Synthesis of some di- and trifluoro quinoxaline and dioxine derivatives from pentafluoropyridine

Article abstract of DOI:10.1007/s13738-012-0091-6

Novel [6,6,6] ring fused tricyclic systems can be readily synthesized in one-pot annulation reaction of pentafluoropyridine or 4-phenylsulfonyl tetrafluoropyridine with appropriate difunctional nitrogen and oxygen nucleophiles attached to aromatic rings. Reaction of 4-phenylsulfonyl tetrafluoropyridine with 2,6-diaminopyridine gave [6,5,6] ring fused systems arising from a tandem SNAr and cyclisation process. From this investigation, di- and trifluorinated quinoxaline and dioxine scaffolds were synthesized. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-012-0091-6

J IRAN CHEM SOC (2012) 9:747–755
DOI 10.1007/s13738-012-0091-6
ORIGINAL PAPER
Synthesis of some di- and trifluoro quinoxaline and dioxine
derivatives from pentafluoropyridine
•
Reza Ranjbar-Karimi Somayeh Hashemi-Uderji
•
Roghayeh Danesteh
Received: 18 September 2011 / Accepted: 15 February 2012 / Published online: 4 May 2012
Ó Iranian Chemical Society 2012
Abstract Novel [6,6,6] ring fused tricyclic systems can
be readily synthesized in one-pot annulation reaction of
pentafluoropyridine or 4-phenylsulfonyl tetrafluoropyridine
with appropriate difunctional nitrogen and oxygen nucle-
ophiles attached to aromatic rings. Reaction of 4-phenyl-
sulfonyl tetrafluoropyridine with 2,6-diaminopyridine gave
[6,5,6] ring fused systems arising from a tandem SNAr and
cyclisation process. From this investigation, di- and triflu-
orinated quinoxaline and dioxine scaffolds were
synthesized.
hand, this site-reactivity order may be altered by reaction of
pentafluoropyridine with bidentate nucleophiles [11].
Sandford and his co-worker recently demonstrated the
reactions of various 2,3,5,6-tetrafluoropyridine derivatives
1 (X = CN, NO2, H, MeO, EtO, Et2N, i-PrNH, CF(CF3)2
and Br) to assess the influence of the substituent at the
4-position upon reactions with difunctional N-nucleophile
such as N,N-diethylamine, and N,N’-dimethylethylene dia-
mine (Scheme 1) [12].
There are few papers concerning the reactions involving
identical bidentate nucleophiles attached to the aromatic
rings with pentafluoropyridine derivatives [2]. In this
paper, we report our studies concerning synthesis of
[6,6,6]- and [6,5,6]-ring fused tricyclic systems by carrying
out the reactions of pentafluoropyridine and 4-phenylsul-
fonyl tetrafluoropyridine and appropriate difunctional
nitrogen and oxygen nucleophiles attached to aromatic
rings.
Keywords Quinoxaline ꢀ Pentafluoropyridine ꢀ Fused
tricyclic system ꢀ Synthesis
Introduction
Pentafluoropyridine has attracted considerable interest due
to its synthetic utility. Several polyfunctional pyridine
derivatives and preparation of new heterocyclic, aromatic
heterocyclic and macrocyclic systems could be accessed
from simple reaction conditions [1–7]. All five fluorine
atoms in pentafluoropyridine may be substituted by an
appropriate nucleophile due to its highly electron efficient
aromatic ring system. It is well established that the order of
nucleophilic attack on pentafluoropyridine is 4 [ 2 [ 3, for
monosubstitution reactions involving a range of nucleo-
philes [8–10]. However, this may be depended on the effect
of each substituent once attached to the heterocyclic ring as
well as the nature of the attacking nucleophile. On the other
Results and discussion
The reaction of pentafluoropyridine (1a X = F) with
pyrocatechol 2a in the presence of cesium carbonate in
DMSO solvent gave 1,3,4-trifluorobenzo[5,6][1,4]dioxi-
no[2,3-c]pyridine 3a, arising from the substitution of the
most activated fluorine atom at the 4-position of the
pyridine ring followed by intermolecular ring closure at
the geometrically accessible 3-position (Table 1, entry 1).
A small amount of non-cyclised product 3b was obtained
reflecting the lower reactivity of 3 or 5-position which
allows intermolecular substitution to compete effectively
with the intramolecular cyclisation process. Purification of
3a and 3b was achieved by column chromatography.
Identification of 3a was done by 19F NMR analysis, in
R. Ranjbar-Karimi (&) ꢀ S. Hashemi-Uderji ꢀ R. Danesteh
Department of Chemistry, Faculty of Science, Vali-e-Asr
University, 77176 Rafsanjan, Islamic Republic of Iran
e-mail: r.ranjbarkarimi@vru.ac.ir
123

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J IRAN CHEM SOC (2012) 9:747–755
X
N
X
b]oxazine, quinoxaline or pyrazine systems by substitution
at the 2-position of the pyridine ring followed by inter-
molecular ring closure at the geometrically accessible
3-position.
