Iron-catalyzed selective oxidative arylation of phenols and biphenols

Article abstract of DOI:10.1016/j.tet.2017.03.094

The single-step synthesis of protected fucols and unnatural polyaryls by biomimetic oxidative cross-coupling between phenolic components and 1,3,5-trimethoxybenzene catalyzed by FeCl₃ in fluorinated solvents is reported. The regioselectivity (o

Full text of DOI:10.1016/j.tet.2017.03.094

Accepted Manuscript
Iron-catalyzed selective oxidative arylation of phenols and biphenols
Vlada Vershinin, Alina Dyadyuk, Doron Pappo
PII:
S0040-4020(17)30362-9
10.1016/j.tet.2017.03.094
TET 28600
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 January 2017
Revised Date: 28 March 2017
Accepted Date: 31 March 2017
Please cite this article as: Vershinin V, Dyadyuk A, Pappo D, Iron-catalyzed selective oxidative arylation
of phenols and biphenols, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.094.
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ACCEPTED MANUSCRIPT
Iron-Catalyzed Selective Oxidative Arylation of Phenols and Biphenols
Leave this area blank for abstract info.
Iron-catalyzed selective oxidative arylation of phenols and biphenols
Vlada Vershinin, Alina Dyadyuk and Doron Pappo*
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Iron-Catalyzed Selective Oxidative Arylation of Phenols and Biphenols
Vlada Vershinin a , Alina Dyadyuk a , Doron Pappo a,
a Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The single-step synthesis of protected fucols and unnatural polyaryls by biomimetic oxidative
cross-coupling between phenolic components and 1,3,5-trimethoxybenzene catalyzed by FeCl3
in fluorinated solvents is reported. The regioselectivity (ortho, meta or para) and the
chemoselectivity (C−C vs C−O) in this highly efficient transformation are controlled by the
Available online
phenolic ortho-groups of the growing phenolic oligomer. The reaction scope was examined by
coupling biphenol derivatives with the nucleophilic arene to afford large polyaryl compounds
that are not easily accessible by other means. The versatility of the catalytic system in designing
polyaryl frameworks was demonstrated by performing a sequential oxidative phenol-phenol and
phenol-arene coupling reaction that afforded a single polyaryl product in high efficiency.
Keywords:
Consecutive reactions
Iron catalysis
Oxidative coupling
Phenols
2009 Elsevier Ltd. All rights reserved
.
Polyphenols
Corresponding author. Tel.: +972-8-6428692; fax: +972-8-6428693; e-mail: pappod@bgu.ac.il

2
1. Introduction
Since the historical synthesis of tropinone by
number of synthetic steps; it is therefore likely that a
ACCEPTED MANUSCRIPT
biomimetic reaction will provide a superior pathway.
However, the mechanisms and the factors that affect the
selectivity of the oxidative polymerization processes that
produce phlorotannins in algae are still unknown.23 We
therefore sought to probe this important process by
developing a catalytic system that will serve as a model.
In the laboratory setting, oxidative phenol-phenol and
Robinson1,2 in 1917, exactly a century ago, biomimetic
syntheses have been recognized as highly efficient and, very
often, as the only possible route to complex natural
products.3-6 The success of biomimetic strategies depends
mainly on an in-depth mechanistic understanding of the
natural processes and on the ability of the synthetic chemist
to develop highly selective conditions that imitate the
reactions in nature. Of particular interest to us here is the
oxidative coupling of phenols, an important biological
process that provides plants and algae with a reliable method
for preparing diverse chemical architectures from limited
number of phenolic units with minimum energy loss.
Although these transformations involve the generation of
highly reactive radical species, in many cases the selectivity
of these processes is enzymatically controlled, which
enables highly efficient and stereospecific transformations
that produce a single stereoisomer.7-9
phenol-arene
coupling
reactions,
whether
via
iodine
electrochemical
techniques,24-30
hypervalent
chemistry,31-34 inorganic peroxo compounds35 or metal
catalysis,36-42 offer atom- and step-economic methods for
preparing biaryls with good control over their chemo-, regio-
and stereoselectivity. Recently, our group developed a
system for selective oxidative coupling of phenols by a
catalytic amount of FeCl3 in 1,1,1,3,3,3-hexafluoropropan-2-
ol (HFIP),33,43-48 in the presence of
t-BuOOt-Bu. Under these
general conditions, the selective oxidation of phenols yields
phenoxyl radicals that, in turn, react with nucleophilic
arenes or second phenolic coupling partners via radical-
nucleophile coupling or radical-anion coupling mechanisms,
respectively.49,40,50-54
As in the case in biological systems, the laboratory-
synthesized product of oxidative coupling reactions may
often preserve its phenolic unit(s), which expose(s) it to
further oxidations. In most cases, these oxidations produce
undesirable quinone or catechol side products that affect the
overall efficiency of the process. However, under conditions
that favor coupling, this process can be exploited as an
efficient synthetic tool for preparing complex phenolic
frameworks in a single operation.
In the synthesis of complex phenols, it is not always
realized that the main advantage of bioinspired
transformations is the extension beyond natural products to
access new materials that are still unreachable by common
synthetic tools. Phlorotannins,10,11 for example, is
a
structurally diverse group of polyphenols, for which
selective syntheses are still to be developed (Fig. 1). These
compounds, which consist of oligomeric and polymeric
phloroglucinol units, are produced in the cell walls of brown
algae, and as such play a role in UV protection and defense
against herbivores.12 In some cultures, brown algae
constitute a part of the human diet13 and of traditional
medicines14 and are currently held to play extensive
biological roles,15,14,16 exhibiting anti-allergic,17,13 anti-
oxidation,18 and anti HIV-119 activities.
OR
OR
OR
OH
RO
RO
RO
RO
RO
RO
OR
OR
O
O
O
OR
OR
OR
OR
OR
O
O
HO
OH
phloroglucinol
OR
OR
OR
OR
RO
RO
O
OR
O
OR
RO
RO
O
Oxidative
oligomerization
O
RO
OR
OR
OR
R = H (natural form)
R = Ac (isolated form)
OR
OR
RO
tetrafucol A
[fucol]
pentaphlorethol A
[phloroethol]
phlorofucofuroeckol A
[eckol]
Fig. 1. Selected phlorotannins produced by oxidative oligomerization of
phloroglucinol.
