New Approach to 1,4-Benzoxazin-3-ones by Electrochemical C?H Amination

Article abstract of DOI:10.1002/chem.201701979

1,4-Benzoxazin-3-ones are important structural motifs in natural products and bioactive compounds. Usually, the synthesis of benzoxazinones requires transition-metal catalysts and pre-functionalized substrates such as aryl halides. However, the anodic C?H

Full text of DOI:10.1002/chem.201701979

A Journal of
Accepted Article
Title: New Approach to 1,4-Benzoxazin-3-ones by Electrochemical
C,H-Amination
Authors: Siegfried R Waldvogel, Lars Wesenberg, Sebastian Herold,
Akihiro Shimizu, and Jun-ichi Yoshida
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To be cited as: Chem. Eur. J. 10.1002/chem.201701979
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New Approach to 1,4-Benzoxazin-3-ones by Electrochemical C,H-
Amination
Lars Julian Wesenberg,[a] Sebastian Herold,[a, b] Akihiro Shimizu,[c] Jun-ichi Yoshida,[c] and Siegfried R.
Waldvogel*[a, b]
Dedicated to Hans J. Schäfer on the occasion of his 80th birthday
Abstract: 1,4-Benzoxazin-3-ones are important structural motifs in
natural products and bioactive compounds. Usually the synthesis of
benzoxazinones requires transition metal catalysts and pre-
functionalized substrates, e.g. aryl halides. However, the anodic C,H
amination of phenoxy acetates offers a very efficient and sustainable
access to these heterocycles. The herein presented electrochemical
protocol can be applied to a broad scope of alkylated substrates. Even
tert-butyl moieties or halogen substituents are compatible with this
versatile method.
The 1,4-benzoxazin-3-one scaffold has been recognized as an
important heterocyclic motif in natural products as well as in
pharmaceutically active compounds.[1] Naturally occurring
benzoxazin-3-ones, like 2,4-dihydroxy-1,4-benzoxazin-3-one
(DIBOA, 1) and 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one
(DIMBOA, 2) were found in gramineous plants like maize, wheat,
rye, and rice (Figure 1).[2,3] Biosynthesis of DIMBOA (2) is
Figure 1. Naturally occurring 1,4-benzoxazin-3-ones DIBOA (1) and DIMBOA
(2) and pharmaceutically relevant compounds 3 and 4 with the benzoxazinone
scaffold.
accomplished via hydroxylation of indole derivatives by P450
monooxogenase. Intermediates of this reaction pathway can also
be found in tryptophan biosynthesis.[4] On the other hand,
benzoxazinones
3 and 4 are interesting compounds for
in the presence of a metal promoter. However, a disadvantage of
such approaches is the need for transition metal catalysts as well
as pre-functionalized substrates, e.g. aryl halogenides or
nitroaromatic compounds. In particular, nitroaromatic starting
materials are sometimes difficult to obtain selectively, since
nitration usually leads to regioisomeric mixtures.[10] Purification of
such mixtures often is a tedious process. Recently, Yoshida and
co-workers reported in a series of accounts a powerful and
selective electrochemical C,N bond formation reactions[11,12,13]
including a novel method for the synthesis of benzoxazoles 7
(Scheme 1).[14]
pharmaceutical applications. The former is an inhibitor of bacterial
histidine protein kinase,[5] whereas the latter is a potential agent
for the treatment of anxiety and depression symptoms (Figure
1).[6,7]
Common synthetic strategies to construct benzoxazin-3-ones
employ ortho-substituted nitrophenols or halophenols as starting
materials.[2,8] Recently, El Kaïm et al. reported a three component
reaction to access the benzoxazinone scaffold via a Passerini-
Smiles rearrangement, followed by hydrogenation and in-situ
cyclization.[9] Moreover, Liu and co-workers developed
copper(I)-catalyzed one-pot synthesis of benzoxazinones.[6] In
a
this approach, ortho-halophenols react with -chloroacetamides
[a]
L. J. Wesenberg, Dr. S. Herold, Prof. Dr. S. R. Waldvogel
Institut für Organische Chemie
Johannes Gutenberg Universität Mainz
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: waldvogel@uni-mainz.de
http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/
Dr. S. Herold, Prof. Dr. S. R. Waldvogel
Graduate School Material Science in Mainz
Johannes Gutenberg Universität Mainz
Staudingerweg 9, 55128 Mainz, Germany
Dr. A. Shimizu, Prof. Dr. J-i. Yoshida
[b]
[c]
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto 615-8510, Japan
Scheme 1. Electrochemical synthesis of oxazoles 7[14] and oxazinones 10.
