Reactions of 1,3,5-triazinylnitroformaldoximes 5. Synthesis of 5-R-3-(1,3,5-triazinyl)-4,5-dihydro-isoxazoles

Article abstract of DOI:10.1007/s10593-012-1076-1

1,3,5-Triazinylnitrile oxides, formed by heating (2-methoxy-4-R-1,3,5- triazin-6-yl)nitroformaldoximes, react with monosubstituted and 1,1-disubstituted ethylenes with the formation of 3-(1,3,5-triazinyl)-5- monosubstituted and 3-(1,3,5-triazinyl)-5,5-dis

Full text of DOI:10.1007/s10593-012-1076-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
REACTIONS OF 1,3,5-TRIAZINYLNITROFORMALDOXIMES
5*. SYNTHESIS OF 5-R-3-(1,3,5-TRIAZINYL)-4,5-DIHYDRO-
ISOXAZOLES
V. V. Bakharev1**, A. A. Gidaspov1, E. V. Selezneva1, and O. S. El'tsov2
1,3,5-Triazinylnitrile oxides, formed by heating (2-methoxy-4-R-1,3,5-triazin-6-yl)nitroformaldoximes,
react with monosubstituted and 1,1-disubstituted ethylenes with the formation of 3-(1,3,5-triazinyl)-
5-monosubstituted and 3-(1,3,5-triazinyl)-5,5-disubstituted 2-isoxazolines. The cycloaddition occurs
with high regioselectivity to give exclusively 2-isoxazolines substituted at the positions 3 and 5.
Keywords: 3-(1,3,5-triazinyl)-4,5-dihydroisoxazoles, 1,3,5-triazinylnitrile oxides, 1,3,5-triazinylnitro-
formaldoximes, cycloaddition.
2-Isoxazolines are widely used in organic synthesis as starting materials for preparation of β-hydroxy
ketones [2-6], γ-amino alcohols [6, 7], α,β-unsaturated ketones [8], β-hydroxynitriles and β-hydroxycarboxylic
acids [2, 9, 10], α- and β-amino acids [11-13], and a series of natural biologically active compounds [14, 15].
Derivatives of these heterocycles possess various types of biological activity: antimicrobial [16], antiviral [17],
antidepressive [18], antidiabetic [19], antiasthmatic [20], anti-inflammatory [20, 21]. A series of derivatives of
2-isoxazoline are used as herbicides and for plant protection [22-24].
One of the basic methods for the preparation of 3,5-disubstituted 4,5-dihydroisoxazoles is the
regioselective cycloaddition of nitrile oxides to alkenes [25-28]. We have previously synthesized 3,5-di-
substituted isoxazoles by 1,3-dipolar cycloaddition of 1,3,5-triazinylnitrile oxides, generated by thermolysis of
the corresponding 2,4-disubstituted 1,3,5-triazinylnitroformaldoximes, to monosubstituted acetylenes [29].
With the objective of synthesizing 5-mono- and 5,5-disubstituted 3-(1,3,5-triazinyl)-4,5-dihydroisox-
azoles we have studied the thermolysis of (4-methoxy-6-R-1,3,5-triazin-2-yl)nitroformaldoximes 1 in the presence
of monosubstituted and 1,1-disubstituted ethylenes. Heating a suspension of (4-methoxy-6-R-1,3,5-triazin-2-yl)-
nitroformaldoximes 1a-c with a 5-fold excess of acrylonitrile in toluene at 80-120°C resulted in the formation of
3-(4-methoxy-6-R-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carbonitriles 2a-c (39-45% yield) and 3,4-di(2-meth-
oxy-4-R-1,3,5-triazin-6-yl)furoxanes 3a-c (30-36% yield).
_______
*For Communication 4, see [1].
**To whom correspondence should be addressed, e-mail: knil@sstu.smr.ru.
1Samara State Technical University, 244 Molodogvardeiskaya St., Samara 443100, Russia.
2Ural Federal University named after the First President of Russia B. N. Eltsin, 19 Mira St., Yekaterinburg
620002, Russia; e-mail: oleg-eltsov@yandex.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 982-988, June, 2012. Original article
submitted March 11, 2011.
