Development of the radical C–O coupling reaction of phenols toward the synthesis of natural products comprising a diaryl ether skeleton

Article abstract of DOI:10.1016/j.tet.2019.05.035

Compounds comprising a diaryl ether skeleton exist among natural phenols. The diaryl ether skeleton is thought to be biosynthesized through the coupling of two or more phenols. It is an important structural feature in medicines and agrochemicals, and it is imperative to develop methods for constructing such skeletons in organic synthesis. However, by the synthesis method through the coupling of phenols, coupling occurs preferentially at the ortho-substituted carbon atom of phenols. In this study, various radical-generating reagents and conditions were investigated with the aim of developing a short-step construction method of the diaryl ether skeleton by the radical homo-coupling of two phenol molecules. In addition, cross-coupling reactions between radicals of 2,4,6-tri-tert-butylphenol and p-substituted phenol were conducted to synthesize eight C (ortho)–O coupling products. Based on the results, a computational chemical approach was employed to verify the cause of C (ortho)–O bond formation.

Full text of DOI:10.1016/j.tet.2019.05.035

Accepted Manuscript
Development of the radical C–O coupling reaction of phenols toward the synthesis of
natural products comprising a diaryl ether skeleton
Kumpei Tanaka, Hiroaki Gotoh
PII:
S0040-4020(19)30575-7
https://doi.org/10.1016/j.tet.2019.05.035
TET 30356
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2019
Revised Date: 16 May 2019
Accepted Date: 16 May 2019
Please cite this article as: Tanaka K, Gotoh H, Development of the radical C–O coupling reaction of
phenols toward the synthesis of natural products comprising a diaryl ether skeleton, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.05.035.
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Development of the radical C–O coupling
reaction of phenols toward the synthesis of
natural products comprising a diaryl ether
skeleton
Kumpei Tanaka, Hiroaki Gotoh*

ACCEPTED MANUSCRIPT
Development of the radical C–O coupling reaction of phenols toward the synthesis of
natural products comprising a diaryl ether skeleton
Kumpei Tanaka, Hiroaki Gotoh*
Department of Chemistry and Life Science, YOKOHAMA National University, 79-5
Tokiwadai, Hodogaya-ku, Yokohama, Japan
gotoh-hiroaki-yw@ynu.ac.jp
Abstract
Compounds comprising a diaryl ether skeleton exist among natural phenols.
The diaryl ether skeleton is thought to be biosynthesized through the coupling of two or
more phenols. It is an important structural feature in medicines and agrochemicals, and it is
imperative to develop methods for constructing such skeletons in organic synthesis.
However, by the synthesis method through the coupling of phenols, coupling occurs
preferentially at the ortho-substituted carbon atom of phenols. In this study, various
radical-generating reagents and conditions were investigated with the aim of developing a
short-step construction method of the diaryl ether skeleton by the radical homo-coupling of
two phenol molecules. In addition, cross-coupling reactions between radicals of
2
,4,6-tri-tert-butylphenol and p-substituted phenol were conducted to synthesize eight C
(ortho)–O coupling products. Based on the results, a computational chemical approach was
employed to verify the cause of C (ortho)–O bond formation.
Keywords: diaryl ether skeleton, phenol, radical, coupling reaction
1
. Introduction
Phenols are known to be typical representative compounds found in nature . Some
1
phenols are beneficial even for these simple substances, but the phenol moiety can undergo
dimerization, trimerization, or cyclization within the molecule to exhibit interesting
2
,3,4
biological activity
(Figure 1). In addition, phenols exhibit different activities depending
on the coupling position. For example, isomagnolol and magnolol are dimers of
allylphenol, but these compounds exhibit different activities. In addition, obovatol, which is
1

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a typical natural phenol comprising a diaryl ether skeleton, exhibits several activities,
5
6
7
including antitumor , anti-inflammatory , and anxiolytic activities . Reactions using
8
peroxidase have been reported with the attempt to obtain these compounds by the
homo-coupling of phenols. In these studies, isomagnolol, which is the C (ortho)–O form, is
obtained as a side product (5%), in addition to magnolol (21%) as the main product. The
dimerization of unprotected phenol by an enzymatic reaction has been reported; however, it
is difficult to selectively obtain the diaryl ether skeleton.
Figure 1. Natural products of related phenols including dimers and trimers.
In synthetic organic chemistry, several examples for the synthesis of symmetrical
products have been reported in which C (ortho)–C (ortho) is coupled by a direct
9
homo-coupling reaction . For example, in the radical coupling reaction of 4-allylphenol, a
high
yield
of
magnolol
is
obtained
(77%)
by
using
1
,2-dichloro-4,5-dicyano-p-benzoquinone (DDQ), which is a one-electron oxidizing agent,
1
0
and AlCl
3
. However, in synthetic organic chemistry, a high-yield synthetic method by the
direct or preferential use of asymmetric diaryl ether (C (ortho)–O) has not been reported.
Hence, a diaryl ether is synthesized by using a protected phenol and/or a halogenated
2

