Hydrogen-bonding catalysis: Mild and highly chemoselective oxidation of sulfides

Article abstract of DOI:10.1002/adsc.200900020

N,N′-Bis[3,5-bis(trifluoromethyl)phenyl]thiourea, employed at only 1 mol% loading, was found to be a very effective catalyst for the oxidation of sulfides with tert-butyl hydroperoxide (TBHP), affording the sulfoxides in high yield, excellent chemoselecti

Full text of DOI:10.1002/adsc.200900020

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DOI: 10.1002/adsc.200900020
Hydrogen-Bonding Catalysis: Mild and Highly Chemoselective
Oxidation of Sulfides
Alessio Russoa and Alessandra Lattanzia,*
a
Dipartimento di Chimica, Universitꢀ di Salerno, Via Ponte don Melilllo, 84084 Fisciano, Italy
Fax : (+39)-089-969-603; e-mail: lattanzi@unisa.it
Received: January 13, 2009; Published online: March 5, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900020.
Abstract:
N,N’-Bis
[3,5-bis(trifluoromethyl)phe-
tion, we envisaged the possibility to employ an organ-
ic compound having good hydrogen-bonding donating
ability as a catalytic activator of the oxygen donor in
sulfoxidation. Recently, ureas and thioureas have
been shown to behave as excellent organocatalysts,
operating through double hydrogen-bonding activa-
tion of different electrophiles.[8] The readily accessi-
ble, electron-poor diaryl thiourea 3 displayed high
catalytic efficiency in carbon-carbon bond forming re-
actions,[9] acetalisation,[10] epoxide opening[11] and re-
duction of imines[12] (Figure 1). Herein, we report the
first example of a thiourea employed as promoter in
an oxidative process. An efficient, chemoselective and
diastereoselective sulfoxidation protocol was estabil-
nyl]thiourea, employed at only 1 mol% loading,
was found to be a very effective catalyst for the oxi-
dation of sulfides with tert-butyl hydroperoxide
(TBHP), affording the sulfoxides in high yield, ex-
cellent chemoselectivity, fairly good diastereoselec-
tivity.
Keywords: chemoselectivity; hydrogen bonds; oxi-
dation; sulfoxides; thioureas
Sulfoxides are both useful elements of stereocontrol ished using N,N’-bis
in asymmetric synthesis and important targets of thiourea 3 at low loadings and TBHP as the oxidant.
pharmaceutical interest.[1] The oxidation of sulfides is Electron-poor diarylureas 1[9] and 2[11b] (Figure 1)
ACHTUNGTRENN[UNG 3,5-bis(trifluoromethyl)phenyl]
undoubtly the most direct and easy approach for the were firstly employed at 10 mol% loading in the oxi-
preparation of sulfoxides and several transition metal- dation of model compound methyl p-tolyl sulfide 5a
based methodologies have been reported to date em- in CH2Cl2 at room temperature with TBHP (Table 1).
ploying different sources of oxygen donors.[2] More re-
Compound 1 and more acidic urea 2 afforded sulf-
cently, particular attention has been paid to the devel- oxide 6a in low yields after 22 h, but with complete
opment of efficient and highly selective methodolo- chemoselectivity, since traces of sulfone were not de-
1
gies of sulfoxidation with favourable environmetal tected by H NMR analysis of the crude reaction mix-
impact. Thus, the most important issues to be ad- ture (entries 1 and 2). The experiment carried out
dressed are i) the use of as low as possible catalyst under otherwise identical conditions, but in the ab-
loading, cheap and environmentally friendly oxidants, sence of the catalyst (entry 3), proved that the uncata-
ii) high control of the chemoselectivity, iii) mild reac- lysed oxidation was a negligible process and con-
tion conditions amenable to tolerate other oxidable firmed that ureas could moderately catalyse the sul-
functional groups present in the molecule. Some ex- foxidation.
amples of Brønsted acid-catalysed oxidation of sul-
When using thiourea 3, we were very pleased to ob-
fides have been reported.[3] Interestingly, alcohols[4] serve complete conversion to sulfoxide (entry 4) and
and phenol,[5] used as solvents, in the presence of hy- the chemoselectivity was mantained high with a 99/1
drogen peroxide, proved to be suitable systems for sulfoxide/sulfone ratio.[13] A different double hydro-
the sulfoxidation. These neutral hydrogen-bonding gen-bonding donor, (R)-BINOL, was then checked
donors were suggested to provide electrophilic activa- (entry 5). Compound 4 proved to be as active as ureas
tion of hydrogen peroxide through hydrogen-bonding 1 and 2. In apolar toluene and chloroform, thiourea 3
interactions.
could be equally employed although displaying lower
Given our interest in the development of metal- activity than in CH2Cl2 as solvent (entries 6–8). As ex-
based[6] and organocalysed[7] methodologies of oxida- pected, in hydrogen-bonding acceptor THF, catalyst
Adv. Synth. Catal. 2009, 351, 521 – 524
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521

