Facile and Selective Cross-Coupling of Phenols Using Selenium Dioxide

Article abstract of DOI:10.1002/ejoc.201600886

Nonsymmetric biphenols are important structural motifs in organic chemistry. Therefore, an easy and versatile protocol for oxidative cross-coupling is essential to generate these so-called “privileged ligands”. We developed an efficient and selective oxidative pathway to synthesize 2,2′-biphenols as well as 2,4′- and 4,4′-biphenols. The use of selenium dioxide, a stable, powerful, and commercially available oxidizer, in 1,1,1,3,3,3-hexafluoroisopropanol allowed the oxidative coupling of alkyl-, alkoxy-, and halogen-substituted phenols.

Full text of DOI:10.1002/ejoc.201600886

A Journal of
Accepted Article
Title: Facile and Selective Cross-coupling of Phenols Using Selenium dioxide
Authors: Siegfried R Waldvogel; Thomas Quell; Nicole Beiser; Katrin Dyballa; Ro-
bert Franke
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post their Accepted Article online prior to editing, proofing, and formal publication
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600886
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600886
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European Journal of Organic Chemistry
10.1002/ejoc.201600886
COMMUNICATION
Facile and Selective Cross-coupling of Phenols Using Selenium
dioxide
Thomas Quell,[a] Nicole Beiser,[a] Katrin M. Dyballa,[b] Robert Franke,[b,c] and Siegfried R. Waldvogel*[a]
Abstract: Non-symmetric biphenols are important structural motifs
in organic chemistry. Therefore, an easy and versatile protocol for
oxidative cross-coupling is essential to generate these so called
“privileged ligands”. We developed an efficient and selective
oxidative pathway to synthesize 2,2’-biphenols as well as 2,4’- or
4,4’-biphenols. The use of selenium dioxide, a stable, powerful and
commercially available oxidizer, in 1,1,1,3,3,3-hexafluoroisopropanol
allows the oxidative coupling of alkyl, alkoxy and halogen substituted
phenols.
particular, homo-coupling products, C-O-coupled structures, or
polycyclic by-products may occur.[14] In order to circumvent this
[15]
kind of structural diversity,
template concepts were
established increasing the number of synthetic manipulations.[16]
Employing solvents with a high capability for hydrogen bonding
and outstanding stability towards oxidation turned out to be the
key for the selective cross-coupling reactions of phenols,
phenol-aniline, or phenol-arene substrate combinations.
Particularly, 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), a highly
fluorinated solvent with a high capability for hydrogen bonding, is
able to stabilize reactive intermediates like radicals or radical
Biphenols are well-known structures in organic chemistry
due to their widespread applications. Symmetric and non-
symmetric biphenols are present in various natural products,[1]
drugs[2] and in material sciences.[3] Their outstanding significance
as ligand building blocks for catalytic systems underlines the
importance for scientific and industrial applications.[4] Therefore,
the selective synthesis of biphenols is of utmost interest.
Transition-metal catalyzed C-C cross-coupling reactions give
access to biphenol structures, but they need highly
functionalized compounds and costly catalysts.[5] In particular,
the introduction of specific leaving groups enhances the
synthetic effort of this method to synthesize non-symmetric
biphenols. Oxidative coupling reactions by direct C-H activation
avoid these disadvantages. Recent investigations are dealing
with chromium,[6] vanadium,[7] copper[8] or iron[9] based catalytic
systems, using oxygen or difficult to handle peroxides to
generate the desired biphenols. A very prominent method uses
hypervalent iodine reagents to synthesize biphenyls.[10] Other
oxidants, like potassium persulfate and copper(II)-chloride, are
less expensive, but require additives to increase the
selectivity.[11] Anodic cross-coupling to non-symmetric biphenols
[17]
cations.
Additionally, the solvent is highly stable under
oxidative conditions and can be recycled after the reaction.[12,18]
Selenium dioxide is a versatile, easy to handle and in each
synthetic laboratory readily available oxidizer which is obtained
by roasting of copper, lead, zinc or iron ores.[19] In the course of
oxidative transformations elemental selenium is generated. This
can be reoxidized by heating at aerobic conditions.[20] Therfore it
is an excellent oxidizer for scientific and industrial applications.
Recently, we reported the first selective oxidative homo-coupling
of phenols using selenium dioxide as oxidizer.[21] In that study,
solvent turned out to be crucial for the transformation to obtain
selectively either the diaryl selenides or the 2,2’-biphenols.
Here, we report the first, selenium dioxide-mediated, phenol-
phenol cross-coupling. Initially, we determined the best solvent
system for a selective cross-coupling process.
is
a
cutting-edge sustainable concept of contemporary
rather specific laboratory set-up
research.[12] However,
a
including electrode materials and supporting electrolyte is
necessary. This might be a barrier for the applicability in
standard laboratories.[13]
Scheme 1. Test substrate combination for cross-coupling.
Especially, the selective cross-coupling of phenols is still
challenging because of broad scope of possible by-products. In
Therefore, we tested the conversion of 2,4-bis(1,1-
dimethylethyl)phenol (1) and 2,6-dimethoxyphenol (2) in acetic
acid at 85 °C (Scheme 1). However, gas chromatographic
analysis of those runs indicated no significant selectivity for the
formation of mixed biphenols. Instead, the homo-coupling
products (4, 5) were preferentially obtained. Similar solvents
like formic acid[12,18] generated further by-products, but not the
displayed biphenol structures (3-5). However, 1,1,1,3,3,3-
hexafluoropropan-2-ol (HFIP) yielded the desired product
(3).For better reaction rates, we performed the reaction at 55 °C.
In addition, other fluorinated solvents like trifluoroacetic acid
lead to very sluggish reaction. Next, we optimized the ratios of
the phenolic components 1 and 2 with respect to yield and
selectivity. Former studies indicated that the oxidation of 1 is
[a]
T. Quell, N. Beiser, 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
Dr. K. M. Dyballa, Prof. Dr. R. Franke
Evonik Performance Materials GmbH
Paul-Baumann-Straße 1, 45772 Marl (Germany)
Prof. Dr. R. Franke
[b]
[c]
Department of Theoretical Chemistry
Ruhr-Universität Bochum
44780 Bochum (Germany)
Supporting information for this article is given via a link at the end of
the document.

