[1-Hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates and -phosphinates: Convenient synthesis through intramolecular Abramov reaction and protective activity against influenza A

Article abstract of DOI:10.1016/j.tet.2013.11.007

A combination of intramolecularization and tandem reaction methodologies has been applied to the synthesis of diethylammonium[1-hydroxy-1-(2- hydroxyphenyl)ethyl]phosphonates and -phosphinates, which were found to be unavailable through a standard intermolecular hydrophosphonylation/hydrolysis sequence. A mild hydrolysis of amidophosphites and -phosphonites, bearing 2-acetylphenoxy-fragment and a hydrolytically labile diethylamino-group at the same trivalent phosphorus atom, directly afforded the title compounds. The overall process probably consists of three steps: (i) selective hydrolysis of the P(III)-N bond to generate the hydrophosphoryl-type intermediates; (ii) formation of the strained 2-substituted 3-hydroxy-2-oxo-2,3-dihydro-1,2- benzoxaphospholes through intramolecular Abramov reaction; (iii) hydrolysis of the endocyclic P(IV)-O bond in the 1,2-benzoxaphospholes to give the acyclic products. Being only modestly active in vitro, at high dosage non-toxic water-soluble title α,γ-dihydroxyphosphonates and -phosphinates exhibited beneficial, but short-lasting effect against experimental influenza A infection (H3N2) in mice.

Full text of DOI:10.1016/j.tet.2013.11.007

Tetrahedron 69 (2013) 11109e11115
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
[1-Hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates
and -phosphinates: convenient synthesis through intramolecular
Abramov reaction and protective activity against influenza A
,
b
Edward E. Korshin a , Oskar K. Pozdeev
*
a Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
b Department of Microbiology, Kazan State Medical University, 49 Butlerov Str., Kazan 420012, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A combination of intramolecularization and tandem reaction methodologies has been applied to the
synthesis of diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates and -phosphinates,
which were found to be unavailable through a standard intermolecular hydrophosphonylation/hydro-
lysis sequence. A mild hydrolysis of amidophosphites and -phosphonites, bearing 2-acetylphenoxy-
fragment and a hydrolytically labile diethylamino-group at the same trivalent phosphorus atom, directly
afforded the title compounds. The overall process probably consists of three steps: (i) selective hydrolysis
of the P(III)eN bond to generate the hydrophosphoryl-type intermediates; (ii) formation of the strained
2-substituted 3-hydroxy-2-oxo-2,3-dihydro-1,2-benzoxaphospholes through intramolecular Abramov
reaction; (iii) hydrolysis of the endocyclic P(IV)eO bond in the 1,2-benzoxaphospholes to give the acyclic
Received 12 September 2013
Received in revised form 23 October 2013
Accepted 4 November 2013
Available online 13 November 2013
Keywords:
One-pot synthesis
Domino reactions
Ketones
Hydrophosphonylation
Antiviral activity
products. Being only modestly active in vitro, at high dosage non-toxic water-soluble title
a,g-dihy-
droxyphosphonates and -phosphinates exhibited beneficial, but short-lasting effect against experimental
influenza A infection (H3N2) in mice.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
impregnated by KF or CsF,12 impregnated natural phosphates and
fluoroapatites,13 homogeneous catalysis by moderately basic com-
Ternary
a
-hydroxyphosphonates and the parent
a
-hydrox-
plex of Et3N with MgCl214 or by alkaloid organocatalysts.15 In 2012,
Abramov addition to acetophenones and some aliphatic ketones
was found to proceed efficiently at rt in the presence of TMS2N-
supported rare earth complexes with calix[4]-pyrrolyl-ligand16 or
more structurally simple 2-(arylaminomethyl)pyrrolyl-ligand.17
Intermolecular hydrophosphonylation of acetophenones and even
benzophenones was also accomplished using TMS2N-supported
alkaline earth complexes of sterically hindered monoanionic ortho-
yphosphonic acids have attracted significant attention due to their
fascinating biological activity, particularly as enzyme inhibitors,1
antitumor,2 antibacterial,3 and antiviral agents.4 The most general
method for preparation of
a-hydroxyphosphonates and related
species consists of addition of various hydrophosphoryl com-
pounds to aldehydes and activated ketones (Abramov reaction).5e7
However, synthesis of quaternary
a-hydroxyphosphonates by
conventional intermolecular Abramov hydrophosphonylation of
less electrophilic unactivated ketones is frequently troublesome.
Although hydrophosphonylation of unactivated ketones can be
promoted by heating and/or strong base catalysis,5e7 the same
factors favor the competing retro-Abramov reaction8,9 and
phospha-Brook rearrangement,9,10 thus hampering production of
arylamino N-arylbenzalimines and b
-diaryliminoketones.18 How-
ever, catalytic activity of these complexes was essentially sup-
pressed for aromatic ketones with any substituents in the ortho-
position.17,18
Over the last 2 decades, the most significant progress in the
Abramov phosphonylation have been achieved owing to use of
Lewis acid catalysts, which essentially activates both reaction
components. Application of chiral Lewis acid catalysts allowed
elaboration of highly efficient enantioselective syntheses of ternary
quaternary a-hydroxyphosphonates. These drawbacks stimulated
a search of milder methods for hydrophosphonylation of ketones,
such as heterogeneous catalysis with basic alumina,11 alumina
a
-hydroxyphosphonates from aldehydes.19 In 2009 Feng et al. re-
ported that (i-PrO)4Ti can efficiently catalyze Abramov hydro-
phosphonylation of some acetophenones and aliphatic ketones.20
Application of aluminum halide complexes with chiral tridentate
hydrogenated Schiff bases granted remarkable enantioselectivity in
* Corresponding author. Tel.: þ972 8934 2558; fax: þ972 8934 4142; e-mail
addresses: edward.korshin@weizmann.ac.il, edward.korshin@gmail.com (E.E.
