1-Methyl-1,4-cyclohexadiene as a Traceless Reducing Agent for the Synthesis of Catechols and Hydroquinones

Article abstract of DOI:10.1021/acs.joc.9b01898

Pro-aromatic and volatile 1-methyl-1,4-cyclohexadiene (MeCHD) was used for the first time as a valid H-atom source in an innovative method to reduce ortho or para quinones to obtain the corresponding catechols and hydroquinones in good to excellent yields. Notably, the excess of MeCHD and the toluene formed as the oxidation product can be easily removed by evaporation. In some cases, trifluoroacetic acid as a catalyst was added to obtain the desired products. The reaction proceeds in air and under mild conditions, without metal catalysts and sulfur derivatives, resulting in an excellent and competitive method to reduce quinones. The mechanism is attributed to a radical reaction triggered by a hydrogen atom transfer from MeCHD to quinones, or, in the presence of trifluoroacetic acid, to a hydride transfer process.

Full text of DOI:10.1021/acs.joc.9b01898

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Article
1-Methyl-1,4-cyclohexadiene as a traceless reducing
agent for the synthesis of catechols and hydroquinones
Andrea Baschieri, Riccardo Amorati, Luca Valgimigli, and Letizia Sambri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01898 • Publication Date (Web): 19 Sep 2019
Downloaded from pubs.acs.org on September 21, 2019
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-Methyl-1,4-cyclohexadiene as a traceless reducing agent for
the synthesis of catechols and hydroquinones
,
a
, a
a
b
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Andrea Baschieri,* Riccardo Amorati,* Luca Valgimigli and Letizia Sambri
a
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via S. Giacomo 11, 40126 Bologna, Italy.
E-mail: andrea.baschieri2@unibo.it (A.B.); riccardo.amorati@unibo.it (R.A.)
b
Dipartimento di Chimica Industriale “T. Montanari”, Università di Bologna, Viale Risorgimento 4, 40136
Bologna, Italy.
ABSTRACT
Pro-aromatic and volatile 1-methyl-1,4-cyclohexadiene (MeCHD) was used for the first time as a
valid H-atom source in an innovative method to reduce ortho or para quinones to obtain the
corresponding catechols and hydroquinones in good to excellent yields. Notably, the excess of
MeCHD and the toluene formed as the oxidation product can be easily removed by evaporation. In
some cases, trifluoroacetic acid as a catalyst was added to obtain the desired products. The reaction
proceeds in air and under mild conditions, without metal catalysts and sulfur derivatives, resulting
in an excellent and competitive method to reduce quinones. The mechanism is attributed to a radical
reaction triggered by a hydrogen atom transfer from MeCHD to quinones, or, in the presence of
trifluoroacetic acid, to a hydride transfer process.
INTRODUCTION
The use of dihydroxybenzene isomers (hydroquinones, catechols, and resorcinols) seeps into
various aspects of our lives. They are high-value chemicals employed as important intermediates in
the pharmaceutical industry, as building blocks of organic frameworks and as valuable precursors
1
for organic synthesis. Hydroquinone (1,4-dihydroxybenzene) and catechol (1,2-dihydroxybenzene)
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have similar structure and properties, and together with their derivatives find wide applications in
various fields. In fact, they are extensively used as preservatives, stabilizer, antioxidants,
polymerization inhibitors, and photography chemicals, and they are also used in the preparation of
pesticides, flavouring agents and medicines 2, 3 as well as in water treatment. For these reasons,
they attract a great deal of industrial interest. Catechols and hydroquinones are exploited in the
cosmetics, dyes, agro-food, chemical, and pharmaceutical industries 5-8 (Figure1).
4
0
1
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3
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1
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0
1
2
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0
1
2
3
4
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9
0
OH
HO
HO
HO
HO
O
O
OH
O
O
Esculetin
(
anti-inflammatory, anti-diabetic drug)
HO
OH
HO
OH
OH
2
,5-Di-tert-octylhydroquinone
photographic film paper)
Quercetin
(natural antioxidant)
(
OH
HO
OH
HO
HO
3
-Hydroxytyrosol
natural anti-hyperlipidemic)
(
O
O
O
HO
O
O
O
O
OH
Tert-butylhydroquinone
O
OH
O
O
HO
CHO
OH
O
O
Vanillin ester
(anti-melanogenic)
(
preservatives)
OH
O
OH
OH
HO
HO
OH
O
HO
OH
OH
O
O
HO
HO
N
H
OH
Arbutin
releases hydroquinone,
natural anti-melanogenic)
HO
OH
5
,6-Dihydroxyindole
monomer of melanin polimers)
Tannin
(cosmetics)
(
OH
(
Figure 1. Examples of hydroquinones and catechols of major relevance
Furthermore, as these structures exist in several natural products, these compounds are of great
importance for their biological activities such as anti-inflammatory, antibacterial, anticonvulsants.9
A growing number of studies deals with the beneficial properties of plant polyphenols; in fact,
many phenolic compounds found in food and beverages are reputed chemopreventive agents, useful
in mitigating degenerative diseases.10 Therefore, the development of a robust strategy for the
synthesis of hydroquinone and catechol derivatives is highly desirable.
Quinones are a class of non-aromatic cyclic diketones that can be reduced to the corresponding
1
1
hydroquinones or catechols. A variety of quinone-like structures have been prepared, the most
common ones being the 1,2- (ortho-benzoquinone) and 1,4- (para-benzoquinone) scaffolds.
Colourless hydroquinones and catechols, when exposed to oxygen, oxidize under mild conditions to
the corresponding coloured quinones. This process may be catalyzed by enzymes such as catechol
oxidase or tyrosinase (e.g. as when a potato or an apple is cut and exposed to air) and may lead to
polymerization to form dark melanoid pigments (Scheme 1).12,13
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COOH
HO
HO
COOH
NH2
O
O
COOH
NH2
DOPAquinone
TYR
TYR
NH2
O2
O2
HO
Tyrosine
DOPA
O
Eumelanin polymer
COOH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
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2
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9
0
1
2
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8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
HO
DOPAchrome
Scheme 1. Melanin biosynthesis catalized by enzyme tyrosinase (TYR)
Many methods and various reagents have been used for the reduction of quinones to hydroquinones
or catechols. For example, tin (II) chloride, zinc and acetic acid, iron and hydrochloric acid, sodium
dithionite, sodium borohydride, ascorbic acid, polymethylhydrosiloxane, molecular hydrogen and
vanadium (II) chloride have been reported as reducing agents for quinones.14 However, these
existing methods are far from being perfect. In fact, most of them suffer from drawbacks such as the
1
harsh reaction conditions, the use of aggressive reagents forming a large amount of waste, the
requirement of expensive catalysts, the difficulty to purify products from traces of toxic reactants
and by-products and the need for oxygen-free conditions. These reactions are often difficult to
control when the starting quinones contain other reducible and/or labile groups. It is important for
the choice of the reducing method to consider the compatibility with other functional groups, the
cost of reactants and the ease of product isolation. New methods and new reagents, which offer
alternatives to those already known, are constantly being sought.
In a previous work, some of us demonstrated that the hydroperoxyl radical (HOO•), besides being
an oxidizing agent, can also work as an effective reducing agent, being able to regenerate the
physiologic antioxidant -tocopherol by reduction of the corresponding phenoxyl radical.15
Although HOO• is short-lived and difficult to be selectively generated in solution, it is known to be
the chain-propagating species in the spontaneous autoxidation of 1,4-cyclohexadiene to benzene in
1
6
the presence of air. Indeed we have recently shown that the autoxidation of 1,4-cyclohexadiene to
benzene is a valuable model for the controlled generation of HOO• in solution (Scheme 2), which
enabled us to reduce nitroxides (>NO•) to the corresponding hydroxylamine (>NOH).17
Interestingly, on studying the behavior of a variety of potential antioxidants in the autoxidation of
1
,4-cyclohexadiene we came across an unexpected finding: ortho-quinones - which normally
represent the exhaust oxidation products formed in those processes in which a catechol is used as
the antioxidant to protect some organic substrates - were reduced to the corresponding catechols
1
5
when added to autoxidizing 1,4-cyclohexadiene. Given the relevance of this process in synthetic
chemistry, we set to explore it in detail.
