Synthesis of nitrogen-containing phenoxyacetic acid derivatives

Article abstract of DOI:10.1007/s11178-005-0201-3

Nitrogen-containing phenoxyacetic acid derivatives were synthesized by reactions of substituted phenoxyacetic acids with amines, urea, and ethyl carbamate.

Full text of DOI:10.1007/s11178-005-0201-3

Russian Journal of Organic Chemistry, Vol. 41, No. 4, 2005, pp. 546–550. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005,
pp. 557–561.
Original Russian Text Copyright © 2005 by Yamansarova, Kukovinets, Zainullin, Galin, Abdullin.
Synthesis of Nitrogen-Containing Phenoxyacetic Acid Derivatives
E. T. Yamansarova, O. S. Kukovinets, R. A. Zainullin, F. Z. Galin, and M. I. Abdullin
1 Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: chemorg@fnrb.ru
2 Bashkir State University, Ufa, Bashkortostan, Russia
Received March 9, 2004
Abstract—Nitrogen-containing phenoxyacetic acid derivatives were synthesized by reactions of substituted
phenoxyacetic acids with amines, urea, and ethyl carbamate.
Analysis of published data on pharmacological and
pesticide activity of compounds possessing a phenoxy-
acetate moiety revealed a number of substances
exhibiting phytohormone and herbicide properties.
Moreover, derivatives of phenoxyacetic acid are char-
acterized by a broad spectrum of physiological activity
whose kind and strength depends on the substituents in
both the aromatic ring and the acid fragment [1–4].
Introduction of nitrogen-containing groups was shown
to improve the activity [2–4]. Taking the above stated
into account, we converted aroxyacetic acids I–IV into
N,N-diisopropyl and N-benzyl amides V–XII by reac-
tion with the corresponding amines in the presence of
POCl3 (Scheme 1). The synthesis of acids I–IV was
described previously [5]. From p-nitrophenoxyacetic
acid (II) we also obtained N-methyl amide XIII.
through intermediate aroxyacetyl chlorides XIV–XVII
and in one step, by heating a mixture of the corre-
sponding acid, urea, and thionyl chloride in an ap-
propriate solvent. The latter procedure ensures a higher
yield of the target products. We succeeded in avoiding
formation of diacylated ureas by carrying out the
reaction with 2–2.5 equiv of urea (Scheme 2). The
reactions of phenoxyacetic acids I–IV with ethyl
carbamate in the presence of thionyl chloride and
pyridine afforded compounds XXII–XXV which
attract interest as potential insect growth regulators. It
was found that the product obtained by reaction of
carbamic acid with 2,4-decadienol exhibits a strong
juvenilizing effect toward large mealworm (Tenebrio
molitor) [6–9] and that the presence of a phenoxy
fragment improves the juvenoid activity [10].
Substituted phenoxyacetic acids I–IV were also
used to obtain the corresponding ureides XVIII–XXI.
These compounds can be synthesized in two steps
Scheme 2.
O
O
SOCl2, pyridine
NH2COR2
O
N
H
R2
I–IV
R1
Scheme 1.
80–83%
O
XVIII–XXV
O
+
R2R3NH
OH
R1
O
SOCl2, pyridine
O
Cl
I–IV
I–IV
R1
O
POCl3, pyridine, CH2Cl2
72–83%
O
XIV–XVII
NR2R3
R1
NH2CONH2
XVIII–XXI
V–XIII
I, XIV, XVIII, XXII, R1 = H; II, XV, XIX, XXIII,
R1 = 4-O2N; III, XVI, XX, XXIV, R1 = 3-PhO; IV, XVII,
XXI, XXV, R1 = 2,4-Cl2; XVIII–XXI, R2 = NH2; XXII–
XXV, R2 = EtO.
I, V, IX, R1 = H; II, VI, X, XIII, R1 = 4-O2N; III, VII, XI,
R1 = 3-PhO; IV, VIII, XII, R1 = 2,4-Cl2; V–VIII, R2 = R3 =
i-Pr; IX–XII, R2 = H, R3 = PhCH2; XIII, R2 = H, R3 = Me.
