Synthesis of new aryl(hetaryl)-substituted tandospirone analogues with potential anxiolytic activity via reductive Heck type hydroarylations

Article abstract of DOI:10.2478/s11696-013-0338-4

Tandospirone (I), developed as an anxiolytic drug, is an aryl-piperazine compound that binds to both 5-HT_1A and dopamine D4 receptors. Palladium-catalysed hydroarylation reactions of tandospirone analogues containing an oxygen bridge and 3-(trifluoromethyl)phenyl or 2,3-dichlorophenyl groups were studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted derivatives with potential biological activity.

Full text of DOI:10.2478/s11696-013-0338-4

Chemical Papers 67 (6) 643–649 (2013)
DOI: 10.2478/s11696-013-0338-4
ORIGINAL PAPER
Synthesis of new aryl(hetaryl)-substituted tandospirone analogues
with potential anxiolytic activity via reductive Heck type
hydroarylations
a
a
b
aOmer Tahir Gunkara, Bilgesu Onur Sucu, Nuket Ocal*, Dieter E. Kaufmann
aDepartment of Chemistry, Yildiz Technical University, Faculty of Science and Arts, Davutpasa Campus,
34220 Esenler, Istanbul, Turkey
bInstitute of Organic Chemistry, University of Technology, Leibnizstr. 6, Clausthal, D-38678 Clausthal-Zellerfeld, Germany
Received 30 July 2012; Revised 20 November 2012; Accepted 2 December 2012
Tandospirone (I ), developed as an anxiolytic drug, is an aryl-piperazine compound that
binds to both 5-HT1A and dopamine D4 receptors. Palladium-catalysed hydroarylation reac-
tions of tandospirone analogues containing an oxygen bridge and 3-(trifluoromethyl)phenyl or 2,3-
dichlorophenyl groups were studied in order to find a new stereoselective access to a series of new
exo-aryl(hetaryl)-substituted derivatives with potential biological activity.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: tandospirone, arylpiperazines, C–C coupling, hydroarylation, heterocycles
Introduction
N-Arylpiperazines are heterocyclic compounds im-
portant as intermediates in organic synthesis. They
are commonly found as fragments in natural products,
receptor ligands, and in many pharmacologically ac-
tive molecules. A series of aryl-piperazine compounds
Fig. 1. Structure of tandospirone (I).
are effective pharmaceuticals for the treatment of con-
ditions related to or affected by the serotonin 1A re-
ceptor; as they are particularly effective antagonists to
this receptor and are particularly useful for alleviat-
ing the symptoms of nicotine and tobacco withdrawal
(Godfrey et al., 2006; Kulig et al., 2009; Sarswat et al.,
2011). Tandospirone (I ) (Fig. 1), developed as an anx-
iolytic drug marketed in Japan, is an aryl-piperazine
compound that binds to both 5-HT1A and dopamine
D4 receptors (Kishimoto et al., 2000; Amano et al.,
2001; Nishikawa et al., 2007; Takahashi et al., 2008).
There are a few reports in the literature on the
synthesis of tandospirone analogues with changes
in the bicyclic system or the pyrimidin-2-yl group
(Kossakowski & Jarocka, 2001; Kossakowski et al.,
2008; Makan et al., 2009). Therefore, the synthe-
sis of more bioactive aryl- and heteroaryl substi-
tuted tandospirones by reductive Heck reactions and
isoxazoline derivatives via 1,3-dipolar cycloadditions
came into attention (Kulu, 2012). In this work, the
pyrimidine group in the tandospirone molecule was
replaced with 3-(trifluoromethyl)phenyl or the 2,3-
dichlorophenyl group, which are structurally similar
to 1-(3-(trifluoromethyl)phenyl)piperazine (TFMPP)
and 1-(2,3-dichlorophenyl)piperazine analogues, re-
spectively. TFMPP is a recreational drug of the piper-
azine class. It shows affinity to the 5-HT1A, 5-HT1B
,
*Corresponding author, e-mail: nocal@yildiz.edu.tr

644
O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
5-HT1D, 5-HT2A, and 5-HT2C receptors, and func-
tions as a full agonist at all sites except for the 5-
HT2A receptor, where it acts as a weak partial ago-
nist or antagonist (Przegalin´ski et al., 1994; Pickard
& Rea, 1997). 1-(2,3-Dichlorophenyl)piperazine is also
a psychoactive drug of the phenylpiperazine class
(Grundt et al., 2005, 2007). The synthesis of aryl- and
heteroaryl substituted tandospirone analogues with
an oxygen bridge with 3-(trifluoromethyl)phenyl and
2,3-dichlorophenyl on the aromatic ring and contain-
ing an exo-ring in the tricyclic system as potentially
biologically active molecules was studied.
by a similar reaction work-up and column chromatog-
raphy as given for IV to afford compound V (360 mg,
80 %) as white crystals; m.p. 133–134◦C; Rf = 0.41.
General method for reductive Heck reaction
A solution of Pd(OAc)2 (5.6 mg, 0.025 mmol) and
triphenylarsine (33.7 mg, 0.11 mmol) in dry DMF
(3 mL) was stirred in a Schlenk tube in a nitrogen
atmosphere at 65◦C for 15 min to form the catalyst
complex. Then, aryl iodide (1.5 mmol), alkene (IV or
V, 1 mmol), triethylamine (354 mg, 3.5 mmol), and
formic acid (138 mg, 3.0 mmol) were added. The mix-
ture was heated at 65◦C for 24–48 h followed by a
similar reaction work-up and column chromatography
as given for IV.
Experimental
All the reactions were carried out in a nitrogen
atmosphere unless otherwise indicated. The solvents
used in the Heck reactions were dried by standard
methods. Reaction progress was monitored by thin-
layer chromatography (TLC). Visualisation was per-
formed using either UV light or a KMnO4 stain. Prod-
ucts were purified by column chromatography using
silica gel 60 (Merck, Germany) and a suitable sol-
vent mixture for the elution of the title compounds.
IR spectra were obtained with a Perkin–Elmer FTIR
instrument. Melting points were determined on a Gal-
lenkamp digital thermometer and are uncorrected. 1H
(500 MHz) and 13C (125 MHz) NMR spectra (in
CDCl3) were recorded with a Bruker Avance III-500
spectrometer using tetramethylsilane (TMS) as an in-
ternal standard. Mass spectra were measured either
on an Agilent 6890N/5973 GC/IMSD system or an
Agilent 6460 Triple Quad LC/MS system.
