A useful one-pot procedure for obtaining 2-aryl-5-nitrothiophenes from bromonitromethane and 3-aryl-3-chloro-propenals

Article abstract of DOI:10.1055/s-2007-1000881

A one-pot procedure was developed to prepare new 2-aryl-5-nitrothiophenes efficiently from bromonitromethane and 3-chloro-3-aryl-propenals. Nitrothiophenes were synthesized in good yields with a simple and easy workup procedure. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2007-1000881

286
LETTER
A Useful One-Pot Procedure for Obtaining 2-Aryl-5-nitrothiophenes from
Bromonitromethane and 3-Aryl-3-chloro-propenals
Synthesis
u
of 2-Aryl-5-n
a
itrothiophe
n
ne
s
C. Rodríguez-Domínguez,a David Thomae,a Pierre Seck,b Gilbert Kirsch*a
a
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843,
Université Paul Verlaine-Metz, 1 Boulevard Arago, Metz, 57070, France
Fax +33(3)87315801; E-mail: kirsch@univ-metz.fr
Faculté des Sciences, de la Technologie et de la Communication, Université du Luxembourg,
162 A, Avenue de la Faiencerie, 1511 Luxembourg
b
Received 19 October 2007
Another way for preparing 2-aryl-5-nitrothiophenes is the
Suzuki coupling of the 2-bromo-5-nitrothiophene with the
corresponding aryl boronic acids (Scheme 2).2
Abstract: A one-pot procedure was developed to prepare new 2-
aryl-5-nitrothiophenes efficiently from bromonitromethane and 3-
chloro-3-aryl-propenals. Nitrothiophenes were synthesized in good
yields with a simple and easy workup procedure.
B(OH)2
Key words: 5-nitrothiophenes, bromonitromethane, 3-aryl-3-chlo-
ro-propenals
Pd(0)
NO2
+
S
Br
NO2
S
toluene
reflux
16 h
F
82%
F
2-Aryl-5-nitrothiophenes show inhibitory activity against
some microorganisms1 and are used as intermediates in
the preparation of potent inhibitors of 5-lipoxygenase.2
They were prepared by direct nitration of the 2-phenyl-
thiophene with either nitric acid or different proportions
of Cu(NO3)2 in acetic anhydride3 but in all cases mononi-
tration was not selective and also dinitration took place.
When nitric acid was employed, a mixture of 2-nitro-5-
phenyl and 3-nitro-2-phenylthiophenes was obtained. If
the reaction was carried out with Cu(NO3)2, mixtures of 3-
nitro-2-phenyl, 2-nitro-5-phenyl, 3,5-dinitro-2-phenyl,
and 2-nitro-5-(2-nitrophenyl)thiophenes were recovered
as final products (Scheme 1).
Scheme 2 Synthesis of the 5-(4-fluorophenyl)-2-nitrothiophene by
Suzuki coupling (palladium complexes were used)
This coupling reaction was applied for the same purpose
in order to obtain the 2-nitro-5-(4-methoxy)phenyl-
thiophene from the corresponding iodophenyl derivative
(Scheme 3).4,5 Even if Suzuki coupling allows the obtain-
ment of the aryl nitrothiophene in good yield (Scheme 2),
usually palladium catalysis requires long reaction times to
prepare the targeted derivatives (Schemes 2 and 3). In the
case when p-iodoanisole was employed (Scheme 3), the
isolated yield was low.5
Cu(NO3)2
OMe
NO2
S
Ac2O
S
Pd(AcO)2
+
+
NO2
MeCN
H2O
80 °C, 54 h
S
NO2
S
O2N
MeO
concd HNO3
37%
X
Ac2O
S
X = I
Scheme 3 Synthesis of the 5-(4-methoxyphenyl)-2-nitrothiophene
by Suzuki coupling (palladium acetate was used)
+
NO2
S
O2N
+
O2N
Bromonitromethane is a versatile reagent used in stabi-
lized solutions as biocide,6 in the synthesis of 1-bromo-1-
nitroalkan-2-ols,7 polyfunctionalized nitrocyclopro-
panes,8 aryl nitromethanes, and as bromine donor.9 It has
also been utilized in the synthesis of 2-nitrobenzofuran
and 2-nitro-2,3-dihydrobenzofuran-3-ols,10,11 nitroben-
zothiophenes, and nitrothiazoles.12
NO2
S
+
S
NO2
NO2
S
Scheme 1 Direct nitration of 2-phenylthiophene by either concen-
trated nitric acid or copper nitrate in acetic anhydride
In the thiophene series only few examples have been de-
scribed; in the case of 2-tert-butyl-5-nitrothiophene,13 no
experimental details are given. In order to synthesize new
2-aryl-5-nitrothiophenes, we have developed a one-pot
procedure allowing access to thiophene derivatives in
SYNLETT 2008, No. 2, pp 0286–0288
x
x.
x
x.
