Synthesis of hexahydro-2-pyrindine (=hexahydrocyclopenta[c]pyridine) derivatives as conformationally restricted analogs of the nicotinic ligands arecolone and isoarecolone

Article abstract of DOI:10.1002/1522-2675(200201)85:1<96::AID-HLCA96>3.0.CO;2-7

Two hexahydropyrindine derivatives, 1,2,3,4,6,7-hexahydro-2-methyl-5H-cyclopenta[c]pyridin-5-one (1) and 1,2,3,4,5,6-hexahydro-2-methyl-7H-cyclopenta[c]pyridin-7-one (2), and their methiodides 14 and 26, respectively, were synthesized. They can be considered rigid analogues of the known nicotinic agonists arecolone (=1-(1,2,5,6-tetrahydro-1-methylpyridin-3-yl)ethanone) and isoarecolone (=1-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)ethanone). The affinity for the central nicotinic receptor were measured on rat cerebral cortex. Although only the methiodide 14, among the four conformationally restricted compounds, shows an appreciable affinity, the results obtained provide useful information on the molecular requirements at the interaction site of the central nicotinic receptors.

Full text of DOI:10.1002/1522-2675(200201)85:1<96::AID-HLCA96>3.0.CO;2-7

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Helvetica Chimica Acta Vol. 85 (2002)
Synthesis of Hexahydro-2-pyrindine (ˆ Hexahydrocyclopenta[c]pyridine)
Derivatives as Conformationally Restricted Analogs of the Nicotinic Ligands
Arecolone and Isoarecolone
by Luca Guandalinia), Silvia Deia), Fulvio Gualtieria), Maria Novella Romanellia)*, Serena Scapecchia),
Elisabetta Teodoria), Katia Varanib)
a
¡
) Dipartimento di Scienze Farmaceutiche, Universita di Firenze, Via Gino Capponi 9, I-50121 Firenze
b
¡
) Dipartimento di Farmacologia, Universita di Ferrara, Via Fossato di Mortara 17 19, I-44100 Ferrara
Two hexahydropyrindine derivatives, 1,2,3,4,6,7-hexahydro-2-methyl-5H-cyclopenta[c]pyridin-5-one (1)
and 1,2,3,4,5,6-hexahydro-2-methyl-7H-cyclopenta[c]pyridin-7-one (2), and their methiodides 14 and 26,
respectively, were synthesized. They can be considered rigid analogues of the known nicotinic agonists
arecolone (ˆ1-(1,2,5,6-tetrahydro-1-methylpyridin-3-yl)ethanone) and isoarecolone (ˆ1-(1,2,3,6-tetrahydro-1-
methylpyridin-4-yl)ethanone). The affinity for the central nicotinic receptor were measured on rat cerebral
cortex. Although only the methiodide 14, among the four conformationally restricted compounds, shows an
appreciable affinity, the results obtained provide useful information on the molecular requirements at the
interaction site of the central nicotinic receptors.
Introduction. The nicotinic receptor is the prototype of the family called ligand-
gated ion channels (LGIC). Interest in the nicotinic receptor subtypes present in the
central nervous system (nAChR) is steadily growing, since they play a role in many
important physiological processes such as cognition, memory, and pain, and are
involved in severe central nervous system pathologies, such as Alzheimer×s and
Parkinson×s diseases, Tourette×s syndrome, and schizophrenia [1]. Therefore, selective
nicotinic agonists, acting in the central nervous system and devoid of the side effects
shown by nicotine, are, at present, good drug candidates for a variety of pathological
conditions [2].
An H-bond acceptor group and a charged N-atom located a certain distance from
each other, are considered critical for interaction with nicotinic receptors [3][4].
Classical nicotinic agonists belong to two main structural categories: pyridine derivatives
(such as nicotine) and carbonyl derivatives. In the carbonyl class, both esters (such as
acetylcholine) and a,b-unsaturated ketones, such as arecolone (ˆ1-(1,2,5,6-tetrahydro-
1-methylpyridin-3-yl)ethanone) and isoarecolone (ˆ1-(1,2,3,6-tetrahydro-1-methyl-
pyridin-4-yl)ethanone) [5][6], are found. The latter are two potent centrally acting
nicotinic agonists derived from chemical manipulation of arecoline, a naturally
occurring alkaloid extracted from the seeds of Areca catechu L. [7]. It has been shown
that replacement of the Me group with small alkyl groups does not greatly affect
activity, showing that some space is available in this region of the interaction site [6].
Some years ago, the synthesis and biological activity of AG 4 (ˆ N,N,N,3-
tetramethyl-2-oxocyclopentanemethanaminum iodide), a compound previously stud-
ied only on the peripheral nAChR, was reported [8]. This compound, which presents

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97
lower affinity for the central nAChR with respect to (À)-(S)-nicotine (ˆ 3-[(2S)-1-
methylpyrrolidin-2-yl]pyridine) (Ki values are 26 mm and 8 nm, resp.), nevertheless is
able to produce an analgesic effect, after i.c.v. injection in mice, with higher efficacy
than (À)-(S)-nicotine, even if it seems less potent [9]. However, AG 4 is useless as a
drug, since it is a quaternary ammonium compound, and, aiming to improve its
pharmacological and pharmacokinetics properties, compounds 1 and 2 were designed.
These can be considered conformationally restricted analogs [10] of AG 4, where the
cationic N-group is incorporated into a tetrahydropyridine ring. Compounds 1 and 2
can also be viewed as frozen analogs of isoarecolone and arecolone, respectively, and
their study could give additional information on the topography of the active site of the
receptor. In this paper, the synthesis and biological evaluation of compounds 1 and 2, as
well as that of their methiodides 14 and 26, are reported.
