Catalytic asymmetric oxidation of aryl sulfides with a Ti/H2O/(R,R)- diphenylethane-1,2-diol complex: A versatile and highly enantioselective oxidation protocol

Article abstract of DOI:10.1021/jo981346j

A new catalytic procedure for the asymmetric oxidation of aryl alkyl and aryl benzyl sulfides to optically active sulfoxides by hydroperoxides is described. This oxidation of sulfides is mediated by a chiral Ti complex formed in situ by reacting Ti(i-PrO)₄, (R,R)-diphenylethane-1,2-diol (1), and water. The conditions of the reaction (stoichiometric composition of the catalyst, temperature, and the presence of additives and solvent) have been determined in order to reach the highest enantioselectivity and avoid the intervention of a kinetic resolution process. The oxidation protocol described herein is quite versatile as the values of chemical yields (60- 73%) and of enantioselectivity (ee 70-80%) achieved for aryl alkyl sulfides are almost independent of the nature of the aryl substituent and of the size of the alkyl group. Notably, aryl benzyl sulfides, which are poor substrates for the Ti/DET catalyzed oxidations, afforded very high ee's (92-99%) with this oxidation system.

Full text of DOI:10.1021/jo981346j

9392
J . Org. Chem. 1998, 63, 9392-9395
Ca ta lytic Asym m etr ic Oxid a tion of Ar yl Su lfid es w ith a Ti/H2O/
(R,R)-Dip h en yleth a n e-1,2-d iol Com p lex: a Ver sa tile a n d High ly
En a n tioselective Oxid a tion P r otocol
Maria Irene Donnoli, Stefano Superchi, and Carlo Rosini*
Dipartimento di Chimica, Universita` della Basilicata, via Nazario Sauro 85, 85100 Potenza, Italy
Received J uly 10, 1998
A new catalytic procedure for the asymmetric oxidation of aryl alkyl and aryl benzyl sulfides to
optically active sulfoxides by hydroperoxides is described. This oxidation of sulfides is mediated
by a chiral Ti complex formed in situ by reacting Ti(i-PrO)4, (R,R)-diphenylethane-1,2-diol (1), and
water. The conditions of the reaction (stoichiometric composition of the catalyst, temperature, and
the presence of additives and solvent) have been determined in order to reach the highest
enantioselectivity and avoid the intervention of a kinetic resolution process. The oxidation protocol
described herein is quite versatile as the values of chemical yields (60-73%) and of enantioselectivity
(ee 70-80%) achieved for aryl alkyl sulfides are almost independent of the nature of the aryl
substituent and of the size of the alkyl group. Notably, aryl benzyl sulfides, which are poor
substrates for the Ti/DET catalyzed oxidations, afforded very high ee’s (92-99%) with this oxidation
system.
In tr od u ction
as a common feature the formation in situ of a catalytic
precursor by reaction of Ti(i-PrO)4 with chiral dihydroxyl
ligands such as (R,R)-diethyl tartrate (DET),6a,b 2,2′-
dihydroxy-1,1′-binaphthyl,6c trialkanolamines,6d and simple
1,2-diols.6e,f These catalytic procedures, however, present
some limitations; in fact, the Kagan method6a,b requires
0.1 equiv of Ti(i-PrO)4 and 0.4 equiv of DET with respect
to the sulfide and hence cannot be considered as truly
catalytic. In addition, in most of the catalytic procedures
reported, the high ee’s obtained are mainly due to a
kinetic resolution process7 (i.e., the two enantiomers of
the sulfoxide are oxidized to sulfone by the chiral reagent
at different rates) with detriment to the chemical yields.
We preliminarily described6e a different oxidation system
based on a catalyst formed in situ by reacting Ti(i-PrO)4,
enantiopure 1,2-diphenylethane-1,2-diol (1), and water
(Scheme 1), aimed at inducing enantioselectivity only in
the formation of the sulfoxides and making negligible the
kinetic resolution. In this paper we will discuss in detail
the efficiency of our oxidation method, by analyzing the
dependence of ee and chemical yield on the reaction
conditions, on the composition of the catalyst, and on the
structure of the substrate.
