Synthesis of Schiff bases on the basis of the isosteviol terpenoid

Article abstract of DOI:10.1134/S1070363207020168

The transformation of the carboxy and keto groups of the isosteviol (ent-16-ketobeyeran-19-oic acid) diterpenoid was used to synthesize its new nitrogen-containing derivatives, including Schiff bases by the C⁴ and C¹⁶ atoms of the is

Full text of DOI:10.1134/S1070363207020168

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 2, pp. 285 296
Original Russian Text O.I. Militsina, I.Yu. Strobykina, G.I. Kovylyaeva, G.A. Bakaleinik, V.E. Kataev, A.T. Gubaidullin, R.Z. Musin, A.G. Tolstikov,
007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 2, pp. 313 324.
Pleiades Publishing, Ltd., 2007.
2
Synthesis of Schiff Bases on the Basis of the Isosteviol Terpenoid
a
a
a
a
O. I. Militsina , I. Yu. Strobykina , G. I. Kovylyaeva , G. A. Bakaleinik ,
a
a
a
b
V. E. Kataev , A. T. Gubaidullin , R. Z. Musin , and A. G. Tolstikov
a
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center,
Russian Academy of Sciences, ul. Arbuzova 8, Kazan, 420088 Russia
e-mail: kataev@iopc.knc.ru
b
Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences, Perm, Russia
Received July 24, 2006
Abstract The transformation of the carboxy and keto groups of the isosteviol (ent-16-ketobeyeran-19-oic
acid) diterpenoid was used to synthesize its new nitrogen-containing derivatives, including Schiff bases by the
4
16
C and C atoms of the isosteviol frame. The structure of the resulting compounds was established by X-ray
diffraction.
DOI: 10.1134/S1070363207020168
1
Schiff bases derived from salicylaldehyde and their
derivatives are applied as ligands of the so-called
salen type in catalytically active metal complexes
group bands at 1200 and 2160 cm . By refluxing
azide III in absolute benzene we obtained isocyanate
IV as colorless crystals. The IR spectrum of the latter
1
[1 10]. They were first successfully applied in asym-
compound lack bands at 1200 and 2160 cm , cor-
metric epoxidation of various olefins [1] and later,
after the discovery of their high potential as chiral
inductors in asymmetric synthesis, such compounds
gained acceptance as catalysts for a wide range of
organic reactions [2 10]. Chirality of salen ligands is
most commonly provided by asymmetrically sub-
stituted ethylenediamine fragments.
responding to the azide group, and shows isocyanate
bands ( 1380 and 2270 cm ). The structure of com-
1
pound IV was proved by X-ray diffraction analysis
(Fig. 1). Acid hydrolysis of isocyanate IV by heating
in benzene with a 30-fold molar excess of HCl gave
amine V hydrochloride. Its IR spectrum displays
1
bands at 1531, 1608, and 2500 2700 cm , charac-
+
teristic of the NH groups, and no longer shows iso-
3
Unlike chiral organophosphorus ligands, most of
which are produced by enantiospecific transformations
of natural optically pure compounds, nitrogen-contain-
ing ligands derived from natural compounds are
scarcely known. The use of salicyalaldimines derived
from dehydroabietic acid as nitrogen-containing
ligands for asymmetric catalysis has only been men-
tioned [11]. Therefore, we considered it expedient to
synthesize Schiff bases on the basis of another di-
terpenoid, isosteviol (ent-16-ketobeyeran-19-oic acid)
1
cyanate bands at 1380 and 2270 cm . The structure
of amine V hydrochloride was established by X-ray
diffractin analysis (Fig. 2). In further reactions we
applied free amine V obtained immediately before use
by neutralization of its hydrochloride with equimolar
amount of NaOH followed by extraction of the amine
with diethyl ether.
Schiff bases VI X were synthesized by refluxing
in benzene equimolar reagent amounts. The reaction
progress was followed by TLC in petroleum ether
diethyl ether benzene, 1:1:1. After removal of the
solvent colored crystals remain. Their IR spectra
(
[
I) [12, 13]. Earlier we obtained esters [14], amides
15], azomethines [16], and halo derivatives [17, 18]
on the basis of keto acid I.
4
contain bands characteristic of C=N, C
H, Carom
arom
Schiff bases isosteviol derivatives by C . The
amine required for synthesis of Schiff bases was ob-
tained by the transformation of the isosteviol carboxy
group by the Curtius reaction (Scheme 1).
1
Carom, as well as OH bonds. The H NMR spectra of
compounds VI X show, along with isosteviol frame
signals at 2.75 0.82 ppm, aromatic and N=CH proton
signals. In the synthesis of Schiff base XI, a slight
excess of Na SO was added to the reaction mixture
Isosteviol azide III was prepared by the reaction
of isosteviol chloride II [19] with aqueous sodium
azide. The IR spectrum of compound III contains,
along with bands characteristic of isosteviol, azide
2
4
(cf. [11]). The molecular structures of Schiff bases
VII IX in crystal were established by X-ray diffrac-
tion analysis (Figs. 3 5).
285

286
MILITSINA et al.
Scheme 1.
O
O
O
HO
Cl
N3
O
O
O
I
II
III
O
O
H N
2
O=C=N
IV
V
O
O
N
OH N
N
X
Y
VI X
XI
VI, X = Y = H; VII, X = Y = t-Bu; VIII, X = H, Y = Br; IX, X = Y = Br; X, X = H, Y = NO2.
1
6
Schiff bases isosteviol derivatives by C . The
By heating isosteviol I or its methyl ester XII with
excess formamide in 90% formic acid we obtained
crystalline substances whose IR spectra contained
formamide and carboxyl absorption bands, as well as
transformation of the keto group of isosteviol I into
an amino group was performed by the Leuckart reac-
tion [20] using as starting compounds both isosteviol
I and its methyl ester XII [17, 21] (Scheme 2).
1
a band near 3300 cm characteristic of the N H bond.
C2
C12
C3
C1
C9
C11
C17
C5
C10
C4
C18
C7
C8
C6
C16
C20
C15
N1
O16
C21
O22
Fig. 1. Molecular geometry of isocyanate IV by X-ray diffraction data. Hydrogen atoms are not shown.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

