Formation of the dinitro-3H-pyrazole derivative of cycloartemisiaketone oxime

Article abstract of DOI:10.1023/B:CONC.0000033928.00722.fa

(3aR*,6aR*)-3,3,5,5-Tetramethyl-3a,6a-dinitro-3a, 6a-dihydro-3H-cyclopentano[c]pyrazol-2-oxide was formed by reaction of cycloartemisiaketone oxime [4,4-dimethyl-2-(1-methylethylidene)cyclopentanone oxime] with AcOH and NaNO₂ in CHCl₃ solution. The structure was solved by x-ray structure analysis.

Full text of DOI:10.1023/B:CONC.0000033928.00722.fa

Chemistry of Natural Compounds, Vol. 40, No. 2, 2004
FORMATION OF THE DINITRO-3H-PYRAZOLE DERIVATIVE
OF CYCLOARTEMISIAKETONE OXIME
E. M. Suleimenov,1 G. A. Atazhanova,1 A. T. Kulyyasov,1
V. A. Raldugin,2 I. Yu. Bagryanskaya,2 Yu. V. Gatilov,2
M. M. Shakirov,2 and S. M. Adekenov1
UDC 547.913+548.737
*
*
(3aR ,6aR )-3,3,5,5-Tetramethyl-3a,6a-dinitro-3a,6a-dihydro-3H-cyclopentano[c]pyrazol-2-oxide was
formed by reaction of cycloartemisiaketone oxime [4,4-dimethyl-2-(1-methylethylidene)cyclopentanone
oxime] with AcOH and NaNO in CHCl solution. The structure was solved by x-ray structure analysis.
2
3
Key words: artemisiaketone, cycloartemisiaketone, dinitro-3H-pyrazole derivative N-oxide, X-raystructure analysis.
The monoterpenoid artemisiaketone is the principal component of the essential oil of
L. (annual
Artemisia annua
wormwood),
L. (common tansy), and other Asteraceae species [1]. Artemisiaketone is an acyclic
Tanacetum vulgare
monoterpene and has an irregular fusion of isoprene units. This molecule has two double bonds, monosubstituted and
trisubstituted, with the latter conjugated to the ketone. The presence of such reaction centers was proved by various chemical
transformations and total syntheses of artemisiaketone [2-4].
In order to synthesize new N-containing derivatives based on available monoterpenoids, we continued the study of
chemical transformations of3,3,6-trimethylhepta-1,5-dien-4-one, a component ofcertain essential oils[1]thatweusedin a two-
step synthesis of 3H-pyrazole derivative 1 [4]. We attempted to prepare by the same method an analogous compound from
cycloartemisiaketone 2, a known derivativeofacidic cyclization ofartemisiaketone [5, 6], in order tostudyits biological activity.
O
NO
2
6
N
N
1
6a
3a
5
O
N
N
O
4
3
R
NO
2
2, 3
2: R = O; 3: R = NOH
1
4
The product of the first synthetic step was oxime 3, which was smoothly formed under conditions analogous to those
in the literature [4]. Treatment of 3 with AcOH in CHCl in the presence of NaNO gave a mixture of products, only one of
3
2
which was easily isolated using adsorption chromatography and crystallization. According to high-resolution mass
spectrometry, the fragment peak from the isolated product with the highest / value corresponded to the empirical formula
m z
C H N O . The presence of the third N atom made it impossible to propose a structure so an x-ray structure analysis was
10 16
3 3
performed. As it turned out, the structure of the isolated product has formula 4 (Fig. 1).
1) Institute of Phytochemistry, Ministry of Education and Science of the Republic of Kazakhstan, Republic of
Kazakhstan, 470032, Karaganda, ul. Gazalieva 4, fax (3212) 43 37 73, e-mail: arglabin@phyto.kz; 2) Novosibirsk Institute of
OrganicChemistry, Siberian Division, Russian AcademyofSciences, 630090, Novosibirsk, pr. Akad. Lavrent′eva, 9, fax (3832)-
34-47-52, e-mail: raldugin@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 115-117, March-April,
2004. Original article submitted February 4, 2004.
0009-3130/04/4002-0134 ©2004 Plenum Publishing Corporation
134

