Obtaining symmetric and asymmetric bisphosphoramidates and bisphosphoramidothioates by a single step multicomponent reaction

Article abstract of DOI:10.1080/10426507.2021.1878358

We present a new single-step multicomponent reaction strategy for the synthesis of symmetric and (novel) asymmetric bisphosphoramidate and bisphosphoramidothioate derivatives. Reactions proceed under routine experimental conditions, do not require the aid of any catalyst, and provide moderate yields after a short time. We synthesized 18 different compounds, 10 of them for the first time. The cytotoxic activity of our adducts was assessed by measuring their inhibitory capacity (IC₅₀) against two different cell lines, the A549 (lung cancer cells) and the SW1353 (chondrosarcoma cells).

Full text of DOI:10.1080/10426507.2021.1878358

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Obtaining symmetric and asymmetric
bisphosphoramidates and
bisphosphoramidothioates by a single step
multicomponent reaction
Angel Zamudio-Medina, Nury Pérez-Hernández, José Luis Castrejón-Flores,
Susana Romero-García, Heriberto Prado-García, Angel Bañuelos-Hernández
& Marco Franco-Pérez
To cite this article: Angel Zamudio-Medina, Nury Pérez-Hernández, José Luis Castrejón-
Flores, Susana Romero-García, Heriberto Prado-García, Angel Bañuelos-Hernández &
Marco Franco-Pérez (2021): Obtaining symmetric and asymmetric bisphosphoramidates and
bisphosphoramidothioates by a single step multicomponent reaction, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2021.1878358
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2021.1878358
Obtaining symmetric and asymmetric bisphosphoramidates and
bisphosphoramidothioates by a single step multicomponent reaction
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Angel Zamudio-Medina , Nury Perez-Hernandez , Jose Luis Castrejon-Flores , Susana Romero-Garcıa , Heriberto
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Prado-Garcıa , Angel Banuelos-Hernandez , and Marco Franco-Perez
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Unidad Profesional Interdisciplinaria de Biotecnologıa, Instituto Politecnico Nacional, CDMX, Mexico; Escuela Nacional de Medicina y
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Homeopatıa, Instituto Politecnico Nacional, CDMX, Mexico; Department of Chronic-Degenerative Diseases, National Institute of Respiratory
Diseases “Ismael Cosıo Villegas”, Mexico City, Mexico; Departamento de Fısica y Quımica Teorica, Facultad de Quımica, Universidad
Nacional Autonoma de Mexico, Ciudad Universitaria, CDMX, Mexico
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ABSTRACT
ARTICLE HISTORY
Received 23 November 2020
Accepted 16 January 2021
We present a new single-step multicomponent reaction strategy for the synthesis of symmetric
and (novel) asymmetric bisphosphoramidate and bisphosphoramidothioate derivatives. Reactions
proceed under routine experimental conditions, do not require the aid of any catalyst, and provide
moderate yields after a short time. We synthesized 18 different compounds, 10 of them for the
first time. The cytotoxic activity of our adducts was assessed by measuring their inhibitory capacity
(IC50) against two different cell lines, the A549 (lung cancer cells) and the SW1353 (chondrosar-
coma cells).
KEYWORDS
Multicomponent reaction;
bisphosphoramidates;
bisphosphoramidothioates;
symmetric and asymmetric
derivatives; cytotoxicity;
double addition–elimination
GRAPHICAL ABSTRACT
Introduction
the synthesis of phosphoramidates and bisphosphoramidates.
For instance, Atherton et al. synthesized dibenzyl-amino-
phosphonates through the reaction between carbon tetra-
chloride and phosphite species, providing firstly
trichloromethylphosphonate and then the forementioned
products, once both ammonia and a secondary amine
(depending on the desired product) are added to the reaction
medium.[30,31] A variant of this strategy was reported by
Hackenberger et al. who synthesized several N,N-disubstituted
phosphoramidates by mixing organic azides with phosphite
ions, following a Lewis acid-catalyzed reaction. Although
these procedures provide yields from moderate to good, the
reactants involved are highly toxic and even explosive in the
Organophosphates are important organic compounds with
broad applications in science and engineering,[1] such as addi-
tives in polymers,[2] pesticides in agriculture[3–6] and drugs in
pharmaceutics,[7] among others. Particularly, phosphorami-
dates and bisphosphoramidates, formed by one and two nitro-
gen–phosphorus–oxygen (N–P ¼ O) bond sequence(s)
respectively, display several applications in medical science as
antivirals,[8–11] antineoplastics,[12–15] bactericides[16–18] and
steroids,[19] as well as DNA intercalators.[20–23] As a represen-
tative example, remdesivir, the only approved antiviral against
COVID-19,[24–27] the disease caused by the SARC-CoV-2
virus is constituted by a phosphoramidate frame.[28,29] Due to
their importance, several strategies have been developed for presence of moisture, requiring stringent experimental
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Unidad Profesional Interdisciplinaria de Biotecnologıa, Instituto Politecnico Nacional, Av.
CONTACT Angel Zamudio-Medina
jazamudiom@ipn.mx
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Departamento de Fısica y
Acueducto, La Laguna Ticoman, Gustavo A. Madero, 07340, CDMX, Mexico; Marco Franco-Perez
qimfranco@hotmail.com
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Quımica Teorica, Facultad de Quımica, Universidad Nacional Autonoma de Mexico, Ciudad Universitaria, CDMX, Mexico.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2021.1878358.
ß 2021 Taylor & Francis Group, LLC

2
A. ZAMUDIO-MEDINA ET AL.
S
P
H
N
asymmetric phosphoramidates and phosphoramidothioates.