Results. Chemistry. A simple retrosynthetic analysis (Scheme 1) suggests the
heterocycle 3 as a suitable starting material for our synthesis. Compound 3, 6,7-dihydro-
5H-cyclopenta[c]pyridine, can be found in both the Chemical Abstracts and Beilstein
databases as 6,7-dihydro-5H-2-pyrindine, a name which we use in the General Part. In
fact, 3 can be transformed into both of the desired compounds 1 and 2 by simple known
methods [11][5]. Prelog and Metzler [12a] described the synthesis of 3 with a 30%
Scheme 1

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Scheme 2
a) H2, PdCl2, MeCOONa.
yield, but Ayerst and Schofield [12b], by the same procedure, obtained much lower
yields (4 11%). Later, Cavill et al. [13] worked on similar natural products. In our
hands, the reported methods [12] afforded 3 in even lower overall yields (2%).
Since several steps were required to transform 3 into the final compounds 1 and 2,
considerable amounts of 6,7-dihydro-5H-2-pyrindine (3) were needed, and we tried to
improve its preparation by designing different synthetic routes. Starting from the
commercially available ethyl 2-oxocyclopentanecarboxylate and by reported proce-
dures [14], 1,3-dichloro-6,7-dihydro-5H-2-pyrindine 4 was obtained and transformed
into compound 3, however, without any substantial improvement in the yields
(Scheme 2).
In a second attempt (Scheme 3), addition of ethyl (tributylphosphoranyl)acetate
[15] to the carbonyl group of ethyl 2-oxocyclopentanecarboxylate gave the unsaturated
ester 5 [16], which was hydrogenated to 6 [17] and reduced to the dialdehyde 7 [18].
Unfortunately, 7 proved to be unstable: all attempts at chromatographic purification
resulted in loss of product. Therefore, after the workup, the residue was immediately
treated with hydroxylamine [19] to give the desired compound 3. As a consequence, the
overall yield of this process was low (5% at best) and, due to the instability of 7, the
procedure was not always reproducible.
Scheme 3
a) Bu3PCHCOOEt. b) H2, Pd/C. c) Diisobutylaluminium hydride (DIBALH). d) NH2OH ¥ HCl.
Therefore, we thought it wiser to switch to different synthetic pathways to
implement the synthesis of the two isomers separately. Accordingly, compound 5
(Scheme 4) was oxidized at the allylic position, yielding ketone 8 [20], which was
protected with ethane-1,2-dithiol to give 9. Apparently, the hydrolysis of 9 with 1 equiv.
of NaOH gave only one of the two possible acids, which was identified as 10, since only
the ester group at lower field had disappeared from the NMR spectrum. However, the
following reaction with ethyl carbonochloridate and methylamine gave two isomeric
amides 11 (in 65 :35 ratio), which were not separated, since treatment with base yielded

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99
Scheme 4
t
t
a) Pyridinium dichromate, BuOOH. b) Ethane-1,2-dithiol. c) NaOH. d) ClCOOEt, MeNH2. e) BuOK. f)
LiAlH4. g) Tl(NO3)3. h) MeI.
the same dicarboximide 12. Subsequent reduction with LiAlH4 afforded the protected
amine 13. Deprotection of the carbonyl function was attempted in several ways (acid
hydrolysis, Hg salts [21]), but only the method of Smith and Hanna [22] was effective.
Compound 1 proved to be unstable as a free base and was transformed into the oxalate
salt and the methiodide 14.
For the synthesis of compound 2, the analogous synthetic pathway was first
attempted (Scheme 5). Compound 15 [23] was prepared according to [24] and
protected with ethane-1,2-dithiol to give 16. Contrary to what happened with its isomer
9, basic hydrolysis of 16 gave only traces of the desired acid 17, which was instead
obtained by acid hydrolysis; reaction with ethyl carbonochloridate and methylamine
again gave two isomeric amides 18, in a 9 :1 ratio. Reaction with tBuOK then yielded
Scheme 5
a) Ethane-1,2-dithiol. b) HCl. c) ClCOOEt, MeNH2. d) tBuOK.

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Scheme 6
a) H2,Pd/C. b) Ethane-1,2-dithiol. c) LiAlH4. d) (CF3CO)2O, DMSO, Et3N. e) NH2OH ¥ HCl. f) MeI. g)
NaBH4. h) Tl(NO3)3.
the dicarboximide 19. Unlike dicarboximide 12, compound 19 proved to be unstable,
and any attempt to reduce it to the corresponding amine failed. Therefore, we had to
design a new synthetic pathway (Scheme 6), similar to that shown in Scheme 3, which
involved the synthesis of a pyrindine intermediate. The diester 15 was hydrogenated to
20 [25] and protected in the usual way to give 21. The dialdehyde 23, obtained by
reduction of 21 to the dialcohol 22 and subsequent oxidation, was immediately reacted
with hydroxylamine to give the protected pyrindinone 24, which was transformed into
25 by reaction with MeI and subsequent reduction with NaBH4. Deprotection of the
carbonyl function gave then compound 2 which, like its isomer 1, was unstable as a free
base and was thus transformed into the oxalate salt and into the methiodide 26.
Pharmacology. Compounds 1 and 2 (as oxalates) and methiodides 14 and 26 were
tested in vitro on rat brain homogenates to evaluate their affinity for the central
nicotinic receptors labeled by [3H]cytisine, that is believed to label a4b2 which
represents up to 90% of the high-affinity agonist binding sites in rat brain [26][27].
Their binding affinity is reported in Table 1, together with those of the compounds
reported in the Introduction.
Discussion. The data reported in Table 1 show that, among the new compounds,
only the methiodide 14 possesses some modest affinity for the central nicotinic receptor
as 1, 2, and 26 do not displace [3H]cytisine from rat cerebral cortex up to a 100 mm
concentration. Compared to AG 4, the incorporation of the cationic side chain into a
six-membered ring resulted in a 6-fold increase of affinity for compound 14 and in
complete loss of affinity for 26. Surprisingly, freezing the acetyl moiety of arecolone and
isoarecolone into a five-membered ring (compounds 1 and 2) resulted in a complete
loss of affinity, showing that to maintain nicotinic receptor affinity, no restriction of the
conformational freedom of that function is allowed. A reasonable explanation for this

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Table 1. Binding Affinity of the Synthesized and Reference Compounds
AG 4
Isoarecolone
Arecolone
Nicotine
1
2
14
26
Ki/mma) 26 Æ 1.4b) 0.048 Æ 0.0022c) 0.033 Æ 0.0055c) 0.0082 Æ 0.0005b) > 10 > 10 4.2 Æ 0.058 > 10
a) On rat brain homogenates. The nicotinic receptors were labeled by [3H]cytisine. See [9] for the exper.
protocol. b) See [9]. c) See [6].
result can be found by looking at the conformational and steric characteristics of the
two molecules with respect to the parent compounds.
