DOI: 10.1002/ajoc.

201200010

Synthesis and Antiproliferative Activity of Polysubstituted

Tetrahydropyridine and Piperidin-4-one-3-carboxylate Derivatives

Raghunath Aeluri,[a] Manjula Alla,*[a] Vittal Rao Bommena,[a]

Ramalinga Murthy,[b] and Nishant Jain[b]

Abstract: A highly atom-economic one-pot multicomponent synthesis of poly-

substituted tetrahydropyridines (THPs) is described. The reaction of anilines, ar-
omatic aldehydes, and b-keto esters proceeds in the presence of catalytic amount Keywords: antiproliferation ·
of zirconium tetrachloride, and the products can be further converted to the cor- multicomponent reactions · piper-
responding piperidin-4-one-3-carboxylates under acidic conditions. The two sets idin-4-ones · tetrahydropyridines ·
of products were evaluated for their anticancer activity and some of these com- zirconium tetrachloride
pounds, particularly the piperidin-4-one-3-carboxylates have significant anticanc-
er activity.

Introduction Piperidone is an important scaffold that is used as an in-

Tetrahydropyridine (THP) derivatives have been in the
limelight recently as active pharmaceutical ingredients for
alleviating symptoms of neuropsychiatric disorders, espe-
cially because of their structural similarities with the class
of piperidine-containing compounds that are currently on
the market, such as Ritalin and Risperidone. Droperidol
and Tazomeline are examples of known THPs that are ef-
fective as anti-emetic and antipsychotic agents in the treat-
ment of cognitive dysfunctional diseases, such as Alzheim-
ers disease and schizophrenia.[1] 1-Methyl-4-phenyl-1,2,5,6-
tetrahydropyridine is a known neurotoxin which induces
Parkinsons disease.[2] Suitable modification of the THP
skeleton is being extensively explored for generating novel
molecules, such as GTS-21 (for Alzheimers disease)[3] and
Ro10-5824 (a nootropic), as potential drugs for the treat-
ment of central nervous system (CNS) disorders.[4] THPs
are also reported to have anti-inflammatory, analgesic,[5]
and hyperglycemic activities.[6] Recently, Tripathi et al. re-
ported THP derivatives as active antimalarial compounds.[7]
Their role as inhibitors of farnesyl transferase[8] and dihy-
droorotate dehydrogenase[9] has also been well established.
[a] R. Aeluri, M. Alla, V. R. Bommena
Crop Protection Chemicals Division
Indian Institute of Chemical Technology
Tarnaka, Hyderabad, 500607 (India)
Fax: (+ 91) 40-27160387
E-mail: manjula@iict.res.in
manjula_alla@yahoo.com
[b] R. Murthy, N. Jain
Centre for Chemical Biology
Indian Institute of Chemical Technology
Tarnaka, Hyderabad, 500607 (India)
Fax: (+ 91) 40-27160921
termediate in the manufacture of chemicals, pharmaceuti-
cals (e.g., Fentanyl), and as precursor for biologically active
natural alkaloids.[10] 2-Aryl piperidin-4-ones are used as key
intermediates for the synthesis of tachykinin antagonists
and indolizidine alkaloids.[11] N-substituted pipeidin-4-ones
are also interesting compounds[12] and have been found to
display a number of important biological activities, such as
antimicrobial,[13] anti-inflammatory,[14] analgesic,[15] CNS
stimulatory,[16] antifungal,[17] antituberculosis,[18] local anes-
thetic,[19] herbicidal,[20] and anticancer,[21] as well as inhibi-
tion of acetyl-CoA carboxylase,[22] and potentially human
placental aromatase in vitro.[23]
The interesting spectrum of biological activities displayed
by THPs as well as piperidin-4-ones, and their key role in
many disease processes has inspired us to explore the po-
tential of THPs and piperidin-4-ones for applications as
agrochemicals and pharmaceuticals. Numerous methods
have been reported for their synthesis, such as imino-Diels–
Alder reactions,[24] aza-Prins cyclizations,[25] intramolecular
Michael reactions,[26] and intramolecular Mannich reac-
tions[27] with iminium ions and so on. However, these reac-
tions are multistep synthetic sequences that involve expen-
sive reagents and catalysts. Of late, multicomponent reac-
tions (MCRs) have emerged as improved alternatives,[28]
largely because they are one-pot atom- and step-economic
protocols. Although independent MCRs are available for
the construction of both THPs and piperidin-4-ones it was
envisaged that piperidin-4-ones could be obtained readily
by simple hydrolysis of the enamine bond of THPs. A
modified version of the Hantzsch synthesis[29] was envisaged
for this purpose. Thus, a MCR protocol for construction of
THPs starting from aromatic aldehydes, substituted ani-
lines, and b-keto esters with ZrCl4 as the catalyst was de-
signed. Zirconium tetrachloride has emerged as an efficient,