F
F
N
N
F
F
F
H
N
+
N
H
F
N
The reaction of 4-phenylsulfonyl tetrafluoropyridine
with pyrocatechol 2a bearing two nucleophilic sites, after
refluxing in DMSO, gave 3h, arising from the initial attack
of oxygen nucleophile at the 2-position of the pyridine ring
and subsequent cyclization, respectively. By similar pro-
cedures, the related 3,4-dihydroxy nitrobenzene 2e gave
the mixture of analogous products 3i and 3j in the ratio of
2:1 by 19F NMR analysis of the reaction mixture and
4-methylbenzene-1,2-diol 2f, gave the mixture of analo-
gous products 3k and 3l in the ratio of 1:4 by 19F NMR
analysis of the reaction mixture (Table 1, entries 5–7). The
reaction of 1b with benzene-1,2,3-triol 2b (Table 1, entry
8) bearing three nucleophilic sites gave 3m as the only
product, arising from initial attack at the 2-position of the
two pyridine rings and subsequent cyclization, respec-
tively. Identification of 3h–m was done by 19F NMR
analysis, in which the resonance attributed to fluorine
located ortho to ring nitrogen have a chemical shift in the
range of –91.95 to –95.29 ppm similar to the shift observed
for the 3a and 3b. The corresponding resonance for the
fluorine located meta to ring nitrogen occurs at the range of
–144.03 to –165.64 ppm similar to the analogous system.
Bifunctional nucleophiles 2c and 2d, where both
nucleophilic sites are amino groups, reacted efficiently with
1b to give high yields of azatricyclic fused systems 3n and
3o, respectively (Table 1, entries 9 and 10). Purification of
3n was achieved by recrystallization of the crude product
mixture from dichloromethane, while 3o was purified by
column chromatography on silica gel, resulting in a lower
isolated yield.
1
X= CN, NO2, H, MeO, EtO, Et2N, i-PrNH, CF(CF3)2 and Br
Scheme 1 Reactions of various 2,3,5,6-tetrafluoropyridine deriva-
tives with diamines
which the resonance attributed to fluorines located ortho
to ring nitrogen have a chemical shift of –104.58 ppm and
–93.41 ppm similar to the shift observed for the 3c.
The corresponding resonance for F-3 in 3a occurs at
–164.27 ppm similar to the analogous system 3c. The
reaction of 1a with benzene-1,2,3-triol 2b bearing three
nucleophilic sites gave 3c as only product, arising from
initial attack at the 2-position of the two pyridine rings
and subsequent cyclization, respectively (Table 1, entry
2). Identification of 3c was done from 19F NMR analysis
in which the resonance attributed to four fluorine atoms
located ortho positions of both nitrogen rings had a
chemical shift in the range -88.8 to -89.9 ppm and the
resonance attributed to three fluorine atoms located meta
positions of both nitrogen rings had a chemical shift of
-156.1 and -163.1 ppm.
By a similar procedure, 1a reacted with benzene-1,2-
diamin 2c and 4-methylbenzene-1,2-diamine 2d to give the
corresponding tricyclic system 3d and 3f. But a trace
amount of these compounds was obtained and in contrast,
bis-pyridyl bridged products 3e and 3g were isolated as the
major products reflecting the lower reactivity of the meta
position which allows intermolecular substitution to com-
pete effectively with the intramolecular cyclisation
process.
Identification of 3n and 3o was done by 19F NMR
analysis in which the resonance attributed to fluorine
located ortho to ring nitrogen had a chemical shift of
-112.9 and -113.0 ppm, respectively, similar to the
analogous system in which ortho fluorine was adjacent to
the NH group (-105.7 ppm) [14]. The corresponding res-
onance for F-3 in 3n and 3o occurs at -165.7 and
-166.0 ppm.
In order to further develop routes to [6,6,6] tricyclic
systems, we studied reactions of 4-phenylsulfonyl tetra-
fluoropyridine (1b X = SO2Ph), bearing phenylsulfonyl
functionality at the 4-positions, with appropriate difunc-
tional nitrogen or oxygen nucleophiles (Table 1, entry
5–11).
The phenylsulfonyl group is strong electron withdraw-
ing group that helps to maintain the reactivity of pyridine
ring toward further nucleophilic substitution processes.