A tenet of the frozen-analog approach is that, to maintain maximum affinity, the
parent compound has to be constrained into a biologically active conformation, and the
additional volume of the moiety used to reduce conformational freedom must be
compatible with the space available at the interaction site [10]. Therefore, a
conformational analysis of the lead compounds and of the rigid analogs is required
to understand the reasons for the inactivity.
In the case of arecolone and isoarecolone, two stable conformations are possible,
with the enone moiety in a s-cis or s-trans arrangement (Table 2), which can be
converted to each other at a small energy cost (Fig. 1). Ab initio calculations predict a
planar disposition of the enone group, while semiempirical methods predict a deviation
from planarity. Both methods show that the s-trans conformer is more stable than the
s-cis one. The distance between the N-atom (charged group) and the O-atom (H-bond-
acceptor group) is a feature thought to be critical for interaction with the nicotinic
receptor [3][4]: the two conformations of isoarecolone do not differ in this respect
while, in the case of arecolone, the s-trans conformer shows a shorter distance (4.2 ä)
with respect to the s-cis one (4.8 ä).
The conformational characteristics of compounds 1 and 2 are also reported in
Table 2. Both molecules represent the rigid analogs of the s-trans (more stable)
conformation of the lead compounds: in case of 1, the N ¥¥¥ O distance is very close to
that of isoarecolone, while the N ¥¥¥ O distance of 2 is intermediate between those of the
Fig. 1. Dihedral driver calculation for arecolone (.) and isoarecolone (&). The dihedral angle is defined as
CˆCÀCˆO.

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Table 2. Results of ab initio and Semiempirical Calculations
DE [kcalmolÀ1
]
NÀO distance [ä]
Dihedral angle OˆCÀCˆC [8]
ab initio
AM1
ab initio
AM1
ab initio
AM1
Isoarecolone
Arecolone
2.7
0
5.8
0
0.4
0
2.4
0
5.0
4.9
4.8
4.1
5.1
4.4
5.1
4.4
5.1
5.1
4.8
4.2
5.2
4.5
5.2
4.5
2
178
4
À 179
180
178
180
178
8
155
11
164
179
180
180
180
1
2
14
26
two conformers of arecolone and close to that of other classic nicotinic agonists such as
anatoxin [2][28]. Therefore, this feature alone does not account for the loss of affinity.
In Fig. 2,a, the superimposition of both conformations of arecolone (s-cis and s-
trans) and isoarecolone (s-cis and s-trans) is reported. While the two conformations of
isoarecolone coincide, those of arecolone are different: the best fit is obtained with the
s-cis conformation, which overlaps isoarecolone with a lower r.m.s. value (0.11) with
respect to the s-trans one (0.39). The tetrahydropyridine ring occupies a volume similar
to that occupied by isoarecolone. Compound 2 (Fig. 2,b) overlaps perfectly with s-
trans-arecolone, which is obviously not the active conformation, since 2 is completely
inactive. Therefore, a reasonable explanation for the lack of affinity of compounds 1
and 2 appears to be the extra volume occupied by the CH2CH2 part of the
tetrahydropyridine ring, which lies in an area probably occupied by the receptor.
Even if the analogs 1 and 2 differ from the lead by only one additional CH2 group, the
conformational constraint of the ring puts it in a region that prevents an efficient fitting
to the receptor.
Fig. 2. a) Overlap of isoarecolone and arecolone (yellow, s-cis-isoarecolone; green, s-trans-isoarecolone; black,
s-trans-arecolone; blue, s-cis-arecolone). b) Overlap of compounds 1 and 2, isoarecolone, and arecolone (green,
s-trans-isoarecolone; black, s-trans-arecolone; blue, s-cis-arecolone; red, compound 1; magenta, compound 2).
c) Overlap of AG 4 and compounds 14 and 26 (cyano, s-cis-and s- trans AG 4 [8]; red, compound 14; magenta,
compound 26).

Helvetica Chimica Acta Vol. 85 (2002)
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As far as the methiodides are concerned, in Fig. 2,c, the overlap of 14 and 26 with
AG 4 is shown. The lack of affinity of 26 can be explained as above. The fact that,
contrary to the tertiary amine 1, methiodide 14 shows some affinity may depend on a
different mode of interaction with the receptor, due to the presence of the quaternary
ammonium group, which is characterized by a different volume and charge distribution
[29].
In conclusion, the reduction of conformational flexibility of our leads produced
different results. The nicotinic affinity of AG 4 was slightly improved in 14, but the
affinity of arecolone and isoarecolone was completely abolished in compounds 1 and 2.
Of course, our efforts to develop new centrally active nicotinic agonists have been
frustrated, as 1 and 2 do not show any affinity for the nicotinic receptors, while 14 is still
a quaternary ammonium compound and, as a consequence, will not cross the blood-
brain barrier. Nevertheless, the results obtained have provided information that may
cast further light on the molecular requirements of central nicotinic receptors.
Experimental Part
General. All reagents and solvents were purchased from commercial suppliers and used without further
purification with the following exceptions: anh. THF was distilled from Na/benzophenone, and toluene from Na
wire. Yields are given after purification, unless otherwise stated. Column chromatography (CC): silica gel 40
(0.063 0.200 mm; Merck). Flash chromatography (FC): silica gel 40 (0.040 0.063 mm, Merck). M.p.: B¸chi
apparatus; uncorrected. IR Spectra: Perkin-Elmer-681 spectrophotometer; nujol mull for solids and neat for
liquids; in cmÀ1. NMR Spectra: d in ppm J in Hz. Gemini-200 spectrometer. Mass spectra: Carlo-Erba QMD-
1000 spectrometer. HR-MS: VG-70-250S (VG Analytical Ltd., Manchester, UK) double-focus mass
spectrometer; resolution 5000.