Asian J. Org. Chem. 2012, 1, 71 – 79  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 71
 FULL PAPER
safe, economical, and environmentally benign Lewis acid[30] 1,2,5,6-tetrahydropyridine-3-carboxylate (1 p) was obtained
for catalyzing various organic transformations. As a result in 91 % yield. The generality and scope of this MCR was in-
of its low toxicity (LD50 (ZrCl4 oral rate) = 1688 mg kg1), vestigated by employing a variety of substituted anilines, ar-
low cost, high activity, and easy handling, it has wide appli- omatic aldehydes, and b-keto esters, as shown in Scheme 1,
cations as catalyst[31] in vari-
ous reactions, such as Man-
nich reactions,[32] Michael ad-
ditions[33] and Biginellis re-
action[34] . Moreover, it has
been proven to be a mild
and efficient Lewis acid for
catalyzing the construction
of various heterocycles.
Herein, we report an effi- Scheme 1. Synthesis of THPs and their corresponding piperidin-4-one-3-carboxylate derivatives.
cient ZrCl4 catalyzed synthe-
sis of 1,2,3,4,6-pentasubsti-
tuted-1,2,5,6-tetrahydropyridine-3-carboxylates (1 a–1 q), and the results are summarized in Table 3. The stereochem-
their conversion to corresponding piperidin-4-one-3-carbox- istry of the two chiral centers at the C2 and C6 positions
ylates (2 a–2 h), and the evaluation of the cytotoxicity of were found to be anti, as our spectroscopic data exactly
both types of compounds against cancer cell lines. matched with that from previous reports.[28c] Aromatic alde-
hydes with substitutions such as alkyl and nitro groups, as
well as heterocyclic aldehydes successfully reacted with var-
Results and Discussion ious anilines possessing methoxy, halo, and alkyl substitu-
ents, and either methyl or ethyl acetoacetate. The yields
Chemistry
were low with para-nitrobenzaldehyde and 2-naphthalde-
At the outset, we chose the simple reaction of aromatic al- hyde even after prolonged reaction times. Heterocyclic al-
dehydes, substituted anilines, and b-keto esters with ZrCl4 dehydes gave moderate yields. All of the substituted aniline
as catalyst for optimization studies by varying the amount derivatives that were tested underwent the MCR smoothly
of catalyst (Table 1) as well as the reaction solvent to provide the corresponding THPs. Both the b-keto esters,
(Table 2). The results of optimization studies suggest that either methyl or ethyl, were equally effective. Aliphatic al-
ethanol is the best solvent and that 15 mol % ZrCl4 is the dehydes were not productive and the reaction with these
ideal catalyst concentration required for effective conver- compounds failed to give the corresponding THPs. The
sion. Thus, by reacting benzaldehyde, aniline, and ethyl ace- yields were also low with aliphatic amines.
toacetate (in a 2:2:1 ratio, respectively) in ethanol in the An investigation into the effects of various catalysts on
presence of 15 mol % ZrCl4 at ambient temperature, the the reaction was carried out by comparing different cata-
corresponding THP ethyl 1,2,6-triphenyl-4-phenylamino- lysts with ZrCl4. ZrCl4 was more effective both in terms of
yield and shorter reaction time relative to other catalysts
(Table 4).
Table 1. Optimization of catalyst concentration.[a]
Several of the THPs could be hydrolyzed to the corre-
Entry Catalyst [mol %] Yield [%] t [h]
sponding piperidin-4-one-3-carboxylates for a comparative
1 0 6 28 study of the antiproliferative activity. The piperidin-4-one-
2 5 47 15
3 10 89 15
3-carboxylates were synthesized from the corresponding
4 15 91 15 polysubstituted THPs by simple enamine hydrolysis under
5 20 91 16 acidic conditions at ambient temperature with acetone as
[a] Experiments performed at ambient temperature. the solvent (Scheme 1). The product structures and yields
are summarized in Table 3. Polysubstituted THPs with elec-
tron-donating substituents on any phenyl ring were hydro-
Table 2. Solvent selection.[a] lyzed more easily relative to THPs with halogen substitu-
Entry Solvent Yield [%] t [h] ents on the phenyl rings. The hydrolysis of the enamine to
1 EtOH 91 15 a ketone was equally facile with either ethyl or methyl
2 CH3OH 87 15 esters. The products obtained were the trans isomers (with
3 CH3CN 49 17 respect to C2C3) as deduced from the 1H NMR spectra
4 EtOAc 51 20
(J values ca. 10 Hz). All of the synthesized compounds
5 CH2Cl2 58 16
6 THF 55 16 were completely characterized by spectroscopic methods
7 Neat 39[b] 24 before proceeding further.
[a] Experiments performed at ambient temperature. [b] Stopped at this
stage as no further starting material is consumed.

72 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 71 – 79
Tetrahydropyridine and Piperidin-4-one-3-carboxylates as Anticancer Agents

Table 3. ZrCl4 catalyzed synthesis of substituted THPs and their corresponding piperidine-4-one3-carboxylate derivatives.
Entry b-keto ester THP t [h] Yield [%] Piperidine-4-one-3-carboxylate[a] Yield [%]

1 16 78 – –

2 18 79 97

3 16 78 – –

4 17 84 – –

5 29 50 – –

6 21 72 – –

7 19 80 96

8 16 86 95

Asian J. Org. Chem. 2012, 1, 71 – 79  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 73
 Manjula Alla et al.
FULL PAPER
Table 3. (Continued)
Entry b-keto ester THP t [h] Yield [%] Piperidine-4-one-3-carboxylate[a] Yield [%]

9 16 83 93

10 20 60 – –

11 18 76 92

12 32 51 – –

13 16 87 97

14 17 81 – –

15 17 86 96

16 15 91 97

17 15 85 – –

[a] The stereochemistry of piperidin-4-one-3-carboxylates is explained in the Experimental section.

74 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 71 – 79
Tetrahydropyridine and Piperidin-4-one-3-carboxylates as Anticancer Agents

Table 4. Catalysts tested for the formation of THPs.[a] yl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3