This allows annulation and further functionalization to
proceed. Annulation processes involving the reaction
between 4-phenylsulfonyl tetrafluoropyridine and difunc-
tional nitrogen or oxygen nucleophiles in the presence of
sodium bicarbonate in diluted acetonitrile solution to
minimize intermolecular reaction were studied. Nitrogen or
oxygen binucleophiles reacted efficiently with 4-phenyl-
sulfonyl tetrafluoropyridine to give tetrahydropyrido[2,3-
2-Aminophenol 2g, have both nitrogen and oxygen
nucleiphilic site, reacted efficiently with 1b to give good
yields of tricyclic fused systems 3p (Table 1, entry 11). A
small amount (3 %) of 3q product was identified by 19F
NMR analysis but could not be isolated. Purification of 3p
was achieved by recrystallization of the crude product
mixture from n-hexane/ethyl acetate. Identification of 3p
and 3q was done by 19F NMR analysis in which the res-
onance attributed to fluorine located at ortho to ring
nitrogen had a chemical shift of -103.0 and -92.2 ppm
for 3p and 3q, respectively, similar to the shifts observed
123

J IRAN CHEM SOC (2012) 9:747–755
749
Table 1 Nucleophilic substitution of 1 with 2
X
CH3CN
Na2CO3
F
F
F
Y
Y
R
+
Product
F
Reflux
N
2
3
1 (1a; X = F, 1b; X = SO2Ph)
Entry
X
F
Binucleophile
Product(s)
1
F
F
O
O
N
F
F
3a, 29%
F
N
F
O
F
F
O
F
3b, 11%
N
F
F
2
3
F
F
F
F
N
O
O
F
F
O
F
F
3c, 25%
F
F
N
F
H
N
N
N
H
3d, trace
F
F
N
F
F
F
F
N
F
NH HN
F
F
3e, 65%
4
F
F
F
H
N
F
N
N
H
3f, trace
F
N
F
F
F
F
F
N
F
NH HN
F
3g, 48%
123

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J IRAN CHEM SOC (2012) 9:747–755
Table 1 continued
Entry
X
Binucleophile
Product(s)
5
SO2Ph
X
F
F
O
N
O
3h, 80%
6
SO2Ph
X
F
F
O
O
N
X
NO2
NO2
3i, 50%
F
O
F
N
X
O
3j, 25%
7
SO2Ph
F
O
F
N
X
O
CH3
CH3
3k, 17%
F
O
F
N
O
3l, 78%
8
SO2Ph
SO2Ph
SO2Ph
X
F
O
F
N
O
OH
3m, 76%
9
X
H
N
F
F
N
N
H
3n, 35%
10
X
N
H
F
F
N
CH3
N
H
3o, 46%
11
SO2Ph
X
F
O
F
N
N
H
3p, 70%
X
H
N
F
F
N
O
3q, trace
123

J IRAN CHEM SOC (2012) 9:747–755
751
SO2Ph
SO2Ph
N
SO2Ph
N
HN
N
F
F
NH
N
F
F
N
N
F
F
F
F
F
F
F
F
F
PhO2S
+
+
SO2Ph
H2N
N
NH2
N
N
H
N
N
H
F
NH
HN
1b
4
5
6
Scheme 2 Synthesis of macrocycel from pentafluoropyridine
for the analogous systems. The regioselectivity of nucleo-
philic substitution of 1 with 2 may be explained by the
activating influences of the pyridine ring’s nitrogen that
significantly activates the ortho and para sites to itself.
With this encouraging result in hand, we interested to
obtain macrocycle 6 or bis-pyridyl product 5 by reaction of
4-phenylsulfonyl tetrafluoropyridine with pyridine-2,6-
diamine 4. However, the attempt to obtain 6 and 5 was
failed (Scheme 2).
A postulated mechanism for this process that leads to 7a
and 7b is shown in Scheme 3, and provides an indication of
how the products arise from initial nucleophilic attack by 4 at
the 2- and 3- positions of the pyridine ring, adapting a
mechanism postulated by Sandford [13] concerning reac-
tions between 4-phenylsulfonyl tetrafluoropyridine and
2-amino-3-picoline. Displacement of fluorine at the 2-posi-
tion leads directly to product 7b, whilst displacement of
fluorine at the 3-position gives intermediate 7c, which gives
rise to 7d or 7e by intramolecular cyclisation at the 4- or
2-position, displacing phenylsulfonyl or fluorine, respec-
tively. Reaction of 7d with the phenylsulfonyl anion, which
is now present in the reaction mixture, gives 7a. This
process is, therefore, complicated by the fact that the
phenylsulfonyl group, which is attached to the site para to
The reaction of 4 with 1b was less selective than the
reactions described above and two major products, 7a and
7b, were present in the reaction mixture as determined by
19F NMR spectroscopy. Purification allowed the isolation
of small quantities of the two major products 7a and 7b. 7a
and 7b were identified by 19F NMR spectroscopy.
SO2Ph
F
N
N
SO2Ph
N
F
F
F
F
N
F
F
+
N
F
+
NH2
H2N
N
NH2
N
N
SO2Ph
NH2
1b
4
7a
7b
SO2Ph
F
SO2Ph
N
N
F
F
F
Attack
at C-3
NH2
N
F
N
N
7b
NH2
NH2
SO2Ph
F
F
N
N
N
F
F
N
F
F
N
F
F
NH2
NH2
SO2Ph
NH2
Attack
at C-2
1b
N
SO2Ph
N
F
F
F
N
7d
7a
H2N
NH2
F
N
SO2Ph
N
7c
F
F
N
N
H
7e
Scheme 3 Synthesis of difluoro dipyridoimidazolylamine
123

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J IRAN CHEM SOC (2012) 9:747–755
1,3,4-trifluorobenzo[e]pyridino[3,2-b]1,4-dioxin (3a)
and 1,2-bis[2,3,5,6-tetrafluoro]-pyrid-4-yloxy]benzene
(3b)
ring nitrogen that remains most activated towards nucleo-
philic attack, is labile and may be readily displaced by
nucleophiles.
