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Formation of Oxazoles from 2-Methylsulfanyl-N-phenacylpyridinium Salts
Eugene V. Babaev,* Anatoliy F. Nasonov Department of Chemistry, Moscow State University, Moscow 119899, Russia E-mail: babaev@org.chem.msu.su; nasonov@babaev.chem.msu.su Dedicated in honor of Prof. Fritz Sauter on his 70th Anniversary _______________________________________________________________________
Abstract With piperidine reacting both as base and nucleophile 2-methylsulfanyl-N-phenacylpyridinium salts 4a, b undergo ring transformation affording 2-[4-(1-piperidino)-(1Z,3E)-1,3-butadienyl]oxazoles 5a, b.

________________________________________________________________________ Keywords: 2-Methylsulfanyl-N-phenacylpyridinium salts; 2-[4-(1-piperidino)-(1Z,3E)1,3-butadienyl]oxazoles; ring transformation.

Introduction
A strategy to build oxazole rings is the closure of the chain ZCNCCO upon attack of a nucleophilic O-atom at an electrophilic C-atom with Z as a leaving group (5-exotet) (eq. 1). This approach has been rarely used to obtain monocyclic oxazoles;1 nevertheless, it is a useful procedure to construct oxazoles in fused ring systems (eq. 2).
Z N O -Z N O eq. 1 N Z O -Z N O eq. 2

In particular, the oxazoloazinium salts of types III and VIII have been obtained by this strategy (Scheme 1).2,3 Tertiary amines induce the cyclization of N-phenacylazinium salts bearing suitable leaving groups like the methylsulfanyl group as in pyrimidinium salts I,2 or halogen as in pyridinium salts IV.3 In both reactions the initial step was proposed to be the conversion of the phenacyl group into the enolates II and V, respectively. The betaine

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intermediates II or V, in turn, undergo the oxazole ring closure affording the bicyclic heterocyclic salts III and VIII, respectively.
Y N I, IV, VI Y I, II IV, V VI, VII N CH CH Z SMe halogen SMe III VIII Z

O R

R'3N -H

Y N

Z

O R -Z

Y N

O R

II, V, VII

III, VIII Y N CH

Scheme 1 The pyrido[2,1-b][1,3]oxazol-4-ium salts VIII are useful precursors for the preparation of other heterocycles because they provide both the oxazole and the pyridine fragment.4,5 On the other hand, 2-methylsulfanylpyridinium salts VI upon conversion into the enolate intermediates VII are considered to be suitable precursors of the salts VIII; up to now, there are no reports on the synthesis of salts VI and their reaction with bases and nucleophiles.

Results and Discussion
The starting materials 2-methylsulfanyl-N-phenacylpyridinium salts 4a, b can be readily obtained either by introducing phenacyl groups into 2-methylsulfanylpyridine (1) as well as by methylation of N-phenacylpyridine-2-thiones (3) with methyl iodide.

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SMe N 1 N MeI O R X RCOCH2Br 2a, b SMe O

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R N H R MeCN; 20 °C, 1h N 5a, b 2-5 a b R 4-BrC6H
4

N

O

S N

4a, b X = Br, I

3a, b

4-O2NC6H4

Scheme 2 We found that in a one-pot reaction piperidine readily transformed the salts 4a, b into 2-[4-(1-piperidino)-1,3-butadienyl][1,3]oxazoles (5a, b) at room temperature (Scheme 2). The 1H NMR spectra of the products 5 are lacking the CH2 singlet of the phenacyl group of 4, and only the signals of the piperidine fragment are displayed in the aliphatic region. The multiplets of proton signals in the aromatic region are typical for 4substituted 1-azolylbutadienes,6 and the singlet of 4-H of the oxazole ring appears at 6.86.9. The coupling constants of the olefinic signals indicate the (1Z,3E)-configuration of the 1,3-butadienyl moiety of 5a,b. Spectral and physical properties of the diene 5b are identical with those of the (1E,3Z)-isomer described earlier.5a The mass spectrum of product 5a exhibits the most intensive peak at m/z = 195 (loss of the piperidine fragment, M-C5H10N),which is typical for 2-(4-amino-1,3-butadienyl[1,3]oxazoles.7 We suppose that the conversion of the pyridinium salt 4 to oxazoles 5 is initiated by piperidine causing deprotonation and convertion of the salt 4 to the enol betaine 6; this intermediate 6, in turn, undergoes ring closure to give the pyrido[2,1-b][1,3]oxazol-4-ium intermediate 7 (Scheme 3). In a subsequent step, piperidine acting as a nucleophile adds to the pyridinium ring of 7 forming the adduct 5-piperidino-5H-pyrido[2,1-b][1,3]oxazole 8. Eventually, intermediate 8 undergoes ring-opening (cycloreversion) furnishing the final product 5. This type of reactivity of salts 7 with secondary amines is well known.
5