The phlorotannins are classified according to their
coupling modes, namely, Ar−Ar or Ar−O−Ar. A crude
extract of algal powder consists of phlorogluciol and
mixtures of phenolic oligomers that have been condensed
via biaryl bonds (fucols), diaryl ethers (phlorethols) or
dibenzodioxin linkages (eckols).20 In general, these
compounds are sensitive under oxidation, basic and acid-
catalyzed conditions and therefore have been isolated in
their polyacetylated form (Fig. 1). It is therefore necessary to
develop reliable synthetic methods for preparing
phlorotannins for biological studies. In view of the
complexity of these compounds, it is to be expected that
synthetic approaches based on common cross-coupling
chemistry21,22 will not be facile and will require large
Scheme 1. ortho-Directed consecutive oxidative cross-coupling of
phenols and arenes by iron catalysis.

3
To accommodate this reactivity in target-oriented
synthesis, it is necessary to characterize the factors that
determine the chemo- and regioselectivity in each of the
oxidative coupling steps. To this end, a structure-selectivity
relationship study (that included EPR spectroscopy and
kinetic studies) was performed by our group (Scheme 1).55
That study revealed that the first step in the consecutive
reaction between substituted phenols and nucleophilic arene
is para-selective, while the selectivity in the following
for the production of each of the reaction intermediates.
ACCEPTED MANUSCRIPT
This is not a trivial challenge, as any change in one of the
reaction parameters affects the kinetic profile of each of the
coupling steps in a different manner. Therefore, we initiated
the study by developing the tools that would aid us to
identify the conditions for selective synthesis of each
phenolic oligomer that is formed during the stages of the
oxidative coupling. To achieve this objective, the kinetic
profiles of the consecutive oxidative arylation were studied
by HPLC, and the oxidation potentials of the phenolic
intermediates were measured by cyclic voltammetry. This
information was used to follow the progress of each
arylation step as function of time under different conditions.
With this data in hand, we were able to identify the
particular conditions for preparing each phenol oligomer
with a high degree of selectivity. For example, in the
consecutive oxidative cross-coupling between 3,5-
coupling steps is controlled by the identity of the ortho
-
substituents (R = H, Me or OMe, Scheme 1).55 To further
study the factors that control the selectivity in iron-catalyzed
consecutive oxidative arylation of phenols, we set out to
examine the reactivity of biphenols that have either two
identical or two different phenolic units. Successful coupling
of these biphenols opens the door for the preparation of
larger and more complex natural and unnatural polyaryls.
In this article, the iron-catalyzed consecutive oxidative
arylation of biphenols with phloroglucinol trimethyl ether
dimethoxyphenol (1a) and 1,3,5-trimethoxybenzene (2), the
phenolic components have relatively high Eox values (0.61 V
– 0.82 V; Table 1).49 Therefore, the rates of the oxidative
coupling are relatively slow and selective conditions for
(2, Scheme 2) is reported. This sequential reaction provides
a highly selective method for preparing complex polyaryls
that are not accessible by other means. In view of our
previous observations that the phenolic ortho-groups control
the regioselectivity and the chemoselectivity during the
coupling steps, the scope of the reaction was examined for
the preparation of protected phlorotannins and unnatural
polyaryls. The power of this technology, which is concealed
preparing all three possible fucol oligomers
3−5 were
identified (Scheme 2). Our kinetic studies implied that in
2,2,2-trifluoroethanol (TFE) the first arylation step is the
rate-determining step, and therefore the concentration of
Me5-difucol 3 was expected to increase at the beginning of
the reaction (Fig. 2A). Indeed, when the reaction was carried
in obtaining multiple C
−
C and C
−
O bonds in a single event,
out in TFE [
2 (1.2 equiv)], arylphenol 3 was isolated in 51%
was evaluated for the preparation of polyaryl 16 via one-pot
oxidative phenol-phenol and biphenol-arene coupling
reactions (scheme 3).
yield.51
2. Results and discussion
One of the difficulties in developing multi-step
processes relies in the ability to identify selective conditions
Me
Me
O
Me
MeO
MeO
O
O
OMe
Consecutive oxidative
phenol-arene coupling
OH
OH
OH
OH
MeO
MeO
MeO
OMe
OMe
MeO
MeO
OMe
OMe
MeO
MeO
OMe
OMe
Conditions
OMe
MeO
OMe
MeO
1a
OMe
OMe
OMe
Me11-tetrafucol B (5), 48%
oxidative
phenol-phenol t-BuOO+t-Bu
coupling
FeCl3 (5 mol %)
Me5-difucol (3), 51%
[2 (1.2 equiv), TFE, 24 h]
Me8-fucol (4), 46%
[2 (2.1 equiv), 4 h]
TFE, rt, 46 h
OH
[FeCl3 (15 mol %), 2 (5 equiv),24 h]
Me
O
OH
Consecutive oxidative phenol-
arene coupling conditions
HO
MeO
MeO
OMe
OMe
+
Conditions
OMe
OMe
MeO
OMe
2 (1.2-5 equiv)
Consecutive oxidative
phenol-arene coupling
OH
MeO
OMe
unsym-Me4-difucol (6b), 22%
sym-Me4-difucol (6a), 33%
FeCl3 (15 mol %),
t-BuOOt-Bu (1.5-5 equiv), HFIP, rt
Me
Me
Me
O
Me
Me
Me
OMe
O
OMe
MeO
O
O
OMe
MeO
O
O
OMe
HO
HO
HO
HO
OMe
OMe
OMe
OMe
MeO
MeO
OMe
OMe
MeO
MeO
OMe
OMe
MeO
MeO
MeO
MeO
OMe
OMe
MeO
MeO
OMe
MeO
MeO
OMe
OMe
MeO
OH
OH
OH
OH
MeO
O
MeO
O
MeO
O
O
OMe
Me
Me Me
Me
Me7-fucol (7), 30%
[FeCl3 (5 mol %), 22 h]
Me10-tetrafucol A (8), 36%
9, 25%
[t-BuOOH, 1.5 h]
Me14-hexafucol B (10), 10 %
[FeCl3 (20 mol %), 11 days]
[22 h]
Scheme 2. Biomimetic oxidative oligomerization of protected fucol natural products. Conditions: phenol 1a or biphenol 6a (1 equiv), arene
2

4
(1.2-7 equiv), FeCl3 (15 mol %),
t-BuOOt-Bu (1.5-7 equiv), HFIP or TFE (0.5 M), room temperature.
ACCEPTED MANUSCRIPT
consecutive oxidative arylation of symmetrical biphenol 6a
with arene was much more selective, and four ( and
Table 1. Oxidation potentials of selected compounds in HFIP.
