Synthesis and SAR studies of 3-substituted 1′-benzylspiro[[2]benzoxepine1,4′-piperidines]

Article abstract of DOI:10.1002/ejoc.200390111

The preparation of the hitherto unknown spiro[[2]benzoxepine-1,4′-piperidine] ring system is described. The synthesis consists of a Wittig reaction of 2-bromobenzaldehyde (4) and (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (5) to yield an α,β-unsaturated acetal. The double bond of 6 was subsequently hydrogenated. The resulting brominated acetal 7 was treated with n-butyllithium and then with 1-benzylpiperidin-4-one (9) to yield the hydroxy acetal 10. Acid-catalyzed cyclization of 10 with p-toluenesulfonic acid or aqueous HCl resulted in the formation of the 1′-benzylspiro[[2]benzoxepine-1,4′-piperidines] 11 and 12, respectively. The substituents in the 3-position of the spiro compounds 11 and 12 were further modified by reaction with trimethylsilyl cyanide or (cyanomethylene)triphenylphosphorane in order to introduce residues with one or two carbon atoms, respectively. The synthesized compounds were evaluated for σ₁- and σ₂-receptor affinity in vitro. The most potent σ₁-ligand was the methoxy derivative 11 (K_i = 2.56 nM), whereas the cyanomethyl derivative 20 turned out to be the most σ₁-selective compound (σ₁/σ₂ selectivity 768). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390111

FULL PAPER
Synthesis and SAR Studies of 3-Substituted 1Ј-Benzylspiro[[2]benzoxepine-
1,4Ј-piperidines][‡]
Christoph A. Maier[a] and Bernhard Wünsch*[a]
Keywords: Medicinal chemistry / Structure-activity relationships / σ-Receptors / Spiro compounds / Heterocycles
The preparation of the hitherto unknown spiro[[2]benzox-
respectively. The substituents in the 3-position of the spiro
epine-1,4Ј-piperidine] ring system is described. The syn-
compounds 11 and 12 were further modified by reaction with
thesis consists of a Wittig reaction of 2-bromobenzaldehyde trimethylsilyl cyanide or (cyanomethylene)triphenylphos-
(4) and (1,3-dioxolan-2-ylmethyl)triphenylphosphonium
bromide (5) to yield an α,β-unsaturated acetal. The double
bond of 6 was subsequently hydrogenated. The resulting
brominated acetal 7 was treated with n-butyllithium and
then with 1-benzylpiperidin-4-one (9) to yield the hydroxy
acetal 10. Acid-catalyzed cyclization of 10 with p-toluene-
sulfonic acid or aqueous HCl resulted in the formation of the
1Ј-benzylspiro[[2]benzoxepine-1,4Ј-piperidines] 11 and 12,
phorane in order to introduce residues with one or two car-
bon atoms, respectively. The synthesized compounds were
evaluated for σ1- and σ2-receptor affinity in vitro. The most
potent σ1-ligand was the methoxy derivative 11 (Ki
=
2.56 n ), whereas the cyanomethyl derivative 20 turned out
M
to be the most σ1-selective compound (σ1/σ2 selectivity 768).
(( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
disclosed high-affinity and selective σ1-receptor ligands. In
particular, compounds with R ϭ OCH3 or CN and n ϭ 1
possess σ1 affinities in the range of 1Ϫ3 n. In order to
further extend the structure affinity studies, our intention
was to synthesize homologous 2-benzoxepines 3. Thereby,
we focused on those compounds bearing residues that were
expected to show high σ1-receptor affinity and selectivity
(e.g., R ϭ OCH3, CN; 1Ј-benzyl).
σ-Receptors were originally defined as subtypes of the
opioid receptors.[1] Later, they were classified as a separate
receptor family consisting of σ1- and σ2-subtypes.[2] The
amino acid sequence of the σ1-receptor protein is structur-
ally unrelated to any known mammalian protein.[3] The
physiological role of σ-receptors and the mechanism of sig-
nal transduction are not yet completely understood,[4] al-
though they seem to be involved in certain pathophysiologi-
cal processes such as psychosis, depression, and uncon-
trolled cell proliferation. Therefore, selective σ-receptor li-
gands might be useful in the treatment of psychosis,
depression, neurodegeneration, and cancer. Some com-
pounds are already in clinical trials for treatment of psy-
chosis (e.g., BMY14802)[5] and depression (e.g., E-5842).[6]
The well-known antipsychotic haloperidol is a highly po-
tent σ-receptor ligand (see Table 1). Among various
classes of compounds with high σ-receptor affinity, some
spiropiperidines are highly potent and selective σ-ligands.[7]
In Parts 1[8] and 2[9] of this series we have already reported
on the synthesis of novel spiro[[2]benzofuran-1,4Ј-piperid-
ines] 1 (n ϭ 1Ϫ2) and spiro[[2]benzopyran-1,4Ј-piperidines]
2 (n ϭ 0Ϫ4) with various residues R in the 3-position of
the spirocycle (Figure 1). Among these compounds, we have
Figure 1. Homologous spirocyclic σ-receptor ligands
In this contribution, we describe the preparation and in
vitro evaluation of a series of novel 3-substituted 1Ј-benzyl-
spiro[[2]benzoxepine-1,4Ј-piperidines] 3.
Results and Discussion
[‡]
Novel σ Receptor Ligands, 3. Part 2: Ref.[9] Part 1: Ref.[8]
Institut für Pharmazeutische und Medizinische Chemie der
Chemistry
[a]
Westfälischen Wilhelms-Universität Münster,
Hittorfstr. 58Ϫ62, 48149 Münster, Germany
Fax: (internat.) ϩ 49-(0)251/833-2144,
E-mail: wuensch@uni-muenster.de
First, we assumed that a WittigϪHornerϪEmmons
reaction of 2-bromobenzaldehyde (4) with diethyl (2,2-
dimethoxyethyl)phosphonate [(CH3O)2CHCH2P(O)(OEt)2]
714
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0714 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 714Ϫ720

3-Substituted 1Ј-Benzylspiro[[2]benzoxepine-1,4Ј-piperidines]
FULL PAPER
could be the initial step in the synthesis of the desired spiro- THF, was treated with 1-benzylpiperidin-4-one (9) to afford
[[2]benzoxepine-1,4Ј-piperidines]. However, in spite of the hydroxy acetal 10 in 49% yield (Scheme 2). Cyclization
extensive variation of the base, solvent and temperature, of the hydroxy acetal 10 led to the racemic spirocyclic ring
this reaction did not succeed.
system: With p-toluenesulfonic acid in methanol the methyl
This prompted us to use the Wittig reagent (1,3-dioxolan- acetal 11 was obtained in 65% yield, whereas the lactol 12
2-ylmethyl)triphenylphosphonium bromide (5) instead of was formed with aqueous hydrochloric acid in THF in
the phosphonate to obtain the 2-bromocinnamic aldehyde 72% yield.
acetal 6 (Scheme 1). According to ref.[10] the phase-transfer
Wittig reaction of the aldehyde 4 with the phosphonium
salt 5 afforded the α,β-unsaturated ethylene acetal (Z/E)-6
in 91% yield using a saturated aqueous solution of potas-
sium carbonate as base. Tris[2-(2-methoxyethoxy)ethyl]am-
ine in dichloromethane was added to the reaction mixture
in order to activate the base by chelation of the potassium
1
cation.[10] The H NMR spectrum of the crude product re-
vealed a (Z)-6/(E)-6 ratio of 65:35, whereas according to
the literature the (Z)/(E) ratio should be around 52:48.[10]
Since both isomers have almost identical chromatographic
properties the separation of (Z)-6 and (E)-6 turned out to
be difficult. A pure sample of (Z)-6 could be isolated by
flash chromatography, but the complete separation of (Z)-
6 from (E)-6 was not successful.
