Chemical transformations of betulonic aldehyde

Article abstract of DOI:10.1134/S1070428016020160

Chemical transformations of 3-oxolup-20(29)-en-28-al in oxidation, reduction, reductive amination, aldol crotonic condensation, cyclopropanation, Grignard, and Wittig reactions were investigated. The structure of reaction products was established by X-ray diffraction (XRD) analysis.

Full text of DOI:10.1134/S1070428016020160

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 2, pp. 249–260. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.N. Semenenko, N.L. Babak, A.M. Eremina, I.M. Gella, S.V. Shishkina, V.I. Musatov, V.V. Lipson, 2016, published in Zhurnal
Organicheskoi Khimii, 2016, Vol. 52, No. 2, pp. 266–277.
Chemical Transformations of Betulonic Aldehyde
a
a
c
a,c
a,c
A. N. Semenenko , N. L. Babak , A. M. Eremina , I. M. Gella , S. V. Shishkina ,
a
a–c
V. I. Musatov , and V. V. Lipson
a
Institute of Single Crystals, National Academy of Sciences of Ukraine, pr. Lenina 60, Kharkiv, 61001 Ukraine
e-mail: lipson@ukr.net
b
Danilevskii Institute of Endocrinal Pathology Problems, National Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine
c
Karazin Kharkiv National University, Kharkiv, Ukraine
Received October 9, 2015
Abstract—Chemical transformations of 3-oxolup-20(29)-en-28-al in oxidation, reduction, reductive amination,
aldol crotonic condensation, cyclopropanation, Grignard, and Wittig reactions were investigated. The structure
of reaction products was established by X-ray diffraction (XRD) analysis.
DOI: 10.1134/S1070428016020160
Natural molecular platforms with a complex carbon
We attempted to extend the synthetic potential of 3-
oxolup-20(29)-en-28-al 5 mainly at the expense of the
transformations of carbonyl groups and the active
methylene fragment in the ring А.
scaffold, like triterpenoids of lupane, oleanane, or ursane
series, are important chirality sources for designing
new optically active substances for medical chemistry
and materials science. The enantiomeric purity and the
rigid scaffold make them attractive objects for the
synthesis of molecules of definite configuration
ensuring the high affinity to stereospecific sites for
fixing biotargets and are also significant for inducing
helicoid supramolecular texture in liquid crystals
utilized in electro optical devices [1–5]. The usefulness
from the practical viewpoint of the search for the ways
of such substances modification depends both on the
availability and reproducibility of the raw material
sources and on the functional groups present in the
structure. Triterpenoids of lupane series [betulin (1),
betulinic (2) and betulonic (3) acids, betulinic (4) and
betulonic (5) aldehydes] fit to these requirements.
They are present everywhere in trees’ bark, especially,
in the birch bark. The content of diol 1 in the latter
reaches 10–35% of the dry mass [3, 5].
E
C
R2
D
A
B
R1
1_
5
1
2
1
2
R = OH, R = CH OH (1), COOH (2), R = O=,
2
1
2
R = COOH (3), CHO (5), R = OH, R = CHO (4).
Several procedures of betulin 1 oxidation into alde-
hyde 5 and acid 3 are described in papers and patents.
We prepared betulonic aldehyde 5 in 75% yield using
pyridinium chlorochromate in dichloromethane
The presence in the structure of compounds 1–5 of
several reactive groups provides multiple ways of the
chemical transformation. Betulinic acid 2 [5–10] is the
best studied among these compounds. The possibility
of conversion of diol 1 in aldehydes 4 and 5 opens the
way to their wider utilization in the organic synthesis
yet the properties of betulonic aldehyde 5 are poorly
investigated.
(
Scheme 1). The subsequent oxidation of compound 5
with chromic anhydride in acetic acid affords acid 3.
The physicochemical characteristics of compounds 3
and 5 coincide with the published data [5–13].
The reductive amination involving aldehyde 5 and
aromatic amines was not described in the literature.
Only some examples are published on the preparation
2
49

2
50
SEMENENKO et al.
Scheme 1.
OH
O
OH
PCC
CH Cl
CrO3
O
2
2
HOAc
HO
O
O
1
5
3
of secondary amines by reactions of betulonic
aldehyde 5 with ethanolamine, hydrochlorides of
methyl glycinate and 2-chloroethylamine in the
catalyst reduced the С=N bond and the isopropenyl
fragment leaving intact the С=О group in the А ring.
Azomethines 7а and 7b were reduced with NaBH4–
МeОН into amino alcohols 8a and 8b. At treating the
presence of NaCNBH . The reduction occurred not
3
only at the exocyclic imino group but also at the keto
group in the ring А [14]. We synthesized secondary
amines 6–9 under various conditions (Scheme 2) and
established that hydrogen in the presence of Pd/C
azomethines with NaBH –НОАс in toluene we
4
obtained a mixture of amino ketone 9 and amino
alcohol 8 in the ratio 3 : 1 that was successfully sepa-
rated by column chromatography.
Scheme 2.
H
N
Bu
O
6
/
C
d
P
,
c
A
O
H
,
H
O
e
M
O
H
N
N
RNH2
MeOH, HOAc
NaBH4
MeOH
R
R
O
O
HO
5
7
a, 7b
8a, 8b
H
N
O
+
8b
N
H
O
9
6 5 6 4
R = C H (a), C H (NHAc)-4 (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

CHEMICAL TRANSFORMATIONS OF BETULONIC ALDEHYDE
251
Scheme 3.
O
R
O
O
OH
R
RCHO
NaBH
4
CH OC H OH,
MeOH,
CH Cl2
3
2
4
KOH
2
O
HO
5
10c
11
R
O
R
O
O
Me SOI
3
1
0a, 10b
+
DMF, NaH
O
1
: 3
1
2a, 12b
13a, 13b
R =
N N
(a),
N N
(b),
4-ClC H (c).
6 4
O
The structure of compounds 6–9 was confirmed by
and 9 gives rise to two doublets of methylene group
1
28
IR and Н NMR spectra. IR spectra of compounds 6,
a, 7b, and 9 contain strong bands of methyl and
methylene groups of lupane scaffold in the region
977–2855, a broadened band of the associated NH
protons С Н , δ 2.55–2.74, 3.01–3.24 ppm. The
2
7
reduction of the isopropenyl fragment in amino ketone
6 is confirmed by the absence of the doublet of the
methylene protons at 4.66 ppm.
2
group at 3403–3342 (characteristic of amino ketones 6
and 9), and a band of stretching vibrations of the
carbonyl group in the range 1707–1688 cm . In the
The presence in the structure of compound 5 of an
aldehyde and a keto groups makes it possible to
prepare from it α,β-unsaturated ketones. We formerly
synthesized such compounds by aldol crotonic
condensation using pyrazole-4-carbaldehydes as
carbonyl component and ketoaldehyde 5 as the
methylene component of the reaction [15]. In this
study we obtained by the condensation of 4-
chlorobenzaldehyde with betulonic aldehyde 5 in basic
medium 2-ylidene derivative 10c (Scheme 3). Its
–
1
spectra of amino alcohols 8a and 8b a broad band is
–
1
observed in the region 3403–3342 cm formed by
overlapping of absorption bands of hydrogen-bonded
1
NН and ОН groups. The Н NMR spectra of secondary
amines 6, 8a, 8b, and 9 differ from the spectrum of the
initial aldehyde 5, first of all, in the resonance region
of the aromatic protons. Although the hydroxy group
signal was not observed in the spectra registered in
СDCl3 the reduction of the carbonyl group was
reduction with NaBH in the mixture of МeОН–
4
СН Cl , 1 : 1, led to the formation of 2-[(4-chloro-
2
2
3
confirmed by the appearance of a multiplet of Н
phenyl)methylidene]lup-20(29)-en-3,28-diol 11. From
the previously synthesized α,β-unsaturated ketones 10a
and 10b [15] and trimethylsulfoxonium methylide in
the presence of NaН in DMF a mixture was obtained
of isomeric spirocyclopropanes 12a, 12b, 13a, and 13b
proton in the range δ 3.13–3.81 ppm. The signal of the
28
methine proton Н in the spectra of imines 7a and 7b
appears as a downfield singlet at δ 7.88 ppm. The
reduction of the imino group in compounds 6, 8a, 8b,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

