Towards a robust and reliable method for the reduction of functionalized sulfoxides

Article abstract of DOI:10.1021/op800088x

Several functionalized sulfoxides in the modafinil series, which bear another reducible function, were chemoselectively reduced to thioethers using the KI/AcCl system.

Full text of DOI:10.1021/op800088x

Organic Process Research & Development 2008, 12, 614–617
Towards a Robust and Reliable Method for the Reduction of Functionalized
Sulfoxides
†
,‡
§
§
‡
†
James Ternois, Fr e´ d e´ ric Guillen,* Guy Piacenza, S e´ bastien Rose, Jean-Christophe Plaquevent, and G e´ rard Coquerel
UPRES-EA 3233, SMS, IRCOF, UniVersit e´ de Rouen, rue Tesni e` re, F-76821 Mont-Saint-Aignan Cedex, France, UMR-CNRS
6
014, IRCOF, UniVersit e´ de Rouen, rue Tesni e` re, F-76821 Mont-Saint-Aignan Cedex, France, and Cephalon, France, ZI Mitry
Compans, 77292 Mitry Mory, France
Abstract:
(RS)-modafinic acid.3,5 However, such nondynamic resolution
procedures suffer from a major drawback with respect to
enantioselective syntheses, i.e. the inherent limitation to 50%
maximum theoretical yield. In order to improve the maximum
theoretical yield, one can either racemize the unwanted enan-
tiomer during the resolution process (dynamic resolution) or
after isolation, allowing it to be submitted to the resolution
procedure again. As the sulfoxide function of modafinil and
its derivatives is configurationally stable in both resolution
conditions, we focused on the study of the ex situ racem-
ization of (S)-modafinil and its derivatives, modafinic acid
and methyl 2-(diphenylmethylsulfinyl)acetate (DMSAM).
Several functionalized sulfoxides in the modafinil series, which bear
another reducible function, were chemoselectively reduced to
thioethers using the KI/AcCl system.
Introduction
Organosulfur compounds that contain a chirogenic
sulfoxide unit play an important role in asymmetric
synthesis (as either chiral auxiliaries or ligands), or in
1
,2
pharmaceutical chemistry. For example, esomeprazole
a powerful proton pump inhibitor used as an antiulcer
(
agent), OPC-29030 (a platelet adhesion inhibitor), or (R)-
modafinil (an atypical psychostimulant recently approved
in the United States as a treatment for excessive daytime
sleepiness associated with narcolepsy and work-shift sleep
disorder), among others, exhibit such a chiral functional
group.
The more interesting substrate for this purpose is
modafinic acid, which can be resolved by preferential
crystallization using the AS3PC method.6
Our first attempts using reported racemization methods
7
8
for chiral sulfoxides (i.e., thermal activation, acid or
9
base catalysis) were unsuccessful, owing mainly to the
S-benzhydryl labile bond that is easily cleaved in these
rather drastic conditions. We therefore turned to a second
strategy based on a reduction/oxidation sequence (Scheme
1
).
2 2
Since the oxidation by H O had previously been optimized
As part of our ongoing studies on the synthesis (R)-
on an industrial scale,10 our primary goal was to develop a
modafinil and its derivatives, we previously described both
reliable method for reducing a sulfoxide unit with complete
chemoselectivity in the presence of reducible functions such
as carboxylic acid, amide, and ester, as well as the labile
benzhydryl unit. Indeed, most of the reported sulfur deoxygen-
3
4
resolution and enantioselective methods. (R)-Modafinil
can be obtained by resolution using either chiral chroma-
tography or preferential crystallization of its precursor,
*
Corresponding author. Telephone: +33 235522465. Fax: +33 235522971.
ation methods do not show any chemoselectivity when other
E-mail: frederic.guillen@univ-rouen.fr.
reducible functions are present on the same molecule.11–13 From
†
UPRES-EA 3233, SMS, IRCOF, Universit e´ de Rouen.
UMR-CNRS 6014, IRCOF, Universit e´ de Rouen.
Cephalon, France.
‡
the many available methods, we selected the reduction systems
using activated iodide salts or sodium borohydride (Table 1).
§
(
(
(
1) Carre nˇ o, M. C. Chem. ReV. 1995, 95, 1717–1760.
2) Fern a´ ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651–3706.
3) Neckerbrock, O.; Courvoisier, L.; Graf, S.; Serrure, G.; Coquerel, G.;
Rose, S.; Besselievre, C.; Mallet, F.; Van Langevelde, A. J. Method
for the production of crystalline forms and crystalline forms of optical
enantiomers of modafinilPatent WO2004060858, July 22, 2004.
4) Ternois, J.; Guillen, F.; Plaquevent, J.-C.; Coquerel, G. Tetrahedron:
Asymmetry 2007, 18, 2959–2964.
(5) (a) Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo M.; Swenson,
D. Tetrahedron: Asymmetry 2004, 15, 1053–1058. (b) Hauck, W.;
Ludemann-Himbourger, O.; Ruland, Y. Methods for the separation
of modafinilPatent EP1634861, March 15, 2006.
(
6
14
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development
10.1021/op800088x CCC: $40.75  2008 American Chemical Society
Published on Web 06/11/2008

