Facile synthesis of 3-nitro-2-substituted thiophenes

Article abstract of DOI:10.1021/jo902656y

A new approach to 3-nitro-2-substituted thiophenes has been developed. Exposure of commercially available 1,4-dithane-2,5-diol to nitroalkenes in the presence of 20% triethylamine results in a tandem Michael?intramolecular Henry reaction to form the corresponding tetrahydrothiophene. Subsequent microwave irradiation on acidic alumina in the presence of chloranil effects the solvent free dehydration and aromatization to form 3-nitro-2-substituted thiophenes cleanly and rapidly. A simple workup procedure removes the requirement for purification by chromatography in most cases.

Full text of DOI:10.1021/jo902656y

pubs.acs.org/joc
Facile Synthesis of 3-Nitro-2-substituted Thiophenes
Cornelius J. O’ Connor,† Mark D. Roydhouse,† Anna M. Przybyz,†,‡ Michael D. Wall,§ and
J. Mike Southern*,†
†Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College,
Dublin 2, Ireland, ‡Focas Institute, Dublin Institute of Technology, Camden Row, Dublin 8, Ireland, and
§Discovery Medicinal Chemistry, GlaxoSmithKline, Gunnels Wood Rd., Stevenage, SG1 2NY,
United Kingdom
southerj@tcd.ie
Received January 5, 2010
A new approach to 3-nitro-2-substituted thiophenes has been developed. Exposure of commercially
available 1,4-dithane-2,5-diol to nitroalkenes in the presence of 20% triethylamine results in a
tandem Michael-intramolecular Henry reaction to form the corresponding tetrahydrothiophene.
Subsequent microwave irradiation on acidic alumina in the presence of chloranil effects the solvent
free dehydration and aromatization to form 3-nitro-2-substituted thiophenes cleanly and rapidly. A
simple workup procedure removes the requirement for purification by chromatography in most
cases.
Introduction
emitting diodes (OLEDs),10-12 organic field effect transistors
(OFETs),3,13 lasers,14 sensors, and photovoltaic cells.13,15-19
Interest in organic electronics stems from the possibility to
produce low-cost, large-area, lightweight, and flexible devices
with integrated functionalities of conventional silicon-based
components.3,20-25 The electronic properties of oligo-
and polythiophenes can be efficiently tuned by varying the
Thiophene-based materials have emerged as an important
class of electrically conducting organic materials.1-4
The seminal work of Shirakawa, MacDiarmid and Heeger
in conducting organic polymers in the late 1970s created a
new field of chemistry the growth of which has been nothing
short of phenomenal.5,6 Oligomeric and polymeric thio-
phenes have generated significant interest with potential
applications as organic semiconductors,7-9 organic light
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2534 J. Org. Chem. 2010, 75, 2534–2538
Published on Web 03/22/2010
DOI: 10.1021/jo902656y
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2010 American Chemical Society

O’ Connor et al.
JOCArticle
substitution of the thiophene core. Typically electron-donat-
ing substituents tend to produce p-type conducting materials
whereas electron-withdrawing substituents such as fluori-
nated hydrocarbons have a propensity toward n-type beha-
vior.26 Especially pertinent to the work reported herein is the
growing interest in n-type oligothiophenes (as opposed to the
more comprehensively studied p-type oligothiophenes).26,27
SCHEME 1. Formation of 3-Nitro-2-substituted Thiophenes
3-nitrothiophene in itself is protracted.35 In an alternative
approach, Devarie-Baez et al.36 reported a “one-pot” synthe-
sis of 2,3-disubstituted thiophenes starting from 3-bromo-
2-silylthiophene, which was employed as a 2,3-thienyldi-
anion equivalent. Unfortunately, this methodology requires
the synthesis of 3-bromo-2-silylthiophene and the use of
strong base. Reported herein is a rapid and general methodo-
logy for the preparation of 3-nitro-2-substituted thiophenes
from nitroalkenes. This approach involves a tandem Michael-
intramolecular Henry reaction between a thiolate anion
(formed in situ by dissociation of commercially available
dithiane 4) and a nitroalkene, which led to the formation of a
2,3,4-substituted tetrahydrothiophene (THT). Subsequent
dehydration and oxidation provided the 3-nitro-2-substi-
tuted thiophene (NT) (Scheme 1).
