Alkylation of Diethylphosphonoacetic Aldehyde and Triethyl Phosphonoacetate with Ethyl α-Bromopropanoate

Article abstract of DOI:10.1134/S1070363219070077

The alkylation reactions of phosphonoacetic aldehyde and ethyl phosphonoacetate with ethyl α-bromopropanoate in DMSO in the presence of K₂CO₃ have been studied.

Full text of DOI:10.1134/S1070363219070077

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 7, pp. 1394–1397. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 7, pp. 1033–1037.
Alkylation of Diethylphosphonoacetic Aldehyde
and Triethyl Phosphonoacetate with Ethyl α-Bromopropanoate
B. M. Ismailova, G. G. Ibragimovaa, G. E. Allakhverdiyevaa, N. D. Sadikhovaa,
I. A. Mamedova, A. R. Mamedbeylia, and N. N. Yusubova*
Baku State University, ul. Z. Khalilova 23, Baku, AZ-1148 Azerbaijan
*e-mail: yniftali@gmail.com
Received November 30, 2018; revised November 30, 2018; accepted January 27, 2019
Abstract—The alkylation reactions of phosphonoacetic aldehyde and ethyl phosphonoacetate with ethyl
α-bromopropanoate in DMSO in the presence of K2CO3 have been studied.
Keywords: phosphonoacetic aldehyde, ethyl α-bromopropanoate, ethyl phosphonoacetate, 1,3-dichloroacetone,
phosphite
DOI: 10.1134/S1070363219070077
α-Phosphorylated carbonyl compounds are interest-
ing from fundamental and practic viewpoints, due to the
presence of highly reactive carbonyl and active methy-
lene groups. Systematical investigations of alkylation
of phosphorous-substituted CH-acids with mono and
polyhalogenoalkanes have been performed over the re-
cent decade [1–4]. The obtained data indicate low yield
of alkylation products from phosphonoacetic aldehyde
and phosphonoacetates [1, 5, 6]. Thus, detailed study of
alkylation of more reactive phosphonoacetic aldehyde and
less reactive phosphonoacetates with an active alkylating
agent (ethyl α-bromopropanoate) is interesting.
We suggested that the reaction in alkali medium started
with proton elimination from either phosphonoacetic
aldehyde (anion A) or α-bromopropionate (anion B,
Scheme 2). The anion B condensation with the second
α-bromopropionate molecule gave compounds 3 and 4.
The reaction of carbanion A with α-bromopropionate led
to the formation of insignificant amount of enol ether 2.
The structure of that compound was confirmed by the
presence of weak signals at δ 5.0 and 7.1 ppm in 1Н NMR
spectrum. The formation of compound 1 could be con-
sidered a result of the reaction of anion B with phospho-
noacetic aldehyde via the Darzens reaction (Scheme 3).
Dimethylsulfone 5 was formed as a result of the reac-
tion of DMSO with phosphonoacetic aldehyde. Spectral,
physical, and chemical constants of the obtained sulfone
were identical to those described in [7].
Alkylation of phosphonoacetic aldehyde with ethyl
α-bromopropanoate was carried out at relatively low
temperature (40–50°С) in dimethylsulfoxide medium in
the presence of excess of K2CO3. The products of Darzens
condensation (1), О-alkylation (2), self-condensation of
α-bromopropionate (3, 4), and dimethylsulfone 5 were
isolated (Scheme 1).
Detailed investigation of those reactions led to conclu-
sion that low yield of the alkylation products was caused
by self-condensation of phosphonoacetic aldehyde under
Scheme 1.
OEt CH3
O
OEt
P
H
OEt
P
CH3
H3C
Br
O
K2CO3
DMSO
P
+
+
O
EtO
OEt
EtO
O
EtO
O
OEt
O
O
O
O
OEt
2
1
O
EtO2C
H3C
CH3
EtO2C
H3C
CO2Et
+ H3C S
CH3
+
+
CO2Et
O
CH3
5
4
3
1394

