ω-haloalkylphosphoryl compounds: Synthesis and properties

Article abstract of DOI:10.1134/S1070363212120055

A general method of the synthesis of ω-haloalkylphosphoryl compounds was developed, a series of compounds of phosphonic and phosphine oxide type were synthesized. The ability of some ω-haloalkylphosphonates to undergo intramolecular cyclization into the corresponding 1,2-oxaphospholane and 1,2-oxaphosphorine was investigated depending on the solvent polarity, the presence of halogen ions in the solution, and temperature. Tetrahydrofuran was chosen as one of the most suitable solvents for the alkylation of CH acids with ω-haloalkylphosphoryl compounds.

Full text of DOI:10.1134/S1070363212120055

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 12, pp. 1928–1937. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.V. Ragulin, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 12, pp. 1973–1982.
ω-Haloalkylphosphoryl Compounds: Synthesis and Properties
V. V. Ragulin
Institute of Physiologically Active Substances, Severnyi pr. 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: rvalery@clio.ru
Received October 11, 2011
Abstract—A general method of the synthesis of ω-haloalkylphosphoryl compounds was developed, a series of
compounds of phosphonic and phosphine oxide type were synthesized. The ability of some ω-
haloalkylphosphonates to undergo intramolecular cyclization into the corresponding 1,2-oxaphospholane and
1,2-oxaphosphorine was investigated depending on the solvent polarity, the presence of halogen ions in the
solution, and temperature. Tetrahydrofuran was chosen as one of the most suitable solvents for the alkylation of
CH acids with ω-haloalkylphosphoryl compounds.
DOI: 10.1134/S1070363212120055
Phosphorylation of organic compounds is a usual
method of constructing a molecule of potential
physiologically active structural isostere of a natural
molecule. Direct phosphorylation is sometimes
difficult for various electronic or steric reasons. An
alternative way to solve this problem may be a
synthesis of some intermediate compounds containing
phosphoryl moiety and capable to functionalize the
substrate molecule, for example, the synthesis of ω-
haloalkylphosphoryl compounds.
The synthetic approaches to the ω-haloalkyl-
phosphoryl compounds have been considered in the
pioneering work by Kosolapov dedicated to the
synthesis of diethyl 2-bromoethylphosphonic acid by
the reaction of triethyl phosphite with 1,2-dibromo-
ethane at a 4-fold excess of the latter [7]. However, he
reported that this procedure does not allow syn-
thesizing its analog, the diethyl ester of 3-bromo-
propylphosphonic acid. The hydrolysis with hydro-
bromic acid of the residue in the reaction mixture after
removal of the unreacted 1,3-dibromopropane gave 3-
bromopropylphosphonic acid [8]. On the basis of
further research, we can explain now this fact by the
formation of cyclic product, 1,2-oxaphospholane. The
hydrolysis of the latter with hydrobromic acid also
leads to 3-bromopropylphosphonic acid. Pudovik and
coworkers [9] were first who observed the formation
of cyclic 1,2-oxaphosphoryl compounds, isolated and
characterized them. However, these studies did not
lead to a method of synthesis of ω-haloalkyl-
phosphoryl compounds.
In this regard, the search of a convenient method of
synthesis of ω-haloalkylphosphoryl compounds as
alkylating agents for the introduction of phosphorus
fragment into molecules of various compounds
containing diverse nucleophilic “coupling sites” is
relevant. Moreover, the problem of synthesis of ω-
haloalkylphosphoryl compounds is defined by the
interest to some physiologically active compounds, the
phosphonic analogs of glutamic and aspartic acids,
which are ligands in the glutamate receptors that are
involved in the transmission and processing
information by the central nervous system [1–4]. 2-
Amino-5-phosphonovaleric (AR5), 2-amino-7-phos-
phonoheptanoic (AR7), and 4-(3-phosphonopropyl)-
piperazine-2-carboxylic (CPP) acids are selective
antagonists of N-methyl-D-aspartate receptors and
possess antiepileptic, anti-ischemic, and other useful
properties [2–6]. The synthesis of these compounds
and a number of structural analogs of natural amino
acids is based on the use of ω-haloalkylphosphonates
as the key intermediates.
More recent publications on the synthesis of ω-
haloalkylphosphonates resulted from the interest in the
ω-phosphonic acid analogs of monoaminodicarboxylic
acids [10–13]. In [10] a method was described of the
synthesis of 2-amino-5-phosphonovaleric acid (AR5)
using diethyl 3-bromopropylphosphonate, which was
obtained by heating triethyl phosphite with 20-fold
excess of 1,3-dibromopropane. But the subsequent
alkylation of acetamidomalonic ester in toluene or
diethyl carbonate resulted only in 25% yield of the
1928

1929
ω-HALOALKYLPHOSPHORYL COMPOUNDS: SYNTHESIS AND PROPERTIES
Scheme 1.
O
P
O
P
Х
Х
A
A
RO
Ph
Ph2POSiMe3
_Me3SiХ
(RO)2POEt
_EtХ
OR
I_Х
Ph
ХI_ХV
A
Х
Х
P(OEt)3
_EtХ
'
2R2POY
n > 2
_2ХY
_2EtХ
O
P
O
P
O
O
A
R'
P
R'
A
EtO
R'
R'
ХVIII, ХIХ
ХVI, ХVII
X = Br, Cl; R = Et, Ph; Y = Et, SiMe3; R' = EtO, Ph; A = (CH2)n, n = 2–6; o-CH2C6H4CH2, p-CH2C6H4CH2;
CH2CH=CHCH2; CH2CH2OCH2CH2.
desired product, due to the secondary processes [10].
Later on a method was suggested for the synthesis of
diethyl 3-bromopropylphosphonate from 3-bromo-
propyl alcohol with pre-protection of the alcohol group
and the subsequent phosphorylation, removal of
tetrahydropyranyl protection, and bromination [11].
reaction. This technique minimizes the formation of
the products of bis-phosphorylation, which were
detected at the synthesis of ω-halophosphoryl com-
pounds of phosphonic and phosphine oxide types. In
some cases, the α,ω-alkylenebisphosphoryl compounds
XVI, XVII were isolated and characterized.
Further investigation of the conditions of the
synthesis of phosphorus-containing target phosphonic
halides of I–IX type, as well as their use as alkylating
agents [13], showed, however, that in addition to the
products of bis-phosphorylation, the formation of by-
products of cyclic structure XVIII, XIX (Scheme 1)
was possible depending on the reaction conditions.
