Planar chiral flavinium salts - Prospective catalysts for enantioselective sulfoxidation reactions

Article abstract of DOI:10.1002/ejoc.201000592

A novel planar chiral flavinium salt, 3-benzyl-5-ethyl-10-(8- phenylnaphthalen-1-yl)isoalloxazinium perchlorate (2b), which bears a phenyl cap that covers one side of the isoalloxazinium skeleton plane, has been prepared as a potential catalyst for the enantioselective H₂O₂ oxidation of sulfides. The rate of H₂O₂ oxidation of sulfides in the presence of racemic 2b is comparable to that of the reaction catalysed by 5-ethyl-3,10-dimethylisoalloxazinium perchlorate, which indicates that the bulky shielding substituent does not influence the catalytic activity of the flavinium unit. The turnover frequency for the oxidation of thioanisole with hydrogen peroxide with 2b is 870 h^-1. The enantiomerically pure salts (+)-2b and (-)-2b were prepared from the pure enantiomers (+)-3b and (-)-3b of 3-benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine (3b) obtained by HPLC separation of racemic 3b on a chiral stationary phase. The enantiomerically pure salts (+)-2b and (-)-2b catalyse the H₂O₂ oxidation of para-substituted thioanisoles with enantiomeric excesses of 34-44%. The highest enantioselectivity (54% ee) was observed in the oxidation of methyl naphthyl sulfide.

Full text of DOI:10.1002/ejoc.201000592

FULL PAPER
DOI: 10.1002/ejoc.201000592
Planar Chiral Flavinium Salts – Prospective Catalysts for Enantioselective
Sulfoxidation Reactions
[a]
[a]
[b]
[a]
ˇ
ˇ
Radek Jurok, Radek Cibulka,* Hana Dvoráková, Frantisek Hampl, and
[a]
ˇ
Jana Hodacová
Keywords: Organocatalysis / Asymmetric catalysis / Sulfoxidation / Flavinium salts / Peroxides
A novel planar chiral flavinium salt, 3-benzyl-5-ethyl-10-(8-
phenylnaphthalen-1-yl)isoalloxazinium perchlorate (2b),
which bears a phenyl cap that covers one side of the isoallox-
azinium skeleton plane, has been prepared as a potential cat-
alyst for the enantioselective H2O2 oxidation of sulfides. The
rate of H2O2 oxidation of sulfides in the presence of racemic
2b is comparable to that of the reaction catalysed by 5-ethyl-
3,10-dimethylisoalloxazinium perchlorate, which indicates
that the bulky shielding substituent does not influence the
catalytic activity of the flavinium unit. The turnover fre-
quency for the oxidation of thioanisole with hydrogen perox-
ide with 2b is 870 h–1. The enantiomerically pure salts (+)-2b
and (–)-2b were prepared from the pure enantiomers (+)-3b
and (–)-3b of 3-benzyl-10-(8-phenylnaphthalen-1-yl)isoallox-
azine (3b) obtained by HPLC separation of racemic 3b on a
chiral stationary phase. The enantiomerically pure salts (+)-
2b and (–)-2b catalyse the H2O2 oxidation of para-substituted
thioanisoles with enantiomeric excesses of 34–44%. The
highest enantioselectivity (54% ee) was observed in the oxi-
dation of methyl naphthyl sulfide.
tive sulfoxidation reactions.[1a,4c,6] Recently, much interest
has been focused on environmentally friendly oxidation re-
actions, in particular those using hydrogen peroxide or oxy-
gen as terminal oxidants.[7] Interesting results have been ob-
tained in biological sulfoxidation reactions.[1a,8] In particu-
lar, flavin- and haem-dependent monooxygenases and per-
oxidases are efficient catalysts achieving excellent enantio-
selectivity, but they are strongly dependent on the substrate
structure. Steric factors also dramatically affect the yield
of biological oxidation reactions. The majority of catalytic
systems developed for sulfoxidation reactions are based on
metal-ion complexes with chiral ligands that oxidize pro-
chiral sulfides with good or even excellent enantio-
selectivity.[6,9] Although the loading of metal ions in oxi-
dation reactions catalysed by these complexes has been re-
duced substantially, the removal of metal traces is a perma-
nent problem in the pharmaceutical industry. Thus, the se-
arch for stereoselective, metal-free (organocatalytic) sulf-
oxidation systems is of high importance.[10]
Introduction
Methods for the preparation of enantiomerically pure
chiral sulfoxides are currently of particular importance be-
cause they are useful as intermediates or chiral auxiliaries in
organic synthesis.[1] Many drugs, including prazoles (proton
pump inhibitors[2a]) or the psychostimulants modafinil[2b]
and adrafinil,[2c] are racemic sulfoxides that challenge the
so-called chiral switch, that is, the launch of an enantiomer-
ically pure version of a formerly used racemic drug.[3] The
proton-pump inhibitor esomeprasol [(S)-omeprazol, NEX-
IUM®],[4] a pharmaceutical “blockbuster”, and psycho-
stimulant armodafinil [(R)-modafinil, NUVIGIL][5] are
recent examples of enantiomerically pure sulfoxides used as
pharmaceutical substances.
