Synthetic transformations of higher terpenoids: XXIV.* synthesis of cyanoethyl derivatives of lupane triterpenoids and their transformation into 1,2,4-oxadiazoles

Article abstract of DOI:10.1134/S1070428011040208

Cyanoethylation of lupane triterpenoids was performed. Amide oximes of 3β-O-(2-cyanoethyl)- betulinic acid methyl ester and 3β-O-acetyl-28-O- (2-cyanoethyl)betulin and the corresponding O-[2-(1,2,4-oxadiazol- 3-yl)ethyl] lupane derivatives were obtained. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011040208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 4, pp. 589–601. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.N. Antimonova, N.V. Uzenkova, N.I. Petrenko, M.M. Shakirov, E.E. Shul’ts, G.A. Tolstikov, 2011, published in Zhurnal
Organicheskoi Khimii, 2011, Vol. 47, No. 4, pp. 586–596.
Synthetic Transformations of Higher Terpenoids:
XXIV.* Synthesis of Cyanoethyl Derivatives of Lupane
Triterpenoids and Their Transformation into 1,2,4-Oxadiazoles
A. N. Antimonova, N. V. Uzenkova, N. I. Petrenko, M. M. Shakirov,
E. E. Shul’ts, and G. A. Tolstikov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: schultz@nioch.nsc.ru
Received June 1, 2010
Abstract—Cyanoethylation of lupane triterpenoids was performed. Amide oximes of 3β-O-(2-cyanoethyl)-
betulinic acid methyl ester and 3β-O-acetyl-28-O-(2-cyanoethyl)betulin and the corresponding O-[2-(1,2,4-oxa-
diazol-3-yl)ethyl] lupane derivatives were obtained.
DOI: 10.1134/S1070428011040208
Pentacyclic triterpenoids of the lupane series attract
researchers’ attention as substrates for synthetic trans-
formations due to their accessibility, as well as due to
pharmacological importance of some semisynthetic
derivatives which are often available via relatively
simple modifications. In the past decade, particular
emphasis was put on such pharmacological properties
of lupane derivatives as antiviral (HIV-1) and anti-
tumor activity [2]. While developing our studies on the
transformations of plant metabolites produced by Sibe-
Scheme 1.
29
CH2
CH2
30
Me
20
13
Me
21
H2C=CHCN
19
17
12
26
22
dioxane, BTEAC
30% KOH, 20°C, 2 h
18
11
25
31 32 33
CH2OCH2CH2CN
28
Me
Me
Me
Me
CH2OH
14 16
1
4
9
6
2
3
10
8
7
Me15
Me
5
27
AcO
AcO
2M3 e Me
Me Me
24
I
II
CH2
CH2
Me
Me
Me
Me
Me
Me
CH2OCH2CH2CN
CH2OCH2CH2CN
Me
Me
36 35 34
HO
NCCH2CH2O
Me Me
Me Me
III
IV
* For communication XXIII, see [1].
589

ANTIMONOVA et al.
590
Scheme 2.
CH2
CH2
Me
Me
Me
Me
H2C=CHCN
dioxane, BTEAC
30% KOH, 20°C
NC
Me
Me
NC
CH2OH
CH2OCH2CH2CN
Me
Me
O
O
Me Me
Me Me
V
VI
CH2
CH2
Me
Me
Me
Me
H2C=CHCN
dioxane, BTEAC
30% KOH, 20°C
NC
O
O
Me
Me
NC
OMe
OMe
Me
Me
O
O
Me Me
Me Me
VII
VIII
rian flora [3], we examined cyanoethylation of triter-
penoids of the lupane series with a view to obtain
homologous derivatives which can be used in the syn-
thesis of polyamines, peptides, and various hetero-
cycles. Cyanoethylation of 3β-O-acetylbetulin (I) hav-
ing a primary hydroxy group on C28 with acrylonitrile
smoothly afforded the corresponding cyanoethyl deriv-
ative II (Scheme 1). The reaction was carried out at
room temperature in dioxane or methylene chloride in
the presence of alkali and benzyl(triethyl)ammonium
chloride (BTEAC). Addition of BTEAC to the reaction
mixture made it possible to considerably shorten the
reaction time (from 24 h [4] to 2–3 h) and improve the
purity of the product. When the reaction was carried
out in the absence of BTEAC, long reaction time
(24 h) favored formation (though insignificant) of by-
products III and IV as a result of hydrolysis of the
acetate moiety.
3-Oxobetulin (V) reacted with acrylonitrile under
analogous conditions to give compound VI which was
isolated as the only product in 84% yield (Scheme 2).
In this case, cyanoethylation of the 28-OH group was
accompanied by introduction of two cyanoethyl groups
into the α-position with respect to the C3=O group,
which is consistent with published data [5]. In the re-
action with betulonic acid methyl ester (VII), 2,2-bis-
(cyanoethyl) derivative VIII was obtained in 60%
yield. Compounds VI and VIII attract interest, taking
into account that some 2-cyanolupane derivatives were
found to exhibit high cytotoxic activity against a num-
ber of tumor cells [6].
The reaction of acrylonitrile with 3-oxobetulin
oxime (IX) involved both alcoholic and oxime groups,
and the product was di-O-(2-cyanoethyl) derivative X
(yield 85%, Scheme 3).
Scheme 3.
CH2
CH2
Me
Me
Me
H2C=CHCN
dioxane, BTEAC
30% KOH, 20°C
Me
Me
Me
CH2OH
CH2OCH2CH2CN
Me
Me
HO
O
N
NC
N
Me Me
Me Me
IX
X
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
591
Scheme 4.
CH2
Me
PCC, CH2Cl2
20°C, 3 h
4N NaOH, MeOH–THF
20°C, 24 h
II
III
Me
Me
CH2OCH2CH2CN
Me
O
Me Me
XI
CH2
Me
H2C=CHCN
NH2OH · HCl, EtOH
pyridine, 20°C, 6 days
dioxane, BTEAC
30% KOH, 20°C, 2 h
X
Me
Me
CH2OCH2CH2CN
Me
HO
N
Me Me
XII
3-Oxo and 3-hydroxyimino lupane derivatives
which cannot be obtained by direct cyanoethylation of
the corresponding betulin derivatives V and IX were
synthesized by chemical modification of 3-O-acetyl-
28-O-(2-cyanoethyl)betulin (II) (Scheme 4). Alkaline
hydrolysis of compound II by the action of 4 M NaOH
in a mixture of methanol and tetrahydrofuran at room
temperature smoothly afforded 96% of 3-hydroxy
derivative III which was oxidized to 3-oxo derivative
XI (yield 91%) with pyridinium chlorochromate (PCC)
in methylene chloride. Ketone XI was treated with hy-
droxylamine hydrochloride in ethanol in the presence
of pyridine at room temperature to obtain the corre-
sponding oxime XII in almost quantitative yield.
Oxime XII reacted with acrylonitrile in dioxane in the
presence of alkali and BTEAC at room temperature to
give 87% of X. The latter was identical to the product
obtained by cyanoethylation of IX (Scheme 3).
anoethyl) derivatives III/IV and XXI/XXII. Longer
reaction time, elevated temperature, or increased
amount of acrylonitrile did not ensure complete con-
version of the 3-OH group, which was consistent with
our preliminary data on the cyanoethylation of betulin
(XIX) [4]. The conversion of the secondary hydroxy
group ranged from 45 to 75%, depending on the reac-
tion conditions and structure of the initial compound.
Cyanoethylation of 28-O-acetylbetulin (XXIII)
under standard conditions gave compound XXIV in
64% yield; in addition, compounds III, IV, and XIX
were formed in 5, 9, and 22% yield, respectively
(according to the GC–MS data), as a result of partial
hydrolysis of the ester group and subsequent cyano-
ethylation. The yield of XXIV increased to 88% when
the reaction was carried out in methylene chloride
instead of dioxane (Scheme 6).
Successful synthesis of cyano derivatives of the
lupane series both via cyanoethylation of appropriate
triterpenoids and by chemical transformations of com-
pounds already having a cyanoethyl group prompted
us to perform their further modifications. We were in-
terested in synthesizing heterocyclic lupane derivatives
possessing an 1,2,4-oxadiazole substituent. Introduc-
tion of this structural fragment into molecules of tri-
terpenoids seemed to be promising from the viewpoint
of biological activity. It is known that compounds
containing an 1,2,4-oxadiazole fragment exhibit anti-
phlogistic, antiviral, and other kinds of pharmacolog-
Cyanoethylation of compounds having a secondary
hydroxy group on C3 (dioxane, 30% KOH, BTEAC,
20°C) always resulted in the formation of a mixture of
products whose composition depended on the substit-
uent on C28 (Scheme 5). In the reactions with com-
pounds XIII–XV, cyanoethylation products XVI–
XVIII were formed in 45, 53, and 57% yield, respec-
tively; the conversion was not complete, and the initial
compounds were present in the reaction mixtures.
Cyanoethylation of betulin (XIX) and betulinaldehyde
oxime (XX) gave mixtures of mono- and di-O-(2-cy-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ANTIMONOVA et al.