Entry Catalyst Yield [%] t [h] carboxylate (1 o) has inhibitory activity against all the four
1 ZrCl4 91 15 cell lines at approximately 100 mm.
2 CAN 74 24 On the other hand, all of the piperidin-4-one-3-carboxy-
3 NH4Cl 48 22 lates 2 a–2 h tested have good activity below 100 mm against
4 CeCl3.7H2O 51 24
the A549 cell line, except 2 g. Most of the piperidin-4-one-
5 NH4Cl & CeCl3·7 H2O 50 25
6 I2[b] 81 8 3-carboxylates, except 2 f and 2 g, inhibit the growth of the
7 TBATB[b] 74 24 DU145 cell line, with IC50 values of under 100 mm. Com-
8 BDMS[b] 75 5 pounds 2 a, 2 c, and 2 d are the most potent against the
[a] Experiments performed at ambient temperature. [b] Reported in lit- HeLa cell line. Among all piperidin-4-one-3-carboxylates,
erature. methyl 2,6-bis(4-methoxyphenyl)-4-oxo-1-phenylpiperidine-
3-carboxylate (2 a) and methyl 2,6-bis(3-chlorophenyl)-4-
oxo-1-phenylpiperidine-3-carboxylate (2 b) have high effica-
In Vitro Anticancer Activity
cy against SK-N-SH cell line, whereas 2 c, 2 f, 2 g, and 2 h
Eight THPs and their corresponding piperidin-4-one-3-car- are moderate. Methyl 2,6-bis(4-methoxyphenyl)-4-oxo-1-
boxylates were tested for anticancer activity in vitro against phenylpiperidine-3-carboxylate (2 a) has good activity
four human cancer cell lines; A549 (human epithelial lung against all the four cell lines, with the best activity against
carcinoma), DU145 (human prostate cancer), HeLa SK-N-SH and A549 at 11.0 and 27.5 mm, respectively. A
(human epithelial cervical cancer), and SK-N-SH (human comparison of the THPs with the corresponding piperidin-
neuroblastoma). The inhibition concentrations (IC50 values) 4-one-3-carboxylates shows that, in general, the piperidin-4-
are summarized in Table 5. one-3-carboxylates were more effective antiproliferative
agents than the THPs.
Table 5. Cytotoxic effects of selected THPs and piperidine-4-one3-car-
boxylates on A549, DU145, HeLa, and SK-N-SH human cancer cells.[a]
Compound IC50 values [mM][b]
Conclusions
A549 DU145 HeLa SK-N-SH
1b 58  4.1 96  2.9 180  5.9 > 200 In summary, an efficient MCR protocol for the construction
1g > 200 101  3 200 > 11  1.3 of polysubstituted THPs starting from aromatic aldehydes,
1h > 200 102  3.1 200 > 67  2.3 substituted aromatic amines, and b-keto esters, and cata-
1i 139  3.2 165  4.2 94  2.9 > 200 lyzed by ZrCl4 has been developed. Piperidin-4-one-3-car-
1k 181  3.8 157  4 119  3.5 154  4.1
boxylates were obtained by simple acid hydrolysis of the
1m 99  2.8 116  3.2 169  5.9 75  2.4
1o 95  2.2 116  3.2 169  5.9 75  2.4 enamines of polysubstituted THPs. The antiproliferative ac-
1p > 200 > 200 > 200 22  1.3 tivity of various THPs and piperidin-4-one-3-carboxylates
2a 27  1.2 64  2.5 52  1.3 11  1.2 were evaluated in four human cancer cell lines. Piperidin-4-
2b 81  2.9 69  1.2 145  2.5 22  2.2
one-3-carboxylates have better efficacy against four cancer
2c 51  3.3 96  2.3 40  1.1 75  3.2
2d 84  4.2 76  1.9 62  1.5 163  4.5 cell lines relative to the THPs. This may be a result of the
2e 76  3.8 71  1.8 > 200 N/A more hydrophobic nature of THPs, which leads to poor bio-
2f 29  2.9 170  5.6 170  4.2 100  3.8 availability. Redesign and synthesis of the series to incorpo-
2g > 200 135  3.5 > 200 100  3.2 rate more hydrophilic groups as well as other derivatives of
2h 76  3.2 90  2.8 > 200 65  2.5
the active molecules, and studies on identifying the target
[a] Cell lines were treated with different concentrations of compounds protein are underway.
for 48 h as described in the Experimental section. [b] IC50 values are in-
dicated as mean of three independent experiments.

As is evident from the Table, all piperidin-4-one-3-car-
boxylates showed better activity against all the four cell
lines relative to the THPs. Analysis of MTT assay results
with the THPs suggests that 1 b, 1 m, and 1 o are the potent
against the A549 cell line. Compound 1 b also inhibits
DU145 cell line growth, whereas 1 i inhibits growth of the
HeLa cell line. Except for 1 b and 1 i, all THPs showed
good activity against the SK-N-SH cell line with IC50 values
below 100 mm. Among all of the THPs tested, methyl 2,6-
bis(3-chlorophenyl)-1-phenyl-4-phenylamino-1,2,5,6-tetra-
hydropyridine-3-carboxylate (1 g) inhibited the growth of
the SK-N-SH cell line effectively, with an IC50 value of
11.0 mm. Ethyl 2,6-Bis(3-chlorophenyl)-1-(4-methoxyphen-
Experimental Section
Melting points were determined in open capillaries and are uncorrected.
NMR spectra were obtained on JCAMP DX-50 instrument (300 MHz
for 1H and 75 MHz for 13C) and CDCl3 and [D6]DMSO used as solvents
with tetramethylsilane as an internal standard. Electrospray ionization
mass spectra were recorded on Thermo Finnigan ESI ion trap mass
spectrometer. Infrared spectra were recorded on a Thermo Nicolet
NEXUS 670 spectrometer. Elemental analysis for CHNS was recorded
on Elementar Vario Micro Cube instrument.
General procedure for synthesis of 1,2,5,6-tetrahydropyridine-3-
carboxylates.
The aromatic or heterocyclic aldehyde (2 mmol) and ZrCl4 (0.15 mmol)
were added to a solution of the amine (2 mmol) and methyl acetoacetate
or ethyl acetoacetate (1 mmol) in 5 mL of ethanol, and the reaction mix-
ture was stirred at room temperature until the reaction was complete (as

Asian J. Org. Chem. 2012, 1, 71 – 79  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 75