Among the reported organocatalytic sulfoxidation meth-
ods,[10,11] that using 4a-hydroperoxyflavin (Fl-OOH),
formed in situ from the corresponding flavinium salt
In addition to chiral stoichiometric oxidizing agents, sev-
eral catalytic systems have been developed for enantioselec-
–
(Fl+ClO4 ) and hydrogen peroxide (Scheme 1), seems to be
the most promising.[10a,11] This method is highly chemo-
selective, producing sulfoxides without overoxidation to
sulfones.[11–13] Hitherto, the vast majority of studies were
performed with non-chiral flavinium salts and attention has
been directed predominantly towards the efficiency and
chemoselectivity of catalytic systems. There are only a few
reports of chiral flavinium salts employed as catalysts in
enantioselective oxidation reactions. The first involves the
View this journal online at
[a] Department of Organic Chemistry, Institute of Chemical
Technology,
Technická 5, 166 28 Prague, Czech Republic
Fax: +420-220-444288
E-mail: cibulkar@vscht.cz
[b] Central Laboratories, Institute of Chemical Technology,
166 28 Prague, Czech Republic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000592.
wileyonlinelibrary.com
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R. Jurok, R. Cibulka, H. Dvorˇáková, F. Hampl, J. Hodacˇová
FULL PAPER
oxidation reactions of substituted thioanisoles[14a] and alkyl aryl sulfide, it is reasonable to assume mutual orienta-
methyl naphthyl sulfide[14b] catalysed by chiral flavinium tion of the substrate and the catalyst, as depicted in
salts possessing a cyclophane moiety. The observed ee val- Scheme 2. In this arrangement the alkyl group is directed
ues were up to 65 and 72%, respectively. However, a rela- away from the flavin skeleton plane and only one of the
tively high loading of the catalyst (up to 12 mol-% relative enantiotopic lone-pair electrons at the sulfur atom can in-
to the substrate) was necessary to achieve the above-men- teract with the hydroperoxy function of the catalyst. As the
tioned enantioselectivity. Another example of enantioselec- covering cap and rigid spacer, we chose a phenyl group and
tive oxidation catalysed by a chiral flavinium salt is the a naphthalene-1,8-diyl, respectively. In comparison with the
Baeyer–Villiger oxidation of para-substituted 3-phenylcy- planar chiral flavinium salt 1 previously reported by Mura-
clobutanones. In the presence of the planar chiral bis-fla- hashi et al.,[15] we assume better blocking of the corre-
vinium salt 1 the ee values of the resulting lactones ranged sponding site of the isoalloxazinium skeleton plane.
from 61 to 74%.[15]
Scheme 2. Proposed asymmetric induction in the oxidation of an
aromatic substrate with a planar chiral flavinium salt “covered”
with a cap.
The key intermediates in the synthesis of flavinium salts
2 are non-quaternized flavins 3, which were prepared start-
ing from commercially available naphthalene-1,8-diamine
Scheme 1. Catalytic cycle of H2O2 sulfoxidation mediated by a fla-
(Scheme 3). First, naphthalene-1,8-diamine was converted
into 8-bromonaphthalene-1-amine (5) via naphthotriazine
(4).[16] After amino group protection,[17] the bromo deriva-
tive 6 was coupled with phenylboronic acid and the amide
vinium salt.
Herein we report the design, synthesis and study of novel
planar chiral salts 2 as potential catalysts for enantioselec-
tive sulfoxidation reactions.
Results and Discussion
Design and Synthesis of the Flavinium Salts
The rationale for the design of the planar chiral fla-
vinium salts 2 is shown in Scheme 2. The cap attached by
a rigid spacer to a nitrogen atom at the 10-position of the
flavin skeleton is expected to allow access of the substrate
only from the “uncovered” face of the flavin moiety. Conse-
quently, only one of the hydroperoxyflavin diastereomers
formed in the reaction mixture can oxidize the substrate,
which is supposed to be bound to the flavin moiety by π–π
Scheme 3. Synthesis of flavins 3. Reagents and conditions:
(i) 1 equiv. NaNO2, AcOH, H2O, –6 to 0 °C, 95%; (ii) 48% HBr,
Cu, reflux, 67%; (iii) Ac2O, pyridine, 100 °C, 90%; (iv) PhB(OH)2,
Pd(OAc)2, PPh3, Na2CO3, nPrOH, H2O, reflux, 93%; (v) HCl,
EtOH, reflux, 90 (10a) or 95% (10b); (vi) 180 °C, 95%; (vii) AcOH,
stacking. Owing to steric demands of the alkyl group in reflux, 65 (3a) or 69% (3b).
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Catalysts for Enantioselective Sulfoxidation Reactions
7 obtained in this fashion was hydrolysed to 8-phenyl- Catalytic Activity of (؎)-2b in H2O2 Sulfoxidation
naphthalene-1-amine (8). Heating of the amine 8 with chloro- Reactions
uracil 9 at 180 °C resulted in aminouracil 10. Chlorouracils
First, we wished to establish the effect of the phenyl cap
9a (R = CH3) and 9b (R = Bn) were obtained from com-
on the catalytic activity of the flavinium salts. Therefore the
mercially available methyl- or benzylurea via the corre-
efficiency of the racemic salt (Ϯ)-2b in sulfoxidation reac-
sponding barbituric acids[18] (for the synthesis of chloroura-
tions of various substrates was compared with that of the
cils 9 see the Supporting Information). The flavin skeleton
simple “uncovered” salt 11. The reactions were performed
was formed by the reaction of aminouracil 10 with ni-
under the usual conditions, that is, with a small excess of
trosobenzene. We first applied the conditions described by
hydrogen peroxide in the presence of 1.5 mol-% of the cata-
Yoneda et al. for the preparation of simple flavins, that is,
lyst (relative to the substrate) at room temperature (for de-
by heating the reagents in a mixture of acetic anhydride/
tails see the Exp. Sect.).[12,13] The conversion can be moni-
acetic acid (4:1).[19] Unfortunately, in our case a lot of impu-
1
tored easily by H NMR spectroscopy. Therefore the reac-
rities resulted from the reaction mixture and flavins 3 were
tions were carried out in NMR tubes in deuteriated meth-
isolated in relatively low yields (23–28%). Optimization of
anol as solvent. Based on our previous experience,[12c] we
the reaction conditions increased the yields to 65–69%; we
did not assume any isotope effect of the solvent on the reac-
found pure acetic acid to be a much better solvent for this
tion kinetics. For all the substrates used in this study, the
cyclization. In this way, we prepared planar chiral flavins
oxidation reactions catalysed by both (Ϯ)-2b and 11 were
3a and 3b.
