Iron(III) chloride-promoted, solvent-free, facile, and efficient Friedlaender synthesis of quinolines

Article abstract of DOI:10.1080/00397910701575541

A mild, efficient, and solvent-free version of Friedlaender annulation of 2-amino ketones and α-methylene carbonyl compounds for the synthesis of polysubstituted quinolines using a catalytic amount of commercially available iron(III) chloride at room temp

Full text of DOI:10.1080/00397910701575541

This article was downloaded by: [University of Missouri Columbia]
On: 14 March 2013, At: 11:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Iron(III) Chloride–Promoted, Solvent‐Free,
Facile, and Efficient Friedländer Synthesis of
Quinolines
a
a
a
Sanjay Kumar , Anil Saini & Jagir S. Sandhu
a
Department of Chemistry, Punjabi University, Patiala, India
Version of record first published: 19 Nov 2007.
To cite this article: Sanjay Kumar , Anil Saini & Jagir S. Sandhu (2007): Iron(III) Chloride–Promoted,
Solvent‐Free, Facile, and Efficient Friedländer Synthesis of Quinolines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:22, 4071-4078
To link to this article: http://dx.doi.org/10.1080/00397910701575541
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

w
Synthetic Communications , 37: 4071–4078, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575541
Iron(III) Chloride–Promoted, Solvent-Free,
Facile, and Efficient Friedl a¨ nder Synthesis
of Quinolines
Sanjay Kumar, Anil Saini, and Jagir S. Sandhu
Department of Chemistry, Punjabi University, Patiala, India
Abstract: A mild, efficient, and solvent-free version of Friedl a¨ nder annulation of
2-amino ketones and a-methylene carbonyl compounds for the synthesis of polysub-
stituted quinolines using a catalytic amount of commercially available iron(III)
chloride at room temperature in excellent yields is described.
Keywords: 2-amino ketones, Friedl a¨ nder synthesis, iron(III) chloride, a-methylene
carbonyl compounds, quinolines
Quinolines and their derivatives are of unique significance because they are
[
1]
ubiquitous in nature and have wide-ranging biological activities. The
broad spectrum of activities includes antimalarial, anti-inflammatory, antihy-
[2]
pertensive, antibacterial, and tyrosine kinase-inhibiting properties. New
quinoline derivatives continue to unfold further biological activities, such as
[3]
the histamine H receptor antagonist. Apart from these pharmaceutical
3
activities, quinolines are important synthetic materials for the preparation of
[
4]
nano- and mesostrutures. The industrial, biological, and synthetic signifi-
cance places this scaffold at a prestigious position. For the synthesis of
these quinolines, well-known reactions such as Skraup, Doebner–von
[
5]
Miller, and Friedl a¨ nder are available to chemists.
[
The Friedl a¨ nder
reaction appears to be simple and continues to attract the considerable
6]
Received in India March 29, 2007
Address correspondence to Jagir S. Sandhu, Department of Chemistry, Punjabi
University, Patiala, India. E-mail: j_sandhu2002@yahoo.com
4
071

