Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

Article abstract of DOI:10.1016/S0040-4020(03)00513-1

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.

Full text of DOI:10.1016/S0040-4020(03)00513-1

Tetrahedron 59 (2003) 3665–3672
Synthesis of new compounds containing the
2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system
as a substructure
M. Soukri,a,b S. Lazar,b M. D. Pujol,c M. Akssira,b J. M. Leger,d C. Jarryd and G. Guillaumeta
,
*
a
´
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite d’Orleans, BP 6759, 45067 Orleans Cedex 2, France
Laboratoire de Chimie Bioorganique et Analytique, Universite Hassan II-Mohammedia, BP 146, 20650 Mohammedia, Maroc
´
´
b
´
´
´
c
´
`
`
Laboratori de Quımica Farmaceutica, Universitat de Barcelona, Facultat de Farmacia, 08028 Barcelona, Spain
´
Pharmacochimie, EA 2962, Universite Victor Segalen Bordeaux II, 33076 Bordeaux Cedex, France
d
Received 26 November 2002; revised 25 February 2003; accepted 10 March 2003
Abstract—2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,30-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,40-
piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,30 (8B) and 2,40 (9B) isomers were obtained via
the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under
the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine
derivatives were described. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
the dioxinopyridines,11 we report here the preparation and
the pharmacological activity of spiro dioxino–pyridine–
pyrrolidine and spiro dioxino–pyridine–piperidine deriva-
tives functionalized at the oxygenated moiety in position 3
(A) or position 2 (B) (Fig. 1). These new ring systems could
be regarded as analogues of spiro(benzofurane)12 and
spiro(benzoindole) ones.13
Serotonin (5-HT) is an important neurotransmitter that
mediates a wide variety of physiological responses in both
peripheral and central nervous systems. The receptors
activated by 5-HT have been divided into at least seven
classes (5-HT1–5-HT7) and each class has been further
divided into different subtypes.1 Among them, the 5-HT1A
receptor is one of the best studied; it is generally accepted
that it is implicated in numerous physiological and
pathological processes including the regulation of
cognition, psychosis, anxiety, feeding satiety, temperature
regulation, depression sleep, pain perception and sexual
activity.2
Figure 1.
Many structurally different compounds showed high affinity
and selectivity for 5-HT1A receptors.3 Nevertheless, it was
noticed that the 2,3-dihydro-1,4-benzodioxin moiety is
found in several compounds exhibiting high affinity for
5-HT1A receptors, such as MDL72832,4 Spiroxatrine,5
Flesinoxan,6 HT-907 and MKC-242.8
2. Results and discussion
Our initial attempts at the synthesis of spiro dioxino–
pyridine–pyrrolidines 6 and spiro dioxino–pyridine–piper-
idines 7 were directed to the formation of the dioxino–
pyridine system.
In connection with the development of new potential
5-HT1A ligands, we have described the synthesis and the
pharmacological activity of aza-analogues of MDL72832.9,10
Now, in continuation of our research program concerning
Accordingly, the 2-chloro-3-hydroxypyridine 1 was treated
with NaH/DMF, forming in situ the corresponding alkoxide,
which reacted with the appropriate epoxide 2 or 3 obtained
by the known procedure14 to afford the corresponding
tertiary alcohol 4 or 5. Then, 4 or 5 was cyclised to the spiro
compound 6 or 7 using a basic treatment, which induced a
Keywords: 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridines; 5-HT1A
serotonin receptors; Smiles rearrangement.
*
Corresponding author. Fax: þ33-238417078;
e-mail: gerald.guillaumet@univ-orleans.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00513-1

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M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
Scheme 1. Reaction conditions: (a) NaH, DMF, 1208C; (b) base, solvent, T (8C), t (h) (see Table 1). pThe desired alcohol 4 was obtained in 25% yield along
with a small amount of cyclic isomers 6 (10%) and the starting material 2 which was recovered in 25% yield.
The formation of the B isomer (Scheme 2) can be explained
by an intramolecular nucleophilic substitution at the 3
position of the pyridine ring with displacement of the
alkoxide, and the subsequent closure of the delivered
alkoxide into the 2 position of the pyridine ring.15 This
reaction known as the Smiles rearrangement16 is usually
carried out on deactivated compounds such as pyridinyl or
nitrophenyl derivatives.
Table 1. Conditions for the cyclization of the compounds 4 and 5
Base/solvent
T/t
(8C)/h
Compound 6a
Compound 7b
Yieldc Ratiod
Yieldc
(%)
Ratiod
(A/B)
(%)
(A/B)
NaH/DME
NaH/THF
NaH/THF–HMPT
NaH/DMF
t-BuOK/t-BuOH
80/te
55/tf
55/24
80/24
80/24
60
62
58
60
63
90/10
95/5
20/80
5/95
20/80
51
53
57
44
39
45/55
65/35
0/100
0/100
0/100
The 1H NMR spectrum of a (7A17B) isomers mixture
presents two singlets at 3.89 and 4.09 ppm (O–CH2–C).
Ratio of each isomer was determined from 1H NMR
comparison of integration intensity of these two singlets
(Table 1).
a
From the alcohol 4.
From the alcohol 5.
b
c
Yields of mixture 6A16B (or 7A17B) isolated after filtration on silica
gel column chromatography.
d
Ratio of each isomer determined from 1H NMR comparison of absorption
areas of the CH2-dioxinopyridine ring.
24 h for 4 and 8 h for 5.
The availability of both isomers 6 and 7 was ensured by the
formation of their sulfamide derivatives 10 and 11 suitable
for column chromatography separation on silica gel. Thus,
each mixture of (6A16B) or (7A17B), resulting from the
cyclization by NaH/DME, was transformed into the
corresponding amines 8 or 9 by catalytic 10% Pd/C
hydrogenolysis in MeOH with a few drops of concentrated
hydrochloric acid, in 91 and 90% yield, respectively. It’s
worth to note that both isomeric mixtures (8Aþ8B) and
(9Aþ9B) cannot be separated by column chromatography.