6,7-Dihydro-5H-cyclopenta[c]pyridine (3) [12]. Method A (Scheme 2). A mixture of 1,3-dichloro-6,7-
dihydro-5H-cyclopenta[c]pyridine (4) [11] (1.65 g, 9 mmol), MeCOONa (1.5 g, 18 mmol) and PdCl2 (0.15 g) in
abs. EtOH (20 ml) was hydrogenated in a Parr apparatus at 48 psi for 20 h. After filtration and evaporation, the
residue was treated with NaHCO3 soln. and extracted with CHCl3. The extract was dried and evaporated: 57%
of 3. Overall yield, starting from the commercially available ethyl 2-oxocyclopentanecarboxylate, 1%.
Method B (Scheme 3): A mixture of crude 7 [18] (1.8 g, 0.0129 mol) and NH2OH ¥ HCl (2.7 g, 0.039 mol) in
glacial MeCOOH (30 ml) was kept under reflux for 4 h. After evaporation, the residue was treated with
NaHCO3 and extracted with CHCl3. The extract was dried and evaporated and the residue purified by CC: 26%
(from 6) of 3. 1H-NMR (CDCl3): 2.01 2.19 (m, CH2CH2CH2); 2.86 2.99 (m, CH2CH2CH2); 7.16 (d, J ˆ 5.0,
1 arom. H); 8.34 (d, J ˆ 5.0, 1 arom. H); 8.46 (s, 1 arom. H).
Ethyl 2-(Ethoxycarbonyl)cyclopent-1-ene-1-acetate (5) [16]. A mixture of ethyl 2-oxocyclopentanecarbox-
ylate (18 ml, 19 g, 0.12 mol) and ethyl (tributylphosphoranyl)acetate [15] (35 g, 0.12 mol) in toluene (20 ml) was
kept under reflux for 5 h. After evaporation, the unreacted ketone was distilled off under vacuum and the
residue submitted to FC (cyclohexane/AcOEt 7:3): 69% of 5. Oil. B.p. 1208/2 Torr ([16]: 1558/20 Torr).
1H-NMR (CDCl3): 1.26 (t, J ˆ 7.0, 1 Me); 1.28 (t, J ˆ 7.0, 1 Me); 1.78 1.95 (m, CH2CH2CH2); 2.52 2.72
‡
(m, CH2CH2CH2); 3.68 (s, CH2CO); 4.15 (q, J ˆ 7.0, 1 CH2O); 4.18 (q, J ˆ 7.0, 1 CH2O). MS: 226 (1, M ), 180
(100), 152 (91), 134 (73), 124 (40), 79 (80).
Ethyl 2-(Ethoxycarbonyl)cyclopentaneacetate (6) [17]. A soln. of 5 (1.2 g) in abs. EtOH (20 ml) was
hydrogenated in a Parr apparatus at 20 psi over 10% Pd/C (0.1 g) overnight. Filtration and evaporation gave
92% of 6. 1H-NMR (CDCl3): 1.25 (t, J ˆ 7.2, 2 Me); 1.61 2.08 (m, 6 H); 2.23 2.64 (m, 4 H); 4.11 (q, 1 CH2O);
4.13 (q, J ˆ 7.2, 1 CH2O).
2-Formylcyclopentaneacetaldehyde (7) [18]. To a soln. of 6 (0.56 g, 2.5 mmol) in anh. toluene (20 ml), kept
at À908, 1.5m DIBALH in toluene (3.33 ml, 2 equiv.) was added, and the mixture was stirred at low temp. for
4 h. The reaction was quenched with ice, and the mixture was allowed to reach r.t. The aq. layer was washed with
CHCl3 and the combined org. phase dried and evaporated: crude 7. 1H-NMR (CDCl3): 9.64 (d, J ˆ 2.9, 1 CHO);
9.76 (s, 1 CHO).
Any attempt to purify crude 7 by CC failed, and the product was treated as such in the following step.

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Ethyl 2-(Ethoxycarbonyl)-5-oxocyclopent-1-ene-1-acetate (8) [20]. A suspension of 5 (6.9 g, 0.03 mol),
Celite (25 g), and pyridinium dichromate (52.7 g, 0.14 mol) in benzene (200 ml) was kept at 08, and 70%
tBuOOH/H2O (12.4 g, 0.137 mol) was added. The mixture was vigorously stirred at r.t. for 17 h, then it was
diluted with Et2O, the solid material filtered off, and the filtrate evaporated. The residue was submitted to FC
1
(cyclohexane/AcOEt 8 :2): 5 (2.1 g) and 8 (2.9 g). 8: Oil. H-NMR (CDCl3): 1.25 (t, J ˆ 7.2, 1 Me); 1.34 (t, J ˆ
7.2, 1 Me); 2.50 2.58 (m, 1 CH2); 2.81 2.89 (m, 1 CH2); 3.61 (s, CH2CO); 4.14 (q, J ˆ 7.2, 1 CH2O); 4.30
(q, J ˆ 7.2, 1 CH2O). 13C-NMR (CDCl3): 14.49 (q); 27.13 (t); 29.99 (t); 34.28 (t); 61.43 (t); 61.87 (t); 143.79 (s);
158.01 (s); 165.03 (s); 169.80 (s); 208.44 (s).
Ethyl 7-(Ethoxycarbonyl)-1,4-dithiaspironon-6-ene-6-acetate (9). A mixture of 8 (2.2 g, 0.009 mol), ethane-
1,2-dithiol (1.48 ml, 1.66 g, 0.018 mol), and TsOH (0.30 g) in anh. toluene was kept under reflux for 3 h (Stark
trap). The mixture was then treated with 5% NaHCO3 soln., the org. phase dried (Na2SO4) and evaporated, and
the residue purified by FC (cyclohexane/AcOEt 5 :5): 2.4 g (83%) of 9. Oil. IR: 1740 (CO), 1710 (CO).