FULL PAPER
monitored by TLC). On completion of the reaction, a thick precipitate
was obtained. The solid product was filtered off and washed with etha-
nol to give pure product.
Ethyl 2,6-bis(4-fluorophenyl)-1-(4-tolyl)-4-(4-tolylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (1 c)
White solid; 78 % yield; m.p. 169–172 8C; 1H NMR (300 MHz, CDCl3):
d = 1.45 (t, J = 6.8 Hz, 3 H), 2.16 (s, 3 H), 2.28 (s, 3 H), 2.64–2.70 (dd, J =
3.0, 15.1 Hz, 1 H), 2.71–2.81 (dd, J = 5.3, 15.1 Hz, 1 H), 4.22–4.35 (m,
1 H), 4.37–4.5 (m, 1 H), 5.02 (br, 1 H), 6.23–6.35 (m, 5 H), 6.82 (d, J =
9.1 Hz, 2 H), 6.87–6.99 (m, 6 H), 7.03–7.12 (m, 2 H), 7.17–7.24 (m, 2 H),
10.24 ppm (s, 1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.78, 20.08,
20.86, 33.68, 54.68, 57.30, 59.65, 97.43, 112.98, 114.76, 115.23, 115.05,
115.51, 125.75, 127.85, 127.95, 128.14, 128.04, 129.49, 135.03, 135.74,
138.13, 139.76, 144.44, 156.22, 168.07 ppm; IR (KBr): ñ = 3236, 2983,
2920, 1650, 1598, 1513, 1251 cm1; MS (ESI): m/z: 539 [M] + ; elemental
analysis calcd (%) for C34H32O2N2F2 : C 75.82, H 5.99, N 5.20; found: C
76.78, H 5.85, N 6.01.
Ethyl 1,2,6-tri-(4-tolyl)-4-(4-tolylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (1 d)
White solid; 84 % yield, m.p. 184–186 8C; 1H NMR (300 MHz, CDCl3):
d = 1.45 (t, J = 7.2 Hz, 3 H), 2.14 (s, 3H), 2.26 (s, 3 H), 2.31 (s, 3 H), 2.34
(s, 3 H), 2.68 (dd, J = 2.3, 15.1 Hz, 1 H), 2.79 (dd, J = 5.3, 15.1 Hz, 1 H),
4.18–4.36 (m, 1 H), 4.37–4.49 (m, 1 H), 4.94–5.05 (br, 1 H), 6.18 (d, J =
8.1 Hz, 2 H), 6.27 (s, 1 H), 6.34 (d, J = 8.5 Hz, 2 H), 6.74–7.16 (m, 12 H),
10.22 ppm (s, 1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.78, 20.08,
20.83, 35.52, 55.16, 58.19, 59.51, 97.68, 112.86, 124.99, 125.87, 126.13,
126.40, 126.62, 126.98, 128.20, 128.54, 129.35, 129.39, 135.20, 135.47,
143.00, 144.34, 144.82, 156.38, 168.23 ppm; IR (KBr): ñ = 3236, 3024,
1255, 1515, 1596, 1650, 2978 cm1; MS (ESI): m/z: 531 [M] + ; elemental
analysis calcd (%) for C36H38O2N2 : C 81.48, H 7.22, N 5.28; found: C
82.43, H 6.96, N 5.79.
Ethyl 1-(4-bromophenyl)-4-(4-bromophenylamino)-2,6-dinaphthalen-2-
yl-1,2,5,6-tetrahydropyridine-3-carboxylate (1 e)
White solid; 50 % yield; m.p. 179–182 8C; 1H NMR (300 MHz, CDCl3):
d = 1.56 (t, J = 6.8 Hz, 3 H), 2.79–2.88 (dd, J = 1.5, 15.1 Hz, 1 H), 2.95–
3.05 (dd, J = 5.3, 15.1 Hz, 1 H), 4.36–4.59 (m, 2 H), 5.33 (br, 1 H), 6.01 (d,
J = 8.4 Hz, 2 H), 6.42 (d, 9.1 Hz, 2 H), 6.52 (s, 1 H), 7.02 (d, J = 9.1 Hz,
2 H), 7.07 (d, J = 9.1 Hz, 2 H), 7.38–7.51 (m, 5 H), 7.57 (d, J = 5.3 Hz,
2 H), 7.68–8.02 (m, 7 H), 10.21 ppm (s, 1 H, NH); 13C NMR (75 MHz,
CDCl3): d = 14.88, 33.75, 55.74, 58.39, 60.01, 98.67, 108.62, 114.83, 119.10,
124.56, 124.38, 124.58, 125.15, 125.70, 125.97, 126.13, 126.29, 127.20,
127.66, 127.97, 128.38, 128.61, 129.10, 131.61, 131.84, 132.38, 132.82,
133.09, 133.37, 136.76, 139.32, 140.59, 145.97, 155.54, 168.05 ppm; IR
(KBr): ñ = 3231, 2977, 1647, 1599, 1492, 1251 cm1; MS (ESI): m/z: 755
[M+Na] + .
Ethyl 1-(4-bromophenyl)-4-(4-bromophenylamino)-2,6-dithiophen-2-yl-
1,2,5,6-tetrahydropyridine-3-carboxylate (1 f)
White solid; 72 % yield; m.p. 208–209 8C; 1H NMR (300 MHz, CDCl3):
d = 1.46 (t, J = 6.9 Hz, 3 H), 2.79–2.88 (dd, J = 2.3, 15.3 Hz, 1 H), 3.01–
3.12 (dd, J = 5.3, 15.3 Hz, 1 H), 4.22–4.35 (m, 1 H), 4.38–4.5 (m, 1 H),
5.28–5.33 (br, 1 H), 6.29 (s, 1 H), 6.41 (d, J = 8.5 Hz, 2 H), 6.56 (d, J =
9.07 Hz, 2 H), 6.76 (d, J = 3.4 Hz, 1 H), 6.79 (d, J = 3.2 Hz, 1 H), 6.83 (q,
J = 5.1 Hz, 1 H), 6.89 (q, J = 4.9 Hz, 1 H), 7.09 (dd, J = 4.9, 5.1 Hz, 1 H),
7.12 (dd, J = 4.9, 5.1 Hz, 1 H), 7.16 (d, J = 9.1 Hz, 2 H), 7.28 (m, 2 H),
10.44 ppm (s, 1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.65, 34.11,
52.56, 53.74, 60.01, 98.12, 109.48, 114.92, 118.05, 119.07, 123.76, 124.09,
124.51, 126.47, 126.74, 127.01, 131.57, 132.14, 137.02, 145.06, 146.53,
148.21, 155.13, 167.16 ppm; IR (KBr): ñ = 3233, 2916, 1646, 1601, 1490,
1251 cm1; MS (ESI): m/z: 667 [M+Na] + ; elemental analysis calcd (%)
for C28H24O2N2S2Br2 : C 52.18, H 3.754, N 4.35, S 9.95; found: C 53.24, H
