Green synthesis and cytotoxic activity of dibenzyl α-hydroxyphosphonates and α-hydroxyphosphonic acids

Article abstract of DOI:10.1002/hc.21436

A series of dibenzyl α-hydroxyphosphonates and the corresponding α-hydroxyphosphonic acids, mostly new compounds, have been synthesized. The dibenzyl α-hydroxyphosphonates have been obtained in the Pudovik reaction of substituted benzaldehydes and dibenzyl phosphite in the presence of triethylamine as the catalyst. The amount of the solvent was minimized during the reaction, and the workup involved crystallization from the reaction mixture. A new protocol was developed to transform the dibenzyl 1-hydroxyphosphonates to the corresponding phosphonic acids by catalytic hydrogenation. The derivatives prepared were screened as potential cytotoxic agents against Mes-Sa human uterine sarcoma cell line.

Full text of DOI:10.1002/hc.21436

Received: 31 May 2018
DOI: 10.1002/hc.21436
Accepted: 20 August 2018
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R E S E A R C H A R T I C L E
Green synthesis and cytotoxic activity of dibenzyl
α-hydroxyphosphonates and α-hydroxyphosphonic acids
Zita Rádai1
Petra Szeles1
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Nóra Zsuzsa Kiss1
László Hegedűs1
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|
|
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Tímea Windt2
Veronika Nagy2
György Keglevich1
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1Department of Organic Chemistry and
Technology, Budapest University of
Technology and Economics, Budapest,
Hungary
2Institute of Enzymology, Research Centre
for Natural Sciences, Hungarian Academy
of Sciences, Budapest, Hungary
Abstract
A
series of dibenzyl α-hydroxyphosphonates and the corresponding α-
hydroxyphosphonic acids, mostly new compounds, have been synthesized. The
dibenzyl α-hydroxyphosphonates have been obtained in the Pudovik reaction of
substituted benzaldehydes and dibenzyl phosphite in the presence of triethylamine as
the catalyst. The amount of the solvent was minimized during the reaction, and the
workup involved crystallization from the reaction mixture. A new protocol was de-
veloped to transform the dibenzyl 1-hydroxyphosphonates to the corresponding
phosphonic acids by catalytic hydrogenation. The derivatives prepared were screened
as potential cytotoxic agents against Mes-Sa human uterine sarcoma cell line.
Correspondence
György Keglevich, Department of Organic
Chemistry and Technology, Budapest
University of Technology and Economics,
Budapest, Hungary.
Email: gkeglevich@mail.bme.hu
Funding information
National Research Development and
Innovation Fund, Grant/Award Number:
K119202; Chinoin-Sanofi Pharmaceuticals;
József Varga Foundation; New National
Excellence Program of the Ministry of
Human Capacities, Grant/Award Number:
ÚNKP-17-4-I-BME-133
α-Hydroxyphosphonates are not only in the focus due
to their possible use in pharmacology, but they also repre-
1
INTRODUCTION
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The continuing interest in α-hydroxyphosphonates is owing
to the versatile bioactive effect of a series of compounds con-
taining this scaffold. A number of related derivatives were
identified as enzyme inhibitors,[1] pesticides,[2] and antibac-
terial,[3,4] antimicrobial,[5,6] or antifungal[3] agents, as well as
antioxidants,[7,8] which underline their importance in organo-
phosphorus chemistry. The investigation of their cytotoxic
effect is still in its infancy, as only one paper reported their
effectiveness against human cancer lines.[9]
sent a privileged class in modern synthetic chemistry, as
may be starting materials for a number of potentially bio-
active compounds. One of the most prominent classes of
α-hydroxyphosphonate derivatives is the family of the cor-
responding α-hydroxyphosphonic acids mainly known as the
inhibitors of CD45 tyrosine phosphatase[10] and undecaprenyl
diphosphate phosphatase (UPPP).[11] Related molecules were
also tested as potential inhibitors of P5C reductase[12] and as
possible ligands binding in the pocket of protein Src SH2.[13]
Contract grant sponsor: National Research Development and Innovation Fund
Contract grant number: K119202
Contract grant sponsor: Chinoin-Sanofi Pharmaceuticals
Contract grant sponsor: József Varga Foundation
Contract grant sponsor: New National Excellence Program of the Ministry of Human Capacities
Contract grant number: ÚNKP-17-4-I-BME-133
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Heteroatom Chemistry. 2018;e21436.
https://doi.org/10.1002/hc.21436
wileyonlinelibrary.com/journal/hc
© 2018 Wiley Periodicals, Inc.
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As for the syntheses of these valuable bioactive com-
pounds, the most frequently applied synthetic strategy to α-
hydroxyphosphonates is the nucleophilic addition of dialkyl
phosphites to an aldehyde or ketone.[14] Since the so-called
Pudovik reaction was first reported using alkali alcoholates
as the catalyst to deprotonate the >P(O)H reagent,[15] proce-
dures in the presence of a wide range of base catalysts, using,
for example, sodium ethylate in ethanol[16] were published.
