Application of pfitzinger reaction in synthesis of hetero ring annelated quinoline carboxylic acid derivatives

Article abstract of DOI:10.14233/ajchem.2016.19532

The diazotized 8-aminoquinoline (4) was reacted with 2-(hydroxymethylidine)cyclohexanone and N-benzyl 3-(hydroxymethylidine)-piperidine-4-one (5, 6) (generated from the reaction of cyclohexanone and N-benzyl-4-piperidone with ethyl formate in the presence of NaOEt) under the conditions of Japp-Klingemann reaction, followed by Fisher-indolization of the resulting hydrazones in acid, formed the quinolinooxocarbazole (7) and N-benzyl quinolinooxoazacarbazole (8), respectively. Pfitzinger reaction of compounds 7 and 8 with isatin in alkali afforded the corresponding quinoline carboxylic acid derivatives 10 and 11, respectively. In accord to generally accepted mechanism of Pfitzinger reaction, we suggest that the reaction of compounds 7 and 8 with isatin in alkali proceeds with the formation of isatoic acid which undergoes instantaneous cyclocondensation with carbonyl species 7 and 8 to generate compounds 10 and 11, respectively.

Full text of DOI:10.14233/ajchem.2016.19532

Asian Journal of Chemistry; Vol. 28, No. 6 (2016), 1177-1180
A
SIAN
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OURNAL OF HEMISTRY
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http://dx.doi.org/10.14233/ajchem.2016.19532
Application of Pfitzinger Reaction in Synthesis of Hetero Ring
Annelated Quinoline Carboxylic Acid Derivatives
1,*
1
2
3
1
TARUNA YADAV , NEELAM K. YADAV , MANJU YADAV , BHAWANI SINGH and D. KISHORE
1Department of Chemistry, Banasthali University, Banasthali-304 022, India
2Department of Chemistry, RPS Degree College, Balana, Mahendergarh-123 029, India
3Department of Pure & Applied Chemistry, University of Kota, Kota-324 005, India
*Corresponding author: E-mail: taruna1311@gmail.com
Received: 28 July 2015;
Accepted: 28 December 2015;
Published online: 29 February 2016;
AJC-17770
The diazotized 8-aminoquinoline (4) was reacted with 2-(hydroxymethylidine)cyclohexanone and N-benzyl 3-(hydroxymethylidine)-
piperidine-4-one (5, 6) (generated from the reaction of cyclohexanone and N-benzyl-4-piperidone with ethyl formate in the presence of
NaOEt) under the conditions of Japp-Klingemann reaction, followed by Fisher-indolization of the resulting hydrazones in acid, formed
the quinolinooxocarbazole (7) and N-benzyl quinolinooxoazacarbazole (8), respectively. Pfitzinger reaction of compounds 7 and 8 with
isatin in alkali afforded the corresponding quinoline carboxylic acid derivatives 10 and 11, respectively. In accord to generally accepted
mechanism of Pfitzinger reaction, we suggest that the reaction of compounds 7 and 8 with isatin in alkali proceeds with the formation of
isatoic acid which undergoes instantaneous cyclocondensation with carbonyl species 7 and 8 to generate compounds 10 and 11, respectively.
Keywords: Quinoline, Carbazole, Azacarbazole, Japp-Klingemann reaction, Pfitzinger reaction, Quinoline 4-carboxylic acid.
system and produced a favourable impact on cytotoxicity in
the new materials.
INTRODUCTION
Ubiquitous presence of carbazoles and azacarbazoles [1]
in a vast array of bio-active molecules (such as ellipticine and
olivacine) has stimulated intense research efforts to develop
their structural analogues where different constitution and
chemical reactivity could allow them to be used as novel
chemotherapeutic agents. Heterocycles that incorporate the
quinoline ring have been known in the literature to exhibit a
wide array of biological activities including antimicrobial,
antibacterial, antifungal [2-4], antiulcer [5], antitumor [6],
antimalarial [7], anticancer [8], antihypertensive [9] and
antiprotozoal activities [10]. Quinoline nucleus exhibits
antitumor activity due to the formation of a stable complex
with DNA.
Recent demonstrations [11] that quinoline carboxylic
acid can be used as potential anti-HIV agents has stimulated
further interest on these molecules with yet another perspective.
Heterocyclic scaffolds bearing pyrazole nucleus in their
molecular framework are endowed with a wide array of
biological activities. It was therefore, considered of interest to
prepare some examples of quinolino condensed carbazole and
azacarbazole derivatives to which quinoline nucleus was
appended into their molecular framework, to examine if such
an association enhanced the DNA binding abilities of the
EXPERIMENTAL
Melting points were determined in open glass capillaries
and are uncorrected. The IR spectra were recorded on CE
(SHIMADZU) FTIR-8400S. 1H NMR spectra were recorded
on model AC-300F (Brucker) using CDCl3/DMSO-d6 as
solvent and TMS as an internal reference. Chemical shift are
expressed in δ ppm. Mass spectra were taken on a Joel SX-
102(EI/CI/FAB) mass spectrometer at 70 eV. 8-Amino-4-
methyl quinolin-2-ol required in synthesis was prepared from
the reduction of 4-methyl-8-nitro quinolin-2-ol.
Preparation of 2-hydroxymethylidine cyclohexanone
and 1-benzyl-3-hydroxymethylidine-4-piperidone (5, 6):A
mixture of NaOEt (0.06 g, 0.01 mol), dry ether (10 mL), redis-
tilled cyclohexanone (0.9 g, 01 mol) or 1-benzylpiperidine-4-
one (1.8 g, 01 mol), ethyl formate (10 mL) were placed in a
two necked flask equipped with a stirrer and stopper. The
reaction was initiated by the addition of 3 mL of ethanol to
the stirred mixture, which was then placed in an ice cold water
bath. Stirring was continued for 6 h. After standing overnight,
2.5 mL of ethanol was added. The mixture was stirred for
additional 1 h.After the addition of 20 mL of water the mixture

