Selective Fluorodesulfurization of Benzo- and Pyrido-oxazine Derivatives

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.

Extensive growth in the synthetic chemistry of organofluorine compounds during last few decades has mainly been attributed to the unique chemical, physical, and biological properties of this class of compound. In particular, the biological potency of fluorinated heterocyclic compounds has been widely documented. [¹] On the other hand, a number of benzo- and pyrido-oxazine derivatives have been synthesized to investigate their various pharmaceutical activities in areas such as the modulation of skeletal muscle ATP-sensitive-K⁺ channels (K_ATP), [²a-c] central nervous system (CNS) depressants, [²d] 5-HT₃ receptor antagonists, [²e] antiproliferative activity, [²f] and analgesic activity. [²g] Therefore, fluorinated benzo-oxazine and pyridooxazine derivatives are expected to have unique and pronounced biological activities. However, selective direct fluorination of the oxazine moiety of these compounds has not been performed to date.

Oxidative fluorodesulfurization is one of the most useful fluorination methods. For example, oxidative fluorodesulfurization of dithioacetals and thiocarbonyl compounds using organic oxidizing reagents such as N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin has been achieved in the presence of fluoride salts such as pyridinium polyhydrogen fluoride (pyridine˙nHF; Olah’s reagent) and Bu₄NF˙2HF, to provide gem-difluorinated products. [³] Recently, López and co-workers reported the use of N-iodosuccinimide (NIS), NBS or bis(2,4,6-collidine)iodonium perchlorate (IDCP) as a source of electrophilic halonium ion for the transformation of partially unprotected 1-thioglycosides into glycosyl fluorides in the presence of pyridine˙nHF or Et₃N˙3HF in dichloromethane under low-temperature reaction conditions. [4]

With these facts in mind, we studied the fluorination and fluorodesulfurization of benzo-oxazine and pyrido-­oxazine derivatives in this work. First, we attempted the fluorination of 3-phenyl-2H-benzo[b][1,4]oxazine [5] using fluorinating reagents such as Selectfluor™ both in the presence and absence of NaH; however, the reaction did not proceed at all and the starting material was mostly recovered (Scheme  [¹] ).

We then prepared 3-aryl-2-phenylthio-2H-benzo-[b][1,4]oxazine derivatives 1a-d [6-¹0] and 3-aryl-2-phenyl-thio-2H-pyrido[3,2-b][1,4]oxazine derivatives 2a-d [¹¹-¹4] from α-bromo-α-(phenylthio)acetophenone derivatives [¹5] as shown in Scheme  [²] , and investigated their oxidative fluorodesulfurization. The reaction was carried out using various N-halogenosuccinimides in the presence of Et₃N˙3HF at room temperature. [¹6] Initially, compound 1a was used as a model substrate and treated with one equivalent of N-chlorosuccinimide (NCS) in Et₃N˙3HF and dichloromethane. It was found that the corresponding monofluorinated product 3a [¹7] was formed selectively in 40% ^¹9F NMR yield, and half the initial amount of substrate 1a was recovered (Table  [¹] , Run 1). In order to perform the fluorodesulfurization completely, two equivalents of NCS were employed under the same conditions. In this case, the starting material was mostly consumed and the yield was increased to 64% (Table  [¹] , Run 2).

Next, a weak oxidizing reagent, NIS, was examined for the fluorodesulfurization of 1a. When one equivalent of this reagent was used, the corresponding monofluorinated product 3a was obtained in a slightly higher yield (48%) compared to the fluorodesulfurization using NCS under the same conditions (Table  [¹] , Run 3). Notably, the desired product 3a was quantitatively obtained in pure form when two equivalents of NIS were used (Table  [¹] , Run 4). NBS was also found to be a good choice as the halonium ion source, and an excellent result was obtained using this reagent (Table  [¹] , Run 5). Since NCS is a stronger oxidizing reagent compared to NBS and NIS, over-oxidation of the product seems to occur using the former reagent, which results in lower fluorination yield.

