New procedures for the enantioselective oxidation of sulfides under stoichiometric and catalytic conditions

Article abstract of DOI:10.1016/S0957-4166(02)00326-9

Acid-catalyzed oxidation of 2-furylcarbinols with hydrogen peroxide affords alternatively 2-(1-hydroperoxyalkyl)-furans 2 or 6-hydroperoxy-2H-pyran-3(6H)-ones 3. Compounds of the type 2 and 3 have been used as oxygen donors in efficient stoichiometric or catalytic procedures for the asymmetric sulfoxidation of prochiral sulfides in the presence of Ti(O-i-Pr)₄/L-DET or Ti(O-i-Pr)₄/(R)-BINOL/H₂O systems. Positive non linear effects, (+)-NLE, were observed in the enantioselective oxidation of methyl p-tolyl sulfide, promoted by enantiomerically enriched Ti(IV)/BINOL/H₂O complexes.

Full text of DOI:10.1016/S0957-4166(02)00326-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1277–1283
New procedures for the enantioselective oxidation of sulfides
under stoichiometric and catalytic conditions
Antonio Massa, Francesca R. Siniscalchi, Valeria Bugatti, Alessandra Lattanzi and Arrigo Scettri*
Dipartimento di Chimica, Universita` di Salerno, Via S. Allende 84081 I Baronissi, Salerno, Italy
Received 10 May 2002; accepted 19 June 2002
Abstract—Acid-catalyzed oxidation of 2-furylcarbinols with hydrogen peroxide affords alternatively 2-(1-hydroperoxyalkyl)-
furans 2 or 6-hydroperoxy-2H-pyran-3(6H)-ones 3. Compounds of the type 2 and 3 have been used as oxygen donors in efficient
stoichiometric or catalytic procedures for the asymmetric sulfoxidation of prochiral sulfides in the presence of Ti(O-i-Pr)4/L-DET
or Ti(O-i-Pr)4/(R)-BINOL/H2O systems. Positive non linear effects, (+)-NLE, were observed in the enantioselective oxidation of
methyl p-tolyl sulfide, promoted by enantiomerically enriched Ti(IV)/BINOL/H2O complexes. © 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
been successfully employed in convenient procedures
for the asymmetric epoxidation of allylic alcohols,8 the
oxidation of sulfides to chiral sulfoxides and the kinetic
resolution of racemic sulfoxides.9
The asymmetric oxidation of sulfides is an important
preparative reaction because of the ever increasing use
of chiral sulfoxides both as bioactive compounds1 and
chiral auxiliaries.2
One of the main targets of advanced organic synthesis
is represented by the achievement of highly efficient,
cheap and environmentally acceptable processes. This
result allows the formation of unwanted waste to be
minimized and tedious and expensive purification pro-
cedures to be avoided, so that crude intermediates or
reagents can be used directly.
In 1984 the groups of Kagan3 and Modena4 discovered
independently that a combination of Ti(O-i-Pr)4/(R,R)-
diethyl tartrate (DET)/H2O (1:2:1) or Ti(O-i-Pr)4/
(R,R)-DET (1:4) could be conveniently exploited for
the asymmetric sulfoxidation of some sulfides with tert-
butyl hydroperoxide (TBHP) or cumyl hydroperoxide
(CHP), as oxidants.
With these considerations in mind, our efforts have
recently been addressed to the realization of a new,
efficient and resource-saving procedure for the rapid
synthesis of easily renewable hydroperoxides, for use in
asymmetric oxidative processes.
Suitable modifications by Kagan of his original proto-
col have allowed the achievement of catalytic asymmet-
ric processes. Recently other reported procedures are
usually based on the in situ formation of the catalytic
species by reaction of Ti(O-i-Pr)4 with chiral binaph-
thols,5 variously substituted 1,2-diols,6 trialkanol-
amines.7 Particular attention has been evidently paid to
the influence of the chiral ligand on the level of
efficiency and enantioselectivity of the asymmetric sulf-
oxidation although the structure of the used hydroper-
oxide has shown to be an important factor. In fact,
besides the most widely used oxidants TBHP and CHP,
for example, functionalized furylhydroperoxides have
2. Results and discussion
2.1. Synthesis of hydroperoxides 2 and 3
Hydroperoxides 2, chosen as target compounds, proved
to be easily accessible by treatment of the correspond-
ing furylcarbinols 1 with hydrogen peroxide in 1,2-
dimethoxyethane (DME) in the presence of
p-toluenesulfonic acid (PTSA). In all the experiments
reported in Table 1, the formation of 2 took place in
high yield and with good selectivity (85–95%), as sup-
ported by 1H NMR analysis on the isolated crude
* Corresponding author. Tel.: +39 089 965374; fax: +39 089 965296;
e-mail: scettri@unisa.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00326-9

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A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
Table 1. Acid-catalyzed conversion of 1 into hydroperox-
ides 2 with 30% H2O2
Although the reaction pathway affording 3 has not yet
been clarified, it seems reasonable that the formation of
intermediates of the type 4 could be involved (Scheme
3).
