Asymmetric vanadium- and iron-catalyzed oxidations: New mild (R)-modafinil synthesis and formation of epoxides using aqueous H2O2 as a terminal oxidant

Article abstract of DOI:10.1016/j.tet.2012.07.052

The enantioselective oxidation of thioanisole to methyl phenyl sulfoxide and the epoxidation of several alkenes, including terminal ones, have been realized by using new iron(III) complexes, generated in situ from primary amine-derived non-symmetrical Schiff base ligands and aqueous H ₂O₂ as environmentally benign oxidant. Further investigations on vanadium catalysis and the application of both catalytic systems in the synthesis of enantiomerically-enriched chiral drug (R)-modafinil were undertaken. It was found that the vanadium-based catalytic system (VO(acac)₂/ligand 6), is able to provide (R)-modafinil in quantitative yield and acceptable enantiomeric excess within a very short reaction time (15 min).

Full text of DOI:10.1016/j.tet.2012.07.052

Tetrahedron 68 (2012) 8493e8501
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Asymmetric vanadium- and iron-catalyzed oxidations: new mild (R)-modafinil
synthesis and formation of epoxides using aqueous H2O2 as a terminal oxidant
*
Kerstin A. Stingl, Katharina M. Weiß, Svetlana B. Tsogoeva
Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestraße 42, 91054 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2012
Received in revised form 9 July 2012
Accepted 16 July 2012
Available online 24 July 2012
The enantioselective oxidation of thioanisole to methyl phenyl sulfoxide and the epoxidation of several
alkenes, including terminal ones, have been realized by using new iron(III) complexes, generated in situ
from primary amine-derived non-symmetrical Schiff base ligands and aqueous H2O2 as environmentally
benign oxidant. Further investigations on vanadium catalysis and the application of both catalytic sys-
tems in the synthesis of enantiomerically-enriched chiral drug (R)-modafinil were undertaken. It was
found that the vanadium-based catalytic system (VO(acac)2/ligand 6), is able to provide (R)-modafinil in
quantitative yield and acceptable enantiomeric excess within a very short reaction time (15 min).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(R)-Modafinil
Enantioselective sulfoxidation
Enantioselective epoxidation
Non-heme iron catalysts
Non-heme vanadium catalysts
1. Introduction
While in particular heme containing oxidation catalysts are al-
ready well investigated,1,2a the application of non-heme iron and/or
The development of environmentally friendly enantioselective
oxidation reactions is still an important challenge for chemical re-
search. Thereby, epoxidation of alkenes1 and sulfoxidation2 repre-
sent two of the most important oxidation reactions in organic
synthesis. More and more frequently, chiral epoxides become
useful building blocks in natural product synthesis and in the
synthesis of biologically active compounds.3 Chiral sulfoxides are of
great interest for organic chemistry and biochemistry since they
serve as intermediates in the synthesis of numerous sulfur con-
taining drugs and can also be considered as an independent class of
targets suitable for pharmaceutical applications.4,5 Furthermore,
chiral sulfoxides are also used as chiral auxiliaries6 and organo-
catalysts7 (Fig. 1).
vanadium complexes as enantioselective oxidation catalysts is less
well studied so far.11e13
The most prominent chiral ligands for enantioselective vana-
dium- and iron-catalyzed sulfoxidations, developed by Bolm and
co-workers, are presented in Fig. 2.11
Chiral sulfoxides, often found in pharmaceutical products, con-
tinue to gain attention in the development of new drugs and their
analogues.4,13m,15 For instance, armodafinil (NuvigilÒ), which was
patented by the pharmaceutical company Cephalon in 2005 and
approved by the food and drug administration in 2007 (USA), rep-
resents an effective drug in the treatment of sleep disorders asso-
ciated with narcolepsy, obstructive sleep apnea/hypopnea
syndrome or shift work sleep disorders.15,16 Since it has been found
Diverse oxygenase- and peroxigenase-enzymes are applied in
enantioselective oxidations of olefins8 and sulfides.5,9 Analogously
to natural models, metal containing enzyme-mimetic oxidation
catalysts can be classified into heme and non-heme metal com-
plexes. In the last three decades, biomimetic approaches to oxida-
tion reactions mostly concentrated on synthetic ironeheme
complexes and their interactions with oxygen donors such as
iodosobenzene, peracids, and hydro-peroxides.1,2a,10
Fig. 1. Selected examples of sulfoxides applied as a drug: (R)-modafinil (I), a chiral
auxiliary (II) and an organocatalyst (III). Epoxide moiety included in pheromone of
gypsy moth (IV).
* Corresponding author. Tel.: þ49 (0)9131 85 22541; fax: þ49 (0)9131 85 26865;
e-mail address: tsogoeva@chemie.uni-erlangen.de (S.B. Tsogoeva).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.052

8494
K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
Fig. 2. Bolm’s chiral ligands.
that armodafinil (consisting of the pure R-enantiomer of modafinil)
was more active due to the slower metabolism of the R-enantio-
mer,17 chemists endeavor to improve or to develop new synthetic
routes for the synthesis of this chiral drug.
Several methods such as resolution18 (e.g., chromatography,18e
fractional crystallization,18e,c separation via diastereomers18a,b,d
)
and the oxidation of prochiral sulfides (using metal catalysts,16,18e,19
chiral oxaziridines,19 microbial oxidation20 or a biocatalytic ap-
proach21) have been described. In 2007, Guillen and co-workers19
applied the above-mentioned well-known catalytic systems11 to
the enantioselective synthesis of modafinil. However, only low to
moderate yields and low enantioselectivities were achieved in case
of the studied iron- and vanadium-catalyzed oxidation: 45%, 12% ee
with V-catalyst and 10%, 15% ee with Fe-catalyst using H2O2 as an
oxidizing agent.19
Therefore, there is still a large research potential for vanadium-
or iron-based catalysts in enantioselective (R)-modafinil synthesis
using simple and inexpensive oxidizing agents like H2O2. This
prompted our present study. Our effort has been directed toward
the development of improved vanadium- or iron-based catalytic
systems for the synthesis of the enantiomerically-enriched chiral
drug (R)-modafinil. The potential of the selected iron-catalyst for
the epoxidation of unfunctionalized alkenes has also been
demonstrated.
Fig. 3. Designed ligands.
synthesized according to literature known procedures. As depicted
in Table 1, the catalytically active species were generated in situ,
using inexpensive nontoxic iron(III) chloride hexahydrate and the
corresponding ligands (1e8) in the ratio of 1:2. The oxidation re-
action was carried out in THF using a low catalyst loading (4 mol %
of ligand, 2 mol % of FeCl3$6H2O) under ambient conditions. First,
the investigation of the commercially available chiral diamine 1
furnished the corresponding sulfoxide in 17% yield as a nearly ra-
cemic product (3% ee (S), entry 1). The introduction of the sterically
hindered 3,5-di-tert-butylsalicylaldehyde forming Schiff base li-
gand 2 resulted in a sound enhancement of both yield and enan-
tioselectivity (50% yield, 34% ee, entry 2). In this case, the opposite
enantiomer (R) was formed. Carrying out the reaction under ni-
trogen atmosphere resulted in no improvement of yield and en-
antiomeric excess. To ascertain the importance of the primary
amine group, we tested the corresponding salen ligand 3.
