Green synthesis of highly substituted pyridines via the one-pot multi-component reaction in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1016/j.molliq.2014.07.012

Highly substituted pyridine derivatives are synthesized from both electron-deficient and electron-rich substrates in a fast, high yielding, and operationally simple protocol in 2,2,2-trifluoroethanol (TFE). The solvent (TFE) can be readily separated from

Full text of DOI:10.1016/j.molliq.2014.07.012

Journal of Molecular Liquids 198 (2014) 263–266
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Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Green synthesis of highly substituted pyridines via the one-pot
multi-component reaction in 2,2,2-trifluoroethanol
⁎
Mehdi Daryabari, Samad Khaksar
Chemistry Department, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2014
Received in revised form 25 June 2014
Accepted 12 July 2014
Available online 27 July 2014
Highly substituted pyridine derivatives are synthesized from both electron-deficient and electron-rich substrates
in a fast, high yielding, and operationally simple protocol in 2,2,2-trifluoroethanol (TFE). The solvent (TFE) can be
readily separated from reaction products and reused in several reactions without any noticeable loss of activity.
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Heterocycle
Multicomponent
Fluorinated alcohols
Reusable
Green chemistry
1. Introduction
an elegant synthesis of indenopyridines from various aldehyde, 1,3-
indandione, 2-acetylthiophene or 2-acetylfluorene and ammonium
Pyridine derivatives have become increasingly important in the past
few years because they are widely found in natural products with biolog-
ical activity [1]. They have also found in many active pharmaceuticals and
functional materials [2–4]. Among these compounds, indenopyridines
(azafluorenes) have been reported to possess cytotoxic [5], phosphodies-
terase inhibitory [6], adenosine A2a receptor antagonistic [7], anti-
inflammatory/anti-allergic [8], coronary dilating [9] and calcium
modulating activities [10]. They can cure the hyperlipoproteinemia and
arteriosclerosis [11] as well as neurodegenerative diseases [12]. Several
compounds of this type act as calcium antagonistic activators and
herbicides [13]. Considering the above reports, the development of new
synthetic methodologies for the construction of indenopyridine scaffolds
is a beneficial and interesting challenge.
Researchers recently have developed several alternate and more ef-
ficient methods for the construction of this kind of fused heterocycles
from suitable precursors [14–22]. Some new methods are available in
the literature for the synthesis of these indenopyridine compounds
from aldehydes, dimedone, and different anilines or ammonium acetate
via the condensation of a aldehydes, 1,3-indandione or 1-indenone and
aromatic ketones in the presence of ammonium acetate under micro-
wave irradiation [23,24], by Pummerer reaction of imidosulfoxides
[25], and Pd(0)-catalyzed cross-coupling reaction between arylboronic
acids and 2-halopyridines [26]. In 2010, Mukhopadhyay et al. reported
acetate using L-proline as a catalyst [27]. Recently, Alinezhad et al.
have described an efficient method for the synthesis of substituted
indenopyridines using aldehydes, 1,3‐indandione, aromatic ketones,
and ammonium acetate in the presence of Cu‐doped ZnO nanocrystal-
line powder [28]. These methods show varying degrees of successes as
well as limitations, such as multistep reaction processes, harsh reaction
conditions, expensive reagents, cumbersome product isolation proce-
dures, lower product yields, metal catalysts as well as more than
stoichiometric amount of reagents. Therefore, a simple and efficient
method for indenopyridine synthesis remains an attractive goal. In re-
cent years, fluorinated alcohols have been introduced as new alternative
sustainable solvents for organic transformations [29–31]. These sol-
vents have been applied to oxidation reactions [32–38], aza-Diels–
Alder [39], Hantzsch reaction [40], and Ferrier reaction [41]. The synthe-
sis of pyrazoles [42], quinolines [43,44], and 2,3-dihydro-4(1H)-
quinazolinones [45], has been reported by using 2,2,2-trifluoroethanol
(TFE) and Hexafluoro-2-propanol (HFIP) as solvents. The peculiar
physical and chemical properties of fluorinated alcohols, such as low
nucleophilicity, high polarity, strong hydrogen bond donating ability
and ability to solvate water, prompted us to extend their use as green
solvents in organic synthesis. As part of our ongoing programme to de-
velop highly efficient and environmentally benign synthetic processes
[46–50], we turned our attention toward the four-component conden-
sation of 1,3-indanedione, aldehyde, aromatic ketones and ammonium
acetate in TFE as solvent. Herein, we describe a novel, efficient, and
green procedure for the synthesis of indeno[1,2-b]pyridine derivative
5 via the four-component condensation (Scheme 1).
⁎
Corresponding author. Fax: +98 121 2517043.
E-mail address: S.khaksar@iauamol.ac.ir (S. Khaksar).
http://dx.doi.org/10.1016/j.molliq.2014.07.012
0167-7322/© 2014 Elsevier B.V. All rights reserved.