C 7
O 2
C 4
C 9
N 3
C 3A
C 3
C 8
C 5
C 10
O 1
O 3
N 2
O 4
C 6A
C 6
N 1
O 5
N 4
Fig. 1. Crystal structure of the dinitropyrazole
derivative of artemisiaketone 4 from XSA.
We did not find any report of the formation of such dinitro compounds under analogous conditions. We managed to
isolate only the N-oxide and not the N,N′-dioxide like in known transformations of 3H-pyrazole derivatives of oximes of two
other monoterpene ketones, artemisiaketone [4] and pulegone [7].
EXPERIMENTAL
Melting points were determined on a Boetius apparatus. IR spectra were obtained on a Vector 22 instrument; UV
1
spectra, on a Specord UV-VIZ; NMR spectra, on a DRX-500 (Bruker) spectrometer (working frequency 500.13 MHz for H;
13
125.76 MHz, C, δ-scale). High-resolution mass spectra (EI, 70 eV) were recorded on a Finnigan MAT 8200 instrument.
Column chromatographywas performed on SiO (Armsorbsil 200/400, Aldrich) with a compound:sorbent ratio~1:20. Weused
2
Silufol plates for TLC with development by spraying with vanillin in H SO (1% solution) and aqueous KMnO solution.
2
4
4
Owing to the low content of 1 in essential oil of A. annua, we prepared it by vacuum distillation of the lipophilic
fractions of the extract of annual wormwood which, in turn, were a side product from column chromatographic isolation of the
sesquiterpene lactone artemisinin. Raw A. annua was collected at the beginning of August 2000 in Almaty district. According
to GC-MS, the artemisiaketone content was 5.1%, which is sufficient for its isolation. Lipophilic fractions containing
artemisiaketone were combined, separated by fractional distillation, and purified as necessary by column chromatography.
Starting artemisiaketone was also isolated from essential oil of T. vulgare [1]. Ketone 2 was obtained from
artemisiaketone by the literature method [5].
4,4-Dimethyl-2-(1-methylethylidene)cyclopentanone (2). Yellow oil, UV spectrum (EtOH, λ , nm): 252
max
(logε 4.30) (lit. [5] λ
251.5, log ε 4.30).
max
-1
IR spectrum (CCl , ν, cm ): 2957, 2928, 2866, 1817, 1771, 1711 (C=O), 1636 (C=C), 1462, 1410, 1369, 1311, 1266,
4
1223, 1194, 1163, 1069, 1032, 968, 893, 804.
4
PMR spectrum (δ, ppm, J/Hz, CCl +CDCl , 1:1): 2.19 (2H, t, J = 2.0, 2H-5), 2.37 (2H, narrowm, 2H-3), 2.13 (3H,
4
3
3,5
br.s, 3H-8), 1.79 (3H, br.s, 3H-7), 1.07 (6H, s, 2Me-4).
4,4-Dimethyl-2-(1-methylethylidene)cyclopentanone Oxime (3). A solution of 2 (0.96 g, 6.3 mmol) in pyridine
(5 mL) was treated with ground hydroxylamine hydrochloride (0.53 g, 7.6 mmol). The resulting mixture was refluxed for
30 min, cooled, treated with EtOAc (20 mL), washed with HCl (50 mL, 3%) and water (20 mL), and dried over Na SO . After
2
4
solvent was removed, the solid was recrystallized from petroleum ether to afford 3 (0.97 g, 92%) as colorless needles, mp 105-
106°C. UV spectrum (EtOH, λ , nm): 250 (log ε 4.00).
max
-1
IR spectrum (CCl , ν, cm ): 3291, 3114, 2954, 1665, 1617, 1462, 1443, 1273, 1234, 1215, 1046, 926, 910, 727, 624.
4
+
+
Mass spectrum (m/z, I , %): 167 (49) [M] , 152 (100) [M - CH3] , 100 (52), 94 (51), 85 (43), 77 (13), 67 (38), 57 (21), 43 (36),
rel
41 (43). Found, m/z: 167.13197; calc. for C H NO, 167.1310.
10 17
135

