Green Protocol for the Friedlaender Synthesis: KAL(SO4)2·12H2O-SiO2 (ALUM-SiO2) A Highly Efficient Catalyst in the Synthesis of Quinolines

Article abstract of DOI:10.3987/COM-07-11273

In this letter, an efficient synthesis of an array of poly-substituted quinolines from 2-aminoaryl ketones and β-ketoester, β-diketones and α-methylene ketones using KAl(SO₄)₂·12H₂O-SiO₂ (Alum-SiO₂) u

Full text of DOI:10.3987/COM-07-11273

HETEROCYCLES, Vol. 75, No. 4, 2008
947
HETEROCYCLES, Vol. 75, No. 4, 2008, pp. 947 - 954. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd November, 2007, Accepted, 9th January, 2008, Published online, 11th January, 2008. COM-07-11273
GREEN PROTOCOL FOR THE FRIEDLÄNDER SYNTHESIS:
KAl(SO4)2·12H2O-SiO2 (ALUM-SiO2) A HIGHLY EFFICIENT CATALYST
IN THE SYNTHESIS OF QUINOLINES
Ali A. Mohammadi,* Javad Azizian, Armin Hadadzahmatkesh, and
Mohammad R. Asghariganjeh
Department of Chemistry, Faculty of Science, Shahid Beheshti University, P. O.
Box 19395-4716, Tehran, Iran E-mail: a-mohammadi@cc.sbu.ac.ir
Abstract – In this letter, an efficient synthesis of an array of poly-substituted
quinolines from 2-aminoaryl ketones and β-ketoester, β-diketones and
α-methylene ketones using KAl(SO4)2·12H2O-SiO2 (Alum-SiO2) under
solvent-free conditions is described. Compared with the classical Friedländer
synthesis this new synthetic method has the advantage of excellent yields
(90-98%), shorter reaction time, and reusability of the catalyst.
Quinolines are an important class of heterocyclic compounds having remarkable biological activities such
as antimalarial, antibacterial, antiasthmatic, antibacterial, antihypertensive, anti-inflammatory and
tyrosine kinase PDGF-RTK inhibiting agents.1,2 In addition, they are also applied for the preparation of
nano-structures and polymers that combine enhanced electronic, optoelectronic or non-linear optical
properties with excellent mechanical properties.3 Thus, the synthesis of quinolines is an important and
useful task in organic chemistry. Various methods such as the Skraup,4 Friedländer,5 Pfitzinger,6
Combes,7 and Conrad-Limpach-Knorr 8 have been developed for the synthesis of quinoline derivatives.
However, the Friedländer annulation is one of the most simple and straightforward methods that is
employed to produce poly-substituted quinolines. This method involves the acid or base catalyzed or
thermal condensation (150-220 °C) between a 2-aminoaryl ketone and a second carbonyl compound
possessing a reactive α-methylene group followed by cyclodehydration.9-12 Subsequent works showed
that acid catalysts are more effective that base catalysts for the Friedländer annulation. Several acids such
as p-toluenesulphonic acid,13 SnCl2,14 Bi(OTf)3,15 AuCl3,16 NaAuCl4·2H2O,17 HCl,18 NH2SO3H,19
22
Sc(O3SOC12H25)3,20 silica sulfuric acid,21 and ionic liquids have also recently been utilized for this
synthesis.

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HETEROCYCLES, Vol. 75, No. 4, 2008
23
In connection with our ongoing work on synthesis of heterocyclic compounds and in view of our
interest in the KAl(SO4)2·12H2O-SiO2 catalyzed reactions,24 we now wish to report a facile and rapid
procedure of preparation of quinolines derivatives via Friedländer synthesis with SiO2-Alum as a non-
toxic, reusable, inexpensive, and easily available reagent under solvent-free conditions at 30 °C. This
method not only affords excellent yields, but also avoids problems associated with catalyst cost, handling,
safety, and pollution.
The reaction of 2-amino-5-chlorobenzophenone 1a (1 mmol) and 5,5-dimethyl-1,3-cyclohexanedione 2a
(1.2 mmol) in the presence of 25 mol% Alum-SiO2 [Alum- SiO2 contains 25% of KAl(SO4)2·12H2O (see
EXPERIMENTAL)] under solvent-free conditions at 30 °C in 99, 98, 98, 96, 95, and 93% yields over six
cycles.(Scheme 1, Figure 1)
Figure 1: The same catalyst was used for each of the six runs
100
99
98
97
96
95
94
93
92
91
90
1
2
3
4
5
6
Ph
Ph
N
R2
R3
R1
R1
R2
R3
O
Alum-SiO2
30 oC
+
O
NH2
1
2
3
Scheme 1
Promoted by this success, we extended this reaction of 2-aminoaryl ketones 1 with a range of other
α-methylene ketones 2 under similar conditions; furnishing the respective poly-substituted quinolines 3 in
excellent yields. Several examples that illustrate this novel and generally usable method for the synthesis
of the quinolines are summarized in Table 1.
In summary, we have developed a simple, convenient, and effective method for the synthesis of
quinolines employing KAl(SO4)2·12H2O-SiO2 under mild conditions. The catalyst can be prepared easily
with readily available inexpensive regents that are heterogeneous, reusable, and non-hazardous. To the

