2364
B. J. Marsh, D. R. Carbery / Tetrahedron Letters 51 (2010) 2362–2365
Table 1
It is noted that the electronic character of the sulfide plays an
important role in the rate of the reaction. Alkyl and electron-rich
aromatic sulfides were oxidised, in particular the amino thioani-
sole (Table 1, entry 3) was fully consumed within 30 min and tet-
rahydrothiophene (Table 1, entry 9) was fully consumed within
1 h. However, when electron-deficient aromatic systems were
examined, increased reaction times were required, or in the case
of the cyano thioanisole (Table 1, entry 5) elevated temperature
to achieve full conversion.
In conclusion, bridged flaviniums 3a–c are efficient catalysts for
the chemoselective oxidation of sulfides to sulfoxides with no
over-oxidation to sulfones observed using this protocol. The flavi-
nium catalysts are simple to access via a telescoped procedure
and are bench-stable. Further investigations are ongoing to im-
prove the catalytic efficiency and to apply this procedure to differ-
ent flavin-catalysed transformations.
Effect of solvent on suppression of the background reaction
3c
O
S
H2O2 (1.75 eq),
S
[0.371 M], rt, 5 h,
Solvent
Entry
Solvent
Loading 3c (mol %)
Conversiona (%)
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOHb
MeOHb
MeCN
MeCN
CH2Cl2
CH2Cl2
DMF
1.8
0
1.8
0
1.8
0
1.8
0
>99
45
>99
25
70
25
71
5
1.8
0
25
8
10
DMF
Note added in proof: After submission of this Letter, the authors
became aware of sulfide oxidation catalysed by structurally similar
N1,N10-ethylene-bridged flavinium catalysts derived from
valinol.12
a
Assessed by 1H NMR spectroscopy of the crude reaction mixture.
1.2 equiv of H2O2.
b
after lowering the loading of H2O2 to 1.2 equiv (Table 1, entries 3
and 4). This change in protocol offered a pragmatic balance be-
tween solubility, reproducibility and background reaction
suppression.
With optimal conditions at hand, a range of sulfides was
examined to ascertain the generality of this sulfoxidation protocol
(Table 2).11 Pleasingly, all the substrates were oxidised cleanly to
the corresponding sulfoxide, without any over-oxidation to sulfone
observed for all substrates.
Acknowledgements
We are grateful to The Leverhulme Trust for a research fellow-
ship (B.J.M.). Astra Zeneca is kindly acknowledged for unrestricted
funding support.
References and notes
1. For recent general reviews on organocatalysis, see: (a) Dondoni, A.; Massi, A.
Angew. Chem., Int. Ed. 2008, 47, 4638–4660; (b) Bertelsen, S.; Jorgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178–2189; (c) Buckley, B. R. Annu. Rep. Prog. Chem.
Sect. B: Org. Chem. 2009, 105, 113–128; (d) MacMillan, D. W. C. Nature 2008,
455, 304–308.
2. For reviews of flavin-mediated transformations, see: (a) Gelalcha, F. G. Chem.
Rev. 2007, 107, 3338–3361; (b) Imada, Y.; Naota, T. Chem. Recl. 2007, 7, 354–
361.
Table 2
Substrate scope
O
S
3c (1.8 mol%)
S
R2
5a-j
R1
R1
R2
H2O2 (1.2 eq),
MeOH
4a-j
3. For recent reviews of H2O2 oxidations within a green context, see: (a) Sheldon,
R. A. Chem. Commun. 2008, 3352–3365; (b) Piera, J.; Backvall, J.-E. Angew. Chem.,
Int. Ed. 2008, 47, 3506–3523; (c) Arends, I. W. C. E. Angew. Chem., Int. Ed. 2006,
45, 6250–6252; (d) Ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev.
2004, 104, 4105–4123; (e) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003,
1977–1986; (f) Grigoropoulou, G.; Clark, J. H.; Elings, J. A. Green Chem. 2003, 5,
1–7.
