Reactions of 1,3,5-triazinylnitro-formaldoximes. 2*. the reaction of 1,3,5-triazinylnitroformaldoximes with monosubstituted acetylenes

Article abstract of DOI:10.1007/s10593-009-0382-8

1,3,5-Triazinylnitrile oxides were prepared in situ from 2-R-4-R′-1,3,5-triazin-6-ylnitroformaldoximes and were treated with substituted acetylenes to give 3,5-disubstituted isoxazoles. The X-ray data obtained for 5-hydroxymethyl-3-(4′-dimethylamino-2′-me

Full text of DOI:10.1007/s10593-009-0382-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
REACTIONS OF 1,3,5-TRIAZINYLNITRO-
FORMALDOXIMES. 2*. THE REACTION OF
1,3,5-TRIAZINYLNITROFORMALDOXIMES
WITH MONOSUBSTITUTED ACETYLENES
V. V. Bakharev1**, A. A. Gidaspov1, E. V. Peresedova1,
D. B. Krivolapov2, E. V. Mironova2, and I. A. Litvinov2
1,3,5-Triazinylnitrile oxides were prepared in situ from 2-R-4-R'-1,3,5-triazin-6-ylnitroformaldoximes
and were treated with substituted acetylenes to give 3,5-disubstituted isoxazoles. The X-ray data
obtained for 5-hydroxymethyl-3-(4'-dimethylamino-2'-methoxy-1,3,5-triazin-6'-yl)isoxazole is discussed.
Keywords: 3,5-disubstituted isoxazoles, acetylene derivatives, 1,3,5-triazinylnitrile oxides, 1,3,5-tri-
azinylnitroformaldoximes.
We have previously shown that deprotonation of 1,3,5-triazinylnitroformaldoximes occurs in the
presence of base but the anion formed is unstable and loses nitrite ion to form a 1,3,5-triazinylnitrile oxide. The
latter reacts with the enolates of dicarbonyl compounds to give 5-methyl-4-R-3-(1,3,5-triazinyl)isoxazoles [1].
Continuing study of the chemistry of 1,3,5-triazinylnitroformaldoximes we have investigated a thermal method
of generating 1,3,5-triazinylnitrile oxides with their subsequent involvement in a [3+2] dipolar cycloaddition.
The monosubstituted acetylenes phenylacetylene and propargyl alcohol were used as the dipolarophiles.
Heating a suspension of 2-R-4-R'-1,3,5-triazin-6-ylnitroformaldoximes 1a-e with phenylacetylene or
propargyl alcohol at 80-100ºC resulted in the formation of, respectively, the 3-(2-R-4-R'-1,3,5-triazin-6-yl)-
5-phenylisoxazoles 2a-e and 5-hydroxymethyl-3-(2-R-4-R'-1,3,5-triazin-6-yl)isoxazoles 3a-e.
Carrying out the thermolysis of compounds 1a-e in the dipolarophile medium (i.e. without dilution with
an inert solvent) fully suppressed the dimerization of the intermediately formed 1,3,5-triazinylnitrile oxides to
3,4-di(2-R-4-R'-1,3,5-triazin-6-yl)furoxans.
_______
* For Communication 1 see [1].
** To whom correspondence should be addressed, e-mail: knil@sstu.smr.ru.
1Samara State Technical University, Samara 443100, Russia.
2A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center of the Russian Academy of
Sciences, Kazan 420088, Tatarstan Republic; e-mail: litvinov@iopc.knc.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1345-1351, September, 2009.
Original article submitted October 9, 2008.
0009-3122/09/4509-1075©2009 Springer Science+Business Media, Inc.
1075

1
According to their H NMR data the reaction products are exclusively the 3,5-disubstituted isoxazoles
1
with total absence of 3,4-disubstituted isoxazoles. This conclusion was based on a comparison of the H NMR
spectra of the synthesized compounds 2a-e and 3a-e and 3-, 3,4-, and 3,5-substituted isoxazoles [2-5]. The
formation of only 3,5-disubstituted isoxazoles points to a stereoselective addition of the monosubstituted
acetylenes to the 1,3,5-triazinylnitrile oxides. In this way we were able to carry out a thermal method of
generating 1,3,5-triazinylnitrile oxides from 2-R-4-R'-1,3,5-triazin-6-ylnitroformaldoximes, treatment of which
with monosubstituted acetylenes gave high yields of the 3,5-disubstituted isoxazoles containing a 1,3,5-triazine
ring in the 3 position.
