Synthesis and spectroscopic evaluation of novel N-, S-, and O-substituted 1,4-naphthoquinone derivatives

Article abstract of DOI:10.1080/10426507.2011.602376

Novel O- S,O- S,S- N,N- and N,S-substituted naphthoquinone compounds were prepared by reaction of 2,3-dichloro-1,4-naphthoquinone and the corresponding nucleophiles in the presence of chloroform and triethylamine or ethanol solution of Na₂CO

Full text of DOI:10.1080/10426507.2011.602376

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Phosphorus, Sulfur, and Silicon and the
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Synthesis and Spectroscopic Evaluation
of Novel N-, S-, and O-Substituted 1,4-
Naphthoquinone Derivatives
Cemil Ibis a & Sibel Sahinler Ayla a
a Department of Chemistry, Faculty of Engineering , University of
Istanbul , Avcilar, İstanbul, Turkey
Published online: 31 Oct 2011.
To cite this article: Cemil Ibis & Sibel Sahinler Ayla (2011) Synthesis and Spectroscopic Evaluation of
Novel N-, S-, and O-Substituted 1,4-Naphthoquinone Derivatives, Phosphorus, Sulfur, and Silicon and
the Related Elements, 186:12, 2350-2356, DOI: 10.1080/10426507.2011.602376
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Phosphorus, Sulfur, and Silicon, 186:2350–2356, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.602376
SYNTHESIS AND SPECTROSCOPIC EVALUATION
OF NOVEL N-, S-, AND O-SUBSTITUTED
1,4-NAPHTHOQUINONE DERIVATIVES
Cemil Ibis and Sibel Sahinler Ayla
Department of Chemistry, Faculty of Engineering, University of Istanbul,
˙
Avcilar, Istanbul, Turkey
GRAPHICAL ABSTRACT
O
C
O
O
O
SH
O
O
HS
C
O
O
S
S
Cl
Cl
C
O
2
O
CHCl3, TEA
C
O
O
1
3
Abstract Novel O- S,O- S,S- N,N- and N,S-substituted naphthoquinone compounds were
prepared by reaction of 2,3-dichloro-1,4-naphthoquinone and the corresponding nucleophiles
in the presence of chloroform and triethylamine or ethanol solution of Na2CO3. The structures
of the novel naphthoquinone compounds were characterized by micro analysis, FT-IR, UV/Vis,
1H NMR, 13C NMR, MS, and fluorescence spectroscopy.
Keywords 1,4-Naphthoquinones; thioethers; coumarin
INTRODUCTION
The 1,4-naphthoquinone structure exists in numerous natural products and causes
diverse pharmacological properties; such as antiviral, antimalarial, antifungal, and antipro-
liferative activities.1–4 The 1,4-naphthoquinone pharmacophore also exhibits important
anticancer activity in a number of drugs; such as streptonigrin, mitomycins, and actino-
mycins.5–7 It is also evident from some patents that the substitution of 1,4-naphthoquinones
with S-, N-, and O-nucleophiles leads to an observable increase in the biological activity
profile.8,9
2,3-Bis-(2-hydroxyethylthio)-1,4-naphthoquinone (NSC 95397) and 6-Chloro-7-[2-
(4-morpholinyl)ethyl]amino-5,8-quinolinedione (NSC 663284) are potent and selective
Received 12 April 2011; accepted 24 June 2011.
The Authors thank the Research Fund of Istanbul University for financial support of this work.
Address correspondence to Cemil Ibis, Department of Chemistry, Faculty of Engineering, University of
˙
Istanbul, Avcilar, Istanbul, Turkey. E-mail: ibiscml@istanbul.edu.tr
2350

EVALUATION OF NOVEL N-, S- AND O-SUBSTITUTED 1,4-NAPHTHOQUINONE
2351
irreversible inhibitors of CDC25 dual specificity phosphatase that is implicated in cancer
and Alzheimer’s diseases.10,11
The pharmacological importance of the aforementioned compounds has stimulated
the synthesis and biological evaluation of new agents exhibiting the quinone moiety in
recent years.12–19
The aim of this study is to synthesize of novel nitrogen, sulfur, and oxygen containing
1,4-naphthoquinones as potential biologically active agents and to characterize them with
spectroscopic methods.
