Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot strategy to the synthesis of quinoline carboxylic acid derivatives of pyrazolo-carbazoles and azacarbazoles

Article abstract of DOI:10.1007/s12039-012-0240-6

Interaction of 5-indazolyldiazonium chloride 2 with 2-hydroxymethylidene cyclohexanone 5 and N-benzyl-3-hydroxymethylidene-4-piperidone 6 under the conditions of Japp-Klingemann reaction, followed by Fischer-indolization of the resulting hydrazones, formed the 5,7,8,9-tetrahydropyrazolo[4,3-b]carbazol-6(1H) -one 9 and 9-benzyl-5,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3- f]indazol-6(1H)-one 10, respectively. Pfitzinger reaction of 9 and 10 with isatin in alkali afforded the corresponding quinoline carboxylic acid derivatives 12 and 13, respectively. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-012-0240-6

c
J. Chem. Sci. Vol. 124, No. 2, March 2012, pp. 431–435. ꢀ Indian Academy of Sciences.
Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot
strategy to the synthesis of quinoline carboxylic acid derivatives of
pyrazolo-carbazoles and azacarbazoles
RUCHI TYAGI, BHAWANI SINGH∗ and D KISHORE
Department of Chemistry, Banasthali University, Banasthali (Rajasthan)-304022, India
e-mail: bsyadav2000@gmail.com
MS received 2 December 2010; revised 22 December 2011; accepted 20 January 2012
Abstract. Interaction of 5-indazolyldiazonium chloride 2 with 2-hydroxymethylidene cyclohexanone 5 and
N-benzyl-3-hydroxymethylidene-4-piperidone 6 under the conditions of Japp–Klingemann reaction, followed
by Fischer-indolization of the resulting hydrazones, formed the 5,7,8,9-tetrahydropyrazolo[4,3-b]carbazol-
6(1H)-one 9 and 9-benzyl-5,7,8,9-tetrahydropyrido[2ꢁ,3ꢁ:4,5]pyrrolo[2,3-f]indazol-6(1H)-one 10, respec-
tively. Pfitzinger reaction of 9 and 10 with isatin in alkali afforded the corresponding quinoline carboxylic acid
derivatives 12 and 13, respectively.
Keywords. Japp–Klingemann reaction; tetrahydropyrazolo[4,3-b]carbazol-6(1H)-one;
9-benzyl-5,7,8,9-tetrahydropyrido[2ꢁ,3ꢁ:4,5]pyrrolo[2,3-f]indazol-6(1H)-one; Pfitzinger reaction; quinoline
4-carboxylic acid.
1. Introduction
molecular framework to examine if such an association
enhanced the DNA binding abilities of the system and
produced a favourable impact on cytotoxicity in the new
materials.
The proven record of bioactive carbazoles and azacar-
bazoles reveal that these materials form interesting tar-
gets in synthesis,1 since such structures have potential
for development of compounds with antitumor activ-
ity that could mimic to the activity of ellipticene. The
ellipticene exhibits significant antitumor activity due to
its DNA intercalating properties.2 Quinoline carboxylic
acid and their analogues show wide variety of medicinal
properties including antitumor,3 antiviral4 and estro-
genic activity.5 It has been shown that 1,2,3-triazole
fused quinolines exhibit photo-cleavage activity6 due
to the formation of stable complex with DNA. Recent
demonstrations reveal that quinoline carboxylic acid can
be used as potential anticancer agents7 have stimulated
further interest on these molecules with yet another per-
spective. Heterocyclic scaffolds bearing indole nucleus
in their molecular framework are endowed with a wide
array of biological activities.8 Therefore, it was con-
sidered of interest to prepare some examples of pyra-
zolo condensed carbazole and azacarbazole derivatives
to which quinoline nucleus was appended into their
2. Experimental
Melting points were determined on an open capillary
and are uncorrected. The IR spectra were recorded
1
on Schimadzu FTIR-8400S. H NMR spectra were
recorded in DMSO-d6 and CDCl3 on Bruker DRX-300
spectrometer using TMS as internal reference and val-
ues are expressed in δ ppm. Mass spectra were taken
on a Joel SX-102 (EI/CI/FAB) mass spectrometer at
70 eV. 5-Aminoindazole required in synthesis was pre-
pared from the reduction of commercially available
5-nitroindazole.9
2.1 General procedure for the preparation of 9 and 10
2.1a Preparation of (E)-2-(2-(1H-indazol-5-yl)hy-
drazono)cyclohexanone 7 or (E)-3-(2-(1H-indazol-5-
yl)hydrazono)-1-benzylpiperidin-4-one 8 using Japp–
Klingemann reaction: A solution of 5-indazolyl am-
ine 1 (1.00 g, 0.050 mol) in aqueous HCl (2 ml conc.