2
52
SEMENENKO et al.
Scheme 4.
O
+
_
PPh3 Br
O
O
R
t-BuOH, t-BuONa
O
O
R
5
14a, 14b
R= Cl (a), OMe (b).
1
in the ratio 3 : 1, as showed the Н NMR data. We
failed to separate the mixture into individual
compounds both by chromatography and fractional
crystallization.
observed at 7.25–7.26 ppm. The multiplets of methine
and methylene protons of the lupane scaffold are
observed at 1.01–1.74 ppm, and the singlets of five
methyl groups appear in the range of 0.76–1.13 ppm.
The isopropylidene fragment is present as a singlet of
In the IR spectrum of α,β-unsaturated ketones 10a–
0c the maximum of the absorption band of the
stretching vibrations of the keto group shifts from 1705
in ketoaldehyde 5) to 1670–1683 cm due to the
conjugation of this group with the double bond. The
band of the formyl group retains its position [ν(С=О)
723–1717 cm ]. The IR spectrum of diol 11 lacks the
absorption band of the carbonyl group, a wide band is
observed in the region 3461–3435 cm corresponding
to the vibrations of the associated ОН groups. The
position of the absorption band of the keto group in the
spectra of spirocyclopropanes 12a, 12b, 13a, and 13b
does not change as compared to the spectra of the
initial ketones 10a and 10b [15] due to the specific
distribution of the electron density in the cyclopropane
fragment.
the СН group (δ 1.71–1.73) and a doublet of vinyl
3
1
1
protons of the СН group (4.70–4.72 ppm). The Н
2
–
1
NMR spectrum of diol 11 is distinguished from the
spectrum of the α,β-unsaturated ketone 10c by the
(
3
signal of the proton at the С atom of the lupane
–
1
scaffold (δ 3.83–3.88 ppm) and by the absence of the
signal from the formyl proton, and the singlet of the
vinyl proton is shifted upfield (δ 6.45–6.55 ppm). The
1
–
1
2
8
protons of the С Н group form the АВ system, δ
3
2
1
.32–3.77 ppm, J ~11 Hz. In the Н NMR spectra of
the mixture of spirocyclopropanes 12a, 12b, 13a, and
3b the singlet of the formyl proton is conserved, and
the triplets appeared from the Н protons of the
cyclopropane fragment (δ 2.74–3.15 ppm).
1
2
'
Recently a vinylog of ethyl betulonate was prepared
by the reaction of aldehyde 5 with triethylphospho-
nium acetate in the presence of NaН in toluene [16].
We synthesized α,β-unsaturated ketones14а and 14b
by Wittig reaction (Scheme 4).
1
The Н NMR spectrum of compound 10c contains a
singlet of the formyl proton (δ 9.65) and a multiplet of
the protons of the aryl ring in the range 7.28–7.92 ppm.
The singlet corresponding to the vinyl proton is
Scheme 5.
O
O
OH
PhMgBr
THF
TFA
CH Cl
2
2
O
O
O
5
15a, 15b
16
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

CHEMICAL TRANSFORMATIONS OF BETULONIC ALDEHYDE
253
2
5
C
C
2
5
2
4
C
C
23
26
C
1
1
C
1
1
1
0
C
C
12
1
2
10
C
13
9
C
C
7
8C
8C
C
7
9
2
28
C
C
2
C
O
C
2
9
32
6
C
C
31
1
3
C
33
6
C
O
C
3
14
C
C
C
C
C
27
2
5
5
26
C
C
4C
27
23
3
33
14
C
1
4C
C
18
15
C
C
C
17
C
O
C
16
17
16C
34
C
C
15
30
C
2
C
C
C
C
36
C
C
32
22
C
C
35
3
4
C
31
C
2
4
28
C
C
C
2
2
C
C
1
1
8
21
19
C
C
C
21
C
C
29
3
0
C
20
20
1
C
1
C
C
C
O
19
C
3
5
C
C
36
C
1
5b
16
Fig. 1. Molecular structure of 28-hydroxy-28-phenyllup-20(29)-en-3-one 15b and 28-phenylallobetulone 16 by XRD data.
In the IR spectra of compounds 14a and
4b absorption bands of two С=О groups at 1706–
664 cm are observed, and the Н NMR spectra
contain the signals of the protons of the aromatic ring
and two doublets of vinyl protons, δ 6.92–6.97 and
The information on betulonic aldehyde reaction with
Grignard reagents is very limited. The reaction of aldehyde
5 with ethynylmagnesium bromide was shown to afford
28-hydroxy-28-ethynyllup-20(29)-en-3-one [17]. We
obtained 28-hydroxy-28-phenyllup-20(29)-en-3-one 15
applying phenylmagnesium bromide (Scheme 5). The
1
1
–
1
1
7
.34–7.37 ppm, J ~16 Hz.
Scheme 6.
OH
R
OH
R
OH
RCHO
NaBH
MeOH,
CH Cl
4
CH OC H OH,
3
2
4
KOH
2
2
O
O
HO
_
1
5b
17a 17c
19a, 19b
O
R
O
R
RCHO
NaBH4
MeOH,
CH OC H OH,
3
2
4
KOH
CH Cl2
2
HO
O
1
6
18a, 18b
20a, 20b
N N
N N
R =
(a),
(b), 4-ClC H (c).
6 4
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

