Synthesis of new tandospirone analogues carrying 1-(3-(trifluoromethyl) phenyl)piperazine

Article abstract of DOI:10.1080/00397911.2013.865236

New tandospirone analogues containing a 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP) moiety have been synthesized by hydroarylation reactions with Pd(OAc)₂. The perhydroisoindole derivatives were obtained by the reaction of reduced starting material with aryl-(heteroaryl) iodides under the same conditions. Spiro-1,3-indandionolylpyrrolidine derivatives having an array of stereocenters are reported.

Full text of DOI:10.1080/00397911.2013.865236

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Synthesis of New Tandospirone
Analogues Carrying 1-(3-
(Trifluoromethyl)phenyl)piperazine
Omer Tahir Gunkara a , Bilgesu Onur Sucu a , Muge Guleli a & Nuket
Ocal a
a Faculty of Science and Arts , Yildiz Technical University , Istanbul ,
Turkey
Accepted author version posted online: 10 Feb 2014.Published
online: 14 May 2014.
To cite this article: Omer Tahir Gunkara , Bilgesu Onur Sucu , Muge Guleli & Nuket Ocal (2014)
Synthesis of New Tandospirone Analogues Carrying 1-(3-(Trifluoromethyl)phenyl)piperazine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:11, 1619-1628, DOI: 10.1080/00397911.2013.865236
To link to this article: http://dx.doi.org/10.1080/00397911.2013.865236
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Synthetic Communications1, 44: 1619–1628, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.865236
SYNTHESIS OF NEW TANDOSPIRONE ANALOGUES
CARRYING 1-(3-(TRIFLUOROMETHYL)PHENYL)
PIPERAZINE
Omer Tahir Gunkara, Bilgesu Onur Sucu, Muge Guleli, and
Nuket Ocal
Faculty of Science and Arts, Yildiz Technical University, Istanbul, Turkey
GRAPHICAL ABSTRACT
Abstract New tandospirone analogues containing a 1-[3-(trifluoromethyl)phenyl]piperazine
(TFMPP) moiety have been synthesized by hydroarylation reactions with Pd(OAc)2.
The perhydroisoindole derivatives were obtained by the reaction of reduced starting
material with aryl-(heteroaryl) iodides under the same conditions. Spiro-1,3-indandionolyl-
pyrrolidine derivatives having an array of stereocenters are reported.
Keywords Antidepressant drugs; C-C coupling; isoindoles; spiro-1,3-indandionolylpyr-
rolidines; tandospirone
Received October 11, 2013.
Address correspondence to Nuket Ocal, Yildiz Technical University, Faculty of Science and Arts,
Davutpasa Campus, 34210 Esenler-Istanbul, Turkey. E-mail: nocal@yildiz.edu.tr
1619

