Regioselective synthesis of functionalized [1,6]-naphthyridines by KF/basic alumina as a recyclable catalyst and a brief study of their photophysical properties

Article abstract of DOI:10.1080/00397911.2016.1209778

An efficient, one-pot, solvent-free, regioselective synthesis of functionalized [1,6]-naphthyridines was explored by a heterogeneous catalyst via a three-component multicomponent reaction (MCR). KF/basic alumina–catalyzed double heteroannulation of aryl a

Full text of DOI:10.1080/00397911.2016.1209778

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Regioselective Synthesis of Functionalized
[1,6] Naphthyridines by KF/Basic Alumina as a
Recyclable Catalyst and a Brief Study of Their
Photophysical Properties
Sibaji Nandi, Mullah Muhaiminul Islam, Mithu Saha, Sivaprasad Mitra,
Snehadrinarayan Khatua & Amarta Kumar Pal
To cite this article: Sibaji Nandi, Mullah Muhaiminul Islam, Mithu Saha, Sivaprasad
Mitra, Snehadrinarayan Khatua & Amarta Kumar Pal (2016): Regioselective Synthesis
of Functionalized [1,6] Naphthyridines by KF/Basic Alumina as a Recyclable Catalyst
and a Brief Study of Their Photophysical Properties, Synthetic Communications, DOI:
10.1080/00397911.2016.1209778
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1209778
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Date: 23 July 2016, At: 00:08

Regioselective synthesis of functionalized [1,6] naphthyridines by KF/basic alumina
as a recyclable catalyst and a brief study of their photophysical properties
Sibaji Nandi1, Mullah Muhaiminul Islam1, Mithu Saha2, Sivaprasad Mitra1,
Snehadrinarayan Khatua1, Amarta Kumar Pal1
1Centre for Advance Studies in Chemistry, North-Eastern Hill University, Shillong, India
2State Key Laboratory of Physical Chemistry for Solid Surfaces, College of Chemistry,
and Chemical Engineering, Xiamen University, China
Corresponding author Amarta Kumar Pal Centre for Advance Studies in Chemistry,
North-Eastern Hill University, Mawlai Campus, Shillong 793022, India E-mail:
amartya_pal22@yahoo.com; akpal@nehu.ac.in
Abstract
An efficient, one pot, solvent free, regioselective synthesis of functionalized [1,6]-
naphthyridines was explored by a heterogeneous catalyst via a three component MCR.
KF/basic alumina catalyzed double heteroannulation of aryl alkyl ketones, malononitrile
and alkyl amines generates the said compounds with high appendage diversity
combinatorially via Knoevenagel condensation followed by Michael addition and
cyclisation pathway. Short reaction time, high yield, simple reaction technique and
recoverability and reusability of the catalyst without compromising the yield and purity
of the compounds are the salient features of this methodology. Additionally, these
compounds exhibit promising photophysical properties.
Graphical Abstract
1

KEYWORDS: Functionalized[1,6]-naphthyridine; Photophysical study; KF/ basic
alumina; Solvent-free; Regioselective
1. INTRODUCTION
Heterocycles are very important in terms of biological activity. Taking into account their
ubiquitous presence in natural products and drugs, the development of new, fast and
efficient preparative protocols for these structures remain an urgent task in organic
synthesis. Several approaches which allow the construction of complex heterocyclic
compounds from simple starting materials have been investigated. MCR is one of the
most promising routes for the construction of heterocycles. Thus most academic chemists
have renewed their interest in MCR for the construction of biologically relevant or
natural product-like molecular frameworks. There are many examples of known MCRs
suffering from several drawbacks. Thus development of a methodology of a known MCR
is always promising. We were interested in applying logic-based approaches, as a way
both to improve a known MCR and design new efficient methodology of a known
multiple-component reaction to bioactive structures.
One important type of “privileged structure” in drug discovery are [1,6]-naphthyridine
derivatives, which are nitrogen containing heterocycles that contain two fused pyridine
rings[1]. Functionalized [1,6]-naphthyridines shows important biological activities such
as antiprofileative activity,[2] anticancer activity,[3-5] selective antagonists activity of 5-ht4
receptors.[6] Also, compounds having [1,6]-naphthyridine moieties are paramount interest
2