2. Results and discussion
2.1. Enantioselective sulfoxidation
Table 1
2.1.1. Iron(III)-catalyzed
oxidation
of
thioanisole
with
Screening of ligands 1e8
H2O2. Compared with those advancements in metal-catalyzed
sulfoxidation reactions achieved with symmetrical Schiff base li-
gands, much less is known about the sulfoxidation chemistry using
non-symmetrical Schiff base ligands. However, transition metals
occur in oxygenase- and peroxigenase-enzymes bound to donor
atoms of peptide chains, usually in a non-symmetrical environ-
ment. Thus, the identification of new non-symmetrical metal cat-
alyst systems, especially Fe-catalyzed11def,14 methods, for this
important asymmetric reaction remains a challenge.
In particular, metal-catalyzed sulfoxidation using primary
amine-derived non-symmetrical Schiff base ligands finds itself just
in the early stage.13h,j,l Recently, Romanowski and co-workers
reported on chiral dioxovanadium(V) primary amine Schiff base
complexes for sulfoxidation reactions using cumene hydroperoxide
(CHPO)13h,j or even hydrogen peroxide7l as oxidants and DMSO as
solvent yielding the corresponding sulfoxides with 19e39% ee.13h,7l
Following our interest in the application of primary amine-
based catalysts22 and taking the aspect of green chemistry into
account, we investigated primary amine-derived Schiff bases 2 and
8e10 as potential ligands for the iron-catalyzed oxidation of thio-
anisole (chosen for preliminary studies as a well-known model
reaction) using aqueous hydrogen peroxide as environmentally
friendly oxidant.
Entry
Ligand
Yielda (%)
eeb (%)
1
1
2
2
3
4
5
6
7
17
50
51
36
48
49
68
72
74
9
3 (S)
34 (R)
36 (R)
rac
6 (R)
21 (R)
6 (R)
7 (R)
rac
2
3c
4
5
6
7
8
9
8
2
d
10d
11
12d
rac
rac
n.d.
78
13
d
a
Yield of isolated product.
ee was determined by HPLC (OD, hexane/i-PrOH (93:7), flow 1.0 mL/min).
Reaction was carried out under N2-atmosphere.
b
c
d
Reaction was carried out without iron salt.
The yield decreased to 36% and a racemic sulfoxide was obtained
(entry 4). The yield remained almost constant when reduced ligand
4 was used for this model reaction, but the enantiomeric excess
Our initial work started with the screening of different ligands
(Fig. 3): 1 is commercially available and ligands 2e8 were

K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
8495
decreased to 6% (entry 5 vs entry 2). Next, we studied ligand 5 in
which the primary amino function is protected as a hydrochloride
salt. The desired product was isolated in 49% yield and with 21% ee
(entry 6).
The application of ligand 9 for the oxidation of thioanisole under
selected reaction conditions resulted in 65% yield (Table 3, entry 2),
but the enantioselectivity decreased to 36% ee (Table 3, entry 2).
The best result was obtained when the reaction was performed
using ligand 10, containing a trityl group in position-5 instead of
position-3 of the salicylaldehyde. Both yield and enantiomeric ex-
cess were moderate (66% yield, 53% ee, Table 3, entry 3). The yield
could be slightly increased to 69% when 1.7 equiv of hydrogen
peroxide was added within 7 h, whereas the enantioselectivity of
the product remained nearly constant (54% ee, Table 3, entry 4).
It is assumed that ligand 5 releases hydrochloric acid during the
complex formation (or the oxidation process) through which the
free amino group is partly recovered. Additionally, we synthesized
the known Schiff base ligands 6 and 7 containing a hydroxy instead
of a primary amino group and verified their efficiency in our cat-
alytic system. In both cases the yield could be increased (68%, entry
7 and 72%, entry 8), but the enantiomeric excess decreased signif-
icantly (6% ee, entry 7 and 7% ee, entry 8). The use of ligand 8,
containing a binaphthyl moiety as a chiral building block, resulted
in a good yield of the methyl phenyl sulfoxide (74%, entry 9), but no
enantioselectivity was observed.
Table 3
Application of ligands 9 and 10 to the oxidation of thioanisole
We tried to further improve the current reaction conditions by
reducing the reaction time from 24 h to 5 h (Table 2). To our delight,
we observed no loss of both yield and enantioselectivity (Table 2,
entry 2 vs entry 1). Moreover, we changed the way of adding the
hydrogen peroxide to the reaction mixture by using a syringe pump
instead of the addition in one portion. The enantioselectivity in-
creased to 43%, while the yield remained constant (Table 2, 52%,
entry 3). Additional efforts to achieve better yields and enantiose-
lectivities remained unsuccessful (Table 2, entries 4e9). A further
reduction of reaction time (3 h, 1 h) resulted in a reduction of both
yield and enantioselectivity (Table 2, entries 10 and 11).
Entry
Ligand
Yielda (%)
eeb (%)
1
2
2
9
10
10
52
65
66
69
43
36
53
54
3
4c
a
Yield of isolated product.
ee was determined by HPLC (OD, hexane/i-PrOH (93:7), flow 1.0 mL/min).
Reaction was carried out within 7 h; after 5 h and after 6 h further addition of
b
c
10
m
L H2O2 (overall addition of H2O2 was 1.7 equiv).
Table 2
Optimization of reaction conditions with selected ligand 2
Additionally, we aimed to investigate whether the use of the
isolated complexes in contrast to those formed in situ had any in-
fluence on the model reaction. We prepared complexes 11e13,
using 2 equiv of the corresponding ligands 2, 9 or 10 and 1 equiv of
iron(III) chloride hexahydrate in THF. The complex formation was
carried out within 2 h under ambient conditions. No further puri-
fication was necessary due to only one characteristic peak m/
z¼910.48 [MꢀCl]þ in ESI-MS, except for the free ligand at m/
z¼429.28 [MþH]þ (e.g., complex 11, Fig. 5). While the actual
structures of the catalysts in the reaction medium, as well as the
exact role of the primary amine group are unclear yet, we postulate
structures of all complexes as depicted in Scheme 1. The simulated
isotopic pattern of postulated mononuclear complexes (co-
ordination of two tridentate Schiff base ligands to iron(III)) is
identical with the measured ones, obtained for all synthesized
complexes (11e13). Further, we assume that the primary amine
group may promote the release of a Clꢀ anion from the iron center.
Detailed investigations (e.g., crystallization) are currently ongoing
in our laboratory.
Entry
H2O2 (equiv)
Concn (mol/L)
Time (h)
Yielda (%)
eeb (%)
1
1.2
1.2
1.2
1.2
1.2
1.2
2.0
1.2
1.2
1.2
1.2
0.8
0.8
0.8
0.8
0.8
1.2
0.8
0.8
0.8
0.8
0.8
24
5
5
5
5
5
5
5
5
3
1
50
52
52
48
52
39
56
28
31
46
41
34
31
43
44
32
49
35
24
24
39
36
2
3c
4c,d
5c,e
6c
7c
8c,f
9c,g
10c
11c
a
Yield of isolated product.
ee was determined by HPLC (OD, hexane/i-PrOH (93:7), flow 1.0 mL/min).
H2O2 was added via a syringe pump.
Ligand 2 contaminated with 3% of bis-imine 3.
Reaction was carried out in CH3CN.
Reaction was carried out at 0 ꢁC.
b
c
d
e
f
5
x10
g
910.4851
Sulfide was added by a syringe pump simultaneously.
2.0
For this reason we modified the structure of primary amine-
based ligand 2 and introduced sterically more hindered salicy-
laldehyde derivatives, which are shown in Fig. 4 (ligands 9 and 10).
1.5
1.0
429.2892
0.5
0.0
200
400
600
800
1000
1200
1400
m/z
Fig. 4. New sterically hindered ligands 9 and 10.
