A Convenient Multigram Scale Synthesis of Tetrahydrothiophene-3-one-1,1-dioxide

Article abstract of DOI:10.1081/SCC-120027703

A short and efficient multigram scale synthesis of tetrahydrothiophene-3-one-1,1-dioxide is described.

Full text of DOI:10.1081/SCC-120027703

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A Convenient Multigram Scale Synthesis of
Tetrahydrothiophene‐3‐one‐1,1‐dioxide
Robert J. Altenbach a , Ladislav Kalvoda b & William A. Carroll a
a Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and
Development, Dept R4MN, Bldg AP9A, 100 Abbott Park Rd., Abbott Park, Illinois,
60064‐6123, USA
b Synlab, Laboratory of Organic Chemistry, Czech Republic
Version of record first published: 16 Aug 2006
To cite this article: Robert J. Altenbach, Ladislav Kalvoda & William A. Carroll (2004): A Convenient Multigram Scale
Synthesis of Tetrahydrothiophene‐3‐one‐1,1‐dioxide, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:4, 567-570
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 4, pp. 567–570, 2004
A Convenient Multigram Scale Synthesis of
Tetrahydrothiophene-3-one-1,1-dioxide
2
Robert J. Altenbach,1, Ladislav Kalvoda,
*
and William A. Carroll1
1Abbott Laboratories, Neuroscience Research, Global Pharmaceutical
Research and Development, Abbott Park, Illinois, USA
2Synlab, Laboratory of Organic Chemistry, Czech Republic
ABSTRACT
A short and efficient multigram scale synthesis of tetrahydrothiophene-3-
one-1,1-dioxide is described.
Key Words: Tetrahydrothiophene-3-one-1,1-dioxide; Sulfone; Mole-
scale two pot synthesis.
We recently required multigram quantities of tetrahydrothiophene-3-one-
1,1-dioxide (3a) for the synthesis of sulfone containing dihydropyridines. We
have developed a mole scale synthesis of 3a from commercially available
*
Correspondence: Robert J. Altenbach, Abbott Laboratories, Neuroscience Research,
Global Pharmaceutical Research and Development, Dept R4MN, Bldg AP9A,
100 Abbott Park Rd., Abbott Park, IL 60064-6123, USA; E-mail: robert.j.altenbach@
abbott.com.
567
DOI: 10.1081/SCC-120027703
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Altenbach, Kalvoda, and Carroll
Scheme 1. Synthesis of ketosulfones 3a–3c.
tetrahydrothiophen-3-one (1a) that is an alternative to existing published
methods.[1,2]
The synthesis of compound 3a is illustrated in Sch. 1. Tetrahydrothio-
phene-3-one (1a, 101 g, 1.05 mol) was protected as the diethyl ketal using
triethyl orthoformate in the presence of para-toluenesulfonic acid and then
directly oxidized with aqueous hydrogen peroxide in the presence of a
catalytic amount of sodium tungstate and sodium acetate. The crystalline
product was isolated by filtration and washed with water. This one pot process
yielded 195 g (94%) of intermediate 2a. Deprotection of 2a in aqueous acid
provided, after crystallization from ethanol, 116 g (86% overall yield) of the
desired tetrahydrothiophene-3-one-1,1-dioxide (3a).
The key step in this process is the generation of intermediate 2a via the
one pot diethyl ketal formation and tungsten catalyzed oxidation of com-
mercially available tetrahydrothiophen-3-one (1a). Belletire and Spletzer
arrived at a similar intermediate via reaction of 3,4-dibromotetrahydrothio-
phene-1,1-dioxide with excess sodium methoxide in methanol.[1] Miklos and
Senning generated a spiro ketal version of intermediate 2a using a two step
process.[3] The advantage of our method is that 2a can be isolated on large
scale simply by filtration and the overall process of generating 3a is higher
yielding. The use of toxic oxidants such as Jones reagent is also avoided.[2]
To investigate the scope of this process, the six and seven membered ring
thiopyran-3-one (1b)[4] and thiepan-3-one (1c)[4] were subjected to the above
sequence. The one pot protection/oxidation of 1b provided the intermediate
diethyl ketal sulfone 2b in 59%. Deprotection of 2b provided 3b in a
quantitative yield. In the case of 1c, the protection/oxidation step did not yield
the intermediate ketal 2c. Instead, a 39% yield of 3c was directly obtained. The
lower yield of 2b and the lack of isolation of 2c under these reaction