FIGURE 1. Some biologically important thiophenes.
This route possesses significant advantages over much
current methodology as it obviates the need for a blocking
group in the 5-position. The final dehydration/oxidation step
employed microwave irradiation on a solid support, using
solvent free conditions, furnishing the desired products in good
yield and high purity without the need for chromatography.
Since the appearance of the first article on the application of
microwaves for chemical synthesis in polar solvents,37 the
approach has developed considerably and is now considered
a general and useful technique for a variety of applications in
organic synthesis and functional group transformations.38-42
In recent years the focus has shifted to solvent-free methods,
wherein neat reactants, often in the presence of mineral oxides
or supported catalysts, undergo reactions to provide high
yields of products thus eliminating or minimizing the use of
organic solvents.38-41 The clear advantages of solvent-free
organic syntheses using supported reagents and microwave
irradiation has been concisely reviewed by Varma.42
Moreover, thiophenes have significant biological applica-
tions: the blockbuster drug Plavix is a potent antiplatelet
agent used in the treatment of coronary artery disease;28
Articaine is the most commonly used dental anesthetic in
Europe;29 and PaTrin-2 is an inhibitor of the DNA repair
enzyme O6-methylguanine-DNA methyl transferase with
potential to increase the effectiveness of alkylating agents
as cancer therapeutics (Figure 1).30 Thiophenes have recently
been shown to have excellent selective activity at the GLUk5
receptor31 and they also have exhibited potent activity
toward CB1 receptors with good CB1/CB2 selectivity.31,32
Despite the significant, long-standing interest in aromatic
heterocycles, the synthesis of 2,3-disubstituted thiophenes is
not always trivial. When possible, electrophilic aromatic
substitution (EAS) reactions take place preferentially (although
not exclusively) at the 2- and 5-positions often necessitating
the use and removal of blocking groups.33 Note that nitra-
tion of thiophene under standard conditions generates
an 85:15 ratio of 2-nitro:3-nitrothiophene that is difficult
to purify.33 Ballini et al.34 have reported the synthesis of
3-nitro-2-substituted thiophenes via addition of Grignard
reagents to 3-nitrothiophene; however, the synthesis of
Results and Discussion
Initial studies on the formation of the THTs were carried
out with the commercially available trans-β-nitrostyrene.
The first phase of the reaction sequence required the forma-
tion of the thiolate anion. This was achieved in situ by
treatment of dithiane 4 with a catalytic quantity of triethy-
lamine in the presence of nitroalkene 6 in dichloromethane at
room temeperature. The reaction proceeded smoothly and
the desired THT 8a was isolated in excellent 99% yield as a
3:2 mixture of diastereomers.
(26) Ie, Y.; Umemoto, Y.; Okabe, M.; Kusunoki, T.; Nakayama, K. i.;
Pu, Y. J.; Kido, J.; Tada, H.; Aso, Y. Org. Lett. 2008, 10, 833–836.
(27) Ie, Y.; Nitani, M.; Ishikawa, M.; Nakayama, K. i.; Tada, H.;
Kaneda, T.; Aso, Y. Org. Lett. 2007, 9, 2115–2118.
(28) Bristol-MyersSquib. http://www.bms.com (accessed December 9,
2009)
(29) Schulze, K. E.; Cohen, P. R.; Nelson, B. R. Dermatol. Surg. 2006, 32,
407–410.
(35) Blatt, A.; Bach, S.; Kresch, L. J. Org. Chem. 1957, 22, 1693–1695.
(36) Devarie-Baez, N. O.; Shuhler, B. J.; Wang, H.; Xian, M. Org. Lett.
2007, 9, 4655–4658.
(37) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge,
L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279–282.
(38) Varma, R. S.; Meshram, H. M. Tetrahedron Lett. 1997, 38, 5427–
5428.
