Selective fluorodesulfurization of benzo- and pyrido-oxazine derivatives

Article abstract of DOI:10.1055/s-0030-1258517

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 Et ₃N3HF to provide the corresponding monofluo

Full text of DOI:10.1055/s-0030-1258517

2146
LETTER
Selective Fluorodesulfurization of Benzo- and Pyrido-oxazine Derivatives
S
elective Fluorod
i
esulfur
n
ization of Benzo-
a
nd Pyrido-oxazine
i
D
eriv
n
atives , 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
Received 13 May 2010
oxazine derivatives in this work. First, we attempted the
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 monofluorinat-
fluorination of 3-phenyl-2H-benzo[b][1,4]oxazine5 using
fluorinating reagents such as Selectfluor™ both in the
presence and absence of NaH; however, the reaction did
ed products in excellent yields. Selective fluorodesulfurization of not proceed at all and the starting material was mostly re-
the corresponding pyrido[3,2-b][1,4]oxazine derivatives was also
achieved similarly.
covered (Scheme 1).
Key words: heterocycles, fluorine, halides, desulfurization, substi-
tution
N
SelectfluorTM, NaH
MeCN, 5 h
N
O
O
F
Extensive growth in the synthetic chemistry of organoflu-
orine 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 bi-
ological potency of fluorinated heterocyclic compounds
has been widely documented.1 On the other hand, a num-
ber of benzo- and pyrido-oxazine derivatives have been
synthesized to investigate their various pharmaceutical
activities in areas such as the modulation of skeletal mus-
cle ATP-sensitive-K+ channels (KATP),2a–c central nervous
system (CNS) depressants,2d 5-HT3 receptor antago-
nists,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 fluorina-
tion of the oxazine moiety of these compounds has not
been performed to date.
Scheme 1
We then prepared 3-aryl-2-phenylthio-2H-benzo-
[b][1,4]oxazine derivatives 1a–d6–10 and 3-aryl-2-phenyl-
thio-2H-pyrido[3,2-b][1,4]oxazine derivatives 2a–d11–14
from a-bromo-a-(phenylthio)acetophenone derivatives15
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 equiv-
alent of N-chlorosuccinimide (NCS) in Et3N·3HF and
dichloromethane. It was found that the corresponding
monofluorinated product 3a17 was formed selectively in
40% 19F NMR yield, and half the initial amount of sub-
strate 1a was recovered (Table 1, Run 1). In order to per-
form the fluorodesulfurization completely, two
equivalents of NCS were employed under the same condi-
tions. In this case, the starting material was mostly con-
sumed and the yield was increased to 64% (Table 1, Run
2).
Oxidative fluorodesulfurization is one of the most useful
fluorination methods. For example, oxidative fluorodes-
ulfurization of dithioacetals and thiocarbonyl compounds
using organic oxidizing reagents such as N-bromosuccin-
imide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin has
been achieved in the presence of fluoride salts such as py-
ridinium polyhydrogen fluoride (pyridine·nHF; Olah’s re-
agent) 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-colli-
dine)iodonium perchlorate (IDCP) as a source of electro-
philic halonium ion for the transformation of partially
unprotected 1-thioglycosides into glycosyl fluorides in
the presence of pyridine·nHF or Et3N·3HF in dichlo-
romethane under low-temperature reaction conditions.4
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 re-
agent (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.
With these facts in mind, we studied the fluorination and
fluorodesulfurization of benzo-oxazine and pyrido-
SYNLETT 2010, No. 14, pp 2146–2150
x
x
.x
x
.2
0
1
0
The fluorodesulfurization of other derivatives 1b–d was
then carried out under the optimized conditions; the re-
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258517; Art ID: U03610ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Fluorodesulfurization of Benzo- and Pyrido-oxazine Derivatives
2147
Table 2 Fluorodesulfurization of Benzo[b][1,4]oxazine Derivatives 1
O
O
Br
Br
SPh
R
R
1) PhSH, K2CO3, EtOH, r.t.
2) NBS, CCl4, 60 °C
N
O
N
O
R
R
NXS
Et3N⋅3HF, CH2Cl2
R
SPh
1b–d
30 min, r.t.