1H-NMR (CDCl3): 1.26 (t, J ˆ 7.0, 1 Me); 1.28 (t, J ˆ 7.0, 1 Me); 2.48 2.58 (m, 1 CH2); 2.63 2.72 (m, 1 CH2);
3.23 (s, 2 CH2S); 3.64 (s, CH2CO); 4.14 (q, J ˆ 7.0, 1 CH2O); 4.18 (q, J ˆ 7.0, 1 CH2O). 13C-NMR (CDCl3): 14.62
(q); 31.40 (t); 33.48 (t); 41.18 (t); 44.97 (t); 60.83 (t); 61.18 (t); 79.06 (s); 133.18 (s); 149.49 (s); 165.13 (s); 170.78
(s). Anal. calc. for C14H20O4S2: C 53.14, H 6.37; found: C 53.34, H 6.48.
1,2,3,4,6,7-Hexahydro-2-methylspiro[5H-cyclopenta[c]pyridine-5,2'-[1,3]dithiolane]-1,3-dione (12). A soln.
of 9 (0.5 g, 0.0016 mol) and NaOH (0.064 g, 0.0016 mol) in EtOH/H2O 10 :1 was stirred at r.t. for 24 h. The
solvent was then removed and the residue partitioned between H2O and Et2O. The org. phase was dried
(Na2SO4) and evaporated, to give 0.17 g of unreacted 9. The aq. phase was acidified to pH 3 with dil. HCl soln.
1
and extracted with CH2Cl2. The extract was dried (Na2SO4) and evaporated: 0.25 g of 10. H-NMR (CDCl3):
1.27 (t, J ˆ 7.0, Me); 2.52 2.60 (m, 1 CH2); 2.65 2.75 (m, 1 CH2); 3.34 (s, 2 CH2S); 3.66 (s, CH2CO); 4.17
(q, J ˆ 7.0, CH2O).
To a soln. of crude 10 in CHCl3 stabilized with amylene (15 ml), kept at 08, Et3N (0.2 ml) and ethyl
carbonochloridate (0.13 ml, 1.3 equiv.) were added. After 1 h at 08, 5m MeNH2 in toluene (1.5 ml) was added,
and the mixture was allowed to warm to r.t. The mixture was treated with H2O and extracted with CHCl3. The
extract was dried and evaporated: 0.25 g of crude 11. Pale yellow oil. IR: 3337 (NH), 1728 (COO), 1655, 1629
(CON). 1H-NMR (CDCl3): 1.18 1.38 (m, MeCH2O); 2.50 2.74 (m, 2 CH2); 2.79 (d, J ˆ 4.0, 35%) and 2.85
(d, J ˆ 4.0, 65%) (MeN); 3.20 3.36 (m, 2 CH2S); 3.41 (s, CH2CO); 4.05 4.35 (m, MeCH2O); 7.4 (br. s, NH).
Crude 11 was dissolved in anh. dimethoxyethane, and tBuOK (0.1 g, 1.1 equiv.) was added under N2. After
2 h stirring at r.t., the solvent was evaporated and the residue treated with dil. HCl soln. and extracted with
CHCl3. The extract was dried and evaporated: 0.2 g (50% from 9) of 12. M.p. 92 938. IR: 3330 (br.), 1720, 1659.
1H-NMR (CDCl3): 2.65 2.72 (m, CH2CH2); 3.22 (s, MeN); 3.32 3.43 (m, 2 CH2S); 3.62 3.68 (m, CH2CO).
13C-NMR (CDCl3): 28.2 (q); 30.3 (t); 34.1 (t); 43.6 (t); 45.8 (t); 76.1 (s); 131.7 (s); 155.5 (s); 165.8 (s); 173.1 (s).
‡
MS: 255 (100, M ), 227 (87), 195 (50), 194 (92), 162 (91), 110 (45), 61 (65). Anal. calc. for C11H13NO2S2:
C 51.74, H 5.13, N 5.49; found: C 51.57, H 5.25, N 5.31.
1,2,3,4,6,7-Hexahydro-2-methylspiro[5H-cyclopenta[c]pyridine-5,2'-[1,3]dithiolane] (13). A suspension of
LiAlH4 (0.37 g, 0.01 mol) in anh. 1,2-dimethoxyethane (20 ml) was heated under reflux under N2, and a soln. of
12 (0.9 g, 0.0035 mol) in anh. (10 ml) 1,2-dimethoxyethane was added dropwise. The suspension was heated for a
further 5 h. After evaporation, the residue was treated with dil. HCl soln. and extracted with CHCl3. The aq.
layer was alkalinized and extracted again with CHCl3. The org. phase was dried and evaporated and the residue
separated by CC (abs. EtOH/petroleum ether/Et2O/CHCl3/NH4OH 40 :500 :200 :200 :2.5): 20% of 13. M.p.
1
43 478. H-NMR (CDCl3): 2.23 2.41 (m, 4 H); 2.39 (s, MeN); 2.54 2.64 (m, 4 H); 2.88 2.94 (m, 1 CH2N);
3.30 (s, 2 CH2S). 13C-NMR (CDCl3): 23.1 (t); 32.3 (t); 41.2 (t); 45.8 (q); 46.2 (t); 52.5 (t); 55.9 (t); 76.3 (s); 135.5
‡
(s); 136.2 (s). MS: 227 (8, M ), 207 (8), 166 (22), 156 (12), 134 (14), 109 (100), 91 (13). Anal. calc. for
C11H17NS2: C 58.10, H 7.54, N 6.16; found: C 57.96, H 7.59, N 6.32.
1,2,3,4,6,7-Hexahydro-2-methyl-5H-cyclopenta[c]pyridin-5-one (1). To a soln. of 13 (0.06 g, 0.26 mmol) in
MeOH (5 ml) and THF (1 ml), a soln. of Tl(NO3)3 ¥ 3 H2O (0.22 g, 0.49 mmol) in MeOH (2 ml) was added.
