Metal- and Reagent-Free Dehydrogenative Formal Benzyl–Aryl Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol

Article abstract of DOI:10.1002/anie.201804997

A selective dehydrogenative electrochemical functionalization of benzylic positions that employs 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) has been developed. The electrogenerated products are versatile intermediates for subsequent functionalizations as they act as masked benzylic cations that can be easily activated. Herein, we report a sustainable, scalable, and reagent- and metal-free dehydrogenative formal benzyl–aryl cross-coupling. Liberation of the benzylic cation was accomplished through the use of acid. Valuable diarylmethanes are accessible in the presence of aromatic nucleophiles. The direct application of electricity enables a safe and environmentally benign chemical transformation as oxidizers are replaced by electrons. A broad variety of different substrates and nucleophiles can be employed.

Full text of DOI:10.1002/anie.201804997

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Metal- and Reagent-Free Dehydrogenative Benzyl-Aryl
Formal Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-
Hexafluoropropan-2-ol
Authors: Siegfried R Waldvogel, Yasushi Imada, Johannes L Röckl,
Anton Wiebe, Tile Gieshoff, Dieter Schollmeyer, Kazuhiro
Chiba, and Robert Franke
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804997
Angew. Chem. 10.1002/ange.201804997
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http://dx.doi.org/10.1002/ange.201804997

10.1002/anie.201804997
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COMMUNICATION
Metal- and Reagent-Free Dehydrogenative Formal Benzyl-Aryl
Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-
Hexafluoropropan-2-ol
Yasushi Imada,[a,b,c] Johannes L. Röckl,[a] Anton Wiebe,[a,d] Tile Gieshoff,[a,c] Dieter Schollmeyer,[a]
Kazuhiro Chiba,[b] Robert Franke,[e,f] and Siegfried R. Waldvogel*[a,c,d]
involves a multi-step sequence, being cost- and time-consuming, and
lacking atom efficiency. Pre-functionalized starting materials have to
Abstract:
The
selective
dehydrogenative
positions
electrochemical
by 1,1,1,3,3,3-
be prepared under difficult reaction conditions. Catalysts, mostly Pd-
based, are also required for the final coupling reaction. Furthermore,
reagent waste is generated in each individual step. The activation of
C-H bonds in such reactions has only been achieved in a few
examples, with a limited substrate scope.[5] A considered as a Friedel-
Crafts-type conversion. Hydroxyl-, halogens or acetoxy substituents
are cleaved in benzylic positions by metal catalysts to generate
cationic intermediates. These can undergo coupling reactions with
nucleophilic arenes. The activation by metal catalysts is indispensable
in most cases and a variety of catalysts has been employed (RhCl3,[6]
IrCl3,[6] H2PdCl4,[6] H2PtCl6,[6] HAuCl4,[7] FeCl3[8], and Bi(OTf)3).[9]
functionalization
of benzylic
hexafluoropropan-2-ol (HFIP) is presented for the first time. The
electro-generated products are versatile intermediates for subsequent
functionalizations, as they act as masked benzylic cations, which can
be easily activated. Herein, we report a sustainable, scalable,
reagent- and metal-free dehydrogenative formal benzyl-aryl cross-
coupling. Liberation of the benzylic cation is accomplished by acid.
Valuable diarylmethanes are accessible in the presence of aromatic
nucleophiles. The direct application of electricity enables a safe and
environmentally benign chemical transformation, since oxidizers are
replaced by electrons. A broad variety of different substrates and
nucleophiles is suitable.
Diarylmethanes are an important motif in biologically active
compounds,[1] medicinal chemistry,[2] and material science.[3] In
general, two different synthetic approaches to symmetric and non-
symmetric diarylmethanes are available. Common protocols exploit
transition metal-catalyzed coupling reactions of benzyl halides with
pre-functionalized aromatic nucleophiles, or aryl halides with benzylic
nucleophiles.[4] However, conventional cross-coupling reactions (e.g.