In the past few years, the synthesis of optically active
sulfoxides through asymmetric oxidation of prochiral
sulfides1 has constituted a very active research area,
owing to the relevance of enantiopure sulfoxides as chiral
auxiliaries,2 synthetic intermediates, and bioactive com-
pounds.3 In the most widely studied procedure, the
oxidation is performed by achiral hydroperoxides in the
presence of stoichiometric amounts of chiral Ti(IV)
complexes4 and, very recently, the use of chiral hydro-
peroxides with achiral Ti species has been reported as
well.5 Several appealing asymmetric catalytic processes
also have been described in the literature,6 all showing
* To whom correspondence should be addressed: (fax, +39-0971-
474223; tel, +39-0971-474241; e-mail, rosini@unibas.it).
(1) Kagan, H. B. Asymmetric Oxidation of Sulfides. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 203-
226.
(2) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717. Solladie´, G. Synthesis
1981, 185. Andersen, K. K. In The Chemistry of Sulfones and
Sulfoxides; Patai, S., Rappoport, Z., Stirling, C. J . M., Eds.; J ohn Wiley
& Sons, Ltd.: Chichester, England, 1988; Chapter 3, pp 53-94. Posner,
G. H. In The Chemistry of Sulfones and Sulfoxides; Patai, S., Rap-
poport, Z., Stirling, C. J . M., Eds.; J ohn Wiley & Sons, Ltd.: Chichester,
England, 1988; Chapter 16, pp 823-849.
(3) (a) RP 73163: Pitchen, P. Chem. Ind. 1994, Aug 15, 636. (b)
P a n top r a zole: Tanaka, M.; Yamazaki, H.; Hakasui, H.; Nakamichi,
N.; Sekino, H. Chirality 1997, 9, 17. (c) Om ep r a zole: von Unge, S.;
Langer, V.; Sjo¨lin, L. Tetrahedron: Asymmetry 1997, 8, 1967. (d)
Su lfor a fa n e: Holland, H. L.; Brown, F. M.; Larsen, B. G. Tetrahe-
dron: Asymmetry 1994, 5, 1129. (e) Ustiloxin e: Hutton, C. A.; White,
J . M. Tetrahedron Lett. 1997, 38, 1643. (f) OP C-29030: Morita, S.;
Matsubara, J .; Otsubo, K.; Kitano, K.; Ohtani, T.; Kawano, Y.; Uchida,
M. Tetrahedron: Asymmetry 1997, 8, 3707. (g) Meth ion in e Su lfox-
id e: Holland, H. L.; Brown, F. M. Tetrahedron: Asymmetry 1998, 9,
535.
Resu lts a n d Discu ssion
As briefly discussed in the Introduction, the main
target of the present investigation was to set up a method
for the asymmetric catalytic oxidation of sulfides devoid
of kinetic resolution, in order to keep both the enanti-
oselectivity and the chemical yield of the overall process
(4) (a) Pitchen, P.; Dun˜ach, E.; Deshmukh, M. N.; Kagan, H. B. J .
Am. Chem. Soc. 1984, 106, 8188. (b) Zhao, S.; Samuel, O.; Kagan, H.
B. Tetrahedron 1987, 43, 5135. (c) Kagan, H. B.; Rebiere, F. Synlett
1990, 643. (d) Brunel, J .-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J .
Org. Chem. 1995, 60, 8086. (e) Di Furia, F.; Modena, G.; Seraglia, G.
Synthesis 1984, 325. (f) Yamamoto, K.; Ando, H.; Shuetake, T.;
Chikamatsu, H. J . Chem. Soc., Chem. Commun. 1989, 754.
(5) (a) Adam, W.; Korb, M. N.; Roschmann, K. J .; Saha-Mo¨ller, C.
J . Org. Chem. 1998, 63, 3423. (b) Hamann, H.-J .; Ho¨ft, E.; Mostowicz,
D.; Mishnev, A.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahe-
dron 1997, 53, 185.
(6) (a) Brunel, J .-M.; Kagan, H. B. Synlett 1996, 404. (b) Brunel,
J .-M.; Kagan, H. B. Bull. Soc. Chim. Fr. 1996, 133, 1109. (c) Komatsu,
N.; Hashizume, M.; Sugita, T.; Uemura, S. J . Org. Chem. 1993, 58,
4529. (d) Di Furia, F.; Licini, G.; Modena, G.; Motterle, R.; Nugent,
W. A. J . Org. Chem. 1996, 61, 5175. (e) Superchi, S.; Rosini, C.
Tetrahedron: Asymmetry 1997, 8, 349. (f) Yamanoi, Y.; Imamoto, T.
