3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)oxazolidines and 3-(4,5-dihydro-1H- pyrazol-1-ylmethyl)perhydro-1,3-oxazines

Article abstract of DOI:10.1134/S1070428007070147

3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)oxazolidines and 3-(4,5-dihydro-1H- pyrazol-1-ylmethyl)perhydro-1,3-oxazines were synthesized in 54-85% yield by reactions of α-amino alcohols and 3-aminopropan-1-ol, respectively, with formaldehyde and 4,5-dihydro-1H-pyrazoles.

Full text of DOI:10.1134/S1070428007070147

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 7, pp. 1027–1029. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © B.F. Kukharev, V.K. Stankevich, N.A. Lobanova, G.R. Klimenko, E.Kh. Sadykov, 2007, published in Zhurnal Organicheskoi Khimii,
2007, Vol. 43, No. 7, pp. 1033–1035.
3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)oxazolidines
and 3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)perhydro-
1,3-oxazines
B. F. Kukharev, V. K. Stankevich, N. A. Lobanova, G. R. Klimenko, and E. Kh. Sadykov
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: irk_inst_chem@irioch.irk.ru
Received September 5, 2006
Abstract—3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)oxazolidines and 3-(4,5-dihydro-1H-pyrazol-1-ylmethyl)per-
hydro-1,3-oxazines were synthesized in 54–85% yield by reactions of α-amino alcohols and 3-aminopropan-1-
ol, respectively, with formaldehyde and 4,5-dihydro-1H-pyrazoles.
DOI: 10.1134/S1070428007070147
Acetals and their N,O- and N,N-analogs exhibit
versatile biological activity and are intermediate prod-
ucts in fine organic synthesis [1]. The same applies to
4,5-dihydropyrazoles [2]. Obviously, compounds con-
taining an N,N- or N,O-acetal moiety and a 4,5-dihy-
dropyrazole fragment in a single molecule attract
interest from the viewpoint of studying their biological
activity. The present communication reports on the
synthesis of such compounds.
was complete (water no longer separated), 4,5-dihy-
dropyrazole IIIa–IIIc and an additional amount of
paraformaldehyde were added, and the mixture was
heated again. At an amino alcohol–formaldehyde–di-
hydropyrazole ratio of 1:2:1, the yields of compounds
IVa–IVh ranged from 54 to 85%. The reactions were
accompanied by formation of symmetric aminals as
by-products. For exampe, fractional distillation of the
reaction mixture obtained from amino alcohol Ia,
formaldehyde, and dihydropyrazole IIIb gave com-
pound IVb as the major product and previously de-
scribed compounds V and VI [3, 4] in 5 and 7% yield,
respectively (Scheme 2). The structure of compounds
Initially, amino alcohols Ia–Ic were brought into
condensation with formaldehyde to obtain oxazoli-
dines IIa and IIb and perhydro-1,3-oxazine IIc
(Scheme 1). The reactions were carried out by heating
the reactants in benzene under reflux with simultane-
ous removal of water as azeotrope. When the reaction
1
IVa–IVh and VI was confirmed by IR and H NMR
spectroscopy and elemental analysis.
Scheme 1.
R
R
R
R
( )n
O
+
CH2O
HO
( )n
HN
NH2
Ia–Ic
IIa–IIc
Me
R
R
R'
R'
N
N
( )n
IIa–IIc
+
CH2O
+
N
R'
Me
N
O
N
H
R'
IIIa–IIIc
IVa–IVh
I, II, n = 1, R = H (a), Me (b); n = 2, R = H (c); III, R′ = H (a), Me (b), Et (c); IV, n = 1 (a–e), 2 (f–h); R = R′ = H (a, f);
R = H, R′ = Me (b, g); R = H, R′ = Et (c, h); R = Me, R′ = H (d), R = R′ = Me (e).
1027

KUKHAREV et al.
1028
Scheme 2.
1320, 1355, 1375, 1425, 1455, 1615, 2865, 2880, 2910,
2920, 2935, 2955, 2965, 3020. H NMR spectrum, δ,
1
N
N
2Ia
+
CH2O
ppm: 1.16 s (6H, 5′-CH3), 1.94 s (3H, 3′-CH3), 2.43 s
3
O
O
(2H, 4′-H), 3.14 t (2H, 4-H, J = 6.9 Hz), 3.61 s (2H,
V
3
NCH2N), 3.72 t (2H, 5-H, J = 6.9 Hz), 4.44 s (2H,
Me
Me
2-H). Found, %: C 61.36; H 10.11; N 21.48.
