Syntheses of hitherto unknown thiazole, ylidene and pyridinethione derivatives having a piperidin-1-yl moiety and their use as antimicrobial agents

Article abstract of DOI:10.1002/jccs.200400020

The novel hydrazone derivatives 2a-c were prepared by treatment of aldehydes 1a,b with some hydrazines. Thiocarbamoyl functional group in compound 2a was subjected to cyclization reactions with some α-halocarbonyl reagents and furnished the novel thiazoles 4-6, 8 and 9. Enaminonitrile 10 and pyridinone 13 derivatives were synthesized by interaction of active methylene compound 2b with N,N-dimethylformamide-dimethylacetal and ketene dithioacetal 11, respectively. Aliphatic, aromatic and heteroaromatic active methylene compounds were condensed with aldehydes 1a,b to afford the new ylidenes 15a-d, 19a,b, 20 and 21. Substituted pyridinethiones 22 and 23 were prepared in high yields by cyclocondensation of 15c with malononitrile and ethyl cyanoacetate, respectively. Indeno[1,2-b]pyridines 26a,b were obtained by the reaction of ylidenes 19a,b with cyanothioacetamide in ethanol and in the presence of sodium ethoxide under reflux. The structures of the synthesized compounds were established from their analytical and spectral data. The prepared compounds were also screened for their antimicrobial activity.

Full text of DOI:10.1002/jccs.200400020

Journal of the Chinese Chemical Society, 2004, 51, 125-134
125
Syntheses of Hitherto Unknown Thiazole, Ylidene and Pyridinethione
Derivatives Having a Piperidin-1-yl Moiety and Their Use as Antimicrobial
Agents
Mohamed Sayed A. El-Gaby
Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
The novel hydrazone derivatives 2a-c were prepared by treatment of aldehydes 1a,b with some hy-
drazines. Thiocarbamoyl functional group in compound 2a was subjected to cyclization reactions with some
a-halocarbonyl reagents and furnished the novel thiazoles 4-6, 8 and 9. Enaminonitrile 10 and pyridinone 13
derivatives were synthesized by interaction of active methylene compound 2b with N,N-dimethylform-
amide-dimethylacetal and ketene dithioacetal 11, respectively. Aliphatic, aromatic and heteroaromatic active
methylene compounds were condensed with aldehydes 1a,b to afford the new ylidenes 15a-d, 19a,b, 20 and
21. Substituted pyridinethiones 22 and 23 were prepared in high yields by cyclocondensation of 15c with
malononitrile and ethyl cyanoacetate, respectively. Indeno[1,2-b]pyridines 26a,b were obtained by the reac-
tion of ylidenes 19a,b with cyanothioacetamide in ethanol and in the presence of sodium ethoxide under re-
flux. The structures of the synthesized compounds were established from their analytical and spectral data.
The prepared compounds were also screened for their antimicrobial activity.
Keywords: Thiazole; Ylidene; Pyridinethione; Piperidin-1-yl; Antimicrobial activity.
INTRODUCTION
Scheme I
X
Recently it was reported that a considerable number of
piperidine derivatives are known to possess a wide range of
pharmacological activities. For example, 4-arylpiperidines
exhibited potent anticonvulsant effects1 and various other de-
rivatives act as acetylcholinesterase inhibitors,2 matrix met-
alloproteinases (MMPs) inhibitors,3 antagonists of leuko-
cyte,4 potent and selective b3 agonists,5 neuroprotective
agents,6 antidepressants,7 antimicrobial agents8 and in the
management of pain.9 This contribution represents a continu-
ation of our studies of antimicrobial agents10-15 and deals with
the synthesis of heterocyclic compounds having in their
structure the piperidin-1-yl moiety in order to investigate the
antimicrobial activity.
N
H
F
CHO
X
X
N
CHO
DMSO / K2CO3
1a,b
NH2NHR
N
CH=N.NHR
2a-c
1a; X = CH2
1b; X = O
2a; X = CH2 , R= CSNH2
2b; X = CH2, R = COCH2CN
2c; X = O, R = COCH2CN
The behaviour of thiocarbamoyl functional group in
compound 2a towards some a-halocarbonyl reagents was in-
vestigated. Thus, compound 2a was reacted with phenacyl
bromide in absolute ethanol in the presence of fused sodium
acetate at room temperature to afford the corresponding N-
(4-phenyl-thiazol-2-yl)-N¢-(4-piperidin-1-yl-benzylidene)
hydrazine 4 (Scheme II). Formation of thiazole derivative 4
was substantiated by its elemental analyses and spectral data.
The infrared spectrum of compound 4 showed the CH-
aliphatic at 2931 and 2815 cm-1 and the absence of NH band.