1070-4280/05/4104-0546 © 2005 Pleiades Publishing, Inc.

SYNTHESIS OF NITROGEN-CONTAINING PHENOXYACETIC ACID DERIVATIVES
547
Scheme 3.
O
PhO
O
PhO
O
PhCH2N=C=O
OH
O
N
Ph
H
XXVI
XXVII
Me
(1) PBr3
(2) Me2CHCH=NOH
PhO
O
N
O
Me
XXVI
XXVIII
By reaction of 2-phenoxyethanol XXVI with
benzyl isocyanate we obtained carbamate XXVII. As
starting material we selected a compound containing
a phenoxy group, for an analogous fragment is present
in the molecule of one of the most active juvenile
hormone analog, Phenoxycarb (3-phenoxyphenyl
ethylcarbamate) [11]. The presence of an oxime moiety
is also known to enhance biological activity of juve-
noids [12]. We synthesized such a juvenile hormone
analog by treatment of 2-(m-phenoxyphenoxy)ethanol
(XXVI) with 2-methylpropanal oxime (Scheme 3).
The structure of product XXVIII thus obtained was
confirmed by the spectral data.
mixture was stirred for 1 h at 0°C and for 1 h at 20°C
and poured into 5.2 ml of water. The organic phase
was separated, and the aqueous phase was extracted
with diethyl ether. The extracts were combined with
the organic phase, washed with a 10% solution of
NaHCO3 and a saturated solution of NaCl, and dried
over MgSO4. The solvent was removed, and the
residue was subjected to chromatography on silica gel
using petroleum ether–ethyl acetate (6:1) as eluent.
N,N-Diisopropylphenoxyacetamide (V). Yield
0.46 g (79%), yellow–brown amorphous substance,
mp 89–93°C. IR spectrum, ν, cm–1: 1500 m, 1520 s,
1
1540 s, 1600 w, 1650 s, 1680 s. H NMR spectrum, δ,
Preliminary tests showed that the prepared com-
pounds exhibit herbicide and growth-regulating activ-
ity with respect to dicotyledons at a level comparable
with the activity of 2,4-dichlorophenoxyacetic acid.
ppm: 1.25 d (12H, Me, J = 6.0 Hz), 3.78 m (2H, CH),
4.64 s (2H, CH2O), 7.28 m (5H, Harom). 13C NMR spec-
trum, δC, ppm: 13.82 q and 14.94 q (Me), 44.31 d
(CH), 65.42 t (CH2O), 114.64 d (Cp), 121.83 d (Co),
129.18 d (Cm), 158.61 q (Ci), 178.54 s (C=O). Found,
%: C 70.98; H 8.62; N 5.64. C14H21NO2. Calculated,
%: C 71.48; H 8.96; N 5.96.
EXPERIMENTAL
The IR spectra were recorded on UR-20 and
Specord M-80 spectrometers from samples prepared as
N,N-Diisopropyl(4-nitrophenoxy)acetamide (VI).
Yield 0.56 g (80%), yellow oily liquid. IR spectrum, ν,
cm–1: 1495 m, 1510 s, 1540 s, 1600 w, 1645 s, 1675 s.
1H NMR spectrum, δ, ppm: 1.26 d (12H, Me, J =
6.0 Hz), 3.72 m (2H, CH), 4.68 s (2H, CH2O), 7.12 d
(o-H, J = 8.0 Hz), 8.21 d (m-H, J = 8.0 Hz). 13C NMR
spectrum, δC, ppm: 13.86 q and 14.76 q (Me), 44.59 d
(CH), 64.87 t (CH2O), 114.88 d (Co), 158.63 s (Ci),
163.17 s (Cp), 168.51 s (C=O). Found, %: C 60.06;
H 7.24; N 10.41. C14H20N2O4. Calculated, %: C 60.00;
H 7.14; N 10.00.