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H
H
H
H
H
HOO
O2
+
H O
2 2
H
H
H
+ HOO
0
1
2
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0
1
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9
0
H
H
Scheme 2. Generation of hydroperoxyl radicals in solution by autoxidation of 1,4-cyclohexadiene.
In this work, we describe the reduction of ortho and para quinones (1 and 3, Scheme 3) to the
corresponding catechols (2) and hydroquinones (4) using pro-aromatic 1-methyl-1,4-
cyclohexadiene (MeCHD) as the H-atom source. The reactions are performed under air, in mild
conditions, and without any metal catalysts. Notably, the choice of MeCHD as the reducing agent
results in the formation of toluene as co-product of the redox process, making this methodology
more environmentally convenient than those producing benzene. In addition, both the reaction co-
product (toluene) which is coincident with the solvent (under typical embodiments of the method)
and excess of MeCHD are easily and quantitevly removed from the reaction product simply by
evaporation, making it a traceless reductant.
O
OH
R1
R2
R1
R2
O
OH
MeCHD
R4
Toluene, 30 °C
R4
R3
R3
1
2
R1
MeCHD,
CF COOH
(
R1
R2
3
R2
O
OH
0 to 40 eq.)
R3
Toluene, 30 °C
R3
O
HO
R4
R4
3
4
1
-methyl -1,4 cyclohexadiene (MeCHD)
Scheme 3. Reaction of quinones with MeCHD
RESULTS AND DISCUSSION
,5-Di-tert-butyl-1,2-benzoquinone (1a) and 2,5-di-tert-butyl-1,4-benzoquinone (3a) are
3
characterized by high solubility in most common organic solvents and high chemical stability. In
addition, the presence of two bulky electron-donating substituents makes them among the most
difficult compounds to be reduced in this class of molecules. Therefore, they appeared suitable
substrates for optimizing the reduction reaction.
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Table 1: Optimization of Reaction Conditions.[a]
OH
O
tBu
OH
tBu
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeCHD (20eq.)
Solvent
Temperature
tBu
tBu
1a
2a
tBu
O
tBu
OH
O
tBu
HO
tBu
3a
4a
Temperature Conv.[b]
Entry Comp. Prod.
Solvent
[
°C]
25
25
40
60
60
25
25
25
25
25
25
[%]
98
1
2
3
4
5
6
7
8
9
1a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
2a
4a
4a
4a
4a
4a
4a
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
< 1
< 1
< 1
[c]
< 1
< 1
< 2
< 1
Acetonitrile
4a (CF ) CHOH
3 2
[
d]
4a
4a
4a
/
< 2
[e]
10
11
Toluene
Toluene
28
[
e],[f]
<1
[a]
Reaction conditions: 1a or 3a (0.18 mmol), 1-methyl-1,4-cyclohexadiene (3.6 mmol), solvent (2.0
[b]
1
[c]
mL), 24 h. Conversion was determined by H NMR spectroscopy, Experiment performed under
[d]
nitrogen atmosphere, Experiment performed with 7.2 mmol of 1-methyl-1,4-cyclohexadiene,
Experiment performed with trifluoroacetic acid (2.52 mmol, 14 equiv), Experiment performed
[e]
[f]
in the absence of 1-methyl-1,4-cyclohexadiene.
The first experiment was conducted with 1a in the presence of 20 equiv of 1-methyl-1,4-
cyclohexadiene as a reducing agent in toluene at room temperature. Gratifyingly, these reaction
conditions led to a 98% conversion of 1a into 2a after 24 h (Table 1, entry 1). Conversely,
compound 3a is inert under these conditions and the desired product 4a has been detected only in
traces (Table 1, entry 2). Similar results were obtained by changing the reaction temperature (Table
1, entry 3 and 4), or performing the reaction in the absence of oxygen (Table 1, entry 5). Despite the
fact that H-bond formation with the solvent could stabilize the possible semiquinone intermediate
(
see below),18,19 using either a H-bond accepting (i.e. MeCN) or a H-bond donating solvent (i.e.
20
hexafluoropropanol) did not improve the yield of 4a (Table 1, entry 6-8), and a similar lack of
conversion was obtained in the absence of solvent with a slight excess of MeCHD (Table 1, entry
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
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). Eventually, we found that the addition of trifluoroacetic acid enables the reaction of 3a to give
4a in 28% conversion after 24 h (Table 1, entry 10). Clearly, even in the presence of the acid, a
reducing species is still needed to afford the expected hydroquinone 4a, as confirmed by the
reaction carried out without MeCHD (Table 1, entry 11).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2: Optimization of the reaction conditions for para-quinone 3a. Representative results of the
screening of acids.
[a]
tBu
O
tBu
OH
Toluene
0° C, 24 h
+
+ Acid
3
O
tBu
HO
tBu
3a
4a
[b]
Entry Acid
Acid [equiv] 2a Conv. [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
CH COOH
14
14
14
14
30
40
40
0.1
0.5
1
<1
3
20
40
87
3
CHCl COOH
2
CCl COOH
3
CF COOH
3
CF COOH
3
[
c]
c]
CF COOH
>99 (91)
3
[d]
CF COOH
60
3
H SO
2
62
97
>99 (33)
1
2
4
4
4
4
H SO
2
0
1
2
3
H SO
2
[
H SO
2
2
p-TolSO H
14
0.1
0.5
1
3
CH SO H
14
20
65
3
3
14
15
CH SO H
3
3
CH SO H
3
3
[c]
1
6
CH SO H
2
>99 (82)
3
3
[a]
Reaction conditions: 3a (0.09 mmol), 1-methyl-1,4-cyclohexadiene (3.6 mmol), acid, solvent (1.0
[b]
1
[c]
mL), 30 °C, 24 h. Conversion was determined by H NMR spectroscopy, Yield of the isolated
product after chromatography on silica gel, T = 16 °C.
[d]
Encouraged by this result, the reaction conditions were further optimized by investigating different
acids at different concentrations (Table 2). The reaction proceeds only in the presence of an acid
with strength not lower than that of trifluoroacetic acid (Table 2, entries 1-3 vs 6, 11, 16) and its
concentration is critical to afford high conversions. However, under highly acidic harsh conditions,
such as in the presence of H SO or methanesulfonic acid (Table 2, entry 11, 16), degradation by-
2
4
products are also formed, lowering the isolated yields of the hydroquinone 4a. The best results were
obtained with 40 equiv of trifluoroacetic acid at 30 °C, while lowering the reaction temperature
decreases the conversion (Table 2, entry 7).
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Lastly, the roles of different suitable organic solvents (Table S1) and of the concentration of
MeCHD (Table S2) were systematically investigated to further optimize the reaction conditions.
The results revealed that dichloromethane and toluene were superior to other solvents (Table S1,
entry 3 and 8): in general, non-polar solvents, unable to form or to accept hydrogen bonds, proved
to be better than polar solvents. Since toluene is anyway formed as a co-product from the reaction
of MeCHD with quinones, it was logical to use it as the reaction solvent. Interestingly, by
progressively increasing the equivalents of MeCHD from 0 to 40, we observed a plateau value
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table S2, entry 6, 7) in which the conversion of desired product was complete, therefore 30 equiv
of MeCHD was identified as the optimal amount.
On the basis of the collected results, we explored the scope of the reaction by treating various ortho
and para quinones (1 and 3) with MeCHD in toluene, with the addition of trifluoroacetic acid when
necessary. The results of the reduction reactions are shown in Table 3. We were pleased to find that
a broad range of ortho-quinones (1a-g), with both electron-donating and electron-withdrawing
groups, can be smoothly reduced to the corresponding catechols (2a-g) in good yields with only 1-
methyl-1,4-cyclohexadiene as the reducing agent. (Table 3, entry 1-5). Also, polycyclic substrates
proved to be reactive under these conditions (Table 3, entry 6, 7), even if product 2g could not be
isolated, due to its instability during chromatography in a silica gel column.