Korshin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.007

11110
E.E. Korshin, O.K. Pozdeev / Tetrahedron 69 (2013) 11109e11115
the intermolecular Abramov hydrophosphonylation of some simple
ketones under very mild conditions.21 Nonetheless, a reliable syn-
20e60 ꢀC in different solvents (EtOH, 1,4-dioxane, toluene). As
observed by 31P NMR spectra, upon heating of 3a or 4a with 2 and
EtONa at 80e110 ꢀC a number of reactions took place to give
a complex reaction mixture. Our continuous attempts to accom-
plish selective hydrophosphonylation of 2 by phosphite 4a using
other simple catalysts like basic alumina,11 KF, and CsF alone or
being impregnated on alumina,12 complex MgCl2ꢁEt3N14 and (i-
PrO)4Ti were also unsuccessful.20 On the other hand, similarly to
the previously reported reactions of substituted in the benzene ring
TMS-protected 2-acetylphenols28 and 2-trifluoroacetylphenols,29
phosphonylation of 2 with excess trimethylsilyl diethylphosphite
(6) at 90e100 ꢀC smoothly afforded the bis-silylated quaternary
thesis of multifunctionally substituted quaternary
yphosphonates still remains a challenge.
a-hydrox-
Inspired by enzymatic catalysis intramolecularization of chem-
ical processes,22 which relies on an artificial pre-organization of the
reaction centers into a close proximity to each other, serves as one
of the most fruitful and general strategies for synthesis of struc-
turally complex organic compounds.23 So far, intramolecular
Abramov hydrophosphonylation24 and the mechanistically related
KabachnikeFields reaction have been sporadically applied for the
synthesis of phosphorus heterocycles,25 but have never been ex-
tended to the preparation of acyclic
aminophosphonates.
a
-hydroxy- or
a
-
a,g-dihydroxyphosphonate 7 in 82% yield (Scheme 2). Desilylation
of 7 with excess ethanol at 50 ꢀC under slightly acidic conditions
gave the dihydroxyphosphonate 5a quantitatively.
In the course of our studies toward novel anti-influenza
agents,26 we were interested in preparation and testing of
dihydroxyphosphonates and -phosphinates of type 1 (Scheme 1),
possessing a quaternary -hydroxyphosphonate (-phosphinate)
a,g-
a
scaffold. Herein, we report an expedient synthesis of
racemic diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]
phosphonates and -phosphinates 1aee through
a hydrolytic
tandem-type three-steps process, in which the key step proceeds
presumably as an intramolecular Abramov addition to an aceto-
phenone moiety. We also disclose the results on in vitro and in vivo
evaluation of compounds 1 against influenza A (H3N2).
Scheme 2. Synthesis of a,g-dihydroxyphosphonate 5a using silylphosphite 6.
Since water soluble compounds are the most suitable entities
for biological studies, we attempted to convert the diester 5a
to some salts of ethyl[1-hydroxy-1-(2-hydroxyphenyl)ethyl]
phosphonic acid of type 1 (Scheme 1). So far, only a few examples of
selective dealkylation of ternary30 and quaternary dialkyl
hydroxyphosphonates to the corresponding salts of alkyl
a
a
-
-
hydroxyphosphonic acids using alkali metal iodides have been re-
ported.31 However, NaI in boiling acetonitrile did not dealkylate the
diester 5a. Upon attempting an alkaline hydrolysis of 5a at rt, it
decomposed to 2 and 4a (retro-Abramov reaction) similarly to the
reported ternary a
-hydroxyphosphonate.32
To overcome the troubles derived from the standard in-
termolecular Abramov reaction (Scheme 1), we designed a syn-
thetic
route
to
1,
which
takes
advantage
from
intramolecularization22,23 of the key hydrophosphonylation step
and a tandem character of the overall process.33 According to this
design, masked hydrophosphoryl or hydrophosphonyl function
should be temporary connected to phenolic oxygen of 2-
acetylphenoxy-fragment to arrange the reaction centers in pro-
Scheme 1. Initially proposed synthesis of monoanionic [1-hydroxy-1-(2-
hydroxyphenyl)ethyl]phosphonates and -phosphinates
Abramov hydrophosphonylation.
1 through intermolecular
pinquity. Upon unmasking,
a viable intramolecular Abramov
hydrophosphonylation should take place followed by disconnec-
tion of phosphonyl function from phenolic oxygen atom. Amido-
phosphites and amidophosphonites were considered as suitable
immediate precursors of hydrophosphoryl and hydrophosphonyl
compounds, because the latter could be generated upon a selective
hydrolysis of P(III)eN bonds.34 Appropriate for our purpose ami-
dophosphites and -phosphonites 8, in which 2-acetyl-phenoxy-
fragment and a hydrolytically labile diethylamino-group are lo-
cated at the same trivalent phosphorus atom, are readily available
from 2 (Eq. 1).35
2. Results and discussion
2.1. Chemistry
At the outset of this work, we considered preparation of racemic
compounds 1 using a common intramolecular version of the
Abramov reaction as outlined in Scheme 1.