592
Scheme 5.
CH2
CH2
Me
Me
Me
Me
H2C=CHCN, dioxane
BTEAC, 30% KOH
Me
Me
R
R
Me
Me
NC
HO
O
Me Me
XIII–XV
Me Me
XVI–XVIII
CH2
Me
H2C=CHCN, dioxane
BTEAC, 30% KOH
III
+
IV
Me
Me
CH2OH
(14%)
(75%)
Me
HO
Me Me
XIX
CH2
CH2
CH2
Me
Me
Me
Me
H2C=CHCN
dioxane, BTEAC
30% KOH
+
Me
Me
Me
Me
Me
N
N
N
Me
Me
Me
OH
OR
OR
HO
HO
RO
Me Me
Me Me
Me Me
XXII (45%)
XX
XXI (35%)
XIII, XVI, R = CHO; XIV, XVII, R = HOCO; XV, XVIII, R = MeOCO; XXI, XXII, R = NCCH2CH2.
ical activity [7]. The key precursors of 1,2,4-oxadi-
azoles are amide oximes which are generally prepared
by reaction of nitriles with hydroxylamine hydro-
chloride in the presence of bases [8]. However, by
treatment of lupane nitrile II with hydroxylamine
hydrochloride under standard conditions we obtained
only ~10% of the corresponding amide oxime. We
succeeded in improving the yield of amide oxime
XXV to 55% by carrying out the reaction of nitrile II
with hydroxylamine as free base in butyl alcohol (in-
stead of ethanol). The reaction of XXV with benzoyl
chloride in the presence of pyridine, followed by
Scheme 6.
CH2
CH2
Me
Me
Me
H2C=CHCN
III
+
IV
+
XIX
+
Me
Me
Me
CH2OAc
CH2OAc
Me
Me
NC
HO
O
Me Me
Me Me
XXIV
XXIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
593
Scheme 7.
CH2
CH2
Me
Me
Me
(1) PhCOCl, CH2Cl2
pyridine
(2) PhH, 80°C
Ph
N
NH2OH, BuOH
60°C, 24 h
5′
O
N
II
Me
Me
Me
3′
O
O
Me
Me
12′
N
13′
AcO
AcO
OH
H2N
Me Me
Me Me
XXV
XXVI
Scheme 8.
CH2
Me
Me
NH2OH, BuOH
60°C, 24 h
XVIII
OMe
Me
HO
N
O
Me
H2N
O
Me Me
XXVII
CH2
Me
Me
(CF3CO)2O, CH2Cl2
OMe
Me
O
N
O
Me
F3C
N
O
Me Me
XXVIII
heating in benzene afforded 59% of 1,2,4-oxadiazole
XXVI (Scheme 7). Likewise, amide oxime XXVII ob-
tained from nitrile XVIII smoothly reacted with tri-
fluoroacetic anhydride in methylene chloride at room
temperature to produce oxadiazole XXVIII in 85%
yield (Scheme 8).
region 1650–1660 cm–1 due to stretching vibrations of
the C=N bond.
1
The NH2 protons resonated in the H NMR spectra
of amide oximes XXV and XXVII at δ 5.00–
1
5.05 ppm. Complete assignment of signals in the H
and 13C NMR spectra was made using two-dimensional
proton–proton and carbon–proton correlation tech-
niques with account taken of published data for betulin
The structure of the isolated compounds was con-
firmed by their elemental compositions and IR, NMR,
and mass spectra. The IR spectra of the cyanoethyl
derivatives contained an absorption band in the region
2200–2252 cm–1 due to stretching vibrations of the
C≡N group. In the 1H NMR spectra of the products we
observed characteristic signals from the 3-H, 28-H,
and 29-H protons, as well as signals typical of protons
in the CH2CH2CN group. The IR spectra of amide
oximes XXV and XXVII and oxadiazoles XXVI and
XXVIII lacked C≡N absorption band at 2200–
2252 cm–1, but an absorption band appeared in the
1
and its derivatives [9]. The H and 13C NMR spectra
of oxime XII, as well as of 3-(2-cyanoethoxyimino)-
lupane derivative XI indicated that these compounds
were formed as a single isomer with respect to the
1
C=N bond. Compound XII displayed in the H NMR
spectrum one one-proton signal at δ 9.30 ppm. E-Con-
figuration of the double C=N bond followed from
comparison of the chemical shifts of C2 and C4 in the
13C NMR spectra of XI and XII and the corresponding
carbonyl compound. The C2 signal of XI and XII ap-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ANTIMONOVA et al.
594
pears in a considerably stronger field (ΔδC ≈ 16 ppm)
relative to the C2 signal of 3-oxo analog, while the
difference in the chemical shifts of C4 does not exceed
6.0 ppm. These findings suggest that the N–OH group
is oriented toward C2 (E isomer) rather than C4 (Z).
Compounds XXI and XXII having a 2-cyanoethoxy-
imino group on C28 were also formed as a single
were measured on a Kofler hot stage. The progress of
reactions and the purity of products were monitored by
TLC on Silufol UV-254 plates using chloroform–
acetonitrile (15:1) as eluent; spots were developed by
spraying with 20% sulfuric acid and subsequent heat-
ing to 100°C. Aluminum oxide was used as sorbent for
column chromatography.
1
isomer. In the H NMR spectra of XXI and XXII, the
Betulin (XIX) was isolated by extraction of Betula
pendula Roth birch bark. 3β-O-Acetylbetulin (I) and
betulonic acid were synthesized as described in [10],
betulinic acid and its methyl ester were prepared as
reported in [11], and triterpenoid oximes were obtained
according to [12].
28-H proton resonated as a singlet at δ 7.50–7.51 ppm
(cf. δ 7.51 ppm for initial oxime XX), which corre-
sponds to E configuration of the double C28=N bond.
The 13C NMR spectra of heterocyclic derivatives
XXVI and XXVIII contained singlets at δC 164.08,
169.76 (C3′) and 65.49, 65.82 ppm (C5′), respectively,
which are typical of 1,2,4-oxadiazole ring.
28-O-(2-Cyanoethyl)lup-20(29)-en-3β-yl acetate
(II). A mixture of 1.0 g (2.07 mmol) of compound I,
2.7 ml (41.4 mmol) of acrylonitrile, 0.23 g (1.06 mmol)
of BTEAC, and 2.7 ml of 30% KOH in 25 ml of
dioxane was stirred for 2 h at room temperature under
argon. The mixture was poured into a mixture of ice
with hydrochloric acid, the precipitate was filtered off,
washed with water until neutral washings, dried in air,
and dissolved in methylene chloride, the solution was
filtered, and the filtrate was evaporated. Yield 1.07 g
(97%). An analytical sample was obtained by chroma-
tography on aluminum oxide using hexane–chloroform
(1:1) as eluent; mp 135–137°C (from methanol);
[α]D20 = +23° (c = 1.32, CHCl3). IR spectrum, ν, cm–1:
2251 (C≡N), 1730 (C=O, ester). 1H NMR spectrum, δ,
ppm (J, Hz): 0.75 m (1H, 5-H), 0.80 s (9H, C23H3,
C24H3, C25H3), 0.92 s (3H, C27H3), 0.94–0.96 m (1H,
1-H), 0.99 s (3H, C26H3), 1.00–1.04 m (3H, 12-H,
15-H, 22-H), 1.11–1.21 m (2H, 11-H, 16-H), 1.23–
1.29 m (1H, 9-H), 1.31–1.41 m (5H, 6-H, 7-H, 11-H,
21-H), 1.44–1.54 m (2H, 6-H, 18-H), 1.55–1.63 m
(6H, 1-H, 2-H, 12-H, 13-H, 15-H), 1.64 s (3H, C30H3),
1.84–1.96 m (3H, 16-H, 21-H, 22-H), 1.99 s (3H,
C35H3), 2.31–2.38 m (1H, 19-H), 2.55 t (2H, 32-H, J =
6.4), 3.13 d and 3.54 d (1H each, 28-H, J = 8.8), 3.61 t
(2H, 31-H, J = 6.5), 4.43 d.d (1H, 3-H, J = 10.4, 4.8),
4.54 br.s and 4.63 br.s (1H each, 29-H). 13C NMR
spectrum, δC, ppm: 14.53 q (C27), 15.79 q (C26),
15.95 q (C25), 16.29 q (C24), 17.96 t (C6), 18.64 t (C32),
18.70 q (C30), 20.63 t (C11), 21.08 q (C35), 23.48 t (C2),
24.92 t (C12), 26.95 t (C15), 27.73 q (C23), 29.63 t (C21),
29.67 t (C16), 33.91 t (C7), 34.48 t (C22), 36.84 s (C10),
37.33 d (C13), 37.57 s (C4), 38.16 t (C1), 40.70 s (C8),
42.45 s (C14), 47.10 s (C17), 47.77 d (C19), 48.51 d
(C18), 50.06 d (C9), 55.14 d (C5), 65.98 t (C31), 69.58 t
(C28), 80.65 d (C3), 109.48 t (C29), 117.70 s (C33),
150.20 s (C20), 170.69 s (C34). Mass spectrum:
EXPERIMENTAL
The IR spectra were recorded in KBr on a Bruker
Vector-22 spectrometer. The NMR spectra were meas-
ured from solutions in CDCl3 on Bruker AV-300
1
(300.13 MHz for H and 75.47 MHz for 13C) and AV-
1
400 instruments (400.13 MHz for H and 100.78 MHz
for 13C). Multiplicities of signals in the 13C NMR
spectra were determined using standard J-modulation
(JMOD) technique with off-resonance decoupling
from protons. The two-dimensional H–1H (COSY)
1
and 13C–1H NMR spectra (HXCO 125 Hz, COLOC
7 Hz) were recorded on a Bruker DRX-500 spectrom-
1
eter (500.13 MHz for H and 125.76 MHz for 13C)
from solutions in CDCl3 using standard Bruker proce-
dures. The chemical shifts were determined relative to
the carbon and residual proton signals of the solvent
(CDCl3, δC 76.90; CHCl3, δ 7.24 ppm). The mass
spectra (electron impact, 70 EV) were obtained on
a Finnigan MAT 8200 high-resolution mass spectrom-
eter. The specific optical rotations [α]D20 were measured
on Polamat A and PolAAr3005 polarimeters in chloro-
form at room temperature (20–25°C). The product
mixture obtained by cyanoethylation of compound
XXIII was analyzed by gas chromatography–mass
spectrometry on a Hewlett–Packard HP 5890 Series II
chromatograph coupled with an HP 5971 quadrupole
mass-selective detector (HP-5MS quartz capillary col-
umn, 30 m×0.25 mm, 5% diphenyl–95% dimethyl-
polysiloxane, film thickness 0.25 μm; oven tempera-
ture programming from 50 to 280°C at a rate of 4 deg×
min–1, 15 min at 280°C). The components were quan-
titated by peak areas with no correction factors.
