Conversion of Simple Cyclohexanones into Catechols

Article abstract of DOI:10.1021/jacs.6b07269

A novel I₂-catalyzed direct conversion of cyclohexanones to substituted catechols under mild and simple conditions has been described. This novel transformation is remarkable with the multiple oxygenation and dehydrogenative aromatization processes enabled just by using DMSO as the solvent, oxidant, and oxygen source. This metal-free and simple system demonstrates a versatile protocol for the synthesis of highly valuable substituted catechols and therefore streamlines the synthesis and modification of biologically important molecules for drug discovery.

Full text of DOI:10.1021/jacs.6b07269

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Article
Conversion of Simple Cyclohexanones into Catechols
Yu-Feng Liang, Xinyao Li, Xiaoyang Wang, Miancheng
Zou, Conghui Tang, Yujie Liang, Song Song, and Ning Jiao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07269 • Publication Date (Web): 26 Aug 2016
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Conversion of Simple Cyclohexanones into Catechols
Yu-Feng Liang,†,§ Xinyao Li,†,§ Xiaoyang Wang,† Miancheng Zou,† Conghui Tang,† Yujie Liang,† Song
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Song,† and Ning Jiao*,†,‡
† State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking
University, Xue Yuan Rd. 38, Beijing 100191, China
‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Weijin Road 94, Tianjin 300071, China
KEYWORDS：Catechol, Metal-free, Oxygenation, Dehydrogenation, Aromatization, Iodine, Dimethyl sulfoxide.
ABSTRACT: A novel I2-catalyzed direct conversion of cyclohexanones to substituted catechols under mild and simple conditions
has been described. This novel transformation is remarkable with the multiple oxygenation and dehydrogenative aromatization
processes enabled just by using DMSO as the solvent, oxidant and oxygen source. This metal-free and simple system demonstrates
a versatile protocol for the synthesis of highly valuable substituted catechols and therefore streamlines the synthesis and
modification of biologically important molecules for drug discovery.
process is very complicated as reported in the reported meth-
INTRODUCTION:
ods (Scheme 1a-b); 2) The transformation from cyclohexa-
nones to catechols requires multiple processes including oxy-
genation, oxidation, and aromatization, which should be effi-
cient, compatible, and orderly in good relay.
Catechols are ubiquitous structural motifs of various natural
products, bioactive molecules and drugs (Figure 1).1 There are
more than 300,000 compounds containing a catechol compo-
nent that bear useful pharmacological activity. Moreover, cat-
echols are also used extensively in the chemical industries and
more than 3.0×107 kg/year are produced.2 Hence, the devel-
opment of a simple and efficient approach to substituted cate-
chols is of considerable interest. The traditional synthetic
methodologies generally involve an ortho-formylation of phe-
nols followed by a subsequent Dakin oxidation or oxidation of
phenols into ortho-quinones with subsequent reduction
(Scheme 1a).3 However, these approaches always provide
lower regioselectivity and afford a mixture of ortho-, meta-
and para-isomers. Recently, transition metal catalyzed direct-
ing group assisted C-H bond hydroxylation4,5 of phenol de-
rivatives has been significantly developed, which features high
site selectivity and a broad functional group tolerance (Scheme
1b).6 However, multi-step procedures with charging and re-
moving the directing groups of aromatic substrates, and the
requirement of transition-metal catalysis with strong oxidants
limit their application.
Figure 1. Natural products and drugs with catechol sub-
structure.
Herein, we describe a novel I2-catalyzed aromatization of
cyclohexanones for the synthesis of substituted catechols with
simple DMSO as the solvent, hydrogen acceptor and oxygen
source (Scheme 1d). The advantages of the current protocol
can be summarized as follows: 1) This is a novel and efficient
metal-free approach to catechols. The simple and readily
available I2 has emerged as an efficient catalyst instead of a
transition metal catalyst which is often expensive and required
to be completely removed from products especially in the
synthesis of pharmaceutical compounds.10 2) DMSO, a cheap
and common solvent which has been widely used as a nontox-
ic solvent with no risk to human health by the U.S. Environ-
mental Protection Agency (EPA)11, was employed as a mild
oxidant and oxygen source. Therefore, the I2-DMSO system is
simple, mild, practical, easily handled, and shows great poten-
tial for industrial applications. 3) Diverse of readily available
cyclohexanones could be used for the synthesis of high-value
substituted catechols. The modification of bioactive
compound could also be applied by this protocol.