Scheme 2. Reagents and conditions: (a) 1. n-butyllithium, THF,
Ϫ78 °C, 2. 1-benzylpiperidin-4-one (9), THF (49%); (b) p-tolu-
enesulfonic acid, CH3OH, room temp. (65%); (c) 2  HCl, THF,
room temp. (72%), Bn ϭ benzyl
One aim of our structure-affinity relationship studies was
to evaluate the influence of a double bond in position 4/
5 of the spiro[[2]benzoxepine-1,4Ј-piperidine] system on σ-
receptor affinity. For the synthesis of a 2-benzoxepine ring
with an additional double bond, the brominated α,β-unsat-
urated acetal (Z)-6 was treated with n-butyllithium and
treated with 1-benzylpiperidin-4-one (9) (Scheme 3). The re-
sulting alcohol 13 was subsequently cyclized according to
the methods described above. Surprisingly, the reaction of
13 with p-toluenesulfonic acid in methanol for a period of
2 h led to a mixture of the spiro[[2]benzoxepine-1,4Ј-piper-
idine] 14 and the spiro[[2]benzofuran-1,4Ј-piperidine] 15. In
order to rationalize these findings, we varied the reaction
Scheme 1. Reagents and conditions: (a) tris(methoxyethoxyethyl)-
amine, CH2Cl2, (1,3-dioxolan-2-ylmethyl)triphenylphosphonium
bromide (5), saturated aqueous solution of K2CO3 [(Z)-6 ϩ (E)-6:
91%]; (b) H2, Raney nickel, CH3OH (77%, 7/8 ؍ 90:10)
In the next step, the double bond of the brominated ace- time and found that after 20 min the desired 2-benzoxepine
tal 6 should be hydrogenated to yield the (2-bromophenyl)- 14 could be isolated exclusively (66% yield), whereas longer
propionaldehyde acetal 7. Attempts were made using the reaction times favored the formation of the 2-benzofuran
catalysts Pd/C, PtO2, and Raney nickel at different hydro- 15. After 48 h, the 2-benzofuran 15 was isolated as the only
gen pressures. The reactions with Pd/C and PtO2 were not product in 68% yield. Thus, kinetic control affords the 2-
successful: Either the α,β-unsaturated acetal 6 was com- benzoxepine 14, whereas thermodynamic control leads to
pletely decomposed or the debrominated derivative 8 was the 2-benzofuran 15.
formed as the main product. Finally, the reaction succeeded
Reaction of 13 with p-toluenesulfonic acid in ethanol for
with Raney nickel in methanol at a hydrogen pressure of 1 15 min led to the ethoxy derivative 16. The cyclization of
bar for 3 h to afford the (2-bromophenyl)propionaldehyde 13 with dilute hydrochloric acid provided the spiro[[2]ben-
acetal 7. However, even under these very mild reaction con- zofuran-1,4Ј-piperidine]acetaldehyde 17.
ditions, hydrogenolysis of the bromine atom was not com-
The unexpected formation of the spiro[[2]benzofuran-
pletely suppressed and the product 7 contained about 10% 1,4Ј-piperidine] 15 can be explained in the following way:
of the debrominated by-product 8. The flash chromato- After protonation of the dioxolane 13 by p-toluenesulfonic
graphic separation of 7 and 8 was not possible. However, acid the hydroxy group attacks the positively charged C-2
the presence of 8 did not disturb the following reaction atom of the dioxolane ring to yield, after transacetalization
steps.
with methanol, the methyl acetal 14. A prolonged reaction
The aryllithium derivative, obtained by treatment of 2- time in the presence of acid and methanol leads to ring
bromophenyl acetal 7 with n-butyllithium at Ϫ78 °C in contraction of 14 affording the dimethyl acetal 15.
Eur. J. Org. Chem. 2003, 714Ϫ720
715

C. A. Maier, B. Wünsch
FULL PAPER
synthesis of the corresponding spiro[[2]benzopyran-1,4Ј-pi-
peridine]-3-carbonitrile[8] the Lewis acid catalyzed elimina-
tion of CH3OH was not favored because the new double
bond is not in conjugation with the benzene ring. The use
of tetracyanoethylene[12] instead of BF3·Et2O led to a
significant decrease of the yield of 18 (only 3.5%).
Starting from the lactol 12 the introduction of a two-
carbon residue in the 3-position of the spirocycle was suc-
cessful. Compound 12 was refluxed with (cyanomethylene)-
triphenylphosphorane and Cs2CO3 in toluene to afford the
ethanenitrile 20 in 92% yield. This tandem reaction includes
a sequence of ring opening of the lactol to afford a hydroxy-
aldehyde, a Wittig reaction and an intramolecular Michael
addition.
Receptor Binding Studies
The σ-receptor affinities of the spiropiperidines 3 were
determined in radioligand binding experiments. In the σ1-
assay homogenates of guinea pig brains were used as recep-
tor material. The σ1-selective compound [3H]-(ϩ)-pentazoc-
ine was employed as radioligand. A rat liver membrane pre-
paration served as the source of σ2-receptors in the σ2-as-
say. Since a σ2-selective radioligand is not available the non-
selective radioligand [3H]-ditolylguanidine was employed in
the presence of non-radiolabeled (ϩ)-pentazocine (100 n)
for the selective masking of σ1-receptors.[8]
Scheme 3. Reagents and conditions: (a) 1. n-butyllithium, THF,
Ϫ78 °C, 2. 1-benzylpiperidin-4-one (9), THF (44%); (b) 2  HCl,
THF, room temp. (45%); (c) p-toluenesulfonic acid, CH3OH or
C2H5OH, room temp. (yields see table in the scheme)
The σ-receptor affinities of the synthesized compounds
are shown in Table 1. For comparison, the Ki values of the
spiro[[2]benzofuran-1,4Ј-piperidine] 1a (R ϭ OCH3, n ϭ
1)[8] and the spiro[[2]benzopyran-1,4Ј-piperidine] 2a (R ϭ
OCH3, n ϭ 1)[8] are also included. Additionally, the Ki
values of the reference compounds haloperidol, ditolylgu-
anidine (usually referred to as DTG), and BMY14802 are
given.
One of the major goals of our structure-affinity relation-
ship studies was to evaluate the effect of the side chain in
the 3-position of the spirocyclic system 3 on σ-receptor af-
finity and selectivity. For this purpose the methyl acetal 11
and the lactol 12 were used as starting materials for the
synthesis of modified spiro[[2]benzoxepine-1,4Ј-piperi-
dines].
