A convenient racemic synthesis of two isomeric tetrahydropyridyl alkaloids: Isoanatabine and anatabine

Article abstract of DOI:10.1002/jhet.359

(Chemical Equation Presented) Anatabine is a major alkaloid in Nicotiana tabacum and its isomer, isoanatabine, was recently found in a marine worm. Reduction of 1-methylpyridinium iodide with sodium borohydride gave 1-methyl-3-piperideine, which was transformed with hydrogen peroxide into the N-oxide. Reaction of the N-oxide successively with trifluoroacetic anhydride and potassium cyanide gave 2-cyano-1-methyl-3-piperideine. Its reaction with 3-pyridylmagnesium chloride gave (±)-N-methyl-isoanatabine. This was transformed with m-chloroperbenzoic acid into the N-oxide which was N-demethylated with iron(II) sulfate, giving (±)-isoanatabine. The successive applications of literature procedures for the N-demethylation by decomposition of N-oxide contributed to the knowledge of the mechanism of this oxidative rearrangement. On the other hand, the reduction of 1-methylpyridinium iodide with sodium borohydride and with potassium cyanide present since the start of the reaction in a two layer ether-water system, gave 2-cyano-1-methyl-4-piperideine. This was transformed into (±)-anatabine by the same sequence of reactions used for the synthesis of (±)- isoanatabine.

Full text of DOI:10.1002/jhet.359

May 2010
A Convenient Racemic Synthesis of Two Isomeric
Tetrahydropyridyl Alkaloids: Isoanatabine and Anatabine
569
Anne Rouchaud and William R. Kem*
Department of Pharmacology and Therapeutics, University of Florida, College of Medicine,
Gainesville, Florida 32610-0267
*E-mail: wrkem@ufl.edu
Received June 28, 2009
DOI 10.1002/jhet.359
Published online 29 April 2010 in Wiley InterScience (www.interscience.wiley.com).
Anatabine is a major alkaloid in Nicotiana tabacum and its isomer, isoanatabine, was recently found
in a marine worm. Reduction of 1-methylpyridinium iodide with sodium borohydride gave 1-methyl-3-
piperideine, which was transformed with hydrogen peroxide into the N-oxide. Reaction of the N-oxide
successively with trifluoroacetic anhydride and potassium cyanide gave 2-cyano-1-methyl-3-piperideine.
Its reaction with 3-pyridylmagnesium chloride gave (6)-N-methyl-isoanatabine. This was transformed
with m-chloroperbenzoic acid into the N-oxide which was N-demethylated with iron(II) sulfate, giving
(6)-isoanatabine. The successive applications of literature procedures for the N-demethylation by
decomposition of N-oxide contributed to the knowledge of the mechanism of this oxidative rearrange-
ment. On the other hand, the reduction of 1-methylpyridinium iodide with sodium borohydride and with
potassium cyanide present since the start of the reaction in a two layer ether-water system, gave 2-
cyano-1-methyl-4-piperideine. This was transformed into (6)-anatabine by the same sequence of reac-
tions used for the synthesis of (6)-isoanatabine.
J. Heterocyclic Chem., 47, 569 (2010).
INTRODUCTION
To our knowledge, only the procedure of Flann et al.
has been published for the synthesis of (6)-isoanatabine,
i.e., 2-(3-pyridyl)-3-piperideine [5] (Scheme 2). This
multistep procedure starts with 3-butyn-1-ol and synthe-
sized 1-amino-4-trimethylsilyl-but-3-ene. The condensa-
tion of the latter with 3-pyridinecarboxaldehyde gave
the aldimine, which with trifluoroacetic acid cyclized by
1,2-addition to the imine group of the trimethylsilylated
vinylcarbon, giving (6)-isoanatabine.
On the other hand, several procedures have been
developed for the synthesis of anatabine, i.e., 2-(3-pyri-
dyl)-4-piperideine (Scheme 3). In general, they start
from a 3-substituted pyridine and the piperideine ring is
constructed at the substituent moiety. Quan et al. started
In fresh tobacco leaves of the Nicotina tabacum spe-
cies, the alkaloid mixture consists of 93% (S)-nicotine,
3.9% (S)-anatabine, 2.4% (S)-nornicotine, 0.5% (S)-
anabasine, and several other pyridine alkaloids which
are detected in lower amounts [1]. (S)-Nicotine and sev-
eral of its minor metabolites have potent modulatory
effects on nicotinic acetylcholine receptors in the central
and peripheral nervous systems. Thus, a variety of nico-
tinic agonists are being developed for the treatment of
neurodegenerative and mental diseases [2]. As part of a
search for biologically active compounds acting upon
these receptors, we synthesized anatabine and isomeric
isoanatabine (Scheme 1), found in a marine worm [3,4].
C
V
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570
A. Rouchaud and W. R. Kem
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Scheme 1
unsaturated aminoalcohol generated the phenylsulfonyl
substituted (S)-anatabine. Reductive elimination of the
phenylsulfonyl substituent gave (S)-anatabine.
Ayers et al. synthesized (S)-anatabine starting with 3-
(aminomethyl)-pyridine [10]. Its condensation with (þ)-
2-hydroxy-3-pinanone in the presence of boron trifluor-
ide diethyl etherate gave an enantiomerically pure keti-
mine. The carbanion (generated with LDA) of the meth-
ylene a to the nitrogen of the imine group was enantio-
selectively monoalkylated with cis-1-bromo-4-(tetrahy-
dropyran-2-yloxy)-but-2-en. The 4-tetrahydropyran and
2-hydroxy-3-pinanone groups were removed. The Mitsu-
nobu cyclization of the unsaturated 1,5-aminoalcohol
gave (S)-anatabine. The use of (ꢀ)-2-hydroxy-3-pina-
none ketimine gave (R)-anatabine by the same
procedure.
from 3-formylpyridine [6]. The formyl group was trans-
formed with ethyl carbamate into diethyl N,N0-(3-pyri-
dylmethyl)-biscarbamate. With boron trifluoride etherate,
the biscarbamate was decomposed by heating in benzene
into an intermediate imine which cyclized with 1,3-buta-
diene (Diels Alder reaction), giving the N-ethoxycar-
bonyl-anatabine and, after hydrolysis, (6)-anatabine.
Deo and Crooks started from 3-(aminomethyl)-pyridine
[7]. This was transformed with benzophenone into a keti-
mine. Its reaction with LDA gave the carbanion of the
activated methylene, which was then monoalkylated with
cis-1,4-dichloro-2-butene. Hydrolysis made free the 1-
amino group which cyclized by reaction with the 5-chloro
substituent of the pent-3-ene, giving (6)-anatabine.
Felpin et al. synthesized (S)-anatabine starting with the
asymmetric addition of (þ)-B-allyl-diisopinocampheyl-
borane to 3-formylpyridine, giving the enantiomerically
pure alcohol [8]. This was successively transformed into
the mesylate, azide, and amine. The amino group
previously transformed into carbamate was alkylated
with allylbromide. Metathesis with the Grubb’s ruthe-
nium catalyst cyclized the two allyl groups into the
N-carbamate protected (S)-anatabine, which was then
deprotected.
On the other hand, (R)-anatabine was synthesized
starting with 1-(2,4-dinitrobenzene-1-yl)-pyridinium
chloride and (R)-phenylglycinol [11].
The addition of lithium aluminum hydride to pyridine
gives
lithium
tetrakis(N-dihydropyridyl)aluminate
(LDPA) [12a]. The addition at 0ꢁC of water to the solu-
tion of LDPA in pyridine, gives a mixture of 1,4-, 1,2-,
and 2,5-dihydropyridines in a ratio of 26:37:38 [12b].
