Iodine-catalyzed Friedlander quinoline synthesis under solvent-free conditions

Article abstract of DOI:10.1002/jccs.200700039

Polyfunctional quinolines were synthesized using Friedlander method catalyzed by molecular iodine in high yields at 60 °C under solvent-free conditions.

Full text of DOI:10.1002/jccs.200700039

Journal of the Chinese Chemical Society, 2007, 54, 267-271
267
Communication
Iodine-Catalyzed Friedlander Quinoline Synthesis under Solvent-Free
Conditions
Mohammad Ali Zolfigol,a* Peyman Salehi,b Arash Ghaderia and Morteza Shiria
aFaculty of Chemistry, Bu-Ali Sina University, Hamadan, 6517838683, Iran
bDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University,
Evin, Tehran, Iran
Polyfunctional quinolines were synthesized using Friedlander method catalyzed by molecular iodine
in high yields at 60 °C under solvent-free conditions.
Keywords: Quinolines; Molecular iodine; Friedlander synthesis; Solvent-free; Catalyst.
Quinolines occur in numerous natural compounds,1
and have wide applications in medicinal chemistry such as
anti-malarial, anti-inflammatory, anti-bacterial, anti-hyper-
tensive activities and as tyrosine kinase inhibiting agents.2
In addition, quinolines are valuable synthons used for the
preparation of nano and mesostructures with enhanced
electronic and photonic properties.3 There are many re-
ported methods for the synthesis of quinoline rings;4 the
Friedlander procedure5 is still one of the most simple and
straightforward methods for the synthesis of polyfunc-
tional quinolines. Alternatively, this reaction was also in-
vestigated using different protic and Lewis acids such as
Bi(OTf)3,6 ZnCl2,7 FeCl3 and Mg(ClO4)2,8 AcOH under mi-
crowave irradiation,9 HCl,10 sodium fluoride,11 silvertung-
stophosphate,12 Y(OTf)3,13 sulfamic acid,14 ionic liquid,15
and NaAuCl4.16
harmful solvents such as acetonitrile, THF, DMF, and
DMSO, leading to difficult product isolation and recovery
procedures.
In recent years, molecular iodine has received consid-
erable attention as an inexpensive, non-toxic, and readily
available catalyst for various organic transformations un-
der mild and convenient conditions.17,18 Most of the re-
ported reactions which have been promoted by molecular
iodine produced the corresponding products with high
yields and selectivity. Thus, to continue our investigation
on developing new methodologies in organic chemistry,19
synthesis of 1,4-dihydropyridines,20 and quinolines,21 and
to explore the applicability of the molecular iodine in vari-
ous reactions, we interested in I2-promoted Friedlander
synthesis of quinolines containing reactive functionalities.
Firstly, we studied the synthesis of 6-chloro-3-(ethylfor-
mato)-2-methyl-4-phenylquinoline from 2-amino-5-chlo-
robenzophenone and ethyl acetoacetate in the presence of
SiO2/I2 as catalyst.
However, most of the synthetic protocols reported so
far suffer from high temperatures (150-200 °C), prolonged
reaction times, low yields and the use of hazardous and of-
ten expensive catalysts. Moreover, the synthesis of these
heterocyclic compounds have been usually carried out in
We found that the above mentioned reaction was
completed after 2 h at 60 °C under neat conditions, and the
Scheme I
O
2
R
1
R
2
3
4
1
R
O
R
R
R
SiO /I
2
2
3
+
R
4
R
NH
°
neat/60C
2
N
1
2
3
* Corresponding author. Fax: +98 811 8257407; E-mail: zolfi@basu.ac.ir, mzolfigol@yahoo.com