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1
1
phenol by the arylation of a phenol by the Ullmann coupling using Cu and the aromatic
1
2
nucleophilic substitution reaction (S Ar) .
N
Scheme 1. Selective examples of the direct synthesis of diaryl ethers by a radical reaction
in homo- or cross-coupling.
1
3
Statistical studies on the selectivity for homo-coupling reactions using phenol and
1
4, 15
16,17
p-cresol
and radical initiators have been conducted (Scheme 1 eq1, eq2, eq3). By using allylphenol
and K Fe(CN) as the substrate and the oxidizing agent, respectively, isomagnolol (C
ortho)–O) and magnolol (C (ortho)–C (ortho) are isolated in 8% and 11% yields,
or other substituted phenols
as substrates using various oxidizing agents
3
6
(
1
8
respectively, and coupling products at other positions, trimers, and tetramers are obtained .
3

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The UV and MW–UV irradiation of 4-tert-butylphenol affords C(ortho)–O and C(ortho)–
C(ortho) products to be the isomerization products, and their ratio depends on the nature of
1
9
the solvents and sensitizers used , and the C(ortho)–O form (yield 6%) is obtained by the
triplet sensitization reaction using acetophenone as the photosensitizer in a hexane solution.
The homo-coupling reaction of a para-substituted compound often does not proceed with
selectivity, and, depending on the reagent, it is possible to obtain a coupling compounds
with dimers, trimers or more with selectivity for different positions.
In the cross-coupling reaction, phenol derivatives and a simple phenol bearing bulky
substituents have been reported to be coupled with each other between radicals. A study has
reported that a radical of 2,4,6-tri-tert-butylphenol (BHTs) is coupled with the phenol at the
2
0
para position, affording a quinone form (Scheme 1 eq4). Various studies have been
2
1, 22, 23, 24
conducted to synthesize a thyroxine derivative (C (para)–O coupling product)
. In
addition, the coupling reaction between BHTs and para-substituted (electron-withdrawing
group) phenol occurs at C (para)–O at low temperature, but o-hydroxydiphenyl ethers are
2
5
obtained in low yield at high temperatures .
Furthermore, the cross-coupling reactions of phenol derivatives have been reported to
proceed by oxidation potential differences. A cross-coupling reaction between p-cresol and
2
6
p-methoxyphenol has been reportedly achieved by the combination of AlCl and DDQ .
3
Recently, in a fluoroalcohol solvent (HFIP), cross-coupling with unprotected phenols is
achieved by the combined use of an iron catalyst as a one-electron oxidizing agent and a
reoxidant, affording an asymmetric biphenol (C (ortho)–C (ortho)) in a high isolated yield
of 96%. The cross-coupling of C (ortho)–C (ortho) in the case of unprotected phenols
predominantly occurs by the combination of an iron catalyst as a one-electron oxidizing
2
7
agent and a reoxidant in an HFIP . In addition, oxidative phenol–allen cross-coupling
2
8
reactions using visible-light redox catalysts have been developed . Moreover, the coupling
2
9, 30, 31, 32
reaction of substituted phenols has been studied via an electrochemical method
.
However, even by using these methods, it is difficult for the cross-coupling reactions of
phenols to progress by C (ortho)–O.
In the organic synthesis methods for the dimerization of two phenols, C(ortho)–C(ortho)
is the predominant product, and a selective synthesis method for the direct homo-coupling
reaction of the C(ortho)–O form is not established. In addition, the cross-coupling reaction
between different phenols is extremely difficult because of the competition between
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homo-coupling and cross-coupling, in addition to position selectivity. In this study, to
realize a short-step synthesis method for obovatol, isodityrosine, and natural phenols
comprising various diaryl ether skeletons, the C(ortho)–O coupling and homo- and
cross-coupling reactions are discussed. In addition, reaction selectivity factors of C(ortho)–
C(ortho), C(para)–O, and C(ortho)–O are clarified by changing the reaction time through
the analysis of the byproducts and calculation chemistry.
2
. Results
2
.1. Model reaction
First, p-cresol with a simple phenol structure was selected as a model substrate, and a
homo-coupling reaction was conducted. As the radicalizing reagent of phenol, metal
1
4, 15
26
reagents
and p-benzoquinone, which are one-electron oxidizing agents, and
13, 14, 16
peroxides,
which are radical initiators, are used, and the yield to p-cresol (Table 1).
The high-temperature reaction was conducted under pressure in a sealed container to
suppress the volatilization of solvents and reagents.
Table 1. Reaction conditions for the dimerization of p-cresol
Yield [%]*
Temp. Time
2a
3a
(C–
C)
Entry
Ox.
0.1
Add.
Solv.
Atmo.
CO:CC
[
°C]
[h]
24
3
(C–O)
1***
-
-
-
PhCl
PhCl
PhCl
130
130
130
air
air
air
14
10
18
29
33:67
>95:<5
>95:<5
t
eq( BuO)
2
2
1 eq
<1
<1
t
(
BuO)
2
3
5 eq
3
5

