Understanding the regioselectivity in the oxidative condensation of catechins using pyrogallol-type model compounds

Article abstract of DOI:10.1021/acs.joc.0c01612

Catechins are found in many foods, including tea. These compounds are bioactive. Previous studies have shown that catechins form dimers on oxidation, and there seem to be distinct regioselective effects. However, the dimerization mechanism and regioselectivity are not well understood. Therefore, we investigated the oxidation of four pyrogallol-type model compounds of epigallocatechin (EGC) having various substituents with 1 equiv of copper chloride and 30% dioxane in water. Compounds having 2C-2C or 2C-4C bonds in the B-ring were obtained in different product ratios. Comparison of the oxidation rates of each compound revealed that the model compounds having an oxygen atom corresponding to the 1-position of the C-ring of EGC underwent slow oxidation. In addition, using density functional theory calculations, we found that the highest occupied molecular orbital energies of these compounds were higher than those of the others. Further, the 2C-2C-bonded oxidation product having an A-ring and an oxygen atom at the C-ring 1-position was confirmed to have the highest thermodynamic stability. From these results, it is suggested that the regioselective condensation reaction of the catechin B-ring is related to interactions between the A-rings, as indicated by earlier studies, and the presence of oxygen at the 1-position of the C-ring in EGC.

Full text of DOI:10.1021/acs.joc.0c01612

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Article
Understanding the Regioselectivity in the Oxidative Condensation
of Catechins Using Pyrogallol-Type Model Compounds
Yuto Ochiai, Sayumi Hirose, and Emiko Yanase
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01612 • Publication Date (Web): 03 Sep 2020
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Understanding the Regioselectivity in the Oxidative
Condensation of Catechins Using Pyrogallol-Type
Model Compounds
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Yuto Ochiai, Sayumi Hirose, and Emiko Yanase*
Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193,
Japan
ABSTRACT
Catechins are found in many foods, including tea. These compounds are bioactive.
Previous studies have shown that catechins form dimers on oxidation, and there seem to
be distinct regioselective effects. However, the dimerization mechanism and
regioselectivity are not well understood. Therefore, we investigated the oxidation of four
pyrogallol-type model compounds of epigallocatechin (EGC) having various substituents
with 1 eq copper chloride and 30% dioxane in water. Compounds having 2C-2C or 2C-
4C bonds in the B-ring were obtained in different product ratios. Comparison of the
oxidation rates of each compound revealed that the model compounds having an oxygen
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atom corresponding to the 1-position of the C-ring of EGC underwent slow oxidation. In
addition, using density functional theory calculations, we found that the highest occupied
molecular orbital energies of these compounds were higher than those of the others.
Further, the 2C-2C-bonded oxidation product having an A-ring and an oxygen atom at the
C-ring 1-position was confirmed to have the highest thermodynamic stability. From these
results, it is suggested that the regioselective condensation reaction of the catechin B-
ring is related to interactions between the A-rings, as indicated by earlier studies, and the
presence of oxygen at the 1-position of the C-ring in EGC.
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O
R
O
R
O
OH
O
2'
HO
HO
2'
4'
2
4'
2
4
4
OH
OH
O
OH
OH
B
R
R
O
R
O
OH
OH
oxidation
OH
R
OH
O
3'
2'
2
OH
4
H
OH
OH
R
O
KEYWORDS: Catechins, Flavanols, Natural product, Mechanistic study, Polyphenols,
DFT
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INTRODUCTION
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Catechins are polyphenols that are abundant in tea leaves and are known to have
various biological effects, including antioxidant and antitumor activities.1,2 In the
manufacture of oolong and black teas, the catechins present in the tea leaves are oxidized
by polyphenol oxidase, resulting in the formation of dimers, such as theaflavin,
theasinensin, and oolongtheanin.3,4,5 These compounds are characteristic catechin
dimers; they are formed by condensation reactions between the B-rings (see Scheme 1)
and have been predicted to exert various bioactive effects.6 Therefore, we have previously
investigated the formation mechanism of theaflavins and oolongtheanins from
catechins.7,8 Because these compounds are products of the condensation reaction
between B-rings, the oxidation reaction mechanism was investigated using catechol and
pyrogallol derivatives as model catechins. Previously, it has been shown that
benzotropolone derivatives, which represent part of the structure of theaflavins, are
obtained by oxidative condensation reaction between 5-methylpyrogallol (1) (see Scheme
1 for labeling scheme), corresponding to pyrogallol-type catechin (EGC or EGCg), and 4-
methylcatechol (2), corresponding to catechol-type catechin (EC or ECg).8 On the other
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hand, compounds 4 and 5 are obtained by the oxidative self-condensation reaction of 5-
