Glycidol esters from diethylamido-(4-phenylthiazolyl-2-amido)- ketophosphonates and their chemical modification

Article abstract of DOI:10.1134/S1070363209040136

Thiazolyl-containing esters of α-ketophosphonic acids (KPE) unknown earlier were synthesized and investigated in Darzens-Claisen reaction. Reactions were demonstrated to proceed by a classic scheme to form the corresponding phosphorylated glycidol esters

Full text of DOI:10.1134/S1070363209040136

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 4, pp. 755–758. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © L.K. Sal’keeva, E.V. Minayeva, M.T. Nurmaganbetova, B.Z. Kokzhalova, A.I. Mantel’, 2009, published in Zhurnal Obshchei
Khimii, 2009, Vol. 79, No. 4, pp. 591–594.
Glycidol Esters from Diethylamido-(4-phenylthiazolyl-2-amido)-
ketophosphonates and Their Chemical Modification
L. K. Sal’keeva, E. V. Minayeva, M. T. Nurmaganbetova,
B. Z. Kokzhalova, and A. I. Mantel’
Buketov Karaganda State University,
Universitetskaya ul. 28, Karaganda, 100028 Kazakhstan
е-mail: LSalkeeva@mail.ru
Received March 4, 2008
Abstract―Thiazolyl-containing esters of α-ketophosphonic acids (KPE) unknown earlier were synthesized
and investigated in Darzens–Claisen reaction. Reactions were demonstrated to proceed by a classic scheme to
form the corresponding phosphorylated glycidol esters whose alkaline hydrolysis gave rise to phosphorylated
aldehydes of interesting nature.
DOI: 10.1134/S1070363209040136
Thiazole and its phosphorus-containing derivatives
belong to heterocycles playing a significant role in the
many vital activity processes, mainly in fauna. The
thiazole ring is found in the composition of В1 vitamin,
of carboxylase enzyme, penicillin antibiotic,and many
of other pharmacologic preparations [1].
reactions proceeded regioselectively involving the
phosphorus(III) atom and affording the corresponding
ketophosphonates IV, V and phosphono-substituted
phenylthiocarbamate VI (Scheme 1).
α-Ketophosphonates (KPE) compose a class of
highly reactive organophosphorus compounds. Despite
the lability of P–C bond, KPE proved to be interesting
key compounds for some syntheses basing on the use
of increased activity of the carbonyl group, including
the syntheses of α-aminophosphonic acids and
phosphorylcarbenes [7].
Many simple types of heterocyclic systems with
phosphorus-containing substituents are not easily
accessible or have not been obtained at all despite the
fact that these compounds are of significant theoretical
and practical interest [2]. It has been known that the
most general and simple method of synthesis of
phosphorylated (thiophosphorylated) heterocyclic
amines is the reaction of the corresponding amines
with acid chlorides and isocyanates of phosphorus
acids as well as by the Todd–Atherton method. The
phosphorylated thiazoles with dialkylphosphoric acids
residue in position 5 of thiazole ring and diphenyl-
phosphonic acids residue in position 4 are also known
[3, 4].
For the systematic evaluation of the synthetic
potential of ketophosphonates IV, V obtained and to
estimate their reactivity we studied a possibility of
using KPE as basic structures for the synthesis of
phosphorylated glycidol esters. The phosphorylated
glycidol esters are known to be convenient synthons,
which are appropriate for easy introduction of lipo-
philic phosphonolipid fragments into new and known
potential drug structures to facilitate the trans-mem-
brane transfer of biologically active substrates.
Earlier we succeeded to prepare tert-butyl di-
ethylamido-(4-phenylthiazolyl-2-amido)phosphite III
not described in the literature by transamidation of
tert-butyl tetraethylamidophosphite I with 2-amino-4-
phenylthiazole II [5, 6]. The complex polyfunctional
structure of amidophosphite III obtained allows
simultaneous electrophilic attack on several reaction
centers. However, by the study of reaction of the latter
with carboxylic acid halides it was established that this
Brel and coworkers [8] carried out synthesis of 3-
dialkoxyphosphorylpropyl glycidyl ethers by homo-
lytic phosphorylation of allyl glycidyl ether with the
corresponding dialkylphosphites in the presence of
tert-butylbenzoylperoxide as initiator at 140–170°С
and molar reagents ratio dialkylphosphite : allyl glucidyl
ether : peroxide = 3.0–4.0:1.0:0.02–0.03.
755

