Stereoselective synthesis of (z)-1-benzhydryl-4-cinnamylpiperazines via the wittig reaction

Article abstract of DOI:10.1080/00397911.2013.826808

A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a-c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a-c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a-c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a-c gave the corresponding aldehydes 4a-c, which when subjected to the Wittig reaction followed by column purification to afford 1a-c (E-isomers) and 6a-c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright

Full text of DOI:10.1080/00397911.2013.826808

This article was downloaded by: [Moskow State Univ Bibliote]
On: 04 January 2014, At: 16:49
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Stereoselective Synthesis of (Z)-1-
Benzhydryl-4-cinnamylpiperazines via
the Wittig Reaction
S. Shivprakash a & G. Chandrasekara Reddy a
a Department of Chemistry , Vittal Mallya Scientific Research
Foundation , Bangalore , India
Published online: 27 Dec 2013.
To cite this article: S. Shivprakash & G. Chandrasekara Reddy (2014) Stereoselective Synthesis of
(Z)-1-Benzhydryl-4-cinnamylpiperazines via the Wittig Reaction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:5, 600-609, DOI:
10.1080/00397911.2013.826808
To link to this article: http://dx.doi.org/10.1080/00397911.2013.826808
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 600–609, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.826808
STEREOSELECTIVE SYNTHESIS OF
(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
VIA THE WITTIG REACTION
S. Shivprakash and G. Chandrasekara Reddy
Department of Chemistry, Vittal Mallya Scientific Research Foundation,
Bangalore, India
GRAPHICAL ABSTRACT
Abstract A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-
cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is
described. Of the three compounds synthesized (5a–c), the ratio of E=Z-isomers remained
around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine
derivatives (3a–c), were prepared by nucleophilic substitution reaction of benzhydrylpi-
perazines (2a–c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%).
Hydrolysis of 3a–c gave the corresponding aldehydes 4a–c, which when subjected to
the Wittig reaction followed by column purification to afford 1a–c (E-isomers) and
6a–c (Z-isomers) in pure form. The isolated compounds were characterized by NMR
and mass spectral analysis.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Benzhydrylpiperazines; cinnarizine; clocinizine; flunarizine; Wittig reaction
Received May 17, 2013.
Address correspondence to G. Chandrasekara Reddy, Department of Chemistry, Vittal Mallya
Scientific Research Foundation, Bangalore 560 076, India. E-mail: gcreddy@vmsrf.org
600

(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
601
INTRODUCTION
The piperazine moiety is an ubiquitous pendant group found in a variety of
biologically active molecules.[1,2] In the early 20th century, piperazine compounds
were used for the treatment of gout and introduced into medicine as a solvent for
uric acid.[3,4] The anthelmintic activity of piperazine was established by Giroud in
1942, and this observation was confirmed by Bayard in 1949.[5]
Piperazine and its derivatives are gaining more attention in today’s drug devel-
opment because of their wide range of therapeutic activities. Moreover, they have
wide clinical applications in various therapeutic segments such as antibacterial,[6–9]
antifungal,[10,11] anticancer,[12–14] antiparasitic,[15,16] antihistaminic,[17] psycholy-
tic,[18] and in antidepressive domains.[19] Many marketed drugs, such as crixivan[20]
and piperazinyl-linked ciprofloxacin dimers, have been reported as potent antibac-
terial agents against resistant strains.[21] Piperazine derivatives containing a tetrazole
nucleus have been reported as antifungal agents.[11] In particular, the benzhydryl
groups attached to the piperazine moiety exhibited antihistaminic activity with
potent nonpeptidic delta opioid receptor agonist properties.[22] Thus piperazine deri-
vatives bearing a diphenylmethyl group at N(1) and a benzyl group at N(4) position
possess cerebral vasodilating activity.[23] Cinnarizine,[24] flunarizine, and clocinizine
(Fig. 1), which are clinically used as antihistamines and calcium channel antagonists,
bear a benzhydryl moiety on one side and cinnamyl group with (E) geometry
attached to opposite N-atom of piperazine.
The greater biological importance of (E)-isomers of 1-benzhydryl-4-cinnamyl-
piperazines prompted us to search for newer ways of preparing these molecules along
with the (Z)-isomers and study their structure–activity relationships.
Several synthetic methods are described for the preparation of (E)-1-
benzhydryl-4-cinnamyl piperazine compounds,[25] but none of the methods revealed
the process of producing (Z)-isomers. In this article we describe the synthesis of
(Z)-isomers of 1-benzhydryl-4-cinnamyl piperazines in preference over (E)-isomers
in a stereoselective manner by a novel synthetic approach. (E)=(Z)-isomers were
resolved and their ratios were determined by high-performance liquid chromoto-
1
graphy (HPLC). Structural characterization was carried out by H and 13C NMR
and mass spectral (MS) analysis.
1
Figure 1. Structure of antihistamine compounds (E-isomers). R, R H (cinnarizine) (1a); R, R
1
=
=
F
1
(flunarizine) (1b); R H, R Cl (clocinizine) (1c).
=
=