3.842, N 4.76, S 9.128.
76 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Manjula Alla et al.
Ethyl 2,6-diphenyl-1-(4-tolyl)-4-(4-tolylamino)-1,2,5,6-tetrahydropyridine-
3-carboxylate (1 h)
White solid; 86 % yield; m.p. 185–186 8C; 1H NMR (300 MHz, CDCl3):
d = 1.47 (t, J = 6.7 Hz, 3 H), 2.14 (s, 3 H), 2.26 (s, 3 H), 2.66–2.74 (dd, J =
3.0, 15.1 Hz, 1 H), 2.74–2.83 (dd, J = 5.2, 15.1 Hz, 1 H), 4.24–4.37 (m,
1 H), 4.39–4.51 (m, 1 H), 5.03–5.09 (br, 1 H), 6.14 (s, 1 H), 6.17 (s, 1 H),
6.35 (d, J = 8.3 Hz, 3 H), 6.83 (m, 4 H), 7.11–7.30 (m, 10 H), 10.23 ppm (s,
1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.78, 20.08, 20.83, 33.55,
55.23, 58.26, 59.45, 97.81, 112.84, 124.78, 125.84, 126.11, 126.45, 126.63,
126.90, 128.15, 128.52, 129.30, 129.35, 135.27, 135.51, 143.10, 144.33,
144.82, 156.45, 168.26 ppm; IR (KBr): ñ = 3238, 3025, 1649, 1593, 1515,
1250 cm1; MS (ESI): m/z: 503 [M] + ; elemental analysis calcd (%) for
C34H34O2N2 : C 81.25, H 6.82, N 5.57; found: C 81.74, H 7.07, N 5.44.
Ethyl 1-(3-bromophenyl)-2,6-bis(4-bromophenyl)-4-(3-
bromophenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1 k)
White solid; 76 % yield; m.p. 177–179 8C; 1H NMR (300 MHz, CDCl3):
d = 1.35 (t, J = 7.2 Hz, 3 H), 2.61–2.71 (dd, J = 4.9, 16.6 Hz, 1 H), 2.93–
3.03 (dd, J = 5.9, 16.6 Hz, 1 H), 4.22–4.33 (m, 1 H), 4.34–4.42 (m, 1 H),
4.96 (t, J = 5.3 Hz, 1 H), 5.74 (s, 1 H), 6.3–6.36 (m, 1 H), 6.63–6.66 (m,
1 H), 6.79–6.9 (m, 3 H), 6.96–7.1 (m, 6 H), 7.35–7.41 (m, 5 H), 11.99 ppm
(br, 1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.34, 36.62, 56.39, 57.07,
61.17, 101.55, 115.10, 121.05, 121.29, 121.78, 122.89, 128.13, 128.39,
129.97, 131.52, 131.88, 140.28, 140.87, 147.80, 169.69, 170.51 ppm; IR
(KBr): ñ = 3232, 2978, 1662, 1589, 1482, 1241 cm1; MS (ESI): m/z: 786
[M+2] + ; elemental analysis calcd (%) for C32H26O2N2Br4 : C 48.65, H
3.32, N 3.55; found: C 49.72, H 3.39, N 3.32.
Ethyl 1-(4-bromophenyl)-4-(4-bromophenylamino)-2,6-diphenyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (1 q)
White solid; 85 % yield; m.p. 190–192 8C; 1H NMR (300 MHz, CDCl3):
d = 1.48 (t, J = 7.3 Hz, 3 H), 2.66–2.73 (dd, J = 1.8, 15.5 Hz, 1 H), 2.80–
2.86 (dd, J = 5.5, 15.5 Hz, 1 H), 4.24–4.41 (m, 1 H), 4.44–4.51 (m, 1 H),
5.06 (br, 1 H), 6.12 (d, J = 9.1 Hz, 2 H), 6.30–6.39 (m, 3 H), 7.05–7.31 (m,
14 H), 10.26 ppm (br,1 H, NH); 13C NMR (75 MHz, CDCl3): d = 14.74,
33.42, 55.19, 58.26, 59.92, 98.78, 114.54, 117.75, 119.09, 126.25, 126.43,
126.54, 127.23, 127.45, 128.36, 128.79, 131.56, 131.95, 136.89, 142.11,
143.12, 145.86, 155.21, 168.08 ppm; IR (KBr): ñ = 3235, 2973, 1645, 1600,
1492, 1253 cm1; MS (ESI): m/z: 632 [M+2] + ; elemental analysis calcd
(%) for C32H28O2N2Br2 : C 60.78, H 4.46, N 4.43; found: C 61.93, H 4.42,
N 4.29.
General procedure for synthesis of poly substituted piperidin-4-one-3-
carboxylates
Polysubstituted 1,2,5,6-tetrahydropyridine-3-carboxylic acid ester
(1 mmol) was dissolved in acetone (5 mL) and concentrated HCl (2
equiv) was added. The reaction mixture was stirred at room tempera-
ture. After completion of the reaction (as monitored by TLC), the ace-
tone was evaporated under vacuum, then the reaction mixture was dilut-
ed with water and extracted with ethyl acetate. The combined organic
layers were dried over anhydrous Na2SO4 and the solvent was evaporat-
ed. The product was recrystallized from hexane.
All of the piperidin-4-one-3-carboxylates were synthesized from a single
isomer of their corresponding starting material (2,6-anti isomer of the
THP). After enamine hydrolysis under acidic conditions the major
isomer was isolated by crystallization and the minor isomer could not
isolated from the mixture of the starting material and the minor isomer.
The stereochemistry of the three chiral centers (C2, C3, and C6) was de-
termined by comparing 1H NMR spectra. For example, in the 1H NMR
spectrum of methyl 2,6-bis(4-methoxyphenyl)-4-oxo-1-phenylpiperidine-
3-carboxylate (2 a), the protons H2 and H3 give doublets at d = 3.92 ppm
and 4.76 ppm with J values of 9.82 Hz, which indicates that H2 and H3
