Synthesis of 2-Nitrothiophenes via Tandem Henry Reaction and Nucleophilic Substitution on Sulfur from β-Thiocyanatopropenals

Article abstract of DOI:10.1002/jhet.3446

A new synthetic route of 2-nitrothiophenes was described through a tetra-n-butylammonium fluoride-promoted or diisopropylethylamine-promoted tandem Henry reaction and nucleophilic substitution of nitromethane with 3-thiocyanatopropenals, which were conveniently prepared by the replacement reaction of 3-chloropropenals with potassium thiocyanate under a mild acidic condition.

Full text of DOI:10.1002/jhet.3446

Month 2019
Synthesis of 2-Nitrothiophenes via Tandem Henry Reaction and Nucleo-
philic Substitution on Sulfur from β-Thiocyanatopropenals
a
b
a
b
*
*
Lin Rong, Yingxia Shen, Guoxi Xiong, and Yuefa Gong
aTechnology Center of China Tabacco, Hubei Industrial Co. Ltd., Wuhan 430040, People’s Republic of China
bSchool of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road,
Wuhan 430074, People’s Republic of China
*E-mail: xionggx@hbtobacco.cn; gongyf@mail.hust.edu.cn
Received July 23, 2018
DOI 10.1002/jhet.3446
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A new synthetic route of 2-nitrothiophenes was described through a tetra-n-butylammonium fluoride-
promoted or diisopropylethylamine-promoted tandem Henry reaction and nucleophilic substitution of nitro-
methane with 3-thiocyanatopropenals, which were conveniently prepared by the replacement reaction of 3-
chloropropenals with potassium thiocyanate under a mild acidic condition.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
cyclic dienolates from cyclic β-haloenals under mild
conditions [21,22] and fluoride-promoted tandem reaction
between cyclic β-thiocyanatoenals and terminal electron-
deficient alkenes [23]. In this work, we designed an
alternative synthesis route of nitrothiophene through a
tandem Henry reaction and nucleophilic substitution on
sulfur of thiocyanate as outlined in Scheme 1b.
The structural motif of thiophene widely exists as a key
unit in naturally occurring products, pharmaceuticals, some
of the top-selling marketed drugs (Plavix, Spriva,
raloxifene, zileuton, and clopidogrel) [1–4], and
functional materials [5–9] owing to their structural
rigidity and specific electronic properties. Accordingly, a
variety of synthetic methodologies have been developed
for functionalized thiophenes [10,11]. Among these, the
representative method is classical PaalꢀKnorr reaction
[12,13], which involves sulfuration of the corresponding
1,4-dicarbonyl precursors using reagents such as H2S/
HCl, P2S5, and Lawesson’s reagent. In addition, the
Gewald reaction is applied to synthesis of 2-
aminothiophenes via a multicomponent condensation
between sulfur, an α-methylene carbonyl compound, and
an α-cyanoester [14–16]. An alternative method to access
substituted thiophenes involves the use of inorganic
sulfide salts as the sulfur source. For example, Xi’s group
described an approach to variously substituted thiophenes
through copper-catalyzed tandem S-alkenylation of
potassium sulfide with 1,4-diiodo-1,3-dienes [17]. Jiang
and co-workers reported a CuI-catalyzed synthesis of 2,5-
disubstituted thiophenes from haloalkynes or 1,3-diynes
in the presence of excessive Na2S·9H2O [18].
Additionally, several diversely substituted thiophenes
were prepared by the reaction of substituted 1,3-dienyl
bromides with K2S in the presence of iodine without
using any metal [19]. In addition, Kirsch and co-workers
reported a transition metal-free method for the synthesis
of 2-nitrothiophene (Scheme 1a), in which Na2S, 3-
chloroenals, and bromonitromethane were employed [20].