By conducting this hydrolysis under an atmosphere of
oxygen, Yang and Tanner obtained (6)-anatabine with a
yield of 59% [12c].
In this work, a short procedure has been developed
for the synthesis of (6)-isoanatabine starting with 1-
methylpyridinium iodide. By modifying the first reduc-
tion step, this procedure has been extended to the syn-
thesis of (6)-anatabine.
RESULTS AND DISCUSSION
Balasubramanian and Hassner synthesized (S)-anata-
bine starting from 3-pyridinecarboxaldehyde [9]. Its con-
densation with (S)-p-toluenesulfinamide gave an enantio-
merically pure imine. After the enantioselective 1,2-
addition to its imino group of the 4-carbanion of cis-1-
hydroxy-4-phenylsulfonyl-but-2-ene (the dianion of
which being obtained with LiHMDS), the amino group
was deprotected. The Mitsunobu cyclization of the 1,5-
Synthesis of (6)-isonanatabine.
Synthesis of (ꢂ)-N-methyl-isoanatabine 3a and (ꢂ)-N-ben-
zyl-isoanatabine 3b. Reaction of pyridine with methyl
iodide in acetone gave 1-methylpyridinium iodide
(Scheme 4). According to a described procedure, the
reaction of 1-methylpyridinium iodide with sodium bor-
ohydride in methanol yielded 1-methyl-3-piperideine,
which was not isolated [13]. Oxidation with hydrogen
Scheme 2
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Scheme 3
Scheme 4. Reagents and conditions: (i, ii) see refs. [13] and [14]. (iii) 3-PyrMgCl, THF/Et2O, ꢀ10ꢁC to rt, 16 h for 3a (yield: 77%); 0ꢁC to rt, 16
h for 3b (yield: 67%).
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A. Rouchaud and W. R. Kem
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Scheme 5. Reagents and conditions: (i) ACE-Cl, 1,2-dichloroethane, reflux, 16 h. (ii) 2.5% NaOH, EtOH/H2O (9:1), 0ꢁC (1 h) to rt (24 h), 75%.
peroxide gave 1-methyl-3-piperideine N-oxide. The N-
oxide in methylene chloride was treated with trifluoro-
acetic anhydride. After 1 h, an aqueous solution of po-
tassium cyanide was added while the pH of the aqueous
layer was maintained at 4, giving (6)-2-cyano-1-
methyl-3-piperideine 1a.
tion of MgBr2 through a cannula under argon to the so-
lution of 3-pyridyllithium was easier.
(6)-1-Benzyl-2-cyano-3-piperideine 1b was synthe-
sized according to the procedure of Bonin et al. [14].
This procedure is similar to the one used for the synthe-
sis of 1a, except for some modifications. Sodium boro-
hydride was reacted with 1-benzyl-pyridinium bromide
(obtained by reaction of benzyl bromide with pyridine
in toluene [18]) in ethanol, giving the 1-benzyl-1,2,5,6-
tetrahydropyridine, which was isolated with a yield of
75%. Its solution in dichloromethane was reacted with
m-chloroperbenzoic acid, giving 1-benzyl-1,2,5,6-tetra-
hydropyridine-N-oxide isolated with a yield of 80%. To
the solution of the N-oxide in dichloromethane was
added trifluoroacetic anhydride; after 1 h at room tem-
perature, an aqueous solution of potassium cyanide was
added, during which the pH was maintained at 4. 1-Ben-
zyl-2-cyano-3-piperideine 1b was obtained with a yield
of 57%. The subsequent alkylation of the a-amino nitrile
1b with 3-pyridylmagnesium chloride was made accord-
ing to the Bruylants reaction, generating (6)-1-benzyl-
2-(3-pyridyl)-3-piperideine 3b, i.e., (6)-N-benzyl-isoa-
natabine. The solution of the Grignard reagent in THF
was added at 0ꢁC to the solution of the a-amino nitrile
1b in THF. The (6)-N-benzyl-isoanatabine 3b was
Alkylation of the a-amino nitrile 1a with 3-pyridyl-
magnesium chloride (or 3-pyridylmagnesium bromide)
was made according to the Bruylants reaction, i.e., the
reaction of an a-tertiary-amino nitrile with a Grignard
reagent [15]. The metal of the Grignard reagent prob-
ably mediates the formation of the conjugated iminium
2a, on which subsequently adds the Grignard reagent.
The stability and the reactivity of the iminium 2a is the
most likely reason why the Grignard reagent substitutes
the CN in the a-aminonitrile 1a, generating 1-methyl-2-
(3-pyridyl)-3-piperideine 3a, i.e., (6)-N-methyl-isoanata-
bine, rather than adding to it. The THF solution contain-
ing 5 equiv of the Grignard reagent was added at
ꢀ10ꢁC to a solution of the a-amino nitrile 1a, also in
THF. After stirring the mixture at room temperature
overnight, 3a was obtained with a yield of 77%. For the
preparation of 3-pyridylmagnesium chloride, 1 equiv of
3-bromopyridine was added to 1 equiv of i-propylmag-
nesium chloride in THF at room temperature, and the
mixture was stirred for 1 h [16].
obtained with a yield of 67%.
Attempts at N-demethylation and N-debenzylation by a
chloroformate of the (ꢂ)-N-methyl- and (ꢂ)-N-benzyl-
isoanatabines. To obtain (6)-isoanatabine 4, the N-deme-
thylation of 3a was attempted by reacting 3a with a
chloroformate [19a]. The mixture of 3a and 1 equiv of
a-chloroethyl chloroformate (ACE-Cl) in 1,2-dichloro-
ethane was refluxed for 16 h (monitored by TLC). After
evaporation of the solvent, the residue was refluxed in
methanol for 1 h, giving a mixture of unidentified
The 3-pyridylmagnesium bromide was also used for
the alkylation of a-amino nitrile 1a. In this case, 3a was
obtained with a lower yield of 65%. The procedure pre-
viously described in the literature for the synthesis of 3-
pyridylmagnesium bromide was modified [17]. The ratio
of the reagents was changed and the reaction generating
MgBr2 was made in ether instead of THF, MgBr2 being
more soluble in ether than in THF as MgBr2 forms a
complex with ether. In this way, the transfer of the solu-
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A Convenient Racemic Synthesis of Two Isomeric Tetrahydropyridyl Alkaloids:
Isoanatabine and Anatabine
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Scheme 6. Reagents and conditions: (i) ACE-Cl, CH2Cl2, 0ꢁC to rt, 16 h. (ii) 2.5% NaOH, EtOH/H2O (9:1), 0ꢁC (1 h) to rt, 5 h, 78%.
products. To solve the problem, the mixture of 3a and
ACE-Cl in 1,2-dichloroethane was refluxed for 16 h, but
instead of the intermediate carbamate 6, the N-[5-
chloro-5-(pyridin-3-yl)-pent-3-enyl]-N-methyl-carbamic
acid 1-chloro-ethyl ester 7 was isolated and analyzed
(Scheme 5). Thereafter, 7 was treated with 2.5% sodium
hydroxide in aqueous ethanol, and (6)-N-methyl-isoana-
tabine 3a was recovered with a yield of 75% relative to
the starting amount of 3a.
The opening of the piperideine ring when 3a is
reacted with a-chloroethyl chloroformate can be
explained by the intermediate formation of the quater-
nary ammonium salt 5 followed by the attack of the
chloride ion at the benzylic carbon, following the path-
way b instead of the attack at the methyl group (path-
way a). This corresponds to the benzyl effect, i.e., the
benzyl cleavage is preferred over the methyl loss on
account of the great stability of the benzyl carbocation.