Entry
R
R1
R2
t (h)
2
Yield (%)a
1
2
3
4
5
H
H
Me
Me
Me
H
Me
H
H
H
n-Hexyl
Me
n-Hexyl
n-Pentyl
n-Octyl
14
3
7
8
7
2a 65
2b 70
2c
2d 71
2e 65
75
a All yields refer to isolated chromatographically pure compounds 2,
whose structures were confirmed by IR, 1H, 13C NMR and elemen-
tal analysis data.
Scheme 3.
products 2, that, in every case, could be easily purified
by silica gel chromatography. This level of selectivity
can be considered rather surprising considering of the
well-known lability of the OꢀO peroxidic bond in acidic
medium and the strong tendency of compounds of type
1 to undergo acid-catalyzed opening of the furan
nucleus (Scheme 1).10,11
In fact, the conversion of furyl alcohols 1 into 4 with a
variety of oxidants, such as m-chloroperbenzoic acid,13
pyridinium chlorochromate,14 dimethyl dioxirane15 etc.,
has been widely reported in the literature; furthermore,
compounds 4, under the usual conditions, are quantita-
tively converted into 3.
R1
R2
R1
R2
30% H2O2 (2 eq.)
R
O
The achievement of a new, economical and safe
approach to compounds 3 can be considered an impor-
tant preparative result since, besides representing a new
class of hydroperoxides, they can be quantitatively
reduced (either directly in situ or after purification) to
the corresponding 6-hydroxy-2H-pyran-3(6H)-one
derivatives 4, which are well-known both as bio-active
compounds and versatile synthetic intermediates.16
O
R
DME, PTSA, r.t.
OOH
OH
2
1
Scheme 1.
More interestingly, the unusual oxidant system H2O2/
PTSA showed an unprecedented reactivity towards the
furan moiety of hydroperoxides 2. In fact, under appro-
priate conditions (higher amounts of H2O2 and PTSA),
starting materials 1 underwent two sequential oxida-
tions leading, through the intermediates 2, to com-
pounds 3 (Scheme 2, Table 2).
2.2. Asymmetric sulfoxidation by Modena’s procedure
A set of experiments was planned in order to verify the
possibility of exploiting hydroperoxides of the type 2
and 3 in the asymmetric sulfoxidation of prochiral
sulfides. In the preliminary phase hydroperoxide 2c and
methyl p-tolyl sulfide were used as representative
reagents in a modified version of the stoichiometric
Modena’s procedure (Scheme 4). It should be noted
that compound 2c could be obtained in ꢀ95% yield by
oxidative treatment of the corresponding furyl alcohol
in acidic medium, being contaminated with very small
Table 2. Acid-catalyzed conversion of 1 into hydroperox-
ides 3 with 30% H2O2
Entry
R
R1
R2
t (h)
3
Yield (%)a,b
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
H
H
H
Me
Et
H
n-Hexyl
c-Hexyl
i-Propyl
Me
n-Hexyl
n-Octyl
18
23
16
7
5
20
3a 75 (90/10)
3b 77 (93/7)
3c
64 (92/8)
3d 77
3e
3f
65 (50/50)
65 (94/6)
1
amounts of starting material (<5%, H NMR analysis
on crude 2c); therefore, 2c was generally used directly
without purification.
a All yields refer to isolated chromatographically pure compounds 3,
whose structures were confirmed by IR, 1H, 13C NMR and elemen-
tal analysis data. Furthermore, 3 were reduced quantitatively by
treatment with dimethyl sulfide (1.5 equiv.) in Et2O solution a 0°C
and the spectroscopic data (IR, 1H, 13C NMR) of the resulting
compounds 4 matched with those of authentic sample prepared
according to a literature procedure.12
Using Modena’s catalytic system, Ti(O-i-Pr)4/L-DET
under stoichiometric conditions gave good results and
the levels of efficiency and enantioselectivity were found
to depend on the amount of hydroperoxide and the
reaction time (Table 3).
b Values in parentheses refer to diastereomeric ratios.
Scheme 2.

A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
1279
yield, 88.3% e.e., based on the specific rotation of the
pure enantiomer), the alternative employment of 2c
allows a much higher level of enantioselectivity since 6a
was obtained in 61% yield and 98% e.e. (HPLC).
Less satisfactory results have been obtained by using
hydroperoxides of the type 3, as supported by some
experiments, reported in Table 5.
Ti (O-i-Pr)4, L-DET, 2c
O
S
1c
+
p-Tol
Me
S
CH2Cl2, -20°C
p-Tol
Me
5
6
Scheme 4.