Organic bases, such as quinine[17,18] and tetramethylguani-
dine,[19] were also proved to catalyze the Pudovik reaction. The
addition was also performed applying organometallic reagents
including butyl lithium,[20] lithium diisopropyl amide,[21]
and Grignard reagents.[22] Accomplishments applying
metal-amido complexes are also known.[23-27] Although the
use of base catalysts in the addition of dialkyl phosphite to
oxo compounds is more widespread, a few acid-catalyzed
procedures were also reported employing Lewis acid-like
MoO2Cl2,[28] NbCl5,[29] or Ti(OiPr)4.[30] According to another
protocol, the Pudovik reaction was performed on the sur-
face of silica-supported tungstic acid.[31] The appearance of
the principles of green chemistry brought about a paradigm
shift also in the synthesis of α-hydroxyphosphonates. Recent
articles targeted to perform the addition under mild and
solvent-free reaction conditions. These methods mainly em-
ployed simple and inexpensive oxides/bases/salts as catalysts,
including aluminum oxide,[32,33] magnesium oxide,[34-36]
barium hydroxide,[37,38] sodium carbonate,[39-41] potassium
hydrogen sulfate,[7] and inorganic phosphates,[42,43] as well
as triethylamine[44] or piperazine.[45] In a few cases, the com-
ponents were activated by grinding[41,45] or microwave (MW)
irradiation.[39,40,46,47] The new, environmentally friendly
protocols emphasize the lack of solvent during the reaction;
however, the use of volatile organic compounds could not be
eliminated from the workup process, as it comprised intensive
use of solvents in operations like extraction, column chroma-
tography, and recrystallization.
α-Hydroxyphosphonic acids are usually prepared from
the corresponding α-hydroxyphosphonates. One synthetic
route to α-hydroxyphosphonic acids involves the hydro-
lysis of α-hydroxyphosphonates in the presence of hydro-
chloric acid used in an excess.[11] Another widely applied
method is the fission of the C–O bond of the ester function
of α-hydroxyphosphonates using trimethylsilyl bromide,
followed by hydrolysis.[48-50] An oxidative method is also
known, starting from α-hydroxyalkyl-H-phosphinic acids,
employing I2/DMSO as the oxidizing system.[51] In most
cases, the main goal was to synthesize a potentially bio-
active target molecule, and the method itself represented
a secondary issue. As a consequence of this approach,
less attention was devoted to find the optimal conditions
of the reactions that usually remained excessive regarding
temperature, time, and amount of the reagents. A few of the
related articles came up with the idea of applying catalytic
hydrogenation for the synthesis of α-hydroxyphosphonic
acids starting from the corresponding benzyl phospho-
nates.[52-55] However, in most cases, the removal of the
benzyl groups is only one transformation of a multistep
synthesis; thus, the catalytic hydrogenation was not studied
in detail.
A new and benign method was developed for the synthesis
of α-hydroxyphosphonates starting from substituted benzalde-
hyde and dimethyl or diethyl phosphite by us.[56] Our protocol
employed triethylamine as an inexpensive catalyst and targeted
to minimize the use of organic solvents during the reaction, as
well as the work-up procedure, in contrast to the methods pre-
viously described in the literature. The new protocol under dis-
cussion allowed the preparation of α-hydroxyphosphonates by
a simple crystallization from the reaction mixture eliminating
the need for further purification steps.
Dimethyl and diethyl α-hydroxyphosphonates are ex-
tensively studied compounds; however, the synthesis of the
corresponding dibenzyl phosphonates has hardly been
investigated, as so far only a few papers reported their
synthesis.[57-60] Two dibenzyl α-hydroxyphosphonates were
synthesized on the surface of Al2O3-KF.[57] Extraction with
CH2Cl2 afforded the products in low yields of 50%. The same
method was used for the preparation of another derivative in a
resolution study.[58] In another article,[59] not any detail on the
preparation was provided. Finally, reference[60] covers a pro-
cedure that involves the use of an exotic V-containing catalyst,
and the workup may involve recrystallization or column chro-
matography to afford the hydroxyphosphonates in yields of
84%-92%. Prompted by the recognition that a green synthetic
route toward dibenzyl α-hydroxyphosphonates is still missing
from the literature, we aimed at the extension of our method
starting from dibenzyl phosphite and substituted benzalde-
hydes to prepare dibenzyl α-hydroxyphosphonates as new
compounds. We also wished to transform the derivatives
so obtained to the corresponding α-hydroxyphosphonic acids
by hydrogenolytic debenzylation, making thus available two
series of potentially cytotoxic compounds. The investiga-
tion of the anticancer effect of α-hydroxyphosphonates is a
pioneering work, as their cytotoxic activity was studied only
in one case, but on other cell lines that we aimed at in our
study.[9]
2
RESULTS AND DISCUSSION
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At first, dibenzyl α-hydroxyphosphonates (1) were syn-
thesized from substituted benzaldehydes and dibenzyl
phosphite by the extension of our method reported pre-
viously.[56] An equimolar mixture of the starting compo-
nents was stirred at reflux in a minimal amount of acetone
(1 mL for 11.0 mmol benzaldehyde) in the presence of
10 mol% triethylamine as the catalyst (Scheme 1). The

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1.) , 0.5-6.5 h
∆
OH
0.1
Et N
equiv.
