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Synlett 2010(14): 2146-2150  
DOI: 10.1055/s-0030-1258517
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Selective Fluorodesulfurization of Benzo- and Pyrido-oxazine Derivatives

Bin Yin, Shinsuke Inagi, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax: +81(45)9245406; e-Mail: fuchi@echem.titech.ac.jp;
Further Information

Publication History

Received 13 May 2010
Publication Date:
22 July 2010 (online)

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Abstract

Selective fluorodesulfurization of 3-aryl-2-phenylthio-2H-benzo[b][1,4]oxazine derivatives was successfully carried out using various N-halogenosuccinimides as oxidizing reagent in the presence of Et3N˙3HF to provide the corresponding monofluorinated products in excellent yields. Selective fluorodesulfurization of the corresponding pyrido[3,2-b][1,4]oxazine derivatives was also achieved similarly.

Key words

heterocycles - fluorine - halides - desulfurization - substitution

    References and Notes

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6

General procedure for the synthesis of benzo- or pyrido-oxazine derivatives 1 and 2. To a solution of 2-amino-phenol or 2-amino-3-pyridinol (1 mmol) in N,N-dimethyl-acetamide (DMA; 2 mL), was added NaH (1.1 mmol, 1.1 equiv) followed by stirring at 0 ˚C for 10 min. A solution of α-bromo-α-(phenylthio)acetophenone derivative (1 mmol) in DMA (1 mL) was then added dropwise and the mixture was kept at 0 ˚C for another 10 min. The resulting solution was warmed to room temperature and stirred overnight. The solution was mixed with water and the product was extracted with ethyl acetate (× 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude products were then purified by column chromatography on silica gel (EtOAc-hexane) to give pure benzooxazine derivatives 1 or pyridooxazine derivatives 2.

7

3-Phenyl-2-(phenylthio)-2 H -benzo[ b ][1,4]oxazine (1a). Pale-yellow solid; mp 92-93 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.71 (s, 1 H), 7.04 (dd, J = 7.83, 1.35 Hz, 1 H), 7.10 (td, J = 7.56, 1.62 Hz, 1 H), 7.23 (dd, J = 7.83, 1.62 Hz, 1 H), 7.28 (dd, J = 4.59, 1.35 Hz, 1 H), 7.30-7.34 (m, 2 H), 7.43 (dd, J = 7.56, 1.35 Hz, 2 H), 7.46-7.54 (m, 4 H), 8.03-8.10 (m, 2 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.90, 117.13, 123.27, 126.92, 127.53, 128.46, 128.69, 128.97, 129.02, 131.13, 132.28, 133.47, 134.22, 142.98, 155.06. HRMS (ESI): m/z [M + H]+ calcd for C20H16NOS: 318.0953; found: 318.0947.

8

3-(4-Bromophenyl)-2-(phenylthio)-2 H -benzo[ b ][1,4]-oxazine (1b). Pale-yellow solid; mp 111-112 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.65 (s, 1 H), 7.04 (dd, J = 8.10, 1.35 Hz, 1 H), 7.10 (td, J = 7.56, 1.35 Hz, 1 H), 7.24 (dd, J = 5.67, 1.62 Hz, 2 H), 7.28-7.34 (m, 2 H), 7.40 (dd, J = 7.56, 1.62 Hz, 1 H), 7.46-7.50 (m, 2 H), 7.61 (dt, J = 8.64, 2.16 Hz, 2 H), 7.93 (dt, J = 8.64, 2.16 Hz, 2 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.67, 117.16, 123.36, 125.81, 127.59, 128.41, 128.59, 129.01, 129.30, 131.90, 132.00, 133.10, 133.52, 134.03, 142.92, 153.92. HRMS (ESI): m/z [M + H]+ calcd for C20H15BrNOS: 396.0058; found: 396.0052.

9

3-(4-Nitrophenyl)-2-(phenylthio)-2 H -benzo[ b ][1,4]-oxazine (1c). Yellow solid; mp 148-149 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.70 (s, 1 H), 7.08 (dd, J = 8.10, 1.35 Hz, 1 H), 7.13 (td, J = 7.56, 1.35 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.44 (dd, J = 7.56, 1.62 Hz, 2 H), 7.47-7.50 (m, 2 H), 8.23 (dt, J = 9.18, 1.89 Hz, 2 H), 8.33 (dt, J = 9.18, 1.89 Hz, 2 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.84, 117.28, 123.58, 123.86, 127.82, 128.11, 128.86, 129.13, 130.27, 131.56, 133.64, 133.84, 139.83, 142.99, 148.98, 152.60. HRMS (ESI): m/z [M + H]+ calcd for C20H15N2O3S: 363.0803; found: 363.0798.

