Synthetic strategies to 2′-hydroxy-4′- methylsulfonylacetophenone, a key compound for the preparation of flavonoid derivatives

Article abstract of DOI:10.1016/j.crci.2013.10.004

Different strategies for the synthesis of 2′-hydroxy-4′- methylsulfonylacetophenone are reported in the present paper. This compound is considered as a key synthon for the synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors. The retrosynthetic approach via 3′-methylsulfonylacetophenone, which included three synthetic pathways, did not allow us to obtain the expected compound. However, a synthesis from 3-mercaptophenol led to the desired acetophenone in three steps: thiophenol methylation, Friedel-Crafts acetylation and oxidation of the sulphide to the corresponding sulfone. The desired compound, 2′-hydroxy-4′- methylsulfonylacetophenone, will be used as a synthon for the preparation of novel flavonoid derivatives, such as 2′-hydroxychalcones, flavanones, flavones, and flavonols.

Full text of DOI:10.1016/j.crci.2013.10.004

C. R. Chimie 17 (2014) 443–449
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´
Full paper/Memoire
Synthetic strategies to 20-hydroxy-40-
methylsulfonylacetophenone, a key compound for
the preparation of flavonoid derivatives
a
b
a
Rokhaya Gueye a, , Christelle Pouget , Yves Champavier , Jacques Buxeraud ,
*
a
a
`
Jean-Luc Duroux , Catherine Fagnere
a Laboratoire de chimie des substances naturelles–EA 1069, faculte´ de pharmacie, 2, rue du Docteur-Marcland, 87025 Limoges cedex,
France
b
´
´
´
Service commun de recherche et d’analyse de biomolecules de Limoges, facultes de medecine et de pharmacie,
2, rue du Docteur-Marcland, 87025 Limoges cedex, France
A R T I C L E I N F O
A B S T R A C T
Different strategies for the synthesis of 20-hydroxy-40-methylsulfonylacetophenone are
reported in the present paper. This compound is considered as a key synthon for the
synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors.
The retrosynthetic approach via 30-methylsulfonylacetophenone, which included three
synthetic pathways, did not allow us to obtain the expected compound. However, a
synthesis from 3-mercaptophenol led to the desired acetophenone in three steps:
thiophenol methylation, Friedel–Crafts acetylation and oxidation of the sulphide to the
corresponding sulfone. The desired compound, 20-hydroxy-40-methylsulfonylacetophe-
none, will be used as a synthon for the preparation of novel flavonoid derivatives, such as
20-hydroxychalcones, flavanones, flavones, and flavonols.
Article history:
Received 12 December 2012
Accepted after revision 3 October 2013
Available online 26 February 2014
Keywords:
Ketones
Synthetic methods
Acylation
Electrophilic substitution
Lewis acids
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
(Scheme 1) [5,6]. Therefore, we were interested in the
synthesis of 20-hydroxy-40-methylsulfonylacetophenone
Flavonoids, a wide family of natural compounds, are
known to possess an anti-inflammatory effect due to their
inhibitory potency towards cyclooxygenase-2 enzyme
[1,2]. Besides, considering structure-activity relationship
studies mainly about 1,2-diaryl substituted heterocycles,
the methylsulfonyl group was found to be critical for
cyclooxygenase-2 inhibitory activity and is also believed to
induce cyclooxygenase-2 selectivity [3,4]. Thus, our efforts
are directed towards the synthesis of flavonoid derivatives
bearing this pharmacophore. 20-Hydroxychalcones are the
main precursors for the synthesis of flavonoids and the
Claisen–Schmidt condensation between an acetophenone
and a benzaldehyde is a key reaction for their preparation
(1) as a synthon for the preparation of novel flavonoid
derivatives that would be potential cyclooxygenase-2
selective inhibitors.
2. Results and discussions
A first strategy for the synthesis of 20-hydroxy-40-
methylsulfonylacetophenone (1) was considered as shown
in Scheme 2. This product might be synthesized from
30-methylsulfonylacetophenone (3) through a Baeyer–
Villiger oxidation followed by a Fries rearrangement from
compound 2. Three synthetic pathways were envisaged in
order to prepare compound 3:
ꢀ
pathway A consisted of the chlorosulfonation of ace-
tophenone (5) followed by the conversion of the sulfonyl
chloride group to methylsulfonyl group;
*
Corresponding author.
