Synthesis of 6-nitro-4-sulfanyl-1H-indole derivatives from 2,4,6-trinitrotoluene

Article abstract of DOI:10.1016/j.tet.2014.03.107

The synthesis of 6-nitro-4-sulfanyl-1H-indoles from 2,4,6-trinitrotoluene (TNT) is described. The first step is the nucleophilic substitution of an ortho-nitro group with a thiol to give the corresponding sulfide. The latter were transformed into the corr

Full text of DOI:10.1016/j.tet.2014.03.107

Tetrahedron 70 (2014) 3595e3600
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 6-nitro-4-sulfanyl-1H-indole derivatives from 2,4,6-
trinitrotoluene
Vladimir V. Rozhkov
The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov St., Kyiv 03187, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 6-nitro-4-sulfanyl-1H-indoles from 2,4,6-trinitrotoluene (TNT) is described. The first
step is the nucleophilic substitution of an ortho-nitro group with a thiol to give the corresponding sulfide.
The latter were transformed into the corresponding enamines upon treatment with dimethylformamide
dimethyl acetal (DMF DMA). The enamines were converted into the indoles applying the Batch-
oeLeimgruber synthetic protocol.
Received 4 February 2014
Received in revised form 19 March 2014
Accepted 31 March 2014
Available online 4 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2,4,6-Trinitrotoluene
Nucleophilic substitution
Enamines
BatchoeLiemgruber synthetic protocol
6-Nitro-4-sulfanyl-1H-indoles
1. Introduction
2. Results and discussion
The synthesis and reactivity of indole derivatives has been
a topic research since indole was first synthesized. The main reason
of such interest is the wide range of biological activity found among
indoles. The indole ring is present in the amino acid tryptophan;
indole-3-acetic acid is a plant growth hormone,1 while 3-(2-
aminoethyl)-5-hydroxyindole (serotonin) is one of the key neuro-
transmitters in animals.2 The indole ring is also present in many
natural products, such as the indole alkaloids,3 fungal metabolites,4
and marine natural products.5 Indoles having sulfur substituents in
position 4 have been shown to exhibit strong antibacterial activity.6
In connection with this, the development of synthetic methods for
preparation of indole derivatives with a programmed substitution
pattern is of significance for medicinal chemistry and drug dis-
covery. In this contribution we describe an efficient synthesis of 6-
nitroindoles bearing a sulfide substituent at position 4. The moti-
vation for the undertaken research is twofold. First, 4,6-
disubstituted indoles are generally difficult to synthesize. Second,
to suggest a way of a useful utilization of 2,4,6-trinitrotoluene in the
synthesis of the biologically potent heterocycles.
The first step of the synthesis is the nucleophilic substitution of
an ortho-nitro group in 2,4,6-trinitrotoluene with thiols in the
presence of K2CO3. This type of the nucleophilic substitution has
been studied in detail by Dutov and co-workers.7 It has been shown
that TNT reacts with thiols8,9 containing various substituents and
thiophenols.8,10 The reaction occurred with primary thiols, sec-
ondary thiols (propane-2-thiol, ethyl 2-mercaptopropanoate,11
cyclohexanethiol), and with 2-aminothiophenol.
Consequently, for the reaction we selected both simple thiols
(thiophenol) and thiols containing functional groups such as hy-
droxy group, protected amino group, and carbomethoxy group.
Also we have examined a possibility to substitute the ortho-nitro
group with dithiols. For this purpose, ethane-1,2-dithiol was used.
The reaction of TNT with thiols proceeded smoothly at 20e25 ꢀC in
an aprotic polar solvent, e.g. DMF, NMP, HMPTA (Scheme 1).
The NMR analysis of the crude product showed the presence of
i
the para-isomer (3e5%) but its re-crystallization from PrOH or
MeCN allowed isolation of the desired ortho-product in 70e85%
isolated yields.
In present paper a facile synthesis of 6-nitro-4-sulfanyl-1H-in-
dole derivatives from 2,4,6-trinitrotoluene has been developed. The
method consists of 3 steps and involves cheap commercially
available reagents.
The compounds 1aei readily reacted with dimethylformamide
dimethyl acetal in toluene at 80 ꢀC to furnish enamines 2aef and 2i
with 80e90% isolated yields (Scheme 2). The synthesized enamines
are dark red solids readily soluble in toluene, DCM, and alcohol. The
high purity (>92%) of the isolated products allowed compounds
2aef and 2i to be used in the next step without further purification.
E-mail address: vladimir_rozhkov@mail.ru.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.107

3596
V.V. Rozhkov / Tetrahedron 70 (2014) 3595e3600
Scheme 4. The reaction of compound 1g with DMF DMA. Yields (%) given in brackets.
On the basis of the above experimental evidence the retro-Michael
mechanism was proposed for the formation of 4,6-
dinitrobenzothiophene 4 (Scheme 5). The presence of methyl ac-
rylate detected by 1H NMR analysis of the reaction mixture is an-
other evidence of the suggested mechanism.
Scheme 1. The preparation of 4,6-dinitro-2-sulfanyltoluene derivatives. Yields (%)
given in brackets.
Scheme 5. The plausible mechanism of the formation of 4,6-dinitrobenzothiophene 4.
A reaction of sulfide 1h with DMF DMA gave no individual
product but a complex mixture. However, product 1h was utilized
as a precursor for the synthesis of sulfonyl chloride 6. It readily
reacted with N-chlorosuccinimide in the presence of HCl to furnish
the corresponding sulfonyl chloride (Scheme 6). Unlike formerly
reported multistep preparation13e15 of compound 6 our method
gave the product in two steps from easily available TNT in 85%
isolated yield.
Scheme 2. The preparation of enamine 2. Yields (%) given in brackets.
The analytically pure samples of
crystallization from CHCl3/hexane.