The 1H NMR spectrum of compound 4 in DMSO-d6 revealed
the presence of CH-thiazole, methine proton at 7.98 ppm in
RESULTS AND DISCUSSION
The starting materials, 4-piperidinobenzaldehyde 1a
and 4-morpholinobenzaldehyde 1b were prepared by nucleo-
philic substitution of 4-fluorobenzaldehyde with cyclic sec-
ondary amines in dimethylsulfoxide and in the presence of
potassium carbonate.16 Treatment of aldehydes 1a,b with
hydrazines, namely thiosemicarbazide and cyanoacetic hy-
drazide, in refluxing ethanol gave the novel hydrazone deriv-
atives 2a-c (Scheme I).

126 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
El-Gaby
Scheme II
N
CH=NNH
N
6
S
O
R= OC2H5
RCOCH2X
N
CH=NNH
2a
C
NH
O
3
C
S
R
CH2
R= CH3
R= Ph
N
CH=NNH
N
N
CH=NNH
N
N
N
5
S
S
S
CH3
Ph
Ph
CH2-N=N
4
N
N
CH=NNH
N
Cl
7
S
CH3COCHCOOC2H5
O
2a
H
COCH3
O
Cl
CH=NNH
N
Cl
O
8
S
CH3
O
O
COOC2H5
N
S
N=N-CH2
N
9
1
addition to NH proton at 11.89 ppm besides other signals due
to methylene and aromatic protons. In the mass spectrum a
molecular ion peak at m/z 362 (11.3%) was observed. Forma-
tion of 4 is assumed to proceed via initial alkylation17 to form
intermediate 3 followed by intramolecular cyclization through
elimination of water molecule. In the same manner, cyclo-
alkylation of compound 2a with chloroacetone and ethyl
chloroacetate in refluxing ethanol and in the presence of so-
dium acetate yielded the novel thiazole derivatives 5 and 6,
respectively. Compound 6 showed an intense molecular ion
peak at m/z 302 corresponding to the molecular formula
C15H18N4OS. The molecular ion peak was found to be the
base peak in the spectrum. The H NMR spectrum of com-
pound 6 recorded in DMSO-d6 showed a singlet of two pro-
tons at 3.91 ppm which is assigned to the methylene group of
thiazolidinone. Reaction of compound 2a with ethyl a-chlo-
roacetoacetate in ethanol in the presence of fused sodium ace-
tate at reflux temperature yielded the corresponding 5-eth-
oxycarbonyl-4-methyl-thiazol-2-yl derivative 8 instead of
the expected product 7. The absorption bands due to NH,
CH-aliph, C=O and C=N functional groups in the infrared
1
spectrum were observed. The H NMR spectrum of 8 in
DMSO-d6 exhibited the presence of ethoxycarbonyl, methyl,
five methylenes, NH and methine protons in addition to

Hitherto Unknown Thiazole, Ylidene and Pyridinethione Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 127
aromatic protons. Formation of 8 was assumed to proceed
through initial alkylation followed by intramolecular cycliza-
tion via elimination of water. Naphtho[2,3-d]thiazole deriva-
tive 9 was synthesized by cyclocondensation of compound 2a
with 2,3-dichloronaphthoquinone in dimethylformamide in
the presence of anhydrous potassium carbonate at reflux tem-
perature.
condensation of aldehydes 1 with aliphatic, aromatic and
heteroaromatic active methylene compounds. Thus, com-
pounds 1a,b were reacted with malononitrile 14a and
cyanothioacetamide 14b in ethanol in the presence of trieth-
ylamine at room temperature to produce the novel benzyl-
idenes 15a-d. (Scheme IV). Similarly, indan-1,3-dione 16,
benzimidazol-2-ylacetonitrile 17 and thiobarbituric acid 18
were condensed with aldehyde 1 at reflux temperature in
dioxane in the presence of piperidine to furnish the corre-
sponding ylidenes 19, 20 and 21, respectively.
Our investigation was extended to study the reactivity
of compound 2b towards some electrophilic reagents. Thus,
condensation of compound 2b with N,N-dimethylform-
amide-dimethylacetal in refluxing m-xylene furnished the
novel enaminonitrile 10. 1H NMR spectrum of compound 10
recorded in DMSO-d6 exhibited signal characteristic for
N,N-dimethyl protons. The molecular ion peak of 10 was ob-
served at m/z 325 (25%) corresponding to the molecular for-
mula C18H23N5O. Compound 2b was reacted with ketene
dithioacetal 11 as another electrophile in the presence of an-
hydrous potassium carbonate in dimethylformamide and
gave pyridinone derivative 13. The structure of 13 was in-
ferred from their analytical and spectral data. The infrared
spectrum of compound 13 showed absorption bands charac-
teristic for NH2, CºN and C=O functional groups. 1H NMR
spectrum recorded in DMSO-d6 displayed the thiomethyl
group at 2.58 ppm, a broad band at 4.27 ppm assigned to
amino function, a singlet at 8.01 ppm assigned to methine
proton in addition to methylene and aromatic protons. For-
mation of 13 was assumed to proceed via Michael addition18
of active methylene in 2b to ketene 11 to form 12 followed by
intramolecular cyclization and tautmerization to afford 13
(Scheme III).