Results and discussion
In the last decade, organopalladium-catalysed
C—C bond formation has become one of the most effi-
cient approaches in the synthesis of organic molecules.
The Heck reaction, in particular, is widely used as
an important method for the preparation of biolog-
ically active compounds in synthetic chemistry and
pharmaceutical industry (Mitchell & Yu, 2003; Wei et
al., 2003). As an extension of the Heck reaction, Pd-
catalysed hydroarylation of alkynes and alkenes con-
tinues to attract interest in simple coupling processes
and cyclisation reactions (Negishi & de Meijere, 2002;
Beletskaya & Cheprakov, 2000).
In the presence of triphenylarsine as a ligand
(Namyslo & Kaufmann, 1999; Namyslo et al., 2010),
the palladium-catalysed hydroarylation of the easily
accessible unsaturated tricyclic N-substituted imides
has been proven to be a stereoselective, versatile, and
high-yield approach for the synthesis of the corre-
sponding aryl and heteroaryl derivatives (Yolacan et
al., 2006; Bagdatli et al., 2007; Go¨ksu et al., 2008;
Goksu et al., 2010). Palladium(II) acetate catalysed
asymmetric Heck-type hydroarylations of bicyclic and
tricyclic alkenes such as epibatidine analogues, and
their domino-Heck applications by treating with aryl
(or heteroaryl) iodides have been introduced (Ce-
lik et al.; 2009; Kulu & Ocal, 2011). In this paper,
we focused on reductive Heck reactions of tricyclic
N-[4-(3-(Trifluoromethyl)phenyl)piperazin-
1-yl)butyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-
exo,3-exo-dicarboximide (IV)
A mixture of III (300 mg, 1 mmol), 1-(3-(trifluoro-
methyl)phenyl)piperazine (460 mg, 2 mmol), and an-
hydrous K2CO3 (276 mg, 2 mmol) in DMF (50 mL)
was heated at 55◦C for 4 h. After cooling to ambient
temperature, brine (50 mL) was added and the reac-
tion product was extracted with EtOAc (3 × 25 mL).
The combined organic phases were dried with MgSO4,
the solvent was evaporated and the residue was puri-
fied by column chromatography using CHCl3/MeOH
(ϕr = 20 : 1) as the eluent to give IV (381.6 mg, 85
%); m.p. 103–104◦C; Rf = 0.42.
—
molecules containing a strained C C bond, an oxy-
—
gen bridge, and an arylpiperazine group with potential
biological activity similar to I.
Synthesis started with the reaction of II (Tindale et
al., 2010) with 1,4-dibromobutane to afford III (Ishi-
hara et al., 2007) which was condensed with TFMPP
or 1-(2,3-dichlorophenyl)piperazine providing the new
compounds IV and V, respectively, in good yields. Re-
actions of IV or V with various aryl iodides under
reductive Heck reaction conditions gave VIa–VId or
VIIb–VIIe as single 5-exo-diastereomers in 50–87 %
yields (Fig. 2, Table 1). 2-Chloro-5-iodopyridine was
N-[4-(2,3-Dichlorophenyl)piperazin-1-
yl)butyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-
exo,3-exo-dicarboximide (V)
A mixture of III (300 mg, 1 mmol), 1-(2,3-
dichlorophenyl)piperazine hydrochloride (535.1 mg,
2 mmol), and anhydrous K2CO3 (276 mg, 2 mmol)
in DMF (50 mL) was heated at 55◦C for 6 h followed

O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
645
Fig. 2. Synthesis of compounds IV, V, VIa–VId, and VIIb–VIIe. Reaction conditions: i) 1,4-dibromobutane, DMF, K2CO3,
55◦C; ii) 1-(3-(trifluoromethyl)phenyl)piperazine (for IV ) or 1-(2,3-dichlorophenyl)piperazine hydrochloride (for V ), DMF,
K2CO3, 55◦C; iii) aryl iodide (R1I), Pd(OAc)2, AsPh3, DMF, Et3N, HCOOH, 65◦C; for substituents R and R1, see Table 1.
Table 1. Characterisation data of newly prepared compounds
Substituenta
Yield
%
M.p.
◦C
Compound
Formula
Appearance
R
R1
IV
V
3-(trifluoromethyl)phenyl
2,3-dichlorophenyl
–
–
C23H26F3N3O3
C22H25Cl2N3O3
C29H32F3N3O3
C29H31ClF3N3O3
C27H30F3N3O3S
85
80
87
85
80
78
82
50
72
72
103–104
133–134
colourless crystals
colourless crystals
colourless oil
colourless oil
colourless crystals
yelow oil
VIa
VIb
VIc
VId
VIIb
VIIc
VIId
VIIe
3-(trifluoromethyl)phenyl
3-(trifluoromethyl)phenyl
3-(trifluoromethyl)phenyl
3-(trifluoromethyl)phenyl
2,3-dichlorophenyl
phenyl
4-chlorophenyl
2-thienyl
2-chloropyridin-2-yl C28H30ClF3N4O3
4-chlorophenyl
2-thienyl
–
–
120–121
–
–
C28H30Cl3N3O3
C26H29Cl2N3O3S
C27H29Cl3N4O3
C29H33Cl2N3O4
yelow oil
2,3-dichlorophenyl
2,3-dichlorophenyl
2,3-dichlorophenyl
133–134
162–163
–
colourless crystals
colourless crystals
yelow oil
2-chloropyridin-2-yl
4-methoxyphenyl
a) For the position of substituent, see Fig. 2.
selected as the arylation reagent because of its simi-
larity with the structures of epibatidine (Yolacan et
al., 2006).
licit drug market as a new group of designed drugs.
