Synthesis of 1-hetarylethylphosphonates

Article abstract of DOI:10.1134/S1070428010060011

Previously unknown potentially biologically active diethyl 1-(pyridin-3-yl)-, 1-(quinolin-3-yl)-, and 1-(quinolin-6-yl)ethylphosphonates were synthesized by palladium-catalyzed reduction of the corresponding α,β-unsaturated precursors with ammonium formate. The reduction of diethyl 1-(quinolin-6-yl)ethenylphosphonate was accompanied by formation of diethyl 1-(1,2,3,4-tetrahydroquinolin-6-yl)ethylphosphonate as by-product.

Full text of DOI:10.1134/S1070428010060011

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 6, pp. 781–784. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.S. Gulyukina, I.P. Beletskaya, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 6, pp. 791–794.
Synthesis of 1-Hetarylethylphosphonates
N. S. Gulyukina and I. P. Beletskaya
Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: goulioukina@org.chem.msu.ru
Received December 20, 2009
Abstract—Previously unknown potentially biologically active diethyl 1-(pyridin-3-yl)-, 1-(quinolin-3-yl)-, and
1-(quinolin-6-yl)ethylphosphonates were synthesized by palladium-catalyzed reduction of the corresponding
α,β-unsaturated precursors with ammonium formate. The reduction of diethyl 1-(quinolin-6-yl)ethenylphos-
phonate was accompanied by formation of diethyl 1-(1,2,3,4-tetrahydroquinolin-6-yl)ethylphosphonate as
by-product.
DOI: 10.1134/S1070428010060011
Interest in 1-arylethylphosphonic acids and their
esters is determined primarily by their biological activ-
ity. 1-Arylethylphosphonates are cyclooxygenase in-
hibitors [1], Ca2+ antagonists [2, 3], neuroprotectors
[3], psychotropic [3] and negative inotropic agents [2],
and reactive immunization haptens [4, 5]. These com-
pounds may be regarded as phosphorus-containing
structural analogs of 2-arylpropionic acids that are
widely used in modern medical practice as nonsteroi-
dal analgesic, antiphlogistic, and antipyretic drugs;
examples are ibuprofen, naproxen, ketoprofen, flurbi-
profen, tiaprofen, etc.
example is (S)-2-amino-3-[3-hydroxy-5-(pyridin-2-yl)-
isoxazol-4-yl]propionic acid which is a considerably
more potent AMPA receptor agonist than its 5-phenyl
analog [12]. Likewise, replacement of the benzene ring
in diethyl 4-(benzothiazol-2-yl)benzylphosphonate
(calcium antagonist Fostedil) by pyridine appreciably
enhances coronary vasodilating effect [13].
We previously proposed a convenient synthetic ap-
proach to 1-arylethylphosphonates, which is based on
catalytic reduction of the corresponding α,β-unsatu-
rated precursors. Homogeneous enantioselective hy-
drogenation of 1-arylethenylphosphonic acids and their
esters was performed in the presence of chiral ruthe-
nium [14, 15] and iridium catalysts [16], respectively.
This approach was then successfully developed by
other authors [17, 18]. A number of racemic 1-aryl-
ethylphosphonates containing substituted phenyl and
naphthyl groups were synthesized using ammonium
formate as reducing agent and carbon-supported pal-
ladium as catalyst [14, 15]. The goal of the present
study was to synthesize under analogous conditions
1-hetarylethylphosphonates.
Synthetic applications of 1-arylethylphosphonates
are related mainly to their use as reagents in the
Horner–Wadsworth–Emmons reactions, which is re-
flected in numerous patents (see, e.g., [6–9]). It was
also shown that vanadyl 1-arylethylphosphonates are
characterized by layered structure which makes them
promising for the design of functional materials [10].