Cyclohexanones are cheap, stable, readily available bulk
chemicals.7 Therefore, the selective dehydrogenative aromati-
zation of cyclohexanones has been widely used as a comple-
mentary and attractive approach to substituted phenols, even
though required stoichiometric oxidants such as DDQ or harsh
conditions (≥200 oC).8 Especially, the Stahl group recently
developed an elegant Pd-catalyzed aerobic dehydrogenation of
cyclohexanones for the synthesis of phenols (Scheme 1c),9
which significantly improved the wide application of cyclo-
hexanones for the synthesis of aromatic molecules. In contrast,
to the best of our knowledge, the direct transformation of this
cheap bulk chemical cyclohexanones to catechols is still un-
known, because there are two challenging issues: 1) One oxy-
gen atom lacks from cyclohexanones to catechols which re-
quires an additional O-source. Generally, the O-incorporation
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in excellent yields. When 4-hydroxycyclohexanone was used
Scheme 1. Strategies for the Synthesis of Catechols or
Phenols.
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as the substrate, catechol 2n could be obtained under the
standard conditions. Moreover, interesting results were also
observed for 4-methoxy or pivalate substituted cyclohexanone
that catechol 2n was the formed via 4-oxygen-substitutent
elimination, which indicates that a reverse Michael addition
reaction may occur in these reactions.
Table 1. Optimization of the Reaction Conditionsa
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RESULTS AND DISCUSSION:
aReaction conditions: 1a (0.5 mmol), cat. (20 mol %), solvent (1
mL), under air for 12 h. bIsolated yields. cWith 3.0 equiv of
DMSO. dUnder argon atmosphere.
Inspired by recently developed DMSO oxidative reactions,12,13
we envisioned that halide-containing reagent could be used as
the catalyst for the oxygenation of C-H bond. At the outset of
our study, we examined the reaction of 4-
methylcyclohexanone 1a with DMSO as solvent and oxidant
(Table1). Disappointingly, no reaction was observed when KI
was employed as catalyst (entry 1). To our surprise, the
hydroxylation and aromatization product, 4-methylcatechol 2a,
was obtained as the unexpected product in 51% yield when
NIS was used as the catalyst (entry 2). Subsequently, various
iodide-containing reagents were investigated. Among them, HI
was also an efficient catalyst for this transformation (entry 3),
whereas ZnI2, NH4I, TBAI failed to give the product (entries
4-6). To our delight, the yield of 4-methylcatechol could be
improved to 62% when I2 was employed as the catalyst (entry
7). The yield decreased significantly when the reaction was
Interestingly, the reaction of 3-ester and carboxyl
substituted cyclohexanones 1q and 1r selectively generated 2k
and 2l as the product respectively, which is consistent with the
reaction of corresponding 4-substituted cyclohexanones 1k
and 1r, which indicates that the oxygenation step highly
regioselectively occurred at the less hindered position of
ketone group. This reaction is sensitive to 2-substitutents,
affording 3-substituted catechols 2s-2u in relative low yields.
When 2-ester substituted cyclohexanone was tested, the
catechol 2v and pyrogallol 2v’ products were obtained in a
combined yield of 79%. Moreover, the reaction of 1g could be
easily performed in gram scale affording 2g in 72% yield.
