Electrophilic (phenylsulfonyl)difluoromethylation of thiols with a hypervalent iodine(III)-CF2SO2Ph reagent

Article abstract of DOI:10.1016/j.tetlet.2008.06.064

A hypervalent iodine(III)-CF₂SO₂Ph compound (3) has been successfully prepared with selective nucleophilic reaction using PhSO₂CF₂SiMe₃ reagent, and this previously unkown compound 3 was found to act as a new electrophilic (phenylsulfonyl)difluoromethylation reagent for a variety of S-nucleophiles under very mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2008.06.064

Tetrahedron Letters 49 (2008) 5006–5008
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Tetrahedron Letters
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Electrophilic (phenylsulfonyl)difluoromethylation of thiols with a hypervalent
iodine(III)–CF2SO2Ph reagent
*
Wei Zhang, Jieming Zhu, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A hypervalent iodine(III)–CF2SO2Ph compound (3) has been successfully prepared with selective nucleo-
philic reaction using PhSO2CF2SiMe3 reagent, and this previously unkown compound 3 was found to act
as a new electrophilic (phenylsulfonyl)difluoromethylation reagent for a variety of S-nucleophiles under
very mild reaction conditions.
Received 29 April 2008
Revised 10 June 2008
Accepted 13 June 2008
Available online 18 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Elctrophilic fluoroalkylation
Hypervalent iodine compound
As ‘a small atom with a big ego’,1 fluorine plays increasingly
important roles in many fields such as medicinal and pharmaceu-
tical research and material science.2 As a result, many endeavors
have been drawn to develop new efficient synthetic methods for
selective introduction of fluorinated moieties into organic mole-
cules.3 In the past four decades, nucleophilic and radical fluor-
oalkylations have been widely applied in organic synthesis.3,4
However, the elctrophilic fluoroalkylation is much less generally
used, partly as a result of the high cost and less availability of
electrophilic fluoroalkylating reagents.5 The currently known
electrophilic fluoroalkylating reagents are mainly based on the
structures of (fluoroalkyl)aryliodonium salts and (fluoroalkyl)aryl-
chalcogen salts, which were developed by Yagupolskii,6 Umemot-
o,5,7 Shreeve,8 Magnier,9 Prakash,10 among others.11 Recently,
Togni and co-workers reported several neutral compounds, 10-I-
3 hypervalent iodine(III) compounds, as a new family of electro-
philic trifluoromethylating agents.12
Previously, we had been interested in developing efficient meth-
ods for selective introduction of (phenylsulfonyl)difluoromethyl
group (PhSO2CF2) into organic molecules, based on the fact that
the PhSO2CF2 group is a versatile functionality that can be readily
converted to other highly useful difluorinated moieties such as
difluoromethyl (CF2H), difluoromethylene (–CF2–), and difluorome-
thylidene (@CF2) groups.13 In this context, we have successfully
applied PhSO2CF2H (1) and PhSO2CF2SiMe3 (2) as powerful nucleo-
philic (phenylsulfonyl)difluoromethylating reagents.14 More re-
cently, an efficient radical (phenylsulfonyl)difluoromethylation
has also been developed by us using PhSO2CF2I reagent.15 However,
electrophilic (phenylsulfonyl)difluoromethylation reaction has
never been reported. Herein, we wish to report the first electrophilic
(phenylsulfonyl)difluoromethylation with
a hypervalent iodi-
ne(III)–CF2SO2Ph reagent 3.
In an attempt to prepare the hypervalent iodine(III)–CF2SO2Ph
reagent (3), we applied a one-pot protocol in which the ligand
exchange reaction was carried out at the iodine(III) center (see
Table 1).16 Thus, the chloride substituent in 4 was replaced by an
acetoxy group upon treatment with KOAc; after 1 h in dry acetoni-
trile, the insoluble salts were removed and the filtrate was evapo-
rated under reduced pressure to afford the intermediate product 5.
Thereafter, the second reaction was carried out by a fluoride-med-
iated substitution of 5 with PhSO2CF2SiMe3 (2), which corresponds
to a formal umpolung of the PhSO2CF2 group from being in nucle-
ophilic PhSO2CF2SiMe3 to electrophilic in 3. When acetonitrile was
used as solvent and the molar ratio between 4 and PhSO2CF2SiMe3
(2) was 1:2 (in the presence of catalytic tetrabutylammonium
difluorotriphenylsilicate (TBAT)), only trace amount of product 3
was detected by 19F NMR (Table 1, entry 1), with the major by-
product being PhSO2CF2H. When 2.0 equiv of starting material 4
was used, the yield increased to 74% in MeCN (entries 2 and 3).