268 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Zolfigol et al.
desired quinoline was isolated in 80% yield. When I2 was
used alone, a sticky mixture was formed and the yield was
low. For overcoming this limitation we used a small amount
of SiO2 together with molecular iodine. Then we applied
the same conditions for the other substrates 1 and 2 (Scheme
I, Table 1). The reactions proceeded with moderate to high
yields. Surprisingly, under this new condition, 1,3-cyclo-
hexanedione reacted faster than other diketones with 1a
and 1b to produce the corresponding quinolines in high
yields (Table 1, entries 1, 8). In addition, the results showed
that the reaction of acetophenone with 1a proceeded
smoothly in moderate yield (Table 1, entry 12). Other b-
dicarbonyl compounds also reacted satisfactorily with
2-aminobenzophenone and its 5-chloro derivative to pro-
duce the desired quinolines containing diverse reactive
functional groups (Table 1).
ylquinoline as a yellow crystal was obtained in 80% yield
(0.265 g).
Spectral data for some quinolines as typical
(3a): Yellow solid; mp 185 °C; FT-IR (KBr): u 3024,
2956, 1684, 1551, 1476, 1075, 838, 697, cm-1. 1H NMR (90
MHz, CDCl3): d (ppm) 2.24 (q, 2H, J = 4.3, 7.7, 6.4), 2.71
(t, 2H, J = 6.4, 7.7), 3.36 (t, 2H, J = 4.3, 7.7), 7.20-7.95 (m,
8H). 13C NMR (22.5 MHz, CDCl3): d (ppm) 20.91, 34.16,
40.20, 124.15, 127.92, 128.28, 129.94, 132.00, 136.51,
146.66, 149.90, 162.17, 196.98. HRMS: m/z 306.
(3b): Yellow solid; mp 101 °C; FT-IR (KBr): u 3076,
2977, 2930, 1719, 1602, 1564, 1479, 1381, 1308, 1216,
1162, 1069, 885, 797, 609 cm-1. 1H NMR (90 MHz, CDCl3):
d (ppm) 0.95 (t, 3H, J = 6.4, 8.6), 2.78 (s, 3H), 4.03 (q, 2H, J
= 6.4, 6.4, 8.6), 7.46-7.96 (m, 8H). 13C NMR (22.5 MHz,
CDCl3): d (ppm) 13.42, 23.50, 61.11, 124.90, 125.70,
128.19, 128.51, 129.15, 130.41, 130.73, 132.09, 134.92,
145.03, 145.88, 154.74, 167.71, 195.83. HRMS: m/z 325.
(3c): White solid; mp 217 °C; FT-IR (KBr): u 3390,
1672, 1569, 1480, 1226, 1022, 967, 831, 785, 699 cm-1. 1H
NMR (90 MHz, CDCl3): d (ppm) 2.62 (s, 3H), 7.25-8.03
(m, 13H). 13C NMR (22.5 MHz, CDCl3): d (ppm) 23.95,
124.97, 126.12, 128.22, 128.51, 129.19, 129.93, 130.65,
130.91, 132.45, 133.62, 134.20, 136.99, 144.71, 148.28,
155.07, 197.24. HRMS: m/z 356.
In conclusion, we have successfully developed an
easy and efficient method for the preparation of various
quinolines from different ketones and diketones with 2-
aminoarylketones in the presence of catalytic amounts of
iodine and silica gel at 60 °C under solvent-free conditions.
The catalytic activity of iodine is remarkable and the use of
low cost and commercially available iodine as catalyst for
the synthesis of quinolines in moderate to excellent yields
is also significant under the aspect of environmentally be-
nign processes.
(3d): Yellow solid; mp 211 °C; FT-IR (KBr): u 3074,
2952, 2866, 1696, 1554, 1477, 1384, 1297, 1198, 1079,
837, 699 cm-1. 1H NMR (90 MHz, CDCl3): d (ppm) 1.15 (s,
6H), 2.56 (s, 2H), 3.25 (s, 2H), 7.21-7.95 (m, 8H). 13C
NMR (22.5 MHz, CDCl3): d (ppm) 28.32, 32.16, 48.34,
54.18, 123.34, 126.73, 127.87, 128.07, 128.30, 130.26,
132.41, 136.82, 147.44, 150.03, 161.43, 197.49. HRMS:
m/z 334.
EXPERIMENTAL SECTION
General
Chemicals were purchased from Fluka, Merck and
Aldrich chemical companies. Yields refer to isolated pure
products. The products were characterized by comparison
of their spectral (IR, UV, 1H-NMR and HRMS) and physi-
cal data with authentic samples. Silica gel mesh 70-230
was used.
(3e): Yellow solid; mp 135 °C; FT-IR (KBr): u 3455,
3049, 2948, 1736, 1559, 1481, 1378, 1283, 1214, 1161,
1067, 828, 759, 712, 679 cm-1. 1H NMR (90 MHz, CDCl3):
d (ppm) 2.76 (s, 3H), 3.58 (s, 3H), 7.47-7.96 (m, 9H). 13
C
Typical procedure
NMR (22.5 MHz, CDCl3): d (ppm) 23.65, 52.07, 125.12,
125.79, 128.40, 128.71, 129.12, 130.54, 131.02, 132.32,
134.97, 145.39, 148.10, 154.84, 168.47. HRMS: m/z 311.
(3f): Yellow solid; mp 157 °C; FT-IR (KBr): u 3076,
2977, 1720, 1561, 1479, 1380, 1219, 1068, 840, 711 cm-1.
1H NMR (90 MHz, CDCl3): d (ppm) 2.00 (s, 3H), 2.68 (s,
3H), 7.35-7.95 (m, 8H). HRMS: m/z 297.
A mixture of 2-amino-5-chlorobenzophenone (0.233
g, 1 mmol), ethyl acetoacetate (0.195 g, 1.5 mmol), SiO2
(0.1 g) and I2 (0.050 g, 0.2 mmol) was stirred at 60 °C for 2
h. After completion of the reaction confirmed by TLC,
Na2S2O3 solution was added to the reaction mixture and fil-
tered. The filtrate was washed with acetone (20 mL). After
evaporation of the solvent, the product was recrystallized
by ethanol. 6-Chloro-3-(ethylformato)-2-methyl-4-phen-
1
(3g): Yellow solid; H NMR (90 MHz, CDCl3): d
(ppm) 2.64 (s, 3H), 7.23-8.11 (m, 14H).

