B(HSO4)3: An efficient and recyclable catalyst for the Friedlaender synthesis of substituted quinolines

Article abstract of DOI:10.2298/JSC121017061S

Substituted quinolines have been synthesized in the presence of catalytic amounts of boron hydrogen sulfate (BHS) under solvent-free conditions. This methodology offers some advantages, including high yield, short reaction time, low cost of the catalyst,

Full text of DOI:10.2298/JSC121017061S

J. Serb. Chem. Soc. 78 (10) 1481–1489 (2013)
UDC 547.368+546.27:547.831+542.9
JSCS–4511
Original scientific paper
B(HSO4)3: An efficient and recyclable catalyst for the
Friedländer synthesis of substituted quinolines
1
2
*
SEYYED JAFAR SAGHANEZHAD and HAMID REZA SAFAEI
1Young Researchers Club, Shiraz Branch, Islamic Azad University, Shiraz, Iran and
2Department of Applied Chemistry, College of Science, Shiraz Branch, Islamic Azad
University, P. O. Box 71993-5, Shiraz, Iran
(Received 17 October 2012, revised 26 May 2013)
Abstract: Substituted quinolines have been synthesized in the presence of
catalytic amounts of boron hydrogen sulfate (BHS) under solvent-free condi-
tions. This methodology offers some advantages, including high yield, short
reaction time, low cost of the catalyst, green conditions by avoiding toxic sol-
vents and recoverable catalyst.
Keywords: boron hydrogen sulfate; substituted quinolines; solvent-free
conditions; Friedländer reaction.
INTRODUCTION
The presence of quinoline moiety core in several natural compounds, such as
1
cinchona alkaloids, and pharmacologically active substances with a broad range
2
3
of biological activities, including anti-asthmatic, antibacterial, anti-inflamma-
4
5
tory and antihypertensive properties, has raised the interest of organic chemists
for finding straightforward routes for the synthesis of these compounds.
Considering the above reports, and due to great importance of quinolines, it
is not surprising that many synthetic procedures, such as the Skraup, Doebner
von Miller, Conrad–Limpach–Knorr, Pfitzinger, Friedländer and Combes reac-
6,7
tions, were developed for the preparation of these compounds. Nevertheless,
the development of novel synthetic approaches for the synthesis of quinolones
remain an active area of research.
Amongst various methodologies reported for the preparation of quinolines,
the Friedländer reaction is still one of the simplest and most straightforward
protocols. Friedländer synthesis involves a condensation followed by a cyclo-
dehydration between an aromatic 2-aminoaldehyde or ketone and an aldehyde or
8
ketone possessing α-active methylene groups. While different catalysts have
*Corresponding author. E-mail: hrs@iaushiraz.net
doi: 10.2298/JSC121017061S
1481

1482
SAGHANEZHAD and SAFAEI
been proposed for Friedländer annulations, it has been shown that acidic catalysts
9
are superior to basic ones. Other than different acidic catalysts, such as Brønsted
10–14
15–17
18
19,20
acids
and Lewis acids,
ionic liquids, and other catalysts
have
also been employed to promote this reaction. Friedländer reaction has recently
21
been reviewed.
Uncatalyzed Friedländer syntheses require drastic reaction conditions, with
temperatures in the range 150–220 °C. Most of the synthetic protocols for
quinolines reported so far suffer from harsh conditions, low yields, prolonged
reaction time and the use of hazardous and often expensive catalysts. Moreover,
the syntheses of these heterocycles have usually been performed in polar
solvents, such as acetonitrile, THF, DMF and DMSO, leading to complex iso-
lation and recovery procedures. These processes also generate waste-containing
solvent and catalyst, which have to be recovered, treated and disposed of.
Solid acids have many advantages both in industry and the laboratory, such
as simplicity in handling, reduced reactor and plant corrosion problems, and more
22
environmentally safe disposal in chemical processes. Solid acids are employed
under heterogeneous conditions and hence can be conveniently handled and
removed from the reaction mixture by simple filtration and recovered for reuse.
Boron hydrogen sulfate has recently been successfully used as an efficient solid
acid catalyst for the preparation of thiocyanohydrins under solvent-free condi-
23
tions.
In continuation of efforts in the synthesis of new solid acid catalysts, and
23–25
their application in organic synthesis,
boron hydrogen sulfate was utilized in
the present study as an efficient solid acid catalyst for the preparation of sub-
stituted quinolines by Friedländer annulation (Scheme 1).
Scheme 1. Preparation of substituted quinolines in the presence of BHS.
RESULTS AND DISCUSSION
Boron hydrogen sulfate, BHS, was easily prepared by simply mixing boric
acid and chlorosulfonic acid in CH Cl at room temperature (Scheme 2). This
2
2
reaction is easy and clean, because the evolved HCl gas leaves the reaction vessel
immediately.

