Synthesis of heterocyclic derivatives of abietane

Article abstract of DOI:10.1134/S1070427210080331

The methods of synthesis of some new derivatives of abietane including pyridines and indoles fused with diterpene skeleton were described. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070427210080331

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2010, Vol. 83, No. 8, pp. 1494−1502. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.A. Glushkov, A.V. Tarantin, V.I. Karmanov, A.G. Tolstikov, 2010, published in Zhurnal Prikladnoi Khimii, 2010, Vol. 83, No. 8,
pp. 1388−1395.
Synthesis of Heterocyclic Derivatives of Abietane
V. A. Glushkov, A. V. Tarantin, V. I. Karmanov,
and A. G. Tolstikov
Institute of the Engineering Chemistry, Ural Branch, Russian Academy of Sciences, Perm, Russia
Received March 10, 2010
Abstract—The methods of synthesis of some new derivatives of abietane including pyridines and indoles fused
with diterpene skeleton were described.
DOI: 10.1134/S1070427210080331
In recent years interest in abietane diterpene was
renewed due to versatile biological activity found in its
derivatives. In nature, were found anticancer diterpenoids
[1, 2] and drugs against leishmaniasis [3, 4]. Activators
of potassium channels [5], hypocholesterolemic [6],
anticancer [7] and antiulcer [8] substances, plant growth
regulators [9], compounds with antimicrobial activity
[10–12] were found among the synthetic derivatives of
abietane.
Povarov reaction [17–22].
The aim of this work is to study Povarov reaction
with acetaldehyde and trifluoroacetaldehyde. Since Schiff
bases of aliphatic aldehydes are unstable and prone to
trimerization, we used an approach described in [23],
when vinyl ethyl ether was used instead of acetaldehyde
in the presence of Lewis acid. 1,1,1,3,3,3-Hexafluoro-
propanol-2 (HFP) acts analogously [24, 25] (Scheme 1).
As a result a nucleophilic attack of amine occurs at
α-atom of a double bond with removal of ethanol and
formation of ethylidene derivative (B) entering further
in Povarov reaction according a usual scheme. Thus,
application of HFP and 2,2,2-trifluoroethanol (TFE)
allows using vinyl ethyl ether instead of acetaldehyde
without employing catalysts [26]. It should be noted that
in recent years fluorinated alcohols (TFE and HFP) have
found wide application to organic synthesis due to their
specific feature: large ionizing power, low nucleophility
and high acidity [25, 27].
Dehydroabietic acid as a natural product was found
in the galipot of a number of coniferous species [13] and
can be separated from the mixture of resin acids through
ethanolamine salt. Dehydroabietic acid can also be pro-
duced by dehydrogenation of levopimaric, palustric acids
or by disproportionation of abietic or other resin acids. In
developing the concept of the use of renewable natural
raw materials for producing chiral reagents and reagents
for asymmetric synthesis [14–16], we suggested one pos-
sible way to utilize a waste of a pine rosin: a synthesis
of some heterocyclic derivatives of dehydroabietic acid
from pyridines and indoles with diterpene skeleton using
We stated that compound II was formed on conden-
sation of the methyl ether of 12-aminohydroabietic acid
Scheme 1.
H
ORf
HN
HN
OR
N
OR
OEt
HFP
OR
PhNH2
A
B
1494

SYNTHESIS OF HETEROCYCLIC DERIVATIVES OF ABIETANE
1495
Scheme 2.
3
NH2
N4
2
NH
N
5
1
EtO
12
EtO
EtO
ÃÔÏ
6
12à
8
HFP
7
H
9
H
H
H
COOCH3
COOCH3
COOCH3
COOCH3
I
B
II
(I) with two equivalents of ethyl vinyl ether in HFP in
60 % yield. Intermediate tetrahydroquinoline easily lost
ethanol and was oxidized in air to compound II in releas-
ing (Scheme 2).
of amine I. As a result we produced compound IV with
17% yield as a blend of (1R)- and (1S)-diastereomers of
about 1 : 1 ratio according to 1H NMR data (Scheme 3).
Reaction of imine III with ethyl vinyl ether in 3,3,3-tri-
fluoroethanol was peculiar: Instead of trifluoromethyl-
substituted product with 53% yield we obtained methyl-
substituted quinoline (II) that was confirmed by a peak
of a molecular ion with m/z = 379 in its mass spectrum.
Apparently, the hydrolysis of imine III to amine I occurs
and then the synthesis proceeds similarly to producing of
compound II described above (Scheme 4).
Two doublet signals with coupling constant J =
9.3 Hz in 1H NMR spectra of compound II at δ 8.81 and
8.07 ppm belonging to protons at atoms C(1) and C(2),
respectively, and also a signal in the form of a singlet of
protons of methyl group at C(3) atom at δ 2.67 ppm point
to the presence of an aromatic structure in the formed ring.
It is known that some 2-trifluoromethyl substituted
quinolines demonstrate activity malaricidal and against
leishmaniasis [28]. The Povarov’s reaction was described
for imines based on trifluoroacetaldehyde in [29, 30]. The
Schiff base (III) that was introduced into a reaction of cy-
clopentadiene in the presence of 15 % mol boron trifluo-
ride etherate was prepared to synthesize compounds with
trifluoromethyl group at α-carbon atom of the heterocycle
Afterward we developed preparative techniques for
O-methylation and O-benzylation of 18-hydroxyabieta-
8,11,13-trienes (Va, Vb) to 18-methoxy- or 18-benzy-
loxyabieta-8,11,13-trienes (VIa, VIb) and (VIIa, VIIb)
and then we produced their 7-oxo-derivatives (VIIIa,
VIIIb) and (IXa, IXb). Compounds (VI–IX) can be used
as syntons in organic synthesis.
