An eco-benign and highly efficient access to dihydro-1H-indeno[1,2-b] pyridines in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1016/j.molliq.2014.03.030

4-Aryl-4,5-dihydro-1H-indeno[1,2-b]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

Full text of DOI:10.1016/j.molliq.2014.03.030

Journal of Molecular Liquids 196 (2014) 159–162
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
An eco-benign and highly efficient access to dihydro-1H-indeno[1,2-b]
pyridines in 2,2,2-trifluoroethanol
⁎
Samad Khaksar , Milad Gholami
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:
4-Aryl-4,5-dihydro-1H-indeno[1,2-b]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 recovered in excellent purity for
direct reuse.
Received 19 January 2014
Received in revised form 18 March 2014
Accepted 20 March 2014
Available online 1 April 2014
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Heterocycle
Multicomponent
Fluorinated alcohols
Reusable
Hydrogen bonding
1. Introduction
cardiovascular diseases including hypertension [28,29]. In recent
years, indenopyridines (azafluorenes) have received more attention
Over the last years, fluorinated alcohols are attracting increasing
attention as alternative solvents for a wide range of catalytic and organic
reactions, because they display many advantages over common organic
solvents, such as high hydrogen bonding donor ability, nonvolatility,
nonflammability, polarity, high ionizing power, and low nucleophilicity
[1–3]. In addition, highly fluorinated alcohols exhibit lower boiling
points than do their parent alcohols. Based on these unique properties,
these alcohols have met noteworthy applications in various domains.
These alcohols display interesting properties, such as solvent, co-
solvent, and additives in various catalytic processes: oxidation reactions
with H2O2 (epoxidation of olefins, transformations of sulfides into sulf-
oxides, and Baeyer–Villiger oxidation) or sodium hypochlorite [4–9],
aza-Michael reaction [10], protection and deprotection of amine groups
[11,12], cyclopropanation of alkenes [13], and oxirane ring-opening
without any catalyst [14,15]. Recently, we and others have demonstrat-
ed the usefulness of fluorous alcohols as a novel medium for the synthe-
sis of heterocyclic compounds [16–27]. Dihydropyridines and related
heterocyclic systems occur widely in natural products as well as in
synthetic molecules, exhibiting a broad spectrum of biological activities
such as vasodilators, bronchodilators, antiatherosclerotics, antitumor,
hepatoprotective, and antidiabetic agents for the treatment of
because of the wide range of useful pharmacological activities that
include cytotoxic [30], phosphodiesterase inhibitory [31], adenosine
A2a receptor antagonistic [32], antiinflammatory/antiallergic [33],
coronary dilating [34] and calcium modulating activities [35]. Some
of these compounds have been reported as cyclin-dependent kinase
[36] and selective monoamine oxidase B (MAO-B) [37] inhibitors. As
a result chemists and biologists alike have been attracted toward
these compounds. According to the literature, several synthetic
methods have been developed for the construction of this kind of
fused heterocycles from suitable precursors [38–47]. In addition,
they can also be accessed by the condensation of aldehydes, 1,3-
indandione or 1-indenone and aromatic ketones in the presence of
ammonium acetate under microwave irradiation [48], by Pummerer
reaction of imidosulfoxides [49], and Pd(0)-catalyzed cross-coupling
reaction between arylboronic acids and 2-halopyridines [50]. These
methods show varying degrees of successes as well as limitations,
such as harsh reaction conditions, expensive and detrimental metal
reagents, tedious work-up, low product yields, long reaction times,
and co-occurrence of several side products. Therefore, the develop-
ment of novel methods for the synthesis of indenopyridines remains
an attractive goal. In this article, we have presented a new, conve-
nient, and highly efficient protocol for the synthesis of 4-aryl-4,5-
dihydro-1H-indeno[1,2-b]pyridine derivatives via one-pot four-
component cyclocondensation of 1,3-indanedione, aldehyde, alkyl
acetoacetate and ammonium acetate in trifluoroethanol (TFE)
(Scheme 1).
⁎
Corresponding author. Fax: +98 121 2517043.
E-mail addresses: S.khaksar@iauamol.ac.ir, Samadkhaksar@yahoo.com (S. Khaksar).
http://dx.doi.org/10.1016/j.molliq.2014.03.030
0167-7322/© 2014 Elsevier B.V. All rights reserved.