The general rule indicates that the group that cleaves is
the one that gives the most stable carbocation and the
most reactive halide (e.g., benzyl or allyl); for simple
alkyl groups, the smallest are the most readily cleaved
[19]. A similar reactivity to that of 3a is observed with
nicotine. When nicotine is reacted with chloroformates,
the pyrrolidine ring is opened and the d-chlorocarba-
mates are obtained [20].
The treatment of 9 with 2.5% sodium hydroxide in
aqueous ethanol permitted recovery of the starting (6)-
N-benzyl-isoanatabine 3b with a yield of 78%.
Attempted N-debenzylation of (ꢂ)-N-benzyl-isoanatabine
3b with CAN. Yamaura et al. observed that the N-(4-
methoxybenzyl) group on 2,5-piperazinediones can be
oxidatively removed with (NH4)2Ce(NO3)6 (CAN), but
not the unsubstituted benzyl group [21]. However, Bull
et al. observed that the treatment of a range of N-unsub-
stituted benzyl tertiary amines with CAN at room tem-
perature results in N-debenzylation to afford the corre-
sponding secondary amine [22]. Therefore, the oxidative
N-debenzylation of 3b with CAN was assayed. A solu-
tion of 3b and 2 equiv of CAN in 5:1 acetonitrile:water
was stirred for 2 h at rt. Only the starting material 3b
was obtained. In another assay, 4 equiv of CAN were
added to a solution of 3b in 5:1 acetonitrile:water, and
the solution was stirred 24 h at rt. Again only the start-
ing 3b was recovered. The concentration of CAN in the
reaction mixture of each of these assays was greater
than 0.25M as it is known that no oxidation is obtained
at lower concentration [21]. A further assay was made
with 3b and 4 equiv of CAN, and stirring at 50ꢁC over-
night; isoanatabine 4 was not obtained but 3b was com-
pletely transformed into a lot of unidentified products.
The use of tetrahydrofuran instead of acetonitrile and
higher concentrations of CAN at room temperature also
led to the recovering of the starting (6)-N-benzyl-isoa-
An assay was made for the N-debenzylation of 3b by
its reaction with a-chloroethyl chloroformate in
dichloromethane at room temperature, as it is known
that the benzyl group needs lower temperatures to be
cleaved.
natabine 3b.
N-Demethylation of the (ꢂ)-N-methyl-isoanatabine 3a by
decomposition of its N-oxide 10 (nonclassical Polonovski
reaction). Several possible methods for N-demethylation
In the intermediate quaternary ammonium salt 8, it
was hoped that the breaking of the N-Bn (bond A)
would be favored over the breaking of the N-(C-2 of the
3-piperideine) bond (bond B), generating (6)-isoanata-
bine 4 (Scheme 6). The reverse however occurred and
1-chloro-1-(3-pyridyl)-5-benzylamino-pent-2-ene 9 was
formed. This could be due to the fact that the B bond
breaking in 8 generates at the 2-C of the 3-piperideine a
more stable carbocation because it is simultaneously a
benzyl and allyl cation. The A bond breaking would
generate a carbocation benzyl lacking the further allyl
stabilization.
of 3a were tested, starting from the N-oxide of 3a, 10.
The N-oxide 10 was obtained by reaction of (6)-N-
methyl-isoanatabine 3a with m-chloroperoxybenzoic
acid (1.1 equiv) in CH2Cl2 at 0ꢁC to avoid the possible
epoxidation of the double bond [23]. The usual work
up, i.e., treatment of the reaction mixture by aq. NaOH
to pH 10–11 and then extraction by CHCl3 led to the
isolation of the N-oxide only in low yield. The low yield
was probably due to the high solubility of the N-oxide
at basic pH. This problem was overcame by concentrat-
ing the reaction mixture and pouring the concentrate
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A. Rouchaud and W. R. Kem
Vol 47
over alumina and chromatographing. In this way, the
(6)-N-methyl-isoanatabine-N-oxide 10 was obtained
with a yield of 91% as a mixture of diastereomers in a
6:4 ratio (undefined stereochemistry). The diastereomers
were not separated and were used in next step as a
mixture.
tivity to the benzyl effect and prompted to select assays
able to avoid this benzyl effect.
Another secondary reaction that competes with the N-
demethylation is the deoxygenation of the N-oxide,
which is catalyzed by the iron salt or chelate. It gener-
ates back the tertiary amine from which was made the
N-oxide. Moreover, the deoxygenation of the N-oxide
may be accompanied by the oxidation (oxidative dehy-
drogenation) of the N-demethylated product or of the N-
methylated one. Other secondary degradative reactions
occur when the reaction temperature is too high.
The nonclassical Polonovski reaction for the N-deme-
thylation of the N-oxide of (6)-N-methyl-isoanatabine
3a was investigated [24a]. The desired reaction is the
catalyzed decomposition of the tertiary amine N-oxide
through an internal oxidation into the secondary amine,
the N-methyl being oxidized to formaldehyde. When the
reaction is catalyzed by an iron salt, the mechanism is
believed to involve two successive one-electron transfers
involving Fe(II)/Fe(III) redox reactions [24b,c]. Cations,
free radicals and radical-cations ions stabilized as imi-
nium ions and radicals, are considered as intermediates.
Often the catalyst (the iron salt or complex, selenium
dioxide, etc.) is engaged in stoichiometric amounts. The
N-demethylation of the hydrochloride salts of the N-
oxides of opiate alkaloids (codeine, codeine methyl
ether, thebaine, thevinone, etc.) was realized with
FeSO4ꢃ7H2O in methanol; the N-oxide of codeine gave
norcodeine with a yield of 49%, in mixture with co-
deine, i.e., the product of N-deoxygenation [25]. When
the same reaction was made using a porphyrin chelate
of iron(II), the yield of norcodeine was increased to
91% [26]. The same reaction has been applied to the N-
demethylation of the N-oxides of piperidines, benzomor-
phans, and morphinans using iron(II) chloride [27].
For the nonclassical Polonovski reaction of the N-
oxides of tertiary amine catalyzed with iron salts in
water or in nonpolar solvents, the ease of alkyl conver-
sion to the corresponding carbonyl compound decreases
in the order C6H5CH2 > CH3 > RCH2 > R2CH; this is
the decreasing order for the ease of the breaking of the
bond between the N-oxide nitrogen atom and one of the
three alkyl groups linked to this nitrogen [24b,c]. This
reactivity order for the rearrangement was assigned
among others to the acidity of the protons on the carbon
adjacent to the nitrogen atom; the greater stability of the
intermediate benzyl carbocation, benzyl radical and ben-
zyl radical-carbocation also explains the reactivity order
and that benzyl cleavage is preferred over methyl loss
(benzyl effect). For the N-demethylation of the N-oxides
of opiates (codeine, codeine methyl ether, thebaine, the-
vinone, etc.) cited earlier, there was no benzyl group
linked to the nitrogen atom; there was no competition
from the benzyl effect and the N-demethylation was
obtained with a good yield [25]. The N-oxide of N-
methyl-isoanatabine and the N-oxide of the N-benzyl-
isoanatabine are subjected to the benzyl effect. The fail-
ure of the trials for their N-demethylation and N-deben-
zylation with a chloroformate showed their high sensi-
Selective N-demethylation of the N-oxides of tertiary
aminofumagillols to the corresponding secondary amino-
fumagillols has been made by heating the N-oxide with
selenium dioxide in ethanol [28]. The N-oxides of terti-
ary aminofumagillols do not sustain the concurrence of
the benzyl effect. However, they contain two epoxy and
the a,b-unsaturated ester sensitive functionalities. These
remained intact during the reaction.
