Selective electrochemical fluorodesulfurization of benzo- and pyrido-fused oxazine derivatives using ex-cell halogen mediators

Article abstract of DOI:10.1055/s-0030-1260085

Although the direct anodic fluorination of 3-phenyl-2H-1,4-benzoxazine was not very effective, the fluorodesulfurization of 3-aryl-2-(phenylsulfanyl)-2H-1, 4-benzoxazines using various anodically generated halogen mediators in the presence of triethyl-ami

Full text of DOI:10.1055/s-0030-1260085

2372
SPECIAL TOPIC
Selective Electrochemical Fluorodesulfurization of Benzo- and Pyrido-Fused
Oxazine Derivatives Using Ex-cell Halogen Mediators
Electrochemical
i
luorod
n
esulfurization of
O
Y
xazine
D
erivative
in, 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 15 April 2011
zothiazine and its dehydro dimer in addition to the
Abstract: Although the direct anodic fluorination of 3-phenyl-2H-
1,4-benzoxazine was not very effective, the fluorodesulfurization of
3-aryl-2-(phenylsulfanyl)-2H-1,4-benzoxazines using various an-
odically generated halogen mediators in the presence of triethyl-
corresponding mono-, di-, and trifluorinated products in
moderate total yield. The anodic fluorination of benzothi-
azine dehydro dimer derivatives afforded 2,2-difluo-
amine tris(hydrogen fluoride) by an ex-cell method efficiently and robenzothiazine derivatives selectively in moderate
yields.7
selectively provided the corresponding monofluorinated products.
In sharp contrast, in-cell halogen mediators did not work well. Fur-
In 2008, López et al. reported that the use of N-iodosuc-
thermore, the selective fluorodesulfurization of pyrido[3,2-
cinimide (NIS), N-bromosuccinimide (NBS), or bis(2,4,6-
trimethylpyridyl)iodonium perchlorate containing an
electrophilic halonium ion could transform unprotected 1-
thioglycosides into glycosyl fluorides in the presence of
Olah’s reagent (70% HF–pyridine)8 or Et3N·3HF in
dichloromethane at low temperature.9 Similarly, we
achieved the fluorodesulfurization of 2-(phenylsulfa-
nyl)oxazine derivatives using various N-halosuccinimides
in the presence of Et3N·3HF.10
b][1,4]oxazine derivatives was also successfully carried out using
the same ex-cell method to provide the corresponding monofluori-
nated products in moderate yields.
Key words: halogenation, fluorine, heterocycles, electron transfer,
oxidations
Benzo- or pyrido-fused oxazine derivatives have been in-
vestigated because of their various pharmaceutical activi-
ties, e.g. as modulators of the skeletal muscle ATP-
sensitive-K+ channels (KATP),1a–c as central nervous sys-
tem (CNS) depressants,1d and as 5-HT3 receptor
antagonists1e and for their antiproliferative1f and analgesic
activities.1g In addition, much attention has been paid to
organofluorine heterocycles owing to their unique and
pronounced biological properties.2 We developed the ef-
fective and selective anodic fluorination of various organ-
ic compounds which included introducing fluorine
atom(s) onto the heterocyclic rings or side chains of com-
plex heterocyclic derivatives.3
In this paper, we report an effective electrochemical meth-
od for the fluorodesulfurization of 3-aryl-2-(phenysulfa-
nyl)-2H-1,4-benzoxazines and -pyrido[3,2-b][1,4]oxa-
zines using various mediators to generate active halonium
ions for use in the presence of Et3N·3HF in dichlo-
romethane; we obtained the corresponding monofluori-
nated products in moderate to good yields.
