Solvent-Dependent Facile Synthesis of Diaryl Selenides and Biphenols Employing Selenium Dioxide

Article abstract of DOI:10.1002/open.201500206

Biphenols are important structure motifs for ligand systems in organic catalysis and are therefore included in the category of so-called "privileged ligands". We have developed a new synthetic pathway to construct these structures by the use of selenium dioxide, a stable, powerful, and commercially available oxidizer. Our new, and easy to perform protocol gives rise to biphenols and diaryl selenides depending on the solvent employed. Oxidative treatment of phenols in acetic acid yields the corresponding biphenols, whereas conversion in pyridine results in the preferred formation of diaryl selenides. As a consequence, we were able to isolate a broad scope of novel diaryl selenides, which could act as pincer-like ligands with further applications in organic synthesis or as ligands in transition metal catalysis.

Full text of DOI:10.1002/open.201500206

DOI: 10.1002/open.201500206
Solvent-Dependent Facile Synthesis of Diaryl Selenides
and Biphenols Employing Selenium Dioxide
Thomas Quell,[a] Michael Mirion,[a] Dieter Schollmeyer,[a] Katrin M. Dyballa,[b] Robert Franke,[b, c] and
Siegfried R. Waldvogel*[a]
Biphenols are important structure motifs for ligand systems in
organic catalysis and are therefore included in the category of
so-called “privileged ligands”. We have developed a new syn-
thetic pathway to construct these structures by the use of sele-
nium dioxide, a stable, powerful, and commercially available
oxidizer. Our new, and easy to perform protocol gives rise to
biphenols and diaryl selenides depending on the solvent em-
ployed. Oxidative treatment of phenols in acetic acid yields the
corresponding biphenols, whereas conversion in pyridine re-
sults in the preferred formation of diaryl selenides. As a conse-
quence, we were able to isolate a broad scope of novel diaryl
selenides, which could act as pincer-like ligands with further
applications in organic synthesis or as ligands in transition
metal catalysis.
to be the singular example of commercial interest.[5j] Recently,
a few examples for the conversion of phenols using SeOCl2 or
SeCl2/AlCl3 mixtures were reported.[7] Consequently, a facile
synthetic approach to such diaryl selenides would be of gener-
al interest. The oxidative treatment of phenols can provide bi-
phenols,[8] which are of tremendous academic and industrial
significance as building blocks for ligands in homogenous cat-
alysis,[9] building blocks for material science,[10] or in natural
product synthesis.[11] In particular, the conversion of simple
methyl substituted phenols, that is 2,4-dimethylphenol, has
turned out to be challenging.[12] The formation of polycyclic
by-products is very dominant and can lead to high structural
diversity.[13] Several concepts were elaborated to obtain the in-
teresting 2,2’-biphenol in acceptable selectivity.[14] However,
most of them require an electrochemical setup.[15] Therefore,
a simple and easy-to-perform method to access the 2,2-biphe-
nols is also highly desired.
The use of selenium dioxide as catalytic or stoichiometric re-
agent is currently experiencing a renaissance.[1] Selenium di-
oxide is a readily available and stable selenium reagent, which
is commonly employed for oxygenation reactions.[2] Remarka-
bly, the product distribution in stereoselective selenation reac-
tions seems to be strongly solvent dependent.[3] The chemistry
of diaryl selenides is only moderately explored despite the
stable molecular entity and interesting structural feature.[4] In
particular, hydroxy-substituted compounds have potential use
as ligands or building blocks.[5] However, the synthesis requires
a multistep approach usually starting with aryl halides, seleni-
um, and a reducing agent, for example, sodium.[6] The employ-
ment of phenols would require a set of protective groups. In-
terestingly, the direct conversion of 2,4-di-tert-butylphenol with
selenium dioxide to the corresponding diaryl selenide seems
Here, we report a solvent-dependent conversion of simple
phenols with selenium dioxide, yielding the corresponding bi-
phenols or diaryl selenides (Scheme 1).
Scheme 1. Test reaction using selenium dioxide.
Initial studies were performed with 2,4-dimethylphenol (1)
as test substrate, since we already have experience with the
complex product diversity formed in this particular conversion
to biphenol 2.[12] The analysis of the reaction mixtures revealed
that indeed, the desired biphenol 2 was formed. In addition,
two by-products were identified: First, a derivative of Pummer-
er’s ketone (3) which is an isomer to 2 and often preferentially
formed upon oxidative treatment.[16] Secondly, a previously not
observed by-product in the oxidation of 1 was isolated. Mass
spectrometric analysis of the gas chromatography (GC) peak
clearly indicated the typical isotope pattern of selenium. Based
on NMR spectroscopic data, the structure of 4 could be pro-
posed, wherein two phenolic moieties are tethered by a seleni-
um atom. X-ray analysis of suitable single crystals verified the
molecular structure of bis(3,5-dimethyl-2-hydroxyphenyl)seleni-
um (Figure 1.). Therein the CÀSeÀC motif has an angle of
97.(22)8 with a distance of 0.28 nm between both oxygen
[a] T. Quell, Dr. M. Mirion, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel
Department of Organic Chemistry, Johannes Gutenberg University Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
[b] Dr. K. M. Dyballa, Prof. Dr. R. Franke
Evonik Performance Materials GmbH
Paul-Baumann-Straße 1, 45772 Marl (Germany)
[c] Prof. Dr. R. Franke
Department of Theoretical Chemistry, Ruhr-Universität Bochum, 44780
Bochum (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/open.201500206.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
made.