chemoselective, no overoxidation to sulfones was observed
Our strategy for the synthesis of enantiomerically pure
in any case. The rate enhancements of the sulfoxidation re-
catalysts 2 was based on the separation of enantiomers of
actions catalysed by (Ϯ)-2b and 11 are summarized in
flavins 3 by HPLC on a chiral stationary phase followed by
Table 1. A comparison of the kinetics of sulfoxidation cata-
their transformation into the final optically pure salts (+)-
lysed by (Ϯ)-2b and 11 is shown in Figure 1; the given ex-
2 and (–)-2 (Scheme 4). This approach was possible because
ample represents the oxidation of thioanisole (for the data
of the rigidity of planar chiral flavins preventing racemiza-
referring to other substrates, see the Supporting Infor-
tion during the final step of the synthesis. Unfortunately, in
mation). The data show clearly that the catalytic efficiency
preliminary experiments, we found the methyl derivative 3a
of (Ϯ)-2b is practically the same as that of 11, which indi-
to be almost insoluble in solvents suitable as a mobile phase
cates that the bulky shielding substituent does not diminish
for HPLC separations. On the other hand, the solubility of
the catalytic activity of the flavinium unit. The catalytic ac-
the more lipophilic benzyl derivative 3b was substantially
tivity of (Ϯ)-2b is very high: the rate enhancement of the
higher and we succeeded in separating it even on the 100 mg
oxidation of thioanisole performed under the afore-men-
scale using the Whelk stationary phase and the dichloro-
tioned conditions is approx. 200 in comparison with the
methane mobile phase (for details see the Exp. Sect. and
non-catalysed process and the turnover frequency of the
the Supporting Information). The enantiomerically pure
catalyst calculated from the initial reaction rate is 870 h–1.
salts (+)-2b and (–)-2b were synthesized from optically pure
The observed high ratio of the rates of the reaction cata-
flavins (+)-3b and (–)-3b, respectively, by reductive alk-
lysed by (Ϯ)-2b and the non-catalysed reaction represents a
ylation followed by oxidation of the thus-obtained 1,5-dihy-
necessary (although not sufficient) condition for enantiose-
droflavins (not isolated) with sodium nitrite in dilute per-
lective sulfoxidation catalysed by optically pure salts (+)-2b
chloric acid. Racemic flavinium perchlorate (Ϯ)-2b, em-
and (–)-2b as the non-catalysed side-reaction leads to race-
ployed in the basic screening of catalytic activity, was ob-
mic sulfoxides.
tained from (Ϯ)-3b in an analogous procedure (see
Scheme 4).
Table 1. Comparison of the catalytic efficiency of 2b and 11 in
H2O2 sulfoxidation reactions.
Entry
Substrate
Rate enhancement[a]
2b
11
1
2
3
4
5
Ph-S-Me
200
170
170
17
200
180
150
18[c]
100
p-MePh-S-Me
p-ClPh-S-Me
p-NO2Ph-S-Me
Ph-S-Bn
120
Scheme 4. Synthesis of the flavinium catalyst 2b. Reagents and con-
ditions: (i) (R,R)-Whelk-O1, dichloromethane; (ii) CH3CHO, 10%
Pd/C, H2, AcOH, H2O, room temp.; (iii) NaNO2, HClO4, MeOH,
H2O, NaClO4, 10 °C, 85% (two steps).
[a] Rate enhancement was calculated as the ratio of the rates of the
catalysed and non-catalysed reactions at low conversion[12,13] (up
to 10%).
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R. Jurok, R. Cibulka, H. Dvorˇáková, F. Hampl, J. Hodacˇová
FULL PAPER
creased the enantioselectivity. However, the observed effect
was small and, below –20 °C, even negligible (entries 1 vs.
2 and 7 vs. 8).