R
N
N
MeO
N
Ph
R
N
N
HC CPh
R
N
O
2a–e
∆
N
N
N
N
– HNO2
C+
N
N
MeO
MeO
OH
HC CCH2OH
NO2
O
R
N
1a–e
N
N
MeO
N
OH
O
3a–e
R1 =
;
d R =
e R1 =
;
1–3 a R = OMe; b R = NMe2 ; c
1
N
N
N
O
The structure of isoxazole 3b was confirmed from X-ray analysis. The asymmetric part of the unit cell
of compound 3b contains one molecule of 3-(4-dimethylamino)-5-hydroxymethyl-2-methoxy-1,3,5-triazin-
6-yl)isoxazole (Fig. 1).
Fig. 1. Molecular geometry of the compound 3b molecule crystal.
1076

The triazine and isoxazole rings in the molecule are planar within the limits 0.021(2) and 0.007(2) Å
respectively. The dihedral angle between the ring planes is 2.7(1)º. The dimethylamino group (which has a
planar conformation, the angle of rotation relative to the triazine ring being 4.2(2)º) and the methoxy group lie in
the triazine ring plane hence it can be regarded overall as a seventeen atom framework molecular plane.
According to calculations made using the PLATON program this fragment is planar within the limits 0.072(3) Å.
Only atom O(18) of the hydroxymethyl group deviates from this plane by 1.274(1) Å.
It is significant that the dihedral angles between the 1,3,5-triazine and isoxazole rings for the two
independent molecules of 4-ethoxycarbonyl-3-(2-methoxy-4-pyrrolidinyl-1,3,5-triazin-6-yl)-5-methylisoxazole
are 84.0(2)º and 64.1(2)º [1]. This is evidently due to the presence of the substituent in position 4 of the
isoxazole ring which leads to repulsion of the unshared electron pairs of the 1,3,5-triazine ring nitrogen atom
and the oxygen atom of the ethoxycarbonyl group. With the absence of a 4 substituent in the 3-(4-
dimethylamino-2-methoxy-1,3,5-triazin-6-yl)-5-hydroxymethylisoxazole (3b) the rings virtually lie in a single
plane. Moreover, an insignificant (0.02 Å) decrease was seen in the inter ring C–C bond when compared with
4-ethoxycarbonyl-3-(2-methoxy-4-pyrrolidinyl-1,3,5-triazin-6-yl)-5-methylisoxazole [1].
The crystal packing of compound 3b is primarily determined by intermolecular hydrogen bonds of the
type OH···N. Due to these bonds the compound 3b molecules form centrosymmetric hydrogen bonded dimers (as in
Fig. 2). The hydrogen bond parameters are: O(18)–H(18)···(N(1)' bond (1-x, 1-y, 2-z), d O(18)–H(18) = 0.91(2), d
H(18)···N(1)' = 2.04(2), d O(18)···N(1)' = 2.926(2) Å, ω O(18)H(18)N(1)' = 164(2)º.
Fig. 2. H-Dimers in the molecule of compound 3b formed via
O(18)–H(18)···N(1)' hydrogen bonding in the crystal.
TABLE 1. Bond Lengths (d) in the Compound 3b Molecule
Bond
d, Å
Bond
d, Å
Bond
d, Å
N(1)–C(6)
N(1)–C(2)
N(3)–C(2)
N(3)–C(4)
N(5)–C(6)
N(5)–C(4)
C(2)–O(10)
1.340(3)
1.341(2)
1.317(2)
1.357(3)
1.322(2)
1.352(2)
1.333(3)
C(4)–N(7)
1.333(2)
1.474(2)
1.311(2)
1.410(3)
1.401(2)
1.346(2)
1.341(2)
C(15)–C(17)
C(11)–O(10)
N(7)–C(8)
1.492(3)
1.446(3)
1.450(3)
1.464(4)
1.408(2)
C(6)–C(12)
C(12)–N(13)
C(12)–C(16)
N(13)–O(14)
O(14)–C(15)
C(16)–C(15)
N(7)–C(9)
O(18)–C(17)
1077

TABLE 2. Valence Angles (ω) in the Compound 3b Molecule
Angle
ω, deg
Angle
ω,deg
C(6)–N(1)–C(2)
C(2)–N(3)–C(4)
C(6)–N(5)–C(4)
N(3)–C(2)–O(10)
N(3)–C(2)–N(1)
O(10)–C(2)–N(1)
N(7)–C(4)–N(5)
N(7)–C(4)–N(3)
N(5)–C(4)–N(3)
N(5)–C(6)–N(1)
N(5)–C(6)–C(12)
N(1)–C(6)–C(12)
N(13)–C(12)–C(16)
112.46(15)
113.94(16)
114.52(15)
119.70(16)
127.71(16)
112.59(15)
117.60(16)
118.15(16)
124.24(16)
