Synthesis of 6,7-dihydrodibenzo[b,j]phenanthroline derivatives by pfitzinger condensation of isatin and cyclic diketones

Article abstract of DOI:10.3987/COM-13-12894

All two kinds of 6,7-dihydrodibenzo[b,j]phenanthroline derivatives were synthesized by Pfitzinger condensation of isatins with 1,3-cyclohexanedione and 1,4-cyclohexanedione respectively. Structures of the derivatives were confirmed by NMR and other spectr

Full text of DOI:10.3987/COM-13-12894

HETEROCYCLES, Vol. 89, No. 1, 2014
209
HETEROCYCLES, Vol. 89, No. 1, 2014, pp. 209 - 215. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 20th November, 2013, Accepted, 2nd December, 2013, Published online, 12th December, 2013
DOI: 10.3987/COM-13-12894
SYNTHESIS
OF
6,7-DIHYDRODIBENZO[b,j]PHENANTHROLINE
DERIVATIVES BY PFITZINGER CONDENSATION OF ISATIN AND
CYCLIC DIKETONES
Lizhen Fang,*1 Jinshuo Ma,1 Chenjuan Lu,1 Huanhuan Li,1 and Xiaoli Yang2
1School of Pharmacy, Xinxiang Medical University, Henan, 453003, P. R. China;
E-mail: 2002flz@163.com
2Diagnostic Laboratory, Xinxiang Medical University
Abstract – All two kinds of 6,7-dihydrodibenzo[b,j]phenanthroline derivatives
were synthesized by Pfitzinger condensation of isatins with 1,3-cyclohexanedione
and 1,4-cyclohexanedione respectively. Structures of the derivatives were
confirmed by NMR and other spectra data.
The family of acridine derivatives includes many pharmacologically significant compounds such as
actinomycin-D, daunomycin, and adriamycin, and some of which show the significant bioactivity of
inhibiting topoisomerase emzyme.1-3 As one type of acridine compounds, the 6,7-dihydrodi-
benzo[b,j]phenanthroline derivatives may be of new use and interesting. The Pfitzinger reaction4 is
probably a shortcut to obtain these derivatives, yet there are few successful examples synthesized by
1,3-diketones and isatins via this reaction up to date. During our investigation of synthetic
methodologies,5,6 we had established a simple method for synthesis of quinoline-4-carboxylic acid
derivatives by an improved Pfitzinger protocol, then we further explored synthesis of
6,7-dihydrodibenzo[b,j]phenanthroline derivatives by Pfitzinger condensation. Herein, we will report
successful synthesis of several 6,7-dihydrodibenzo[b,j]phenanthroline derivatives by double
condensations of isatins with 1,3-cyclohexanedione and 1,4-cyclohexanedione in aqueous media.
The 6,7-dihydrodibenzo[b,j]phenanthroline derivatives seem to be readily synthesized by Pfitzinger
condensation of isatin and1,4-cyclohexanedione or 1,3-cyclohexanedione in a 2:1 molar ratio. However,
the cyclic diketones generally react with one molecule of istain to give the quinoline, few of them react
with two molecules of isatins and it usually requires higher reaction temperature (>160 °C) for the
formation of the biquinoline. On the other hand, it showed impossible to obtain the corresponding pure
quinolines7 by reaction of isatins with such cyclic diketones as 1,3-cyclohexanedione or