Similar results were also obtained when THF was used as solvent
(entry 4), while the reaction in DMF gave better yields (entries
5–8). It was found that, by using 1.3 equiv of 4 and DMF as solvent
at ꢀ16 °C for 18 h, we were able to obtain the hypervalent
iodine(III)–CF2SO2Ph reagent 3 in 71% isolated yield (Table 1, entry
8). However, when PhSO2CF2H (1)/LHMDS14a was used to replace
PhSO2CF2SiMe3 (2)/TBAT as
reagent, product 3 could only be obtained in low yield (18%).
a nucleophilic PhSO2CF2 transfer
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail address: jinbohu@mail.sioc.ac.cn (J. Hu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.064

W. Zhang et al. / Tetrahedron Letters 49 (2008) 5006–5008
5007
Table 1
ation reaction does not require extra base, because a stoichio-
metric amount of alkoxide is formed upon formal ‘PhSO2CFþ’
One-pot synthesis of reagent 3
2
I
O
I
O
Cl
AcO
transfer, and 2-(2-iodophenyl)propan-2-ol is found as a by-product
which is the starting material for preparation of reagent 4.
KOAc, dry MeCN
rt., 1h
Having established the optimized reaction conditions with re-
agent 3, we studied the scope of the current electrophilic (phenyl-
sulfonyl)difluoromethylation chemistry with a range of sulfur-
nucleophiles. The results are summarized in Table 3. It was found
that a variety of structurally diverse thiophenol derivatives showed
high reactivity with reagent 3 at low temperature (ꢀ78 °C), and the
4
5
I
O
PhSO2CF2
PhSO2CF2SiMe3 (2)
cat.TBAT, Solvent
corresponding (phenylsulfonyl)difluoromethylated products
7
3
were obtained in good yields (68–85%, see Table 3, entries 1–5
and 10). Furthermore, 1-phenyl-1,2,3,4-tetrazole-5-thiol (6f), phen-
ylmethanethiol (6g), 2-benzothiazolethiol (6h), and pyridine-2-
Entry
Solvent
Ratio (4:2)
Time (h)
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
THF
DMF
DMF
1:2
2:1
2:1
2:1
2:1
2:1
2:1
1.3:1
18
5
12
5
5
5
ꢀ16
ꢀ45
ꢀ16
ꢀ16
ꢀ16
ꢀ45
ꢀ16
ꢀ16
Trace
75
74
69
88
Table 3
Electrophilic (phenylsulfonyl)difluoromethylation of thiols 6 with compound 3
86
DMF
DMF
18
18
86
Entry
1
Substrate
SH
Product
Yielda (%)
87 (71b)
SCF2SO2Ph
The yield was determined by 19F NMR based on the ratio of product 3 and by-
a
75
product PhSO2CF2H (1).
b
7a
6a
Isolated yield.
SH
SCF2SO2Ph
2
3
4
68
72
77
It should be noted that the above-obtained product 3 was found
to be more stable than Togni’s hypervalent iodine(III)–CF3 com-
pound.12 Compound 3 can be purified by silica gel column chroma-
tography and stored in a refrigerator for months without any
detectable decomposition, while Togni’s reagent can only be
exposed to and manipulated in moist air for a much shorter period
of time.12 Thus, starting from easily accessible materials, we were
able to synthesize I(III)–CF2SO2Ph reagent 3 in one-pot with rea-
sonably good yield, and this method also facilitated a scale-up to
multigram quantities.