2 were obtained by re-
To transform the enamines into the corresponding indoles the
BatchoeLiemgruber synthetic protocol was applied (Scheme 3).12
The reaction was carried out in a mixture of CH2Cl2/MeOH (1:1)
with tin(II) chloride as a reducing agent. Tin(II) chloride was used
for two reasons. First, the tin salt did not affect the para-nitro group
of the enamine. Second, the reaction proceeded at room tempera-
ture. Upon treatment with SnCl2$2H2O enamines 2aef and 2i were
transformed into the corresponding indoles with yields over 50%.
Scheme 6. Synthesis of sulfonamide 7 and its transformation into indole 9. Yields (%)
given in brackets.
Sulfonyl chloride 6 was examined in the synthesis of sulfon-
amides. For this, morpholine was used as an example. The reaction
proceeded in water/THF at room temperature in the presence of
NaHCO3 yielding sulfonamide 7 in 97% yield. It also was converted
into corresponding indole 9 using the BatchoeLiemgruber syn-
thetic protocol in a good yield.
Scheme 3. The LiemgrubereBatcho synthesis of indoles 3. Yields (%) given in brackets.
Compounds 1g, h did not react properly with dimethylforma-
mide dimethyl acetal. Heating of sulfide 1g with DMF DMA in tol-
uene gave formerly unknown 4,6-dinitrobenzothiophene 4 and
aldehyde 5 (Scheme 4). Compounds 4 and 5 were easily separated
by chromatography and product 4 was obtained in a good yield.
Aldehyde 5 slowly decomposed upon standing at room tempera-
ture. Therefore, it was characterized only by NMR spectroscopy.
Most likely, product 5 is a result of a silica gel mediated hydrolysis
of the corresponding enamine.
3. Conclusions
The reaction of TNT with thiols(thiophenol) provides
2
substituted 4,6-dinitrotoluenes, which can be transformed into 6-

V.V. Rozhkov / Tetrahedron 70 (2014) 3595e3600
3597
nitro-4-sulfanyl-1H-indoles by BatchoeLiemgruber indole synthe-
sis. Benzyl(2-methyl-3,5-dinitrophenyl)sulfane 1h has been con-
verted into 4-((2-methyl-3,5-dinitrophenyl)sulfonyl)morpholine 7,
which also has been turned into the corresponding indole. The
method shows a versatility of TNT for the synthesis of the bi-
ologically potent compounds. The obtained indoles can be useful
scaffolds for medicinal chemistry.
NMR (125 MHz, CDCl3)
d
(ppm): 150.7, 145.8, 143.3, 137.1, 123.0,
115.6, 60.5, 35.8, 16.58. nmax (KBr): 3350 (OH), 3100 (CH), 2950 (CH),
2890 (CH), 1580 (NO2), 1520 (NO2), 1390 (NO2) cmꢁ1. Anal. found %:
C 41.89; H 3.91; N 10.91; S 12.51; Anal. Calcd for C9H10N2O5S %: C,
41.86; H, 3.90; N, 10.85; S, 12.42.
4.2.5. tert-Butyl (2-((2-methyl-3,5-dinitrophenyl)thio)ethyl)carba-
mate (1f). Yield: 5.7 g, 72%; mp¼120e122 ꢀC. 1H NMR (500 MHz,
4. Experimental
4.1. General
CDCl3) d (ppm): 8.37 (1H, d, J 2.1 Hz, Harom), 8.32 (1H, d, J 2.1 Hz,
H
arom), 4.96 (1H, br, NH), 3.47 (2H, m, SCH2CH2NHBoc), 3.25(2H, t, J
6.2 Hz, SCH2CH2NHBoc), 2.56 (3H, s, Me), 1.45 (9H, s, tBu). 13C NMR
(125 MHz, CDCl3) (ppm): 155.7, 150.8, 146.0, 143.0, 137.0, 122.9,
d
1H and 13C NMR were recorded on a Bruker Avance DRX500
spectrometer (500 MHz and 125 MHz, respectively). Chemical
115.6, 80.1, 39.2, 33.3, 28.4, 16.6. nmax (KBr): 3290 (NH), 3070 (CH),
2980 (CH), 1680 (C]O), 1530 (NO2), 1370(NO2) cmꢁ1. Anal. found %:
C 47.09; H 5.41; N 11.81; S 9.05; Anal. Calcd for C14H19N3O6S %: C,
47.05; H, 5.36; N, 11.76; S, 8.97.
shifts are reported in
d values from TMS as internal standard (s,
singlet; d, doublet; m, multiplet; q, quartet; t, triplet; br, broad
signal). Coupling constants (J) are given in hertz. Melting points
measured with a Buchi melting point apparatus. IR spectra were
recorded on a Vertex 70 spectrometer. tert-Butyl(2-sulfanylehtyl)
carbamate, compounds 1d and h were synthesized according to
Refs. 16,9,10, respectively.
4.2.6. Methyl
3-((2-methyl-3,5-dinitrophenyl)thio)propanoate
(1g). Yield: 5.0 g, 75%; mp¼89e93 ꢀC. 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.40 (1H, d, J 2.1 Hz, Harom), 8.27 (1H, d, J 2.1 Hz, Harom),
3.76 (3H, s, OMe), 3.37 (2H, t, J 7.1 Hz, SCH2CH2CO2Me), 2.78(2H, t, J
7.1 Hz, SCH2CH2CO2Me), 2.56 (3H, s, Me). 13C NMR (125 MHz, CDCl3)
4.2. General procedure for the synthesis of 4,6-dinitro-2-
sulfanyltoluenes 1
d (ppm): 171.2, 150.8, 145.9, 142.9, 137.2, 123.1, 115.8, 55.2, 33.0, 28.1,
16.6. nmax (KBr): 3090 (CH), 1740 (C]O), 1530 (NO2), 1350 (NO2)
cmꢁ1. Anal. found %: C 43.96; H 4.10; N 9.41; S 10.73; Anal. Calcd for
To a solution of 2,4,6-trinitrotoluene (5 g, 0.022 mol) and a cor-
responding thiol (0.022 mol) in 50 mL of DMF K2CO3 (3.1 g,
0.022 mol) was added. The mixture was stirred at room tempera-
ture for 2 h (TLC monitoring) and poured into 500 mL of 5% HCl. The
precipitate was collected by filtration and re-crystallized from
iPrOH (in case of 1i from MeCN) to give an analytically pure prod-
ucts 1.