160
S. Khaksar, M. Gholami / Journal of Molecular Liquids 196 (2014) 159–162
Scheme 1. Synthesis of 4-aryl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridines in TFE.
2. Experimental
CDCl3): δ = 14.1, 16.5, 41.1, 55.3, 58.9, 101.9, 103.5, 121.7, 126.7,
128.6, 134.4, 135.9, 139.5, 142.2, 143.5, 145.8, 150.1, 156.5, 166.2, 192.2.
2.1. Apparatus and analysis
3. Results and discussion
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 apparatus.
Infrared spectra were recorded on a Rayleigh WQF-510 Fourier
transform instrument. Commercially available reagents were used
throughout without further purification.
Typical experimental procedure: A mixture of aldehyde (1 mmol),
1,3-indanedione (1 mmol), alkyl acetoacetate (1 mmol), and ammoni-
um acetate (1.5 mmol) was stirred in one-pot in TFE (2 mL) at room
temperature 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 4-aryl-4,5-dihydro-1H-
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 literature [39]. Spectroscopic data for selected examples are
shown below.
Initially, we carried out the four-component condensation of
4-chlorobenzaldehyde (1 mmol), 1,3-indanedione (1 mmol), alkyl
acetoacetate (1 mmol), and ammonium acetate (1.5 mmol) in
trifluoroethanol at room temperature. The reaction was remarkably
fast (2 min) and, after distilling off the HFIP, the 4-aryl-4,5-dihydro-
1H-indeno[1,2-b]pyridine 5a was obtained in high yield (95%) (Table 1,
entry 1). At the beginning of the reaction, the reagents itself were dis-
solved completely in the medium to form a homogeneous mixture
(Fig. 1a), but near the completion of the reaction, the system became a
suspension, and the product precipitated at the end of the reaction
(Fig. 1b).
Encouraged by this success, we extended this reaction to a range of
aldehydes 1a-m under similar conditions to furnish the respective
substituted 4,5-dihydro-1H-indeno[1,2-b]pyridine 5a-m in good yields.
The results are summarized in Table 1.
Both the electron-rich and -deficient aldehydes worked well leading
to good yields of products 5. Aromatic aldehydes with several function-
alities such as Cl, Br, Me, OMe, OH and NO2 were found to be compatible
2-Methyl-4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]
pyridine-3-carboxylic acid ethyl ester (5a): mp: 227–229 °C; FT-IR (KBr,
cm−1): 1640, 1705, 3270; 1H NMR (400 MHz, CDCl3): δ = 1.11
(t, J = 7.1 Hz, 3H), 2.42 (s, 3H), 4.05 (q, J = 7.1 Hz, 2H), 4.75 (s, 1H),
7.60-7.21 (m, 8H), 9.16 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3):
δ = 14.5, 18.5, 36.3, 50.7, 106.1, 108.1, 118.9, 120.3, 128.2, 129.4,
130.2, 130.7, 132.1, 133.2, 135.9, 145.3, 145.7, 153.4, 167.2, 190.5.
2-Methyl-4-(4-nitrophenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]
pyridine-3-carboxylic acid ethyl ester (5d): mp: 216-218 °C; FT-IR
(KBr, cm−1): 1595, 1640, 1704, 3290; 1H NMR (400 MHz, CDCl3):
δ = 1.19 (t, J = 7.1 Hz, 3H), 2.55 (s, 3H), 4.05 (q, J = 7.1 Hz, 2H),
5.13 (s, 1H), 6.55 (s, 1H, NH), 7.09-7.29 (m, 4H), 7.52 (d, J =
8.2 Hz, 2H), 8.13 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ = 14.1, 20.2, 37.5, 60.2, 106.7, 109.5, 116.9, 122.1, 123.6, 128.5,
130.8, 132.1, 133.5, 135.1, 143.2, 145.5, 153.0, 153.2, 167.5, 191.6.
2-Methyl-4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]
pyridine-3-carboxylic acid ethyl ester (5f): mp: 176-178 °C; FT-IR (KBr,
cm−1): 1640, 1703, 3280; 1H NMR (400 MHz, CDCl3): δ = 1.15 (t,
J = 7.3 Hz, 3H), 2.42 (s, 3H), 3.99 (q, J = 7.3 Hz, 2H), 4.95 (s, 1H) 6.75
(s, 1H, NH), 6.98 (d, J = 6.40 Hz, 2H), 7.14-7.30 (m, 6H); 13C NMR
(100 MHz, CDCl3): δ = 13.2, 18.5, 36.1, 56.4, 105.1, 109.2, 112.22,
123.1, 123.6, 128.5, 129.6, 131.5, 133.2, 134.5, 142.4, 145.8, 153.1,
153.3, 166.1, 191.4.
2-Methyl-4-(4-phenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]pyridine-
3-carboxylic acid ethyl ester (5 g): mp: 220-221 °C; FT-IR (KBr, cm−1):
1580, 1630, 1705, 2975, 3260; 1H NMR (400 MHz, CDCl3): δ = 1.08 (t,
J = 7.3 Hz, 3H), 2.48 (s, 1H), 4.03 (q, J = 7.3 Hz, 2H), 5.02(s, 1H, CH),
7.11 (s, 1H, NH), 7.65-6.81 (m, 9H); 13C NMR (100 MHz, CDCl3): δ =
13.4, 18.2, 42.1, 61.5, 102.4, 109.6, 113.5, 123.4, 125.7, 128.7, 128.9,
133.9, 136.5, 141.3, 142.2, 145.7, 150.1, 168.1, 167.3, 192.3.
2-Methyl-4-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]
pyridine-3-carboxylic acid ethyl ester (5i): mp: 213-214 °C; FT-IR (KBr,
cm−1): 1633, 1700, 3260; 1H NMR (400 MHz, CDCl3): δ = 1.03 (t,
J = 7.2 Hz, 3H), 2.45 (s, 3H), 3.67 (s, 3H), 4.01 (q, J = 7.2 Hz, 2H),
4.87 (s, 1H), 6.54 (s, 1H, NH), 6.96–7.30 (m, 8H); 13C NMR (100 MHz,
Table 1
Synthesis of indenopyridines (azafluorenes) in TFE.
Entry
1
Aldehyde
1R
Et
Time (min)
2
Product
Yieldref
9539
%
5a
2
3
4
Et
Et
Et
8
5
3
5b
5c
5d
9039
9240
9539
5
6
Et
Et
7
5
5e
5f
9542
9542
7
8
Et
Et
8
5 g
5 h
9040
9239
10
9
Et
Et
Et
15
15
10
5i
9041
9042
8542
10
11
5j
5 k
12
13
Me
Me
2
5
5 l
9539
9240
5 k
14
Me
10
5 m
9042