OBn
OBn
3
CHO
+ HP(OBn)2
O
acetone
P
O
pentane, 5 °C
2.)
Y
Y
3.) crystallization
1
SCHEME 1 A solvent-economic,
green protocol for the synthesis of dibenzyl
α-hydroxyphosphonates (1a-i)
a
b
c
d
e
f
g
h
i
Y = H ( ), 2-Cl ( ), 3-Cl ( ), 4-Cl ( ), 2-NO2 ( ), 4-NO2 ( ), 3-Me ( ), 4-Me ( ), 2-MeO ( )
reaction times depended highly on the substituent in the
aromatic ring. The reaction of benzaldehyde and dibenzyl
phosphite was completed after 0.5 hours (Table 1, entry 1).
Aryl aldehydes with electron-withdrawing chloro and nitro
substituents were of similar reactivity, requiring a reaction
time of 0.5 hours (Table 1, entries 2-6). However, starting
from aryl aldehydes bearing electron-donating substitu-
ents, a longer reaction time was necessary. In case of tolu-
aldehydes, completion of the reaction required 5.5 hours
(Table 1, entries 7 and 8). 2-Methoxybenzaldehyde re-
vealed the lowest reactivity, as in this case, the amount
of the catalyst had to be increased to 20 mol%, and
completion of the addition required 6.5 hours (Table 1, entry
9). The workup included the addition of pentane (6 mL),
followed by cooling the reaction mixture to 5°C. The
product crystallized from the reaction mixture on cooling.
The dibenzyl α-hydroxyphosphonates (1a-i) were obtained
by a simple filtration in yields of 88%-99%, in a purity of
>99%.
After the synthesis of dibenzyl α-hydroxyphosphonates
(1a-i), we aimed at the preparation of α-hydroxyphosphonic
acids (2a-i) by catalytic hydrogenation of the corresponding
benzyl phosphonates under mild conditions, as an alternative
route to classical hydrolysis. The hydrogenation reactions
were performed using 10% Pd/C (with a catalyst/substrate
ratio of 0.05 g/g) in methanol at 25°C and 10 bar (Scheme 2).
In all but one cases, the reactions took place rather
easily, and a short reaction time of 5-15 minutes was sufficient
(Table 2). With one exception, the α-hydroxyphosphonic
acids were obtained in yields of 72%-90% after purification.
In case of dibenzyl 1-hydroxy-1-(4-nitrophenyl)
-methylphosphonate (1f), in the first 2 minutes the hydro-
gen uptake was as fast as in the other cases. After 2 minutes,
the hydrogen uptake slowed down dramatically and lasted
for 2.5 hours. The longer reaction time and higher hydrogen
uptake are due to the reduction of the nitro function in the
aromatic ring taking place in parallel to the debenzylation.
The product so-obtained was 1-(4-aminophenyl)-1-hydro-
xymethylphosphonic acid (2j). It is worthy to mention that
interrupting the catalytic hydrogenation, different intermedi-
ates could be pointed out from the mixture making use of 31
NMR analysis (Table 3).
P
The catalytic debenzylation is a more robust and efficient
way for the preparation of α-hydroxyphosphonic acids than
the traditional acidic hydrolysis.
All together, nine dibenzyl α-hydroxyphosphonates and
eight α-hydroxyphosphonic acids were synthesized. The new
derivatives, four α-hydroxyphosphonates (1b, 1c, 1e, and 1g)
and four α-hydroxyphosphonic acids (2j, 2g-i), were fully
characterized by 31P, 13C, and 1H NMR, as well as HRMS data
by us. 1a, 1d, 1f, 1h, and 1i already known from the literature
were identified by 31P NMR chemical shifts and HRMS data.
