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Chemistry Letters Vol.34, No.3 (2005)
¨
A Simple, Efficient and Solvent-Free Protocol for the Friedlander Synthesis of Quinolines
.
by Using SnCl2 2H2O
Pandurangan Arumugam, Ganesan Karthikeyan, Raji Atchudan,
D. Muralidharan, and Paramasivan T. PerumalÃ
Organic Chemistry Division, Central Leather Research Institute, Adayar, Chennai-20, India
(Received December 6, 2004; CL-041481)
A variety of polysubstituted quinolines have been synthe-
sized under solvent free condition by using tin(II) chlorideÁdihy-
drate. The reaction proceeds smoothly at room temperature in
short reaction time. The yields and purity are excellent.
Ph
Ph
N
O
O
O
Cl
Cl
SnCl2.2H2O
Neat, rt
O
OEt
+
OEt
NH2
Scheme 1.
Quinoline and its derivatives display a wide spectrum of bi-
ological activities such as antimalarial, antibacterial, antidiabet-
ic, and anti-inflammatory1,2 behaviour. Furthermore cytotoxic
agents like benzo[5,6]pyrrolizino[1,2-b]quinolines,3 antitumor
agents like camptothecin4 also contain the quinoline nuclei.
The benzo[5,6]pyrrolizino[1,2-b]quinoline system which dis-
plays potent in vitro cytotoxic activity against MCF7 cell is syn-
scale (Entries 1 and 6), and it proceeds even when both of the
precursors are solids (Entry 6).
The protocol was further extended to a various ꢀ-keto esters
such as methyl acetoacetate, t-butyl acetoacetate, ethyl propio-
nylacetate and dicarbonyl compound like acetylacetone. In all
cases the reaction proceeds rapidly with o-amino substituted ar-
omatic ketones like 5-chloro-o-aminobenzophenone, o-amino-
benzophenone, and o-aminoacetophenone at room temperature
with high efficiency. The results are summarized in Table 1.
Unlike earlier reports the current protocol doesn’t require heat-
ing of the reaction mixture, use of strong acids or alkalis or
the use of toxic solvents to produce quinolines.
thesized using the Friedlander quinoline synthesis as a key step.3
¨
Recently quinolines are also shown to be potential agents for the
treatment of erectile dysfunction as they exhibit more potent and
selective PDE5 inhibitor activity.5
Though numerous methods are available for the synthesis of
quinolines, the synthesis reported by Friedlander is of great im-
¨
portance because it is simple and leads to a variety of polysub-
We next extended our methodology to the synthesis of fused
tricyclic quinolines by using cyclic ketones such as cyclopenta-
none, cyclohexanone, cycloheptanone and cyclooctanone. This
kind of cyclic ketones which give usually unsatisfactory yields
even at 100 ꢀC by using HCl13 or stirring at room temperature
for 48 h,8 gave >95% yield in our reaction condition.
stituted quinolines. The Friedlander annulation is catalyzed by
¨
both acids and bases, but the acids are more effective.6 The
Brꢀnsted acids like hydrochloric acid, sulfuric acid, p-toluene
sulphonic acid, and phosphoric acids were widely used to effect
the Friedlander condensation. However many of these classical
¨
methods require high temperature, prolonged reaction time and
drastic reaction conditions and the yields are unsatisfactory
due to the occurrence of several side reactions. The Lewis acids
O
Ph
Ph
N
O
7
8
such as ZnCl2, AuCl3 3H2O, and Bi(OTf)39 are also found to
.
SnCl2.2H2O
Neat, rt
Cl
Cl
O
be effective in the Friedlander condensation. But the use of en-
¨
+
.
vironmentally toxic zinc chloride, and expensive AuCl3 3H2O
limits their application to the synthesis of quinolines.
O
NH2
Scheme 2.
In order to avoid the toxic and chronic effects of organic sol-
vents, the solvent free microwave-assisted synthesis of quino-
lines are reported by Ranu et al.10 and Song et al.,11 but the mi-
crowave-assisted synthesis are not applicable to large scale pro-
duction. Since quinoline derivatives are increasingly useful and
important in drugs and pharmaceuticals, the development of
simple, eco-benign, room temperature and high yielding proto-
col is desirable.
In the case of unsymmetrical ketone such as 2-butanone
exclusively single regioisomer was obtained (Entry 6).
In conclusion we have developed a simple, efficient and eco-
benign protocol for the Friedlander synthesis of quinolines. The
¨
merits of the current protocol are (a) the reaction is conducted
under solvent free condition (b) the reaction proceeds at room
temperature (c) the use of hazardous strong acids or bases are
avoided (d) it does not require inert atmosphere or azeotropic re-
moval of water (e) the reaction time is short (f) work up is simple
(g) purifications like column chromatography or recrystalliza-
tion are not needed (h) operable on large scale (i) yields are
excellent.
Herein we wish to report a simple, efficient and solvent free
synthesis of quinolines by using tin(II) chloride. dihydrate at
room temperature. Thus the treatment of o-amino substituted
aromatic ketones with dicarbonyl compounds in the presence
of tin(II) chlorideÁdihydrate leads to the formation of various
2,3,4-trisubstituted quinolines (Scheme 1) in excellent yields
and in short reaction time.12 In the absence of SnCl2 2H2O the
.
We thank the Council of Scientific and Industrial Research,
New Delhi, India for financial support.
reaction doesn’t proceed. The main advantage of this solvent
free, room temperature protocol is that it is operable on large
Copyright Ó 2005 The Chemical Society of Japan