Late-stage C-H bond arylation of spirocyclic σ1 ligands for analysis of complementary σ1 receptor surface

Article abstract of DOI:10.1002/ejoc.201200837

Direct C-H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the ca

Full text of DOI:10.1002/ejoc.201200837

Job/Unit: O20837
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FULL PAPER
DOI: 10.1002/ejoc.201200837
Late-Stage C–H Bond Arylation of Spirocyclic σ1 Ligands for Analysis of
Complementary σ1 Receptor Surface
Christina Meyer,[a] Dirk Schepmann,[a] Shuichi Yanagisawa,[b] Junichiro Yamaguchi,[b]
Kenichiro Itami,*[b] and Bernhard Wünsch*[a]
Keywords: C–C coupling / Arylation / Sulfur heterocycles / Ligand design / Spiro compounds / Protein structures
Direct C–H bond arylation in the α- and β-positions of spi-
rocyclic thiophenes containing various functional groups
(amine, ether, acetal, lactone) was accomplished. Selective
phenylation in the α-position of the thiophene ring was
achieved by using the catalytic system PdCl2/bipy/Ag2CO3.
The introduction of phenyl moieties to the β-position was
performed with the catalytic system PdCl2/P[OCH(CF3)2]3/
Ag2CO3. Even the five-membered lactone 10 with an elec-
tron-withdrawing carbonyl moiety directly attached to the
thiophene ring was arylated. Spirocyclic thiophenes substi-
tuted with a phenyl moiety in position A (top position) or B
(left position) display low nanomolar σ1 affinities (e.g., 4a: Ki
= 1.6 nM; 5a: Ki = 2.4 nM), indicating an additional hydro-
phobic pocket on the complementary σ1 receptor protein. A
phenyl moiety in position C (at the bottom position) is not
tolerated by the σ1 receptor (e.g., 12: Ki = 483 nM). However,
an additional phenyl moiety in position A is able to compen-
sate at least partially the unfavorable effects of the phenyl
moiety in position C.
conformationally restricted compounds with extended lipo-
philic regions will provide deeper insights into the elusive
complementary surface of the σ1 receptor protein (Fig-
ure 1). In this respect, the influence of the position of an
additional phenyl moiety and the sulfur atom on the σ1
receptor affinity are of particular interest. Therefore, it was
planned to attach a lipophilic phenyl moiety at various po-
sitions A (top position), B (left position), and C (bottom
position) of regioisomeric spirocyclic thiophene derivatives.
1. Introduction
The class of σ receptors consists of at least two subtypes
termed σ1 and σ2 receptors.[1] Whereas the σ1 receptor has
been cloned from various tissues and species including hu-
man brain, the σ2 subtype has not been characterized at the
molecular level so far.[2] It has been shown that various ion
channels (e.g., K+ and Ca2+ channels) and neurotransmitter
systems (e.g., glutamatergic, dopaminergic, and cholinergic
neurotransmission) are modulated by σ1 receptors. There-
fore, ligands interacting with σ1 receptors are of great inter-
est for the treatment of acute and chronic neurological dis-
orders (e.g., schizophrenia, depression, Alzheimer’s disease,
and neuropathic pain).[3]
As reported recently, the spirocyclic thiophene deriva-
tives 2a, 2b,[4] and 3b[5] possess very high affinity toward σ1
receptors. According to relevant pharmacophore models[6]
the lipophilic region of the thiophene moiety should be en-
larged to achieve even higher σ1 affinity. Moreover, potent
[a] Institut für Pharmazeutische und Medizinische Chemie der
Westfälischen Wilhelms-Universität Münster,
Hittorfstraße 58–62, 48149 Münster, Germany
Fax: +49-251-8332144
E-mail: wuensch@uni-muenster.de
Figure 1. Direct C–H bond arylation of spirocyclic thiophenes.
Homepage: http://www.uni-muenster.de/Chemie.pz/forschen/ag/
wuensch/
[b] Department of Chemistry, Graduate School of Science, Nagoya
University,
The phenyl group should be introduced at a very late
stage of the synthesis so as to provide access to diverse sets
of arylated thiophenes. For this purpose, direct C–H bond
functionalization of regioisomeric thiophene cores was en-
visaged. Enormous efforts have provided useful catalytic
systems for reactions that assemble arenes through C–H
Chikusa, Nagoya 464-8602, Japan
Fax: +81-52-788 6098
E-mail: itami.kenichiro@a.mbox.nagoya-u.ac.jp
Homepage: http://synth.chem.nagoya-u.ac.jp/wordpress/
?cat=13&lang=en
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200837.
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K. Itami, B. Wünsch et al.
FULL PAPER
bond functionalization. The first Pd-catalyzed direct C–H
bond arylation was reported by Ohta et al. in 1990.[7] Sub-
sequently, various catalysts (Pd,[8] Rh,[9] Ir,[10] Cu[11]) pro-
moting the C–H bond arylation of thiophenes with haloar-
enes have been developed. Typically these arylation reac-
tions occur regioselectively in the α-position of thiophenes.
Nevertheless, some unique catalysts leading to selective β-
arylation of thiophene have been established.[12] However,
most of the developed catalysts were only applied on simple
thiophenes without further functional groups.
Herein, we report the regioselective α-arylation of com-
plex spirocyclic thiophene derivatives with additional func-
tional groups including amine, ether, acetal, and lactone
with the catalytic system PdCl2/2,2Ј-bipyridyl/Ag2CO3.[13]
Moreover, the same complex thiophenes were subjected to
β-arylation by using the catalytic system PdCl2/
P[OCH[CF3]2]3/Ag2CO3.[12a,12b] The effect of the additional
phenyl moiety and the position of the sulfur atom on σ1
receptor binding was studied with radioligand receptor
binding studies.
2. Chemistry
spirocyclic thiophenes 1 were first treated with iodo-
benzene, PdCl2/bipy and Ag2CO3 (catalyst B)[13] in boiling
m-xylene (150 °C) to provide the α-phenylated products 5
in 38–64% yields (Scheme 1). Clearly, the functional groups
ether, acetal, lactone, and tertiary amine were compatible
with the catalyst system and the reaction conditions.
Because the pharmacological properties of the positional
isomers 4 were also of great interest, compounds 1 were
treated with iodobenzene and PdCl2/P[OCH[CF3]2]3/
Ag2CO3 (catalyst A).[12a,12b] These reaction conditions led
predominantly to the β-arylated thiophenes 4 and addition-
ally to small amounts of the regioisomeric α-arylated prod-
ucts 5. Due to similar properties of the regioisomeric thio-
phenes 4 and 5, the final purification of 4 for the pharmaco-
logical evaluation reduced the yields considerably. However,
it should be noted that even the lactones 4c (31%) and 5c
(47%) were formed in the presence of basic Ag2CO3.
To synthesize regioisomers with respect to the sulfur-
atom in the spirocyclic system, the regioisomeric spirocyclic
thiophenes 2[4] and 3[5] were phenylated. The α-phenylation
of 2a and 2b using catalyst B has already been reported to
produce 6a and 6b.[4] The same reaction conditions were
used for the phenylation of lactone 2c and the regioisomeric
thiophene 3b to provide the phenylated products 6c and 7b
in 57% yields, respectively, showing the stability of the pres-
ent functional groups (lactone, acetal) under the given con-
ditions.
Scheme 1. Synthesis of a series of isomers by catalyst-controlled
regioselective C–H bond arylation; catalyst A: PdCl2/P[OCH-
(CF3)2]3/Ag2CO3; catalyst B: PdCl2/bipy/Ag2CO3; bipy = 2,2Ј-bi-
pyridyl; yields after gel permeation chromatography.
