Syntheses based on anabasine. Preparation and transformations of N-oxides

Article abstract of DOI:10.1007/s11172-006-0256-5

The oxidation of N-acetyl-and N-benzoylanabasine with the tert-butyl hydroperoxide (TBHP)- MoCl₅ system or MCPBA proceeds selectively at the nitrogen atom of the pyridine ring. The oxidation of N-methylanabasine under similar conditions gives a

Full text of DOI:10.1007/s11172-006-0256-5

Russian Chemical Bulletin, International Edition, Vol. 55, No. 2, pp. 331—337, February, 2006
331
Syntheses based on anabasine.
Preparation and transformations of Nꢀoxides
L. A. Musina,a E. E. Shul´ts,aꢀ L. A. Krichevskii,b S. M. Adekenov,b
M. M. Shakirov,a and G. A. Tolstikova
aN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: schultz@nioch.nsc.ru
bInstitute of Phytochemistry, Ministry of Education and Science of the Republic of Kazakhstan,
4 ul. M. Gazalieva, 100009 Karaganda, Kazakhstan.
Fax: +7 (321 2) 43 3773
The oxidation of Nꢀacetylꢀ and Nꢀbenzoylanabasine with the tertꢀbutyl hydroperoxide
(TBHP)—МoCl5 system or МCРBA proceeds selectively at the nitrogen atom of the pyridine
ring. The oxidation of Nꢀmethylanabasine under similar conditions gives a mixture of stereoꢀ
isomeric Nꢀoxides at the piperidine nitrogen atom, their ratio depending on the reagent used.
The oxidation of anabasine by TBHP—МoCl5 or МCРBA is accompanied by dehydrogenation
and results in anabaseine Nꢀoxide. The reactions of anabasine and anabaseine pyridine Nꢀoxides
with acetic anhydride were investigated. The substituted 1Hꢀ3ꢀpyridinꢀ2ꢀones were prepared.
Key words: anabasine, oxidation, anabaseine Nꢀoxide, Nꢀbenzoylanabasine pyridine
Nꢀoxide, Nꢀacetyl anabasine pyridine Nꢀoxide, methylanabasine Nꢀoxide, Nꢀbenzoylpiperidylꢀ
2ꢀpyridone, Nꢀacetylpiperidylꢀ2ꢀpyridone, anabaseinꢀ3ꢀone.
Anabasine, 3ꢀ(2ꢀpiperidyl)pyridine (1), is the princiꢀ
pal alkaloid of the Anabasis aphylla L. plant.1 Anabasine
hydrochloride is used as a means for giving up smoking;2
the mechanism of its action includes binding to nicotineꢀ
sensitive receptors. The anabasine base exhibits clearꢀcut
physiological activity. The action of this alkaloid is due to
affection of the Hꢀcholinoreactive structures of various
parts of the nervous system and violation of the memꢀ
brane permeability of cells, which results in a faulty course
of redox processes in the organism.3
Anabasine is an initial base in the synthesis of reversꢀ
ible and irreversible choline esterase inhibitors,4 in parꢀ
ticular, phosphamide,5 carbamide derivatives,6 and a
number of pharmacologically valuable compounds obꢀ
tained by reactions at the piperidineꢀring nitrogen atom.7,8
Anabasine derivatives containing bulky acyl and alkyl subꢀ
stituents at the piperidineꢀring nitrogen atom exert an
antinicotinic action,9 and its hydrogenated derivatives exꢀ
hibit analgesic activities.10
Thus, targeted synthetic transformations of anabasine
may produce effective analogues with other types of physiꢀ
ological activities.
This paper describes a study of the oxidation of anaꢀ
basine (1) and its Nꢀacetyl (2), Nꢀbenzoyl (3) and
Nꢀmethyl (4) derivatives on treatment with tertꢀbutyl
hydroperoxide (TBHP) and МCРBA and some transforꢀ
mations of the Nꢀoxides thus formed.
Results and Discussion
Previously,11 we demonstrated that anabasine oxidaꢀ
tion with hydrogen peroxide in acetic acid is accompaꢀ
nied by cleavage of the piperidine ring. No Nꢀoxidation of
anabasine or its derivatives 2—4 by other reagents has yet
been carried out. We found that refluxing of anabasine (1)
in the presence of the TBHP—MoCl5 system in benzene
with water removal gives crystalline anabaseine Nꢀoxide
(5) in 54% yield (Scheme 1). Thus, the hydroperoxide
serves as a dehydrogenating agent. The oxidation of
Nꢀacetylꢀ (2) or Nꢀbenzoylanabasine (3) under the acꢀ
tion of TBHP—MoCl5 affords individual Nꢀacetylꢀ and
Nꢀbenzoylanabasine pyridine Nꢀoxides 6 and 7 in 79 and
89% yields, respectively. It should be emphasized that
previously, this reagent has been successfully used for
Nꢀoxidation of diverse pyridine derivatives.12—14 The use
of VO(acac)2 as the catalyst proved inefficient. The atꢀ
tempted Nꢀoxidation of anabasine derivatives 2 and 3
with 3 equiv. TBHP in the presence of VO(acac)2 (see
Ref. 14) resulted in the recovery of the initial bases.
The oxidation of Nꢀmethylanabasine (4) with the
TBHP—МoCl5 system results in a mixture of two stereoiꢀ
someric Nꢀmethylanabasine piperidineꢀNꢀoxides 8´ and 8″
(yield 51%) in a NꢀMeax : NꢀMeeq ratio of 1 : 4. The
attempts of further oxidation of monoꢀNꢀoxides 6—8 with
an excess of TBHP—МoCl5 did not yield dioxides. In all
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 322—328, February, 2006.
1066ꢀ5285/06/5502ꢀ0331 © 2006 Springer Science+Business Media, Inc.