SYNTHESIS OF SCHIFF BASES ON THE BASIS OF THE ISOSTEVIOL TERPENOID
287
Scheme 2.
O
~~~ NHC(O)H
RO
RO
O
O
I, XII
XIII, XVII
Y
HO
~~ N
~
X
~~~ NH2
RO
RO
O
O
XIV, XVIII
XVI, XX
R = H (I, XIII, XIV), CH (XII, XVII, XVIII, XX); X = Y = t-Bu (XVI); X = NO , Y = H (XX).
3
2
1
The H NMR spectrum of the products shows an al-
dehyde proton signal at 8 ppm. The spectral evi-
dence suggests that the resulting compounds are form-
temperature. The resulting yellow oily material was
dissolved in hexane and washed with dilute HCl to
obtain, after removal of the solvent, crystals. Accord-
ing to the IR spectrum, the main product was Schiff
base XVI. Unfortunately, we failed to separate com-
pound XVI from the starting aldehyde XV. The frac-
1
amides XIII and XVII. According to the H NMR
spectrum, they are diastereoisomers by C in a 87:13
ratio. According to single-crystal X-ray diffraction
data, formamide XIII is a R diastereoisomer (Fig. 6).
By refluxing formamides XIII and XVII in aqueous-
alcoholic NaOH we obtained amines XIV and XVIII.
1
6
1
6
1
tion of the admixture, by H NMR data, comprised
1
0%.
-Nitro-2-hydroxybenzaldehyde (XIX) easier than
5
Amine XIV with 3,5-di-tert-butyl-2-hydroxybenz-
aldehyde (XV) under reflux failed to form salicyalal-
dimine even after 8 h. Therefore, the reaction was
performed by the procedure described in [11]. Sodium
methoxide in absolute methanol and equimolar
amount of aldehyde XV were added in succession to
amine XIV, the mixture was stirred for 6 h at room
aldehyde XV reacts with isosteviol derivatives with an
1
6
NH group on C . Schiff base XX was obtained by
2
refluxing equimolar amounts of amine XVIII and
aldehyde XIX in benzene for 6 h. After removal of
the solvent at reduced pressure, a yellow product
1
crystallized, which, based on IR and H NMR data,
was assigned structure XX.
C2A
C5A
C12A
C3A
C1A
C10A
C9A
C11A
C4A
C17A
C13A
C7A
C14A
H1K
C8A
C6A
N1A
1
J
C20A
C16A
H
H1L
O16A
C15A
Fig. 2. Geometry of one of the symmetrically independent molecules of aminoketone V hydrochloride by X-ray diffraction data.
Ammonium hydrogen atoms are only shown.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

288
MILITSINA et al.
C3
C2
C1
C18
C9
C10
C4
C11
C12
C5
H23
N1
H21
C6
C13
C17
C14
0C C7
C8
H2
O23
C20
C21
H20A
C30
H20B
C15
C23
C16
O16
C22
C24
C27
C27
C31
C29
C26
C25
C35
C33 C32
C34
Fig. 3. Molecular geometry of Schiff base VII by X-ray diffraction data. Selected hydrogen atoms are shown.
Cl2
C1
C12
C3
C2
C17
C11
C9
Cl1
C18
C28
C10
C8
C13
C14
C4
C7
Cl3
H28
C6
H21
C20
C16
C15
C21
N1
O16
H20C
H20A
H20B
H23
C22
C27
C23
O23
C26
Br26
C24
C25
Fig. 4. Molecular geometry Schiff base VIII chloroform solvate of the chloroform solvate by X-ray diffraction data. Selected
hydrogen atoms are shown. Dotted line shows the hydrogen bond.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

SYNTHESIS OF SCHIFF BASES ON THE BASIS OF THE ISOSTEVIOL TERPENOID
289
Cl2
Cl1
C28
H28
Cl3
C11
C12
C17
C3
C1
C9
C2
C14
C13
C10
C18
C5
C4
7 C8
C16
C
C15
C6
O16
H21
C20
N1
H20B
H20C
C21
C22
H20A
H23
C27
C23
O23
C26
C24
C25
Br26
Br24
Fig. 5. Molecular geometry Schiff base IX chloroform solvate by X-ray diffraction data. Selected hydrogen atoms are shown.
Dotted line shows the hydrogen bond.
C3
C2
C1
C10
C18
C9
C12
C4
C11
C17
C5
C14
C13
O2
C6
C7 C8
C19
C20
C16
C15
161
H
O1
N16
C22 O22
H16
C21
H221
Fig. 6. Molecular geometry of compound XVII by X-ray diffraction data. Formamide hydrogen atoms are only shown.
Schiff bases VII IX were analyzed by X-ray dif-
fraction (Figs. 3 5) to find that they all contain an
intramolecular hydrogen bond O H N with the
following parameters.
Comp. no.
VII
d(H N),
1.86
(OH N), deg
141
152
148
VIII
IX
1.75
1.88
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

