Regiochemistry of nucleophilic substitution of 4-phenylsulfonyl tetrafluoropyridine with unequal bidentate nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2010.01.006

The regiochemistry of nucleophilic substitution of 4-phenylsulfonyl tetrafluoropyridine with unequal bidentate nucleophiles was investigated. The first nucleophilic substitution occurs at the 2-position of the pyridine ring by nitrogen nucleophile site (s

Full text of DOI:10.1016/j.jfluchem.2010.01.006

Journal of Fluorine Chemistry 131 (2010) 587–591
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regiochemistry of nucleophilic substitution of 4-phenylsulfonyl
tetrafluoropyridine with unequal bidentate nucleophiles
*
Reza Ranjbar-Karimi , Mirrasoul Mousavi
Department of Chemistry, Faculty of Science, Vali-e-Asr University, Rafsanjan 77176, Islamic Republic of Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
The regiochemistry of nucleophilic substitution of 4-phenylsulfonyl tetrafluoropyridine with unequal
bidentate nucleophiles was investigated. The first nucleophilic substitution occurs at the 2-position of
the pyridine ring by nitrogen nucleophile site (secondary or primary amine) followed by intermolecular
ring closure at the geometrically accessible 3-position of the pyridine ring (by S, O and N nucleophiles).
From this investigation, difluorinated tetrahydropyrido[3,4-b][1,4]oxazine, thiazine and pyrazine
Received 20 December 2009
Received in revised form 11 January 2010
Accepted 13 January 2010
Available online 22 January 2010
scaffolds were synthesized very readily by
tetrafluoropyridine with appropriate unequal bidentate nucleophiles.
Crown Copyright ß 2010 Published by Elsevier B.V. All rights reserved.
a one-pot annelation reaction of 4-phenylsulfonyl
Keywords:
Pentafluoropyridine
Heterocycle
Multi-functional
Synthesis
Ring closure
Bidentate
1. Introduction
reactivity into hard and soft nucleophiles was achieved by partial
replacement of fluorine by bromine in pentafluoropyridine [15]
(Scheme 2).
There are several papers concerning the reactions involving
equal bidentate nucleophiles with pentafluoropyridine derivatives
Synthesis of polyfunctional heterocyclic fused ring systems
with low molecular weight are important in life science industries
[1,2]. Pentafluoropyridine has attracted considerable interest due
to its synthetic utility. Various multi-functional pyridine deriva-
tives and construction of new heterocyclic and macrocyclic
systems could be accessed from simple reaction conditions [3–
10]. These include reaction of various bifunctional nucleophiles
with pentafluoropyridine. All five fluorine atoms in pentafluor-
opyridine may be substituted by an appropriate nucleophile due to
its highly electron efficient aromatic ring system. The site-
reactivity order of pentafluoropyridine is well known [11–13]
that, the order of activation toward nucleophilic attack follows the
sequence 4-fluorine > 2-fluorine > 3-fluorine. Reactions of penta-
fluoropyridine with various nucleophiles are summarized and
discussed in detail [14]. Representative examples of these
reactions are given in Scheme 1.
[4]. Reaction of 4-phenylsulfonyl tetrafluoropyridine
2 with
unequal bidentate nucleophiles has not been described previously
in the literature. In this paper, we will describe our initial
investigations on the regiochemistry nucleophilic substitution of 2
with a various unequal bidentate nucleophiles. We further develop
our general annelation strategy to the synthesis of [6,6] and [6,6,6]
ring fused bi- or tricyclic systems.
2. Results and discussion
Reaction of pentafluoropyridine 1 with sodium phenylsulfinate
led to 4-phenylsulfonyl tetrafluoropyridine 2 following a literature
procedure (Scheme 3) [16].