TFMPP, a 1-arylpiperazine, is known as a centrally
active compound with serotoninergic properties and
it has been widely used as a pharmacological probe
drug for drug discrimination procedures in animals
(Staack et al., 2003). Here, I was combined with
TFMPP or 1-(2,3-dichlorophenyl)piperazine at the
aromatic ring to obtain IV and V. The new com-
pounds possess a positively ionisable nitrogen atom
and a phenyl ring corresponding to the positively ion-
isable atom (piperazine nitrogen) and the hydrophobic
aromatic region. The oxygen bridged tricyclic part of
the imide molecule is connected to the phenylpiper-
azine by a linker ((CH2)4 group) which can show
hypotensive and antiarrhythmic activities due to the
hydrogen bond acceptor region (Kulig et al., 2009).
The palladium-catalysed hydroarylation of the eas-
ily accessible new unsaturated tandospirone analogues
(VIa–VId and VIIb–VIIe) has been proven to be a
stereoselective, versatile, and high-yield approach for
the synthesis of aryl and heteroaryl derivatives in this
work. The newly prepared compounds will be useful
for the preparation of novel heterocycles of potential
pharmacological interest.
The exo-stereochemistry of each Heck reaction
1
product was inferred from H NMR spectra including
diagnostic spin-spin interactions. The exo-position of
the C-5 substituent was confirmed by the fact that
H5n showed no significant interaction with H1. The
geminal protons at C-6 were identified by their vicinal
coupling to H1. Therefore, H1 occurred as doublets
and H4 as singlets in the expected region. Addition-
ally, the 1H–1H-COSY spectra showed cross peaks be-
tween H2 and H3 and between H5 and H6, respectively.
In addition to the 13C NMR and HSQC spectral data
which were in agreement with the proposed structures,
the mass spectra of all new compounds showed the
expected molecular ion peaks. FTIR spectra of the
hydroarylation products exhibited strong absorption
bands due to the symmetric and asymmetric stretch-
—
ing vibrations of the C O bonds, C—H bonds in the
—
methylene groups, and C—H bonds in unsaturated
fragments (Table 2).
Conclusions
Tandospirone, I, a serotonin-1A (5-HT1A) recep-
tor-related anxiolytic used in Japan and China, is
similar to buspirone and ipsapirone used in the
USA and Europe. On the other hand, TFMPP and
1-(2,3-dichlorophenyl)piperazine have entered the il-
Acknowledgements. We gratefully acknowledge financial
support of this work by the Scientific and Technological Re-
search Council of Turkey (TUBITAK project No. 109T380)
and Yildiz Technical University Scientific Research Projects
Coordination Department (project No. 2011-01-02-KAP03).

646
O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
Table 2. Spectral data of some newly synthesised compounds
Compound
Spectral data
IR, ν˜/cm−1: 3017, 2941, 2873, 2821, 2777, 1772, 1697, 1608, 1587, 1496, 1448, 1117, 719
IV
1H NMR (CDCl3, 500 MHz), δ: 1.47 (pent, J = 7.2 Hz, 2H, γ-CH2), 1.59 (pent, J = 6.9 Hz, 2H, β-CH2), 2.40 (t,
J = 7.5 Hz, 2H, δ-CH2), 2.58 (t, J = 5.0 Hz, 4H, 4 × Hpiperazine), 2.84 (s, 2H, H2, H3), 3.23 (t, J = 5.0 Hz, 4H,
4 × Hpiperazine), 3.52 (t, J = 7.2 Hz, 2H, α-CH2), 5.27 (s, 2H, H1, H4), 6.52 (s, 2H, H5, H6), 7.05 (t, J = 7.5 Hz,
2H, 2 × ArH), 7.10 (s, 1H, ArH), 7.33 (t, J = 7.8 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz) δ: 23.7 (β-C), 25.5 (γ-C), 38.7 (δ-C), 47.3 (C2, C3), 48.5 (2N-C), 52.9 (2N-C), 57.8
—
(α-C), 80.9 (C1, C4), 112.1 (ArC), 115.7 (ArC), 118.6 (ArC), 129.5 (ArC), 131.2 (CF3), 131.4 (Cq), 136.5 (C5—C6),
—
151.3 (Cq), 176.3 (C O)
—
LC–MS, m/z (Ir/%): for C23H26F3N3O3 [M+] calcd.: 449.1926 (100.0), 450.1960 (24.9), 451.1993 (3.0), 450.1897
(1.1); found: 449.7 (100), 450.6 (57.8), 451.6 (8.3)