4
072
S. Kumar, A. Saini, and J. S. Sandhu
[7]
attention of the scientific community. The typical Friedl a¨ nder procedure
involves refluxing aqueous or alcoholic solution of amino ketones and
suitably substituted carbonyl compound. The refluxing time ranged up to
several hours, and high temperatures on the order of 150–2208C were used.
In a few reports, the reaction mixture was heated for more than 24 h using
5
highly toxic m-cresol solvent.
–10 equivalents of an acidic catalyst such as diphenylphosphate (DPP) in
[
4,8]
Even then, reaction was not fairly general
[9]
in scope; it failed in the case of acetoacetic ester and several other
ketones such as cyclohexanone and deoxybenzion. These failures prompted
a search for fairly general catalytic system that followed reports of use of
[
5,10,11]
inorganic bases,
and sulfuric acid derivatives; and phosphoric acids.
strong Brønsted acid catalysts such as HCl, H SO ,
2 4
[12,13]
Even classical
catalysis required harsh conditions and long reaction times. To overcome
these problems, Lewis acids such as ZnCl , AuCl , and inorganic salts and
2
3
[14]
microwave- and ionic liquid–catalysed conditions were used,
few metal triflates such as Y(OTf) . But these are accompanied by one or
including a
3
another drawback, such as environmental toxicity or expense, and the use
of microwaves is not practical for large-scale production. In view of
foregoing industrial, pharmacological, and commercial importance of quino-
lines, we feel a further simple, convenient, and environmentally benign
protocol in still timely.
In recent years, iron(III) chloride has emerged as efficient catalyst for
various prominent reactions of organic chemistry such as Michael
[
15]
[16]
[17]
reaction,
Recently, Christoffers et al. have systematically investigated and established
Biginelli and Biginelli-like reactions,
and several others.
[
15,18]
the superiority of this catalyst over other transition-metal Lewis acids
in Michael and other related reactions. Prompted by these recent reports of
the superiority of iron(III) chloride in literature, we employed this catalyst
in the Friendl a¨ nder reaction for the synthesis of quiniolines, which is fairly
cheap and commercially available as a shelf chemical (Scheme 1).
In the course of optimizating the reaction condition, 10 mol% of FeCl3
was found to be the optimum amount. Use of a higher amount of catalyst
did not improve the yield while a decrease in the amount of catalyst
decreases the yield. In the absence of FeCl , the reaction did not proceed
3
even after a long reaction time (18–20 h). Increase in reaction time did not
prove fruitful. To see the scope of this protocol, several examples were
Scheme 1.

Friedl a¨ nder Synthesis of Quinolines
4073
studied. Various substituted 2-aminoketones such as 2-aminobenzophenone
0
and 2-amino-5,2 -dichlorobenzophenone reacted effectively with a-methylene
carbonyl compound such as acetyl acetone, ethyl acetoacetate, 1,3-
cyclohexanedione, 5,5-dimethyl cychohexanedione, and cyclohexanone
(
Table 1). The reaction proceeds smoothly without the formation of any side
products.
In summary, we describe a simple, facile, one-pot, solvent-free, and
efficient version of Friedl a¨ nder annulation for the synthesis of quinolines
using a commercially available bench chemical, FeCl . The operational sim-
3
plicity, lack of harsh reaction conditions, and use of an inexpensive catalyst
are other merits of this protocol.
EXPERIMENTAL
Melting points were determined on a Buchi melting-point apparatus and are
uncorrected. IR spectra were recorded by using KBr disc on a Perkin-Elmer
1
40c analyzer. H NMR spectra were obtained on Brucker AC 300 spec-
2
trometers (chemical shifts in d, ppm) using tetramethylsilane as internal
standard. All the solvents were distilled before use. The progress of the
reaction was monitored by thin-layer chromatography (TLC) using silica
gel G (Merck), and spots were exposed in iodine vapor. Chromatographic
purification was performed with silica gel (100–200 mesh, Merck). FeCl is
3
used as procured from Merck.
General Procedure for the Synthesis of Quinolines (3a–l)
An equimolar solution of 2-amino ketone, a-methylene carbonyl compound,
and FeCl (0.1 equiv.) were stirred at room temperature for a specified time.
3
After the completion of reaction (vide TLC), water (20 mL) was added to
reaction mixture and extracted with ethyl acetate (3 ꢀ 15 mL). The product
was dried over anhydrous Na SO , and the solvent was evaporated under
2
4
reduced pressure. The solid, thus obtained, was purified chromatographically
to give pure quinolines.
Spectral Data of Some Selected Compounds
Ethyl-2-methyl-4-phenylquinoline-3-carboxylate (3a): mp 99–1008C, IR
2
1
1
(KBr): 3061, 2975, 1724, 1610 cm
.
H NMR (200 MHz, CDCl3):
d ¼ 0.97 (t, J ¼ 6.8 Hz, 3H), 2.75 (s, 3H), 4.02 (q, J ¼ 6.8 Hz, 2H), 7.28–
1
3
7
.50 (m, 7H), 7.65–7.73 (m, 2H), 8.05 (d, J ¼ 8.1 Hz, 1H). C NMR:
(
75 MHz, CDCl ): d ¼ 13.5, 23.1, 60.8, 96.3, 125.2, 126.1, 126.4, 127.7,
3
1
28.2, 129.2, 129.7, 135.7, 145.8, 147.6, 153.9, 167.5. EIMS: m/z

