Alloxazine-cyclodextrin conjugates for organocatalytic enantioselective sulfoxidations

Article abstract of DOI:10.1039/c1ob05934c

Four structurally different alloxazine-cyclodextrin conjugates were prepared and tested as catalysts for the enantioselective oxidation of prochiral sulfides to sulfoxides by hydrogen peroxide in aqueous solutions. The alloxazinium unit was appended to the primary face of α- and β-cyclodextrins via a linker with variable length. A series of sulfides was used as substrates: n-alkyl methyl sulfides (n-alkyl = hexyl, octyl, decyl, dodecyl), cyclohexyl methyl sulfide, tert-butyl methyl sulfide, benzyl methyl sulfide and thioanisol. α-Cyclodextrin conjugate having alloxazinium unit attached via a short linker proved to be a suitable catalyst for oxidations of n-alkyl methyl sulfides, displaying conversions up to 98% and enantioselectivities up to 77% ee. β-Cyclodextrin conjugates were optimal catalysts for the oxidation of sulfides carrying bulkier substituents; e.g. tert-butyl methyl sulfide was oxidized with quantitative conversion and 91% ee. Low loadings (0.3-5 mol%) of the catalysts were used. No overoxidation to sulfones was observed in this study.

Full text of DOI:10.1039/c1ob05934c

Organic &
Biomolecular
Chemistry
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Volume 9 | Number 21 | 7 November 2011 | Pages 7257–7580
ISSN 1477-0520
COMMUNICATION
Viktor Mojr, Miloš Buděšínský, Radek Cibulka and Tomáš Kraus
Alloxazine–cyclodextrin conjugates for organocatalytic enantioselective sulfoxidations

Organic &
Biomolecular
Chemistry
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PAPER
Alloxazine–cyclodextrin conjugates for organocatalytic enantioselective
sulfoxidations†
a
b
a
b
Viktor Mojr, Milo sˇ Bud eˇ sˇ ´ı nsk y´ , Radek Cibulka* and Tom a´ sˇ Kraus*
Received 10th June 2011, Accepted 11th July 2011
DOI: 10.1039/c1ob05934c
Four structurally different alloxazine–cyclodextrin conjugates were prepared and tested as catalysts for
the enantioselective oxidation of prochiral sulfides to sulfoxides by hydrogen peroxide in aqueous
solutions. The alloxazinium unit was appended to the primary face of a- and b-cyclodextrins via a
linker with variable length. A series of sulfides was used as substrates: n-alkyl methyl sulfides (n-alkyl =
hexyl, octyl, decyl, dodecyl), cyclohexyl methyl sulfide, tert-butyl methyl sulfide, benzyl methyl sulfide
and thioanisol. a-Cyclodextrin conjugate having alloxazinium unit attached via a short linker proved to
be a suitable catalyst for oxidations of n-alkyl methyl sulfides, displaying conversions up to 98% and
enantioselectivities up to 77% ee. b-Cyclodextrin conjugates were optimal catalysts for the oxidation of
sulfides carrying bulkier substituents; e.g. tert-butyl methyl sulfide was oxidized with quantitative
conversion and 91% ee. Low loadings (0.3–5 mol%) of the catalysts were used. No overoxidation to
sulfones was observed in this study.
Introduction
by Ti(O-iPr) /(R,R)-DET/t-BuOOH (Kagan and Modena pro-
4
tocols; DET = diethyl tartarate) being one of the most widely
Chiral sulfoxides represent an important class of compounds.
Due to their high configurational stability, their efficiency at
carrying chiral information, and their accessibility in both enan-
tiomeric forms they serve as prominent chiral auxiliaries in
organic asymmetric synthesis. In medicinal chemistry, various
structures containing chiral sulfoxide moieties exhibit remarkable
1a,5,8
studied methods.
When binol ligands were used in place of
DET, enantioselectivities up to 96% enantiomeric excess (ee) were
9
achieved in thioanisole oxidations. Recently, oxidation systems
employing hydrogen peroxide as the terminal oxidant have been
studied due to their low cost and modest environmental impact.
Metal-catalyzed oxidations with hydrogen peroxide are usually
highly enantioselective (ee >90%) and require low loadings (1–2
mol%) of the catalyst. Mostly, these catalytic systems are based on
1
2
biological activities; for example, chiral sulfoxides appended to
imidazole moiety-containing compounds constitute a large family
of structures termed prazoles. These are known as gastric proton
pump inhibitors (PPI), which are clinically used as antiulcer
10
11
12
salen complexes with vanadium, aluminium, or iron formed
in situ in the reaction mixture. Some of these catalysts, namely
1
a,3
4
agents or psychostimulants (e.g. Modafinil ).
12d
11b
13
Fe(salan), Al(salalen) and platinum diphosphine complexes
were employed even in aqueous solutions.
The most straightforward synthetic approach to chiral sulfox-
ides rests in the enantioselective oxidation of prochiral sulfides
by chiral oxidants or by achiral oxidants under enantioselec-
The majority of the described methods are efficient in the oxida-
tion of alkyl aryl sulfides. In contrast, dialkyl sulfides are generally
1
a,5
tive catalysis.
Historically, the most successful enantioselec-
oxidized with only poor enantioselectivity and reports on their
tive catalytic approaches were realized with enzymes, namely
monooxygenases and peroxidases. Both classes of these enzymes
afforded good to excellent yields and enantioselectivities with a
relatively wide range of substrates.
In the realm of transition metal catalysis several systems have
been developed, oxidation under Sharpless conditions mediated
11,12d,14
successful oxidation appeared only recently.
Using Kagan
6
7
or Modena protocol with cumyl hydroperoxide as stoichiometric
14c
14a
reagent, methyl octyl sulfide and benzyl methyl sulfide were
oxidized with ee 83% and 90%, respectively. Oxidation of benzyl
methyl sulfide with urea–hydrogen peroxide adduct in methanol
in the presence of 2 mol% of Ti(salen) complex proceeded with ee
6f,6g,6i
14e
up to 93%. Oxidation of tert-butyl methyl sulfide with hydrogen
peroxide in chloroform catalyzed by V(salan) complex or with
PhIO in acetonitrile in the presence of Mn(salen) complex afforded
a
Department of Organic Chemistry, Institute of Chemical Technology,
Prague, Technick a´ 5, Prague 6, Czech Republic. E-mail: cibulkar@vscht.cz;
Fax: +420 220444288
14h,15
sulfoxide with ee 76% in both cases.
