Microwave-assisted synthesis of quinoline derivatives from isatin

Article abstract of DOI:10.1080/00397910500184719

Microwave irradiation has been used for a rapid and efficient synthesis of quinoline-4-carboxylic acids 5a-g and 1,2,3,4-tetrahydroacridine-9-carboxylic acid (6) from the reaction of isatins 1-3 with acyclic and cyclic ketones in basic medium. 2-Hydroxyquinoline-4-carboxylic acid (11) was also obtained by irradiating a mixture of isatin 1 and malonic acid in AcOH. The esters of 5f and 11 and their respective hydrazides 8 and 13 were also prepared under MWI. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500184719

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Microwave‐Assisted Synthesis
of Quinoline Derivatives from
Isatin
El Sayed H. El Ashry a , El Sayed Ramadan a , Hamida
Abdel Hamid a & Mohamed Hagar a
a Department of Chemistry, Faculty of Science,
Alexandria University, Alexandria, Egypt
Version of record first published: 18 Aug 2006.
To cite this article: El Sayed H. El Ashry , El Sayed Ramadan , Hamida Abdel Hamid
& Mohamed Hagar (2005): Microwave‐Assisted Synthesis of Quinoline Derivatives from
Isatin, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 35:17, 2243-2250
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Synthetic Communicationsw, 35: 2243–2250, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500184719
Microwave-Assisted Synthesis of Quinoline
Derivatives from Isatin
El Sayed H. El Ashry, El Sayed Ramadan,
Hamida Abdel Hamid, and Mohamed Hagar
Department of Chemistry, Faculty of Science, Alexandria University,
Alexandria, Egypt
Abstract: Microwave irradiation has been used for a rapid and efficient synthesis of
quinoline-4-carboxylic acids 5a–g and 1,2,3,4-tetrahydroacridine-9-carboxylic acid
(6) from the reaction of isatins 1–3 with acyclic and cyclic ketones in basic
medium. 2-Hydroxyquinoline-4-carboxylic acid (11) was also obtained by irradiating
a mixture of isatin 1 and malonic acid in AcOH. The esters of 5f and 11 and their
respective hydrazides 8 and 13 were also prepared under MWI.
Keywords: Hydrazide, isatin, ketone, microwave, quinoline
INTRODUCTION
The synthesis of quinolines and their derivatives has been of considerable
interest because a large number of natural products and drugs contain this
heterocyclic unit.[1–5] Quinoline-4-carboxylic acids and their analogs have a
wide variety of medicinal applications including antitumor, antiviral, and
antibacterial activities.[6,7] 2-(4-Bromophenyl)-quinoline-4-carboxylic acid
selectively inhibited C. albicans prolyl-tRNA synthetase and 2-phenylquino-
line-4-carboxamides are used as analgesic, tranquillizer, antitumor, and
antitubercular agents.[8–11]
Received in the U.K. November 12, 2004
Address correspondence to El Sayed H. El Ashry, Department of Chemistry,
Faculty of Science, Alexandria University, Alexandria, Egypt. Fax: þ20-3-4271360;
E-mail: eelashry60@link.net; eelashry60@hotmail.com
2243