To show the inherent biological features exhibited by com-
pounds synthesized this way, we evaluated the inhibitory
capacity of our (symmetric and asymmetric) compounds
against two different cell lines: the lung adenocarcinoma cell
line A-549 and the human bone chondrosarcoma cell line
(SW 1353), as representative of lung cancer malignant cells
in bones.[38,39]
OEt
OEt
EtO
EtO
N
H
P
S
9
14%
, n = 1,
S
EtO
EtO
P
Cl
Cl
O
H
N
OEt
P
S
PhO
P
PhO
7
NH2
, n = 1
N
H
OEt
+
H2N
0 °C
O
P
1
10
38%
, n = 1,
PhO
PhO
O
P
H
N
8
OPh
OPh
PhO
PhO
N
H
P
O
Results and discussion
Our multicomponent reactions proceed from the following
three starting materials: aliphatic diamines, 1, 1,3-diamino-
propane 2, 1,4-diaminobutane 3, 1,5-diaminopentane 4, 1,6-
diaminohexane 5 and 1,7-diaminoheptane 6), O, O0-diethyl
chlorothiophosphate 7, and diphenyl phosphoryl chloride 8.
It is worthy to mention that this novel procedure is part of
a patent, still in process.[40] One may observe that three
derivatives are obtained for each of the diamines used as
reagent: two symmetric (a phosphoramidate and a phos-
phoramidothioate) and the asymmetric analog (phosphora-
midate-phosphoramidothioate). For instance, note that if
diamine 1 is mixed with the two phosphoryl chlorides men-
tioned above (compounds 7 and 8), the following two sym-
metric derivatives are obtained, O,O,O’,O’-tetraethyl ethane-
1,2-diylbis (phosphoramidothioate) 9 and tetraphenyl eth-
ane-1,2-diylbis(phosphoramidate) 11, conjointly with the
asymmetric analogue diphenyl (2-((diethoxyphosphorothioy-
l)amino)ethyl)phosphoramidate 10 (Scheme 1). The set of
MCR reactions performed in this work are summarized in
11
10%
, n = 1,
Scheme 1. MCR procedure to obtain symmetric 9, 11 and asymmetric 10
derivatives.
conditions, as well as appropriate purification techniques.[32]
Phenyl-phosphoramidates are commonly obtained with the
aid of a metallic catalyst. Examples of these procedures were
reported by Chang et al.[33] and by Fraser et al.,[31] who separ-
ately synthesized several derivatives using iridium- and cop-
per-based catalysts, respectively. The use of a catalyst agent
substantially improves reaction efficiencies, but at the cost of
forming some unwanted secondary products. A few bisphos-
phoramidates have been synthesized, commonly by mixing
aliphatic diamines with a phosphoryl chloride derivative,
obtaining symmetric (phosphorous atoms, belonging to each
of the two phosphoramidate moieties, display the same con-
nectivity) species according to a double addition–elimination
reaction.[34,35] As far as we know, no experimental technique
has been designed for the synthesis of asymmetric
phosphoramidates.
In this work, we present a novel experimental procedure
for the synthesis of both symmetric and asymmetric
(bis)phosphoramidate and (bis)phosphoramidothioate deriv-
atives following a one-pot multicomponent reaction (MCR)
strategy.[36] MCRs are powerful procedures for the synthesis
of organic species with a high structural complexity, involv-
ing short reaction times and relative soft experimental con-
ditions. Previously, we designed a new a tricomponent free
catalyst reaction strategy for the synthesis of (dihydro-1H-
benzo[d]imidazole) phosphonate, using benzimidazoles
(component one), aliphatic amines (component two), and
phosphorous chloride (component three) as starting materi-
als.[37] Unlike other techniques, our methodology requires
relative short reaction times (less than 12 h) and routine
experimental conditions (room temperature and atmospheric
pressure) to obtain the corresponding compound.
1
Scheme 2 (Recorded H, 13C, and 31P NMR chemical shifts
for adducts 9–26 are available in the Supplemental data).
As can be seen in diagrams 1 and 2, the reaction yields
are severely affected by the solubility of the diamine used as
a reagent. The highest yields were obtained for reactions
involving light diamines 1–3 with overall yields of 62%,
58%, and 50%, respectively (short alkyl chain lengths), while
the lowest yields were obtained with diamines 4–6 as a
reagent with overall yields of 13%, 16%, and 17%, respect-
ively (long alkyl chain lengths). As explained in the text
(and represented in diagrams 1 and 2), our strategy provides
a mixture of products constituted by symmetric (9 (14%),
11 (10%), 12 (23%), 14 (10%), 15 (24%), 17 (14%), 18 (5%),
20 (5%), 21 (2%), 23 (4%), 24 (7%), and 26 (5%)) and
asymmetric (10 (38%), 13 (25%), 16 (12%), 19 (3%), 22
(10%), and 25 (5%)) species.