C11H12N2O6S %: C, 44.00; H, 4.03; N, 9.33; S, 10.68.
4.2.7. 1,2-Bis((2-methyl-3,5-dinitrophenyl)thio)ethane (1i). Yield:
8.5 g, 85%; mp¼195e197 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm):
8.49 (2H, d, J 2.2 Hz, Harom), 8.31 (2H, d, J 2.2 Hz, Harom), 3.57 (4H, s,
SCH2CH2S), 2.45 (6H, s, Me). 13C NMR (125 MHz, DMSO-d6)
d (ppm):
150.8, 146.2, 141.6, 137.1, 124.7, 116.4, 31.9,16.7. nmax (KBr): 3090
(CH), 1580 (NO2), 1340 (NO2) cmꢁ1. Anal. found %: C 42.25; H 3.15; N
12.39; S 14.16; Anal. Calcd for C16H14N4O8S2 %: C, 42.29; H, 3.11; N,
12.33; S, 14.11.
4.2.1. Methyl(2-methyl-3,5-dinitrophenyl)sulfane (1a). Yield: 3.9 g,
78%; mp¼95e97 ꢀC. 1H NMR (500 MHz, CDCl3)
d (ppm): 8.37 (1H, d,
J 2.0 Hz, Harom), 8.15 (1H, d, J 2.0 Hz, Harom), 2.66 (3H, s, SMe), 2.54
(3H, s, Me). 13C NMR (125 MHz, CDCl3)
d (ppm): 150.4, 146.1, 145.4,
135.6, 120.5, 114.7, 16.1, 15.7. nmax (KBr) 3070 (CH), 2980 (CH), 1530
(NO2), 1340 (NO2) cmꢁ1. Anal. found %: C 42.18; H 3.61; N 12.23; S
14.11; Anal. Calcd for C8H8N2O4S %: C, 42.10; H, 3.53; N, 12.27; S,
14.05.
4.3. General procedure for the synthesis of enamines 2
To a solution of 4,6-dinitro-2-sulfanyltoluenes 1 (0.01 mol) in
30 mL of toluene 1,1-dimethoxy-N,N-dimethylmethanamine (3.6 g,
0.03 mol) (in case of 1i 7.2 g (0.06 mol) of 1,1-dimethoxy-N,N-
dimethylmethanamine was used) was added. The mixture was
stirred at 80 ꢀC for 72 h and the solvent was evaporated in vacuo.
The product was recrystallized from hexane/CHCl3 (1:1) (in case of
2i from CHCl3). All enamines showed in IR spectra a broad band
4.2.2. Ethyl(2-methyl-3,5-dinitrophenyl)sulfane (1b). Yield: 4.3 g,
81%; mp¼72e74 ꢀC. 1H NMR (500 MHz, CDCl3)
d (ppm): 8.35 (1H, d,
J 2.1 Hz, Harom), 8.20 (1H, d, J 2.1 Hz, Harom), 3.14 (2H, q, J 7.3 Hz,
SCH2CH3), 2.54 (3H, s, Me), 1.47 (3H, t, J 7.3 Hz, SCH2CH3). 13C NMR
(125 MHz, CDCl3)
d
(ppm): 150.6, 145.9, 144.2, 136.4, 121.9, 114.9,
from 3600 to 2200 cmꢁ1
.
27.0, 16.4, 13.2. nmax (KBr): 3090 (CH), 2990 (CH), 1580 (NO2), 1530
(NO2), 1340 (NO2) cmꢁ1. Anal. found %: C 44.69; H 4.22; N 11.51; S
13.29; Anal. Calcd for C9H10N2O4S %: C, 44.62; H, 4.16; N, 11.56; S,
13.24.
4.3.1. (E)-N,N-Dimethyl-2-(2-(methylthio)-4,6-dinitrophenyl)ethen-
amine (2a). Yield: 2.4 g, 86%; mp¼93e95 ꢀC. 1H NMR (500 MHz,
CDCl3)
d (ppm): 8.19 (1H, d, J 2.1 Hz, Harom), 8.01 (1H, d, J 2.1 Hz,
H
arom), 6.95 (1H, d, J 13 Hz, HC]CH), 5.19 (1H, d, J 13 Hz, HC]CH),
4.2.3. (2-Methyl-3,5-dinitrophenyl)(propyl)sulfane (1c). Yield: 4.7 g,
2.97 (6H, s, NMe2), 2.58 (3H, s, SMe). 13C NMR (125 MHz, CDCl3)
83%; mp¼89e91 ꢀC. 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.34 (1H, d,
d (ppm): 148.1, 146.2, 141.6, 139.9, 137.5, 120.9, 116.2, 87.2, 40.8, 16.6.
J 2.1 Hz, Harom), 8.19 (1H, d, J 2.1 Hz, Harom), 3.06 (2H, t, J 7.1 Hz,
SCH2CH2CH3), 2.53 (3H, s, Me), 1.81 (2H, m, SCH2CH2CH3), 1.13 (3H,
nmax (KBr) 1560 (NO2), 1510 (NO2), 1330 (NO2) cmꢁ1. Anal. found %:
C 46.69; H 4.71; N 14.79; S 11.29; Anal. Calcd for C11H13N3O4S %: C,
46.63; H, 4.63; N, 14.83; S, 11.32.
t, J 7.3 Hz, SCH2CH2CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 150.7,
145.9, 144.4, 136.4, 122.1, 114.9, 34.9, 21.6, 16.4, 13.5. nmax (KBr) 3080
(CH), 2990 (CH), 1540 (NO2), 1340(NO2) cmꢁ1. Anal. found %: C
46.89; H 4.81; N 11.61; S 12.59; Anal. Calcd for C10H12N2O4S %: C,
46.87; H, 4.72; N, 11.56; S, 12.51.