E-mail address: rokhaya.gueye@unilim.fr (R. Gueye).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.10.004

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R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
Scheme 1. Synthetic pathways of flavonoids.
ꢀ
ꢀ
pathway B involved a Friedel–Crafts acetylation on
methylsulfonylbenzene (6);
pathway C was directed towards the synthesis of the
methyl ketone from the corresponding carboxylic acid
(7) through a methylation reaction.
compound 8, but 2-(2-(chlorosulfonyl)acetyl)benzene-1-
sulfonyl chloride (9) [12]. Woodruff also described the
synthesis of compound 9 and showed that the chlorosul-
fonation of acetophenone, depending on the conditions,
was able as well to give the
a, meta-sulfonation product
(10) [13,14]. Finally, Chapman claimed the formation of
another new compound identified as 3-chlorobenzothio-
phen-1,1-dioxide-2-sulfonyl chloride (11) [15].
Considering the pathway A, the synthesis of
30-chlorosulfonylacetophenone (4) was envisaged through
the action of chlorosulfonic acid upon acetophenone (5).
This acid is considered as the reagent of choice for the
direct conversion of aromatic compounds into their
sulfonyl chlorides [7–9]. However, several studies, which
investigated the chlorosulfonation of acetophenone,
showed contradictory results despite similar reaction
conditions (Scheme 3). Thus, the work of Shingare and
Ingle was the only one to describe the synthesis of the
expected 30-chlorosulfonylacetophenone (4) through this
reaction [10]. Otherwise, Riesz and Frankfurter reported
that this reaction yielded 5-acetylbenzene-1,3-disulfonyl
dichloride (8) [11,12], even if, a few years later, Weston and
Suter had shown that the resulting product was not
Our investigations dealing with the chlorosulfonation
of acetophenone (5) were performed by varying the
reaction conditions, but did not allow us to obtain
the desired product. In most cases, no evolution of the
reaction medium was noticed; in a few cases, even when
using the procedure described by Shingare and Ingle
[10], acetophenone (5) was partly transformed into
benzothiophen-3(2H)-one-1,1-dioxide (12), which had
never been described in the previous reports (Scheme 4).
As seen for the action of chlorosulfonic acid on ethyl
phenyl ketone, the reaction probably involves an initial
chlorosulfonation of the enolic form of acetophenone (5)
followed by a rearrangement to form the intermediate
Scheme 2. Retrosynthesis of 20-hydroxy-40-methylsulfonylacetophenone (1) from 30-methylsulfonylacetophenone (3).

R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
445
Scheme 3. Reaction of acetophenone (5) with chlorosulfonic acid.
the use of two equivalents of the organometallic reagent;
one equivalent acts as a base by deprotonation of the
carboxylic acid while the second one acts as a nucleophilic
agent on the carbonyl group of the lithium carboxylate
[17]. Thus, the methylation was performed in a successful
way to afford compound 3 (Scheme 6). However, in order
to optimize the synthesis yield, reaction conditions had to
be changed. The results of our investigations are shown in
Table 1. In our work, the optimal yield (35%) was obtained
when the synthesis was performed with 4 equiv. of
methyllithium, by adding the starting materials at 0 8C,
then stirring the reaction medium at room temperature.
On the other hand, by introducing the reactants at –78 8C,
the reaction yield decreased from 35% to 22% due to the
formation of a side product (compound 13, 10% yield)
(Scheme 6). The excess of methyllithium should deproto-
nate the methylsulfonyl moiety of compound 3; then, the
attack of the formed carbanion on the carbonyl group of
the undeprotonated 30-methylsulfonylacetophenone (3)
leads to compound 13 as a by-product.
Thus, the synthesis of the expected 30-methylsulfo-
nylacetophenone (3) has been achieved through the
methylation of the corresponding benzoic acid (7) and a
Baeyer–Villiger oxidation followed by a Fries rearrange-
ment, which should be the next step to further obtain
20-hydroxy-40-methylsulfonylacetophenone (1).
The Baeyer–Villiger oxidation of 30-methylsulfonylace-
tophenone (3) was carried out using meta-chloroperoxy-
benzoic acid (m-CPBA) as the oxidizing agent in the
presence of a catalytic amount of ceric ammonium nitrate
Scheme 4. Formation of benzothiophen-3(2H)-one-1,1-dioxide (12)
through chlorosulfonation of acetophenone (5).