602
S. SHIVPRAKASH AND G. CHANDRASEKARA REDDY
RESULTS AND DISCUSSION
The novel route for the stereoselective synthesis of (Z)-isomer in preference
over (E)-isomer of 1-diphenylmethyl-4-cinnamylpiperazine derivatives is indicated
in Scheme 1. The intermediate diphenylmethylpiperazines (2a–c) were prepared by
slight modification of the reported synthetic method[26] from the corresponding
benzophenones by replacing SOCl2 with concentrated HCl in the chlorination.
The reaction of 2a–c with equimolar amounts of chloro=bromoacetaldehyde
dimethylacetal in dimethylformamide (DMF) or toluene as a solvent and in the pres-
ence of anhydrous K2CO3 as a base gave compounds 3a–c in 83–88% yield. These
compounds on further treatment with aqueous HBr (48%) at room temperature
afforded aldehydes 4a–c, which were taken up immediately for the next step as these
intermediates were prone to undergo aerial oxidation after long standing. The Wittig
reaction of 4a–c with benzyltriphenyl phosphonium chloride in the presence of t-
BuOK in dichloromethane as a solvent resulted in the formation of compounds
5a–c as a mixture of (E)- and (Z)-isomers with 10–15% of (E) and 85–90% of (Z)
determined based on HPLC analysis (Table 1).
The reaction of semistabilized ylides generated in the reaction mixture during
the Witting olefination from benzyltriphenyl phosphonium chloride with the corre-
sponding aldehydes (4a–c) largely produced (Z)-alkenes to the extent of 85% and
lower amounts of (E)-alkenes. This type of stereoselectivity in the Wittig process
is quite unusual with semistabilized ylides.[27] Generally, nonstabilized phosphonium
ylides when react with aldehydes give largely (Z)-alkenes, except under special
Scheme 1. Synthesis of (E=Z)-1-benzhydryl-4-cinnamylpiperazine derivatives.

(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
Table 1. HPLC data showing (E)=(Z)-isomer ratio of 5a–c
603
Compound
(E)-isomer (%)
(Z)-isomer (%)
5a
11.9
12.4
14.0
88.0
85.2
85.9
5ba
5c
aNo baseline separation in HPLC and hence the discrepancy.
conditions like in the Schlosser modifications and in the presence of anionic,
nucleophilic groups in triphenyl phosphonium ylide moiety,[28] whereas stabilized
ylides give predominantly (E)-alkenes, but semistabilized ylides generally give a mix-
ture of (Z)=(E)-alkenes in a ratio of about 50:50. In the present scenario, where we
obtained largely (Z)-isomers, clearly points out that not only do the type of ylides
and the reaction conditions play key roles but also the bulkiness of reacting aldehyde
influences the stereochemistry.
Bond geometry of compounds was established by comparison of the 1H NMR
spectra of isomeric pairs (Table 2). All the (Z)-isomers (6a, 6b, and 6c) showed b-
vinylic protons at d ꢀ 5.7 ppm upfield compared to their (E)-isomers (d ꢀ 6.2 ppm)
(1a, 1b, and 1c). The coupling constant of vinylic protons in (Z)-isomers was about
12.0 Hz, whereas the (E)-isomer showed 16.0 Hz.[29] This is because in all
(E)-isomers, the b proton comes in the p-zone of aromatic ring, causing deshielding
effect compared to (Z)-isomers, wherein this proton is away from the deshielding
aromatic zone.
The stereoselective formation of (Z)-isomers over (E)-isomers in the Wittig
reaction can be explained by the proposed mechanism as shown in Scheme 2. The
key intermediate oxaphosphetane obtained during the Wittig reaction probably pro-
ceeds via two possible orientations. In the present scenario, perhaps type 1 orien-
tation is more predominant over the other, where the bulky triphenyl phosphene
group orients itself away from benzhydryl piperazine moiety. Hence with the elimin-
ation of triphenylphosphine oxide, the preferred product formed would be
(Z)-isomer over (E)-isomer.
Finally, chromatographic separation of 5a–c over silica gel and using EtOAc=
hexane as eluent afforded (E)-1-benzhydryl-4-cinnamylpiperazines (1a–c) and (Z)-1-
benzhydryl-4-cinnamylpiperazines (6a–c) in pure form (Fig. 2). The (E)- and
(Z)-isomers were characterized by NMR and MS analysis.
Table 2. 1H NMR data of isomeric protons 6a–c and 1a–c
Chemical shift (d) of vinylic protons (J value)
Compound
a-Proton
b-Proton
1a (E-isomer)
6a (Z-isomer)
1b (E-isomer)
6b (Z-isomer)
1c (E-isomer)
6c (Z-isomer)
6.50 (16.0 Hz)
6.55 (12.0 Hz)
6.50 (16.0 Hz)
6.50 (12.0 Hz)
6.50 (16.0 Hz)
6.56 (12.0 Hz)
6.26 (16.0 Hz)
5.77 (12.0 Hz)
6.25 (16.0 Hz)
5.76 (12.0 Hz)
6.25 (16.0 Hz)
5.76 (12.0 Hz)