Br
7b
Br
6b
SH
SCF2SO2Ph
7c
6c
Cl
Cl
SH
SCF2SO2Ph
Cl
Cl 7d
6d
With the electrophilic compound 3 in hand, next we explored
its reactivity with sulfur-nucleophiles by using thiophenol (6a) as
a model compound.17 As shown in Table 2, the reactions were car-
ried out in CH2Cl2, DMF, or CH3OH to give the product 7a in 66–77%
yields (entries 1, 3–4 and 6–9), while in THF or MeCN much lower
yields were observed (entries 2 and 5). Additionally, the reaction
temperature did not affect the yields significantly (entries 1 and
3). An optimal product yield (75%) was observed when the reaction
proceeded in CH2Cl2 at ꢀ78 °C for 3 h with 1.2 equiv thiophenol
being used (Table 2, entry 7). Similar to Togni’s trifluoromethyl-
ation,12 the present electrophilic (phenylsulfonyl)difluoromethyl-
SH
SCF2SO2Ph
5
85
80
87
7e
6e
N
N
N
SH
SCF2SO2Ph
N
N
6b
N
N
N
Ph
7f
6f
Ph
SH
SCF2SO2Ph
7
7g
6g
Table 2
Survey of reaction conditions
S
N
S
8b
82
80
SH
SCF2SO2Ph
7h
N
SH
PhSO2CF2
I
O
SCF2SO2Ph
6h
Solvent
+
9b
SH
SCF2SO2Ph
N
N
6i
7i
6a
7a
3
SH
SCF2SO2Ph
Entry
Solvent
Ratio (6a:3)
Time (h)
Temp (°C)
Yielda (%)
10
83c
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
CH2Cl2
DMF
CH3CN
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
2:1
2:1
2:1
2:1
2:1
2:1
1.2:1
2:1
0.8:1
3
3
3
3
3
3
3
7
3
ꢀ78
ꢀ78
ꢀ45
ꢀ45
ꢀ45
ꢀ78
ꢀ78
ꢀ78
ꢀ78
76
39
66
77
58
74
75
67
66
NO2
AcO
6j
OAc
NO2
AcO
7j
OAc
O
O
11
78
SH
SCF2SO2Ph
7k
AcO
AcO
AcO
AcO
6k
a
Isolated yield.
b
c
The reaction was carried in CH2Cl2–EtOH (2:1, v/v).
Determined by 19F NMR using PhCF3 as an internal standard.
a
Yields were determined by 19F NMR using PhCF3 as an internal standard.

5008
W. Zhang et al. / Tetrahedron Letters 49 (2008) 5006–5008
2. (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (b) Thayer, A. M.
SCF2SO2Ph
SCF2H
Na(Hg), Na2HP O4
CH3OH, -18oC
Chem. Eng. News 2006, 84, 15–24. 27–32; (c) Organofluorine Compounds:
Chemistry and Applications; Hiyama, T., Ed.; Springer: New York, 2000; (d)
Organofluorine Chemistry: Principles and Commercial Applications; Banks, R. E.,
Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York, 1994.
(1)
7e
8 (80%)
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P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004; (c) Chambers,
R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004.
HCF2
I
O
4. (a) Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; ACS: Washington, DC,
2005; (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996; (c) Ma, J.-
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6. (a) Yagulpol’skii, L. M.; Maletina, I. I.; Kondratenko, N. V.; Orda, V. V. Synthesis
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Org. Khim. 1984, 20, 115–118.
PhSO2CF2
I
O
Na(Hg), Na2HPO4
CH3OH, -18oC
(2)
9
CH2F2
7. (a) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156–2164; (b)
Umemoto, T. J. Fluorine Chem. 2000, 105, 211–213.
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thiol (6i) were all able to be efficiently (phenylsulfonyl)difluoro-
methylated by reagent 3 with 80–87% product yields (entries
6–9), while in some cases EtOH was required to dissolve the sub-
strates (Table 3, entries 6, 8 and 9). It is particularly remarkable
that with reagent 3, the (phenylsulfonyl)difluoromethylation of
pyranose derivative 6k could also be accomplished with good yield
(78%) under very mild reaction conditions (Table 3, entry 11). On
the other hand, we found that simple aliphatic thiols did not show
reactivity toward compound 3 under the similar reaction condi-
tions. Moreover, the current electrophilic (phenylsulfonyl)difluo-
romethylation reaction failed to transfer CF2SO2Ph group to many
carbon nucleophiles we examined.
As demonstrated earlier,13,14 the phenylsulfonyl group in the
final products can be readily removed via a reductive desulfonyl-
ation procedure. As shown in Scheme 1, the product 7e was
converted to difluoromethylated sulfide product in high yield
(80%, see Scheme 1, Eq. 1). However, when we tried to remove
the phenylsulfonyl group in the reagent 3 under the similar condi-
tions to obtain a desired direct electrophilic difluoromethylating
reagent 9, the reaction failed and compound 3 was converted to
difluoromethane (CH2F2), which was detected by 19F NMR spec-
15. Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem. 2007, 72, 5824–5827.
16. Preparation of the hypervalent iodine(III)–CF2SO2Ph reagent 3: Under N2
atmosphere, the compound 4 (0.925 g, 3.1 mmol) and dry KOAc (0.520 g,
5.3 mmol) were stirred in dry MeCN (18 ml) for 1.5 h at ambient temperature.