2-oxo-2-phenylethanesulfonyl chloride. Subsequent
electrophilic aromatic substitution might afford the
compound 12 (Scheme 5) [16].
At the same time, the Friedel–Crafts acetylation on
methylsulfonylbenzene (6) with acetyl chloride in the
presence of aluminium trichloride was undertaken (path-
way B, Scheme 2). Different reaction parameters were
explored but unfortunately, no conversion of the starting
material was observed.
The difficulty of these meta electrophilic substitutions
prompted us to direct our efforts towards the transforma-
tion of a pertinent meta-substituted methylsulfonylben-
zene. 3-Methylsulfonylbenzoic acid (7) was selected to
envisage its methylation using methyllithium (pathway C,
Scheme 2). For this reaction, the literature describes
Scheme 5. Proposed mechanism for the formation of benzothiophen-3(2H)-one-1,1-dioxide (12).

446
R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
Scheme 6. Reaction of 3-methylsulfonylbenzoic acid (7) with methyllithium.
Table 1
also recovered: the starting material was mono- and
Conversion of 3-methylsulfonylbenzoic acid (7) to 30-methylsulfonyla-
di-chlorinated (compounds 14 and 15 respectively) in
a to
cetophenone (3).
the carbonyl group.
Entry
CH3Li
Reaction
Yield (%)
Due to the low yield of the Baeyer–Villiger oxidation,
the Fries rearrangement was not undertaken and a second
synthetic strategy had to be considered (Scheme 8). This
latter started from 3-mercaptophenol (16) from which the
thioether 17 was selectively formed through a methylation
reaction [19]. A subsequent Friedel–Crafts acetylation
provided the desired intermediate (18) [20,21]. The site of
acetylation was first assigned by comparison of proton
nuclear magnetic resonance spectra of products 17 and 18.
The hydroxyl group signal was shifted from 9.47 ppm for
3-(methylthio)phenol (17) to 12.53 ppm for compound
18. This deshielding effect is due to the intramolecular
hydrogen bond between the oxygen atom of the carbonyl
and the phenolic proton [22]. This attractive interaction
could not occur if the acetyl was introduced at the para
(equiv.)
conditions
(compound 3)
1
2
3
4
5
6
7
2.2
3.0
3.0
4.0
4.0
4.0
5.0
0 8C to rt
0 8C to rt
6
8
0 8C to reflux
0 8C to reflux
0 8C to rt
–78 8C to rt
0 8C to reflux
13
20
35
22
12
rt: room temperature.
(CAN) in methylene chloride (Scheme 7) [18]. Unfortu-
nately, the expected 3-(methylsulfonyl)phenyl acetate (2)
was obtained in a low yield; indeed, an appreciable
amount of the starting 30-methylsulfonylacetophenone
(3) was not transformed, while two side products were
Scheme 7. Baeyer–Villiger oxidation of 30-methylsulfonylacetophenone (3).
Scheme 8. Synthesis of 20-hydroxy-40-methylsulfonylacetophenone (1) from 3-mercaptophenol (16).

R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
447
position relative to the hydroxyl function. In addition, a long
4.2. Syntheses
range (4J) correlation between the phenolic proton and the
carbonyl carbon was observed on the heteronuclear multi-
ple bond correlation spectrum and further confirmed the
structure of the acetophenone 18. Compounds 19, 20 and
21 were also isolated as the minor side products. Finally, 20-
hydroxy-40-methylsulfonylacetophenone (1) was obtained
through an oxidation of the corresponding sulphide (18)
using oxone1 [23]. This second strategy is an alternative
synthetic route to compounds 1 and 18, which have already
been prepared from 40-fluoro-20-methoxyacetophenone
[24]. Compound 1 has also been used for the synthesis of
a chalcone derivative designed as an antioxidant and an
anti-microbial agent [25].
4.2.1. Benzothiophen-3(2H)-one-1,1-dioxide (12)
Acetophenone (5) (0.20 mL, 1.71 mmol) was added
dropwise to an ice-cooled solution of HSO3Cl (1.10 mL,
17.11 mmol) in CHCl3 (5 mL). The reaction mixture was
stirred at room temperature for 3 h then refluxed during
4 h. A biphasic mixture was formed and stirred at room
temperature overnight. After addition of H2O and concen-
trated NaOH, the product was extracted with CHCl3.
