Synthesis, characterization and pharmacological investigations of some novel heterocyclic derivatives incorporating pyrene and sugar moieties

Article abstract of DOI:10.1007/s11164-013-1061-z

A series of substituted pyrene derivatives 2-15 incorporated heterocyclic and sugar moieties were synthesized and evaluated as antiviral activities using 1-acetylpyrene as a starting material. The structure assignment of the new compounds was based on chemical and spectroscopic evidence. The detailed synthesis, spectroscopic data and pharmacological activities of the synthesized compounds were reported.

Full text of DOI:10.1007/s11164-013-1061-z

Res Chem Intermed
DOI 10.1007/s11164-013-1061-z
Synthesis, characterization and pharmacological
investigations of some novel heterocyclic derivatives
incorporating pyrene and sugar moieties
•
Nagy M. Khalifa Mosaad S. Mohamed
•
•
Magdi E. Zaki Mohamed A. Al-Omar
Yasser M. Zohny
•
Received: 30 December 2012 / Accepted: 15 January 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A series of substituted pyrene derivatives 2–15 incorporated heterocy-
clic and sugar moieties were synthesized and evaluated as antiviral activities using
1-acetylpyrene as a starting material. The structure assignment of the new com-
pounds was based on chemical and spectroscopic evidence. The detailed synthesis,
spectroscopic data and pharmacological activities of the synthesized compounds
were reported.
Keywords Pyrene derivatives ꢀ Nucleoside analogues ꢀ Anti-HIV-1 activities
Introduction
The development of synthetic molecules that bind to, modify or cleave DNA, and
ultimately result in cell death has been under intense research for the last couple of
decades [1]. DNA binding affinity and orientation affect the biological activities of
N. M. Khalifa (&) ꢀ M. A. Al-Omar
Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC),
College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
e-mail: nagykhalifa@hotmail.com
N. M. Khalifa
Department of Therapeutical Chemistry, Pharmaceutical and Drug Industries Division,
National Research Centre, Dokki, Cairo 12622, Egypt
M. S. Mohamed ꢀ Y. M. Zohny
Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
M. E. Zaki
Photochemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
M. A. Al-Omar
Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
123

N. M. Khalifa et al.
the molecules [2]. The interaction of DNA with drug molecules involve four types
of binding modes: (1) electrostatic binding, (2) external binding, (3) groove binding
(groove binder), and (4) intercalative binding (intercalator), which is the most
effective for drugs targeted to DNA [3]. Pyrene is considered one of the most
promising candidates for the intercalating moiety [4], because it has almost the same
surface area as a regular Watson–Crick base pair, which makes a large stabilization
through base stacking with neighboring base pairs. The fluorescence properties of
pyrene have made its derivatives suitable to be used as biological probes for the
investigation of structural properties of proteins and peptides [5], DNA recognition
[6, 7], DNA oligomers, and duplexes in terms of their distances [8, 9], fluorescence
probes [10–15], surfactant micelles, and vesicles properties [16]. Moreover, several
glycosides have exhibited good biological inhibitions [17–21], inducers, and ligands
[22]. Having the above aspects in mind, and as a continuation of our work on the
synthesis of glycosides and nucleosides having biological activity [23–26],
glycosylatives have been planned to target a group of pyridine compounds
functionalized with cyano and pyrene ring. The anti-HIV activities of the newly
synthesized compounds have been established.
Results and discussion
Chemistry
The reaction of 1-acetylpyrene (1) with an excess of ethyl acetate in the presence of
sodium metal afforded the corresponding 1,3-dicarbonyl compound 1-(pyren-3-
yl)butane-1,3-dione (2), which was reacted with o-phenylenediamine in ethanol to
afford (1Z,4E)-2-methyl-4-(pyren-3-yl)-3H-benzo[b][1,4]diazepine (3). Also, com-
pound 2 was condensed with phenyl hydrazine to afford 5-methyl-1-phenyl-3-
(pyren-3-yl)-1H-pyrazole (4). Compound 1 was treated with thiosemicarbazide in
ethanol to afford (E)-1-[1-(pyren-1-yl)ethylidene]thiosemicarbazide 5, which was
condensed with chloroacetic acid to give 4-thiazolidinones derivative 6. The latter
compound 6 was condensed with 3,4,5-trimethoxybenzaldehyde in glacial acetic
acid in the presence of anhydrous sodium acetate afforded 5-arylidene-4-
thiazolidinones derivative 7 (Scheme 1).