Table 3. Stoichiometric enantioselective oxidation of
methyl p-tolyl sulfide by 2c
Table 5. Stoichiometric enantioselective oxidation of 5
with 3d,f
Entry
2c (equiv.)
t (h)
Yield (%)a
E.e. (%)b
Entry
Ar
3
Yield (%)a,b
E.e. (%)c
1
2
3
4
1.1
1.7
2.0
2.5
1.45
1.45
18
63 (B5)c
97 (nd)
72 (15)c
61 (30)c
70
74
84
98
1
2
3
p-MeC6H4
p-ClC6H4
p-MeOC6H4
3d
3d
3f
77 (15)
88 (10)
77 (10)
68
64
62
22
a All yields refer to isolated chromatographically pure compound 6,
obtained with (R)-enantiomer in excess.
a All the yields refer to isolated chromatographically pure compound
6, obtained with (R)-enantiomer in excess.
b E.e.s were determined by HPLC on a Daicel Chiralcel OB column.
c Values in parentheses refer to isolated sulfone.
b Values in parentheses refer to isolated sulfone.
c E.e.s were determined by HPLC on a Daicel Chiralcel OB column.
In particular, a strong enhancement of the e.e. was
strictly related to the amount of sulfone produced. This
result suggested that a process of convergent kinetic
resolution could follow the asymmetric oxidation, thus
increasing the e.e. of the sulfoxide. This hypothesis was
confirmed by submitting racemic methyl p-tolyl sulfox-
ide to treatment with 2c (1.3 equiv.) under the condi-
tions reported in Table 3. After 18 h the expected
sulfone was obtained in 59% yield while the starting
material was recovered in 41% yield and 98% e.e.
((R)-enantiomer predominant; stereoselectivity factor
S=23, calculated according to Ref. 17).
In fact, although asymmetric oxidation was shown to
proceed with good efficiency, only moderate e.e.s were
observed, in spite of the formation of sulfone at levels
of 10–15% (Scheme 5).
2.3. Catalytic asymmetric sulfoxidation by Uemura’s
procedure5a
Further investigations were devoted to the achievement
of a catalytic procedure, leading to chiral sulfoxides,
based on the use of the Ti(O-i-Pr)4/(R)-BINOL/H2O
system. Nevertheless, the modified version, involving
the use of hydroperoxide 2c as an oxygen donor,
proved to be unsuccessful: in many experiments, per-
formed on methyl p-tolyl sulfide in toluene solution the
formation of a white solid precipitate could be observed
and the corresponding sulfoxide was usually isolated in
low yields and very poor e.e.s.
The above procedure proved to be successful with other
aryl methyl sulfides (Table 4) and good yields and
moderate e.e.s were observed by carrying out the asym-
metric oxidation under catalytic conditions involving
the presence of only 0.2 equiv. of Ti(O-i-Pr)4 and 0.8
equiv. of L-DET with respect to the starting sulfide
(entry 5).
On the contrary, more satisfactory results were
achieved by using furylhydroperoxide 2b, pointing out
again the strong influence exerted by the structure of
It is noteworthy that, in all the above experiments,
chromatographic purification of crude sulfoxides 6
afforded 1c in almost quantitative yield, which can be
converted into 2c according to the previously reported
approach (Scheme 1).
Ti (O-i-Pr)4, L-DET, 3
CH2Cl2, -20°C
O
S
4
+
Ar
Me
S
Ar
Me
5
6
On the basis of the results obtained by the standard
Modena procedure for methyl p-tolyl sulfoxide (60%
Scheme 5.
Table 4. Stoichiometric enantioselective oxidation of 5 with hydroperoxide 2c
Entry
Ar
5
t (h)
Yield (%)a,b
E.e. (%)c
1
2
3
4
5
p-MeC6H4
p-ClC6H4
Ph
p-MeOC6H4
p-MeC6H4
5a
5b
5c
5d
5a
22
22
22
24
24
61 (30)
82 (16)
89 (5)
70 (30)
79 (9)
98
93
78
99
62
a All yields refer to chromatographically isolated pure compound 6, obtained with (R)-enantiomer in excess.
b Values in parentheses refer to isolated sulfone.
c E.e.s were determined by HPLC on a Daicel Chiralcel OB column.

1280
A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
the oxidant on the efficiency and enantioselectivity of
the reaction.
corresponding sulfoxide was isolated in 56% yield and
56% e.e.
In fact, under the conditions reported in Scheme 6 and
Table 6 no precipitation was observed and the forma-
tion of the expected sulfoxides took place in satisfac-
tory yield. Furthermore, the level of enantioselectivity
was again found to depend on the reaction time and the
amount of sulfone produced (entries 1–4). The occur-
rence of a convergent process of kinetic resolution of
the enantiomerically enriched sulfoxide deriving from
the initial asymmetric oxidation was confirmed by sub-
mitting racemic methyl p-tolyl sulfoxide to reaction
with 2b in the presence of the usual amounts of the
catalytic system Ti(IV)/(R)-BINOL/H2O; after 19 h the
corresponding sulfone was isolated in 37% yield, while
the starting material was recovered in 67% yield with
41% e.e. ((R)-enantiomer in excess; stereoselectivity fac-
tor S=16). Regarding the preparative aspects, the com-
bination of asymmetric sulfoxidation and convergent
kinetic resolution afforded chiral methyl aryl sulfoxides
in appreciable yield and very satisfactory e.e.s. It is
noteworthy that the employment of 2b, in place of
TBHP, has allowed a significant improvement of the
original Uemura’s procedure, involving a moderately
enantioselective sulfoxidation (ꢀ50% e.e.), while the
concomitant process of kinetic resolution took place
with much lower stereoselectivity factors (S=2–3).