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E. S. H. El Ashry et al.
In a continuation of our studies on microwave-assisted reactions,[12–15]
we report a versatile approach for the formation of quinoline-4-carboxylic
acids, esters, and hydrazides using microwave irradiation (MWI).
RESULTS AND DISCUSSION
Recently, efficient procedures for the synthesis of various quinoline derivatives
were achieved using microwave irradiation.[16–24] However, the role of MWI
on the performance of the Pfitzinger reaction[25] for the synthesis of quinoline-4-
carboxylic acids has not been reported yet. The reaction between isatin and
dialkyl ketones, in basic medium, required heating for about 70–96 h to give a con-
siderable yield.[26] However, it did not give appreciable amounts of the products
when a strong steric hindrance was present in the ketone.[27] Moreover,
employing aqueous acid conditions required heating in an oil bath for 16 h.[28]
However, we found that MWI has successfully accelerated the conden-
sation of isatins 1–3 with a number of ketones, such as acetone, diethyl
ketone, isobutyl methyl ketone, acetophenone, and benzyl methyl ketone, in
alcoholic potassium hydroxide solution, whereby the corresponding
quinoline-4-carboxylic acids 5a–g were obtained in 12.5 min; the reactions
were carried out in a closed Teflon vessel and the yield of products ranged
between 50 and 96%. The highest yield observed in the cases of acetophenone
(95%) and benzyl methyl ketone (96%) can be attributed to the stability of
their carbanions, whose attack on the carbonyl group of the presumably
formed isatic acid derivative 4 resulted from the ring opening of the isatin
derivatives 1–3 and subsequent cyclization (Scheme 1).
Esterification of 2-phenylquinoline-4-carboxylic acid (5f) with ethanol in
the presence of a catalytic amount of concentrated sulphuric acid under MWI
in a closed Teflon vessel required 10 min to afford ethyl 2-phenylcinchoninate
(7) in 94% yield; under the conventional conditions the reaction required
heating under reflux for 22 h to give a comparable yield.[29] Under MWI
activation, the ester 7 was transformed into the corresponding acid
hydrazide 8 in a much shorter time (6 min) compared with conventional
heating (15.5 h). Furthermore, the yield of 8 was improved to 80%
compared with 61%.[29] When isatin 1 was reacted with cyclohexanone as
the ketonic reagent under MWI, 1,2,3,4-tetrahydroacridine-9-carboxylic
acid (6) was produced in 95% yield within 12.5 min, but under conventional
heating, the reaction required 72 h and gave only a 55% yield.[30]
Conventionally, isatin (1) was acetylated by heating with acetic anhydride
for 2 h to give 75–80% yield of N-acetylisatin (10).[31] However, when the
reaction was conducted under MWI, the reaction time was dramatically
reduced to 5 min to give 70% yield of 10. When a mixture of 10 and
aqueous sodium hydroxide was irradiated by MW for 3 min, 2-hydroxyquino-
line-4-carboxylic acid (11) was produced in 65% yield; the reaction required
1 h of conventional heating to give a comparable yield.[32] Another route for

Microwave-Assisted Synthesis of Quinoline Derivatives from Isatin
2245
Scheme 1.
the preparation of 11 involved heating a mixture of isatin 1 and malonic acid in
the presence of acetic acid for 2 days,[33] but when the reaction was carried out
under MWI in a closed Teflon vessel, it required only 15 min to give a
68% yield (Scheme 2).
Isatin (1) has also been condensed with malonic acid in ammonia solution
under MWI to give 94% yield of ammonium-3-(methylene di-acid)-oxindole 9
in a much shorter time (2 min) than under classical heating conditions (1 h).[34]
However, in our hands the treatment of 9 with hydrochloric acid at room temp-
erature did not give 11 as previously reported.[34] Esterification of 11 to the
ethyl ester 12 and its subsequent transformation to the acid hydrazide 13 were
carried out under MWI within 6–10 min to give 99 and 92% yields, respectively.
In conclusion, the use of MWI provides an efficient, clean, and quick
methodology for the synthesis of quinoline-4-carboxylic acids as well as
their esters and hydrazides with greater yields than the previously reported
conventional methods.
EXPERIMENTAL
General Methods
Melting points were determined with a Mel-Temp apparatus and are uncor-
rected. TLC was performed on Baker-Flex silica gel 1B-F plates using ethyl

2246
E. S. H. El Ashry et al.
Scheme 2.
acetate–petroleum ether (3 : 2) and ethyl acetate–methanol (4 : 1) as eluents;
the compounds were detected by UV light absorption. Irradiation was
achieved using a domestic microwave oven EM-230M (800-W output
power). IR spectra were recorded on Perkin-Elmer 1430 spectrometer.
1H NMR spectra were recoded on Jeol spectrometer (500 MHz). Chemical
shifts (d) are given in ppm relative to TMS as internal standard.
General Procedure
Quinoline-4-carboxylic acids (5a–g): A mixture of isatin, 5-chloro, or
5-bromoisatin 1–3 (3.4 mmol), ketone (8.6 mmol), and potassium hydroxide
(0.63 g, 11 mmol) in 20% aqueous ethanol (2 ml) was placed in a closed
Teflon vessel and irradiated by MWI for 12.5 min. The reaction mixture
was acidified with acetic acid and the product was recrystallized from EtOH
or MeOH–CHCl3.
2-Methylquinoline-4-carboxylic acid (5a): Yield 0.318 g, 50%; mp 244–
2458C, lit.[35] mp 2428C.
2-Ethyl-3-methylquinoline-4-carboxylic acid[36] (5b): Yield 0.373 g, 51%;
1
mp 287–2888C; IR (KBr): 2940 cm21 (OH), 1708 cm21 (C55O); H NMR