This is consistent with the results of [9]. We succeeded
to show that these substances were five- and six-
membered cyclic compounds formed by intramole-
cular cyclization of the ω-haloalkylphosphonates con-
taining a halogen atom in the third or fourth position
with respect to the phosphoryl fragment. The driving
force is likely to be the energy gain in the formation of
five- and six-membered rings.
We report here on a simple and general method of
the synthesis of ω-haloalkylphosphoryl compounds by
gradual adding the corresponding ester of trivalent
phosphorus to the α,ω-dihaloalkane pre-heated to the
boiling point [12, 13]. In this case, a sufficiently large
excess of α,ω-dihalide with respect to the phosphoric
component appears under the conditions similar to
those required for the formation of phosphorus–carbon
bond, while the side reactions are minimized.
Therefore, the ω-haloalkylphosphoryl compounds of
phosphonic (IX) and phosphine oxide (XI–XV) series
were synthesized with good or satisfactory yields
(Scheme 1).
The expected by-products in the reaction of tri-
valent phosphorus with α,ω-dihaloalkanes are α,ω-
alkylene-bisphosphorylated compounds XVI, XVII
(Scheme 1). The procedure with the gradual addition
of phosphoric components to the pre-heated dihalides
creates a large excess of the latter over the trivalent
phosphorus compound at the moment of the addition
and provides a rapid transformation of this reagent into
Our study showed that ω-haloalkylphosphonates, 3-
bromopropylphosphonate
I
and
o-chloro-
methylbenzylphosphonate X in particular, fairly easily
underwent intramolecular cyclization to give 2-oxo-2-
ethoxy-1,2-oxaphospholane XVIII [9] and 2-oxo-2-
ethoxy-4,5-benzo-1,2-oxaphosphorinane XIX, respec-
tively, which were isolated and characterized.
the
target
ω-haloalkylphosphoryl
compound.
Therefore, the reaction conditions (temperature,
solvent, or the absence of the latter) must comply with
the reactivity of dihalide and phosphorus components
to provide their interaction according to the Arbuzov
The ability of 3-bromopropylphosphonate I to
undergo intramolecular cyclization into 1,2-oxaphos-
pholane XVIII was greater compared with the other ω-
haloalkylphosphonates that led to a marked reduction
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

1930
RAGULIN
Scheme 2.
O
_
O
_
O
O
O
O
Δ, Br
_EtBr
P
P
Br
P
Br
_Br_
O
O
O
I
ХVIII
O
_
O
O
O
O
P
P
P
O
O
_
O
Cl
Cl
Δ, Cl
_EtCl
_Cl_
O
Х
ХIХ
in the yield of desired products in alkylation reactions
of CH acids, for example, reduced the overall yield of
2-amino-5-phosphonovaleric acid (AR5) [10]. We
investigated the properties of 3-bromopropyl-
phosphonate I in various solvents, as well as under
different conditions of alkylation. This allowed us the
development of a more efficient use of this alkylating
agent. We did not study the 4-brombutylphosphonate
III, which apparently was capable of cyclization to
form similar six-membered 1,2-oxaphosphorine.
fragment and C3–Br carbon, respectively, as a function
of solvent polarity (Table 1).
These data can be attributed to the fact that with the
increasing solvent polarity the C3–Br bond polarization
increases creating more favorable conditions for the
attack of the electrophilic C3 carbon atom in 3-
bromopropylphosphonate I by the oxygen of the
phosphoryl group with the subsequent formation of the
energy favorable five-membered 1,2-oxaphospholane
ring.
Our study showed that 3-bromopropylphosphonate
I undergoes cyclization with the release of ethyl
bromide and the formation of 1,2-oxaphospholane XVIII
when heated in a polar solvents like dimethyl-
formamide. In the less polar but rather high boiling sol-
vents, for example, in toluene, this process is much slower.
Perhaps, under the conditions of alkylation of CH
acids the attacking center is the negatively charged
oxygen atom at the phosphorus atom that forms as a
result of the dealkylation of P–O–C ester fragment
formed in the process of alkylation with the halide ion
(Scheme 2).
In addition, we found that the chemical shift of
diethyl 3-bromopropylphosphonate I in the 31P NMR
spectrum increased with increasing solvent polarity. In
The modeling of the alkylation conditions
confirmed that in the process of cyclization a very
significant factor is the presence in the solution of a
halide ion. Study of the behavior of 3-bromopropyl-
phosphonate I in various solvents revealed the great
influence of the halide ion (sodium chloride or
bromide) on the process of cyclization of bromide I to
form 1,2-oxaphospholane XVIII. Probably the halide
ion dealkylates the ester P–O–C bond “provoking” the
attack of the charged oxygen atom on the most
electrophilic third carbon atom (C3–Br) of the bromide
I with the subsequent formation of the ester oxygen–
carbon bond in the thermodynamically favorable five-
membered ring. The study showed that the effect of
halide ions is more pronounced with increasing
temperature and solvent polarity (see below the
procedure of isolation of the cyclic product).
1
turn, in H and 13C NMR spectra we registered a
downfield shift of the signals of proton in BrCH2
Table 1. Chemical shifts (ppm) in the 1H, 13C, and 31P NMR
spectra of diethyl 3-bromopropylphosphonate I, depending
on the solvent
δ, ppm
δP
C6D6
30.3
3.00
_
CDCl3
31.1
(CD3)2S(O)
31.4
δН, СН2Br, t
3.48
3.60
26.9а
(4.1)
δС, С3Br, d
26.1
(4.1)
(3JPC Hz)
a Solvent CD3CN.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

1931
ω-HALOALKYLPHOSPHORYL COMPOUNDS: SYNTHESIS AND PROPERTIES
A similar process of intramolecular cyclization to
form six-membered ring XIX was found in o-
chloromethylbenzylphosphonate X (Scheme 2), both at
the synthesis of the latter, and as a result of alkylation
with it of acetamidomalonic ester in dimethylform-
amide. The greatest tendency to cyclization in the
series of ω-haloalkylphosphonates exhibited 3-bromo-
propylphosphonate I and o-chloromethylbenzylphos-
phonate X in solutions of dimethylformamide in the
presence of sodium halides. The presence of the halide
ions in the solutions was due to our attempt to simulate
the conditions of alkylation of CH acids with ω-
haloalkylphosphonates [13].
because of a slightly lower yield of the target
phosphine oxide, as well as due to the easier synthesis
of the initial phosphoric component Ph2POSiMe3.