Because α-arylation of six-membered lactones 1c and 2c
took place with high regioselectivity, α-arylation of the cor-
responding five-membered lactone 10 was envisaged
(Scheme 2). Lactone 10 was prepared in a one-pot, three piperidin-4-one and CO2, respectively, and a final cycliza-
step reaction sequence, which involved two sequential tion with acetic anhydride. A similar synthesis of an N-
bromine/lithium exchange reactions followed by trapping of methylated derivative has already been reported in the lit-
the corresponding aryllithium intermediates with 1-benzyl- erature.[14]
2
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Late-Stage C–H Bond Arylation of Spirocyclic σ1 Ligands
Table 1. The σ1 affinities of phenylated spirocyclic thiophenes com-
pared with non-phenylated parent compounds and reference com-
pounds.
X
σ1 Affinity[a]
Ki ϮSEM [nM] (n = 3)
1a
H/H
H/OCH3
O
H/H
H/OCH3
O
H/OCH3
H/H
H/OCH3
O
H/H
H/OCH3
O
H/H
H/OCH3
O
1.0Ϯ0.30
1.9Ϯ0.44
255
0.35Ϯ0.06
0.22Ϯ0.06
40Ϯ13
0.32Ϯ0.10
1.6Ϯ0.70
5.4Ϯ0.97
5.3Ϯ0.88
2.4Ϯ0.69
16Ϯ5.8
23Ϯ9.9
4.5Ϯ2.9
1.0Ϯ0.4
2.5Ϯ0.91
5.5Ϯ1.5
16Ϯ6.8
11Ϯ3.2
483
1b
1c
2a[4]
2b[4]
2c
3b[5]
4a
4b
4c
5a
5b
5c
6a[4]
6b[4]
6c
Scheme 2. Synthesis and phenylation of lactone 10.
7b
H/OCH3
10
–
–
–
–
11
Reaction of lactone 10 with iodobenzene and catalyst B
led to a mixture of three arylated products 11, 12, and 13.
Unexpectedly, phenylation of the otherwise unreactive 6-
position (compounds 1–3) had taken place. The attack of
the 6-position is explained by electronic and steric reasons.
In particular, the electron density in the 4-position of the
thiophene ring is reduced by the carbonyl moiety directly
attached to the thiophene ring. Additionally, the five-mem-
bered lactone leads to an expanded angle of the spirocyclic
system, which allows the approach of the arylpalladium
species to the 6-position. Altogether the arylation of 10 is
remarkable because its electron density is considerably
lower than those of spirocyclic thiophenes 1–3.
12
13
87Ϯ52
(+)-pentazocine
Haloperidol
5.7Ϯ2.2
6.3Ϯ1.6
[a] Ki values were determined in competition experiments with
{3H}-(+)-pentazocine.
ety at the left position (position B compounds 5 and 7),
whereas attachment of the phenyl group at the bottom posi-
tion (position C, compounds 12 and 13) resulted in con-
siderably reduced σ1 affinity. With the exception of the pair
4a/6a, the phenylated compounds 6 with the S-atom at the
left position (B) are more potent than the phenylated com-
pounds 6 with the S-atom at the top position (A).
Generally, spirocyclic thiophenes with a lactone moiety
(c-series) show considerably lower σ1 receptor affinities
than their analogues without a substituent (a-series) or with
an acetalic group (b-series). However, the σ1 affinity of the
phenylated lactones 4c, 5c, and 6c is more than tenfold in-
creased compared to the less potent nonphenylated lactones
1c and 2c. It is assumed that additional lipophilic interac-
tions of the phenyl moiety are able to compensate for the
unfavorable binding properties of the lactone moiety.
Introduction of a phenyl moiety in the top position (A)
of the five-membered lactone 10 led to a slight increase of
σ1 affinity (11). However, the regioisomer 12, with the
phenyl moiety in the bottom position (C), is almost inactive
at the σ1 receptor. An additional phenyl moiety in the top
position (13) is able to compensate a little for the negative
effect of the 6-phenyl moiety of 12.
3. Receptor Affinity
The σ1 receptor affinities of the arylated compounds
were determined in receptor binding studies using guinea
pig brain preparations and the radioligand [3H]-(+)-pentaz-
ocine.[15] In Table 1 the Ki values of the arylated compounds
are compared with the Ki values of the parent compounds
without a phenyl substituent; reference compounds are also
included.
The nonarylated spirocyclic thiophene derivatives 1–3 in-
teract in the low nanomolar or even subnanomolar range
(e.g., 2a, 2b, and 3b) with σ1 receptors. In the group of
nonphenylated compounds the σ1 affinity increases in the
order 1 (S bottom position) Ͻ 2 (S left position) ≈ 3 (S top
position).
Although the σ1 affinity of phenylated compounds is
comparable (e.g., 1a/5a) or slightly reduced (e.g., 3b/7b, 2a/
6a) compared to the nonphenylated parent compounds,
they all bind in the low nanomolar range at σ1 receptors.
Clearly the σ1 receptor tolerates an additional lipophilic
moiety in its binding pocket. As a general trend, a phenyl
4. Conclusion
It was shown that the direct regioselective α-arylation of
moiety at the top position (position A, compounds 4 and complex spirocyclic thiophenes containing various func-
6) is better tolerated by the σ1 receptor than a phenyl moi- tional groups (amine, ether, acetal, lactone) is possible by
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FULL PAPER
General Procedures
C–H bond functionalization with iodobenzene and the
catalytic system PdCl2/bipy/Ag2CO3. The corresponding β-
arylated thiophenes were obtained by using the catalytic
system PdCl2/P[OCH(CF3)2]3/Ag2CO3. The advantage of
these catalytic systems is their compatibility with several
functional groups, allowing the introduction of the phenyl
moiety as last step of the synthesis. Spirocyclic thiophenes
with various functional groups containing the S-atom and
the phenyl moiety at different ring positions are available
through this novel synthetic strategy. Thus, the pharmaco-
logical properties of a diverse set of spirocyclic thiophenes
could be investigated. To achieve high σ1 receptor affinity
the spirocyclic thiophenes should contain the S-atom in the
left or top position, the phenyl moiety at the top position,
and either a proton or a methoxy group adjacent to the
ring O-atom. The promising σ1 affinity of the phenylated
compounds indicate a hydrophobic pocket of the σ1 recep-
tor protein in this region.
General Procedure A for the α-Arylation of Spirocyclic Thiophenes
with Iodoarenes: A 20 mL glass vessel was equipped with a mag-
netic stirring bar and closed by a J. Young O-ring tap. The flask
was flame-dried under vacuo and filled with Ar after cooling to
room temp. Under a permanent stream of Ar, the catalyst PdCl2/
bipy (10 mol-%) and Ag2CO3 (1 equiv.) were added into the vessel
and suspended in anhydrous m-xylene (0.4 mL). The mixture was
stirred at 60 °C for 30 min. Finally, a solution of iodobenzene
(1.1 equiv.) and a solution of the spirocyclic starting material
(1 equiv.) in anhydrous m-xylene (0.6 mL in total) were added drop-
wise. The vessel was sealed with the O-ring tap and heated at
150 °C for 12 h in an eight-well reaction block. After cooling the
vessel to room temp., the mixture was filtered through a short silica
pad (EtOAc). The filtrate was concentrated in vacuo and the crude
product was purified by gel permeation chromatography (CHCl3)
followed by preparative thin-layer chromatography or flash
chromatography (short column) to yield the corresponding arylthi-
ophene in high purity.
