A one-pot synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes

Article abstract of DOI:10.1016/j.tet.2015.05.032

A one-pot approach to the synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes has been developed. Exposure of 1,4-dithane-2,5-diol to nitroacetates or nitroalkenes in the presence of 25% triethylamine and subsequent treatment with molecular sieves and combinations of silica gel or acidic alumina with DDQ or chloranil formed 3-nitrothiophene or a number of 3-nitro-2-substituted thiophenes with complete regiocontrol. A simple work-up procedure removes the requirement for purification by chromatography for most post-synthetic applications.

Full text of DOI:10.1016/j.tet.2015.05.032

Accepted Manuscript
A one-pot synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes
Neasa McNabola, Cornelius J. O’Connor, Mark D. Roydhouse, Michael D. Wall,
J.Mike Southern
PII:
S0040-4020(15)00690-0
10.1016/j.tet.2015.05.032
TET 26750
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2015
Revised Date: 24 April 2015
Accepted Date: 11 May 2015
Please cite this article as: McNabola N, O’Connor CJ, Roydhouse MD, Wall MD, Southern JM, A one-
pot synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.05.032.
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A one-pot synthesis of 3-nitrothiophene and
3-nitro-2-substituted thiophenes
Leave this area blank for abstract info.
Neasa McNabola,a Cornelius J. O’Connor,a Mark D. Roydhouse,a Michael D. Wallb and J. Mike Southern,*a
a Trinity Biomedical Sciences Institute, School of Chemistry, Trinity College Dublin, Dublin 2, Ireland. b Discovery Medicinal
Chemistry, GlaxoSmithKline, Gunnels Wood Rd, Stevenage, SG1 2NY, UK; Current address: Medicinal Chemistry (Early Discovery)
Charles River Laboratories Chesterford Research Park, CB10 1XL, U.K.

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Tetrahedron
journal homepage: www.elsevier.com
A one-pot synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes
Neasa McNabola,a Cornelius J. O’Connor,a Mark D. Roydhouse,a Michael D. Wall#b and J. Mike
Southern,*1a
a Trinity Biomedical Sciences Institute, School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
b Discovery Medicinal Chemistry, GlaxoSmithKline, Gunnels Wood Rd, Stevenage, SG1 2NY, UK,
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot approach to the synthesis of 3-nitrothiophene and 3-nitro-2-substituted thiophenes has been
developed. Exposure of 1,4-dithane-2,5-diol to nitroacetates or nitroalkenes in the presence of 25%
triethylamine and subsequent treatment with molecular sieves and combinations of silica gel or acidic
alumina with DDQ or chloranil formed 3-nitrothiophene or a number of 3-nitro-2-substituted
thiophenes with complete regiocontrol. A simple work-up procedure removes the requirement for
purification by chromatography for most post-synthetic applications.
Available online
Keywords:
3-Nitrothiophenes
Conjugate addition
Intramolecular nitroaldol
Addition-cyclisation reactions
One-pot synthesis
2009 Elsevier Ltd. All rights reserved.
Figure 1 Some important thiophenes
1.1. Introduction
A 2,3-disubstituted thiophene also features in the selective Gluk5
receptor antagonist 1 developed by Jane and co-workers.2 Articaine®
is a voltage gated sodium channel blocker and a popular dental
anaesthetic in Europe3 and displays a 2,3,4-trisubstituent pattern.
Thiophenes are also found in polymeric form in materials conferring
interesting electronic and optical properties Oligomeric and
polymeric thiophenes have been shown to have a variety of uses,
including as organic semiconductors, organic light emitting diodes
(OLEDs), organic field effect transistors (OFETs), lasers, sensors
and photovoltaic cells.4
Thiophene is an important heterocycle that features in numerous
biologically active compounds. For example, Plavix® (Clopidogrel
bisulfate) is a medication that inhibits ADP induced platelet
aggregation and is used to prevent the formation blood clots
particularly in patients who have recently suffered from a heart
attack or stroke.1
Although many methods of producing thiophenes have been reported
each has drawbacks, particularly with respect to formation of a 2,3-
disubstitution pattern. Elegant methodologies have been devised to
prepare thiophenes from acyclic starting materials such as
condensations with dicarbonyl compounds and the Gewald Synthesis
but providing the 2-substituted-3-nitro pattern by these methods is
not simple.5 Electrophilic aromatic substitution reactions have a
preference for the 2- and 5-positions which means that producing the
2,3-substitution pattern, described herein, requires the use of
blocking groups.5 Although there is a preference for the 2- and 5-
positions reaction at these positions is not completely selective; the
nitration of thiophene via a SEAr process results in an 85:15 mixture
of 2-nitrothiophene:3-nitrothiophene that is troublesome to separate.5
———
1 *Corresponding Author Tel. +35318963411; Fax. +3531 6772274, email address southerj@tcd.ie
#Current address: Medicinal Chemistry (Early Discovery), Charles River Laboratories, Chesterford Research Park, CB10 1XL, U.K.

