Synthesis, antimicrobial properties, and inhibition of catalase activity of 1,4-naphtho-and benzoquinone derivatives containing N-, S-, O-substituted

Article abstract of DOI:10.1155/2019/1658417

A series of new 1,4-naphtho-and benzoquinone derivatives possessing N-, S-, O-substituted groups which has not been reported yet has been synthesized from 2,3-dichloro-1,4-naphthoquinone 1 and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione 15 involving

Full text of DOI:10.1155/2019/1658417

Hindawi
Heteroatom Chemistry
Volume 2019, Article ID 1658417, 12 pages
https://doi.org/10.1155/2019/1658417
Research Article
Synthesis, Antimicrobial Properties, and Inhibition of
Catalase Activity of 1,4-Naphtho- and Benzoquinone Derivatives
Containing N-, S-, O-Substituted
Semih Kurban ,1 Nahide Gulsah Deniz ,1 Cigdem Sayil ,1
Mustafa Ozyurek ,2 Kubilay Guclu ,3 Maryna Stasevych ,4 Viktor Zvarych ,4
4
Olena Komarovska-Porokhnyavet ,4 and Volodymyr Novikov
1 Division of Organic Chemistry, Department of Chemistry, Engineering Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
2Division of Analytical Chemistry, Department of Chemistry, Engineering Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
3Faculty of Arts and Sciences, Department of Chemistry, Aydın Adnan Menderes University, Aydın, Turkey
4Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology, Lviv Polytechnic National University,
Lviv, Ukraine
Correspondence should be addressed to Cigdem Sayil; sayil@istanbul.edu.tr
Received 3 October 2018; Accepted 10 December 2018; Published 2 January 2019
Academic Editor: Gianluigi Broggini
Copyright © 2019 Semih Kurban et al. Tis is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A series of new 1,4-naphtho- and benzoquinone derivatives possessing N-, S-, O-substitutedgroups whichhas not been reportedyet
has been synthesized from 2,3-dichloro-1,4-naphthoquinone 1 and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione 15 involving
a Michael addition. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906,
Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-
1119 fungi in comparison with controls was identifed. 2-Chloro-3-((2-(piperidin-1-yl)ethyl)amino)naphthalene-1,4-dione 3g and
2,5-dichloro-3-ethoxy-6-((2,4,6-trifuorophenyl)amino)cyclohexa-2,5-diene-1,4-dione 17 were the most potent, with a minimum
inhibitory concentration value of 15.6 ꢀg/mL against test-culture M. luteum and S. aureus, respectively. Furthermore, in this work,
a catalase activity of benzo- and naphthoquinone derivatives was examined for the frst time. Te catalase activity of benzo- and
naphthoquinone derivatives was determined, showing that compound 3g had signifcant inhibition activity for catalase enzyme.
1. Introduction
mitochondrial respiration. Quinone-based fungicides are
classifed as “organic fungicides” and are known multisite
inhibitors. Tis may be advantageous in the prevention
of resistance development in fungal pathogens. Similarly,
quinone-based natural herbicides were also described with
multisite inhibitors.
As a part of a program directed towards the design
and synthesis of N-, S-, O-substituted quinones as potential
antibacterial, antifungal, and anticancer agents, we have
reported the synthesis and antimicrobial as well as anticancer
activities of N-, S-, O-substituted quinones [6, 9, 10]. Tis
paper describes the synthesis, characterization, and discov-
ering promising pharmacologically active compounds. In
this work, a catalase activity of benzo- and naphthoquinone
Natural and synthetic quinonoid compounds are well-known
substances which possess a variety of biological properties
such as anticancer, antibacterial, or antimalarial drugs as
well as fungicides [1]. Te heterocyclic derivatives of 1,4-
naphthoquinones have been identifed that have potent bio-
logical activities towards viral [2], molluscicidal [3], malarial
[4], leishmanial [5], cancer [6], and bacterial and fungal
diseases [7] due to their redox potentials [8]. Some of these
pharmacological efects have been attributed to the formation
of DNA-damaging anion-radical intermediates formed by
bioreduction of the quinone nucleus. Quinones are known
to inhibit electron transport involved in photosynthesis and

2
Heteroatom Chemistry
derivatives was examined for the frst time. Te catalase
medium (meat-extract agar for bacteria and wort agar for
fungi). Te microbial loading was 109 cells (spores)/1 mL.
Te required incubation periods were 24 h at 35∘C for
bacteria and 48–72 h at 28–30∘C for fungi. Te results were
recorded by measuring the zones surrounding the disk. Te
control disk contained vancomycin (for bacteria) or nystatin
(for fungi) as a standard. Testing was performed in a fat-
bottomed 96-well tissue culture plate. Te tested compounds
were dissolved in DMSO applying the necessary concen-
tration. Te exact volume of the solution of compounds is
brought into a nutrient medium. Te bacteria and fungi
were inoculated in a nutrient medium (meat-extract agar for
bacteria and wort agar for fungi). Te duration of incubation
was 24–72h at 37∘C for bacteria and 30∘C for fungi. Te
results were estimated according to the degree of the growth
inhibition.
enzyme plays an important role in removing toxic H O
2
2
from the cells. For this purpose, the activities of the cells
of this enzyme decompose H O generated as a result of
2
2
the cell activities H O and O before dispersion into the
2
2
body tissues. Te catalase enzyme also exhibits peroxidic
activity on compounds (i.e., formaldehyde, phenols, formic
acid, and alcohols). In this reaction, low molecular weight
alcohols serve as an electron donor. In addition to having
peroxidase activity, this enzyme can use one molecule of
H O as an electron donor and the other as an oxidant
2
2
[11, 12].
Consequently, the synthesis of new active derivatives
with potential applications in this area and prepared by
simple chemical procedures should be of increasing interest.
Here we described the synthesis, characterization, antimicro-
bial activity, and inhibition of catalase of 1,4-naphtho- and
benzoquinone derivatives. Teir structures of synthesized
compounds were characterized by using elemental analysis,
FT-IR, 1H NMR, 13C NMR, MS, and UV-Vis spectroscopy.
2.3. Catalase Enzyme Inhibition Activity of Quinone Deriva-
tives. Catalase activity was determined by the rate of H O
2
2
decomposition, measured spectrophotometrically at 450 nm
using the method described by Bekdeser et al. [15]. Te
reaction mixtures contained 1.0 mM H O , 3.691 U mL−1
2. Experimental
2
2
catalase solution, and 1.0 mM synthesized compound. Tis
mixture (total volume 2.6 mL) was then incubated at 25∘C.
Afer 30 min incubation period, the optical CUPRAC sensor
was taken out and immersed in a test tube consisted of 2.0 mL
of the incubation reaction mixture + 6.2 mL of EtOH. Afer
30 min agitation, the colored membrane was taken out and
its absorbance was recorded at 450 nm and activities were
expressed in U mL−1.
2.1. Material and Methods. Infrared (FT-IR) spectra were
recorded for liquids as flm and for solids as KBr discs
on a Perkin Elmer Precisely Spectrum One FTIR spec-
trometry. Microanalyses were carried out with a Termo
Finnigan Flash EA 1112 Elemental analyser. Mass spectra
were obtained on a Termo Finnigan LCQ Advantage MAX
LC/MS/MS spectrometer according to either APCI or ESI
1
techniques. H NMR and 13C NMR spectra were recorded
on Bruker Avance III 500 MHz, Chemical shifs ꢁ (ppm)
were reported relative to tetramethylsilane (TMS) with the
solvent resonance employed as the internal standard. 1H
2.4. General Procedure for the Synthesis of N-, N,N- N,O-
N,S-, and S,S- Substituted Naphtho- and Benzoquinone Com-
pounds 3a, 3c, 3d, 3f, 3g, 4e, 6b, 7a, 17-25. Sodium car-
bonate was dissolved in ethanol (60 mL), and equimolar
amounts of 2,3-dichloro-1,4-naphthoquinone 1 and amines
or thiols were added slowly. Te mixture was heated
between 20-45∘C and it was stirred in a single reaction
vessel between 2 and 11 h. Similarly, sodium carbonate
was dissolved in ethanol (50 mL), and equimolar amounts
of 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione 15 and
amines were added slowly. Without heating, the mixture
was stirred in a single reaction vessel between 3-6 h. Te
color of the solution quickly changed (from yellow to red
color), and the extent of the reaction was monitored by TLC.
Chloroform (30 mL) was added to the reaction mixture. Te
organic layer was separated, washed with water (4 × 30 mL),
and dried with Na SO . Afer the solvent was evaporated,
NMR and 13C NMR spectra in CDCl refer to the solvent
3
signal center at ꢁ = 7.26 and ꢁ = 77.0 ppm, respectively.
Moisture was excluded from the glass apparatus using CaCl
2
drying tubes. Spectrophotometric catalase enzyme activity
measurements of synthesized compounds were performed
by using a Perkin Elmer Lambda 35 UV-Vis spectropho-
tometer using a pair of matched quartz cuvettes of 1 cm
thickness.
Te following chemicals were supplied from the cor-
responding sources: sodium carbonate, sodium sulfate,
aniline, ethanethiol, 2,3-diaminopyridine, 4-fuorobenzyl-
amine, 2-(piperidin-1-yl)ethan-1-amine, 2,4,6-trifuoroani-
line, 4-fuorothiophenol, 2,3-difuoroaniline, and 1,3-dimeth-
ylbutylamine from Merck Chemicals (Darmstadt, Germany);
acetone, absolute ethanol, and neocuproine (Nc) from Sigma-
Aldrich Chemicals (Steinheim, Germany); 2,3-dichloro-1,4-
naphthoquinone (Fluka).
2
4
the residue was purifed by column chromatography on silica
gel.
2.5. 2-Phenylamino-3-chloro-naphthalene-1,4-dione (3a)
[16, 17]. Compound 3a was synthesized from aniline 2a
(0.4 ml, 4.404 mmol) and 2,3-dichloro-1,4-naphthoquinone
1 (1 g, 4.404 mmol) according to the general method. Yield:
2.2. Antibacterial and Antifungal Evaluations [13, 14]. Tested
microorganisms included the following: bacteria Escherichia
coli B-906, Staphylococcus aureus 209-P, and Mycobacterium
luteum B-917 and fungi Candida tenuis VKM Y-70 and
Aspergillus niger F-1119. Te antimicrobial activity of com-
pounds was evaluated by difusion in peptone on a nutrient
94.7%. Red crystal. M.p.: 215-216∘C. Rf (1PET:1CHCl ): 0.44.
3
FT-IR (KBr): ꢂ (cm−1) = 3065, 2918 (C-H ), 1673 (C=O), 1588,
.
1537 (C=C), 3238 (N-H).