The cyclization of target compounds similar to that
observed for the series of phosphonic compounds is
impossible in this case, so the only byproduct of the
synthesis is the product of bis-phosphorylation, α,ω-
alkylenebisphosphine oxide, whose formation was
detected by TLC on Silufol, the Rf of bis-phosphine
oxides was 0.10–0.15 (chloroform:acetone = 4: 1),
while for the target ω-haloalkylphosphine oxides the Rf
value was about 0.50 under the same conditions. The
31P NMR method also revealed the formation of alkyl-
enebisphosphine oxides (5 to 15%), however, these
compounds usually were not isolated in the individual
form.
In order to compare with diethyl ester I we
synthesized diphenyl 3-bromopropylphosphonate VI,
which was not capable to suffer the dealkylation of the
ester P–OPh group, and therefore, as expected, turned
out to be a stable compound. This allows us to recom-
mend the bromide VI as an alternative agent in similar
alkylation reactions.
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were taken on a
Bruker DPX-200 and a Bruker CXP-300 Fourier
spectrometers with internal reference TMS and
external reference 85% H3PO4. The melting points of
compounds were determined on a Boëtius PHMK
device or in a block in an open capillary. The solvents
were carefully dried before use. The TLC analysis of
individual compounds and the reaction mixtures was
performed on Silufol, Alufol (Kavalier) (neutral
alumina on aluminum foil), and Merck glass plates
with a UV-254 silica gel layer thickness of 0.2 mm
(eluent chloroform–acetone, 5–10:1.)
Our research on a number of solvents containing
halide ions showed that the highest stability of bromide
I, as well as chloride X, to the process of formation of
the corresponding cyclic 1,2-oxaphosphoryl com-
pounds XVIII and XIX, respectively, was found at the
use of tetrahydrofuran. Therefore, we recommend the
tetrahydrofuran as a medium for the alkylation of CH
acids with ω-haloalkylphosphonates as the most
suitable solvent, which allows efficient use of alkylat-
ing properties of ω-haloalkylphosphonates and
minimize or eliminate completely the process of
secondary cyclization.
Hexamethyldisilazane, α,ω-dihaloalkanes, and tri-
ethyl phosphite were provided by Reakor (Alfa Aesar).
Synthesis of ω-haloalkylphosphoryl compounds
consisted in a slow addition of the corresponding ester
of trivalent phosphorus to the α,ω-dihaloalkane pre-
heated to the boiling point. Below are some examples
of the synthesis of ω-haloalkylphosphonates and phos-
phine oxides.
The considered method makes it possible to syn-
thesize a variety of ω-haloalkylphosphoryl compounds
with diverse modifications of both the hydrocarbon
chain, and the phosphorus fragment of the molecule.
The method is of the general nature, the developed
synthesis procedure was used to obtain a number of ω-
haloalkylphosphine oxides effective as alkylating
agents, which might be used in the synthesis of
potential complexing compounds [14].
Diethyl 3-bromopropylphosphonate (I). To 3.30 g
(0.15 mol) of freshly distilled 1,3-dibromopropane,
pre-heated to boiling, was added slowly dropwise with
stirring 8.3 g (0.05 mol) of triethyl phosphite within
0.5 h. By a vacuum distillation the unreacted excess
(~19 g) of 1,3-dibromopropane and 10.0 g (76%) of
bromide I, bp 77–80ºC (0.05 mm Hg) were isolated.
1H NMR spectrum (CDCl3, δ, ppm): 1.34 t (6H,
2CH3), 1.90 m (2H, CH2P), 2.14 m (2H, CH2), 3.48 t
(2H, CH2Br), 4.10 d.q (4H, 2CH2OP). 13C NMR
The synthesis of ω-haloalkylphosphine oxides was
performed in accordance with the same procedure, by
adding the phosphoric component to the boiling α,ω-
dihaloalkane. As a phosphoric component trimethyl-
silyl diphenylphosphinite Ph2POSiMe3 was used
(Scheme 1) obtained preliminary by the reaction of
diphenylphosphinic acid with hexamethyldisilazane.
The use of the appropriate ethyl ester is less effective
3
spectrum (CDCl3, δ, ppm): 16.5 d (CH3, JPC 5.4 Hz),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

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RAGULIN
24.4 d (CH2P, 1JPC 142.4 Hz), 26.1 d (CH2Br, 3JPC 4.1 Hz),
33.5 d (CH2C, 2JPC 19.0 Hz), 61.6 d (CH2OP, 2JPC 5.4 Hz).
13C NMR spectrum (CD3CN, δ, ppm): 16.7 d (CH3,
The constants and analytical data of the ω-haloalkyl-
phosphonates I–V are listed in Table 1. Below we list
1
the H, 13C and 31P NMR parameters of bromoalkyl-
1
3JPC 5.4 Hz), 24.5 d (CH2P, JPC 141.1 Hz), 26.9 d
phosphonates IV and V.
3
2
(CH2Br, JPC 4.1 Hz), 34.8 d (CH2C, JPC 19.0 Hz),
Diethyl 5-bromopentylphosphonate (IV). 1H NMR
spectrum (CDCl3, δ, ppm): 1.30 t (6H, 2CH3), 1.56 m
(2H, CH2), 1.65 m (2H, CH2), 1.82 m (4H, 2CH2), 3.38
t (2H, CH2Br), 4.08 d.q. (4H, 2CH2OR). 13C NMR
62.0 d (CH2OP, JPC 6.8 Hz). 31P NMR spectrum
2
(CDCl3, δ, ppm): 31.0. Found, %: C 32.6, 32.8; H 6.0,
6.1; Br 29.9, 30.1; P 11.7, 11.8. C7H16BrO3P.
Calculated, %: C 32.5; H 6.2; Br 30.2; P 12.0.
3
spectrum (CDCl3, δ, ppm): 15.6 d (CH3, JPC 5.2 Hz),
20.8 d (CH2, 3JPC 4.8 Hz), 24.5 d (CH2R, 1JPC 141.0 Hz),
At a ratio of reagents 1:1 the yield of bromide I is
55%, with a 5:1 excess of 1,3-dibromopropane the
yield of I reaches 80%.