Recently, we developed a simple protocol to generate
RESULTS AND DISCUSSION
In the beginning, a model reaction of 3-chloro-3-
phenylpropenal 1a (1.0 mmol) with potassium
thiocyanate (1.5 mmol) was performed in typical polar
solvents at room temperature in view of the solubility of
potassium thiocyanate. The reaction was followed by
thin-layer chromatography (TLC), and almost no
substitution product 2a was provided in CH3OH, acetone,
dimethylformamide, CH3CN, or dimethyl sulfoxide after
24 h (Table 1, entries 1–5). In contrast, the reaction in
glacial acetic acid underwent readily, affording the
desired product, 3-phenyl-3-thiocyanatopropenal (2a) in
moderate yield (Table 1, entry 6). This result encouraged
us to evaluate the effect of acidic additives on the
replacement reaction. Accordingly, a surprisingly big
acceleration to the earlier substitution was achieved when
2.0 mmol of 1 M aqueous HCl solution was added into
the reaction mixture, and the replacement product 2a was
produced in all the used solvents, despite of the different
yields (Table 1, entries 1–5). The highest yield of 2a was
isolated in the case of CH3CN (Table 1, entry 4).
Estimation of the effect of amount of HCl on the reaction
clearly showed that addition of 2.0 mmol of HCl was the
best choice (entries 7–9). In addition, the weakly acidic
© 2019 Wiley Periodicals, Inc.

L. Rong, Y. Shen, G. Xiong, and Y. Gong
Vol 000
Table 2
Preparation of 3-thiocyanatoenals from 3-haloenals and KSCN.
Scheme 1. Synthesis of 2-nitrothiophenes from 3-chloroenals.
benzoic acid almost cannot improve the reaction yield
(Table 1, entry 10).
Based on the optimized reaction parameters, a variety of
3-thiocyanatoenals were prepared in moderate-to-high
yields under the optimized conditions. The chemical
structures and yields of the substitution products are
summarized in Table 2. It should be noted that both the
geometric isomers are simultaneously generated in the
cases of 2a–e during the reaction, despite of the initial
geometric configuration of 3-haloenals 1a–e. This
observation in stereochemistry clearly indicates that the
replacement of chloro group by thiocyanate followed a
KSCN, potassium thiocyanate.
stepwise process, namely, nucleophilic addition and 1,2-
elimination.
After optimizing preparation of 3-thiocyanatoenals, we
started to investigate their Henry reactions with
nitromethane in the presence of a commonly used base.
The initial reaction was performed between 3-phenyl-3-
Table 1
Optimized preparation of 3-thiocyanatoenal 2a.a
thiocyanatopropenal (2a, 0.2 mmol, Z/E
=
1:1),
nitromethane (1.0 mL), and tetra-n-butylammonium
fluoride (0.2 mmol) at room temperature. The reaction
was followed by TLC and almost completed within 4 h.
Product analysis showed that the earlier reaction
furnished 35% yield of the desired product 3a, as well as
a certain amount of 2-nitro alcohol (Table 3, entry 1).
Then some common inorganic and organic bases
involving NaOH, Cs2CO3, 4-(N,N-dimethylamino)
pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]
undec-7-ene, triethylamine, and diisopropylethylamine
(DIPEA) were assessed; unfortunately, the product yields
cannot be improved well in all the cases (Table 3, entries
2–8). The dosage of base has also little effect on the
product yield (Table 3, entries 9–10).
Under the earlier reaction conditions, the reaction of
different 3-thiocyanatoenals 2b–i with nitromethane was
next studied. The results listed in Table 4 showed that all
the 3-thiocyanatoenals prepared earlier could undergo the
tandem reaction, giving moderate yields of 2-
nitrothiophenes. A good yield of product 3f was isolated
in the case of 2f with only Z-isomer. To our delight, the
use of sterically bulky DIPEA could improve the reaction
yields of cyclic 3-thiocyanatoenals 2g–i to a considerable
extent. For example, the yield of product 3g was raised
from 44 to 71%.
