.09 (d, J = 7.8, 4H, ArH), 6.40 (s, 4H,
HC(2)[A]), 6.39 (s, 4H, HC(2)[B]), 4.55 (d, J = 23.5,
Tetraethyl (benzene-1,4-diylbis{imino[(4-fluoro-
phenyl)methanediyl]})bis(phosphonate) (4d). Yield:
0.88 g (74%, method I), 0.81 g (68%, method II);
white crystals; mp 160–162°C; 31P NMR (CDCl3,
162 MHz): δ 23.02 and 22.98; 13C NMR (CDCl3,
125 MHz): δ 162.36 (d, J = 246.6, C(4ꢁ)[A]), 162.34
(d, J = 246.1, C(4ꢁ)[B]), 139.1 (d, J = 15.1, C(1ꢁ)[A]),
138.9 (d, J = 15.1, C(1ꢁ)[B]), 131.9 (d, J = 3.0, C(1)[A,
B]), 129.4 (d, J = 5.8, C(3ꢁ)[A]), 129.3 (d, J = 7.3,
C(3ꢁ)[B]), 115.5 (d, J = 2.4, C(2ꢁ)[A]), 115.4 (d, J = 5.9,
C(2)[A, B]) 115.3 (d, J = 2.5, C(2ꢁ)[B]), 63.2 (d, J =
7.9, CH2[A, B]), 63.1 (d, J = 7.9, CH2[A, B]), 56.4 (d,
J = 155.8, PCH[A]), 56.1 (d, J = 151.4, PCH[B]), 16.4
(d, J = 5.9, CH3[A, B]), 16.2 (d, J = 5.9, CH3[A, B]); 1H
NMR (CDCl3, 500 MHz): δ 7.40–7.37 (m, 4H, ArH),
7.01–6.97 (m, 4H, ArH), 6.38 (s, 4H, ArH), 4.60–4.55
Heteroatom Chemistry DOI 10.1002/hc

T3PꢀR -Mediated One-Pot Synthesis of Bis(α-aminophosphonates)
7
(m, 2H, CH), 4.35–4.33 (m, 2H, NH), 4.09–4.04 (m,
4H, CH2), 3.95–3.91 (m, 2H, CH2), 3.75–3.73 (m, 2H,
CH2), 1.25 (t, J = 7.1, 6H, CH3), 1.12 (t, J = 7.0, 6H,
CH3); IR (KBr): ν 3298, 2986, 1604, 1510, 1234, 1016
cm−1. HRMS calcd. for C28H37F2N2O6P2 [M + H]+
597.2095; found 597.2089.
4.01–4.00 (m, 4H, 2CH2), 3.74–3.33 (m, 2H, CH2),
3.88–3.82 (m, 2H, CH2), 1.14 (t, J = 7.0, 6H, 2CH3),
1.02 (t, J = 7.2, 6H, 2CH3) [49]}; IR (KBr): ν 3202,
2984, 1515, 1485, 1234, 1039 cm−1. HRMS calcd.
for C28H37Cl2N2O6P2 [M + H]+ 717.0409; found
717.0409.