Thereafter, treatment of both isomeric mixtures with
p-bromobenzenesulfonyl chloride in the presence of Et3N
in DMF at 608C gave the corresponding sulfamides 10 or 11
in a 70% total yield (Scheme 3). Finally, the 10A and 10B
isomers (or 11A and 11B) were easily separated by column
chromatography.
e
f
24 h for 4 and 10 h for 5.
nucleophilic displacement of chlorine atom (Scheme 1).
Different experimental conditions selected for the cycliza-
tion of compounds 4 were studied. They always led to a
mixture of A and B isomers, proved to be non-separable by
silica gel column chromatography (Table 1).
Similarly, a mixture of 7A and 7B isomers was obtained
when 5 was treated with NaH/DME or NaH/THF.
Conversely, only the isomer 7B was isolated under other
conditions (NaH/THF–HMPT, NaH/DMF, t-BuOK/
t-BuOH). The best yields were obtained with a THF–
HMPT mixture as solvent. The experimental data used in
the conversion of 5 into the spiro dioxino–pyridine
piperidines 7 are shown in Table 1.
In order to assign the structures, we performed 2D NMR
Scheme 2.

M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
3667
Scheme 3. Reaction conditions: (a) H2, 10% Pd/C, HCl, MeOH; (b) (i) p-BrC6H4SO2Cl, Et3N, DMF, 608C, (ii) flash chromatography; (c) LiAlH4, DME,
reflux.
experiments (HMQC and HMBC) for compounds 10A,
10B, 11A and 11B. Moreover, the structure of 10B and 11B
was established by X-ray diffraction, clearly identifying the
substitution position on the dioxine ring (Figs. 2 and 3).
Both compounds are racemic mixtures as indicated by the
spatial groups. In the solid state, the conformation of 10B is
folded, with an angle between the pyridine plan and the
phenyl one¼39.3(2)8. Moreover, a chelate is formed with a
bond between C(4)H(4) and O(9): C(4)H(4)–
˚
˚
O(9)¼2.88(5)A and H(4)–O(9)¼2.51 A, the angle C(4)
H(4) O(9) is 104.68. Consequently, the orientation of the
phenyl ring is blocked with respect to the sulfur atom.
The same phenomenum is found for 11B. A chelate is
defined by two intramolecular bonds: C(12)H(12)–
˚
˚
O(9)¼2.922(7) A and H(12)–O(9)¼2.48 A; C(16)H(16)–
˚
˚
O(10)¼2.881(7) A and H(16)–O(10)¼2.42 A, leading to a
blocked conformation of the molecule. There are four
independent molecules in the cell unit, all in a folded form
with angles between the phenyl ring and the pyridine
varying from 65.9(2)8, 66.9(2)8, 67.7(2)8 to 74.6(2)8.
Such results enlightening the folded molecular could be
discussed in terms of preliminary structure–activity
Figure 2. The ORTEP drawing of 10B with thermal ellipsoids at 30% level.
Figure 3. The ORTEP drawing of 11B with thermal ellipsoids at 30% level.

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M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
Scheme 4. Reaction conditions: (a) NaH, DMF, 1208C, 36 h; (b) H2, 10% Pd/C, HCl, MeOH.
relationships. Hence, as previously described for hypo-
thetical HT1A receptor,17 the pocket available for binding
3. Conclusion
seems to give restricted spatial access to the ligand since
only pseudo-linear compounds are well-tolerated. More-
over, this hypothesis is confirmed by recently published
results exploring the computational three dimensional
structure of the receptor, constructed from the crystal
structure of bovine rhodopsin.18,19 Consequently, the folded
conformation of 10B and 11B could be found detrimental
for a 5-HT1A activity.
This study reports a convenient and effective synthetic route
to isomeric 2- and 3-substituted-2,3-dihydro-spiro[1,4]di-
oxino[2,3-b]pyridine amino derivatives 12A, 12B and 13A,
13B, developed as potential 5-HT1A ligands. The ratio of
both A and B isomers of spiro compound 6 or 7 was shown
to be greatly affected by the experimental conditions chosen
for the cyclization of the intermediates 4 and 5. It was
observed that the conversion of the A and B isomers of
amine 8 or 9 into the corresponding sulfamides (10 or 11)
constitutes an interesting way for the subsequent chromato-
graphic separation of each isomer.
The removal of the sulfamide function of each isomer 10A,
10B and 11A, 11B was achieved under soft conditions
described by Tuladhar et coll.,20 using LiAlH4 in DME
under reflux overnight. This sequence afforded the amines
8A, 8B and 9A, 9B in 79, 80, 75 and 77% yields,
respectively (Scheme 3).
The structures of 10B and 11B were established by X-ray
crystallography. Data were discussed in terms of a
preliminary understanding of structure–activity relation-
ships concerning their affinity for the 5-HT1A serotonin
receptor.
As depicted in Scheme 4, a new way towards the synthesis
of compound 9B was explored, starting from 2-nitro-3-
pyridinol (14). Compound 7B was prepared in 65% yield,
via a Smiles rearrangement, by condensation of the anion of
14 on the epoxide 3, using NaH in DMF at 1208C. Then, 9B
was obtained in a good yield (90%) through catalytic Pd/C
hydrogenolysis of 7B.
4. Experimental
1H and 13C NMR spectra were, respectively, recorded at 250
and 62.9 MHz on a Bruker Avance DPX250. Chemical
shifts (d values) were reported in ppm and coupling
constants (J values) in Hz. Me4Si was the internal standard.
IR spectra were obtained with a Perkin–Elmer FT Paragon
1000PC. Elemental analyses were performed by CNRS
On the other hand, the various attempts for the condensation
of 2-nitro-3-pyridinol (14) on the epoxide 2 achieved under
several conditions failed. In all cases, the starting material 2
was recovered or degradation products were detected.
´
laboratory (Vernaison, France) and Serveis Cientıfico-
Tecnics de la Universitat de Barcelona (Spain). MS data
`
Finally, we prepared 12A, 12B, 13A and 13B in acceptable
yields by alkylation of the corresponding 8A, 8B, 9A and 9B
with 8-(4-bromobutyl)-8-azaspiro[4,5]decane-7,9-dione21
in DMF, in the presence of Et3N at 608C (Scheme 5).
were taken on a Perkin–Elmer SCIEX type API 300.
Melting points were determined in capillary tubes with
¨
Bu¨chi SMP-20 or on a Kofler apparatus and are uncorrected.