912
0009-3122/12/4806-0912©2012 Springer Science+Business Media New York

So, despite the use of a large excess of the dipolarophile, dimerization of the intermediate 1,3,5-tria-
zinylnitrile oxides occurred to give the furoxanes 3a-c. Carrying out the reaction directly in the dipolarophile
without dilution with an inert solvent allowed to completely suppress this side reaction. Heating compounds 1a-
e in monosubstituted ethylenes (acrylonitrile, allyl alcohol, methyl acrylate, styrene) and 1,1-disubstituted
ethylenes (butyl methacrylate) at 80-120°C gave 5-R1-3-(4-methoxy-6-R-1,3,5-triazin-2-yl)-4,5-dihydro-
isoxazoles 2a-k with 65-80% yield and butyl 3-(4-methoxy-6-R-1,3,5-triazin-2-yl)-5-methyl-4,5-dihydro-
isoxazol-5-carboxylates 4a-b in 68-70% yields.
R
R
N
Toluene

– HNO2
H2C
N
N
N
N
N
N
MeO
C+
MeO
N
OH
R
N
NO2
O
1a–c
OMe
N
OMe
N
N
N
N
N
R
R
+
N
N
MeO
N
CN
N
N+
N
O
O
O
2a–c
3a–c
a R = OMe, b R = NMe2, c R = N(CH2CH2)2O
R
H2C
R1
N
6
N
2
4
3
R1
R
N
MeO
MeO
N
5
N
O
2a–k
N
N

1a–e
– HNO2
MeO
C+
Me
CO2Bu
R
N
O
CH2
6
N
N
2
4
Me
N
3
5
CO2Bu
N
O
4a,b
1d, 4a R = N(CH2)4; 1e, 4b R = N(CH2)5; 2 d R = OMe, R1 = CH2OH; e R = NMe2, R1 = CH2OH;
f R = NMe2, R1 = C5H11; g R = NMe2, R1 = C6H13; h R = OMe, R1 = CO2Me;
i R = NMe2, R1 = CO2Me; j R = N(CH2CH2)2O, R1 = CO2Me; k R = N(CH2)5, R1 = Ph
The formation of the 4,5-dihydroisoxazoles 2a-k and 4a,b was confirmed by the presence in their
13C NMR spectra of signals in the regions of 35-44, 67-87, and 156-158 ppm (Table 1), which are characteristic
of the carbon atoms C-4, C-5, and C-3, respectively, in the 4,5-dihydroisoxazole ring [9, 27, 29-32].
The signals of the C-4 and C-5 carbons of the 4,5-dihydroisoxazole ring are very sensitive to the type of
substituent at the position 5, which is also confirmed and in excellent agreement with known data [10, 28,
30-33]. In the IR spectra of compounds 2a-c, there is a weak stretching band of the cyano group in the
2246-2250 cm-1 range. In the IR spectra of compounds 2d,e, hydroxyl stretching band was noted (quite sharp at
3448 cm-1 for compound 2d and broader at 3392 cm-1 for compound 2e). In the IR spectra of
913

TABLE 1. 13C NMR Spectra of Dihydroisoxazoles 2a-k and Butyl Esters 4a,b
Chemical shifts, , ppm
Com-
pound
4,5-Dihydro-
isoxazole
1,3,5-Triazine
С-2 С-4 С-6
4-OСH3, R, R1
С-3 С-4
С-5
172.7 172.7 167.2 156.6 40.1 68.2
166.1 170.8 164.9 157.4 40.6 67.6
165.6 171.2 165.3 157.2 40.5 67.7
116.4 (CN); 55.9 (OСH3)
2a
2b
2c
116.7 (CN); 54.6 (OСH3); 36.6 (N(CH3)2)
116.5 (CN); 66.6 (2OCH2); 54.9 (OСH3);
44.2, 43.8 (2NCH2)
172.6 172.6 168.5 157.1 35.0 84.0
166.1 170.7 166.0 157.8 35.6 83.3
166.4 170.8 166.2 157.3 39.0 83.3
63.4 (CH2OH); 55.1 (OСH3)
2d
2e
2f
63.3 (CH2OH); 54.4 (OСH3); 36.5 (N(CH3)2)
54.4 (OСH3); 36.4 (N(CH3)2);
35.3, 24.6 (CH2); 13.9 (СH3)
166.5 170.8 166.2 157.3 39.0 83.3
54.4 (OСH3); 36.6, 36.3 (N(CH3)2);
2g