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R'2NH 4 - HX N

SMe O R 6 - M eS N

O R

R'2NH -H N H

O R
2

5

NR' 8

7

Scheme 3 Thus, the strategy utilized for the synthesis of bicyclic oxazoles can also be applied for the preparation of monocyclic oxazoles (cf. eq. 2). Dienes of type 5 have been previously reported to posess antimicrobial activity.5b The ring transformation reaction reported here offers a novel route to these compounds. Presently, we are investigating analogous ring transformation reactions with other azinium salts containing a 2-methylsulfanyl group (e.g. I, Scheme 1).

Experimental
General Remarks. The starting compounds 2-methylsulfanylpyridine (1),8 N-phenacylpyridine-2-thiones (3)9 were synthesized using previously described procedures. GLCMS spectra were obtained from a HP 5989 (with SE 30 column; EI 70 eV). NMR spectra were measured with a Bruker AM-300 (300 MHz) or with a Bruker AC-200 (200 MHz). Preparation of N-phenacylpyridinium salts (4a, b): (a) From 2-methylsulfanylpyridine (1) and phenacylbromides 2a,b. A mixture of 2-methylsulfanylpyridine (1) (2.8 g, 22.4 mmol) and the phenacylbromide 2a,b (22.4 mmol) in acetonitrile (4556 mL) was stirred at room temperature for 10 days. The white precipitate formed was filtered off, and the filtrate was refluxed for 1 h, cooled, and the resulting precipitate was filtered off. An additional crop separated from the filtrate after prolonged standing. 1-(4-Bromophenyl)-2-[2-(methylsulfanyl)-1-pyridiniumyl]-1-ethanone bromide (4a, X = Br): Colorless crystals. Yield: 4.24 g (47%); mp (decomp.) 200201 єC. 1H NMR (CD3OD): 2.9 (s, 3H), 6.4 (s, 1.5 H, deuterium exchange10), 7.807.85 (m, 3H), 8.03

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8.15 (m, 3H), 8.50 (t, 1H), 8.79 (d, 1H). Anal. calcd. for C14H13Br2NOS (403.14): C, 41.69; H, 3,23; N, 3,47. Found: C, 41,33; H, 3,23; N, 3,37. 2-[(2-Methylsulfanyl)-1-pyridiniumyl]-1-(4-nitrophenyl)-1-ethanone bromide (4b, X = Br): Colorless crystals. Yield: 5.37 g (65%); mp (decomp.) 204206 єC. 1H NMR (CD3OD): 3.06 (s, 3H), 6.66 (s, 0.46 H, deuterium exchange10), 8.05 (dd, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 9.3 Hz, 2H), 8.648.75 (m, 3H), 9.01 (d, J = 9.4 Hz, 1H). Anal. calcd. for C14H13BrN2O3S (369.24): C, 45,53; H, 3,52; N, 7,59. Found: C, 45,57; H, 3,45; N, 7,50. (b) From N-phenacyl-1,2-dihydropyridine-2-thiones (3a,b). To a solution of N-phenacylpyridine-2-thione (3a,b) (2 mmol) in acetonitrile (5 mL) was added iodomethane (284 mg), and the resulting solution was stirred at room temperature for 2 days. The yellow precipitate formed was filtered off, washed with acetonitrile and dried. 1-(4-Bromophenyl)-2-[2-(methylsulfanyl)-1-pyridiniumyl]-1-ethanone iodide (4a, X = I): Yield: 604 mg (67%) of 4a, mp (decomp.) 184 єC. N-2-(4-Bromophenyl)oxazolo[3,2-a]pyridinium perchlorate (7a, X = ClO4). N-2-(4-1(4-Bromophenyl)-2-[2-(methylsulfanyl)-1-pyridiniumyl]-1-ethanone bromide 4a (X=Br) (200 mg, 0.5 mmol) was dissolved in acetonitrile (15 ml), and after addition of triethylamine (0,2 mL) the mixture was refluxed for 3 h. Upon cooling the resulting precipitate was collected by filtration and dissolved in water. Addition of 70% perchloric acid (10- to 12-fold excess) afforded a white precipitate, which was filtered off, washed with water and dried affording the perchlorate 7a (X = ClO4); yield: 117 mg (63%). 4-[5-(4-Bromophenyl)-2-[(1Z,3E)-4-(1-piperidino)-1,3-butadienyl]oxazole (5a). To a solution of the pyridinium bromide 4a (121 mg, 0.3 mmol) in acetonitrile (15 mL) was added piperidine (1.2 mL, 12 mmol), and the mixture was stirred at room temperature for 1 h. To the resulting orange solution was added water (60 mL), and the precipitate thus formed was collected, washed with water and dried at room temperature.5b Orange solid 5a (74 mg, 68.5%), mp 101103 °C. 1H NMR (DMSO-d6): 1.58 (m, 4H), 3.22 (m, 6H), 5.53, (d, J = 10.4 Hz, 1H), 6.336.55, (m, 2H), 6.79 (d, J = 12,4 Hz, 1H), 7.347.96 (m,