RESULTS AND DISCUSSION
The reactions of 2,3-dichloro-1,4-naphthoquinone 1 with various nucleophiles re-
sulted in a substitution of one or both chlorine atoms.14,15 The N,N-substituted dinaphtho-
quinone 3 was obtained by the reaction of 1 with homopiperazine 2 in chloroform with
triethylamine (Et3N) (Scheme 1).
O
O
O
O
S
S
C
O
O
C
Cl
O
O
SH
O
C
O
C
O
HS
O
CHCl3, TEA
HO
O
9
7
6
CHCl3, TEA
8
O
O
HO
O
HN
NH
O
O
O
Cl
Cl
O
O
N
N
4
2
Cl
CHCl3, TEA
CHCl3, TEA
Cl
Cl
O
O
O
3
Cl
1
S
5
HS
HS (CH2)2 COO (CH2)3 CH3
N
10
12
EtOH,Na2CO3
Cl
EtOH,Na2CO3
O
O
O
S
S
S
(CH2)2 COO (CH2)3 CH3
(CH2)2 COO (CH2)3 CH3
S
N
O
CH2 CH3
O
13
11
Scheme 1
The 13C NMR spectrum of 3 gave two carbon signals for C O groups at 178.40
and 182.60 ppm due to the naphthoquinone unit. The O-substituted naphthoquinone 5 was
obtained by the reaction of 1 with 2-phenoxyethanol 4 in chloroform with Et3N. The OCH2
1
protons of 5 appeared in the low-field region of the H NMR spectrum as triplets at 4.2
and 4.8 ppm. The constitution of 5 is a result of a Michael-Type addition to 1 followed by
chloride elimination to afford a quinonyl intermediate that then reacts with an alcohol to
yield the final product 5.
The reaction of 1 with ethylene glycol dithioacetate 6 gave rise to an interesting
ring closure resulting in the S,S-substituted cyclic naphthoquinone derivative 7 that was
obtained with high yield. The molecular ion peak of compound 7 was identified at m/z (%)

2352
C. IBIS AND S. S. AYLA
364 (100) [M]− in the negative ion mode for ESI technique. The 13C NMR of 7 showed
one signal at 177.20 ppm for the carbonyl groups of the napthoquinone unit and a second
one at 167.61 ppm for the ester carbonyl group.
The O-substituted naphthoquinone 9 was obtained by reaction of 1 with 2
phenylethanol 8 in chloroform with Et3N. Its 13C NMR spectrum showed two signals at
178.80 and 179.98 ppm for the C O groups of the naphthoquinone unit.
The asymmetric naphthoquinone 11 was obtained by reaction of with 5-chloro-2-
mercaptobenzothiazol 10 and Na2CO3 in ethanol. The protonated molecular ion peak was
identified at m/z (%) 402 (100) [M+H]+ for this compound. The compound 11 showed
two signals at 178.83 and 179.56 ppm indicating C O groups in the naphthoquinone unit.
The S,S-disubstituted naphthoquinone compound 13 was obtained by reaction with butyl
3-mercaptopropionate 12 and Na2CO3 in ethanol. Because of the symmetrical structure
of compound 13 the 13C NMR gave only one carbonyl signal at 177.80 ppm for the
napthoquinone unit and, similar as in 7, another one at 170.40 ppm for the ester group.
The N,S-disubstituted naphthoquinone 15 was obtained by the reaction of the novel
compound 3 with 7-mercapto-4-methylcoumarin 14 in chloroform in the presence of tri-
ethylamine (Scheme 2). The 1H NMR spectrum of 15 showed the presence of vinyl protons
of the lactone ring at 6.20 ppm. The excitation and emission value are detected at 336 and
394 nm respectively for compound 15 as shown in Figure 1.