2
Tetrahedron
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Ballini and co-workers have reported the addition of Grignard
investigated. Ballini and co-workers reported the dehydration of
reagents to 3-nitrothiophene to produce a number of 3-nitro-2-
substituted thiophenes.6 This method requires the synthesis of 3-
nitrothiophene and is limited to reagents suitable to Grignard
formation. Devarie-Baez and co-workers have reported the use of 3-
bromo-2-silylthiophene as a 2,3-dithienylanion equivalent that can
serve as a precursor to 3-nitro-2-substituted thiophenes.7 However,
this synthetic approach does not circumvent the initial problem of
installing the 2,3-pattern and also requires the use of strong base.
Despite the long and distinguished history associated with the
chemistry of thiophenes,5 the ongoing development of new, elegant
synthetic strategies and methodologies to produce thiophenes is
testament to their importance and requirement for improved
synthetic options.8
nitroalcohols using basic alumina in dichloromethane at reflux.11 We
found that treatment of THT 4 with basic alumina (4 eq. w/w with
respect to the starting material) in dichloromethane at reflux for 41
hours provided the desired nitrothiophene 6 (by aerobic oxidiative
aromatisation), however the starting material was not completely
consumed and 2-phenyl thiophene 7 (aromatisation by loss of HNO2)
was also produced as a competing side product in approximately
equimolar quantities (Table 1). Neutral alumina (4 eq. w/w) gave
similar results (a 1:1 ratio of 6:7) whereas acidic alumina (4 eq. w/w)
gave a more promising 2:1 ratio after 41 hours.
We have recently reported a microwave based method to produce
2-substituted-3-nitrothiophenes9 but we felt that a complimentary
thermal based strategy would be useful. A thermal approach has
clear advantages in removing the requirement for microwave
equipment and potentially offering a one-pot protocol, both of which
are advantageous when considering the production of compounds on
a large scale.
1.2. Results and discussion
The previously described microwave based approach9 involved the
preparation of a tetrahydrothiophene (THT) by treatment of 1,4-
dithiane-2,5-diol 2, a dimeric mercaptoacetaldehyde equivalent10
with 20 mol% of triethylamine and
dichloromethane. A tandem conjugate-addition/nitroaldol ring
closure reaction gave the corresponding THT as a mixture of
diastereoisomers in high yields. Dehydration and subsequent
oxidative aromatisation under microwave irradiation formed the
corresponding 3-nitro-2-substituted thiophene in good yields.
a nitroalkene (NA) in
Table 1: Optimisation of the dehydration and aromatisation of 4
Additive (eqs)
Basic alumina (4)
Neutral alumina (4)
Acidic alumina (4)
Acidic alumina (4)
and DDQ (2)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4 Consumed
6:7 (% yield)
No
No
No
No
1:1
1:1
2:1
1:0
Acidic alumina (4)
and DDQ (2)
Acidic alumina (4),
DDQ (2) and 4Å mol.
sieves (2)
CHCl3
CHCl3
No
1:0
Yes
1:0 (88)
Silica gel (8), DDQ
(4) and 4 Å mol.
sieves (4)
CHCl3
Yes
1:0 (98)
It was postulated that the addition of DDQ would facilitate rapid
aromatisation and suppress the loss of HNO2 from dihydrothiophene
5. Indeed, repeating the reaction in the presence of DDQ (2 eq.) did
prevent the aromatisation through loss of HNO2. Although
nitrothiophene 6 was cleanly formed after 62 hours it was evident
that THT 4 had not been completely consumed. Heating at reflux in
the higher boiling chloroform gave a slightly improved 30:70 ratio of
4:7 after 40 hours and it was postulated that the removal of water
from THT 4 was reversible. Repetition of the reaction in the
presence of 4Å activated molecular sieves (2 eq. w/w) generated 3-
nitro-2-phenylthiophene (6) exclusively in 88% yield after 64 hours
at reflux. Finally, exchanging acidic alumina for silica gel (8 eq.
w/w) and using DDQ (4 eq.) and molecular sieves (4 eq. w/w)
allowed the isolation of 6 in 98% yield after heating at reflux for 24
hours. This was considered the preferred protocol and is herein
referred to as Method A (Scheme 2).