Additionally, compound 1 was condensed with aromatic and heterocyclic
aldehydes and ethyl cyanoacetate in the presence of ammonium acetate to afford
the corresponding cyanopyridone derivatives 8a–c, respectively. Compound 8a was
reacted with 2-deoxy-3,5-di-O-(p-toluyl)-a-D-erythropentafuranosyl chloride in DMF
in the presence of triethylamine at room temperature to afford the corresponding
N-ribosyl pyridine derivative 9. Deprotection of the acetoxy groups in the nucleoside 9
with ammonia in methanol afforded the product 10. Compound 8a was reacted with
some alkyl halides, namely chloromethylmethylsulfide, chloromethylethylether or
3-bromo-1-propanol in dry DMF in the presence of anhydrous potassium carbonate at
room temperature afforded the corresponding S-alkylated derivatives 11a–c, respec-
tively. Also, reaction of the pyridine-2-(1H)one 8a with cycloalkyl halides, namely
cyclopentyl bromide or cyclohexyl bromide in the presence of sodium hydride as a
123

Investigations of novel heterocyclic derivatives
N
N
NH2
NH2
O
O
O
3
Na / Ethylacetate
N
N
2
1
RNHNH2
O
O
NC
S
C
H
3 C
O
O
A
Ar
N
H2N
NHNH2
r
-
H
C
+
H
4
O
4
CN
O
H
N
H
N
NH2
N
S
a, Ar= C6H4-(OCH3)-4
b, Ar= 2-thiophene
c, Ar= 4-pyridine
8a-c
5
O
MeO
OMe
AcOH
Cl
OH
N
CHO
OMe
OMe
N
N
S
S
N
MeO
OMe
HN
HN
O
O
7
6
Scheme 1 Synthesis of compounds 2–7
base afforded the N-substituted derivatives 12a, b, respectively. On the other hand, the
interaction of compound 8a with a-bromo-c-butyrolactone caused the formation of
N-lactone derivative 13 (Scheme 2).
Pharmacological screening
Compounds 7, 8a, 8b, 9, 11c, and 12b were evaluated for their antiviral activity
against wild-type HIV-1 in MT-4 cells. Expression of HIV in culture medium was
quantified by HIV antigen detection ELISA, and the results were compared with the
antiviral activity of Emivirine (MKC-442), a well-examined HEPT analogue. All
tested compounds were inactive against human immunodeficiency virus HIV-1 at
the highest tested concentration of 100 lM.
123

N. M. Khalifa et al.
O
O
NH3 / MeOH
O
N
O
N
NC
O
NC
OTol
CH3
OH
O
O
OTol
OH
9
10
O
C
Tol=
TolO
Cl
TolO
Br
O
O
(
)
n
a, n= 1
b, n= 2
NH
N
NC
NC
Br
( )n
O
O
8a
12a,b
O
O
Y
X
R
a, Y= Cl , X= S,
b, Y= Cl , X= O,
R= H
R= CH3
a, Y= Br , X= CH2, R= OH
O
O
N
NC
N
NC
X
O
O
O
11a-c
O
R
13
a, R= H
b, R=CH3
c, R=OH
Scheme 2 Synthesis of compounds 8–13
Inhibition of HIV-1 replication
Compounds were examined for possible antiviral activity against both strains of HIV-
1 using MT-4 cells as target cells. For screening studies, MT-4 cells were incubated
with the virus for 2 h, washed, and thereafter added in a proportion of 1:10 to
uninfected cells which had been preincubated in growth medium containing the test
compound for 2 h. Cultures were maintained with the test compound for 7 days in
123

Investigations of novel heterocyclic derivatives
parallel with virus-infected control cultures without addition of the compound.
