Iodine-Mediated Synthesis of Methylthio-Substituted Catechols from Cyclohexanones

Article abstract of DOI:10.1002/adsc.201900069

A novel and efficient I₂-mediated direct synthesis of methylthio-substituted catechols from cyclohexanones was developed. Various cyclohexanones underwent oxygenation, methylthiolation, and dehydrogenative aromatization in one pot to form the desired products in moderate to good yields. DMSO was utilized as the solvent, oxygen source, and methylthiolation agent. A possible reaction mechanism is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201900069

Title: Iodine-Mediated Synthesis of Methylthio Substituted Catechols
from Cyclohexanones
Authors: Yue-Hua Wu, Nai-Xing Wang, Tong Zhang, Zhan Yan, Bao-
Cai Xu, Joan Inoa, and Yalan Xing
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900069
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodine-Mediated Synthesis of Methylthio-Substituted Catechols
from Cyclohexanones
Yue-Hua Wu,a Nai-Xing Wang,a* Tong Zhang,a Zhan Yan,a Bao-Cai Xu,b* Joan Inoa c
and Yalan Xingc*
a
Technical Institute of Physics and Chemistry & University of Chinese Academy of Sciences, Chinese Academy of
Sciences, Beijing, 100190, China. E-mail: nxwang@mail.ipc.ac.cn
School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, 100048, China. E-
b
mail: xubac@163.com
c
Department of Chemistry, William Paterson University of New Jersey, New Jersey, 07470, United States. E-mail:
xingy@wpunj.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
found that 2-sulfanylphenols could be synthesized by
sulfanylation of phenols under an oxygen atmosphere
using the toxic reagent MeSSMe and a stoichiometric
amount of FeCl3 (Scheme 1b).[8] Mixtures of ortho-
and para-substituted thioethers of phenols were
obtained under Friedel-Crafts conditions. Recently
Xiao reported the synthesis of aryl sulfides from
sodium sulfinates and phenols under aqueous
conditions (Scheme 1c).[9]
Abstract. A novel and efficient I2-mediated direct
synthesis of methylthio-substituted catechols from
cyclohexanones was developed. Various cyclohexanones
underwent
oxygenation,
methylthiolation,
and
dehydrogenative aromatization in one pot in moderate to
good yields. DMSO was utilized as the solvent, oxygen
source, and methylthiolation agent. A possible reaction
mechanism is proposed.
Keywords: catechol; cyclohexanone; methylthiolation;
one pot reaction; synthetic methods
Thioethers and their derivatives are ubiquitous
functionalities in pharmaceuticals and agrochemicals
(Figure 1).[1] Among them, aryl methyl sulfides,
especially sulfanylphenols, are high-value compounds
with important biological activities.[2] Aryl methyl
sulfides are useful substrates for C-C cross-coupling
reactions[3] and also versatile precursors for
sulfoxides,[4] arenes, and thiols.[5] Additionally,
phenols are key building blocks in organic synthesis.[6]
Scheme 1. Strategies for the synthesis of 2-
sulfanylphenols.
Dimethyl sulfoxide (DMSO) is a readily available
and less toxic polar solvent. It has also been widely
used as oxidant in well-known name reactions such as
the Kornblum reaction[10] and Swern oxidation.[11]
Besides, in the past decades, DMSO was reported as a
useful building block for the synthesis of many organic
motifs.[12] DMSO could serve as the source in
Figure 1. Bioactive molecules with alkylthio-substituted
catechol motif.
There are only a limited number of efficient and
environmentally friendly methods to form C-S bonds
at the ortho position of phenols. The traditional
approaches utilize methylation of 2-sulfanylphenol
(Scheme 1a).[7] The substrates need to be pre-
synthesized and the selectivity was poor. Takaki and
co-workers reported an alternative method. They
methylthiolation,[12a-d]
sulfonylation,[12e]
formylation,[12f] and even as methylene source.[12g]
Using the I2/DMSO system for the synthesis of
1
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
complex compounds has attracted considerable
attention from the synthetic community. Our group has
been dedicated to research for realizing the high-value
transformation of bulk chemicals. We previously
reported the difunctionalization of styrene with
alcohols, ketones, and nitriles to provide complex
products only in one step.[13] Recently,
functionalization of readily available bulk chemical
cyclohexanones attracts our attention. Jiao reported the
conversion of cyclohexanones into catechols using
I2/DMSO.[14] It is worth noting that only catechols
were obtained in their work without methylthio
substitutions. Herein, we wish to report that
cyclohexanones can be transformed to methylthio-
substituted catechols under facile, economical, and
transition metal-free conditions. We speculated that
methylthiolation promoted by in situ generated DMS
in the oxidation step, followed by dehydrogenation
and aromatization with I2 and DMSO afforded this
novel conversion. In this study, by means of controlled
experiments and intermediates trapping experiments,
the mechanism of this transformation was confirmed.