Table 1. FeCl
3
-mediated Friedl a¨ nder synthesis of quinolines 3a–l
a
b
c
Entry
1
2-Aminoketone
a-Methylene carbonyl
Quinoline
Yield (%)
Time (min)
40
Mp (8C)
89
99–100 (99–100)
2
3
4
1a
1a
1a
1a
90
88
91
45
55
45
155–156 (156–157)
190–191 (190–192)
114–115 (115)
d
78
5
6
7
60
45
60
139–141 (140–142)
Liquid
84
d
78
1b
76–79 (78–79)

8
1b
86
50
106–107 (105–106)
9
0
81
89
45
40
150–152 (151–152)
80–81 (80–81)
1
c
1
1c
1
1
84
82
50
50
137–138 (138)
110–112 (112)
1
d
12
1d
a
b
c
1
All products were characterized by mp, IR, and H NMR.
Yields refer to pure isolated product.
Literature melting points given in parentheses.
d
0
.2 Equivqlents of catalyst were used.

4
076
S. Kumar, A. Saini, and J. S. Sandhu
þ
(
Anal. calcd. for C H NO : C, 78.33; H, 5.88; N, 4.81. Found: C, 78.31;
%) ¼ 291 (85) [M ], 263 (10), 246 (100), 218 (60), 176 (40), 150 (20).
1
9
17
2
H, 5.84; N, 4.78.
9
3
-Phenyl-3,4-dihydroacridin-1(2H)-one (3b): mp 155–1568C, IR (KBr):
21 1
060, 2951, 1712, 1610, 1575, 1204 cm . H NMR (200 MHz, CDCl ):
3
d ¼ 2.25–2.30 (m, 2H), 2.70 (t, J ¼ 6.6 Hz, 2H), 3.36 (t, J ¼ 6.4 Hz, 2H),
.15–7.18 (m, 2H), 7.45–7.50 (m, 6H), 8.12 (d, J ¼ 8.7 Hz, 1H). Anal.
calcd. for C H NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.56; H, 5.49;
7
1
9 15
N, 5.135.37.
3
1
,3-Dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-one (3c): mp 190–
1
2
1
918C, IR (KBr): 3065, 2954, 1718, 1605, 1570, 1210 cm . H NMR
(
(
200 MHz, CDCl ): d ¼ 1.20 (s, 6H), 2.60 (s, 2H), 3.35 (s, 2H), 7.15–7.25
3
m, 2H), 7.40–7.50 (m, 5H), 7.80 (t, J ¼ 7.9 Hz, 1H), 8.10 (d, J ¼ 8.1 Hz,
þ
1
H). EIMS: m/z (%) ¼ 301 (100) [M ], 272 (72), 246 (60), 218 (50), 190
(
10). Anal. calcd. for C H NO: C, 83.69; H, 6.35; N, 4.65. Found: C,
21 19
83.79; H, 6.51; N, 4.66.
1
-(2-Methyl-4-phenylquinolin-3-yl)ethanone (3d): mp 114–1158C, IR
2
1
1
(
KBr): 3050, 2970, 1701, 1620 cm
.
H NMR (200 MHz, CDCl3):
d ¼ 2.01 (s, 3H), 2.61 (s, 3H), 7.32–7.75 (m, 8H), 8.03 (d, J ¼ 8.0 Hz,
þ
1
H). EIMS: m/z (%) ¼ 261 (75) [M ], 246 (100), 218 (80), 176 (50), 150
(
Found: C, 82.81; H, 5.81; N, 5.37.
20), 43 (30). Anal. calcd. for C H NO: C, 82.73; H, 5.79; N, 5.36.
18 15
9
2
1
7
-Phenyl-1,2,3,4-tetrahydroacridine (3e): mp 139–1418C, IR (KBr): 3055,
2
1 1
940, 1612 cm . H NMR (200 MHz, CDCl ): d ¼ 1.70–1.82 (m, 2H),
3
.98–2.04 (m, 2H), 2.59 (t, J ¼ 7.0 Hz, 2H), 3.18 (t, J ¼ 7.2 Hz), 7.19–
1
3
.30 (m, 3H), 7.38–7.58 (m, 5H), 8.1 (d. J ¼ 8.1 Hz, 1H).
C
NMR: (75 MHz, CDCl ): d ¼ 22.8, 23.1, 27.6, 34.2, 96.2, 125.2, 126.3,
3
126.7, 127.6, 128.1, 128.6, 129.2, 137.7, 145.9, 146.6, 158.9. Anal.
calcd. for C H N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.06; H, 6.58;
N, 5.36.
1
9 17
3
,3,9-Trimethyl-3,4-dihydroacridin-1(2H)-one (3h): mp 106–1078C, IR
2
KBr): 2949, 2965, 1685, 1557, 1498, 1370, 1280, 1222 cm . H NMR
1 1
(
(
(
200 MHz, CDCl ): d ¼ 1.10 (s, 6H), 2.63 (s, 2H), 3.10 (s, 3H), 7.53–7.57
3
m, 1H), 7.76–7.79 (m, 1H), 8.06 (d, J ¼ 8.4, 1H), 8.25 (d, J ¼ 8.4 Hz,
1
H). Anal. calcd. for C H ClNO: C, 80.30; H, 7.16; N, 5.85. Found: C,
18 14
8
0.41; H, 7.12; N, 5.84.
1
-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)-2,2,2-trifluoroethanone (3j):
1
21
. H NMR (200 MHz,
mp 80–818C, IR (KBr): 3030, 1745, 1624 cm
CDCl ): d ¼ 2.51 (s, 3H), 7.33–7.72 (m, 8H), 8.05 (d, J ¼ 8.03 Hz, 1H).
3