Combined organic layers were dried (Na2SO4), filtered
and concentrated under reduced pressure. The residue
(0.098 g) was purified by preparative TLC on silica gel
(eluent: 7:3 hexane/EtOAc) to afford yellowish crystals
(yield14%, 0.041 g); Mp: 131 8C;IR(CH2Cl2, cmꢁ1):523, 768,
1145, 1199, 1312, 1724; UV (EtOH, nm):
NMR (400 MHz, CDCl3): 4.11 (s, 2H, CH2), 7.84 (br ddd,
J = 1.2, 7.3, 7.8 Hz, 1H, H-6), 7.96 (td, J = 1.1, 8.0 Hz, 1H, H-7),
8.00–8.05 (m, 2H, H-5, H-8); 13C NMR (100 MHz, CDCl3):
l
max = 208, 244; 1H
3. Conclusion
d
In summary, different synthetic routes to 20-hydroxy-
40-methylsulfonylacetophenone were described.
d
The first strategy via 30-methylsulfonylacetophenone
did not allow the preparation of the expected 20-hydroxy-
40-methylsulfonylacetophenone. Indeed, in contrast to the
previous reports, the chlorosulfonation of acetophenone
produced benzothiophen-3(2H)-one-1,1-dioxide. In the
same way, the Friedel–Crafts acetylation of methylsulfo-
nylbenzene failed. Then, even if 30-methylsulfonylaceto-
phenone was obtained from the corresponding benzoic
acid, the low yield of the Baeyer–Villiger oxidation led us to
consider another approach.
57.5 (C-2), 122.0 (C-8), 124.9 (C-5), 133.3 (C-4), 134.4 (C-6),
137.4 (C-7), 148.0 (C-9), 187.0 (C-3); HRMS (ESI+): m/z
calculated for C8H6O3NaS: 204.9935, found: 204.9937.
4.2.2. 30-methylsulfonylacetophenone (3) and
1-(30-(200-hydroxy-200-(3000
-
(methylsulfonyl)phenyl)propylsulfonyl)phenyl)ethanone
(13)
To a solution of 3-methylsulfonyl benzoic acid (7)
(0.200 g, 1 mmol) in anhydrous THF (15 mL) was added
dropwise MeLi (1.6 M in Et2O, 2.50 mL, 4 mmol) at –78 8C
under N2. The reaction mixture was then allowed to warm
to room temperature, stirred during 2 h 25 min and treated
with saturated aqueous NH4Cl. EtOAc was added and the
organic layer was separated. The aqueous layer was
extracted with EtOAc. Combined organic layers were dried
(Na2SO4), filtered and concentrated under reduced pres-
sure. The residue (0.149 g) was purified by preparative TLC
on silica gel (eluent: 8:2 CH2Cl2–EtOAc) to provide:
30-methylsulfonylacetophenone (3) as yellowish crys-
tals (yield 22%, 0.044 g); Mp: 106 8C; IR (CH2Cl2, cmꢁ1):
539, 1149, 1262, 1300, 1316, 1693; UV (EtOH, nm):
Thus, the methylation of 3-mercaptophenol followed
by a Friedel–Crafts acetylation provided 20-hydroxy-40-
methylthioacetophenone, which was then oxidized using
oxone1
.
Therefore, 20-hydroxy-40-methylsulfonylaceto-
phenone was synthesized in a three-step pathway. This
compound is now considered as a key synthon for the
synthesis of new flavonoid derivatives designed as
potential cyclooxygenase-2 inhibitors.
4. Experimental
4.1. General
l
max = 205, 236; 1H NMR (400 MHz, CDCl3):
d 2.68 (s, 3 H,
Chemical reagents and solvents were purchased from
Alfa Aesar (Schiltigheim, France), Fisher Scientific (Ill-
kirch, France), Sigma–Aldrich (Saint-Quentin-Fallavier,
COCH3), 3.10 (s, 3 H, SO2CH3), 7.72 (br t, J = 7.8 Hz, 1 H, H-
50), 8.15 (ddd, J = 1.2, 1.6, 7.8 Hz, 1 H, H-40), 8.24 (dt, J = 1.3,
7.8 Hz, 1 H, H-60), 8.50 (br t, J = 1.6 Hz, 1 H, H-20); 13C NMR
´
France) or Carlo Erba Reactifs–SDS (Val-de-Reuil, France)
(100 MHz, CDCl3): d 26.9 (COCH3), 44.6 (SO2CH3), 127.4
and were used without further purification. TLC was
performed using Merck silica gel 60 F254 plates. Merck
silica gel 60 H was used for preparative TLC. The spots
were visualized with a UV lamp. Melting points were
determined with a Wagner & Munz Kofler bench WME.