Fe(salan) complex is
b
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo
more general; it was applied as a catalyst for the enantioselective
oxidation of various alkyl methyl sulfides (alkyl = octyl, decyl,
dodecyl, cyclohexyl and benzyl) with hydrogen peroxide in wa-
n a´ m. 2, 166 10, Prague 6, Czech Republic. E-mail: kraus@uochb.cas.cz;
Fax: +420 220183560
†
1
Electronic supplementary information (ESI) available. See DOI:
0.1039/c1ob05934c
12d,14d
ter with ee values 87%–94%.
Metal catalysts are efficient
7
318 | Org. Biomol. Chem., 2011, 9, 7318–7326
This journal is © The Royal Society of Chemistry 2011

Scheme 1 Catalytic cycle of sulfoxidation by hydrogen peroxide mediated by alloxazinium salts.
2
5
in the enantioselective sulfoxidation of aromatic and aliphatic
sulfides; with most of them, however, high enantioselectivities
are achieved partly by overoxidation of one of the sulfoxide
enantiomers to sulfone (kinetic resolution) at the expense of the
yield.
We have recently described very efficient organocatalytic
systems for the enantioselective oxidation of aromatic sulfides by
hydrogen peroxide based on conjugates of b-cyclodextrin with
5-ethylflavin derivatives (both isoalloxazines and alloxazines).
Presumably, these systems take advantage of the pre-coordination
of the substrate with respect to the flavin-hydroperoxide (the actual
oxidant) by means of its inclusion in the cyclodextrin cavity.
In particular, the conjugate of b-cyclodextrin with alloxazine
afforded excellent conversions within minute reaction times and
enantioselectivities up to 80% ee in the oxidation of various
aromatic sulfides with small amount (£1 mol%) of the catalyst.
In this paper, we describe the syntheses and catalytic properties of
four structurally related alloxazine–cyclodextrin conjugates. We
focused our attention on the oxidation of aliphatic sulfides, for
which no organocatalysts have been reported so far.
Overoxidation to sulfones is usually absent in oxidation reac-
16
tions promoted by organocatalysts. Metal-free procedures are
also attractive from the point of view of potential practical ap-
plications because removal of metal traces is a persisting problem
in the pharmaceutical industry. However, enantioselectivities of
organocatalytic sulfoxidations published so far have been only
moderate in most cases. In general, 5-ethylflavin hydroperoxides
formed in situ from the corresponding flavinium salts and hydrogen
17
peroxide have been shown to oxidize sulfides efficiently. When
chiral flavinium catalysts with a cyclophane moiety were em-
ployed, substituted thioanisoles and methyl naphthyl sulfide were
18
oxidized with ee up to 65 or 72%, respectively. However, relatively
high loading of the catalyst (up to 12 mol%) was necessary
to achieve the above-mentioned enantioselectivity. Recently, the
oxidation of aryl methyl sulfides using hydrogen peroxide in the
presence of 5 mol% of planarly chiral flavinium salt affording ee
Results and discussion
1.
Design of catalysts
1
7a,26
The accepted mechanism
of sulfoxidations catalyzed by 5-
19
up to 54% has been reported.
27
ethylalloxazine derivatives is depicted in Scheme 1. Both oxidized
The stereodiscrimination in oxidation reactions catalyzed by
chiral flavin derivatives studied so far is assumed to be induced by
weak p–p interactions between the oxidant (flavin hydroperoxide)
26
and reduced forms, i.e. 5-ethylalloxazinium salt A and 5-
ethyldihydroalloxazine C, can be used for catalysis. In the latter
case, pre-activation of the alloxazine moiety with molecular
oxygen precedes the catalytic cycle.
19–20
and the aromatic substrate.
Therefore, flavin-based catalysts
are inefficient for the oxidation of aliphatic sulfides in terms of
enantioselectivity due to the absence of p–p interactions. Their
performance thus could be improved by a chiral substrate-binding
site attached to the molecule of the flavin catalyst. In particular,
cyclodextrins forming inclusion complexes with a wide range of
organic molecules could be used for this purpose since they were
found to increase reaction rates of various transformations in
We have designed four alloxazine–cyclodextrin conjugates 1a,
1b, 2a and 2b (Fig. 1) which differ in the size of the cyclodextrin
macrocycle and the length of the linker between the cyclodextrin
and alloxazine moieties. A suitable size of the macrocycle for
a particular substrate can be estimated using known stability
28
constants of a broad range of cyclodextrin inclusion complexes.
It was expected that a-cyclodextrin macrocycles should preferably
form inclusion complexes with aliphatic hydrocarbon chain-
containing sulfides, whereas larger cavity of b-cyclodextrin should
better accommodate sulfides bearing more bulky alkyl (cyclohexyl,
tert-butyl) and aromatic substituents. Slight variation of the length
of the linkage (x = 1 or 2) connecting cyclodextrin and alloxazine
should allow the design of a catalyst with an optimal fit between the
21
aqueous media. In addition, cyclodextrin cavities provide a chiral
environment allowing, in principle, an enantioselective course of
22
the reaction. D’Souza observed an enhanced rate of the oxidation
23
of benzylmercaptans to the corresponding disulfides and of
24
photooxidation of benzylalcohols to benzaldehydes mediated by
flavin moieties appended to b-cyclodextrin.
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7318–7326 | 7319

Fig. 1 Alloxazine–cyclodextrin conjugates prepared and tested as sulfox-
idation catalysts.
alloxazinium moiety and the sulfide group in the binary inclusion
complex. Amidic group was chosen as a connecting function
because of its chemical stability under the reaction conditions
employed and the viability of its formation from relatively easily
accessible reacting components, i.e. alloxazine carboxylic acids
and 6-amino-6-deoxy-cyclodextrins.
2
. Synthesis
The synthesis commenced with the preparation of alloxazine
carboxylic acids 3 and 4 (Scheme 2). 2-(3-Methylalloxazin-1-
yl)acetic acid 3 was prepared by alkylation of 3-methylalloxazine
25
with ethyl bromoacetate followed by acid hydrolysis. 3-(3-
Methylalloxazin-1-yl)propanoic acid 4 was obtained by addition
of 3-methylalloxazine to methoxy poly(ethylene glycol) monoacry-
29
late (mPEG-acrylate) under microwave irradiation and removal
of the PEG group by acid hydrolysis. Then conjugates 1a, 1b, 2a
and 2b were prepared using the methodology recently described
25
by us (Scheme 2). In general, aminocyclodextrin was allowed
to react with a slight excess of alloxazine carboxylic acid and
PyBOP in the presence of N,N-diisopropylethylamine (DIPEA).
Products 6a, 6b, 7a and 7b were isolated by means of reversed
phase chromatography with yields 53–78%. The actual catalysts,
i.e. N-ethylalloxazinium salts, were prepared by means of reductive
25
alkylation with acetaldehyde and hydrogen under catalysis by
palladium in acidic media.