Indeed, a trivial retrosynthetic heterolytic dislocation of PeC
and OeH bonds in 1 leads to 2-acetylphenol (2) and the salts of
hypophosphites (hypophosphonites) 3. It indicates that in-
termolecular hydrophosphonylation of 2 as a carbonyl substrate
might directly give the desired compounds 1 using 3 as hydro-
phosphoryl reagents (path A).6,27 According to path B, the same
carbonyl component 2 and dialkylphosphites or alkylphosphonites
4 could be applied for constructing of a,g-dihydroxyphosphonates
or -phosphinates 5, but subsequent hydrolysis is required to obtain
the target compounds 1. However, in spite of a formally simple
character of both routes A and B, we encountered severe troubles in
each step of the way. In our hands, neither diethylammonium
ethylhypophosphite (3a) (R¼EtO, Catþ¼Et2NH2þ) nor dieth-
ylphosphite (4a) (R¼AlkO¼EtO) reacted with 2 being alone or in
the presence of standard basic catalysts like Et2NH or EtONa6a,b at
We were pleased to observe that a mild hydrolysis of 8 directly
afforded
the
desired
diethylammonium[1-hydroxy-1-(2-
in
hydroxyphenyl)ethyl]phosphonates and -phosphinates
1
54e76% isolated yield (Scheme 3). The hydrolyses of 8 leading to 1
were carried out at 5e8 ꢀC in 10e20 mmol scale, and water-soluble
(5e10 mg/mL) microcrystalline products 1aee were isolated by
a simple crystallization from the reaction mixture.

E.E. Korshin, O.K. Pozdeev / Tetrahedron 69 (2013) 11109e11115
11111
31P NMR monitoring a hydrolysis of amidophosphite 8a at
5e8 ꢀC in THF revealed a gradual disappearance of the 8a signal (dP
146.3 ppm) with simultaneous rise of a major broadened signal at
dP 33.3 ppm (ca. 75%), a minor signal at dP 12.2 ppm (1JPH¼620 Hz)
(10e15%) and few minute singlets in the interval 24e2 ppm. While
the characteristics of the minor signal are analogous to ones of
Et2N(EtO)P(O)H (15a),39 the major signal at dP 33.3 ppm should be
attributed to 2-ethoxy-3-hydroxy-1,2-benzoxaphosphole 11a
(Scheme 3, R¼EtO). Indeed, most of the reported 3-heteroatom-
substituted 2-ethoxy-1,2-benzoxaphospholes related to 11a
revealed a phosphorus nuclei resonance within a rather narrow
region dP 40e33 ppm.28,35,36,40 After 8 h at 5e8 ꢀC a hydrolysis of 8a
completed. A subsequent stirring of the reaction mixture at 25 ꢀC
led to a slow vanishing of the major signal with a synchronized
growth of the final product 1a peak at dP 23.9 ppm. Similar ten-
dencies were also observed upon 31P NMR monitoring of amido-
phosphonites 8c and 8e hydrolyses.
Few reported data on reactivity of aminohydrophosphoryl
compounds of type Et2N(AlkO)P(O)H 15, which could be derived
from a minor hydrolysis of P(III)eOAr bond in 8 according to Eq. 3,
indicated enhanced reactivity of 15 in addition to ketones com-
pared with dialkylphosphites 4.41 However, in our experiments
a specially prepared Et2N(EtO)P(O)H (15a)39 was inert toward 2 at
rt and reacted slowly in THF at 50 ꢀC to give a complex mixture of
products. Thus, an efficient formation of 1 at rt through a common
intermolecular hydrophosphonylation looks very unlikely.
The presented observations support a rationalization of events
leading to the peculiar formation of 1 from 8 in terms of a domino-
type sequential process as outlined in Scheme 3. The initial step
consists presumably of the NeP(III) bond hydrolysis with formation
of hydrophosphoryl compounds 10 and release of diethylamine.
Indeed, hydrolyses of various amidophosphites to give the corre-
sponding hydrophosphoryl compounds proceed rapidly, especially
in the presence of acidic catalysts, including ammonium salts.34
According to the preparation of 8 from 2 and 9 (Eq. 1),35 starting
compounds 8 are ultimately contaminated with small amount of
triethylamine hydrochloride. Moreover, the final products 1 pos-
sess acidic phenolic hydroxyl and ammonium salt functionalities,
which could also serve as catalysts in the hydrolysis of 8. As gen-
erally accepted, the initially formed hydrophosphoryl compounds
10 in the presence of basic amine exist in equilibrium with a very
minor, but reactive as nucleophile anionic phosphites (phosphon-
ites) 11. A proper arrangement of the reaction centers in intra-
molecular processes could provide 104e108 times rate acceleration
at ambient temperature.22,42 So, an anionic form 11 would undergo
extremely fast cyclization through intramolecular Abramov addi-
tion to carbon atom of the carbonyl group to give the five-mem-
Scheme 3. Tandem hydrolysis of amidophosphites and -phosphonites 8 leading to
diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates and -phos-
phinates 1.
