Synthesis of biologically active 1-arylethylphosphonates

Article abstract of DOI:10.1023/A:1016511609369

A convenient and inexpensive general preparation method for 1-arylethylphosphonic acids and their esters was developed involving in reduction of the corresponding 1-ethenylphosphonates by ammonium formate in the presence of palladium on carbon. A homogeneous enantioselective hydrogenation of 1-arylethenylphosphonic acids in the presence of chiral ruthenium catalysts provided optically active 1-arylethylphosphonic acids of enantiomeric purity up to 86%. The preliminary data on biological activity testing of the 1-arylethylphosphoic acids synthesized evidence that some among the compounds obtained are low-toxic substances with the properties of immunosuppressors of the central type of action.

Full text of DOI:10.1023/A:1016511609369

Russian Journal of Organic Chemistry, Vol. 38, No. 4, 2002, pp. 573 587. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 4, 2002,
pp. 600 613.
Original Russian Text Copyright
2002 by Gulyukina, Dolgina, G. Bondarenko, Beletskaya, N. Bondarenko, Henry, Lavergne, Ratovelomanana-
Vidal, Genet.
Synthesis of Biologically Active 1-Arylethylphosphonates*
N. S. Gulyukina1, T. M. Dolgina1, G. N. Bondarenko1, I. P. Beletskaya1, N. A. Bondarenko2,
J.-C. Henry3, D. Lavergne3, V. Ratovelomanana-Vidal3, and J.-P. Genet3
1Lomonosov Moscow State University, Moscow, 119899 Russia
2Foundation Development of pharmacology of emotional stress
3Laboratoire de Synthese Selective Organique et Produits Naturels,
UMR-C.-N.R.S. 7573, Ecole Nationale Superieure de Chimie de Paris, France
Received August 2, 2000
Abstract A convenient and inexpensive general preparation method for 1-arylethylphosphonic acids and
their esters was developed involving in reduction of the corresponding 1-ethenylphosphonates by ammonium
formate in the presence of palladium on carbon. A homogeneous enantioselective hydrogenation of
1-arylethenylphosphonic acids in the presence of chiral ruthenium catalysts provided optically active
1-arylethylphosphonic acids of enantiomeric purity up to 86%. The preliminary data on biological activity
testing of the 1-arylethylphosphoic acids synthesized evidence that some among the compounds obtained are
low-toxic substances with the properties of immunosuppressors of the central type of action.
1-Arylethylphosphonates are of interest as
potential biologically active compounds, primarily as
phosphorus analogs of 2-arylpropionic acids that are
known as nonsteroid antiphlogistic and analgetic
drugs, such as naproxen and ibuprofen which are
widely used in the medical practice. It was reported
[1] that 1-arylethylphosphonates exhibit negative
inotropic and Ca2+ -antagonistic activity. In experi-
ments in vitro 1-arylethylphosphonic acids inhibit the
activity of cyclooxygenase [2]. In experiments in vivo
it was demonstrated that 1-arylethylphosphonates
caused formation in animal organism of antibodies
possessing properties of catalysts of stereospecific
hydrolysis [3, 4].
phosphite (Michaelis Becker reaction) [12]. The
other approach to the synthesis of esters of 1-arylalk-
ylphosphonic acids is based on metallation (effected
by sodium amide, butyllithium, or lithium hexameth-
yldisilazide) followed by alkylation of arylmethyl-
phosphonic acid esters [2, 13]. The preparation of
diethyl 1-phenylethylphosphonates and diethyl
1-tolylethylphosphonates by treating a lithium salt of
diethyl 1-chloroethylphosphonate with Ph2CuLi or
phenylor tolyllithium in the presence of catalytic
amounts of CuI was described [14 16]. Dimethyl
1-phenylethylphosphonate was obtained by addition
of dimethylphosphoric acid to , -bis(methylsulfon-
yl)styrene followed by reduction of the product by
hydrogen on Raney nickel [17] or to tosylhydrazone
of acetophenone with subsequent reduction by sodium
borohydride [18]. It was shown by an example of
diethyl 1-oxybenzylphosphonate that the hydroxy
group could be removed either by substitution with
chlorine followed by hydrogenation on Raney nickel
or by transformation of it into TsO group and reduc-
tion of the latter with sodium borohydride. One more
approach to the synthesis of 1-arylethylphosphonates
involves in aromatization of the products of 1,4- or
1,2-addition of an -lithiated derivative of diethyl
ethylphosphonate to substituted cyclohexen-2-ones
[20]. Chloride of 1-phenylethylphosphonic acid
formed by Kinner Perrin Clay reaction at partial
hydrolysis of a complex obtained from 1-phenyl-1-
chloroethane and PCl3 in the presence of AlCl3 [21].
1-Arylethylphosphonates find wide synthetic
application, in particular, as reagents in Horner reac-
tion that is mentioned in numerous patents (see, e.g.,
[5 8]).
Although the described synthetic procedures for
1-arylethylphosphonates are numerous most of them
are not general, tested on single examples, and often
require special experimental technique or inaccessible
reagents.
The most traditional methods are reactions of
1-aryl-1-bromoethanes with triethyl phosphite
(Arbuzov reaction) [1, 9 11] or with sodium dimethyl-
*
The study was carried out under financial support from the
Russian Foundation for Basic Research (grant no. 99-03-
33487) and INTAS (grant INTAS-99-1541).
1070-4280/01/3804-573$27.00 2002 MAIK Nauka/Interperiodica