Alessio Russo and Alessandra Lattanzi
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Figure 1. Catalysts checked in the sulfoxidation.
Table 1. Oxidation of sulfide 5a with TBHP promoted by
catalysts 1–4.
72 h, compound 3 was recovered in 89% yield. This is
a clear indication that thiourea 3 is not prone to de-
composition and catalyst preservation is assured
throughout the oxidation of the sulfide. With the opti-
mised conditions in hand, a variety of sulfides were
reacted with TBHP and catalyst 3 at room tempera-
ture to study the scope of the oxidation (Table 2).
Different types of phenyl substitution in the methyl
aryl sulfides are well-tolerated although sulfides bear-
ing para-electron-withdrawing groups or ortho-Lewis
basic substituents required longer reaction times in
order to be converted to sulfoxides in high yields (en-
tries 2–4). The ethyl substitution at sulfur significantly
slowed down the reaction rate (entry 5). This result
showed that steric effects seem to play an important
role in the sulfoxidation. The less reactive diphenyl
sulfide was oxidised in good yield (entry 6).
Sulfides having functional groups susceptible to oxi-
dation were selectively sulfoxidated (entries 7 and 8).
Aryl benzyl and dialkyl sulfides afforded the sulfox-
ides in high yields and general excellent chemoselec-
tivity (entries 9–11). Finally, the issue of diastereose-
lectivity was briefly investigated. Interestingly, 2-
phenly-1,3-dithiane and dithiolane gave the trans-
monosulfoxides in high yield and diastereoselectivity
(entries 12 and 13). The stereocontrol achieved with
thiourea 3/TBHP system is comparable to that ob-
Entry Cat.
[mol%]
Solvent Conc.
[M]
Time
[h]
Yield 6a
[%][a]
1
2
3
4
5
6
7
8
1 [10]
2 [10]
–
3 [10]
4 [10]
3 [10]
–
3 [10]
3 [10]
3 [5]
3 [1]
3 [0.1]
3 [1]
–
CH2Cl2 0.25
CH2Cl2 0.25
CH2Cl2 0.25
CH2Cl2 0.25
CH2Cl2 0.25
toluene 0.25
toluene 0.25
CHCl3 0.25
22
22
22
15
30
22
22
22
23
20
20
47
16
22
29
31
5
99
26
84
7
56
29
99
99
99
99
20
9
THF
0.25
10
11
12
13
14
CH2Cl2 0.25
CH2Cl2 0.25
CH2Cl2 0.25
CH2Cl2 0.5
CH2Cl2 0.5
[a]
Isolated yields after flash chromatography.
activity was almost suppressed (entry 9). Loadings of served in metal-catalysed[14] sulfoxidation processes
3 as low as 1 mol% led to completion of the reaction and better than the diastereoselectivity afforded by
within the same reaction time (entries 10 and 11) and classical and strong oxidants such as m-chloroperben-
although a longer reaction time was required, only zoic acid[15] or NaIO4.[14a]
0.1 mol% loading can be successfully employed
It is interesting to note that the catalytic perfor-
(entry 12). Working at 1 mol% loading under more mance of thiourea 3 in terms of turnover numbers
concentrated conditions (0.5M), enabled us to speed (TON up to 990) competes well with transition metal
up the reaction, whereas a poor contribution of the complexes generally used in the oxidation of sulfides
uncatalysed oxidative pathway was demonstrated (en- with alkyl hydroperoxides. The effectiveness in the ac-
tries 13 and 14).
tivation of TBHP could be rationalised according to a
In order to check the stability of the catalyst under double hydrogen-bonding interaction of 3 with the
oxidative degradation, compound 3 was reacted with proximal oxygen of TBHP, which should significantly
TBHP (12 equiv.) in the absence of the sulfide at enhance the electrophilic character of the distal
room temperature. After a prolonged reaction time of oxygen attacked by the sulfide (Figure 2).
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Adv. Synth. Catal. 2009, 351, 521 – 524