Table 1 Fluorodesulfurization of 1a with N-Halogenosuccinimides

Run	Halogen reagent	Equivalent	Yield (%)a
1	NCS	1.0	41
2	NCS	2.0	64
3	NIS	1.0	48
4	NIS	2.0	100 (65)
5	NBS	2.0	100
a Determined by ¹9F NMR. Isolated yield in parentheses.

Table 2 Fluorodesulfurization of Benzo[b][1,4]oxazine Derivatives 1

Run	Substrate	R	NXS	Product	Yield (%)a,b
1	1b	Br	NIS	3b	100 (65)
2	1c	NO2	NIS	3c	100 (65)
3	1d	OMe	NIS	3d	64c
4	1b	Br	NBS	3b	100
5	1c	NO2	NBS	3c	100
6	1d	OMe	NBS	3d	74
a Determined by ¹9F NMR. b Purification was achieved through flash chromatography; isolated yields were shown in parentheses. c Pure product could not be obtained due to its instability.

The fluorodesulfurization of other derivatives 1b-d was then carried out under the optimized conditions; the results are summarized in Table  [²] . The p-bromophenyl and p-nitrophenyl derivatives 1b and 1c, respectively, also provided the corresponding monofluorinated product 3b [¹8] and 3c [¹9] in excellent yields (Table  [²] , Runs 1, 2, 4, and 5). However, p-methoxyphenyl derivative 1d gave monofluorinated product 3d [²0] in moderate yields regardless of which N-halogenosuccinimide was used (Table  [²] , Runs 3 and 6). The product 3d could not be purified due to its instability. [²¹]

Finally, as shown in Table  [³] , fluorodesulfurization of various pyrido[3,2-b][1,4]oxazine derivatives 2, which are analogous to benzooxazine derivatives, was also achieved using NIS or NBS as halonium ion source in Et₃N˙3HF and CH₂Cl₂ to provide the corresponding monofluorinated products 4 [²²-²5] in good yields. However, in these cases, a larger amount of oxidizing reagent was required compared to the fluorodesulfurization of benzo[b][1,4]oxazine derivatives. Particularly, when the weakest oxidizing reagent, NIS, was used, a large excess of NIS was required to obtain good fluorination yields.

Table 3 Fluorodesulfurization of Pyrido[3,2-b][1,4]oxazine Derivatives 2

Run	Substrate	R	NXS (equiv)	Product	Yield (%)a
1	2a	H	NBS (2)	4a	61
2	2a	H	NBS (3)	4a	67 (65)
3	2b	Br	NBS (3)	4b	89 (73)
4	2c	NO2	NBS (3)	4c	80 (77)
5	2d	OMe	NBS (3)	4d	51 (51)
6	2a	H	NIS (2)	4a	48
7	2a	H	NIS (3)	4a	54
8	2a	H	NIS (4)	4a	77
9	2a	H	NIS (6)	4a	92 (79)
10	2b	Br	NIS (6)	4b	84 (70)
11	2c	NO2	NIS (6)	4c	75 (68)
12	2d	OMe	NIS (6)	4d	83 (73)
a Determined by ¹9F NMR. Isolated yield in parentheses.

A possible mechanism for the selective fluorodesulfurization of 1 and 2 is illustrated in Scheme  [³] . In this mechanism an active halonium ion derived from N-halogenosuccinimide reacts with the phenylthio group followed by elimination of the phenylthio group to generate the oxocarbenium ion, which reacts with a fluoride ion to provide the corresponding monofluorinated product 3 or 4.

In conclusion, selective fluorodesulfurization of 3-aryl-2-phenylthio-2H-benzo[b][1,4]oxazine derivatives was successfully carried out using various N-halogenosuccinimide to provide the corresponding 2-fluoro products in excellent yields. Furthermore, selective fluorodesulfurization of 3-aryl-2-phenylthio-2H-pyrido[3,2-b][1,4]oxazine derivatives was similarly achieved. This method is useful since the fluorination is easily carried out in a short time at room temperature.

