Chiral non-racemic sulfoxides by asymmetric alkylation of alkanesulfenates in the presence of a chiral ammonium phase-transfer catalyst derived from Cinchona alkaloid

Article abstract of DOI:10.1080/17415993.2013.795226

Based on a previous study involving arenesulfenates, the enantioselective S-alkylation of benzyl and alkyl sulfenates R¹SO^- with alkyl halides, mediated by a cinchonidinium phase-transfer catalyst, was evaluated as a conceptually dif

Full text of DOI:10.1080/17415993.2013.795226

This article was downloaded by: [USC University of Southern California]
On: 13 March 2015, At: 02:37
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Sulfur Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gsrp20
Chiral non-racemic sulfoxides
by asymmetric alkylation of
alkanesulfenates in the presence of
a chiral ammonium phase-transfer
catalyst derived from Cinchona alkaloid
Fabien Gelata, Annie-Claude Gaumonta & Stéphane Perrioa
a Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS
6507, INC3M, FR 3038, ENSICAEN & Université de Caen Basse-
Normandie, 14050, Caen, France
Published online: 28 May 2013.
To cite this article: Fabien Gelat, Annie-Claude Gaumont & Stéphane Perrio (2013) Chiral non-
racemic sulfoxides by asymmetric alkylation of alkanesulfenates in the presence of a chiral
ammonium phase-transfer catalyst derived from Cinchona alkaloid, Journal of Sulfur Chemistry,
34:6, 596-605, DOI: 10.1080/17415993.2013.795226
To link to this article: http://dx.doi.org/10.1080/17415993.2013.795226
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Journal of Sulfur Chemistry, 2013
Vol. 34, No. 6, 596–605, http://dx.doi.org/10.1080/17415993.2013.795226
SHORT COMMUNICATION
Chiral non-racemic sulfoxides by asymmetric alkylation of
alkanesulfenates in the presence of a chiral ammonium
phase-transfer catalyst derived from Cinchona alkaloid†
Fabien Gelat, Annie-Claude Gaumont and Stéphane Perrio*
Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038,
ENSICAEN & Université de Caen Basse-Normandie, 14050 Caen, France
(Received 14 March 2013; final version received 9 April 2013)
Based on a previous study involving arenesulfenates, the enantioselective S-alkylation of benzyl and
alkyl sulfenates R1SO− with alkyl halides, mediated by a cinchonidinium phase-transfer catalyst, was
evaluated as a conceptually different synthetic approach to chiral sulfoxides. Direct application of our
standard organocatalytic protocol, with methyl iodide as the electrophile, was rather disappointing mainly
as a result of a sluggish release of the sulfur nucleophiles. However, slight modifications of the reaction
conditions allowed the isolation of (R)-benzyl methyl sulfoxide in a 60% yield and a 38% ee, whereas
(R)-cyclohexyl methyl sulfoxide was produced in a 34% yield and a 47% ee.
O
O
S
30% aq NaOH
PhMe/CH2Cl2 (8:2)
S
SO2Ph
Me
cat 1 (5mol%)
MeI, 12 h, 25°C
34% yield
47% ee
cat 1 =
(R)-configuration
N
OH
N
Cl
Keywords: sulfenate salt; sulfoxide; phase transfer; organocatalysis; Cinchona alkaloid
1. Introduction
Enantiopure sulfoxides represent an important class of compounds that are widely employed as
building blocks, chiral auxiliaries or ligands in asymmetric synthesis.[1–5] Furthermore, this sul-
fur functional group is present in some natural products [6, 7] or pharmaceuticals, the most notable
example being the anti-ulcer agent esomeprazole.[8] Conventional routes for the preparation of
optically active sulfoxides fall roughly in two categories,[9] namely (i) the enantioselective oxida-
tion of parent sulfides (creation of the sulfur–oxygen bond) or (ii) the nucleophilic displacement
of a leaving group from an enantiopure sulfinyl derivative by an organometallic species, pioneered
by K.K. Andersen (formation of the carbon–sulfur bond). Although each of these approaches has
*Corresponding author. Email: perrio@ensicaen.fr
†Dedicated to the memory of Prof. Alessandro Degl’Innocenti (1950–2012).
© 2013 Taylor & Francis

Journal of Sulfur Chemistry 597
clearly its own virtues, limitations still exist with respect to the substrate scope (the access to
enantiopure dialkyl compounds is a critical case), the formation of by-products (over oxidation
into sulfones) and the presence of residual metal impurities.[9] Thus, the development of a gen-
eral, metal-free, catalytic and enantioselective process to sulfoxides is still challenging and in
high demand.[10, 11]
In this context and as part of our continued interest in sulfenate salt chemistry [12–14] (sulfenic
acid anion RSO−), we recently reported a complementary and conceptually novel route to chiral
sulfoxides, exploiting chiral phase-transfer catalysis (PTC).[15] Treatment of the unusual and
prochiral sulfenate species with alkyl or benzyl halides, in the presence of a catalytic amount
of Cinchona-derived ammonium salt 1 (5 mol%), smoothly led to the sulfinyl targets of (R)-
configuration with good yields and enantiomeric excesses up to 58% (Scheme 1). The highly
reactive sulfenates [16, 17] were generated in situ from a sulfinyl sulfone precursor, according
to a retro-Michael process, initiated by deprotonation with aqueous NaOH at the interface of the
biphasic reaction medium. It is important to note that, in contrast to the plethora of examples
−
−
−
dedicated to the asymmetric C C, C O and C N bond formation with PTC,[18–20] reports
−
related to the C S bond remain surprisingly sporadic.[15, 21]
O
O
S
30% aq NaOH
PhMe/CH2Cl2 (8:2)
S
SO2Ph
R
Ar
Ar
cat 1 (5mol%)
0°C, RX
16 examples
ee up to 58%
cat 1 =
(R)-configuration
N
OH
N
Cl
Scheme 1. Aryl alkyl sulfoxides by asymmetric alkylation of arenesulfenates under PTC
conditions.