290
MILITSINA et al.
C3
C2
C18
C1
C4
C5
C9
C12
C11
C10
H21
C17
C7
C21
C6
C14
C8
N1
C13
H20B
H20A
H20C
C27
C22
O16
H23
O23
C15 C16
C23
Br2
C26
H28
H30B
C25
O28
H30C
C24
C30
C29
H30A
Br1
H29B
H29A
Fig. 7. Molecular geometry of ethanol solvate XXI of Schiff base IX by X-ray diffraction data. Selected hydrogen atoms
are shown. Dotted lines show hydrogen bonds.
Compounds VII IX feature quite different orienta-
from the other, qualitative conformational analysis
was employed. For Schiff bases VI IX we calculated,
by the PM3 method by the Hyperchem 6.0 program,
the formation enthalpies at varied rotation angle of
tions of the salicylaldimine fragment with respect to
the isosteviol frame. In compound VII it is almost
orthogonal [the C C N C dihedral angle (Fig. 3) is
5
4
1 21
4
1
8
5.6 ]. In compounds VIII and IX, the salicylal-
the salicyaldimine fragment about the C N bond
(Figs. 3 5). For the reference point we took a con-
dimine fragment points by its hydroxyl group inward
5
4
1
21
5
4
1 21
the isosteviol frame [the C C N C dihedral angles
Figs. 4 and 5) are 170.4 and 176.1 , respectively]. To
formation with a zero C C N C angle, in which the
hydroxy group of the aromatic fragment points out-
ward and the azine hydrogen atom points inward
the isosteviol fragment. Rotation was effected clock-
(
find out whether the fragment orientation is solvent-
dependent, we compared the X-ray diffraction ana-
lyses of a chloroform solvate of Schiff base IX
4
23
23
wise about the C N bond so that the O
H
hyd-
(
Fig. 5) and solvate XXI of the same compound with
roxy group in the variation range of the rotation angle
ethanol (Fig. 7). No differences were revealed, even
though the ethanol molecule residing in the unit cell
proved to be bound with the molecule of compound
IX with an intermolecular hydrogen bond O H O
2
0
(
0 120 ) rotated toward the C H group of the iso-
3
5
4
1 21
steviol fragment. Thus, the C C N C angles in the
structures in Figs. 3 and 4 are 85.6 and 170.4 ,
respectively.
(
Fig. 7) with the following parameters: d(H O)
1
.98 and (OH O) 165 . The structure of ethanol-
Table 1 lists the calculation results for compounds
VI IX. Regardless of the fact that a fairly rough ap-
proximation was applied (without geometry optimiza-
tion for each varied angle value), the resulting data
give insight into the problem, at least on a qualitative
solvate XXI of compound IX is similar to those of
chloroform solvates of compounds VIII and IX: The
C C N C dihedral angle (Fig. 7) of 173.2 scarcely
differs from the above-listed respective angles in
compounds VIII and IX. Parameters of the O H N
intramolecular hydrogen bond in ethanol solvate XXI
of compound IX (Fig. 7), too, are close to those listed
5
4
1 21
5
4
1 21
level. Table 1 shows that, as the C C N C angle
varies in the range 60 210 , the formation enthalpy
of all the compounds studied varies as little as from 0
above: d(H N) 1.83
and (O H N) 149 .
1
to 12.6 kJ mol ; therewith, in most cases the energy
5
4
1 21
To find out the reasons for the different orienta-
tions of the salicyaldimine fragments in compound
VII, on the one hand, and compounds VIII and IX,
gap between conformers with the C C N C angles
180 (Figs. 4, 5, and 7) and 90 (Fig. 3) is close to
1
4.2 kJ mol , i.e. they are energetically equivalent.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

SYNTHESIS OF SCHIFF BASES ON THE BASIS OF THE ISOSTEVIOL TERPENOID
291
As would be expected, the rotation energy of the
salicylaldimine fragment about the C N bond is
Table 1. Formation enthalpies (kJ mol) of compounds
VI IX at varied rotation angle of the salicyalaldimine
fragment about the C N bond by PM3 data
4
4
1
determined by the through-space interaction of the
azine H21 (Figs. 3 5 and 7) and isosteviol frame
hydrogens. As seen from the corresponding inter-
atomic distances, during rotation of the salicylaldi-
Angle,
deg
VI
VII
VIII
IX
1
4
5
4
1 21
mine fragment about the N C bond (the C C N C
2
1
varies from 0 to 60 ), the distance between H and,
first, C H and, second, isosteviol H hydrogens be-