Heteroatom Chemistry
3
2.6. 2-Chloro-3-((2,5-difluorobenzyl)amino)naphthalene-1,4-
dione (3c). Compound 3c was synthesized from (2,5-difuo-
rophenyl) methanamine 2c (0.308 ml, 2.634 mmol) and 2,3-
dichloro-1,4-naphthoquinone 1 (0.6 g, 2.634 mmol) accord-
ing to the general method. Yield: 77.9%. Orange crystal.
65.82, H 6.24, N 4.81%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]:
3
max
238(3.2), 277(3.4), 343(3.4), 469(2.6).
2.9. 2-Chloro-3-((2-(piperidin-1-yl)ethyl)amino)naphtha-
lene-1,4-dione (3g) [18]. Compound 3g was synthesized fro
m 2-(piperidin-1-yl) ethan-1-amine2g (0.317ml, 2.202mmol)
and 2,3-dichloro-1,4-naphthoquinone 1 (0.5 g, 2.202mmol)
according to the general method. Yield: 80.9%. Red crys-
Rf [PET/CHCl (5:2)]: 0.52. M.p.: 123–125∘C. FT-IR (KBr)
3
(cm−1): 3276 (N-H), 3019 (C-Harom.), 2925, 2851 (C-Haliph.),
1
1676 (C=O), 1576 (C=C). H NMR (499.74MHz, CDCl ) ꢁ
3
tal. Rf [PET/CHCl (3:1)]: 0.48. M.p.: 108–110∘C. FT- IR
(ppm) = 5.00 (d, 2H, J 6.68 Hz, -NH-CH2), 6.21 (bs, 1H,
NH), 6.88-7.00 (m, 3H, Cꢀarom), 7. 55-7. 66 (tt, 2H, J 7. 5 4, 1. 46
3
(KBr) (cm−1): 3016 (C-Harom.), 2938, 2853 (C-Haliph.), 1677
(C=O), 1603, 1573 (C=C), 3355 (N-H). 1H NMR (499.74MHz,
Hz, Cꢀ
), 7.96-8.08 (dd, 2H, J 7. 72, 1. 46 Hz, Cꢀ
).
napht.
132.7, 135.0 (ꢁ
napht.
13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 155.6, 157.8 (-F-
CDCl ) ꢁ (ppm) = 1.36-1.58 (m, 6H, -CH2circle-), 2.34-2.42
3
3
ꢁ
arom), 115.6, 116.7, 116.9 (CHarom), 129.8 (ꢁarom), 143.7 (-NH-
(m, 4H, -N-Cꢀ2circle), 2.53 (t, 2H, J 5.96 Hz, -CH2-N-), 3.80
ꢁ
), 115.8 (-Cl-ꢁ
), 126.9,128.8, 130.9, 132.4 (CHnapht.),
(t, 2H, J 5.88 Hz, -NH-CH2), 6.98 (bs, 1H, NH), 7.48-7.63 (tt,
napht.
napht.
), 177.1, 180.2 (C=O). MS [+ESI] = m/z 334.1
2H, J 7.55, 1.46 Hz, Cꢀ
), 7.86-8.02 (dd, 2H, J 7. 2 5, 1. 46 Hz,
napht.
napht.
[M+H]+, Anal. Calc. for C H ClF NO (333.04): C 61.18, H
Cꢀnapht). 13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 24.4,
17 10
2
2
3
3.02, N 4.20. Found: C 61.41, H 3.34, N 4.14%. UV-vis [CHCl ,
26.1 (CH
), 41.2 (-NH-CH ), 56.8 (-N-CH ), 53.8 (-N-
3
2piper.
2
2
ꢃ
max (nm)(log ꢄ)]: 210(2.2), 274(2.4), 336(1.4), 559(1.5).
CH
), 144.8 (-NH-ꢁ
), 110.9 (-Cl-ꢁ
), 126.5, 129.8,
2piper.
napht.
napht.
132.2 (CHnapht.), 132.7, 134.6 (ꢁ
), 176.2, 180.4 (C=O). MS
napht.
[+ESI] = m/z 319.2 [M+H]+, Anal. Calc. for C H ClN O
17 19
2
2
2.7. 2-Chloro-3-((2,3-difuorophenyl)amino)naphthalene-
1,4-dione (3d). Compound 3d was synthesized from 2,3-
difuoroaniline 2d (0.287 g, 2.212 mmol) and 2,3-dichloro-
1,4-naphthoquinone 1 (0.5 g, 2.212 mmol) according to
the general method. Yield: 71.1%. Orange crystal. Rf
[PET/CHCl (5:2)]: 0.51. M.p.: 106–109∘C. FT-IR (KBr)
(318.11): C 64.05, H 6.01, N 8.79. Found: C 63.97, H 6.26, N
8.69%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]: 211(2.8), 277(3.4),
3
max
339(2.3), 473(2.5).
2.10. 2-Ethoxy-3-((2-methyl-4-oxo-4H-chromen-7-yl)ami-
no)naphthalene-1,4-dione (4e). Compound 4e was syn-
thesized from 7-amino-2-methyl-4H-chromen-4-one 2e
(0.385 g, 2.202 mmol) and 2,3-dichloro-1,4-naphthoquinone
1 (0.5 g, 2.202 mmol) according to the general method.
3
(cm−1): 3019 (C-Harom.), 2925 (C-Haliph.), 1650 (C=O), 1520
(C=C), 3340 (N-H). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm)
3
= 7.33 (bs, 1H, NH), 6.81-6.03, 7.45-7.48 (m, 3H, Cꢀarom),
7. 63-7. 75 (tt, 2H, J 7. 5 4, 1. 5 6 Hz, Cꢀ
), 8.04-8.14 (dd, 2H,
napht.
Yield: 54.9%. Red crystal. Rf [PET/CHCl (5:2)]: 0.58. M.p.:
). 13C NMR (125.66 MHz, CDCl )
3
J 7. 7 1, 1. 5 6 Hz, Cꢀ
napht.
3
140–142∘C. FT-IR (KBr) (cm−1): 2971 (C-Harom.), 2926, 2850
ꢁ (ppm) = 129.8 (-NH-ꢁarom), 146.2, 149.7 (-F-ꢁarom), 114.5,
1
(C-Haliph.), 1682 (C=O), 1599, 1520 (C=C), 3306 (N-H). H
121.4, 123.0 (CHarom), 135.1 (-NH-ꢁ
), 116.6 (-Cl-ꢁ
),
napht.
napht.
NMR (499.74MHz, CDCl ) ꢁ (ppm) = 0.83 (t, 3H, J= 7.52Hz,
3
127.1, 127.2, 130.9, 141.5 (CHnapht.), 133.2, 132.2 (ꢁ
), 177.5,
napht.
Cꢀ3ethoxy), 1.17 (bs, 3H, CH ), 4.01-4.04 (q, 2H, J 7. 0 6 Hz,
179.9 (C=O). MS [-ESI] = 318.2 [M-H]−, Anal. Calc. for
3
O-Cꢀ2ethoxy), 5.65 (bs, 1H, CH ), 6.08 (bs, 1H, O-CH),
2
C H ClF NO (319.02): C 60.11, H 2.52, N 4.38. Found: C
16
8
2
2
6.28-6.29 (d, 1H, J 7. 0 6 Hz, Cꢀphenyl), 7.44-7.46 (d, 1H, J
60.12, H 2.50, N 4.40%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]:
3
max
7. 0 6 Hz, Cꢀphenyl), 7.54-7.66 (tt, 2H, J 7. 53, 1. 46 Hz, Cꢀ
),
).
napht.
napht.
223(3.9), 274(4.0), 348(3.2), 453(3.1).
5.96 (bs, 1H, NH), 7.94-8.09 (dd, 2H, J 7. 7, 1. 46 Hz, Cꢀ
13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 11.0 (-CH3ethoxy),
3
2.8. 2-Chloro-3-((4-methylpentan-2-yl)amino)naphthalene-
1,4-dione (3f). Compound 3f was synthesized from 4-
methylpentan-2-amine 2f (0.433 ml, 3.083 mmol) and 2,3-
dichloro-1,4-naphthoquinone 1 (0.7 g, 3.083 mmol) accord-
ing to the general method. Yield: 89.6%. Orange crystal. Rf
14.1 (-CH
), 68.2 (-O-CH2ethoxy), 109.9, 112.2, 119.4, 127.0
3subst.
(CHsubst.), 120.5 (ꢁsubst.), 167.3 (CH -ꢁsubst.), 162.0 (C-Osubst.),
3
160.8 (NH-ꢁsubst.), 173.8 (C=Osubst.), 134.9 (O-ꢁ
), 115.5
napht.
(-NH-ꢁ
), 128.0, 128.4, 130.8, 130.9 (CHnapht.), 132.5 132.6
napht.
(ꢁ
), 176.9, 180.5 (C=O). MS [-ESI] = m/z 372.9 [M-2H]−,
napht.
[PET/CHCl (2:1)]: 0.48. M.p.: 98–99∘C. FT-IR (KBr) (cm−1):
3
Anal. Calc. for C H NO (375.11): C 70.39, H 4.56, N 3.73.
22 17
5
3015 (C-Harom.), 2959, 2928 (C-Haliph.), 1643 (C=O), 1600,
Found: C 70.24, H 4.45, N 3.80%. UV-vis [CHCl , ꢃ
3
max
1
1573 (C=C), 3322 (N-H). H NMR (499.74MHz, CDCl ) ꢁ
(nm)(log ꢄ)]: 243(3.0), 276(3.1), 344(2.3), 468(2.1).
3
(ppm) = 0.85 (d, 3H, J 7. 52 Hz, -Cꢀ ), 0.87 (d, 3H, J 6.62 Hz,
3
-Cꢀ ), 1.20 (d, 3H, J 6.37 Hz, -Cꢀ ), 4.65-4.75, 1.56-1.66 (m,
2H, -CH), 1.44-1.51, 1.26-1.34 (m,32H, -CH2), 5.81 (bs, 1H,
3
2.11. 2,3-Bis((4-fluorophenyl)thio)naphthalene-1,4-dione (6b)
[19]. Compound 6b was synthesized from 4-fuoroben-
zenethiol 5b (0.375 ml, 3.523 mmol) and 2,3-dichloro-1,4-
naphthoquinone 1 (0.4 g, 1.761 mmol) according to the gen-
NH), 7.52-7.66 (tt, 2H, J 7. 5 4, 1. 5 6 Hz, Cꢀ
), 7.94-8.06
napht.
(dd, 2H, J 7. 7 1, 1. 5 6 Hz, Cꢀ
). 13C NMR (125.66 MHz,
napht.
CDCl ) ꢁ (ppm) = 22.4, 22.6, 22.9 (-CH ), 25.2, 48.2 (-CH-
eral method. Yield: 79.1%. Orange crystal. Rf [PET/CHCl
3
3
3
(2:1)]: 0.55. M.p.: 175–177∘C. FT-IR (KBr) (cm−1): 3008 (C-
), 47.1 (-CH -), 143.5 (-NH-ꢁ
), 126.9 (-Cl-ꢁ
), 128.8,
2
napht.
napht.
Harom.), 2923, 2853 (C-H), 1665 (C=O), 1586 (C=C). 1H
129.8, 130.9, 132.2 (CHnapht.), 132.5, 135.0 (ꢁ
), 176.4, 182.1
napht.
(C=O). MS [+ESI] = m/z 292.1 [M+H]+, Anal. Calc. for
NMR (499.74MHz, CDCl ) ꢁ (ppm) = 7.41-7.46 ppm (m,
3
C H ClNO (291.78) C 65.86, H 6.22, N 4.80. Found: C
4H, Cꢀarom), 7.01-7.06 (m, 4H, Cꢀarom), 7.68-7.72 (m, 2H,
16 18
2