The optimized conditions [methanol/water, 2:1, –20 °C,
c(substrate) = 0.01 molL–1, 5 mol-% 2b relative to the sub-
strate] were used to investigate the enantioselectivity in the
oxidation of various sulfides (Table 3). As expected, cataly-
sis of the oxidation of thioanisole, both with (+)-2b and
with (–)-2b, afforded the product with the same ee but of
course with the opposite configuration (entries 1 and 2). In
the case of para-substituted thioanisoles, the ee values
ranged from 36 to 44% (entries 3–5). Interestingly, the ef-
fect of substitution at the para position of the phenyl ring
on the enantioselectivity seems to be relatively small. The
highest enantioselectivity (54% ee; entry 6) was observed in
the oxidation of methyl 2-naphthyl sulfide, most probably
due to its more extensive π system that may bind more ef-
ficiently to the catalyst. The enantioselectivity of the oxi-
dation of alkyl phenyl sulfides is practically independent of
the steric demands of the alkyl group; on going from the
methyl (entries 1 and 2) to the isopropyl (entry 7) and the
tert-butyl (entry 8) sulfides, the ee values decrease by only
3%. On the other hand, the enantioselectivities of dihy-
drobenzothiophene (entry 9) and cyclohexyl methyl sulfide
(entry 10) oxidation are poor. This is in accordance with
our assumption of the origin of the enantioselectivity of
alkyl aryl sulfide oxidation catalysed by planar chiral fla-
vinium salts 2 (Scheme 2). In the case of alkyl phenyl sul-
fides, the bulkiness of the alkyl group should not influence
the course of the oxidation because of its orientation rela-
tive to the flavinium unit. However, decreased conforma-
tional flexibility of the cyclic sulfide dihydrobenzothio-
phene does not allow this substrate to adopt the optimum
orientation depicted in Scheme 2 that is necessary for the
enantioselectivity of sulfoxidation. Low enantioselectivity
of the sulfoxidation of cyclohexyl methyl sulfide, which can-
not be bound to the catalyst by π–π stacking, also supports
our hypothesis of asymmetric induction (Scheme 2). 4-Ni-
trothioanisole is reported to afford high enantioselectivity
Figure 1. Oxidation of thioanisole with H2O2 catalysed by the fla-
vinium salt (Ϯ)-2b (᭿) and the flavinium salt 11 (∆). Non-catalysed
reaction: (᭺).
Enantioselective Sulfoxidation Reactions Catalysed by 2b
The conditions for the enantioselective sulfoxidation re-
actions catalysed by single enantiomers of 2b were opti-
mized by using thioanisole as a model substrate. In these
experiments we focused on the effects of the solvent, reac-
tion temperature and concentration of the reagents. In each
case the reaction was quenched at 70% conversion by the
addition of sodium dithionate. The ratio of enantiomers in
the isolated product was determined by HPLC on a Chi-
ralcel OD column. The results are summarized in Table 2.
Table 2. The effects of solvent, temperature and concentration of
reagents on asymmetric H2O2 sulfoxidation of thioanisole catalysed
by the flavinium salt (+)-2b.
Entry Solvent
T
[°C]
c (substrate)
ee
[molL–1]
[%][a]
1
2
3
4
5
6
7
8
CH3OH
CH3OH
CH3OH
0
0.2
0.2
0.01
0.2
0.01
0.01
0.01
0.01
8
–20
–20
–20
–20
–20
–20
–40
11
14
17
24
29
34
35
CF3CH2OH/CH3OH/H2O (6:3:1)
CF3CH2OH/CH3OH/H2O (6:3:1)
CH3OH/H2O (3:1)
CH3OH/H2O (2:1)
CH3OH/H2O (2:1)
Table 3. Enantioselective H2O2 sulfoxidation reactions of various
sulfides catalysed by the flavinium salts (+)-2b or (–)-2b.
[a] The enantiomeric ratios were determined by HPLC on a chiral
stationary phase (Chiralcel OD column).
Entry
Substrate
Catalyst ee [%][a] Config.[b]
1
2
3
4
5
6
7
8
9
10
Ph-S-Me
Ph-S-Me
(–)-2b
(+)-2b
(–)-2b
(–)-2b
(–)-2b
(–)-2b
(–)-2b
(–)-2b
(–)-2b
(–)-2b
34
34
42
36
44
54
32
31
5
(S)-(–)
(R)-(+)
(S)-(–)
(S)-(–)
(S)-(–)
(S)-(–)
(S)-(–)
(S)-(–)
(R)-(–)
–
The choice of solvents was inspired by previous experi-
ence with enantioselective oxidations catalysed by chiral fla-
vinium salts reported by Murahashi[14b,15] and Shinkai and
their co-workers.[14a] Similarly, as in the case of sulfoxid-
ation reactions catalysed by cyclophane-based flavinium
salts,[14] the presence of water as well as the dilution of the
reaction mixture were found to increase the enantio-
selectivity. The best results were obtained in a methanol/
water (2:1, v/v) mixture. Unfortunately, a further increase
in the water content led to inhomogeneity of the system.
The presence of trifluoroethanol[15] in the reaction mixtures
(entries 4 and 5) did not lead to higher enantioselectivity.