Consequently, chiral sulfoxides could be obtained with
high e.e.s only in rather low yields. When a methyl
group was replaced with an ethyl group (for example,
phenyl ethyl sulfide) the starting material was recovered
almost completely unreacted after prolonged treatment
(24 h) under the standard conditions. In every case,
moderate reactivity and enantioselectivity were
observed by performing the reaction at 25°C since the
Rather surprisingly, Uemura’s approach afforded inter-
esting results in the presence of reduced amounts of
chiral ligand. In fact, when the catalytic system Ti(O-i-
Pr)4/R-BINOL/H2O was generated according to
0.1:0.1:20 stoichiometric ratio (with respect to the start-
ing materials), the formation of the chiral sulfoxides
occurred in good yields and improved chemoselectivity
(Scheme 7, Table 7).
O
Ti (O-i-Pr)4 / R-BINOL / H2O / 2b
toluene, 0°C
S
1b
+
S
Ar
Me
Ar
Me
5
6
Scheme 7.
Table 7. Catalytic asymmetric sulfoxidation by Ti(O-i-Pr)4
(0.1 equiv.)/(R)-BINOL (0.1 equiv.)/H2O (20 equiv.) sys-
tem
Entry
Ar
t (h)
Yield (%)a,b
E.e. (%)c
1
2
3
4
5
p-MeC6H4
p-MeC6H4
p-MeC6H4
Ph
4
6
24
24
26
49 (nd)
59 (6)
79 (14)
77 (9)
47
65
80
80
78
p-MeOC6H4
66 (17)
a All the yields refer to isolated chromatographically pure compound
6, obtained with (R)-enantiomer in excess.
b Values in parentheses refer to isolated sulfone.
c E.e.s were determined by HPLC on a Daicel Chiralcel OB column.
The usual process of kinetic resolution was once again
found to follow the asymmetric sulfoxidation (entries
1–3). In all the experiments performed by the two
procedures, the ready recovery of 1b by chromato-
graphic techniques allowed the regeneration of 2b as
previously reported.
O
Ti (O-i-Pr)4 / R-BINOL / H2O / 2b
S
1b
+
S
R
Me
R
Me
toluene, 0°C
5
6
2.4. Non-linear effects (NLE) in the asymmetric
sulfoxidation
Scheme 6.
In recent years particular attention has been paid to the
detection of NLE in a variety of asymmetric reac-
tions,18 since they can be used to prepare compounds
with high e.e.s starting from only enantiomerically
enriched ligands or auxiliaries and, furthermore, to
obtain mechanistic information.
Table 6. Catalytic asymmetric sulfoxidation with Ti(O-i-
Pr)4 (0.1 equiv.)/(R)-BINOL (0.2 equiv.)/H2O (20 equiv.)
Entry
R
t (h)
Yield (%)a,b
E.e. (%)c
1
2
3
4
5
6
7
8
9
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
Ph
p-MeOC6H4
p-BrC6H4
C6H5CH2
3
4
71 (nd)
76 (nd)
75 (B5)
63 (37)
67 (33)
69 (25)
56 (16)
79 (21)
95 (5)
49
52
61
87
80
85
93
51
51
5.5
24
16.5
16
16
17
23
As regards the asymmetric sulfoxidation, Kagan
pointed out a negative NLE, (−)-NLE, for the oxida-
tion of methyl p-tolyl sulfide in the presence of the
modified Sharpless reagent Ti(O-i-Pr)4/L-DET/H2O,
that affected the level of enantioselectivity until the
value of 70% e.e. was reached for diethyl tartrate; then,
the linear relationship was observed until enantiomeri-
cally pure L-DET was used.19
a All the yields refer to isolated chromatographically pure compound
6, obtained with (R)-enantiomer in excess.
b Values in parentheses refer to isolated sulfone.
In Table 8 the results from the asymmetric sulfoxida-
tion of methyl p-tolyl sulfide with 2b, performed in the
c E.e.s were determined by HPLC on a Daicel Chiralcel OB column.

A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
1281
presence of partially resolved BINOL, according to the
above procedures, are reported.
and distilled before use. Light petroleum refers to the
fraction of petroleum ether boiling in the range 40–
60°C. The sulfoxidation reactions were carried out
under an argon atmosphere and using flame dried
glassware. Flash chromatography and TLC were per-
formed on Merck silica gel. Proton (400 MHz) and
carbon (100 MHz) NMR spectra were recorded on a
Bruker DRX 400. Chemical shifts are reported in (l)
Table 8. (+)-NLE in the asymmetric sulfoxidation of
methyl p-tolyl sulfide with Ti(IV) (0.1 equiv.)/(R)-BINOL
(0.2 equiv.)/H2O (20 equiv.) system
Entry
(R)-BINOL (e.e.)