The model compound 3-phenyl-2H-1,4-benzoxazine (1a)
was synthesized according to a procedure in the litera-
ture.11 The corresponding 2-(phenylsulfanyl)-substituted
oxazine derivatives 2 and 3 were prepared from a-bromo-
a-(phenylsulfanyl)-substituted acetophenone derivatives
in a similar manner (Scheme 1).10,12
Previously, we reported that the anodic fluorination of N-
substituted 2H-1,4-benzoxazin-3(4H)-one and 2H-pyri-
do[3,2-b][1,4]oxazin-3(4H)-one derivatives in tetraethyl-
ammonium fluoride tetrakis(hydrogen fluoride)/1,2-
dimethoxyethane (Et4NF·4HF/DME) at platinum plate
electrodes in a divided cell provided the corresponding
monofluorinated products selectively.4 In addition, the
anodic fluorination of (E)-3-benzylidenethiochroman-4-
ones was successfully carried out in Et4NF·4HF/DME to
provide the corresponding monofluorinated products,
fluorinated at the a-position to the sulfur atom.5 Under the
same electrolytic conditions, the anodic fluorination of
(E)-3-benzylidenechroman-4-one derivatives was also
achieved.6 In contrast, the direct anodic fluorination of 3-
phenyl-2H-1,4-benzothiazine in triethylamine tris(hydro-
gen fluoride) (Et3N·3HF)/DME provided dimeric ben-
First, the anodic fluorination of 3-phenyl-2H-1,4-benzox-
azine (1a) (Epox = 1.58 V vs SCE), as a model compound,
was examined in detail under various electrolytic condi-
tions. 1,2-Dimethoxyethane was found to be a more effec-
tive solvent than acetonitrile when Et3N·3HF was used as
the fluorine source. This can be explained by the nucleo-
philicity of the fluoride ions being significantly enhanced
in 1,2-dimethoxyethane.13 As shown in Scheme 2, the
corresponding monofluorinated product 4a was obtained
in low yield along with a trace amount of difluorinated
product 5a {19F NMR: d = –32.57 (m, 1 F), –35.74 (d, 1 F,
J = 53.6 Hz); MS: m/z = 245 [M+], 227}. In contrast, much
lower total yield was obtained when stronger fluorinating
reagents (e.g., Et4NF·4HF and Et3N·5HF) were used.
In our previous work, we found that the anodic fluorode-
sulfurization of dithioacetals of ketones in the presence of
Et3N·3HF provided the corresponding gem-difluoro com-
SYNTHESIS 2011, No. 15, pp 2372–2376
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260085; Art ID: C01011SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Electrochemical Fluorodesulfurization of Oxazine Derivatives
2373
O
N
H2N
HO
Br
NaH, DMA
+
0 °C, 10 min;
r.t., overnight
O
1a (76%)
R
N
O
2-aminophenol
SPh
O
NaH, DMA, r.t.
2a: R = H (48%)
2b: R = Br (34%)
Br
SPh
R
R
2-amino-3-pyridinol
NaH, DMA, r.t.
N
N
O
SPh
Figure 1 Highest occupied molecular orbital energies and oxidation
potentials of benzoxazines 1a and 2a
DMA = N,N-dimethylacetamide
3a: R = H (53%)
3b: R = Br (43%)
respectively) when a theoretical quantity of electric
charge was passed (2 F/mol). The yield of the difluorinat-
ed product gradually increased to 5% when further elec-
trolysis was applied in these solvents (6 F/mol).
