β-oxalylamino-substituted O-ethyl N-arylcarbamates and N-ethyl-N′-arylureas encapsulated into micelles of vinylimidazole–vinylcaprolactam copolymer

Article abstract of DOI:10.1134/S0012500817040103

Low-molecular-weight compounds—β-oxalylamino-substituted O-ethyl carbamates and unsymmetrical ureas showing biological activity—have been synthesized and encapsulated into micelles of vinylimidazole–vinylcaprolactam copolymers. Solubilization in micelles has provided a preparation of water-soluble colloidal formulation of these compounds suitable for practical application.

Full text of DOI:10.1134/S0012500817040103

ISSN 0012-5008, Doklady Chemistry, 2017, Vol. 473, Part 2, pp. 84–87. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.M. Vorob’ev, L.V. Kovalenko, A.V. Kalistratova, M.S. Oshchepkov, V.S. Filippova, A.A. Khodak, K.A. Kochetkov, 2017, published in Doklady
Akademii Nauk, 2017, Vol. 473, No. 6, pp. 669–672.
CHEMISTRY
β-Oxalylamino-Substituted O-Ethyl N-Arylcarbamates
and N-Ethyl-N'-arylureas Encapsulated into Micelles
of Vinylimidazole–Vinylcaprolactam Copolymer
M. M. Vorob’eva, L. V. Kovalenkob, **, A. V. Kalistratovab, M. S. Oshchepkovb,
V. S. Filippovab, A. A. Khodaka, and K. A. Kochetkova, *
Presented by Academician A. R. Khokhlov December 19, 2016
Received December 23, 2016
Abstract—Low-molecular-weight compounds—β-oxalylamino-substituted O-ethyl carbamates and unsym-
metrical ureas showing biological activity—have been synthesized and encapsulated into micelles of vinylim-
idazole–vinylcaprolactam copolymers. Solubilization in micelles has provided a preparation of water-soluble
colloidal formulation of these compounds suitable for practical application.
DOI: 10.1134/S0012500817040103
Physiological functions of phytohormonal cytoki- β-oxalylamino-substituted O-ethyl carbamates and
nins deal with stimulation of plant cell division, inten- ureas are stable crystalline compounds poorly soluble
sification of nutrients transport into cells, inhibition of in water and organic solvents, which considerably
root meristem, retardation of leaf ageing [1], and other hampers their transformation in formulations. At the
regulatory effects. Up to date, cytokinin activity of same time, it is known that micellar media increase
synthetic analogs of natural phytohormones was considerably the solubility of hydrophobic com-
mainly used to obtain compounds with herbicide pounds, this fact can be used to design transport sys-
properties (Phenmedipham) and defoliants (Thidi- tems for the delivery of physiologically active com-
azuron, Cytodef), as well as antistress-type plant pounds [6].
growth regulators that protect plants from water lack
In this work, we report the results of study on the
and frost [2, 3]. The methods of preparation of syn-
encapsulation of the prepared low-molecular-weight
thetic analogues of cytokinins with defoliant activity
compounds—beta-oxalylamino-substituted O-ethyl
are based mainly on the reaction of amino-substituted
carbamate and unsymmetrical ureas with potential
heterocycles with aryl isocyanates [4]. The resultant
biological activity—into micelles of vinylimidazole–
unsymmetrical ureas show definite structural resem-
vinylcaprolactam copolymers with the aim to obtain
blance with natural cytokinins, one of which is
water-soluble colloidal formulations suitable for the
diphenylurea [1].
practical application of these compounds in agricul-
β-Oxalylamino-substituted O-ethyl N-arylcarba-
mates and N-ethyl-N'-arylureas are a new class of
phytoactive compounds showing growth regulatory
activity [5]. These carbamates and unsymmetrical
ureas are structural analogs of herbicidal and growth-
regulatory biscarbamates, including well-known
Phenmedipham and Kartolin 2 [1]. The obtained
ture.