Therefore, our first attempt at the N-demethylation of
10 by means of the nonclassical Polonovski reaction uti-
lized SeO2. A mixture of 10 and 1.5 equiv of SeO2 in
95% ethanol was heated to reflux for 4 h under an
atmosphere of argon. (6)-N-methyl-isoanatabine 3a was
formed with a yield of 65%, indicating that only N-
deoxygenation occurred.
Several studies have been reported for the N-deme-
thylation of the N-oxides of tertiary amines subjected to
the benzyl effect, by means of their decomposition cata-
lyzed by iron salts (generally engaged in stoichiometric
amounts) in aqueous solutions containing large amounts
of tartaric or citric acids (present as such or as their
salts). The FeSO4-catalyzed dealkylation of the N-oxide
of N,N-dimethyl-benzylamine showed the importance of
the benzyl effect relatively to the N-demethylation.
When the N-oxide of N,N-dimethyl-benzylamine in an
aqueous solution at pH 1–2 containing iron(II) sulfate
was heated, benzaldehyde was produced with a yield of
85%, no N-demethylation being obtained [24b,c]. Under
the same conditions at pH 1, the N-oxide of N,N-di-
methyl-butylamine gave mainly formaldehyde and N-
methyl-butylamine. On the other hand at pH 6–7, when
the mixture in water of the N-oxide of N,N-dimethyl-
benzylamine, L-(þ)-tartaric acid and FeSO4ꢃ7H2O (or of
Fe(NO3)3ꢃ9H2O) was heated, a mixture of formaldehyde
(the product of N-demethylation) and benzaldehyde
(2.3:1) was formed [24b,29]. At pH 6–7, the Feþ2/Feþ3
system is as a complex with the anion of tartaric acid.
The N-oxide would occupy some coordination positions
of this complex [30]. The rearrangement of the N-oxide
would then occur at the coordination positions of the
complex so the regioselectivity of the rearrangement
would be directed by the geometry of the complex and
thus by steric factors. This would explain the
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production of formaldehyde and thus the N-demethyla-
tion, what did not occur when the iron ions were not
chelated.
However, the N-demethylation of the N-oxide was
obtained by stirring a mixture of N-oxide, meso-(tetra-
phenylporphinato)iron(III) chloride, Fe(TPP)Cl, and im-
idazole in dichloromethane at room temperature. The
product of N-demethylation was obtained with a yield of
68%, accompanied by 25% of the deoxygenation prod-
uct of the N-oxide. When imidazole was replaced by tet-
razole, the secondary amine was produced with a yield
of 86%, and the product of deoxygenation was no more
detected. This showed the influence of the additives im-
idazole or tetrazole. They could make some association
with the N-oxide and the iron porphyrin, orienting in
this way the decomposition of the N-oxide toward the
N-demethylation, and overcoming the benzyl effect. In
the N-demethylation of the N-oxides of the N,N-di-
methyl-benzylamine [24b,c] noscapine [31] and nicotine
[32] cited earlier, the chelation of the iron ions by the
tartaric and citric acids and their salts present in large
excess, would explain the orientation by steric effects of
the rearrangement of the N-oxide toward the N-demethy-
lation. The increase of the yield of the N-demethylation
of the N-dimethyl benzazepine N-oxide by the use of
the additives imidazole or tetrazole corroborated that
hypothesis.
In previous experiments on the dealkylation of amine
oxides, it was observed that reaction mixtures of iron
(III) and tartaric or oxalic acid (reducing acids) gener-
ated iron(II) in situ, and that iron(II) was the initiator of
the rearrangement [24b,c]. That iron(II) and not iron(III)
was the initiator of the reaction was shown by experi-
ments with iron(III) salts coordinated to nonreducing
acids (sulfuric, succinic) [24b,c]. Under these conditions,
the Polonovski reaction did not occur. When as little as
3% iron(II) sulfate was added to the reaction medium,
secondary amine production began. On the other hand,
iron(II) was converted to iron(III) during the course of
the rearrangement; this was mainly due to the oxidation
of iron(II) by the amine-oxide with formation of the ter-
tiary amine (the secondary reaction of the amine-oxide:
deoxygenation).
Noscapine (also called narcotine) has been converted
by N-demethylation to nornarcotine in 35% overall yield
via the noscapine N-oxide and in spite of the concur-
rence of a benzyl effect [31]. Therefore, the mixture of
noscapine-N-oxideꢃHCl and iron(III) citrate, in water
acidified to pH 1–2, was heated. Nicotine-N-oxide also
suffers the competition of the benzyl effect during its N-
demethylation by the nonclassical Polonovski reaction.
A mixture in water at pH 6 of nicotine-N-oxide,
Fe(NO3)3, L-(þ)-tartaric acid and sodium carbonate was
heated [32]. Nornicotine was obtained with a yield of
56%, besides several other alkaloids arising from the
transformation of nicotine: myosmine (6.9%), N-methyl-
myosmine (2.1%), and nicotine (3.0%).
Therefore, N-demethylation of (6)-N-methyl-isoanata-
bine 3a was assayed in the conditions used by Kawano
et al. [33]. The mixture of 10, 1 equiv of Fe(TPP)Cl
and 1 equiv of tetrazole in dichloromethane was stirred
at room temperature during 16 h in the dark. The
N-oxide 10 was recovered untransformed with a yield of
80%. The assay was repeated but without the addition
of tetrazole; again the N-oxide 10 was recovered
untransformed.
N-demethylation of (6)-N-methyl-isoanatabine 3a by
decomposition of its N-oxide 10 was attempted under
the conditions used by Craig et al. for the N-demethyla-
tion of nicotine [32]. The pH of a mixture in water of
10, 3 equiv of Fe(NO3)3, and 30 equiv of L-(þ)-tartaric
acid was adjusted to 6.3 by adding a solution of sodium
carbonate. After heating at 80ꢁC for 40 min, (6)-isoana-
tabine 4 was obtained but only with a low yield of 9%.
The major compound isolated was the (6)N-methyl-ana-
tabine 3a, obtained with a yield of 49%, indicating that
deoxygenation of the N-oxide was the main reaction.
The results obtained in the two preceding assays sug-
gested that heating could induce the deoxygenation of
10 generating (6)-N-methyl-isoanatabine 3a. Therefore,
a method was searched for the decomposition of the
N-oxide at room or lower temperature.
The N-demethylation of the galanthamine-N-oxide is
sensitive to the competition from the benzyl effect [34].
However, the N-demethylation has been obtained with a
yield of 76% by stirring at 10ꢁC the N-oxide in metha-
nol containing iron(II) sulfate. No cleavage at the ben-
zylic carbon was observed. The selective demethylation
of the galanthamine-N-oxide in the presence of iron salts
indicated the preference for oxidation at the methyl cen-
ter of the N-methyl substituted amine oxide. This is at
the opposite of the general rule which gives the prefer-
ence to the oxidation of the benzylic carbon. The bulky
structure of galanthamine would induce the N-demethy-
lation by a steric effect, the N-methyl being deprotected
to oxidation outside of the bulky structure.
The N-demethylation of the N-oxide of the alkaloid
glaucine suffers also from the competition of the benzyl
effect [35]. However, the N-demethylation has been per-
formed under the same conditions as for galanthamine
without addition of a complexing agent. The N-oxide of
glaucine was treated in methanol with iron(II) sulfate at
10ꢁC. Norglaucine was formed with a yield of 52%. It
The secondary amine 5-dimethylamino-1-[4-[(2-meth-
ylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1H-benzaze-
pine is a metabolite of a new vasopressin V2 receptor
antagonist [33]. The N-demethylation of its N-oxide was
sensitive to the competition from the benzyl effect.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

576
A. Rouchaud and W. R. Kem
Vol 47
Scheme 7. Reagents and conditions: (i) m-CPBA, CH2Cl2, 0ꢁC, 1.5 h, 91%. (ii) FeSO4ꢃ7H2O, CH3OH, 10ꢁC, 1.5 h, 55%.
was accompanied by the formation for 13% of the prod-
uct of the benzyl effect, which was further reduced.
