Urea–hydrogen peroxide prompted the selective and controlled oxidation of thioglycosides into sulfoxides and sulfones

Article abstract of DOI:10.3762/bjoc.13.113

A practical method for the selective and controlled oxidation of thioglycosides to corresponding glycosyl sulfoxides and sulfones is reported using urea–hydrogen peroxide (UHP). A wide range of glycosyl sulfoxides are selectively achieved using 1.5 equiv of UHP at 60 °C while corresponding sulfones are achieved using 2.5 equiv of UHP at 80 °C in acetic acid. Remarkably, oxidation susceptible olefin functional groups were found to be stable during the oxidation of sulfide.

Full text of DOI:10.3762/bjoc.13.113

Urea–hydrogen peroxide prompted the selective and
controlled oxidation of thioglycosides into sulfoxides
and sulfones
Adesh Kumar Singh, Varsha Tiwari, Kunj Bihari Mishra, Surabhi Gupta
and Jeyakumar Kandasamy*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1139–1144.
Department of Chemistry, Indian Institute of Technology, Banaras
Hindu University, Varanasi-221005, India
doi:10.3762/bjoc.13.113
Received: 23 March 2017
Accepted: 23 May 2017
Published: 13 June 2017
Email:
Jeyakumar Kandasamy* - jeyakumar.chy@iitbhu.ac.in
* Corresponding author
This article is part of the Thematic Series "Biomolecular systems".
Guest Editor: P. H. Seeberger
§ Tel.: +91-0542-6702879; fax: +91- 0542-6702876
Keywords:
monosaccharides; oxidation; sulfones; sulfoxides; thioglycosides;
urea–hydrogen peroxide
© 2017 Singh et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A practical method for the selective and controlled oxidation of thioglycosides to corresponding glycosyl sulfoxides and sulfones is
reported using urea–hydrogen peroxide (UHP). A wide range of glycosyl sulfoxides are selectively achieved using 1.5 equiv of
UHP at 60 °C while corresponding sulfones are achieved using 2.5 equiv of UHP at 80 °C in acetic acid. Remarkably, oxidation
susceptible olefin functional groups were found to be stable during the oxidation of sulfide.
Introduction
Organosulfur compounds such as sulfides, sulfoxides oxide donors usually provide excellent anomeric selectivity
and sulfones are useful intermediates for the construction of during the synthesis of various glycosyl linkages not only in
highly functionalized natural products [1,2]. Sulfur moieties are solution phase but also in solid-phase oligosaccharide synthesis
found in several therapeutically important molecules that pos- [6-9,11]. Glycosyl sulfones were also used as donors in the
sess antibacterial, antifungal, anti-ulcer, anti-atherosclerotic, preparation of various C- and O- linked oligosaccharides and
antihypertensive activities, etc. [3,4]. Sulfur compounds also functionalized glycols [8,9,12]. In addition, glycosyl sulfones
play an important role in carbohydrate synthesis. Thioglyco- are known to be potential glycosyltransferase inhibitors [13].
sides, glycosyl sulfoxides and sulfones have been widely used
as glycosyl donors in oligosaccharide synthesis which can be Glycosyl sulfoxides and sulfones are prepared from the corre-
activated under mild reaction conditions [5-10]. Glycosyl sulf- sponding sulfides using various oxidizing reagents [5-7,10]. Al-
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Beilstein J. Org. Chem. 2017, 13, 1139–1144.
though a number of oxidation methods were developed for the as solid-phase organic syntheses [25-28]. In fact, we have
oxidation of simple organic sulfides to corresponding sulfox- recently reported the oxidation of arylboronic acids into corre-
ides and sulfones [14-16], there are only limited reports avail- sponding phenols by using UHP as a selective oxidizing agent
able for the preparation of glycosyl sulfoxides and sulfones [29]. In continuation to our effort in developing green method-
from corresponding thioglycosides [5-7,17-23]. Moreover, there ologies [29-33], here we disclose an efficient and practical
is no report available where a given oxidant is suitable for con- method for the conversion of glycosyl sulfides into sulfoxides
trolled oxidation of thioglycosides to glycosyl sulfoxides and sulfones in a selective and controlled manner using
and sulfones selectively by altering the reaction conditions. It is urea–hydrogen peroxide in acetic acid.