Scheme 2 Syntheses of flavin–cyclodextrin conjugates 1a, 1b, 2a and
b; (a) PyBOP, DIPEA, DMF; (b) 1. CH CHO, Pd/C, H , EtOH, H O,
HClO ; 2. O , H O, HClO
2
3
2
2
In principle, reduced forms of the catalysts, i.e. N-ethyl-1,5-
25
4
2
2
4
.
dihydroalloxazine derivatives, are formed under these conditions.
However, both UV and mass spectrometries (vide infra) revealed
that the primary products of the reaction undergo oxidation in the
presence of air oxygen to the corresponding N-ethylalloxazinium
salts 1a, 1b, 2a, 2b. Despite our great efforts, we were unable to
record clear NMR spectra of the N-alkylated conjugates neither
in their reduced nor oxidized forms due to peak broadening, pre-
sumably as a result of the presence of radical species. Nevertheless,
in mass spectra only signals of alloxazinium ions (i.e. oxidized
form; see mass spectra in ESI†) were found. UV spectra of all
the prepared catalysts showed maxima at approximately 445 and
30
382 nm which are characteristic of alloxazinium salts. As an
example, the UV spectrum of 1b is compared with that of an
authentic sample of 5-ethyl-1,3-dimethylalloxazinium perchlorate
and its reduced form in Fig. 2 (for the spectra of other conjugates
1a, 2a and 2b see ESI†).
7
320 | Org. Biomol. Chem., 2011, 9, 7318–7326
This journal is © The Royal Society of Chemistry 2011

a
Table 1
H
2
O
2
-sulfoxidations catalyzed by conjugate 1a
b
e
Entry Sulfide
Time [min] Conv. [%] ee [%]
Opt. rot.
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
n-C
n-C
n-C
n-C
n-C
6
6
8
8
8
H
H
H
H
H
H
H
H
H
13SCH
13SCH
17SCH
17SCH
17SCH
21SCH
21SCH
25SCH
25SCH
3
3
3
3
3
10
20
10
60
54
90
19
78
47
47
(+)
(+)
c
c
d
67 (70 ) (+)
c
d
34 (37 ) (+)
c
d
5 (5 mol%) 63
77 (76 ) (+)
c
n-C10
n-C10
n-C12
n-C12
3
3
3
3
10
20
10
20
10
10
60
10
60
60
24
98
29
98
98
50
68
33
93
33
11
(+)
(+)
(+)
(+)
c
9
c
c
12
12
c
0
1
2
3
4
5
t-C
4
H
H
H
9
SCH
3
0
6
8
0
0
0
c
c-C
c-C
6
11SCH
11SCH
3
3
(+)
(+)
d
6
d
BnSCH
BnSCH
PhSCH
3
d
3
d
3
Fig. 2 UV–VIS spectra of the conjugate 1b (—) and 5-ethyl-1,3-
dimethylalloxazinium perchlorate (---) in aqueous solution at pH 2 (phos-
phate buffer). Spectrum of 5-ethyl-5,10-dihydro-1,3-dimethylalloxazine
a
Conditions: substrate (0.03–0.04 mmol), H O (2.3 equiv.), phosphate
2
2
buffer pH 7.5, R.T., catalyst loading 1 mol% (related to the substrate) if not
b
1
-5
-1
stated otherwise; vigorous shaking; conversion determined by H-NMR;
(
◊ ◊ ◊ ) in acetonitrile is shown for comparison; c = 5 ¥ 10 mol L .
Catalysis
We have studied the abilities of the four N-ethylalloxazinium salts
a, 1b, 2a and 2b to catalyze the oxidation of sulfides by hydrogen
c
1
enantiomeric excess determined by H-NMR using chiral shift agent;
d
3
.
enantiomeric excess determined by HPLC on a chiral stationary phase
e
(
see ESI†); sense of optical rotations derived from Chiralyser (426 nm)
detector in the course of analyses in heptane–isopropyl alcohol mixture.
1
peroxide (Scheme 3). A series of sulfides was used: n-alkyl methyl
sulfides (n-alkyl = hexyl, octyl, decyl, dodecyl), cyclohexyl methyl
sulfide, tert-butyl methyl sulfide and benzyl methyl sulfide. In
addition, thioanisol was included in the series of sulfides as a
representative of aromatic sulfides.
a
Table 2
H
2
O
2
-sulfoxidations catalyzed by conjugate 2a
b
e
Entry Sulfide
Time [min] Conv. [%]
ee [%]
Opt. rot.
c
1
2
3
4
5
6
7
8
n-C
n-C
n-C10
n-C12
6
8
H
H
13SCH
17SCH
21SCH
25SCH
3
3
10
10
10
10
10
10
10
60
36
13
14
16
79
33
24
25
24
17
(-)
(-)
c
c
H
H
H
3
3
0
0
0
0
0
0
c
c
t-C
c-C
BnSCH
PhSCH
4
9
SCH
3
d
6
H
11SCH
3
d
3
d
3
Scheme 3 Catalytic oxidation of sulfides by hydrogen peroxide.
a
2 2
Conditions: substrate (0.03–0.04 mmol), H O (2.3 equiv.), phosphate
buffer pH 7.5, R.T., catalyst loading 1 mol% (related to the substrate) if not
In general, oxidation reactions (Tables 1–4) were carried out
in aqueous buffered solutions (phosphate buffer, pH 7.5) with
b
1
stated otherwise; vigorous shaking; conversion determined by H-NMR;
c
1
enantiomeric excess determined by H-NMR using chiral shift agent;
d
1
mol% (except for entry 5, Table 1 and entries 6 and 14,
enantiomeric excess determined by HPLC on a chiral stationary phase
see ESI†); sense of optical rotations derived from Chiralyser (426 nm)
e
(
Table 3) of the N-ethylalloxazinium salt as the catalyst and 2.3
equivalents of hydrogen peroxide. In addition, control oxidation
experiments without conjugates were performed with selected
substrates to check the rate of the non-catalyzed oxidations
detector in the course of analyses in heptane–isopropyl alcohol mixture.
In addition, a set of randomly chosen samples representing all
n-alkyl methyl sulfoxide structures was also analyzed by HPLC
method using both UV and optical rotation (Chiralyser) detectors
in order (i) to verify the consistency of the results obtained by the
two approaches and (ii) to correlate the sense of optical rotations
of the sulfoxides with the NMR shifts of the diastereomeric
complexes. The latter allowed evaluation of the dependence of
the configuration of a major enantiomer on the structure of the
catalyst in all samples.