J . Org. Chem. 1997, 62, 8560.
(7) (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J . Org.
Chem. 1993, 58, 7624. (b) Lattanzi, A.; Bonadies, F.; Senatore, A.;
Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 1997, 8, 2473.
10.1021/jo981346j CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/14/1998

Asymmetric Oxidation of Aryl Sulfides
J . Org. Chem., Vol. 63, No. 25, 1998 9393
Sch em e 1
with those in CCl4. More detailed investigations on the
nature and activity of both the solution and the solid
phase are now in progress.
We then investigated if a kinetic resolution process was
present under our reaction conditions: to this end,
racemic p-tolyl methyl sulfoxide (3a ) was reacted under
the standard conditions using (R,R)-1 as chiral ligand,
and a time profile of the amount of sulfoxide 3a and of
sulfone, as well as the ee of the sulfoxide was plotted
(Figure 1). We can observe from the plot that the kinetic
resolution process leads to significant levels of sulfoxide
ee (30%) only for very long reaction times and at high
levels of conversion. This means that the efficiency of
the kinetic resolution is low (a selectivity factor9 S )
1.5-2 can be calculated) and that, in the short reaction
times employed under our standard conditions (≈2 h),
its effect is negligible.
Once the best reaction conditions were set up in terms
of both chemical yield and enantioselectivity, it was
important to evaluate the scope and limitations of this
method. To this end, several aryl alkyl and benzyl
sulfides (compounds 2-13, Table 3), differing in the
nature of the Ar and R groups, were prepared using
standard procedures10 and then submitted to the action
of our oxidation system, obtaining the corresponding
sulfoxides 2a -13a . The results of such reactions are
collected in Table 3.
Compounds 2a -12a have been already reported in
optically active form,4a,6b,11 so the absolute configuration
of the samples in our hands has been assigned on the
basis of their [R]D values (Table 3, entries 1-11). To the
best of our knowledge, the absolute configuration of
p-anisyl benzyl sulfoxide (13a ) (entry 12) is unknown,
so it was necessary to compare its CD spectrum (350-
200 nm range) with that of the known (R)-(+)-p-tolyl
benzyl sulfoxide (11a ).12 The CD spectrum of our sample
of (-)-13a shows a negative Cotton effect at 252 nm
followed by a positive Cotton effect at 230 nm, while the
CD spectrum of (R)-(+)-11a shows13 bands of opposite
sign at the same frequencies. This indicates that the
levorotatory sample in our hands has the S absolute
configuration. The ee’s of our samples have been deter-
mined by HPLC analysis upon the chiral stationary
phases Chiralcel OB and OJ , using hexane/i-PrOH
mixtures as mobile phases. The racemic sulfoxides
necessary to test the products’ separation were prepared
by standard procedures.14
at high levels. In our preliminary study6e we optimized
the reaction conditions (temperature, reaction time, and
amount of catalyst and oxidant). Moreover, we observed
that extending the reaction time for more than 2 h
resulted in an increase in the amount of sulfone without
raising either the yield or the ee of the sulfoxide. This
was due to an inactivation process of the catalyst
determined by decomposition of the diol6e and/or com-
plexation of the titanium center by the sulfoxide.4a,5a The
complexation at titanium can also promote the further
oxidation of sulfoxide to sulfone.8 We then found that
the best compromise to limit the sulfone formation and
to have satisfactory conversion and good ee’s was achieved
using the reagent ratio sulfide:(R,R)-1:Ti:H2O ) 1:0.1:
0.05:1.0 with 2 equiv of TBHP 70% in water as oxidant
and performing the reaction at 0 °C in CCl4 under N2
atmosphere. These optimized reaction conditions, here-
after named as standard, were then used as the basis
for the following investigations.
