Synthesis and characterization of some novel multisubstituted 6,7-Dihydro-5 H -cyclopenta[ b ]pyridine derivatives

Article abstract of DOI:10.1080/00397911.2013.840004

In this study, we describe systematic preparation of a series of aryl-substituted pyridine derivatives. The 1,5-dicarbonyls (3a-i) were prepared in the solvent-free conditions starting from chalcone derivatives (1a-i). The target compounds, 4-aryl-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]-pyridine derivatives (5a-i), were synthesized by a cyclization reaction of the 1,5-dicarbonyls (3a-i) with ammonium acetate (NH₄OAc) in acetic acid. The characterization of synthesized compounds was proved by elemental analyses, infrared, mass spectrometry, and ¹H and ¹³C NMR spectroscopy. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.840004

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Synthesis and Characterization of Some
Novel Multisubstituted 6,7-Dihydro-5H-
cyclopenta[b]pyridine Derivatives
Meliha Burcu Gürdere a , Burhan Yilmaz a & Yakup Budak a
a Department of Chemistry, Faculty of Arts and Sciences ,
Gaziosmanpasa University , Tokat , Turkey
Accepted author version posted online: 08 Nov 2013.Published
online: 24 Feb 2014.
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To cite this article: Meliha Burcu Gürdere , Burhan Yilmaz & Yakup Budak (2014) Synthesis and
Characterization of Some Novel Multisubstituted 6,7-Dihydro-5H-cyclopenta[b]pyridine Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:7, 981-986, DOI: 10.1080/00397911.2013.840004
To link to this article: http://dx.doi.org/10.1080/00397911.2013.840004
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Synthetic Communications1, 44: 981–986, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.840004
SYNTHESIS AND CHARACTERIZATION OF SOME
NOVEL MULTISUBSTITUTED 6,7-DIHYDRO-5H-
CYCLOPENTA[b]PYRIDINE DERIVATIVES
Meliha Burcu Gu¨rdere, Burhan Yilmaz, and Yakup Budak
Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa
University, Tokat, Turkey
GRAPHICAL ABSTRACT
Abstract In this study, we describe systematic preparation of a series of aryl-substituted
pyridine derivatives. The 1,5-dicarbonyls (3a–i) were prepared in the solvent-free con-
ditions starting from chalcone derivatives (1a–i). The target compounds, 4-aryl-2-
(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]-pyridine derivatives (5a–i), were synthe-
sized by a cyclization reaction of the 1,5-dicarbonyls (3a–i) with ammonium acetate
(NH4OAc) in acetic acid. The characterization of synthesized compounds was proved by
elemental analyses, infrared, mass spectrometry, and 1H and 13C NMR spectroscopy.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords 4-Aryl-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]-pyridine;
1,5-dicarbonyl
chalcone;
INTRODUCTION
Thiophenes[1–3] and pyridines[4] are among the most important five- and
six-membered heterocycles. Additionally, thiophene units are available in many com-
pounds of materials science.[5–7] In particular, the pyridine substructure, as organic elec-
tronic material,[8,9] is very common in biologically active and pharmaceutically relevant
compounds[10,11] as well as in building blocks used in supramolecular chemistry.[12–14]
Received July 26, 2013.
Address correspondence to Meliha Burcu Gurdere, Department of Chemistry, Faculty of Arts and
¨
Sciences, Gaziosmanpasa University, 60250 Tokat, Turkey. E-mail: burcugurdere@gmail.com
981

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M. B. GURDERE, B. YILMAZ, AND Y. BUDAK
982
The synthesis of highly substituted pyridines is of special interest because they
are partial structures of many natural products, pharmaceuticals, and organic func-
tional materials.[15] It has been reported in the literature that substituted pyridine
derivatives display antitumor activity, topoisomerase (topo) I and II inhibitory
activities, cytotoxicity, and antiasthmatic, antibacterial, antiinflammatory, and
antihypertensive properties.[16–20] Particularly, alkyl-substituted pyridines are widely
used in many fields including applied chemistry, polymer, and pharmacological
industries.[21] Also, the alkyl derivatives of pyridines are often by-products in many
industrial processes: as mixtures they are relatively cheap and effective enough to
protect the steel surface against acid corrosion.[22,23]
The aim of this study is to synthesize novel 4-aryl-2-(thiophen-3-yl)-6,
7-dihydro-5H-cyclopenta[b]pyridine derivatives (5a–i) through cyclization reactions
of 1,5-diketone derivatives (3a–i) with ammonium acetate in the presence of acetic
acid.
RESULTS AND DISCUSSION
The chalcone drivatives (1a–i) were easily synthesized according to our pre-
viously published procedure.[24,25] Then, the 1,4-Michael addition of cyclopentanone
(2) to the chalcone derivatives (1a–i) gave the 1,5-dicarbonyls (3a–i).[26,27] This
addition was performed in basic medium (KOH) in the presence of benzyltriethylam-
monium chloride at room temperature (Scheme 1). Addition of cyclopentanone (2)
Scheme 1. Synthesis of 1,5-dicarbonyls (3a–i) and 4- aryl-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]-
pyridine derivatives (5a–i).