126.96(16)
114.68(15)
118.35(15)
111.75(16)
N(13)–C(12)–N(6)
C(12)–C(16)–C(6)
C(12)–N(13)–O(14)
C(15)–O(14)–N(13)
C(15)–C(16)–C(12)
C(16)–C(15)–O(14)
C(16)–C(15)–C(17)
O(14)–C(15)–C(17)
C(4)–N(7)–C(8)
121.28(16)
126.97(15)
104.87(14)
109.16(13)
104.74(15)
109.47(15)
133.70(16)
116.71(16)
121.83(18)
120.54(17)
117.59(20)
112.32(15)
117.67(16)
C(4)–N(7)–C(9)
C(8)–N(7)–C(9)
O(18)–C(17)–C(15)
C(2)–O(10)–C(11)
EXPERIMENTAL
IR spectra were recorded on an Avatar 360ESP spectrophotometer for KBr tablets and 1H NMR spectra
on a Bruker AM-300 (300 MHz) spectrometer using DMSO-d6 (compounds 2a-e) or CDCl3 (compounds 3a-e)
with TMS as internal standard.
Compounds 1a-e were prepared as in method [6].
X-ray Structural Analysis of the Crystals of Compound 3b was carried out at 20ºC on a Bruker Smart
APEX II CCD diffractometer (λMoKα radiation [λ = 0.71073 Å], graphite monochromator, ω-scanning). The
SAINT Plus program [7] was used in the treatment of the starting group of experimental intensities. The structure
was solved by a direct method and refined by F2 full matrix least squares analysis in the anisotropic approximation
for non-hydrogen atoms. All of the calculations were performed using the SHELXTL PLUS5 program package [8].
Hydrogen atoms were revealed in difference Fourier synthesis and refined isotropically. All of the figures and
analysis of the intermolecular interactions were carried out using the PLATON program [9].
Crystals of compound 3b were prepared from a mixture of dichloroethane and methanol (1:1) as colorless,
transparent, triclinic prisms. C10H13N5O3. M = 251.25, a = 8.1898(8), b = 8.6088(8), c = 9.5926(9) Å;
α = 67.721(1), β = 88.074(1), γ = 70.766(1)º; V = 587.7(1) Å3, dcalc = 1.42 g/cm3, Z = 2, space group P-1. Scanning
angle 2.3º ≤ θ ≤ 26.0º. 2209 Independent reflections were measured, 1444 of which had I > 2σ. Calculation of
absorbance was not included due to its insignificance (µ(Mo) = 1.1 cm-1). The final divergence factor values were
Rob = 0.037 and Rwob = 0.096. The study of the single crystal study was carried out in the Department of X-ray
Structure Investigation of the Shared Use Center at Laboratory of Research by Diffraction Methods of the
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center of the Russian Academy of
Sciences. The atomic coordinates and structural parameters have been placed in the Cambridge crystallographic
database (CCDC 704356).
3-(2,4-Dimethoxy-1,3,5-triazin-6-yl)-5-phenylisoxazole (2a). A suspension of compound 1a (2.46 g,
1 mmol) in phenylacetylene (15 ml) was heated to 90-100ºC and held at this temperature with stirring until the
starting 1a had disappeared (TLC, 1-1.5 h). After this time the excess phenylacetylene was removed under
reduced pressure and the residue was treated with cold ethyl acetate (2×5 ml). The crystalline product was
filtered off and washed on the filter with cold ethyl acetate (5 ml). Yield 2.33 g (82%); mp 168-170ºC. IR
spectrum, ν, cm-1: 3151, 3045, 3006, 2952, 2877, 1610, 1544, 1521, 1467, 1448, 1430, 1396, 1350, 1228, 1199,
1078

1
1105, 1052, 995, 933, 850, 831, 808, 771, 692. H NMR spectrum, δ, ppm: 3.99 (6H, s, OCH3); 7.55 (4H, m,
CH isoxazole and 3H Ph) and 7.94 (2H, m, Ph). Found, %: C 59.35; H 4.32; N 19.60. C14H12N4O3. Calculated,
%: C 59.15; H 4.25, N 19.71.
