Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ6-sulfanyl-Substituted Pyridines

Article abstract of DOI:10.1002/anie.201605008

Although there are ways to synthesize ortho-pentafluoro-λ⁶-sulfanyl (SF₅) pyridines, meta- and para-SF₅-substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF₅-substituted pyridines and SF₅-substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF₄Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF₅-pyridines. After enabling the synthesis of an SF₅-substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an S_NAr pathway. This methodology provides access to a variety of previously unavailable SF₅-substituted pyridine building blocks.

Full text of DOI:10.1002/anie.201605008

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605008
German Edition: DOI: 10.1002/ange.201605008
Halogenation
Importance of a Fluorine Substituent for the Preparation of meta- and
6
para-Pentafluoro-l -sulfanyl-Substituted Pyridines
Mikhail Kosobokov, Benqiang Cui, Andrii Balia, Kohei Matsuzaki, Etsuko Tokunaga,
Norimichi Saito, and Norio Shibata*
Abstract: Although there are ways to synthesize ortho-penta-
Owing to the success of trifluoromethylpyridines on the
6
[5,6]
fluoro-l -sulfanyl (SF ) pyridines, meta- and para-SF -substi-
market
and the inherent recent difficulty in developing
5
5
tuted pyridines are rare. We disclose herein a general route for
their synthesis. The fundamental synthetic approach is the same
new small drugs by the current strategies, we became
6
interested in pentafluoro-l -sulfanyl (SF )-substituted pyri-
5
[8]
as reported methods for ortho-SF -substituted pyridines and
dines as novel potential building blocks for pharmaceuticals.
5
SF -substituted arenes, that is, oxidative chlorotetrafluorination
The SF group has garnered substantial attention in recent
5
5
of the corresponding disulfides to give pyridylsulfur chlorote-
years for specialty materials, pharmaceuticals, and agrochem-
icals. Owing to its extreme combination of lipophilicity,
[
9]
trafluorides (SF Cl-pyridines), followed by chloride/fluoride
4
exchange with fluorides. However, the trick in this case is the
presence on the pyridine ring of at least one fluorine atom,
which is essential for the successful transformation of the
bulkiness, and electron-withdrawing properties, SF has been
5
[
9]
named a “super CF group”. Substantial efforts in synthetic
3
SF chemistry have made simple SF -substituted aromatic
5
5
[9]
disulfides into m-and p-SF -pyridines. After enabling the
compounds readily available. However, the preparation of
SF -substituted pyridines remains a challenge. SF -substi-
5 5
5
[
10]
synthesis of an SF -substituted pyridine, ortho-F groups can
5
be efficiently substituted by C, N, S, and O nucleophiles
tuted benzenes can be prepared on an industrial scale by the
[
11]
through an S Ar pathway. This methodology provides access
direct fluorination of aryl disulfides or by the procedure
N
[
12]
to a variety of previously unavailable SF -substituted pyridine
developed by Umemoto et al.
involving the oxidative
5
building blocks.
chlorotetrafluorination of aryl disulfides to give arylsulfur
chlorotetrafluorides (SF Cl-arenes), followed by a chloride/
4
F
luorinated aromatic heterocyclic compounds containing
fluoride exchange reaction with fluoride; however, this
approach has not been successful for heteroaromatic systems,
for which different strategies are used. In 2015, Kanishchev
and Dolbier reported the first general method for the
one or two nitrogen atom(s) in the aromatic ring have gained
the attention of medicinal chemists owing to their distinctive
physical, chemical, and biological properties arising from the
reduced basicity of the nitrogen atom(s) as a result of the
strongly electron withdrawing nature of fluorine and fluori-
[13]
synthesis of ortho-SF -substituted pyridines on the basis of
5
[
10b]
the method described by Umemoto et al.,
in which 2,2’-
[1]
nated substituent(s). Fluorine substituents and fluorinated
functional groups also modulate the lipophilicity/hydrophi-
licity balance of the parent heteroaromatic compounds to
improve the bioavailability of drugs.
and trifluoromethylpyridines are massively sought after
building blocks for the preparation of pharmaceuticals and
dipyridyl disulfides interacted with the KF/Cl /MeCN system
2
to afford SF Cl-pyridines. For the further transformation of
4
these sulfur chlorotetrafluorides into SF -pyridines, silver
5
[
1g,2]
[3]
Fluoropyridines
fluoride (AgF) was found to be the most suitable reagent
(Scheme 1).
