Sulfur-containing derivatives of 1,4-naphthoquinone, part 1: Disulfide synthesis

Article abstract of DOI:10.1002/hc.20112

Bisulfides of 1,4-naphthoquinone were synthesized, and different methods of their synthesis were investigated. High yields and purity of disulfides were obtained from the oxidation of thiol derivatives. The latter were prepared in high yields and purity from isothiuronic salts. The obtained disulfides are synthones for compounds with a wide spectrum of biological activity.

Full text of DOI:10.1002/hc.20112

Heteroatom Chemistry
Volume 16, Number 3, 2005
Sulfur-Containing Derivatives of 1,4-
Naphthoquinone, Part 1: Disulfide Synthesis
Maryna V. Stasevych, Maxym Yu. Plotnikov, Mykola O. Platonov,
Svitlana I. Sabat, Rostyslav Ya. Musyanovych,
and Volodymyr P. Novikov
Department of Technology of Biologically Active Substances, Pharmacy, and Biotechnology,
Institute of Chemistry and Chemical Technology, National University “Lviv Polytechnic,” Bandera
str. 12, 79013, Lviv-13, Ukraine
Received 7 December 2004; revised 5 February 2005
ple, gliotoxin and sporidesmin), which have antifun-
ABSTRACT: Disulfides of 1,4-naphthoquinone were
gal, antibacterial, and antivirus activities, are rep-
synthesized, and different methods of their synthesis
resented among disulfides [1]. Some disulfides are
were investigated. High yields and purity of disulfides
widely used as accelerators of the rubbers’ vulcan-
were obtained from the oxidation of thiol derivatives.
ization [2].
The latter were prepared in high yields and purity from
Due to the lability of S S bond, its ability to be
isothiuronic salts. The obtained disulfides are syntho-
broken under action of the nucleophilic and elec-
nes for compounds with a wide spectrum of biological
trophilic reagents, disulfides are widely used in mul-
ꢀ
C
activity. 2005 Wiley Periodicals, Inc. Heteroatom Chem
tistage organic synthesis.
16:205–211, 2005; Published online in Wiley InterScience
Investigations during the last 10–15 years were
(www.interscience.wiley.com). DOI 10.1002/hc.20112
dedicated to the further development of already
known disulfides syntheses and to the search of new
methods (synthesis of the base of alkylthiotrimethyl-
silanes, thiocyanates, sulfenylthiocyanates etc.).
INTRODUCTION
The combination of disulfide bond and naphtho-
quinone fragment will allow different chemical con-
versions. Only bis-[2-amino-1,4-naphthoquinone]-3-
disulfide (4a) is described in the literature at present
[3]. We investigated various methods of synthe-
sis of new disulfides from 3-chloro-, -thiolo-, and
-thiocyano-1,4-naphthoquinone and unsubstituted
1,4-naphthoquinone.
Disulfides are found in natural products frequently.
They are included as binding elements into sec-
ondary structure of fibers. It provides rather stable
position of the peptide circuits, which formed at the
expense of weaker binding forces, in particular of
the hormones (somathostatin, insulin, vasopresin,
oxytocin, calcitonin). Disulfide bonds are found in
the structures of alkaloids (cassipurin, zherardin)
and antibiotics. Disulfides are used as antiradiation
preparations, nootropic psychostimulators, and as
drugs for the treatment of the alcoholism. The com-
pounds that have high biological activity (for exam-
RESULTS AND DISCUSSION
Interaction of 2-Amino-3-chloro-1,4-
naphthoquinones with Sodium Disulfide
As an initial compound for synthesis of 2-amino-
Correspondence to: V. P. Novikov; e-mail: vnovikov@poly-
net.lviv.ua.
2005 Wiley Periodicals, Inc.
3-chloro-1,4-naphthoquinones
2 was used 2,3-
c
ꢀ
dichloro-1,4-naphthoquinone (1). The preparation
205

206 Stasevych et al.
SCHEME 1
of 2 from 1 was modernized, and the yields and pu-
rity of products were improved [4].
