2-Polyfluoroalkyl thiopyrylium salts: Synthesis and reactions with nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2010.09.131

2-Polyfluoroalkylthiopyrylium salts have been synthesized by oxidative aromatization of 2-polyfluoroalkyl-2H-thiopyrans with triphenylmethane tetrafluoroborate. Nucleophilic addition of methanol, sodium azide, or urea to 2-trifluoromethylthiopyrylium tetrafluoroborate in a basic medium proceeds at the α-position to give the corresponding 2-substituted 6-trifluoromethyl-2H-thiopyrans whereas imidazoles, fluorine-containing 1,2,3-triazole, potassium thiolacetate, and sodium nitromethane afford mixtures of 2H- and 4H-thiopyrans. cis-Dihydroxylation of 6-trifluoromethyl-2-methoxy-2H- thiopyran affords the fluorine-containing thiohexenopyranoside derivative 8.

Full text of DOI:10.1016/j.tetlet.2010.09.131

Tetrahedron Letters 51 (2010) 6406–6409
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-Polyfluoroalkyl thiopyrylium salts: synthesis and reactions with nucleophiles
⇑
Sergiy A. Siry, Vadim M. Timoshenko
Institute of Organic Chemistry, NAS of Ukraine, Murmanska 5, 02094 Kyiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2010
Revised 8 September 2010
Accepted 27 September 2010
Available online 7 October 2010
2-Polyfluoroalkylthiopyrylium salts have been synthesized by oxidative aromatization of 2-poly-
fluoroalkyl-2H-thiopyrans with triphenylmethane tetrafluoroborate. Nucleophilic addition of methanol,
sodium azide, or urea to 2-trifluoromethylthiopyrylium tetrafluoroborate in a basic medium proceeds
at the a-position to give the corresponding 2-substituted 6-trifluoromethyl-2H-thiopyrans whereas imi-
dazoles, fluorine-containing 1,2,3-triazole, potassium thiolacetate, and sodium nitromethane afford mix-
tures of 2H- and 4H-thiopyrans. cis-Dihydroxylation of 6-trifluoromethyl-2-methoxy-2H-thiopyran
affords the fluorine-containing thiohexenopyranoside derivative 8.
Keywords:
Polyfluoroalkyl
Hetero-Diels–Alder reaction
Thiopyrylium
Ó 2010 Elsevier Ltd. All rights reserved.
Nucleophilic addition
Dihydroxylation
Thiopyrylium salts are known as six-membered heteroaromatic
compounds with a variety of applications because of their remark-
able photophysical and photochemical properties.1 Substances
with the thiopyrylium core have been investigated for the prepara-
tion of diverse photosensitive materials for both technical and
medical purposes.2 Being a highly reactive species, thiopyrylium
salts have found use as scaffolds in the synthesis of sulfur-contain-
ing heterocyclic compounds. The chemistry of thiopyrylium cat-
ions is relatively well studied and a number of substituted
derivatives,3 as well as an unsubstituted one,4 have been described.
However, no fluoroalkyl-containing thiopyrylium salt is known to
date. It has been well documented that the incorporation of fluo-
rine into a heterocycle may substantially modify the physicochem-
ical and biological properties of the compound.5 As a part of our
ongoing interest in fluorine-containing sulfur heterocycles6 we
report herein the synthesis of the first polyfluoroalkyl thiopyryli-
um salt and its reactivity toward nucleophiles.
One method employed for the synthesis of thiopyrylium salts
involves the aromatization of 2H-thiopyrans. Polyfluoroalkyl-con-
taining thiopyrans are easily obtained by thia-Diels–Alder reac-
tions of thiocarbonyl compounds.7 Trifluoromethyl-2H-thiopyran
was reported by Middleton8 who observed its formation during
the slow elimination of HF from the cycloadduct of trifluorothio-
acetyl fluoride and buta-1,3-diene. It has also been reported that
cycloaddition of tetrafluorothiopropionyl chloride with 2,3-dim-
ethylbuta-1,3-diene proceeds with spontaneous loss of hydrogen
chloride to afford 6-tetrafluoroethyl-3,4-dimethyl-2H-thiopyran.9
Taking into account that polyfluorothioalkanoyl chlorides 1 can
be easily obtained from the corresponding 1,1-dichloropolyfluoro-
alkyl benzylsulfides on a multigram scale (Scheme 1),9,10 we have
used these thiocarbonyl dienophiles for preparing fluoroalkyl
2H-thiopyrans, the starting compounds for syntheses of thiopyry-
lium salts.