10

3-(4-Methoxyphenyl)-2-(phenylthio)-2 H -benzo[ b ][1,4]-oxazine (1d). Yellow oil. ¹H NMR (270 MHz, CDCl3): δ = 3.87 (s, 3 H), 6.69 (s, 1 H), 6.99 (dd, J = 7.75, 2.16 Hz, 2 H), 7.03 (dd, J = 7.83, 1.35 Hz, 1 H), 7.09 (dd, J = 5.67, 1.62 Hz, 1 H), 7.22 (td, J = 7.56, 1.89 Hz, 1 H), 7.29-7.34 (m, 3 H), 7.40 (dd, J = 7.56, 1.89 Hz, 1 H), 7.49-7.53 (m, 2 H), 8.03 (td, J = 9.99, 2.56 Hz, 2 H). ¹³C NMR (68 MHz, CDCl3): δ = 55.46, 79.76, 114.09, 117.07, 123.23, 126.75, 127.20, 128.37, 128.47, 128.67, 128.94, 132.45, 134.36, 133.40, 142.79, 154.57, 161.95. HRMS (FAB): m/z [M + H]+ calcd for C21H18NO2S: 348.1058; found: 348.1060.

11

3-Phenyl-2-(phenylthio)-2 H -pyrido[3,2- b ][1,4]oxazine (2a). Dark-red solid; mp 102-103 ˚C. ¹H NMR (270 NHz, CDCl3): δ = 6.76 (s, 1 H), 7.19 (dd, J = 8.10, 4.86 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.38 (dd, J = 7.83, 1.62 Hz, 1 H), 7.44-7.59 (m, 5 H), 8.16-8.21 (m, 1 H), 8.18 (dd, J = 7.83, 1.62 Hz, 1 H), 8.30 (dd, J = 4.59, 1.62 Hz, 1 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.49, 123.94, 125.13, 127.62, 128.74, 128.86, 129.12, 131.60, 132.08, 133.36, 133.50, 139.51, 143.87, 146.95, 159.00. HRMS (ESI): m/z [M + H]+ calcd for C19H15N2OS: 319.0905; found: 319.0900.

12

3-(4-Bromophenyl)-2-(phenylthio)-2 H -pyrido[3,2- b ][1,4]oxazine (2b). Pale-yellow solid; mp 131-132 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.69 (s, 1 H), 7.20 (dd, J = 8.10, 4.86 Hz, 1 H), 7.28-7.36 (m, 2 H), 7.38 (dd, J = 8.10, 1.62 Hz, 1 H), 7.42-7.48 (m, 3 H), 7.64 (dd, J = 9.18, 4.59 Hz, 1 H), 7.64 (d, J = 8.91 Hz, 1 H), 8.04 (dd, J = 9.18, 4.59 Hz, 1 H), 8.04 (d, J = 8.91 Hz, 1 H), 8.29 (dd, J = 4.86, 1.62 Hz, 1 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.28, 124.18, 125.18, 126.98, 129.00, 129.03, 129.15, 131.25, 132.01, 132.23, 133.54, 139.49, 143.95, 146.66, 157.94. Anal. Calcd for C19H13BrN2OS: C, 57.44; H, 3.30; Br, 20.11; N, 7.05; S, 8.07. Found: C, 57.33; H, 3.30; Br, 20.40; N, 6.88; S, 8.13.

13

3-(4-Nitrophenyl)-2-(phenylthio)-2 H -pyrido[3,2- b ][1,4]oxazine (2c). Yellow solid; mp 206-207 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.74 (s, 1 H), 7.26 (dd, J = 8.10, 4.86 Hz, 1 H), 7.29-7.38 (m, 3 H), 7.40-7.48 (m, 3 H), 8.3-8.38 (m, 5 H). ¹³C NMR (68 MHz, CDCl3): δ = 79.50, 123.86, 125.03, 125.43, 128.51, 129.27, 130.74, 133.65, 138.94, 139.69, 144.25, 146.22, 149.47, 156.63. HRMS (FAB): m/z [M + H]+ calcd for C19H14N3O3S: 364.0756; found: 364.0764.

14

3-(4-Methoxyphenyl)-2-(phenylthio)-2 H -pyrido[3,2- b ][1,4]oxazine (2d). Dark-red oil. ¹H NMR (270 MHz, CDCl3): δ = 3.89 (s, 3 H), 6.74 (s, 1 H), 7.01 (dd, J = 9.99, 5.13 Hz, 1 H), 7.01 (d, J = 9.18 Hz, 1 H), 7.16 (dd, J = 8.10, 4.86 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.37 (d, J = 1.62 Hz, 1 H), 7.44-7.51 (m, 2 H), 8.15 (dd, J = 9.99, 5.13 Hz, 1 H), 8.15 (d, J = 9.18 Hz, 1 H), 8.28 (dd, J = 4.86, 1.62 Hz, 1 H). ¹³C NMR (68 MHz, CDCl3): δ = 55.53, 79.34, 114.18, 123.37, 124.95, 125.83, 128.75, 129.09, 129.57, 131.81, 133.41, 139.24, 143.76, 147.22, 158.46, 162.76. HRMS (FAB): m/z [M + H]+ calcd for C20H17N2O2S: 349.1011; found: 349.1006.