The elemental compositions were determined on
a Carlo Erba 1106 CHN analyzer. The melting points
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
595
m/z 537.41814 [M]+. Found, %: C 78.15; H 10.50;
N 2.68. C35H55NO3. Calculated, %: C 78.16; H 10.31;
N 2.61. M 537.31817.
(C24), 25.33 t (C12), 29.40 t (C15), 29.40 q (C23), 30.38 t
(C21), 31.87 t (C16), 32.19 t (C7), 32.56 t and 37.22 t
(C31, C34), 36.64 s (C10), 36.74 t (C22), 38.13 d (C13),
40.36 s (C8), 42.40 s (C14), 45.91 s (C4), 46.74 d (C19),
48.00 s (C2), 49.16 d (C18), 49.69 d (C9), 51.00 d (C5),
51.15 q (C37), 51.48 t (C1), 56.32 s (C17), 109.60 t
(C29), 118.51 s and 119.31 s (C33, C36), 150.15 s (C20),
176.39 s (C28), 218.51 s (C3). Mass spectrum: m/z
574.4138 [M]+. C37H54N2O3. Calculated: M 574.4129.
2,2,28-O-Tris(2-cyanoethyl)lup-20(29)-en-3-one
(VI). A mixture of 0.3 g (0.68 mmol) of compound V,
0.89 ml (1.36 mmol) of acrylonitrile, 0.072 g
(0.34 mmol) of BTEAC, and 0.89 ml of 30% KOH in
10 ml of dioxane was stirred for 7 h at room tempera-
ture under argon. The mixture was then poured into
a mixture of ice with hydrochloric acid, and the precip-
itate was filtered off, washed with water until neutral
washings, dried in air, and purified by chromatography
on Al2O3 using hexane–chloroform (1:1) as eluent.
Yield 0.34 g (84%), mp 116–118°C. IR spectrum, ν,
3-[3-(2-Cyanoethoxyimino)lup-20(29)-en-28-yl-
oxy]propanenitrile (X). A mixture of 1 g (1.78 mmol)
of compound IX, 0.19 g (0.89 mmol) of BTEAC,
2.3 ml (35.65 mmol) of acrylonitrile, and 2.3 ml of
30% KOH in 25 ml of dioxane was stirred for 2 h at
room temperature under argon. The mixture was
poured into a mixture of ice with hydrochloric acid, the
precipitate was filtered off, washed with water until
neutral washings, dried in air, and washed with meth-
ylene chloride, the washings were evaporated, and the
residue was subjected to chromatography on aluminum
oxide using hexane–chloroform (1:1) as eluent. Yield
1.05 g (85%), mp 127–131°C, [α]D20 = +9° (c = 3.6,
CDCl3). IR spectrum, ν, cm–1: 2250 (C≡N), 1641
1
cm–1: 2249 (C≡N), 1689 (C=O). H NMR spectrum
(only characteristic signals are given), δ, ppm (J, Hz):
0.67 s (3H, C25H3), 0.99 s (3H, C26H3), 1.01 s (3H,
C27H3), 1.05 s (3H, C24H3), 1.11 s (3H, C23H3), 1.65 s
(3H, C30H3), 2.57 t (2H, 32-H, J = 6.2), 3.15 d (1H,
28-H, J = 8.3), 3.56 t (1H, 28-H, J = 8.6), 4.55 br.s and
4.65 br.s (1H each, 29-H). 13C NMR spectrum, δC,
ppm: 12.23 t and 12.36 t (C35, C38), 14.61 q (C25),
15.25 q (C27), 17.53 q (C26), 18.80 t (C32), 18.96 q
(C30), 20.05 t (C6), 21.60 t (C11), 24.97 q (C24), 25.04 t
(C12), 26.97 t (C15), 29.63 t (C21), 29.67 t (C16), 30.02 q
(C23), 32.21 t and 32.44 t (C34, C37), 34.58 t (C22),
36.65 s (C10), 37.27 t (C7), 37.55 d (C13), 40.62 s (C8),
42.74 s (C14), 46.00 s (C17), 47.18 s (C4), 47.81 d (C19),
48.06 t (C2), 48.47 d (C18), 49.52 d (C9), 50.98 d (C5),
51.49 t (C1), 66.12 t (C31), 69.70 t (C28), 109.80 t (C29);
117.90 s, 118.60 s, and 119.46 s (C33, C36, C39); 150.15 s
(C20), 218.64 s (C3). Mass spectrum: m/z 599.4567
[M]+. C39H57N3O2. Calculated: M 599.4589.
1
(C=C). H NMR spectrum (only characteristic signals
are given), δ, ppm (J, Hz): 0.86 s (3H, CH3), 0.92 s
(3H, CH3), 0.99 s (3H, CH3), 1.01 s (3H, CH3), 1.02 s
(3H, CH3), 1.63 s (3H, C30H3), 2.21 (1H, 2-H), 2.34 m
(1H, 19-H), 2.55 t (2H, 32-H, J = 6.3), 2.64 t (2H,
35-H, J = 6.3), 2.79 d.t (1H, 2-H, J = 4.2, 13.9), 3.13 d
and 3.54 d (1H each, 28-H, J = 8.6), 3.61 t (2H, 31-H,
J = 6.3), 4.15 t (2H, 34-H, J = 6.3), 4.53 br.s and
4.63 br.s (1H each, 29-H). 13C NMR spectrum, δC,
ppm: 14.48 q (C27), 15.53 q (C26), 15.68 q (C25), 17.80 t
(C2), 18.13 t (C32), 18.61 t (C35), 18.83 t (C6), 18.86 q
(C30), 20.93 t (C11), 22.78 q (C24), 24.98 t (C12), 26.94 t
(C15), 27.03 q (C23), 29.63 t (C21), 29.68 t (C16), 33.51 t
(C7), 34.47 t (C22), 36.85 s (C10), 37.40 d (C13), 38.41 t
(C1), 40.05 s (C4), 40.71 s (C8), 42.50 s (C14), 47.10 s
(C17), 47.71 d (C19), 48.48 d (C18), 49.68 d (C9),
47.10 d (C5), 65.98 t (C34), 67.08 t (C31), 69.60 t (C28),
109.47 t (C29), 117.72 s (C33), 118.33 s (C36), 150.13 s
(C20), 167.91 s (C3). Mass spectrum: m/z 561.42574
[M]+. C36H55N3O2. Calculated: M 561.42940.