The effect of the composition of the catalytic precursor
and the presence of additives was then studied in the
oxidation of p-tolyl methyl sulfide (3) (Table 1). The use
of anhydrous TBHP (entry 2) led to a similar chemical
yield and to a slightly lower ee with respect to the levels
obtained with the standard conditions (entry 1). Chang-
ing the Ti:diol ratio from 1:2 (standard condition) to 1:1
reduced both the chemical yield and the enantioselectiv-
ity, which dropped to 18% ee (entry 3). The addition of
molecular sieves and 2-propanol as additives, which were
beneficial under the Kagan conditions,6a,b proved to be
detrimental in our hands, because both in CCl4 and in
CH2Cl2 we obtained a reduced yield and a lower enan-
tiomeric excess of sulfoxide, with significant formation
of sulfone (entries 4 and 5).
Good chemical yields of isolated products, in the 60-
80% range, were obtained for all cases, with these being
almost independent of the structure of the sulfide.
Furthermore, the use of (R,R)-1 as ligand always induced
the formation of sulfoxides having the S absolute con-
figuration, thus indicating that the same mechanism
seems to be operative independently of the structure of
the substrate. This behavior parallels what is observed
In Table 2, the results of a systematic change of the
solvent are reported: the highest ee’s were obtained in
CCl4 (entry 4) and toluene (entry 5), while CH2Cl2 (entry
3) and ethereal solvents (entries 1, 2) reduced both the
chemical yield and the ee of the sulfoxide. In hexane, a
white solid precipitated when water was added to the
reaction mixture, while all other solvents tested gave rise
to homogeneous mixtures. The chemical yields and the
enantioselectivities (entry 6) were, however, comparable
(9) Kagan, H. B.; Fiaud, J . C. Top. Stereochem. 1988, 18, 249.
(10) Ipatieff, V. N.; Pines, H.; Friedmann, B. S. J . Am. Chem. Soc.
1938, 60, 2731.
(11) (a) Sakuraba, H.; Natori, K.; Tanaka, Y. J . Org. Chem. 1991,
56, 4124. (b) Sugimoto, T.; Kokubo, T.; Miyazaki, J .; Tanimoto, S.;
Okano, M. J . Chem. Soc., Chem. Commun. 1979, 402.
(12) The assignment of absolute configuration of sulfoxides via
analysis of CD spectra has already been reported: Sagae, T.; Ogawa,
S.; Furukawa, N. Bull. Chem. Soc. J pn. 1991, 64, 3179.
(13) Saeva, F. D.; Rayner, D. R.; Mislow, K. J . Am. Chem. Soc. 1968,
90, 4176.
(8) Some exploratory runs showed that diol 1 slowly decomposes in
the presence of Ti(i-PrO)4, while a partial decomposition to benzalde-
hyde results after further addition of TBHP. Moreover, we observed
that TBHP alone does not oxidize the sulfoxide while it promotes a
slow oxidation of the sulfide.
(14) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.

9394 J . Org. Chem., Vol. 63, No. 25, 1998
Donnoli et al.
Ta ble 1. En a n tioselective Oxid a tion of p-Tolyl Meth yl Su lfid e: Effect of Ca ta lyst Com p osition a n d Ad d itives
entry
conditions:a sulfide/(R,R)-1/Ti
solvent
additive (equiv)
H2O (1.0)
H2O (1.0)
H2O (1.0)
i-PrOH (0.2) + 4 Å MS
i-PrOH(0.2) + 4 Å MS
oxidant (equiv)
sulfoxide (%)b
eec (%) (ac)d
1
2
3
4
5
1/0.1/0.05
1/0.1/0.05
1/0.05/0.05
1/0.1/0.05
1/0.1/0.05
CCl4
CCl4
CCl4
CH2Cl2
CCl4
TBHP (2.0)e
TBHP (2.0)f
TBHP (2.0)e
CHP (2.0)g
CHP (2.0)g
62 (8)
63 (7)
50 (12)
45 (32)
30 (26)
80 (S)
60 (S)
18 (S)
20 (S)
24 (S)
a
b
Under N2 atmosphere, reaction time 2 h. Isolated yields, in parentheses sulfone (%). c Determined by HPLC on a Daicel Chiralcel
OB column. Absolute configuration (ac) determined by comparison of [R]D with literature values; see ref 4a. e TBHP 70% in water.
d
f TBHP 5-6 M in decane. CHP 80% in cumylic alcohol.