35.2, 31.6, 29.0, 25.1, 22.5 (CH2); 14.0 (СH3)
171.3 172.7 168.0 156.4 37.8 79.4
166.2 170.8 165.5 157.1 38.3 79.2
175.0 (C=O); 55.7 (OСH3); 51.8 (CO2СH3)
2h
2i
174.9 (C=O); 54.5 (OСH3); 52.8 (CO2СH3);
36.5 (N(CH3)2)
165.9 171.8 165.5 157.0 38.2 79.1
166.5 171.2 165.3 157.3 42.3 84.2
172.3 (C=O); 66.6 (2OCH2); 54.8 (OСH3);
52.9 (CO2СH3); 44.3 (2NCH2)
2j
140.5, 128.7, 128.0, 127.6, 126.05 (C Ph);
54.6 (OСH3); 44.6 (2NCH2);
2k
25.8, 25.7 (2CH2); 24.4 (2CH2)
177.3 (C=O); 64.6 (CO2CH2); 54.4 (OСH3);
46.5 (2NCH2); 30.1 (CH2);
25.0 (CH2 pyrrolidine); 23.5 (CH3);
19.2 (CH2); 13.7 (СH3)
165.7 170.7 164.0 156.9 44.1 87.8
4a
4b
166.1 171.3 165.1 156.9 44.1 87.6 177.4 (C=O); 64.7 (CO2CH2); 54.4 (OСH3);
45.0, 44.4 (2NCH2); 30.3 (CH2);
25.7 (CH2 piperidine);
24.4 (CH2 piperidine); 23.5 (СH3);
19.1 (CH2); 13.6 (СH3)
compounds 2h-j and 4a,b, a weak stretching band of the carbonyl group in the 1727-1745 cm-1 range was
observed. In the 1H NMR spectra of the compounds synthesized, proton signals of the substituents in the 1,3,5-tri-
azine and 4,5-dihydroisoxazole rings are observed, and also signals of the protons H-4 (doublet or multiplet in
the 3.6-3.9 ppm region) and H-5 (triplet in the 4.7-5.5 ppm region, except for compounds 4a,b).
So we have developed a method for regioselective synthesis of 2-isoxazolines, substituted in the
positions 3 and 5, based on the 1,3-dipolar cycloaddition of 1,3,5-triazinylnitrile oxides to mono- and
disubstituted alkenes.
EXPERIMENTAL
1
13
IR spectra were recorded on an Avatar 360ESP spectrophotometer. H and C NMR spectra of CDCl3
solutions with TMS as internal standard were recorded on a Bruker Avance II spectrometer (400 and 100 MHz,
respectively). Elemental analyses were determined with a Eurovector EA 3000 apparatus. Melting points of the
compounds synthesized were determined with a Gallenkamp melting block. The course of reactions and the
purity of products were monitored by TLC on Silufol UV-254 plates. For the isolation and purification of the
synthesized compounds by column chromatography, silica gel MN Kieselgel 60 (0.063-0.200 μm) was used.
Compounds 1a-e were synthesized by a known method [34].
914

Reactions of (4-Methoxy-6-R-1,3,5-triazin-2-yl)nitroformaldoximes 1a-c with Acrylonitrile in
Toluene (General Method). A suspension of nitroformaldoxime 1a-c (0.5 mmol) and acrylonitrile (1.64 ml,
2.5 mmol) in toluene (20 ml) was heated for 4 h at 80-100°C. The toluene and excess acrylonitrile were
evaporated in vacuum, the residue was dissolved in AcOEt and separated on a column with a 4:1
dichloroethane–AcOEt eluent. Yields of 4,5-dihydroisoxazoles 2a 45%, 2b 42%, 2c 39%, of furoxanes 3a 30%,
3b 35%, 3c 36%. The analytical data for 3-(4-methoxy-6-R-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carbo-
nitriles 2a-c are given below, while for the furoxanes 3a-c correspond fully to the literature data [34].
