Nonracemic menthyl phosphorylacetates

Article abstract of DOI:10.1007/s11172-007-0047-7

Phosphorylacetic acid esters containing the menthoxy fragment at the phosphorus atom or at the carbonyl group were synthesized. The configurations of the enantiomerically pure compounds, viz., methyl (ethoxy)(menthyloxy) phosphorylacetate and menthyl [(2-

Full text of DOI:10.1007/s11172-007-0047-7

Russian Chemical Bulletin, International Edition, Vol. 56, No. 2, pp. 290—297, February, 2007
290
Nonracemic menthyl phosphorylacetates
a
b
b
a
A. A. Bredikhin,a R. M. Eliseenkova, R. I. Tarasova, O. V. Voskresenskaya, A. A. Balandina,
ꢀ
A. B. Dobrynin,a Sh. K. Latypov,a I. A. Litvinov,a D. R. Sharafutdinova,a and Yu. Ya. Efremova
aA. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253. Eꢀmail: baa@iopc.knc.ru
bS. M. Kirov Kazan State Technological University,
68 ul. K. Marksa, 420015 Kazan, Russian Federation.
Fax: +7 (843) 238 5694. Eꢀmail: mukattisg@mail.ru
Phosphorylacetic acid esters containing the menthoxy fragment at the phosphorus atom or
at the carbonyl group were synthesized. The configurations of the enantiomerically pure
compounds, viz., methyl (ethoxy)(menthyloxy)phosphorylacetate and menthyl [(2ꢀchloroꢀ
ethoxy)(4ꢀdimethylaminophenyl)phosphoryl]acetate, were established by Xꢀray diffraction and
NMR spectroscopy.
Key words: phosphorylacetic acids, menthol, stereoisomerism, diastereomers, configuraꢀ
tion, Xꢀray diffraction analysis, NMR spectroscopy.
Since phosphorylcarboxylic acid derivatives are anaꢀ
With the aim of preparing enantiopure biologically
active organophosphorus compounds and determining
their configurations, we synthesized phosphorylacetic acid
esters containing the (1R,2S,5R)ꢀmenthol fragment at the
phosphorus atom or the carbonyl group. Some of the
isolated enantiomerically pure diastereomers were studied
by different twoꢀdimensional NMR methods. The indiꢀ
rect results for menthyl [(2ꢀchloroethoxy)(4ꢀdimethylꢀ
aminophenyl)phosphoryl]acetate were compared with the
direct Xꢀray diffraction data.
logs of biogenic compounds, they can exhibit high bioꢀ
logical activity.1,2 For example, the study of the strucꢀ
ture—biological activity relationship in a series of phosꢀ
phorylacetic acids revealed promising representatives
having unique effects on the central nervous system.3
For example, [(2ꢀchloroethoxy)(4ꢀdimethylaminopheꢀ
nyl)phosphoryl]acethydrazide (CAPAH) not only exhibꢀ
its antidepressant activity but also improves memory and
trainee's ability.4 The molecule of this compound conꢀ
tains the asymmetric phosphorus atom. According to
Xꢀray diffraction data, the CAPAH racemate crystallizes
as a racemic compound containing equal amounts of
(R) and (S) enantiomers in the unit cell.5 Since individual
enantiomers usually differ substantially in biological acꢀ
tivity, the synthesis of phosphorylacetic acid derivaꢀ
tives in the enantiomerically pure form is an important
problem. One of approaches to the solution of this probꢀ
lem is based on the synthesis of derivatives containing a
chiral fragment with the authentic absolute configuration
followed by the separation of individual diastereomers
and the determination of the absolute configuration of
the chiral center in question relative to the reference
center. This problem can easily be solved by Xꢀray difꢀ
fraction if highꢀquality single crystals are available. Eviꢀ
dently, modern methods of multidimensional NMR specꢀ
troscopy providing information on the mutual arrangeꢀ
ment of fragments in a molecule can be used for the
determination of the relative configuration of liquid or
dissolved compounds.
Results and Discussion
The reaction of diethyl menthyl phosphite (1) or
diꢀO,Oꢀmenthyl phenylphosphonite (2) with menthyl
chloroacetate (Scheme 1) proceeds under more drastic
conditions than the reaction with methyl chloroacetate,
requires the presence of catalytic amounts of zinc chloꢀ
ride, and is accompanied by elimination of chloroethane,
while the menthoxy substituent remains intact. The presꢀ
ence of the latter in products 3—5 was confirmed by mass
1
spectrometry and H NMR spectroscopy. The CI mass
spectra of compounds 3 and 5 contain peaks of the protoꢀ
nated molecular ions [MH]+, whose weights correspond
to the calculated values.
The reactions of 2ꢀchloroethoxy esters of phosphoꢀ
rus(III) acids with menthyl chloroacetate afforded target
products 9—11 (Scheme 2). However, this reaction, like
the reaction with ethyl chloroacetate studied earlier,6 is
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 281—288, February, 2007.
1066ꢀ5285/07/5602ꢀ0290 © 2007 Springer Science+Business Media, Inc.