ALKYLATION OF DIETHYLPHOSPHONOACETIC ALDEHYDE
1395
Scheme 2.
leinate (3) and diethyl dimethylfumarate (4) were isolated
from the reaction mixture (Scheme 5).
O
CH3CCO2Et
Probably, self-condensation of active α-bromopropio-
nate occurred at low temperature with the formation of
compounds 3 and 4. At higher temperature (70–80°С),
unreacted phosphonoacetate was condensed at the phos-
phorous atom of the second phosphonoacetate molecule,
forming product 7 due to nucleophilic properties of the
phosphoryl group [8] (Scheme 6).
(EtO)2PCHCH
Br
B
O
A
the action of DMSO (the reaction medium). Apparently,
nucleophilic attack of carbanion A on the phosphorous
atom of the second phosphonoacetic aldehyde molecule
resulted in the formation of intermediate C, decompo-
sition of which led to bis(diethoxyphosphoryl)acetic
aldehyde 6 (Scheme 4).
It was also interesting to investigate the reactions of the
phosphorylated ketones with α-bromopropanoate in view
of preparation of the (EtO)2P(O)CH2C(O)CH2P(O)(OEt)2
phosphorylated ketones via the Arbuzov reaction of
1,3-dichloroacetone with 2 eq. of triethyl phosphite.
However, it was shown that the mentioned reaction in
toluene occurred as the Perkov reaction with the forma-
tion of phosphate. Then, the second chlorine atom in the
obtained phosphate was substituted with an ethoxy group
The reaction of triethyl phosphonoacetate with ethyl
α-bromopropanoate in the presence of large excess of
K2СО3 in DMSO was also investigated. The analysis
of the reaction products (either raw or purified) did not
reveal the formation of an alkylation product. Anhydride
of tetraethyl phosphonoacetate 7 and diethyl dimethylma-
Scheme 3.
CO2Et
O
H
C
O
Br
C
O
H3C
H3C
H
C
H
C
O
H3C C
+
P(OEt)2
P(OEt)2
P(OEt)2
C
Br
O
EtO2C
EtO2C
O
O
EtO
P(OEt)2
O
CH3
O
1
Scheme 4.
O
H2
C
O
H
O
ДМСО
H+

(EtO)2P CH2C
O
(EtO)2P CH
O
+
C
C
(EtO)2P
O
H
H
O
H
O

(EtO)2P CH
H2C
+
C
C
H
O
O
CHO
2
6
(EtO)2P
stable
P(OEt)2
O
O
O
+ EtO
CH2CHO

EtOPCH2C
C
H
CHCHO
(EtO)2P
O
less stable
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