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4,5-dihydroxazole-5-carbonitrile (2a).
A
suspension of
nitroformaldoxime 1a (2.29 g, 1 mmol) in acrylonitrile (15 ml) was heated to 85-95°C and maintained at this
temperature for 8 h. The excess of acrylonitrile was removed in vacuum, the residue was dissolved in AcOEt
and passed through a layer of silica gel, the AcOEt was removed in vacuum, and the residue was treated with
water (20 ml). The insoluble residue was filtered off, washed with water (5 ml), and dried in air. Yield 1.79 g
(76%); mp 123-125°C. IR spectrum (KBr), ν, cm-1: 3025, 3002, 2977, 2950, 2877, 2246, 1604, 1560, 1504,
1
1467, 1421, 1398, 1373, 1297, 1240, 1205, 1147, 1108, 1031, 1000, 935, 923, 881, 835, 819. H NMR
spectrum, δ, ppm (J, Hz): 3.80 (2H, d, J = 6.8, 4-CH2); 4.05 (6H, s, 2OCH3); 5.52 (1H, t, J = 6.8, 5-CH). Found,
%: C 45.83; H 3.82; N 29.92. C9H9N5O3. Calculated, %: C 45.96; H 3.86; N 29.78.
3-(6-Dimethylamino-4-methoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carbonitrile (2b) was
prepared analogously to compound 2a from nitroformaldoxime 1b (2.42 g, 1 mmol). Yield 1.98 g (80%); mp
130-132°C. IR spectrum (KBr), ν, cm-1: 2993, 2956, 2939, 2857, 2804, 2248, 1598, 1567, 1517, 1471, 1413,
1
1365, 1294, 1224, 1141, 1070, 1024, 910, 891, 813. H NMR spectrum, δ, ppm (J, Hz): 3.18 (3H, s) and 3.21
(3H, s, N(CH3)2); 3.77-3.81 (2H, m, 4-CH2); 3.95 (3H, s, OCH3); 5.43 (1H, t, J = 7.6, 5-CH). Found, %:
C 48.50; H 4.98; N 33.72. C10H12N6O2. Calculated, %: C 48.38; H 4.87; N 33.85.
3-(4-Methoxy-6-morpholino-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carbonitrile
(2c)
was
obtained analogously to compound 2a from nitroformaldoxime 1c (2.84 g, 1 mmol). Yield 1.98 g (72%); mp
150-153°C. IR spectrum (KBr) ν, cm-1: 2998, 2966, 2929, 2894, 2856, 2250, 1612, 1565, 1513, 1473, 1450,
1
1373, 1299, 1268, 1234, 1112, 1068, 1043, 999, 910, 885, 865, 811. H NMR spectrum, δ, ppm (J, Hz):
3.74-3.81 (10H, m, N(CH2CH2)2O, 4-CH2); 4.01 (3H, s, OCH3); 5.44 (1H, t, J = 9.2, 5-CH). Found, %: C 49.53;
H 4.94; N 28.79. C12H14N6O3. Calculated, %: C 49.65; H 4.86; N 28.95.
[3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (2d). A suspension of
nitroformaldoxime 1a (2.29 g, 1 mmol) in allyl alcohol (15 ml) was heated to 85-95°C and maintained at that
temperature for 5 h. The excess allyl alcohol was evaporated in vacuum. The residue was treated analogously to
the compound 2a. Yield 1.63 g (68%); mp 117-119°C (decomp.). IR spectrum (KBr), ν, cm-1: 3448, 3012, 2954,
2904, 2858, 1600, 1544, 1508, 1465, 1450, 1390, 1363, 1290, 1238, 1193, 1108, 1070, 1039, 937, 846, 823,
1
790. H NMR spectrum, δ, ppm (J, Hz): 2.84 (1H, br. s, OH); 3.29-3.46 (2H, m CH2OH); 3.69 (1H, dd,
Jgem = 8.0, J4,5 = 4.5) and 3.87 (1H, dd, Jgem = 8.0, J4,5 = 3.0, 4-CH2); 4.06 (6H, s, 2OCH3); 4.95 (1H, m, 5-CH).
