Synthesis of Caryophyllane Oximes and Hydrazone and Their O- and N-Acylated Derivatives

Article abstract of DOI:10.1007/s10600-021-03286-1

Kobusone oxime and hydrazone were synthesized for the first time in yields of 78 and 71%, respectively, via condensation of the sesquiterpene ketone kobusone, which was prepared by oxidation of caryophyllene oxide, with hydroxylamine and hydrazine. Acylation of the caryophyllane oxime and hydrazone produced series of O- and N-derivatives in preparative yields up to 90%. The molecular structures of the acyloximes and acetylhydrazone were established by X-ray crystal structure analyses.

Full text of DOI:10.1007/s10600-021-03286-1

DOI 10.1007/s10600-021-03286-1
Chemistry of Natural Compounds, Vol. 57, No. 1, January, 2021
SYNTHESIS OF CARYOPHYLLANE OXIMES AND
HYDRAZONE AND THEIR O- AND N-ACYLATED
DERIVATIVES
1*
1
Yu. V. Gyrdymova, S. A. Rubtsova,
2
and P. A. Slepukhin
Kobusone oxime and hydrazone were synthesized for the first time in yields of 78 and 71%, respectively, via
condensation of the sesquiterpene ketone kobusone, which was prepared by oxidation of caryophyllene
oxide, with hydroxylamine and hydrazine. Acylation of the caryophyllane oxime and hydrazone produced
series of O- and N-derivatives in preparative yields up to 90%. The molecular structures of the acyloximes
and acetylhydrazone were established by X-ray crystal structure analyses.
Keywords: caryophyllene oxide, kobusone, oximes, hydrazone, acyloximes.
Oximes and hydrazones are widely used in organic chemistry as synthons to prepare various classes of compounds
[1–8] and in medicinal chemistry as biologically active compounds. For example, several oximes exhibit antifungal [9] and
anticancer properties [10, 11]. O-Alkylated oximes with antifungal, antimicrobial, and anticonvulsant activity are also promising
for research and practical application [10]. Oxime esters of natural compounds, e.g., verbenone, were active against
phytopathogenic fungi Fusarium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piricola, Alternaria
solani, Gibberella zeae, Rhizoctonia solani, Bipolaris maydis, and Colleterichum orbicalare [12]. Carvone oxime ethers
could be used in perfumery as fragrances [13].
Herein, syntheses of oximes and the hydrazone of the sesquiterpene caryophyllene oxide and their esters are reported.
The classical method for preparing oximes is condensation of carbonyl compounds with hydroxylamine. For this,
caryophyllene oxide (1) was oxidized by KMnO in Me CO to the sesquiterpene ketone kobusone (2). Oximation of 2 with
4
2
a ketone–NH OH·HCl mole ratio of 1:1.2 formed 3–5 (Scheme 1).
2
OH
OH
O
O
O
4
6
9
3
a
b
5
8
8
+
+
1
OH
OH
OH
N
O
N
N
H
H
H
H
H
H
H
H
H
H
1
3
4
5
2
a. KMnO , Me CO; b. NH OH⋅HCl, reflux
4
2
2
Scheme 1
The main reaction product was oxime 3. The resonance for quaternary C-8 was shifted in its C NMR spectrum to
13
stronger field (162.3 ppm) as compared to starting epoxyketone 2 (214.0 ppm). The OH proton was recorded in the PMR
spectrum as a singlet at 9.00 ppm.
A chromatographically inseparable mixture of oximes 4 and 5 was formed in addition to 3 during the reaction.
13
The epoxide ring was transformed in 4 and 5 into an OH group and a double bond in the cyclononane moiety. The C NMR
spectrum (Jmod) of the mixture of 4 and 5 showed resonances for C-5 bound to the OH group in the range 70–71 ppm.
1) Institute of Chemistry, Federal Research Center, Komi Scientific Center, Ural Branch, RussianAcademy of Sciences,
48 Pervomaiskaya, Syktyvkar, e-mail: gyrdymova-jw@chemi.komisc.ru; 2) I. Ya. Postovsky Institute of Organic Synthesis,
Ural Branch, RussianAcademy of Sciences, 22 S. Kovalevskaya St., Ekaterinburg, 620137. Translated from Khimiya Prirodnykh
Soedinenii, No. 1, January–February, 2021, pp. 59–64. Original article submitted April 21, 2020.