Methyl 2,2-bis(2-cyanoethyl)-3-oxolup-20(29)-
en-28-oate (VIII). A mixture of 0.5 g (1.07 mmol) of
compound VII, 1.40 ml (21.37 mmol) of acrylonitrile,
0.11 g (0.54 mmol) of BTEAC, and 1.4 ml of
30% KOH in 10 ml of dioxane was stirred for 7 h at
room temperature under argon. The mixture was then
poured into a mixture of ice with hydrochloric acid and
treated as described above. Yield 0.4 g (60%),
mp 109–111°C, [α]D20 = +17.4° (c = 2.38, CHCl3). IR
spectrum, ν, cm–1: 2248 (C≡N), 1725 (C=O, ester),
1
1689 (C=O). H NMR spectrum (only characteristic
Hydrolysis of 28-O-(2-cyanoethyl)lup-20(29)-en-
3β-yl acetate (II). A solution of 0.20 g (0.37 mmol) of
compound II in a mixture of 2 ml of THF and 4 ml of
methanol was cooled to 0°C, 0.4 ml (1.6 mmol) of
a 4 M solution of sodium hydroxide was added under
argon, and the mixture was kept for 24 h at room tem-
perature and poured into a mixture of ice with hydro-
chloric acid. The precipitate was filtered off, washed
signals are given), δ, ppm: 0.65 s (3H, C25H3), 0.89 s
(3H, C26H3), 0.97 s (3H, C27H3), 1.03 s (3H, C24H3),
1.10 s (3H, C23H3), 1.65 s (3H, C30H3), 2.95 m (1H,
19-H), 3.63 s (3H, C37H3), 4.56 br.s and 4.70 br.s (1H
each, 29-H). 13C NMR spectrum, δC, ppm: 12.16 t and
12.29 t (C32, C35), 14.46 q (C25), 15.15 q (C27), 17.47 q
(C26), 19.20 q (C30), 20.00 t (C6), 21.61 t (C11), 22.89 q
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ANTIMONOVA et al.
596
with water, and dried in air. Yield of 3-[3β-hydroxylup-
20(29)-en-28-yloxy]propanenitrile (III) 0.18 g (96%),
mp 200–202°C (from methanol), [α]D20 = +9.1° (c =
1.32, CHCl3) (cf. [4]). IR spectrum: ν 2200 cm–1
24.80 t (C12), 26.32 q (C23), 26.80 t (C15), 29.44 t (C21),
29.50 t (C16), 33.10 t (C7), 33.81 t (C2), 34.36 t (C22),
36.51 s (C10), 37.29 d (C13), 39.25 t (C1), 40.48 s (C8),
42.38 s (C14), 46.96 s (C17), 46.99 s (C4), 47.59 d (C19),
48.29 d (C18), 49.35 d (C9), 54.47 d (C5), 65.84 t (C31),
69.36 t (C28), 109.45 t (C29), 117.75 s (C33), 150.04 s
(C20), 217.81 s (C3). Mass spectrum: m/z 493.39156
[M]+. C33H51NO2. Calculated: M 493.39196.
1
(C≡N). H NMR spectrum, δ, ppm (J, Hz): 0.63 m
(1H, 5-H), 0.70 s (3H, C24H3), 0.77 s (3H, C25H3),
0.80–0.89 m (1H, 1-H), 0.91 s (6H, C23H3, C27H3),
0.99 s (3H, C26H3), 1.00–1.06 m (3H, 12-H, 15-H,
22-H), 1.08–1.18 m (2H, 11-H, 16-H), 1.19–1.24 m
(1H, 9-H), 1.28–1.39 m (5H, 6-H, 7-H, 11-H, 21-H),
1.45–1.65 m (8H, 1-H, 2-H, 6-H, 12-H, 13-H, 15-H,
18-H), 1.62 s (3H, C30H3), 1.83–1.94 m (3H, 16-H,
21-H, 22-H), 2.30–2.36 m (1H, 19-H), 2.55 t (2H,
32-H, J = 6.5), 3.09–3.14 m (2H, 3-H, 28-H), 3.52 d
(1H, 28-H, J = 8.6), 3.59 t.d (2H, 31-H, J = 6.5, 1.6),
4.52 br.s and 4.62 br.s (1H each, 29-H). 13C NMR
spectrum, δC, ppm: 14.52 q (C27), 15.16 q (C24),
15.73 q (C26), 15.85 q (C25), 18.02 t (C6), 18.58 t (C32),
18.65 q (C30), 20.55 t (C11), 24.89 t (C12), 26.89 t (C15),
27.08 t (C2), 27.74 q (C23), 29.57 t (C21), 29.60 t (C16),
33.92 t (C7), 34.42 t (C22), 37.85 s (C10), 37.26 d (C13),
38.43 t (C1), 38.57 s (C4), 40.61 s (C8), 42.38 s (C14),
47.03 s (C17), 47.67 d (C19), 48.44 d (C18), 50.07 d
(C9), 54.98 d (C5), 65.89 t (C31), 69.47 t (C28), 78.55 d
(C3), 109.41 t (C29), 117.72 s (C33), 150.16 s (C20).
Mass spectrum: m/z 495.40688 [M]+. C33H53NO2. Cal-
culated: M 495.40761.
28-O-(2-Cyanoethyl)lup-20(29)-en-3-one oxime
(XII). Compound IX, 0.40 g (0.81 mmol), was dis-
solved in 13 ml of ethanol, 0.11 g (1.58 mmol) of
hydroxylamine hydrochloride, and 2.6 ml of pyridine
were added, and the mixture was kept for 6 days at
room temperature with intermittent stirring. The mix-
ture was then poured into a mixture of ice with hydro-
chloric acid, and the precipitate was filtered off,
washed with water, and dried in air. Yield 0.39 g
(96%), mp 197–203°C, [α]D20 = –3° (c = 4.84, CDCl3).
IR spectrum, ν, cm–1: 2252 (C≡N), 1641 (C=C).
1H NMR spectrum (only characteristic signals are
given), δ, ppm (J, Hz): 0.89 s (3H, CH3), 0.92 s (3H,
CH3), 1.02 s (6H, CH3), 1.11 s (3H, CH3), 1.64 s (3H,
C30H3), 2.22 m (1H, 2-H), 2.35 m (1H, 19-H), 2.57 t
(2H, 32-H, J = 6.4), 2.95 d.t (1H, 2-H, J = 14.4, 4.1),
3.14 d and 3.55 d (1H each, 28-H, J = 8.9), 3.62 t (2H,
31-H, J = 6.4), 4.54 br.s and 4.64 br.s (2H, 29-H),
9.30 br.s (1H, NOH). 13C NMR spectrum, δC, ppm:
14.47 q (C27), 15.62 q (C26), 15.75 q (C25), 17.00 t (C2),
18.67 t (C32), 18.73 t (C6), 18.83 q (C30), 20.91 t (C11),
22.69 q (C24), 24.97 q (C12), 26.93 t (C15), 27.05 q
(C23), 29.61 t (C21), 29.66 t (C16), 33.58 t (C7), 34.49 t
(C22), 37.00 s (C10), 37.39 d (C13), 38.56 t (C1), 40.17 s
(C4), 40.72 s (C8), 42.49 s (C14), 47.12 s (C17), 47.75 d
(C19), 48.47 d (C18), 49.75 d (C9), 55.29 d (C5), 65.99 t
(C31), 69.58 t (C28), 109.52 t (C29), 117.76 t (C33),
150.21 s (C20), 166.72 s (C3). Mass spectrum:
m/z 508.40324 [M]+. C33H52N2O2. Calculated:
M 508.40286.
28-O-(2-Cyanoethyl)lup-20(29)-en-3-one (XI).
Pyridinium chlorochromate, 2.90 g (13.46 mmol), was
added under argon to 100 ml of anhydrous methylene
chloride, the solution was stirred for 10 min at room
temperature, and 2.22 g (4.48 mmol) of compound III
was added. The mixture was stirred for 2.5 h at room
temperature and filtered through a thin layer of Al2O3,
and the filtrate was evaporated. Yield 2.02 g (91%),
mp 160–163°C, [α]D20 = +45° (c = 4.3, CHCl3). IR
spectrum, ν, cm–1: 2249 (C≡N), 1705 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 0.85 s (3H, C25H3), 0.91 s
(3H, C27H3), 0.95 s (3H, C24H3), 0.99 s (6H, C26H3,
C23H3), 0.99–1.07 m (3H, 12-H, 15-H, 22-H), 1.09–
1.15 m (1H, 16-H), 1.16–1.21 m (1H, 21-H), 1.23–
1.28 m (1H, 5-H), 1.28–1.42 m (8H, 1-H, 6-H, 7-H,
9-H, 11-H), 1.48 t (1H, 18-H, J = 11.7), 1.55–1.64 m
(3H, 5-H, 12-H, 13-H), 1.60 s (3H, C30H3), 1.78–
1.95 m (4H, 1-H, 16-H, 21-H, 22-H), 2.29–2.36 m
(2H, 2-H, 19-H), 2.37–2.45 m (1H, 2-H), 2.55 t (2H,
32-H, J = 6.4), 3.10 d and 3.52 d (1H each, 28-H, J =
8.8), 3.59 t (1H, 31-H, J = 6.4), 4.50 br.s and 4.61 br.s
(1H each, 29-H). 13C NMR spectrum, δC, ppm: 14.39 q
(C27), 15.47 q (C26), 15.68 q (C25), 18.56 t (C32),
18.77 q (C30), 19.31 t (C6), 20.73 q (C24), 21.01 t (C11),
Cyanoethylation of 28-O-(2-cyanoethyl)lup-
20(29)-en-3-one oxime (XII). A mixture of 0.2 g
(0.39 mmol) of compound XII, 0.2 g (0.88 mmol) of
BTEAC, 0.5 ml (7.53 mmol) of acrylonitrile, and
0.5 ml of 30% KOH in 5 ml of dioxane was stirred for
2 h at room temperature under argon. The mixture was
then poured into a mixture of ice with hydrochloric
acid, the precipitate was filtered off, washed with
water until neutral washings, dried in air, and washed
with methylene chloride, and the washings were evap-
orated to isolate 0.19 g (87%) of compound X whose
spectral parameters were identical to those of a sample
of X obtained by cyanoethylation of oxime IX.