European Journal of Organic Chemistry
10.1002/ejoc.201600886
COMMUNICATION
more facile than 2.[21] Thus, we decided to use component 1 in
excess compared to phenol 2. Table 1 summarizes the results of
this study: The use of equimolar amounts of 1 and 2 lead to
acceptable ratios of the desired product 3 compared to the
undesired homo-coupling products 4 and 5. However, the yield
was rather low. (Table 1, entry 1).
offer subsequent options for functionalization. The use of
halogen-equipped starting materials in oxidative coupling
reactions is very challenging. These substituents (particularly
iodine is a good leaving group) and oxidative treatment in the
presence of water can lead to quinone formation.
Table 2. Scope for ortho-para coupling to 2,4’-biphenols.
Table 1. Selectivity of phenol-phenol cross-couplings dependent on the
component ratio.
Product
Yield[a]
/%
Product
Yield[a]
/%
Entry
Ratio 1:2
1:1
Selectivity 3 to 4 to 5[a]
77:11:12
Yield of 3 /%
1
2
3
4
21
38
49
74
2:1
87:5:8
74
52
3:1
92:4:4
5:1
94:3:3
[a] Data obtained by gas chromatography.
Increasing excess of 1 lead to a preferential generation of
the cross-coupling product 3 coming along with enhanced yields
(Table 1, entries 2 and 3). The best result was obtained by
application of five equivalents of 1 providing good yields up to
74% (Table 1, entry 4). Non-converted phenol 1 can be easily
recycled by bulb-to-bulb distillation leading to a quick and
synthetically applicable transformation. Consequently, this ratio
was employed for the elucidation of the scope. Based on the
minor component 2, only one equivalent selenium dioxide was
required, independent from the amount of phenol 1 used. This
implies a preferred oxidation of phenol 2 followed by reaction
with abundant component 1. This protocol gave rise to
49
44
35
39
generating selectively
biphenols.
a broad scope of non-symmetrical
42
40
Table 2 displays a variety of novel ortho-para coupled
products. Therefore, 2,6-dimethoxyphenol (1) turned out to be a
suitable phenol in excess since the free position in para acts as
preferred reaction site. Conversions with other phenols
exhibiting more or less bulky alkyl groups, e.g. methyl, ethyl, 1,1-
dimethylethyl, or 1,1-dimethylpropyl, in position 2 and 4 yielded
the desired products 3, 6-10 in moderate to good yields. It is
also viable to use other, methoxy substituted, phenols as excess
components with a free position in ortho (10-13).
29
The optimized protocol was applied to a broad range of
phenols to generate the corresponding ortho-ortho cross-
coupling products (Table 3). Here, 2-methoxy-4-methylphenol is
a versatile excess component providing access to 14-19. Similar
phenols such as 4-ethyl-2-methoxyphenol are also applicable
leading to 20. These methoxy-substituted phenols give rise to a
lot of other cross-coupling products. Interestingly, in addition to a
wide range of different alkyl substituents, 2,4,5-trisubstitued
phenols turned out to be suitable. The additional steric demand
in position five seems to have no negative impact (14-15).
Ratio phenol A (blue) to phenol B (red): 1 : 5.
[a] Isolated yield. All reactions were carried out in HFIP as solvent with 0.6
equivalents of selenium dioxide at 55 °C
We applied a variety of halogen-substituted phenols as
excess component with good results, yielding the desired
products in up to 54% (Table 3). The reaction of 2,4-bis(1,1-
dimethylethyl)phenol with 3-iodo-4-methoxyphenol yielded a
2,2’-biphenol 21. But surprisingly the new bond was formed at
the more sterically congested position between hydroxyl and
iodo substituent. Enlarging the alkyl-substituent from 1,1-
dimethylethyl to 1,1-dimethypropyl changed the selectivity
generating biphenol 22 at the less hindered position. The use of
Since 2,2’-biphenols are the most important derivatives for
various applications,[4] we tried to expand our method in this field.
In particular, halogenated products are interesting because they
3-bromo-4-methylphenol
in
combination
with
2-(1,1-

