Oxidative Alkoxylation/Dehydrogenation of Unactivated Cyclic Ketones with Simple Alcohols: Direct Route to α-Alkoxy Cycloenones

Article abstract of DOI:10.1002/ejoc.202001140

An oxidative functionalization of cyclopentanones or cyclohexanones with simple alcohols was first demonstrated, affording a series of 2-alkoxycyclopent-2-en-1-ones or 2-alkoxycyclohex-2-en-1-ones in moderate to excellent yields. The reaction was involved in tandem iodization, substitution, oxidation and addition-elimination processes in one pot. This method is highly atom-economical and operationally simple.

Full text of DOI:10.1002/ejoc.202001140

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Oxidative Alkoxylation/Dehydrogenation of Unactivated Cyclic
Ketones with Simple Alcohols: Direct Route to α-Alkoxy
Cycloenones
Authors: Yizhe Yan, Shaoqing Li, and Jianyong Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001140
Link to VoR: https://doi.org/10.1002/ejoc.202001140
01/2020

10.1002/ejoc.202001140
European Journal of Organic Chemistry
COMMUNICATION
Oxidative Alkoxylation/Dehydrogenation of Unactivated Cyclic
Ketones with Simple Alcohols: Direct Route to α-Alkoxy
Cycloenones
Yizhe Yan,*[a] Shaoqing Li,[a] and Jianyong Wang*[b]
Abstract: An oxidative functionalization of cyclopentanones or
cyclohexanones with simple alcohols was first demonstrated,
affording
a
series of 2-alkoxycyclopent-2-en-1-ones or 2-
alkoxycyclohex-2-en-1-ones in moderate to excellent yields. The
reaction was involved in tandem iodization, substitution, oxidation
and addition-elimination processes in one pot. This method is highly
atom-economical and operationally simple.
α-Alkoxy cycloenones are a valuable class of cyclic compounds,
which can be used as the precursors for drug synthesis.[1]
Generally, α-alkoxy cycloenones were prepared from cyclic 1,2-
dione with the alkoxy reagents, such as alcohols[1,2] and
alkoxytrimethylsilanes[3] in the presene of acid (Scheme 1a).
Moreover, α-alkoxy cycloenones could also be obtained from
cyclohex-2-en-1-one and sodium alkoxide via a tandem per-
oxidation and ring-opening reaction (Scheme 1b).[4] However,
narrow substrate scope, unsatisfactory yield and tedious
operation have limited their further applications. Therefore, the
development of a simple and efficient protocol for the synthesis
of α-alkoxy cycloenones remains highly desirable.
Cyclic ketones as cheap and readily available bulk chemicals
have been widely used in mono-functionalization of cyclic
ketones including α and β-functionalization.[5,6] Recently, direct
oxidative multi-functionalization of unactivated cyclic ketones in
single step has also been studied due to step-economy and low
cost. In 2016, Jiao’s group reported a novel iodine-catalyzed
direct conversion of cyclohexanones to substituted catechols
under simple conditions via multiple oxygenation and
dehydrogenative aromatization processes with DMSO as the
oxidant and oxygen source.[7] Recently, Fu’s,[8] Zhao’s[9] and
Wang’s[10] group also developed oxidative multi- functionalization
of unactivated cyclic ketones with O-benzoylhydroxylamines or
arylamines for the direct synthesis of cyclic α-enaminones,
respectively. Although great advances have been made in
oxidative multi-functionalization of unactivated cyclic ketones,
the development of oxidative multi-functionalization of
unactivated cyclic ketones with low nucleophilic alcohols
remains challenging.
Scheme 1. Strategies for the synthesis of α-alkoxy cycloenones
As a continuous study about oxidative functionalization of C-H
bond,[11] herein we report a novel oxidative functionalization of
unactivated cyclic ketones, such as cyclopentanones or
cyclohexanones, with simple alcohols (Scheme 1c). A series of
2-alkoxycyclopent-2-en-1-ones or 2-alkoxycyclohex-2-en-1-ones
were obtained in moderate to excellent yields via tandem
iodization, substitution, oxidation and addition-elimination
processes in one pot. This method is highly atom-economical
and operationally simple.
Table 1. Optimization of reaction conditions.[a]
Entry
XI
[Cu]
X (mL)
Yield (%)[b]
1
I2
I2
I2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
6
20
2
Cu(OAc)2
CuCl2
CuBr
CuI
29
3
46
4
I2
I2
34
5
28
I2
I2
6
Cu
17
7
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
51
8
nBu4NI
36
9
n.d.
52
[a]
Prof. Dr. Y. Yan, S. Li,
I2
I2
I2
I2
I2
I2
10[c]
11[d]
12[d,e]
13[d,f]
14[d]
15[d]
School of Food and Biological Engineering, Henan Collaborative
Innovation Center of Food Production and Safety, Henan Key
Laboratory of Cold Chain Food Quality and Safety Control
Zhengzhou University of Light Industry
Zhengzhou, 450000, P. R. China