574
GULYUKINA et al.
ruthenium catalyst. We published previously a pre-
As the most versatile preparation method for
liminary communication covering this subject [40].
1-arylethylphosphonates would be hydrogenation of
the corresponding 1-arylethenylphosphonates that can
be obtained by relatively well developed synthetic
method (see, for instance, [22]). However this proce-
dure is poorly considered in the literature. The
, -unsaturated phosphonates are commonly hydro-
genated under pressure (3.4 80 at) in the presence of
heterogeneous catalysts: palladium (5 or 10%),
platinum (5%) or rhodium (5%) on carbon [23 27],
but the majority of studies are treating the hydrogen-
ation of 2-substituted ethenylphsphonates. For
1-substituted compounds was the hydrogenation of
dimethyl ethenylphosphonate containing a sugar rest
in the -position described [23].
Apparently the simplest preparation method for
1-arylethenylphosphonic acids is phosphorylation
of acetylarenes with phosphorus trichloride in the
presence of glacial acetic acid [41 44]. The mecha-
nism of the reaction is still under discussion [45]. The
reaction is usually carried out with 23 60 mol%
excess of PCl3 and 2.5 5.25 equiv of glacial acetic
acid. Depending on the workup of the reaction mix-
ture the primary products are either 1-chloro- or
1-hydroxybenzylphosphonic acids [41, 42]. To obtain
unsaturated acid I the reaction mixture is subjected to
hydrolysis, 1,1,2,2-tetrachloroethylene is added, and
the mixture is boiled with distillation of water [43,
44]. We used this reaction for the synthesis of a series
of initial 1-arylethenylphosphonic acids Ia f that were
isolated in 60 83% yield (Table 1).
The homogeneous hydrogenation of , -unsaturat-
ed phosphonates was first performed [28] with di-
phenyl and diethyl 1- and 2-phenylethenylphospho-
nates with the use of relatively hard-to-get catalyst,
[Pd(O2PBu2-t)(OPBu2-t)(HOPBu2-t)], arising at oxid-
ation of a binuclear complex [(Bu2-tPH)Pd(PBu2-t)]2
[29]. The reduction of , -unsaturated phosphonic
acids was not described in the literature.
The enantioselective catalytic hydrogenation of
1-substituted ethenylphosphonates seems a convenient
approach to the synthesis of optically active 1-sub-
stituted ethylphosphonates with an -C*-stereocenter.
This goal is obviously urgent for it is well known
that biological activity of chiral compounds can be
strongly dependent on the absolute configuration of
the chiral center. For instance, the S-isomers of
-arylpropionic acids are as a rule more active than
R-isomers [30]: antiphlogistic activity of the (S)-2-(6-
methoxy-2-naphthyl)propionic acid is 28 times
greater than that of its R-isomer [31]. We found in the
literature rare examples of enantioselective hydro-
genation of , -unsaturated phosphonates with a
functional group in -position [32, 33]. The synthesis
of optically active 1-arylethylphosphonates up till
now was only performed through stereoselective
alkylation of functional derivatives of benzylphos-
phonic acid containing an auxiliary chirality source
[34 36], and by stereoselective Arbuzov rearrange-
ment [37].
Ar = Ph (a), 4-MeC6H4 (b), 4-PhC6H4 (c), 4-ClC6H4
(d), 1-Nf (e), 2-Nf (f); X = Cl, OH.
The reaction procedure was somewhat simplified:
after the hydrolysis the reaction mixture was
evaporated in a porcelain evaporating dish, the
residue was dissolved in boiling concentrated hydro-
chloric acid, and the resulting solution was boiled for
3.5 4 h. On cooling the unsaturated acid Ia, b, d f
precipitated, it was filtered off and washed on filter
with cold benzene.
In the synthesis of acid Ic the intermediate saturated
adduct 4-PhC6H4CX(CH3)P(O)(OH)2 was insoluble at
boiling both in concentrated and diluted hydro-
chloric acid, and even after prolonged boiling formed
only a mixture ( 1: 1) of unsaturated and saturated
acids. The presence of the latter is evidenced by
1H NMR spectrum of the separated product: along-
side the double doublets of vinyl protons appears a
complicated pattern in the resonance region of
aromatic protons and a doublet at 1.87 ppm (3JHP
14.8 Hz) corresponding to a methyl group. The
In the present study was developed a convenient
preparative method of the chemoselective reduction of
1-arylethenylphosphonic acids and their esters with
ammonium formate [38, 39] in the presence of pal-
ladium on carbon, and also was carried out a homo-
geneous enantioselective hydrogenation of 1-aryl-
ethenylphosphonic acids with hydrogen on chiral
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

SYNTHESIS OF BIOLOGICALLY ACTIVE 1-ARYLETHYLPHOSPHONATES
575
elimination reaction was completed by dissolving the
acid mixture in toluene and boiling with water distil-
lation.
Looking for a convenient preparative procedure
for the synthesis of racemic -arylethylphosphonic
acids and their esters from the respective -aryl-
ethenylphosphonates we tested various hydrogenating
agents: sodium borohydride in the presence of
CoCl2 6H2O [52], formamide in the presence of
palladium (5%) on carbon, and ammonium formate in
the presence of Raney nickel or Pd/C (5%). The
selection of the optimum reduction conditions for
1-arylethenylphosphonates was carried out by an
example of compound IIa. The reaction progress was
monitored with 31P NMR spectroscopy by dis-
appearance of the signal from the initial IIa at
17.1 ppm, and accumulation of the signal from reac-
tion product diethyl 1-phenylethylphosphonate (IIIa)
at 30.2 ppm.
All the acids obtained Ia f were characterized by
31P, 1H (Tabl1e 2), 13C NMR, and IR spectra (Table 1).
In the 31P{ H} NMR spectra of the compounds
appeared a signal in 14.5 16.0 ppm region character-
istic of ethenylphosphonic acids [46]. The assignment
of vinyl protons (cis-PC=CH and trans-PC=CH) in
the 1H NMR spectra was done by the values of
coupling constants with phosphorus [47] (Table 2).
The protons in cis-position with respect to phos-
phorus resonate in the region 6.18 6.57 ppm (3JHP
21.6 22.0 Hz), and the signals from trans-protons
are observed at 5.88 6.21 ppm (3JHP 44.0 45.1 Hz).
The observed upfield shift of these proton signals
may be attributed to the shielding by the phenyl
ring that according to X-ray diffraction data [48] is
not coplanar with the double bond and is situated at
an angle of 35 to the latter. This is consistent with
the published data [47] on negligible contribution
from the magnetic anisotropy of P=O group in the
1H NMR spectra of unsubstituted ethenylphos-
phonates resulting in small difference in the chemical
shifts of the two terminal protons (not exceeding
0.1 ppm).
The results presented in Table 3 show that reduc-
tion of compound IIa with ammonium formate
(6 equiv.) in boiling methanol in the presence of
2.8 mol% of Pd/C completed in 3 h affording ester
IIIa as a single product (run no. 1). Therewith the
catalyst can be filtered off from the reaction mixture
and used repeatedly, although with some loss of the
catalytic activity(runs nos. 2 and 3). The use of Raney
nickel instead of palladium on carbon resulted in con-
siderable decrease in the reduction rate (run no.4).
The systems NaBH4/CoCl2 6H2O and HCONH2 in
the presence of Pd/C (runs nos. 6 and 5) were
inefficient.
In the 13C NMR spectra the signal from the vinyl
carbon C1 in the region 143.7 144.4 ppm is the most
1
characteristic ; the spin-spin coupling constant JCP
amounts to 174.9 176.1 Hz.
In the IR spectra of compounds Ia e a set of ab-
sorption bands characteristic of group P(O)(OH)2
vibrations is observed: strong band of the stretching
1
vibrations of P=O bond at 1270 1180 cm
(commonly two bands presumably from two rotamers
[50]); as a rule, prominent bands in the region 1025
1
Under the optimal conditions found we carried out
reduction of diethyl 1-arylethenylphosphonates
IIg, h and a series of 1-arylethenylphosphonic acids
Ia f. The results obtained are presented in Table 4.
985 and 955 930 cm belonging to P O bond vibr-
ations, and a very broad band of OH-vibrations in the
1
region 2725 1600 cm
with maxima at 2900
1
2700 s, 2400 2200 m and 1700 1600 w cm .
The saturated 1-arylethylphosphonic acids IVa c,
e, f) (runs nos. 1, 2, 4, 5, 7 9) and diethyl 1-aryl-
phosphonates IIIa, g, h (runs nos. 3, 10 11) were
We failed to involve into Conant reaction acetyl-
arenes containing in the ring strong electron-donor
substituents: the reaction of 4-methoxyacetophenone
with PCL3 in the presence of glacial acetic acid gave
rise to intractable mixture of products. Therefore the
synthesis of diethyl 1-(4-methoxyphenyl)ethenylphos-
phonete (IIg) and diethyl 1-(6-methoxy-2-naphthyl)-
ethenylphosphonate (IIh), and also of diethyl
1-phenylethenylphosphonate (IIa) was carried out by
palladium-catalyzed hydrophosphorylation of the cor-
responding terminal acetylenes with diethylphos-
phorous acid [51].
isolated in 70 88% yield. In none of the above
31
experiments was observed (by
NMR monitoring)
formation of any side product. At acids reduction the
reaction rate increased on replacing methanol with
water (runs nos. 1, 2, 7, 8). The latter fact may be
due to the adsorption of methanol on the catalyst sur-
face decreasing its catalytic activity. The opportunity
of avoiding application of organic solvent obviously
improves the environmental quality of the methods.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