Sodium carbonate (0.25 g, 3 mmol), pyrocatechol 2a
(0.11 g, 1 mol), pentafluoropyridine (0.17 g, 1 mol) and
acetonitrile (10 mL) gave an oily product that was purified
by column chromatography on silica gel (ethyl acetate/
hexane, 2:3) gave 1,3,4-trifluorobenzo[e]pyridino[3,2-
b]1,4-dioxin 3a and 1,2-bis[2,3,5,6-tetrafluoro]-pyrid-4-
yloxy]benzene 3b, 3a: 0.03 gr, (29 %), white solid; mp:
210–215 °C. 19F NMR (470 MHz, CDCl3): dF -164.3
(m,1F, F-4), -104.8 (m, 1F, F-1), -93.4 (m, 1F, F-3). MS
(EI, 70 Ev): m/z (%) = 24.0 (M?, 30.1), 223.9, 222.9
(100), 193.9, 148.9, 92.9, 52.0. 3b: 0.02gr, (11 %), white
solid; mp: 279–283 °C. 19F NMR (470 MHz, CDCl3): dF
-165.3 (m,4F, F-3,5), -87.8 (m, 4F, F-2,6). MS (EI,
70 eV): m/z (%) = 408.9 (M?, 3.1), 407.8, 239.9, 238.9,
209.9, 191.9, 162.9, 119.4 (100), 73.9, 62.9.
Conclusion
In conclusion, we showed that pentafluoropyridine 1a can be
used as a substrate for the synthesis of some trif-
luorobenzo[5,6][1,4]dioxino derivatives upon reaction with
various aromatic dioles. In contrast, aromatic diamines give
bis-pyridyl bridged compounds as the major products. Also,
tricyclic difluoro-8-nitro-4-phenylsulfonylbenzo[5,6][1,4]
dioxino[2,3-b]pyridine difluoro 4-benzenesulfonyl-5,10-di
hydro-pyrido[2,3-b]quinoxaline scaffolds can be readily
synthesized in one-pot processes from pentafluoropyridine
and various aromatic diols and diamines, respectively. The
regioselectivity of nucleophilic substitution in this process
may be explained by the activating influence of pyridine ring
nitrogen that significantly activates the ortho and para sites
to itself.
1,2,3-trifluoro-9-(2,3,5,6-tetrafluoro-pyridin-4-yloxy)-
benzo[5,6][1,4]dioxino[2,3-c]pyridine (3c)
Sodium carbonate (0.25 g, 3 mmol), pyrogallol 2b (0.13 g,
1 mol), pentafluoropyridine (0.17 g, 1 mol) and acetonitrile
(10 mL) gave an oily product that was purified by column
chromatography on silica gel (ethyl acetate/hexane, 2:3)
gave 1,3,4-trifluoro-9-(2,3,5,6-tetrafluoro-pyridin-5-yloxy)-
benzo[5,6][1,4]dioxino[3,2-c]pyridine 3c, 0.05 g (25 %),
Experimental section
All solvents were dried using the literature procedures and
distilled before use. The reactions were carried out under
an atmosphere of air unless otherwise specified. The ele-
mental analyses for C, H, and N were performed using
Heraeus CHN-O-Rapid analyzer. The 1H NMR spectra
were recorded at 500 MHz. The 13C NMR spectra were
recorded at 125 MHz. The 19F NMR spectra were recorded
at 470 MHz. In the 19F NMR spectra, upfield shifts were
quoted as negative and referred to CFCl3. Mass spectra
were obtained by a Micromass Platform II: EI mode
(70 eV). Column chromatography was performed using
silica (Merck #60). Silica plates (Merck) were used for
TLC analysis.
1
white solid; mp: 93–95 °C. H NMR (CDCl3): d (ppm)
6.86–7.09 (m, 3H, Ar–H). 13C NMR (CDCl3): d (ppm) 114.7
(Ar–C), 116.3 (Ar–C), 124.7 (Ar–C), 125.6 (Ar–C), 131.5
1
2
3
(ddd, JCF = 258.8, JCF = 30.8, JCF = 6.8 Hz, C-3),
134.5 (Py–C), 134.3 (ddd, 1JCF = 260.4, 2JCF = 28.5, 3JCF
= 14.0 Hz, C-3), 142.1 (dd, 1JCF = 181.6, 2JCF = 16.1 Hz,
1
C-3), 140.2 (Ar–C), 142.2 (m, Py-C), 142.5 (ddm, JCF
=
2
1
233.5, JCF = 12.3 Hz, C-2), 143.2 (ddm, JCF = 200.5,
2JCF = 14.6 Hz, C-2), 143.3 (Ar–C). 19F NMR (470 MHz,
CDCl3): dF -163.1 (1F, m,F-4), -156.1 (2F, m, F-3,5),
-89.9 (1F, m, F-1), -89.1 (1F, m, F-3), -88.8 (2F, F-2,6).
MS (EI), m/z (%) = 404 (M?, 100), 403 (80). Anal. Calcd
for C16H3N2F7O3: C, 47.5; H, 0.7; N; 6.9. Found: C, 47.6; H,
0.7; N, 6.8.
General procedure for preparation of 6,7-difluoro-2,3-
dihydro-8-(phenylsulfonyl)pyrido[3,2-b][1,4]oxazin
or pyrazine system
Sodium carbonate (3 mmol) was added to the mixture of 2
(1 mol) in acetonitrile (10 mL) under argon. Then 1
(1 mol) was added and the resulting solution was refluxed
at 95 °C for 2 d. The reaction mixture was cooled to room
temperature and the solvent was evaporated. The reaction
mixture was poured onto 0.2 M hydrochloric acid (30 ml)
and then extracted with dichloromethane. The solvent was
evaporated to yield the crude product, which was then
purified by recrystallization or column chromatography on
silica gel.