E-mail: yanyizhe@mail.ustc.edu.cn
73
n.d.
n.d.
77
https://www.researchgate.net/profile/Yizhe_Yan
Prof. Dr. J. Wang
[b]
80 (76[g]
)
School of Light Industry and Engineering
Qilu University of Technology (Shandong Academy of Sciences)
Jinan, 250353, P. R. China
E-mail: wjy@mail.ustc.edu.cn
http://qgxy.qlu.edu.cn/_s57/2018/1115/c6889a118740/page.psp
[a] Reaction conditions: 1a (0.5 mmol), 2a (x mL), XI (0.5 mmol), [Cu] (0.5
mmol), 100 °C (oil bath), 12 h. [b] The yields were determined by 1H NMR
analysis using CH3NO2 as the internal standard. [c] CuO (0.25 mmol) was
added. [d] CuO (0.75 mmol) was added. [e] 4 Å molecular sieve powder (50
mg) was added. [f] NaOAc (1 mmol) was added. [g] Isolated yield.
Supporting information for this article is given via a link at the end
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10.1002/ejoc.202001140
European Journal of Organic Chemistry
COMMUNICATION
Initially, a model reaction of cyclopentanone (1a) and ethanol
(2a) was chosen to optimize the reaction conditions. When 1
equiv of 1a and 2 mL of ethanol with iodine as an oxidant were
heated at 100 °C for 12 h, 2-ethoxycyclopent-2-en-1-one (3aa)
was obtained in 20% yield (Table 1, entry 1). When various
copper sources, such as Cu(OAc)2, CuCl2, CuBr, CuI, Cu and
CuO were employed as the additives, CuO led to a highest 51%
yield (Table 1, entries 2-7). Moreover, the iodine effect was also
investigated. When nBu4NI was used instead of iodine, 3aa was
obtained in 36% yield (Table 1, entry 8). Notably, 3aa was not
detected in the absence of iodine, indicating that the iodine was
essential to this reaction (Table 1, entry 9). Increasing the
amount of CuO could significantly improve the reaction yield
(Table 1, entries 10 and 11). When 4 Å molecular sieve or
NaOAc was added into the reaction system, no desired product
was detected (Table 1, entries 12 and 13). In addition, when the
volume of ethanol was increased to 4 mL or 6 mL, the reaction
yields were slightly increased to 77% or 80%, respectively
(Table 1, entries 14 and 15). Therefore, the optimal conditions
were established as described in entry 15.
the synthesis of 2-alkoxycyclopent-2-en-1-ones 3 (Scheme 2).
First, the substrate scope of simple aliphatic alcohols 2 was
investigated in this reaction. Expectedly, aliphatic alcohols, such
as ethanol (2a), methanol (2b), n-propyl alcohol (2c), n-butyl
alcohol (2d), isobutyl alcohol (2e) and isopropanol (2f) could
smoothly afford the desired 2-alkoxycyclopent-2-en-1-ones (3aa-
3af) in 39-83% yields. Notably, methanol showed low reactivity
due to low boiling point and nucleophilicity. However, the desired
product was not obtained when tert-butyl alcohol (2g) or
hexafluoroisopropanol (2h) was used instead of ethanol.
Futhermore, when phenylmethanol (2i), cyclohexanol (2j), glycol
(2k) and phenol (2l) were employed as the nucleophile, no
desired products were obtained with benzaldehyde and
cyclohexanone as byproducts generated. In addition, the
substrate scope with various cyclopentanones was also
explored. The cyclopentanones (1b and 1c) with methyl and
ethyl group at the C3 position could give the corresponding
products 3ba and 3ca in 46% and 59% yields with an excellent
regioselectivity at the C5 position, respectively. Unfortunately,
the reaction of cyclopentanone (1d) bearing methyl group at the
C2 position with ethanol failed under standard conditions
because the presence of methyl might inhibit the subsequent
reaction process.
Scheme 2. Oxidative functionalization of cyclopentanones with aliphatic
alcohols. [a] Reaction conditions: 1 (0.5 mmol), 2 (6 mL), I2 (0.5 mmol), CuO
(0.75 mmol), 100 °C, 12 h; isolated yield. [b] 10 mmol scale. [c] 10 equiv of 2l
in CH3CN (2 mL).
Scheme 3. Oxidative functionalization of cyclohexanones with aliphatic
alcohols. Reaction conditions: 4 (0.5 mmol), 2 (6 mL), I2 (0.5 mmol), CuO (0.75
mmol), 100 °C, 12 h; isolated yield.
With the optimal reaction conditions in hand, various
cyclopentanones 1 and aliphatic alcohols 2 were employed for
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10.1002/ejoc.202001140
European Journal of Organic Chemistry
COMMUNICATION
Subsequently, we expected to synthesize 2-alkoxycyclohex-2-
en-1-ones 5 with this synthetic protocol (Scheme 3). Delightedly,
the oxidative functionalization of cyclohexanone (4a) with
ethanol (2a) could afford the desired 2-ethoxycyclohex-2-en-1-
one (5aa) in 60% isolated yield. Similarly, other aliphatic
alcohols, such as n-propyl alcohol (2c), n-butyl alcohol (2d) and
isopropanol (2f) also gave the corresponding products 5ac, 5ad
and 5af in moderate yields. Then the substrate scope of