since they shows HCMV inhibitory as well as (Fig. 1-a)[7] ,allosteric inhibitory properties
(Fig. 1-b).[7] Furthermore, these compounds act as a PKD inhibitor in vitro cells and in
vivo cells following oral administration.[4- 8] Only few reports are there for the
construction of this moiety via MCRs using malononitrile as a starting material [9-12] Most
of the reported processes involve several multistep sequences [13-17]
.
In the most of the chemical processes catalyst plays a prime role. Catalyst can be
generally divided into two branches, homogeneous catalyst and heterogeneous catalyst.
In a homogeneous catalytic system, both the active catalytic site and the reactants are in
the same phase. This catalytic system allows easier interaction between the components,
which leads to better yield. Heterogenation can be achieved by entrapment of the active
molecules on the surface or inside the pore of the solid support like alumina, silica etc. A
catalyst system that not only shows high activity and selectivity like a homogeneous
system but also possesses properties of heterogeneous catalyst like easy separation and
reusability is highly desirable. In this solvent free methodology the reactant and the
catalyst are in the same phase as both of the system is solid thus the catalyst shows the
desirable attribute of both homogeneous and heterogeneous catalyst. Organic reactions
promoted on heterogeneous surfaces are advantageous because of operational simplicity,
high selectivity, clean and easy separation of the product as well as recycling of the
catalyst.[18,19] The basic sites on KF/alumina may be related to a very hard anion (F-
anion), which possibly due to the surface to be active as a potential base.[20] The
KF/alumina catalyzed reactions are in many cases carried out without using any solvent,
thus providing a clean and “green” reaction set up followed by easy product isolation.[21]
3

Several methods have been developed for the preparation of naphthyridine derivatives.
Most of these methods involve multistep sequences, [22, 23] or use of expensive catalysts,
[24,25] or inert atmosphere [26]. Moreover some of the reported methods requires laborious
workup [27,28] and long reaction time.[1, 28, 29, 30, 31] . Khan et et al reported the synthesis of
functionalized [1,6]-naphthyridine derivatives using a combination of either aryl methyl
ketones or alkyl methyl ketones, malononitrile, and either alcohols or thiols, in the
presence of sodium hydroxide as a base and ethanol as a solvent with prolonged heating
for 7-10 hrs.[30] Mukhopadhaya et al reported the synthesis of the similar compounds
using triethyl amine as a base where time required was 1-4 hrs [31]. Earlier the same group
reported a promising on-water synthesis of the similar functionalized [1,6]-
naphthyridines from aryl alkyl ketones, malononitrile and different non-aromatic bases in
the absence of any catalysts where time required for this conversion was 3 hrs.[28]
Inspired by their work we came to realize there is still a wide scope to develop a new
methodology of the said compounds promoted by a suitable catalyst.
This is the first report of the synthesis of a library of compounds containing highly
substituted functionalized [1,6]-naphthyridine moiety catalyzed by KF/basic alumina as a
heterogeneous catalyst, between different aryl alkyl ketones 1(a-d), malononitrile (2) and
various non-aromatic amines 3(a-e) (Scheme 1) under solvent free neat condition in a
single operation. All the reactions take place smoothly within 15-75 min, with an
additional advantage of recoverability and recyclability of the catalyst. Our methodology
is promising as it eliminates the wastage of solvent, formation of side product and
4

additionally short reaction time making it overall green, sustainable and industrially
attractive To the best of our knowledge, fused polycyclic compounds especially the fused
heterocycles shows efficient luminescence. Naphthyridine derivatives were used as
luminescence materials in molecular recognition because of their rigid planar structure.[30,
31-38] We therefore screened the fluorescence properties of our synthesized functionalized
[1,6]- naphthyridine derivatives [4a-4p] which exhibit strong fluorescence in DMSO and
Chloroform.
2. RESULT AND DISCUSSION
Keeping the biological importance of [1,6]-naphthyridines in mind and in continuation
of our quest for developing green protocols [39-42] we set up a preliminary experiment for
the synthesis of the said compounds [4a-4p] with a mixture of acetophenone (2 mmol),
malononitrile (2 mmol) and N, N-diethylamine (1 mmol) under solvent free condition
(Scheme 1). The reaction mixture was heated at 100o C under conventional heating
without presence of any catalyst and progress of the reaction was monitored by TLC (thin
Layer chromatography). To our disappointment we found that the reaction did not
proceed even after ½ h of heating. We further increased our course of reaction time and
observed that the reaction proceeded sluggishly and isolated 17% yield of the desired
product after a 1h of heating. This result inspired us to use a catalyst. It was well known
to us that Potassium fluoride impregnated over aluminum oxide (KF/alumina) has been
recognized as remarkably useful heterogeneous catalyst to promote many base-catalyzed
organic transformations. A closer look of the literature reveals that KF/ alumina has been
used in a diverse range of solvent free reaction involving steps like condensation,
5