2
31.5 (CH2), 28.0 d (CH2 , JPC2 16.3 Hz), 31.3 (CH2),
32.4 (CH2), 60.4 d (CH2OR, JPC 6.3 Hz). 31P NMR
spectrum (CDCl3, δ, ppm): 32.4.
The synthesis of diethyl 2-bromethylphosphonate in
accordance with this procedure is relatively less
effective because of the lower boiling point of a
mixture of 1,2-dibromoethane and triethyl phosphite,
which is insufficient for complete proceeding of the
reaction according to the scheme of Arbuzov
rearrangement within 0.5 h. The increase in the yield is
observed with the increase in the 1,2-dibromoethane
excess and the total time of boiling the mixture.
1
Diethyl 6-bromohexylphosphonate (V). H NMR
spectrum (CD3OD + CCl4, δ, ppm): 1.31 t (6H, 2CH3),
1.80 m (8H, 4CH2), 1.90 m (2H, CH2), 3.35 t (2H,
CH2Br), 4.10 d.q (4H, 2CH2OR). 13C NMR spectrum
3
(CD3OD + CCl4, δ, ppm): 15.7 d (CH3, JPC 5.4 Hz),
21.5 d (CH2, 3JPC 4.5 Hz), 24.7 d (CH2R, 1JPC 140.8 Hz),
2
26.8 (CH2), 31.5 (CH2), 28.8 d (CH2, JPC 16.2 Hz),
2
31.6 (CH2), 32.8 (CH2), 60.5 d (CH2OR, JPC 6.2 Hz).
31P NMR spectrum (CD3OD + CCl4, δ, ppm): 32.8.
Diethyl 3-chloropropylphosphonate (II). To 24.0 g
(0.15 mol) of boiling 1-bromo-3-chloropropane while
stirring was slowly added dropwise 8.3 g (0.05 mol) of
triethyl phosphite within 1.5 h. By vacuum distillation
the excess (~15 g) of 1-bromo-3-chloropropane was
isolated, and by the distillation of the residue in a high
vacuum 7.2 g (67.0%) of chloride II was isolated
containing an impurity (5–10%) of bromide I. This
sample can be used in all subsequent transformations.
The repeated distillation provided 5.5 g (51.2%) of
pure chloride II (Table 1).
Diphenyl 3-bromopropylphosphonate (VI). To
157.1 g (0.78 mol) of boiling 1,3-dibromopropane was
added slowly dropwise within 1.5 h 38.0 g (0.14 mol)
of diphenyl ethyl phosphite, and the mixture was
further stirred at reflux for 3 h. Then 1,3-dibromo-
propane excess (~120 g) was distilled off in vacuo, and
the residue was distilled in a high vacuum. After a
double vacuum distillation 32.2 g (62.5%) of the
desired bromide VI, bp 175–180ºC (0.1 mm Hg) was
isolated. Oil, nD20 1.5590. H NMR spectrum (CDCl3,
1
δ, ppm): 2.15–2.45 m (4H, CH2P + CH2C), 3.52 t (2H,
Diethyl 4-bromobutylphosphonate (III). To 43.2 g
(0.20 mol) of freshly distilled 1,4-dibromopropane,
pre-heated to boiling, was added slowly dropwise 8.3 g
(0.05 mol) of triethyl phosphite while stirring within
0.5 h. By vacuum distillation the unreacted excess
(~19 g) of 1,4-dibromopropane and 10.1 g (70%) of
CH2Br), 7.17 m (6H, arom.), 7.30 m (4H, arom.). 13C
1
NMR spectrum (CDCl3, δ, ppm): 24.6 d (CH2R, JPC
142.4 Hz), 25.7 d (CH2Br, 3JPC 4.1 Hz), 33.1 d (CH2C,
2JPC 20.4 Hz), 120.4, 120.5, 125.2, 129.8 (2C), 150.1 d
(2JPC 9.5 Hz). 31P NMR spectrum (CDCl3, δ, ppm):
24.5. Found, %: C 50.52, 50.55; H 4.58, 4.63; Br
22.50, 22.71; P 8.77, 8.80. C15H16BrO3P. Calculated,
%: C 50.73; H 4.54; Br 22.50; P 8.72.
1
bromide III were isolated. The H NMR spectrum
(CDCl3, δ, ppm): 1.33 t (6H, 2CH3), 1.85 m (4H,
2CH2), 2.05 m (2H, CH2), 3.43 t (2H, CH2Br), 4.10 d.q
(4H, 2CH2OP). The 13C NMR spectrum (CD3OD +
CCl4, δ, ppm): 15.1 d (CH3, 3JPC 5.6 Hz), 19.8 d (CH2,
3JPC 5.4 Hz), 23.3 d (CH2P, 1JPC 141.2 Hz), 31.5 (CH2),
Diethyl 3-oxa-5-bromopentylphosphonate (VII).
To 41.1 g (0.27 mol) of freshly distilled β,β'-
dibromodiethyl ether [bp 90–94ºC (11 mm Hg)] heated
to 160–170ºC was slowly added dropwise 12.0 ml
(0.07 mol) of triethyl phosphite within an hour. The
reaction mixture was evacuated and 1.25 g of un-
reacted β,β'-dibromodiethyl ether was distilled off, the
residue was distilled in a high vacuum. 10.8 g (53.4%).
2
2
31.7 d (CH2, JPC 17.4 Hz), 60.0 d (CH2OP, JPC
6.3 Hz). The 31P NMR spectrum (CD3OD + CCl4, δ,
ppm): 31.7.
Diethyl 5-bromopentylphosphonate IV and 6-
bromohexylphosphonate V were synthesized similarly.
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ω-HALOALKYLPHOSPHORYL COMPOUNDS: SYNTHESIS AND PROPERTIES
Table 2. Yields and physicochemical characteristics of ω-haloalkylphosphonates XAP(O)(OEt)2 (I–V)
Comp.
no.
Yield,
%
bp, °С
(mm Hg)
MRD,
found
MRD,
calculated
X
A
d420
nD20
Br
Cl
Br
Br
Br
(CH2)3
(CH2)3
(CH2)4
(CH2)5
(CH2)6
76
67(51а)
70
77–80 (0.05)
82–84 (0.07)
86–88 (0.08)
112–115 (0.08)
130–133 (0.10)
1.3478
1.1782
1.2990
1.2826
1.2659
1.4616
1.4585
1.4611
1.4625
1.4652
52.69
49.79
57.80
61.60
65.80
52.90
I
50.03
II
57.50
III
74
62.09
IV
72
66.69
V
a Redistillation.