References and Notes

• 1a Bioorganic and Medicinal Chemistry of Fluorine   Beque JP. Donnet-Delpon D. Wiley; New Jersey: 2008. 
• 1b Organofluorine Compounds   Hiyama T. Springer; Berlin: 2000. 
• 1c Fluorine in Bioorganic Chemistry   Welch JT. Eswarakrishnan S. Wiley; New York: 1991. 
• 1d Biomedicinal Aspects of Fluorine Chemistry   Filler R. Kobayashi Y. Kondansha & Elsevier Biomedical; Tokyo: 1982. 
• 2a Tricarico D. Mele A. Camerino GM. Laghezza A. Carbonara G. Fracchiolla G. Tortorella P. Loiodice F. Camerino DC. Mol. Pharmacol.  2008,  74:  50 
  Search in Google Scholar
• 2b Tricarico D. Barbieri M. Laghezza A. Tortorella P. Loiodic F. Camerino DC. Br. J. Pharmacol.  2003,  139:  255 
  Search in Google Scholar
• 2c Matsumoto Y. Tsuzuki R. Matsuhisa A. Takayama K. Yoden T. Uchida W. Asano M. Fujita S. Yanagisawa I. Fujikura T. Chem. Pharm. Bull.  1996,  44:  103 
  Search in Google Scholar
• 2d Kajino M. Shibouta Y. Nishikawa K. Meguro K. Chem. Pharm. Bull.  1991,  39:  2896 
  Search in Google Scholar
• 2e Kuroita T. Sakamori M. Kawakita T. Chem. Pharm. Bull.  1996,  44:  56 
  Search in Google Scholar
• 2f Matsuoka H. Ohi N. Mihara M. Suzuki H. Miyamoto K. Maruyama N. Tsuji K. Kato N. Akimoto T. Takeda Y. Yano K. Kuroki T. J. Med. Chem.  1997,  40:  105 
  Search in Google Scholar
• 2g Savelon L. Bizot-Espiard JG. Gaignard DH. Pfeiffer B. Renard P. Viaud MC. Guillaumet G. Bioorg. Med. Chem.  1998,  6:  133 
  Search in Google Scholar
• 3a Olah GA. Welch JT. Vankar YD. Nojima M. Kerekes I. Olah JA. J. Org. Chem.  1979,  44:  3872 
  Search in Google Scholar
• 3b Sondej SC. Katzenellenbogen JA. J. Org. Chem.  1986,  51:  3508 
  Search in Google Scholar
• 3c Kuroboshi M. Mizuno K. Kanie K. Hiyama T. Tetrahedron Lett.  1995,  36:  563 
  Search in Google Scholar
• 3d Kuroboshi M. Hiyama T. Synlett  1999,  909 
• 3e Motherwell WB. Wilkinson JA. Synlett  1999,  191 
• 3f Chambers RD. Sandford G. Atherton M. J. Chem. Soc., Chem. Commun.  1995,  177 
• 4 López JC. Bernal-Albert P. Uriel C. Gómez AM. Eur. J. Org. Chem.  2008,  5037 
  Crossref
• 5 Banzatti C. Heidemepergher F. Melloni P. J. Heterocycl. Chem.  1983,  20:  259 
  CrossrefSearch in Google Scholar
• 15a Padmanabhan S. Ogawa T. Suzuki H. Bull. Chem. Soc. Jpn.  1989,  62:  1358 
  Search in Google Scholar
• 15b Groebel W. Chem. Ber.  1960,  93:  896 
  Search in Google Scholar
• 20 Fluorinated product 3d was determined by both NMR and GCMS. ^¹H NMR (270 MHz, CDCl₃): δ = 6.73 (d, J = 54.82 Hz, 1 H). ^¹9F NMR (254 MHz, CDCl₃): δ = 35.56 (d, J = 55.89 Hz, 1 F). GCMS: m/z (%) = 226 (100) [M⁺ - OMe]
• 21 Purification of 3d through flash chromatography gave 3-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one, the structure of which was determined by ^¹H and ^¹³C NMR analysis, see: Rueping M. Antonchik AP. Theissmann T. Angew. Chem. Int. Ed.  2006,  45:  6751 
  CrossrefPubMedSearch in Google Scholar