V
IR, ν˜/cm−1: 3073, 3011, 2947, 2880, 2822, 2788, 2757, 1765, 1698, 1578, 1445, 786
1H NMR (CDCl3, 500 MHz), δ: 1.40 (pent, J = 7.8 Hz, 2H, γ-CH2), 1.52 (pent, J = 7.8 Hz, 2H, β-CH2), 2.34 (t, J
= 7.8 Hz, 2H, δ-CH2), 2.53 (br s, 4H, 4 × Hpiperazine), 2.76 (s, 2H, H2, H3), 2.98 (br s, 4H, 4 × Hpiperazine), 3.44
(t, J = 7.8 Hz, 2H, α-CH2), 5.19 (s, 2H, H1, H4), 6.44 (s, 2H, H5, H6), 6.87 (dd, J = 2.9 Hz, J = 6.8 Hz, 1H, ArH),
7.04–7.08 (m, 2H, 2 × ArH)
13C NMR (CDCl3, 125 MHz), δ: 22.8 (β-C), 24.5 (γ-C), 37.7 (δ-C), 46.3 (C2, C3), 50.2 (2N-C), 52.2 (2N-C), 56.8
—
(α-C), 79.8 (C1, C4), 117.5 (ArC), 123.4 (ArC), 126.3 (ArC), 126.4 (Cq), 132.9 (Cq), 135.5 (C5—C6), 150.2 (Cq),
—
175.2 (C O)
—
LC–MS, m/z (Ir/%): for C22H25Cl2N3O3 [M+] calcd.: 449.1273 (100.0), 451.1243 (63.9), 450.1307 (23.8), 452.1277
(15.2), 453.1214 (10.2), 451.1340 (2.7), 454.1248 (2.4), 453.1311 (1.7), 450.1243 (1.1); found: 449.9 (100), 451.9
(84.5), 450.9 (43.1), 452.9 (30), 453.9 (22.3)
VIa
VIb
VIc
IR, ν˜/cm−1: 3027, 2937, 2873, 2821, 2777, 1697, 1673, 1608, 1587, 1495, 1448, 1117, 730, 730, 697
1H NMR (CDCl3, 500 MHz), δ: 1.47 (pent, J = 6.9 Hz, 2H, γ-CH2), 1.59 (pent, J = 7.2 Hz, 2H, β-CH2), 1.94 (dt,
J = 5.0 Hz, J = 12.9 Hz, 1H, H6n), 2.21 (dd, J = 9.0 Hz, J = 12.8 Hz, 1H, H6x), 2.40 (t, J = 7.5 Hz, 2H, δ-CH2),
2.58 (t, J = 5.0 Hz, 4H, 4 × Hpiperazine), 2.96 (d, J = 6.9 Hz, 1H, H2), 3.02 (d, J = 7.1 Hz, 1H, H3), 3.22 (t, J =
5.0 Hz, 4H, 4 × Hpiperazine), 3.40 (dd, J = 4.3 Hz, J = 8.5 Hz, 1H, H5n), 3.51 (t, J = 6.9 Hz, 2H, α-CH2), 4.78
(s, 1H, H4), 5.00 (d, J = 5.0 Hz, 1H, H1), 7.05 (t, J = 8.2 Hz, 2H, 2 × ArH), 7.10 (s, 1H, ArH), 7.20–7.24 (m, 3H,
3 × ArH), 7.27 (d, J = 7.2 Hz, 2H, 2 × ArH), 7.33 (t, J = 7.8 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 23.7 (β-C), 25.54 (γ-C), 38.8 (δ-C), 40.0 (C6), 47.3 (C5), 48.5 (2N-C), 49.6 (C2),
50.0 (C3), 52.9 (2N-C), 57.7 (α-C), 79.1 (C1), 84.8 (C4), 112.1 (ArC), 115.7 (ArC), 118.6 (ArC), 126.8 (ArC), 127.1
—
—
(ArC), 128.6 (ArC), 129.5 (ArC), 131.2 (CF3), 131.4 (Cq), 144.0 (Cq), 151.3 (Cq), 176.8 (C O), 177.1 (C O)
—
—
LC–MS, m/z (Ir/%): for C29H32F3N3O3 [M+] calcd.: 527.2396 (100.0), 528.2429 (31.4), 529.2463 (4.7), 528.2366
(1.1); found: 527.4 (100), 528.2 (20.9), 1116.5 (12.3), 528.7 (11.9), 1118.6 (11.2), 550.5 (8.3), 549.8 (7.1)
IR, ν˜/cm−1: 2945, 2884, 2819, 2781, 1773, 1696, 1608, 1589, 1493, 1447, 1116, 729, 822
1H NMR (CDCl3, 500 MHz), δ: 1.47 (pent, J = 8.1 Hz, 2H, γ-CH2), 1.58 (pent, J = 7.2 Hz, 2H, β-CH2), 1.88 (dt,
J = 5.0 Hz, J = 12.9 Hz, 1H, H6n), 2.22 (dd, J = 9.0 Hz, J = 12.8 Hz, 1H, H6x), 2.40 (t, J = 7.5 Hz, 2H, δ-CH2),
2.58 (t, J = 5.0 Hz, 4H, 4 × Hpiperazine), 2.97 (d, J = 6.9 Hz, 1H, H2), 2.99 (dd, J = 4.9 Hz, J = 9.1 Hz, 1H, H5n),
3.01 (d, J = 6.9 Hz, 1H, H3), 3.23 (t, J = 5.0 Hz, 4H, 4 × Hpiperazine), 3.51 (t, J = 7.2 Hz, 2H, α-CH2), 4.74 (s,
1H, H4), 5.01 (d, J = 5.3 Hz, 1H, H1), 7.06 (t, J = 8.8 Hz, 2H, 2 × ArH), 7.10 (s, 1H, ArH), 7.17 (d, J = 8.5 Hz,
2H, 2 × ArH), 7.25 (d, J = 7.5 Hz, 2H, 2 × ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 23.8 (β-C), 25.5 (γ-C), 38.9 (δ-C), 40.1 (C6), 46.7 (C5), 48.6 (2N-C), 49.5 (C2),
49.9 (C3), 52.9 (2N-C), 57.8 (α-C), 79.1 (C1), 84.7 (C4), 112.0 (ArC), 115.7 (ArC), 118.6 (ArC), 128.5 (ArC), 128.7
—
—
—
(ArC), 129.5 (ArC), 131.2 (CF3), 131.5 (Cq), 132.6 (Cq), 142.5 (Cq), 151.3 (Cq), 176.6 (C O), 176.9 (C O)
—
LC–MS, m/z (Ir/%): for C29H31ClF3N3O3 [M+] calcd.: 561.2006 (100.0), 563.1977 (32.0), 562.2040 (31.4), 564.2010
(10.0), 563.2073 (4.7), 565.2044 (1.5), 562.1976 (1.1); found: 561.7 (100), 563.6 (71.2), 562.6 (65.6), 564.6 (22.7)
IR, ν˜/cm−1: 2984, 2948, 2880, 2827, 2793, 1768, 1693, 1605, 1589, 1497, 1438, 1122, 729, 696