The a-cyclodextrin conjugate 1a showed preferential catalytic
activity in the oxidation reactions of aliphatic sulfides (Table
1). In this series of experiments, each reaction was first run for
ten minutes; if the conversion was lower than 90%, then longer
reaction time (20 or 60 min at maximum) was allowed. High
conversions (≥90%) were attained within 20 min of reaction time
with most aliphatic substrates except for octyl- and cyclohexyl-
substituted sulfides which gave 78% and 68% conversions, re-
spectively, in 60 min. Thioanisol afforded only 33% conversion.
The rate acceleration in the course of reactions of decyl methyl
(
Table 5). Since the sulfides were very poorly soluble in the
reaction media and some of them tended to stick to the glass
walls of the vials, preventing efficient stirring with a conventional
magnetic stirrer, the reaction mixtures were vigorously shaken
with a wrist-action shaker. Each substrate was allowed to react
for an indicated period of time and then the oxidation was
quenched by addition of sodium dithionite. Sulfoxide in common
with remaining sulfide was extracted to deuterated chloroform
and, subsequently, to tetrachloromethane. The conversion was
determined as the ratio of peaks of the respective S-methyl
1
groups in H NMR spectra recorded in combined chloroform–
tetrachloromethane solution. The enantiomeric excesses of the
1
n-alkyl methyl sulfoxides were determined by H NMR using (R)-
31,32
(
-)-3,5-dinitro-N-(1-phenylethyl)benzamide as a shift reagent.
This method proved less useful for aryl-, benzyl-, tert-butyl-
and cyclohexyl methyl sulfoxides because of insufficient peak
separation in the NMR spectra. In these cases, enantiomeric
excess was determined by HPLC using a chiral phase column.
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7318–7326 | 7321

a
Table 3
H
2
O
2
-sulfoxidations catalyzed by conjugate 1b
explained by the relatively slow oxidation of alloxazine moieties
to alloxazinium salts by molecular oxygen in the initial step of the
catalytic reaction. A similar induction period has been already
observed in oxidation of thioanisoles with hydrogen peroxide
b
e
Entry Sulfide
Time [min]
Conv. [%] ee [%]
Opt. rot.
c
d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
n-C
n-C
6
8
H
H
13SCH
17SCH
3
3
60
60
60
60
90
99
99
91
99
99
90
93
84
93
75
97
74
0 (0 )
c d
33
18 (17 ) (+)
catalyzed by 5-ethyldihydroalloxazines. It must be noted that
c
d
n-C10
n-C12
H
H
21SCH
25SCH
3
3
9 (10 )
(+)
(+)
(-)
(-)
(-)
(-)
(+)
(+)
(+)
(+)
(+)
(+)
kinetics of oxidation reactions in this system could also be affected
by the dissolution rate of poorly soluble sulfides. Last but not
least, both starting materials and products may, in principal, form
inclusion complexes of variable solubility which may also affect
the activity of the catalyst.
c
4
d
t-C
t-C
4
H
H
9
SCH
SCH
3
60
88
91
78
80
d
4
9
3
60 (5 mol%)
60
60 (5 C)
60
20
60 (5 C)
10
60 (5 C)
60 (0.3 mol%) 99 (91 )
d
c-C
c-C
6
H
H
11SCH
11SCH
3
3
◦
d
6
d
BnSCH
PhSCH
PhSCH
p-MePhSCH
p-MePhSCH
p-MePhSCH
3
30f
The oxidation reactions of n-alkyl sulfides with 1a revealed
various degrees of enantioselectivity, the highest values being
observed for n-hexyl methyl sulfoxide (47% ee) and n-octyl methyl
0
1
2
3
4
3
64
◦
d
3
64f
3
80
◦
d
3
3
80
78
1
sulfoxide (34–77%, entries 3–5, based on H NMR). While
g
h
d
with most substrates consistent values of enantiomeric excesses
independent of reaction time were observed, the reaction of n-
octyl methyl sulfide showed decreasing enantioselectivity with
increasing reaction time. These results were reproduced in several
repetitive experiments ruling out experimental artifacts. Since
control experiments (Table 5, entries 1 and 2) showed negligible
non-catalyzed oxidation of n-octyl methyl sulfide, we hypothesized
that autoinhibition with the product might be the cause of the
unexpected effect; with growing concentration of the product, a
new equilibrium between inclusion complexes of 1a with both
starting material and the product could be established, the latter
preventing proper pre-organization of the substrate with respect
to flavinium moiety. The uncomplexed sulfide could be oxidized
by alloxazinium moiety outside the cavity with lower (or without)
transfer of chirality. Thus, an analogous experiment with 5 mol
percent of the catalyst and shorter reaction time (Table 1, entry 5)
was carried out, which allowed for 77% ee, supporting the hypoth-
esis. No enantioselectivity was observed in the oxidation reaction
of tert-butyl methyl sulfide, benzyl methyl sulfide or thioanisole.
The homologous catalyst 2a having a longer linker between the
cyclodextrin and flavin proved to be less efficient in terms of both
conversions and enantioselectivities (Table 2). In most cases no
enantioselectivity was observed at all, although a slight preference
was encountered with hexyl and octyl sulfides (Table 2, entries 1
and 2). Therefore, this conjugate was not further investigated.
b-Cyclodextrin conjugates 1b and 2b were expected to be better
catalysts for the oxidation of bulkier substrates, such as phenyl-,
tert-butyl-, cyclohexyl- and benzyl methyl sulfides. Our earlier
preliminary results clearly showed that the conjugate 1b was
a very efficient catalyst for the oxidation of aromatic sulfides
a
Conditions: substrate (0.03–0.04 mmol, unless otherwise stated), H
2 2
O
(
2.3 equiv.), phosphate buffer pH 7.5, R.T., catalyst loading 1 mol% (related
b
to the substrate) if not stated otherwise; vigorous shaking; conversion
1
c
1
determined by H-NMR; enantiomeric excess determined by H-NMR
using chiral shift agent; enantiomeric excess determined by HPLC on
a chiral stationary phase (see ESI†); sense of optical rotations derived
from Chiralyser (426 nm) detector in the course of analyses in heptane–
isopropyl alcohol mixture; from ref. 25; preparative run (4.86 mmol of
substrate, 0.3 mol% of 1b, 7.9 mmol H
d
e
f
g
h
2
O
2
); isolated yield.
a
Table 4
H
2
O
2
-sulfoxidations catalyzed by conjugate 2b
b
e
Entry Sulfide
Time [min] Conv. [%]
ee [%]
Opt. rot.