Yield (%)a,b
E.e. (%)c
1
ppm relative to internal CDCl3 l (7.26) for H NMR
1
2
3
4
23
44
59
50 (3)
85 (6)
69 (2)
76 (3)
22
41
49
52
and CDCl3 (77.0) for 13C NMR. IR spectra were
recorded on a Bruker Vector 22 (frequencies 400–4000
cm−1, resolution 2 cm−1). Starting materials 1 were
prepared by reacting 2-formyl-furan, 5-methyl-2-for-
myl-furan or 2-acetyl furan with the appropriate Grig-
100
a All the yields refer to isolated chromatographically pure compound
6, obtained with (R)-enantiomer in excess.
1
nard reagent and their structure were confirmed by H
b Values in parentheses refer to isolated sulfone.
c E.e.s have been determined by HPLC on a Daicel Chiralcel OB
column.
and 13C NMR analysis.
4.2. Standard procedure for synthesis of 2-(1-hydroper-
oxyalkyl)furans, 2
Short reaction times (4 h for Ti(O-i-Pr)4 (0.1 equiv.)/
(R)-BINOL (0.2 equiv.)/H2O (20 equiv.) system) were
chosen in order to minimize the formation of sulfone
and, consequently, to reduce the superimposition of the
process of kinetic resolution. A (+)-NLE was detected
and it has to be noted that very close values of e.e.s
have been obtained with 59% e.e. and enantiopure
(R)-BINOL (Fig. 1).
To a solution of 1 (4.0 mmol), in 1,2-dimethoxyethane
(DME, 40 mL) was added 30% aqueous H2O2 (0.820
mL, 8 mmol) and p-toluenesulfonic acid (PTSA, 84 mg,
0.45 mmol). The mixture was stirred at room tempera-
ture for the appropriate reaction time (see Table 1). At
the end of the reaction, the mixture was diluted with
Et2O (160 mL) and washed with saturated NaHCO3
solution (2×10 mL) and saturated NaCl solution (3×10
mL) and finally dried over dry Na2SO4 for a few
minutes. After filtration and evaporation of the solvent,
the crude product was purified by flash chromatogra-
phy (95/5 light petroleum/Et2O) to afford pure 2-(1-
hydroperoxyalkyl)-furans 2.
4.2.1. 1-(Furan-2-yl)-hept-1-yl-hydroperoxide, 2a. Pale
1
yellow oil. H NMR (CDCl3, 400 MHz) l: 0.87 (t, 3H,
J 7.2 Hz), 1.0–1.5 (m, 8H), 1.82 (m, 1H), 1.93 (m, 1H),
4.90 (t, 1H, J 7.2 Hz), 6.37 (bs, 2H), 7.42 (bs, 1H), 8.00
(s 1H). 13C NMR (CDCl3, 100.16 MHz) l: 14.0, 22.5,
25.5, 28.9, 30.7, 31.5, 80.8, 109.0, 110.2, 142.5, 153.1.
IR w (neat, cm−1): 3398, 2936, 2864, 1559, 1470, 1332,
1034, 797. Anal. calcd for C11H18O3: C, 66.64; H, 9.15.
Found: C, 66.76; H, 9.26%.
Figure 1. Ti(IV)/(R)-BINOL=1/2; react. time=4 h.
3. Conclusion
In conclusion two new classes of hydroperoxides, easily
accessible by a simple and inexpensive procedure, have
shown their synthetic utility both as key intermediates
and reagents in asymmetric oxidative processes. In par-
ticular, chiral sulfoxides have been obtained in very
satisfactory yields and e.e.s by stoichiometric or cata-
lytic procedures involving the employment of a sec-
ondary or a tertiary furyl hydroperoxide, respectively,
in the presence of different Ti(IV) chiral complexes.
More interestingly, the unprecedented detection of a
(+)-NLE was pointed out in the asymmetric oxidation
of methyl p-tolyl sulfide catalyzed using a Ti(O-i-Pr)4/
(R)-BINOL/H2O system.
4.2.2. 2-(Furan-2-yl)-prop-2-yl-hydroperoxide, 2b. Pale
yellow oil. 1H NMR (CDCl3, 400 MHz) l: 1.60 (s, 6H),
6.34 (m, 2H), 7.39 (bs, 1H), 7.71 (bs, 1H). 13C NMR
(CDCl3, 100.16 MHz) l: 24.0, 80.4, 108.0, 110.7, 142.7,
156.7. IR w (neat, cm−1): 3300, 2986, 2939, 1575, 1380,
1362, 1276, 1164, 1018, 822. Anal. calcd for C7H10O3:
C, 59.14; H, 7.09. Found: C, 59.22; H, 7.20%.
