A novel synthesis and transformations of isothiochroman 2,2-dioxide

Article abstract of DOI:10.1016/j.tetlet.2012.05.163

A convenient synthesis of isothiochromen-4-one 2,2-dioxide was carried out via cyclisation of o-cyanobenzyl thioacetate by a Thorpe reaction. The reactions of isothiochromen-4-one 2,2-dioxide with nitrogen-containing nucleophilic reagents have been investigated.

Full text of DOI:10.1016/j.tetlet.2012.05.163

Tetrahedron Letters 53 (2012) 4296–4299
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Tetrahedron Letters
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A novel synthesis and transformations of isothiochroman 2,2-dioxide
Olena O. Shyshkina a, , Tetyana M. Tkachuk a, Tetiana A. Volovnenko a, Yulian M. Volovenko a,
⇑
Roman I. Zubatyuk b, Volodymyr V. Medviediev b, Oleg V. Shishkin b,c
a Department of Chemistry, Kyiv Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
b Division of Functional Materials Chemistry, SSI ‘Institute for Single Crystals’ of National Academy of Science of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine
c Department of Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq, Kharkiv 61122, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of isothiochromen-4-one 2,2-dioxide was carried out via cyclisation of o-cyanob-
enzyl thioacetate by a Thorpe reaction. The reactions of isothiochromen-4-one 2,2-dioxide with nitrogen-
containing nucleophilic reagents have been investigated.
Received 1 February 2012
Revised 10 May 2012
Accepted 31 May 2012
Available online 9 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isothiochromen-4-one 2,2-dioxide
Cyclisation
X-ray diffraction
Nitrogen-containing nucleophilic reagents
Sulfones are an important class of compounds that have at-
tracted considerable attention.1 Isothiochromen-4-one 2,2-dioxide
is an interesting compound, the chemistry of which has proved
useful because thiochromanones and isothiochromanones are re-
ported as valuable biological agents2–9 and are useful precursors
in the synthesis of steroid heterocycles.10–12 Only a few isothio-
chromanones and their dioxides are described in the litera-
ture2,3,5,7,9–14 which were prepared by cyclocondensation of
arylmethylthioacetic acids,2,5,7,13–16 by oxidative cleavage of oxi-
mes17 or by cyclisation of 1-o-alkylphenylpropane-1,2-diones.18,19
All previously known methods for obtaining the isothiochromen-
4-one 2,2-dioxide system have several disadvantages including
multi-step processes and low yields of target product (up to 60%).
There is no generally accepted method for obtaining isothio-
chromen-4-one. Earlier, the isothiochromanone system was pre-
pared via Friedel–Crafts cyclisation of benzylthioacetic acid or its
chloride,14 however, the authors were unable to obtain any isothio-
chromen-4-one by way of this method, using a wide range of cat-
alysts and experimental conditions.
Figure 1. Molecular structure of isothiochromen-4-one 2,2-dioxide according to
X-ray diffraction data (ORTEP).
In this Letter, we introduce a novel method for the synthesis of
isothiochromen-4-one 2,2-dioxide in high yield. Also, we consider
some of the chemical properties of this compound.
The novel synthesis of isothiochromen-4-one 2,2-dioxide is de-
picted in Scheme 1. Initially, 2-(chloromethyl)benzonitrile was re-
acted with alkyl mercaptoacetate in the presence of K2CO3 in
CH3CN at reflux to afford quantitative yields of 1a,b. Oxidation of
the sulfur under standard conditions (33% H2O2, AcOH, ice-bath)
resulted in the corresponding sulfone 2a,b. Cyclisation of the sul-
fone 2 into isothiochromen-4-one 2,2-dioxide (3) in 93% yield via
a Thorpe reaction was effected with NaOR1 (R1:Et, i-Pr) in a polar
solvent (absolute EtOH, i-PrOH) at reflux (10 h) with. The structure
of isothiochromen-4-one 2,2-dioxide (3) was proved by X-ray dif-
fraction (Fig. 1).
We found that enamine 4 was obtained in the presence of
⇑
Corresponding author. Tel.: +38 067 984 1970.
E-mail address: shishkina_lo@mail.ru (O.O. Shyshkina).
NaOR1 (R1:Et, i-Pr) in a polar solvent (absolute EtOH, i-PrOH) on
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.163

