Benzyltrifluoromethyl (or Fluoroalkyl) Selenide: Reagent for Electrophilic Trifluoromethyl (or Fluoroalkyl) Selenolation

Article abstract of DOI:10.1021/acs.joc.6b01344

Trifluoromethylseleno substituent (CF₃Se) is an emerging group, but its direct introduction onto organic molecules is still quite limited and mainly restricted to nucleophilic methods. Herein, we describe a new approach to easily and safely perform electrophilic trifluoromethylselenolation starting from a simple and easily accessible reagent, namely, benzyltrifluoromethyl selenide. This strategy can be generalized to various fluoroalkylselanyl groups, even functionalized ones.

Full text of DOI:10.1021/acs.joc.6b01344

Article
pubs.acs.org/joc
Benzyltrifluoromethyl (or Fluoroalkyl) Selenide: Reagent for
Electrophilic Trifluoromethyl (or Fluoroalkyl) Selenolation
Quentin Glenadel,† Ermal Ismalaj,† and Thierry Billard*
́
Institute of Chemistry and Biochemistry (ICBMS−UMR CNRS 5246), Universite Lyon 1, CNRS, 43 Bd du 11 novembre 1918,
F-69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: Trifluoromethylseleno substituent (CF3Se) is an emerging
group, but its direct introduction onto organic molecules is still quite
limited and mainly restricted to nucleophilic methods. Herein, we describe
a new approach to easily and safely perform electrophilic trifluorome-
thylselenolation starting from a simple and easily accessible reagent,
namely, benzyltrifluoromethyl selenide. This strategy can be generalized to
various fluoroalkylselanyl groups, even functionalized ones.
Scheme 1. Previous Syntheses of Trifluoromethyl Selenides
INTRODUCTION
■
In recent decades, fluorinated compounds have received
extraordinary growing interest mainly due to the very specific
properties from fluorine addition inside their structures.1,2 Such
specificities could find a large panel of various applications,
from materials to life sciences.3−11 More recently, it has been
well-demonstrated that new properties such as high electron-
withdrawing characteristics and high lipophilicity can be
expected from the association of fluorinated moieties with a
heteroatom. This paved the way for the development of new
molecules, in particular, as agrochemicals and pharmaceuticals.
This associative concept has been particularly illustrated with
the growing interest in the trifluoromethylsulfanyl group
(CF3S).12,13 In the same chalcogen family, the selenium atom
possesses properties similar to those of sulfur. Selenium belongs
to the essential oligo-elements for living species,14,15 and some
endogenous compounds are selenylated as, for instance,
selenocysteine and selenoproteins.16−21 Furthermore, selenium
has demonstrated beneficial roles in human health.22−26
Organoselenium compounds can also be used for interesting
applications in material sciences and nanotechnology.27 This
has focused some interests to the synthesis of trifluorome-
thylselenolated molecules. Indeed, from an electronic point of
view, the CF3Se group presents properties similar to those of
CF3S (Hammett constants σp = 0.45, σm = 0.44; Swain−Lupton
constants F = 0.43, R = 0.02)28 but with a lower resonance
effect, which could offer some modulations in molecular
properties.
improved in aromatic series with a one-pot process,35 the
required preformation of selenylated substrates can constitute a
major drawback. It should be noticed that some radical
trifluoromethylations of diselenides or selenols have also been
reported but are generally more limited.36−41 From a
retrosynthetic point of view, the direct way provides the most
elegant approach because the introduction of the CF3Se group
can be envisaged without preliminary introduction of a
selenium atom. Thus, recently, trifluoromethylselenolate
anion (CF3Se−) chemistry has been revisited and has furnished
good results in some nucleophilic substitutions or coupling
reactions with alkyl,42 vinyl,43−45 and aryl46−50 halogenides,
boronic acids,51 terminal alkynes,51,52 or aromatic diazonium
salts.53 The reagents used in these reactions are mainly
CF3SeCu42−46,48,52 or CF3SeNMe4,49,51,53 which have been
generally prepared from CF3SiMe3 and selenium metal. It is
noteworthy that a one-pot process has been developed by an in
Because such molecules are relatively unknown, only a few
methods have been described in the literature to obtain CF3Se
molecules. These strategies can be divided into two parts
(Scheme 1). The indirect way, consisting in the trifluorome-
thylation of selenylated substrates. The most useful procedure
is based on the nucleophilic trifluoromethylation of dis-
eledines29 or, more interestingly, selenocyanates.30 The main
variations of this technique were the nucleophilic trifluor-
omethylating reagents.31−34 Even if this strategy was recently
Received: June 3, 2016
© XXXX American Chemical Society
A
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situ preforming CF3Se− species.47 However, these methods
require the use of a stoichiometric amount of selenium metal
and sometimes a stoichiometric amount of copper when
CF3SeCu is used. Furthermore, in aromatic series, prefunction-
alized substrates (halogenides, boronic acids, diazoniums, etc.)
are necessary.
One of the best ways to functionalize aromatic compounds is
electrophilic aromatic substitution, which is formally a hydro-
gen substitution. To extend such a strategy to trifluorome-
thylselenolation, an electrophilic reagent is then required. Some
years ago, CF3SeCl was described with such purpose.
Nevertheless, its synthesis was performed in harsh conditions,
with toxic reagents and with poor yields.54,55 Furthermore, by
analogy with CF3SCl,56 we can suppose that this highly volatile
reagent must be toxic, explaining its very few applications.57−61
In 2002, Magnier et al.62 published a very elegant and mild
procedure to prepare CF3SeCl, which was more efficient than
the previous methods. This approach is based on the oxidative
chlorination of benzyltrifluoromethyl selenide.
chlorination of 2a, is observed with an excess of SO2Cl2
(entries 3−6). This side reaction seems to be an equilibrium
because, after 1 h, a steady-state appears to be achieved (entries
4−6). Finally, the best solvent to form CF3SeCl efficiently and
rapidly is THF, with only 1 equiv of sulfuryl chloride.
Trifluoromethylselenolation of aromatic compounds with the
preformed CF3SeCl (2a) was then investigated. To our delight,
by simply adding aromatic substrates 3, the SEAr reaction was
observed (Scheme 2). With electron-rich substrates, the
Scheme 2. Trifluoromethylselenolation of Aromatic
a
Compounds
RESULTS AND DISCUSSION
■
This last compound is very easy to synthesize starting from
CF3SiMe3 and benzylselenocyanate,30 which is obtained from
potassium selenocyanate, an inexpensive source of selenium.
Consequently, we decided to develop a procedure based on this
starting material, avoiding the isolation of CF3SeCl, to perform
electrophilic aromatic substitutions.
In Magnier’s procedure, CF3SeCl is formed by reaction of
SO2Cl2 with benzyltrifluoromethyl selenide (1a) in solvent-free
conditions. To extrapolate this strategy to a one-pot procedure,
without isolation of CF3SeCl (2a), optimization of this reaction
with a solvent was first studied (Table 1). If the formation of 2a
Table 1. Formation of CF3SeCl
a
a
a
entry
SO2Cl2 (x)
solvent
time
2a (%)
2a′ (%)
Yields shown are of isolated products; values in parentheses are yields
as determined by 19F NMR spectroscopy using PhOCF3 as an internal
standard. 1a (2.2 equiv), SO2Cl2 (2.2 equiv). 1a (1.2 equiv), SO2Cl2
(1.2 equiv), BF3·Et2O (0.3 equiv), ClCH2CH2Cl, 80 °C.
