JOURNAL OF CHEMICAL RESEARCH 2008
DECEMBER, 679-682
RESEARCH PAPER 679
A facile one-pot Friedlander synthesis of quinoline derivatives
P. Prabhakar Reddy, B. China Raju and J. Madhusudana Rao*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 607, India
A facile one-pot Friedlander synthesis has been developed for quinolines using GdCI3.6H20 as the novel catalyst.
The method is simple, efficient and rapid to afford the quinolines in very good yields.
Keywords: quinolines, carbonyl compounds, GdCI3.6H20
Quinolines are important heterocyclic compounds and are
present in many biological systems. They possess anti-
malarial, anti-bacterial, anti-asthmatic, anti-hypertensive
and anti-inflammatory properties. 1-3 Because of their
importance in natural products, a straight forward quinoline
synthesis was developed by Friedliinder.4-9 The FriedliinderlO
annulation is a condensation reaction between an aromatic
ortho-aminoaldehyde and an aldehyde or ketone bearing
a-methylene group. In the presence of Lewis acids.ll-15
However many of these procedures have drawbacks such as
expensive reagents, harsh reaction conditions, low yields, high
temperature and a tedious work-up. Therefore, a practical,
simple and environmentally benign method is required.
us to study further reactions with o-aminoacetophenone
and 5-cWoro-o-aminobenzophenone with active methylene
ketones such as methyl acetoacetate, ethyl acetoacetate,
2,5-pentanedione, 2,5-hexanedione; cyclic ketones such
as cyclopentanone, cyclohexanone and 5,5-dimethyl-I,3-
cyclohexanedione gave corresponding quinolines (entries
3i-x). All the products were characterised by 1H NMR,
IR and mass spectra and compared with authentic samples.
The results were tabulated in Table land show the efficiency
of the catalyst.
In conclusion, we have developed a mild, rapid and
efficient Friedliinder protocol for the synthesis of quinolines
using catalytic amounts of GdCI3.6H20. The present method
offers several advantages such as a short reaction times,
cleaner reaction products, simple experimental and work
up procedures making this an attractive alternate method
compared to reported methods.
Our continuing interest16,17in bioactive compounds and
on heterocyclic compounds led us to report a facile and an
efficient method for the synthesis of various quinolines from
o-aminobenzophenones,
or o-aminoacetophenones
with
a-methylene carbonyl compounds in presence of catalytic
amount of GdCI3.6H20 (3 mol%) in ethyl alcohol (5 ml) under
reflux. Organic reactions using mild catalysts that tolerate
water have received attention in recent years as they are eco-
friendly and can conveniently be handled in the laboratory for
various organic transformations. GdCI3.6H2018,19has received
attention for a few organic transformations such as those
of homoallylic alcohols, a-aminonitriles and Diels-Alder
reactions,2o-22and there is further scope to develop synthetic
methodologies using GdCI3.6H20 as catalyst. However, to
the best of our knowledge there is no report on Friedliinder
synthesis of quinolines using the GdCI3.6H20. Initially we
have carried out the reaction of o-aminobenzophenone (la)
and ethyl acetoacetate (2b) in the presence of GdCI3.6H20
(3 mol%) in ethyl alcohol under reflux. The reaction was
monitored by TLC (25 min) and upon workup afforded ethyl-
Experimental
IH NMR spectra were determined on Varian Gemini 200 MHz
spectrometer using TMS as intemal standard. IR spectra were
recorded on Nicollet 740 FT spectrometer. Mass spectra were recorded
on Agilent LCMS II 00 instrument. Flash column chromatography
was performed with 100-200 silicagel and analytical TLC was
performed on precoated silica- gel plates (60F-254). Melting points
were measured on Buchi-510 apparatus and are uncorrected. C,
H and N analysis was carried out using Elementar Vario EL, Germany
instrument.
General procedure
A
mixture of 2-arninoacetophenone (1 mmol), a-methylene
carbonyl compound (1.2 mmol) and GdC13.6H20 (3 mol%) in ethyl
alcohol (5 mL) was refluxed for an appropriate time (Table 1).
After completion of the reaction (TLC), the solvent was removed
under reduced pressure and the crude product was purified by column
chromatography to afford pure quinolines in very good yields.
The spectral data (lH NMR, IR and MS) of some of the
representative compounds are given below.
(3a): IR (KBr): 3070,2930,1725,1614,1590,1485,1405,1295,579
cm-I.IHNMR(CDC13,200MHz): /)8.08 (d,J= 8.0 Hz, lH),7.80-7.23
(m, 8H), 3.55 (s, 3H), 2.72 (s, 3H); Mass (LCMS): m/e 278 [M++H].
(3c): IR (KBr): 3027,2960, 1725, 1614, 1590, 1485, 1405, 1295,
704 cm-I. IH NMR (CDC13, 200 MHz): /) 8.03 (d, J = 8.2 Hz, lH,
aromatic), 7.80-7.23 (m, 8H, aromatic), 2.69 (s, 3H), 1.94 (s, 3H).
BC NMR: /)203.56, 153.57, 147.56, 143.96, 135.23, 134.86, 130.29,
130.29, 130.13, 129.12, 128.93, 128.90, 128.73, 126.54, 126.19,
125.07,31.97,23.90; Mass (LCMS): m/e 262 [M++ H].
2-methyl-4-phenyl-3-quinolinecarboxylate
(entry 3b) in
97% yield (Scheme I). The product was characterised by its
spectral data (lH NMR, IR and MS) and compared with an
authentic sample. A similar reaction at room temperature was
slower and did not give good yields.
We have conducted similar reactions of substituted
benzophenones with various active methylene ketones such
as methyl acetoacetate, 2,5-pentanedione, 2,5-hexanedione;
cyclic ketones such as cyclopentanone, cyclohexanone and
5,5-dimethyl-I,3-cyclohexanedione to give the corresponding
quinolines in good yields (entries 3a-h). The results encouraged
GdCI3·6H20
O~
Ethanol, 6.
2
3
Scheme
1
Reddy, P. Prabhakar