332
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Musina et al.
Scheme 1
figuration of the quaternary nitrogen atom in the Nꢀoxide
diastereomers was established in the following way. The
major differences between the 1H NMR spectra of a mixꢀ
ture of Nꢀoxides with an equatorial or axial orientation of
the NꢀMe group is in the chemical shifts of the H(2)
(δ 3.98 and 3.89) and H(4´) (δ 8.00 and 8.21) signals for
isomers 8´ and 8″, respectively. The isomer ratio was found
from the integral intensity ratio of these signals. The conꢀ
figuration analysis of a mixture of Nꢀoxide diastereomers
shows that in the major reaction product, the NꢀMe group
is equatorial (8″). With this arrangement of the NꢀMe
group, the axial proton in the αꢀposition at C(2) would
undergo a smaller downfield shift. Otherwise, the proton
at C(2) would shift downfield due to the effect of the
Nꢀoxide fragment.
We also studied Nꢀoxidation of compounds 1—4 with
МCРBA. The results were similar to those obtained using
the TBHP—МoCl5 system. The oxidation of anabasine
(1) at the pyridine nitrogen atom is also accompanied by
dehydrogenation of the piperidine ring, giving rise to
anabaseine Nꢀoxide (5) (yield 62%). Note that comꢀ
pound 5 is of interest as a potential agonist of muscle and
neuronal nicotinacetyl choline receptors,16 while its deꢀ
rivatives are selective ligands of pꢀacetyl choline receptors
of the α7ꢀtype.17 The synthesis of 3ꢀsubstituted anabaseine
derivatives, agents suitable for the therapy of neuronal
diseases, has also been described.18 The oxidation of comꢀ
pounds 2 and 3 with МCРBA gives the corresponding
pyridine Nꢀoxides 6 and 7 in >90% yield. The oxidation
of Nꢀmethylanabasine (4) with МCРBA gives a mixture
of configurational isomers of Nꢀoxides at the piperidine
nitrogen atom 8´ and 8″ (yield 81%, 1 : 2 ratio) with
predominance of isomer 8″ with an equatorial configuraꢀ
tion of the nitrogenꢀattached Me group. NꢀOxide 8″ was
isolated in the crystalline state. Treatment of a mixture of
Nꢀoxides 8´ and 8″ (1 : 2 ratio) with picric acid afforded a
single stereoisomer, picrate 9a, with the axial orientation
of the NꢀMe group (for compound 8´). It should be noted
that oxidation of Nꢀmethylanabasine with H2O2 in acetic
acid has been reported11 to give the monoꢀNꢀoxide at the
piperidine ring in which the configuration of the NꢀMe
group has not been determined. This compound was charꢀ
acterized as a dipicrate and, according to the melting
point, it was identical to the dipicrate 9b, which we preꢀ
pared from isomer 8″. Thus, according to our data, the
product formed upon the reported11 oxidation of comꢀ
pound 4 with hydrogen peroxide is the piperidine Nꢀoxide
with an equatorial orientation of the NꢀMeꢀgroup (8″).
The oxidation of compound 4 on treatment with МCРBA
or TBHP—МoCl5 yields two piperidine Nꢀoxides 8, the
oxidation with the TBHP—МoCl5 system being more
stereoselective.
R = H (1), Ac (2, 6), Bz (3, 7), Me (4)
Reagents and conditions: i. TBHP—MoCl5, benzene, refluxing,
5—8 h. ii. MCPBA, CHCl3, 20 °C, 3—5 h.
cases, the starting compounds 6—8 were quantitatively
recovered. Thus, hydroperoxide oxidation proceeds seꢀ
lectively at the pyridine nitrogen atom for compounds
1—3 or for the piperidine nitrogen atom for Nꢀmethylꢀ
anabasine (4).
The structures of the synthesized compounds were
determined by spectroscopy. The 1H NMR spectra of
pyridine Nꢀoxides 5—7 show an upfield shift of the signals
of the H(2´), H(4´), and H(6´) protons of the pyridine
ring. For example, for compounds 2 and 6, the differꢀ
ences between the chemical shifts (∆δ) of these proton
signals are 0.42, 0.20, and 0.42, respectively. The upfield
shift was also noted for the 13C NMR signals of the C(2´),
C(4´), and C(6´) atoms in compounds 5—7. The differꢀ
ences between the C(2´), C(4´), and C(6´) chemical shifts
for Nꢀoxide 7 and anabasine derivative 3 are 10.86, 8.82,
and 10.55 ppm, respectively. The formation of the pyriꢀ
dine Nꢀoxides is also confirmed by UV spectra. A comꢀ
parison of the UV absorption spectra of compounds 1—3
with the spectra of Nꢀoxides 5—7 shows a pronounced
shift of the absorption peaks to longer wavelengths. In
addition, the absorption intensity increases (the ε values
increase from 2670 to 6375 and from 3594 to 11220 for 5
and 6, respectively). Similar changes in the UV spectra of
pyridine Nꢀoxides have been noted previously.15
In the 1H NMR spectra of piperidine Nꢀoxides 8´
and 8″, the singlets of the NꢀMeꢀgroup protons (δ 2.65
and 2.74) are shifted downfield with respect to their posiꢀ
tions in the spectrum of compound 4 (δ 1.95). The conꢀ
The ready availability of Nꢀoxides promoted our inꢀ
terest in the study of their transformations, in particular,
acylation. We found that treatment of pyridine Nꢀoxides 6

Synthetic transformations of anabasine
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
333
Scheme 3
and 7 with acetic anhydride followed by hydrolysis affords
pyridinꢀ2ꢀones 10 and 11 in moderate yields (Scheme 2).