Scheme 1 A microwave based approach
When considering the development and optimisation of the process
for a thermal approach, the initial reaction to form the THTs was
high yielding. The quantity of triethylamine was increased from 20
mol% to 25 mol% for this study but further investigation was not
required. To optimise the dehydration and oxidiation reactions we
chose to employ the commercially available -nitrostyrene and the
THT 4 was formed in 99% yield.
Initial studies aimed at nitrothiophene formation involved the
treatment of the THT with trifluoroacetic anhydride, two equivalents
of base, then DDQ as the oxidant. Although this approach was
successful it was troublesome experimentally, requiring anhydrous
conditions at -15 ºC and provided low yields (particularly in the case
of aliphatic substituents) so
a more efficient approach was

3
For aromatic substituents, the one-pot Method C was developed.
ACCEPTED MANUSCRIPT
In this case, the nitroalkene was stirred overnight with dithiane 2 and
25% triethylamine in chloroform before the addition of silica gel (8
equivalents w/w), DDQ (4 equivalents) and molecular sieves (4
equivalents w/w) and heating at reflux for 24 hours.
In the case of aliphatic substituents we were pleased to discover that
the initial addition/cyclisation reactions proceeded smoothly in butyl
acetate and this led to the development of Method D. The
appropriate nitroalkene, dithiane 2 and 25% triethylamine were
stirred overnight in butyl acetate before the addition of acidic
alumina (8 equivalents w/w), chloranil (4 equivalents) and molecular
sieves (4 equivalents w/w) and heating at reflux for 40 hours. In
Method D acidic alumina can be replaced with 8 equivalents of silica
gel with a small reduction in yield.
The same isolation protocol (stirring with 500 mg/mmol KOH and
charcoal) was attempted using the one-pot methodology and were
pleased to find that for the majority of post-synthetic uses further
purification was not required. The results for a range of 3-nitro-2-
substituents are shown in Table 2.
Scheme 2 Method A dehydration and aromatisation
Having established methodology to prepare 6 we turned our attention
to the installation of alkyl substituents at the 2-position. Treating
nitroalkene 8 under the conditions optimised for -nitrostyrene did
produce the expected nitrothiophene 10 but in addition
approximately 20% of an aldehyde, tentatively assigned as 11, was
isolated (Scheme 3).
Table 2: One-pot formation of nitrothiophenes
Nitro-
Scheme 3 Early problems with aliphatic substituents
R =
Method
Yield
42%
thiophene
Screening a range of solvents in order to eliminate this side-product
indicated that 10 could be produced cleanly, albeit slowly, in ethyl
acetate. Screening higher boiling esters, different supports and
conditions allowed us to isolate the desired nitrothiophene 10 in 55%
yield when employing acidic alumina (8 eq. w/w), molecular sieves
(4 eq. w/w) and chloranil (4 eq.) in butyl acetate (b.pt 126 ºC) at
reflux for 40 hours. This was the preferred protocol for the inclusion
of alkyl substituents and is herein referred to as Method B (Scheme
4).
12
C
13
C
37%
O
14
15
C
C
C
23%
27%
77%
O
NO2
16
17
O2N
Scheme 4 Method B dehydration and aromatisation
D
D
45%
46%
18
In our previous work employing microwave irradiation we
developed a rapid work up/purification procedure in which the crude
reaction mixture was stirred with 500 mg/mmol KOH (based on the
mass of the starting THT) and 500 mg/mmol activated charcoal, for
1 hour.9 Subsequent filtration through a pad of silica and washing
with DCM gave the nitrothiophene without the requirement for
further purification by column chromatography. We applied the
same isolation protocol when employing the thermal methodology
and were pleased to find that further purification was not required for
most post synthetic applications.
6
Having developed chemistry to prepare alkyl or aromatic 2-
substituted-3-nitrothiophenes we turned our attention to the
preparation of 3-nitrothiphene itself. In order to achieve this using
the methodology described, the use of volatile and reactive
nitroethene would have been required required. Fortunately,
chemistry developed by De Rosi et al12 allowed us to circumvent the
use of nitroethene by employing a nitroacteate precursor 19.