General Procedure B for the β-Arylation of Spirocyclic Thiophenes
with Iodoarenes: A 20 mL glass vessel was equipped with a mag-
netic stirring bar and closed by a J. Young O-ring tap. The flask
was flame-dried under vacuo and filled with Ar after cooling to
room temp. Under a permanent stream of Ar, PdCl2 (10 mol-%)
and Ag2CO3 (1 equiv.) were added to the vessel. The phosphite
ligand P[OCH(CF3)2]3 (20 mol-%) and subsequently anhydrous m-
xylene (0.5 mL) were added and the mixture was stirred at 60 °C
for 30 min to form the active catalyst. Finally, a solution of the
iodoarene (1.1 equiv.) and a solution of the spirocyclic starting ma-
terial (1 equiv.) in anhydrous m-xylene (0.5 mL in total) were
added. The vessel was sealed with the O-ring tap and heated at
150 °C for 12 h in an eight-well reaction block. After cooling the
vessel to room temp., the mixture was filtered through a short silica
pad (EtOAc). The filtrate was concentrated in vacuo and the crude
product was purified by gel permeation chromatography (CHCl3)
followed by preparative thin-layer chromatography or flash
chromatography (short column) to yield the corresponding aryl-
thiophene in high purity.
Experimental Section
General: Unless otherwise noted, moisture- and oxygen-sensitive
reactions were conducted in dry glassware (Schlenk flask sealed
with a rubber septum) under N2 [dried with phosphorus pentoxide
(Granusic® A, Baker)]. THF and Et2O were dried with sodium/
benzophenone and were freshly distilled before use. Thin-layer
chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash
chromatography (fc): Silica gel 60, 40–64 μm (Merck); parentheses
include: diameter of the column [cm], length of the stationary phase
[cm], eluent, fraction size [mL] and retention factor Rf. Gel permea-
tion chromatography (gpc): LC-9204 instrument (JAI) with JAI-
GEL-1H/JAIGEL-2H columns, eluent CHCl3; preparative thin-
layer chromatography (prep. tlc): Wako-gel® B5-F silica coated
plates (0.75 mm) prepared in the Itami laboratory. IR were ob-
1
tained with a 480Plus FT-ATR-IR (Jasco) spectrophotometer. H
Procedures for the Preparation of Compounds
NMR (400 MHz, 300 MHz, 600 MHz) and 13C NMR (100 MHz)
spectra were recorded with a Unity Mercury Plus 400 (400 MHz)
NMR spectrometer (Varian), JNM-ECA-400 (400 MHz) spectrom-
eter (JEOL), Bruker AV 300 (300 MHz), or Varian Unity Plus 600
(600 MHz) operating at 23 °C. Chemical shifts δ are reported in
parts per million (ppm) against the reference compound tetrameth-
ylsilane and calculated using the chemical shift of the signal of
the residual nondeuterated solvent. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet
of doublets, t = triplet, q = quatet, m = multiplet), coupling con-
stant [Hz] and integration. HRMS (ESI): Finnigan MAT 4200s,
Bruker Daltonics Micro Tof and Waters Micromass Quatro LCZ,
peaks are given in m/z (% of basis peak). EI, electron impact, MAT
GCQ (Thermo-Finnigan). HRMS: JMS-T100TD instrument
(DART); HPLC: Agilent Technologies® equipment: UV detector:
1-Benzyl-3Ј-phenyl-4Ј,5Ј-dihydrospiro(piperidine-4,7Ј-thieno[2,3-c]-
pyran) (4a): According to General Procedure B, spirocyclic thio-
phene 1a (31.3 mg, 0.105 mmol) was treated with iodobenzene
(12.8 μL, 0.11 mmol), Ag2CO3 (28.1 mg, 0.10 mmol), PdCl2
(2.0 mg, 0.01 mmol), and P[OCH(CF3)2]3 (7.1 μL, 0.02 mmol) in
m-xylene (1.2 mL). The crude product was purified by CHCl3-gpc
and prep. tlc (h = 15 cm; hexane/EtOAc = 10:1; Rf = 0.06; 4 runs).
Pale-yellow resin; yield 8.2 mg [21% after gpc, mixture of regioiso-
mers; HPLC: tR = 8.11 (4a; 89.5%), 8.46 (regioisomer 5a; 9.4%)
min]; colorless resin, yield 2.5 mg (6% after prep. tlc). 1H NMR
(400 MH, CDCl3): δ = 1.96–2.08 [m, 4 H, N(CH2CH2)2], 2.44 [td,
J = 11.4, 4.0 Hz, 2 H, N(CH2CH2)2], 2.69 (t, J = 5.4 Hz, 2 H,
thiophCH2CH2), 2.75 [d, J = 11.5 Hz, 2 H, N(CH2CH2)2], 3.57 (s,
2 H, NCH2Ph), 3.90 (t, J = 5.4 Hz, 2 H, thiophCH2CH2), 7.13
Agilent 1200 variable wavelength detector G13143/G1314C (SL); (s, 1 H, 2Ј-H-thioph), 7.27–7.42 (m, 10 H, Ph-H) ppm. 13C NMR
autosampler: Agilent 1200; pump: quaternary pump for gradient
analysis; degasser: Agilent 1200 micro vacuum degasser; column:
ZORBAX Eclipse Plus X18 2.1ϫ150 mm, 3.5 μm; temperature:
23 °C; flow rate: 0.40 mL/min; injection volume: 1.0 μL; detection
at λ = 254 nm; solvents: A: water with 5 mm NH4HCO2; B: acetoni-
trile; gradient elution: (A%): 0–5 min: gradient from 80 to 0%, 5–
13 min: 0%, 13–18 min: 0 to 80%. The purity of all test compounds
was greater than 95%.
(100 MHz, CDCl3): δ = 27.2 (1C, thiophCH2CH2), 38.7 [2C,
N(CH2CH2)2], 49.4 [2C, N(CH2CH2)2], 59.5 (1C, thiophCH2CH2),
63.5 (1C, NCH2Ph), 73.3 (1C, thiophCspiro), 119.7 (1C, CH-2Ј-thio-
ph), 127.2 (Ph-CH), 127.3 (Ph-CH), 128.4 (Ph-CH), 128.4 (Ph-
CH), 128.7 (Ph-CH), 129.5 (Ph-CH), 131.8 (1C, Cquat), 136.5 (1C,
Cquat), 138.8 (1C, Cquat), 141.7 (1C, Cquat), 144.0 (1C, Cquat) ppm.
HRMS (APCI): calcd. for C24H26NOS [MH+] 376.1730; found
376.1684.
