Simple, economical and environmentally friendly sulfone synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00598-1

Chemoselective sulfur oxidation of functionalized sulfides was developed using catalytic amounts of MnSO₄·H₂O (1 mol%) and 30% H₂O₂ in the presence of a buffer solution of NaHCO₃. Aromatic and aliphatic sulfides were oxidized to sulfones in quantitative yields in 15 min. Different functional groups including double bonds, alcohols, ethers of THP and TBDMS groups were tolerated under these mild and green reaction conditions.

Full text of DOI:10.1016/S0040-4039(02)00598-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3459–3461
Simple, economical and environmentally friendly sulfone
synthesis
Diego A. Alonso, Carmen Na´jera* and Montserrat Varea
Departamento de Qu´ımica Orga´nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 21 March 2002; accepted 26 March 2002
Abstract—Chemoselective sulfur oxidation of functionalized sulfides was developed using catalytic amounts of MnSO4·H2O (1
mol%) and 30% H2O2 in the presence of a buffer solution of NaHCO3. Aromatic and aliphatic sulfides were oxidized to sulfones
in quantitative yields in 15 min. Different functional groups including double bonds, alcohols, ethers of THP and TBDMS groups
were tolerated under these mild and green reaction conditions. © 2002 Elsevier Science Ltd. All rights reserved.
The use of sulfones in organic synthesis has become a
classic strategy in the synthesis of many of the most
demanding and sophisticated complex molecules.1
From the methodological point of view, sulfones have
been employed in the preparation and functionalization
of a wide variety of products by stabilizing a-radicals,2
a-anions3 and acting as cationic synthons.4 Among the
different protocols to prepare sulfones, the oxidation of
sulfides has become the most popular and straightfor-
ward method in organic synthesis.5 During the last
years, very useful procedures involving aqueous hydro-
gen peroxide (H2O2) as terminal oxidant and a catalytic
activator have been developed to promote this transfor-
mation, due to the effective oxygen-content, low cost,
safety in storage and operation and environmentally
friendly character of H2O2.6 The activator is essential
for the success of the reaction because H2O2 is a rather
slow oxidizing agent. A novel method for activating
hydrogen peroxide by using bicarbonate ion, was
described by Drago and co-workers7 and studied in
detail by Richardson et al.8 Very recently, and based on
amounts of MnSO4.9 Herein, we report our studies in
the chemoselective oxidation of aromatic and aliphatic
sulfides using a mixture of 30% H2O2 and a buffer
solution of NaHCO3 in the presence of catalytic
amounts of MnSO4·H2O.
From initial studies carried out with methyl phenyl
sulfide 1, we found the best reaction conditions by
using the sulfide (1 mmol), a 0.2 M buffer solution of
NaHCO3 (17 mL), 30% H2O2 (5 equiv.) and a catalytic
amount of MnSO4·H2O (1 mol%) in the presence of
different solvents (23 mL) (Scheme 1). The results are
summarized in Table 1. We initially chose DMF as
solvent as it was previously reported for this oxidation
system in olefin epoxidation processes.9 The oxidation
was efficiently achieved under these conditions in only
15 min, and the presence of the catalyst was crucial to
obtain full conversion of the sulfide to the sulfone
(Table 1, entries 1 and 2). The same catalytic activity of
the promoter, was also observed when using CH3CN as
solvent (Table 1, entry 3). However, when lower
amounts of oxidant (3 equiv.) were employed, a signifi-
cant increase in the reaction time was observed (Table
1, entries 4 and 5). In the absence of NaHCO3 (Table 1,
−
the peroxymonocarbonate ion chemistry (HCO4 ),
Burgess et al. have described a novel and successful
protocol for the epoxidation of olefins using catalytic
O
30% H2O2, NaHCO3
S
O
O
+
S
Ph
Me
S
Mn catalyst, solvent, rt
Ph
Me
Ph
Me
1
2
3
Scheme 1.
Keywords: green chemistry; hydrogen peroxide; oxidation; sulfides; sulfones.
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00598-1