4. (a) Murahashi, S.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989, 111, 5002–5003; (b)
Lindén, A. A.; Krüger, L.; Bäckvall, J. E. J. Org. Chem. 2003, 68, 5890–5896; (c)
Linden, A. A.; Hermanns, N.; Ott, S.; Krueger, L.; Bäckvall, J. E. Chem. Eur. J. 2005,
11, 112–119; (d) Miller, A. E.; Bischoff, J. J.; Bizub, C.; Luminoso, P.; Smiley, S. J.
Am. Chem. Soc. 1986, 108, 7773–7778; (e) Imada, Y.; Iida, H.; Ono, S.;
Murahashi, S. J. Am. Chem. Soc. 2003, 125, 2868–2869; (f) Bergstad, K.;
Bäckvall, J. E. J. Org. Chem. 2003, 68, 6650–6655.
Entry Substrate
Temp (°C) Time (h) Product Yield (%)
S
1
25
25
3.5
2
5a
5b
95
99
4a
S
2
MeO
4b
S
3
25
25
25
25
0.5
12
5c
5d
5e
5f
93
94
97
92
H2N
4c
S
5. Shinkai, S.; Yamaguchi, T.; Manabe, O.; Toda, F. J. Chem. Soc., Chem. Commun.
1988, 1399–1401.
4
6. Minidis, A. B. E.; Bäckvall, J.-E. Chem. Eur. J. 2001, 7, 297–302.
7. Imada, Y.; Ohno, T.; Naota, T. Tetrahedron Lett. 2007, 48, 937–939.
8. Li, W. S.; Zhang, N.; Sayre, L. M. Tetrahedron 2001, 57, 4507–4522.
9. For selected recent examples of catalytic sulfoxidations, see: (a) Kinen, C. O.;
Rossi, L. I.; de Rossi, R. H. J. Org. Chem. 2009, 74, 7132–7139; (b) Ricoux, R.;
Allard, M.; Dubuc, R.; Dupont, C.; Marechal, J. D.; Mahy, J. P. Org. Biomol. Chem.
2009, 7, 3208–3211; (c) Hussain, S.; Bharadwaj, S. K.; Pandey, R.; Chaudhuri, M.
K. Eur. J. Org. Chem. 2009, 3319–3322; (d) Kamata, K.; Hirano, T.; Mizuno, N.
Chem. Commun. 2009, 3958–3960; (e) Wu, Y.; Liu, J.; Li, X.; Chan, A. S. C. Eur. J.
Org. Chem. 2009, 2607–2610; (f) Mueller, N. J.; Stueckler, C.; Hall, M.;
Macheroux, P.; Faber, K. Org. Biomol. Chem. 2009, 7, 1115–1119; (g)
Cojocariu, A. M.; Mutin, P. H.; Dumitriu, E.; Fajula, F.; Vioux, A.; Hulea, V.
Chem. Commun. 2008, 5357–5359; (h) Gamelas, C. A.; Lourenco, T.; Pontes da
Costa, A.; Simplicio, A. L.; Royo, B.; Romao, C. C. Tetrahedron Lett. 2008, 49,
4708–4712; (i) Noguchi, T.; Hirai, Y.; Kirihara, M. Chem. Commun. 2008, 3040–
3042; (j) Matsumoto, K.; Yamaguchi, T.; Katsuki, T. Chem. Commun. 2008,
1704–1706; (k) Kienle, M.; Argyrakis, W.; Baro, A.; Laschat, S. Tetrahedron Lett.
2008, 49, 1971–1974.
Br
4d
S
5
3.5
24
NC
4e
S
6
CO2Me
4f
CO2H
S
7
8
25
25
12
12
5g
5h
94
91
4g
S
4h
S
S
10. NMR experimental procedure: Flaviniums 3a–c (1.8 mol %) and p-tolyl methyl
9
25
25
1
1
5i
5j
89
93
4i
sulfide (31 mg, 0.223 mmol) were dissolved in CD3OD (600
yellow solution was then treated with H2O2 (35% wt, 37
l
l, 0.371 M). The
l
l, 1.75 equiv) and
10
CO2Me
shaken vigourously until the solution attained homogeneity. Spectra were
recorded every 2 min for 20 min or until conversion had reached 20%.
4j