When the reaction temperature was 50ꢁC or when the
reagent was changed to ferrous chloride, only the prod-
uct due to the benzyl effect was formed.
thesis of (6)-anatabine 15 (Scheme 8). (6)-2-Cyano-1-
methyl-4-piperideine 12 is the isomer of (6)-2-cyano-1-
methyl-3-piperideine 1a. The sequence of transforma-
tions applied to compound 1a for the synthesis of (6)-
isoanatabine 4 could in principle be applied to 12 for
the preparation of (6)-anatabine 15. Therefore, a proce-
dure for the synthesis of compound 12 was developed.
Like for compound 1a it started with the reduction of 1-
methylpyridinium iodide with NaBH4, but the experi-
mental conditions were changed to obtain the double
bond in the right position. A two phases solvent system
was used [36]. To an aqueous solution of 4 equiv of po-
tassium cyanide was added 1.5 equiv of hydrochloric
acid at 0ꢁC. This aqueous phase was layered with the
same volume of ether. 1-Methylpyridinium iodide was
added followed by 1.2 equiv of NaBH4. After 5 h at
room temperature, compound 12 was obtained with a
yield of 95%.
N-demethylation of the (6)-N-methyl-isoanatabine 3a
by decomposition of its N-oxide 10 was tested under the
same conditions as the N-oxides of galanthamine [34]
and glaucine [35] (Scheme 7). A mixture of 10 and 2
equiv of FeSO4ꢃ7H2O in methanol was stirred for 1.5 h
at 10ꢁC. The (6)-isoanatabine 4 was obtained with a
yield of 55%. It was accompanied by the formation of
23% of (6)-N-methyl-isoanatabine 3a, the product of
deoxygenation. As with galanthamine and glaucine, the
structure of the N-oxide 10 of isoanatabine would
induce by a steric effect the N-demethylation without
requiring an additive. The N-methyl would be more ac-
cessible to oxidation because of its greater exposure.
For the N-demethylation by decomposition of the N-ox-
ide, the search by the successive applications of
described procedures thus contributes, by the analysis of
the generated products, to the knowledge of the mecha-
nism and of the experimental parameters orienting the
selectivity of the oxidative rearrangement of the non-
classical Polonovski reaction.
The presence of the solution of potassium cyanide in
water underlayering the ether phase since the beginning
of the reduction of 1-methylpyridinium iodide by
NaBH4 permitted to limit the reduction to the formation
of 1-methyl-1,2-dihydro-pyridine which in acidic condi-
tion was trapped by potassium cyanide, generating com-
pound 12.
Synthesis of (6)-anatabine. The procedure for the
synthesis of (6)-isoanatabine 4 was extended to the syn-
The isomerization of (6)-2-cyano-1-methyl-4-piperi-
deine 12 into (6)-2-cyano-1-methyl-3-piperideine 1a
Scheme 8. Reagents and conditions: (i) NaBH4, KCN, HCl, H2O/Et2O, 0ꢁC to rt, 5 h, 95%. (ii) 3-PyrMgCl, THF, ꢀ10ꢁC to rt, 16 h, 83%. (iii)
m-CPBA, CH2Cl2, 0ꢁC, 1.5 h, 88%. (iv) FeSO4ꢃ7H2O, CH3OH, 10ꢁC, 3 h, 44%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
A Convenient Racemic Synthesis of Two Isomeric Tetrahydropyridyl Alkaloids:
Isoanatabine and Anatabine
577
was attempted [37a,b]. If it succeeded, the aminonitrile
12 could be another starting point for the synthesis of
(6)-isoanatabine 4. The isomerization was attempted by
heating 12 in 6N HCl. Thereafter, the solution was
made basic by addition of potassium cyanide. However,
the aminonitrile 12 was recovered untransformed.
The same sequence of transformations applied to
compound 1a for the synthesis of isoanatabine 4, was
applied to compound 12 for the preparation of anatabine
15. The 3-pyridylmagnesium chloride was reacted with
the a-amino nitrile 12 in THF, giving the N-methyl-ana-
tabine 13 with a yield of 83%. Compound 13 was oxi-
dized by m-CPBA in dichloromethane, giving the N-
methyl-anatabine-N-oxide 14 with a yield of 88% as a
mixture of two diastereomers in a 7:3 ratio. The diaster-
eomers can be separated by chromatography on
alumina.
CH3OH/NH3 (95:5:1) as eluent afforded (6)-N-methyl-
isoanatabine, 3a (167 mg, 0.96 mmol, 77%). IR (NaCl):
3031, 2945, 2785, 1650, 1577, 1425, 1362, 1281, 1057,
1
850 cmꢀ1. H NMR (300 MHz, CDCl3): d 8.51 (d, 1H,
J ¼ 2.4 Hz, ArH), 8.50 (dd, 1H, J ¼ 1.8, 4.8 Hz, ArH),
7.68 (dt, 1H, J ¼ 1.8, 7.8 Hz, ArH), 7.25 (ddd, 1H, J ¼
0.6, 4.8, 7.8 Hz, ArH), 5.86 (m, 1H, CH¼¼CH), 5.45
(dq, 1H, J ¼ 1.5, 9.9 Hz, CH¼¼CH), 3.66 (app quintet,
1H, J ¼ 1.2 Hz, NCHAr), 2.93 (m, 1H, NCH2), 2.50
(m, 2 H, NCH2 þ CH2ACH¼¼CH), 2.12 (m, 1H,
CH2ACH¼¼CH). 13C NMR (75.3 MHz, CDCl3): d 150.3
(CH), 149.0 (CH), 138.7 (C), 136.3 (CH), 129.3 (CH),
125.5 (CH), 123.8 (CH), 65.9 (CH), 51.9 (CH2), 44.0
(CH3), 26.2 (CH2). ESI-HRMS: m/z ¼ 175.1244 (calcu-
lated for [M þ H]þ: 175.1230); 197.1064 (calculated for
[M þ Na]þ: 197.1049); 371.2228 (calculated for [2M þ
Na]þ: 371.2206).
(ꢂ)-1-Benzyl-2-(3-pyridyl)-3-piperideine: (ꢂ)-N-Benzyl-iso-
The N-demethylation of 14 was made on the mixture
of diastereomers by their decomposition at 10ꢁC in
methanol containing 2 equiv of FeSO4ꢃ7H2O leading to
the anatabine 15 with a yield of 44%. It was accompa-
nied by the formation of 44% of N-methyl-anatabine 13,
product of deoxygenation of the N-oxide 14 which could
be recovered from the reaction mixture.
anatabine, 3b. 3-Bromopyridine (130 lL, 213 mg, 1.35
mmol) was added to i-PrMgCl (2M/THF, 675 lL, 1.35
mmol) in THF (1 mL) at room temperature under argon.