2
54
SEMENENKO et al.
2
5
C
38
C
37
2
3
1
1
C
1
24
C
26
C
Cl
C
39
C
36
C
25
1
0
9
12
C
C
C
C
40
11
35
C
C
4
1
42
7
2
28
10
12
C
O
C
C
C
C
27C
29
C
C
8
C
2
49 50
1
9
C
C
13
N
N
7
C
4
0
13
C
4
3
6
C
2
C
C
3
3C
C
46
34
8
O
C
C
51
C
26
C
33
C
27C
C
1
6
C
6
14
48
14C
C
C
4
5
32
C
C
3
8
3
5
C
C
23
3
C
39
C
C
4C
C
30
C
17
C
15
4
1
C
5
C
C
C
44
4
C
2
C
15
32
C
2
C
C
O
C
53
C
17
C
31
16
52
C
C
42
31
18
28C
C
C
3
7
34
C
C
24
22
C
C
2
2
C
43
1
C
19C
1
8
47
C
C
1
C
C
1
21
C
C
21
C
C
C
20
O
C
20
C
19
C
C
30
C
29
1
C
O
35
3
6
C
C
1
7c
18a
Fig. 2. Molecular structure of (E)-28-hydroxy-2-[(4-chlorophenyl)methylidene]-28-phenyllup-20(29)-en-3-one 17с and (E)-2-{[3-
4-methylphenyl)-1-phenyl-1H-pyrazol-4-yl]methylidene}-28-phenylallobetulone 18а by XRD data.
(
compound isolated directly from the reaction mixture
contains additionally a singlet of the methine proton
Н (δ 3.68 ppm).
1
9
is a mixture of R,S-enantiomers 15а and 15b in the
1
ratio 1 : 5 as indicated by the Н NMR spectrum of
The structure of compounds 15b and 16 was
unambiguously established by XRD analysis (Fig. 1).
uncrystallized sample. The major isomer 15b was
isolated by recrystallization. The secondary alcohol
1
5b in acid environment suffers Wagner–Meerwein
Ketones 15b and 16 were converted into 2-ylidene
derivatives 17а–17c, 18а, and 18b, and the latter were
rearrangement into 28-phenylallobetulone 16.
subjected to reduction with NaBH in the mixture
4
The structure of compounds 15b and 16 was
established from the data of IR, Н NMR spectra, and
1
МeОН–СН Cl , 1 : 1, to obtain alcohols 19а, 19b and
2 2
2
0а, 20b (Scheme 6).
XRD analysis of the corresponding single crystals. IR
spectra of compounds 15b and 16 in contrast to
the spectrum of initial ketoaldehyde 5 lack the
absorption bands of the formyl fragment in the region
In the IR spectra of α,β-unsaturated ketones 17a–
17c the most characteristic absorption bands are those
–
1
of the keto (1673–1670 cm ) and hydroxy groups
–
1
–1
1
726–1714 cm , and in the spectrum of alcohol 15b a
(3467–3447 cm ). The absorption of the С=О group is
wide band is present of the associated ОН group in the
absent from the spectra of alcohols 19a and 19b, and
the vibrations of the associated ОН groups give rise to
a wide band in the region 3500–3440 cm . In the IR
spectra of 2-ylidene compounds 18a and 18b the
characteristic bands are those of the stretching
–
1
1
range 3475–3447 cm . The Н NMR spectra of
compounds 15b and 16 contain the signals of the
protons of the phenyl ring and the singlet of the proton
–
1
2
8
Н (δ 5.22 ppm), and the spectrum of allobetulone 16
Scheme 7.
N
N
N
N
O
O
Me SOI
3
NaH, DMF
O
O
1
8a
21, 22
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

CHEMICAL TRANSFORMATIONS OF BETULONIC ALDEHYDE
Crystallographic data and parameters of compounds 15–18
255
Parameter
15
16
17c
11.020(1)
13.395(1)
15.912(1)
69.971(8)
89.860(7)
83.946(8)
2193.1(3)
692
18a
6.9308(4)
12.6941(9)
49.230(3)
90.0
a, Å
12.0066(4)
15.4935(5)
16.2139(6)
90.0
11.4738(4)
15.7914(7)
16.9884(8)
90.0
b, Å
c, Å
α, deg
β, deg
γ, deg
90.0
90.0
90.0
90.0
90.0
90.0
3
V, Å
3016.2(2)
1136
3078.1(2)
1136
4331.3(5)
1648
F(000)
Crystal system
Rhombic
Rhombic
Triclinic
Р1
Rhombic
Space group
P2
1
2
1
2
1
P2
1
2
1
2
1
1 1 1
P2 2 2
Z
4
4
2
4
T, K
293
0.068
1.138
60
293
0.066
1.115
60
293
293
0.070
1.167
60
–1
μ, mm
0.116
3
D
calc, g/cm
max, deg
0.968
2
θ
50
Reflections measured
Independent reflections
30371
8753
0.060
4588
18728
8921
0.031
5253
15140
10260
0.055
48388
12583
0.156
4272
R
int
Reflections with F > 4σ(F)
5312
Number of refined parame-
ters
3
56
350
840
522
R
1
0.070
0.177
0.062
0.145
0.107
0.296
0.073
0.129
wR
S
2
0.932
0.975
0.955
0.847
CCDC
1432950
1432951
1432952
1432953
–
1
vibrations of the keto group at 1670 cm and of the
The structure of compounds 17с and 18a was
unambiguously established by XRD analysis (Fig. 2).
–
1
fragment С–О–С (1035–1026 cm ) of the tetrahydro-
furan ring. No absorption of the carbonyl group is
observed in the spectra of compounds 20а and 20b,
and a wide band appears at 3480–3445 cm , charac-
teristic of OH groups involved in the hydrogen bonds.
The band corresponding to the vibrations of the bonds
in the fragment С–О–С retains its position in the
spectrum in going from ketones 18a and 18b to
alcohols 20a and 20b.
The conversion of α,β-unsaturated ketone 18а in a
mixture of isomers 21 and 22 in a ratio 2 : 1 according to
Н NMR data was performed by treating with trimethyl-
sulfoxonium iodide in the presence of NaН in DMF
Scheme 7). We failed to isolate individual compounds
–
1
1
(
2
1 and 22 by chromatography or recrystallization.
IR spectra of compounds 21 and 22 possess low
information since they differ from the spectrum of its
1
The Н NMR spectra of 2-ylidene derivatives 17a–
7c, 18a, and 18b are distinguished from the spectra of
precursor 18a only in the “fingerprint” region. The
1
1
signal of vinyl proton is absent from the Н NMR
their precursors 15 and 16 respectively by a singlet of
vinyl proton and a multiplet of the aromatic protons, δ
spectra of compounds 21 and 22. The cyclopropane
2
'
fragment gives rise to the triplet of the proton Н , δ
2.77–3.14 ppm, and the signals of the methylene group
of the three-membered ring overlapped with the
resonances of the methylene protons of the lupane
scaffold.
7
.16–7.80 ppm. The reduction of the keto group into
the alcohol in compounds 19a, 19b and 20a, 20b is
3
confirmed by the singlets of the methine proton Н
(
δ 3.88) and of vinyl proton (δ 6.63–6.45 ppm).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