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t
t
t
(
(
(
BuO)2
5 eq
4
5
-
PhCl
PhCl
130
130
2
3
Ar
air
21
<1
<1
22
>95:<5
<5:>95
BuO)2
5 eq
Cs CO3
2
BuO)2
6
7
1 eq FeCl3 Na CO3
H O
r.t.
r.t.
24
1
air
N2
0
0
21
21
<5:>95
<5:>95
2
2
0.75 eq
DDQ
1 eq
AlCl3 MeNO2
8
9
-
MeNO2 100
2
2
air
air
14
3
<1
12
>95:<5
20:80
Ag CO3
2
1 eq
Cs CO3 MeNO2 100
2
Ag CO3
2
*
0
Isolated yield.
.1 eq (tBuO)2
**Concentration of 1a was 0.02 M. *** Yield was determined from
The selectivity for the C (ortho)–O and C (ortho)–C (ortho) forms at the coupling
position varied depending on the reaction conditions such as the reagents and equivalent
t
amount used. Notably, by using ( BuO)
2
or Ag
2
CO
3
, a high selectivity for C (ortho)–O was
achieved, unlike in a previously reported study, by fine-tuning the reaction conditions. In
comparison to entries 1 and 3, the proportion of the C (ortho)–C (ortho) form was initially
high because a low concentration of the radical initiator was used. Different coupling
modes for the main products were observed depending on the type and presence of metal.
The comparison of entries 3 and 5 with those of entries 8 and 9 revealed that different
coupling modes for the main products are observed due to the metal. From the comparison
of entries 3 and 4, excess reaction was suppressed under Ar under air, and the yield of the
desired compound was slightly improved. The suppression of the side reaction by oxygen is
considered to have led to the improved yield. Under any condition, a byproduct having an
excessive reaction with a molecular weight greater than that of the coupled product was
confirmed. In entries 5, 6, and 9, 9%, 1%, and 8% of the Pummerer's ketone (C (ortho)–C
(
para) form), corresponding to one of the dimers of the C (ortho)–C (ortho) coupling, were
t
obtained, respectively. With respect to the reaction by ( BuO)
2
, studies were conducted with
the increase in the temperature, equivalent amount, and concentration, and the extension of
6

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reaction time; however, in both cases, the yield was not observed. In addition, radical
t
initiators other than ( BuO) were investigated, but the yield decreased (e.g., AIBN, PINO,
2
and TBHP). Moreover, by using benzoyl peroxide (BPO) as the radical initiator, a product
was not obtained because a compound was formed in which p-cresol was coupled with a
BPO-derived benzoyloxy radical.
2
.2 Time course of the homo-coupling reaction
In the homo-coupling reaction of p-cresol, the change in the product yield over time was
investigated. An LC–MS analysis was conducted for estimating the yields obtained at each
time (Figure 2). The formation of the C (ortho)–O form has been reported to preferentially
occur even in the early stages of the reaction. Furthermore, as the yield of the C (ortho)–O
form decreased with the lapse of time, the overreaction to the C (ortho)–O form as
2 3
homo-coupling was confirmed to progress. In addition, by using Ag CO as the oxidant, the
reaction was confirmed to not proceed after 30 min. Furthermore, with the increase in the
equivalent amount of Ag
2
CO
3
, the overreaction progressed, and the yield decreased.
7

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t
t
A) ( BuO) in air
B) ( BuO) in Ar
2
2
1
00
100
80
60
40
20
0
1
2
a
a
1a
2a
80
60
40
20
0
3a
3
a
0
100
200
0
100
Reaction time / min
200
Reaction time / min
C) 1 eq Ag CO in air
D) 2 eq Ag CO in air
2 3
2
3
1
00
100
80
60
40
20
0
1
2
3
a
a
a
1a
2a
3a
8
6
4
2
0
0
0
0
0
0
50
Reaction time / min
100
0
50
Reaction time / min
100
Figure 2. Temporal change in the product yield obtained from the coupling reaction: A)
t
t
(
BuO) in air; B) ( BuO) in Ar; C) 1 eq Ag CO in air; D) 2 eq Ag CO in air. 1a: p-cresol,
2 2 2 3 2 3
2
a: C (ortho)–O coupling compound, 3a: C (ortho)–C (ortho) coupling compound.
2
.3 Identification of the coupling mode by IR analysis
To specify the coupling mode in case of the overreaction, the C (ortho)–O and C (ortho)–
1
C (ortho) byproducts shown in entries 4 and 6 of Table 1 were analyzed by H NMR and IR
spectroscopy. Each crude product was separated from the product with a larger molecular
weight, which was detected by gel permeation chromatography (GPC) at an earlier flow
1
time compared to the dimer and then analyzed. As a complex mixture was obtained, H
NMR spectra could not be recorded. Figure 3 shows the IR spectrum obtained in each
condition.
8

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Figure 3. IR spectra of the (A) C (ortho)–O dimer, (B) C (ortho)–C (ortho) dimer, (C)
oligomers of entry 4 in Table 1, and (D) Oligomers of entry 6 in Table 1.
By comparison of the IR spectra of the C (ortho)–O and C (ortho)–C (ortho) forms, sharp
−1
peaks for the C (ortho)–O form in the vicinity of 1,600 cm were observed, corresponding
to the diaryl ether skeleton. By the comparison of the IR spectra of the polymers in entries 4
−1
and 6, the peak in the vicinity of 1,600 cm was more prominent in the byproducts of entry
. From this result, the reaction condition of entry 4 affords a higher C (ortho)–O selectivity
compared to that of entry 6 also as the functional group contained in the byproduct. In both
4
−1
cases, a peak corresponding to the carbonyl carbon at ~1,700 cm was confirmed.
Although the carbonyl carbon was present in trace amounts, phenol was thought to be
generated as a side reaction, and quinone oxidized by oxygen in the reaction system was
observed.
9