Table 3. Data of elemental analyses of compounds I–V
Found, %
Comp.
Calculated, %
Formula
no.
С
Н
P
Hlg
С
Н
Р
Hlg
32.7
32.3
6.1
6.2
11.9
11.7
29.6
29.9
C7H16BrO3P
32.5
6.2
12.0
14.4
11.3
10.8
10.3
30.2
I
39.0
38.9
7.9
8.0
14.7
14.8
16.1
16.2
C7H16ClO3P
C8H18BrO3P
C9H20BrO3P
39.2
35.2
37.7
39.9
7.5
6.6
7.0
7.4
16.5
29.3
27.8
26.5
II
III
IV
V
35.4
35.3
6.3
6.5
11.0
11.2
29.0
29.2
38.0
37.9
6.8
6.9
10.4
10.5
27.4
27.7
40.1
39.8
7.0
7.2
10.2
10.4
26.3
26.4
C10H22BrO3P
of compound VII was isolated, bp 135–138ºC (0.1 mm
toluene was added dropwise 6.8 ml (0.04 mol) of
triethyl phosphite within 1.0–1.5 h. The reaction
mixture was stirred for additional 0.5 hour at reflux,
cooled, and evaporated in vacuo, and the residue was
chromatographed on silica gel, eluent hexane, chloro-
form–hexane mixture, 1:1. The yield of bromide VIII
8.2 g (76%), nD20 1.4800. The TLC (chloroform–
Hg), nD20 1.4630. H NMR spectrum (CDCl3, δ, ppm):
1
2
1.34 t (6H, 2CH3), 2.13 d.t (2H, CH2P, JPH 20.0 Hz),
3.46 t (2H, CH2Br), 3.71 t (2H, CH2OC), 3.75 d.t (2H,
3
3
CH2OC, JPH 2.0 Hz), 4.09 d.q (4H, 2CH2OP, JPH
2.0 Hz). 31P NMR spectrum (CDCl3, δ, ppm): 28.6. 13C
NMR spectrum (CDCl31, δ, ppm): 15.2 d (CH3, JPC
3
1
5.6 Hz), 25.7 d (CH2P, JPC 139.5 Hz), 29.2 (CH2Br),
60.3 d (CH2OP, 2JPC 5.8 Hz), 63.7 (OCH2CH2Br), 69.5
(CH2CH2P). Found, %: C 32.97, 33.18; H 6.30, 6.37;
Br 27.90, 27.77; P 10.73, 10.80. C8H18BrO4P. Cal-
culated, %: C 33.24; H 6.28; Br 27.64; P 10.71.
acetone, 5:1), Rf 0.5 (Silufol). H NMR spectrum
2
(CDCl3), 1.30 t (6H, CH3), 2.63 d.d (2H, CH2P, JPH
24Hz), 3.96 d.d (2H, CH2), 4.08 d.q (4H, CH2O), 5.82
m (2H, 2CH). 31P NMR spectrum (CDCl3), δP, ppm:
26.6 (E-isomer, 95%), 26.3 (Z-isomer, 5%). Found, %:
C 35.26, 35.00; H 5.70, 6.18, Br 29.13, 29.48, P 11.55,
11.70. C8H16BrO3P. Calculated, %: C 35.44; H 5.95,
Br 29.48, P 11.43. Using chloroform as eluent, 0.4 g of
bis-phosphorylation compound, 1,4-bis(diethoxy-
phosphinyl)-2-butene XVI, oil was isolated. The TLC
Below are examples of modification of the general
method of synthesis, for example, the use of solvents
in the reaction of phosphite with α,ω-alkylene-
dihalides, and chromatographic separation of the reac-
tion products.
1
(chloroform–acetone, 5:1), Rf 0.1 (Silufol). H NMR
spectrum (CDCl3), δ, ppm: 1.30 t (12H, CH3), 2.65 d.d
2
Diethyl 4-bromo-2-butenylphosphonate (VIII).
To a stirred solution of 4.21 g (0.10 mol) g of 1,4-
dibromo-2-butene in 20 ml of boiling benzene or
(4H, CH2P, JPH 22.5 Hz), 4.10 d.q (8H, CH2O), 5.60
m (2H, 2CH). 31P NMR spectrum (CDCl3), δP, ppm:
27.3 (E-isomer, ~95%), 27.5 (Z-isomer, ~5%).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

1934
RAGULIN
Diethyl p-chloromethylbenzylphosphonate (IX).
Further chromatography with eluent hexane–
chloroform, 1:1, furnished 2.7 g (21.3%) of 2-oxo-2-
ethoxy-4,5-benzo-1,2-oxaphosphorine XIX, oil, nD20
To a boiling solution–melt of 5.3 g (0.03 mol) of p-
xylylene dichloride in 3 ml of anhydrous benzene or
toluene was slowly added dropwise 1.7 ml (0.01mol)
of triethyl phosphite within 1.0–1.5 h, and the reaction
mixture was stirred at reflux for additional 0.5 h. TLC
analysis (chloroform–acetone, 5:1) of the reaction
mixture showed the presence of unreacted initial
dichloride (Rf 0.95–1.0), p-xylylenediphosphonate (Rf
~0.2), and target chloride IX (Rf 0.65–0.70). The
reaction mixture was evaporated in a vacuum and the
residue was chromatographed on 75 ml column with
silica gel of “Silpearle” grade, using as eluents chloro-
form–hexane (1:1), chloroform. 3.3 g of p-xylyl-
endichloride was isolated, then using as eluent a mix-
ture of chloroform and 3% of isopropanol p-chloro-
methylbenzylphosphonate IX was isolated. Yield 2.3 g
(85.2%), oil, nD20 1.5055. 1H NMR spectrum (CDCl3, δ,
1
1.5375. Rf 0.33 (chloroform–acetone, 4:1). H NMR
spectrum (CDCl3, δ, ppm): 1.28 t (3H, CH3), 3.17 d
2
(1H, one of CH2R, JPH 16.0 Hz), 3.20 d (1H, the
2
second of CH2R, JPH 18.0 Hz), 4.12 m (2H, POCH2),
3
5.24 d (1H, one of ROCH2C (arom.), JPH 10.0 Hz),
3
5.26 d (1H, the second of ROCH2C (arom.), JPH
13
16.0 Hz), 7.05–7.25 m (4H, arom.). C NMR spectrum
3
(CDCl3, δ, ppm): 15.8 d (CH3, JPC 5.5 Hz), 25.7 d
1
3
(CH2R, JPC 129.5 Hz), 61.5 d (CH2OR, JPC 6.6 Hz),
69.2 d (CH2OR, 3JPC 6.6 Hz) , 124.8, 126.6, 127.6 (4JPC
1.5 Hz), 129.1 (3JPC 7.7 Hz), 130.0 (2JPC 14.3 Hz),
132.0 (3JPC 11.0 Hz). 31P NMR spectrum (CDCl3, δ,
ppm): 23.8. Found, %: C 56.50, 56.43; H 6.13, 6.19; P
14.62, 14.55. C10H13O3P. Calculated, %: C 56.61; H
6.18; P 14.60.