Tetraethyl (benzene-1,4-diylbis{imino[(4-chloro-
phenyl)methanediyl]})bis(phosphonate) (4e). Yield:
0.91 g (72%, method I), 0.88 g (70%, method II);
white crystals; mp 144–147°C; 31P NMR (CDCl3,
162 MHz): δ 22.7; 13C NMR (CDCl3, 125 MHz): δ
139.0 (d, J = 15.1, C(1ꢁ)[A]), 138.9 (d, J = 16.6,
C(1ꢁ)[B]), 134.9 (C(4ꢁ)[A, B]), 133.6 (d, J = 3.9,
C(1)[A, B]), 129.2 (d, J = 1.8, C(2ꢁ)[A]), 129.1 (d,
J = 1.5, C(2ꢁ)[B]), 128.6 (d, J = 1.5, C(3ꢁ)[A, B]),
115.4 (d, J = 5.9, C(2)[A, B]), 63.3 (d, J = 7.3, CH2[A,
B]), 63.1 (d, J = 6.7, CH2[A, B]), 56.6 (d, J = 150.1,
PCH[A]), 56.5 (d, J = 150.6, PCH[B]), 16.4 (d, J =
5.9, CH3[A, B]), 16.2 (d, J = 5.9, CH3[A, B]); 1H
NMR (CDCl3, 500 MHz): δ 7.36–7.36 (m, 5H, ArH),
7.28–7.26 (m, 3H, ArH), 6.37 (s, 4H, HC(2)[A]), 6.36
(s, 4H, HC(2)[B]), 4.60–4.53 (m, 2H, CH), 4.36–4.34
(m, 2H, NH), 4.12–4.04 (m, 4H, CH2), 3.98–3.93 (m,
2H, CH2), 3.79–3.76 (m, 2H, CH2), 1.25 (t, J = 7.1,
Tetraethyl
(benzene-1,4-diylbis{imino[(4-nitro-
phenyl)methanediyl]})bis(phosphonate) (4g). Yield:
0.99 g (72%, method I), 1.11 g (85%, method II);
brick-red crystals; mp 212–214°C; 31P NMR (CDCl3,
162 MHz): δ 21.4; 13C NMR (CDCl3, 125 MHz): δ
147.5 (d, J = 3.9, C(4ꢁ)[A, B]), 144.3 (d, J = 3.4,
C(1)[A, B]), 138.9 (d, J = 15.2, C(C1ꢁ)[A]), 138.7 (d,
J = 15.1, C(1ꢁ)[B]), 128.6 (d, J = 4.9, C(2ꢁ)[A, B]),
123.6 (d, J = 2.9, C(3ꢁ)[A, B]), 115.4 (d, J = 7.3,
C(2)[A, B]), 63.6 (d, J = 6.9, CH2[A, B]), 63.3 (d,
J = 6.8, CH2[A, B]), 57.0 (d, J = 148.1, PCH[A]),
56.0 (d, J = 148.1, CH[B]), 16.3 (d, J = 5.4, CH3[A,
1
B]), 16.2 (d, J = 5.8, CH3[A, B]); H NMR (CDCl3,
500 MHz): δ 8.17–8.15 (m, 4H, ArH), 7.61–7.58
(m, 4H, ArH), 6.35 [s, 4H, HC(2)[A]), 6.34 [s, 4H,
HC(2)[B]), 4.72–4.71 (m, 1H, CH), 4.67–4.66 (m,
1H, CH), 4.46–4.42 (m, 2H, NH), 4.12–4.07 (m, 4H,
CH2), 4.03–3.98 (m, 2H, CH2), 3.88–3.83 (m, 2H,
CH2), 1.26 (t, J = 7.0, 6H, CH3), 1.16 (t, J = 7.1,
6H, CH3); IR (KBr): ν 3416, 3312, 2982, 1519, 1346,
1232, 1017 cm−1. HRMS calcd. for C28H37N4O10P2
[M + H]+ 651.1985; found 651.1964.
1
6H, CH3), 1.13 (t, J = 7.0, 6H, CH3) {lit.: H NMR
(400 MHz, DMSO): δ 7.46–7.43 (m, 4H, ArH), 7.31
(d, J = 8.0, 4H, ArH), 6.48 (d, J = 8.8, 4H, ArH),
5.60–5.50 (m, 2H, 2NH), 4.85 (2d, J = 10.4, 2H,
2P CH), 4.03–3.96 (m, 4H, 2CH2), 3.88–3.81 (m, 2H,
CH2), 3.73–3.32 (m, 2H, CH2), 1.14 (t, J = 7.0, 6H,
2CH3), 1.02 (t, J = 7.0, 6H, 2CH3) [49]}; IR (KBr): ν
3296, 3029, 1512, 1235, 1015 cm−1. HRMS calcd.
for C28H37Cl2N2O6P2 [M + H]+ 629.1504; found
629.1474.
Tetraethyl (benzene-1,4-diylbis{imino[(4-meth-
oxyphenyl)methanediyl]})bis(phosphonate)
(4h).