protons are oriented axially and that the trans isomer is formed. The
double of doublets signal at d = 2.75 ppm with J values of 3.02 Hz (gemi-
nal coupling) and 15.1 Hz (3JH6, H5eq) is from H5eq proton and the double
of doublets signal at d = 4.50 ppm with J values of 3.02 Hz (geminal cou-
pling) and 10.57 Hz (3JH6, H5ax) is from H5ax proton. From the above, it is
clear that the substituents at C2 and C3 carbons are equatorially orient-
Asian J. Org. Chem. 2012, 1, 71 – 79
Tetrahydropyridine and Piperidin-4-one-3-carboxylates as Anticancer Agents
ed and the substituent at C6 carbon is axially oriented.[13a, 27] The reason
for the diaxially oriented H2 and H3 protons may be repulsion between
the lone pair on the nitrogen atom and the oxygen atom of the ester car-
bonyl group, as shown in Figure 1.
Figure 1. General structure of compounds 2 a–2 h in chair form.
Methyl 2,6-bis(4-methoxyphenyl)-4-oxo-1-phenylpiperidine-3-carboxylate
(2 a)
1
Light-yellow solid; 97 % yield; m.p. 133–136 8C; H NMR (300 MHz,
CDCl3): d = 2,75 (dd, J = 3.02, 15.1 Hz, 1 H), 3.00 (br, J = 11.33, 15.1 Hz,
1 H), 3.53 (s, 3 H), 3.69 (s, 6 H), 3.92 (d, J = 9.82 Hz, 1 H), 4.50 (dd, J =
3.02, 10.57 Hz, 1 H), 4.76 (d, J = 9.82 Hz, 1 H), 6.59–6.74 (m, 5 H), 6.76–
6.92 (m, 4 H), 7.09–7.19 (m, 4 H); 13C NMR (75 MHz, CDCl3): d = 49.25,
52.03, 54.98, 55.06, 64.30, 65.54, 67.84, 113.43, 113.61, 118.07, 124.07,
125.87, 128.04, 128.55, 129.30, 131.81, 133.61, 148.63, 158.57, 168.13,
202.49; IR (KBr): ñ = 3057, 3001, 2952, 2836, 1747, 1716, 1599, 1509,
1210, 1131, 756, 703, 671 cm1; MS (ESI): m/z: 446 [M+H] + ; elemental
analysis calcd (%) for C27H27O5N: C 72.79, H 6.11, N 3.14; found: C
71.99, H 5.88, N 2.92.
Methyl 2,6-bis(3-chlorophenyl)-4-oxo-1-phenylpiperidine-3-carboxylate
(2 b)
1
White solid; 96 % yield; m.p. 126–129 8C; H NMR (300 MHz, CDCl3):
d = 2.56 (br, 1 H), 2,81 (dd, J = 3.0, 15.01 Hz, 1 H), 3.57 (s, 3 H), 3.68 (s,
1 H), 5.17 (s, 1 H), 5.29 (s, 1 H),6.83 (d, J = 7.01 Hz, 1 H), 6.89 (t, J =
8.01 Hz, 1 H), 7.0 (t, J = 8.01 Hz, 2 H), 7.04–7.18 (m, 4 H), 7.19–7.30 (m,
2 H), 7.41–7.55 (m, 3 H); 13C NMR (75 MHz, CDCl3): d = 45.44, 49.75,
50.50, 54.39, 55.74, 90.79, 99.66, 114.90, 122.15, 124.53, 126.63, 128.08,
129.15, 132.60, 133.42, 141.01, 143.00, 171.16, 199.93; IR (KBr): ñ = 3041,
3030, 2956, 1755, 1719, 1597, 1493, 1206, 1128, 790, 758, 693 cm1; MS
(ESI): m/z: 456 [M+H] + ; elemental analysis calcd (%) for
C25H21O3NCl2 : C 66.09, H 4.66, N 3.08; found: C 65.88, H 4.42, N 3.21.
Ethyl 4-oxo-2,6-diphenyl-1-(4-tolyl)piperidine-3-carboxylate (2 c)
White solid; 95 % yield; m.p. 121–124 8C; 1H NMR (300 MHz, CDCl3):
d = 1.02 (t, J = 7.18 Hz, 3 H), 2.03 (s, 3 H), 2,77 (dd, J = 3.21, 14.54 Hz,
1 H), 2.99 (br, J = 11.33, 14.54 Hz, 1 H), 3.90–4.04 (m, 3 H), 4.54 (dd, J =
3.02, 11.33 Hz, 1 H), 4.78 (d, J = 10.01 Hz, 1 H), 6.63 (d, J = 8.31 Hz, 2 H),
6.70 (d, J = 8.12 Hz, 2 H), 6.93–7.25 (m, 10 H); 13C NMR (75 MHz,
CDCl3): d = 13.83, 20.65, 49.38, 61.03, 64.24, 66.21, 68.78, 117.24, 120.20,
124.27, 125.64, 127.28, 127.52, 128.03, 128.37, 128.65, 133.45, 139.83,
141.65, 145.81, 167.57, 202.37; IR (KBr): ñ = 3062, 3028, 2981, 2924,
1749, 1718, 1512, 1492, 1217, 1195, 1034, 771, 753, 699 cm1; MS (ESI):
m/z: 414 [M+H] + ; elemental analysis calcd (%) for C27H27O3N: C 78.43,
H 6.58, N 3.39; found: C 78.10, H 6.22, N 3.22.
Methyl 2,6-bis(4-chlorophenyl)-4-oxo-1-phenylpiperidine-3-carboxylate
(2 d)
White solid; 93 % yield; m.p. 178–180 8C; 1H NMR (300 MHz, CDCl3):
d = 2,75 (dd, J = 3.02, 14.35 Hz, 1 H), 2.98 (br, J = 11.89, 14.16 Hz, 1 H),
3.56 (s, 3 H), 3.92 (d, J = 10.19 Hz, 1 H), 4.50 (dd, J = 3.02, 11.33 Hz, 1 H),
4.76 (d, J = 10.38 Hz, 1 H), 6.79 (d, J = 7.93 Hz, 3 H), 6.90 (t, J = 7.55 Hz,
2 H), 7.04–7.28 (m, 8 H); 13C NMR (75 MHz, CDCl3): d = 47.93, 50.58,
62,76, 64.63, 66.98, 99.70, 119.72, 123.84, 125.83, 126.94, 127.48, 127.81,
127.99, 128.72, 137.06, 138.75, 139.57, 166.32, 199.93; IR (KBr): ñ = 3055,
Asian J. Org. Chem. 2012, 1, 71 – 79  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3029, 2952, 2815, 1744, 1717, 1596, 1491, 1216, 1135, 788, 757, 675 cm1;