Our initial work showcased the potential and versatility of the catalytic conditions essen-
tially with arenesulfenates ArSO−.[15] We wish to present herein our attempts to extend our
methodology in the alkyl (and benzylic) series. In addition to the benefit of expanding the scope
of the protocol, this study could also allow us to have information about the nature of non-
covalent bindings, which are involved in the sulfenate–ammonium ion pairing, and hence to
gain some mechanistic insight concerning the identification of design principles for the origin of
enantioselectivity. Clearly, π-staking interactions can be ruled out with aliphatic sulfenates.
2. Results and discussion
As the phenylsulfonyl substituent was previously identified as the optimal activating group
(α-hydrogen with a pKa value around 31 in DMSO) for the generation of aromatic sulfenates
in the case of our organocatalytic asymmetric protocol,[15] the analogous structures 3a–3c were
first evaluated. They were conveniently prepared according to the two-step sequence described in
Scheme 2. Michael addition of benzyl (R1 = Bn) and alkyl thiols (R1 = n-dodecyl, cylohexyl) to
phenyl vinyl sulfone afforded sulfanyl sulfones 2a–2c in 83–93% yields. Subsequent oxidation
of the sulfur center, with hydrogen peroxide/2,2,2-trifluoroethanol combination,[22] led to the
sulfinyl targets 3a–3c in good yields (67–97%).
We then initiated our study with the conditions previously established in the aromatic series,
using 5 mol% of commercially available cinchonidinium salt 1 comprising a free secondary

598 F. Gelat et al.
(O)n
S
1) H2C=CH–SO2Ph
K2CO3 (cat.), CH2Cl2, 20h
R1SH
SO2Ph
R1
2) H2O2, F3CCH2OH
rt, 20h
R1 = Bn, n-dodecyl, cyclohexyl
n = 0 2a–2c
n = 1 3a–3c
Scheme 2. Synthesis of sulfenate precursors 3.
Table 1. Synthesis of enantioenriched sulfoxides 4 from sulfenate salts under PTC conditions.
O
O
S
30% aq NaOH
PhMe/CH2Cl2 (8:2)
S
R1
R1
Me
EWG
MeI, cat 1 (5mol%)
4
3
6
EWG = SO2Ph
EWG = NO2
Entry
3
R1
EWG
Conditionsa
4
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
3a
3b
3c
3a
3b
3c
3c
3c
3c
6
Bn
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
NO2
0◦C, 3 d
0◦C, 3 d
4a
4b
4c
4a
4b
4c
4c
4c
4c
4c
60
nr
nr
52
43
34
34
76
99
20
38 (R)
–
–
36 (R)
20 (R)
43 (R)
47 (R)
4 (R)
0
n-dodecyl
Cyclohexyl
Bn
n-dodecyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
0◦C, 3 d
10◦C, 2 d
10◦C, 4 d
10◦C, 10 d
25◦C, 12 h
0◦C, 14 hd
–60◦C, 14 he
0◦C, 14 h
10
7 (R)
Notes: aReactions performed at 0◦C on a 0.08 mmol scale using 5 equiv. of MeI and 10 equiv. of 33% aqueous NaOH in the presence of
5 mol% catalyst in 8:2 PhMe/CH2Cl2 (3 ml), unless otherwise noted.
bIsolated yield.
cDetermined by HPLC analysis using a Chiralpak OB–H column. See Section 4 for conditions.
dSolid t-BuOK (10 equiv.) as a base.
ePhosphazene P2-Et (5 equiv.) as a base (see [26]).
alcohol and an anthracenylmethyl substituent on the quinuclidine moiety as structural features
(Scheme 1). Liquid–liquid biphasic conditions, consisting in a 33% aqueous sodium hydroxide
solution (10 equiv.), and a mixture of toluene and dichloromethane (8:2 ratio) at 0◦C, were
employed. Methyl iodide (5 equiv.) was systematically used as the electrophile.
Use of these standard conditions with benzyl substrate 3a (R1 = Bn) led to the formation of the
anticipated benzyl methyl sulfoxide 4a, but with a very low reaction rate (Table 1, Entry 1). An 1H
NMR assay indicated that only 70% of starting material was consumed after 3 days of reaction.
However, purification of the crude product on silica gel led to the isolation of 4a in a reasonable
60% yield and 38% enantiomeric excess in favor of the (R) enantiomer. Pro-nucleophiles 3b–3c
possessing, respectively, an n-dodecyl- or a cyclohexylsulfinyl substituent were inert under the
previous conditions (Entries 2 and 3). Even if the difficulty to generate alkanesulfenates was
already pointed out in the literature,[14, 16] this lack of reactivity was not previously observed in
the racemic version of the retro-Michael process without PTC catalysis.[12]
Modification of the catalytic conditions was then investigated. Elevation of the temperature to
10◦C had a beneficial impact on the conversion rate. Benzyl compound 3a was totally reacted
after a shorter reaction time of 2 days (Table 1, Entry 4). Sulfoxide 4a was produced with a similar
36% ee value, but contrary to our expectations, there was no gain in the chemical yield (52%).