0
30
60
134.7
56.5
9.6
134.3
56.5
9.6
136.8
99.6
25.9
11.7
11.3
7.5
125.9
84.1
13.8
2.5
11.3
3.8
2
0
6
3
comes shorter than the sum of the van der Waals radii.
5
4
1 21
Similarly, as the C C N C angle increases from
90
0
8.8
6.7
5.4
0
8.8
6.3
5.4
2
1
2
20 to 360 , the distance between H and, first, the
equatorial hydrogen atom on C , second, the axial
hydrogen atom on C , and, third, C H hydrogens
120
150
180
210
240
270
300
330
3
2
20
0
2.5
0
2.1
3
become shorter than the sum of the van der Walls
radii. It is these steric interactions that determine the
structure of Schiff bases derived from isosteviol,
specifically, the orientation of the salicylaldimine
13.8
39.3
114.6
224.3
545.2
134.7
13.8
39.3
114.6
224.7
545.2
134.3
15.9
75.3
368.6
296.2
136.8
18.8
84.5
202.5
595.4
125.9
4
fragnet on C of the diterpenoid hydrocarbon frame.
3
60
To find out whether Schiff bases VI XI and XX
can be used as ligands for metal-complex catalysis of
asymmetric reactions, we studied their behavior in the
oxidation of thioanisole with hydrogen peroxide in
the presence of vanadium acetylacetonate. Unfortu-
nately, phenyl methyl sulfoxide obtained in quantita-
tive yield contained only little S enantiomer (the op-
tical purity was always no more than 0.9%). This
result suggests that, under the reaction conditions, no
vanadium complex with isosteviol ligands forms. The
reason follows from the X-ray diffraction data. In the
conformations having the hydroxy group of the sali-
cyaldimine fragment pointing inward the tetracyclic
diterpenoid frame (Figs. 4, 5, and 7), vanadium cannot
approach the N H O system. In the alternative,
the rider model. All calculations were performed
using the MolEN [24] and WinGX programs [25].
Intermolecular contacts, including hydrogen atoms in
crystals were analyzed using the PLATON program
[26]. The absolute configurations of IV and VII were
determined by comparing with the configuration of
isosteviol (I) [13], and the absolute configurations of
the other compounds, by the Flack procedure [27].
The unit cell parameters, experimental details, and
refinement results are given in Table 2. The atomic
coordinates and geometric parameters of structures
IV, V, VII IX, XVII, and XXI are deposited in the
Cambridge Structural Database.
5
4
1 21
orthogonal conformation with the C C N C angle
of about 90 (Fig. 3), complex formation is probably
The IR spectra were recorded on a UR-20 spec-
trophotometer in the range 400 3600 cm 1 and on a
1
8
20
sterically hindered by the C H and C H hydrogens,
3
3
Bruker Vector 22 Fourier spectrometer in the range
as well as by the equatorial and axial hydrogen atoms
1
3
2
400 4000 cm for mulls in mineral oil or KBr pellets.
on C and C , respectively.
The mass spectra were obtained on an MX-1310
instrument (R 10000) at an ionizing energy of 60 eV,
collector current 30 A. Samples were introduced
through a direct probe inlet, the ampule was heated
from 120 to 250 C, and the ion source was operated
at 120 C. The exact mass numbers were measured
against perfluorokerosene.
EXPERIMENTAL
X-ray diffraction analysis was performed on Enraf-
Nonius CAD-4 automated four-circle diffractomers on
MoK (V) and CuK (IV, VII, VIII, XI, XVII, XXI)
radiations at 20oC; no intensity decay of control ref-
lections occurred. For all the samples, except for V
and VII, absorption corrections were applied. The
structures were solved by the direct method by the
SIR program [22] and refined first isotropically and
then anisotropically by the SHELX-97 program [23].
The hydroxyl and ammonium hydrogen atoms were
located by difference synthesis, and the other atoms
were located by stereochemical criteria and refined by
1
The H NMR spectra were obtained on Avance 600
and Bruker WM 250 spectrometers. Column chroma-
tography was performed on silica gel (Chemapol).
Reaction mixtures were analyzed by TLC on Silufol
UV-254 plates.
4 -Azido-19-nor-ent-16-ketobeyeran (III).
A
solution of 0.021 g of sodium azide in 2 drops of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