Synthesis of Quinolines under Solvent-Free Conditions
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 269
Table 1. I2 catalysed synthesis of quinolines under solvent-free conditions
Entry
Substrate 1
Ketone 2
Quinoline 3
Time (h)
1.5
Yield (%)a
O
Ph
O
O
O
Cl
Cl
1
97
NH2
N
1a
3a
O
Ph
O
O
Cl
OEt
2
3
4
5
6
7
1a
1a
1a
1a
2
3.5
12
80
72
50
77
86
66
OEt
N
3b
Ph
O
O
O
Cl
Ph
Ph
O
N
3c
Ph
O
O
Cl
N
3d
O
Ph
Cl
O
O
OMe
1.5
2.75
4
OMe
N
3e
O
Ph
Cl
O
O
1a
N
3f
O
O
Ph
O
O
Ph
Ph
NH2
N
1b
3g
Ph
O
O
O
8
9
1b
1b
1.75
1.25
80
54
N
3h
O
Ph
O
O
OEt
OEt
N
3i

270 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Zolfigol et al.
Table 1, continued
Entry
Substrate 1
Ketone 2
Quinoline 3
Time (h)
2.25
Yield (%)a
O
Ph
O
O
OMe
10
1b
67
80
60
OMe
N
3j
O
Ph
O
O
11
1b
3
N
3k
Ph
Cl
O
12
1a
15
Ph
N
Ph
3l
a Isolated yields.
1
(3h): Yellow solid; H NMR (90 MHz, CDCl3): d
(ppm) 2.21 (q, 2H, J = 5.8, 6.2, 5.8), 2.69 (t, 2H, J = 6.2,
6.4), 3.36 (t, 2H, J = 5.9, 5.9). 13C NMR (22.5 MHz,
CDCl3): d (ppm) 20.86, 34.09, 40.09, 123.38, 125.90,
127.00, 127.67, 128.09, 131.11, 137.20, 148.21, 150.65,
161.73, 197.08.
edged.
Received June 6, 2006.
(3i): Yellow solid; mp 99 °C; FT-IR (KBr): u 3064,
2978, 2928, 1712, 1561, 1402, 1297, 1237, 1182, 1070,
872, 767 cm-1. 1H NMR (90 MHz, CDCl3): d (ppm) 0.86 (t,
3H, J = 7.7, 8.6), 2.71 (s, 3H), 3.93 (q, 2H, J = 7.7, 8.6, 7.7),
7.35-7.95 (m, 9H). 13C NMR (22.5 MHz, CDCl3): d (ppm)
13.48, 23.39, 61.19, 125.10, 126.44, 127.37, 128.40, 129.25,
130.33, 135.52, 146.61, 147.09, 154.45, 168.00. HRMS:
m/z 291.
REFERENCES
1. (a) Morimoto, Y.; Matsuda, F.; Shirahama, H. Synlett 1991,
202. (b) Isobe, M.; Nishikawa, T.; Yamamoto, N.; Tsukiyama,
T.; Ino, A.; Okita, T. J. Heterocycl. Chem. 1992, 29, 619. (c)
Michael, J. P. Nat. Prod. Rep. 1997, 14, 605.
2. (a) Ko, T. C.; Hour, M. J.; Lien, J. C.; Teng, C. M.; Lee, K. H.;
Kuo, S. C.; Huang, L. J. Bioorg. Med. Chem. Lett. 2001, 11,
279. (b) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A.
P.; Zilberstein, A. J. Med. Chem. 1994, 37, 2129. (c) Larsen,
R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.; Davis, P.;
Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.;
Xiang, Y. B.; Zamboni, R. J. J. Org. Chem. 1996, 61, 3398.
(d) Chen, Y. L.; Fang, K. C.; Sheu, J.-Y.; Hsu, S. L.; Tzeng,
C. C. J. Med. Chem. 2001, 44, 2374. (e) Roma, G.; Braccio,
M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem.
2000, 35, 1021.
(3j): White solid; FT-IR (KBr): u 3064, 2950, 2885,
1731, 1582, 1562, 1486, 1426, 1392, 1373, 1295, 1229,
1170, 1125, 1067, 1029, 967, 761, 700, 601 cm-1. 1H NMR
(90 MHz, CDCl3): d (ppm) 2.78 (s, 3H), 3.55 (s, 3H), 7.41-
8.03 (m, 9H). HRMS: m/z 277.
ACKNOWLEDGMENT
3. Jenekhe, S. A.; Lu, L.; Alam, M. M. Macromolecules 2001,
34, 7315.
Financial support for this work by the Management
and Programming Organization of I.R. Iran (special finan-
cial support due to selection by ESI as a top 1% researcher
on the basis of paper citation) and Research Affairs, Bu-Ali
Sina University, Hamadan, Iran, is gratefully acknowl-
4. See an excellent review: Kouznetsov, V. V.; Mendez, L. Y.
V.; Gomez, C. M. M. Cur. Org. Chem. 2005, 9, 141.
5. (a) Friedlander, P. Ber. 1882, 15, 2572. (b) Elderfield, R. C.
In Heterocyclic Compounds; Vol. 4, Elderfield, R. C., Ed.;