210
HETEROCYCLES, Vol. 89, No. 1, 2014
1,4-cyclohexanedione under the usual Pfitzinger conditions, although many other synthetic methods for
synthesis had been developed due to their importance for drug researches in recent years.8
In our improved protocol as shown in Scheme 1, the 6,7-dihydrodibenzo[b,j]phenanthroline derivatives
could be achieved from isatins 1 and 1,3-cyclohexanedione by two steps. In the first step, ring-opening
reaction of 1 occurred under alkaline condition and then transferred to the intermediate keto-acid 2 by
acidification, which consequently condensated with 1,3-cyclohexanedione to give the monocondensed
product 3. In the second step, the corresponding quinoline-4-carboxylic acid 3 was isolated and
condensed again with one molecule of isatin at about 82 °C to give the 6,7-dihydrodibenzo[b,j]-
phenanthroline derivative 5. It should be noted that the two steps of condensations using different
keto-acid substrates should be separately performed, the final productions would be very complex if they
were successively performed in one pot. Unsimilar with the common Pfitzinger in the first step, the
keto-acid 2 was necessary for the condensation, but the keto-acid salt 4 should be still used in the second
step. In addition, in the first step, the copper sulphate appeared to be the best catalyst and the pH should
be always kept at 2-3 with hydrochloric acid till the quinoline 3 precipitated from water completely
according to our previous work.6
O
O
OH
OH
O
O
O
R
R
R
1. KOH/H2O
2. H3O+
O
1,3-cyclohexanedione
N
NH2
N
H
p-TsOH, rt
1
2
3
R
HO
O
KO
O
N
O
keto-acid 2
R
OH
R
5% KOH/EtOH
reflux,82 C
then acidified to pH = 3
O
N
N
5
4
5a
5b
5d: R = Cl, 5e: R = Br
5c
: R = H, : R = Me, : R = F,
Scheme 1. The 6,7-dihydrodibenzo[b,j]phenanthroline derivatives prepared from isatins and
1,3-cyclohexanedione in two steps
The generality of this procedure was also explored. The same protocol could also be applied to other
similar diquinolines from the corresponding alkyl or halogen-substituted acid salts and
1,3-cyclohexanedione. The highest yield was achieved with 5-methylindoline-2,3-dione in 85%, and the
lowest, with 5-bromoindoline-2,3-dione in 57%.

HETEROCYCLES, Vol. 89, No. 1, 2014
211
Surprisingly, the 1,4-cyclohexanedione was showed to react readily with two molecules of the alkyl or
halogen-substituted isatin 1 to form biquinoline 6 as Scheme 2. Consendation of 1,4-cyclohexanedione
with isatin under acid condition would give the biquinoline 6 in one step regardless of the ratio of
1,4-cyclohexanedione to 1 in the reaction was 1:2 or not. The double condensations could go on
successfully in one step and gave the biquinolines 6 .The reason why this reaction happened was probably
due to 1,4-cyclohexanedione with two keto groups separated by more than one carbon atom and the steric
hindrance became smaller for condensation.9 The lowest yield for 6e was 35%, although the yields
were not very high, the corresponding biquinolines can be conveniently prepared by this method with
isatins. Other diketones such as 5,5-dimethyl-1,3-cyclohexanedione, 1,3-indanedione were also tried to be
used to prepare the biquinolines but failed.
R
OH
1,4-cyclohexanedione
O
HO2C
HO2C
O
R
1. KOH/H2O
2. H3O+
R
R
N
O
O
rt, cat.
N
H
NH2
N
6
1
2
6a: R = H, 6b: R = Me, 6c: R = F,
6d: 6e:
R = Cl,
R = Br
Scheme 2. The 6,7-dihydrodibenzo[b,j]phenanthroline derivatives prepared from isatins and
1,4-cyclohexanedione in one-step
Constructions of all the compounds 5 and 6 were confirmed by NMR and other spectra data. The
symmetrical configuration of the compounds 6a-e was proved by NMR, Specifically, the resonance
signals of the 13C-NMR and DEPT were clearly half of the total number of carbons in biquinolines 6 for
each corresponding compound. Because of their poor solubility in DMSO-d6 and other common
deuterated reagents, the compounds 6d and 6e were elucidated by the solid state NMR Spectroscopy, MS
and element analysis.
The detailed mechanism of the Pfitzinger reaction we preferred to think was probably the Claisen
condensation path as shown in our previous work.6
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
1
AVANCE 400 NMR spectrometer at 400 MHz in DMSO-d6 using TMS as internal standard. H MAS