Carbamate I was obtained by Scheme 1. Diethyl
oxalate was prepared by esterification by azeotropi-
cally removing water with carbon tetrachloride. The
amidation of diethyl oxalate with ethanolamine was
carried out using fourfold excess of the initial ester to
reduce the yield of byproduct, N,N'-bis(2-
hydroxyethyl)oxamide. Target carbamate
I was
obtained by the reaction of β-hydroxyethyloxamate
a Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow, 119991 Russia,
with the appropriate isocyanate.
b Mendeleev University of Chemical Technology of Russia,
Moscow, 125047 Russia
Urea II was synthesized by the aminolysis of
diethyl oxalate with β-aminoethyl-(p-chlorophe-
nyl)urea according to Scheme 2. Initial β-aminoethyl-
(p-chlorophenyl)urea was prepared by the reaction of
*e-mail: const@ineos.ac.ru
**e-mail: lkovalenko@muctr.ru
84

β-OXALYLAMINO-SUBSTITUTED O-ETHYL N-ARYLCARBAMATES
85
OH
O
O
O
O
O
O
H2N
EtOH, CCl4
PTSA
OH
EtOH, 0°C
HO
OH
EtO
OEt
EtO
NH
71%
O
89%
Cl
O
C
N
O
Cl
O
EtO
NH
I, 90%
NH
O
Scheme 1.
Cl
NH NH
O
O
O
O
O
EtOH, 5−10°C
H2N
+
NH
EtO
OEt
EtO
NH
II, 75%
NH
Cl
O
Scheme 2.
p-chlorophenyl isocyanate with excess of ethylenedi- studied compounds outside of micelles (Fig. 1, peak A)
amine at 0–5°С.
and the growth of their fluorescence inside micelles
(Fig. 1, peak B). The obtained spectra display an isos-
bestic point (about 340 nm), which facilitates the
determination of component concentration from flu-
orescence spectra. Thus, the solubilization in micelles
provides a possibility to prepare water-soluble colloi-
dal formulation of these compounds suitable for prac-
tical application.
We used micelles of copolymers of N-vinylcapro-
lactam (NVCL) with N-vinylimidazole (NVI) in water
(Scheme 3). The synthesis of the corresponding
NVCL–NVI copolymers was carried out in a solution
at temperature above phase separation point of the
reaction system, which, as was shown previously in
theoretical [7] and experimental works [8–10], pro-
vides coil–globule conformational transition for
oligo(NVCL) blocks of resulting macromolecules and
formation of heteroblock protein-like sequence of the
corresponding polymer chains.
EXPERIMENTAL
NVCL–NVI copolymers as a soluble fraction
NVCL/NVI-S [8] were provides by the laboratory by
Professor V.I. Lozinsky (Nesmeyanov Institute of
Organoelement Compounds, Russian Academy of
Sciences). 1H and 13C NMR spectra were recorded on
a Bruker AVANCE™ 400 spectrometer using CDCl3
and DMSO-d6 as internal references. IR spectra were
registered on a Nicolet 380 IR Fourier-transform
spectrophotometer coupled with ATR add-on unit
(ThermoFisher Scientific Inc.). Fluorescence spectra
were obtained with the use of a Perkin Elmer LS55
luminescent spectrometer. Excitation wavelength was
280 nm, slits were 10 and 5 nm. Fluorescence was
monitored continuously in the range from 295 to
495 nm at scanning rate 150 nm/min. Titration condi-
tions were as follows: a freshly prepared solution of
1.5 mg of carbamate in 1 mL of acetonitrile was diluted
with 24 mL of water and 2 mL of this solution was
placed into a cuvette (1-cm path length) of the lumi-
nescent spectrometer. This solution was used for
These copolymers at concentrations above critical
micelle concentration were used to reveal the features
of encapsulation of the prepared low-molecular-
weight O-ethyl carbamate I and urea II with oxamate
functional groups. To control solubilization in
micelles, we used fluorescent spectroscopy (excitation
at 280 nm). The addition of separate portions of the
copolymer into aqueous solutions of compounds I and
II that sequentially increased their concentration by
0.15 wt % led to decrease in the fluorescence of the
(CH2 CH)n (CH2 CH)m
O
N
N
N
Scheme 3. Vinylcaprolactame–vinylimidazole copoly-
mers.
DOKLADY CHEMISTRY Vol. 473 Part 2 2017

86
VOROB’EV et al.
encapsulation by the sequential addition of a solution
(30 mg/mL aqueous solution) of the copolymer by
portions of 10 μL each (Fig. 1).
