Metal-Free I2-Catalyzed Highly Selective Dehydrogenative Coupling of Alcohols and Cyclohexenones

Article abstract of DOI:10.1002/cjoc.201700743

The I₂ catalyzed highly selective oxidative condensation of cyclohexenones and alcohols for the synthesis of aryl alkyl ethers has been described. DMSO is employed as the mild terminal oxidant. This novel methodology offers a metal-free reaction condition, operational simplicity and broad substrate scope to afford valuable products from inexpensive reagents. Various meta-substituted aromatic ethers which are hardly synthesized from the reported methods requiring meta-substituted phenols, are efficiently prepared by the present protocol.

Full text of DOI:10.1002/cjoc.201700743

Metal-Free I2-Catalyzed Highly Selective Dehydrogenative Coupling of
Alcohols and Cyclohexenones
Yu-Feng Liang,a Yizhi Yuan,a Tao Shen,a Song Song,a and Ning Jiao a, b*
ABSTRACT The I2 catalyzed highly selective oxidative condensation of cyclohexenones and alcohols for the synthesis of aryl alkyl ethers has been
described. DMSO is employed as the mild terminal oxidant. This novel methodology offers a metal-free reaction condition, operational simplicity and
broad substrate scope to afford valuable products from inexpensive reagents. Various meta-substituted aromatic ethers which are hardly synthesized
from the reported methods requiring meta-substituted phenols, are efficiently prepared by the present protocol.
KEYWORDS metal-free, dehydrogenative coupling, oxidation, selectivity, alcohols
condensation of cyclohexenones and alcohols for the efficient
synthesis of aromatic ethers (Scheme 1b, path d).
Introduction
Aryl alkyl ethers are ubiquitous motifs in molecules
essential to diverse industries including pharmaceutical,
agrochemical, and high-tech.1 Numerous synthetic methods
have been developed to prepare aryl alkyl ethers.2-6 In the
well developed methods from the corresponding aromatic
and non-aromatic substrates including the Ullmann and
Scheme 1 Dehydrogenative conversion of cyclohexenones and alcohols
Buchwald-Hartwig coupling reactions,
a transition-metal
catalyst is usually required which would present a problem in
the isolated products. Especially for pharmaceutically active
ingredients there are typically strict guidelines to limit the
levels of heavy metals for the compound to be used for
testing and ultimate medicinal use.7 In addition, the
meta-substituted aromatic ethers are hardly synthesized by
these methods because these methods require meta-substituted
phenol substrates which are not readily prepared.
Cyclohexenones are readily available, stable, easy to
handle and widely used as bulk materials to prepare other
important fine chemicals.8 Recently, some elegant
dehydrogenative reactions9 of cyclohexenones have been
developed by the groups of Stahl,10 Li,11 Deng,12 and others.13
Significantly, Li and coworkers realized the Cu-mediate aryl
Results and Discussion
Our studies began by optimizing the reaction conditions on
1-naphthaleneethanol 1a and 2-cyclohexanone 2a. When this
reaction was carried out in MeNO2 at 130 oC, using 10 mol% NBS
as the catalyst, to our delight, the desired dehydrogenative
aromatization product 3aa was obtained in 33% yield (entry 1).
The reaction efficiency could be improved by the employment of
NIS as catalyst (entry 2), however, NCS, TBAB, KI, or TBAI catalyst
could not deliver the desired product (entries 3-6). The best
result was obtained by using I2 as catalyst, leading to a 94% yield
of the desired aryl ether 3aa (entry 7). Replacing MeNO2 with
other solvent led to inferior results (entries 8-11). A high
temperature is necessary to ensure good conversion of the
starting materials (entry 12). When 5.0 equiv of DMSO was used,
3aa was isolated in slight low yield (entry 13). It is noteworthy
that this reaction underwent well under Ar atmosphere (entry
14), whereas failed to give 3aa in the absence of I2 catalyst or
DMSO oxidant (entries 15-16).
ethers synthesis from the
cyclohexenones and alcohols
(Scheme 1a).11a Dispite the significance, stoichiometric amount
of copper, or a copper/NHPI catalysis with stoichiometric of KI
were required, which might be the reason for the low efficiency
especially for the substituted cyclohexenones substrates.