Found, %: C 45.09, H 5.11, N 23.25. C9H12N4O4. Calculated, %: C 45.00; H 5.04; N 23.32.
[3-(6-Dimethylamino-4-methoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (2e) was
prepared analogously to compound 2d from nitroformaldoxime 1b (2.42 g, 1 mmol). Yield 1.77 g (70%); mp
136-138°C (decomp.). IR spectrum (KBr), ν, cm-1: 3392, 3008, 2939, 2871, 1610, 1591, 1556, 1511, 1475,
1
1413, 1369, 1292, 1220, 1081, 1022, 989, 935, 898, 817, 784. H NMR spectrum, δ, ppm (J, Hz): 3.10 (3H, s)
and 3.15 (3H, s, N(CH3)2); 3.25-3.35 (3H, m, CH2OH); 3.64 (1H, dd, Jgem = 8.0, J4,5 = 4.8) and 3.76 (1H, dd,
Jgem = 8.0, J4,5 = 3.3, 4-CH2), 3.89 (3H, s, OCH3); 4.82-4.86 (1H, m, CH). Found, %: C 47.53, H 5.78, N 27.72.
C10H15N5O3. Calculated, %: C 47.43, H 5.97, N 27.65.
[4-Methoxy-6-(5-pentyl-4,5-dihydroisoxazol-3-yl)-1,3,5-triazin-2-yl]dimethylamine (2f). A suspension
of nitroformaldoxime 1b (2.42 g, 1 mmol) in 1-heptene (15 ml) was heated to 90-95°C and maintained at this
temperature for 4 h. The excess of 1-heptene was evaporated in vacuum. The residue was dissolved in AcOEt
and passed through a layer of silica gel. The AcOEt was evaporated in vacuum, and the residue was dried in
vacuum. Yield 1.96 g (67%). Light-yellow viscous liquid. IR spectrum (thin film), ν, cm-1: 2954, 2931, 2860,
915

1
1587, 1560, 1519, 1469, 1411, 1365, 1292, 1261, 1222, 1093, 1022, 929, 902, 815, 790. H NMR spectrum, δ,
ppm (J, Hz): 0.81 (3H, t, J = 7.2, CH3); 1.24-1.78 (8H, m, (CH2)4); 3.12 (3H, s) and 3.18 (3H, s, N(CH3)2);
2.93-2.98 (1H, m) and 3.26-3.36 (1H, m, 4-CH2); 3.91 (3H, s, OCH3); 4.72 (1H, m, 5-CH). Found, %: C 57.43;
H 7.99; N 23.72. C14H23N5O2. Calculated, %: C 57.32; H 7.90; N 23.87.
[6-(5-Hexyl-4,5-dihydroisoxazol-3-yl)-1,3,5-triazin-2-yl]-4-methoxydimethylamine (2g) was obtained
analogously to the compound 2f from nitroformaldoxime 1b (2.42 g, 1 mmol) and 1-octene (15 ml) at
115-120°C. Yield 2.24 g (73%). Light-yellow viscous liquid. IR spectrum (thin film), ν, cm-1: 2952, 2927, 2856,
1587, 1560, 1517, 1457, 1411, 1365, 1292, 1261, 1222, 1091, 1022, 929, 904, 815. 1H NMR spectrum, δ, ppm
(J, Hz): 0.82 (3H, t, J = 6.8, CH3); 1.23-1.72 (10H, m, (CH2)5); 3.14 (3H, s) and 3.20 (3H, s, N(CH3)2);
2.94-2.99 (1H, m) and 3.29-3.39 (1H, m, 4-CH2); 3.92 (3H, s, OCH3); 4.72-4.76 (1H, m, 5-CH). Found, %:
C 58.76, H 8.24, N 22.63. C15H25N5O2. Calculated, %: C 58.61; H 8.20; N 22.78.