Fluorescence intensity, arb. units
40
A
B
Preparation of O-ethyl N-2-hydroxyethyloxamate.
Diethyl oxalate [11] (11.7 g, 0.08 mol) was placed into
a 100-mL round-bottomed flask and 4 mL of ethanol
was added. The mixture was cooled in an ice bath,
1.2 mL (0.02 mol) of monoethanolamine in 10 mL of
ethanol was added dropwise with stirring, and cooling was
terminated after that. According to NMR spectros-
copy, the precipitate formed during warming the reac-
tion mixture to ambient temperature was N,N'-bis(2-
hydroxyethyl)oxamide with mp 133–136°C; it was
separated by filtration. The filtrate was concentrated
by rotary evaporation, the excess ester was removed in
a vacuum of water-jet pump. The residue was the
oxamate sufficiently pure for further transformations.
Yield 89%, mp 133–135°C (lit.: mp 133–134°C [12]).
7
6
5
30
20
4
3
2
1
10
0
1H NMR (400 MHz, CDCl3, δ, ppm, J, Hz): 1.38
(t, 3H, CH3, J = 7.3); 3.05 (br s, 1H, –OH); 3.53 (dt,
2H, NH–CH ,
= 4.9,
= 5.4); 3.8 (t,
CH2 −CH2
J
J
2
NH−CH2
295
345
395
445
495
2H, CH2–OH, J = 5.4); 4.35 (q, 2H, CH2–CH3, J =
7.3). 13C NMR (100 MHz, CDCl3, δ, ppm): 13.9
(CH3), 42.4 (NH–CH2), 61.1 (CH2OH); 63.3
(–CH2–CH3), 157.3 (–O–C(O)), 160.5 (–C(O)–NH).
Wavelength, nm
Fluorescence spectra of O-alkyl carbamate I in the
absence (curve 1) and in the presence (curves 2–7) of
NVCL–NVI copolymer micelles. Micelle concentration
increases as an aqueous copolymer solution (30 mg/mL)
was added in 10-μL portions (from 2 to 7). (1) Spectrum of
initial carbamate I (0.06 mg/mL).
Preparation of N-(2-aminoethyl)-N'-(4-chlorophe-
nyl)urea. A solution of 39 g (0.25 mol) of 4-chlorophe-
nyl isocyanate in 100 mL of acetonitrile was added
dropwise to a solution of 78 g (1.3 mol) of ethylenedi-
amine in 200 mL of dry acetonitrile on cooling in an
ice bath with vigorous stirring. The resultant precipi-
tate was separated by filtration on a Schott filter funnel
(byproduct, N-[(4-chlorophenyl)carbamoyl]ethylene-
diamine). The mother liquor was concentrated by
rotary evaporation. Excess ethylenediamine was
removed in vacuum of water-jet pump (bp 114°C at
15–20 mmHg). The crystalline target product was
recrystallized from acetonitrile, mp 139–142°С. Yield
90%. (lit.: mp 140–142°C [13]).
was stirred at ambient temperature for 1 h. The resul-
tant precipitate was separated by filtration and recrys-
tallized from isopropanol. Yield of the target product
is 90%, mp 179–180°C.
For C13H15ClN2O5 anal. calcd. (%): C, 49.61; H,
4.80; Cl, 11.26; N, 8.90; O, 25.42.
Found (%): C, 49.11; H, 5.27; N, 13.40.
1H NMR (400 MHz, DMSO-d6, δ, ppm, J, Hz):
1.27 (t, 3H, CH3, J = 4); 3.45 (dt, 2H, NHCH2,
1H NMR (400 MHz, DMSO-d6, δ, ppm, J, Hz):
2.64 (m, 2H, CH2NH2); 3.09 (m, 4H, CH2NH and
= 8,
= 4); 4.19 (t, 2H, CH2CH2NH,
J
J
CH2 −CH2
CH2 −NH
J = 4); 4.24 (q, 2H, CH2CH3, J = 8); 7.33 (d, 2H,
CH2arom, J = 8); 7.49 (d, 2H, CH2arom, J = 8); 9.05 (t,
1H, CH2CH2NH, J = 4); 9.84 (s, 1H, CHCNH). 13C
NMR (100 MHz, DMSO-d6, δ, ppm): 14.3 (CH3);
NH2); 6.64 (t, 1 H, NHCH2, J = 8); 7.24 (d, 2H, CHarom
,
J = 8); 7.43 (d, 2H, CHarom, J = 8); 9.04 (s, 1H,
C(O)NHC). 13C NMR (100 MHz, DMSO-d6, δ,
ppm): 41.9 (NH2CH2); 42.3 (NH2CH2); 119.5
(HNCCH); 124.6 (ClC); 128.8 (ClCCH); 140.2
(HNCCH); 155.8 (NHC(O)NH).