Expression of HIV-1 in the culture medium was quantitated by HIV antigen detection
ELISA [27]. Compounds mediating less than 30 % reduction of antigen expression
were considered to be without biological activity. Compounds mediating a reduction
of 30 % or more were examined for cytotoxic potential using concentration-dependent
inhibition of MT-4 cells proliferation as a measure of cytotoxicity. A 30 % inhibition
of cell growth relative to control cultures was considered significant.
Experimental
Chemistry
All melting points were uncorrected and were taken on a Boetius melting point
microscope. The infrared (IR) spectra were recorded on a Mattson 5000 FIR
1
spectrometer, using KBr discs, at Cairo University. HNMR and 13CNMR spectra
were performed on a Varian EMNMR spectrometer at the Microanalytical Center,
Cairo University, Egypt, and on a Varian EM-360 270 MHz NMR Spectropho-
tometer at the University of Southern Denmark, Denmark, using tetramethylsilane
(TMS) as internal standard. All chemical shifts are quoted in d values using parts
per million (ppm) scale downfield from TMS. Mass Spectra were recorded on a
Finnigan SSQ 700 mass spectrometer at the University of Southern Denmark.
Elemental analysis were performed by the micro-analytical unit at Cairo University
and the results were within 0.3 of the theoretical values. All reactions were
monitored by TLC using precoated aluminum sheet silica gel 60F254 plates (Merck)
and detection of the components was made by short and long UV light. The silica
gel (0.004–0.063 mm) used for column chromatography was purchased from
Merck. The antiviral screening in vitro through the Retrovirus Laboratory,
Department of Virology, State Serum Institute, Copenhagen, Denmark.
2-Methyl-4-pyren-1-yl-3H-benzo[b][1,4]diazepine (3)
A mixture of o-phenylenediamine (0.01 mol) and 1-pyren-1-yl-butan-1,3-dione (2)
(0.01 mol) was heated under reflux in ethanol (40 mL) for 4 h. The reaction mixture
was allowed to cool to room temperature and the separated precipitate was filtered
off, washed with ethanol and crystallized from aqueous DMF to give 3 in yield of
67 %; m.p.[300 °C; 1HNMR (DMSO-d6) d: 1.70 (s, 3H, CH3), 2.80 (s, 2H, CH2),
6.8–8.5 (m, 13H, ArH).
5-Methyl-1-phenyl-3-(pyren-3-yl)-1H-pyrazole (4)
A mixture of 1-pyren-1-yl-butan-1,3-dione (2) (0.005 mol) and phenyl hydrazine
(0.02 mol) in acetic acid (10 mL) was refluxed for 5 h. The reaction mixture was
concentrated under reduced pressure. The obtained precipitate was filtered off and
crystallized from ethanol to afford compound 4 in yield of 65 %; m.p.[300 °C; 1H
NMR (DMSO-d6) d: 1.6 (s, 3H, CH3), 6.3 (s, 1H, CH), 6.8–8.6 (m, 14H, ArH).
123

N. M. Khalifa et al.
(E)-1-[1-(pyren-1-yl)ethylidene] thiosemicarbazide (5)
A mixture of compound 1 (0.01 mol) and thiosemicarbazide (0.01 mol) in absolute
ethanol (25 mL) was refluxed for 8 h. After cooling, the obtained product was
filtered off, dried and then crystallized from ethanol to give 5 in 73 % yield; m.p.
200 °C; 1H NMR (DMSO-d6) d: 2.6 (s, 3H, CH3), 4.5 (s, 2H, NH2 exchangeable with
D2O), 8.20–8.75 (m, 9H, ArH), 10.36 (s, 1H, NH exchangeable with D2O); 13CNMR
(DMSO-d6) d: 14.3, 123.81, 124.12, 124.21, 124.75, 125.10, 125.14, 126.23, 126.95,
127.28, 127.30, 127.51, 128.74, 130.09, 130.49, 130.91, 134.28, 168.27 and 181.93;
MS: m/z 317 (M?) consistent with the molecular formula (C19H15N3S).