2
56
SEMENENKO et al.
0.1 mL of acetic acid, and 10 wt % Pd/С was added.
EXPERIMENTAL
The reaction mixture was saturated with hydrogen and
stirred for 12 h. On completion of the reaction the
solvent was evaporated, the residue was subjected to
chromatography on silica gel, eluting with a mixture
dichloromethane–methanol, 10 : 1. Yield 0.20 g
(71%). White amorphous powder, mp 230–232°C
IR spectra were recorded on a spectrophotometer
Perkin Elmer Spectrum One FTIR from pellets with
1
KBr. Н NMR spectra were registered on spectro-
meters Varian Mercury VX 200 (200 МHz) and Varian
MR-400 (400 МHz) in CDCl , internal reference TMS.
3
–
1
Elemental analysis was carried out on an analyzer EA
000 Eurovektor (CHNS–analysis). Melting points
(decomp.). IR spectrum, ν, cm : 3403 (NH), 2956–
1
3
2782 (CH , CH ), 1707 (C=O). H NMR spectrum, δ,
3
2
were measured on a Koeffler heating block. The
reaction progress was monitored and the purity of
compounds obtained was checked by TLC on
ppm: 0.73 s, 0.75 s, 0.81 s, 0.83 s, 0.91 s, 0.93 s, 1.00
28A
s, 1.05 s (24H, 8CH ), 2.55 d (1Н, H , J 12.2 Hz),
3
2
8B
3.01 d (1Н, H , J 12.9 Hz). Found, %: С 82.15; Н
11.83; N 2.70. С Н NО. Calculated, %: С 82.03; Н
®
Alugram Xtra SIL G/UV254 plates in the systems
34
59
dichloromethane, hexane–ethyl acetate, 10 : 1, dichlo-
romethane–methanol, 100 : 1.
11.95; N 2.81.
2
8-(Phenylimino)lup-20(29)-en-3-one (7а). In
3
-Oxolup-20(29)-en-28-al (1). In 0.6 L of dichlo-
25 mL of methanol was dissolved at heating 0.50 g
(1.14 mmol) of betulonic aldehyde, 0.12 g (1.20 mmol)
of aniline and 0.1 mL of acetic acid was added. The
reaction was carried out at 40°С. After 10 h the
reaction product was precipitated with water, filtered
off, and dried in air. Yield 0.48 g (81%). Yellow amor-
romethane was dissolved at heating 10 g (0.023 mol)
of betulin, and to the warm solution was added at
vigorous stirring 11 g (0.05 mol) of pyridinium chloro-
chromate. The reaction proceeded for 25–35 min (TLC
monitoring). On completion of the reaction 2/3 of
dichloromethane volume was removed on a rotary eva-
porator, and the residue was passed through a 5–8 cm
bed of silica gel. The column was washed with 500 mL
of dichloromethane. The solution was evaporated on a
rotary evaporator till oily state, and 10–15 mL of
methanol was added. The white needle crystals of
aldehyde formed almost immediately, they were
filtered off, washed with methanol, and dried in air.
Yield 7.63 g (76%), mp 129–131°C [11].
–
1
phous powder, mp 84–86°C. IR spectrum, ν, cm :
1
2943–2866 (CH , CH ), 1706 (C=O), 1641 (C=N). H
3
2
NMR spectrum, δ, ppm: 0.91 s, 1.01 s, 1.06 s, 1.71 s
2
9
(18H, 6CH ), 4.67 d (2Н, C H , J 22.1 Hz), 6.86–7.45
3
2
2
8
m (5Harom), 7.88 s (1Н, H ). Found, %: С 84.22; Н
10.14; N 2.67. С Н NО. Calculated, %: С 84.16; Н
3
6
51
10.00; N 2.73.
N-[4-(3-Oxolup-20(29)-en-28-ylideneamino)phe-
nyl]acetamide (7b) was synthesized similarly. Yield
0.55 g (84%). Light-brown amorphous powder, mp
Betulonic acid (3). In a mixture of 20 mL of glacial
acetic acid and 3 mL of water was dissolved 0.1 g of
chromic anhydride. The solution was cooled, and at
stirring 0.2 g (0.46 mmol) of betulonic aldehyde was
added (TLC monitoring). After 45–60 min the reaction
product was precipitated by adding 10% water solution
of sodium chloride, the precipitate was filtered off, washed
with water solution of sodium chloride, and dried. The
dry residue was dissolved in a mixture of 20 mL of
methanol and 5 mL of dichloromethane and 0.1 g of
potassium hydroxide was added. The separated
precipitate was filtered off, the filtrate was evaporated
by half, to the residue 10 mL of acetic acid and water
was added till an amorphous precipitate formed. The
latter was filtered off and dried in air. Yield 0.16 g
–
1
101–103°C. IR spectrum, ν, cm : 3335 br (NH),
3
2944–2860 (CH , CH ), 1704 (C =O), 1688 (C=O),
3
2
1672 (NHCO, amide I), 1642 (N=C), 1533 (NHCO,
1
amide II). H NMR spectrum, δ, ppm: 0.90 s, 1.00 s,
1.05 s, 1.70 s (18H, 6CH ), 2.16 s (3H, CH CO), 4.66
3
3
2
9
3',5'
d (2Н, C H , J 44.7 Hz), 6.94 d (2H, H , J 7.7 Hz),
7.35 s (1H, Hamide), 7.45 d (2H, H , J 7.6 Hz), 7.87 s
(1Н, H ). Found, %: С 79.83; Н 9.59; N 4.88.
С Н N О . Calculated, %: С 79.95; Н 9.53; N 4.91.
2
2
',6'
2
8
3
8
54
2
2
2
8-(Phenylamino)lup-20(29)-en-3-ol (8а). 0.25 g
(
0.49 mmol) of imine 7а was dissolved in methanol,
and a 5-fold excess of NаВН was added at stirring.
4
The reaction product was precipitated with water,
filtered off, and dried in air. Yield 0.23 g (92%). White
amorphous powder, mp 101–103°C. IR spectrum, ν,
(
80%). White amorphous powder, mp 243–245°C [7].
–
1
1
2
8-(Butylamino)lupan-3-one (6). In 15 mL of
cm : 3422 br (NH, OH), 2942–2868 (CH , CH ). H
3 2
methanol was dissolved 0.25 g (0.57 mmol) of
betulonic aldehyde, 0.05 g (0.62 mmol) of butylamine,
NMR spectrum, δ, ppm: 0.74 s, 0.82 s, 0.95 s, 0.98 s,
1
9
1.02 s, 1.68 s (18H, 6CH ), 2.45–2.56 m (1H, H ),
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