Suzuki-Miyaura or Kumada-Corriu coupling reactions) share several
major disadvantages: the synthesis of the desired diarylmethanes
[a]
Y. Imada, J. L. Röckl, Dr. A. Wiebe, Dr. T. Gieshoff, Dr. D.
Schollmeyer, Prof. Dr. S. R. Waldvogel
Institute of Organic Chemistry
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: waldvogel@uni-mainz.de
Homepage: http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/
Y. Imada, Prof. Dr. K. Chiba
[b]
[c]
[d]
Department of Applied Biological Science
Tokyo University of Agriculture and Technology
3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
Y. Imada, Dr. T. Gieshoff, Prof. Dr. S. R. Waldvogel
Graduate School Materials Science in Mainz
Johannes Gutenberg University Mainz
Staudingerweg 9, 55128 Mainz, Germany
Dr. A. Wiebe, Prof. Dr. S. R. Waldvogel
Max Planck Graduate Center
Johannes Gutenberg University Mainz
Forum universitatis 2, 55122 Mainz, Germany
Prof. Dr. R. Franke
Evonik Performance Materials GmbH
Paul-Baumann-Str. 1, 45772 Marl, Germany
Prof. Dr. R. Franke
[e]
[f]
Scheme 1. Strategies to benzyl-aryl coupling in comparison to our new method.
Lehrstuhl für Theoretische Chemie
Ruhr-Universität Bochum
Universitätstraße 150, 44801 Bochum, Germany
In addition to the complex reaction conditions required (elevated
temperature, dry solvents, and/or inert atmosphere), low
regioselectivity and large amounts of salts as reagent waste are
further disadvantages.[6]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804997
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The avoidance of the use of stoichiometric reagents and reagent
waste is an important factor in developing an environmentally
benign, “greener” route to diarylmethanes.[10] For this purpose,
methods for dehydrogenative coupling reactions are of great
interest. Electrochemistry, in particular anodic conversion, is a
valuable tool for the development of such metal- and reagent-free
sustainable transformations.[11] This has been recently
demonstrated with an electrochemical benzylic-arylic coupling for
the synthesis of diarylmethanes developed by Yoshida.[12] For
accumulation of the electrochemically oxidized species in this
procedure, the intermediates require trapping of the benzylic
cations formed with an additional reagent, due to their highly
reactive nature. Subsequent elimination of the stabilizing reagent
and coupling with aromatic nucleophiles was then carried out.
Due to separation of oxidative and coupling events, bond
formation occurs in a selective manner. However, this method
exhibits some drawbacks. The stabilizing reagent is not
commercially available and has to be used in large excess. The
coupling reaction can require up to 35 hours to completion, and
all conversions were only demonstrated at small scale (0.1 mmol).
The application of free phenols for the anodic step has not been
reported. In addition, due to the complex electrolysis set-up (a
divided cell equipped with a very specific carbon fiber anode) the
procedure is not easily scalable. Consequently, a simple,
sustainable, and scalable approach for the synthesis of
diarylmethanes is still highly desired. In a recent contribution by
Stahl and co-workers, an electrochemical mediated iodination
delivers substates for benzylic-arylic coupling.[13]
N-ethyl-N,N-di(methylethyl)amine (DIPEA) (Table 1, Entry 1). We
attributed this to the base character of the additive. A similar effect,
but in lower yield and selectivity, was observed using
triethylamine (TEA), K2CO3, or Cs2CO3 as bases (Table 1, Entry
2 and SI). k 2.2 F and 7.2 mA/cm2 were found to be the optimal
electrolytic conditions (Table 1, entries 3–7).