Systematic exploitation of perfluoroheteroaromatic com-
pounds with different susceptibilities due to different positioning
can be used as a tool for combinatorial synthesis of other
compounds. Chambers and co-workers recently demonstrated
the feasibility of this concept. Further differentiation of its
The phenylsulfonyl group is strong electron withdrawing group
that helps to maintain the reactivity of pyridine ring toward
further nucleophilic substitution processes. This allows annelation
and further functionalization to proceed. Annelation processes
involving the reaction between 2 and unequal binucleophiles in
the presence of sodium bicarbonate and also in diluted acetonitrile
solution to minimize intermolecular reaction were studied
(Table 1). Unequal binucleophiles reacted efficiently with 2 to
give tetrahydropyrido[2,3-b]oxazine, thiazine or pyrazine systems
* Corresponding author. Tel.: +98 913 291 6602; fax: +98 391 322 6800.
E-mail address: karimi_r110@yahoo.com (R. Ranjbar-Karimi).
0022-1139/$ – see front matter. Crown Copyright ß 2010 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.01.006

588
R. Ranjbar-Karimi, M. Mousavi / Journal of Fluorine Chemistry 131 (2010) 587–591
Scheme 1. Reactions on pentafluoropyridine.
4a and 4b in the ratio of 1.6:1 by 19F NMR analysis of the reaction
mixture, arising from the initial attack of the secondary or primary
amine site at the 2-position of the pyridine ring and subsequent
cyclization, respectively. Purification of 4a and 4b was achieved by
column chromatography. Identification of 4a was done by 19F NMR
analysis, in which the resonance attributed to fluorine located
ortho to ring nitrogen have a chemical shift of À92.8 ppm similar to
the shift observed for the 4c and 4f. The corresponding resonance
for F-6 in 4b occurs at À108.3 ppm similar to the analogous system
4d, in which F-6 was adjacent to the NH group (À105.7 ppm). The
major product 4a was most likely formed from the initial attack of
the secondary amine site, reflecting the higher nucleophilicity of
the secondary amines over the primary systems. The [6,6] fused
ring systems, 4c and 4d, were synthesized from the reaction 2 with
diethanolamine 3b and ethanolamine 3c, respectively (Table 1).
The reaction of 2 with diethylene triamine 3d bearing three
nucleophilic sites gave a mixture of 4e, 4f and 4g in the ratio of
10:1.4:1 by 19F NMR analysis of the reaction mixture, arising from
initial attack of the secondary or primary amine sites at the 2-
position of the pyridine ring and subsequent cyclization, respec-
tively. Purification of 4e, 4f and 4g was achieved by column
chromatography. Identification of 4e followed from 19F NMR
analysis in which the resonance attributed to fluorine located ortho
to ring nitrogen (F-6) had a chemical shift of À108.4 ppm and the
resonance attributed to fluorine located meta to ring nitrogen (F-7)
had a chemical shift of À157.4 ppm, similar to shift observed for
the 4d in which F-6 is adjacent to the NH group (À105.7 ppm). The
corresponding resonances for F-6 and F-7 in 4f occur at À93.4 and
À154.3 ppm, respectively, similar to the analogous system 4c and
4a. In 4g, the resonance attributed to fluorine located ortho to ring
nitrogen (F-6) had a chemical shift of À103.9 ppm similar to the
shift observed for the 4d and4e in which F-6 is adjacent to the NH
group and the resonance attributed to fluorine located meta to ring
nitrogen (F-7) had a chemical shift of À182.1 ppm. The major
product 4e is most likely formed from the initial attack of the
Scheme 2. Reaction of pentahalopyridine with hard and soft nucleophiles.
by substitution at the 2-position of the pyridine ring followed by
intermolecular ring closure at the geometrically accessible 3-
position (Table 1). The regioselectivity of nucleophilic substitution
of 2 with 3 may be explained by the high nucleophilicity of the
secondary or primary amino groups and also the activating
influences of the pyridine ring’s nitrogen that significantly
activates the ortho and para sites to itself.
The reaction of 2 with unequal binucleophile 3a bearing three
nucleophilic sites, after refluxing in acetonitrile, gave a mixture of
Scheme 3. Reaction of pentafluoropyridine with sodium phenylsulfinate.