Fig. 5. Selected ESI-MS spectrum for complex 11.

8496
K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
Table 4
Further investigations of ligand 2 and 6 in the oxidation of thioanisole with H2O2
Entry
Ligand
MXn
Time (h)
Yielda (%)
eeb (%)
1
2
2
6
6
6
2
6
VO(acac)2
VO(acac)2
VO(acac)2
VO(acac)2
FeCl3$6H2O
FeCl3$6H2O
48
48
24
24
48
48
79
67
79
81
20
8
9
43
45
34
33
28
3
Scheme 1. Syntheses of new iron(III) complexes.
4c
5
6
a
We proved the activity of complex 11 for the oxidation of thi-
oanisole and obtained comparable results to those in which the
complex formation was carried out in situ (Scheme 2 vs Table 3,
entry 1). The methyl phenyl sulfoxide was produced in 49% yield
and 42% ee (Scheme 2).
Yield of isolated product.
ee was determined by HPLC (OD, hexane/i-PrOH (93:7), flow 1.0 mL/min).
Sequence of the addition of single components was changed: ligand and metal
b
c
were stirred for 1 h, then H2O2 followed by thioanisole were added (vs general
procedure in Experimental section).
2.1.3. Application of the catalytic systems for the synthesis of (R)-
modafinil. Next, our effort has been directed toward the application
of the above shown iron- and vanadium-based catalytic systems for
the synthesis of enantiomerically-enriched (R)-modafinil.
Regarding the iron-catalyzed oxidation using primary amine-
based ligand 10 as potential chiral source in the synthesis of
(R)-modafinil, unsatisfying results were obtained (45%, rac,
Table 5, entry 1) even though this catalytic system has proven to
be quite active for the oxidation of thioanisole. We next replaced
FeCl3$6H2O by VO(acac)2 and investigated ligand 10 in chloroform
as solvent. High yields (89%) could be achieved for (R)-modafinil,
but again a low enantioselectivity (9% ee) (Table 5, entry 2). Based
on these results, primary amine-based ligands seemed not to be
suitable for the synthesis of (R)-modafinil under the current re-
action conditions. Thus, we verified Schiff base ligand 6, derived
from the aminoalcohol (1S,2R)-2-amino-1,2-diphenylethanol with
the metal source VO(acac)2 in chloroform as solvent. Surprisingly,
after 24 h (R)-modafinil could be isolated in high yields (92%)
with an enantiomeric excess of 33% (Table 5, entry 3). By carrying
out the reaction at 0 ꢁC, the yield of (R)-modafinil could be in-
creased to 99% but the enantioselectivity dropped to 22% (Table 5,
entry 4). A further reduction of the reaction time to only 15 min
resulted in excellent yields (>99%) without any loss of enantio-
selectivity (32% ee) under ambient conditions (Table 5, entry 6 vs
entries 3 and 5).
Scheme 2. Application of isolated complex 11 for the oxidation of thioanisole.
2.1.2. Vanadium-catalyzed oxidation of thioanisole with H2O2. Since
vanadium was found in active centers of non-heme enzymes (e.g.,
vanadiumbromoperoxidase9b,23), great efforts have been devoted
to the development of analogous models, which might be able to
mimic their biological activity.13l,n,24
According to our results obtained in the iron-catalyzed oxida-
tion of thioanisole with primary amine-based ligand 2, we in-
vestigated VO(acac)2 as potential metal source. In general,
chlorinated solvents are known as well suitable solvents for the
vanadium-catalyzed oxidation of sulfides to sulfoxides.13c,d,g Hence,
we applied ligand 2 with VO(acac)2 for the model reaction using
similar reaction conditions as mentioned before, but CHCl3 instead
of THF as solvent.
After 48 h, methyl phenyl sulfoxide was isolated in high yields
(79%), but unfortunately only low enantioselectivity (9% ee) could
be observed (Table 4, entry 1). Due to the knowledge that Schiff
base ligands derived from aminoalcohols are powerful ligands in
the vanadium-catalyzed sulfoxidation,25 we investigated Schiff
base ligand 6 under identical conditions. Moderate yield and
enantioselectivity were achieved for the corresponding sulfoxide
(67% yield, 43% ee, Table 4, entry 2). A further reduction of the re-
action time, to 24 h, resulted in a higher yield (79%) and a compa-
rable enantioselectivity (45% ee) (Table 4, entry 3). Moreover, the
effect of a sequence altering of the single component addition was
examined. Thus, H2O2 was added first to a stirred solution of Schiff
base ligand 6 and VO(acac)2 in chloroform, subsequently followed
by the addition of the substrate thioanisole. Interestingly, the yield
of the sulfoxide remained almost constant (81%), but the enantio-
selectivity dropped to 34% ee (Table 4, entry 4). Additional in-
vestigations prompted us to the assumption that primary amine-
based ligand 2 is more reliable for the iron-catalyzed oxidation of
methyl phenyl sulfoxide conducted in tetrahydrofuran, whereas
ligand 6 delivered more convenient results in the vanadium-
catalyzed oxidation using chloroform as solvent (Table 1, entry 2
vs Table 4, entry 3).
Table 5
Application of selected ligands 10 and 6 to the synthesis of enantiomerically-
enriched (R)-modafinil
Entry Ligand MXn
Oxidant Solvent Temp Time Yielda eeb (%)
(ꢁC)
(h)
(%)
1c
2
3
4
5
6
7
10
10
6
6
6
FeCl3$6H2O H2O2
THF
rt
rt
rt
0
rt
rt
rt
24
24
24
24
45
89
92
>99
rac
9 (R)
33 (R)
22 (R)
35 (R)
32 (R)
VO(acac)2
VO(acac)2
VO(acac)2
VO(acac)2
VO(acac)2
VO(acac)2
H2O2
H2O2
H2O2
H2O2
H2O2
PhIO
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
3.5 93
0.25 >99
24
6
6
Traces n.d.
a
Yield of isolated product.
ee was determined by HPLC (AS, hexane/i-PrOH (60:40), flow 0.9 mL/min).
Ligand 10 of 4.0 mol % was used.
b
c

K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
8497
Table 6
Notably, using iodosobenzene (PhIO) as an oxidizing agent, no
oxidation product was observed even after 24 h reaction time.
Thus, to our delight, we could establish a remarkably improved
vanadium-catalyzed system to obtain enantiomerically-enriched
(R)-modafinil in >99% yields within a very short reaction time
(15 min) and at room temperature using hydrogen peroxide as
simple, inexpensive, and environmentally benign oxidant.
Application of the primary amine-based ligand 2 to the enantioselective epoxidation
of different alkenes
2.2. Enantioselective epoxidation
Despite the potential of chiral epoxides as highly useful in-
termediates and precursors for the synthesis of different bi-
ologically active compounds and natural products,3,26 effective
synthetic methods (among them organocatalytic and transition
metal procedures), in particular, Fe-catalyzed methods, for the
preparation of the chiral epoxides, are limited.12 Notably, iron is
ubiquitous and also one of the most versatile transition metals
known. Thus, our particular focus lies on the development of en-
vironmentally friendly non-heme iron-catalyzed epoxidation of
alkenes using H2O2 as oxidation agent.