4.2.3. 1-(5-Methyl-furan-2-yl)-hept-1-yl-hydroperoxide,
2c. Pale yellow oil. 1H NMR (CDCl3, 400 MHz) l: 0.87
(t, 3H, J 6.9 Hz), 1.0–1.5 (m, 8H), 1.81 (m, 1H), 1.91
(m, 1H), 2.30 (s, 3H), 4.83 (t, 1H, J 7.2 Hz), 5.94 (d,
1H, J 02.5 Hz), 6.25 (d, 1H, J 2.5 Hz), 7.81 (s, 1H). 13C
NMR (CDCl3, 100.16 MHz) l: 13.6, 14.0, 22.5, 25.6,
28.9, 30.6, 31.5, 81.0, 106.1, 150.9, 512.4. IR w (neat,
cm−1): 3380, 2921, 2851, 1567, 1468, 1223, 1015, 778.
Anal. calcd for C12H20O3: C, 67.89; H, 9.50. Found: C,
67.70; H, 9.61%.
4. Experimental
4.1. Materials and general methods
CH2Cl2 and toluene were dried over calcium hydride

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A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
4.2.4.
1-(5-Methyl-furan-2-yl)-hex-1-yl-hydroperoxide,
4.3.3.
6-Hydroperoxy-6-methyl-2-i-propyl-2H-pyran-
1
2d. Pale yellow oil. H NMR (CDCl3, 400 MHz) l:
0.87 (t, 3H, J 5.7 Hz), 1.0–1.5 (m, 6H), 1.80 (m, 1H),
1.92 (m, 1H), 2.29 (s, 3H), 4.82 (t, 1H, J 7.2 Hz), 5.94
(d, 1H, J 3.0 Hz), 6.24 (d, 1H, J 3.0 Hz). 13C NMR
(CDCl3, 100.16 MHz) l: 13.5, 13.9, 22.4, 25.3, 30.5,
31.5, 81.0, 106.1, 110.0, 151.0, 152.4. IR w (neat, cm−1):
3396, 2944, 2870, 1560, 1460, 1229, 1024, 789. Anal.
calcd for C11H18O3: C, 66.64; H, 9.15. Found: C, 66.52;
H, 9.07%.
3(6H)-one, 3c. Viscous oil. Mixture of inseparable
diastereoisomers (92/8 ratio). 1H NMR (CDCl3, 400
MHz) l: 0.82 (d, J 6.8 Hz), 0.93 (d, J 6.8 Hz), 1.50 (s),
1.62 (s), 2.34 (m), 4.05 (d, J 6.8 Hz), 1.50 (s), 1.62 (s),
2.34 (m), 4.05 (d, J 2.9 Hz), 4.37 (d, J 3.0 Hz), 6.13 (d,
J 10.1 Hz), 6.68 (d, J 10.1 Hz), 6.90 (d, J 10.3 Hz), 8.87
(s), 9.04 (s). 13C NMR (CDCl3, 100.16 MHz) l: 15.9,
16.48, 18.8, 19.8, 23.1, 29.6, 80.3, 82.0, 100.0, 128.9,
129.9, 144.6, 149.4, 197.1, 201.4. IR w (KBr, cm−1):
3357, 2942, 1677, 1618, 1395, 1078, 861. Anal. calcd for
C9H14O4: C, 58.05; H, 7.58. Found: C, 57.89; H, 7.70%.
4.2.5. 1-(5-Methyl-furan-2-yl)-non-1-yl-hydroperoxide,
2e. Pale yellow oil. 1H NMR (CDCl3, 400 MHz) l: 0.87
(t, 3H, J 7.2 Hz), 1.0–1.5 (m, 12H), 1.77 (m, 1H), 1.90
(m, 1H), 2.26 (s, 3H), 4.79 (t, 1H, J 7.2 Hz), 5.91 (d,
1H, J 3.0 Hz), 6.21 (d, 1H, J 3.0 Hz), 8.35 (s, 1H). 13C
NMR (CDCl3, 100.16 MHz) l: 13.4, 14.0, 22.6, 25.6,
29.1, 29.2, 30.5, 31.7, 80.8, 106.0, 110.0, 151.0. IR w
(neat, cm−1): 3384, 2924, 2855, 1563, 1465, 1222, 1020,
784. Anal. calcd for C14H24O3: C, 69.96; H, 10.07.
Found: C, 70.09; H, 9.97%.
4.3.4. 6-Hydroperoxy-2,2,6-trimethyl-2H-pyran-3(6H)-
one, 3d. Viscous oil. H NMR (CDCl3, 400 MHz) l:
1
1.41 (s, 3H), 1.57 (s, 3H), 1.65 (s, 3H), 6.12 (d, 1H, J
10.2 Hz), 6.71 (d, 1H, J 10.2 Hz), 8.00 (bs). 13C NMR
(CDCl3, 100.16 MHz) l: 24.4, 26.4, 26.9, 79.4, 100.3,
127.1, 144.3, 198.9. IR w (KBr, cm−1): 3340, 2932, 1679,
1625, 1405, 1058, 831. Anal. calcd for C8H12O4: C,
55.81; H, 7.02. Found: C, 55.95; H, 6.90%.
4.3. Standard procedure for the synthesis of 6-hydro-
peroxy-2H-pyran-3(6H)-ones, 3
4.3.5.