(30) McMurry, T. B. H. DNA Repair 2007, 6, 1161–1169.
(31) Dolman, N. P.; Troop, H. M.; More, J. C. A.; Alt, A.; Knauss, J. L.;
Nistico, R.; Jack, S.; Morley, R. M.; Bortolotto, Z. A.; Roberts, P. J.;
Bleakman, D.; Collingridge, G. L.; Jane, D. E. J. Med. Chem. 2005, 48, 7867–
7881.
(32) Dolman, N. P.; More, J. C. A.; Alt, A.; Knauss, J. L.; Pentikainen,
O. T.; Glasser, C. R.; Bleakman, D.; Mayer, M. L.; Collingridge, G. L.; Jane,
D. E. J. Med. Chem. 2007, 50, 1558–1570.
(39) Varma, R. S.; Dahiya, R.; Saini, R. K. Tetrahedron Lett. 1997, 38,
7029–7032.
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(33) Gronowitz, S.; Hornfeldt, A.-B. Thiophenes; Elsevier Academic
Press: San Diego, CA, 2003.
(40) Varma, R. S.; Dahiya, R. Tetrahedron Lett. 1998, 39, 1307–1308.
(41) Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav, J. S. Green
Chem. 1999, 1, 141.
(34) Ballini, R.; Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.
Tetrahedron 1988, 44, 6435–6440.
(42) Varma, R. S. Green Chem. 1999, 1, 43.
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TABLE 1. Substrate Scope for Formation of THTs
Attempts to expand the scope of the reaction proved
successful and a wide range of R groups (H, aromatic,
heterocyclic, aliphatic, and CH2OTBS) are tolerated and
the THTs were isolated in good yield (Table 1). Nitroalkenes
which were not commercially sourced were prepared accord-
ing to procedures by Denmark et al.43 or Kawai et al.44
Despite the inevitable loss of the chiral centers upon
conversion to 3-nitro-2-phenyl thiopene (8b), the diastereo-
mers of 8a were separated with column chromatography,
thereby enabling more facile NMR assignment for sub-
sequent diastereomeric mixtures. A combination of X-ray
structural analysis and 1H NMR indicated that there was an
anti relationship between the nitro group and the R group in
both diastereomers (presumably arising from the (E)-stereo-
chemistry of the nitroalkenes employed). In the major dia-
stereomer there was an anti relationship between the nitro
group and the hydroxyl group whereas in the minor diaster-
eomer there was a syn relationship between the nitro group
and the hydroxyl group. In general, assignment of the major
and minor THT diastereomers was possible from the magni-
tude of the coupling constants between H3 and H4 of the
THT ring in each diastereomer and also the separation of the
signals arising from the diastereotopic H5 protons. The
THTs were formed with diastereomeric ratios between 1:1
and 3:1 for larger R groups (see the Supporting Information
for specific ratios); in some cases, NMR data indicated that
traces of other isomers were present.
Dehydration and aromatization of the phenyl-substituted
THT 8a was initially attempted by using thermal and solu-
tion-based methodologies (Scheme 2). Initial studies in-
volved treatment of a solution of 8a in dichloromethane
with trifluoroacetic anhydride and triethylamine at -15 °C
with subsequent addition of DDQ and heating at reflux for
48 h. This gave 3-nitro-2-phenylthiophene after a protracted
workup and extensive column chromatography in a max-
imum yield of 59%. Unfortunately, when this methodology
was extended to aliphatic substrates, the yields were con-
siderably lower, <30%.
SCHEME 2. Two-Pot Dehydration and Aromatization of 8a
Fortunately, it was later discovered that a one-pot dehydra-
tion/aromatization procedure employing microwave irradia-
tion and a solid support under solvent-free conditions genera-
ted the corresponding 3-nitro-2-phenylthiophene extremely
rapidly in good yield.