Compounds 3b–3c are again distinctly more robust. Four days were required to observe a full
conversion at 10◦C of the dodecyl substrate 3b (Entry 5). The final sulfoxide was isolated in a

Journal of Sulfur Chemistry 599
43% yield and a 20% ee. A far slower process occurred with the cyclohexyl compound 3c. An
extended reaction time of 10 days was necessary to observe total disappearance of the starting
material (Entry 6). The anticipated methyl sulfoxide 4c was produced in a 34% yield and an
interesting 43% ee. Raising the temperature to 25◦C with this reluctant substrate 3c allowed to
significantly shorten the reaction time to an overnight process (Entry 7). An improved 47% ee
was measured for 4c, the chemical yield staying at 34%. The rather disappointing chemical yields
obtained in the current study, even when full conversion of the starting material is observed, can
be interpreted by a low reactivity of the alkyl and benzyl sulfenates toward the alkyl halide under
the reaction conditions, as already witnessed by the group of A.L. Schwan (this is not the case
with the aromatic congeners).[23, 24] A competing oxidation event, leading to the corresponding
sulfinate R1SO2−, probably occurs as a side reaction. We believe that the latter sulfur nucleophile
fails to react with the electrophile and, surviving in the reaction mixture, undergoes extraction in
the aqueous layer upon workup.[25]
A uniform (R)-configuration was unambiguously assigned to the final sulfoxides 4, by
comparison of optical rotations and/or HPLC retention times with literature data (see Section 4).
Worthnotingisthatthisstereochemistryissimilartothatpreviouslyobservedinthearylseries.[15]
Stronger bases were then examined in attempt to improve the overall process. The more basic
t-BuOK (solid–liquid transfer conditions) did initiate efficiently the sulfenate liberation. With 10
equiv. of the alkoxide, the cyclohexyl precursor 3c was consumed at 0◦C within 14 h (Entry 8). The
anticipated sulfoxide 4c was isolated in a satisfactory 76% yield but in a poor 4% ee. Switching
to the Schwesinger base P2-Et (5 equiv.) [26] allowed the reaction to proceed rapidly at a low
temperature of –60◦C (Entry 9).[27] The anticipated sulfoxide 4c was produced quantitatively
but unfortunately in a racemic form.
The last modification we investigated concerned the nature of the precursor. The nitro sulfoxide
6 was prepared by treatment of acetic acid 2-nitroethyl ester with cyclohexanethiol in the presence
of Et3N, followed by mono-oxidation on sulfur with m-CPBA (see Section 4). With the activating
nitro group, the increased α-hydrogen atom acidity (pKa value of 17 in DMSO) should facilitate
the sulfenate release.[15] Application of the biphasic catalytic condition with aqueous NaOH as
base at 0◦C led to a rapid process (14 h) but the chemical yield poorly reached 20% and the ee
7% (Entry 10).
3. Conclusions
In conclusion, we showed that commercial Cinchona phase-transfer catalyst 1 is able to promote
the enantioselective S-alkylation of alkyl (and benzyl) sulfenates with methyl iodide under mild
conditions. Interestingly, cyclohexyl methyl sulfoxide possessing an (R)-configuration was pro-
duced with an enantiomeric excess of 47%. This stereochemical outcome and also the induction
level are consistent with those described in our exploratory work carried out with arenesulfenates.
An important issue of the present work is that the chiral ammonium–sulfenate ion pair, postu-
lated in the process, is effectively able to provide lone pair discrimination of the prochiral sulfur
anion, without any option of π-staking interactions. Further studies are warranted to have a better
understanding of the ion pair organization and also to improve our catalytic system.
4. Experimental
Reaction temperatures stated were those of the reaction mixtures and were maintained constant
using a Huber immersion cooler or a minichiller. Dry THF, CH2Cl2, acetonitrile and toluene
were dispensed by a PURESOLV™ developed by Innovative Technology Inc. All other reagents

600 F. Gelat et al.
and solvents were used as received from commercial sources. Due to the stench of thiols, all
glassware and syringes were washed with bleach after use. Melting points were obtained on
an Electrothermal IA9000 capillary apparatus and are uncorrected. NMR spectra were obtained
on a Bruker DRX 400 spectrometer. IR spectra were recorded on an ATR Spectrum One Perkin
Elmer apparatus. Low-resolution mass spectra were recorded on aVarian GC/MS/MS instrument
equipped with CP 3800 (GC) and Saturn 2000 (MS/MS) modules. Only peaks of an intensity
>10% (except decisive ones) are listed. HRMS spectra were recorded on a Waters QTOF Micro
instrument.
Enantiomeric excesses were determined using an Alliance HPLC system (Waters 600 pump
(717 injector), Waters 996 photodiode array detector (200–300 nm) and Empower software) and a
Chiralpak (4.6 × 250 mm) OB-H column. In all cases, the analysis was calibrated with a sample
of the racemate. Racemic references were prepared by S-alkylation of sulfenate salts in THF
generated by treatment of the sulfinyl sulfone precursor 3 with commercial t-BuOK solution (1 M
in THF) as previously described by us.[15]
Optical rotations were measured at room temperature (20◦C) on a polarimeter using a 1 ml cell
with a 1 dm path length at 589 nm (sodium D light).
Acetic acid 2-nitroethyl ester was prepared by Fischer esterification of acetic acid with 2-
nitroethanol.[15]
4.1. Synthesis of sulfanyl sulfones (2)
General procedure. Phenyl vinyl sulfone (1 equiv.) was added dropwise (exothermic reaction)
to a mixture of thiol (1 equiv.) and potassium carbonate (0.55 mmol, 0.05 equiv.) in CH2Cl2.