16

General procedure for fluorodesulfurization: To a solution of the benzooxazine or pyridooxazine derivative (0.1 mmol) in anhydrous CH2Cl2 (5 mL) under nitrogen at room temperature, was added N-halogenosuccinimide (0.2 mmol, 2.0 equiv) followed by Et3N˙3HF (0.3 mL, 2.5 mmol) using a Teflon syringe. After the starting materials had been consumed (ca. 30 min, reaction monitored by TLC), the reaction mixture was quenched by addition of Et3N and partially concentrated under reduced pressure to remove most of the CH2Cl2. The remaining solution was then passed through a short pad of silica gel, then subjected to flash silica gel chromatography (EtOAc-hexane) to provide fluorinated benzooxazine derivatives. The yields were determined by ¹9F NMR analysis using monofluorobenzene (C6H5F; δ = -36.5 ppm) as internal standard. Attempts to purify the fluorinated products further using HPLC failed because of their instability, and the corresponding hydroxy byproducts were obtained. However, in the case of fluorinated pyridooxazine derivatives, the purification was performed by HPLC (Shiseido Superiorex ODS column, MeCN).

17

2-Fluoro-3-phenyl-2 H -benzo[ b ][1,4]oxazine (3a). Colorless solid; mp 102-103 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.75 (d, J = 55.09 Hz, 1 H), 7.18-7.24 (m, 2 H), 7.33 (td, J = 7.56, 1.62 Hz, 1 H), 7.50-7.55 (m, 3 H), 7.65 (dd, J = 1.62, 7.56 Hz, 1 H), 8.02-8.07 (m, 2 H). ¹9F NMR (254 MHz, CDCl3): δ = 35.44 (d, J = 55.38 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 95.93 (d, J = 225.91 Hz), 116.45, 123.73, 126.91, 128.47, 128.88, 129.41, 131.31, 131.61 (d, J = 2.23 Hz), 134.29, 141.70, 152.00 (d, J = 24.54 Hz). GC-MS: m/z (%) = 227 (94.3), 209 (8.9), 152 (29.2), 76 (34.8). HRMS (ESI): m/z [M + H]+ calcd for C14H11FNO: 228.0825; found: 228.0819.

18

3-(4-Bromophenyl)-2-fluoro-2 H -benzo[ b ][1,4]oxazine (3b). Pale-yellow solid; mp 90-91 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.70 (d, J = 55.09 Hz, 1 H), 7.20 (dt, J = 7.56, 1.35 Hz, 1 H), 7.21 (td, J = 8.91, 1.35 Hz, 1 H), 7.34 (td, J = 7.83, 1.62 Hz, 1 H), 7.62-7.66 (m, 2 H), 7.65 (dd, J = 2.16, 8.91 Hz, 1 H), 7.91 (dd, J = 8.64, 1.08 Hz, 1 H), 7.91 (dd, J = 9.18, 5.67 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 34.97 (d, J = 55.38 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 95.64 (d, J = 226.45 Hz), 116.48, 123.82, 126.13, 128.35, 128.51, 129.70, 131.41 (d, J = 2.24 Hz), 132.10, 133.12 (d, J = 1.70 Hz), 141.62, 150.91 (d, J = 24.54 Hz). GC-MS: m/z (%) = 307 (94.5), 305 (100), 226 (10.3), 208 (2.9). HRMS (ESI): m/z [M + H]+ calcd for C14H10BrFNO: 305.9930; found: 305.9924.

19

2-Fluoro-3-(4-nitrophenyl)-2 H -benzo[ b ][1,4]oxazine (3c). Yellow solid; mp 241-242 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.76 (d, J = 55.09 Hz, 1 H), 7.22 (dd, J = 4.32, 1.35 Hz, 1 H), 7.24-7.29 (m, 1 H), 7.40 (td, J = 7.83, 1.35 Hz, 1 H), 7.68 (dd, J = 1.62, 7.83 Hz, 1 H), 8.20-8.24 (m, 2 H), 8.37 (d, J = 8.91 Hz, 1 H), 8.37 (dd, J = 9.18, 4.32 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 34.28 (d,
J = 53.60 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 95.54 (d, J = 226.99 Hz), 116.62, 124.03, 124.08, 127.81, 129.02, 129.19, 130.74, 135.82 (d, J = 1.70 Hz), 139.71 (d, J = 1.70 Hz), 141.69, 149.68 (d, J = 24.54 Hz). HRMS (ESI): m/z [M + H]+ calcd for C14H10FN2O3: 273.0675; found: 273.0670.