g
Ta ble 2. En a n tioselective Oxid a tion of p-Tolyl Meth yl
can heavily affect the stereochemical outcome of a Ti-
catalyzed asymmetric sulfoxidation.15 It is noteworthy
that our system is almost unaffected also by the size of
the alkyl R group on the sulfur. In fact, high ee’s have
been obtained with both ethyl (ee 70%) and n-butyl (ee
80%) substituted sulfides (entries 7, 8), the latter being
the highest ee obtained so far in the Ti-catalyzed enan-
tioselective oxidation of aryl butyl sulfides. Only the
presence of a branched and sterically demanding alkyl
substituent, like the isopropyl moiety in 10 (entry 9), led
to a significant drop of the enantioselectivity.
In summary, the present oxidation protocol looks quite
versatile because the chemical and stereochemical out-
comes are only slightly dependent on the nature of the
Ar and R groups of the sulfides. On the contrary, the
diethyltartrate6a,b and binaphthol-based6c catalysts are
effective only on sulfides having small R groups, while
the trialkanolamine reagent6d is sensitive to the nature
of the Ar substituents. Finally, it is important to point
out that aryl benzyl sulfides 11-13, oxidized with the
Ti/DET complex in very low ee,4a were, on the contrary,
transformed to the corresponding sulfoxides with almost
complete stereoselectivity (ee 92-99%) by the oxidation
system described herein. Taking into account the pres-
ence of several benzene rings, both on the substrate and
on the catalyst, it is tempting to ascribe to π-π interac-
tions16 the main cause of such a selectivity.17 In addition,
the high enantioselectivity that is achievable for aryl
benzyl sulfides is very promising with regard to the
synthesis of chiral bioactive sulfoxides.3 As a matter of
fact, several of these sulfoxides have an aryl(heteroaryl)
benzyl structure, and their preparation through the
enantioselective oxidation of the corresponding sulfides
could be particularly appealing.
Su lfid e: Effect of Solven ta
entry
solvent
sulfoxide (%)b
eec (%) (ac)d
1
2
3
4
5
6
THF
Et2O
CH2Cl2
CCl4
toluene
hexane
56 (5)
50 (18)
74 (4)
62 (8)
70 (9)
55 (3)
16 (S)
36 (S)
54 (S)
80 (S)
70 (S)
80 (S)
a
Conditions: sulfide/(R,R)-1/Ti(i-PrO)4/H2O ) 1.0/0.1/0.05/1.0
at 0 °C under N2 atmosphere, reaction time 2 h, 2 equiv of 70%
TBHP in water as oxidant. b Isolated yields, in parentheses sulfone
(%). c Determined by HPLC on a Daicel Chiralcel OB column.
d
Absolute configuration (ac) determined by comparison of [R]D
with literature values; see ref 4a.
F igu r e 1. Time profile of the oxidation of racemic sulfoxide
3a under the standard conditions. (Study of the intervention
of kinetic resolution.)
in sulfoxidation with Ti/DET complexes, where (R,R)-
DET, having absolute configuration opposite to that of
(R,R)-1, induces the formation of R sulfoxides. Surpris-
ingly, the similar diol (3S,4S)-2,2,5,5-tetramethyl-3,4-
hexanediol induces the formation of S sulfoxides.6f Re-
markably, only negligible amounts of sulfone were formed
in all the entries, confirming that the enantioselectivity
obtained was completely induced during the sulfide
oxidation process and not due to a concomitant kinetic
resolution. By changing the aromatic substituents in aryl
methyl sulfides, we showed that our oxidation system is
almost unaffected by the nature of the aryl moiety.
Sulfides with electron-donating groups (entries 2-4) on
the phenyl ring, as well as those with a larger naphthyl
ring, were oxidized affording ee’s in the 70-80% range.
The lower ee obtained in the case of p-NO2-substituted
sulfide 6 (entry 5) could be attributed either to the strong
electron-withdrawing power or, even more reasonably,
to the coordinating capability of the nitro group, which
can effect a change of the reaction mechanism and then
a reduction of the enantioselectivity. Recently it has been
shown that the presence of nitro groups on the ligand
Con clu sion s
We have herein described the catalytic asymmetric
oxidation of aryl sulfides with TBHP mediated by 0.05
equiv of a chiral Ti complex formed in situ by reacting
Ti(i-PrO)4, (R,R)-1, and water. In this way, optically
active sulfoxides are obtained in good yields (60-75%)
and good to high ee’s (up to 99%).