R. Ranjbar-Karimi, M. Mousavi / Journal of Fluorine Chemistry 131 (2010) 587–591
589
Table 1
Nucleophilic substitution of 2 with 3
.
Entry
1
Binucleophile
Product(s)
2
3
4

590
R. Ranjbar-Karimi, M. Mousavi / Journal of Fluorine Chemistry 131 (2010) 587–591
Table 1 (Continued )
Entry
5
Binucleophile
Product(s)
primary amine site, reflecting the less steric hindrance around the
primary amine over the secondary amine and then intramolecular
analyses for C, H, and N were performed using Heraeus CHN-O-
Rapid analyzer. The 13C NMR spectra were recorded at 75 or
125 MHz. The 19F NMR spectra were recorded at 470 MHz. In the
19F NMR spectra, upfield shifts were quoted as negative and
referenced to CFCl3. Mass spectra were taken by a Micromass
Platform II: EI mode (70 eV). Medium pressure (‘flash’) column
chromatography was performed using silica (Merck #60). Silica
plates (Merck) were used for TLC analysis.
cyclization.
A small amount (5%) of 4g formed from the
intramolecular cyclization of 4e.
The [6,6,6] fused ring system 4h was synthesized from the
reaction of 2 with 2-aminothiophenol 3e (Table 1). Cyclization
processes could also be affected by microwave heating, and in a
much shorter reaction time, a similar yield of 4h was obtained from
2 and 3e. The acceleration of reactions by microwave results from
material-wave interactions leading to thermal effects connected to
the intervention of ‘‘hot spots’’ (localized microscopic high
temperatures) and specific (non-thermal) effects [17]. A small
amount (4%) of 4i product was identified by 19F NMR and GC–MS
analysis but could not be isolated. Purification of 4h was achieved
by recrystallization of the crude product mixture from n-hexane/
ethyl acetate. Identification of 4h and 4i followed from 19F NMR
analysis in which the resonance attributed to fluorine located at
ortho to ring nitrogen had a chemical shift of À91.19 and
À106.13 ppm for 4h and 4i, respectively, similar to the shifts
observed for the analogous systems.
The structures of all [6,6] and [6,6,6]-fused ring systems were
confirmed by 13C NMR analysis. For example, comparisons of the
published 13C NMR data of 6,7-difluoro-1,4-dimethyl-1,2,3,4-
tetrahydropyrido[2,3-b]pyrazine-8-carbonitrile of which structure
was proved unambiguously by X-ray crystallography [6] (C-2b
142.0; C-3b 133.5 ppm) and other similar compounds [4,5] with 4a
(C-2b 146.1; C-3b 133.1 ppm) confirm the structure of 4a.
4.1. 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 (15 mmol) was added to the mixture of 3
(5 mmol) in acetonitrile (150 mL) under argon. Then 2 (2.5 mmol)
was added and the resulting solution was refluxed at 95 8C 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 (50 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.