3,3’,4,4’-Tetrahydroxybiphenyl
3
could inhibit the
o
o
conducted as lower (60 C) or higher temperature (100 C)
(entries 8-9). Only a trace amount of product was observed
when the reaction was carried out in other solvents such as
DCE, CH3CN, dioxane or CH3NO2 (entries 10-13). The
reaction failed to give product in the absence of I2 catalyst
(entry 14). It is noteworthy that this transformation worked
well under Ar atmosphere, which indicates that the terminal
oxidant was DMSO (entry 15).
aggregation of Alzheimer’s amyloid-β peptide (Aβ).14
Furthermore, it has been widely used as a ligand for transition
metals in coordination chemistry.15 This valuable molecule
was synthesized by the traditional Pd-catalyzed Suzuki
coupling of 3,4-dimethoxyphenylboronic acid 4 with 3,4-
dimethoxybromobenzene 5 followed by the cleavage of the
methyl ethers with boron tribromide.14 However, the harsh
reaction conditions result in low yields of the biaryl
Subsequently, the scope of this oxidative aromatization of
various cyclohexanones for the synthesis of mono-substituted
catechols was investigated (Table 2). Cyclohexanones bearing
an alkyl substituent at the para position were smoothly
converted to the corresponding products 2a-2f in good yields.
Table 2. Conversion of Cyclohexanones to Catechols.a
Aryl
substituted
cyclohexanones
1g and
such
as
4-
phenylcyclohexanone
4-(4-hydroxyphenyl)-
cyclohexanone 1h also participated well in this process,
converting to the corresponding products 2g and 2h efficiently.
To our delight, functional groups, such as cyano, aldehyde,
ester, carboxyl and amide groups, were all well tolerated in
this transformation to afford the corresponding products 2i-2m
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readily commercial available substrate which could be simply
prepared from 1,4-cyclohexadione,16 in 51% yield by this
present approach (Scheme 2a). It also should be mentioned
that the complete removal of Pd-catalyst from products is
avoided by the present protocol.
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Scheme 2. Synthetic Utilities of this Protocol.
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Within the broad substrate scope and the mild reaction
conditions, we applied the present method to the
diversification of bioactive molecules. Remarkably, the
derivative of cholesterol 7 could be converted to catechol
product 8 in good yield under the standard conditions without
affecting the complex steroid structure (Scheme 2b).
Interestingly, norethindrone 9 delivered the α-carbonylation
product 10 instead of aromatization product in moderate yield
(Scheme 2c), providing valuable information for the reaction
mechanism.
When the reaction of 1g was performed with 18O-labeled
DMSO, the 18O-labeled product 18O-2g was detected, along
with the O-isotope exchange product 2g and 18O2-2g, with the
ratio of 1:0.28:1.03 based on HRMS analysis (Scheme 3a).
When 3.0 equiv of H218O was added into the control reaction
of 2g under the standard conditions, the three products could
also be obtained with the ratio 1:0.52:0.52 (Scheme 3b).
Interestingly, the I2 catalyst is essential for the O-isotope
exchange and DMSO is not required (Scheme 3b). The above
18O-labeling experiments suggest that the additional oxygen
atom in catehol product is original form DMSO, and the O-
isotope exchange products are probably generated from
exchange with H218O, which was the byproduct in the 18O-
DMSO oxidative regeneration of iodine catalyst (for a
proposed mechanism for O-exchange, see SI). In contrast to
the reaction of 1g, the corresponding cyclohexenone 11
reacted under the standard conditions to afford the phenol
product 12 instead of the catechol product 2g, which excludes
the possibility of the cyclohexenone intermediate for the
formation of catechol product (Scheme 3c). Although the α-
iodo cyclohexanone was not detected by GC-MS and NMR
aReaction conditions: mono-substituted cyclohexanones 1 (0.5
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mmol), I2 (20 mol %), DMSO (1 mL), under air, at 80 oC for 12 h.
bIsolated yields. cGram scale. d2v (23%), 2v’ (56%).
intermediate and the desired 3,3’,4,4’-tetrahydroxybiphenyl
(48% and 43% yields, respectively). In contrast, it can be
easily prepared from 4,4'-bicyclohexanone 6, a simple and
analysis
during
the
reaction,
when
2-iodo-4-
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phenylcyclohexanone 13 was employed as the starting material
under the standard conditions, 2g was selectively obtained in
77% yield (Scheme 3d). Moreover, the reaction of 1g with
DMSO could also preceed efficiently when 13 was used as
catalyst (Scheme 3e), which indicates that α-iodo
cyclohexanone is a possible intermediate for this reaction.