2
7, 8, 9
10, Scheme 2) out of the five possible oligomeric products
were identified by HPLC and later isolated. The kinetic
profile of this reaction suggested that the slow coupling
steps are the second and the third arylations and the kinetics
of the subsequent steps became much slower as the
molecular structure grew (Fig. 2D). This observation was
Entry Compound
Eox [V]a
1
2
3
4
5
6
7
8
9
1a
3
0.69
0.61
0.73
0.82
0.57
0.62
0.57
0.71
0.71
4
supported by the oxidation potential values of polyaryls 6a
and (Table 1, entries 5, 7-9). On the basis of the
kinetic profile, we were able to identify different conditions
for obtaining oligomers 10, yet in only moderate
,
5
7,
8
9
6a
6b
7
7
−
selectivity. When the iron-catalysed consecutive oxidative
cross-coupling of biphenol 6a was performed with a low
loading of catalyst (5 mol %), Me7-fucol (7) was isolated in
8
9
only 30% yield. However, by increasing the loading of the
redox catalyst (FeCl3 15 mol %), the second arylation took
place, and Me10-tetrafucol A15,16
(
8
) was afforded in 36%
yield. Under harsher reaction conditions that involved the
use of -BuOOH instead of -BuOO -Bu [FeCl3 (5 mol %),
1.5 h], the third coupling step took place, affording
polyphenol in 25% yield, while the use of higher loading
aCyclic voltammetry conditions: Phenol (3 mM), supporting
electrolyte: tetrabutylammonium hexafluorophosphate (50 mM) in
HFIP (5 mL) vs. Ag/0.01 M AgNO3 in 0.1 M TBAP/CH3CN, 50 mV s-
t
t
t
1
.
The importance of HFIP in oxidative coupling
reactions of phenols has been studied by number of
groups,26,27,34,32,29,33,56,57 including our group,51,58,49 who
demonstrated that HFIP has a significant acceleration effect
in iron-catalyzed cross-dehydrogenative coupling (CDC)
reactions59-65 of phenols. Indeed, when the above reaction
was carried out in HFIP (Fig. 2B), complete consumption of
phenol 1a was observed in 30 min (versus 80 min in TFE).
9
of the redox catalyst (20 mol %), excess of arene (7 equiv)
and prolonged reaction time (11 days) afforded hexafucol B
66
(10
)
in 10% yield. Because of the structural similarity of
compounds 7−
10, their separation from the reaction mixture
by silica-gel chromatography is not a trivial task. Therefore,
to obtain pure samples of the products, it was necessary to
use preparative HPLC separation. Importantly, this work
demonstrates that by changing between only four of the
reaction parameters, namely, the loading of the redox
catalyst, the oxidant type, the fluorinated alcohol solvent and
the reaction time duration, it was possible to access a large
Moreover, in this solvent, the coupling product arylpenol
3
(Eox = 0.61 V, Table 1, entry 2) had a lower oxidation
potential than the parent phenol 1a (Eox = 0.69, entry 1), and
therefore it immediately reacted with a second arene unit,
affording Me8-fucol
product became the rate-determining step in HFIP, as it
has the highest oxidation potential (Eox of = 0.73 V, entry
4. The oxidative coupling of the latter
number of fucol products. Unfortunately, our initial attempts
4
to remove the protecting groups by common methods were
unsuccessful, probably as result of the instability of the
polyphenols in their free phenolic form, as discussed earlier.
An added – sometimes concealed – value in developing
biomimetic catalytic system lies in the ability of the chemist
to expand the use of the evolved chemistry, beyond naturally
occurring substrates, to devise new synthetic opportunities
to produce unique materials with novel properties. To
exploit the knowledge acquired, we therefore instituted an
examination of the consecutive oxidative cross-coupling
reaction between unnatural biphenol derivatives and arenes.
This reaction provides direct entry to large polyaryls that are
not easily accessible by other means. The first step was to
examine the factors that affect the selectivity in the reaction
of biphenols according to the principles that were identified
for substituted phenols (Scheme 1 and Fig. 3A).55 For that
purpose, a series of biphenols, including 4,4’-biphenol 11a
4
3). Product
4 was obtained in 46% yield when the reaction
was limited to 4 h and 2.1 equiv of arene (Scheme 2).51 To
drive the third arylation step, higher loading of the iron
catalyst (25 mol %), excess of arene (5 equiv) and prolonged
reaction time were needed (Fig. 2C) affording Me11-
tetrafucol
5 in 48% (Scheme 2).
After establishing the methodology to optimize consecutive
oxidative arylation of phenols, we went on to examine the
reactivity of biphenols, since these compounds provide
further opportunities for synthesizing large and more
structurally complex polyaryls. Symmetrical Me4-difucols
6a and unsymmetrical Me4-difucols 6b (Scheme 2) were
obtained in 33% and 22% yields, respectively, by the self-
coupling of phenol 1a [FeCl3 (10 mol %), t-BuOOt-Bu,
TFE, rt] under modified oxidative phenol-phenol coupling
conditions (Scheme 2).49 In theory, the consecutive
oxidative cross-coupling reactions of arylphenols 6a and 6b
and compounds 11b-11g (Fig. 3A), which had been
prepared in a single step by iron- catalyzed oxidative
with arene
different oligomers of different sizes. Indeed, as observed by
HPLC analysis, the reaction of 6b with arene was not
2 could yield, respectively, either five or eleven
phenol-phenol cross-coupling,49 were reacted with arene
under our general conditions.
2
2
selective, and HPLC analysis revealed a complex reaction
mixture. Despite intensive attempts, we were unable to
achieve satisfying selectivity in this reaction. In contrast, the

5
ACCEPTED MANUSCRIPT
A) FeCl3 (15 mol %), TFE
B) FeCl3 (15 mol %), HFIP
1a
3
4
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1a
3
4
5
5
0
50
100
150
200
250
300
350
0
50
100
150
200
250
300
350
Reaction progress [min]
Reaction progress [min]
C) FeCl3 (25 mol %), HFIP
D) FeCl3 (25 mol %), HFIP
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
6a
7
8
1a
3
4
9
5
0
50
100
150
200
250
300
350
0
50
100
150
200
250
300
350
Reaction progress [min]
Reaction progress [min]
Fig. 2. Progress of the consecutive oxidative cross-coupling of phenol 1a (A
conditions. Conditions: A) phenol 1a (1 equiv), arene (5 equiv), FeCl3 (15 mol %),
similar to A except HFIP instead of TFE; C) similar to A except FeCl3 (25 mol %) and HFIP instead of TFE; D) biphenol 6a (1 equiv), arene
equiv), FeCl3 (25 mol %), HFIP (0.5 M), room temperature. The reaction progress was analyzed by HPLC, with mesitylene as the internal standard.