European Journal of Organic Chemistry
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COMMUNICATION
equivalents of selenium dioxide at 55 °C
dimethylethyl)-4-ethylphenol yielded a brominated biphenol 23
comparable to 21. Additionally, a variety of chlorinated products
were isolated in moderate yields using 4-chloro-5-methyl-2-(1-
methylethyl)phenol (24-26)
Finally, we could show that 4,4’-biphenols by the
combination of two 2,6-substitued phenols are accessible. Again,
2,6-dimethoxyphenol was employed as the excess phenolic
compound yielding the biphenols 27 and 28 in good yields
(Table 4).
Table 3. Scope for ortho-ortho coupling to 2,2’-biphenols.
Product
Yield[a]
/%
Product
Yield[a]
/%
Table 4. Substrate scope of the selenium dioxide-mediated coupling of
electron-rich arenes.
Product
Yield[a]
/%
Product
Yield[a]
/%
66
55
44
51
71
56
Ratio phenol A (blue) to phenol B (red): 1 : 5.
[a] Isolated yield. All reactions were carried out in HFIP as solvent with 0.6
equivalents of selenium dioxide at 55 °C
In conclusion, we found a very simple to perform and
versatile protocol for the oxidative cross-coupling of phenols. By
this method selectively either 2,2’-, 2,4’-, or 4,4’- biphenols are
accomplished. The substituents on the biphenols range from
alkyl to alkoxy, chloro, bromo and iodo. Selenium dioxide as
common reagent in organic synthesis laboratories serves as
oxidizer and 1,1,1,3,3,3-hexafluoroisopropanol as selectivity
directing solvent. By this method, 19 novel biphenols could be
quickly generated in very good selectivity. Even if the yield is in
the moderate range, the desired products can be easily isolated.
The fluorinated solvent can be efficiently recycled and excess
phenolic components directly recovered by bulb-to-bulb
distillation.
38
45
32
23
54
31
Experimental Section
For experimental details and analytical data see SI.
Acknowledgements
26
22
26
Financial support by Evonik Performance Materials GmbH (Marl,
Germany) is highly appreciated. S.R.W. in particular appreciates
the donation of selenium dioxide by RETORTE GmbH (Arubis),
Röthenbach.
Keywords: selenium • oxidation • C-C coupling • arenes •
biaryls
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European Journal of Organic Chemistry
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Layout 2:
COMMUNICATION
T. Quell, N. Beiser, K. M. Dyballa,
R. Franke, S. R. Waldvogel*
Page No. – Page No.
Facile and Selective Cross-coupling
of Phenols Using Selenium dioxide
With a little help from the solvent 1,1,1,3,3,3-hexafluroisopropanol (HFIP) and
the common oxidizer selenium dioxide, phenolic substrates are selectively
converted into the mixed respective biphenols.