Reactions of 2-benzylidene-3-methyl-4-nitro-2,5-dihydrothiophene 1,1-dioxide with CH acids

Article abstract of DOI:10.1134/S1070428009120100

2-Benzylidene-3-methyl-4-nitro-2,5-dihydrothiophene 1,1-dioxide reacted with acyclic CH acids (acetylacetone, diethyl malonate, and its derivatives) according to the 1,4-addition pattern, whereas reactions of the title compound with cyclohexane-1,3-dione

Full text of DOI:10.1134/S1070428009120100

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1814–1817. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.M. Berestovitskaya, M.V. Selivanova, M.I. Vakulenko, I.E. Efremova, G.A. Berkova, 2009, published in Zhurnal Organicheskoi
Khimii, 2009, Vol. 45, No. 12, pp. 1818–1821.
Reactions of 2-Benzylidene-3-methyl-4-nitro-2,5-dihydro-
thiophene 1,1-Dioxide with CH Acids
V. M. Berestovitskaya, M. V. Selivanova, M. I. Vakulenko, I. E. Efremova, and G. A. Berkova
Hertzen Russian State Pedagogical University, nab. r. Moiki 48, St. Petersburg, 191186 Russia
e-mail: kohrgpu@yandex.ru
Received December 24, 2008
Abstract—2-Benzylidene-3-methyl-4-nitro-2,5-dihydrothiophene 1,1-dioxide reacted with acyclic CH acids
(acetylacetone, diethyl malonate, and its derivatives) according to the 1,4-addition pattern, whereas reactions of
the title compound with cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-1,3-dione (dimedone) were com-
plicated by subsequent intramolecular heterocyclization leading to thieno[3,2-b]chromene derivatives.
DOI: 10.1134/S1070428009120100
Persistent interest in dihydrothiophene 1,1-dioxides
originates from their versatile synthetic potential and
broad spectrum of practically important properties
[1, 2]. Compounds possessing antiphlogistic, psycho-
tropic, antiasthmatic, and antinarcotic activity, pesti-
cides, antioxidants, and rubber accelerators were syn-
thesized on the basis of dihydrothiophene 1,1-dioxides
[3, 4]. 2-Benzylidene-4-nitro-2,5-dihydrothiophene
1,1-dioxide and its analogs occupy a specific place
among functionally substituted dihydrothiophene
1,1-dioxides [5, 6]. Polarization of the conjugated
diene system in their molecules makes these com-
pounds highly reactive toward nitrogen- and sulfur-
centered nucleophiles [7]. The ability of 2-benzyli-
dene-4-nitro-2,5-dihydrothiophene 1,1-dioxides to
readily take up carbon-centered nucleophiles (in the
absence of a catalyst at 18–20°C) was demonstrated
previously by their reaction with 1-phenyl-3-methyl-
pyrazol-5-one [6]. We believed to be important to
examine the behavior of 2-benzylidene-4-nitro-2,5-di-
hydrothiophene 1,1-dioxides in the Michael reaction
with typical CH acids.
In fact, 2-benzylidene-3-methyl-4-nitro-2,5-dihy-
drothiophene 1,1-dioxide (I) reacted with a number of
linear β-dicarbonyl compounds (malononitrile, di-
methyl and diethyl malonates, acetylacetone, and ethyl
acetoacetate) in alcohol or diethyl ether in the presence
of bases (NaOMe, Et3N) to give the corresponding
1,4-addition products II–VI (Scheme 1).
High degree of enolization and specific steric struc-
ture of cyclic β-diketones (such as dimedone and
cyclohexane-1,3-dione) favored their reactions with
diene I to follow a more complicated pattern. Pre-
sumably, the initial step is nucleophilic addition ac-
cording to the classical based-catalyzed Michael reac-
tion scheme. However, this process is followed by
double bond transfer to the β-position of the thiophene
ring and nucleophilic attack by the enolic hydroxy
group on the C3 atom in the nitroethene fragment,
leading to thieno[3,2-b]chromene derivatives VII and
VIII [8] (Scheme 2).