Scheme 1. Reduction/oxidation sequence
Table 1. Selected literature conditions for sulfoxide
reduction
method
R1
R2
yield (%) ref
KI/AcCl
C
C
6
H
H
5
-CH
-CH
2
(CH
6
2
H
)
2
-COOH quant.
14
15
16
17
18
NaI/(COCl)
2
6
5
2
C
5
-CH
2
99
a
KI/PTSA
methionine sulfoxide
93
NaI/TiCl
4
C
C
6
H
H
5
-CH
-CH
2
C
C
6
H
H
5
-CH
-CH
2
90-98
98
4 2
NaBH /I
6
5
2
6
5
2
2 4 2
However, NaI/(COCl) and NaBH /I are not convenient for
a
p-Toluenesulfonic acid.
the reduction of modafinic acid, as they can react with the
carboxylic acid function, and were therefore discarded from this
study.
of the acid, amide, or ester function was observed. These
encouraging results proved that the deoxygenation of our
substrates was efficient and chemoselective using this
method. Fractional factorial design of experiments was
used to optimize temperature and concentrations of the
modafinic acid, KI, and AcCl, confirming that the more
efficient procedure relied on the initial Allenmark condi-
tions (Scheme 2). Lowering the amount of KI (and, to a
lesser degree, of acetyl chloride), or increasing the reaction
temperature, led to an increased formation of benzhydrol
as a side product. Nevertheless in order to scale up the
reaction, we needed to improve the productivity of the
method. As the solubility of the (benzhydrylthio)acetic
acid is higher than that of modafinic acid, we devised an
alternative procedure using a saturated solution of sul-
foxide and KI, in which the solid reagents slowly dissolve
as the reaction proceeds. The concentration of sulfoxide
and KI can therefore be kept constant throughout most of
the reaction, and the acetyl chloride is always in large
excess to the dissolved sulfoxide, preventing the formation
of benzhydrol.
Results and Discussion
Allenmark developed in 1966 a reductive system based on
the use of potassium iodide and acetyl chloride, primarily
14
intended as an analytical tool for sulfoxide assay. This system
was successfully used on a sulfoxide compound having
structural similarities to modafinic acid (Table 1, line 1). We
applied the same experimental procedure (Scheme 2) and set
up a workup (quenching with ice/water, followed by addition
of solid sodium thiosulfate until disappearance of the brown
coloration and extraction) because the initial analytical method
did not require isolation of the obtained thioether.
Thioethers were obtained from modafinic acid and
modafinil in excellent isolated yields (87-88%) on a 2
mmol scale in 45 mL of acetic acid. The reduction of
DMSAM gave an even better yield of 95%. No reduction
(
6) The initial system (solvent + substrate) containing an enantiomeric
excess (e.g. of R) is heated at TB so that only the S-enantiomer in
default is completely dissolved. Thus, the slurry is composed of crystals
of the enantiomer in excess in thermodynamic equilibrium with its
saturated solution. The system (a suspension and not a solution) is
therefore self-seeded by crystals of the pure enantiomer; one-third of
the future crops is already present in the system as fine crystals (an in
situ wet grinding can be applied if necessary). The suspension is then
submitted to an adapted cooling program and stirring mode without
any need of additional seeds so that the crystal growth is favoured
instead of an uncontrolled secondary nucleation. At the end of the
entrainment, the crystals of the R-enantiomer are collected by filtration
or centrifugation, and the mother liquor contains an excess of the
antipode S. A mass of racemic mixture, equal to the collected mass
of R crystals, is then added to the mother liquor which is then reheated
at TB. This process can be repeated as many times as necessary,
allowing by alternative crystallization of R and S enantiomers the
resolution of any quantities of racemic mixture crystallizing as a stable
conglomerate. (a) Coquerel, G.; Petit, M.-N.; Bouaziz, R. Method of
Resolution of Two Enantiomers by CrystallizationPatent WO9508522.
March 30, 1995. (b) Coquerel, G. Preferential Crystallization In NoVel
Optical Resolution Technologies; Sakai, K., Hirayama, N., Tamura,
R. Eds.;Topics in Current Chemistry 619; Springer GmbH: Berlin,
Heidelberg, 2007; pp 1-50.
Scheme 2. Reduction of modafinil derivatives using
KI/AcCl system
First, the amounts of potassium iodide and acetyl
chloride were optimized to 2.25 equiv and 1.75 equiv,
respectively, for the reduction of 15 g of modafinic acid
-2
-1
in 450 mL of acetic acid (12 × 10 mol · L ) (Figure
1). Then the amounts of modafinic acid, potassium iodide,
and acetyl chloride were increased, the solvent volume
being kept constant (Figure 1).
(
7) (a) Rayner, D. R.; Miller, E. G.; Bickart, P.; Gordon, A. J.; Mislow,
K. J. Am. Chem. Soc. 1966, 88, 3138–3139. (b) Mislow, K. Rec. Chem.
Prog. 1967, 28, 217–240.
(
(
8) Mislow, K.; Simmons, T.; Melillo, J. T.; Ternay, A. L. J. Am. Chem.
Soc. 1964, 86, 1452–1453.
9) (a) Wolfe, S.; Rauk, A. Chem. Commun. 1966, 778–779. (b) Khim,
Y. H.; Tagaki, W.; Kise, M.; Furukawa, N.; Oae, S. Bull. Chem. Soc.
Jpn. 1966, 39, 2556–2557. (c) Cram, D. J.; Pine, S. H. J. Am. Chem.
Soc. 1963, 85, 1096–1100.
Up to 30 g of modafinic acid was reduced in 450 mL
-2
-1
of solvent (24 × 10 mol · L ) without any decrease of
the yield. This improved procedure uses a much lower
amount of potassium iodide and acetyl chloride and
operates at higher concentration than the initial procedure
devised by Allenmark. After addition of a water/ice
mixture, the iodine generated during the reaction is
reduced by addition of sodium thiosulfate, and the solid
(
10) Lafon, L. Acetamides Derivatives U.S. Patent 417,729, December 4,
1
979.
(
(
11) Madesclaire, M. Tetrahedron 1988, 44, 6537–6580.
12) Drabowicz, J.; Numata, T.; Oae, S. Org. Prep. Proced. Int. 1977, 9,
6
3–83.
(
(
13) Kukushkin, V. Y. Coord. Chem. ReV. 1995, 139, 375–407.
14) Allenmark, S. Acta Chem. Scand. 1966, 20, 910–911.
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615