Detailed analysis of the reaction mixture shows that no
isomeric 6ꢀpyridinꢀ2ꢀones resulting from oxidation of the
Nꢀpyridinium salt of anabasine19 have been formed. The
structures of pyridinꢀ2ꢀones 10, 11 were confirmed by
1H NMR data. The signals of the protons of the pyridinꢀ
2ꢀone ring in the spectrum of compound 10 resonate at
δ 6.25 (dd, H(5´), J = 6.5 Hz, J = 6.7 Hz), 7.28 (d, H(4´),
J = 6.7 Hz), and 7.33 (d, H(6´), J = 6.5 Hz). With H(5)
proton decoupling, the doublets for H(4) and H(6) are
transformed into singlets.
Scheme 2
Reagents and conditions: i. (1) Ac2O, refluxing, 6 h;
(2) treatment with 10% HCl, 100—110 °C, 2.5—3 h.
nitrile with substituted 2ꢀpyridone 10 occurs as a substiꢀ
tutive addition giving rise to compounds 13 and 15
(Scheme 4). Alkaline hydrolysis of ester 13 yields acid 14.
Scheme 4
R = Ac (10), Bz (11)
Reagents and conditions: i. (1) Ac2O, refluxing, 6 h;
(2) treatment with 10% HCl, 100—110 °C, 2.5—3 h.
Under similar conditions, the reaction of anabaseine
Nꢀoxide (5) with acetic anhydride (Scheme 3) gives rise
to a mixture of Nꢀacetylanabasine (2) and anabaseinꢀ3ꢀ
one (12) (yields 22 and 18%, respectively). The structure
of compound 12 was determined on the basis of spectroꢀ
1
scopy. The H NMR spectrum of anabaseinꢀ3ꢀone (12)
exhibits a set of signals for the pyridineꢀring protons (two
αꢀprotons, one βꢀproton, and one γꢀproton) and for
three methylene groups of the piperidine fragment. The
13C NMR signal for the carbonyl carbon occurs at
δ 196.86.
Reagents and conditions: i. CH2=CHCOOEt, toluene,
115—120 °C, 24 h. ii. 2% solution of NaOH, 20 °C, 1 h.
iii. CH2=CHCN, toluene, 115—120 °C, 22 h.
The synthesis of anabaseinone 12 from anabaseine
Nꢀoxide (5) probably involves a second molecule of comꢀ
pound 5, which is an oxidant. As regards Nꢀacetylꢀ
anabasine (2), the process starts, most likely, with the
formation of the acyloxamine salt A, which is converted
into salt B with the subsequent hydride transfer (see
Scheme 3).
NꢀUnsubstituted 2ꢀpyridinones are known20 to enter
into the Diels—Alder or substitutive addition reactions.
We found that the reaction of ethyl acrylate and acryloꢀ
Thus, we have studied the oxidation of anabasine and
its derivatives with the TBHP—MoCl5 system or with
МCРBA. NꢀAcetylanabasine and Nꢀbenzoylanabasine
pyridine Nꢀoxides and anabaseine Nꢀoxide were syntheꢀ
sized. It was shown that Nꢀoxidation of Nꢀmethylꢀ
anabasine furnishes stereoisomeric Nꢀmethylanabasine
piperidine Nꢀoxides, the reaction in the presence of the
TBHP—MOCl5 systems having a higher selectivity. Pyriꢀ
dine Nꢀoxides react with acetic anhydride to give pyridinꢀ

334
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Musina et al.
NꢀAcetylanabasine N´ꢀoxide (3ꢀ(Nꢀacetylpiperidinꢀ2ꢀyl)pyriꢀ
dine Nꢀoxide) (6). A. Molybdenum(V) chloride (0.01 g) and
Nꢀacetylanabasine (2) (1.01 g, 4.93 mmol) were added succesꢀ
sively to a 70% aqueous solution in TBHP (0.89 g, 9.86 mmol)
in benzene (50 mL). The reaction mixture was refluxed for 7 h
with a Dean—Stark trap, cooled, and workedꢀup as described in
method A. The oily residue was purified by column chromatoꢀ
graphy on silica gel (CHCl3—EtOH, 100 : 2) to give 0.85 g
2ꢀones. The reaction of anabaseine Nꢀoxide with acetic
anhydride yields Nꢀacetylanabasine and anabaseinꢀ3ꢀone.
The reaction of Nꢀacetylanabasinꢀ2´ꢀone with ethyl acryꢀ
late and acrylonitrile occurs according to the substitutive
addition pattern.
Experimental
23
(79%) of compound 6, [α]578 –114.4 (c 4.7, CHCl3).
All experiments were carried out in solvents purified by stanꢀ
dard procedures. Commercial TBHP (Aldrich) and МCРBA
(Fluka) were used. The reactions were monitored by TLC on
Silufol UVꢀ254 plates (using CHCl3—EtOH, 1 : 1, as the eluꢀ
Found (%): C, 65.10; H, 7.42; N, 12.61. C12H16N2O2. Calcuꢀ
lated (%): C, 65.45; H, 7.27; N, 12.72. 1H NMR (CDCl3), δ:
1.34—1.49, 1.55—1.66 (both m, 2 H each, H(4), H(5)); 1.79
(dm, 1 H, H(3), Jgem = 13.5 Hz); 2.11 (s, 3 H, Me); 2.15 (dm,
1 H, H(3), Jgem = 13.5 Hz); 2.87 (dm, 1 H, H(6), Jgem = 13.5);
3.62 (d, 1 H, H(6), J = 13.5 Hz); 5.75 (br.s, 1 H, H(2)); 7.04 (d,
1 H, H(4´), J = 7.0 Hz); 7.18 (t, 1 H, H(5´), J1 = 7.0 Hz); 8.00
(s, 1 H, H(2´)); 8.01 (d, 1 H, H(6´), J = 7.0 Hz). 13C NMR
(CDCl3), δ: 19.01 (C(5)), 21.36 (Me), 25.36 (C(4)), 26.31
(C(3)), 42.75 (C(6)), 48.03 (C(2)), 124.8 (C(5´)), 125.5 (C(4´)),
137.05 (C(2´)), 137.86 (C(6´)), 139.40 (C(3´)), 169.60 (C=O).
