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Synlett 2009(1): 103-105  
DOI: 10.1055/s-0028-1087483
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Construction of Diversely Functionalized Oxazoles from Enolizable Cyclic 1,3-Dicarbonyls and 5(4H)-Oxazolones

Massimiliano Cordaro, Giovanni Grassi*, Francesco Risitano, Angela Scala
Dipartimento di Chimica Organica e Biologica, Università, Vill. S. Agata, 98166 Messina, Italy
Fax: +39(090)393897; e-Mail: ggrassi@unime.it;
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Publikationsverlauf

Received 22 September 2008
Publikationsdatum:
12. Dezember 2008 (online)

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Abstract

A new method for the synthesis of diversely functionalized oxazoles has been developed. The transformation consists of an acylation of enolizable cyclic 1,3-dicarbonyls by 5(4H)-oxazolones followed by rapid cyclization promoted by trifluoroacetic anhydride. Cyclization precursors have been prepared by a chemo- and regioselective method using DBU as catalyst under microwave irradiation.

Key words

oxazoles - 1,3,3′-tricarbonyls - C-acylations - cyclizations - microwave

5

Typical Procedure
DBU (1.5 mmol) was added to a solution of 1,3-dicarbonyl compound 6 (3 mmol) in anhyd MeCN (20 mL). After stirring for 15 min at r.t., a solution of 2-phenyl-4-methyl-(4H)-oxazol-5-one 7 (6 mmol) in anhyd MeCN was added, and the reaction mixture was heated by MW irradiation at 85 ˚C for 1 h. The progress of the reaction was monitored by TLC (CHCl3-EtOAc, 95:5). After the solvent was removed, the crude product was purified by column chromatography on SiO2 (CHCl3-EtOAc, 95:5) to afford 8.

6

Under conditions thus identified, compounds 8 were the only isolated products.

7

Selected Data for 8a-g Compound 8a: white solid; mp 150-151 ˚C. IR (Nujol): 3312, 1653, 1636 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.48 (d, J = 7.1 Hz, 3 H), 1.98-2.05 (m, 2 H), 2.50-2.56 (m, 2 H), 2.73 (t, J = 6.3 Hz, 2 H), 5.91 (dq, J = 7.1, 7.6 Hz, 1 H), 6.91 (d, J = 7.6 Hz, NH), 7.41-7.82 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.6, 19.0, 32.4, 38.4, 52.1, 111.6, 127.1, 128.4, 131.5, 134.1, 166.6, 191.0, 194.6, 204.0. MS (EI): m/z = 287.4.
Compound 8b: white solid; mp 149-150 ˚C. IR (Nujol): 3310, 1650, 1631 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.09 (s, J = 8.6 Hz, 6 H), 1.48 (d, J = 7.0 Hz, 3 H), 2.40 (d, J = 7.4 Hz, 2 H), 2.59 (s, 2 H), 5.91 (dq, J = 7.0, 8.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, NH), 7.41-7.82 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.6, 27.7, 28.4, 30.8, 45.9, 52.0, 52.2, 110.6, 127.0, 128.5, 131.5, 134.1, 166.5, 194.4, 196.6, 204.3. MS (EI): m/z = 314.6.
Compound 8c: white solid; mp 108-110 ˚C. IR (Nujol): 3257, 1658, 1629 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.09 (d, J = 3.0 Hz, 3 H), 1.11 (d, J = 2.1 Hz, 3 H), 1.46 (d, J = 3.0 Hz, 3 H), 1.48 (d, J = 3.0 Hz, 3 H), 2.18-2.78 (m, 5 H), 5.85 (m, 1 H), 6.92 (m, N H), 7.41-7.82 (m, arom.,
5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.7, 20.8, 26.4, 40.2, 46.5, 52.0, 111.1, 127.0, 128.5, 131.5, 134.1, 166.5, 194.5, 197.2, 204.7. MS (EI): m/z = 302.0.
Compound 8d: pink solid; mp 195-197 ˚C. IR (Nujol): 3306, 1751, 1681, 1640 cm-¹. ¹H NMR (300 MHz, DMSO-d 6): δ = 1.41 (d, J = 7.0 Hz, 3 H), 5.79 (dq, J = 7.0 Hz, 1 H), 7.44-7.89 (m, arom., 5 H), 8.73 (m, NH). ¹³C NMR (75 MHz, DMSO-d 6): δ = 15.0, 46.8, 90.8, 125.3, 126.0, 129.2, 131.4, 146.8, 164.0, 197.0. MS (EI): m/z = 302.8.
Compound 8e: white solid; mp 185-186 ˚C. IR (Nujol): 3303, 1721, 1681, 1642 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.58 (d, J = 5.3 Hz, 3 H), 3.38 (s, 6 H), 6.12 (dq, J = 5.3, 7.0 Hz, 1 H), 6.77 (d, J = 7.0 Hz, NH), 7.42-7.82 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.2, 27.9, 49.2, 93.9, 127.0, 128.5, 131.7, 133.6, 150.0, 160.1, 166.9, 170.1, 198.3. MS (EI): m/z = 330.8.
Compound 8f: brown solid; mp 49-50 ˚C. IR (neat): 3320, 1657 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.52 (d, J = 7.0 Hz, 3 H), 3.32-3.69 (m, 4 H), 5.84 (dq, J = 7.0, 6.4 Hz, 1 H), 6.76 (d, J = 6.4 Hz, NH), 7.42-7.81 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.3, 32.3, 36.5, 51.2, 110.7, 127.0, 128.3, 131.5, 134.5, 166.7, 188.8, 195.1, 204.0. MS (EI): m/z = 305.8.
Compound 8g: white solid; mp 168-170 ˚C. IR (Nujol): 3372, 1716, 1646 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.45-1.47 (m, 6 H), 2.75-3.04 (m, 4 H), 3.40-3.60 (m, 1 H), 5.89 (m, 1 H), 6.09 (m, 1 H), 6.31 (m, 1 H), 6.87 (d, J = 7.0 Hz, NH), 6.94 (d, J = 8.7 Hz, NH), 7.35 (m, 1 H), 7.42-7.82 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 18.2, 30.4, 36.9, 42.8, 52.1, 105.3, 110.2, 111.4, 127.0, 128.5, 130.0, 131.6, 133.9, 154.4, 166.7, 193.0, 196.0, 204.7. MS (EI): m/z = 354.0.