Treatment of the dithiane 2 with nitroacetate 19 in the presence of 25
mol% of triethylamine formed THT 20 in 73% yield. Unfortunately
attempts to induce dehydration/aromatisation reaction using either
Method A or Method B failed to provide any 3-nitrothiophene (21,
Having secured the two step process, we turned our attention to the
further development of the methodology to provide a “one-pot”
protocol for preparation of 2-substituted-3-nitrothiophenes directly
from the appropriate nitroalkene.

4
Tetrahedron
Scheme 5).
(J) are quoted in Hertz. Carbon NMR spectra were recorded on the
ACCEPTED MANUSCRIPT
previously mentioned instruments (100.64 MHz, 100.61 MHz &
150.9 MHz, respectively) with total proton decoupling. Fluorine
NMR spectra were recorded on the Bruker DPX400 machine at
376.5 MHz). HSQC, HMBC, TOCSY and nOe NMR experiments
were used to aid assignment of NMR peaks when required.
A
Waters micromass LCT-tof mass spectrometer was used in ES
positive and ES negative modes for electrospray mass spectrometry.
Electron impact mass spectra were determined on a Quatro-II mass
spectrometer in the EI mode. Mass spectra were recorded in CSCB
Trinity College Dublin, CSCB University College Dublin. Flash
chromatography was performed using Merk Kiesegel 60 (art. 9385)
and aluminium oxide 90, standardized (activity II-III). Merk
precoated Kiesegel 60F254 were used for thin-layer chromatography
and slides were visualised by UV irradiation, KMnO4, or
anisaldehyde staining. Toluene, CH2Cl2, and triethylamine were
distilled from calcium hydride.
Scheme 5 A failed attempt to prepare 3-nitrothiophene
Despite the failure of the two-pot method in the synthesis of 3-
nitrothiophene we wanted to assess utilisation of the nitroacetate
methodology in a one-pot reaction (Scheme 6). Nitroacetate 19,
dithiane 2 and triethylamine (25 mol%) were stirred for 16 hours in
butyl acetate at room temperature, before acidic alumina (8
equivalents w/w), chloranil (4 equivalents) and molecular sieves (4
equivalents w/w) were added. The resultant mixture was heated at
reflux for 40 hours which gave 3-nitrothiophene (21) in 41% yield.
Once again the rapid isolation protocol (stirring with 500 mg/mmol
KOH and charcoal) was successful and further purification was not
required. Surprisingly, if the reaction was attempted with 1.25
equivalents of triethylamine (to provide an extra equivalent to
facilitate the elimination of acetate) the yield for the reaction
dropped to 14%.
Method A – general aromatic two-pot procedure
Step 1: To a stirred solution of the appropriate nitroalkene (1.0 eq.)
in CH2Cl2 (0.1 M) were added 2,5-dihydroxy-1,4-dithiane (0.75 eq.)
and triethylamine (0.25 eq) under an inert atmosphere. The reaction
was stirred at room temperature overnight. The reaction was diluted
with CH2Cl2 and the suspended solid was removed by filtration. A
solution of saturated ammonium chloride was added to the filtrate
and the aqueous layer was twice extracted with CH2Cl2. The
combined organic layers were washed with water and brine and then
dried over magnesium sulfate. Volatiles were removed at reduced
pressure and the crude reaction product used directly in step 2.
Step 2: To a solution of the appropriate aromatic substituted THT in
anhydrous chloroform (0.1 M) were added DDQ (4 eq), silica gel (8
eq w/w) and 4 Å molecular sieves (4 eq w/w). The reaction mixture
was heated at reflux and stirred for approximately 24 hours until
TLC indicated that the starting material had been consumed. After
this time, the reaction was allowed to cool to room temperature and
charcoal (500 mg/mmol, with respect to the THT) and powdered
KOH (500 mg/mmol, with respect to the THT) were added. The
mixture was stirred for an hour before being filtered through a pad of
silica which was then rinsed with CH2Cl2. The volatiles were
removed at reduced pressure to give the desired 3-nitro-2-
substituted-thiophene.
Scheme 6 The synthesis of 3-nitrothiophene
1.3. Conclusions
A simple one-pot procedure which allows for the completely
regioselective formation of 3-nitrothiophene as well as a range of 2-
sustituted-3-nitrothiophenes from easily accessible starting materials
is reported. To access thiophenes with this substitution pattern
would usually require the use of a blocking group strategy.
Exploitation of the powerful directing effect of the nitro group in
addition to its further manipulation by reduction and diazotization
are ongoing.
