Efficient reduction of sulfoxides with 2,6-dihydroxypyridine

Article abstract of DOI:10.1016/S0040-4039(00)00502-5

2,6-Dihydroxypyridine was found to be an efficient reagent in the deoxygenation of sulfoxides. The mild reaction conditions were compatible with functional groups such as ester and carbamate. It was also found that approximately 0.25 equivalents of 2,6-dihydroxypyridine was required for effective reduction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00502-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3781–3783
Efficient reduction of sulfoxides with 2,6-dihydroxypyridine
Samantha J. Miller, Talia R. Collier and Weiming Wu ∗
Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Avenue, San Francisco,
CA 94132, USA
Received 7 March 2000; accepted 21 March 2000
Abstract
2,6-Dihydroxypyridine was found to be an efficient reagent in the deoxygenation of sulfoxides. The mild
reaction conditions were compatible with functional groups such as ester and carbamate. It was also found that
approximately 0.25 equivalents of 2,6-dihydroxypyridine was required for effective reduction. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: sulfoxides; sulfides; reduction; pyridines.
During the course of our studies on the decarboxylation of orotic acid and citrazinic acid (2,6-
dihydroxyisonicotinic acid) and the nature of the reaction intermediates,1–3 we observed that citrazinic
acid and related compounds react with tetramethylene sulfoxide to give the corresponding sulfide. In this
communication, we report that 2,6-dihydroxypyridine (1) is an efficient reducing agent for the conversion
of sulfoxides to sulfides.
Sulfoxides are important reagents in the application of organosulfur compounds in organic synthesis.4,5
Sulfoxides are usually eliminated by a two-step process involving deoxygenation to sulfides which are
then removed by catalytic hydrogenation or other chemical methods.4 There are numerous methods
available for the deoxygenation of sulfoxides; however, many of them involve reagents which are either
strong acids, strong nucleophiles, or very reactive species such as carbenes.5,6 We have found that
2,6-dihydroxypyridine (1) or its hydrochloride salt effects sulfoxide reduction under neutral and mild
conditions.
Reductions were carried out in refluxing acetonitrile. The workup is very simple since 1 and its
oxidation products are not soluble in the reaction solvent and can be filtered off. Concentration of the
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00502-5
tetl 16781

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filtrate gives essentially pure sulfide.7 The percent yields shown in Table 1 are from reactions using 0.5
equivalents of 1. In our experiments to determine the stoichiometry of the reaction, we found that 1 could
reduce approximately 4 equivalents of sulfoxide. The reaction is compatible with protective functional
groups such as those examined with the methionine derivative in Table 1. Under the reaction conditions
described here, diphenyl sulfoxide gave relatively low yields; however, the use of tetramethylene sulfone
as solvent dramatically improved the yield. On the other hand, since it has a high boiling point and is
often difficult to remove from the reaction mixture, tetramethylene sulfone is not a convenient solvent.
Not surprisingly, sulfones are not reduced by 1, as seen with many other reducing agents for sulfoxides.4
The mechanism of this reaction remains conjectural and mechanistic studies are currently underway.†
Table 1
Reduction of sulfoxides with 1 in CH3CN
The above results have demonstrated that 2,6-dihydroxypyridine (1) is an efficient reducing agent
for sulfoxides. Both aromatic and aliphatic, cyclic and acyclic, sulfoxides can be reduced to sulfides in
high yield. Sulfoxides with other functional groups such as ester and carbamate also give good results.
The reaction described here is thus a useful and convenient alternative to existing methods for sulfoxide
deoxygenation.
Experimental details: Methyl L-2-(benzyloxycarbonylamino)-4-(methylsulfinyl)butanoate was prepa-
red as reported by Carrasco et al.8 All other reagents were obtained from commercial sources and used
without further purification. The reactions were run in an open atmosphere.
Typical experimental procedure: Dibenzyl sulfoxide (2.00 g, 8.70 mmol) and 2,6-dihydroxypyridine
hydrochloride (0.64 g, 4.35 mmol) were mixed in acetonitrile (20 mL) in a round-bottom flask and
the mixture was refluxed for 3–5 h. Upon cooling, the reaction mixture was filtered and the filtrate was
†
We were not able to identify the oxidation product of pyridine 1, which would have provided insight on the mechanism.

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concentrated to give dibenzyl sulfide (1.82 g, 98%) as the product. The identity of the product was verified
by co-injection with an authentic sample onto a capillary gas chromatography column. The product was
judged to be pure according to its NMR spectrum.
Acknowledgements
This investigation was supported by a ‘Research Infrastructure in Minority Institutions’ award from the
National Center for Research Resources with funding from the Office of Research on Minority Health,
National Institutes of Health No. 5 P20 RR11805. We are indebted to Dr. Clifford Berkman and Mr. Wee
Tam (SFSU) for assisting us on the use of gas chromatography and obtaining NMR spectra, respectively.
We thank Dr. Ihsan Erden (SFSU) for helpful discussions. We also thank Ms. Venus Manalo (CCSF) for
her assistance in the laboratory.
References
1. Wu, W.; Ley-han, A.; Wong, F. M.; Austin, T. J.; Miller, S. M. Bioorg. Med. Chem. Lett. 1997, 7, 2623–2628.
2. Nakanishi, M. P.; Wu, W. Tetrahedron Lett. 1998, 39, 6271–6272.
3. Feng, W. Y.; Austin, T. J.; Chew, F.; Gronert, S.; Wu, W. Biochemistry 2000, 39, 1778–1783.
4. March, J. Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 4th ed.; Wiley: New York, 1992.
5. For a review on reduction of sulfoxides, see: Madesclaire, M. Tetrahedron 1988, 44, 6537–6580.
6. For an earlier review, see: Drabowicz, J.; Togo, H.; Mikolajczyk, M.; Oae, S. Org. Prep. Proc. Int. 1984, 16, 171–198.
7. All products have identical NMR spectra to those of authentic samples. Many of them can be found in: Pouchert, C. J.;
Behnke, J. The Aldrich Library of 13C and 1H FT-NMR Spectra; Aldrich: Milwaukee, 1992.
8. Carrasco, M.; Jones, R. J.; Kamel, S.; Rapoport, H.; Truong, T. Org. Synth. Coll. 1998, 9, 63–67.