2
ppm): 1.22 t (6H, 2CH3), 3.15 d (2H, CH2P, JPH
The subsequent chromatography with a mixture
chloroform–isopropanol, 19:1, as eluent provided the
bis-phosphorylated product as an oil. Yield 1.2 g
(5.3%), of tetraethyl o-xylylenediphosphonate XVII,
oil, nD20 1.5052. The substance crystallizes on standing
after about 1–2 days, mp 53–55ºC (in bulk). Rf 0.15
(chloroform–acetone, 4:1). 1H NMR spectrum (CDCl3,
22.0 Hz), 4.00 d.q (4H, CH2O), 4.53 s (2H, CH2Cl),
7.28 m (4H, C6H4). 31P NMR spectrum (CDCl3, δ,
ppm): 26.6. Found, %: C 51.87, 51.83; H 6.71, 6.67;
Cl 12.90, 13.01; P 11.27, 11.08. C12H18ClO3P. Cal-
culated, %: C 52.09; H 6.56; Cl 12.81; P 11.19. The
by-product p-xylylenebisphosphonate was not isolated.
2
Diethyl o-chloromethylbenzylphosphonate (X).
To a boiling solution of 30.0 g (0.17 mol) of o-
xylylene dichloride in 30 ml of anhydrous toluene was
slowly added dropwise 10.3 ml (0.06 mol) of triethyl
phosphite within 1 h. The reaction mixture was further
refluxed with stirring for 10 min and evaporated in
vacuo, the residue was chromatographed on 240 ml
column with the “Silpearle” silica gel. With eluent
hexane–chloroform (3:1) 4.15 g of unreacted o-
xylylene dichloride was isolated, then eluting with a
mixture of hexane–chloroform (1:1) gave 8.2 g
(53.0%) of o-chloromethylbenzylphosphonate X, oil,
nD20 1.5165, Rf 0.7 (chloroform–acetone, 4:1). 1H NMR
spectrum (CDCl3, δ, ppm): 1.20 t (6H, 2CH3), 3.30 d
(2H, CH2P, 2JPH 21.2 Hz), 4.00 d.q (4H, CH2O), 4.80 s
(2H, CH2Cl), 7.30 m (4H, arom.). 13C NMR spectrum
δ, ppm): 1.20 t (12H, 4CH3), 3.12 d (4H, 2CH2R, JPH
21.5 Hz), 4.00 d.q (4H, CH2O), 7.40 m (4H, arom.).
31P NMR spectrum (CDCl3, δ, ppm): 27.0. Found, %:
C 50.60, 50.65; H 7.53, 7.49; P 16.32, 16.37.
C16H28O6P2. Calculated, %: C 50.79; H 7.46; P 16.37.
Synthesis of ω-haloalkylphosphine oxides. As a
component of trivalent phosphorus trimethylsilyl
diphenylphosphinite was used obtained by boiling di-
phenylphosphinic acid with 1.0–1.5 equivalents of hexa-
methyldisilazane followed by distillation in a vacuum.
The target ester has bp 107–110°C (0.3 mm Hg).
Using diphenylsilylphosphinite in situ, namely, using
the resulting mixture (after the cessation of ammonia
release) without additional vacuum distillation was
markedly less effective. Attempts to use ethyl di-
phenylphosphinite was also rather unsuccessful, as
showed the lower yield of the target reaction products.
3
(CDCl3, δ, ppm): 16.0 d (CH3, JPC 6.2 Hz), 30.2 d
(CH2P, 1JPC 138.0 Hz), 44.2 d (CH2Cl), 61.8 d (CH2O,
2JPC 7.0 Hz), 127.1 d (4JPC 3.3 Hz), 128.5 d (4JPC
3.3 Hz), 130.1 d (5JPC 2.9 Hz), 130.5 d (2JPC 9.5 Hz),
131.2 d (3JPC 5.5 Hz), 136.0 d (3JPC 6.2 Hz). 31P NMR
spectrum (CDCl3, δ, ppm): 26.1. Found, %: C 52.15,
52.23; H 6.51, 6.49; Cl 12.67, 12.77; P 11.05, 11.12.
C12H18ClO3P. Calculated, %: C 52.09; H 6.56; Cl
12.81; P 11.19.
2-Bromoethyldiphenylphosphine oxide (XI). To
62.5 ml (0.72 mol) of boiling dibromoethane at stirring
was slowly added dropwise 34.4 g (0.13 mol) of
freshly distilled trimethylsilyl diphenylphosphinite
within 1 h in a weak stream of argon. Using a top-
down condenser the continuously formed bromo-
trimethylsilane was distilled off. The reaction mixture
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1935
ω-HALOALKYLPHOSPHORYL COMPOUNDS: SYNTHESIS AND PROPERTIES
was stirred under the same conditions for 0.5 h after
the addition of all calculated amount of silyl phos-
phinite continuously removing bromotrimethylsilane
from the reaction mixture. After the release of 14 ml
(~85%) of bromotrimethylsilane, the reaction mixture
was evacuated and the 1,2-dibromoethane excess was
distilled off. After the removal from the reaction
mixture of 39 ml (~75%) of unreacted 1,2-dibromo-
ethane, the residue was dissolved in 150 ml of chloro-
form and washed with saturated sodium carbonate
solution (3×50 ml) until complete removal of
diphenylphosphinic acid, the byproduct of the reaction
(Rf 0.15–0.30 with chloroform–acetone, 4:1; gray spot
in iodine vapor stretching along the front). The organic
phase was washed with water, dried over magnesium
sulfate, and evaporated in vacuo. The oily crystallizing
residue was chromatographed on silica gel, eluent
chloroform, chloroform–isopropanol (5%). After the
evaporation of the eluate and the crystal-lization of the
residue 6.16 g (42.7%) of the desired bromide XI was
isolated, mp 119–121ºC (ether). Rf 0.50, chloroform–
eluent chloroform, chloroform–isopropanol (3%).