α-Hydroxyphosphonic acids 2a-d were mentioned in the litera-
ture; however, their characterization remained incomplete. For
this, they were also characterized by us by 13C NMR data. It is
noted that a part of the hydroxyphosphonic acids (2b, 2c, 2j,
TABLE 1 Experimental details for the preparation of dibenzyl
α-hydroxyphosphonates (1a-i)
Entry
Y
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
H
2-Cl
3-Cl
4-Cl
2-NO2
4-NO2
3-Me
4-Me
2-MeO
0.5
0.5
0.5
0.5
0.5
0.5
5.5
5.5
6.5a
1a
1b
1c
1d
1e
1f
1g
1h
1i
95
93
88
95
91
99
88
94
96
25 °C, 5-150 min
OH
OH
H2
OBn
OBn
OH
OH
10% Pd/C (Selcat Q)
P
O
P
O
MeOH
Y
Y
1
2
a
b
c
d
f
Y = H ( ), 2-Cl ( ), 3-Cl ( ), 4-Cl ( ), 4-NO2 ( )
g
h
i
j
3-Me ( ), 4-Me ( ), 2-MeO ( ), 4-NH2 ( )
SCHEME 2 Catalytic hydrogenation of dibenzyl α-
hydroxyphosphonates (1a-i)
aIn this case, 20 mol% of triethylamine was used.

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TABLE 2 Experimental details for the
Entry
Y
Starting HP
Time (min)
Product
Yield (%)
preparation of α-hydroxyphosphonic acids
1
2
3
4
5
6
7
8
H
2-Cl
3-Cl
4-Cl
4-NO2
3-Me
4-Me
2-MeO
1a
1b
1c
1d
1f
1g
1h
1i
15
10
5
7
150
9
2a
2b
2c
2d
80
85
76
88
50a
77
90
72
2j (Y = NH2)
2g
2h
2i
9
5
aDue to insolubility in methanol, 2j was purified only by digeration in dichloromethane.
TABLE 3 The course of the catalytic
hydrogenation of dibenzyl 1-hydroxy-1-(4-
nitrophenyl)-methylphosphonate (1f)
Time (min)
Components (%)a
2
15
150
12
10
0
OH
N
O2
O
P
BnO
P 21.4
OBn
δ
51
48
0
0
b
OH
N
O2
O
P
BnO
P 17.2
OH
δ
37
0
29
13
OH
N
O2
O
P
HO
P 16.4
OH
δ
100 (Yield: 50%)
H
O
H2N
O
P
H
O
H
O
δ
P 19.2
aDetermined on the basis of relative 31P NMR intensities from the crude mixtures (DMSO-d6).
bHRMS: [M − H]−found = 322.04790. C14H13NO6P requires 322.04860.
and 2g) could not be identified by MS analysis due to their de-
composition under the conditions of the measurements. A few
derivatives (2a, 2d, 2h, and 2i) appeared as dimers [2M + H].
passed to the second step. As confirmatory cytotoxicity tests,
“hit” compounds were tested using a concentration range
(extending from 500 μmol/L down to 7.62 nmol/L in 3-fold
dilutions) in order to obtain dose-response curves (Figure 2).
Via similar screening approaches that were applied here,
potent cancer targeting compounds have been identified
previously.[61-63]
2.1
Primary and confirmatory screening
|
assay on 384-well plates
All compounds were dissolved in DMSO and stored at
−20°C. To determine growth inhibitory potential, we
conducted the cytotoxicity experiments in two steps. As
a primary screen, each compound was tested at a final
concentration of 20 and 200 μmol/L to exclude nontoxic
compounds (Figure 1). Compounds that showed 50% growth
inhibition in 200 μmol/L were scored as “hits” and were
The primary screen returned 8 compounds showing at
least 50% growth inhibition at 200 μmol/L. When 20 μmol/L
of the 17 compounds was added to the cell line, none of them
could kill at least 50% of the cells.
The cytotoxic compounds were all dibenzyl α-
hydroxyphosphonates, while the nontoxic compounds be-
long all to the group of α-hydroxyphosphonic acids, with

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α-hydroxyphosphonates are promising, as the in vitro cytotoxic
activity in general was within the range of the effect (expressed
as IC50 values) of three well-known chemotherapeutics, which
we also tested against the Mes-Sa cell line and which are typi-
cally applied to treat uterine sarcoma (doxorubicin, 0.36 μmol/L;
carboplatin, 24.8 μmol/L; dacarbazine, 349.8 μmol/L).[64-66]
However, the in vivo tolerability of these structures has to be
evaluated. Our future aim will be to assess the effects of the
α-hydroxyphosphonates on different cancer types and their pos-
sible impact on drug resistance, and, moreover, to reveal the
possible intracellular targets of these compounds.
3
CONCLUSION
|
FIGURE 1 Cytotoxicity of the synthesized compounds against
Mes-Sa mCherry cell line. Growth inhibition of the compounds at
200 μmol/L concentration in the primary screen
In conclusion, two reactions were realized using green
methods. At first, the Pudovik reaction of substituted al-
dehydes and dibenzyl phosphite was performed to obtain
dibenzyl α-hydroxyphosphonates (1a-i) including four new
compounds in a simple way. The main novelty of this protocol
is that the excessive use of organic solvents during the workup
procedures can be avoided by applying a few mLs of ace-
tone and pentane during the synthesis. The method involves
a one-pot synthesis and a crystallization step. The dibenzyl
α-hydroxyphosphonates (1a-i) were transformed to the cor-
responding α-hydroxyphosphonic acids (2a-j) by catalytic
hydrogenation.Alloftheninedibenzylα-hydroxyphosphonates
(1a-i) and eight α-hydroxyphosphonic acids (2a-g and 2j)
were tested against the Mes-Sa uterine sarcoma cell line, and
eight of the hydroxyphosphonates showed promising cyto-
toxic effect.