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SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
597
3-O-(2-Cyanoethyl)lup-20(29)-en-28-al (XVI).
A mixture of 0.5 g (1.14 mmol) of betulinaldehyde
(XIII), 0.12 g (0.57 mmol) of BTEAC, 1.5 ml
(22.8 mmol) of acrylonitrile, and 1.5 ml of 30% KOH
in 25 ml of dioxane was stirred for 24 h at room tem-
perature. The mixture was poured into a mixture of ice
with hydrochloric acid, the precipitate was filtered off,
washed with water until neutral washings, dried in air,
and washed with methylene chloride, the washings
were evaporated, and the residue containing (according
CH3), 1.60 t (1H, 18-H, J = 11.5), 1.68 s (3H, C30H3),
2.55 t (2H, 32-H, J = 6.3), 2.81 d.d (1H, 3-H, J = 11.0,
3.0), 2.98 m (1H, 19-H), 3.51 m and 3.80 m (1H each,
31-H), 4.60 br.s and 4.72 br.s (1H each, 29-H).
13C NMR spectrum, δC, ppm: 14.65 q (C27), 16.02 q
and 16.09 q (C24, C25, C26), 18.16 t (C32), 19.26 t (C6),
19.37 q (C30), 20.84 t (C11), 22.94 t (C2), 25.48 t (C12),
28.07 q (C23), 29.66 t (C15), 30.57 t (C21), 32.15 t (C16),
34.28 t (C7), 36.03 t (C22), 37.12 s (C10), 38.40 d (C13),
38.44 t (C1), 38.86 s (C4), 40.70 s (C8), 42.40 s (C14),
46.90 d (C19), 49.27 d (C18), 50.45 d (C9), 55.75 d (C5),
56.37 s (C17), 64.12 t (C31), 87.72 d (C3), 109.64 t
(C29), 118.16 s (C33), 150.40 s (C20), 182.01 s (C28).
Mass spectrum: m/z 509.3860 [M]+. C33H51NO3. Cal-
culated: M 509.3864.
1
to the H NMR data) 45% of aldehyde XVI and 55%
of initial compound XIII was subjected to chromatog-
raphy on aluminum oxide using hexane–chloroform
(1:1) as eluent. Yield 0.2 g (36%), mp 155–157°C,
[α]D20 = +33.9° (c = 2.25, CHCl3). IR spectrum, ν, cm–1:
2253 (C≡N), 1725 (CHO), 1641 (C=C). 1H NMR spec-
trum (only characteristic signals are given), δ, ppm
(J, Hz): 0.63 (1H, 5-H), 0.72 s (3H, CH3), 0.79 s (3H,
CH3), 0.88 s (3H, CH3), 0.93 s (3H, CH3), 0.94 s (3H,
C23H3), 1.66 s (3H, C30H3), 2.53 t (2H, 32-H, J = 6.6),
2.75–2.87 m (2H, 3-H, 19-H), 3.49 m and 3.77 m (1H
each, 31-H), 4.59 br.s and 4.72 br.s (1H each, 29-H),
9.64 s (1H, 28-H). 13C NMR spectrum, δC, ppm:
14.15 q (C27), 15.82 q (C26), 16.04 q (C24, C25), 18.08 t
(C6), 18.93 q (C30), 19.18 t (C32), 20.68 t (C11), 22.84 t
(C2), 25.43 t (C12), 27.98 q (C23), 28.69 t (C15), 29.14 t
(C16), 29.76 t (C21), 33.11 t (C22), 34.21 t (C7), 37.00 s
(C10), 38.38 t (C1), 38.56 d (C13), 38.76 s (C4), 40.77 s
(C8), 42.45 s (C14), 47.42 d (C19), 47.95 d (C18),
50.35 d (C9), 55.62 d (C5), 59.21 s (C17), 64.04 t (C31),
87.56 d (C3), 110.06 t (C29), 118.10 s (C33), 149.62 s
(C20), 206.48 s (C28). Mass spectrum: m/z 493.3918
[M]+. C33H51NO2. Calculated: M 493.3914.
Methyl 3β-O-(2-cyanoethyl)lup-20(29)-en-28-
oate (XVIII). A mixture of 1.0 g (2.13 mmol) of
compound XV, 0.23 g (1.06 mmol) of BTEAC, 2.8 ml
(42.6 mmol) of acrylonitrile, and 2.8 ml of 30% KOH
in 25 ml of dioxane was stirred for 24 h at room tem-
perature under argon. The mixture was poured into
a mixture of ice with hydrochloric acid, the precipitate
was filtered off, washed with water until neutral wash-
ings, dried in air, and washed with methylene chloride,
the washings were evaporated, and the residue was
subjected to chromatography on aluminum oxide using
hexane–chloroform (1 :1) as eluent. Yield 0.82 g
(57%), mp 183–185°C, [α]D20 = +24° (c = 3.38, CDCl3).
IR spectrum, ν, cm–1: 2250 (C≡N), 1715 (C=O), 1640
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 0.62 m
(1H, 5-H), 0.72 s (3H, C24H3), 0.78 s (3H, C25H3),
0.82 m (1H, 1-H), 0.87 s (3H, C26H3), 0.92 s (3H,
C27H3), 0.93 s (3H, C23H3), 0.98 m (1H, 12-H), 1.08–
1.12 m (1H, 15-H), 1.17–1.24 m (2H, 9-H, 11-H),
1.28–1.40 m (8H, 6-H, 7-H, 11-H, 15-H, 16-H, 21-H,
22-H), 1.42–1.47 m (2H, 2-H, 4-H), 1.53 t (1H, 18-H,
J = 12.3), 1.64 s (3H, C30H3), 1.65–1.69 m (3H, 1-H,
2-H, 12-H), 1.81–1.89 m (2H, 21-H, 22-H), 2.12–
2.21 m (2H, 13-H, 16-H), 2.52 t (2H, 32-H, J = 6.5),
2.78 d.d (1H, 3-H, J = 12.2, 3.8), 2.95 m (1H, 19-H),
3.48 m (1H, 31-H), 3.62 s (3H, C34H3), 3.78 m (1H,
31-H), 4.56 br.s and 4.69 br.s (1H each, 29-H).
13C NMR spectrum, δC, ppm: 14.48 q (C27), 15.75 q
(C26), 15.91 q and 15.93 q (C24, C25), 17.99 t (C6),
19.06 t (C32), 19.19 q (C30), 20.71 t (C11), 22.73 t (C2),
25.31 t (C12), 27.87 q (C23), 29.45 t (C15), 30.40 t (C21),
31.95 t (C16), 34.10 t (C7), 36.74 t (C22), 36.91 s (C10),
38.03 d (C13), 38.26 t (C1), 38.65 s (C4), 40.50 s (C8),
42.17 s (C14), 46.75 d (C19), 49.26 d (C18), 50.33 d
(C9), 51.05 q (C34), 55.57 d (C5), 56.33 s (C17), 63.92 t
(C31), 87.47 d (C3), 109.38 t (C29), 117.99 s (C33),
3β-O-(2-Cyanoethyl)lup-20(29)-en-28-oic acid
(XVII). A mixture of 0.87 g (1.9 mmol) of betulinic
acid (XIV), 0.2 g (0.95 mmol) of BTEAC, 2.5 ml
(38 mmol) of acrylonitrile, and 2.5 ml of 30% KOH in
25 ml of dioxane was stirred for 24 h at room tem-
perature. The mixture was poured into a mixture of ice
with hydrochloric acid, the precipitate was filtered off,
washed with water until neutral washings, dried in air,
and washed with methylene chloride, the washings
were evaporated, and the residue containing (according
1
to the H NMR data) compounds XIV and XVII at
a ratio of 1:4 was subjected to chromatography on
aluminum oxide using hexane–chloroform (1:1) as
eluent. Yield 0.51 g (53%), mp 271–274°C. IR spec-
trum, ν, cm–1: 2250 (C≡N), 1725 (C=O), 1641 (C=C).
1H NMR spectrum (only characteristic signals are
given), δ, ppm (J, Hz): 0.66 m (1H, 5-H), 0.74 s (3H,
CH3), 0.81 s (3H, CH3), 0.91 s (3H, CH3), 0.92 s (6H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ANTIMONOVA et al.
598
150.34 s (C20), 176.38 s (C28). Mass spectrum:
m/z 523.40325 [M]+. C34H53NO3. Calculated:
M 523.40252.