On the contrary, for para-quinones (3a-n and 3CoQ ), the type, the number, the nature and the
0
position of the substituents greatly influence their reactivity. Since the optimization of the reaction
conditions was carried out on 3a that, bearing two bulky tert-butyl groups, is one of the least
reactive substrates, a specific adjustment of the acid amount was undertaken depending on the
quinone to be reduced. The results are reported in Table 3.
Table 3: Reduction of quinones to the corresponding catechols or hydroquinones.[a]
O
OH
R1
O
R1
OH
tBu
tBu
MeCHD
O
O
R2
R4
Toluene, 30 °C
R2
R4
R3
R3
tBu
tBu
3jj
1
2
R1
MeCHD,
R1
CF COOH
R2
R2
3
O
O
OH
R3
(0 to 40 eq.)
R3
Toluene, 30 °C
HO
O
OCH3
O
R4
R4
OCH3
3CoQ0
3
4
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Conv.[b] Yield[c]
t
TFA
Entry Comp. R1
R2
R3
R4
Prod.
[
h] [equiv]
[%]
>99
>99
>99
>99
>99
>99
75
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
94
[%]
95
94
95
96
97
95
1
2
3
4
5
1a
1b
1c
1d
1e
1f
tBu
Cl
H
H
H
H
Cl
Me
tBu
Cl
H
H
H
H
Cl
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
4a
4b
4b
4c
4d
4e
4f
4f
4f
4f
4g
4h
4i
2
2
4
2
2
18
48
15
15
2
2
15
2
2
1
0.3
0.1
2
2
2
24
5
24
24
24
24
/
/
/
/
/
/
/
40
/
5
/
/
/
5
40
40
40
5
5
5
tBu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C H CO Me
2
4
2
6
C H
H
6
4
[d]
7
8
9
1g
3a
3b
C H
6
C H
/
90
4
6
4
[e]
tBu
H
H
H
H
H
tBu
H
92
89
93
94
90
89
25
44
85
70
75
78
89
85
90
25
/
10
1
1
1
1
1
1
2
3
4
5
3c
3d
3e
3f
Cl
F
Cl
Me
H
F
Cl
H
H
F
Cl
H
Cl
F
Cl
H
16
17
1
1
2
2
2
8
9
0
1
2
3g
3h
3i
tBu
Me
Me
tBu
tBu
OMe
Me
H
H
H
H
H
H
H
Me
tBu
tBu
H
Me
OMe OMe
C H
H
Me
H
H
H
3j
4j
40
40
40
40
40
40
5
3jj
3k
3l
3m
3n
4jj
4k
4l
4m
4n
>99
95
30
23
H
Me
OMe
Me
2
2
2
2
4
5
6
7
C H
5
6
4
C H
6
/
/
4
6
4
3CoQ0 Me
H
OMe OMe 4CoQ0 15
71
35
[
a]
Reaction conditions: 1 (0.18 mmol), 1-methyl-1,4-cyclohexadiene (5.4 mmol), toluene (2.0 mL),
30 °C. Conversion was determined by H NMR spectroscopy, Yield of the isolated product after
chromatography on silica gel, It was not possible to isolate this compound due to its instability
after chromatography on silica gel. The reaction was also performed on a 4.5 mmol scale (Yield =
[b]
1
[c]
[d]
[e]
8
4%).
1
,4-Benzoquinone (3b) can be easily reduced to hydroquinone (4b) with only MeCHD or by
adding 5 equiv of trifluoroacetic acid to the reaction mixture to decrease the reaction time (Table 3,
entry 9 vs entry 10). The presence of chlorine atoms boosts the reactivity of the quinone, regardless
of their position and number, while the presence of fluorine atoms, does not change the reactivity of
the quinone (Table 3, entries 11-13). On the contrary, with electron donating groups, the reactivity
is greatly influenced also by the steric hindrance of the substituents. In fact, p-toluquinone (3f)
having only one methyl substituent can be reduced in the presence of only 5 equiv of trifluoroacetic
acid within 2 h. To further decrease the reaction time, the reaction was tested also with 40 equiv of
the acid (Table 3, entry 14-17), however, some uncharacterized by-products are formed, decreasing
the isolated yields of 4f.
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On the other hand, the presence of only one tert-butyl or two methyl groups as substituents lets the
quinones undergo smooth reduction, with 5 equiv of trifluoroacetic acid (Table 3, entry 18-20).
A different situation occurs with quinones where two bulky tert-butyl groups are adjacent to one of
the two carbonyl groups. In these cases, 40 equiv of trifluoroacetic acid are necessary for the
reaction to proceed to completion (Table 3, entries 21-22). The same behavior is observed for
electron-donating -OMe groups (Table 3, entry 23). 2,3,5,6-Tetramethyl-1,4-benzoquinone (3l),
with all 4 positions occupied by a methyl group, gives modest yields of durohydroquinone (4l)
probably due to a combination of ring deactivation, steric hindrance and instability of the final
product in the presence of oxygen, similarly to what observed for compounds 3m and 3n (Table 3,
entry 24-26).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Finally, to extend the scope of the work, this new facile reduction method was successfully tested
on a biomolecule with redox active properties, coenzyme Q (3CoQ ). Also in this case, with 1-
0
0
methyl-1,4-cyclohexadiene and 5 equiv of trifluoroacetic acid it is possible to obtain the reduced
coenzyme Q (4CoQ ) with good conversion, albeit in a moderate yield (Table 3, entry 27), which
0
0
could provide potential handles for further modification.
The reaction conditions were amenable to a large-scale reaction: 4a could be prepared on a 4.5
mmol scale in a yield similar to that found on a 0.18 mmol scale (Table 3, entry 8).
Preliminary work aimed at testing structurally related reducing agents indicated that other
compounds bearing the cyclohexadiene core could replace MeCHD. For instance, reduction of 1a
and 3a by simple 1,4-cyclohexadiene or by natural -terpinene (4-methyl-1-(1-methylethyl)-1,4-
cyclohexadiene) afforded results similar to those obtained with MeCHD (data not shown);
however, their oxidation products were carcinogenic benzene or high-boiling p-cymene (1-
isopropyl-4-methylbenzene), hence their removal from the reaction mixture was (for different
reasons) a more critical issue. Overall MeCHD was judged as the most convenient compromise.
To gain insight into the mechanism, several control experiments were carried out (Table S3-S5,
Figure S1-S5). We initially focused our attention on those reactions where trifluoroacetic acid is
absent, in which a radical mechanism appears feasible.
First, it was observed that MeCHD reacts stoichiometrically with compound 1a. We performed
different reactions directly in an NMR tube in CD Cl as the solvent with 3,5-di-tert-butyl-o-
2
2
benzoquinone (1a) and MeCHD at 30 °C and we followed the conversion of the ortho-quinone to
the corresponding catechol and the simultaneous toluene formation. In an experiment without
compound 1a, it was possible to see that in fresh MeCHD about 2.5% of toluene is already present,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
6
and after 24 h, in the reaction conditions, it increases to about 3%. When compound 1a was present,
the toluene concentration rapidly increased to 6% (the conversion of 1a is almost complete), and
after 24 h it becomes about 6.5%. It's clear, that about 3-3.5% additional MeCHD is consumed
compared to the control experiment. This 3-3.5% MeCHD corresponds to the moles of 3,5-di-tert-
butyl-o-benzoquinone (1a) added in the reaction mixture (Table S3, Figure S1-S3). Therefore, the
MeCHD concentration affects only the reaction rate (see above) and even if 30 equivalents are
used, no side reaction is found to occur. This also demonstrates the possibility to recycle unreacted
MeCHD.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To better understand the different reactivity between ortho and para quinones, further experiments
were performed. When 3,5-di-tert-butyl-1,2-benzoquinone (1a) and 2,5-di-tert-butyl-1,4-
benzoquinone (3a) are simultaneously present in the reaction mixture (in a 10:90 or 50:50 ratio) in
the presence of MeCHD, a small but significant amount of 3a is converted to the hydroquinone 4a
without adding trifluoroacetic acid. Conversely, in the control experiments in which MeCHD was
absent or 3,5-di-tert-butylcatechol (2a) was used instead of 3,5-di-tert-butyl-o-benzoquinone (1a),
only a negligible amount of product 4a could be found (Table S4, Figure S4-S5). This experiment
shows that the presence of 1a allows the onset of the reduction, in which occasionally 3a is also
involved. The role of O was investigated by performing matched experiments of MeCHD with 1a
2
or with 3a (the latter catalyzed by CF COOH) under air or nitrogen, as reported in Table S5. The
3
reaction conditions were the same as those reported in Table 3 for 1a and 3a reduction, with the
exception of the reaction time that was shortened so to avoid that the reaction could proceed to
completion and highlight more markedly the effect of the inert athmosphere. The results showed
that performing the reactions under N increased the conversion of 1a from 55% to 71%, and that of
2
3a from 45% to 72% (see Table S5), compared to the reactions performed under air. This result
clearly excludes any role of O in the initiation of the reduction, and suggests that O participates
2
2
into side reactions that account for a smaller fraction of the overall reduction rate. Indeed, the effect
of O appears surprisingly small, if considering the susceptibility of both MeCHD and
2
hydroquinones to be oxidized under air. However, it allows the reactions to be carried out under
open athmosphere, making them particularly facile and practical.