1
2
1
1
2
2
2
2
1
1
1
1
2
2
2
THF
4 min
15 min
4 min
15 min
1.5 h
3 h
95
95
82
58
46
59
19
62
67
67
34
83
88
b
c
THF
3
THF
10
40
52
41
4
THF
5
THF
reaction gave good to excellent yields, even in heteroaromatic
series. By doubling the amount of reagents, bis-trifluorome-
thylselenolation could also be observed (4c). With less
electron-rich aromatic compounds, the reaction failed in these
conditions. To try to activate CF3SeCl, to obtain a better
electrophile, some Lewis acid was screened as catalyst. With
BF3·Et2O in 1,2-dichloroethane at 80 °C, good yields with
anisole (4l) and mesitylene (4m) were obtained. Nevertheless,
only low yield was observed with toluene (4k). A stronger
Lewis acid, such as AlCl3 or TiCl4, failed to favor this reaction.
Because it could be interesting to modulate properties of
targeted molecules, depending on the field of applications,
modulation of the fluorinated part could be of interest.
Consequently, this efficient method has been extended to
other fluoroalkylselenolations. Thus, bromodifluoromethanese-
lenylated molecules were obtained starting from benzylbromo-
difluoromethyl selenide 1b, obtained from bromodifluorome-
thylsilane (Scheme 3). Similar to 1a, good to excellent results
were achieved. The only difference between both procedures is
the preforming time of reactive species BrCF2SeCl (2b), which
6
THF
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
15 min
1.5 h
3 h
8
9
10
11
12
13
4 h
15 min
1.5 h
3 h
a
Yields as determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard.
is nearly instantaneous in THF (entries 1 and 2), the kinetics of
the reaction in CH2Cl2 is rather low (entries 7−10). This
kinetic difference can be rationalized by the promoted SO2Cl2
dissociation with basic solvents63 (DNTHF = 20, DNCH Cl
=
2
2
1).64,65 The use of 2 equiv of SO2Cl2 can accelerate the
formation of CF3SeCl (2a) in CH2Cl2 (entries 11−13). In
THF, the formation of CF3SeCl3 (2a′),66 arising from
B
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Scheme 3. Bromodifluoromethylselenolation of Aromatic
a
Compounds
Figure 1. Fluoroalkylselenolation of aromatic compounds. Yields
shown are of isolated products; values in parentheses are yields as
determined by 19F NMR spectroscopy using PhOCF3 as an internal
standard.
Table 2. Preformation of Reagents 2
a
Yields shown are of isolated products; values in parentheses are yields
as determined by 19F NMR spectroscopy using PhOCF3 as an internal
standard. 1b (2.2 equiv), SO2Cl2 (2.2 equiv). 1b (1.2 equiv), SO2Cl2
b
c
(1.2 equiv), BF3·Et2O (0.3 equiv), ClCH2CH2Cl, 80 °C.
entry
RFSeBn
RF = CF3
time (min)
1
2
3
4
5
6
15
15
15
30
30
30
45
requires slightly more time. With highly reactive pyrrole 3g,
only bis-substituted product 5g was obtained. Less electron-rich
aromatic compounds also required BF3·Et2O catalysis with
heating. Nevertheless, lower yields were observed possibly due
to a partial decomposition of the SeCF2Br by interaction with
the Lewis acid.
RF = CF2CF3
RF = CF2CF2CF3
RF = CF2Br
RF = CF2COOMe
RF = CF2SO2Ph
RF = CF2H
a
7
a
To validate the generality of this strategy, various other
benzylfluoroalkyl selenides were synthesized and engaged in
fluoroalkylselenolation reactions (Figure 1). This strategy
appears very versatile and furnishes good to excellent yields
of fluoroalkaneselenylated aromatic compounds. The only
adaptation of the procedure was the preforming time of
reacting species 2, depending on the reagent 1. This
preformation of 2 is summarized in Table 2.
Reaction performed at 0 °C.
Scheme 4. Synthesis of Difluorodeuteriomethylselanyl
Indole ([D]10h)
Therefore, difluoromethylated (10) and higher fluorinated
homologues (6 and 7) have been obtained. Some function-
alized groups were also introduced (8 and 9). To the best of
our knowledge, these last substituents have never been
described to this day.
Inspired by the “chemical chameleon” characteristic of the
PhSO2 group,67 we have recently demonstrated the easy access
to deuterated molecules,68 which have received some recent
interest in medicinal chemistry.69−71 Consequently, an example
of synthesis of a molecule bearing the substituent DCF2Se was
performed (Scheme 4). Thus, difluorodeuteriomethylselanyl
indole [D]10h was obtained with satisfactory yield from 9h.
Except during a mechanistic study,72 this DCF2Se group was
never described, and molecules bearing it were never isolated.
Such a strategy opens access to a new substituent for screening
in drug design.
CONCLUSION
■
To conclude, electrophilic trifluoro- and fluoroalkylselenola-
tions of aromatic and heteroaromatic compounds can be easily
performed starting from corresponding benzylfluoroalkyl
selenides. These simple reagents, easily obtained from a
common and moderately toxic source of selenium, constitute
valuable electrophilic sources of fluoroalkylseleno groups and
should favor the development of new substrates bearing such
substituents. Furthermore, the possibility to also introduce
functionalized moieties opens the way to post-transformations.
By this method, molecules with a DCF2Se group could be
C
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stirred for 16 h. The conversion was checked by 19F NMR with
PhOCF3 as internal standard. The reaction mixture was then
partitioned between water and pentane, and the aqueous layer was
extracted with pentane. The combined organic layers were washed
with brine, dried over MgSO4, filtered through a pad of silica (rinsed
with pentane), and concentrated to dryness (under moderate
vacuum). The crude residue was purified by chromatography
(pentane: 100) to afford the desired product 1c as a colorless liquid
obtained for the first time. No doubt that these reagents should
find their place in the toolbox of emerging fluorinated groups.
EXPERIMENTAL SECTION
■
General Information. Commercial reagents were used as
supplied. Anhydrous solvents were used as supplied. NMR spectra
were recorded at 400 MHz (1H NMR), 101 MHz (13C NMR), 376
MHz (19F NMR), or at 300 MHz (1H NMR) and 282 MHz (19F
NMR). Multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), p (quintet), sext (sextet), m (multiplet). The
term massif is used to define a group of different protons. All coupling
constants were reported in hertz. Melting points were determined
1
(3.21 g, 78% yield): H NMR (400 MHz, CDCl3) δ = 7.39−7.28
(massif, 5H), 4.28 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 135.5,
1
2
129.3, 129.1, 128.0, 119.1 (qt, J(C,F) = 285 Hz, J(C,F) = 35 Hz),
1
2
3
116.5 (tq, J(C,F) = 303 Hz, J(C,F) = 43 Hz), 28.6 (t, J(C,F) = 3
Hz); 19F NMR (376 MHz, CDCl3) δ = −83.66 (t, J(F,F) = 4.3 Hz,
3
3F), −91.75 (q, 3J(F,F) = 4.3 Hz, 2F). Anal. Calcd (%) for C9H7F5Se:
C, 37.39; H, 2.44; Se, 27.31. Found: C, 37.54; H, 2.53; Se, 27.10.
{[(Heptafluoropropyl)selanyl]methyl}benzene (1d). To a dry
round-bottom flask equipped with a magnetic stirrer were added
(benzylselanyl)carbonitrile (720 mg, 3.7 mmol, 1.0 equiv) and dry
THF (7 mL). The flask was evacuated and refilled with nitrogen three
times, and TMSCF2CF2CF3 (1.5 mL, 7.3 mmol, 2.0 equiv) was added.
The reaction mixture was cooled to 0 °C and TBAF in 1 M THF (0.73
mL, 0.73 mmol, 0.2 equiv) was added dropwise. After 10 min at 0 °C
under nitrogen, the reaction was allowed to warm to 23 °C and stirred
for 16 h. The conversion was checked by 19F NMR with PhOCF3 as
internal standard. The reaction mixture was then partitioned between
water and pentane, and the aqueous layer was extracted with pentane.