Pyridinethione and its derivatives are known to possess
various biological activities.19,20 Substituted pyridinethiones
are prepared by the reaction of benzylidene derivatives of
cyanothioacetamide with active methylene compounds.21
Thus, the pyridinethiones 22, 23 and 24 were prepared in high
yields by cyclocondensation of compunds 15c,d with a vari-
ety of active methylene compounds as malononitrile 14a,
ethyl cyanoacetate 14c and ethyl acetoacetate 14d in eth-
anolic solution containing a catalytic amount of piperidine at
reflux temperature. (Scheme V) A molecular ion peak of
pyridinethione 22 was observed at m/z 335 (88.8%) corre-
sponding to the molecular formula C18H17N5S. The molecular
ion of 22 underwent fragmentation to produce a peak at m/z
84 characteristic for the base peak and corresponding to the
piperidinyl moiety. Also, the mass spectrum of compound 24
showed the molecular ion peak at m/z 383 which is the base
peak in the spectrum. The reaction of 1,3-indanedione 16
with ylidenes 15c,d in ethanol in the presence of piperidine
as a catalyst under reflux for five hours did not produce
indeno[1,2-b]pyridines 26a,b but yielded instead the benzyl-
idenes 19a,b. The structure of 19 was established from their
In this contribution, novel ylidenes were prepared by
Scheme III
DMF-DMA
2b
CONHN=CH
N
NC
N
C
C
10
H3C
H
H3C
O
N=CH
NH
N
H3CS
CN
CN
NC
C
C
H3CS
CN
12
H3CS
11
CN
O
O
H
NC
N
N=CH
NH
N
N
N=CH
NH2
N
NC
H3CS
H3CS
CN
CN
13

128 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
El-Gaby
(NCTC-289) and two strains of the fungi: Aspergillus ochraceus
Wilhelm (AUCC-230) and Penicillium chrysogenum Thom
(AUCC-530) by the agar diffusion techniques.23 The tested
compounds were dissolved in N,N-dimethylformamide
(DMF) to get a solution of 1000 mg mL-1 concentration. The
bacteria and fungi cultures were maintained on nutrient agar
and Czapek’s-Dox agar media, respectively. DMF showed no
inhibition zones. The agar media were incubated with differ-
ent microorganisms culture tested. After 24 h. of incubation
at 30 °C for bacteria and 48 h of incubation at 28 °C for fungi,
the diameter of inhibition zone (mm) was measured (Table
1). Ampicillin in a concentration 25 mg mL-1 and Mycostatine
in a concentration 30 mg mL-1 were used as references for an-
tibacterial and antifungal activities, respectively. The mini-
mal inhibitory concentration (MIC) of the active compounds
was measured by a twofold serial dilution method.24 The re-
sults are illustrated in Table 1. Compounds 4, 5, 6, 8, 20, 21
and 22 were found to be the more active compounds against
Staphylococcus aureus (NCTC-7447) (MIC values 40 mg
mL-1). On the other hand, compounds 2c, 9 (MIC values 40
mg mL-1) and 20 (MIC values 50 mg mL-1) possess high activ-
ity against Bacillus cereus (NCTC-14579) while only com-
pound 8 (MIC values 40 mg mL-1) exhibited high activity
against Penicillium chrysogenum Thom. However, none of
the tested compounds showed superior activity over the refer-
ence.
Scheme IV
Y
H2C
Y
Z
X
N
CH C
14a-d
Z
15a-d
O
O
O
O
CH
N
X
16
19a,b
N
1
CN
N
H
N
CN
17
N
H
CH
N
O
20
HN
O
S
O
N
H
HN
CH
N
18
S
O
N
H
21
14a; Y = Z = CN
14c; Y = CN, Z= COOC2H5
15a; X = CH2, Y = Z = CN
15c X = CH2, Y = CN, Z = CSNH2
19a; X = CH2
14b; Y = CN, Z = CSNH2
14d; Y = COCH3, Z = COOC2H5
15b; X = O, Y = Z = CN
15d; X = O, Y = CN, Z = CSNH2
19b; X = O
infrared spectra which exhibit a carbonyl functional group
and lack of nitrile functional group. The formation of 19 is as-
sumed to proceed via the addition of methylene moiety in 16
to benzylidene 15 to form a Michael adduct 25 which under-
goes a retro-Michael elimination22 to yield 19 (Scheme V).