On the basis of the results above and of the thermochemistry calculated at the CBS-QB3 level of
theory, reported in Table 4, a plausible mechanism for the reaction between quinones and MeCHD
in the absence of trifluoroacetic was proposed (Scheme 4).
1
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Table 4. Computed thermochemistry at the CBS-QB3 level for elementary reactions potentially
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
involved in the radical-mediated reduction of quinones (Q) 1a and 3a by MeCHD.
a
a
Reaction
H 1a (kcal/mol)
H 3a (kcal/mol)
Q + MeCHD  QH• + MeCHD(-H•)
A
B
C
+3.6
-1.8
+18.7
-6.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
QH• + MeCHD  QH + MeCHD(-H•)
2
Q + MeCHD(-H•)  QH• + MeCHD
-45.9
-30.8
D
E
J
HOO• + Q  QH• + O2
-21.1
-6.0
-7.1
HOO• + QH  QH• + H O
2
-11.9
2
2
+
-
-25.4b
-1.7
QH + MeCHD  QH + MeCHD(-H )
-
-
2
+
•+
K
QH + MeCHD  QH + MeCHD(-H•)
2
a
The structures of 1a and 3a were simplified by replacing the tert-butyl groups with methyl groups.
b
Value relative to the hydride transfer to the O-atom. The enthalpies for the hydride transfer to the
other positions of the ring are: C1 = -4.3, C3 = -7.9, C5 = -6.8 (in kcal/mol), the numbering starting
from the protonated carbonyl group, see Scheme 5.
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tBu
tBu
O
Initiation:
O
A
+
O
H +
tBu
tBu
O
H
1a
MeCHD
tBu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Propagation:
O
O
O2
tBu
tBu
D
E
OH
tBu
tBu
OH
O
O
B
+ HOO
H
tBu
+ O2
tBu
O
Initiation
tBu
Initiation
H
OH
tBu
O
H
H2O2
C
tBu
OH
tBu
O
O
tBu
tBu
tBu
tBu
Termination:
O
O
OH
OH
F
H +
+
tBu
tBu
H
2a
tBu
O
O
OH
G
H + HOO
+
O2
tBu
tBu
tBu
OH
tBu
tBu
O
O
OH
OH
H
2
H
O
+
tBu
tBu
O
tBu
I
2
HOO
H O + O
2 2
2
Scheme 4. Key steps of the radical mechanism for the reduction of quinones.
The mechanism of the reaction between quinones and MeCHD in the absence of trifluoroacetic
acid is therefore attributed to a (spontaneously initiated) radical reaction. The initiation process

happens thanks to a hydrogen transfer (H ) from MeCHD to the quinone, leading to the formation
of a radical on the MeCHD ring and the semiquinone (Scheme 4, Reaction A).21-24 This first step is
only slightly endothermic for 1a, where an intramolecular H-bond can be formed in the radical,25
whereas it is strongly endothermic for 3a (Table 4), in agreement with the observation that para-
quinones with alkyl substituents are not reduced under these conditions. If these two radicals
interact “in cage” with each other, and a second hydrogen transfer happens, catechol 2a (reduction
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product) and toluene (as the co-product) are formed (Scheme 4, Reaction F). Alternatively, the
semiquinone can interact with additional MeCHD to give a radical chain (propagation step) and 2a
with a moderately exothermic step (Scheme 4, Reaction B). The cyclohexadienyl radical formed, in
turn, reacts with 1a to form the semiquinone in a very exothermic reaction step (Scheme 4, Reaction
C).
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Notably, the cyclohexadienyl radical is able to propagate the radical chain by reacting with 1a as
well as with the oxygen present in the reaction environment. Indeed, a similar radical chain is also

possible by involving oxygen in the reaction mechanism. Hydroperoxyl radicals (HOO ), formed by
1
6
the reaction of oxygen with cyclohexadienyl radical in an exothermic step (H = -24.8 kcal/mol at
the CBS-QB3 level), act as the propagating radicals and they are also able to reduce quinones to the
corresponding semiquinones in a very exothermic step (Scheme 4, Reaction D and Table 4), then to
1
5
the final hydroquinones or catechols, by formal H-atom transfer. The termination step can occur
also with the reaction between two semiquinones to form the starting quinone and the reduction
product (Scheme 4, Reaction H), or with the reaction between semiquinones and HOO• to afford
either hydroquinone and O (Scheme 4, Reaction G) or quinone and H O (not shown in Scheme 4).
2
2
2
Assuming this radical mechanism, MeCHD is consumed stoichiometrically and the reaction stops
when the concentration of quinone approaches zero. Only when addition products involving alkyl
radicals or hydrogen peroxide are formed (see for instance Reactions E and I in Scheme 4), the
MeCHD is wasted. Probably, these side-reactions do not occur in appreciable extent due to the low
steady-state concentration of the radical species involved, compared to the concentration of the
other reagents. In principle initiation could also be provided by reaction of MeCHD with molecular
oxygen to afford the methylcyclohexadienyl radical and the hydroperoxyl radical (eq 1), which
would then sustain the oxidation of the catechol via reactions E and G previously discussed.
However reaction 1 is thermodynamically uphill by 24.7 kcal/mol as can be judged from the
calculated BDE (C-H) of MeCHD (74.0 kcal/mol) and the calculated BDE (O-H) of the
hydroperoxyl radical (49.3 kcal/mol). Our experiments under N athmosphere (see Table S5) allow
2
to exclude any significant contribution of reaction 1 in the initiation process, and suggest a
secondary contribution of the radical chain based on hydroperoxyl radicals in the overall rate of
reduction of Q to QH2.
+
O2
+ HOO
H
(1)
At variance with the previously described mechanism, when trifluoroacetic acid is present, the
reaction reasonably proceeds via an initiation process that involves of the protonation of the
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
quinone (Scheme 5). Simple H-bond donation from the acid to the quinone appears less likely
because the strong H-bond donating solvent 1,1,1-3,3,3-hexafluoro-2-propanol has no positive
effect on the conversion (Entry 8 Table 1). After protonation, the resulting cation – which likely
forms an ion-couple with the conterion trifluorocatetate in the apolar medium - is stabilized by
resonance, being the positive charge delocalized on the quinone ring. The protonated quinone may
react with MeCHD following two pathways, reported in Scheme 5: A) by hydride transfer,
similarly to the reaction mechanism of dihydropyridines (Hantzsch esters) when used as a hydrogen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
source; B) by hydrogen atom transfer, by a mechanism reminiscent of that previously proposed to
explain the enhanced antioxidant activity of phenols and nitroxides in the presence of organic
acids27,28 (see Scheme 5). Since the hydride transfer from MeCHD to the protonated quinone could
occur at different positions of the ring,21 we calculated the energies relative of the various
tautomers. In all cases, hydride transfer is exothermic, ranging from -4 to -8 kcal/mol for the
addition to carbons, down to -25.4 kcal/mol for the addition to the (unprotonated) oxygen (see
Table 4). Interestingly in the case of the reaction between 2,5-di-chloro-1,4-benzoquinone and 1,4-
cyclohexadiene, Mayr et al. demonstrated by deuterium labeling experiments and theoretical
calculations that the hydride transfer occurs directly to the oxygen, rather than to the carbons. In this
2
1
respect, 1,4-cyclohexadiene behaved differently than B-H and Sn-H hydride donors. In any case,
the results of our calculations, reported in Table 4, show that protonation renders both reactions J
and K significantly easier than H-atom transfer to the neutral quinone (Scheme 4, Reaction A), both
being thermodynamically favoured, hence fully justifying the experimental results.