NMR spectra were recorded with a Bruker DPX-400
spectrometer (1H: 400 MHz; 13C: 100 MHz) using Me4Si
as an internal standard. IR spectra (solutions in CH2Cl2)
were recorded with a Mattson Satellite FT–IR spectro-
meter and only major peaks are reported. UV spectra
(solutions in EtOH) were recorded with a Shimadzu
UV-2401PC spectrophotometer. Mass spectra were
(C-20), 130.2 (C-50), 131.6 (C-40), 133.3 (C-60), 138.3 (C-10),
141.7 (C-30), 196.3 (C5O); HRMS (ESI+): m/z calculated for
C9H10O3NaS: 221.0248, found: 221.0246.
1-(30-(200-hydroxy-20-(3000-(methylsulfonyl)phenyl)pro-
pylsulfonyl)phenyl)ethanone (13) as a colourless paste
(yield 10%, 0.041 g); IR (CH2Cl2, cmꢁ1): 535, 1145, 1262,
1300, 1689, 3492; UV (EtOH, nm):
(400 MHz, DMSO-d6): 1.61 (s, 3 H, C(OH)CH3), 2.62 (s, 3 H,
l
max = 204; 1H NMR
d
COCH3), 3.15 (s, 3 H, SO2CH3), 3.98 (d, J = 15.0 Hz, 1 H,
H-100), 4.10 (d, J = 15.0 Hz, 1 H, H-1‘‘), 5.71 (s, 1 H, OH), 7.44
(br t, J = 7.8 Hz, 1 H, H-5000), 7.64 (br t, J = 7.8 Hz, 1 H, H-50),
7.66–7.72 (m, 2 H, H-4000, H-6000), 7.91–7.92 (m, 2 H, H-40, H-
2000), 8.12 (br s, 1 H, H-20), 8.16 (br d, J = 7.8 Hz, 1 H, H-60);
13C NMR (100 MHz, DMSO-d6): 26.8 (C-2), 30.4 (C-300),
d
43.5 (SO2CH3), 65.5 (C-100), 71.6 (C-200), 123.4 (C-2000), 125.1
´
acquired at the ‘‘Centre regional de mesures physiques
de l’Ouest’’ (Rennes, France) using a Waters Q-TOF 2
spectrometer.

448
R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
(C-6000), 127.1 (C-20), 128.7 (C-5000), 129.5 (C-50), 130.4 (C-
4000), 131.9 (C-40), 132.7 (C-60), 136.9 (C-10), 140.3 (C-3000),
141.7 (C-30), 147.7 (C-1000), 196.7 (C-1); HRMS (ESI+): m/z
calculated for C18H20O6NaS2: 419.0599, found: 419.0596.