Indeno[1,2-b]pyridines 26a,b were obtained by reaction of
2-arylidene-1,3-indanedione 19a,b with cyanothioacetamide
14b in the presence of sodium ethoxide at reflux temperature.
The infrared spectra of 26a,b revealed characteristic bands
for NH, CºN and C=O functional groups. Also, a molecular
ion peak at m/z 399 was observed in the mass spectrum of
compound 26b which is the base peak in the spectrum. The
formation of indenopyridines 26a,b is assumed to proceed
through the Michael adduct 25 followed by intramolecular
cyclization to afford 26a,b.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were re-
corded (KBr) on a Perkin Elmer 1650 spectrophotometer. 1H
NMR spectra were recorded on a Varian Gemini spectrometer
200 (200 MHz), using DMSO-d6 as a solvent and TMS as in-
ternal standard. Chemical shifts are expressed as d ppm units.
Mass spectra were recorded on a gas chromatographic GC-
MS qp 1000 Ex Shimadzu instrument at 70 eV. Microanalyt-
ical data were obtained from the Microanalytical Data Unit at
Cairo University. Found: C, H, N for all compounds were
within ± 4% from the theoretical value. Physical data for the
synthesized compounds are given in Table 2. Also, the spec-
tral data are collected in Table 3.
ANTIMICROBAL ACTIVITY
[4-(Piperidin-1-yl)benzylidenyl]thiosemicarbazide (2a)
and cyanoacetic acid [4-(piperidin-1-yl)benzylidenyl/or
4-(morpholin-4-yl)benzylidenyl]hydrazide (2b,c)
General procedure
Twenty-three compounds were screened in vitro for
their antimicrobal activities against four strains of bacteria:
Staphylococcus aureus (NCTC-7447), Bacillus cereus (NCTC-
14579), Serratia marcesens (IMRU-70) and Proteus mirabilis
A mixture of aldehyde 1 (0.01 mole) and hydrazine deriv-

Hitherto Unknown Thiazole, Ylidene and Pyridinethione Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 129
Scheme V
Ar
H
H
H
14a,d
15c
CN
N
Y
C
S
Y = CN
H2N
N
CN
NC
H
Ar
H
H
N
H
H2N
S
CN
Y
22
HN
S
N
H
15
O
N
Y = COOC2H5
N
14d
15d
CN
S
H5C2OOC
H2N
H5C2OOC
H3C
CN
S
N
H
23
N
H
24
O
O
CSNH2
CH2CN
CN
H
O
19a,b
CSNH2
15c,d
Ar
O H
25
X
N
O
CN
CN
S
CH2CSNH2
C2H5ONa
19a,b
N
H
26a,b
26a; X = CH2
26b; X = O
ative (0.012 mole) in ethanol (50 mL) was heated under reflux
for 1 h, then allowed to cool. The solid product was collected
and recrystallized from the proper solvent to give 2a-c, Table 2.
(0.01 mole) and fused sodium acetate (1 gm) in ethanol (50
mL) was stirred at room temperature for 5 min. The solid
product was collected and recrystallized from the proper sol-
vent to give 4, Table 2.
N-(4-Phenyl-thiazol-2-yl)-N¢-[4-(piperidin-1-yl)benzyl-
idenyl]hydrazine (4)
MS: 362 (11.3%), 363 (M+1; 3.0%), 187 (13.7%), 186
(18.4%), 185 (19.0%), 176 (100%), 134 (23.7%), 104 (12%),
77 (14.2%).
A mixture of 2a (0.01 mole) and phenacyl bromide

130 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
El-Gaby
Table 1. Antimicrobial Activity of the Synthesized Compounds and Inhibition Zones (mm)
Gram positive bacteria
Gram negative bacteria
Fungi
Compd.
No.
Staphylococcus
aureus
Bacillus
cereus
Serratia
Proteus
Aspergillus
ochraceus
Wilhelm
Penicillium
marcesens
mirabilis
chrysogenum
Thom
(NCTC-7447) (NCTC-14579)
(IMRU-70)
(NCTC-289)
(AUCC-230)
(AUCC-530)
2a
2b
2c
4
5
6
8
9
++
++
++
+++
+++
+++
+++
++
+
+
+
+
+
++
+
+
++
++
+
+
+
+
+
+
+
+
++
+
++
+
+
+
++
+
+
+
+
++
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
++
++
+
+
+
+
+
+
+
+
++
+
++
+
++
++
+
+
+++
+
+
++
+
+
++
+
+
+
+
++
+
+
+
+
+
+++
++
++
++
+
+++
++
+
10
13
15a
15b
15c
15d
19a
19b
20
21
22
23
24
+
++
++
++
+
++
+++
+
++
+
+
+
+++
+++
+++
++
++
++
++
++++
++
++
+
+
++
+
+
+
+
++
++
++
+
+
++
++
++
++++
26a
26b
Standard
+
+
++++
++++
++++
++++
+: Less active (2-5 mm).