Cyanoethylation of 3β-hydroxylup-20(29)-en-28-
al oxime (XX). A mixture of 0.5 g (1.13 mmol) of
compound XX, 0.1 g (0.44 mmol) of BTEAC, 7 ml
(105.35 mmol) of acrylonitrile, and 1 ml of 30% KOH
in 20 ml of dioxane was kept for 24 h at room tempera-
ture under argon. The mixture was poured into a mix-
ture of ice with hydrochloric acid, and the precipitate
was filtered off, washed with water until neutral wash-
Cyanoethylation of betulin (XIX). A mixture of
0.5 g (1.13 mmol) of compound XIX, 0.1 g
(0.44 mmol) of BTEAC, 1.5 ml (22.6 mmol) of acrylo-
nitrile, and 1 ml of 30% KOH in 20 ml of dioxane was
kept for 24 h at room temperature under argon. The
mixture was poured into a mixture of ice with hydro-
chloric acid, and the precipitate was filtered off,
washed with water until neutral washings, and dried in
1
ings, and dried in air. According to the H NMR data,
the product contained 45% of monosubstituted com-
pound XXI and 55% of disubstituted derivative XXII
which were separated by chromatography on alumi-
num oxide using hexane–chloroform (1:1) as eluent.
Yield of 3-{28-[(E)-(2-cyanoethoxyimino)]lup-20(29)-
en-3β-yloxy}propanenitrile (XXII) 0.16 g (45%),
mp 178–180°C. IR spectrum, ν, cm–1: 2250 (C≡N),
1
air. According to the H NMR data, the product con-
tained 21% of monosubstituted compound III and 79%
of disubstituted derivative IV which were separated by
chromatography on aluminum oxide using hexane–
chloroform (1:1) as eluent. Yield of 3β,28-di-O-(2-cy-
anoethyl)lup-20(29)-ene (IV) 0.45 g (75%), mp 178–
180°C (from methanol), [α]D20 = +27° (c = 0.81, CHCl3)
1
1646 (C=C). H NMR spectrum, δ, ppm (J, Hz): 0.63
(1H, 5-H), 0.72 s (3H, C25H3), 0.78 s (3H, C26H3),
0.79–0.82 m (1H, 1-H), 0.94 s (9H, C23H3, C24H3,
C27H3), 1.00–1.05 m (1H, 21-H), 1.15–1.23 m (2H,
9-H, 11-H), 1.26–1.49 m (9H, 2-H, 6-H, 7-H, 11-H,
15-H, 16-H, 22-H), 1.58 t (1H, 18-H, J = 11.8), 1.65 s
(3H, C30H3), 1.63–1.80 m (7H, 1-H, 2-H, 12-H, 13-H,
15-H, 22-H), 1.84–1.96 m (2H, 16-H, 21-H), 2.45 t.d
(1H, 19-H, J = 5.7, 11.1), 2.53 t (2H, 35-H, J = 6.5),
2.68 t (2H, 32-H, J = 6.3), 2.78 d.d (1H, 3-H, J = 4.3),
3.48 m and 3.77 m (1H, 34-H), 4.19 t (2H, 31-H, J =
6.3), 4.57 br.s and 4.68 br.s (2H, 29-H), 7.50 s (1H,
28-H). 13C NMR spectrum, δC, ppm: 14.56 q (C27),
15.88 q (C24), 15.97 q (C25), 16.01 q (C26), 17.99 t (C6),
18.33 t (C32), 19.03 q (C30), 19.14 t (C35), 20.60 t (C11),
22.75 t (C2), 24.97 t (C12), 27.70 t (C21), 27.93 q (C23),
29.53 t (C15), 31.91 t (C16), 34.09 t (C7), 36.87 t (C22),
36.91 s (C10), 38.25 t (C1), 38.46 d (C13), 38.69 s (C4),
40.71 s (C8), 42.67 s (C14), 47.66 d (C19), 49.16 d (C18),
49.92 s (C17), 50.14 d (C9), 55.50 d (C5), 63.97 t (C34),
67.40 t (C31), 87.47 s (C3), 110.01 t (C29), 117.59 s
(C33), 118.18 s (C36), 149.55 s (C20), 155.89 t (C28).
Mass spectrum: m/z 561.42574 [M]+. C36H55N3O2. Cal-
culated: M 561.42940.
1
(cf. [4]). IR spectrum: ν 2250 cm–1 (C≡N). H NMR
spectrum, δ, ppm (J, Hz): 0.64 m (1H, 5-H), 0.74 s
(3H, C24H3), 0.75–0.78 m (1H, 1-H), 0.80 s (3H,
C25H3), 0.94 s (3H, C27H3), 0.95 s (3H, C23H3), 1.00 s
(3H, C26H3), 1.01–1.04 m (3H, 12-H, 15-H, 22-H),
1.16 t.d (1H, 16-H, J = 13.2, 3.2), 1.20–1.26 m (2H,
9-H, 11-H), 1.31–1.41 m (5H, 6-H, 7-H, 7-H, 11-H,
21-H), 1.46–1.50 m (2H, 2-H, 6-H), 1.51 t (1H, 18-H,
J = 11.3), 1.57–1.70 m (5H, 1-H, 2-H, 12-H, 13-H,
15-H), 1.64 s (3H, C30H3), 1.86–1.96 m (3H, 16-H,
21-H, 22-H), 2.32–2.39 m (1H, 19-H), 2.53 t (2H,
35-H, J = 6.5), 2.56 t (2H, 32-H, J = 6.5), 2.79 d.d
(1H, 3-H, J = 12.1, 3.8), 3.14 d (1H, 28-H, J = 8.9),
3.47–3.52 m (1H, 34-H), 3.55 d (1H, 28-H, J = 8.9),
3.62 t.d (2H, 31-H, J = 6.5, 1.6), 3.74–3.80 m (1H,
34-H), 4.55 br.s and 4.65 br.s (1H each, 29-H).
13C NMR spectrum, δC, ppm: 14.60 q (C27), 15.85 q
(C26), 15.92 q (C25), 15.96 q (C24), 18.03 t (C6), 18.68 t
(C32), 18.94 q (C30), 19.10 t (C35), 20.71 t (C11), 22.80 t
(C2), 25.06 t (C12), 27.02 t (C15), 27.92 q (C23), 29.73 t
(C21 or C16), 29.77 t (C16 or C21), 34.05 t (C7), 34.54 t
(C22), 36.93 s (C10), 37.41 d (C13), 38.31 t (C1), 38.71 s
(C4), 40.80 s (C8), 42.52 s (C14), 47.17 s (C17), 47.80 d
(C19), 48.61 d (C18), 50.21 d (C9), 55.55 d (C5), 63.98 t
(C34), 66.04 t (C31), 69.67 t (C28), 87.51 d (C3),
109.45 t (C29), 117.71 s (C33), 117.98 s (C36), 150.29 s
(C20). Mass spectrum: m/z 548.43521 [M]+. Found, %:
C 78.72; H 10.21; N 4.90. C36H56N2O2. Calculated, %:
C 78.72; H 10.21; N 5.11. M 548.43415. Further
elution gave 0.08 g (14%) of compound III whose
spectral parameters were identical to those of a sample
obtained by hydrolysis of compound II.
Further elution gave 0.12 g (35%) of 28-[(E)-(2-
cyanoethoxyimino)]lup-20(29)-en-3β-one (XXI),
mp 197–199°C. IR spectrum, ν, cm–1: 2252 (C≡N),
1
1648 (C=C). H NMR spectrum (only characteristic
signals are given), δ, ppm (J, Hz): 0.89 s (3H, Me),
0.92 s (3H, Me), 1.02 s (3H, Me), 1.11 s (3H, Me),
1.64 s (3H, C30H3), 2.22 m (1H, 2-H), 2.35 m (1H,
19-H), 2.57 t (2H, 32-H, J = 6.4), 2.95 d.t (1H, 2-H,
J = 14.4, 4.1), 3.62 t (2H, 31-H, J = 6.4), 4.54 br.s and
4.64 br.s (1H each, 29-H), 7.50 s (28-H), 9.30 br.s (1H,
NOH). 13C NMR spectrum, δC, ppm: 14.47 q (C27),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
599
15.62 q (C26), 15.75 q (C25), 17.00 t (C2), 18.67 t (C32),
18.23 t (C6), 18.80 q (C30), 20.91 t (C11), 22.69 q (C24),
24.97 q (C12), 26.93 t (C15), 27.05 q (C23), 29.61 t
(C21), 29.66 t (C16), 33.58 t (C7), 34.49 t (C22), 37.00 s
(C10), 37.39 d (C13), 38.56 t (C1), 40.17 s (C4), 40.72 s
(C8), 42.49 s (C14), 47.12 s (C17), 47.75 d (C19), 48.47 d
(C18), 49.75 d (C9), 55.29 d (C5), 65.99 t (C31), 69.58 t
(C28), 109.52 t (C29), 117.76 t (C33), 150.21 s (C20),
166.72 s (C3).
171.29 s (C34). Mass spectrum: m/z 537.8345 [M]+.
C35H55NO3. Calculated: M 537.8252.