1
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OH
O
OH
O
O
O
OH
OH
O
1
tBu
tBu
tBu
tBu
2
3
tBu
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
5
+
CF3COOH
+
CF COO
3
tBu
tBu
tBu
tBu
tBu
4
O
0
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OH
O
OH
tBu
tBu
J
(
A)
+
+
tBu
tBu
H
OH
+
+
CF COO
CF COOH
3
3
H
OH
OH
OH
tBu
tBu
tBu
K
(
B)
+
+
tBu
tBu
H
O
O
OH
tBu
+
CF COO
+ CF COOH
3
3
tBu
tBu
OH
OH
Scheme 5. Possible mechanisms for the reduction of quinones in the presence of trifluoroacetic
acid: (A) hydride transfer from MeCHD to the protonated quinone, or (B) hydrogen atom transfer
from MeCHD to the protonated quinone.
CONCLUSIONS
We have developed an efficient protocol for the reduction of ortho and para substituted quinones (1
and 3) to the corresponding catechols (2) or hydroquinones (4) under air, using volatile 1-methyl-
1
,4-cyclohexadiene as a valid H-atom source thanks to its pro-aromatic behaviour. This method is
simple, it works under mild conditions and in the absence of both metal catalysts and sulfur
derivatives. In some cases, it is necessary to add acid as the catalyst to obtain the desired products.
In the absence of acids, the mechanism is attributed to a reductive radical reaction involving
MeCHD-derived and semiquinone radicals. In the presence of CF COOH acid, the reaction
3
mechanism can be either a hydride transfer or H-atom transfer to the protonated quinone. The
proposed method(s) allows facile access to a diverse range of polyphenolic compounds in good to
excellent yields and with a broad substrate scope. Finally, the simplicity of these reactions, makes
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this method competitive with respect to the methods used to reduce quinones, previously reported in
the literature.
EXPERIMENTAL SECTION
General Information. Analytical grade solvents and commercially available reagents were used as
received unless otherwise stated. Chromatographic purifications were performed using 70−230
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mesh silica gel. H, F, and C NMR spectra were recorded on Varian Inova (300 and 600 MHz
1
1
for H) and Varian Mercury (400 MHz for H) spectrometers. Chemical shifts (δ) are reported in
1
13
1
ppm relative to residual solvent signals for H and C NMR ( H NMR: 7.26 ppm for CDCl , 1.94
3
1
3
ppm for CD CN, 3.34 ppm for CD OD, 2.05 ppm for (CD ) CO, 2.50 ppm for (CD ) SO; C
3
3
3 2
3 2
NMR: 77.0 ppm for CDCl , 1.32 ppm for CD CN, 48.9 ppm for CD OD, 29.8 ppm for (CD ) CO,
3
3
3
3 2
19
3
9.5 ppm for (CD ) SO). F NMR spectra were recorded at 376.25 MHz or at 564.3 MHz using
3
2
1
3
1
trichlorofluoromethane as an external standard. C NMR spectra were acquired with H broadband
decoupled mode. Coupling constants are given in Hz.
Synthesis of Starting Materials
4
-Methyl-1,2-benzoquinone (1c) and 4-(tert-butyl)-1,2-benzoquinone (1d) were synthesized
following a previously reported procedure with slight modifications.29
General procedure. A 50 mL round-bottom flask, equipped with a Teflon-coated stir bar and a
rubber septum, was charged with the catechol (2 mmol, 1.0 equiv) and NaIO (2 mmol, 0.43 g).
4
CH Cl (10 mL) and water (5 mL) was then added, and the resulting biphasic mixture was stirred at
2
2
room temperature for 10 minutes. Layers were then separated, and the aqueous layer was washed
one time with CH Cl (10 mL). The combined organic fractions were dried over Na SO , filtered
2
2
2
4
and concentrated in vacuo to afford the corresponding quinone without further purification. The
yield was almost quantitative.
3
0
4
- (2-Methoxycarbonyl-ethyl) - (1,2) - benzoquinone (1e), 3,3’,5,5’ - tetra - tert – butyl - 1,1’ bi
3
1
(
cyclohexane-2,5-dien-1-ylidene) - 4,4’ - dione (3jj) and 2,5 – dimethoxy - 1,4 - benzoquinone
32
(
3k) were prepared according to reported methods.
Synthesis of catechols (2a-g) and hydroquinones (4a-l and 4CoQ0).
General procedure. To a solution of compound 1a-g or 3a-l or 3CoQ (1.0 equiv, 0.18 mmol) in
0
toluene (2 mL) was added 1-methyl-1,4-cyclohexadiene (30 equiv, 5.4 mmol, 600 L) and
trifluoroacetic acid (0, 5 or 40 equiv, 0, 0.9 or 7.2 mmol, 0, 70 or 550 L,). The mixture was heated
with an oil bath at 30 °C and stirred for the required time to give compound 2a-g or 4a-l or 4CoQ0.
After this time, the solvent was evaporated and the crude was purified by flash chromatography on
SiO using a mixture of hexane/ethyl acetate to give the expected product.
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NMR spectra of previously reported compounds were in agreement with those of the authentic
samples and/or available literature data (see Figure S6-S28).
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3
,5-Di-tert-butylcatechol (2a).33,34 2 hours, eluent: hexane/ethyl acetate 8:2, 38.0 mg, yield = 95%.
1
H NMR (CDCl , 300 MHz) δ 6.89 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 5.42 (s, OH), 4.75
3
0
1
2
3
4
5
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(s, OH), 1.41 (s, 9H), 1.27 (s, 9H).
3
5
1
Tetrachlorocatechol (2b). 2 hours, eluent: hexane/ethyl acetate 8:2, 41.9 mg, yield = 94%. H
1
3
1
NMR (CDCl , 400 MHz) δ 5.91 (bs, 2OH); C{ H} NMR (CDCl , 100 MHz) δ 140.0 (C), 123.8
3
3
(C), 118.9 (C).
3
6
1
4-Methylcatechol (2c). 4 hours, eluent: hexane/ethyl acetate 8:2, 21.2 mg, yield = 95%. H NMR
(CDCl , 300 MHz) δ 6.78-6.57 (m, 2H), 6.60 (d, J = 9.1 Hz, 1H), 5.07 (bs, 2 OH), 2.24 (s, 3H).
3
3
6
1
4
-tert-Butylcatechol (2d). 2 hours, eluent: hexane/ethyl acetate 8:2, 28.7 mg, yield = 96%. H
NMR (CDCl , 300 MHz) δ 6.92 (d, J = 2.2 Hz, 1H), 6.82-6.79 (m, 2H), 4.98 (bs, 2 OH), 1.27 (s,
3
9H).
3
7
3
7
-(3,4-Dihydroxyphenyl)-propionic acid methyl ester (2e). 2 hours, eluent: hexane/ethyl acetate
1
:3, 34.2 mg, yield = 97%. H NMR (CDCl , 300 MHz) δ 6.76 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 2.0
3
Hz, 1H), 6.59 (dd, J = 8.1 Hz, J = 2.0 Hz, 1H), 5.99 (bs, OH), 5.84 (bs, OH), 3.67 (s, OMe), 2.82 (t,
J = 7.9 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H).
3
8
1
,2-Dihydroxynaphthalene (2f). 18 hours, eluent: hexane/ethyl acetate 7:3, 27.4 mg, yield = 95%.