−
C) or biphenol 6a (D) with arene
-BuOO -Bu (5 equiv), TFE (0.5 M), room temperature; B)
(5
2 under different reaction
2
t
t
2
The oxidative coupling of 11a (four ortho-H groups,
Fig. 3B) under our general conditions was sluggish and
suffered from low conversion. Under these conditions [arene
Further studies revealed that two non-equivalent phenolic
units, as in biphenol 11d, exhibit different coupling rates. The
first oxidative cross-coupling of 11d with arene 2 was highly
selective at the oxygen atom of the 4-OH group (Fig. 3). The
position of this phenolic group para to the biaryl bond provided
the electronic requirement for the O-arylation, affording product
15 in 72% yield. Furthermore, the coupling at the 3’-OH group,
which was found in the meta-position to the biaryl bond, was
much slower and occurred only, but readily, after the arylation at
the 6’ position had taken place (40 οC), affording product
polyaryl 16 in 56% yield. In our previous publication,55 the
unusual meta-coupling selectivity that had been observed for
phenols with ortho-methyl substituents (Scheme 1) was
explained by a two-step mechanism that involves oxidative
coupling at the ortho-ipso-methyl carbon to generate a high-
energy dienone intermediate, which undergoes a dienone−phenol
rearrangement. This process directs the aryl group to the meta-
position of the phenol. However, when the meta-position is
blocked, as in biphenols 11e and 11f, the aryl migration is
prevented, and therefore dienones 19 and 20 were obtained in
47% and 33% yields, respectively. Finally, the formation of
polyaryl 21 from biphenol 11g is an example that this
rearrangement also takes place from the para-ipso-methyl group
to the neighboring meta-position.
2
(5 equiv), FeCl3 (15 mol %),
t
-BuOO
40 C, 48 h], (3,3’,5,5’-tetraaryl)biphenol 12 was isolated in
a poor 18% yield. Replacing the terminal oxidant with
t-Bu (5 equiv), HFIP,
ο
t
-
BuOOH solved the conversion problem, yet, under the
modified conditions product 12 was obtained together with
its corresponding diphenoquinone by-product. The addition
of a reduction step (NaBH4) at the end of the process was
rewarding, and polyaryl 12 was obtained in 70% yield,
meaning that the average yield for the four coupling steps
was 92%. Symmetrical biphenol 11b (four ortho-OMe
groups, Fig. 3) reacted, as expected, at the oxygen atoms of
the 4 and 4’-phenolic groups to afford polyaryl 13 in 63%
yield. On the other hand, the arylation of biphenol 11c
,
which has two ortho-methoxy groups on one ring and two
ortho-methyl groups on the second ring, took place at the
oxygen atom of the 4-OH and the 2’ and 6’ meta-positions
(via dienone-phenol rearrangement), affording polyaryl 14
in 46% yield. These results provided experimental evidence
that biphenols follow a similar regio- and chemoselectivity
trend to that of phenols and (4-aryl)phenols (Scheme 1),55
suggesting that each ortho-group directs the selectivity only
on its own phenolic ring and has no effect on the coupling of
the second phenolic unit.

6
A) Biphenols
ACCEPTED MANUSCRIPT
Predicted coupling sites
OH
OH
OH
OH
OH
OH
4
4
4
4
4
4
= coupling sites
OH
MeO
OMe MeO
OMe MeO
OMe MeO
OMe
Me
OMe MeO
OMe
OH
and
2
OH
OH
R
R
selectivity
ortho
OMe
OH
OH
Me
2'
2'
2'
6'
H
3'
MeO
OMe
Me
Me
Me
Me
Me
meta
4'
4'
4'
OH
11a
B) Polyaryls
OH
OH
OMe
Me
Me
11f
Me
Ar(OH) =
OMe OH
11e
11g
11b
11c
11d
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
OMe OMe
OH
MeO
OMe
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
4
MeO
MeO
MeO
MeO
MeO
MeO
5'
3'
OMe
OMe
OMe
MeO
OMe
MeO
OMe
OMe
6'
2'
6'
OMe
5'
3'
3'
MeO
Me
OMe
Me
MeO
[from
OMe
MeO
OMe
OMe
OH
O
OH
OMe OMe
OMe
OMe
MeO
OH
MeO
[from
OMe
MeO
OMe
12
13
[from
14
15
16
11d
, 70%
, 63%
, 46%
, 72%
, 56%
, 40 C, 24 h]
11a t
11b
11c
11d
,
-BuOOH, 6 h then NaBH4]
]
[from
]
[from
]
OMe
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
O
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
OMe
MeO
OMe
O
Me
O
MeO
Me
O
MeO
O
O
Me
OH
Me
OH
Me
OH
OMe
OMe
OMe
OMe
OMe
6'
Me
5'
5'
5'
MeO
Me
3'
3'
3'
Me
MeO
Me
Me
Me
Me
MeO
OMe
MeO
O
O
OMe
MeO
O
O
OMe
OMe
Me Me
Me
Me
17
18
[from
19
20
[from
21,
[from
, 34%
, 52%
11e
, 3 h]
, 47%
, 33%
11f
48%
11g
]
11e
, 1.5 h]
11e
, 10 h]
[from
[from
]
Fig. 3. Consecutive oxidative cross-coupling reaction of unnatural biphenols 11a-g. General conditions: biphenol 11 (1 equiv, 0.5 M), arene 2 (3-5 equiv), FeCl3
(15 mol %), t-BuOOt-Bu (3-5 equiv), HFIP, room temperature.
oxidative coupling reactions, a one-pot sequential oxidative
phenol-phenol and phenol-arene coupling reaction of
phenol 1b (Scheme 3) was performed. In this process, the
first step involved oxidative homocoupling of phenol 1b to
produce the biphenol 11d intermediate. The addition of
arene
2 at this stage advanced the consecutive reaction
between the biphenol and three arene units, affording
polyaryl 16 in 40% yield. Overall, this sequential reaction
afforded two biaryl and two diaryl ether bonds in a single
highly selective operation. In contrast, when phenol 1b and
arene
2 were mixed together at the beginning of the
reaction, only the consecutive oxidative phenol-arene
coupling reaction took place, affording triaryl ether 22 in
68% yield (X-ray).55
3. Conclusions
In summary, the biomimetic iron-catalyzed
consecutive oxidative cross-coupling of phenolic
components was applied for preparing protected
phlorotannin natural products and unnatural polyaryl
frameworks that are not easily accessible by other means.
We demonstrated that it is possible to achieve selectivity in
this multicomponent process by adjusting between four of
Scheme 3. Selective syntheses of polyaryls 16 and 22 by oxidative
phenol-phenol and phenol-arene coupling reactions.
To demonstrate the versatility of the Fe(III)/
t-BuOOt-
Bu/HFIP catalytic system in catalysing different types of

7
the reaction parameters, namely, the catalyst loading, the
peroxide, the fluoroalcohol solvent, and the reaction time.