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O. T. GUNKARA ET AL.
INTRODUCTION
Aryl piperazines are an important family of heterocyclic compounds that are
attracting significant interest in medicinal chemistry. They are commonly found as
fragments in natural products, receptor ligands, and many pharmacologically active
molecules. A series of aryl piperazines are effective pharmaceuticals for the treatment
of conditions related to or affected by the serotonin 1A receptor. They are parti-
cularly effective as antagonists to this receptor and are useful for alleviating the
symptoms of nicotine and tobacco withdrawal.[1]
1-[3-(Trifluoromethyl)phenyl]piperazine (TFMPP) is a recreational drug of the
piperazine class. It shows affinity to the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and
5-HT2C receptors and functions as a full agonist at all sites except for the 5-HT2A
receptor, where it acts as a weak partial agonist or antagonist.[2] Fluorine plays
a pivotal role in drug discovery, and because of its greater electronegativity
incorporation of fluorine atom(s) within the molecule can enhance its biopotency,
bioavailability, metabolic stability, and lipophilicity. Trifluoromethylation is one of
the most significant strategies to improve pharmacological activities of the molecule
because of its high lipophilicity. 1-(4-(Trifluoromethyl)phenyl)piperazine (pTFMPP)
is also a serotonergic releasing agent. It is rarely encountered as a designer drug but
is much less common than the ‘‘normal’’ isomer meta-TFMPP. On the other hand,
tandospirone (Fig. 1), developed as an anxiolytic drug marketed in Japan, is an aryl
piperazine compound that binds to both 5-HT1A and dopamine D4 receptors.[3]
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.[4] There-
fore, the synthesis of more bioactive aryl- and heteroaryl-substituted tandospirones by
reductive Heck reactions and isoxazoline derivatives via 1,3-dipolar cycloadditions
came into attention.[5] Recently, we reported 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 containing an exo-ring in
the tricyclic system as potentially biologically active molecules.[6] In the present work,
the pyrimidine group in the tandospirone molecule was replaced with the 3-(trifluoro-
methyl)phenyl group. We then investigated its hydroarylation reactions with aryl- and
hetaryl iodides in the presence of triphenylarsine and Pd(OAc)2.
In the presence of triphenylarsine as a ligand,[7] the palladium-catalyzed
hydroarylation of the easily accessible unsaturated tricyclic N-substituted imides
has proven to be a stereoselective, versatile, and high-yield approach for the synthesis
of the corresponding aryl and heteroaryl derivatives.[8] Pd(OAc)2-catalyzed asymmetric
Heck-type hydroarylations of bicyclic and tricyclic alkenes such as epibatidine
Figure 1. Tandospirone.

NEW TANDOSPIRONE ANALOGUE
1621
analogues, and their domino-Heck applications by treatment with aryl (or heteroaryl)
iodides have been introduced.[9]
In this article, we also tried subsequent reduction reactions with LiAlH4 to
open new access to perhydroisoindole derivatives from reductive Heck products
but we were not successful in reducing the new aryl(hetaryl)-substituted tando-
spirone analogues. Therefore, we first reduced the starting material 4 with LiAlH4
and then conducted its hydroarylation reaction by the reductive Heck procedure.
In addition, we focused on the [3þ2] cycloaddition reactions with an
azomethine ylide to obtain fused spiro-1,3-indandionolylpyrrolidine compounds to
have more potentially biologically active molecules available. Spiro compounds
are well known to possess varied pharmacological activities and hence their synthesis
has always been attractive to organic chemists.[10]
RESULTS AND DISCUSSION
Our synthesis started with the reaction of 2[11] with 1,4-dibromobutane to
afford 3,[12] which was condensed with 1-[3-(trifluoromethyl)phenyl]piperazine
(TFMPP), providing the new compound 4 in good yield (Scheme 1).
Reactions of 4 with various aryl iodides under reductive Heck reaction conditions
gave 5a–d as single 5-exo-diastereomers (Scheme 2). 2-Chloro-5-iodopyridine was selected
as the arylation reagent because of its similarity with the structure of epibatidine.[13]
1
The exo-configuration of each Heck reaction 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 interac-
tion with H1. The geminal H atoms at C-(6) were identified by their vicinal coupling
to H1. Therefore, H1 appeared as doublets and H4 as singlets in the expected region.
Additionally, the correlation (1H-1H-COSY) spectra showed cross peaks between
H2 and H3 and between H5 and H6, respectively. In addition, the 13C NMR and
heteronuclear single quantum coherence (HSQC) spectral data were also in agree-
ment with the proposed structures and the mass spectra of all new compounds
showed the expected molecular ion peaks. Fourier transform infrared (FTIR) spectra
of the hydroarylation products exhibited strong absorption bands due to the
=
_
symmetric and asymmetric stretching vibrations of the C O bonds, C H bonds
in the methylene groups, and C_H bonds in unsaturated fragments.
Perhydroisoindoles are selective sigma receptor antagonists and have a low
potential for movement disorder side effects associated with typical antipsychotic
agents.[14] We have reduced 4 with LiAlH4 to obtain 6. After regular workup, the
crude product was purified by column chromatography (Scheme 3).
Scheme 1. (a) 1,4-Dibromobutane, butanone, K2CO3, reflux 24 h; 87%. (b) TFMPP, DMF, K2CO3, reflux
20 h; 90%.