Entry
1
Solvent
CH3OH
Additive
Yield (%)
None
Trace
76
Trace
65
Trace
22
Trace
91
Trace
46
54
Trace
68
Trace
91
1 M HCl (2 mmol)
None
1 M HCl (2 mmol)
None
1 M HCl (2 mmol)
None
1 M HCl (2 mmol)
None
2
3
4
5
Acetone
DMF
CH3CN
DMSO
1 M HCl (2 mmol)
None
6
7
AcOH
CH3CN
None
1 M HCl (1 mmol)
None
1 M HCl (2 mmol)
None
1 M HCl (4 mmol)
PhCOOH
8
CH3CN
CH3CN
CH3CN
9
Trace
70
<10
10
KSCN, potassium thiocyanate; RT, room temperature; DMF,
dimethylformamide; DMSO, dimethyl sulfoxide.
aReaction was conducted by mixing 1a (1.0 mmol) and KSCN (1.5 mmol)
in 3 mL of the given solvent and stirred at room temperature for 24 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of 2-Nitrothiophenes
Table 3
Tandem reaction between 2a and nitromethane.a
Scheme 2. Effect of configuration of 3-thiocyanatoenals on the reaction.
Entry
Base
Base: 2a
Yield (%)b
1
2
3
4
5
6
7
8
9
10
TBAF
NaOH
Cs2CO3
DMAP
NMM
DBU
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
35
20
30
26
Trace
30
12
31
32
35
Scheme 3. A possible mechanism for the formation of 2-nitrothiophene.
TEA
DIPEA
DIPEA
TBAF
RT, room temperature; TBAF, tetra-n-butylammonium fluoride; DMAP,
4-(N,N-dimethylamino)pyridine; NMM, N-methylmorpholine; DBU, 1,8-
diazabicyclo[5.4.0]undec-7-ene; TEA, triethylamine; DIPEA,
diisopropylethylamine.
aReaction between 3-phenyl-3-thiocyanatoenal (Z/E = 1:0.75, 0.2 mmol),
nitromethane (1 mL), and TBAF (0.2 mmol) was carried out at RT for 4 h.
bIsolated yields.
Table 4
Tandem reaction between 2a–i and nitromethane.a
conducted their tandem reactions individually. As a
consequence, the reaction of Z-2a afforded 52% yield of
the desired product 3a, whereas that of E-2a afforded
only 12% yield of 3a under the earlier condition. Similar
results were also observed in the cases of Z-2d and E-2d,
where 65 and 23% yields of 3d were isolated,
respectively (Scheme 2).
Obviously, Z-isomer greatly favored the formation of 2-
nitrothiophenes in comparison with E-isomer. To
understand the earlier phenomenon well, we further
investigated the side product formed in the reaction of
E-2a. Besides the desired 2-nitrothiophene 3a, 34% yield
of the 2-nitro alcohol was also produced, as well as some
complicated side products with high polarity. This result
demonstrated that the configuration of 3-thiocyanatoenals
has a crucial influence on nucleophilic attack on sulfur of
the 2-nitro alcohol. A possible mechanism was supposed
and depicted in Scheme 3.
Entry
Enal 2
Z/E ratio
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
1:1
1:0.4
1:0.75
1:0.9
1:0.5
1:0
1:0
1:0
1:0
3a
3b
3c
3d
3e
3f
3g
3h
3i
33
54
48
42
34
65
44 (71)c
45 (50)c
50 (65)c
aReaction between 3-thiocyanatoenals (0.2 mmol), nitromethane (1 mL),
and tetra-n-butylammonium fluoride (0.2 mmol) was carried out at room
temperature for 4 h.
bIsolated yields.
CONCLUSIONS
cYields in parentheses using diisopropylethylamine as the base.
In conclusion, we have developed a convenient
synthetic way of 2-nitrothiophenes through a tandem
nitroaldol reaction–nucleophilic substitution on sulfur of
thiocyanate between 3-thiocyanatoenals and nitromethane
promoted by fluoride or DIPEA under mild reaction
conditions. This tandem reaction realized the synthesis of
The remaining issue for the replacement reaction is how
the configuration of 3-thiocyanatoenals affected the
reaction and product yield. To solve this problem, we
carefully separated Z-isomer from E-isomer of both 2a
and 2d by silica gel column chromatography and then
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Rong, Y. Shen, G. Xiong, and Y. Gong
Vol 000
2,5-disubstituted and 2,4,5-trisubstituted thiophenes with
high regioselectivity.