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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The phenolic substrates for the electrochemical synthesis of
oxazoles 7 were initially modified with a pyrimidine moiety. This
promotes an intramolecular electrochemical C,N coupling
reaction. The anodic amination proceeds via positively charged
Zincke intermediates 6 and 9, which prevent a further anodic
degradation, thus increasing the selectivity. The corresponding
amino moieties can be liberated in a later step at non-electrolytic
conditions.
In this work, we present a novel and innovative synthetic
approach to the benzoxazinone scaffold by means of
electrochemistry. Electrosynthetic conversions usually are
considered sustainable as they take place at ambient conditions
and avoid the use of stoichiometric amounts of oxidizing or
reducing agents. As direct C,H functionalization can be achieved,
pre-functionalized starting materials are not necessary. Thus,
electro-synthetic processes can offer a higher atom economy
compared to traditional methodologies.[15] As extraordinary
reaction pathways can be realized by electrochemical oxidation
efficient manner.[20] As anode materials, different carbon felts,
carbon fleeces, boron-doped diamond as well as isostatic
graphite were employed. The outcome of these screening
reactions was quantified by 1H NMR analysis with 1,1,2,2-
tetrachloroethane as internal standard (ISTD).
Porous electrode materials like carbon fleece and carbon felt can
be beneficial in electrosynthetic transformations since they exhibit
a high surface area. However, anodically generated highly
reactive intermediates need to diffuse into the bulk solution for
desired follow-up reactions. This diffusion can be inhibited by
absorption of the intermediates by the porous material. For carbon
felt and carbon fleece as anode materials, a current of 8 mA was
applied. These conditions were adopted from previous studies by
Yoshida and co-workers.[11] With an applied charge of 3.5 F, a
maximum yield of 37% (NMR, ISTD) of 11b was obtained. Next,
boron-doped diamond, which has recently attracted a lot of
attention in electrosynthesis, was evaluated.[17,21] Initially, a
current density of 10 mA∙cm−2 and an applied charge of 3.5 F
were investigated. At these conditions, the desired
benzoxazinone 11b was formed in 45% yield (NMR, ISTD). So far,
best results were obtained by using an isostatic graphite anode at
similar reaction conditions as used before. Therefore, this anode
material was investigated in detail. First, the current density was
altered in the range of 0.5-13 mA∙cm−2 at an applied charge of
3.5 F. We anticipated that a low current density might be
beneficial for the selectivity as the amount of reactive
intermediates generated is lower than at a high current density
(Figure 2).
or reduction, electrosynthesis has recently experienced
renaissance.[16,17]
a
Phenoxyacetate derivatives 8 served as starting materials for the
envisioned electrochemical conversion to benzoxazinones.
Anodic oxidation of such phenoxyacetates 8 in the presence of
pyridine should lead to the positively charged pyridinium
intermediates 9 (Zincke-type salts).[11,18] Upon treatment with
piperidine the released primary aniline immediately attacks the
ester moiety to form the desired benzoxazinones 10. However,
the anodic functionalization by pyridine needs to take place at the
position ortho to the carboxymethoxy substituent. Only in this
case, the desired fused heterocycle with the 1,4-oxazin-3-one
substitution pattern will be formed. Therefore, an accessible and
activated ortho position is required for the direct electrochemical
C,H amination.
100
80
60
40
20
0
At first, a screening for suitable electrode materials was carried
out, since previous studies revealed a significant impact of the
anode material onto the anodic amination.[19] For this investigation,
methyl 4-iodophenoxyacetate (11a) was chosen as test substrate
(Scheme 2).
0
2
4
6
8
10
12
14
j / mA∙cm−2
Figure 2. Electrochemical amination of methyl 4-iodophenoxy acetic acid (11a);
screening of current density at isostatic graphite. [a] 1H NMR yield, internal
standard: 1,1,2,2-tetrachloroethane.
Scheme 2. Electrochemical amination of methyl 4-iodophenoxyacetate (11a);
as test substrate for electrochemical synthesis of benzoxazinone (11b).