1622
O. T. GUNKARA ET AL.
Scheme 2. (a) Aryl iodide, Pd(OAc)2, AsPh3, DMF, Et3N, HCOOH, 65 ꢀC, 24–48 h.
As part of our continuing study to obtain new perhydroisoindole derivatives,
we continued to prepare 7a–d from 6 by the reductive Heck procedure in good yields
(Scheme 4).
The structural identification of the new reduced compound (6) and its
hydroarylation products (7a–d) succeeded. In the FTIR spectra the characteristic
=
C O bands of 6 and 7a–d were absent. NMR and gas chromatography–mass
spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS)
were also in agreement with the proposed structures.
The reaction of 4 with azomethine ylide obtained from ninhydrine and
N-methylglycine did not give the expected spiro-1,3-indandionolylpyrrolidine, 10.
Therefore, we first carried out the [3þ2]-cycloaddition of 2 with the azomethine
ylide derived from ninhydrine and N-methylglycine to obtain compound 8. The
Scheme 3. (a) LiAlH4, dry ether, 0 ꢀC ! rt, 20 h; 97%.
Scheme 4. (a) Aryl iodide, Pd(OAc)2, AsPh3, DMF, Et3N, HCOOH, 65 ꢀC, 24–48 h.

NEW TANDOSPIRONE ANALOGUE
1623
Scheme 5. (a) N-methylglycine, ninhydrine, EtOH=1,4-dioxane (1:1), 65 ꢀC, 24 h; 65%. (b) 1,4-dibromobutane,
DMF, K2CO3, 55ꢀC, 20 h; 60%. (c) TFMPP, DMF, K2CO3, 55ꢀC, 24 h; 84%.
latter was reacted with 1,4-dibromobutane in dimethylformamide (DMF) using
K2CO3 to give 9. Finally, compound 9 combined with TFMPP led to the desired
10 (Scheme 5).
1H NMR spectra of 10 showed four aromatic protons at 7.84–7.97 ppm as
additional. LC-MS result also confirmed the structure of 10. The absence of alkenic
protons in the 1H NMR spectrum of 10, as well as its 13C NMR and LC-MS spectra,
confirmed the structure of 10.
All compounds were prepared in good yields (Table 1).
Table 1. Yield, reaction time, appearance, and melting points of all compounds
Product
Time (h)
Yield (%)
Appearance
Mp (ꢀC)
187
2[11]
3[12]
4
20
24
24
24
26
27
24
4
58
80
85
90
91
72
85
97
55
45
62
37
65
60
84
White crystal
White crystal
Yellow oil
White crystal
Colorless oil
Colorless oil
Yellow oil
Yellow oil
Yellow oil
Yellow oil
Yellow oil
Yellow oil
Yellow oil
Yellow oil
76.5–79.7
5a
5b
5c
5d
6
—
145–147
—
—
—
7a
7b
7c
7d
8
24
25
29
24
24
20
24
—
—
—
—
—
—
9
10
—