p-MePh-S-Me
p-MeOPh-S-Me
p-ClPh-S-Me
2-Naphthyl-S-Me
Ph-S-iPr
Ph-S-tBu
2,3-Dihydrobenzo[b]thiophene
Cyclohexyl-S-Me
4
[a] The enantiomeric ratios were determined by HPLC on a chiral
stationary phase (Chiralcel OD column) or by 1H NMR (entry 10)
in the presence of (R)-N-(3,5-dinitrobenzoyl)-1-phenylethan-1-
amine as a chiral shift reagent.[20] [b] The absolute configurations
were assigned by comparing optical rotations and HPLC elution
As expected, a decrease of the reaction temperature in- orders with known literature data.[9e,21]
5220 Eur. J. Org. Chem. 2010, 5217–5224
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Catalysts for Enantioselective Sulfoxidation Reactions
s, 3 H, N+CH2CH3), 4.75–5.25 (br. s, 1 H), 5.09 (d, J = 14.1 Hz, 1
H), 5.24 (d, J = 14.3 Hz, 1 H), 5.40–5.90 (br. s, 1 H), 6.35 (m, 1
H), 6.49 (m, 1 H), 6.54 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.0 Hz, 1
H), 7.02 (m, 1 H), 7.19 (d, J = 8.2 Hz, 1 H), 7.25 (d, J = 7.0 Hz, 1
H), 7.34 (t, J = 7.2 Hz, 1 H), 7.39 (d, J = 7.2 Hz, 1 H), 7.39–7.41
(m, 2 H), 7.42–7.50 (m, 3 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.85 (t, J
= 7.8 Hz, 1 H), 7.88 (t, J = 7.8 Hz, 1 H), 7.97 (t, J = 7.7 Hz, 1 H),
8.22 (d, J = 8.5 Hz, 1 H), 8.35 (d, J = 7.9 Hz, 1 H), 8.40 (d, J
= 8.5 Hz, 1 H) ppm. The signals are assigned in the Supporting
Information. 13C NMR (CDCl3, 125 MHz): δ = 15.0, 47.0, 121.3,
122.7, 126.1, 127.1, 127.3, 127.4, 127.7, 127.8, 128.9, 129.1, 129.3,
129.4, 129.5, 129.6, 129.7, 130.7, 131.4, 131.7, 132.7, 134.0, 136.5,
136.6, 136.7, 136.74, 139.5, 140.6, 141.6, 151.3, 152.6, 155.3 ppm.
C35H27ClN4O6 (634.16): calcd. C 66.19, H 4.29, N 8.82; found C
65.85, H 3.93, N 8.87.
in the case of oxidation reactions catalysed by chiral metal
complexes.[9] Unfortunately, in our case, the results of the
oxidation of 4-nitrothioanisole were not reproducible be-
cause of its low solubility in the reaction mixture.
Conclusions
We have demonstrated that the novel planar chiral fla-
vinium salt 2b catalyses the enantioselective oxidation of
alkyl aryl sulfides with hydrogen peroxide to yield the corre-
sponding sulfoxides with up to 54% ee. The catalytic effi-
ciency of 2b towards various sulfides is relatively high, com-
parable to that of simple isoalloxazinium salts. However,
the observed enantioselectivity is lower than that reported
Compounds (+)-2b and (–)-2b were obtained from (+)-3b and (–)-
3b, respectively, following the above-described procedure. Specific
for chiral metal complexes. Nevertheless, it is comparable rotation: (+)-2b: [α]2D5 = 785 (c = 0.2, CHCl3); (–)-2b: [α]2D5 = –798
(c = 0.2, CHCl3).
with the results obtained with the organocatalytic systems
reported until now.[10,14] Moreover, the structure of the cat-
alyst 2b can be modified easily by substitution on the
phenyl or pyrimidine ring, which could increase the
enantioselectivity. The novel planar chiral flavinium salt 2b
may also be applied to other types of oxidation reactions,
for example, Baeyer–Villiger oxidation reactions.
3-Methyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine (3a): A mixture
of aminouracil 10a (343 mg, 1 mmol) and nitrosobenzene (321 mg,
3 mmol) was stirred in acetic acid (8 mL) at reflux for 45 min. Then
the solvent was evaporated and the residue was purified by column
chromatography (chloroform/methanol, 100:2) and crystallization
from chloroform/diethyl ether to afford 3a (280 mg, 65%) as yellow
1
needles; m.p. Ͼ350 °C. H NMR (CDCl3, 500 MHz): δ = 3.49 (s,
3 H), 6.14 (d, J = 7.4 Hz, 1 H), 6.48 (t, J = 7.4 Hz, 1 H), 6.56 (d,
J = 8.2 Hz, 1 H), 6.89 (t, J = 7.4 Hz, 1 H), 7.01 (t, J = 7.4 Hz, 1
H), 7.12 (d, J = 7.5 Hz, 1 H), 7.15 (d, J = 6.9 Hz, 1 H), 7.31 (d, J
= 7.4 Hz, 1 H), 7.52 (m, 3 H), 7.69 (t, J = 8.0 Hz, 1 H), 8.04 (d, J
= 8.2 Hz, 1 H), 8.15 (d, J = 8.2 Hz, 1 H), 8.18 (d, J = 8.2 Hz, 1
H) ppm. The signals are assigned in the Supporting Information.
13C NMR (CDCl3, 125 MHz): δ = 28.7, 117.3, 125.8, 126.0, 126.2,
126.4, 126.6, 127.0, 127.9, 128.6, 129.0, 129.4, 131.3, 131.5, 132.2,
132.3, 134.7, 135.7, 136.0, 136.9, 137.2, 140.3, 149.9, 155.6,
159.2 ppm. C27H18N4O2 (430.47): calcd. C 75.34, H 4.21, N 13.02;
found C 75.16, H 4.34, N 10.99.
Experimental Section
General: Melting points were measured with a Boetius Block appa-
ratus. NMR spectra were recorded with a Varian Mercury Plus 300
(299.97 MHz for 1H anup>H and 125.77 MHz for 13C), and a
Bruker 600 Avance III spectrometer (600.13 MHz for 1H and
150.92 MHz for 13C). The 1H and 13C NMR chemical shifts are
reported in ppm relative to tetramethylsilane as an internal stan-
dard. Optical rotations were measured with a Perkin–Elmer M-241
digital polarimeter. All reagents were purchased from commercial
sources and used without any treatment unless otherwise indicated.