FIGURE 2 IC50 values of the compounds exerting at least 50%
growth inhibition in the primary screen
4
EXPERIMENTAL
|
4.1
General information
|
the exception of species 1d that showed only 31% growth
inhibition, albeit it belongs to the former group. Interestingly,
hydroxyphosphonates 1d and 1h having a chloro or a methyl
substituent in the para position of the aromatic ring were
the least toxic among the dibenzyl α-hydroxyphosphonates,
while their ortho- and meta-substituted analogues were more
toxic.
During the preliminary cytotoxicity assays, dimethyl and
diethyl α-hydroxybenzylphosphonates were also measured in a
concentration of 200 μmol/L. None of the more than 25 methyl
and ethyl esters showed remarkable cytotoxic effect. Therefore, it
is concluded that only the benzyl esters display anticancer effect.
Taken together, dibenzyl α-hydroxyphosphonates show
moderate, but significant anticancer cytotoxicity, with the low-
est IC50 value of 69.5 μmol/L exerted by compound 1c. As ob-
served, the position of the substituent of the aromatic ring might
have a greater impact on the cytotoxicity than the substituents
(Cl, NO2, Me, OMe) themselves. The results obtained on the
The 31P, 13C, and H NMR spectra were taken on a Bruker
Avance 300 as well as a Bruker DRX 500 instrument. 1H-15N
HMBC (heteronuclear multiple bond connectivity) spectrum
was measured on a Bruker Avance III HDX 800 instrument;
15N chemical shift is given in parts per million relative to neat
nitromethane. The exact mass measurements were performed
using a Q-TOF Premier mass spectrometer in positive or
negative electrospray mode.
1
The cytotoxic activity of the compounds was investigated
against Mes-Sa, a human uterine sarcoma cell line, purchased
from ATCC. Mes-Sa cells were engineered to stably express
the mCherry fluorescent protein using a lentiviral system.[61]
Mes-Sa mCherry cell line was cultivated in DMEM (Sigma-
Aldrich, Hungary) supplemented with 10% fetal bovine serum,
5 mmol/L glutamine, and 50 unit/mL penicillin and streptomy-
cin (Life Technologies), and was kept at 37°C, under 5% CO2
atmosphere.

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128.44 and 128.48 (C4′), 128.51 and 128.55 (C3′), 129.4
(d, 4J 2.7, C5)*, 134.2 (d, 4J 3.0, C3), 135.8 (d, 3J 5.9, C1′),
138.4 (C1); δH (500.1 MHz, CDCl3) 4.76-5.13 (6H, m,
2×OCH2, PCH, OH), 7.15-7.47 (14H, m, Ar), *may be re-
versed; [M + H]+, found 403.0881. C21H20O4PCl requires
403.0860.
4.2
General procedure
|
for the synthesis of dibenzyl 1-hydroxy-1-
phenylmethylphosphonates (1a-i)
A mixture of 11.0 mmol of substituted benzaldehyde
(benzaldehyde: 1.2 g, 3-methylbenzaldehyde: 1.3 g,
4-methylbenzaldehyde: 1.3 g, 2-methoxybenzaldehyde:
1.5 g, 2-chlorobenzaldehyde: 1.5 g, 3-chlorobenzaldehyde:
1.5 g, 4-chlorobenzaldehyde: 1.5 g, 2-nitrobenzaldehyde:
1.7 g, 4-nitrobenzaldehyde: 1.7 g), 11.0 mmol (2.4 mL) of
dibenzyl phosphite, and 1.1 mmol (153 μL) of triethylamine
was stirred in acetone (1.0 mL) at reflux for 0.5-6.5 hours
(for details, see Table 1). After adding pentane (6.0 mL),
the reaction mixture was cooled to 5 °C. On cooling, the
product crystallized from the reaction mixture. A simple
filtration afforded products 1a-i in yields of 88%-99% and
in purity of >99% (Table 1).
4.3.4
Dibenzyl 1-(4-chlorophenyl)-1-
|
hydroxymethylphosphonate (1d)
Yield: 95%; δP (121.5 MHz, CDCl3) 21.7; δP,[li5t9(]161.0 MHz,
CDCl3)[59] 22.4; Mp: 132-133°C; Mplit
: 126-128;
[M + H]+, found 403.0869. C21H20O4PCl requires 403.0860.