4
Heteroatom Chemistry
Cꢀnapht), 7.96-8.00 (m, 2H, Cꢀnapht). 13C NMR (125.66MHz,
3019 (C-Harom.), 2926, 2860 (C-H), 1624 (C=O), 1524 (C=C).
CDCl ) ꢁ (ppm) = 128.4 (-S-ꢁarom), 161.6-163.6 (-F-ꢁarom),
1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 2.30 (bs, 3H,
3
3
116.3-116.5, 133.7-133.9 (CHarom), 132.6 (-S-ꢁnapht), 127.2, 133.6
(CHnapht), 148.9 (ꢁnapht), 178.7, 178.7 (C=O). MS [+ESI] =
-CH3arom), 7.13 (d, 1H, J 7. 81 Hz, -Cꢀarom-), 7.08 (t, 1H,
J 7. 83 Hz, -Cꢀarom-), 6.37 (d, 1H, J 7. 88 Hz, -Cꢀarom-),
m/z 411 [M+H]+, Anal. Calc. for C H F O S (410.02): C
7. 53-7. 61 (m, 2H, Cꢀ
), 7.95-7.99 (m, 2H, Cꢀ
).
)
napht.
napht.
22 12
2
2
2
13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 18.1 (CH
64.38, H 2.95, S 15.62. Found: C 64.38, H 2.94, S 15.62%. UV-
3
3arom
vis [CHCl , ꢃ
(nm)(log ꢄ)]: 211(2.6), 253(2.5), 342(1.9),
114.1, 120.7, 128.0 (-CHarom), 132.6 (CH -ꢁarom), 137.7, 139.0
3
max
3
458(1.7).
(-N=ꢁarom), 131.7, 133.7 (-N-ꢁ
), 121.8, 126.0, 126.2
napht.
(CHnapht.), 130.6, 130.7 (ꢁ
), 180.7, 180.8 C=O). MS [+ESI]
napht.
= 276.1 [M+2H]+. Anal. Calc. for C H N O (274.07): C
2.12. 2-(Ethylthio)-3-(phenylamino)naphthalene-1,4-dione
(7a) [20]. Compound 7a was synthesized from ethanethiol
5a (0.110 ml, 1.762mmol) and 2-chloro-3-(phenylamino)
naphthalene-1,4-dione3a (0.5 g, 1.762mmol) according to the
17 10
2
2
74.44, H 3.68, N 10.21. Found: C 74.63, H 3.45, N 10.18%. UV-
vis [CHCl , ꢃ
(nm)(log ꢄ)]: 241(2.5), 298(2.6), 429(1.2),
3
max
544(1.6).
general method. Yield: 91.5%. Red crystal. Rf [PET/CHCl
3
(5:2)]: 0.57 M.p.: 92–94∘C. FT-IR (KBr) (cm−1): 3008 (C-
Harom.), 2923, 2853 (C-H), 1665 (C=O), 1586 (C=C). 1H NMR
(499.74MHz, CDCl ) ꢁ (ppm) = 0.96 (t, 3H, J 7. 3 8 Hz, CH ),
2.16. 2-Chloro-3-(m-tolylamino)naphthalene-1,4-dione (13)
[16, 23]. Compound 13 was synthesized from m-toluidine 12
(0.188 g, 1.761 mmol) and 2,3-dichloro-1,4-naphthoquinone
1 (0.4 g, 1.761 mmol) according to the general method.
3
3
2.56 (q, 2H, J 7. 39 Hz, S-CH ), 6.97 (d, 2H, J 7. 74 Hz, Cꢀarom),
2
7.08 (t, 1H, J 7. 44 Hz, Cꢀarom), 7.27 (t, 2H, J 7. 5 6 Hz, Cꢀarom),
Yield: 75.3%. Red crystal. Rf [PET/CHCl (1:1)]: 0.41. M.p.:
3
177–179∘C. FT-IR (KBr) (cm−1): 3045, 2915 (C-H ), 1675
7. 58-7. 68 (tt, 2H, J 7. 53, 1. 46 Hz, Cꢀ
), 7.76 (bs, 1H,
napht.
.
NH), 8.00-8.09 (dd, 2H, J 7. 7, 1. 46 Hz, Cꢀnapht). 13C NMR
(C=O), 1593, 1560 (C=C), 3237 (N-H).
(125.66MHz, CDCl ) ꢁ (ppm) = 14.5 (-CH ), 28.0 (SCH -),
3
3
2
122.5, 124.7, 126.6 (CHarom.), 124.5 (S-ꢁ
), 126.8 (-NH-
2.17. 2-Methylbenzo[b]phenazine-6,11-dione (14) [22].
Compound 14 was synthesized from sodium azide 10
(0.087 g, 1.344 mmol) and 2-chloro-3-(m-tolylamino) naph-
thalene-1,4-dione 13 (0.2 g, 0.672 mmol) according to the
general method. Yield: 73.0%. Dark navy blue crystal. Rf
[PET/CHCl )(2:1)]: 0.50. M.p.: 193–195∘C. IR (KBr) (cm−1):
napht.
ꢁ
), 129.4, 130.8, 132.8 (CHnapht.), 134.6, 138.5 (ꢁ
),
napht.
napht.
145.0 (NH-C), 180.5, 181.1 (C=O). MS [-ESI] = m/z 308.01 [M-
H]−, Anal. Calc. for C H NO S (309.08): C 69.88, H 4.69, N
18 15
2
4.53. Found: C 70.04, H 4.88, N 4.57%. UV-vis [CHCl , ꢃ
3
max
(nm)(log ꢄ)]: 210(2.4), 283(2.6), 382(1.9), 511(1.7).
3
3019 (C-Harom.), 2926, 2850 (C-H), 1616 (C=O), 1577, 1522
(C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 2.35 (bs,
2.13. 2-Chloro-3-(o-tolylamino)naphthalene-1,4-dione (9)
[16, 21]. Compound 9 was synthesized from o-toluidine 8
(0.235g, 2.202 mmol) and 2,3-dichloro-1,4-naphthoquinone
1 (0.5 g, 2.202 mmol) according to the general method.
3
3H, -CH3arom), 7.18-7.22 (t, 1H, J 7. 81 Hz, -Cꢀarom-), 6.78-
6.82 (d, 1H, J 7. 49 Hz, -Cꢀarom-), 6.57-6.60 (d, 1H, J 7. 52 Hz,
-Cꢀarom-), 7.63-7.69 (m, 2H, Cꢀ
), 8.04-8.08 (m, 2H,
napht.
Cꢀ
). 13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 21.5
Yield: 72.7%. Red crystal. Rf [PET/CHCl (1:1)]: 0.41. M.p.:
3
napht.
3
162–163∘C. FT-IR (KBr) (cm−1): 3060, 2946 (C-H ), 1672
(CH3arom) 119.0, 120.3, 122.4 (-CHarom.), 132.8 (CH -ꢁarom),
.
3
(C=O), 1595, 1573 (C=C), 3244 (N-H).
139.1, 139.7 (-N=ꢁarom), 131.8, 133.7 (-N-ꢁ
), 115.5, 126.0,
napht.
126.2 (CHnapht.), 128.9, 129.5 (ꢁ
), 180.7, 180.8 (C=O). MS
napht.
[+ESI] = m/z 276.0 [M+2H]+, Anal. Calc. for C H N O
2.14. General Procedure for the Synthesis of N,N-Substituted
Naphthoquinone Compounds (1-Methylbenzo[b]phenazine-
6,11-dione 11 and 2-Methylbenzo[b]phenazine-6,11-dione 14
[22]). Mono substituted naphthoquinone derivatives 9 [21]
and 13 (1 mol) were dissolved in DMF (100 mL) and sodium
17 10
2
2
(274.07): C 74.44, H 3.68, N 10.21. Found: C 74.49, H 3.34, N
10.19%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]: 212(2.2), 241(2.1),
3
max
298(2.2), 539(1.2).
azide (NaN ) (2 mol) dissolved in 10 ml of water was slowly
2.18. 2,5-Dichloro-3-ethoxy-6-((2,4,6-trifuorophenyl)ami-
no)cyclohexa-2,5-diene-1,4-dione (17). Compound 17
was synthesized from 2,4,6-trifuoroaniline 16 (0.597g,
2.440 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-
1,4-dione 15 (1.0 g, 4.067 mmol) according to the general
3
added. Te reaction was heated to refux with stirring. Te
color of the solution quickly changed (from yellow to red
color), and the extent of the reaction was monitored by TLC.
Chloroform (40 mL) was added to the reaction mixture. Te
organic layer was separated, washed with water (4 × 50 mL),
and dried with Na SO . Afer the solvent was evaporated, the
method. Yield: 28.3%. Red crystal. Rf [PET/CHCl (3:1)]:
3
2
4
0.51. M.p.: 131–132∘C. FT-IR (KBr) (cm−1): 3341 (N-H),
residue was purifed by column chromatography on silica gel.
3018, 2956 (C-Harom), 2923, 2851 (C-H), 1712, 1640 (C=O),
1588-1522 (C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) =
3
0.80 (t, 3H, J 7.08 Hz, -CH3ethoxy), 4.33 (q, 2H, J 7.05 Hz, -O-
2.15. 1-Methylbenzo[b]phenazine-6,11-dione (11). Com-
pound 11 was synthesized from sodium azide 10 (0.131 g,
2.015mmol) and 2-chloro-3-(o-tolylamino) naphthalene-
1,4-dione 9 [21] (0.3 g, 1.007 mmol) according to the
general method. Yield: 75.7%. Dark blue crystal. Rf
Cꢀ2ethoxy), 6.52 (bs, 1H, -NH-), 6.63-6.67 (m, 6H, -Cꢀarom).
13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 100.5, 100.5
3
(-CHarom), 150.3-152.1, 152.1-154.0 (C-F-), 124.3 (NH- ꢁarom),
14.2 (-Cꢀ3ethoxy), 68.1 (-Cꢀ2ethoxy), 146.9 (-NH-ꢁbenzo),
114.2, 118.9 (C-Cl-), 158.0 (C-O-), 164.5, 166.1 (C=O). MS
[PET/CHCl (1:1)]: 0.53. M.p.: 139–141∘C. FT-IR (KBr)(cm−1):
3