Table 1. Optimization of the anodic functionalization of 4-methylguaiacol by
HFIP.[a]
Entry
Deviation from standard conditions
Yield[b] (%)
1
2
3
4
5
6
7
8
-
TEA instead of DIPEA
1.9 F
72
42
64
78
56
67
63
76
2.2 F
2.4 F
2.2 F, 5 mA/cm2
2.2 F, 10 mA/cm2
Graphite electrodes, 2.2 F
Graphite electrodes, without supporting
electrolyte, 2.2 F
Following our interest in electrochemical conversions, our
group has developed efficient electrochemical C-C and N-N
coupling reactions involving phenols,[14] anilides,[15] and dianilides
as substrates.[16] Key to these conversions was the application of
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as solvent. HFIP has
unique properties. It stabilizes reactive intermediates,[17] has a
unique solvent microstructure,[18] as well as interesting solvation
properties, and as such, it can enable selective
transformations.[14e,19] HFIP has also been used as a solvent by
Paquin et al. in a non-electrochemical approach for the activation
of benzyl fluorides in benzyl-aryl coupling reactions.[20] Due to its
low nucleophilicity, reactions involving nucleophilic attack of HFIP
are rarely reported.[21] Recently, our group demonstrated the
anodic functionalization of anilides with HFIP at the benzylic and
aromatic position.[16b]
9
72
78
69
0
10
11
12
Without supporting electrolyte, 2.2 F
Without supporting electrolyte, 2.2 F, 1.14
equiv. DIPEA
Without DIPEA
[a] All reactions were carried out on a 1.0 mmol scale of phenol 1 in 5 mL of
HFIP in an undivided cell. [b] Yields were determined by 1H NMR spectroscopy
with benzaldehyde as standard.
Notably, oxidation at graphite anodes, which are less
expensive than boron-doped diamond (BDD) anodes, provides
the desired HFIP ether in similar yields (Table 1, entry 8). This is
particularly interesting for technical large scale applications.
However, it should be noted that we proceeded here with BDD
anodes in the subsequent electrolysis because of a slightly better
yield according to optimization studies. A significant step towards
a greener protocol was made with the observation that DIPEA
forms in-situ a supporting electrolyte and additional salt is not
necessary in this transformation (entries 9 and 10). This can be
rationalized by salt formation between the solvent HFIP (pKa
=9.3)[21] and DIPEAH+ (pKa = 11.4)[23] which enables sufficient
electrical conductivity. Doubling the amount of DIPEA did not
improve the yield (entry 11). In a control experiment (entry 12) the
significance of DIPEA as an additive was determined. Without
additive, phenol homo-coupling and oligomerization dominated.
Herein, we report the selective electrochemical
functionalization of benzylic positions by HFIP. Those direct
electrochemical C-H functionalizations often require catalyst
systems.[22] The ether acts as a molecular mask for the benzylic
cation, and stabilizes this reactive intermediate by solvent-
trapping in a less reactive state. The activation of such masked
cations to facilitate an efficient and selective benzyl-aryl coupling
reaction is reported for the first time. We present a simple,
sustainable, easily scalable, reagent- and metal-free
electrochemical benzyl-aryl cross-coupling reaction in a two-step,
one-pot sequence (Scheme 1).
Initially, the electrochemical HFIP ether formation was
optimized (Table 1). Phenol 1 was selected as a test substrate.
The electrochemical parameters for anodic phenol-thiophene
cross-coupling were used as initial conditions.[14c] Screening of
additives resulted in efficient HFIP ether formation with 0.57 equiv.
While the selective formation of benzylic HFIP ethers using
HFIP as a nucleophile is an unprecedented transformation, we
were particularly interested in exploring applications of this motif
in further synthesis. The ether can be seen as a molecular mask
for the benzylic cation in this case. However, compared to a
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10.1002/anie.201804997
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COMMUNICATION
recently presented approach demonstrating the trapping of
cations in the α-position of amides in Shono-oxidation products of
lactams,[24] the stabilization and subsequent activation of benzylic
cations is a challenging task. We found that treatment with 2,2,2-
trifluoroacetic acid led to subsequent formation of an active
benzylic cation. If this activation is carried out in the presence of
an equimolar to three-fold excess of an aromatic nucleophile,
selective benzyl-aryl cross-coupling can be achieved. We
optimized this coupling reaction with 1,2,4-trimethoxybenzene as
a test substrate. With optimized conditions for the first and second
step in hand, we explored the scope of potential substrates for
HFIP ether formation. For the subsequent benzylic cross-coupling
reaction, 1,2,4-trimethoxybenzene served as test nucleophile
(Scheme 2).
test system, and the subsequent coupling step was investigated
(Scheme 3). The reaction was found to succeed with a broad
variety of different nucleophiles. Arenes with strongly electron-
releasing groups (3 and 11), as well as methylated arenes (12 and
13) were successfully cross-coupled with 4-methylguaiacol. The
reaction with a free phenol proceeded in good yield (23).