After 2 h, the mixture was cooled at 0ꢁC, then a solu-
tion of 1b (51 mg, 0.26 mmol) in THF (1 mL) was
added. The resulting reaction mixture was stirred over-
night at room temperature. After 16 h, water (5 mL)
was added. Extraction with CH2Cl2 (3 ꢄ 10 mL), drying
over magnesium sulfate and column chromatography
using CH2Cl2/CH3OH/NH3 (97:3:1) as eluent afforded
3b (43 mg, 0.17 mmol, 67%). IR (NaCl): 3029, 2918,
EXPERIMENTAL
General. ESI-HRMS were performed on an Agilent
6210 TOF mass spectrometer. GC/CI analyses were per-
formed on a Thermo Trace GC DSQ–Single Quadru-
1
2707, 1655, 1576, 1424, 1027, 849 cmꢀ1. H NMR (300
MHz, CDCl3): d 8.62 (d, 1H, J ¼ 2.1 Hz, ArH), 8.49
(dd, 1H, J ¼ 1.8, 4.8 Hz, ArH), 7.80 (dt, 1H, J ¼ 2.1,
7.8 Hz, ArH), 7.26 (ddd, 1H, J ¼ 0.6, 4.8, 7.8 Hz,
ArH), 5.85 (m, 1H, CH¼¼CH), 5.49 (dq, 1H, J ¼ 1.5,
9.9 Hz, CH¼¼CH), 4.00 (app quintet, 1H, J ¼ 2.4 Hz,
NCHAr), 3.52 (d, J ¼ 13.5 Hz, 1H, CH2 (Bn)), 3.43 (d,
J ¼ 13.5 Hz, 1H, CH2 (Bn)), 2.93 (m, 1H, NCH2),
2.41–2.25 (m, 2H, NCH2 þ CH2ACH¼¼CH), 2.06 (bd,
1H, J ¼ 14.1 Hz, CH2ACH¼¼CH). 13C NMR (75.3
MHz, CDCl3): d ¼ 150.4, 148.9, 139.4, 139.2, 136.3,
129.6, 128.8, 128.4, 127.1, 125.7, 123.8, 63.8, 59.0,
47.3, 25.9. ESI-HRMS: m/z ¼ 251.1567 (calculated for
[M þ H]þ: 251.1543); 273.1372 (calculated for [M þ
Na]þ: 273.1362).
1
pole. The H NMR spectra were recorded in CDCl3 at
300 MHz with a Varian Mercury 300 and are reported
in ppm from internal TMS on the d scale. The 13C
NMR spectra were recorded in CDCl3 at 75.4 MHz with
a Varian Mercury 300 instrument. The IR spectra were
recorded with a Bruker Vector 22 instrument as films on
a NaCl disk. Thin layer chromatography analyses (TLC)
were performed with 0.20 mm Silica Gel 60, F-254 pre-
coated plates (Selecto Scientific). Chromatographies
were performed on silica gel columns (Fisher, Silica Gel
Sorbent, 230–400 Mesh) using the flash technique or on
alumina (Aluminoxid 90, Activity II–III, EMD).
(ꢂ)-1-Methyl-2-(3-pyridyl)-3-piperideine: (ꢂ)-N-methyl-
isoanatabine, 3a. 3-Bromopyridine (598 lL, 981 mg,
Assays of N-demethylation of (6)-N-methyl-isoana-
tabine 3a and N-debenzylation of (6)-N-benzyl-isoa-
natabine 3b with 1-chloroethyl chloroformate.
Attempted N-demethylation of (ꢂ)-N-methyl-isoanatabine
3a. 1-Chloroethyl chloroformate (80 lL, 106 mg, 0.74
mmol) was added at 0ꢁC to a stirred solution of 3a (107
mg, 0.61 mmol) in dry 1,2-dichloroethane (6 mL) under
argon. The resulting mixture was heated to reflux for 16
h. The solvent was removed under reduced pressure to
give the N-[5-chloro-5-(pyridin-3-yl)-pent-3-enyl]-N-
6.22 mmol) was added to i-PrMgCl (2M/THF, 3.11 mL,
6.22 mmol) in THF (1 mL) at room temperature under
argon. After 2 h, the mixture was cooled at ꢀ10ꢁC, then
a solution of 1a (152 mg, 1.24 mmol) in THF (2 mL)
was added. The resulting reaction mixture was allowed
to stir for 1 h at ꢀ10ꢁC then left overnight at room tem-
perature. After 16 h, water (5 mL) was added. Extrac-
tion with CH2Cl2 (3 ꢄ 10 mL), drying over magnesium
sulfate and column chromatography using CH2Cl2/
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

578
A. Rouchaud and W. R. Kem
Vol 47
methyl-carbamic acid 1-chloro-ethyl ester (7). 7 was dis-
solved in 40 mL of 2.5% sodium hydroxide in aqueous
ethanol (1:9) at 0ꢁC; after 1 h at 0ꢁC, the mixture was
stirred at room temperature during 24 h. The mixture
was extracted with dichloromethane (3 x 50 mL). The
combined organic extracts were dried with MgSO4 and
the solvent removed under reduced pressure to yield 3a
as yellow oil (80.3 mg, 0.46 mmol, 75%). N-[5-chloro-
5-(pyridin-3-yl)-pent-3-enyl]-N-methyl-carbamic acid 1-
Assay for the N-debenzylation of (6)-N-benzyl-iso-
anatabine 3b with CAN (ammonium cerium (IV)
nitrate). To compound 3b (37 mg, 0.15 mmol), dis-
solved in a 5:1 mixture of CH3CN-H2O (2.4 mL), CAN
(329 mg, 0.60 mmol) was added portionwise. After stir-
ring 24 h at room temperature, the mixture was basified
with an aqueous saturated solution of NaHCO3 and then
extracted with CH2Cl2. The organic phase was dried
(MgSO4), filtered, and concentrated under vacuo to
obtain the starting compound 3b (33 mg, 0.13 mmol,
88%).
1
chloro-ethyl ester (7): H NMR (300 MHz, CDCl3): d
9.06 (m, 1H, ArH), 8.83 (d, 1H, J ¼ 4.5 Hz, ArH), 8.54
(d, 1H, J ¼ 8.4 Hz, ArH), 8.05 (m, 1H, ArH), 6.89 (m,
1H, CH¼¼CH), 6.74 (m, 1H, CH¼¼CH), 6.57 (m, 1H,
CHClCH3), 4.66 (app quint., 1H, NCHAr), 3.49 (m, 2H,
NCH2), 2.99 (s, 3H, NCH3), 2.21 (m, 2H,
CH2ACH¼¼CH), 1.83 (d, 3H, J ¼ 5.7 Hz, CHClCH3). -
13C NMR (75.3 MHz, CDCl3): d 153.5 (CO), 153.3
(CO), 142.5 (CH), 139.4 (CH), 139.0 (CH), 137.0 (CH),
136.9 (CH), 136.2 (C), 127.3 (CH), 125.0 (CH), 124.8
(CH), 124.7 (CH), 124.1 (CH), 83.3 (CH), 58.4 (CH),
46.7 (CH2), 45.9 (CH2), 36.2 (CH2), 35.6 (CH2), 35.4
(ꢂ)-N-methyl-isoanatabine-N-oxide, 10. To a solution of
3a (206 mg, 1.18 mmol) in CH2Cl2 (6 mL) at 0ꢁC was
added a solution of 70–75% aq. m-CPBA (320 mg, 1.3
mmol) in CH2Cl2 (11 mL). After stirring 1.5 h at 0ꢁC
under argon, the reaction mixture was concentrated in
vacuo to a volume of 7 mL and then poured over alu-
mina and chromatographed using CH2Cl2/CH3OH (95:5)
as eluent to afford the N-oxide 10 as a mixture of two
diastereomers in a 6:4 ratio (204 mg, 1.07 mmol, 91%).
The diastereomers were not separated and were used in
1
the next step as a mixture. H NMR (300 MHz, CDCl3):
(CH2), 34.7 (CH2), 25.4 (CH3), 25.1 (CH3).