The structures of the products 1 were determined by 1H, 13C, 31
P
NMR, and IR-spectra, the combustion analyses data matched the
molecular composition of 1. In 31P{1H} NMR spectra (DMSO-d6) the
products 1a and 1b exhibit characteristic for acyclic dialkyl
a-
hydroxyphosphonates singlets at dP 23.6 and 22.5 ppm, re-
spectively. The corresponding signal for phenylphosphinate 1c is
observed at dP 32.3 ppm, while the resonance signal of the phos-
phorus nuclei in alkylphosphinates 1d,e is detected in the typical
interval dP 47.6e42.5 ppm. In 1H NMR (D2O) spectra of products 1
the most characteristic fragments CH3eCeP(O) are detected as
doublets at dH 2.18e2.05 ppm, 3JH,P¼14.2e13.2 Hz. In 13C{1H} NMR
spectra (DMSO-d6) the fragments CH3eC(OH)eP(O) reveal a dou-
blet of methyl group at dC 24.7e23.3 ppm (2JC,P¼5.6e4.2 Hz) and
a
doublet of quaternary carbon at 76.2e74.8 ppm
(1JC,P¼158.8e157.2 Hz). The typical patterns of substituents R at the
phosphorus (IV) atom are observed in all the 1H and 13C NMR
spectra of 1. Absence of the coupling to phosphorus nuclei in
diethylammonium methylene group signals in 1H and 13C NMR
spectra of 1 is evidence of the PeN bond cleavage. The salt 1a was
converted to a free acid 13a being treated with cold aqueous HCl.
Addition of diethylamine to 13a restored the diethylammonium
salt 1a quantitatively (Eq. 2).
bered cyclic a-hydroxyphosphonate (-phosphinate) intermediates
12.43 Final hydrolysis of the endocyclic P(IV)eO bonds in strained
heterocycles 12 to form 1 could proceed rapidly under the mild
reaction conditions as reported for a number of 2-substituted-2-
oxo-2,3-dihydro-benzo[d]oxaphospholes.28,29,40,44 Thus, intra-
molecularization of the Abramov hydrophosphonylation as a key
stage of three-step tandem process allowed an efficient one-pot
preparation of diethylammonium[1-hydroxy-1-(2-hydroxy-phe-
nyl)ethyl]phosphonates and -phosphinates 1.
When amino-derivatives 8 were subjected to hydrolysis at
25 ꢀC, yields of 1 decreased dramatically due to acceleration of
competing side processes. According to 31P and 1H NMR spectra,
addition of water (4 equiv) to the structurally related to 8 diethyl
(2-acetylphenyl)phosphite (14)36 in THF resulted in hydrolysis of
the P(III)eOAr bond.37 The hydrolysis led to consumption of 14 (dP
137.7 ppm) after 8 h at rt to form diethylphosphite (4a) (dP 7.3 ppm,
1JPH¼705 Hz)38 and 2 (Eq. 3).
2.2. Biological evaluation
The in vitro antiviral activity against influenza A virus strain St.
Petersburg/34/72 (H3N2) and cytotoxicity toward MadineDarby
canine kidney (MDCK) cells of diethylammonium[1-hydroxy-1-(2-
hydroxyphenyl)ethyl]phosphonates and -phosphinates 1aee were
evaluated similarly to the reported methods.26,45 In short, MDCK
cells in the maintenance medium were pre-treated with each
compound at various concentrations followed by infection with 1

11112
E.E. Korshin, O.K. Pozdeev / Tetrahedron 69 (2013) 11109e11115
or 100 infective doses of influenza A virus (1 virus dose caused
50ꢂ3% cells death under the standard experimental conditions)
and incubation for 48 h at 37 ꢀC under a 5% CO2 atmosphere. Anti-
influenza A drug rimantadine was also examined as a reference
under the same conditions. The inhibition of the virus-induced
cytopathic effects for each sample was recorded relative to the
cell control and the virus control. The measured effective concen-
trations for 50%-inhibition of virus-induced cytopathogenicity
(EC50) and the cytotoxic concentrations (CC50), which induced 50%
damage of MDCK cells, are summarized in Table 1.
In vivo anti-influenza protective activity was tested in the in-
fluenza virus A/Aichi/2/68 (H3N2)-infected Balb/c mice of both
sexes according to the reported method.26 In brief, to the groups of
mice (10 animals in each group) the tested compounds 1 were SC
administered. Each mouse was five-times dosed with 10% of LD50
dose of the tested compounds in saline-DMSO solution (4:1, total
100 L). Administration of the tested compounds was provided in
/
m
prophylaxis 24 h and 1 h before infecting, followed by treatment at
24 h, 48 h, and 72 h after infecting. The reference drug Rimantadine
was examined under the same conditions. Control group of animals
Table 1
Anti-influenza virus A activity and cytotoxicity of diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonates 1a,b and -phosphinates 1cee in MDCK cellsa
Therapeutic index, TId
1 Dose
b
c
Compound
R
Antiviral activity, EC50
1 Dose
(
m
M)
Cytotoxicity, CC50 (mM)
100 Doses
100 Doses
1a
1b
1c
1d
EtO
n-PrO
Ph
Me
Et
60
47
45
28
53
5.0
300
222
266
185
316
42
7515
6000
8540
10370
9230
1395
125
128
190
368
175
280
25
27
32
56
29
33
1e
Rimantadine
a
Virus strain and abbreviations used: influenza virus A: St. Petersburg/34/72 (H3N2); MDCK cells: MadineDarby canine kidney cells.
Effective concentration (EC50) that required to reduce virus-induced cytopathogenicity by 50% in 48 h experiment.
Cytotoxic concentration (CC50) that caused 50% reduction of MDCK cell viability after 48 h incubation.
b
c
d
TI represents the ratio of CC50 to EC50
.