We, therefore, investigated the potential of the selected Fe-
catalytic systemdprimary amine-derived Schiff base ligand 2 (as
used for the sulfide oxidation) in combination with iron(III) chlo-
ride hexahydratedfor the epoxidation of alkenes. Under the con-
ditions shown in Table 6, trans-stilbene oxide was yielded in 84%
with an enantiomeric excess of 19% (Table 6, entry 1). Further ap-
plication of this catalytic system to the trans-stilbene derivative
with methyl groups in para-position, a yield of 70% and an enan-
tioselectivity of 9% (Table 6, entry 2) were obtained. Next we
replaced the groups in para-position with the more bulky iso-pro-
pyl (Table 6, entry 3) and tert-butyl (Table 6, entry 4) residues,
which resulted in decreased yields of 61% and 50% and enantiose-
lectivities of 5% and 24%.
Entry
1d,g
Substrate
Yield (%)
84a
ee (%)
19b
2e,g
70a
61a
9b
3f,g
5b
4e,g
50a
24b
5f,g
44c
47c
21c
30c
In particular, the epoxidation of terminal alkenes is still a chal-
lenging subject in the field of oxidation chemistry.12b,c,d Thus we
also carried out the epoxidation of styrene furnishing the corre-
sponding styrene oxide in 44% conversion and 21% ee (Table 6,
6f,g
entry 5). Changing the substrate to trans-b-methyl styrene resulted
in a conversion of 47% with a slightly increased enantiomeric excess
of 30% (Table 6, entry 6).
a
Yield of isolated product.
ee was determined by HPLC (IA-column).
b
c
d
e
f
Conversion and ee were determined by GC analysis (Hydrodex
Impurities of 2 with bis-imine 3 were: 3%.
Impurities of 2 with bis-imine 3 were: 6%.
Impurities of 2 with bis-imine 3 were: 9%.
Addition of H2O2 in one portion.
b-TBDAc).
3. Conclusion
g
Although the iron-catalyzed oxidation of thioanisole is well
documented,11def,14 we demonstrate here the first examples of
primary amine-derived non-symmetrical Fe-catalysts for the
enantioselective sulfoxidation under mild conditions and with
H2O2 as oxidant. Moderate yields (up to 69%) and reasonable en-
antiomeric excesses (up to 54% ee) could be achieved when the
reaction was carried out in THF using a syringe pump within 5 or
7 h. It turned out that the primary amino function, as well as the
unsymmetric environment of the ligand played an important role
in order to observe enantioselectivity in this new catalytic system.
We also showed the application of the selected primary amine-
based ligand 2 in the iron-catalyzed epoxidation of different al-
kenes. In case of trans-stilbene and derivatives, yields of up to 84%
and ee values of up to 30% were obtained.
performs moderately with thioanisole (79e81% yields and 34e45%
ee after 24 h), is able to provide (R)-modafinil in excellent yield of
>99% and acceptable enantiomeric excess of 32% within a very
short reaction time (15 min).
The presented results are laying the basis for further successful
design of new highly active and enantioselective non-heme vana-
dium catalysts for (R)-modafinil synthesis and non-heme iron
catalysts for enantioselective epoxidation of olefins using H2O2 as
environmentally friendly oxidation agent.
4. Experimental
Our further studies on enantioselective oxidation of thioanisole
and of a modafinil precursor using VO(acac)2/ligand 6 as a catalytic
system provided us with an interesting observation. Intriguingly,
while well-known vanadiumeSchiff base complexes11aec,13c,g are
successful catalysts for the thioanisole oxidation, their application
as chiral catalysts for (R)-modafinil synthesis provides disap-
pointingly low yields and enantioselectivities (e.g., 45%, 12% ee,
after 16 h reaction time).19 In stark contrast, we found that the
vanadium-based catalytic system (VO(acac)2/ligand 6), which
4.1. General information
Chemicals were used as received from common commercial
sources. All solvents were distilled before use and all reactions were
carried out under nitrogen atmosphere if not mentioned otherwise.
NMR spectra were recorded on Jeol (400 MHz) or Bruker Avance
(300 MHz or 400 MHz). NMR spectra were referenced to the re-
sidual solvent signal (1H: CDCl3, 7.24 ppm; 13C: CDCl3, 77.0 ppm)

8498
K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
and recorded at ambient probe temperature. IR spectra were
recorded as thin films on a Varian IR-660 spectrometer. Mass
spectra (MALDI-TOF) were recorded on a Shimadzu Biotech Axima
Confidence spectrometer. High mass accuracy ESI spectra were
recorded on an ultra-high-resolution ESI-Time-Of-Flight MS,
a Bruker Daltoniks (Bremen, Germany) maXis. Spectra were
obtained in positive-ion mode, with the capillary held at 4000 V.
The drying gas flow rate was 7.0 L/min at 240 ꢁC. The nebulizer gas
was at a pressure of 30.5 psi/2 bar. The m/z range was detected from
100 to 2000. A calibration tune mix (Agilent Technologies) was
sprayed immediately prior to analysis to ensure a high mass ac-
curacy to assist in the identification of peaks. The flow rate of the
1.0 equiv) was dissolved in anhydrous methanol (9 mL) and anhy-
drous ethanol (9 mL). After the addition of 3,5-di-tert-butylsalicy-
laldehyde (329.7 mg, 1.40 mmol, 1.0 equiv), the reaction mixture
was stirred for 24 h at room temperature. The solvent was evapo-
rated to approximately 1 mL and the solid was filtered and washed
with ethanol. The filtrate was concentrated and the resulting pre-
cipitate was washed with diethylether to remove unreacted alde-
hyde. The product was obtained in 87% yield as a white solid
(568.6 mg). 1H NMR (300 MHz, MeOH-d4):
d¼1.30 (s, 9H), 1.46 (s,
9H), 4.87 (d, overlapping with water signal, 1H), 4.92 (d, J¼9.9 Hz,
1H), 7.16e7.27 (m, 6H), 7.32 (s, 5H), 7.45 (d, J¼2.4 Hz, 1H), 8.71 (s,
1H). Maldi-TOF: m/z¼429 [MꢀCl]þ.
solutions was 300 m
L/h. HPLC spectra were recorded at 25 ꢁC with
an Agilent Technologies 1200 Series HPLC. TLC chromatography
was performed on precoated aluminum silica gel SIL G/UV254
plates (Marcherey, Nagel & Co.). Flash column chromatography was
performed using silica gel 60M (Macherey-Nagel). Syringe pump:
KD Scientific, Model 100 Series. Gas chromatography (GC) was
carried out on a Thermo Instrument Trace GC Ultra (Hydrodex
4.2.5. 2,4-Di-tert-butyl-6-((E)-(((1R,2S)-2-hydroxy-1,2-diphenylethyl)
imino)methyl)phenol (6).30 To a solution of (1S,2R)-(þ)-2-amino-1,2-
diphenylethanol (400.0 mg, 1.87 mmol, 1.0 equiv) in anhydrous
methanol (10 mL) and Na2SO4 (1.0 g, 4.0 equiv) a solution of 3,5-di-
tert-butylsalicylaldehyde (438.2 mg, 1.87 mmol, 1.0 equiv) in metha-
nol(2 mL)wasaddeddropwise. Afterthereactionmixturewasstirred
for 3 d at room temperature, the solution was concentrated and pu-
rified by flash column chromatography (SiO2, PE/EtOAc 3:1) to afford
the desired product in 87% yield (699.0 mg) as a yellow foam.1H NMR
b-TBDAc, 25 mꢂ0.25 mm ID (Macherey-Nagel)).