HETEROCYCLES, Vol. 75, No. 4, 2008
949
best of our knowledge, this is the first report of an efficient general method for the synthesis of some new
quinolines by using a simple catalyst.
EXPERIMENTAL
Melting points were measured on the Electrothermal 9100 apparatus and are uncorrected. IR spectra were
measured on a Shimadzu IR-470 Spectrophotometer. 1H NMR and 13C NMR spectra were determined on
Bruker 300 DRX Avance instrument at 300 and 75MHz. respectively. MS spectra were recorded on a
Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental
analyses were performed using a Heracus CHN-O-Rapid analyzer.
Table 1: KAl(SO4)2·12H2O-SiO2 catalyzed Friedländer reaction under solvent free conditionsa
2-Aminoaryl
Ketone 1
α-Methylene
Ketone 2
O
Time
(h)
Yield
(%)b
Entry
Product 3
MP (°C)
208-921
Ph
O
Ph
Cl
Cl
O
a
1.5
1.5
99
97
93
O
NH2
Ph
N
O
Ph
O
Me
Cl
Cl
Cl
b
c
152-421
O
Me
Me
O
NH2
Ph
N
Me
Ph
Ph
Cl
Ph
O
2.45
-
O
Me
NH2
Ph
N
Me
Ph
Ph
Cl
Ph
Cl
O
d
e
f
2.45
2.5
2
91
95
90
-
-
-
N
CH2CH2CH3
O
CH2CH2CH3
O
NH2
Ph
Ph
Cl
Cl
Cl
Cl
Cl
O
N
NH2
Ph
O
Ph
O
O
N
NH2
Ph
O
Ph
O
Cl
O
g
2.45
90
-
N
NH2

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HETEROCYCLES, Vol. 75, No. 4, 2008
O
Ph
N
Ph
Cl
Cl
O
h
2.45
85
-
NH2
Ph
O
Ph
O
O
i
j
1.45
97
85
191-321
224-618
N
NH2
Ph
O
Ph
N
O
O
2.45
NH2
Ph
O
O
Ph
O
Me
113-425
O
Me
k
2
96
Me
NH2
Ph
N
Me
O
Ph
O
O
OEt
OEt
l
2
97
92
93
100-125
N
Me
NH2
Ph
O
Me
Ph
Ph
Ph
O
m
n
2.45
2.45
-
-
O
Me
NH2
Ph
N
Me
Ph
N
Ph
Ph
O
O
CH2CH2CH3
O
CH2CH2CH3
NH2
Ph
Ph
O
o
2.5
94
-
N
NH2
aReaction conditions: 2-aminoaryl ketone (1 mmol), α-methylene ketone (1.2 mmol), Alum-SiO2 (25
mol%), under solvent-free conditions at 30 °C.
bIsolated products.
General procedure: A mixture of o-aminobenzophenones (1 mmol), ketones (1.2 mmol), and
KAl(SO4)2·12H2O-SiO2 (0.6 g, 25 mol%) was heated with stirring at 30 °C for the time periods that are
recorded in Table 1. After completion of the reaction, as indicated by TLC (AcOEt/n-hexane, 1/1), the
reaction mixture was washed with hot EtOH and filtered through a sinter funnel to recover the catalyst.
The organic portion from filtrate was separated and concentrated under reduced pressure. The crude
product was recrystallized from EtOH to afford the quinolines derivatives.
The recovered catalyst was washed with acetone and dries at rt and used consecutively six times to afford