Attempted N-debenzylation of (ꢂ)-N-benzyl-isoanatabine
d 8.76 (d, 0.6 H, J ¼ 1.8 Hz, ArH), 8.68 (dd, 0.6 H, J
¼ 1.8, 4.8 Hz, ArH), 8.64 (d, 0.4 H, J ¼ 1.5 Hz, ArH),
8.63 (dd, 0.4 H, J ¼ 1.5, 4.8 Hz, ArH), 8.10 (dt, 0.4 H,
J ¼ 2.1, 7.8 Hz, ArH), 7.97 (dt, 0.6 H, J ¼ 1.8, 7.8 Hz,
ArH), 7.40 (ddd, 0.6 H, J ¼ 0.6, 4.8, 7.8 Hz, ArH), 7.36
(ddd, 0.4 H, J ¼ 0.6, 4.8, 7.8 Hz, ArH), 6.18 (m, 1H,
CH¼¼CH), 5.84 (dq, 0.6 H, J ¼ 1.8, 10.2 Hz, CH¼¼CH),
5.66 (dq, 0.4 H, J ¼ 2.1, 10.5 Hz, CH¼¼CH), 5.07 (app
quintet, 0.6 H, J ¼ 2.7 Hz, NCHAr), 4.90 (app quintet,
0.4 H, J ¼ 2.4 Hz, NCHAr), 3.60 (m, 1.2 H, NCH2),
3.43 (m, 0.8 H, NCH2), 3.19 (s, 1.2 H, NCH3), 2.92 (m,
0.6 H, CH2CH¼¼CH), 2.75 (s, 1.8 H, NCH3), 2.58 (m,
1H, CH2CH¼¼CH), 2.41 (m, 0.4 H, CH2CH¼¼CH). 13C
NMR (CDCl3): Major diastereomer, d 151.5 (CH),
150.5 (CH), 139.0 (CH), 129.1 (C), 126.4 (CH), 123.8
(CH), 123.1 (CH), 76.4 (CH), 64.2 (CH2), 51.1 (CH3),
24.1 (CH2). 13C NMR (CDCl3): Minor diastereomer, d
152.0 (CH), 150.1 (CH), 139.8 (CH), 129.3 (C), 126.3
(CH), 123.6 (CH), 122.9 (CH), 73.2 (CH), 61.9 (CH2),
56.9 (CH3), 23.2 (CH2). ESI-HRMS: m/z ¼ 191.1192
(calculated for [M þ H]þ: 191.1179); 213.1006 (calcu-
lated for [M þ Na]þ: 213.0998); 381.2312 (calculated
for [2M þ H]þ: 381.2285); 403.2114 (calculated for
[2M þ Na]þ: 403.2104).
3b. 1-Chloroethyl chloroformate (9 lL, 12 mg, 0.08
mmol) was added at 0ꢁC to a stirred solution of 3b (21
mg, 0.08 mmol) in dry dichloromethane (3 mL) under
argon. The resulting mixture was stirred at room temper-
ature for 16 h. The solvent was removed under reduced
pressure to give the 1-chloro-1-(3-pyridyl)-5-benzyla-
mino-pent-2-en (9). Compound 9 was then stirred with 5
mL of 2.5% sodium hydroxide in aqueous ethanol (1:9)
at 0ꢁC; after 1 h at 0ꢁC, the mixture was stirred at room
temperature during 5 h. The mixture was extracted with
dichloromethane (3 ꢄ 7 mL). The combined organic
extracts were dried with MgSO4, filtered and the sol-
vent removed under reduced pressure to yield 3b as a
yellow oil (15.6 mg, 0.06 mmol, 78%). 1-Chloro-1-(3-
pyridyl)-5-benzylamino-pent-2-en (9): 1H NMR (300
MHz, CDCl3): d 9.73 (bs, 1H, ArH), 9.32 (bs, 1H,
ArH), 8.73 (bs, 1H, ArH), 8.03 (bs, 1 H, ArH), 7.74
(bs, 2 H, ArH), 7.35 (s, 3 H, Bn-H), 6.32 (bs, 1 H),
6.03 (bs, 1 H), 5.72 (bs, 1 H), 4.64 (bs, 2 H), 3.40 (bs,
1 H), 3.23 (bs, 1 H), 3.05 (m, 1 H), 2.42 (m, 1 H).
The ESI-MS of 9 indicated polymeric material; this
probably arised in the MS apparatus by the intermolec-
ular substitution in 9 of the chlorine by the amino
group. On the other hand, the GC-MS of 9 gave the
MS spectrum of 3b; at the temperature of the GC col-
umn oven (Rxi-5ms column, program: injector 200ꢁC,
detector 280ꢁC, program: 40ꢁC (1 min), 30ꢁC/min to
280ꢁC, 280ꢁC (15 min); RT:12.08 min), 9 spontane-
ously cyclized into 3b by the intramolecular substitu-
tion of the chlorine by the amino group.
Attempted N-demethylation of (6)-N-methyl-isoa-
natabine-N-oxide 10.
With selenium dioxide. To a
stirred mixture of 10 (193 mg, 1.02 mmol) in 95% etha-
nol (10 mL) was added portionwise selenium dioxide
(169 mg, 1.52 mmol) for 10 min. The mixture was
heated to reflux for 4 h under an atmosphere of argon.
The reaction was monitored by TLC. After 4 h, the
starting material was still present. The mixture was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
A Convenient Racemic Synthesis of Two Isomeric Tetrahydropyridyl Alkaloids:
Isoanatabine and Anatabine
579
refluxed for 4 h more. The residue obtained by evapora-
tion of the reaction mixture was purified by column
chromatography through silica gel column, using
CH2Cl2/CH3OH/NH3 (90:10:1) as eluent to give 115 mg
(0.66 mmol, 65%) of 3a and 19 mg (0.1 mmol, 10%) of
10.
NMR (75.3 MHz, CDCl3): d 125.5 (CH), 120.9 (CH),
116.3 (CN), 51.2 (CH), 50.0 (CH2), 43.6 (CH3), 29.5
(CH2). ESI-HRMS: m/z ¼ 123.0925 (calculated for [M
þ H]þ: 123.0917); 145.0745 (calculated for [M þ Na]þ:
145.0736).
Attempt of isomerization of 12 into 1a. The amino
nitrile 12 (52 mg, 0.43 mmol) in 1 mL of 6N HCl was
heated at 80ꢁC. After refluxing for 4 h, the mixture was
cooled and enough aqueous sodium cyanide was added
until the final solution was alkaline (pH 10). After stir-
ring for 2 h, the mixture was extracted by CH2Cl2 (3 ꢄ
10 mL). The CH2Cl2 extracts were combined, dried
over MgSO4 and concentrated to yield the starting
amino nitrile 12 (48 mg, 0.39 mmol, 92%).
With FeSO4ꢃ7H2O. N-oxide 10 (95 mg, 0.50 mmol)
was dissolved in MeOH (10 mL) and cooled at 10ꢁC.
FeSO4ꢃ7H2O (278 mg, 1 mmol) was added then the
reaction mixture was stirred at 10ꢁC for 1.5 h. Evapora-
tion of the solvent afforded an orange solid, which was
dissolved in 0.1M EDTA. Then, the pH was raised to 10
by addition of concentrated NH4OH. The solution was
extracted with CHCl3 (3 ꢄ 20 mL), and the dried or-
ganic extracts over MgSO4 were filtered and evaporated
to yield a mixture of 4 and 3a (2.3:1). These were sepa-
rated by column chromatography on silica gel using
CH2Cl2/CH3OH/NH3 (90:10:1) as an eluent. Pure (6)-
isoanatabine (4) was obtained with a yield of 55% (44
mg, 0.28 mmol); pure (6)-N-methyl-isoanatabine (3a)
was obtained with a yield of 23% (20 mg, 0.12 mmol).