Scheme 1
N
Ph
F
In a previous paper, we reported the indirect anodic fluo-
rination of dithioacetals using a bromine (Br+/Br–) redox
mediator in Et3N·3HF/CH2Cl2 which provided the corre-
sponding monofluorinated products selectively.18 Based
on this result, the indirect anodic fluorination of 2a was
investigated using various mediators, and the results are
summarized in Table 1. Using tetrabutylammonium io-
dide (n-Bu4NI) as a mediator, no fluorinated product was
obtained at all and the substrate was mostly recovered (en-
try 1). Tetraethylammonium bromide (Et4NBr) was not a
O
N
Ph
4a (23%)
Et3N⋅3HF, DME
+
3 F/mol
N
Ph
F
O
1a
O
F
5a (1%)
Scheme 2
pounds in relatively good yields.14 In addition, oxidative
fluorodesulfurization of dithioacetals using organic oxi-
dizing reagents, such as NBS and 1,3-dibromo-5,5-di-
methylimidazolidine-2,4-dione, has been achieved in the
presence of fluorinating agents, such as Olah’s reagent,8
tetrabutylammonium dihydrogen trifluoride, and 4-(di-
fluoroiodo)toluene, to provide gem-difluorinated prod-
ucts.15 Considering these results, we assumed that partial
fluorodesulfurization could be carried out for benzox-
azines in which a phenylsulfanyl group is introduced as an
electroauxiliary.9,16
Table 1 Anodic Fluorodesulfurization of 2-(Phenylsulfanyl)-
Substituted Benzoxazine 2a Using Various Mediators
N
Ph
O
F
N
O
Ph
4a
constant current
+
Et3N⋅3HF
divided cell
N
Ph
F
SPh
2a
O
F
6a
The oxidation potential of 3-phenyl-2-(phenylsulfanyl)-
2H-1,4-benzoxazine (2a) was measured by cyclic voltam-
metry. Unexpectedly, it was found that the Ep value of
Entry Solvent
Mediator
Charge passed Yielda (%)
ox
(5 mol%)
n-Bu4NI
Et4NBr
(F/mol)
4a
6ab
2a was appreciably higher than that of 2-unsubstituted
compound 1a. The calculated highest occupied molecular
orbital (HOMO) energy value17 also indicated that the ox-
idation of compound 2a would be more difficult com-
pared with that of 1a (Figure 1).
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
8
2
6
2
6
–
–
2
4
1
3
Et4NCl
17
3
2
Next, the anodic fluorination of 2-(phenylsulfanyl)-sub-
stituted compound 2a was conducted in the presence of
Et3N·3HF using various solvents. Unfortunately, the elec-
trolysis of 2a in 1,2-dimethoxyethane, acetonitrile, and
dichloromethane provided the corresponding mono- and
difluorinated products in very low yields (3–9 and <2%,
4c
Et4NCl
0
5
(4-BrC6H4)3N
9
1
a Determined by 19F NMR spectroscopy.
b
19F NMR: d = –22.28 (s, 2 F); MS: m/z = 245 [M+].
c Et4NF·3HF was used as a supporting electrolyte.
Synthesis 2011, No. 15, 2372–2376 © Thieme Stuttgart · New York

2374
B. Yin et al.
SPECIAL TOPIC
suitable mediator because only small amounts of the cor- strate occurs to result in lower fluorination yields. Previ-
responding mono- and difluorinated products were detect- ously, we showed that the fluorodesulfurization reaction
ed (entry 2). It was found that tetraethylammonium of 2a with N-chlorosuccinimide gave a much lower yield
chloride (Et4NCl) was the most efficient mediator among compared with that achieved using NBS or NIS.10
the halide salts used for the anodic fluorodesulfurization
Table 2 Anodic Fluorodesulfurization of 2-(Phenylsulfanyl)-
Substituted Benzoxazine 2a Using Ex-cell Mediators
of compound 2a in the presence of Et3N·3HF; however,
the yields of the products were still low (entries 3 and 4).
ox
The use of tris(4-bromophenyl)amine (Ep = 1.06 V vs
– 2 e
X–
X+
SCE)19 as a mediator also resulted in low yields (entry 5).
divided cell
N
O
Ph
N
O
Ph
F
Et3N⋅3HF
In the case of the anodic fluorodesulfurization of 2a using
Et4NCl as a mediator, we supposed that anodically gener-
ated chloronium (Cl+) might attack the sulfur atom of the
phenylsulfanyl group of 2a to form an active leaving
group. Then, the resulting intermediate would react with a
fluoride ion to afford monofluorinated product 4a
(Scheme 3). However, the desired fluorinated product 4a
was not formed in good yield. Thus, the in-cell mediator
was not effective. We anticipated that the fluorodesulfur-
ization would be achieved in the presence of stoichiomet-
ric amounts of electrophilic halonium ions.