©
72
0009-3130/21/5701-0072 2021 Springer Science+Business Media, LLC

TABLE 1. Optimization of Conditions for Oximation of Kobusone (2)
Synthesis conditions
Product yields
Synthesis conditions
Product yields
4 + 5 – 47%
EtOH, 5 mol% NaOAc, Na2SO4, reflux
EtOH, Na2SO4, reflux
MeOH, KOH, Na2SO4, reflux
4 + 5 – 74%
3 – 74%, 4 + 5 – 25%
3 – 84%
5 mol% NaOAc, H2O, MeOH, 60°C, 12 h
C6H6, reflux
C6H6, 3 drops Py, reflux
–
–
–
C6H6, 5 mol% NaOAc, reflux
13
The C NMR spectrum (Jmod) of oxime 4 had C-3 and C-4 resonances of the endocyclic double bond at δ 125 and 137 ppm,
respectively. The C-4 and C-14 resonances of the exocyclic C=C bond in 5 were observed at δ 148 and 113 ppm, respectively.
C-5 resonated at δ 70.2 ppm. In general, these were characteristic of the α-betulenol structure. The PMR spectrum of 5
exhibited the resonance of the C-14 terminal methylene as a doublet at 5.30 ppm.
The reaction conditions were varied to increase the selectivity for and yield of 3 (Table 1).
The condensation of kobusone (2) with NH OH⋅HCl was not promoted by using benzene as the solvent. A mixture
2
of 4 and 5 was formed in overall yield 47% with significant polymerization of the reaction mixture if the condensation was
performed in MeOH with added (5 mol%) NaOAc. Replacing the solvent by EtOH increased the yield of hydroxyoximes 4
and 5 to 74%. The formation of 4 and 5 decreased substantially for oximation in EtOH without a catalyst so that the major
condensation product became 3 in 74% yield. Condensation of ketone 2 in MeOH with preliminary treatment of NH OH⋅HCl
2
with KOH produced 3 in preparative yield 84%, 4 and 5 practically not formed in this instance.
Esters 6–9 were synthesized via O-acylation of epoxyoxime 3 (Scheme 2).
14
O
*
O
O
6
25
15
4
a
23
24
1
R =
9
OH
OR
17
18
21
N
N
H
H
H
H
13
20
10
12
3
9, 90%
6 - 9
R = Ac (6) 87%; Bz (7) 84%; p-NO Bz (8) 70%
2
a. RCl, DCM, Et N
3
Scheme 2
The conditions for preparing the acyloximes were optimized using acetylation of kobusone oxime 3 as a model.
Acetylation of 3 in benzene or CH Cl at 0°C gave 6 in 43% yield in both cases. Use of anhydrous CH Cl at 0°C under an Ar
2
2
2
2
atmosphere produced 6 in 87% yield. Esters 7–9 were synthesized under these conditions because this version gave the
maximum acylation yield.
The molecular structures of crystalline acyloximes 6–8 and the E-configuration of the substituents on the C=N bond
were unambiguously proven by X-ray crystal structure analyses (XSAs) (Fig. 1).
Condensation of kobusone (2) with hydrazine hydrate produced hydrazone 10 (90% yield), N-acetylation of which
synthesized 11 in 70% yield (Scheme 3).
14
O
O
O
6
4
a
b
H
N
18
17
NH
1
9
2
O
N
N
H
H
13
H
H
H
H
O
10
2
11, 70%
12
10, 90%
a. NH NH ⋅H O, PhH, reflux; b. AcCl, Et N, PhH
2
2
2
3
Scheme 3
13
The PMR spectrum of 10 gave the NH resonance as a broad singlet at 5.03 ppm. The C NMR spectrum showed the
C=N resonance at 154.1 ppm. The C NMR spectrum of acetylhydrazone 11 exhibited the C-8 C=N resonance at 155.3 ppm.
2
13
The PMR spectrum contained an NH resonance as a singlet at 8.78 ppm.