For the introduction of a one-carbon residue in the 3-
position of the spiro[[2]benzoxepine-1,4Ј-piperidines] the
methoxy derivative 11 was treated with trimethylsilyl cyan-
ide in the presence of the Lewis acid boron
trifluorideϪdiethyl ether complex (BF3·Et2O) at Ϫ20 °C.[11]
This reaction afforded the nitrile 18 in 47% yield and the
by-product 19 in 6% yield (Scheme 4). In contrast to the
All tested compounds showed σ1-receptor affinities in the
low nanomolar range. The methoxy derivative 11 with a Ki
value of 2.56 n reveals the highest σ1-receptor affinity
within the spirobenzoxepine series. However, its affinity is
slightly lower than those of the 2-benzofuran 1a and the 2-
benzopyran 2a. The 2-benzoxepine 14 with a double bond
in position 4/5 displays a somewhat lower affinity (Ki ϭ
4.05 nM) than the saturated analogue 11. The polar lactol
12 has a fourfold lower affinity than the methoxy derivative
11. Similar σ1-receptor affinities were found for the homo-
logous nitriles 18 (Ki ϭ 3.54 n) and 20 (Ki ϭ 4.66 n),
although 20 possesses an additional methylene spacer be-
tween the ring system and the cyano group. The ethoxy de-
rivative 16 has a fivefold lower σ1-receptor affinity than the
methoxy derivative 14; it shows the lowest σ1/σ2 receptor
selectivity within the 2-benzoxepine series. The 2-benzofu-
ran derivative 15 (Ki ϭ 28.8 n) has a much lower σ1-affin-
ity than the 2-benzoxepines and the 2-benzofuran 1a.
Generally, the σ2-receptor affinities of all compounds are
considerably lower than their σ1-receptor affinities. The
most σ2-active compound in the 2-benzoxepine series is the
methoxy derivative 11 with a Ki value of 475 n, leading to
a low σ1/σ2 receptor selectivity (185-fold). Due to the rela-
Scheme 4. Reagents and conditions: (a) trimethylsilyl cyanide,
BF3·Et2O, CH2Cl2, Ϫ20 °C (18: 47%, 19: 6%); (b) Ph3PϭCHCN,
Cs2CO3, toluene, reflux (92%)
716
Eur. J. Org. Chem. 2003, 714Ϫ720

3-Substituted 1Ј-Benzylspiro[[2]benzoxepine-1,4Ј-piperidines]
FULL PAPER
Table 1. σ-Receptor affinities of the synthesized spiro[2]benzoxepines
Compd.
R
C4ϪC5
Ki Ϯ SEM [n] (n ϭ 3)
Selectivity
σ1/σ2
σ1
σ2
1a[8]
OCH3
OCH3
OCH3
OCH3
OH
CN
CH2CN
OCH2CH3
CH2CH(OCH3)2
1.14 Ϯ 0.22
1280 Ϯ 137
1130
2710
185
257
107
427
768
33
42
16
0.39
1.5
[a]
[b]
2a[8]
1.29 Ϯ 0.18
2.56 Ϯ 0.96
4.05 Ϯ 0.42
11.4 Ϯ 3.20[c]
3.54 Ϯ 0.67[c]
4.66 Ϯ 1.06[c]
20.4 Ϯ 0.39
28.8 Ϯ 5.03
2.20 Ϯ 0.31
164 Ϯ 47.4[c]
265 Ϯ 32.0
3500 Ϯ 352
475 Ϯ 138
1040 Ϯ 158
1230 Ϯ 25.0
1510 Ϯ 421
3570 Ϯ 667
678 Ϯ 142
1200 Ϯ 79.7
34.2 Ϯ 2.3[c]
63.9 Ϯ 10.8
11
CH2ϪCH2
CHϭCH
CH2ϪCH2
CH2ϪCH2
CH2ϪCH2
14
12
18
20
16
CHϭCH
[a]
15
Haloperidol
Ditolylguanidine (DTG)
BMY14802
390.7 Ϯ 62.2
[a]
[b]
[c]
Spiro[2]benzofuran. Spiro[2]benzopyran. n ϭ 4.
at 70 eV or chemical ionization (CI). IR spectra were obtained with
a PerkinϪElmer 1605 FT-IR spectrophotometer and wavenumbers
are given in cmϪ1. 1H (300 MHz) and 13C NMR (75 MHz) spectra
were recorded with a Varian Unity 300 NMR spectrometer operat-
ing at 27 °C. Chemical shifts (δ) are reported in ppm downfield
from tetramethylsilane. Coupling constants (J) are given with
0.5 Hz resolution. The assignments of 1H and 13C NMR signals
were supported by 2D NMR techniques (correlation spectro-
scopy, COSY).
tively low σ2-affinity the highest σ1/σ2 selectivity was found
for the cyanomethyl derivative 20 with a selectivity factor
of 768.
Conclusion
A four-step synthesis of the spiro[[2]benzoxepine-1,4Ј-pi-
peridines] 11 and 12 has been described. The spiro com-
pounds 11 and 12 serve as starting materials for further
modifications in the 3-position. The in vitro evaluation with
(Z/E)-2-[2-(2-Bromophenyl)vinyl]-1,3-dioxolane (6): 2-Bromobenzal-
dehyde (4) (1.077 g, 5.83 mmol) and tris[2-(2-methoxyethoxy)ethyl-
radioligand binding assays allows the determination of rela- ]amine (TDA-1, 1.884 g, 5.83 mmol) were dissolved in CH2Cl2
(70 mL) under nitrogen. Then, a saturated solution of K2CO3
(70 mL) and (1,3-dioxolan-2-ylmethyl)triphenylphosphonium
tionships between substitution in the 3-position of the spi-
robenzoxepines and their σ1- and σ2-receptor affinity and
selectivity. The ligands with a methoxy (11) and cyano (18)
group displayed Ki values in the range of 2Ϫ4 n. As a rule,
the σ1-receptor affinities and the σ1/σ2-receptor selectivities
of the 2-benzoxepines are somewhat lower than those values
of the corresponding 2-benzofurans and 2-benzopyrans.[8,9]
bromide (5; 2.50 g, 5.83 mmol) were added. This mixture was re-
fluxed for 3 d and then the CH2Cl2 layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried with Na2SO4, silica gel was added and the solvent
was removed under reduced pressure. The residue was purified by
FC (5.5 cm, petroleum ether/EtOAc, 95:5, 50 mL) to afford two
fractions: first (Z)-6 was eluted (Rf ϭ 0.12), then (E)-6 (Rf ϭ 0.06),
which could not be completely separated from (Z)-6. Yields: (Z)-
6: 0.50 g (34%), colorless oil, which solidified on standing, m.p. 54
°C, (ZϩE)-6: 0.85 g (57%) colorless oil, overall yield: 1.35 g (91%).
According to the 1H NMR spectrum of the unpurified product the
ratio (Z)-6 to (E)-6 was 65:35.