292
MILITSINA et al.
1
+
water was added to a solution of 0.1 g isosteviol
chloride II in 5 ml of acetone. After 15 min, an ad-
ditional 5 ml of water was added. A precipitate
formed and was filtered off, washed with water, and
dried in air to obtain 0.07 g (70%) of compound III
spectrum, , cm : 1531, 1608, 2500 2800 (NH ),
3
1
1740 (C=O). HNMR spectrum (D O), , ppm (J, Hz):
0.94 2.1 m (20H, isosteviol frame), 0.94 s (3H, 20-
CH ); 0.95 s (3H, 17-CH ); 1.36 s (3H, 18-CH ); 2.65
d.d (1H, H , J 18.5, 3.8). Mass spectrum, [M HCl] :
m/zexp 289.2491, m/zcalc 289.2406 (C H NO).
2
3
3
3
1
5
+
as a colorless powder, mp 137 140 C. IR spectrum,
19
31
1
,
cm : 1200, 2160 (N ), 1690 (COOH), 1735 (C=O).
3
+
Shiff bases VI X. A mixture of equimolar amounts
of the corresponding aldehyde and freshly prepared
amine V for refluxed in absolute benzene for 2 h. The
solvent was removed by distillation to leave colored
powders that were recrystallized from petroleum ether.
Mass spectrum, [M N ] : m/z
315.2207, m/zcalc
2
exp
3
15.2198 (C H NO ).
20 29 2
4
-Isocyanato-19-nor-ent-16-ketobeyeran (IV).
A solution of 0.07 g of azide III in 3 ml of absolute
benzene was refluxed for 6 h. The solvent was re-
moved by distillation, and the reaction product was
N-(2-Hydroxyphenylmethylene)-4 -amino-19-
nor-ent-16-ketobeyeran (VI). Yield 0,06 g (93%),
recrystallized from petroleum ether. Yield 0.06 g
2
0
1
mp 50 52 C, [ ]n
32.3 (c 0.73, C H ). IR spec-
6 6
(
2
86%), mp 118 120 C. IR spectrum, , cm : 1380,
1
1
270 (N=C=O), 1740 (C=O). H NMR spectrum
trum, , cm : 765 (H C
1646 (C=N), 1735 (C=O), 3425 (OH). H NMR spec-
), 1500, 1600 (C Carom),
arom
1
(
CDCl ), , ppm (J, Hz): 0.8 1.9 m (20H, isosteviol
3
frame), 0.97 s (3H, 20-CH ), 0.99 s (3H, 17-CH ),
trum (C D ), , ppm (J, Hz): 0.8 1.8 m (19H, iso-
3
3
6
6
1
5
1
.36 s (3H, 18-CH ), 2.72 d.d (1H, H , J 18.5, 3.6).
steviol frame) 0.8 s (3H, 20-CH ), 0.96 s (3H, 17-
3
3
3
CH ), 1.22 s (3H, 18-CH ), 2.1 d (1H, H , J 14.6),
.68 d.d (1H, H , J 18.5, 3.4 ), 6.82 6.93 m
2Harom), 7.22 7.28 m (2Harom), 8.32 s (1H, N=CH).
3
3
e
4
-Amino-19-nor-ent-16-ketobeyeran hydro-
15
2
(
chloride (V). To a solution of 1.2 g of isocyanate IV
in benzene, 3 ml of conc. HCl was added, and the
mixture was refluxed for 6 h. The solvent was re-
moved to leave a white powder that was recrystallized
from benzene. Yield 0.66 g (55%), mp 273 C. IR
+
Mass spectrum, [M] : m/z
393.2675, m/zcalc
exp
3
93.2668 (C H NO ).
26 35 2
N-(3,5-Di-tert-butyl-2-hydroxyphenylmethylene)-
Table 2. Crystal parameters of compounds IV, V, VII, VIII, XI, XVII, and XXI and conditions of X-ray diffraction
experiments
Parameter
IV
V
VII
Color, habitus
Formula
colorless, prismatic
C H NO
C H NO Cl
C H NO
2
2
0
9
2
19 32
34 51
Molecular weight
Syngony
Space group
Unit cell parameters,
314.55
rhombic
325.91
monoclinic
I 2
a 16.784(11),
b 28.06(2),
c 17.250(10),
505.76
monoclinic
P 21
a 8.927(1),
b 6.849(2),
c 24.70(2),
93.22(8)
1508(1)
2
P 2 2 2
1 1 1
a 7.439(5),
b 8.87(1),
c 26.11(2)
9
3.91(6)
3
V,
1723(3)
4
1.38
5.69
688
8105(9)
16
1.07
1.91
2848
Z
d, gcm 3 (calc)
1.11
5.13
556
1
Absorption coefficient, cm
F(000)
Number of measured reflections
Number of observed reflections with I > 2 (I)
Flack parameter
1924
1722
13338
3449
0.02(8)
R 0.0532,
RW 0.1190
0.937
6066
1667
Final divergence factors
R 0.0645,
RW 0.1804
1.048
R 0.0968,
RW 0.2243
1.052
Fit parameters
Number of refined parameters
Number of unique reflections
237
1924
793
7599
335
3597
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