4.3.2. (E)-2-[2-(Ethylsulfanyl)-4,6-dinitrophenyl]-N,N-dimethyle-
thenamine (2b). Yield: 2.6 g, 88%; mp¼95e97 ꢀC. 1H NMR
(500 MHz, CDCl3) d (ppm): 8.18 (1H, d, J 2.0 Hz, Harom), 8.07 (1H, d, J
2.0 Hz, Harom), 6.94 (1H, d, J 13.4 Hz, HC]CH), 5.23 (1H, d, J 13.4 Hz,
HC]CH), 3.05 (2H, q, J 7.3 Hz, SCH2CH3), 2.97 (6H, s, NMe2), 1.41
4.2.4. 2-((2-Methyl-3,5-dinitrophenyl)thio)ethanol (1e). Yield: 4.1 g,
72%; mp¼70e72 ꢀC. 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.38 (1H, d,
(3H, t, J 7.3 Hz, SCH2CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 148.2,
J 2.2 Hz, Harom), 8.34 (1H, d, J 2.2 Hz, Harom), 3.99 (2H, t, J 6.3 Hz,
146.3, 141.2, 138.2, 138.2, 122.8, 116.6, 87.6, 40.8, 27.7, 13.3. nmax
SCH2CH2OH), 3.33 (2H, t, J 6.3 Hz, SCH2CH2OH), 2.58 (3H, s, Me). 13
C
(KBr) 1550 (NO2), 1510 (NO2), 1330 (NO2), 1310 (NO2) cmꢁ1. Anal.

3598
V.V. Rozhkov / Tetrahedron 70 (2014) 3595e3600
found %: C 48.43; H 5.13; N 14.19; S 10.69; Anal. Calcd for
12H15N3O4S %: C, 48.47; H, 5.08; N, 14.13; S, 10.78.
layers were combined, and dried over Na2SO4. Sodium sulfate was
filtered off, the solvent was evaporated, and the crude product was
purified on silica gel using hexane/EtOAc as an eluent to furnish
pure indole 3.
C
4.3.3. (E)-2-(2,4-Dinitro-6-(propylthio)phenyl)-N,N-dimethylethen-
amine (2c). Yield: 2.5 g, 81%; mp¼85e89 ꢀC. 1H NMR (500 MHz,
CDCl3)
d
(ppm): 8.16 (1H, d, J 1.9 Hz, Harom), 8.07 (1H, d, J 1.9 Hz,
4.4.1. 4-(Methylthio)-6-nitro-1H-indole (3a). Yield: 1.4 g, 68%;
Harom), 6.95 (1H, d, J 13.5 Hz, HC]CH), 5.25 (1H, d, J 13.5 Hz, HC]CH),
mp¼155e158 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.03 (1H,
br, NH), 8.12 (1H, d, J 1.6 Hz, Harom), 7.92 (1H, d, J 3.0 Hz, Hind), 7.65
(1H, d, J 1.6 Hz, Harom), 6.48 (1H, d, J 3.0 Hz, Hind), 2.65 (3H, s, SMe).
2.99 (2H, q, J 7.2 Hz, SCH2CH2CH3), 2.97 (6H, s, NMe2), 1.77 (2H, m,
SCH2CH2CH3), 1.11 (3H, t, J 7.1 Hz, SCH2CH2CH3). 13C NMR (125 MHz,
CDCl3)
35.7, 21.7, 13.6. nmax (KBr) 1560 (NO2), 1520 (NO2), 1320 (NO2) cmꢁ1
Anal. found %: C 50.13; H 5.59; N 13.59; S 10.39; Anal. Calcd for
13H17N3O4S %: C, 50.15; H, 5.50; N, 13.50; S, 10.30.
d
(ppm): 148.2, 146.2, 141.1, 138.4, 139.3, 123.0, 116.6, 87.6, 40.8,
13C NMR (125 MHz, DMSO-d6)
d (ppm): 143.4, 132.4, 131.6, 130.6,
.
125.8, 109.2, 103.2, 96.3, 14.4. nmax (KBr) 3350 (NHind), 2970 (CH),
1540 (NO2), 1310 (NO2) cmꢁ1. Anal. found %: C 51.95; H 3.93; N
13.49; S 15.58; Anal. Calcd for C9H8N2O2S %: C, 51.91; H, 3.87; N,
13.45; S, 15.40.
C
4.3.4. (E)-2-[2,4-Dinitro-6-(phenylsulfanyl)phenyl]-N,N-dimethyle-
thenamine (2d). Yield: 2.7 g, 79%; mp¼100e104 ꢀC. 1H NMR
4.4.2. 4-(Ethylthio)-6-nitro-1H-indole (3b). Yield: 1.4 g, 65%,
(500 MHz, CDCl3)
d
(ppm): 8.21 (1H, d, J 1.8 Hz, Harom), 7.87 (1H, d, J
mp¼160e163 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.41
1.8 Hz, Harom), 7.44 (5H, m, Ph), 6.99 (1H, d, J 13.2 Hz, HC]CH), 5.33
(1H, br, NH), 8.09 (1H, d, J 1.7 Hz, Harom), 7.89 (1H, d, J 2.7 Hz, Hind),
7.72 (1H, d, J 1.7 Hz, Harom), 6.46 (1H, d, J 2.7 Hz, Hind), 3.16 (2H, q, J
7.6 Hz, SCH2CH3), 1.31 (3H, t, J 7.6 Hz, SCH2CH3). 13C NMR
(1H, d, J 13.2 Hz, HC]CH), 2.96 (6H, s, NMe2). 13C NMR (125 MHz,
CDCl3)
d (ppm): 148.6, 146.3, 141.0, 138.6, 137.5, 133.0, 132.1, 130.1,
129.1, 126.6, 117.9, 87.9, 40.8. IR (KBr): 1640 (NO2), 1580 (NO2), 1330
(NO2). Anal. found %: C 55.59; H 4.45; N 12.21; S 9.33; Anal. Calcd
for C16H15N3O4S %: C, 55.64; H, 4.38; N, 12.17; S, 9.28.