Microwave-Assisted Synthesis of Quinoline Derivatives from Isatin
2247
(CDCl3): d 1.47 (t, 3H, J ¼ 7.7 Hz, CH3CH2), 2.69 (s, 3H, CH3), 3.33 (q, 2H,
CH2CH3), 7.92 (t, 1H, J7,6 ¼ 7.7 Hz, J7,8 ¼ 8.6 Hz, H-7), 8.05–8.08 (m, 2H,
H-6, H-8), 8.21 (d, 1H, J5,6 ¼ 8.6 Hz, H-5), 14.58 (s, 1H, COOH).
2-Isobutylquinoline-4-carboxylic acid (5c): Yield 0.467 g, 60%; mp 156–
1588C, lit.[27] mp 1928C; IR (KBr): 2729 cm21 (OH), 1692 cm21 (C55O);
1H NMR (DMSO-d6): d 0.89 (d, 6H, J ¼ 6.9 Hz, (CH3)2CH), 2.10–2.18 [m,
1H, CH(CH3)2], 2.81 (d, 2H, J ¼ 7.7 Hz, CH2CH), 7.61 (t, 1H,
J7,6 ¼ 6.9 Hz, J7,8 ¼ 8.4 Hz, H-7), 7.75 (ddd, 1H, J6,5 ¼ 8.4 Hz,
J6,7 ¼ 6.9 Hz, J6,8 ¼ 1.5 Hz, H-6), 7.78 (s, 1H, H-3), 8.01 (d, 1H,
J8,7 ¼ 8.4 Hz, H-8), 8.61 (d, 1H, J5,6 ¼ 8.4 Hz, H-5).
6-Chloro-2-isobutylquinoline-4-carboxylic acid (5d): Yield 0.538 g, 60%;
1
mp 182–1848C; IR (KBr): 2758 cm21 (OH), 1705 cm21 (C55O); H NMR
(CDCl3): d 1.02 (d, 6H, J ¼ 6.1 Hz, (CH3)2CH), 2.27–2.29 [m, 1H,
CH(CH3)2], 3.06 (d, 2H, J ¼ 7.7 Hz, CH2CH), 7.77 (dd, 1H, J7,8 ¼ 8.4 Hz,
J7,5 ¼ 1.5 Hz, H-7), 8.00 (s, 1H, H-3), 8.31 (d, 1H, J8,7 ¼ 8.4 Hz, H-8), 8.93
(s, 1H, H-5), 9.75 (s, 1H, COOH). Anal. calcd. for C14H14NO2Cl: C, 63.76;
H, 5.31; N, 5.31. Found: C, 63.84; H, 5.19; N, 5.22.
6-Bromo-2-isobutylquinoline-4-carboxylic acid (5e): Yield 0.627 g, 60%;
mp 186–1888C, lit.[27] mp 1898C.
2-Phenylquinoline-4-carboxylic acid (5f): Yield 0.805 g, 95%; mp 212–
2148C, lit.[37] mp 209–2108C, lit.[38] mp 210–2128C.
2-Methyl-3-phenylquinoline-4-carboxylic acid[26] (5 g): Yield 0.859 g,
96%; mp . 3008C; IR (KBr): 2735 cm21 (OH), 1644 cm21 (C55O); 1H
NMR (CDCl3): d 2.4 (s, 3H, CH3), 7.35 (d, 2H, J ¼ 6.9 Hz, Ph-H), 7.40–
7.48 (m, 3H, Ph-H), 7.62 (t, 1H, J7,8 ¼ 6.9 Hz, J7,6 ¼ 7.7 Hz, H-7), 7.76
(t, 1H, J6,7 ¼ 7.7 Hz, J6,5 ¼ 7.7 Hz, H-6), 7.79 (d, 1H, J8,7 ¼ 6.9 Hz, H-8),
8.02 (d, 1H, J5,6 ¼ 7.7 Hz, H-5).
1,2,3,4-Tetrahydroacridine-9-carboxylic acid (6): A mixture of isatin 1
(0.5 g, 3.4 mmol), cyclohexanone (0.9 ml, 8.7 mmol), and potassium
hydroxide (0.63 g, 11 mmol) in 20% aqueous ethanol (2 ml) was placed in a
closed Teflon vessel and irradiated by MWI for 12.5 min. The reaction
mixture was processed as previously described to give 6; yield 0.734 g,
95%; mp 2848C (dec.), lit.[30] mp 285–2868C.
Ammonium 3-(methylene di-acid)-oxindole (9): A mixture of isatin 1 (1.0 g,
6.8 mmol) and malonic acid (0.8 g, 7.7 mmol) in 10% absolute ethanolic
ammonia (3 ml) was placed in an Erlenmeyer flask (250 ml) and irradiated
by MWI for 2 min. The product was filtered and washed with hot CHCl3;
yield 1.707 g, 94%; mp 168–1708C; mp was not determined in lit.[34] IR
(KBr): 3581–2633 cm21 (NH4, NH), 1725 cm21 (C55O).
N-Acetylisatin (10): A mixture of isatin 1 (0.5 g, 3.4 mmol) and acetic
anhydride (10 ml) was placed in an Erlenmeyer flask (250 ml) and irradiated