Heteroatom Chemistry
5
[-ESI] = m/z 364.0 [M]−, Anal. Calc. for C H Cl F NO
(C-Cl-), 129.6 (C-O-), 171.5, 175.3 (C=O). MS [+ESI] = m/z
14
8
2
3
3
(364.98): C 45.93, H 2.20, N 3.83. Found: C 45.98, H 2.19, N
433.3 [M+H]+, Anal. Calc. for C H ClF N O (432.11): C
22 19
2
2
3
3.94%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]: 225(2.2), 301(2.7),
61.05, H 4.42, N 6.47. Found: C 61.14, H 4.76, N 6.51%. UV-
3
max
377(1.4), 462(1.2).
vis [CHCl , ꢃ
(nm)(log ꢄ)]: 205(1.9), 240(1.7), 303(2.1),
3
max
430(0.5).
2.19. 2,5-Dichloro-3,6-bis((2,4,6-trifuorophenyl)amino)cy-
clohexa-2,5-diene-1,4-dione (18). Compound 18 was synthe-
sized from 2,4,6-trifuoroaniline 16 (0.597g, 2.440 mmol)
and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione 15
(1.0 g, 4.067 mmol) according to the general method. Yield:
2.22. 2-Chloro-5,6-diethoxy-3-((4-fuorobenzyl)amino)cy-
clohexa-2,5-diene-1,4-dione (21). Compound 21 was syn-
thesized from (4-fuorophenyl) methanamine 2h (0.275 ml,
2.440 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-
dione 15 (0.6 g, 2.440 mmol) according to the general
39.2%. Light yellow crystal. Rf [PET/CHCl (3:1)]: 0.55. M.p.:
3
154–156∘C. FT-IR (KBr) (cm−1): 3380 (N-H), 3019, 2961
method. Yield: 18.2%. Dark red crystal. Rf [PET/CHCl (5:2)]:
3
1
(C-Harom), 2927, 2858 (C-H), 1716 (C=O), 1519 (C=C). H
0.51. M.p.: 104–106∘C. FT-IR (KBr) (cm−1): 3242 (N-H), 3003-
NMR (499.74MHz, CDCl ) ꢁ (ppm) = 4.26 (bs, 2H, -NH-),
2957 (C-Harom), 2926, 2855 (CH), 1690 (C=O), 1579-1519
3
7. 93-7. 98 (m, 4H, -Cꢀarom). 13C NMR (125.66 MHz, CDCl )
(C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 1.35 (t, 3H,
3
3
ꢁ (ppm) = 101.2 (-CHarom), 153.9-155.8, 155.8-157.3 (C-F-),
J 7.05 Hz, -CH3ethoxy), 1.37 (t, 3H, J 7.05 Hz, -CH3ethoxy), 4.19-
124.3 (NH- ꢁarom), 141.0 (-NH-ꢁbenzo), 111.3 (C-Cl-), 166.0
4.53 (q, 4H, J 7.05 Hz, -O-Cꢀ2ethoxy), 1.68 (d, 2H, J 4.97 Hz, -
(C=O). MS [-ESI] = m/z 464.9 [M-H]−, Anal. Calc. for
NH-Cꢀ2-), 5.49 (bs, 1H, -NH-), 6.15-6.30 (m, 4H, -Cꢀarom-).
C H Cl F N O (465.97 g/mol): C 46.28, H 1.29, N 6.00.
13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 163.6-161.7 (-C-
18
6
2
6
2
2
3
Found: C 46.40, H 1.25, N 6.09%. UV-vis [CHCl , ꢃ
F
arom), 129.4, 129.6, 116.0, 116.2 (-CHarom), 132.9 (-Carom), 29.8
3
max
(nm)(log ꢄ)]: 247(3.1), 292(3.0), 377(2.7), 462(2.4).
(-N-CH -), 68.2, 71.6, 11.0, 14.1 (-Cꢅ2ethoxy) ve (-CH3ethoxy),
2
143.5 (-ꢁbenzo-NH-), 128.7 (C-Cl-), 135.9, 142.0 (C-O-), 169.9,
174.2 (C=O). MS [-ESI] = m/z 352.33 [M-H]−, Anal. Calc. for
C H ClFNO (353.08): C 57.72, H 4.84, N 3.96. Found: C
2.20. 2-Chloro-3,6-diethoxy-5-((4-fuorobenzyl)amino)cy-
clohexa-2,5-diene-1,4-dione (19). Compound 19 was syn-
the-sized from (4-fuorophenyl) methanamine 2h (0.275ml,
2.440 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-
1,4-dione 15 (0.6 g, 2.440 mmol) according to the gen-
eral method. Yield: 21.1%. Dark red crystal. Rf [(PET/
17 17
4
57.92, H 4.68, N 3.98%. UV-vis [CHCl , ꢃ
(nm)(log ꢄ)]:
3
max
206(2.0), 241(2.1), 298(2.4), 430(0.5).
2.23. 2,5-Diethoxy-3,6-bis((4-fluorobenzyl)amino)cyclo-
hexa-2,5-diene-1,4-dione (22). Compound 22 was syn-
thesized from (4-fuorophenyl)methanamine 2h (0.275 ml,
2.440 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-
dione 15 (0.6 g, 2.440 mmol) according to the general
CHCl (5:2)]: 0.58. M.p.: 60–62∘C. FT-IR (KBr) (cm−1): 3345
3
(N-H), 3001 (C-Harom), 2982, 2929 (C-H), 1682 (C=O),
1570 (C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) =
3
1.37 (t, 3H, J 7. 0 6 Hz, -CH3ethoxy), 1.36 (t, 3H, J 7. 0 6 Hz,
-CH3ethoxy), 4.12-4.52 (m, 4H, -O-Cꢀ2ethoxy), 1.71 (d, 2H, J
method. Yield: 16,4%. Pale pink crystal. Rf [PET/CHCl
3
4.97 Hz, -NH-Cꢀ2-), 5.66 (bs, 1H, -NH-), 6.13-6.35 (m, 4H,
(5:2)]: 0.48. M.p.: 226–228∘C. FT-IR (KBr) (cm−1): 3244 (N-
-Cꢀarom-).13C NMR (125.66 MHz, CDCl ) ꢁ (ppm) = 171.5-
H), 3019 (C-Harom), 2929, 2850 (CH), 1663 (C=O), 1586
3
1
173.3 (-C-Farom), 140.5, 138.6, 110.8, 111.4 (-CHarom), 144.3
(C=C). H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 0.84 (t,
3
(-Carom), 29.5 (-N-CH -) 70.3, 71.5, 15.9, 20.7 (-CH2ethoxy),
6H, J 7. 46 Hz, -CH3ethoxy), 4.10-4.18 (m, 4H, -O-Cꢀ2ethoxy),
2
(-CH3ethoxy), 125.8 (-ꢁbenzo-NH-) 102.0 (C-Cl-), 143.9, 154.4
4.88 (d, 2H, J 6.18 Hz, -NH-Cꢀ2-), 6.00 (bs, 2H, -NH-),
6.98-7.64 (m, 8H, -Cꢀarom-).13C NMR (125.66 MHz, CDCl )
(C-O-), 171.7, 172.8 (C=O). MS [-ESI] = m/z 352.3 [M-H]−,
3
ꢁ (ppm) = 161.2, 163.0 (-C-Farom), 130.8, 131.0, 112.9,113.1
Anal. Calc. for C H ClFNO (353.08): C 57.72, H 4.84, N
17 17
4
(-CHarom), 140.2 (-Carom), 32.0 (-N-CH -), 71.4, 15.9 (-
3.96. Found: C 57.89, H 4.58, N 3.98%. UV-vis [CHCl , ꢃ
2
3
max
Cꢅ2ethoxy) ve (-CH3ethoxy), 122.4 (-ꢁbenzo-NH-), 132.7 (C-O-),
(nm)(log ꢄ)]: 217(1.7), 241(1.8), 298(2.1), 430(0.3).
175.1 (C=O). MS [+ESI] = m/z 445.0 [M+2H]+, Anal. Calc.
For C H F N O (443.17): C 65.15, H 5.47, N 6.33. Found:
2.21. 2-Chloro-5-ethoxy-3,6-bis((4-fuorobenzyl)amino)cy-
clohexa-2,5-diene-1,4-dione (20). Compound 20 was syn-
thesized from (4-fuorophenyl) methanamine 2h (0.275ml,
2.440 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-
dione 15 (0.6 g, 2.440 mmol) according to the general
24 24
2
2
4
C 65.08, H 5.80, N 6.27%. UV-vis [CHCl , ꢃmax (nm)(log ꢄ)]:
3
219(3.7), 245(3.8), 462(2.4), 557(2.6).
2.24. 2,5-Dichloro-3-((2,5-difuorobenzyl)amino)-6-ethox-
ycyclohexa-2,5-diene-1,4-dione (23). Compound 23 was
synthesized from (2,5-difluorophenyl)methanamine 2c
(0.290g, 2.033mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-
diene-1,4-dione 15 (0.5 g, 2.033 mmol) according to the
general method. Yield: 52.4%. Dark purple crystal. Rf
method. Yield: 37.3%. Orange crystal. Rf [PET/CHCl (5:2)]:
3
0.55. M.p.: 82–84∘C. FT-IR (KBr) (cm−1): 3300 (N-H), 3009,
2961 (C-Harom), 2930, 2874 (C-H), 1682 (C=O), 1624, 1579
(C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 1.35 (t, 3H,
3
J 7.05 Hz, -CH3ethoxy), 4.40 (q, 2H, J 7.05 Hz, -O-Cꢀ2ethoxy),
4.50 (d, 4H,, J 8.09 Hz, -NH-Cꢀ2-), 5.81, 6.78 (bs, 2H, -NH-),
[PET/CHCl (3:1)]: 0.47. M.p.: 73–74∘C. FT-IR (KBr) (cm−1):
3
7.08-7.65 (m, 8H, -Cꢀarom-).13C NMR (125.66 MHz, CDCl )
3346 (N-H), 3020 (C-Harom), 2927, 2856 (CH), 1667 (C=O),
3
ꢁ (ppm) = 174.2-176.3 (-C-Farom), 123.4, 125.9, 128.9, 131.0 (-
1522 (C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 1.36
3
CHarom), 132.4 (-Carom), 29.0, 30.3 (-N-CH -), 71.3, 15.9 (-
(t, 3H, J 7.05 Hz, -CH3ethoxy), 4.62 (q, 2H, J 7. 03 Hz, -O-
Cꢀ2ethoxy), 4.95 (d, 2H, J 6.72Hz, -NH-CH2), 6.27 (bs, 1H,
2
CH2ethoxy) ve (-CH3ethoxy), 154.1, 153.1 (-ꢁbenzo-NH-), 105.9