(125 MHz, DMSO-d6) d (ppm): 143.0, 131.7, 130.9, 130.1, 127.0,
111.5, 103.9, 96.4, 26.1, 14.4. nmax (KBr) 3380 (NHind), 3010 (CH),
1530 (NO2), 1340 (NO2), 1300 (NO2) cmꢁ1. Anal. found %: C 54.09;
H 4.59; N 12.64; S 14.51; Anal. Calcd for C10H10N2O2S %: C, 54.04;
H, 4.53; N, 12.60; S, 14.43.
4.3.5. (E)-2-((2-(2-(Dimethylamino)vinyl)-3,5-dinitrophenyl)thio)eth-
anol (2e). Yield: 2.5 g, 81%; mp¼76e79 ꢀC.1H NMR (500 MHz, CDCl3)
d
(ppm): 8.16 (1H, d, J 2.1 Hz, Harom), 8.07 (1H, d, J 2.1 Hz, Harom), 6.91
4.4.3. 6-Nitro-4-(propylthio)-1H-indole (3c). Yield: 1.6 g, 69%;
(1H, d, J 13.5 Hz, HC]CH), 5.25 (1H, d, J 13.5 Hz, HC]CH), 3.92 (2H, t,
J 6.8 Hz, SCH2CH2OH), 3.22 (2H, t, J 6.8 Hz, SCH2CH2OH), 2.97 (6H, s,
mp¼84e87 ꢀC. 1H NMR (500 MHz, CDCl3)
d (ppm): 12.39 (1H, br,
NH), 8.11 (1H, d, J 1.8 Hz, Harom), 7.73 (1H, d, J 2.9 Hz, Hind), 7.49 (1H,
d, J 1.8 Hz, Harom), 6.49 (1H, d, J 2.9 Hz, Hind), 3.05 (2H, t, J 7.8 Hz,
SCH2CH2CH3), 1.75 (2H, m, SCH2CH2CH3), 1.09 (3H, t, J 6.9 Hz,
NMe2). 13C NMR (125 MHz, CDCl3)
d (ppm): 149.7, 144.8, 142.3, 141.2,
132.1, 130.6, 119.0, 106.6, 61.5, 42.8, 35.6. nmax (KBr) 3070 (OH), 1560
(NO2), 1510 (NO2), 1340 (NO2) cmꢁ1. Anal. found %: C 46.03; H 4.73; N
13.49; S 10.39; Anal. Calcd for C12H15N3O5S %: C, 46.00; H, 4.83; N,
13.41; S, 10.23.
SCH2CH2CH3). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 143.2, 140.0,
131.1, 130.7, 127.6, 112.5, 103.6, 97.4, 34.6, 22.3, 14.5. nmax (KBr) 3250
(NHind), 2980 (CH), 1530 (NO2), 1340 (NO2) cmꢁ1. Anal. found %: C
55.96; H 5.17; N 11.91; S 15.61; Anal. Calcd for C11H12N2O2S %: C,
55.91; H, 5.12; N, 11.86; S, 13.57.
4.3.6. (E)-tert-Butyl (2-((2-(2-(dimethylamino)vinyl)-3,5-
dinitrophenyl)thio)ethyl)carbamate (2f). Yield: 3.6 g, 87%;
mp¼130e133 ꢀC. 1H NMR (500 MHz, CDCl3)
d
(ppm): 8.20 (1H, d, J
4.4.4. 6-Nitro-4-(phenylthio)-1H-indole (3d). Yield: 1.6 g, 61%;
2.0 Hz, Harom), 8.17 (1H, d, J 2.0 Hz, Harom), 6.95 (1H, d, J 13.5 Hz,
HC]CH), 5.30 (1H, d, J 13.5 Hz, HC]CH), 4.90 (1H, br, NH), 3.41 (2H,
mp¼120e124 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.01 (1H,
br, NH), 8.25 (1H, d J 1.2 Hz, Harom), 7.97 (1H, d, J 3.1 Hz, Hpyrr), 7.67
(1H, d J 1.2 Hz, Harom), 7.42e7.39 (5H, m, Ph), 6.40 (1H, d, J 3.1 Hz,
br, SCH2CH2NHBoc), 3.14 (2H, t, J 7.0 Hz, SCH2CH2NHBoc), 2.99 (6H,
t
s, NMe2), 1.25 (9H, s, Bu). 13C NMR (125 MHz, CDCl3)
d
(ppm):
H d (ppm): 142.9, 133.1, 132.5,
pyrr). 13C NMR (125 MHz, DMSO-d6)
155.64, 148.6, 146.1, 140.9, 139.2, 136.3, 124.8, 117.5, 87.6, 79.7, 40.8,
39.2, 34.2, 28.4. nmax (KBr) 1690 (C]O),1560 (NO2), 1520 (NO2),
1330 (NO2), 1310 (NO2) cmꢁ1. Anal. found %: C 49.54; H 5.93; N
13.59; S 7.72; Anal. Calcd for C17H24N4O6S %: C, 49.50; H, 5.86; N,
13.58; S, 7.77.