212
HETEROCYCLES, Vol. 89, No. 1, 2014
and 13C CP/MAS NMR experiments were performed on Bruker AVANCE III 600 spectrometer at a
resonance frequency of 600.1 MHz and 150.9 MHz, respectively. The chemical shifts of 1H and 13C NMR
were externally referenced to TMS. 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 6,7-dihydrodibenzo[b,j][1,7]phenanthroline-8,14-
dicarboxylic acid (5a).
The mixture of keto-acid salt 2 (203 mg, 1 mmol) and compound 4 (279 mg, 1 mmol) in 5% ethanolic
KOH solution (5 mL) was heated to reflux for 5 h. After cooling, the solvent was evaporated. Water was
added and the mixture was acidified with concentrated hydrochloric acid to pH 2-3 and the precipitate
appeared. After filtration, the yellow solid 5a was purified by chromatography on silica gel eluting with
CHCl3/MeOH (3:1).
6,7-Dihydrodibenzo[b,j][1,7]phenanthroline-8,14-dicarboxylic acid (5a): A yellow powder; 288.9 mg
yield 78%; mp 273–274 °C; Rf 0.49 (2:1 CHCl3–MeOH); 1H NMR (400 MHz, DMSO-d6) δ 3.23 (dd, J =
4.0, 7.2 Hz, 2H), 3.34 (dd, J = 4.0, 7.2 Hz, 2H), 7.63–7.67 (m, 1H), 7.68–7.72 (m, 1H), 7.78–7.82 (m,
1H), 7.83–7.89 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 8.05 (t, J = 8.0 Hz, 2H), 13.78 (s, 2H); 13C NMR (100
MHz, DMSO-d6) δ 24.9, 31.8, 122.3, 123.0, 123.6, 125.2, 125.7, 127.2, 127.6, 128.7, 129.0, 129.5, 130.8,
139.2, 146.0, 147.3, 150.2, 159.9, 168.8, 169.1. Anal. Calcd for C22H14N2O4: C, 71.35; H, 3.81; N, 7.56.
Found: C, 71.33; H, 3.80; N, 7.58.
2,10-Dimethyl-6,7-dihydrodibenzo[b,j][1,7]phenanthroline-8,14-dicarboxylic acid (5b): A brown
1
powder; 338.7 mg, yield 85%, mp 291–293 °C; Rf 0.51(2:1 CHCl3–MeOH); H NMR (400 MHz,
DMSO-d6) δ 2.55 (s, 3H), 2.56 (s, 3H), 3.25 (dd, J = 4.0, 7.2 Hz, 2H), 3.34 (dd, J = 4.0, 7.2 Hz, 2H),
7.65–7.71 (m, 4H), 7.96–8.00 (m, 2H), 13.67 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 21.4, 21.6, 25.1,
31.6, 122.2, 122.7, 123.3, 123.5, 124.1, 126.5, 128.5, 128.9, 132.0, 133.0, 136.8, 138.0, 138.4, 144.6,
145.9, 149.5, 158.7, 168.3, 169.1. Anal. Calcd for C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.34; H, 4.56; N, 7.01.
2,10-Difluoro-6,7-dihydrodibenzo[b,j][1,7]phenanthroline-8,14-dicarboxylic acid (5c): A brown
1
powder; 329.1 mg, yield 81%, mp 304–305 °C; Rf 0.43 (2:1 CHCl3–MeOH); H NMR (400 MHz,
DMSO-d6) δ 3.28–3.30 (m, 2H), 3.32–3.34 (m, 2H), 7.58–7.65(m, 2H), 7.77–7.83 (m, 2H), 8.09–8.17 (m,
2H), 13.62 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 25.0, 31.4, 108.6, 108.8, 120.0, 121.0, 122.9, 124.0,
124.2, 127.7, 131.8, 132.1, 138.6, 143.2, 144.6, 149.7, 158.9, 159.4, 161.3, 161.9, 168.0, 168.7. Anal.
Calcd for C22H14F2N2O4: C, 65.03; H, 2.98; F, 9.35; N, 6.89. Found: C, 65.03; H, 2.97; F, 9.36; N, 6.88.
2,10-Dichloro-6,7-dihydrodibenzo[b,j][1,7]phenanthroline-8,14-dicarboxylic acid (5d): A yellow
1
powder; 276.7 mg, yield 63%, mp 301–302 °C; Rf 0.46 (2:1 CHCl3–MeOH); H NMR (400 MHz,