As shown in Table 1, all the tested compounds 1 are practically
was similarly treated five times with the vehicle (100
mL of saline/
non-toxic for MDCK cells and exhibited moderate antiviral activity
against the examined influenza A strain. The most active tested
phosphinate 1d with the smallest substituent R at the phosphorus
atom was only 4e5 times less potent in vitro compared to com-
mercial anti-influenza drug Rimantadine. Other tested derivatives
1 revealed lower efficacy as in vitro influenza virus inhibitors.
DMSO 4:1 v/v each dose). The protective efficacies of compounds 1
in mice were evaluated on the basis of the number of survived
rodents at the day 8 and 14 post infecting with experimental in-
fluenza A infection (Table 2).
The data of Table 2 indicate that compounds 1 revealed a sig-
nificant anti-influenza A protective activity providing with pro-
longation the life of animals during the time of the compound
administration. Thus, the control mice began to die from day the 2
after the virus infection, and by the day 8 only four from the control
ten mice survived. In contrast to that, in the group of mice treated
with ethylphosphinate 1e, a mortality of animals started from the
day 6, and by the day 8 seven from ten animals were still alive. In
Nevertheless, due to
a very low cytotoxicity a,g-dihydrox-
yphosphonates 1a,b and -phosphinates 1cee have comparable
with Rimantadine therapeutic index (TI) values. Surprisingly that
being tested in vivo compounds 1 revealed a superior to expected
protective activity against experimental influenza A infection
(Table 2).
Table 2
Protective activity against experimental influenza A infection and acute toxicity of
a
,
g
-dihydroxyphosphonate 1a and -phosphinates 1cee in micea
c
Compound
R
No. of infected survivors/total no. of infected miceb
Acute toxicity, LD50
(mg/kg)
8 Days
14 Days
Control (saline/DMSO)
1a
1c
1d
4/10
6/10
7/10
7/10
7/10
9/10
1/10
2/10
2/10
2/10
3/10
7/10
ND
EtO
Ph
Me
Et
3500
4000
2000
2500
175
1e
Rimantadine
a
Mice were infected intranasally by mouse-adapted influenza virus A/Aichi/2/68 (H3N2).
Mice were dosed daily, totally five times, each time with 10% of LD50. The compounds were administered subcutaneously (SC) in saline/DMSO (4:1, total 100
Lethal dose (LD50) corresponds to 50% mortality of the animals upon a single dose SC administration in saline/DMSO (4:1, total 200 L). The toxicity was estimated in the 5
b
c
mL).
m
days test.
Prior the experiments on in vivo antiviral activity, the acute
mice treated with phenyl- 1c and methylphosphinate 1d a survival
of rodents by the day 8 was found to be the same, whereas the
phosphonate 1a was slightly less active. However, a considerable
anti-influenza effect of substances 1 was observed upon high
dosage (10% of LD50) and continuous treatment only. Indeed, while
at the day 8 (3 days after the last administration of the tested
compounds 1) an antiviral protective effect in mice was well ob-
served, at the day 14 this effect mostly vanished. In view of the
modest in vitro antiviral activity, a substantial in vivo protective
toxicities (a median lethal doses LD50) of compounds 1 were
roughly estimated in the groups of male mice (four in each group)
upon SC administration in increasing single doses from 1000 mg/kg
up to 4000 mg/kg (500 mg/kg step). The LD50 values indicate a very
low acute toxicity of compounds 1 in rodents (Table 2). Moreover,
preliminary sub-acute toxicity studies in mice showed no signifi-
cant toxicity upon 6 days 500 mg/kg/day SC treatment with the
phosphonate 1a and phosphinate 1e.

E.E. Korshin, O.K. Pozdeev / Tetrahedron 69 (2013) 11109e11115
11113
effect could be attributed to some unidentified metabolites of 1.
Anyway, compounds are probably the first -hydrox-
yphosphonates (-phosphinates) with the documented considerable
anti-influenza activity in vivo. In view of the urgent need in novel
anti-influenza pharmaceuticals,46 the reported herein data inspire
(50 mL) and evaporated. The oily residue was treated with dry
diethyl ether (30 mL) and crystallized at ꢃ25 ꢀC. The resulted solid
1 was collected by filtration through a glass sinter. Recrystallization
from di-iso-propyl ether and dichloromethane afforded analytically
pure colorless microcrystalline products 1.
1
a
a further search of antiviral agents in
derivatives.
a-hydroxyphosphonic acid
4.2.1. Diethylammonium ethyl[1-hydroxy-1-(2-hydroxyphenyl)ethyl]
phosphonate (1a). Yield 1.99 g (62%), mp¼110e112 ꢀC (decomp.).
3. Conclusions
1H NMR (D2O):
d
7.67e6.98 (m, 4H, ArH), 4.01 (dq,
3JH,P¼3JH,H¼7.2 Hz, 2H, POCH2CH3), 3.08 (q, J¼7.1 Hz, 4H, NCH2CH3),
3
A convenient synthesis of diethylammonium[1-hydroxy-1-(2-
hydroxyphenyl)ethyl]phosphonates 1a,b and -phosphinates 1cee
by a domino-type hydrolysis of diethylamido(2-acetylphenyl)
phosphites 8a,b and -phosphonites 8cee have been elaborated.