4
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Late-Stage C–H Bond Arylation of Spirocyclic σ1 Ligands
1-Benzyl-5Ј-methoxy-3Ј-phenyl-4Ј,5Ј-dihydrospiro(piperidine-4,7Ј-
thieno[2,3-c]pyran) (4b): According to General Procedure B, spi-
rocyclic thiophene 1b (48 mg, 0.15 mmol) was treated with iodo-
benzene (17.9 μL, 0.16 mmol), Ag2CO3 (46.6 mg, 0.17 mmol),
PdCl2 (2.9 mg, 0.016 mmol), and P[OCH(CF3)2]3 (10.3 μL,
0.032 mmol) in m-xylene (1.5 mL). The crude product was purified
by CHCl3-gpc and prep. tlc (h = 15 cm; hexane/EtOAc = 14:1, NEt3
2%; Rf = 0.10; 7 runs). Colorless solid, yield 18.9 mg (32% after
gpc, mixture of regioisomers); colorless solid, yield 7.5 mg (13%
after prep. tlc). 1H NMR (400 MHz, CDCl3): δ = 1.97 [td, J = 12.8,
3.3 Hz, 1 H, N(CH2 CH2 )2 ], 2.02–2.16 [m, 3 H, N(CH2 -
CH2)2], 2.49 [td, J = 12.1, 2.4 Hz, 1 H, N(CH2CH2)2], 2.59 [td, J
= 11.6, 2.9 Hz, 1 H, N(CH2CH2)2], 2.74–2.86 [m, 4 H, N(CH2-
CH2)2, thiophCH2CH], 3.54 (s, 3 H, OCH3), 3.58 (d, J = 13.7 Hz,
1 H, NCH2Ph), 3.61 (d, J = 13.4 Hz, 1 H, NCH2Ph), 4.85 (dd, J
= 6.8, 3.7 Hz, 1 H, thiophCH2CH), 7.16 (s, 1 H, 2Ј-H-thioph),
7.27–7.41 (m, 10 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 32.8 (1C, thiophCH2CH), 37.9 [1C, N(CH2CH2)2], 40.9 [1C,
N(CH2CH2)2], 49.4 [2C, N(CH2CH2)2], 56.7 (1C, OCH3), 63.4 (1C,
NCH2Ph), 74.2 (1C, thiophCspiro), 97.5 (1C, thiophCH2CH), 120.6
(1C, CH-2Ј-thioph), 127.4 (Ph-CH), 127.4 (Ph-CH), 128.4 (Ph-
CH), 128.5 (Ph-CH), 128.7 (Ph-CH), 129.6 (1C, Cquat), 129.7 (1C,
Cquat), 136.2 (1C, Cquat), 141.6 (1C, Cquat), 143.0 (1C, Cquat) ppm.
HRMS (ESI): calcd. for C25H27NO2S [M+] 405.1762; found
405.1780.
N(CH2CH2)2], 49.3 [2C, N(CH2CH2)2], 59.2 (1C, thiophCH2CH2),
63.5 (1C, NCH2Ph), 73.0 (1C, thiophCspiro), 123.1 (1C, CH-3Ј-
thioph), 125.8 (Ph-CH), 127.2 (Ph-CH), 127.5 (Ph-CH), 128.4 (Ph-
CH), 129.0 (Ph-CH), 129.4 (Ph-CH), 134.2 (1C, Cquat), 134.6 (1C,
Cquat), 138.9 (1C, Cquat), 141.6 (1C, Cquat), 142.4 (1C, Cquat) ppm.
HRMS (APCI): calcd. for C24H26NOS [MH+] 376.1730; found
376.1679.
1-Benzyl-5Ј-methoxy-2Ј-phenyl-4Ј,5Ј-dihydrospiro(piperidine-4,7Ј-
thieno[2,3-c]pyran) (5b): According to General Procedure A, spi-
rocyclic thiophene 1b (19.5 mg, 0.060 mmol) was treated with iodo-
benzene (7.5 μL, 0.07 mmol), Ag2CO3 (17.3 mg, 0.06 mmol), and
PdCl2/bipy (2.1 mg, 0.006 mmol) in m-xylene (1.0 mL). The crude
product was purified by CHCl3-gpc and prep. tlc (h = 15 cm; hex-
ane/EtOAc = 3:2; Rf = 0.5). Colorless solid, yield 9.2 mg (38% after
1
CHCl3-gpc); colorless solid, yield 4.5 mg (19% after prep. tlc). H
NMR (400 MHz, CDCl3): δ = 1.91–2.07 [m, 2 H, N(CH2CH2)2],
2.08–2.17 [m, 2 H, N(CH2CH2)2], 2.47 [td, J = 11.5, 2.8 Hz, 1 H,
N(CH2CH2)2], 2.57 [td, J = 11.8, 2.9 Hz, 1 H, N(CH2CH2)2], 2.72
(dd, J = 15.5, 7.4 Hz, 1 H, thiophCH2CH), 2.77–2.84 [m, 2 H,
N(CH2CH2)2], 2.87 (dd, J = 15.5, 3.3 Hz, 1 H, thiophCH2CH),
3.57 (s, 3 H, OCH3), 3.57 (d, J = 13.2 Hz, 1 H, NCH2Ph), 3.61
(d, J = 13.2 Hz, 1 H, NCH2Ph), 4.92 (dd, J = 7.3, 3.3 Hz, 1 H,
thiophCH2CH), 6.94 (s, 1 H, 3Ј-H-thioph), 7.27–7.39 (m, 8 H, Ph-
H), 7.49–7.54 (m, 2 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 32.4 (1C, thiophCH2CH), 37.6 [1C, N(CH2CH2)2], 40.8 [1C,
N(CH2CH2)2], 49.4 [2C, N(CH2CH2)2], 56.7 (1C, OCH3), 63.4 (1C,
NCH2Ph), 74.1 (1C, thiophCspiro), 97.2 (1C, thiophCH2CH), 122.9
(1C, CH-3Ј-thioph), 125.7 (Ph-CH), 127.3 (Ph-CH), 127.6 (Ph-
CH), 128.4 (Ph-CH), 129.0 (Ph-CH), 129.5 (Ph-CH), 132.0 (1C,
Cquat), 134.4 (1C, Cquat), 138.4 (1C, Cquat), 141.0 (1C, Cquat), 142.6
(1C, Cquat) ppm. HRMS (ESI): calcd. for C25H27NO2S [M+]
405.1762; found 405.1781.
1-Benzyl-3Ј-phenylspiro(piperidine-4,7Ј-thieno[2,3-c]pyran)-5Ј-
(4ЈH)-one (4c): According to General Procedure B, spirocyclic thio-
phene 1c (30.6 mg, 0.098 mmol) was treated with iodobenzene
(12 μL, 0.11 mmol), Ag2CO3 (29.2 mg, 0.11 mmol), PdCl2 (1.7 mg,
0.01 mmol), and P[OCH(CF3)2]3 (6.3 μL, 0.02 mmol) in m-xylene
(1.2 mL). The crude product was purified by CHCl3-gpc and prep.
tlc (h = 15 cm; hexane/EtOAc = 7:3; Rf = 0.06; 4 runs). Colorless
solid; m.p. 115 °C; yield 11.8 mg [31%, mixture of regioisomers,
HPLC: tR = 7.25 (4c; 96.3%) min]; colorless solid, yield 3.7 mg
1-Benzyl-2Ј-phenylspiro(piperidine-4,7Ј-thieno[2,3-c]pyran)-5Ј-
(4ЈH)-one (5c): According to General Procedure A, spirocyclic thio-
phene 1c (30.8 mg, 0.098 mmol) was treated with iodobenzene
(12.1 μL, 0.11 mmol), Ag2CO3 (30.2 mg, 0.11 mmol), and PdCl2/
bipy (3.4 mg, 0.01 mmol) in m-xylene (1.2 mL). The crude product
was purified by CHCl3-gpc and fc (Ø = 1.5 cm, h = 5 cm; hexane/
EtOAc = 4:1, 3 mL; Rf = 0.20). Colorless solid; m.p. 140 °C; yield
17.8 mg (47% after gpc); colorless solid, yield 12.5 mg (33% after
1
(9.7% after prep. tlc). H NMR (400 MHz, CDCl3): δ = 2.11 [d, J
= 12.8 Hz, 2 H, N(CH2CH2)2], 2.19 [td, J = 14.4, 3.8 Hz, 2 H,
N(CH2CH2)2], 2.63 [td, J = 11.6, 2.7 Hz, 2 H, N(CH2CH2)2], 2.82
[d, J = 11.6 Hz, 2 H, N(CH2CH2)2], 3.61 (s, 2 H, NCH2Ph), 3.70
(s, 2 H, thiophCH2), 7.23 (s, 1 H, 2Ј-H-thioph), 7.27–7.48 (m, 10
H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.0 (1C, thio-
phCH2C=O), 38.8 [2C, N(CH2CH2)2], 48.7 [2C, N(CH2CH2)2],
63.2 (1C, NCH2Ph), 81.4 (1C, thiophCspiro), 121.9 (CH-2Ј-thioph),
127.4 (Ph-CH), 128.0 (Ph-CH), 128.3 (Ph-CH), 128.5 (Ph-CH),
129.0 (Ph-CH), 129.2 (1C, Cquat), 129.4 (Ph-CH), 135.2 (1C, Cquat),
138.5 (1C, Cquat), 139.5 (1C, Cquat), 141.1 (1C, Cquat), 169.3 (1C,
C=O) ppm. HRMS (APCI): calcd. for C24H24NO2S [MH+]
390.1522; found 390.1545.