MS (ESI): m/z: 456 [M+H] + ; elemental analysis calcd (%) for
C25H21O3NCl2 : C 66.09, H 4.66, N 3.08; found: C 65.91, H 4.56, N 3.27.
Ethyl 1-(3-bromophenyl)-2,6-bis(4-bromophenyl)-4-oxopiperidine-3-
carboxylate (2 e)
White solid; 92 % yield; m.p. 146–149 8C; 1H NMR (300 MHz, CDCl3):
d = 1.41 (t, J = 7.43 Hz, 3 H), 2.54–2.58 (br, 2 H), 2.65 (dd, J = 4.24,
16.98 Hz, 1 H), 4.36–4.48 (m, 2 H), 5.11–5.22 (br, 1 H), 5.81 (s, 1 H), 6.39
(d, J = 7.43 Hz, 1 H), 6.60 (s, 1 H), 6.76 (d, J = 7.43 Hz, 1 H), 6.89 (t, J =
7.43 Hz, 1 H), 7.07 (d, J = 8.49 Hz, 2 H), 7.17 (d, J = 7.43 Hz, 2 H), 7.40
(d, J = 8.49 Hz, 4 H); 13C NMR (75 MHz, CDCl3): d = 14.39, 36.69, 49.36,
56.44, 57.05, 61.24, 101.62, 115.06, 119.28, 121.34, 121.78, 128.12, 128.41,
130.04, 131.58, 131.93, 140.34, 140.92, 147.84, 170.56, 202.12; IR (KBr):
ñ = 3060, 3030, 2964, 2936, 1748, 1717, 1599, 1493, 1210, 1130, 785, 753,
698 cm1; MS (ESI): m/z: 636 [M] + ; elemental analysis calcd (%) for
C26H22O3NBr3 : C 49.09, H 3.49, N 2.20; found: C 49.15, H 3.42, N 2.21.
Ethyl 1-(4-methoxyphenyl)-4-oxo-2,6-bisACHTUNGRE(4-tolyl)piperidine-3-carboxylate
(2 f)
White solid; 97 % yield; m.p. 164–167 8C; 1H NMR (300 MHz, CDCl3):
d = 1.05 (t, J = 7.55 Hz, 3 H), 2.21 (s, 6 H), 2,69 (dd, J = 3.02, 13.59 Hz,
1 H), 2.99 (br, J = 12.08, 13.59 Hz, 1 H), 3.54 (s, 3 H), 3.89–4.05 (m, 3 H),
4.36 (dd, J = 3.02, 12.08 Hz, 1 H), 4.58 (d, J = 10.58 Hz, 1 H), 6.33 (d, J =
9.06 Hz, 2 H), 6.71 (d, J = 9.06 Hz, 2 H), 6.90 (t, J = 7.55 Hz, 4 H), 7.03–
7.13 (m, 4 H); 13C NMR (75 MHz, CDCl3): d = 13.85, 20.97, 50.07, 54.87,
60.83, 64.85, 67.17, 69.56, 112.96, 113.28, 124.48, 127.51, 128.06, 128.35,
128.62, 128.88, 136.56, 136.76, 138.57, 141.21, 156.08, 167.60, 202.54; IR
(KBr): ñ = 3053, 2965, 2833, 1747, 1715, 1584, 1463, 1208, 1137, 805, 751,
692 cm1; MS (ESI): m/z: 458 [M+H] + ; elemental analysis calcd (%) for
C29H31O4N: C 76.12, H 6.83, N, 3.06, found: C 76.02, H 6.69, N 2.92.
Ethyl 2,6-bis(3-chlorophenyl)-4-oxo-1-(4-tolyl)piperidine-3-carboxylate
(2 g)
Light-red solid; 96 % yield; m.p. 132–135 8C; 1H NMR (300 MHz,
CDCl3): d = 1.08 (t, 7.55 Hz, 3 H), 2,73 (dd, J = 3.02, 13.59 Hz, 1 H), 2.99
(br, J = 12.08, 13.59 Hz, 1 H), 3.57 (s, 3 H), 3.90 (d, J = 10.57 Hz, 1 H),
3.96–4.14 (m, 2 H), 4.37 (dd, J = 3.77, 12.08 Hz, 1 H), 4.60 (d, J =
10.57 Hz, 1 H), 6.40 (d, J = 8.31 Hz, 2 H), 6.75 (d, J = 9.06 Hz, 2 H), 7.01–
7.12 (m, 6 H), 7.23–7.31 ppm (m, 2 H); 13C NMR (75 MHz, CDCl3): d =
13.75, 38.89, 49.82, 55.14, 61.54, 65.25, 69.50, 100.89, 113.45, 113.56,
126.01, 126.73, 127.07, 127.30, 128.03, 128.43, 128.67, 129.42, 129.61,
170.34, 201.19 ppm; IR (KBr): ñ = 3067, 2980, 2933, 1748, 1713, 1596,
1510, 1476, 1210, 1128, 859, 753, 694 cm1; MS (ESI): m/z: 500 [M+H] + ;
elemental analysis calcd (%) for C27H25O4NCl2 : C 65.07, H 5.06, N 2.81;
found: C 64.78, H 4.84, N 2.68.
Ethyl 4-oxo-1,2,6-triphenylpiperidine-3-carboxylate (2 h)
White solid; 97 % yield; m.p. 194–197 8C; 1H NMR (300 MHz, CDCl3):
d = 1.00 (t, J = 7.55 Hz, 3 H), 2,80 (dd, J = 3.77, 15.12 Hz, 1 H), 2.99 (br,
J = 10.58, 15.12 Hz, 1 H), 3.90–4.05 (m, 3 H), 4.64 (dd, J = 3.02, 11.33 Hz,
1 H), 4.91 (d, J = 9.82 Hz, 1 H), 6.65–6.73 (m, 1 H), 6.77–6.93 (m, 4 H),
7.03–7.20 (m, 6 H), 7.22–7.34 ppm (m, 4 H); 13C NMR (75 MHz, CDCl3):
d = 12.54, 35.58, 45.98, 59.90, 70.02, 90.73, 122.22, 124.19, 126.28, 127.11,
127.33, 127.74, 128.10, 128.37, 129.63, 133.22, 135.19, 143.15, 164.60,
168.16, 191.08, 196.68 ppm; IR (KBr): ñ = 3060, 3030, 2964, 2936, 1748,
1717, 1599, 1493, 1210, 1130, 785, 753, 698 cm1; MS (ESI): m/z: 400
[M+H] + ; elemental analysis calcd (%) for C26H25O3N: C 78.17, H 6.31,
N 3.51; found: C 78.13, H 5.92, N 3.51.
Evaluation of the antiproliferative activity against HeLa,
DU145, A549, and SK-N-SH cell lines
Materials and Methods
All cell lines used in this study were purchased from the American Type
Culture Collection (ATCC, USA). A549, SK-N-SH, and HeLa cells
were grown in Dulbeccos modified Eagles medium containing fetal
www.AsianJOC.org 77