Naphthalene derivatives including 1-methoxynaphthalene and
unprotected 2-naphthol were coupled in high yields of up to 81%
(14 and 15). Coupling of 4-methylguaiacol with heterocycles such
as benzofuran, benzothiophene, N-methyl indole, N-methyl
pyrrole, and thiophene derivatives is possible moderate to high
yields (16–22b). The transformation tolerates a variety of
substituents (methoxy, methyl, hydroxyl, chloro, and bromo). In
most cases, the coupling reaction occurs smoothly and selectively.
Only in the case of 3-methylthiophene was the formation of
regioisomers (22a and 22b) observed. Importantly, the benzyl-
aryl cross-coupling reaction can be conducted in much shorter
time compared to Yoshida’s approach.[12] It should be noted that
HFIP was used as both the solvent and nucleophile in this
procedure, and can be fully recovered and reused.[21] This leads
to a total reaction balance with only hydrogen as a by-product for
the C-C cross-coupling reaction.
Scheme 2. Scope for anodic functionalization by HFIP and subsequent coupling
to 1,2,4-trimethoxybenzene. Electrolyses were carried out in 5 mL HFIP on 1
mmol of substrate in an undivided cell. a) Yield of the benzylic HFIP ether after
electrolysis, determined by 19F NMR, b) 0.5 mmol of substrate have been used
instead and 3.0 F were applied for optimum electrochemical conversion, c)
electrolysis with 1.8 F, activation for second reaction carried out with p-TsOH
instead of TFA, reaction time 3 h.
Electrochemical functionalization with HFIP at the benzylic
position and subsequent benzyl-aryl cross-coupling was achieved
with a variety of substrates in yields up to 93% (5). Unprotected
phenols can be coupled at primary (3, 5, 6) and secondary
benzylic positions (4). Additionally, functionalization of biphenols
was demonstrated (7). Our method proved to be complementary
to the “stabilized cation-pool” since anisole and anisole
derivatives could be coupled in high yields (8–10). Product 10 is
particularly interesting, since the nitrile moiety allows further facile
functionalization. When dehydrodimerization or oligomerization
became noticeable during electrolysis (8 and 9), the concentration
of the starting material was reduced, leading to high yields (83%
and 88%) of the desired coupling products. As a logical step we
carried on investigations for the coupling with different
nucleophiles. For this approach, the electrolysis was carried out
under optimized reaction conditions with 4-methylguaiacol as a
Scheme 3. Variation of the nucleophile in the coupling reaction with 4-
methylguaiacol. Electrolyses were carried out in 5 mL HFIP on 1 mmol of phenol
1 in an undivided cell.
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10.1002/anie.201804997
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beaker-type cell (Figure 1). No erosion of selectivity has been
observed for the anodic functionalization with HFIP. This mixture
was directly subjected to the coupling reaction with
benzothiophene to give 6.91 g of the desired 17 in a single batch
(64% yield). The yield is slightly lower compared to the 5 mL scale
(76%). This can be rationalized by a not yet optimized addition of
TFA on larger scale. Nevertheless, the reaction time could be
even decreased from 2 h to 1 h within this upscaling approach.
In order to explore the full potential of this method, its
application to natural product derivatization was of high interest.