756
SAL’KEEVA et al.
Scheme 1.
AcOEt, Δ
−Εt2ΝΗ
(Et2N)2POBu-t +
N
N
OBu-t
NH
P
S
S
NH2
NEt2
III
II
I
RCOCl
O
P
O
N
S
PhH, Δ
NH
C R + t-BuCl
NEt2
III
IV, V
Ph−Ν=C=S
PhH, Δ
O
P
S
N
S
NH
C NHPh
NEt2
VI
R = CH3- (IV), Ph- (V).
Evaluation of the current status of this line shows
that the known method of glycidol esters synthesis,
Darzans–Claisen reaction, was not used earlier to obtain
some phosphorus-containing esters of glycidic acid.
(4'-phenylthazolyl-2'-amido)phosphono]ethyl epoxy-
propionate VII and 2-phenyl-2-[diethylamido-N-(4'-
phenylthiazolyl-2'-amido)phosphono]ethyl epoxypro-
pionate VIII in 75 and 76% yields respectively.
Obviously the reaction is complicated by the formation
of the alkoxyacetic ester. Nevertheless, the method
described above is processible and suitable for the
preparative synthesis of phosphorylated glycidol esters
[9] (Scheme 2).
We established that ketophosphonates IV, V syn-
thesized by a condensation reaction with ethyl mono-
chloroacetate in the presence of sodium ethylate pro-
duce the corresponding 2-methyl-2-[diethylamido-N-
Scheme 2.
O
C
Ph
Ph
O
P
R
C
O
P
O
C
N
N
OEt
ClCH2
COOEt
NH
CH
R
NH
EtONa
EtOH, Δ
S
S
O
Et2N
VII, VIII
NEt2
IV, V
R = CH3- (IV, VII), Ph- (V, VIII).
The interest to epoxy compounds is undoubtedly
related to the possibility of their transformation into
aldehydes and ketones containing by one carbon atom
more than the initial carbonyl compounds. This
transformation proceeds as a result of a common
alkaline hydrolysis followed by decarboxylation of
glycidic acid, and the aldehyde formation is accom-
panied by a rearrangement [10].
However, at the alkaline hydrolysis of epoxy
compounds VII and VIII the prepared by us we
observed that the formation of the corresponding
phosphorylated aldehydes IX and X was possible even
under the experimental conditions of the hydrolysis
and did not require additional intermediate stages of
isolation and work up that facilitated the preparation of
the aldehydes (Scheme 3).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 4 2009