604
S. SHIVPRAKASH AND G. CHANDRASEKARA REDDY
Scheme 2. Proposed mechanism for the formation of (E) and (Z)-1-benzhydryl-4-cinnamyl piperazines.
1
Figure 2. Structure of (Z)-1-benzhydryl-4-cinnamylpiperazine derivatives (Z-isomers). R, R H (6a); R,
=
1
1
=
= =
F (6b); R H, R Cl (6c).
R

(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
605
Conversion of (Z)-isomers (6a–c) into (E)-isomers (1a–c) did not take place
either by heating in the presence of mineral acids or directly (without acid). This
suggests that (Z)-isomers are thermally stable.
CONCLUSION
In conclusion, we have developed a new stereoselective synthetic method
of producing 1-benzhydryl-4-cinnamylpiperazine compounds. The formation of
(Z)-isomers (85–90%) in preference over (E)-isomers during the Wittig reaction
has been explained. All the new compounds were characterized by NMR and MS
analysis. This method can be used for preparing various derivatives of (Z)-1-
-benzhydryl-4-cinnamyl piperazines in multigram levels, and ours is the first report
of their synthesis. We would like to explore the biological importance of (Z)-isomers
over (E)-isomers as no such studies have been reported so far.
EXPERIMENTAL
All chemicals purchased were of laboratory reagent (LR) grade from
Sigma-Aldrich, Merck, and Loba-chemie; solvents used were of commercial grade.
Melting points were determined on an Acro melting-point apparatus (using a
calibrated thermometer). Thin-layer chromatography (TLC) was run on silica gel
precoated on aluminium sheet (silica gel 60F254, Merck). Chromatographic
separation of mixtures was performed in open glass columns packed with silica gel
(Merck grade 7734, 70–230 mesh) and eluted with ethyl acetate=hexane solvent
mixture. Analytical HPLC was recorded with Shimadzu (CLASS-VP) equipped with
LC-10AT VP high-pressure pumps, a SPD-M10A VP photodiode array detector, a
CTO-10AS VP oven, and a SCL-10A VP controller (RP column: Atlantis-T3,
5.0 mm, 4.6 ꢁ 150 mm; mobile phase: 1% ammonium acetate and 0.2% acetic acid
in acetonitrile gradient elution; UV detector: 230 nm). The mass spectra were
recorded on GCMS-QP2010S (direct probe) instrument and high-resolution mass
spectral (HRMS) data were obtained on the Micromass Q-Tof micro instrument
1
using electrospray ionization (ESI). H and 13C NMR spectra were recorded on a
Bruker spectrometer at 200 MHz and 50 MHz respectively using CDCl3 as solvent
and tetramethylsilane (TMS) as an internal reference.
General Method for the Preparation of 1-Benzhydrylpiperazine
Derivatives (2a–c)[26,30]
NaBH4 (0.6 mol) was added to a stirred solution of benzophenones (1.0 mol)
in methanol (2 vol) portionwise at room temperature for 45 min. The mixture was
stirred for 2–3 h at ambient temperature (completion of reaction was monitored
by TLC), and was diluted with water (750 ml), acidified with acetic acid to pH ꢀ4,
and extracted with dichloromethane (2 ꢁ 400 ml). The organic layer was washed
with water (200 ml) and dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure to get pure benzhydrol derivatives as a white
to off-white solid in 93–97% yield.