After stirring at room temperature for ∼20 h, CH2Cl2 (5 ml) was added. The reaction mixture was
washed successively with aqueous 1 M NaOH solution (10 ml), saturated aqueous NaCl solution
(2 × 10 ml), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product
was then purified by column chromatography on silica gel to afford pure sulfide 2.
4.1.1. {[2-(Benzylsulfanyl)ethyl]sulfonyl}benzene (2a) [28]
Obtained from benzyl mercaptan (R1 = benzyl, 0.59 ml, 5.0 mmol) and phenyl vinyl sulfone
(0.84 g, 5.0 mmol) in CH2Cl2 (2.5 ml). Yield 89% (1.30 g, 4.5 mmol). White solid. mp 66–68◦C.
TLC (pentane/EtOAc, 85:15) Rf = 0.25.1H NMR (400 MHz, CDCl3): δ 2.66–2.72 (m, 2H),
3.14–3.21 (m, 2H), 3.66 (s, 2H), 7.16–7.20 (m, 2H), 7.21–7.30 (m, 3H), 7.53–7.59 (m, 2H), 7.65–
7.70 (m, 1H), 7.82–7.86 (m, 2H).13C NMR (100.6 MHz, CDCl3): δ 23.9, 36.5, 56.2, 127.4, 128.2
(2C), 128.8 (two signals overlapping, 4C), 129.4 (2C), 134.0, 137.4 (Cq), 138.7 (Cq). IR (cm−1):
1582, 1446, 1321 (SO2), 1288, 1145 (SO2), 1083, 796, 761, 744, 688, 672. MS (ESI): m/z 607
[(2M+Na)+, 25], 315 [(M+Na)+, 100], 293 (MH+, 12). HRMS (ESI) calcd for C15H17O2S2
(MH+) 293.0670, found 293.0677.
4.1.2. {[2-(Dodecylsulfanyl)ethyl]sulfonyl}benzene (2b)
Obtained from 1-dodecanethiol (R1 = n-dodecyl, 1.22 ml, 5.0 mmol) and phenyl vinyl sulfone
(0.84 g, 5.0 mmol) in CH2Cl2 (2.5 ml). Yield 93% (1.73 g, 4.7 mmol). White solid. mp 36–38◦C.
TLC (cyclohexane/EtOAc, 90:10) Rf = 0.2.1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.1, 3H),
1.20–1.37 (m, 18H), 1.51 (quint, J = 7.4, 2H), 2.47 (t,J = 7.4, 2H), 2.75–2.82 (m, 2H), 3.28–
3.35 (m, 2H), 7.55–7.62 (m, 2H), 7.65–7.74 (m, 1H), 7.89–7.94 (m, 2H).13C NMR (100.6 MHz,
CDCl3): δ 14.3, 22.8, 24.4, 28.9, 29.3, 29.45, 29.48, 29.6, 29.71, 29.76, 29.77, 32.1, 32.4, 56.6,
128.3 (2C), 129.6 (2C), 134.1, 138.9 (Cq). IR (cm−1): 2917, 2848, 1446, 1292 (SO2), 1151 (SO2),

Journal of Sulfur Chemistry 601
1086, 790, 728, 684. MS (ESI): m/z 763 [(2M+Na)+, 57], 393 [(M+Na)+, 100], 371 (MH+, 60),
229 (60). HRMS (ESI) calcd for C20H35O2S2 (MH+) 371.2078, found 371.2082.
4.1.3. {[2-(Cyclohexylsulfanyl)ethyl]sulfonyl}benzene (2c)
Obtained from cyclohexanethiol (R1 = cyclohexyl, 0.73 ml, 6.0 mmol) and phenyl vinyl sul-
fone (1.01 g, 6.0 mmol) in CH2Cl2 (3 ml). Yield 83% (1.41 g, 5.0 mmol). Colorless oil. TLC
(cyclohexane/EtOAc, 9:1) Rf = 0.26.1H NMR (400 MHz, CDCl3): δ 1.16–1.32 (m, 5H), 1.55–
1.62 (m, 1H), 1.69–1.78 (m, 2H), 1.82–1.90 (m, 2H), 2.55–2.64 (m, 1H), 2.78–2.84 (m, 2H),
3.28–3.34 (m, 2H), 7.55–7.62 (m, 2H), 7.65–7.70 (m, 1H), 7.89–7.94 (m, 2H).13C NMR
(100.6 MHz, CDCl3): δ 22.5, 25.8, 26.1, 33.5, 44.0, 56.9, 128.2 (2C), 129.5 (2C), 134.1, 138.9
(Cq). IR (cm−1): 2927, 2852, 1447, 1309 (SO2), 1146 (SO2), 1085, 734, 687. MS (ESI): m/z 307
(M+Na+, 100), 285 (MH+, 12). HRMS (ESI) calcd for C14H21O2S2 (MH+) 285.0983, found