F
3b–d
N
2-aminophenol
NaH, DMA, r.t.
1a: R = H
1b: R = Br
1c: R = NO2
1d: R = OMe
Run
1
Substrate
R
NXS
NIS
Product
Yield (%)a,b
100 (65)
100 (65)
64c
O
SPh
1b
1c
1d
1b
1c
1d
Br
3b
3c
3d
3b
3c
3d
1
2
R
2
NO2
OMe
Br
NIS
N
N
O
3
NIS
2-amino-3-pyridinol
NaH, DMA, r.t.
2a: R = H
2b: R = Br
2c: R = NO2
2d: R = OMe
4
NBS
NBS
NBS
100
SPh
5
NO2
OMe
100
Scheme 2
6
74
a Determined by 19F NMR.
Table 1 Fluorodesulfurization of 1a with N-Halogenosuccinimides
b Purification was achieved through flash chromatography; isolated
yields were shown in parentheses.
c Pure product could not be obtained due to its instability.
N
N
halogen oxidizing reagent
Et3N⋅3HF, CH2Cl2
O
SPh
O
F
30 min, r.t.
Table 3 Fluorodesulfurization of Pyrido[3,2-b][1,4]oxazine Deriv-
atives 2
1a
3a
R
R
Run
1
Halogen reagent
Equivalent
Yield (%)a
N
N
O
N
N
O
NXS
NCS
NCS
NIS
1.0
2.0
1.0
2.0
2.0
41
Et3N⋅3HF, CH2Cl2
2
64
SPh
2a–d
30 min, r.t.
F
4a–d
3
48
Run
1
Substrate
2a
R
NXS (equiv) Product Yield (%)a
4
NIS
100 (65)
100
H
NBS (2)
NBS (3)
NBS (3)
NBS (3)
NBS (3)
NIS (2)
NIS (3)
NIS (4)
NIS (6)
NIS (6)
NIS (6)
NIS (6)
4a
4a
4b
4c
4d
4a
4a
4a
4a
4b
4c
4d
61
5
NBS
a Determined by 19F NMR. Isolated yield in parentheses.
2
2a
H
67 (65)
89 (73)
80 (77)
51 (51)
48
3
2b
Br
sults are summarized in Table 2. The p-bromophenyl and
p-nitrophenyl derivatives 1b and 1c, respectively, also
provided the corresponding monofluorinated product 3b18
and 3c19 in excellent yields (Table 2, Runs 1, 2, 4, and 5).
However, p-methoxyphenyl derivative 1d gave monoflu-
orinated product 3d20 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 in-
stability.21
4
2c
NO2
OMe
H
5
2d
6
2a
7
2a
H
54
8
2a
H
77
9
2a
H
92 (79)
84 (70)
75 (68)
83 (73)
Finally, as shown in Table 3, fluorodesulfurization of var-
ious 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 monofluorinat-
ed products 422–25 in good yields. However, in these cases,
a larger amount of oxidizing reagent was required com-
pared to the fluorodesulfurization of benzo[b][1,4]ox-
azine derivatives. Particularly, when the weakest
oxidizing reagent, NIS, was used, a large excess of NIS
was required to obtain good fluorination yields.
10
11
12
2b
Br
2c
NO2
OMe
2d
a Determined by 19F NMR. Isolated yield in parentheses.
A possible mechanism for the selective fluorodesulfuriza-
tion of 1 and 2 is illustrated in Scheme 3. In this mecha-
nism an active halonium ion derived from N-
halogenosuccinimide reacts with the phenylthio group
Synlett 2010, No. 14, 2146–2150 © Thieme Stuttgart · New York

2148
B. Yin et al.
LETTER
Wilkinson, J. A. Synlett 1999, 191. (f) Chambers, R. D.;
Sandford, G.; Atherton, M. J. Chem. Soc., Chem. Commun.
1995, 177.
followed by elimination of the phenylthio group to gener-
ate the oxocarbenium ion, which reacts with a fluoride ion
to provide the corresponding monofluorinated product 3
or 4.