However, low current densities of up to 1 mA∙cm−2 resulted in
moderate yields of up to 45% (1H NMR, ISTD). The best
performance was observed at an elevated current density of
10 mA∙cm−2 with 61% yield of 11b (1H NMR, ISTD). Thus, for
further experiments, a current density of 10 mA∙cm−2 was used.
Furthermore, the applied charge was varied in a range of
2.0-5.0 F in steps of 0.5 F (see Supporting Information). Best
results were obtained at an applied charge of 3.5 F (61% of 11b).
Phenoxyacetate 11a fulfilled all requirements, such as good
access to the position ortho of the phenoxy moiety and
additionally, a leaving group for subsequent functionalization
reactions. The optimization experiments were conducted in
divided Teflon cells with a porous glass-frit as separator (see
Supporting Information). This screening methodology is simple
and allows the variation of different important electrolysis
parameters, e.g. current density and applied charge, in a time
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At lower applied charge the yield decreased drastically to approx.
30% of 11b (1H NMR, ISTD). In this case, an incomplete
conversion was observed. Application of more charge, e.g. 5 F
led to roughly 40% of benzoxazinone 11b. The identified,
optimized electrolysis conditions consist of an isostatic graphite
anode, a current density of 10 mA∙cm−2, and an applied charge of
3.5 F. These optimized reaction conditions were then subjected
to a collection of phenoxy acetates (Table 1).
9
62
12
10
Table 1. Scope of the anodic benzoxazinone formation.
Yield/
%
Entry
Substrate
Product
[b]
11
22
1
51
12
23
2
3
4
5
6
7
8
38
39
54
66
78
42
58
Anode: isostatic graphite, j = 10 mA∙cm−2, Q = 3.5 F, T = 25 °C, divided cell;
[b] isolated yield.
As illustrated by Table 1, the electrochemical protocol is
applicable to a broad scope of phenoxy acetates. Halide
derivatives, e.g. chloro, bromo, and iodo phenoxy acetates (11a-
16a), were compatible with this methodology. The corresponding
benzoxazinones (11b-16b) were obtained in moderate to good
yields of up to 78% (Table 1, Entries 1-6). Para-substituted alkyl
derivatives 17a, 18a, and 19a were transformed to the
corresponding heterocycles 17b, 18b, and 19b in yields of up to
62% (Table 1, Entries 7-9). Despite the cationic nature of
intermediates, this method is even suitable for tert-butyl groups in
which case the corresponding benzoxazinone 19b was obtained
in a good yield of 62% (Table 1, Entry 9). Substrates as 19a might
undergo dealkylation processes upon anodic treatment thus
causing by-products. However, this seemed not to be the case.
Starting materials 20a and 21a exhibit two alkyl substituents in
both meta positions, leading to a lower yield than the congener
with a single substituent (Table 1, Entries 10 and 11). Surprisingly,
even the more sterically demanding alkyl substrate 21a with two
tert-butyl groups was better accessible compared to phenoxy
acetate 20a. However, to circumvent more hindered adjacent
locations, we tested different substitution patterns. Unfortunately,
an ortho and para alkyl substituent did not result in better yields
(Table 1, Entry 12). Furthermore, we investigated the less-
activated fluoro derivative 23a as substrate. However, in this case
the use of an isostatic graphite anode did not lead to the desired
benzoxazinone 23b. Next, we used boron-doped diamond as
anode since this material proved to be a powerful tool for the
electroconversion of electron deficient starting materials.[19]
Indeed, by employing boron-doped diamond as anode 23b was
obtained in a moderate yield of 28% (Scheme 3).
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electron-deficient
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Experimental Section
For experimental details, setup and analytical data see
Supporting Information.
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Acknowledgements
The support by The Advanced Lab for Electrochemistry and
Electrosynthesis – ELYSION (Carl Zeiss Stiftung) is highly
appreciated.
Keywords: amination • electrochemistry • nitrogen heterocycles
• benzoxazinone • sustainable chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An electrified amination provides
direct and highly selective access to
1,4-benzoxazin-3-ones starting from
simple and readily available phenoxy
acetates. This approach allows the
generation of complex fused
L. J. Wesenberg, S. Herold, A. Shimizu,
J.-i. Yoshida, S. R. Waldvogel*
Page No. – Page No.
New Approach to 1,4-Benzoxazin-3-
ones by Electrochemical C,H-
Amination
((Insert TOC Graphic here))
heterocycles by electro-organic
synthesis.
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