c
d
1
2
3
4
5
6
7
8
9
n-C
n-C
n-C10
n-C12
6
8
H
H
H
H
13SCH
17SCH
21SCH
25SCH
3
3
60
60
60
60
60
60
60
60
60
92
44
99
98
98
92
92
70
96
64 (61 ) (-)
d
29
(-)
c
3
3
0
0
c
d
d
d
d
d
t-C
c-C
BnSCH
PhSCH
p-MePhSCH
4
H
9
SCH
3
86
80
58
36
69
(-)
(-)
(+)
(+)
(+)
6
H11SCH
3
3
3
3
a
2 2
Conditions: substrate (0.03–0.04 mmol), H O (2.3 equiv.), phosphate
buffer pH 7.5, R.T., catalyst loading 1 mol% (related to the substrate) if not
b
1
stated otherwise; vigorous shaking; conversion determined by H-NMR;
c
1
enantiomeric excess determined by H-NMR using chiral shift agent;
d
enantiomeric excess determined by HPLC on a chiral stationary phase
e
(
see ESI†); sense of optical rotations derived from Chiralyser (426 nm)
detector in the course of analyses in heptane–isopropyl alcohol mixture.
a
2 2
Table 5 Control experiments for H O -sulfoxidations of sulfides
b
Entry
Sulfide
Catalyst
Time [min]
Conv. [%]
(
thioanisoles) allowing high and rapid conversions in aqueous
25
1
2
3
4
5
6
7
8
n-C
n-C
8
8
H
H
17SCH
17SCH
3
3
3
3
3
a-CD
b-CD
a-CD
b-CD
—
a-CD
b-CD
—
60
60
60
60
60
60
60
60
4
3
media with enantioselectivities up to 80% ee. In the present
study, we have tested its catalytic activity against a broader scope
of substrates (Table 3). Unexpectedly, conjugate 1b proved also
efficient for the oxidation of n-alkyl methyl sulfides (Table 3, entries
1–4) allowing conversions 90–99% within 60 min of reaction time,
for n-octyl methyl sulfide the conversion being even higher than
in the case of 1a. Enantioselectivities were low, up to 18% ee for
n-octyl methyl sulfoxide (Table 3, entry 2). In contrast, tert-butyl
methyl sulfide was oxidized not only with an excellent conversion
but also with a significant enantioselectivity (88% ee; Table 3, entry
c-C
c-C
c-C
6
6
6
H
H
H
11SCH
11SCH
11SCH
28
31
39
95
95
98
t-C
t-C
t-C
4
H
H
H
9
9
9
SCH
SCH
SCH
3
3
3
4
4
a
2 2
Conditions: substrate (0.1 mmol), H O (2.3 equiv.), phosphate buffer pH
7
.5, R.T., catalyst loading 1 mol% (related to the substrate) if not stated
b
1
otherwise; vigorous shaking; conversion determined by H-NMR.
5). Since control experiments revealed that tert-butyl methyl sulfide
sulfide (cf. entries 6 and 7) and dodecyl methyl sulfide (cf. entries
is prone to rapid non-catalyzed oxidation (Table 5, entries 6–8) we
assumed that the product could be contaminated with racemic
sulfoxide arising from non-catalyzed reaction. Therefore, another
8
and 9) is remarkable and difficult to understand at first sight.
Lower activity of the catalyst in the initial period of time may be
7
322 | Org. Biomol. Chem., 2011, 9, 7318–7326
This journal is © The Royal Society of Chemistry 2011

experiment was carried out with 5 mol% of the catalyst, which
raised the enantiomeric excess to 91% (Table 3 entry 6) indicating
only a slight influence of the non-catalyzed oxidation. Cyclohexyl
methyl sulfide (Table 3, entry 7) also proved to be a good substrate
for 1b, allowing 90% conversion within 60 min and 78% ee. Benzyl
methyl sulfide (Table 3, entry 9) allowed a good conversion (84%
in 60 min) but a lower enantioselectivity (30% ee). Oxidation of
phenyl- and p-tolyl methyl sulfides proceeded with the excellent
conversions within 20 and 10 min and allowed 64% and 80% ee,
fides to sulfoxides by hydrogen peroxide. The common denomina-
tor for all conjugates is the alloxazinium structural unit appended
to cyclodextrin macrocycles of variable diameter via a linker with
variable length. It was expected that smaller a-cyclodextrin conju-
gates should be better catalysts for the oxidation of n-alkyl methyl
sulfides while the larger b-cyclodextrin conjugates should better
accommodate bulkier substituents such as cyclohexyl or tert-
butyl. However, n-alkyl methyl sulfides turned out to be the least
predictable of all substrates used, being oxidized by a-cyclodextrin
conjugate 1a as well as by both b-cyclodextrin conjugates 1b and
2b with high conversions within 60 min in most cases. Within
the series of n-alkyl methyl sulfides, catalysts 1a and 2b exerted
a relatively high degree of enantioselectivity in the oxidation
reactions of n-octyl and n-hexyl methyl sulfides, respectively.
Sulfides containing more bulky substituents, namely benzyl,
phenyl, cyclohexyl or tert-butyl gave higher conversions and
higher enantioselectivities with b-cyclodextrin-containing conju-
gates. The enantioselectivity of 91% ee achieved in the oxidation
of tert-butyl methyl sulfide catalyzed by 1b represents the highest
value reported to date for this substrate taking into account
synthetic (non-enzymatic) catalysts. Catalysis by the conjugate 1b
also afforded a very good enantioselectivity in the oxidation of
cyclohexyl methyl sulfide.
respectively. Lowering the temperature of the reaction mixture to
◦
5
C had negligible effect on enantioselectivities in oxidation of
selected substrates (Table 3, cf. entries 7–13). Finally, a preparative
run (Table 3, entry 14) was carried out to demonstrate scalability
of the catalytic system. Thus, oxidation of 4.9 mmol (672 mg) of p-
tolyl methyl sulfide with 7.9 mmol of hydrogen peroxide catalyzed
with only 0.3 mol% of the conjugate 1b allowed 99% conversion
(
91% of isolated yield) in 60 min of reaction time and 78% ee.
The oxidation of n-alkyl methyl sulfides with the conjugate 2b
gave somewhat lower conversions (Table 4) as compared with
b. The enantioselectivities tended to decrease with the growing
1
chain length; a remarkable 64% ee was achieved in the oxidation
of n-hexyl methyl sulfide but no preference was observed for n-
decyl- and n-dodecyl methyl sulfides. tert-Butyl and cyclohexyl
methyl sulfides were oxidized with both high conversions and very
good enantioselectivities (86% and 80% ee, respectively, Table 4,
entries 5 and 6). Benzyl methyl sulfide (Table 4, entry 7) was
oxidized with a slightly higher conversion and a significantly
higher enantioselectivity (58% ee) as compared to 1b. Thioanisole
Overall, the cyclodextrin–alloxazine conjugates reported in this
paper proved to be very efficient organocatalysts of the oxidation
of sulfides by hydrogen peroxide allowing good to excellent
conversions within 60 min in aqueous media using 1 mol% of
the organocatalyst. Importantly, no overoxidation to sulfones was
observed in this study.