0.1 M n-Bu4NBF4/CH2Cl2
SPh
2a
4a
Entry Halogen source (equiv) Charge passed (F/mol) Yielda (%)
1
2
3
4
5b
6
7
Et4NCl (1)
Et4NCl (2)
Et4NBr (1)
Et4NBr (2)
Et4NBr (2)
Et4NI (2)
2
2
2
2
2
2
3
9
40
45
81 (72)
2
N
Ph
N
O
Ph
N
Ph
F
55
F–
Cl+
Et4NI (2)
76
O
2a
SPh
SPh
Cl
O
4a
a Determined by 19F NMR spectroscopy; isolated yield is shown in pa-
rentheses.
b In-cell method.
Scheme 3
Next, the anodic fluorodesulfurization of 1,4-benzoxazine
derivative 2b and pyrido[3,2-b][1,4]oxazine derivatives
3a and 3b was carried out under the optimized conditions.
The results are shown in Table 3. 4-Bromophenyl deriva-
tive 2b also gave the corresponding monofluorinated
product in good yield (entry 2). However, in the case of
pyrido[3,2-b][1,4]oxazine derivative 3a, three equivalents
With this in mind, we performed the anodic fluorode-
sulfurization using mediators by an ex-cell method, i.e.
the substrate was mixed with anodically generated active
halonium ions, followed by the addition of the fluorine
source. The results are summarized in Table 2. Initially,
we used stoichiometric amounts of Et4NCl (1 equiv)
(Epox = 1.12 V vs SCE) as the mediator, and the fluorode-
sulfurization of compound 2a was carried out in Et3N·3HF/
CH2Cl2 using the ex-cell method. The corresponding
monofluorinated product 4a was formed selectively in 9%
yield (entry 1), and a large amount of the recovered sub-
strate was also detected by 1H NMR spectroscopy. When
two equivalents of Et4NCl were used, the substrate was
consumed completely; however, the yield was moderate
(entry 2). We then used the bromonium ion (Br+) as an ox-
idant, generated from Et4NBr (Epox = 0.84 V vs SCE). The
use of one equivalent of Et4NBr resulted in the formation
of the corresponding monofluorinated product 4a in high-
er yield compared with that achieved with Et4NCl (cf. en-
tries 3 and 1). Notably, the desired product 4a was
obtained in good yield when two equivalents of Et4NBr
were used (entry 4). Using the in-cell method under the
same conditions, a small amount of monofluorinated
product 4a was obtained (entry 5). Tetraethylammonium
Table 3 Anodic Fluorodesulfurization of 2-(Phenylsulfanyl)-Sub-
stituted Benzoxazine Derivatives 2 and Pyrido[3,2-b][1,4]oxazine
Derivatives 3 Using Tetraethylammonium Bromide as an Ex-cell
Mediator
– 2 e
Br–
Br+
divided cell
2 F/mol
Y
N
O
Ar
Y
N
O
Ar
F
Et3N⋅3HF
0.1 M n-Bu4NBF4/CH2Cl2
SPh
2 Y = CH
3 Y = N
4 Y = CH
7 Y = N
Entry Compound Y
Ar
Amount of
Et4NBr (equiv)
Product Yielda
(%)
1
2
3
4
5
2a
2b
3a
3a
3b
CH Ph
2
2
2
3
3
4a
4b
7a
7a
7b
81 (72)
70 (60)
44
CH 4-BrC6H4
N
N
N
Ph
ox
iodide (Et4NI) (Ep = 0.42 V vs SCE) was also a good
Ph
61 (51)
54 (42)
choice as the halonium ion source, and a relatively good
result was obtained when 3 F/mol of charge was passed
(entries 6 and 7). Because Cl+ is a much stronger oxidant
than either Br+ or iodonium (I+), overoxidation of the sub-
4-BrC6H4
a Determined by 19F NMR spectroscopy; isolated yields are shown in
parentheses.