Menthylꢀcontaining phosphorylacetic acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
291
Scheme 1
substantially different and can be used for the determinaꢀ
tion of their ratio. For example, the 1H NMR spectrum of
Ph2P(O)OMnt shows only the signal of the methyl groups
of the isopropyl fragment at δ 0.57, whereas the spectrum
of Ph(Me)P(O)OMnt has two signals at δ 0.34 and 0.89
corresponding to these groups.7
The chemical shifts of the protons of the C(9´)H3
group in the resulting compounds are given in the Experiꢀ
mental section. These protons in the spectra of derivaꢀ
tives 1 and 9 containing the achiral phosphorus atom are
characterized by the only highꢀfield doublet. The shift δ
for the C(9´)H3 group remains virtually unchanged reꢀ
gardless of whether the menthyl substituent is present at
the phosphorus atom or in the ester fragment. Derivatives
containing the chiral phosphorus center are characterized
by two signals of the C(9´)H3 group. In the spectra of
Pꢀarylꢀsubstituted compounds 4 and 10, one of the signals
is substantially shifted upfield (the considerable shielding
effect of diamagnetic anisotropy of the aryl ring7).
R = R´ = OEt (1); R = Ph, R´ = OMnt (2)
R = OEt, R″ = Me (3); R = Ph, R″ = Me (4); R = OEt, R″ = Mnt (5)
complicated by isomerization giving rise to compounds
12—14 as byꢀproducts.
This effect is consistent with our estimates of the
shielding of the protons of all Me groups in the menthyl
fragment of ester 4 by the aryl substituent for both (RP
and SP) diastereomers (the geometry was optimized by
the MM2 method, the semiclassical model of ring curꢀ
rents,8 the Shields program). According to the calculaꢀ
tions, a considerable (up to 0.6 ppm) shielding effect
should be observed for the protons of the C(9´)H3 group
in the SP isomer (for the C(10´)H3 group, this efꢀ
fect ≤0.2 ppm; for C(8´)H, ≤0.5 ppm). By contrast, an
insignificant effect of the aromatic moiety (at most
0.1 ppm) should be observed only for the protons of the
C(7´)H3 group in the RP isomer.
Scheme 2
An analysis of the NMR spectroscopic data for the
reaction mixtures (see Schemes 1 and 2 and the Experiꢀ
mental section) demonstrated that the reactions are
stereoselective and produce predominantly one of diasteꢀ
reomers. Apparently, higher stereoselectivity of these reꢀ
actions is favored by the steric and electronic effects of
the aryl substituent.9 Samples substantially enriched in
one of diastereomers were obtained by column chromaꢀ
tography and fractional crystallization. In the case of esꢀ
ters 3b and 11b, we succeeded in isolating individual diaꢀ
stereomers, and the assignment of their configurations
was made by NMR spectroscopy and Xꢀray diffraction.
Since the individual diastereomer of methyl
(ethoxy)(menthyloxy)phosphorylacetate (3b) was obꢀ
tained as lowꢀmelting crystals (see the Experimental secꢀ
tion), the determination of its structure by Xꢀray diffracꢀ
tion presented difficulties. The information on its conꢀ
stitution (the chemical structure and the binding of
fragments) was obtained by 1D and 2D NMR experiꢀ
ments (DEPT, 2D COSY, 2D HSQC, 2D HMBC, and
1D DPFGNOE).10,11
R = R´ = Ph (6, 9, 12); R = Ph, R´ = Et (7, 10, 13);
R = 4ꢀMe2NC6H4, R´ = OCH2CH2Cl (8, 11, 14)
Due to the presence of the enantiomerically pure menꢀ
thol fragment in molecules 3—5, 10, and 11, the reacꢀ
tions produce mixtures of two diastereomers, which differ
in the configuration of the chiral center at the phosphorus
atom. The ratios of diastereomers were determined based
on the integral intensities of the signals for the phosphoꢀ
rus atoms in the 31P NMR spectra (see the Experimental
section).*
The presence of the menthyl fragment provides an
additional possibility to identify diastereomers. Earlier,7
studies of menthyl phosphinates have demonstrated that a
doublet belonging to one of the Me groups, C(9´)H3, of
the isopropyl substituent in the menthyl fragment (see
Scheme 1) is characterized by an upfield shift in the
1H NMR spectra. If the phosphorus atom is chiral, the
chemical shifts of these signals for two diastereomers are
* Hereinafter, the diastereomers are denoted by the letters а
and b, the letter a is ascribed to the stereoisomer characterized
by smaller δ in the 31P NMR spectrum. The letters a and b are
not directly related to the configuration of the phosphorus atom.