addition and elimination reactions e.g aldol condensation,[43-45] Knoevenagel
condensation,[46-48] Michael addition,[49-51] hetero Michael reaction,[52] Rap-Stoermer
Condensation,[53] elimination reactions [54-58]and last but not the least is several one pot
MCR [59-62] reactions. There are examples where the Knoevenagel condensation, Michael
addition and cyclodehydration have taken place consecutively in one pot catalyzed by
KF/alumina.[48] Therefore we choose KF/basic alumina as the catalyst of choice and
utilized it in our model reaction under solvent free condition.
To our enchantment we got the naphthyridine moiety when a mixture of acetophenone (2
mmol), malononitrile (2 mmol) and N,N diethylamine (1 mmol) was heated at 100o C.
The combination of solvent free condition and KF/ basic alumina results in
unprecedented coupling of the three component MCR reaction within a time period of ½
h of heating under neat condition giving the products in an excellent yield (92%) (Table
1). Several other catalysts were screened to compare their efficiency with KF/basic
alumina like basic alumina, Silica and combination of KF/ neutral alumina. Apart from
these catalysts, we also used a bunch of other catalysts like KF, iodine and molecular
sieves. Interestingly we found that all of these screened catalysts can also catalyzed the
reaction but none of them can be compared with the unparalleled results obtained when
we used the combination of both KF/basic alumina (Table 1) to generate the
naphthyridine moiety showing its superiority as a strikingly efficient, inexpensive,
nontoxic, green catalyst, surpassing its homogeneous counterpart. It was also found that
the catalyst shows enhanced activity compare to their single use. The synergistic effect of
both KF and basic alumina as a catalyst is nicely observed and a probable mechanism has
6

been proposed which highlight that how they are complement of each other for their
enhanced activity compare to their independent use for this particular model reaction.
To confirm the structure another model reaction was set up with 4-chloroacetophenone (2
mmol), malononitrile (2 mmol), morpholine (1 mmol) and KF/basic alumina. The desired
product was purified through column chromatography and the compound was identified
by the analysis of analytical and spectral data. Finally the structure of the compound was
confirmed through single crystal X-ray diffraction analysis (Figure 2)
The reaction was carried out using 10 mol% of catalyst under solvent free condition at
100oC temp with a a mixture of acetophenone (2 mmol), malononitrile (2 mmol) and N,N
diethylamine (1 mmol) Optimization of solvent effect using 10 mol% of KF/basic
alumina using mixture of acetophenone (2 mmol), malononitrile (2 mmol) and N,N
diethylamine (1 mmol) under refluxing condition.
In our effort to see the solvent effect, we have used various solvents such as THF,
chloroform, ethylacetate, methanol, acetonitrile in the presence of KF/basic alumina. It
was of note that in THF and chloroform the reaction takes place slowly with the
formation of the desired product in low yield whereas methanol, ethyl acetate and
acetonitrile gave the desired product at moderate yield (Table 2) but the best result was
obtained under solvent free condition in presence of 10 mol% of the catalyst. Lower
catalyst concentration producing lower yield but higher catalyst concentration (>10mol
%) did produce any significant improvement of the product yield (Chart 1). This
7