28-[3-Amino-3-(hydroxyimino)propoxy]lup-
20(29)-en-3β-yl acetate (XXV). A solution of 0.054 g
(1.63 mmol) of hydroxylamine in 5 ml of butan-1-ol
was added to 0.29 g (0.54 mmol) of compound II. The
mixture was heated for 10 h at 60°C and poured into
a mixture of ice with hydrochloric acid, and the precip-
itate was filtered off, washed with water until neutral
1
washings, and dried in air. According to the H NMR
3β-O-(2-Cyanoethyl)lup-20(29)-en-28-yl acetate
(XXIV). a. A mixture of 0.5 g (1.03 mmol) of com-
pound XXIII, 1.35 ml (20.6 mmol) of acrylonitrile,
0.11 g (0.51 mmol) of BTEAC, and 1.35 ml of
30% KOH in 20 ml of dioxane was kept for 24 h at
room temperature under argon. The mixture was
poured into a mixture of ice with hydrochloric acid,
and the precipitate was filtered off, washed with water
until neutral washings, and dried in air. According to
the GC–MS data, the product contained 64% of com-
pound XXIV, 22% of betulin (XIX), 9% of IV, and
5% of III.
data, the product was a mixture of initial compound II
and amide oxime XXV at a ratio of 1:5. Compound
XXV was isolated by chromatography on silica gel
using chloroform–methanol (10:1) as eluent. Yield
0.17 g (55%), mp 141–143°C. IR spectrum, ν, cm–1:
1730 (C=O), 1671 (C=N), 1642 (C=C). 1H NMR spec-
trum, δ, ppm (J, Hz): 0.77 m (1H, 5-H), 0.81 s (3H,
C23H3), 0.82 s (6H, C24H3, C25H3), 0.94 s (3H, C27H3),
0.99 s (3H, C26H3), 1.65 s (3H, C30H3), 2.02 (3H,
C35H3), 2.38 t (2H, 32-H, J = 5.4), 3.09 d (1H, 28-H,
J = 9.1), 3.53 d (1H, 28-H, J = 8.9), 3.60 t (2H, 31-H,
J = 5.64), 4.45 m (1H, 3-H), 4.56 br.s and 4.65 br.s
(2H, 29-H), 5.00 br.s (2H, NH2). 13C NMR spectrum,
δC, ppm: 14.73 q (C27), 15.97 q (C26), 16.14 q (C25),
16.47 q (C24), 18.14 t (C6), 19.05 q (C30), 20.80 t (C11),
21.30 q (C35), 23.65 t (C2), 25.10 t (C12), 27.09 t (C15),
27.91 q (C23), 29.80 t (C16), 30.08 t (C21), 31.24 t (C32),
34.09 t (C7), 34.82 t (C22), 37.03 s (C10), 37.47 d (C13),
37.76 s (C4), 38.33 t (C1), 40.88 s (C8), 42.64 s (C14),
47.11 s (C17), 47.92 d (C19), 48.71 d (C18), 50.24 d
(C9), 55.33 d (C5), 69.57 t (C31), 69.67 s (C28), 80.89 d
(C3), 109.71 t (C29), 150.39 s (C20), 154.31 s (C33),
171.01 s (C34). Mass spectrum: m/z 570.8525 [M]+.
C35H58N2O4. Calculated: M 570.8382.
b. A mixture of 0.5 g (1.03 mmol) of compound
XXIII, 1.35 ml (20.6 mmol) of acrylonitrile, 0.11 g
(0.51 mmol) of BTEAC, and 1.35 ml of 30% KOH in
20 ml of methylene chloride was stirred for 2 h at
room temperature under argon. The mixture was
washed with 10% hydrochloric acid and water, dried
over MgSO4, and evaporated. According to the GC–
MS data, the product contained 88% of XXIV, 7% of
IV, and 5% of III. Compound XXIV was isolated
from the product mixture by chromatography on
aluminum oxide using hexane–chloroform (1 : 1) as
eluent. Yield 0.45 g (84%). IR spectrum, ν, cm–1: 2251
1
(C≡N), 1735 (C=O), 1642 (C=C). H NMR spectrum
28-[2-(5-Phenyl-1,2,4-oxadiazol-3-yl)ethoxy]lup-
20(29)-en-3β-yl acetate (XXVI). Pyridine, 0.021 ml
(0.26 mmol), and benzoyl chloride, 0.02 ml
(0.17 mmol), were added under argon to a solution of
0.1 g (0.17 mmol) of compound XXV in 3 ml of meth-
ylene chloride. The mixture was stirred for 24 h at
room temperature, washed with 10% hydrochloric acid
and water, dried over anhydrous MgSO4, and evaporat-
ed. The residue was heated for 6 h in boiling benzene,
the solvent was distilled off, and the residue was puri-
fied by chromatography on silica gel using chloroform
as eluent. Yield 0.07 g (59%), mp 118–120°C. IR spec-
(only characteristic signals are given), δ, ppm (J, Hz):
0.64 m (1H, 5-H), 0.74 s (3H, CH3), 0.80 (3H, CH3),
0.95 s (3H, CH3), 0.99 s (3H, CH3), 1.65 s (3H, C30H3),
1.99 s (3H, C34H3), 2.35 m (1H, 19-H), 2.52 t (2H,
32-H, J = 6.4), 3.47 m and 3.74 m (1H each, 31-H),
3.79 d and 4.20 d (1H each, 28-H, J = 8.9), 4.52 br.s
and 4.62 br.s (2H, 29-H). 13C NMR spectrum, δC, ppm:
14.50 q (C27), 15.78 q (C24), 15.91 q (C26), 15.92 q
(C25), 17.98 t (C26), 18.89 q (C30), 19.04 t (C32), 20.64 t
(C11), 20.82 q (C34), 22.72 q (C12), 24.98 t (C15),
26.82 t (C2), 27.86 q (C23), 28.97 t (C21), 29.55 t (C16),
33.77 t (C7), 34.99 t (C22), 36.84 s (C10), 37.04 d (C13),
38.22 t (C1), 38.63 s (C4), 40.72 s (C8), 42.46 s (C14),
47.53 s (C17), 47.53 d (C19), 48.53 d (C18), 50.14 d
(C9), 55.47 d (C5), 60.09 t (C31), 63.91 t (C28), 87.45 d
(C3), 109.42 t (C29), 118.01 t (C33), 150.29 s (C20),
1
trum, ν, cm–1: 1733 (C=O), 1640 (C=C). H NMR
spectrum, δ, ppm (J, Hz): 0.75 m (1H, 5-H), 0.81 s
(3H, C23H3), 0.82 s (6H, C24H3, C25H3), 0.94 s (3H,
C27H3), 1.00 s (3H, C26H3), 1.66 s (3H, C30H3), 2.01 s
(3H, C32H3), 2.36 t.d (1H, 19-H, J = 5.8, 10.7), 2.60 t
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ANTIMONOVA et al.
600
(2H, 12′-H, J = 5.4), 3.15 d (1H, 28-H, J = 9.0), 3.57 d
(1H, 28-H, J = 8.8), 3.70 t (2H, 13′-H, J = 5.5), 4.45 m
(1H, 3-H), 4.56 br.s and 4.66 br.s (1H each, 29-H),
7.39–7.47 m (2H, Harom), 7.51–7.58 m (1H, Harom),
7.99–8.05 m (2H, Harom). 13C NMR spectrum, δC, ppm:
14.74 q (C27), 15.99 q (C26), 16.13 q (C25), 16.45 q
(C24), 18.12 t (C6), 19.06 q (C30), 20.78 t (C11), 21.30 q
(C32), 23.65 t (C2), 25.09 t (C12), 27.10 t (C15), 27.90 q
(C23), 29.77 t (C16), 30.11 t (C21), 31.00 t (C12′), 34.09 t
(C7), 34.83 t (C22), 37.03 s (C10), 37.49 d (C13), 37.76 s
(C4), 38.34 t (C1), 40.88 s (C8), 42.65 s (C14), 47.11 s
(C17), 47.87 d (C19), 48.70 d (C18), 50.24 d (C9),
55.33 d (C5), 65.82 s (C5′), 69.33 t (C13′), 69.75 s (C28),
80.87 d (C3), 109.82 t (C29), 128.42 d (Cm), 129.38 d
(Co), 132.86 d (Cp), 150.20 s (C20), 159.05 s (Ci),
164.08 s (C3′), 171.01 s (C31). Mass spectrum: m/z
656.4654 [M]+. C42H60N2O4. Calculated: M 6561.4638.
fluoroacetic anhydride, 0.018 ml (0.13 mmol), was
added under argon to a solution of 0.073 g
(0.13 mmol) of compound XVIII in 3 ml of methylene
chloride. The mixture was kept for 24 h at room
temperature, washed with 10% hydrochloric acid and
water, dried over anhydrous MgSO4, and evaporated.