The 1H NMR spectrum of isomer 3b shows a group of
multiplets at δ 0.7—4.4. The spin systems belonging to

292
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Bredikhin et al.
the protons of two functional groups (the ethoxy and
menthoxy fragments) were unambiguously distinguished
in the 2D COSY spectrum. Taking into account the
2D HSQC spectroscopic data, the signals of the protonꢀ
containing carbon atoms of these fragments were reliably
identified. The structures of the fragments and their bindꢀ
ing to the phosphorus atom were conclusively determined
based on H—13C HMBC and H—31P HSQC correlaꢀ
tions. In the 2D HMBC (1H—13C) spectrum, there are
correlations between the C(2)H2 protons (δ 2.95) and the
C(4) atom (δ 52.34), between the C(4)H3 protons (δ 3.72)
and the C(2) atom (δ 35.25), and between the C(2)H2
(δ 2.95) and C(4)H3 (δ 3.72) protons and the C(3) atom
(δ 166.32) (Fig. 1). The 2D HSQC (1H—31P) spectrum
shows crossꢀpeaks between the C(2)H2 (δ 2.95) and
C(4)H3 (δ 3.72) protons and the P(1) atom (δ 18.72)
(Fig. 2). The combined analysis of the spectroscopic reꢀ
sults allowed the establishment of the structure of the
P—CH2—CO—OCH3 fragment up to the phosphorus
atom inclusive (Fig. 3).
The crossꢀpeaks between the C(5)H2 (δ 4.17) and
C(6)H3 (δ 1.33) protons and the P(1) atom (δ 18.72)
observed in the 2D HSQC (1H—31P) spectrum (see Fig. 2)
confirm the presence of the bond between the ethoxy
fragment and the phosphorus atom (see Fig. 3). In addiꢀ
tion, this spectrum shows crossꢀpeaks between the proton
of the oxymenthyl substituent C(3´)H (δ 4.27) and the
P(1) atom (δ 18.72) (see Fig. 2). The presence of this
crossꢀpeak is indicative of the presence of a covalent bond
between the menthoxy fragment of this isomer and the
phosphorus atom (see Fig. 3). Therefore, the combined
use of different homoꢀ (1H—1H) and heterocorrelation
1
(1H—13C and H—31P) experiments made it possible to
successively determine the constitution of compound 3b
(along with that of diastereomer 3а).
Unlike enantiomers, diastereomers differ in scalar
characteristics, including intramolecular internuclear disꢀ
tances. This means that the absolute configuration of the
phosphorus atom in crystalline stereoisomer 3b can be
determined based on the correlations due to NOE diꢀ
rectly dependent on internuclear distances,11 if the absoꢀ
lute configuration of the starting menthyl fragment and
the conformation of the chain between the chiral phosꢀ
phorus atom and the menthoxy fragment are known.
According to the published data,7,12 the nearly synꢀ
periplanar orientation of the P=O bond with respect to
the C(3´)—H bond is dominant for the analogous chain
in menthyl phosphinates and other related compounds.
The analysis of the possible conformers with respect to
the (P)O—C(3´) bond in ester 3b by the MM2 method13
showed that the synperiplanar conformers are dominant
in this case as well (Fig. 4).
1
1
The 1D DPFGNOE spectra of stereoisomer 3b show
intense NOEs between C(4)H3 (δ 3.72) and C(8´)H
(δ 2.08), C(9´)H3 (δ 0.79) and between C(2)H2 (δ 2.95)
and C(8´)H (δ 2.08), C(9´)H3 (δ 0.79). This is indicative
of the spatial proximity of the isopropyl group of the menꢀ
thyl fragment and the P—CH2—CO2Me fragment (see
C(4)H3
C(10´)H3
C(7´)H3
H(2´)
H(5´)
C(6)H3
C(2)H2
H(5´)
C(9´)H3
H(4´)
C(5)H2
H(6´)
H(6´)
H(8´)
H(2´)
H(3´)
H(1´)
δ
C(9´)
C(7´)
C(10´)
C(10´)H3/C(9´)
H(8´)/C(9´)
H(8´)/C(5´)
H(8´)/C(10´)
20
C(4)H3/C(2)
C(8´)
H(3´)/C(8´)
H(3´)/C(4´)
C(1´)
C(2)
C(6´)
C(2´)
40
60
H(2´),H(8´)/C(4´)
H(2´),H(8´)/C(3´)
C(2)H2/C(4)
C(4´)
C(4)
C(5)
H(2´)/C(3´)
80
C(3´)
100
120
140
160
C(4)H3/C(3)
C(2)H2/C(3)
C(3)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
δ
Fig. 1. 2D HMBC (1H—13C) spectrum of stereoisomer 3b in CDCl3 (T = 303 K).

Menthylꢀcontaining phosphorylacetic acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
293
C(6)H3
C(4)H3
C(10´)H3
C(2)H2
C(7´)H3
H(5´)
C(9´)H3
H(4´)
H(6´)
H(1´)
C(5)H2
H(2´)
H(6´)
H(8´)
H(3´)
H(5´)
H(2´)
δ
12
14
16
C(2)H2/P(1)
C(6)H3/P(1)
C(5)H2/P(1)
C(4)H3/P(1)
18
20
22
24
26
28
P(1)
H(3´)/P(1)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
δ
Fig. 2. 2D HSQC (1H—31P) spectrum of stereoisomer 3b in CDCl3 (T = 303 K).
1
Fig. 3. Principal H—13C HMBC correlations (from protons to
carbon atoms) and 1H—31P HSQC correlations (from protons
to the phosphorus atom) for compound 3b.
Fig. 4). In another diastereomer (in which the OEt and
CH2CO2Me substituents change places), such spatial
proximity is hardly probable. Therefore, the experimental
Overhauser effects suggest that the phosphorus atom in
the diastereomer under study has an S configuration shown
in Fig. 4.