After stirring for 3 h at r.t., the mixture was diluted with CH2Cl2 and the solid material filtered off. The solvent
was removed, and the residue treated with H2O and CH2Cl2. The aq. layer was alkalinized and extracted with
‡
CHCl3. The extract was dried and evaporated: 0.03 g (75%) of 1. Oil. IR: 1700, 1650. MS: 151 (80, M ), 150
(56), 123 (100), 122 (59), 108 (76), 94 (38), 79 (71). 1H-NMR (CDCl3): 2.23 2.34 (m, 2 H); 2.45 (s, MeN);
2.38 2.64 (m, 6 H); 3.23 (s, 1 CH2N). 13C-NMR (CDCl3): 21.5 (t); 30.1 (t); 35.0 (t); 45.8 (q); 51.8 (t); 57.2 (t);
137.2 (s); 170.6 (s); 207.9 (s).
On standing, tarry materials were formed from 1. Thus, 1 was immediately transformed into the oxalate salt,
which, however, is so hygroscopic that no m.p. was determined. HR-MS: 151.09980 (calc. 151.09971).

Helvetica Chimica Acta Vol. 85 (2002)
105
2,3,4,5,6,7-Hexahydro-2,2-dimethyl-5-oxo-1H-cyclopenta[c]pyridinium Iodide (14). To a soln. of 1 (0.04 g,
0.3 mmol) in anh. Et2O (10 ml), an excess of MeI was added. After stirring at r.t. in the dark for 24 h, the solid
was collected and dried. 1H-NMR (D2O): 2.42 2.62 (m, 3 CH2); 3.07 (s, 2 MeN); 3.44 3.50 (m, 1 CH2N); 4.25
(s, 1 CH2N). 13C-NMR (CD3OD): 16.6 (t); 27.0 (t); 33.9 (t); 51.6 (q); 59.0 (t); 62.8 (t); 133.5 (s); 162.4 (s); 206.3
(s). Anal. calc. for C10H16INO: C 40.97, H 5.50, N 4.78; found: C 41.15, H 5.71, N 4.91.
Ethyl 2-(Ethoxycarbonyl)-3-oxocyclopent-1-ene-1-acetate (15) [23] was prepared according to [24], starting
from potassium ethyl malonate (instead of potassium methyl malonate). Diethyl 3,6-dioxooctanedioate was
obtained in 91% yield (1H-NMR (CDCl3): 1.28 (t, J ˆ 7.3, 2 Me); 2.86 (s, COCH2CH2CO); 3.49 (s, 2 COCH2-
CO); 4.19 (q, J ˆ 7.3, 2 CH2O)). This intermediate was treated with NaOH as described in the literature to give
1
15 (quant.). H-NMR (CDCl3): 1.27 (t, J ˆ 7.3, 1 Me); 1.33 (t, J ˆ 7.3, 1 Me); 2.48 2.59 (m, 1 CH2); 2.73 2.81
(m, 1 CH2); 3.82 (s, 1 CH2); 4.18 (q, J ˆ 7.3, 1 CH2O); 4.30 (q, J ˆ 7.3, 1 CH2O). 13C-NMR (CDCl3): 14.58 (q);
31.62 (t); 35.48 (t); 38.38 (t); 61.43 (t); 61.91 (t); 134.65 (s); 162.90 (s); 168.45 (s); 178.39 (s); 203.19 (s).
Ethyl 6-(Ethoxycarbonyl)-1,4-dithiaspironon-6-ene-7-acetate (16). As described for 9, from 15 (3.6 g):
2.27 g (48%) 16; after purification by FC. IR: 1740 (CO), 1710 (CO). 1640 (CˆC). 1H-NMR (CDCl3): 1.26
(t, J ˆ 7.3, 1 Me ) ; 1.32 (t, J ˆ 7.3, 1 Me); 2.49 2.56 (m, CH2CH2); 3.24 3.39 (m, 1 CH2S); 3.46 3.52
(m, 1 CH2S); 3.56 (s, CH2CO); 4.12 (q, J ˆ 7.3, 1 CH2O); 4.26 (q, J ˆ 7.3, 1 CH2O). 13C-NMR (CDCl3): 14.60
(q); 36.55 (t); 37.12 (t); 41.75 (t); 45.80 (t); 60.72 (t); 61.31 (t); 74.20 (s); 135.18 (s); 150.46 (s); 164.21 (s); 169.85
(s). Anal. calc. for C14H20O4S2: C 53.14, H 6.37; found: C 52.97, H 6.21.
1,2,3,4,5,6-Hexahydro-2-methylspiro[7H-cyclopenta[c]pyridine-7,2'-[1,3]dithiolane]-1,3-dione (19). A soln.
of 16 (1.47 g) in EtOH (22 ml) and 2n HCl (7 ml) was kept at 808 for 4 h. After evaporation, the residue was
treated with NaHCO3 and extracted with CHCl3. The extract was dried and evaporated: 1.1 g (75%) of 16. The
aq. layer was acidified and extracted with CHCl3 and the extract dried and evaporated: 0.26 g (19%) of 17.
1H-NMR (CDCl3): 1.34 (t, J ˆ 7.3, Me); 2.49 2.67 (m, CH2CH2); 3.35 3.41 (m, 1 CH2S); 3.46 3.58
(m, 1 CH2S); 3.56 (s, CH2CO); 4.30 (q, J ˆ 7.3, CH2O). 13C-NMR (CDCl3): 14.58 (q); 36.63 (t); 37.40 (t);
41.80 (t); 45.94(t); 61.34 (t); 73.92 (s); 135.78 (s); 150.33 (s); 165.10 (s); 174.40 (s).