N,N1-Bis-(2,3,5,6-tetrafluoro-pyridine-4-yl)
benzene-1,2-diamine 3e
Sodium carbonate (0.25 g, 3 mmol), benzene-1,2-diamine
2c (0.11 g, 1 mol), pentafluoropyridine (0.17 g, 1 mol) and
acetonitrile (10 mL) gave an oily product that was purified
by column chromatography on silica gel (ethyl acetate/
hexane, 1:4) gave 1,3,4-trifluorobenzo[e]pyridino[3,2-
b]1,4-dioxin 3e: 0.13 gr, (65 %), white solid; mp:
123

J IRAN CHEM SOC (2012) 9:747–755
753
148–149 °C. 1H NMR (500 MHz, DMSO): dH 6.6 (Ar–H),
7.0 (m, Ar–H), 8.7 (s, 2H, NH). 13C NMR (125 MHz,
DMSO): dC 115.3 (Ar–C), 123.7 (s, Ar–C), 126.9 (Ar–C),
2,3-difluoro-8-nitro-4-phenylsulfonylbenzo[5,6][1,4]
dioxino[2,3-b]pyridine 3i and 2,3-difluoro-7-nitro-4-
phenylsulfonylbenzo[5,6][1,4]dioxino[2,3-b]pyridine 3j
1
2
131.0 (dd, JCF = 249.0 Hz, JCF = 32.8 Hz, 4C, C-3,5),
2
137.2 (m, JCF = 11.5 Hz, 2C, C-4), 143.6 (dd,1JCF
=
Sodium carbonate (0.25 g, 3 mmol), 3,4 dihydroxy nitroben-
zene 2e (0.15 g, 1 mol), 4-phenylsulfonyl tetrafluoropyridine
(0.29 g, 1 mol) and acetonitrile (10 mL) gave an oily product
that was purified by column chromatography on silica gel
(ethyl acetate/hexane, 1:1) gave 2,3-difluoro-8-nitro-4-phenyl
sulfonylbenzo[5,6][1,4]dioxino[2,3-b]pyridine 3i and 2,3-di
fluoro-7-nitro-4-phenylsulfonylbenzo[5,6][1,4]dioxino[2,3-b]
yridine 3j, 3i: 0.20 g (50 %), brown solid; mp: 135–137 °C.
1H NMR (CDCl3): d (ppm) 7.21–8.52 (m, 8H, Ar–H) 13C
NMR (CDCl3): d (ppm) 112.90 (Ar–C), 115.32 (Ar–C),
118.11 (Ar–C), 125.94 (Ar–C), 126.23 (m, C-4), 127.93
(Ar–C), 128.20(Ar–C), 133.26 (m, C-5a), 133.85 (Ar–C),
137.00 (dd, 1JCF = 264.6 Hz, 2JCF = 28.1 Hz, C-3), 141.12
240.6 Hz, 2JCF = 21.1 Hz, 4C, C-2,6). 19F NMR (470 MHz,
DMSO): dF -160.5 (m, 4F, F-3,5), -97.3 (m, 4F, F-2,6).
4-Methyl-N,N1-Bis-(2,3,5,6-tetrafluoro-pyridine-4-
yl)benzene-1,2-diamine 3g
Sodium carbonate (0.25 g, 3 mmol), 4-methylbenzene-1,2-
diamine 2d (0.12 g, 1 mol), pentafluoropyridine (0.17 g,
1 mol) and acetonitrile (10 mL) gave an oily product that
was purified by column chromatography on silica gel (ethyl
acetate/hexane, 1:3) gave 4-Methyl-N,N1-Bis-(2,3,5,6-tet-
rafluoro-pyridine-4-yl)benzene-1,2-diamine 3g: 0.1 gr,
(48 %), white solid; mp: 156–160 °C.
1
2
(Ar–C), 142.10 (dd, JCF = 230.9, JCF = 18.0 Hz, C-2),
3
144.33 (Ar–C), 146.47 (Ar–C), 154.71 (d, JCF = 9.0 Hz,
1H NMR (500 MHz, DMSO): dH 2.2 (s, 3H, CH3), 6.5
C-10a), 19F NMR (CDCl3):
d (ppm) –165.93 (d,
(s, Ar–H), 6.6 (s, Ar–H), 6.7 (s, Ar–H), 8.7 (s, 2H, NH). 13
C
3JFF = 22.3 Hz, 1F, F-3), –94.89 (d, JFF = 22.3 Hz, 1F,
F-2). MS (EI), m/z (%) = 406 (M?, 100), 266 (80). Anal.
Calcd for C17H8N2F2O6S: C, 50.3; H, 2.0; N; 6.9. Found: C,
50.2; H, 2.1; N, 6.7.
3
NMR (125 MHz, DMSO): dC 20.9 (s, CH3), 115.2 (s, Ar–C),
116.5 (s, Ar–C), 121.3 (s, Ar–C), 126.6 (s,Ar–C), 127.8
(s, Ar–C), 131.3 (dd, 1JCF = 250.1 Hz, 2JCF = 34.9 Hz, 4C,
2
C-3,5), 137.5 (m, JCF = 14.1 Hz, 2C, C-4), 143.5
1
1
2
(dd, JCF = 199.9 Hz, JCF = 16.1 Hz, 4C, C-2,6). 19F
NMR (470 MHz, DMSO): dF -161.0 (m, 2F, F-30,50),
-160.5 (m, 2F, F-3,5), -97.4 (m, 2F, F-20,60), -97.3(m, 2F,
F-2,6).