The major diastereomer of menthyl [(2ꢀchloroꢀ
ethoxy)(4ꢀdimethylaminophenyl)phosphoryl]acetate
(11b), whose percentage in the crude reaction mixture is
higher than 80%, can easily be isolated in the crystalline
state (see the Experimental section). The singleꢀcrysꢀ
tal Xꢀray diffraction study of compound 11b demonꢀ
strated that this compound crystallizes in the chiral
space group P21 (Z = 2), i.e., there is one molecule per
Fig. 4. Calculated major conformation of diastereomer 3b and
asymmetric unit cell (Fig. 5).
the observed principal NOEs.

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Bredikhin et al.
C(8)
C(7)
C(4)
N(1)
C(18)
C(5)
C(19)
C(13)
C(6)
C(17)
C(3)
C(2)
C(1)
C(12)
C(14)
C(15)
C(11)
P(1)
O(4)
O(1)
C(10)
Cl(2)
O(2)
O(3)
C(16)
C(20)
C(21)
C(22)
C(9)
Fig. 5. Geometry of the menthyl [(2ꢀchloroethoxy)(4ꢀdimethylꢀ
aminophenyl)phosphoryl]acetate molecule (11b).
The bond lengths at the P(1) atom are typical of such
bonds (P(1)=O(1), 1.486(6) Å; P(1)—O(2), 1.615(6) Å).
Classical hydrogen bonds in this structure are absent, and
the main supramolecular motif, viz., the zigzag chains
along the crystallographic axis 0у, is stabilized by the
C(9)—H(92)...O(1´) (–х, –1/2 + у, –z) (C—H, 0.96 Å;
H...O, 2.48 Å; C...O, 3.408(9) Å; C—H...O, 165°) and
C(22)—H(222)...O(3´) (C—H, 0.91 Å; H...O, 2.51 Å;
C...O, 3.168(16) Å; C—H...O, 129°) hydrogen bonds.
Since the configuration of the chiral carbon atoms of
the menthyl fragment is known in advance (C(11R),
C(12S), C(15R)), the configuration of the P(1) atom was
identified as S. Figure 5 shows that diastereomer 11b is
characterized by the spatial proximity of the isopropyl
group of the menthyl fragment and the aryl substituent at
the phosphorus atom.
The data on the structure of 11b in solution obtained
by NMR spectroscopy are consistent with the Xꢀray difꢀ
fraction data. The chemical structure of compound 11b
was established according to the scheme analogous to that
used for the structure of 3. Hence, we analyzed only the
observed Overhauser effects for this compound (Fig. 6).
In this case, the determination of the configuration of the
phosphorus atom based only on NOEs is complicated by
the presence of the potentially conformationally flexible
P—CH2—C(O)—O—C(3´) chain between the menthyl
fragment and the phosphorus atom. However, the fact that
the NOEs are observed between the isopropyl substituent
and the atoms of the aromatic ring provides evidence for
the similarity of the conformations of this diastereomer in
the crystal and solution. To the contrary, when assuming
the conformational restrictions reasonable for this chain
(the sꢀcis conformation of the ester group and the sinclinal
orientation along the P—CH2 bond), the expected NOEs
Fig. 6. Principal NOEs and their correlation with the structure
of diastereomer 11b.
are consistent with those observed for the SP diastereomer
of ester 11.
In summary, the results of a series of 2D NMR experiꢀ
ments allowed us to unambiguously determine the constiꢀ
tutions of compounds 3b and 11b in solution. The conꢀ
figurations of the compounds under study were initially
assumed based on the quantitative consideration of the
anisotropic magnetic shielding due to the presence of the
aromatic fragments of the molecules. The absolute conꢀ
figuration of the phosphorus atom in both compounds
was more reliably established based on the detailed conꢀ
sideration of the experimental nuclear Overhauser effects.
The validity of the established conformations of the moꢀ
lecular fragments in compound 11b was confirmed by
comparing the data from NMR spectroscopy for solutions
with the singleꢀcrystal Xꢀray data.
Experimental
The 1H, 13C, and 31P 1H NMR spectra were recorded on
a Bruker AVANCEꢀ600 instrument (600.00 MHz for 1H,
150.864 MHz for 13C, and 242.88 MHz for 31P) in CDCl3
at 30 °C. The chemical shifts of the protons are given relative to
Me4Si; the chemical shifts of the phosphorus atoms, relative to
85% phosphoric acid.

Menthylꢀcontaining phosphorylacetic acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
295
2
The electron ionization mass spectra were obtained on a
Finnigan MATꢀ212 mass spectrometer (the electron current was
0.1 mA, the ionizing voltage was 60 V, the ion source temperaꢀ
ture was 120 °C, direct inlet system, the temperature of the
direct inlet probe was 60 °C). If the compounds under study did
not give molecular ion peaks, the chemical ionization mass specꢀ
tra were measured (pentane as the reagent gas). The composiꢀ
tions were determined by superposing the peaks of the reference
compound with the peak of the molecular or protonated ion at
the instrumental resolution of 7000. The optical rotation was
measured on a Perkin—Elmer 341A polarimeter equipped with
a sodium lamp (λ = 589 nm).