The molecular structure of 11 was proven by an XSA. A distinguishing feature of the crystal of this compound was
the presence of intermolecular H-bonds between NH groups and acyl O atoms that joined molecules into spiral structures.
In general, the configuration of 11 (Fig. 1) was analogous to those described above for oxime esters 6–9.
73

O1
C20
C6
C19
C5
C21
C16
C16
C4
C7
O2
C18
C3
C15
O3
C14
C17
C15
O2
C8
O3
N1
N1
C7
C2
C1
C8
C9
C10
C9
C6
C13
C10
C14
C11
C5
C12
C11
C1
C12
C4
O1
C13
C2
C3
6
7
C12
C3
C4
C2
C9
C13
C11
O2
C15
C14
C1
C16
C10
O1
C5
C6
N2
N1
N1
C8
C10
C1
C8
C9
O3
C15
C7
C7
C11
O2
C6
C5
C14
C13
C16
C17
C12
C4
C2
C21
C20
C18
C19
C3
O5
N2
O4
11
8
Fig. 1. X-ray molecular structures of acyloximes 6–8 and acetylhydrazone 11.
Thus, kobusone oxime 3 and hydrazone 10 and their acylated derivatives 6–9 and 11 were synthesized for the first
time. The synthesized compounds could be promising for use in organic synthesis as intermediates.
EXPERIMENTAL
IR spectra were recorded from thin layers or KBr pellets on a Shimadzu IR Prestige 21 FT-IR spectrometer. PMR and
13
C NMR spectra were taken in CDCl with residual solvent resonances as internal standards on a Bruker Avance-300
3
1
13
13
spectrometer (300.17 MHz for H and 75.48 MHz for C). C NMR spectra were recorded in J-modulation mode. Resonances
of H and C were fully assigned using 2D homo- ( H– H COSY, H– H NOESY) and heteronuclear experiments
( H– C HSQC, H– C HMBC). Mass spectra were recorded on a Thermo Finnigan LCQ Fleet instrument equipped with an
1
13
1
1
1
1
1
13
1
13
74

MS detector. Masses were scanned in the m/z range 50–2000 (ESI, 10 eV). Melting points were determined on a Gallenkamp
MPD350BM3.5 apparatus (Sanyo) and were uncorrected. Optical rotation angles were measured on a PolAAr 3001 automated
digital polarimeter (Optical Activity, England).
The XSAs were performed on an Xcalibur 3 automated four-circle diffractometer with a CCD detector using the
standard procedure [Mo Kα-radiation, graphite monochromator, ω-scanning in 1° steps, 295(2) K]. Absorption corrections
were made empirically. Anomalous scattering was neglected. The structures were solved and refined using the SHELXL
software [14]. The structures were solved by direct methods using the SHELXS program and refined by anisotropic
2
full-matrix least-squares methods over F for all nonhydrogen atoms. H atoms in C–H bonds were placed in the calculated
positions and refined using a rider model with dependent thermal parameters. N–H hydrogen atoms were isotropically refined
independently.
Data from the XSAs were deposited in the Cambridge Structural Database and can be obtained free upon request to
www.ccdc.cam.ac.uk/data_request/cif.
TLC used Sorbfil plates with detection by vanillin and phosphomolybdic acid. Column chromatography used Alfa
Aesar silica gel (0.06–0.2 mm). The sesquiterpene derivatives were synthesized using commercial (–)-caryophyllene
26
oxide (95%), [α] –70.0° (c 1.0, EtOH) (Sigma-Aldrich). Adamantane-1-carboxylic acid (AdCOOH, 99%) was purchased
D
(Alfa Aesar).
Adamantane-1-carboxylic acid chloride was prepared as before [15].
4,6
(1R,4R,6R,10S)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodcan-9-one (2). Caryophyllene oxide (1, 3 g,
14 mmol) in a mixture of Me CO (36 mL) and H O (2.5 mL) was chilled in ice, stirred, and treated in portions with powdered
2
2
KMnO (7.5 g, 47 mmol). The course of the reaction was monitored by TLC (CHCl eluent). When the reaction was finished,
4
3
the precipitate was filtered off. The filtrate was evaporated in vacuo. The product was chromatographed (CHCl eluent).