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The reaction result of norethindrone 9 (Scheme 2c)
suggested that cyclohexane-1,2-dione may also be the reaction
intermediate in the transformation. To explore whether this
reaction went through cyclohexane-1,2-dione intermediate
specifically, we monitored the reaction kinetics. The kinetic
time course revealed the formation and disappearance of 1,2-
cyclohexanedione intermediate (Scheme 4a). In addition,
when 4-phenylcyclohexane-1,2-dione 14 was tested as the
substrate, 2g was isolated in 86% yield (Scheme 4b). These
results demonstrate that the corresponding cyclohexane-1,2-
dione is another key intermediate of this novel transformation.
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Scheme 3. Mechanistic studies.
To further understand the mechanism of this transformation
and the chemoselectivity between catechol and phenol, we
conducted a density functional theory (DFT) calculation
investigation into the aromatization reaction of 4-
phenylcyclohexanone 1g and 4-phenylcyclohexenone 11 as
model reactions (Figure 2a).17 After iodination of 1g, the
formed iodocyclohexanone could undergo the key step of SN2
or E2 reactions with DMSO to provide catechol or phenol,
respectively. The SN2 reaction of iodocyclohexanone with
DMSO undergoing Kornblum reaction18 using DMSO as the
O-source19 via transition state TSa-SN2-1g and TSe-SN2-1g
requires an activation free energy of 27.6 and 20.1 kcal/mol to
afford catechol. The iodocyclohexanone undergoes an
alternative pathway corresponding to the E2 process with
DMSO with an activation free energy of 27.9 and 23.3
kcal/mol to form phenol. TSe-SN2-1g is 3.2 kcal/mol lower in
energy than TSa-E2-1g, and this difference is qualitatively
consistent with the experimentally observed good
chemoselectivity for the catechol 2g formation under the
standard conditions. When 11 was used as the starting material,
the SN2 reaction via transition state TSa-SN2-11 and TSe-SN2-
11 requires an activation free energy of 31.3 and 27.5 kcal/mol
to afford catechol. An alternative pathway corresponds to E2
process with DMSO with an activation free energy of 22.1 and
27.2 kcal/mol to form phenol product. As a result, TSa-E2-11
is favored over TSe-SN2-11 by 5.4 kcal/mol, once again in
complete accord with the experimental good chemoselectivity
for the phenol 12 formation. The low energy for TSa-E2-11
may be attributed to the formation of π-conjugated system and
large dipole moment in transition state. In the case of 1g, E2
process with DMSO is no more stabilized by the π-conjugated
system, making the SN2 reaction kinetically favorable. Our
calculation further confirms the chemoselectivity for the
catechol and phenol formation also has universality, in which
mono-substituted cyclohexanone tends to give catechol
product, while cyclohexenone is favored to deliver phenol
product.
Scheme 4. Kinetic Profile and Conformed Reaction.
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Figure 3. DFT Calculation for Multi-substituted Cyclohexa-
nones.
Although the mechanism is not completely clear yet, a
possible reaction pathway for the formation of catechols is
proposed (Figure 2b). Initially, electrophilic iodization of
cyclohexanones by the iodine catalyst occurs to afford α-iodo
cyclohexanones A. And then Kornblum oxidation18 occurs to
generate 1,2-cyclohexanediones B, followed by further α-
iodization to give intermediates C. Subsequently the
intermediates C undergo HI elimination and then tautomerize
to afford catechol products. The oxidation of HI in the
presence of DMSO would generate (CH3)2S, H2O and
regenerate iodine catalyst for the next catalytic cycle.22 In
addition, dimethyl sulfide was detected by GC-MS analysis of
reaction products. The whole energy profiles were calculated to
better understand the mechanism (see Figure S1 in SI for
detail).
Figure 2. DFT Calculation and the Proposed Mechanism.