Interaction of 2-Amino-1,4-Naphthoquinones
and 1,4-Naphthoquinone with Disulfur
Dichloride
Synthesis of disulfides 4a–g and bis-disulfide 5
was carried out similarly to the method described
[5]. Long boiling of the reaction mixture leads to
desulfurization of disulfides with the formation
of the sulfides 7a–g,8,9 (Scheme 1). Structures
of bis-(2-amino-1,4-naphthoquinone)sulfide (7a),
bis-(2-anilino-1,4-naphthoquinone)sulfide (7f), and
cyclic sulfide 9 were confirmed by NMR, IR, the
element analysis and were identified as described
earlier [3,20]. It is established that bis-[2-hydroxy-
1,4-naphthoquinone]-3-disulfide (6) turns into bis-
(2-hydroxy-1,4-naphthoquinone)-sulfide (9), des-
cribed in the the literature [3]. The desulfurization
to 9 takes place at weak heating of reaction mix-
ture. Therefore, reaction carried below at room
temperature.
Synthesis of disulfides by the previous method at
nonconstant temperature led to by-products, which
reduced yields of disulfides. Therefore, we carried
out the interaction of 2-amino-1,4-naphthoquinones
12a–g, obtained similarly to the methods [6,7], and
6 was processed in bis-[2-chloro-1,4-naphtho-
quinone]-3-disulfide 10 by thionyl chloride in dry
carbon tetrachloride (Scheme 2).
SCHEME 2

Sulfur-Containing Derivatives of 1,4-Naphthoquinone, Part 1: Disulfide Synthesis 207
SCHEME 3
of 1,4-naphthoquinone 11 with disulfur dichloride in
inert solvents in the presence of the base (Scheme 3)
[3]. The reaction passes easily, but with formation of
by-products.
Synthesis of Disulfides from 2-Amino-, 2-Chloro-,
2-Hydroxy-3-thiolo- 1,4-naphthoquinones
2-Amino-, 2-chloro-, 2-hydroxy-3-thiolo-1,4-naphth-
oquinones were prepared similar to [11,12] by the
interaction of 2,3:
Interaction of 11 with disulfur dichloride led to
formation of a product mixture (Scheme 4).
Attempts to separate the mixture by chromatog-
raphy on silica gel (benzene/ethyl acetate, 80:20)
gave the individual compounds, three of which were
structures 13, m = 2 (2.5%); 5 (15%); and 8 (50%).
Other compounds, isolated from a reaction mixture,
are impossible to identify. Formation of the reaction
products can be explained by a mechanism similar
to [8].
A—with sodium sulfide in water, followed by acidi-
fication of the reaction mixture;
B—with thiourea in alcohol, alkaline hydrolysis of
isothiuronic salts, and acidification of the reac-
tion mixture.
18a,f obtained by the method A were described
in the literature [13,14] earlier.
It is known that thiols are easily oxidized to
disulfides [9,15–17]. We carried out oxidation of
18–20 by nitric acid and hydrogen peroxide [9].
Disulfides were obtained with high yields and purity
(Scheme 6).
Hydrolysis of Thiocyanate Derivatives
of 1,4-Naphthoquinone
Two previous methods of disulfide synthesis did not
increase the purity and yields of products. There-
fore, we considered method of disulfide prepara-
tion from thiocyanate derivatives. It is known that
disulfides are obtained from thiocyanates by hydrol-
ysis [9]. We synthesized disulfides from 2-amino-, 2-
hydroxy-3-thiocyanate-1,4-naphthoquinone and 2,3-
dichloro-1,4-naphthoquinone by a modified method
[10]. Disulfides were obtained with higher yields and
purity as compared to the above-mentioned methods
(Scheme 5).
Attempts to obtain disulfides from thiols by chlo-
rine, sulfuryl chloride, or phosphorus pentachloride
in inert solvents failed because products cannot be
separated.
The structures of the obtained compounds were
confirmed by NMR, IR, and the element analysis.
Obtained disulfides are poorly soluble and high
melting point compounds. They are synthones
for the further chemical transformations with the
purpose of preparation of new biologically active
compounds.
SCHEME 4

208 Stasevych et al.
spectrometer as solutions in DMSO-d6 with TMS as
a internal standard. IR spectra were recorded on
Specord M80 in tablets KBr.