3
–1
Yield 40–45%. Colorless oil. IR spectrum (KBr, ν, ñm ): 1695 (C=O). Mass spectrum (ESI, 10 eV), m/z (I , %): 223.08
(100) [M + H] . MÌ 222.3232, C H O . Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.87–0.99 (1H, m, H-3a),
rel
+
1
14 22
2
3
1.02 (6H, s, CH -12, 13), 1.30 (3H, s, CH -14), 1.35–1.75 (5H, m, H-2a, 2b, 6a, 6b, 10a), 1.93 (1H, t, J = 9.7, H-9), 2.20–2.21
3
3
(1H, m, H-10b), 2.30–2.46 (1H, m, H-6b), 2.47–2.59 (1H, m, H-7b), 2.68 (1H, dd, J = 9.8, 4.8, H-5), 3.05 (1H, q, J = 8.8,
13
H-1). C NMR spectrum (75 MHz, CDCl , δ, ppm): 52.58 (CH, C-1), 24.75 (CH , C-2), 39.00 (CH , C-3), 58.91 (C, C-4),
3
2
2
61.62 (CH, C-5), 26.46 (CH , C-6), 37.67 (CH , C-7), 214.08 (C, C-8), 51.33 (CH, C-9), 35.28 (CH , C-10), 34.47 (C, C-11),
2
2
2
22.18 (CH , C-12, 13), 29.30 (CH , C-13, 12), 16.18 (CH , C-14).
3
3
3
4,6
(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-one Oxime (3). Asolution of NH OH⋅HCl
2
(10.80 mmol) in MeOH (20 mL) was treated with KOH (10.80 mmol) and stirred for 10 min. The precipitate was filtered off
(the filtration step could be omitted if the reaction was performed with smaller quantities). The filtrate was treated with
kobusone (2, 9.00 mmol) in MeOH (15 mL) and a small amount of anhydrous Na SO as a dehydrating agent. The mixture
2
4
was refluxed until the reaction was finished (TLC monitoring, petroleum ether–EtOAc eluent, 2:1). The solvent was evaporated.
The solid was extracted with EtOAc. The extract was washed with NaCl solution, dried over Na SO , and evaporated
2
4
in vacuo. The solid was chromatographed over silica gel with elution by petroleum ether–EtOAc (2:1). Yield 84%. Colorless
26
–1
oil, [α] –6.3° (c 0.5, CHCl ). IR spectrum (KBr, ν, ñm ): 3305 (OH), 1460 (C=N). Mass spectrum (ESI, 10 eV), m/z (I , %):
D
3
rel
+
1
238.19 (100) [M + H] . MM 237.3379, C H NO . Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.93–1.02 (1H, m,
14 23
2
3
H-3a), 1.02, 1.03 (3H each, s, CH -12, 13), 1.15 (3H, s, CH -14), 1.34–1.53 (1H, m, H-7a), 1.55–1.80 (4H, m, H-6a, 7b, 10a,
3
3
10b), 1.95 (1H, t, J = 10, H-1), 2.09 (1H, d, J = 12.6, H-3b), 2.25–2.49 (2H, m, H-2a, 6b), 2.55–2.68 (1H, m,
13
H-2b), 2.74–2.51 (2H, m, H-5, 9), 8.97 (1H, br.s, OH). C NMR spectrum (75 MHz, CDCl , δ, ppm): 49.49 (CH, C-1), 23.06
3
(CH , C-2), 38.46 (CH , C-3), 59.76 (C, C-4), 64.23 (CH, C-5), 23.71 (CH , C-6), 26.56 (CH , C-7), 162.30 (C, C-8), 45.90
2
2
2
2
(CH, C-9), 37.68 (CH , C-10), 35.23 (C, C-11), 21.19 (CH , C-12, 13), 29.77 (CH , C-13, 12), 16.04 (CH , C-14).
2
3
3
3
General Method for Acylation of Kobusone Oxime 3. A solution of oxime 3 (0.42 mmol) in dry CH Cl (3 mL)
2
2
was treated dropwise in the cold under a stream of Ar with the acyl chloride (0.42 mmol) and Et N (2 drops) and stirred (TLC
3
monitoring, petroleum ether–EtOAc eluent, 2:1). When the reaction was finished, the mixture was diluted with CH Cl
2
2
(10–15 mL), washed with NaCl solution, dried over Na SO , and evaporated. The solid was chromatographed over silica gel
2
4
with elution by petroleum ether-–Et O (1:1).