1
13
thin films or dispersed in mineral oil. The H and C
NMR spectra were measured on a Bruker AM-300
instrument (300 and 75.46 MHz, respectively) from
solutions in CDCl3 and acetone-d6 using tetramethyl-
silane as internal reference. GLC analysis was per-
formed on a Chrom-5 chromatograph equipped with
a 1.2-m column; stationary phase SE-30 on Chromaton
N-FW-DMCS (0.16–0.20 mm); carrier gas helium;
oven temperature programming from 50 to 300°C at
12 deg/min. TLC analysis was performed on Silufol
UV-366 plates.
N,N-Diisopropyl(3-phenoxyphenoxy)acetamide
(VII). Yield 0.59 g (72%), yellow–brown oily liquid.
IR spectrum, ν, cm–1: 1500 m, 1520 s, 1540 s, 1605 w,
Amides V–XIII (general procedure). Acid I–IV
[5], 2.5 mmol, was dissolved in 5 ml of methylene
chloride, and 2.5 mmol of anhydrous pyridine and
3 mmol of the corresponding amine were added at
0°C. A solution of 2.5 mmol of POCl3 in methylene
chloride was then added dropwise at 0°C, and the
1
1650 s, 1680 s. H NMR spectrum, δ, ppm: 1.25 d
(12H, Me, J = 6.0 Hz), 3.68 m (2H, CH), 4.64 s (2H,
CH2O), 6.48 s (1H, o-H), 6.53–6.59 m (3H, o-H, m-H,
p-H), 6.93–7.34 m (5H, H'arom). 13C NMR spectrum, δC,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

YAMANSAROVA et al.
548
ppm: 13.73 q and 14.82 q (Me), 44.52 d (CH), 65.04 t
(CH2O), 101.97 d (C2), 107.38 d (C6), 112.08 d (C4),
117.90 d (C2', C6'), 120.32 d (C4), 129.60 d and 129.64
d (C5, C3', C5'), 156.29 d (C3), 158.73 s (C1'), 159.18 s
(C1), 168.81 s (C=O). Found, %: C 73.41;
H 7.84; N 4.18. C20H25NO3. Calculated, %: C 73.39;
H 7.65; N 4.28.
δ, ppm: 4.34 s (2H, CH2O), 4.57 s (2H, CH2N), 6.70–
7.4 m (14H, Harom), 7.41 s (1H, NH). Found, %:
C 75.51; H 5.84; N 4.33. C21H19NO3. Calculated, %:
C 75.68; H 5.71; N 4.20.
N-Benzyl(2,4-dichlorophenoxy)acetamide (XII).
Yield 0.61 g (80%), yellow–brown oily liquid. IR
spectrum, ν, cm–1: 1505 w, 1510 s, 1540 s, 1600 m,
1
1640 s, 1690 s, 3080 w, 3200–3300 br.s. H NMR
N,N-Diisopropyl(2,4-dichlorophenoxy)acetamide
(VIII). Yield 0.63 g (83%), yellow–brown oily liquid.
IR spectrum, ν, cm–1: 1500 m, 1510 s, 1555 s, 1600 w,
spectrum, δ, ppm: 4.42 s (2H, CH2O), 4.63 s (2H,
CH2N), 6.75 d (1H, 6-H, J = 8.8 Hz), 6.90 d (2H, o'-H,
J = 8.0 Hz), 7.01 d (2H, 5-H, J = 8.8 Hz), 7.32 m
(3H, m'-H, p'-H), 7.39 d (1H, 3-H), 7.46 s (1H, NH).
13C NMR spectrum, δ, ppm: 43.41 t (CH2N), 65.98 t
(CH2O), 114.65 d (C6), 122.18 d (Cp'), 124.10 s (C2),
126.92 s (C4), 127.36 d (Co'), 127.63 d (C5), 127.98 d
(Cm'), 130.24 d (C3), 137.44 s (Ci'), 155.87 s (C1),
169.02 s (C=O). Found, %: C 58.17; H 4.01; Cl 22.76;
N 4.73. C15H13Cl2NO2. Calculated, %: C 58.06;
H 4.19; Cl 22.90; N 4.52.