++: Moderately active (6-14 mm).
+++: Highly active (15-20 mm).
++++: Very highly activity (> 20 mm).
Standard: For Gram positive and Gram negative bacteria: Ampicillin 25 mg mL-1: for fungi: Mycostatine 30 mg
mL-1.
N-(4-Methyl-thiazol-2-yl)-N¢-[4-(piperidin-1-yl)benzyl-
idenyl]hydrazine (5) and 2-[N¢-(4-piperidin-1-yl)benzyl-
idenyl]hydrazino]-4,5-dihydro-thiazol-4-one (6)
A mixture of 2a (0.01 mole) and chloroacetone or ethyl
chloroacetate (0.01 mole) and sodium acetate (2 gm) in etha-
nol (40 mL) was heated under reflux for 2 h, then allowed to
cool and poured into water (70 mL). The solid product was
collected and recrystallized from the proper solvent to give 5
and 6, respectively, Table 2.
N-(5-Ethoxycarbonyl-4-methyl-thiazol-2-yl)-N¢-[4-
(piperidin-1-yl)benzylidenyl]hydrazine (8)
A mixture of 2a (0.01 mole) and ethyl a-chloroaceto-
acetate (0.01 mole) and sodium acetate (2 gm) in ethanol (50
mL) was heated under reflux for 12 h, then allowed to cool
and poured into cold water (60 mL). The solid product was
collected and recrystallized from the proper solvent to give 8,
Table 2.
MS (5): 300 (17.3%), 301 (M+1; 3.6%), 186 (38%),
185 (42%), 114 (100%), 104 (8.6%), 91 (6.1%), 77 (14.7%),
76 (6.0%).
MS (6): 302 (M+; 100%), 301 (M-1; 18.8%), 187
(76%), 185 (31%), 159 (27%), 130 (21.6%), 104 (15.4%), 90
(21.9%), 77 (26%), 76 (13.4%).
2-[N¢-(4-(Piperidin-1-yl)benzylidenyl)hydrazino]naphtho-
[2,3-d]thiazol-4,9-dione (9)
A mixture of 2a (0.01 mole) and 2.3-dichloronaphtho-
quinone (0.01 mole) and potassium carbonate (2 gm) in
dimethylformamide (10 mL) was heated under reflux for 1 h,
then allowed to cool and poured into cold water (40 mL). The

Hitherto Unknown Thiazole, Ylidene and Pyridinethione Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 131
Table 2. Physical Data for the Synthesized Compounds
2-Cyano-3-dimethylamino-acrylic acid [4-(piperidin-1-yl)-
benzylidenyl]hydrazide (10)
Compd M.p.
Yield (%)
(color)
Solvent
cryst.
Molecular
formula
A mixture of compound 2b (0.01 mole) and dimethyl-
formamide-dimethylacetal (0.01 mole) in dry m-xylene (30
mL) was refluxed for 3 h, then cooled. The precipitated prod-
uct was filtered off, washed with ether and recrystallized
from the proper solvent to give 10, Table 2.
No.
(°C)
(Mol.wt)
2a
2b
2c
105-6
190-2
145-7
225-7
200-1
270-2
308-10
> 300
222-4
>300
84
(yellow)
75
(orange)
67
(yellow)
73
(yellow)
64
(yellow)
65
(yellow)
70
(yellow)
63
(violet)
78
(orange)
57
(violet)
83
(yellow)
80
(orange)
87
(orange)
85
(orange)
77
(violet)
76
(yellow)
62
Ethanol
Ethanol
Ethanol
Dioxane
Benzene
Ethanol
Dioxane
Dioxane
Dioxane
Ethanol
Ethanol
Ethanol
DMF
C13H18N4S
(262.38)
C15H18N4O
(270.34)
C14H16N4O2
(272.31)
C21H22N4S
(362.50)
C16H20N4S
(300.43)
C15H18N4OS
(302.40)
C19H24N4O2S
(372.48)
C23H20N4O2S
(416.51)
C18H23N5O
(325.42)
C20H20N6OS
(392.49)
C15H15N3
(237.31)
C14H13N3O
(239.28)
C15H17N3S
(271.39)
C14H15N3OS
(273.36)
C21H19NO2
(317.39)
C20H17NO3
(319.36)
C21H20N4
(328.42)
C16H17N3O2S
(315.40)
C18H17N5S
(335.43)
C20H22N4O2S
(382.48)
C20H21N3O3S
(383.47)
C24H19N3OS
(397.50)
C23H17N3O2S
(399.47)
MS: 325 (25%), 326 (M+1; 5.6%), 202 (14.8%), 187
(17.4%), 186 (63.7%), 185 (52.8%), 123 (100%), 104 (4.3%),
77 (7.7%), 76 (4.0%).