3j: 0.10 g (25 %), orange solid; mp: 120–125 °C. H
NMR (CDCl3): d (ppm) 6.88–9.21 (m, 8H, Ar–H) 13C NMR
(CDCl3): d (ppm) 111.95 (Ar–C), 116.44 (Ar–C), 118.38
(Ar–C), 126.81 (Ar–C), 126.87 (m, C-4), 128.00 (Ar–C),
128.29 (Ar–C), 133.52 (m, C-5a), 134.26 (Ar–C), 136.23
(dd, 1JCF = 261.0 Hz, 2JCF = 27.8 Hz, C-3), 140.77 (Ar–C),
2,3-difluoro-4-phenylsulfonylbenzo[5,6][1,4]
dioxino[2,3-b]pyridine 3h
1
2
142.13 (dd, JCF = 231.1, JCF = 18.8 Hz, C-2), 146.21
3
(Ar–C), 147.81 (Ar–C), 155.21 (d, JCF = 7.1 Hz, C-10a).
3
19F NMR (CDCl3): d (ppm) -165.64 (d, JFF = 22.4 Hz,
Sodium carbonate (0.25 g, 3 mmol), pyrocatechol 2a
(0.11 g, 1 mol), 4-phenylsulfonyl tetrafluoropyridine
(0.29 g, 1 mol) and acetonitrile (10 mL) gave an oily
product that was purified by column chromatography on
silica gel (ethyl acetate/hexane, 1:3) gave 2,3-difluoro-4-
phenylsulfonylbenzo[5,6][1,4]dioxino[2,3-b]pyridine 3h,
3
1F, F-3), –95.29 (d, JFF = 22.4 Hz, 1F, F-2). MS (EI),
m/z (%) = 406 (M?, 100), 266 (75). Anal. Calcd for
C17H8N2F2O6S: C, 50.3; H, 2.0; N; 6.9. Found: C, 50.2; H,
1.8; N, 6.8.
1
4-Benzenesulfonyl-2,3-difluoro-5,10-dihydro-pyrido[2,3-
b]quinoxaline 3n
0.28 g (80 %), yellow solid; mp: 206–208 °C. H NMR
(CDCl3): d (ppm) 6.86–8.14 (m, 9H, Ar–H) 13C NMR
(CDCl3): d (ppm) 116.39 (Ar–C), 125.03 (Ar–C), 125.28
(m, C-4), 125.58 (Ar–C), 125.72 (Ar–C), 128.26 (Ar–C),
128.41 (Ar–C), 129.24 (Ar–C), 129.40 (Ar–C), 129.27 (d,
Sodium carbonate (0.25 g, 3 mmol), benzene-1,2-diamine
2c (0.11 g, 1 mol), 4-phenylsulfonyl tetrafluoropyridine
(0.29 g, 1 mol) and acetonitrile (10 mL) gave an oily prod-
uct that was purified by column chromatography on silica gel
(ethyl acetate/hexane, 2:3) gave 4-benzenesulfonyl-2,3-
difluoro-5,10-dihydro-pyrido[2,3-b]quinoxaline 3n, 0.13 g
(35 %), orange solid; mp: 240–245 °C. 19F NMR(470 MHz,
3
3JCF = 9.3 Hz, C-3b), 134.71 (d, JCF = 8.6 Hz, C-2b),
1
2
137.74 (dd, JCF = 265.9 Hz, JCF = 30.1 Hz), 140.79
(Ar–C), 142.23 (Ar–C), 144.82 (dd, J = 234.6, J = 19.2
3
Hz) 19F NMR (CDCl3): d (ppm) -144.03 (d, JFF = 23.6
Hz, 1F, F-3), –91.95 (d, 3JFF = 23.6 Hz, 1F, F-2). MS (EI),
m/z (%) = 361 (M?, 100), 220 (80). Anal. Calcd for
C17H9NF2O4S: C, 56.5; H, 2.5; N; 3.9. Found: C, 56.4; H,
2.3; N, 3.8.
3
CDCl3): dF -165.7 (1F, d, JFF = 28.2 Hz, F-3), -112.9
(1F, d, 3JFF = 28.2 Hz, F-2). MS (EI, 70 Ev): m/z (%) = 359.7
(M?, 2.41), 238.1, 157.0, 132.0, 77.03 (100).
123

754
J IRAN CHEM SOC (2012) 9:747–755
9H, Ar–H). 19F NMR (470 MHz, CDCl3): dF -163.4 (1F, d,
3JFF = 21.0 Hz, F-3), -93.6 (1F, d, 3JFF = 21.0 Hz, F-2).