S. Khaksar, M. Gholami / Journal of Molecular Liquids 196 (2014) 159–162
161
to the steric hindrance (Table 1, entries 2,3 and 11). Satisfactorily, the
reactions displayed high functional group tolerance and afforded the
corresponding indenopyridines with great efficiency. The structure of
the products (5a–m) was established from their IR spectral data and
comparison of their melting points with those of authentic 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.
After the reaction, TFE can be easily separated (by distillation) and
reused without decrease in its activity.
A plausible mechanism for the formation of dihydro-1H-indeno[1,2-
b]pyridines is shown in Scheme 2.
In this process, TFE acts as Brønsted acid [51] and plays a significant
role in increasing the electrophilic character of the electrophiles. In ad-
dition, the polar transition state of the reaction could be stabilized
well by the high ionizing solvent TFE. The reaction may proceed via
enamine I, which formed from alkyl acetoacetate and ammonium
acetate, and then activated by TFE, reacts with intermediate II (from
condensation of aldehyde with 1,3-indanedione) to give 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 II formation.
Fig. 1. (a) Homogeneous mixture during the reaction, and (b) at the end of the reaction;
the product has precipitated.
under the optimized reaction 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
rings 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
4. Conclusion
In conclusion, an extremely efficient and green process has been de-
veloped for the synthesis of 4-aryl-4,5-dihydro-1H-indeno[1,2-b]pyri-
dine derivatives via one-pot four-component cyclocondensation of 1,3-
Scheme 2. Proposed mechanism for the synthesis of 4-aryl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridines.

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indanedione, aldehyde, alkyl acetoacetate and ammonium acetate in
trifluoroethanol (TFE). This method is bestowed with merits like
avoiding the use of any base, metal or Lewis acid catalyst, ease of product
isolation/purification by non-aqueous work-up, high chemoselectivity,
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of indenopyridines (azafluorenes). Further exploration of the scope of
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Acknowledgment
This research is supported by the Islamic Azad University, Ayatollah
Amoli Branch.
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