Scheme 3.
CF3
CF3
CF3
NH
13
12
1
N
NH 2
10d
11
10
3
/ BF3 OEt2
CF3CH2OH
4
+
10a
5
8
7
6
H
H
H
COOCH3
COOCH3
(1R)-(IV)
COOCH3
(1S)-(IV)
III
Scheme 4.
Et
Et
O
O
Hydrolysis
II
III
I
(B)
.
.
BF3 OEt2
BF3 OEt2
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010

1496
GLUSHKOV et al.
Scheme 5.
16
15
R1
12
R1
11
17
13
14
20
10
1
2
R2X
9
8
7
19
3
5
4
6
18CH2OR2
CH2OH
Va, Vb
VIa, VIb, VIIa, VIIb
R1
R1
MnO
MnO
2
2
Pyridine
O
CH2OR2
CH2OR2
VIa, VIb, VIIa, VIIb
(V)–(IX): R1 – H (а), Br (b); R2 – Me (VI), (VIII), CH2Ph (VII), (IX).
,
VIIIa, VIIIb IXa, IXb
We tested two techniques for alkylation of compounds
indolization possibility.
EXPERIMENTAL
Va, Vb: an interaction of sodium alcoholate generated
from sodium hydride with alkyl halides (technique A)
and alkylation under condition of interphase catalysis
(technique B). We noted that an increase in temperature
more than 25°С on the stage of alcoholate formation was
resulted in a partial reduction of brominr atom in com-
pound Vb by molecular hydrogen (Scheme 5).
The melting temperatures were measured with
an Optimelt MPA100 (Stanford Research Systems). IR
spectra were recorded with a Specord M-80 instrument
in liquid paraffin.
1H and 13C NMR are recorded in CDCl3 or DMSO-d6
7-Oxo-derivatives of abietane (VIIIa, VIIIb) (IXa,
IXb) were synthesized by oxidizing VIa, VIIa with
KMnO4–Al2O3 mixture in acetone [31] or MnSO4–
KMnO4 in pyridine [32]. The first method gives good
yield (up to 80 %) only for charges in a range of
1–10 mmol, while the yield falls for loads in the range
of 10–50 mmol, in this case an application of the second
method is more reasonable.
on Varian Mercury+300 at 300 and 75 MHz, respectively.
1
To record H NMR spectra we used internal reference
GMDS, and the solvent in the case of 13C NMR recording.
Assignment of signals in 1H and 13C NMR spectra were
made on the basis of data in [21, 35, 36].Aspecific rotation
was measured by a Perkin-Elmer 341 device, the value of
[α]D were given in units of deg g–1 cm2. Chromato-mass
spectra were received on anAgilent Technologies 5975B
Network instrument (EC, 70 eV), connected to anAgilent
Technologies 6890N chromatograph, capillary column
HP-5MS 3000 × 0.25 mm, evaporator temperature 240°C
with temperature programming within 20–40 deg min–1,
carrier gas helium. Column chromatography was
performed on silica gel (Silicagel 60 with particle
size 0.035–0.070 mm of “Merck”), a solvent mixture
As s result of further studies of [33, 34] we synthesized
indoles condensed with the abietane skeleton
Starting from compound VIIIa we obtained intermedi-
ate hydrazone X that according to Fischer reaction was
converted in indole XI.
Thus, we showed that a nature of the functional
group at C18 atom of abietic system did not affect the
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SYNTHESIS OF HETEROCYCLIC DERIVATIVES OF ABIETANE
1497
Scheme 6.
R1
MnO2
(VIa, VIb), (VIIa,VIIb)
Pyridine
O
CH2OR2
(VIIIa, VIIIb), (IXa, IXb)
R1
R1
6
6
5
5
7
8
7
4
4
8
3
HCl/AcOH, To
3
2
PhNHNH2
VIa
9
13c
2
NNHPh
1
9 NH
1
10
CH2OR2
CH2OR2
10
11
13
12
XI
X
of hexane–ethyl acetate was as eluent. Monitoring
the progress of reactions and purity of products was
carried out by TLC in the system hexane–ethyl acetate
(10 : 1) with silufol (unless specified) or silasorb
with developing by solution of phosphorus-molybdic
acid in ethanol at heating to 100–150°C. Elemental
analysis was performed on a Leco CHNS 9321P instru-
ment. We used sodium hydride, trifluoroacetaldehyde,
vinyl ethyl ether, 2,2,2-trifluoroethanol and
1,1,1,3,3,3-hexafluoropropylene-2-propanol of Lancaster
Co. (Alfa Aesar).
by column chromatography on silica gel (hexane–ethyl
acetate, 20 : 1). Pale yellow transparent oil. Yield
60%. H NMR spectrum, δ, ppm: 1.31 (d, 3Н, Н3С,
1
J = 6.6 Hz), 1.32 (d, 3Н, СН3, J = 6.6 Hz), 1.33 s (3Н,
Н3С), 1.65 s (3Н, Н3С), 1.42–1.91 m (7Н, Н2С8, Н2С10,
Н2С11, НaxС12), 2.23 m (1Н, НС8а), 2.67 s (3Н, Н3СAr),
2.76–3.13 m (3Н, Н2С7, НequivС12), 3.69 s (3Н, ОСН3),
4.21–4.28 m (1Н, НСAr), 7.15 s (1Н, НС6), 8.07 d (1Н,
НС2, J = 9.3 Hz), 8.81 d (1Н, НС1, J = 9.3 Hz). Found,
%: С 78.98, Н 8.72, N 3.55. C25H33NO2. Calculated, %:
C 79.11, Н 8.76, N 3.69.
