Transformations of bis(2-chloroethyl) arylphosphonites in the presence of haloacetic acid esters

Article abstract of DOI:10.1134/S1070428016030052

The reaction of aryl(dichloro)phosphines with (2-chloroethoxy)trimethylsilane in the presence of haloacetic acid esters was studied with the goal of developing a new method for the synthesis of ethyl [(2-chloroethoxy)(4-dimethylaminophenyl)phosphoryl]acet

Full text of DOI:10.1134/S1070428016030052

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 3, pp. 324–328. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © I.A. Krutov, R.N. Burangulova, E.L. Gavrilova, R.I. Tarasova, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 3, pp. 344–349.
Transformations of Bis(2-chloroethyl) Arylphosphonites
in the Presence of Haloacetic Acid Esters
I. A. Krutov, R. N. Burangulova, E. L. Gavrilova, and R. I. Tarasova
Kazan National Research Technological University, ul. K. Marksa 68, Kazan, 420015 Tatarstan, Russia
e-mail: cat_the_chemist@mail.ru
Received July 29, 2015
Abstract—The reaction of aryl(dichloro)phosphines with (2-chloroethoxy)trimethylsilane in the presence of
haloacetic acid esters was studied with the goal of developing a new method for the synthesis of ethyl
[(2-chloroethoxy)(4-dimethylaminophenyl)phosphoryl]acetate. The effect of various factors, such as substituent
in the para position of the aromatic ring in the initial aryl(dichloro)phosphine, halogen nature in haloacetic acid
ester, and chloro(trimethyl)silane, on the reaction course was analyzed.
DOI: 10.1134/S1070428016030052
Modern medicine operates with a large number of
various drugs for the prophylactics and treatment of
neuropsychic disorders. On the other hand, there are
increasing demands for medicinal agents improving
mental activity, i.e., nootropics. In 1960s, Prof.
A.I. Razumov (Kirov Kazan Institute of Chemical
Technology) initiated systematic studies of phos-
phorylated carboxylic acid derivatives, which underlay
the design of nootropic agents based thereon [1]. As
a result, [(2-chloroethoxy)(4-dimethylaminophenyl)-
phosphoryl]acetohydrazide (5, CAPAH), was synthe-
sized. Compound 5 is a novel drug for the treatment of
neuropsychic disorders; it improves memory and
exhibits neuroprotective and antidepressant activity
and is characterized by unusual mechanism of action in
the treatment of neurodegenerative dementia (includ-
ing Alzheimer’s disease), chronic depression, cerebro-
vascular insufficiency with impairment of memory and
attention; it also improves resistance in immuno-
deficiency states [2].
It was proposed to synthesize compound 5 ac-
cording to Scheme 1 which involves the use in the first
step of a very toxic, inflammable, and explosive
ethylene oxide (oxirane). Therefore, development of
a new method for the synthesis of 5 is an important
problem. As follows from Scheme 1, they key inter-
mediate product therein is bis(2-chloroethyl) [4-(di-
methylamino)phenyl]phosphonite (2a) which is ob-
tained by reaction of phosphine 1a with oxirane. The
present study was aimed at modifying the step of syn-
thesis of phosphonite 2a.
It is well known that phosphonous acid esters can
be prepared from phosphonous dichlorides and silyl
Scheme 1.
Cl
Cl
O
O
O
O
O
PCl2
P
Cl
P
ClCH2C(O)OEt (3)
O
OEt
Me2N
Me2N
Me2N
1a
2a
4a
Cl
O
O
O
NH2NH2
–EtOH
P
NH2
N
H
Me2N
5
324