cyclohexanones 4 was also investigated under the optimal
reaction conditions. When cyclohexanones bearing propyl,
pentyl, isopropyl, tert-butyl and tert-pentyl group at the C4
position (4b-4f) were employed, the corresponding products
5ba-5fa could be obtained. Notably, their isomers 5ba’-5fa’
were also obtained at the same time. Because two isomers
could be hardly effectively separated, the mixture was isolated in
good yield and the content of them was determined by 1H NMR.
might undergo a radical pathway. Moreover, three trace amount
of potential intermediates including cyclohex-2-en-1-one (6),
cyclohexane-1,2-dione (7) and 2-ethoxycyclohexan-1-one (8)
were detected by GC-MS. Notably, 7 as the substrate generated
the desired 5aa in 60% yield, but 6 and 8 failed in the presence
of I2 and CuO. In addition, cyclohexane-1,2-dione (7) could react
with alcohols and produce two possible isomers, which were
consistent with the experimental results in Scheme 3. Therefore,
these results indicated that 7 should be the key intermediate of
the reaction (Scheme 4b-4d).
Similarly,
4-phenylcyclohexanone
(4g)
or
4-(p-
tolyl)cyclohexanone (4h) also gave the mixture of two isomers
(5ga/5ga’ or 5ha/5ha’) in 80% or 81% yield, respectively.
Moreover, 4,4-dimethylcyclohexanone (4i) with a quaternary
carbon center also gave 5ia and 5ia’ in 67% yield. In addition to
alkyl and aryl groups, COOEt (4j) or phthalimide (4k) group was
introduced into the C4 position of cyclohexanone, generating
two isomers (5ja/5ja’ or 5ka/5ka’), which could be separated by
column chromatography. Unfortunately, the reaction of 3-
substituted or 2-substituted cyclohexanone with ethanol failed
under standard conditions.
Scheme 5. A plausible mechanism
On the basis of the above results and previous reports, a
plausible mechanism was proposed (Scheme 5). Initially, the
substrate 4 gives a 2-iodocyclohexanone (9) in the presence of
iodine.[7,10] A nucleophilic substitution of 9 with water generates
2-hydroxycyclohexanone 10, which can be further converted into
a cationic radical 11 by iodine. An intermediate 7 is obtained by
removing one hydrogen radical and one hydrogen ion. Finally,
the corresponding products 5 (path a) and 5’ (path b) can be
formed via a tandem addition and elimination process.[1,2] In a
word, iodine plays an important role in the oxidative
alkoxylation/dehydrogenation of cyclic ketones.
In summary, we have developed
a
novel oxidative
functionalization of cyclopentanones or cyclohexanones with
simple alcohols for the synthesis of 2-alkoxycyclopent-2-en-1-
ones or 2-alkoxycyclohex-2-en-1-ones. Compared to previous
reports, this novel protocol is distinguished by (1) high atom-
economy, (2) cheap oxidants, (3) readily available substrates, (4)
operational simplicity. The oxidative functionalization of cyclic
ketones with other nucleophiles for the synthesis of valuable
compounds is ongoing in our laboratory.
Scheme 4. Control experiments for mechanistic studies
To gain an insight into the mechanism, several control
experiments were carried out (Scheme 4). First, the oxidative
functionalization of cyclopentanone or cyclohexanone with
ethanol was completely inhibited in the presence of one equiv of
Acknowledgments
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as
a
radical
inhibitor (Scheme 4a). This result indicated that this reaction
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10.1002/ejoc.202001140
European Journal of Organic Chemistry
COMMUNICATION
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We are grateful to the National Natural Science Foundation of
China (21502177), the Program for Science and Technology
Innovation Talents in Universities of Henan Province
(20HASTIT037), Henan Youth Talent Support Project
(2020HYTP046) and the Higher Education School Young
Backbone Teacher Training Program of Henan Province
(2018GGJS093).
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Keywords: alkoxylation • dehydrogenation • cyclic ketone •
alcohol • α-alkoxy cycloenone
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10.1002/ejoc.202001140
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Alkoxylation/Dehydrogenation*
Yizhe Yan,* Shaoqing Li, Jianyong
Wang*
Page No. – Page No.
Oxidative
An oxidative functionalization of cyclopentanones or cyclohexanones with simple
alcohols was first demonstrated, affording a series of 2-alkoxycyclopent-2-en-1-
ones or 2-alkoxycyclohex-2-en-1-ones in moderate to excellent yields.
Alkoxylation/Dehydrogenation
of
Unactivated Cyclic Ketones with
Simple Alcohols: Direct Route to α-
Alkoxy Cycloenones
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