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Tetrahydrothiophene-3-one-1,1-dioxide
569
conditions may be a result of intermediates 2b and 2c being less stable and
possibly less crystalline than 2a.
In summary, we have developed a convenient and efficient mole-scale
two pot synthesis of 3a from commercially available 1a. This sequence
requires no chromatography and avoids the use of cumbersome and environ-
mentally hazardous oxidants such as Jones reagent.
EXPERIMENTAL SECTION
Proton NMR spectra were obtained on a General Electric QE 300 MHz
instrument with chemical shifts (d) reported relative to tetramethylsilane as an
internal standard. Melting points were determined on a Thomas–Hoover
capillary melting point apparatus and are uncorrected. Elemental analyses
were performed by Robertson Microlit Laboratories. Thin layer chroma-
tography (TLC) was performed using 250 mm silica gel 60 glassbacked plates
with F254 as indicator.
3,3-Diethoxytetrahydrothiophene-1,1-dione (2a). A mixture of tetra-
hydrothiophen-3-one (1a, 101 g, 1 mol), ethanol (20 mL) and triethyl ortho-
formate (155 g, 1.05 mol) was treated with p-toluenesulfonic acid (0.5 g,
0.0026 mol) and stirred for 20 hours. The mixture was treated with anhydrous
sodium acetate (3.3 g, 0.04 mol), sodium tungstate dihydrate (2.8 g,
0.0085 mmol) and water (280 mL). A 35% solution of hydrogen peroxide in
water (285 mL) was added dropwise while keeping the mixture cooled to
308C. After stirring over night at ambient temperature, the resulting crystalline
product was collected by filtration, washed with water and dried (not
necessary for the next step) to provide 195 g (94%) of 3,3-diethoxytetra-
1
hydrothiophene-1,1-dione. m.p. 80–828C; H NMR (CDCl3) d 1.22 (t, 6H,
J ¼ 7.1 Hz), 2.43 (t, 2H, J ¼ 7.2 Hz), 3.22 (t, 2H, J ¼ 7.4 Hz), 3.30 (d, 2H,
J ¼ 0.9 Hz), 3.52 (m, 4H); MS (DCI/NH3) m/z 226 (M þ NH4)þ; Anal.
Calcd. for C8H16O4S: C, 46.13; H, 7.74; S, 15.40. Found: C, 46.30; H, 7.54;
S, 15.41.
Tetrahydrothiophene-3-one-1,1-dioxide (3a). A suspension of com-
pound 2a (195 g, 0.94 mol) in a mixture of concentrated HCl (6 mL) and water
(600 mL) was stirred at 608C for 2 hours. The mixture was concentrated to a
thick syrup and treated with dichloromethane (600 mL). The dichloromethane
layer was isolated, dried (MgSO4), filtered and concentrated. The residue was
crystallized from hot ethanol (150 mL). The resulting crystals were collected
by filtration, washed with ethanol and dried to provide 116 g (86% overall) of
1
tetrahydrothiophene-3-one-1,1-dioxide. m.p. 60–628C; H NMR (CDCl3) d
3.0 (d, 2H, J ¼ 7.9 Hz), 3.58 (m, 2H), 3.71 (s, 2H); MS (DCI/NH3) m/z 152