606
S. SHIVPRAKASH AND G. CHANDRASEKARA REDDY
To the benzhydrol derivatives (1.0 mol) in toluene (370 ml) was added
concentrated HCl (35% in H2O, 370 ml) and tetrabutylammonium bromide
(0.01 mol) at room temperature under stirring. Stirring was continued at 40–45 ꢂC
for 6–7 h. After completion of the reaction as indicated by TLC, the mixture was
cooled to room temperature. The organic layer was separated and concentrated
under vacuum to obtain crude benzhydryl chloride derivatives as a light brown
liquid in 95–97% yield.
To this benzhydryl chloride (0.96 mol) derivatives in toluene (380 ml) was
added anhydrous piperazine (5.0 mol) at 60–70 ꢂC for 45–60 min. The resulting mix-
ture was heated under stirring at 90–100 ꢂC for 8–10 h. The mixture was cooled after
completion of the reaction. Water (380 ml) was added, and the organic layer was
separated. The latter was washed with a 1:1 mixture of concentrated HCl=water
(2 ꢁ 350 ml) and neutralized with 20% NaOH solution (750 ml). The water layer
was re-extracted into toluene (2 ꢁ 300 ml), dried over anhydrous sodium sulfate,
and concentrated under vacuum to result pure diphenylmethylpiperazine com-
pounds (2a–c) as a white to off-white solid with yields up to 88%.
General Method for the Preparation of 1-Benzhydryl-4-
(2,2-dimethoxyethyl)piperazine Derivatives (3a–c)
Chloroacetaldehyde dimethyl acetal (43.7 mmol) was added to a stirred sol-
ution of 2a–c (39.7 mmol) in DMF (20 ml) in one lot at room temperature, anhy-
drous K2CO3 (43.7 mmol) and KI (2.0 mmol) were added, and the mixture was
stirred at 85–90 ꢂC for 6–7 h. The progress of the reaction was monitored by TLC.
The reaction mixture was quenched in ice water (200 ml) and extracted with hexane
(2 ꢁ 50 ml). The hexane layer was separared, dried over anhydrous sodium sulfate,
and concentrated under vacuum. The crude material obtained was purified by col-
umn chromatography over SiO2 using EtOAc=hexane (0.5:9.5) as an eluent afforded
3a–c as a pale yellow to light brown viscous oily liquid with yields up to 90%.
General Method for the Preparation of 1-Benzhydryl-4-
(2-acetaldehyde)piperazine Derivatives (4a–c)
In a 250-ml round-bottom flask, 48% aqueous HBr (50 mL) and 3a–c
(29.4 mmol) were added, and the mixture was stirred at room temperature for
1–1.5 h. The completion of the reaction was monitored by TLC. The reaction was
quenched by pouring the mixture into ice water (200 ml), basified with 20% NaOH
(90 ml), and extracted with dichloromethane (2 ꢁ 50 ml). The organic layer was sepa-
rated, dried over anhydrous sodium sulfate, and concentrated under vacuum to
obtain crude aldehyde (unstable) 4a–c as an off-white solid with yields up to 80%.
General Method for the Preparation of E/Z-1-Benzhydryl-4-
cinnamylpiperazine Derivatives (5a–c)
Benzyltriphenyl phosphonium chloride (17.9 mmol) (prepared according to the
reported procedure[31]) was added to a solution of 4a–c (17.0 mmol) in dichloro-
methane (50 ml) under N2 atmosphere. The mixture was cooled to 5 ꢂC and t-BuOK