Hydrogen-Bonding Catalysis: Mild and Highly Chemoselective Oxidation of Sulfides
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1H NMR analysis of the 3/TBHP 1/1 mixture, under
diluted conditions (0.02M) in CDCl3 (400 MHz), sup-
ported the formation of the TBHP-catalyst 3 complex.
Indeed, the chemical shift of Ha was downfield shifted
from 7.96 to 8.12 ppm after the addition of TBHP.
The aromatic protons Hb were downfield shifted from
7.88 to 7.91 ppm. Finally, the Hc proton of TBHP was
downfield shifted from 7.14 to 7.42 ppm.[16]
Table 2. Chemoselective oxidation of sulfides with thiourea
3/TBHP system.[a]
Entry
1
5
Time [h]
16
Yield 6 [%][b]
In conclusion, we have disclosed that simple and
readily accessible N,N’-bisACTHNUTRGENUGN[3,5-bis(trifluoromethyl)-
99
phenyl] thiourea 3 can efficiently activate an oxygen
donor such as tert-butyl hydroperoxide at remarkable
low loadings of up to 0.1 mol%. A mild, metal-free
methodology of sulfoxidation has thus been devel-
oped. A variety of sulfoxides were obtained in high
yields, excellent chemoselectivity, fairly good diaste-
reoselectivity. This study opens new possibilities for
the employment of thioureas in the area of organoca-
talysed oxidations.
2
3
48
36
95 (99/1)
99
4
69
85
5
40
72
21
41
17
87
69
79
98
84
Experimental Section
6
7
General Procedure
8[c]
Sulfide 5 (0.2 mmol) and 3 (0.002 mmol, 1 mg) were dis-
solved in anhydrous CH2Cl2 (400 mL) at room temperature.
TBHP (0.24 mmol, 44 mL of 5–6M decane solution) was
then added. After the completion of the reaction, as moni-
tored by TLC, the solvent was removed under reduced pres-
9
10
11
46
22
91 (98/2)
99
1
sure and the crude mixture was analysed by H NMR to de-
termine the sulfoxide/sulfone ratio. The sulfoxide was then
isolated by flash chromatography eluting with PE/ethyl ace-
tate mixtures (8/2 to pure ethyl acetate). All sulfoxides are
known compounds, their analytical data were identical to
those reported in the literature.[2,3,6b]
12
40
47
92 t/c: 96/4[d]
92 t/c: 81/19[d]
13
[a]
Molar ratios: 5/3/TBHP 1/0.01/1.2. The sulfoxide/sulfone
ratio is reported in parenthesis whenever detected by
1H NMR analysis.
Acknowledgements
MIUR is acknowledged for financial support.
[b]
[c]
[d]
Isolated yields after flash chromatography.
5 mol% of 3 was used.
1
The trans/cis ratio determined by H NMR analysis.
References
[1] For reviews, see: a) M. C. CarreÇo, Chem. Rev. 1995,
95, 1717; b) I. Fernꢂndez, N. Khiar, Chem. Rev. 2003,
103, 3651; c) J. Legros, J. R. Dehli, C. Bolm, Adv.
Synth. Catal. 2005, 347, 19.
[2] For selected examples, see: a) F. Di Furia, G. Modena,
R. Seraglia, Synthesis 1984, 325; b) P. Pitchen, E.
DuÇach, M. N. Desmukh, H. B. Kagan, J. Am. Chem.
Soc. 1984, 106, 8188; c) N. Komatsu, M. Hashizume, T.
Sugita, S. Uemura, J. Org. Chem. 1993, 58, 4529; d) C.
Bolm, F. Bienewald, Angew. Chem. 1995, 107, 2883;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2640; e) M. Pal-
ucki, P. Hanson, E. N. Jacobsen, Tetrahedron Lett. 1992,
33, 7111; f) C. Kokubo, T. Katsuki, Tetrahedron 1996,
52, 13895; g) H. Q. N. Gunaratne, M. A. McKervey, S.
Figure 2. Proposed mode of activation of TBHP by thiourea
3.
Adv. Synth. Catal. 2009, 351, 521 – 524
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
523