TLC and flash chromatography separations were respect-
ively performed on silica gel (Merck 60 F254) plates and on
silica gel (Merck 60, 230–400 mesh) columns. All reactions
involving moisture-sensitive reagents were performed under
an argon atmosphere. 8-(4-Bromobutyl)-8-azaspiro[4,5]de-
cane-7,9-dione was prepared by condensation of the anion
of tetramethyleneglutarimide with 1,4-dibromobutane using
K2CO3 in CH3CN at 608C for 24 h according to the method
described in the literature.21 All organic solvents were
distilled immediately prior to use, and magnesium sulfate
was used for drying solutions of organic solvents.
Compounds 10A, 11A, 12A and 13A and their correspond-
ing B isomers were tested as potential SNC agents.
However, none of them showed any noticeable affinity for
the 5-HT1A serotonin receptors.
The solid state of 10B and 11B compounds have been
determined by single-crystal X-ray diffraction techniques.
The data were collected on a CAD4 Enraf-Nonius
diffractometer with graphite monochromatized Cu Ka
radiation. The cell parameters were determined by least-
squares from the setting angles for 25 reflexions.
The positions of non-H atoms were determined by the
program SHELXS 8622 and the position of the H atoms were
deduced from coordinates of the non-H atoms and
Scheme 5. Reaction conditions: (a) 8-(4-Bromobutyl)-8-azaspiro[4,5]-
decane-7,9-dione, DMF, Et3N, KI, 608C.

M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
3669
confirmed by Fourier synthesis. H atoms were included for
structure factor calculations but not refined. Full crystal-
lographic results have been deposited at the Cambridge
Crystallographic Data Centre (CCDC), UK as Supplemen-
tary Materials.23
4.2.1. 2,3-Dihydro-10-benzylspiro(1,4-dioxino[2,3-b]pyri-
dine)-3,30-pyrrolidine and 2,3-dihydro-10-benzyl-
spiro(1,4-dioxino[2,3-b]pyridine)-2,30-pyrrolidine
6Aþ6B. Oil; IR (film) n 1270 and 1185 (C–O–C) cm21
;
1H NMR (CDCl3) d 1.92–2.18 (m, 2H, CH2–CH2–N),
2.60–2.99 (m, 4H, C–CH2–N, CH2–CH2–N), 3.63 (d, 1H,
J¼13.0 Hz, N–CH2–Ph), 3.78 (d, 1H, J¼13.0 Hz, N–
CH2–Ph), 3.92 (d, 1H, J¼11.3 Hz, O–CH2–C for 6A), 4.06
(d, 1H, J¼11.3 Hz, O–CH2–C for 6B), 4.16 (d, 1H,
J¼11.3 Hz, O–CH2–C for 6A), 4.30 (d, 1H, J¼11.3 Hz,
O–CH2–C for 6B), 6.84 (dd, 1H, J¼4.9, 7.8 Hz, Hb), 7.17
(dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.20–7.40 (m, 5H, Harom), 7.82
(dd, 1H, J¼1.6, 4.9 Hz, Ha); 13C NMR (CDCl3) d 29.9
(CH2), 49.1 (CH2), 59.4 (CH2), 61.8 (CH2), 63.5 (CH2), 74.1
(C), 116.6 (CH), 121.5 (CH), 127.1 (CH), 128.5 (CH), 129.6
(CH),138.7 (C), 140.8 (C), 146.3 (CH), 157.3 (C); MS (CI)
m/z 283 (Mþ1).
4.1. General procedure for the preparation of the
alcohols 4 and 5
To a suspension of NaH (335 mg of 60% oil dispersion,
14.78 mmol) in DMF (10 mL) was added dropwise a
solution of 2-chloro-3-hydroxypyridine (1.24 g, 9.6 mmol)
in DMF (10 mL). After 15 min, a solution of epoxide 2 or 3
(9.5 mmol) in DMF (10 mL) was added and the mixture was
stirred at 1208C during 30 min and 36 h for 2 and 3,
respectively. After cooling to room temperature, the DMF
was evaporated to dryness. The residue was washed with
H2O and extracted with AcOEt. The organic layer was dried
over MgSO4, evaporated and chromatographed (eluent:
MeOH/CH2Cl2, 1:9) to give the alcohol 4 (25%) or 5 (77%).
4.2.2. 2,3-Dihydro-10-benzylspiro(1,4-dioxino[2,3-b]pyri-
dine)-3,40-piperidine and 2,3-dihydro-10-benzylspiro(1,4-
dioxino[2,3-b]pyridine)-2,40-piperidine 7Aþ7B. Oil; IR
(film) n 1270 and 1190 (C–O–C) cm21; 1H NMR (CDCl3)
d 1.65–1.92 (m, 4H, CH2–CH2–N), 2.51–2.71 (m, 4H,
CH2–CH2–N), 3.55 (s, 2H, N–CH2–Ph), 3.89 (s, 2H, O–
CH2–C for 7A), 4.09 (s, 2H, O–CH2–C for 7B), 6.82 (dd,
1H, J¼4.9, 7.8 Hz, Hb), 7.15 (dd, 1H, J¼1.6, 7.8 Hz, Hg),
7.21–7.33 (m, 5H, Harom), 7.82 (dd, 1H, J¼1.6, 4.9 Hz, Ha);
13C NMR (CDCl3) d 31.8 (CH2), 48.3 (CH2), 63.1 (CH2),
71.1 (CH2), 73.4 (C), 118.1 (CH), 124.5 (CH), 127.4 (CH),
127.5 (CH), 129.3 (CH), 138.4 (C), 138.5 (C), 140.5 (CH),
150.3 (C); MS (CI) m/z 297 (Mþ1).