Scheme 3. Reduction of modafinic acid using KIPTSA
system
significantly the reaction time, the isolation of thioether
was difficult because of the formation of TiO after
2
Figure 1. Reduction of modafinic acid at constant volume with
hydrolysis. Furthermore, decomposition of modafinic acid
into benzhydrol occurred when THF was replaced by
acetic acid.
KI/AcCl system for 1 h.
modafinic acid is collected by filtration, dissolved in
dichloromethane, washed with a sodium thiosulfate solu-
tion, and concentrated in Vacuo. Simple washing of the
resulting solid with a water/cyclohexane mixture (5:1 v/v)
allowed the obtention of pure (benzhydrylthio)acetic acid.
Conclusions
In this study, we have tested a series of reported
methods for the deoxygenation of sulfoxides on modafinic
derivatives that are important compounds in pharmaceuti-
cal area. It has been shown that a careful adaptation of
After oxidation with H
2 2
O , the resulting racemic sulfoxide
(
71% overall yield from the optically pure modafinic acid)
1
4
the analytical Allenmark conditions into a preparative
procedure was the best method to reduce chemoselectively
the sulfoxide function of polyfunctionalized materials,
bearing both a labile benzhydryl moiety and another
reducible function. The only drawback, high dilution, can
be circumvented by an elegant use of the solubility of
the resulting thioether, allowing multigram-scale reduction.
In addition, a solvent-free method seems a powerful
alternative, which remains to be optimized.
was suitable for resolution by means of preferential
crystallization using the AS3PC procedure.19
In addition we carried out the reduction of DMSAM
2
0
in the same conditions on up to 6 g scale in 45 mL of
acetic acid and were delighted to obtain a quantitative
yield (99%). However, attempts to reduce modafinil were
not as successful as when using “unoptimized” Allenmark
conditions (Scheme 2). Indeed, the reaction was performed
four times and gave a yield ranging from 52 to 76% along
with various amounts of benzhydrol, benzophenone, and
benzhydrylacetate, showing a lower efficiency for this
Experimental Section
General Methods. Infrared spectra were recorded on a
Perkin-Elmer 16 PC FT-IR spectrometer, and NMR
spectra were recorded on a Br u¨ ker Avance 300 (300 MHz).
substrate than the two others investigated in this study.
The system described by Fujiki16 using potassium
iodide and a solid Brønsted acid as activating agent is an
appealing alternative to avoid the use of solvent (Scheme
1
3
C NMR spectra were determined with complete proton
decoupling. Proton and carbon chemical shifts are reported
in ppm (δ) downfield from signal of residual solvent in
which NMR analysis was performed. High-pressure liquid
chromatography (HPLC) was performed on a Ther-
moseparation products P100.
3
). Indeed, the reaction proceeds upon grinding the three
reagents in the solid state (Scheme 3).
The reduction of 5 g of modafinic acid using a Brønsted
acid as the activating agent without any solvent and under
mechanical stirring (method A, Scheme 3) gave 78% yield.
Attempts to decrease the duration of the reaction by either
microwave or ultrasound activation resulted in low yields
and partial or complete degradation of the starting
material. We also wanted to assess this deoxygenating
system in acetic acid (method B, Scheme 3). Thus 2.5 g
of sulfoxide was reduced with 80% yield in 1 h. The use
of solvent significantly decreased the reaction time from
Reduction of (S)-(+)-Modafinic Acid. In a thermostatted
00 mL double jacket vessel, (S)-(+)-modafinic acid (25
5
g, 0.092 mol, 1 equiv) was partially dissolved in glacial
acetic acid (450 mL) at 20 °C, then potassium iodide
(
68.85 g, 0.414 mol, 2.25 equiv) was added followed by
acetyl chloride (11.34 mL, 0.161 mol, 1.75 equiv).
Instantaneously, iodine was formed and strongly colored
the mixture. After 1 h the reaction was quenched with
1
8 to 1 h without loss of efficiency.
Activation of NaI by TiCl as a Lewis acid was also
evaluated by using the protocol described by Balicki:
reduction of modafinic acid gave 77% yield in THF within
0 min. Although the NaI/TiCl combination decreased
0
.5 L of water + 0.5 L of ice with precipitation of
4
1
7
thioether. Iodine was reduced with sodium thiosulfate until
disappearance of the brown color. The precipitate was
gathered on a sintered glass filter, then dissolved in CH
2 2
Cl
2
4
(
200 mL) in a 500 mL separatory funnel. The organic layer
(
(
15) Olah, G. A.; Malhotra, R.; Narang, S. C. Synthesis 1975, 58–59.
16) Fujiki, K.; Kurita, S.; Yoshida, E. Synth. Commun. 1996, 26, 3619–
(20) Since DMSAM is a viscous liquid at room temperature, the workup
was modified as follows: after addition of the water/ice mixture and
destruction of the iodine formed with solid sodium thiosulfate, the
sulfide was extracted with CH2Cl2 and washed with aqueous thiosul-
fate; the organic layer was dried on MgSO4 and concentrated in Vacuo
to give a yellowish oil.
3
626.
(
(
(
17) Balicki, R. Synthesis 1991, 155–156.
18) Karimi, B.; Zareyee, D. Synthesis 2003, 335–336.
19) Wermester, N.; Lambert, O.; Coquerel, G. CrystEngComm 2008, 10,
7
24–733.
6
16
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development