1H NMR (CDCl3, 500 MHz), δ: 1.46 (pent, J = 8.1 Hz, 2H, γ-CH2), 1.58 (pent, J = 7.2 Hz, 2H, β-CH2), 2.02 (dt,
J = 5.0 Hz, J = 12.9 Hz, 1H, H6n), 2.22 (dd, J = 8.8 Hz, J = 12.9 Hz, 1H, H6x), 2.40 (t, J = 7.5 Hz, 2H, δ-CH2),
2.57 (t, J = 5.0 Hz, 4H, 4 × Hpiperazine), 2.94 (d, J = 6,9 Hz, 1H, H2), 3.01 (d, J = 6,9 Hz, 1H, H3), 3.22 (t, J =
5.0 Hz, 4H, 4 × Hpiperazine), 3.38 (dd, J = 4.4 Hz, J = 8.8 Hz, 1H, H5n), 3.51 (t, J = 7.2 Hz, 2H, α-CH2), 4.78 (s,
1H, H4), 5.01 (d, J = 5.3 Hz, 1H, H1), 6.85 (d, J = 3.1 Hz, 1H, ArH), 6.90 (dd, J = 3.5 Hz, J = 5.0 Hz, 1H, ArH),
7.04 (t, J = 7.2 Hz, 2H, 2 × ArH), 7.10 (s, 1H, ArH), 7.15 (dd, J = 0.9 Hz, J = 5.0 Hz, 1H, ArH), 7.33 (t, J =
7.8 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 23.8 (β-C), 25.5 (γ-C), 38.9 (δ-C), 40.4 (C6), 42.9 (C5), 48.5 (2N-C), 49.2 (C2),
49.3 (C3), 52.9 (2N-C), 57.7 (α-C), 79.0 (C1), 84.9 (C4), 112.0 (ArC), 115.6 (ArC), 118.5 (ArC), 123.9 (ArC), 124.1
—
—
(ArC), 126.6 (ArC), 129.5 (ArC), 131.2 (CF3), 131.4 (Cq), 147.0 (Cq), 151.3 (Cq), 176.5 (C O), 176.8 (C O)
—
—
LC–MS, m/z (Ir/%): for C27H30F3N3O3S [M+] calcd.: 533.1960 (100.0), 534.1994 (29.2), 535.1918 (4.5), 535.2027
(4.1), 536.1951 (1.3), 534.1930 (1.1); found: 533.7 (100), 534.6 (71.3), 535.6 (24.7)

O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
647
Table 2. (continued)
Compound
Spectral data
VId
VIIb
VIIc
VIId
VIIe
IR, ν˜/cm−1: 3059, 2945, 2884, 2821, 1693, 1608, 1586, 1497, 1451, 1109, 729, 694
1H NMR (CDCl3, 500 MHz), δ: 1.49–1.58 (m, 2H, γ-CH2), 1.60–1.65 (m, 2H, β-CH2), 1.85 (dt, J = 4.7 Hz, J =
12.9 Hz, 1H, H6n), 2.27 (dd, J = 9.0 Hz, J = 12.9 Hz, 1H, H6x), 2.47 (br s, 2H, δ-CH2), 2.66 (br s, 4H, 4 × Hpiperazine),
3.01 (d, J = 6.9 Hz, 1H, H2), 3.05 (dd, J = 5.9 Hz, J = 8.5 Hz, 1H, H5n), 3.06 (d, J = 7.2 Hz, 1H, H3), 3.27 (br s,
4H, 4 × Hpiperazine), 3.52 (t, J = 7.2 Hz, 2H, α-CH2), 4.75 (s, 1H, H4), 5.05 (d, J = 5.3 Hz, 1H, H1), 7.06 (t, J =
8.3 Hz, 1H, ArH), 7.10 (d, J = 5.3 Hz, 1H, ArH), 7.26 (s, 1H, ArH), 7.27 (d, J = 8.3 Hz, 1H, ArH), 7.35 (t, J =
7.8 Hz, 1H, ArH), 7.59 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H, ArH), 8.25 (d, J = 2.2 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 24.1 (β-C), 25.7 (γ-C), 39.2 (δ-C), 40.3 (C6), 44.3 (C5), 48.8 (2N-C), 49.7 (C2),
49.9 (C3), 53.1 (2N-C), 58.0 (α-C), 79.3 (C1), 84.6 (C4), 112.3 (ArC), 115.9 (ArC), 118.8 (ArC), 124.7 (ArC), 129.7
(ArC), 131.4 (CF3), 131.7 (Cq), 137.5 (ArC), 138.7 (Cq), 148.7 (ArC), 150.4 (Cq), 151.6 (Cq), 176.4 (C O), 176.7
—
—
—
(C O)
—
LC–MS, m/z (Ir/%): for C28H30ClF3N4O3 [M+] calcd.: 562.1959 (100.0), 564.1929 (32.0), 563.1992 (30.3), 565.1963
(9.7), 564.2026 (4.4), 563.1929 (1.5), 566.996 (1.4); found: 562.6 (100), 564.6 (36.7), 563.6 (30.8), 565.6 (11)
IR, ν˜/cm−1: 3064, 2988, 2943, 2821, 2775, 1771, 1696, 1667, 1577, 1446, 1090, 780
1H NMR (CDCl3, 500 MHz), δ: 1.40 (pent, J = 6.8 Hz, 2H, γ-CH2), 1.51 (pent, J = 6.8 Hz, 2H, β-CH2), 1.80 (dt,
J = 4.8 Hz, J = 12.6 Hz, 1H, H6n), 2.14 (dd, J = 8.7 Hz, J = 12.6 Hz, 1H, H6x), 2.34 (t, J = 7.8 Hz, 2H, δ-CH2),
2.54 (br s, 4H, 4 × Hpiperazine), 2.89 (d, J = 7.8 Hz, 1H, H2), 2.91 (dd, J = 4.7 Hz, J = 8.9 Hz, 1H, H5n), 2.93 (d,
J = 6.9 Hz, 1H, H3), 2.98 (br s, 4H, 4 × Hpiperazine), 3.44 (t, J = 6.8 Hz, 2H, α-CH2), 4.67 (s, 1H, H4), 4.93 (d, J
= 5.8 Hz, 1H, H1), 6.86 (dd, J = 1.9 Hz, J = 6.8 Hz, 1H, ArH), 7.06 (d, J = 6.8 Hz, 2H, 2 × ArH), 7.09 (d, J =
8.7 Hz, 2H, 2 × ArH), 7.17 (d, J = 8.7 Hz, 2H, 2 × ArH)
13C NMR (CDCl3, 125 MHz), δ: 24.1 (β-C), 25.8 (γ-C), 39.2 (δ-C), 40.3 (C6), 47.0 (C5), 49.8 (C2), 50.1 (C3), 51.5
(2N-C), 53.4 (2N-C), 58.0 (α-C), 79.3 (C1), 84.9 (C4), 118.8 (ArC), 124.7 (ArC), 127.6 (ArC), 127.7 (Cq), 128.7
—
—
(ArC), 129.0 (ArC), 132.9 (Cq), 134.2 (Cq), 142.8 (Cq), 151.5 (Cq), 176.8 (C O), 177.1 (C O)