1
1640 s, 1675 s. H NMR spectrum, δ, ppm: 1.25 d
(12H, Me, J = 6.0 Hz), 3.54 m (2H, CH), 4.58 s (2H,
CH2O), 6.75 d (1H, 6-H, J = 8.8 Hz), 7.01 d (1H, 5-H,
13
J = 8.8 Hz), 7.36 s (1H, 3-H). C NMR spectrum, δC,
ppm: 13.84 q and 14.65 q (Me), 44.58 d (CH), 64.92 t
(CH2O), 114.65 d (C6), 124.10 s (C2), 126.92 s (C4),
127.53 d (C5), 130.24 d (C3), 152.37 s (C1), 163.18 s
(C=O). Found, %: C 55.34; H 6.21; Cl 23.48; N 4.82.
C14H19Cl2NO2. Calculated, %: C 55.26; H 6.25;
Cl 23.36; N 4.61.
N-Methyl(4-nitrophenoxy)acetamide (XIII).
Yield 0.39 g (81%), yellow–brown viscous oily sub-
stance. IR spectrum, ν, cm–1: 1500 m, 1520 s, 1560 s,
N-Benzyl(phenoxy)acetamide (IX). Yield 0.49 g
(81%), yellow–brown oily liquid. IR spectrum, ν,
cm–1: 1500 w, 1510 s, 1550 s, 1600 m, 1630 s, 1670 s,
1
1600 m, 1640 s, 1670 s, 3200–3300 br.s. H NMR
1
3080 w, 3240 br.s. H NMR spectrum, δ, ppm: 4.45 s
spectrum, δ, ppm: 2.80 br.s (3H, MeN), 4.64 s (2H,
CH2O), 7.05 d (2H, o-H, J = 8.5 Hz), 7.71 d (2H, m-H,
J = 8.5 Hz). Found, %: C 51.18; H 4.89; N 13.01.
C9H10N2O4. Calculated, %: C 51.43; H 4.76; N 13.30.
(2H, CH2O), 4.51 s (2H, CH2N), 6.90 d (2H, o'-H, J =
8.0 Hz), 6.95 d (2H, o-H, J = 8.0 Hz), 7.05 m (1H,
p-H), 7.30 m (5H, m-H, m'-H, p'-H). 13C NMR spec-
trum, δC, ppm: 43.38 t (CH2N), 67.13 t (CH2OAr),
114.52 d (C4), 121.54 d (Cp'), 122.18 d (Co), 127.50 d
(Co'), 127.58 d (Cm'), 129.54 d (Cm), 137.63 s (Ci'),
156.98 s (Ci), 168.51 s (C=O). Found, %: C 74.56;
H 6.34; N 5.91. C15H15NO2. Calculated, %: C 74.69;
H 6.22; N 5.81.
Phenoxyacetylureas XVIII–XXI (general proce-
dure). a. Urea, 13 mmol, and pyridine, 7 mmol, were
added to a solution of 5.9 mmol of phenoxyacetyl
chloride XIV–XVII (prepared by standard procedure
from the corresponding acid I–IV) in 3 ml of toluene.
The mixture was heated for 2–2.5 h at 70–75°C until
the initial acetyl chloride disappeared (TLC, petroleum
ether–ethyl acetate, 6:1). The mixture was cooled to
50°C, 1.4 ml of water was added, the mixture was
stirred for 0.5 h, and the organic phase was separated,
washed with a 5% solution of NaHCO3 and with water
until neutral reaction, and dried over MgSO4. The
solvent was distilled off, and the residue was purified
by column chromatography on silica gel using petro-
leum ether–ethyl acetate (6:1) as eluent.
N-Benzyl(4-nitrophenoxy)acetamide (X). Yield
0.58 g (82%), yellow oily substance. IR spectrum, ν,
cm–1: 1500 w, 1505 s, 1550 s, 1600 m, 1630 s, 1690 s,
1
3080 w, 3240 br.s. H NMR spectrum, δ, ppm: 4.46 s
(2H, CH2O), 4.63 s (2H, CH2N), 6.90 d (2H, o'-H,
J = 8.0 Hz), 7.05 d (2H, o-H, J = 8.0 Hz), 7.30 m
(3H, m'-H, p'-H), 7.68 d (2H, m-H), 7.44 s (1H, NH).