Materials. 2-Amino-3-chloro-1,4-naphthoquino-
nes (2a–g) [4], 2-piperidyl-1,4-naphthoquinone
(12d) [6,7], 2-hydroxy-3-chloro-1,4-naphthoquinone
(3) [18], 2-chloro-3-thiocyano-1,4-naphthoquinone
(15) from 1, and 2,3-dithiocyano-1,4-naphthoquin-
one (16) from 1 [19].
2-Amino-3-chloro-1,4-naphthoquinone (2a). Am-
monia was slowly passed through dense suspension
of 1 in DMSO at stirring. After 5 min the reac-
tion mixture begins to redden, 1 dissolves. Ammo-
nia passed for 3 h; reaction mixture was left for night,
and then warmed up to 50◦C to remove excess ammo-
nia. A mixture was filtered. Orange crystals, which
do not require clearing, separated from the filtrate
at cooling. All constants for 2a match with those de-
scribed in [14].
General Procedure of Synthesis
of Bis-[2-R-1,4-naphthoquinone]-3-disulfides
4a–g from 2a–g
SCHEME 5
2a–g (0.07 mol) was suspended in 60 mL of ethanol.
Mixture was brought to boiling and sodium disul-
fide (0.05 mol) added. Boiling was continued for 3 h.
The reaction mixture was chilled and the product
collected; residue was washed by water till water did
not become colorless (see Table 1).
EXPERIMENTAL
Melting points were measured on a Nagema melt-
ing point apparatus and are uncorrected. H NMR
spectra were recorded on Varian VXR (300 MHz)
1
Preparation of the bis-[2-hydroxy-1,4-naphtho-
quinone]-3-disulfide (6) is carried out at <15◦C. The
TABLE 1 Disulfides 4a–g,5,6 from 3-chloro-1,4-naphthoqu-
inones 2a–g,1,3, and Na2S2
Calculated Found (%)
Yield (%)
61
C
H
N
S
Cl
4a
4b
4c
4d
4e
4f
58.82
59.01
64.62
64.54
66.67
66.85
66.18
66.25
65.63
65.59
68.57
68.25
61.05
61.12
58.54
58.75
54.55
54.21
2.94
2.85
5.38
5.42
6.25
6.11
5.15
5.01
4.69
4.45
3.57
3.78
2.86
2.94
2.44
2.36
1.82
2.02
6.86
6.91
5.38
5.35
4.86
4.93
5.15
5.23
5.47
5.69
5.01
5.12
4.45
4.12
15.69
15.65
12.30
12.35
11.11
11.25
11.76
11.82
12.50
12.25
11.43
11.45
10.17
10.05
15.60
15.78
29.09
29.21
64
58
52
53
56
4g
6
59
11.29
11.40
45
5
42
SCHEME 6

Sulfur-Containing Derivatives of 1,4-Naphthoquinone, Part 1: Disulfide Synthesis 209
TABLE 3 Disulfides 4a–g,6,10 from 3-Thiolo-1,4-naphtho-
quinones 18a–g, 19, 20, and H2O2(A) or HNO3(B)
reaction mixture was filtered, filtrate was acidified,
and orange brown crystals were collected. Residue
was washed by diluted hydrochloric acid and dried.
Found (%)
Yield (%)
A/B
C
H
N
S
Cl
General Procedure of Synthesis
of Bis-[2-R-1,4-naphthoquinone]-3-disulfides
4b–g from 12b–g
4a
4b
4c
4d
4e
4g
4h
6
88/86
87/88
89/86
87/89
85/87
86/88
87/85
89/87
83/81
58.80
64.59
66.63
66.25
65.57
68.50
61.10
58,65
53.73
2.95
5.40
6.20
5.20
4.72
3.64
2.81
2,50
1.73
6.84
5.36
4.90
5.11
5.52
5.06
4.50
15.72
12.35
11.07
11.69
12.43
11.52
10.01
15,71
14.39
The mixture of 12b–g (0.06 mol), triethylamine (0.12
mol), and disulfur dichloride (0.06 mol) was stirred
in benzene, heated to 40–50◦C for 2 h. The reaction
mixture was cooled, product collected, washed by
water, and dried (see Table 2).