Method B – general aliphatic two-pot procedure
Step 1: To a stirred solution of the appropriate nitroalkene (1.0 eq.)
in CH2Cl2 (0.1 M) were added 2,5-dihydroxy-1,4-dithiane (0.75 eq.)
and triethylamine (0.25 eq) under an inert atmosphere. The reaction
was stirred at room temperature overnight. The reaction was diluted
with CH2Cl2 and the suspended solid was removed by filtration. A
solution of saturated ammonium chloride was added to the filtrate
and the aqueous layer was twice extracted with CH2Cl2. The
combined organic layers were washed with water and brine and then
dried over magnesium sulfate. Volatiles were removed at reduced
pressure and the crude reaction product used directly in step 2.
Step 2: To a solution of the appropriate aliphatic THT in anhydrous
butyl acetate (0.1 M) was added chloranil (4 eq), acidic alumina (8
eq w/w) and 4 Å molecular sieves (4 eq w/w). The reaction mixture
was heated at reflux and stirred for approximately 40 hours until
TLC indicated that the starting material had been consumed. After
this time, the reaction was allowed to cool to room temperature and
charcoal (500 mg/mmol) and powdered KOH (500 mg/mmol) were
General Experimental section
Melting points were determined using a standard melting point
apparatus and are uncorrected. Infrared spectra were obtained on a
Perkin Elmer Spectrum 100 FT-IR spectrometer equipped with a
universal ATR sampling accessory. Proton nuclear magnetic
resonance (NMR) spectra were recorded on: Bruker Avance III 400
MHz, Bruker DPX400 400 MHz and Bruker Avance II 600 MHz
spectrometers (1H NMR spectra were recorded at 400.23 MHz,
400.13 MHz and 600.13 MHz respectively). Chemical shifts are
reported in ppm relative to tetramethylsilane and coupling constants

5
added. The mixture was stirred for an hour before being filtered
mmol) in butyl acetate which gave 10 as a yellow oil (42 mg, 0.29
mmol, 52%)
ACCEPTED MANUSCRIPT
through a pad of silica which was then rinsed with CH2Cl2. The
volatiles were removed at reduced pressure to give the desired 3-
nitro-2-substituted-thiophene.
Rf (10% EtOAc/hexane) 0.63; 1H NMR (600 MHz, CDCl3):  =
0.99 (d, J = 6.7 Hz, 6H), 2.05 (nonet, J = 6.7 Hz, 1H), 3.09 (d, J =
6.7 Hz, 2H), 7.08 (d, J = 5.8 Hz, 1H), 7.57 ppm (d, J = 5.8 Hz, 1H);
13C NMR (151 MHz, CDCl3):  = 21.9, 29.5, 37.3, 121.1, 124.1,
143.7, 148.0 ppm; IR υmax: 3122, 3105, 2959, 1539, 1500, 1374,
1327, 1182, 841, 703 cm-1; HRMS: (m/z-EI) calcd for C8H11NO2S
(M)+ 185.0511, found 185.0512.
Method C – general aromatic one-pot procedure
A solution of an aromatic nitroalkene (1.0 eq.), 2,5-dihydroxy-1,4-
dithiane (0.75 eq.) and triethylamine (0.25 eq.) in chloroform (0.1 M)
was stirred overnight at room temperature under an inert atmosphere,
and monitored by TLC. When the nitroalkene had been consumed
(typically around 16 hours) DDQ (4.0 eq.), acidic alumina (8.0 eq.
w/w) and 4 Å molecular sieves (4.0 eq. w/w) were then added and
the resulting mixture was heated to reflux for 48 hours. The reaction
mixture was allowed to cool to room temperature before charcoal
(500 mg/mmol, with respect to the THT (assuming 100% yield)) and
powdered KOH (500 mg/mmol, with respect to the THT (assuming
100% yield)) were added. The mixture stirred for 1 hr before being
filtered through a thick pad of silica which was then rinsed with
CH2Cl2. The volatiles were removed at reduced pressure to give the
desired 3-nitro-2-substituted-thiophene.
Method C: One-pot aromatic - 3-Nitro-2-phenyl-thiophene (6):
Prepared via method C using trans--nitrostyrene (300 mg, 2.01
mmol), 2,5-dihydroxy-1,4-dithiane (230 mg, 1.51 mmol) and
triethylamine (70 L, 0.51 mmol) in chloroform. After consumption
of the nitroalkene (monitored by TLC), DDQ (1.80 g, 7.93 mmol),
silica gel (2.40 g) and 4 Å molecular sieves (1.20 g) were added and
the reaction mixture heated for the appropriate time. After treatment
with KOH, charcoal and filtration through a pad of silica gel, 6 was
obtained as a yellow solid (173 mg, 0.84 mmol, 42%).