4.1.1. 2-(6,7-Difluoro-2,3-dihydro-8-(phenylsulfonyl)pyrido-[2,3-
b]pyrazin-4(1H)-yl)ethanol 4a
Sodium carbonate (1.26 g, 15 mmol), 2-(2-aminoethylami-
no)ethanol 3a (0.52 g, 5 mmol), 4-phenylsulfonyl tetrafluoropyr-
idine 2 (0.72 g, 2.5 mmol) and acetonitrile (150 mL) gave an oily
product that was purified by column chromatography on silica gel
(ethyl acetate/hexane, 1:3) gave 2-(6,7-difluoro-2,3-dihydro-8-
(phenylsulfonyl)pyrido-[2,3-b]pyrazin-4(1H)-yl)ethanol 4a and 2-
(6,7-difluoro-3,4-dihydro-8-(phenylsulfonyl)pyrido[2,3-b]pyra-
zin-1(2H)-yl)ethanol 4b. 4a: 0.36 g (42%), yellow solid; mp: 152–
3. Conclusion
In conclusion, we showed that 4-phenylsulfonyl tetrafluor-
opyridine can successfully react with
a variety of unequal
154 8C. 13C NMR (CDCl3):
d (ppm) 35.48 (s, CH2NH2), 41.68 (s,
bidentate nucleophiles. The regioselectivity of nucleophilic sub-
stitution in this process may be explained by the high nucleophi-
licity of the secondary or primary amino groups and by the
activating influence of pyridine ring nitrogen that significantly
activates the ortho and para sites to itself. In contrast, the aromatic
unequal bidentate nucleophiles such as 2-aminothiophenol, the
major product is most likely formed from the initial attack of the S-
nucleophile and subsequent cyclization. From this investigation, it
was revealed that difluorinated tetrahydropyrido[3,4-b][1,4]oxa-
zine, thiazine and pyrazine scaffolds were synthesized very readily
by a one-pot annelation reaction.
CH2N), 58.62 (s, CH2N), 59.31 (s, CH2O), 124.96 (m, C-8), 127.85 (s,
3
Ar-C), 129.01 (s, Ar-C), 133.12 (d, JCF = 7.3 Hz, C-3b), 132.77 (dd,
1JCF = 284.2 Hz, 2JCF = 30.7 Hz, C-7), 134.21 (s, Ar-C), 141.13 (s, Ar-
3
1
C), 146.17 (d, JCF = 16.2 Hz, C-2b), 147.30 (dd, JCF = 251.6 Hz,
2JCF = 16.5 Hz, C-6). 19F NMR (CDCl3):
d
(ppm) À154.08 (d,
3JFF = 27.9 Hz, 1F, F-7), À92.87 (d, JFF = 27.9 Hz, 1F, F-6). MS (EI),
3
m/z (%) = 355 (M+, 100), 310 (25), 214 (30). Anal. Calcd for
C
15H15N3F2O3S: C, 50.7; H, 4.2; N, 11.8. Found: C, 50.8; H, 4.3; N,
11.8. 4b: 0.31 g (36%), yellow solid; mp 113–116 8C. 13C NMR
(CDCl3): (ppm) 38.93 (s, CH2OH), 46.70 (s, CH2N), 52.31 (s, CH2N),
60.70 (s, CH2N), 127.17 (s, Ar-C), 127.18 (s, Ar-C), 129.30 (s, Ar-C),
d
3
2
115.75 (d, JCF = 15.5 Hz, C-3b), 131.20 (dd, JCF = 18.2 Hz,
4. Experimental
3JCF = 2.4 Hz, C-8), 134.21 (s, Ar-C), 140.69 (dd, JCF = 298.4 Hz,
1
All solvents were dried using the literature procedures and
distilled before use. The reactions were carried out under an
atmosphere of argon unless otherwise specified. The elemental
2JCF = 23.0 Hz, C-7), 141.50 (s, Ar-C), 128.67 (d, 3JCF = 2.9 Hz, C-2b),
140.67 (dd, 1JCF = 240.1 Hz, 2JCF = 16.6 Hz, C-6). 19F NMR (CDCl3):
d
(ppm) À159.83 (d, 3JFF = 25.5 Hz, 1F, F-7), À108.33 (d,

R. Ranjbar-Karimi, M. Mousavi / Journal of Fluorine Chemistry 131 (2010) 587–591
3
591
3JFF = 25.5 Hz, 1F, F-6). MS (EI), m/z (%) = 355 (M+, 100), 310 (20),
214 (40). Anal. Calcd for C15H15N3F2O3S: C, 50.7; H, 4.2; N, 11.8.
Found: C, 50.8; H, 4.3; N, 11.8.