131.9, 131.4, 130.2, 128.6, 128.3, 127.9, 115.7, 105.4, 97.0. nmax (KBr)
3340 (NHind), 1520 (NO2), 1330 (NO2), 1300 (NO2). Anal. found %: C
62.25; H 3.76; N 10.40; S 11.92; Anal. Calcd for C14H10N2O2S %: C,
62.21; H, 3.73; N, 10.36; S, 11.86.
4.4.5. 2-((6-Nitro-1H-indol-4-yl)thio)ethanol (3e). Yield: 1.7 g, 72%;
4.3.7. (1E,10E)-2,20-((Ethane-1,2-diylbis(sulfanediyl))bis(2,4-dinitro-
mp¼135e139 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.04 (1H,
6,1-phenylene))bis(N,N-dimethylethenamine)(2i). Yield: 4.9 g, 89%;
br, NH), 8.14 (1H, d, J 1.3 Hz, Harom), 7.93 (1H, d, J 2.9 Hz, Hpyrr), 7.82
(1H, d, J 1.3 Hz, Harom), 6.52 (1H, d, J 2.9 Hz, Hpyrr), 5.07 (1H, t, J
5.2 Hz, OH), 3.66 (2H, dd, SCH2CH2OH), 3.23 (2H, t, J 4.5 Hz,
mp¼165e168 ꢀC. 1H NMR (500 MHz, CDCl3)
d (ppm): 8.21 (2H, d, J
2.1 Hz, Harom), 8.14 (2H, d, J 2.1 Hz, Harom), 6.94 (2H, d, J 14.2 Hz,
HC]CH), 5.30 (2H, d, J 14.2 Hz, HC]CH), 3.24 (4H, s, SCH2CH2S),
SCH2CH2OH). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 143.1, 131.7,
2.98 (12H, s, NMe2). 13C NMR (125 MHz, DMSO-d6)
d
(ppm): 149.5,
130.8, 130.4, 127.1, 111.8, 103.8, 96.6, 60.2, 34.9. nmax (KBr) 3390
(NHind), 3190 (OH), 1530 (NO2), 1350 (NO2), 1310 (NO2) cmꢁ1. Anal.
found %: C 50.46; H 4.29; N 11.81; S 13.51; Anal. Calcd for
145.5, 140.3, 139.0, 135.1, 125.3, 118.1, 87.1, 79.7, 40.3 (inside of
DMSO multiplet), 32.2. nmax (KBr) 1570 (NO2), 1520 (NO2), 1330
(NO2) cmꢁ1. Anal. found %: C 46.83; H 4.33; N 12.19; S 11.43; Anal.
Calcd for C22H24N6O8S2 %: C, 46.80; H, 4.28; N, 12.17; S, 11.36.
C10H10N2O3S %: C, 50.41; H, 4.23; N, 11.76; S, 13.46.
4.4.6. tert-Butyl
(2-((6-nitro-1H-indol-4-yl)thio)ethyl)carbamate
4.4. General procedure for the synthesis of indoles 3
(3f). Yield: 2.2 g, 65%; mp¼138e140 ꢀC. 1H NMR (500 MHz, DMSO-
d6) d (ppm): 12.02 (1H, br, NH), 8.17 (1H, d, J 1.3 Hz, Harom), 7.94 (1H,
To a solution of enamine 2 (0.01 mol) in a mixture of MeOH/
CH2Cl2 (50 mL, 1:1 ratio) SnCl2$2H2O (6.8 g, 0.04 mol) was added in
one portion. The mixture was stirred at room temperature over-
night and poured into 500 mL of H2O. The organic layer was sep-
arated, the water layer extracted with EtOAc (3ꢂ25 mL), the organic
d, J 3.1 Hz, Hpyrr), 7.85 (1H, d, J 1.3 Hz, Harom), 7.05 (1H, br, NH), 6.52
(1H, d, J 3.1 Hz, Hpyrr), 3.19 (4H, br, SCH2CH2NHBoc), 1.37 (9H, s, tBu).
13C NMR (125 MHz, DMSO-d6)
d (ppm): 156.0, 143.1, 131.9, 130.9,
129.6, 127.5, 112.7, 104.1, 96.7, 78.3, 32.1, 28.7. nmax (KBr) 3440
(NHind), 3195 (NH), 3000 (NH), 1700 (C]O), 1530 (NO2), 1330 (NO2)

V.V. Rozhkov / Tetrahedron 70 (2014) 3595e3600
3599
cmꢁ1. Anal. found %: C 50.46; H 5.74; N 12.51; S 9.54; Anal. Calcd for
15H19N3O4S %: C, 50.40; H, 5.68; N, 12.45; S, 9.50.
1.9 Hz, Harom), 8.74 (1H, d, J 1.9 Hz, Harom), 3.64 (4H, br, CH2OCH2),
3.22 (4H, br, CH2NCH2), 2.72 (3H, s, Me). 13C NMR (125 MHz, DMSO-
d6): 152.7, 146.0, 139.6, 138.3, 128.0, 123.6, 66.1, 45.6, 16.1. nmax
(KBr): 3079 (CH), 2863 (CH), 1539 (NO2), 1350 (NO2), 1353 (NO2),
1173 (S]O), 1147 (S]O), 1107 (S]O) cmꢁ1. Anal. found %: C 39.86;
H 3.91; N 12.62; S 9.59; Anal. Calcd for C11H13N3O7S %: C, 39.88; H,
3.96; N, 12.68; S, 9.68.