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Table 1. Solvent-dependent product distribution in the conversion of 1.
Solvent
T [8C]
t [min]
Yield [%][a]
2
3
4
None
1,4-Dioxane
THF
Toluene
Xylene
85
85
65
85
85
85
85
60
55
55
60
60
60
340
300
450
120
300
1380
300
300
45
36
–
21
48
22
84
88
81
2
4
9
–
2
19
5
22
8
–
10
4
25
3
1
1
85
9
–
Figure 1. Molecular structure of bis(3,5-dimethyl-2-hydroxyphenyl)selenium
(4) as top and side view.
DMF
Acetic acid
Formic acid
HFIP
1
Traces
1
Traces
Traces
–
atoms and 0.31 nm between the selenium and oxygen atoms.
This gap specifies the size of a complexation center.
90
Pyridine
4320
1440
5760
180
Next, the influence of the solvent onto the product distribu-
tion was studied. Since 2,4-dimethylphenol is liquid, the con-
version was carried out neat. Although a pronounced selectivi-
ty for the biphenol is apparent, significant amounts of the or-
ganoselenium species are observed (Table 1, entry 1). Most im-
portantly, only traces of the common by-product 3 are detect-
ed. During the course of reaction, the mixture solidifies and
therefore, the use of solvents was indicated. The conversion in
cyclic ethers rendered both lower selectivity and productivity.
Interestingly, the earlier report employed such solvents,[17] and
this might explain why this conversion was not studied further
because of the sluggish reaction mixture.
Quinoline
1-Methylimidazole
Triethylamine
Traces
–
–
–
–
[a] Data were obtained by gas chromatographic analysis.
was obtained in its black elemental modification, which can be
directly filtered off from the reaction mixture for recycling pur-
Table 2. Substrate scope of the selenium-dioxide-mediated phenol
coupling.
The absence of the desired product in tetrahydrofuran (THF)
can be attributed to the oxidation of the solvent. Conducting
the reaction in aromatic solvents like toluene did not improve
the reactivity. Interestingly, the use of xylene lead to a change
in selectivity with 3 becoming more dominant. A protic polar
solvent such as dimethylformamide (DMF) led to almost no se-
lectivity between 2 and 4. Switching to protic media changed
the situation dramatically. Acetic acid at 858C promoted the
formation of the desired biphenol 2 in high selectivity. Formic
acid turned out to be also a suitable solvent, but the instability
towards selenium dioxide required a lower temperature, and
the hazard of spontaneous decomposition is still a hazard chal-
lenge. 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) represents
a protic solvent with high capability for hydrogen bonding,
which turned out to be useful in phenol-coupling reactions.[18]
In this media, almost exclusively 3,3’,5,5’-tetramethyl-2,2’-bi-
phenol (2) was formed in high quantity. Both by-products
were only detected in trace amounts. When switching to the
basic solvent pyridine, a complete reversal of selectivity in
favour of 4 was observed. The selenium compound is by far
the major product.
Product
Yield[a]
[%]
Product
Yield[a]
[%]
61[b]
57[c]
38[c]
33[c]
36[b]
39[b]
The optimal reaction temperature was 558C. Higher temper-
atures led to decreased selectivity, and operation at lower tem-
perature required significantly prolonged reaction times. It is
noteworthy, that other nitrogen-based basic solvents showed
very low or almost no conversion. The lack of product forma-
tion in the presence of triethylamine could be attributed to
the oxidation of the solvent by the selenium reagent. The low
costs, good environmental footprint, and simple-to-perform
work-up when using acetic acid prompted us to conduct the
studies for biphenol synthesis with this particular solvent.
On a preparative scale (81 mmol), the generation of 2 was
achieved in 61% isolated yield. The reagent waste selenium
50[b]
47[b]
41[c]
47[b]
[a] Isolated yield. All reactions were carried out in acetic acid as solvent
with selenium dioxide (0.6 equiv) at [b] 858C, [c] 1008C.