The cycloaddition of thiocarbonyl chlorides 1a–c to buta-1,3-
diene proceeded rapidly: bubbling buta-1,3-diene through a violet
solution of compound 1 in an inert solvent at 0 °C caused decolor-
ation indicating the end of the reaction. The stability of the cyc-
loadducts formed depended on the length of the fluoroalkyl
chain. Trifluorothioacetyl chloride (1a) afforded a relatively stable
adduct 2 (92% yield) which was isolated and characterized. Chlo-
rides with longer fluoroalkyl chains (1b, RF = HCF2CF2) and (1c,
RF = H(CF2)4), gave directly, after evaporation of the mixture,
2H-thiopyrans 3b and 3c which were isolated after distillation in
55% and 80% yields, respectively (Scheme 2). Dehydrochlorination
of 2 to thiopyran 3a was achieved by heating a solution in DMF at
100 °C for 2 h. 6-Polyfluoroalkyl-2H-thiopyrans 3 are distillable
liquids, compounds 3a and 3c are stable enough for storage in a
freezer; compound 3b decomposed in one day.
RFCH(SBn)2
S
SO2Cl2
P2O5
or
RFCCl2SBn
Cl
RF
180 °C
RFCH2SBn
1a-c
RF = CF3 (a), HCF2CF2 (b), H(CF2)4 (c); Bn = CH2Ph
Scheme 1. Synthesis of polyfluorothioalkanoyl chlorides 1.9,10
⇑
Corresponding author. Tel.: +380 44 499 4938; fax: +380 44 573 2643.
E-mail address: vadim@ioch.kiev.ua (V.M. Timoshenko).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.131

S. A. Siry, V. M. Timoshenko / Tetrahedron Letters 51 (2010) 6406–6409
6407
the presence of K2CO3. Compounds 5a and 5b were isolated in
61% and 90% yields, respectively, after work-up of the reaction
mixtures with purities >95%. Treatment of 4b with primary or sec-
ondary amines (ethylamine, toluidine, benzylamine, morpholine)
immediately led to the appearance of a deep-violet color and re-
sulted in complex mixtures. The color of the reaction mixture
may be the result of the formation of deeply-colored dienylammo-
nium salts as one of the products, as reported for similar reactions
of an unsubstituted thiopyrylium salt.14 However, with heterocy-
cles, such as imidazole and benzimidazole, salt 4b reacted
smoothly to produce mixtures of the isomeric 2H- and 4H-thiopy-
rans 5c,6c and 5d,6d, respectively, with predominant formation of
the 2H-isomers.
S
ii
i
RF
Cl
Cl
RF
S
1a-c
2: RF=CF3, 92%
iii or iv
S
RF
S
RF
A
3a-c
4a-c
1,3: RF = CF3 (a), H(CF2)2 (b), H(CF2)4 (c);
4: RF = CF3, A = ClO4 (a) (55% yield);
RF = CF3, A = BF4 (b) (81% yield);
Another azaheterocycle, which was found to add to salt 4b, was
4-(x-H-hexafluoropropyl)-5-tosyl-1,2,3-triazole, the potassium
RF = H(CF2)2, A = BF4 (c) (60% yield);
RF = H(CF2)4, A = ClO4 (d) (45% yield)
salt of which15 gave a mixture of isomers with little preference
for the 4H-isomer 6e over the 2H-isomer 5e. Only a 2H-adduct
was obtained in the reaction of 4b with urea. The isolated yield
of 5f was only 33% because of losses during crystallization,
although in the reaction mixture it was the sole product. The reac-
tion of 4b with sodium azide afforded exclusively the 2-azido-2H-
thiopyran 5g in a 90% yield. The regioselectivity of the addition of
an S-nucleophile such as potassium thiolacetate was insignificant,
the ratio of 5h:6h being 3:1.