13C NMR spectrum, δC, ppm: 43.44 t (CH2N), 66.92 t
(CH2O), 114.65 d (Co), 121.25 d (Cm), 122.18 d (Cp'),
127.36 d (Co'), 127.94 d (Cm'), 137.53 s (Ci'), 156.94 s
(Ci), 168.10 s (Cp), 168.51 s (C=O). Found, %: C 63.04;
H 4.85; N 9.68. C15H14N2O4. Calculated, %: C 62.94;
H 4.90; N 9.79.
b. Phenoxyacetic acid I–IV, 3.5 mmol, was dis-
solved in 10 ml of anhydrous benzene, and 7 mmol of
urea, 4.2 mmol of freshly distilled thionyl chloride,
and 4.2 mmol of anhydrous pyridine were added. The
mixture was heated for 2–2.5 h under reflux until the
initial acid disappeared (TLC, petroleum ether–ethyl
acetate, 6:1). It was then cooled to 50°C, 1.4 ml of
water was added, the mixture was stirred for 0.5 h at
N-Benzyl(3-phenoxyphenoxy)acetamide (XI).
Yield 0.62 g (75%), yellow–brown oily liquid. IR
spectrum, ν, cm–1: 1500 m, 1510 s, 1550 s, 1605 m,
1
1630 s, 1690 s, 3080 w, 3250 br.s. H NMR spectrum,
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SYNTHESIS OF NITROGEN-CONTAINING PHENOXYACETIC ACID DERIVATIVES
549
that temperature, and the product was isolated as
described above in a.
1230 s, 1498 m, 1588 s, 1690 s, 1730 s, 3380 br.s.
1H NMR spectrum, δ, ppm: 1.25 t (3H, Me, J =
7.0 Hz), 4.21 q (2H, CH3CH2O, J = 7.0 Hz), 4.69 s
(2H, CH2OPh), 6.90–7.15 m (5H, Harom), 7.30 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 14.06 q (CH3),
51.24 t (OCH2), 64.03 t (CH2OPh), 114.64 d (Cp),
121.18 d (Co), 129.80 d (Cm), 158.34 s (Ci), 163.18 s
(C=O), 171.98 s (C=O). Found, %: C 59.35; H 5.77;
N 6.04. C11H13NO4. Calculated, %: C 59.19; H 5.83;
N 6.28.
(Phenoxyacetyl)urea (XVIII). Yield 0.43 g
(63%, a), 0.48 g (81%, b), light brown crystalline sub-
stance, mp 90–93°C [13].
(4-Nitrophenoxyacetyl)urea (XIX). Yield 0.48 g
(65%, a), 0.69 g (83%, b), brown viscous oily liquid.
IR spectrum, ν, cm–1: 780 m, 870 s, 1110 s, 1510 m,
1520 m, 1600 m, 1690 s, 1705 s, 2600–3300 br.s.
1H NMR spectrum, δ, ppm: 4.69 s (2H, CH2O),
5.15 br.s (2H, NH2), 6.95 d (2H, o-H, J = 8.8 Hz),
8.21 d (2H, m-H, J = 8.8 Hz), 12.10 br.s (1H, NH).
Found, %: C 45.34; H 3.62; N 17.73. C9H9N3O5. Cal-
culated, %: C 45.19; H 3.77; N 17.57.
Ethyl (4-nitrophenoxyacetyl)carbamate (XXIII).
Yield 0.91 g (87%), light brown amorphous substance,
mp 100–104°C. IR spectrum, ν, cm–1: 1240 s, 1490 m,
1
1510 m, 1605 m, 1690 s, 1715 s. H NMR spectrum,
δ, ppm: 1.25 t (3H, Me, J = 7.0 Hz), 4.21 q (2H,
CH3CH2O, J = 7.0 Hz), 4.64 s (2H, CH2OC6H4),
7.15 d (2H, o-H, J = 8.8 Hz), 7.20 br.s (1H, NH),
8.16 d (2H, m-H, J = 8.8 Hz). 13C NMR spectrum,
δC, ppm: 14.13 q (Me), 52.03 t (OCH2), 64.21 t
(CH2OC6H4), 114.10 d (Co), 124.82 d (Cm), 141.12 s
(Cp), 161.64 s (C=O), 167.86 s (C=O), 162.34 s (Ci).