The physicochemical studies were performed in the Departꢀ
ments of NMR, Xꢀray Diffraction Methods, and Chromatoꢀ
graphic Methods of Analysis of the MultipleꢀAccess Center, the
Spectroanalytical Center (SC SAC) for Physicochemical Invesꢀ
tigations of Structure, Properties, and Composition of Substances
and Materials, and the Federal Center for Collective Use of
Physicochemical Investigations of Substances and Materials
(FCCU PI) (State Contracts of the Ministry of Education and
Science of the Russian Federation, Nos 02.451.11.7036 and
02.451.11.7019).
6.6 Hz); 78.48 (d, C(3´), JP,C = 7.6 Hz); 62.85 (d, CH2O,
2JP,C = 6.1 Hz); 52.34 (OMe); 48.39 (d, C(4´), 3JP,C = 6.6 Hz);
42.94 (C(2´)); 35.25 (d, PCH2, 1JP,C = 135.3 Hz); 33.98 (C(6´));
31.52 (C(1´)); 25.46 (C(8´)); 22.83 (C(5´)); 21.87 (C(7´)H3);
3
20.83 (C(10´)H3); 16.28 (d, Me, JP,C = 6.6 Hz); 15.61
(C(9´)H3). 31P NMR, δ: 18.72. Further elution with ethyl acꢀ
etate gave a mixture of diastereomers 3a,b in a yield of 2.9 g
(46%) as a transparent oil. Found (%): C, 56.44; H, 9.10; P, 9.87.
C15H29O5P. Calculated (%): C, 56.25; H, 9.06; P, 9.68. MS,
m/z: 321.18 [M + H]+. 31P NMR, δ: 17.94, 18.75 (1 : 3 ratio).
1H NMR, δ: 4.03 (m, 2 H, CH3CH2OP); 3.64 (s, 3 H, MeO);
2.95 (dd, 2 H, CH2P, 2JH,P = 21.8 Hz); 1.28 (t, 3 H, CH3CH2OP,
3JH,H = 7.0 Hz); 0.92 and 0.90 (both d, 6 H, 2 MeMnt, J =
7.0 Hz); 0.80 and 0.79 (both d, 1 : 3 ratio, 3 H, MeMnt
,
3JH,H = 7.0 Hz).
Methyl (menthyloxy)(phenyl)phosphorylacetates 4a,b were
synthesized by heating compound 2 (4.18 g, 0.01 mol) in a 10ꢀ
fold excess of methyl chloroacetate (12.3 g, 0.11 mol) at 100 °C
for 4 h. Then the excess methyl chloroacetate was removed
under vacuum (10 Torr) at 100 °C. The reaction mixture
(
31P NMR, δ: 32.90, 33.96 sh) was purified by silica gel column
chromatography. Elution with chloroform afforded diastereomer
4b in a yield of 1.4 g (40%). Found (%): C, 64.57; H, 8.14;
P, 8.52. C19H29O4P. Calculated (%): C, 64.73; H, 8.23; P, 8.80.
MS, m/z: 352. 31P NMR, δ: 33.96. 1H NMR, δ: 7.48—7.82 (m,
5 H, Ph); 4.21 (m, 1 H, OCHMnt); 4.08 (s, 3 H, MeO); 3.61 (d,
Menthyl diethyl phosphite (1). Pyridine (8.7 g, 0.11 mol) was
added to a solution of lꢀmenthol (15.6 g, 0.1 mol) in anhydrous
benzene (150 mL) under argon with cooling to 0 °C. Then
diethyl chlorophosphite (15.65 g, 0.1 mol) was added dropwise.
The reaction mixture was stirred at –5—0 °C for 2 h. The preꢀ
cipitate of pyridine hydrochloride was filtered off, benzene was
removed in vacuum, and the residue was distilled. Compound 1
was obtained in a yield of 17.2 g (62%), b.p. 126—128 °C
(0.01 Torr), [α]D20 –58.9 (c 0.54, CHCl3). Found (%): C, 60.55;
H, 10.50; P, 10.27. C14H29O3P. Calculated (%): C, 60.87;
2
2 H, CH2P, JH,P = 18.2 Hz); 0.97 and 0.83 (both m, 6 H,
2 MeMnt); 0.45 (d, 3 H, MeMnt, 3JH,H = 7.0 Hz). Further elution
with a 1 : 1 chloroform—ethyl acetate mixture gave a mixture of
diastereomers 4a,b in a yield of 0.7 g (20%) as an oil. 31P NMR,
δ: 32.90, 33.96 (3 : 5 ratio).
Menthyl (ethoxy)(menthyloxy)phosphorylacetates 5a,b were
synthesized by refluxing compound 1 (5.52 g, 0.02 mol) with
menthyl chloroacetate (6.95 g, 0.03 mol) in toluene (20 mL) in
the presence of catalytic amounts of ZnCl2 for 4 h. Volatile
products were removed under vacuum (10 Torr) at 100 °C.