[
4]
However, m- and p-pyridine disulfides failed to form
[
10b]
agrochemicals. In particular, CF -substituted pyridines occur
SF Cl-pyridines under the same conditions.
Very recently,
3
4
widely in marketed drugs; the HIV protease inhibitor
tipranavir (Aptivus) is a representative example (see Fig-
ure SI-1 in the Supporting Information). Most widespread in
Carreira and co-workers reported the preparation of 3-SF -
5
[5]
[10a]
substituted quinolines, quinolones, and pyridones.
The
method involves an aldol reaction of an SF -substituted
5
biologically active compounds of this type is meta-CF
acetate enolate with aldehydes, followed by ring-formation
3
[
5,6]
substitution of the pyridine ring (see Figure SI-1 ), followed
steps. However, to the best of our knowledge, there is no
[
7]
[10,14]
by ortho- and para-CF substitution.
straightforward route to m- and p-SF -pyridines.
Herein
3
5
we disclose a general method for the preparation of m- and p-
[*] Dr. M. Kosobokov, B. Cui, Dr. A. Balia, K. Matsuzaki, E. Tokunaga,
SF -pyridines. First, the presence of at least one fluorine atom
5
Prof. Dr. N. Shibata
Department of Nanopharmaceutical Sciences
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
in the pyridine ring effectively reduces the basicity of the
nitrogen atom, thus inhibiting the major decomposition
pathway. Second, this fluorine substituent induces greater
stability of the SF Cl moiety. Moreover, a CÀF bond at the
4
ortho position of the pyridine ring can be readily activated
N. Saito
towards nucleophilic aromatic substitution (S Ar) under
N
Pharmaceutical Division, Ube Industries, Ltd.
Seavans North Bldg, 1-2-1 Shibaura, Minato-ku, Tokyo 105-8449
suitable conditions, thus providing straightforward access to
(
Japan)
various SF -pyridine building blocks (Scheme 1).
5
We first attempted to find the reasons for decomposition
during the oxidative chlorotetrafluorination of m- and p-
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605008.
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Table 1: Preparation of SF Cl-pyridines 2.
4
Scheme 1. Synthesis of SF -substituted pyridines and quinolines.
Bn=benzyl, Tf=trifluoromethanesulfonyl.
5
[a]
[a]
Entry
1
2, yield [%]
No. of F atoms
on ring
3, yield [%]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
–
–
3
0
0
0
0
2
1
1
1
2
1
2
0
0
0
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
15
trace
67
70
–
–
–
–
–
–
–
pyridine disulfides
tions.
1
under Umemoto/Dolbier condi-
After stirring pyridine disulfides 1 with excess
chlorine and dry potassium fluoride at room temperature for
[
10b,12]
20
78
77
76
74
90
68
95
–
[b]
b]
[
4
8 h, we carefully examined the crude reaction mixture by
1
9
[b]
[b]
F NMR spectroscopy (Table 1). In most cases, degradation
2
of the C(sp )ÀS bond to furnish SF Cl was detected (Table 1,
5
[
[
[
b]
b]
c]
[
15]
entries 1–4). We noticed that the distribution of decom-
position products strongly depended on the original substitu-
ents on the pyridine ring. The reaction of unsubstituted 3,3’-
pyridine disulfide 1a, “m-pyridine”, did not provide the
desired pyridine-SF Cl 2a; instead, the SF -containing com-
10
11
12
13
6
23
–
–
–
4
3
14
pound 3a (15%) was detected (Table 1, entry 1). The steri-
cally demanding and electron-rich disulfide 1b did not
provide any detectable products (entry 2). When the reaction
was examined using 2,6-dimethylpyridine 1c, the desired
19
[
a] Yield determined by F NMR spectroscopy with HFB as an internal
standard. [b] Yield of the isolated product. [c] Total yield for a mixture of
2k and cis-2k isomers.