The combined organic layers were washed with brine, dried over
MgSO4, filtered through a pad of silica (rinsed with pentane), and
concentrated to dryness (under moderate vacuum). The crude residue
was purified by chromatography (pentane: 100) to afford the desired
using a Kofler bench apparatus (calibration substances were specified).
̈
(Benzylselanyl)carbonitrile. To a dry round-bottom flask equipped
with a magnetic stirrer were added potassium selenocyanate (12.6 g,
87.7 mmol, 1.1 equiv), dry THF (60 mL), and benzylbromide (13.6 g,
79.7 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C for
17 h. The reaction mixture was then partitioned between water and
Et2O, and the organic layer was dried over MgSO4, filtered, and
1
concentrated to dryness to afford the desired product: H NMR (300
MHz, CDCl3) δ = 7.39−7.33 (massif, 5H), 4.31 (s, 2H), in accordance
with literature.73
{[(Trifluoromethyl)selanyl]methyl}benzene (1a). To a dry round-
bottom flask equipped with a magnetic stirrer were added
(benzylselanyl)carbonitrile (13.7 g, 70.0 mmol, 1.0 equiv) and dry
THF (140 mL). The flask was evacuated and refilled with nitrogen
three times, and TMSCF3 (20.7 mL, 140 mmol, 2.0 equiv) was added.
The reaction mixture was cooled to 0 °C, and TBAF in 1 M THF
(14.0 mL, 14.0 mmol, 0.2 equiv) was added dropwise. After 10 min at
0 °C under nitrogen, the reaction was allowed to warm to 23 °C and
stirred for 7 h. The conversion was checked by 19F NMR with
PhOCF3 as internal standard. The reaction mixture was then
partitioned between water and pentane, and the aqueous layer was
extracted with pentane. The combined organic layers were washed
with brine, dried over MgSO4, filtered through a pad of silica (rinsed
with pentane), and concentrated to dryness (under moderate
vacuum). The crude residue was purified by chromatography
(pentane: 100) to afford the desired product 1a as a colorless liquid
1
product 1d as a colorless liquid (1.09 g, 87% yield): H NMR (400
MHz, CDCl3) δ = 7.38−7.27 (massif, 5H), 4.30 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ = 135.5, 129.4, 129.1, 128.1, 119.4 (tt, 1J(C,F) =
1
2
304 Hz, 2J(C,F) = 38 Hz), 117.8 (qt, J(C,F) = 288 Hz, J(C,F) = 35
Hz), 108.9 (tsext, J(C,F) = 262 Hz, 2J(C,F) = 36 Hz), 28.6 (m); 19F
NMR (376 MHz, CDCl3) δ = −79.78 (t, J(F,F) = 9.3 Hz, 3F),
1
4
−87.74 (m, 2F), −122.77 (br s, 2F). Anal. Calcd (%) for C10H7F7Se:
C, 35.42; H, 2.08; Se, 23.28. Found: C, 35.18; H, 2.23; Se, 23.13.
Methyl 2-(Benzylselanyl)-2,2-difluoroacetate (1e). To a dry
round-bottom flask equipped with a magnetic stirrer was added
(benzylselanyl)carbonitrile (392 mg, 2.0 mmol, 1.0 equiv). The flask
was evacuated and refilled with nitrogen three times before adding
THF (4 mL, 0.5 M) and TMSCF2COOMe (0.71 mL, 4 mmol, 2.0
equiv) to the flask. The reaction mixture was cooled to 0 °C, and
TBAF in 1 M THF (0.4 mL, 0.4 mmol, 0.2 equiv) was added
dropwise. After 10 min at 0 °C under nitrogen, the reaction was
allowed to warm to 23 °C and stirred for 15 h. The reaction mixture
was then partitioned between water and EtOAc, and the aqueous layer
was extracted with EtOAc. The combined organic layers were washed
with water and brine, dried over MgSO4, filtered, and concentrated to
dryness. The crude residue was purified by chromatography (pentane/
Et2O 99/1 to 98/2) to afford the desired product 1e as a pale yellow
1
(11.7 g, 70% yield): H NMR (300 MHz, CDCl3) δ = 7.37−7.27
(massif, 5H), 4.26 (s, 2H); 19F NMR (282 MHz, CDCl3) δ = −34.47
(s, 3F), in accordance with literature.30
{[(Bromodifluoromethyl)selanyl]methyl}benzene (1b). To a dry
round-bottom flask equipped with a magnetic stirrer was added
(benzylselanyl)carbonitrile (3.92 g, 20 mmol, 1.0 equiv). The flask was
evacuated and refilled with nitrogen three times before adding THF
(40 mL, 0.5 M) and TMSCF2Br (6.2 mL, 40 mmol, 2.0 equiv) to the
flask. The reaction mixture was cooled to 0 °C, and TBAF in 1 M
THF (4.0 mL, 4.0 mmol, 0.2 equiv) was added dropwise. After 10 min
at 0 °C under nitrogen, the reaction was allowed to warm to 23 °C and
stirred for 4 h. The reaction mixture was then partitioned between
water and pentane, and the aqueous layer was extracted with pentane.
The combined organic layers were washed with water and brine, dried
over MgSO4, filtered, and concentrated to dryness (under moderate
vacuum). The crude residue was purified by chromatography
(pentane: 100) to afford the desired product 1b as a colorless liquid
1
liquid (350 mg, 62% yield): H NMR (400 MHz, CDCl3) δ = 7.36−
7.24 (massif, 5H), 4.24 (s, 2H), 3.88 (s, 3H); 13C NMR (101 MHz,
2
CDCl3) δ = 163.0 (t, J(C,F) = 31 Hz), 136.4, 129.3, 128.9, 127.7,
115.1 (t, 1J(C,F) = 302 Hz), 54.0, 28.8 (t, 3J(C,F) = 3 Hz); 19F NMR
(376 MHz, CDCl3) δ = −83.07 (s, 2F). Anal. Calcd (%) for
C10H10F2O2Se: C, 43.03; H, 3.61; Se, 28.29. Found: C, 43.32; H, 3.92;
Se, 28.10.
1
(5.28 g, 88% yield): H NMR (400 MHz, CDCl3) δ = 7.36−7.28
(massif, 5H), 4.31 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 135.6,
129.3, 129.0, 127.8, 107.9 (t, 1J(C,F) = 355 Hz), 32.7; 19F NMR (376
MHz, CDCl3) δ = −16.54 (s, 2F). Anal. Calcd (%) for C8H7BrF2Se:
C, 32.03; H, 2.35; Br, 26.63; Se, 26.32. Found: C, 31.95; H, 2.47; Se,
26.11.
({[(Benzenesulfonyl)difluoromethyl]selanyl}methyl)benzene (1f).