(6)-Isoanatabine (4): IR (NaCl): 3285, 3029, 2914,
(6)-1-Methyl-2-(3-pyridyl)-4-piperideine:
(6)-N-
methyl-anatabine, 13. 3-Bromopyridine (210 lL, 346
mg, 2.19 mmol) was added to i-PrMgCl (2M/THF, 1.1
mL, 2.19 mmol) in THF (1 mL) at room temperature
under argon. After 2 h, the mixture was cooled at
ꢀ10ꢁC, then a solution of 12 (89 mg, 0.73 mmol) in
THF (2 mL) was added. The resulting reaction mixture
was allowed to stir for 1 h at ꢀ10ꢁC then left overnight
at room temperature. After 16 h, water (5 mL) was
added. Extraction with CH2Cl2 (3 ꢄ 10 mL), drying
over magnesium sulfate and column chromatography
using CH2Cl2/CH3OH/NH3 (95:5:1) as eluent afforded
(6)-N-methyl-anatabine 13 (106 mg, 0.61 mmol, 83%).
IR (NaCl): 3034, 2985, 2910, 2773, 1666, 1577, 1427,
2832, 1650, 1578, 1477, 1102, 1028, 716 cmꢀ1 1H
.
NMR (300 MHz, CDCl3): d 8.59 (d, 1H, J ¼ 1.8 Hz,
ArH), 8.51 (dd, 1H, J ¼ 1.5, 4.8 Hz, ArH), 7.70 (dt,
1H, J ¼ 1.5, 7.5 Hz, ArH), 7.25 (ddd, 1H, J ¼ 0.9, 5.1,
7.8 Hz, ArH), 6.01 (m, 1H, CH¼¼CH), 5.71 (dq, 1H, J
¼ 1.8, 9.3 Hz, CH¼¼CH), 4.52 (app quintet, 1H, J ¼ 2.7
Hz, NHCHAr), 3.0 (m, 2 H, NHCH2), 2.2 (m, 3 H,
CH2CH¼¼CH þ NH). 13C NMR (75.3 MHz, CDCl3): d
149.7 (CH), 149.0 (CH), 139.3 (C), 135.6 (CH), 128.9
(CH), 127.6 (CH), 123.7 (CH), 56.2 (CH), 41.9 (CH2),
25.7 (CH2). ESI-HRMS: m/z ¼ 161.1087 (calculated for
[M þ H]þ: 161.1073); 183.0893 (calculated for [M þ
Na]þ: 183.0893).
1321, 1258, 1051, 718 cmꢀ1 1H NMR (300 MHz,
.
CDCl3): d 8.53 (d, J ¼ 2.1 Hz, 1H, ArH), 8.52 (dd, J ¼
1.8, 5.1 Hz, 1H, ArH), 7.70 (dt, J ¼ 2.1, 7.8 Hz, ArH),
7.29 (ddd, 1H, J ¼ 0.6, 4.8, 7.8 Hz, ArH), 5.80 (m, 2H,
CH¼¼CH), 3.35 (m, 2H, NCH2 þ NCHAr), 2.95 (m,
1H, NCH2), 2.32 (m, 2H, CH2ACH¼¼CH), 2.07 (s, 3H,
NCH3). 13C NMR (75.3 MHz, CDCl3): d 149.8 (CH),
149.0 (CH), 138.6 (C), 135.6 (CH), 125.5 (CH), 124.9
(CH), 123.9 (CH), 63.1 (CH), 55.2 (CH2), 44.6 (CH3),
35.3 (CH2). ESI-HRMS: m/z ¼ 175.1223 (calculated for
[M þ H]þ: 175.1230).
(ꢂ)-2-Cyano-1-methyl-4-piperideine, 12. To a stirred so-
lution of potassium cyanide (5.45 g, 83.6 mmol) in
water (11 mL) layered with ether (16 mL) was added a
solution of 5N HCl (6.5 mL, 32.5 mmol). The mixture
was stirred at 0ꢁC, then 1-methylpyridinium iodide (5 g,
22.6 mmol) was added portionwise followed by NaBH4
(1.03 g, 27.1 mmol). The stirring was continued for 5 h
at room temperature. Water was added and the mixture
was extracted with ether. The organic phases were com-
bined, dried and evaporated to dryness. The resulting
yellow oil was flash chromatographed on silica gel
(CH2Cl2/CH3OH 95:5 þ 1% conc. NH4OH). This
yielded 12 (2.62 g, 21.5 mmol, 95%) as a colorless oil.
IR (NaCl): 3043, 2945, 2789, 2223, 1658, 1452, 1260,
(6)-1-Methyl-2-(3-pyridyl)-4-piperideine-N-oxide:
(6)-N-methyl-anatabine-N-oxide, 14. To a solution of
13 (210 mg, 1.2 mmol) in CH2Cl2 (17 mL) at 0ꢁC was
added, in several portions, 70–75% aq. m-CPBA (327
mg, 1.33 mmol). After stirring 1.5 h at 0ꢁC under argon,
the reaction mixture was concentrated in vacuo to a vol-
ume of 3 mL and then poured over alumina and chro-
matographed using CH2Cl2/CH3OH (95:5) as eluent to
afford the N-oxide 14 as a mixture of two diastereomers
in a 7:3 ratio. The major diastereomer was isolated as a
white solid and the minor diastereomer as an oil (com-
bined 200 mg, 1.06 mmol, 88%). Major diastereomer,
1H NMR (300 MHz, CDCl3): d 8.68 (d, J ¼ 1.8 Hz,
1H, ArH), 8.64 (dd, J ¼ 1.5, 4.8 Hz, 1H, ArH), 8.40
1
1141, 1002, 793 cmꢀ1. H NMR (300 MHz, CDCl3): d
5.74 (m, 2H, CH¼¼CH), 3.81 (dd, 1H, J ¼ 1.5, 6 Hz,
NCHCN), 3.24 (bd, 1H, J ¼ 16.5 Hz, NCH2), 2.96 (bd,
1H, J ¼ 16.5 Hz, NCH2), 2.69 (m, 1H, CH2ACH¼¼CH),
2.44 (s, 3H, NCH3), 2.33 (m, 1H, CH2ACH¼¼CH). 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

580
A. Rouchaud and W. R. Kem
Vol 47
Acknowledgment. The support of this research by a Florida
SeaGrant is gratefully acknowledged. The authors thank
the Mass Spectrometry Laboratory at the University of
Florida for recording the mass spectra and Dr. Ferenc Soti
for his comments on the manuscript.
(bd, J ¼ 7.8 Hz, 1H, ArH), 7.37 (dd, J ¼ 4.5, 8.1 Hz,
1H, ArH), 6.07 (m, 1H, CH¼¼CH), 5.72 (m, 1H,
CH¼¼CH), 4.27 (dd, J ¼ 4.2, 10.8 Hz, 1H, NCHAr),
4.16 (m, 1H, NCH2), 3.92 (m, 1H, NCH2), 3.24 (m, 1H,
CH2ACH¼¼CH), 2.93 (s, 3H, NCH3), 2.32 (m, 1H,
CH2ACH¼¼CH). 13C NMR (75.3 MHz, CDCl3): d 150.9
(CH), 150.8 (CH), 137.8 (CH), 131.0 (C), 125.9 (CH),
123.7 (CH), 120.2 (CH), 71.4 (CH), 68.8 (CH2), 58.6
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A Convenient Racemic Synthesis of Two Isomeric Tetrahydropyridyl Alkaloids:
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Journal of Heterocyclic Chemistry
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