Method C: One-pot aromatic
thiophene (16)
- 3-Nitro-2-(4-nitrophenyl)-
Method D – general aliphatic one-pot procedure
A solution of an aliphatic nitroalkene (1.0 eq.), 2,5-dihydroxy-1,4-
dithiane (0.75 eq.) and triethylamine (0.25 eq.) in butyl acetate (0.1
M) was stirred overnight at room temperature under an inert
atmosphere, monitored by TLC. When the nitroalkene had been
consumed (approximately 16 hours), chloranil (4.0 eq.), acidic
alumina (8.0 eq. w/w) and 4 Å molecular sieves (4.0 eq. w/w) were
then added and the resulting mixture was heated at reflux for 48
hours. The reaction mixture was allowed to cool to room temperature
before charcoal (500 mg/mmol, with respect to the THT (assuming
100% yield)) and powdered KOH (500 mg/mmol, with respect to the
THT (assuming 100% yield)) were added. The mixture stirred for 1
hr before being filtered through a thick pad of silica which was then
rinsed with CH2Cl2. The volatiles were removed at reduced pressure
to give the desired 3-nitro-2-substituted-thiophene.
Prepared via method C using p-nitro-trans--nitrostyrene (50 mg,
0.26 mmol), 2,5-dihydroxy-1,4-dithiane (30 mg, 0.20 mmol) and
triethylamine (9 L, 0.07 mmol) in chloroform. After consumption
of the nitroalkene (monitored by TLC), DDQ (236 mg, 1.04 mmol),
silica gel (400 mg) and 4 Å molecular sieves (200 mg) were added
and the reaction mixture heated for the appropriate time. After
treatment with KOH, charcoal and filtration through a pad of silica
gel, 16 was obtained as a yellow solid (50 mg, 0.20 mmol, 77%).
m.p.153-155 ºC, lit.13 146-148 ºC; Rf (20% CH2Cl2/hexane) 0.18; 1H
NMR (400 MHz, CDCl3):  = 7.44 (d, J = 5.5 Hz, 1H), 7.70 (d, J =
8.0 Hz, 2H), 7.75 (d, J = 5.5 Hz, 1H), 8.34 ppm (d, J = 8.0 Hz, 2H);
13C NMR (151 MHz, CDCl3):  = 123.6, 125.3, 125.5, 130.8, 137.0,
142.0, 143.9, 148.3 ppm; IR υmax: 3140, 3121, 1593, 1540, 1509,
1497, 1340, 1313, 1103, 851, 840, 747, 704, 691 cm-1; HRMS:
(m/z-EI) calcd for C10H6N2NaO4S (M+Na)+ 272.9946, found
272.9939.
Method A: Two pot aromatic - 3-Nitro-2-phenyl-thiophene (6):
Prepared via Method A using using -nitrostyrene (333 mg, 2.23
mmol), 2,5-dihydroxy-1,4-dithiane (255 mg, 1.67 mmol) and
triethylamine (78 L, 0.56 mmol) in chloroform under an inert
atmosphere. The crude THT was treated with silica gel (2.60 g), 4 Å
molecular sieves (1.30 g) and DDQ (2.02 g, 8.92 mmol) in
chloroform which gave 6 as a yellow solid (450 mg, 2.19 mmol,
98%)
Method
nitrophenyl)thiophene (15)
C:
One-pot
aromatic
-
3-nitro-2-(2-
Prepared via method C using o-nitro-trans--nitrostyrene (150 mg,
0.77 mmol), 2,5-dihydroxy-1,4-dithiane (88 mg, 0.58 mmol) and
triethylamine (26 L, 0.19 mmol) in chloroform. After consumption
of the nitroalkene (monitored by TLC), DDQ (700 mg, 3.01 mmol),
silica gel (1.2 g) and 4 Å molecular sieves (600 mg) were added and
the reaction mixture heated for the appropriate time. After treatment
with KOH, charcoal and filtration through a pad of silica gel, 15 was
obtained as an orange solid (52 mg, 0.21 mmol, 27%).
m.p. 101-103 ºC, lit.13 101.5-102.5 ºC; Rf (10% EtOAc/hexane)
0.33; 1H NMR (400 MHz, CDCl3):  = 7.30 (d, J = 5.5 Hz, 1H),
7.45-7.54 (m, 5H), 7.68 ppm (d, J = 5.5 Hz, 1H); 13C NMR (151
MHz, CDCl3):  = 123.6, 124.5, 128.0, 129.15, 129.19, 130.1,
142.5, 145.1 ppm; IR υmax: 2926, 1546, 1506, 1372, 1331, 1261,
752 cm-1; HRMS: (m/z-EI) calcd for C10H8NO2S (M+H)+ 206.0276,
found 206.0270.