285.0977. Anal. calcd for C14H20O2S2: C 59.12, H 7.09, found: C 59.14, H 7.27.
4.2. Synthesis of 1-[(2-nitroethyl)sulfanyl]cyclohexane (5)
Asolutionofaceticacid2-nitroethylester(0.53 g, 4 mmol, 1equiv.)andcyclohexanethiol(464 mg,
4 mmol, 1 equiv.) in CH3CN (7 ml) was cooled to 0◦C. A solution of triethylamine (0.55 ml,
4 mmol, 1 equiv.) in CH3CN (3 ml) was then added dropwise. The mixture was stirred at 0◦C
for 3 h. An aqueous HCl solution (1 M) was added (50 ml) and the aqueous layer was extracted
with CH2Cl2 (4 × 10 ml). The organic layer was dried over MgSO4, filtered and evaporated under
reduced pressure. The crude product was then purified by column chromatography on silica gel
to afford pure sulfide 5.Yield 84% (640 mg, 3.4 mmol). Colorless oil. TLC (cyclohexane/EtOAc,
90:10) Rf = 0.33.1H NMR (400 MHz, CDCl3): δ 1.18–1.39 (m, 5H), 1.58–1.67 (m, 1H), 1.73–
1.84 (m, 2H), 1.90–2.00 (m, 2H), 2.63–2.73 (m, 1H), 3.11 (t, J = 7.4, 2H), 4.52 (t, J = 7.4,
2H).13C NMR (62.9 MHz): δ 25.8, 26.1, 26.6, 33.7, 44.2, 75.3. IR (cm−1): 2928, 2853, 1550
(NO2), 1375 (NO2). MS (EI): m/z 189 (M+, 5), 143 (M+–NO2, 7), 83 (57), 82 (21), 81 (71), 79
(14), 77 (22), 67 (34), 61 (27), 59 (16), 55 (100), 54 (10), 53 (11), 45 (17), 41 (16). Anal. calcd
for C8H15NO2S: C 50.77, H 7.99, N 7.40, S 16.94, found: C 50.44, H 8.23, N 7.83, S 17.11.
4.3. Synthesis of sulfinyl sulfones (3)
General procedure. To a 2 M solution of sulfide 2 (4.1 mmol) in 2,2,2-trifluoroethanol (2.05 ml),
cooled to 0◦C, H2O2 (30% in water, 7.0 mmol, 1.7 equiv.) was added dropwise. The reaction
mixture was allowed to warm to room temperature and stirred for 20 h. Solid sodium sulfite
(7.0 mmol, 1.7 equiv.) was added and then the reaction mixture was stirred for 30 min. The
resulting mixture was filtered on celite, dried over MgSO4, filtered and evaporated under reduced
pressure. The crude product was then purified by column chromatography on silica gel to afford
the anticipated sulfoxide 3.
4.3.1. {[2-(Benzylsulfinyl)ethyl]sulfonyl}benzene (3a)
Obtained from sulfide 2a (R1 = benzyl, electron withdrawing group (EWG) = SO2Ph, 0.11 g,
3.8 mmol) using the oxidation protocol described above. Yield 67% (0.78 g, 2.5 mmol). White
1
solid. mp 115–117◦C. TLC (CH2Cl2/EtOAc, 80:20) Rf = 0.30. H NMR (400 MHz, CDCl3):
δ 2.82–2.93 (m, 1H), 2.99–3.11 (m, 1H), 3.38–3.47 (m, 2H), 3.97 and 4.07 (AB, JAB = 13.0,
2H), 7.22–7.28 (m, 2H), 7.34–7.41 (m, 3H), 7.54–7.61 (m, 2H), 7.66–7.72 (m, 1H), 7.85–7.90
(m, 2H).13C NMR (100.6 MHz, CDCl3): δ 42.4, 49.5, 58.8, 128.2 (2C), 128.8 (Cq), 129.0, 129.4

602 F. Gelat et al.
(2C), 129.7 (2C), 130.1 (2C), 134.4, 138.7 (Cq). IR (cm−1): 3059, 1455, 1312 (SO2), 1294, 1144
(SO2), 1087, 1026 (SO), 802, 759, 690. MS (ESI): m/z 639 (2M+Na+, 7), 331 (M+Na+, 100),
309 (MH+, 32), 201 (5), 91 (13). HRMS (ESI) calcd for C15H17O3S2 (MH+) 309.0619, found
309.0610.Anal. calcd for C15H16O3S2: C 58.41, H 5.23, S 20.79, found: C 58.41, H 5.49, S 20.78.
4.3.2. {[2-(Dodecylsulfinyl)ethyl]sulfonyl}benzene (3b)
Obtained from sulfide 2b (R1 = n-dodecyl, EWG = SO2Ph, 1.65 g, 4.5 mmol) using the oxida-
tion protocol described above. Yield 97% (1.67 g, 4.3 mmol). White solid. mp 87–89◦C. TLC
(cyclohexane/EtOAc, 50:50) Rf = 0.26.1H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 7.1, 3H),
1.20–1.36 (m, 16H), 1.36–1.50 (m, 2H), 1.65–1.78 (m, 2H), 2.60–2.70 (m, 1H), 2.70–2.79 (m,
1H), 2.90–2.99 (m, 1H), 3.09–3.18 (m, 1H), 3.45–3.52 (m, 2H), 7.56–7.62 (m, 2H), 7.66–7.73
(m, 1H), 7.91–7.95 (m, 2H).13C NMR (100.6 MHz, CDCl3): δ 14.3, 22.7, 22.8, 28.9, 29.2, 29.42,
29.43, 29.6, 29.7 (two signals overlapping), 32.0, 43.8, 49.7, 53.1, 128.2 (2C), 129.7 (2C), 134.5,
138.7 (Cq). IR (cm−1): 2917, 2848, 1447, 1310 (SO2), 1290, 1147 (SO2), 1088 (SO), 814, 721,
686. MS (ESI): m/z 409 (M+Na+, 33), 387 (MH+, 100). HRMS (ESI) calcd for C20H35O3S2
(MH+) 387.2028, found 387.2032.