(16) (0.61 mL, 7.93 mmol) in H2O (5 mL). The resulting
mixture was stirred at room temperature for 4 h 20 min
then the product was extracted with EtOAc. Combined
organic layers were dried (Na2SO4), filtered and concen-
trated under reduced pressure to afford a brown liquid
(yield 96%, 1.066 g); IR (CH2Cl2, cmꢁ1): 687, 776, 1215,
4.2.3. 3-(methylsulfonyl)phenyl acetate (2), 2-chloro-1-
(3-(methylsulfonyl)phenyl)ethanone (14) and 2,2-dichloro-
1-(3-(methylsulfonyl)phenyl)ethanone (15)
1440, 1475, 1584, 3363; UV (EtOH, nm):
1H NMR (400 MHz, DMSO-d6):
lmax = 215, 254;
d
2.41 (s, 3 H, SCH3), 6.53 (br
CAN (0.056 g, 0.1 mmol) and m-CPBA (0.602 g,
2.5 mmol) were added to a solution of 3-methylsulfony-
lacetophenone (3) (0.200 g, 1 mmol) in CH2Cl2 (10 mL). The
reaction mixture was kept at room temperature during
45 days then worked up by pouring into H2O. The products
were extracted with Et2O. The organic layers were
combined then successively washed with aqueous solu-
tions of KI, Na2S2O3 and NaHCO3. The organic extract was
dried (Na2SO4), filtered and evaporated under reduced
pressure. The residue (0.196 g) was purified twice by
preparative TLC on silica gel (eluents: 9.5:0.5 CH2Cl2/EtOAc
then 8:2 Et2O/hexane) to give:
dd, J = 1.8, 8.0 Hz, 1 H, H-6), 6.63 (br t, J = 1.8 Hz, 1 H, H-2),
6.66 (br d, J = 7.8 Hz, 1 H, H-4), 7.09 (br t, J = 7.9 Hz, 1 H, H-
5), 9.47 (s, 1 H, OH); 13C NMR (100 MHz, DMSO-d6):
d 14.5
(SCH3), 112.0 (C-6), 112.4 (C-2), 116.5 (C-4), 129.7 (C-5),
139.1 (C-3), 157.7 (C-1); HRMS (ESI+): m/z calculated for
C7H9OS: 141.0374, found: 141.0373.
4.2.5. 20-hydroxy-40-methylthioacetophenone (18),
30-acetyl-20-hydroxy-40-methylthioacetophenone (19),
50-acetyl-20-hydroxy-40-methylthioacetophenone (20) and
3-acetyl-2-methyl-7-(methylthio)-4H-chromene-4-one (21)
TiCl4 (0.17 mL, 1.57 mmol) was slowly added to 3-
(methylthio)phenol (17) (0.200 g, 1.43 mmol) placed in a
flask flushed with N2. The reaction mixture was kept at
room temperature during 2 h and AcCl (0.17 mL,
2.14 mmol) was added. The resulting thick solution was
kept at room temperature for 15 min then brought to
120 8C and left at this temperature for an additional hour.
The reaction mixture was cooled to room temperature,
diluted with CH2Cl2 and quenched with H2O. The products
were extracted with CH2Cl2. Combined organic layers
were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue (0.233 g) was purified by
preparative TLC on silica gel (eluent: 8:2 hexane-EtOAc) to
provide:
ꢀ
ꢀ
ꢀ
ꢀ
3-(methylsulfonyl)phenyl acetate (2) as a colourless oil
(yield 8%, 0.018 g); IR (CH2Cl2, cmꢁ1): 531, 760, 1145,
1196, 1300, 1771; UV (EtOH, nm):
(400 MHz, CDCl3): 2.34 (s, 3 H, OCOCH3), 3.07 (s, 3 H,
l
max = 204; 1H NMR
d
SO2CH3), 7.40 (br dd, J = 1.4, 8.1 Hz, 1 H, H-6), 7.60 (br t,
J = 8.0 Hz, 1 H, H-5), 7.71 (br t, J = 1.8 Hz, 1 H, H-2), 7.82
(br d, J = 7.8 Hz, 1 H, H-4); 13C NMR (100 MHz, CDCl3):
d
21.0 (OCOCH3), 44.5 (SO2CH3), 121.0 (C-2), 124.7 (C-4),
127.2 (C-6), 130.5 (C-5), 141.9 (C-3), 151.0 (C-1), 168.8
(C5O); HRMS (ESI+): m/z calculated for C9H10O4NaS:
237.0198, found: 237.0198;
2-chloro-1-(3-(methylsulfonyl)phenyl)ethanone (14) as
a colourless oil (yield 3%, 0.011 g); IR (CH2Cl2, cmꢁ1):
20-hydroxy-40-methylthioacetophenone (18) as yellow-
ish crystals (yield 53%, 0.137 g); Mp: 85 8C; IR (CH2Cl2,
cmꢁ1): 803, 838, 1219, 1347, 1549, 1631; UV (EtOH, nm):
539, 1145, 1300, 1708; UV (EtOH, nm):
lmax = 206, 238;
1H NMR (400 MHz, CDCl3):
d
3.11 (s, 3 H, SO2CH3), 4.72 (s,
2 H, CH2), 7.76 (br t, J = 7.8 Hz, 1 H, H-5), 8.20 (br d,
J = 7.8 Hz, 1 H, H-4), 8.26 (br d, J = 7.8 Hz, 1 H, H-6), 8.51
l d 2.49 (s, 3
max = 215, 248, 307; 1H NMR (400 MHz, CDCl3):
H, SCH3), 2.58 (s, 3 H, COCH3), 6.72–6.74 (m, 2 H, H-30,
(br s, 1 H, H-2); 13C NMR (100 MHz, CDCl3):
d
44.4
H-50), 7.57 (d, J = 8.2 Hz, 1 H, H-60), 12.53 (s, 1 H, OH); 13C
(SO2CH3), 45.4 (CH2), 127.6 (C-2), 130.3 (C-5), 132.2
(C-4), 133.5 (C-6), 135.2 (C-1), 141.8 (C-3), 189.7 (C5O);
HRMS (ESI+): m/z calculated for C9H10O3ClS: 233.0039,
found: 233.0039;
NMR (100 MHz, CDCl3): d 14.5 (SCH3), 26.3 (COCH3), 112.9
(C-30), 116.3 (C-50), 116.4 (C-10), 130.5 (C-60), 150.3 (C-40),
162.8 (C-20), 203.3 (C5O); HRMS (ESI+): m/z calculated for
C9H10O2NaS: 205.0299, found: 205.0301.