4-Benzenesulfonyl-2,3-difluoro-7-methyl-5,10-dihydro-
pyrido[2,3-b]quinoxaline 3o
Sodium carbonate (0.25 g, 3 mmol), 4-methylbenzene-1,2-
diamine 2d (0.10 g, 1 mol), 4-phenylsulfonyl tetrafluoro-
pyridine (0.29 g, 1 mol) and acetonitrile (10 mL) gave an
oily product that was purified by column chromatography on
silica gel (ethyl acetate/hexane, 1:1) gave 4-benzenesulfonyl
-2,3-difluoro-7-methyl-5,10-dihydro-pyrido[2,3-b]quinoxa-
2,3-difluoro-4-phenylsulfonyl-10H-benzo[b]pyrido[2,3-
e][1,4]oxazine 3p
Sodium carbonate (0.25 g, 3 mmol), 2-aminophenol 2 g (0.10 g,
1 mol), 4-phenylsulfonyl tetrafluoropyridine (0.29 g, 1 mol) and
acetonitrile (10 mL) gave an oily product that was purified by
column chromatography on silica gel (ethyl acetate/hexane, 1:3)
gave 2,3-difluoro-4-phenylsulfonyl-10H-benzo[b]pyrido[2,3-
e][1,4]oxazine 3p, 0.25 g (70 %), yellow solid; mp:
1
line 3o, 0.17 g (46 %), orange oily. H NMR (500 MHz,
CDCl3): dH 1.2 (s, 3H, CH3), 7.5–8.4 (m, Ar–H). 19F NMR
(470 MHz, CDCl3): dF -166.0 (1F, d, 3JFF = 28.2 Hz, F-3),
-113.0 (1F, d, JFF = 28.2 Hz, F-2). MS (EI, 70 Ev):
3
1
230–231 °C. H NMR (CDCl3): d (ppm) 5.82 (bs, 1H, NH),
m/z(%) = 373.8 (M?, 2.4), 263.0, 148.9 (100), 103.9, 77, 57.0.
6.82–8.36 (m, 9H, Ar–H) 13C NMR (CDCl3): d (ppm) 114.8
(Ar–C), 116.6 (Ar–C), 119.9 (m, C-4a), 123.8 (Ar–C), 125.6
2
(Ar–C), 126.7 (d, JCF = 4.5 Hz, C-4), 127.0 (Ar–C), 127.8
4-Benzenesulfonyl-2,3-difluoro- 8-methyl-
benzo[5,6][1,4]dioxino[2,3-b]pyridine 3k and 4-
benzenesulfonyl-2,3-difluoro-7-methyl-
(Ar–C), 128.7 (Ar–C), 135.3 (Ar–C), 137.2 (dd, 1JCF = 256.2
Hz, 2JCF = 28.3 Hz, C-3), 140.2 (Ar–C), 142.4 (Ar–C), 142.21
1
2
benzo[5,6][1,4]dioxino[2,3-b]pyridine 3l
(dd, JCF = 234.2, JCF = 17.2 Hz, C-2), 144.27 (m, C-10a),
19F NMR (CDCl3): d (ppm) -145.81 (d, 3JFF = 22.7 Hz, 1F,
F-3), –103.00 (d, 3JFF = 22.7 Hz, 1F, F-2). MS (EI), m/z (%) =
360 (M?, 100), 2219 (70). Anal. Calcd for C17H10N2F2O3S: C,
56.7; H, 2.8; N; 7.8. Found: C, 56.8; H, 2.9; N, 7.8.
Sodium carbonate (0.25 g, 3 mmol), 4-methylbenzene-1,2-
diol 2f (0.12 g, 1 mol), 4-phenylsulfonyl tetrafluoropyridine
(0.29 g, 1 mol) and acetonitrile (10 mL) gave an oily prod-
uct that was purified by column chromatography on silica gel
(ethyl acetate/hexane, 2:1) gave 2,3-difluoro-8-methyl-
4-phenylsulfonylbenzo[5,6][1,4]dioxino[2,3-b]pyridine 3k
and 2,3-difluoro-7-methyl-4-phenylsulfonylbenzo[5,6][1,4]
dioxino[2,3-b]pyridine 3l, 3k: 0.09 (17 %), brown solid; mp:
3-Benzenesulfonyl-1,4-difluoro-dipyrido[1,2-a;30,40-
d]imidazol-6-ylamine (7a) and 4-Benzenesulfonyl-2,3-
difluoro-dipyrido[1,2-a;30,20-d]imidazol-9-ylamine (7b)
and 4-Benzensulfonyl-2,3-difluoro-dipyrido[2,1-a;20,30-
d]imidazol-6-ylamine (7e)
264–268 °C. 19F NMR (CDCl3): d (ppm) –147.2 (d, 3JFF
=
3
21.6 Hz, 1F, F-3), -95.2 (d, JFF = 21.6 Hz, 1F, F-2). 3l:
1
0.32 gr (78 %), yellow solid; mp 245–249 °C. H NMR
Sodium carbonate (0.25 g, 3 mmol), 2,6-diaminopyridine 4
(0.11 g, 1 mol), 4-phenylsulfonyl tetrafluoropyridine (0.29 g,
1 mol) and acetonitrile (10 mL) gave an oily product that was
purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:1) gave 3-benzenesulfonyl-1,4-difluoro-dipyrido[1,2-
a;30,40-d]imidazol-6-ylamine 7a and 4-benzenesulfonyl-2,
3-difluoro-dipyrido[1,2-a;30,20-d]imidazol-9-ylamine 7b and
4-benzensulfonyl-2,3-difluoro-dipyrido[2,1-a;20,30-d]imidazol-
6-ylamine 7e, 7a: 0.09 g (23 %), orange solid; mp: 274–276 °C
.19F NMR (470 MHz, DMSO): dF -117.4 (d, 5JFF = 28.9 Hz,
(500 MHz, DMSO): dH 2.2 (s, 3H, CH3), 6.8 (m, 1H, Ar–H),
6.9 (Ar–H), 7.7 (m, 2H, Ar–H), 7.8 (m, 1H, Ar–H), 8.1 (m,
2H, Ar–H). 13C NMR (125 MHz, CDCl3): dC 20.1 (s, CH3),
113.0 (s, Ar–C), 114.3 (d, Ar–C), 115.8 (s, Ar–C), 116.3
(s, Ar–C), 116.5 (s, Ar–C), 116.9 (s, Ar–C), 125.3 (m, C-3b),
127.9 (s, Ar–C), 129.4 (s, Ar–C), 131.6 (m, C-4), 132.2
(s, Ar–C) 137.7 (dd, C-3), 140.1 (m, C-2b), 141.3
(s, Ar–C),141.6 (m, Ar–C), 144.8 (m, C-2). 19F NMR
(470 MHz, DMSO): dF -147.3 (m, 1F, F-3), -95.0 (m, 1F,
F-2). MS (EI, 70 Ev): m/z (%) = 375.0 (M?, 3.11), 318.0,
233.8, 149.0, 77.0 (100).
