Activation of H2O2 by chiral confined Bronsted acids: A highly enantioselective catalytic sulfoxidation

Article abstract of DOI:10.1021/ja3035637

Confined chiral Bronsted acids are shown to catalyze asymmetric oxidations of sulfides to sulfoxides with hydrogen peroxide. The wide generality and high enantioselectivity of the developed method compare even to the best metal-based systems and suggest utility in other asymmetric oxidations.

Full text of DOI:10.1021/ja3035637

Communication
pubs.acs.org/JACS
Activation of H2O2 by Chiral Confined Brønsted Acids: A Highly
Enantioselective Catalytic Sulfoxidation
̌
Saihu Liao, Ilija Coric, Qinggang Wang, and Benjamin List*
́
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
catalysts for the oxidation of sulfides were reported in 1984 by
the groups of Kagan10 and Modena,11 who used modified
Sharpless epoxidation catalysts, several elegant metal-based
asymmetric sulfoxidation reactions have been developed.12−14
Challenges to such methods include attainment of broad
substrate scope and elimination of potential product con-
tamination with sulfone overoxidation byproduct or residual
metal impurities.15 Among metal-free methods, high enantio-
selectivity has been achieved with chiral imine or oxaziridine
reagents and catalysts,16 but these systems are less general.6,17
In view of the importance of optically pure sulfoxides, a general,
metal-free, and highly enantioselective catalytic sulfoxidation
reaction is highly desirable.
In accordance with our concept in eq 1, we initially
investigated asymmetric sulfoxidation reactions with BINOL-
derived phosphoric acid catalysts.18 Indeed, a catalytic amount
of phosphoric acid 4a promoted the oxidation of phenyl methyl
sulfide (1a) to sulfoxide 2a with an aqueous 35% solution of
H2O2, although the enantiomeric ratio (e.r.) was low (e.r.
63:37) and some overoxidation to sulfone 3a was observed
(Table 1, entry 1). Encouraged by this initial result, we
performed an extensive screening of phosphoric acid catalysts
(entries 2 to 9). Unfortunately, none of these well-investigated
catalysts provided significantly improved enantioselectivity,
although essentially perfect selectivity for the monooxidation
product could be achieved in several cases (entries 2, 3, and 7−
9). Catalyst 4g with 4-tBuC6H4 substituents gave the best
enantiomeric ratio of 78:22, but further increasing the size of
the para substituent on the phenyl ring resulted in slightly
decreased stereoselectivity (entries 7 and 8). STRIP (5), a
phosphoric acid based on the SPINOL backbone, proved
equally unsuccessful (entry 9).19 A solvent screening with
catalyst 4g also did not provide an improvement, although CCl4
was revealed as an equally useful solvent as cyclohexane (see
the Supporting Information).
ABSTRACT: Confined chiral Brønsted acids are shown
to catalyze asymmetric oxidations of sulfides to sulfoxides
with hydrogen peroxide. The wide generality and high
enantioselectivity of the developed method compare even
to the best metal-based systems and suggest utility in other
asymmetric oxidations.
nantioselective catalytic oxidations, in particular those
E
involving oxygen atom transfer, have propelled the
development of asymmetric catalysis during the last several
decades.1 Both enzymes and synthetic catalysts containing a
metal as the active principle are commonly employed to
facilitate this reaction class.1,2 Organocatalysts represent an
attractive alternative, and several systems have been developed.3
The nature of the terminal oxidant is often crucial for the
efficiency of oxidation reactions, and typical oxygen-transfer
reagents include alkyl hydroperoxides, iodosobenzene, perox-
ycarboxylic acids, hypochlorite, and oxone.1 Despite significant
efforts to utilize H2O2 in asymmetric oxidation catalysis,1,2 only
a few general systems work well with this abundant,
environmentally benign, atom-economical, and relatively safe
oxidant. In asymmetric organocatalysis, H2O2 has been
employed in epoxidations of α,β-unsaturated carbonyl com-
pounds,3b,4 Baeyer−Villiger reactions,5 and oxidations catalyzed
by ketones, iminium salts, or carboxylic acids.3a,c All of these
reactions rely on the nucleophilic properties of H2O2, forming
covalent adducts with electrophilic substrates or catalysts. We
envisioned an alternative scenario in which H2O2 could be
electrophilically activated toward nucleophilic substrates with a
chiral Brønsted acid catalyst (eq 1):
In asymmetric Brønsted acid catalysis, the bifunctional
activation of both the electrophile and the nucleophile, which
preorganizes the substrates, is commonly assumed to be crucial
for high enantioselectivity.18c,d We hypothesized that such
preorganization is lacking in our system because of the absence
of specific interactions of the sulfide with the phosphate
catalyst. In the present reaction, both Brønsted acidic and basic
sites of the catalyst are suggested to be involved in the
activation of hydrogen peroxide only (eq 1). Consequently, the
approach of the nucleophile to the catalyst−electrophile
Such a noncovalent activation mode has previously been used
in non-enantioselective oxidation reactions,6 including an alkyl
hydrogen sulfate-catalyzed sulfoxidation.7 However, the poten-
tial of this approach in asymmetric catalysis has not been
recognized.22 Here we demonstrate its successful utilization in a
highly enantioselective and general oxidation of sulfides to
sulfoxides that is catalyzed by a confined chiral Brønsted acid.
Chiral sulfoxides are widely used as intermediates, auxiliaries,
and ligands in modern organic synthesis8 and constitute
important biologically active compounds, including several
marketed pharmaceuticals.9 Since the first enantioselective
Received: April 13, 2012
Published: June 25, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/ja3035637 | J. Am. Chem. Soc. 2012, 134, 10765−10768