—
—
LC–MS, m/z (Ir/%): for C28H30Cl3N3O3 [M+] calcd.: 561.1353 (100.0), 563.1323 (95.9), 565.1294 (30.6), 562.1386
(30.3), 564.1357 (29.0), 566.1327 (9.3), 563.1420 (4.4), 565.1390 (4.2), 567.1264 (3.3), 567.1361 (1.4), 562.1323 (1.1),
564.1294 (1.1); found: 563.9 (100), 561.9 (99.6), 565.8 (54.8), 564.9 (49.5), 562.9 (46.9), 566.9 (16.2), 567.9 (7.7)
IR, ν˜/cm−1: 3069, 2941, 2877, 2819, 2770, 1770, 1689, 1577, 1395, 1171, 696
1H NMR (CDCl3, 500 MHz), δ: 1.39 (pent, J = 6.8 Hz, 2H, γ-CH2), 1.51 (pent, J = 6.8 Hz, 2H, β-CH2), 1.94
(dt, J = 4.8 Hz, J = 12.6 Hz, 1H, H6n), 2.14 (dd, J = 8.7 Hz, J = 12.6 Hz, 1H, H6x), 2.34 (t, J = 7.8 Hz, 2H,
δ-CH2), 2.54 (br s, 4H, 4 × Hpiperazine), 2.87 (d, J = 6.8 Hz, 1H, H2), 2.93 (d, J = 6.8 Hz, 1H, H3), 2.98 (br s, 4H,
4 × Hpiperazine), 3.30 (dd, J = 3.9 Hz, J = 8.7 Hz, 1H, H5n), 3.44 (t, J = 6.8 Hz, 2H, α-CH2), 4.71 (s, 1H, H4),
4.94 (d, J = 4.8 Hz, 1H, H1), 6.78 (d, J = 2.9 Hz, 1H, ArH), 6.82 (dd, J = 2.9 Hz, J = 4.8 Hz, 1H, ArH), 6.86 (dd,
J = 2.9 Hz, J = 6.8 Hz, 1H, ArH), 7.04 (dd, J = 7.8 Hz, J = 12.6 Hz, 2H, 2 × ArH), 7.06 (d, J = 6.8 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 24.1 (β-C), 25.8 (γ-C), 39.2 (δ-C), 40.7 (C6), 43.1 (C5), 49.5 (C2), 49.6 (C3), 51.5
(2N-C), 53.4 (2N-C), 58.0 (α-C), 79.2 (C1), 85.2 (C4), 118.8 (ArC), 124.1 (ArC), 124.3 (ArC), 124.7 (ArC), 126.9
—
—
—
(ArC), 127.6 (ArC), 127.7 (Cq), 134.2 (Cq), 147.3 (Cq), 151.5 (Cq), 176.7 (C O), 177.0 (C O)
—
LC–MS, m/z (Ir/%): for C26H29Cl2N3O3S [M+] calcd.: 533.1307 (100.0), 535.1277 (63.9), 534.1340 (28.1), 536.1311
(18.0), 537.1248 (10.2), 535.1265 (4.5), 535.1374 (3.8), 537.1235 (2.9), 538.1281 (2.9), 537.1344 (2.4), 536.1298 (1.3),
534.1277 (1.1); found: 534.0 (100), 536.0 (75.8), 534.9 (30.8), 536.9 (16.1), 537.9 (11.4)
IR, ν˜/cm−1: 3058, 2943, 2880, 2819, 1768, 1690, 1578, 1445, 1108, 785
1H NMR (CDCl3, 500 MHz), δ: 1.40 (pent, J = 8.7 Hz, 2H, γ-CH2), 1.52 (pent, J = 7.8 Hz, 2H, β-CH2), 1.78 (dt,
J = 4.8 Hz, J = 12.6 Hz, 1H, H6n), 2.19 (dd, J = 8.7 Hz, J = 12.6 Hz, 1H, H6x), 2.35 (t, J = 7.8 Hz, 2H, δ-CH2),
2.54 (br s, 4H, 4 × Hpiperazine), 2.91 (d, J = 7.8 Hz, 1H, H2), 2.97 (d, J = 6.8 Hz, 1H, H3), 2.98–3.01 (m, 5H,
4 × Hpiperazine, H5n), 3.45 (t, J = 7.8 Hz, 2H, α-CH2), 4.67 (s, 1H, H4), 4.97 (d, J = 4.8 Hz, 1H, H1), 6.87 (dd, J
= 2.9 Hz, J = 6.8 Hz, 1H, ArH), 7.05 (dd, J = 7.8 Hz, J = 12.6 Hz, 1H, ArH), 7.06 (d, J = 6.8 Hz, 1H, ArH), 7.19
(d, J = 6.8 Hz, 2H, 2 × ArH), 7.51 (dd, J = 2.9 Hz, J = 8.7 Hz, 1H, ArH)
13C NMR (CDCl3, 125 MHz), δ: 24.1 (β-C), 25.8 (γ-C), 39.3 (δ-C), 40.3 (C6), 44.3 (C5), 49.7 (C2), 49.9 (C3), 51.5
(2N-C), 53.4 (2N-C), 58.0 (α-C), 79.3 (C1), 84.6 (C4), 118.8 (ArC), 124.7 (ArC), 124.7 (ArC), 127.6 (ArC), 127.7
—
—
—
—
(Cq), 134.2 (Cq), 137.5 (ArC), 138.7 (Cq), 148.7 (ArC), 150.4 (Cq), 151.5 (Cq), 176.4 (C O), 176.7 (C O)
LC–MS, m/z (Ir/%): for C27H29Cl3N4O3 [M+] calcd.: 562.1305 (100.0), 564.1276 (95.9), 566.1246 (30.6), 563.1339
(29.2), 565.1309 (28.0), 567.1280 (8.9), 564.1372 (4.1), 566.1343 (3.9), 568.1217 (3.3), 563.1276 (1.5), 565.1246 (1.4),
568.1313 (1.3); found: 564.9 (100), 562.9 (96), 566.8 (52), 563.8 (45.8), 565.8 (45.1), 567.8 (15), 568.9 (7.1)
IR, ν˜/cm−1: 3069, 2997, 2942, 2873, 2818, 2770, 1771, 1695, 1673, 1577, 1446, 1089, 780
1H NMR (CDCl3, 500 MHz), δ: 1.39 (pent, J = 6.8 Hz, 2H, γ-CH2), 1.51 (pent, J = 6.8 Hz, 2H, β-CH2), 1.82 (dt,
J = 4.8 Hz, J = 12.6 Hz, 1H, H6n), 2.11 (dd, J = 8.7 Hz, J = 12.6 Hz, 1H, H6x), 2.34 (t, J = 7.8 Hz, 2H, δ-CH2),
2.54 (br s, 4H, 4 × Hpiperazine), 2.87 (d, J = 6.8 Hz, 1H, H2), 2.90 (dd, J = 3.9 Hz, J = 8.7 Hz, 1H, H5n), 2.92 (d,
J = 6.8 Hz, 1H, H3), 2.98 (br s, 4H, 4 × Hpiperazine), 3.44 (t, J = 7.8 Hz, 2H, α-CH2), 3.70 (s, 3H, OCH3), 4.65 (s,