SF Cl-pyridine product 2c was detected in only 3% yield
4
[
10b]
along with SF -pyridine product 3c in 67% yield (entry 3).
(Table 1, entries 12 and 13).
The nonsubstituted p-pyridine
3
The yield of desired SF Cl-pyridine product 2d was increased
disulfide 1n decomposed entirely to release SF Cl (entry 14),
4
5
to 20% with the 2,6-dichlororopyridine derivative 1d,
a result similar to that observed with the meta-substituted
analogue (entry 1). Comparison of the results of the reactions
of m-sulfur-substituted pyridines 1a, 1c, 1d, 1e, 1 f, and 1g
and p-sulfur-substituted pyridines 1k, 1l, and 1n with H, Me,
Cl, and F substituents led to initial conclusions on the fluorine
although undesired SF -pyridine 3d was the major compound
3
obtained, in 70% yield. We next examined the reaction of 2,6-
difluoropyridine 1e. Gratifyingly, the desired SF Cl-pyridine
4
product 2e was obtained exclusively in 78% yield (Table 1,
entry 5). Thus, ortho-fluorine substitution led to a large
increase in the yield of 2 as compared to ortho-chlorine
substitution (entries 4 and 5).
effect on the formation of SF Cl-pyridines.
4
The oxidative chlorotetrafluorination reaction of fluori-
1
9
nated pyridine disulfides proceeded very cleanly. F NMR
Encouraged by this result, we further attempted the
reaction with fluorinated pyridine disulfides 1 f–h. As
spectra showed only a single peak for SF Cl-pyridine products
2. After filtration and evaporation of the solvent, compounds
4
expected, the corresponding SF Cl products 2 f–h were
2 were isolated. SF Cl-pyridines 2 are highly unstable under
4
4
produced in good yields (74–77%; Table 1, entries 6–8).
Fluorine substitution was also effective for the reaction of
para-substituted pyridine disulfides. Disulfides of 2,6-
difluoropyridine, 2-fluoropyridine, and 3,5-difluoropyridine
humidity. When they enter into contact with glass vessels, they
slowly decompose and cause the perceptible erosion of glass
within 1 h. However, if they are stored in Teflon vessels under
an inert atmosphere, SF Cl-pyridines 2 are stable for at least
4
were very nicely converted into the corresponding p-SF Cl-
2 weeks at room temperature.
4
pyridine products 2i–k in 68–95% yield (Table 1, entries 9–
Among the SF Cl-pyridine compounds 2 prepared, the
4
1
1
1). On the other hand, the para-substituted chloropyridines
l and 1m did not give the desired compounds, and SF3-
3,5-difluoro compound 2k existed as a mixture of isomeric
tetrafluorosulfanyl chlorides in a 2:1 trans/cis ratio, whereas
pyridines 3 were detected as by-products in low yields
for the other SF Cl compounds 2, no cis isomer was observed.
4
2
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[
a]
The compound cis-2k had a peculiar appearance in the
F NMR spectrum (see Figure SI-2). This result implies that
Table 2: Preparation of SF -pyridines.
5
1
9
the nearest two fluorine atoms even stabilize the unstable cis
conformation of the SF Cl functionality (see discussion below
4
and Figure SI-3). A similar phenomenon was reported for
[
12]
other SF -arene compounds.