4.3.5
Dibenzyl 1-hydroxy-1-(2-
|
nitrophenyl)-methylphosphonate (1e)
Yield: 91%; δP (121.5 MHz, CDCl3) 21.1; δC (75.5 MHz,
1
2
CDCl3) 66.0 (d, J 160.0, PCH), 68.7 (d, J 7.5, OCH2),
4.3
Characterization data for products 1
Dibenzyl 1-hydroxy-1-
|
2
4
69.2 (d, J 7.3, OCH2), 124.7 (d, J 2.5, C3), 127.8 and
3
128.0 (C2′), 128.3-128.5 (m, C4′, C4, C3′), 129.1 (d, J 4.6,
4.3.1
|
2
4
C6), 132.7 (d, J 1.1, C1), 133.4 (d, J 3.0, C5), 135.7 (d,
phenylmethylphosphonate (1a)
3J 5.4, C1′), 135.8 (d, J 5.6, C1′), 147.4 (d, J 6.1, C2); δH
3
3
3
Yield: 95%; δP (121.5 MHz, CDCl3) 22.1; δP,lit (161.0 MHz,
CDCl3)[59] 22.4; Mp: 104-105°C; Mplit[59]: 117-118; δH
(500.1 MHz, CDCl3) 4.84-4.99 (4H, m, 2×OCH2), 5.06 (1H,
d, 2JP,H 10.4, PCH), 7.17-7.49 (15H, m, Ar); [M + H]+, found
369.1256. C21H21O4P requires 369.1250.
(500.1 MHz, CDCl3) 4.93 (2H, ~d, JP,H 8.4, OCH2) 4.97-
2
5.07 (2H, m, OCH2), 6.28 (1H, d, JP,H 14.3, PCH), 7.13-
7.34 (10H, m, 2×CH2Ph), 7.39-7.44 (1H, m, H4), 7.57-7.63
3
(1H, m, H5), 7.92 (1H, ~d, JH,H 7.9, H6)*, 7.95 (1H,
~d, JH,H 8.2, H3)*, *may be reversed; [M + H]+, found
3
414.1114. C21H20NO6P requires 414.1101.
4.3.2
Dibenzyl 1-(2-chlorophenyl)-1-
|
hydroxymethylphosphonate (1b)
4.3.6
Dibenzyl 1-hydroxy-1-(4-
|
nitrophenyl)-methylphosphonate (1f)
Yield: 93%; δP (121.5 MHz, CDCl3) 21.9; δC (125.8 MHz,
1
2
CDCl3) 67.2 (d, J 161.2, PCH), 68.4 (d, J 7.2, OCH2),
Yield: 99%; δP (121.5 MHz, CDCl3) 20.8; δP,lit
2
4
(161.0 MHz, CDCl3)[59] 20.6; Mp: 104-105°C; Mplit
:
[59]
68.7 (d, J 7.2, OCH2), 127.0 (d, J 3.1, C5), 127.8 and
127.9 (C2′), 128.25 and 128.29 (C4′), 128.39 and 128.43
87-88; [M + H]+, found 414.1105. C21H20NO6P requires
414.1101.
3
(C3′), 129.2-129.4 (m, C3, C4, C6), 133.0 (d, J 8.3, C2),
3
134.7 (C1), 136.0 (d, J 5.9, C1′); δH (500.1 MHz, CDCl3)
2
4.68-5.23 (5H, m, 2×OCH2, OH), 5.69 (1H, d, JP,H
4.3.7
Dibenzyl 1-hydroxy-1-(3-
|
11.2, PCH), 7.16-7.34 (13H, m, Ar), 7.73-7.80 (1H, m,
H3); [M + H]+, found 403.0869. C21H20O4PCl requires
403.0860.
methylphenyl)methylphosphonate (1g)
Yield: 88%; δP (121.5 MHz, CDCl3) 22.3; δC (75.5 MHz,
CDCl3) 21.4 (CH3), 68.3 (d, 2J 7.2, OCH2), 68.5 (d, 2J 7.1,
OCH2), 71.1 (d, 1J 158.7, PCH), 124.3 (d, 3J 6.0, C6), 127.8-
128.0 (m, C2′, C2), 128.2 (d, 4J 2.5, C5)*, 128.28 and 128.31
4.3.3
Dibenzyl 1-(3-chlorophenyl)-1-
|
5
(C4′3), 128.4 and 128.5 (C3′), 128.9 (d, J 3.2, C4)*, 136.1
hydroxymethylphosphonate (1c)
4
(d, J 6.1, C1′), 136.1-136.3 (m, C1′, C1), 137.9 (d, J 2.6,
Yield: 88%; δP (121.5 MHz, CDCl3) 22.3; δC (75.5 MHz,
C3); δH (300.1 MHz, CDCl3) 2.30 (3H, s, CH3), 4.83-5.07
(5H, m, 2×OCH2, PCH), 7.06-7.42 (14H, m, Ar), *may be
reversed; [M + H]+, found 383.1409. C22H23O4P requires
383.1407.