Table 1. Yields, constants, IR spectra and elemental analyses data of arylethenylphosphoric acids CH2= C(Ar)P(O)(OH)2 (Ia f)
Compd.
no.
Yield,
%
mp.,
C
Found, %
Formula
Calcd.,
C
%
H
1
Ar
Ph
IR spectrum , cm
C
H
Ia
83
100 101 (HClaq), 2900 br.s, 2300 br.s, 1602, 1492, 1267, 1207, 1170,
112-113
1078, 987, 960, 836, 779, 711
(C6H6/CH2Cl2a
Ib
Ic
Id
Ie
If
4-MeC6H4 71
120 121 (HClaq) 2800 br.s, 2300 br.s, 1610, 1513, 1259, 1189, 1140, 54.56
1016, 958, 935, 823
5.58
5.09
C2HnC^P
54.55
5.59
5.04
3.69
4.73
4.73
4-PhC6H4
4-ClC6H4
1-Nf
60
76
68
71
186 (toluene)
2900 br.s, 2350 br.s, 1598, 1486, 1403, 1257, 1213, 64.65
1072, 985, 954, 850, 771, 738, 694
C14H13O3P 64.62
137 139 (HClaq)c 2850 br.s, 2300 br.s, 1592, 1492, 1398, 1259, 1189, 44.29
1137, 1074, 1008, 952, 933, 846, 835, 752, 728
3.67 C8H8ClO3P 43.96
133 134 (water) 2800 br.s, 2200 br.s, 1591, 1506, 1205, 1182, 61.73
1150, 1093, 1016, 931, 869, 809, 781
180 180.5 (water) 2850 br.s, 2250 br.s, 1594, 1506, 1270, 1191, 1097, 60.89
1074, 1021, 937, 898, 858, 815, 746
4.72
4.62
Cl2HnO2P
61.54
2-Nf
Cl2HnO2P 61.54
a
b
c
mp 112113 C. [42].
mp 105 C [44]. mp 141 143 C
[43].
1
Table 2. H NMR and 31P NMR spectra of arylethenylphosphonic acids CH2=C(Ar)P(O)(OH)2 (Ia f)
Compd.
no.
1H NMR spectrum (CD3OD), , ppm (J, Hz)
31P NMR
spectrum
Ar
trans-PC=CH (d.d, IH)
cis-PC=CH (d.d, 1H)
Ar
(CD2OD), , ppm
3
3
Ia
Ib
Ic
Ph
6.05 (2JHH 1.6, JHP 44.4) 6.23 (2JHH 1.6, JHP 21.6) 7.31-7.41 m(3H), 7.61 m (2H)
15.9a
15.9
16.0
b
3
3
3
3
4-MeC6H4 6.03 (2JHH 1.6, JHP 44.4) 6.18 (2JHH 1.6, JHP 22.0) 7.19 a (2H, JAB 8.0), 7.51 d.d (2H, JAB 8.0)
3
3
3
3
4-PhC6H4 6.12 (2JHH 1.6, JHP 44.0) 6.25 (2JHH 1.6, JHP 22.0) 7.36 t (IH, JHH 7.2), 7.46 t (2H, JHH 7.2), 7.63-
7.67 m (4H), 7.71 m (2H)
3
3
3
3
Id
Ie
If
4-ClC6H4
1-Nf
2-Nf
6.07 (2JHH 1.5, JHP 43.8) 6.24 (2JHH 1.5, JHP 21.6) 7.38 a (2H, JAB 8.3), 7.60 d.d (2H, JAB 8.3)
15.7
14.5
15.8
5.88 (2JHH 2.2, JHP 45.1) 6.57 (2JHH 2.2, JHP 21.9) 7.50 m (4H), 7.88 m (2H), 8.07 m (IH)
3
3
6.21 (2JHH 1.6, JHP 44.2) 6.32 (2JHH 1.6, JHP 21.6) 7.51 m (2H), 7.73 m (IH), 7.86-7.90 m (3H), 8.15 s(IH)
3
3
a
b
In D2O.
62.36 s (3H, CH3).

SYNTHESIS OF BIOLOGICALLY ACTIVE 1-ARYLETHYLPHOSPHONATES
577
Table 3. Reduction of diethyl 1-phenylethenylphosphonate IIa with various hydrogenating agents
Run no.
Reagent
Solvent
MeOH
MeOH
MeOH
MeOH
Temperature,
C
Time, h
Yield, % (31P NMR)
1
2
3
4
5
6
HCOONH4/Pd C
(6 equiv)/(2.8 mol%)
HCOONH4/Pd C
65
65
65
65
65
78
3
100
97
0.3
0.3
1.75
6.5
2
(6 equiv)/(4.7 mol%)
HCOONH4/Pd Ca
70
(6 equiv)/(4.7 mol%)
HCOONH4/Raney Ni
(6 equiv)/(30 mol%)
HCONH2/Pd C
(6 equiv)/(2.8 mol%)
NaBH4/CoCl2 6H2O
(2 equiv)/( 1 equiv)
40
<10
20
EtOH
a
At repeated use of Pd/C.
Table 4. Reduction of 1-arylethenylphosphonic acids Ia f and diethyl 1-arylethenylphosphonates IIa, g, h by ammonium
formate (6 equiv) in the presence of 5% Pd/C (2.8 mol%)
Yield, %
No. of initial
compound
Reaction
product no.
Run no.
Solvent
Time, h
31P NMR
preparative
1
2
3
4
5
6
7
8
Ia
Ia
H2O
MeOH
MeOH
MeOH
H2O+ MeOH
MeOH
MeOH
H2O
2.5
4
3
4
4
4
5
4
4
IVa
IVa
IIIa
IVb
IVc
IVd+ IVa
IVe
IVe
IVf
IIIg
100
100
100
100
100
50+ 50
60
100
100
100
70
87
87
78
IIa
Ib
Ic
Id
Ie
Ie
If
IIg
IIh
74
76
88
88
9
H2O
MeOH
MeOH
10a
11a
10
10
IIIh
100
a 5% Pd/C (5 mol%), HCOONH4 (7.5 equiv).
Only with poorly soluble in water acid Ic is
required the use as solvent of a mixture H2O MeOH
1: 1 (run no. 5).
Esters IIIg, h containing electron-donor sub-
stituents in the ring turned out to be less reactive than
unsubstituted analogs (cf. runs nos. 10, 11 and 3).
In these cases an increased amount was required
of reductant HCOONH4 (to 7.5 equiv) and of catalyst
Pd/C (to 5 mol%), and the reaction time was pro-
longed to 10 h instead of 2.5 5 h. The structure of
the isolated saturated 1-arylethylphosphonic acids and
diethyl 1-arylethylphosphonates was confirmed by
spectral data and elemental analyses (Tables 5 7).
In the 31P NMR spectra of acids IVa f ap-
peared a signal at 27.9 31.3 ppm, and in the spectra
of esters IIIa, g, h a peak at 29,4 30.6 ppm. In the
I, IV$(24), R = H: Ar = Ph (a), 4-MeC6H4 (b),
4-PhC6H4 (c), 4-ClC6H4 (d), 1-Nf(e), 2-Nf (f); II, III,
R= Et: Ar = Ph (a), 4-MeOC6H4 (g), 6-MeO-2-Nf(h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