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5H); MS: m/z (%) 358 (13.8, M+), 274 (100, M C5H10N), 195 (26.3, M C5H10N, Br), 183 (27.4, COC6H4Br), 155 (31,6, C6H4Br).13 4-[5-(4-Nitrophenyl)-2-[(1Z,3E)-4-(1-piperidino)-1,3-butadienyl]oxazole (5b). To a solution of pyridinium bromide 4b (65 mg, 0.176 mmol) in acetonitrile (8.5 mL) was added piperidine (0.7 mL), and the mixture was stirred at room temperature for 1 h. To the resulting purple solution was added water (35 mL), and the precipitate thus formed was collected, washed with water and dried at room temperature. Dark-violet solid 5b (42 mg, 71%), mp 170171 °C (lit.5a mp 160161 °C). 1H NMR (DMSO-d6): 1.57 (m, 4H), 3.24 (m, 6H), 5.54 (d, J = 10,5 Hz, 1H), 6.366.62 (m, 2H), 6.88 (d, J = 12,4 Hz, 1H), 7.83, 7.88 (AA', 2H), 7.95 (s, 1H), 8.26, 8.30 (BB', 2H). Anal. calcd. for C18H19N3O3 (325.37): N, 12.9. Found: N, 12.4.

References and Notes
1. 2. 3. 4. 5. Hartner F. V. Jr. In Comprehensive Heterocyclic Chemistry 2, Katritzky A. R.; Rees C. W.; Scriven E. F. V., Eds., Elsevier: N.Y., 1996, Vol. 3, pp. 261-318. Liebscher J.; Hassoun A., Synthesis 1988, 10, 816. (a) Bradsher C. K.; Brandau R. D.; Boilek J. E.; Hough T. L. J. Org. Chem. 1969, 34, 2129. (b) Pauls H.; Krohnke F. Chem. Ber. 1976, 109, 3646. (a) Markl G.; Pflaum S. Tetrahedron Lett. 1988, 28, 1511. (b) Katritzky A. R.; Zia A. J. Chem. Soc. Perkin Trans. I 1982, 131. (a) Babaev E. V.; Efimov A. V.; Maiboroda D. A.; Jug K. Eur. J. Org. Chem. 1998, 1, 193. (b) Maiboroda D. A.; Babaev E. V.; Goncharenko L. V., Russ. Khim.Pharm. Zhurn. 1998, 6, 24; Chem. Abstr. 1998, 124, 275864 (c) Babaev E. V. In: Targets in Heterocyclic Systems - Chemistry and Properties, Attanasi O. A.; Spinelli D. Eds., Societa Chimica Italiana, Rome, 1997, 105. (d) Review: Babaev E. V. J. Heterocycl. Chem. 2000, 37, 519. (a) Hajos Gy.; Messmer A. J. Heterocycl. Chem. 1984, 21, 809. (b) Messmer A.; Hajos Gy.; Timari G. Tetrahedron 1992, 48, 8451. Babaev E. V.; Tsisevich A. A. J. Chem. Soc, Perkin Trans. 1999, 4, 399. Renualt J. Ann. de Chim. Ser.12 1955, 10, 135; Chem. Abstr. 1956, 50, 9408. Bradsher C.K.; Boliek J. E. J. Org. Chem. 1967, 32, 2409. The spectra have been measured immediately after dissolving the compound in the solvent; after 3 h this signal exhibited a lower intensity.

6. 7. 8. 9. 10.

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11. Bradsher C. K.; Braundau R.D.; Boliek J. E.; Hough T. L. J. Org. Chem. 1969, 34, 2129. 12. 13. Bradsher, C. K.; Zinn M. F. J. Heterocycl. Chem. 1967, 4, 66. The isolated product contains beside (1Z,1E)-5a as small amount (< 10%) of the (1E,1E)-5a isomer as indicated by NMR signals in the olefinic region [ 5.86 (d) and 7.20 (dd)] as well as by additional GC peak.

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