Syntheses of 4-(3,5-bisphenylmethylene-4-oxopiperidin-1-yl)-4-oxo-but-2Z-enoic acid arylamides as candidate cytotoxic agents

Article abstract of DOI:10.1081/SCC-120017198

The title compounds were designed and synthesized as candidate cytotoxic agents. They were synthesized by reacting 3,5-bisphenylmethylene-piperidin-4-one with the appropriate 3-arylcarbamoylacrylic acids. These reactions follow an unusual mechanism and deviate from the previously reported reactions on similar substrates.

Full text of DOI:10.1081/SCC-120017198

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Syntheses of 4-(3,5-Bisphenylmethylene-4-oxo-
piperidin-1-yl)-4-oxo-but-2 Z -enoic Acid Arylamides as
Candidate Cytotoxic Agents
a b
a
Amitabh Jha
& Jonathan R. Dimmock
a
College of Pharmacy and Nutrition , University of Saskatchewan , Saskatoon, Canada
b
ALviva Biopharmaceuticals Inc. , Saskatoon, S7N, Canada
Published online: 21 Aug 2006.
To cite this article: Amitabh Jha & Jonathan R. Dimmock (2003) Syntheses of 4-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-
yl)-4-oxo-but-2 Z -enoic Acid Arylamides as Candidate Cytotoxic Agents, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 33:7, 1211-1223, DOI: 10.1081/SCC-120017198
To link to this article: http://dx.doi.org/10.1081/SCC-120017198
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 7, pp. 1211–1223, 2003
Syntheses of 4-(3,5-Bisphenylmethylene-4-oxo-
piperidin-1-yl)-4-oxo-but-2Z-enoic Acid
Arylamides as Candidate Cytotoxic Agents
#
Amitabh Jha and Jonathan R. Dimmock*
College of Pharmacy and Nutrition, University of
Saskatchewan, Saskatoon, Canada
ABSTRACT
The title compounds were designed and synthesized as candidate
cytotoxic agents. They were synthesized by reacting 3,5-bisphenyl-
methylene-piperidin-4-one with the appropriate 3-arylcarbamoyl-
acrylic acids. These reactions follow an unusual mechanism
and deviate from the previously reported reactions on similar
substrates.
*
Current address: ALviva Biopharmaceuticals Inc., Saskatoon, S7N, Canada.
y
Correspondence: Jonathan R. Dimmock, College of Pharmacy and Nutrition,
University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9,
Canada; E-mail: dimmock@skyway.usask.ca.
1
211
DOI: 10.1081/SCC-120017198
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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212
Jha and Dimmock
Key Words: Arylmaleamic acids; N-Acyl-3,5-bisphenylmethylene-
-piperidones; Stereochemistry; Molecular modeling.
4
A numberof 3,5-bisa ry lidene-pipe ri din-4-ones including 3,5-bisphe-
nylmethylene-piperidin-4-one (1) possess significant cytotoxic proper-
[
1–3]
ties.
N-acryloyl analogs in general led to significant increases in cytotoxicity
which was considered to be due, inter alia, to the presence of an addi-
Conversion of some of these molecules into the corresponding
[
4]
[
3–8]
tional site forelect or philic attack with cellularconstituents.
In the
present investigation, replacement of one of the methylene protons of
the N-acryloyl group by an arylcarbamoyl substituent was planned for
the following reasons. First, the arylcarbamoyl group will increase the
electrophilicity of the double bond; for example, the Taft ꢀ* value of the
[
9]
phenylcarbamoyl group is 1.56. Second, an aryl group was incorpo-
rated into the design of the N-acyl function in order that the polarity of
the olefinic double bond would vary being dependent on the electronic
nature of the aryl substituents. A correlation between cytotoxicity and
the Hammett ꢀ values of the aryl substituents may emerge which would
guide amplification of the series. The aryl ring was positioned so that
Figure 1. Structures of compounds 1–3.