1624
O. T. GUNKARA ET AL.
EXPERIMENTAL
All the reagents and solvents were reagent grade and used without further
purification unless specified otherwise; the organic solvents used in this study
were dried over appropriate drying agents. Chemicals were purchased from Merck.
Technical-grade AcOEt and n-hexane used for column chromatography were
distilled prior to use. The progress of the reactions was monitored by analytical
thin-layer chromatography (TLC) performed on Merck SiO2 60F254 plates. Column
chromatography used silica gel (SiO2; 70–230 mesh) packed in glass columns.
Melting points were measured on a Gallenkamp melting-point apparatus and
are uncorrected. FTIR spectra were determined with a Perkin-Elmer Spectrum One
1
FTIR spectrometer. H and 13C NMR spectra used Bruker spectrometers, at 500 or
125 MHz, respectively, in CDCl3 solvent; d is in parts per million (ppm) relative to
Me4Si as internal standard; J in hertz. GC-MS were measured on a Agilent 6890N
GC-System-5973 IMSD spectrometer in m=z. LS-MS were determined on an Agilent
6460-A LC-Triple Quadrupole MS=MS spectrometer; in m=z. Elemental analyses
were carried out on a Thermo Flash EA 1112 series apparatus.
N-(f4-[3-(Trifluoromethyl)phenyl]piperazin-1-ylgbutyl)bicyclo[2.2.1]
hept-5-ene-2-endo,3-endo-dicarboximide (4)
A mixture of 3 (298 mg, 1 mmol), 1-[3-(trifluoromethyl)phenyl]piperazine
(460 mg, 2 mmol), and anhydrous K2CO3 (276 mg, 2 mmol) in butanone (15 ml)
was magnetically stirred under reflux for 24 h. After cooling to room temperature,
the organic phase was concentrated and the residue was purified by column chroma-
tography using CHCl3=MeOH (20:1) as the eluent to give 4. Yield: 381.6 mg (85%).
White crystal. Mp 76.5–79.7 ꢀC. Rf (CHCl3=MeOH 20:1) 0.42. IR (ATR): n 3067,
1
2943, 2876, 2820, 2781, 1767, 1692, 1116, 722 cmꢁ1. H NMR (500 MHz, CDCl3):
d 1.48 (t, J ¼ 3.5 Hz, 4H); 1.53 (d, J ¼ 8.8 Hz, 1H); 1.68 (brs, 2H); 1.73 (d, J ¼ 8.8 Hz,
1H); 2.38 (t, J ¼ 6.9 Hz, 2H); 2.58 (t, J ¼ 4.7 Hz, 4H); 3.23 (t, J ¼ 5.0 Hz, 4H); 3.36 (t,
J ¼ 6.6 Hz, 2H); 3.39 (s, 2H); 6.10 (s, 2H); 7.06 (t, J ¼ 7.6 Hz, 2H); 7.10 (s, 1H); 7.34
(t, J ¼ 7.8 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 24.1; 25.8; 38.2; 44.9 (ꢂ2);
45.7 (ꢂ2); 48.6 (ꢂ2); 52.2; 52.9 (ꢂ2); 57.9; 112.1; 115.72; 118.6; 129.5; 131.5; 134.4
(ꢂ2); 151.4 (ꢂ2); 177.8 (ꢂ2) ppm. LC-MS: m=z 447.9 (Mþ). Anal. calcd for
C24H28F3N3O2: C, 64.42; H, 6.31; N, 9.39%. Found: C, 64.58; H, 6.19; N, 9.16%.
Compounds 5a–5d and 7a–7d: General Procedure
A solution of Pd(OAc)2 (5.6 mg, 0.025 mmol) and Ph3As (33.7 mg, 0.11 mmol)
in dry DMF (3 ml) was stirred in a Schlenk flask under N2 at 65 ꢀC for 15 min to
form the catalyst complex. Then, aryl iodide (1.5 mmol), alkene (4 and 6, respect-
ively; 1 mmol), Et3N (354 mg, 3.5 mmol), and HCOOH (138 mg, 3 mmol) were
added. The mixture was heated to 65 ꢀC for 24–48 h. After cooling to room tempera-
ture, brine (50 ml) was added, and the mixture was extracted with AcOEt, dried
(MgSO4) and concentrated. The residue purified by column chromatography (5a–5d;
CH2Cl2=MeOH 20:1; 7a–7d; CH2Cl2=MeOH 10:1 as eluent systems respectively).