1
All our adducts were characterized by H, 13C and 31P
NMR; As an example, we explain the characterization of
compound 10. Asymmetric bisphosphoramidate 10 has two
different bonds, nitrogen–phosphorus–oxygen (N–P @ O)
The MCR strategy reported in this work involves reagents
with a low toxicity profile without compromising the bene-
fits of these reactions; that is, it requires routine experimen-
tal conditions and short reaction times and it proceeds in a
single pot, in the absence of catalysts. As an outstanding fea-
ture, our procedure is particularly convenient for the synthe-
1
and nitrogen–phosphorus–sulfur (N–P @ S). In the H NMR
spectrum, it displayed a signal (dt) at 1.27 ppm with two
coupling constants of 7.6 and 14 Hz, for –CH2CH3. In
3 ppm, we observed a (dt) at –CH2NPS, with two coupling
constants of 6.4 and 12.8 Hz. In 13C NMR, a (d) was
sis
of
both
symmetric
(bisphosphoramidate
or
bisphosphoramidothioate) and asymmetric (phosphoramida- observed at 15.9 ppm for carbons belonging to –OCH2CH3,
te–phosphoramidothioate) derivatives. Consequently, this with a coupling constant of 8.1 Hz. At 62.9 ppm, a signal (d)
work constitutes the first report regarding the synthesis of was also observe for carbons in –OCH2CH3, with a coupling

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 2. Set of three-component reactions performed in this work. Reaction yields are reported as percentage.
23, 24, and 26, as well as the whole set of asymmetric ana-
logues 10, 13, 16, 19, 22, and 25 were synthesized for the
first time in this work, through our MCR procedure.
As a final task, we measured the half maximal inhibitory
concentration (IC50) values for the six organophosphorus
derivatives (9–14) here synthesized, against the A-549 and
SW-1353 cell lines. In Table 1, we report those species able
to inhibit the grown of these cell cultures. Note that three of
our compounds (12, 13, and 14) displayed a good inhibitory
capacity over the SW-1353 cell line, in the same concentra-
tion rande to doxorubicin, one of the most widely used
antineoplastics.[41]
Table 1. Half-Growth inhibition (IC50) in lung adenocarcinoma and chondro-
sarcoma cells. Values are expressed as the mean standard error of the
mean (SEM).
Compound
IC50 A549
IC50 SW-1353
ꢁꢁ
9
10
11
12
>100
111.15 4.53
105.51 7.16
>100
465.70 2.46
>100
ꢁ
19.53 1.31
12.77 1.37
13
47.59 1.97
14
CDDP
Doxorubicin
Colchicine
>100
10.37 1.31
ꢁꢁ
32.93 1.48
ꢁꢁ
8.53 3.35
1.69 1.53
ꢁꢁ
ꢁ
Limited solubility.
ꢁꢁ
Not determined.
Experimental
constant of 5 Hz. At 150.64 ppm for the carbon ipso as a sig-
nal (d) with a coupling constant of 6.8 Hz. In the 31P NMR The chemical structures corresponding to all our synthesized
spectrum, we observed two signals, one at ꢀ2.69 ppm compounds were revealed by H NMR, 13C NMR, 31P NMR
1
(P @ O) and the other at 69.83 ppm (P @ S).
spectroscopic and mass spectrometric records (correspond-
ing data can be found in the supplemental data). H, 13C,
1
From the set of symmetric and asymmetric adducts here and 31P NMR data were recorded at room temperature
obtained, compounds 9, 11, 12, 14, 15, 17, 18, and 20 were using the Bruker BioSpin GmbH (Billerica, MA). All our
previously synthesized through addition–elimination reac- experiments were performed using deuterated chloroform
tions.[25,34,35] In this context, the symmetric derivatives 21, (CDCl3) as solvent. Chemical shifts (d) are reported in parts

4
A. ZAMUDIO-MEDINA ET AL.
per million. Multiplicities were recorded as singlet (s), doub- 5.0 Hz, OCH2CH3, 2 C), 120.17 (d, JPC ¼ 4.8 Hz, 4 Cortho),
let (d), triplet (t), doublet of doublets (dd), and multiplet 124.98 (2 Cpara), 129.71 (4 Cmeta), 150.70 (d, JPC ¼ 6.8 Hz,
(m). Coupling constants (J) are given in Hz. High-resolution 2 Cipso). 31P NMR (161.9 MHz, CDCl3): d ¼ ꢀ2.69 (s,
mass spectra were recorded on a JEOL AccuTOF JMS- P ¼ O), 69.83 (s, P ¼ S). HRMS (DART) C18H27N2O5P2S
[M þ H]þ calc. 445.1038, found 445.1119.
T100LC mass spectrometer with TOF mass analyzer (JEOL
USA, Inc., Peabody, MA). FAB þ mass spectra were obtained
on a 3-nitrobenzyl alcohol matrix in the positive ion mode
Tetraphenyl ethane-1,2-diylbis(phosphoramidate) (11)
on a JEOL MStationJMS-700 spectrometer, operated at an
accelerating voltage of 10 kV by using Xenon atoms at 6 keV
(JEOL USA, Inc., Peabody, MA). Melting points were deter-
Yield: 10%; solid white; mp: 134–135 ꢂC. (lit [27]). H NMR
1
(400 MHz, CDCl3, 25 ꢂC, TMS, ppm): d ¼ 3.09 (dd, JHH
6.4 Hz, JPNCH ¼ 6.8 Hz, 4H, –CH2NH), 4.33 (dt, JPNH
¼
mined using Fisher Johns melting point apparatus (uncor-
rected) (168 Third Avenue Waltham, MA). Supplemental
¼
6 Hz, 2H, NH), 7.10–7.28 (m, 20H). 13C NMR (100 MHz,
CDCl3, 25 ꢂC, TMS, ppm): d ¼ 42.95 (d, JPC ¼ 5.3 Hz, 2 C,
–CH2NH–), 120.20 (s, 8 Cortho), 125.01 (s, 4 Cpara), 129.72 (s,
8 Cmeta), 150.67 (d, JPC ¼ 6.8 Hz, 4 Cipso). 31P NMR
(161.98 MHz, CDCl3): d ¼ ꢀ0.41 (s). HRMS (DART)
C26H27N2O6P2 [M þ H]þ calc. 525.1344, found 525.1361.