FULL PAPER
bovine serum (FBS, 10 %) in a humidified atmosphere of 5 % CO2 at
37 8C. DU145 cells were cultured in Eagles minimal essential medium
containing nonessential amino acids, sodium pyruvate (1 mm), bovine in-
sulin (10 mg mL1), and FBS (10 %). Cells were trypsinized when sub-
confluent from T75 flasks/90 mm dishes, and seeded in 12-well or 6-well
plates at a concentration of 2.5  105 cells mL1 in complete medium, and
treated with the test compounds at the desired concentrations for 48 h,
then harvested as required. For immunohistochemistry experiments,
wells were seeded on cover slips in a 6-well plate.[35]
Antiproliferative Assay
The synthesized compounds (1 a–1 p & 2 a–2 h) were evaluated for their
in vitro cytotoxicity. A protocol of 48 h continuous drug exposure was
used, and a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) protein assay was used to estimate cell viability or growth. The
cell lines were grown in the respective media containing FBS (10 %) and
2 mm L-glutamine and were inoculated into 96-well microtiter plates in
200 mL aliquots at plating densities depending on the doubling time of
individual cell lines. The microtiter plates were incubated at 37 8C, 5 %
CO2, 95 % air, and 100 % relative humidity for 24 h prior to addition of
the experimental drugs. Aliquots of 2 mL of the drug dilutions were
added to the appropriate microtiter wells already containing 200 mL of
cells, resulting in the required final drug concentrations. For each com-
pound, four concentrations (1, 10, and 100 mm) were evaluated and each
was performed in triplicate wells. Plates were incubated further for 48 h,
and the assay was terminated by the addition of MTT (5 %, 10 mL) and
incubated for 60 min at 37 8C. Later, the plates were air dried. Bound
stain was subsequently eluted with DMSO (100 mL), and the absorbance
was read on an ELISA plate reader at a wavelength of 560 nm. Percent
growth was calculated on a plate-by-plate basis for test wells relative to
control wells. The above determinations were repeated three times. The
inhibitory effects of the compounds on cell growth were analyzed by
generating dose-response curves as a plot of the percentage of surviving
cells versus drug concentration. Sensitivity of the cancer cells to the
drug treatment was expressed in terms of IC50 value, a value defined as
the concentration of compound that produced a 50 % reduction relative
to the control absorbance. The percentage of cells killed was obtained
from the formula:
100  mean OD sample
Percentage cells killed ¼  100
mean OD at day 0
Acknowledgements
We thank the Director of the I.I.C.T and the Head of the Crop Protec-
tion Chemicals Division, for the facilities. A.R.N. thanks CSIR, New
Delhi for financial support.
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Received: April 9, 2012
Revised: May 9, 2012
Published online: July 2, 2012
www.AsianJOC.org 79