1178 Yadav et al.
Asian J. Chem.
was shaken in a separatory funnel. The combined aqueous
extracts were washed with ether. The aqueous layer was
acidified with 5 mL of 6 N HCl and the mixture was extracted
twice with ether. The ether solution was washed with 5 mL
saturated NaCl solution. The solid was dried by the addition
of approximately 5 g of anhydrous MgSO4 powder. The drying
agent was removed by filteration and the ether was evaporated
on the steam bath. The residue was distilled under reduced
pressure to give 5. Yield 0.5 g, 66 %, m.p. 295-96 °C.
Similarly compound 11 was prepared. 0.76 g.Yield 76 %,
m.p. 204-206 °C.
Spectral data ofcompound 10: IR (KBr, νmax, cm-1): 3450
(OH str.), 3010-2505 (CO and OH overtones), 2920, 2850 (CH
str.), 1640 (C=N str.), 1570 (NH str.), 1455 (C-H bend.), 755
(C-H str.). 1H NMR (300 MHz, CDCl3 + DMSO-d6) δ ppm:
12.74 (1H, s, OH), 12.06 (1H, s, OH), 11.33 (1H, s, NH),
8.23-7.93 (4H, m, ArH), 8.12 (1H, d, CH), 7.67 (1H, d, CH),
6.32 (1H, s, CH), 2.93 (2H, t, CH2), 2.88 (2H, t, CH2), 2.63
(3H, s, CH3). MS: m/z 395.41 [M+].
Preparation of 2-hydroxy-4-methyl-7,8,9,11-tetrahydro-
4aH-pyrido[2,3a]carbazol-10(5H)-one (7, 8)
Spectral data of compound 11: IR (KBr, νmax, cm-1): 3420
(OH str.), 3020-2550 (CO and OH over tones), 2955, 2870
(CH str.), 1655 (C=N str.), 1580 (N-H bend), 1470 (C-H bend.),
720 (CH out of plane-1, 2-disub. ring). 1H NMR (300 MHz,
CDCl3 + DMSO-d6) δ ppm: 12.74 (1H, s, OH), 12.07 (1H, s,
OH), 11.34 (1H, s, NH), 8.23-7.93 (4H, m, ArH), 8.12 (1H, d,
CH), 7.69 (1H, d, CH), 7.33-7.23 (4H, m, ArH), 6.31 (1H, s,
CH), 4.71 (2H, s, CH2), 4.32 (2H, s, CH2), 2.61 (3H, s, CH3).
MS: m/z 486.52 [M+].
(A) Preparation of hydrazone: A solution of 3 (1.6 g,
005 mol) in aqueous hydrochloric acid (0.5 mL conc. HCl in
1 mL water) was treated with a cold saturated solution of
sodium nitrite (0.1 g in 2 mL water) while the temperature
was kept at 0-5 °C. It was then added portion wise to an ice
cooled mixture containing 5 (0.05 mL), sodium acetate
trihydrate (0.3 g), methanol (1.5 mL) and water (1 mL) over a
period of 5 h with stirring. The contents were allowed to stand
for further 5 h and the resulting solid mass was filtered, washed
with water, dried and recrystallized from ethanol to give the
hydrazone. Hydrazone was used as such in the second step
without further purification.
(B) Cyclization of hydrazone: A solution of hydrazone
(1.7 g, 005 mol) in a mixture of acetic acid (0.5 mL) and hydro-
chloric acid (0.2 mL) was refluxed on an oil bath preheated to
125-130 °C for 0.5 h. The content were then cooled and poured
in ice cooled water with continous stirring. The separated
brown solid 7 was purified by passing through a column of
silica gel using 50 % benzene in petroleum ether as eluant to
give 1.23 g. Yield-67 %, 297-99 °C.
RESULTS AND DISCUSSION
The synthetic plan adopted for the preparation of the
compounds 10 and 11 (Scheme-I) required it to be accomplished
in two stages. The first stage of this strategy involved the con-
version of quinolinyldiazonium chloride (4) to the quinolino
fused oxocarbazole and oxoazacarbazole derivatives 7 and 8,
respectively. These were realized by the interaction of 1 with
(a) 2-hydroxymethylidene cyclohexanone (5) and (b) N-