optimum concentration of the catalyst was investigated by five experimental reaction for
each four set of reaction with 5, 10, 15, and 20 mol % of catalyst loading successively
and the mean yield for this four set of run was found to be 88.6, 91.6, 91.6, and 91.8
respectively where error bars were reported by using standard deviation method (Chart
1).
The reusability of our heterogeneous catalyst was also explored. KF/basic alumina was
easily separated from the reaction mixture by simple dissolving the reaction mixture in
chloroform followed by filtration. The catalyst was washed successively with chloroform
and acetone unless no reactant remains in the catalyst followed by drying it in an oven at
60o C. It was then used for further reaction and to our delight we found that the catalyst
can be used for five successive runs without any further decrease in the product yield.
This reusability of the reaction was investigated by performing five experimental
reactions for each set under the same reaction condition. The recovered catalyst was used
for the reproducibility of the reaction to calculate the mean yield for each set of reactions
under same condition (89.6, 88.6, 88.0, 86.6, and 84.2) and the error bars were reported
by using standard deviation method (Chart 2).
Reusability of the catalyst was performed with 10 mol% of KF/basic alumina under
refluxing condition using a mixture of acetophenone (2 mmol), malononitrile (2 mmol)
and N,N-diethylamine (1 mmol) To further expand the scope of the reaction, we
investigated the present protocol with various substituted ketones (1a-e) and amines 3(a-
e). It was observed that, all the reaction proceeded smoothly and desired products were
8

obtained in excellent to good yields (Table 3). The electron withdrawing or donating
group in aryl alkyl ketones have no effect in product yields (Table 3).
The basicity of KF/basic alumina is explained in the light of very hard anion (F– ion)
where 19F NMR and IR spectroscopic measurements have already shown that F– species
in KF/ Al2O3 is more electron-rich than F– ions in solid potassium fluoride [20, 21].We also
found that the reaction was efficiently catalyzed by KF / basic alumina compare to their
single use. (Table 1). But we came to realize that the increased basicity is not only the
key reason for this dramatic rate enhancement in this model reaction. Apart from the
stronger basicity of KF/ basic alumina compare to sole KF, the synergistic effect of
combined KF and basic alumina is shown in the mechanism which may probably explain
the exclusive rate enhancement of this model reaction by this catalyst compare to their
solitary use and most probably due to this combination they are complement of each
other for their enhanced catalytic activity than the lone one and catalyse this model
reaction dramatically which is pictorially depicted in this mechanism.
Mechanism: Plausible mechanism for this transformation reaction is shown in Scheme 2.
We supposed that the reaction proceeded through Knoevenagel condensation followed by
Michael addition and cyclisation path way [1,28,30,31]. First, intermolecular Knoevenagel
condensation of aryl alkyl ketones with malononitrile generates intermediate 5. Al+3
coordinate with the Knoevenagel Adduct (5) which in turn results for the increased
acidity of methyl and imine hydrogens followed by faster elimination of these hydrogens
by F- ions accelerating the Michael addition to generate intermediate 6. Malonontrile
9

induced-intramolecular cyclization of 6 (felicitate by F- ions) gives another intermediate
7. Finally base 3 induced cyclization of 7 furnished double hetero-annulation to generate
the final products 4.
3. PHOTOPHYSICAL PROPERTIES
It is well known that highly planer, conjugated fused polycylic heterocycles shows
efficient luminescence properties. We observe that our compounds show bright UV
active blue spot in TLC plate. Therefore we studied the photophysical behavior of the
synthesized systems in two representative solvents, viz. chloroform and DMSO The
steady state spectral properties of the synthesized selective compounds in two
representative solvents like chloroform and DMSO are given in Table S1 ( supplementary
information). For all the compounds, in DMSO, there was an intense, broad absorption
peak centred at around 325 nm, while in chloroform the peak appears in the range of 275-
325 nm (Figure 3). From the large value of the molar absorptivity (εmax ~ 2.0 ×104 M-
1cm-1), it can be concluded that this transition is mainly π* ← π in nature [63]. Excitation
at the absorption maximum, in case of DMSO, all the compounds give fluorescence
emission peak in the range of 375-475 nm, with a peak position at 420 ± 15 nm.
However, in chloroform, the fluorescence emission peak was largely blue shifted and
appear with 330-420 nm spectral range. The large spectral shift in polar DMSO solvent,
while comparing with relatively less polar chloroform, indicates that the excited state of
the probe molecules are stabilized to a large extent with increasing polarity of the
medium. A closer look into the emission spectral profile reveals that the emission peak
maximum of the synthesized compounds in DMSO show excellent correlation with the
10