The residue was purified by chromatography on silica
gel using chloroform as eluent. Yield 0.07 g (85%),
mp 128–131°C. IR spectrum, ν, cm–1: 1735 (C=O),
1
1643 (C=C). H NMR spectrum, δ, ppm (J, Hz):
0.59 m (1H, 5-H), 0.65 s (3H, C24H3), 0.76 s (3H,
C25H3), 0.78 s (3H, C26H3), 0.88 s (3H, C27H3), 0.93 s
(3H, C23H3), 1.55 t (1H, 18-H, J = 11.3), 1.66 (3H,
C30H3), 2.74 d.d (1H, 3-H, J = 4.1), 2.93–3.15 m (3H,
7-H, 19-H) 3.64 s (3H, C31H3), 3.99 m (1H, 8-H),
4.58 br.s and 4.72 br.s (1H each, 29-H). 13C NMR
spectrum, δC, ppm: 14.67 q (C27), 15.94 q (C26),
16.08 q (C25, C24), 18.18 t (C6), 19.37 q (C30), 20.90 t
(C11), 22.89 t (C2), 25.53 t (C12), 27.34 q (CF3), 27.73 q
(C23), 29.66 t (C15), 30.61 t (C21), 32.17 t (C16), 27.26 t
(C7′) 34.30 t (C7), 36.97 t (C22), 37.13 s (C10), 38.25 d
(C13), 38.49 s (C1), 38.76 t (C4), 40.70 s (C8), 42.38 s
(C14), 46.97 d (C19), 49.48 d (C18), 50.53 d (C9),
51.24 q (C31), 55.75 d (C5), 56.55 s (C17), 65.49 t (C8′),
65.49 s (C5′), 87.46 d (C3), 109.55 t (C29), 150.60 s
(C20), 169.76 s (C3′), 176.63 s (C28). 19F NMR spec-
trum: δF 96.25 ppm (3F, CF3). Mass spectrum:
m/z 634.3954 [M]+. C36H53F3N2O4. Calculated:
M 634.3952.
Methyl 3β-[3-amino-3-(hydroxyimino)propoxy]-
lup-20(29)-en-28-oate (XXVII). A solution of 0.093 g
(2.81 mmol) of hydroxylamine in 10 ml of butan-1-ol
was added to 0.49 g (0.94 mmol) of compound XVIII,
the mixture was heated for 10 h at 60°C and poured
into a mixture of ice with hydrochloric acid, and the
precipitate was filtered off, washed with water until
neutral washings, and dried in air. The product was
isolated by preparative thin-layer chromatography on
silica gel using chloroform–methanol (20:1) as eluent.
Yield 0.28 g (53%), mp 191–194°C. IR spectrum, ν,
cm–1: 1716 (C=O), 1665 (C=N), 1642 (C=C). 1H NMR
spectrum (only characteristic signals are given), δ, ppm
(J, Hz): 0.64 (1H, 5-H), 0.72 s (3H, C24H3), 0.79 s (3H,
C25H3), 0.88 s (3H, C26H3), 0.91 s (3H, C23H3), 0.92 s
(3H, C27H3), 1.55 t (1H, 18-H, J = 11.3), 1.65 s (3H,
C30H3), 1.81–1.92 m (2H, 21-H, 22-H), 2.10–2.24 m
(2H, 13-H, 16-H), 2.35 m (2H, 32-H), 2.74 d.d (1H,
3-H, J = 4.1), 2.96 t.d (1H, 19-H, J = 4.5, 10.8), 3.45 m
(1H, 31-H), 3.64 s (3H, C30H3), 3.77 m (1H, 31-H),
4.57 br.s and 4.71 br.s (1H each, 29-H), 5.04 br.s (2H,
NH2). 13C NMR spectrum, δC, ppm: 14.23 q (C27),
15.50 q (C26), 15.61 q (C25), 15.93 q (C24), 17.77 t (C6),
18.93 q (C30), 20.45 t (C11), 22.36 t (C2), 25.06 t (C12),
27.75 q (C23), 29.20 t (C32), 30.15 t (C15), 31.19 t (C21),
31.72 t (C16), 33.85 t (C7), 36.51 t (C22), 36.68 s (C10),
37.80 d (C13), 38.04 t (C1), 38.26 s (C4), 40.24 s (C8),
41.92 s (C14), 46.51 d (C19), 49.02 d (C18), 50.07 d
(C9), 50.82 q (C34), 55.30 d (C5), 56.10 s (C17), 66.98 t
(C31), 87.03 d (C3), 109.13 t (C29), 150.12 s (C20),
154.06 s (C33), 176.21 s (C28). Mass spectrum: m/z
556.4274 [M]+. C34H56N2O4. Calculated: M 556.4264.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00183).
REFERENCES
1. Mironov, M.E., Kharitonov, Yu.V., Shul’ts, E.E., Shaki-
rov, M.M., Gatilov, Yu.V., and Tolstikov, G.A., Russ. J.
Org. Chem., 2010, vol. 46, p. 1869.
2. Krasutsky, P.A., Nat. Prod. Rep., 2006, vol. 23, p. 919;
Dzubak, P., Hajduch, M., Vydra, D., Hustova, A.,
Kvasnica, M., Biedermann, D., Markova, L., Urban, M.,
and Sarek, J., Nat. Prod. Rep., 2006, vol. 23, p. 394;
Saxena, B.B., Zhu, L., Hao, M., Kisilis, E., Katdare, M.,
Oktem, O., Bomshteyn, A., and Rathnam, P., Bioorg.
Med. Chem., 2006, vol. 14, p. 6349; Santos, R.S., Salva-
dor, J.A.R., Marin, S., and Cascante, M., Bioorg. Med.
Chem., 2009, vol. 17, p. 6241; Kuo, R.-Y., Qian, K.,
Morris-Natschke, S.L., and Lee, K.-H., Nat. Prod. Rep.,
2009, vol. 26, p. 1321.
3. Shintyapina, A.B., Shul’ts, E.E., Petrenko, N.I., Uzenko-
va, N.V., Tolstikov, G.A., Pronkina, N.V., Kozhevni-
kov, V.S., and Pokrovskii, A.G., Bioorg. Khim., 2007,
vol. 33, p. 624; Antimonova, A.N., Uzenkova, N.V.,
Methyl 3β-[2-(5-trifluoromethyl-1,2,4-oxadiazol-
3-yl)ethoxy]lup-20(29)-en-28-oate (XXVIII). Tri-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS: XXIV.
601
Petrenko, N.I., Shakirov, M.M., Shul’ts, E.E., and Tolsti-
kov, G.A., Khim. Prirodn. Soedin., 2008, vol. 44, p. 259.
8. Poplavskaya, I.A. and Kurmangalieva, R.G., Khimiya
amidoksimov (Chemistry of Amide Oximes), Alma-Ata,
Gylym, 1988, p. 7.
9. Wenkert, E., Baddeley, G.V., Burfitt, I.R., and More-
no, I.N., Org. Magn. Reson., 1978, vol. 11, p. 337;
Patra, A., Chaudhuri, S.K., and Panda, S.K., J. Nat.
Prod., 1988, vol. 51, p. 217.
4. Petrenko, N.I., Shul’ts, E.E., and Tolstikov, G.A., Khim.
Prirodn. Soedin., 1999 (special issue), p. 22.
5. Terent’ev, A.P. and Kost, A.N., Reaktsiya tsianoetiliro-
vaniya (Cyanoethylation Reaction), Moscow: Goskhim-
izdat, 1952, p. 47.
10. Petrenko, N.I., Elantseva, N.V., Petukhova, V.Z., Shaki-
rov, M.M., Shchul’ts, E.E., and Tolstikov, G.A., Khim.
Prirodn. Soedin., 2002, p. 276.
6. Koohang, A., Majewski, N.D., Szotek, E.L., Mar, A.A.,
Eiznhamer, D.A., Flavin, M.T., and Xu, Z.-Q., Bioorg.
Med. Chem. Lett., 2009, vol. 19, p. 2168.
11. Akihisa, T., Takamine, Y., Yoshizumi, K., Tokuda, H.,
Kimura, Y., Ukiya, M., Nakahara, T., Yokochi, T.,
Ichiishi, E., and Nishino, H., J. Nat. Prod., 2002,
vol. 65, p. 278.
12. Flekhter, O.B., Boreko, E.I., Nigmatullina, L.R., Pavlo-
va, N.I., Medvedeva, N.I., Nikolaeva, S.N., Tret’yako-
va, E.V., Savinova, O.V., Baltina, L.A., Karachuri-
na, L.T., Galin, F.Z., Zarudii, F.S., and Tolstikov, G.A.,
Khim.-Farm. Zh., 2004, vol. 38, p. 31.
7. Diana, G.D., Volkots, D.L., Nitz, T.J., Bailey, T.R.,
Long, M.A., Vescio, N., Aldous, S., Pevear, D.C., and
Dutko, F.J., J. Med. Chem., 1994, vol. 37, p. 2421;
Borzilleri, R.M., Zheng, X., Qian, L., Ellis, C., Cai, Z.-
wei, Wautlet, B.S., Mortillo, S., Jeyaseelan, S.R.,
Kukral, D.W., Fura, A., Kamath, A., Vyas, V., Tokar-
ski, J.S., Barrish, J.C., Hunt, J.T., Lombardo, L.J.,
Fargnoli, J., and Bhide, R.S., J. Med. Chem., 2005,
vol. 48, p. 3991.
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