SYNTHESIS OF SCHIFF BASES ON THE BASIS OF THE ISOSTEVIOL TERPENOID
293
Table 2. (Contd.)
Parameter
VIII
yellow, prismatic
C H Br NO
XI
X
XI
Color, habitus
Formula
colorless,
prismatic
yellow,
prismatic
C H BrNO
C H NO3
C H Br NO
2
6
34
2
26 33
2
2
22 35
26 33 2 2
CHCl3
591.82
rhombic
CHCl3
670.72
monoclinic
P 21
CH O
C H O
2 6
4
Molecular weight
Syngony
Space group
393.55
monoclinic
P 21
597.42
monoclinic
P 21
P 2 2 2
1 1 1
Unit cell parameters,
a 10.697(2),
b 11.340(3),
c 21.950(6)
a 10.983(9),
b 10.598(7),
c 12.291(12),
a 7.429(1),
b 9.495(3),
c 16.380(3),
90.65(1)
1155.3(4)
2
a 10.90(2),
b 10.503(13),
c 11.954(9),
90.34(7)
1369(3)
2
9
8.85(7)
3
V,
2663(1)
4
1.48
49.79
1224
3118
2083
1414(2)
2
1.58
65.49
680
Z
d, gcm 3 (calc)
Absorption coefficient, cm
F(000)
1.13
6.03
432
2623
1.45
40.01
616
3049
1
Number of measured reflections
Number of observed reflections with
I > 2 (I)
3157
2640
1970
2612
Flack parameter
Final divergence factors
0.00(3)
R 0.0432,
RW 0.1109
1.061
0.03(4)
R 0.0541,
RW 0.1498
1.081
0.1(4)
R 0.0417,
RW 0.1126
1.049
0.02(4)
R 0.0683,
RW 0.1837
1.061
Fit parameters
Number of refined parameters
Number of unique reflections
309
3118
318
2998
285
2439
308
2900
4
0
-amino-19-nor-ent-16-ketobeyeran (VII). Yield
(1Harom, J 8.9, 2.1 ), 7.74 s (1H, N=CH). Mass spec-
+
2
0
trum, [M] : m/z
471.1796, m/zcalc 471.1773
.073 g (93%), mp 225 C (from C H ), [ ]
29.0
exp
6
12
n
1
(C H NO Br).
2
6
34
2
(c 0.54, C H ). IR spectrum, , cm : 880 (H Carom),
6 6
1
3
470, 1600 (C Carom), 1623 (C=N), 1734 (C=O),
N-(3,5-Dibromo-2-hydroxyphenylmethylene)-4 -
1
452 (OH). H NMR spectrum (CDCl ), , ppm (J,
3
amino-19-nor-ent-16-ketobeyeran (IX). Yield 0.21 g
Hz): 0.82 1.9 m (19H, isosteviol frame), 0.82 s (3H,
20
(
83%), mp 60 63 C (from CHCl ), [ ]
13.0
3
n
20-CH ), 0.98 s (3H, 17-CH ), 1.22 s (3H, 18-CH ),
1
3
3
3
(c 0.74, C H ). IR spectrum, , cm : 679 (C Br), 868
6 6
3
1
.31 s (9H, t-Bu), 1.44 s (9H, t-Bu), 2.12 d (1H, H ,
(H Carom), 1493, 1600 (C Carom), 1623 (C=N), 1735
e
1
5
1
J 13.6), 2.73 d.d (1H, H , J 18.6, 3.4), 7.05 s
1Harom), 7.35 s (1Harom), 8.32 s (1H, N=CH). Mass
(C=O), 3444 (OH). H NMR spectrum (C D ), , ppm
6
6
(
(J, Hz): 0.4 1.7 m (20H, isosteviol frame), 0.54 s
+
spectrum, [M] : m/z
505.3983, m/zcalc 505.3920
(3H, 20-CH ), 0.82 s (3H, 17-CH ), 1.01 s (3H, 18-
exp
3
3
(C H NO ).
15
3
4
51
2
CH ), 2.43 d.d (1H, H , J 18.3, 2.6), 6.76 s (1Harom),
3
7
.50 s (1Harom), 7.54 s (1H, N=CH). Mass spectrum,
N-(5-Bromo-2-hydroxyphenylmethylene)-4 -
+
[M] : m/z 549.0895, m/zcalc 549.0877 (C H NO
exp 26 33 2
amino-19-nor-ent-16-ketobeyeran (VIII). Yield
Br2).
2
0
0
(
8
1
.2 g (83%), mp 86 89 C (from CHCl ), [ ]
87.1
3
n
1
N-(2-Hydroxy-5-nitrophenylmethylene)-4 -
amino-19-nor-ent-16-ketobeyeran (X). Yield 0.09 g
(83%), mp 105 107 C, [ ]n 28.1 (c 0.24, C H ).
c 0.78, CH OH). IR spectrum, , cm : 683 (C Br),
3
16 (C Harom), 1472, 1600 (C Carom), 1623 (C=N),
1
20
740 (C=O), 3432 (OH). H NMR spectrum (C D ),
6
6
6
6
1
,
0
ppm (J, Hz): 0.55 1.8 m (20H, isosteviol frame),
IR spectrum, , cm : 1337, 1544 (C NO ), 1488,
2
.64 s (3H, 20-CH ), 0.87 s (3H, 17-CH ), 1.01 s (3H,
3
3
1612 (C Carom), 1634 (C=N), 1733 (C=O), 3355 (OH).
1
5
1
1
8-CH ), 2.50 d.d (1H, H , J 18.3, 3.6), 6.76 d
H NMR spectrum (C D ), , ppm (J, Hz): 0.4 1.7 m
3
6
6
(1Harom, J 8.4), 7.00 d (1Harom, J 2.1), 7.11 d.d
(20H, isosteviol frame), 0.57 s (3H, 20-CH ), 0.80 s
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