O. O. Shyshkina et al. / Tetrahedron Letters 53 (2012) 4296–4299
4297
CN
CN
H2O2 / HOAc
HS
CO2R
S
CO2R
CH3CN / K2CO3
Cl
1a,b
96-98%
O
CN
NaOR1
R1OH
O
O
SO2
S
CO2R
93%
3
2a,b
NaOR1
R1OH
10 % H2SO4
75-77%
79%
NH2
CO2R1
SO2
93-95%
4a,b
4 a
1
1
1 2 a
b
b
R =Et; R =i-Pr
, : R=Me; R=Et;
:
Scheme 1. Synthesis of isothiochromen-4-one 2,2-dioxide (3).
short reflux (3 h).20 Enamine 4 gave the desired product 3 in 79%
yield on boiling in 10% H2SO4. The structure of enamine 4a was
proved by X-ray diffraction (Fig. 2).
Therefore the direct synthesis of 3 is more preferable. Isothio-
chromen-4-one 2,2-dioxide 3 and enamines 4a,b are colorless
crystalline substances.
In contrast to the synthesis of isothiochromen-4-one 2,2-diox-
ide (3), its transformations are scarcely reported in the
literature.2,7,16
We used enamine 4 to prepare isothiochromen-4-amine 2,2-
dioxide (5). Compound 5 was formed by vigorous stirring of enam-
ine 4 in 20% sodium hydroxide solution as a consequence of decar-
boxylation (Scheme 2). The structure of compound 5 was proved
by X-ray diffraction (Fig. 3).
Earlier,21–24 it was demonstrated that thiapyran-3-one 1,1-
dioxide underwent reactions with nitrogen-containing nucleo-
philic reagents. Taking into account the similarity in structure of
this compound and isothiochromen-4-one 2,2-dioxide (3) it is pos-
sible to suppose that similar reactions may occur with compound
3. Isothiochromen-4-one 2,2-dioxide (3) was found to react with
compounds containing an amino group in a polar solvent (MeOH,
i-PrOH) at reflux giving colorless oxime 6a, hydrazone 6b and
NPh-hydrazone 6c, respectively (Scheme 3). The structure of oxime
6a was proved by an X-ray diffraction study (Fig. 4).
Boiling a solution of isothiochromen-4-one 2,2-dioxide (3)
with excess pyrrolidine in toluene resulted in yellow crystals
of 1-(2,2-dioxide-3,4-dihydroisothiochromen-4-yl)pyrrolidine (7)
(Scheme 4) as was established by an X-ray diffraction study
(Fig. 5).
John et al.7 prepared 3,4-dihydroisothiochromen-4-amine 2,2-
dioxide which is an analogue of compound 5. The keto group
was converted into an amino group directly via reductive amina-
tion, or indirectly through the generation of an oxime, which was
then reduced to form the amine. Transition metal catalysis and
hydrogen or another reducing agent, such as NaBH4, LiAlH4 or NaC-
NBH3, can be used to effect the reduction.
As expected, the reactivity of isothiochromen-4-one 2,2-dioxide
(3) with nitrogen-containing nucleophilic reagents was similar to
that of thiapyran-3-one 1,1-dioxide.
The structures of all the compounds were proved by IR and
NMR spectroscopy (1H and 13C), mass spectrometry and elemental
analysis. (see Supplementary data). According to X-ray diffraction
Figure 2. Molecular structure of 4a according to X-ray diffraction data (ORTEP).

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O. O. Shyshkina et al. / Tetrahedron Letters 53 (2012) 4296–4299
NH2
NH2
CO2R1
N
O
aqueous NaOH
SO2
SO2
NH
5
89%
4a,b
a R1=Et; b R1=i-Pr
PhMe
SO2
SO2
90%
7
3
Scheme 2. Synthesis of isothiochromen-4-amine 2,2-dioxide (5).
Scheme 4. Synthesis of 1-(2,2-dioxide-3,4-dihydroisothiochromen-4-yl)pyrroli-
dine (7).
Figure 3. Molecular structure of compound 5 according to X-ray diffraction data
(ORTEP).
NR3
O
H2NR3
SO2
SO2
Figure 5. Molecular structure of 7 according to X-ray diffraction data (ORTEP).
88-95%
6a-c
3
a R3=OH; b R3=NH2; c R3=NHPh
Scheme 3. Synthesis of novel compounds 6a–c.
data, the six-membered ring in molecules 4a, 5 and 7 adopts a
twist-boat conformation with the value of the C6-C7-S1-C8 torsion
angle being within 52.0–54.3o. The presence of both strong elec-
tron-donating (amino group) and electron-withdrawing (COOEt)
groups at the endocyclic double bond in molecule 4a results in
considerable elongation of the C8–C9 bond [1.388(3) Å] and short-
ening of the C9–N1 bond [1.324(2) Å] as compared to structures 5
and 7 where these bond lengths are 1.355(2) Å, 1.367(4) Å and
1.359(2) Å, 1.365(3) Å, respectively. In contrast, the conformation
of the six-membered ring in molecules 3 and 6a is considerably dif-
ferent. The sulfone ring in 3 adopts a sofa conformation with devi-
ation of the S1 atom from the mean plane of the remaining atoms
of the ring by 0.88 Å. In the case of 6a, the sulfone ring has a twist-
boat conformation [the value of the C6-C7-S1-C8 torsion angle is
57.9(1)o].
In summary, we have identified a novel and simple method for
the synthesis of isothiochromen-4-one 2,2-dioxide 3 in high yield
(93%) from easily accessible reagents.
Acknowledgments
We are grateful to the Analytical Department for performing
spectral analysis. Research was performed at the ISRA «French-
Ukrainian association in Molecular Chemistry».
Figure 4. Molecular structure of 6a according to X-ray diffraction data (ORTEP).