Methyl 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carboxylate (2h). A suspension
of nitroformaldoxime 1a (2.29 g, 1 mmol) in methyl acrylate (15 ml) was heated to 80-85°C and maintained at
this temperature for 5 h. The excess methyl acrylate was evaporated in vacuum, the residue was dissolved in
AcOEt and passed through a layer of silica gel. The AcOEt was evaporated in vacuum and the residue was dried
in vacuum. Yield 1.98 g (74%). Colorless transparent viscous liquid. IR spectrum (thin film), ν, cm-1: 3002,
1
2954, 2929, 2850, 1733, 1596, 1556, 1508, 1436, 1392, 1357, 1199, 1164, 1124, 1108, 1037, 825. H NMR
spectrum, δ, ppm (J, Hz): 3.70 (2H, d, J = 4.0, 4-CH2); 3.80 (3H, s, CO2CH3); 4.08 (6H, s, 2OCH3); 5.28-5.32
(1H, m, 5-CH). Found, %: C 44.92; H 4.47; N 20.95. C10H12N4O5. Calculated, %: C 44.78; H 4.51; N 20.89.
Methyl 3-(6-dimethylamino-4-methoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carboxylate (2i)
was prepared analogously to compound 2h from nitroformaldoxime 1b (2.42 g, 1 mmol). Yield 2.22 g (79%).
Colorless transparent viscous liquid. IR spectrum (thin film), ν, cm-1: 2989, 2956, 2914, 2875, 1753, 1735,
1
1608, 1564, 1513, 1473, 1436, 1371, 1294, 1224, 1162, 1081, 1068, 1020, 921, 894, 815, 676. H NMR
spectrum, δ, ppm (J, Hz): 3.14 (3H, s) and 3.18 (3H, s, N(CH3)2); 3.61 (2H, d, J = 4.2, 4-CH2); 3.74 (3H, s,
CO2CH3); 3.93 (3H, s, OCH3); 5.18 (1H, t, J = 8.2, 5-CH). Found, %: 47.05, H 5.27; N 24.99. C11H15N5O4.
Calculated, %: C 46.97; H 5.38; N 24.90.
Methyl 3-(4-methoxy-6-morpholino-1,3,5-triazin-2-yl)-4,5-dihydroisoxazole-5-carboxylate (2j) was
obtained analogously to compound 2h from nitroformaldoxime 1b (2.42 g, 1 mmol). Yield 2.42 g (75%).
Colorless transparent viscous liquid. IR spectrum (thin film) ν, cm-1: 2996, 2958, 2923, 2858, 1745, 1565, 1517,
1467, 1448, 1371, 1282, 1230, 1114, 1043, 1002, 892, 815. 1H NMR spectrum, δ, ppm (J, Hz): 3.66-3.88 (10H,
m, N(CH2CH2)2O, 4-CH2); 3.81 (3H, s, CO2CH3); 3.98 (3H, s, OCH3); 5.24 (1H, t, J = 8.0, 5-CH). Found, %:
C 48.43; H 5.44; N 21.76. C13H17N5O5. Calculated, %: C 48.30; H 5.30; N 21.66.
4-Methoxy-2-(5-phenyl-4,5-dihydroisoxazol-3-yl)-6-(piperidin-1-yl)-1,3,5-triazine (2k). A suspension of
nitroformaldoxime 1e (2.82 g, 1 mmol) in styrene (10 ml) was heated to 115-120°C and maintained at this
temperature until the starting compound 1e disappeared (4 h, according to TLC data). The excess styrene was
evaporated in vacuum. The residue was treated analogously to compound 2h. Yield 2.20 g (65%). Colorless
transparent viscous liquid. IR spectrum (thin film), ν, cm-1: 3060, 3010, 2933, 2917, 2848, 1600, 1550, 1508,
1
1457, 1367, 1288, 1232, 1124, 1099, 1024, 981, 914, 887, 817, 761, 702, 669. H NMR spectrum, δ, ppm (J,
Hz): 1.49-1.68 (6H, m, 3CH2); 3.40-3.48 (2H, m, 4-CH2); 3.78-3.84 (4H, m, N(CH2)2); 3.97 (3H, s, OCH3); 5.79
(1H, t, J = 8.0, 5-CH); 7.28-7.36 (5H, m, H Ph). Found, %: C 63.79; H 6.11; N 20.55. C18H21N5O2. Calculated,
%: C 63.70; H 6.24; N 20.63.