(s, Ar-C), 136.31 (d, JCF = 18.0 Hz, C-2b), 141.21 (s, Ar-C), 142.01
(dd, 2JCF = 8.1 Hz, 3JCF = 3.1 Hz, C-8). (dd, 1JCF = 220.8 Hz,
2JCF = 11.6 Hz, C-6), 159.85. 19F NMR (CDCl3):
d
(ppm) À157.40
3
3
(d, JFF = 25.9 Hz, 1F, F-7), À108.42 (d, JFF = 25.9 Hz, 1F, F-6). MS
(EI): m/z (%) = 354 (M+, 40), 311 (100), 214 (30), 171 (25). Anal.
Calcd for C15H16N4F2O2S: C, 50.8; H, 4.5; N, 15.8. Found: C, 50.9; H,
4.6; N, 15.9.
4.1.2. 2-(6,7-Difluoro-2,3-dihydro-8-(phenylsulfonyl)pyrido-[3,2-
b][1,4]oxazin-4-yl)ethanol 4c
Sodium carbonate (1.26 g, 15 mmol), diethanolamine 3b
(0.52 g, 5 mmol), 4-phenylsulfonyl tetrafluoropyridine 2 (0.72 g,
2.5 mmol) and acetonitrile (150 mL) gave an oily product that was
purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:3) gave 2-(6,7-difluoro-2,3-dihydro-8-(phenylsulfonyl)-
pyrido-[3,2-b][1,4]oxazin4-yl)ethanol 4c, 0.59 g (67%), yellow
4.1.5. 4-Benzenesulfonyl-2,3-difluoro-5H-benzo[b]pyrido[3,2-
e][1,4]thiazine 4h
Sodium carbonate (1.26 g, 15 mmol), 2-aminobenzenethiol 3e
(0.62 g, 5 mmol), 4-phenylsulfonyl tetrafluoropyridine 2 (0.72 g,
2.5 mmol) and acetonitrile (150 mL) gave an oily product that was
purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:5) gave 4-benzenesulfonyl-2,3-difluoro-5H-benzo[b]-
pyrido[3,2-e][1,4]thiazine 4h, 0.63 g (46%), brown solid; mp 137–
solid; mp 123–124 8C. 13C NMR (CDCl3):
d (ppm) 46.43 (s,
CH2N), 51.53 (s, CH2N), 60.64 (s, CH2OH), 64.27 (s, CH2O),
128.11 (s, Ar-C), 129.03 (s, Ar-C), 129.19 (s, Ar-C), 129.52 (d,
1
2
3JCF = 22.9 Hz, C-3b), 131.37 (dd, JCF = 256.0 Hz, JCF = 32.0 Hz, C-
7), 133.98 (s, Ar-C), 134.09 (d, 3JCF = 23.0 Hz, C-2b), 141.00 (s, Ar-C),
139 8C, 13C NMR (CDCl3):
d (ppm) 110.10 (s, Ar-C), 115.69 (s, Ar-C),
119.03 (s, Ar-C), 127.44 (s, Ar-C), 130.55 (m, C-3b), 132.32 (s, Ar-C),
141.14 (dd, 2JCF = 7.4 Hz, 3JCF = 3.5 Hz, C-8), 144.35 (dd,
1JCF = 234.1 Hz, JCF = 16.2 Hz, C-6). 19F NMR (CDCl3):
d
(ppm)
132.56 (m, C-8), 137.25 (s, Ar-C), 138.41 (s, Ar-C), 139.72 (s, Ar-C),
2
1
2
À160.08 (d, 3JFF = 25.4 Hz, 1F, F-7), À97.13 (d, 3JFF = 25.4 Hz, 1F, F-
6). MS (EI): m/z (%) = 356 (M+, 15), 311 (30), 215 (50). Anal. Calcd
for C15H14N2F2O4S: C, 50.6; H, 4.0; N, 7.7. Found: C, 50.5; H, 3.9; N,
7.8.