1
fc). HPLC: tR = 7.42 (97.3%) min. H NMR (400 MHz, CDCl3):
δ = 2.08 [dd, J = 14.5, 2.3 Hz, 2 H, N(CH2CH2)2], 2.17 [td, J =
14.2, 4.4 Hz, 2 H, N(CH2CH2)2], 2.62 [td, J = 11.7, 2.8 Hz, 2 H,
N(CH2CH2)2], 2.81 [d, J = 11.5 Hz, 2 H, N(CH2CH2)2], 3.60 (s, 2
H, NCH2Ph), 3.70 (s, 2 H, thiophCH2), 7.00 (s, 1 H, 3Ј-H-thioph),
7.27–7.43 (m, 8 H, Ph-H), 7.49–7.58 (m, 2 H, Ph-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 31.7 (1C, thiophCH2C=O), 39.0 [2C,
N(CH2CH2)2], 48.7 [2C, N(CH2CH2)2], 63.2 (1C, NCH2Ph), 81.8
(1C, thiophCspiro), 121.7 (1C, CH-3Ј-thioph), 126.0 (Ph-CH), 127.4
(Ph-CH), 128.3 (Ph-CH), 128.6 (Ph-CH), 129.3 (Ph-CH), 129.4
(Ph-CH), 130.5 (1C, Cquat), 133.8 (1C, Cquat), 137.5 (1C, Cquat),
138.6 (1C, Cquat), 144.7 (1C, Cquat), 169.1 (1C, C=O). HRMS
(APCI): calcd. for C24H24NO2S [MH+] 390.1522; found 390.1531.
1-Benzyl-2Ј-phenyl-4Ј,5Ј-dihydrospiro(piperidine-4,7Ј-thieno[2,3-c]py-
ran) (5a): According to General Procedure A, spirocyclic thiophene
1a (29.4 mg, 0.098 mmol) was treated with iodobenzene (12.1 μL,
0.11 mmol), Ag2CO3 (29.2 mg, 0.11 mmol), and PdCl2/bipy
(3.4 mg, 0.01 mmol) in m-xylene (1.2 mL). The crude product was
purified by CHCl3-gpc and fc (Ø = 1.5 cm, h = 5 cm; hexane/
EtOAc = 3:2, 3 mL; Rf = 0.52). Colorless resin, yield 23.6 mg (64%
after gpc); colorless resin, yield 14.5 mg (40% after fc). HPLC: tR
=
1-Benzyl-1Ј-phenyl-6Ј,7Ј-dihydrospiro(piperidine-4,4Ј-thieno[3,4-c]-
1
8.57 (90%), 8.24 (8.0% regioisomer 4a) min. H NMR (400 MHz, pyran) (6a):[4] According to General Procedure A, spirocyclic thio-
CDCl3): δ 1.94–2.09 [m, 4 H, N(CH2CH2)2], 2.43 [td, J = 11.3,
phene 2a (27.7 mg, 0.093 mmol) was treated with iodobenzene
4.1 Hz, 2 H, N(CH2CH2)2], 2.69 (t, J = 5.5 Hz, 2 H, thio- (11.3 μL, 0.10 mmol), Ag2CO3 (28 mg, 0.10 mmol), and PdCl2/bipy
phCH2CH2), 2.74 [d, J = 11.6 Hz, 2 H, N(CH2CH2)2], 3.57 (s, 2 (3.6 mg, 0.01 mmol) in m-xylene (1.2 mL). The crude product was
H, NCH2Ph), 3.94 (t, J = 5.5 Hz, 2 H, thiophCH2CH2), 6.96 (s, 1 purified by CHCl3-gpc and prep. tlc (h = 15 cm, hexane/EtOAc =
H, 3Ј-H-thioph), 7.22–7.25 (m, 1 H, Ph-H), 7.27–7.29 (m, 1 H, Ph-
H), 7.29–7.41 (m, 6 H, Ph-H), 7.51–7.56 (m, 2 H, Ph-H) ppm. 13C orless solid, yield 12.0 mg (35 % after prep. tlc). 1H NMR
NMR (100 MHz, CDCl3): δ = 26.6 (1C, thiophCH2CH2), 38.4 [2C, (400 MHz, CDCl3): δ = 1.95–2.06 [m, 4 H, N(CH2CH2)2], 2.42 [td,
9:1; Rf = 0.42). Colorless solid, yield 18.8 mg (54% after gpc); col-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O20837
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Date: 05-09-12 18:22:58
Pages: 9
K. Itami, B. Wünsch et al.
FULL PAPER
J = 10.8, 4.9 Hz, 2 H, N(CH2CH2)2], 2.74 [d, J = 11.5 Hz, 2 H, rocyclic thiophene 3b (33.2 mg, 0.101 mmol) was treated with iodo-
N(CH2CH2)2], 2.86 (t, J = 5.5 Hz, 2 H, thiophCH2CH2), 3.58 (s, 2 benzene (12.4 μL, 0.11 mmol), Ag2CO3 (27.5 mg, 0.01 mmol), and
H, NCH2Ph), 3.82 (t, J = 5.5 Hz, 2 H, thiophCH2CH2), 6.97 (s, 1 PdCl2/bipy (3.2 mg, 0.01 mmol) in m-xylene (1.2 mL). The crude
H, 3Ј-H-thioph), 7.27–7.50 (m, 10 H, Ph-H) ppm. 13C NMR product was purified by CHCl3-gpc and fc (Ø = 1.5 cm, h = 5 cm;
(100 MHz, CDCl3): δ = 27.8 (1C, thiophCH2CH2), 37.9 [2C,
hexane/EtOAc = 4:1, 3 mL; Rf = 0.10). Colorless solid; m.p.
N(CH2CH2)2], 49.3 [2C, N(CH2CH2)2], 59.3 (1C, thiophCH2CH2), 137 °C; yield 23.4 mg (57% after gpc); colorless solid, yield 18.9 mg
1
63.6 (1C, NCH2Ph), 73.9 (1C, thiophCspiro), 118.0 (1C, CH-3Ј-thio-
(46% after fc). HPLC: tR = 7.83 (96%) min. H NMR (400 MHz,
ph), 127.3 (Ph-CH), 127.5 (Ph-CH), 128.5 (Ph-CH), 128.6 (Ph- CDCl3): δ = 1.84–2.01 [m, 3 H, N(CH2CH2)2], 2.15 [td, J = 13.2,
CH), 128.9 (Ph-CH), 129.6 (Ph-CH), 131.1 (1C, Cquat), 134.6 (1C,
Cquat), 137.5 (1C, Cquat), 138.6 (1C, Cquat), 145.5 (1C, Cquat).