Synthesis 2011, No. 15, 2372–2376 © Thieme Stuttgart · New York

SPECIAL TOPIC
Electrochemical Fluorodesulfurization of Oxazine Derivatives
2375
Table 4 Fluorodesulfurization of 2-(Phenylsulfanyl)-Substituted
Benzoxazine 2a Using Iodine as an Oxidant or Mediator
of Et4NBr were necessary to provide product 7a in reason-
able yield (cf. entries 3 and 4). Under the same modified
conditions, the anodic fluorodesulfurization of bromo de-
rivative 3b was also successful (entry 5).
– 2 e
2 I+
I2
divided cell
N
Ph
N
Ph
F
Et3N⋅3HF
A plausible mechanism for the anodic fluorodesulfuriza-
tion of 2 and 3 is shown in Scheme 4. In this mechanism,
active halonium ions are generated by the anodic oxida-
tion of halide salts, such as Et4NBr and Et4NI, and react
with the phenylsulfanyl group of 2 and 3. This is followed
by desulfurization to form an oxocarbenium ion. The in-
termediate thus generated is then attacked by a nucleo-
philic fluoride ion to produce the corresponding
monofluorinated product selectively.
0.1 M n-Bu4NBF4/CH2Cl2
O
SPh
O
2a
4a
Entry
I2 (equiv)
Charge passed (F/mol) Yielda (%)
1
2
3
4
1
2
1
1
–
–
2
3
43
92 (85)
60
86 (75)
– 2 e
X–
X+
a Determined by 19F NMR spectroscopy; isolated yields are shown in
parentheses.
divided cell
X = Br, I
Y
N
O
Ar
Y
N
O
Ar
– XSPh
SPh
SPh
X
In conclusion, the anodic fluorodesulfurization of 3-aryl-
2-(phenylsulfanyl)-2H-1,4-benzoxazine derivatives 2 was
achieved using halonium cations generated by anodic ox-
idation of the corresponding halide salts as mediators by
an ex-cell method, providing the corresponding mono-
fluorinated products 4 in good yields. Furthermore, the
anodic fluorodesulfurization of 3-aryl-2-(phenylsulfa-
nyl)-2H-pyrido[3,2-b][1,4]oxazine derivatives 3 was also
successfully carried out using the same procedure to give
monofluorinated products 7 in moderate yields. In addi-
tion, molecular iodine was found to be highly effective for
oxidative fluorodesulfurization.
2 Y = CH
3 Y = N
Y
N
O
Ar
Y
N
O
Ar
F
F–
oxocarbenium ion
4 Y = CH
7 Y = N
Scheme 4
In addition, the fluorodesulfurization of 2a was examined
using iodine as a mediator; iodine has a higher oxidation
ox
potential (Epox = 0.73 V vs SCE) than Et4NI (Ep = 0.42
The 1H, 19F, and 13C NMR spectra were recorded at 270, 254, and
68 MHz, respectively, using a JEOL JNM EX-270 (270.05 MHz)
spectrometer in CDCl3 solution relative to TMS (d = 0.00 ppm) as
an internal standard; monofluorobenzene (d = –36.5 ppm) was used
as an internal standard for the 19F NMR spectra. Purification of the
fluorinated products was achieved by flash chromatography using
Nacalai Tesque silica gel 60 (spherical, neutral) or by HPLC per-
formed using a Shiseido column (SUPERIOREX ODS, 5 mm, 20
mm i.d. × 250 mm). Electron impact MS was obtained using a
Shimadzu GCMS-QP5050A instrument. High-resolution MS was
performed on a JEOL JMS-700 or Bruker Daltonics micrOTOF II
mass spectrometer. Cyclic voltammetry was measured using ALS
CH Instruments Electrochemical Analyzer Model 600 C. Electroly-
sis experiments were carried out using Metronix Corp. constant cur-
rent power supply model 5944 monitored with Hokuto Denko
coulomb/ampere hour meter HF-201.