There are very scanty published data on 1-hetarylethyl-
phosphonates (see, e.g., [11]), though their synthesis
and estimation of their biological activity attract un-
doubted interest. For instance, among the above noted
profens, just tiaprofen [(RS)-2-(5-benzoylthiophen-2-
yl)propionic acid] exhibits the highest selectivity in the
inhibition of synthesis of prostaglandin F2α. Another
As model substrates we selected diethyl 1-(pyridin-
3-yl)-, 1-(quinolin-3-yl)-, and 1-(quinolin-6-yl)ethenyl-
phosphonates Ia–Ic which were prepared by palladi-
um-catalyzed hydrophosphorylation of the correspond-
Scheme 1.
(1) Pd(PPh3)2Cl2, CuI, Et3N, THF
(2) K2CO3, MeOH
HP(O)(OEt)2, Pd2(dba)3 ·CHCl3
PPh3, THF, 67°C
CH2
Ht Br
+
HC
SiMe3
HC
Ht
Ht
P(O)(OEt)2
Ia–Ic
Ht = pyridin-3-yl (a), quinolin-3-yl (b), quinolin-6-yl (c).
781

GULYUKINA, BELETSKAYA
782
ing hetarylacetylenes. The latter were synthesized in
turn by cross-coupling of trimethylsilylacetylene with
hetaryl bromides according to Sonogashira, followed
by removal of trimethylsilyl protection under basic
conditions [19] (Scheme 1).
EtOAc) in 60 and 27% yield, respectively, and were
characterized by spectral data. The structure of the by-
product was confirmed by H NMR spectroscopy. The
1
carbocyclic fragment retains its aromaticity, as follows
from the multiplicity of signal from the CH proton,
which appears as a doublet of quartets at δ 3.01 ppm
1-Hetarylethenylphosphonates Ia–Ic were reduced
with 6 equiv of ammonium formate in boiling meth-
anol in the presence of 10% Pd/C (3 mol %). The prog-
ress of reactions was monitored by 31P NMR spect-
roscopy following disappearance of the signal of initial
compound Ia–Ic (δP 15.5–16.3 ppm) from the 31P
NMR spectrum of the reaction mixture. We found that
the reduction of phosphonates Ia and Ib is complete
in 2–3 h, leading exclusively to the corresponding
1-hetarylethylphosphonates IIa and IIb (Scheme 2);
no other products were detected by 31P NMR spectros-
copy. Compounds IIa and IIb were isolated in 84 and
90% yield, respectively; their structure was confirmed
by elemental analyses and spectral data. The presence
of a characteristic set of signals in the aromatic region
2
(3JHH = 7.2, JHP = 22.4 Hz), and from the presence of
a one-proton doublet (3JHH = 8.4 Hz) and a two-proton
multiplet in the aromatic region (δ 6.43 and 6.92 ppm,
respectively). Methylene protons in the heterocyclic
fragment resonated as three two-proton multiplets at
δ 1.93, 2.75, and 3.28 ppm.
Selective reduction of the heteroaromatic ring in
substituted quinolines, isoquinolines, and indoles by
the action of formic acid salts in the presence of
carbon-supported palladium was reported in [20–22];
this procedure was successfully used for the prepara-
tion of 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydro-
isoquinoline, and dihydroindole derivatives. Compari-
son of our results in the reduction of substrates Ib and
Ic shows that the ability of quinoline ring to undergo
partial hydrogenation strongly depends on the substi-
tution pattern.
1
of the H NMR spectra of phosphonates IIa and IIb
indicated conservation of the heteroaromatic fragment.
According to [11], reduction of structurally related
systems with hydrogen in the presence of Pd/C is
generally accompanied by hydrogenation of hetero-
aromatic ring.
To conclude, we have shown that palladium-cata-
lyzed reduction of 1-hetarylethenylphosphonates with
ammonium formate leads to the formation of the corre-
sponding diethyl 1-(pyridin-3-yl)- and 1-(quinolin-3-
yl)ethylphosphonates in nearly quantitative yields.
Under analogous conditions, the yield of diethyl
1-(quinolin-6-yl)ethylphosphonate appreciably de-
creases due to side formation of diethyl 1-(1,2,3,4-
tetrahydroquinolin-6-yl)ethylphosphonate. The results
of biological tests on diethyl 1-hetarylethylphospho-
nates IIa–IIc will be reported elsewhere.