6
Heteroatom Chemistry
O
O
O
2, 3, 4, 5, 6, 7
a
R
R
NH-２1
２1-N（2
NH-２1
Cl
2
-C（2-C（3
+
(N；2C／3/EtOH)
Cl
OC（2C（3
F
Cl
b
c
F
O
4
O
1
O
3
C（2
F
２2-SH
5
F
F
２2-SH
(N；2C／3/EtOH)
(N；2C／3/EtOH)
5
d
O
O
O
O
e
f
C（3
C（3
NH-２1
S-２2
S-２2
S-２2
C（3
C（3
-C（2-C（2
N
O
7
g
O
6
F
h
Scheme 1: Te synthesis of N-, S-, O-substituted naphthoquinone derivatives (3a, 3c-d, 3f-g, 4e, 6b, 7a).
-NH-), 6.85-7.15 (m, 3H, -Cꢀcircle).13C NMR (125.66 MHz,
(0.208 g, 1.626 mmol) and 2,3,5,6-tetrachlorocyclohexa-
2,5-diene-1,4-dione 15 (0.4 g, 1.626 mmol) according to
the general method. Yield: 36.3%. Dark red crystal. Rf
CDCl ) ꢁ (ppm) = 116.4, 117.5, 120.3 (-CHarom), 126.5 (-
3
ꢁ
arom), 155.5-157.4, 157.8-159.7 (C-F-), 42.4 (-CH -NH-), 16.1
2
(-CH3ethoxy), 68.0 (-Cꢀ2ethoxy), 156.4 (-NH-ꢁbenzo), 115.8,
[PET/CHCl (3:1)]: 0.54. M.p.: 241–243∘C. FT-IR (KBr)
3
119.4 (C-Cl-), 162.2 (C-O-), 175.9, 173.8 (C=O). MS [-ESI] =
(cm−1): 3295 (N-H), 3019, 2923 (CH), 1678 (C=O), 1570
m/z 360.0 [M-H]−, Anal. Calc. for C H Cl F NO (361.01):
(C=C). 1H NMR (499.74MHz, CDCl ) ꢁ (ppm) = 0.81 (t, 3H,
15 11
2
2
3
3
C 49.75, H 3.06, N 3.87. Found: C 49.96, H 3.00, N 3.91.
J 7. 03 Hz, -CH3ethoxy), 1.15-1.55, 2.10-2.24 (m, 20H, -Cꢀ2circle
-
UV-vis [CHCl , ꢃmax (nm)(log ꢄ)]: 219(2.2), 241(2.4), 311(2.3),
N-), 2.26-2.28, 2.38-2.41 (m, 4H, -Ncircle-CH ), 4.13-4.23 (m,
3
2
492(1.2).
4H, -NH-CH ), 4.50 (q, 2H, J= 5.35Hz, O-CH2ethoxy-), 5.67,
2
5.90 (bs, 2H, -NH). 13C NMR (125.66 MHz, CDCl ) ꢁ (ppm)
3
= 23.0, 23.7, 55.7 (-CH2circle), 44.4, 58.6 (-N-CH -CH -N-),
2
2
2.25. 2,3,5-Trichloro-6-((2-(piperidin-1-yl)ethyl)amino)cy-
clohexa-2,5-diene-1,4-dione (24). Compound 24 was syn-
thesized from 2-(piperidin-1-yl) ethan-1-amine 2 g (0.208 g,
1.626 mmol) and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-
dione 15 (0.4 g, 1.626 mmol) according to the general method.
14.8 (-Cꢀ3ethoxy), 66.1 (-Cꢀ2ethoxy) 136.3, 140.5 (-C-NH-),
100.2 (C-Cl-), 127.8 (C-O-), 169.2, 175.0 (C=O). MS [+ESI]
= 441.4 [M+2H]+, Anal. Calc. for C H ClN O (439.0): C
22 35
4
3
60.19, H 8.04, N 12.76. Found: C 60.14, H 8.21, N 12.68%. UV-
vis [CHCl , ꢃ
(nm)(log ꢄ)]: 223(2.8), 292(3.0), 333(1.7),
3
max
Yield: 33.3%. Dark red crystal. Rf [PET/CHCl (3:1)]: 0.51.
3
483(1.5).
M.p.: 60–62∘C. FT-IR (KBr) (cm−1): 3332 (N-H), 3019, 2932
(CH), 1639 (C=O), 1522 (C=C). 1H NMR (499.74MHz,
CDCl ) ꢁ (ppm) = 1.22-1.32, 2.44-2.76 (m, 10H, -Ncircle-CH ),
3. Results and Discussion
3
2
3.15 (t, 2H, J 5.67 Hz, -Cꢀ2circle-N-), 4.17-4.20 (m, 2H, -NH-
CH ), 8.03 (bs, 1H, -NH). 13C NMR (125.66 MHz, CDCl )
3.1. Chemistry. In this study that we have done, reac-
tions of thiol and amine compounds with 2,3-dichloro-1,4-
naphthoquinone and 2,3,5,6-tetrachloro-1,4-benzoquinone
as a starting compounds were investigated. Firstly, the mul-
ticomponent reactions of 2,3-dichloro-1,4-naphthoquinone 1
with various thiol and amine nucleophiles were investigated.
Similarly, 2,3,5,6-tetrachloro-1,4-benzoquinone 15 with var-
ious amine nucleophiles was investigated. As shown in
Scheme 1, the reaction of 1 with diferent amines 2a, 2c,
2d, 2e, 2f, 2 g in ethanol in the presence of Na CO gave
2
3
ꢁ (ppm) = 20.0, 23.8, 23.9, 54.1, 54.2 (-CH2circle), 44.0, 56.1
(-N-CH -CH -N-), 148.4 (-C-NH-), 120.0, 140.1, 142.7 (C-
2
2
Cl-), 162.3, 174.9 (C=O). MS [+ESI] = m/z 339.4 [M+2H]+,
Anal. Calc. for C H Cl N O (337.63): C 46.25, H 4.48, N
13 15
3
2
2
8.30. Found: C 46.22, H 4.72, N 8.25%. UV-vis [CHCl , ꢃ
3
max
(nm)(log ꢄ)]: 217(2.8), 293(1.9), 354(2.0), 587(1.9).
2.26. 2-Chloro-5-ethoxy-3,6-bis((2-(piperidin-1-yl)ethyl)ami-
no)cyclohexa-2,5-diene-1,4-dione (25). Compound 25
was synthesized from 2-(piperidin-1-yl)ethan-1-amine 2 g
2
3
known and unknown compounds 3a [16, 17], 3c, 3d, 3f, 3g
[18], 4e. Compound 6b [19] obtained the reaction of 1 with