Alessio Russo and Alessandra Lattanzi
COMMUNICATIONS
Feutren, J. Finlay, J. Boyd, Tetrahedron Lett. 1998, 39,
5655; h) J. Legros, C. Bolm, Angew. Chem. 2004, 116,
4321; Angew. Chem. Int. Ed. 2004, 43, 4225; i) M. Mba,
L. J. Prins, G. Licini, Org. Lett. 2007, 9, 21. For a metal-
free procedure of sulfoxidation, see: F. Shi, M. K. Tse,
H. M. Kaiser, M. Beller, Adv. Synth. Catal. 2007, 349,
2425.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550;
Angew. Chem. Int. Ed. 2006, 45, 1520; d) S. J. Connon,
Chem. Eur. J. 2006, 12, 5418.
[9] a) D. P. Curran, L. H. Kuo, J. Org. Chem. 1994, 59,
3259; b) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002,
4, 217; c) P. R. Schreiner, A. Wittkopp, Chem. Eur. J.
2003, 9, 407; d) G. Dessole, R. P. Herrera, A. Ricci,
Synlett 2004, 13, 2374; e) D. J. Maher, S. J. Connon, Tet-
rahedron Lett. 2004, 45, 1301; f) M. Kirsten, J. Rehben,
M. Hiersemann, T. Strassner, J. Org. Chem. 2007, 72,
4001.
[10] M. Kotke, P. R. Schreiner, Tetrahedron 2006, 62, 434.
[11] a) C. M. Kleiner, P. R. Schreiner, Chem. Commun.
2006, 4315; b) E. M. Fleming, C. Quigley, I. Rozas, S. J.
Connon, J. Org. Chem. 2008, 73, 948.
[12] a) Z. Zhang, P. R. Schreiner, Synlett 2007, 1455; b) Z.
Zhang, P. R. Schreiner, Synthesis 2007, 2559.
[13] The oxidation of 6a carried out with 3 (20 mol%) and
TBHP (1.2 equiv.) in CH2Cl2 at room temperature af-
forded after 63 h the sulfone in 5% yield.
[3] a) F. Bonadies, F. De Angelis, L. Locati, A. Scettri, Tet-
rahedron Lett. 1996, 37, 7129; b) S. Vayssiꢃ, H. Elias,
Angew. Chem. 1998, 110, 2246; Angew. Chem. Int. Ed.
1998, 37, 2088; c) V. G. Shukla, P. D. Salgaonkar, K. G.
Akamanchi, J. Org. Chem. 2003, 68, 5422; d) G. P. Ro-
manelli, P. G. Vꢂzquez, P. Tundo, Synlett 2005, 75; e) H.
Firouzabadi, N. Iranpoor, A. A. Jafari, E. Riazymontaz-
er, Adv. Synth. Catal. 2006, 348, 434.
[4] a) M. A. P. Dunkleff, R. Curci, J. O. Edwards, H.-Y.
Pyun, J. Am. Chem. Soc. 1968, 90, 3209; b) K. S. Ravi-
kumar, J.-P. Bꢃguꢃ, D. Bonnet-Delpon, Tetrahedron
Lett. 1998, 39, 3141.
[5] W. L. Xu, Y. Z. Li, Q. S. Zhang, H. S. Zhu, Synthesis
2004, 2, 227.
[14] a) F. Di Furia, G. Licini, G. Modena, Gazz. Chim. Ital.
1990, 120, 165; b) G. Della Sala, S. Labano, A. Lattanzi,
C. Tedesco, A. Scettri, Synthesis 2002, 505.
[6] a) A. Lattanzi, P. Iannece, A. Vicinanza, A. Scettri,
Chem. Commun. 2003, 1440; b) A. Lattanzi, S. Picciril-
lo, A. Scettri, Adv. Synth. Catal. 2007, 349, 357.
[7] a) A. Lattanzi, Org. Lett. 2005, 7, 2579; b) A. Russo, A.
Lattanzi, Adv. Synth. Catal. 2008, 350, 1991.
[8] a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289; b) Y.
Takemoto, Org. Biomol. Chem. 2005, 3, 4299; c) M. S.
[15] F. A. Carey, O. D. Dailey, O. Hernandez, J. R. Tucker,
J. Org. Chem. 1976, 41, 3975.
[16] 1H NMR spectra are reported in the Supporting Infor-
mation.
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