UV, λmax/nm (ε): 214 (14134), 266 (11220).
B. A solution of Nꢀacetylanabasine (2) (1.00 g, 4.9 mmol) in
CHCl3 (10 mL) was added to a solution of 70% МCРBA (2.42 g,
9.8 mmol) in CHCl3 (40 mL). The reaction mixture was stirred
for 5 h at ~20 °C and workedꢀup as described above in method
B. The residue was chromatographed on a column with silica gel
(elution with CHCl3—EtOH, 100 : 2) to give 0.98 g (91%) of
compound 6.
1
ent). The H and 13C NMR spectra were recorded on a Bruker
AC 200 instrument in CDCl3 and (CD3)2SO. The signals in the
NMR spectra were assigned using 1H—1H 2D (COSY) and
1H—13C (COLOC) spectra. Mass spectra were recorded on a
Finnigan MAT 8200 mass spectrometer (EI, 70 eV). IR spectra
were measured on a VECTORꢀ22 instrument in KBr. UV abꢀ
sorption spectra were recorded on an HP 8453 UV—Vis instruꢀ
ment in ethanol. The optical rotation was measured on a Polamat
A polarimeter at 578 nm and 20—23 °C.
Anabasine used in the study was isolated from Anabasis
aphylla L. according to a published procedure;1 purity 99.0%
(GLC data), [α]57823 –72.3 (c 5.2, CHCl3).
NꢀAcetylanabasine (2), Nꢀbenzoylanabasine (3), and Nꢀmeꢀ
thylanabasine (4) were prepared by known procedures.21—23
NꢀOxidation of compounds 1—4 was carried out by treatment
with TBHP—MoCl5 (method A) and МCРBA (method B).
Anabaseine N´ꢀoxide (3,4,5,6ꢀtetrahydro[2,3´]bipyridinyl
1´ꢀoxide) (5). A. Anabasine (1) (1.04 g, 6.4 mmol) was added to
a mixture of 70% aq. TBHP (2.32 g, 12.88 mmol) and MoCl5
(0.01 g) in benzene (50 mL). The reaction mixture was reꢀ
fluxed for 5 h with a Dean—Stark trap, cooled, treated with
10% aq. NaOH, and washed with distilled water (3×5 mL).
The resulting aqueous layer was extracted with chloroform
(7×10 mL). The benzene and chloroform fractions were dried
over MgSO4, combined, and concentrated. The residue was reꢀ
crystallized from diethyl ether to give 0.58 g (54%) of comꢀ
NꢀBenzoylanabasine N´ꢀoxide (3ꢀ(Nꢀbenzoylpiperidinꢀ2ꢀ
yl)pyridine Nꢀoxide) (7). A. Molybdenum(V) chloride (0.01 g)
and Nꢀbenzoylanabasine (3) (0.63 g, 2.35 mmol) were added
successively to a mixture of 70% aq. TBHP (0.61 g, 4.70 mmol)
in benzene (50 mL). The reaction mixture was refluxed for 7 h
with a Dean—Stark trap, cooled, and workedꢀup as described in
23
method A to give 0.59 g (89%) of compound 7, [α]578 –125.3
(c 4.1, CHCl3). Found (%): C, 72.58; H, 6.58; N, 9.17.
C
17H18N2O2. Calculated (%): C, 72.34; H, 6.38; N, 9.92.
1H NMR (CDCl3), δ: 1.39—1.52 (m, 3 H, H(4), 2 H(5)); 1.67
(dm, 1 H, H(4), Jgem = 13.2 Hz); 1.91 (dm, 1 H, H(3), Jgem
=
23
pound 5, m.p. 103—104 °C (Et2O), [α]578 –13.3 (c 1.5,
13.2 Hz); 2.19 (d, 1 H, H(3), J = 13.2 Hz); 2.77, 3.75 (both m,
1 H each, H(6)); 5.71 (br.s, 1 H, H(2)); 7.15 (d, 1 H, H(5´), J =
8.0 Hz); 7.21 (dd, 1 H, H(4´), J1 = 6.4 Hz, J2 = 8.0 Hz);
7.29—7.36 (m, 5 H, Ph); 8.04 (d, 1 H, H(6´), J = 6.4 Hz); 8.12
(s, 1 H, H(2´)). 13C NMR (CDCl3), δ: 19.3 (C(5)); 25.6 (C(4));
26.99 (C(3)); 43.10 (C(6)); 50.52 (C(2)); 124.5 (C(5´)); 125.3
(C(4´)); 125.14, 125.64, 128.35, 129.40, 129.64, 132.35 (Ph);
137.2 (C(6´)); 137.9 (C(2´)); 139.2 (C(3´)); 171.1 (C=O). UV,
CHCl3). Found (%): C, 68.12; H, 6.67; N, 15.97. C10H12N2O.
Calculated (%): C, 68.18; H, 6.81; N, 15.91. 1H NMR (CDCl3),
δ: 1.82—2.10 (m, 4 H, 2 H(4), 2 H(5)); 2.81 (t, 2 H, 2 H(3), J =
6.2 Hz); 3.99 (t, 2 H, 2 H(6), J = 6.2 Hz); 7.31 (m, 1 H, H(5´));
8.53 (dt, 1 H, H(4´), J1 = J2 = 2.0 Hz, J3 = 5.4 Hz); 8.65 (dt,
1 H, H(6´), J1 = J2 = 2.0 Hz, J3 = 8.2 Hz); 9.08 (dd, 1 H, H(2´),
J1 = J2 = 2.0 Hz). 13C NMR (CDCl3), δ: 21.69 (C(4)), 25.71
(C(5)), 31.07 (C(3)), 63.39 (C(6)), 125.37 (C(5´)), 132.58
(C(2)), 138.27 (C(4´)), 141.75 (C(3´)), 151.27 (C(2´)), 152.52
(C(6´)). UV, λmax/nm (ε): 289 (6376).