4
5
6-Amino-4-methylsulfanyl-2-oxo-1-[(4-(piperidin-1-yl)-
benzylidenyl)amino]-1,2-dihydro-pyridine-3,5-dicarbo-
nitrile (13)
6
A mixture of 2b (0.01 mole) and ketene dithioacetal 11
(0.01 mole) and potassium carbonate (2 gm) in dimethyl-
formamide (10 mL) was heated under reflux until the evolu-
tion of methyl mercaptan had stopped. After cooling, the re-
action mixture was poured into cold water (100 mL) and acid-
ified with HCl. The product was collected by filtration and
recrystallization from the proper solvent to give 13, Table 2.
8
9
10
13
15a
15b
15c
15d
19a
19b
20
21
22
23
24
26a
26b
120-1
195-6
225-7
220-1
190-2
240-2
280-2
235-6
245-6
100-2
280-2
282-4
260-1
2-[4-(Piperidin-1-yl)benzylidenyl/or 4-(morpholin-4-yl)-
benzylidenyl]malononitriles (15a,b) and 2-cyano-3-[4-
(piperidin-1-yl)phenyl/or 4-(morpholin-4-yl)phenyl]thio-
acrylamides (15c,d)
General procedure
DMF
A mixture of aldehyde 1 (0.01 mole) and active methy-
lene compound (0.01 mole) and triethylamine (0.01 mole) in
ethanol (50 mL) was stirred at room temperature for 15 min.
The solid product was collected and recrystallized from the
proper solvent to give 15a-d, Table 2.
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
MS (15d): 273 (100%), 274 (M+1; 28%), 239 (45.9%),
214 (45.6%), 187 (55.9%), 181 (67.6%), 180 (23.9%), 153
(21.1%), 126 (19%), 104 (3.4%), 90 (8.2%), 76 (8.7%), 77
(27%).
(orange)
54
(violet)
78
(orange)
87
(orange)
82
(orange)
69
(orange)
65
2-[4-(Piperidin-1-yl)benzylidenyl/or 4-(morpholin-4-yl)-
benzylidenyl]indan-1,3-diones (19a,b), 2-(1H-benzyimi-
dazol-2-yl)-3-[4-(piperidin-1-yl)phenyl]acrylonitrile (20)
and 5-[4-(piperidin-1-yl)benzylidenyl]-2-thioxo-dihydro-
pyrimidine-4,6-dione (21)
General procedure
(red)
A mixture of 1 (0.01 mole) and active methylene com-
pound (0.01 mole) and piperidine (0.01 mole) in dioxane (30
mL) was heated under reflux for 1 h. The solid product which
was produced on heating was collected and recrystallized
from the proper solvent to give 19-21, Table 2.
solid product was collected and recrystallized from the
proper solvent to give 9, Table 2.

132 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
El-Gaby
Table 3. Spectral Data for the Synthesized Compounds
Compd.
IR/nmax (cm-1)
No.
1H NMR (d/ppm) (DMSO-d6)
2a
2b
2c
4
3433, 3263, 3147 (NH, NH2), 2931,
2823 (CH-aliph), 1610 (C=N).
3394 (NH), 2923, 2839 (CH-aliph), 2268 1.60 (s, 6H, 3CH2), 3.20 (s, 4H, N(CH2)2), 4.18 (s, 2H, CH2CN), 6.95, 7.52 (2d,
(CºN), 1705 (C=O), 1604 (C=N). 4H, Ar-H), 7.90 (s, 1H, CH=N), 11.57 (s, 1H, NH).
3209 (NH), 2962, 1854 (CH-aliph), 2206 2.56 (s, 4H, N(CH2)2), 3.81 (s, 4H, O(CH2)2), 4.21 (s, 2H, CH2CN), 7.00-7.66
1.59 (s, 6H, 3CH2), 3.25 (s, 4H, N(CH2)2), 6.89, 7.59 (2d, 4H, Ar-H), 7.80,
11.23 (2s, 2H, two NH), 7.96 (s, 1H, SH), 7.80 (s, 1H, CH=N).
(CºN), 1685 (C=O), 1600 (C=N).
2931, 2815 (CH-aliph), 1604 (N=N).
(m, 4H, Ar-H), 7.95 (s, 1H, CH=N), 11.64 (s, 1H, NH).
1.65 (s, 6H, 3CH2), 3.28 (s, 4H, N(CH2)2), 6.99, 7.89 (2d, 4H, Ar-H), 7.31-7.56
(m, 6H, Ar-H + thiazole-H), 7.98 (s, 1H, CH=N), 11.89 (s, 1H, NH).