Me
Me
C10H19N3O. Calculated, %: C 60.88; H 9.71; N 21.30.
N
N
2IIIb
+
CH2O
3-(3,5-Diethyl-5-methyl-4,5-dihydro-1H-pyrazol-
1-ylmethyl)oxazolidine (IVc). Yield 70%, bp 164–
169°C (18 mm), d420 = 1.0274, nD20 = 1.5028. IR spec-
trum, ν, cm–1: 460, 545, 575, 600, 665, 720, 780, 845,
865, 890, 910, 925, 960, 995, 1050, 1085, 1090, 1130,
1210, 1300, 1360, 1370, 1430, 1455, 1615, 2875, 2930,
N
N
Me
Me
VI
EXPERIMENTAL
1
2965. H NMR spectrum, δ, ppm: 0.89 m (3H,
The IR spectra were recorded on a Specord 75IR
spectrophotometer from samples prepared as thin films
(neat). The 1H NMR spectra were measured at 26°C on
a Bruker DPX-400 instrument (400 MHz) from solu-
tions in CDCl3 using HMDS as internal reference.
5′-CH2CH3), 1.08 m (6H, 3′-CH2CH3, 5′-CH3), 1.61 m
(2H, 5′-CH2), 1.85–2.54 m (4H, 3′-CH2, 4′-H), 3.15 m
(2H, 4-H), 3.59–3.73 m (4H, 5-H, NCH2N), 4.39 d
2
2
(1H, 2-H, J = 6.1 Hz), 4.46 d (1H, 2-H, J = 6.1 Hz).
Found, %: C 64.04; H 10.27; N 18.69. C12H23N3O.
Calculated, %: C 63.96; H 10.29; N 18.65.
3-(4,5-Dihydro-1H-pyrazol-1-ylmethyl)oxazoli-
dines IVa–IVe and 3-(4,5-dihydro-1H-pyrazol-1-yl-
methyl)perhydro-1,3-oxazines IVf–IVh (general
procedure). A mixture of 0.1 mol of amino alcohol Ia–
Ic and 0.1 mol of paraformaldehyde in 100 ml of ben-
zene was heated under reflux in a flask equipped with
a Dean–Stark trap until water no longer separated.
Dihydropyrazole IIIa–IIIc, 0.1 mol, and an additional
amount of paraformaldehyde, 0.1 mol, were added,
and the mixture was again heated under reflux until
water no longer separated. The products were isolated
by vacuum distillation.
4,4-Dimethyl-3-(5-methyl-4,5-dihydro-1H-pyra-
zol-1-ylmethyl)oxazolidine (IVd). Yield 61%, bp 126–
129°C (9 mm), d420 = 1.0208, nD20 = 1.4850. IR spec-
trum, ν, cm–1: 430, 450, 470, 505, 530, 575, 615, 680,
730, 755, 805, 840, 860, 875, 890, 920, 935, 955,
1005, 1030, 1055, 1090, 1120, 1140, 1155, 1170, 1195,
1240, 1260, 1315, 1330, 1350, 1365, 1400, 1420, 1445,
1
1490, 1650, 2830, 2860, 2920, 2955, 3045. H NMR
spectrum, δ, ppm: 1.11–1.28 m (9H, CH3), 2.29 m (1H,
4′-H), 2.82 m (1H, 4′-H), 3.36–3.52 m (3H, 5′-H, 5-H),
3.93 d (1H, NCH2N, 2J = 12.5 Hz), 4.01 d (1H, NCH2,
2J = 12.5 Hz), 4.48 m (2H, 2-H), 6.64 m (1H, 3′-H).
Found, %: C 60.04; H 10.14; N 21.47. C10H19N3O.
Calculated, %: C 60.88; H 9.71; N 21.30.