2
0
0
7
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000881; Art ID: G31507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aryl-5-nitrothiophenes
287
good yields with
(Scheme 4).14
a
simple workup procedure
Acknowledgment
We are grateful to the French Ministry of National Education, Hig-
her Education and Research for a PhD grant (D.T). We also thank
the Ministère de la Culture, de l’Enseignement Supérieur et de la
Recherche de Luxembourg for the financial support and Mrs. Véro-
nique Poddig for recording the NMR spectra.
Starting 3-aryl-3-chloro-2-propenals were prepared as de-
scribed earlier and spectroscopic data match with those re-
ported in literature.15 New 3-(3-bromophenyl)-3-chloro-
2-propenal was adequately characterized.16
Bromonitromethane was prepared according to Fishwick
et al.12 Freshly distilled nitromethane was used and bro-
mine was dropped in 5 seconds instead of 35 seconds as
reported. With this slight modification only monobromi-
nation is effected and bromonitromethane could be used
without further purification.17
References and Notes
(1) Morley, J. O.; Matthews, T. P. Org. Biomol. Chem. 2006, 4,
359.
(2) Beers, S. A.; Malloy, E. A.; Wu, W.; Wachter, M.; Ansell,
J.; Singer, M.; Steber, M.; Barbone, A.; Kirchner, T.;
Ritchie, D.; Argentieri, D. Bioorg. Med. Chem. 1997, 5, 779.
(3) (a) Gronowitz, S.; Gjos, N. Acta Chem. Scand. 1967, 21,
2823. (b) Gronowitz, S.; Gjos, N. Acta Chem. Scand. 1972,
26, 1851.
(4) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.;
Lemaire, M. J. Organomet. Chem. 1998, 567, 49..
(5) Gozzi, C.; Lavenot, L.; llg, K.; Penalva, V.; Lemaire, M.
Tetrahedron Lett. 1997, 38, 8867.
In order to obtain 2-nitrophenylthiophenes, we performed
reactions in a one-pot procedure from 3-aryl-3-chloro-2-
propenals, which are converted into the corresponding so-
dium 3-aryl propenal-3-thiolates by reacting with
Na2S·9H2O in dimethylformamide. Addition of bromoni-
tromethane and subsequent basic catalyzed intramolecu-
lar cyclization gave the desired mononitrothiophenes in
good yields with an easy workup procedure.
(6) Termine, E. J.; Dallmier, A. W.; Yeoman, A. M. US
5866511, 1999.
(7) Concellón, J. M.; Rodríguez-Solla, H.; Concellón, C.;
García-Granda, S.; Díaz, M. R. Org. Lett. 2006, 8, 5979.
(8) Ballini, R.; Fiorini, D.; Palmieri, A. Synlett 2003, 1704.
(9) Sherrill, M. L. J. Am. Chem. Soc. 1924, 46, 2753.
(10) Ohishi, Y.; Doi, Y.; Nakanishi, T. Chem. Pharm. Bull. 1984,
32, 4260.
R1
1. Na2S⋅9H2O
DMF
R1
R2
CHO
Cl
R2
NO2
2. BrCH2NO2
3. NaOH (aq)
S
(11) Tromelin, A.; Demerseman, P.; Royer, R. Synthesis 1985,
1074.
(12) Fishwick, B. R.; Rowles, D. K.; Stirling, C. J. M. J. Chem.
Soc., Perkin Trans. 1 1986, 1171.
Scheme 4 Developed procedure to obtain mononitrophenylthio-
phenes from 3-chloroacroleins and bromonitromethane
(13) Cagniant, P.; Kirsch, G. C. R. Seances Acad. Sci., Ser. C
1975, 273, 35.
Structures of prepared compounds are referred to in Table 1.
(14) Typical Experimental Procedure for Obtaining
Mononitrophenylthiophenes
Table 1 Prepared Mononitrophenylthiophenes
Entry
R1
H
H
H
H
H
H
H
R2
Yield (%)
71.3
Sodium sulfide (Na2S·9H2O, 0.05 mol) was suspended in
DMF (98 mL) and stirred at 40 °C for 30 min. After that time
the corresponding 2-chloroacrolein (0.05 mol) was added.
The mixture was then heated at 55 °C for 90 min and left to
reach r.t. Bromonitromethane (0.05 mol) was slowly
dropped at r.t. and left to stir at 55 °C for another 90 min. The
reaction was followed by TLC (n-hexane–EtOAc, 3:1) and,
once finished, NaOH (0.05 mol) in H2O (10 mL) was added
and the mixture was left to stir 30 min at the same
temperature. The mixture was poured onto H2O with good
stirring and the obtained precipitate was filtered, washed
with H2O, and dried at r.t. until the weight was constant.