To a dry round-bottom flask equipped with a magnetic stirrer was
added (benzylselanyl)carbonitrile (1.08 g, 5.5 mmol, 1.0 equiv). The
flask was evacuated and refilled with nitrogen three times before
adding diglyme (11 mL, 0.5 M) and TMSCF2SO2Ph (11.0 mmol, 2.0
equiv) to the flask. The reaction mixture was cooled to 0 °C, and CsF
(166 mg, 1.1 mmol, 0.2 equiv) was carefully added. After 10 min at 0
°C under nitrogen, the reaction was allowed to warm to 23 °C and
stirred for 15 h. The reaction mixture was then partitioned between
water and Et2O, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with water and brine, dried over
{[(Pentafluoroethyl)selanyl]methyl}benzene (1c). To a dry round-
bottom flask equipped with a magnetic stirrer were added
(benzylselanyl)carbonitrile (2.8 g, 14.2 mmol, 1.0 equiv) and dry
THF (30 mL). The flask was evacuated and refilled with nitrogen
three times, and TMSCF2CF3 (4.9 mL, 28.5 mmol, 2.0 equiv) was
added. The reaction mixture was cooled to 0 °C and TBAF in 1 M
THF (2.8 mL, 2.8 mmol, 0.2 equiv) was added dropwise. After 10 min
at 0 °C under nitrogen, the reaction was allowed to warm to 23 °C and
D
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MgSO4, filtered, and concentrated to dryness. The crude residue was
purified by chromatography (pentane/Et2O 9/1) to afford the desired
product 1f as a white solid (2.64 g, 80% yield): mp 63−65 °C,
filtered, and concentrated to dryness. The crude residue was purified
by chromatography to afford the desired product 10.
2,4-Dimethoxy-1-[(trifluoromethyl)selanyl]benzene (4a). Proce-
dure 1. Eluent for the flash chromatography: pentane/toluene 90/10
to 85/15; 1H NMR (300 MHz, CDCl3) δ = 7.61 (d, J = 8.1 Hz, 1H),
6.52−6.48 (massif, 2H), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (282
MHz, CDCl3) δ = −36.54 (s, 3F), in accordance with literature.35
4-[(trifluoromethyl)selanyl]benzene-1,3-diol (4b). Procedure 1.
White solid (mp 68−70 °C, calibration substance: azobenzol at 68.0
°C). Eluent for the flash chromatography: pentane/acetone 80/20; 1H
NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 2.7
Hz, 1H), 6.45 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (br s, 1H), 5.44 (br s,
1H); 13C NMR (101 MHz, CDCl3) δ = 160.6, 158.8, 140.3, 121.9 (q,
1J(C,F) = 336 Hz), 109.8, 102.7, 100.3; 19F NMR (376 MHz, CDCl3)
1
calibration substance: azobenzol at 68.0 °C; H NMR (400 MHz,
CDCl3) δ = 8.02 (m, 2H), 7.77 (m, 1H), 7.64 (m, 2H), 7.40−7.27
(massif, 5H), 4.45 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 135.59,
1
135.57, 131.9, 131.0, 129.5, 129.4, 129.0, 128.0, 126.0 (t, J(C,F) =
3
339 Hz), 30.7 (t, J(C,F) = 3 Hz); 19F NMR (376 MHz, CDCl3) δ =
−78.53 (s, 2F). Anal. Calcd (%) for C14H12F2O2SSe: C, 46.55; H,
3.35; Se, 21.86, S 8.87. Found: C, 46.65; H, 3.58; Se, 21.64, S 9.07.
{[(Difluoromethyl)selanyl]methyl}benzene (1g). To a dry round-
bottom flask equipped with a magnetic stirrer were added
(benzylselanyl)carbonitrile (2.05 g, 10.45 mmol, 1.0 equiv) and dry
THF (20 mL). The flask was evacuated and refilled with nitrogen
three times, and TMSCF2H (2.85 mL, 20.9 mmol, 2.0 equiv) was
added. The reaction mixture was cooled to 0 °C, and CsF (1.59 g,
10.45 mmol, 1.0 equiv) was carefully added. After 30 min at 0 °C
under nitrogen, the reaction was allowed to warm to 23 °C and stirred
for 15 h. The conversion was checked by 19F NMR with PhOCF3 as
internal standard. The reaction mixture was then partitioned between
water and pentane, and the aqueous layer was extracted with pentane.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated to dryness (under moderate
vacuum). The crude residue was purified by chromatography
(pentane/DCM 97/3 to 95/5) to afford the desired product 1g as a
δ = −36.74 (s, 3F). Anal. Calcd (%) for C7H5F3O2Se: C, 32.71; H,
1.96; Se, 30.72. Found: C, 32.59; H, 1.91; Se, 30.48.
4,6-Bis[(trifluoromethyl)selanyl]benzene-1,3-diol (4c). To a flask
equipped with a magnetic stirrer were added 1a (274 mg, 1.15 mmol,
2.2 equiv), sulfuryl chloride (93 μL, 1.15 mmol, 2.2 equiv), and dry
THF (1.1 mL, 1 M). The reaction mixture was stirred at 23 °C for 15
min, and it was cooled to 0 °C. Resorcinol 3c (57 mg, 0.52 mmol, 1.0
equiv) was added, and the reaction was stirred at 0 °C for 15 min and
then at 23 °C for 22 h (the conversion was checked by 19F NMR with
PhOCF3 as internal standard). The reaction mixture was then
partitioned between an aqueous 10% NaOH solution and EtOAc.
The aqueous layer was acidified with an aqueous 1 M HCl solution
and twice extracted with EtOAc. The combined organic layers were
dried over MgSO4, filtered, and concentrated to dryness. The crude
residue was purified by chromatography (pentane/acetone 80/20) to
afford the desired product 4c as a white solid (195 mg, 93% yield): mp
64−66 °C, calibration substance: azobenzol at 68.0 °C; 1H NMR (400
MHz, CDCl3) δ = 8.01 (s, 1H), 6.84 (s, 1H), 6.47 (br s, 2H); 13C
1
colorless liquid (450 mg, 19% yield): H NMR (400 MHz, CDCl3) δ
2
= 7.37−7.31 (massif, 4H), 7.27 (m, 1H), 7.08 (t, J(H,F) = 55.2 Hz,
1H), 4.12 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 137.4, 129.1,
128.9, 127.5, 115.8 (t, 1J(C,F) = 287 Hz), 26.4 (t, 3J(C,F) = 3 Hz); 19
NMR (376 MHz, CDCl3) δ = −92.95 (d, J(F,H) = 55.3 Hz, 2F).
Anal. Calcd (%) for C8H8F2Se: C, 43.46; H, 3.65; Se, 35.71. Found: C,
43.29; H, 3.40; Se, 35.63.
F
2
1
NMR (101 MHz, CDCl3) δ = 162.1, 149.3, 121.7 (q, J(C,F) = 336
General Procedure 1 for Fluoroalkylselenolation without
BF3·Et2O. To a flask equipped with a magnetic stirrer were added 1
(0.5 mmol, 1.0 equiv), sulfuryl chloride (0.5 mmol, 1.0 equiv), and dry
THF (0.5 mL, 1 M). The reaction mixture was stirred at 23 °C until
complete formation of the intermediate 2 (cf Table 2); it was then
cooled to 0 °C, followed by the addition of 3 (0.5 mmol, 1.0 equiv).
The reaction mixture was stirred at 0 °C for 15 min, and it was then
allowed to warm to 23 °C until complete conversion of the
intermediate 2 (the conversion takes between 15 min and 3 h, as
checked by 19F NMR with PhOCF3 as internal standard). The reaction
mixture was then partitioned between water and Et2O, and the
aqueous layer was extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated
to dryness. The crude residue was purified by chromatography to
afford the desired product 4, 5, 6, 7, 8, or 9.
General Procedure 2 for Fluoroalkylselenolation with BF3·
Et2O. To a flask equipped with a magnetic stirrer were added 1 (0.6
mmol, 1.2 equiv), sulfuryl chloride (0.6 mmol, 1.2 equiv), and dry
DCE (0.5 mL, 1 M). The reaction mixture was stirred at 23 °C for 3.5
h followed by the addition of 3 (0.5 mmol, 1.0 equiv) and BF3·Et2O
(0.15 mmol, 30 mol). The reaction mixture was heated to 80 °C for 15
h. The conversion was checked by 19F NMR with PhOCF3 as internal
standard. The reaction mixture was then partitioned between water
and pentane, and the aqueous layer was extracted with pentane. The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated to dryness. The crude residue was purified
by chromatography to afford the desired product 4 or 5.