294
MILITSINA et al.
(
3H, 17-CH ), 1.02 s (3H, 18-CH ), 2.47 d.d (1H,
ent-16-aminobeieran-19-oic acid (XVI). Sodium
methoxide, 0,14 ml of a 1 N solution, was added to a
solution of 0.2 g of amino acid XIV hydrochloride in
20 l of absolute methanol, followed by 0.11 g
(0.5 mmol) of 3,5-di-tert-butyl-2-hydroxybenaldehyde
3
3
1
5
H , J 18.6, 3.4), 6.64 d (1Harom, J 9.4), 7.52 d
(
1Harom, J 2.1), 7.82 d (1Harom, N=CH, J 2.1), 7.88 d
+
(1Harom, J 9.2, 2.4). Mass spectrum, [M] : m/z
exp
4
38.2549, m/zcalc 438.2518. (C H N O ).
26 34 2 4
(
XV), and the mixture was stirred for 6 h at 20 C. The
N-(Pyridin-2-ylmethylene)-4 -amino-19-nor-ent-
6-ketobeyeran (XI). Pyridine-2-carbaldehyde,
.038 g, was added to a solution of 0.1 g of free
amine V in absolute benzene. The mixture was left to
stand at room temperature for 6 h. Sodium sulfate,
solvent was removed by distillation, the yellow oily
residue was dissolved in hexane, washed with 3% HCl,
water to pH 7, and dried over molecular sieves.
Hexane was removed at reduced pressure, and the
yellow oily residue was recrystallized from aceto-
nitrile to obtain light yellow crystals. Yield 0.16 g
(60%), mp 85 87 C. IR spectrum, , cm : 780 (H
Carom), 1470, 1600 (C Carom), 1640 (C=N), 1690
(COOH). H NMR spectrum (C D ), , ppm (J, Hz):
0.76 1.9 m (19H, isosteviol frame), 0.76 s (3H,
20-CH ), 0.91 s (3H, 17-CH ), 1.14 s (3H, 18-CH ),
1
0
0
.5 g (3.5 mmol) was added, the mixture was refluxed
for 1 h, and Na SO was filtered off. The solvent was
1
2
4
removed by distillation to leave a colorless powder.
2
0
1
Yield 0.1 g (74%), mp 65 68 C. [ ]n
42.8
6
6
1
(
c 0.85, C H ). IR spectrum, , cm : 774 (C H ),
1
6
6
arom
1
567, 1586 (C Carom), 1644 (C=N), 1740 (C=O). H
3
3
3
3
1
.34 s (9H, t-Bu), 1.65 s (9H, t-Bu); 2.28 d (1H, H ,
NMR spectrum (C D ), , ppm (J, Hz): 0.7 2.0 m
e
6
6
15
J 13.3), 3.02 d.d (1H, H , J 11.1, 4.5), 7.09 s
(
(
20H, isosteviol frame), 0.88 s (3H, 20-CH ), 1.00 s
3
1
5
(1Harom), 7.59 s (1Harom), 7.98 s (1H, N=CH); 11.6 s
3H, 17-CH ), 1.02 s (3H, 18-CH ), 2.57 d.d (1H, H ,
+
3
3
(1H, CHO, admixture). Mass spectrum, [M] : m/z
exp
J 18.8, 3.1), 6.70 6.73 m (1Harom), 7.18 7.21 m
1Harom), 8.06 d (1Harom, J 7.8), 8.50 br.s (1Harom),
5
35.4092, m/zcalc 535.4026 (C H NO ).
35 53 3
(
+
8
3
.52 s (1H, N=CH). Mass spectrum, [M] : m/zexp
78.2694, m/zcalc 378.2670 (C H N O).
Methyl ent-16-formamidobeieran-19-oate
(XVII). A mixture of 0.82 g isosteviol methyl ester
XII), 4.7 g of formamide, and 2.5 g of 90% formic
25
34
2
(
ent-16-Formamidobeieran-19-oic acid (XIII).
acid was heated for 6 h at 190 C. Excess formamide
and formic acid were removed by distillation. The
reaction product was isolated by column chromato-
graphy on silica gel (chloroform petroleum ether,
1:3). Recrystallization from methanol gave 0.45 g
A mixture of 0.3 g of isosteviol I, 2 g of formamide
and 1 g of 90% formic acid was heated for 18 h at a
bath temperature of 170 C. After cooling, crystal
formed and were washed with petroleum ether. Yield
1
0
1
.3 g (90%), mp 284 287 C. IR spectrum, , cm :
(51%) of colorless crystals, mp 202 205 C. IR spec-
541, 1644, 1665 (O=C N), 1697 (COOH), 3334
NH). H NMR spectrum (CD OD), , ppm (J, Hz):
1
1
trum, , cm : 1530, 1657 (O=C N), 1726 (COCH ),
3
(
3
1
3
283 (NH). H NMR spectrum (CD OD), , ppm (J,
3
0
.78 1.95 m (19H, isosteviol frame), 0.78 s (3H, 20-
Hz): 0.68 2.2 m (20H, isosteviol frame), 0.68 s (3H,
20-CH ), 0.90 s (3H, 17-CH ), 1.15 s (3H, 18-CH ),
CH ), 0.81 s (3H, 17-CH ), 1.10 s (3H, 18-H ),
2
3
3
3
3
1
5
3
3
3
.12 d (1H, 3-H , J 14.1), 3.42 3.58 m (2H, H ),
.97 d.d (1H, H , J 11.4, 6.0), 7.98 s (1H, O=CH).
e
2
16
3
.61 s (3H, 19-OCH ), 4.12 br.s (1H, H ), 8.21 s
1
6
3
+
(1H, O=CH). Mass spectrum, [M] : m/z 361.2693,
+
exp
Mass spectrum, [M] : m/zexp 347.2493, m/zcalc
47.2460 (C H NO ).
m/zcalc 361.2619 (C H NO ).
22
35
3
3
2
1
33
3
Methyl ent-16-aminobeieran-19-oate (XVIII).
Formamide XVII, 0.4 g, was refluxed in aqueous-
ethanolic NaOH (1.5 g of NaOH, 15 ml of ethanol,
and 15 ml of water) for 3 h. Ethanol was removed at
reduced pressure, the reaction products were extracted
with ether, and the extract was dried with MgSO4.
The solvent was removed to obtain 0.32 g (87%) of
ent-16-Aminobeieran-19-oic acid hydrochlo-
ride (XIV). Formamide XIII, 0.2 g, was refluxed in
aqueous-ethanolic NaOH (0.75 g of NaOH, 5 ml of
ethanol, and 5 ml of water) for 3 h, after which it was
acidified with 5% HCl, and the reaction product was
extracted with butan-1-ol. The solvent was removed
by distillation to leave a colorless powder. Yield 0.1 g
1
compound XVIII as a colorless powder, mp 109 C.
(
1
50%), mp 365 367 C. IR spectrum, , cm : 1520,
1
+
3
IR spectrum, , cm : 1721 (C=O), 3394, 3421 (NH ).
616, 2500 2700 (NH ), 1689 (COOH). 1H NMR
2
1
H NMR spectrum (C D ), , ppm (J, Hz): 0.7 2.3 m
spectrum (D O), , ppm (J, Hz): 0.86 2.0 m (19H,
6
6
2
(
(
20H, isosteviol frame), 0.81 s (3H, 20-CH ), 0.84 s
isosteviol frame), 0.86 s (3H, 20-CH ), 1.07 s (3H,
3
3
1
6
3
e
3H, 17-CH ), 1.12 s (3H, 18-CH ), 2.76 d.d (1H, H ,
1
1
7-CH ), 1.27 s (3H, 18-CH ), 2.11 d (1H, H , J
3.1), 3.40 3.43 m (1H, H ). Mass spectrum, [M
HCl] : m/z 319.2583, m/zcalc 319.2512 (C H NO ).
3
3
3
3
+
1
6
J 10.7, 6.3), 3.32 s (3H, 19-OCH ). [M] : m/z
3
exp
+
3
33.2696, m/zcalc 333.2668 (C H NO ).
21 35 2
exp
20 33
2
N-(3,5-Di-tert-butyl-2-hydroxyphenylmethylene)-
Methyl N-(2-hydroxy-5-nitrophenylmethylene)-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