HETEROCYCLES, Vol. 89, No. 1, 2014
213
DMSO-d6) δ 3.32 (dd, J = 3.8, 7.2 Hz, 2H), 3.38 (dd, J = 3.8, 7.2 Hz, 2H), 7.89–7.94 (m, 4H), 8.07–8.12
13
(m, 2H), 13.88 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 25.0, 31.4, 122.9, 123.4, 123.6, 124.0, 124.2,
128.4, 130.6, 131.0, 131.2, 131.5, 131.9, 132.9, 137.6, 138.4, 144.3, 145.8, 150.5, 160.5, 167.5, 168.5.
Anal. Calcd for C22H14Cl2N2O4: C, 60.16; H, 2.75; Cl, 16.14; N, 6.38. Found: C, 60.14; H, 2.76; Cl,
16.16; N, 6.36.
2,10-Dibromo-6,7-dihydrodibenzo[b,j][1,7]phenanthroline-8,14-dicarboxylic acid (5e): A yellow
1
powder; 301.0 mg, yield 57%, mp 303–305 °C; Rf 0.48 (2:1 CHCl3–MeOH); H NMR (400 MHz,
DMSO-d6) δ 3.17–3.24 (m, 4H), 7.77–7.97 (m, 4H), 8.12–8.14 (m, 2H), 12.95 (s, 2H). 13C NMR (100
MHz, DMSO-d6) δ 24.8, 31.1, 122.7, 123.2, 123.4, 123.8, 124.0, 128.2, 130.4, 130.8, 131.0, 131.3, 131.7,
132.7, 137.4, 138.2, 144.1, 145.6, 150.3, 160.3, 167.2, 168.3. Anal. Calcd for C22H14Br2N2O4: C, 50.03;
H, 2.29; Br, 30.26; N, 5.30. Found: C, 50.03; H, 2.27; Br, 30.26; N, 5.31.
General procedure for the synthesis of 6,7-dihydrodibenzo[b,j][4,7]phenanthroline-13,14-
dicarboxylic acid (6a). The mixture of isatin (294 mg, 2 mmol) and potassium hydroxide (250 mg) in
water (5 mL) was stirred at room temperature for 30 min. Then the mixture was acidified with
concentrated hydrochloric acid to pH 2-3 and added 1,4-cyclohexanedione (112 mg, 1 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, 3:1, v/v). After the starting material
had vanished, the precipitate was filtered out, washed with water, and recrystalized to afford the
compound 6a.
6,7-Dihydrodibenzo[b,j][4,7]phenanthroline-13,14-dicarboxylic acid (6a): A yellow powder, 281.5
mg, yield 76%, mp 264–265 °C (MeOH); Rf 0.49 (4:1 CHCl3–MeOH); 1H NMR (400 MHz, DMSO-d6): δ
3.19 (d, J = 10.7 Hz, 2H), 3.30 (d, J = 10.5 Hz, 2H), 7.68 (t, J = 7.4 Hz, 2H), 7.85 (t, J = 7.5 Hz, 2H),
8.09 (d, J = 8.0 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 13.90 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 31.6,
121.9, 123.3, 124.1, 125.7, 127.2, 129.0, 137.0, 145.2, 159.4, 165.6. Anal. Calcd for C22H14N2O4: C,
71.35; H, 3.81; N, 7.56; O, 17.28. Found: C, 71.33; H, 3.81; N, 7.57; O, 17.29.
2,11-Dimethyl-6,7-dihydrodibenzo[b,j][4,7]phenanthroline-13,14-dicarboxylic acid (6b): A yellow
1
powder, 235.7 mg, yield 79%, mp 349–350 °C (MeOH). Rf 0.48 (4:1 CHCl3–MeOH); H NMR (400
MHz, DMSO-d6): δ 2.25 (s, 2H), 2.53 (s, 2H), 3.13–3.27 (m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H),
7.40 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 13.69 (s, 2H).
13C NMR (100 MHz, DMSO-d6): δ 25.1, 33.0, 109.3, 109.5, 120.6, 131.8, 131.9, 144.3, 159.1, 160.6,
161.6, 167.0. Anal. Calcd for C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.34; H, 4.56; N, 7.02.
2,11-Difluoro-6,7-dihydrodibenzo[b,j][4,7]phenanthroline-13,14-dicarboxylic acid (6c): A yellow
powder; 264.0 mg, yield 65%, mp 293–294 °C (MeOH); Rf 0.40 (4:1 CHCl3–MeOH); 1H NMR (400
MHz, DMSO-d6) δ 3.18–3.31 (m, 4H), 7.81 (td, J = 2.8, 8.4 Hz, 2H), 8.05 (dd, J = 2.2, 10.8 Hz, 2H), 8.17