NEW TANDOSPIRONE ANALOGUE
1625
N-f4-[3-(Trifluoromethyl)phenyl]piperazin-1-ylgbutyl-5-
phenylbicyclo[2.2.1]heptane-2-endo,3-endo-dicarboximide (5a)
Yield: 473 mg (90%). Yellow oil. Rf (CH2Cl2=MeOH 20:1) 0.44. IR (ATR): n
2948, 2881, 2820, 2779, 1767, 1695, 1608, 1587, 1496, 1448, 1116, 729, 696 cmꢁ1
.
1H NMR (500 MHz, CDCl3): d 1.47–1.53 (m, 3H); 1.56–1.62 (m, 3H); 1.67–1.72
(m, 1H); 1.79 (dt, J ¼ 1.4, 10.3 Hz, 1H); 2.33 (dt, J ¼ 3.4, 6.8 Hz, 2H); 2.49
(t, J ¼ 4.9 Hz, 4H); 2.71 (dd, J ¼ 5.64, 8.76 Hz, 1H); 2.81–2.84 (m, 2H); 3.04–3.07
(m, 1H); 3.10–3.13 (m, 5H); 3.48 (dt, J ¼ 1.3, 7.2 Hz, 2H); 6.94 (d, J ¼ 8.2 Hz, 1H);
6.98 (d, J ¼ 8.0 Hz, 2H); 7.10 (d, J ¼ 7.9 Hz, 2H); 7.19 (s, 1H); 7.20 (t, J ¼ 7.6 Hz,
2H); 7.24 (t, J ¼ 8.1 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 24.5; 26.2;
32.58; 38.7; 39.6; 39.9; 42.1; 46.1; 48.5; 48.8; 49.1; 53.2 (ꢂ2); 58.1 (ꢂ2); 112.3;
115.9; 118.8; 126.5; 127.3; 128.7 (ꢂ2); 129.7 (ꢂ2); 131.5; 131.7; 144.5; 151.6; 178.3;
178.3 ppm. LC-MS: m=z 525.70 (Mþ). Calcd for C30H34F3N3O2: C, 68.55; H, 6.52;
N, 7.99%. Found: C, 68.66; H, 6.34; N, 8.19%.
2-f4-[3-(Trifluoromethyl)phenyl]piperazinylbutylg-4,7-endomethylene-
1H-isoindole (6)
A solution of 4 (447 mg, 1 mmol) was added in small portions under stirring to
a suspension of LiAlH4 (151.8 mg, 4 mmol) in dry diethyl ether at N2 atmosphere
at 0 ꢀC. Then the mixture was heated to room temperature and stirred for 4 h. Excess
reducing agent was decomposed with cold water, the precipitate was filtered off,
the organic phase was dried (MgSO4) and concentrated, and the residue was purified
by column chromatography. Yield: 406 mg (97%). Yellow oil. Rf (CH2Cl2=MeOH
1
20:1) 0.05. IR (ATR): n 3055, 2936, 2868, 2809, 1495, 1116, 729 cmꢁ1. H NMR
(500 MHz, CDCl3): d 1.43–1.54 (m, 4H); 1.55 (d, J ¼ 8.2 Hz, 1H); 1.68 (d, J ¼ 8.2 Hz,
1H); 1.80–1.81 (m, 2H); 2.34 (dd, J ¼ 8.2, 14.8 Hz, 4H); 2.58 (t, J ¼ 4.7 Hz, 4H); 2.78
(brs, 2H); 2.88–2.91 (m, 4H); 3.23 (t, J ¼ 4.7 Hz, 4H); 6.12 (s, 2H); 7.05 (t, J ¼ 7.9 Hz,
2H); 7.10 (s, 1H); 7.33 (t, J ¼ 7.9 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 25.0;
26.6; 44.6 (ꢂ2); 46.5 (ꢂ2); 48.6 (ꢂ2); 53.0 (ꢂ2); 53.8; 56.1; 56.8 (ꢂ2); 58.5; 112.1;
115.6; 118.5; 129.5; 131.3; 131.5; 137.3 (ꢂ2); 151.4 ppm. GC-MS: m=z 419 (Mþ).
Calcd. for C24H32F3N3: C, 68.71; H, 7.69; N, 10.02%. Found: C, 68.62; H, 7.74; N,
10.21%.
Compound 10
A solution of 1-[3-(trifluoromethyl)phenyl)]piperazine (460 mg, 2 mmol) and
anhydrous K2CO3 (276 mg, 2 mmol) in butanone (25 ml) was heated. Then a solution
of 9 (485 mg, 1 mmol) in butanone (10 mL) was added to the mixture and refluxed
for 24 h. After cooling to room temperature, K2CO3 was filtered, the organic phase
was concentrated, and the residue was purified by column chromatography using
CH2Cl2=MeOH (20:1) as the eluent to give 10. Yield: 533 mg (84%). Yellow oil. Rf
(CH2Cl2=MeOH 20:1) 0.61. IR (ATR): n 3064, 2948, 2873, 1766, 1740, 1691,
1116, 722 cmꢁ1. 1H NMR (500MHz, CDCl3): d 1.48–1.58 (m, 5H); 2.05 (d, J ¼ 7.6 Hz,
1H); 2.18 (s, 3H); 2.41 (t, J ¼ 6.3 Hz, 2H); 2.46 (t, J ¼ 8.8 Hz, 1H); 2.59–2.62 (m, 5H);
2.76–2.79 (m, 2H); 2.95 (dd, J ¼ 2.5, 9.4 Hz, 1H); 2.99 (dd, J ¼ 5.3, 9.4 Hz, 1H); 3.05