264
M. Daryabari, S. Khaksar / Journal of Molecular Liquids 198 (2014) 263–266
Scheme 1. Synthesis of highly substituted pyridines in TFE.
2. Experimental
3. Results and discussion
2.1. Apparatus and analysis
Initially, we carried out the four-component condensation of
4-chlorobenzaldehyde (1 mmol), 1,3-indanedione (1 mmol),
acetophenone (1 mmol), and ammonium acetate (1.3 mmol) in
trifluoroethanol at room temperature. After 24 h, only 60% of product
5a was obtained after recrystallization of the crude product from
ethanol. Much to our surprise, when we carried out the reaction in
trifluoroethanol at 80 °C, the corresponding indeno[1,2-b]pyridine de-
rivative 5a (Table 1, entry 1) was obtained in high yield (95%) after 2 h.
The scope and generality of this four-component condensation were
examined in more detail. Both the electron-rich and -deficient
aldehydes worked well leading to good yields of product 5.
NMR spectra were determined on an FT-NMR Bruker AV-400
spectrometer in CDCl3 and are expressed in δ values relative to
tetramethylsilane; coupling constants (J) are measured in Hertz.
Melting points were determined on an Electrothermal 9100 appara-
tus. Infrared spectra were recorded on a Rayleigh WQF-510 Fourier
transform instrument. Commercially available reagents were used
throughout without further purification.
2.2. Typical experimental procedure
Aromatic aldehydes with several functionalities such as Cl, F, Me,
OMe, and NO2 were found to be compatible under the optimized reac-
tion condition. The electronic effect seemed to have a slight influence
on the reaction since either the electron-withdrawing or the electron-
donating groups on the different aromatic ring resulted in the hardly
discriminate yields. In the case of ortho-substituted aldehydes the
reaction time was longer and yields were somewhat lower than other
aldehydes which were probably attributed to the steric hindrance
(Table 1, entry 6). Satisfactorily, the reactions displayed high functional
group tolerance and afforded the corresponding indenopyridines with
great efficiency. To expand the scope of carbonyl substrates,
propiophenone and acetophenone derivatives were applied to this pro-
tocol. In all cases, the desired reactions took place successfully to afford a
series of indeno[1,2-b]pyridin-5-one (5b–o) in good yields (Table 1).
The structure of the products (5a–o) was established from their IR
spectral data and comparison of their melting points with those of au-
thentic samples. Also, the structure of some products was confirmed
by 1H NMR and 13C NMR spectral data. Interestingly, the reaction did
not proceed to completion when either ethanol or water alone was
used as solvent.
A mixture of aldehyde (1 mmol), 1,3-indanedione (1 mmol),
acetophenone (1 mmol), and ammonium acetate (1.5 mmol) was
stirred in TFE (2 mL) at 80 °C for the stipulated time. The progress of
the reaction is monitored by TLC. After completion of the reaction, the
corresponding solid product 5 was obtained through simple filtering,
and recrystallized from hot ethanol affording the highly pure indeno
[1,2-b]pyridine derivatives. The physical data (mp, IR, NMR) of known
compounds were found to be identical with those reported in the liter-
ature [23]. Spectroscopic data for selected examples are shown below.
4-(4-Chlorophenyl)-2-phenyl-indeno[1,2-b]pyridin-5-one (Table 1,
entry 1), solid, mp 187–189 °C; IR (KBr): 3072, 1715, 1560, 1521,
1345 cm−1 1H NMR (400 MHz, CDCl3) δ: 7.15 (s, 1H), 7.23–7.73 (m,
.
11H), 7.93–8.2 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 111.2, 117.5,
121.7, 123.8, 128.3, 128.9, 129.3, 129.7, 129.5, 131.3, 134.2, 135.1,