(Z/E)-3-(4-Methylphenyl)-3-thiocyanatoacrylaldehyde
(2b). Yellow oil; Z/E ratio = 1/0.4 (from H-NMR); for
1
(Z)-isomer, 1H-NMR (400 MHz, CDCl3): δ 9.77 (d,
J = 3.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 2.35 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 188.63, 149.45, 142.15,
130.05, 129.73, 128.41, 128.01, 109.37, 21.48. For (E)-
isomer, 1H-NMR (400 MHz, CDCl3): δ 9.34 (d,
J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d,
J = 8.0 Hz, 2H), 6.57 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 188.45, 153.11, 142.80,
133.19, 129.78, 128.78, 126.96, 107.29, 21.51; IR (film):
ν 2922, 2856, 2159, 1671, 1550, 1506, 1447, 1226,
EXPERIMENTAL
Reactions were monitored by TLC analysis using silica
gel 60
Å F-254 thin-layer plates. Flash column
chromatography was performed on silica gel 60 Å, 10–
40 μm. 1H-NMR spectra were recorded on a Bruker
instrument (400 MHz, Bruker AV, Switzerland). Chemical
shifts are reported in parts per million from tetramethylsilane
(TMS) with the solvent resonance as the internal standard.
Data are reported as follows: chemical shift, multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; and m; multiplet),
coupling constants (Hz), and integration. 13C-NMR spectra
were recorded on a Bruker instrument (101 MHz) with
complete proton decoupling. Chemical shifts are reported in
parts per million from the TMS with the solvent resonance
as internal standard. IR spectra were recorded on a Bruker
Fourier transform infrared spectroscopy spectrometer. High-
resolution mass spectrometry was measured on a Waters
Micromass GCT (Milford, Massachusetts, USA) Premier
with an electron impact source.
1117, 1017, 815, 771 cmꢀ1
.
(Z/E)-3-(4-Methoxyphenyl)-3-thiocyanatoacrylaldehyde
(2c). Yellow oil; Z/E ratio = 1/0.75 (from 1H-NMR); for
(Z)-isomer, 1H-NMR (400 MHz, CDCl3): δ 9.89 (d,
J = 3.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.00 (d,
J = 8.8 Hz, 2H), 6.64 (d, J = 3.6 Hz, 1H), 3.86 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 188.41, 162.45, 149.42,
130.20, 127.81, 126.74, 114.54, 109.16, 55.56. For (E)-
isomer, 1H-NMR (400 MHz, CDCl3): δ 9.40 (d,
J = 7.2 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.00 (d,
J = 8.8 Hz, 2H), 6.61 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 188.68, 162.67, 152.96,
131.63, 127.99, 123.23, 114.79, 107.26, 55.63; IR (film):
ν 3035, 2967, 2932, 2840, 2157, 1666, 1599, 1554,
General
procedure
for
the
preparation
of
3-thiocyanatoenals.
Dissolved potassium thiocyanate
(102 mg, 1.5 mmol) into acetonitrile (6.0 mL) and into
the solution 3-chloroenal (1.0 mmol) was added with
magnetic stirring at room temperature. After the mixture
was stirred for 10 min, 2.0 mL of 1 M aqueous HCl
solution was added with continuous stirring, and the
reaction mixture was kept at room temperature for 24 h.
The solvent was evaporated under reduced pressure, and
into the residue, 5 mL of water was added. The mixture
was extracted with dichloromethane for three times
(3 × 6 mL). The combined organic phase was washed
with dilute aqueous solution of NaHCO3 and water and
dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was
isolated by silica gel column chromatography using
petroleum ether/ether (8:1 v/v) to give the desired product
2. The spectroscopic data for the prepared 3-
1503, 1459, 1252, 1173, 1112, 1020, 992, 825, 793 cmꢀ1
.
(Z/E)-2-Methyl-3-phenyl-3-thiocyanatoacrylaldehyde
(2d). Yellow oil; Z/E ratio = 0.90/1 (from 1H-NMR); for
1
(Z)-isomer, H-NMR (400 MHz, CDCl3): δ 9.98 (s, 1H),
7.53–7.47 (m, 3H), 7.34–7.31 (m, 2H), 1.93 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 190.63, 143.18, 136.09,
135.12, 130.30, 129.15, 128.41, 109.24, 16.41. For (E)-
isomer, 1H-NMR (400 MHz, CDCl3): δ 9.27 (s, 1H),
7.53–7.47 (m, 3H), 7.40–7.37 (m, 2H), 2.05 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 188.50, 148.67, 137.88,
132.75, 130.93, 130.25, 128.99, 107.08, 13.31; IR (film):
ν 3059, 2920, 2857, 2742, 2161, 1675, 1589, 1486,
1443, 1390, 1254, 1214, 1022, 902, 857, 762, 711 cmꢀ1
.