General Procedure 3 for Difluoromethylselenolation. To a
flask equipped with a magnetic stirrer were added 1g (0.4 mmol, 1.0
equiv) and dry THF (0.2 mL). The solution was cooled to 0 °C, and
sulfuryl chloride (0.4 mmol, 1.0 equiv) and dry THF (0.2 mL) were
added. The reaction mixture was stirred at 0 °C for 45 min, and 3 (0.4
mmol, 1.0 equiv) was added. The reaction mixture was stirred at 0 °C
until complete conversion of the intermediate 2g (the conversion takes
around 2 h; it was checked by 19F NMR with PhOCF3 as internal
standard). The reaction mixture was then partitioned between water
and Et2O, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over MgSO4,
Hz), 102.6, 101.9 (br s); 19F NMR (376 MHz, CDCl3) δ = −36.47 (s,
6F). Anal. Calcd (%) for C8H4F6O2Se2: C, 23.78; H, 1.00; Se, 39.09.
Found: C, 23.67; H, 0.89; Se, 39.14.
2-[(Trifluoromethyl)selanyl]naphthalen-1-ol (4d). Procedure 1.
Brown solid (mp 64−66 °C, calibration substance: azobenzol at 68.0
°C). Eluent for the flash chromatography: pentane/EtOAc 95/5 to
85/15; 1H NMR (400 MHz, CDCl3) δ = 8.46 (br d, J = 8.4 Hz, 1H),
8.26 (ddd, J = 8.3, 1.4, 0.7 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.66
(ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.57 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H),
6.80 (d, J = 7.8 Hz, 1H), 5.84 (br s, 1H); 13C NMR (101 MHz,
CDCl3) δ = 154.8, 139.4, 136.8, 128.3, 128.3, 126.1, 125.3, 122.7 (q,
1J(C,F) = 335 Hz), 122.4, 113.2 (q, 3J(C,F) = 2 Hz), 108.9; 19F NMR
(376 MHz, CDCl3) δ = −36.38 (s, 3F). Anal. Calcd (%) for
C11H7F3OSe: C, 45.38; H, 2.42; Se, 27.12. Found: C, 45.59; H, 2.65;
Se, 27.31.
N,N-Dimethyl-4-[(trifluoromethyl)selanyl]aniline (4e). Procedure
1. Eluent for the flash chromatography: pentane/EtOAc 99/1 to 98/2;
1H NMR (300 MHz, CDCl3) δ = 7.57 (m, 2H), 6.68 (m, 2H), 3.01 (s,
6H); 19F NMR (282 MHz, CDCl3) δ = −37.84 (s, 3F), in accordance
with literature.35
3-Ethyl-2,5-dimethyl-4-[(trifluoromethyl)selanyl]-1H-pyrrole (4f).
Procedure 1. Dark brown liquid. Eluent for the flash chromatography:
1
pentane/Et2O 100/0 to 98/2; H NMR (400 MHz, CDCl3) δ = 7.85
(br s, 1H), 2.44 (q, J = 7.6 Hz, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 1.10 (t,
J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ = 129.6, 129.4,
1
3
123.0, 122.3 (q, J(C,F) = 338 Hz), 100.5 (q, J(C,F) = 2 Hz), 18.2,
15.4, 11.4, 10.8; 19F NMR (376 MHz, CDCl3) δ = −38.58 (s, 3F).
Anal. Calcd (%) for C9H12F3NSe: C, 40.01; H, 4.48, N 5.18; Se, 29.23.
Found: C, 39.76; H, 4.71, N 5.46; Se, 29.52.
3-[(Trifluoromethyl)selanyl]-1H-indole (4h). Procedure 1. Brown
solid (mp 63−65 °C, calibration substance: azobenzol at 68.0 °C).
Eluent for the flash chromatography: pentane/EtOAc 90/10 to 85/15;
1H NMR (400 MHz, CDCl3) δ = 8.44 (br s, 1H), 7.82 (m, 1H), 7.48
(d, J = 2.7 Hz, 1H), 7.43 (m, 1H), 7.36−7.30 (massif, 2H); 13C NMR
(101 MHz, CDCl3) δ = 136.1, 133.0, 130.1, 123.4, 122.4 (q, 1J(C,F) =
335 Hz), 121.6, 120.1, 111.7, 93.2 (q, 3J(C,F) = 2 Hz); 19F NMR (376
MHz, CDCl3) δ = −37.54 (s, 3F). Anal. Calcd (%) for C9H6F3NSe: C,
E
DOI: 10.1021/acs.joc.6b01344
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1
40.93; H, 2.29, N 5.30; Se, 29.90. Found: C, 41.02; H, 2.48, N 5.13;
Se, 29.74.
= 151.7, 138.8, 112.6, 111.4, 109.9 (t, J (C, F) = 357 Hz), 40.2; 19F
NMR (376 MHz, CDCl3) δ = −19.35 (s, 2F). Anal. Calcd (%) for
C9H10BrF2NSe: C, 32.85; H, 3.06, Br 24.28, N 4.26; Se, 24.00. Found:
C, 32.69; H, 3.11, Br 24.20, N 4.35; Se, 23.79.
4-Bromo-3-[(trifluoromethyl)selanyl]-1H-indole (4i). Procedure 1.
Brown solid (mp 98−100 °C, calibration substance: benzil at 95.0 °C).
Eluent for the flash chromatography: pentane/EtOAc 85/15 to 80/20;
1H NMR (400 MHz, CDCl3) δ = 8.65 (br s, 1H), 7.56 (d, J = 2.8 Hz,
1H), 7.43−7.38 (massif, 2H), 7.10 (t, J = 7.9 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ = 137.1, 135.5, 126.6, 126.2, 124.2, 122.0 (q, 1J(C,F)
3,4-Bis[(bromodifluoromethyl)selanyl]-2,5-dimethyl-1H-pyrrole
(5g). To a flask equipped with a magnetic stirrer were added 1b (190
mg, 0.63 mmol, 2.2 equiv), sulfuryl chloride (51 μL, 0.63 mmol, 2.2
equiv), and dry THF (0.6 mL, 1 M). The reaction mixture was stirred
at 23 °C for 15 min, and it was cooled to 0 °C. The pyrrole derivative
3g (29 μL, 0.29 mmol, 1.0 equiv) was added, and the reaction was
stirred at 0 °C for 35 min (the conversion was checked by 19F NMR
with PhOCF3 as internal standard). The reaction mixture was then
partitioned between water and Et2O, and the aqueous layer was
extracted with Et2O. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated to dryness. The
crude residue was purified by chromatography (pentane/Et2O 80/20
to 70/30) to afford the desired product 5g as a pale yellow liquid (106
3
= 335 Hz), 115.0, 111.3, 93.3 (q, J(C,F) = 2 Hz); 19F NMR (376
MHz, CDCl3) δ = −38.70 (s, 3F). Anal. Calcd (%) for C9H5BrF3NSe:
C, 31.51; H, 1.47, Br 23.30, N 4.08; Se, 23.02. Found: C, 31.70; H,
1.70, Br 23.22, N 4.21; Se, 22.96.
Methyl 3-[(Trifluoromethyl)selanyl]-1H-indole-5-carboxylate (4j).
