A rapid, high-yielding, and efficient Friedlander synthesis of quinolines catalyzed by 2,4,6-trichloro-1,3,5-triazine

Article abstract of DOI:10.1246/cl.2007.796

A general procedure for the synthesis of quinolines via the Friedlander annulation using 2,4,6-trichloro-1,3,5-triazine (TCT) (4 mol%) as a novel catalyst is described. The method is simple, efficient, and rapid to afford quinolines in high yields. Copyri

Full text of DOI:10.1246/cl.2007.796

796
Chemistry Letters Vol.36, No.6 (2007)
A Rapid, High-yielding, and Efficient Friedlander Synthesis of Quinolines
Catalyzed by 2,4,6-Trichloro-1,3,5-triazine#
Biswanath Das,ꢀ Kongara Damodar, Nikhil Chowdhury, and Kanaparthy Suneel
Organic Chemistry Division – I, Indian Institute of Chemical Technology, Hyderabad–500 007, India
(Received March 6, 2007; CL-070245)
Table 1. TCT-catalysed Friedlander synthesis of quinolinesa
A general procedure for the synthesis of quinolines via
the Friedlander annulation using 2,4,6-trichloro-1,3,5-triazine
(TCT) (4 mol %) as a novel catalyst is described. The method
is simple, efficient, and rapid to afford quinolines in high yields.
α-Methylene
carbonyl
compound 2
O
Entry
2-Aminoaryl
Quinoline 3
Time
/min
Isolated
yield/%
ketone 1
Me
Me
O
1
35
89
NH2
N
Me
Me
O
Quinolines occur widely in natural products1 and biological-
ly active compounds.2 They are important in medicinal chemis-
try as antiasthmatic, antibacterial, antihypertensive, anti-inflam-
matory, antimalarial, and tyrosine kinase inhibiting agents.2,3
They are also useful synthons for preparation of nano- and
meso-structures with enhanced electronic and photonic proper-
ties.4 Thus, considering the useful applications in the fields of
medicine, industry, and synthetic organic chemistry, the devel-
opment of efficient methods for the synthesis of quinolines is
highly desirable. The Friedlander annulation is the most simple
and straightforward method for the synthesis of these com-
pounds.5 This method involves the acid- or base-catalyzed or
thermal condensation between a 2-aminoaryl ketone and a sec-
ond carbonyl compound having a reactive ꢀ-methylene group
followed by cyclodehydration. Various Brønsted acids have
been used6 as catalysts but the methods using these catalysts
are associated with harsh reaction conditions and side reactions.
Under thermal or base catalysis conditions 2-aminobenzophe-
none could not react with cyclohexanone and ꢁ-keto esters.
Some Lewis acids such as ZnCl2, Bi(OTf)3, Sc(OTf)3, and
AuCl3 and ionic liquids have recently been utilized for the syn-
thesis of quinolines.7 However, most of the methods suffered
from certain drawbacks such as drastic conditions, long reaction
times, unsatisfactory yields, difficulties in work up, and the
use of stoichiometric quantities of the reagents. So although
different methods are available for the synthesis of quinolines,
development of an efficient and high-yielding preparation is
still of great importance. In continuation of our work8 on the de-
velopment of useful synthetic methodologies, we have observed
that 2,4,6-trichloro-1,3,5-triazine (TCT, cyanuric chloride) acts
as an efficient catalyst for the synthesis of quinolines via the
Friedlander annulation (Scheme 1). Among the solvents used
(EtOH, THF, MeCN, CHCl3, and CH2Cl2) EtOH was found to
be the best.