Experimental Section
General: Moisture-sensitive reactions were conducted under dry ni-
trogen. Tetrahydrofuran (THF), Et2O, and toluene were distilled
from sodium/benzophenone, CH2Cl2 from CaH2, and CH3CN
from P2O5 prior to use. For thin layer chromatography (TLC)
Merck silica gel 60 F254 plates were used. Flash chromatography
(FC) was carried out with Merck silica gel 60, 0.040Ϫ0.063 mm,
the terms in parentheses for FC include the following: diameter of
(Z)-6: IR (film): ν˜ ϭ 2956, 2884 (CϪH), 1115 (CϪO), 1031
(CϪBr), 767, 744 (CϪH) cmϪ1. 1H NMR (CDCl3): δ ϭ 3.87Ϫ3.96
(m, 2 H, OCH2CH2O), 4.04Ϫ4.10 (m, 2 H,OCH2CH2O), 5.37 (dd,
J ϭ 7.7, 0.8 Hz, 1 H, ArCHϭCHCH), 5.80 (dd, J ϭ 11.7, 7.7 Hz,
the column [cm], eluent, fraction size [mL], Rf. Melting points were 1 H, ArCHϭCHCH), 6.88 (d, J ϭ 11.7 Hz, 1 H, ArCHϭCHCH),
determined with an SMP 2 (Stuart Scientific) apparatus and are
uncorrected. Elemental analyses were conducted with a VarioEL
(Elementaranalysesysteme GmbH). The mass spectrometers used
were models MAT 312, MAT 8200, MAT 44, and TSQ 7000 (Fin-
nigan). As specified, ionization methods were electron impact (EI)
7.17 (td, J ϭ 8.1, 1.8 Hz, 1 H, 4Ј-H), 7.31 (td, J ϭ 7.3, 1.5 Hz, 1 H,
5Ј-H), 7.48 (dd, J ϭ 7.3, 1.8 Hz, 1 H, 6Ј-H), 7.59 (dd, J ϭ 8.1,
1.5 Hz, 1 H, 3Ј-H) ppm. MS (EI): m/z ϭ 254/256 [Mϩ], 182/184
[BrC6H4CHϭCHϩ], 175 [Mϩ
Ϫ
Br], 73 [OCH2CH2OCHϩ].
C11H11BrO2 (255.11): calcd. C 51.8, H 4.35; found C 51.8, H 4.23.
Eur. J. Org. Chem. 2003, 714Ϫ720
717

C. A. Maier, B. Wünsch
FULL PAPER
In ref.[10] the spectroscopic data of 6 are not provided.
8-H), 7.24Ϫ7.40 (m, 6 H, arom) ppm. 13C NMR (CDCl3): δ ϭ
30.2 (1 C, ArCH2CH2CH), 32.8 [1 C, N(CH2CH2)2], 34.2 (1 C,
ArCH2CH2CH), 39.7 [1 C, N(CH2CH2)2], 49.5 [1 C, N(CH2CH2)2],
49.5 (1 C, N(CH2CH2)2], 56.3 (1 C, OCH3), 63.3 (1 C, NCH2Ph),
78.1 (1 C, ArCO), 100.3 (1 C, ArCH2CH2CH), 125.4 (1 C, C-9),
126.9 (1 C, C-4ЈЈ), 127.0 (1 C, C-8), 127.3 (1 C, C-7), 128.2 (2 C,
C-3ЈЈ ϩ C-5ЈЈ), 129.2 (2 C, C-2ЈЈ ϩ C-6ЈЈ), 130.4 (1 C, C-6), 138.2
(1 C, C-5a), 138.7 (1 C, C-1ЈЈ), 143.9 (1 C, C-9a) ppm. MS (EI): m/
z ϭ 337 [Mϩ], 322 [Mϩ Ϫ CH3], 246 [Mϩ Ϫ CH2Ph], 91 [CH2Phϩ].
C22H27NO2 (337.46): calcd. C 78.3, H 8.06, N 4.15; found C 77.6,
H 7.07, N 3.80. HRMS: calcd. 337.2042; found 337.2046.
2-[2-(2-Bromophenyl)ethyl]-1,3-dioxolane (7): A mixture of 6 [(Z)/
(E) ϭ 1:1, 1.134 g, 4.4 mmol)] and Raney nickel (B, 113 W,
DegussaϪHüls, 0.3 g) in CH3OH (20 mL) was shaken for 3.3 h un-
der H2 (1.0 bar) in a Parr apparatus. Then, the mixture was filtered
through Celite and the solvent was removed under reduced pres-
sure. The residue was purified by FC (4 cm, petroleum ether/
EtOAc, 96:4, 50 mL, Rf ϭ 0.19). Colorless oil, yield 880 mg (77%).
The product contained about 10% of dehalogenated compound 8
which could not be separated. IR (film): ν˜ ϭ 2954, 2880 (CϪH),
1
1139 (CϪO), 1025 (CϪBr), 751 (CϪH) cmϪ1. H NMR (CDCl3):
(؎)-1Ј-Benzyl-4,5-dihydro-3H-spiro[[2]benzoxepine-1,4Ј-piperidin]-
3-ol (12): A solution of the hydroxy acetal 10 (100 mg, 0.27 mmol)
in THF (2 mL) and HCl (2 , 10 mL) was stirred at room temper-
ature for 2 h. Then, an aqueous solution of NaOH (2 , 12 mL)
was added (pH ϭ 10). This mixture was extracted with CH2Cl2.
The organic layer was dried (Na2SO4), then some silica gel was
added and the solvents were evaporated under reduced pressure.
The residue was purified by FC (1 cm, petroleum ether/EtOAc, 3:1,
5 mL, Rf ϭ 0.01) to afford a colorless oil which solidified on
standing (m.p. 121 °C), yield 63 mg (72%). IR (film): ν˜ ϭ 3392
(OϪH), 2942, 2824 (CϪH), 1068, 1034 (CϪO), 747, 698 (CϪH)
δ ϭ 1.94Ϫ2.04 (m, 2 H, ArCH2CH2CH), 2.83Ϫ2.92 (m, 2 H,
ArCH2CH2CH), 3.86Ϫ3.94 (m, 2 H, OCH2CH2O), 3.96Ϫ4.04 (m,
2 H, OCH2CH2O), 4.94 (t, J ϭ 4.6 Hz, 1 H, ArCH2CH2CH),
7.02Ϫ7.09 (m, 1 H, 5Ј-H), 7.18Ϫ7.31 (m, 2 H, arom), 7.53 (dd, J ϭ
7.6, 1.2 Hz, 1 H, 3Ј-H) ppm. C11H13BrO2 (257.13) ppm. MS (CI,
isobutane): m/z ϭ 257/259 [Mϩ ϩ H], 177 [Mϩ Ϫ Br], 73
[OCH2CH2OCHϩ].
1-Benzyl-4-{2-[2-(1,3-dioxolan-2-yl)ethyl]phenyl}piperidin-4-ol (10):
Under nitrogen a solution of n-butyllithium in hexane (1.6 ,
1.43 mL, 2.28 mmol) was slowly added to a cooled (Ϫ78 °C) solu-
tion of 7 (586 mg, 2.28 mmol) in THF (5 mL). The mixture was
stirred at Ϫ78 °C for 10 min, then a solution of 1-benzylpiperidin-
4-one (9) (345 mg, 1.82 mmol) in THF (3 mL) was slowly added
and the mixture was stirred at Ϫ78 °C for 2.5 h and another 3 h at
room temperature. Then, water was added and the mixture was
extracted with CH2Cl2. The organic layer was dried (Na2SO4), and
the solvent was removed under reduced pressure. The residue was
purified by FC (3 cm, first petroleum ether/EtOAc, 95:5, then pe-
troleum ether/EtOAc, 75:25, 20 mL, Rf ϭ 0.05) to afford a colorless
oil, yield 326 mg (49%). IR (film): ν˜ ϭ 3450 (OϪH), 2927, 2873
cmϪ1 1H NMR (CDCl3): δ ϭ 1.83 [td, J ϭ 12.9, 5.0 Hz, 1 H,
.