In addition, by reacting a variety of biphenols, it was
NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.59 (s, 1H), 6.04
ACCEPTED MANUSCRIPT
(s, 2H), 6.01 (s, 2H), 3.69 (s, 3H), 3.53 (s, 3H), 3.52 (s, 6H);
13C NMR (100 MHz, DMSO-d6) δ 159.5, 159.2, 158.8, 158.0,
156.6, 103.3, 102.8, 93.7, 92.1, 89.8, 55.3, 55.2, 54.8; HRMS
(ESI): m/z calcd for C16H18O6 [M+Na]+ 329.0996, found
329.0990.
confirmed that the coupling regioselectivity (ortho
, meta or
para) and the chemoselectivity (C C vs C O coupling) in
−
−
biphenol derivatives is controlled, as in phenols, by the
phenolic ortho-groups. Finally, a sequential oxidative
phenol-phenol and phenol-arene coupling reaction was
performed, emphasizing the power of the chemistry for
preparing natural products and their unnatural analogous.
We intend to expand the consecutive oxidative cross-
coupling reaction to other classes of phenolic units and to
apply this efficient strategy for preparing natural and
unnatural polyphenols that are needed for drug discovery.67
4.3. General procedure for the synthesis of biphenols (11b-11d)
and (11g)
Compounds: 3,3',5,5'-tetramethoxy-[1,1'-biphenyl] -4,4'-
diol (11b), 3,5-dimethoxy-3',5'-dimethyl-[1,1'-biphenyl]-4,4'-
diol
(11c),
2,3',4,5'-tetramethoxy-[1,1'-biphenyl]-3,4'-diol
(11d), 3',5'-dimethoxy-4,5-dimethyl-[1,1'-biphenyl]-2,4'-diol
(11g) were prepared according to the procedure reported
previously by our group49
4. Experimental section
4.4. General procedure for the synthesis of biphenols (11e-11f)
4.1. General information
To a solution of FeCl3 (10 mol %), phenol (1 equiv, 0.25
mmol) and 2,3-dimethylphenol (3 equiv, 0.75 mmol) in HFIP
(0.5M), t-butyl hydroperoxide (1.5 equiv, 0.38 mmol) was
added drop-wise with constant stirring at 0 ºC. Then stirring
was continued at room temperature for 24 hours. After
complete consumption of the limiting starting material
(indicated by TLC and HPLC), the volatiles were removed
under reduced pressure and the crude residue was purified by
column chromatography (silica gel 40-60 µm) to afford the
pure product.
All reagents were of reagent grade quality, purchased
commercially from Sigma-Aldrich, Alfa-Aesar, or Fluka, and
used without further purification. FeCl3 anhydrous 98%
purchased from Strem Chemicals. Purification by column
chromatography was performed on Merck chromatographic
silica gel (40‒63 ꢀm). TLC analyses were performed using
Merck silica gel glass plates 60 F254. NMR spectra were
recorded on Bruker DPX400 or DMX500 instruments; chemical
shifts, given in, are relative to Me4Si as the internal standard or
to the residual solvent peak. HRMS data were obtained using a
Thermoscientific LTQU XL Orbitrap HRMS equipped with
APCI (atmospheric-pressure chemical ionization). HPLC
analysis was carried out on Agilent 1260 instrument equipped
with a G4212-60008 photodiode array detector, ES-MS Advion
Expression unit and an Agilent reverse phase ZORBAX Eclipse
plus C18 3.5 ꢀm column (4.6 X 100 mm).
4.4.1
3',5'-dimethoxy-3,4-dimethyl-[1,1'-Biphenyl]-2,4'-diol
(11e)
The crude residue was purified by column chromatography
(ethyl acetate/hexane, 1:4) to afford compound 11e (13.0 mg,
1
20% yield) as a gray solid; H NMR (400 MHz, CDCl3) δ 6.97
(d, J = 7.7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.63 (s, 2H), 5.58
(s, 1H), 5.40 (s, 1H), 3.90 (s, 6H), 2.31 (s, 3H), 2.23 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 150.3, 147.7, 137.8, 134.4,
128.5, 126.5, 125.5, 123.0, 121.7, 105.8, 56.4, 20.1, 11.9;
HRMS (ESI): m/z calcd for C16H18O4 [M+Na]+ 297.1097,
found 297.1099.
4.2. General procedure for the synthesis of Me4-difucols (6a)
and (6b)
To a solution of FeCl3 (8.1 mg, 10 mol %), 3,5-
dimethoxyphenol (154 mg, 1 mmol) in TFE (1 ml, 0.5M), di-t-
butylperoxide (0.75 mmol) was added drop-wise at room
temperature. Then stirring was continued for 48 hours. After
complete consumption of the limiting starting material
(indicated by TLC and HPLC), the volatiles were removed
under reduced pressure and the crude residue was purified by
column chromatography (silica gel 40-60 µm) to afford the pure
product.
4.4.2 3'-methoxy-3,4,5'-trimethyl-[1,1'-Biphenyl]-2,2'-diol (11f)
The crude residue was purified by column chromatography
(ethyl acetate/hexane 1:9) to afford the compound 11f (35.4
mg, 56% yield) as a brownish oil; 1H NMR (400 MHz, CDCl3)
δ 7.02 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.72 (s,
2H), 6.12 (s, 1H), 6.03 (s, 1H), 3.93 (s, 3H), 2.33 (s, 3H), 2.31
(s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.3,
146.4, 139.5, 138.0, 130.4, 127.4, 124.7, 124.1, 123.9, 122.4,
122.2, 110.9, 56.1, 21.2, 20.1, 12.1; HRMS (ESI): m/z calcd
for C16H18O3 [M+H]+ 259.1329, found 259.1328.
4.2.1 Sym-Me4-difucol (6a)
The crude residue was purified over silica-gel column
chromatography (ethyl acetate/hexane, 2:3) to afford
1
4.5. General procedure for the Biomimetic oxidative
oligomerization of protected fucols
compound 6a (46 mg, 33% yield) as a pale brown solid; H
NMR (400 MHz, DMSO-d6) δ 9.26 (s, 2H), 6.04 (s, 4H), 3.52
(s, 12H); 13C NMR (100 MHz, DMSO-d6) δ 158.7, 157.9,
103.1, 92.2, 55.2; HRMS (ESI): m/z calcd for C16H18O6
[M+Na]+ 329.0996, found 329.0998.
General Method A: To a stirred solution of the 3,5-
dimethoxyphenol/Me4-difucol
(1.0
equiv),
1,3,5-
trimethoxybenzene (3-7 equiv) and FeCl3 (5-20 mol %) in
HFIP (0.5 M), di-t-butylperoxide (3-7 equiv, respectively to the
arene) was added drop-wise at room temperature. Upon
completion of the consecutive reaction, as indicated by TLC
and HPLC analysis, the volatiles were removed under reduced
4.2.2 Unsym-Me4-difucol (6b)
The crude residue was purified over silica-gel column
chromatography (ethyl acetate/hexane, 2:3) to afford
1
compound 6b (22 mg, 22% yield) as an off-white solid; H

8
pressure. The crude residue was purified by silica-gel column
chromatography affording pure polyaryl products.