Yield: 0.79 g (64%, method I), 0.82 g (66%, method
II); white crystals; mp 162–164°C; 31P NMR (CDCl3,
162 MHz): δ 23.6; 13C NMR (CDCl3, 125 MHz): δ
159.2 (d, J = 2.9, C(4ꢁ)[A, B]), 139.2 (d, J = 15.6,
C(1ꢁ)[A]), 139.1 (d, J = 16.1, C(1ꢁ)[B]), 129.0 (d, J =
1.5, C(1)[A]), 128.9 (d, J = 1.5, C(1)[B]), 128.06 (d,
J = 3.4, C(2ꢁ)[A]), 128.03 (d, J = 2.9, C(2ꢁ)[B]), 115.4
(d, J = 4.4, C(2)[A, B]), 113.9 (d, J = 2.4, C(3ꢁ)[A,
B]), 63.1 (d, J = 6.8, CH2[A, B]), 63.0 (d, J = 5.9,
CH2[A, B]), 57.0 (d, J = 151.9, PCH[A]), 56.6 (d, J =
151.9, PCH[B]), 55.19 (OCH3[A]), 55.18 (OCH3[B]),
16.4 (d, J = 5.8, CH3[A, B]), 16.2 (d, J = 5.9, CH3[A,
B]); 1H NMR (CDCl3, 500 MHz): δ 7.33–7.30 (m,
4H, ArH), 6.83–6.81 (m, 4H, ArH), 6.399 (s, 4H,
HC(2)[A]), 6.395 (s, 4H, HC(2)[B]), 4.57–4.51 (m,
2H, CH), 4.31–4.30 (m, 2H, NH), 4.09–4.03 (m, 4H,
CH2), 3.94–3.89 (m, 2H, CH2), 3.76 (s, 6H, CH3),
3.71–3.68 (m, 2H, CH2), 1.24 (t, J = 7.1, 6H, CH3),
Tetraethyl (benzene-1,4-diylbis{imino[(4-bromo-
phenyl)methanediyl]})bis(phosphonate) (4f). Yield:
1.01 g (70%, method I), 1.22 g (85%, method II);
white crystals; mp 193–195°C; 31P NMR (CDCl3,
162 MHz): δ 22.5; 13C NMR (CDCl3, 125 MHz): δ
139.0 (d, J = 15.2, C(1ꢁ)[A, B]), 135.5 (C(1)[A, B]),
131.6 (C(2ꢁ)[A, B]), 129.5 (d, J = 4.8, C(3ꢁ)[A, B]),
121.7 (C(4ꢁ)[A, B]), 115.5 (C(2)[A, B]), 63.3 (d, J = 7.4,
CH2[A, B]), 63.1 (d, J = 6.8, CH2[A, B]), 56.6 (d, J =
149.9, PCH[A, B]), 16.4 (d, J = 5.4, CH3[A, B]), 16.2
(d, J = 5.8, CH3[A, B]); 1H NMR (CDCl3, 500 MHz):
δ 7.43–7.41 (m, 4H, ArH), 7.30–7.28 (m, 4H, ArH),
6.36 (s, 4H, ArH), 4.57–4.52 (m, 2H, CH), 4.36–4.32
(m, 2H, NH), 4.10–4.04 (m, 4H, CH2), 3.97–3.93 (m,
2H, CH2), 3.78–3.76 (m, 2H, CH2), 1.25 (t, J = 7.1,
1
1.11 (t, J = 7.1, 6H, CH3) {lit.: H NMR (400 MHz,
1
6H, CH3), 1.14 (t, J = 7.0, 6H, CH3) {lit.: H NMR
DMSO): δ 7.32 (t, J = 8.4, 4H, ArH), 6.80 (d, J = 8.8,
4H, ArH), 6.46 (d, J = 6.0, 4H, ArH), 5.43–5.39 (m,
2H, 2NH), 4.71 (2d, J = 10.4, 2H, 2P CH), 3.98 (t,
J = 7.0, 4H, 2CH2), 3.82–3.77 (m, 4H, 2CH2), 3.66 (s,
(400 MHz, DMSO): δ 7.38 (d, J = 8.4, 4H, ArH), 7.34
(d, J = 8.4, 4H, ArH), 6.47 (d, J = 8.2, 4H, ArH), 5.60–
5.55 (m, 2H, 2NH), 4.85 (d, J = 10.4, 2H, 2P–CH),
Heteroatom Chemistry DOI 10.1002/hc

8
Milen et al.
6H, 2OCH3), 3.63–3.60 (m, 4H, 2CH2), 1.14 (t, J =
7.0, 6H, 2CH3), 1.00 (t, J = 7.0, 6H, 2CH3) [49]}; IR
(KBr): ν 3300, 2981, 1515, 1233, 1024 cm−1. HRMS
calcd. for C30H43N2O8P2 [M + H]+ 621.2495; found
621.2473.
Tetraethyl
(benzene-1,4-diylbis{[(4-methyl-
phenyl)amino]methanediyl})bis(phosphonate) (8b).