Scheme 2. Reagents and conditions: (i) buta-1,3-diene, Et2O, 0 °C; (ii) for RF = CF3,
DMF, 100 °C; (iii) SO2Cl2/CHCl3, À50 °C, then HClO4, À50 °C; (iv) Ph3CBF4, CH3CN,
0 °C.
Two synthetic approaches to thiopyrylium salts by aromatiza-
tion of 2H-thiopyrans 3 were investigated. Initially the known pro-
tocol11 consisting of oxidation of 2H-thiopyrans with sulfuryl
chloride followed by treatment of the intermediate formed with
perchloric acid was studied. Thiopyrylium perchlorates 4a and 4d
were obtained by this procedure as fairly insoluble crystals with
melting points of 130 °C and 205 °C, respectively, but perchlorates
are potentially explosive at elevated temperatures and must be
handled with precautions. Therefore, we decided to prepare less
dangerous and more soluble salts with the tetrafluoroborate coun-
terion. Reactions of thiopyrans 3a,b with trityl tetrafluoroborate in
CH3CN at 0 °C afforded salts 4b,c in good yields12 (Scheme 2).
Tetrafluoroborates 4b,c are stable crystalline compounds and
are moderately soluble in CH3CN and 1,2-dimethoxyethane
(DME). They are hydrolytically unstable and decompose in wet sol-
vents in contrast to unsubstituted thiopyrylium salts, which show
a remarkable stability with respect to H2O.4 This indicated the high
reactivity of the 2-polyfluoroalkyl substituted thiopyrylium nu-
cleus, hence the electrophilic properties of the trifluoromethyl
derivative 4b were investigated.
Among the C-nucleophiles used, the reaction of 4b with sodium
nitromethane gave a mixture of isomers 5i and 6i in a ratio of 1:2
in an 88% combined yield. When potassium cyanide was applied, a
complex mixture was formed; NMR and GC–MS analyses allowed
the assignment of the products as compounds 7a–c in the ratio
of 0.8:0.2:1 (Scheme 3). Attempts to separate this mixture by
chromatography on SiO2 led to the isolation of a 2:1 mixture of
6-(trifluoromethyl)-2H-thiopyran-2-carbonitrile (7a) and 2-(tri-
fluoromethyl)-2H-thiopyran-6-carbonitrile (7b) in a 10% overall
yield. The 1H NMR spectrum of isomer 7a displayed a similar
pattern to that found for the other 2H-adducts 5. The formation
of isomer 7b can be explained as a result of a 1,5-proton shift in
7a. The structure of 7b was established by the presence, in its 1H
and 19F NMR spectra, of the characteristic signal of the CF3–CH
3
moiety (a quintet at 4.1 ppm with JHF = 2JHH = 7.7 Hz in its 1H
3
NMR and a doublet at À76 ppm with JFH = 7.7 Hz in its 19F NMR
spectra).
It is known that thiopyrylium salts can be attacked by nucleo-
philes at the two reactive
Next, we examined the potential of adduct 5a as a precursor for
thioglycoside synthesis. Selective cis-dihydroxylation of 5a was
achieved with the K3[Fe(CN)6]–K2CO3 system in water-tert-butanol
using OsO4 (10 mM solution in 0.05 M sulfuric acid) as catalyst.16
After work-up of the reaction mixture and chromatography, the
thiohexenopyranoside derivative 8 was isolated as a single diaste-
reomer in a 10% yield (Scheme 4), although in the crude reaction
mixture compound 8 was the main product as indicated by NMR
and GC–MS analyses, so the low yield of 8 can be explained by dif-
ficulties in isolation.
a- and c
-positions.1,13 To explore the
synthetic utility of fluorine-containing salts 4, a series of O-, N-,
S-, and C-nucleophiles were tested in reactions with the trifluoro-
methyl derivative 4b. The reactions were carried out in DME or
CH3CN at ambient temperature under basic conditions to neutral-
ize the HBF4 formed. The reactions were usually complete within
1–2 h (monitoring by 19F NMR), the reaction mixtures were then
diluted with CHCl3 to precipitate insoluble material and, after
evaporation, the residues were analyzed by NMR spectroscopy.