also observed that thioglycoside oxidation suffers from low
yields, poor selectivity (i.e., sulfoxide vs sulfone), use of incon- Results and Discussion
venient reaction conditions and expensive oxidants, intolerance Initially, phenyl-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyrano-
of other oxidation susceptible functional groups, etc. side (1) was chosen as a substrate for the optimization study and
Thus, developing a mild and efficient method for the controlled oxidation was performed in various solvents at different temper-
oxidation of sulfides to corresponding glycosyl sulfoxides atures in the presence of urea–hydrogen peroxide (UHP)
and sulfones, is of great interest.
(Table 1). Polar aprotic solvents such as dichloromethane and
acetonitrile gave a negligible amount of corresponding sulf-
The utility of hydrogen peroxide–solid adducts in organic syn- oxide (1a) while no sulfone (1b) was detected at room tempera-
thesis is well explored [24]. Most of them are found to be stable ture even after 6 hours (Table 1, entries 1 and 2). However,
which can be easily handled and stored. One such solid adduct protic solvents such as methanol, ethanol, tert-butanol and
is urea–hydrogen peroxide (UHP) which is considered to be a acetic acid were found to be relatively efficient media for the
safer and efficient alternative to high concentrated aqueous oxidation when compared with dichloromethane and aceto-
hydrogen peroxide solution [25]. In addition, UHP is also com- nitrile (Table 1, entries 3–6). Among them, acetic acid gave
mercially available, inexpensive and nontoxic. The application 37% of the glycosyl sulfoxide (1a) after 6 h at room tempera-
of UHP as oxidant is well explored in various solution- as well ture with one equiv of UHP (Table 1, entry 6) while alcoholic
Table 1: Optimization of reaction conditions.a
Entry
UHP
Solvent
Temperature
Time
Yield (%)b
(equiv)
1ac
1b
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
2.0
2.5
DCM
CH3CN
MeOH
EtOH
rt
rt
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
2 h
2 h
3 h
10 h
<5
<10
12
15
13
37
64
90
92
87
65
<5
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
<5
3
rt
4
rt
5
t-BuOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
rt
6
rt
7
rt
8
40 °C
60 °C
80 °C
80 °C
80 °C
9
10
11
12
7
31
93
aReaction conditions: Thioglycoside (0.25 mmol), solvent (2.5 mL) and urea–hydrogen peroxide (UHP) together stirred for appropriate time at differ-
ent temperature. bIsolated Yield. cObtained as R and S mixture.
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Beilstein J. Org. Chem. 2017, 13, 1139–1144.
solvents gave a low yield. When we increased the amount of in different ratio. However, by increasing the amount of UHP to
UHP to 1.5 equiv, the reaction provides only 64% of the desired 2.5 equiv, sulfide 1 is fully converted to the corresponding
sulfoxide at room temperature (Table 1, entry 7). Therefore, the sulfone 1b in an excellent yield, i.e., 93% in 10 h at 80 °C (Ta-
reaction was further investigated at elevated temperatures using ble 1, entry 12).
1.5 equiv of UHP (Table 1, entries 8 and 9) in acetic acid. Inter-
estingly, the reaction was driven to completion with the desired With optimized conditions in hand (Table 1, entries 9 and 12), a
sulfoxide (1b) in 92% yield within 2 h at 60 °C (Table 1, entry controlled oxidation of various glycosyl sulfides to correspond-
9). It is also worth noting that less than 5% of the correspond- ing sulfoxides and sulfones was studied with urea-hydrogen
ing sulfone was detected in the crude product by 1H NMR peroxide in acetic acid (Table 2). For this study, a series of α-
under these conditions.