137.4, 140.1, 141.9, 143.1, 145.1, 147.4, 162.5, 194.1.
3-Methyl-4-(4-nitrophenyl)-2-phenyl-indeno[1,2-b]pyridin-5-one
(Table 1, entry 10), solid, mp 248–250 °C; IR (KBr): 3070, 1717, 1560,
1520, 1347 cm−1 1H NMR (400 MHz, CDCl3) δ: 2.06 (s, 3H), 7.40
.
(t, J = 7.6 Hz, 1H), 7.43–7.73 (m, 9H), 7.93 (d, J = 7.2 Hz, 1H), 8.35
(d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 17.6, 121.2, 123.5,
123.7, 123.8, 128.3, 128.9, 129.2, 129.4, 129.5, 131.3, 135.2, 135.5,
140.1, 141.9, 142.8, 146.9, 147.6, 162.5, 163.8, 192.1.
A plausible mechanism for the formation of indeno[1,2-b]pyridines
is shown in Scheme 2.
In this process, TFE can increase the electrophilic character of the
electrophiles by virtue of its inherent Brønsted acidity which makes it
capable of bonding with the carbonyl oxygen [51]. Moreover, the
polar transition state of the reaction could be stabilized well by the
high ionizing solvent TFE. Whereas, the hydrogen bond donating ability
of these solvents drops as temperature rises owing to the fact that
hydrogen-bond formation is exothermic, this ability has a slight influ-
ence on the reaction [52,53].
Table 1
Synthesis of 5H-indeno[1,2-b]pyridin-5-ones in TFE.
Entry
R1
R2
R3
Product
Yield (%)
mp °Cref
1
2
3
4
5
6
7
8
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-F-C6H4
3-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
C6H5
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
95
92
90
88
85
92 (3 h)
95
88
95
90
90
85
90
92
92
187–18924
201–20229
214–21629
223–22524
227–22924
265–26624
193–19424
220–22124
203–20523
248–25023
222–22523
221–22324
162–16429
213–21529
225–22724
A possible mechanism for this reaction is shown in Scheme 2. A pro-
ton from TFE is donated to the oxygen atom of the aldehyde. Next, the
carbonyl carbon is attacked by the nucleophilic 1,3-indanedione to
form intermediate I. The second key intermediate is enamine II, which
formed from acetophenone and ammonium acetate. Condensation of
these two fragments gives intermediate III, followed by intramolecular
cyclization to afford the final product. It may be assumed that the water
exclusion of TFE may favor both imine and intermediate I formation.
After the reaction, TFE can be easily separated (by distillation) and
reused without decrease in its activity. The possibility of recycling
the trifluoroethanol was examined using the reaction of 4-
chlorobenzaldehyde (1a), 1,3-indanedione (2a), acetophenone (3a)
and ammonium acetate (4a) under the optimized conditions. Upon
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-Cl-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
C6H5
C6H5
C6H5
C6H5
4-OMe-C6H4
4-Cl-C6H4
4-Cl-C6H4
9
10
11
12
13
14
15
H
H

M. Daryabari, S. Khaksar / Journal of Molecular Liquids 198 (2014) 263–266
265
Scheme 2. Proposed mechanism for the synthesis of 5H-indeno[1,2-b]pyridin-5-ones.
completion, the corresponding solid product 5 was obtained through
simple filtering, and recrystallized from ethanol to yield the highly
pure indeno[1,2-b]pyridine derivatives. The filtrate was evaporated
under reduced pressure at 80 °C.
Upon evaporation of the solvent, pure TFE was obtained (by NMR
analysis). The recovered TFE was reused ten times in the condensation
of 4-chlorobenzaldehyde, 1,3-indanedione, acetophenone and ammo-
nium acetate without any loss of activity.
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In conclusion, an extremely efficient and green process has been de-
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The authors thank the Research Committee of Islamic Azad University
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