22

2-Fluoro-3-phenyl-2 H -pyrido[3,2- b ][1,4]oxazine (4a). Pale-yellow solid; mp 132-133 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.81 (d, J = 54.28 Hz, 1 H), 7.32 (dd, J = 8.10, 4.59 Hz, 1 H), 7.58 (dd, J = 8.10, 1.62 Hz, 1 H), 7.67 (d, J = 8.64 Hz, 1 H), 7.67 (dd, J = 9.18, 4.32 Hz, 2 H), 8.02 (dd, J = 8.91, 1.08 Hz, 2 H), 8.47 (dd, J = 4.59, 1.62 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 34.93 (d, J = 53.60 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 94.80 (d, J = 228.69 Hz), 124.38, 124.89, 127.65, 128.94, 132.33, 133.38 (d, J = 1.70 Hz), 138.04, 144.22 (d, J = 2.24 Hz), 144.78, 155.88 (d, J = 24.54 Hz). GCMS: m/z (%) = 228 (100), 210 (8.5), 153 (7.5), 77 (28.2). HRMS (ESI): m/z
[M + Na]+ calcd for C13H9FN2ONa: 251.0597; found: 251.0591.

23

3-(4-Bromophenyl)-2-fluoro-2 H -pyrido[3,2- b ][1,4]-oxazine (4b). Pale-yellow solid; mp 137-138 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.76 (d, J = 54.28 Hz, 1 H), 7.20 (dt, J = 7.56, 1.35 Hz, 1 H), 7.21 (td, J = 8.91, 1.35 Hz, 1 H), 7.34 (td, J = 7.83, 1.62 Hz, 1 H), 7.62-7.66 (m, 1 H), 7.65 (dd, J = 2.16, 8.91 Hz, 1 H), 7.91 (dd, J = 8.64, 1.08 Hz, 1 H), 7.91 (dd, J = 9.18, 5.67 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 34.97 (d, J = 55.38 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 95.64 (d, J = 228.68 Hz), 124.61, 124.93, 127.39, 128.99, 129.34 (d, J = 1.63 Hz), 132.22, 137.99, 143.92 (d, J = 2.23 Hz), 144.87, 154.87 (d, J = 24.54 Hz). HRMS (ESI): m/z [M + Na]+ calcd for C13H8BrFN2ONa: 328.9702; found: 328.9696.

24

2-Fluoro-3-(4-nitrophenyl)-2 H -pyrido[3,2- b ][1,4]-oxazine (4c). Yellow solid; mp 258-259 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 6.82 (d, J = 54.28 Hz, 1 H), 7.39 (dd, J = 8.10, 4.59 Hz, 1 H), 7.62 (dd, J = 8.10, 1.62 Hz, 1 H), 8.32-8.42 (m, 4 H), 8.53 (dd, J = 4.86, 1.62 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 34.32 (d, J = 53.60 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 94.78 (d, J = 229.30 Hz), 124.09, 125.26, 125.56, 128.56, 138.21, 138.74 (d, J = 1.63 Hz), 143.51 (d, J = 2.17 Hz), 145.27, 149.66, 153.71 (d, J = 24.54 Hz). HRMS (ESI): m/z [M + Na]+ calcd for C13H8FN3O3Na: 296.0447; found: 296.0442.

25

2-Fluoro-3-(4-methoxyphenyl)-2 H -pyrido[3,2- b ][1,4]-oxazine (4d). Yellow solid; mp 113-114 ˚C. ¹H NMR (270 MHz, CDCl3): δ = 3.90 (s, 3 H), 6.79 (d, J = 54.55 Hz, 1 H), 7.03 (d, J = 8.91 Hz, 1 H), 7.03 (dd, J = 9.72, 5.13 Hz, 1 H), 7.26 (dd, J = 8.10, 4.59 Hz, 1 H), 7.53 (dd, J = 8.10, 1.62 Hz, 1 H), 8.14 (dd, J = 8.91, 1.08 Hz, 1 H), 8.14 (dd, J = 9.99, 6.21 Hz, 1 H), 8.43 (dd, J = 4.59, 1.62 Hz, 1 H). ¹9F NMR (254 MHz, CDCl3): δ = 35.41 (d, J = 53.60 Hz, 1 F). ¹³C NMR (68 MHz, CDCl3): δ = 55.53, 95.06 (d, J = 228.15 Hz), 114.37, 123.71, 124.61, 125.98 (d, J = 1.62 Hz), 129.59, 137.78, 144.47 (d, J = 2.23 Hz), 144.57, 155.29 (d, J = 24.54 Hz), 162.95. HRMS (ESI): m/z [M + Na]+ calcd for C14H11FN2O2Na: 281.0702; found: 281.0697.