4.1.1. 2-Chloro-3-(N-benzyl-30-pyrrolidinol-30-methoxy)-
pyridine 4. Oil; IR (film) n 3500–3180 (OH), 1286 (C–O–
C) cm21
;
1H NMR (CDCl3) d 1.85–2.00 (m, 1H,
CH2–CH2–N), 2.02–2.15 (m, 1H, CH2–CH2–N), 2.50–
2.62 (m, 1H, C–CH2–N), 2.64–2.88 (m, 3H, CH2–CH2–
N, C–CH2–N), 3.60 (s, 2H, N–CH2–Ph), 3.97 (s, 2H,
O–CH2–C), 4.01 (s, 1H, OH), 7.07–7.40 (m, 7H, Hb, Hg,
Harom), 7.93 (dd, 1H, J¼1.7, 4.4 Hz, Ha); 13C NMR (CDCl3)
d 36.9 (CH2), 53.2 (CH2), 60.4 (CH2), 64.3 (CH2), 75.1
(CH2), 79.3 (C), 121.3 (CH), 123.6 (CH), 127.5 (CH), 128.7
(2CH), 129.3 (2CH), 138.7 (CH), 141.5 (CH), 141.6 (C),
151.3 (C); MS (CI) m/z 319 (Mþ1); Anal. calcd for
C17H19N2O2Cl: C 64.05, H 6.01, N 8.79, found: C 64.01, H
5.97, N 8.75.
4.3. General procedure for the preparation of the
sulfamides 10 and 11
A solution of dioxinopyridines 6 or 7 (0.68 mmol) in MeOH
(25 mL) with a few drops of HCl was shaken with Pd/C
(10%, 20 mg) under hydrogen atmosphere. When the
reaction was complete, the catalyst was removed by
filtration and the combined filtrate was concentrated in
vacuo to give 8 or 9 in 91% yield. Spectral data will be given
further for each isolated isomer A and B after their
separation.
4.1.2. 2-Chloro-3-(N-benzyl-40-piperidinol-40-methoxy)-
pyridine 5. Oil; IR (film) n 3500–3200 (OH), 1285 (C–
O–C) cm21 1H NMR (CDCl3) d 1.75–1.95 (m, 4H,
;
2£CH2–CH2–N), 2.43–2.63 (m, 3H, CH2–CH2–N, OH),
2.68–2.85 (m, 2H, C–CH2–N), 3.63 (s, 2H, N–CH2–Ph),
3.94 (s, 2H, O–CH2–C), 7.20–7.75 (m, 7H, Hb, Hg, Harom),
8.06 (dd, 1H, J¼2.6, 3.6 Hz, Ha); 13C NMR (CDCl3) d 33.8
(2CH2), 48.7 (2CH2), 63.0 (CH2), 68.9 (CH2), 76.9 (C),
120.6 (CH), 123.1 (CH), 126.9 (CH), 128.1 (2CH), 129.1
(2CH), 138.3 (C), 140.9 (CH), 141.1 (C), 150.8 (C); MS
(CI) m/z 333 (Mþ1); Anal. calcd for C18H21N2O2Cl: C
64.95, H 6.36, N 8.42, found: C 64.87, H 6.41, N 8.51.
To a solution of amines 8 or 9 (10 mmol) in DMF (15 mL)
were added p-bromobenzenesulfonyl chloride (3829 mg,
15 mmol) in DMF (5 mL) and Et3N (4.2 mL, 30 mmol). The
mixture was heated at 608C until total consumption of
amine. The solvent was removed under reduced pressure
and the separation of the mixture of the two isomers 10A
and 10B (or 11A and 11B) was carried out by flash column
chromatography (eluent: AcOEt/petroleum, 3:7). The yields
of each isomer 10A, 10B, 11A and 11B were 60, 7, 30 and
38%, respectively.
4.2. General procedure for the preparation of
dioxinopyridines 6 and 7
To a solution of appropriate base (NaH or t-BuOK, 3 mmol)
in solvent (DME, THF, THF–HMPT 85:15, DMF or
t-BuOH, 5 mL) was added 3 or 4 (1.5 mmol). The resulting
mixture was heated (55–808C) for 8–14 h. After cooling to
room temperature, The reaction was hydrolysed with H2O
and extraced with AcOEt. The organic layer was dried
(MgSO4) and concentrated in vacuo to give a residue which
was purified by flash chromatography (eluent: MeOH/
CH2Cl2, 1:9) to afford an inseparable mixture of two
isomers 6A and 6B (58–68%) or 7A and 7B (39–57%) (see
Table 1).
4.3.1. 2,3-Dihydro-10-p-bromobenzenesulfonylspiro(1,4-
dioxino[2,3-b]pyridine)-3,30-pyrrolidine 10A. Mp 224–
1
2258C; IR (KBr) n 1432 (SO2), 1280 (C–O–C) cm21; H
NMR (CDCl3) d 2.06–2.13 (m, 2H, CH2–CH2–N), 3.25 (d,
1H, J¼11.2 Hz, C–CH2–N), 3.40 (td, 1H, J¼7.4, 19.1 Hz,
CH2–CH2–N), 3.57–3.70 (m, 2H, CH2–CH2–N, C–
CH2–N), 3.93 (d, 1H, J¼11.3 Hz, O–CH2–C), 4.15 (d,
1H, J¼11.3 Hz, O–CH2–C), 6.90 (dd, 1H, J¼4.7, 7.8 Hz,

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M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
Hb), 7.21 (dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.60–7.75 (m, 4H,
Harom), 7.83 (dd, 1H, J¼1.6, 4.7 Hz, Ha); 13C NMR (CDCl3)
d 33.5 (CH2), 4.68 (CH2), 55.1 (CH2), 68.7 (CH2), 80.9 (C),
119.1 (CH), 125.7 (CH), 128.2 (C), 129.3 (CH), 132.6 (CH),
135.3 (C), 136.8 (C), 140.7 (CH), 150.0 (C); MS (CI) m/z
411 (Mþ1 for 79Br), 413 (Mþ1 for 81Br); Anal. calcd for
C16H15BrN2O4S: C 46.72, H 3.67, N 6.81, found: C 46.88,
H 3.62, N 6.98.
temperature, the reaction mixture was diluted in H2O and
extracted with AcOEt. The organic layer was dried and
concentrated to give a residue, which was purified by flash
column chromatography (eluent: MeOH/CH2Cl2, 1:9) to
afford amines 8A, 8B, 9A and 9B in 79, 80, 75 and 77%
yield, respectively.