2
4,6
(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-one O-Acetyloxime (6). Yield 87%, white
25
–1
powder, mp 166°Ñ, [α] +43.7° (c 0.3, CHCl ). IR spectrum (KBr, ν, ñm ): 1751 (C(O)O-), 1458 (C=N). Mass spectrum
D
3
+
1
(ESI, 10 eV), m/z (I , %): 302.58 (100) [M + Na] . MÌ 279.3746, C H NO . Í NMR spectrum (300 MHz, CDCl , δ,
rel
16 25
3
3
ppm, J/Hz): 0.98–1.00 (1H, m, H-3a), 1.02, 1.03 (3H each, s, CH -12, 13), 1.12 (3H, s, CH -14), 1.36–1.84 (5H, m, H-6a, 7a, 7b,
3
3
75

10a, 10b), 1.98–2.12 (2H, m, H-3b, 9), 2.15 (3H, s, CH -16), 2.25–2.47 (2H, m, H-2a, 6b), 2.74 (1H, ddd,
3
13
J = 12.5, 6.3, 3.5, H-2b), 2.87 (1H, dd, J = 11.2, 3.8, H-5), 3.11 (1H, q, J = 10.15, H-1). C NMR spectrum (75 MHz, CDCl ,
3
δ, ppm): 48.29 (CH, C-1), 23.72 (CH , C-2), 38.05 (CH , C-3), 69.60 (C, C-4), 63.79 (CH, C-5), 24.72 (CH , C-6), 26.21
2
2
2
(CH , C-7), 169.67 (C, C-8), 45.46 (CH, C-9), 37.68 (CH , C-10), 36.01 (C, C-11), 20.86 (CH , C-12, 13), 29.70 (CH , C-13,
2
2
3
3
12), 16.15 (CH , C-14), 168.34 (C, C-15), 19.59 (CH , C-16). A colorless prismatic crystal of the orthorhombic system had
3
3
°
size 0.46 × 0.37 × 0.25 mm, space group P2 2 2 , a = 7.6753(10), b = 11.4677(13), c = 17.900(3) A , α = β = γ = 90°,
V = 1575.5(4) A , Z = 4, μ(Mo Kα) = 0.080 mm . A dataset of 6448 reflections was collected at scattering angles
1 1 1
° 3
–1
3.73° < θ < 30.93°, of which 3859 were independent (R = 0.0457), including 1830 reflections with I > 2σ(I). The final
int
refinement parameters were R = 0.1512, wR = 0.1972 (all data), R = 0.0642, wR = 0.1330 [I > 2σ(I)] with GooF = 1.007.
1
2
1
2
° –3
Δρ = 0.203/–0.187 e A ; Flack parameter = 2(2). CCDC 1991154.
(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-one O-Benzoyloxime (7). Yield 84%,
White powder, mp 132°Ñ, [α] +102.3° (c 0.21, CHCl ). IR spectrum (KBr, ν, ñm ): 1741 (C(O)O-), 1454 (C=N).
e
4,6
25
–1
D
3
+
1
Mass spectrum (ESI, 10 eV), m/z (I , %): 364.69 (100) [M + Na] . MÌ 341.4439, C H NO . Í NMR spectrum (300 MHz,
rel
21 27
3
CDCl , δ, ppm, J/Hz): 0.95–1.08 (1H, m, H-3a), 1.07, 1.08 (3H each, s, CH -12, 13), 1.18 (3H, s, CH -14), 1.37–1.94 (5H, m,
3
3
3
H-6a, 7a, 7b, 10a, 10b), 2.01–2.18 (2H, m, H-1, 6b), 2.35–2.60 (2H, m, H-2a, 3b), 2.84–3.01 (2H, m, H-2b, 5), 3.17–3.33 (1H, m,
13
H-9), 7.42 (2H, t, J = 7.6, H-18, 20), 7.53–7.69 (1H, m, H-19), 7.95–8.09 (2H, m, H-17, 21). C NMR spectrum (75 MHz,
CDCl , δ, ppm): 48.26 (CH, C-1), 23.91 (CH , C-2), 38.08 (CH , C-3), 59.79 (C, C-4), 63.92 (CH, C-5), 24.98 (CH , Ñ-6), 26.27
3
2
2
2
(CH , C-7), 170.71 (C, C-8), 45.59 (CH, C-9), 37.84 (CH , C-10), 36.23 (C, C-11), 20.91 (CH , C-12, 13), 29.77 (CH , C-13, 12),
2
2
3
3
16.26 (CH , C-14), 163.64 (C, C-15), 129.06 (C, C-16), 129.49 (2CH, C-17, 21), 128.60 (2CH, C-18, 20), 133.33 (CH, C-19).