3-(4-Dimethylamino-2-methoxy-1,3,5-triazin-6-yl)-5-phenylisoxazole (2b) was prepared similarly to
compound 2a from compound 1b (2.42 g, 1 mmol). Yield 2.38 g (80%); mp 163-165ºC. IR spectrum, ν, cm-1:
3153, 3062, 3012, 2927, 2869, 1591, 1567, 1525, 1467, 1446, 1429, 1367, 1315, 1259, 1214, 1070, 1047, 938,
946, 817, 802, 771, 698. 1H NMR spectrum, δ, ppm: 3.18 and 3.24 (6H, two s, ∆ν = 18 Hz, NCH3); 3.98 (3H, s,
OCH3); 7.53 (4H, m, CH isoxazole and 3H Ph) and 7.90 (2H, m, Ph). Found, %: C 60.52; H 5.21; N 23.67.
C15H15N5O2. Calculated, %: C 60.60; H 5.09; N 23.55.
3-(2-Methoxy-4-pyrrolidinyl-1,3,5-triazin-6-yl)-5-phenylisoxazole (2c) was prepared similarly to
compound 2a from compound 1c (2.68 g, 1 mmol). Yield 2.39 g (74%); mp 205-207ºC. IR spectrum, ν, cm-1:
3147, 3068, 3056, 2971, 2954, 2883, 1587, 1560, 1523, 1479, 1461, 1432, 1359, 1338, 1311, 1226, 1062, 985,
1
946, 804, 769, 692. H NMR spectrum, δ, ppm (J, Hz): 2.00 (4H, m, CH2); 3.62 and 3.74 (4H, two t, J = 6.8,
NCH2); 4.02 (3H, s, OCH3); 7.51 (4H, m, CH isoxazole and 3H Ph); 7.84 (2H, m, Ph). Found, %: C 63.04;
H 5.46; N 21.50. C17H17N5O2. Calculated, %: C 63.15; H 5.30; N 21.66.
3-(2-Methoxy-4-piperidino-1,3,5-triazin-6-yl)-5-phenylisoxazole (2d) was prepared similarly to
compound 2a from compound 1d (2.82 g, 1 mmol). Yield 2.60 g (77%); mp 152-153ºC. IR spectrum, ν, cm-1:
3141, 3039, 3000, 2941, 2921, 2858, 1577, 1525, 1465, 1448, 1429, 1369, 1286, 1228, 1095, 1054, 1002, 977,
948, 923, 889, 815, 773, 696. 1H NMR spectrum, δ, ppm (J, Hz): 1.60 (6H, m, CH2); 3.82 and 3.92 (4H, two t,
J = 7.0, NCH2); 3.99 (3H, s, OCH3); 7.55 (4H, m, CH isoxazole and 3H Ph), and 7.98 (2H, m, Ph). Found, %:
C 64.15; H 5.74; N 20.78. C18H19N5O2. Calculated, %: C 64.08; H 5.68; N 20.76.
3-(2-Methoxy-4-morpholino-1,3,5-triazin-6-yl)-5-phenylisoxazole (2e) was prepared similarly to
compound 2a from compound 1e (2.84 g, 1 mmol). Yield 2.75 g (81%); mp 184-186ºC. IR spectrum, ν, cm-1:
3142, 3054, 3037, 2958, 2929, 2869, 1610, 1569, 1525, 1471, 1446, 1363, 1278, 1226, 1116, 1064, 1014, 981,
948, 887, 802, 769, 696. 1H NMR spectrum, δ, ppm: 3.70, 3.82 and 3.91 (8H, three m, NCH2CH2O); 3.99 (3H,
s, OCH3); 7.56 (4H, m, CH isoxazole and 3H Ph), and 7.92 (2H, m, Ph). Found, %: C 60.28; H 5.00; N 20.52.
C17H17N5O3. Calculated, %: C 60.17; H 5.05; N 20.64.
3-(2,4-Dimethoxy-1,3,5-triazin-6-yl)-5-hydroxymethylisoxazole (3a). A suspension of compound 1a
(2.46 g, 1 mmol) in propargyl alcohol (10 ml) was heated to 85-95ºC and held at this temperature with stirring
until the starting compound 1a had disappeared (TLC, 1-1.5 h). Excess propargyl alcohol was then removed at
reduced pressure and the residue was treated with cold ethyl acetate (2×5 ml). The crystalline product was
filtered off and washed on the filter with cold ethyl acetate (5 ml). Yield 2.07 g (86%); mp 130-132ºC
(decomp.). IR spectrum, ν, cm-1: 3423, 3158, 3008, 2962, 2917, 1608, 1560, 1529, 1490, 1477, 1457, 1430,
1394, 1359, 1199, 1110, 1079, 1045, 983, 945, 825, 800. 1H NMR spectrum, δ, ppm; 4.01 (6H, s, OCH3); 3.80
(1H, br. s, OH); 4.81 (2H, s, CH2); 6.86 (1H, s, CH). Found, %: C 45.47; H 4.15; N 23.46. C9H10N4O4.
