An Efficient Oxidation of Sulfides to Sulfones with Urea-Hydrogen Peroxide in the Presence of Phthalic Anhydride in Ethyl Acetate

Article abstract of DOI:10.1055/s-0037-1609446

A metal-free, environmentally benign oxidation of substituted sulfides directly to their corresponding sulfones is described. Using urea-hydrogen peroxide and phthalic anhydride in ethyl acetate clean conversion into the sulfone was achieved without observation of the possible sulfoxide oxidation product.

Full text of DOI:10.1055/s-0037-1609446

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–D
paper
A
en
M. Lutz et al.
Paper
Synthesis
An Efficient Oxidation of Sulfides to Sulfones with Urea–Hydrogen
Peroxide in the Presence of Phthalic Anhydride in Ethyl Acetate
Marlon Lutz
urea–hydrogen peroxide
phthalic anhydride
O
S
O
O
Marta Wenzler
Igor Likhotvorik*
S
S
R1
R2
R1
R2
R1
R2
EtOAc, r.t.
R = aryl, alkyl
R
not observed
• 13 examples
• up to 99% yield
1 = R2 and R1 ≠ R2
Process Research and Development, Regis Technologies,
8210 Austin Ave., Morton Grove, IL 60053, USA
ilikhotvorik@registech.com
metal-free, gentle, scalable conditions
providing direct access to the sulfone
Received: 27.02.2018
Accepted after revision: 14.03.2018
Published online: 04.04.2018
Previous Work
S
O
O
O
+
S
S
R1
R2
DOI: 10.1055/s-0037-1609446; Art ID: ss-2018-m0127-op
R1
• peroxides and peracids
R2
R1
R2
• metal-centered oxidants
• hypochlorites
• hypervalent iodine
Abstract A metal-free, environmentally benign oxidation of substitut-
ed sulfides directly to their corresponding sulfones is described. Using
urea-hydrogen peroxide and phthalic anhydride in ethyl acetate clean
conversion into the sulfone was achieved without observation of the
possible sulfoxide oxidation product.
This Work
UHP
O
O
phthalic anhydride
S
R1
R2
S
R1
R2
EtOAc, r.t.
Key words sulfones, sulfoxides, sulfide oxidation, urea–hydrogen per-
• no observed sulfoxide
• no toxic metals
oxide, UHP, phthalic anhydride
• gentle reaction conditions
• clean isolation
Sulfones are a valuable functional group that confer ac-
tivity in a variety of industrially relevant categories includ-
ing pharmaceuticals,1 agrochemicals,2 and biologically ac-
tive natural products.3 Sulfones also provide useful func-
tional handles for synthetic manipulation.4
Scheme 1 General conditions for accessing the sulfone from sulfide
starting materials
Typical UHP oxidation methods require acetic anhydride8 or
trifluoroacetic anhydride (TFAA);9 however, these reaction
conditions can lead to the formation of diacyl peroxides,
which are volatile, highly explosive side products.8 More re-
cently, transition metal catalysts have been developed for
more gentle oxidation conditions;10 however, these are also
unfavorable due to their high cost and potential toxicity. Or-
ganocatalysts for UHP oxidation would provide mild condi-
tions for sulfur atom oxidation without the hazards associ-
ated with low-boiling acid anhydrides or metal catalysts.
Previously reported sulfide oxidation upon treatment
with an excess of up to 5 equivalents of UHP and 2.5 equiv-
alents of phthalic anhydride in either acetonitrile or metha-
nol provided clean conversion into the sulfoxide exclusively,
surprisingly without the production of the sulfone.11 How-
ever, when we performed this reaction in ethyl acetate, we
found that the sulfoxides were relatively short-lived inter-
mediates, transformed quickly to the sulfone terminal oxi-
dation product, and the reaction required less oxidative re-
Selective oxidation of a sulfide to either the sulfoxide or
the sulfone is the most common challenge in sulfur chemis-
try. Currently, sulfide oxidation methods utilize less than
desirable oxidizing reagents including heavy metals or
strong oxidants, such as hydrogen peroxide, meta-chloro-
perbenzoic acid, potassium permanganate, and sodium
(meta)periodate. These reagents generally require long re-
action times, high temperatures, or relatively strong basic,
acidic, or aqueous conditions (Scheme 1).5 These harsh con-
ditions are typically not appropriate for the oxidation of
sulfides containing sensitive functional groups including
highly electron-withdrawing substituents or acid-/base-la-
bile functionalities.6 Our goal was to design mild conditions
with easy to use and readily available materials to access
sulfones via sulfide oxidation.
Urea–hydrogen peroxide (UHP) is a safer alternative to
hydrogen peroxide that is compatible with a wide variety of
gentle and environmentally friendly reaction conditions.7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