Luna C18, 21.2 X 250 mm, 10 micron, CH3CN-H2O) to afford
ACCEPTED MANUSCRIPT
compound 9 (21 mg, 25% yield) as a brown oil; 1H NMR (500
MHz, DMSO-d6) δ 8.60 (s, 1H), 6.55 (s, 1H), 6.28 (s, 1H), 6.27
(d, J = 2.3 Hz, 2H), 6.22 (d, J = 2.3 Hz, 2H), 6.21 (s, 2H), 3.79
(s, 6H), 3.79 (s, 3H), 3.70 (s, 6H), 3.66 (s, 3H), 3.58 (s, 6H),
3.53 (s, 6H), 3.09 (s, 3H), 3.08 (s, 6H); 13C NMR (125 MHz,
DMSO-d6) δ 160.3, 160.0, 159.1, 158.8, 158.7, 157.3, 155.5,
153.3, 112.6, 110.2, 108.8, 107.5, 105.6, 105.3, 94.7, 91.6, 91.4,
90.9, 59.0, 58.9, 55.6 (x 2C), 55.3, 55.1, 55.0; HRMS (ESI): m/z
calcd for C43H48O15 [M+Na]+ 827.2885, found 827.2867.
General Method B: To a stirred solution of the sym-Me4-
difucol (1.0 equiv), 1,3,5-trimethoxybenzene (6 equiv) and
FeCl3 (15% mol %) in HFIP (0.5 M), t-butyl hydroperoxide (6
equiv, respectively to the arene) was added drop-wise at room
temperature. Upon completion of the consecutive reaction, as
indicated by TLC and HPLC analysis, the volatiles were
removed under reduced pressure. The crude residue was
purified by silica-gel column chromatography affording pure
polyaryl product.
4.5.6 Me14-hexafucol B (10)
Biphenol 6a 46 mg, 0.15 mmol) and 1,3,5-trimethoxybenzene
(2, 176 mg, 1.05 mmol) were reacted according to method A
with FeCl3 (4.8 mg, 20 mol%) for 11 days. The crude residue
was purified by column chromatography (ethyl acetate/hexane,
3:2) and then over preparative HPLC chromatography
(Phenomenex Luna C18, 21.2 X 250 mm, 10 micron, CH3CN-
H2O) to afford compound 10 (14 mg, 10% yield) as a brown oil;
1H NMR (400 MHz, DMSO-d6) δ 6.25 (s, 8H), 3.79 (s, 15H),
3.60 (s, 24H), 3.16 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ
160.3, 159.0, 157.2, 153.3, 113.7, 110.3, 105.3, 91.4, 59.2, 55.5,
55.1; HRMS (ESI): m/z calcd for C52H58O18 [M+Na]+ 993.3515,
found 993.3522.
4.5.1 Me5-difucol (3) and Me8-fucol (4) were prepared
according to the procedure reported previously by our group.51
4.5.2 Me11-tetrafucol B (5)
3,5-dimethoxyphenol (1a, 38 mg, 0.25 mmol) and 1,3,5-
trimethoxybenzene (2, 210 mg, 1.25 mmol) were reacted
according to method A with FeCl3 (6.1 mg, 15 mol %) for 24 h.
The crude residue was purified by column chromatography
(DCM/acetone, 24:1) to afford compound 5 (78 mg, 48% yield)
as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 6.23 (s, 4H),
6.22 (s, 2H), 5.04 (s, 1H), 3.82 (s, 9H), 3.74 (s, 18H), 3.19 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 161.2, 160.6, 159.5, 159.3,
158.2, 152.6, 113.3, 110.1, 107.0, 104.9, 92.1, 91.8, 60.3, 56.4,
56.2, 55.4; HRMS (ESI): m/z calcd for C35H40O12 [M+Na]+
675.2412, found 675.2408.
4.6. General procedure for the Consecutive Oxidative Cross-
Coupling of Biphenols with Arenes
General method C: To a stirred solution of the phenol/biphenol
derivative (1.0 equiv), 1,3,5-trimethoxybenzene (3-5 equiv) and
FeCl3 (15 mol %) in HFIP (0.5 M), di-t-butylperoxide (3-5
equiv, respectively to the arene) was added drop-wise at room
temperature. Upon completion of the sequential oxidative cross-
coupling reaction, as indicated by TLC and HPLC analysis, the
volatiles were removed under reduced pressure. The crude
residue was purified by silica-gel column chromatography
affording pure polyaryl products.
4.5.3 Me7-fucol (7)
Biphenol 6a (46 mg, 0.15 mmol) and 1,3,5-trimethoxybenzene
(2, 76 mg, 0.45 mmol) were reacted according to method A
with FeCl3 (1.2 mg, 5 mol%) for 22 h. The crude residue was
purified by column chromatography (ethyl acetate/hexane, 3:2)
and then over preparative HPLC chromatography (Phenomenex
Luna C18, 21.2 X 250 mm, 10 micron, CH3CN-H2O) to afford
compound 7 (21 mg, 30% yield) as an off-white solid; 1H NMR
(400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.58 (s, 1H), 6.24 (s, 1H),
6.23 (s, 2H), 6.06 (s, 2H), 3.79 (s, 3H), 3.62 (s, 6H), 3.55 (s,
9H), 2.92 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 160.1,
158.9, 158.8, 158.7, 157.9, 157.3, 155.5, 107.5, 107.3, 105.5,
103.9, 94.9, 92.3, 91.1, 58.9, 55.4, 55.3, 55.1, 55.0; HRMS
(ESI): m/z calcd for C25H28O9 [M+K]+ 511.1365, found
511.1356.
General method D: To a stirred solution of the biphenol
derivative (1.0 equiv), 1,3,5-trimethoxybenzene (3-5 equiv) and
FeCl3 (15 mol %) in HFIP (0.5 M), di-t-butylperoxide (3-5
equiv, respectively to the arene) was added drop-wise at room
temperature and the stirring was continued at 40 0C.
Upon completion of the consecutive reaction, as indicated by
TLC and HPLC analysis, the volatiles were removed under
reduced pressure. The crude residue was purified by silica-gel
column chromatography affording pure polyaryl products.