Yield: 0.94 g (80%, method III), 1.07 g (91%, method
IV); white crystals; mp 161–163°C; 31P NMR (CDCl3,
162 MHz): δ 23.1 and 23.0 (lit.: δ 22.4 [50]); 13C
NMR (CDCl3, 125 MHz): δ 143.86 (d, J = 14.7,
C(1ꢁ)[A]), 143.83 (d, J = 15.1, C(1ꢁ)[B]), 135.9
(d, J = 2.0, C(1)[A, B]), 129.55 (C(3ꢁ)[A]), 129.52
(C(3ꢁ)[B]), 128.2 (d, J = 8.3, C(4ꢁ)[A]), 128.1 (d,
J = 4.9, C(4ꢁ)[B]), 127.6 (d, J = 1.5, C(2)[A, B]),
114.1 (C(2ꢁ)[A]), 114.0 (C(2ꢁ)[B]), 63.20 (d, J = 3.9,
CH2[A]), 63.18 (d, J = 3.4, CH2[B]), 56.2 (d, J =
150.9, PCH[A, B]), 20.3 (CH3[A, B]), 16.38 (d, J =
2.9, CH3[A]), 16.36 (d, J = 2.4, CH3[B]), 16.13 (d,
J = 2.9, CH3[A]), 16.11 (d, J = 2.9, CH3[B]), 16.02
General Procedure for the Synthesis of
Bis(α-aminophosphonates) (8a–i)
Bis(α-aminophosphonates) 8a–i were prepared
in
a similar manner using terephthaladehyde
(0.27 g, 2.0 mmol) and amine (4.0 mmol, ani-
line: 0.37 mL, 4-toluidine: 0.43 g, ethyl 4-
aminobenzoate: 0.66 g, 4-fluoroaniline: 0.39 mL,
4-bromoaniline: 0.48 g, 4-nitroaniline: 0.53 g,
4-methoxyaniline: 0.50 g, 2-(methylthio)aniline:
0.50 mL, 3-(trifluoromethyl)aniline: 0.50 mL). The
work-up was carried out as above to give products
8a–i as a mixture of two isomers (A and B).
1
(d, J = 2.9, CH3[A]), 16.00 (d, J = 2.9, CH3[B]); H
NMR (CDCl3, 500 MHz): δ 7.42 (s, 4H, HC(2)[A]),
7.41 (s, 4H, HC(2)[B]), 6.87–6.85 (m, 4H, ArH),
6.47–6.45 (m, 4H, ArH), 4.73–4.61 (m, 4H, CH, NH),
4.10–4.00 (m, 4H, CH2), 3.87–3.79 (m, 2H, CH2),
3.62–3.60 (m, 1H, CH2), 3.53–3.48 (m, 1H, CH2),
2.16 (s, 3H, CH3), 2.15 (s, 3H, CH3), 1.25 (t, J = 7.1,
3H, CH3), 1.22 (t, J = 7.1, 3H, CH3), 1.04 (t, J = 7.1,
EtO
OEt
O
O
2
P
P
EtO
OEt
1
4'
NH
HN
1'
1
R
R
3H, CH3), 0.96 (t, J = 7.1, 3H, CH3) {lit.: H NMR
3'
2'
8a–i
(200 MHz, CDCl3): δ 7.42 (s, C6H4, 4H), 6.86 (d, J =
7.8, p-C6H4, 4H), 6.45 (d, J = 7.8, p-C6H4, 4H), 4.69
2
Tetraethyl {benzene-1,4-diylbis[(phenylamino)-
methanediyl]}bis(phosphonate) (8a). Yield: 1.03
g (92%, method III), 1.06 g (95%, method IV);
white crystals; mp 172–175°C; 31P NMR (CDCl3,
162 MHz): δ 22.9 (lit.: δ 22.5 [50]); 13C NMR (CDCl3,
125 MHz): δ 146.2 (d, J = 14.6, C(1ꢁ)[A, B]), 135.8
(C(1)[A, B]), 129.04 (C(3ꢁ)[A]), 129.01 (C(3ꢁ)[B]),
128.24 (C(2)[A]), 128.17 (C(2)[B]), 118.4 (C(4ꢁ)[A,
B]), 113.92 (C(2ꢁ)[A]), 113.89 (C(2ꢁ)[B]), 63.4 (d, J =
2.9, CH2[A]), 63.3 (d, J = 3.4, CH2[B]), 63.19 (d,
J = 7.8, CH2[A]), 63.16 (d, J = 6.8, CH2[B]), 55.8 (d,
J = 150.9, PCH[A, B]), 16.4 (d, J = 2.5, CH3[A]), 16.3
(d, J = 2.9, CH3[B]), 16.01 (d, J = 2.9, CH3[A]), 15.98
(d, JPH = 23.4, CHP, 2H), 4.07 (m, OCH2CH3, 4H),
3.86–3.41 (m, OCH2CH3, 4H), 2.16 (s, CH3, 6H),
1.25 and 1.23 (2t, J = 6.8, OCH2CH3, 6H), 1.04 and
0.94 (2t, J = 7.0, OCH2CH3, 6H) [50]}; IR (KBr): ν
3304, 2988, 1618, 1521, 1391, 1235 cm−1. HRMS
calcd. for C30H43N2O6P2 [M + H]+ 589.2596; found
589.2568.