and β-thioglycosides, 1–19 were initially prepared by using lit-
erature procedures (see Supporting Information File 1). In addi-
Considering the importance of glycosyl sulfones, we further in- tion, structurally diverse aglycone moieties were selected in
vestigated the suitable conditions for the direct oxidation of order to study the breadth and scope of the current methodolo-
sulfide to sulfone using UHP in acetic acid. For this, we have gy. Initially, the oxidation of O-acetylated and benzoylated phe-
tried the reactions with an increased amount of UHP and nyl and p-tolyl thioglucopyranosides was examined (Table 2,
elevated temperature (Table 1, entries 10–12). It was observed entries 1–4). These aryl sulfides underwent oxidation very effi-
that with 1.5 to 2.0 equiv of UHP at 80 °C, the reaction yields a ciently to provide the corresponding sulfoxides 1a–4a in excel-
mixture of sulfoxide 1a and sulfone 1b (Table 1, entries 10–11) lent yields, i.e., 85–93% under optimized conditions. Similarly,
Table 2: Controlled oxidation of various thioglycosides to corresponding sulfoxides and sulfones using urea–hydrogen peroxide (UHP).a,b.
Entry
Substrate
Sulfoxide (a)c
Sulfone (b)
Yield (%)d
Time
Yield (%)d
Time
10 h
1
2
2 h
2 h
2 h
92
93
91
94
1
2
3
85
93
10 h
10 h
3
4
5
6
2 h
89
90
87
10 h
8 h
92
94
89
4
5
6
1.5 h
1.5 h
8 h
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Beilstein J. Org. Chem. 2017, 13, 1139–1144.
Table 2: Controlled oxidation of various thioglycosides to corresponding sulfoxides and sulfones using urea–hydrogen peroxide (UHP).a,b. (continued)
7
8
1.5 h
1.5 h
2.0 h
2.0 h
2 h
92
92
87
83
90
8 h
8 h
94
93
93
91
92
7
8
9
10 h
10 h
10 h
9
10
11
10
11
12
12
2 h
87
10 h
90
13
14
15
16
1.5 h
82
89
91
80
6 h
8 h
64
91
82
89
13
14
2 h
2.5 h
2.5 h
8 h
15
16
17
10 h
17
2.5 h
77
11 h
87
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Beilstein J. Org. Chem. 2017, 13, 1139–1144.
Table 2: Controlled oxidation of various thioglycosides to corresponding sulfoxides and sulfones using urea–hydrogen peroxide (UHP).a,b. (continued)
18
19
2 h
2 h
85
86
10 h
11 h
92
89
18
19
aReaction Conditions: Thioglycoside (0.25 mmol), acetic acid (2.5 mL) and UHP (1.5 equiv) stirred at 60 °C. bReaction conditions: Thioglycoside (0.25
mmol), acetic acid (2.5 mL) and UHP (2.5 equiv) stirred at 80 °C. cObtained as R and S mixture. dIsolated Yield.
corresponding glycosyl sulfones 1b–4b were also achieved in The scope of the oxidation reaction was subsequently investi-
91–94% yield by simply altering the reaction conditions as de- gated with other monosaccharides such as galacto and manno-
scribed in the optimization study.
thioglycosides under optimized conditions (Table 2). Similar to
glucopyranosides, galacto and mannothioglycosides 16–19 were
We further examined the oxidation of O-acetyl- (Ac) and successfully oxidized to corresponding sulfoxides and sulfones
benzoyl- (Bz) protected benzyl thioglucopyranosides, which in good to excellent yields (Table 2, entries 16–19). Overall,
showed a good selectivity during the controlled oxidation with sulfoxides were achieved within the time period of 1.5–2.5 h
UHP and provided >87% and >89% of the desired sulfoxides while sulfones were obtained in 6–11 h.