4.5.4 Me10-tetrafucol (8)
Biphenol 6a (46 mg, 0.15 mmol) and 1,3,5-trimethoxybenzene
(2, 76 mg, 0.45 mmol) were reacted according to method A
with FeCl3 (3.6 mg, 15 mol%) for 22 h. The crude residue was
purified by column chromatography (ethyl acetate/hexane, 3:2)
and then over preparative HPLC chromatography (Phenomenex
Luna C18, 21.2 X 250 mm, 10 micron, CH3CN-H2O) to afford
compound 8 (35 mg, 36% yield) as a brown oil; 1H NMR (400
MHz, DMSO-d6) δ 8.61 (s, 2H), 6.26 (s, 2H), 6.24 (d, J = 2.2
Hz, 2H), 6.21 (d, J = 2.2 Hz, 2H), 3.79 (s, 6H), 3.65 (s, 6H),
3.59 (s, 6H), 3.54 (s, 6H), 3.03 (s, 6H); 13C NMR (125 MHz,
DMSO-d6) δ 160.1, 158.9, 158.8, 158.7, 157.4, 155.5, 108.2,
107.4, 105.5, 95.0, 91.0, 90.9, 58.9, 55.4, 55.3, 55.10 (x 2C);
HRMS (ESI): m/z calcd for C34H38O12 [M+Na]+ 661.2256,
found 661.2246.
General method E: To a stirred solution of biphenol (1.0
equiv), 1,3,5-trimethoxybenzene (6 equiv) and FeCl3 (15 mol
%) in HFIP (0.5 M) at 0 ºC was added drop-wise t-butyl
hydroperoxide (6 equiv. respectively to the arene). The reaction
was further stirred at room temperature until full consumption
of the biphenol starting material. NaBH4 (1.1 equiv) was added
in one portion and the mixture stirred for 3 h. The reaction was
quenched with 1 N HCl aq. sol. and extracted with
dichloromethane (3 X 10 mL). The combined organic phase
was dried over MgSO4, the volatiles removed under reduced
pressure and the crude residue purified by silica-gel column
chromatography affording pure polyaryl product.
4.5.5 Compound (9)
4.6.1 Compound 12
Biphenol 6a (31 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 101 mg, 0.60 mmol) were reacted according to method B
with FeCl3 (2.4 mg, 15 mol%) for 1.5 h. The crude residue was
purified by column chromatography (ethyl acetate/hexane, 3:2)
and then over preparative HPLC chromatography (Phenomenex
Biphenol 11a (19 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 101 mg, 0.60 mmol) were reacted according to method E for
6 h. The crude residue was purified by column chromatography
(ethyl acetate/hexane, 7:3) to afford compound 12 (59 mg, 70%
1
yield) as red solid; H NMR (400 MHz, CDCl3) δ 7.43 (s, 4H),

9
6.25 (s, 8H), 5.31 (s, 2H), 3.83 (s, 12H), 3.72 (s, 24H); 13C
NMR (100 MHz, CDCl3) δ 160.9, 158.9, 150.7, 132.4, 130.1,
121.3, 108.7, 91.5, 56.2, 55.4; HRMS (ESI): m/z calcd for
C48H50O14 [M]+ 850.3195, found 850.3191.
MHz, CDCl3) δ 6.91 (s, 1H), 6.71 (s, 2H), 6.24 (s, 2H), 5.55
ACCEPTED MANUSCRIPT
(s, 1H), 5.42 (s, 1H), 3.89 (s, 6H), 3.87 (s, 3H), 3.73 (s, 6H),
2.27 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6,
158.7, 149.4, 147.7, 137.6, 134.3, 129.8, 128.9, 125.9, 124.9,
123.0, 112.0, 106.0, 90.7, 56.5, 55.9, 55.5, 17.1, 12.8; HRMS
(ESI): m/z calcd for C25H28O7 [M+H]+ 441.1908, found
441.1900.
4.6.2 Compound 13
Biphenol 11b (34 mg, 0.11 mmol) and 1,3,5-trimethoxybenzene
(2, 56 mg, 0.33 mmol) were reacted according to method C for
24 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 1:1) to afford
compound 13 (44 mg, 63% yield) as a yellowish solid; 1H NMR
(500 MHz, CDCl3) δ 6.72 (s, 4H), 6.14 (s, 4H), 3.77
(overlapped, 18H), 3.73 (s, 12H); 13C NMR (125 MHz, CDCl3)
δ 155.6, 152.3, 151.8, 137.5, 135.8, 131.9, 105.5, 92.4, 57.1,
56.7, 55.5; HRMS (ESI): m/z calcd for C34H38O12 [M+K]+
677.0000, found 677.2015.
4.6.7 Compound 18
Biphenol 11e (27 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 51 mg, 0.30 mmol) were reacted according to method C for
3 h. The crude residue was purified by column chromatography
(ethyl acetate/hexane, 2:3) to afford compound 18 (31 mg, 52%
1
yield) as a brown oil; H NMR (400 MHz, CDCl3) δ 6.92 (s,
1H), 6.66 (s, 2H), 6.24 (s, 2H), 6.15 (s, 2H), 5.50 (s, 1H), 3.87
(s, 3H), 3.78 (s, 3H), 3.73 (s, 12H), 3.72 (s, 6H), 2.27 (s, 3H),
2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 158.7,
155.7, 152.3 (x 2C), 149.3, 137.6, 137.0, 131.8 (x 2C), 129.5,
125.9, 124.8, 122.9, 112.1, 107.1, 92.3, 90.7, 56.8, 56.8, 55.9,
55.6, 55.5, 17.1, 12.7; HRMS (ESI): m/z calcd for C34H38O10
[M+Na]+ 629.2357, found 629.2366.
4.6.3 Compound 14
Biphenol 11c (27 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 84 mg, 0.50 mmol) were reacted according to method C for
10 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 1:1) to afford
compound 14 (36 mg, 46% yield) as a yellow oil; 1H NMR (400
MHz, CDCl3) δ 6.14 (s, 2H), 6.06 (s, 2H), 5.97 (s, 4H), 4.70 (s,
1H), 3.76 (s, 6H), 3.74 (s, 3H), 3.59 (s, 12H), 3.50 (s, 6H), 3.37
(s, 6H), 1.98 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 160.4,
158.1, 155.2, 152.1, 150.9, 149.7, 136.7, 136.6, 135.8, 132.6,
131.7, 122.3, 111.5, 108.3, 92.6, 90.0, 56.7, 56.6, 55.5, 55.2,
13.5; HRMS (ESI): m/z calcd for C43H48O13 [M+Na]+ 795.2987,
found 795.2990.