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Candidate Cytotoxic Agents
1213
steric impedance to attack by cellular nucleophiles would be unlikely to
occur.
We wish to report herein the unusual chemistry involved in the
syntheses of these compounds and to offerthe most plausible justification
for the deviation from the expected route which is supported by calcula-
tions and experiments.
Eight arylmaleamic acids (Z-2a–h) were synthesized by a literature
[
10]
procedure.
data are summarized in Table 1.
The structures are portrayed in Figure 1 and the physical
Initially, the conventional condensation conditions of acyl halide
with amine were considered for the condensation of 3,5-diphenylmethy-
lene-piperidin-4-one (1) with the acid chlorides of the aryl maleamic acids
(
Z-2a–h). Various attempts to prepare the acid chlorides were undertaken
including the use of thionyl chloride, oxalyl chloride and phosphorus
pentachloride. However the desired compounds were not obtained
which was probably due to decomposition of one of the starting materials
[
11]
(
electrophilicity of the maleamic acid double bond
acids), a phenomenon noted earlier from our laboratory.
[
The high
is perhaps re-
12]
sponsible forthe decomposition of the a ry l maleamic acids underthese
conditions.
[
12]
Subsequently we discovered a literature report forthe synthesis of
compounds similar to our desired products via reactions that involved
the use of ethyl chloroformate under cold, inert and aprotic conditions.
The reported mechanism involved the formation of an active isoimide B
rather than a mixed anhydride from arylmaleamic acids A (Sch. 1). Some
[
16]
of these isoimides have been isolated and characterized.
imides react like mixed anhydrides with primary or secondary amines
These iso-
[12,16,17]
to yield the amides C.
The geometry of the added double bond of the product isolated was
found to be temperature dependent. Reactions carried out at ꢀ60 C
resulted in products with mainly the Z configuration of the N-acyl group
[
12]
ꢁ
ꢁ
double bond while those carried out at ꢀ12 C resulted in products with
exclusively the E configuration of the same double bond. Isomerization
of Z-C noted at ꢀ12 C was attributed to a Michael-type addition of the
ꢁ
[
12]
excess of amine to the double bond.
Subsequent elimination of the
amine led to the formation of thermodynamically more stable products
E-C (Sch. 2).
In the present investigation, a modification of the method was
ꢁ
employed in which the temperatures used were between 0 C and room
temperature (see Experimental). Condensation between the aryl male-
amic acids Z-2a–h and 1 took place leading to Z-3a–h. Unlike the earlier
[12]
report, we consistently isolated the products with the Z configuration

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214
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Candidate Cytotoxic Agents
1215
Scheme 1.
Scheme 2.
of the double bond of the N-acyl group under the reaction conditions
1
used. The H NMR spectra revealed coupling constants of the olefinic
[
18]
protons to be 11.7 Hz, which is characteristic of the Z geometry.
To ascertain the geometry unequivocally we decided to synthesize one

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216
Jha and Dimmock
geometrical isomer with the E configuration and examine its physical and
spectral properties.
[
Encouraged with the literature report of reversible addition/elimi-
12]
nation of dimethylamine across the double bond leading to the E geo-
ꢁ
metry at ꢀ12 C or higher temperatures, we thought that it should be easy
to isomerize compounds Z-3a–h to the E isomers by treating them with
dimethylamine in a suitable solvent. Also, we performed energy minimi-
Õ
[19]
zation studies using CS Chem3D Pro software on the E and Z forms
of compounds 3a–h and as expected we found that the E isomers
are consistently more stable than the Z forms by 1.38–7.11 kCal/mol
(
Table 2). So the isomerization reaction should, in principle, be favored.
All attempts of isomerizing compounds Z-3a–h to the E geometry by
ꢁ
treating them with dimethylamine at temperatures between 0 and 50 C in
chloroform failed to give the desired product. Instead a mixture of prod-
ucts were formed with very similar tlc behavior (CHCl :MeOH; 19:1).
3
1
The H NMR of the crude products indicated the presence of a complex
mixture of dimethylamine adducts. No attempts were made to purify
them. In fact, an irreversible addition of dimethylamine can indeed
lead to a very complex mixture, as there are at least three sites of addition
in every molecule subjected to the isomerization reactions.
We then chose to synthesize compound E-3b by reacting 4-chloro-
phenyl-fumaramic acid (E-2b) with 1. E-2b was synthesized by a literature
[20]
procedure
and was condensed with 1 using the same procedure that
was used forthe synthesis of compounds Z-3a–h (c.f. Experimental). The
coupling constant of the olefinic protons of E-3b was found to be 15.0 Hz,
which is distinctly characteristic of the E geometry. This proved that the
Table 2. Minimized energy of compounds 3a–h with the
stereochemistry.
E and Z
E
Z
ÁEmin
E
min(E)
E
min(Z)
Emin(Z)ꢀEmin(E)
Compound
3
3
3
3
3
3
3
3
a
b
c
d
e
f
40.81
33.74
33.17
3.35
44.47
37.51
36.82
6.99
3.66
3.77
3.65
3.64
7.11
3.54
3.40
1.38
43.62
28.67
27.06
29.23
50.73
32.21
30.46
30.61
g
h