(5a and 6a) and sulfones (5b and 6b), respectively (Table 2,
entries 5 and 6). Similar to phenyl and benzyl sulfides, alkyl Conclusion
sulfides such as ethyl, n-hexyl and cyclohexyl glycosyl sulfides In conclusion, we have developed a practical method for the
were also successfully oxidized in a controlled and selective selective and controlled oxidation of thioglycosides to corre-
manner with equal efficiency (Table 2, entries 7–12).
sponding glycosyl sulfoxides and sulfones using the stable,
inexpensive and commercially available oxidant urea–hydro-
Having studied the oxidation of electron deficient thioglucopy- gen peroxide (UHP). Glycosyl sulfoxides were achieved using
ranosides, we further investigated the oxidation of O-benzyl 1.5 equiv of UHP at 60 °C while sulfones were achieved using
protected 4-methylphenyl thioglycoside 13 under optimized 2.5 equiv of UHP at 80 °C. Remarkably, oxidation susceptible
conditions (Table 2, entry 13). This substrate was found to be olefin functional groups were found to be stable during the
more reactive than O-acetylated and benzoylated thioglyco- sulfide oxidation.
sides and gave the sulfoxide in a good yield within 1.5 h. How-
ever, corresponding sulfone was obtained in a moderated yield
Supporting Information
due to instability which undergoes partial amount of decompo-
sition.
Supporting Information File 1
Experimental part and NMR spectra.
In general, olefins functional groups are known to undergo
epoxidation or dihydroxylation with different oxidizing agents
(e.g. m-CPBA, t-BuOOH, oxone, etc.) [34]. Therefore, the
scope of this methodology was further investigated with oxida-
tion of allyl group protected thioglycoside 14 (Table 2, entry
14). Remarkably, allyl groups were found to be very stable
during the oxidation while sulfide underwent selective oxida-
tion to corresponding sulfoxide and sulfone in 89% and 91%,
respectively. Further, we have studied the oxidation of pro-
tected glucosamine thioglycoside (Table 2, entry 15) which pro-
vided 91% of sulfoxide and 82% of sulfone.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-113-S1.pdf]
Acknowledgements
J. K. gratefully acknowledges DST-India for young scientist
start-up research grant (YSS/2014/000236). J. K. also acknowl-
edges Max-Planck Society-Germany and DST-India (DST/INT/
MPG/P-09/2016) for financial support through Indo-Max
Planck partner group project. A. K. S acknowledges CSIR for
junior research fellowship (JRF). S. G acknowledges IIT (BHU)
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Beilstein J. Org. Chem. 2017, 13, 1139–1144.
27.Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Lett. 2000, 41, 2299.
doi:10.1016/S0040-4039(00)00165-9
for a research fellowship. J. K. thanks to Mr. Albert Pape and
Dr. K. Murugan for a helpful discussion during the manuscript
preparation. J. K. thanks Central Instrumentation Facility Center
(CIFC)-IIT BHU for the NMR facilities.
28.Ankudey, E. G.; Olivo, H. F.; Peeples, T. L. Green Chem. 2006, 8, 923.
doi:10.1039/B604984B
29.Gupta, S.; Chaudhary, P.; Srivastava, V.; Kandasamy, J.
Tetrahedron Lett. 2016, 57, 2506. doi:10.1016/j.tetlet.2016.04.099
30.Chaudhary, P.; Gupta, S.; Popuri, S.; Sabiah, S.; Kandasamy, J.
Green Chem. 2016, 18, 6215. doi:10.1039/C6GC02444K
31.Gupta, S.; Chaudhary, P.; Seva, L.; Sabiah, S.; Kandasamy, J.
RSC Adv. 2015, 5, 89133. doi:10.1039/C5RA18080E
References
1. Rayner, C. M. Advances in Sulfur Chemistry; Jai Press: Stamford
Connecticut, 2000.
2. Cremlyn, R. J. An introduction to oranosulfur chemistry; Wiley: New
York, 1996.
32.Chaudhary, P.; Gupta, S.; Muniyappan, N.; Sabiah, S.; Kandasamy, J.
Green Chem. 2016, 18, 2323. doi:10.1039/C5GC02880A
33.Gupta, S.; Sureshbabu, P.; Singh, A. K.; Sabiah, S.; Kandasamy, J.