Procedure 1. Pale pink solid (mp 169−171 °C, calibration substance:
benzanilide at 163.0 °C). Eluent for the flash chromatography:
1
pentane/EtOAc 80/20 to 70/30; H NMR (400 MHz, (CD3)2CO) δ
= 11.34 (br s, 1H), 8.42 (s, 1H), 7.95−7.92 (massif, 2H), 7.64 (d, J =
1
8.9 Hz, 1H), 3.91 (s, 3H); 13C NMR (101 MHz, (CD3)2CO) δ =
mg, 72% yield): H NMR (400 MHz, CDCl3) δ = 8.50 (br s, 1H),
2.45 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 136.1, 110.2 (t,
1J(C,F) = 359 Hz), 109.3, 13.5; 19F NMR (376 MHz, CDCl3) δ =
1
167.8, 140.3, 137.1, 130.6, 124.7, 124.2, 123.4 (q, J(C,F) = 334 Hz),
122.6, 113.1, 93.5, 52.2; 19F NMR (376 MHz, (CD3)2CO) δ = −38.93
(s, 3F). Anal. Calcd (%) for C11H8F3NO2Se: C, 41.01; H, 2.50, N 4.35;
Se, 24.51. Found: C, 40.88; H, 2.66, N 4.16; Se, 24.81.
−18.97 (s, 4F). Anal. Calcd (%) for C8H7Br2F4NSe2: C, 18.81; H,
1.38, Br 31.28, N 2.74; Se, 30.91. Found: C, 19.05; H, 1.57, Br 31.33,
N 2.59; Se, 30.98.
1-Methoxy-4-[(trifluoromethyl)selanyl]benzene (4l). Procedure 2.
1
3-[(Bromodifluoromethyl)selanyl]-1H-indole (5h). Procedure 1.
Brown solid (mp 49−51 °C, calibration substance: azobenzol at 68.0
°C). Eluent for the flash chromatography: cyclohexane/EtOAc 9/1 to
8/2; 1H NMR (400 MHz, CDCl3) δ = 8.54 (br s, 1H), 7.81 (m, 1H),
7.53 (d, J = 2.7 Hz, 1H), 7.44 (m, 1H), 7.34−7.27 (massif, 2H); 13C
NMR (101 MHz, CDCl3) δ = 136.1, 133.2, 130.0, 123.5, 121.7, 120.3,
111.6, 109.9 (t, 1J(C,F) = 359 Hz), 98.0; 19F NMR (376 MHz,
CDCl3) δ = −18.92 (s, 2F). Anal. Calcd (%) for C9H6BrF2NSe: C,
33.26; H, 1.86, Br 24.58, N 4.31 Se 24.29. Found: C, 33.18; H, 2.02, Br
24.90, N 4.49; Se, 24.21.
Eluent for the flash chromatography: cyclohexane/toluene 98/2; H
NMR (300 MHz, CDCl3) δ = 7.66 (m, 2H), 6.91 (m, 2H), 3.83 (s,
3H); 19F NMR (282 MHz, CDCl3) δ = −37.18 (s, 3F), in accordance
with literature.35
1,3,5-Trimethyl-2-[(trifluoromethyl)selanyl]benzene (4m). Proce-
1
dure 2. Eluent for the flash chromatography: pentane: 100; H NMR
(300 MHz, CDCl3) δ = 7.05 (s, 2H), 2.60 (s, 6H), 2.34 (s, 3H); 19F
NMR (282 MHz, CDCl3) δ = −35.16 (s, 3F), in accordance with
literature.48
1-[(Bromodifluoromethyl)selanyl]-2,4-dimethoxybenzene (5a).
Procedure 1. Off white solid (mp <46 °C, calibration substance:
azobenzol at 68.0 °C). Eluent for the flash chromatography:
cyclohexane/toluene 9/1; 1H NMR (400 MHz, CDCl3) δ = 7.63
(m, 1H), 6.52−6.49 (massif, 2H), 3.86 (s, 3H), 3.84 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ = 163.8, 161.2, 140.5, 109.3 (t, 1J(C,F) =
359 Hz), 106.9, 105.8, 99.2, 56.2, 55.6; 19F NMR (376 MHz, CDCl3)
δ = −18.20 (s, 2F). Anal. Calcd (%) for C9H9BrF2O2Se: C, 31.24; H,
2.62, Br 23.09; Se, 22.82. Found: C, 31.49; H, 2.92, Br 23.17; Se,
22.96.
4-[(Bromodifluoromethyl)selanyl]benzene-1,3-diol (5b). Proce-
dure 1. Pale yellow solid (mp 116−118 °C, calibration substance:
acetanilide 114.5 °C). Eluent for the flash chromatography: cyclo-
hexane/EtOAc 8/2; 1H NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.5
Hz, 1H), 6.58 (dd, J = 2.7, 0.5 Hz, 1H), 6.45 (ddd, J = 8.5, 2.7, 0.5 Hz,
1H), 6.27 (br s, 1H), 5.52 (br s, 1H); 13C NMR (101 MHz, CDCl3) δ
= 161.0, 158.8, 140.3, 109.7, 108.8 (t, 1J(C,F) = 359 Hz), 104.4, 102.7;
19F NMR (376 MHz, CDCl3) δ = −18.98 (s, 2F). Anal. Calcd (%) for
4-Bromo-3-[(bromodifluoromethyl)selanyl]-1H-indole (5i). Proce-
dure 1. Dark brown solid (mp 90−92 °C, calibration substance:
azobenzol at 68.0 °C). Eluent for the flash chromatography:
1
cyclohexane/EtOAc 8/2; H NMR (400 MHz, CDCl3) δ = 8.67 (br
s, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.44−7.40 (massif, 2H), 7.11 (t, J =
7.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 137.0, 135.8, 126.7,
126.2, 124.2, 115.1, 111.3, 109.7 (t, 1J(C,F) = 359 Hz), 98.0; 19F NMR
(376 MHz, CDCl3) δ = −20.24 (s, 2F). Anal. Calcd (%) for
C9H5Br2F2NSe: C, 26.76; H, 1.25, Br 39.57, N 3.47 Se 19.55. Found:
C, 26.52; H, 1.07, Br 39.83, N 3.24; Se, 19.87.
Methyl 3-[(Bromodifluoromethyl)selanyl]-1H-indole-5-carboxy-
late (5j). Procedure 1. Pale pink solid (mp 188−190 °C, calibration
substance: salophen at 191.0 °C). After removing volatiles, pentane
was added to the residue and the precipitate was filtered off and
1
washed with pentane: H NMR (400 MHz, CDCl3) δ = 8.83 (br s,
1H), 8.51 (br s, 1H), 8.01 (dd, J = 8.5, 1.6 Hz, 1H), 7.64 (d, J = 2.6
Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ = 167.9, 138.8, 134.5, 129.8, 124.9, 124.0, 123.2, 111.5,
109.5 (t, 1J(C,F) = 359 Hz), 99.5, 52.3; 19F NMR (376 MHz, CDCl3)
δ = −19.07 (s, 2F). Anal. Calcd (%) for C11H8BrF2NO2Se: C, 34.49;
H, 2.11, Br 20.86, N 3.66 Se 20.61. Found: C, 34.37; H, 2.34, Br 21.05,
N 3.75; Se, 20.85.
C7H5BrF2O2Se: C, 26.44; H, 1.59, Br 25.13; Se, 24.83. Found: C,
26.53; H, 1.87, Br 25.39; Se, 24.97.
4-[(Bromodifluoromethyl)selanyl]naphthalen-1-ol (5d). Proce-
dure 1. Brown solid (mp 95−97 °C, calibration substance: azobenzol
at 68.0 °C). Eluent for the flash chromatography: cyclohexane/EtOAc
1
4-[(Pentafluoroethyl)selanyl]benzene-1,3-diol (6b). Procedure 1.
White solid (mp 91−93 °C, calibration substance: benzil at 95.0 °C).