1
data contain sample H, 13C, and 31P NMR spectra for the
products (Figures S 1–S 54).
General method
The general synthesis procedure was as follows: Under mag-
netic stirring and at 0 ꢂC, a 50-mL round bottom flask con-
taining the diamine (1 mmol) was placed in CH2Cl2 2 mL
with NEt3 (1 mmol) and O, O0-diethyl chlorothiophosphate
(0.5 mmol) was added dropwise and left stirring for add-
itional 30 min at 0 ꢂC. Subsequently, NEt3 (1 mmol) was
added and left stirring for 5 min, followed by a diphenyl
phosphoryl chloride (0.5 mmol) addition, dropwise. The
reaction mixture was left stirring for 1 h. The reaction mix-
ture was then concentrated in vacuo. The crude products
were purified by flash column chromatography. The purifi-
cation of adducts was carried out using two different mix-
tures of eluents, i.e., a hexane/EtOAc (4:1) mixture followed
by a hexane/EtOAc (1:1) mixture.
O,O,O’,O’-tetraethyl propane-1,3-
diylbis(phosphoramidothioate) (12)
Yield: 23%; yellow liquid. (lit [25]). 1H NMR (300 MHz,
CDCl3, 298ꢂK): d ¼ 1.32 (dt, JHH ¼ 6.9, 7.2 Hz, –OCH2CH3,
12H), 1.63 (dd, JHH ¼ 6.3, 6.6 Hz, –CH2CH2CH2–, 2H), 3.05
(dt, JHH ¼ 6, JPNCH ¼ 11.7 Hz, –CH2NP, 4H), 3.09–3.11 (m,
PNH, 2H), 4.05 (dq, JHH
¼
6.9, JPOCH
¼
7.2 Hz,
–OCH2CH3, 8H) ppm. 13C NMR (75.48 MHz, CDCl3,
298ꢂK): d ¼ 15.98 (d, JP-C ¼ 7.5 Hz, –OCH2CH3, 4 C), 32.88
(d, JP-C ¼ 5.2 Hz, –CH2CH2CH2–, 1 C), 38.49 (–CH2NP,
2 C), 63.0 (d, JP-C ¼ 4.5 Hz, –OCH2CH3, 4 C) ppm. 31P
NMR (242.95 MHz, CDCl3): d ¼ 72.60 (s) ppm. HRMS
(DART) C11H29N2O4P2S2 [M þ H]þ calc. 379.1044,
found 379.1041.
O,O,O’,O’-tetraethylethane-1,2diylbis
(phosphoramidothioate) (9)
Diphenyl (3-((diethoxyphosphorothioyl)
amino)propyl)phosphoramidate (13)
Yield: 23%; solid white; mp: 79–80 ꢂC. (lit [25]). 1H NMR
(400 MHz, CDCl3, 298 K): d ¼ 1.32 (dt, JHH ¼ 6.9, 7.2 Hz,
–OCH2CH3, 12H), 3.05 (dt, JHH ¼ 6.8, JPNCH ¼ 9.6 Hz,
1
Yield: 25%; solid white; mp: 54–55 ꢂC. H NMR (300 MHz,
–CH2NP, 4H), 3.25–3.28 (m, PNH, 2H), 4.05 (dq, JHH
¼
CDCl3, 298 K): d ¼ 1.27 (dt, JHH ¼ 7.2, 14.4 Hz, –OCH2CH3,
6H), 1.56 (dt, JHH ¼ 6.3, 12.9 Hz, –CH2CH2CH2–, 2H), 2.99
(dt, JHH ¼ 6.6, JSPOCH2 ¼12.9 Hz, SPNCH2–, 2H), 3.15 (dt,
JHH ¼ 6.6, JOPNHCH2 ¼ 11.7 Hz, OPNCH2–, 2H), 3.25–3.27
(m, SPNH), 3.80–3.82 (m, OPNH), 3.98 (dq, JHH ¼ 7.2,
JPOCH2 ¼ 14.0 Hz, –OCH2CH3, 4H), 7.16–7.35 (m, 10H).
6.8, JPOCH ¼ 7.2 Hz, –OCH2CH3, 8H) ppm. 13C NMR
(100.53 MHz, CDCl3, 298 K): d ¼ 15.94 (d, JP-C ¼ 8.1 Hz,
–OCH2CH3, 12 C), 42.79 (–CH2CH2, 4 C), 63.10 (d, JP-C
¼
5.1 Hz, –OCH2CH3, 8 C) ppm. 31P NMR (161.91 MHz,
CDCl3): d ¼ 69.62 (s) ppm. HRMS (DART) C10H27N2O4P2S2
[M þ H]þ calc. 365.0887, found 365.0881.
13C NMR (75.48 MHz, CDCl3, 298 K): d ¼ 15.94 (d, JPC
¼
7.7 Hz, –OCH2CH3, 2 C), 32.62 (d, JPC ¼ 4.2 Hz, –CH2–,
1 C), 38.27 (1 C), 38.42 (1 C), 62.91 (d, JPC ¼ 4.7,
OCH2CH3, 2 C), 120.17 (d, JPC ¼ 4.9 Hz, 4 Cortho), 124.97
(2 Cpara), 129.73 (4 Cmeta), 150.7 (d, JPC ¼ 6.8 Hz, 2 Cipso).
31P NMR (161.9 MHz, CDCl3): d ¼ ꢀ2.51 (s, P ¼ O), 69.93
(s, P ¼ S). HRMS (DART) C19H29N2O5P2S [M þ H]þ calc.