2,2-dichloro-1-(3-(methylsulfonyl)phenyl)ethanone
(15) as a colourless oil (yield 4%, 0.007 g); IR (CH2Cl2,
cmꢁ1): 535, 1149, 1300, 1716; UV (EtOH, nm):
A mixture of 30-acetyl-20-hydroxy-40-methylthioaceto-
phenone (19) and 50-acetyl-20-hydroxy-40-methylthioace-
tophenone (20) as a dark paste (yield 2% 0.006 g); IR
(CH2Cl2, cmꢁ1): 990, 1258, 1351, 1557, 1635, 2924; UV
l
max = 203; 1H NMR (400 MHz, CDCl3):
d 3.12 (s, 3 H,
SO2CH3), 6.63 (s, 1 H, CHCl2), 7.78 (br t, J = 7.8 Hz, 1 H, H-
5), 8.23 (ddd, J = 1.2, 1.7, 7.9 Hz, 1 H, H-4), 8.42 (ddd,
J = 1.2, 1.6, 7.9 Hz, 1 H, H-6), 8.66 (br t, J = 1.6 Hz, 1 H, H-
(EtOH, nm):
(400 MHz, CDCl3):
l
max = 203, 261, 317; compound 19: 1H NMR
0
d
2.47 (s, 3 H, SCH3), 2.61 (s, 3 H, 3 C–CO–
0
CH3), 2.62 (s, 3 H, 1 C–CO–CH3), 6.80 (d, J = 8.6 Hz, 1 H, H-
50), 7.70 (d, J = 8.6 Hz, 1 H, H-60), 13.06 (s, 1 H, OH);
2); 13C NMR (100 MHz, CDCl3):
d 44.4 (SO2CH3), 67.7
(CHCl2), 128.8 (C-2), 130.2 (C-5), 132.3 (C-1), 132.7 (C-4),
134.6 (C-6), 141.9 (C-3), 184.4 (C5O); HRMS (ESI+): m/z
calculated for C9H9O3Cl2S: 266.9649, found: 266.9655;
30-methylsulfonylacetophenone (3) as yellowish crystals
(yield 25%, 0.050 g).
compound 20: 1H NMR (400 MHz, CDCl3):
d
2.43 (s, 3 H,
0
SCH3), 2.63 (s, 3 H, 0C(CO)CH3), 2.67 (s, 3 H, 1 C(CO)CH3),
5
6.83 (s, 1 H, H-30), 8.26 (s, 1 H, H-60), 12.78 (s, 1 H, OH);
compound 19: 13C NMR (100 MHz, CDCl3):
d 15.8 (SCH3),
1
30
0
26.5 ( C–CO–CH3), 31.9 ( C–CO–CH3), 114.9 (C-50), 116.4
(C-10), 127.5 (C-30), 131.9 (C-60), 149.4 (C-40), 160.7 (C-20),
3
1
0
0
201.5 ( C–CO–CH3), 203.6 ( C–CO–CH3); compound 20:
4.2.4. 3-(methylthio)phenol (17)
MeI (0.50 mL, 7.93 mmol) and Et3N (1.20 mL,
8.46 mmol) were added to a solution of 3-mercaptophenol
13C NMR (100 MHz, CDCl3):
d 16.1 (SCH3), 26.2
1
5
0
0
( C(CO)CH3), 27.5 ( C(CO)CH3), 113.4 (C-30), 114.9 (C-
10), 125.5 (C-50), 134.9 (C-60), 154.7 (C-40), 164.6 (C-20),

R. Gueye et al. / C. R. Chimie 17 (2014) 443–449
449
5
1
+
0
0
196.2 ( C(CO)CH3), 203.0 ( C(CO)CH3); HRMS (ESI ): m/z
calculated for C11H12O3NaS: 247.0405, found: 247.0404.