4.4.1. 2,3-Dihydrospiro(1,4-dioxino[2,3-b]pyridine)-3,30-
pyrrolidine 8A. Oil; IR (film) n 3600–3200 (NH), 1288
4.3.2. 2,3-Dihydro-10-p-bromobenzenesulfonylspiro(1,4-
dioxino[2,3-b]pyridine)-2,30-pyrrolidine 10B. Mp 215–
(C–O–C) cm21; H NMR (CDCl3) d 1.98–2.06 (m, 2H,
1
CH2–CH2–NH), 2.78 (d, 2H, J¼11.2 Hz, C–CH2–NH),
3.25–3.40 (m, 2H, CH2–CH2–NH), 4.12 (d, 1H,
J¼11.2 Hz, O–CH2–C), 4.33 (d, 1H, J¼11.2 Hz, O–
CH2–C), 6.88 (dd, 1H, J¼4.9, 7.8 Hz, Hb), 7.23 (dd, 1H,
J¼1.7, 7.8 Hz, Hg), 7.84 (dd, 1H, J¼1.7, 4.9 Hz, Ha), 9.07
(bs, 1H, NH); 13C NMR (CDCl3) d 28.3 (CH2), 45.8 (CH2),
57.1 (CH2), 63.9 (CH), 75.4 (C), 116.0 (CH), 121.6 (CH),
139.2 (C), 140.8 (CH), 149.9 (C); MS (CI) m/z 193 (Mþ1);
Anal. calcd for C10H12N2O2: C 62.55, H 6.30, N 14.91,
found: C 62.86, H 6.39, N 15.23.
1
2168C; IR (KBr) n 1435 (SO2), 1285 (C–O–C) cm21; H
NMR (CDCl3) d 1.99–2.20 (m, 2H, CH2–CH2–N), 3.26 (d,
1H, J¼11.0 Hz, C–CH2–N), 3.40 (td, 1H, J¼7.5, 18.8 Hz,
CH2–CH2–N), 3.56–3.72 (m, 2H, CH2–CH2–N, C–
CH2–N), 4.07 (d, 1H, J¼11.2 Hz, O–CH2–C), 4.29 (d,
1H, J¼11.2 Hz, O–CH2–C), 6.79 (dd, 1H, J¼4.7, 7.8 Hz,
Hb), 6.88 (dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.60–7.75 (m, 4H,
Harom), 7.84 (dd, 1H, J¼1.6, 4.7 Hz, Ha); 13C NMR (CDCl3)
d 34.0 (CH2), 46.7 (CH2), 55.3 (CH2), 68.2 (CH2), 82.0 (C),
119.1 (CH), 125.1 (CH), 128.5 (C), 129.1 (CH), 132.7 (CH),
135.0 (C), 138.1 (C), 140.9 (CH), 149.3 (C); MS (CI) m/z
411 (Mþ1 for 79Br), 413 (Mþ1 for 81Br); Anal. calcd for
C16H15BrN2O4S: C 46.72, H 3.67, N 6.81, found: C 46.50,
H 3.59, N 6.74.
4.4.2. 2,3-Dihydrospiro(1,4-dioxino[2,3-b]pyridine)-2,30-
pyrrolidine 8B. Oil; IR (film) n 3600–3200 (NH), 1290
(C–O–C) cm21; 1H NMR (CDCl3) d 2.04 (t, 2H, J¼6.9 Hz,
CH2–CH2–NH), 2.57–2.66 (m, 1H, CH2–CH2–NH), 2.71
(s, 2H, C–CH2–NH), 2.80–2.91 (m, 1H, CH2–CH2–NH),
4.14 (d, 1H, J¼11.5 Hz, O–CH2–C), 4.36 (d, 1H,
J¼11.5 Hz, O–CH2–C), 6.87 (dd, 1H, J¼4.9, 7.8 Hz,
Hb), 7.20 (dd, 1H, J¼1.7, 7.8 Hz, Hg), 7.82 (dd, 1H, J¼1.7,
4.9 Hz, Ha), 9.03 (bs, 1H, NH); 13C NMR (CDCl3) d 28.4
(CH2), 45.8 (CH2), 57.1 (CH2), 63.9 (CH), 75.3 (C), 116.0
(CH), 121.7 (CH), 139.1 (C), 140.8 (CH), 150.0 (C); MS
(CI) m/z 193 (Mþ1); Anal. calcd for C10H12N2O2: C 62.55,
H 6.30, N 14.91, found: C 62.71, H 6.41, N 15.17.
4.3.3. 2,3-Dihydro-10-p-bromobenzenesulfonylspiro(1,4-
dioxino[2,3-b]pyridine)-3,40-piperidine 11A. Mp 210–
1
2118C; IR (KBr) n 1430 (SO2), 1290 (C–O–C) cm21; H
NMR (CDCl3) d 1.74–2.00 (m, 4H, CH2–CH2–N), 2.86
(td, 2H, J¼2.9, 12.0 Hz, CH2–CH2–N), 3.66–3.80 (m, 2H,
CH2–CH2–N), 3.90 (s, 2H, O–CH2–C), 6.86 (dd, 1H,
J¼4.9, 7.8 Hz, Hb), 7.19 (dd, 1H, J¼1.7, 7.8 Hz, Hg), 7.62
(dd, 2H, J¼2.2, 6.6 Hz, Harom), 7.68 (dd, 2H, J¼2.2, 6.6 Hz,
Harom), 7.80 (dd, 1H, J¼1.7, 4.9 Hz, Ha); 13C NMR (CDCl3)
d 29.1 (CH2), 42.1 (CH2), 68.3 (CH2), 82.0 (C), 117.6 (CH),
124.1 (CH), 127.5 (C), 129.0 (CH), 132.4 (CH), 135.7 (C),
137.0 (C), 140.0 (CH), 150.6 (C); MS (CI) m/z 425 (Mþ1 for
79Br), 427 (Mþ1 for 81Br); Anal. calcd for C17H17BrN2O4S: C
47.98, H 4.08, N 6.59, found: C 47.81, H 4.02, N 6.41.