Friedl a¨ nder Synthesis of Quinolines
4077
Anal. calcd. for C H ClFNO: C, 61.82; H, 3.17; N, 4.00. Found: C, 61.88; H,
1
8 13
3
.18; N, 3.97.
1
1
-[6-Chloro-4-(2-chlorophenyl)-2-methylquinolin-3-yl]ethanone (3k): mp
2
1 1
37–1388C, IR (KBr): 3058, 2962, 1695, 1626 cm . H NMR (200 MHz,
CDCl ): d ¼ 1.01–1.05 (m, 3H), 2.81 (s, 3H), 4.06–4.10 (m, 2H), 7.25–
3
7
.48 (m, 6H), 8.06 (d, J ¼ 9.1 Hz, 1H). Anal. calcd. for C H Cl NO: C,
1
8
13
2
6
5.47; H, 3.97; N, 4.24. Found: C, 65.46; H, 3.92; N, 4.18.
Ethyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-3-carboxylate (3l):
2
1
1
mp 110–1128C, IR (KBr): 3071, 2962, 1715, 1605, 1248 cm
.
H
NMR (200 MHz, CDCl ): d ¼ 2.18 (s, 3H), 2.65 (s, 3H), 7.25–7.30
3
(
m, 2H), 7.40–7.58 (m, 4H), 8.08 (d, J ¼ 9.0 Hz, 1H). Anal. calcd.
for C H Cl NO : C, 63.35; H, 4.20; N, 3.89. Found: C, 63.48; H, 4.14;
19 15 2 2
N, 3.82.
ACKNOWLEDGMENT
The authors thank the Council of Scientific and Industrial Research, New
Delhi, India, for financial support.
REFERENCES
1
2
3
4
. Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., and Scriven, E. F. V. Eds.; Pergamon: New York,
1996; Vol. 5, p. 245.
. Chen, Y. L.; Fang, K. C.; Sheu, J.-Y.; Hsu, S. L.; Tzeng, C. C. Synthesis and anti-
bacterial evaluation of certain quinolone derivatives. J. Med. Chem. 2001, 44,
2374–2377.
. Zaragoza, F.; Stephensen, H.; Peschke, B.; Rimvall, K. 2-(4-Alkylpiperazin-1-yl)
quinolines as a new class of imidazole-free histamine H receptor antagonists.
3
J. Med. Chem. 2005, 48, 306–311.
. Jenekhe, S. A.; Lu, L.; Alam, M. M. New conjugated polymers with donor–
acceptor architectures: Synthesis and photophysics of carbazole-quinoline and
phenothiazine-quinoline copolymers and oligomers exhibiting large intramole-
cular charge transfer. Macromolecules 2001, 34, 7315–7324.
5
6
7
. Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., and Scriven, E. F. V. Eds.; Pergamon: New York, 1996; Vol. 5,
p. 167.
. Elderfield, R. C. For a comprehensive review of the Friedl a¨ nder synthesis. In
Heterocyclic Compounds; Elderfield, R. C. Ed.; John Wiley and Sons:
New York, 1950; Vol. 4, pp. 45–47, 209.
. (a) Katritzky, A. R.; Arend, M. A convenient and highly regioselective one-pot
synthesis of quinolines by addition of a Vilsmeier-type reagent to N-arylimines.