Table 5. Yields, constants, IR spectra and elemental analyses data of arylethenylphosphoric acids CH2= C(Ar)P(O)(OH)2 (Ia f)
Compd.
no.
mp, C or
bp,
(p, mm Hg)
Found, %
H
Calcd.,
H
%
1
Ar
C
IR spectrum , cm
Formula
C
P
C
P
IIIa
IVa
IVb
IVc
IVe
IVf
IIg
Ph
Ph
90 92 (0.1)a 2981, 2935, 1604, 1494, 1245, 1186, 1054, 1027,
962, 806, 765, 700
Not determined
Not determined
1516
2850 br, 2300 br, 1602, 1494, 1454, 1247, 1193,
1137, 1006, 931, 767, 696
4-MeC6H4
4-PhC6H4
1-Nf
129 130
215
2850 br, 2300 br, 1515, 1459, 1243, 1201, 1120, 53.81 6.64 15.24 C9H13O3P 54.00 6.55 15.47
1051, 1000, 948, 819, 700
2900 br, 2350 br, 1486, 1249, 1191, 1133, 1068, 64.13 5.78
1006, 929, 835, 767, 696
Cl4Hi5O3P 64.12 5.76
181 182
169.5 170
2850 br, 2300 br, 1596, 1511, 1186, 1130, 987, 60.96 5.42 13.00 C12H13O3P 61.02 5.55 13.11
933, 796, 779
2900 br, 2300 br, 1600, 1508, 1234, 1155, 1101, 60.96 6.08
1020, 937, 858, 821, 740
2-Nf
C12H13O3P 61.02 5.55
4-MeOC6H4 137 141(0.1 2981, 2937, 1612, 1513, 1249, 1182, 1054, 1025, 57.26 8.05 11.12 C13H21O4P 57.35 7.77 11.38
964, 838, 800
6-MeO-2-Nf
IIIh
Oily
2981, 2937, 1606, 1506, 1484, 1392, 1232, 1176,
322.1330c
C17H23O4P
322.1334
substances 1054, 1033, 962, 923, 854, 750
a
b
c
bp103 C (0.4 mm Hg) [15], 159 160 C (15 mm Hg) [13]. mp 151 152 C [11]. HRMS data.

1
Table 6. H NMR and 31P NMR spectra of arylethylphosphonic acids CH2=C(Ar)P(O)(OH)2 IVa f
Compd.
no.
Ar
1H NMR spectrum (CD3OD), , ppm (J, Hz)
31P NMR
spectrum
CH3 (d.d, 3H)
CH (d.q, 1H)
Ar
, ppm(solvent)
3
3
IVa
Ph
1.59 (3JHH 7.6, JHP 18.0)
3.16 (3JHH 7.6, JHP 22.6) 7.24 m (2H), 7.32 m (2H), 7.38 m (1H)
31.0 (EtOAc)
30.4 (CD3OD)
a
3
3
3
3
IVb
IVc
4-MeC6H4 1.56 (3JHH 7.4, JHP 18.2)
3.14 (3JHH 7.4, JHP 22.4) 7.14 d (2H, JAB 8.0), 7.26 d.d (2H, JAB 8.0) 27.9 (CD3OD)
3
3
4-PhC6H4 1.62 (3JHH 7.1, JHP 17.8)
3.21 (3JHH 7.1, JHP 22.8) 7.33 m (1H, 3JHH 7.2), 7.41-7.48 m (4H), 7.58 d (2H, 28.9 (EtOAc)
3
3JHH 8.0), 7.61 d (2H, JHH 7.2)
3
3
3
3
IVd
Ve
4-ClC6H4
1-Nf
1.57 (3JHH 7.6, JHP 18.0)
3.17 (3JHH 7.6, JHP 22.4) 7.32 d (2H, JAB 8.4), 7.37 d.d (2H, JAB 8.4) 29.3 (CD3OD)
3
3
1.71 (3JHH 7.4, JHP 17.8)
4.14 (3JHH 7.4, JHP 22.8) 7.4-7.6 m (3H), 7.7-7.8 m (2H), 7.86 d (1H, 3JHH 8.0), 28.6 (CD3OD)
3
8.19 d (1H, JHH 8.0)
31.3 (EtOAc)
3
3
IVf
2-Nf
1.69 (3JHH 7.2, JHP 18.0) 3.35 (3JHH 7.2, JHP 22.4) 7.42-7.50 m (2H), 7.55 m (1H), 7.80-7.85 m (4H) 29.2 (EtOAc)
a
Table 7. 1H NMR and 31P NMR spectra of diethyl 1-arylethylphosphonates ArCH(CH3)P(O)(OEt)2 (IIIa c)
1H NMR spectrum (CDCl3), , ppm (J, Hz)
31P NMR
spectrum,
, ppm
Compd.
no.
Ar
OCH2CH3
CH3 (d.d, 3H)
CH (d.q, 1H)
Ar
(solvent)
CH2 (m)
CH3 (t)
3
IIIa
Ph
1.57
3.17
7.20-7.35 m (5H)
3.78 (1H),
3.92 (1H),
4.02 (2H)
3.79 (1H),
3.90 (1H),
4.01 (2H)
3.76 (1H),
3.93 (1H),
4.04 (2H)
1.13 (3H, JHH 7.1),
30.2 (MeOH)
30.6 (CDC13)
29.4 (Et2O)
30.6 (MeOH)
3
3
3
(3JHH 7.4, JHP 18.5) (3JHH 7.4, JHP 22.6)
1.26 (3H, JHH 7.1)
a
3
IIIg
IIIh
4-MeOC6H4
1.53
3.11
6.85 d(2H, 3JAB 8.7),
1.14 (3H, JHH 7.0),
3
3
3
3
(3JHH 7.4, JHP 18.5) (3JHH 7.4, JHP 22.5) 7.26 d (2H, JAB 8.7)
1.26 (3H, JHH 7.0)
3
6-MeO-2-Nfb
1.61
3.30
7.0-7.7 m (6H)
1.06 (3H, JHH 7.0),
30.0 (MeOH)
3
3
(3JHH 7.2, JHP 18.4) (3JHH 7.2, (3JHP 22.5)
1.22 (3H, JHH 7.0)
a
b
3.78 s (3H, OCH3).
3.80 s (3H, OCH3).