m.p. 142-143 ºC, lit.9 142-143 ºC; Rf (hexane-CH2Cl2 1:1) 0.45; 1H
NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 5.7 Hz, 1H), 7.47 (d, J =
7.4 Hz, 1H), 7.64-7.73 (m, 3H), 8.24 ppm (d, J = 8.0 Hz, 1H); 13C
NMR (101 MHz, CDCl3): δ = 124.2, 125.0, 125.2, 126.2, 130.7,
132.5, 133.1, 140.6, 144.1, 148.5 ppm; IR υmax: 3110, 3096, 1547,
1518 (NO2), 1501 (NO2), 1349, 1323, 855, 729, 698 cm-1; HRMS:
(m/z-ES) calcd for C10H5N2O4S (M-H)- 248.9976, found 248.9966.
Method B: Two-pot aliphatic - 2-Isobutyl-3-nitrothiophene (10)
Prepared via Method B using (E)-4-methyl-1-nitropent-1-ene (72
mg, 0.56 mmol), chloroform, 2,5-dihydroxy-1,4-dithiane (65 mg,
0.42 mmol) and triethylamine (20 L, 0.14 mmol) under an inert
atmosphere. The crude THT was treated with acidic alumina (720
mg), 4 Å molecular sieves (360 mg) and chloranil (550 mg, 2.24
Method C: One-pot aromatic
nitrothiophene (14)
-
2-(4-Methoxyphenyl)-3-

6
Tetrahedron
Prepared via method C using p-methoxy-trans--nitrostyrene (100
triethylamine (15 L, 0.11 mmol) in butylacetate.
After
consumption of the nitroalkene (monitored by TLC), chloranil (432
mg, 1.76 mmol), acidic alumina (600 mg) and 4 Å molecular sieves
(300 mg) were added and the reaction mixture heated for the
appropriate time. After treatment with KOH, charcoal and filtration
through a pad of silica gel, 18 was obtained as a yellow oil (46 mg,
0.23 mmol, 46%).
ACCEPTED MANUSCRIPT
mg, 0.58 mmol), 2,5-dihydroxy-1,4-dithiane (64 mg, 0.42 mmol) and
triethylamine (20 L, 0.15 mmol) in chloroform. After consumption
of the nitroalkene (monitored by TLC), DDQ (510 mg, 2.24 mmol),
silica gel (800 mg) and 4 Å molecular sieves (400 mg) were added
and the reaction mixture heated for the appropriate time. After
treatment with KOH, charcoal and filtration through a pad of silica
gel, 14 was obtained as a yellow solid (28 mg, 0.12 mmol, 23%).
m.p. 93-94 ºC, lit.9 93-94 ºC; Rf (10% EtOAc/hexane) 0.33; 1H
NMR (600 MHz, CDCl3): δ = 3.88 (s, 3H), 6.99 (d, J = 8.9 Hz, 2H),
7.23 (d, J = 5.7 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.65 ppm (d, J =
5.7 Hz, 1H); 13C NMR (151 MHz, CDCl3): δ = 55.2, 113.8, 122.5,
123.2, 124.9, 131.0, 142.4, 145.6, 160.6 ppm; IR υmax: 3103, 2966,
2836, 1609 (NO2), 1507 (NO2), 1455, 1328, 1243, 1027, 835, 700
cm-1; HRMS: (m/z-EI) calcd for C11H9O3NS (M)+ 235.0303, found
235.0294.
Rf (4% EtOAc/hexane on neutral alumina plates) 0.85; 1H NMR
(400 MHz, CDCl3):  = 0.92 (t, J = 7.0 Hz, 3H), 1.24-1.50 (m, 8H),
1.76 (p, J = 7.7 Hz, 2H), 3.24 (t, J = 7.7 Hz, 2H), 7.08 (d, J = 5.8
Hz, 1H), 7.60 ppm (d, J = 5.8 Hz, 1H); 13C NMR (101 MHz,
CDCl3):  = 114.1, 22.6, 28.9, 29.3, 29.5, 30.3, 31.7, 121.2, 124.6,
143.8, 150.4 ppm; IR υmax: 3121, 3103, 2954, 2924, 2854, 1538,
1500, 1458, 1374, 1331, 840, 776, 701 cm-1; HRMS: (m/z-EI) calcd
for C11H17NO2S (M)+ 227.0980, found 227.0984.