TLC analyses were carried out on DC Alufolien Kieselgel 60H
3-Benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine (3b): Isoalloxa-
zine 3b was prepared analogously to 3a from aminouracil 10b
(840 mg, 2 mmol) and nitrosobenzene (643 mg, 6 mmol) in acetic
F254 (Merck). Preparative column chromatography was performed acid (15 mL). Column chromatography (chloroform/ethyl acetate,
on Kieselgel 60 silica gel (0.040–0.063 mm, Merck). Elemental 4:1) and crystallization from chloroform/diethyl ether afforded 3b
analyses were performed with a Perkin–Elmer 240 analyser. Prepar-
ative HPLC was carried out with an Agilent 1100 Series instru-
ment.
(700 mg, 69%) as yellow needles; m.p. 289–291 °C. 1H NMR
(CDCl3, 500 MHz): δ = 5.24 (m, 2 H), 6.06 (d, J = 7.5 Hz, 1 H),
6.16 (t, J = 7.4 Hz, 1 H), 6.40 (t, J = 7.5 Hz, 1 H), 6.55 (d, J =
8.3 Hz, 1 H), 6.82 (t, J = 7.4 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 1 H),
7.10 (d, J = 6.9 Hz, 1 H), 7.24–7.34 (m, 4 H), 7.40–7.54 (m, 3 H),
7.64–7.69 (m, 3 H), 8.01 (d, J = 8.2 Hz, 1 H), 8.11 (d, J = 7.9 Hz,
1 H), 8.16 (d, J = 8.2 Hz, 1 H) ppm. The signals are assigned in
the Supporting Information. 13C NMR (CDCl3, 125 MHz): δ =
44.8, 117.2, 125.9, 126.0, 126.1, 126.3, 126.6, 126.7, 127.8, 128.3,
128.6, 128.9, 129.3, 129.9, 131.3, 131.5, 132.1, 132.2, 134.7, 134.8,
135.7, 135.9, 137.0, 137.2, 137.4, 140.2, 149.8, 155.1, 158.8 ppm.
C33H22N4O2 (506.57): calcd. C 78.25, H 4.38, N 11.06; found C
78.31, H 4.32, N 11.02.
3-Benzyl-5-ethyl-10-(8-phenylnaphthalen-1-yl)isoalloxazinium Per-
chlorate (2b): Palladium on charcoal (10%; 50 mg) and acetalde-
hyde (0.5 mL) were added to a solution of 3b (101 mg, 0.2 mmol)
in a mixture of acetic acid (20 mL) and water (2 mL). The resulting
mixture was stirred for 36 h in an autoclave under H2 (0.2 MPa) at
room temperature. Then the catalyst was filtered off, acetic acid
was evaporated under reduced pressure and the remaining solid
was dried in vacuo. The residue was dissolved in a minimum vol-
ume of methanol (ca. 1 mL) and 2  perchloric acid (2 mL) and
sodium perchlorate (500 mg) were added. Sodium nitrite (110 mg)
was added in several portions to the stirred mixture at 10 °C within
30 min. After stirring for an additional 45 min at the same tempera-
ture, the precipitate was filtered off, washed with water and dried.
The solid obtained was dissolved in acetonitrile, reprecipitated by
the addition of diethyl ether and dried in vacuo at room tempera-
Resolution of Racemic Flavin 3b: Enantiomers of 3b were separated
by HPLC on a chiral stationary phase. Conditions for preparative
chromatography: (R,R)-Whelk-O1 column (ø 1 cm, length 25 cm),
dichloromethane as eluent, flow rate: 2.0 mL/min, detection: UV
254 nm; retention times: 15.2 [(–)-3b] and 28.5 min [(+)-3b]. Condi-
tions for analytical chromatography: (R,R)-Whelk-O1 column (ø
ture to obtain 2b (108 mg, 85%) as a black microcrystalline pow-
1
der; m.p. 181–183 °C. H NMR (CD3CN, 600 MHz): δ = 1.82 (br. 0.46 cm, length 25 cm), dichloromethane as eluent, flow rate =
Eur. J. Org. Chem. 2010, 5217–5224
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R. Jurok, R. Cibulka, H. Dvorˇáková, F. Hampl, J. Hodacˇová
FULL PAPER
0.5 mL/min, detection: UV 254 nm, retention times: 10.3 [(–)-3b]
and 19.3 min [(+)-3b]. For the chromatogram, see Figure S3 of the
Supporting Information. Specific rotation: (+)-3b: [α]D = 870 (c =
0.5, CHCl3); (–)-3b: [α]2D5 = –879 (c = 0.5, CHCl3).
H), 8.03 (d, J = 7.3 Hz, 1 H, Ar-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.0, 119.4, 121.0, 122.9, 123.1, 125.7, 125.8, 126.0,
127.7, 128.0, 133.0, 133.4, 134.4, 137.9, 138.7, 168.7 ppm.
8-Phenylnaphthalene-1-amine (8):
A mixture of 7 (14.11 g,
1H-Naphtho[1,8,8a-de][1,2,3]triazine (4):[16a] A solution of NaNO2
(9.12 g, 132 mmol) in water (53 mL) was added to a solution of
naphthalene-1,8-diamine (20.00 g, 126 mmol) in a mixture of acetic
acid (240 mL) and water (175 mL) at –6 °C. Then the reaction mix-
ture was diluted with water (40 mL) and stirred at 0 °C for 45 min.