V vs SCE). The results are shown in Table 4. First, model
compound 2a was treated with one equivalent of molecu-
lar iodine as the halogen source in Et3N·3HF/CH2Cl2 at
room temperature without any passage of charge. The cor-
responding monofluorinated product 4a was obtained in
43% yield (entry 1), and half the amount of substrate 2a
was recovered. When two equivalents of molecular iodine
were used under the same conditions, 2a was mostly con-
sumed (monitored by TLC) and monofluorinated product
4a was formed in excellent yield (entry 2). Thus, molecu-
lar iodine was also effective for the fluorodesulfurization
of 2a, although double amounts of iodine were necessary
for successful fluorination. To our knowledge, the two-
electron oxidation of molecular iodine affords two I+ cat-
ions.20 Based on the results of the fluorodesulfurization of
2 and 3 using halide salts and the ex-cell method, the
fluorodesulfurization of 2a was carried out with one
equivalent of iodine as the halonium ion source using the
same method.21 When 2 F/mol of charge was passed, the
corresponding monofluorinated product 4a was obtained
Anodic Fluorodesulfurization of Oxazine Derivatives (Ex-cell
Method); General Procedure
The anodic oxidation of the halide salt (0.2 or 0.3 mmol) was carried
out with Pt plate electrodes (1 cm × 1 cm) in 0.1 M n-Bu4NBF4 in
CH2Cl2 (10 mL) using a divided cell under a N2 atmosphere at r.t. A
constant current (8 mA/cm2) was applied and a theoretical charge of
2 F/mol was passed. After electrolysis, substrate 2 or 3 (0.1 mmol)
in moderate yield (entry 3), and unreacted substrate 2a was added, followed by stirring at r.t. for 10 min, and then
was also detected by 1H NMR spectroscopy. However, af-
Et3N·3HF (0.3 mL, 2.5 mmol) was added using a Teflon syringe.
When the starting material was mostly consumed (monitored by
TLC), the mixture was quenched with Et3N (ca. 1 mL) and passed
through a short column (silica gel, EtOAc) to remove fluoride salts.
The eluent was evaporated under reduced pressure, and the residue
ter electrolysis with 3 F/mol of charge passed, 2a was con-
sumed completely and monofluorinated product 4a was
obtained in good yield (entry 4).
Synthesis 2011, No. 15, 2372–2376 © Thieme Stuttgart · New York

2376
B. Yin et al.
SPECIAL TOPIC
was further purified by flash chromatography (silica gel, EtOAc–
hexane) to provide monofluorinated products 4 or 7.
Spectral data of 4 and 7 were reported in our previous paper.10
Momomota, K.; Fuchigami, T. J. Org. Chem. 1999, 64, 133.
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Fuchigami, T. J. Org. Chem. 2001, 66, 5633.
Anodic Fluorodesulfurization of 2a Using Iodine (Ex-cell
Method)
This was carried out in a similar manner to the procedure shown
above, using iodine instead of the halide salt.
(4) (a) Shaaban, M. R.; Fuchigami, T. Synlett 2001, 1644.
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To a solution of the 3-phenyl-2-(phenylsulfanyl)-2H-1,4-benzox-
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atmosphere at r.t. was added I2, followed by Et3N·3HF (0.3 mL, 2.5
mmol) using a Teflon syringe. After the starting materials had been
completely consumed (ca. 30 min, monitored by TLC), the reaction
mixture was quenched by the addition of Et3N (ca. 1 mL) and then
partially concentrated under reduced pressure. The residue was
passed through a short pad of silica gel, then subjected to flash silica
gel chromatography (EtOAc–hexane as eluent) to provide pure
product 4a.
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Acknowledgment
We gratefully acknowledge Morita Chemical Industries Co., Ltd for
supplying Et3N·3HF, used as a fluorine source. One of the authors
(Y. B.) acknowledges the Ministry of Education, Culture, Sports,
Science and Technology of Japan for awarding a national scholar-
ship to conduct this research.
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