Found, %: C 49.18; H 4.51; N 10.37. C11H12N2O6. Cal-
culated, %: C 49.25; H 4.48; N 10.45.
Ethyl (3-phenoxyphenoxyacetyl)carbamate
(XXIV). Yield 1.02 g (72%), light brown oily liquid.
IR spectrum, ν, cm–1: 1210 s, 1480 m, 1570 m, 1600 m,
1640 s, 1730 s, 3300 br.m. 1H NMR spectrum, δ, ppm:
1.25 t (3H, Me, J = 7.0 Hz), 4.16 q (2H, CH3CH2O,
J = 7.0 Hz), 4.53 s (2H, CH2OC6H4), 6.47 s (1H, 2-H),
6.71 d (1H, 6-H, J = 8.0 Hz), 6.76 d (1H, 4-H, J =
8.0 Hz), 6.96 d (2H, o'-H, J = 8.0 Hz), 7.02 m (1H,
p'-H), 7.14 m (2H, m'-H), 7.42 m (1H, 5-H), 11.55 br.s
(1H, NH). Found, %: C 64.47; H 5.61; N 4.37.
C17H17NO5. Calculated, %: C 64.76; H 5.40; N 4.44.
Ethyl (2,4-dichlorophenoxyacetyl)carbamate
(XXV). Yield 0.96 g (85%), brown amorphous sub-
stance, mp 93–95°C. IR spectrum, ν, cm–1: 1240 s,
1490 s, 1500 m, 1600 w, 1705 s, 1740 s, 3200 br.m.
1H NMR spectrum, δ, ppm: 1.25 t (3H, Me, J =
7.0 Hz), 4.23 q (2H, CH3CH2O, J = 7.0 Hz), 4.58 s
(2H, CH2OC6H3), 6.94 s (1H, 6-H, J = 8.5 Hz), 7.06 d
(1H, 5-H, J = 8.5 Hz), 7.36 s (1H, 3-H), 8.60 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 13.96 q (Me),
51.18 t (OCH2CH3), 64.37 t (CH2OC6H3), 114.66 d
(C6), 124.15 d (C2), 126.68 s (C4), 126.98 d and
127.53 d (C3, C5), 152.06 s (C1), 157.18 s (C=O),
163.96 s (C=O). Found, %: C 45.39; H 3.26; Cl 24.76;
N 4.83. C11H11Cl2NO4. Calculated, %: C 45.21; H 3.77;
Cl 24.32; N 4.79.
(3-Phenoxyphenoxyacetyl)urea (XX). Yield 0.70 g
(60%, a), 0.94 g (80%, b), light brown oily substance.
IR spectrum, ν, cm–1: 1490 m, 1510 s, 1600 m, 1615 s,
1690 s, 1715 s, 3150 m, 3300 br.s. 1H NMR spectrum,
δ, ppm: 4.55 s (2H, CH2O), 5.15 br.s (2H, NH2), 6.36 s
(1H, 2-H), 6.61 d (1H, 6-H, J = 8.0 Hz), 6.76 m
(1H, 4-H), 6.96 d (2H, o'-H, J = 8.0 Hz), 7.03 m (1H,
p'-H, J = 8.0 Hz), 7.15 m (2H, m'-H), 7.40 s (1H, NH),
13
7.54 (1H, 5-H), 13.29 br.s (1H, NH). C NMR spec-
trum, δC, ppm: 61.61 (OCH2), 106.09 d (C2), 110.25 d
(C6), 110.65 d (C4), 119.20 d (Co'), 123.39 d (Cp'),
129.68 d (Cm'), 130.28 d (C5), 156.76 s (C3), 158.73 s
(Ci'), 159.00 s (C1), 163.01 s and 163.16 s (C=O).
Found, %: C 62.87; H 4.99; N 9.66. C15H14N2O4.