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Candidate Cytotoxic Agents
1217
compounds resulting from the reaction of Z-2a–h with 1 have the Z
configuration.
The question arises as to why isomerization occurs when the reacting
[
12]
amine is dimethylamine
but not when it is 1. It is likely that a low
molecularweight amine (dimethylamine) may er act with the olefinic
double bond as indicated in Sch. 2. On the otherhand, the size of the
secondary amine 1 may be excessive for reaction with the olefinic group
present in the N-acyl function of Z-3a–h. In addition, compound 1 is a
3-aminoketone and the pKa values of various 3-aminoketones are in the
region of 7.0–7.3 approximately
[
21,22]
in contrast to dimethylamine for
[
23]
example, which possesses a pKa of 10.73. Hence the nucleophilicity of
1
previously reported study.
will be substantially lowerthan the smalleramines employed in the
[
12]
CONCLUSION
Though the reaction between an isoimide (formed in situ by the
reaction between an aryl maleamic acid and ethyl chloroformate and
triethylamine in THF) and secondary amine leads to the formation of
amides, the geometry of the maleamic acid amide double bond likely
depends on the steric bulk and basicity of the amine. Greater bulk
and/or weak basicity leads to the kinetically controlled reaction giving
rise to the relatively less stable Z geometry. The E geometry on the
double bond of the N-acyl group of title compounds can be conveniently
obtained from aryl fumaramic acids. The cytotoxicity of many of these
compounds described in this study will be reported subsequently.
EXPERIMENTAL
General
All the chemicals used in the synthetic methods were purchased from
the Aldrich Chemical Company. Compound 1 was made by a literature
[1]
procedure. Melting points were recorded on an electrothermal appara-
tus and are uncorrected. Precoated fluorescent silica gel tlc plates pur-
chased from EM Science were used to monitor the progress of reactions.
1
H NMR spectra were recorded on an AC Bruker 500 MHz NMR spec-
trometer. Elemental analyses were undertaken by Mr. Ken Thoms,
Department of Chemistry, University of Saskatchewan.

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Jha and Dimmock
General Procedure for the Syntheses of the Aryl Maleamic
Acids (Z-2a–h)
Maleic anhydride (0.02 mole) and the appropriate aryl amine
0.02 mole) were dissolved in chloroform (100 mL) and stirred for 7 h
(
under anhydrous conditions. The resultant precipitate was removed by
filtration, washed with chloroform and dried. The aryl maleamic acids
were obtained as powders in high yields (76–99%) and were quite pure as
evident by theirmelting points and elemental analysis data. The pe rc ent-
age yield, melting points, literature melting points (whenever known),
and elemental analysis data are reported in Table 1.
Synthesis of 3-(4-chlorophenylcarbamoyl)-E-acrylic acid (E-2b).
Thionyl chloride (150 mmol) was added dropwise to suspension of fuma-
ric acid (60 mmol) in dry chloroform (50 mL) followed by the addition of
DMF (4 drops) as a catalyst. The solution was heated under reflux at
ꢁ
90 C for16 h. The excess of SOCl and chloroform were removed in
2
vacuo. The residue was dissolved in chloroform (100 mL) and a solution
of 4-chloroaniline (30 mmol) in chloroform (50 mL) was added dropwise
over 5 min and the mixture was stirred for 10 min at room temperature.
The mixture was then extracted with 1N aqueous NaOH. The NaOH
soluble aqueous fraction was acidified with concentrated HCl to pH ꢂ 1.
The precipitate was collected at suction and was boiled in water for
2
0 min. The insoluble solid was filtered quickly when hot to yield the
product as light yellow solid.
-(4-Chlorophenylcarbamoyl)-E-acrylic acid (E-2b). Light yellow solid
3
ꢁ
16%), rf 0.22 (7:3 CHCl :CH OH); M.p. 268–269 C; H NMR (DMSO-
3 3
1
(
d , 500 MHz, ꢁ): 6.65 & 7.11 (1H each, d, J ¼ 15.4 Hz; E-vinylic-H), 7.38
6
&
7.69 (2H each, d, J ¼ 8.9 Hz, Ar-H), 10.61 (1H, s, NHCO) and 13.00
(
1H, bs, COOH).
General Procedure for the Synthesis of 4-(3,5-
Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2-enoic
Acid Arylamides (Z-3a–h) and E-3b
The appropriate arylcarbamoyl acrylic acid (0.003 mole) and triethyl-
amine (0.003 mole) were dissolved in dry tetrahydrofuran (60 mL) and
ꢁ
cooled to 0 C using an ice bath. Underanhyd or us conditions, ethyl
chloroformate (0.003 mole) in dry tetrahydrofuran (40 mL) was added
dropwise over a 10 min period. The mixture was stirred for 12 h
ꢁ
at room temperature, cooled to 0 C and 3,5-bisphenylmethylene-piperi-
din-4-one hydrochloride (0.003 mole) was added. Subsequently