580
GULYUKINA et al.
Table 8. Optimization of conditions for enantioselective reduction of compounds Ia and IIa (conversion 100%)
No. of initial
compound
Product no.
of reaction
Enantiomer
excess, %
Run no.
H2 pressure, at.
Temperature,
C
1
2
3
4
5
Ia
Ia
Ia
Ia
IIa
1
1
10
100
80
20
80
80
80
80
IVa
IVa
IVa
IVa
IIIa
54
68
73
63
66
1H NMR spectra of compounds III and IV
instead of two double doublets of vinyl protons
characteristic of 1-arylethenylphosphonates appears a
double doublet of methyl group in the 1.54 1.71 ppm
region (3JHP 17.8 18.5 Hz) and a double quartet of
methine proton (2JHP 22.4 22.8 Hz). The latter is
located in the region 3.11 3.21 ppm in the spectra of
phenyl derivatives IVa g and IIIa, g, and is
shifted downfield in the spectra of 2-naphthyl deriv-
atives IVf and IIIh, and especially of 1-naphthyl
derivative IVe. The shift is apparently due to
stronger deshielding effected by the naphthalene ring.
The presence of a C-stereocenter results in two sets
halides with ammonium formate in the presence of
palladium on carbon is a well known process [55],
but a chemoselective reduction of 2-(4-chlorophenyl)-
ethenylphosphonic acid without cleavage of C Cl
bond has been reported [38].
We performed enantioselective hydrogenation of
1-arylethenylphosphonic acids Ia, b, d, e with the
use of optically active ruthenium catalysts. The pre-
liminary optimization of conditions was carried out
by an example of compounds Ia and IIa and
a ruthenium complex of bis(2,2 -diphenylphosphino)-
di-1,1 naphthyl [(S)-Binap]RuBr2 (1 mol%) in
methanol (Table 8).
1
of signals both in the H and 13C NMR spectra. In the
13C NMR spectra of phosphonic acids IV and
diethyl phosphonates III the resonance signal from
C1 appears at 34.1 40.8 ppm. The coupling constant
1JCP is considerably smaller than that observed for
unsaturated phosphonate I and II and amounts
to 135.0 142.8 Hz. This observation is consistent
with the general rule of decreasing of coupling con-
R = H (Ia, IVa), Et (IIa, IIIa).
1
stant JCP on going from sp2- to sp3-hybridized carbon
Enantiomer excess with ester IIIa was measur-
ed by GLC (column Megadex 5). The enantiomers
ratio in the product containing (+) and ( ) IVa was
determined from 31P NMR spectra by integral in-
tensities of signals belonging to diastereomeric salts
prepared by treating compound IVA with an optically
pure diamine. We tested (S)-1-phenylethylamine,
atom [53].
The conservation of a phosphoryl moiety in com-
pounds IIIa, g, h and IVa f is proved by the
presence of the corresponding set of absorption bands
in the IR spectra. It should be noted that in the IR
spectra of saturated phosphonic acids and diethyl
phosphonates as well as in the spectra of their un-
saturated analogs appears a band in the region 1600
1
1700 cm belonging presumably to the aromatic ring
vibrations and frequently erroneously attributed to
vibrations of a C=C bond [54].
We did not succeed to carry out chemoselective
reduction of acid Id: after 4 h of boiling of Id
solution in methanol in the presence of 6 equiv of
HCOONH4 and 2.8 mol% Pd/C (5%) was isolated a
mixture of IVd and IVa products in 1: 1 ratio (run
no. 6). We failed to avoid dehalogenation also at
performing the reaction at room temperature. It
should be noted that reductive dehalogenation of aryl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

SYNTHESIS OF BIOLOGICALLY ACTIVE 1-ARYLETHYLPHOSPHONATES
581
Table 9. Ru(II)-catalyzed enantioselective hydrogenation of 1-arylethenylphosphonic acids Ia, b, d, e
No. of initial
compound
Reaction
product no.
Run no.
Ar
Ph
(PP)
ee, %
1
2
Ia
Ia
Ia
Ia
Ib
Ib
Ib
Ib
Id
Id
Id
Id
(S)-Binap
(R)-IVa
(S)-IVa
(S)-IVa
(R)-IVa
(R)-IVb
(S)-IVb
(S)-IVb
(R)-IVb
(R)-IVd
(S)-IVd
(S)-IVd
(R)-IVd
73
77
24
21
71
78
25
16
73
86
32
37
Ph
(R)-MeO-BIPHEP
(R)-2-furyl-MeO-BIPHEP
(R,R)-Me-DuPHOS
(S)-Binap
3
Ph
4
Ph
5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
6
(R)-MeO-BIPHEP
(R)-2-furyl-MeO-BIPHEP
(R,R)-Me-DuPHOS
(S)-Binap
7
8
9
10
11
12
(R)-MeO-BIPHEP
(R)-2-furyl-MeO-BIPHEP
(R,R)-Me-DuPHOS
13
14
15
16
Ie
Ie
Ie
Ie
1-Nf
1-Nf
1-Nf
1-Nf
(S)-Binap
(R)-IVe
(S)-IVe
(S)-IVe
(R)-IVe
74
80
19
25
(R)-MeO-BIPHEP
(R)-2-furyl-MeO-BIPHEP
(R,R)-Me-DuPHOS
(1R,2R)-( )-1,2-cyclohexyldiamine, (1S,2S)-( )-1,2-
diphenylethylene-1,2-diamine, and (1S,2S)-( )-N,N -
dimethyl-1, 2-diphenylethylene-1,2-diamine. As
solvent was used CDCl3 or CDCl3 with 4 10% of
CD3OD. The maximum difference between chemical
shifts of the signals from two diastereomeric salts
reactivity of acid Ia was higher than that of cor-
responding diethyl ester IIa. Phosphonate IIa
underwent reduction only under stringent conditions
(80 C, 80 at of H2) affording ester IIIa in quantita-
tive yield and enantiomer excess 66%.
Under the developed optimal conditions we carried
out reduction of acids Ia, b, d, e with a series of
ruthenium catalysts prepared in situ [56] and contain-
ing various optically active diphosphine ligands
(Table 9).
(
0.4 ppm) was observed at the use as diamine of
(1S,2S)-( )-N,N‘-dimethyl-1,2-diphenylethylene-1,2-
diamine dissolved in CDCl3 containing 4% of
CD3OD.
As seen from Table 8, the enantioselectivity of
acid Ia hydrogenation on [(S)-Binap]RuBr2
increased with rising temperature in the range 20
80 C (runs nos.1 and 2), and the dependence on
hydrogen pressure between 1 and 100 at has a bell
shape with a maximum at 10 20 at (runs nos. 2 4).
The maximum selectivity, 73% ee, was obtained at
80 C and hydrogen pressure of 10 at (run no. 3). The
I, IV, Ar = Ph (a), 4-MeC6H4 (b), 4-ClC6H4 (d),
1-Nf (e).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