4.3.3. {[2-(Cyclohexylsulfinyl)ethyl]sulfonyl}benzene (3c)
Obtained from sulfide 2c (R1 = cyclohexyl, EWG = SO2Ph, 1.14 g, 4.0 mmol) using the oxi-
dation protocol described above. Yield 80% (0.96 g, 3.2 mmol). White solid. mp 96–98◦C. TLC
(CH2Cl2/EtOAc, 70:30) Rf = 0.35.1H NMR (400 MHz, CDCl3): δ 1.20–1.51 (m, 5H), 1.68–1.76
(m, 1H), 1.80–1.97 (m, 3H), 2.06–2.14 (m, 1H), 2.56–2.65 (m, 1H), 2.94–3.03 (m, 1H), 3.07–3.16
(m, 1H), 3.44–3.58 (m, 2H), 7.57–7.64 (m, 2H), 7.67–7.73 (m, 1H), 7.91–7.97 (m, 2H). 13C NMR
(100.6 MHz, CDCl3): δ 25.1, 25.29, 25.30, 25.5, 26.2, 40.7, 50.0, 60.0, 128.2 (2C), 129.7 (2C),
134.4, 138.8 (Cq). IR (cm−1): 2927, 2853, 1447, 1311 (SO2), 1145 (SO2), 1024 (SO), 738, 688.
MS (ESI): m/z 623 (2M+Na+, 10), 323 (M+Na+, 100), 301 (MH+, 27), 219 (40). HRMS (ESI)
calcd for C14H21O3S2 (MH+) 301.0932, found 301.0947. Anal. calcd for C14H20O3S2 C: 55.97,
H 6.71, S 21.35, found: C 56.20, H 7.08, S 21.55.
4.4. Synthesis of 1-[(2-nitroethyl)sulfinyl]cyclohexane (6)
To a solution of nitro sulfide 5 (R1 = cyclohexyl, EWG = NO2, 536 mg, 2.8 mmol) in CH2Cl2
(5 ml), cooled at 0◦C, a solution of 70–75% m-CPBA (690 mg, 2.8 mmol, 1.0 equiv.) in CH2Cl2
(15 ml) was added dropwise. The mixture was stirred for 30 min at 0◦C and then washed with a
saturated aqueous solution of Na2SO3 (20 ml), a saturated aqueous solution of NaHCO3 (20 ml)
and water (20 ml). The organic layer was dried over MgSO4, filtered and concentrated to dryness.
The crude product was purified by column chromatography on silica gel to afford the anticipated
sulfinyl derivative 6. Yield 93% (540 mg, 2.6 mmol). Colorless oil. TLC (cyclohexane/EtOAc,
50:50) Rf = 0.15. 1H NMR (400 MHz, CDCl3): δ 1.22–1.58 (m, 5H), 1.61–1.78 (m, 1H), 1.85–
2.00 (m, 3H), 2.10–2.19 (m, 1H), 2.66 (tt, J = 3.5 and 11.4, 1H), 3.13 (ddd, J = 5.4, 6.5 and
13.5, 1H), 3.38 (ddd, J = 7.0, 8.3 and 13.5, 1H), 4.80 (ddd, J = 5.4, 7.0 and 15.2, 1H), 4.91 (ddd,
J = 6.5, 8.3 and 15.2, 1H). 13C NMR (62.9 MHz): δ 25.1, 25.2, 25.4, 25.5, 26.2, 45.1, 60.4, 68.3.
IR (cm−1): 2931, 2856, 1552 (NO2), 1373 (NO2), 1031. MS (ESI): m/z 228 (M+Na+, 33), 206
(MH+, 100), 83 (20). HRMS (ESI): calcd for C8H16NO3S (MH+) 206.0851, found 206.0843.
Anal. calcd for C8H15NO3S: C 46.81, H 7.37, N 6.82, found: C 46.85, H 7.22, N 6.92.

Journal of Sulfur Chemistry 603
4.5. Synthesis of Enantioenriched Sulfoxides 4
General procedure. In a 10 ml test tube under nitrogen was successively added sulfinyl sulfone 3
(0.08 mmol), cinchonidinium phase-transfer catalyst 1 (0.004 mmol, 0.05 equiv.), methyl iodide
(0.4 mmol, 5.0 equiv.) and a mixture of toluene (2.4 ml) and CH2Cl2 (0.6 ml). This solution was
cooled to 0◦C or 25◦C and 33% aqueous NaOH (0.8 mmol, 10 equiv.) was added dropwise. The
reaction mixture was stirred at the same temperature and TLC was used to monitor disappearance
of the starting material. The reaction was then quenched by hydrolysis with 1 M aqueous HCl
solution(1 ml).Afteradditionofwater(5 ml)andextractionwithCH2Cl2 (3 × 5 ml), thecombined
organic layers were dried over MgSO4, filtered and concentrated. The crude product was then
purified by column chromatography on silica gel to afford the anticipated sulfoxide 4.
4.5.1. (R)-(–)-1-[(Methylsulfinyl)methyl]benzene (4a) [29]
Obtained from sulfinyl sulfone 3a (R1 = benzyl, EWG = SO2Ph, 25 mg, 0.08 mmol) at 0◦C for 3
days.Yield 60% (7.5 mg, 0.048 mmol, 38% ee). Pale yellow oil.TLC (CH2Cl2/EtOAc) Rf = 0.21.