Based on the NMR monitoring and model experiments, a reason-
able three-step mechanisms involving intramolecular Abramov
reaction in the key step have been suggested for formation of
2.15 (d, JH,P¼13.4 Hz, 3H, CH3CP), 1.43 (t, J¼7.1 Hz, 6H, NCH2CH3),
1.28 (br t, J¼7.2 Hz, 3H, OCH2CH3). 13C{1H}/DEPT NMR (DMSO-d6):
d
158.7 (d, J¼3.6 Hz, CAr), 133.4 (d, J¼2.2 Hz, CAr), 130.5 (d, J¼4.7 Hz,
CArH), 130.1 (br s, CArH), 122.6 (br s, CArH), 121.0 (d, J¼1.0 Hz, CArH),
74.8 (d, J¼158.8 Hz, HOCP), 64.3 (d, J¼5.4 Hz, POCH2), 47.9 (s, NCH2),
24.7 (d, J¼4.2 Hz, CH3CP), 18.3 (d, J¼5.8 Hz, POCH2CH3), 13.9 (s,
NCH2CH3). 31P{1H} NMR (DMSO-d6):
d 23.6. IR (Nujol): n 3305
compounds 1. Being very nontoxic,
a
-hydroxyphosphonates and
(OeH), 3190e3080 (OeH), 2780e2420 (NþeH), 1178 (P]O), 1055
-phosphinates 1 revealed moderate activity against influenza A
virus in vitro, but exhibited a substantial protective potency against
experimental influenza A infection in mice.
(PeOAlk) cmꢃ1
.
HRMS (ESI): m/z calcd for C10H16O5P
[MHþꢃEt2NH]: 247.0730; found: 247.0727. Anal. Calcd for
C14H26NO5P: C, 52.66; H, 8.21; N, 4.39; P, 9.70. Found: C, 52.60; H,
8.25; N, 4.27; P, 9.98.
4. Experimental section
4.1. General procedures
4.2.2. Diethylammonium n-propyl[1-hydroxy-1-(2-hydroxyphenyl)
ethyl]phosphonate (1b). Yield 1.795 g (54%), mp¼107e109 ꢀC
(decomp.). 1H NMR (D2O):
d 7.64e7.01 (m, 4H, ArH), 3.96 (dt,
1H, 13C/DEPT, and 31P NMR spectra were recorded on a Bruker
Avance-250 spectrometer, operating at 250.1 MHz, 62.9 MHz, and
101.3 MHz, respectively. 1H and 13C NMR chemical shifts were re-
ported relative to TMS. 1H NMR spectra were referenced to the
residual peak CHCl3 (7.26 ppm) or to external TMS standard
(0 ppm). 13C NMR spectra were referenced to the central peak of
CDCl3 (77.0 ppm) and DMSO-d6 (39.7 ppm) solvents or to external
TMS standard (0 ppm). 31P NMR spectra were referenced to 85%
H3PO4 (external standard, 0 ppm). Abbreviations used in the de-
scription of NMR data are as follows: br, broad (or broadened); s,
singlet; d, doublet; t, triplet; q, quartet; and m, multiplet. IR spectra
were obtained with a Nicolet-6700 FT-IR instrument in Nujol films
or neat films. High resolution electron spray ionization (ESI) mass
spectra were recorded using Micromass Platform LCZ-4000, elec-
tron impact (EI) HRMS was measured on a MX-1310 mass spec-
trometer. Microanalyses were performed in the Microanalytical
Laboratory of the Arbuzov Institute of Organic and Physical
Chemistry (Kazan, Russia). Melting points were measured with
3JH,P¼3JH,H¼7.0 Hz, 2H, POCH2CH2CH3), 3.05 (q, J¼7.2 Hz, 4H,
3
NCH2CH3), 2.12 (d, JH,P¼13.2 Hz, 3H, CH3CP), 1.68e1.54 (m, 2H,
POCH2CH2CH3), 1.41 (t, J¼7.2 Hz, 6H, NCH2CH3), 0.96 (t, J¼6.8 Hz,
3H, POCH2CH2CH3). 31P{1H} NMR (DMSO-d6):
d 22.5. IR (Nujol): n
3308 (OeH), 3194e3085 (OeH), 2790e2410 (NþeH), 1175 (P]O),
1057 (PeOAlk) cmꢃ1. Anal. Calcd for C15H28NO5P: C, 54.05; H, 8.47;
N, 4.20; P, 9.29. Found: C, 53.81; H, 8.77; N, 3.93; P, 9.12.
4.2.3. Diethylammonium[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phe-
nylphosphinate (1c). Yield 2.68 g (76%), mp¼166e167 ꢀC (decomp.).
1H NMR (D2O):
d
7.94e6.97 (m, 9H, ArH), 3.01 (q, J¼7.1 Hz, 4H,
3
NCH2CH3), 2.18 (d, JH,P¼14.2 Hz, 3H, CH3CP), 1.42 (t, J¼7.1 Hz, 6H,
NCH2CH3). 13C{1H}/DEPT NMR (DMSO-d6):
d
158.5 (d, J¼3.8 Hz, CAr),
133.8 (d, J¼3.0 Hz, CAr), 132.2 (d, J¼2.8 Hz, CPhH), 131.6 (d,
J¼133.8 Hz, CPh),131.2 (d, J¼9.8 Hz, 2CPhH),130.2 (d, J¼4.2 Hz, CArH),
130.0 (br s, CArH), 128.4 (d, J¼12.5 Hz, 2CPhH), 122.3 (br s, CArH),
120.2 (d, J¼1.6 Hz, CArH), 76.2 (d, J¼157.2 Hz, HOCP), 47.6 (s, NCH2),
23.8 (d, J¼5.6 Hz, CH3CP), 13.5 (s, NCH2CH3). 31P{1H} NMR (DMSO-
€
a Buchi-510 micro melting point apparatus.
d6): d 32.3. IR (Nujol): n 3302 (OeH), 3200e3080 (OeH),
All the manipulations with trivalent phosphorus compounds
were conducted under atmosphere of argon. THF, diethyl ether, and
toluene were distilled from Na/benzophenone under nitrogen.