benzyl-3-hydroxymethylidene-4-piperidone (6), respectively,
under the conditions of Japp-Klingemann reaction, followed
by Fischer indolization of the resulting crude hydrazones with
Kent’s acid (HCl:AcOH; 1:4 v/v). The compounds 5 and 6
required in the synthesis were in turn obtained, following the
reported procedure [12] which consisted of treating cyclo-
hexanone and N-benzyl-4-piperidone, respectively with ethyl
formate in presence of sodium ethoxide. The second stage of
the strategy required the conversion of 7 and 8 to the corres-
ponding quinoline carboxylic acid derivatives 10 and 11,
respectively. The Pfitzinger reaction of isatin on compounds
containing the COCH2 group is known to provide a very conve-
nient one pot synthetic entry to quinoline-4-carboxylic acid
[13] derivatives. It is reported [14] that enolizable ketones show
great facility to condense with isatin in strongly alkaline medium
to subsequently cyclize to give quinoline products.Application
of this strategy on 7 and 8 allowed 10 and 11 to be formed in
moderate to good yield.
Similarly compound 8 was prepared.Yield: 0.92 g, 58 %,
m.p. 318-320 °C.
Spectral data of compound 7: IR (KBr, νmax, cm-1): 3555
(OH str.), 3110 (NH str.), 2920, 2850 (CH str.), 1720 (C=O
str.), 1660 (C=N str.),1570-1475 (C=C str.), 1332 (NH def.),
1
1080 (C-N), 946 (CH def.). H NMR (300 MHz, CDCl3 +
DMSO-d6) δ ppm: 12.07 (1H, s, OH), 11.63 (1H, s, NH), 8.12
(1H, d, CH), 7.69 (1H, d, CH), 6.31 (H, s, CH), 3.01 (2H, t,
CH2), 2.61 (3H, s, CH3), 2.58 (2H, t, CH2), 2.11 (2H, m, CH2).
MS (m/z): 266.29 [M+].
Spectral data of compound 8: IR (KBr, νmax, cm-1): 3540
(OH str.), 3110 (NH str.), 2940, 2845 (CH str.), 1705 (C=O
str.), 1640 (C=N str.), 1578-1480 (C=C str.), 1331 (NH def.),
1
1076 (C-N), 949 (CH def.). H NMR (300 MHz, CDCl3 +
DMSO-d6) δ ppm: 12.07 (1H, s, OH), 11.63 (1H, s, NH), 8.12
(1H, d, CH), 7.69 (1H, d, CH), 7.33-7.23 (5H, m, ArH), 6.31
(H, s, CH), 4.51 (2H, s, CH2), 3.39 (2H, t, CH2), 2.63 (2H, s,
CH2), 2.61 (3H, s, CH3). MS: m/z 357.40 [M+].
Preparation of 11-hydroxy-9-methyl-6,13-dihydro-5H-
diquinolino[2,3-a:3',2'-i]carbazole-4-carboxylic acid (10,
11): A solution of compound 7 (1 g, 0.004 mol), isatin (0.9 g,
0.005 mol) and 1.2 g of KOH in 5 mL of ethanol was refluxed
for 24 h. After distillation of most of the solvent, water was
added, the netural impurities were removed by ether extraction
and the aqueous layer was acidified with acetic acid and solid
10 was isolated by repeated crystallization from ethanol. 0.74
g, Yield 74 %, m.p. 231-233 °C.
The structure of compounds 7, 8, 10 and 11 were estab-
lished on the basis of their microanalysis (for N), IR, 1H NMR
and MS spectral data. The data shown in experimental section
were found in good agreement to the assigned structures. The
IR spectrum of all the compounds showed the presence of a
strong absorption band near 1710 cm-1 for CO group. The
presence of carboxylic acid group in 10 and 11 was ascertained
by the appearance of a broad band of OH group in the region
1
of 3510-3420 cm-1. The H NMR spectrum displayed the
corresponding peak for OH proton of carboxylic acid in the
region of δ 12.71-1274 ppm. The most diagnostic evidence
which established the formation of the compounds 7, 8, 10