(
Table 4, entry 8) was oxidized with moderate conversion and
enantioselectivity while p-tolyl phenyl sulfide (Table 4, entry 9)
showed high conversion but lower ee by 11% as compared with 1b.
Finally, the control oxidations of selected substrates with or
without a- or b-cyclodextrins showed no catalytic effect of native
cyclodextrins (Table 5), thus confirming the indispensable role
of the flavin moiety connected to the macrocycle. Unexpectedly,
tert-butyl methyl sulfide showed high conversions under all
conditions indicating that the competing non-catalyzed reaction
could have significant impact on enantioselectivities of those
catalyzed reactions that proceed with a slower rate. Cyclohexyl
methyl sulfide also exhibited non-negligible conversions.
Experimental section
General procedures
NMR spectra were acquired with spectrometers Bruker AVANCE
1
13
1
500 ( H at 500.1 MHz and C at 125.8 MHz), AVANCE 600 ( H at
1
3
600.1 MHz and C at 150.9 MHz, equipped with a cryoprobe) and
1
13
Varian Mercury Plus ( H at 299.97 MHz and C at 75.44 MHz)
in CDCl , d -DMSO or D O at 300 K. Homonuclear 2D-NMR
3
6
2
spectra (H,H-COSY) and heteronuclear 2D-NMR spectra (H,C-
HSQC and H,C-HMBC) were used for structural assignment of
proton and carbon signals of compounds 6a, 7a and 7b. Mass
spectra were measured using ES ionization either in positive or
negative mode (Waters micromass ZQ). High resolution mass
spectra were measured using nanoESI ionization on LTQ Orbitrap
XL (Thermo Fisher Scientific). Elemental analyses were carried
out on Perkin Elmer 2400 II. UV spectra were measured on
Varian Cary 50 spectrophotometer. Preparative reversed-phase
chromatography (RP) was carried out using medium pressure
columns containing C-18 modified silica (Phenomenex Luna,
15 mm). Thin-layer (TLC) and reversed-phase thin-layer (RPTLC)
chromatographies were performed with precoated Silica Gel 60 F
and RP-18 F plates (E. Merck). HPLC analyses were recorded
on Knauer Smartline with UV detector and detector of optical
rotatory power CHIRALYSER.
The sense of the optical rotations relevant to configurations
of the preferred enantiomers tended to depend on the catalytic
system used. Interestingly, a clear trend is observed for n-alkyl
methyl sulfoxides: (+)-enantiomers were obtained with catalysts
1a and 1b while (-)-enantiomers were preferred with 2a and 2b.
This suggests that the length of the linker between the flavinium
group and the macrocycle rather than the size of the macrocycle
is important for the absolute configuration of the products of
oxidations of n-alkyl methyl sulfides. Other sulfoxides cannot be
compared over the whole series of catalysts, yet limited conclusions
can be drawn: the configurations of tert-butyl methyl sulfoxide,
cyclohexyl methyl sulfoxide, benzyl methyl sulfoxide and phenyl
methyl sulfoxide, respectively, obtained by the oxidation under
catalysis with 1b remained the same also under catalysis with 2b.
25
2
zine,
-(3-Methylalloxazin-1-yl)acetic acid
3, 3-methylalloxa-
Conclusions
27,34
30
5-ethyl-1,3-dimethylalloxazinium perchlorate, 5-ethyl-
34
Four structurally different alloxazine–cyclodextrin conjugates pre-
pared in this study were tested as catalysts of the oxidation of sul-
5,10-dihydro-1,3-dimethylalloxazine,
mono-6-deoxy-6-amino-
35
36
b-cyclodextrin
5b, mono-6-deoxy-6-bromo-a-cyclodextrin,
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7318–7326 | 7323

25
25
conjugate 6b and its N-ethylated derivative 1b were prepared ac-
cording to the described procedures. All other chemicals used were
commercially available. Correct elemental analysis for compounds
by centrifugation, washed twice with acetone and dried in vacuo.
White fine powder (185 mg, 58% over two steps) was obtained. H
1
NMR [D O, 600.13 MHz] d: 5.091 (1H, d, J(1,2) = 3.3 Hz, H-1);
2
6
a, 7a and 7b could not be obtained unless variable numbers
5.074 (1H, d, J(1,2) = 3.5 Hz, H-1); 5.058 (1H, d, J(1,2) = 4.0 Hz,
H-1); 5.051 (1H, d, J(1,2) = 3.5 Hz, H-1); 5.046 (2H, d, J(1,2) = 3.5
Hz, H-1); 4.00–3.95 (6H, m, 6 ¥ H-3); 3.93–3.79 (16H, 6 ¥ H-5, 5 ¥
H-6a and 5 ¥ H-6b); 3.66–3.61 (6H, m, 6 ¥ H-2); 3.60–3.51 (6H, m,
6 ¥ H-4); 3.47 (1H, dd, J(6a,6b) = 13.7 and J(6a,5) = 2.8 Hz, H-6a)
and 3.15 (1H, dd, J(6b,6a) = 13.7 and J(6b,5) = 7.6 Hz, H-6b).
of water molecules were taken into account. Thus, calculations
based on accurate weights of these compounds (molarity, optical
rotation, yields) were corrected with respect to the water content
as deduced from elemental analysis. Hard copies of NMR and
mass spectra of conjugates and compounds 4 and 5a can be found
in the ESI.†
1
3
C NMR [D
04.03 (C-1); 103.86 (C-1); 84.05 (C-4); 83.98 (C-4); 83.93 (C-4);
83.91 (2 ¥ C-4); 83.83 (C-4); 76.05 (C-3); 76.01 (C-3); 76.00 (C-3);
2
O, 150.9 MHz] d: 104.12 (2 ¥ C-1); 104.07 (2 ¥ C-1);
1
Syntheses
7
7
5.97 (C-3); 75.87 (C-3); 75.84 (C-3); 74.81 (C-5); 74.77 (2 ¥ C-5);
4.72 (2 ¥ C-5); 74.70 (C-5); 74.38 (2 ¥ C-2); 74.35 (2 ¥ C-2); 74.22
3
-(3-Methylalloxazin-1-yl)propionic acid (4). A mixture of
3
0
-methylalloxazine (200 mg, 0.88 mmol), DABCO (98 mg,
.88 mmol) and tetrabutylammonium bromide (56 mg, 0.18 mmol)
was crushed in a mortar to give fine homogeneous powder. The
mixture was mixed with mPEG-acrylate (1.55 mL, 3.50 mmol)
and irradiated in a microwave reactor with max. power of 540
(
(
C-2); 74.20 (C-2); 63.23 (C-6); 63.16 (3 ¥ C-6); 63.11 (C-6); 43.55
C-6). H and C NMR shifts were consistent with the published
1 13
37
+
data. MS (ESI) m/z: [M + Na] calcd for C36H61NO29 994, found
994. Anal. Calcd for C36
H
61NO29·6H
2
O: C 40.04%, H 6.81%, N
1
.30%. Found: C 40.21%, H 6.79%, N 1.33%.