It is important to point out that even compounds such
as p-substituted phenyl benzyl sulfides, which afford low
(15) Reetz, M. T.; Merk, C.; Naberfeld, G.; Rudolph, J .; Griebenow,
N.; Goddard, R. Tetrahedron Lett. 1997, 38, 5273.
(16) The importance of π-π interaction in asymmetric synthesis has
been recently pointed out: J ones, G. B.; Chapman, B. J . Synthesis
1995, 475. For a recent discussion about the arene-arene interactions
see: Hunter, C. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1585.
Hunter, C. A. Chem. Soc. Rev. 1994, 101. Cozzi, F.; Siegel, J . S. Pure
Appl. Chem. 1995, 67, 1995.
(17) It is interesting to point out that also in Ti-trialkanolamine
catalyzed oxidations, (see ref 6d) the highest enantioselectivity (ee 84%)
is achieved when phenyl benzyl sulfide is oxidized with the (R,R,R)-
tris(2-hydroxy-2-phenylethyl)amine complex, i.e., with a ligand bearing
phenyl groups.

Asymmetric Oxidation of Aryl Sulfides
J . Org. Chem., Vol. 63, No. 25, 1998 9395
Ta ble 3. En a n tioselective Oxid a tion of Su lfid es 2-13
(Ar SR)a
mercially available tert-butyl hydroperoxide (TBHP) (70% in
water and 5-6.0 M in decane) and cumyl hydroperoxide (CHP)
(80% in cumyl alcohol) were purchased (Aldrich) and used
without further purification. Phenyl methyl sulfide (2), p-tolyl
methyl sulfide (3) and phenyl benzyl sulfide (11) were used
as purchased (Aldrich); p-nitrophenyl methyl sulfide (6) (Al-
drich) was recrystallized from hexane prior to use. The other
aryl alkyl sulfides were prepared from the corresponding thiols
according to literature procedure.10 Enantiomerically pure
(R,R)-1,2-diphenylethane-1,2-diol (1) was prepared by asym-
metric dihydroxylation19 of (E)-stilbene. Racemic sulfoxides
were prepared by oxidation of the corresponding sulfides with
0.5 M KIO4 according to a literature procedure.14 The identity
of sulfones was established by 1H NMR and GLC-MS when
their amounts were sufficient for isolation; otherwise, traces
of sulfone were directly detected by GLC-MS of the crude
mixture. Analytical and preparative TLC were performed on
Merck 60 F-254 silica gel plates (0.2 mm and 2.0 mm,
respectively), and column chromatography was carried out
with Merck 60 silica gel (80-230 mesh).
Sta n d a r d P r oced u r e for Ca ta lytic Oxid a tion of Su l-
fid es. To a suspension of (R,R)-1 (34.3 mg, 0.16 mmol) in CCl4
(5 mL) were added dropwise in sequence Ti(i-PrO)4 (23.6 µL,
0.08 mmol) and H2O (28.8 µL, 1.6 mmol). To the resulting
homogeneous solution was added phenyl methyl sulfide (2)
(189 µL, 1.61 mmol), and the mixture was stirred at room
temperature for 15 min. The solution was then cooled at 0
°C, and TBHP (70% in water, 440 µL, 3.22 mmol) was added.
The mixture was stirred at 0 °C for 2 h, then diluted with CH2-
Cl2, and dried over Na2SO4 for a few minutes. After filtration
and evaporation of solvent, the residue was immediately
purified by preparative TLC (Et2O as eluent) or column
chromatography (EtOAc) isolating the phenyl methyl sulfoxide
(2a ) in 63% yield and phenyl methyl sulfone in 8% yield. The
spectral data of the sulfoxides 2a -12a matched those
reported.4a,6b,11 The ee of sulfoxides 2a -10a was determined
by HPLC on a Daicel Chiralcel OB column (λ 254 nm;
n-hexane:i-PrOH ) 80:20; flow ) 0.8 mL/min for 2a , 3a , 4a ;
flow ) 0.5 mL/min for 5a , 7a ; flow ) 1.0 mL/min for 6a , 10a ;
n-hexane:i-PrOH ) 90:10; flow ) 1.0 mL/min for 8a , 9a ) and
the ee of sulfoxides 11a -13a on a Daicel Chiralcel OJ column
(λ 254 nm; n-hexane:i-PrOH ) 80:20; flow ) 0.8 mL/min for
11a ; flow ) 1.0 mL/min for 12a , 13a ). In all cases the S
enantiomer eluted first.