(E)-2[(1-(pyren-1-yl)ethylidene)hydrazono]thiazolidin-4-one (6)
A mixture of 5 (0.01 mol), chloroacetic acid (0.01 mol) and anhydrous sodium
acetate (0.5 g) in ethanol (30 mL) was heated under reflux for 3 h. The solvent was
evaporated and the reaction mixture was poured onto water. The formed product
was filtered off and crystallized from ethanol to afford a pale yellow needles of 6 in
1
59 % yield; m.p. 243 °C; HNMR (DMSO-d6) d: 2.55 (s, 3H, CH3), 3.91 (s, 2H,
CH2), 7.90–8.47 (m, 9H, ArH), 12.11 (s, 1H, NH exchangeable with D2O);
13CNMR (DMSO-d6) d: 14.7, 33.4, 123.65, 124.23, 124.48, 124.82, 125.12, 125.19,
126.36, 126.89, 127.29, 127.41, 127.57, 128.86, 130.12, 130.56, 130.98, 134.39,
160.59, 163.76 and 173.25; MS: m/z 357 (M?) consistent with the molecular
formula (C21H15N3OS).
(E)-2-{[1-pyren-1-yl)ethylidene]-hydrazono}-5-[1-(3,4,5-trimethoxyphenyl)-
meth-(Z)-ylidene]-thiazolidin-4-one (7)
A mixture of 6 (0.01 mol), 3,4,5-trimethoxybenzaldehyde (0.01 mol) and anhydrous
sodium acetate (0.5 g) was refluxed for 5 h in glacial acetic acid (15 mL). The
reaction mixture was cooled and poured onto crushed ice. The obtained orange solid
was filtered off, washed with water and crystallized from glacial acetic acid to
1
afford 7 in a 80 % yield; m.p. [300 °C; H NMR (DMSO-d6) d: 2.6 (s, 3H, CH3),
3.7 (s, 3H, OCH3), 3.8 (s, 6H, 2 OCH3), 6.8 (s, 1H, CH), 8.0–8.8 (m, 11H, ArH),
12.1 (s, 1H, NH exchangeable with D2O); 13CNMR (DMSO-d6) d: 14.61, 55.32,
55.60, 104.11, 116.53, 123.51, 124.34, 124.45, 124.89, 125.08, 125.26, 126.42,
126.92, 127.26, 127.38, 127.73, 128.91, 129.44, 130.22, 130.49, 130.90, 134.41,
138.49, 143.06, 151.13, 162.79, 164.21, and 169.01; MS: m/z 535 (M?) consistent
with the molecular formula (C31H25N3O4S).
1,2-Dihydro-4-(substituted-aryl)-2-oxo-6-(pyren-8-yl)pyridin-3-carbonitrile
8a–c
General method: a mixture of 1-(pyren-3-yl)ethanone (1) (0.01 mol), appropriate
aromatic or heterocyclic aldehydes namely, p-methoxy benzaldehyde, 2-thiophene
aldehyde and 4-pyridine aldehyde (0.01 mol), ethylcyanoacetate (0.01 mol) and
ammonium acetate (0.08 mol) in ethanol (50 mL) was heated under reflux for
123

Investigations of novel heterocyclic derivatives
4–6 h. The formed precipitate was filtered off, washed successively with water and
finally with ether, and crystallized from glacial acetic acid to afford the
corresponding pyridones (8a–c), respectively.
1,2-Dihydro-4-(4-methoxyphenyl)-2-oxo-6-(pyren-8-yl)pyridin-3-carbonitrile (8a)
Yield 90 %; m.p.[300 °C; IR (KBr, cm-1) mmax: 3,415 (NH), 2,219 (C:N), 1,678
(C=O); 1HNMR (DMSO-d6) d: 3.89 (s, 3H, OCH3), 6.19 (s, 1H, CH), 6.72–8.13 (m,
13 H, ArH), 12.90 (s, 1H, NH exchangeable with D2O); 13CNMR (DMSO-d6) d:
56.11, 103.23, 114.26, 115.38, 115.59, 123.72, 124.25, 124.37, 124.80, 124.95,
125.06, 125.38, 126.28, 126.92, 127.24, 127.32, 127.43, 127.65, 128.69, 130.15,
130.55, 130.98, 134.46, 156.57, 160.21, 162.34, 166.58; MS: m/z 426 (M?)
consistent with the molecular formula (C29H18N2O2).