Diethyl
phosphoryl)methanediyl]imino})dibenzoate
4,4ꢁ-(benzene-1,4-diylbis{[(diethoxy-
(8c).
Yield: 1.14 g (81%, method III), 1.16 g (82%, method
IV); white crystals; mp 187–189°C; 31P NMR (CDCl3,
162 MHz): δ 22.1; 13C NMR (CDCl3, 125 MHz):
δ 166.5 (d, J = 5.9, C = O[A, B]), 150.2 (d, J =
14.1, C(1ꢁ)[A]), 149.9 (d, J = 13.7, C(1ꢁ)[B]), 135.5
(d, J = 4.9, C(1)[A, B]), 131.2 (d, J = 4.9, C(3ꢁ)[A,
B]), 128.2 (d, J = 8.3, C(2)[A, B]), 120.2 (C(4ꢁ)[A]),
119.9 (C(4ꢁ)[B]), 112.7 (d, J = 10.7, C(2ꢁ)[A, B]), 63.5
(CH2[A, B]), 63.33 (d, J = 3.4, CH2[A]), 63.31 (d,
J = 2.9, CH2[B]), 60.24 (CH2[A, B]), 60.18 (CH2[A,
B]), 55.3 (d, J = 150.9, PCH[A]), 55.2 (d, J = 152.4,
CH[B]), 16.37 (d, J = 2.9, CH3[A]), 16.35 (d, J =
2.9, CH3[B]), 16.08 (d, J = 2.9, CH3[A]), 16.05 (d,
J = 3.9, CH3[B]), 14.4 (CH3[A, B]); 1H NMR (CDCl3,
500 MHz): δ 7.78–7.75 (m, 4H, ArH), 7.46 (s, 4H,
HC(2)[A]), 7.44 (s, 4H, HC(2)[B]), 6.58–6.53 (m, 4H,
ArH), 5.79 (bs, 1H, NH), 5.26 (bs, 1H, NH), 4.79 (d,
J = 23.8, 2H, CH), 4.30–4.24 (m, 4H, CH2), 4.14–4.03
(m, 4H, CH2), 3.86–3.85 (m, 2H, CH2), 3.61–3.52
1
(d, J = 2.4, CH3[B]); H NMR (CDCl3, 500 MHz): δ
7.43 (s, 4H, ArH), 7.07–7.03 (m, 4H, ArH), 6.67–6.64
(m, 2H, ArH), 6.55–6.53 (m, 4H, ArH), 4.79 (bs,
2H, NH), 4.76–4.68 (m, 2H, CH), 4.10–4.06 (m, 4H,
CH2), 3.83–3.78 (m, 2H, CH2), 3.49–3.47 (m, 2H,
CH2), 1.25 (t, J = 7.1, 6H, CH3), 0.94 (t, J = 6.9, 6H,
CH3) {lit.: 1H NMR (200 MHz, CDCl3): δ 7.44 (s,
C6H4, 4H), 7.06 (dd, J = 7.8 and 7.6, CHm, 4H), 6.67
(t, J = 7.6, CHp, 2H), 6.54 (d, J = 7.8, CHo, 4H), 4.73
2
(d, JPH = 23.3, CHP, 2H), 4.08 (m, OCH2CH3, 4H),
3.83 and 3.54 (2m, OCH2CH3, 2 × 2H), 2.17 (s, NH,
2H), 1.26 and 1.23 (2t, J = 6.9, OCH2CH3, 6H), 1.04,
0.93 (2t, J = 7.1, OCH2CH3, 6H) [50]}; IR (KBr): ν
3297, 2980, 1603, 1499, 1235, 1016 cm−1. HRMS
calcd. for C28H39N2O6P2 [M + H]+ 561.2283; found
561.2297.