214
HETEROCYCLES, Vol. 89, No. 1, 2014
13
(dd, J = 5.6, 9.2 Hz, 2H), 14.11 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 32.8, 109.2, 120.4, 120.6,
124.0, 124.1, 131.7, 144.1, 158.9, 160.4, 161.4, 166.9. Anal. Calcd for C22H14F2N2O4: C, 65.03; H, 2.98;
F, 9.35; N, 6.89. Found: C, 65.04; H, 2.96; F, 9.35; N, 6.88.
2,11-Dichloro-6,7-dihydrodibenzo[b,j][4,7]phenanthroline-13,14-dicarboxylic acid (6d): A brown
powder; 224.0 mg, yield 51%, mp 296–297 °C; Rf 0.39 (4:1 CHCl3–MeOH); 13C CP/MAS NMR δ 33.1,
122.3, 124.7, 130.1, 144.3, 160.3, 177.4. Anal. Calcd for C22H12Cl2N2O4: C, 60.16; H, 2.75; Cl, 16.14; N,
6.38. Found: C, 60.16; H, 2.76; Cl, 16.15; N, 6.38. HRMS-ESI (m/z): [M+H]+ calcd for C22H12Cl2N2O4,
438.1921; found, 438.1915.
2,11-Dibromo-6,7-dihydrodibenzo[b,j][4,7]phenanthroline-13,14-dicarboxylic acid (6e): A brown
powder; 184.9 mg, yield 35%, mp 289–290 °C; Rf 0.43 (4:1 CHCl3–MeOH); 13C CP/MAS NMR δ 32.4,
121.3, 124.4, 129.9, 144.2, 160.2, 177.7. Anal.Calcd for C22H12Br2N2O4: C, 50.03; H, 2.29; Br, 30.26; N,
5.30. Found: C, 50.02; H, 2.26; Br, 30.25; N, 5.32. HRMS-ESI (m/z): [M+H]+ calcd for C22H12Br2N2O4,
525.9196; found, 525.9193.
ACKNOWLEDGEMENTS
This project was supported by the National Natural Science Foundation of China (81172952), the
Foundation for University Key Teacher by the Education Department of Henan Province (2012) and the
Natural Science Program of the Education Department of Henan Province (2010B32007).
REFERENCES
1. K. Dzierzbicka, A. M. L Kolodziejczyk, B. Wysocka-Skrzela, A. Mysliwski, and D. Sosnowska, J.
Med. Chem., 2001, 44, 3606.
2. K. Dzierzbicka and A. M. Kolodziejczyk, J. Med. Chem., 2003, 46, 183.
3. H. Ravi, T. Padma, C. Y. Mayur, K. Gowdahalli, N. T. Kuntebommanahalli, J. H. Peter, and M.
Yerigeri, Eur. J. Med. Chem., 2004, 39, 161.
4. (a) W. Pfitzinger, J. Prakt. Chem., 1886, 33, 100; (b) M. G. A. Shvekhgeimer, Chem. Heterocycl.
Compd., 2004, 40, 257.
5. Q. H. Lv, L. Z. Fang, P. F. Wang, C. J. Lu, and F. L. Yan, Heterocycles, 2012, 85, 1457.
6. Q. H. Lv, L. Z. Fang, C. J. Lu, and P. F. Wang, Monatsh. Chem., 2013, 144, 391.
7. A. V. Ivachtchenko, V. V. Kobak, A. P. Il’yin, A. S. Trifilenkov, and A. A. Busel, J. Comb. Chem.,
2003, 5, 645.
8. For selected reviews of quinolines, see: (a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166, and
previous reviews of this series; (b) V. V. Kouznetsov, L. Y. V. Méndez, and C. M. M. Gómez, Curr.
Org. Chem., 2005, 9, 141; (c) J. P. Michael, Nat. Prod. Rep., 2004, 21, 650.

HETEROCYCLES, Vol. 89, No. 1, 2014
215
9. C. C. Cheng and S. J. Yan, 'In the Friedländer synthesis of quinolines in Organic Reactions,' Vol. 28,
ed. by W. G. Dauben, R. A. Bunce, and W. R. Baker, 1982, p. 13.