N(CH2CH2)2], 1.88Ϫ2.06 [m, 3 H, N(CH2CH2)2 (2 H),
ArCH2CH2CH (1 H)], 2.08Ϫ2.21 (m, 1 H, ArCH2CH2CH), 2.45
[td, J ϭ 13.1, 4.3 Hz, 2 H, N(CH2CH2)2 (1 H), ArCH2CH2CH
(1 H)], 2.60Ϫ2.94, [m, 4 H, N(CH2CH2)2], 3.37 (td, J ϭ 12.5,
6.7 Hz, 1 H, ArCH2CH2CH), 3.63 (s, 2 H, NCH2Ph), 4.36 (br. s,
1 H, OH), 4.98 (dd, J ϭ 8.5, 4.9 Hz, 1 H, ArCH2CH2CH), 7.07 (d,
J ϭ 6.7 Hz, 1 H, arom), 7.10Ϫ7.39 (m, 8 H, arom) ppm. 13C NMR
(CDCl3): δ ϭ 30.7 (1 C, ArCH2CH2CH), 32.4 [1 C, N(CH2CH2)2],
36.0 (1 C, ArCH2CH2CH), 39.0 [1 C, N(CH2CH2)2], 49.0 [1 C,
N(CH2CH2)2], 49.1 [1 C, N(CH2CH2)2], 62.8 (1 C, NCH2Ph), 79.0
(1 C, ArCO), 92.3 (1 C, ArCH2CH2CH), 125.7 (1 C, arom. CH),
127.1 (1 C, arom. CH), 127.2 (1 C, arom. CH), 127.3 (1 C, arom.
CH), 128.3 (2 C, arom. CH), 129.5 (2 C, arom. CH), 130.7 (1 C,
arom. C-9), 137.3 (1 C, arom. C), 137.7 (1 C, arom. C), 144.0 (1
C, arom. C) ppm. MS (EI): m/z ϭ 323 [Mϩ], 232 [Mϩ Ϫ CH2Ph],
91 [CH2Phϩ]. C21H25NO2 (323.44): calcd. C 78.0, H 7.79, N 4.33;
found C 77.3, H 8.28, N 4.19. HRMS: calcd. 323.1885; found
323.1885.
(CϪH), 1133, 1039 (CϪO), 749, 701 (CϪH) cmϪ1
.
1H NMR
(CDCl3): 1.90Ϫ2.07 [m, 4 H, ArCH2CH2CH (2 H),
δ
ϭ
N(CH2CH2)2 (2 H)], 2.21 [td, J ϭ 13.1, 4.3 Hz, 2 H, N(CH2CH2)2],
2.56 [td, J ϭ 11.9, 2.4 Hz, 2 H, N(CH2CH2)2], 2.79 [br. d, J ϭ
11.3 Hz, 2 H, N(CH2CH2)2], 3.12Ϫ3.18 (m, 2 H, ArCH2CH2CH),
3.59 (s, 2 H, NCH2Ph), 3.83Ϫ3.92 (m, 2 H, OCH2CH2O),
3.93Ϫ4.02 (m, 2 H, OCH2CH2O), 4.92 (t, J ϭ 4.7 Hz, 1 H,
ArCH2CH2CH), 7.14 (td, J ϭ 7.0, 1.8 Hz, 1 H, arom), 7.20 (td,
J ϭ 7.3, 1.5 Hz, 1 H, arom), 7.23Ϫ7.41 (m, 7 H, arom) ppm. MS
(EI): m/z ϭ 367 [Mϩ], 276 [Mϩ Ϫ CH2Ph], 91 [CH2Phϩ]. HRMS
for C23H29NO3: calcd. 367.2147; found 367.2149.
(Z)-1-Benzyl-4-{2-[2-(1,3-dioxolan-2-yl)vinyl]phenyl}piperidin-4-ol
(13): Under nitrogen a solution of n-butyllithium in hexane (1.6 ,
(؎)-1Ј-Benzyl-3-methoxy-4,5-dihydro-3H-spiro[[2]benzoxepine-1,4Ј- 0.76 mL, 1.21 mmol) was slowly added to a cooled (Ϫ78 °C) solu-
piperidine] (11): A solution of 10 (457 mg, 1.24 mmol) and p-tolu- tion of (Z)-6 (280 mg, 1.10 mmol) in THF (4 mL). The color of the
enesulfonic acid monohydrate (284 mg, 1.49 mmol) in CH3OH mixture turned brown. Then, a solution of 1-benzylpiperidin-4-one
(10 mL) was stirred for 24 h at room temperature. Then, an aque-
ous solution of NaOH (2 , 5 mL) was added and the mixture was
extracted with CH2Cl2. The organic layer was dried (Na2SO4) and
the solvent was removed under reduced pressure. The crude prod-
(9) (166 mg, 0.88 mmol) in THF (2 mL) was slowly added. The
color of the solution changed to yellow. The mixture was stirred at
Ϫ78 °C for 7 h. Water was then added and the mixture was ex-
tracted with CH2Cl2. The organic layer was dried (Na2SO4) and
uct was purified by FC (3 cm, petroleum ether/EtOAc, 3:1, 20 mL, the solvent was removed under reduced pressure. The crude prod-
Rf ϭ 0.04) to afford a colorless oil, which solidified on standing uct was purified by FC (2 cm, petroleum ether/EtOAc, 2:3, 10 mL,
(m.p. 75 °C), yield 272 mg (65%). IR (film): ν˜ ϭ 2945, 2821 (CϪH), Rf ϭ 0.08) to afford a colorless oil, yield 142 mg (44%). IR (film):
1127, 1039, 1007 (CϪO), 745, 698 (CϪH) cmϪ1
(CDCl3): δ ϭ 1.72 [td, J ϭ 13.7, 4.9 Hz, 1 H, N(CH2CH2)2],
.
1H NMR ν˜ ϭ 3453 (OϪH), 2884, 2815 (CϪH), 1114, 1043 (CϪO), 766, 700
1
(CϪH) cmϪ1. H NMR (CDCl3): δ ϭ 1.90 [dd, J ϭ 14.0, 2.6 Hz,
1.90Ϫ2.05 [m, 3 H, N(CH2CH2)2 (1 H), ArCH2CH2CH (2 H)], 2.13 2 H, N(CH2CH2)2], 2.14 [td, J ϭ 13.1, 4.3 Hz, 2 H, N(CH2CH2)2],
[ddd, J ϭ 13.7, 5.6, 2.7 Hz, 1 H, N(CH2CH2)2], 2.44Ϫ2.75 [m, 5 H, 2.47 [td, J ϭ 11.9, 2.4 Hz, 2 H, N(CH2CH2)2], 2.73 [br. d, J ϭ
N(CH2CH2)2 (1 H), ArCH2CH2CH (1 H), N(CH2CH2)2 (3 H)], 11.3 Hz, 2 H, N(CH2CH2)2], 3.54 (s, 2 H, NCH2Ph), 3.75Ϫ3.81 (m,
2.85Ϫ2.93, [m, 1 H, N(CH2CH2)2], 3.29Ϫ3.41 (m, 1 H,
2 H, OCH2CH2O), 3.94Ϫ4.00 (m, 2 H, OCH2CH2O), 5.23 (dd, J ϭ
ArCH2CH2CH), 3.42 (s, 3 H, OCH3), 3.57 (d, J ϭ 13.1 Hz, 1 H, 7.9, 0.6 Hz, 1 H, ArCHϭCHCH), 5.63 (dd, J ϭ 11.3, 7.9 Hz, 1 H,
NCH2Ph), 3.62 (d, J ϭ 13.1 Hz, 1 H, NCH2Ph), 4.48 (dd, J ϭ 7.6, ArCHϭCHCH), 7.19Ϫ7.35 (m, 8 H, arom), 7.40 (d, J ϭ 7.3 Hz,
5.2 Hz, 1 H, ArCH2CH2CH), 7.08 (dd, J ϭ 7.3, 1.8 Hz, 1 H, 6-H), 1 H, arom), 7.47 (d, J ϭ 11.6 Hz, 1 H, ArCHϭCHCH) ppm.
7.15 (td, J ϭ 7.0, 1.8 Hz, 1 H, 7-H), 7.21 (td, J ϭ 8.2, 1.8 Hz, 1 H,
C23H27NO3 (365.47). MS (CI, NH3): m/z ϭ 366 [Mϩ ϩ H].