5
The effect of fluorine on the successful oxidative chloro-
tetrafluorination of meta- and para-substituted pyridine
disulfides 1 can be explained as follows. First, a strong
electron-withdrawing effect of fluorine effectively reduces the
basicity of the nitrogen atom of pyridine, and thus inhibits
[
a] Yields are for the isolated product after distillation. Yields determined
intermolecular decomposition between the SF Cl-pyridine 2
4
1
9
by F NMR spectroscopy are given in parentheses. [b] The reaction was
examined with dichloride 2d instead of fluoride 2e.
and the starting materials 1 (and/or product 2) to form SF -
3
[
16]
pyridine products 3 (Scheme 2a,b).
The reported pKa
SF -pyridines 4 were isolated as clear liquids in 35–41% yield
5
1
9
by distillation. The yields calculated by F NMR spectrosco-
py for SF -pyridines 4 were quite high. The low yields of the
5
isolated products can be explained by the rather small
reaction scale (10 mmol) and the high volatility of the
products. Product 4j was formed in very low yield because
the starting SF Cl-pyridine 2j is unstable under these reaction
4
conditions. The replacement of the SF Cl moiety of 2j with
4
fluoride provided 2,4-difluoropyridine and 2-chloro-4,6-
difluoropyridine as by-products (detected by NMR spectros-
Scheme 2. a) Potential decomposition pathway of SF Cl-pyridines 2 to
4
SF -pyridines 3 as promoted by 1. b) A fluorine substituent in 1 reduces
3
copy and GC–MS). The SF Cl-pyridine dichloride 2d
the nucleophilicity of the nitrogen atom. c) A fluorine substituent
4
increases the stability of the SF Cl moiety.
(Table 1, entry 4) could be used for this transformation, but
4
instead of corresponding SF -pyridine dichloride, difluoride
5
4
e was obtained in 24% yield by additional chloride–fluoride
values of pyridine, 2-fluoropyridine, 2-chloropyridine, and
exchange at the two ortho positions. This result also supports
the use of fluoro-substituted pyridines rather than chlorides.
The chemistry of 2-fluorinated pyridines (ortho-fluori-
nated pyridines) has gained great attention in recent years.
Even though the strong CÀF bond stabilizes the structure,
3
-fluoropyridine are 5.23, À0.44, 0.49, and 2.97, respec-
[17]
tively. Hence, this effect is maximized by ortho-fluorine
substitution. Furthermore, the electron-withdrawing effect of
fluorine also stabilizes the hypervalent sulfur atom, which
possesses a characteristic three-center–four-electron (3c-4e)
bond (Scheme 2c).
not clear.
these compounds readily react with nucleophiles under
[
18,19]
The formation of by-product SF Cl is
suitable conditions through S Ar substitution to provide
5
N
[
3,20]
2-substituted pyridine derivatives.
of 2-fluoropyridines has also been studied.
The selective lithiation
[
21]
DFT calculations were next attempted. The three com-
pounds 2i, 2k, and 2n were selected, and their bond lengths,
charge distributions, and electrostatic potential maps were
calculated (DFT/B3LYP/6-31G** level of theory; see Fig-
ure SI-3). The lengths of the SÀCl bonds of 2i, 2k, and 2n are
Thus, our
fluorinated SF -pyridines 4 should be versatile building
5
blocks. The electron-deficient SF group in the pyridine ring
5
[
22]
should facilitate such transformations.
We demonstrated
the further derivatization of 2-fluorinated SF -pyridines 4.