C
4.4.7. 1,2-Bis((6-nitro-1H-indol-4-yl)thio)ethane (3i). Yield: 2.8 g,
67%; mp¼110e114 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.04
(2H, br, NH), 8.15 (2H, d, J 1.5 Hz, Harom), 7.92 (2H, d, J 2.9 Hz, Hpyrr),
7.85 (2H, d, J 1.5 Hz, Harom), 6.49 (2H, d, J 2.9 Hz, Hpyrr), 3.39 (4H, s,
SCH2CH2S). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 142.9, 132.0,
131.0, 128.3, 127.8, 113.6, 104.5, 96.7, 32.2. nmax (KBr) 3410 (NHind),
1550 (NO2), 1320 (NO2) cmꢁ1. Anal. found %: C 52.19; H 3.44; N
13.59; S 15.54; Anal. Calcd for C18H14N4O4S2 %: C, 52.16; H, 3.40; N,
13.52; S, 15.47.
4.8. (E)-N,N-Dimethyl-2-(2-(morpholinosulfonyl)-4,6-
dinitrophenyl)ethenamine 8
To a solution of compound 7 (2 g, 0.006 mol) in 30 mL of toluene
1,1-dimethoxy-N,N-dimethylmethanamine (2.14 g, 0.018 mol) was
added. The mixture was stirred at 80 ꢀC for 72 h and the solvent was
evaporated in vacuo. The product 8 was re-crystallized from hex-
ane/CHCl3 (1:1). Yield: 1.5 g, 75%; mp¼182e184 ꢀC. 1H NMR
4.5. 4,6-Dinitrobenzo[b]thiophene 4 and methyl 3-((3,5-
dinitro-2-(2-oxoethyl)phenyl)thio)propanoate 5
A solution of compound 1g (2 g, 0.007 mol) and 1,1-dimethoxy-
N,N-dimethylmethanamine (2.5 g, 0.021 mol) was stirred in 30 mL
of toluene at 80 ꢀC for 72 h. The solvent was evaporated and the
residue was chromatographed on silica gel eluting with hexane/
EtOAc (4:1) to give thiophene 4, and then gradually increasing the
eluent ratio to 2:1 to obtain aldehyde 5.
(500 MHz, CDCl3) d (ppm): 8.78 (1H, d J 2.0 Hz, Harom), 8.40 (1H, d, J
2.0 Hz, Harom), 6.87 (1H, d, J 13 Hz, CH]CH), 5.85 (1H, d, J 13 Hz,
CH]CH), 3.74 (4H, br, CH2OCH2), 3.27 (4H, br, CH2NCH2), 3.04 (6H,
s, NMe2). 13C NMR (125 MHz, CDCl3)
d (ppm): 149.6, 146.9, 139.1,
138.9, 133.9, 128.6, 123.5, 87.9, 66.4, 66.0, 45.9. nmax (KBr) 1570
(NO2), 1320 (NO2) cmꢁ1. Anal. found %: C 43.55; H 4.75; N 14.55; S
8.23; Anal. Calcd for C14H18N4O7S %: C, 43.52; H, 4.70; N, 14.50; S,
8.30.
4.5.1. 4,6-Dinitrobenzo[b]thiophene (4). Yield: 1.1 g, 69%;
mp¼159e162 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 9.61 (1H,
d, J 0.8 Hz, Harom), 8.95 (1H, d, J 0.8 Hz, Harom), 8.65 (1H, d, J 5.5 Hz,
H
thiop), 8.20 (1H, d, J 5.5 Hz, Hthiop). 13C NMR (125 MHz, DMSO-d6)
4.9. 4-((6-Nitro-1H-indol-4-yl)sulfonyl)morpholine 9
d
(ppm): 143.2, 143.1, 142.1, 142.8, 136.3, 126.0, 122.9, 117.3, 79.7.
nmax (KBr) 3110 (CH), 1520 (NO2), 1350 (NO2), 1310 (NO2), 790
(thiophene). Anal. found %: C 42.86; H 1.83; N 12.58; S 14.39; Anal.
Calcd for C8H4N2O4S %: C, 42.86; H, 1.80; N, 12.50; S, 14.30.
To a solution of enamine 8 (1 g, 2.59 mmol) in a mixture of
MeOH/CH2Cl2 (25 mL, 1:1 ratio) SnCl2$2H2O (2.33 g, 10.36 mmol)
was added in one portion. The mixture was stirred at room tem-
perature overnight and poured into 300 mL of H2O. The organic
layer was separated, the water layer extracted with EtOAc
(3ꢂ25 mL), the organic layers were combined, and dried over
Na2SO4. Sodium sulfate was filtered off, the solvent was evaporated,
and the crude product was purified on silica gel using hexane/
EtOAc (4:1) as an eluent to furnish pure indole 9. Yield: 0.5 g, 65%;
4.5.2. 3-((3,5-Dinitro-2-(2-oxoethyl)phenyl)thio)propanoate
(5). Yield: 0.2 g,10%. 1H NMR (500 MHz, CDCl3)
d (ppm): 9.82 (1H, s,
CHO), 8.66 (1H, d, J 1.82 Hz, Harom), 8.48 (1H, d, J 1.82 Hz, Harom),
4.42 (2H, s, CH2CHO), 3.74 (3H, s, OCH3), 3.34 (2H, t, J 7.0 Hz, SCH2),
2.72 (2H, t, J 7.0 Hz, CH2CO2CH3). 13C NMR (125 MHz, CDCl3): 194.7,
171.2, 150.5, 146.7, 143.5, 134.4, 126.5, 117.4, 52.1, 45.0, 33.1, 29.7.
mp¼245e247 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d (ppm): 12.37 (1H,
br, NH), 8.58 (1H, d, J 2.0 Hz, Harom), 8.20 (2H, Harom and Hpyrr), 6.84
(1H, d, J 2.9 Hz, Hpyrr), 3.60 (4H, br, CH2OCH2), 3.01 (4H, br,
4.6. 2-Methyl-3,5-dinitrobenzene-1-sulfonyl chloride 6
CH2NCH2). 13C NMR (125 MHz, DMSO-d6)
d (ppm): 141.5, 134.5,
To a mixture of benzyl(2-methyl-3,5-dinitrophenyl)sulfane 1h
(5 g, 0.016 mol) in 10 mL of glacial AcOH and 10 mL (0.1 mol) conc.