TRANSFORMATIONS OF BIS(2-CHLOROETHYL) ARYLPHOSPHONITES
325
ethers [3]. When phosphine 1a reacted with 2-chloro-
ethyl trimethylsilyl ether (6) in methylene chloride at
–5 to 0°C, the 31P NMR spectrum of the reaction mix-
ture contained only one signal at δP 161 ppm corre-
sponding to phosphonite 2a (Scheme 2). This signal
disappeared after keeping for 24 h at room tempera-
ture, and two new signals appeared at δP 23.3 and
26 ppm (intensity ratio 0.15:1). These findings indicat-
ed that phosphonite 2a is stable at a relatively low tem-
perature and that in undergoes various transformations
as the temperature rises. In order to avoid decompo-
sition of 2a, the first and second steps were combined
by reacting 1a with 6 in the presence of ethyl chloro-
acetate (3). We anticipated that phosphonite 2a once
being formed will react with 3 to give 4a.
the initial arylphosphine does not affect further trans-
formations of 2a–2c.
It is known that Arbuzov reaction is catalyzed by
Lewis acids [4, 5]; silicon compounds are also classed
with Lewis acids. To exclude the effect of silicon com-
pounds, volatile components were removed from the
reaction mixtures by low-temperature evacuation
before addition of ethyl chloroacetate (3). In fact, the
yield of 4 was thus improved to 50%, which confirmed
catalytic effect of silicon compounds.
We also examined the stability of intermediate
phosphonite 2b in the absence of silicon compounds.
For this purpose, compound 2b was synthesized in
a different way, by reaction of 1b with 2-chloroethanol
in the presence of triethylamine (Scheme 3).
Scheme 2.
Scheme 3.
1a
3
Cl
Cl
2a
4a
Me3SiO
O
–Me3SiCl
–ClCH2CH2Cl
Et3N
PhPCl2
+
2ClCH2CH2OH
6
P
Cl
–Et3N·HCl
Ph
O
Insofar as phosphine 1a is insoluble in ester 3, it
was dissolved in methylene chloride, the solution was
cooled to 0°C, ether 6 and ester 3 were added in
succession, and the mixture was allowed to warm up to
room temperature. In the 31P NMR spectrum of the
reaction mixture we observed a signal at δP 36.8 ppm
(4a), a very strong signal at δP 161.5 ppm (2a), and
signals at δP 27.8 and 22.9 ppm due to by-products.
After heating for 3 h at 80–100°C, the signal of 2a dis-
appeared, while the signal of target ester 4a increased
together with those of the by-products. The formation
of by-products may be favored by the effect of the
dimethylamino group on the reactivity of the phos-
phorus atom, which could give rise to inter- and intra-
molecular Arbuzov reactions; furthermore, the pres-
ence of silicon compounds may also affect the reaction
course.
1b
2b
According to the 31P NMR data, the reaction mix-
ture contained target phosphonite 2b and phosphorus
compounds with δP 19.4 (11.7%) and 26.3 ppm (27%).
The spectral pattern (i.e., the position of signals and
their intensity) did not change at room temperature.
However, after addition of chloro(trimethyl)silane to
the reaction mixture kept at room temperature, the
signal of 2b disappeared while the intensities of the
two other signals proportionally increased. By thin-
film molecular distillation we isolated two pure com-
pounds which were identified as bis(2-chloroethyl)
phenylphosphonate (7b) and (2-chloroethyl) phenyl-
phosphinate (8b) on the basis of their 1H and 31P NMR
spectra and elemental compositions (Scheme 4). This
result is fully consistent with published data [6, 7].
Scheme 4.
In order to elucidate the role of the para-substituent
in the initial aryl(dichloro)phosphine, model reactions
were carried out under analogous conditions with di-
chloro(phenyl)phosphine (1b) and dichloro(4-chloro-
phenyl)phosphine (1c). After heating at 80–100°C, the
31P NMR spectra of the reaction mixtures showed
a signal belonging to phosphonite 2b or 2c (δP 160 or
158.3 ppm), a signal of ester 4b or 4c (δP 35.2 or
34.5 ppm), and signals at δP 24.6 and 18.7 or 26.0 and
19.4 ppm, respectively. Thus, analysis of the 31P NMR
spectra of the reaction mixtures obtained in the reac-
tions of phosphines 1a–1c with silyl ether 6 and
chloroacetate 3 indicated that the para-substituent in
Cl
Cl
Me3SiCl
O
P
O
P
Cl
Cl
Ph
Ph
O
O
O
2b
7b
O
+
P
O
Cl
Ph
H
8b
Additional information on the structure of com-
pounds formed in the reactions of 1a–1c with 6 and 3
was obtained by GC/MS analysis of the reaction mix-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