After filtration in air, the filtrate was transferred to another 50-mL three-neck
flask protected by N2 atmosphere, and then the solvent was evaporated under
reduced pressure to get the in situ generation of compound 5, to which dry
DMF (18 ml) was added. The solution was cooled to ꢀ16 °C and PhSO2CF2SiMe3
2 (0.634 g, 2.4 mmol, dissolved in 5 mL of DMF) was added via a needle,
followed by addition of catalytic tetrabutylammonium triphenyl-
difluorosilicate (TBAT). After stirring for 18 h at ꢀ16 °C, the reaction was
quenched by adding excess amount of H2O, followed by extraction with diethyl
ether. The organic phase was washed with brine and then dried over
anhydrous MgSO4. After the solution was filtered and the solvent was
evaporated under vacuum, the residue was subjected to silica gel column
chromatography using a mixture of ethyl acetate and petroleum ether (1:5, v/
v) as eluent to give product 3 (0.770 g, 1.7 mmol, yield: 71%) as a white solid.
2
troscopy (d = ꢀ144.8 (t), JH,F = 51.1 Hz) (Scheme 1, Eq. 2).18
In conclusion, we have successfully prepared a hypervalent io-
dine(III)–CF2SO2Ph compound (3) with PhSO2CF2SiMe3 reagent
(2). This reagent can be used as a useful electrophilic (phenylsulf-
onyl)difluoro-methylation reagent for a variety of S-nucleophiles
under very mild reaction conditions. The phenylsulfonyl group in
the final products can be readily removed via a reductive desulf-
onylation procedure, so that reagent 3 can be considered as a use-
ful electrophilic difluoromethylating reagent. Further investigation
of this chemistry is currently underway in our laboratory.
Mp: 89–90 °C. IR (film): 2971, 1448, 1332, 1159, 1106, 1052, 770, 566 cmꢀ1 1H
.
NMR: d 7.93 (d, J = 6.9 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),
7.57 (t, J = 7.8 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.33–7.39 (m, 1H), 7.26–7.29 (m,
1H), 1.44 (s, 6H). 19F NMR: d ꢀ84.2 (s, 2F). 13C NMR: d 150.0, 135.5, 131.5,
130.5, 129.8, 129.5, 129.4, 127.1 120.5 (t, J = 370.9 Hz), 111.7, 77.6, 30.6. MS
(ESI): m/z 453 (M+H+). Anal. Calcd for C16H15F2IO3S: C, 42.49; H, 3.34. Found: C,
42.74; H, 3.58.
17. Typical procedure for electrophilic (phenylsulfonyl)difluoro-methylation of
thiols 6 with compound 3: Under N2 atmosphere, the compound 3 (0.096 g,
0.21 mmol) and thiophenol (6a) (0.028 g, 0.25 mmol) were stirred in dry
CH2Cl2 (3 ml) for 3 h at ꢀ78 °C. Then, the reaction was quenched by adding
excess amount of H2O, followed by extraction with CH2Cl2. The organic phase
was washed successively with NaOH (5%) and brine, and then dried over
anhydrous MgSO4. After the solution was filtered and the solvent was
evaporated under vacuum, the residue was subjected to silica gel column
chromatography using a mixture of ethyl acetate and petroleum ether (1:50,
v/v) as eluent to give product 7a (0.047 g, 0.16 mmol, yield: 75%) as a colorless
Acknowledgments
We gratefully thank the National Natural Science Foundation of
China (20502029, 20772144), Shanghai Rising-Star Program
(06QA14063), and the Chinese Academy of Sciences (Hundreds-
Talent Program) for financial support.
liquid. 1H NMR: d 7.87–7.92 (m, 2H), 7.48–7.71 (m, 5H), 7.28–7.40 (m, 3H). 19
F
Supplementary data
NMR:
d
79.0 (s, 2F). MS (EI, m/z, %): 300 (M+, 0.26), 159 (100.00). The
characterization data was consistent with the previous report, see: Stahly, G. P.
J. Fluorine Chem. 1989, 43, 53.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.064.
18. Although difluoromethane (CH2F2) is a gaseous compound (bp ꢀ51.6 °C), it
dissolves in the reaction solvent (methanol) and thus enables us to
characterize it by 19F NMR. Our characterization data for CH2F2 was
consistent with the previous report, see: Weigert, F. J. J. Org. Chem. 1980, 45,
3476–3483.
References and notes
1. Smart, B. E. J. Fluorine Chem. 2003, 122, 1.