Oxidation of 3-Aryl-4-(1-hydroxyethyl)sydnones using DMSO-Ac2O as Oxidant Shaw-Tao Lin,*a Hsien-Ju Tienb and Jinn-Tsair Chenb aDepartment of Applied Chemistry, Providence University, Sha-Lu, Taichung Hsien, 433, Taiwan, ROC bDepartment of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan, ROC Treatment of 3-aryl-4-(1-hydroxyethyl)sydnones with DMSO-Ac2O yielded esters and ketones, depending on the amount of Ac2O used; application of a limited amount of Ac2O with DMSO as an oxidant has been found to be the only method to convert the title compounds to the ketones.Transformation of functional groups is a very important topic in organic chemistry.1 The reactivity of any speci®c functional group is strongly dependent on the nature of its environment, i.e., electron density, steric factors etc. The sydnone ring is a non-benzenoid heterocyclic aromatic ®ve- membered ring and possesses some unusual characteristics. It can be regarded as a mesoionic system with positive and negative charges distributed around the ring depending on their resonance forms.2 In general it is believed that C(4) possesses negative character and N(2) is positive, based on their orientation and calculations.Reduction and oxidation (redox) reactions involve electron transfer from one reactant to another. The feasibility of a redox process therefore strongly depends on the electron density of a functional group. Although, reduction of the carbonyl group of ketones or aldehydes by using sodium tetrahydroborate is a very feasible process,3 only the carbonyl group at the C(4) position in the sydnone ring can be reduced by NaBH4 in methanol media, because of the electron-donating char- acter of the C(4) position.4 On the other hand, a number of attempts to oxidize C(4) of 1-hydroxyethylsydnone to form an acetyl group have consistently failed.These attempts mainly involved use of dichromate±sulfuric acid in acetone or manganese dioxide in acetic acid with ultrasonic agitation4 as the oxidation conditions.Strong oxidants (former) are hence likely to decompose the sydnone ring, while weaker oxidant (latter) does not cause any reaction. In the present work, a combination of dimethyl sulfoxide (DMSO) and acetic anhydride (Ac2O) is used as an oxidant to convert the hydroxyl group to a carbonyl group. Esteri®cation can be achieved along with this reaction in the presence of an excess of anhydride.Results and Discussion DMSO is known as a mild oxidant and is able to convert primary or secondary alcohols to the corresponding aldehydes or ketones without formation of acid or other oxidation products.6 The oxidation is often activated by the presence of electrophilic reagents, such as thionyl chloride, oxalyl chloride, halogens, sulfuric trioxide/pyridine or acetic anhydride. Among these electrophilic agents, acetic anhydride is the most convenient. In this study, a solution of 4-(1-hydroxyethyl)sydnone, DMSO and acetic anhydride was heated at 100 8C for 10 min to achieve oxidation.After the work-up process, ketones and/or esters were obtained from 3-aryl-4-(1- hydroxyethyl)sydnones, which contained various sub- stituents on the phenyl ring. The relative fractions of ester and ketone thus produced have been found to depend on the amount of acetic anhydride used (Table 1). When a limiting amount of acetic anhydride was used as a catalyst, the reaction led to formation of ketones as the only product (condition A) while large amounts of acetic anhydride in the mixture yielded more ester products (conditions B and C).The esteri®cation can be directed between the alcohol and acetic anhydride or acetyl