Our initial approaches to this end using 2,2,2-trifluoroacetic acid
led to complex mixtures. Further attempts using Lewis acids in
dichloromethane proved promising. Using beta-estradiol as a
nucleophile and aluminium chloride led to a 32% yield of the
coupled product. Further optimization of this system using
BF3OEt2 (2.2 equiv.) increased the yield of the coupled product to
44%. Based on these initial results, we were able to carry out late-
stage functionalization of a range of natural products and
biologically active compounds in moderate yields (Scheme 4).
Five different classes of natural product (steroids 27,
umbelliferones 26, psolarenes 25, phenylethylamines 29 and
flavones 28) were successfully derivitized. The coupling was
achieved at a range of positions, illustrating the generality of this
method for exclusive C-functionalization even in the presence of
nucleophilic oxygen (26, 27 and 28) or nitrogen moieties (29).
Additionally, crystal structures of the psolarene and umbelliferone
derivatives were obtained (see Supporting Information). These
novel derivatives may be of interest as potentially biologically
active compounds. Testing of biological activity is ongoing.
Figure 1. 5 mL and 200 mL beaker-type cells employed for scale-up studies.
For size comparison, a 2 € coin (diameter 25.75 mm ≈ 1.01 inches) was placed
between both cells. More details are given in the Supporting Information.
In conclusion, we established a very efficient protocol for the
electrochemical functionalization of benzylic groups by HFIP.
Small amounts of DIPEA can be used as an additive to selectively
lead to this reaction pathway and fully replace any additional
supporting electrolyte. The scope was demonstrated with phenols
anisoles and the late-stage functionalization of natural products.
The benzylic HFIP functionalization can be activated with acid to
undergo a dehydrogenative benzyl-aryl cross-coupling reaction
with a variety of different nucleophiles in high yields. This protocol
provides a scalable, metal-free, and reagent-saving route to
diarylmethanes, which has the potential to short-cut a variety of
synthetic routes. Activation of electro-generated HFIP ethers for
applications in various reactions with nucleophiles can be
imagined. Additionally, this method could be extended and
optimized for anilides, as already shown from our group for the
first step. Therefore, this route provides a general pathway for
numerous chemical transformations.
Acknowledgements
Scheme 4. Benzylated natural products and bioactive compounds using
BF3OEt2 (2.2 equiv.), 0.1M in CH2Cl2, rt, 2-12 h;
The authors thank the DFG (GSC 266, Wa 1276/17-1, Wa
1276/14-1) for financial support. Support of the Advanced Lab of
Electrochemistry and Electrosynthesis – ELYSION (Carl Zeiss
Stiftung) is gratefully acknowledged. Y.I. gratefully acknowledges
the support from the Program for Leading Graduate School of
TUAT granted by the Ministry of Education, Culture, Science and
Technology (MEXT), Japan. Y.I. and T.G. thanks the Material
Science in Mainz (MAINZ) graduate school for financial support.
A.W. thanks the Max Planck Graduate Center for financial support.
To demonstrate the scalability of our method we chose the
synthesis of compound 17 as model reaction. The structural
moiety of 17 is of significant interest in pharmaceutically active
compounds.[25] Therefore, a simple and scalable method for the
synthesis of these diarylmethanes will provide a new versatile
strategy. We scaled-up the electrolysis by a factor of 40. So
electrolysis was conducted with 40 mmol of phenol 1 in a 200 mL
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10.1002/anie.201804997
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D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur.
J. 2015, 21, 12321–12325.
Keywords: benzylic coupling • electrochemistry • HFIP • green
chemistry • natural products
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10.1002/anie.201804997
Angewandte Chemie International Edition
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Y. Imada, J. L. Röckl, A. Wiebe, T.
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Franke, and S. R. Waldvogel*
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Metal- and Reagent-Free
Dehydrogenative Formal Benzyl-Aryl
Cross-Coupling by Anodic Activation
in 1,1,1,3,3,3-Hexafluoropropan-2-ol
Simply the base makes the difference for the electrified benzylic cross-coupling via
intermediate ethers of 1,1,1,3,3,3-hexafluoroisopropanol. These ethers can serve for the
selective arene functionalization of various substrates and late-stage functionalization.
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