(Z/E)-3-Thiocyanato-3-(thiophen-2-yl)acrylaldehyde (2e).
1
Yellow oil; Z/E ratio = 1/0.5 (from H-NMR); for (Z)-
isomer, 1H-NMR (400 MHz, CDCl3): δ 10.06 (d,
J = 4.8 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.62 (d,
J = 5.2 Hz, 1H), 7.20 (dd, J = 5.2 Hz, 4.0 Hz, 1H), 6.75
(d, J = 4.8 Hz, 1H); 13C-NMR (CDCl3, 100 MHz): δ
188.55, 139.23, 133.05, 132.07, 128.98, 128.45, 108.30.
thiocyanatoenals are listed in the following.
(Z/E)-3-Phenyl-3-thiocyanatoacrylaldehyde (2a). Yellow
1
1
oil; Z/E ratio = 1/1 (from H-NMR); for (Z)-isomer, H-
NMR (400 MHz, CDCl3): δ 9.88 (d, J = 2.8 Hz, 1H),
7.57–7.46 (m, 5H), 6.71 (d, J = 2.8 Hz, 1H); 13C-NMR
(CDCl3, 100 MHz): δ 188.44, 152.85, 136.06, 132.02,
1
For (E)-isomer, H-NMR (400 MHz, CDCl3): δ 9.70 (d,
1
J = 7.2 Hz, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.44 (d,
J = 4.0 Hz, 1H), 7.21 (dd, J = 5.2 Hz, 4.0 Hz, 1H), 6.67
(d, J = 7.2 Hz, 1H); 13C-NMR (CDCl3, 100 MHz): δ
188.14, 138.19, 132.40, 131.66, 128.82, 128.69, 106.95;
IR (film): ν 3105, 2921, 2851, 2161, 1667, 1571, 1509,
129.73, 129.06, 128.45, 109.04. For (E)-isomer, H-NMR
(400 MHz, CDCl3): δ 9.40 (d, J = 7.2 Hz, 1H), 7.57–7.46
(m, 5H), 6.68 (d, J = 7.2 Hz, 1H); 13C-NMR (CDCl3,
100 MHz): 188.38, 150.35, 131.50, 131.12, 129.39,
128.35, 126.71, 106.84; IR (film): ν 3059, 2923, 2853,
1415, 1232, 1112, 848, 772, 719 cmꢀ1
.
2748, 2161, 1723, 1672, 1557, 1116, 761, 696 cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of 2-Nitrothiophenes
7-Methoxy-1-thiocyanato-3,4-dihydronaphthalene-2-
J = 4.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, Hz, 2H), 7.25 (d,
J = 8.0 Hz, 2H), 7.20 (d, J = 4.4 Hz, 1H), 2.40 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 152.42, 140.54, 130.07,
129.74, 126.21, 121.82, 21.37; IR (film): ν 3115, 3095,
2918, 2853, 1602, 1534, 1510, 1486, 1421, 1355, 1328,
carbaldehyde (2f). 1H-NMR (400 MHz, CDCl3): δ 10.42 (s,
1H), 7.87 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8 Hz, 2.4 Hz,
1H), 6.79 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 2.81 (m, 2H),
2.66 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ 188.12,
161.53, 140.35, 139.11, 136.40, 128.46, 122.61, 113.44,
111.37, 108.06, 54.54, 26.03, 21.89; IR (film): ν 2965,
2938, 2866, 2836, 2158, 1649, 1596, 1543, 1490, 1450,
1251, 1039, 953, 803, 728 cmꢀ1
.
2-(4-Methoxyphenyl)-5-nitrothiophene (3c).