Trimethylsilyl diethylphosphite (6)47 and amidophosphites
2775e2415 (NþeH), 1154 (P]O) cmꢃ1. Anal. Calcd for C18H26NO4P:
C, 61.53; H, 7.46; N, 3.99; P, 8.81. Found: C, 61.36; H, 7.44; N, 3.73; P,
8.77.
(-phosphonites)
8
were prepared according to the reported
4.2.4. Diethylammonium
methyl[1-hydroxy-1-(2-hydroxyphenyl)
methods.35
ethyl]phosphinate (1d). Yield 1.70
g
(59%), mp¼126e128 ꢀC
Biological evaluations were carried out similarly to the pre-
viously described procedures.26,45
(decomp.). 1H NMR (D2O):
d 7.69e7.00 (m, 4H, ArH), 2.99 (q,
J¼7.1 Hz, 4H, NCH2CH3), 2.06 (d, 3JH,P¼13.6 Hz, 3H, CH3CP), 1.44 (t,
J¼7.1 Hz, 6H, NCH2CH3), 1.38 (d, JH,P¼17.6 Hz, 3H, CH3P). 13C{1H}/
2
4.2. General procedure for the synthesis diethylammonium
salts of [1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonic
1a,b and -phosphinic acids 1cee by hydrolysis of dieth-
ylamido(2-acetylphenyl)phosphites and -phosphonites 8
DEPT NMR (DMSO-d6):
d
157.9 (d, J¼3.9 Hz, CAr), 133.1 (d, J¼2.4 Hz,
CAr), 130.6 (d, J¼4.7 Hz, CArH), 130.0 (br s, CArH), 122.2 (br s, CArH),
120.6 (d, J¼1.4 Hz, CArH), 75.4 (d, J¼156.5 Hz, HOCP), 47.6 (s, NCH2),
23.5 (d, J¼4.8 Hz, CH3CP), 13.8 (s, NCH2CH3), 12.30 (d, J¼148.6 Hz,
CH3P). 31P{1H} NMR (DMSO-d6):
d 42.5. IR (Nujol): n 3286 (OeH),
To a cold (5 ꢀC) solution of amidophosphite (-phosphonite) 8
(10.0 mmol) in dry deaerated THF (30 mL) a solution of water
(0.72 mL, 720 mg, 40 mmol) in deaerated THF (5 mL) was added
dropwise. After stirring at 5e8 ꢀC for 6e8 h until starting 8 con-
sumed (31P NMR monitoring), the reaction mixture was allowed to
warm to ambient temperature (22e25 ꢀC) and stirred for 1 day
(22e24 h). The reaction mixture was diluted with dry toluene
3185e3070 (OeH), 2790e2425 (NþeH), 1148 (P]O) cmꢃ1. Anal.
Calcd for C13H24NO4P: C, 53.97; H, 8.36; N, 4.84; P, 10.71. Found: C,
53.76; H, 7.62; N, 4.65; P, 10.79.
4.2.5. Diethylammonium ethyl[1-hydroxy-1-(2-hydroxyphenyl)ethyl]
phosphinate (1e). Yield 2.22 g (73%), mp¼159e160 ꢀC (decomp.).
1H NMR (D2O):
d
7.66e6.95 (m, 4H, ArH), 3.03 (q, J¼7.1 Hz, 4H,

11114
E.E. Korshin, O.K. Pozdeev / Tetrahedron 69 (2013) 11109e11115
3
NCH2CH3), 2.05 (d, JH,P¼13.8 Hz, 3H, CH3CP), 1.68 (dq,
OCH2CH3). 13C{1H}/DEPT NMR (D2O):
d
159.2 (d, J¼3.8 Hz, CAr),
2JH,P¼17.8 Hz, JH,H¼7.2 Hz, 2H, PCH2CH3), 1.42 (t, J¼7.1 Hz, 6H,
132.1 (d, J¼2.4 Hz, CAr), 130.2 (d, J¼4.3 Hz, CArH), 129.7 (br s, CArH),
121.9 (br s, CArH), 120.6 (d, J¼1.5 Hz, CArH), 75.6 (d, J¼160.3 Hz,
HOCP), 63.6 (d, J¼5.8 Hz, POCH2), 24.9 (d, J¼4.8 Hz, CH3CP), 18.6 (d,
3
NCH2CH3), 1.14 (dt, JH,P¼18.6 Hz, JH,H¼7.2 Hz, 3H, PCH2CH3). 13C
3
3
{1H}/DEPT NMR (DMSO-d6):
d
158.1 (d, J¼3.8 Hz, CAr), 133.0 (d,
J¼2.2 Hz, CAr), 130.8 (d, J¼4.6 Hz, CArH), 130.2 (br s, CArH), 122.5 (br
s, CArH),120.4 (d, J¼1.6 Hz, CArH), 75.6 (d, J¼156.2 Hz, HOCP), 47.5 (s,
NCH2), 23.3 (d, J¼5.1 Hz, CH3CP), 18.7 (d, J¼145.8 Hz, CH3CH2P), 13.6
(s, NCH2CH3), 6.8 (d, J¼6.6 Hz, CH3CH2P). 31P{1H} NMR (DMSO-d6):
J¼5.5 Hz, POCH2CH3). 31P{1H} NMR (D2O):
d 22.3. HRMS (ESI): m/z
calcd for C10H16O5P [MHþ]: 247.0730; found: 247.0724. Anal.