To the best of our knowledge, this is the first report of
the conversion of cyclohexanones into methylthio-
substituted catechols in one pot.
sterically hindered alkyl groups tend to give lower
reaction yields (2b VS 2g).
Table 1. Optimization of the reaction conditions.[a]
Entry cat.(equiv)
temp(oC) time(h) Yield[b](%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[c]
18[d]
19[d]
I2 (0.2)
KI (0.2)
NBu4I (0.2)
CuI (0.2)
CuI2 (0.2)
I2 (0.1)
I2 (0.5)
I2 (1.0)
I2 (1.2)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (0.5)
80
80
80
80
80
80
80
80
80
40
60
100
120
80
80
80
80
80
80
8
8
8
8
8
8
8
8
8
8
8
8
8
21
N.R.
N.R.
N.R.
N.R.
Trace
35
59
51
11
55
44
Trace
45
71
84
4
12
24
24
24
12
81
86
54
We
commenced
our
investigation
with
cyclohexanone 1a as the model substrate for the
optimization studies (Table 1). A series of iodide
containing catalysts were examined. Unfortunately, KI,
NBu4I, CuI, and CuI2 exhibit no reactivity. I2 was
proven to be the optimal catalyst for this
transformation (entries 1-5). When I2 was reduced to
10 mol%, only trace amount of product was observed
(entry 6). We found that 59% of the product yield was
achieved when 1.0 equiv of I2 was utilized (entries 7-
8). However, when the amount of I2 was increased to
1.2 equiv, the yield of 2a could not be further
improved (entry 9). Testing to find the optimal
reaction temperature revealed that the reaction
temperature was very crucial for this transformation.
80 oC was identified as the optimal reaction
temperature. Reactions ran at temperatures below or
[a] Reaction conditions: cyclohexanone
1
(1.0 mmol, 1.0
equiv), DMSO (2.0 mL) in sealed tube.
[b] Isolated yields.
[c] Under N2 atmosphere.
[d] 1.0 equiv of DMS was added.
Table 2. Substrate scope for the transformation of
cyclohexanone.[a]
o
above 80 C resulted in decreased product yields
(entries 10-13). To our delight, when the reaction time
was prolonged to 24 h at 80 oC, product 2a was isolated
with a yield of 84% (entries 14-16). It is worth
mentioning that the product yield was not improved
when the reaction was performed under N2 atmosphere
(entry 17). When an extra 1.0 equiv of DMS was added
to the reaction system, the yield of 2a was improved
from 84% to the 86%. Under the conditions of entry 7,
but with extra DMS added, the yield of 2a improved
significantly from 35% to 54%. The results show that
an extra amount of DMS could be beneficial to the
reaction (entries 18 and 19).
With the optimal reaction conditions in hands, a
wide range of cyclohexanones were converted to the
corresponding methylthio-substituted catechols (Table
2). An array of monosubstituted cyclohexanone at
para position with alkyl substituents (such as Me-, Et-,
Pr-, t-Bu-, amyl- and t-amyl-) were found to provide
the desired products 2b-2g in favorable yields. More
2
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
When 4,4’- bicyclohexanone was used as the
substrate, 2h was obtained instead of 4,4’-
bimethylthiocatechol. We speculated that the amount
of I2 was insufficient. When 1i was used as starting
material, 2i was obtained in 39% yield, whereas
cyclohexanone 1j gave the same product in 41% yield.
Unfortunately, the amide group was not tolerated
under the optimal conditions, and therefore product 2k
was not obtained. Cyclohexanones bearing a carboxyl
or an ester group could give the corresponding
products (2l, 2m) and the major side product is the
catechols without methylthiolation. The ortho-
substituted cyclohexanone 1n and 1o generated the
desired compounds 2n and 2o in 28% and 42% yield,
separately. Using 3-methylcyclohexanone as starting
material, 2b was obtained in 36% yield. Additionally,
α-tetralone and its derivatives provided the
corresponding methylthiolated naphthol 2q-2s in 37%
- 43% yield. However, β-tetralone was transformed
into 1-iodonaphthalen-2-ol instead of 2t. When n-
butyl sulfoxide (n-BuSOn-Bu) was used as solvent,
butylthiocatechol 2u was isolated in 52% yield. And
when cyclohex-2-en-1-one 1v was used as starting
material, 2i was obtained in 53% yield. By adding
extra 1.0 equiv of DMS to the reaction system, the
yields of the products were improved (entries 15-17).