The reaction mixture (31P NMR, δ: 18.99, 19.21 (3 : 2 ratio))
was purified by silica gel column chromatography (chloroꢀ
form as the eluent). A mixture of diastereomers 5a,b was obꢀ
tained in a yield of 5.7 g (64%) as a transparent oil. Found (%):
C, 64.52; H, 10.12; P, 6.43. C24H45O5P. Calculated (%):
C, 64.86; H, 10.13; P, 6.76. MS, m/z: 445.3 [M + H]+.
31P NMR, δ: 18.81, 19.15 (1 : 1 ratio). 1H NMR, δ: 4.63 and
4.21 (both m, 2 H, 2 OCHMnt); 4.08 (m, 2 H, CH3CH2OP);
1
H, 10.51; P, 10.69. 31P NMR, δ: 138.65. H NMR, δ: 3.82 (m,
3
4 H, CH3CH2OP); 1.21 (t, 6 H, CH3CH2OP, JH,H = 7.0 Hz);
0.87 and 0.83 (both d, 6 H, 2 MeMnt, J = 7.0 Hz); 0.78 (d, 3 H,
C(9´)H3, 3JH,H = 7.0 Hz).
DiꢀO,Oꢀmenthyl phenylphosphonite (2) was synthesized
analogously to compound 1 from phenyldichlorophosphine
(8.95 g, 0.05 mol), a solution pyridine (8.7 g, 0.11 mol) in
anhydrous diethyl ether (100 mL), and a solution of lꢀmenthol
(15.6 g, 0.1 mol) in anhydrous diethyl ether (75 mL). Product 2
was isolated by silica gel column chromatography (chloroform
as the eluent) in a yield of 10.1 g (47%) as a transparent oil,
20
[α]D –61.2 (c 0.62, CHCl3). Found (%): C, 74.44; H, 10.28;
2
P, 7.13. C26H43O2P. Calculated (%): C, 74.64; H, 10.28;
P, 10.41. 31P NMR, δ: 159.27.
3.03 (d, 2 H, CH2P, JH,P = 21.3 Hz); 1.28 (m, 3 H,
CH3CH2OP); 0.67, 0.72, and 0.74 (all d, 2 : 4 : 1 ratio, 3 H,
MeMnt, 3JH,H = 7.0 Hz).
Methyl (ethoxy)(menthyloxy)phosphorylacetates 3a,b were
synthesized by heating compound 1 (6.5 g, 0.02 mol) in a 5ꢀfold
excess of methyl chloroacetate (12.3 g, 0.11 mol) at 100 °C
for 4 h. Then the excess methyl chloroacetate was removed
under vacuum (10 Torr) at 100 °C. The reaction mixture
Menthyl diphenylphosphorylacetate (9). Ethylene oxide
(4.05 g, 0.072 mol) was added to a solution of a mixture of
diphenylchlorophosphine (5.3 g, 0.24 mol) and menthyl chloroꢀ
acetate (8.9 g, 0.04 mol) in anhydrous benzene (20 mL) under
dry nitrogen with cooling to –5—0 °C. The reaction mixture was
kept at 5 °C for 15 min. Then the temperature was slowly raised
to ~20 °C. The excess ethylene oxide was purged with dry nitroꢀ
gen under atmospheric pressure for 0.5 h and then under vacuum
(10 Torr) for 15 min. Then the temperature of the reaction
mixture was slowly raised to 125 °C for 1 h, benzene being
simultaneously distilled off. The reaction was completed after
evacuation at 100—110 °C (10 Torr). An oil was obtained in an
amount of 13.4 g (31P NMR, δ: 35.80 (6.5%), 25.85 (93.5%)).
The reaction mixture was purified by silica gel column chromaꢀ
(
31P NMR, δ: 17.94, 18.75 (the ratio of diastereomers was 2 : 3))
was purified by silica gel column chromatography. Elution with
chloroform afforded diastereomer 3b in a yield of 0.6 g (10%),
m.p. 40 °C. 1H NMR, δ: 4.27 (m, 1 H, H(3´)); 4.17 (m, 2 H,
2
CH2O); 3.72 (s, 3 H, OMe); 2.95 (d, 2 H, PCH2, JH,P
=
21.6 Hz); 2.22 (m, 1 H, H(2´)); 2.08 (m, 1 H, H(8´)); 1.65 (m,
2 H, H(5´), H(6´)); 1.44 (br.s, 1 H, H(1´)); 1.33 (m, 4 H, H(4´),
Me); 1.18 (m, 1 H, H(2´)); 0.99 (m, 1 H, H(5´)); 0.91 (m, 6 H,
C(7´)H3, C(10´)H3); 0.85 (m, 1 H, H(6´)); 0.79 (d, 3 H,
C(9´)H3, 3JH,H = 7.0 Hz). 13C NMR, δ: 166.32 (d, C(3), 2JP,C
=

296
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
Bredikhin et al.
2
tography (chloroform as the eluent). After extraction with
hexane, the eluted fraction crystallized out. Compound 9 was
obtained in a yield of 3.76 g (71%), m.p. 63—65 °C. Found (%):
P, 7.53. C24H31O3P. Calculated (%): P, 7.79. 31P NMR, δ: 25.96.