1
H NMR (CDCl , 300 MHz) δ 8.02 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.3 Hz,
3
1H), 7.39-7.30 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 5.50 (bs, OH), 5.17 (bs, OH).
3
9
1
Phenanthrene-9,10-diol (2g). 48 hours, eluent: hexane/ethyl acetate 7:3. H NMR (CDCl , 300
3
MHz) δ 8.72 (d, J = 8.5 Hz, 2H), 8.17 (dd, J = 8.3 Hz, J = 1.1 Hz, 2H), 7.70-7.56 (m, 4H), 6.79 (bs,
2
OH).
4
0
2,5-Di-tert-butylhydroquinone (4a). 40 equiv trifluoroacetic acid, 15 hours, eluent: hexane/ethyl
1
acetate 95:5, 36.0 mg, yield = 90%. H NMR (CDCl , 300 MHz) δ 6.59 (s, 2H), 4.89 (bs, 2OH),
3
1
.37 (s, 18H).
4
1
1
Hydroquinone (4b). 15 hours, eluent: hexane/ethyl acetate 7:3, 18.2 mg, yield = 92%. H NMR
(CDCl , 300 MHz) δ 6.72 (s, 4H), 4.39 (bs, 2OH).
3
4
2
2
,5-Dichlorohydroquinone (4c). 2 hours, eluent: hexane/ethyl acetate 95:5, 30.0 mg, yield = 93%.
1
H NMR (CDCl , 300 MHz) δ 7.03 (s, 2H), 5.19 (bs, 2OH).
3
4
3
Tetrafluorohydroquinone (4d). 15 hours, eluent: hexane/ethyl acetate 7:3, 30.8 mg, yield = 94%.
1
19
H NMR (CDCl , 300 MHz) δ 5.01 (bs, 2OH); F NMR (CDCl , 376 MHz) δ -164.4
3
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1
Tetrachlorohydroquinone (4e). 2 hours, eluent: hexane/ethyl acetate 9:1, 40.0 mg, yield = 90%. H
1
3
1
NMR (CD ) SO, 400 MHz) δ 10.2 (bs, 2OH); C{ H} NMR ((CD ) SO, 100 MHz) δ 144.1 (C),
3
2
3 2
1
20.7 (C).
4
5
Methylhydroquinone (4f). 5 equiv trifluoroacetic acid, 2 hours, eluent: hexane/ethyl acetate 7:3,
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
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2
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4
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4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
9.9 mg, yield = 89%. H NMR (CDCl , 300 MHz) δ 6.67-6.61 (m, 2H), 6.57-6.52 (m, 1H), 4.34
3
(bs, 2OH), 2.21 (s, 3H).
4
6
tert-Butylhydroquinone (4g). 5 equiv trifluoroacetic acid, 2 hours, eluent: hexane/ethyl acetate
1
7
:3, 20.9 mg, yield = 70%. H NMR (CDCl , 300 MHz) δ 6.77 (t, J = 1.6 Hz, 1H), 6.54 (d, J = 1.7
3
Hz, 2H), 3.89 (bs, 2OH), 1.39 (s, 9H).
4
7
2
9
2
,5-Dimethylhydroquinone (4h). 5 equiv trifluoroacetic acid, 2 hours, eluent: hexane/ethyl acetate
1
:1, 18.7 mg, yield = 75%. H NMR (CDCl , 300 MHz) δ 6.56 (s, 2H), 4.23 (s, 2OH), 2.17 (s, 6H).
3
48
,6-Dimethylhydroquinone (4i). 5 equiv trifluoroacetic acid, 2 hours, eluent: hexane/ethyl acetate
1
7:3, 19.4 mg, yield = 78%. H NMR (CDCl , 300 MHz) δ 6.49-6.47 (m, 2H), 4.24 (bs, OH), 4.20
3
(
bs, OH), 2.20 (t, J = 0.6 Hz, 6H).
2
,6-Di-tert-butyl-4-hydroxyphenol (4j).49 40 equiv trifluoroacetic acid, 24 hours, eluent:
1
hexane/ethyl acetate 9:1, 35.5 mg, yield = 89%. H NMR (CDCl , 300 MHz) δ 6.68 (s, 2H), 4.73
3
(bs, OH), 1.42 (s, 18H).
4
,4'-Dihydroxy-3,3',5,5'-tetra-tert-butylbiphenyl (4jj).50 40 equiv trifluoroacetic acid, 5 hours,
1
eluent: hexane/ethyl acetate 98:2, 62.7 mg, yield = 85%. H NMR (CDCl , 300 MHz) δ 7.30 (s,
3
4H), 5.17 (bs, 2OH), 1.49 (s, 36H).
5
1
2
,5-dimethoxyhydroquinone (4k). 40 equiv trifluoroacetic acid, 24 hours, eluent: hexane/ethyl
1
acetate 8:2, 27.5 mg, yield = 90%. H NMR (CDCl , 300 MHz) δ 6.58 (s, 2H), 5.21 (bs, 2OH), 3.82
3
(s, 6H).
Durohydroquinone (4l).52,53 40 equiv trifluoroacetic acid, 24 hours, eluent: hexane/ethyl acetate
1
8
2
5:15, 7.5 mg, yield = 25%. H NMR (CDCl , 300 MHz) δ 4.47 (bs, 2OH), 2.17 (s, 12H).
3
54
,3-Dimethoxy-5-methyl-1,4-dihydroxybenzene (4CoQ ). 5 equiv trifluoroacetic acid, 15 hours,
0
1
eluent: hexane/ethyl acetate 85:15, 11.6 mg, yield = 35%. H NMR (CDCl , 300 MHz) δ 6.48 (d, J
3
=
0.7 Hz, 1H), 5.30 (bs, OH), 5.15 (bs, OH), 3.91 (s, OCH ), 3.88 (s, OCH ), 2.17 (d, J = 0.7 Hz,
3 3
3
H).
Gram-scale reaction of 4a. To a solution of compound 3a (1.0 equiv, 4.5 mmol) in toluene (50
mL) was added 1-methyl-1,4 cyclohexadiene (30 equiv, 135 mmol, 15 mL) and trifluoroacetic acid
(
40 equiv, 180 mmol, 13.8 mL,). The mixture was heated with an oil bath at 30 °C and stirred for 15
hours to give compound 4a. After this time, the solvent was evaporated and the crude was purified
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product in 84% yield (839 mg).
Theoretical calculations
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5
Calculations were carried out by using the CBS-QB3 complete basis set method as implemented
in the Gaussian09 suite of programs.56 In the case of reaction involving charged species, the
Polarizable Continuum Model was used (solvent = toluene).
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website at DOI:
XXX
Representative results of the screening of solvents and MeCHD equivalents; MeCHD conversion
to toluene in absence or presence of quinone 1a; conversion of para-quinone 3a in the presence of
ortho-quinone 1a; results from theoretical calculations and NMR spectra of compounds 2a-f, 4a-l
and 4CoQ0.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: andrea.baschieri2@unibo.it (A.B.)
*
E-mail: riccardo.amorati@unibo.it (R.A.)
ORCID
Andrea Baschieri: 0000-0002-2108-8190
Riccardo Amorati: 0000-0002-6417-9957
Luca Valgimigli: 0000-0003-2229-1075
Letizia Sambri: 0000-0003-1823-9872
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Funding from the MIUR (Rome) and the University of Bologna is gratefully acknowledged.
REFERENCES
1) Ivanov, D. P.; Sobolev, V. I.; Pirutko, L. V.; Panov G. I. New Way of Hydroquinone and
Catechol Synthesis using Nitrous Oxide as Oxidant. Adv. Synth. Catal. 2002, 344, 986 – 995
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
) Wang, J.; Park, J-N.; Wei, X-Y; Lee, C. W. Room-temperature heterogeneous hydroxylation of
2
+
2+
phenol with hydrogen peroxide over Fe , Co ion-exchanged Na zeolite. Chem. Commun. 2003,
6
28 – 629
3
) Wu, Y.; Lei, W.; Xia, M.; Wang, F.; Li, C.; Zhang, C.; Hao, Q.; Zhang, Y. Simultaneous
electrochemical sensing of hydroquinone and catechol using nanocomposite based on palygorskite
and nitrogen doped graphene. Applied Clay Science 2018, 162, 38 – 45
4) Ayala, A.; Stoytcheva, M.; Zlatev, R.; Velkova, Z.; Gochev, V.; Valdez, B.; Montero, G.