Journal of the American Chemical Society
Communication
6 also exhibited significantly higher reactivity than phosphoric
acids, and the catalyst loading could be reduced to 2 mol %.
The reaction efficiency could be further improved by adding
MgSO4 to remove water, which is both present in aqueous
hydrogen peroxide and also formed in the reaction. Thus, the
reaction time was shortened from 24 h to only 2 h and only
1.05 equiv of hydrogen peroxide was required (entry 13).
Water has a detrimental effect on the reaction rate, presumably
as a result of competition with hydrogen peroxide for binding
to the catalyst. The catalyst loading could be further reduced to
1 mol % without erosion of the enantioselectivity, and even a
catalyst loading of 0.1 mol % gave a high e.r. of 95:5 (entries 14
and 15). CCl4 and toluene were also found to be suitable
solvents for this reaction, although slightly lower enantiose-
lectivity (e.r. 97.5:2.5) was observed in toluene (see the
Supporting Information).
Table 1. Evaluation of Different Brønsted Acid Catalysts
The reaction scope was examined next using a series of
representative substrates (Table 2). A remarkably broad range
of aryl methyl sulfides could be converted to the corresponding
sulfoxides in high yields with excellent chemo- and
enantioselectivity. Various electron-rich substrates, including
methoxy-substituted sulfide 2b, and electron-poor substrates
with nitro or cyano groups were equally well tolerated (entries
2−6). Excellent enantioselectivity was preserved even when
varying a p-, m-, and o-chloro substituent on the aromatic ring
(entries 7−9). Substrates with larger alkyl groups instead of
methyl could also be oxidized with high enantioselectivity,
although a small amount of sulfone (5−9%) was observed
(entries 10 and 11). A high e.r. of 97.5:2.5 was achieved with
vinyl sulfide 2l (entry 12). Remarkably, high yields and
enantioselectivities could be achieved even with simple dialkyl
thioethers (entries 13 and 14). Sulfoxide 2n substituted with a
methyl group and a simple linear aliphatic group was obtained
with an enantiomeric ratio of 95.5:4.5 (entry 14).
The synthetic value of our method was demonstrated by the
enantioselective synthesis of the nonsteroidal anti-inflammatory
drug sulindac, which has recently found additional utility in
cancer treatment (Scheme 1).21 The oxidation of sulfide 7 with
confined acid catalyst 6b was performed in CCl4 because of the
solubility of the substrate, and the reaction proceeded with
excellent enantioselectivity. Following the hydrolysis of the
ester intermediate, (R)-sulindac was obtained in 95% overall
yield from sulfide 7 with an e.r. of 99:1. As a further
demonstration of the utility of our reaction, a large-scale
sulfoxidation of sulfide 7 was performed, yielding 3 g of the
product in 97% yield with an e.r. of 97.5:2.5.
a
a
entry
catalyst
t (h) conv. (%)
3a (%)
e.r.
1
2
4a (5 mol %)
4b (5 mol %)