group. This process is enhanced by the addition of acetate ions from either sodium acetate or triethylamine in the mixture of DMSO and acetic anhydride (entries 6, 7). To bring about oxidation of the hydroxy group, DMSO ®rst reacts with an electrophilic reagent (i.e., acetic anhydride) to form an intermediate a with a positive charge on the sulfur atom (Scheme 1).Thus sulfur facilitates a nucleophilic attack by the oxygen atom of the hydroxy group that separates from the acetic acid to J. Chem. Research (S), 1998, 626±627 J. Chem. Research (M), 1998, 2783±2791 Table 1 Product distributions from the reaction of 4-(2-hydroxyethyl)sydnones by using DMSO±Ac2O oxidant Yield (%) Entry Reactant Conditiona Ketone (K) Ester (E) 1 1 A 84 – 2 1 B 46 38 3 1 C 31 53 4 1 D – – 5 1 E – 40 6 1 F – 75 7 1 G – 63 8 2 A 70 – 9 2 C 35 40 10 3 A 83 – 11 3 C 15 70 12 4 A 76 – 13 4 C – 70 14 5 A 65 – 15 5 C 20 40 16 6 A 80 – 17 6 C 8 80 18 7b A 63 – 19 7b C 20 47 20 8 A 50 – 21 8 C 15 42 22 9 A 54 – 23 9 C 16 46 aIsolated yields.The mixtures containing sydnone (2.4 mmol) were heated at 100 8C for 10 min. A, DMSO±Ac2O [10.0 ml: 0.5 ml (2.0 equiv)]; B, DMSO±Ac2O (5.0 ml: 5.0 ml); C, DMSO±Ac2O [0.2 ml (1.0 equiv.)/10.0 ml]; D, AcOH (10.0 ml) used only; E, Ac2O (10.0 ml) used only; F, NaOAc (1.0 g, 12.2 mmol) was added to solution B; G, Et3N (1.0 ml, 7.2 mmol) was added to solution B.bReaction time was 20 min instead of 10 min. *To receive any correspondence. 626 J. CHEM. RESEARCH (S), 1998form intermediate b. This pathway involves abstraction of hydrogen from a methyl group next to the sulfur atom in intermediate b to form c. Notably, the acidity of the hydrogens of the methyl group is enhanced by the positive charge on the sulfur atom. The methylene anion in c sub- sequently abstracts a hydrogen from the carbon attached at C(4) of the sydnone ring, followed by loss of dimethyl sul¢çde to form the ketone as the ¢çnal product.Abstraction of a hydrogen from the carbon attached at C(4) of the sydnone ring followed by loss of a DMSO molecule might be an alternative pathway for the formation of ketones. In general, the presence of a nitro group lowered the yield of both ketones and esters.At least 20 min reaction time is required to yield comparable results for 4-(1-hydroxyethyl)- 3-(4-nitrophenyl)sydnone (7, entries 18¡¾23). The electron- withdrawing group on the phenyl ring decreases the electron density at the C(4) position on the sydnone ring which further destabilizes intermediate b, and consequently a€ords a lower yield. This mechanism shows the presence of a positive charge on intermediates b.Experimental 3-Substituted 4-(1-hydroxyethyl)sydnones were prepared by the reactions of the corresponding 4-lithiosydnones with acetaldehyde according to the literature.7 Typical Oxidation of 3-Aryl-4-(1-hydroxyethyl )sydnone using DMSO¡¾Ac2O.�¢After the mixture of DMSO¡¾Ac2O (10 ml, with ratios as given in Table 1), containing 3-aryl-4-(1-hydroxyethyl)- sydnone, was heated at 100 8C for 10 min, the solution was cooled and chloroform (30 ml) added. This mixture was then washed with water (50 ml5) to remove DMSO and acetic acid.The organic layer was dried (MgSO4), evaporated, and then absorbed by silica gel for chromatographic separation by using ethyl acetate¡¾n-hexane (1:2, v/v) as eluent. The product ester was washed out before the product ketone. Melting points of the known 4-acetyl derivatives were compared with those of the authentic compounds. All of the 4-(1-ethoxycarbonyl)sydnones are new compounds synthesized in this study and their properties are reported in Table 2 (CHN elemental analyses within20.05%).Financial support for this work by the National Science Council of the Republic of China is gratefully acknowl- edged. Techniques used: 1H NMR, MS, IR, elemental analysis References: 7 Received, 4th March 1998; Accepted, 6th May 1998 Paper E/8/01789A References 1 R. C. Larock, in Comprehensive Organic Transformations: A Guide to Functional Group Preparation, VCH Publishers, Inc., New York, NY, 1989. 