◦
W under max. temperature at 130 C for 40 min. Every 10
min (3 times) the reaction tube was removed from the reactor
and a dose of mPEG-acrylate (0.39 mL, 0.88 mmol) was added,
the mixture was dispersed by ultrasound and the reaction tube
was placed back into the reactor. After that, the reaction tube
was washed with DCM and the washings were collected and
evaporated. Hydrochloric acid (35%, 10 mL) was added to the
dry residue and the reaction mixture was heated to reflux for 45
min. Reaction mixture was diluted with water to approximately
quadruple volume and filtered. Filter cake was washed with water
and ether. Crude product was recrystallized from 2 M aqueous
acetic acid (20 mL). Green–yellow crystals (75 mg, 29%) were
N-(6-Deoxy-a-cyclodextrin-6-yl)
2-(3-methylalloxazin-1-yl)-
acetamide (6a). Acid 3 (26.5 mg, 92.6 mmol), mono-6-deoxy-
6-amino-a-cyclodextrin 5a (60.0 mg, 55.8 mmol, calculated for
hexahydrate) and PyBOP (48.2 mg, 92.6 mmol) were dissolved in
DMF (0.6 mL). Then DIPEA (43 mL, 0.25 mmol) was added.
The mixture was stirred overnight under an inert atmosphere at
ambient temperature. Then DMF was evaporated under reduced
pressure, and the resulting solid was purified by reversed phase
chromatography. Collected main fractions were concentrated
in vacuo and lyophilized. Light yellow fluffy solid (39.4 mg,
53%, calculated for hexahydrate) was obtained. UV–VIS (nm):
◦
1
+
obtained. M.p. 292–294 C. H-NMR[d
d: 2.69 (2H, t, J(1,2) = 7.8 Hz, CH ), 3.39 (3H, s, CH
2H, t, J(1,2) = 7.8 Hz, CH ), 7.84 (1H, m, Ar-H), 7.99 (1H, m,
Ar-H), 8.05 (1H, d, J(1,2) = 7.0 Hz, Ar-H), 8.25 (1H, d, J(1,2)
6
-DMSO, 600.13 MHz]
328, 378. HRMS (ESI) m/z: [M + Na] calcd for C H N O
1262.38179, found 1262.38155. For H NMR and C NMR data:
4
9
69
5
32
1
13
2
3
), 4.53
(
2
see Tables S1 and S2 in ESI.† Anal. Calcd for C H N O ·6H O:
4
9
69
5
32
2
C 43.65%, H 6.06%, N 5.19%. Found: C 43.89%, H 5.87%, N
5.16%.
1
3
=
7.0 Hz, Ar-H), 12.45 (1H, bs, COOH). C-NMR[d -DMSO,
6
1
50.9 MHz] d: 29.05, 32.05, 38.39, 127.99, 129.42, 130.45, 131.68,
N-(6-Deoxy-a-cyclodextrin-6-yl)
propanamide (7a). Acid 4 (37.0 mg, 123 mmol), mono-6-deoxy-
-amino-a-cyclodextrin 5a (100.0 mg, 93.0 mmol, calculated for
3-(3-methylalloxazin-1-yl)-
134.08, 139.32, 142.51, 145.51, 150.69, 159.82, 172.92. MS (ESI)
-
m/z: [M] calcd for C14
C
H
12
N
4
O
4
299, found 299. Anal. Calcd for
6
14
H
12
N
4
O
4
: C 56.00%, H 4.03%, N 18.66%. Found: C 55.92%, H
hexahydrate) and PyBOP (64.0 mg, 123 mmol) were dissolved in
DMF (1.0 mL). Then DIPEA (36 mL, 0.38 mmol) was added.
The mixture was stirred overnight under an inert atmosphere at
ambient temperature. Then DMF was evaporated under reduced
pressure, and the resulting solid was purified by reversed phase
chromatography. Collected main fractions were concentrated
in vacuo and lyophilized. Light yellow fluffy solid (91.0 mg,
4
.08%, N 18.28%.
Mono-6-deoxy-6-amino-a-cyclodextrin (5a). Mono-6-deoxy-
-bromo-a-cyclodextrin (335 mg, 0.32 mmol) was dissolved in
6
DMF (1.25 mL), then sodium azide (210 mg, 3.2 mmol) and
potassium iodide (27 mg, 0.16 mmol) were added and the reaction
mixture was heated at 80 C overnight under stirring. Then the in-
soluble material was filtered off and the filtrate was evaporated and
dried in vacuo. The resulting solid was purified by reversed phase
chromatography. Collected main fractions containing mono-6-
azido-6-deoxy-a-cyclodextrin were partly concentrated and the
product was precipitated by addition of acetone. The precipitate
was collected by means of centrifugation, then it was washed twice
with acetone and dried in vacuo. The obtained white fine powder
◦
7
3
1
8%, calculated for pentahydrate) was obtained. UV–VIS (nm):
+
81, 328. HRMS (ESI) m/z: [M + H] calcd for C50
H
72
N
5
O
32
1
13
254.41549, found 1254.41595. For H NMR and C NMR data:
see Tables S1 and S2 in ESI.† Anal. Calcd for C50
C 44.68%, H 6.07%, N 5.21%. Found: C 44.79%, H 6.13%, N
H
71
N
5
O
32·5H
2
O:
5
.79%.
(
220 mg) was dissolved in water (30 mL), 23 mg of palladium
N-(6-Deoxy-b-cyclodextrin-6-yl)
3-(3-methylalloxazin-1-yl)-
on charcoal (10%, 22 mmol) was added and the reaction mixture
was stirred in an autoclave for 4 h under atmosphere of hydrogen
propanamide (7b). Acid 4 (58.1 mg, 0.19 mmol), mono-6-deoxy-
6-amino-b-cyclodextrin 5b (200.0 mg, 0.16 mmol, calculated for
heptahydrate) and PyBOP (101.0 mg, 0.19 mmol) were dissolved
in DMF (2 mL). Then DIPEA (65 mL, 0.32 mmol) was added.