3
A colorless prismatic crystal of the monoclinic system had size 0.44 × 0.37 × 0.28 mm, space group P2 , a = 9.5078(8),
1
°
° 3
–1
b = 10.3720(9), c = 10.0501(8)A, α = γ = 90°, β = 103.621(8)°, V = 963.21(14) A , Z = 2, μ(Mo Kα) = 0.078 mm . A dataset
of 7034 reflections was collected at scattering angles 3.90° < θ < 30.87°, of which 2731 were independent (R = 0.0353),
int
including 1759 reflections with I > 2σ(I). The final refinement parameters were R = 0.0908, wR = 0.1864 (all data),
1
2
° –3
R = 0.0526, wR = 0.1404 [I > 2σ(I)] with GooF = 1.003. Δρ = 0.129/–0.209 e A , Flack parameter = 0. CCDC 1991153.
(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-one O-(4-Nitrobenzoyl)oxime (8). Yield
70%. White powder, mp 144°Ñ (dec.), [α] +97.7° (c 0.13, CHCl ). IR spectrum (KBr, ν, ñm ): 1739 (C(O)O-), 1523
(PhNO ), 1456 (C=N). Mass spectrum (ESI, 10 eV), m/z (I , %): 409.68 (100) [M + Na] . MM 387.4494, C H N O .
Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.96–1.05 (1H, m, H-3a), 1.08, 1.09 (3H each, s, CH -12, 13), 1.18 (3H,
1
2
e
4,6
25
–1
D
3
+
2
rel
21 27 2 5
1
3
3
s, CH -14), 1.42–1.60 (1H, m, H-7a), 1.61–1.80 (2H, m, H-6a, 7b), 1.80–1.94 (2H, m, H-10), 2.06–2.19 (2H, m, H-1, 3b), 2.47
3
(1H, ddd, J = 12.8, 6.5, 3.4, H-6b), 2.51–2.64 (1H, m, H-2a), 2.83–3.02 (2H, m, H-2b, 5), 3.18–3.31 (1H, m, H-9), 8.21 (2H,
13
d, J = 9.1, H-17, 21), 8.33 (2H, d, J = 9.1, H-18, 20). C NMR spectrum (75 MHz, CDCl , δ, ppm): 48.35 (CH, C-1), 24.04
3
(CH , C-2), 37.99 (CH , C-3), 59.71 (C, C-4), 63.65 (CH, C-5), 25.02 (CH , C-6), 26.22 (CH , C-7), 171.91 (C, C-8), 45.50
2
2
2
2
(CH, C-9), 37.84 (CH , C-10), 36.29 (C, C-11), 20.91 (CH , C-12, 13), 29.77 (CH , C-13, 12), 16.26 (CH , C-14), 161.85
2
3
3
3
(C, C-15), 134.50 (C, C-16), 130.57 (2 CH, C-17, 21), 123.79 (2 CH, C-18, 20), 150.72 (C, C-19). A colorless prismatic
crystal of the orthorhombic system had size 0.49 × 0.36 × 0.24 mm, space group P2 2 2 , a = 7.4143(5), b = 11.6984(9),
1 1 1
°
° 3
–1
c = 23.653(2) A, α = β = γ = 90°, V = 2051.5(3) A , Z = 4, μ(Mo Kα) = 0.090 mm . A dataset of 13,958 reflections was
collected at scattering angles 3.59° < θ < 30.94°, of which 3324 were independent (R = 0.0486), including 1927 reflections
int
with I > 2σ(I). The final refinement parameters were R = 0.1053, wR = 0.1904 (all data), R = 0.0536, wR = 0.1425
1
2
1
2
° –3
[I > 2σ(I)] with GooF = 1.003. Δρ = 0.193/–0.172 eA , Flack parameter = 0. CCDC 1991152.