CH3
O
O
O
O
HS
O O
N
N
14
CH3
3
RS
SR
CHCl3, TEA
R:
O O
15
CH3
O
S
HS
SH
CH3
O
O
S
O
O
O
O
S
S
S
S
CH3
16
+
1
S
S
S
O
CHCl3, TEA
H3C
S
O
O
CH3
CH3
17
18
Scheme 2
The interestingcyclicnaphthoquinonederivatives 17 and 18 were obtainedbyreaction
of 1 with toluene-3,4-dithiol 16 (Scheme 2). The mass spectra of these compounds for the
positive ion mode of ESI gave the molecular ion peaks with Na adduct at m/z 643 and 954
(%) (100) [M+Na]+, respectively.
The spectroscopic data of all compounds are reported in Experimental section.

EVALUATION OF NOVEL N-, S- AND O-SUBSTITUTED 1,4-NAPHTHOQUINONE
2353
250
200
150
336.00
394.00
100
50
0
300
350
400
Wavelength (nm)
450
Figure 1 Excitation and emission spectra was measured for 10−4 M solution of compound 15 in CHCl3. Excitation
and emission slit widths were set at 5 nm.
EXPERIMENTAL
Material and Methods
Melting points were determined on a Buchi B-540 melting point apparatus and are
uncorrected. Microanalyses were performed on a Thermo Finnigan Flash EA 1112 Series
elemental analyzer. IR spectra (ν in cm−1, KBr pellets in Nujol mulls) were recorded on
a Perkin Elmer Precisely Spectrum One FTIR spectrometer. UV spectra were recorded
in CHCl3 on a TU-1901 UV-Vis spectrophotometer. Fluorescence Spectra were run on a
VARIAN Cary Eclipse Fluorescence Spectrophotometer. 13C NMR spectra were recorded
in CDCl3 at 499.74 MHz (1H) and 125.66 MHz (13C) on a Varian UNITY INOVA spec-
trometer. Chemical shifts δ are given in ppm, coupling constants in Hz. TMS was used
as internal standard. Mass spectra were obtained on a Thermo Finnigan LCQ Advantage
MAX LC/MS/MS spectrometer using ion-trap mass analyzer for ESI source.
Products were isolated by column chromatography on Silica gel (Fluka silica gel
60, particle size 63–200 µm). TLC plates silica 60F254 (Merck, Darmstadt) and detection
was carried out with UV light (254 nm). All reagents and solvents were of reagent-grade,
obtained from commercial suppliers and used without further purification.
General Procedure 1
1.0 g (4.43 mmol) 2,3-dichloro-1,4-naphthoquinone 1 and 8.86 mmol of the corre-
sponding nucleophille were stirred in CHCl3 (30 mL) with triethyl amine (3 mL) solution
for 2–3 h at room temperature. The color of the solution quickly changed and the reaction
was monitored by TLC. Chloroform (30 mL) was added to the reaction mixture. The or-
ganic layer was washed with water (4 × 30 mL), and dried over Na2SO4. After evaporation
of the solvent the residue was purified by column chromatography on silica gel.
General Procedure 2
1.0 g (4.43 mmol) 2,3-dichloro-1,4-naphthoquinone 1 and 8.86 mmol nucleophile
were stirred in EtOH (65 mL) solution of Na2CO3 (1.52 g) for 2 to 3 h at room tempera-
ture. The color of the solution quickly changed and the reaction was monitored by TLC.
Chloroform (30 mL) was added to the reaction mixture. The organic layer was washed with

2354
C. IBIS AND S. S. AYLA
water (4 × 30 mL), and dried over Na2SO4. After evaporation of the solvent the residue
was purified by column chromatography on silica gel.