4.4.3. 2,3-Dihydrospiro(1,4-dioxino[2,3-b]pyridine)-3,40-
piperidine 9A. Oil; IR (film) n 3600–3200 (NH), 1277
1
(C–O–C) cm21; H NMR (CDCl3) d 1.80–2.10 (m, 4H,
CH2–CH2–NH), 2.78–3.29 (m, 4H, CH2–CH2–NH), 4.07
(s, 2H, O–CH2–C), 6.68 (dd, 1H, J¼4.5, 7.8 Hz, Hb), 6.96
(dd, 1H, J¼1.5, 7.8 Hz, Hg), 7.74 (dd, 1H, J¼1.5, 4.5 Hz,
Ha), 9.10 (bs, 1H, NH); 13C NMR (CDCl3) d 28.1 (CH2),
39.9 (CH2), 69.5 (C), 70.9 (CH), 118.0 (CH), 124.6 (CH),
135.9 (C), 139.0 (CH), 150.0 (C); MS (CI) m/z 207 (Mþ1);
Anal. calcd for C11H14N2O2: C 64.13, H 6.85, N 13.60,
found: C 64.28, H 7.02, N 13.68.
4.3.4. 2,3-Dihydro-10-p-bromobenzenesulfonylspiro(1,4-
dioxino[2,3-b]pyridine)-2,40-piperidine 11B. Mp 203–
1
2048C; IR (KBr) n 1427 (SO2), 1291 (C–O–C) cm21; H
NMR (CDCl3) d 1.67–1.95 (m, 4H, CH2–CH2–N), 2.76
(td, 2H, J¼3.4, 11.7 Hz, CH2–CH2–N), 3.58–3.72 (m, 2H,
CH2–CH2–N), 4.06 (s, 2H, O–CH2–C), 6.84 (dd, 1H,
J¼4.9, 7.9 Hz, Hb), 7.09 (dd, 1H, J¼1.5, 7.9 Hz, Hg), 7.64
(dd, 2H, J¼2.1, 6.6 Hz, Harom), 7.71 (dd, 2H, J¼2.1, 6.6 Hz,
Harom), 7.81 (dd, 1H, J¼1.5, 4.9 Hz, Ha); 13C NMR (CDCl3)
d 30.7 (CH2), 41.2 (CH2), 70.5 (CH2), 71.3 (C), 118.8 (CH),
125.1 (CH), 127.9 (C), 129.0 (CH), 132.4 (CH), 135.5 (C),
136.8 (C), 140.0 (CH), 159.9 (C); MS (CI) m/z 425 (Mþ1 for
79Br), 427 (Mþ1 for 81Br); Anal. calcd for C17H17BrN2O4S: C
47.98, H 4.08, N 6.59, found: C 47.90, H 3.98, N 6.54.
4.4.4. 2,3-Dihydrospiro(1,4-dioxino[2,3-b]pyridine)-2,40-
piperidine 9B. Oil; IR (film) n 3600–3200 (NH), 1287
1
(C–O–C) cm21; H NMR (CDCl3) d 1.76–2.05 (m, 4H,
CH2–CH2–NH), 2.92–3.30 (m, 4H, CH2–CH2–NH), 4.24
(s, 2H, O–CH2–C), 6.98 (dd, 1H, J¼4.7, 7.8 Hz, Hb), 7.36
(dd, 1H, J¼1.5, 7.8 Hz, Hg), 7.76 (dd, 1H, J¼1.5, 4.7 Hz,
Ha), 9.03 (bs, 1H, NH); 13C NMR (CDCl3) d 27.1 (CH2),
38.3 (CH2), 69.5 (C), 69.9 (CH), 118.7 (CH), 125.0 (CH),
136.5 (C), 139.1 (CH), 149.5 (C); MS (CI) m/z 207 (Mþ1);
Anal. calcd for C11H14N2O2: C 64.13, H 6.85, N 13.60,
found: C 64.35, H 6.80, N 13.34.
4.4. General procedure for the preparation of the amines
8 and 9
To stirred solution of sulfamides 10A, 10B, 11A or 11B
(1.21 mmol) in DME (10 mL) was added dropwise LiAlH4
(1140 mg, 3.63 mmol) in DME (5 mL). The mixture was
heated to reflux during overnight. After cooling to room
4.5. Preparation of the amine 9B from 2-nitro-3-
hydroxypyridine 14
To a suspension of NaH (335 mg of 60% oil dispersion,

M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
3671
14.78 mmol) in DMF (10 mL) was added dropwise a
solution 2-nitro-3-hydroxypyridine (14) (1.34 g, 9.6 mmol)
in DMF (10 mL). After 15 min, a solution of epoxide 3
(1.5 g, 9.5 mmol) in DMF (10 mL) was added and the
mixture was stirred at 1208C during 36 h. After cooling to
room temperature, the DMF was evaporated to dryness.
The residue was washed with H2O and extracted with
AcOEt. The organic layer was dried over MgSO4,
evaporated and purified by column chromatography
(eluent: MeOH/CH2Cl2, 1:9) to give the 7B (65%) as oil.
Then, catalytic Pd/C hydrogenolysis of compound 7B
according to the procedure described for the preparation
of 8 or 9 gave debenzylated product 9B in good yield (90%).
The analytical data were identical with those reported
above.
(Mþ1); Anal. calcd for C23H31N3O4: C 66.81, H 7.56, N
10.16, found: C 66.51, H 7.45, N 10.21.
4.6.3. 2,3-Dihydro-10-[4-(8-azaspiro[4,5]decane-7,9-
dione)butyl]spiro(1,4-dioxino[2,3-b]pyridine)-3,40-piper-
idine 13A. Oil; IR (film) n 1710 and 1640 (NCO), 1280
1
(C–O–C) cm21; H NMR (CDCl3) d 1.35–1.60 (m, 8H,
H1, H2, H3, H4), 1.61–1.84 (m, CH2–CH2–N, N–CH2–
(CH2)2–CH2–N), 2.30–2.47 (m, 4H, CH2–CH2–N), 2.55
(s, 4H, H6, H10), 2.63–2.70 (m, 2H, N–CH2–(CH2)3–N),
3.71 (t, 2H, J¼6.6 Hz, CH2–N–CO), 4.05 (s, 2H, O–CH2–
C), 6.86 (dd, 1H, J¼4.7, 7.8 Hz, Hb), 7.15 (dd, 1H, J¼1.6,
7.8 Hz, Hg), 7.77 (dd, 1H, J¼1.6, 4.7 Hz, Ha); 13C NMR
(CDCl3) d 24.2 (CH2), 25.2 (CH2), 26.1 (CH2), 31.0 (CH2),
37.5 (CH2), 39.3 (C), 39.5 (CH2), 44.9 (CH2), 48.4 (CH2),
58.0 (CH2), 71.4 (CH2), 71.7 (C), 118.7 (CH), 125.0 (CH),
137.4 (CH), 140.0 (C), 150.4 (C), 172.2 (CO); MS (CI) m/z
428 (Mþ1); Anal. calcd for C24H33N3O4: C 67.42, H 7.78,
N 9.83, found: C 67.73, H 7.67, N 10.12.