39.1
(NHCH2);
62.5
(CH3CH2O–);
62.7
(CH2CH2O–); 120.1 (HN–C–CH); 126.5 (ClCCH);
129.1 (ClC); 138.6 (HN–C–CH); 153.7 (OC(O)C–);
157.7 (OC(O)NH); 161.0 (C(O)C(O)NH). IR (ν, cm–1):
1542.77 (0.530) (NH def.; N–C=O, amide); 1696.90
(0.559) (С(O), amide); 1724.68 (0.557) (С(О)–,
ester); 3306.92 (0.456) (NH).
Preparation of N-(N-ethoxycarbonylcarbonyl-2-
aminoethyl)-N'-(4-chlorophenyl)urea (I). O-Ethyl-N-
2-aminoethyloxamide (0.60 g, 3.7 mmol) was placed
into a 50-mL round-bottomed flask and dissolved in
5 mL of toluene, a solution of 0.57 g (3.7 mmol) of p-
chlorophenyl isocyanate in 4 mL of toluene was added
to the resultant solution at ambient temperature with noethyl N-(4-chlorophenyl)carbamate (II). Diethyl
stirring. Four drops of triethylamine was added to the oxalate (4.5 g, 0.05 mol) was dissolved in 5 mL of eth-
resultant mixture with stirring. The reaction mixture anol in a round-bottomed flask equipped with a ther-
Preparation of N-ethoxycarbonylcarbonyl)-2-ami-
DOKLADY CHEMISTRY
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β-OXALYLAMINO-SUBSTITUTED O-ETHYL N-ARYLCARBAMATES
87
2. Kieber, J.J., J. Plant Growth Reg., 2002, vol. 21, pp. 1–2.
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mometer and a dropping funnel, a solution of 0.885 g
(0.004 mol) of N-[(4-chlorophenyl)carbamoyl]eth-
ylenediamine in 15 mL of ethanol was added to the
resultant solution with stirring and cooling on an ice
bath. The reaction mixture was allowed to stand at
ambient temperature for 1 h, the resultant white pre-
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For C13H16ClN3O4 anal. calcd. (%): C, 49.77; H,
5.14; Cl, 11.30; N, 13.39.
Found (%): C, 49.91; H, 5.07; N, 13.18.
1H NMR (400 MHz, DMSO-d6, δ, ppm, J, Hz):
1.27 (t, 3H, CH3, J = 8); 3.22–3.24 (m, 4H, CH2);
3.35 (s, 1H, NH); 4.23 (q, 2H, CH2–CH3, J = 4); 7.26
(d, 2H, CHarom, J = 8); 7.42 (d, 2H, CHarom, J = 8);
9.05 (s, 1H, C(O)–NH–); 9.84 (s, 1H, C–NH–
C(O)). 13C NMR (100 MHz, DMSO-d6, δ, ppm):
14.3 (CH3); 38.7 (CH2); 39.1 (CH2); 40.0 (CH2); 62.5
(CH); 120.1 (NH–C–CH); 126.5 (Cl–C); 129.1 (Cl–
C–CH); 138.6 (NH–C–); 153.7 (HN–C(O)–NH);
157.7 (O–C(O)); 161.0 (C(O)–C(O)–NH).
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ACKNOWLEDGMENTS
11. Zhang, G.-Sh., Synth. Commun., 1998, vol. 28, no. 7,
pp. 1159–1162.
This work was supported by the Russian Founda-
tion for Basic Research (projects nos. 15–54–
45051ind_a, 15–29–05785ofi_m, and 16–03–
00061a).
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DOKLADY CHEMISTRY Vol. 473 Part 2 2017