Access to new sulfolene derivatives via formylation of thiolan-3-one

Article abstract of DOI:10.1016/j.tetlet.2013.05.107

New tetrahydrothiophene derivatives, which are demonstrated to be reactive towards various nucleophiles and provide access to [b]- and [c]-fused sulfolenes are described. Application of heterocyclic sulfides as o-quinodimethane precursors is documented.

Full text of DOI:10.1016/j.tetlet.2013.05.107

Accepted Manuscript
Access to new sulfolene derivatives via formylation of thiolan-3-one
Olga Gordivska, Dmytro Listunov, Kirill Popov, Tatyana Volovnenko, Yulian
Volovenko
PII:
S0040-4039(13)00886-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.107
TETL 43007
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 December 2012
11 May 2013
24 May 2013
Please cite this article as: Gordivska, O., Listunov, D., Popov, K., Volovnenko, T., Volovenko, Y., Access to new
sulfolene derivatives via formylation of thiolan-3-one, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.05.107
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Access to new sulfolene derivatives via formylation of thiolan-3-one
Olga Gordivskaa,b, Dmytro Listunova, Kirill Popova,b*, Tatyana Volovnenkoa,
Yulian Volovenkoa
a
Department of Ogranic Chemistry, Kiev National University, 64 Volodymirska str., Kiev
01033, Ukraine
b Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Getingevägen
60, 221 00 Lund, Sweden
*Corresponding Author:
Dr. Kirill Popov
Kiev National University, Ukraine
Department of Ogranic Chemistry
Hospitalny st. 1A apt. 54
01133 Kiev
Ukraine
Phone: +380679436067
Fax: not available
E-mail: kirillpopov@bk.ru, Kirill.Popov@chem.lu.se

Access to new sulfolene derivatives via formylation of thiolan-3-one
Olga Gordivska, Dmytro Listunov, Kirill Popov*, Tatyana Volovnenko, Yulian Volovenko
*Corresponding Author: Tel. +380679436067. E-mail address: kirillpopov@bk.ru (Popov K.)
Abstract: New tetrahydrothiophene derivatives, which are demonstrated to be reactive towards various nucleophiles
and provide access to [b]- and [c]-fused sulfolenes are described. Application of heterocyclic sulfides as o-
quinodimethane precursors is documented.
Keywords: o-Quinodimethanes; Cheletropic extrusion of sulfur dioxide; Thiolanes; Formylation; Regioselectivity
In our previous work1-3 we utilized the formylation of α-methyleneketones as
a robust transformation providing access to a variety of heterocyclic derivatives.
Our current study was influenced by a question: would the formylation of thiolan-
3-one (2) be consistent with a known anomaly in its keto-enol tautomerism?
More specifically: while measurement of the kinetic acidity in 1-
(methylthio)propan-2-one (1) predictably demonstrates 137-fold faster C-1 proton-
deuterium exchange compared to C-3, thiolan-3-one (2) has the reverse kinetic
acidity: the С-4 protons exchange 3.375-times faster than the С-2 hydrogen atoms
(Scheme 1).4
The reason for such an anomaly is the remarkable steric hindrance between
the hydrogen atoms at C-4 and C-5 in thiolanone 2. This strain is released upon
enolisation at C-4, rendering this process highly preferable.
Thus, the goal of current study was to establish the regioselectivity of the
formylation of thiolan-3-one and to test the reactivity of the resulting derivatives.
We chose N,N-dimethylformamide dimethyl acetal (DMFDMA) as the
formylating agent. The reaction of thiolan-3-one (2) with DMFDMA was found to
afford mixtures of isomeric dimethylaminovinyl ketones 3 and 4 (Scheme 2).5
Correlations between the product ratios of 3:4 with the reaction conditions were
observed (Table 1). Treatment of 2 with phosphorus oxychloride under Vilsmeier
conditions resulted in no reaction.