HCl in 4 ml water) was treated with a cold saturated
∗For correspondence
431

432
Ruchi Tyagi et al.
solution of sodium nitrite (0.7 g in 2 ml water) while 128.8, 127.9 for benzene ring); MS: m/z316 [M+];
the temperature was kept at 0–5◦C. The solution was Anal. Calcd/found for C19H16N4O: N, 17.71/17.62.
kept aside for 10 min. It was then added portion-
wise to an ice-cooled mixture containing 2-(hydroxy-
2.2 General procedure for the preparation of 12 and
13 from the ketone 9 and 10
methylene)cyclohexanone 5 or 1-benzyl-3-(hydroxy-
methylene)piperidin-4-one (1.30 g, 0.050 mol),
6
sodium acetate trihydrate (1.80 g) in methanol (10 ml)
and water (6 ml) over a period of 0.5 h with stirring.
The contents were allowed to stand for further 0.5 h
and the resulting solid mass was filtered, washed with
water and dried.
A solution of ketone 9 or 10 (0.07 mol), isatin
(0.07 mol) and potassium hydroxide (0.2 mol) in
ethanol (25 ml) was refluxed for 24 h. After the distilla-
tion of most of the solvent, water was added. The neu-
tral impurities were removed by ether extraction, and
the aqueous layer was acidified with acetic acid till neu-
tralization. The brown coloured precipitate of 12 or 13
formed was collected and recrystalized from ethanol.
2.1b General procedure for the cyclization of hydra-
zones by using Fischer-indole reaction: A solution of
crude hydrazone 7 or 8 (0.01 mol) suspended in a mix-
ture of HCl:AcOH (1:4) was refluxed on a pre-heated
oil bath to (125–130◦C) for 0.5 h. The contents were
then cooled and poured into ice-cooled water with stir-
ring and then basified with ammonia. The separated
brown solid was purified by passing through a column
of silica gel using 50% benzene in pet ether as eluant.
2.2a 6,7,9,13-Tetrahydropyrazolo[3ꢁ,4ꢁ:5,6]indolo[3,
2-c]acridine-5-carboxylic acid 12: This was prepared
following the general procedure described above. Yield:
73%; m. p. 208–10◦C; IR (KBr) cm−1: 3500, 3300,
1
2900, 1810, 1790, 1480, 1030; H NMR (300 MHz,
CDCl3 + DMSO-d6) δ ppm: 12.9 (1H, s, NH), 11.3
(1H, s, COOH), 10.1 (1H, s, NH), 8.25–8.87 (4H, m,
ArH), 8.20 (1H, s, CH), 7.60 (2H, s, ArH), 2.82 (2H, t,
J = 6.4 Hz, CH2), 2.76 (2H, t, J = 6.4 Hz, CH2); 13C
NMR (δ ppm):C (143.4, 126.1, 123.7, 121.3 for inda-
zole), CH (128.8, 121.5, 113.1 for indazole), C (132.2,
116.1 for indole), CH2 (24.8, 23.3 for aliphatic carbon),
C (156.1, 152.1, 146.8, 133.4, 123.7 for quinoline), CH
(129.2, 128.7, 128.3, 123.8 for quinoline), C (168.9 for
1-carboxyl); MS: m/z354 [M+]; Anal. Calcd./found
for C21H14N4O2: N, 15.81/15.73.