CHEMICAL TRANSFORMATIONS OF BETULONIC ALDEHYDE
257
2
8A
3
1
2
.74 d (1H, H , J 11.6 Hz), 3.13–3.21 m (1H, H ), 3.24
(C=C). H NMR spectrum, δ, ppm: 0.76 s, 0.94 s, 1.01
2
8B
29
1a
d (1H, H , J 11.6 Hz), 4.65 d (2Н, C H , J 45.3 Hz),
.57–6.71 m (2H, H ), 7.12–7.20 m (3H, H
Found, %: С 83.35; Н 10.63; N 2.52. С Н NО.
Calculated, %: С 83.50; Н 10.71; N 2.70.
s, 1.10 s, 1.13 s, 1.72 s (18H, 6CH ), 2.15 d (1H, H , J
15.7 Hz), 2.81–2.92 m (1H, H ), 2.97 d (1H, H , J
16.2 Hz), 4.71 d (2Н, C H , J 43.2 Hz), 7.25 s
(1Hvinyl), 7.28–7.92 m (4H, C
2
3
3
',5'
2',4',6'
19
1e
6
).
2
9
3
6
55
2
2
8
H ), 9.64 s (1H, Н ).
6 4
Found, %: С 79.31; Н 8.89; Cl 6.45. С Н ClО .
Calculated, %: С 79.18; Н 8.80; Cl 6.32.
37
49
2
N-[4-(3-Hydroxylup-20(29)-en-28-ylamino)phe-
nyl]acetamide (8b) was similarly prepared. Yield 0.24 g
(
E)-2-[(4-Chlorophenyl)methylidene]lup-20(29)-
(
95%). Light-brown amorphous powder, mp 146–148°C.
–
1
en-3,28-diol (11). In 6–8 mL of a mixture of 2-pro-
panol and dichloromethane, 1 : 1, was dissolved 0.1 g
IR spectrum, ν, cm : 3435 br (OH), 3332 br (NH),
943–2866 (CH , CH ), 1666 (NHCO, amide I), 1552
2
(
0
3
2
1
(
0.18 mmol) of α,β-unsaturated ketone 10c, and to the
solution was added at stirring a 5-fold excess of
NаВН . The reaction proceeded for 2–3 h. The excess
NHCO, amide II). H NMR spectrum, δ, ppm: 0.93 s,
.99 s, 1.01 s, 1.06 s, 1.69 s (18H, 6CH ), 2.13 s (3H,
3
28A
28B
CH CO), 2.74 d (1H, H , J 11.4 Hz), 3.23 d (1H, H ,
J 11.6 Hz), 3.58–3.81 m (1H, H ), 4.66 d (2Н, C H , J
2
H
4
3
3
29
of NаВН was quenched with water at heating to 50–
4
2
3
',5'
6
0°C. The separated precipitate was filtered off and
2.2 Hz), 6.60 d (2H, H , J 8.5 Hz), 7.26 d (2H,
2
',6'
dried in air. Yield 0.09 g (90%). White amorphous
, J 8.4 Hz). Found, %: С 79.18; Н 10.10; N 4.72.
–
1
powder, mp 150–152°C. IR spectrum, ν, cm : 3435 br
С Н N О . Calculated, %: С 79.39; Н 10.17; N 4.87.
3
8
58
2
2
1
(
OH), 2942–2868 (CH , CH ), 1641 (C=C). H NMR
3 2
N-[4-(3-Oxolup-20(29)-en-28-ylamino)phenyl]-
spectrum, δ, ppm: 0.65 s, 0.73 s, 0.97 s, 0.98 s, 1.12 s,
1
9
1e
acetamide (9). A mixture of 0.5 g (1.14 mmol) of
aldehyde 5 and 0.19 g (1.27 mmol) of amine with a
catalytic quantity of acetic acid was boiled in toluene
1
.66 s (18H, 6CH ), 2.35 s (1H, H ), 2.89 d (1H, H ,
3
2
8A
J 12.8 Hz), 3.32 d (1H, H , J 10.6 Hz), 3.77 d (1H,
, J 10.9 Hz), 3.83 s (1H, H ), 4.62 d (2Н, C H , J
18.9 Hz), 6.63 s (1Hvinyl), 7.10 d (2H, H , J 8.3 Hz),
2
8B
3
29
H
2
3
',5'
for 4 h, cooled, and excess NаВН was added. The
4
2
',6'
reaction was continued at room temperature, 2 h later
7
.25 d (2H, H , J 8.0 Hz). Found, %: С 78.73; Н
the reaction mixture was filtered, excess of NаВН was
4
9.34; Cl 6.22. С Н ClО . Calculated, %: С 78.62; Н
3
7
53
2
quenched with water, the organic layer was separated,
and the solvent was removed. The dry residue was
dissolved in dichloromethane and chromatographed on
silica gel eluting with a mixture dichloromethane–
methanol, 10 : 1. Yield 0.39 g (60%). Light-brown
amorphous powder, mp 138–140°C. IR spectrum, ν,
9
.45; Cl 6.27.
(
E)-28-[2-Oxo-2-(4-chlorophenyl)ethylidene]lup-
2
2
0(29)-en-3-one (14a). Betulonic aldehyde 5 (1 g,
.28 mmol) was dissolved in 35 mL of a solution of t-
BuONa. To the solution a mixture was added of 0.6 g
(2.5 mmol) of ω-bromoacetophenone and 0.68 g
–
1
cm : 3369–3342 (NH), 2944–2868 (CH , CH ), 1704
3
2
(
2.6 mmol) of triphenylphosphine in tert-butyl alcohol.
(
C=O), 1667 (NHCO, amide I), 1536 (NHCO, amide II).
1
The reaction proceeded at room temperature for 24 h.
The separated precipitate was filtered off, the reaction
product was precipitated from the filtrate with water,
the formed oily substance was extracted with ethyl
acetate. The organic layer was separated, dried with
Nа SO , filtered, the solvent was removed at a reduced
pressure. The residue was dissolved in dichlorome-
thane and chromatographed on silica gel eluting with
dichloromethane–ethyl acetate, 10 : 1. Yield 0.27 g
(21%). Light-brown amorphous powder, mp 97–99°C.
H NMR spectrum, δ, ppm: 0.87 s, 0.93 s, 0.95 s, 1.00
s, 1.63 s (18H, 6CH ), 2.06 s (3H, CH CO), 2.68 d (1H,
H
(
7
3
3
2
8A
28B
, J 11.2 Hz), 3.17 d (1H, H , J 11.8 Hz), 4.60 d
2Н, C H , J 21.9 Hz), 6.53 d (2H, H , J 8.7 Hz),
2
9
3',5'
2
2
',6'
.02–7.30 m (3H, H , NHamide). Found, %: С 79.52;
2
4
Н 9.68; N 4.81. С Н N О . Calculated, %: С 79.67;
38
56
2
2
Н 9.85; N 4.89.
(
E)-3-Oxo-2-[(4-chlorophenyl)methylidene]lup-
20(29)-en-28-al (10c). A mixture of 0.50 g (1.14 mmol)
–
1
of betulonic aldehyde 5 and 0.18 g (1.20 mmol) of 4-
chlorobenzaldehyde in 10–15 mL of ethyleneglycol
monomethyl ether was boiled for 6–8 h in the presence
of a catalytic quantity of KOH. On cooling the
separated precipitate was filtered off and washed with
alcohol. Yield 0.51 g (79%). White amorphous
IR spectrum, ν, cm : 2943–2869 (CH
3
, C1H
). H NMR
spectrum, δ, ppm: 0.90 s, 0.97 s, 0.99 s, 1.00 s, 1.09 s,
1.70 s (18H, 6CH ), 3.88 s (3H, CH O), 4.68 d (2Н,
2
), 1706
3
(C =O), 1664 (C=O), 1258 (O–CH
3
3
3
2
9
3',5'
C H
, J 23.1 Hz), 6.91–7.05 m (3H, H , Hvinyl), 7.34
2
2
8
2',6'
d (1H, H , J 15.7 Hz), 7.96 d (2H, H , J 8.7 Hz).
Found, %: С 81.91; Н 9.44. С39
С 82.06; Н 9.53.
–
1
powder, mp 195–197°C. IR spectrum, ν, cm : 2943–
796 (CH , CH ), 1723 (CHO), 1684 (C=O), 1639
Н О . Calculated, %:
54 3
2
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