B. A solution of anabasine (1) (1.04 g, 6.4 mmol) in CHCl3
(15 mL) was added with stirring to a solution of 70% aq. МCРBA
(3.17 g, 12.88 mmol) in CHCl3 (35 mL). After 3 h, the reacꢀ
tion mixture was alkalized with 10% aq. NaOH (~5 mL) to
pH 10—11, and the organic layer was separated and washed with
distilled water (2×2 mL). The aqueous layer was extracted with
chloroform (5×10 mL). The chloroform extracts were combined
and dried with MgSO4. The solvent was evaporated. The resultꢀ
ing oily substance was purified by column chromatography on
silica gel (elution with CHCl3—EtOH, 100 : 1) and recrystalꢀ
lized from diethyl ether to give 0.71 g (62%) of compound 5.
λ
max/nm (ε): 216 (1598), 266 (857).
B. A solution of Nꢀbenzoylanabasine (3) (1.0 g, 3.75 mmol)
in CHCl3 (10 mL) was added to a solution of 70% aq. МCРBA
(1.85 g, 7.50 mmol) in CHCl3 (40 mL). The reaction mixture
was stirred for 5 h at ~20 °C and workedꢀup as described in
method B to give 0.98 g (92%) of compound 7.
NꢀMethylanabasine Nꢀoxide (1ꢀmethylꢀ3,4,5,6ꢀtetrahydroꢀ
2Hꢀ[2,3´]bipyridinyl 1ꢀoxide) (isomer mixture 8´ and 8″).
A. Molybdenum(V) chloride (0.02 g) and Nꢀmethylanabasine
(4) (0.41 g, 2.3 mmol) were added to a mixture of 70% aq. TBHP
(0.83 g, 9.2 mmol) in C6H6 (50 mL). The reaction mixture was
refluxed for 5 h with a Dean—Stark trap, cooled, and alkalized
with 10% aq. NaOH дo pH 10—11. The organic layer was sepaꢀ
rated, and the aqueous layer was extracted with chloroform

Synthetic transformations of anabasine
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
335
(6×15 mL). The benzene and chloroform extracts were dried
with MgSO4 and concentrated. The benzene extract contained
unreacted Nꢀmethylanabasine (0.18 g). The chloroform extract
contained 0.23 g (51%) of a stereoisomer mixture 8´ and 8″ in
1 : 4 ratio.
N, 17.12. C23H22N8O15. Calculated (%): C, 42.46; H, 3.38;
N, 17.23. 1H NMR ((CD3)2CO), δ: 1.82—2.91 (m, 6 H, 2 H(3),
2 H(4), 2 H(5)); 3.59 (s, 3 H, Me); 4.07, 4.31 (both td, 1 H each,
H(6), J1 = 3.6 Hz, J2 = 12.8 Hz); 5.41 (d, 1 H, H(2), J =
12.2 Hz); 8.12—8.23 (m, 1 H, H(5´)); 8.79 (s, 4 H, 2 C6H2);
8.89 (t, 1 H, H(4´), J = 6.8 Hz); 9.05 (d, 1 H, H(6´), J =
6.8 Hz); 9.22 (br.s, 1 H, H(6´)).
B. A solution of Nꢀmethylanabasine (4) (0.61 g, 3.4 mmol)
in CHCl3 (20 mL) was added to a solution of 70% aq. МCРBA
(0.85 g, 3.4 mmol) in CHCl3 (30 mL). The reaction mixture was
stirred for 5 h and treated with 10% aq. NaOH (~5 mL) to
рH 10—11. The organic layer was separated, dried with MgSO4,
and concentrated, and the aqueous layer was extracted with
chloroform (6×15 mL). The chloroform extract was dried with
MgSO4 and concentrated to give a mixture of compounds 8´
and 8″ in 1 : 2 ratio in an overall yield of 0.54 g (81%). Recrystalꢀ
1ꢀAcetylꢀ1,2,3,4,5,6ꢀhexahydroꢀ1´Hꢀ[2,3´]bipyridinylꢀ
2´ꢀone (10). A solution of Nꢀacetylanabasine N´ꢀoxide (6)
(0.85 g, 3.86 mmol) in acetic anhydride (9.74 g, 95.38 mmol)
was refluxed for 5 h. Then excess Ac2O was evaporated in vacuo,
the resulting mass was diluted with 10% aq. HCl (5 mL) and
heated for 2.5 h at a bath temperature of 110 °C. The mixture
was cooled, alkalized with 10% NaOH to рH 10—11, and exꢀ
tracted with chloroform (5×10 mL). The aqueous layer was
completely dried in air, and the product was extracted with
chloroform (4×10 mL). The combined chloroform extracts were
dried with MgSO4 and concentrated. Recrystallization from acꢀ