B
M. Lutz et al.
Paper
Synthesis
agent than previously reported for oxidation in acetoni-
trile.12
All reagents and solvents used were of commercial grade. Reaction
progression was analyzed on an Agilent 1100 HPLC utilizing a Waters
Symmetry Shield RP18 column (100Å, 5 μm, 4.6 mm × 250 mm). NMR
spectra were acquired on Bruker DPX-400 (400 MHz), spectrometers
and are reported relative to deuterated solvent signals (CDCl3 = 7.26
and DMSO-d6 = 2.50). Data for 1H NMR spectra are reported as fol-
lows: chemical shift δ (ppm), multiplicity (standard abbreviations).
Mass spectra were recorded on a Waters Acquity I Class UPLC with a
Xevo G2-XS QTof utilizing a Waters Acquity UPLC HSS T3 column (100
Å, 1.8 μm, 2.1 mm × 50 mm) or an Agilent series 7890A gas chromato-
graph with a Agilent series 5975C mass selective detector utilizing an
Agilent J & W HP-5 GC column (30 m × 0.32 mm, 0.25 μm, 7 inch
cage).
Herein we describe sulfide oxidation conditions with
UHP and phthalic anhydride that apply to sulfides contain-
ing a variety of functional groups, are easy to use on a large
scale, and provide high-purity sulfones, in most cases with-
out additional purification.
Both symmetric and asymmetric alkyl, aryl, and hetero-
cyclic sulfides were successfully oxidized to their respective
sulfones (Scheme 2). Sulfides containing electron-with-
drawing groups, electron-donating groups, acid-sensitive
protecting groups, esters and benzylic ketones were well
tolerated, providing the respective sulfones in near quanti-
tative yields following either procedure A or procedure B.
Procedure A was useful for most crystalline sulfones and
enabled isolation of pure products by filtration, eliminating
a lengthy extractive workup. Procedure B was followed
when the sulfone products were non-crystalline or exhibit-
ed relatively high solubility in ethyl acetate.
Sulfide Oxidation to the Sulfone; General Procedures
Procedure A: To a solution of sulfide 1 (200 mg, 1–2 mmol, 1 equiv) in
EtOAc (5 mL) was added UHP (3 equiv) and phthalic anhydride (3
equiv) and the solution was allowed to stir for 12–16 h at r.t. The reac-
tion slurry was quenched with sat. aq Na2SO3 (10 mL) and the crystal-
line solids were isolated by filtration. The solids were washed with aq
1 N NaOH (2 × 10 mL), H2O (2 × 15 mL), and EtOAc (5 mL) to provide
the desired sulfone, as a spectroscopically pure product.
O
O
UHP
phthalic anhydride
Procedure B: To a solution of sulfide 1 (200 mg, 1–2 mmol, 1 equiv) in
EtOAc (5 mL) was added UHP (3 equiv) and phthalic anhydride (3
equiv) and the solution was allowed to stir for 12–16 h at r.t. The reac-
tion was quenched with sat. aq Na2SO3 (10 mL) and then diluted with
EtOAc (5 mL). The organics were washed with 1 N aq NaOH (2 × 10
mL), H2O (10 mL), and brine (10 mL). The organics were dried (Na2-
SO4) and concentrated to give the desired, spectroscopically pure sul-
fone product.
S
S
R1
R2
R1
R2
EtOAc, 12–16 h, r.t.
1a–m
2a–m
O
O
O
O
O
O
O O
S
S
S
S
Me
Me
Me
Me
Me
O
Cl
Cl
98%, 2a
97%, 2b
96%, 2c
96%, 2d
O
(Methylsulfonyl)benzene (2a)13
O
O
O
O
S
S
S
Me
Me
O2N
Prepared via procedure B to give 248 mg of white crystalline solid
(98%); mp 82–84 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.96 (d, J = 7.5 Hz, 2 H, ArH), 7.67 (t, J =
7.3 Hz, 1 H, ArH), 7.58 (t, J = 7.4 Hz, 2 H, ArH), 3.06 (s, 3 H, CH3).
O2N
NO2
N
99%, 2e
99%, 2f
96%, 2g
O
O
O
O
O O
Me
Me
13C NMR (CDCl3, 100 MHz): δ = 140.7, 136.2, 133.8, 129.5, 127.4,
S
S
S
125.8.
HRMS (ESI): m/z [M + H]+ calcd for C7H8O2S: 157.0318; found:
99%, 2h
quant, 2j
98%, 2i
157.0316.
O
O
O O
S
EtO
1-Methyl-4-(methylsulfonyl)benzene (2b)
O
O
S
Prepared via procedure A to give 238 mg of white crystalline solid
(97%); mp 87–92 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.83 (d, J = 8.3 Hz, 2 H, ArH), 7.37 (d, J =
F
S
Hexyl
Hexyl
N
O
O
Boc
98%, 2m
99%, 2k
99%, 2l
8.0 Hz, 2 H, ArH), 3.04 (s, 3 H, CH3), 2.45 (s, 3 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 144.8, 137.8, 130.0, 127.5, 44.7, 21.7.
Scheme 2 Substrate scope for UHP, phthalic anhydride oxidation to
the sulfone
HRMS (ESI): m/z [M + H]+ calcd for C8H10O2S: 171.0474; found:
171.0464.
In summary, UHP and phthalic anhydride provide clean,
organocatalytic oxidation of sulfides directly to the sulfones
under conditions that tolerate various substrate functional-
ities without issue. These conditions scale well, affording
high yields and high purity of the sulfone product without
the need for column chromatography, thus providing a met-
al-free, environmentally benign, clean oxidation of sulfides
directly to sulfones.
1-Chloro-4-(methylsulfonyl)benzene (2c)14
Prepared via procedure A to give 230 mg of white crystalline solid
(96%); mp 95–103 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.89 (d, J = 7.5 Hz, 2 H, ArH), 7.56 (d, J =
7.5 Hz, 2 H, ArH), 3.06 (s, 3 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 140.55, 139.1, 129.8, 129.0, 44.6.
GCMS: m/z calcd for C7H7ClO2S: 190.0; found: 190.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