Methyl ester of (1R,4aS,10aR)-1,4a-di-
methyl-7-isopropyl-1,2,3,4,4a,9,10,10a-octa-
hydrophenanthrene-6-[(E)-(2,2,2-trifluoroethylidene)
amino]-1-carboxylic acid (III). To a solution of 0.82 g
(2.5 mmol) of compound I in 40 ml of toluene was added
0.134 g (2.5 mmol) 75% solution of CF3CHO in water
and about 200 mg of molecular sieves 4Å. The blend was
stirred for 3 h at room temperature, then the molecular
sieves was separated, a volatile matter was distilled by
a vacuum water-jet pump. The obtained yellowish oil
without treatment was immediately used in compounds
IV synthesis.
Methyl ester of (8aR,9R,12aS)-5-isopropyl-
3, 9, 12a-trimethyl-7, 8, 8a, 9, 10, 11, 12, 12a-
octahydronaphtho[1,2-f]quinoline-9-carboxylic acid
(II). Ethyl vinyl ether (0.0065 g: 0.0086 ml, 0.09 mmol)
dropwise was added at stirring to a solution of 0.01 g
(0.03 mmol) of methyl ether of 12-aminodehydroabi-
etic acid (I) synthesized according to [20] in 10 ml of
1,1,1,3,3,3-hexafluoro-2-propanol. The reaction monitor-
ing was conducted by TLC in hexane–ethylacetate system
of 9 : 1 ratio. The solvent was distilled under a vacuum,
10 ml of saturated aqueous NaHCO3 and 20 ml of ethyl
acetate were added to the residue, the organic layer was
separated, washed with a saturated solution of NaCl,
dried over MgSO4. The reaction product was purified
Methyl ester of (1RS,6aR,7R,10aS,10dR,13aS)-
7,10a-dimethyl-2,5,6,6a,7,8,9,10,10a,10d,13,13a-
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1498
GLUSHKOV et al.
dodecahydro-3-isopropyl-1-(trifluoromethyl)-1H-
cyclopentane[c]naphtho[1,2-f]quinoline-7-carboxylic
acid [the mixture of diastereomers (1R)-(IV) and (1S)-
(IV)]. Shciff bases III [82 mg (0.20mM)] were dissolved
in 10 ml of 2,2,2-trifluoroethanol. After 3.8 ml (4.3 mg,
0.03 mmol) of boron trifluoride etherate was added, and
stirred for 10 min, then 75 ml (40 mg, 0.6 mmol) of
freshly distilled cyclopentadiene was dropwise added.
Separation was performed as in the case of compound
II. Yellow-brown oil. Yield 17%. The 1H NMR spectrum
of (1R)-(IV)-diastereomer, δ, ppm: 1.14 d (3Н, СН3, J =
6.9 Hz), 1.18 d (3Н, СН3, J = 6.9 Hz), 1.31 s (3Н, СН3),
1.43 s (3Н, СН3), 1.38–1.89 m (7Н, Н2С6, Н2С8, Н2С9,
НaxС10), 2.18–2.33 m (3Н, НС6а, Н2С13), 2.71–3.35 m
(6Н, НС1, Н2С5, НequivС10, НС13а, НСAr), 3.65 s (3Н,
ОСН3), 4.89–4.92 m (1Н, НС10d), 5.16–5.17 m (1Н,
НС11), 5.67–5.71 m (1Н, НС12), 6.69 s (1Н, НС4).
1H NMR spectrum of (1S)-(IV)-diastereomer, δ, ppm:
1.14 d (3Н, СН3, J = 6.9 Hz), 1.18 d (3Н, СН3, J =
6.9 Hz), 1.27 s (3Н, СН3), 1.46 s (3Н, СН3), 1.38–1.89 m
(7Н, Н2С6, Н2С8, Н2С9, НaxС10), 2.18–2.33 m (3Н, НС6а,
pecially pure, dried by annealed molecular sieves 4Å).
A flask with the mixture was blew with argon and in
argon flow 1.56 g (65 mmol) of sodium hydride (obtained
from 2.60 g of 60% suspension of NaH in mineral oil by
dry hexane processing) was quickly added. The mixture
was stirred at 40°C to complete the alcoholate formation
(~ 1 h), then cooled to 20°C, and after 4.02 ml (9.23 g,
65 mmol) of iodomethane dropwise added within 10 min.
After 4 h stirring another 1.5 ml of MeI was added and
stirred for 2 h, then 5 ml of ethanol and 5 ml of water
were cautiously dropwise added, DMSO was distilled by
the vacuum water-jet pump (temperature 80°C), 150 ml
of water and 150 ml of ethyl acetate were added to the
residue, the organic layer was separated, the aqueous
layer was extracted with 60 ml of ethyl acetate, the
organic layers were washed with saturated NaCl solution
and dried over magnesium sulfate. After distillation of
the solvent the residue [pale-yellow oil, yield 15.37 g
(90%)] without additional purification was directed to
the oxidation stage. For identification about 2 g of oil
was purified by silica gel column (hexane–ethyl acetate,
10 : 1); Rf 0.80. Acolorless oil (colorless oil according to
[40]). 1H NMR spectrum coincided with the data of [40].
Н2С13), 2.71–3.35 m (6Н, НС1, Н2С5, НequivС10, НС13а
,
НСAr), 3.68 s (3Н, ОСН3), 4.80–4.83 m (1Н, НС10d),
5.39–5.42 m (1Н, НС11), 5.84–5.86 m (1Н, НС12), 6.74 s
(1Н, НС4). Found (for the misture of diastereomers)
(%): С 70.75, Н 7.84, N 2.67. C28H36F3NO2. Calculated,
%:C 70.71, Н 7.63, N 2.95.