459.1194, found 459.1272.
Diphenyl(2((diethoxyphosphorothioyl)amino)
ethyl)phosphoramidate (10)
Yield: 38%; yellow liquid. 1H NMR (400 MHz, CDCl3,
298 K): d ¼ 1.27 (dt, JHH ¼ 7.6, 14 Hz, –OCH2CH3, 6H),
3.01 (dt, JHH¼ 6.4, JCH2NPS ¼ 12.8 Hz, CH2NPS, 2H), 3.11
(dt, JHH ¼ 6, JOPOCH2 ¼ 12.9 Hz, OPNCH2, 2H), 3.55–3.56
(m, SPNH), 3.96 (dq, JHH ¼ 7.2, JSPNHCH2 ¼ 14.8 Hz, 4H),
4.21–4.22 (m, OPNH), 7.12–7.32 (m, 10H).
Tetraphenyl propane-1,3-diylbis(phosphoramidate) (14)
13C NMR (100.53 MHz, CDCl3, 298 K): d ¼ 15.82 (d, Yield: 12%; solid white; mp 85-86 ꢂC. (lit [27]). 1H NMR
JPC ¼ 8.1 Hz, –OCH2CH3, 2 C), 42.75 (d, JPC ¼ 4.7 Hz, (400 MHz, CDCl3, 298ꢂK): d ¼ 1.49–1.57 (m, 2H,
CNPS), 42.90 (d, JPC ¼ 4.9 Hz, CNPO), 62.98 (d, JPC
¼
–CH2CH2CH2–), 3.03 (dd, JHH¼ 6 Hz, JPNCH ¼ 6.8 Hz, 4H,

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
–CH2NH), 3.80 (dt, JPNH ¼ 6.4 Hz, 2H, NH), 7.09–7.31 (m, O,O,O’,O’-tetraethyl pentane-1,5-
13
20H). C NMR (100 MHz, CDCl3, 298ꢂK): d ¼ 32.47 (s, 1 C,
diylbis(phosphoramidothioate) (18)
–CH2CH2CH2–), 38.06 (s, 2 C, –CH2NH), 120.20 (s,
8 Cortho), 124.96 (s, 4 Cpara), 129.70 (s, 8 Cmeta), 150.79 (d,
JPC ¼ 6.7 Hz, 4 Cipso). 31P NMR (161.98 MHz, CDCl3):
d ¼ 0.02 (s). HRMS (DART) C27H29N2O6P2 [M þ H]þ calc.
539.1422, found 539.1503.
Yield: 5%; yellow liquid. 1H NMR (500 MHz, CDCl3,
298ꢂK): d ¼ 1.32 (dt, JHH ¼ 7, 7.5 Hz, –OCH2CH3, 12H),
1.33–1.36 (m, 2H), 1.47–1.53 (m, 4H), 2.93–2.94 (m, 4H),
3.17–3.18 (m, NH, 2H), 4.05 (dq, JHH ¼ 7, JPOCH ¼ 7.5 Hz,
13
–OCH2CH3, 8H) ppm. C NMR (125 MHz, CDCl3, 298ꢂK):
d ¼ 15.82 (d, JP-C ¼ 8.1 Hz, –OCH2CH3, 4 C), 23.60 (s),
31.02 (d, JP-C ¼ 6.1 Hz, –CH2CH2CH2CH2–, 2 C), 41.42 (d,
JP-C ¼ 3 Hz, –CH2NP, 2 C), 62.62 (d, JP-C ¼ 4.7 Hz,
–OCH2CH3, 4 C)
O,O,O’,O’-tetraethyl butane-1,4-
diylbis(phosphoramidothioate) (15)
31P NMR (202 MHz, CDCl3): d ¼ 71.52 (s). HRMS
(DART) C13H33N2O4P2S2 [M þ H]þ calc. 407.1357,
found 407.1334.
Yield: 24%; yellow liquid. (lit [25]). 1H NMR (400 MHz,
CDCl3, 298ꢂK): d ¼ 1.28 (dt, JHH ¼ 6.9, 7.2 Hz, –OCH2CH3,
12H), 1.46–1.48 (m, 4H), 2.91–2.94 (m, 6H), 4.05 (dq,
JHH ¼ 6.9, JPOCH ¼ 7.2 Hz, –OCH2CH3, 8H) ppm. 13C
NMR (100 MHz, CDCl3, 298ꢂK): d ¼ 15.90 (d, JP-C ¼ 8.1 Hz,
Diphenyl (5-((diethoxyphosphorothioyl)
amino)pentyl)phosphoramidate (19)
–CH2CH3,
4 C),
28.60
(d,
JP-C
¼
6.1 Hz,
–CH2CH2CH2CH2–, 2 C), 41.25 (d, JPC ¼2.9 Hz, –CH2NP,
2 C), 62.81 (d, JPC ¼ 5.0 Hz, –OCH2CH3, 4 C) ppm. 31P
NMR (242.95 MHz, CDCl3): d ¼ 72.40 (s). HRMS (DART)
C12H31N2O4P2S2 [M þ H]þ calc. 393.1200, found 393.1198.