(4) López, J. C.; Bernal-Albert, P.; Uriel, C.; Gómez, A. M. Eur.
J. Org. Chem. 2008, 5037.
(5) Banzatti, C.; Heidemepergher, F.; Melloni, P. J. Heterocycl.
Chem. 1983, 20, 259.
X
N
O
Ar
X
N
Ar
X+
(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
a-bromo-a-(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)-2H-benzo[b][1,4]oxazine (1a).
Pale-yellow solid; mp 92–93 °C. 1H NMR (270 MHz,
CDCl3): d = 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): d = 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.
– XSPh
+
SPh
O
SPh
X
1: X = C
2: X = N
X
N
Ar
F
X
N
Ar
F–
+
O
O
3: X = C
4: X = N
oxocarbenium ion
Scheme 3
In conclusion, selective fluorodesulfurization of 3-aryl-2-
phenylthio-2H-benzo[b][1,4]oxazine derivatives was suc-
cessfully carried out using various N-halogenosuccinim-
ide to provide the corresponding 2-fluoro products in
excellent yields. Furthermore, selective fluorodesulfur-
ization of 3-aryl-2-phenylthio-2H-pyrido[3,2-b][1,4]ox-
azine derivatives was similarly achieved. This method is
useful since the fluorination is easily carried out in a short
time at room temperature.
(8) 3-(4-Bromophenyl)-2-(phenylthio)-2H-benzo[b][1,4]-
oxazine (1b). Pale-yellow solid; mp 111–112 °C. 1H NMR
(270 MHz, CDCl3): d = 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): d = 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)-2H-benzo[b][1,4]-
oxazine (1c). Yellow solid; mp 148–149 °C. 1H NMR (270
MHz, CDCl3): d = 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): d = 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)-2H-benzo[b][1,4]-
oxazine (1d). Yellow oil. 1H NMR (270 MHz, CDCl3):
d = 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): d = 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.
References and Notes
(1) (a) Bioorganic and Medicinal Chemistry of Fluorine; Beque,
J. P.; Donnet-Delpon, D., Eds.; Wiley: New Jersey, 2008.
(b) Organofluorine Compounds; Hiyama, T., Ed.; Springer:
Berlin, 2000. (c) Fluorine in Bioorganic Chemistry; Welch,
J. T.; Eswarakrishnan, S., Eds.; Wiley: New York, 1991.
(d) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.;
Kobayashi, Y., Eds.; Kondansha & Elsevier Biomedical:
Tokyo, 1982.
(2) (a) Tricarico, D.; Mele, A.; Camerino, G. M.; Laghezza, A.;
Carbonara, G.; Fracchiolla, G.; Tortorella, P.; Loiodice, F.;
Camerino, D. C. Mol. Pharmacol. 2008, 74, 50.
(b) Tricarico, D.; Barbieri, M.; Laghezza, A.; Tortorella, P.;
Loiodic, F.; Camerino, D. C. Br. J. Pharmacol. 2003, 139,
255. (c) 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. (d) Kajino, M.; Shibouta, Y.; Nishikawa, K.; Meguro,
K. Chem. Pharm. Bull. 1991, 39, 2896. (e) Kuroita, T.;
Sakamori, M.; Kawakita, T. Chem. Pharm. Bull. 1996, 44,
56. (f) 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. (g) Savelon, L.; Bizot-Espiard, J. G.; Gaignard,
D. H.; Pfeiffer, B.; Renard, P.; Viaud, M. C.; Guillaumet, G.
Bioorg. Med. Chem. 1998, 6, 133.
(3) (a) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.;
Kerekes, I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872.
(b) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem.
1986, 51, 3508. (c) Kuroboshi, M.; Mizuno, K.; Kanie, K.;
Hiyama, T. Tetrahedron Lett. 1995, 36, 563. (d)Kuroboshi,
M.; Hiyama, T. Synlett 1999, 909. (e) Motherwell, W. B.;
Synlett 2010, No. 14, 2146–2150 © Thieme Stuttgart · New York

LETTER
Selective Fluorodesulfurization of Benzo- and Pyrido-oxazine Derivatives
2149
(11) 3-Phenyl-2-(phenylthio)-2H-pyrido[3,2-b][1,4]oxazine
(2a). Dark-red solid; mp 102–103 °C. 1H NMR (270 NHz,
CDCl3): d = 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): d = 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)-2H-pyrido[3,2-
b][1,4]oxazine (2b). Pale-yellow solid; mp 131–132 °C.