1H NMR, δ: 7.71 and 7.44 (both m, 10 H, 2 Ph); 3.45 (d, 2 H,
CH2P, 2JH,P = 18.5 Hz); 4.52 (td, 1 H, OCHMnt, 3JH,H = 11 Hz,
3JH,H = 4.4 Hz); 0.77 and 0.74 (both m, 6 H, 2 MeMnt); 0.55 (d,
13C NMR, δ: 165.37 (d, C(3), JP,C = 4.8 Hz); 152.01 (br.s,
2
C(7)); 133.50 (C(5), JP,C = 12.0 Hz); 116.49 (d, C(4), JP,C
=
150.2 Hz); 112.84 (d, C(6), 3JP,C = 13.8 Hz); 64.11 (d, POCH2,
2JP,C = 5.4 Hz); 42.64 (d, CH2Cl, JP,C = 6.6 Hz); 40.90
3
(s, Me2N); 38.94 (d, PCH2, JP,C = 90.7 Hz); 75.54 (C(3´));
46.65 (C(4´)); 40.49 (C(2´)); 34.07 (C(6´)); 31.28 (C(1´));
25.74 (C(8´)); 23.09 (C(5´)); 21.87 (C(7´)H3); 20.83 (C(10´)H3);
16.01 (C(9´)H3).
3 H, MeMnt,
3JH,H = 7.0 Hz). Further elution with a 3 : 1
chloroform—ethanol mixture afforded (2ꢀchloroethyl)diphenylꢀ
phosphine oxide (12) as a byꢀproduct of isomerization in a yield
of 0.41 g (6.5%), m.p. 125—126 °C. Found (%): Cl, 12.78;
P, 12.55. C14H14ClOP. Calculated (%): Cl, 13.42; P, 11.72.
31P NMR, δ: 35.56.
2ꢀChloroethyl (2ꢀchloroethyl)(4ꢀdimethylaminophenyl)phosꢀ
phinate (14). Ethylene oxide (2 g, 0.048 mol) was added to a
solution of (4ꢀdimethylaminophenyl)dichlorophosphine (2.7 g,
0.012 mol) in anhydrous benzene (4 mL) under dry argon at 0 °C.
The reaction mixture was kept at 0 °C for 0.5 h, warmed to
~20 °C, and stirred for 1 h. The excess ethylene oxide was
removed by purging with dry nitrogen under atmospheric presꢀ
sure followed by storage under vacuum using a waterꢀjet pump.
Then the reaction mixture was slowly warmed to 80—100 °C
for 1 h, benzene being simultaneously distilled off. Silica gel
column chromatography of the residue (chloroform—ethyl acꢀ
etate, 1 : 1, as the eluent) afforded a viscous oil. Found (%):
C, 44.93; H, 6.08; Cl, 22.40; N, 4.28; P, 9.27. C12H18Cl2NO2P.
Calculated (%): C, 45.00; H, 5.62; Cl, 22.18; N, 4.37; P, 9.69.
Menthyl (ethyl)(phenyl)phosphorylacetates 10a,b. Ethylene
oxide (1.6 g, 0.036 mol) was added to a solution of a mixture of
phenylethylchlorophosphine (4.7 g, 0.017 mol) and menthyl
chloroacetate (6.1 g, 0.026 mol) in anhydrous benzene (20 mL)
under dry nitrogen with cooling to –5—0 °C. Then the synthesis
was performed analogously to compound 9. An oil was obtained
in a amount of 8.45 g. 31P NMR, δ: 39.30 (23%), 36.74 (60%),
36.40 (17%). The reaction mixture was purified by silica
gel column chromatography. Elution with a 9 : 1 chloroꢀ
form—ethanol mixture afforded a mixture of diastereomers 10a,b
in a yield of 3.56 g (60%). Found (%): P, 8.61. C20H31O3P.
Calculated (%): P, 8.85. 31P NMR, δ: 36.40 (26%), 36.70 (74%).