1,2-Dihydro-2-oxo-6-(pyren-8-yl)-4-(thiophen-2-yl)pyridin-3-carbonitrile (8b)
Yield 79 %; m.p.[300 °C; IR (KBr, cm-1) mmax: 3,446 (NH), 2,223 (C:N), 1,665
1
(C=O); HNMR (DMSO-d6) d: 6.37 (s, 1H, CH), 7.21–8.12 (m, 12 H, ArH), 12.36
(s, 1H, NH exchangeable with D2O); 13CNMR (DMSO-d6) d: 105.21, 116.07,
121.34, 123.70, 124.05, 124.29, 124.81, 125.12, 125.18, 126.33, 126.89, 127.11,
127.26, 127.39, 127.57, 128.24, 128.68, 130.14, 130.45, 130.59, 130.99, 134.19,
137.15, 156.42, 161.86, 169.64; MS: m/z 402 (M?) consistent with the molecular
formula (C26H14N2OS).
1,2-Dihydro-2-oxo-6-(pyren-8-yl)-4-(pyridin-4-yl)pyridin-3-carbonitrile (8c)
Yield 80 %; m.p.[300 °C; IR (KBr, cm-1) mmax: 3,450 (NH), 2,213 (C:N), 1,680
1
(C=O); HNMR (DMSO-d6) d: 6.81 (s, 1H, CH), 7.50–8.82 (m, 13 H, ArH), 13.40
(s, 1H, NH exchangeable with D2O); 13CNMR (DMSO-d6) d: 104.91, 116.36,
120.83, 122.01, 123.66, 124.17, 124.35, 124.80, 125.03, 125.29, 126.38, 126.87,
127.23, 127.34, 127.62, 128.77, 130.21, 130.45, 130.91, 134.43, 149.38, 149.85,
157.04, 161.71, 166.90; MS: m/z 397 (M?) consistent with the molecular formula
(C27H15N3O).
1-[2-Deoxy-3,5-di-O-(4-methylbenzoyl)-D-erythropentafuranosyl]-3-cyano-
6-pyren-1-yl-4-(4-methoxyphenyl)pyridine-2(1H)one (9)
A mixture of 8a (0.01 mol) and 2-deoxy-3,5-di-(4-methylbenzoyl)-a-D-erythropen-
tafuranosyl chloride (0.01 mol) in dry DMF (15 mL) and triethylamine (1 mL) was
stirred at room temperature overnight and then evaporated to dryness under reduced
pressure. After dilution with water (20 mL), the solution was extracted with
dichloromethane (3 9 50 mL). The combined extracts were removed in vacuo to
give the crude product which was purified by column chromatography on silica gel
(eluent: ethylacetate/pet. Ether 60/80 30 %) to give 9 in 55 % yield as a yellowish
1
foam; m.p. 127 °C; HNMR (CDCl3) d: 2.44 (s, 6H, 2 CH3), 3.17 (m, 2H, 20-H),
3.76 (s, 3H, OCH3), 4.60 (m, 2H, 50-H), 4.69 (m, 1H, 40-H), 5.73 (m, 1H, 30-H), 6.89
123

N. M. Khalifa et al.
(s, 1H, CH pyridine ring), 7.11 (m, 1H, 10-H), 7.30–8.20 (m, 21 H, Ar–H); 13CNMR
(CDCl3) d: 21.79, 37.56, 55.39, 63.11, 74.67, 84.17, 96.17, 103.98, 114.25, 115.53,
116.19, 123.67, 124.05, 124.30, 124.78, 124.97, 125.02, 125.19, 126.47, 126.86,
127.20, 127.23, 127.35, 127.42, 127.59, 128.68, 129.06, 129.85, 130.12, 130.55,
130.94, 134.37, 135.11, 142.79, 157.31, 159.86, 166.34, 167.95; MS, FAB: m/z 778
(M?) consistent with the molecular formula (C50H38N2O7).