Yellowish
1
crystals; mp 129–131°C; H-NMR (400 MHz, CDCl3): δ
7.89–7.88 (d, J = 4.0 Hz, 1H), 7.58–7.56 (d, J = 8.8 Hz,
2H), 7.13 (d, J = 4.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H),
3.87 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 161.25,
152.43, 129.95, 127.79, 124.83, 121.22, 114.82, 55.51;
IR (film): ν 3099, 3013, 2959, 2928, 2831, 1601, 1534,
1509, 1477, 1427, 1355, 1319, 1256, 1202, 1174, 1055,
1381, 1310, 1249, 1182, 1104, 909, 866, 827, 799 cmꢀ1
Yellow
.
2-Thiocyanatocyclohex-1-enecarbaldehyde (2g).
1
oil; H-NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 2.79–
2.75 (m, 2H), 2.55–2.50 (m, 2H), 1.89–1.83 (m, 2H),
1.79–1.74 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ
190.78, 141.59, 134.26, 109.73, 33.29, 26.58, 22.98,
21.06; IR (film): ν 2940, 2863, 2756, 2154, 1730, 1677,
1027, 956, 813, 732 cmꢀ1
.
1564, 1419, 1126, 987, 744, 698 cmꢀ1
.
3-Methyl-5-nitro-2-phenylthiophene (3d).
Yellowish
1
2-Thiocyanatocyclopent-1-enecarbaldehyde (2h).
This
crystals; mp 73–74°C; H-NMR (400 MHz, CDCl3): δ
7.76 (s, 1H), 7.48–7.44 (m, 5H), 2.33 (s, 3H); 13C-NMR
(CDCl3, 100 MHz): δ 146.48, 133.51, 132.27, 131, 79,
129.28, 129.01, 15.12; IR (film): ν 3100, 3055, 2964,
2923, 1624, 1600, 1538, 1483, 1444, 1410, 1390, 1325,
compound was obtained as yellow liquid; 1H-NMR
(400 MHz, CDCl3, 25°C, TMS): δ 9.69 (s, 1H), 3.07–
3.02 (m, 2H), 2.90–2.85 (m, 2H), 2.22–2.14 (m, 2H);
13C-NMR (CDCl3, 100 MHz): δ 187.66, 144.11, 138.21,
109.07, 39.59, 31.69, 22.25; IR (film): ν 2966, 2930,
1239, 1073, 1008, 969, 872, 806, 765, 729, 695 cmꢀ1
.
2880, 2158, 1657, 1549, 1465, 1111, 979, 727 cmꢀ1
.
5-Nitro-2,20-bithiophene (3e). Brown crystals; mp 113–
113.5°C; 1H-NMR (400 MHz, CDCl3): δ 7.85 (d,
J = 4.0 Hz, 1H), 7.41 (dd, J = 5.2 Hz, 0.4 Hz, 1H), 7.36
(dd, J = 3.6 Hz, 0.4 Hz, 1H), 7.10 (dd, J = 5.2 Hz,
3.6 Hz, 1H), 7.09 (d, J = 4.0 Hz, 1H); 13C-NMR (CDCl3,
100 MHz): δ 145.15, 134.96, 129.69, 128.56, 127.93,
126.63, 122.45; IR (film): ν 3084, 2922, 2851, 1635,
1595, 1543, 1512, 1485, 1434, 1374, 1328, 1220, 1033,
2-Thiocyanatocyclohept-1-enecarbaldehyde (2i).
Yellow
1
oil; H-NMR (400 MHz, CDCl3): δ 9.73 (s, 1H), 3.03–
3.00 (m, 2H), 2.71–2.68 (m, 2H), 1.91–1.85 (m, 2H),
1.76–1.70 (m, 2H), 1.60–1.54 (m, 2H); 13C-NMR
(CDCl3, 100 MHz): δ 190.18, 147.90, 140.74, 110.15,
37.99, 31.47, 28.91, 25.52, 24.90; IR (film): ν 2925,
2884, 2847, 2147, 1670, 1655, 1531, 1398, 1212, 1106,
952, 826, 770 cmꢀ1
.
892, 838, 804, 718 cmꢀ1
.