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poses. The excellent selectivity for the biphenol in acetic acid
allowed the isolation of the desired product by a simple ex-
traction and subsequent crystallization protocol. This simple-
to-perform work-up could be the crucial basis for a latter po-
tential scalability. The method was applied to variety of
different phenolic substrates to elucidate the scope of
this method. Here, we focused on different alkyl substitu-
tion patterns on the phenolic substrates including
methyl, isopropyl, tert-butyl, and 1,1-dimethylpropyl frag-
ments. These biphenols play an important role as ligand
precursors in homogeneous catalysis.
With this procedure in hand, we treated a broad variety of
phenols in order to elucidate the scope (Table 3). Almost all
counterparts of the alkyl-substituted biphenols were generated
by switching the solvent to pyridine. The unique selectivity for
Table 3. Substrate scope of the selenium-dioxide-mediated synthesis of diaryl
selenides.
Product
Yield[a]
[%]
Product
Yield[a]
[%]
To generate 2,2’-biphenols selectively, the position 4
should be blocked to avoid the formation of regioisom-
ers. Conversely, blocking of the ortho-positions provides
synthetic access to 4,4’-biphenols. Oxidation of phenols
with a substitution pattern could result in the formation
of quinones.[19] The optimized conversions of the differ-
ent alkyl-substituted phenols required reaction times in
the range of 30–300 min (Table 2). The reaction tempera-
tures are as noted either 858C or 1008C and represent
optimized conditions. All products were purified by a fil-
tration column and subsequent crystallization. Only bi-
phenol 12 had to be purified by a bulb-to-bulb distilla-
tion. In general, a 2,4-disubstituion pattern seems to be
suitable for this biphenol synthesis. If the positions ortho
were blocked, the coupling proceeded in para yielding
4,4’-biphenol 10 in 50% yield. The 2,4,5,-trisubstition pat-
tern turned out to be beneficial as well, and the biphe-
nols were reliably isolated in 41–47% yield. The added
steric demand of the positions 5 seemed to have no ad-
verse effect.
56[b]
25[b]
38[b]
36[b]
25[b]
27[b]
53[b]
36[b]
In addition to the biphenol homocoupling, we identi-
fied bis(3,5-dimethyl-2-hydroxyphenyl)selenium (4) as un-
expected by-product. The use of pyridine propelled the
organoselenium compound to be the major product. The
previous difficulties in preparation of these diaryl sele-
nides could be a reason for the rare use of such com-
pounds. The molecular architecture is very close to the
biphenol structure; however, the selenium center may
act as an additional complexation position. Thus, these
components could be classified as tridentate, pincer-like
ligands. Consequently, diaryl selenides could be new and
useful building blocks for ligands in homogeneous catal-
ysis.[20] Currently, no general and easy-to-perform synthet-
ic pathway is available. Therefore, the scope was eluci-
dated for the generation of diaryl selenides starting from
the simple phenols. As outlined in Table 1, pyridine was
stable under oxidative conditions.[21] When conducting
the conversion at 558C, only traces of the biphenol 2
were detected but no Pummerer’s ketone. The outstand-
ing selectivity at lower temperatures caused significantly
prolonged reactions times. For an isolated yield of 56%
4, a reaction time of to three days was required. How-
ever, the work-up of the reaction mixture turned out to
be reasonably simple and scalable as well. The reaction
mixture was subjected to a simple protocol of extraction
and crystallization.
39[b]
19[b]
48[b]
40[b]
37[b]
64[b]
40[b]
[a] Isolated yield. All reactions were carried out in pyridine as solvent with
0.6 equivalents of selenium dioxide at [b] 558C, [c] 858C.
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the diaryl selenides was verified for all of these phenolic sub-
strates. In addition to the alkyl substitution pattern at the phe-
nols, we subjected even more functionalized phenols to this
protocol. Interestingly, an additional methoxy group, which in-
creases the electron density on the substrate, was successfully
converted, but the reaction rate was dramatically decreased.
This seemed to be contradictory for an oxidative process.
Other heteroatoms such as halogens would change the elec-
tronic properties, lipophilicity, and might offer subsequent
modifications on the diaryl selenides scaffold. We were pleased
to see that chloro and bromo substituents were compatible
with this transformation leading to the compounds 23–25 in
acceptable yield for this simple protocol. However, due to the
deactivated nature of the starting materials, reaction times of
seven to ten days were required. For the treatment of fluoro-
phenols, elevated reaction temperatures to 858C were required
but gave access to these highly halogenated diaryl selenides in
excellent selectivity.
Experimental Section
For experimental details and analytical data, see the Supporting
Information.
Acknowledgements
Financial support by Evonik Performance Materials GmbH (Marl,
Germany) is highly appreciated. S. R. W., in particular, appreciates
the literature support and fruitful discussions with R. Daniel Little
(University of California, Santa Barbara, USA).
Keywords: arenes
·
biaryls
·
catalysis
·
CÀC coupling
·
oxidation · selenium dioxide
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