139.9 (dd, JCF = 272.8 Hz, JCF = 26.4 Hz, C-7), 140.92 (s, Ar-C),
3
1
142.26 (d, JCF = 12.7 Hz, C-2b), 144.37 (dd, JCF = 262.1 Hz,
2JCF = 17.5 Hz, C-6), 144.56 (s, Ar-C). 19F NMR (CDCl3):
(ppm)
d
À138.62 (d, 3JFF = 24.9 Hz, 1F, F-7), À91.19 (d, 3JFF = 24.9 Hz, 1F, F-
6). MS (EI): m/z (%) = 376 (M+, 51), 375 (60), 236 (35), 300 (41), 255
(20), 156 (35). Anal. Calcd for C17H10N2F2O2S2: C, 54.2; H, 2.7; N,
7.4. Found: C, 54.3; H, 2.6; N, 7.5.
4.1.3. 6,7-Difluoro-3,4-dihydro-8-(phenylsulfonyl)-2H-pyrido-[3,2-
b][1,4]oxazine 4d
Sodium carbonate (1.26 g, 15 mmol), 2-aminoethanol 3c
(0.30 g, 5 mmol), 4-phenylsulfonyl tetrafluoropyridine 2 (0.72 g,
2.5 mmol) and acetonitrile (150 mL) gave an oily product that was
purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:3) gave 6,7-difluoro-3,4-dihydro-8-(phenylsulfonyl)-
2H-pyrido[3,2-b][1,4]oxazine 4d, 0.43 g (56%), brown oil; 13C
Acknowledgement
The authors wish to thank Rafsanjan Vali-e-Asr University
(Rafsanjan, Iran) for the partial support of this work.
NMR (CDCl3): d (ppm) 38.80 (s, CH2NH), 64.76 (s, CH2O), 119.90 (d,
References
3JCF = 15.2 Hz, C-3b), 127.43 (s, Ar-C), 127.44 (s, Ar-C), 127.95 (d,
3JCF = 6.5 Hz, C-8), 129.41 (s, Ar-C), 134.60 (s, Ar-C), 136.28 (dd,
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1JCF = 257.4 Hz, JCF = 29.2 Hz, C-7), 139.54 (dd, JCF = 229.3 Hz,
2JCF = 19.1 Hz, C-6), 140.92 (s, Ar-C), 142.80 (d, 3JCF = 13.0 Hz, C-2b).
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3
d
(ppm) À147.60 (d, JFF = 24.6 Hz, 1F, F-7),
À105.68 (d, 3JFF = 24.6 Hz, 1F, F-6). MS (EI): m/z (%) = 312 (M+, 43),
311 (100), 171 (35). Anal. Calcd for C13H10N2F2O3S: C, 50.0; H, 3.2;
N, 9.0. Found: C, 50.1; H, 3.2; N, 8.9.
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4.1.4. 2-(6,7-Difluoro-3,4-dihydro-8-(phenylsulfonyl)pyrido[2,3-
b]pyrazin-1(2H)-yl)ethanamine 4e
Sodium carbonate (1.26 g, 15 mmol), diethylene triamine 3d
(0.51 g, 5 mmol), 4-phenylsulfonyl tetrafluoropyridine 2 (0.72 g,
2.5 mmol) and acetonitrile (150 mL) gave an oily product that was
purified by column chromatography on silica gel (ethyl acetate/
hexane, 1:4) gave 2-(6,7-difluoro-2,3-dihydro-8-(phenylsulfonyl)-
pyrido[2,3-b]pyrazin-4(1H)-yl)ethanamine 4e, 0.72 g (52%), yel-
low solid; mp 143–145 8C,
d (ppm) 40.46 (s, CH2NH2), 40.83
(s, CH2N), 47.15 (s, CH2N), 47.84 (s, CH2N), 127.31 (s, Ar-C), 127.41
3
(s, Ar-C), 128.71 (s, Ar-C), 130.37 (d, JCF = 20.2 Hz, C-3b), 126.81
1
2
(dd, JCF = 232.1 Hz, JCF = 31.5 Hz, C-7), 134.82, (s, Ar-C), 135.75