nature of substituent at the para position of the phenyl ring present at 2 and 4 position and
shifts toward the red side of the spectrum with increasing electron withdrawing group
(Figure 4). For example, the emission maximum appears at 410 nm for the p-methyl
substitution of the phenyl ring (compound 4k, 4l and 4m), whereas, the un-substituted
system (compound 4b, 4c and 4d) emits at 418 nm. On the other hand, the fluorescence
peaks for the p-bromo (compound 4n and 4o) and p-chloro (compound 4i) substitution of
the phenyl ring appear at 424 nm and 437 nm, respectively. However, in chloroform, the
emission peak can be divided only into two groups, one centred at around 395 nm for the
compounds with p-methyl substitution of the phenyl ring with N-cyclohexylamine and
N,N-dimethylamine groups at position 7 (compounds 4l and 4m) and un-substituted
phenyl ring [compound 4b, 4c and 4d] and other is a cluster of band in between 325 to
360 nm for all other compounds (Figure 4). The excitation spectrum of all the compounds
also resembles the absorption spectra with 10~15 nm red shifted only in case of DMSO
(Figure 5)
Table S1
(supplementary information), was observed for the compounds with amine group at
position 7 (entry 3, 4, 6, 7, 9 in Table S1) than for the compounds with morpholine ring at
the same position (entry 1, 2, 5, 8 in Table S1, supplementary information). Except for
the compound with bromo substitution of the phenyl ring with dimethyl amine group
[compound 4o], the fluorescence yield of all the compounds in DMSO is much larger
than in chloroform. Very low fluorescence quantum yield for p-bromo substitution of the
phenyl ring, even in DMSO might be due to the heavy atom effect.
11

Fluorescence quantum yields ( ) were calculated by comparing the total fluorescence
intensity (F) under the whole fluorescence spectral range with that of p-(dimethylamino)
cinnamic acid (DMACA) in water (
= 0.002) [64]
.
Ai
2
Fi
Fs
ni
ns
1 10
i
f
s
f
As
1 10
Where, Ai and As are the optical density of the sample and standard, respectively, and ni
is the refractive index of solvent at 293 K. The relative experimental error of the
measured quantum yield was estimated within ±10%
4. CONCLUSION
In conclusion we have synthesized a library of functionalized [1,6] naphthyridines
catalyzed by highly efficient KF/ basic alumina as a pseudo-heterogeneous catalyst
through an one-pot three component double hetero annulation reaction under solvent free
reaction condition and also investigated their phtophysical properties. The compounds
were generated with high appendage diversity combinatorially. The features of this
procedure are mild condition, short reaction time, high yields, operational simplicity and
environmental friendliness. We reduced the reaction time from the earlier report of
several hours to several minute labels. The recoverability and reusability of the catalyst
without compromising the yield and purity of the synthesized compounds is one of the
salient features of this methodology. We also found that the single use of KF and basic
alumina is less effective compare to the dramatic rate enhancement by KF/basic alumina
for this model reaction making it mutually exclusive. The photophysical behavior of the
synthesized systems was studied in two representative solvents, viz. chloroform and
12

DMSO. From the large value of the molar absorptivity it can be concluded that the
transition is mainly π* ← π in nature The large shift in emission maximum as well as the
high value of fluorescence quantum yield in polar medium point toward potential use of
the synthesized systems as fluorescence based polarity sensors.
5. EXPERIMENTAL
General Procedure For The Synthesis Of Functionalized [1,6] Naphthyridine
Derivatives.
A mixture of aryl alkyl ketones (2 mmol), malononitrile (2 mmol) and nonaromatic
amine (1 mmol) was taken in a 10 ml RB followed by addition of 10 mol% KF/ basic
alumina. The resulting magnetically stirred mixture was heated in the RB at 100o C
for15-75 mins until the TLC showed the disappearance of starting materials. On
completion, the reaction mass was cooled at room temperature, dissolve in chloroform
and the catalyst was filtered through a simple filtration. The product was extracted with
choloroform (3 × 5 mL), washed with water (3 × 5 mL), brine solution and dried over
anhydrous sodium sulphate. The solvent was removed under high vacuum and the
residual was purified by column chromatography using ethyl acetate and hexane as
eluent. The washed catalyst was dried in a oven and was reused for another set of same
reaction.
Materials And Methods
Melting points were determined in open capillary and uncorrected. IR spectra were
recorded on Spectrum BX FT-IR, Perkin Elmer (υmax in cm-1) on KBr disks. 1H NMR and
13