Heteroatom Chemistry DOI 10.1002/hc

T3PꢀR -Mediated One-Pot Synthesis of Bis(α-aminophosphonates)
9
(m, 2H, CH2), 1.33–1.23 (m, 12H, CH3), 1.04 (t, J =
6.9, 3H, CH3), 0.99 (t, J = 7.0, 3H, CH3); IR (KBr):
ν 3278, 2982, 1702, 1604, 1276, 1023 cm−1. HRMS
calcd. for C34H47N2O10P2 [M + H]+ 705.2706; found
705.2742.
2H, CH2), 3.49–3.47 (m, 2H, CH2), 1.27 (t, 6H, J =
7.2, 2CH3), 0.98 (t, 6H, J = 7.2, 2CH3) [52]} IR (KBr):
ν 3304, 2981, 1596, 1489, 1235, 1025 cm−1. HRMS
calcd. for C28H37Br2N2O6P2 [M + H]+ 717.0494;
found 717.0525.
Tetraethyl (benzene-1,4-diylbis{[(4-fluorophenyl)
amino]methanediyl})bis(phosphonate) (8d). Yield:
0.64 g (54%, method III), 0.55 g (46%, method IV);
white crystals; mp 202–204°C; 31P NMR (CDCl3,
162 MHz): δ 22.8 (lit.: δ 20.5 [51]); 13C NMR (CDCl3,
125 MHz): δ 156.2 (d, J = 236.8, C(4ꢁ)[A, B]),
142.42 (d, J = 15.6, C(1ꢁ)[A]), 142.35 (C(1ꢁ)[B]), 135.7
(C(1)[A, B]), 128.3 (d, J = 8.3, C(2)[A]), 128.2 (d,
J = 7.8, C(2)[B]), 115.4 (d, J = 22.5, C(2ꢁ)[A, B]),
114.9 (d, J = 7.3, C(3ꢁ)[A, B]), 63.3 (CH2[A]), 63.22
(CH2[B]), 63.18 (d, J = 6.8, CH2[A, B]), 56.5 (d, J =
151.2, PCH[A, B]), 16.4 (d, J = 2.9, CH3[A]), 16.3
(d, J = 2.4, CH3[B]), 16.0 (d, J = 2.6, CH3[A]), 15.9
(d, J = 2.9, CH3[B]); 1H NMR (CDCl3, 500 MHz):
δ 7.41 (s, 4H, ArH), 6.77–6.73 (m, 4H, ArH), 6.50–
6.46 (m, 4H, ArH), 4.78–4.74 (m, 2H, NH), 4.68–4.62
(m, 2H, CH), 4.12–4.07 (m, 4H, CH2), 3.84–3.79 (m,
2H, CH2), 3.53–3.48 (m, 2H, CH2), 1.26 (t, J = 7.1,
Tetraethyl (benzene-1,4-diylbis{[(4-nitrophenyl)
amino]methanediyl})bis(phosphonate) (8f). Yield:
1.16 g (89%, method III), 1.18 g (91%, method IV);
yellow crystals; mp 240–243°C; 31P NMR (DMSO,
162 MHz): δ 22.3 (lit.: δ 21.6 [50]); 13C NMR (DMSO,
125 MHz): δ 153.6 (d, J = 11.7, C(1ꢁ)[A]), 153.5
(d, J = 11.7, C(1ꢁ)[B]), 137.2 (d, J = 1.4, C(4ꢁ)[A,
B]), 135.5 (C(1)[A, B]), 128.3 (C(2)[A, B]), 125.9
(C(3ꢁ)[A, B]), 112.5 (C(2ꢁ)[A, B], 62.9 (d, J = 7.3,
CH2[A, B]), 53.9 (d, J = 151.4, PCH[A]), 52.8 (d, J =
151.9, PCH[B]), 16.4 (d, J = 2.4, CH3[A, B]), 16.2 (d,
J = 4.9, CH3[A, B]); 1H NMR (DMSO, 500 MHz):
δ 7.94–7.92 (m, 4H, ArH), 7.88–7.85 (m, 2H, NH),
7.54 (s, 4H, ArH), 6.94–6.92 (m, 4H, ArH), 5.31–5.26
(m, 2H, CH), 4.05–3.97 (m, 4H, CH2), 3.88–3.83 (m,
2H, CH2), 3.74–3.68 (m, 2H, CH2), 1.14 (t, J = 7.1,
6H, CH3), 1.00 (t, J = 6.9, 6H, CH3); IR (KBr): ν
3272, 2980, 1598, 1311, 1236, 1112 cm−1. HRMS
calcd. for C28H37N4O10P2 [M + H]+ 651.1985; found
651.1978.
