Improved synthesis of 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acids from isatins and 1,3-cyclohexanedione

Article abstract of DOI:10.3987/COM-12-12479

An improved protocol for the preparation of 1-oxo-1,2,3,4- tetrahydroacridine-9-carboxylic acid derivatives via Pfitzinger condensation under acidic conditions is described, it provides a simple one-pot synthetic method for some useful 1-oxo-1,2,3,4-tetra

Full text of DOI:10.3987/COM-12-12479

HETEROCYCLES, Vol. 85, No. 6, 2012
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HETEROCYCLES, Vol. 85, No. 6, 2012, pp. 1457 - 1463. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 4th April, 2012, Accepted, 24th April, 2012, Published online, 2nd May, 2012
DOI: 10.3987/COM-12-12479
IMPROVED SYNTHESIS OF 1-OXO-1,2,3,4-TETRAHYDROACRIDINE-9-
CARBOXYLIC ACIDS FROM ISATINS AND 1,3-CYCLOHEXANEDIONE
Qinghua Lv,1 Lizhen Fang,1 Chenjuan Lu,1 and Pengfei Wang1
＊
1College of Pharmacy, Xinxiang Medical University, Henan, 453003, P. R. China
E-mail: 2002flz@163.com
Abstract
–
An
improved
protocol
for
the
preparation
of
1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid derivatives via Pfitzinger
condensation under acidic conditions is described, it provides a simple one-pot
synthetic method for some useful 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic
acids which could not be synthesized successfully by Pfitzinger reactions under
usual conditions using the corresponding isatins and 1,3-diketones. All the
synthesized compounds are characterized by spectral data.
The Pfitzinger reaction1 of isatins with α-methylene carbonyl compounds is widely used for the synthesis
of physiologically active derivatives of substituted quinoline-4-carboxylic acids.2 This condensation
reaction is commonly performed by boiling isatins with ketones (or aldehydes) and KOH in water/ethanol
and subsequent adjustment of pH then filtering or extraction and recrystallization to obtain the various
quinoline-4-carboxylic acid derivatives (Scheme 1).
COOH
R'
O
KOH
R
EtOH/H2O
HCl
O
+
R'
N
O
N
R
H
3
2
1
Scheme 1
However, as some studies3 showed that it was impossible to obtain the corresponding pure
1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acids by the reaction of isatins with some diketones such as
1,3-cyclohexandione in aqueous KOH (the usual conditions for Pfitzinger reaction) because of the large
amounts of resin-like reaction byproducts. Though many years ago two similar derivatives were prepared

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HETEROCYCLES, Vol. 85, No. 6, 2012
under solvent free condition,4 the results were not satisfactory for the harsh reaction conditions and
modest yields. Moreover, for the preparation of quinolinecarboxylic acids by Pfitzinger reaction using
isatin and the cyclic diketones, most of the previous methods are waste of reagents due to the large excess
of cyclic ketones added in order to raise the yields of the target productions.5 Therefore, a simple,
convenient and efficient method for preparation of these important heterocyclic compounds is still in
demand. Herein, we would like to report the simple one-pot synthesis of
1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid derivatives via the Pfitzinger reaction which the
condensation is performed under acidic conditions in aqueous media.
Interested in synthetic methodology of organic compounds and their bioactivities,6 we explored the
Pfitzinger reaction using isatin 1 and 1,3-cyclohexandione 5 under the usual condition for synthesis of
1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid 7, and obtained little of target material but a large
amount of resin-like reaction byproduct. The reasons why such type of compounds could not be
synthesized by this system were discussed in the related literatures.3 Thinking of the condensation
reaction may proceed under the acidic conditions too, we decided to modify the usual procedures to avoid
the decomposition of 1,3-cyclohexandione 5 and some other analogous cyclic diketone substrates with the
formation of resinous by-product under basic conditions. In our improved procedure, we hydrolyzed
isatin 1 in aqueous potassium hydroxide and subsequently adjusted pH with caution to give the keto-acid
4 (Scheme 2), then added the 1,3-cyclohexandione 5 into the flask to react immediately without any
separation. Fortunately, the consequent condensation reaction went soomthly and the desired white
1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid 7 formed and precipitated from water soon. Unlike the
usual Pfitzinger reaction, not the keto-acid salt but the intermediate keto-acid 4 was obtained to for
condensation reaction with the 1,3-diketone 5 under the acid condition to give 6 in our improved protocol.
The alteration may seem to trivial but it provided the different and more stable reactants and conditions
for condensation, and was indeed the key to prepare the 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic
acid 7 successfully. The mechanism of this condensation may by way of enamine 6 as the proposed
mechanism in the Friedlander synthesis,7 as shown in Scheme 2.
O
OH
O
O
O
O
OH
OH
O
O
O
O
1.KOH/H2O
2.H3O+
5
O
NH
N
-H2O
NH2
H
N
1
O
4
7
6
Scheme 2