1-(b-D-ribofuranos-2-yl)-4-(4-methoxy-phenyl)-2-oxo-6-pyrene-1yl-1,2-
dihydro-pyridin-3-carbonitrile (10)
Compound 9 (0.0014 mol) was dissolved in absolute methanol (20 mL) and freshly
prepared sodium methoxide (0.0014 mol) was added and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was neutralized with
NH4Cl (0.014 mol) and stirring was continued for half an hour. The product was
then purified by column chromatography on silica gel (eluent: 0–50 % Methanol/
1
CH2Cl2) to afford 10 in 40 % yield; m.p. 269 °C; HNMR (DMSO-d6) d: 2.19 (m,
2H, 20 H), 3.50–3.85 (m, 3H, 40 H and 50 H), 4.17 (m, 1H, 30 H), 4.6 (s, 1H, 50 OH),
4.9 (s, 1H, 30 OH), 6.23 (t, 1H, 10 H), 6.59 (s, 1H, CH), 7.35–8.40 (m, 13 H, ArH).
1-[(Alkylthio)methyl]-4-(4-methoxyphenyl)-2-oxo-6-(pyren-1-yl)-1,2-dihydro-
pyridin-3-carbonitrile 11a–c
General method: a mixture of 8a (0.001 mol), alkyl halides namely, chlorometh-
ylmethyl sulfide, chloromethylethylether and 3-bromo-1-propanol (0.001 mol) in
dry DMF (15 mL) in the presence of anhydrous potassium carbonate (0.001 mol)
was stirred at room temperature overnight and then evaporated to dryness under
reduced pressure. After dilution with water (20 mL), the solution was extracted with
dichloromethane (3 9 50 mL). The combined extracts were removed in vacuo to
give the crude product which was purified by column chromatography (pet. Ether/
ethylacetate 20 %) to give 11a–c, respectively.
1-[(Methylthio)methyl]-4-(4-methoxyphenyl)-2-oxo-6-(pyren-1-yl)-1,2-dihydro-
pyridin-3-carbonitrile (11a)
1
Yield 43 %; m.p. 197–199 °C; HNMR (DMSO-d6) d: 2.23 (s, 3H, CH3), 3.79
(s, 3H, OCH3), 4.34 (s, 2H, CH2), 6.65 (s, 1H, CH), 6.80–8.13 (m, 13H, ArH); MS:
m/z 486 (M?) consistent with the molecular formula (C31H22N2O2S).
1-[(Ethoxymethyl]-4-(4-methoxyphenyl)-2-oxo-6-(pyren-1-yl)-1,2-dihydro pyridin-
3-carbonitrile (11b)
Yield 49 %; m.p. 161–163 °C; 1HNMR (DMSO-d6) d: 1.1 (t, 3H, CH3), 3.45 (q, 2H,
OCH2), 3.79 (s, 3H, OCH3), 5.3 (s, 2H, NCH2), 6.87 (s, 1H, CH), 7.04–8.50 (m,
13H, ArH); MS: m/z 484 (M?) consistent with the molecular formula
(C32H24N2O3).
123

Investigations of novel heterocyclic derivatives
1[-(3-Hydroxypropyl)]-4-(4-methoxyphenyl)-2-oxo-6-(pyren-1-yl)-1,2-dihydro-
pyridin-3-carbonitrile (11c)
Yield 57 %; m.p. 211–212 °C; 1HNMR (DMSO-d6) d: 2.0 (m, 2H, CH2-CH2-CH2),
3.47 (s, 1H, OH), 3.66 (t, 2H, NCH2), 3.79 (s, 3H, OCH3), 4,71 (t, 2H, CH2OH),
6.87 (s, 1H, CH), 7.04–8.50 (m, 13H, ArH); 13CNMR (DMSO-d6) d: 31.03, 39.26,
55.49, 62.34, 105.08, 114.32, 115.62, 116.17, 123.81, 124.12, 124.21, 124.75,
124.93, 125.10, 125.14, 126.23, 126.95, 127.28, 127.30, 127.42, 127.51, 128.74,
130.09, 130.49, 130.91, 134.28, 135.21, 157.23, 160.09, 167.18; MS: m/z 484 (M?)
consistent with the molecular formula (C32H24N2O3).