5
3178 (NH), 2923, 2854 (CH-aliph), 1604 1.30 (s, 6H, 3CH2), 2.21 (s, 3H, CH3), 3.29 (s, 4H, N(CH2)2), 6.35 (s, 1H,
(C=N).
thiazole-H), 6.97, 7.42 (2d, 4H, Ar-H), 7.96 (s, 1H, CH=N), 11.45 (hump, 1H,
NH).
6
8
2931, 2777 (CH-aliph), 1720 (C=O),
1635 (C=N), 1604 (N=N).
3192 (NH), 2931, 2854 (CH-aliph), 1717 1.26 (t, 3H, CH3), 1.57 (s, 6H, 3CH2), 1.78 (s, 3H, CH3), 3.23 (s, 4H, N(CH2)2),
1.65 (s, 6H, 3CH2), 3.34 (s, 4H, N(CH2)2), 3.91 (s, 2H, SCH2), 6.99, 7.65 (2d,
4H, Ar-H), 8.30 (s, 1H, CH=N), 11.87 (s, 1H, NH).
(C=O), 1573 (C=N).
4.16 (q, 2H, OCH2), 6.91, 7.51 (2d, 4H, Ar-H), 8.01 (s, 1H, CH=N), 8.10 (s, 1H,
NH).
9
2931, 2815 (CH-aliph), 1651 (C=O),
1589 (N=N).
1.69 (s, 6H, 3CH2), 3.50 (s, 4H, N(CH2)2), 7.07-7.93 (m, 8H, Ar-H), 8.46
(Hump, 1H, NH), 8.75 (s, 1H, CH=N).
10
13
3355 (NH), 2931, 2854 (CH-aliph), 2191 1.65 (s, 6H, 3CH2), 3.28 (s, 4H, N(CH2)2), 3.38 (s, 6H, N(CH3)2), 6.98, 7.51 (2d,
(CºN), 1666 (C=O), 1604 (C=N).
3402, 3360 (NH2), 2931, 2862 (CH-
aliph), 2206 (CºN), 1620 (C=O), 1542
(C=N).
4H, Ar-H), 7.81, 8.30 (2s, 2H, two CH), 10.63 (s, 1H, NH).
1.69 (s, 6H, 3CH2), 2.58 (s, 3H, SCH3), 3.51 (s, 4H, N(CH2)2), 4.27 (Hump, 2H,
NH2), 7.56, 8.20 (2d, 4H, Ar-H), 8.01 (s, 1H, CH=N).
15a
15b
15c
15d
19a
19b
20
2928, 2956 (CH-aliph), 2210 (CºN).
1.63 (s, 6H, 3CH2), 3.23, 3.29 (2s, 4H, N(CH2)2), 7.02, 7.81 (2d, 4H, Ar-H),
8.01 (d, 1H, CH).
3.55 (s, 4H, N(CH2)2), 3.81 (s, 4H, O(CH2)2), 7.12, 7.89 (2d, 4H, Ar-H), 8.18 (s,
1H, CH).
1.63 (s, 6H, 3CH2), 3.32 (s, 4H, N(CH2)2), 7.03, 7.87 (2d, 4H, Ar-H), 8.07 (s,
1H, CH), 9.17 (s, 1H, NH), 9.71 (s, 1H, SH).
3.37 (s, 4H, N(CH2)2), 3.79 (s, 4H, O(CH2)2), 7.06, 7.91 (2d, 4H, Ar-H), 8.08 (s,
1H, CH), 9.22 (s, 1H, NH), 9.71 (s, 1H, SH).
1.69 (s, 6H, 3CH2), 3.62 (s, 4H, N(CH2)2), 7.07, 8.59 (2d, 4H, Ar-H), 7.91 (s,
4H, Ar-H), 7.70 (s, 1H, CH).
3.52 (s, 4H, N(CH2)2), 3.81 (s, 4H, O(CH2)2), 7.11, 8.57 (2d, 4H, Ar-H), 7.94 (s,
4H, Ar-H), 7.77 (s, 1H, CH).
2954, 2854 (CH-aliph), 2214 (CºN).
3348, 3283, 3163 (NH2), 2933, 2851
(CH-aliph), 2215 (CºN).
3381, 3302, 3190 (NH2), 2960, 2877
(CH-aliph), 2197 (CºN).
2950, 2854 (CH-aliph), 1666 (C=O).
2920, 2860 (CH-aliph), 1650 (C=O).
3263 (NH), 2931, 2854 (CH-aliph), 2221 1.60 (s, 6H, 3CH2), 3.41 (s, 4H, N(CH2)2), 7.02, 7.90 (2d, 4H, Ar-H), 7.22, 7.59
(CºN). (2m, 4H, Ar-H), 8.16 (s, 1H, CH), 12.72 (Hump, 1H, NH).