4.2. Synthesis of the ligands
(400 MHz, CDCl3):
d
¼1.28 (s, 9H), 1.47 (s, 9H), 2.08 (d, J¼3.0 Hz, 1H),
4.2.1. 2-((E)-(((1R,2R)-2-Amino-1,2-diphenylethyl)imino)methyl)-
4.54 (d, J¼6.8 Hz, 1H), 5.10 (dd, J¼3.0 Hz, J¼6.8 Hz, 1H), 6.96 (d,
4,6-di-tert-butylphenol (2).27 To
diphenylethylenediamine (500.0 mg, 2.35 mmol, 1.01 equiv) in an-
hydrous DCM (8 mL) with molecular sieve 3 A (5.3 g), a solution of
a
solution of (1R,2R)-(þ)-1,2-
J¼2.4 Hz, 1H), 7.26e7.40 (m, 12H), 8.17 (s, 1H), 13.43 (s, 1H). 13C NMR
(100 MHz, CDCl3):
d
¼29.3, 31.3, 33.9, 34.9, 78.3, 80.0, 117.8, 126.3,
ꢀ
127.2, 127.9, 127.9, 128.1, 128.1, 128.7, 136.6, 139.6, 140.1, 140.2, 157.9,
3,5-di-tert-butylsalicylaldehyde (546.5 mg, 2.33 mmol,1.0 equiv) in
DCM (10 mL) was added dropwise over a period of 30 min. After the
reaction mixture was stirred for 3 h at room temperature, the so-
lution was concentrated (at 30 ꢁC) and quickly purified by flash
column chromatography (SiO2, PE/EtOAc 7:3) to afford the desired
product in 37% yield (367.3 mg) as a yellow foam.1H NMR (400 MHz,
167.1. Maldi-TOF: m/z¼431 [MþH]þ.
4.2.6. 2-((E)-(((1R,2S)-2-Hydroxy-1,2-diphenylethyl)imino)methyl)-
4,6-diiodophenol (7).31 To a solution of (1S,2R)-(þ)-2-amino-1,2-
diphenylethanol (200.0 mg, 0.94 mmol, 1.0 equiv) in anhydrous
methanol (3 mL) and MgSO4 (564.4 mg, 5.0 equiv) a solution of 3,5-
diiodosalicylaldehyde (350.6 mg, 0.94 mmol, 1.0 equiv) in methanol
(14 mL) was added dropwise. After the reaction mixture was stirred
for 3 d at room temperature, MgSO4 was filtered off, and the solution
was concentrated and purified by flash column chromatography
(SiO2, PE/EtOAc 3:1) to afford the desired product in 56% yield
CDCl3):
d
¼1.27 (s, 9H), 1.46 (s, 9H), 1.64 (br s, 2H), 4.29 (d, J¼7.8 Hz,
1H), 4.40 (d, J¼7.8 Hz,1H), 7.06 (d, J¼2.4 Hz,1H), 7.11e7.20 (m,10H),
7.38 (d, J¼2.4 Hz, 1H), 8.45 (s, 1H), 13.59 (s, 1H). 13C NMR (100 MHz,
CDCl3):
d
¼29.4, 31.4, 34.0, 34.9, 62.1, 82.2, 117.8, 126.4, 127.2, 127.3,
127.4, 127.7, 127.8, 128.1, 128.2, 136.6, 140.3, 140.6, 141.8, 158.0, 167.2.
(300.0 mg) as an orange foam. 1H NMR (300 MHz, CDCl3):
d¼2.04 (br
4.2.2. 6,60-((1E,10E)-(((1R,2R)-1,2-Diphenylethane-1,2-diyl)bis(aza-
nylylidene))bis(methanylylidene))bis(2,4-di-tert-butylphenol)
(3).27 The desired product was isolated in a yield of 34% as
s,1H), 4.48 (d, J¼7.3 Hz,1H), 5.00 (d, J¼7.3 Hz,1H), 7.19e7.39 (m,11H),
7.77 (s, 1H), 7.98 (d, J¼2.0 Hz, 1H), 14.44 (s, 1H). 13C NMR (100 MHz,
CDCl3): 78.0, 79.3, 79.7, 87.3, 119.8, 127.0, 127.9, 128.3, 128.4, 128.9,
138.4, 139.7, 139.9, 148.7, 160.4, 163.6. FAB: m/z¼570 [MþH]þ.
abyproductofcompound2.1HNMR(300 MHz,CDCl3):
d¼1.21(s, 9H),
1.41 (s, 9H), 4.72 (s, 2H), 6.98 (d, J¼2.4 Hz, 2H), 7.16e7.19 (m,10H), 7.30
(d, J¼2.4 Hz, 2H), 8.40 (s, 2H), 13.6 (s, 2H). 13C NMR (75 MHz, CDCl3):
4.2.7. (E)-2-(((20-Amino-[1,10-binaphthalen]-2-yl)imino)methyl)-4,6-
di-tert-butylphenol (8).31 To a solution of R-(þ)-2,2`-diamino-1,1-
binaphthalene (200.0 mg, 0.70 mmol, 1.0 equiv) in anhydrous meth-
anol (4 mL)/toluene (4 mL) and MgSO4 (423.3 mg, 5.0 equiv) a solu-
tion of 3,5-di-tert-butylsalicylaldehyde (164.8 mg, 0.70 mmol,
1.0 equiv) in DCM (4 mL) was added dropwise. After the reaction
mixture was stirred for 3 d at room temperature, MgSO4 was filtered
off, and the solution was concentrated and purified by flash column
chromatography (SiO2, PE/EtOAc/Et3N 8:2:0.1) to afford the desired
product in 26% yield (91.6 mg) as an orange foam. 1H NMR (300 MHz,
d
¼29.4, 31.4, 34.0, 34.9, 80.0, 117.8, 126.3, 127.1, 127.3, 127.9, 128.2,
136.3, 139.7, 139.9, 157.9, 167.2. Maldi-TOF: m/z¼645 [MþH]þ.
4.2.3. 2-((((1R,2R)-2-Amino-1,2-diphenylethyl)amino)methyl)-4,6-
di-tert-butylphenol (4).28 Compound
2 (200.0 mg, 0.46 mmol,
1.0 equiv) was dissolved in anhydrous methanol (5 mL) followed by
the addition of NaBH4 (70.8 mg, 1.87 mmol, 4.0 equiv) in portions.
The reaction mixture was stirred overnight at room temperature.
Water (10 mL) was added and the product was extracted with
dichloromethane (3ꢂ2 mL). The combined organic phases were
dried over MgSO4. After evaporation the product was obtained in
76% yield (154.0 mg) as a white solid without further purifications.
CDCl3):
d
¼1.23 (s, 9H),1.24 (s, 9H), 3.60(s, 2H), 6.88e6.91 (m,1H), 7.02
(d, J¼2.4 Hz, 1H), 7.08e7.19 (m, 3H), 7.27 (d, J¼2.4 Hz, 1H), 7.30e7.35
(m, 1H), 7.43e7.49 (m, 2H), 7.63 (d, J¼8.8 Hz, 1H), 7.73e7.78 (m, 2H),
7.94 (d, J¼8.1 Hz,1H), 8.03 (d, J¼8.6 Hz,1H), 8.64 (s,1H),12.75 (s,1H).
1H NMR (300 MHz, CDCl3):
d
¼1.22 (s, 9H), 1.39 (s, 9H), 3.53e3.62
(m, 1H), 3.74e3.80 (m, 2H), 4.04e4.14 (m, 1H), 6.61e6.68 (m, 1H),
6.91e7.28 (m, 12H). 13C NMR (100 MHz, CDCl3): 29.6, 31.6, 34.0,
34.8, 51.3, 61.0, 68.9, 122.5, 122.9, 123.4, 127.0, 127.3, 127.5, 127.9,
128.3, 128.4, 135.9, 139.5, 140.5, 142.9, 154.5.