12-Bromo-18-methoxyabieta-8,11,13-triene (VIb)
was synthesized according to method A from 14.16
g (39 ммоль) of compound Vb, 1.7 g (40.5 ммоль) of
60% suspension of NaH in 100 ml of dry THF and 9.8 g
(4.5 ml, 69 mM) of iodomethane. Purification was carried
out by silica gel column (hexane–ethyl acetate, 10 : 1);
Rf 0.9. Yield 8.43 g (57%). Colorless prisms from metha-
nol, mp 112–113°С. [α]D22 +96.3 (c 1, CHCl3). 1H NMR
spectrum (DMSO-d6), δ, ppm: 0.80 s (3Н, С20Н3), 1.13 s
(3Н, С19Н3), 1.15 s (3Н, С16Н3), 1.19 s (3Н, С17Н3),
1.30–1.76 m (7Н, НaxС1, Н2С2, Н2С3, Н2С6), 2.16 m (1Н,
12-Bromo-18-hydroxyabieta-8,11,13-triene (Vb).
It was prepared by reduction of methyl ester of 12-bro-
modehydroabietic acid [37] with the aid of LiAlH4 in
THF, mp 112–114°C (MeOH–water) (according to [38]
mp 116°С). Yield 66%. [α]D26 +59.0 (c 1, CHCl3). Rf 0.16.
IR spectrum, ν, cm–1: 3300 br (OH in H-bond); 1500,
1320, 1060, 1040, 1015. 1H NMR spectrum (300 MHz,
DMSO-d6), δ, ppm: 0.81 s (3Н, С20Н3), 1.11 d (3Н, СН3,
J = 6.6 Hz), 1.14 d (3Н, СН3, J = 6.6 Hz), 1.16 s (3Н,
С19Н3), 1.32–1.74 m (8Н, Н2С1, С2Н2, Н2С3, Н2С6),
2.15 m (1Н, С5Н), 2.77 m (2Н, С7Н2), 3.14 d (1Н,
СН2ОН, J = 11.1 Hz), 3.19 m (1Н, С15Н), 3.40 d (1Н,
СН2ОН, J = 11.1 Hz), 6.84 s (1Н, С14Н), 7.30 s (1Н,
С11Н). 13C NMR spectrum (75 МHz, CDCl3), δ, ppm:
15.34, 16.46, 16.60, 20.75, 20.92, 23.07, 27.50, 32.97,
35.35, 35.78, 36.30, 41.49, 70.00, 119.33, 124.95, 126.55,
132.49, 141.75, 147.34.
Н
equivС1), 2.71 m (1Н, НС5), 2.77 m (2Н, Н2С7), 2.87 d
(1Н, СН2ОН, J = 10.2 Hz), 3.12 d (1Н, СН2ОН, J =
10.2 Hz), 3.20 m (1Н, НС15), 3.22 s (3Н, СН3О), 6.83 s
(1Н, НС14Н), 7.29 s (1Н, НС11). Found, %: С 66.17,
Н 8.28. C21H31BrO. Calculated, %: С 66.49, Н 8.24.
18-Benzyloxyabieta-8,11,13-triene (VIIа) (method
B). A mixture of 9.36 g (32.7 mM) of compound Vа,
5.64 g (3.92 ml, 33 mM) of benzyl bromide, 40 ml dichlo-
romethane, 14.50 g (25 mM) of tetrabutylammonium
sulfate, and 23 ml of 50% KОН was intensively stirred
for 6 h (monitoring by TLC), 100 ml of dichloromethane
and 300 ml of water were added, the organic layer was
separated, washed until neutral medium, dried over
MgSO4, the solvent was distilled. By chromatography
18-Methoxyabieta-8,11,13-triene (VIа) (method А).
18-Hydroxyabieta-8,11,13-triene (Va) (obtained accord-
ing to [39], colorless oil, mp 163°C/0.2 mm Hg) [16.35 g
(57.2 mM)] was dissolved in 100 ml of dry DMSO (es-
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SYNTHESIS OF HETEROCYCLIC DERIVATIVES OF ABIETANE
1499
of the residue on silica gel (hexane–ethyl acetate, 10 : 1)
2.07 g (16%) of compound VIIa was obtained in the
form of a thick colorless oil, Rf 0.78. [α]D22 +24.4 (c 1.84,
CHCl3). IR spectrum, ν, cm–1: 1600 (С=С)arom. 1H NMR
spectrum (DMSO-d6) δ, ppm: 0.80 s (3Н, С20Н3), 1.12 s
(3Н, С19Н3), 1.15 d (6Н, С16Н3 and С17Н3, J = 7 Hz),
1.19–1.37 m (2Н, Н2С1), 1.55–1.77 m (6Н, Н2С2, Н2С3,
Н2С6), 2.17 m (1Н, НС5), 2.75 m (1Н, НС15Н), 2.77 m
(2Н, Н2С7), 2.91 d (1Н, НС18, J = 11.1 Hz), 3.21 d (1Н,
НС18, J = 11.1 Hz), 4.34 d (1Н, OCH2Ph, J = 12.4 Hz),
4.42 d (1Н, OCH2Ph, J = 12.4 Hz), 6.80 d (1Н, НС14,
71.23 (С18), 77.45 (ОСН2Ph), 119.40, 125.02, 125.40,
126.29, 126.76, 127.07, 132.77, 136.38, 141.68, 147.64.
Found, %: С 71.18, H 7.64, Br 16.88. С27Н35BrO.
Calculated, %: C 71.20, Н 7.75, Br 16.54.
18-Methoxy-7-oxoabieta-8,11,13-triene (VIIIа).
Oxidation was carried out by method suggested in [32].