HETEROCYCLES, Vol. 85, No. 6, 2012
1459
Optimization studies were then carried out for this typical procedure and resulted in an improvement of
the isolated yield of 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid 7 to 87% by using 2.0 equivalent
1,3-cyclohexandione and p-TsOH·H2O as the catalyst at room temperature (Table 1, entry 11). It was of
no significant effect by further increasing the amount of 1,3-cyclohexandione 5 on the product yield
(Table 1, entry 9). It should be noted that the formation of the intermediate keto-acid 4 was essential for
this method by addition of hydrochloric acid and the target product formed in best yield when the pH
always kept at 2-3 with hydrochloric acid till the product 7 precipitated from water completely. At higher
pH(≥5) the product 7 formed in low yield less than 10% and could not precipitate from water ( Table 1,
entries 1, 2, 3). At lower pH (≤2) the yield of 7 was modest in 2% (Table 1, entry 7) and most of the
remained reactant was determined to be the isatin which converted from the keto-acid 4 by excessive
acidification. The Brønsted acid such as p-TsOH·H2O showed to be helpful for the reaction and obviously
shorten the reaction time (Table 1, entries 10 and 11), and we deduced it may benefit the condensation
reaction of the keto-acid with the diketone by accelerating the generation of enamine intermediate 6, and
it was very commonly used as the catalyst in such type of condensations.8 Other catalysts used in the
same protocol and the detailed mechanism will be investigated in the future.
Table 1. The reaction conditions and yields for the synthesis of 7 with different pH values
Entry
pH
Catalyst
Ratio (1,3-diketone Time
Isolated
5: isatin 1)
(h)
Yield(%)
1
≥7
no
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
4.0
1.0
2.0
24
24
24
24
18
18
14
14
10
6
3-5
7-9
10
25
44
55
2
2
6-7
5-6
4-5
3-4
2-3
1-2
2-3
2-3
2-3
2-3
no
3
no
4
no
5
no
6
no
7
no
8
no
84
82
60
87
9
no
10
11
p-TsOH
p-TsOH
5

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HETEROCYCLES, Vol. 85, No. 6, 2012
The generality of this procedure was also explored (Table 2). The same protocol used to prepare 7 could
also be applied to other similar 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid systems from the
corresponding alkyl or halogen-substituted acid salts and 1,3-cyclohexandione. The highest yield was
achieved with 5-methylindoline-2,3-dione (Table 2, entry 1), and the lowest, with
5-bromoindoline-2,3-dione (Table 2, entry 4). Although the yields were not very high, the corresponding
tetrahydroacridine-9-carboxylic acid can be conveniently prepared by this method with isatins except the
5-nitro isatin. It is noted that 5-nitro isatin acid is not soluble and precipitated soon from water, the
subsequent reaction can not follow up.
Table 2. Preparation of quinolines with isatin and various ketonesa
O
OH
O
O
O
R
R
1.KOH\H2O
O
+
N
2.HCl, p-TsOH
pH=2-3, rt
O
N
H
7a-e
1a-e
5
Entry
1
7 (Yield/ %)b
7a (63)
7b (51)
7c (40)
7d (36)
/
1
2
3
4
5
1a (R=Me)
1b (R=F)
1c (R=Cl)
1d (R=Br)
1e (R=NO2)
Note: a Reaction conditions as exemplified in the typical experimental procedure; b Isolated yields.
In conclusion, we have demonstrated that a straightforward and highly cost-effective synthesis of
biologically active tetrahydroacridine-9-carboxylic acid can be achieved by p-TsOH-catalyzed Pfitzinger
reaction in water. 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid 7, 7a-d were synthesized for the
first time by this improved protocol. The current method presents a very appealing synthetic process for
tetrahydroacridine-9-carboxylic acids because of the following advantages: (1) use of water as
environmentally benign reaction media, (2) use of very cheap and readily available materials, (3) short
reaction time and easy work-up procedure.