1-Cycloalkyl-4-(4-methoxyphenyl)-2-oxo-6-pyren-1-yl-1,2-dihydropyridine-3-
carbonitrile 12a, b
General method: compound 8a (0.002 mol) and sodium hydride (0.002 mol) were
dissolved in anhydrous DMF (15 mL). After approximately 1 h of stirring, the
appropriate cyclo alkyl halides, namely cyclopentyl bromide and cyclohexyl
bromide (0.002 mol), were added, and the stirring was continued at room
temperature overnight. The mixture was evaporated to dryness under reduced
pressure. After dilution with water, the solution was extracted with dichloromethane
(3 9 100 mL). The combined extracts were evaporated to dryness in vacuo to give
the crude products which upon purification by column chromatography (pet. Ether/
methanol 9:1) afforded compounds 12a, b, respectively.
1-Cyclopentyl-4-(4-methoxyphenyl)-2-oxo-6-pyren-1-yl-1,2-dihydropyridin-3-
carbonitrile (12a)
Yield 65 %; m.p.[300 °C; 1HNMR (DMSO-d6) d: 1.20–1.84 (m, 8H, 4 CH2), 3.76
(m, 1H, CH), 3.89 (s, 3H, OCH3), 6.70 (s, 1H, CH), 6.73–8.12 (m, 13H, ArH); MS:
m/z 494 (M?) consistent with the molecular formula (C34H26N2O2).
1-Cyclohexyl-4-(4-methoxyphenyl)-2-oxo-6-pyren-1-yl-1,2-dihydropyridin-3-
carbonitrile (12b)
Yield49 %;m.p.[300 °C;1HNMR(DMSO-d6)d: 1.32–1.82 (m, 10H, 5 CH2),3.61(m,
1H, CH), 3.86 (s, 3H, OCH3), 6.34 (s, 1H, CH), 6.68–8.13 (m, 13H, ArH); 13CNMR
(DMSO-d6) d: 24.0, 27.98, 32.04, 56.19, 57.24, 105.02, 114.62, 115.38, 116.49, 123.81,
124.12, 124.21, 124.75, 125.10, 125.14, 125.39, 126.23, 126.95, 127.28, 127.30, 127.43,
127.51, 128.74, 130.09, 130.49, 130.91, 134.28, 135.41, 157.12, 161.37, 166.89; MS:m/
z 508 (M?) consistent with the molecular formula (C35H28N2O2).
1,2-Dihydro-1-(tetrahydro-2-oxofuran-3-yl)-4-(4-methoxyphenyl)-2-oxo-
6-(pyren-8-yl)pyridine-3-carbonitrile (13)
To a stirred solution of 8a (0.001 mol) in dry dimethylformamide (10 mL),
(0.001 mol) of a-bromo-c-butyrolactone and (0.001 mol) of anh. K2CO3 were
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N. M. Khalifa et al.
added. The reaction mixture was stirred at room temperature overnight and then
evaporated to dryness in vacuo. The residue was purified by silica gel column
chromatography (CH2Cl2/CH3OH) to afford the desired derivative 13 in yield 73 %;
1
m.p. 253–255 °C; HNMR (DMSO-d6) d: 2.29 (m, 2H, CH2), 3.86 (s, 3H, OCH3),
4.52 (t, 2H, CH2), 4.63(t, 1H, CH); 6.65 (s, 1H, CH), 6.72–8.12 (m, 13H, ArH); MS:
m/z 510 (M?) consistent with the molecular formula (C33H22N2O4).
Acknowledgment The authors thank the Deanship of Scientific Research at King Saud University for
funding through the research group project No. RGP-VPP-099.
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