2,2ꢁ-(1,4-Diazacycloheptane-1,4-diyl)-bis(3-chloro-1,4-dinaphthoquinone) (3):
Yield 0.3 g (14%); Red solid; m.p: 176–177◦C; Rf = 0.40 (CHCl3); IR: 3057 (CHarom),
2932 (C H), 1673, 1645 (C O), 1592, 1548 (C C); UV-Vis [λmax(nm)(log ε)]: 495
1
(4.4), 285 (5.0), 249 (3.9); H NMR: δ 2.10 (quintet, J = 5.8, 2H, CH2), 3.81–3.91 (m,
8H, NCH2), 7.90 (m, 4H, 6-H, 6ꢁ-H, 7-H, 7ꢁ-H), 8.12 (m, 4H, 5-H, 5ꢁ-H, 8-H, 8ꢁ-H); 13C
NMR: δ 30.17 (CH2), 53.60, 55.52 (NCH2); 126.85, 127.15, 131.77, 131.85, 133.44,
134.30 (CHnapht., Cnapht.), 151.73 ( C N), 178.40, 182.60 (C O); MS (+ESI): m/z 503
(M+Na)+; C25H18Cl2N2O4 (481.33). Calcd. C, 62.38; H, 3.77; N, 5.82. Found C, 62.03;
H, 3.65; N, 5.79%.
2-Chloro-3-(2-phenoxyethoxy)-1,4-naphthoquinone (5): Yield 0.7 g (64%); Red
solid; m.p: 79–80◦C; Rf = 0.35 (CHCl3); IR: 3067 (CHarom), 2928 (C H), 1673 (C O),
1597, 1573 (C C); UV-Vis [λmax(nm)(log ε)]: 360 (3.2), 338 (4.0), 284 (4.3); 1H NMR: δ
4.20 (t, J = 8.7, 2H, OCH2), 4.81 (t, J = 9.2, 2H, OCH2), 6.71–7.20 (m, 5H, PhH), 7.73
(m, 2H, 6-H, 7-H.), 8.10 (m, 2H, 5-H, 8-H); 13C NMR: δ 67.70, 72.61 (OCH2); 121.54,
127.12, 127.14, 127.23, 127.75, 129.72, 129.74, 131.07, 131.34, 134.19, 134.56 (CHarom
,
Carom, CHnapht., Cnapht.), 156.90, 158.41 ( C O), 179.90, 178.80 (C O); MS (+ESI): m/z
351 (M+Na)+; C18H13ClO4 (328.75). Calcd. C, 65.76; H, 3.99. Found C, 65.60; H, 3.67%.
2,3-Cyclo-[ethylene-bis(acetoxythio)]-1,4-naphthoquinone (7): Yield 0.6 g (62%);
Orange solid; m.p: 214–215◦C; Rf = 0.45 (CHCl3); IR: 3022 (CHarom), 2960 (C H), 1658
(quinone C O), 1735 (ester C O), 1591 (C C); UV-Vis [λmax(nm)(logε)]: 311 (4.6), 261
(4.2), 253 (4.1); 1H NMR: δ 3.81 (s, 4H, SCH2), 4.20 (s, 4H, OCH2), 7.61 (dd, J = 9.2, J =
5.8, 2H, CHnapht), 8.12 (dd, J = 8.7, J = 5.8, 2H, CHnapht); 13C NMR: δ 60.80 (OCH2); 34.90
(SCH2); 126.41, 131.74, 132.98 (CHnapht, Cnapht), 149.12 ( C S), 167.61 ( O C O),
177.20 (quinone C O); MS ( ESI): m/z 364 [M]−; C16H12O6S2 (M, 364.39). Calcd. C,
52.74; H, 3.32; S, 17.60. Found C, 52.64; H, 3.22; S, 16.90%.