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Candidate Cytotoxic Agents
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triethylamine (0.003 mole) in dry tetrahydrofuran (40 mL) was added
dropwise over 10 min. The reaction was then stirred for 16 h during
which time the temperature slowly rose to room temperature. The
solvents were then evaporated under vacuum. Water (30 mL) was
added to the residue and the product was triturated and filtered.
The solid product thus obtained was digested in methanol (30 mL)
to remove unwanted side products and unreacted starting
materials. It was then filtered, washed with cold methanol (30 mL) and
dried.
4-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid phenylamide (Z-3a). Yellow solid (36%), rf 0.70 (19:1 CHCl :
3
ꢁ
1
CH OH); M.p. 197 C; H NMR (DMSO-d , 500 MHz, ꢁ): 4.75 & 4.91
3
6
(
2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ), 6.03 & 6.42 (1H each, d,
a
b
J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 7.05–7.11 (1H, m), 7.24–7.46 (7H, m),
.49–7.59 (8H, m), 7.76 (1H, s) and 10.05 (1H, bs, NHCO). Elemental
analysis: Calcd. forC 29H N O : C 77.66, H 5.39, N 6.25, Found: C 77.57,
7
24
2
3
H 5.44, N 6.27.
-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (4-chlorophenyl)amide (Z-3b). Yellow solid (57%), rf 0.64 (19:1
4
ꢁ
1
CHCl :CH OH); M.p. 208–209 C; H NMR (DMSO-d , 500 MHz, ꢁ):
3
3
6
4
.75 & 4.91 (2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ), 6.00 & 6.45 (1H
a
b
each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 7.26–7.27 (2H, m), 7.36–7.39
5H, m), 7.45–7.61 (8H, m), 7.75 (1H, s) and 10.17 (1H, bs, NHCO).
Elemental analysis: Calcd. forC 29H ClN O : C 72.12, H 4.80, N 5.80,
(
23
2
3
Found: C 71.99, H 4.59, N 6.03.
-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (4-methylphenyl)amide (Z-3c). Yellow solid (56%), rf 0.70 (19:1
4
ꢁ
1
CHCl :CH OH); M.p. 196 C; H NMR (DMSO-d , 500 MHz, ꢁ): 2.26
3
3
6
(
&
7
3H, s, ArCH ), 4.75 & 4.91 (2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ), 6.01
3
a
b
6.39 (1H each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 7.12 (2H, d, J ¼ 8.2)
.26–7.28 (2H, m), 7.37–7.54 (9H, m), 7.58–7.60 (2H, m), 7.75 (1H, s) and
9.96 (1H, bs, NHCO). Elemental analysis: Calcd. forC 30H N O :
C 77.90, H 5.67, N 6.06, Found: C 77.72, H 5.81, N 5.93.
26
2
3
4-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (4-methoxyphenyl)amide (Z-3d). Yellow solid (53%), rf 0.66 (19:1
ꢁ
1
CHCl :CH OH); M.p. 204 C; H NMR (DMSO-d , 500 MHz, ꢁ): 3.74
3
3
6
(
6
7
3H, s, OCH ), 4.75 & 4.91 (2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ), 5.99 &
3
a
b
.38 (1H each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 6.89 (2H, d, J ¼ 8.97 Hz),
.27–7.29 (2H, m), 7.37–7.39 (3H, m), 7.45–7.49 (3H, m), 7.51–7.54 (3H,
m), 7.58–7.60 (2H, m), 7.75 (1H, s) and 9.92 (1H, bs, NHCO). Elemental
analysis: Calcd. forC 30H N O : C 75.30, H 5.48, N 5.85, Found: C 75.29,
H 5.38, N 5.87.
26
2
4