4.6.8 Compound 19
Biphenol 11e (27 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 84 mg, 0.50 mmol) were reacted according to method C for
10 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 1:1) to afford
compound 19 (36 mg, 47% yield) as a yellow oil; 1H NMR (400
MHz, CDCl3) δ 6.97 (s, 1H), 6.85 (s, 2H), 6.20 (d, J = 2.1 Hz,
1H), 6.18 (d, J = 2.1 Hz, 1H), 6.12 (s, 2H), 6.11 (s, 2H), 3.84 (s,
3H), 3.79 (s, 6H), 3.76 (s, 3H), 3.71 (s, 15H), 3.69 (s, 6H), 1.80
(s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0,
160.7, 159.9, 158.9, 158.6, 155.6, 155.1, 152.5, 151.0, 143.9,
137.4, 131.5, 130.5, 120.9, 120.8, 113.5, 111.3, 107.6, 92.3,
91.9, 91.0, 59.2, 57.2, 56.8, 56.1, 55.9, 55.7, 55.6, 55.5, 55.3,
25.2, 17.8; HRMS (ESI): m/z calcd for C43H48O13 [M+Na]+
795.2987, found 795.2991.
4.6.4 Compound 15
Biphenol 6a (31 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 51 mg, 0.30 mmol) were reacted according to method C for
5 h. The crude residue was purified by column chromatography
(ethyl acetate/hexane, 2:3) to afford compound 15 (34 mg, 72%
yield) as a brown oil; 1H NMR (500 MHz, CDCl3) δ 6.85 (d, J =
8.6 Hz, 1H), 6.76 (s, 2H), 6.71 (d, J = 8.6 Hz, 1H), 6.15 (s, 2H),
5.74 (s, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.74 (s, 6H), 3.72 (s,
6H), 3.52 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.6, 152.3,
151.6, 147.0, 144.7, 138.8, 137.0, 132.2, 132.1, 128.0, 120.3,
107.1, 105.8, 92.4, 60.5, 56.9, 56.7, 56.4, 55.6; HRMS (ESI):
m/z calcd for C25H28O9 [M+Na]+ 495.1631, found 495.1632.
4.6.9 Compound 20
Biphenol 11f (26 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 51 mg, 0.30 mmol) were reacted according to method D for
72 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 1:1) to afford
1
compound 20 (19 mg, 33% yield) as a yellow solid; H NMR
4.6.5 Compound 16
(400 MHz, CDCl3) δ 7.14 (s, 1H), 6.86 (s, 1H), 6.65 (s, 1H),
6.23 (s, 2H), 5.46 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.69 (s,
6H), 3.60 (s, 6H), 2.34 (s, 3H), 2.11 (s, 3H), 2.00 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 186.7, 167.0 (x 2C), 160.7, 158.6,
152.3, 148.8, 138.4, 137.7, 135.0, 132.2, 131.1, 129.6, 128.9,
127.1, 121.1, 112.4, 111.3, 100.1, 91.0, 56.1, 56.0, 55.9, 55.5,
21.7, 17.2, 13.2; HRMS (ESI): m/z calcd for C33H34O9 [M+Na]+
597.2095, found 597.2093.
Biphenol 11d (31 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 84 mg, 0.50 mmol) were reacted according to method D for
24 h. The crude residue was purified by column
chromatography; (ethyl acetate/hexane, 3:2) to afford
1
compound 16 (45 mg, 56% yield) as a pale brown solid; H
NMR (500 MHz, CDCl3) δ 6.53 (s, 1H), 6.37 (s, 2H), 6.16 (s,
2H), 6.08 (s, 2H), 5.98 (s, 2H), 3.77 (s, 3H), 3.75 (overlapped,
6H), 3.74 (overlapped, 9H), 3.59 (s, 6H), 3.56 (s, 6H), 3.50 (s,
6H), 3.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.5, 158.3,
155.5, 155.3, 152.2, 152.0, 150.5 (x 2C), 149.0, 140.4, 136.3,
132.6, 132.3, 132.0, 129.8, 128.3, 112.7, 111.3, 108.7, 93.0,
92.5, 90.4, 60.2, 56.8, 56.6, 56.5, 55.6, 55.6, 55.5, 55.3; HRMS
(ESI): m/z calcd for C43H48O15 [M+Na]+ 827.2891, found
827.2909.
4.6.10 Compound 21
Biphenol 11g (27 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 84 mg, 0.50 mmol) were reacted according to method C for
24 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 1:1) to afford
1
compound 21 (37 mg, 48% yield) as an off-white solid; H
NMR (400 MHz, CDCl3) δ 6.39 (s, 2H), 6.27 (s, 2H), 6.08 (s,
2H), 6.00 (s, 2H), 4.86 (s, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.76
(s, 6H), 3.75 (s, 3H), 3.61 (s, 6H), 3.59 (s, 6H), 3.54 (s, 6H),
2.01 (s, 3H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.0,
160.4, 159.0, 158.1, 155.4, 152.1, 151.2, 148.3, 136.5, 136.3,
132.7, 132.2, 131.8, 127.6, 126.0, 119.6, 111.9, 108.2, 107.8,
92.4, 91.2, 90.1, 56.6 (x 2C), 56.1, 55.5 (x 2C), 55.4, 55.2, 17.6,
4.6.6 Compound 17
Biphenol 11e (27 mg, 0.10 mmol) and 1,3,5-trimethoxybenzene
(2, 51 mg, 0.30 mmol) were reacted according to method C for
1.5 h. The crude residue was purified by column
chromatography (ethyl acetate/hexane, 3:7)
compound 17 (15 mg, 34% yield) as a green oil; H NMR (400
to afford
1

10
16.9; HRMS (ESI): m/z calcd for C43H48O13 [M+Na]+ 795.2987,
found 795.2993.
21.
22.
Ragan, M. A. Can. J. Chem. 1985, 63, 291-293.
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23.
24.
Bertoni, G. The Plant Cell 2013, 25, 2770-2770.
Lips, S.; Wiebe, A.; Elsler, B.; Schollmeyer, D.; Dyballa,
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4.7. General procedure for one-pot sequential oxidative
coupling for the formation of compound 16
To a solution of FeCl3 (6 mg, 15 mol %), 2,6-dimethoxyphenol
(77 mg, 0.5 mmol) in HFIP (0.5 ml, 0.5M), di-t-butylperoxide
(0.38 mmol) was added drop-wise at room temperature. Then
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trimethoxybenzene (2, 210 mg, 1.25 mmol) and di-t-
butylperoxide (1.25 mmol) were added drop-wise at room
25.
26.
27.
0
temperature. Then the stirring was continued at 40 C upon
completion of the consecutive reaction the volatiles were
removed under reduced pressure and the crude residue purified
by silica-gel column chromatography to afford compound 16
(78 mg, 40% yield) as a yellow solid.
28.
29.
Kirste, A.; Elsler, B.; Schnakenburg, G.; Waldvogel, S.
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Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.;
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Kirste, A.; Nieger, M.; Malkowsky, I. M.; Stecker, F.;
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Acknowledgments
This research was supported by the Israel Science Foundation
(grant No. 164/16).
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