4c (5 mol %)
4d (5 mol %)
4e (5 mol %)
4f (5 mol %)
4g (5 mol %)
4h (5 mol %)
5 (5 mol %)
24
24
24
24
24
24
24
24
15
24
24
24
2
80
80
12
−
−
24
20
10
−
−
−
−
−
63:37
69:31
58:42
64:36
70:30
44:56
78:22
76:24
58:42
92:8
3
38
4
76
5
86
6
53
7
71
8
75
9
38
10
11
12
6a (2 mol %)
6b (2 mol %)
6c (2 mol %)
6b (2 mol %)
6b (1 mol %)
6b (0.1 mol %)
90
80
99:1
85
<5
99:1
bc
,
13
>99
>99
−
−
−
99:1
bc
,
14
bcd
10
72
98.5:1.5
95:5
,
,
15
75
a
b
c
0.1 mmol scale, determined by GC−MS. With MgSO4. With 1.05
d
equiv of 35% aq. H2O2. 0.5 mmol scale.
complex is governed largely by steric control. However, because
of the open cone geometry of phosphoric acid catalysts, steric
interactions with the sulfide may be insufficient for effective
enantiodiscrimination. We recently developed highly sterically
demanding Brønsted acids based on a C2-symmetric
imidodiphosphate anion for the activation of small and
unbiased molecules.20 A distinctive feature of these catalysts
is the confinement of the active site within a deep chiral pocket.
We therefore hypothesized that with the use of such confined
Brønsted acids, H2O2 could be activated in a well-defined and
narrow position within a chiral cavity (see the Supporting
Information for a plausible model). This in turn would restrict
the number of possible trajectories of the incoming sulfide
nucleophile and thereby increase the enantioselectivity by
limiting the diversity of productive transition states.
In summary, a novel oxidation system based on a chiral
confined Brønsted acid catalyst and aqueous H2O2 has been
developed. Imidodiphosphoric acid catalyst 6b, which presum-
ably binds hydrogen peroxide inside its chiral cavity, was found
to catalyze an efficient sulfoxidation reaction of sulfides. To the
best of our knowledge, the obtained levels of enantioselectivity
are the highest reported to date for organocatalytic
sulfoxidations6 and rival those of the best metal-catalyzed
variants.10−15
To our delight, confined imidodiphosphoric acids 6a−c did
indeed enable the highly enantioselective electrophilic oxidation
of sulfide 1a with H2O2 (Table 1, entries 10−12). An excellent
e.r. of 99:1 was observed with catalysts 6b and 6c (entries 11
and 12). It is noteworthy that imidodiphosphoric acid catalysts
Further exploration of our new chiral confined Brønsted acid
motif in general and especially in other asymmetric oxidation
reactions is currently in progress in our laboratories.
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Journal of the American Chemical Society
Communication
Table 2. Substrate Scope of Asymmetric Sulfoxidation
Scheme 1. Enantioselective Synthesis of Sulindac
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
list@kofo.mpg.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge generous support from the Max
Planck Society and the European Research Council (Advanced
Grant to B.L.).
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