Oxidation of sulfides with hydrogen peroxide catalyzed by 10,10′-linked bisflavinium perchlorates

Article abstract of DOI:10.1016/j.tetlet.2006.12.017

A series of bisflavinium perchlorates linked with methylene spacer at N¹⁰-position exhibit high catalytic activities for the oxidation of sulfides with hydrogen peroxide affording the corresponding sulfoxides. The kinetic studies revealed that the reaction rates are dependent on the spacer length of the catalysts due to their specific intramolecular electrochemical behaviors.

Full text of DOI:10.1016/j.tetlet.2006.12.017

Tetrahedron Letters 48 (2007) 937–939
Oxidation of sulfides with hydrogen peroxide catalyzed
by 10,100-linked bisflavinium perchlorates
Yasushi Imada,* Takashi Ohno and Takeshi Naota*
Department of Chemistry, Graduate School of Engineering Science, Osaka University,
Machikaneyama, Toyonaka, Osaka 560-8531, Japan
Received 18 November 2006; revised 6 December 2006; accepted 7 December 2006
Abstract—A series of bisflavinium perchlorates linked with methylene spacer at N10-position exhibit high catalytic activities for the
oxidation of sulfides with hydrogen peroxide affording the corresponding sulfoxides. The kinetic studies revealed that the reaction
rates are dependent on the spacer length of the catalysts due to their specific intramolecular electrochemical behaviors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Organocatalytic oxidations with hydrogen peroxide
attract much attention as an important tool for environ-
mentally benign oxidative transformations,1 since they
have potential designability for a variety of catalyses
bearing high selectivity and sustainability. A limited
number of electrophilic compounds including ketones,2
sulfonylimines,3 and flavins4 are reported as efficient
organocatalysts for the oxidations of olefins,2 sul-
fides,3,4a–c amines,4a,d and ketones4e,f with hydrogen
peroxide. During the course of our studies on the
creation of flavin-based molecular devices, we examine
dynamic behaviors and functions of polyflavins
connected with flexible methylene spacers. In this Letter,
we wish to describe the synthesis of novel 10,100-linked
bisflavinium perchlorates 1 and their catalytic activities
for the oxidation of sulfides with hydrogen peroxide,
Eq. 1.
afforded bisflavin derivatives 3. Reductive ethylation
6
followed by oxidation with NaNO2 gave 1, which was
characterized by UV–vis, IR, and HRMS analyses.7
The catalytic activities of bisflavins 1a–c (0.5 mol %)
were examined for the reaction of 4-(methylthio)toluene
(4, 2.95 · 10ꢀ2 M) with hydrogen peroxide (1.1 equiv) in
1
MeOH-d4 by means of H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard. Initial
consumption rates of 4 ðꢀd½4ꢁ=dt ¼ kobsÞ at 298 K were
determined to be 4.66 · 10ꢀ5 M sꢀ1(1a), 5.33 · 10ꢀ5
M sꢀ1 (1b), and 5.50 · 10ꢀ5 M sꢀ1 (1c). The results indi-
cate that bisflavins bearing longer methylene spacers
exhibit higher catalytic activity. The kobs value of 1c is
comparable to that of 5-ethylisoalloxazinium perchlo-
rate (1.0 mol %, 6.83 · 10ꢀ5 M sꢀ1), which is the best
monoflavin catalyst among those examined.4a Although
initial rates of the present oxidation are altered by
spacer length of 1, all of the bisflavin catalysts gave full
conversion of various sulfides within 6 h affording the
corresponding sulfoxides in excellent yields. Representa-
tive results are summarized in Table 1.8
O
bisflavin 1 (cat.)
S
S
ð1Þ
R1
R2
R1
R2
H2O2 (1.1 equiv)
MeOH
The mechanism of flavin-catalyzed oxidations with
hydrogen peroxide has been established by the previous
studies.4a Flavinium cation (FlEt+) reacts with hydrogen
peroxide to give active hydroperoxy species (FlEtOOH),
which undergoes oxygen transfer to substrates and sub-
sequent rate-determining dehydration of hydroxyflavin
(FlEtOH) to regenerate FlEt+. The observed spacer
dependency of the oxidation rates can be rationalized
by the mechanism as shown in Scheme 2. After the
A series of bisflavinium perchlorates 1 were prepared
starting from o-fluoronitrobenzene as shown in Scheme
1. Treatment of 1,x-diaminoalkanes with o-fluoronitro-
benzene gave nitroanilines 2. Reduction of the nitro
group and subsequent condensation with alloxan5
*
Corresponding authors. Tel./fax: +81 6 6850 6222; e-mail addresses:
imada@chem.es.osaka-u.ac.jp; naota@chem.es.osaka-u. ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.017