The results are summarized in Table 1 (details of experimental pro-
cedures and NMR spectra of compounds obtained are presented as
Supplementary data). The position of nucleophile addition can be
unambiguously established by NMR in so much as 2H- or 4H-
substituted thiopyrans display different chemical shifts, multiplic-
ities, and coupling constants (see Supplementary data). 4H-Prod-
ucts have characteristic signals due to H-5 (a doublet of doublets
at 5.7–6.0 ppm with J5,4 = 3.7–5.6 Hz and J5,6 = 9.3–10.3 Hz) and
H-6 (a doublet at 6.3–6.6 ppm with corresponding J5,6 values),
whereas for 2H-products the most recognizable features are down-
field signals due to H-5 (a doublet of quartets at 6.8–7.0 ppm with
The values of the coupling constants in the 1H NMR spectrum of
817 (J2,3 = 4.8 Hz, J3,4 = 4.1 Hz) did not reveal unambiguously its
stereochemistry, but the relationship between the OMe and the
two cis-hydroxy groups in 8 can be deduced as follows. The OMe
group in the starting material 5a preferably adopts the pseudoaxial
position, although it is known that the anomeric effect for sulfur
compounds is lower than for the corresponding oxygen analogs.18
This suggestion agrees well with our DFT calculations (RI-BP86/
TZVPP) for 5a which indicate that the anomeric product with the
pseudoaxial position of the OMe group is, by ca. 4.5 kcal/mol, lower
in energy than the structure with pseudoequatorial OMe group
(see Supplementary data). It is possible to assume that cis-dihydr-
oxylation occurs from the less hindered face, opposite to the OMe
group, providing the product with a trans-orientation of the OMe
and OH groups. DFT calculations show only an insignificant energy
4
J5,4 = 3.7–5.6 Hz and JHF = 1.0–1.5 Hz).
Alcohols gave only 2-substituted products, no significant 4H-
isomers being observed in the crude reaction mixture from the
reactions of salt 4b with an excess of methanol or isopropanol in

Table 1
Reactions of salt 4b with various nucleophiles
R
Nu
+
CF3
S
CF3
S
R
CF3
S
BF4
4b
5
6
O
O
H(CF2)3
To s
N
N
N
N
H2N NH
Me
S
N
N
MeO
i-PrO
N3
CH2NO2
N
R
a
b
c
d
e
f
g
h
i
Nu, Reaction
Excess CH3OH,
K2CO3, 1 h
Excess i-PrOH,
K2CO3, 1 h
Imidazole,
2 equiv,
DME, 0.5 h
5:1
Benzimidazole,
2 equiv,
DME, 0.5 h
3:1
1 equiv, DME,
0.5 h
Urea, 4 equiv,
CH3CN, 0.5 h
NaN3, 2 equiv,
DME, 0.5 h
CH3COSK,
1.5 equiv,
DME, 2 h
3:1
NaCH2NO2,
2.2 equiv,
DME, 8 h
1:2
conditionsa
Ratio of 5:6b
1:0
61
1:0
90
1:1.5
70
1:0
33
1:0
90
Yieldc
98
95
65
88
a
b
c
All reactions were carried out at room temperature.
Molar ratio determined by NMR analyses.
Isolated yield of isomers.

S. A. Siry, V. M. Timoshenko / Tetrahedron Letters 51 (2010) 6406–6409
6409
References and notes
CN
4
4
4
KCN
S 2 CN+
2 S CN
CF3
+ CF3
2S
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4418; (d) Wagner, S. J.; Skripchenko, A.; Salata, J.; Cardo, L. J. Transfusion 2007,
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CF3
CF3
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BF4
4b
7a
7b
7c
Scheme 3. Reaction of thiopyrylium salt 4b with potassium cyanide.
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687–754.; (b) Rudorf, W.-D. Sci. Synth. 2003, 14, 649–710.
OH
3
K3[Fe(CN)6], K2CO3
H2O-t-BuOH
OH
4
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5. (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214–231; (b) Kirk, K.
L. J. Fluorine Chem. 2006, 127, 1013–1029; (c) Begue, J. P.; Bonnet-Delpon, D. J.
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3–11.
OsO4 cat.
CF3
S
OMe
CF3 S2 OMe
8
5a
Scheme 4. Dihydroxylation of 2H-thiopyran 5a.