6,7-DIHYDRO-5H-CYCLOPENTA[b]PYRIDINE
983
to the chalcone derivatives (1a–i) was performed in solvent-free conditions.
1,5-Dicarbonyl derivatives (3a–i) were obtained in good yields (in the range of
70–92%) (Table 1). The crude products were purified by chromatography or
crystallization, and their structures were elucidated by spectroscopic methods.
1
In the H NMR spectrum of 3a–i, the protons of PhCOCH2 gave an AB system
that is characteristic for these compounds. While the part A of the AB system is
shown as a doublet of doublets at d ¼ 3.42–3.20 (J ¼ 17.6–15.6 and 8.0–7.2 Hz),
part B is shown as a doublet of doublets at d ¼ 3.28–3.04 (J ¼ 17.6–15.4 and
7.6–6.8 Hz).
Finally, the 4-aryl-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine
derivatives (5a–i) were obtained by the cyclization reaction of 1,5-dicarbonyls (3a–
i) in the presence of ammonium acetate in acetic acid (Scheme 1). We think that
the oxidation occurred by effect of air oxygen. The structures of the synthesized
cyclization products (5a–i) were elucidated by the spectroscopic methods. In the
1H NMR spectrum of 5a–i, the H3 proton gave a singlet (between d ¼ 9.19 and
8.08 ppm) that is characteristic signals for these compounds. All spectral data con-
firm the proposed structures.
As a result, we have described a mild, efficient, and convenient method for the
synthesis of 4-aryl-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine deriva-
tives from cheap and easily available materials such as 1-(thiophen-3-yl)ethanone,
benzaldehyde derivatives, cyclopentanone, and ammonium acetate.
EXPERIMENTAL
All reagents were dried and distilled by standard procedures. Melting points
were measured on an Electrothermal 9100 apparatus. Infrared (IR) spectra (KCl
1
or liquid) were recorded on a Jasco FT=IR-430 spectrometer. H and 13C NMR
spectra were recorded on a Bruker Avance III 400 instrument. Internal standards tet-
ramethylsilane (TMS) (d 0.00) for 1H NMR and CDCl3 (d 77.0) for 13C NMR spec-
troscopy were used, and J values are given in hertz (Hz). The multiplicities of the
signals in the 1H NMR spectra are abbreviated by s (singlet), d (doublet), t (triplet),
q (quarted), p (pentuplet or quintuplet), m (multiplet), br (broad), and combinations
thereof. Elemental analyses were obtained from a Leco CHNS 932 Elemental
Analyzer.
General Procedure for the Synthesis of 1,5-Diketone Compounds
(3a–i)[24,25]
Benzyltriethylammonium chloride (6% mol) and KOH (6% mol) were added
to a mixture of chalcone derivatives (1a–i) (5 mmol) and cyclopetanone (2)
(20 mmol). The reaction mixture was magnetically stirred at room temperature
for 3–6 h. The crude product was dissolved with chloroform (10 mL), neutralized
by 2% HCl solution and extracted by chloroform (2 ꢀ 10 mL). The organic layer
was dried over Na2SO4, and the solvent was removed in a vacuum. The raw pro-
duct was purified by crystallization from CHCl3=n-hexane (1:4) and=or CCl4=n-
hexane (2:3).

¨
M. B. GURDERE, B. YILMAZ, AND Y. BUDAK
984
Table 1. Synthesized compounds 3a–i and 5a–i
Melting point
(ꢁC) and yield
(%)
Melting point
(ꢁC) and yield
(%)
Reactant
Product 3a–i
Product 5a–i
108–111, 85
102–105, 92
113–116, 86
115–117, 80
130–133, 95
Viscous oil, 89
Viscous oil, 81
136–139, 92
129–133, 72
120–122, 80
Viscous oil, 88
Viscous oil, 86
89–92, 85
128–130, 79
Viscous oil, 70
Viscous oil, 88
108–112, 93
Viscous oil, 84

6,7-DIHYDRO-5H-CYCLOPENTA[b]PYRIDINE
985
General Procedure for the Synthesis of 4-Aryl-2-(thiophen-3-yl)-6,7-
dihydro-5H-cyclopenta[b]pyridine Derivatives (5a–i)[26,27]
Ammonium acetate (NH4OAc) (4.5 mmol) was added to a solution of
1,5-dicarbonyls (3a–i) (1.5 mmol) in 25 mL of acetic acid and refluxed in open system
for 2–6 h. Then, the acetic acid was removed under reduced pressure; the crude pro-
duct was extracted by chloroform (3 ꢀ 10 mL) and dried over Na2SO4. After removal
of the solvent, the crude product was purified on a silica-gel column eluting with
CH2Cl2=n-hexane (1:3) and=or crystallized from CHCl3=n-hexane (1:2).
FUNDING
This investigation was partially supported by Scientific Research Grant BAP=
2011-38, awarded by Gaziosmanpasa University.
SUPPORTING INFORMATION
Full spectral data and melting points can be found via the ‘‘Supplementary
Content’’ section of this article’s Web page.
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