HETEROCYCLES, Vol. 75, No. 4, 2008
951
the products with minimum variation of the yields.
Preparation of the supported catalyst: To a suspension of silica gel (7.5 g, Merck, Silica gel 0.063–200
mm) in water (20 mL) KAl(SO4)2·12H2O (2.5 g) was added. The suspension stirred at rt for 6 h, then was
water evaporated under reduced pressure and the residue dried at 50 °C.
Spectral data for new product:
6-Chloro-2-methyl-3,4-diphenylquinoline (3c): White powder; mp 200-201 ˚C; IR (KBr), νmax 3015,
2909, 1602, 1568 cm-1; 1H NMR (CDCl3) δH: 2.54 (s, CH3), 7.05 (m, 5H, ArH), 7.24 (m, 5H, ArH), 7.48
(s, ArH), 7.62 (d, J=8.8 Hz, ArH), 8.05 (d, J=8.8 Hz, ArH); 13C NMR (CDCl3) δC: 25.40, 125.39,
127.04, 127.13, 127.56, 127.93, 128.01, 129.88, 129.99, 130.04, 130.25, 131.69, 134.93, 136.05, 138.20,
145.38, 145.95, 158.30; MS (m/z, %): 329 (M+, 100). Anal. Calcd for C22H16ClN: C, 80.11; H, 4.89; N,
4.25. Found: C, 80.02; H, 4.78; N, 4.13.
6-Chloro-3,4-diphenyl-2-propylquinoline (3d): White powder; mp 148-150 ˚C; IR (KBr), νmax 3055,
1
2956, 1603, 1559 cm-1; H NMR (CDCl3) δH: 0.87 (t, J=7.2 Hz, CH3), 1.71 (m, CH2), 2.78 (t, J=8.0 Hz,
CH2), 7.06 (m, 5H, ArH), 7.25 (m, 5H, ArH), 7.46 (s, ArH), 7.62 (d, J=8.8 Hz, ArH), 8.08 (d, J=8.9 Hz,
ArH); 13C NMR (CDCl3) δC: 14.22, 22.82, 39.20, 125.35, 126.96, 127.06, 127.46, 127.76, 127.87, 129.98,
130.16, 130.21, 130.45, 131.65, 134.81, 136.25, 137.98, 145.48, 146.22, 161.66; MS (m/z, %): 357 (M+,
35). Anal. Calcd for C24H20ClN: C, 80.55; H, 5.63; N, 3.91. Found: C, 80.42; H, 5.52; N, 3.83.
8-Chloro-10-phenyl-11H-indeno[1,2-b]quinoline (3e): White powder; mp 172-173 ˚C; IR (KBr), νmax
1
3053, 1602, 1562 cm-1; H NMR (CDCl3) δH: 3.85 (d, J=4.0 Hz, CH2), 7.48 (m, 5H, ArH), 7.62 (m, 4H,
ArH), 7.66 (s, 1H, ArH), 8.18 (d, J=8.5 Hz, ArH), 8.31 (d, J=7.2 Hz, ArH); 13C NMR (CDCl3) δC: 34.01,
122.22, 124.66, 125.38, 127.12, 127.61, 128.58, 128.94, 129.18, 129.53, 130.27, 130.73, 131.42, 133.89,
135.81, 140.12, 142.85, 145.19, 146.83,161.31; MS (m/z, %): 327 (M+, 90). Anal. Calcd for C22H14ClN:
C, 80.61; H, 4.30; N, 4.27. Found: C, 80.52; H, 4.21; N, 4.16.
8-Chloro-10-phenyl-11H-indeno[1,2-b]quinolin-11-one (3f): White powder; mp 238-239 ˚C; IR (KBr),
1
νmax 3051, 1712, 1617, 1588 cm-1; H NMR (CDCl3) δH: 7.42-7.75 (m, 10H, ArH), 8.13 (m, 2H, ArH);
13C NMR (CDCl3) δC: 121.81, 123.39, 123.90, 124.00, 127.36, 128.38, 128.68, 129.32, 131.27, 131.86,
132.16, 132.39, 133.13, 135.50, 137.44, 143.36, 147.18, 159.98, 162.20, 189.88; MS (m/z, %): 341 (M+,
90). Anal. Calcd for C22H12ClNO: C, 77.31; H, 3.54; N, 4.10. Found: C, 77.19; H, 3.42; N, 4.01.
9-Chloro-5,6-dihydro-7-phenylbenzo[c]acridine (3g): White powder; mp 139-140 ˚C; IR (KBr), νmax
3050, 2951, 1566, 1549 cm-1; 1H NMR (CDCl3) δH: 2.83-2.91 (m, 2 CH2), 7.25-7.61 (m, 10H, ArH), 8.12
(d, J=8.9 Hz, ArH), 8.60 (d, J=7.4 Hz, ArH); 13C NMR CDCl3) δC: 26.53, 28.11, 124.86, 126.36, 127.35,