(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatriyclo[8.2.0.0 ]dodecan-9-one O-[(3S,5S,7S)-Adamantyl-1-
carbonyl]oxime (9). Yield 90%. White powder, mp 207–208°Ñ (dec.), [α] +55.2° (c 0.31, CHCl ). IR spectrum (KBr, ν,
cm ): 1761 (C(O)O-), 1454 (C=N). Mass spectrum (ESI, 10 eV), m/z (I , %): 438.82 (63) [M + Na] . MÌ 415.6086,
C H NO . Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.91–1.01 (1H, m, H-3a), 1.04 (6H, s, CH -12, 13), 1.13
e
4,6
25
D
3
–1
+
rel
1
26 41
3
3
3
(3H, s, CH -14), 1.37–1.55 (1H, m, H-6a), 1.56–1.86 (10H, m, 2H-7, 10, 18, 20, 24), 1.96 (6H, br.s, 2H-16, 22, 23), 1.98–2.15
3
(5H, m, H-1, 3b, 17, 19, 21), 2.29–2.48 (2H, m, H-2a, 6b), 2.68–2.70 (1H, m, H-2b), 2.91 (1H, dd, J = 11.0, 3.7, H-5),
13
3.09–3.23 (1H, m, H-9). C NMR spectrum (75 MHz, CDCl , δ, ppm): 48.23 (CH, C-1), 23.72 (CH , C-2), 37.71 (CH ,
3
2
2
C-3), 59.82 (C, C-4), 63.93 (CH, C-5), 24.85 (CH , C-6), 26.22 (CH , C-7), 169.97 (C, C-8), 45.58 (CH, C-9), 38.08 (CH ,
2
2
2
C-10), 36.13 (C, C-11), 20.86 (CH , C-12, 13), 29.71 (CH , C-13, 12), 16.22 (CH , C-14), 40.74 (C, C-15), 38.91 (3 CH ,
3
3
3
2
C-16, 22, 23), 27.85 (3 CH, C-17, 19, 21), 36.29 (3 CH , Ñ-18, 20, 24), 173.98 (C, C-25).
2
4,6
(E)-{(1R,4R,6R,10S)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-ylidene}hydrazine (10). A solution
of kobusone (2, 0.68 mmol) in anhydrous benzene (5 mL) was treated with NH NH ⋅H O (0.68 mmol) and a small amount of
2
2
2
76

anhydrous Na SO as a dehydrating agent. The mixture was refluxed until the reaction was finished (TLC monitoring,
2
4
CHCl –i-PrOH eluent, 50:1), diluted with benzene (15 mL), washed with NaCl solution, dried over Na SO , and evaporated.
3
2
4
The product was purified by column chromatography over silica gel with elution by CHCl –i-PrOH (50:1). Yield 90%. White
3
25
–1
powder, mp 106–107°Ñ, [α] –43.5° (c 0.30, CHCl ). IR spectrum (KBr, ν, ñm ): 3222, 3292 (NH ), 1635, 1456 (C=N).
D
3
2
+
1
Mass spectrum (ESI, 10 eV), m/z (I , %): 237.20 (100) [M + H] . MÌ 236.3531, C H N O. Í NMR spectrum (300 MHz,
rel
14 24 2
CDCl , δ, ppm, J/Hz): 0.90–1.05 (1H, m, H-3a), 1.00, 1.01 (3H each, s, CH -12, 13), 1.22 (3H, s, CH -14), 1.36–1.59 (2H, m,
3
3
3
H-2a, 7a), 1.59–1.94 (4H, m, H-1, 7b, 10a, 10b), 2.10 (1H, dt, J = 12.9, 3.5, H-7b), 2.21–2.39 (2H, m, H-2b, 6a),
13
2.42–2.60 (1H, m, H-6b), 2.66–2.88 (2H, m, H-5, 9), 5.03 (2H, s, NH ). C NMR spectrum (75 MHz, CDCl , δ, ppm): 50.38
2
3
(CH, C-1), 21.87 (CH , C-2), 38.69 (CH , C-3), 59.79 (C, C-4), 63.71 (CH, C-5), 22.88 (CH , C-6), 26.99 (CH , C-7),
2
2
2
2
154.06 (C, C-8), 48.92 (CH, C-9), 37.68 (CH , C-10), 34.52 (C, C-11), 21.45 (CH , C-12, 13), 29.70 (CH , C-13, 12), 15.94
2
3
3
(CH , C-14).