Compounds II–VIII are stable under normal condi-
tions. On the other hand, heating of II–VI in alcoholic
solution could promote the reverse reaction with
Scheme 1.
NO2
Me
NO2
Me
Ha
4
HX
3
*
7
Y
X
2
HA
HB
+
5
X
Y
1
S
*
6
S
Ph
Ph
O
O
O
O
Hb
I
II–VI
II, X = Y = CO2Me; III, X = Y = CO2Et; IV, X = COMe, Y = CO2Et; V, X = Y = COMe; VI, X = Y = CN.
1814

REACTIONS OF 2-BENZYLIDENE-3-METHYL-4-NITRO-2,5-DIHYDROTHIOPHENE
1815
Scheme 2.
O
R
R
Me
NO2
OH
OH
H
Me
O
Me
O
NO2
NO2
R
R
+
S
R
S
S
O
Ph
Ph
Ph
O
O
H
R
O
O
O
O
I
O2N
HX
Me
R
3
O
5
R
HA
HB
*
1
S
2
6
7
*
*
8
*
9
H
O
dO
Ph
Hc
O
VII, VIII
VII, R = H; VIII, R = Me.
formation of initial 2-benzylidene-3-methyl-4-nitro-
2,5-dihydrothiophene 1,1-dioxide (I) and the corre-
sponding CH acid. The driving force of this process is
likely to be high energetic favorability of conjugated
structure I.
spectrum contained signals from protons in the ali-
phatic groups of the X and Y substituents, which were
also doubled. Likewise, protons in the 3-methyl group
gave a doubled signal at 2.0 ppm.
1
We also recorded the H NMR spectra of II–V in
The IR spectra of compounds II–VI contained
absorption bands belonging to stretching vibrations of
nonconjugated nitro (1580–1570, 1375–1365 cm–1)
and sulfonyl groups (1340–1320, 1170–1140 cm–1).
Compounds II–V also displayed doubled absorption
bands in the region 1760–1710 cm–1, which are typical
of β-dicarbonyl fragment, and stretching vibrations of
the cyano group in VI gave rise to absorption band
at 2230 cm–1.
a series of solvents with different polarities and dielec-
tric constants [CDCl3, C6D6, and (CD3)2CO] to make
sure that the observed doubling of signals originates
from the presence of diastereoisomers rather than of
conformers resulting from restricted conformational
1
transitions. In addition, the H NMR spectra were
recorded in C6D6 in the temperature range from 25 to
75°C. Neither signal coalescence nor change of their
intensity ratio was observed, and the coupling con-
stants also remained unchanged. We observed only
characteristic temperature-induced shifts and weak
broadening of proton signals. These findings indicated
the lack of conformational transition and the existence
of each diastereoisomer of II–V as a single conformer.
The structure of the latter for the major stereoisomer
may be derived from the coupling constant Jab which is
equal to 12.0 Hz for compounds II–V. In keeping with
the Karplus equation for ethane-like structures, the
coupling constant Jab = 12.0 Hz corresponds to a di-
hedral angle of ~150° which implies transoid orienta-
tion of the Ha and Hb protons [9, 10].
Molecules II, III, V, and VI possess two chiral
centers (C4 and C6), while three asymmetric carbon
atoms (C4, C6, and C7) are present in structure IV.
Therefore, these compounds may be formed as mix-
tures of diastereoisomers. In fact, in the 1H NMR spec-
tra of II–VI we observed two sets of signals, indicating
the presence of at least two diastereoisomers denoted
with boldface characters “a” and “b.” We failed to
separate diastereoisomers by fractional crystallization
or chromatographically, and all our attempts resulted in
isolation of mixtures enriched with one or another
stereoisomer. Protons in the thiophene ring of II–VI
1
1
appear in the H NMR spectra as an ABX three-spin
The H NMR spectra of compounds VII and VIII
in different solvents contained only one set of signals,
indicating that these compounds are configurationally
homogeneous [8]. For example, the methyl groups in
molecule VIII turned out to be magnetically equiv-
alent; they gave rise to a singlet at δ 1.37 ppm in the
1H NMR spectrum of VIII recorded in (CD3)2CO.
Methylene protons in the thiophene ring of VIII
pattern: the HA and HB methylene protons resonated at
δ 3.94–3.36 ppm (JAB = 11.5–15 Hz), and the HX signal
was located considerably more downfield, at δ 5.80–
5.32 ppm (JAX = 3–4, JBX = 7.5–8 Hz) due to deshield-
ing effect of the neighboring nitro group. The side-
chain Ha and Hb protons (AB spin system) resonated in
the region δ 4.47–5.30 ppm. The upfield region of the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

BERESTOVITSKAYA et al.
1816
(HA and HB, δ 3.92 and 4.09 ppm, JAB = 13.5 Hz) and
the 3-H proton neighboring to the nitro group (HX,
δ 5.67 ppm) formed an ABX spin system (JAX = 11.0,
JBX = 7.5 Hz). Methylene protons in the cyclohexene
ring (5-H, 7-H) resonated as a multiplet in a strong
field (δ 2.40 ppm), and the 9-H (Hc) and 9a-H (Hd)
signals were located at δ 4.38 and 4.02 ppm, respec-
tively. Protons in the benzene ring on C9 gave a multi-
plet signal centered at δ 7.25 ppm.
poured onto ice, and the precipitate was filtered off and
washed with methanol and diethyl ether. Yield 0.66 g
(88%), mp 128–130°C (from MeOH). IR spectrum, ν,
cm–1: 1760, 1740 (C=O); 1610 (C=C); 1580, 1370
1
(NO2); 1340, 1160 (SO2). NMR spectrum (CDCl3),
δ, ppm: major diastereoisomer a: 2.04 (3H, Me), 3.40
(3H, OMe), 3.69 (3H, OMe), 3.59 (2H, CH2), 4.63
(1H, Hb), 4.77 (1H, Ha), 5.41 (1H, HX), 7.20 (5H,
C6H5); diastereoisomer b: 1.98 (3H, Me), 3.37 (3H,
OMe), 3.62 (3H, OMe), 3.51 (2H, CH2), 4.51 (1H, Hb),
4.70 (1H, Ha), 5.40 (1H, HX), 7.20 (5H, C6H5). Found,
%: C 50.98, 51.00; H 5.07, 5.02; N 3.47, 3.48.
C17H19NO8S. Calculated, %: C 51.31; H 4.78; N 3.52.
The IR spectra of VII and VIII contained absorp-
tion bands corresponding to stretching vibrations of the
sulfonyl group (1350, 1140 cm–1), nonconjugated nitro
group (1570, 1380 cm–1), and carbonyl group con-
jugated with the double C=C bond (one strong band
at 1660 cm–1); the reduced carbonyl stretching vibra-
tion frequency is typical of conjugated C=C–C=O
fragment.
Diethyl [(3-methyl-4-nitro-1,1-dioxido-4,5-dihy-
drothiophen-2-yl)(phenyl)methyl]malonate (III)
(mixture of diastereoisomers, a:b = 1.1:1). Diethyl
malonate sodium salt prepared from 2.40 g (15 mmol)
of freshly distilled diethyl malonate and 0.35 g
(15 mmol) of metallic sodium in 10 ml of anhydrous
ethanol was added to a suspension of 2.65 g (10 mmol)
of 2-benzylidene-3-methyl-4-nitro-2,5-dihydrothio-
phene 1,1-dioxide (I) in 10 ml of anhydrous diethyl
ether, and the mixture was stirred for 3 h at room
temperature. The mixture was neutralized with con-
centrated acetic acid to a weakly acidic reaction and
poured onto ice, and the precipitate was filtered off and
washed with methanol and diethyl ether. Yield 2.82 g
(70%), mp 118–120°C (from Et2O). IR spectrum, ν,
cm–1: 1760, 1740 (C=O); 1620 (C=C); 1580, 1370
On the whole, the results of our study showed that
conjugated nitro diene system incorporated into dihy-
drothiophene ring (2-benzylidene-3-methyl-4-nitro-
2,5-dihydrothiophene 1,1-dioxide) readily and regio-
selectively reacts with CH acids according to the
1,4-addition pattern. Analogous reactions with readily
enolizable cyclic β-diketones are accompanied by sub-
sequent intramolecular heterocyclization leading to
thieno[3,2-b]chromene derivatives.
EXPERIMENTAL
1
(NO2); 1340, 1160 (SO2). H NMR spectrum (CDCl3),
The IR spectra were recorded on InfraLYuM FT-02,
UR-20, and IKS-14 instruments from solutions in
chloroform with a concentration of 40 mg/ml (LiF and
δ, ppm: diastereoisomer a: 0.80 and 1.17 (3H each,
CH2Me), 1.99 (3H, Me), 3.80 and 4.11 (2H each,
OCH2), 3.36 (1H, HB), 3.70 (1H, HA), 4.47 (1H, Hb),
4.68 (1H, Ha), 5.57 (1H, HX), 7.23 (5H, C6H5); dia-
stereoisomer b: 0.86 and 1.19 (3H, CH2Me), 2.04 (3H,
Me), 3.84 and 4.12 (2H, OCH2), 3.58 (2H, CH2), 4.56
(1H, Hb), 4.76 (1H, Ha), 5.57 (1H, HX), 7.25 (5H,
C6H5). Found, %: C 53.58, 53.64; H 5.81, 5.84;
N 3.23, 3.20. C19H23NO8S. Calculated, %: C 53.65;
H 5.41; N 3.29.
1
NaCl prisms). The H NMR spectra were measured
on Tesla BS-487C (80 MHz) and Bruker AC-200
(200 MHz) spectrometers.
2-Benzylidene-3-methyl-4-nitro-2,5-dihydrothio-
phene 1,1-dioxide (I) was synthesized according to the
procedure described in [5].
Dimethyl [(3-methyl-4-nitro-1,1-dioxido-4,5-di-
hydrothiophen-2-yl)(phenyl)methyl]malonate (II)
(mixture of diastereoisomers, a:b = 2.7:1). Dimethyl
malonate sodium salt prepared from 0.43 g (2.7 mmol)
of freshly distilled diethyl malonate and 0.06 g
(2.7 mmol) of metallic sodium in 10 ml of anhydrous
methanol was added to a suspension of 0.5 g
(1.8 mmol) of 2-benzylidene-3-methyl-4-nitro-2,5-di-
hydrothiophene 1,1-dioxide (I) in 5 ml of anhydrous
methanol, and the mixture was stirred for 3 h at room
temperature. The mixture was neutralized with concen-
trated acetic acid to a weakly acidic reaction and
Ethyl 2-[(3-methyl-4-nitro-1,1-dioxido-4,5-dihy-
drothiophen-2-yl)(phenyl)methyl]-3-oxobutanoate
(IV) (mixture of diastereoisomers, a:b = 1.4:1) was
synthesized from dihydrothiophene dioxide I and ethyl
acetoacetate as described above for compound III.
Yield 51%, mp 125–127°C (the product was washed
with hot diethyl ether). IR spectrum, ν, cm–1: 1760,
1740 (C=O); 1630 (C=C); 1580, 1375 (NO2); 1330,
1
1170 (SO2). H NMR spectrum (CDCl3), δ, ppm: dia-
stereoisomer a: 0.87 (3H, CH2Me), 2.06 (3H, Me),
2.25 (3H, COMe), 3.85 (2H, OCH2), 3.40 (1H, HB),
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REACTIONS OF 2-BENZYLIDENE-3-METHYL-4-NITRO-2,5-DIHYDROTHIOPHENE
1817
3.72 (1H, HA), 4.69 (1H, Hb), 4.95 (1H, Ha), 5.41 (1H,
HX), 7.25 (5H, C6H5); diastereoisomer b: 0.90 (3H,
CH2Me), 2.09 (3H, Me), 2.30 (3H, COMe), 3.87 (2H,
OCH2), 3.49 (1H, HB), 3.76 (1H, HA), 4.67 (1H, Hb),
4.91 (1H, Ha), 5.32 (1H, HX), 7.29 (5H, C6H5). Found,
%: C 54.59, 54.69; H 5.51, 5.52; N 3.79, 3.80.
C18H21NO7S. Calculated, %: C 54.68; H 5.31; N 3.54.
concentrated acetic acid to a weakly acidic reaction
and poured onto ice, and the precipitate was filtered off
and washed with methanol and diethyl ether. Yield 1.0 g
(79%), mp 197–198°C (from benzene–hexane, 3:7).
Found, %: C 57.27, 57.29; H 4.94, 4.96; N 3.81, 3.74.
C18H19NO6S. Calculated, %: C 57.29; H 5.04; N 3.71.
3a,6,6-Trimethyl-3-nitro-9-phenyl-2,3,3a,5,6,7,-
9,9a-octahydro-8H-thieno[3,2-b]chromen-8-one
1,1-dioxide (VIII). 5,5-Dimethylcyclohexane-1,3-
dione, 0.21 g (1.5 mmol), and three drops of triethyl-
amine were added to a suspension of 0.26 g (1 mmol)
of dihydrothiophene dioxide I in 10 ml of benzene, and
the mixture was stirred for 3 h at room temperature.
The precipitate was filtered off and washed with di-
ethyl ether. An additional amount of the product can
be isolated by concentration of the filtrate. Yield 0.3 g
(72%), mp 216–217°C (from benzene–chloroform,
3:1). Found, %: C 59.60, 59.67; H 5.30, 5.29; N 3.33,
3.32. C20H23NO6S. Calculated, %: C 59.25; H 5.67;
N 3.45.
3-[(3-Methyl-4-nitro-1,1-dioxido-4,5-dihydro-
thiophen-2-yl)(phenyl)methyl]pentane-2,4-dione
(V) (mixture of diastereoisomers, a:b = 2.1:1) was
synthesized from dihydrothiophene dioxide I and
acetylacetone as described above for compound II.
Yield 97%, mp 136–137°C (from MeOH). IR spec-
trum, ν, cm–1: 1750, 1710 (C=O); 1620 (C=C); 1570,
1
1365 (NO2); 1325, 1160 (SO2). H NMR spectrum
(CDCl3), δ, ppm: diastereoisomer a: 1.81 and 2.00 (3H
each, COMe), 2.17 (3H, Me), 3.50 (1H, HB), 3.75 (1H,
HA), 4.71 (1H, Hb), 5.02 (1H, Ha), 5.43 (1H, HX), 7.25
(5H, C6H5); diastereoisomer b: 1.88 and 2.07 (3H
each, COMe), 2.26 (3H, Me), 3.43 (1H, HB), 3.69 (1H,
HA), 4.82 (1H, Hb), 5.14 (1H, Ha), 5.37 (1H, HX), 7.25
(5H, C6H5). Found, %: C 55.71, 55.79; H 5.67, 5.57;
N 3.92, 3.94. C17H19NO6S. Calculated, %: C 55.89;
H 5.20; N 3.83.
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nitrile as described above for compound III. Yield
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from 0.56 g (5.3 mmol) of cyclohexane-1,3-dione
and 0.12 g (5.3 mmol) of metallic sodium in 10 ml of
anhydrous ethanol was added to a suspension of 0.93 g
(3.5 mmol) of dihydrothiophene dioxide I in 10 ml of
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009