GLYCIDOL ESTERS FROM DIETHYLAMIDO-(4-PHENYLTHIAZOLYL-2-AMIDO)-...
757
Scheme 3.
Ph
Ph
O
P
R
C
O
P
R
KOH(aqueous solution),
N
O
N
Δ
COOEt
NH
CH
HC
NH
C
−K2CO3
−EtOH
S
S
O
H
Et2N
VII, VIII
NEt2
IX, X
R = CH3- (VII, IX), Ph- (VIII, X).
The high reactivity of the aldehyde group allows
the compounds obtained to be considered as synthons
for the synthesis of a great variety of compounds
possessing useful properties.
hydrazine hydrate. This choice of reagent is deter-
mined by a possibility of obtaining cyclic compounds
interesting by their structure, pyrazolidones, on the
basis of some phosphorylated thiazolyl-containing
glycidol esters VII and VIII.
Alongside the transformation into aldehydes and
ketones, the glycidol esters are capable of entering into
numerous reactions, which also are valuable for the
fine organic synthesis.
4-R-4-[Diethylamido-(4'-phenylthiazoleyl-2'-amido)-
phosphono]-5-oxypyrazolidones [R = CH3– (XI), R =
Ph– (XII)] were obtained as a result of the prolonged
heating (10 h) of glycidol esters VII and VIII with
hydrazine hydrate at 170–180°С and were charac-
terized by physicochemical constants (Scheme 4).
Specifically, we studied reaction of epoxy
compounds VII and VIII with amines, namely, with
Scheme 4.
OH
CH
Ph
Ph
O
P
R
C
O
P
R
C
N
N
C
O
NH2−ΝΗ2
EtOH, Δ
H2O
COOEt
NH
CH
NH
S
S
O
NH NH
Et2N
NEt2
XI, XII
VII, VIII
R = CH3- (VII, XI), Ph- (VIII, XII).
Structure of compounds obtained was proved by IR
and NMR spectroscopy and by independent syntheses.
phosphonate IV while stirring and cooling with ice
water. After the completion of reaction monitored by
TLC the reaction mixture was left overnight at room
temperature. Then it was neutralized with equimolar
quantity of glacial acetic acid and poured into 100 ml
of ice water. The water layer was extracted several
times with ether. The extract was washed with water
and dried over sodium sulfate. The solvent was
evaporated and the residue was purified by recrystal-
lization from ethanol. Yield 6.34 g (75%), mp 202–
203°С. 1Н NMR spectrum, δ, ppm: 7.25–7.40 m
(С6Н5, СН), 1.15 t (СН3–СН2,, 3Н), 2.56 m (СН3–СН2,
4Н), 7.8 s (NH, 1Н). IR spectrum, ν, сm–1: 1749
(СOOEt), 1483 (C=N), 1205 (Р=О), 1442, 1547
(С=С), 3345 (NH). Found, %: С 53.76; Н 6.67; N
9.45; P 7.18; S 7.84. C19H26N3O4PS. Calculated, %: С
53.90; Н 6.15; N 9.93; P 7.33; S 7.56.
EXPERIMENTAL
The IR spectra were registered on Specord IR-75
and Nicolet Avatar 360ESP spectrometers in thin layer
1
in the range of 3700–400 cm–1. The Н NMR spectra
were taken on a Bruker DRX500 spectrometer (500
МHz) relative to internal ТМS.
2-Methyl-2-[diethylamido-N-(4'-phenylthiazoleyl-
2'-amido)phosphono]ethyl epoxy-propionate (VII).
Sodium alkoxylate solution was prepared from 0.3 mol
of sodium and 300 ml of anhydrous alcohol. After the
completed dissolution to this solution was added
dropwise a mixture of 3.67 g (0.03 mol) of ethyl
monochloroacetate and 6.74 g (0.02 mol) of acetyl-
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758
SAL’KEEVA et al.
C17H24N5O3PS. Calculated, %: С 49.88; Н 5.87; N
1-Methyl-4-[diethylamido-(4'-phenylthiazolyl-2'-
amido)phosphono]acetic aldehyde (IX). A mixture
of 4.24 g (0.01 mol) glycidol ester VII, 1.96 g (0.035 mol)
of potassium hydroxide, 25 ml of water, and 50 ml of
ethanol was refluxed for 4 h. After the completion of
reaction the bulk of ethanol was evaporated. The
residue was dissolved in a minimum volume of water
and was acidified by hydrochloric acid to рН = 1 at
cooling with ice. Then the reaction mixture was
extracted with ether 4–5 times. Extracts were dried
over anhydrous sodium sulfate. After the solvent
removal the residue was recrystalled from ethanol.
17.11; P 7.58; S 7.82.
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1
Yield 2.31 g (65%), mp 182°С. Н NMR spectrum, δ,
ppm: 7.45–7.55 m (С6Н5, СН), 1.20 t (СН3–СН2, 3Н),
2.62 m (СН3–СН2, 4Н), 7.82 s (NH, 1Н), 7.15 s
(thiazole, С5Н), 8.57 (СН=О). IR spectrum, ν, сm–1:
1475 (C=N), 1194 (Р=О), 1476, 1564 (С=С), 1685
(СН=О), 3372 (NH). Found, %: С 54.56; Н 6.67; N
11.45; P 8.94; S 9.42. C16H22N3O2PS. Calculated, %: С
54.70; Н 6.27; N 11.97; P 8.83; S 9.12.
7. Zhdanov, Yu.А., Uzlova, L.А., and Glebova, Z.I., Usp.
Khim., 1980, vol. 49, no. 9, p. 1730.
4-Methyl-4-[diethylamido-(4'-phenylthiazolyl-2'-
amido)phosphono]-5-oxypyrazolidone (XI). A mixture
of 4.24 g (0,01 mol) of glycidol ester VII, 0.5 g of
hydrazine hydrate in alcohol were heated at 150–180°С
for 10 h. After the completion of reaction the
precipitate was filtered off and recrystalled from
8. Brel’, А.K., Petrov, V.I., Ozerov, A.А., Gunger, А.А.,
and Sazhin, V.А., Khim. Farm. Zh., 1992, no. 3, p. 86.
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1
alcohol. Yield 2.86 g (72%), mp 231°С. Н NMR
spectrum, δ, ppm: 7.23–7.40 m (С6Н5, СН), 1.15 (СН3,
3Н), 7.8 s (NH, 1Н), 7.2 s (thiazole, С5Н). IR spec-
trum, ν, сm–1: 1461 (C=N), 1201 (Р=О), 1463, 1582,
(С=С), 1600 (С=О), 3260 (NH), 3435 (ОН). Found,
%: С 49.56; Н 5.67; N 17.45; P 7.94; S 7.42.
10. Organikum (Organicum), Reutov, O.A., Ed., Moscow:
Mir, vol. 2, 1992, p. 162.
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