(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
607
(41.3 mmol) was added under stirring. After completion, the reaction mixture was
quenched into water (100 ml). The organic layer was separated, dried over anhydrous
sodium sulfate, and concentrated under vacuum to obtain crude material 5a–c. The
crude was then subjected to column purification over SiO2 using EtOAc=hexane as
an eluent to afford 1a–c[25] and 6a–c in pure form.
General Method for the Preparation of 6a–c HCl Salts
Concentrated HCl (35% in H2O, 0.08 ml) was added to a solution of 6a–c
(2.5 mmol) in absolute EtOH (10 ml) and stirred for 2–3 h at 50 ꢂC.The reaction
mixture was cooled, and the solid thus obtained was filtered and air dried to afford
6a–c ꢃ 2HCl salts as white solid [6a ꢃ 2HCl (66% yields), 6b ꢃ 2HCl (88% yields), and
6c ꢃ 2HCl (83% yields)].
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR, HRMS spectra of 1a–c and 6a–c,
and HPLC charts of 5a–c can be found via the Supplementary Content section of
this article’s Web page.
ACKNOWLEDGMENTS
The authors thank Anil Kush, CEO of Vittal Mallya Scientific Research
Foundation, Bangalore, for his kind support and encouragement, and A. C.
Karunakara and Aparna Bhat for analytical help.
REFERENCES
1. Todorovic, A.; Luevano, H. C. A review of melanocortin receptor small molecule ligands.
Peptides 2005, 26, 2026–2036.
2. Kundu, B. Solid-phase strategies for the design and synthesis of heterocyclic molecules of
medicinal interest. Curr. Opin. Drug Discov. Develop. 2003, 6, 815–826.
3. Atherden, L. H. Bentley and Driver’s Text Book of Pharmaceutical Chemistry, 8th ed.;
Oxford Medicinal Publication: Oxford, UK, 2004; pp. 372–377 and 204–205.
4. Beckett, A. H.; Stenlake, J. B. Practical Pharmaceutical Chemistry, 4th ed.; CBS
Publishers 2003.
5. Andrejus, K. Essentials of Medicinal Chemistry, 2nd ed.; Wiley-Interscience, 1988; p. 601.
6. Phillips, O. A.; Udo, E. E.; Samuel, S. M. Synthesis and structure–antibacterial activity of
triazolyl oxazolidinones containing long-chain acyl moiety. Eur. J. Med. Chem. 2008, 43,
1095–1104.
7. Foroumadi, A.; Emami, S.; Mansouri, S.; Javidnia, A.; Saeid-Adeli, N.; Shirazi, F. H.;
Shafiee, A. Synthesis and antibacterial activity of levofloxacin derivatives with certain
bulky residues on piperazine ring. Eur. J. Med. Chem. 2007, 42, 985–992.
8. Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.; Gupta, S.; Solanki, M.; Pandya, P.;
Kapadnis, P. Novel 4-N-substituted aryl pent-2-ene-1,4-dione derivatives of piperaziny-
loxazolidinones as antibacterials. Bioorg. Med. Chem. Lett. 2006, 16, 1557–1561.
9. Foroumadi, A.; Ghodsi, S.; Emami, S.; Najjari, S.; Samadi, N.; Faramarzi, M. A.;
Beikmohammadi, L.; Shirazi, F. H.; Shafiee, A. Synthesis and antibacterial activity of