11.35
15.92
10
TABLE 4 Disulfides 4a, 10, 5, 6 from the hydrolysis of 3-
General Procedure of Synthesis of
Bis-[2-R-1,4-naphthoquinone]-3-disulfides 4a–g
from 2-R-3-Thiolo-1,4-naphthoquinones 18a–g
Thiocyanato-1,4-naphthoquinones
Found (%)
Method A. 7.1 mmol of 30% of a solution of
hydrogen peroxide was added to a water solution
9.7 mmol of 2-amino-3-thiolo-1,4-naphthoquinone.
The reaction mixture was left at constant stirring for
2 days. Then mixture was filtered, the precipitate was
washed by water, and dried.
Yield (%)
C
H
N
S
Cl
4a
10
5
80
68
54
72
58.93
53.47
54.49
58.65
2.84
1.95
1.90
2.50
6.94
14.21
29.12
15.71
15.61
15.73
6
TABLE 5 3-Thiolo-1,4-naphthoquinones 18a–g,19 from 3-
Chloro-1,4-naphthoquinones 2a–g,3, and Na2S (A) or
(NH2)2CS (B)
Method B. 2-Amino-3-thiolo-1,4-naphthoquin-
one was suspended in 3 N solution of nitric acid and
left at stirring for 4 days, then reaction mixture was
filtered and washed by water, and dried (see Table 3).
Calculated Found (%)
Yield (%)
A/B
C
H
N
S
General Procedure of Synthesis of
Bis-[2-R-1,4-naphthoquinone]-3-disulfides
4a,5,6,10 from Thiocyanates Derivatives 14–17
18a
18b
18c
18d
18e
18f
88/81
75/84
69/87
78/85
75/83
78/85
77/87
85/91
58.54
58.47
64.37
64.42
66.44
66.37
65.93
65.85
61.09
61.12
68.33
68.42
77.41
77.52
58.25
58.32
3.41
3.35
5.75
5.82
6.57
6.48
5.49
5.52
4.72
4.65
3.91
3.87
4.03
3.98
2.91
2.98
6.83
6.78
5.36
5.31
4.84
4.91
5.13
5.21
5.09
6.99
4.98
4.87
5.65
5.52
15.61
15.59
12.26
12.34
11.07
11.02
11.72
11.68
11.64
11.71
11.38
11.45
12.90
12.82
15.53
15.64
0.01 mol of 14 and 0.02 mol of ammonium acetate
was suspended in 20 mL of acetic acid, and mixture
was heated at 100–105◦C. The reaction mixture was
left at room temperature for 6 h and filtered. The
precipitate was washed by small amount of water
and dried (see Table 4).
18g
19
TABLE 2 Disulfides 4b–g,5 from 1,4-Naphthoquinones
12b–g,11, and S2Cl2
Found (%)
TABLE 6 3-Chloro-1,4-naphthoquinones 20, 10 from 3-Hy-
droxy-1,4-naphthoquinones 19,6, and SOCl2
Yield (%)
C
H
N
S
Cl
4b
4c
4d
4e
4f
4g
5
73
75
81
74
72
78
15
64.52
66.42
65.98
65.12
68.12
60.91
55.01
5.51
6.11
5.01
4.35
4.12
2.74
1.96
6.01
4.75
5.16
5.53
5.12
4.53
11.99
11.01
11.12
12.12
11.27
9.92
Calculated Found (%)
Yield (%)
C
H
S
Cl
20
10
88
74
53.45
53.54
53.45
2.22
2.13
2.01
14.25
14.34
14.45
15.81
15.96
15.97
11.11
29.15