2
58
SEMENENKO et al.
E)-28-[2-Oxo-2-(4-methoxyphenyl)ethylidene]-
(
(E)-28-Hydroxy-2-{[3-(4-methylphenyl)-1-phe-
nyl-1H-pyrazol-4-yl]methylidene}-28-phenyllup-20-
(29)-en-3-one (17a). Yield 0.5 g (85%). White amor-
lup-20(29)-en-3-one (14b) was obtained similarly.
Yield 0.30 g (23%). Slightly colored amorphous powder,
–
1
–1
mp 88–90°C. IR spectrum, ν, cm : 2945–2868 (CH ,
phous powder, mp 126–128°C. IR spectrum, ν, cm :
3
3
1
CH ), 1704 (C =O), 1667 (C=O). H NMR spectrum,
3447 (OH), 2937–2860 (CH , CH ), 1670 (C=O), 1640
2
3
2
1
δ, ppm: 0.90 s, 0.96 s, 1.00 s, 1.05 s, 1.69 s (18H,
(C=C). H NMR spectrum, δ, ppm: 0.88 s, 1.11 s, 1.19
2
9
6
CH ), 4.67 d (2Н, C H , J 22.2 Hz), 6.92 d (1H,
s, 1.23 s, 1.76 s (18H, 6CH ), 2.40 s (3H, 4'-CH ), 2.94 d
3
2
3
3
2
8
1e
19
Hvinyl, J 15.9 Hz), 7.37 d (1H, H , J 16.2 Hz), 7.45 d
2H, H , J 8.6 Hz), 7.88 d (2H, H , J 8.4 Hz).
(1H, H , J 14.8 Hz), 3.02–3.20 m (1H, H ), 4.71 d (2Н,
C H , J 27.4 Hz), 5.28 s (1H, H ), 7.20–7.62 m (13H,
2H , 2C H , Hvinyl), 7.80 d (2H, 2H , J 8.0 Hz),
3
',5'
2',6'
29
28
(
2
',5'
3
2',6'
Found, %: С 79.24; Н 8.78; Cl 6.05. С Н ClО .
38
51
2
6
5
Calculated, %: С 79.34; Н 8.94; Cl 6.16.
8.06 s (1H, Нpyrazole). Found, %: С 83.73; Н 8.55; N
3
3
.73. С Н N О . Calculated, %: С 83.64; Н 8.48; N
53 64 2 2
2
8-Hydroxy-28-phenyllup-20(29)-en-3-one (15a
.68.
(E)-28-Hydroxy-2-{[3-(4-methoxyphenyl)-1-phe-
and 15b). To a solution of 6 g (13.67 mmol) of
betulonic aldehyde 5 in THF was added at stirring an
excess of freshly prepared Grignard reagent. The
solvent was removed at a reduced pressure from the
formed gel-like mass, the dry residue was mixed with
nyl-1H-pyrazol-4-yl]methylidene}-28-phenyllup-20-
(29)-en-3-one (17b). Yield 0.48 g (81%). White amor-
phous powder, mp 158–160°C. IR spectrum, ν, cm :
–
1
1
50 mL of 20% acetic acid. The mixture was stirred
3467 (OH), 2939–2867 (CH , CH ), 1673 (C=O), 1639
3
2
1
for 10–12 h at room temperature. The white precipitate
was filtered off, washed with water, dried in air, and
recrystallized from ethanol. Yield of compound 15b
(C=C), 1250 (O–CH ). H NMR spectrum, δ, ppm:
3
0.89 s, 1.12 s, 1.19 s, 1.23 s, 1.76 s (18H, 6CH ), 2.96
3
1
e
19
d (1H, H , J 16.4 Hz), 3.11 s (1H, H ), 3.86 s (3H, 4'-
OCH ), 4.71 d (2Н, C H , J 27.8 Hz), 5.28 s (1H,
H ), 7.01 d (2H, 2H , J 8.8 Hz), 7.21–7.68 m (11H,
2C H , Hvinyl), 7.80 d (2H, 2H , J 8.3 Hz), 8.05 s
2
9
4.84 g (69%). White amorphous powder, mp 188–190°C.
3 2
–
1
28
3',5'
IR spectrum, ν, cm : 3475 br (OH), 2937–2600 (CH ,
CH ), 1694 (C=O). H NMR spectrum, δ, ppm: 0.97 s,
1
2
3
1
2',6'
2
6
5
2
9
.04 s, 1.08 s, 1.72 s (18H, 6CH ), 4.67 d (2Н, C H , J
8.2 Hz), 5.26 s (1H, H ), 7.19–7.48 m (5H, C H ).
(1H, Нpyrazole). Found, %: С 82.02; Н 8.39; N 3.66.
С Н N О . Calculated, %: С 81.92; Н 8.30; N 3.60.
3
2
2
8
6
5
53 64
2
3
Found, %: С 83.55; Н 10.12. С Н О . Calculated, %:
С 83.67; Н 10.14. A single crystal for XRD experi-
ment was grown from methanol.
36
52
2
(
E)-28-Hydroxy-2-[(4-chlorophenyl)methylide-
ne]-28-phenyllup-20(29)-en-3-one (17c). Yield 0.30 g
81%). White amorphous powder, mp 121–123°C. IR
(
–1
2
8-Phenylallobetulone (16). In 40 mL of dichloro-
methane was dissolved 2.2 g (4.26 mmol) of compound
5b and at cooling was added dropwise 10 mL of
spectrum, ν, cm : 3515 br (OH), 2948–2867 (CH , CH ),
1680 (C=O), 1639 (C=C). H NMR spectrum, δ, ppm:
0.72 s, 1.03 s, 1.05 s, 1.07 s, 1.67 s (18H, 6CH ), 2.34
d (1H, H , J 17.2 Hz), 2.92 d (1H, H , J 17.2 Hz),
3.09–3.22 m (1H, H ), 4.61 d (2Н, C H , J 46.7 Hz),
4.98 s (1H, OH ), 5.07 s (1H, H ), 7.03–7.62 m (10H,
C H , C H , Hvinyl). Found, %: С 80.86; Н 8.79; Cl
5.50. С Н N О . Calculated, %: С 80.78; Н 8.67; Cl
3 2
1
1
3
1
а
1e
trifluoroacetic acid. After the addition of the acid the
reaction proceeded for 4 h (TLC monitoring). The
solution was thrice washed with water, once with
sodium hydrogen carbonate and once more with water.
The organic layer was separated, dried with Nа SO ,
1
9
29
2
2
8
28
6
4
6
5
2
4
53 64
2
3
and evaporated. Yield 2.13 g (97%). White amorphous
5.54. A single crystal for XRD experiment was grown
from ethyl acetate.
–
1
powder, mp 206–208°C. IR spectrum, ν, cm : 2942–
1
2
790 (CH , CH ), 1702 (C=O), 1027 (C–O–C). H
3 2
(
E)-2-{[3-(4-Methylphenyl)-1-phenyl-1H-pyra-
NMR spectrum, δ, ppm: 0.84 s, 0.95 s, 1.00 s, 1.03 s,
1
9
zol-4-yl]methylidene}-28-phenylallobetulone (18a).
1
(
.04 s, 1.08 s (21H, 7CH ), 3.68 s (1Н, H ), 5.22 s
3
2
8
Yield 0.55 g (93%). White amorphous powder, mp 230–
1H, H ), 7.14–7.60 m (5H, C H ). Found, %: С
6 5
–1
2
1
32°C. IR spectrum, ν, cm : 2971–2860 (CH , CH ),
3
2
8
1
3.74; Н 10.23. С Н О . Calculated, %: С 83.67; Н
0.14. A single crystal for XRD experiment was grown
1
36
52
2
670 (C=O), 1024 (C–O–C). H NMR spectrum, δ,
ppm: 0.88 s, 0.89 s, 1.06 s, 1.08 s, 1.10 s, 1.12 s, 1.18 s
from ethyl acetate.
1a
(
21H, 7 CH ), 2.14 d (1Н, H , J 16.9 Hz), 2.41 s (3H,
3
1
e
19
Compounds 17a–17c and 18a, 18b were prepared
analogously to compound 10с from compounds 15b
and 16 respectively.
4'-CH ), 2.99 d (1H, H , J 16.1 Hz), 3.72 s (1Н, H ),
5.25 s (1H, H ), 7.20–7.65 m (13H, 2H, 2H , 2 C H ,
Hvinyl), 7.78 d (2H, 2H , J 7.8 Hz), 8.05 s (1H,
3
2
8
3,5
6
5
2
,6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