etone gave compound 10. Yield 0.24 g (28%), m.p. 189—190 °C
1
lization from ether gave isomer 8″, m.p. 171—174 °C. H NMR
for isomer 8″ (CDCl3), δ: 1.36—1.46 (dd, 1 H, Heq(4), J1 =
4.0 Hz, J2 = 13.5 Hz); 1.51—1.62 (m, 2 H, Hax(4), Heq(5)); 1.84
(dm, 1 H, Hax(5), Jgem = 13.5 Hz); 2.41—2.57 (dd, 1 H, Hax(3),
J1 = 5.0 Hz, J2 = 13.5 Hz); 2.57—2.67 (dd, 1 H, Heq(3), J1 =
4.0 Hz, J2 = 13.5 Hz); 2.74 (s, 3 H, Meeq); 3.25 (td, 1 H, Hax(6),
J1 = 2.0 Hz, J2 = 12.0 Hz); 3.36 (dt, 1 H, Heq(6), J1 = 2.0 Hz,
J2 = 12.0 Hz); 3.89 (dd, 1 H, Hax(2), J1 = 2.0 Hz, J2 = 12.0 Hz);
7.24 (dd, 1 H, H(5´), J1 = 5.0 Hz, J2 = 7.8 Hz); 8.19 (t, 1 H,
H(4´), J = 7.8 Hz); 8.51 (dd, 2 H, H(2´), H(6´), J1 = 1.5 Hz,
J2 = 5.0 Hz). 13C NMR for isomer 8″ (CDCl3), δ: 20.41 (C(5)),
23.05 (C(4)), 27.67 (C(3)), 58.47 (Me), 68.99 (C(6)), 74.87
(C(2)), 123.33 (C(5´)), 131.51 (C(3´)), 137.78 (C(4´)), 150.30
(C(6´)), 150.60 (C(2´)). UV, λmax/nm (ε): 261 (3584), 266
(3525). 1H NMR for isomer 8´ (CDCl3), δ: 1.27—1.73 (m, 4 H,
2 H(4), 2 H(5)); 2.65 (s, 3 H, Me); 2.12—2.88 (m, 2 H, 2 H(3));
3.18—3.36 (m, 2 H, 2 H(6)); 3.98 (d, 1 H, H(2), J = 11.2 Hz);
7.00—7.12 (m, 1 H, H(5´)); 8.02 (d, 1 H, H(4´), J = 5.8 Hz);
8.28 (dd, 1 H, H(6´), J1 = 5.8 Hz, J2 = 8.6 Hz); 8.34 (d, 1 H,
H(2´), J = 5.2 Hz). 13C NMR for isomer 8´ (CDCl3), δ: 22.39
(C(5)), 23.24 (C(4)), 26.81 (C(3)), 58.06 (Me), 71.06 (C(6)),
77.13 (C(2)), 122.09 (C(5´)), 129.02 (C(3´)), 139.93 (C(4´)),
149.34 (C(6´)), 150.99 (C(2´)).
23
(from acetone), [α]578 –13.1 (c 3.1, CHCl3). Found (%):
C, 65.20; H, 7.24; N, 12.26. C12H16N2O2. Calculated (%):
C, 65.45; H, 7.27; N, 12.72. 1H (CDCl3), δ: 1.27—1.36 (m, 1 H,
H(5)); 1.43—1.62 (m, 2 H, H(4), H(5)); 1.67—1.75 (m, 1 H,
H(4)); 1.79—1.92 (m, 1 H, H(3)); 2.00 (s, 3 H, Me); 2.36 (br.d,
1 H, H(3), Jgem = 12.2 Hz); 2.88 (t, 1 H, H(6), J = 12.2 Hz);
4.61 (d, 1 H, H(6), J = 12.2 Hz); 5.11 (br.s, 1 H, H(2)); 6.25
(dd, 1 H, H(5´), J1 = 6.5 Hz, J2 = 6.7 Hz); 7.28 (d, 1 H, H(4´),
J = 6.7 Hz); 7.33 (d, 1 H, H(6´), J = 6.5 Hz); 12.93 (br.s, 1 H,
NH). 13C NMR (CDCl3), δ: 171.30, 163.43 (C=O); 137.20
(C(6´)); 133.13 (C(4´)); 131.63 (C(3´)); 106.26 (C(5´)); 53.19
(C(2)); 39.02 (C(6)); 27.16 (C(3)); 24.45 (C(4)); 21.42 (Me);
19.08 (C(5)). IR, ν/cm–1: 3431 (NH), 1631 (N—(C=O)). UV,
λ
max/nm (ε): 229 (6382), 302 (5194).
1ꢀBenzoylꢀ1,2,3,4,5,6ꢀhexahydroꢀ1´Hꢀ[2,3´]bipyridinylꢀ
2´ꢀone (11). A solution of Nꢀbenzoylanabasine N´ꢀoxide (7)
(0.6522 g, 2.312 mmol) in acetic anhydride (7.57 g, 74.2 mmol)
was refluxed for 5 h, then excess Ac2O was evaporated in vacuo,
and the remainder was diluted with 10% aq. HCl (5 mL) and
heated for 3 h at 110 °C. The reaction mixture was cooled,
treated with 10% NаOH to pH 10—11, and extracted with chloꢀ
roform (6×10 mL). The aqueous phase was dried in air to dryꢀ
ness and the remaining product was extracted with chloroform
(5×10 mL). The chloroform extracts were dried with MgSO4,
combined, and concentrated. Crystallization from diethyl ether
gave compound 11 as yellow crystals. Yield 0.24 g (37%),
NꢀMethylanabasine Nꢀoxide picrate (9a). A solution of picric
acid (1 equiv.) in EtOH (5 mL) was added to an isomer mixture
8´, 8″ (0.15 g, 1 : 4 ratio) in EtOH (5 mL). After 24 h, the solvent
was evaporated and the material was crystallized from ethanol.
Picrate 9a was filtered off and dried. Yield 0.06 g (93%), m.p.
144—147 °C (EtOH). Found (%): C, 48.58; H, 4.15; N, 16.62.
C
17H19N5O8. Calculated (%): C, 48.45; H, 4.51; N, 16.62.