1
6H, CH3), 0.95 (t, J = 7.1, 6H, CH3) {lit.: H NMR
(600 MHz, CDCl3): δ 7.10–7.00 (m, 4H, ArH), 6.99–
6.96 (m, 8H, ArH), 6.00 (br, 2H, NH), 5.06 (d, 2H, J =
17.2, CH P), 3.96–3.91 (m, 8H, CH2), 1.25 (t, 12H,
J = 7.2, CH3) [51]}; IR (KBr): ν 3295, 2987, 1511,
1236, 1017 cm−1. HRMS calcd. for C28H37F2N2O6P2
[M + H]+ 597.2095; found 597.2122.
Tetraethyl
(benzene-1,4-diylbis{[(4-methoxy-
phenyl)amino]methanediyl})bis(phosphonate) (8g).
Yield: 0.85 g (69%, method III), 0.86 g (70%, method
IV); white crystals; mp 140–142°C; 31P NMR (CDCl3,
162 MHz): δ 23.13 and 23.08 (lit.: δ 23.9 [50]); 13C
NMR (CDCl3, 125 MHz): 152.69 (C(4ꢁ)[A]), 152.68
(C(4ꢁ)[B]), 140.3 (d, J = 3.9, C(1ꢁ)[A]), 140.1 (d,
J = 3.9, C(1ꢁ)[B]), 135.9 (C(1)[A, B]), 128.2 (C(2)[A,
B]), 115.3 (d, J = 2.9, C(2ꢁ)[A, B]), 114.7 (d, J =
1.9, C(3ꢁ)[A, B]), 63.2 (d, J = 2.9, CH2[A, B]), 56.8
(d, J = 150.9, PCH[A, B]), 55.6 (OCH3[A]), 55.5
(OCH3[B]), 16.4 (d, J = 2.5, CH3[A]), 16.13 (d, J =
2.9, CH3[B]), 16.11 (d, J = 2.9, CH3[A]), 16.0 (d, J =
2.4, CH3[B]); 1H NMR (CDCl3, 500 MHz): δ 7.42
[s, 4H, HC(2)[A]), 7.41 [s, 4H, HC(2)[B]), 6.66–6.63
(m, 4H, ArH), 6.51–6.50 (m, 4H, ArH), 4.67–4.62
(m, 2H, NH), 4.54–4.51 (m, 2H, CH), 4.12–4.02 (m,
4H, CH2), 3.88–3.80 (m, 2H, CH2), 3.672 (s, 6H,
OCH3[A]), 3.666 (s, 6H, OCH3[B]), 3.64–3.60 (m,
1H, CH2), 3.53–3.50 (m, 1H, CH2), 1.27–1.22 (m,
6H, CH3), 1.04 (t, J = 7.1, 3H, CH3), 0.96 (t, J = 7.0,
Tetraethyl
(benzene-1,4-diylbis{[(4-bromo-
phenyl)amino]methanediyl})bis(phosphonate) (8e).