13C NMR (75 MHz, CDCl3):
d¼29.1, 31.4, 34.0, 34.9, 114.2, 117.8, 118.1,
118.1, 122.0, 123.9, 125.9, 126.3, 126.4, 126.4, 127.1, 127.6, 127.9, 128.1,
128.3, 129.2, 129.7, 132.6, 133.3, 133.9, 136.7, 139.8, 141.7, 144.3, 158.3,
162.7. Maldi-TOF: m/z¼502 [MþH]þ.
4.2.4. 2-((E)-(((1R,2R)-2-Amino-1,2-diphenylethyl)imino)methyl)-
4.2.8. 2-((E)-(((1R,2R)-2-Amino-1,2-diphenylethyl)imino)methyl)-4-
(tert-butyl)-6-tritylphenol (9). To a solution of (1R,2R)-(þ)-1,2-
diphenylethylenediamine (150.5 mg, 0.71 mmol, 1.02 equiv) in
4,6-di-tert-butylphenol$hydrochloride (5).29 (1R,2R)-1,2-Di-phenyl-
ethylenediaminemonohydrochloride
(350.0 mg,
1.40 mmol,

K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
8499
ꢀ
anhydrous DCM (8 mL) and molecular sieve 3 A (1.7 g) a solution of
aqueous H2O2 (30%, 1.2 equiv). The reaction mixture was stirred at
room temperature for 24 h. The product was directly purified by
column chromatography on silica gel (EtOAc/PE 4:1). The isolated
methyl phenyl sulfoxide was identified through comparison of 1H
NMR spectra with literature data (see Refs. 11e and 14a). The en-
antiomeric excess of the product was determined by chiral HPLC
analysis (Macherey-Nagel OD, flow 1.0 mL/min, Hex/i-PrOH 93:7,
25 ꢁC, 30e32 bar).
5-(tert-butyl)-2-hydroxy-3-tritylbenzaldehyde32
(293.9 mg,
0.69 mmol, 1.0 equiv) in DCM (7 mL) was added dropwise over
a period of 10 min. After the reaction mixture was stirred for 3 h at
room temperature, the solution was concentrated at 30 ꢁC and
quickly purified by flash column chromatography (SiO2, PE/EtOAc
7:3, then 1:1) to afford the desired product in 42% yield (185.0 mg)
as a yellow foam. 1H NMR (300 MHz, CDCl3):
d
¼1.11 (s, 9H), 1.85 (br
s, 2H), 4.21 (s, 2H), 6.94e7.21 (m, 26H), 7.29 (d, J¼2.4 Hz, 1H), 8.34
(s, 1H), 13.10 (br s, 1H). 13C NMR (75 MHz, CDCl3):
d¼31.2, 34.0, 62.0,
4.4.2. General proceduredslow addition of H2O2 via syringe
pump. FeCl3$6H2O (2 mol %) and corresponding ligands 2, 9, 10
63.4, 82.0, 118.1, 125.5, 127.0, 127.1, 127.2, 127.4, 127.5, 127.6, 127.8,
127.9, 128.0, 131.0, 132.0, 134.0, 140.0, 140.3, 141.6, 145.5, 157.5,
166.7. ESI-MS: calcd for [C44H42N2OþHþ] m/z¼615.3369. Found:
m/z¼615.3381. Anal. Calcd for C44H42N2O: C, 85.96; H, 6.89; N, 4.56.
Found: C, 85.22; H, 6.99; N, 4.39.
(4 mol %) were dissolved in THF (500
mediately dark violet and was stirred for 30 min. Thioanisole
(50.0 mg, 47.6 L, 0.40 mmol) was added, followed by the dropwise
mL). The solution turned im-
m
addition of aqueous H2O2 (30%, 1.2 equiv) via syringe pump over
a period of 5 h. The product was directly purified by column
chromatography on silica gel (EtOAc/PE 4:1).
4.2.9. 2-((E)-(((1R,2R)-2-Amino-1,2-diphenylethyl)imino)methyl)-6-
(tert-butyl)-4-tritylphenol (10). To a solution of (1R,2R)-(þ)-1,2-
diphenylethylenediamine (200.0 mg, 0.94 mmol, 1.02 equiv) in
4.5. Vanadium-catalyzed oxidation of thioanisole
ꢀ
anhydrous DCM (10 mL) and molecular sieve 3 A (2.2 g) a solution
of 3-(tert-butyl)-2-hydroxy-5-trityl-benzaldehyde32 (396.4 mg,
0.94 mmol, 1.0 equiv) in DCM (10 mL) was added dropwise over
a period of 30 min. After the reaction mixture was stirred for 3 h at
room temperature, the solution was concentrated at 30 ꢁC and
quickly purified by flash column chromatography (SiO2, PE/EtOAc
7:3) to afford the desired product in 37% yield (214.0 mg) as a yel-
4.5.1. General procedure. VO(acac)2 (2 mol %) and ligand 6 (3 mol %)
were dissolved in CHCl3 (500
green-brown after stirring for 60 min. Thioanisole (50.0 mg,
47.6 L, 0.40 mmol) was added, followed by the addition of aqueous
mL). The solution turned slightly
m
H2O2 (30%, 1.2 equiv) in one portion. The reaction mixture was
stirred at room temperature for 24 h. The product was directly
purified by column chromatography on silica gel (EtOAc/PE 4:1).
low foam. 1H NMR (300 MHz, CDCl3):
d
¼1.26 (s, 9H), 1.95 (br s, 2H),
4.19 (d, J¼8.2 Hz, 1H), 4.37 (d, J¼8.2 Hz, 1H), 6.89 (d, J¼2.4 Hz, 1H),
7.04e7.23 (m, 26H), 8.27 (s, 1H), 13.75 (s, 1H). 13C NMR (75 MHz,
4.6. General procedure for the synthesis of (R)-mod-
afinildvanadium catalysis
CDCl3):
d
¼29.3, 34.9, 62.1, 64.3, 117.3, 125.9, 127.3, 127.4, 127.6,
128.0, 128.1, 131.0, 131.9, 133.8, 136.0, 136.1, 146.8, 158.4. ESI-MS:
calcd for [C44H42N2OþHþ] m/z¼615.3369. Found: m/z¼615.3368.
Anal. Calcd for C44H42N2O: C, 85.96; H, 6.89; N, 4.56. Found: C,
86.40; H, 7.14; N, 4.41.
4.6.1. General procedure. VO(acac)2 (2 mol %) and ligand 6 or 10
(3 mol %) were dissolved in CHCl3 (145 mL). The solution turned
slightly green-brown after stirring for 60 min. 2-(Benzhydrylthio)
acetamide (30 mg, 0.12 mmol) was added, followed by the addition
of aqueous H2O2 (30%, 1.2 equiv) in one portion. The reaction mix-
ture was stirred at room temperature for a certain time (see Table 5,
entries 2e7). The product was directly purified by column chroma-
tography on silica gel (EtOAc). The isolated enantiomerically-
enriched (R)-modafinil was identified through comparison of 1H
NMR spectra with literature data (see Ref. 19). The enantiomeric
excess of the product was determined by chiral HPLC analysis (Daicel
Chiralpak AS, flow 0.9 mL/min, Hex/i-PrOH 60:40, 25 ꢁC, 31 bar).