3-(5-Methyl-4,5-dihydro-1H-pyrazol-1-ylmeth-
yl)oxazolidine (IVa). Yield 65%, bp 131-134°C
(25 mm), d420 = 1.0940, nD20 = 1.5010. IR spectrum, ν,
cm–1: 440, 540, 600, 620, 660, 675, 715, 735, 765, 815,
860, 900, 920, 945, 990, 1025, 1045, 1090, 1125, 1140,
1155, 1205, 1245, 1270, 1300, 1350, 1425, 1445, 1645,
4,4-Dimethyl-3-(3,5,5-trimethyl-4,5-dihydro-1H-
pyrazol-1-ylmethyl)oxazolidine (IVe). Yield 69%,
bp 124–127°C (5 mm), d420 = 0.9845, nD20 = 1.4793. IR
spectrum, ν, cm–1: 460, 475, 530, 560, 590, 645, 655,
670, 700, 710, 745, 780, 825, 850, 885, 895, 930, 945,
1020, 1030, 1065, 1100, 1130, 1160, 1205, 1220, 1235,
1255, 1320, 1355, 1365, 1420, 1430, 1460, 1620, 2800,
1
2735, 2875, 2930, 2955, 3055. H NMR spectrum, δ,
ppm: 1.16 d (3H, CH3, 3J = 6.4 Hz), 2.17 m (1H, 4′-H),
2.68 m (1H, 4′-H), 2.95–3.26 m (3H, 5′-H, 4-H),
2
3.72 m (2H, 5-H), 3.81 d (1H, NCH2N, J = 12.0 Hz),
2
3.97 d (1H, NCH2N, J = 12.0 Hz), 3.99 d (1H, 2-H,
1
2J = 10.4 Hz), 4.17 d (1H, 2-H, J = 10.4 Hz), 6.54 m
2
2810, 2870, 2910, 2930, 2970. H NMR spectrum, δ,
ppm: 1.12 s and 1.17 s (3H each, 4-CH3), 1.22 s and
1.24 s (3H each, 5′-CH3), 1.91 s (3H, 3′-CH3), 2.43 s
(2H, 4′-H), 3.63 s (2H, 5-H), 3.81 s (2H, NCH2N),
4.61 s (2H, 2-H). Found, %: C 63.41; H 10.18;
N 18.29. C12H23N3O. Calculated, %: C 63.96; H 10.29;
N 18.65.
(1H, 3′-H). Found, %: C 56.12; H 8.91; N 24.84.
C8H15N3O. Calculated, %: C 56.78; H 8.93; N 24.83.
3-(3,5,5-Trimethyl-4,5-dihydro-1H-pyrazol-1-yl-
methyl)oxazolidine (IVb). Yield 54%, bp 89–93°C
(1 mm), d420 = 1.0446, nD20 = 1.4995. IR spectrum, ν,
cm–1: 475, 480, 530, 560, 605, 650, 655, 715, 760, 780,
825, 860, 895, 925, 935, 945, 960, 985, 995, 1025,
1055, 1090, 1130, 1140, 1160, 1200, 1220, 1240, 1300,
3-(5-Methyl-4,5-dihydro-1H-pyrazol-1-ylmeth-
yl)perhydro-1,3-oxazine (IVf). Yield 64%, bp 128–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

3-(4,5-DIHYDRO-1H-PYRAZOL-1-YLMETHYL)OXAZOLIDINES
1029
2
130°C (12 mm), d420 = 1.0474, nD20 = 1.4931. IR spec-
trum, ν, cm–1: 435, 460, 495, 520, 535, 615, 645, 670,
730, 760, 780, 785, 810, 830, 865, 895, 940, 965,
1020, 1040, 1085, 1120, 1150, 1165, 1185, 1230, 1245,
1265, 1315, 1325, 1340, 1350, 1370, 1425, 1440, 1620,
10.1 Hz), 4.53 d (1H, 2-H, J = 10.1 Hz). Found, %:
C 65.11; H 10.55; N 17.46. C13H25N3O. Calculated, %:
C 65.23; H 10.53; N 17.56.
Bis(oxazolidin-3-yl)methane (V) was isolated by
vacuum distillation of the reaction mixture in the
synthesis of compound IVb. Yield 5%, bp 105–107°C
(11 mm), d420 = 1.0731, nD20 = 1.4851; published data
[3]: bp 108–110°C (12 mm), nD20 = 1.4890. Found, %:
C 53.45; H 8.81; N 17.55. C7H14N2O. Calculated, %:
C 53.15; H 8.92; N 17.71.
