Transition-metal-free phenylselenylation of arenes with triflic anhydride activated methyl phenyl selenoxide

Full text of DOI:10.1016/j.tetlet.2018.07.005

Accepted Manuscript
Transition-metal-free Phenylselenylation of Arenes with Triflic Anhydride Ac-
tivated Methyl Phenyl Selenoxide
Yuyao Shi, Pingfan Li
PII:
S0040-4039(18)30856-6
https://doi.org/10.1016/j.tetlet.2018.07.005
TETL 50114
DOI:
Reference:
Tetrahedron Letters
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29 April 2018
27 June 2018
2 July 2018
Please cite this article as: Shi, Y., Li, P., Transition-metal-free Phenylselenylation of Arenes with Triflic Anhydride
Activated Methyl Phenyl Selenoxide, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.005
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Transition-metal-free Phenylselenylation of Arenes with Triflic
Anhydride Activated Methyl Phenyl Selenoxide
Yuyao Shi and Pingfan Li*
Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, China
*E-mail: lipf@mail.buct.edu.cn
Table of Content/Abstract graphic
Phenylselenylation of arenes were achieved in a one-pot procedure by treating arene substrates with triflic
anhydride activated methyl phenyl selenoxide, and then demethylation with diisopropylamine. This reaction
provide a convenient method to prepare diarylselenide products under transition-metal-free conditions.
Organoselenides, in particular diarylselenides,1 are a class of molecules with important biological activity.2
Traditional methods for the synthesis of diarylselenides usually involves the reaction between aryl Grignard
or aryllithium reagents with electrophilic arylselenium reagents,3 or alternatively, aryldiazonium salts with
nucleophilic arylselenium reagents.4 Transition-metal catalyzed cross-coupling reactions between aryl
halides or aryl boronic acids with phenylselenyl chloride, diphenyl diselenide or phenylselenyl tributyltin
reagents were also extensively examined.5 Recently, a number of transition-metals have been used to
catalyzed the phenylselenylation of arene C-H bonds ortho to the directing groups, including palladium,6
rhodium,7 ruthenium,8 copper,9 and iron (Scheme 1a).10 For the synthesis of α,β-unsaturated carbonyl
compounds through oxidation and elimination of corresponding α-selenylated carbonyl compounds,
phenylselenylation of enol derivatives were widely used to prepare such precursors.11 Phenylselenylation of
alkenes were also accomplished with electrophilic arylselenium reagents, and there has been some great
interest to render such reactions catalytic enantioselective.12 However, if phenylselenylation of arenes were
attempted with PhSeCl, except for electron-rich aniline type substrates, chlorination products were obtained
in most cases instead of the desired selenylation products (Scheme 1b).13

Scheme 1. Phenylselenylation of arene C-H bonds. DG = directing groups, Tf2O =
trifluoromethanesulfonic anhydride
In connection with our group’s continuous interest in sulfur mediated C-H functionalization reactions,14 and
Procter’s report for the synthesis of diarylthioethers through triflic anhydride activated sulfoxides,15 we would like to
extend such reactions to the corresponding selenium versions. It should be noted that despite the recent interest in
studying various reactivity of triflic anhydride activated sulfoxides,16 research work on corresponding selenium
version is still very rare. We report herein our results for the preparation diarylselenides under transition-metal-free
conditions through a one-pot, two-step sequence: electrophilic substitution of arenes with triflic anhydride activated
methyl phenyl selenoxide, and then demethylation of the initially formed diaryl methyl selenonium salt with
diisopropylamine (Scheme 1c).
The reaction between p-xylene (1a) and triflic anhydride activated methyl phenyl selenoxide (2) was chosen as the
model reaction to optimize the reaction conditions (Scheme 2). When 2.1 equivalent of DBU was used as the base for
the demethylation step, the desired product 3a was isolated in 13% yield (entry 1). The use of pyridine type bases did
not improve the reaction yield (entries 2-5), while MeONa/MeOH gave 31% yield (entry 6). We then screened a
number of amine bases (entries 7-12), and the best result was obtained with diisopropylamine (entry 12). By
increasing the amount of diisopropylamine, up to 87% yield of 3a was obtained (entries 13-15). Increasing the
reaction time for the second step did not increase the isolated yield (compare entries 14 and16), while the yield
dropped at higher temperature (entry 17). Finally, 92% yield of 3a was obtained when we lowered the reaction
temperature for the second step to 0 ºC (entry 18). Thus, the optimized one-pot, two-step reaction procedure was:
dissolve 2 with CH2Cl2, add Tf2O at −35 ºC, and then add 1a. After 15 min, the reaction tube was warmed up to room
temperature for 1.5 h. After cooling down to 0 ºC, diisopropylamine was added and stirred for 11 h before
quenching.