2248
E. S. H. El Ashry et al.
by MWI for 5 min. The product was filtered, washed with ether, and recrystal-
lized from benzene; yield 0.45 g, 70%; mp 144–1458C, lit.[31] mp 143–1448C.
2-Hydroxyquinoline-4-carboxylic acid (11): Method (a): A mixture of N-
acetylisatin (10) (0.5 g, 2.6 mmol) and sodium hydroxide (0.26 g, 6.5 mmol)
in water (10 ml) was placed in an Erlenmeyer flask (250 ml) and irradiated
by MWI for 3 min; the reaction mixture was acidified with acetic acid and
the product was recrystallized from EtOH; yield 0.325 g, 65%; mp 332–
3368C, lit.[31] mp 335–3388C.
Method (b): A mixture of isatin 1 (1.0 g, 6.8 mmol) and malonic acid (1.07 g,
10.3 mmol) in acetic acid (3 ml) was placed in a closed Teflon vessel and irra-
diated by MWI for 15 min. The product (0.874 g, 68%), was found to be
identical with that obtained from the previous method.
Ethyl 2-substituted quinoline-4-carboxylate (7) and (12): A mixture of
compound 5f or 11 (2.02 mmol), ethyl alcohol (3 ml), and concentrated
sulfuric acid (0.5 ml) was placed in a closed Teflon vessel and irradiated by
MWI for 10 min. The mixture was neutralized with sodium bicarbonate
solution and the products were recrystallized from EtOH.
Ethyl 2-phenylquinoline-4-carboxylate (7): Yield 0.523 g, 94%; mp 56–
588C, lit.[29] mp 58–598C.
Ethyl 2-hydroxyquinoline-4-carboxylate (12): Yield 0.432 g, 99%; mp
210–2128C, lit.[32] mp 2068C.
2-Substituted quinoline-4-carboxylic acid hydrazides (8) and (13): A
mixture of the ethyl ester 7 or 12 (1.38 mmol) in ethyl alcohol (3 ml) was
treated with hydrazine hydrate (4.6 mmol) and then irradiated by MWI for
6 min in a closed Teflon vessel. The products were recrystallized from EtOH.
2-Phenylquinoline-4-carboxylic acid hydrazide (8): Yield 0.29 g, 80%; mp
222–2248C, lit.[29] mp 2248C.
2-Hydroxyquinoline-4-carboxylic acid hydrazide (13): Yield 0.257 g, 92%;
mp 288–2908C, lit.[39] mp 287–2888C.
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