2-Chloro-3-(2-phenylethoxy)-1,4-naphthoquinone (9): Yield 0.15 g (11%); Red
viscous oil; Rf = 0.35 (CHCl3); IR: 3064 (CHarom), 2937 (C H), 1673 (C O), 1594, 1569
(C C); UV-Vis [λmax(nm)(logε)]: 336 (4.6), 280 (4.2), 254 (4.3); 1H NMR: δ 3.10 (t, J =
6.8, 2H, CH2), 4.81 (t, J = 6.8 Hz, 2H, CH2), 7.10–7.35 (m, 5H, PhH), 7.73 (m, 2H, 6-H,
7-H), 8.10 (m, 2H, 5-H, 8-H); 13C NMR: δ 37.32 (CH2); 75.16 (OCH2); 126.95, 127.06,
127.14, 127.20, 127.84, 128.75, 128.93, 129.41, 131.02, 131.28, 134.06, 134.50, 137.45
(CHarom, Carom, CHnapht., Cnapht.), 156.73 ( C O), 179.98, 178.80 (C O); C18H13O3Cl
(312.75). Calcd. C, 69.13; H, 4.19. Found C, 68.85; H, 4.10%.
2-(6-Chloro-2-benzothiazolylthio)-3-ethoxy-1,4-naphthoquinone (11): Yield 0.3
g (34%); Red solid; m.p: 155–156◦C; Rf = 0.45 (CHCl3); IR: 3069 (CHarom), 2934, 2980
(C H), 1671 (C O), 1589, 1550 (C C); UV-Vis [λmax(nm)(log ε)]: 434(4.5), 285(4.6),
253(4.6); 1H NMR: δ 1.23 (t, J = 7.3, 3H, CH3), 4.62 (q, J = 7.3, 2H, OCH2), 7.21–8.10
(m, 7H, CHnapht, CHarom); 13C NMR: δ 14.80 (CH3), 70.30 (OCH2); 121.09, 123.60, 124.21,
125.91, 126.12, 130.37, 131.32, 133.25, 132.74, 130.99 (CHnapht, Cnapht, CHarom, Carom),
153.03, 133.47 ( C S), 160.32 ( C N), 165.03 ( C O), 178.83, 179.56 (C O); MS
(+ESI): m/z 402 (M+H)+; C19H12ClNO3S2 (401.89). Calcd. C, 56.78; H, 3.01; S, 15.96,
N; 3.49. Found C, 56.15; H, 2.95; S, 14.50; N, 3.01%.
2,3-Bis-[2-(butyloxycarbonyl)ethyl]thio-1,4-naphthoquinone (13): Yield 0.4 g
(19%); Oil; Rf = 0.24 (CHCl3); IR: 3065 (CHarom), 2959 (C H), 1659 (quinone C O),
1733 (ester C O), 1591 (C C); UV-Vis [λmax(nm)(log ε)]: 239(4.6), 279(4.7), 351(3.4),
460(3.4); 1H NMR : δ 0.91 (t, J = 7.3, 6H, CH3), 1.10–1.6 (m, 8H, CH2), 2.65 (t, J = 7.3,

EVALUATION OF NOVEL N-, S- AND O-SUBSTITUTED 1,4-NAPHTHOQUINONE
2355
4H, COCH2), 3.41 (t, J = 7.3, 4H, SCH2), 4.10 (t, J = 7.3, 4H, OCH2), 7.63 (dd, J = 5.4,
J = 5.9, 2H, CHnapht), 7.96 (dd, J = 5.4, J = 5.9, 2H, CHnapht); 13C NMR: δ 12.66 (CH3);
29.61, 28.87, 18.11 (CH2); 63.28 (OCH2); 34.54 (SCH2); 125.96, 131.87, 132.58 (CHnapht
,
Cnapht), 146.36 (C S), 170.40 ( O C O), 177.79 (quinone C O); MS (+ESI): m/z 479
(M+H)+; C24H30O6S2 (478.62). Calcd. C, 60.23; H, 6.32; S, 13.40. Found C, 60.14; H,
6.21; S, 12.50%.