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2
.4 Application to various phenols
In addition, reaction conditions shown in entry 4 of Table 1 affording a high yield for
the C (ortho)–O form were utilized for various phenol coupling reactions. Table 2
summarizes the results.
Table 2. Product yields from the homo-coupling reaction of
p
-substituted phenol.
Structure
Yield [%]
21
Entry
1
R
OH
O
Me (a)
2
a
OH
O
t
2
3
4
Bu (b)
7
tBu
tBu
OH
2b
O
Allyl (c)
11
18
2
c
OH
O
n
5
-C H11 (d)
n-C H
5 11
2
d
n-C H
5
11
1
0

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OH
O
NHBoc
CH CH(COOMe)NHBoc
2
5
7
COOMe
(
e)
NHBoc 2e
COOMe
By the developed reaction, the C (ortho)–O form of phenol with various substituents
including isomagnolol, which is a natural substance, was synthesized. The reaction was
confirmed to progress even with substituents other than Me, albeit with decreased product
yield. C (ortho)–O was selective for either substrate. Different yields were observed
t
depending on the reaction substrate because the abstraction of the hydrogen atom by BuO·
was more likely to occur with respect to the substituent and/or the side reaction due to
higher product reactivity. In addition, the C (ortho)–O coupling reaction possibly
progressed to a minimal extent because of steric factors.
2
.5. Cross-coupling
t
(
BuO) was used as the radical initiator to investigate the cross-coupling reaction
2
between p-cresol and various phenols. In the cross-coupling reaction between p-cresol (1a)
and o-cresol (1g), homo-coupling and cross-coupling reactions of the respective substrates
proceeded, with a low product yield. It is difficult to perform the cross-coupling reaction of
compounds with different substitution positions using this approach. In the cross-coupling
reaction between
p-cresol (1a) and 4-methylanisole (1h), the MS peaks for the
cross-coupled compound and the homo-coupled form of anisole were not confirmed even
after the LC–MS profile of the crude product was recorded. The formation of 2a, which is
the homo-coupling product of p-cresol (1a), was confirmed. Unlike using a one-electron
oxidizing agent in this method, the coupling of free phenols may be preferential. When the
homo-coupling of 4-methylanisole (1h) was conducted, a complicated excessive reaction
progressed. In the cross-coupling reaction with 2,4-ditert-butylphenol (1i), the
homo-coupling of 1i was the main reaction, with the predominant formation of the C
(ortho)–C(ortho) form (3i). Furthermore, 4ai, which was a trimer obtained by the C
(ortho)–C(ortho) cross-coupling, was obtained in a yield of 15%. In addition, in this
1
1

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method, the steric factors of the substrate, particularly ortho substituents, affect the
selectivity of the C (ortho)–O and C(ortho)–C(ortho) forms.
Scheme 2. Investigation of the cross-coupling reaction between p-cresol and various
phenols.
When BHTs, which are known to be extremely stable radicals, as a coupling partner
were treated with
p-cresol, a cross-coupling reaction between p-cresol and BHTs
progressed, affording 2ai. Hence, the cross-coupling of BHTs and p-substituted phenols
with various substituents was conducted to synthesize the C (ortho)–O form. Table 3
summarizes the results. In phenol bearing various substituents, the C (ortho)–O form was
obtained with a comparatively good yield. Under this reaction condition, the
ortho-substituted product was the main product in any case; however, when some phenol
was used as the substrate, C (para)–O cross-coupling products were also obtained (7a: 2%,
7
c: 2%, and 7e: 4%).
1
2

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Table 3. Product yield from the cross-coupling reaction of BHTs with p-substituted
phenols.
Structure
Yield [%]*
Yield [%]
Entry
1
R
6
7
OH
O
2
Me (a)
40 (57)
57 (64)
39 (43)
43 (55)
6
a
OH
-
2
-
O
*
*
t
2
Bu (b)
6
b
OH
O
3
4
Allyl (c)
6c
OH
O
n
5
-C H11 (d)
n-C H
5
11
6d
1
3

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OH
4
-
O
NHBoc
CH CH(COOMe)
2
5
6
56 (69)
16 (16)
COOMe
NHBoc (e)
6
e
OH
O
OMe (f)
OMe
6
f
-
OH
O
7
α-Cumyl (g)
23 (18)
6g
*
h
Yield within parentheses is based on the recovered starting material. **Reaction time: 6.5
2
.6. Computational chemistry approach
The theoretical consideration for the selectivity of the homo- and cross-coupling
reactions was examined by calculation chemistry. The starting materials, intermediates, and
products expected to be involved in the reaction were calculated to examine the changes in
the enthalpy, electronic properties of radicals, and bond dissociation energy (BDE) of
hydrogen atoms. The initial structure used for input files was generated by a conformational
search, which was conducted 2000 times via the MM3 molecular force field calculation
3
3
using the Medit program . Using this initial structure as an input file, the structure with the
3
4
(
U)B3LYP/6-31G* basis function in Gaussian 09 was optimized . The Winmostar
3
5
program was employed to visualize each structure. From these results, selectivity factors
for the reaction were discussed.
2
.6.1. Enthalpy change of the coupling reaction
36, 37
The coupling of phenols is known to be a reaction occurring between radicals
.
Additionally, herein, we attempted to couple p-cresol with 4-methylanisole; however, only
homo-coupling of p-cresol was observed (Scheme 2). No coupling compound between
1
4