3460
D. A. Alonso et al. / Tetrahedron Letters 43 (2002) 3459–3461
Table 1. Reaction conditions study
Entry
MnSO4·H2O (mol%)
H2O2 (equiv.)
Solvent
t (h)
2:3a
1
2
3
4
5
6
7
8
0
1
1
0
1
1
1
1
5
5
5
3
3
5b
5
5
5
5
5
5
DMF
DMF
0.25
0.25
0.25
24
24
24
24
24
24
24
52:48
0:100 (85)
0:100 (93)
43:57
6:94
100:0
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
62:38
NMP
75:25
9
1
Acetone
CH3CN
CH3CN
100c
10
11
12
1d
1e
1
77:17
0.25
0.25
31:69f
0:100 (70)
a Conversion and ratio determined by 1H NMR analysis (300 MHz) based on starting material. In brackets isolated yield after work-up.
b The reaction was carried out in the absence of NaHCO3.
c A mixture of 2/3=78:22 was obtained after 24 h in the absence of catalyst.
d MnCO3 (1 mol%) was used as catalyst.
e MnCl2 (1 mol%) was used as catalyst.
f Full conversion was observed after 2 h by 1H NMR analysis.
fone with an excellent yield (entry 16).12 Ester 11 was
converted to the sulfone as major reaction product only
in CH3CN (Table 2, entries 17–18). Very deactivated
substrates such as ester 12 was converted to the sulfox-
ide (Table 1, entry 19). With respect to the selectivity
towards double bonds, both vinylic and allylic sulfides
were cleanly transformed to the corresponding sulfones
with no traces of epoxidation byproducts (Table 2,
entries 20–23). Surprisingly, even normally reactive tri-
substituted olefinic moieties in sulfides 17 and 18 were
inert as well under these oxidation conditions (Table 2,
entries 24 and 25).
entry 6), only sulfoxide 210 was obtained, which clearly
indicated the existence of a ternary catalytic system
(H2O2–NaHCO3–MnSO4). Lower catalytic activities
were observed with other solvents such as EtOH, NMP
and acetone (Table 1, entries 7–9). Other Mn(II) salts
such as MnCO3 and MnCl2 proved to be less effective
promoters than MnSO4 (Table 1, entries 10 and 11).
We were also delighted to see that the reaction could be
run under organic solvent-free conditions6 affording the
corresponding methyl phenyl sulfone in a good yield
(Table 1, entry 12).
In order to establish the general applicability of the
method, various functionalized sulfides were subjected
to the oxidation protocol (Scheme 2, Table 2). In the
case of diphenyl sulfide 4, both in DMF and CH3CN
full oxidation of the starting material to the sulfone was
obtained even in the absence of catalyst (Table 2,
entries 1–3). Yields were always very high and acetoni-
trile showed to be the best solvent again as demon-
strated in the oxidation of benzyl phenyl sulfide (Table
2, entries 4 and 5).11 In the oxidation of p-anisyl methyl
sulfide 6, a substrate with a high nucleophilic character,
the reaction was much faster in DMF than in CH3CN
where the absence of the catalyst had a beneficial effect
in the reaction scope (Table 2, entries 6–9). However, in
other examples CH3CN was better solvent than DMF
to get full oxidation to the sulfone (Table 2, entries
10–18).
As conclusion, MnSO4 is an excellent catalyst promot-
ing the highly chemoselective and fast oxidation of
functionalized sulfides with 30% H2O2 and NaHCO3
under very mild conditions. Different functional groups
including double bonds, alcohols, ethers of THP and
TBDMS groups and esters were tolerated under this
environmentally friendly sulfone synthesis protocol.13
Typical experimental procedure: To a stirred solution of
sulfide (1 mmol) and MnSO4 monohydrate (2 mg, 1
mol%) in the corresponding solvent (23 mL), was added
at room temperature an aqueous mixture comprised by
30% H2O2 (5 mmol, 515 mL) and a 0.2 M buffer
solution of NaHCO3 (17 mL) previously prepared at
0°C. After 15 min the reaction was quenched with a
saturated NaCl solution, extracted with ethyl acetate
and dried with anhydrous MgSO4. Filtration and evap-
oration afforded the corresponding pure crude sulfones.
The chemoselectivity of the procedure was noteworthy.
Under these conditions, various functional groups
including alcohols, tetrahydropyranyl (THP) and tert-
butyldimethylsilyl (TBDMS) ethers were tolerated
(Table 2, entries 10–15). Aryl alkyl sulfide 10, bearing
electron withdrawing groups such us CF3 in the aro-
matic ring did not affect the synthetic efficiency of the
method and afforded the corresponding p-deficient sul-
30% H2O2, NaHCO3
RSO2R'
RSR'
MnSO4. H2O, solvent, rt
Scheme 2.

D. A. Alonso et al. / Tetrahedron Letters 43 (2002) 3459–3461
Table 2. Oxidation of sulfides to sulfones catalyzed by MnSO4·H2O
3461
Entry
Sulfide
H2O2 (equiv.)
Solvent
t (h)
Yield (%)a
1
2
3
4
PhSPh (4)
PhSPh (4)
PhSPh (4)
PhSCH2Ph (5)
3
CH3CN
DMF
CH3CN
DMF
0.25
0.25
0.25
24
100 (94)
100 (94)
100
3
2b
5
55
5
6
7
8
PhSCH2Ph (5)
5
5
CH3CN
DMF
DMF
CH3CN
CH3CN
DMF
CH3CN
DMF
CH3CN
DMF
CH3CN
CH3CN
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
0.25
0.25
0.25
24
100 (99)
100 (70)
100
63
98
72
100 (88)
80
4-MeOC6H4SMe (6)
4-MeOC6H4SMe (6)
4-MeOC6H4SMe (6)
4-MeOC6H4SMe (6)
PhSCH2CH2OH (7)
PhSCH2CH2OH (7)
PhSCH2CH2OTHP (8)
PhSCH2CH2OTHP (8)
PhSCH2CH2OTBDMS (9)
PhSCH2CH2OTBDMS (9)
3,5-(CF3)2C6H3SCH2CH2OH (10)
PhSCH2CO2CH2Ph (11)
PhSCH2CO2CH2Ph (11)
3-CF3C6H4SCO2CH2Ph (12)
PhSCHꢀCH2 (13)
5b
3.5
3.5b
5
9
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
24
0.25
0.25
0.25
0.25
0.25
0.25
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
100 (85)
72c
100 (86)
100
100d
80e
100d
100 (93)
100 (80)
95
100 (94)
100 (90)
100 (87)
PhSCH2CHꢀCH2 (14)
(CH2ꢀCHCH2)2S (15)
PhCH2SCH2CHꢀCH2 (16)
PhSCH2CHꢀC(Me)2 (17)
PhSCH2CHꢀC(Me)CHꢀC(Me)2 (18)
CH3CN
a Conversion determined by 1H NMR analysis based on initial methyl phenyl sulfide. In brackets isolated yield after work-up. All products were
pure by 1H NMR analysis (300 MHz).
b The reaction was run in the absence of catalyst.
c Yield of sulfoxide. Only traces of sulfone (6%) were detected by 1H NMR analysis.
d Yield of sulfoxide. No sulfone was detected in the crude reaction mixture by 1H NMR analysis.
e 20% of the corresponding sulfoxide was obtained as by-product.
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Ciencia y Tecnolog´ıa for a contract under the program
Ramo´n y Cajal.