Butyl 3-[4-Methoxy-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl]-5-methyl-4,5-dihydroisoxazole-5-carboxy-
late (4a). A suspension of nitroformaldoxime 1d (2.68 g, 1 mmol) in butyl methacrylate (10 ml) was heated to
105-110°C and maintained at this temperature for 3 h. The excess of butyl methacrylate was removed in
vacuum, and the residue was treated analogously to compound 2h. Yield 2.54 g (70%). Light-yellow viscous
liquid. IR spectrum (thin film), ν, cm-1: 2960, 2935, 2873, 1729, 1577, 1564, 1513, 1459, 1369, 1342, 1272,
1
1241, 1180, 1155, 1064, 1020, 966, 945, 819, 750. H NMR spectrum, δ, ppm (J , Hz): 0.86 (3H, t, J = 7.6,
CH3); 1.26-1.34 (2H, m, CH2); 1.55-1.58 (2H, m, CH2); 1.60 (3H, s, 5-CH3); 1.91 (4H, d, J = 9.6, 2CH2);
916

3.48-3.54 (4H, m, N(CH2)2); 3.83 (2H, s, 4-CH2); 3.89 (3H, s, OCH3); 4.09 (2H, t, J = 6.4, CO2CH2). Found, %:
C 56.30; H 7.11; N 19.15. C17H25N5O4. Calculated, %: C 56.19; H 6.93; N 19.27.
Butyl
3-[4-methoxy-6-(piperidin-1-yl)-1,3,5-triazin-2-yl]-5-methyl-4,5-dihydroisoxazole-5-carb-
oxylate (4b) was prepared analogously to compound 4a from nitroformaldoxime 1e (2.82 g, 1 mmol). Yield
2.56 g (68%). Light-yellow viscous liquid. IR spectrum (thin film), ν, cm-1: 2958, 2935, 2873, 1727, 1558,
1
1515, 1465, 1371, 1290, 1272, 1241, 1176, 1155, 1064, 1022, 966, 945, 819, 750. H NMR spectrum, δ, ppm
(J, Hz): 0.86 (3H, t, J = 7.6, CH3); 1.27-1.34 (2H, m, CH2); 1.47-1.55 (8H, m, 4CH2); 1.59 (3H, s, CH3);
3.77-3.81 (4H, m, N(CH2)2); 3.81 (2H, s, 4-CH2); 3.87 (3H, s, OCH3); 4.09 (2H, t, J = 6.4, CO2CH2). Found, %:
C 57.34; H 7.35; N 18.40. C18H27N5O4. Calculated, %: C 57.28; H 7.21; N 18.55.
REFERENCES
1.
V. V. Bakharev, A. A. Gidaspov, E. V. Selezneva, V. E. Parfenov, I. V. Ul'yankina, I. S. Nazarova,
Yu. T. Palatova, and O. S. El'tsov, Khim. Geterotsikl. Soedin., 1521 (2011). [Chem. Heterocycl. Compd.,
47, 1258 (2011)].
2.
3.
4.
E. V. Koroleva and F. A. Lakhvich, Usp. Khim., 66, 31 (1997).
S. S. Ghabrial, I. Thomsen, and K. G. B. Torsell, Acta Chem. Scand., B41, 426 (1987).
J. A. Kenar, J. Am. Oil Chem. Soc., 79, 351 (2002).
5.
6.
A. P. Kozikovski and M. Adamczyk, Tetrahedron Lett., 23, 3123 (1982).
D. Jiang and Y. Chen, J. Org. Chem., 73, 9181 (2008).
7.
8.
V. Jäger, V. Buß, and W. Schwab, Tetrahedron Lett., 19, 3133 (1978).
H. Grund and V. Jäger, Liebigs Ann. Chem., 80 (1980).
9.