KRUTOV et al.
326
Scheme 5.
+·
+
+
Cl
Cl
Cl
O
P
O
O
P
·
–Cl
Cl
P
–C2H4O
O
O
CH2
O
O
O
Cl
Cl
Cl
m/z 316
m/z 281
m/z 237
+·
+
Cl
Cl
Cl
O
O
P
O
P
H2C
O
P
P
O
O
OH
OH
·
·
+·
CH –CH2CHCl
Cl
–Cl
O
OH
O
O
H
Cl
Cl
Cl
Cl
Cl
m/z 254
–CH2CHCl
m/z 219
–CH2CH2O
+·
+
OH
P
OH
P
OH
O
·
–OH
O
Cl
Cl
m/z 192
m/z 175
tures [8]. The reaction mixtures were found to contain
three structurally related components.
hydroxyoxophosphonium ion; in addition, [M –
C8H9Cl2P]+ (m/z 63), [M – C4H8Cl2O2P]+ (m/z 111),
and other ion peaks were present. These findings
suggest similarity of the fragmentation patterns of
2-chloroethyl (2-chloroethyl)(4-chlorophenyl)phos-
phinate and bis(2-chloroethyl) (4-chlorophenyl)phos-
phonate.
The first (minor) component of the reaction mixture
obtained from 1c showed the molecular ion peak
corresponding to bis(2-chloroethyl) (4-chlorophenyl)-
phosphonate and [M – Cl]+ ion peak with m/z 281.
Cleavage of one P–O bond in the molecular ion gives
[M – C2H4OCl]+ ion with m/z 237. The ion with m/z
219 is likely to be formed as a result of McLafferty
rearrangement followed by elimination of chlorine
atom. Therefore, the presence of a ion peak with
m/z 254 might be expected. However, its relative inten-
sity was as low as 4%. Presumably, this ion undergoes
subsequent rearrangement to ion with m/z 192 which
loses hydroxy group to give a fragment ion with
m/z 175. The fragmentation pattern of bis(2-chloro-
ethyl) (4-chlorophenyl)phosphonate is shown in
Scheme 5.
Scheme 6.
Cl
Cl
O
P
O
P
Cl
∆
O
O
Cl
Cl
Cl
2c
9c
The third component was ethyl 2-[(2-chloroethoxy)-
(4-chlorophenyl)phosphoryl]acetate which displayed
in the mass spectrum [M – Cl]+ ion peak with m/z 289.
Unlike the first two components, its decomposition
under electron impact involved elimination of the
CH2COOEt fragment with formation of ion with
m/z 237 (Scheme 7).
The second component was characterized by a low-
abundance molecular ion corresponding to 2-chloro-
ethyl (2-chloroethyl)(4-chlorophenyl)phosphinate
(Scheme 6). Analogous isomerization of P(III) esters
was reported in [9]. The peak with m/z 265 was
assigned to [M – Cl]+. Cleavage of the P–C bond in the
molecular ion gives [M – C2H4Cl]+ with m/z 237. The
base peak in the mass spectrum of the second com-
ponent was that with m/z 175 due to (4-chlorophenyl)-
The molecular ion peaks derived from compounds
with Ar = 4-ClC6H4 had low intensity, compounds with
Ar = Ph showed no molecular ion at all, while the
molecular ions of those with Ar = 4-Me2NC6H4 were
the most abundant.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