3
4,6
N′-{(1R,4R,6R,10S,E)-4,12,12-Trimethyl-5-oxatricyclo[8.2.0.0 ]dodecan-9-ylidene}acetohydrazide (11).
A solution of hydrazone 10 (100 mg, 0.42 mmol) in anhydrous benzene (5 mL) and Et N (2 drops) was treated dropwise with
3
AcCl (0.42 mmol) and stirred at room temperature. When the reaction was finished, the mixture was diluted with benzene
(15 mL), washed with NaCl solution and H O, dried over Na SO , and evaporated in vacuo. The solid was chromatographed
2
2
4
25
with elution by CHCl –i-PrOH (50:2). Yield 70%, White powder, mp 155°Ñ, [α] –41.1° (c 0.10, CHCl ). IR spectrum
(KBr, ν, ñm ): 3190 (NH), 1674 (C=O), 1456 (C=N). Mass spectrum (ESI, 10 eV), m/z (I , %): 279.51 (100) [M + H] .
MÌ 278.3898, C H N O . Í NMR spectrum (CDCl , δ, ppm, J/Hz): 0.90–1.00 (1H, m, H-3a), 1.03, 1.04 (3H each, s,
3
D
3
–1
+
rel
1
16 26
2
2
3
CH -12, 13), 1.19 (3H, s, CH -14), 1.33–1.58 (2H, m, H-2a, 7a), 1.61–1.80 (2H, m, H-7b, 10a), 1.81–1.97 (2H, m, H-1, 6b),
3
3
2.04–2.18 (1H, m, H-3b), 2.27 (3H, s, CH -18), 2.23–2.40 (2H, m, H-2b, 6a), 2.52–2.88 (1H, m, H-6b), 2.69–2.85 (2H, m,
3
13
H-5, 9), 8.78 (1H, s, NH). C NMR spectrum (CDCl , δ, ppm): 51.06 (CH, C-1), 22.91 (CH , C-2), 38.71 (CH , C-3),
3
2
2
59.42 (C, C-4), 62.69 (CH, C-5), 24.44 (CH , C-6), 26.69 (CH , C-7), 155.32 (C, C-8), 48.74 (CH, C-9), 37.78 (CH ,
2
2
2
Ñ-10), 34.36 (C, C-11), 21.70 (CH , C-12, 13), 29.84 (CH , C-13, 12), 15.93 (CH , C-14), 173.61 (C, C-17), 20.45 (CH ,
3
3
3
3
Ñ-18). Acolorless prismatic crystal of the monoclinic system had size 0.48 × 0.41 × 0.37 mm, space group C2, a = 17.8793(19),
°
° 3
–1
b = 7.1832(6), c = 13.5585(11)A, α = γ = 90°, β = 109.651(10)°, V = 1639.9(3) A , Z = 4, μ(Mo Kα) = 0.074 mm . A dataset
of 6159 reflections was collected at angles 3.65° < θ < 30.91°, of which 2456 were independent (R = 0.0334), including
int
1683 with I > 2σ(I). The final refinement parameters were R = 0.0774, wR = 1487 (all data), R = 0.0466, wR = 0.1166
1
2
1
2
° –3
[I > 2σ(I)] with GooF = 1.003. Δρ = 0.119/–0.155 eA , Flack parameter = 0. CCDC 1991151.
e
ACKNOWLEDGMENT
The work was financially supported by the RFBR (Project 18-33-00846 mol_a) and used equipment at the Khimiya
Common Use Center, Institute of Chemistry, Federal Research Center, Komi Scientific Center, Ural Branch, RAS.
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