718
Eur. J. Org. Chem. 2003, 714Ϫ720

3-Substituted 1Ј-Benzylspiro[[2]benzoxepine-1,4Ј-piperidines]
FULL PAPER
(؎)-1Ј-Benzyl-3-methoxy-3H-spiro[[2]benzoxepine-1,4Ј-piperidine]
(14) and (؎)-2-{1Ј-Benzyl-3H-spiro[[2]benzofuran-1,4Ј-piperidin]-3-
yl}acetaldehyde Dimethyl Acetal (15)
der reduced pressure. The crude product was purified by FC (1 cm,
petroleum ether/EtOAc, 5:2, 5 mL, Rf ϭ 0.06) to afford a colorless
oil, yield 53 mg (69%). IR (film): ν˜ ϭ 2939, 2810 (CϪH), 1650
1
(CϭC), 1179, 1047 (CϪO), 996, 757, 699 (CϪH) cmϪ1. H NMR
Procedure A: A solution of the (Z)-configured hydroxydioxolane
(Z)-13 (70 mg, 0.19 mmol) and p-toluenesulfonic acid monohydrate
(54 mg, 0.28 mmol) in CH3OH (10 mL) was stirred at room tem-
perature for 2 h. Then, solid NaOH (30 mg) was added and the
solvent was removed under reduced pressure. The crude product
was purified by FC (2 cm, petroleum ether/EtOAc, first 2:1, then
1:1, 5 mL, Rf ϭ 0.06) to afford a colorless oil, yield 28 mg. The
resulting product contained 14 and 15 in a ratio of 1:2.
(CDCl3): δ ϭ 1.29 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.75 [dd, J ϭ
14.0, 2.5 Hz, 2 H, N(CH2CH2)2], 1.91 [td, J ϭ 12.8, 4.6 Hz, 1 H,
N(CH2CH2)2], 2.13 [td, J ϭ 12.8, 4.6 Hz, 1 H, N(CH2CH2)2],
2.45Ϫ2.58 [m, 2 H, N(CH2CH2)2], 2.78Ϫ2.88, [m, 2 H,
N(CH2CH2)2], 3.60 (s, 2 H, NCH2Ph), 3.73Ϫ3.85 (m, 2 H,
OCH2CH3), 4.81 (dd, J ϭ 12.8, 9.2 Hz, 1 H, ArCHϭCHCH), 5.48
(d, J ϭ 9.2 Hz, 1 H, ArCHϭCHCH), 6.66 (d, J ϭ 12.8 Hz, 1 H,
ArCHϭCHCH), 7.08Ϫ7.18 (m, 2 H, arom), 7.23Ϫ7.39 (m, 7 H,
arom) ppm. MS (EI): m/z ϭ 349 [Mϩ], 320 [Mϩ Ϫ CH2CH3], 258
[Mϩ Ϫ CH2Ph], 91 [CH2Phϩ]. HRMS for C23H27NO2: calcd.
349.2042; found 349.2041.
Procedure B: The product of Procedure A (28 mg, 0.08 mmol) was
dissolved in CH3OH (3 mL). Then, p-toluenesulfonic acid
monohydrate (19 mg, 0.10 mmol) was added and the mixture was
stirred at room temperature for 2 d. A solution of NaOH (2 ) was
then added (pH ϭ 10) and the mixture was extracted with CH2Cl2.
The organic layer was dried (Na2SO4) and the solvent was removed
under reduced pressure. The residue contained 15 as a colorless oil,
yield 20 mg (68%).
(؎)-2-{1Ј-Benzyl-3H-spiro[[2]benzofuran-1,4Ј-piperidin]-3-
yl}acetaldehyde (17): The hydroxydioxolane 13 (60 mg, 0.16 mmol)
was dissolved in THF (2 mL) and HCl (2 , 10 mL) and the mix-
ture was stirred at room temperature for 15 h. Then, an aqueous
solution of NaOH (2 ) was added (pH ϭ 8) and the mixture was
extracted with CH2Cl2. The organic layer was dried (Na2SO4) and
the solvent was removed under reduced pressure. The crude prod-
uct was purified by FC (1 cm, petroleum ether/EtOAc, 1:1, 5 mL,
Rf ϭ 0.04) to afford a colorless oil, yield 24 mg (45%). IR (film):
ν˜ ϭ 2917, 2812 (CϪH), 1725 (CϭO), 1109, 1048 (CϪO), 741, 699
Procedure C: A solution of the (Z)-configured hydroxydioxolane
(Z)-13 (35 mg, 0.096 mmol) and p-toluenesulfonic acid mono-
hydrate (22 mg, 0.12 mmol) in CH3OH (5 mL) was stirred at room
temperature for 20 min. Then, an aqueous solution of NaOH (2 )
was added (pH ϭ 10) and the mixture was extracted with CH2Cl2.
The organic layer was dried (Na2SO4) and the solvent was removed
under reduced pressure. The crude product was purified by FC
(2 cm, petroleum ether/EtOAc, 2:1, 5 mL, Rf ϭ 0.06) to afford 14
as colorless oil, yield 21 mg (66%).
(CϪH) cmϪ1 1H NMR (CDCl3): δ ϭ 1.65Ϫ1.77 [m, 2 H,
.
N(CH2CH2)2], 1.95 [td, J ϭ 12.8, 4.6 Hz, 1 H, N(CH2CH2)2], 2.16
[td, J ϭ 12.8, 4.3 Hz, 1 H, N(CH2CH2)2], 2.47 [td, J ϭ 11.9, 2.4 Hz,
2 H, N(CH2CH2)2], 2.73Ϫ2.97 [m, 4 H, N(CH2CH2)2 (2 H),
ArCHCH2CHO (2 H)], 3.62 (s, 2 H, NCH2Ph), 5.68 (dd, J ϭ 6.7,
4.9 Hz, 1 H, ArCHCH2CHO), 7.13Ϫ7.19 (m, 2 H, arom),
7.24Ϫ7.41 (m, 7 H, arom), 9.84 (t, J ϭ 2.1 Hz, 1 H, ArCHCH2-
CHO) ppm. MS (EI): m/z ϭ 321 [Mϩ], 230 [Mϩ Ϫ CH2Ph], 91
[CH2Phϩ].