TRANSFORMATIONS OF BIS(2-CHLOROETHYL) ARYLPHOSPHONITES
327
Scheme 7.
+·
Cl
+
O
P
O
O
O
Cl
P
·
O
–CH2COOEt
OEt
Cl
Cl
m/z 324
m/z 237
Obviously, the product ratio may be changed in
favor of ester 4 by increasing the rate of the main
reaction. It is known that the reactivity series of halo-
gen derivatives looks like RI > RBr > RCl, other con-
ditions being equal. [10]. Therefore, apart from ethyl
chloroacetate (3), we tried methyl bromoacetate and
ethyl iodoacetate; the latter was generated in situ from
3 and potassium iodide. In the reactions with methyl
bromoacetate, the signal intensity ratio in the 31P NMR
spectra of the reaction mixtures was almost the same
as in the reactions with 3, and the target ester was
formed as minor product. The reaction with ethyl iodo-
acetate gave an intractable mixture of numerous prod-
ucts, in agreement with published data [11].
trometric analyses were obtained on a Thermo
Electron DFS instrument (electron impact, 70 eV; ion
source temperature 290°C; ID-BPX5 capillary column,
50 m×0.32 mm; carrier gas helium).
All solvents used were preliminarily dried and pu-
rified. Initial aryl(dichloro)phosphines 1a–1c and silyl
ether 6 were synthesized according to the procedures
described in [12, 13]. Final products were not isolated,
and their concentrations were determined by 31P NMR.
Bis(2-chloroethyl) [4-(dimethylamino)phenyl]-
phosphonite (2a). A solution of 1.5 g (6.75 mmol) of
dichloro[4-(dimethylamino)phenyl]phosphine (1a) in
6 mL of methylene chloride was added at –5°C under
argon to a solution of 2.21 g (14.5 mmol) of (2-chloro-
ethoxy)trimethylsilane (6) in 3 mL of methylene
chloride, and the mixture was stirred for 30 min at
–5 to 0°C. 31P NMR spectrum (CH2Cl2): δP 161 ppm.
Thus, the reaction of aryl(dichloro)phosphines with
(2-chloroethoxy)trimethylsilane and haloacetic acid
esters leads to a mixture of target ethyl [aryl(2-chloro-
ethoxy)phosphoryl]acetate and bis(2-chloroethyl) aryl-
phosphonate, (2-chloroethyl) arylphosphinate, and
2-chloroethyl aryl(2-chloroethyl)phosphinate as by-
products (Scheme 8).
Reaction of aryl(dichloro)phosphines 1a–1c with
(2-chloroethoxy)trimethylsilane (6) in the presence
of haloacetic acid esters (general procedure). A solu-
tion of 7 mmol of phosphine 1a–1c and 10 mmol of
haloacetic acid ester in 8 mL of methylene chloride
was cooled to –5°C, 15 mmol of silane 6 was added,
and the mixture was stirred for 30 min at –5 to 0°C and
then for 3 h at 80–100°C with simultaneous removal of
volatile components by distillation.
Scheme 8.
Cl
∆
O
P
Ar
Ar
Ar
Cl
O
9
Reaction of dichloro[4-(dimethylamino)phenyl]-
phosphine (1a) with (2-chloroethoxy)trimethyl-
silane (6) in the presence of ethyl chloroacetate (3).
The reaction mixture was stirred for 30 min at 20–
22°C. 31P NMR spectrum, δP, ppm: 161 (72%), 36.8
(5%), 27.8 (18%), 22.9 (5%). The mixture was then
heated for 3 h at 80–100°C. 31P NMR spectrum, δP,
ppm: 36.6 (25%), 27.3 (61%), 22.9 (15%).
Cl
Me3SiCl
O
P
O
P
Cl
Cl
Cl
Ar
O
O
H
2
8
Cl
[O]
O
P
O
O
7
Reaction of dichloro(phenyl)phosphine (1b) with
(2-chloroethoxy)trimethylsilane (6) in the presence
of ethyl chloroacetate (3). 31P NMR spectrum of the
reaction mixture, δP, ppm: 160 (10%), 35.2 (30%), 26
(40%), 19.4 (20%).
EXPERIMENTAL
The H and 31P NMR spectra were recorded on
a Bruker MSL-400 spectrometer at 400 and 166 MHz,
respectively, relative to tetramethylsilane (1H) or
85% H3PO4 (31P). Gas chromatographic–mass spec-
1
Reaction of dichloro(4-chlorophenyl)phosphine
(1c) with (2-chloroethoxy)trimethylsilane (6) in the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

KRUTOV et al.
328
presence of ethyl chloroacetate (3). 31P NMR spec-
trum of the reaction mixture, δP, ppm: 158.3 (28%),
34.5 (26%), 24.6 (32%), 17.8 (15%).
(2H, Harom). Found, %: Cl 24.21; P 11.12. Calculated,
%: Cl 24.05; P 10.94.
2-Chloroethyl phenylphosphinate (8b). Yield
2.76 g (45%). 31P NMR spectrum: δP 26 ppm (J =
Reaction of dichloro(phenyl)phosphine (1b) with
(2-chloroethoxy)trimethylsilane (6) in the presence
of ethyl chloroacetate (3) and potassium iodide. A
solution of 1.35 g (11 mmol) of ethyl chloroacetate (3)
in 5 mL of anhydrous acetone was added to 1.67 g
(10 mmol) of finely powdered potassium iodide. The
mixture was stirred for 2 h at 20–22°C and cooled to
–5°C, 1.8 g (10 mmol) of phosphine 1b and 3.35 g
(22 mmol) of silane 6 were added in succession, and
the mixture was heated for 2 h under reflux with
stirring. 31P NMR spectrum, δP, ppm: 44.9 (63%), 43.4
(12 %), 35.3 (18%), 19.6 (7%).
1
570 Hz). H NMR spectrum, δ, ppm: 3.4 m (2H,
CH2Cl), 3.7 m (2H, CH2O), 7.56 d (1H, PH, J =
570 Hz), 7.3 m (2H, Harom), 7.4 m (1H, Harom), 7.6 m
(2H, Harom). Found, %: Cl 17.42; P 15.23. Calculated,
%: Cl 17.33; P 15.14.
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was added at –5°C under argon to a solution of 1.6 g
(9 mmol) of phosphine 1b in 4 mL of benzene. The
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triethylamine and 4.5 g (60 mmol) of 2-chloroethanol
in 35 mL of anhydrous benzene on cooling to –5°C.
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precipitate was filtered off. 31P NMR spectrum of the
filtrate, δP, ppm: 159.7 (61%), 26.3 (12%), 19.4 (27%).
Chloro(trimethyl)silane, 0.32 g (3 mmol), was then
added, and the mixture was stirred for 1 h at 60°C.
31P NMR spectrum of the reaction mixture, δP, ppm:
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016