In the context of synthetic chemistry, dimethyl sulfoxide
(DMSO),14-15 an inexpensive, low-toxic aprotic polar solvent,16
has been widely used as the oxidant17 in many well-known
named reactions such as Swern oxidation,18 Pwtizner-Moffatt
oxidation,19 as well as Corey-Chaykovsky reactions.20 We have
been interested in metal-free oxidative functionalization
under simple conditions using DMSO as a mild oxidant.21,22
Stimulated by the reaction mechanism, we envisioned that it
should be very attractive if the oxidative dehydrogenation
process could be realized by a metal-free conditions using
mild DMSO oxidant. But, it is still a challenging task, because
several competitive selectivity should be addressed: 1) It is
well-known that the alcohols could be easily oxidized to
aldehydes or ketones, and stop the reaction (Scheme 1b, path
a);17 2) The dehydrogenation to phenols is strongly
competitive side reaction (Scheme 1b, path b);21 3) The DMSO
is also potential nucleophile which enables the unfavored
side reaction (Scheme 1b, path c).22 Herein, by using a mild I2
catalyst with DMSO as oxidant, we report a metal-free oxidative
Table 1 Optimization of the reaction conditionsa
a State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Weijin Road 94, Tianjin 300071, China
E-mail: jiaoning@pku.edu.cn
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201700743
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Scheme 2 Oxidative condensation of 2-cyclohexenone with different
alcohols
Entry
1
Cat.
NBS
NIS
NCS
TBAB
KI
Solvent
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
PhCl
Yield/%b
33
2
74
3
0
4
0
5
0
6
TBAI
I2
0
7
94
8
I2
31
9
I2
1,4-dioxane
DMF
23
10
11
12c
13d
14e
15f
I2
trace
trace
70
I2
DMSO
I2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
I2
80
I2
89
I2
trace
0
16
--
a
Reaction conditions: 1a (0.3 mmol), 2a (2.0 equiv), catalyst (10 mol%),
DMSO (8.0 equiv), solvent (1.5 mL), stirred at 130 oC for 24 h. Isolated
b
yields. c 110 oC. d 5.0 equiv DMSO. e Under Ar. f In the absence of DMSO
With the optimized catalytic system in hand (Table 1, entry
7), we subsequently investigated the substrate scope of various
alcohol derivatives (Scheme 2). The results indicated that
different phenylethyl alcohols bearing either electron-donating
or -withdrawing substituents at the aryl ring afforded the
desired phenyl alkyl ethers in good to excellent yields (3ba-3ja).
In particular, the hydroxyl group was well tolerated in this
transformation (3ha), without the formation of diaryl ether. It is
interesting to find that alcohols bear an internal or terminal
alkyne functionality can also be functionalized (3ma, 3oa, 3pa).
Moreover, heterocycle-containing alcohol also worked well (3qa).
To our delight, the secondary alcohols could also produce the
corresponding aryl ethers (3ra-3xa) in moderate to good yield.
Unfortunately, no desired product was observed when a tertiary
alcohol was used as the substrate.
Moreover, to further evaluate the synthetic utility of this
system, we subjected natural alcohols 4 to this system (Scheme
4). To our satisfaction, the desired ethers 5 were obtained with
moderate to excellent yields, highlighting the generality and
great potential of this new catalytic reaction. The diol substrates
6 were also tested and the diether products 7 were obtained in
moderate to good yields (eq. 1). The reaction of
1,3-cyclohexanedione 8 with 1a also afforded diether product 9
(eq. 2).
Scheme 3 Scope of cyclohexenones for the synthesis of aryl ethers
A variety of cyclohexenones were then probed under this
metal-free system, and the results are summarized in Scheme 3.
Notably, various meta-substituted aromatic ethers, which are
challenging products for traditional synthetic methods starting
from meta-substituted phenols,2-6 could be selective prepared by
the present protocol from the readily available 3-substituted
cyclohexenones. Alkyl or aryl substituted cyclohexenones
reacted smoothly to produce the desired functionalized aryl
ethers (3ab-3ae). The sulfide and ester group were also well
tolerated (3af, 3ag). Moreover, thiophene and naphthalene
motifs were compatible with this transformation (3ah-3aj). It
also should be mentioned that the substituted cyclohexenones
were challenging substrates and only low to moderate yield of
corresponding products were obtained in the reported
method.11a
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Scheme 4 Oxidative arylation of natural alcohols
the muscle relaxant Metaxalone.23
Scheme 5 Gram-scale reaction
Definitely, the mechanism is not completely clear, yet. A
possible reaction pathway is proposed as shown in Scheme 6.