1H, H4), 4.91 (d, J = 4.8 Hz, 1H, H1), 6.73 (d, J = 7.8 Hz, 2H, 2 × ArH), 6.86 (dd, J = 2.9 Hz, J = 6.8 Hz, 1H,
ArH), 7.04 (dd, J = 8.7 Hz, J = 12.6 Hz, 2H, 2 × ArH), 7.07 (d, J = 7.8 Hz, 2H, 2 × ArH)
13C NMR (CDCl3, 125 MHz), δ: 24.1 (β-C), 25.8 (γ-C), 39.1 (δ-C), 40.3 (C6), 46.8 (C5), 49.8 (C2), 50.1 (C3), 51.5
(2N-C), 53.4 (2N-C), 55.5 (OCH3), 58.0 (α-C), 79.3 (C1), 85.2 (C4), 114.2 (ArC), 118.8 (ArC), 124.7 (ArC), 127.6
—
—
(ArC), 127.7 (Cq), 128.3 (ArC), 134.2 (Cq), 136.5 (Cq), 151.5 (Cq), 158.6 (Cq), 177.0 (C O), 177.3 (C O)
—
—
LC–MS, m/z (Ir/%): for C29H33Cl2N3O4 [M+] calcd.: 557.1848 (100.0), 559.1819 (63.9), 558.1882 (31.4), 560.1852
(20.0), 561.1789 (10.2), 559.1915 (4.7), 562.1823 (3.2), 561.1886 (3.0), 558.1818 (1.1); found: 558.0 (100), 560.0
(63.3), 562.4 (5)

648
O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
References
pean Journal of Medicinal Chemistry, 44, 3954–4003. DOI:
10.1016/j.ejmech.2009.04.028.
Kulu, I.,
&
Ocal, N. (2011). The synthesis of epiboxi-
Amano, T., Akbar, M., Matsubayashi, H., & Sasa, M. (2001).
Inhibitory effects of tandospirone, a 5-HT1A agonist, on me-
dial vestibular nucleus neurons responding to lateral roll
tilt stimulation in rats. Brain Research, 910, 195–198. DOI:
10.1016/s0006-8993(01)02698-1.
Bagdatli, E., Ocal, N., & Kaufmann, D. E. (2007). An in-
vestigation into domino-Heck reactions of N-acylamino-
substituted tricyclic imides: Synthesis of new prospective
pharmaceuticals. Helvetica Chimica Acta, 90, 2380–2385.
DOI: 10.1002/hlca.200790244.
dine and related analogues as potential pharmacologi-
cal agents. Helvetica Chimica Acta, 94, 2054–2060. DOI:
10.1002/hlca.201100140.
Kulu, I., Kopruceli, A., Goksu, G., & Ocal, N. (2012). Synthesis
of new aryl(hetaryl)-substituted tandospirones under reduc-
tive Heck type hydroarylations and isoxazoline derivatives
via 1,3-dipolar cycloaddition reactions with expected anx-
iolytic activity. Current Organic Synthesis. In press. DOI:
10.2174/1570212700121661794.
Beletskaya, I. P., & Cheprakov, A. V. (2000). The Heck reac-
tion as a sharpening stone of palladium catalysis. Chemical
Reviews, 100, 3009–3066. DOI: 10.1021/cr9903048.
Celik, C., Kulu, I., Ocal, N., & Kaufmann, D. E. (2009).
Domino-Heck reactions of carba- and oxabicyclic, unsatu-
rated dicarboximides: Synthesis of aryl-substituted, bridged
perhydroisoindole derivatives. Helvetica Chimica Acta, 92,
1092–1101. DOI: 10.1002/hlca.200800388.
Makan, S. Y., Tsymbal, D. I., Soboleva, S. G., Tarabara,
I. N., Kas’yan, L. I., & Andronati, S. A. (2009). N-[4-
(Arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-endo-2,
endo-3-dicarboximides and their epoxy derivatives. Synthesis
and affinity for 5-HT1a receptors. Russian Journal of Gen-
eral Chemistry, 79, 292–296. DOI: 10.1134/s1070363209020
212.
Mitchell, D.,
& Yu, H. (2003). Synthetic applications of
Godfrey, A. G., Kohlman, D. T., O’Toole, J. C., Xu, Y. C., &
Zhang, T. Y. (2006). U.S. Patent No. 7001908 B2. Washing-
ton, DC, USA: U.S. Patent and Trademark Office.
palladium-catalyzed hydroarylation and related systems.
Current Opinion in Drug Discovery and Development, 6,
876–883.
Namyslo, J. C., & Kaufmann, D. E. (1999). Chemistry in the
ambient field of the alkaloid epibatidine. Part 2. Triphenylar-
sine as an efficient ligand in the Pd-catalyzed synthesis of epi-
batidine and analogs. Synlett, 1999, 114–116. DOI: 10.1055/s-
1999-2528.
Namyslo, J. C., Storsberg, J., Klinge, J., Gärtner, C., Yao, M.
L., Ocal, N., & Kaufmann, D. E. (2010). The hydroarylation
reaction—scope and limitations. Molecules, 15, 3402–3410.
DOI: 10.3390/molecules15053402.
Negishi, E. I., & de Meijere, A. (2002). Handbook of organopal-
ladium chemistry for organic synthesis. New York, NY, USA:
Wiley.