608
S. SHIVPRAKASH AND G. CHANDRASEKARA REDDY
new fluoroquinolone containing a substituted N-(phenethyl)piperazine moiety. Bioorg.
Med. Chem. Lett. 2006, 16, 3499–3503.
10. Watkins, W. J.; Chong, L.; Cho, A.; Hilgenkamp, R.; Ludwikow, M.; Garizi, N.; Iqbal,
N.; Barnard, J.; Singh, R..; Madsen, D.; Lolans, K.; Lomovskaya, O.; Oza, U.;
Kumaraswamy, P.; Blecken, A.; Bai, S.; Loury, D. J.; Griffitha, D. C.; Dudley, M. N.
Quinazolinone fungal efflux pump inhibitors, part 3: (N-Methyl) piperazine variants
and pharmacokinetic optimization. Bioorg. Med. Chem. Lett. 2007, 17, 2802–2806.
11. Upadhayaya, R. S.; Sinha, N.; Jain, S.; Kishore, N.; Chandra, R.; Arora, S. K. Optically
active antifungal azoles: Synthesis and antifungal activity of (2R,3S)-2-(2,4-
difluorophenyl)-3-(5-f2-[4-aryl-piperazin-1-yl]-ethylg-tetrazol-2-yl=1-yl)-1-[1,2,4]-triazol-1-
yl-butan-2-ol. Bioorg. Med. Chem. 2004, 12, 2225–2238.
12. Rokosz, L. L.; Huang, C. Y.; Reader, J. C.; Stauffer, T. M.; Chelsky, D.; Sigal, N. H.;
Ganguly, A. K.; Baldwin, J. J. Surfing the piperazine core of tricyclic farnesyltransferase
inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 5537–5543.
13. Chen, J. J.; Lu, M.; Jing, Y. K.; Dong, J. H. The synthesis of l-carvone and limonene
derivatives with increased antiproliferative effect and activation of ERK pathway in
prostate cancer cells. Bioorg. Med. Chem. 2006, 14, 6539–6547.
14. Shami, P. J.; Saavedra, J. E.; Bonifant, C. L.; Chu, J. X.; Udupi, V.; Malaviya, S.; Carr, B. I.;
Kar, S.; Wang, M. F.; Jia, L.; Ji, X. H.; Keefer, L. K. Antitumor activity of JS-K [O2-(2,4-
dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related
O2-aryl diazeniumdiolates in vitro and in vivo. J. Med. Chem. 2006, 49, 4356–4366.
15. Mayence, A.; Eynde, J. J. V.; LeCour Jr., L.; Walker, L. A.; Tekwani, B. L.; Huang, T.
L.Jr. Piperazine-linked bisbenzamidines: A novel class of antileishmanial agents. Eur. J.
Med. Chem. 2004, 39, 547–553.
16. Cunico, W.; Gomes, C. R. B.; Moreth, M.; Manhanini, D. P.; Figueiredo, I. H.;
Penido, C.; Henriques, M. G. M. O.; Varotti, F. P.; Krettli, A. U. Synthesis and anti-
malerial activity of hydroxyethylpiperazine derivatives. Eur. J. Med. Chem. 2009, 44,
1363–1368.
17. Smits, R. A.; Lim, H. D.; Hanzer, A.; Zuiderveld, O. P.; Guaita, E.; Adami, M.; Coruzzi,
G.; Leurs, R.; Esch, I. J. P. Fragment based design of new H4 receptorꢄligands with
anti-inflammatory properties in vivo. J. Med. Chem. 2008, 51, 2457–2467.
ˇ
ˇ
ꢀ
´
´
´
´
ˇ ´
ꢀ
´
´
18. Penjisevic, J.; Sukalovic, V.; Andric, D.; Kostic-Rajacic, S.; Soskic, V.; Roglic, G.
1-Cinnamyl-4-(2-methoxyphenyl) piperazines: Synthesis, binding properties, and docking
to dopamine (D2) and serotonin (5-HT1A) receptors. Arch. Pharm. Chem. Life Sci. 2007,
340, 456–465.
19. Becker, O. M.; Dhanoa, D. S.; Marantz, Y.; Chen, D.; Shacham, S.; Cheruku, S.; Heifetz,
A.; Mohanty, P.; Fichman, M.; Sharadendu, A.; Nudelman, R.; Kauffman, M.; Noiman,
S. An integrated in silico 3D model-driven discovery of a novel, potent, and selective ami-
dosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.
J. Med. Chem. 2006, 49, 3116–3135.
20. (a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levine, R. B.; McDaniel, S. L.; Darke, P.
L.; Zugay, J.; Quintero, J. C.; Blahy, O. M. An orally bioavailable human immunodefi-
ciency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096–
4100; (b) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levine, R. B.; McDaniel, S. L.;
Darke, P. L.; Zugay, J. The design of a potent and orally bioavailable HIV protease
inhibitor. J. Med. Chem. 1994, 37, 3443–3451; (c) Askin, D.; Eng, K. K.; Rossen, K.;
Purick, R. M.; Wells, K. M.; Volante, R. P.; Reider, P. J. Highly diastereoselective reac-
tion of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate: Synthesis of the
orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett. 1994, 35, 673–676;
(d) Rossen, K.; Weissman, S. A.; Sagar, J.; Reamer, R. A.; Askin, D. A.; Volante, R.
P.; Reider, P. J. Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of