3-acetyl-2-methyl-7-(methylthio)-4H-chromene-4-
one (21) as a dark paste (yield 2%, 0.008 g); IR (CH2Cl2,
cmꢁ1): 1425, 1549, 1619, 1635, 1701; UV (EtOH, nm):
Pharmacy for its support and the ‘‘CRMPO’’ (Rennes,
France) for recording the high-resolution mass spectra.
References
[1] S.R. Kang, K.I. Park, H.S. Park, D.H. Lee, J.A. Kim, A. Nagappan, E.H. Kim,
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1721.
l
max = 203, 262, 319; 1H NMR (400 MHz, CDCl3):
d 2.50 (s, 3
H, CH3), 2.56 (s, 3 H, SCH3), 2.63 (s, 3 H, COCH3), 7.16 (d,
J = 1.6 Hz, 1 H, H-8), 7.24 (dd, J = 1.7, 8.5 Hz, 1 H, H-6), 8.05
[2] K.A.S. O’Leary, D. Pascual-Tereasa, P.W. Needs, Y.-P. Bao, N.M. O’Brien,
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245.
(d, J = 8.4 Hz, 1 H, H-5); 13C NMR (100 MHz, CDCl3):
d 15.0
(SCH3), 20.0 (CH3), 32.5 (COCH3), 112.7 (C-8), 120.6 (C-4a),
123.4 (C-6), 124.0 (C-3), 126.1 (C-5), 148.2 (C-7), 156.0
(C-8a), 168.3 (C-2), 175.6 (C-4), 200.8 (C5O); HRMS
(ESI+): m/z calculated for C13H12O3NaS: 271.0405, found:
271.0407.
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4.2.6. 20-hydroxy-40-methylsulfonylacetophenone (1)
Oxone1 (2.350 g, 3.82 mmol) was added to 20-hydroxy-
40-methylthioacetophenone (18) (0.620 g, 3.41 mmol)
previously dissolved in a mixture of MeOH (9 mL), THF
(9 mL) and H2O (9 mL). The resulting mixture was stirred at
room temperature for 1 h 25 min then the product was
extracted with EtOAc. Combined organic layers were dried
(Na2SO4), filtered and concentrated under reduced pres-
sure to afford yellowish crystals (yield 91%, 0.663 g); Mp:
141 8C; IR (CH2Cl2, cmꢁ1): 772, 1149, 1203, 1285, 1308,
1650; UV (EtOH, nm):
l
max = 213, 249; 1H NMR (400 MHz,
CDCl3): 2.71 (s, 3 H, COCH3), 3.07 (s, 3 H, SO2CH3), 7.46
d
(dd, J = 1.7, 8.3 Hz, 1 H, H-50), 7.56 (d, J = 1.6 Hz, 1 H, H-30),
7.95 (d, J = 8.3 Hz, 1 H, H-60), 12.34 (s, 1 H, OH); 13C NMR
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(2009) 749.
(100 MHz, CDCl3): d 27.3 (COCH3), 44.2 (SO2CH3), 117.0 (C-
30), 118.2 (C-50), 122.8 (C-10), 132.1 (C-60), 147.0 (C-40),
162.7 (C-20), 204.4 (C5O); HRMS (ESI+): m/z calculated for
C9H10O4NaS: 237.0197, found: 237.0205.
[20] A. Bensari, N.T. Zaveri, Synthesis 2 (2003) 267.
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´
´
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´
The authors gratefully thank the ‘‘Region Limousin’’ for
the PhD grant to Rokhaya Gueye, the Organic and
Therapeutic Chemistry Laboratory of Limoges School of