Heteroatom Chemistry
7
（3C
O
O
（3C
（2N
O
O
C（3
H
Cl
Cl
N
N
N
Na．3
8
10
(N；2C／3/EtOH)
(DMF/（2O)
Cl
(10:1)
O
O
9
1
11
C（3
（2N
(N；2C／3/EtOH)
12
C（3
O
O
O
Na．3
N
N
C（3
H
N
10
(DMF/（2O)
(10:1)
Cl
O
13
14
Scheme 2: Te synthesis of phenazine compounds 11 and 14 via the condensation reaction of naphthoquinones 9 and 13.
5b. Te reaction of 3a with 5a gave compound 7a [20].
When 1 reacted with an equimolar amount of various amines
and thiols in ethanol in the presence of sodium carbonate
solution at room temperature but under diferent conditions,
the corresponding products (3c, 3d, 3f, 3g, 4e, 6b, 7a) were
obtained in diferent yields. All synthesized compounds were
gave one carbonyl signal at 116.6 ppm (-Cl-Cnapht.) similarly
giving a single peak at 126.9 ppm in the compound 3f. Te
FT-IR spectra of compounds 3c, 3d, 3f, 3g, 4e, 7a showed
bands around at 3300 cm−1 for the (–NH) stretching. Also,
(C-Harom) bond was observed ] = 3000 cm−1. With the
aid of the positive ion mode of electron spray ionization
(ESI) mass spectrum of the compounds 3c, 6b, and 3f, the
respective molecular ion peaks were observed at m/z (%)
334 (100) [M+H]+, 411 (100) [M+H]+, 292 (100) [M+H]+,
respectively.
1
confrmed by spectroscopic methods comprising H NMR
and 13C NMR, FT-IR, elemental analysis, and MS.
In the second step of this study, diferent molar amount of
N-substituted naphthoquinone compounds 9 [16, 21], 13 [16,
23] was reacted with sodium azide in DMF. Te phenazine
compounds 11 and 14 [22] were synthesized and compound
11 has not yet been described in the literature (Scheme 2).
In the last step of this study, 2,3,5,6-tetrachloro-1,4-
benzoquinone 15 compound was reacted with compounds
containing N-nucleophiles (2b, 2c, 2 g, 16) that novel ben-
zoquinones (17-25) not yet described in the literature were
synthesized in Scheme 3. Te synthesis, spectroscopic data
(1H NMR, 13C NMR, MS, UV, FT-IR), elemental analysis, and
melting points of compounds were reported in studies. Te
1H NMR signal of the hydrogen atoms of the naphthoquinone
unit of compounds 3c, 3d, 3f, 3g, 4e, 7a was observed at
(CH) ꢁ= 7.9-8.1 and 7.5-7.7 ppm like as doublet of doublets
and triplet of triplets, respectively. Similarly, 6b, 11, 14 were
observed at (CH) ꢁ= 7.9-8.1 and 7.5-7.7ppm like as multiplets,
respectively. Substituted aromatic ring hydrogens showed
peaks around 6.8-7.4 ppm. Aliphatic groups in compounds
3f, 7a were shifed to a higher feld and displayed peaks
at 0.8-1.2 ppm. Te 13C NMR spectra of compound 3d
gave two carbonyl signals at 177.5 and 179.9ppm (C=O).
Unlike other studies, the carbon atoms attached to the
fuorine atoms in the 3c compound give cleavage peaks
155.6, 157.8 ppm (F-Carom) in aromatic unit. Compound 3d
2-Chloro-3-(o-tolylamino)naphthalene-1,4-dione 9 and
sodium azide 10 required for the synthesis of 11, sim-
ilarly, 2-chloro-3-(m-tolylamino)naphthalene-1,4-dione 13
and sodium azide (NaN ) 10 required for the synthesis of
3
compound 14 have been synthesized according to Scheme 2.
Te nucleophilic displacement reaction of compound 9
with sodium azide (NaN ) in DMF-H O (10:1) aforded 1-
3
2
methylbenzo[b]phenazine-6,11-dione 11 and this analog 2-
methylbenzo[b]phenazine-6,11-dione 14 as the only isolated
products as exhibited in Scheme 2. Te proposed mecha-
nism of condensation reaction of naphthoquinones agrees
well with the related literatures [24, 25]. Both synthesized
compounds were characterized by using the H NMR, 13C
1
NMR, FT-IR spectral data, and elemental analysis. Te frst
compound 11 was obtained by an interesting ring closure and
is a phenazine derivative. Te 13C NMR spectra of compound
11 gave two carbonyl signals at 180.7 and 180.8 ppm (C=O).
Te FT-IR spectra of compounds 11 and 14 showed bands
at 3019 cm−1 for the (C-Harom) stretching and (–NH) bonds
were not observed in the FT-IR. 1H NMR peak of the hydro-
gen atoms of the naphthoquinone group gave on (CHarom) ꢁ=
7.53-7.61ppm and 7.95-7.99ppm as multiplets for compound
11. Molecular ion peaks were observed at m/z (%) 276.1 (100)