A. P. Kozikovski and M. Adamczyk, J. Org. Chem., 48, 366 (1983).
10.
11.
12.
S. Yang, W. Hayden, K. Faber, and H. Griengl, Synthesis, 365 (1992).
R. A. Mosey, J. S. Fisk, and J. J. Tepe, Tetrahedron: Asymmetry, 19, 2755 (2008).
G. Cremonesi, P. D. Croce, F. Fontana, C. Fiorelli, and C. La Rosa, Tetrahedron: Asymmetry, 19, 2850
(2008).
13.
14.
15.
16.
17.
A. A. Fuller, B. Chen, A. R. Minter, and A. K. Mapp, J. Am. Chem. Soc., 127, 5376 (2005).
J. Zhang and D. P. Curran, J. Chem. Soc., Perkin Trans. 1, 2627 (1991).
A. P. Kozikovski, Acc. Chem. Res., 17, 410 (1984).
I. Zadroźna, J. Kurkowska, N. Kruszewska, and I. Makuch, Farmaco, 55, 499 (2000).
H. Kai, H. Matsumoto, N. Hattori, A. Takase, T. Fujiwara, and H. Sugimoto, Bioorg. Med. Chem. Lett.,
11, 1997 (2001).
18.
19.
20.
Y. R. Prasad, P. R. Kumar, and D. Ramesh, Int. J. Chem. Sci., 5, 542 (2007).
A. L. Norman and M. D. Mosher, Tetrahedron Lett., 49, 4153 (2008).
W. Schwab, N. Anagnostopolus, R. R. Barlett, R. Schleyerbach, and K. U. Weithmann, US Pat. Appl.
5814627.
21.
22.
B. R. Dravyakar, D. P. Kavade, P. B. Khedekar, and K. P. Bhusari, Ind. J. Chem., 47B, 1559 (2008).
I. T. Hwang, H. R. Kim, D. J. Jeon, K. S. Hong, J. H. Song, and K. Y. Cho, J. Agric. Food Chem., 53,
8639 (2005).
23.
24.
H. J. Loher, W. Schwab, K. Bauer, and H. Bieringer, US Pat. Appl. 5314863.
Basappa, M. P. Sadashiva, K. Mantelingu, S. Nanjunda Swamy, and K. S. Rangappa, Bioorg. Med.
Chem., 11, 4539 (2003).
25.
S. A. Lang, Jr. and Y.-I. Lin, in: A. R. Katritzky and C. W. Rees (editors), Comprehensive Heterocyclic
Chemistry, Vol. 6, Pergamon, Oxford (1984), pp.1-130.
26.
27.
I. Morao, B. Lecea, and F. P. Cossio, J. Org. Chem., 62, 7033 (1997).
K. V. Gothelf and K. A. Jorgensen, Chem. Rev., 98, 863 (1998).
917

28.
29.
G. Giacomelli, L. De Luca, and A. Porcheddu, Tetrahedron, 59, 5437 (2003).
V. V. Bakharev, A. A. Gidaspov, E. V. Peresedova, D. B. Krivolapov, E. V. Mironova, and
I. A. Litvinov, Khim. Geterotsikl. Soedin., 1345 (2009). [Chem. Heterocycl. Compd., 45, 1075 (2009)].
O. Tsuge, S. Kanemasa, H. Suga, and N. Nakagawa, Bull. Chem. Soc. Jpn., 60, 2463 (1987).
A. T. Hamme II, J. Xu, J. Wang, J. Cook, and E. Ellis, Heterocycles, 65, 2885 (2005).
P. Li, H.-J. Gi, L. Sun, and K. Zhao, J. Org. Chem., 63, 366 (1998).
V. Singh, S. Madapa, G. P. Yadav, P. R. Maulik, and S. Batra, Synthesis, 1995 (2006).
V. V. Bakharev, A. A. Gidaspov, E. V. Peresedova, V. G. Granik, N. B. Grigor'ev, V. I. Levina,
I. S. Severina, A. Yu. Shchegolev, D. E. Dmitriev, and A. B. Sheremetev, Izv. AN, Ser. Khim., 1900
(2009).
30.
31.
32.
33.
34.
918