4.4 Hz, 1 H, N(CH2CH2)2], 2.45 [td, J = 11.6, 3.3 Hz, 1 H,
N(CH2CH2)2], 2.54 [td, J = 12.4, 2.5 Hz, 1 H, N(CH2CH2)2], 2.74–
HRMS (ESI): calcd. for C24H25NOS [M+] 375.1657; found 2.81 [m, 2 H, N(CH2CH2)2], 2.86 (dd, J = 15.8, 7.2 Hz, 1 H, thio-
375.1643.
phCH2CH), 2.99 (dd, J = 15.8, 3.3 Hz, 1 H, thiophCH2CH), 3.57
(s, 3 H, OCH3), 3.57 (d, J = 13.0 Hz, 1 H, NCH2Ph), 3.61 (d, J =
13.1 Hz, 1 H, NCH2Ph), 4.91 (dd, J = 7.2, 3.3 Hz, 1 H, thio-
phCH2CH), 7.02 (s, 1 H, 3Ј-H-thioph), 7.27–7.41 (m, 8 H, Ph-H),
7.49–7.54 (m, 2 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
31.6 (1C, thiophCH2CH), 35.6 [1C, N(CH2CH2)2], 38.6 [1C,
N(CH2CH2)2], 49.3 [1C, N(CH2CH2)2], 49.4 [1C, N(CH2CH2)2],
56.7 (1C, OCH3), 63.6 (1C, NCH2Ph), 74.5 (1C, thiophCspiro), 96.8
(1C, thiophCH2CH), 120.0 (1C, CH-3Ј-thioph), 125.8 (Ph-CH),
127.3 (Ph-CH), 127.7 (Ph-CH), 128.5 (Ph-CH), 129.1 (Ph-CH),
129.5 (Ph-CH), 130.3 (1C, Cquat), 134.5 (1C, Cquat), 138.8 (1C,
Cquat), 141.9 (1C, Cquat), 142.4 (1C, Cquat) ppm. HRMS (APCI):
calcd. for C25H28NO2S [MH+] 406.1835; found 406.1846.
1-Benzyl-6Ј-methoxy-1Ј-phenyl-6Ј,7Ј-dihydrospiro(piperidine-4,4Ј-
thieno[3,4-c]pyran) (6b):[4] According to General Procedure A, spi-
rocyclic thiophene 2b (87.8 mg, 0.27 mmol) was treated with iodo-
benzene (35.2 mg, 0.17 mmol), Ag2CO3 (49.3 mg, 0.18 mmol), and
PdCl2/bipy (5.5 mg, 0.016 mmol) in m-xylene (1.5 mL). The crude
product was purified by CHCl3-gpc and prep. tlc (h = 15 cm, hex-
ane/EtOAc = 3:2; Rf = 0.4). Pale-yellow resin, yield 46.3 mg (67%
after gpc); colorless resin, yield 33.2 mg (48% after prep. tlc). 1H
NMR (400 MHz, CDCl3): δ = 1.91 [td, J = 13.6, 4.6 Hz, 1 H,
N(CH2CH2)2], 2.01 [dd, 13.9, 3.2 Hz, 1 H, N(CH2CH2)2], 2.06–
2.19 [m, 2 H, N(CH2CH2)2], 2.47 [td, J = 11.8, 2.3 Hz, 1 H,
N(CH2CH2)2], 2.58 [td, J = 11.9, 2.7 Hz, 1 H, N(CH2CH2)2], 2.74–
2.84 [m, 2 H, N(CH2CH2)2], 2.88 (dd, J = 15.5, 7.4 Hz, 1 H, thi-
ophCH2CH), 3.02 (dd, J = 15.5, 3.0 Hz, 1 H, thiophCH2CH), 3.52
(s, 3 H, OCH3), 3.58 (d, J = 13.0 Hz, 1 H, NCH2Ph), 3.62 (d, J =
13.0 Hz, 1 H, NCH2Ph), 4.80 (dd, J = 7.4, 3.1 Hz, 1 H, thio-
phCH2CH), 6.96 (s, 1 H, 3Ј-H-thioph), 7.27–7.46 (m, 10 H, Ph-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.3 (1C, thio-
phCH2CH), 37.5 [1C, N(CH2CH2)2], 39.9 [1C, N(CH2CH2)2], 49.4
[2C, N(CH2CH2)2], 56.7 (1C, OCH3), 63.4 (1C, NCH2Ph), 74.0
(1C, thiophCspiro), 97.5 (1C, thiophCH2CH), 117.5 (1C, CH-3Ј-thi-
oph), 127.5 (Ph-CH), 128.1 (Ph-CH), 128.2 (Ph-CH), 128.5 (Ph-
CH), 128.5 (Ph-CH), 128.8 (Ph-CH), 129.1 (Ph-Cquat), 129.6 (Ph-
CH), 131.6 (Ph-CH), 134.0 (1C, Cquat), 138.1 (1C, Cquat, Ph-C),
138.4 (1C, Cquat, Ph-C), 144.2 (1C, Cquat). HRMS (ESI): calcd. for
C25H27NO2S [M+] 405.1762; found 405.1782.
1-Benzylspiro(piperidine-4,1Ј-thieno[3,4-c]furan)-3Ј-one (10): In a
three-necked flask, 3,4-dibromothiophene (8; 654 mg, 2.7 mmol)
was dissolved in freshly distilled Et2O (8 mL) and cooled under N2
to –78 °C. After 15 min stirring at –78 °C, n-butyllithium (1.35 m
in n-hexane, 2 mL, 2.7 mmol) was added and the mixture was
stirred for 10 min. 1-Benzylpiperidin-4-one (511 mg, 2.7 mmol),
dissolved in Et2O (3 mL), was added dropwise and the solution
was stirred for 30 min. The reaction mixture was diluted with Et2O
(15 mL). For the second halogen–metal exchange reaction, a sec-
ond equivalent of n-butyllithium (1.35 m in n-hexane, 2 mL,
2.7 mmol) was added slowly and the mixture was stirred for 10 min
at –78 °C. Finally, CO2 (generated from dry ice and dried with
H2SO4) was bubbled through the mixture for 1 h while the tempera-
ture was kept below –70 °C. The flask was then warmed to room
temp. and the solvent was removed in vacuo almost completely.
The remaining crude product was poured into water (20 mL), basi-
fied with 2 m NaOH, and extracted twice with Et2O. The aqueous
layer was acidified with 2 m HCl and washed several times with
Et2O. The aqueous layer was concentrated in vacuo and the inter-
mediate salt was directly used for cyclization without purification.