14: IR (film): ν˜ ϭ 2939, 2809 (CϪH), 1650 (CϭC), 1210, 1159,
1
1047 (CϪO), 935, 752, 741, 699 (CϪH) cmϪ1. H NMR (CDCl3):
δ ϭ 1.75 [br. d, J ϭ 13.7 Hz, 2 H, N(CH2CH2)2], 1.91 [td, J ϭ
12.5, 4.6 Hz, 1 H, N(CH2CH2)2], 2.14 [td, J ϭ 12.8, 4.6 Hz, 1 H,
N(CH2CH2)2], 2.45Ϫ2.59 [m, 2 H, N(CH2CH2)2], 2.78Ϫ2.89 [m,
2 H, N(CH2CH2)2], 3.58 (s, 3 H, OCH3), 3.60 (s, 2 H, NCH2Ph),
4.81 (dd, J ϭ 12.5, 8.9 Hz, 1 H, ArCHϭCHCH), 5.50 (d, J ϭ
8.9 Hz, 1 H, ArCHϭCHCH), 6.72 (d, J ϭ 12.8 Hz, 1 H, ArCHϭ
CHCH), 7.08Ϫ7.18 (m, 2 H, arom), 7.23Ϫ7.40 (m, 7 H, arom)
(؎)-1Ј-Benzyl-4,5-dihydro-3H-spiro[[2]benzoxepine-1,4Ј-piperidine]-
3-carbonitrile (18) and 1Ј-Benzyl-5H-spiro[[2]benzoxepine-1,4Ј-pi-
peridine] (19)
Method A: Under nitrogen tetracyanoethylene (21 mg, 0.16 mmol)
was dissolved in CH3CN (2 mL). Then, a solution of the methyl
acetal 11 (272 mg, 0.81 mmol) in CH3CN (2 mL) was added. After
5 min, trimethylsilyl cyanide (0.5 mL) was added and the mixture
was refluxed. Three further portions of trimethylsilyl cyanide
(0.5 mL each) were added over a period of 24 h. On completion of
the reaction, the solvent was carefully evaporated under reduced
pressure and the residue was dissolved in CH2Cl2. Silica gel was
then added and the solvent was removed under reduced pressure.
The residue was purified by FC (3 cm, petroleum ether/EtOAc, 3:1,
20 mL, Rf ϭ 0.05). At first, a nonpolar compound was eluted, the
structure of which could not be elucidated (Rf ϭ 0.80), followed by
the carbonitrile 18. Colorless oil, yield 10 mg (3.5%).
ppm. MS (EI): m/z ϭ 335 [Mϩ], 320 [MϩϪCH3], 244 [Mϩ
Ϫ
CH2Ph], 91 [CH2Phϩ]. HRMS for C22H25NO2: calcd. 335.1885;
found 335.1887.
15: IR (film): ν˜ ϭ 2940, 2809 (CϪH), 1125, 1048 (CϪO), 757, 743,
699 (CϪH) cmϪ1 1H NMR (CDCl3): δ ϭ 1.65Ϫ1.75 [m, 2 H,
.
N(CH2CH2)2], 1.86 [ddd, J ϭ 13.7, 9.5, 3.4 Hz, 1 H, ArCHCH2-
CH(OCH3)2], 1.92 [td, J ϭ 13.4, 4.6 Hz, 1 H, N(CH2CH2)2], 2.10
[td, J ϭ 13.1, 4.6 Hz, 1 H, N(CH2CH2)2], 2.17 [ddd, J ϭ 14.0, 8.2,
3.4 Hz, 1 H, ArCHCH2CH(OCH3)2], 2.47 [td, J ϭ 11.8, 3.0 Hz,
1 H, N(CH2CH2)2], 2.48 [td, J ϭ 12.5, 2.7 Hz, 1 H, N(CH2CH2)2],
2.77Ϫ2.88 [m, 2 H, N(CH2CH2)2], 3.35 (s, 3 H, OCH3), 3.47 (s,
3 H, OCH3), 3.59 (s, 2 H, NCH2Ph), 4.79 [dd, J ϭ 7.9, 3.4 Hz, 1 H,
ArCHCH2CH(OCH3)2], 5.26 [dd, J ϭ 9.5, 3.4 Hz, 1 H, ArCHCH2-
CH(OCH3)2], 7.12Ϫ7.18 (m, 2 H, arom), 7.23Ϫ7.41 (m, 7 H, arom)
ppm. MS (EI): m/z ϭ 367 [Mϩ], 91 [CH2Phϩ]. HRMS for
C23H29NO3: calcd. 367.2147; found 367.2145.
Method B: Under nitrogen 11 (50 mg, 0.15 mmol) was dissolved in
CH2Cl2 (4 mL) and the solution was cooled to Ϫ25 °C with dry
ice/acetone. Then, trimethylsilyl cyanide (0.3 mL, 2.2 mmol) and
BF3·Et2O (70 µL, 0.54 mmol) were added successively and the mix-
ture was stirred at Ϫ25 °C for 25 min. The mixture was then stirred
at 0 °C for 1.5 h, CH3OH and an aqueous solution of NaOH (2
) were added and the mixture was extracted with CH2Cl2. The
organic layer was dried (Na2SO4) and the solvent was removed un-
(؎)-1Ј-Benzyl-3-ethoxy-3H-spiro[[2]benzoxepine-1,4Ј-piperidine]
(16): A solution of the (Z)-configured hydroxydioxolane (Z)-13
(80 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate
(50 mg, 0.26 mmol) in C2H5OH (6 mL) was stirred at room temper-
ature for 15 min. Then, an aqueous solution of NaOH (2 ) was der reduced pressure. The crude product was purified by FC (1 cm,
added (pH ϭ 10) and the mixture was extracted with CH2Cl2. The
petroleum ether/EtOAc, 4:1, 7 mL) to afford two colorless oils: at
organic layer was dried (Na2SO4) and the solvent was removed un-
first, the elimination product 19 (Rf ϭ 0.05), yield 3 mg (6%), and
Eur. J. Org. Chem. 2003, 714Ϫ720
719

C. A. Maier, B. Wünsch
afterwards the carbonitrile 18 (Rf ϭ 0.04), yield 23 mg (47%) ArCH2CH2CH), 80.7 (1 C, ArCO), 117.8 (1 C, CN), 126.0 (1 C,
FULL PAPER
were eluted.