582
Table 10. The study of biological activity of 1-arylethylphosphonic acids IVa, c, e, f
Direction of effect
GULYUKINA et al.
1
Compounds
Ar
Ld50, mg kg
1
dose, mg kg
effect, %
direction of effect
IVa
IVc
IVe
IVf
Ph
4-PhC6H4
1-Nf
700
300
500
500
10
10
50
5
10
0.5
200
40
Tends to increase the activity
of serotonin system
Suppression of dopamine system activity
Increase of serotonin system activity
40
80a
60a
80a
90
2-Nf
Trifluoropyrazine
5-Oxytryptophan
Suppression of dopamine system activity
Increase of serotonin system activity
100
a
p< 0.05 is valid with respect to intact animals.
The catalysts with ligands (R,R)-Me-DuPHOS
(runs nos. 4, 8, 12, 16) and (R)-2-furyl-MeO-BIPHEP
(runs nos. 3, 7, 11, 15) furnished saturated 1-arylethyl-
phosphonic acids IVa, b, d, e of low enantiomeric
purity (ee 16 37 and 19 32% respectively). High
enantiomeric purity (ee 71 74%) was obtained with
(S)-Binap (runs nos. 1, 5, 9, 13). The highest dif-
ferentiating power demonstrated 6,6 -dimethoxy-2,2 -
diphenylphosphinodiphenyl (R)-MeO-BIPHEP (77
86%% ee, runs nos. 2, 6, 10, 14).
phosphonate obtained by treating the isolated sample
of (R)-(IIIa) with diazomethane. The absolute con-
figuration was assigned to compound (S)-(IIIb)
(run no. 6) was also assigned proceeding from the
sign of the specific rotation of the corresponding
(S)-dimethyl
1-(4-methylphenyl)ethylphosphonate.
An authentic sample of (S)-dimethyl 1-(4-methyl-
phenyl)ethylphosphonate used for comparison was
synthesized along procedure from [36].
It was shown formerly that enantioselective hydro-
genation of 2-arylacrylic acids on Ru(II)-catalysts
containing atropoisomeric ligands gave rise to com-
pounds with configuration of C*-stereocenter same as
in the applied ligand [57]. We obtained the opposite
results. For instance, in hydrogenation of compound
Ia in the presence of [(S)-Binap]RuBr2 prevailed the
product (R)-(IVa).
Assignment of the absolute configuration to com-
pound (R)-(IIIa) (run no. 1) was done by comparison
with the published data [36] of the specific rotation
sign of the corresponding (R)-dimethyl 1-phenylethyl-
The results of preliminary testing of 1-arylethylphos-
phonic acids IVa, c, e, f for biological activity are
given in Table 10. The data obtained on Ld50 show
that the acids IVa, e, f are low-toxic. In order to
reveal the possible antidopaminergic and proserotonin-
ergic activity of compounds IVa, c, e, f their interac-
tion with the central effects of L-dioxyphenylalanine
(L-DOPA, precursor of dopamine). The results
obtained demonstrated that acid IVe possesses a
pronounced antidopaminergic activity on the par with
the known dopaminblockader, trifluoropyrazine. The
activity of acid IVf is like that of nonselective
serotoninmimetics and 5-oxytryptophan. The complete
data on the studies of biological activity of 1-aryl-
ethylphosphonic acids will be published elsewhere.
EXPERIMENTAL
1H, 13C, and 31P NMR spectra were registered
on spectrometer Varian VXR-400 at operating fre-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