4
078
S. Kumar, A. Saini, and J. S. Sandhu
J. Org. Chem. 1998, 63, 9989–9991; (b) Jiang, B.; Si, Y.-G. J. Org. Chem. 2002,
7, 9449–9451, and references cited therein.
6
8
9
. Jegou, G.; Jenekhe, S. A. Highly fluorescent poly(arylene ethynylene)s containing
quinoline and 3-alkylthiophene. Macromolecules 2001, 34, 7926–7928.
. For unusual behaviour of b-keto esters in these condensations, see, Fehnel, E. A.;
Deyrup, J. A.; Davidson, M. B. Quinoline analogs of podophyllotoxin, II: Friedl a¨ n-
der reactions with tetronic acid: A general method for the preparation of 2-hydro-
xymethyl-3-quinolinecarboxylic acid lactones. J. Org. Chem. 1958, 23,
1
996–2000.
0. Hu, Y-Z.; Zang, G.; Thummel, R. P. Friedl a¨ nder approach for the incorporation of
-bromoquinoline into novel chelating ligands. Org. Lett. 2003, 5, 2251–2253.
1. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.;
Reider, P. J.; Sager, J. W.; Volante, R. P. Highly regioselective Friedl a¨ nder annu-
lations with unmodified ketones employing novel amine catalysts: Syntheses of
1
1
6
2-substituted quinolines, 1,8-naphthyridines, and related heterocycles. J. Org.
Chem. 2003, 68, 467–477.
1
1
2. McNaughton, B. R.; Miller, B. L. A mild and efficient one-step synthesis of
quinolines. Org. Lett. 2003, 5, 4257–4259.
3. Song, S. J.; Cho, S. J.; Park, D. K.; Kwon, T. W.; Jenekhe, S. A. Microwave
enhanced solvent-free synthesis of a library of quinoline derivatives. Tetrahedron
Lett. 2003, 44, 255–257.
1
4. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Ionic
liquid–promoted regiospecific Friedlander annulation: Novel synthesis of quino-
lines and fused polycyclic quinolines. J. Org. Chem. 2003, 68, 9371–9378.
5. Christoffers, J.; Oertling, H.; Frey, W. Regioselective spiroannulations of a-acetyl
lactones. Eur. J. Org. Chem. 2003, 1665–1671.
1
1
6. Lu, J.; Bai, Y. Catalysis of the biginelli reaction by ferric and nickel chloride hex-
ahydrates: One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Synthesis
2
002, 466–469.
1
7. Wang, Z.-T.; Xu, L.-W.; Xia, C.-G.; Wang, H.-Q. Novel Biginelli-like three-
component cyclocondensation reaction: Efficient synthesis of 5-unsubstituted
3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2004, 45, 7951–7953.
8. Christoffers, J.; Oertling, H. Intramolecular Michael reactions by iron(III)
catalysis. Tetrahedron 2000, 56, 1339–1344.
1