1H NMR (400 MHz, CDCl3): δ 2.46 (s, 3H), 3.93 and 4.07 (AB, J = 12.8, 2H), 7.26–7.39 (m,
5H). 13C NMR (100.6 MHz, CDCl3): δ 37.4, 60.4, 128.6, 129.1 (2C), 129.8 (Cq), 130.1 (2C).
IR (cm−1): 1724, 1454, 1026 (SO). MS (EI): m/z 154 (M+, 3), 137 (4), 91 (100), 77 (4), 65
(13). HPLC: tR (S) = 11.4 min, tR (R) = 14.9 min (Chiralpak OB-H; flow rate = 1.0 ml min−1
;
20
heptane/2-propanol 80:20; 20◦C). [α]D −40 (c 0.22, CHCl3) (lit. (S)-isomer (87% ee); [α]D +98
(c 0.25, EtOH)) [29].
4.5.2. (R)-(–)-1-(Methylsulfinyl)dodecane (4b) [29]
Obtained from sulfinyl sulfone 3b (R1 = n-dodecyl, EWG = SO2Ph, 31 mg, 0.08 mmol) at 25◦C
for 2 days (without work-up due to the high water solubility of sulfoxide 4b. The reaction
mixture was concentrated and directly subjected to column chromatography). Yield 43% (7 mg,
1
0.034 mmol, 20% ee). White solid. mp 59–61◦C. TLC (CH2Cl2/EtOAc) Rf = 0.14. H NMR
(400 MHz, CDCl3): δ 0.85–0.91 (m, 3H), 1.20–1.37 (m, 16H), 1.38–1.50 (m, 2H), 1.71–1.80
(m, 2H), 2.56 (s, 3H), 2.60–2.78 (m, 2H). 13C NMR (100.6 MHz, CDCl3): δ 14.3, 22.7, 22.8,
29.0, 29.4, 29.47, 29.5, 29.67, 29.74 (two signals overlapping), 32.0, 38.7, 55.0. IR (cm−1): 2915,
2848, 1471, 1079, 1018 (SO), 951, 721. MS (ESI): m/z 487 (2M+Na+, 16), 255 (M+Na+, 62),
233 (MH+, 100). HPLC: tR (S) = 10.9 min, tR (R) = 12.2 min (Chiralpak OB-H; flow rate =
20
1.0 ml min−1; heptane/2-propanol 98:2; 20◦C). [α]D −12 (c 0.21, CHCl3) (lit. (S)-isomer (94%
ee); [α]D +61 (c 1.17, acetone)) [29].
4.5.3. (R)-(–)-1-(Methylsulfinyl)cyclohexane (4c) [29]
Obtained from sulfinyl sulfone 3c (R1 = cyclohexyl, EWG = SO2Ph, 24 mg, 0.08 mmol) at 25◦C
for 15 h (without work-upduetothehighwatersolubilityof sulfoxide 4c.Thereactionmixturewas
concentrated and directly subjected to column chromatography). Yield 34% (4 mg, 0.027 mmol,
47% ee).Yellow oil. TLC (EtOAc) Rf = 0.10. 1H NMR (400 MHz, CDCl3): δ 1.17–1.50 (m, 5H),
1.65–1.75 (m, 1H), 1.82–1.96 (m, 3H), 2.08–2.17 (m, 1H), 2.43–2.55 (m, 1H) and an overlapping
signal at 2.49 (s, 3H). 13C NMR (100.6 MHz, CDCl3): δ 24.9, 25.2, 25.5, 25.6, 26.1, 35.3, 61.0. IR
(cm−1): 2928, 2855, 1451, 1020 (SO). MS (ESI): m/z 315 (2M+Na+, 26), 169 (M+Na+, 98), 147
(MH+, 100), 83 (32). HPLC: tR(S) = 11.4 min, tR(R) = 13.8 min (Chiralpak OB-H; flow rate =
20
0.5 ml min−1; heptane/2-propanol 80:20; 20◦C). [α]D −29 (c 0.15, CHCl3) (lit. (S)-isomer (88%
ee); [α]D +55 (c 0.42, acetone)).[29]

604 F. Gelat et al.
Acknowledgements
We acknowledge financial support from the “Ministère de la Recherche”, CNRS (Centre National de la Recherche
Scientifique) and the “Région Basse-Normandie”. ERDF funding (ISCE-Chem & INTERREG IVa program) is grate-
fully thanked for financial support. We also thank Yohann Berhault and Valentine Choubrac (Université de Caen
Basse-Normandie) for the synthesis of starting materials.
References
[1] O’Mahony GE, Kelly P, Lawrence SE, Maguire AR. Synthesis of enentioeriched sulfoxides. Arkivoc. 2011;Part
(i):1–110.
[2] Wojaczyñska E, Wojaczyn`ski J. Enantioselective synthesis of sulfoxides 2000—2009. Chem Rev. 2010;110:4303–
4356.
[3] Carreño MC, Hernández-Torres G, Ribagorda M, Urbano A. Enantiopure sulfoxides: recent applications in
asymmetric synthesis. Chem Commun. 2009;45:6129–6144.
[4] Mellah M, Voituriez A, Schulz E. Chiral sulfur ligands for asymmetric catalysis. Chem Rev. 2007;107:5133–5209.
[5] Fernández I, Khiar N. Recent developments in the synthesis and utilization of chiral sulfoxides. Chem Rev.
2003;103:3651–3706.
[6] Putra MY, Ianaro A, Panza E, Bavestrello G, Cerrano C, Fattorusso E, Taglialatela-Scafati O. Sinulasulfox-
ide and sinulasulfone, sulfur-containing alkaloids from the Indonesian soft coral Sinularia sp. Tetrahedron Lett.