Product distribution
Overall
yield
Reaction conditions
3 : 4 : 5
DMFDMA (1.2 eq.), PhH, 80 ˚C, 4 h
~35:65:0
~25:75:0
~20:65:15
92%
98%
DMFDMA (1.2 eq.), PhCH3, 110 ˚C, 4 h
DMFDMA (1.2 eq.), PhCH3, 110 ˚C, 5-6 h
~99%
Table 1. The results of the reaction of 2 with DMFDMA, depending on the conditions.
Formylation was found to occur in full compliance with the enolisation
studies. Isomeric dimethylaminovinyl ketones 3 and 4 were formed in 1:2 to 1:3
ratios with respect to the temperature. Upon extended heating (over 5 h) with
excess DMFDMA, a new mixture of components was formed. This was
established to be 2,4-bis[(dimethylamino)methylene]dihydrothiophen-3(2H)-one
(5), which was previously synthesized by a different route.6
Flash-chromatographic separation allowed the isolation of pure novel
compounds 3 and 4. We found that dimethylaminovinyl ketones 3 and 4 were
highly reactive towards 1,2- and 1,3-bis-nucleophiles. Treatment of 3 and 4 with
hydrazines, amidines, guanidine and thiourea furnished isomeric fused pyrazoles
and pyrimidines 6-9 (Scheme 3).7-8

Dimethylaminovinyl ketone 3 was found to be slightly more reactive than 4.
The reactions of 3 with nucleophiles proceeded faster and gave higher yields
(Scheme 3). Presumably, this was the result of sulfur atom influence on the
electronic properties of the masked carbonyl group.
It is noteworthy that the reactions with arylhydrazines were higher yielding
compared to those with alkylhydrazines. Among the 1,3-bis-nucleophiles,
guanidine and benzamidine were found to react more efficiently, while thiourea
afforded the corresponding pyrimidine in only moderate yield, and urea gave no
reaction.
We next investigated the possibility of employing tetrahydrothiophenes 8
and 9 as precursors for the synthesis of o-quinodimethanes (o-QDMs).9-12
Oxidation of 8 and 9 using a modified literature procedure13 afforded the
corresponding sulfolenes 10 and 11 in quantitative yields (Scheme 4).14 We
observed a dramatic decrease in the conversion time (10 h to 2-3 h) upon the
addition of vanadium dioxide as the catalyst (5 mol%).

When heated to 215 ˚С in 1,2,4-trichlorobenzene (1,2,4-TCB) under
microwave irradiation for 5 minutes, compounds 10 and 11 underwent cheletropic
extrusion of sulfur dioxide15 yielding o-quinodimethanes. To the best of our
knowledge, such a route to o-QDMs has not been reported. If a dienophile is
present in the reaction mixture a very rapid Diels-Alder reaction occurs.
Compounds 12 and 13 were isolated after flash-chromatographic purification
(Scheme 5).16 When ethyl ester 10d was subjected to these reaction conditions,
decarboxylation occurred yielding N-methyl adduct 12d.
In conclusion, we have described new dimethylaminovinyl ketones 3 and 4,
which are demonstrated to be reactive towards various nucleophiles and provide
access to [b]- and [c]-fused sulfolenes. Heterocyclic sulfides 8 and 9 are useful as
o-quinodimethane precursors.