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4299
7. John V., Maillard M., Fang L., Tucker J., Brogley L., Aquino J., Bowers J., Probst G.,
Tung J., Patent WO 2005/087714, 2005; Chem. Abstr. 2005, 143, 326226.
8. Zhu, Q.; Fang, L.; Zhang, G. Zhongguo Yaowu Huaxue Zazhi 2000, 10, 1–4.
9. Dey, D., Neogi, P, Sen, A., Sharma, S. D., Nag, B., Patent WO 02/30888, 2002;
Chem. Abstr. 2002, 136, 309858.
10. Krishna, M. V.; Ramadas, S. R. Heterocycles 1981, 16, 405–409.
11. Ramadas, S. R.; Chenchaiah, C. Steroids 1981, 37, 353–359.
12. Terasawa, T.; Okada, T. J. Chem. Soc., Perkin Trans. 1 1979, 990–1003.
13. Reddy, N. S.; Reddy, E. P.; Reddy, M. V. R. Synth. Commun. 2004, 34, 2691–2695.
14. Pulman, D. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1973, 410–418.
15. Bose, D. S.; Srinivas, P. Synlett 1998, 977–978.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.163. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
16. Still, I. W. J.; Wilson, D. K. T. Can. J. Chem. 1992, 70, 964–973.
17. Hill, R. K.; Cullison, D. A. J. Am. Chem. Soc. 1973, 95, 2923–2927.
18. Hamer, N. K. J. Chem. Soc., Chem. Commun. 1975, 8, 557–558.
19. Hamer, N. K. J. Chem. Soc., Perkin Trans. 1 1979, 508–511.
20. Smith, M. B.; March, J. March’s advanced organic chemistry, fifth ed.; John Wiley
& Sons: New York, 2001. p. 2083.
21. Fatutta, S.; Pitacco, G.; Valentin, E. J. Chem. Soc., Perkin Trans. 1 1983, 2735–
2738.
22. Fatutta, S.; Pitacco, G.; Valentin, E. J. Heterocycl. Chem. 1989, 26, 183–187.
23. Fatutta, S.; Pitacco, G.; Valentin, E. J. Chem. Soc., Perkin Trans. 1 1986, 2111–
2115.
1. Simpkins, N. S. In Sulfones in Organic Synthesis; Magnus, P., Baldwin, J. E., Eds.;
Pergamon Press: Oxford, 1993; p 381.
2. Peixoto, Ch.; Laurin, P.; Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne,
P.; Bonnefoy, A.; Musicki, B. Tetrahedron Lett. 2000, 41, 1741–1745.
3. Pfizer Corporation, Patent Specification, USA, 1259415, 1972; Chem. Abstr.
1972, 76, 92907.
4. Toshima, K.; Ohta, K.; Ohtasuka, A.; Matsumura, Sh.; Nakata, M. J. Chem. Soc.
Chem. Commun. 1993, 1406–1407.
5. Sohda, T., Tsuda, M., Yamazaki, I., US Pat. 5071841, 1991; Chem. Abstr. 1991,
114, 23804.
6. Ohta T., Komoriya S., Yoshino T., Uoto K., Nokomoto Y., Naito H., Mochizuki A.,
Nagata T., Kanno H., Haginoya N., Yoshikawa K., Nagamochi M., Kobayashi S.,
Ono M., EP 1405852, 2004; Chem. Abstr. 2004, 138, 73271.
24. Fatutta, S.; Pitacco, G.; Russo, C.; Valentin, E. J. Chem. Soc., Perkin Trans. 1 1982,
2045–2050.