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HETEROCYCLES, Vol. 75, No. 4, 2008
127.77, 128.00, 128.25, 128.80, 129.11, 129.41, 129.93, 131.16, 131.74, 134.71, 136.19, 139.30, 144.69,
145.51, 153.39; MS (m/z, %): 341 (M+, 70). Anal. Calcd for C23H16ClN: C, 80.81; H, 4.72; N, 4.10.
Found: C, 80.72; H, 4.59; N, 4.01.
2-Chloro-6,7,8,9,10,11,12,13,14,15-decahydro-16-phenylcyclododeca[b]quinoline
(3h):
White
1
powder; mp 114-116 ˚C; IR (KBr), νmax 3052, 2929, 2851, 1602, 1563 cm-1; H NMR (CDCl3) δH: 1.31
(brod, CH2), 1.57 (m, 6 CH2), 2.03 (brod, CH2), 2.64 (t, J=7.5 Hz, CH2), 3.07 (t, J=7.6 Hz, CH2), 7.17-
13
7.51 (m, 7H, ArH), 7.96 (d, J=8.8 Hz, ArH); C NMR (CDCl3) δC: 22.77, 23.22, 26.87, 27.07, 27.75,
28.01, 28.38, 28.47, 28.78, 33.73, 124.89, 127.66, 127.98, 128.50, 129.26, 129.28, 129.98, 131.23,
133.24, 136.96, 144.36, 146.64; MS (m/z, %): 377 (M+, 80). Anal. Calcd for C25H28ClN: C, 79.45; H,
7.47; N, 3.71. Found: C, 79.32; H, 7.38; N, 3.60.
2-Methyl-3,4-diphenylquinoline (3m): White powder; mp 173-175 ˚C; IR (KBr), νmax 3056, 2911,
1
1562 cm-1; H NMR (CDCl3) δH: 2.56 (s, CH3), 7.09 (m, 4H, ArH), 7.21 (m, 6H, ArH), 7.41 (m, 1H,
ArH), 7.50 (d, J=7.7 Hz, ArH), 7.70 (m, 1H, ArH), 8.15 (d, J=7.8 Hz, ArH); 13C NMR (CDCl3) δC: 25.42,
125.90, 126.31, 126.63, 126.85, 127.24, 127.70, 127.93, 128.55, 129.18, 130.04, 130.10, 134.09, 136.76,
138.61, 146.70, 146.95, 157.86; MS (m/z, %): 295 (M+, 95). Anal. Calcd for C22H17ClN: C, 89.46; H,
5.80; N, 4.74. Found: C, 89.33; H, 5.68; N, 4.63.
3,4-Diphenyl-2-propylquinoline (3n): White powder; mp 125-127 ˚C; IR (KBr), νmax 3059, 2968, 2932,
1
1601, 1565 cm-1; H NMR (CDCl3) δH: 0.87 (t, J=7.1 Hz, CH3), 1.71 (m, CH2), 2.80 (t, J=7.8 Hz, CH2),
7.09 (m, 4H, ArH), 7.20 (m, 6H, ArH), 7.39 (m, 1H, ArH), 7.48 (d, J=7.1 Hz, ArH), 7.70 (m, 1H, ArH),
8.15 (d, J=7.8 Hz, ArH); 13C NMR (CDCl3) δC: 14.25, 23.01, 39.27, 125.85, 126.15, 126.61, 126.76,
127.13, 127.65, 128.74, 129.07, 130.08, 130.32, 133.95, 136.97, 138.39, 147.07, 161.28; MS (m/z, %):
323 (M+, 45). Anal. Calcd for C24H21N: C, 89.12; H, 6.54; N, 4.33. Found: C, 89.02; H, 6.42; N, 4.24.
10-Phenyl-11H-indeno[1,2-b]quinoline (3o): White powder; mp 138-140 ˚C; IR (KBr), νmax 3058,
1
1616,1599, 1568 cm-1; H NMR (CDCl3) δH: 3.89 (s, CH2), 7.43-7.66 (m, 9H, ArH), 7.71-7.76 (m, 2H,
ArH), 8.29 (d, J=8.5 Hz, ArH), 8.38 (d, J=6.9 Hz, ArH); 13C NMR (CDCl3) δC: 34.00, 122.25, 125.35,
125.70, 125.81, 126.39, 127.52, 128.28, 128.73, 129.18, 129.28, 130.03, 132.98, 136.52, 140.45, 143.70,
145.26, 148.41, 161.01; MS (m/z, %): 293 (M+, 85). Anal. Calcd for C22H15N: C, 90.07; H, 5.15; N, 4.77.
Found: C, 90.01; H, 5.13; N, 4.66.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the Research Council of Shahid Beheshti
University.