Simultaneous Determination of Hydroquinone and Catechol by Differential Alternative Pulses
Voltammetry. Electroanalysis 2018, 30, 1913 – 1917
5
) Salazar, R.; Vidal, J.; Martìnez-Cifuentes, M.; Araya-Maturana, R.; Ramìrez-Rodrìguez, O.
Electrochemical characterization of hydroquinone derivatives with different substituents in
acetonitrile. New J. Chem. 2015, 39, 1237 – 1246.
6
) T. Dunlap, T.; Chandrasena, R. E. P.; Wang, Z.; Sinha, V.; Wang, Z.; Thatcher, G. R. J. Quinone
Formation as a Chemoprevention Strategy for Hybrid Drugs: Balancing Cytotoxicity and
Cytoprotection. Chem. Res. Toxicol. 2007, 20, 1903 – 1912
7
) Chigr, M.; Fillion, H.; Rougny, A.; Berlion, M.; Riondel J.; Beriel, H. Diels-Alder Reactions
between Dienamides and Quinones : Stereochemistry of the Cycloadditions and Cytotoxic Activity
of the Adducts. Chem. Pharm. Bull. 1990, 38, 688 – 691
8
) Haruna, K.; Kanezaki, H.; Tanabe, K.; Dai W. M.; Nishimoto, S. Effects of structural
modification on the DNA binding properties and photo-induced cleavage reactivity of propargylic
sulfones conjugated with an anthraquinone structure. Bioorg. Med. Chem. 2006, 14, 4427 – 4432
9
) da Silva, A. R. L.; dos Santos, A. J.; Martìnez-Huitle, C. A. Electrochemical measurements and
theoretical studies for understanding the behavior of catechol, resorcinol and hydroquinone on the
boron doped diamond surface. RSC Adv. 2018, 8, 3483 – 3492
2
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0) Baschieri, A.; Pulvirenti, L.; Muccilli, V.; Amorati, R.; Tringali, C. Chain-breaking antioxidant
5
6
7
8
9
1
1
1
1
1
1
1
1
1
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6
activity of hydroxylated and methoxylated magnolol derivatives: the role of H-bonds. Org. Biomol.
Chem. 2017, 15, 6177 – 6184
11) Miyamura, H.; Tobita., F; Suzuki, A.; Kobayashi, S. Direct Synthesis of Hydroquinones from
Quinones through Sequential and Continuous-Flow Hydrogenation-Derivatization Using
Heterogeneous Au–Pt Nanoparticles as Catalysts. Angew. Chem. Int. Ed. 2019, 58,
doi.org/10.1002/anie.201904159
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
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0
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2
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6
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0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2) Prexler, S. M.; Frassek, M.; Moerschbacher, B. M.; Dirks-Hofmeister, M. E. Catechol Oxidase
versus Tyrosinase Classification Revisited by Site-Directed Mutagenesis Studies. Angew. Chem.
Int. Ed. 2019, 58, 8757 –8761.
1
3) Harisha, K.V.; Swamy, B.E.K.; Ebenso, E. E. Poly (glycine) modified carbon paste electrode
for simultaneous determination of catechol and hydroquinone: A voltammetric study. J.
Electroanal. Chem. 2018, 823, 730 – 736
1
4) Fujita, S.; Sano, K. Reduction of Quinones and Quinonemonosulfonimides with N,N-
Diethylhydroxylamine. J. Org. Chem. 1979, 44, 2647 – 2651
1
5) Cedrowski, J.; Litwinienko, G.; Baschieri, A.; Amorati, R. Hydroperoxyl Radicals (HOO*):
Vitamin E Regeneration and H-Bond Effects on the Hydrogen Atom Transfer. Chem. Eur. J. 2016,
22, 16441 – 16445
1
6) Howard, J. A.; Ingold, K. U. Absolute rate constants for hydrocarbon autoxidation. V. The
hydroperoxy radical in chain propagation and termination. Can. J. Chem. 1967, 45, 785 – 792
1
7) Baschieri, A.; Valgimigli, L.; Gabbanini, S.; DiLabio, G. A.; Romero-Montalvo, E.; Amorati,
R. Extremely Fast Hydrogen Atom Transfer between Nitroxides and HOO· Radicals and
Implication for Catalytic Coantioxidant Systems. J. Am. Chem. Soc. 2018, 140, 10354 – 10362
1
8) R. Amorati, R.; Franchi, P.; Pedulli, G. F. Intermolecular Hydrogen Bonding Modulates the
Hydrogen-Atom-Donating Ability of Hydroquinones. Angew. Chem. Int. Ed. 2007, 46, 6336 – 6338
1
9) Amorati, R.; Pedulli, G. F. Hydrogen bond donating ability of meta and parahydroxy phenoxyl
radicals. Org. Biomol. Chem. 2012, 10, 814 – 818
2
0) Lucarini, M.; Mugnaini, V.; Pedulli, G. F.; Guerra, M. Hydrogen-Bonding Effects on the
Properties of Phenoxyl Radicals. An EPR, Kinetic, and Computational Study. J. Am. Chem. Soc.
2003, 125, 8318 – 8329
2
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1) Guo, X.; Zipse, H.; Mayr, H. Mechanisms of Hydride Abstractions by Quinones. J. Am. Chem.
Soc. 2014, 136, 13863 − 13873
2
2) Chan, B.; Radom, L. Uncatalyzed Transfer Hydrogenation of Quinones and Related Systems:ꢀ
A Theoretical Mechanistic Study. J. Phys. Chem. A 2007, 111, 6456 − 6467
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3) Rüchardt, C.; Gerst, M.; Ebenhoch, J. Uncatalyzed Transfer Hydrogenation and Transfer
Hydrogenolysis: Two Novel Types of Hydrogen‐Transfer Reactions. Angew. Chem. Int. Ed. 1997,
36, 1406 – 1430.
2
4) Wurche, F.; Sicking, W.; Sustmann, R.; Klärner, F.-G.; Rüchardt, C. The Effect of Pressure on
Hydrogen Transfer Reactions with Quinones. Chem. Eur. J. 2004, 10, 2707 – 2721
2
5) Amorati, R.; Valgimigli, L. Modulation of the Antioxidant Activity of Phenols by Non-
Covalent Interactions. Org. Biomol. Chem. 2012, 10, 4147 – 4158
2
6) Zheng, C.; You, S.-L. Transfer hydrogenation with Hantzsch esters and related organic hydride
donors. Chem. Soc. Rev. 2012, 41, 2498 – 2518
2
7) Valgimigli, L.; Amorati, R.; Petrucci, S.; Pedulli, G. F.; Hu, D.; Hanthorn, J. J.; Pratt, D. A.
Unexpected Acid Catalysis in Reactions of Peroxyl Radicals with Phenols. Angew. Chem. Int. Ed.
2
009, 48, 8348 – 8351
2
8) Haidasz, E. A.; Meng, D.; Amorati, R.; Baschieri, A.; Ingold, K. U.; Valgimigli, L.; Pratt, D. A.
Acid Is Key to the Radical-Trapping Antioxidant Activity of Nitroxides. J. Am. Chem. Soc. 2016,
138, 5290 − 5298
2
9) Huang, Z.; Lumb, J.-P. A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols
Applied to the Synthesis of Aryl Ethers. Angew. Chem. Int. Ed. 2016, 55, 11543 – 11547
3
0) Omote, Y.; Tomotake, A.; Kashima, C. Trapping of dopachrome with 2,3-dihidro-1H-
cyclopent[b]indole. Tetrahedron Lett. 1984, 25, 2993 – 2994
3
1) Alberti, A.; Astolfi, P.; Carloni, P.; Greci, L.; Rizzoli, C.; Stipa, P. The reactivity of manganese
dioxide towards different substrates in organic solvents. New J. Chem. 2015, 39, 8964 – 8970
3
2) Hanss, D.; Walther, M. E.; Wenger, O. S. Accelerated hole transfer across a molecular double
barrier. Chem. Commun. 2010, 46, 7034 – 7036
2
2
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
3
3) Anbu, S.; Alegria, E. C. B. A.; Pombeiro, A. J. L. Catalytic activity of a benzoyl hydrazone
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
based dimeric dicopper(II) complex in catechol and alcohol oxidation reactions. Inorganica Chim.