2-Ethyl-2-hexyl-6-hydroperoxy-6-methyl-2H-
pyran-3(6H)-one, 3e. Viscous oil. Mixture of insepara-
1
ble diastereoisomers (50/50 ratio). H NMR (CDCl3,
The products 3 were prepared treating a solution of 1 (4
mmol) in DME (20 mL) with 30% aqueous H2O2 (2.0
mL) and PTSA (323 mg, 1.7 mmol). The resulting
mixture was stirred at room temperature for the appro-
priate time (see Table 2). At the end of the reaction, the
mixture was diluted with Et2O (80 mL) and washed
with saturated NaHCO3 solution (2×10 mL) and satu-
rated NaCl solution (3×10 mL) and finally dried over
dry Na2SO4 for a few minutes. After filtration and
evaporation of solvent, the crude product was purified
by flash chromatography (85/15 light petroleum/Et2O)
to afford pure 6-hydroperoxy-2H-pyran-3(6H)-ones 3.
400 MHz) l: 0.79–0.86 (m), 0.95 (t, J 7.5 Hz), 1.20–1.4
(m), 1.64 (s), 1.8–1.9 (m), 6.10 (bd, J 10.2 Hz), 6.67 (d,
J 10.2 Hz), 6.68 (d, J 10.2 Hz), 8.16 (s), 8.21 (s). 13C
NMR (CDCl3, 100.16 MHz) l: 14.0, 22.5, 23.2, 23.3,
24.4, 29.5, 29.6, 29.8, 31.4, 31.6, 36.4, 38.3, 71.8, 85.1,
100.3, 100.4, 128.2, 143.6, 143.8, 198.6. IR w (KBr,
cm−1): 3390, 2972, 1680, 1625, 1387, 1075, 882. Anal.
calcd for C14H24O4: C, 65.60; H, 9.44. Found: C, 65.71;
H, 9.55%.
4.3.6. 6-Hydroperoxy-2-octyl-6-methyl-2H-pyran-3(6H)-
one, 3f. Viscous oil. Mixture of inseparable
diastereoisomers (94/6 ratio). 1H NMR (CDCl3, 400
MHz) l: 0.86 (m), 1.24 (m), 1.38 (m), 1.55 (s), 1.63 (s),
1.88 (m), 4.20 (dd, J1 7.0 Hz, J2 4.0 Hz), 4.52 (dd, J1 7.0
Hz, J2 4.0 Hz), 6.13 (d, J 10.1 Hz), 6.69 (d, J 10.1 Hz),
6.89 (d, J 10.3 Hz), 8.72 (bs), 8.80 (bs). 13C NMR
(CDCl3, 100.16 MHz) l: 14.7, 21.1, 23.2, 23.8, 24.7,
25.1, 25.4, 25.8, 26.2, 29.8, 30.0, 30.1, 30.8, 32.0, 32.4,
76.6, 78.8, 100.8, 102.7, 129.2, 129.9, 145.1, 149.1,
196.7, 197.5. IR w (cm−1): 3342, 2922, 1673, 1628, 1389,
1089, 852. Anal. calcd for C14H24O4: C, 65.60; H, 9.44.
Found: C, 65.41; H, 9.58%.
4.3.1.
2-Hexyl-6-hydroperoxy-6-methyl-2H-pyran-
3(6H)-one, 3a. Viscous oil. Mixture of inseparable
1
diastereoisomers (90/10 ratio). H NMR (CDCl3, 400
MHz) l: 0.87 (m), 1.30 (m), 1.41 (m), 1.57 (s), 1.66 (s),
1.73 (m) 1.92 (m), 4.20 (dd, J1 7.6 Hz, J2 3.9 Hz), 4.50
(dd, J1 7.6 Hz, J2 3.9 Hz), 6.15 (d, J 10.1 Hz), 6.16 (d,
J 10.4 Hz), 6.68 (d, J 10.1 Hz), 6.89 (d, J 10.4 Hz), 7.90
(bs), 8.40 (bs). 13C NMR (CDCl3, 100.16 MHz) l: 14.1,
20.5, 22.6, 23.2, 42.8, 29.0, 30.0, 31.4, 31.7, 73.1, 75.9,
78.2, 128.8, 129.5, 143.8, 148.0, 196.0, 201.0. IR w (KBr,
cm−1): 3347, 2932, 1670, 1630, 1380, 1095, 842. Anal.
calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.01;
H, 8.95%.
4.4. Standard procedure for stoichiometric asymmetric
sulfoxidation
4.3.2. 2-Cyclohexyl-6-hydroperoxy-6-methyl-2H-pyran-
3(6H)-one, 3b. Viscous oil. Mixture of inseparable
diastereoisomers (93/7 ratio). 1H NMR (CDCl3, 400
MHz) l: 1.0–1.4 (m), 1.5–1.75 (m), 2.06 (m), 4.03 (d, J
3.0 Hz), 4.33 (d, J 2.1 Hz), 6.14 (d, J 10.1 Hz), 6.67 (d,
J 10.1 Hz), 6.92 (d, J 10.1 Hz), 8.54 (bs), 8.82 (bs). 13C
NMR (CDCl3, 100.16 MHz) l: 23.1, 26.0, 26.4, 29.1,
39.3, 80.2, 100.1, 129.0, 129.8, 144.3, 149.1, 196.9,
201.1. IR w (KBr, cm−1): 3340, 2919, 1675, 1620, 1380,
1085, 859. Anal. calcd for C12H18O4: C, 63.70; H, 8.02.