2
2
CDCl3) 68.5 (d, J 7.4, OCH2), 68.9 (d, J 7.2, OCH2),
1
3
3
70.4 (d, J 159.0, PCH), 125.3 (d, J 5.7, C6), 127.3 (d, J
5
5.7, C2), 127.90 and 127.92 (C2′), 128.2 (d, J 3.4, C4)*,

RÁDAI et Al.
7 of 9
|
4.3.8
Dibenzyl 1-hydroxy-1-(4-
4.5.2
1-(2-Chlorophenyl)-1-
|
|
methylphenyl)methylphosphonate (1h)
hydroxymethylphosphonic Acid (2b)
Yield: 94%; δP (121.5 MHz, CDCl3) 22.4; δP,lit (161.0 MHz,
CDCl3)[59] 22.4; Mp: 110-111°C; Mplit[59]: 87-88; [M + H]+,
found 383.1392. C22H23O4P requires 383.1407.
Yield: 85%; δP (121.5 MHz, D2O) 18.5; δP,lit (121.5 MHz,
D2O)[12] 16.3; δC (75.5 MHz, D2O) 66.8 (d, 1J 159.3, PCH),
4
3
5
127.0 (d, J 2.8, C5), 128.5 (d, J 4.2, C6), 129.1 (d, J 2.2,
C4)*, 129.2 (d, 4J 2.9, C3)*, 132.2 (d, 3J 8.0, C2), 135.0 (C1);
2
δH (300.1 MHz, D2O) 5.38 (1H, d, JP,H 12.9, PCH), 7.16-
4.3.9
Dibenzyl 1-hydroxy-1-(2-
|
7.39 (3H, m, Ar), 7.51-7.59 (1H, m, H3); dH,lit (300.1 MHz,
methoxyphenyl)methylphosphonate (1i)
D2O)[12] 4.92 (1H, d, JP,H 12.6, PCH), 7.05 (3H, m, ArH),
2
Yield: 96%; δP (121.5 MHz, CDCl3) 22.9; δP,lit (161.0 MHz,
CDCl3)[59] 22.9; Mp: 91-92°C; Mplit[59]: 99-101; δH
(500.1 MHz, CDCl3) 3.58 (1H, br, OH), 3.70 (3H, s, OCH3),
4.79-4.97 (2H, m, OCH2) 5.01-5.12 (2H, m, OCH2), 5.46
7.40 (1H, d, 3JH,H 7.5, ArH).
4.5.3
1-(3-Chlorophenyl)-1-
|
hydroxymethylphosphonic Acid (2c)
2
3
(1H, d, JP,H 12.1, PCH), 6.84 (1H, ~d, JH,H 8.3, H3), 6.97
3
(1H, ~t, JH,H 7.5, H5), 7.15-7.20, 7.27-7.37 and 7.46-7.52
Yield: 76%; δP (121.5 MHz, D2O) 18.2; δP,lit (121.5 MHz,
D2O)[12] 20.1; δC (75.5 MHz, D2O) 70.2 (d, 1J 157.0, PCH),
125.2 (d, 3J 4.8, C6)*, 126.7 (d, 3J 4.9, C2)*, 127.8 (C4), 129.7
(C5), 133.4 (d, 4J 1.9, C3), 139.6 (C1); δH (300.1 MHz, D2O)
(12H, m, Ar); [M + H]+, found 399.1378. C22H23O5P re-
quires 399.1356.
2
4.85 (1H, d, JP,H 12.8, PCH), 7.24-7.42 (4H, m, Ar), δH,lit
4.4
General procedure for the synthesis of
2
(300.1 MHz, D2O)[12] 4.90 (1H, d, JP,H 12.9, PCH), 7.29
|
1-hydroxy-1-phenylmethylphosphonic acids
(2a-j)
(3H, s, ArH), 7.41 (1H, s, ArH).
α-Hydroxyphosphonates (4.1 mmol, 1a: 1.5 g, 1b: 1.7 g,
1c: 1.7 g, 1d: 1.7 g, 1f: 1.7 g, 1g: 1.6 g, 1h: 1.6 g, 1i:
1.6 g) were hydrogenated in the presence of 10% Pd/C
(Selcat Q) (with a catalyst/substrate ratio of 0.05 g/g,
0.08-0.09 g) in methanol (30 mL) in a 80-mL stainless
steel autoclave equipped with a magnetic stirrer (stir-
ring speed = 1100 rpm). The hydrogenations took place
at 10 bar and 25°C in 5-150 minutes. Then, the catalyst
was filtered off, and activated carbon (0.15-0.17 g) was
added to the solution. After a 1-h stirring, the absorbent
was filtered off, and the organic solvent was evaporated.