ACCEPTED MANUSCRIPT
4
-methylanisole and p-cresol was observed, indicating that the coupling reaction between
radials is progressing preferentially, and it is expected that the coupling reaction via this
t
mechanism is different from that via other redox reactions. In this study, using ( BuO) as
2
the radical initiator, phenoxy radicals are generated via the hydrogen-atom transfer
mechanism (HAT mechanism), and dimerization is expected to occur via the coupling of
these radicals.
Figure 4 shows the enthalpy changes of intermediates and coupling products of the C
(
ortho)–O and C (ortho)–C (ortho) forms. In the cross-coupling reaction, the enthalpy of the
t
product is a value including 1,2-dimethylethene formed by the elimination of the Bu group.
In the homo-coupling reaction of
ortho) form, but the intermediate was stable in the C (ortho)–O form (Figure 4A). Even for
the cross-coupling reaction of BHTs and -cresol, the C (ortho)–O form in the intermediate
p-cresol, the final product was stable in the C (ortho)–C
(
p
was stable (Figure 4B). In the case of cross-coupling, there is also selectivity as to which
reaction proceeds from which oxygen; however, intermediates were unstable because of
steric hindrance for reaction from the oxygen of BHTs. In addition, regarding the C
(ortho)–C (ortho) cross-coupled product between BHTs and p-cresol, a more unstable
intermediate due to the steric bulk of the substituents was observed. It was difficult for the
homo-coupling of BHTs to proceed because of steric hindrance. The calculation results
revealed that the intermediate is unstable by 21.4 kcal/mol with respect to the BHTs.
1
5

ACCEPTED MANUSCRIPT
A) Homo-coupling of p-cresol
B) Cross-coupling between p-cresol and BHTs
Figure 4. Enthalpy change for the A) homo-coupling reaction of p-cresol and B)
cross-coupling reaction between p-cresol and BHTs.
1
6

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2
.6.2. Electronic properties and bond dissociation energy of phenols
In the radical reaction of phenols, the regioselectivity of the reaction was examined using
3
7
the spin density . Table 4 summarizes the spin densities of the phenoxy radicals and
calculated BDEs of the starting materials and coupling products. BDE is one of the indices
reflecting the ease with which a phenol undergoes a reaction. In homo-coupling, the BDEs
for the C (ortho)–O forms of the starting material (78.0 kcal/mol) and product (78.0
kcal/mol) were equal, but the C (ortho)–C (ortho) coupling product (3a, 73.1 kcal/mol)
exhibited a low BDE and underwent facile radical formation. In the cross-coupling
reaction, the coupling energy increased in the order of BHTs (5, 69.7 kcal/mol),
cross-coupling product (6a, 76.4 kcal/mol), and p-cresol (1a, 78.0 kcal/mol).
Table 4 Spin densities of the phenoxy radicals and BDEs of the phenols
Spin density
Compound No.
BDE [kcal/mol]
O
o-C
0.31
0.24
0.16
0.32
0.22
p-C
0.40
0.35
0.29
0.40
0.35
p-cresol (1a)
0.43
0.39
0.30
0.37
0.37
78.0
78.0
73.1
69.7
76.4
2
a
a
3
BHTs (5)
6a
3
Discussion
When a para-substituted phenol is treated at high temperature based on the HAT
mechanism, coupled products between the phenol oxygen and the ortho-substituted phenol,
which are relatively advantageous both thermodynamically and kinetically, are obtained.
However, as this selectivity is subtle, with the variation in temperature, presence or absence
of a coordination metal, and radical concentration, the selection of a radical generator and
control of reaction temperature and time are indispensable. Typically, the coupling reaction
at the para position of oxygen and phenol of phenol with a high spin density is more likely
to proceed kinetically. Calculation results revealed that the spin density of the alkyl
substituent at the para position of the phenol is greater than that at the ortho position. ESR
studies also revealed that spin densities for a range of alkyl substituents in the para position
3
8
of phenols are approximately twice those at the ortho positions . However, under high
1
7

ACCEPTED MANUSCRIPT
temperature, C (para)–O coupling product is thermodynamically unstable and returns to the
starting material. However, the final coupling product between the ortho-substituted
phenols was the most stable thermodynamically, but it was not favorable kinetically at the
stage at which the intermediate cyclohexadienone was obtained.
The selectivity for the cross-coupling reaction between BHTs and p-substituted phenols
selectively occurred at C (ortho)–O, as was the case with homo-coupling, because of the
intermediate stability (Figure 4 B). The coupling reaction of the ortho-substituted type
proceeded instead of the para-substituted type, but elimination at the ortho position was
39
easier than that at the para position of the phenol because the ortho-substituted phenol
promotes intramolecular elimination.
Scheme 3. Relation between the kinetic selectivity and thermodynamic stability for the
coupling of para-substituted phenols
3
.1 Cross-coupling using BHTs compared with the homo-coupling of phenol
The cross-coupling reaction of the para-substituted phenol and BHTs proceeded more
efficiently than its homo-coupling. This factor was considered from the obtained results. By
the comparison of BDEs summarized in Table 4, the BDE of BHTs was significantly less
than that of p-cresol, with the preferential generation of BHT radicals. However, in the
homo-coupling of BHTs, the intermediate was more unstable than the starting material
because of considerable steric hindrance (Figure 4), and the reaction did not proceed. The
hydrogen abstraction of p-cresol progressed gradually, and radical cross-coupling occurred
between phenoxy radicals generated in trace amounts and BHT-derived radicals in large
amounts. From the quantitative relation of the radicals in the reaction system, the progress
of cross-coupling became dominant.
1
8