Vol. 28, No. 6 (2016)
Application of Pfitzinger Reaction in Synthesis of Quinoline Carboxylic Acid Derivatives 1179
CH3
CH3
(a)CH3COCH2COOC2H5
Reduction
NH2
Paal-Knorr synthesis
(b) H2SO4
HO
N
HO
N
NO2
NO2
NH2
3
2
1
Diazotization
(i)Japp-Klingemann
Reaction
CH3
N
X
(ii) Fischer indolization
X
5 X=CH2
H3C
N N
H
HO
6 X=N-CH2C6H5
HOHC
O
N2Cl
N
4
O
OH
Fischer indolization
H+
Kent acid
X
O
COOH
X
O
O
H3C
N
H
N
H
9
H3C
N
N
N
H
N
Pfitzinger reaction
KOH
OH
7 X=
CH2
8 X
=N-CH2C6H5
10 X= CH2
11 X= N-CH2C6H5
OH
Scheme-I
and 11 was the appearance of the proton of indole NH in the
regionof 11.33 in all the compounds. The appearance of the
M+ peaks corresponding to their molecular formula in MS
spectrum sustained further the formation of the compounds
and unequivocally established their structures.
The mechanistic pathway that can rationalize the forma-
tion of 10 and 11 from 7 and 8 has been shown in Scheme-II.
It is assumed that the reaction proceeds through the formation
of a non-isolable isatoic acid from isatin which undergoes
instantaneous cyclocondensation with 7 and 8 to generate 10
and 11, respectively.
acid may lead to novel heterocyclic scaffolds with interesting
biological activities. Two noteworthy features of the strategy
employed in synthesis of the reported compounds are apparent
from our study. Firstly it has established that the Fisher
indolization of the 5-quinolylhydrazones of cyclohexanone
and N-substituted piperidin-4-ones provides a very convenient
synthetic entry to the difficultly accessible fused azacarbazole
derivatives. Secondly, it has established further, the versatility
of the Japp-Klingemann reaction to provide a one pot synthetic
approach to the preparation of heteroarylhydrazones (from an
adjacent methylene carbon of a cyclic nitrogen containing
carbonyl species) which are not normally accessible by the
conventional procedures.
Conclusion
In conclusion, an efficient methodology for the synthesis
of quinolino fused carbazolesazacarbazolo fused quinoline
carboxylic acids was developed. Heterocyclic scaffolds bearing
these structures are widely studied because of their impressive
pharmacological activities. It was therefore reasoned, that the
fusion of quinoline, azacrabazole and quinoline carboxylic
ACKNOWLEDGEMENTS
The authors are grateful to the Director, SAIF, Punjab
University, Chandigarh, India for providing the analytical and
spectral data of the compounds.

1180 Yadav et al.
Asian J. Chem.
H3C
HO
X
X
O
COO
O
COO
N
H
KOH
N
H3C
N
O
N
O
O
H
N
H
N
7 X=
CH2,
or
H2N
8 X=N-CH2C6H5
OH
9
COO
X
AcOH
H3C
10 X= CH2
N
N
11 X= N-CH2C6H5
H
N
OH
Scheme-II: Mechanism of formation of compounds 10 and 11 from compounds 7 and 8
7. K.J. Raynes, P.A. Stocks, S.A. Ward, P.M. O‘Neill and B.K. Park, Chem.
Abstr., 133, 193087e (2000).
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