(15) Prim, D.; Fuss, A.; Kirsch, G.; Silva, A. M. S. J. Chem. Soc.,
Perkin Trans. 2 1999, 1175.
1
2
3
4
5
6
7
4-Chlorophenyl
4-Fluorophenyl
4-Methylphenyl
4-Methoxyphenyl
4-Nitrophenyl
1,1¢-Biphenyl-4-yl
3-Bromophenyl
61.7
82.6
73.5
74.8
61.5
70.6
(16) 3-(3-Bromophenyl)-3-chloro-2-propenal
Yield 74.3%; orange solid, mp 64–65 °C (from EtOH). 1H
NMR (250 MHz, DMSO-d6): d = 10.10 (d, J = 6.5 Hz, 1 H,
HCO), 8.04 (d, J = 3.3 Hz, 1 H, PhH), 7.87 (dd, 1 H, PhH),
7.75 (dd, 1 H, PhH), 7.46 (m, 1 H, PhH), 7.04 (d, J = 6.6 Hz,
1 H, H2). 13C NMR (62.9 MHz, DMSO-d6): d = 191.30,
148.43, 136.99, 134.49, 130.96, 129.53, 126.25, 125.39,
122.23. Anal. Calcd for C9H6BrClO (245.50): C, 44.03; H,
2.46; Br, 32.55; Cl, 14.44. Found: C, 43.99; H, 2.50; Br,
32.59; Cl, 14.41.
8
85.2
NO2
S
All prepared nitrothiophenes were purified by recrystallization.
Chemical properties and spectroscopic data of known and new 2-
aryl-5-nitrothiophenes are shown.18
(17) Purity was checked by 1H NMR spectroscopy using a Bruker
250 MHz instrument.
Synlett 2008, No. 2, 286–288 © Thieme Stuttgart · New York

288
J. C. Rodríguez-Domínguez et al.
LETTER
d6): d = 160.95, 152.04, 148.05, 130.44, 127.47, 123.71,
122.66, 114.86, 55.19. Anal. Calcd for C11H9NO3S (235.26):
C, 50.11; H, 2.52; Cl, 14.79; N, 5.84; S, 13.38. Found: C,
56.16; H, 3.86; N, 5.95; S, 13.63.
2-(4-Nitrophenyl)-5-nitrothiophene (5): mp 166–170 °C
(from EtOH); mpLit 179 °C (from EtOH–H2O).3 IR (KBr):
n = 1516 (NO2), 1345 (NO2) cm–1. 1H NMR (250 MHz,
DMSO-d6): d = 8.29 (d, J = 8.65 Hz, 2 H, HPh), 8.21 (dd, 1
H), 8.09 (d, J = 8.75 Hz, 2 H, HPh), 7.87 (dd, 1 H). 13C NMR
(62.9 MHz, DMSO-d6): d = 151.17, 147.81, 137.35, 131.02,
130.27, 127.24, 126.51, 124.41.
2-[1,1¢-Biphenyl]-4-yl-5-nitrothiophene (6): mp 166–
169 °C (from EtOH). IR (KBr): n = 1485 (NO2), 1300 (NO2)
cm–1. 1H NMR (250 MHz, DMSO-d6): d = 8.37–7.82 (m, 11
H). 13C NMR (62.9 MHz, DMSO-d6): d = 152.2, 148.8,
148.7, 138.3, 132.1, 131.1, 128.3, 128.1, 127.5, 125.4,
125.1, 124.7. Anal. Calcd for C16H11NO2S (281.33): C,
68.31; H, 3.94; N, 4.98; S, 11.40. Found: C, 68.38; H, 4.01;
N, 4.95; S, 11.36.
2-(3-Bromophenyl)-5-nitrothiophene (7): mp 76–79 °C
(from EtOH). IR (KBr): n = 1534 (NO2), 1470 (NO2) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.16 (d, J = 5.0 Hz, 1
H, H3-Thioph), 8.07–8.05 (m, 1 H), 7.82–7.79 (m, 1 H), 7.75
(d, J = 5.0 Hz, H4-Thioph), 7.68–7.64 (m, 1 H), 7.44 (t, 1 H).
13C NMR (62.9 MHz, DMSO-d6): d = 150.06, 133.65,
132.81, 131.48, 131.08, 128.57, 125.34, 125.08, 122.74,
122.72. Anal. Calcd for C10H6BrNO2S (284.13): C, 42.27;
H, 2.13; Br, 28.12; N, 4.93; S, 11.29. Found: C, 42.22; H,
2.16; Br, 28.08; N, 4.89; S, 11.25.