Compound VIa [15.37 g (51 mmol)] was dissolved
in 270 ml of pyridine, 20.5 g of MnSO4 · H2O and 32.5 g
KMnO4 were added, the mixture was heated in a boiling
water bath (the temperature in the flask 85–90°C) for
6 h, monitoring by TLC (Rf 0.6). After completion of
the reaction precipitate of MnO2 was filtered through
a layer of Al2O3 (5 cm) and washed with its 300 ml of
ethanol, the ethanol and pyridine were distilled off under
a vacuum, the residue was dissolved in 300 ml of ethyl
acetate, washed with water and 5% HCl to extinction
of pyridine smell, and dried over MgSO4, the solvent
was distilled off, the oily residue was chromatographed
on silica gel (hexane–ethyl acetate, 10 : 1). Yield 9.6 g
(60%). Colorless prisms from ethanol, mp 115–116°С,
4
3
4J = 1.2 Hz), 6.89 dd(1Н, НС12, J = 1.2 Hz, J =
3
8.4 Hz), 7.09 d (1Н, НС11, J = 8.4 Hz), 7.13–7.22 m
(5Н, Ph). 13C NMR spectrum (CDCl3), δ, ppm: 15.95,
16.84, 17.01, 22.04, 23.47, 28.36, 31.48, 33.92, 35.43,
35.61, 36.50, 42.14, 71.22, 77.69, 121.76, 122.34,
124.80, 125.36, 126.24, 132.92, 137.02, 143.34, 145.52.
Found, %: С 86.28, Н 9.57. С27Н36О. Calculated, %:
C 86.12, Н 9.64.
12-Bromo-18-benzyloxyabieta-8,11,13-triene
(VIIb) (method A). Compound Va 2.95 g (7.7 mmol)
was dissolved in 30 ml of dimethylacetamide and 0.184 g
of 60% suspension of NaH in mineral oil was added
in the argon flow, the mixture was stirred for 30 min,
then within 20 minutes the solution of 1.32 g (0.92 ml,
7.7 mmol) of benzyl bromide in 3 ml of dry toluene was
added. The mixture was heated with stirring at 70°C for
5 h, and another 0.15 g of NaH and after 0.5 h 0.46 g of
benzyl bromide in 2 ml of toluene were added with the
following heating to 70°C for 3 h. The reaction mixture
was poured into 500 ml of water, extracted with ether
(70 ml, 5 times). Essential extracts were washed with
twice 50 ml of saturated solution of NaCl, dried over
MgSO4, the residue from the distillation of the solvent
was chromatographed on silica gel (hexane–ethyl
acetate, 10 : 1), Rf 0.60. Yield 1.47 g (40%), colorless
waxy substance, mp 72–78°С, [α]D26 +54.4 (c 1, CHCl3).
IR spectrum, ν, cm–1: 1600, 1300, 1205, 1110, 1070,
1040, 960, 900, 880. 1H NMR spectrum (DMSO-d6), δ,
ppm: 0.79 s (3Н, С20Н3), 1.12 d (6Н, С16Н3 and С17Н3,
J = 6.3 Hz), 1.19 s (3Н, С19Н3), 1.32 m (2Н, Н2С1),
[α]D +41.1 (с 1, CHCl3). UR spectrum, ν, cm–1 (liq-
17
uid paraffin): 1670 (С=О), 1600 (С=С), 1300, 1270,
1250, 1195, 1175, 1105, 1030, 985, 935, 845. 1H NMR
spectrum (CDCl3), δ, ppm: 0.86 s (3Н, С20Н3), 1.16 d
(6Н, С16Н3 and С17Н3, J = 6.6 Hz), 1.17 s (3Н, С19Н3),
1.27–1.76 m (5Н, НaxС1, Н2С2, Н2С3), 2.22 m (2Н,
Н
equivС1 and НaxС6), 2.58 m (2Н, НС5 and НequivС6),
2.77 d (1Н, НС18, J = 11.1 Hz), 2.87 m (1Н, НС15),
3.09 d (1Н, НС18, J =11.1 Hz), 3.17 s (3Н, OСН3), 7.21 d
(1Н, НС11, 3J = 8.1 Hz), 7.30 dd (1Н, НС12, 3J = 8.1 Hz,
4J = 2.1 Hz), 7.79 d (1Н, НС14, 4J = 2.1 Hz). 13С NMR
spectrum (CDCl3), δ, ppm: 15.6, 16.3, 21.8, 21.9, 31.6,
33.5, 35.2, 34.0, 35.5, 40.7, 57.1 (ОСН3), 79.3 (ОСН2),
121.7, 122.8, 128.8, 130.4, 144.5, 151.7, 197.7 (С=О).
Found, %: С 80.18, Н 9.60. C21H30O2. Calculated, %:
С 80.21, Н 9.62.
12-Bromo-7-oxo-18-methoxy-7-oxoabieta-8,11,13-
triene (VIIIb) was obtained analogous to compound
VIIIа. Yield 52%, mp 135–136°С (colorless prisms from
ethanol). [α]D22 +71.4 (c 1, CHCl3). IR spectrum, ν, cm–1
(liquid paraffin): 1675 (С=О), 1590 (С=С), 1245, 1105,
1.52–1.72 m (6Н, Н2С2, Н2С3 Н2С6), 2.12 m (1Н,
,
1
НС5), 2.72 m (2Н, Н2С7), 2.90 d (1Н, НС18, J = 8.7 Hz),
3.17 m (1Н, НС15Н), 3.22 d (1Н, НС18Н, J = 8.7 Hz),
4.40 m (2Н, OCH2Ph), 6.84 s (1Н, НС14), 7.26 m (5Н,
Ph), 7.30 s (1Н, НС11). 13C NMR spectrum (CDCl3), δ,
ppm: 15.96 (С20), 16.67 (С19), 16.77 (С2), 20.88 (С16),
21.05 (С17), 23.36 (С6), 27.83 (С15), 30.36 (С7), 33.78
(С3), 35.52 (С10), 35.60 (С1), 36.38 (С5), 41.71 (С4),
995, 920. H NMR spectrum (CDCl3) δ, ppm: 0.87 s
(3Н, С20Н3), 1.16 d (3Н, СН3, J = 6.9 Hz), 1.18 s (3Н,
С19Н3), 1.20 d (3Н, СН3, J = 6.9 Hz), 1.28–1.78 m (5Н,
НaxС1, Н2С2, Н2С3), 2.20 m (2Н, НequivС1 and НaxС6),
2.56 m (2Н, НС5 and НequivС6), 2.78 d (1Н, НС18, J =
9 Hz), 3.09 d (1Н, НС18, J = 9 Hz), 3.19 s (3Н, OСН3),
3.25 m (1Н, НС15), 7.47 s (1Н, НС11), 7.83 s (1Н, НС14).