4.6. General procedure for the preparation of the
N-substituted amines 12 and 13
To a solution of each isolated isomer 8A, 8B, 9A or 9B
(1.2 mmol) and 8-(4-bromobutyl)-8-azaspiro[4,5]decane-
7,9-dione (43 mg, 1.4 mmol) in DMF (12 mL) were added
Et3N (0.5 mL, 6 mmol) and KI (40 mg, 0.20 mmol). The
reaction was stirred at 608C for 24 h and the solvent was
then removed under reduced pressure. Water was added and
then the suspension was extracted with AcOEt to give crude
N-alkylamine. This was purified by flash column chroma-
tography (eluent: CH2Cl2) to afford compounds 12A (66%),
12B (60%), 13A (77%) and 13B (64%).
4.6.4. 2,3-Dihydro-10-[4-(8-azaspiro[4,5]decane-7,9-
dione)butyl]spiro(1,4-dioxino[2,3-b]pyridine)-2,40-piper-
idine 13B. Oil; IR (film) n 1720 and 1660 (NCO), 1267
1
(C–O–C) cm21; H NMR (CDCl3) d 1.38–1.57 (m, 8H,
H1, H2, H3, H4), 1.60–1.84 (m, CH2–CH2–N, N–CH2–
(CH2)2–CH2–N), 2.33–2.48 (m, 4H, CH2–CH2–N), 2.53
(s, 4H, H6, H10), 2.60–2.71 (m, 2H, N–CH2–(CH2)3–N),
3.72 (t, 2H, J¼6.6 Hz, CH2–N–CO), 4.13 (s, 2H, O–CH2–
C), 6.84 (dd, 1H, J¼4.8, 7.8 Hz, Hb), 7.15 (dd, 1H, J¼1.6,
7.8 Hz, Hg), 7.77 (dd, 1H, J¼1.6, 4.8 Hz, Ha); 13C NMR
(CDCl3) d 24.2 (CH2), 25.2 (CH2), 26.0 (CH2), 31.1 (CH2),
37.5 (CH2), 39.2 (C), 39.5 (CH2), 44.9 (CH2), 48.5 (CH2),
58.0 (CH2), 71.5 (CH2), 71.6 (C), 118.7 (CH), 125.1 (CH),
137.5 (CH), 139.5 (C), 150.4 (C), 172.2 (CO); MS (CI) m/z
428 (Mþ1); Anal. calcd for C24H33N3O4: C 67.42, H 7.78,
N 9.83, found: C 67.68, H 7.76, N 10.01.
4.6.1. 2,3-Dihydro-10-[4-(8-azaspiro[4,5]decane-7,9-
dione)butyl]spiro(1,4-dioxino[2,3-b]pyridine)-3,30-
pyrrolidine 12A. Oil; IR (film) n 1715 and 1650 (NCO),
1
1280 (C–O–C) cm21; H NMR (CDCl3) d 1.40–1.77 (m,
12H, H1, H2, H3, H4, N–CH2–(CH2)2–CH2–N), 2.00–2.20
(m, 2H, CH2–CH2–N), 2.58 (s, 4H, H6, H10), 2.65–2.75
(m, 2H, CH2–CH2–N), 3.25–3.71 (m, 6H, C–CH2–N, N–
CH2–(CH2)3–N, CH2–N–CO), 3.95 (d, 1H, J¼11.0 Hz,
O–CH2–C), 4.14 (d, 1H, J¼11.0 Hz, O–CH2–C), 6.86 (dd,
1H, J¼4.8, 7.8 Hz, Hb), 7.25 (dd, 1H, J¼1.5, 7.8 Hz, Hg),
7.87 (dd, 1H, J¼1.5, 4.8 Hz, Ha); 13C NMR (CDCl3) d 24.1
(CH2), 24.6 (CH2), 25.8 (CH2), 27.8 (CH2), 31.2 (CH2), 37.4
(CH2), 39.3 (C), 39.6 (CH2), 44.8 (CH2), 48.4 (CH2), 58.1
(CH2), 71.3 (CH2), 72.2 (C), 118.5 (CH), 124.9 (CH), 138.4
(CH), 139.8 (C), 150.1 (C), 172.2 (CO); MS (CI) m/z 414
(Mþ1); Anal. calcd for C23H31N3O4: C 66.81, H 7.56, N
10.16, found: C 66.48, H 7.50, N 10.10.
Acknowledgements
´
We thank the Serveis Cientıfico-Tecnics de la Universitat de
Barcelona (Spain) for carrying out the elemental analyses.
`
References
1. Martin, G. R. IUPHAR Compendium of Receptors, Charac-
terization and Classification; IUPHAR Media, 1988; p 167.
2. Raymond, J. R.; Mukhin, Y. V.; Gettys, T. W.; Garnovskaya,
M. N.; Br, J. Pharmacol. 1999, 127, 175.
4.6.2. 2,3-Dihydro-10-[4-(8-azaspiro[4,5]decane-7,9-
dione)butyl]spiro(1,4-dioxino[2,3-b]pyridine)-2,30-
pyrrolidine 12B. Oil; IR (film) n 1720 and 1640 (NCO),
1
1275 (C–O–C) cm21; H NMR (CDCl3) d 1.40–1.76 (m,
3. Romero, A. G.; McColl, R. B. Ann. Rep. Med. Chem. 1992,
270, 21.