2-Nitro-4,5-dihydronaphtho[1,2b]thiophene (8): mp 114–
116 °C (from EtOH). IR (KBr): n = 1531 (NO2), 1326 (NO2)
cm–1. 1H NMR (250 MHz, DMSO-d6): d = 8.09 (s, 1 H, H3-
Thioph), 7.55 (d, J = 7.5 Hz, 1 H), 7.37–7.32 (m, 3 H), 2.96–
2.93 (m, 2 H, CH2), 2.87–2.84 (m, 2 H, CH2). 13C NMR (62.9
MHz, DMSO-d6): d = 147.75, 143.91, 137.50, 136.20,
130.63, 130.03, 128.64, 128.49, 127.52, 123.99, 27.43,
22.78. Anal. Calcd for C12H9NO2S (231.27): C, 62.32; H,
3.92; N, 6.06; S, 13.87. Found: C, 62.40; H, 3.99; N, 6.10; S,
13.84.
(18) Reagents were purchased from ACROS Organics. Thin-
layer chromatography (TLC) was carried out by using
SilicaGel 60 F-254 plates and n-hexane–EtOAc (3:1) as an
eluent. Melting points were determined on a Stuart Scientific
SMP 3 capillary melting point apparatus and are
uncorrected. IR spectra were performed in a Perkin Elmer
Spectrum BxFT-IR spectrophotometer. Elemental analyses
were conducted in a LECO CHNS 932 instrument.
2-(4-Chlorophenyl)-5-nitrothiophene (1): mp 121–124 °C
(from EtOH). IR (KBr): n = 1534 (NO2), 1333 (NO2) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.19 (d, J4,3 = 7.5 Hz, 1
H, H4), 7.88 (d, J = 10.0 Hz, 2 H, HPh), 7.72 (d, J3,4 = 5.0
Hz, 1 H, H3), 7.58 (d, J = 10 Hz, 2 H, HPh). 13C NMR (62.9
MHz, DMSO-d6): d = 149.83, 149.57, 134.86, 131.27,
129.44, 129.31, 127.79, 124.56. Anal. Calcd for
C10H6ClNO2S (239.68): C, 50.11; H, 2.52; Cl, 14.79; N,
5.84; S, 13.38. Found: C, 50.20; H, 2.60; Cl, 14.70; N, 5.80;
S, 13.32.
2-(4-Fluorophenyl)-5-nitrothiophene (2): mp 124–126 °C
(from EtOH); mpLit 129–130 °C.2 IR (KBr): n = 1536
(NO2), 1334 (NO2) cm–1. 1H NMR (250 MHz, DMSO-d6):
d = 8.14 (d, J = 4.25 Hz, 1 H), 7.87 (dd, 2 H, HPh), 7.63 (d,
J = 4.25 Hz, 1 H), 7.33 (m, 2 H, HPh). 13C NMR (62.9 MHz,
DMSO-d6): d = 161.1, 150.2, 131.3, 128.6, 128.4, 124.1,
116.8, 116.5.
2-(4-Methylphenyl)-5-nitrothiophene (3): mp 86–87 °C
(from diisopropyl ether). IR (KBr): n = 1510 (NO2), 1333
(NO2) cm–1. 1H NMR (250 MHz, DMSO-d6): d = 8.13 (d,
J = 4.45 Hz, 1 H), 7.71 (d, J = 8.07 Hz, 2 H, HPh), 7.61 (d,
J = 4.37 Hz, 1 H), 7.30 (d, J = 7.72 Hz, 2 H, HPh), 2.34 (s, 3
H, CH3). 13C NMR (62.9 MHz, DMSO-d6): d = 151.85,
140.36, 131.37, 130.02, 128.71, 126.12, 123.38, 20.85.
Anal. Calcd for C11H9NO2S (219.26): C, 60.26; H, 4.14; N,
6.39; S, 14.62. Found: C, 60.30; H, 4.19; N, 5.32; S, 14.68.
2-(4-Methoxyphenyl)-5-nitrothiophene (4): mp 129–131 °C
(from cyclohexane); mpLit 135 °C.5 IR (KBr): n = 1536
(NO2), 1337 (NO2) cm–1. 1H NMR (250 MHz, DMSO-d6):
d = 8.14 (d, J = 5.0 Hz, 1 H, H4), 7.79 (d, J = 7.5 Hz, 2 H,
HPh), 7.57 (d, J3,4 = 5.0 Hz, 1 H, H3), 7.06 (d, J = 7.5 Hz, 2
H, HPh), 3.83 (s, 3 H, OCH3). 13C NMR (62.9 MHz, DMSO-
Synlett 2008, No. 2, 286–288 © Thieme Stuttgart · New York