2.1c 5,7,8,9-Tetrahydropyrazolo[4,3-b]carbazol-6(1H)-
one 9: The compound 9 was obtained by applying the
general procedure mentioned above. Yield: 65%; m.p.
238–240◦C; IR (KBr) cm−1: 3290, 2920, 1720, 1510,
1
1020; H NMR (300 MHz, CDCl3+DMSO-d6) δ ppm:
12.4 (1H, s, NH), 10.1 (1H, s, NH), 8.20 (1H, s, CH),
7.85 (2H, s, ArH), 2.43 (2H, t, J = 6.4 Hz, CH2), 2.10
(2H, m, CH2), 1.89 (2H, t, J = 6.4 Hz, CH2); 13C NMR
(δ ppm): C (141.2, 124.8, 122.2, 122.0 for indazole
ring), CH (128.9, 121.1, 112.0 for indazole ring), C
(133.6, 124.1 for indole ring), C (183.0 for carbonyl
carbon), CH2 (37.2, 26.4, 24.3 for aliphatic carbons);
MS: m/z 225 [M+]; Anal. calcd./found for C13H11N3O:
N, 18.52/18.46.
2.2b 7-Benzyl-6,7,9,13-tetrahydrobenzo[b]pyrazolo[3ꢁ,
4ꢁ: 5,6]indolo[3,2-h][1,6] naphthyridine-5-carboxylic
acid 13: This was prepared following the general pro-
cedure described above. Yield: 75%; m. p. 215–217◦C;
IR (KBr) cm−1: 3480, 3290, 2910, 1800, 1780, 1470,
2.1d 9-Benzyl-5,7,8,9-tetrahydropyrido[2ꢁ,3ꢁ:4,5]pyr-
rolo[2,3-f]indazol-6(1H)-one 10: The compound 10
was obtained by applying the general procedure
mentioned above. Yield: 70%; m.p. 277–279◦C; IR
1
1020 1030; H NMR (300 MHz, CDCl3 + DMSO-d6)
δ ppm: 12.1 (1H, s, NH), 11.6 (1H, s, COOH), 10.3
(1H, s, NH), 8.25–8.87 (4H, m, ArH), 8.17 (1H, s,
CH), 7.55 (2H, s, ArH), 7.14–7.06 (5H, m, ArH), 4.37
(2H, s, CH2), 2.48 (2H, s, CH2); 13C NMR (δ ppm):C
(141.8, 124.6, 123.7, 121.2 for indazole), CH (128.3,
121.3, 112.1 for indazole), C (158.1, 149.7, 144.7,
131.8, 125.1, 123.5, 104.3 for quinoline), CH (128.3,
127.2, 126.6, 123.4 for quinoline), CH2 (56.2, 53.8 for
aliphatic carbon), C (137.4 for 1-benzene), CH (128.8,
128.5, 128.3, 128.1 127.8 for benzene), C (169.9 for
1-carboxyl); MS: m/z 469 [M+]; Anal. Calcd/found
for C29H19N5O2: N, 14.92/14.84.