HETEROCYCLES, Vol. 85, No. 6, 2012
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EXPERIMENTAL
The melting points were measured on WRS-1B digital melting points apparatus and are uncorrected. The
1
progress of the reaction was monitored by TLC. H NMR spectra were determined on a Brucker
AVANCE 400 NMR spectrometer at 400 MHz in DMSO-d6 using TMS as internal standard. Elemental
analysis were estimated on an Elementar Vario EL-III element analyzer.
General procedure for the synthesis of 1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acids: The
mixture of isatin (147 mg, 1 mmol) and potassium hydroxide (250 mg) in water (5 mL) was stirred at
room temperature for 5-30 min (Table 1). Then the mixture was acidified with concentrated hydrochloric
acid to pH 2-3 and added 1,3-cyclohexandione(224 mg, 2 mmol), p-TsOH·H2O (17 mg, 0.1 mmol). The
resulting mixture was stirred and the precipitate appeared. The reaction progress was monitored by TLC
(silica gel; CHCl3/MeOH, 19:3, v/v). After the starting material had vanished, the precipitate was filtered
out, washed with water, and recrystalized to afford the pure product 1-oxo-1,2,3,4-
tetrahydroacridine-9-carboxylic acid (7, 210 mg, 87%).
1
1-Oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid (7): A white powder; mp 279-280 °C; H NMR
(400 MHz, DMSO-d6) δ 2.11–2.24 (m, 2H), 2.79 (t, J = 6.4 Hz, 2H), 3.21–3.29 (t, J = 6.2 Hz, 2H), 7.70
(dd, J = 7.4, 7.2 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.92 (dd, J = 7.7, 7.4 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H),
13.98 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 20.9, 33.1, 38.6, 120.4, 122.2, 126.2, 127.7, 128.6,
132.7, 142.3, 148.6, 162.3, 168.5, 196.8. Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81; O, 19.90.
Found: C, 69.69; H, 4.62; N, 5.81; O, 19.88.
7-Methyl-1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid (7a, Table 2) A pale yellow powder; mp
293-294 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.11 – 2.22 (m, 2H), 2.52 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H),
3.24 (t, J = 6.0 Hz, 2H), 7.57 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 13.79 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 21.0, 21.2, 33.0, 38.7, 120.3, 122.2, 124.6, 128.4, 134.9, 137.3, 141.6,
147.4, 161.4, 168.6, 196.9. Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49; O, 18.80. Found: C,
70.57; H, 5.15; N, 5.50; O, 18.79.
7-Fluoro-1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid (7b, Table 2) A pale yellow powder; mp
286-287 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.12 – 2.22 (m, 2H), 2.80 (t, J = 6.0 Hz, 2H), 3.26 (t, J =
5.6Hz, 2H), 7.46 (ddd, J = 8.0, 7.9, 2.0Hz, 1H), 7.87 (dd, J = 8.0, 2.0 Hz, 1H), 8.13 (dd, J = 7.9, 4.9Hz,
1H), 13.98 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 20.8, 32.9, 38.6, 109.2 (d, J = 23 Hz), 121.0, 122.8
(d, J = 26 Hz), 123.1 (d, J = 8 Hz), 131.7 (d, J = 9 Hz), 141.8 (d, J = 6 Hz), 145.9, 158.8 (d, J = 246 Hz),
161.9, 168.2, 196.8. Anal. Calcd for C14H10FNO3: C, 64.86; H, 3.89; F, 7.33; N, 5.40; O, 18.52. Found: C,

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HETEROCYCLES, Vol. 85, No. 6, 2012
64.82; H, 3.89; F, 7.36; N, 5.39; O, 18.54.
7-Chloro-1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid (7c, Table 2) A yellow powder; mp
286-287 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.11-2.20 (m, 2H), 2.80 (t, J = 6.0 Hz, 2H), 3.26 (t, J =5.6
13
Hz, 2H), 7.76 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 14.06(s, 1H); C NMR (100
MHz, DMSO-d6) δ 20.7, 33.0, 38.5, 121.1, 123.0, 124.4, 130.8, 131.9, 133.0, 141.6, 147.0, 163.0, 168.0,
196.6. Anal. Calcd for C14H10ClNO3: C, 60.99; H, 3.66; Cl, 12.86; N, 5.08; O, 17.41. Found: C, 60.96; H,
3.68; Cl, 12.85; N, 5.13; O, 17.40.
7-Bromo-1-oxo-1,2,3,4-tetrahydroacridine-9-carboxylic acid (7d, Table 2) A white powder; mp
287-288 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.13 – 2.23 (m, 2H), 2.81 (t, J = 6.0 Hz, 2H), 3.26 (t, J =
6.0 Hz, 2H), 7.91 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 14.06 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 20.7, 33.0, 38.5, 120.5, 121.1, 123.5, 127.6, 130.9, 135.6, 141.2, 147.2, 163.1, 168.0,
196.6. Anal. Calcd for C14H10BrNO3: C, 52.52; H, 3.15; Br, 24.96; N, 4.38; O, 14.99. Found: C, 52.52; H,
3.17; Br, 24.95; N, 4.39; O, 14.97.
ACKNOWLEDGEMENTS
This project was supported by the National Natural Science Foundation of China (81172952), the Natural
Science Program of the Education Department of Henan Province (2010B32007) and the fund of key
disciplines in Xinxiang Medical University (ZD200969).
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