210 Stasevych et al.
TABLE 7 Data of the Synthesized Compounds
Formula mp ( ◦C)
1H NMR (δ, ppm)
IR (cm−1
)
4ad
4ba
C24H12N2S2O4 309–310
C28H28N2S2O4 >300
δ 7.63–8,29 (6H, m, ArH and NH2)
1.08 (12H, t, CH3), 3.41 (8H, q, CH2),
7.66; 7.56 (4H, td, CHAr), 8.12;8.05
1655 (C O), 1358 (tert-N)
1650 (C O), 1350 (tert-N)
(4H, dd, CHAr
)
4ca
C32H36N2S2O4 >300
0.84 (12H, t,3 JHH = 9.3 Hz, CH3), 1.32
(16H, m, CH2), 3.06 (8H, m, CH2),
8.03; 8.04 (4H, td, CHAr), 8.12;8.17
1655 (C O), 1360 (tert-N)
(4H, dd, CHAr
1.31 (12H, m, CH2), 3.71 (8H, m, CH2),
7.46; 7.78 (4H, td, CHAr), 7.98; 8.17
(4H, dd, CHAr
δ 3.49 (16H, m, CH2morpholine), 7.56; 7.67
)
4da
4ea
4fa
C30H28N2S2O4 >300
C28H24N2S2O6175
C32H20N2S2O4 >300
1620, 1656 (C O), 1340 (tert-N)
1612, 1648 (C O), 1355 (tert-N)
3160 ( NH ), 1610, 1650 (C O)
)
(4H, td, CHAr), 8.02;8.05 (4H, dd,
CHAr
)
δ 7.05 (10H, m, Ar), 7.33 (2H, s broad,
NH), 7.62; 7.82 (4H, td, CHAr), 7.66;
8.05 (4H, dd, CHAr
)
4ga
C32H18S2O4Cl2 270
6.94 (4H, d, 3 JHH = 8, 4 Hz, CHAr), 7.1
(4H, d, 3 JHH = 8.4 Hz, CHAr), 7.41
(2H, s broad, NH), 7.63; 7.70 (4H, td,
3160 ( NH ), 1612, 1648 (C O)
CHAr), 8.16; 8.19 (4H, dd, CHAr
7.65 (4H, tm, CHAr); 8.22 (4H, dd, CHAr
7.45; 7.79 (4H, td, CHAr), 7.92; 8.17 (4H,
dd, CHAr), 8.5 (2H, s broad, OH)
7.7 (4H, m, CHAr), 8.2, 8.16 (4H, dd,
)
5a
6b
C20H8S4O4 >300
C20H10S2O6 165–167
)
1650 (C O)
3535 (OH), 1652 (C O)
10b
C20H8S2Cl2O4 163–165
1660 (C O)
CHAr
)
14c
17b
C11H6SN2O2 210
C11H5SNO2 191
δ 7.63–8.29 (6H, m, ArH and NH2)
δ 7.79; 7.81 (2H, td, CHAr), 8.05; 8.15
(2H, dd, CHAr), 8.71 (1H, s broad, OH)
δ 7.63–8.29 (6H, m, ArH and NH2); 8.51
(1H, s, SH)
δ 1.08 (6H, t, CH3), 3.42 (4H, q, CH2),
7.56; 7.68 (2H, td, CHAr), 7.99; 8.03
(2H, dd, CHAr), 8.52 (1H, s, SH)
1655 (C O)
3540 (OH), 2100 (SCN), 1662 (C O)
18ad
18bd
C12H12SNO2 290–292
C14H15SNO2 245–247
2850 (SH), 1660 (C O), 1351 (tert-N)
2850 (SH), 1664 (C O), 1350 (tert-N)
18cd
C16H19SNO2 278
δ 0.89 (6H, t, 3 JHH = 9, 2 Hz, CH3),
1.28 (8H, m, CH2), 3.07 (4H, m, CH2),
7.56;7.65 (2H, td, CHAr), 7.98;8.08
(2H, dd, CHAr), 8.53 (1H, s, SH)
δ 1.31 (6H, m, CH2), 3.72 (4H, m, CH2),
7.6; 7.74 (2H, td, CHAr), 7.98; 8.03
(2H, dd, CHAr), 8.48 (1H,s,SH)
δ 3.51 (8H, m, CH2morpholine), 7.47;7.67
(2H, td, CHAr), 8.03;8.06 (2H, dd,
CHAr), 8.49 (1H,s,SH)
2858 (SH), 1658 (C O), 1360 (tert-N)
18dd
18ed
18fd
C15H15SNO2 197
C14H13SNO3 285
C16H11SNO2 281
2852 (SH), 1654 (C O), 1362 (tert-N)
2855 (SH), 1658 (C O), 1340 (tert-N)
3175 ( NH ), 2860 (SH), 1650 (C O)
δ 7.11 (5H, m, Ar), 7.35 (1H, s broad,
NH), 7.59; 7.77 (2H, td, CHAr),
7.61;8.11 (2H, dd, CHAr), 8.49 (1H, s,
SH)
18gd
C16H10SNO2 178–179
δ 6.98 (2H, d, 3 JHH = 8.3 Hz, CHAr),
7.2 (2H, d, 3 JHH = 8.4 Hz, CHAr),
7.42 (2H, s broad, NH), 7.66; 7.74 (2H,