9

The effect of C-acylation products 8 on HCV viral replication is still under investigation. However, first results of biological assays show a promising activity of the
C-acylation derivative obtained from the reaction of asymmetrical oxazolone 7 and 4-hydroxy-6-methylpyran-
2-one (ref. 4).

11

Typical Procedure
Trifluoroacetic anhydride (20 equiv) was added to a solution of 8 (1 equiv) in abs. DCE at 0 ˚C. The mixture was stirred at that temperature for 5 h. After completion of the reaction, as indicated by TLC (CHCl3-EtOAc, 9:1), the solvent was removed under reduced pressure, and the residue was purified by recrystallization from Et2O or acetone to afford the solid product 9.

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Selected Data for 9a-g
Compound 9a: white solid; mp 188-189 ˚C. IR (Nujol): 1648, 1633 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 2.09-2.17 (m, 2 H), 2.13 (s, 3 H), 2.52 (m, 2 H), 2.70 (m, 2 H), 7.32-7.81 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 11.9, 20.0, 20.1, 104.9, 125.8, 126.2, 128.4, 130.1, 136.9, 138.2, 161.1, 188.3. MS (EI): m/z = 269.1.
Compound 9b: white solid; mp 117-120 ˚C. IR (Nujol): 3493, 1633, 1605 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.10 (s, 6 H), 2.11 (s, 3 H), 2.37 (s, 4 H), 7.52-7.98 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 9.2, 28.0, 31.7, 46.7, 101.2, 121.6, 126.9, 129.4, 129.8, 133.6, 142.8, 160.3, 188.3. MS (EI): m/z = 296.8.
Compound 9c: brown solid; mp 200-202 ˚C. IR (Nujol): 1642, 1623 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.13 (d, J = 4.9 Hz, 3 H), 2.01 (s, 3 H), 2.29-2.40 (m, 3 H), 2.58-2.62 (m, 2 H), 7.22-7.59 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 11.0, 11.9, 20.8, 27.7, 104.5, 125.9, 126.3, 128.5, 130.1, 136.8, 138.2, 161.1, 188.3. MS (EI): m/z = 283.0.
Compound 9d: white solid; mp 230-232 ˚C. IR (Nujol): 3498, 1739, 1680 cm-¹. ¹H NMR (300 MHz, DMSO-d 6): δ = 2.00 (s, 3 H), 7.47-7.92 (m, arom., 5 H). ¹³C NMR (75 MHz, DMSO-d 6): δ = 38.4, 79.9, 125.5, 127.5, 129.0, 130.0, 136.7, 138.1, 150.0, 158.1, 158.6, 159.5. MS (EI): m/z = 284.8.
Compound 9e: white solid; mp 250-252 ˚C. IR (Nujol): 1714, 1641, 1610 cm-¹. ¹H NMR (300 MHz, DMSO-d 6): δ = 1.99 (s, 3 H), 3.15 (s, 6 H), 7.47-7.88 (m, arom., 5 H). ¹³C NMR (75 MHz, DMSO-d 6): δ = 25.7, 36.7, 101.0, 123.2, 125.0, 126.8, 127.8, 136.7, 138.1, 149.1, 156.5, 159.5. MS (EI): m/z = 312.8.
Compound 9g: brown solid; mp 268-270 ˚C. IR (Nujol): 3339, 1651 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 2.17 (s, 3 H), 2.62-2.94 (m, 4 H), 3.50-3.60 (m, 1 H), 6.10 (d, J = 2.4 Hz, 1 H), 6.33 (m, 1 H), 7.37 (m, 1 H), 7.45-7.91 (m, arom., 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.5, 25.9, 41.0, 46.0, 106.0, 110.0, 110.3, 127.5, 128.7, 129.2, 130.6, 138.1, 139.6, 141.5, 156.0, 159.3, 183.3, 199.2. MS (EI): m/z = 335.1.