HCl N-chlorosuccinimide (3.2 g, 0.024 mol) was added in small
portions at 0e5 ꢀC. The mixture was stirred at room temperature
for 5 h and triturated with 100 mL of cold water. The water layer
was decanted; the residue was washed with cold water (3ꢂ50 mL)
with hexane (3ꢂ50 mL) and collected by filtration. The solid was
dried and used without further purification. The analytically pure
sample was obtained by re-crystallization from benzene/hexane
(1:1). Yield: 4.3 g, 95%; mp¼110e112 ꢀC. 1H NMR (500 MHz, CDCl3)
132.9, 126.7, 124.4, 116.2, 110.4, 98.6, 65.9, 46.3. nmax (KBr) 3440
(NHind), 3160 (SO2N), 2940 (SO2N), 1520 (NO2), 1480 (NO2), 1270
(NO2) cmꢁ1. Anal. found %: C 46.35; H 4.25; N 13.55; S 10.23; Anal.
Calcd for C12H13N3O5S %: C, 46.30; H, 4.21; N, 13.50; S, 10.30.
References and notes
1. Schneiderland, E. A.; Wrightman, F. Phytohorm. Relat. Compds. Compr. Treatise
1978, 1, 29.
2. Biology of Serotonergic Transmission; Osborne, N. N., Ed.; Jonh Wiley & Son:
Chichester, UK, 1982.
d
(ppm): 9.17 (1H, d J 2.0 Hz, Harom), 8.90 (1H, d, J 2.0 Hz, Harom), 3.01
3. Southon, I. W.; Buckingham, J. Dictionary of Alkaloids InSaxton, J. E., Ed..
Chemistry of Heterocyclic Compounds; Chapman and Hall: London, UK,
1989e1994; Vol. 25.
4. Betina, V. Dev. Food Sci. 1984, 8, 415.
5. Christophersen, C. Alkaloids 1985, 24, 25; Mar. Nat. Prod. Chem. Biol. Perspect.
(3H, s, Me). 13C NMR (125 MHz, CDCl3)
d
(ppm): 152.6, 146.0, 145.6,
139.2, 126.7, 124.5, 16.1. nmax (KBr): 3095 (CH), 1538 (NO2), 1374
(NO2), 1353 (NO2), 1150 (SO2Cl) cmꢁ1. Anal. found %: C 30.01; H
1.75; N 9.95; S 11.43; Anal. Calcd for C7H5ClN2O6S %: C, 29.96; H,
1.80; N, 9.98; S, 11.43.
1983, 5, 391.
6. Liang, H.-T.; Hsu, H.-D.; Chang, C.-P.; Ku, H.-E.; Wang, W.-S. Hua Hsuesh Hsuesh
Pao 1976, 34, 129; Chem. Abstr. 1977, 87, 1659482; Sci. Sin. (Engl. Ed.) 1977, 20,
106; Chem. Abstr. 1977, 87, 98565g; Brown, M. J.; Carter, P. S.; Fenwick, A. E.;
Fosberry, A. P.; Hamprecht, D. W.; Hibbs, M. J.; Jarvest, R. L.; Mensah, L.; Milner,
P. H.; O’Harlon, P. J.; Pope, A. J.; Richardson, C. M.; West, A.; Witty, D. Bioorg.
Med. Chem. Lett. 2002, 12, 3171.
7. Shevelev, S. A.; Dutov, M. D.; Serushkina, O. V. Russ. Chem. Bull. 1995, 44, 2424.
8. Zlotin, S. G.; Kistitsin, P. G.; Samet, A. V.; Serebryakov, E. A.; Konyushkin,
L. D.; Semenov, V. V.; Buchanan, A. C.; Gakh, A. A. J. Org. Chem. 2000, 65,
8430.
4.7. 4-((2-Methyl-3,5-dinitrophenyl)sulfonyl)morpholine 7
To a solution of NaHCO3 (5 g, 0.059 mol) and morpholine (0.61 g,
0.007 mol) in 100 mL of H2O a solution of sulfonyl chloride 4 (2 g,
0.007 mol) in 5 mL of THF was added at 0e5 ꢀC. The mixture was
stirred at 25 ꢀC for 1 h and the obtained precipitate was collected by
filtration to furnish pure sulfonamide 7. Yield: 1.9 g, 97%;
9. Serushkina, O. V.; Dutov, M. D.; Shevelev, S. A. Russ. Chem. Bull. 2001, 50, 261.
10. Serushkina, O. V.; Dutov, M. D.; Solkan, V. N.; Shevelev, S. A. Russ. Chem. Bull.
2001, 50, 2406.
mp¼185e187 ꢀC. 1H NMR (500 MHz, CDCl3)
d (ppm): 9.01 (1H, d, J

3600
V.V. Rozhkov / Tetrahedron 70 (2014) 3595e3600
11. Tartakovskii, V. A.; Shevelev, M. D.; Dutov, M. D.; Serushkina, O. V.; Kachala, V.
V. Russ. J. Org. Chem. 2003, 39, 397.
12. Batcho, A. D.; Leimgruber, W. U.S. Patent 3,976,639, 1976. Chem. Abstr. 1977, 86,
14. Hirwe, N. W.; Jambhekar, M. R. J. Indian Chem. Soc. 1934, 11, 239.
15. Piskov, V. B.; Oksanova, L. K.; Koblova, I. A. Zh. Org. Khim. 1969, 5, 1642 (in
Russian).
29624; Batcho, A. D.; Leimgruber. Org. Synth. 1985, 63, 214.
16. Saha, U. K.; Roy, R. J. Chem. Soc., Chem. Commun. 1995, 2571.
13. Dutov, M. D.; Serushkina, O. V.; Shevelev, S. A. Russ. J. Org. Chem. 2007, 43, 1167.