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

References and Notes

• 1a Bioorganic and Medicinal Chemistry of Fluorine   Beque JP. Donnet-Delpon D. Wiley; New Jersey: 2008. 
• 1b Organofluorine Compounds   Hiyama T. Springer; Berlin: 2000. 
• 1c Fluorine in Bioorganic Chemistry   Welch JT. Eswarakrishnan S. Wiley; New York: 1991. 
• 1d Biomedicinal Aspects of Fluorine Chemistry   Filler R. Kobayashi Y. Kondansha & Elsevier Biomedical; Tokyo: 1982. 
• 2a Tricarico D. Mele A. Camerino GM. Laghezza A. Carbonara G. Fracchiolla G. Tortorella P. Loiodice F. Camerino DC. Mol. Pharmacol.  2008,  74:  50 
  Search in Google Scholar
• 2b Tricarico D. Barbieri M. Laghezza A. Tortorella P. Loiodic F. Camerino DC. Br. J. Pharmacol.  2003,  139:  255 
  Search in Google Scholar
• 2c Matsumoto Y. Tsuzuki R. Matsuhisa A. Takayama K. Yoden T. Uchida W. Asano M. Fujita S. Yanagisawa I. Fujikura T. Chem. Pharm. Bull.  1996,  44:  103 
  Search in Google Scholar
• 2d Kajino M. Shibouta Y. Nishikawa K. Meguro K. Chem. Pharm. Bull.  1991,  39:  2896 
  Search in Google Scholar
• 2e Kuroita T. Sakamori M. Kawakita T. Chem. Pharm. Bull.  1996,  44:  56 
  Search in Google Scholar
• 2f Matsuoka H. Ohi N. Mihara M. Suzuki H. Miyamoto K. Maruyama N. Tsuji K. Kato N. Akimoto T. Takeda Y. Yano K. Kuroki T. J. Med. Chem.  1997,  40:  105 
  Search in Google Scholar
• 2g Savelon L. Bizot-Espiard JG. Gaignard DH. Pfeiffer B. Renard P. Viaud MC. Guillaumet G. Bioorg. Med. Chem.  1998,  6:  133 
  Search in Google Scholar
• 3a Olah GA. Welch JT. Vankar YD. Nojima M. Kerekes I. Olah JA. J. Org. Chem.  1979,  44:  3872 
  Search in Google Scholar
• 3b Sondej SC. Katzenellenbogen JA. J. Org. Chem.  1986,  51:  3508 
  Search in Google Scholar
• 3c Kuroboshi M. Mizuno K. Kanie K. Hiyama T. Tetrahedron Lett.  1995,  36:  563 
  Search in Google Scholar
• 3d Kuroboshi M. Hiyama T. Synlett  1999,  909 
• 3e Motherwell WB. Wilkinson JA. Synlett  1999,  191 
• 3f Chambers RD. Sandford G. Atherton M. J. Chem. Soc., Chem. Commun.  1995,  177 
• 4 López JC. Bernal-Albert P. Uriel C. Gómez AM. Eur. J. Org. Chem.  2008,  5037 
  Crossref
• 5 Banzatti C. Heidemepergher F. Melloni P. J. Heterocycl. Chem.  1983,  20:  259 
  CrossrefSearch in Google Scholar
• 15a Padmanabhan S. Ogawa T. Suzuki H. Bull. Chem. Soc. Jpn.  1989,  62:  1358 
  Search in Google Scholar
• 15b Groebel W. Chem. Ber.  1960,  93:  896 
  Search in Google Scholar
• 20 Fluorinated product 3d was determined by both NMR and GCMS. ^¹H NMR (270 MHz, CDCl₃): δ = 6.73 (d, J = 54.82 Hz, 1 H). ^¹9F NMR (254 MHz, CDCl₃): δ = 35.56 (d, J = 55.89 Hz, 1 F). GCMS: m/z (%) = 226 (100) [M⁺ - OMe]
• 21 Purification of 3d through flash chromatography gave 3-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one, the structure of which was determined by ^¹H and ^¹³C NMR analysis, see: Rueping M. Antonchik AP. Theissmann T. Angew. Chem. Int. Ed.  2006,  45:  6751 
  CrossrefPubMedSearch in Google Scholar

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.