Acta 2015, 431, 139 –144
34) Jovanovic, S.V.; Konya, K.; Scaiano, J.C. Redox reactions of 3,5-di-tert-butyl-1,2-
benzoquinone. Implications for reversal of paper yellowing. Can. J. Chem. 1995, 73, 1803 – 1810
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Pinacol Boronates by Direct
Arene Borylation with Borenium Cations. Angew. Chem. Int. Ed. 2011, 50, 2102 –2106
3
6) Huang, C.; Ghavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. Synthesis of Catechols from
Phenols via Pd-Catalyzed Silanol-Directed C-H Oxygenation. J. Am. Chem. Soc. 2011, 133, 17630
–
3
17633
7) Baranovsky, A.; Schmitt, B.; Fowler, D. J.; Schneider, B. Synthesis of New Biosynthetically
Important Diarylheptanoids and Their Oxa- and Fluoro- Analogues by Three Different Strategies.
Synth. Commun. 2003, 33, 1019 – 1045
38) Kroc, M. A.; Patil, A.; Carlos, A.; Ballantine, J.; Aguilar, S.; Mo, D.-L.; Wang, H.-Y.; Mueller,
D. S.; Wink, D. J.; Anderson, L. L. Synthesis of -oxygenated ketones and substituted catechols via
the rearrangement of N-enoxy- and N-aryloxyphthalimides. Tetrahedron 2017, 73, 4125 – 4137
39) Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.; Mariano, P. S.; Yoon, U. C.
Photoaddition Reactions of 1,2-Diketones with Silyl Ketene Acetals. Formation of -Hydroxy--
ketoesters. J. Org. Chem. 2008, 73, 4539 – 4547
40) Raj, R. M.; Balasubramanian, K. K.; Easwaramoorthy, D. Diels–Alder trapping of in situ
generated dienes from 3,4-dihydro-2H-pyran with p-quinone catalysed by p-toluenesulfonic acid.
Org. Biomol. Chem. 2017, 15, 1115 – 1121
4
1) González-Calderón, D.; Benítez-Puebla, L. J.; González-González, C. A.; García-Eleno, M. A.;
Fuentes-Benítez, A.; Cuevas-Yáñez, E.; Corona-Becerril, D.; González-Romero, C. Aluminium
chloride hexahydrate (AlCl -6H O): An efficient, facile, mild, catalytic and highly chemoselective
3
2
deprotection of tert-butyldimethylsilyl (TBS) ethers. Synth. Commun. 2014, 44, 1258 –1265
2) Novikov, V. L.; Balaneva, N. N.; Shestak, O. P.; Anufriev, V. Ph.; Glazunov, V. P.
4
Cycloacylation of chloro-substituted hydroquinone dimethyl ethers with dichloromaleic anhydride.
Russ. Chem. Bull. Int. Ed. 2016, 65, 993 – 1003
2
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
3) Kojima, T.; Nakanishi, T.; Harada, R.; Ohkubo, K.; Yamauchi, S.; Fukuzumi, S. Selective
Inclusion of Electron-Donating Molecules into Porphyrin Nanochannels Derived from the Self-
Assembly of Saddle-Distorted, Protonated Porphyrins and Photoinduced Electron Transfer from
Guest Molecules to Porphyrin Dications. Chem. Eur. J. 2007, 13, 8714 – 8725
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
4) Maddala, S.; Mallick, S.; Venkatakrishnan, P. Metal-Free Oxidative C−C Coupling of
Arylamines Using a Quinone-Based Organic Oxidant. J. Org. Chem. 2017, 82, 8958 – 8972
45) Teng, L.-L.; Song, T.-Y.; Xu, Z.-F.; Liu, X.; Dai, R.; Chen, Y.-H.; Li, S.-H.; Zhang, K.-Q. ;
Niu, X.-M. Selected Mutations Revealed Intermediates and Key Precursors in the Biosynthesis of
Polyketide-Terpenoid Hybrid Sesquiterpenyl Epoxy-cyclohexenoids. Org. Lett. 2017, 19, 3923 –
3
926
4
6) Kamitori, Y.; Hojo, M.; Masuda, R.; Izumi, T.; Tsukamoto, S. Silica Gel as an Effective
Catalyst for the Alkylation of Phenols and Some Heterocyclic Aromatic Compounds. J. Org. Chem.
1984, 49, 4161 – 4165
4
7) Menichetti, S.; Amorati, R.; Bartolozzi, M. G.; Pedulli, G. F.; Salvini, A.; Viglianisi, C. A
Straightforward Hetero-Diels-Alder Approach to (2-ambo,4’R,8’R)-α/β/γ/δ-4-Thiatocopherol. Eur.
J. Org. Chem. 2010, 2218 – 2225
4
8) Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D. Three-Component Asymmetric Catalytic Ugi
Reaction-Concinnity from Diversity by Substrate-Mediated Catalyst Assembly. Angew. Chem. Int.
Ed. 2014, 53, 3436 – 3441
49) Altamura, A.; Fusco, C.; D’Accolti, L.; Mello, R.; Prencipe, T.; Curci, R. Oxidatio of
Catechols and of 2,6-di-tert-Butylphenol by Dioxiranes. Tetrahedron Lett. 1991, 132, 5445 – 5448
5
0) Novakova, V.; Miletin, M.; Filandrovà, T.; Lenco, J.; Ruzicka, A.; Zimcik, P. Role of Steric
Hindrance in the Newman-Kwart Rearrangement and in the Synthesis and Photophysical Properties
of Arylsulfanyl Tetrapyrazinoporphyrazines. J. Org. Chem. 2014, 79, 2082 – 2093
51) Yoshida, M.; Maeyama, Y.; Shishido, K. A Synthetic Study on Bauhinoxepin J: Construction of
a Dibenzo[b,f]oxepin Ring System by a DDQ-Promoted Oxidative Dearomatization-Cyclization
Approach. Heterocycles 2010, 80, 623 – 629
5
2) Mitsumi, M.; Ezaki, K.; Komatsu, Y.; Toriumi, K.; Miyatou, T.; Mizuno, M.; Azuma, N.;
Miyazaki, Y.; Nakano, M.; Kitagawa, Y.; Hanashima, T.; Kiyanagi, R.; Ohhara, T.; Nakasuji, K.
5
Proton Order–Disorder Phenomena in a Hydrogen-Bonded Rhodium– -Semiquinone Complex: A
Possible Dielectric Response Mechanism. Chem. Eur. J. 2015, 21, 9682 – 9696
2
4
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
13
5
3) Scheffer, J. R.; Wong, Y.-F.; Patil, A. O.; Curtin, D. Y.; Paul, I. C. CPMAS C NMR Spectra
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of Quinones, Hydroquinones, and Their Complexes. Use of CMR To Follow a Reaction in the Solid
State. J. Am. Chem. Soc. 1985, 107, 4898 – 4904
54) Yu, P.-W.; Chang, Y.-C.; Liou, R.-F.; Lee, T.-H.; Tzean, S.-S. pks63787, a Polyketide Synthase
Gene Responsible for the Biosynthesis of Benzenoids in the Medicinal Mushroom Antrodia
cinnamomea. J. Nat. Prod. 2016, 79, 1485 – 1491
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
55) Montgomery, J. A.; Frisch Jr, M. J.; Ochterski, J. W.; Petersson, G. A. A complete basis set
model chemistry. VI. Use of density functional geometries and frequencies. J. Chem. Phys. 1999,
1
10, 2822 – 2827
5
6) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci,B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H.P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, J. A., Jr.;Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,
E.; Kudin,K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.;Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2009.
2
5
ACS Paragon Plus Environment