C
M. Lutz et al.
Paper
Synthesis
1-Chloro-2-(methylsulfonyl)benzene (2d)
4,6-Dimethyldibenzo[b,d]thiophene 5,5-Dioxide (2j)
Prepared via procedure B to give 231 mg of clear oil (96%) that solidi-
fied upon standing to give a white solid; mp 86–91 °C.
Prepared via procedure A to give 230 mg of white solid (quant.); mp
278–282 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.16 (dd, J = 7.4, 1.5 Hz, 1 H, ArH), 7.58
(dd, J = 6.5, 1.6 Hz, 2 H, ArH), 7.48 (dt, J = 8.3, 2.2 Hz, 1 H, ArH), 3.28 (s,
3 H, CH3).
1H NMR (DMSO-d6, 400 MHz): δ = 7.97 (d, J = 7.6 Hz, 2 H, ArH), 7.65 (t,
J = 7.6 Hz, 2 H, ArH), 7.43 (d, J = 7.6 Hz, 2 H, ArH), 3.32 (s, 6 H, CH3),
2.60 (s, 6 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 138.1, 134.9, 132.6, 132.0, 130.9,
13C NMR (DMSO-d6, 100 MHz): δ = 134.9, 134.6, 134.2, 132.4, 131.9,
127.6, 42.8.
120.0, 16.2.
HRMS (ESI): m/z [M + H]+ calculated for C7H7ClO2S: 190.9928; found:
HRMS (ESI): m/z [M + H]+ calcd for C14H12NO2S: 245.0631; found:
245.0626.
190.9919.
4-(Methylsulfonyl)benzonitrile (2e)
9H-Thioxanthen-9-one 10,10-Dioxide (2k)17
Prepared via procedure A to give 240 mg of white crystalline solid
(99%); mp 143–145 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.09 (d, J = 8.6 Hz, 2 H, ArH), 7.90 (d, J =
8.6 Hz, 2 H, ArH), 3.11 (s, 3 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 144.6, 133.3, 128.3, 117.7, 117.2, 44.3.
Prepared via procedure A to give 199 mg of pale yellow crystalline
solid (99%); mp 189–191 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.38 (d, J = 7.8 Hz, 2 H, ArH), 8.22 (d, J =
7.8 Hz, 2 H, ArH), 7.91 (t, J = 7.6 Hz, 2 H, ArH), 7.83 (t, J = 7.6 Hz, 2 H,
ArH).
GCMS: m/z calcd for C8H7NO2S: 181.0; found: 181.0.
13C NMR (CDCl3, 100 MHz): δ = 178.5, 141.1, 134.8, 133.4, 130.8,
129.3, 123.6.
1-(Methylsulfonyl)-4-nitrobenzene (2f)14
HRMS (ESI): m/z [M + H]+ calcd for C13H8O3S: 245.0267; found:
245.0245.
Prepared via procedure A to give 236 mg of pale yellow crystalline
solid (99%); mp 133–141 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.44 (d, J = 7.4 Hz, 2 H, ArH), 8.17 (d, J =
1-(Hexylsulfonyl)hexane (2l)
7.4 Hz, 2 H, ArH), 3.13 (s, 3 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 151.0, 146.1, 136.2, 129.1, 125.8,
124.8, 44.4.
Prepared via procedure B to give 230 mg of white solid (99%); mp 73–
74 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.94 (t, J = 7.8 Hz, 4 H, CH2), 1.83