Initially, the I2 catalyst activates the carbonyl function of
cyclohexenone, leading to the formation complex A. The
1,2-addition by alcohol should afford hemiacetal B,24 followed by
dehydration to afford alkoxydiene C. Subsequently, iodization
and intramolecular electron transfer occurs to give α-iodo
oxonium intermediate D. Elimination of HI generates
cyclohexadienone oxonium intermediate E, which would
undergo deprotonation and then should quickly tautomerize to
the aryl ether product. Finally, HI was oxidized by DMSO to
regenerate catalyst for the next catalytic cycle along with the
release of dimethyl sulfide and water.21-22
To gain an understanding of the mechanism, we investigated
some control experiments. The result of 18O labeling experiment
proved that the oxygen atom in product originates from alcohol
starting material (eq. 3), instead of cyclohexenone or DMSO. The
reaction performed well in the presence of 1,1-diphenylethylene,
a radical inhibitor, producing the desired product, which indicate
that a radical process might not be involved in the present
reaction system (eq. 4). The oxidative rearrangement reaction
was observed with isophorone 10. 1,2-Migration of the 5-methyl
group resulted in the formation of 3,4,5-trimethylphenyl ether
11 (eq. 5), which indicated that a cation probably formed in this
transformation.
Scheme 6 Possible mechanism
R
O
O
H
I
R
O
O
I
O
S
E
HI
A
R
OH
I
S
, H2O
R
R
O
HO
O
I
R
O
B
D
I
H2O
C
Conclusions
In conclusion, we have developed an efficient approach for
the synthesis of aryl alkyl ethers from non-aromatic
cyclohexenones and alcohols. The simple and readily available I2
was used as the catalyst, and the cheap and common DMSO was
employed as the terminal oxidant in this metal-free system.
Hydroxyl, alkynyl, sulfide and ester were all compatible. It is
noteworthy that various meta-substituted aromatic ethers which
are hardly synthesized from the reported methods requiring
meta-substituted phenols, are efficiently prepared by the
present protocol from the readily available 3-substituted
cyclohexenones. Further studies to elucidate the detailed
reaction mechanism and the synthetic applications are in
progress in our group.
Experimental
Finally,
gram-scale
reactions
of
Alcohol derivative (0.3 mmol, 1.0 equiv) was added to a 25
mL oven-dried Schlenk tube with a stirring bar. Iodine (0.06
mmol, 15.2 mg, 20 mol%) and 1.5 mL of MeNO2 was added
followed by the addition of 2-cyclohexen-1-one derivative (0.6
3,5-dimethylcyclohex-2-enone 12 with glycidol 13 were
performed using the present method (Scheme 5), affording 83%
yield of the ether product 14, which is a potential precursor of
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mmol, 2.0 equiv) and DMSO (2.4 mmol, 187.5 mg, 8.0 equiv).
The tube was sealed with a cap, then heated to 130 C for 24 h.
Front. 2015, 2, 279.
o
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residue, which was purified by column chromatography on silica
gel using a mixture of petroleum ether and ethyl acetate to
afford aryl ether product.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
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We thank National Basic Research Program of China (973
Program) (No. 2015CB856600), the National Natural Science
Foundation of China (No. 21325206, 21632001, 21772002),
National Young Top-notch Talent Support Program, and Peking
University Health Science Center (No. BMU20160541) for
financial support of this work. We thank Xiaojing Wen in this
group for reproducing the results of 3fa and 3na.
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Accepted manuscript online: XXXX, 2018
Version of record online: XXXX, 2018
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2018
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Entry for the Table of Contents
Page No.
Metal-Free I2-Catalyzed Highly Selective
Dehydrogenative Coupling of Alcohols
and Cyclohexenones
The I2 catalyzed oxidative dehydrogenative coupling of cyclohexenones and alcohols has been
described. DMSO is employed as the mild terminal oxidant. This novel methodology offers a
metal-free reaction condition, operational simplicity and broad substrate scope to afford valuable
products from inexpensive reagents. Various meta-substituted aromatic ethers which are hardly
synthesized from the reported methods requiring meta-substituted phenols, are efficiently
prepared by the present protocol.
Y.-F. Liang, Y. Yuan, T. Shen, S. Song, and N.
Jiao*
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