Yield: 3%; yellow liquid. 1H NMR (500 MHz, CDCl3,
298ꢂK):
d ¼ 1.25
(dt,
JHH
¼
6.5,
8.5 Hz,
–CH2CH2CH2CH2CH2–, 2H), 1.29 (dt, JHH ¼7, 14.5 Hz,
6H), 1.36–1-44 (m, 4H), 2.84 (dd, JHH ¼ 7, 14 Hz, 2H),
2.99–3.05 (m, 3H), 3.65–3.67 (m, OPNH), 3.99 (dq, JHH
7.2, JPOCH2 ¼ 14.0 Hz, OCH2CH3, 4H), 7.15 (dd, JHH
¼
¼
7.6 Hz, 2H), 7.25–7.33 (m, 8H). 13C NMR (125 MHz, CDCl3,
298ꢂK): d ¼ 15.90 (d, JPC ¼ 8.2 Hz, –CH2CH3, 2 C), 23.58 (s,
1 C), 31.03 (s, 2 C), 41.56 (s, 2 C), 62.74 (s, 2 C), 120.18 (d,
JPC ¼ 5 Hz, 4 Cortho), 124.88 (s, 2 Cpara), 129.68 (s, 4 Cmeta),
150.67 (s, 2 Cipso). 31P NMR (202 MHz, CDCl3): d ¼ ꢀ0.42
(s, P ¼ O), 71.64 (s, P ¼ S). FAB MS m/e 487(MHþ, 100);
found C21H33N2O5P2S1.
Diphenyl (4-((diethoxyphosphorothioyl)
amino)butyl)phosphoramidate (16)
Yield: 12%; yellow liquid. 1H NMR (400 MHz, CDCl3,
298ꢂK): d ¼ 1.27 (dt, JHH ¼ 7.2, 14.4 Hz, –OCH2CH3, 6H),
1.36–1.38 (m, –CH2CH2–, 4H), 2.78 (dt, JHH ¼ 4 Hz,
JSPOCH2 ¼10.4 Hz, SPNCH2–, 2H), 2.96 (dt, JHH ¼ 6.8,
JOPNHCH2 ¼ 10.8 Hz, OPNCH2–, 2H), 3.14–3.15 (m, SPNH),
3.98 (dq, JHH ¼ 7.2, JPOCH2 ¼ 14.0 Hz, OCH2CH3, 4H),
Tetraphenyl pentane-1,5-diylbis(phosphoramidate) (20)
4.12–4.13 (m, OPNH), 7.08 (dd, JHH
¼
7.6 Hz, 2H),
13
7.18–7.29 (m, 8H). C NMR (100 MHz, CDCl3, 298ꢂK):
d ¼ 15.90 (d, JPC ¼ 8 Hz, –OCH2CH3, 2 C), 28.22 (d,
JPC ¼ 6 Hz, –CH2CH2–, 2 C), 41.11 (1 C), 41.21 (1 C), 62.60
(d, JPC ¼ 4, OCH2CH3, 2 C), 120.10 (d, JPC ¼ 5 Hz,
4 Cortho), 124.80 (2 Cpara), 129.63 (4 Cmeta), 150.70 (d,
JPC ¼ 7 Hz, 2Cipso). 31P NMR (242.9 MHz, CDCl3): d ¼ 0.38
(s, P ¼ O), 72.31 (s, P ¼ S). HRMS (DART) C20H31N2O5P2S
[M þ H]þ calc. 473.1428, found 473.1439.
1
Yield: 5%; solid white; mp: 96–97 ꢂC. H NMR (500 MHz,
CDCl3, 298ꢂK): d ¼ 1.10 (dt, JHH ¼ 8, 15 Hz, 2H), 1.24–1.30
(m, 4H), 2.87 (dt, JHH ¼ 7, 13.5 Hz, 4H), 4.26 (dt, JPNH
¼
6.3 Hz, 2H, NH), 7.07 (dd, JHH¼ 7 Hz, 4H), 7.21–7.26 (m,
13
16H). C NMR (125 MHz, CDCl3, 298ꢂK): d ¼ 23.21 (s,
1 C), 30.37 (s, 2 C), 41.47 (s, 2 C), 119.88 (s, 8 Cortho), 124.83
(s, 4 Cpara), 129. 47 (s, 8 Cmeta), 150.99 (s, 4 Cipso). 31P NMR
(161.98 MHz, CDCl3): d ¼ 0.0 (s). FAB MS m/e 567(MHþ,
100); found C29H33N2O6P2.
Tetraphenyl butane-1,4-diylbis(phosphoramidate) (17)
O,O,O’,O’-tetraethyl hexane-1,6-
1
Yield: 14%; solid white; mp: 125-126 ꢂC. (lit [27]). H NMR
diylbis(phosphoramidothioate) (21)
(300 MHz, CDCl3, 298ꢂK): d ¼ 1.40–1.42 (m, 4H,
Yield: 2%; yellow liquid. 1H NMR (500 MHz, CDCl3,
298ꢂK): d ¼ 1.31–1.34 (m, 16H), 1.48–1.50 (m, 4H),
2.91–2.96 (m, 6H), 4.06 (dq, JHH ¼ 7.5, JPOCH ¼ 8 Hz,
–CH2CH2CH2CH2–), 3.03 (dd, JHH¼ 6.6 Hz, JPNCH
¼
6.8 Hz, 4H, –CH2NH), 3.25 (dt, JPNH ¼ 6.3 Hz, 2H, NH),
13
7.12–7.33 (m, 20H). C NMR (100 MHz, CDCl3, 298ꢂK):
13
–OCH2CH3, 8H) ppm. C NMR (125 MHz, CDCl3, 298ꢂK):