CHEMICAL TRANSFORMATIONS OF BETULONIC ALDEHYDE
259
Нpyrazole). Found, %: С 83.75; Н 8.45; N 3.65.
С Н N О . Calculated, %: С 83.64; Н 8.48; N 3.68.
A single crystal for XRD experiment was grown from
a mixture dichloromethane–ethanol, 1 : 3.
Yield 0.18 g (90%). White amorphous powder, mp 168–
–
1
170°C. IR spectrum, ν, cm : 3445 br (OH), 2925–
5
3
64
2
2
1
2864 (CH , CH ), 1670 (C=C), 1027 (C–O–C). H
3
2
NMR spectrum, δ, ppm: 0.77 s, 0.83 s, 1.02 s, 1.08 s,
.15 s (21H, 7CH ), 2.39 s (3H, 4'-CH ), 3.09 d (1Н,
1
3
3
(
E)-2-{[3-(4-Methoxyphenyl)-1-phenyl-1H-pyra-
1e
19
3
H , J 12.8 Hz), 3.67 s (1Н, H ), 3.88 s (1Н, H ), 5.22
s (1H, H ), 6.55 s (1H, Hvinyl), 7.15–7.80 m (14H,
zol-4-yl]methylidene}-28-phenylallobetulone (18b).
28
Yield 0.52 g (88%). White amorphous powder, mp 270–
C H , 2C H ), 7.87 s (1H, Нpyrazole). Found, %: С
–
1
6
4
6
5
2
72°C. IR spectrum, ν, cm : 2946–2832 (CH , CH ),
3 2
8
3.56; Н 8.87; N 3.72. С Н N О . Calculated, %: С
53 66 2 2
1
671 (C=O), 1610 (C=C), 1248 (O–CH ), 1035 (C–O–C).
3
1
83.42; Н 8.72; N 3.67.
H NMR spectrum, δ, ppm: 0.88 s, 0.89 s, 1.06 s, 1.08
s, 1.10 s, 1.12 s, 1.18 s (21H, 7CH ), 2.14 d (1Н, H , J
1
3
2
7
1
a
(E)-2-{[3-(4-Methoxyphenyl)-1-phenyl-1H-pyra-
zol-4-yl]methylidene}-28-phenylallobetulin (20b).
Yield 0.18 g (90%). White amorphous powder, mp 166–
3
1
e
19
6.0 Hz), 2.99 d (1H, H , J 16.1 Hz), 3.72 s (1Н, H ),
.86 s (3H, 4'-OCH ), 5.25 s (1H, H ), 7.01 d (2H,
28
3
3
',5'
–1
H
, J 8.6 Hz), 7.16–7.70 m (11H, 2C H , Hvinyl),
168°C. IR spectrum, ν, cm : 3480 br (OH), 2943–2864
6
5
2
',6'
1
.78 d (2H, 2H , J 8.0 Hz), 8.04 s (1H, Нpyrazole).
(CH
3
, CH
2
), 1247 (O–CH
3
), 1027 (C–O–C). H NMR
Found, %: С 81.81; Н 8.24; N 3.51. С Н N О .
Calculated, %: С 81.92; Н 8.30; N 3.60.
spectrum, δ, ppm: 0.76 s, 0.82 s, 0.83 s, 1.01 s, 1.08 s,
5
3
64
2
3
1
e
1.14 s (21H, 7 CH ), 3.08 d (1H, H , J 12.8 Hz), 3.67
3
1
9
3
s (1Н, H ), 3.85 s (3H, 4'-OCH ), 3.88 s (1Н, H ),
.22 s (1H, H ), 6.54 s (1H, H ), 6.96 d (2H, 2H
J 8.2 Hz), 7.19–7.80 m (12H 2H , 2C H ), 7.86 s
3
Compounds 19а, 19b and 20а, 20b were prepared
analogously to compound 11 from compounds 17 and
28
3',5'
5
,
vinyl
2',6'
6
5
1
8 respectively.
(
1H, Нpyrazole). Found, %: С 81.63; Н 8.47; N 3.49.
С Н N О . Calculated, %: С 81.71; Н 8.54; N 3.60.
(
E)-2-{[3-(4-Methylphenyl)-1-phenyl-1H-pyra-
53 66
2
3
zol-4-yl]methylidene}-28-phenyllup-20(29)-en-3,28-
(
2S,2'S)- and (2R,2'R)-2'-[3-(4-Methylphenyl)-1-
phenyl-1H-pyrazole-4-yl]-3-oxospiro[lup-20(29)-en-
,1'-cyclopropan]-28-al (12a and 13a). Unsaturated
diol (19a). Yield 0.18 g (90%). Light-brown amor-
–
1
phous powder, mp 133–135°C. IR spectrum, ν, cm :
2
1
3
458 br (OH), 2932–2865 (CH , CH ), 1668 (C=C). H
3 2
ketone 10a (0.20 g, 0.29 mmol) was added by portions
to a solution of excess trimethylsulfoxonium iodide
and NаН in anhydrous DMF. The reaction was carried
out at room temperature. On completion of the process
TLC monitoring) the reaction product was precipita-
ted with water, filtered off, and dried in air. Yield 0.15 g
75%). White amorphous powder, mp 210–212°C. IR
NMR spectrum, δ, ppm: 0.72 s, 0.73 s, 1.02 s, 1.05 s,
1
e
19
1
(
2
(
.65 s (18H, 6CH ), 2.83–3.03 m (2H, H , H ), 2.43 s
3
3
29
3H, 4'-CH ), 3.81 s (1H, H ), 4.62 d (2Н, C H , J
3
2
2
8
8.2 Hz), 5.16 s (1H, H ), 6.41 s (1H, H ), 6.93 d
vinyl
2H, 2H , J 8.7 Hz), 7.03–7.86 m (12H, 2H
(
3
',5'
2',6'
,
2
8
8
C H ), 7.81 s (1H, Нpyrazole). Found, %: С 83.31; Н
6 5
(
.62; N 3.56. С Н N О . Calculated, %: С 83.42; Н
–1
5
3
66
2
2
spectrum, ν, cm : 2944–2866 (CH , CH ), 1716
CHO), 1673 (C=O). H NMR spectrum, δ, ppm: 0.39
3
2
1
.72; N 3.67.
(
s, 0.84 s, 0.89 d, 0.95 s, 0.98 s, 1.00 s, 1.10 s, 1.15 s,
(
E)-2-{[3-(4-Methoxyphenyl)-1-phenyl-1H-pyra-
1
2
7
.64 s, 1.67 s (12 CH ), 2.38 d (4.5H, 1.5 4'-OCH ),
3 3
zol-4-yl]methylidene}-28-phenyllup-20(29)-en-3,28-
diol (19b). Yield 0.19 g (95%). Light-brown amor-
phous powder, mp 152–154°C. IR spectrum, ν, cm :
461 br (OH), 2938–2867 (CH , CH ), 1670 (C=C),
248 (O–CH ). H NMR spectrum, δ, ppm: 0.70 s,
.74 s, 1.00 s, 1.07 s, 1.64 s (18H, 6CH ), 2.85–3.11 m
2
''
29
.77–3.09 m (1.5H, H ), 4.45–4.81 m (3Н, C H ),
2
–
1
.03–7.98 m (~13H, C H , C H , Hpyrazole), 9.65 s
6
4
6
5
(
1.2H, Нformyl).
Compounds 12b, 13b, 21, and 22 were obtained
similarly.
(2S,2'S)- and (2R,2'R)-2'-[3-(4-Methoxyphenyl)-
3
1
0
3 2
1
3
3
3
1
e
19
(
2H, H , H ), 3.77 s (4H, 4'-OCH , H ), 4.59 d (2Н,
3
2
9
28
C H , J 28.4 Hz), 5.18 s (1H, H ), 6.45 s (1H, Hvinyl),
2
3
',5'
1-phenyl-1H-pyrazol-4-yl]-3-oxospiro[lup-20(29)-
en-2,1'-cyclopropan]-28-al (12b and 13b). Yield 0.18 g
6
2
8
8
.88 d (2H, 2H , J 8.7 Hz), 7.11–7.74 m (12H,
2
',6'
H
, 2C H ), 7.77 s (1H, Нpyrazole). Found, %: С
6 5
(
90%). White amorphous powder, mp 122–124°C. IR
1.88; Н 8.46; N 3.54. С Н N О . Calculated, %: С
1.71; Н 8.54; N 3.60.
53
66
2
3
–1
spectrum, ν, cm : 2939–2830 (CH , CH ), 1722
(
3
2
1
CHO), 1674 (C=O), 1250 (O–CH3). H NMR
(
E)-2-{[3-(4-Methylphenyl)-1-phenyl-1H-pyra-
spectrum, δ, ppm: 0.37 s, 0.84 s, 0.88 d, 0.95 s, 1.00 s,
1.14 s, 1.66 d (12 CH ), 2.74–3.15 m (4H, H , H ),
3
2
''
19
zol-4-yl]methylidene}-28-phenylallobetulin (20a).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016