12H, H1, H2, H3, H4, N–CH2–(CH2)2–CH2–N), 2.00–2.23
(m, 2H, CH2–CH2–N), 2.57 (s, 4H, H6, H10), 2.62–2.75
(m, 2H, CH2–CH2–N), 3.25–3.70 (m, 6H, C–CH2–N, N–
CH2–(CH2)3–N, CH2–N–CO), 4.11 (d, 1H, J¼11.3 Hz,
O–CH2–C), 4.33 (d, 1H, J¼11.3 Hz, O–CH2–C), 6.89 (dd,
1H, J¼4.5, 7.8 Hz, Hb), 7.21 (dd, 1H, J¼1.5, 7.8 Hz, Hg),
7.84 (dd, 1H, J¼1.5, 4.5 Hz, Ha); 13C NMR (CDCl3) d 24.1
(CH2), 24.6 (CH2), 25.9 (CH2), 27.8 (CH2), 31.1 (CH2), 37.3
(CH2), 39.1 (C), 39.2 (CH2), 44.6 (CH2), 48.7 (CH2), 58.3
(CH2), 71.1 (CH2), 72.1 (C), 118.4 (CH), 124.6 (CH), 138.2
(CH), 139.9 (C), 149.9 (C), 172.1 (CO); MS (CI) m/z 414
4. Hibert, M. F.; Gittos, M. W.; Milddlemiss, D. N.; Mir, A. K.;
Fozard, J. R. J. Med. Chem. 1988, 31, 1087.
5. Nikam, S. S.; Martin, A. R.; Nelson, D. L. J. Med. Chem. 1988,
31, 1965.
6. Kuipers, W.; Kouse, C. G.; Van Wijngaarden, I.; Standaar,
P. J.; Tulp, M.; Th, M.; Veldman, N.; Spek, A. L.; Ijzerman,
A. P. J. Med. Chem. 1997, 40, 300.
7. Uchida, M.; Kentaro, I.; Tameda, C.; Miyauchi, T. Prog.
Neuro-Psycopharmacol. Biol. Psychiat. 1995, 19, 1201.
8. Matsuda, T.; Yoshikawa, T.; Suzuki, M.; Asano, S.;

3672
M. Soukri et al. / Tetrahedron 59 (2003) 3665–3672
Somboonthum, P.; Takuma, K.; Nakano, Y.; Morita, T.;
Nakasu, Y.; Kim, H. S.; Egawa, M.; Tobe, A.; Baba, A. Jpn.
J. Pharmacol. 1995, 69, 366.
ment des Pharmacochimistes de l’ARC Atlantique, Tours,
11–12 septembre 2000.
16. (a) Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React.
1970, 18, 99. (b) Proudfoot, J. R.; Patel, U. R.; Kapadia, S. R.;
Hargrave, K. D. J. Med. Chem. 1995, 38, 1406.
17. Hammarberg, E.; Nordvall, G.; Leideborg, R.; Nylof, N.;
Hanson, S.; Johansson, L.; Thorberg, S. O.; Tolf, B. R.;
Svantesson, G. T.; Mohell, N.; Ahlgren, C.; Westlind-
Danielsson, A.; Csoregh, I.; Johansson, R. J. Med. Chem.
2000, 43, 2850.
9. Comoy, C.; Benarab, A.; Monteil, A.; Leinot, M.;
Massingham, R.; Guillaumet, G. Med. Chem. Res. 1996, 6,
392.
10. Comoy, C.; Benarab, A.; Leinot, M.; Monteil, A.; Guillaumet,
G. Il Farmaco 1999, 54, 791.
11. (a) Benarab, A.; Poirot, P.; Guillaumet, G. Heterocycles 1993,
36, 1589. (b) Benarab, A.; Guillaumet, G. Heterocycles 1993,
36, 2327. (c) Joseph, B.; Benarab, A.; Guillaumet, G.
Heterocycles 1994, 38, 1355. (d) Benarab, A.; Comoy, C.;
Guillaumet, G. Heterocycles 1994, 38, 1641. (e) Soukri, M.;
Lazar, S.; Akssira, M.; Guillaumet, G. Org. Lett. 2000, 2,
1557.
18. Lopez-Rodriguez, M. L.; Morcillo, M. J.; Fernandez, E.;
Rosado, M. L.; Pardo, L.; Schaper, K. J. Med. Chem. 2001, 44,
198.
19. Lopez-Rodriguez, M. L.; Vicente, B.; Deuoi, X.; Barrondo, S.;
Olivella, M.; Morcillo, M. J.; Behamu, B.; Ballesteros, J. A.
Mol. Pharmacol. 2002, 62, 15.
12. (a) Klioze, S. S.; Allen, R. C.; Wilker, J. C.; Woodward, D. L.
J. Med. Chem. 1980, 23, 677. (b) Klein, J. T.; Davis, L.;
Effland, R. C. J. Heterocycl. Chem. 1987, 24, 725.
13. (a) Efange, S. M. N.; Kamath, A. P.; Khare, A. B.; Kung, M. P.;
Mach, R. H.; Parsons, S. M. J. Med. Chem. 1997, 40, 3905.
(b) Freund, R.; Mederski, W. K. R. Helv. Chim. Acta 2000, 83,
1247.
20. Tuladhar, S. M.; D’Silva, C. Tetrahedron Lett. 1992, 33, 2203.
21. Podona, T.; Guardiola-Lemaitre, B.; Caignard, D. H.; Adam,
G.; Pfeiffer, B.; Renard, P.; Guillaumet, G. J. Med. Chem.
1994, 37, 1779.
22. Sheldrick, G. M. In Crystallographic Computing 3; Sheldrick,
¨
G. M., Kroger, C., Goddard, R., Eds.; Oxford University Press:
14. Epoxides 2 and 3 were prepared, respectively, from N-benzyl-
3-pyrrolidinone and N-benzyl-4-piperidone according to the
method described by Popp, F. D.; Watts, R. F. J. Heterocycl.
Chem. 1978, 15, 675.
Oxford, 1985; p 175.
23. Supplementary X-ray Crystallographic data: Cambridge
Crystallographic Data Centre, University Chemical Lab;
Lensfield Road Cambridge, CB2 1EW, UK, e-mail: http://
www.deposit@chemcrys.cam.ac.uk.
15. Soukri, M.; Lazar, S.; Leger, J. M.; Jarry, C.; Akssira, M.;
´
` ´
Guillaumet, G. IXemes Conferences Europeennes du Groupe-