O
2
3
4
40
40
85
84
89
72
NH2
N
Me
O
O
Me
O
O
O
NH2
N
Me
O
Me
O
NH2
O
N
O
O
Me
O
O
O
O
O
Me
OMe
OEt
OMe
OEt
O
5
30
30
25
35
45
40
85
92
90
92
90
85
93
74
NH2
N
Me
Me
O
6
NH2
N
Me
Me
O
7
O
O
N
NH2
O
O
Ph
Ph
O
8
NH2
N
Ph
Ph
O
9
NH2
N
Ph
Ph
O
O
O
O
10
11
NH2
N
Ph
O
Ph
O
O
N
NH2
O
Ph
Ph
O
O
O
O
O
OMe
OMe
O
12
13
14
15
16
35
35
30
55
40
91
90
95
86
88
NH2
N
Ph
O
O
Ph
OEt
OEt
O
NH2
N
Ph
Ph
O
O
O
NH2
N
Ph
Ph
O
Cl
Cl
Cl
O
NH2
Ph
N
Ph
O
O
O
Cl
OEt
OEt
O
NH2
Various 2-aminoaryl ketones were condensed with different
carbonyl compounds having an active methylene group to form
a series of substituted quinolines (Table 1). TCT with a loading
N
O
Cl
Cl
17
50
82
Cl
Cl
R1
R1
O
NH2
N
R3
R2
O
R3
TCT (4 mol %)
O
O
O
+
R2
OEt
O
EtOH, reflux
25 85 min
Cl
Cl
18
40
86
NH2
N
72 95%
R
R
Cl
Cl
OEt
O
NH2
N
1
2
3
aAll the products were characterized from their spectral
(1H NMR and MS) and analytical data.
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.6 (2007)
797
of only 4 mol % was effective to catalyze this condensation.
The quinolines were formed in high yields within 25–85 min.
The ꢀ-methylene carbonyl compounds used for the preparation
of these quinolines include cycloalkanones, 1,3-diketones
(cyclic and acyclic), and 1,4-diketones. 2-Aminobenzophenone
underwent the conversion smoothly with cyclohexanone and
a ꢁ-ketoester to afford the corresponding quinolines in high
yields (Table 1, Entries 9, 12, and 13). The reaction is clean
and free from side reactions such as self-condensation of ketones
which normally occurs under basic conditions. In the present
synthesis, alkyl, ketone, halogen, and ester remained uneffected.
TCT has recently been utilized in different organic transfor-
mations due to its excellent catalytic activity.9 It is a safe and
inexpensive reagent. It has been applied here for the first time
to the synthesis of quinolines.10 TCT is known to react with
‘‘incipient’’ moisture to form HCl (Scheme 2) which possibly
catalyzes the condensation.8a However, with HCl a reaction
temperature as high as 200 ꢁC is required for the condensation.6
Thus, TCT is more effective catalyst to carry out the synthesis
of quinolines.
6
7
E. A. Fehnel, J. Org. Chem. 1966, 31, 2899.
a) L. Strekowski, A. Czamy, J. Fluoresc. Chem. 2000, 104,
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Synlett 2003, 0203. c) Y. Z. Hu, G. Zang, R. P. Thummel,
Org. Lett. 2003, 5, 2251. d) B. R. McNaughton, B. L.
Miller, Org. Lett. 2003, 5, 4257. e) J. S. Yadav, B. V.
Reddy, P. Sreedhar, R. S. Rao, K. Nagaiah, Synthesis
2004, 2381. f) P. Arumugam, G. Karthikeyan, R. Atchudan,
D. Muralidharan, P. T. Perumal, Chem. Lett. 2005, 34,
314. g) S. K. De, R. A. Gibbs, Tetrahedron Lett. 2005,
46, 1647.
a) B. Das, K. Laxminarayana, B. Ravikanth, B. Rama
Rao, Tetrahedron Lett. 2006, 47, 9103. b) B. Das, K.
Venkateswarlu, M. Krishnaiah, H. Harish, M. Anjoy, Helv.
Chim. Acta 2006, 89, 1417. c) B. Das, R. Ramu, B.
Ravikanth, K. R. Reddy, Synthesis 2006, 1419.