4.3. Synthesis of new iron(III) complexes 11e13
4.3.1. General procedure. FeCl3$6H2O (1.0 equiv, 0.30 mmol) was
added to a solution of Schiff base ligands 2, 9 or 10 (2.0 equiv,
0.60 mmol) in THF (14 mL). The reaction mixture was stirred for 2 h
at room temperature under air after which the solvent was re-
moved completely furnishing the corresponding complexes 11, 12
or 13.
4.3.1.1. Complex 11. ESI-MS: calcd for [C58H70FeN4O2ꢀCl]þ
m/z¼910.4844. Found: m/z¼910.4851; IR (thin film): 3061, 3031,
2950, 2902, 2864, 2340, 2359, 1759, 1725, 1600, 1250, 1170, 772,
4.7. Epoxidation of alkenes
4.7.1. General procedure for the oxidation of trans-stilbene and de-
rivatives. FeCl3$6H2O (0.017 mmol), H2Pydic (0.017 mmol), and li-
gand 2 (0.033 mmol) were dissolved in dichloromethane (1.6 mL).
The mixture was stirred for 1 h at room temperature after which
the addition of the substrate (0.167 mmol) and H2O2 (30%,
0.250 mmol) followed. The reaction mixture was stirred for addi-
tional 1.5 h at room temperature. The reaction was quenched with
Na2SO3. The product was directly purified by column chromatog-
raphy on silica gel. The product was obtained as a colorless solid.
The enantiomeric excess was determined by chiral HPLC analysis.
697 cmꢀ1
.
4.3.1.2. Complex 12. ESI-MS: calcd for [C88H82FeN4O2ꢀCl]þ
m/z¼1282.5785. Found: m/z¼1282.5789; IR (thin film): 3054, 3027,
2957, 2864, 2359, 2340,1768,1719,1599,1442, 1257,1163, 1030, 747,
697 cmꢀ1
.
4.3.1.3. Complex 13. ESI-MS: calcd for [C88H82FeN4O2ꢀCl]þ
m/z¼1282.5785. Found: m/z¼1282.576; IR (thin film): 3055, 3028,
2953, 2866, 2359, 2339, 1768, 1721, 1598, 1441, 1163, 1032, 750,
698 cmꢀ1
.
4.7.1.1. trans-Stilbene oxide. 1H NMR (300 MHz, CDCl3):
d
¼7.42e7.32 (m, 10H), 3.87 (s, 2H). The enantiomeric excess of the
4.4. Iron-catalyzed oxidation of thioanisole
product was determined by chiral HPLC analysis (Daicel Chiralpak
IB, flow 1.0 mL/min, Hex/i-PrOH 92:8, 25 ꢁC, tR(R)¼4.80 min,
tR(S)¼6.52 min).
4.4.1. General proceduredaddition of H2O2 in one por-
tion. FeCl3$6H2O (2 mol %) and one corresponding ligand 1e10
(4 mol %) were dissolved in THF (0.5 mL). The solution, which
turned immediately dark violet, was stirred for 30 min. Thioanisole
4.7.1.2. 2,3-Di-p-tolyloxirane. 1H NMR (300 MHz, CDCl3):
d
¼7.22e7.16 (m, 8H), 3.81 (s, 2H), 2.36 (s, 6H); 13C NMR (100 MHz,
(47.6
mL, 0.40 mmol) was added, followed by the addition of
CDCl3):
d¼138.1, 134.2, 129.2, 125.4, 62.8, 21.2; MS (MALDI) m/z:

8500
K.A. Stingl et al. / Tetrahedron 68 (2012) 8493e8501
224 (5%, Mþ), 210 (10), 195 (55). The enantiomeric excess of the
product was determined by chiral HPLC analysis (Daicel Chiralpak
IA, flow 1.0 mL/min, Hex/i-PrOH 98:2, 25 ꢁC, tR1¼6.58 min,
tR2¼10.92 min).
3. Lindberg, P.; Brandstrom, A.; Wallmark, B.; Mattson, H.; Rikner, L.; Hoffman, K.-
J. Med. Res. Rev. 1990, 10, 1e54.
4. Legros, J.; Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005, 347, 19e31.
ꢁ
5. Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651e3706.
6. (a) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am.
~
Chem. Soc. 1992, 114, 5977e5985; (b) Carreno, M. C. Chem. Rev. 1995, 95,
1717e1760.
4.7.1.3. 2,3-Bis(4-iso-propylphenyl)oxirane. 1H NMR (400 MHz,
7. Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
6610e6611.
8. For enzymatic enantioselective epoxidation, see: (a) de Vries, E. J.; Janssen, D. B.
Curr. Opin. Biotechnol. 2003, 14, 414e420; (b) Archelas, A.; Furstoss, R. Top. Curr.
Chem. 1999, 200, 160e191; (c) de Bont, J. A. M. Tetrahedron: Asymmetry 1993, 4,
1331e1340.
CDCl3):
d
¼7.26e7.21 (m, 8H), 3.82 (s, 2H), 2.95e2.85 (m, 2H), 1.24
(d, J¼6.9 Hz,12H); 13C NMR (100 MHz, CDCl3):
¼149.1,134.6,126.6,
d
125.5, 62.7, 33.9, 24.0. The enantiomeric excess of the product was
determined by chiral HPLC analysis (Daicel Chiralpak IA, flow
1.0 mL/min, Hex/i-PrOH 98:2, 25 ꢁC, tR1¼6.47 min, tR2¼9.94 min).
9. For enzymatic enantioselective sulfoxidation, see: (a) Mata, E. G. Phosphorus
Sulfur Relat. Elem. 1996, 117, 231e286; (b) Andersson, M.; Willetts, A.; Allen-
mark, S. J. Org. Chem. 1997, 62, 8455e8458; (c) Boyd, D. R.; Sharma, N. D.;
Haughey, S. A.; Kennedy, M. A.; McMurray, B. T.; Sheldrake, G. N.; Allen, C. C. R.;
Dalton, H.; Sproule, K. J. Chem. Soc., Perkin Trans. 1 1998, 1929e1933.
10. (a) Collman, J. P.; Brauman, J. I.; Meunier, B.; Raybuck, S. A.; Kodadek, T. Proc.
Natl. Acad. Sci. U.S.A. 1984, 81, 3245e3248; (b) Que, L.; Ho, R. Y. N. Chem. Rev.
1996, 96, 2607e2624; (c) McLain, J. L.; Lee, J. J.; Groves, T. In Biomimetic Oxi-
dations Catalyzed by Transition Metal Complexes; Meunier, B., Ed.; Imperial
College Press: London, 2000; pp 91e169.
11. (a) Bolm, C.; Bienewald, F. Angew. Chem. 1995, 107, 2883e2885; Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2640e2642; (b) Bolm, C.; Schlingloff, G.; Bienewald, F. J.
Mol. Catal., A 1997, 117, 347e350; (c) Bolm, C.; Bienewald, F. Synlett 1998,
1327e1328; (d) Legros, J.; Bolm, C. Angew. Chem. 2003, 115, 5645e5647; Angew.
Chem., Int. Ed. 2003, 42, 5487e5489; (e) Legros, J.; Bolm, C. Angew. Chem. 2004,
116, 4321e4324; Angew. Chem., Int. Ed. 2004, 43, 4225e4228; (f) Legros, J.;
Bolm, C. Chem.dEur. J. 2005, 11, 1086e1092.