1H NMR (CDCl3), δ: 1.57—2.12 (m, 4 H, 2 H(4), 2 H(5));
2.38—2.84 (m, 2 H, 2 H(3)); 3.29 (s, 3 H, Me); 3.50 (td, 1 H,
H(6), J1 = 2.8 Hz, J2 = 12.4 Hz); 4.21 (dd, 1 H, H(6), J1 =
2.8 Hz, J2 = 12.4 Hz); 4.51 (d, 1 H, H(2), J = 12.4 Hz); 7.42
(dd, 1 H, H(5´), J1 = 4.6 Hz, J2 = 7.8 Hz); 8.06 (d, 1 H, H(4´),
J = 7.8 Hz); 8.65 (s, 1 H, H(2´)); 8.67 (d, 1 H, H(6´), J =
7.8 Hz); 8.69 (d, 1 H, H(6´), J = 4.6 Hz); 8.71 (s, 1 H, H(2´));
8.86 (s, 2 H, C6H2). 13C NMR (CDCl3) δ: 20.19 (C(5));
22.49 (C(4)); 27.74 (C(3)); 55.19 (Me); 68.22 (C(6)); 77.10
(C(2)); 124.16 (C(5´)); 126.31, 126.32, 128.42, 129.00, 161.03,
179.91 (C6H2); 137.67 (C(4´)); 141.49 (C(3´)); 150.86 (C(6´));
152.02 (C(2´)).
23
m.p. 78—81 °C (hygroscopic), [α]578 +18.4 (c 2.1, CHCl3).
Found (%): C, 72.11; H, 6.66; N, 9.08. C17H18N2O2. Calcuꢀ
lated (%): C, 72.34; H, 6.38; N, 9.92. 1H NMR (CDCl3), δ:
1.45—2.22 (m, 7 H, 2 H(3), 2 H(4), 2 H(5), H(6)); 2.92 (t, 1 H,
H(6), J = 12.5 Hz); 4.05 (d, 1 H, H(2), J = 12.5 Hz); 6.16 (dd,
1 H, H(5´), J1 = 6.4 Hz, J2 = 7.0 Hz); 7.11—7.39 (m, 5 H, Ph);
7.53 (t, 2 H, H(4´), H(6´), J = 6.4 Hz); 7.92 (d, 1 H, NH, J =
7.0 Hz); 9.40 (br.s, 1 H, NH). 13C NMR (CDCl3), δ: 23.43,
23.10 (C(4), C(5)); 27.75 (C(3)); 45.40 (C(6)); 54.90 (C(2));
107.00 (C(5´)); 127.40, 127.41, 129.25, 130.06, 130.10, 134.40
(Ph); 134.90 (C(3´)); 137.10 (C(4´)); 139.30 (C(6´)); 163.2,
173.10 (C=O). IR, ν/cm–1: 3415 (NH), 3075 (CH arom.), 1648
(N—(C=O)). UV, λmax/nm (ε): 226 (10386), 302 (5027).
NꢀMethylanabasine Nꢀoxide dipicrate (9b). A solution of piꢀ
cric acid (1 equiv.) in EtOH (5 mL) was added to a mixture of
isomers 8´, 8″ (0.29 g, 1 : 2 ratio) in EtOH (5 mL). After 10 min,
the crystals of dipicrate 9b were filtered off. Yield 0.29 g (87%),
m.p. 174—174.5 °C (ЕtOH). Found (%): C, 42.53; H, 3.48;
Anabaseinꢀ3ꢀone (5,6ꢀdihydroꢀ4Hꢀ[2,3´]bipyridinylꢀ3ꢀone)
(12). Anabaseine N´ꢀoxide (5) (0.86 g, 4.88 mmol) and Aс2O
(12.01 g, 0.176 mol) were heated for 3 h at 100 °C, and excess

336
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Musina et al.
Aс2O was evaporated in vacuo. The reaction mixture was diluted
with 10% HCl (5 mL), heated for 1 h, cooled, and alkalized with
10% NaOH to pH 10—11 (~5 mL), and the product was exꢀ
tracted with chloroform (5×10 mL). The solvent was evapoꢀ
rated, and the extract was chromatographed on a column with
silica gel to give successively 0.15 g (18%) of a colorless oil
identified as anabaseinꢀ3ꢀone (12) (elution with CHCl3—EtOH,
100 : 0.5) and 0.21 g (22%) of Nꢀacetylanabasine (2) (elution
with CHCl3—EtOH, 100 : 2). Compound 12. Found (%):
C, 69.06; H, 5.98; N, 16.21. C10H10N2O. Calculated (%):
solvent was evaporated. Column chromatography gave 0.09 g
(48%) of nitrile 15. Found (%): C, 66.13; H, 6.77; N, 15.22.
C15H19N3O2. Calculated (%): C, 65.93; H, 6.96; N, 15.38.
1H NMR (CDCl3), δ: 1.25—1.85 (m, 5 H, H(3), 2 H(4), 2 H(5));
1.98 (s, 3 H, Me); 2.24 (d, 1 H, H(3), J = 10.8 Hz); 2.89 (t, 3 H,
H(6), CH2, J = 6.2 Hz); 4.14 (t, 2 H, CH2, J = 6.2 Hz); 4.59 (d,
1 H, H(6), J = 12.8 Hz); 5.08 (d, 1 H, H(2), J = 2.0 Hz); 6.21
(dd, 1 H, H(5´), J1 = 6.0 Hz, J2 = 6.2 Hz); 7.21 (d, 1 H, H(4´),
J = 6.2 Hz); 7.31 (d, 1 H, H(6´), J = 6.0 Hz). 13C NMR (CDCl3),
δ: 17.13 (CH2), 19.16 (C(5)), 21.45 (Me), 24.45 (C(4)), 27.07
(C(3)), 38.93 (C(6)), 46.39 (CH2), 53.41 (C(2)), 105.86 (C(5´)),
116.93 (CN), 132.29 (C(3´)), 135.58 (C(4´)), 136.19 (C(6´)),
160.66 (C(2´)), 171.23 (C=O). IR, ν/cm–1: 2862, 1416 (CH2),
2249 (C=N), 1720 (C=O), 1650 (N—(C=O)). UV, λmax/nm (ε):
231 (5663), 305 (5546). MS, m/z (Irel (%)): 273.3 [M]+
(1.27), 230.0 (100), 177.1 (29.74), 149.0 (72.16). Found:
m/z 273.14764 [M]+. C15H19N3O2. Calculated: M = 273.14772.