2012;53:3937–3939.
[7] Meyer SW, Mordhorst TF, Lee C, Jensen PR, Fenical W, Köck M. Penilumamide, a novel lumazine peptide isolated
from the marine-derived fungus, Penicillium sp. CNL-338. Org Biomol Chem 2010;8:2158–2163.
[8] Esomeprazolewas the third largest selling drug in 2011 ($6.156 billion U.S.): Top 200 Products of 2011 by
Total Dollars. Pharmacy Times. 2012;78:51 [cited 2012 July 10]. Available from: http://www.pharmacytimes.com/
_media/_pdf/Top_200_Drugs_2011_Total_Dollars.pdf
[9] Kagan HB, In: Toru T, Bolm C, editors. Organosulfur chemistry in asymmetric synthesis asymmetric. Weinheim:
Wiley VCH;2008. p. 1–29.
[10] LiuZM, ZhaoH, LiMQ, LanYB,YaoQB,TaoJC,WangXW. Chiralphosphoricacid-catalyzedasymmetricoxidation
of aryl alkyl sulfides and aldehyde-derived 1,3-dithianes: using aqueous hydrogen peroxide as the terminal oxidant.
Adv Synth Catal. 2012;354:1012–1022.
ˇ
[11] Liao S, Coric´ I, Wang Q, List B. Activation of H2O2 by chiral confined Brønsted acids: a highly enantioselective
catalytic sulfoxidation. J Am Chem Soc. 2012;134:10765–10768.
[12] Caupène C, Boudou C, Perrio S, Metzner P. Remarkably mild and simple preparation of sulfenate anions from
β-sulfinylesters: a new route to enantioenriched sulfoxides. J Org Chem. 2005;70:2812–2815.
[13] Sandrinelli F, Perrio S, Averbuch-Pouchot MT. Novel approach to the synthesis of enantioenriched sulfoxides.
Highly diastereoselective alkylation of sulfenate anions with 1,4-asymmetric induction. Org Lett. 2002;4:3619–
3622.
[14] Foucoin F, Caupène C, Lohier JF, Sopková-de Oliveira Santos J, Perrio S, Metzner P. 2-(Trimethylsilyl)ethyl
sulfoxides as a convenient source of sulfenate anions. Synthesis. 2007;1315–1324.
[15] Gelat F, Jayashankaran J, Lohier JF, Gaumont AC, Perrio S. Organocatalytic asymmetric synthesis of sulfox-
ides from sulfenic acid anions mediated by a Cinchona-derived phase-transfer reagent.Org Lett. 2011;13:3170–
3173.
[16] O’Donnell, JS, SchwanAL. Generation, structure and reactions of sulfenic acid anions. J Sulfur Chem. 2004;25:183–
211.
[17] Aversa MC, Bonaccorsi P, Madec D, Prestat G, Poli G. The fabulous destiny of sulfenic acid. In: Andersson PG,
editor. Innovative catalysis in organic synthesis. Weinheim: Wiley VCH;2012. p. 47–76.
[18] Maruoka K, editor. Asymmetric phase transfer catalysis. Weinheim: Wiley-VCH; 2008.
[19] Shirakawan S, Maruoka K. Recent developments in asymmetric phasetransfer reactions. Angew Chem Int Ed.
2013;52:4312–4348.
[20] Jew SS, Park HG. Cinchona-based phase-transfer catalysts for asymmetric synthesis. Chem Commun.
2009;45:7090–7103.
[21] Marzorati L, Fejfar JL, Tormena CF, Di Vitta C. Kinetic resolution of α-bromophenylacetamides using quinine or
Cinchona alkaloid salts. Tetrahedron: Asymmetry. 2012;23:748–753.
[22] Bégué JP, Bonnet-Delpon D, Crousse B. Fluorinated alcohols: a new medium for selective and clean reaction. Synlett.
2004;18–29.
[23] Söderman SC, Schwan AL. Sulfenate substitution as a complement and alternative to sulfoxidation in the
diastereoselective preparation of chiral β-substituted β-amino sulfoxides. J Org Chem. 2013;78:1638–1649.
[24] Singh SP, O’Donnell JS, Schwan AL. Nucleophilic attack of 2-sulfinyl acrylates: a mild and general approach to
sulfenic acid anions. Org Biomol Chem. 2010;8:1712–1717.
[25] Caupène C, Martin C, Lemarié M, Perrio S, Metzner P. Mild and efficient access to lithium alkanesulfinates based
on oxaziridine-promoted oxidation of thiolates. J Sulfur Chem. 2009;30:338–345.
[26] Palomo C, Oiarbide M, López R, Gómez-Bengoa E. Phosphazene bases for the preparation of biaryl thioethers from
aryl iodides and arenethiols. Tetrahedron Lett. 2000;41:1283–1286.

Journal of Sulfur Chemistry 605
[27] O’Donnell MJ, Delgado F, Domínguez E, de Blas J, Scott WL. Enantioselective solution- and solid-phase synthesis
of glutamic acid derivatives via Michael addition reactions. Tetrahedron: Asymmetry. 2001;12:821–828.
[28] Fong H.O, Hardstaff WR, Kay DG, Langler RF, Morse RH, Sandoval D-N. The chlorosulfonyl moiety as a leaving
group: hybride reduction of sulfonyl chlorides. Can J Chem. 1979;57:1206–1213.
[29] Egami H, Katsuki T. Fe(salan)-catalyzed asymmetric oxidation of sulfides with hydrogen peroxide in water. J Am
Chem Soc. 2007;129:8940–8941.