ACCEPTED MANUSCRIPT
Cross-coupling using BHTs compared to the homo-coupling of phenol led to higher yield
because of the suppression of the overreaction. From Table 4, the BDEs of BHTs were
significantly less than that of product 6a, and the ease of hydrogen abstraction for BHTs
was greater than that of 6a; hence, the overreaction is suppressed in comparison to
homo-coupling. BHTs serve as a reagent and a scavenger to suppress excess reaction.
Hence, the C (ortho)–O coupling between BHTs and para-substituted phenol progresses
selectively, further inhibiting the excess reaction, and the reaction progresses with a
t
relatively good yield. The Bu group can be eliminated by the same procedure as that
4
0
reported previously , and 14 novel C (ortho)–O form products can be expected from the
product obtained this time.
4
Conclusion
In the homo-coupling reaction of phenols through the formation of radicals using a
metal-free peroxide as the initiator, the C (ortho)–O form was predominantly formed on the
basis of the kinetic dominance. This reaction represented an example of the selective
synthesis of the diaryl ether by the extremely atypical C (ortho)–O coupling of phenol in
organic synthesis, although there was room for improvement of the product yield. The
cross-coupling reaction of 2,4,6-tri-tert-butylphenol with the para-substituted phenol was
conducted to synthesize seven C (ortho)–O forms. The cross-coupling reaction according to
this study was proposed to be a synthesis method for the C (ortho)–O compound through
reactions between radicals, affording a novel diaryl ether skeleton by using an unprotected
phenol.
5
Experimental section
.1 General
All reactions were monitored by thin-layer chromatography using a Merck 60 F254
5
1
13
precoated silica gel plate (0.25 mm in thickness). H and C spectra were recorded on
1
BRUKER DRX-300, JEOL ECX-400, and BRUKER DRX-500 instruments. H NMR data
were reported as chemical shifts (
δ ppm), with multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, and m = multiplet), coupling constant (Hz), integration, and assignment.
1
9

ACCEPTED MANUSCRIPT
1
3
C NMR data were also reported as chemical shifts. Liquid chromatography–mass
spectrometry (LC–MS) profiles were recorded on Shimadzu LC-2010CHT and Shimadzu
LCMS-2020 systems using a Wakopack Navi C18-5 2.0 mm × 150 mm (D) column.
φ
Purification by GPC was conducted by using a MULTIPLE PREPARATIVE HPLC
LC-FORTE/R (YMC) and transferring the mobile-phase solvent EtOAc to YMC GPC
T-2000 (21.2 × 600 mm) and T-4000 columns (21.2 × 600 mm) to 10.0 mL/min. FTIR
spectra were recorded on a Nicolet iS10 FTIR spectrometer (KBr pellet method).
High-resolution mass spectra were recorded on a Hitachi Nano Frontier LD spectrometer
(APCI).
5
.2 Chemicals
Reagents purchased from TCI and Wako were used without purification. 4-Allylphenol
4
1
was synthesized by the method reported by Agharahimi et al.
5
.2.1 Typical procedure for the homo-coupling reaction (2a)
First, p-cresol (1a, 96.0 mg, 0.9 mmol, 1 equiv) was added to PhCl (4.5 mL, 0.2 M) in a
t
pressure-resistant vessel, and ( BuO)
2
(655.2 mg, 5 equiv) was added dropwise to this
solution at room temperature. Second, this solution was bubbled with Ar for 15 min and
then heated at 130 ° C in a pressure-resistant vessel. After 2 h, the reaction solution was
cooled to room temperature, and the solvent was then removed under reduced pressure.
Finally, the crude product was purified by PTLC and GPC to obtain homo-coupled product
2
a (19.9 mg, 21%).
1
H NMR (CDCl3)
δ 7.15 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 3H), 6.81 (dd, J = 8.1,
1
3
1
.5 Hz, 1H), 6.65 (d, J = 1.8 Hz, 1H), 5.42 (s, 1H), 2.34 (s, 3H), 2.21 (s, 3H); C NMR
(
CDCl3)
δ
154.6, 145.1, 143.8, 133.3, 130.5, 130.3, 124.9, 119.0, 118.3, 115.7, 20.8, 20.8;
−1
IR (KBr): 3517 (br m), 2922 (m), 1600 (s), 1513 (s), 1504 (s) cm . HRMS (APCI−) m/z
−
calculated for [C H O ] 213.09210; found 213.09191.
1
4
13
2
Compound 2b was prepared using a typical procedure described above using 1b,
affording homo-coupled product 2b in a 7% yield. The product was confirmed by
1
19
comparing with the H NMR spectrum of a known compound .
2
0