Nishikawa, H., Inoue, T., Izumi, T., & Koyama, T. (2007). Syn-
ergistic effects of tandospirone and selective serotonin re-
uptake inhibitors on the contextual conditioned fear stress
response in rats. European Neuropsychopharmacology, 17,
643–650. DOI: 10.1016/j.euroneuro.2007.02.010.
Pickard, G. E., & Rea, M. A. (1997). TFMPP, a 5HT1B re-
ceptor agonist, inhibits light-induced phase shifts of the cir-
cadian activity rhythm and c-Fos expression in the mouse
suprachiasmatic nucleus. Neuroscience Letters, 231, 95–98.
DOI: 10.1016/s0304-3940(97)00534-x.
¨
Go¨ksu, G., Gu¨l, M., Ocal, N., & Kaufmann, D. E. (2008). Hy-
droarylation of bicyclic, unsaturated dicarboximides: access
to aryl-substituted, bridged perhydroisoindoles. Tetrahedron
Letters, 49, 2685–2688. DOI: 10.1016/j.tetlet.2008.02.171.
Goksu, G., Ocal, N., & Kaufmann, D. E. (2010). Reductive Heck
reactions of N-methyl-substituted tricyclic imides. Molecules,
15, 1302–1308. DOI: 10.3390/molecules15031303.
Grundt, P., Carlson, E. E., Cao, J., Bennett, C. J., McElveen,
E., Taylor, M., Luedtke, R. R., & Newman, A. H. (2005).
Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-
dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as se-
lective probes with high affinity for the dopamine D3 re-
ceptor. Journal of Medicinal Chemistry, 48, 839–848. DOI:
10.1021/jm049465g.
Grundt, P., Prevatt, K. M., Cao, J., Taylor, M., Floresca, C.
Z., Choi, J. K., Jenkins, B. G., Luedtke, R. R., & New-
man, A. H. (2007). Heterocyclic analogues of N-(4-(4-(2,3-
dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with
functionalized linking chains as novel dopamine D3 receptor
ligands: Potential substance abuse therapeutic agents. Jour-
nal of Medicinal Chemistry, 50, 4135–4146. DOI: 10.1021/
jm0704200.
Ishihara, Y., Bazzi, H. S., Toader, V., Godin, F., & Sleiman,
H. F. (2007). Molecule-responsive block copolymer micelles.
Przegalin´ski, E., Baran, L., & Siwanowicz, J. (1994). Role
of 5-hydroxytryptamine receptor subtypes in the 1-[3-
Chemistry
- A European Journal, 13, 4560–4570. DOI:
(trifluoromethyl)phenyl]piperazine-induced
increase
in
10.1002/chem.200601423.
threshold for maximal electroconvulsions in mice. Epilepsia,
35, 889–894. DOI: 10.1111/j.1528-1157.1994.tb02528.x.
Sarswat, A., Kumar, R., Kumar, L., Lal, N., Sharma, S.,
Prabhakar, Y. S., Pandey, S. K., Lal, J., Verma, V.,
Kishimoto, K., Koyama, S., & Akaike, N. (2000). Presynaptic
modulation of synaptic -aminobutyric acid transmission by
tandospirone in rat basolateral amygdala. European Jour-
nal of Pharmacology, 407, 257–265. DOI: 10.1016/s0014-
2999(00)00673-7.
Jain, A., Maikhuri, J. P., Dalela, D., Gupta, G.,
&
Sharma, V. L. (2011). Arylpiperazines for management of
benign prostatic hyperplasia: Design, synthesis, quantita-
tive structure–activity relationships, and pharmacokinetic
studies. Journal of Medicinal Chemistry, 54, 302–311. DOI:
10.1021/jm101163m.
Kossakowski, J.,
& Jarocka, M. (2001). Synthesis of new
N-substituted cyclic imides with an expected anxiolytic
activity. XVII. Derivatives of 1-ethoxybicyclo[2.2.2]-oct-
5-one-2,3-dicarboximide. Il Farmaco, 56, 785–789. DOI:
10.1016/s0014-827x(01)01144-2.
Staack, R. F., Fritschi, G., & Maurer, H. H. (2003). New de-
signer drug 1-(3-trifluoromethylphenyl) piperazine (TFMPP):
gas chromatography/mass spectrometry and liquid chro-
matography/mass spectrometry studies on its phase I and
II metabolism and on its toxicological detection in rat
urine. Journal of Mass Spectrometry, 38, 971–981. DOI:
10.1002/jms.513.
Kossakowski, J., Bielenica, A., Mirosꢀlaw, B., Koziol, A. E., Dy-
bala, I., & Struga, M. (2008). 4-Azatricyclo[5.2.2.02,6]un-
decane-3,5,8-triones as potential pharmacological agents.
Molecules, 13, 1570–1583. DOI: 10.3390/molecules13081570.
Kulig, K., Sapa, J., Nowaczyk, A., Filipek, B., & Malawska,
B. (2009). Design, synthesis and pharmacological evalu-
ation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-
3,3-diphenylpyrrolidin-2-one derivatives with antiarrhyth-
mic, antihypertensive, and α-adrenolytic activity. Euro-
Takahashi, T., Mitsuya, H., Murata, T., Murayama, J., & Wada,
Y. (2008). Opposite effects of SSRIs and tandospirone in the

O. T. Gunkara et al./Chemical Papers 67 (6) 643–649 (2013)
649
¨
treatment of REM sleep behavior disorder. Sleep Medicine,
9, 317–319. DOI: 10.1016/j.sleep.2007.05.003.
Yolacan, C¸ ., Bagdatli, E., Ocal, N., & Kaufmann, D. E. (2006).
Epibatidine alkaloid chemistry: 5. Domino-Heck reactions of
azabicyclic and tricyclic systems. Molecules, 11, 603–614.
DOI: 10.3390/11080603.
Tindale, J. J., Hartlen, K. D., Alizadeh, A., Workentin, M. S.,
& Ragogna, P. J. (2010). Maleimide-modified phosphonium
ionic liquids: A template towards (multi)task-specific ionic
liquids. Chemistry - A European Journal, 16, 9068–9075.
DOI: 10.1002/chem.200902610.
Wei, Z. L., George, C., & Kozikowski, A. P. (2003). Synthe-
sis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated ana-
logues of epibatidine. Tetrahedron Letters, 44, 3847–3850.
DOI: 10.1016/s0040-4039(03)00737-8.