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010

1500
GLUSHKOV et al.
phenanthrene-9(1Н)-ylidene]-2-phenylhydrazine
(X). To a solution of 0.5 g (1.59 mmol) of compound
VIIIa in 5 ml of ethanol 0.17 g (0.154 ml, 1.59 mmol) of
phenylhydrazine and 2 drops of HCl (conc) were added.
The mixture was boiled for 5 min and kept for 12 h. The
precipitated yellow crystals of phenylhydrazone were
filtered off and dried; mp 134–136°С. Yield 0.27 g (42%).
IR spectrum (liquid paraffin), ν, cm–1: 3300 br (NH in
H-bond), 1595 (С=С), 1335, 1300 sl, 1255, 1200, 1140,
1095, 1060, 1030, 970, 930, 880, 820 s. 1H NMR spec-
trum, δ, ppm: 0.98 s (3Н, СН3), 1.03 s (3Н, СН3), 1.21 d
(3Н, СН3, J = 6.6 Hz), 1.22 d (3Н, СН3, J = 6.6 Hz),
1.32–2.63 m (5Н, Н2С2, Н2С3, НaxС4), 1.94 dd (1Н,
НaxС10), 2.20 m (1Н, НequivС4), 2.37 dd (1Н, НС10а),
2.60 dd (1Н, НequivС10), 2.83 m (1Н, НСAr), 2.89 d (1Н,
Н2СOМе, J = 9.3 Hz), 3.16 d (1Н, Н2СOМе, J = 9.3 Hz),
3.22 s (3Н, ОСН3), 6.81 m (1Н, Нarom), 7.04–7.27 [m,
6Н, НС(5), НС(6), 4Нarom], 7.33 br.s (1Н, NH), 7.89 s
[1Н, НС(8)]. С27Н36N2O. The exact data of elemental
analysis were not determined due to non-stability of the
compound.
Found, %: С 64.33, Н 7.29. C21H29BrO2. Calculated, %:
С 64.12, Н 7.43.
18-Benzyloxy-7-oxoabieta-8,11,13-triene (IXа) was
obtained by oxidation of compound VIIa analogous to
25
compound VIIIa. Yield 22%, mp 80–83°С, [α]D –1.6
(c 0.5, CHCl3), Rf 0.20 (silasorb). In iodine vapor the
substance gave characteristic orange-yellow color very
quickly disappearing in air. IR soectrum, ν, cm–1: 1715
(С=О), 1675, 1605, 1275, 1250, 1180, 1120, 1070, 1030,
990, 975, 935, 910, 840, 830. 1H NMR spectrum (DMSO-
d6) δ, ppm: 1.07 s (3Н, С20Н3), 1.19 d (6Н, С16Н3 and
С17Н3, J = 6.9 Hz), 1.24 s (3Н, С19Н3), 1.47–1.55 m
(5Н, НaxС1, H2C2, H2C3), 1.75 m (2Н, НequivС1, НaxС6),
2.21 m (1Н, HequivC6), 2.32 m (1Н, НС5), 2.71 m (2Н,
НС18), 2.86 m (1Н, НС15), 3.93 d (1Н, OCH2Ph, J =
10.8 Hz); 4.45 d (1H, OCH2Ph, J = 10.8 Hz), 7.26 d
(1Н, НС11, J = 8.4 Hz), 7.35 m (3Н, Ph), 7.47 m (1Н,
Ph), 7.81 d (1Н, НС14, J = 1.8 Hz), 7.90 m (2Н, НС12,
Нarom). Found, %: С 82.99, Н 8.75. С27Н34О2. Calculated,
%: С 83.03, Н 8.77.
12-Bromo-18-benzyloxy-7-oxoabieta-8,11,13-triene
(IXb) was obtained analogous to compound IXa. It was
purified by silica gel column (hexane–ethyl acetate,
10 : 1). Yield 28%. It was recrystallized from ethyl ac-
etate; mp 144–146°С. [α]D25 +37.4 (c 1, CHCl3), Rf 0.18
(silasorb). This substance as well as compound IXa, gave
in iodine vapor characteristic orange-yellow color very
quickly disappearing in air. IR spectrum, ν, cm–1 (liquid
paraffin): 1720 (С=О), 1680, 1595, 1310, 1275, 1250,
1205, 1170, 1115, 1060, 1045, 1030, 975, 935. 1H NMR
spectrum (DMSO-d6), δ, ppm: 1.06 s (3Н, С20Н3), 1.17 d
(6Н, С16Н3, С17Н3, J = 7 Hz), 1.23 s (3Н, С19Н3), 1.42–
1.56 m (5Н, НaxС1, H2C2, H2C3), 1.75 m (2Н, НequivС1,
НaxС6), 2.18 m (1Н, НэквС6), 2.26 m (1Н, НС5), 2.67 m
(2Н, НС18), 3.26 m (1Н, НС15), 3.92 d (1Н, OCH2Ph,
J = 11.1 Hz), 4.04 d (1Н, OCH2Ph, J = 11.1 Hz), 7.35 t
(2Н, 3',5'-Н, J = 7.8 Hz), 7.45 t (1Н, 4'-Н, J = 7.8 Hz),
7.49 s (1Н, НС14), 7.84 s (1Н, НС11), 7.91 d (2Н, 2',6'-Н,
J = 7.8 Hz). Спектр ЯМР 13C (CDCl3), δ, ppm: 15.44
(С20), 16.10 (С19), 20.71(С16), 20.74 (С17), 21.97 (С2),
30.73(С15), 33.61(С6), 34.10 (С3), 35.17 (С10), 35.45 (С1),
35.83 (С5), 41.97 (С4), 70.28 (С18), 94.20 (ОСН2Ph),
123.77, 126.42, 126.50, 127.61, 128.16, 129.49, 131.04,
143.79, 152.25, 164.39, 195.84 (С7=О). Found, %:
С 68.94, Н 7.12, Br 16.90. С27Н33BrО2. Calculated, %:
С 69.08, Н 7.09, Br 17.02.