Scheme 2. Optimization of reaction conditions
entry
1
2
3
4
5
6
7
8
base
DBU
equiv time (h)
yield (%)a
13
10
trace
10
trace
31
5
15
8
23
15
31
54
87
79
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
4.2
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
pyridine
2,6-lutidine
2,6-dichloropyridine
2,6-difluoropyridine
MeONa/MeOH
Et2NH
Et3N
9
morpholine
10
11
12
13
14
15
16
17
18
nPr2NH
tBuNH2
iPr2NH
iPr2NH
iPr2NH
iPr2NH
6
4
iPr2NH
5
5
5
11
11
11
87
iPr2NH
48b
92c
iPr2NH
a Isolated yields after flash column chromatography. The second step was conducted at 40 oC. The second step was
b
d
o
conducted at 0 C.
We then explored the substrate scope for a number of arene substrates to synthesize corresponding diarylselenide
products (Scheme 3). As expected for the electrophilic substitution reaction during the first step that lead to diaryl
methyl selenonium salt, electron-rich arene substrates generally react better for this reaction. p-Xylene (1a) and
m-xylene (1b) gave 3a and 3b in 92% and 94% yield, respectively. Mesitylene (1c) gave product 3c in a slightly lower
85% yield, probably because the arene substrate 1c is sterically more hindered than 1a and 1b.
1,4-dimethoxybenzene (1d), 1,3,5-trimethoxybenzene (1e) and 1,2,3-trimethoxybenzene (1f) gave products 3d, 3e
and 3f in 82%, 87% and 83% yield, respectively. 2-Iodoanisole (1g) and 3-iodoanisole (1h) gave 3g and 3h in 74% and
69% yield, respectively. Product 3i bearing
a bromo substituent can also be prepared in 64% yield.
2-methoxynaphthalene (1j) gave product 3j in 77% yield. Less electron-rich biphenyl (1k) reacted poorly, and the
desired product 3k was isolated in only 22% yield. For heteroarene substrates, thiophene (1l) also gave corresponding
diarylselenide 3l in 86% yield. All these products were obtained without abnormal regioselectivity issues. Other arene
substrates (data not shown in scheme 3), such as benzene, toluene, halobenzenes, and naphthalene, all gave less
than 10% yield and mixture of regioisomers. Arenes containing electron-withdrawing groups, such as carbonyl groups,
were not reactive under these conditions. On the other hand, electron-rich heteroarenes, such as furan and indole,
gave complex mixture and no major products were isolated.

Scheme 3. Substrate scope
The proposed reaction mechanism is shown in Scheme 4. Oxyselenonium salt A generated from selenoxide and
triflic anhydride was attacked by electron-rich arene substrates to give the electrophilic aromatic substitution
products B as key intermediates after step 1, whose methyl group was attacked by the nucleophilic amine nitrogen to
give the desired phenylselenylation products and ammonium salt C as by-product.
Scheme 4. Proposed mechanism

In summary, we developed
a convenient method for the preparation of diarylselenides through
phenylselenylation of arenes in a one-pot procedure by treating arene substrates with triflic anhydride activated
methyl phenyl selenoxide, and then demethylation with diisopropylamine. We are currently exploring other synthetic
applications of such highly electrophilic selenium reagent generated from selenoxide and triflic anhydride, and those
results will be reported in due course.
Acknowledge
This research was supported in part by National Natural Science Foundation of China (21402005).
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Transition-metal-free Phenylselenylation of Arenes with Triflic Anhydride Activated Methyl
Phenyl Selenoxide
Highlights
Highly electrophilic selenium reagent was generated from selenoxide and triflic anhydride.
The substitution reaction with such selenium reagent proceed with innate regioselectivity of
the aromatic ring.
Demethylation of diaryl methyl selenonium salt is accomplished with diisopropylamine.