The brown precipitate was filtered off, washed with water and dried
at room temperature to give 20.30 g (95%) of a brown powder,
54 mmol), ethanol (70 mL) and conc. hydrochloric acid (30 mL)
was heated at reflux for 10 h. After evaporation of the solvents, the
residue was stirred with diethyl ether (100 mL) and a solution of
NaOH (5 g) in water (50 mL) until the solid was completely dis-
solved. The organic layer was separated and the aqueous layer ex-
tracted with diethyl ether (30 mL). The combined organic layers
were washed with brine (30 mL), dried with MgSO4 and evaporated
1
1
which was sufficiently pure for the next synthesis. H NMR ([D6]-
to afford 8 (11.25 g, 95%) as a light-brown oil. H NMR (CDCl3,
DMSO, 300 MHz): δ = 6.13 (d, J = 7.2 Hz, 1 H, Ar-H), 6.89 (d, J
= 8.2 Hz, 1 H, Ar-H), 7.03 (d, J = 8.4 Hz, 1 H, Ar-H), 7.13 (t, J
300 MHz): δ = 3.72 (br. s, 2 H, NH2), 6.64 (d, J = 7.3 Hz, 1 H,
Ar-H), 7.17 (d, J = 7.0 Hz, 1 H, Ar-H), 7.27–7.49 (m, 8 H, Ar-H),
= 8.0 Hz, 1 H, Ar-H), 7.26 (m, 2 H, Ar-H), 13.29 (br. s, 1 H, 7.80 (d, J = 8.2 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3, 75 MHz):
NH) ppm.
δ = 111.5, 119.3, 120.9, 124.8, 126.8, 127.7, 128.3, 128.5, 128.9,
129.5, 136.1, 138.5, 143.8, 144.0 ppm.
8-Bromonaphthalene-1-amine (5):[16b] Copper powder (6.00 g,
94 mmol), activated by iodine,[16c] was added to a vigorously stir-
ring solution of 4 (20.00 g, 118 mmol) in aqueous HBr (48%,
140 mL) at 50 °C. When the intense evolution of nitrogen had fin-
ished, the mixture was heated at reflux. The mixture was diluted
with water (300 mL), heated to boiling and filtered. The residue
was washed with boiling water (150 mL). The combined filtrates
were neutralised with ammonia and extracted with diethyl ether.
The ethereal solution was washed with water, filtered (to remove
suspended solid) and dried with MgSO4. The crude product ob-
tained after solvent evaporation was purified by column
chromatography (toluene) to afford 5 (17.61 g; 67%) as a pink so-
lid; m.p. 90–91 °C (ref.[16b] 89–90 °C). 1H NMR (CDCl3,
300 MHz): δ = 5.14 (br. s, 2 H, NH2), 6.71–6.77 (m, 1 H, Ar-H),
7.11–7.17 (m, 1 H, Ar-H), 7.23–7.27 (m, 1 H, Ar-H), 7.62 (dd, J =
7.6, J = 1.2 Hz, 1 H, Ar-H), 7.69 (dd, J = 8.2, J = 1.2 Hz, 1 H,
Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.0, 121.3, 121.5,
121.7, 124.4, 125.5, 125.7, 127.4, 134.9, 145.2 ppm.
3-Methyl-6-[(8-phenylnaphthalen-1-yl)amino]uracil (10a): A mixture
of 9a (0.78 g, 5 mmol) and 8 (3.29 g, 15 mmol) was stirred under
nitrogen at 180 °C for 40 min. After cooling, the resulting solid was
filtered off, washed with diethyl ether (3ϫ20 mL) and methanol
(2ϫ10 mL) and dried in vacuo to afford 10a as a white solid
(1.54 g, 90%); m.p. 294–296 °C. 1H NMR ([D6]DMSO, 300 MHz):
δ = 2.95 (s, 3 H, CH3), 3.80 (s, 1 H, CH=), 7.10–7.30 (m, 6 H, Ar-
H), 7.37 (d, J = 7.3 Hz, 1 H, Ar-H), 7.57 (m, 2 H, Ar-H), 8.03 (m,
2 H, Ar-H), 9.46 (br. s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 26.6, 75.4, 126.2, 126.7, 127.0, 127.7, 128.0, 128.1,
129.1, 129.4, 129.5, 131.2, 133.0, 136.1, 138.7, 143.0, 151.1, 152.3,
163.6 ppm. C21H17N3O2 (343.39): calcd. C 73.45, H 4.99, N 12.24;
found C 73.29, H 5.02, N 12.29.
3-Benzyl-6-[(8-phenylnaphthalen-1-yl)amino]uracil (10b): Amino-
uracil 10b was prepared analogously to 10a from 9b (2.13 g,
9 mmol) and 8 (5.92 g, 27 mmol). The resulting solid was washed
with diethyl ether (3ϫ40 mL) and methanol (2ϫ15 mL) and dried
in vacuo to afford 10b as a white solid (3.58 g, 95%); m.p. 296–
298 °C. 1H NMR ([D6]DMSO, 300 MHz): δ = 3.79 (s, 1 H, CH=),
4.78 (s, 2 H, PhCH2), 7.10–7.40 (m, 7 H, Ar-H), 7.50–7.61 (m, 2
H, Ar-H), 8.03 (d, J = 8.2 Hz, 2 H, Ar-H), 9.51 (br. s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 42.5, 75.2, 126.3,
126.7, 127.0, 127.5, 127.7, 128.0, 128.3, 128.8, 129.0, 129.4, 129.6,
131.2, 132.9, 136.1, 138.7, 139.0, 143.0, 120.9, 152.5, 163.2 ppm.