(1R,4aS)-1,4а-Dimethyl-7-isopropyl-1-methoxy-
methyl-2,3,4,4a,10,10а-hexahydro-1Н-dibenzo[a,c]
carbazol (XI). Hydrazone (X) (0.3 g, 0.74 mmol) was
dissolved in 5 ml of glacial acetic acid, 1 ml of HCl(conc.)
was added and the mixture was boiled for 5 h, then
poured into 30 ml of water, and brought to pH 7 by
dry NaHCO3, the precipitate was filtered off, dried and
chromatographed on silica gel (hexane–ethyl acetate,
10 : 1), Rf 0.50. Yield 70 mg, mp 183–184°С (from aque-
ous ethanol), [α]D21 +84.7 (с 0.15, СНCl3). IR spectrum,
ν, cm–1: 3340 br (NH in H-bond), 1600 (С=С). 1Н NMR
spectrum, δ, ppm: 0.95 s (3Н, СН3), 1.24 d (3Н, СН3,
J = 6.9 Hz), 1.25 d (3Н, СН3, J = 6.9 Hz), 1.42 s (3Н,
СН3), 1.33–1.87 m (5Н, Н2С2, Н2С3, НaxС4), 2.22 m (1Н,
НequivС4), 2.88 m (1Н, НСAr), 2.92 s (1Н, НС13с), 3.25 d
(1Н, Н2СOМе, J = 8.7 Hz), 3.26 s (3Н, ОСН3), 3.95 d
(1Н, Н2СOМе, J = 8.7 Hz), 7.08 m (3Н, Нarom), 7.21 m
(2Н, Нarom), 7.37 d (НС6, J = 8.4 Hz), 7.67 d (1Н, НС5,
J = 8.4 Hz), 8.39 br.s (1Н, NH). Found, %: С 83.62,
Н 8.57, N 3.55. С27Н36N2O. Calculated, %: C 83.68,
Н 8.58, N 3.61.
CONCLUSION
(1) It is shown that in the fluorinated alcohols vinyl
ethyl ether acts as the equivalent of acetaldehyde and
can be introduced into condensation with methyl ester
of 12-aminodehydroabietic acid with the formation of
(Е)-1-[(1R,4aS)-1,4a-Dimethyl-7-isopropyl-
1-methoxymethyl-2,3,4,4a,10,10а-hexahydro-
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010

SYNTHESIS OF HETEROCYCLIC DERIVATIVES OF ABIETANE
1501
no. 10, pp. 1412–1417.
pyridine (II), annelated with the abietane skeleton.
12. Honda, T., Yoshizawa, H., Sundararajan, C., and Grib-
ble, G.W., J. Org. Chem., 2006, vol. 71, no. 8, pp. 3314–
3316.
(2) An interaction of methyl ester of 12-amino-
dehydroabietic acid with trifluoroacetaldehyde and
cyclopentadiene in Povarov’s reaction leads to derivatives
of cyclopentenoquinoline containing diterpene fragment.
13. Pentegova, V.A., Dubovenko, Zh.V., Raldugin, V.A., and
Shmidt, E.N., Terpenoidy khvoinykh rastenii (Terpenoids
of Conifers), Novosibirsk: Nauka, 1987.
(3) Preparative techniques for the synthesis of
some 7-oxoderivatives of 18-methoxy- and
18-benzyloxyabieta-8 ,11,13-triene were developed.
14. Tolstikov,A.G., Tolstikova, O.V., Khlebnikova, T.B. et al.,
Mendeleev Commun., 1996, no. 6, pp. 215–217.
(4) Based on the 18-methoxy-7-oxoabieta-8 ,11,13-
triene we synthesized his phenylhydrazone and by
Fischer reaction obtained indol annelated with abietane
skeleton.
15. Tolstikov, A.G., Karpyshev, N.N., Tolstikova, O.V. et al.,
Zh. Org. Khim., 2001, vol. 37, no. 8, pp. 1193–1207.
16. Khlebnikova, T.B., Karpyshev, N.N., Tolstikova, O.V. et
al., Chirality, 2004, vol. 16, no. S1, S40–S50.
17. Povarov, L.S., Uspekhi Khimii, 1967, vol. 36, no. 9,
ACKNOWLEDGMENTS
pp. 1533–1562.
18. Glushkov, V.A. and Tolstikov,A.G., Uspekhi Khimii, 2008,
The authors express their gratitude to the staff of
the Institute of Engineering Chemisitry of Ural Branch
of Russian Academy of Sciences: to O.A. Mayorova
for recording of NMR spectra, E.V. Baygacheva for
conducting the elemental analysis, and A.A. Gorbunov
for chromatography-mass spectrometric study. This work
was supported under the Program of the Presidium of
RAS “Development of Methods for Chemical Substances
and Creation of New Materials. ”
vol. 77, no. 2, pp. 138–160.