PREPARATION OF SUBSTITUTED QUINOLINES
1483
Scheme 2. Preparation of the catalyst.
One of the informative techniques for an investigation of catalyst formation
is FT-IR spectroscopy. Thus, the structure of the catalyst was characterized by
FT-IR spectroscopy (Fig. 1). As seen in Fig. 1, the spectrum of B(HSO ) was
4 3
different from that of boric acid. The FT-IR spectrum of B(HSO ) showed
4 3
absorption bands at 1400 (ν(S=O) asymmetric stretching), 1200 (ν(S=O) sym-
–1
metric stretching) and at 650 cm corresponding to ν(S–O). Moreover, a broad
–1
band from 2700–3400 cm corresponds to acidic O–H stretching.
Figure 1. IR spectra of B(HSO4)3 and B(OH)3.
To evaluate the catalytic activity of BHS in the preparation of substituted
quinolines, a model reaction of 2-aminobenzophenone (1 mmol), and acetylace-
tone (1.2 mmol) under solvent-free conditions at different temperatures and in the
presence of variable catalyst loadings was examined (Scheme 3). It was found
that in the absence of the solid acid catalyst, only a trace amount of the desired
product was observed on the TLC plate even after heating for 2 h. (Table I, Entry
1). When the reaction was performed in the presence of BHS, it proceeded
rapidly to give the desired product.
Scheme 3. Optimization of the reaction conditions for 2-aminobenzophenone and
acetylacetone as a model reaction.

1484
SAGHANEZHAD and SAFAEI
In order to evaluate the appropriate catalyst loading, the model reaction was
performed using 3.5 to 9.5 mol % at different temperatures in the absence of
solvent (Table I). It was found that 5 mol % catalyst gave the maximum yield in
the minimum time. A higher percentage of loading of the catalyst (7–9.5 mol %)
neither increases the yield nor lowers the conversion time substantially. In the
next step, the effect of temperature was evaluated for the model reaction. It was
observed that the reaction did not proceed at room temperature. Elevating the
reaction temperature proved helpful, and the yield of desired product increased
considerably. To our satisfaction, the reaction was found to proceed smoothly,
and almost complete conversion of product was observed at 90 °C, affording 1-
(2-methyl-4-phenylquinolin-3-yl)ethanone (3f) in 91 % yield within a short time.
TABLE I. Optimization of the reaction conditions for 2-aminobenzophenone and acetyl-
acetone as a model reaction under thermal solvent-free conditions
Entry
Catalyst amount, mol %
Temperature, °C
Time, min
Yield, %
1
2
3
4
5
6
7
8
–
3.5
5
5
3.5
5
r.t.
r.t.
r.t.
60
90
90
90
90
120
120
120
60
60
35
10
45
52
65
68
91
92
88
7
9.5
34
45
Subsequently, with the optimal conditions in hand, using 1:1.2 molar ratio of
a 2-aminoaryl ketone, a carbonyl compound and 5 mol % of BHS at 90 °C under
solvent-free conditions, the generality and synthetic scope of this coupling pro-
tocol were demonstrated by synthesizing a series of substituted quinolines (Table
II). Gratifyingly, a wide range of aromatic aldehydes was well tolerated under the
optimized reaction conditions. The time taken for complete conversion (moni-
tored by TLC) and the isolated yields are presented in Table II. All the new com-
pounds were characterized by their satisfactory microanalytical (C, H, N) and
1
13
spectral (IR, H-NMR, C-NMR and MS) studies, and known compounds by
comparison of their physical and spectral data with those of the authentic
samples.
As shown in Table II, the different carbonyl compounds, including ethyl
acetoacetate, acetylacetone, cyclohexanone, cyclohexane-1,3-dione and dime-
done, were uniformly transformed into the corresponding quinolines in good to
excellent yields within 25–62 min.
The reusability of the catalyst in the reaction of 2-aminobenzophenone, and
acetylacetone, under solvent-free conditions at 90 °C was evaluated. In this
procedure, after completion of each reaction, hot ethanol was added and the
catalyst was filtered off. The recovered catalyst was washed with ethanol, dried

PREPARATION OF SUBSTITUTED QUINOLINES
1485
and reused six times. A small decrease in the catalytic activity of the catalyst was
observed after the 6th time of reuse (Table III).
TABLE II. Preparation of substituted quinolines promoted by BHS under solvent-free con-
ditions at 90 °C
Product
1
2
3
Time, min Yield, %
3a
1a
62
65
3b
1a
45
68
3c
1a
1a
48
50
67
62
3d
3e
3f
1a
1b
50
41
72
91
3g
3h
1b
1b
49
46
92
80