The reactions were performed by grinding the THT to-
gether with acidic alumina and chloranil (using a mortar and
pestle) followed by irradiation of the mixture in a laboratory
microwave (CEM Discovery series) for 4 min, with the
maximum temperature set to 125 °C and maximum power
set to 200 W. Table 2 summarizes the studies undertaken to
optimize this step of the reaction.
aThe nitroalkene was generated in situ from the appropriate nitroa-
cetate precursors (see the Supporting Information for the general
procedure).
(43) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1993, 58, 3850–3856.
(44) Kawai, Y.; Inaba, Y.; Tokitoh, N. Tetrahedron: Asymmetry 2001, 12,
309–318.
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TABLE 2. Optimization Experiments for Dehydration and Aromati-
zation of THT 8a
TABLE 3. Substrate Scope for Formation of NTs
alumina
(equiv w/w)
chloranil
(equiv)
yield 8b
(%)
entry
1
2
3
4
5
6
10
15
20
20
20
20
1.1
1.1
0
1.1
1.5
2.0
70
86
54
90
91
91
The best yield, cleanest reaction, and most facile workup
was achieved employing 20 equiv (w/w) of acidic alumina with
1.5 equiv of chloranil, which gave 3-nitro-2-phenylthiophene
in91% yield. It isworth notingthat silicagel and 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ) provide an alternative
solid support and oxidant though yields were reduced.
Fortunately, exposure of the THTs previously prepared
with a variety of substituents to the same conditions gene-
rated the corresponding 3-nitro-2-substituted thiophenes
generally in good yields (Table 3). Surprisingly the majority
of the THTs and NTs described are novel compounds. In
addition to the incorporation of aromatic, heterocyclic, and
aliphatic substituents, formation of the dimeric system 10b,
25b (R = H forming 3-nitrothiophene exclusively), and 32b
(R = CH2OTBS, which provides a functional handle for
further manipulation, such as nitroalkene formation) are of
particular note.
To assess the applicability of this technology to scale-up
and the use of a less sophisticated microwave device, the
reactions (up to 13 mmol) were also attempted in a conven-
tional 800 W kitchen microwave. Irradiation of the THT 8a
(R = Ph) for 6 min at full power with 10 equiv of acidic
alumina and 2 equiv of chloranil in an open vessel gave the
i
expected thiophene 8b in 83% yield. When R = Bu,
irradiation of the THT with 20 equiv of alumina and 4 equiv
of chloranil for 8 min at full power gave the corresponding
thiophene 29b in 78% yield.
In keeping with the microwave-based philosophy of rapid
synthesis we sought to remove the requirement for column
chromatography and devised a less labor intensive method of
purification. It was found that stirring the crude reaction in
dichloromethane for 1 h followed by the addition of solid
potassium hydroxide (500 mg/mmol) and activated charcoal
(500 mg/mmol) with a further 1 h of stirring followed by
filtration through a plug of silica gel gave the desired 3-nitro-
2-substituted thiophenes without the requirement for further
purification. Alternative solvents proved less successful:
diethyl ether gave products with a similar high level of purity
but reduced yield while ethyl acetate gave lower purity and
yield than dichloromethane.
aPoor yield attributed to the limited solubility of 10b in organic
solvent.
wide range of substituents (aromatic, heterocyclic, aliphatic,
H, CH2OTBS) at the 2-position has been developed. The
methodology does not require the use of blocking groups and
the rapid workup/isolation procedure precludes the requirement
Conclusion
In summary, a novel, rapid, and general route to synthe-
tically useful 3-nitro-2-substituted thiophenes bearing a
J. Org. Chem. Vol. 75, No. 8, 2010 2537

O’ Connor et al.
JOCArticle
for chromatography for the majority of postsynthetic applica-
tions. The nitro group can serve two further purposes: Its
powerful directing effect will ensure exclusive (rather than
preferential) electrophilic aromatic substitution reactivity at
the 5-position. The nitro group also provides an excellent
functional handle to install a variety of other substituents by
reduction, diazotization, and substitution with a variety of
nucleophiles. We are currently exploring the properties of the
NTs produced via this methodology and are examining the
possibility of using a similar approach to prepare furans and
pyrroles. In addition, we are currently evaluating the medi-
cinal properties of these compounds.