Synthesis of Quinolines under Solvent-Free Conditions
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 271
Wiley: New York, 1952, 45. (c) Ubeda, J. I.; Villacampa, M.;
Avendano, C. Synthesis 1998, 1176.
18. (a) Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C. F. Tetrahedron
Lett. 2005, 46, 5771. (b) Zacuto, M.; Cai, D. Tetrahedron
Lett. 2005, 46, 8289. (c) Bhosale, R. S.; Sarda, S. R.;
Ardhapure, S. S.; Jadhav, W. N.; Bhusare, S. R.; Pawar, R. P.
Tetrahedron Lett. 2005, 46, 7183. (d) Patil, B. R.; Bhusare, S.
R.; Pawar, R. P.; Vibhute, Y. B. Tetrahedron Lett. 2005, 46,
7179. (e) Ren, B.; Cai, L.; Zhang, L. R.; Yang, Z. J.; Zhang, L.
H. Tetrahedron Lett. 2005, 46, 8083. (f) Yadav, J. S.; Reddy,
B. V. S.; Reddy, P. M. K.; Gupta, M. K. Tetrahedron Lett.
2005, 46, 8493. (g) Chu, C. M.; Gao, S.; Sastry, M. N. V.; Yao,
C. F. Tetrahedron Lett. 2005, 46, 4971. (h) Mori, N.; Togo, H.
Tetrahedron 2005, 61, 5915. (i) Karimi, B.; Golshani, B. J.
Org. Chem. 2000, 65, 7228.
6. Yadav, J. S.; Reddy, B. V. S.; Premalatha, K. Synlett 2004,
963.
7. McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257.
8. Wu, J.; Zhang, L.; Diaoa, T.-N. Synlett 2005, 2653.
9. Perzyna, A.; Houssin, R.; Barbry, D.; Hénichart, J.-P. Synlett
2002, 2077.
10. Bailliez, V.; El Kaim, L.; Michaut, V. Synth. Commun. 2004,
34, 109.
11. Mogilaiah, K.; Reddy, Ch. S. Synth. Commun. 2003, 33,
3131.
12. Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P.; Srinivasa Rao, R.;
Nagaiah, K. Synlett 2004, 2381.
19. (a) Mirjalili, B. F.; Zolfigol, M. A.; Bamoniri, A.; Zarei, A.
J. Chin. Chem. Soc. 2004, 51, 509. (b) Ghorbani-Vaghei, R.;
Zolfigol, M. A. J. Chin. Chem. Soc. 2005, 52, 327. (c)
Mirjalili, B. F.; Zolfigol, M. A.; Bamoniri, A.; Sheikhand, N.
J. Chin. Chem. Soc. 2006, 53, 955.
13. De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 1647.
14. Yadav, J. S.; Purushothama Rao, P.; Sreenu, D.; Srinivasa
Rao, R.; Naveen Kumar, V.; Nagaiah, K.; Prasad, A. R. Tet-
rahedron Lett. 2005, 46, 7249.
15. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J. Org. Chem. 2003, 68, 9371.
16. Arcadi, A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F.
Synlett 2003, 203.
20. (a) Zolfigol, M. A.; Safaiee, M. Synlett. 2004, 827. (b)
Zolfigol, M. A.; Salehi, P.; Safaiee, M. Lett. Org. Chem.
2006, 3, 153.
21. Asgarian-Damavandi, J.; Zolfigol, M. Z.; Karami, B. Synth.
Commun. 2001, 31, 3183.
17. See mini review as spotlight: Wang, S. Y. Synlett 2004,
2642.