SYNTHESIS OF BIOLOGICALLY ACTIVE 1-ARYLETHYLPHOSPHONATES
583
quencies 400, 101, and 162 MHz respectively. The
chemical shifts are given in scale relative to TMS
or 85% H3PO4. In several cases the chemical shifts
were measured relative to the residual protons of the
solvents used (3.34 ppm for CD3OD and 7.25 ppm
for CDCl3). IR spectra were recorded on Fourier-
transform spectrophotometer IKAR (Joint-Stock Co
reflux condenser, dropping funnel, and connected to
supply of dry argon was charged 23.3 ml (0.2 mol)
of acetophenone. At cooling on an ice bath and while
vigorous stirring to the flask was slowly added drop-
wise 24 ml (0.275 mol) of freshly distilled PCl3. The
reaction mixture was stirred for 1 h at room tempera-
ture, then it was again cooled, and slowly (within
30 min) was added dropwise 34.35 ml (0.6 mol) of
glacial acetic acid. Then the reaction mixture was left
overnight.
1
Mikrotekh , Russia), resolution 1 cm , number of
scans 30. Mass spectra were measured on Varian
MAT-212 instrument with direct injection of sample
into the ion source.
The solution obtained was poured on 700 g of ice
and left for 24 h. Then it was evaporated in a
porcelain evaporating dish at 90 92 C till small
volume. The residue was dissolved in 50 ml of boil-
ing concn HCl, and the solution was boiled for 3.5 h.
The crystals that precipitated on cooling were filtered
off and washed with cold benzene. We obtained
30.59 g (83%) of acid Ia. 13C NMR spectrum
The acute toxicity of 1-arylethylphosphonic acids
IVa, c, e, f was estimated on male mice of
C57B1/6 line. The substances were dispersed in water
with added TWEEN-60 and were injected intraperi-
1
toneally in doses of 100, 500, and 1000 mgkg . The
results obtained were treated by procedure of Litch-
field and Wilcockson [58]. The experiments on inter-
action of 1-arylethylphosphonic acids IVa, c, e, f
with the central effects of L-dioxyphenylalanine were
carried out on male rats of Wistar line weighing 220
250 g. The substance studied was dispersed in water
containing TWEEN-80, and was injected intraperi-
toneally simultaneously with L-DOPA (commercial
3
(CD3OD, , ppm): 129.0 d (2CH arom, JCP 5.7 Hz),
2
129.4 s (CH arom), 129.58 d (CH2=C, JCP 7.5 Hz),
2
129.61s (2CH arom), 139.1d (C arom, JCP 12.4 Hz),
1
144.6 d (C P, JCP 174.9 Hz).
1-(4-Methylphenyl)ethenylphosphonic acid (Ib)
was prepared in a similar way from 7.38 g (55 mmol)
of 4-methylacetophenone, 6.5 ml (74 mmol) of PCl3,
and 9.4 ml (164 mmol) of glacial CH3COOH. We
obtained 7.7 g (71%) of acid Ib. 13C NMR spectrum
(CD3OD, , ppm): 21.6 s (CH3), 128.7, 128.8,
1
preparation MADOPAR-125, dose 125 mg kg ). In
60 min was estimated the intensity of stereotypical
reactions and the behavior of animals in the test of
extrapolation release [59, 60].
2
128.85, 130.2 s (2CH arom), 136.0 d (C arom, JCP
Methanol was boiled and distilled over magnesium
methylate. Ammonium formate of pure grade was
dried in a vacuum-desiccator over P2O5.
1
12.2 Hz), 139.2 s (C arom), 144.0 d (C P, JCP
175.3 Hz).
1-(4-Diphenyl)ethenylphosphonic acid (Ic) was
prepared in a similar way from 4.4 g (22.4 mmol)
of 4-acetyldiphenyl, 3.14 ml (36 mmol) of PCl3,
and 4.5 ml (78.6 mmol) of glacial CH3COOH
without cooling of the reaction mixture in the
course of reaction. To the residue obtained after
evaporation was added 150 ml of toluene, and the
solution obtained was boiled for 10 h while distil-
ling off the forming water. The precipitate
separated on cooling was filtered off. Yield 3.5 g
(60%).
1-Acetylnaphthalene was prepared and purified by
the known procedures [61].
Palladium on carbon (5% of Pd). A mixture of
0.167 g of palladium(II) chloride, 0.4 ml of concn
hydrochloric acid, and 1 ml of water was heated on a
water bath till homogeneous solution formed (about
30 min). The solution obtained was fast added drop-
wise while vigorous stirring to a hot (80 C) disper-
sion of 1.9 g of carbon in 24.5 ml of water, and then
dropwise was added 0.5 ml of 37% formalin. The
mixture was stirred for 30 min, then cooled, and 30%
solution of potassium hydroxide was added till weak-
ly alkaline reaction against litmus. Another 30 min
the mixture was maintained at 60 C with intermittent
stirring, and then 2 h more at room temperature.
The catalyst was filtered off and washed with water
till negative reaction for OH ions against phenol-
phthalein, dried in air and then in a desiccator over
potassium hydroxide.
1-(4-Chlorophenyl)ethenylphosphonic acid (Ib)
was prepared in a similar way from 10.4 ml
(80.2 mmol) of 4-chloroacetophenone, 9.6 ml
(110 mmol) of PCl3, and 13.6 ml (237.6 mmol) of
glacial CH3COOH. We obtained 13.3 g (76%) of
acid Id. 13C NMR spectrum (CD3OD, , ppm):
2
129.7 s (2CH arom), 129.9 d (CH2=C, JCP 7.4 Hz),
3
130.5 d (2CH arom, JCP 5.9 Hz), 135.3 s (C arom),
2
1
1-Phenylethenylphosphonic acid (Ia). Into a
137.9 d (C arom, JCP 12.3 Hz), 143.7 d (C P, JCP
round-bottom flask filled with argon equipped with a
175.3 Hz).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

584
GULYUKINA et al.
1-(1-Naphthyl)ethenylphosphonic acid (Ie) was
(4.9 mol% of Pd). Reaction time was 10 h. Yield
0.64 g (88%). 13C NMR spectrum (CDCl3, , ppm):
15.0 d (CH3, JCP 4.6 Hz), 15.7 d (CH3, JCP 5.9 Hz),
prepared in a similar way from 9.16 g (54 mmol) of
1-acetylnaphthalene, 6.4 ml (73 mmol) of PCl3, and
9.4 ml (169 mmol) of glacial CH3COOH. The
residue obtained by evaporation was recrystallized
from water and washed on filter with cold benzene.
We obtained 8.6 g (68%) of acid Ie. 13C NMR spec-
trum (CD3OD, , ppm): 126.2 d (CH arom, JCP
2.0 Hz), 127.1s (CHarom), 127.2s (CHarom), 127.4s
(CH arom), 127.9 d (CH arom, JCP 4.0 Hz), 129.3 d
(CH arom, JCP 3.0 Hz), 129.4 s (CH arom), 132.7 d
1
15.8 d (CH3, JCP 5.5 Hz), 36.7 d (CH P, JCP
2
138.5Hz), 54.4 s (CH3O), 61.2 d (CH2, JCP 7.2 Hz),
2
61.8d (CH2, JCP 6.4 Hz), 113.1 s (2CH arom),
3
129.0 d (2CH arom, JCP 6.1 Hz), 131.3 d (C arom,
2JCP 9.2 Hz), 158.0 s (C OMe).
Diethyl 1-(6-methoxy-2-naphthyl)ethylphos-
phonate (IIIh) was prepared similarly by reduction
of 0.72 g (2.5 mmol) of compound IIh with ammon-
ium formate (1.06 g, 16.8 mmol, 7.5 equiv) in 34 ml
of anhydrous MeOH in the presence of 0.24 g of 5%
Pd/C (5 mol% of Pd). Reaction time was 10 h. The
catalyst was separated by filtration of the reaction
mixture through a thin bed of silica gel. The filtrate
was evaporated in a vacuum, the residue was ex-
tracted with Et2O. The ether extract was washed with
small portion of water, dried on MgSO4, filtered, and
evaporated. The residue was thick red-brown oily
substance. Yield 0.64 g (88%). 13C NMR spectrum
(CDCl3, , ppm): 15.3 d (CH3, JCP 4.5 Hz), 16.0 d
(CH3, JCP 5.4 Hz), 16.1 d (CH3, JCP 5.7 Hz), 37.9 d
2
(CH2=C, JCP 8.1 Hz), 133.4d (C arom, JCP 4.4 Hz),
2
135.6 s (C arom), 137.2 d (C arom, JCP 10.1 Hz),
1
143.9 d (C P, JCP 176.1 Hz).
1-(2-Naphthyl)ethenylphosphonic acid (Ie) was
prepared in a similar way from 9.2 g (54 mmol) of
2-acetylnaphthalene, 7 ml (80 mmol) of PCl3, and
10.0 ml (175 mmol) of glacial CH3COOH. The boil-
ing with HCl continued for 4 h. The residue obtained
by evaporation was recrystallized from water and
washed on filter with cold benzene. We obtained 9 g
(71%) of acid If. 13C NMR spectrum (CD3OD,
,
ppm): 126.7 d (CH arom, JCP 5.6 Hz), 127.6 (CH
arom), 128.1 d (CH arom, JCP 5.7 Hz), 128.8 s
(CH arom), 129.2 s (CH arom), 129.6 s (CH arom),
1
(CH P, JCP 138.0 Hz), 54.8 s (CH3O), 61.6 d (CH2,
2
2JCP 7.1 Hz), 62.1 d (CH2, JCP 6.9 Hz), 105.1 s
2
129.9 d (CH2=C, JCP 7.9 Hz), 134.6 s (C arom),
(CH arom), 118.6 s (CH arom), 126.5 s (CH arom),
126.8, 127.0, 128.3, 128.9 s (CH arom), 132.0,
133.3 s (C arom), 157.3 s (C OMe).
134.9 s (C arom), 136.4 s (C arom), 144.4 d (C P,
1JCP 174.9 Hz).
Diethyl 1-phenylethylphosphonate (IIIa). A mix-
ture of 1.2 g (5 mmol) of compound IIa, 1.91 g
(30 mmol, 6 equiv) of HCOONH4, 0.29 g of 5%
Pd/C (2.7 mol% of Pd) in 70 ml of anhydrous MeOH
was boiled for 3 h in a flow of dry argon. The catal-
yst was separated by filtration of the reaction mixture
through a thin bed of silica gel. The filtrate was
evaporated in a vacuum, the residue was extracted
with Et2O. The ether extract was washed with small
portion of water, dried on MgSO4, filtered, and
evaporated. The residue was distilled under reduced
pressure in a flow of argon. We obtained 1.05 g
(87%) of phosphonate IIIa. 13C NMR spectrum
(CDCl3, , ppm): 15.2 d (CH3, JCP 5.2 Hz), 15.9 d
(CH3, JCP 5.7 Hz), 16.1 d (CH3, JCP 6.1 Hz),
1-Phenylethylphosphonic acid (IVa). A mixture
of 0.92 g (5mmol) of compound Ia, 1.90 g (30mmol)
of ammonium formate, and 0.3 g of 5% Pd/C
(2.8 mol% of Pd) in 70 ml of anhydrous MeOH was
boiled for 4 h in a flow of dry argon. The catalyst
was removed by filtration through a thin bed of silica
gel, methanol was distilled off on rotary evaporator.
The residue was acidified with a small amount of
conc. HCl and extracted with EtOAc. The organic
extracts were dried on MgSO4, filtered therefrom, and
evaporated. The residue (yellowish oily substance)
was recrystallized from a mixture benzene petro-
leum ether. We obtained 0.65 g (70%) of acid IVa.
13C NMR spectrum (CDCl3, , ppm): 14.7 d (CH3),
1
37.6 d (CH P, JCP 140.7 Hz), 127.2 s (CH arom),
2
2
61.6d (CH2, JCP1 7.0 Hz), 62.1 d (CH2, JCP 6.9 Hz),
128.4 s (2CH arom), 128.6 d (2 CH arom), 136.6 d
2
38.1 d (CH P, JCP 137.7 Hz), 126.7 s (CH arom),
(C arom, JCP 6.4 Hz).
2
128.3, 128.4, 128.5, 128.6, 137.6 d (C arom, JCP
1-(4-Methylphenyl)ethylphosphonic acid (IVb)
was prepared similarly by reduction of 0.99 g
(5 mmol) of compound Ib with ammonium formate
(1.9 g, 30 mmol) in 70 ml of anhydrous MeOH in the
presence of 0.3 g of 5% Pd/C. Yield 0.87 g (87%).
13C NMR spectrum (CD3OD, , ppm): 16.3 s
7.0 Hz).
Diethyl 1-(4-methoxyphenyl)ethylphosphonate
(IIIg) was prepared similarly by reduction of 0.72 g
(2.7 mmol) of compound IIg with ammonium formate
(1.27 g, 20.1 mmol, 7.5 equiv) in 40 ml of anhydrous
MeOH in the presence of 0.28 g of 5% Pd/C
1
CH3CH), 21.1 s (CH3Ar), 39.9 d (CH P, JCP
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