arom. CH), 126.8 (1 C, arom. CH), 127.1 (1 C, arom. CH), 127.4
(1 C, arom. CH), 128.1 (2 C, arom. CH), 129.1 (2 C, arom. CH),
130.5 (1 C, arom. C-9), 137.3 (1 C, arom. C), 138.7 (1 C, arom. C),
18: IR (film): ν˜ ϭ 2923, 2853 (CϪH), 2212 (CϵN), 1086 (CϪO),
741, 699 (CϪH) cmϪ1. H NMR (CDCl3): δ ϭ 1.78 [td, J ϭ 13.7,
1
143.5 (1 C, arom. C) ppm. MS (EI): m/z ϭ 346 [Mϩ], 255 [Mϩ
Ϫ
4.9 Hz, 1 H, N(CH2CH2)2], 1.85 [ddd, J ϭ 13.4, 5.2, 2.4 Hz, 1 H,
N(CH2CH2)2], 1.98Ϫ2.14 [m, 2 H, N(CH2CH2)2 (1 H),
ArCH2CH2CH (1 H)], 2.33Ϫ2.64, [m, 5 H, ArCH2CH2CH (1 H),
N(CH2CH2)2 (1 H), N(CH2CH2)2 (2 H), ArCH2CH2CH (1 H)],
2.72 [br. d, J ϭ 11.3 Hz, 1 H, N(CH2CH2)2], 2.85 [br. d, J ϭ
11.0 Hz, 1 H, N(CH2CH2)2], 3.44 (td, J ϭ 13.0, 6.8 Hz, 1 H,
ArCH2CH2CH), 3.59 (s, 2 H, NCH2Ph), 4.35 (dd, J ϭ 11.3, 6.1 Hz,
1 H, ArCH2CH2CH), 7.09 (d, J ϭ 7.0 Hz, 1 H, arom), 7.16Ϫ7.42
(m, 8 H, arom) ppm. 13C NMR (CDCl3): δ ϭ 30.1 (1 C,
ArCH2CH2CH), 32.6 [1 C, N(CH2CH2)2], 32.8 (1 C,
ArCH2CH2CH), 39.0 [1 C, N(CH2CH2)2], 48.9 [1 C, N(CH2CH2)2],
49.2 [1 C, N(CH2CH2)2], 59.1 (1 C, ArCH2CH2CH), 63.2 (1 C,
NCH2Ph), 83.2 (1 C, ArCO), 119.4 (1 C, CN), 126.5 (1 C, arom.
CH), 127.0 (1 C, arom. CH), 127.8 (1 C, arom. CH), 128.0 (1 C,
arom. CH), 128.2 (2 C, arom. CH), 129.2 (2 C, arom. CH), 131.1
(1 C, arom. CH), 135.9 (1 C, arom. C), 138.7 (1 C, arom. C), 142.4
(1 C, arom. C) ppm. MS (EI): m/z ϭ 332 [Mϩ], 241 [Mϩ Ϫ CH2Ph],
91 [CH2Phϩ]. HRMS for C22H24N2O: calcd. 332.1889; found
332.1890.
CH2Ph], 91 [CH2Phϩ]. HRMS for C23H26N2O: calcd. 346.2045;
found 346.2040.
Pharmacology: The σ1- and σ2-receptor binding assays were con-
ducted as previously reported.[8] The σ1-binding assay was per-
formed using a guinea pig brain membrane preparation as receptor
material and [3H]-(ϩ)-pentazocine as radioligand. Nonspecific
binding was determined with 10 µ haloperidol.[13] The σ2-receptor
affinity was determined using rat liver membrane preparations with
the radioligand [3H]-ditolylguanidine in the presence of 100 n
(ϩ)-pentazocine to mask σ1-binding sites. Nonspecific binding was
determined with 10 µ ditolylguanidine.[14,15] Ki values were calcu-
lated according to Cheng and Prusoff[16] and represent data from
at least three independent experiments, each performed in triplicate.
The results are given as mean Ϯ standard error of the mean (SEM).
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie, and the Wissenschaftliche Gesellschaft Frei-
burg for financial support. Thanks are also due to Degussa AG,
JanssenϪCilag GmbH and BristolϪMyers Squibb for the donation
of chemicals and reference compounds.
19: IR (film): ν˜ ϭ 3038, 2922, 2821 (CϪH), 1660 (CϭC), 1095
(CϪO), 744, 700 (CϪH) cmϪ1 1H NMR (CDCl3): δ ϭ 2.09 [td,
.
J
ϭ 12.5, 5.4 Hz, 2 H, N(CH2CH2)2], 2.36Ϫ2.52 [m, 4 H,
N(CH2CH2)2], 2.80 [br. d, J ϭ 12.2 Hz, 2 H, N(CH2CH2)2], 3.56
(s, 2 H, NCH2Ph), 3.59 (d, J ϭ 5.2 Hz, 2 H, ArCH2CHϭCH), 4.77
(dt, J ϭ 7.0, 5.2 Hz, 1 H, ArCH2CHϭCH), 6.27 (dt, J ϭ 7.0,
1.5 Hz, 1 H, ArCH2CHϭCH), 7.04Ϫ7.08 (m, 1 H, 6-H), 7.12Ϫ7.21
(m, 2 H, arom), 7.24Ϫ7.38 (m, 6 H, arom) ppm. 13C NMR
(CDCl3): δ ϭ 34.4 [2 C, N(CH2CH2)2], 34.6 (1 C, ArCH2CHϭ
CH), 49.4 [2 C, N(CH2CH2)2], 63.1 (1 C, NCH2Ph), 78.9 (1 C,
ArCO), 104.5 (1 C, ArCH2CHϭCH), 125.8 (1 C, arom. CH), 126.4
(1 C, arom. CH), 127.1 (1 C, arom. CH), 127.5 (1 C, arom. CH),
128.2 (2 C, arom. CH), 129.3 (2 C, arom. CH), 130.6 (1 C, C-6),
138.4 (1 C, arom. C), 139.0 (1 C, arom. C), 142.5 (1 C, arom. C),
142.8 (1 C, ArCH2CHϭCH) ppm. MS (EI): m/z ϭ 305 [Mϩ].
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EtOAc, 5:2, 10 mL, Rf ϭ 0.09) to afford a colorless oil, which so-
lidified on standing (m.p. 97Ϫ105 °C), yield 70 mg (92%). IR (film):
ν˜ ϭ 2940, 2816 (CϪH), 2250 (CϵN), 1092, 1040 (CϪO), 742, 699
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(CϪH) cmϪ1. H NMR (CDCl3): δ ϭ 1.77 [td, J ϭ 12.8, 4.9 Hz,
1
1 H, N(CH2CH2)2], 1.82Ϫ1.96 [m, 3 H, N(CH2CH2)2 (1 H),
ArCH2CH2CH (2 H)], 2.06 [ddd, J ϭ 13.7, 5.3, 2.5 Hz, 1 H,
N(CH2CH2)2], 2.45 [td, J ϭ 12.2, 4.3 Hz, 1 H, N(CH2CH2)2],
2.49Ϫ2.66 [m, 5 H, N(CH2CH2)2 (2 H), ArCH2CH2CH (1 H),
CH2CN (2 H)], 2.70 [br. d, J ϭ 11.0 Hz, 1 H, N(CH2CH2)2], 2.87
[br. d, J ϭ 11.0 Hz, 1 H, N(CH2CH2)2], 3.33Ϫ3.45 (m, 1 H,
ArCH2CH2CH), 3.59 (s, 2 H, NCH2Ph), 3.83Ϫ3.94 (m, 1 H,
ArCH2CH2CH), 7.08 (dd, J ϭ 7.0, 1.5 Hz, 1 H, arom), 7.14Ϫ7.41
(m, 8 H, arom) ppm. 13C NMR (CDCl3): δ ϭ 24.9 (1 C, CH2CN),
30.7 (1 C, ArCH2CH2CH), 32.7 [1 C, N(CH2CH2)2], 33.8 (1 C,
ArCH2CH2CH), 39.2 [1 C, N(CH2CH2)2], 49.3 [1 C, N(CH2CH2)2],
49.6 [1 C, N(CH2CH2)2], 63.2 (1 C, NCH2Ph), 67.0 (1 C,
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Received August 13, 2002
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Eur. J. Org. Chem. 2003, 714Ϫ720