The crude product so-obtained was dissolved in CH2Cl2
(5 mL) and stirred for 15 minutes at reflux. After filtra-
tion, α-hydroxyphosphonic acids were obtained in yields
of 50%-90%, in a purity of >98.5% (Table 2).
4.5.4
1-(4-Chlorophenyl)-1-
|
hydroxymethylphosphonic Acid (2d)
Yield: 88%; δP (121.5 MHz, D2O) 18.6; δP,lit (121.5 MHz,
D2O)[12] 18.9; δC (125.8 MHz, D2O) 70.2 (d, 1J 158.5, PCH),
128.4 (d, 4J 2.3, C3), 128.5 (d, 3J 5.7, C2), 133.3 (d, 2J 3.7, C1),
136.1 (d, 5J 2.1, C4); δH (500.1 MHz, D2O) 4.87 (1H, d, 2JP,H
12.5, PCH), 7.27-7.35 (4H, bs, Ar); δH,lit (300.1 MHz, D2O)[12]
4.75 (1H, d, JP,H 12.6, PCH), 7.21 (4H, s, Ar); [2M − H]−,
2
found 442.9659. C14H16O8P2Cl2 requires 442.9625.
4.5.5
1-(4-Aminophenyl)-1-
|
hydroxymethylphosphonic Acid (2j)
Yield: 50%; δP (121.5 MHz, DMSO-d6) 18.4; δC (125.8 MHz,
1
4
DMSO-d6) 70.5 (d, J 158.6, PCH), 126.8 (d, J 2.6, C3),
3
2
127.4 (d, J 5.4, C2), 127.5 (d, J 1.8, C1), 140.2 (C4); δH
(500.1 MHz, DMSO-d6) 4.66 (1H, d, 2JP,H 13.9, PCH), 7.19-
7.42 (4H, m, Ar); δN (80.1 MHz, DMSO-d6+TFA): −336.6.
4.5
Characterization data for products 2
1-Hydroxy-1-
|
4.5.1
|
phenylmethylphosphonic Acid (2a)
4.5.6
1-Hydroxy-1-(3-methylphenyl)-
|
Yield: 80%; δP (121.5 MHz, D2O) 19.4; δP,lit (121.5 MHz,
methylphosphonic Acid (2g)
1
CDCl3)[58] 22.4; δC (125.8 MHz, D2O) 70.7 (d, J 158.5,
3
4
PCH), 127.1 (d, J 5.8, C2), 128.2 (d, J 3.0, C3), 128.5 (d,
5J 2.3, C4), 137.1 (C1); δH (500.1 MHz, D2O) 4.88 (1H, d,
2JP,H 12.3, PCH), 7.23-7.38 (5H, m, Ar); [2M + H]+, found
377.0545. C14H18O8P2 requires 377.0550.
Yield: 77%; δP (121.5 MHz, D2O) 19.8; δC (125.8 MHz,
1
3
D2O) 20.4 (CH3), 70.9 (d, J 160.0, PCH), 124.1 (d, J 5.7,
C6), 127.7 (d, 3J 5.8, C2), 128.4 (d, 4J 2.3, C5)*, 128.7 (C4)*,
137.4 (C1), 138.5 (d, 4J 2.1, C3); δH (500.1 MHz, D2O) 2.25

8 of 9
RÁDAI et Al.
|
(3H, s, CH3), 4.84 (1H, d, 2JP,H 12.3, PCH), 7.10-7.26 (4H, m,
Ar), *may be reversed.
Research Department, Gedeon Richter Plc.) for providing
1H-15N HMBC spectral data of 2j.
4.5.7
1-Hydroxy-1-(4-methylphenyl)-
ORCID
|
methylphosphonic Acid (2h)
László Hegedűs
http://orcid.org/0000-0002-7980-0443
http://orcid.
Yield: 90%; δP (121.5 MHz, D2O) 18.8; δC (125.8 MHz, D2O)
György Keglevich
org/0000-0002-5366-472X
1
3
20.2 (CH3), 70.9 (d, J 157.8, PCH), 127.2 (d, J 5.6, C2),
129.0 (C3), 134.6 (C1), 138.3 (d, 5J 3.1, C4); δH (300.1 MHz,
D2O) 2.25 (3H, s, CH3), 4.83 (1H, d, 2JP,H 12.0, PCH), 7.13-
7.33 (4H, m, Ar); [2M − H]−], found 403.0751. C16H22O8P2
requires 403.0717.
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1-Hydroxy-1-(2-methoxyphenyl)-
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How to cite this article: Rádai Z, Szeles P, Kiss NZ,
et al. Green synthesis and cytotoxic activity of
dibenzyl α-hydroxyphosphonates and
α-hydroxyphosphonic acids. Heteroatom Chem.
2018;e21436. https://doi.org/10.1002/hc.21436
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Sulfur Silicon 2013, 188, 819.
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