d ¼ 28.25 (d, JPC ¼ 5.9 Hz, 2 C, CH2CH2CH2CH2–), 41.26
(s, 2 C, –CH2NH), 120.20–120.21 (m, 8 C, Cortho), 124.93 (s,
4 Cpara), 129.70 (s, 8 Cmeta), 150.79 (d, JPC ¼ 6.6 Hz, 4 Cipso).
31P NMR (161.98 MHz, CDCl3): d ¼ ꢀ0.69 (s). HRMS
d ¼ 15.90 (d, JPC ¼ 8.3 Hz, –OCH2CH3, 4 C), 26.29 (s, 2 C),
31.44 (d, JPC ¼ 6.3 Hz, –CH2CH2CH2CH2CH2CH2–, 2 C),
41.52 (d, JPC ¼ 3.5 Hz, –CH2NP, 2 C), 62.79 (d, JPC
¼
5.1 Hz, –OCH2CH3, 4 C) ppm. 31P NMR (202 MHz, CDCl3):
d ¼ 72.3 (s). HRMS (DART) C14H35N2O4P2S2 [M þ H]þ
calc. 421.1513, found 421.1513.
(DART)
C28H31N2O6P2
[M þ H]þ
calc.
553.1657,
found 553.1666.

6
A. ZAMUDIO-MEDINA ET AL.
Diphenyl(6-((diethoxyphosphorothioyl)amino)hexyl)
phosphoramidate (22)
124.76 (2 Cpara), 129.60 (4 Cmeta), 150.88 (d, JPC ¼ 6.2 Hz,
2 Cipso). 31P NMR (202 MHz, CDCl3): d ¼ ꢀ0.23 (s, P ¼ O),
71.69 (s, P ¼ S). HRMS (DART) C23H37N2O5P2S [M þ H]þ
calc. 515.1898, found 515.1916.
1
Yield: 5%; solid white; mp: 42–43 ꢂC. H NMR (500 MHz,
CDCl3, 298ꢂK): d ¼ 1.15–1.23 (m, 2H), 1.25 (dt, JHH ¼ 7.2,
14.4 Hz, –OCH2CH3, 6H), 1.32–1.38 (m, 4H), 2.77–2.84 (m,
2H), 2.93–2.98 (m, 2H), 3.22–3.27 (m, SPNH), 3.95 (dq,
JHH ¼ 7.2, JPOCH2 ¼ 14.0 Hz, OCH2CH3, 4H), 4.02–4.13 (m,
OPNH), 7.08 (dd, JHH¼ 7.6 Hz, 2H), 7.20–7.28 (m, 8H). 13C
NMR (100 MHz, CDCl3, 298ꢂK): d ¼ 15.90 (d, JPC ¼ 8.7 Hz,
–OCH2CH3, 2 C), 26.10 (d, JPC ¼ 8.7 Hz, 2 C), 31.22 (d, JPC
¼ 6 Hz, 2 C), 41.50 (d, JPC ¼ 6.2 Hz, 2 C), 62.63 (d,
JPC ¼ 5, OCH2CH3, 2 C), 120.14 (d, JPC ¼ 5 Hz, 4 Cortho),
124.76 (2 Cpara), 129.60 (4 Cmeta), 150.88 (d, JPC ¼ 6.2 Hz,
2 Cipso). 31P NMR (202 MHz, CDCl3): d ¼ ꢀ0.23 (s, P ¼ O),
71.69 (s, P ¼ S). HRMS (DART) C22H35N2O5P2S [M þ H]þ
calc. 501.1741, found 501.1737.
Tetraphenyl heptane-1,7-diylbis(phosphoramidate) (26)
1
Yield: 5%; solid white; mp: 77–78 ꢂC. H NMR (500 MHz,
CDCl3, 298ꢂK): d ¼ 1.09–1.23 (m, 6H), 1.38 (dt, JHH ¼ 6,
13 Hz, 4H), 3.03 (dt, JHH ¼ 7, 14 Hz, 4H), 3.40 (dt, JPNH
¼
6.3 Hz, 2H, NH), 7.13–7.32 (m, 20H). 13C NMR (125 MHz,
CDCl3, 298ꢂK): d ¼ 26.33 (s, 1 C), 28.69 (s, 2 C), 31.20 (d,
JPC ¼ 6 Hz, 2 C), 41.70 (s, 2 C), 120.20 (s, 8 Cortho), 124.89
(s, 4 Cpara), 129. 69 (s, 8 Cmeta), 150.90 (d, JPC ¼ 6.7 Hz,
4 Cipso). 31P NMR (161.98 MHz, CDCl3): d ¼ ꢀ0.51 (s).
HRMS (DART) C31H37N2O6P2 [M þ H]þ calc. 595.2126,
found 595.2149.
Tetraphenyl hexane-1,6-diylbis(phosphoramidate) (23)
Cell culture
1
Yield: 4%; solid white; mp: 116–117 ꢂC. H NMR (500 MHz,
CDCl3, 298ꢂK): d ¼ 1.15–1.20 (m, 4H), 1.38 (dd, JHH ¼ 7,
15.5 Hz, 4H), 3.04 (dt, JHH ¼ 7, 15 Hz, 4H), 3.50 (dt, JPNH
¼ 6.3 Hz, 2H, NH), 7.14–7.34 (m, 20H). 13C NMR
(125 MHz, CDCl3, 298ꢂK): d ¼ 25.93 (s, 2 C), 31.20 (d,
JPC ¼ 6 Hz, 2 C), 41.54 (s, 2 C), 120.20 (s, 8 Cortho), 124.86
(s, 4 Cpara), 129. 66 (s, 8 Cmeta), 150.90 (d, JPC ¼ 6.7 Hz,
4 Cipso). 31P NMR (161.98 MHz, CDCl3): d ¼ ꢀ0.44 (s).
HRMS (DART) C30H35N2O6P2 [M þ H]þ calc. 581.1970,
found 581.1970.