General procedure for synthesis of 2-nitrothiophenes. 3-
Phenyl-3-thiocyanatoenal 2a (Z/E = 1:1, 0.2 mmol),
nitromethane (1.0 mL), and tetra-n-butylammonium
fluoride (0.2 mmol) were added to a 10-mL flask
equipped with a magnetic stirring bar. The solution was
stirred for 2 h at room temperature, and the reaction
progress was monitored by TLC. After 4 h, the reaction
was completed. The reaction mixture was evaporated
under reduced pressure, and the residue was purified by
flash chromatography on silica gel eluting with petroleum
ether/ethyl acetate (5:1 v/v) to give a yellow solid
product 3a. The other 2-nitrothiophenes were prepared
8-Methoxy-2-nitro-4,5-dihydronaphtho[1,2-b]thiophene
(3f).
Yellowish crystals; mp 130–131°C; 1H-NMR
(400 MHz, CDCl3): δ 7.72 (s, 1H), 7.35–7.26 (m, 1H),
6.79–6.78 (m, 1H), 3.84 (s, 3H), 2.96–2.93 (t, 2H), 2.82–
2.78 (t, 2H); 13C-NMR (CDCl3, 100 MHz): δ 160.98,
147.42, 145.13, 138.19, 134.84, 129.45, 125.44, 122.29,
114.34, 112.73, 55.46, 28.83, 23.46; IR (film): ν 2932,
2835, 1607, 1571, 1529, 1479, 1437, 1388, 1322, 1308,
1277, 1242, 1172, 1117, 1028, 977, 869, 836, 800,
733 cmꢀ1
.
2-Nitro-4,5,6,7-tetrahydrobenzo[b]thiophene
(3g).
Yellowish crystals; mp 73°C; 1H-NMR (400 MHz,
CDCl3): δ 7.61 (s, 1H), 2.80–2.77 (t, J = 7.6 Hz, 2H),
2.64–2.61 (t, J = 7.6 Hz, 2H), 1.90–1.81 (m, 4H); 13C-
NMR (CDCl3, 100 MHz): δ 145.73, 135.86, 129.34,
25.46, 25.27, 22.69, 22.18; IR (film): ν 3096, 3073,
2946, 2898, 2867, 1546, 1496, 1435, 1344, 1326, 1299,
according to the earlier procedure.
2-Nitro-5-phenylthiophene (3a). Yellowish crystals; mp
123–124°C; 1H-NMR (400 MHz, CDCl3): δ 7.91 (d,
J = 4.4 Hz, 1H), 7.64–7.62 (m, 2H), 7.46–7.44 (m, 3H),
7.24 (d, J = 4.4 Hz, 1H); 13C-NMR (CDCl3, 100 MHz):
δ 152.05, 132.14, 130.10, 129.70, 129.42, 126.33,
122.38; IR (film): ν 3106, 3064, 2960, 2924, 1725, 1600,
1580, 1536, 1499, 1446, 1427, 1331, 1224, 1041, 955,
1133, 1083, 859, 804, 732 cmꢀ1
.
2-Nitro-5,6-dihydro-4H-cyclopenta[b]thiophene (3h).
Yellowish crystals; mp 48–50°C; 1H-NMR (400 MHz,
CDCl3): δ 7.71 (s, 1H), 2.98 (t, J = 7.7 Hz, 2H), 2.80 (t,
J = 7.7 Hz, 2H), 2.45 (m, J = 7.7 Hz, 2H); 13C-NMR
(CDCl3, 100 MHz): δ 151.47, 145.30, 124.49, 30.03,
904, 813, 757, 729, 683 cmꢀ1
.
2-Nitro-5-p-tolylthiophene (3b). Yellowish crystals; mp
86–87°C; 1H-NMR (400 MHz, CDCl3): δ 7.89 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Rong, Y. Shen, G. Xiong, and Y. Gong
Vol 000
[6] By, I. F. P.; Dmitrii, F. P.; Hong, M.; Fred, W. Adv Mater
2005, 17, 2281.
[7] Allard, S.; Forster, M.; Souharce, B.; Thiem, H.; Scherf, U.
Angew Chem Int Ed 2008, 47, 4070.
[8] Li, H.; DeCoster, M. E.; Ireland, R. M.; Song, J.; Hopkins, P.