td, CHAr), 8.13; 8.16 (2H, dd, CHAr),
8.47 (1H, s, SH)
3175 ( NH ), 2850 (SH), 1665 (C O)
19d
20d
C10H6SO3 175–177
C10H5SClO2 180
δ 7.65; 7.79 (2H, td, CHAr), 8.05; 8.11
(2H, dd, CHAr), 8.52 (1H, s, SH), 8.7
(1H, s broad, OH)
δ 7.79 (2H, m, CHAr), 8.08; 8.16 (2H, dd,
CHAr), 8.51 (1H,s,SH)
3540 (OH), 2864 (SH), 1662 (C O)
2860 (SH), 1650 (C O)
Recrystallization solvents: achlorobenzene, bbenzene/hexane, cbenzene, dDMF/ethanol.

Sulfur-Containing Derivatives of 1,4-Naphthoquinone, Part 1: Disulfide Synthesis 211
2-Amino-3-thiocyano-1,4-naphthoquinone (14)
filtrate was evaporated and oil residue was treated
with benzene for full dissolution; and then 10 (or
20) was precipitated by hexane, filtered, and dried
(see Table 6), Data of all synthesized compounds are
shown in Table 7.
from 2a. To a chloroform solution of 0.034 mol
2-amino-3-chloro-1,4-naphthoquinone was added
potassium thiocyanate. Mixture was warmed up for
3 h, cooled, filtered, the filtrate was left for night at
cooling then orange red crystals separated from it.
Compound 17 was transferred to potassium salt
of it in the ratio 1:1 and then was hydrolyzed simi-
larly to the method described for 14.
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[13] Fries, K.; Ochwat, P. Chem. Ber 1923, 56, 1291.
[14] Katritzky, A. R.; Fan, W. -Q. J Heterocycl Chem 1988,
25, 901–906.
[15] Koval, I. V. Uspekhi Khim 1993, 62, 813 (in Russian).
[16] Bock, H.; Pittmeyer, P. Phosphorus Sulfur Silicon Re-
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[17] Heydenreich, M.; Kuehn, J.; Runge, R.; Wenschuh, E.
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Method B. 0.024 mol of 2-amino-3-chloro-1,4-
naphthoquinone and 0.024 mol of thiocarbamide
were suspended and then brought to boil during 12 h.
Then solvent was evaporated in vacuo. Water solu-
tion of 0.109 mol of potassium hydroxide was added
to isothiuronic salt and was boiled for 6 h, filtered
the reaction mixture, a filtrate was acidified, crys-
tals was filtered and washed by diluted hydrochloric
acid, and dried (see Table 5).
The constants of compounds 18a,f obtained by
both methods match with those described earlier in
the literature [19].
Synthesis of Bis-[2-chloro-1,4-naphthoquinone]-
3-disulfide (10) and 2-Chloro-3-thiolo-
1,4-naphthoquinone (20)
[18] Shaikh, I. A.; Johnson, F.; Grollman, A. P. J Med Chem
1986, 29(8), 329.
[19] Brit. P., 1959, 814333, Cassella Farbwerke Mainkur
A. G.; C. A. 1959, 53, 20008.
[20] Brass, K.; Kohler, L. Chem. Ber 1921, 54, 594; Chem.
Ber 1922, 55, 2543.
0.005 mol of 6 (or 19) was suspended in 100 mL of
benzene, 0.01 mol of thionyl chloride, and few drops
of DMF were added. Mixture was left at heating
for day. Gradually disulfide passed in solution. The