The crude product was dissolved in a mixture of Ac2O (3 mL) and
NaOAc (532 mg, 6.5 mmol) in toluene (20 mL) and the mixture
was heated to reflux overnight (125 °C). The reaction mixture was
cooled to room temp., poured into saturated K2CO3, and the mix-
ture was stirred for 1 h. When gas formation was finished, the tolu-
ene layer was separated and the aqueous layer was extracted twice
with CH2Cl2. Finally, the combined organic layers were dried
(K2CO3), filtered, and the solvent was removed in vacuo. The re-
maining solid was purified by fc [Ø = 4.5 cm, h = 15 cm; cyclohex-
ane/EtOAc = 7:3 (NHEt2 2%), 30 mL]. In addition to the desired
lactone 10, traces of a brominated side product [Rf = 0.60 (cyclo-
hexane/EtOAc = 3:7)] were separated. Compound 10: Rf = 0.42
(cyclohexane/EtOAc = 3:7); colorless solid; m.p. 95 °C; yield
1-Benzyl-1Ј-phenylspiro(piperidine-4,4Ј-thieno[3,4-c]pyran)-6Ј-
(7ЈH)-one (6c): According to General Procedure A, spirocyclic thio-
phene 2c (32.2 mg, 0.103 mmol) was treated with iodobenzene
(12.6 μL, 0.11 mmol), Ag2CO3 (29.7 mg, 0.11 mmol), and PdCl2/
bipy (3.4 mg, 0.01 mmol) in m-xylene (1.2 mL). The crude product
was purified by CHCl3-gpc and fc (Ø = 1.5 cm, h = 5 cm; hexane/
EtOAc = 4:1, 3 mL; Rf = 0.20). Colorless solid; m.p. 125 °C; yield
22.6 mg (57% after gpc); colorless solid, yield 13.4 mg (34% after
1
fc). HPLC: tR = 7.09 (98.4%) min. H NMR (400 MHz, CDCl3):
δ = 2.09 [dd, J = 14.8, 2.2 Hz, 2 H, N(CH2CH2)2], 2.19 [td, J =
13.7, 4.6 Hz, 2 H, N(CH2CH2)2], 2.61 [td, J = 11.9, 2.6 Hz, 2 H,
N(CH2CH2)2], 2.82 [dd, J = 9.0, 2.4 Hz, 2 H, N(CH2CH2)2], 3.60
(s, 2 H, NCH2Ph), 3.83 (s, 2 H, thiophCH2), 7.10 (s, 1 H, 3Ј-H-
thioph), 7.30–7.47 (m, 10 H, Ph-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 32.7 (1C, thiophCH2C=O), 37.1 [2C, N(CH2CH2)2],
48.7 [2C, N(CH2CH2)2], 63.2 (1C, NCH2Ph), 81.2 (1C, thi-
ophCspiro), 117.7 (1C, CH-3Ј-thioph), 126.4 (1C, Cquat), 127.4 (Ph-
CH), 128.4 (Ph-CH), 128.6 (Ph-CH), 128.8 (Ph-CH), 129.2 (Ph-
CH), 129.5 (Ph-CH), 133.1 (1C, Cquat), 138.1 (1C, Cquat), 141.3
(1C, Cquat), 169.5 (1C, C=O) ppm. One signal for a quaternary car-
bon atom was not visible. HRMS (APCI): calcd. for C24H24NO2S
[MH+] 390.1522; found 390.1528.
353 mg (44%, relative to 3,4-dibromothiophene 8); HPLC: tR
=
13.7 (98.7%) min. IR (neat): ν = 3102 (C–HAr), 2922 (C–H), 2811
˜
(C–H), 1758 (C=O), 698 (C–H) cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 1.96 [d, J = 13.5 Hz, 2 H, N(CH2CH2)2], 2.08 [td, J
= 10.0, 3.9 Hz, 2 H, N(CH2CH2)2], 2.61 [t, J = 9.8 Hz, 2 H,
N(CH2CH2)2], 2.75 [d, J = 11.7 Hz, 2 H, N(CH2CH2)2], 3.61 (s, 2
1-Benzyl-6Ј-methoxy-2Ј-phenyl-6Ј,7Ј-dihydrospiro(piperidine-4,4Ј-
thieno[3,2-c]pyran) (7b): According to General Procedure A, spi-
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Late-Stage C–H Bond Arylation of Spirocyclic σ1 Ligands
H, NCH2Ph), 7.07 (d, J = 2.3 Hz, 1 H, 6Ј-H-thioph), 7.27–7.39 (m,
5 H, Ph-H). 7.88 (d, J = 2.4 Hz, 1 H, 4Ј-H-thioph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 36.8 [2C, N(CH2CH2)2], 49.7 [2C,
N(CH2CH2)2], 63.1 (1C, NCH2Ph), 83.7 (1C, Cspiro), 115.5 (1C, C-
6Ј-thioph), 126.6 (1C, C-4Ј-thioph), 127.4 (1C, Ph-C), 128.5 (2C,
Ph-C), 129.4 (2C, Ph-C), 133.3 (1C, Cquat), 138.0 (1C, Cquat, Ph-
C), 154.7 (1C, Cquat), 162.8 (1C, C=O) ppm. HRMS (APCI): calcd.
for C17H17NO2S [MH+] 300.1053; found 300.1081.
Receptor Binding Studies
σ1 Assay:[15] In the σ1 assay, membrane preparations from guinea
pig brains were used as receptor material and [3H]-(+)-pentazocine
was employed as radioligand.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all synthesized compounds.
1-Benzyl-4Ј-phenylspiro(piperidine-4,1Ј-thieno[3,4-c]furan)-3Ј-one
(11) and 1-Benzyl-6Ј-phenylspiro(piperidine-4,1Ј-thieno[3,4-c]furan)-
3Ј-one (12) and 1-Benzyl-4Ј,6Ј-diphenylspiro(piperidine-4,1Ј-thi-
eno[3,4-c]furan)-3Ј-one (13): According to General Procedure A,
spirocyclic thiophene 10 (31.9 mg, 0.107 mmol) was treated with
iodobenzene (13.1 μL, 0.12 mmol), Ag2CO3 (32.5 mg, 0.12 mmol),
and PdCl2/bipy (4.0 mg, 0.01 mmmol) in m-xylene (1.2 mL). The
residue was purified by CHCl3-gpc to yield the double arylated
product in the first fraction and two monoarylated products in the
second fraction of the gpc. The double arylated product 13 was
purified by fc (Ø = 1.5 cm, h = 5 cm; hexane/EtOAc = 9:1; 3 mL;
Rf = 0.12). The monoarylated products 11 and 12 were separated
by preparative thin layer chromatography [h = 15 cm; hexane/
EtOAc = 7:3; Rf = 0.22 (11), 0.48 (12) min].
Acknowledgments
This work was performed within the framework of the Inter-
national Research Training Group Münster/Nagoya “Complex
Functional Systems in Chemistry: Design, Synthesis and Applica-
tions”. Financial support by the Deutsche Forschungsgemeinschaft
(DFG) and by the Japanese Society of Promotion of Science (JSPS)
(Funding Program for Next Generation World-Leading Research-
ers) are gratefully acknowledged.
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USA 1996, 93, 8072–8077; b) P. Seth, Y. Fei, H. W. Li, W. Hu-
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931; c) R. Kekuda, P. D. Prasad, Y. Fei, F. H. Leibach, V. Gan-
apathy, Biochem. Biophys. Res. Commun. 1996, 229, 553–558.
[3] a) E. J. Cobos, J. M. Entrena, F. R. Nieto, C. M. Cendan, E.
Del Pozo, Centr. Neuropharmacol. 2008, 6, 344–366; b) T. Mau-
rice, T. P. Su, Pharmacol. Ther. 2009, 124, 195–206; c) M. Ishi-
kawa, K. Hashimoto, J. Receptor Ligand Channel Res. 2010, 3,
25–36.
Compound 11: Colorless solid; m.p. 137 °C; yield 19.9 mg (50% af-
ter gpc), mixture of regioisomers; yield 10.1 mg (25% after prep.