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CONCLUSION :
Moreover, for the multi-substituted cyclohexanones, the
calculation of 3,5-dimethylcyclohexanone I as a model
substrate indicates that the TS-SN2-I is less stable over 4.3
kcal/mol than TS-E2-I (Figure 3), which suggests that phenols
would be predicted to be formed instead of catechols. In order
to further understand the DFT calculation, the transformation
of multi-substituted cyclohexanones under the present
conditions was investigated (Table 3). In accordance with the
DFT calculation, the corresponding phenols were formed as
the product in most cases with multi-substituted
cyclohexanones (Table 3). It should be noted that although the
transition-metal-catalyzed oxidative dehydrogenation20 of
cyclohexanones for the synthesis of phenols is known,9,21 to
the best of our knowledge, this is the first example of metal-
free oxidative transformation of cyclohexanones to phenols.
In summary, we have developed a unique I2 catalyzed aro-
matization of easily accessible cyclohexanones for the synthe-
sis of substituted catechols via selective oxygenation and de-
hydrogenation processes. The usage of inexpensive DMSO as
the oxidant, oxygen source, and solvent with easy operation
makes this protocol very green and practical. The current
method also provides an efficient and concise synthetic meth-
odology to valuable aromatic compounds. The modification of
bioactive compounds could also be applied by this protocol.
Further studies to elucidate the detailed reaction mechanism
and synthetic applications are in progress in our laboratory.
Table 3. Oxidative of Multi-substituted Cyclohexanones.a
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aReaction conditions: multi-substituted cyclohexanones 15 (0.5
mmol), I2 (20 mol %), DMSO (1 mL), under air, at 80 oC for 12 h.
bIsolated yields.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical data
for products, NMR spectra of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiaoning@pku.edu.cn
(11) Dimethyl Sulfoxide Producer Association, US Environmental
Protection Agency. IUCLID Data Set; Leesburg, VA, September 8, 2003;
report number 201-14721A.
Author Contributions
§These authors contributed equally.
Notes
(12) For a review, see: (a) Wu, X.-F.; Natte, K. Adv. Synth. Catal. 2016,
358, 336. For some selected examples with DMSO as a reagent, see: (b)
Floyd, M. B.; Du, M. T.; Fabio, P. F.; Jacob, L. A.; Johnson, B. D. J. Org.
Chem. 1985, 50, 5022. (c) Battini, N.; Padala, A. K.; Mupparapu, N.;
Vishwakarma, R. A.; Naveed, Q. RSC. Adv. 2014, 4, 26258. (d) Xu, R.;
Wan, J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531. (e)
Reddi, R. N.; Prasad, P. K.; Sudalai, A. Angew. Chem. Int. Ed. 2015, 54,
14150. (f) Tomita, R.; Yasu, Y.; Koike, T., Akita, M. Angew. Chem. Int. Ed.
2014, 53, 7144. (g) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; Baina, K. E.
L.; Zheng, B,; Walsh, P. J. Angew. Chem. Int. Ed. 2014, 53, 260. (h) Jia, T.;
Bellomo, A.; Baina, K. E. L.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc.
2013, 135, 3740. (i) Chen, J.; Li, G.; Xie, Y.; Liao, Y.; Xiao, F.; Deng, G.-J.
Org. Lett. 2015, 17, 5870. (j) Wu, X.; Gao, Q.; Liu, S.; Wu, A. Org. Lett.
2014, 16, 2888.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Basic Research Program of Chi-
na (973 Program) (No. 2015CB856600) and National Natural
Science Foundation of China (21325206, 21632001) and National
Young Top-notch Talent Support Program are greatly appreciated.
We thank Kai Wu in this group for reproducing the results of 2e
and 2j.
(13) For some DMSO oxidative examples in our group, see: (a) Liang,
Y.-F.; Wu, K.; Song, S.; Li, X.; Huang, X.; N. Jiao, Org. Lett. 2015, 17,
876. (b) Song, S.; Huang, X.; Liang, Y.-F.; Tang, C.; Li, X.; Jiao, N.
Green Chem. 2015, 17, 2727. (c) Song, S.; Sun, X.; Jiao, N. Org. Lett.
2015, 17, 2886. (d) Song, S.; Li, X.; Sun, X.; Yuan, Y.; Jiao, N. Green.
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