SYNTHESIS OF BIOLOGICALLY ACTIVE 1-ARYLETHYLPHOSPHONATES
585
142.8 Hz), 129.5d (2CH arom), 129.9s (2CH arom),
132.8 d (C arom, JCP 13.0 Hz), 137.3 s (Me C
arom).
vol. 44, no. 12, pp. 1167 1191.
2
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1-(4-Diphenyl)ethylphosphonic acid (IVc) was
prepared similarly by reduction of 1.3 g (5 mmol)
of compound Ic with ammonium formate (1.89 g,
30 mmol) in 100 ml of water in the presence of
0.30 g of 5% Pd/C. The compound obtained was
recrystallized from ethyl acetate. Yield 0.8 g (61%).
1-(1-Naphthyl)ethylphosphonic acid (IVe) was
obtained similarly by reduction of 1.22 g (5.2 mmol)
of compound Ie with ammonium formate (1.98 g,
31 mmol) in 40 ml of water in the presence of 0.31 g
of 5% Pd/C. Yield 0.91 g (74%). 13C NMR spectrum
2
(CD3OD, , ppm): 17.3 d (CH3, JCP 4.4 Hz), 34.1 d
1
(CH P, JCP 135.0 Hz), 124.6 s (CH arom), 126.4,
126.45, 126.6, 126.7, 127.0 s (CH arom), 128.2 s
(CH arom), 129.8 s (CH arom), 133.3 d (C arom,
JCP 7.1 Hz), 135.4 s (C arom), 137.0 d (C arom,
JCP 6.2 Hz).
1-(2-Naphthyl)ethylphosphonic acid (IVf) was
obtained similarly by reduction of 1 g (4.27 mmol) of
compound If with ammonium formate (1.62 g,
25.7 mmol) in 60 ml of water in the presence of
0.273 g of 5% Pd/C. Yield 0.7 g (69%). 13C NMR
10. Zimmerman, H.E., Keck, G.E., and Pflederer, J.L.,
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2
spectrum (CD3OD, , ppm): 16.6 d (CH3, JCP
1
4.3 Hz), 40.8 d (CH P, JCP 136.1 Hz), 126.9 s
(CH arom), 127.2 s (CH arom), 128.41, 128.46,
128.5, 128.8 s (CH arom), 129.0 s (CH arom),
134.2 d (C arom, JCP 1.8 Hz), 135.2 d (C arom, JCP
2
2.2 Hz), 138.4 d (C arom, JCP 8.0 Hz).
General procedure for enantioselective hydro-
genation. Into a flask of 50 ml capacity was charged
7 mg (0.012 mmol) of (R)-MeO-BIPHEP and 3.2 mg
(0.01 mmol) of (COD)Ru[ 3-(CH2)2CCH3]. Anhy-
drous acetone (5 ml) was added dropwise, and then
122 l of 0.18 M solution of HBr in methanol. The
reaction mixture was stirred at room temperature for
30 min. The solvent was distilled off in a vacuum. To
the orange solid residue of the catalyst under argon
atmosphere was added 2 ml of methanol and 1 mmol
of acid I. The reaction flask was placed into a steel
pressure reactor of 500 ml capacity, and hydrogen
was supplied to the reactor to the desired pressure.
The reaction mixture was always maintained till
100% conversion.
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