The mixture was stirred overnight under an inert atmosphere at
(
40 bar). After that the mixture was filtered through a pad of
Celite. The filtrate was concentrated in vacuo and the product was
precipitated by addition of acetone. The precipitate was separated
7
324 | Org. Biomol. Chem., 2011, 9, 7318–7326
This journal is © The Royal Society of Chemistry 2011

+
ambient temperature. Then DMF was evaporated under reduced
pressure, and the resulting solid was purified by reversed phase
chromatography. Collected main fractions were concentrated
in vacuo and lyophilized. Light yellow fluffy solid (143.0 mg,
HRMS (ESI) m/z: [M] calcd for C58
1444.49793.
H
86
O
37
5
N 1444.49961; found
Catalytic procedures
6
3
1
0%, calculated for tetrahydrate) was obtained. UV–VIS (nm):
+
All catalytic oxidations of alkyl or aryl methyl sulfides were
performed in 1 mL thick-walled screw-capped vial (Supelco). The
reaction mixtures were prepared by addition of sodium-phosphate
buffer (pH = 7.5, 0.05 M, 300 mL), liquid substrate (3–4 ¥ 10 mol),
appropriate volume of catalyst solution (1–5 mol%) and then the
hydrogen peroxide (2.3 mol. eq. with respect to substrate). The
vial was capped and the reaction mixture was shaken by wrist-
action shaker for a given period of time. Then the reaction was
quenched by addition of a solution of sodium dithionite in water
18, 380. HRMS (ESI) m/z: [M + Na] calcd for C56
438.4503, found 1438.4496. For H NMR and C NMR data:
H
81
N
5
O
37
1
13
see Tables S1 and S2 in ESI.† Anal. Calcd for C56
C 45.23%, H 6.07%, N 4.44%; found: C 45.19%, H 6.03%, N
H
81
N
5
O37·4H
2
O:
-
5
4
.71%.
1-{[N-(6-Deoxy-a-cyclodextrin-6-yl)carbamoyl]methyl}-5-ethyl-
3
3
-methylalloxazin-5-ium perchlorate (1a). Acetaldehyde (170 mL,
.03 mmol) and palladium on carbon (10%, 2.3 mg, 2.14 mmol)
(1.4 M, 170 mL). Product and remaining substrate were extracted
were added to a solution of 6a (14.4 mg, 10.7 mmol) in ethanol
to carbon tetrachloride (2 ¥ 500 mL) and then to CDCl (500 mL).
3
(
(
800 mL), perchloric acid (0.1 M in water, 800 mL) and water
600 mL). The resulting mixture was stirred for 18 h in the
Combined extracts were mixed and dried over sodium sulfate. One
third of extracts was used for the NMR analysis of the conversion.
Remaining solution was used for the analysis of enantiomeric
excess of the isolated sulfoxides by NMR employing chiral shift
autoclave under hydrogen atmosphere (0.6 MPa) at room
temperature. Then the catalyst was filtered off, ethanol and
resulting acetaldehyde were evaporated under reduced pressure.
The resulting solution of 1a was diluted to 2 mL. This stock
solution was frozen and stored at -78 C. The concentration of
the catalyst in the stock solution was recalculated with respect
31
reagent or by HPLC on chiral phases (for details see ESI†).
◦
Preparative oxidation of p-tolyl methyl sulfide
to the concentration of the conjugates prior to the alkylation
p-Tolyl methyl sulfide (672 mg, 4.86 mmol) was dissolved in
sodium-phosphate buffer (pH = 7.5, 0.05 M, 40 mL) and solution
of the catalyst 1b (14.59 mmol) and hydrogen peroxide (1 mL,
and the actual volume of the sample. UV–VIS (nm): 383, 440;
+
HRMS (ESI) (m/z): [M] calcd for C51
H
74
O
32
5
N 1268.43114,
found 1268.43000.
7
.94 mmol) were added. The reaction mixture was shaken in 125
mL bottle for 60 min using a wrist-action shaker. Then the reaction
was quenched by addition of solution of sodium dithionite in water
1
-{2-[N-(6-Deoxy-a-cyclodextrin-6-yl)carbamoyl]ethyl}-5-ethyl-
3
3
-methylalloxazin-5-ium perchlorate (2a). Acetaldehyde (170 mL,
.03 mmol) and palladium on carbon (10%, 2.3 mg, 2.14 mmol)
were added to a solution of 7a (14.3 mg, 10.8 mmol) in ethanol
800 mL), perchloric acid (0.1 M in water, 800 mL) and water
600 mL). The resulting mixture was stirred for 18 h in the
autoclave under hydrogen atmosphere (0.6 MPa) at room
temperature. Then the catalyst was filtered off, ethanol and
resulting acetaldehyde were evaporated under reduced pressure.
The resulting solution of 2a was diluted to 2 mL. This stock
(
1.4 M, 7 mL). Products were extracted to chloroform (3 ¥ 40 mL).
Collected extracts were dried over magnesium sulfate and filtered
over sintered glass. The filtrate was evaporated and dried in vacuo.
White solid (684 mg, 91%) was obtained. Analytical data were
(
(
38
consistent with the published ones.
Acknowledgements
This work was financially supported by Czech Science Foun-
dation (Grants No. 203/07/1246 and 203/09/1919) and IOCB
◦
solution was frozen and stored at -78 C. The concentration of
the catalyst in the stock solution was recalculated with respect
to the concentration of the conjugates prior to the alkylation
(Z40550506).
and the actual volume of the sample. UV–VIS (nm): 382, 444;
+
References
HRMS (ESI) m/z: [M] calcd for C52
H
76
O
32
5
N 1282.44679, found
1282.44373.
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-{2-[N-(6-Deoxy-b-cyclodextrin-6-yl)carbamoyl]ethyl}-5-ethyl-
2
3
3
-methylalloxazin-5-ium perchlorate (2b). Acetaldehyde (170 mL,
.03 mmol) and palladium on carbon (10%, 2.3 mg, 2.14 mmol)
were added to a solution of 7b (15.5 mg, 10.3 mmol) in ethanol
800 mL), perchloric acid (0.1 M in water, 800 mL) and water
600 mL). The resulting mixture was stirred for 18 h in the
2
(
b) C. M. Spencer and D. Faulds, Drugs, 2000, 60, 321–329; (c) A. M.
(
(
Rouhi, Chem. Eng. News, 2004, 82, 47–62.
R. Kumar, Drugs, 2008, 68, 1803–1839.
4
autoclave under hydrogen atmosphere (0.6 MPa) at room
temperature. Then the palladium-catalyst was filtered off, ethanol
and resulting acetaldehyde were evaporated under reduced
pressure. The resulting solution of 2b was diluted to 2 mL. This
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