After evaporation of the eluate and crystallization 34.3
g (53.1%) of the desired bromide XII was isolated, mp
94–96ºC (ether), Rf 0.50 (chloroform–acetone, 4:1). 1H
NMR spectrum (CDCl3, δ, ppm): 2.18 m (2H, CH2P),
2.43 m (2H, CH2C), 3.46 t (2H, CH2Br), 7.48 m (6H,
arom.), 7.80 m (4H, arom.). 31P NMR spectrum
(CDCl3, δ, ppm): 32.3. 13C NMR spectrum (CDCl3, δ,
3
1
ppm): 24.9 d (CH2Br, JPC 2.7 Hz), 28.4 d (CH2P, JPC
2
71.9 Hz), 34.2 d (CH2C, JPC 16.3 Hz), 128.5, 128.8,
130.5, 130.7, 131.8, 132.6 (1JPC 101.2 Hz). 13C NMR
spectrum (CD3CN, δ, ppm): 26.0 (CH2Br), 28.4 d
1
2
(CH2P, JPC 71.9 Hz), 35.1 d (CH2C, JPC 16.3 Hz),
129.2, 129.5, 131.0, 131.3, 132.3, 134.2 (1JPC 97.7 Hz).
Found, %: C 55.62, 55.55; H 5.08, 5.13; Br 24.53,
24.73; P 9.47, 9.40. C15H16BrOP. Calculated, %: C
55.75; H 4.99; Br 24.72; P 9.58.
Attempted isolation of the product by distillation in
a high vacuum was accompanied with a visible
dehydrobromination, however, the produced corres-
ponding to 1-propenylphosphine oxide was not
isolated individually.
1
acetone, 4:1. H NMR spectrum (CD3OD + CCl4, δ,
ppm): 2.32 m (2H, CH2P), 3.52 d.t (2H, CH2Br), 7.47
m (6H, arom), 7.75 m (4H, arom.). 13C NMR spectrum
4-Bromobutyldiphenylphosphine oxide (XIII).
1
Yield 61.2%, mp 86–87ºC (ether), Rf 0.55 (chloro-
(CD3CN, δ, ppm): 25.3 (CH2Br), 34.8 d (CH2P, JPC
1
form–acetone, 4:1). H NMR spectrum (CDCl3, δ,
63.7 Hz), 129.7, 129.9, 131.0, 131.4, 132.8, 133.8
(PCarom, 1JPC 101.2 Hz). 31P NMR spectrum (CD3OD +
CCl4, δ, ppm): 31.2.
ppm): 1.88 m (2H, CH2P), 1.98 m (2H, CH2C), 2.30 m
(2H, CH2C), 3.38 t (2H, CH2Br), 7.50 m (6H, arom),
7.80 m (4H, arom). 31P NMR spectrum (CDCl3, δ,
ppm): 32.6. Found, %: C 56.92, 57.10; H 5.48, 5.33;
Br 23.63, 23.77; P 8.90, 9.05. C16H18BrOP. Calculated,
%: C 57.03; H 5.43; Br 23.70; P 9.18.
3-Bromopropyldiphenylphosphine oxide (XII).
To 117.8 g (0.58 mol) of freshly distilled 1,3-di-
bromopropane, pre-heated to boiling, was slowly
added dropwise while stirring within an hour in a weak
stream of argon 55.4 g (0.20 mol) of freshly distilled
trimethylsilyl diphenylphosphinite with continuous
distilling off the formed in the reaction bromo-
trimethylsilane. After adding the whole amount of the
phosphinite the reaction mixture was stirred under the
same conditions for 0.5 h. After removal of 23 g
(~86%) of bromotrimethylsilane the mixture was
evacuated and the excess of 1,3-dibromopropane was
distilled off. After the removal from the reaction
mixture of 63 g (~81%) of unreacted 1,3-dibromo-
propane, the residue was dissolved in 150 ml of
chloroform and washed with saturated sodium car-
bonate solution until the complete removal of di-
phenylphosphinic acid, the reaction byproduct [Rf
0.15–0.30 (in iodine vapor gray spot stretched along
the front), chloroform–acetone, 4:1]. The chloroform
solution was washed with water and evaporated in
vacuo. The residue was chromatographed on silica gel,
5-Bromopentyldiphenylphosphine oxide (XIV).
Yield 54.1%, mp 72–73ºC (ether), Rf 0.55 (chloro-
1
form–acetone, 4:1). H NMR spectrum (CDCl3, δ,
ppm): 1.68 m (4H, CH2R), 1.86 m (2H, CH2C), 2.30 m
(2H, CH2C), 3.35 t (2H, CH2Br), 7.42 m (6H, arom.),
71.68 m (4H, CH2P), 1.86 m (2H, CH2C), 2.30 m (2H,
CH2C), 3.35 t (2H, CH2Br), 7.42 m (6H, arom), 7.73 m
(4H, arom). 31P NMR spectrum (CDCl3, δ, ppm): 32.5.
Found, %: C 58.12, 58.20; H 5.68, 5.81; Br 22.64,
22.83; P 8.92, 8.85. C17H20BrOP. Calculated, %: C
58.14; H 5.74; Br 22.75; P 8.82.
6-Bromohexyldiphenylphosphine oxide (XV).
Yield 51.3%, mp 65–67ºC (ether), Rf 0.34 (chloro-
1
form–acetone, 10: 1). H NMR spectrum (CDCl3, δ,
ppm): 1.40 m (4H, CH2P), 1.64 m (2H, CH2C), 1.90 m
(2H, CH2C), 2.28 m (2H, CH2C), 3.33 t (2H, CH2Br),
7.52 m (6H, arom.), 7.85 m (4H, arom.). 31P NMR
spectrum (CDCl3, δ, ppm): 32.1. Found, %: C 59.30,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

1936
RAGULIN
59.42; H 6.02, 5.91; Br 22.05, 21.77; P 8.51, 8.30.
C18H22BrOP. Calculated, %: C 59.19; H 6.07; Br 21.88;
P 8.48.