8
Heteroatom Chemistry
O
O
O
H
N
H
N
Cl
N
Cl
Cl
N
+
N
N
O
Cl
H
O
F
24
25
O
(N；2C／3/EtOH)
H
N
F
Cl
N
（2N
2g
F
F
O
O
Cl
F
F
（2N
Cl
F
O
（2N
O
17
H
N
Cl
Cl
F
Cl
F
F
F
2c
16
F
O
+
F Cl
(N；2C／3/EtOH)
H
N
O
Cl
(N；2C／3/EtOH)
F
Cl
O
23
O
F
N
Cl
15
H
O
F
（2N
F
18
(N；2C／3/EtOH)
2h
F
F
F
O
O
O
F
O
O
NH
O
O
NH
O
O
NH
O
NH
+
+
HN
+
Cl
HN
Cl
O
O
O
Cl
O
O
22
F
F
19
21
20
Scheme 3: Te synthesis of N,O-substituted benzoquinone derivatives.
[M+2H]+. Te UV-Vis spectroscopy values for compound 14
were also observed at 212(2.2), 241(2.1), 298(2.2), 539(1.2).
It is known that the reactions of 2,3,5,6-tetrachlorocyclo-
hexa-2,5-diene-1,4 dione 15 with amines proceed by Michael
addition reaction. A series of 2-arylamino-1,4-benzoquinone
derivatives 17-25 were synthesized via the nucleophilic sub-
stitution reaction of 2,3,5,6-tetrachlorocyclohexa-2,5-diene-
1,4-dione 15 by appropriate aryl amines 2c, 2 g, 2h, 16 in
ethanol as shown in Scheme 3. Te reactions were found to
be exceptionally selective and lead to mainly 2- and/or 2,5-
bis(amino substituted)-3,6-dichloro-1,4-benzoquinones of
the corresponding amine. From these reactions we could not
obtain 2,6-bis(amino substituted)-1,4-benzoquinone deriva-
tives. Te steric factors arising from the substituent efect
predominates in these reactions. Te result of selective
formation of 2,5-isomer may be assumed to be due to
attack of two amines to 1,4-benzoquinone. For such attack
to give exclusive product of one isomer (2,5-) would require
approach of two amines from the furthest possible distance.
Tus, exclusively 2- and/or 2,5-isomer were formed due
to electrostatic reasons for compounds 17-25. Te results
agree well with the corresponding mechanism in the similar
compounds [6, 26].
were visible at around 175.9 and 173.8 ppm. For compound 23,
substitute ethoxy group carbons (-CH2etoxy) and (-CH
)
3etoxy
at 68.0 and 16.1 ppm, respectively. Like the naphthoquinone
derivatives, carbon atoms attached to the fuorine atoms in
the 23 compound give cleavage peaks 155.5 and 157.8 ppm
(F-Carom). Te FT-IR spectra of compounds 17-25 showed
the absorption bands of the N–H group at around 3240-
3380 cm−1. Te characteristic stretching band of carbonyl
groups (C = O) was observed at between ] = 1650-1700cm−1.
In the MS of quinone derivatives, the molecular ion peaks of
compounds 17, 22, and 23 were observed at 364 (100) [M]−,
445 (100) [M+2H]+, 360 (100) [M-H]−.
3.2. Antimicrobial Studies. Te profound antifungal and
antibacterial activity exhibited by quinone compounds has
prompted us to synthesize new heteroatom substituted 1,4-
naphtho- and benzoquinones. In our new endeavors, we
have synthesized new 1,4-naphtho- and benzoquinones and
evaluated their antibacterial and antifungal activity by dif-
fusion [13] and serial dilution[14] methods with a view to
search new perspective compounds having broad spectrum
of biological activity. Antibacterial and antifungal activity of
compounds 3c, 3d, 3f, 3g, 6b, 11, 17, 21, and 25 was elucidated
against Escherichia coli B-906, Staphylococcus aureus 209-P,
Mycobacterium luteum B-917, Candida tenuis VKM Y-70, and
Aspergillus niger F-1119 by difusion method (Tables 1 and 2)
and by serial dilution method as shown in Tables 3 and 4.
In 1H NMR spectrum of compounds 17-23, the hydrogen
signals were observed at between ꢁ = 6.1-8.0 ppm as multiplet
peak, assigned to the (-CHarom). In the 13C NMR, charac-
teristic signals of two carbonyl carbons of benzoquinones