References
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Popov, K. S.; Volovnenko, T.A.; Volovenko, Yu. M. Tetrahedron Lett.
2009, 60, 1171.
2.
Popov, K. S.; Volovnenko, T.A.; Volovenko, Yu. M. Beilstein J. Org. Chem.
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3.
Popov, K. S.; Volovnenko, T.A.; Volovenko, Yu. M. J. Heterocycl. Chem.
2013, in press.
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Guth, Ja. J.; Gross, R. L.; Carson, F. W. J. Org. Chem. 1982, 47, 2666.
5.
Formylation of thiolan-3-one. To a solution of 2 (0.1 mol, 10.2 g) in
benzene (100 ml) was added DMFDMA (0.12 mol, 14.28 g). The mixture was
refluxed for 4 h. After evaporation of the solvent, hexane was added to the crude
material. The resulting precipitate was filtered off, washed with hexane and air-
dried. The crude product was purified by column chromatography (EtOAc/hexanes
1:9) to give 3 and 4 as individual pure compounds, in 90% combined yield.
2-[(Dimethylamino)methylene]dihydrothiophen-3(2H)-one (3): Rf 0.54; m.p.
231-233 ˚C; ¹Н-NMR (DMSO-d6), δ: 2.62 (t, J = 14Hz, 2Н), 3.02 (t, J = 14Hz,
2Н), 3.12 (s, 6Н), 7.34 (s, 1Н); MS: m/z 158 (M+H)+; Analysis calculated for
C7H11NOS: C, 53.47; H, 7.05; N, 8.91; S, 20.39. Found: C, 53.52; H, 7.07; N,
8.96; S, 20.43.
4-[(Dimethylamino)methylene]dihydrothiophen-3(2H)-one (4): Rf 0.32; m.p.
122-124 ˚C; ¹Н-NMR (DMSO-d6), δ: 3.14 (s, 6Н), 3.17 (s, 2Н), 3.97 (s, 2Н), 7.09
(s, 1Н); MS: m/z 158 (M+H)+; Analysis calculated for C7H11NOS: C, 53.47; H,
7.05; N, 8.91; S, 20,39. Found: C, 53.42; H, 7.07; N, 8.92; S, 20.34.
6.
Zhang, W.; Henry, Y. Synlett 2001, 7, 1129.
7. General procedure for the synthesis of thieno[3,2-c]pyrazoles 6a-d and
thieno[3,4-c]pyrazoles 8a-d.
The mixture of 3 or 4 (0.01 mol, 1.57 g), substituted hydrazine (0.015 mol) and 30
ml i-PrOH was refluxed for 2.5 h. After cooling down to r.t. the resulting
precipitate was filtered off, washed with ethanol and air-dried to afford pure
product.
5,6-dihydro-1H-thieno[3,2-c]pyrazole (6a): Yield 84%; m.p. >250 ˚C; ¹Н-NMR
(DMSO-d6), δ: 3.58 (t, J = 14Hz, 2Н), 4.02 (t, J = 14Hz, 2Н), 7.92 (s, 1Н), 11.54
(br. s, 1Н); MS: m/z 127 (M+H)+; Analysis calculated for C5H6N2S: C, 47.59; H,
4.79; N, 22.20; S, 25.41. Found: C, 47.66; H, 4.84; N, 22.27; S, 25.45.
4,6-dihydro-1H-thieno[3,4-c]pyrazole (8a): Yield 80%; m.p. >250 ˚C; ¹Н-NMR
(DMSO-d6), δ: 3.67 (s, 2Н), 3.82 (s, 2Н), 7.37 (s, 1Н), 12.11 (br. s, 1Н); MS: m/z
127 (M+H)+; Analysis calculated for C5H6N2S: C, 47.59; H, 4.79; N, 22.20; S,
25.41. Found: C, 48.05; H, 4.84; N, 22.27; S, 25.45.