(Z)-1-BENZHYDRYL-4-CINNAMYLPIPERAZINES
609
(S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV
protease inhibitor indinavir. Tetrahedron Lett. 1995, 36, 6419–6422.
21. Kerns, R. J.; Rybak, M. J.; Kaatz, G. W.; Vaka, F.; Cha, R.; Grucz, R. G.; Diwadkar, V.
U. Structural features of piperazinyl-linked ciprofloxacin dimers required for activity
against drug-resistant strains of Staphylococcus aureus. Bioorg. Med. Chem. Lett. 2003,
13, 2109–2112.
22. Lee, P. H.; McNutt, R. W.; Chang, K. J. A nonpeptidic delta opioid receptor
agonist, BW373U86, attenuates the development and expression of morphine abstinence
precipitated by naloxone in rat. J. Pharmacol. Exp. Ther. 1993, 267, 883–887.
23. Ohtaka, H.; Tsukamoto, G. V. Quantitative structure–activity relationships of 1-benzyl-4-
diphenylmethylpiperazine derivatives for cerebral vasodilating activity. Chem. Pharm.
Bull. 1987, 35, 4117–4123.
24. Paton, D. M.; Webster, D. R. Clinical pharmacokinetics of H1-receptor antagonists
(the antihistamines). Clin. Pharmacokinet. 1985, 10, 477–497.
25. (a) Cignarella, G.; Testa, E. V. J. Synthesis of 2,6-alkylpiperazine derivatives structurally
related to cinnarizine. Med. Chem. 1968, 11, 612–615; (b) Serge, A. A. Process for the
preparation of 1-transcinnamyl-4-diphenylmethylpiperazine. C.A. Patent 942306, 1974;
(c) Younes, S.; Baziard-Mouysset, G.; de Saqui-Sannes, G.; Stigliani, J. L.; Payard, M.;
Bonnafous, R. Synthesis and pharmacological study of new calcium antagonists,
analogues of cinnarizine and flunarizine. Eur. J. Med. Chem. 1993, 28, 943–948.
26. (a) Ananda Kumar, C. S.; Benaka Prasad, S. B.; Vinaya, K.; Chandrappa, S.;
Thimmegowda, N. R.; Sunil Kumar, Y. C.; Sanjay, S.; Rangappa, K. S. Synthesis and
in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against
human cancer cell lines. Eur. J. Med Chem. 2009, 44, 1223; (b) Gubert, S.; Braso, M.
A.; Sacristan, A.; Ortiz, J. A. Synthesis of some N-benzhydrylpiperazine derivatives as
calcium antagonists. Arzneimittel-Forschung 1987, 37, 1103.
27. Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Whittle, R. R.; Olofson, R. A. Stereochem-
istry and mechanism of the Wittig reaction. Diasteromeric reaction intermediates and
analysis of the reaction course. J. Am. Chem. Soc. 1986, 108, 7664–7678.
28. (a) Schlosser, M.; Christmann, K. F. Olefinierungen mit Phosphor-Yliden, I: Mechanis-
mus und Stereochemie der Wittig-Reaktion. Liebigs Ann. Chem. 1967, 708, 1; (b)
Schlosser, M.; Muller, G.; Christmann, K. F. cis-Selective olefin syntheses. Angew. Chem.
Int. Ed. Engl. 1966, 5, 667.
29. Roberti, M.; Pizzirani, D.; Simoni, D.; Rondanin, R.; Baruchello, R.; Bonora, C.;
Buscemi, F.; Grimaudo, S.; Tolomeo, M. Synthesis and biological evaluation of resvera-
trol and analogues as apoptosis-inducing agents. J. Med. Chem. 2003, 46, 3546–3554.
30. (a) Weston, A. W.; Hamlin Jr., K. E. Preparation of Piperazine Derivatives. U.S. Patent
2861072, Nov. 18, 1958; (b) Morren, H. G.; Trolin, S.; Denayer, R.; Grivsky, E.; Maricq,
`
J. Nouvelles substances antihistaminiques a action prolongee: les 1–4 bis (aralcoyl)
piperazines. Bull. Soc. Chim. Belg. 1951, 60, 282–295.
´
´
31. Alonso, F.; Riente, P.; Yus, M. Synthesis of resveratrol, DMU-212 and analogues
through a novel Wittig-type olefination promoted by nickel nanoparticles. Tetrahedron
Lett. 2009, 50, 3070–3073.