As described for 11, 17 (0.26 g) gave 0.24 g of the two isomeric amides 18 (9 :1 ratio). 1H-NMR (CDCl3):
1.19 (t, J ˆ 7.4, 10%) and 1.32 (t, J ˆ 7.4, 90%) (MeCH2O); 2.46 2.68 (m, CH2CH2); 2.74 (d, J ˆ 4.7, 90%) and
2.88 (d, J ˆ 4.7, 10%) (MeN); 3.22 3.56 (m, 2 CH2S); 3.30 (s, CH2CO); 4.06 (q, J ˆ 7.4, 10%) and 4.26 (q, J ˆ
7.4, 90%) (MeCH2O). 13C-NMR (CDCl3): 14.64 (q); 26.91 (q); 36.23 (t); 40.15 (t); 41.73 (t); 46.37 (t); 61.29 (t);
73.96 (s); 134.40 (s); 154.01 (s); 165.77 (s); 169.40 (s).
As described for 12, 18 (0.11 g) gave 19 (0.09 g). Low-melting solid. 1H-NMR (CDCl3): 2.55 2.87
(m, CH2CH2); 3.20 (s, MeN); 3.30 3.52 (m, 1 CH2S); 3.43 (s, CH2CO); 3.64 3.81 (m,1 CH2S).
Compound 19 was unstable: the 1H-NMR spectrum became progressively more complicated, with the
increase of a s at 5.92 ppm. The GC/MS analysis showed only the presence of compounds with molecular mass
(375) higher than that of 19 (255).
Ethyl 2-(Ethoxycarbonyl)-3-oxocyclopentaneacetate (20). A soln. of 15 (1 g) in abs. EtOH (30 ml) was
1
hydrogenated over Pd/C (0.16 g) at 55 psi. Filtration and evaporation gave 0.94 g (93%) of 20. Oil. H-NMR
(CDCl3): 1.20 (t, J ˆ 7.3, 1 Me); 1.26 (t, J ˆ 7.3, 1 Me); 1.43 1.62 (m, 1 H); 2.21 2.61 (m, 5 H); 2.93 (d, J ˆ 4,
CH2COO); 4.10 (q, J ˆ 7.3, 1 CH2O); 4.14 (q, J ˆ 7.3, 1 CH2O). 13C-NMR (CDCl3): 14.54 (q); 27.42 (t); 37.82
(d); 38.60 (t); 38.96 (t); 60.96 (t); 61.03 (d); 61.80 (t); 168.96 (s); 171.65 (s); 210.93 (s).
Ethyl 6-(Ethoxycarbonyl)-1,4-dithiaspirononane-7-acetate (21). As described for 9: 75% of 21. IR: 1740
1
(CO), 1730 (CO). H-NMR (CDCl3): 1.21 (t, J ˆ 7.0, 1 Me); 1.26 (t, J ˆ 7.0, 1 Me); 1.31 1.55 (m, 1 H); 2.01
2.26 (m, 2 H); 2.28 2.53 (m, 3 H); 2.70 2.98 (m, 2 H); 3.19 3.33 (m, 4 H); 4.08 (q, J ˆ 7.0, 1 CH2O); 4.14
(q, J ˆ 7.0, 1 CH2O). 13C-NMR (CDCl3): 14.62 (q); 14.73 (q); 32.24 (t); 39.38 (d); 39.56 (t); 40.09 (t); 40.54 (t);
‡
44.52 (t); 60.81 (t); 61.09 (t); 64.75 (d); 73.05 (s); 172.29 (s); 172.69 (s). MS: 318 (22, M ), 227 (33), 141 (50), 131
(100). Anal. calc. for C14H22O4S2: C 52.80, H 6.96; found: C 52.58, H 6.88.
6-(Hydroxymethyl)-1,4-dithiaspirononane-7-ethanol (22). To a soln. of 21 (1.6 g, 5 mmol) in anh. Et2O
(20 ml) under N2, LiAlH4 (0.64 g) was added portionwise. The mixture was heated under reflux for 3 h. After
cooling, the mixture was treated with ice and extracted with Et2O. The org. layer was dried and evaporated:
1.10 g (93%) of 22. Solid. M.p. 72 738. IR: 3360 (OH). 1H-NMR (CDCl3): 1.12 2.21 (m, 8 H); 3.19 3.36
(m, 2 CH2S); 3.52 3.88 (m, 4 H). 13C-NMR (CDCl3): 30.91 (t); 37.72 (d); 38.89 (t); 39.05 (t); 39.82 (t); 45.83 (t);
57.30 (d); 61.41 (t); 64.07 (t); 74.31 (s). Anal. calc. for C10H18O2S2: C 51.24, H 7.74; found: C 51.42, H 7.59.
5,6-Dihydrospiro[7H-cyclopenta[c]pyridine-7,2'-[1,3]dithiolane] (24).
A mixture of DMSO (1 ml,
0.014 mol) and anh. CH2Cl2 (8 ml) was cooled to À508. Then (CF3CO)2O (2.02 g, 0.01 mol) was added. After
20 min at À508, 22 (0.75 g, 0.0032 mol) in CH2Cl2 (7 ml) was added slowly. After 2 h stirring at À508, the mixture
was treated with Et3N and allowed to warm to r.t. After evaporation, the residue was partitioned between H2O

106
Helvetica Chimica Acta Vol. 85 (2002)
and Et2O. The org. layer was dried and evaporated, giving 1.10 g of a residue containing 6-formyl-1,4-
dithiospirononane-7-acetaldehyde (23). Since all attempts to purify this mixture failed, the residue was used
immediately in the next step. 1H-NMR: 9.71, 9.78 (2 CHO); no trace of CH2OH.