1396
ISMAILOV et al.
Scheme 5.
O
P
O
P
OEt
O
H3C
Br
O
OEt
EtO
K2CO3
DMSO
+ 4
+
O
3
(C2H5O)2P
+
OEt
CH2CO2Et
O
EtO2CH2C
7
Scheme 6.
CH2CO2Et
CH2CO2Et
CH2CO2Et
P(OEt)2
CH2CO2Et
OEt
(EtO)2P+
O
O
+
P
(EtO)2P
EtO
OEt
OEt
O
O
EtO
EtO
Et
O
O
P
O
P
O
EtO
EtO2C
OEt
CO2Et
CO2Et
EtO2C
P
O
P
O
Et2O
+
7
Reaction of phosphonoacetic aldehyde with ethyl
α-bromopropanoate. A mixture of 5 g (0.03 mol) of
phoshomoacetic aldehyde, 4.6 g of K2СО3, and 5.3 g
(0.03 mol) of ethyl α-bromopropanoate in 30 mL of
DMSO was stirred for 4 h at 40–50°С. The mixture was
cooled down, treated with water, and extracted with dieth-
yl ether (3×50 mL). Ether was distilled off, the crystalline
precipitate was filtered off, and the filtrate was distilled.
The first fraction was diethyl dimethylmaleinate (3).
Yield 1.72 g (22%), mp 96–98°С (6 mmHg), nD20 1.4495
[9]. 1Н NMR spectrum, δ, ppm: 1.18 t (6Н, СН3СН2, J
= 7.1 Hz), 2.54 s (6Н, СН3С=), 4.06 q (4Н, СН2О, J =
7.1 Hz). 13С NMR spectrum, δС, ppm: 14.56 (СН3), 20.82
(С=), 60.48 (СН2О), 171.03 (СОО).
under the action of the second equivalent of phosphite.
Finally, compound 8 was formed (Scheme 7).
In summary, we figured out that alkylation of phos-
phonoacetic aldehyde with ethyl α-bromopropanoate in
DMSO in the presence of K2CO3 led to the formation of
the products of О-alkylation, Darzens condensation, and
self-condensation of ethyl α-bromopropanoate (diethyl
dimethylmaleinate, diethyl dimethylfumarate), as well
as dimehylsulfone. Some amount of phosphonoacetic
aldehyde was condensed to form bis(diethoxyphosphoryl)
acetic aldehyde under the reaction conditions. It was
shown that alkylation of ethyl phosphonoacetate with
α-bromoprapanoate led also to the product of self-conden-
sation of ethyl α-bromopropanoate and phosphonoacetate.
The reaction of 1,3-dichloroacetone with phosphite oc-
curred as the Perkov reaction followed by the substitution
of chlorine atom with ethoxy group.
The second fraction was diethyl dimethylfumarate
(4). Yield 2.1 g (24%), bp 105°С, mp 62°С, nD20 1.4457
[10].
The third fraction was ethyl 3-methyl-4-diethoxy-
phosphoryl-2-oxobutanoate (1). Yield 1.8 g (16.8%),
bp 120°С (2 mmHg), nD 1.4287. Н NMR spectrum,
δ, ppm: 1.17–1.22 m (9H, CH3, J = 6.9 Hz), 1.24 d (3H,
CН3CH, J = 6.9 Hz), 1.75 q (1H, CHCH3, J = 6.9 Hz),
2.8 d. d (2H, PCH2, 3JHH = 7.4, 2JHP = 21.3 Hz), 3.95 q
EXPERIMENTAL
20
1
1Н and 13С NMR spectra in DMSO-d6 were registered
usingaBrukerAV-300device[300(1H)and75(13С)MHz];
TMS was used as internal reference. Melting points were
measured using an SMP 30 device.
Scheme 7.
CH2OEt
O
O
EtO
EtO
EtO
O

2
+
P
Cl
Cl
OEt
HB
P
C
toluene
C
EtO
HA
8
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