13C NMR (400 MHz and 100 MHz respectively) spectra were recorded on Bruker
Avance II-400 spectrometer. Mass spectra were recorded on Waters 2695. CHN were
recorded on CHN-OS analyzer (Perkin Elmer 2400, Series II). Silica gel G (E-mark,
India) was used for TLC. Hexane refers to the fraction boiling between 60 and 80οC
X-Ray Specification
The X-ray data of (4g, Figure 2) was collected at 293 K with a Agilent Xcalibur (Eos,
Gemini) diffractometer using graphite-monochromated Mo-Kα radiation (λ = 0.71073
Å). The data was collected and reduced in CrysAlis PRO (Agilent, 2011) [65] software and
cell refinement was done in CrysAlis PRO software. The absorption was corrected by
SCALE3 ABSPACK multi-scan method in CrysAlisPro. The structures were solved by
direct methods using the program SHELXS-97 [66] and refined by full matrix least-
squares calculations (F2) by using the SHELXL-20131 [66] software. All non-H atoms
were refined anisotropically against F2 for all reflections. All hydrogen atoms were
placed at their calculated positions and refined isotropically [67]. Crystal data collection
and refinement details for 4g is given in supplementary information. The *.cif file was
deposited with the Cambridge Crystallographic Data Centre and the following code was
allocated: CCDC-1012535. These data can be obtained free of charge via the Internet:
www.ccdc.cam.ac.uk/data_request/cif
Specification For Fluorescence Experiment
The organic solvents chloroform and dimethylsulfoxide (DMSO), used for the
photophysical characterization, were of spectroscopic grade (>99.5%) as received from
14

Alfa Aesar. Sample concentration (~10 μM ) was kept sufficiently dilute to avoid any
effect from aggregation and/or inner filter effect. Steady state absorption and
fluorescence emission/excitation spectra were recorded in Lambda25 and LS-55 (both
from PerkinElmer Inc.) spectrometers, respectively. Quartz cuvettes of 10 mm optical
path length received from PerkinElmer, USA (part no. B0831009) and Hellma, Germany
(type 111-QS) were used for measuring absorption and fluorescence spectra, respectively.
The sample was excited at the respective absorption maximum for scanning the
fluorescence emission spectrum; whereas, the fluorescence excitation spectra were
scanned by monitoring at the respective emission maxima. In all the cases, 5 nm band
pass was used in both the excitation and emission side.
ACKNOWLEDGEMENTS
We thanks to Department of Chemistry, North Eastern Hill University, SAIF, NEHU for
providing necessary facilities and spectral data respectively. We also thank New Delhi
for supporting this work under Special Assistance Program. We are also thankful to DST
for financial support (sanctioned no: SERC/F/0293/2012-13). We are thankful to NEHU
Non-Net fellowship for providing the fellowship.
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21

Table 1. Catalyst screening for the synthesis of (4e)
Entry Catalyst
Yield (%)
1.
2.
3.
4.
5.
6.
7.
Basic Alumina
28
20
77
92
45
KF
KF/Nutral Alumina
KF/basic alumina
Silica
Molecular sieves(4 Ao) 10
Iodine 25
22

Table 2. Solvent effect for the synthesis of (4e)
Entry Solvent
Yield
38
1.
2.
3.
4.
5.
THF
Chloroform 48
Ethylacetate 57
Methanol
69
Acetonitrile 72
23

Table 3. Synthesis of functionalized [1,6]-naphthyridines [4a-4p]
Entry Ketones
Amines
Product
Yield (%)
1.
88
2.
3.
90
74
3(b)
4.
5.
82
92
24

6.
7.
8.
86
90
75
9.
91
87
10.
25

11.
12.
13.
91
76
82
14.
15.
88
80
26

16.
90
27

Scheme 1.
28

Scheme 2.
29