2 C. G. Newton and C. A. Ramsden, Tetrahedron, 1982, 38, 2965. 3 Reductions in Organic Synthesis: Recent Advances and Practical Applications, ed. A. F. Abdel-Magid, ACS Symp. Ser. 641, 1996. 4 H. J. Tien, J. Y. Cherng and S. T. Lin, J. Chin. Chem. Soc., 1995, 42, 987. 5. Tsuboi, N. Ishii, T. Sakai, I. Tari and M. Utaka, Bull. Chem. Soc. Jpn., 1990, 63, 1888. 6 W. W. Epstein and F. W. Sweat, Chem. Rev., 1967, 67, 247; R. F. Butterworth and S. Hanessian, Synthesis, 1971, 10; M. Hondo, T. Katsuki and H.Yamaguchi, Tetrahedron Lett.. 1984, 25, 3857. 7 H. J. Tien, G. M. Fang, S. T. Lin and L. L. Tien, J. Chin. Chem. Soc., 1992, 39, 107. Scheme 1 Table 2 Physical properties and spectral data of new 4-acetyl- (A) and 4-acetoxy- (B) sydnones Product Mp/8C (colour) IR ( /cm¢§1)a dH (CDCl3) (J/Hz) m/zb 2 102¡¾104 red flakes 1713 1.38 (t, 3 H, J 7.2), 1.57 (d, 3 H, J 7.5), 4.38 (q, 1 H, J 7.2), 4.63 (q, 1 H, J 7.5), 7.81 (d, 2 H, J 8.5), 8.25 (d, 2 H, J 8.5) 278, 176 7 112¡¾114 yellow powder 1731 1.59 (d, 3 H, J 7.2), 4.65 (q, 1 H, J 7.2), 7.81 (d, 2 H, J 8.7), 8.14 (d, 2 H, J 8.7) 251, 148 8 121¡¾123 yellow crystals 1737 1.59 (t, 3 H, J 7.3), 4.65 (q, 1 H, J 7.3), 7.81 (t, 1 H, J 8.7), 8.14 (d, 1 H, J 8.7), 8.70 (d, 1 H, J 8.7), 8.73 (s, 1 H) 251, 148 9 124¡¾126 yellow powder 1719 1.53 (d, 3 H, J 7.3), 4.60 (q, 1 H, J 7.3), 7.80 (d, 1 H, J 8.5), 7.91¡¾ 7.96 (m, 2 H), 8.35 (t, 1 H, J 8.6) 251, 148 2A 132¡¾134 light yellow flakes 1783, 1769 1.24 (t, 3 H, J 7.2), 2.54 (s, 3 H), 4.30 (q, 2 H, J 7.2), 7.88 (d, 2 H, J 8.7), 8.25 (d, 2 H, J 8.7) 251, 176 9A 142¡¾144 light yellow flakes 1731, 1530,c 1350c 2.47 (s, 3 H), 7.55 (d, 1 H, J 8.5), 7.89¡¾7.94 (m, 2 H), 8.44 (d, 1 H, J 8.5) 249, 148 1B 58¡¾60 white flakes 1737 1.59 (d, 3 H, J 8.6), 1.92 (s, 3 H), 5.52 (q, 1 H, J 8.6), 7.47 (m, 5 H) 248, 104 2B 89¡¾91 red granules 1731 1.25 (t, 3 H, J 7.3), 1.61 (d, 3 H), 1.95 (s, 3 H), 4.39 (q, 2 H, J 7.3), 5.50 (q, 1 H, J 8.5), 7.60 (d, 2 H, J 8.7), 8.25 (d, 2 H, J 8.7) 320, 176 3B 51¡¾52 white granules 1746 1.60 (d, 3 H, J 8.5), 1.95 (s, 3 H), 2.46 (s, 3 H), 5.53 (q, 1 H, J 8.5), 7.39 (m, 4 H) 262, 118 4B .red liquid 1743 1.58 (d, 3 H, J 8.5), 2.20 (s, 3 H), 4.63 (q, 1 H, J 8.5), 7.26 (d, 2 H, J 9.0), 7.55 (d, 2 H, J 90) 326, 182 5B 68¡¾70 white granules 1743 1.31¡¾2.08 (m, 10 H), 1.66 (d, 3 H, J 8.5), 2.02 (s, 3 H), 4.62 (m, 1 H), 5.75 (q, 1 H, J 8.5) 254, 84 6B 85¡¾86 white granules 1746 1.32 (t, 3 H, J 7.5), 1.54 (d, 3 H, J 8.5), 1.94 (s, 3 H), 4.01 (q, 2 H, J 7.5), 5.47 (q, 1 H, J 8.5), 6.93 (d, 2 H, J 8.5), 7.32 (d, 2 H, J 8.5) 292, 148 7B 130¡¾131 light yellow powder 1734, 1545,c 1360c 1.65 (d, 3 H, J 8.5), 1.98 (s, 3 H), 5.47 (q, 1 H, J 8.5), 7.79 (d, 2 H, J 9.0), 8.46 (d, 2 H, J 9.0) 293, 267 8B 107¡¾109 light yellow needles 1737, 1550,c 1350c 1.65 (d, 3 H, J 8.5), 1.95 (s, 3 H), 5.48 (q, 1 H, J 8.5), 7.81 (t, 1 H, J 9.0), 8.64 (d, 1 H, J 9.0), 8.78 (m, 2 H) 293, 148 9B 104¡¾106 yellow needles 1740, 1560,c 1355c 1.65 (d, 3 H, J 8.5), 1.96 (s, 3 H), 5.45 (q, 1 H, J 8.5), 7.50 (d, 1 H, J 9.0), 7.68 (t, 1 H, J 9.0), 7.93 (t, 1 H, J 9.0), 8.34 (d, 1 H, J 9.0) 293, 148 a CO; bMass unit of the molecular ion and the base peak. c NO2 . J. CHEM. RESEARCH (S), 1998 627