was washed with aqueous Na
get ride of traces of iodine, dried over MgSO
evaporated under reduced pressure. Purification step was
performed by washing with a 150 mL mixture of water/
cyclohexane (5:1 v/v) in a 500 mL round-bottom flask. A
white solid was filtered and dried at 60 °C to yield
2
S
2
O
3
solution (10 mL) to
and
analysis (Inertsil ODS2 (15 cm × 4.6 mm i.d.); 1 mL/
min; λ ) 220 nm; eluent: acetonitrile 50% (v/v); phosphate
4
-
1
buffer 0.05 mol · L pH) 2.3, 50% (v/v)): t ) 7.6 min).
R
Acknowledgment
We thank Cephalon, Inc., for financial support and a research
grant given to J.T. and for the generous gift of the various
modafinil-related thioethers and sulfoxides used in this study.
(
benzhydrylthio)acetic acid (21.14 g, 89%). White solid;
-
1
1
m.p.:128 °C; IR (cm ): νCdO: 1697 and νC-O: 1303; H
1
NMR(300 MHz, DMSO-d
6
): δ 12.66 (brs, H, CO
2
H);
7
2
1
.24-7.45 (m, 10H, Ar-H); 5.39 (s, 1H, CH); 3.07 (s,
1
3
Received for review April 8, 2008.
OP800088X
H, CH
2 6
). C NMR (75 MHz, DMSO-d ): δ 172.1, 141.2,
29.0, 128.7, 128.5, 128.3, 127.9, 127.6, 53.2, 34.0. HPLC
Vol. 12, No. 4, 2008 / Organic Process Research & Development
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617