Heteroatom Chemistry
9
Table 1: Antibacterial activity of the compounds determined by difusion method.
Concentration
Diameter of inhibition of growth of microorganisms, mm
Compound
%
E. coli
S. aureus
M. luteum
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0
0
0
0
0
0
11
0
0
0
0
0
0
0
0
0
0
0
14
0
0
16
12
0
0
0
24
12
0
3c
3d
3f
0
0
20
14
0
0
0
0
10
6
0
0
20
16
11
8
0
0
11
9
0
0
0
3g
6b
11
17
21
0
0
15
25
0
18
Control∗
∗Vancomycin was used as a control in the tests of antibacterial activity of the synthesized compounds.
Table 2: Antifungal activity of the compounds determined by difusion method.
Concentration
%
Diameter of inhibition of growth of microorganisms, mm
Compound
C. tenuis
A. niger
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0
0
0
0
0
0
0
0
15
13
0
0
0
0
7
0
15
0
0
0
0
0
0
0
0
0
0
0
0
0
15
10
12
6
10
0
3c
3d
3f
3g
6b
11
17
21
25
Control∗
19
20
∗Nystatin was used in the tests of antifungal activity of the synthesized compounds.

10
Heteroatom Chemistry
Table 3: Antibacterial activity of the compound determined by
Table 5: Catalase enzyme activities of the compounds.
serial dilution method.
Catalase activities
Compound
Microorganism
S. aureus
(U/mL)
0.599
0.705
0.715
Compound
E. coli
M. luteum
3c
3d
3f
MIC (ꢀg/mL)
3c
3d
3f
3g
6b
11
+
+
+
250.0
+
+
+
62.5
+
31.2
+
+
31.2
+
15.6
+
3g
4e
6b
7a
14
17
19
22
23
0.722
0.689
0.606
0.608
0.470
0.581
0.550
0.709
0.585
+
+
17
21
25
Control
+
+
+
15.6
+
500.0
3.9 0.2
62.5
+
250.0
7.8 0.2
31.2 0.8
+: growth of microorganisms.
comparison with antibacterial drug vancomycin evaluated by
difusion method.
Table 4: Antifungal activity of the compounds determined by serial
dilution method.
Antifungal activity against C. tenuis was observed for
6b, 21, and 25 at concentration of 0.5% (d = 15, 7 and
15 mm, respectively). Compound 17 showed antifungal activ-
ity against A. niger at 0.5% concentration (d = 15 mm) by the
difusion method (Table 2). Compounds 3c, 3f, and 11 have no
antibacterial and antifungal activity against E. coli, S. aureus,
M. luteum, C. tenuis, and A. niger at 0.5 and 0.1% evaluated
concentrations by difusion method (Tables 1 and 2).
Te biological activity results of the synthesized com-
pounds were classifed as follows: the antimicrobial activities
were considered as signifcant when the minimum inhibition
concentration (MIC) was 100 ꢀg/mL or less; moderate, when
the MIC was 100.0–500.0 ꢀg/mL; weak, when the MIC was
500.0–1.000 ꢀg/mL; and inactive when the MIC was above
1.000 ꢀg/mL. Evaluation of the antibacterial activity of the
synthesized compounds showed that 3g and 17 was the most
potent with MIC=15.6 ꢀg/mL for M. luteum and S. aureus,
respectively (Table 3). Evaluation of antibacterial activity
of synthesized compounds showed that 3d and 3g have
MIC=31.2 ꢀg/mL for M. luteum and S. aureus, respectively
(Table 3).
Microorganism
Compound
C. tenuis
A. niger
MIC (ꢀg/mL)
3c
3d
3f
3g
6b
11
17
21
125.0
+
+
500.0
+
+
15.6
62.5
31.2
7. 8 0.2
+
+
+
500.0
+
+
250.0
125.0
250.0
15.6 0.8
25
Control
+: growth of microorganisms.
Activities of quinone compounds were compared with those
of the known antibacterial agent vancomycin and antifungal
agent nystatin (control C).
Signifcant antifungal activity for 17 and 25 was observed
against C. tenuis fungi at 15.6 and 31.2ꢀg/mL, respectively.
Evaluation of antifungal activity of compounds 3c, 3g, and
21 showed their activity in concentrations 62.5–500.0 ꢀg/mL
against test-culture C. tenuis (Table 4). Compounds 3g, 17, 21,
and 25 showed moderate antifungal activity with MIC value
in the range of 125.0–500.0 ꢀg/mL against A. niger in Table 4.
Te test-culture E. coli appeared not to be sensitive to
any compounds except that 3g. Compound 3g has moderate
activity against E. coli at a concentration of 0.5% and the
diameter of the inhibition zone was 11 mm by difusion
method. Compounds 3d and 3g have strong activity against
S. aureus (16 and 20 mm at 0.5% concentration) and have
moderate activity at a concentration of 0.1% (the diameter of
the inhibition zones were 12 and 14 mm). Te M. luteum strain
was sensitive to compounds 3g, 6b, and 17 at a concentration
of 0.5% and the diameter of the inhibition zone was 20
and 11 mm, respectively (Table 1). Compound 3d has good
antibacterial activity against M. luteum at concentration of
0.5% and the diameter of the inhibition zone was 24 mm by
difusion method (for vancomycin was 18 mm). Compounds
3d and 3g were found to exhibit strong antibacterial activity
against S. aureus and M. luteum (at concentration of 0.5%) on
3.3. Catalase Enzyme Inhibition Activity of Quinone Deriva-
tives. Catalase is a common heme containing enzyme found
in nearly all living organisms that are exposed to O , where
2
it functions to catalyze the decomposition of H O to H O
2
2
2
and O . Compounds 3c, 3d, 3f, 3g, 4e, 6b, 7a, 14, 17, 19, 22,
2
and 23 were tested in vitro for their catalase activities and the
results are shown in Table 5 and Figure 1. As shown in Figure 1,
compound 3g caused signifcant elevation of catalase activity.

Heteroatom Chemistry
11
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Acknowledgments
Te authors would like to express their gratitude to Scientifc
Research Projects Coordination Unit of Istanbul University
for fnancial support (Projects nos. 43723 and 36017).
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1
Compound 3d has good antibacterial activity against
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Conflicts of Interest
Te authors declare no conficts of interest.

12
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International Journal of
Advances in
Journal of
International Journal of
BioMed
Tribology
Chemistry
Research International
Spectroscopy
Electrochemistry
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Enzyme
Research
Journal of
Journal of
Biochemistry
Spectroscopy
Nanotechnology
Research International
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