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Jha and Dimmock
4-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (4-nitrophenyl)amide (Z-3e). Yellow solid (45%), rf 0.49 (19:1
ꢁ
1
CHCl :CH OH); M.p. 220 C (decomposition); H NMR (DMSO-d6,
3
3
5
6
00 MHz, ꢁ): 4.76 & 4.93 (2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ),
a
b
.05 & 6.56 (1H each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 7.24–7.27 (2H,
m), 7.37–7.39 (3H, m), 7.45–7.61 (6H, m), 7.75–7.77 (3H, m), 8.23 (2H, d,
J ¼ 9.2 Hz) and 10.62 (1H, bs, NHCO). Elemental
analysis: Calcd. forC H N O : C 70.58, H 4.70, N 8.51. Found:
2
9
23
3
5
C 70.57, H 4.58, N 8.47.
-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (3,4-dichlorophenyl)amide (Z-3f). Yellow solid (41%), rf 0.55 (19:1
4
ꢁ
1
CHCl :CH OH); M.p. 195 C; H NMR (DMSO-d , 500 MHz, ꢁ): 4.75 &
3
3
6
4
.92 (2H each, bs, 2 ꢃ N-CH , 2 ꢃ N-CH ), 5.99 & 6.50 (1H each,
a
b
d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H), 7.26–7.27 (2H, m), 7.38–7.40 (4H, m),
.45–7.60 (7H, m), 7.76 (1H, s), 7.93 (1H, d, J ¼ 2.3 Hz) and 10.32 (1H,
bs, NHCO). Elemental analysis: Calcd. forC H Cl N O : C 67.32,
7
2
9
22
2
2
3
H 4.29, N 5.41, Found: C 67.15, H 4.25, N 5.37.
-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (3,4-dimethylphenyl)amide (Z-3g). Yellow solid (43%), rf 0.59 (19:1
4
ꢁ
1
CHCl :CH OH); M.p. 196 C; H NMR (DMSO-d , 500 MHz, ꢁ): 2.18
6
3
3
&
2.22 (3H each, s, 2 ꢃ ArCH ), 4.75 & 4.91 (2H each, bs, 2 ꢃ N-CH ,
3
a
2
7
7
ꢃ N-CH ), 6.01 & 6.38 (1H each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H),
b
.05–7.07 (2H, d, J ¼ 8.2 Hz) 7.23–7.28 (3H, m), 7.34–7.40 (4H, m),
.45–7.51 (1H, m), 7.52–7.54 (3H, m), 7.58–7.61 (2H, m) and 9.89
(1H, bs, NHCO). Elemental analysis: Calcd. forC 31H N O : C 78.13,
28 2 3
H 5.92, N 5.88, Found: C 78.23, H 6.18, N 5.85.
4-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2Z-enoic
acid (2,6-dimethylphenyl)amide (Z-3h). Yellow solid (37%), rf 0.64 (19:1
ꢁ
1
CHCl :CH OH); M.p. 200 C; H NMR (DMSO-d , 500 MHz, ꢁ):
3
3
6
2
2
7
.06 (6H, s, 2 ꢃ ArCH ), 4.77 & 4.84 (2H each, bs, 2 ꢃ N-CH ,
3
a
ꢃ N-CH ), 6.15 & 6.46 (1H each, d, J ¼ 11.7 Hz, 2 ꢃ Z-vinylic-H),
b
.02–7.09 (3H, m), 7.43–7.62 (10H, m), 7.63 & 7.69 (1H each, s)
and 9.46 (1H, bs, NHCO). Elemental analysis: Calcd. for
C H N O -0.25H O: C 77.39, H 5.97, N 5.82, Found: C 77.18, H
3
1
28
2
3
2
5
.56, N 5.52.
-(3,5-Bisphenylmethylene-4-oxo-piperidin-1-yl)-4-oxo-but-2E-enoic
acid (4-chlorophenyl)amide (E-3b). Light yellow solid (67%), rf 0.63 (19:1
4
ꢁ
1
CHCl :CH OH); M.p. 231–235 C; H NMR (DMSO-d , 500 MHz, ꢁ):
3
3
6
4
.95 & 4.98 (2H each, bs, 2 ꢃ N-CH and 2 ꢃ N-CH ), 6.88 & 7.20
a
b
(
1H each, d, J ¼ 15.0 Hz, 2 ꢃ E-vinylic-H), 7.35 & 7.61 (4H, d,
J ¼ 8.9 Hz), 7.47–7.57 (10H, m), 7.70 and 7.74 (1H each, s) and 10.46
1H, bs, NHCO).
(

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Candidate Cytotoxic Agents
ACKNOWLEDGMENTS
1221
We thank Purdue Neuroscience Company, USA for financial
support.
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Candidate Cytotoxic Agents
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Received in the USA May 15, 2002

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