PMR spectrum (δ, ppm, CDCl ): 8.78 (1H, br.s, NOH), 2.42 (2H, br.s, 2H-5), 2.22 (2H, m, 2H-3), 2.01 (3H, br.s,
3
3H-8), 1.76 (3H, br.s, 3H-7), 1.02 (6H, s, 2Me-4).
13
C NMR spectrum: singlets at 34.55 (C-4), 128.95 (C-6), 133.71 (C-2), 163.22 (C-1); triplet at 46.19 (C-3 and C-5);
quartets at 22.74, 23.85, and 28.75 (2C).
*
*
(3aR ,6aR )-3,3,5,5-Tetramethyl-3a,6a-dinitro-3a,6a-dihydro-3H-cyclopentano[c]-pyrazol-2-oxide (4). Astirred
solution of oxime 3 (0.97 g, 5.8 mmol) in CHCl (10 mL) was treated with powdered NaNO (1.9 g, 29 mmol) at room
3
2
temperature, stirred further, and treated with AcOH (3 mL) in small portions over 1 h. The reaction mixture was diluted with
EtOAc (25 mL), washed with saturated NaHCO solution (25 mL) and water (10 mL), and dried over Na SO . Solvent was
3
2
4
removed in vacuum. The solid (1 g) was chromatographed over SiO with elution by petroleum ether and its mixture with
2
EtOAc (EtOAc content from 0 to 50%). The fraction that was eluted by the mixture with 50% EtOAc was evaporated to afford
-1
cubic colorless crystals, mp 120-121°C, yield 0.54 g (34%). IR spectrum (CCl , ν, cm ): 2961, 2875, 1625, 1557 (NO ), 1375,
4
2
+
1347, 1319, 1282, 1242, 1215, 1167, 1006, 952, 856, 797, 738, 707, 682. Mass spectrum (m/z, I , %): 226 (13) [M - NO ] ,
180 (49) [M - 2NO ] , 150 (100) [M - 2NO - NO] , 134 (6), 108 (23), 94 (29), 82 (15), 67 (29), 55 (19), 45 (23), 41 (31), 31
rel
2
+
+
2
2
+
(46). Found, m/z: 226.11342 [M - NO ] ; calc. for C H N O , 226.11916.
2
10 16 3 3
PMR spectrum (δ, ppm, J/Hz, CDCl ): 2.82 (H, d, J = 15.0, H-6B), 2.73 (H, dd, J = 15.0, J = 2.0, H-6A),
4B,6A
3
AB
AB
2.70 (H, dd, J = 19.0, J
= 2.0, H-4B), 2.35 (1H, d, J = 19.0, H-4A), 1.84 and 1.75 (both s, 3H each, 2Me-3), 1.20 and
AB
AB
4B,6A
0.89 (both s, 3H each, 2Me-5).
13
C NMR spectrum (ppm): singlets at 34.85, 45.04, 120.72, and 158.81; triplets at 41.74 (C-4) and 49.07 (C-6);
quartets at 23.78 and 24.29 (2CH -C-3), 28.35 and 30.68 (2CH -C-5).
3
3
X-ray structure analysis was performed on a Syntex P2 diffractometer (Cu Kα-radiation with graphite
1
monochromator). Intensities of reflections were measured by 2θ/θ-scanning. Absorption was calculated empirically using
ϕ-scans. The structure was solved by direct methods using the SHELXS-97 program. Structure factors were refined over all
2
F by full-matrix anisotropic (isotropic for H atoms) least-squares methods using the SHELXL-97 program.
3
Crystals of 4 are monoclinic: a = 15.198(2), b = 8.2980(8), c = 20.247(3) Å, β = 94.383(17) , V = 2545.9(6) Å , space
-3
-1
group C2/c, Z = 8, C H N O , M = 272.27, d = 1.421 g·cm , λ = 1.54178 Å, µ = 0.981 mm , transmission 0.625-1.000,
10 16
4 5
2408 independent reflections with 2θ < 140°, wR = 0.1243, S = 1.062, 237 parameters (R = 0.0445 for 2064 F > 4σ).
2
0
Coordinates and equivalent thermal factors for nonhydrogen atoms of 4 were deposited in the Cambridge Structural
Database.
ACKNOWLEDGMENT
The work was supported by the Ministry of Education and Science of the Republic of Kazakhstan (Basic Research
Program Grant F0185). We thank the Russian Foundation for Basic Research for obtaining the license for the Cambridge
Structural Database (project No. 02-07-90322).
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1.
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