Scheme 2.
HCOONH4 (6 equiv)
10% Pd/C (3 mol %)
MeOH, Δ, 2–3 h
CH2
Me
Ht
P(O)(OEt)2
Ia, Ib
Ht
P(O)(OEt)2
IIa, IIb
Ht = pyridin-3-yl (a), quinolin-3-yl (b).
In the reduction of diethyl 1-(quinolin-6-yl)ethenyl-
EXPERIMENTAL
phosphonate (Ic) with ammonium formate the com-
plete conversion was achieved in 3 h, and the reaction
mixture contained two reduction products at a ratio of
7:3. In this case, the reduction of the exocyclic double
C=C bond was accompanied by hydrogenation of the
pyridine fragment. The products, phosphonate IIc and
diethyl 1-(1,2,3,4-tetrahydroquinolin-6-yl)ethylphos-
phonate, were isolated by chromatography (Silufol,
1
The H and 31P–{1H} NMR spectra were recorded
on a Bruker Avance-400 spectrometer at 400 and
162 MHz, respectively. The chemical shifts were deter-
mined relative to 85% H3PO4 (external reference, 31P)
or tetramethylsilane (internal reference, H). The IR
spectra were measured on an Ikar spectrometer with
1
Fourier transform (Mikrotekh Ltd., Russia). The ele-
Scheme 3.
CH2
P(O)(OEt)2
CH3
P(O)(OEt)2
CH3
P(O)(OEt)2
HCOONH4 (6 equiv)
10% Pd/C (3 mol %)
MeOH, Δ, 3 h
+
N
N
N
H
Ic
IIc
IIc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010

SYNTHESIS OF 1-HETARYLETHYLPHOSPHONATES
783
mental compositions were determined on a Carlo Erba
automatic analyzer. Methanol was heated under reflux
over magnesium methoxide and then distilled. Ammo-
nium formate of pure grade was dried under reduced
pressure over P2O5. Carbon-supported palladium
(10% Pd/C) was commercial product (from Aldrich).
Diethyl 1-(quinolin-6-yl)ethylphosphonate (IIc)
was synthesized in a similar way by reduction of
1.01 g (3.5 mmol) of diethyl 1-(quinolin-6-yl)ethenyl-
phosphonate (Ic) with 1.32 g (20.9 mmol) of ammo-
nium formate in 52 ml of methanol in the presence of
0.11 g of 10% Pd/C (3 mol % of Pd); reaction time 3 h.
The product was isolated by chromatography on silica
gel using ethyl acetate as eluent. Yield 0.61 g (60%),
Rf 0.2 (Silufol, EtOAc). IR spectrum (film), ν, cm–1:
2981, 1500, 1456, 1248 (P=O), 1163, 1055, 1022
(O–C), 962 (OC–C), 893, 841, 796, 780, 732. 1H NMR
spectrum (CDCl3), δ, ppm: 1.14 t and 1.29 t (3H each,
Diethyl 1-(pyridin-3-yl)ethylphosphonate (IIa).
A mixture of 0.55 g (2.3 mmol) of diethyl 1-(pyridin-
3-yl)ethenylphosphonate (Ia), 0.88 g (14.0 mmol,
6 equiv) of ammonium formate, and 0.07 g of 10%
Pd/C (3 mol % of Pd) in 34 ml of anhydrous methanol
was heated for 2 h with stirring under reflux in
a stream of dry argon. The mixture was filtered from
the catalyst through a small layer of silica gel, the
solvent was distilled off from the filtrate on a rotary
evaporator, and the residue was treated with diethyl
ether. The ether extracts were combined, washed with
a small amount of water, dried over MgSO4, and evap-
orated, and the residue was subjected to chromatog-
raphy on silica gel using ethyl acetate as eluent. Yield
0.46 g (84%), yellow oily substance, Rf 0.15 (Silufol,
CH2CH3, 3JHH = 7.1 Hz), 1.69 d.d (3H, CHCH3, 3JHH
=
3
3
7.6, JHP = 18.2 Hz), 3.39 d.q (1H, CH, JHH = 7.6,
2JHP = 22.8 Hz), 3.83 m and 3.94 m (1H each, CH2),
3
4.07 m (2H, CH2), 7.40 d.d (1H, 3-H, JHH = 8.0,
4.4 Hz), 7.74 m (1H, 7-H, 3JHH = 8.6 Hz), 7.81 m (1H,
3
5-H), 8.08 d (1H, 8-H, JHH = 8.6 Hz), 8.15 br.d (1H,
4-H, 3JHH = 8.0 Hz), 8.89 br.s (1H, 2-H, 3JHH = 4.4 Hz).