8.
General procedure for the synthesis of thieno[3,2-d]pyrimidines 7a-d
and thieno[3,4-d]pyrimidine 9a-d.
The mixture of 3 or 4 (0.01 mol, 1.57 g), amidine or thiourea (0.15 mol), sodium
bicarbonate (0.15 mol) in 20 ml of DMF was heated to 100 ˚С and stirred for 3 h.
The mixture was cooled down to r.t., resulting precipitate was filtered, washed
with alcohol and air-dried.
6,7-dihydrothieno[3,2-d]pyrimidin-2-amine (7a) : Yield 86%; m.p. 122-123 ˚C;
¹Н-NMR (DMSO-d6), δ: 3.14 (t, J = 7.2Hz, 2Н), 3.36 (t, J = 7.2Hz, 2Н), 7.03 (br.
s, 2Н), 8.11 (s, 1Н); MS: m/z 154 (M+H)+; Analysis calculated for C6H7N3S: C,
47.04; H, 4.61; N, 27.43; S, 20.93. Found: C, 47.11; H, 4.64; N, 27.48; S, 20.97.
5,7-dihydrothieno[3,4-d]pyrimidin-2-amine (9a): Yield 65%; m.p. 115-117 ˚C;
¹Н-NMR (DMSO-d6), δ: 3.54 (s, 2Н), 3.58 (s, 2Н), 6.51 (br. s, 1Н), 8.11 (s, 1Н);
MS: m/z 154 (M+H)+; Analysis calculated for C6H7N3S: C, 47.04; H, 4.61; N,
27.43; S, 20.93. Found: C, 47.11; H, 4.64; N, 27.48; S, 20.97.
9.
Toméa, A. C.; Cavaleiroa, J. A. S.; Storr, R. C. Tetrahedron 1996, 52, 1735.
10. Ko, C.-W.; Chou, T.-s. J. Org. Chem. 1998, 63, 4645.
11. Exon C.; Gallagher, T.; Magnus, P. J. Am. Chem. Soc. 1983, 105, 4739.
12. Connolly, T. J.; Durst, T. Tetrahedron 1997, 53, 15969.
13. Altenbacha, R. J.; Kalvodab, L.; Carrolla, W. A. Synth. Commun. 2004, 34,
567.
14. General procedure for the oxidation of 8a-d and 9a-d to 10a-d and 11a-
d respectively.
To the solution of 8a-d or 9a-d (0.01 mol) in CH2Cl2 (50 mL) were added V2O5 (5
mol%) and m-CPBA (1.5 mol) at 0 ˚C, and the mixture was stirred for 2 h with
gradient temperature increase to 25 ˚C. m-CBA was collected by filtration. The
organic layer was washed with water, sodium bicarbonate and brine. After drying
over magnesium sulfate the solvent was evaporated, residue was air-dried.
4,6-dihydro-1H-thieno[3,4-c]pyrazol-5,5-dioxide (10a): Yield 98%; m.p. >250
˚C; ¹Н-NMR (DMSO-d6), δ: 4.56 (s, 2Н), 4.71 (s, 2Н), 8.08 (s, 1Н), 13.02 (br. s,
1Н); MS: m/z 159 (M+H)+; Analysis calculated for C5H6N2O2S: C, 37.97; H, 3.82;
N, 17.71; S, 20.27. Found: C, 38.04; H, 3.83; N, 17.74; S, 20.31.
5,7-dihydrothieno[3,4-d]pyrimidin-2-amine-6,6-dioxide (11a): Yield 91%; m.p.
138-139 ˚C; ¹Н-NMR (DMSO-d6), δ: 4.61 (s, 2Н), 4.67 (s, 2Н), 7.19 (br. s, 1Н),
8.52 (s, 1Н); MS: m/z 186 (M+H)+; Analysis calculated for C6H7N3O2S: C, 38.91;
H, 3.81; N, 22.69; S, 17.31. Found: C, 38.96; H, 3.83; N, 22.72; S, 17.34.
15. Fernandez , T.; Sordo, J. A.; Monnat, F.; Deguin, B; Vogel, P. J. Am. Chem.
Soc. 1998, 120, 13276.
16. General procedure for the o-QDMs formation and subsequent Diels-
Alder trapping to form 12a-d and 13a,b.

The mixture of 10a-d or 11a-d (1 mmol) and N-phenylmaleimide (1.1 mmol) in
1,2,4-trichlorobenzene (5mL) in a sealed vial was subjected to MW irradiation,
such that the solvent boiled vigorously (220 ˚C) for 5 min. Reaction mixture was
cooled down to r.t. and diluted with ethanol. Resulting precipitate was filtered off
and subjected to flash purification (EtOAc : Hexanes, 2:1) to afford pure Diels-
Alder adducts.
6-Phenyl-4,4a,7a,8-tetrahydropyrrolo[3,4-f]indazole-5,7(1H,6H)-dione (12a):
Yield 62%; m.p. 189-190 ˚C; ¹Н-NMR (DMSO-d6), δ: 2.68-2.71 (m, 2Н), 3.04-
3.14 (m, 4Н), 7.19 (m, 1H), 7.28 (s, 1Н), 7.44-7.48 (m, 4Н), 10.31 (br. s, 1Н); MS:
m/z 268 (M+H)+; Analysis calculated for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72.
Found: C, 67.45; H, 4.91; N, 15.74.
7-Phenyl-2-(thiophen-2-yl)-5,5a,8a,9-tetrahydro-7H-pyrrolo[3,4-
g]quinazoline-6,8-dione (13a): Yield 72%; m.p. 231-232 ˚C; ¹Н-NMR (DMSO-
d6), δ: 2.76-2.79 (m, 2Н), 3.01-3.11 (m, 4Н), 7.16-7.22 (m, 2Н), 7.45-7.51 (m, 4Н),
7.69 (d, J = 6.8Hz, 1H), 7.82 (d, J = 6.8Hz, 1H), 8.79 (s, 1H); MS: m/z 362
(M+H)+; Analysis calculated for C20H15N3O2S: C, 66.46; H, 4.18; N, 11.63; S,
8.87. Found: C, 66.49; H, 4.19; N, 11.65; S, 8.88.