To gain further insight of the mechanism, some
mechanistic studies were designed and performed
(Scheme 2). First, 3.0 equiv of radical inhibitor
tetramethylpiperidin-1-oxyl (TEMPO) was introduced
to the reaction system under standard conditions. As
expected, there was no significant yield loss, which
excluded the free-radical reaction pathway (Scheme
2a). When cyclohexane-1,2-dione was used as the
starting material, methylthio-substituted catechol was
isolated with a yield of 84%, suggesting that
cyclohexane-1,2-dione could be the intermediate of
this reaction (Scheme 2b).
Scheme 2. Mechanistic Studies.
[a] Reaction conditions: cyclohexanones 1 (1.0 mmol), I2 (1.0
mmol, 1.0 equiv), and DMSO (2.0 mL), in sealed tube, at
80 °C for 24 h.
To further verify the mechanism, 1.0 equiv of
tetrahydrothiophene was introduced to the reaction.
After 2 hours, the reaction mixture was tested by ESI-
HRMS, a few intermediates were detected including
(I) and (II) and (III) (other intermediates were included
[b] Isolated yield.
[c]1.0 equiv of DMS was added.
3
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
in Supporting Information) (Scheme 2c). (I) suggested
that the 2-iodocyclohexanone was generated from
cyclohexanone and I2. (II) and (III) suggested that 1,2-
cyclohexanedione and the aromatization process was
involved.
detailed mechanism and the synthetic applications are
currently underway in our laboratory.
Experimental Section
Based on our experimental results and the previous
literature reports,[14] a plausible mechanism was
proposed for the reaction. Although the mechanism is
not completely understood yet, we believe what occurs
is as follows (Scheme 3). First, electrophilic iodization
of cyclohexanone occurs, promoted by the iodine
catalyst, to form 2-iodocyclohexanone C. Then,
Kornblum oxidation takes place to generate the 1,2-
cyclohexanedione D and DMS, followed by further α
- iodization to give intermediate E. Followed by the
reaction of DMS with E to provide intermediate F.
After the loss of MeI, G undergoes iodization to
generate intermediate H. Lastly, HI elimination and
aromatization produces the methylthio-substituted
catechol product.
Unless otherwise specified, all commercially available
reagents were purchased from chemical suppliers without
1
further purification. H NMR (400 MHz or 300 MHz) and
13C NMR (100 MHz or 75 MHz) spectra were recorded in
CDCl3 or DMSO-d6. High-resolution mass spectra (HRMS)
were obtained by ESI or EI. Column chromatography was
performed on silica gel (200-300 mesh). All products were
1
characterized by comparison of H NMR, 13C NMR, and
HRMS.
Typical Experimental Procedure for Synthesis of
Methylthio-Substituted
Cyclohexanones:
Catechols
from
In a sealed tube with magnetic stir bar was charged with I2
(1.0 equiv), DMSO (2.0 mL) and cyclohexanone (1.0 mmol).
Then the tube was sealed with Teflon cape and heated at 80
oC for 24 h. After completion of the reaction, the reaction
mixture was quenched with 4 mL Na2S2O3 (10% in water),
then extracted with ethyl acetate (10 mL) 3 times The
combined organic phase was washed with brine and then
concentrated by a rotary evaporator. The residue was
purified by column chromatography on silica gel (200−300
mesh) using petroleum ether and ethyl acetate as eluent to
provide the desired product (2a-2v).
Scheme 3. Possible Mechanistic Pathways.
To further utilize the methylthio-substituted
catechol, a gram scale reaction was performed, which
resulted in 16% reduction of our original yield
(Scheme 4a). Sulfoxides are important precursors in
the synthesis of various chemical and biological active
molecules.[4b,15] Hence, we treated the methylthio-
substituted catechol 2a with H2O2 (30% in water) and
Sc(OTf)3, due to information collected from
literature,[4d] and the methylsulfinyl-substituted
catechol was obtained in 98% yield (Scheme 4b).
Acknowledgements
Financial support for this research was provided by National Key
R&D Program of China (2017YFB0308700) and the National
Natural Science Foundation of China (21676003).
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4
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201900069
Advanced Synthesis & Catalysis
COMMUNICATION
Iodine-Mediated Synthesis of Methylthio-
substituted Catechols from Cyclohexanones
Adv. Synth. Catal. Year, Volume, Page – Page
Yue-Hua Wu,a Nai-Xing Wang,a* Tong Zhang,a
Zhan Yan,a Bao-Cai Xu,b* Joan Inoa c and Yalan
Xingc*
6
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