31P NMR spectrum, δP, ppm: 33.3 (in CD3OH), 28.8
(in CDCl3). Found, %: C 61.24; H 6.65; N 4.59.
C13H16NO3P. Calculated, %: C 61.43; N 6.87; N 4.78.
1
EtOAc). H NMR spectrum (CDCl3), δ, ppm: 1.18 t
and 1.29 t (3H each, CH2CH3, 3JHH = 7.1 Hz), 1.60 d.d
In addition, 0.28 g (27%) of diethyl 1-(1,2,3,4-tetra-
hydroquinolin-6-yl)ethylphosphonate was isolated.
Rf 0.4 (Silufol, EtOAc). IR spectrum (film), ν, cm–1:
2956, 2920, 2852, 1463, 1234 (P=O), 1162, 1054,
1024 (O–C), 962 (OC–C), 908, 838, 795, 771, 734.
1H NMR spectrum (CDCl3), δ, ppm: 1.17 t and 1.28 t
(3H, CHCH3, 3JHH = 7.4, 3JHP = 18.4 Hz), 3.84–4.02 m
3
2
(2H, CH2), 3.21 d.q (1H, CH, JHH = 7.4, JHP
22.6 Hz), 4.07 m (2H, CH2), 7.30 d.d (1H, 5-H, 3JHH
=
=
8.0, 3JHH = 4.6 Hz), 7.76 br.d (1H, 4-H, 3JHH = 8.0 Hz),
8.51 m (1H, 6-H), 8.54 br.s (1H, 2-H). P NMR spec-
31
3
(3H each, CH2CH3, JHH = 7.2 Hz), 1.51 d.d (3H,
trum (CD3OH): δP 32.6 ppm. Found, %: C 54.77;
H 7.23; N 6.02. C9H14NO3P. Calculated, %: C 54.32;
H 7.46; N 5.76.
3
3
CHCH3, JHH = 7.4, JHP = 18.8 Hz), 1.92 m and
3
2.74 m (2H each, CH2), 3.02 d.q (1H, CH, JHH = 7.4,
2JHP = 22.2 Hz), 3.27 m (2H, CH2), 3.82 m and 3.94 m
Diethyl 1-(quinolin-3-yl)ethylphosphonate (IIb)
was synthesized in a similar way by reduction of
0.97 g (3.3 mmol) of diethyl 1-(quinolin-3-yl)ethenyl-
phosphonate (Ib) with 1.27 g (20.1 mol) of ammonium
formate in 50 ml of methanol in the presence of 0.11 g
of 10% Pd/C (3 mol % of Pd); Reaction time 3 h. Yield
0.88 g (90%), yellow oily substance, Rf 0.25 (Silufol,
EtOAc). IR spectrum (film), ν, cm–1: 2920, 2850,
1464, 1252 (P=O), 1163, 1055, 1024 (O–C), 962
(1H each, OCH2), 4.03 m (2H, OCH2), 6.42 d (1H,
3
8-H, JHH = 8.8 Hz), 6.92 m (2H, 5-H, 7-H). 31P NMR
spectrum, δP, ppm: 35.1 (in MeOH), 30.4 (in CDCl3).
Found, %: C 60.59; H 8.34; N 4.70. C13H20NO3P. Cal-
culated, %: C 60.59; H 8.14; N 4.71.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-01128-a).
1
(OC–C), 789, 756, 730. H NMR spectrum (CDCl3),
3
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