(quint, J = 7.5 Hz, 4 H, CH2), 1.44 (m, 4 H, CH2), 1.32 (m, 8 H, CH2), 0.90
(m, 6 H, CH3).
GCMS: m/z calcd for C7H7NO4S: 201.0; found: 201.0.
13C NMR (CDCl3, 100 MHz): δ = 52.8, 31.3, 28.3, 22.4, 22.0, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H26O2S: 235.1726; found:
4,4′-Sulfonylbis(nitrobenzene) (2g)15
Prepared via procedure A to give 214 mg of white solid (96%); mp
256–261 °C.
235.1749.
1H NMR (DMSO-d6, 400 MHz): δ = 8.44 (t, J = 9.0 Hz, 4 H, ArH), 8.32 (t,
J = 9.0 Hz, 4 H, ArH).
13C NMR (DMSO-d6, 100 MHz): δ = 150.8, 144.8, 129.6, 125.2.
1-(tert-Butyl) 4-Ethyl 4-[(4-Fluorophenyl)sulfonyl]piperidine-1,4-
dicarboxylate (2m)18
Prepared via procedure A to give 213 mg of white solid (98%); mp 89–
97 °C.
GCMS: m/z calcd for C12H8N2O6S: 308.0; found: 308.0.
1H NMR (CDCl3, 400 MHz): δ = 7.82–7.79 (m, 2 H, ArH), 7.27–7.21 (m,
2 H, ArH), 4.23–4.18 (m, 4 H, CH2), 2.71–2.47 (m, 2 H, CH2), 2.32–2.22
(m, 2 H, CH2), 2.01 (td, J = 12.8, 4.8 Hz, 2 H, CH2), 1.42 (s, 9 H, CH3),
1.21 (t, J = 7.14 Hz, 3 H, CH3).
13C NMR (CDCl3, 100 MHz): δ = 167.6, 166.7, 165.1, 154.4, 133.2,
133.1, 131.0, 131.0, 116.3, 116.1, 80.2, 72.5, 62.7, 28.4, 27.7, 14.0.
Sulfonyldibenzene (2h)13
Prepared via procedure A to give 232 mg of white crystalline solid
(99%); mp 121–126 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.95 (d, J = 6.9 Hz, 4 H, ArH), 7.58–7.48
(m, 6 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 141.7, 133.3, 129.4, 127.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H10O2S: 219.0474; found:
HRMS (ESI): m/z [M + Na]+ calcd for C19H26FNO6S: 438.1357; found:
438.1387.
219.0495.
Dibenzo[b,d]thiophene 5,5-Dioxide (2i)16
Funding Information
Prepared via procedure A to give 230 mg of white crystalline solid
(98%); mp 234–237 °C.
This work was supported by Regis Technologies, Inc.
)(
1H NMR (CDCl3, 400 MHz): δ = 7.82 (d, J = 7.7 Hz, 2 H, ArH), 7.79 (d, J =
8.0 Hz, 2 H, ArH), 7.63 (t, J = 7.5 Hz, 2 H, ArH), 7.52 (t, J = 7.5 Hz, 2 H,
ArH).
Acknowledgment
13C NMR (CDCl3, 100 MHz): δ = 137.8, 134.0, 131.7, 130.5, 122.2,
121.7.
We are grateful to Dr. L. Fan for mass spectrometry analyses of poorly
ionizable compounds.
HRMS (ESI): m/z [M + H]+ calcd for C12H8O2S: 217.0318; found:
217.0357.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D

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Synthesis
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609446.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–D