1
2835, 2840, 2955, 3050. H NMR spectrum, δ, ppm:
1.26 d (3H, 5′-CH3, 3J = 6.1 Hz), 1.65 m (2H, 5-H),
2.28 m (1H, 4′-H), 2.81 m (1H, 4′-H), 2.98–3.07 m
(3H, 5′-H, 4-H), 3.35–3.57 m (2H, 6-H), 3.95 d (1H,
2
2
NCH2N, J = 12.3 Hz), 4.19 d (1H, NCH2N, J =
2
12.3 Hz), 4.36 d (1H, 2-HO, J = 8.2 Hz), 4.47 d (1H,
2-H, J = 8.2 Hz), 6.66 m (1H, 3′-H). Found, %:
2
Bis(3,5,5-trimethyl-4,5-dihydro-1H-pyrazol-1-
yl)methane (VI) was isolated by vacuum distillation
of the reaction mixture in the synthesis of compound
IVb. Yield 7%, bp 122–124°C (1 mm), d420 = 0.9651,
nD20 = 1.4921 [4]. IR spectrum, ν, cm–1: 470, 530, 555,
630, 640, 675, 705, 740, 770, 815, 850, 890, 910, 915,
940, 975, 1000, 1015, 1085, 1125, 1155, 1210, 1230,
1310, 1345, 1355, 1375, 1420, 1450, 1545, 1610, 2825,
C 58.85; H 9.34; N 22.53. C9H17N3O. Calculated, %:
C 58.99; H 9.35; N 22.93.
3-(3,5,5-Trimethyl-4,5-dihydro-1H-pyrazol-1-yl-
methyl)perhydro-1,3-oxazine (IVg). Yield 85%,
bp 99–102°C (2 mm), d420 = 1.0200, nD20 = 1.4863. IR
spectrum, ν, cm–1: 450, 465, 495, 530, 555, 620, 645,
665, 690, 710, 745, 765, 780, 790, 805, 820, 835, 865,
890, 900, 940, 975, 1030, 1080, 1100, 1130, 1160,
1185, 1205, 1225, 1280, 1295, 1315, 1345, 1370, 1425,
1
2860, 2875, 2900, 2925, 2955. H NMR spectrum, δ,
ppm: 1.24 s (12H, 5-CH3), 1.91 s (6H, 3-CH3), 2.43 s
(4H, 4-H), 4.18 s (2H, NCH2N). Found, %: C 66.40;
H 10.44; N 23.75. C13H24N4. Calculated, %: C 66.06;
H 10.23; N 23.70.
1
1450, 1615, 2840, 2900, 2930, 2950. H NMR spec-
trum, δ, ppm: 1.19 s (6H, 5′-CH3), 1.64 m (2H, 5-H),
1.92 s (3H, 3′-CH3), 2.43 s (2H, 4′-H), 3.10 m (2H,
4-H), 3.82–3.95 m (4H, 6-H, NCH2N), 4.51 s (2H,
2-H). Found, %: C 62.70; H 10.38; N 19.53.
C11H21N3O. Calculated, %: C 62.52; H 10.02; N 19.89.
REFERENCES
1. Yanovskaya, L.A., Yufit, S.S., and Kucherov, V.F.,
Khimiya atsetalei (Chemistry of Acetals), Moscow:
Nauka, 1975; Rakhmankulov, D.L., Zorin, V.V., Latypo-
va, F.N., Zlotskii, S.S., and Karakhanov, R.A., Khim.
Geterotsikl. Soedin., 1982, p. 435.
3-(3,5-Diethyl-5-methyl-4,5-dihydro-1H-pyrazol-
1-ylmethyl)perhydro-1,3-oxazine (IVh). Yield 76%,
bp 138–142°C (5 mm), d420 = 0.9988, nD20 = 1.4902. IR
spectrum, ν, cm–1: 475, 505, 540, 555, 605, 635, 655,
680, 715, 725, 795, 810, 850, 880, 900, 915, 950, 990,
1040, 1045, 1060, 1100, 1110, 1165, 1175, 1200, 1235,
1290, 1310, 1340, 1365, 1380, 1435, 1460, 1620, 2860,
2. Kost, A.N. and Ershov, V.V., Usp. Khim., 1958, vol. 27,
p. 431.
3. Eggensperger, H. and Diehl, K.H., FRG Patent
no. 2 635 389, 1976; Chem. Abstr., 1978, vol. 88,
no. 170125.
1
2880, 2945, 2970. H NMR spectrum, δ, ppm: 0.89 m
(3H, 5′-CH2CH3), 1.05 m (6H, 3′-CH2CH3, 5′-CH3),
1.61–2.53 m (8H, 5′-CH2, 5-H, 3′-CH2, 4′-H), 3.10 m
(2H, 4-H), 3.82–3.94 m (3H, 6-H, NCH2N), 3.95 d
4. Voronkov, M.G., Dmitrieva, Z.T., Shergina, N.I., Ata-
vin, A.S., Mamedova, L.V., and Kukharev, B.F., Zh. Prikl.
Spektrosk., 1973, vol. 19, p. 449.
2
2
(1H, NCH2N, J = 11.3 Hz), 4.46 d (1H, 2-H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007