1H NMR, δ: 7.64 (m), 7.54 (t), 7.33 (m), 7.26 (t) (5 H, Ph,
3JH,P = 12.1 Hz, 3JH,H = 8.8 Hz); 4.40 (m, 1 H, OCHMnt); 2.98
1
3
31P NMR, δ: 41.87. H NMR, δ: 7.37 (dd, 2 H, oꢀHPh, JH,P
=
12.1 Hz, 3JH,H = 8.8 Hz); 6.51 (d, 2 H, mꢀHPh, 3JH,H = 7.7 Hz);
3.98 and 3.76 (both m, 2 H, POCH2, 3JH,P = 12.0 Hz); 3.44—3.46
(m, 4 H, CH2Cl); 2.87 (s, 6 H, Me2N); 2.25 and 2.15 (both m,
2 H, CH2P, 3JH,P = 5 Hz).
2
and 2.95 (both d, 2 H, CH2P, JH,P = 18.0 Hz); 2.02 and 1.90
Xꢀray diffraction study of compound 11b. Crystallographic
data for compound 11b at 20 °C: crystals of C22H35ClNP are
monoclinic, space group P21, а = 14.260(7) Å, b = 6.035(4) Å,
c = 14.32(1) Å, β = 98.54(5)°, V = 1219(1) Å3, Z = 2, M = 426.95,
dcalc = 1.163 g cm–3, F(000) = 458. The intensities of
4257 reflections were measured on an Enraf Nonius CADꢀ4
diffractometer at 20 °C (λ(CuꢀKα), ω/2θꢀscanning technique,
2
(both q, 2 H, PCH2CH3, JH,H = 7.0 Hz, JH,P = 14 Hz); 0.97
and 0.94 (both t, 3 H, PCH2CH3, JH,H = 7.0 Hz); 0.65 and 0.58
(both m, 6 H, 2 MeMnt); 0.40 and 0.47 (both d, 1 : 3 ratio, 3 H,
MeMnt, JH,H = 7.0 Hz). Further elution with a 1 : 1 chloroꢀ
form—ethanol mixture gave (2ꢀchloroethyl)(ethyl)(phenyl)phosꢀ
phine oxide (13) in a yield of 0.6 g (17%). Found (%): Cl, 15.83;
P, 13.97. C10H14ClOP. Calculated (%): Cl, 16.40; P, 14.32.
31P NMR, δ: 39.03.
θ
< 78.4°), of which 2264 reflections were with I > 3σ. The
max
intensities of three check reflections showed no decrease in the
course of Xꢀray data collection. No absorption correction was
applied, because no strong reflections with χ ≥ 80° were found
for measuring ψꢀscan curves required for the empirical absorpꢀ
tion correction (µ(Cu) = 21.86 cm–1). The structure was solved
by direct methods using the SIR program14 and refined first
isotropically and then anisotropically. The hydrogen atoms were
located in difference electron density maps. Their contributions
to the structure amplitudes were taken into account in the final
step of the refinement with fixed positional and isotropic therꢀ
mal parameters. All calculations were carried out using the
MOLEN program package15,16 on an AlphaStation 200 comꢀ
puter. To establish the absolute structure and, consequently, the
absolute configuration of the molecule, the direct and inverted
structures were refined. The R factors were as follows: R = 0.068,
Rw = 0.069 and R = 0.070, Rw = 0.071 for the direct and inverted
structures, respectively. According to the Hamilton test,17 the
direct structure corresponds to the absolute structure with
the probability of 95%. The final R factors were as follows:
R = 0.068, Rw = 0.070 based on 1439 independent reflections
with F 2 ≥ 3σ.
Menthyl [(2ꢀchloroethoxy)(4ꢀdimethylaminophenyl)phosphoꢀ
ryl]acetates 11a,b. A solution of menthyl chloroacetate (8.65 g,
0.037 mol) in anhydrous benzene (20 mL) was added to a soluꢀ
tion of (4ꢀdimethylaminophenyl)dichlorophosphine (6.8 g,
0.03 mol) in anhydrous benzene (20 mL). Then ethylene oxide
(5.25 g, 0.12 mol) was added with stirring and cooling to 0—5 °C
under dry nitrogen for 1 h at such a rate as to maintain the
temperature of the reaction mixture no higher than 10 °C. Then
the synthesis was performed analogously to compound 9. The
reaction mixture was obtained in a yield of 9.2 g (31P NMR, δ:
36.68, 37.28 (1 : 16 ratio)), and diastereomer 11b was isolated in
20
a yield of 2.1 g (39%), m.p. 123—124 °C, [α]D –34.7 (c 1.0,
MeOH). Found (%): C, 57.62; H, 8.34; Cl, 8.20; N, 3.28; P, 6.81.
C
22H35ClNO4P. Calculated (%): C, 57.52; H, 7.89; Cl, 8.00;
N, 3.16; P, 6.99. MS, m/z: 443.3 [M]+. 31P NMR, δ: 37.28.
1H NMR, δ: 7.68 (dd, 2 H, H(3), H(5), 3JH,P = 12.1 Hz, 3JH,H
8.8 Hz); 6.90 (d, 2 H, H(2), H(6), JH,H = 7.7 Hz); 4.61 (td,
1 H, H(3´), JH,H = 11 Hz, JH,H = 4.4 Hz); 4.24 and 4.08
(both m, 2 H, POCH2, JH,P = 12 Hz); 3.66 (m, 2 H, CH2Cl);
3.12 (d, 2 H, PCH2, 3JH,P = 18.3 Hz); 3.04 (s, 6 H, Me2N); 1.80
(m, 2 H, H(2´), H(8´)); 1.62 (m, 2 H, H(5´), H(6´)); 1.39 (br.s,
=
3
3
3
3
3
3
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 06ꢀ03ꢀ32508a
and 05ꢀ03ꢀ32558a).
1 H, H(1´)); 1.30 (tt, 1 H, H(4´), JH,H = 11.7 Hz, JH,H
=
2.9 Hz); 0.97 (m, 1 H, H(5´)); 0.83 (m, 8 H, H(2´), H(6´),
3
C(7´)H3, C(10´)H3); 0.68 (d, 3 H, C(9´)H3, JH,H = 7.0 Hz).

Menthylꢀcontaining phosphorylacetic acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
297
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Received April 24, 2006;
in revised form December 15, 2006