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Compound 2c was prepared using a typical procedure described above using 1c,
affording homo-coupled product 2c in an 11% yield. The product was confirmed by
1
6
comparing with the H NMR spectrum of a known compound .
Compound 2d was prepared using a typical procedure described above using 1d,
1
affording homo-coupled product 2d in an 18% yield. H NMR (CDCl
3
)
δ
7.14 (d, J = 8.4
Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.83 (dd, J = 8.4 Hz, 2.4 Hz,
1
2
H), 6.70 (d, J = 2.1 Hz, 1H), 5.41 (br s, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.46 (t J = 7.8 Hz,
H), 1.61 (quintet, J = 6.9 Hz, 2H), 1.51 (quintet, J = 6.9 Hz, 2H), 1.42–1.17 (m, 8H), 0.90
1
3
(t, J = 6.9 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H); C NMR (CDCl
3
)
δ
154.9, 145.3, 143.4,
1
2
38.2, 135.6, 129.8, 124.4, 118.7, 117.8, 115.8, 35.3, 35.3, 31.6, 31.5, 31.5, 31.4, 22.7,
−1
2.6, 14.2, 14.2; IR (KBr): 3559, 2928, 1599, 1505 cm . HRMS (APCI-) m/z calculated
−
for [C22
H
29
O
2
] 325.21730; found 325.21618.
The isodityrosine derivative (2e) was prepared using a typical procedure described
above using 1e, affording homo-coupled product 2e in a 7% yield.
1
H NMR (CDCl3)
δ 7.10 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.7
Hz, 2H), 6.80 (dd, J = 8.4, 1.8 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 5.49 (s, 1H), 5.04–4.89
(
m, 2H), 4.63–4.43 (m, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 3.16–2.85 (m, 4H), 1.44 (s, 9H),
13
1
1
2
.41 (s, 9H); C NMR (CDCl )
δ
172.4, 172.3, 155.9, 155.2, 155.1, 146.7, 143.2, 131.4,
3
30.9, 128.5, 125.9, 119.8, 118.1, 116.3, 80.2, 80.1, 54.6, 54.5, 52.5, 52.4, 37.7, 37.7, 28.4,
−1
8.4; IR (KBr): 3367, 2977, 1713, 1595, 1506 cm . HRMS (APCI-) m/z calculated for
-
[C H N O ] 587.26102; found 587.26064.
3
0
39
2
10
5
.3 Typical procedure for the cross-coupling reaction (6a
)
First, 2,4,6-tri-tert-butylphenol (BHTs, 1.0 equiv, 116.2 mg, 0.46 mmol) and p-cresol (1
equiv, 50.1 mg, 0.46 mmol) were added to PhCl (2.3 mL, 0.2 M) in a pressure-resistant
t
vessel, and ( BuO)
2
(335.6 mg, 2.3 mmol, 5 equiv) was added dropwise to this solution at
room temperature. Second, this solution was bubbled with Ar for 15 min and then treated at
30 °C in a pressure-resistant vessel. After 4 h, the reaction solution was cooled to room
1
2
1

ACCEPTED MANUSCRIPT
temperature, and the solvent was then removed under reduced pressure. Finally, the crude
product was purified by PTLC to obtain cross-coupled product 6a (54.8 mg, 40%). The
1
final product was verified by comparing with the H NMR spectrum of a known compound.
Compound 6b was prepared using a typical procedure described above using 1b,
1
affording cross-coupled product 6b in a 57% yield. H NMR (CDCl
3
)
δ
7.34 (d, J = 6.6 Hz,
2
1
1
3
H), 7.08 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 6.6 Hz, 2H), 6.84 (d, J = 1.8 Hz, 1H), 5.73 (s,
13
H), 1.44 (s, 9H), 1.32 (s, 9H), 1.24 (s, 9H); C NMR (CDCl
3
)
δ
155.0, 146.0, 144.1,
42.8, 142.1, 136.2, 126.7, 119.0, 116.8, 114.0, 35.2, 34.6, 34.4, 31.7, 31.6, 29.7; IR (KBr):
−1
33 2
543, 2961, 1593, 1508 cm . HRMS (APCI-) m/z calculated for [C24H O ]- 353.24860;
found 353.24737.
Compound 6c was prepared using a typical procedure described above using 1c,
1
affording cross-coupled product 6c in a 39% yield. H NMR (CDCl )
δ 7.15 (d, J = 8.7 Hz,
3
2
H), 7.07 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.05–5.88
(
m, 1H), 5.73 (s, 1H), 5.15–5.05 (m, 2H), 3.37 (d, J = 6.9 Hz, 2H), 1.44 (s, 9H), 1.23 (s,
1
3
9
1
H); C NMR (CDCl ) δ 155.6, 143.9, 143.0, 142.2, 137.6, 136.2, 135.0, 130.0, 118.9,
3
−1
17.7, 116.0, 113.7, 39.6, 35.2, 34.6, 31.7, 29.7; IR (KBr): 3541, 2958, 1592, 1505 cm .
−
HRMS (APCI-) m/z calculated for [C H O ] 337.21730; found 337.21636.
2
3
29
2
Compound 6d was prepared using a typical procedure described above using 1d,
1
affording cross-coupled product 6d in a 43% yield. H NMR (CDCl )
δ
7.13 (d, J = 8.5 Hz,
3
2
1
1
1
H), 7.07 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 5.75 (s,
H), 2.58 (t, J = 7.8 Hz, 2H), 1.62 (quin, J = 7.5 Hz, 2H), 1.44 (s, 9H), 1.39–1.28 (m, 4H),
13
.24 (s, 9H), 0.90 (t, J = 7.0 Hz, 3H); C NMR (CDCl )
δ
155.2, 143.9, 143.1, 142.1,
3
37.9, 129.7, 128.1, 118.8, 117.6, 113.6, 35.3, 35.2, 34.6, 31.7, 31.6, 31.5, 29.6, 22.7, 14.2;
−1
IR (KBr): 3542, 2957, 1731, 1593, 1506 cm . HRMS (APCI-) m/z calculated for
−
[C H O ] 367.26425; found 367.26322.
2
5
35
2
Compound 6e was prepared using a typical procedure described above using 1e,
1
affording cross-coupled product 6e in a 56% yield. H NMR (CDCl
3
)
δ
7.08 (d, J = 8.7 Hz,
2
2