entry sulfide
Ar
R
sulfoxide (%)b eec (%) (ac)d
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7
8
9
10
11
12
13
Ph
p-MeC6H4
p-MeOC6H4 Me
p-BrC6H4 Me
p-NO2C6H4 Me
2-naphthyl Me
Me
Me
63
62
55
58
74
65
71
69
60
73
65
60
80 (S)
80 (S)
69 (S)
67 (S)
44 (S)
73 (S)
70 (S)
80 (S)
22 (S)
>99e (S)
98e (S)
92e (S)
Ph
Et
Ph
Ph
n-Bu
i-Pr
10
11
12
Ph
p-MeC6H4
PhCH2
PhCH2
p-MeOC6H4 PhCH2
a
Conditions: sulfide/(R,R)-1/Ti(i-PrO)4/H2O ) 1.0/0.1/0.05/1.0
in CCl4 at 0 °C under N2 atmosphere, reaction time 2 h, 2 equiv
b
of 70% TBHP in water as oxidant. Isolated yields, amount of
sulfone < 10%. c Determined by HPLC on a Daicel Chiralcel OB
d
column. Absolute configuration (ac) determined by comparison
of [R]D with literature values; see refs 4a,d, 11. e Determined by
HPLC on a Daicel Chiralcel OJ column.
ee’s in both chemical Ti-catalyzed4a and enzymatic18
sulfoxidation procedures, are oxidized with high or
complete stereoselectivity. This aspect has important
practical (synthesis of bioactive sulfoxides having an aryl
benzyl structure) and theoretical (understanding of the
interaction which determines the stereoselectivity) con-
sequences. Furthermore, the chiral inducer (R,R)-1 is
easily available in both enantiomeric forms via Sharpless
asymmetric dihydroxylation19 of (E)-stilbene. This means
that the present approach can be further developed
considering that many other different 1,2-diarylethane-
1,2-diols can become easily available through dihydroxy-
lation of the corresponding (E)-1,2-diarylethenes. This
could allow the study of the effects of both the steric and
electronic properties of the ligand on the chemical and
stereochemical outcomes of the reaction. This could
further improve the chemical yields and the ee and help
to define the stereochemical aspects of the reaction
mechanism. Studies in this direction are now in progress.
(S)-(-)-p-An isyl Ben zyl Su lfoxid e (13a ). Oxidation of
p-anisyl benzyl sulfide (13) by the standard procedure afforded,
after purification, 148 mg of 13a (60% yield) as a white solid:
Exp er im en ta l Section
1
ee ) 92%; mp 130-132 °C; H NMR δ 3.85 (s, 3H), 3.98 (d, J
Gen er a l P r oced u r es. Melting points are uncorrected. 1H
NMR (300 MHz) spectra were recorded in CDCl3. Toluene,
Et2O, and THF were freshly distilled over sodium benzophe-
none ketyl under a nitrogen atmosphere prior to their use. CCl4
and CH2Cl2 were distilled from CaH2 and P2O5, respectively,
and stored over activated 4 Å molecular sieves. Ti(i-PrO)4 was
distilled under a nitrogen atmosphere prior to use. Com-
) 12.4 Hz, 1H), 4.12 (d, J ) 12.4 Hz, 1H), 6.96 (m, 4H), 7.30
(m, 5H); IR (KBr) 1035 (SdO) cm-1; [R]D ) -47.1 (c ) 1.03,
acetone).
Ack n ow led gm en t . This investigation has been
financially supported by Universita` della Basilicata,
Potenza (“Fondi di Ateneo”), Ministero della Ricerca
Scientifica e Tecnologica, Roma, and Consiglio Nazio-
nale delle Ricerche, Roma.
(18) Holland, L. H. Chem. Rev. 1988, 88, 473.
(19) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
J O981346J