5
1F, F-4), -82.9 (d, JFF = 28.9 Hz, 1F, F-1). 7b: 0.18 g
(52 %), orange solid; mp: 238–243 °C 19 F NMR (470 MHz,
3
CDCl3): df -140.3 (d, JFF = 23.5 Hz, 1F, F-4), -96.7
4-Benzenesulfonyl-2,3-difluoro-
benzo[5,6][1,4]dioxino[2,3-b]pyridine-9-ol 3m
(d, 3JFF = 23.5 Hz, 1F, F-5). 1H NMR (500 MHz, CDCl3): dH
6.1 (m, 1H, Ar–H), 6.5 (s, 1H, Ar–H), 7.6 (m, 2H, Ar–H), 7.6
(m, 1H, Ar–H), 8.3 (m, 2H, Ar–H). MS (EI, 70 Ev):
m/z (%) = 360.9 (M?, 2.7), 359.9, 295.0, 76.9, 69.0, 57.1, 55.0
(100). 7e: 0.05 g (14 %), brown solid; mp: 263–267 °C, 19F
NMR (470 MHz, DMSO): dF -171.0 (d, 3JFF = 11.0 Hz, 1F,
F-3), -101.7 (d, 3JFF = 11.0 Hz, 1F, F-2).
Sodium carbonate (0.25 g, 3 mmol), Pyrogallol 2b (0.13 g,
1 mol), 4-phenylsulfonyl tetrafluoropyridine (0.29 g, 1 mol)
andacetonitrile (10 mL) gave an oily product that was purified
by column chromatography on silica gel (ethyl acetate/hexane,
1:4) gave 4-Benzenesulfonyl-2,3-difluoro-benzo[5,6][1,4]di-
oxino[2,3-b]pyridine-9-ol 3m, 0.29 g (76 %), brown solid;
mp: 195–201 °C. 1H NMR (500 MHz, CDCl3): dH 6.9–8.1(m,
Acknowledgments The authors wish to thank Rafsanjan Vali-e-Asr
University (Rafsanjan, Iran) for the partial support of this work.
123

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755
7. R.D. Chambers, P.R. Hoskin, A. Khalil, P. Richmond, G. Sand-
ford, D.S. Yufit, J.A.K. Howard, J. Fluor. Chem. 116, 19–22
(2002)
8. R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28, 1–71
(1981)
9. G.M. Brooke, J. Fluor. Chem. 86, 1–76 (1997)
10. W.J. Guilford, J. Dallas, D. Arnaiz, J. Labell. Comp. Radiopharm.
44, 247–256 (2001)
References
1. H. Benmansour, R.D. Chambers, P.R. Hoskin, G. Sandford, J.
Fluor. Chem. 112, 133–137 (2001)
2. A. Barone, G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A.
Vong, J. Org. Chem. 70, 9377–9381 (2005)
3. G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J.
Org. Chem. 70, 7208–7216 (2005)
11. H. Amii, K. Uneyama, Chem. Rev. 109, 2119–2183 (2009)
12. C.A. Hargreaves, G. Sandford, R. Slater, D.S. Yufit, J.A.K.
Howard, A. Vong, Tetrahedron 63, 5204–5211 (2007)
13. M.W. Cartwright, L. Convery, T. Kraynck, G. Sandford, D.S.
Yufit, J.A.K. Howard, J.A. Christopher, D.D. Miller, Tetrahedron
66, 519–529 (2010)
4. R.D. Chambers, P.R. Hoskin, G. Sandford, D.S. Yufit, J.A.K.
Howard, J. Chem. Soc, Perkin Trans. I 2788–2795 (2001)
5. R.D. Chambers, P.R. Hoskin, A.R. Kenwright, A. Khalil, P.
Richmond, G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard,
Org. Biomol. Chem. 1, 2137–2147 (2003)
6. R.D. Chambers, A. Khalil, C.B. Murray, G. Sandford, A.S.
Batsanov, J.A.K. Howard, J. Fluor. Chem. 126, 1002–1008
(2005)
14. M. Ranjbar-Karimi, J. Mousavi, Fluor. Chem. 131, 587–591 (2010)
123