C27H21N3O2 (419.49): calcd. C 77.31, H 5.05, N 10.02; found C
77.20, H 5.09, N 10.08.
N-(8-Bromonaphthalen-1-yl)acetamide (6):[17] Acetic anhydride
(7.1 mL, 75 mmol) was added to a solution of 5 (15.50 g, 70 mmol)
in pyridine (40 mL). The mixture was heated at 100 °C for 1 h and
then evaporated in vacuo. The solid residue obtained was crushed,
washed with dilute hydrochloric acid (1:1) and water and then dried
in air. The crude product was purified by crystallization from aque-
ous acetic acid (50%, w/w) to afford 6 (16.58 g; 90%) as colourless
crystals; m.p. 142–144 °C (ref.[16] 143–144 °C). 1H NMR (CDCl3,
300 MHz): δ = 2.29 (s, 3 H, COCH3), 7.23 (t, J = 8.0 Hz, 1 H, Ar-
H), 7.48 (t, J = 7.8 Hz, 1 H, Ar-H), 7.69 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.77 (d, J = 7.8 Hz, 1 H, Ar-H), 7.81 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.99 (d, J = 7.8 Hz, 1 H, Ar-H), 8.79 (br. s, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ = 24.8, 115.7, 124.5, 124.8, 125.9,
126.3, 127.0, 129.6, 132.0, 133.7, 136.6, 168.4 ppm.
5-Ethyl-3,10-dimethylisoalloxazinium Perchlorate (11): Salt 11 was
prepared following a previously described procedure.[23] The NMR
spectrum of 11 is in accord with that reported in the literature.[23]
Kinetic Measurements: Flavinium salt 2b or 11 (3.8 µmol), the sub-
strate (0.255 mmol) and [D4]CD3OD (600 µL) were charged into
an NMR tube. The mixture was homogenized by sonication and
tempered for 15 min at 25 °C. The reaction was started by adding
30% aqueous hydrogen peroxide (40 µL, 0.392 mmol). The conver-
sions were calculated from the integrals of the corresponding sig-
nals in the 1H NMR spectra. The spectra of the products corre-
sponded to the spectra of authentic samples of the sulfoxide. For
the oxidation of p-nitrothioanisole, half the amount of the fla-
vinium salt as well as of the substrate and hydrogen peroxide was
used.
N-(8-Phenylnaphthalene-1-yl)acetamide (7): A solution of Na2CO3
(7.92 g, 75 mmol) in water (95 mL) was added under nitrogen to a
solution of 6 (15.85 g, 60 mmol), phenylboronic acid (7.68 g,
63 mmol), palladium acetate (269 mg, 1.2 mmol) and tri-
phenylphosphane (944 mg, 3.6 mmol) in propanol (300 mL). The
mixture was heated at reflux for 6 h. The solvent was evaporated
in vacuo and water was added to the residue. The mixture was
extracted with chloroform and the extract was dried with Na2SO4.
The crude product obtained after solvent evaporation was crys-
tallized from ethyl acetate with charcoal to obtain 7 (14.58 g; 93%)
as colourless crystals; m.p. 162–164 °C (ref.[22] 163–164 °C). 1H
NMR (CDCl3, 300 MHz): δ = 1.44 (s, 3 H, COCH3), 7.03 (br. s, 1
H, NH), 7.28 (d, J = 7.8 Hz, 1 H, Ar-H), 7.42–7.56 (m, 7 H, Ar-
H), 7.74 (d, J = 8.2 Hz, 1 H, Ar-H), 7.88 (d, J = 8.2 Hz, 1 H, Ar-
Typical Procedure for the Asymmetric Sulfoxidation Reactions: Fla-
vinium salt (+)-2b or (–)-2b (3.2 mg, 5 µmol) and the substrate
(0.1 mmol) were dissolved in methanol/water (2:1, 10 mL). The
mixture was homogenized by sonication and tempered for 30 min
5222
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5217–5224

Catalysts for Enantioselective Sulfoxidation Reactions
[8]
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at –20 °C. A 30% aqueous hydrogen peroxide solution (10.5 µL,
0.1 mmol) was added and the reaction mixture was stirred at
–20 °C. The reaction was monitored by HPLC. When 70% conver-
sion was reached, the reaction was quenched with 5% aqueous so-
dium bisulfite (5 mL). Methanol was carefully evaporated and the
remaining aqueous solution was extracted with dichloromethane.
After the evaporation of the solvents, the residue was purified by
chromatography (ethyl acetate/hexane, 1:1). The enantiomeric ra-
tios were determined by HPLC analysis on a Chiralcel OD column
(hexane/2-PrOH, 9:1) or by 1H NMR in the presence of (R)-N-(3,5-
dinitrobenzoyl)-1-phenylethan-1-amine as a chiral shift reagent.[20]
Supporting Information (see also the footnote on the first page of
this article): Experimental details for the synthesis of 3-alkyl-6-
chlorouracils, 1H NMR spectra of 2b, 3a and 3b, chromatogram of
the racemic mixture of flavin 3b on a chiral HPLC column, CD
spectra of (+)-3b and (–)-3b and the kinetics of the H2O2 sulfoxid-
ation reactions catalysed by flavinium salt 2b.
Acknowledgments
The authors wish to thank the Czech Science Foundation (Grant
No. 203/07/1246) for financial support.
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www.eurjoc.org
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R. Jurok, R. Cibulka, H. Dvorˇáková, F. Hampl, J. Hodacˇová
FULL PAPER
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Received: April 28, 2010
Published Online: August 3, 2010
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