To the residue in MeCOOH (80 ml), NH2OH ¥ HCl (1.07 g) was added and the mixture heated under reflux
for 1.5 h. After evaporation, the residue was treated with H2O and the soln. made alkaline with 10% NaOH soln.
and extracted with CHCl3. The extract was dried and evaporated and the residue purified by FC (CHCl3/MeOH
97:3): 0.31 g (46% from 22) of 24. 1H-NMR (CDCl3): 2.68 (t, J ˆ 6.6, 2 H); 2.97 (t, J ˆ 6.6, 2 H); 3.39 3.62
(m, 2 CH2S); 7.14 (d, J ˆ 5.2, 1 arom. H); 8.41 (d, J ˆ 5.2, 1 arom. H); 8.73 (s, 1 arom. H). 13C-NMR (CDCl3):
31.26 (t); 41.45 (t); 47.54 (t); 70.79 (s); 120.03 (d); 142.81 (s); 146.84 (d); 148.60 (d); 151.86 (s). MS: 209 (32,
‡
M ), 181 (100), 149 (52), 148 (64), 116 (56), 89 (18). Anal. calc. for C10H11NS2: C 57.38, H 5.30, N 6.69; found:
C 57.49, H 5.41, N 6.53.
1,2,3,4,5,6-Hexahydro-2-methylspiro[7H-cyclopenta[c]pyridine-7,2'-[1,3]dithiolane] (25). To a soln. of 24
(0.3 g) in CHCl3 (50 ml), an excess of MeI was added. The mixture was kept under stirring at r.t. in the dark for
20 h. Evaporation gave 5,6-dihydro-2-methylspiro[7H-cyclopenta[c]pyridinium-7,2'-[1,3]dithiolane] iodide
(0.44 g, 88%). 1H-NMR (CDCl3): 2.86 (t, J ˆ 7.1, 2 H); 3.09 (t, J ˆ 7.1, 2 H); 3.46 3.62 (m, 1 CH2S); 3.78
3.95 (m, 1 CH2S); 4.72 (s, MeN); 7.92 (d, J ˆ 7, 1 arom. H); 9.13 (d, J ˆ 7, 1 arom. H); 9.19 (s, 1 arom. H).
13C-NMR (CDCl3): 32.88 (t); 42.26 (t); 45.72 (t); 49.76 (q); 69.32 (s); 124.60 (d); 141.48 (d); 144.83 (d); 150.99
(s); 161.40 (s).
To the soln. of the methiodide (0.43 g, 1.23 mmol) in anh. MeOH (35 ml) at 08, NaBH4 (0.06 g, 1.58 mmol)
was added. The mixture was stirred at r.t. for 1 h, and then treated with ice. After evaporation, the residue was
partitioned between H2O and CHCl3, the extract dried and evaporated, and the residue purified by FC (CHCl3/
MeOH 95 :5): 0.14 g (50%) of 25. 1H-NMR (CDCl3): 2.06 2.18 (m, 2 H); 2.20 2.32 (m, 2 H); 2.37 (s, MeN);
2.45 2.58 (m, 4 H); 3.02 3.10 (m, 1 CH2N); 3.26 (s, 2 CH2S). 13C-NMR (CDCl3): 27.36 (t); 33.83 (t); 41.13 (t);
45.97 (q); 46.85 (t); 52.06 (t); 52.27 (t); 75.98 (s); 135.13 (s); 137.15 (s). Anal. calc. for C11H17NS2: C 58.10, H 7.54,
N 6.16; found: C 57.96, H 7.48, N 5.98.
1,2,3,4,5,6-Hexahydro-2-methyl-7H-cyclopenta[c]pyridin-7-one (2). As described for 1, from 25 (0.14 g) and
Tl(NO3)3 ¥ 3 H2O (0.9 g): 2 (67%). 1H-NMR (CDCl3): 2.36 2.66 (m, 8 H); 2.43 (s, MeN); 3.02 3.10
(m, 1 CH2N).
On standing, tarry materials were formed from 2. Thus, 2 was immediately transformed into the oxalate salt
by reaction with 1 equiv. of oxalic acid in AcOEt. The oxalate salt of 2 was, however, too hygroscopic to
determine the m.p. IR: 1700 (CO), 1660 (CˆC). 1H-NMR (D2O): 2.38 2.46 (m, 2 H); 2.52 2.64 (m, 2 H);
2.68 2.84 (m, 2 H); 2.86 (s, MeN); 3.12 3.36 (m, 1 H, CH2N); 3.46 3.68 (m, 2 H, CH2N); 3.94 (d, J ˆ 15.75,
1 H, CH2N). 13C-NMR (D2O): 25.12 (t); 29.55 (t); 34.96 (t); 41.95 (q); 48.76 (t); 50.18 (t); 130.48 (s); 167.79 (s);
‡
174.37 (s); 210.00 (s). MS: 151 (100, M ), 150 (75), 123 (28), 122 (41), 108 (36), 94 (21), 79 (44). HR-MS:
151.09999 (calc. 151.09971).
2,3,4,5,6,7-Hexahydro-7-oxo-1H-2,2-dimethylcyclopenta[c]pyridinium Iodide (26). As described for 14,
from 2 (0.04 g): 0.03 g of 26. M.p. 209 2158 (dec.). 1H-NMR (D2O): 2.41 2.47 (m, 2 H); 2.57 2.67 (m, 2 H);
2.74 2.88 (m, 2 H); 3.02 (s, 2 MeN); 3.44 3.54 (m, 1 CH2N); 3.94 (s, 1 CH2N). 13C-NMR (D2O): 24.30 (t);
29.42 (t); 35.12 (t); 51.58 (q); 51.65 (q); 57.97 (t); 58.96 (t); 129.92 (s); 172.96 (s); 209.95 (s). Anal. calc. for
C10H16INO: C 40.97, H 5.50, N 4.78; found: C 40.81, H 5.42, N 4.63.
Pharmacology. The new compounds were tested according to the already published protocol [9].
Molecular Modeling. Calculations were performed with the program PC Spartan Pro (version 1.01),
Wavefunction, Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA 92612. The methods used were AM1
(semiempirical) and HF/6-31G* (ab initio). Compounds 1, 2, arecolone, and isoarecolone were calculated as the
protonated form, since this is the form believed to interact with the receptor; the Me group was always
equatorial and the H-atom axial. Superimpositions were performed by means of the program InsightII (MSI),
with the O-atom, the N-atom, and axial NÀH (or NMe group) as fitting points.
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Received June 5, 2001