Calculated, %: C 62.94; H 4.90; N 9.79.
(2,4-Dichlorophenoxyacetyl)urea (XXI). Yield
0.59 g (64%, a), 0.74 g (81%, b), light brown oily
substance. IR spectrum, ν, cm–1: 1490 s, 1600 m, 1650 s,
1690 s, 3150 m, 3250 br.s. 1H NMR spectrum, δ, ppm:
4.60 s (2H, CH2O), 5.00 br.s (2H, NH2), 6.75 d (1H,
C6, J = 8.8 Hz), 7.01 d (1H, 5-H, J = 8.8 Hz), 7.36 s
(1H, 3-H), 12.10 br.s (1H, NH). Found, %: C 41.37;
H 2.96; Cl 27.14; N 10.74. C9H8Cl2N2O3. Calculated,
%: C 41.06; H 3.04; Cl 27.00; N 10.65.
Reaction of phenoxyacetic acid derivatives with
ethyl carbamate (general procedure). Phenoxyacetic
acid I–IV, 3.5 mmol, was dissolved in 10 ml of
anhydrous toluene, and 4.2 mmol of ethyl carbamate,
4.2 mmol of freshly distilled thionyl chloride, and
4.2 mmol of anhydrous pyridine were added. The mix-
ture was heated for 4–4.5 h under reflux until the
initial acid disappeared (TLC, petroleum ether–ethyl
acetate, 6:1), and the products were isolated and pur-
ified as described above for compounds XVIII–XXI.
Ethyl (phenoxyacetyl)carbamate (XXII). Yield
0.77 g (81%), brown oily liquid. IR spectrum, ν, cm–1:
2-(3-Phenoxyphenoxy)ethyl benzylcarbamate
(XXVII). A solution of 46.7 mmol of benzylamine in
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YAMANSAROVA et al.
550
50 ml of ethyl acetate was added dropwise at room
temperature to 50 ml of ethyl acetate, and phosgene,
15 ml, was simultaneously passed through the solution
at such a rate that no disubstituted urea precipitated.
When the addition of benzylamine was complete,
an additional 5 ml of phosgene was bubbled through
the solution. The mixture was then stirred for 1.5 h at
20°C and was carefully heated (to avoid overheating)
to distill the solvent off. The residue was treated with
30 ml of carbon tetrachloride, the precipitate was
filtered off, and the filtrate was evaporated to obtain
24 mmol of benzyl isocyanate. The product was dis-
solved in 20 ml of ethyl acetate, and 24 mmol of 2-(3-
phenoxyphenoxy)ethanol (XXVI) [12] was added. The
mixture was stirred for 8 h at room temperature,
washed with a 10% solution of NaHCO3 and with
a saturated solution of NaCl, and dried over MgSO4.
The solvent was distilled off, and the residue was
purified by column chromatography on silica gel using
petroleum ether–ethyl acetate (8:1) as eluent. Yield
of XXVII 6.60 g (76%), brown oily substance. IR
spectrum, ν, cm–1: 1550 m, 1600 s, 1710 s, 3080 w.
1H NMR spectrum, δ, ppm: 3.94 s (2H, CH2N), 4.41 t
(2H, CH2O, J = 5.5 Hz), 4.51 t (2H, CH2OC6H4, J =
5.5 Hz), 6.60–6.72 m (5H, o-H, m-H, NH), 7.12–
7.50 m (10H, Harom). 13C NMR spectrum, δC, ppm:
44.89 t (CH2N), 62.90 t (OCH2), 65.76 t (CH2OC6H4),
101.97 d (C2), 107.38 d (C6), 112.08 d (C4), 117.90 d
(Co'), 120.32 d (Cp'), 122.18 d (Cp''), 129.60 d and
129.64 d (Cm', C5), 127.36 d (Co''), 127.96 d (Cm''),
137.44 s (Ci''), 156.78 (C3), 158.18 s (Ci'), 159.18 s (C1),
173.28 s (C=O). Found, %: C 72.86; H 5.48; N 3.94.