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4329; (c) Fesun, I. M.; Rozhenko, A. B.; Timoshenko, V. M. J. Fluorine Chem. 2006,
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Me
H
H
O
H
CF3
S
H
CF3
S
H
+0.17 kcal/mol
OH
OH
H
O
OH
H
H
Me
HO
8A
8B
Scheme 5. Conformational equilibrium of 8.
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11. Price, C. C.; Follweiler, D. H. J. Org. Chem. 1969, 34, 3202–3204.
12. Preparation of 4b: 6-Trifluoromethyl-2H-thiopyran (3a) (1.67 g, 10 mmol) was
added to a suspension of trityl tetrafluoroborate (3.4 g, 10.3 mmol) in dry
CH3CN (10 ml) at 0 °C with stirring. The solution was stirred at rt for 30 min,
Et2O (30 ml) was added, and the precipitate of thiopyrylium salt was filtered
off, washed with Et2O and dried. Yield 2.05 g (81%), mp (decomp.) 150–160 °C,
fine colorless crystals which turned pink on standing. 19F NMR (CD3CN,
difference (ca. 0.2 kcal/mol) between the two conformers 8A and
8B, so neither prevails and, in NMR spectra at ambient tempera-
ture, signals of the equilibrium mixture of the conformers (Scheme
5) are observed.
In summary, we have reported the synthesis of the first 2-poly-
fluoroalkyl substituted thiopyrylium salts and have demonstrated
their use as fluoroalkyl-containing thiopyranoside and nucleoside
precursors.
188 MHz):
d
À59.84 (3F, s, CF3), À149.26 (4F, s, BF4). 1H NMR (CD3CN,
400 MHz): d 9.09 (1H, t, J = 8.3 Hz, H-5), 9.21 (1H, d, J = 8.3 Hz, H-3), 9.30 (1H, t,
J = 8.3 Hz, H-4), 10.40 (1H, d, J = 8.3 Hz, H-2). 13C NMR (CD3CN, 100 MHz): d
121.35 (q, J = 277 Hz, CF3), 137.93 (q, J = 3 Hz, C-3), 140.58 (s, C-5), 153.58 (s, C-
4), 156.41 (q, J = 38 Hz, C-2), 160.82 (s, C-6).
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Branchi, B.; Doddi, G.; Ercolani, G. J. Org. Chem. 2005, 70, 6422–6428; (c)
Mouradzadegun, A.; Hezave, F. G.; Karimnia, M. Phosphorous, Sulfur Silicon
Relat. Elem. 2010, 185, 84–87.
Acknowledgments
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3993.
We thank Dr. V.V. Trachevsky, Common Usage Center of Radio-
spectroscopy of NAS of Ukraine, Kyiv for registration of the NMR
spectra.
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M.; Shermolovich, Yu. G. Chem. Heterocycl. Compd. 2007, 43, 1138–1147.
16. Eames, J.; Mitchell, H. J.; Nelson, A.; O’Brien, P.; Warren, S.; Wyatt, P.
Tetrahedron Lett. 1995, 36, 1719–1722.
17. NMR data for compound 8. 19F NMR (CDCl3, 188 MHz): d À67.21 (m, CF3). 1H
NMR (CDCl3, 400 MHz): d 3.52 (3H, s, CH3), 4.10 (1H, dd, J = 4.8 Hz, 4.1 Hz, H-3),
4.41 (1H, dm, J = 4.1 Hz, H-4), 4.94 (1H, d, J = 4.8 Hz, H-2), 6.36 (1H, dq,
J = 3.6 Hz, 4JHF = 1.2 Hz, H-5). 13C NMR (CDCl3, 100 MHz): d 57.55 (s, CH3), 64.82
(s, CH–OH), 66.16 (s, CH–OH), 87.14 (s, C-2), 121.61 (q, J = 274 Hz, CF3), 123.59
(q, J = 33.3 Hz, C-6), 127.48 (q, J = 5.0 Hz, C-5).
Supplementary data
Supplementary data (details of experimental procedures and
NMR spectra of compounds obtained are presented) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.09.131.
18. Pericas, M. A.; Riera, A.; Guilera, J. Tetrahedron 1986, 42, 2717–2724.