3155 (NH), 2931, 2854 (CH-aliph), 1651 1.68 (s, 6H, 3CH2), 3.49 (s, 4H, N(CH2)2), 7.02, 8.45 (2d, 4H, Ar-H), 8.18 (s,
21
(C=O).
1H, CH), 11.93, 12.55 (2s, 2H, two NH).
22
3433, 3340, 3232 (NH, NH2), 2931,
2831 (CH-aliph), 2198 (CºN).
3300, 3210 (NH2), 2931, 2854 (CH-
aliph), 2206 (CºN), 1705 (C=O).
1.62 (s, 6H, 3CH2), 3.04 (s, 4H, N(CH2)2), 3.29 (s, 2H, NH2), 3.60 (s, 1H, SH),
6.79, 7.30 (2d, 4H, Ar-H).
1.28 (t, 3H, CH3), 1.64 (s, 6H, 3CH2), 3.39 (s, 4H, N(CH2)2), 3.52 (s, 2H, NH2),
4.24 (q, 2H, OCH2), 7.03, 7.94 (2d, 4H, Ar-H), 8.12 (s, 1H, NH).
23
24
3433 (NH), 2923, 2854 (CH-aliph), 2225 0.92 (t, 3H, CH3), 2.50 (s, 3H, CH3), 3.28 (s, 4H, N(CH2)2), 3.99 (s, 4H,
(CºN), 1708 (C=O). O(CH2)2), 4.23 (q, 2H, OCH2), 7.08, 7.31 (2d, 4H, Ar-H), 12.27 (s, 1H, NH).
3100 (NH), 2950, 2880 (CH-aliph), 2221 1.67 (s, 6H, 3CH2), 3.31 (s, 4H, N(CH2)2), 6.99-7.73 (m, 8H, Ar-H), 8.25
(CºN), 1681 (C=O). (Hump, 1H, NH).
3415 (NH), 2923, 2854 (CH-aliph), 2221 3.32 (s, 4H, N(CH2)2), 3.82 (s, 4H, O(CH2)2), 7.04, 7.46 (2d, 4H, Ar-H), 7.67-
(CºN), 1708 (C=O). 7.75 (m, 4H, Ar-H), 8.32 (s, 1H, NH).
26a
26b

Hitherto Unknown Thiazole, Ylidene and Pyridinethione Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 133
MS (19b): 319 (100%), 320 (M+1; 23.1%), 261
(79.5%), 260 (74%), 233 (78%), 176 (32%), 151 (12.3%),
104 (26%), 77 (13.6%), 76 (42%), 75 (23.9%).
MS (20): 328 (M+; 54%), 327 (M-1; 100%), 329 (M+1;
11.7%), 303 (4.5%), 271 (16.5%), 244 (8.7%), 164 (11.1%),
122 (12.0%), 104 (0.6%), 91 (3.6%), 77 (4.1%), 76 (2.7%).
ACKNOWLEDGEMENT
The author is grateful to Dr. M. M. Ghorab, Department
of Drug Radiation Research, National Centre for Radiation
Research and Technology, P.O. Box 29, Nasr City, Cairo,
Egypt for antimicrobial activity tests.
6-Amino-4-[4-(piperidin-1-yl)phenyl]-2-thioxo-1,2-dihydro-
pyridine-3,5-dicarbonitrile (22) and 2-amino-4-[4-
(piperidin-1-yl)phenyl]-3-ethoxycarbonyl-6-thioxo-1,6-
dihydro-pyridine-5-carbonitrile (23)
Received March 5, 2003.
General procedure
REFERENCES
A mixture of 15 (0.01 mole) and active methylene com-
pound (0.01 mole) and triethylamine (0.01 mole) in ethanol
(50 mL) was heated under reflux for 8 h, then allowed to cool
and poured into cold water (70 mL) and acidified with HCl.
The solid product was collected and recrystallized from the
proper solvent to give 22 and 23, Table 2.
MS (22): 335 (M+; 88%), 336 (M+1; 32%), 294 (13%),
251 (13%), 190 (12%), 139 (12%), 84 (100%), 77 (4.8%), 76
(5.1%).
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A mixture of 15d (0.01 mole) and ethyl acetoacetate
(0.01mole) and piperidine (0.5 mL) in dioxane (30 mL) was
heated under reflux for 24 h, then allowed to cool and poured
into cold water (70 mL) and acidified with HCl. The solid
product was collected and recrystallized from the proper sol-
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(24.4%), 279 (15.5%), 280 (21.3%), 253 (13.2%), 224
(9.4%), 184 (3.7%), 152 (4.6%), 104 (5.1%), 91 (3.9%), 77
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