Tetrahedron Lett. 2017, 58, 909. doi:10.1016/j.tetlet.2017.01.051
34.Bäckvall, J.-E. Modern Oxidation Methods, 2nd ed.; Wiley-VCH:
Weinheim, 2010. doi:10.1002/9783527632039
3. Feng, M. H.; Tang, B. Q.; Liang, S. H.; Jiang, X. F.
Curr. Top. Med. Chem. 2016, 16, 1200.
doi:10.2174/1568026615666150915111741
4. Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
doi:10.1021/cr950066q
5. Levy, D. E.; Fügedi, P. The Organic Chemistry of Sugars; CRC Press,
Taylor & Francis Group, 2005.
6. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P. Tetrahedron 2008, 64,
7659. doi:10.1016/j.tet.2008.05.051
License and Terms
7. Khan, S. H. Modern Methods in Carbohydrate Synthesis; CRC Press,
Taylor & Francis Group, 1996.
This is an Open Access article under the terms of the
Creative Commons Attribution License
8. Bennett, C. S. Selective Glycosylations: Synthetic Methods and
Catalysts; Wiley-VCH Verlag GmbH & Co. KGaA, 2017.
9. Werz, D. B.; Vidal, S. Modern Synthetic Methods in Carbohydrate
Chemistry: From Monosaccharides to Complex Glycoconjugates;
Wiley-VCH Verlag GmbH & Co. KGaA, 2014.
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
10.Hanessian, S. Marcel Dekker: New York, 1997.
11.Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881. doi:10.1021/ja00199a081
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
12.Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
doi:10.1016/S0040-4020(99)00600-6
13.Gervay, J.; Flaherty, T. M.; Holmes, D. Tetrahedron 1997, 53, 16355.
doi:10.1016/S0040-4020(97)01021-1
The definitive version of this article is the electronic one
which can be found at:
14.Kaczorowska, K.; Kolarska, Z.; Mitka, K.; Kowalski, P. Tetrahedron
2005, 61, 8315. doi:10.1016/j.tet.2005.05.044
doi:10.3762/bjoc.13.113
15.Kowalski, P.; Mitka, K.; Ossowska, K.; Kolarska, Z. Tetrahedron 2005,
61, 1933. doi:10.1016/j.tet.2004.11.041
16.Jeyakumar, K.; Chand, D. K. Tetrahedron Lett. 2006, 47, 4573.
doi:10.1016/j.tetlet.2006.04.153
17.Agnihotri, G.; Misra, A. K. Carbohydr. Res. 2006, 341, 275.
doi:10.1016/j.carres.2005.11.025
18.Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.; Sofia, M. J.
J. Org. Chem. 1996, 61, 8347. doi:10.1021/jo961478h
19.Wang, Q.; Wei, X.; Liao, K. J.; Li, H.; Meng, X. B.; Li, Z. J.
Tetrahedron Lett. 2016, 57, 2277. doi:10.1016/j.tetlet.2016.04.045
20.Nigudkar, S. S.; Demchenko, A. V. Chem. Sci. 2015, 6, 2687.
doi:10.1039/C5SC00280J
21.Agnihotri, G.; Misra, A. K. Tetrahedron Lett. 2005, 46, 8113.
doi:10.1016/j.tetlet.2005.09.132
22.Chen, M.-Y.; Patkar, L. N.; Chen, H.-T.; Lin, C.-C. Carbohydr. Res.
2003, 338, 1327. doi:10.1016/S0008-6215(03)00164-2
23.Morais, G. R.; Humphrey, A. J.; Falconer, R. A. Tetrahedron 2008, 64,
7426. doi:10.1016/j.tet.2008.05.033
24.Jones, C. W. Applications of Hydrogen Peroxide and Derivatives;
Royal Society of Chemistry: Cambridge, 1999.
25.Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533. doi:10.1055/s-1990-21156
26.Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189.
doi:10.1021/ol990522n
1144