1486
SAGHANEZHAD and SAFAEI
TABLE II. Continued
Product
1
2
3
Time, min Yield, %
3i
1b
35
95
3j
1b
1c
28
98
Ph
O
3k
38
94
Cl
N
3l
1c
1c
1c
1c
41
45
32
25
92
88
82
96
3m
3n
3o
Ph
N
O
Cl
Ph
O
Cl
N
TABLE III. The reusability of the catalyst in six cycles for the reaction of 2-aminobenzo-
phenone and acetylacetone under solvent-free conditions at 90 °C
Run
Time, min
Yield, %
1
2
3
4
5
6
41
42
44
46
48
52
91
90
88
85
82
78

PREPARATION OF SUBSTITUTED QUINOLINES
1487
To compare the advantage of the use of BHS over other reported catalysts,
the model reaction of 2-aminobenzophenone and acetylacetone was considered
as a representative example (Table IV). While in most of these cases, compa-
rative yields of the desired product were obtained following the BHS-catalyzed
procedure, the reported procedures required high catalyst loading (entry 2 and 4),
or long reaction times (entry 1 and 2). These results clearly demonstrate that BHS
is an equally or more efficient catalyst for this three-component reaction.
TABLE IV. Comparison of BHS with reported catalysts in the reaction of 2-aminobenzo-
phenone and acetylacetone
Entry
Catalyst/temp., °C
Catalyst loading, mol %
Time, min Yield, %
Ref.
1
2
3
4
5
6
NaAuCl4.2H2O/80
[Hbim]BF4/100
Oxalic acid/80
HClO4–SiO2/60
Sulfamic acid/70
BHS/90
3
100
10
0.2 g
5
1440
198
120
150
45
46
94
90
92
89
91
19
18
13
12
10
5
41
This work
EXPERIMENTAL
Chemicals and apparatus
All chemicals were purchased from Merck or Fluka. All the synthesized compounds are
known and were identified by comparison of their melting points, elemental analyses, mass
spectra, IR, 1H- and 13C-NMR data with those of authentic samples. Monitoring of the
reactions was accomplished by TLC on silica gel Polygram SIL G/UV 254 plates.
Preparation of boron hydrogen sulfate
A 50 mL suction flask was equipped with a constant pressure, dropping funnel. The gas
outlet was connected to a vacuum system through an adsorbing solution (water) and an alkali
trap. Boric acid (1.55 g, 25 mmol) was charged into the flask and chlorosulfonic acid (8.74 g,
ca. 5 mL, 75 mmol) was added dropwise over a period of 1 h at room temperature. HCl was
evolved immediately. After completion of the addition, the mixture was shaken for 1 h, while
the residual HCl was eliminated by suction. Then the mixture was washed with diethyl ether
to remove the unreacted chlorosulfonic acid. Finally, a grayish solid material was obtained in
85 % yield (6.4 g).23
Typical procedure for the preparation of substituted quinolines
A mixture of 2-aminoaryl ketone (1 mmol), a carbonyl compound (1.1 mmol), and BHS
(5 mol %) was heated at 90 °C for 10 min. Completion of the reaction was indicated by TLC
(n-hexane/ethyl acetate, 4:1). After completion of the reaction, the insoluble crude product
was dissolved in hot ethanol and boron hydrogen sulfate was filtered. The crude product was
purified by recrystallization in ethanol to afford the pure product.
CONCLUSION
In summary, a simple and facile protocol was proposed for the synthesis of
substituted quinolines by Friedländer quinoline synthesis using boron hydrogen
sulfate as a novel environmentally safe heterogeneous solid acid catalyst under