ALKYLATION OF DIETHYLPHOSPHONOACETIC ALDEHYDE
1397
(2H, OCH2, J = 6.6 Hz), 4.08 m (4H, POCH2). 13С NMR
spectrum, δС, ppm: 6.40 d (CН3CH, JCP = 8.9 Hz),
38.21; Н 6.76; Р 16.26. С12Н24Р2О9 Calculated, %: С
38.50; Н 6.42; Р 16.04.
3
14.42 (CH3), 16.56 d (CH3CH2O, 3JCP = 6.8 Hz), 21.49
d (PCH2, 1JCP = 150.6 Hz), 40.77 d (CH, 2JCP = 7.2 Hz)
60.83 (OCH2), 61.60 d (CH2OP, 2JCP = 6.0 Hz), 167.22
(COO), 192.06 (CHCOCO). Found, %: С 51.24; Н 8.67;
Р 11.45. С11Н21РО6. Calculated, %: С 49.81; Н 8.30; Р
11.70.
3-Ethoxy-2-diethoxyphosphoryloxyprop-1-ene
(8). A mixture of 6 g (0.2 mol) of triethyl phosphite and
2 g (0.1 mol) of 1,3-dichloroacetone in 10 mL of toluene
was refluxed for 10 h, cooled down, and distilled. Yield
20
5.3 g (68.7%), bp 128–130°С (2 mm Hg), nD 1.4307.
1Н NMR spectrum, δ, ppm: 1.22 t (3Н, СН3, J = 7.2
Hz), 1.27 t (6H, CH3, J = 7.2 Hz), 3.98 q (2H, CH2O, J =
7.5 Hz), 4.05 q (4Н, CH2O, J = 6.9 Hz), 4.27 s (2H,
OCH2), 4.97 d. d (1НА, С=СНА, 2JHH = 2.4, 4JHP = 2.1
Hz), 5.06 d. d (1HB, C=CHB, 2JHH = 2.4, 4JHP = 1.1 Hz).
13С NMR spectrum, δС, ppm: 16.14, 16.22, 16.32 (3СН3),
The colorless crystals were dimethylsulfone (5).
1
Yield 2.4 g (27.6%), mp 109°С. Н NMR spectrum, δ,
ppm: 2.84 s.
Synthesis of diethyl dimethylmaleinate (3) and
diethyl dimethylfumarate (4) from ethyl α-bromopro-
panoate. A mixture of 10 g (0.05 mol) of ethyl
α-bromopropanoate, 15.3 g of K2СО3, and 40 mL of
DMSO was stirred for 10 h at 40–50°С. The mixture
was cooled down, treated with water, and extracted with
diethyl ether. Ether was distilled off, and the crystals of
diethyl dimethylfumarate (4) were filtered off. The
filtrate was diethyl dimethylmaleinate (3).
44.63 d (СН2,3JCP = 8.3 Hz), 63.40 d (CH3CH2OP, 2JCP
=
3
5.9 Hz), 64.71 (ОСН2), 101.6 d (С=, JCP = 3.8 Hz),
2
150.63 d (=СO, JCP = 8.3 Hz). Found, %: С 45.54; Н
7.78; Р 13.16. С9Н19О5Р. Calculated, %: С 45.37; Н 7.9;
Р 13.02.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
Bis(diethylphosphoryl)acetic aldehyde (6). A mix-
ture of 5 g (0.03 mol) of phosphonoacetic aldehyde and
5 mL of DMSO was heated at 60°С for 10 h. The mixture
was cooled down, treated with water, and extracted with
diethyl ether. Ether was distilled off, and the residue was
distilled. Yield 3.4 g (68%), bp 150–153°С (2 mmHg),
nD20 1.4300. 1Н NMR spectrum, δ, ppm: 1.15 t (12Н, СН3,
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J = 6.9 Hz), 2.95 d. d (1Н, СН, 3JHH = 3.3, 2JHP = 21.9 Hz),
3
3.88–4.02 m (8Н, СН2О), 9.46 d. t (1H, CHO, JHH
=
3.3, 3JHP = 2.7 Hz). Found, %: С 37.67; Н 7.09; Р 19.87.
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Cl.1987.357
С10Н22Р2О7. Calculated, %: С 37.97; Н 6.69; Р 19.62.
Anhydride of phosphonoacetic acid (7). 3.4 g
(0.02 mol) of ethyl α-bromopropanoate was dropwise
added to a mixture of 3 g (0.02 mol) of triethyl phos-
phonoacetate, 2.4 g of K2СО3, and 40 mL of DMSO at
room temperature. The obtained mixture was stirred for
2–3 h at 40–50°С, then 12 h at 70–80°С. The mixture
was cooled down, treated with water, and extracted with
diethyl ether (3×50 mL). Ether was distilled off, and the
crystals were filtered off and recrystallized from ethyl
1
acetate. Yield 2.5 g (56%), mp 98°С. Н NMR spec-
trum, δ, ppm: 1.17 t (6Н, СН3, J = 8.4 Hz), 1.22 t (6Н,
2
СН3, J = 8.4 Hz), 2.85 d (4Н, СН2Р, JHР = 22.0 Hz),
3.95 q (4Н, СН2О, J = 7.1 Hz) (4Н, СН2О, J = 7.5 Hz),
4.06 q (4Н, СН2О, J = 6.9 Hz). 13С NMR spectrum, δС,
ppm: 14.41 (СН3), 16.65 (СН3), 36.04 d (РСН2, 1JCP
=
=
2
131.0 Hz), 60.83 (COOCH2), 61.60 d (ОСН2, JCP
2
6.0 Hz), 167.31 d (СОО, JCP = 6.3 Hz). Found, %: С
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019