8
9
a) A. Falchi, G. Giacomelli, A. Porcheddu, M. Taddei, Syn-
lett 2000, 275. b) B. P. Bandgar, S. S. Pandit, Tetrahedron
Lett. 2002, 43, 3413. c) B. Karimi, H. Hazarkhani, Synthesis
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P. R. Krishna, Synthesis 2006, 55.
10 General experimental procedure: To a mixture of 2-amino-
aryl ketone (1 mmol) and ꢀ-methylene carbonyl compound
(1.1 mmol) in EtOH (6 mL) TCT (4 mol %) was added.
The mixture was heated under reflex and the reaction was
monitered by TLC. After completion, the solvent was evapo-
rated and H2O (10 mL) was added. The mixture was extract-
ed with EtOAc (3 ꢂ 10 mL) and the extract was concentrat-
ed. The residue was purified by column chromatography
(silica gel, 8% EtOAc in hexane) to obtain pure quinoline.
The spectral (1H NMR and MS) and analytical data of
some representive products are given below.
OH
N
Cl
HO
N
Cl
H2O
+
3HCl
N
N
N
N
OH
Cl
Scheme 2.
In conclusion, we have developed a simple, rapid, and
efficient general synthesis of quinolines catalyzed by TCT
with low load (4 mol %) to form the products in high yields
via the Friedlander annulation. The method is an easy access to
different substituted quinolines.
Methyl
2,4-dimethylquinoline-3-carboxylate
(3e):
1H NMR (CDCl3, 200 MHz): ꢂ 8.01 (1H, d, J ¼ 8:0 Hz),
7.96 (1H, d, J ¼ 8:0 Hz), 7.69 (1H, t, J ¼ 8:0 Hz), 7.01
(1H, t, J ¼ 8:0 Hz), 3.98 (3H, s), 2.67 (3H, s), 2.62 (3H, s);
FAB-MS: m=z 216 [M + H]þ: Anal. Calcd for C13H13NO2
C, 72.56; H, 6.05; N, 6.98%. Found: C, 72.48; H, 6.12;
N, 6.87%.
The authors thank CSIR and UGC, New Delhi for financial
assistance.
References and Notes
#
1
2
Part 139 in the series ‘‘Studies on novel synthetic methodol-
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1-(2,4-Dimethylquinoline-3-yl)propan-2-one
(3g):
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1H NMR (CDCl3, 200 MHz): ꢂ 7.75 (1H, d, J ¼ 8:0 Hz),
7.59 (1H, t, J ¼ 8:0 Hz), 7.48 (1H, t, J ¼ 8:0 Hz), 7.22
(1H, d, J ¼ 8:0 Hz), 5.88 (2H, s), 1.95 (6H, s), 1.72 (3H, s);
FAB-MS: m=z 214 [M + H]þ:; Anal. Calcd for C14H15NO:
C, 78.87; H, 7.04; N, 7.04%. Found: C, 78.81; H, 7.11;
N, 7.12%.
Methyl 2-methyl-4-phenylquinoline-3-carboxylate (3l):
1H NMR (CDCl3, 200 MHz): ꢂ 8.08 (1H, d, J ¼ 8:0 Hz),
7.80–7.23 (8H, m), 3.55 (3H, s), 2.72 (3H, s); FAB-MS:
m=z 278 [M + H]þ: Anal. Calcd for C18H15NO2: C, 77.98;
H, 5.42; N, 5.42%. Found: C, 77.87; H, 5.48; N, 5.47%.
1-(2-Methyl-4-phenylquinoline-3-yl)propan-2-one (3n):
1H NMR (CDCl3, 200 MHz): ꢂ 7.62–7.06 (9H, m), 5.57
(2H, s), 1.92 (6H, s); FAB-MS: m=z 276 [M + H]þ:; Anal.
Calcd for C19H17NO: C, 82.91; H, 6.18; N, 5.45%. Found:
C, 82.87; H, 6.27, N, 5.38%.
3
4
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Published on the web (Advance View) May 26, 2007; doi:10.1246/cl.2007.796