12. For examples of iron-catalyzed enantioselective epoxidation, see: (a) Francis,
M. B.; Jacobsen, E. N. Angew. Chem. 1999, 111, 987e991; (b) Gelalcha, F. G.;
Bitterlich, B.; Anilkumar, G.; Tse, M. K.; und Beller, M. Angew. Chem. 2007, 119,
7431e7435; (c) Gelalcha, F. G.; Bitterlich, B.; Anilkumar, G.; Tse, M. K.; und
Beller, M. Chem.dEur. J. 2008, 14, 7687e7698; (d) Yeung, H.-L.; Sham, K.-C.;
Tsang, C.-S.; Lau, T. C.; Kwong, H. L. Chem. Commun. 2008, 3801e3803.
13. Selected examples for metal-catalyzed enantioselective sulfoxidation: (a)
Green, S. D.; Monti, C.; Jackson, R. F. W.; Anson, M. S.; Mcdonald, S. J. F. Chem.
Commun. 2001, 2594e2595; (b) Ohta, C.; Shimizu, H.; Kondo, A.; Katsuki, T.
Synlett 2002, 161e163; (c) Pelotier, B.; Anson, M. S.; Campbell, I. B.; McDonald,
S. J. F.; Priem, G.; Jackson, R. F. W. Synlett 2002, 1055e1060; (d) Blum, S. A.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150e155; (e) Zeng, Q.; Wang,
H.; Wang, T.; Cai, Y.; Weng, W.; Zhao, Y. Adv. Synth. Catal. 2005, 347, 1933e1936;
(f) Jeong, Y.-C.; Huang, Y. D.; Choi, S.; Ahn, K.-H. Tetrahedron: Asymmetry 2005,
16, 3497e3501; (g) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem. 2005,
117, 7387e7389; (h) Kwiatkowski, E.; Romanowski, G.; Nowicki, W.; Kwiat-
kowski, M.; Suwinska, K. Polyhedron 2007, 26, 2559e2568; (i) Hsieh, S.-H.; Kuo,
Y.-P.; Gau, H.-M. Dalton Trans. 2007, 97e106; (j) Romanowski, G.; Kwiatkowski,
E.; Nowicki, W.; Kwiatkowski, M.; Lis, T. Polyhedron 2008, 27, 1601e1609; (k)
Koneva, E. A.; Volcho, K. P.; Korchagina, D. V.; Komarova, N. I.; Kochnev, A. I.;
Salakhutdinov, N. F.; Tolstikov, A. G. Russ. Chem. Bull., Int. Ed. 2008, 57, 108e117;
(l) Romanowski, G.; Wera, M. Polyhedron 2010, 29, 2747e2754; (m) Wo-
jaczynska, E.; Wojaczynski, J. Chem. Rev. 2010, 110, 4303e4356; (n) O’Mahony,
G. E.; Kelly, P.; Lawrence, S. E.; Maguire, A. R. Arkivoc 2011, i, 1e110; (o) Wu, Y.;
Mao, F.; Meng, F.; Li, X. Adv. Synth. Catal. 2011, 353, 1707e1712.
4.7.1.4. 2,3-Bis(4-(tert-butyl)phenyl)oxirane. 1H NMR (400 MHz,
CDCl3):
d
¼7.40 (d, J¼8.3 Hz, 4H), 7.27 (d, J¼8.3 Hz, 4H), 3.85 (s, 2H),
1.32 (s, 18H); 13C NMR (100 MHz, CDCl3):
d
¼151.3, 134.3, 125.5,
125.2, 62.7, 34.6, 31.3; MS (EI) m/z: 308 (5%, Mþ), 293 (10), 279 (90).
The enantiomeric excess of the product was determined by chiral
HPLC analysis (Daicel Chiralpak IA, flow 1.0 mL/min, Hex/i-PrOH
98:2, 25 ꢁC, tR1¼5.78 min, tR2¼6.30 min).
4.7.2. General procedure for the oxidation of styrol-de-
rivatives. FeCl3$6H2O (0.017 mmol), H2Pydic (0.017 mmol), and li-
gand 2 (0.033 mmol) were dissolved in dichloromethane (1.6 mL). The
mixture was stirred for 1 h at room temperature after which the ad-
dition of styrol or the derivative (0.166 mmol) and H2O2 (30%,
0.250 mmol) followed. The reaction mixture was stirred for additional
1.5 h at room temperature. The conversion of the products was de-
termined by GC analysis with the internal standard undecan (24.0
mL,
0.118 mmol). A sample of 100 L was taken out of the reaction mix-
m
ture, filtered (SiO2-plug, 1 cm) and washed with diethylether
(2.50 mL). The enantiomeric excess was determined by GC analysis.
4.7.2.1. 2-Methyl-3-phenyloxirane. The enantiomeric excess of
the product was determined by chiral GC analysis (Hydrodex b-
TBDAC-column, 25 m, ID 0.25 mm, 120 ꢁC, carrier gas: N2, flow:
2.0 mL/min, FID: 200 ꢁC, split: 60 mL/min; tR1¼7.26 min,
tR2¼7.65 min). 1H NMR (400 MHz, CDCl3):
¼7.34e7.24 (m, 5H),
d
3.56 (d, J¼1.9 Hz, 1H), 3.05e3.00 (m, 1H), 1.44 (d, J¼5.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d
¼137.7, 128.4, 128.0, 125.5, 59.5, 59.0, 17.9;
MS (MALDI) m/z: 133 (80%, [Mꢀ1]þ).
Acknowledgements
14. For selected examples of iron-catalyzed sulfide oxidation with H2O2 as terminal
ꢁ
oxidant, see: (a) Duboc-Toia, C.; Menage, S.; Ho, R. Y. N.; Que, L., Jr.; Lambeaux,
C.; Fontecave, M. Inorg. Chem. 1999, 38, 1261e1268; (b) Mekmouche, Y.;
Generous financial support from the DFG (Deutsche For-
schungsgemeinschaft) Sonderforschungsbereich SFB 583 ‘Redox-
Active Metal Complexes: Control of Reactivity via Molecular Archi-
tecture’ is gratefully acknowledged. The authors kindly thank Prof.
€
Hummel, H.; Ho, R. Y. N.; Que, Lˇ ., Jr.; Schunemann, V.; Thomas, F.; Trautwein, A.
X.; Lebrun, C.; Gorgy, K.; Lepretre, J.-C.; Collomb, M.-N.; Deronzier, A.; Fonte-
ꢁ
cave, M.; Menage, S. Chem.dEur. J. 2002, 8, 1196e1204; (c) Gosiewska, S.; Lutz,
M.; Spek, A. L.; Klein Gebbink, R. J. M. Inorg. Chim. Acta 2007, 360, 405e417; (d)
Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 8940e8941; (e) Egami, H.;
Katsuki, T. Synlett 2008, 1543e1546; (f) Jayaseeli, A. M. I.; Rajagopal, S. J. Mol.
Catal., A: Chem. 2009, 309, 103e110.
ꢁ
ꢁ
€
Dr. I. Ivanovic-Burmazovic, O. Troppner, and L. Nye for their support
with the mass spectrometric measurements.
15. Liu, KK.-C.; Sakya, S. M.; O’Donnell, C. J.; Flick, A. C.; Li, J. Bioorg. Med. Chem.
2011, 19, 1136e1154.
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17. Wong, Y. N.; King, S. P.; Simcoe, D.; Gorman, S.; Laughton, W.; McCormick, G. C.;
Grebow, P. J. Clin. Pharmacol. 1999, 39, 281e288.
18. (a) Lafon, L. U.S. Patent 4,927,855,1990; Chem. Abstr.1990, 112, 35457; (b) Osorio-
Lozada, A.; Prisinzano, T.; Olivo, H. F. Tetrahedron: Asymmetry 2004, 15,
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.052.
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