1
(KBr) cm−1: 3220, 2910, 1735, 1520, 1040; H NMR
(300 MHz, CDCl3+DMSO-d6) δppm: 11.9 (1H, s, NH),
10.8 (1H, s, NH), 8.15 (1H, s, CH), 7.79 (2H, s, ArH),
7.14–7.06 (5H, m, ArH), 4.32 (2H, s, CH2), 3.39 (2H,
t, J = 6.5 Hz, CH2), 2.14 (2H, t, J = 6.5 Hz, CH2); 13C
NMR (δppm):C (142.4, 126.3, 124.8, 122.1 indazole
ring), CH (128.1, 123.1, 112.8 indazole ring), C (186.5,
135.3, 113.9 indole ring), CH2 (53.6, 37.8, 33.9 for
aliphatic carbon), C (137.4 for 1-benzene), CH (129.1,

Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot strategy to the synthesis
433
3. Results and discussion
to condense with isatin in strongly alkaline medium to
subsequently cyclize to give quinoline products. Appli-
The synthetic plan conceived for the preparation of the cation of this strategy on 9 and 10 allowed 12 and 13 to
materials 12 and 13 in scheme 1 required it to be accom- be formed in moderate to good yield.
plished in two stages. The first stage of this strategy
The structure of compounds 9, 10, 12 and 13 were
involved the conversion of 5-indazolyldiazonium chlo- established on the basis of their microanalysis (for
1
ride 2 to the pyrazolo fused 5,7,8,9-tetrahydropyra- nitrogen), IR, H NMR and MS spectral data. The
zolo[4,3-b]carbazol-6(1H)-one 9 and 9-benzyl-5,7,8,9- data shown in experimental section were found in good
tetrahydropyrido[2ꢁ,3ꢁ:4,5]pyrrolo[2,3-f]indazol-6(1H)- agreement to the assigned structures. The IR spec-
one 10 derivatives, respectively. These were realized by tra of all the compounds showed the presence of a
the interaction of 2 with 2-(hydroxymethylene)cyclo- strong absorption band near 1700 cm−1 for CO group.
hexanone 5 and 1-benzyl-3-(hydroxymethylene)piperi- The presence of carboxylic acid group in 12 and 13
din-4-one 6, respectively under the conditions of was ascertained by the appearance of a broad band of
1
Japp–Klingemann reaction, followed by the Fischer OH group in the region of 3500–3400 cm−1. The H
indolization of the resulting crude hydrazones with NMR spectrum displayed the corresponding peak for
Kent’s acid (HCl:AcOH; 1:4 v/v). The compounds 5 OH proton of carboxylic acid in the region of δ 11.0
and 6 required in the synthesis were in turn obtained, ∼11.4 ppm. The most diagnostic evidence which estab-
following the reported procedure10 which consisted of lished the formation of the compounds 9, 10, 12 and
treating cyclohexanone 3 and N-benzyl-4-piperidone 13 was the appearance of the proton of indole NH
4, respectively with ethyl formate in the presence of in the region of δ 10.1–10.8 in all the compounds.
sodium ethoxide. The second stage of the strategy (The NH proton of indazole nucleus appeared at much
required the conversion of 9 and 10 to the corre- downfield region at δ 12.4 ppm). The appearance of
sponding quinoline carboxylic acid derivatives 12 and the M+ peaks corresponding to their molecular for-
13, respectively. The Pfitzinger reaction of isatin on mula in MS spectrum substantiated further the forma-
compounds containing the COCH2 group is known tion of the compounds and unequivocally established
to provide a convenient one-pot synthetic entry their structures.
to quinoline-4-carboxylic acid derivatives.11 It is
reported12 that enolizable ketones show great facility mation of 12 and 13 from 9 and 10 has been shown
The mechanistic pathway that rationalized the for-
Scheme 1. Formation of 12 and 13 from 9 and 10, respectively.

434
Ruchi Tyagi et al.
Scheme 2. Mechanism of formation of 12 and 13 from 9 and 10, respectively.
in scheme 2. It is assumed that the reaction proceeded strategy employed in synthesis of the reported com-
through the formation of a non-isolable isatoic acid pounds are apparent form our study. Firstly, it has estab-
from isatin 11 that underwent instantaneous cyclo- lished that the Fischer indolization of the 5-indazolyl
condensation with 9 and 10 to generate 12 and 13, hydrazones of cyclohexanone and N-benzyl substituted
respectively.
piperidin-4-ones provided a very convenient synthetic
entry to the difficultly accessible pyrazolo fused car-
bazole and azacarbazole derivatives. Secondly, it has
established further that the versatility of the Japp–
Klingemann reaction to provide a one-pot synthetic
approach to the preparation of heteroaryl hydrazones
(on an adjacent methylene carbon of a cyclic car-
bonyl species) which are not normally accessible by the
conventional procedures.