Eluent for the flash chromatography: pentane/acetone 80/20; 1H
NMR (400 MHz, CDCl3) δ = 7.49 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 2.7
Hz, 1H), 6.44 (dd, J = 8.5, 2.7 Hz, 1H), 6.22 (br s, 1H), 5.42 (br s,
1H); 13C NMR (101 MHz, CDCl3) δ = 160.7, 159.2, 140.8, 118.7 (qt,
95/5; H NMR (400 MHz, CDCl3) δ = 8.46 (br d, J = 8.5 Hz, 1H),
8.26 (ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.65
(ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.56 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H),
6.82 (d, J = 7.8 Hz, 1H), 5.99 (br s, 1H); 13C NMR (101 MHz,
CDCl3) δ = 155.1, 139.5, 136.7, 128.4, 128.3, 126.1, 125.3, 122.4,
117.2, 109.4 (t, 1J(C,F) = 359 Hz), 108.9; 19F NMR (376 MHz,
CDCl3) δ = −18.09 (s, 2F). Anal. Calcd (%) for C11H7BrF2OSe: C,
37.53; H, 2.00, Br 22.70; Se, 22.43. Found: C, 37.28; H, 1.87, Br 22.82;
Se, 22.73.
1J(C,F) = 286 Hz, J(C,F) = 34 Hz), 115.4 (tq, J(C,F) = 305 Hz,
2
1
2J(C,F) = 42 Hz), 109.8, 102.7, 99.2 (t, J(C,F) = 3 Hz); 19F NMR
3
3
(376 MHz, CDCl3) δ = −82.80 (t, J(F,F) = 3.8 Hz, 3F), −91.61 (q,
3J(F,F) = 3.8 Hz, 2F). Anal. Calcd (%) for C8H5F5O2Se: C, 31.29; H,
1.64; Se, 25.71. Found: C, 31.19; H, 1.77; Se, 26.03.
4-[(Bromodifluoromethyl)selanyl]-N,N-dimethylaniline (5e). Pro-
cedure 1. Yellow solid (mp 76−78 °C, calibration substance:
azobenzol at 68.0 °C). After removing volatiles, pentane was added
to the residue and the precipitate was filtered off and washed with
3-[(Pentafluoroethyl)selanyl]-1H-indole (6h). Procedure 1. Pale
pink solid (mp 74−76 °C, calibration substance: azobenzol at 68.0
1
1
pentane: H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.5 Hz, 2H),
°C). Eluent for the flash chromatography: pentane/EtOAc 90/10; H
6.74 (d, J = 8.5 Hz, 2H), 3.02 (s, 6H); 13C NMR (101 MHz, CDCl3) δ
NMR (400 MHz, CDCl3) δ = 8.51 (br s, 1H), 7.79 (m, 1H), 7.50 (d, J
F
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= 2.7 Hz, 1H), 7.43 (m, 1H), 7.34−7.28 (massif, 2H); 13C NMR (101
MHz, CDCl3) δ = 136.1, 133.6, 130.4, 123.4, 121.7, 120.2, 119.1 (qt,
(101 MHz, CDCl3) δ = 136.1, 135.5, 134.2, 132.0, 130.8, 130.5, 129.4,
1
124.9 (t, J(C,F) = 342 Hz), 123.2, 121.5, 120.2, 111.8, 92.3 (m); 19F
2
1
1J(C,F) = 286 Hz, J(C,F) = 35 Hz), 115.4 (tq, J(C,F) = 304 Hz,
NMR (376 MHz, CDCl3) δ = −78.03 (s, 2F). Anal. Calcd (%) for
C15H11F2NO2SSe: C, 46.64; H, 2.87, N 3.63, S 8.30 Se 20.44. Found:
C, 46.43; H, 2.74, N 3.71, S 8.14; Se, 20.27.
3
2J(C,F) = 41 Hz), 111.6, 92.1 (t, J(C,F) = 4 Hz); 19F NMR (376
MHz, CDCl3) δ = −82.75 (t, 3J(F,F) = 3.9 Hz, 3F), −92.62 (q, 3J(F,F)
= 3.9 Hz, 2F). Anal. Calcd (%) for C10H6F5NSe: C, 38.24; H, 1.93, N
4.46; Se, 25.14. Found: C, 38.13; H, 2.14, N 4.71; Se, 25.34.
4-[(Difluoromethyl)selanyl]benzene-1,3-diol (10b). Procedure 3.
Pale yellow oil. Eluent for the flash chromatography: pentane/EtOAc
1
75/25; H NMR (400 MHz, CDCl3) δ = 7.46 (d, J = 8.5 Hz, 1H),
4-[(Heptafluoropropyl)selanyl]benzene-1,3-diol (7b). Procedure
1. White solid (mp 71−73 °C, calibration substance: azobenzol at 68.0
°C). Eluent for the flash chromatography: pentane/acetone 80/20; 1H
NMR (400 MHz, CDCl3) δ = 7.50 (d, J = 8.5 Hz, 1H), 6.58 (s, J = 2.7
Hz, 1H), 6.45 (dd, J = 8.5, 2.7 Hz, 1H), 6.23 (s, 1H), 5.51 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ = 160.8, 159.3, 141.0, 118.2 (tt, 1J(C,F) =
306 Hz, 2J(C,F) = 40 Hz), 117.5 (qt, 1J(C,F) = 289 Hz, 2J(C,F) = 35
6.95 (t, 2J(H,F) = 55.2 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 6.43 (dd, J =
8.5, 2.6 Hz, 1H), 6.37 (br s, 1H), 5.75 (br s, 1H); 13C NMR (101
1
MHz, CDCl3) δ = 159.9, 158.5, 140.0, 116.4 (t, J(C,F) = 292 Hz),
109.6, 102.5, 100.5 (t, 3J(C,F) = 3 Hz); 19F NMR (376 MHz, CDCl3)
δ = −90.05 (d, 2J(F,H) = 55.4 Hz). Anal. Calcd (%) for C7H6F2O2Se:
C, 35.17; H, 2.53; Se, 33.03. Found: C, 34.94; H, 2.62; Se, 32.88.
3-[(Difluoromethyl)selanyl]-1H-indole (10h). Procedure 3. Pale
yellow liquid. Eluent for the flash chromatography: pentane/EtOAc
1
2
Hz), 109.8, 108.8 (tsext, J(C,F) = 263 Hz, J(C,F) = 38 Hz), 102.7,
99.1; 19F NMR (376 MHz, CDCl3) δ = −79.85 (t, J(F,F) = 9.2 Hz,
3F), −87.57 (m, 2F), −122.28 (s, 2F). Anal. Calcd (%) for
C9H5F7O2Se: C, 30.27; H, 1.41; Se, 22.11. Found: C, 30.50; H,
1.71; Se, 22.33.
4
1
90/10 to 85/15; H NMR (400 MHz, CDCl3) δ = 8.44 (br s, 1H),
7.79 (m, 1H), 7.44−7.41 (massif, 2H), 7.33−7.26 (massif, 2H), 7.00
2
(t, J(H,F) = 55.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 136.2,
1
132.2, 130.4, 123.3, 121.3, 120.2, 117.2 (t, J(C,F) = 290 Hz), 111.6,
3-[(Heptafluoropropyl)selanyl]-1H-indole (7h). Procedure 1.