2
3
60
SEMENENKO et al.
.87 d (4.7H, 1.5 4'-OCH ), 4.51–4.89 m (3.7Н,
C H ), 6.80–8.13 m (~16H, C H , C H , Hpyrazole),
2. Ge, R., Huang, Y., Liang, G., and Li, X., Curr. Med.
Chem., 2010, vol. 17, p. 412.
3
2
9
2
6
4
6
5
9
.67 d (1.6H, Нformyl).
3. Tolstikov, G.A., Flekhter, O.B., Shul’ts, E.E., Balti-
na, L.A., and Tolstikov, A.G., Khimiya v interesakh
ustoichivogo razvitiya (Chemistry for Sustainable
Development), 2005, vol. 13, p. 1.
(
2S,2'S)- and (2R,2'R)-2'-[3-(4-Methylphenyl)-1-
phenyl-1H-pyrazol-4-yl]-28-phenylspiro[deoxyallo-
betulin-2,1'-cyclopropan]-3-one (21 and 22). Yield
4
. Yogeeswari, P. and Sriram, D., Curr. Med. Chem.,
0
.09 g (93%). White amorphous powder, mp 173–175°C.
2005, vol. 12, p. 657.
5. Dehaen, W., Mashentseva, A.A., and Seitembetov, T.S.,
–
1
IR spectrum, ν, cm : 2925–2863 (CH , CH ), 1674
3
2
1
(
C=O), 1027 (C–O–C). H NMR spectrum, δ, ppm:
Molecules, 2011, vol. 16, p. 2443.
0
1
2
.43 s, 0.76 d, 0.88 s, 0.92 d, 1.00 s, 1.02 s, 1.09 s,
.13 s, 1.23 d (14 CH ), 2.37 d (4.42H, 1.5 4'-CH ),
6. Swidorski, J., Meanwell, N.A., Regueiro-Ren, A., Sit
Sing-Yuen, Chen, J., and Chen, Y., US Patent
no. 210787, 2013; Chem. Abstr., 2013, vol. 159,
no. 371389.
3
3
2
'
2'
.77–2.88 t (1.23H, H ), 3.04–3.14 t (1.26H, H ), 3.59
1
9
28
d (1.58Н, H ), 5.16 d (1.59H, H ), 7.09–7.86 m
(
~22H, C H , 2C H , Hpyrazole).
7. Barthel, A., Stark, S., and Csuk, R., Tetrahedron, 2008,
6
4
6
5
vol. 64, p. 9225.
X-ray diffraction investigation of compounds
5b, 16, 17c, and 18a. XRD experiments were perfor-
8. Ruzicka, L., Häusermann, H., and Rey, Ed., Helv. Chim.
Acta, 1942, vol. 25, p. 171.
1
med on a diffractometer Xcalibur-3 (MoK -radiation,
α
9
. Saxena, B.B., Rathnam, P., and Bomshteyn, A., WO
Patent no. 112929, 2005; Chem. Abstr., 2005, vol. 144,
no. 572.
ССD-detector, graphite monochromator, ω-scanning).
Structures were solved by the direct method applying
SHELXTL software [18]. Crystals of all the
compounds belong to non-centrosymmetric space
groups indicating the presence of a single enantiomer.
The studied compounds (save compound 17c) contain
no heavy atoms preventing establishing the configure-
tion of the chiral centers by Flack parameter, therefore
for compounds 15b, 16, and 18a only the relative
configuration has been established. For compound 17c
the configuration of the chiral centers was established
basing on the Flack parameter [0.0(2)]. The positions
of hydrogen atoms were found from the difference
synthesis of the electron density and were refined by
the rider model (n = 1.5 for methyl and hydroxy
groups and n = 1.2 for the other hydrogen atoms). The
crystallographic data and experimental parameters are
collected in the table. The atomic coordinates and
complete data on bond lengths and bond angles are
deposited in the Cambridge Crystallographic Data
Center (e-mail: deposit@ccdc.cam.ac.uk), the
respective CCDC numbers are listed in the table.
1
0. Tulisalo, J., Pirttimaa, M., Alakurtti, S., Yli-Kauha-
luoma, J., and Koskimies, S., WO Patent no. 38314,
2012; Chem. Abstr., 2013, vol. 158, no. 474940.
11. Wei, Y., Maa, Ch., and Hattor, M., Eur. J. Med. Chem.,
2009, vol. 44, p. 4112.
12. Flekhter, O.B., Ashavina, O.Y., Boreko, E.I., Kara-
churina, L.T., Pavlova, N.I., Kabal'nova, N.N., and
Tolstikov, G.A., Pharm. Chem. J., 2002, vol. 36, p. 303.
13. Melnikova, N., Burlova, I., Kiseleva, T., Klabukova, I.,
Gulenova, M., Kislitsin, A., Vasin, V., and Tana-
seichuk, B., Molecules, 2012, vol. 17, p. 11849.
4. Ze-Qi, X., Koohang, A., Mar, A.A., Majewski, N.D.,
Eiznhamer, D.A., and Flavin, M.T., US Patent
no. 232577, 2007; Chem. Abstr., 2007, vol. 147,
no. 406972.
5. Babak, N.L., Semenenko, A.N., Gella, I.M., Musatov, V.I.,
Shishkina, S.V., Novikova, N.B., Sofronov, D.S.,
Morina, D.A., and Lipson, V.V., Russ. J. Org. Chem.,
1
1
1
2
015, vol. 51, p. 715.
6. Durst, T., Merali, Z., Cayer, C., Arnason, J.T., and
Baker, J.D., WO Patent no. 71506, 2013; Chem. Abstr.,
2
014, vol. 160, no. 716590.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016