Example 2. A mixture of diethyl ether–chloro-
methylbenzylphosphonate X (2.8 g, 0.01 mol) and
sodium chloride (0.6 g, 0.01 mol) in 10 ml of boiling
dimethylformamide was stirred for 5 h. The reaction
mixture was evaporated and the residue was par-
titioned between chloroform and water (30/30 ml). The
organic phase was separated, dried over sodium
sulfate, and evaporated in vacuo, and the residue was
chromatographed on silica gel eluting with hexane–
chloroform, 1:1, mixture). 0.7 g (25.0%) of o-
chloromethylbenzylphosphonate X was isolated, oil,
nD20 1.5160 . Rf 0.7 (chloroform–acetone, 4:1) and 1.3 g
(61.3%) of 2-oxo-2-ethoxy-4,5-benzo-1,2-oxaphos-
phorine XIX, oil, nD20 1.5380. Rf 0.35 (chloroform–
Study of the propensity of 3-bromopropyl-
phosphonate I and o-chloromethylbenzylphosphonate
X to intramolecular cyclization. The experiments
with heating a mixture of 1,3-dibromopropane and
triethyl phosphite at different reagent ratios (from 1:3
to 1:5) in the absence of a solvent largely confirmed
the data of the earlier study [9], where by vacuum
distillation a cyclic compound, 1,2-oxaphospholane
(40 to 60%) was isolated and the desired product was
obtained in a yield not exceeding 11–23%, depending
on experimental conditions. Besides, in the still
remained an unreacted substance, apparently of
polymeric nature. The ethyl bromide liberated in the
reaction was collected in a cooled (dry ice/chloroform)
trap. Note that the amount of ethyl bromide exceeded
one equivalent, even at a fivefold excess of 1,3-
dibromopropane with respect to triethyl phosphite,
which may indicate the initial formation of 3-
bromopropylphosphonate I with the release of the first
molecule of ethyl bromide and the subsequent process
of cyclization with the formation of a second molecule
of ethyl bromide as a byproduct.
1
acetone, 4:1). H and 31P NMR spectral characteristics
of compounds XI and XII are close to the described
above in the synthesis of o-chloromethylbenzylphos-
phonate X.
A similar attempt (with the same loads of the parent
compounds) of isolation of the products by vacuum
distillation gives mainly the cyclic product, 1.5 g
(73%) of 1,2-oxaphosphorine XIX. This result
suggests that the cyclization process takes place under
conditions of vacuum distillation, that is, under
conditions of continuous removal of the ethyl chloride
byproduct from the reaction sphere, which promotes
the formation of cyclic 1,2-oxaphosphorine XIX.
In addition, the investigation of the ability of 3-
bromopropylphosphonate I and o-chloromethylbenzyl-
phosphonate
X
to undergo the intramolecular
In the experiment with 3-bromopropylphosphonate
I in THF the formation of cyclic 1,2-oxaphospholane
XVIII was not detected, however, after stirring a mix-
ture of o-chloromethylbenzylphosphonate X (0.01 mol)
with sodium chloride (0.01 mol) in 10 ml of boiling
tetrahydrofuran for 5 h 0.17 g (8%) of 2-oxo-2-ethoxy-
4,5-benzo-1,2-oxaphosphorine XIX was isolated (the
treatment of the reaction mixture was carried out as in
Example 2, the product was isolated by chromato-
graphy on silica gel). The research results allow us
recommending tetrahydrofuran as an appropriate
solvent in the reactions of the CH acids alkylation with
ω-haloalkylphosphonates.
cyclization was carried out under conditions simulating
the conditions of the alkylation of CH acids, that is, at
reflux with stirring in various solvents in the presence
of one equivalent of sodium chloride or bromide. The
examples below of the experiments with DMF and
THF show the opposite results.
Example 1. A mixture of 3-bromopropylphos-
phonate I (2.6 g, 0.01 mol) and sodium bromide (1.0 g,
0.01 mol) in 7 ml of DMF was refluxed with stirring
for 5 h. The reaction mixture was evaporated and the
residue was partitioned between chloroform and water
(30/30 ml). The organic phase was separated, dried
over sodium sulfate, and evaporated in vacuo, and the
residue was distilled. 1.2 g (80%) of 2-oxo-2-ethoxy-
1,2-oxaphospholane XVIII was isolated, bp 85–89ºC
(0.02 mm Hg), nD20 1.4540. Published: bp 72–74ºC
Thus, this paper describes a general method of the
synthesis of ω-haloalkylphosphoryl compounds, and a
number of compounds of phosphonic and phosphine
oxide types were synthesized. We investigated the
(0.01 mm Hg), nD20 1.4520. [9]. H NMR spectrum
ability of ω-haloalkylphosphonates containing a
1
(CDCl3, δ, ppm): 1.32 t (3H, CH3), 1.85 m (2H,
CH2R), 2.26 m (2H, CH2C), 4.15 m (4H, OCH2CH3 +
OCH2CH2). 31P NMR spectrum (CD3OD + CCl4, δ,
ppm): 35.1.
halogen atom in the 3 or 4 position with respect to the
phosphoryl moiety to undergo the intramolecular
cyclization into the corresponding 1,2-oxaphospholane
and 1,2-oxaphosphorine depending on several factors
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 12 2012

1937
ω-HALOALKYLPHOSPHORYL COMPOUNDS: SYNTHESIS AND PROPERTIES
6. Boast, C.A., Gerhardt, S.C., Pastor, G., Lehmann, J.,
Etienne, P.E., and Liebman, J.M., Brain Res., 1988,
vol. 442, no. 2, p. 345.
(temperature, polarity of the solvent, the presence of
halide ions in solution). Tetrahydrofuran is recom-
mended the most suitable solvent for the alkylation of
CH acids with ω-haloalkylphosphoryl compounds.
7. Kosolapoff, G.M., J. Am. Chem. Soc., 1948, vol. 70,
no. 5, p. 1971.
ACKNOWLEDGMENTS
8. Kosolapoff, G.M., J. Am. Chem. Soc., 1944, vol. 66,
no. 4, p. 1511.
This work was supported by the Russian
Foundation for Basic Research (grant 10-03-01 058-a).
9. Pudovik, A.N., Muratova, A.A., and Savel’eva V.A.,
Zh. Obshch. Khim., 1964, vol. 34, no. 8, p. 2582.
10. Matoba, K., Yonemoto, H., Fukui, M., and Yamazaki, T.,
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