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Altenbach, Kalvoda, and Carroll
(M þ NH4)þ; Anal. Calcd. for C4H6O3S: C, 35.81; H, 4.51; S, 23.90. Found:
C, 36.18; H, 4.20; S, 23.75.
3,3-Diethoxytetrahydrothiopyran-1,1-dione (2b). Dihydrothiopyran-3-
one[4] (1b, 5.0 g, 43 mmol) provided 5.7 g (59%) of 3,3-diethoxytetrahydro-
thiopyran-1,1-dione. A 30% solution of hydrogen peroxide in water was used
in place of the 35% solution. m.p. 96–978C; 1H NMR (CDCl3) d 1.20 (t, 6H,
J ¼ 7 Hz), 1.88 (m, 2H), 2.11 (m, 2H), 2.98 (m, 2H), 3.25 (s, 2H), 3.44–3.60
(m, 4H); MS (DCI/NH3) m/z 240 (M þ NH4)þ; Anal. Calcd. for C9H18O4S:
C, 48.63; H, 8.16; S, 14.42. Found: C, 48.69; H, 7.97; S, 14.33.
Tetrahydrothiopyran-3-one-1,1-dioxide (2c). Compound 2b (3.3 g,
15 mmol) provided 2.2 g (99%) of tetrahydrothiopyran-3-one-1,1-dioxide.
1
m.p. 139–1418C; H NMR (DMSO-d6) d 2.00 (m, 2H), 2.54 (m, 2H), 3.44
(m, 2H), 4.28 (s, 2H); MS (DCI/NH3) m/z 166 (M þ NH4)þ; Anal. Calcd. for
C5H8O3S: C, 40.53; H, 5.44; S, 21.64. Found: C, 40.43; H, 5.43; S, 21.63.
Thiepan-3-one-1,1-dioxide (3c). Thiepan-3-one[4] (1c, 2.5 g, 19 mmol),
ethanol (1.14 mL) and triethyl orthoformate (7.2 g, 48 mmol) were treated
with p-toluenesulfonic acid (37 mg, 0.19 mmol) and stirred for 44 hours. The
mixture was treated with anhydrous sodium acetate (64 mg, 0.8 mmol), treated
with sodium tungstate dihydrate (54 mg, 0.16 mmol), treated with H2O
(5.5 mL) and treated dropwise with 30% hydrogen peroxide (7 mL, keeping
the reaction temperature below 308C during the addition) and stirred at
ambient temperature for 60 hours. The precipitate was collected by filtration,
washed with water and dried under vacuum to provide 1.21 g (39%) of
1
thiepan-3-one-1,1-dioxide. m.p. 108–1108C; H NMR (DMSO-d6) d 1.94
(m, 4H), 2.55 (m, 2H), 3.45 (m, 2H), 4.49 (t, 2H, J ¼ 1.4 Hz); MS (DCI/NH3)
m/z 180 (M þ NH4)þ; Anal. Calcd. for C6H10O3S: C, 44.43; H, 6.21; S, 19.77.
Found: C, 44.49; H, 6.05; S, 19.68.
REFERENCES
1. Belletire, J.L.; Spletzer, E.G. 3-Oxotetrahydrothiophene-1,1-dioxoide a
versatile synthetic intermediate. Synth. Commun. 1983, 13 (4), 269–272.
2. Dodd, J.H.; Schwender, C.F.; Gray-Nunez, Y. Synthesis of novel cyclic
sulfone dihydropyridines facilitated by a selective ethyl diazoacetate ring
expansion. J. Heterocycl. Chem. 1990, 27 (5), 1453–1456.
3. Miklos, P.; Senning, A. Synthesis and equilibrium studies of new dihydro-
thiophene sulfoxides. Tetrahedron 1987, 43 (1), 249–254.
4. Leonard, N.J.; Figueras, J. Rearrangement of a-thiaketones during clem-
mensen reduction. J. Am. Chem. Soc. 1952, 74 (4), 917–920.
Received in the USA August 14, 2003

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