1
tlc). HPLC: tR = 7.37 (97%) min. H NMR (600 MHz, CDCl3): δ
= 1.99 [d, J = 13.4 Hz, 2 H, N(CH2CH2)2], 2.12 [td, J = 12.0,
3.8 Hz, 2 H, N(CH2CH2)2], 2.64 [td, J = 12.7, 2.6 Hz, 2 H,
N(CH2CH2)2], 2.80 [d, J = 11.8 Hz, 2 H, N(CH2CH2)2], 3.63 (s, 2
H, NCH2Ph), 6.93 (s, 1 H, 6Ј-H-thioph), 7.27–7.49 (m, 8 H, Ph-
H), 8.02–8.08 (m, 2 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 36.9 [2C, N(CH2CH2)2], 49.6 [2C, N(CH2CH2)2], 63.1 (1C,
NCH2Ph), 82.1 (1C, thiophCspiro), 112.4 (1C, CH-6Ј-thioph), 126.5
(1C, Cquat), 127.5 (Ph-CH), 128.2 (Ph-CH), 128.6 (Ph-CH), 129.2
(Ph-CH), 129.5 (Ph-CH), 129.8 (Ph-CH), 131.4 (1C, Cquat), 138.1
(1C, Cquat), 148.4 (1C, Cquat), 156.7 (1C, Cquat), 163.1 (1C,
C=O) ppm. HRMS (APCI): calcd. for C23H22NO2S [MH+]
376.1366; found 376.1352.
[4] C. Meyer, B. Neue, D. Schepmann, S. Yanagisawa, J. Yamagu-
chi, E.-U. Würthwein, K. Itami, B. Wünsch, Org. Biomol.
Chem. 2011, 9, 8016–8029.
[5] C. Oberdorf, D. Schepmann, J. M. Vela, J. L. Diaz, J. Holenz,
B. Wünsch, J. Med. Chem. 2008, 51, 6531–6537.
[6] a) R. A. Glennon, S. Y. Ablordeppey, A. M. Ismaiel, M. B. El-
Ashmawy, J. B. Fischer, K. B. Howie, J. Med. Chem. 1994, 37,
1214–1219; b) R. A. Glennon, Mini-Rev. Med. Chem. 2005, 5,
927–940; c) C. Laggner, C. Schieferer, B. Fiechtner, G. Poles,
R. D. Hoffmann, H. Glossmann, T. Langer, E. F. Moebius, J.
Med. Chem. 2005, 48, 4754–4764; d) D. Zampieri, M. G. Mam-
olo, E. Laurini, C. Florio, C. Zanette, M. Fermeglia, P. Po-
socco, M. S. Paneni, S. Pricl, L. Vio, J. Med. Chem. 2009, 52,
5380–5393; e) C. Oberdorf, T. J. Schmidt, B. Wünsch, Eur. J.
Med. Chem. 2010, 45, 3116–3124; f) E. Rack, R. Fröhlich, D.
Schepmann, B. Wünsch, Bioorg. Med. Chem. 2011, 19, 3141–
3151; g) B. Wünsch, Curr. Pharm. Des. 2012, 18, 930–937.
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Miyafuji, T. Nakata, N. Tani, Y. Aoyagi, Heterocycles 1990, 31,
1951–1955.
[8] B. Liégault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
J. Org. Chem. 2009, 74, 1826, and references cited therein.
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3698; Angew. Chem. Int. Ed. 2009, 48, 3644.
Compound 12: Colorless solid; m.p. 122 °C; yield 19.9 mg (50% af-
ter gpc), mixture of regioisomers; yield 2.2 mg (5% after prep. tlc).
1
HPLC: tR = 7.20 (95.2%) min. H NMR (600 MHz, CDCl3): δ =
1.84 [d, J = 12.9 Hz, 2 H, N(CH2CH2)2], 2.17 [t, J = 14.2 Hz, 2 H,
N(CH2CH2)2], 2.49 [t, J = 9.2 Hz, 2 H, N(CH2CH2)2], 2.78 [d, J =
9.0 Hz, 2 H, N(CH2CH2)2], 3.53 (s, 2 H, NCH2Ph), 7.27–7.34 (m,
4 H, Ph-H), 7.39–7.56 (m, 6 H, Ph-H), 7.84 (s, 1 H, 4Ј-H-thioph).
12 was obtained only in traces and the measurement of a 13C NMR
spectrum was not possible. HRMS (APCI): calcd. for C23H22NO2S
[MH+] 376.1366; found 376.1393.
Compound 13: Colorless solid; m.p. 183 °C; yield 13.2 mg (27% af-
ter gpc); yield 10.2 mg (21% after fc). HPLC: tR
= 8.62
(96.6%) min. 1H NMR (600 MHz, CDCl3): δ = 1.87 [d, J =
12.0 Hz, 2 H, N(CH2CH2)2], 2.17 [td, J = 13.3, 4.7 Hz, 2 H,
N(CH2CH2)2], 2.52 [td, J = 12.3, 2.2 Hz, 2 H, N(CH2CH2)2], 2.78
[dd, J = 11.1, 4.2 Hz, 2 H, N(CH2CH2)2], 3.54 (s, 2 H, NCH2Ph),
7.27–7.56 (m, 13 H, Ph-H), 8.03–8.08 (m, 2 H, Ph-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 36.4 [2C, N(CH2CH2)2], 49.3 [2C,
N(CH2CH2)2], 63.0 (1C, NCH2Ph), 83.0 (1C, thiophCspiro), 127.3
(Ph-CH), 127.3 (1C, Cquat), 128.4 (Ph-CH), 128.5 (Ph-CH), 129.1
(Ph-CH), 129.2 (Ph-CH), 129.2 (Ph-CH), 129.3 (Ph-CH), 129.7
(Ph-CH), 129.9 (Ph-CH), 131.3 (1C, Cquat), 131.6 (1C, Cquat), 132.7
(1C, Cquat), 138.6 (1C, Cquat), 146.9 (1C, Cquat), 151.0 (1C, Cquat),
163.0 (1C, C=O) ppm. HRMS (APCI): calcd. for C29H26NO2S
[MH+] 452.1679; found 452.1687.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20837
/KAP1
Date: 05-09-12 18:22:58
Pages: 9
K. Itami, B. Wünsch et al.
FULL PAPER
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b) C. A. Maier, B. Wünsch, J. Med. Chem. 2002, 45, 4923–
4930; c) E. Große Maestrup, C. Wiese, D. Schepmann, A.
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org. Med. Chem. 2009, 17, 3630–3641; d) R. Holl, D. Schep-
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Received: June 22, 2012
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20837
/KAP1
Date: 05-09-12 18:22:58
Pages: 9
Late-Stage C–H Bond Arylation of Spirocyclic σ1 Ligands
Spirocyclic Thiophenes
Diverse spirocyclic thiophenes were synthe-
sized regioselectively by direct C–H bond
arylation using the catalytic systems PdCl2/
bipy/Ag2CO3 and PdCl2/P[OCH(CF3)2]3/
Ag2CO3. Compounds bearing the phenyl
moiety at the top position and the sulfur
atom in left position show the highest σ1
affinity.
C. Meyer, D. Schepmann, S. Yanagisawa,
J. Yamaguchi, K. Itami,*
B. Wünsch* ....................................... 1–9
Late-Stage C–H Bond Arylation of Spiro-
cyclic σ1 Ligands for Analysis of Comp-
lementary σ1 Receptor Surface
Keywords: C–C coupling / Arylation / Sul-
fur heterocycles / Ligand design / Spiro
compounds / Protein structures
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9