Found: C, 63.53; H, 7.90%.
A solution of titanium tetraisopropoxide (0.142 g, 0.50
mmol), (R,R)-diethyl tartrate (0.415 g, 2.0 mmol) and
sulfide (0.50 mmol) in dry CH2Cl2 (3.2 mL) under an
argon atmosphere was stirred at room temperature for
5 min. Then the temperature was cooled to −20°C and
after 20 min a solution of hydroperoxide 2 or 3 (1.25
mmol in 3.2 mL of dry CH2Cl2) was slowly added.
After the appropriate reaction time, water (2 mL) was
added and the solution was stirred for about 1 h. Then
the resulting gel was recovered with ethyl acetate (20
mL) and filtered on a short pad of SiO2. After remov-

A. Massa et al. / Tetrahedron: Asymmetry 13 (2002) 1277–1283
1283
ing the solvent under reduced pressure, the crude oil
was purified by silica gel flash chromatography (eluent
starting from Et2O to a mixture 1/1 Et2O/ethyl acetate)
to afford the pure sulfoxide.
S.; Matsubara, J.; Otsubo, K.; Kitano, K.; Ohatani, T.;
Kawano, Y.; Uchida, M. Tetrahedron: Asymmetry 1997,
8, 3707.
2. (a) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717; (b)
Solladie´, G. Synthesis 1981, 185; (c) Andersen, K. K. In
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Chichester, UK, 1988; Chapter 3, pp. 53–94; (d) Posner,
G. H. In The Chemistry of Sulfones and Sulfoxides; Patai,
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3. Pitchen, P.; Dun˜ach, E.; Deshmukh, M. N.; Kagan, H. B.
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4.5. Standard procedure for stoichiometric kinetic
resolution
The above reported procedure for stoichiometric sul-
foxidation was used with the substitution of sulfide with
racemic methyl p-tolyl sulfoxide (0.50 mmol).
4.6. Standard procedure for catalytic asymmetric
sulfoxidation
4. Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984,
325.
A solution of (R)-(+)-binaphthol (14 mg, 0.050 mmol
or 28 mg, 0.10 mmol), in dry toluene (5.2 mL) at room
temperature under an argon atmosphere was treated by
dropwise addition (via syringe) of titanium tetra-
isopropoxide (14.2 mg, 0.050 mmol) and H2O (18 mg,
1.0 mmol). After stirring for 1 h, the sulfide (0.50
mmol) was added and then the mixture was cooled to
0°C. After 30 min a solution of hydroperoxide (2b, 2c
or 2e, 1.0 mmol) in dry toluene (2.3 mL), was slowly
added and the mixture was stirred for the appropriate
reaction time. The reaction mixture was filtered
through a short pad of silica gel and the product eluted
with ethyl acetate. After removing the solvent under
reduced pressure, the crude oil was purified by flash
chromatography on silica gel (eluent starting from Et2O
to a mixture 1/1 Et2O/ethyl acetate) to afford the pure
sulfoxide.
5. (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S.
J. Org. Chem. 1993, 58, 4529–4533; (b) Bolm, C.;
Dabard, D. A. G. Synlett 1999, 360–362; (c) Martyn, L.
J. P.; Pandiaraju, S.; Yudin, A. K. J. Organomet. Chem.
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Org. Chem. 1997, 62, 8560–8564.
7. Di Furia, F.; Licini, G.; Modena, G.; Metterle, R.;
Nugent, W. A. J. Org. Chem. 1996, 61, 5175.
8. Lattanzi, A.; Bonadies, F.; Scettri, A. Tetrahedron:
Asymmetry 1997, 8, 2141.
9. (a) Lattanzi, A.; Bonadies, F.; Senatore, A.; Soriente, A.;
Scettri, A. Tetrahedron: Asymmetry 1997, 8, 2473–2478;
(b) Palombi, L.; Bonadies, F.; Pazienza, A.; Scettri, A.
Tetrahedron: Asymmetry 1998, 9, 1817.
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Chemistry; Academic Press: New York, 1966; Vol. 7, pp.
438–441.
4.7. Standard procedure for catalytic kinetic resolution
11. (a) Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron
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Tetrahedron 1977, 83, 69.
The above reported procedure for catalytic sulfoxida-
tion was used with the substitution of sulfide with
racemic methyl p-tolyl sulfoxide (0.50 mmol).
12. Ho, T. L.; Sapp, S. G. Synth. Commun. 1983, 13, 207.
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Acknowledgements
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The authors wish to thank MIUR and CNR for finan-
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