Redish solid (mp 46−48 °C, calibration substance: azobenzol at
68.0 °C). Eluent for the flash chromatography: pentane/EtOAc 90/10;
1H NMR (400 MHz, CDCl3) δ = 8.49 (br s, 1H), 7.82 (m, 1H), 7.48
(d, J = 2.7 Hz, 1H), 7.42 (m, 1H), 7.36−7.30 (massif, 2H); 13C NMR
(101 MHz, CDCl3) δ = 136.2, 133.8, 130.5, 123.4, 121.7, 120.2, 118.1
(tt, 1J(C,F) = 305 Hz, 2J(C,F) = 38 Hz), 117.7 (qt, 1J(C,F) = 289 Hz,
2J(C,F) = 35 Hz), 111.7, 109.0 (tsext, 1J(C,F) = 263 Hz, 2J(C,F) = 38
93.4 (t, 3J(C,F) = 4 Hz); 19F NMR (376 MHz, CDCl3) δ = −90.60 (d,
2J(F,H) = 54.9 Hz). Anal. Calcd (%) for C9H7F2NSe: C, 43.92; H,
2.87, N 5.69; Se, 32.08. Found: C, 43.75; H, 3.12, N 5.74; Se, 32.28.
3-[(Difluorodeuteriomethyl)selanyl]-1H-indole ([D]10h). To a
flask were added magnesium turnings (93 mg, 3.9 mmol, 10 equiv)
and iodine (14.8 mg, 0.12 mmol, 30 mol), and it was heated up with a
heat gun for 10 min under stirring. The flask was evacuated and refilled
with nitrogen three times before adding a solution of 9h (150 mg, 0.38
mmol, 1 equiv) in CD3OD (3.8 mL, 0.1 M). The mixture was stirred
for 1.5 h at 23 °C, then a second portion of magnesium (187 mg, 7.8
mmol, 20 equiv) was added and the reaction was stirred for a further 2
h. The conversion was checked by 19F NMR with PhOCF3 as internal
standard. A saturated aqueous solution of NH4Cl (10 mL) was added,
and the reaction mixture was extracted with Et2O (15 mL × 3). The
combined organic layers were washed with water and brine, dried over
MgSO4, filtered, and concentrated to dryness. The crude residue was
purified by chromatography (pentane/Et2O 85/15 to 75/25) to afford
3
Hz), 92.1 (t, J(C,F) = 4 Hz); 19F NMR (282 MHz, CDCl3) δ =
−79.87 (t, 4J(F,F) = 9.1 Hz, 3F), −88.46 (qt, 4J(F,F) = 9.1 Hz, 3J(F,F)
= 3.4 Hz, 2F), −122.42 (br s, 2F). Anal. Calcd (%) for C11H6F7NSe:
C, 36.28; H, 1.66, N 3.85; Se, 21.69. Found: C, 36.14; H, 1.49, N 4.12;
Se, 21.51.
Methyl 2-[(2,4-Dihydroxyphenyl)selanyl]-2,2-difluoroacetate
(8b). Procedure 1. Yellow oil. Eluent for the flash chromatography:
cyclohexane/EtOAc 8/2; 1H NMR (400 MHz, CDCl3) δ = 7.40 (d, J
= 8.5 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 6.40 (dd, J = 8.5, 2.6 Hz, 1H),
6.45−6.35 (massif, 2H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
1
2
1
the desired product [D]10h as a yellow oil (55 mg, 58% yield): H
= 162.8 (t, J(C,F) = 30 Hz), 160.8, 158.8, 140.4, 115.9 (t, J(C,F) =
304 Hz), 109.8, 102.6, 100.5 (t, 3J(C,F) = 3 Hz), 54.3; 19F NMR (376
MHz, CDCl3) δ = −82.73 (s, 2F). Anal. Calcd (%) for C9H8F2O4Se:
C, 36.38; H, 2.71; Se, 26.58. Found: C, 36.63; H, 2.89; Se, 26.48.
Methyl 2,2-Difluoro-2-(1H-indol-3-ylselanyl)acetate (8h). Proce-
dure 1. Redish solid (mp 94−96 °C, calibration substance: benzil at
95.0 °C). Eluent for the flash chromatography: pentane/EtOAc 80/20
to 75/25; 1H NMR (400 MHz, CDCl3) δ = 8.67 (br s, 1H), 7.71 (m,
1H), 7.35−7.31 (massif, 2H), 7.27−7.23 (massif, 2H), 3.62 (s, 3H);
NMR (400 MHz CDCl3) δ = 8.43 (br s, 1H), 7.79 (m, 1H), 7.44−
7.41 (massif, 2H), 7.33−7.26 (massif, 2H); 13C NMR (101 MHz,
CDCl3) δ = 136.2, 132.2, 130.4, 123.3, 121.3, 120.2, 116.9 (tt, 1J(C,F)
1
3
= 289 Hz, J(C,D) = 32 Hz), 111.6, 93.3 (t, J(C,F) = 4 Hz); 19F
NMR (376 MHz, CDCl3) δ = −91.33 (t, 2J(F,D) = 8.5 Hz, 2F). Anal.
Calcd (%) for C9H6DF2NSe: C, 43.74; H, 3.26, N 5.67; Se, 31.95.
Found: C, 43.54; H, 2.98, N 5.80; Se, 32.06.
2
13C NMR (101 MHz, CDCl3) δ = 163.2 (t, J(C,F) = 30 Hz), 136.2,
ASSOCIATED CONTENT
■
1
133.4, 130.2, 123.2, 121.3, 119.8, 115.7 (t, J(C,F) = 302 Hz), 111.8,
3
93.1 (t, J(C,F) = 3 Hz), 53.7; 19F NMR (376 MHz, CDCl3) δ =
S
* Supporting Information
−84.47 (s, 2F). Anal. Calcd (%) for C11H9F2NO2Se: C, 43.44; H, 2.98,
N 4.61; Se, 25.96. Found C 43.60; H, 3.22, N 4.36; Se, 26.06.
4-{[(Benzenesulfonyl)difluoromethyl]selanyl}benzene-1,3-diol
(9b). Procedure 1. Off white solid (mp 149−151 °C, calibration
substance: acetanilide at 114.5 °C). After removing volatiles, pentane
was added to the residue and the precipitate was filtered off and
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01344.
Copies of NMR spectra (PDF)
1
AUTHOR INFORMATION
washed with pentane; H NMR (400 MHz, CD3OD) δ = 7.97 (m,
■
2H), 7.81 (m, 1H), 7.67 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 6.39 (d, J =
2.6 Hz, 1H), 6.28 (dd, J = 8.5, 2.6 Hz, 1H); 13C NMR (101 MHz,
CD3OD) δ = 163.2, 162.0, 142.0, 136.8, 133.5, 131.9, 130.6, 126.4 (t,
Corresponding Author
*E-mail: thierry.billard@univ-lyon1.fr.
3
1J(C,F) = 340 Hz), 109.3, 103.6, 99.5 (t, J(C,F) = 2 Hz); 19F NMR
Author Contributions
†Q.G. and E.I. contributed equally.
(376 MHz, CD3OD) δ = −75.51 (s, 2F). Anal. Calcd (%) for
C13H10F2O4SSe: C, 41.17; H, 2.66, S 8.45 Se 20.82. Found: C, 41.27;
H, 2.90, S 8.25; Se, 20.96.
3-{[(Benzenesulfonyl)difluoromethyl]selanyl}-1H-indole (9h). Pro-
cedure 1. Pale brown solid (mp 122−124 °C, calibration substance:
acetanilide at 114.5 °C). After removing volatiles, pentane was added
to the residue and the precipitate was filtered off and washed with
pentane; 1H NMR (400 MHz, CDCl3) δ = 8.75 (br s, 1H), 7.95 (d, J =
7.7 Hz, 2H), 7.79 (m, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.57 (t, J = 7.7 Hz,
2H), 7.52 (m, 1H), 7.41 (m, 1H), 7.29−7.25 (massif, 2H); 13C NMR
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the CNRS, the RADIOMI project
(EU FP7-PEOPLE-2012-ITN-RADIOMI), the French Minis-
try of Research and the French Fluorine Network.
G
DOI: 10.1021/acs.joc.6b01344
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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