938
Y. Imada et al. / Tetrahedron Letters 48 (2007) 937–939
O
O
N
Et
N
N
NH
NH
H
H
N
N
N
O
O
N
O
2ClO4
F
N (CH2)n
a
d, e
b, c
(CH2)n
(CH2)n
N
N
N
N
N
O
NO2
NO2 O2N
NH
NH
N
O
Et
O
2a, n = 5, 99%
2b, n = 8, 90%
2c, n = 12, 69%
3a, n = 5, 93%
3b, n = 8, 90%
3c, n = 12, 65%
1a, n = 5, 20%
1b, n = 8, 84%
1c, n = 12, 39%
Scheme 1. Synthesis of bisflavinium perchlorate 1. Reagents and conditions: (a) NH2(CH2)nNH2, Na2CO3, DMSO, 140 ꢁC, overnight; (b) Zn,
AcOH, 60 ꢁC, 1 h; (c) alloxan monohydrate, B(OH)3, AcOH, rt, overnight; (d) CH3CHO, NaBH3CN, Na2S2O4, DMF, 60 ꢁC, 3 h and (e) HClO4,
NaNO2, NaClO4, NH3 aq, H2O, rt, 1 h.
tron transfer.5b,9 This equilibration reduces the concen-
tration of 8, which leads to retardation of the rate-
determining dehydration of the present catalytic cycle.
Thus, the higher catalytic activity of 1c is ascribed to
specifically mobile flavin moieties arising from long
methylene spacer. Further studies are currently under-
way to obtain detailed mechanistic information.
Table 1. Bisflavin-catalyzed oxidation of sulfidesa
Substrate
Catalyst
Time (h)
Yieldb (%)
96
S
Me
1a
5
4
Me
4
4
1b
1c
5
5
97
97
S
Me
Acknowledgment
1a
6
99
5
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports and Culture, Japan.
5
1b
1c
1a
1b
1c
1a
1b
1c
6
6
4
4
4
6
6
6
93
99
90
96
97
88
99
99
5
(C4H9)2S 6
6
6
(C8H17)2S 7
7
7
References and notes
1. (a) Strukul, G. Catalytic Oxidations with Hydrogen Perox-
ide as Oxidant; Kluwer Academic: Dordrecht, 1992; (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138.
a The oxidation was carried out in the presence of a catalyst (1 mol %)
and 30% H2O2 (1.1 equiv) in MeOH (1 mL) at 25 ꢁC.
b Isolated yields.
2. (a) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721; (b)
Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807; (c) Shi, Y.
Acc. Chem. Res. 2004, 37, 488.
3. (a) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E.
W.; Andrews, D. M. Tetrahedron Lett. 1994, 35, 9629; (b)
Page, P. C. B.; Bethell, D.; Stocks, P. A.; Heer, J. P.;
Graham, A. E.; Vahedi, H.; Healy, M.; Collington, E. W.;
Andrews, D. M. Synlett 1997, 1355.
+
FlEt
FlEtOH
9
SubO
Sub
4. (a) Murahashi, S.-I.; Oda, T.; Masui, Y. J. Am. Chem. Soc.
1989, 111, 5002; (b) Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem.
+
+
FlEt
FlEtOH
8
FlEt
FlEtOOH
´
Eur. J. 2001, 7, 297; (c) Linden, A. A.; Kruger, L.; Ba¨ckvall,
¨
J.-E. J. Org. Chem. 2003, 68, 5890; (d) Bergstad, K.;
Ba¨ckvall, J.-E. J. Org. Chem. 1998, 63, 6650; (e) Mazzini,
C.; Lebreton, J.; Furstoss, R. J. Org. Chem. 1996, 61, 8; (f)
Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem., Int.
Ed. 2002, 41, 2366.
H+
H+
H2O
5. (a) Leonard, N. J.; Lambert, R. F. J. Org. Chem. 1969, 34,
3240; (b) Yano, Y.; Ohya, E. Chem. Lett. 1983, 1281.
6. Ghisla, S.; Hartmann, U.; Hemmerich, P. J. Liebigs Ann.
Chem. 1973, 1388.
H2O2
+
+
FlEt
FlEt
Scheme 2. Proposed mechanism for the bisflavin-catalyzed oxidation
with H2O2.
7. Characterization data for 1. Compound 1a: UV (aceto-
nitrile) kmax (loge) 346 (4.13), 539 (3.80) nm; IR (KBr) 1650
(C@O) cmꢀ1
; HRMS (FAB) calcd for C29H31O4N8
(Mꢀ2ClO4ꢀ+H+) 555.2468. Found 555.2446. Compound
1b: UV (acetonitrile) kmax (loge) 329 (4.07), 541 (3.82) nm;
IR (KBr) 1663 (C@O) cmꢀ1; HRMS (FAB) calcd for
similar oxygen transfer to substrates, bisflavin catalysts
are converted into partially hydroxylated species 8,
which is in fast equilibrium with species 9 via single elec-

Y. Imada et al. / Tetrahedron Letters 48 (2007) 937–939
939
C32H37O4N8 (Mꢀ2ClO4ꢀ+H+) 597.2924. Found 597.2936.
Compound 1c: UV (acetonitrile) kmax (loge) 376 (3.88), 543
(3.67) nm; IR (KBr) 1670 (C@O) cmꢀ1; HRMS (FAB)
calcd for C36H45O4N8 (Mꢀ2ClO4ꢀ+H+) 653.3564. Found
653.3476.
tion with CH2Cl2, the combined organic layers were
dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel or Kugelrohr distillation to
afford sulfoxide.
8. A mixture of sulfide (0.22 mM), bisflavins 1a–c (1 mol %)
and 30% H2O2 aqueous solution (1.1 equiv) in MeOH
(1 mL) was stirred at room temperature. After extrac-
9. (a) Mager, H. I. X.; Addink, R. Tetrahedron 1985, 41,
183; (b) Mager, H. I. X.; Tu, S.-C. Tetrahedron 1988, 44,
5669.