E.; Katz, H. E. J Am Chem Soc 2017, 139, 11149.
[9] Li, J.; Terec, A.; Wang, Y.; Joshi, H.; Lu, Y.; Sun, H.; Stuparu,
M. C. J Am Chem Soc 2017, 139, 3089.
[10] Nguyen, T. B. Adv Synth Catal 2017, 359, 1066.
[11] Priebbenow, D. L.; Bolm, C. Chem Soc Rev 2013, 42, 7870.
[12] Andre, A. K.; Paul, S.; Alexander, J. S. J Org Chem 2001, 66,
7925.
28.44, 28.03; IR (film): ν 3110, 2924, 2851, 1562, 1531,
1493, 1439, 1392, 1333, 1299, 1152, 857, 733 cmꢀ1
.
2-Nitro-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene
(3i).
Yellowish crystals; mp 51–53°C; 1H-NMR
(400 MHz, CDCl3): δ 7.61 (s, 1H), 2.84–2.81 (m, 2H),
2.71–2.69 (m, 2H), 1.91–1.86 (m, 2H), 1.76–1.70 (m,
2H), 1.67–1.62 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ
150.37, 145.84, 141.61, 131.32, 32.06, 30.81, 27.81,
27.41; IR (film): ν 3095, 3072, 2960, 2928, 2847, 1541,
1498, 1405, 1335, 1136, 1075, 950, 887, 826, 799,
[13] Zoltán, K.; Brian, T. M.; Tibor, S.; Roman, D. Org Lett 2006,
1625.
738 cmꢀ1
.
[14] Hesse, S.; Revelant, G.; Dunand, S.; Kirsch, G. Synthesis
2011, 2011, 2935.
[15] Zhang, W.; Ma, L.; Yuan, L.; Xu, C.; Li, G.; Tao, M. Synthesis
2012, 45, 45.
[16] Lars, K. R.; Łukasz, A.; Christian, F. W.; Jesper, R. B.; Karl,
A. J. Org Lett 2012, 14, 724.
[17] You, W.; Yan, X. Y.; Liao, Q.; Xi, C. J. Org Lett 2010, 3930.
[18] Jiang, H.; Zeng, W.; Li, Y.; Wu, W.; Huang, L.; Fu, W. J Org
Chem 2012, 77, 5179.
Acknowledgments. This work was supported by grants from the
National Natural Science Foundation of China (nos. 21472053,
21172082, and 20872041). The Analysis and Testing Centre of
Huazhong University of Science and Technology is acknowl-
edged for the characterization of the new compounds.
[19] Pintu, M.; Brindaban, C. R. Adv Synth Catal 2017, 359, 4369.
[20] Rodríguez-Domínguez, J. C.; Thomae, D.; Seck, P.; Kirsch, G.
Synlett 2008, 286.
REFERENCES AND NOTES
[21] Zhang, J. L.; Gong, Y. F. Org Lett 2011, 176.
[22] Zhang, J. L.; Gu, L. H.; Gong, Y. F. Synlett 2012, 23, 468.
[23] Zhang, M.; Gong, Y. F. J Heterocyclic Chem 2015, 52, 573.
[1] Bozorov, K.; Nie, L. F.; Zhao, J.; Aisa, H. A. Eur J Med Chem
2017, 140, 465.
[2] Rajwinder, K.; Akkinepally, R. R.; Renu, C. N. T.; Manish, G.
Int J Pharm Sci Rev Res 2016 104.
[3] Noel, R.; Gupta, N.; Pons, V.; Goudet, A.; Garcia-Castillo, M.
D.; Michau, A.; Martinez, J.; Buisson, D. A.; Johannes, L.; Gillet, D.;
Barbier, J.; Cintrat, J. C. J Med Chem 2013, 56, 3404.
[4] Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.;
Cruz-Lopez, O.; Salvador, M. K.; Preti, D.; Tabrizi, M. A.; Moorman,
A. R.; Vincenzi, F.; Borea, P. A.; Varani, K. J Med Chem 2012, 55, 7719.
[5] Amaresh, M.; Ma, C. Q.; Baüerle, P. Chem Rev 2009, 109,
1141.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet