Nitroketene dithioacetal chemistry. Part 2: Synthesis of novel 4-(alkylsulfanyl)-2-[1-nitromethylidene]-1,3-dithioles from the dipotassium salt of 2-nitro-1,1-ethylenedithiol

Article abstract of DOI:10.1016/S0040-4039(03)01086-4

The reaction of the dipotassium salt of 2-nitro-1,1-ethylenedithiol with long chain alkyl halides in acetonitrile medium furnished the novel heterocyclic, 4-(alkylsulfanyl)-2-[1-nitromethylidene]-1,3-dithioles.

Full text of DOI:10.1016/S0040-4039(03)01086-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4701–4704
Nitroketene dithioacetal chemistry. Part 2: Synthesis of novel
4
-(alkylsulfanyl)-2-[1-nitromethylidene]-1,3-dithioles from the
dipotassium salt of 2-nitro-1,1-ethylenedithiol
H. Surya Prakash Rao,* L. Sakthikumar, S. Vanitha and S. Siva Kumar
Department of Chemistry, Pondicherry University, Pondicherry-605 014, India
Received 17 September 2002; revised 16 April 2003; accepted 25 April 2003
Abstract—The reaction of the dipotassium salt of 2-nitro-1,1-ethylenedithiol with long chain alkyl halides in acetonitrile medium
furnished the novel heterocyclic, 4-(alkylsulfanyl)-2-[1-nitromethylidene]-1,3-dithioles. © 2003 Published by Elsevier Science Ltd.
The nitro ketene dithioacetal functional group is well
known in synthetic organic sulfur chemistry as a two-
carbon push–pull system. While the nitro group acts as
methylidene]-1,3-dithioles (12–18) along with the antici-
pated S,S-dialkylated derivatives (2–11) (Scheme 1).
The results obtained in this study are presented in
Table 1. Even though a few 2-[1-nitromethylidene]-1,3-
dithiole derivatives are known, 4-alkylsulfanyl 2-[1-
nitromethylidene]-1,3-dithiole derivatives are being
reported here for the first time.
1
a powerful electron-withdrawing group, the two alkyl-
ated sulfurs readily donate their lone-pair of electrons
to make the entire atomic framework highly polarized.
Furthermore, the a,b-unsaturated nitro group is an
excellent Michael acceptor; subsequent to the attack of
a nucleophile at the b-carbon, an alkylsulfanyl group
acts as a leaving group. There are several reports in the
literature utilizing these aspects of nitro ketene
dithioacetal chemistry for the synthesis of a variety of
6
The reaction of the dipotassium salt of 2-nitro-1,1-
ethylenedithiol 1 with 2 equiv. of simple short-chain
alkyl iodides such as methyl, ethyl and propyl iodide in
50% aqueous methanol resulted only in the expected
2
7
heterocycles. In spite of the popularity of nitro ketene
S,S-dialkylated products 2–4. However, when the reac-
dithioacetal as a two-carbon synthon, a surprisingly
tion was conducted with isopropyl iodide, in addition
to the bis-alkylated product 5 (43%), a new compound,
4-(isopropylsulfanyl)-2-[1-nitromethylidene]-1,3-dithiole
(12; C H NO S ; MS: molecular ion m/z=235) was
small number of their S,S-dialkylated derivatives have
3
been synthesized. It has been claimed that some of the
sulfoxide derivatives of S,S-dialkylated nitro ketene
7
9
2 3
4
dithioacetals show potent antimicrobial properties.
obtained in low yield (8%). When 1 was treated with
isopropyl iodide in acetonitrile (slow addition of the
alkylating agent to the reaction medium) 1,3-dithole 12
was obtained in 31% yield as a mixture of geometrical
isomers in which the E-isomer predominated. For
short-chain alkyl halides the dithiole product did not
We became interested in the synthesis of a variety of
alkylated derivatives of this synthon in order to study
their physico-chemical and aggregation properties. We
have recently reported the synthesis of several alkyl
derivatives of nitroethylenedithiolate from the reaction
of the dipotassium salt of 2-nitro-1,1-ethylenedithiol 1
with a series of simple alkyl halides in 50% aqueous
5
methanol medium. In this communication we report
that, when the same reaction was conducted in acetoni-
trile as solvent and on slow addition of alkyl halide the
reaction can be engineered towards the formation of
the novel heterocyclic, 4-(alkylsulfanyl)-2-[1-nitro-
Keywords: nitroketene dithioacetals; 2-nitromethylidene-1,3-dithioles;
domino reaction.
*
Corresponding author. E-mail: hspr@satyam.net.in
Scheme 1.
0
040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)01086-4

4
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H. S. P. Rao et al. / Tetrahedron Letters 44 (2003) 4701–4704
Table 1. Reaction of the dipotassium salt of 2-nitro-1,1-ethylenedithiol 1 with alkyl halides in acetonitrile medium
Entry
Alkyl halide (RX)
Bis-alkylated product; yield (%)
1,3-Dithiole; yield (%)
1
2
3
4
5
6
7
8
9
CH3I
2; 60
3; 51
4; 42
–
–
–
CH CH I
3
2
CH CH CH I
3
2
2
(CH ) CHI
5;
6
12; 31
13;
14;
15; 21
16; 28
17; 21
18; 21
3
2
CH (CH ) CH Br
6; 24
7; 20
7
8
3
2 2
2
CH (CH ) CH I
3
2 3
2
CH (CH ) CH Br
8;
9;
10;
11;
7
3
3
3
3
2 4
2
CH (CH ) CH I
3
2 5
2
CH (CH ) CH I
3
2 6
2
1
0
CH (CH ) CH I
3 2 8 2
form even in acetonitrile and only the bis-alkylated
products 2–4 were isolated. The UV spectrum of 12
showed an intense absorption at 416 nm (log m=4.02)
the C-1¦-H (l=2.89 ppm) of the alkylsulfanyl side
chain revealed connectivity to C-4. Since C-5-H
appeared upfield in comparison to C-1%-H, in contrast
to expectations from the structures A and B as shown
in Figure 1, we believe that the 1,3-dithiole heterocyclic
rings in 12–18 do not exhibit aromatic resonance
stabilization.
1
indicating extensive conjugation in the molecule. Its H
NMR spectrum showed a characteristic singlet at 6.93
ppm arising from the C-5-H located on the 1,3-dithiole
ring and a singlet at 7.7 ppm corresponding to the
nitromethylidene hydrogen (C-1%-H). The stereochem-
istry of the major olefin was assigned as E by compari-
When longer chain alkyl halides were employed in the
reaction in acetonitrile, 1,3-dithiole products 13–18 (7–
28%) along with bis-alkylated products 6–11 were
6
a
son with data on similar compounds. In agreement
13
with the proposed structure, the proton-decoupled
NMR spectrum of 12 showed six signals.
C
8
8
formed (Table 1). Interestingly, the ratio of 1,3-dithiole
to bis-alkylated product increased with chain length,
indicating that increased steric bulk in the alkyl halide
favors the formation of the heterocyclic product. For
example, the reaction of 1 with decyl iodide resulted in
1,3-dithiole 18 and bis-alkylated product 11 in a 7:1
ratio, whereas the reaction of 1 with butyl bromide
resulted in 1,3-dithiole 13 and bis-alkylated product 6
in the ratio of 1:3.5. A possible mechanism involving
domino pathways for the formation of the 1,3-dithiole
moiety is given in Scheme 2. Conjugate addition of the
monoalkylated product 20 to protonated species 19 and
subsequent loss of hydrogen sulfide leads to intermedi-
ate 21. Intramolecular cyclization followed by elimina-
tion of the nitro group results in 1,3-dithiole products
12–18.
Previously, based on the X-ray crystal structure analy-
sis, Komarova and co-workers proposed an interesting
resonance stabilization for some 1,3-dithiole derivatives
involving the lone pair of electrons on both the sulfur
atoms. 1,3-Dithioles can potentially exhibit character-
istics of an aromatic ring as shown in Figure 1 (struc-
tures A and B). In such cases the signal for the C-5-H
is expected to appear more downfield since it is next to
a partially positively charged sulfur. Similarly, the
methylidene hydrogen, C-1%-H, is expected to resonate
at a higher field since it resides in a shielded environ-
ment created by the electron rich carbon. Initially the
6
a
2
D NOESY spectrum of octylsulfanyl derivative 17 was
recorded to determine the steric proximity of C-5-H of
the heterocycle and C-1¦-H of the side-chain and thus
assign the chemical shift for C-5-H. Unfortunately, the
spectrum did not reveal the anticipated cross-peaks,
possibly because the side chain does not adopt favor-
able conformation required for observing NOE connec-
tions. The HMBC spectrum of 17 was recorded to
ascertain the chemical shifts of C-5-H and C-1%-H
The bis-alkylated product, 1,1-di(methylsulfanyl)-2-
nitroethylene 2 was subjected to treatment with the
strong base, sodium methoxide (hard nucleophile) with
the expectation that the intermediate anion of the type
20 (Scheme 2) would be generated in the medium which
in the absence of alkyl halide may produce a dithiole
1
13
9
through H– C long range couplings. The 2D NMR
spectrum revealed a long range coupling between C-5-
H (l=6.89 ppm) and quaternary carbon C-4 (l=
product. However, this reaction furnished only the
10
known 1,1,1-trimethoxy-2-nitroethane 22 (Scheme 3).
The bis-alkylated product 2 did not show any reactivity
with DBU, a non-nuclophilic base, even under reflux in
benzene. The reaction of 2 with sodium benzenethiolate
(soft nucleophile) furnished a mixture of geometrical
1
34.14 ppm) and coupling between C-1%-H (l=7.69
ppm) and C-2 (l=165.56 ppm) in the heterocycle.
Furthermore, and in agreement with the assignment,
Figure 1.

H. S. P. Rao et al. / Tetrahedron Letters 44 (2003) 4701–4704
4703
Scheme 2.
Scheme 3.
(
(
c) Coustard, J.-M. Tetrahedron 1995, 51, 10929–10940;
d) Terang, N.; Mehta, B. K.; Ila, H.; Junjappa, H.
Tetrahedron 1998, 54, 12973–12984; (e) Shigemitsu, Y.;
Tominaga, Y. Heterocycles 2001, 55, 2257–2260.
. Coustard, J.-M. Eur. J. Org. 2001, 1525–1531.
. Hsu, A. C.-H.; Osei-Gyimah, P.; Joseph, R. W.; Lange,
B. C. Eur. Pat. Appl. 1997; Chem. Abstr. 1997, 126,
3
4
2
63848.
. Rao, H. S. P.; Sakthikumar, L.; Shreedevi, S. Sulfur Lett.
002, 207–218.
. (a) Komarova, E. N.; Yufit, D. S.; Struchkov, Yu. T.;
Drozd, V. N. Zh. Org. Khim. 1989, 25, 1512–1519;
English translation, J. Org. Chem. USSR 1989, 1365–
5
6
isomers of 1-[1-(methylsulfanyl)-2-nitro-1-ethenyl]-
sulfanylbenzene 23 (Scheme 3) generated by conjugate
addition of the benzenethiolate anion followed by elim-
ination of methanethiolate anion. On the other hand,
the reaction of 2 with TMSCl in the presence of NaI in
THF at reflux resulted in a polymeric product. Thus, it
is clear from these studies that bis-alkylated products
could not be induced to undergo transformation to
dithiole derivative possibly due to the fact that the nitro
ethylene moiety behaves as a good Michael acceptor.
2
1
371; (b) Jackson, Y. A.; Parakka, J. P.; Lakshmikan-
tham, M. V.; Cava, M. P. J. Org. Chem. 1997, 62,
616–2618.
2
7
8
. Gomper, R.; Schaefer, H. Chem. Ber. 1967, 100, 591–604.
. Spectral data for selected compounds:
Compound 12 (C H NO S ): mp 88°C; UV (MeOH) u
7
9
2
3
max
4
1
1
16 nm; IR (Nujol) w 3111, 3058, 2922, 1524, 1462, 1376,
In this report we have shown that the simple reaction of
the dipotassium salt of 2-nitro-1,1-ethylenedithiol 1
with long chain or sterically hindered alkyl halides leads
to interesting 4-alkylsulfanyl 2-nitromethylidene-1,3-
dithioles along with bis-alkylated products. As hetero-
cyclic systems with more than one sulfur atom show
impressive physico-chemical properties, e.g. enhanced
−
1 1
289, 1256, 1189 cm ; H NMR (300 MHz, CDCl :CCl ,
3
4
:1) l 1.35 (d, 6H, J=6.9 Hz) 3.38 (heptet, 1H, J=6.9
13
Hz), 6.93 (s, 1H), 7.7 (s, 1H) ppm; C NMR (75 MHz,
CDCl :CCl , 1:1) l 23.25, 40.90, 121.41, 122.73, 133.09,
3
4
165.59 ppm.
Compound 15 (C H NO S ): mp 90°C; UV (MeOH)
umax 415 nm; IR (Nujol) w 3111, 3076, 2924, 2855, 1475,
10 15
2 3
11
electrical conductivity, our findings should be of gen-
eral interest.
−
1
1
1398, 1294, 1240, 1201 cm ; H NMR (300 MHz,
CDCl :CCl , 1:1) l 0.86 (t, 3H, J=7.2 Hz), 1.3–1.6 (m,
3
4
8
H), 2.34 (t, 2H, J=7.1 Hz), 6.89 (s, 1H), 7.68 (s, 1H)
13
ppm; C NMR (75 MHz, CDCl :CCl , 1:1) l 14.1,
3
4
Acknowledgements
2
1
2.58, 28.14, 29.57, 31.32, 36.71, 120.34, 121.43, 134.15,
65.50 ppm.
Compound 16 (C H NO S ): mp 101°C; UV (MeOH)
11
17
2 3
We thank the University Grants Commission, India for
financial support under SAP program and Professor A.
Srikrishna, Dr. C. V. Asokan and Dr. J. V. Mueller for
helpful discussions and recording of spectra. We thank
Professor Hans Scheeren for 2D NMR spectral data.
umax 417 nm; IR (Nujol) w 3112, 3085, 2935, 1481, 1292,
−1
1
1
242, 1203 cm ; H NMR (300 MHz, CDCl :CCl , 1:1)
3 4
l 0.87 (t, 3H, J=6.9 Hz), 1.28–1.50 (m, 8H), 1.60–1.68
m, 2H,), 2.89 (t, 2H, J=7.2 Hz), 6.89 (s, 1H), 7.68 (s,
(
13
1
2
1
H) ppm; C NMR (75 MHz, CDCl :CCl , 1:1) l 14.15,
3 4
2.63, 28.41, 28.80, 29.58, 31.71, 36.69, 120.38, 121.39,
34.13, 165.57 ppm.
References
Compound 17 (C H NO S ): mp 108°C; UV (MeOH)
12 19 2 3
umax 418 nm; IR (Nujol) w 3112, 3083, 2955, 2854, 1522,
−
1 1
1
2
. Metzner, P.; Thullier, A. Sulfur Reagents in Organic
Synthesis; Academic Press: New York, 1994.
1474, 1390, 1292, 1244, 1203 cm ; H NMR (300 MHz,
CDCl :CCl , 1:1) l 0.86 (t, 3H, J=6.9 Hz), 1.20–1.50 (m,
3
4
. (a) Tominaga, Y.; Matsuda, Y. J. Heterocyclic Chem.
10H), 1.61–1.68 (m, 2H), 2.89 (t, 2H, J=7.2 Hz), 6.89 (s,
1H), 7.69, (s, 1H) ppm; C NMR (75 MHz, CDCl :CCl ,
3 4
13
1
985, 22, 937–949; (b) Kolb, M. Synthesis 1990, 171–190;

4
704
H. S. P. Rao et al. / Tetrahedron Letters 44 (2003) 4701–4704
1
3
:1) l 14.17, 22.68, 28.43, 28.80, 29.35, 29.57, 29.75,
1.80, 120.39, 121.39, 134.14, 165.56 ppm.
Typical experimental procedure: To the solution of the
dipotassium salt of 2-nitro-1,1-ethylenedithiol (1 mmol)
in dry acetonitrile (5 mL), alkyl halide (1 mmol) in
acetonitrile (5 mL) was added dropwise over 3 h. The
reaction mixture was stirred at rt until completion of the
reaction (12–24 h, TLC and GC). The reaction mixture
was then diluted with ice-cold water (25 mL) and
extracted with dichloromethane (3×15 mL). The com-
bined organic fractions were washed with water (10 mL),
brine (10 mL) and dried (anhyd. Na SO ). The crude
Compound 18 (C H NO S ): mp 98°C; UV (MeOH)
umax 418 nm; IR (Nujol) w 3011, 3078, 2923, 2853, 1520,
1
14
23
2 3
−
1 1
463, 1377, 1289, 1242, 1203 cm ; H NMR (300 MHz,
CDCl :CCl , 1:1) l 0.88 (t, 3H, J=7.2 Hz), 1.20–1.50 (m,
3
4
1
1
4H), 1.60–1.67 (m, 2H), 2.89, (t, 2H, J=7.2 Hz), 6.85 (s,
H), 7.69 (s, 1H) ppm;
13
C NMR (300 MHz,
CDCl :CCl , 1:1) l 14.25, 22.77, 28.47, 29.16, 29.38 (2C),
2
ppm.
Compound 11 (C H NO S ): UV (MeOH) u 361,
3
9
3
4
9.57, 29.61, 29.79, 31.69, 120.27, 121.46, 134.13, 164.37
2
4
product obtained after evaporation of the solvent was
subjected to column chromatography on silica gel (100–
22
43
2
2
max
04 nm; IR (neat) w 3129, 2925, 2854, 1524, 1465, 1311,
200 mesh, ACME) using dichloromethane in hexanes
−
1 1
31 cm ; H NMR (300 MHz, CDCl :CCl , 1:1) l 0.84
3
4
(
2:8) to give the S,S-bisalkylated and 1,3-dithiole prod-
(t, 3H, J=7.2 Hz), 0.87 (t, 3H, J=7.2 Hz), 1.20–1.50 (m,
ucts, in that order.
2
2
8H), 1.61–1.69 (m, 4H), 2.91 (t, 2H, J=7.5 Hz), 2.98 (t,
H, J=7.8 Hz), 7.01 (s, 1H) ppm; C NMR (75 MHz,
13
9. We thank the referee for providing this suggestion.
0. Francotte, E.; Verbruggen, R.; Viehe, H. G.; Van Meerss-
che, M.; Germain, G.; Declereq, J. P Bull. Soc. Chim.
Belges 1978, 87, 693–707; Chem. Abstr. 1979, 90, 103308.
1
CDCl :CCl , 1:1) l 14.25 (2 C), 22.77 (2 C), 27.41, 28.62,
2
2
3
4
8.98, 29.01, 29.13, 29.23, 29.39, 29.49, 29.53, 29.59,
9.62, 31.10, 31.98, 34.68, 36.43, 36.81, 125.51, 162.21
ppm.
11. Schukat, G.; Fanghanel, E. Sulfur Rep. 1996, 18, 1–12.