3-Nitrothiophene (21)
Method C: One-pot aromatic
nitrothiophene (13)
-
2-(2-Methoxyphenyl)-3-
A solution of 2-nitro-ethyl acetate (200 mg, 1.50 mmol), 2,5-
dihydroxy-1,4-dithiane (171 mg, 1.12 mmol) and triethylamine (52
l, 0.38 mmol) in butyl acetate (0.1 M) was stirred overnight at room
temperature under an inert atmosphere. After consumption of the 2-
nitro-ethyl acetate (as monitored by TLC, approximately 16 hours)
chloranil (1.48 g, 6.02 mmol), acidic alumina (1.6g) and 4 Å
molecular sieves (800 mg) were added. The resultant mixture was
heated at reflux for 40 hours. The reaction mixture was allowed to
cool to room temperature before charcoal (500 mg/mmol based on
starting nitroaceate) and powdered KOH (500 mg/mmol based on
starting nitroaceate) were added. The mixture was stirred for 1 hr
before being filtered through a pad of silica. The volatiles were
removed at reduced pressure to yield 21 (80 mg, 0.62 mmol, 41%
yield) as a white solid.
Prepared via method C using o-methoxy-trans--nitrostyrene (25
mg, 0.14 mmol), 2,5-dihydroxy-1,4-dithiane (15 mg, 0.10 mmol) and
triethylamine (5 L, 0.05 mmol) in chloroform. After consumption
of the nitroalkene (monitored by TLC), DDQ (118 mg, 0.52 mmol),
silica gel (200 mg) and 4 Å molecular sieves (100 mg) were added
and the reaction mixture heated for the appropriate time. After
treatment with KOH, charcoal and filtration through a pad of silica
gel, 13 was obtained as a pale green solid (12 mg, 0.05 mmol, 37%).
m.p. 79-81, lit9 80-82 ºC; Rf (20% EtOAc/hexane) 0.58; 1H NMR
(600 MHz, CDCl3):  = 3.81 (s, 3H), 7.00 (dd, J = 1.1, 8.4 Hz, 1H),
7.04-7.08 (m, 1H), 7.30 (d, J = 5.5 Hz, 1H), 7.37 (dd, J = 1.5, 7.3
Hz, 1H), 7.44-7.48 (m, 1H), 7.65 ppm (d, J = 5.5 Hz, 1H); 13C NMR
(151 MHz, CDCl3):  = 55.4, 111.0, 119.8, 120.4, 123.8, 124.3,
130.6, 131.0, 140.7, 144.3, 156.7 ppm; IR υmax: 3112, 3096, 2926,
m.p. 77-79 ºC, lit.14 76-77 ºC; 1H NMR (400 MHz, CDCl3):  =
7.31(dd, J = 3.5, 5.3 Hz, 1H), 7.66 (d, J = 5.3 Hz, 1H), 8.31 ppm (d,
J = 3.5 Hz, 1H), 13C NMR (151 MHz, CDCl3):  = 122.9, 127.0,
127.6 ppm, HRMS (m/z-EI) calcd for C4H3NO2S (M)+ 128.9885,
found 128.9884.
1543, 1503, 1488, 1462, 1456, 1375, 1329, 1248, 1018, 757, 724 cm-
1
;
HRMS: (m/z-EI) calcd for C11H9NO3S (M)+ 235.0303, found
235.0298.
Method D: One-pot aliphatic - 2-cyclohexyl-3-nitrothiophene
(17)
Acknowledgements
Prepared via method D using (E)-(2-nitrovinyl)cyclohexane (150
mg, 0.96 mmol), 2,5-dihydroxy-1,4-dithiane (110 mg, 0.72 mmol)
and triethylamine (34 L, 0.24 mmol) in butylacetate. After
consumption of the nitroalkene (monitored by TLC), chloranil (950
mg, 3.86 mmol), acidic alumina (1.20 g) and 4 Å molecular sieves
(600 mg) were added and the reaction mixture heated for the
appropriate time. After treatment with KOH, charcoal and filtration
through a pad of silica gel, 17 was obtained as a pale yellow solid
(93 mg, 0.44 mmol, 45%).
The authors are grateful to IRCSET (Irish Research Council for
Science and Engineering Technology), GlaxoSmithKline (Grant
N02033) and The School of Chemistry, Trinity College Dublin for
financial support to COC, MDR and NM respectively.
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7
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ACCEPTED MANUSCRIPT
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