Yield: 1.24 g (86%, method III), 1.21 g (84%, method
IV); white crystals; mp 201–204°C; 31P NMR (CDCl3,
162 MHz): δ 22.5 and 22.4; 13C NMR (CDCl3,
100 MHz): δ 145.23 (d, J = 14.7, C(4ꢁ)[A]), 145.18 (d,
J = 10.5, C(4ꢁ)[B]), 135.5 (C(1)[A, B]), 131.8 (d, J =
4.2, C(3ꢁ)[A, B]), 128.3 (d, J = 6.8, C(2)[A]), 128.2 (d,
J = 4.3, C(2)[B]), 115.6 (C(4ꢁ)[A, B]), 110.2 (d, J =
9.4, C(2ꢁ)[A, B]), 63.5 (d, J = 6.8, CH2[A]), 63.4 (d,
J = 8.5, CH2[B]), 63.31 (d, J = 5.7, CH2[A]), 63.28
(d, J = 7.0, CH2[B]), 56.5 (d, J = 151.2, PCH[A,
B]), 16.43 (d, J = 2.8, CH3[A]), 16.40 (d, J = 2.9,
CH3[B]), 16.1 (d, J = 2.9, CH3[A]), 16.0 (d, J = 2.9,
1
CH3[B]); H NMR (CDCl3, 400 MHz): δ 7.41 (s, 4H,
ArH), 7.15–7.11 (m, 4H, ArH), 6.47–6.40 (m, 4H,
ArH), 4.95 (bs, 2H, NH), 4.67 (d, J = 23.4, 2H, CH),
4.17–3.98 (m, 4H, CH2), 3.91–3.76 (m, 2H, CH2),
3.66–3.54 (m, 1H, CH2), 3.54–3.44 (m, 1H, CH2),
1.29–1.24 (m, 6H, CH3), 1.06–0.94 (m, 6H, CH3)
1
3H, CH3) {lit.: H NMR (200 MHz, CDCl3): δ 7.41
(s, C6H4, 4H), 6.64 (d, J = 9.0, p-C6H4, 4H), 6.50
2
(d, J = 9.0, p-C6H4, 4H), 4.64 (d, JPH = 22.7, CHP,
2H), 4.52 (large s, NH, 2H), 4.08 (m, OCH2CH3, 4H),
3.80 (m, OCH2CH3, 2H), 3.67 (s, OCH3, 6H), 3.48
(m, OCH2CH3, 2H), 1.26 (t, J = 7.0, OCH2CH3, 6H),
0.95 (t, J = 7.0, OCH2CH3, 6H) [50]}; IR (KBr): ν
1
{lit.: H NMR: δ 7.42 (s, 4H, ArH), 7.16 (d, 4H, J =
3.2, ArH), 6.44 (d, 4H, J = 3.2, ArH), 4.68 (d, 2H, J =
23.2, 2PCH), 4.14–4.09 (m, 4H, 2CH2), 3.84–3.81 (m,
Heteroatom Chemistry DOI 10.1002/hc

10 Milen et al.
for C30H37F6N2O6P2 [M + H]+ 697.2031; found
3310, 2995, 1511, 1230, 1094 cm−1. HRMS calcd. for
C30H43N2O8P2 [M + H]+ 621.2495; found 621.2523.
697.2010.
Tetraethyl [benzene-1,4-diylbis({[2-(methylsulf-
anyl)phenyl]amino]methanediyl)]-bis(phosphornate)
(8h). Yield: 0.98 g (75%, method III), 0.94 g (72%,
method IV); white crystals; mp 153–154°C; 31P
NMR (CDCl3, 162 MHz): δ 22.5; 13C NMR (CDCl3,
100 MHz): δ 146.6 (d, J = 6.6, C(1ꢁ)[A]), 146.5 (d,
J = 6.6, C(1ꢁ)[B]), 135.7 (C(1)[A, B]), 134.2 (C(3ꢁ)[A,
B]), 129.1 (C(6ꢁ)[A, B]), 128.1 (d, J = 7.8, C(2)[A]),
128.0 (d, J = 6.9, C(2)[B]), 121.1 (C(5ꢁ)[A, B]), 118.2
(C(4ꢁ)[A, B]), 111.4 (d, J = 3.0, C(2ꢁ)[A, B]), 63.3 (d,
J = 7.3, CH2[A]), 63.2 (d, J = 6.5, CH2[B]), 56.7 (d,
J = 151.1, PCH[A]), 55.1 (d, J = 151.2, PCH[B]), 18.3
(SCH3[A, B]), 16.38 (d, J = 7.8, CH3[A]), 16.36 (d,
J = 7.5, CH3[B]), 16.12 (d, J = 7.5, CH3[A]). 16.09
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1
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2H, CH), 4.20–4.00 (m, 4H, CH2), 3.90–3.80 (m, 2H,
CH2), 3.62–3.52 (m, 2H, CH2), 1.26 (t, J = 7.3, 6H,
CH3), 1.01 (t, J = 6.7, 6H, CH3); IR (KBr): 3297,
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