General Procedure for the Synthesis of Nitrothiophenes with
Use of a Chemical Microwave, Procedure C. The appropriate
THT (0.44 mmol) and oven-dried acidic alumina (2.00 g) were
ground together in a mortar. (Liquid THTs were adsorbed onto
the oven-dried acidic alumina prior to grinding.) Chloranil (0.15
g, 0.61 mmol) was introduced and the solids were further ground
together. The pale yellow solids were placed in a microwave
sample tube and the sample was irradiated in a chemical micro-
wave (CEM discovery series) at 125 °C for 4 min (maximum
power set to 200 W). To the cooled solids was added CH2Cl2
(15 mL) and the mixture was stirred for 1 h. Ground charcoal
(250 mg) and ground potassium hydroxide powder (250 mg,
4.46 mmol) were added and the mixture was stirred for a further
1 h. The slurry was filtered through a plug of silica (∼50 mL) and
the solids were washed with CH2Cl2 (150 mL). Volatiles were
removed at reduced pressure.
Experimental Section
General Procedure for the Synthesis of Tetrahydrothiophenes
from Nitroalkene Precursors, Procedure A. To a stirred solution
of the appropriate nitroalkene (2.00 mmol) in CH2Cl2 (5.6 mL)
were added 2,5-dihydroxy-1,4-dithiane (0.23 g, 1.50 mmol) and
triethylamine (56 μL, 0.40 mmol) under an argon atmosphere.
The reaction was stirred at room temperature overnight. The
reaction was diluted with CH2Cl2 (20 mL) and the suspended
solid was removed by filtration. A solution of saturated ammo-
nium chloride (20 mL) was added to the filtrate and the aqueous
layer was extracted with CH2Cl2 (2 Â 20 mL). The combined
organic layers were washed with water (20 mL) and brine
(20 mL) and then dried over magnesium sulfate. Volatiles were
removed at reduced pressure and the resulting residue was
purified by column chromatography.
Acknowledgment. IRCSET (Irish Research Council for
Science and Engineering Technology), GlaxoSmithKline
(Grant N02033), and HEA (Strand 1 Technological Sector
Research and Development Skills) are gratefully acknowl-
edged for funding C.J.O’C., M.D.R., and A.P., respectively.
The authors thank Drs. John O’ Brien and Manuel Reuther
for NMR assistance. Dr. Tom McCabe is thanked for X-ray
analysis. The authors would also like to thank the EPSRC
Mass Spectrometry Centre (Swansea University) for their
assistance. Dr. Sarah Rawe and Prof. Mathias Senge are
acknowledged for helpful contributions.
General Procedure for Synthesis of Tetrahydrothiophenes from
Nitroacetate Precursors, Procedure B. To a stirred solution of
the appropriate nitroacetate (2.16 mmol) in CH2Cl2 (6.0 mL)
were added 2,5-dihydroxy-1,4-dithiane (170 mg, 1.08 mmol) and
triethylamine (330 μL, 2.38 mmol) under an argon atmosphere.
Stirring was continued at room temperature overnight. The
reaction was diluted with CH2Cl2 (20 mL) and the suspended
solid was removed by filtration. Water (20 mL) was added to the
filtrate and the aqueous layer was extracted with CH2Cl2 (2 Â
20 mL). The combined organic layers were washed with water
(20 mL) and brine (20 mL) and then dried over magnesium
sulfate. Volatiles were removed at reduced pressure and the
resulting residue was purified by column chromatography.
Supporting Information Available: Detailed experimental
procedures and full characterization including 1H/13C NMR
spectra of new compounds in addition to crystal/refinement
data and thermal elipsoid plots of compounds 21a, 29a, and
19b. This material is available free of charge via the Internet at
http://pubs.acs.org. The crystallographic coordinates have
been deposited with the Cambridge Crystallographic Data
Centre; deposition nos. 739460 (21a), 739461 (29a), and 739459
(19b). These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Rd.,
Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/
retrieving.html.
2538 J. Org. Chem. Vol. 75, No. 8, 2010