Calcd for C10H15O5P: C, 48.78; H, 6.14. Found: C, 48.41; H, 6.49.
d
47.6. IR (Nujol):
n
3282 (OeH), 3190e3075 (OeH), 2790e2420
4.4.2. Diethylammonium ethyl[1-hydroxy-1-(2-hydroxyphenyl)ethyl]
phosphonate (1a). A solution of acid 13a (124 mg, 0.504 mmol) in
(NþeH), 1144 (P]O) cmꢃ1. Anal. Calcd for C14H26NO4P: C, 55.43; H,
8.64; N, 4.62; P, 10.21. Found: C, 55.15; H, 8.83; N, 4.28; P, 10.32.
diethyl ether (5 mL) was treated with diethylamine (70 mL, 50 mg,
0.68 mmol). Evaporation followed by vacuumization afforded
diethylammonium salt 1a (161 mg, quantitative yield) as a colorless
solid. For characterization of 1a, see above.
4.3. Synthesis of diethyl[1-hydroxy-1-(2-hydroxyphenyl)
ethyl]phosphonate (5a)
4.3.1. Diethyl[1-trimethylsiloxy-1-(2-trimethylsiloxyphenyl)ethyl]
phosphonate (7). 2-Acetylphenol (2) (1.08 g, 7.94 mmol) and tri-
methylsilyl diethylphosphite (6) (6.835 g, 32.5 mmol) were placed
into an argon-filled Teflon screw-cup 25 mL round-bottom reactor,
and the reaction mixture was stirred for 4 h at 90e100 ꢀC. The
reaction mixture was fractionated by vacuum distillation, and
subsequent distillation afforded the bis-silylated product 7 (2.72 g,
82%) as a colorless mobile oil, bp¼119e122 (0.02 mmHg). 1H NMR
Acknowledgements
This study was partially supported by the Israel Ministry of
Absorption through the Kamea Fellowship (to E.E.K.), and by the
Kazan Branch of the Russian Academy of Sciences through the
Research Council Grant-in-Aid.
References and notes
(CDCl3):
d 7.41e7.23 (m, 2H, ArH), 7.05e6.88 (m, 2H, ArH),
3
1. (a) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron
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4.05e3.80 (m, 4H, 2OCH2CH3), 1.85 (d, JH,P¼14.6 Hz, 3H, CH3CP),
1.25 (br t, J¼7.0 Hz, 3H, OCH2CH3), 1.21 (br t, J¼7.0 Hz, 3H,
OCH2CH3), 0.38 [s, 9H, (CH3)3SiO], 0.25 [s, 9H, (CH3)3SiO]. 31P{1H}
NMR (CDCl3):
d 23.4. IR (film): n 1198 (P]O), 1055 (PeOAlk), 1016
(CeOSi) cmꢃ1. HRMS (EI): m/z calcd for C18H35O5PSi2 [Mþ]:
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4.3.2. Diethyl[1-hydroxy-1-(2-hydroxyphenyl)ethyl]phosphonate
(5a). To a solution of 7 (2.58 g, 6.16 mmol) in anhydrous ethanol
(20 mL) one drop of acetyl chloride (ca. 8 mg, 0.1 mmol) was added,
and the reaction mixture was stirred for 2 h at 50 ꢀC under argon.
The reaction mixture was evaporated; the residue was dissolved in
a new portion of ethanol (20 mL), evaporated again and subjected
to vacuumization for 2 days at 0.2 mmHg to give the title compound
5a (1.70 g, quantitative yield) as a colorless viscous oil. 1H NMR
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d 12.45 (br s, 1H, OH), 7.45e7.24 (m, 2H, ArH), 7.03e6.82
(m, 2H, ArH), 4.08e3.78 (m, 5H, 2OCH2CH3þOH), 1.91 (d,
3JH,P¼14.8 Hz, 3H, CH3CP), 1.29 (br t, J¼7.0 Hz, 3H, OCH2CH3), 1.20 (t,
J¼7.0 Hz, 3H, OCH2CH3). 13C{1H}/DEPT NMR (CDCl3):
d 158.2 (d,
J¼4.3 Hz, CAr), 130.3 (d, J¼3.0 Hz, CAr), 129.0 (d, J¼4.8 Hz, CArH),
128.1 (d, J¼3.6 Hz, CArH), 121.5 (d, J¼1.2 Hz, CArH), 118.4 (d, J¼2.0 Hz,
CArH), 75.7 (d, J¼161.6 Hz, HOCP), 63.8 (d, J¼7.1 Hz, POCH2), 62.7 (d,
J¼7.1 Hz, POCH2), 24.8 (d, J¼2.3 Hz, CH3CP), 16.3 (d, J¼5.2 Hz,
POCH2CH3), 16.1 (d, J¼5.6 Hz, POCH2CH3). 31P{1H} NMR (CDCl3):
d
24.1. IR (film): n 3340e3120 (OeH), 1188 (P]O), 1052
(PeOAlk) cmꢃ1. HRMS (ESI): m/z calcd for C12H20O5P [MHþ]:
275.1043; found: 275.1036. Anal. Calcd for C12H19O5P: C, 52.55; H,
6.98; P, 11.29. Found: C, 52.31; H, 7.16; P, 10.98.
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d
7.65e6.93 (m, 4H, ArH), 4.04 (dq, JH,P¼3JH,H¼7.1 Hz, 2H,
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