1626
O. T. GUNKARA ET AL.
(dd, J ¼ 5.3, 9.4 Hz, 1H); 3.24 (t, J ¼ 5.0 Hz, 4H); 3.44 (t, J ¼ 8.8 Hz, 2H); 3.48 (t,
J ¼ 9.1 Hz, 1H); 7.05–7.07 (m, 2H); 7.11 (s, 1H); 7.34 (t, J ¼ 7.9 Hz, 1H); 7.84–7.88
(m, 3H); 7.97 (dd, J ¼ 1.3, 7.9 Hz, 1H) ppm. 13C NMR (125MHz, CDCl3): d 24.1;
25.8; 35.6; 38.4; 39.0; 41.8; 42.7; 44.5; 47.7; 48.2; 48.6 (ꢂ2); 50.8; 52.9 (ꢂ2); 57.7;
60.7; 77.6; 112.1; 115.6; 118.6; 123.3; 129.5 (ꢂ2); 136.4; 136.5; 139.61 (ꢂ2); 141.9
(ꢂ2); 151.4; 177.4; 177.6; 200.6; 203.6 ppm. LC-MS: m=z 635.00 (Mþ). C35H37F3N4O4:
C, 66.23; H, 5.88; N, 8.83%. Found: C, 66.45; H, 5.62; N, 8.91%.
CONCLUSION
We have recently synthesized various new tandospirone analogues by reductive
Heck and [3þ2] cycloaddition reactions as possibly antidepressant drugs, a result of
the tandospirone molecule developed as an anxiolytic drug. On the other hand, 1-[3-
(trifluoromethyl)phenyl]piperazine (TFMPP) is an entactogen drug that selectively
promotes the release of serotonin, and it has widely been used as a pharmacological
probe drug for drug discrimination procedures in animals for this reason. Here,
this compound was first linked to a tricyclic imide function via a butyl chain as
new tandospirone analog. Then, we have studied its hydroarylation reactions with
aryl iodides under reductive Heck conditions. Our results have also demonstrated
that the reductive access to aryl-substituted bridged isoindoles will be useful for the
construction of novel heterocycles of potential pharmacological interest. Additionally,
the stereoselective synthesis of fused the spiro-1,3-indandionolylpyrrolidine as a poten-
tially bioactive analog was demonstrated by way of an azomethineylide cycloaddition.
FUNDING
We gratefully acknowledge financial support of this work by the Scientific and
Technological Research Council of Turkey (TUBITAK Project No. 109T380) and
Yildiz Technical University Scientific Research Projects Coordination Department
(Project No. 2011-01-02-KAP03).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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