Q. Lv et al.
The generality of this procedure was also explored as
shown in Table 2. The same protocol used to prepare
1,2,3,4-tetrahydro-1-oxoacridine-9-carboxylic acid from
1,3-cyclohexandione could be applied to other similar
quinoline-4-carboxylic acid systems. The highest yield of
95 % was achieved with pentane-2,4-dione (Table 2, entry
b), and the lowest (12 %) with methyl ethyl ketone (Table 2,
entry c). The experimental results indicated that the
improved protocol was more suited to simple 1,3-diketones,
b-keto esters and some cyclic ketones than to alkyl ketones.
In addition, for 5,5-dimethylcyclohexane-1,3-dione, the
main product was the condensation intermediate 3-hydroxy-
3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl) indolin-
2-one, which could be further converted into 1,2,3,4-tetra-
hydro-3,3-dimethyl-1-oxo-9-acridinecarboxylic acid by
heating (Table 2, entry f) [16]. For 1,3-indanedione, the final
product was 2,20-(2-oxoindoline-3,3-diyl)bis(1H-indene-
1,3(2H)-dione) (Table 2, entry g).
Scheme 1
Scheme 2
1, 3-cyclohexandione at room temperature and keeping the
pH at 2–3 with hydrochloric acid until product 7 precipi-
tated from water completely. To achieve convincing
results, we repeated the experiments on the scale from 150
mg to 1.5 g with isatin and obtained the target production
successfully in similar yields.
In conclusion, we have demonstrated a straightforward
and highly cost-effective synthetic method for some useful
quinoline-4-carboxylic acid derivatives using simple
ketones and isatins, which cannot be obtained easily under
the ordinary conditions. The current method is a mean-
ingful supplement to classic Pfitzinger reactions.
The effect of a Brønsted acid such as p-TsOHꢀH2O on
the yield of product 7 was examined. This catalyst proved
helpful for the reaction and obviously shortened the reac-
tion time. Other Lewis acid catalysts used in the same
protocol were also investigated as shown in Table 1.
Both p-TsOHꢀH2O and the Lewis acids showed an
excellent catalytic effect in our protocol. Among them,
copper sulfate appeared to be the best (Table 1, entry 4).
We deduced that these catalysts might benefit the con-
densation reactions of keto-acids with ketones [12]. The
detailed mechanisms of the Pfitzinger reaction are still not
completely understood to date: two different reaction paths
involving Schiff base formation and Claisen condensation,
respectively, have been postulated [2]. In terms of our
experimental results, we lean towards the Claisen con-
densation path as shown in Scheme 3 because the
intermediate from Claisen condensation was obtained
when we investigated the generality of this procedure.
Experimental
Melting points were measured on a WRS-1B digital
melting point apparatus. The progress of the reaction was
monitored by TLC. Infrared spectra were recorded from
1
KBr pellets on an FT/IR-430 spectrophotometer. H NMR
spectra were determined on a Bruker AVANCE 400 NMR
spectrometer at 400 MHz in DMSO-d6 using TMS as
internal standard. Elemental analysis was estimated on an
Elementar Vario EL-III element analyzer. Mass spectra
were determined using a MSD VL ESI1 spectrometer.
General procedure for the synthesis
of quinolinecarboxylic acids
Table 1 Reaction time and yields for synthesis of 7 with different
catalysts
A mixture of 147 mg isatin (1, 1 mmol) and 250 mg
potassium hydroxide in 5 cm3 water was stirred at room
temperature for 15–30 min (Table 1). The mixture was
then acidified to pH 2–3 with 0.38 cm3 concentrated
hydrochloric acid, and 224 mg 1,3-cyclohexandione (5,
2 mmol) and 25 mg CuSO4ꢀ5H2O (0.1 mmol) were added.
The resulting mixture was stirred and a precipitate
appeared. The reaction progress was monitored by TLC
(Rf = 0.35; CHCl3/MeOH 19:3). After the starting material
had vanished, the precipitate was filtered, washed with
water, and recrystallized to afford the pure product 1,2,3,4-
tetrahydro-1-oxoacridine-9-carboxylic acid (7, 210 mg,
Entry
Catalyst
Time/min
Yield/%
1
2
3
4
5
6
7
8
9
None
90
54
52
22
26
37
55
35
30
74
87
83
87
82
81
78
82
77
p-TsOH
CAN
CuSO4ꢀ5H2O
ZnCl2
FeCl3
MnSO4ꢀH2O
AlCl3
CeCl2ꢀ7H2O
123
Lv, Qinghua