4. Conclusion
In conclusion, an efficient methodology for the
synthesis of pyrazolo condensed oxocarbazoles and
oxoazacarbazoles and their one-pot conversion to cor-
responding carbazolo and azacarbazolo fused quino-
line carboxylic acids was developed. Heterocyclic scaf-
folds bearing these structures have been widely studied
because of their impressive pharmacological activities.
Acknowledgements
It was, therefore, reasoned that the presence of pyrazole, Authors are thankful to the Director of Central Drug
carbazole or azacarbazole and quinoline carboxylic acid Research Institute (CDRI), Lucknow and Sophisticated
in tandem with the same molecular framework could Analytical Instrumentation Facility (SAIF), Punjab
produce the novel heterocyclic scaffolds with interest- University, Chandigarh for providing the spectral data
ing biological activities. Two noteworthy features of the of the compounds.

Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot strategy to the synthesis
435
References
551; (b) Shi F, Zhang S, Wu S-S, Gao Y and Tu S-J
2011 Mol. Divers. 15(2) 497
6. (a) Aravinda T, Bhojya Naik H S and Prakash Naik H R
2009 Int. J. Peptide Res. Therapeutics 15(4) 273; (b)
Prabahkara M C and Naik H S B 2008 Biometals 21(6)
675
7. (a) Tandon V K, Yadav D B, Chaturvedi A K and Shukla
P K 2005 Bioorg. Med. Chem. Lett. 15(13) 3288; (b)
Musiol R, Jampilek J, Kralova K, Richardson D R,
Kalinowski D, Podeszwa B, Finster J, Niedbala H, Palka
A and Polanski J 2007 Bioorg. Med. Chem. 15(3) 1280
8. Eyunni V K, Kumar S, Etukala J R and Ablordeppey S Y
2008 Mini Rev. Med. Chem. 8(6) 538
9. Abdellah M, Douniazed E L A, Herard B and Jean-
Pierre G 2006 Heterocycles 68 2595
10. Danish I A and Prasad K J R 2004 Indian J. Chem.
43B(7) 1548
11. Shvekhgeimer M G A 2004 Chem. Heterocyclic Comp.
40(3) 257
1. Caruso A, Voisin-Chiret S A, Lancelot J-C, Sinicropi
M S, Garofalo A and Rault S 2008 Molecules 13(6)
1312
2. Knolker H-J and Reddy K R 2002 Chem. Rev. 102(11)
4303
3. (a) Atwell G J, Baguley B C and Denny W A 1989 J.
Med. Chem. 32(2) 396; (b) Feng X U, Ding Q, Yang
K and Jing W G 2006 Chinese Chem. Lett. 17(2) 187;
(c) Srivastava S K, Jha A, Agarwal S K, Mukherjee R
and Burman A C 2007 Anti-Cancer Agents Med. Chem.
7(6) 685
4. (a) Gramik V G, Zhidkova A M, Kiselev S S, Glushkov
R G, Polezhaeva A J and Mashkovshi M D 1978 Pharm.
Chem. J. 12(7) 881; (b) Dayam R, Al-Mawsawi L Q,
Zawahir Z, Witvrouw M, Debyser Z and Neamati N
2008 J. Med. Chem. 51(5) 1136
12. Pajouhesh H, Parson R and Popp F D 1983 J. Pharm.
Sci. 72(3) 318
5. (a) Nazrullaev
S
S, Bessonova
I
A
and
Akhmedkhodzhaeva K S 2001 Chem. Nat. Comp. 37(6)