2,2ꢁ-(1,4-Diazacycloheptane-1,4-diyl)-3,3ꢁ-[bis-(4-methylcoumarin-7-sulfanyl)]-
1,4-dinaphthoquinone (15): Yield 0.04 g (1%); Oil; Rf = 0.45 (CHCl3); IR: 3070
(CHarom), 2919, 2850 (C H), 1735 (lactone C O), 1676 (quinone C O), 1598, 1573
1
(C C); UV-Vis [λmax(nm)(log ε)]: 450(3.0), 330(4.2), 277(3.9); H NMR: δ 1.8 (s, 6H,
CH3), 2.34 (quintet, 2H, J = 5.8, CH2), 3.79–3.91 (m, 8H, NCH2), 6.10 (S, 2H, CHvin),
7.11–7.55 (m, 22H, CHnapth, Harom); 13C NMR: δ 17.61 (CH3), 28.68 (CH2), 113.43,
113.94, 113.97, 116.69, 118.08, 118.79, 121.12, 124.25, 127.43, 128.69, 139.85 (CHnapht.
,
Cnapht.), 150.77 ( C S), 153.01 ( C N), 159.12 (lactone C O); 182.56 (quinone
C O); C45H32N2O8S2 (792.87). Calcd. C, 68.17; H, 4.07; N, 3.53; S, 8.09 Found C, C,
67.50; H, 3.90; N, 3.20; S, 9.01%.
[2,13,7,8]-Dinaphthoquinonyl-[4,5,10,11]-[(1-methyl)-dibenzo]-[3,6,9,12]tetrathi
acyclododecene-2,5,8,11-tetraene (17): Yield 0.2 g (7%); Oil; Rf = 0.45 (CHCl3/EtAc
1:1); IR: 3043 (CHarom), 2919, 2980 (C H), 1665 (C O), 1588, 1561 (C C); UV-Vis
1
[λmax(nm)(log ε)]: 360(4.6), 294(4.5), 246(3.6); H NMR: δ 2.15 (s, 6H, CH3), 6.8–7.5
(m, 6H, CHarom), 7.67 (dd, J = 7.8, J = 6.8, 4H, CHnapht), 8.10 (dd, J = 8.7, J = 6.8,
4H, CHnapht); 13C NMR: δ 28.68 (CH3), 143.03, 140.22, 138.27, 136.19, 134.01, 133.02,
130.71, 130.26, 128.67, 127.18, 126.15, 125.91, 120.43 (CHarom, Carom, CHnapht., Cnapht.),
180.98 (C O); MS (+ESI): m/z 643 (M+Na)+; C34H20O4S4 (620.78). Calcd. C, 65.78;
H, 3.25; S, 20.66; Found C, 65.50; H, 3.10; S, 19.56%.
[2,19,7,8,13,14]-Trinaphthoquinonyl-[4,5,10,11,16,17]-[(1-methyl)-tribenzo]-[3,
6,9,12,15,18]-hexathiacyclooctadecene-2,5,8,11,14,17-hexaene (18): Yield 0.35 g (9%);
black solid; m.p: 209–210◦C; Rf = 0.6 (CHCl3/EtAc 1:1); IR: 3043 (CHarom), 2921, 2855
(C H), 1705 (C O), 1588, 1535 (C C); UV-Vis [λmax(nm)(log ε)]: 351(3.6), 296(4.4),
1
253(3.3); H NMR: δ 2.21 (s, 9H, CH3), 6.8–7.5 (m, 9H, CHarom), 7.67 (dd, J = 5.8,
J = 5.8, 6H, CHnapht), 8.12 (dd, J = 5.8, J = 5.8, 6H, CHnapht); 13C NMR: δ 28.80 (CH3),
141.35, 140.21, 138.16, 136.17, 136.05, 134.12, 131.27, 131.25, 130.25, 130.20, 128.02,
126.11,121.27, 120.38 (CHarom, Carom, CHnapht., Cnapht.), 183.30 (C O); MS (+ESI): m/z
953 (M+Na)+; C51H30O6S6 (931.17). Calcd. C, 65.78; H, 3.25; S, 20.66; Found C, 65.27;
H, 3.13; S, 19.55%.
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