1H NMR (270 MHz, CDCl3): d = 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):
d = 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)-2H-pyrido[3,2-
b][1,4]oxazine (2c). Yellow solid; mp 206–207 °C.
1H NMR (270 MHz, CDCl3): d = 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):
d = 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)-2H-pyrido[3,2-
b][1,4]oxazine (2d). Dark-red oil. 1H NMR (270 MHz,
CDCl3): d = 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): d = 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.
(17) 2-Fluoro-3-phenyl-2H-benzo[b][1,4]oxazine (3a).
Colorless solid; mp 102–103 °C. 1H NMR (270 MHz,
CDCl3): d = 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): d = 35.44 (d, J = 55.38 Hz, 1 F). 13
NMR (68 MHz, CDCl3): d = 95.93 (d, J = 225.91 Hz),
C
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-2H-benzo[b][1,4]oxazine
(3b). Pale-yellow solid; mp 90–91 °C. 1H NMR (270 MHz,
CDCl3): d = 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): d = 34.97 (d, J = 55.38 Hz, 1 F). 13C NMR (68
MHz, CDCl3): d = 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)-2H-benzo[b][1,4]oxazine
(3c). Yellow solid; mp 241–242 °C. 1H NMR (270 MHz,
CDCl3): d = 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): d = 34.28 (d,
J = 53.60 Hz, 1 F). 13C NMR (68 MHz, CDCl3): d = 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.
(20) Fluorinated product 3d was determined by both NMR and
GCMS. 1H NMR (270 MHz, CDCl3): d = 6.73 (d,
J = 54.82 Hz, 1 H). 19F NMR (254 MHz, CDCl3): d = 35.56
(d, J = 55.89 Hz, 1 F). GCMS: m/z (%) = 226 (100) [M+ –
OMe].
(15) (a) Padmanabhan, S.; Ogawa, T.; Suzuki, H. Bull. Chem.
Soc. Jpn. 1989, 62, 1358. (b) Groebel, W. Chem. Ber. 1960,
93, 896.
(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, A. P.; Theissmann,
T. Angew. Chem. Int. Ed. 2006, 45, 6751.
(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; d =
–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).
(22) 2-Fluoro-3-phenyl-2H-pyrido[3,2-b][1,4]oxazine (4a).
Pale-yellow solid; mp 132–133 °C. 1H NMR (270 MHz,
CDCl3): d = 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): d = 34.93 (d,
J = 53.60 Hz, 1 F). 13C NMR (68 MHz, CDCl3): d = 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-2H-pyrido[3,2-b][1,4]-
oxazine (4b). Pale-yellow solid; mp 137–138 °C. 1H NMR
(270 MHz, CDCl3): d = 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),
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LETTER
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): d = 34.97 (d, J = 55.38 Hz, 1 F). 13C NMR (68 MHz,
CDCl3): d = 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.
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)-2H-pyrido[3,2-b][1,4]-
oxazine (4d). Yellow solid; mp 113–114 °C. 1H NMR (270
MHz, CDCl3): d = 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): d = 35.41 (d, J = 53.60 Hz,
1 F). 13C NMR (68 MHz, CDCl3): d = 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.
(24) 2-Fluoro-3-(4-nitrophenyl)-2H-pyrido[3,2-b][1,4]-
oxazine (4c). Yellow solid; mp 258–259 °C. 1H NMR (270
MHz, CDCl3): d = 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). 19
F
NMR (254 MHz, CDCl3): d = 34.32 (d, J = 53.60 Hz, 1 F).
13C NMR (68 MHz, CDCl3): d = 94.78 (d, J = 229.30 Hz),
124.09, 125.26, 125.56, 128.56, 138.21, 138.74 (d, J =
Synlett 2010, No. 14, 2146–2150 © Thieme Stuttgart · New York