C22H21NO4. Calculated, %: C 72.73; H 5.79; N 3.86.
was heated for 1 h under reflux and poured into water.
The organic phase was separated and dried over
MgSO4, the solvent was distilled off, and the residue
was purified by column chromatography on silica gel
using hexane–ethyl acetate (9:1) as eluent. Yield of
XXVIII 0.48 g (58%), yellow–brown oily substance.
IR spectrum, ν, cm–1: 1100 s, 1115 s, 1505 m, 1600 s,
1
1630 w, 3100 w. H NMR spectrum, δ, ppm: 0.92 d
and 1.05 d (6H, Me, J = 6.0 Hz), 1.68 m (1H, CH),
1.87 m (2H, CH2C=C),* 4.34 t (2H, CH2O, J =
5.5 Hz), 4.51 t (2H, CH2OC6H4, J = 5.5 Hz), 6.96 t
(1H, CH=N, J = 6.7 Hz), 7.10–7.50 m (9H, Harom).
Found, %: C 72.67; H 7.01; N 4.63. C19H23NO3. Cal-
culated, %: C 72.84; H 7.35; N 4.47.
REFERENCES
1. Ovchinnikov, Yu.A., Bioorganicheskaya khimiya
(Bioorganic Chemistry), Moscow: Prosveshchenie,
1987, p. 784.
2. JPN Patent Appl. no. 90-212460, 1990; Chem. Abstr.,
1991, vol. 114, no. P42281v.
3. Czech. Patent no. 105266, 1962; Ref. Zh., Khim., 1964,
no. 6N230P.
4. Okawara, Ikeda, N., Yamassaki, T., and Furukawa, M.,
Chem. Pharm. Bull., 1988, vol. 36, p. 3628.
5. Yamansarova, E.T., Kukovinets, A.G., Kukovinets, O.S.,
Zainullin, R.A., Galin, F.Z., Kunakova, R.V., Zo-
rin, V.V., and Tolstikov, G.A., Russ. J. Org. Chem.,
2001, vol. 37, p. 246.
6. US Patent no. 3904773, 1975; Ref. Zh., Khim., 1976,
no. 12O319P.
7. Hsing-Jang, L. and Iyer, S.S., Can. J. Chem., 1980,
vol. 58, p. 2645.
2-Methylpropanal O-[2-(3-phenoxyphenoxy)-
ethyl]oxime (XXVIII). Phosphorus(III) bromide,
3.15 mmol, was added dropwise to a solution of
2.63 mmol of 2-(3-phenoxyphenoxy)ethanol (XXVI)
and 2.63 mmol of anhydrous pyridine in 15 ml of
anhydrous THF, stirred at 5°C under argon. The mix-
ture was stirred for 1 h at 5°C and for 12 h at room
temperature, diluted with 20 ml of anhydrous THF,
washed with a saturated solution of ammonium
chloride, and dried over Na2SO4. The solvent was
removed to obtain 0.58 g of 1-bromo-2-(3-phenoxy-
phenoxy)ethane, 15 ml of anhydrous 1,4-dioxane,
4.01 mmol of 2-propanal oxime, and 4.01 mmol of
potassium tert-butoxide were added, and the mixture
8. JPN Patent Appl. no. 55-38921, 1980; Ref. Zh., Khim.,
1981, no. 13O323P.
9. JPN Patent Appl. no. 60-180062, 1985; Ref. Zh., Khim.,
1986, no. 12O402P.
10. Hoffman, F., EP Patent no. 0004334-VI, 1981.
11. Wimmer, Z., Streinz, L., and Romanuk, M., Collect.
Czech. Chem. Commun., 1985, vol. 50, p. 2453.
12. Kukovinets, O.S., Zainullin, R.A., Kasradze, V.G.,
Burov, V.N., Mokrousova, E.P., Odinokov, V.N., and
Tolstikov, G.A., Agrokhimiya, 1999, no. 9, p. 60.
13. Del’nik, V.P., Katsnel’son, M.G., and Ostrovskii, D.I.,
Khim.-Farm. Zh., 1967, no. 6, p. 21.
* As in Russian original.—Publisher.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005