1
C, 68.96; H, 5.74; N, 16.09. H NMR (CDCl3) δ: 2.09 (t, 2 H,
H(5), J = 6.8 Hz); 2.50 (t, 2 H, H(4), J = 6.9 Hz); 3.16 (t, 2 H,
H(6), J = 6.8 Hz); 7.39 (qd, 1 H, H(5´), J1 = 1.6 Hz, J2 =
4.8 Hz); 8.19 (dt, 1 H, H(4´), J1 = 1.6 Hz, J2 = 8.0 Hz); 8.73
(dd, 1 H, H(6´), J1 = 1.6 Hz, J2 = 4.8 Hz); 9.12 (d, 1 H, H(2´),
J = 1.6 Hz). 13C NMR (CDCl3), δ: 16.39 (C(5)), 19.24 (C(4)),
36.48 (C(6)), 118.96 (C(2)), 123.55 (C(5´)), 131.53 (C(3´)),
135.08 (C(4´)), 149.32 (C(2´)), 153.68 (C(6´)), 196.84 (C=O).
UV, λmax/nm (ε): 229 (8385), 267 (3057), 310 (974). MS, m/z (Irel
(%)): 174.1 [M]+ (5.26), 121.0 (7.52), 106.0 (100.0), 78.0 (56.22),
51.0 (30.43).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32365).
3ꢀ(1ꢀAcetylꢀ2´ꢀoxoꢀ1,2,3,4,5,6ꢀhexahydroꢀ2´Hꢀ[2,3´]biꢀ
pyridinylꢀ1´ꢀyl)propionic acid (14). Ethyl acrylate (0.21 g,
3.99 mmol) was added to a solution of pyridinꢀ2ꢀone 10 (0.18 g,
0.80 mmol) in toluene (5 mL) and the reaction mixture was
heated for 24 h at 115—120 °C (TLC monitoring). The solvent
was evaporated. Column chromatography gave successively
0.18 g (67%) of ethyl 3ꢀ(1ꢀacetylꢀ2´ꢀoxoꢀ1,2,3,4,5,6ꢀhexahydroꢀ
2´Hꢀ[2,3´]bipyridinylꢀ1´ꢀyl)propionate (13) (elution with
CHCl3—EtOH, 100 : 2) and 0.09 g of Nꢀacetylanabasinꢀ2´ꢀone
(elution with CHCl3—EtOH, 100 : 9). A suspension of comꢀ
pound 13 (0.18 g, 0.56 mmol) in 2% aq. NaOH (~5 mL) was
stirred for 1 h, and the mixture was neutralized with 5% HCl
(~4 mL) and extracted with chloroform (5×10 mL) to give
acid 14. Yield 0.11 g (69%). Compound 13. 1H (CDCl3), δ: 1.09
(t, 3 H, Me, J = 6.4 Hz); 1.24—2.00 (m, 5 H, H(3), 2 H(4),
2 H(5)); 1.89 (s, 3 H, Me); 2.22 (d, 1 H, H(3), J = 12.0 Hz);
2.73 (t, 2 H, CH2, J = 6.4 Hz); 2.77 (m, 1 H, H(6)); 4.05 (m,
4 H, CH2CH2); 4.48 (d, 1 H, H(6), J = 10.0 Hz); 5.00 (br.s,
1 H, H(2)); 6.02 (dd, 1 H, H(5´), J1 = 6.0 Hz, J2 = 6.2 Hz); 7.03
(d, 1 H, H(4´), J = 6.2 Hz); 7.28 (d, 1 H, H(6´), J = 6.0 Hz).
Compound 14. Found (%): C, 61.78; H, 6.52; N, 9.82.
C15H20N2O4. Calculated (%): C, 61.64; H, 6.85; N, 9.59.
1H NMR (CDCl3), δ: 1.21—1.79 (m, 5 H, H(3), H(4), H(5));
1.91 (s, 3 H, Me); 2.17 (d, 1 H, H(3), J = 12.8 Hz); 2.73 (m,
3 H, H(6), CH2); 4.12 (m, 2 H, CH2); 4.45 (d, 1 H, H(6), J =
12.8 Hz); 5.09 (br.s, 1 H, H(2)); 6.09 (dd, 1 H, H(5´), J1 =
6.0 Hz, J2 = 6.2 Hz); 7.11 (d, 1 H, H(4´), J = 6.2 Hz); 7.39 (d,
1 H, H(6´), J = 6.0 Hz); 8.58 (br.s, 1 H, OH). 13C NMR
(CDCl3), δ: 18.79 (C(5)); 20.97 (Me); 24.12 (C(4)); 26.89
(C(3)); 32.71 (CH2); 39.00 (C(6)); 46.25 (CH2); 53.33 (C(2));
105.26 (C(5´)); 131.14 (C(3´)); 135.63 (C(4´)); 137.44 (C(6´));
160.73 (C(2´)); 172.03, 173.08 (C=O). MS, m/z (Irel (%)):
292.2 [M]+ (5.09), 277.2 (69.19), 249.1 (100), 177.2 (77.14).
Found: m/z 292.14193 [M]+. C15H20N2O4. Calculated:
M = 292.14230.
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Synthetic transformations of anabasine
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Received May 30, 2005;
in revised form November 28, 2005