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REFERENCES
1. G. Roma, M. D. Braccio, G. Grossi, F. Mattioli, and M. Ghia, Eur. J. Med. Chem., 2000, 35, 1021.
2. A. K. Agarwal and S. A. Jenekhe, Macromolecules, 1991, 24, 6806.
3. G. Jegou and S. A. Jenekhe, Macromolecules, 2001, 34, 7926.
4. Z. H. Skraup, Monatsh. Chem., 1880, 1, 316.
5. P. Friedländer, Chem. Ber., 1882, 15, 2572.
6. W. Pfitzinger, J. Prakt. Chem., 1886, 33, 100.
7. E. Roberts and E. E. Turner, J. Chem. Soc.,1927, 1832.
8. N. D. Heindel, T. A. Brodof, and J. E. Kogelschatz, J. Heterocycl. Chem., 1966, 3, 222.
9. C. C. Cheng and S. Yan, Org. React., 1982, 28, 37.
10. R. P. Thummel, Synlett, 1992, 1.
11. H. Eckert, Angew. Chem., Int. Ed. Engl., 1981, 20, 208.
12. S. Gladiali, G. Chelucci, M. S. Mudadu, M. A. Gastaut, and R. P. Thummel, J. Org. Chem., 2001,
66, 400.
13. C. S. Jin, Z. Zhang, S. J. Tu, and G. W. Wang, Org. Biomol. Chem., 2006, 4, 104.
14. P. Arumugan, G. Karthikeyn, R. Atchudan, D. Murlidharan, and P. T. Perumal, Chem. Lett., 2005,
34, 314.
15. J. S. Yadav, B. V. S. Reddy, and K. Premalatha, Synlett., 2004, 963.
16. V. Mamane, P. Hannen, and A. Fürstner, Chem. Eur. J., 2004, 10, 4556.
17. S. Atechian, N. Nock, R. D. Norcross, H. Ratni, A. W. Thomas, J. Verron, and R. Masciadri,
Tetrahedron, 2007, 63, 2811.
18. G. C. Muscia, M. Bollini, J. P. Carnevale, A. M. Bruno, and S. E. Asıs, Tetrahedron Lett., 2006, 47,
8811.
19. J. S. Yadav, P. P. Rao, D. Sreenu, R. S. Rao, V. N. Kumar, K. Nagaiah, and A. R. Prasad,
Tetrahedron Lett., 2005, 46, 7249.
20. L. Zhng and J. Wu, Adv. Synth. Catal., 2007, 349, 1047.
21. A. Shaabani, E. Soleimani, and Z. Badri, Monatsh. Chem., 2006, 137, 181.
22. S. A. Palimkar, S. A. Siddiqui, T. Daniel, R. J. Lahoti, and K. V. Srinivasan, J. Org. Chem., 2003, 68
9371.
23. (a) J. Azizian, A. A. Mohammadi, and A. R. Karimi, Synth. Commun., 2003, 33, 415. (b) J. Azizian,
A. R. Karimi, H. Arefrad, A. A. Mohammadi, and M. R. Mohammadizadeh, Molecular Diversity,
2003, 6, 223. (c) J. Azizian, A. R. Karimi, Z. Kazemizadeh, A. A. Mohammadi, and M. R.
Mohammadizadeh, J. Org. Chem., 2005, 70, 1471. (d) J. Azizian, A. R. Karimi, E. Soleimani, A. A.
Mohammadi, and M. R. Mohammadizadeh, Heteroatom Chem., 2006, 17, 277. (e) J. Azizian, A. A.

954
HETEROCYCLES, Vol. 75, No. 4, 2008
Mohammadi, M. Kohshari, A. R. Karimi, and M. R. Mohammadizadeh, J. Heterocycl. Chem., 2007,
44, 455.
24. (a) J. Azizian, A. A. Mohammadi, A. R. Karimi, and M. R. Mohammadizadeh, J. Org. Chem., 2005,
70 350. (b) M. Dabiri, P. Salehi, S. Otokesh, M. Baghbanzadeh, G. Kozehgarya, and A. A.
Mohammadi, Tetrahedron Lett., 2005, 46, 6123. (c) J. Azizian, A. A. Mohammadi, A. R. Karimi,
and M. R. Mohammadizadeh, Appl. Catal. A: Gen., 2006, 300, 85.
25. S. K. De and R. A. Gibbs, Tetrahedron Lett., 2005, 46, 1647.