SYNTHESIS OF SCHIFF BASES ON THE BASIS OF THE ISOSTEVIOL TERPENOID
295
ent-16-aminobeieran-19-oate (XX). 2-Hydroxy-5-
nitrobenzaldehyde (XIX), 0.15 g , was added to a
solution of 0.3 g of amine XVIII in absolute benzene,
and the mixture was refluxed for 6 h. The solvent was
removed, and the residue was recrystallized from
petroleum ether to obtain a yellow powder. Yield
Nagaoka, Y., and Koga, K., Tetrahedron Lett., 1998,
vol. 39, no. 15, p. 2141.
7
8
. Nishikori, H. and Katsuki, T., Tetrahedron Lett.,
1
996, vol. 37, no. 51, p. 9245.
. Yaozhong, J., Liuzhu, G., Xiaoming, F., Wenhao, H.,
Weidong, P., Zhi, L., and Aiqiao, M., Tetrahedron,
2
0
0
.32 g (74%), mp 70 C, [ ]
28.0 (c 0.26, C H )
n
6 6
1
997, vol. 53, no. 42, p. 14327.
1
IR spectrum, , cm : 774, 880 (H Carom), 1338, 1548
9
. Clark, J.S., Fretwell, M., Whitlock, G.A., Burns, C.J.,
and Fox, D.N.A., Tetrahedron Lett., 1998, vol. 39,
nos. 1 2, p. 97.
C NO ), 1488, 1600 (C Carom), 1631 (C=N), 1724
2
1
6
6
(
J, Hz): 0.69 2.1 m (20H, isosteviol frame), 0.69 s
1
0. Larrow, J.F. and Jacobsen, E.N., Top. Organomet.
Chem., 2004, no. 6, p. 123.
(3H, 20-CH ), 0.77 s (3H, 17-CH ), 1.14 s (3H,
3
3
1
6
1
1
7
8-CH ), 2.87 d.d (1H, H , J 10.9, 4.7), 3.33 s (3H,
3
9-OCH ), 6.63 d (1Harom, J 8.9), 7.35 s (1H, N=CH),
11. Tolstikov, A.G., Karpyshev, N.N., Amosov, Yu.I.,
Tolstikova, O.V., Khlebnikova, T.B., Tolstikov, G.A.,
Mamatyuk, V.I., and Salnikov, G.E., Mendeleev
Commun., 1998, vol. 8, no. 2, p. 60.
3
.79 d (1Harom, J 2.6), 7.86 d.d (1Harom, J 8.9, 2.6).
+
Mass spectrum, [M] : m/z
482.2797, m/zcalc
exp
4
82.2780 (C H N O ).
28 38 2 5
1
2. Hanson, R., The Tetracyclic Diterpenes, Oxford:
Oxidation of thioanisole with Schiff bases VI XI
Pergamon, 1968.
and XX. Thioanisole, 0.1 g, and 0.1 ml of 30% hyd-
rogen peroxide were successively added to a stirred
solution of 2 mg of vanadium acetylacetonate and
.7 mmol of Schiff base (control by TLC). After 1.5
h the reaction mixture was washed with water, and
1
3. Al’fonsov, V.A., Bakaleinik, G.A., Gubaidullin, A.T.,
Kataev, V.E., Kovylyaeva, G.I., Konovalov, A.I.,
Litvinov, I.A., Strobykina, I.Yu., and Strobykin, S.I.,
Zh. Obshch. Khim., 1998, vol. 68, no. 11, p. 1813.
1
2
the organic layer was separated, dried with MgSO4,
and evaporated. The residue was subjected to chro-
matography to isolate, depending on the Schiff base,
14. Al’fonsov, V.A., Andreeva, O.V., Bakaleinik, G.I.,
Beskrovnyi, D.V., Gubaidullin, A.T., Kataev, V.E.,
Kovylyaeva, G.I., Konovalov, A.I., Korochkina, M.G.,
Latypov, Sh.K., Litvinov, I.A., Musin, R.Z., and
Strobykina, I.Yu., Zh. Obshch. Khim., 2003, vol. 73,
no. 7, p. 1186.
0
.035 0.059 mg of methyl phenyl sulfoxide whose
optical rotation was measured on a Perkin Elmer
41 polarimeter in CHCl at 589 nm.
3
3
1
5. Al’fonsov, V.A., Kataev, V.E., Strobykina, I.Yu.,
Korochkina, M.G., Kovylyaeva, G.I., Bakaleinik, G.A.,
Beskrovnyi, D.V., Gubaidullin, A.T., Litvinov, I.A.,
and Musin, R.Z., Zh. Obshch. Khim., 2005, vol. 75,
no. 2, p. 276.
ACKNOWLEDGMENTS
The work was financially supported by the Russian
Foundation for Basic Research (project nos. 04-03-
2133, 04-03-32063, and 05-03-33008). The authors
are grateful to V.V. Grishko and V.V. Mikhalenok
for performing thioanisole oxidation in the presence of
isosteviol-derived Schiff bases.
3
1
6. Al’fonsov, V.A., Andreeva, O.V., Bakaleinik, G.I.,
Beskrovnyi, D.V., Gubaidullin, A.T., Kataev, V.E.,
Kovylyaeva, G.I., Konovalov, A.I., Korochkina, M.G.,
Litvinov, I.A., Militsina, O.I., and Strobykina, I.Yu.,
Zh. Obshch. Khim., 2003, vol. 73, no. 8, p. 1330.
REFERENCES
1
1
7. Alfonsov, V.A., Andreeva, O.V., Bakaleynik, G.A.,
Beskrovny, D.V., Kataev, V.E., Kovyljaeva, G.I.,
Litvinov, I.A., Militsina, O.I., and Strobykina, I.Yu.,
Mendeleev Commun., 2003, vol. 13, no. 5, p. 234.
1
2
3
4
5
. Katsuki, T., J. Mol. Catal., 1996, vol. 113, nos. 1 2,
p. 87.
. Brunel, J.M., Diter, P., Duetsch, M., and Kagan, H.B.,
J. Org. Chem., 1995, vol. 60, no. 24, p. 8086.
8. Mamedov, V.A., Al’fonsov, V.A., Bakaleinik, G.A.,
Kataev, V.E., Kovylyaeva, G.I., Militsina, O.I.,
Strobykina, I.Yu., Beskrovnyi, D.V., Gubaidullin, A.T.,
Litvinov, I.A., Rizvanov, I.H., and Musin, R.Z., Zh.
Obshch. Khim., 2005, vol. 75, no. 4, p. 622.
. Komatsu, N., Hashizume, M., Sugita, T., and Uemu-
ra, S., J. Org. Chem., 1993, vol. 58, no. 17, p. 4529.
. Yamanoi, Y. and Imamoto, T., J. Org. Chem., 1997,
vol. 62, no. 54, p. 8560.
1
9. Al’fonsov, V.A., Bakaleinik, G.A., Kataev, V.E., Ko-
vylyaeva, G.I., Konovalov, A.I., Strobykina, I.Yu.,
Andreeva, O.V., and Korochkina, M.G., Zh. Obshch.
Khim., 2000, vol. 70, no. 8, p. 1406.
. Nishimura, K., Ono, M., Nagaoka, Y., and Tomi-
oka, K., J. Am. Chem. Soc., 1997, vol. 119, no. 52,
p. 12974.
6
. Tomioka, K., Okuda, M., Nishimura, K., Kanai, M.,
20. Rodionov, V.M., Kazanskii, B.A., and Mel’ni-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007

296
MILITSINA et al.
kov, N.N., Reakts. Metody Issled. Org. Soedin., 1954,
vol. 3.
1. Mosetting, E. and Nes, W.R., J. Org. Chem., 1955,
vol. 20, no. 7, p. 884.
2. Altomare, A., Cascarano, G., Giacovazzo, C., and
Viterbo, D., Acta Crystallogr., Sect. A, 1991, vol. 47,
no. 6, p. 744.
3. Sheldrick, G.M., SHELX-97, Programs for Crystal
Structure Analysis, Release 97-2, Gottingen: Univ. of
Gottingen, 1997.
24. Straver, L.H. and Schierbeek, A.J., MolEN. Structure
Determination System. Program Description. Delft:
Nonius B.V., 1994, vol. 1.
2
2
2
5. Farrugia, L.J., J. Appl. Crystallogr., 1999, vol. 32,
no. 4, p. 837.
2
6. Spek, A.L., Acta Crystallogr., 1990, vol. 46, no. 1,
p. 34.
2
27. Flack, H.D., Acta Crystallogr., Sect. A, 1983, vol. 39,
no. 6, p. 876.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 2 2007