Calculated, %: C 45.38; H 4.23; N 23.52.
3-(4-Dimethylamino-2-methoxy-1,3,5-triazin-6-yl)-5-hydroxymethylisoxazole (3b) was prepared
similarly to compound 3a from compound 1b (2.42 g, 1 mmol). Yield 2.03 g (81%); mp 140-143ºC. IR
spectrum, ν, cm-1: 3346; 3172, 3012, 2933, 2875, 1604, 1592, 1525, 1473, 1415, 1373, 1338, 1261, 1216, 1105,
1066, 1037, 981, 921, 900, 815, 802. 1H NMR spectrum, δ, ppm: 3.19 and 3.27 (6H, two s, ∆ν = 24 Hz, NCH3);
4.00 (3H, s, OCH3); 3.85 (1H, br. s, OH); 4.82 (2H, s, CH2); 6.83 (1H, s, CH). Found, %: C 47.68; H 5.30;
N 27.81. C10H13N5O3. Calculated, %: C 47.81; H 5.22; N 27.87.
5-Hydroxymethyl-3-(2-methoxy-4-pyrrolidinyl-1,3,5-triazin-6-yl)isoxazole (3c) was prepared
similarly to compound 3a from compound 1c (2.68 g, 1 mmol). Yield 2.08 g (75%); mp 184-185ºC (decomp.).
IR spectrum, ν, cm-1: 3347, 3155, 3025, 2973, 2925, 2877, 1587, 1565, 1521, 1473, 1434, 1369, 1336, 1236,
1184, 1164, 1110, 1056, 1039, 981, 912, 844, 819, 804. 1H NMR spectrum, δ, ppm (J, Hz): 2.01 (4H, m, CH2);
1079

2.81 (1H, br. s, OH); 3.63 and 3.72 (4H, two t, J = 7.0, NCH2); 4.06 (3H, s, OCH3); 4.85 (2H, s, CH2); 6.88 (1H,
s, CH). Found, %: C 52.10; H 5.49; N 25.20. C12H15N5O3. Calculated, %: C 51.98; H 5.45; N 25.26.
5-Hydroxymethyl-3-(2-methoxy-4-piperidino-1,3,5-triazin-6-yl)isoxazole (3d) was prepared
similarly to compound 3a from compound 1d (2.82 g, 1 mmol). Yield 2.27 g (78%); mp 125-127ºC (decomp.).
IR spectrum, ν, cm-1: 3330, 3128, 3000, 2933, 2861, 1577, 1521, 1475, 1434, 1375, 1290, 1261, 1226, 1110,
1
1043, 995, 979, 919, 817, 794. H NMR spectrum, δ, ppm (J, Hz): 1.69 (6H, m, CH2); 2.48 (1H, br. s, OH);
3.85 and 3.95 (4H, two t, J = 7.2, NCH2); 4.06 (3H, s, OCH3); 4.83 (2H, s, CH2); 6.89 (1H, s, CH). Found, %:
C 53.48; H 6.01; N 23.97. C13H17N5O3. Calculated, %: C 53.60; H 5.88; N 24.04.
5-Hydroxymethyl-3-(2-methoxy-4-morpholino-1,3,5-triazin-6-yl)isoxazole (3e) was prepared
similarly to compound 3a from compound 1e (2.84 g, 1 mmol). Yield 2.34 g (80%); mp 163-165ºC. IR
spectrum, ν, cm-1: 3300, 3133, 2996, 2929, 2854, 1577, 1523, 1479, 1436, 1378, 1282, 1234, 1112, 1045, 1016,
981, 925, 892, 817, 800. 1H NMR spectrum, δ, ppm: 2.62 (1H, br. s, OH); 3.74 and 3.86 (8H, m, NCH2CH2O);
4.04 (3H, s, OCH3); 4.86 (2H, s, CH2); 6.85 (1H, s, CH). Found, %: C 49.22; H 5.28; N 23.99. C12H15N5O4.
Calculated, %: C 49.14; H 5.16; N 23.88.
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