19. Kouznetsov, V.V., Tetrahedron, 2009, vol. 65, no. 14,
pp. 2721–2750.
20. Fieser, L.F. and Campbell, W.P., J. Am. Chem. Soc., 1939,
vol. 61, no. 9, pp. 2528–2534.
21. Tolstikov, A.G., Tarantin, A.V., Glushkov, V.A. et al.,
Heteroatom Chem., 2005, vol. 16, no. 7, pp. 605–612.
22. Tarantin, A.V., Glushkov, V.A., Mayorova, O.A. et al.,
Mendeleev Commun., 2008, vol. 18, no. 4, pp. 188–190.
23. Povarov, L.S. and Mikhailov, B.M., Izv. Akad. Nauk SSSR,
Ser. Khim., 1964, no. 12, pp. 2221–2222.
REFERENCES
24. Di Salvo, A., Spanedda, M.V., Ourévitch, M. et al.,
1. Son, K.-H., Oh, H.-M., Choi, S.-K. et al., Bioorg. Med.
Chem. Lett., 2005, vol. 15, no. 8, pp. 2019–2021.
Synthesis, 2003, no. 14, pp. 2231–2235.
25. Bégué, J.-P., Bonnet-Delpon, D., and Crousse, B., Synlett.,
2. Minami, T., Wada, S., Tokuda, H. et al., J. Nat. Prod., 2002,
2004, no. 1, pp. 18–29.
vol. 65, no. 12, pp. 1921–1923.
26. Spanedda, M.V., Hoang, V.D., Crousse, B. et al.,
3. Tan, N., Kaloga, M., Radtke, O.A. et al., Phytochemistry,
Tetrahedron Lett., 2003, vol. 44, no. 2, pp. 217–219.
2002, vol. 61, no. 8, pp. 881–884.
27. Shuklov, I.A., Dubrovina, N.V., and Börner,A., Synthesis,
4. Roldán, E.J.A.-M., Chahboun, R., Bentaleb, F. et al.,
2007, no., 19, pp. 2925–2943.
Synlett., 2004, no. 15, pp. 2701–2704.
28. Likhar, P.R., Subhas, M.S., Roy, S. et al., Org. Biomol.
Chem., 2009, vol. 7, no. 1, pp. 85–93.
5. Ohwada, T., Nonomura, T., Maki, K. et al., Bioorg. Med.
Chem. Lett., 2003, vol. 13, no. 22, pp. 3971–3974.
29. Crousse, B., Bégué, J.-P., and Bonnet-Delpon, D., Tetra-
hedron Lett., 1998, vol. 39, no. 32, pp. 5765–5768.
6. Fujita, Y., Yoshikuni, Y., Sotomatsu, T. et al., Chem. Pharm.
Bull., 1991, vol. 39, no. 5, pp. 1193–1198.
30. Crousse, B., Bégué, J.-P., and Bonnet-Delpon, D., J. Org.
Chem., 2000, vol. 65, no. 16, pp. 5009–5013.
7. Rao, X., Song, Z., He, L., Heteroatom Chem., 2008,
vol. 19, no. 5, pp. 512–516.
31. Chernenko, G.F., Shmidt, E.N., and Radbil’, B.A., Khim.
Prirod. Soedin., 1995, no. 2, pp. 229–234.
8. Wada, H., Kodato, S., Kawamori, M. et al., Chem. Pharm.
Bull., 1985, vol. 33, no. 4, pp. 1472–1487.
32. Huffman, J.W. and Stockel, R.F., J. Org. Chem., 1963,
9. Japan Patent 55-37524.
vol. 28, no. 2, pp. 506–509.
10. Yang, Z., Kitano, Y., Chiba, K. et al., Bioorg. Med. Chem.,
33. Irismetov, M.P., Tolstikov, G.A., and Goryaev, M.I.,
Sinteticheskie produkty iz kanifoli i skipidara (Synthetic
Products of Rosin and Turpentine), Gor’kii: Volgo-Vyat.
2001, vol. 9, no. 2, pp. 347–356.
11. Tada, M., Ishimaru, K., Chem. Pharm. Bull., 2006, vol. 54,
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010

1502
Izd., 1970, pp. 244–251.
GLUSHKOV et al.
37. Fonseca, T., Gigante, B., Marques, M.M. et al., Bioorg.
Med. Chem., 2004, vol. 12, no. 1–2, pp. 103–112.
34. Tret’yakova, E.V., Flekhter, O.B., Galin, F.Z. et al., Khim.
Prirod. Soedin., 2002, no. 3, pp. 206–208.
38. US Patent 2781400. 6-Bromo-1,2,3,4a,9,10,10a-octahy-
dro-7-isopropyl-4a-methylphe-nanthrene, ketones.
35. Van Beek, T.A., Claassen, F.W., Dorado, J. et al., J. Nat.
Prod., 2007, vol. 70, no. 2, pp. 154–159.
39. US Patent 2781401. 1,2,3,4,4a,9,10,10a-Octahydro-7-
isopropyl-4a-methyl-1,9-dioxophenanth-renes.
36. Rezvukhin, A.I., Solomennikova, I.V., Shmidt, E.N., and
Avdyukova, N.V., Izv. Akad. Nauk SSSR, Ser. Khim., 1979,
no. 12, pp. 2678–2685.
40. Cambie, R.C., Higgs, P.I., Rutledge, P.S. et al., J. Organo-
metal. Chem., 1990, vol. 384, no. 1–2, pp. C6–C8.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010