5
2
.135, 2.134 (shortest), and 2.142 ꢀ. The lengths of the
Parent SF -pyridines 4 were employed as substrates for
5
2
SÀC(sp ) bonds of 2i, 2k, and 2n are 1.829, 1.822 (shortest),
and 1.826 ꢀ, respectively. The sulfur atomic charges (Mul-
liken) of 2i, 2k, and 2n are 1.455, 1.474 (largest), and 1.449,
respectively. These values suggest that fluorine substitution in
nucleophilic substitution reactions with C-, S-, N-, and
O-based nucleophiles. All reactions proceeded very smoothly
to give S Ar substitution products 5 in good to excellent
N
yields (Table 3). A regioselective S Ar reaction of the 2,6-
N
the meta position most stabilizes the SF Cl moiety, in good
difluorinated SF -pyridine 4e furnished 6-substituted
4
5
agreement with the isolation of the unstable cis somer 2k (see
2-fluoro-3-SF -pyridines 5 selectively in high yields of 72–
5
Figure SI-2). The mapping of the electrostatic potential on the
89%. This regioselectivity can be explained by steric hin-
surface of SF Cl shows color similarity of 2i and 2k, whereas
drance by the SF moiety; thus, nucleophiles react predom-
4
5
the Cl group on 2n is very different.
inantly at the
The m- and p-SF Cl-pyridines 2 were smoothly converted
6-position. X-ray crystallographic analysis of 5l
(CCDC 1481076) and 5n (CCDC 1481241) provided not
4
into the target SF -pyridine derivatives 4 by simple heating
5
with anhydrous AgF without a solvent (Table 2). For the full
only the first 3D structures of m- and p-SF -substituted
5
conversion of m-SF Cl-pyridines, heating for 48 h at 1008C
pyridines, but also confirmed the regioselective substitution
4
was required. For p-SF Cl-pyridines, a temperature of 1208C
of 4e to give 5l (see Figure SI-4).
4
was needed for complete chloride–fluoride exchange. The
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Table 3: S Ar reaction of SF -pyridines with C-, S-, N-, and O-based
N
5
[
a]
nucleophiles.
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4
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Acknowledgments
This research was partially supported by the Platform for
Drug Discovery, Informatics and Structural Life Science of
MEXT, Japan and the Japan Agency for Medical Research
and Development (AMED), the Advanced Catalytic Trans-
formation (ACT-C) program of the JST Agency, and the
Kobayashi International Foundation. B.C. thanks the Chinese
Scholarship Council.
Keywords: chlorination · fluorination · fluorine ·
nitrogen heterocycles · pentafluorosulfanyl substitution
4
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terization or experimental procedures were specified. In our
hands, the action of IF on 2,3,5,6-tetrachloro-4-pyridinethiol at
5
room temperature gave 2,3,5,6-tetrachloro-4-iodopyridine as the
major product. We did not detect any trace of a SF fragment by
5
1
9
F NMR spectroscopy of the reaction mixture.
[15] The formation of gaseous products, such as SOF (s, + 77 ppm),
2
SO F (s, + 34 ppm), and SF Cl (p, + 65 ppm, J = 150 Hz, 1F; d,
2
2
5
1
9
+ 125 ppm, J = 150 Hz, 4F), was detected in F NMR spectra of
the reaction mixtures.
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a
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[
[
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Received: May 22, 2016
[
14] In the study reported in Ref. [10c], 2,3,5,6-tetrachloro-4-penta-
fluorosulfanylpyridine was obtained from the reaction of 2,3,5,6-
Revised: June 19, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Halogenation
M. Kosobokov, B. Cui, A. Balia,
K. Matsuzaki, E. Tokunaga, N. Saito,
N. Shibata*
&&&& — &&&&
Importance of a Fluorine Substituent for
the Preparation of meta- and para-
Pentafluoro-l -sulfanyl-Substituted
Pyridines
It had to be you… A general route for the
case, however, at least one fluorine atom
on the pyridine ring is essential for the
success of the transformation. The fluo-
rine substituent can later be substituted
by a C, N, O, or S nucleophile (see
scheme).
6
synthesis of m- and p-SF -substituted
5
pyridines is disclosed. The fundamental
synthetic sequence is the same as those
reported for ortho-SF -substituted pyri-
5
dines and SF -substituted arenes. In this
5
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!