1488
SAGHANEZHAD and SAFAEI
solvent-free conditions. The method offers several advantages, including high
yields, application of an inexpensive catalyst, short reaction times, easy workup
and performing the reaction under solvent-free conditions that is considered rela-
tively environmentally benign.
Acknowledgements. We appreciate the Islamic Azad University (Shiraz Branch) Research
Councils, Iran, for the financial support of this work.
И З В О Д
B(HSO4)3: ЕФИКАСАН И РЕЦИКЛАБИЛАН КАТАЛИЗАТОР ЗА ФРИЛЕНДЕРОВУ
СИНТЕЗУ ХИНОЛИНА
SEYYED JAFAR SAGHANEZHAD1 и HAMID REZA SAFAEI2
1
2
Young Researchers Club, Shiraz Branch, Islamic Azad University, Shiraz, Iran и Department of
Applied Chemistry, College of Science, Shiraz Branch, Islamic Azad University,
P. O. Box 71993-5, Shiraz, Iran
Извршена је синтеза супституисаних хинолина употребом каталитичких количина
бор-хидроген сулфата (BHS), без присутног растварача. У поређењу са другим мето-
дама, описани поступак нуди предности, као што су висок принос, кратко реакционо
време, ниска цена катализатора, еколошки прихватљиви реакциони услови, избегавање
токсичних растварача и катализатор који може да се рециклира.
(Примљено 17. октобра 2012, ревидирано 26. маја 2013)
REFERENCES
1. M. Balasubramanian, J. G. Keay, Pyridines and their Benzo Derivatives: Applications, In
Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees, E. F. V. Scriven,
Eds., Pergamon Press, New York, 1996, Vol. 5, p. 245
2. A. von Sprecher, M. Gerspacher, A. Beck, S. Kimmel, H. Wiestner, G. P. Anderson, U.
Niederhauser, N. Subramanian, M. A. Bray, Bioorg. Med. Chem. Lett. 8 (1998) 965
3. Y. L. Chen, K. C. Fang, J. Y. Sheu, S. L. Hsu, C. C. Tzeng, J. Med. Chem.44 (2001) 2374
4. G. Roma, M. D. Braccio, G. Grossi, F. Mattioli, M. Ghia, Eur. J. Med. Chem. 35 (2000)
1021
5. P. L. Ferrarini, C. Mori, M. Badawneh, V. Calderone, R. Greco, C. Manera, A. Martinelli,
P. Nieri, G. Saccomanni, Eur. J. Chem. 35 (2000) 815
6. G. Jones, Pyridines and their Benzo Derivatives: Synthesis, in Comprehensive Hetero-
cyclic Chemistry II, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Eds., Pergamon, New
York, 1996, Vol. 5, p. 167
7. M. E. Theoclitou, L. A. Robinson, Tetrahedron Lett. 43 (2002) 3907
8. P. Friedländer, Chem. Ber.15 (1882) 2572
9. E. A. Fehnel, J. Org. Chem. 31 (1966) 2899
10. J. S. Yadav, P. P. Rao, D. Sreenu, R. S. Rao, V. N. Kumar, K. Nagaiah, A. R. Prasad,
Tetrahedron Lett. 46 (2005) 7249
11. G. W. Wang, C. S. Jia, Y. W. Dong, Tetrahedron Lett. 47 (2006) 1059
12. M. Narasimhulu, T. Srikanth Reddy, K. Chinni Mahesh, P. Prabhakar, C. Bhujanga Rao,
Y. Venkateswarlu, J. Mol. Catal., A 266 (2007) 114
13. M. Dabiri, M. Baghbanzadeh, M. S. Nikcheh, Monatsh. Chem. 138 (2007) 1249
14. S. Ghassamipour, A. R. Sardarian, Tetrahedron Lett.50 (2009) 514

PREPARATION OF SUBSTITUTED QUINOLINES
1489
15. M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera, Tetrahedron Lett. 51 (2010) 2342
16. M. A. Zolfigol, P. Salehi, A. Ghaderi, M. Shiri, Catal. Commun. 8 (2007) 1214
17. S. Genovese, F. Epifano, M. C. Marcotullio, C. Pelucchini, M. Curini, Tetrahedron Lett.
52 (2011) 3474
18. S. S. Palimkar, S. A. Siddiqui, T. Daniel, R. J. Lahoti, K. V. Srinivasan, J. Org. Chem. 68
(2003) 9371.
19. S. Atechian, N. Nock, R. D. Norcross, H. Ratni, A. W. Thomas, J. Verron, R. Masciadri,
Tetrahedron 63 (2007) 2811
20. B. Das, K. Damodar, N. Chowdhury, R. A. Kumar, J. Mol. Catal., A 274 (2007) 148
21. J. Marco-Contelles, E. Perez-Mayoral, A. Samadi, M. do Carmo Carreiras, E. Soriano,
Chem. Rev.109 (2009) 2652
22. J. H. Clark, Acc. Chem. Res. 35 (2002) 791
23. A R Kiasat, M. Fallah-Mehrjardi, J. Braz. Chem. Soc. 19 (2008) 1595
24. A. R. Kiasat, M. Fallah-Mehrjardi, Synth. Commun. 40 (2010) 1551
25. A. R. Kiasat, A. Mouradezadegun, S. J. Saghanezhad, J. Serb. Chem. Soc. 78 (2013) 469.