Two human cancer cell lines were used for our inhibitory
tests, the lung adenocarcinoma cell line (A-549) and the
human bone chondrosarcoma cell line (SW 1353). Both cell
lines were purchased from ATCC (Manassas, VA, USA). A-
549 cells were cultured in RPMI-1640 medium (Sigma-
Aldrich, St. Louis, MO, USA), while SW-1353 cells were cul-
tured in Leibovitz’s L-15 medium, both media were supple-
mented with 10% heat-inactivated FCS (fetal calf serum,
Hyclone, Logan, UT, USA), 100 l/mL of penicillin and
100 lg/mL of streptomycin. Tumor cells were incubated in a
humidified chamber at 37 ꢂC with filtered atmospheric air
(21% oxygen) and 5% CO2.
O,O,O’,O’-tetraethyl heptane-1,7-
diylbis(phosphoramidothioate) (24)
Yield: 2%; yellow liquid. 1H NMR (500 MHz, CDCl3,
298ꢂK): d ¼ 1.28–1.30 (m, 6H), 1.33 (dt, JHH ¼ 7, 14 Hz,
12H), 1.47 (dt, JHH ¼ 11 Hz, 4H), 2.91–2.95 (m, 6H), 4.06
(dq, JHH ¼ 7.5, JPOCH ¼ 8 Hz, –OCH2CH3, 8H) ppm. 13C
NMR (125 MHz, CDCl3, 298ꢂK): d ¼ 15.95 (d, JP-C ¼ 8.5 Hz,
–OCH2CH3, 4 C), 26.57 (s, 1 C), 28.89 (s, 2 C), 31.44 (d,
JP-C ¼ 6.6 Hz, –CH2CH2CH2CH2CH2CH2CH2–, 2 C), 41.63
(d, JPC ¼ 3.6 Hz, –CH2NP, 2 C), 62.79 (d, JP-C ¼ 5.1 Hz,
–OCH2CH3, 4 C) ppm.31P NMR (202 MHz, CDCl3):
d ¼ 71.6 (s).
Conclusion
We designed an MCR strategy for the synthesis of biphos-
phoramidate and biphosphoramidothioate derivatives. This
new synthesis procedure requires low reaction times and is
carried out under standard conditions. Three different deriv-
atives are synthesized simultaneously: the symmetric biphos-
phoramidate and biphosphoramidothioate species and their
asymmetric counterpart, a phosphoramidate-phosphorami-
dothioate derivative. A total of 18 different compounds were
synthesized in this way, 10 of them for the first time.
Among the set of synthesized compounds, biphosphorami-
dates 12–14 showed significant cytotoxic activity against
SW-1353 cells. The overall yields can be considered low to
good, and these were affected to the low solubility of dia-
mines. Using this methodology, we are currently synthesiz-
ing new symmetric and asymmetric biphosphoramidates and
phosphoramidothioates, using diamines with different solu-
bility profiles, in different reaction media.
Diphenyl (7-((diethoxyphosphorothioyl)
amino)heptyl)phosphoramidate (25)
Yield: 5%; yellow liquid. 1H NMR (500 MHz, CDCl3,
298ꢂK): d ¼ 1.12–1.25 (m, 6H), 1.30 (dt, JHH ¼ 7.2, 14.4 Hz,
–OCH2CH3, 6H), 1.38–1.44 (m, 4H), 2.84–2.91 (m, 2H),
2.98–3.04 (m, 2H), 3.07–3.11 (m, SPNH), 3.65–3.71 (m,
OPNH), 4.05 (dq, JHH ¼ 7.2, JPOCH2 ¼ 14.0 Hz, –OCH2CH3,
4H), 7.15 (dd, JHH¼ 7.6 Hz, 2H), 7.24–7.33 (m, 8H). 13C
NMR (100 MHz, CDCl3, 298ꢂK): d ¼ 15.90 (d, JPC ¼ 8.7 Hz,
–OCH2CH3, 2 C), 26.10 (d, JPC ¼ 8.7 Hz, 2 C), 31.22 (d,
JPC ¼ 6 Hz, 2 C), 41.50 (d, JPC ¼ 6.2 Hz, 2 C), 62.63 (d, JPC
Disclosure statement
¼ 5, –OCH2CH3, 2 C), 120.14 (d, JPC ¼ 5 Hz, 4 Cortho), No potential conflict of interest was reported by the authors.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
[4] Dumitrascu, A.; Howell, B. Flame Retardant Polymeric
Materials Achieved by Incorporation of Styrene Monomers
Containing Both Nitrogen and Phosphorus. Polym. Degrad.
Stab. 2012, 97, 2611–2618. DOI: 10.1016/j.polymdegradstab.
2012.07.012.
Funding
ꢀ
ꢀ
This study was supported by Secretarıa de Investigacion y Posgrado del
Instituto Politecnico Nacional (SIP-IPN), for financial support (Grant
Nos. 20195476 and 20200192).
ꢀ
[5] Harry, R. H.; Max, P. An Approach to the Development of
Organophosphorus Fungicides. Phosphorus Sulfur Silicon Relat.
Elem. 1996, 109–110, 345–348.
[6] (a) Maretto, G. X.; Nascimento, C. P.; Passamani, L. M.;
Schenberg, L. C.; Andrade, T. U.; Figueiredo, S. G.; Mauad. H.;
Sampaio, K. N. Acute Exposure to the Insecticide O,S-Dimethyl
Phosphoramidothioate (Methamidophos) leads to Impairment
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