ACCEPTED MANUSCRIPT
2
1
5
H), 7.09 (d, J = 2.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 2.1 Hz, 1H), 5.69 (s,
H), 5.00 (d, J = 8.1 Hz, 1H), 4.64–4.51 (m, 1H), 3.72 (s, 3H), 3.10 (dd, J = 13.7 Hz, J =
.7 Hz, 1H), 3.02 (dd, J = 14.1 Hz, J = 6.0 Hz, 1H), 1.43 (s, 9H), 1.42 (s, 9H), 1.23 (s, 9H);
1
3
C NMR (CDCl3)
δ 172.4, 156.5, 155.2, 144.0, 142.7, 142.2, 136.4, 130.8, 130.7, 119.2,
1
17.6, 114.0, 80.1, 54.6, 52.4, 37.7, 35.2, 34.6, 31.7, 29.6, 28.4; IR (KBr): 3535 (br m),
−1
−
2
957, 1715, 1591, 1506 cm . HRMS (APCI-) m/z calculated for [C H NO ] 498.28611;
29 40 6
found 498.28716.
Compound 6f was prepared using a typical procedure described above using 1f,
1
affording cross-coupled product 6f in a 16% yield. H NMR (CDCl
3
)
δ
7.03 (d, J = 2.4 Hz,
1
1
1
3
H), 6.98 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 2.4 Hz, 1H), 5.82 (s,
13
H), 3.81 (s, 3H), 1.44 (s, 9H), 1.21 (s, 9H); C NMR (CDCl
3
)
δ
155.8, 150.4, 144.2,
43.4, 142.0, 136.0, 119.6, 118.3, 115.0, 112.4, 55.8, 35.2, 34.6, 31.7, 29.6; IR (KBr):
−1
−
27 3
538, 2956, 1592, 1505 cm . HRMS (APCI-) m/z calculated for [C21H O ] 327.19657;
found 327.19531.
Compound 6g was prepared using a typical procedure described above using 1g, affording
1
cross-coupled product 6g in a 23% yield. H NMR (CDCl )
δ 7.33–7.21 (m, 5H), 7.18 (d, J
3
=
9.0 Hz, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 9.3 Hz, 2H), 6.84 (d, J = 2.1 Hz, 1H),
1
3
5
1
3
.71 (s, 1H), 1.68 (s, 6H), 1.43 (s, 9H), 1.24 (s, 9H); C NMR (CDCl )
δ
155.2, 150.7,
3
45.6, 144.0, 142.7, 142.2, 136.3, 128.2, 128.2, 126.9, 125.8, 119.1, 116.8, 114.1, 42.6,
−1
5.2, 34.6, 31.7, 31.0, 29.6; IR (KBr): 3541, 2963, 1592, 1504 cm . HRMS (APCI-) m/z
−
calculated for [C H O ] 415.26425; found 415.26456.
2
9
35
2
Acknowledgments
We thank Dr. Kazuhisa Sakakibara for helpful discussions and the Instrumental Analysis
Center of YOKOHAMA National University for allowing us to use of their NMR
spectrometer and high-resolution mass spectrometer. We would like to thank Enago
(https://www.enago.jp/) for English language editing.
Supplementary data
Supplementary data to this article can be found online
2
3

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Figure Legends and Schemes
Figure 1. Natural products of related phenols including dimers and trimers.
Figure 2. Temporal change in the product yield obtained from the coupling reaction: A)
t
t
(
BuO) in air; B) ( BuO) in Ar; C) 1 eq Ag CO in air; D) 2 eq Ag CO in air. 1a: p-cresol,
2 2 2 3 2 3
2
a: C (ortho)–O coupling compound, 3a: C (ortho)–C (ortho) coupling compound.
Figure 3. IR spectra of the (A) C (ortho)–O dimer, (B) C (ortho)–C (ortho) dimer, (C)
oligomers of entry 4 in Table 1, and (D) Oligomers of entry 6 in Table 1.
Figure 4. Enthalpy change for the A) homo-coupling reaction of p-cresol and B)
cross-coupling reaction between p-cresol and BHTs.
Scheme 1. Selective examples of the direct synthesis of diaryl ethers by a radical reaction
in homo- or cross-coupling.
Scheme 2. Investigation of the cross-coupling reaction between p-cresol and various
phenols.
Scheme 3. Relation between the kinetic selectivity and thermodynamic stability for the
coupling of para-substituted phenols
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