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methylpyrogallol (1).
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OH
OH
B
Me
OH
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CO2
OH
OH
OH
Me
O
2
HO
O
C
Me
OH
A
Oxid.
OH
OH
OH
3
OH
1
Epigallocatechin
4 OH
OH
2
O
1
Me
Me
O
4
Me
O
OH
OH
O
Me
HO
2
1
2
O
O
4
4
OH
H2O
2
OH
O
3
H
OH
HO
O
2
Oxid.
HO
O
4
OH
Me
OH
5
Me
Me
OH
I
Scheme 1. Oxidation products of 1 and 2.
Theasinensin and oolongtheanine are formed by the 2C-2C bond formation between
the B-rings of two molecules of EGC in the presence of copper chloride.9 These dimers
are known to be condensates of pyrogallol-type catechin and account for the major
product of the condensation reactions. In contrast, 4 and 5 (Scheme 1) contain two 2C-
4C bonds between the two B-rings and account for over 50% of the product yield. Thus,
it has been suggested that the difference in reaction between real catechins and 1 may
be influenced by the steric hindrance or interactions between molecules. Hence, in this
study, we investigated the effect of oxidative condensation on the regioselectivity of the
product using various pyrogallol analogs. As shown in Figure 1, simplified substituents on
the pyrogallol-type B-ring were used. To determine the effects of the A-ring, 1a, which
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does not contain an A-ring, was prepared. To determine the effect of the C-ring oxygen,
compound 1b was used; 1b contains a carbon chain but no oxygen atom. Additional
substituents (1c and 1d) were used to isolate the structural effects further. To understand
the mechanism further, we used density functional theory (DFT) calculations. DFT is a
commonly used quantum chemistry technique for determining molecular structures and
elucidating reactivity.10,11 In addition, chemical parameters such as the highest orbital
molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies,
HOMO–LUMO gap, chemical hardness, and electrophilicity can be obtained from DFT
calculations and can be used to understand the chemical, kinetic, and thermodynamic
behavior of molecules and reactions, thus allowing us to clarify the relationship between
the calculation reaction parameters, reactivity, and reaction yield.
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OH
B
OH
B
OH
B
OH
OH
OH
OH
OH
1
O
2
3
HO
HO
O
C
OH
R
A
C
4
A
OH
1
OH
OH
OH
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Pyrogallol-type B-ring
Epigallocatechin
HO
O
O
O
R=
Me
OH
1e
1a
1d
1b
1c
Figure 1. Catechin (top left) showing C-ring numbering and the framework in bold (top
middle) chosen for our model compounds. The R-group substituent on the B-ring (top
right) was varied from methyl to those containing A-ring substituents with various chain
lengths within and without oxygen; the chain acted as a C-ring mimic (bottom).
OH
O
R
O
R
OH
O
O
O
OH
HO
HO
OH
B
CuCl2
R
OH
OH
O
O
OH
O
OH
O
H
OH
30% dioxane in H2O
R
OH
R
R
R
O
5
6
4
Scheme 2. Oxidation reactions carried out in the presence of copper chloride in aqueous
dioxane. The possible products are represented by compounds 4 and 5, which contain
2C-4C bonds, and compound 6, which contains 2C-2C bonds.
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RESULTS AND DISCUSSION
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Compounds 1a–1d were synthesized using modified literature methods. The NMR and
mass spectrometry (MS) data of the synthesized compounds already reported were in
agreement with the literature values (Schemes S1–S4).12-23 Compound 1a has a simple
methyl group substituent (see Figure 1 for the labeling figure) and was oxidized with 1 eq
of copper chloride in 30% dioxane in water. After removing the copper chloride using an
HP20SS column and subjecting the crude products to high-performance liquid
chromatography (HPLC) analysis, the three main products were isolated and determined
to be 4a, 5a, and 6a by instrumental analysis (see Scheme 2). The product ratio of 2C-
4C and 2C-2C-type compounds was 1.1:1, as determined by NMR peak integration
(Table 1, Figure S1A). As shown in Scheme 2, compounds 4 and 5 contain 2C-4C bonds
and 6 contains a 2C-2C bond, so there was no regioselective effect in this reaction. Thus,
we concluded that the A- and C-rings are involved in determining the regioselectivity,
especially considering that, when 1e was used 4e and 5e were generated in over 50%
yield. Therefore, to investigate the influence of the A-ring on the regioselectivity in the
condensation reaction, the oxidation reaction of 1b was again carried out with 1 eq of
copper chloride and 30% dioxane in water. After removing the copper chloride and
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subjecting the crude mixture to HPLC analysis, 4b, 5b, and 6b were identified as the main
products by instrumental analysis. Compound 5b is a water adduct of 4b. Further, from
the NMR integrals, the product ratio of 2C-4C and 2C-2C-type compounds was 0.7:1
(Table 1, Figure S1B). Because of the presence of the A-ring in the R-group substituent
in 1b but the lack of C-ring oxygen atom, we suggest that the A-ring is important for the
selective formation of the 2C-2C bond.
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Matsuo et al. reported that the stereoselectivity in the oxidative condensation of 1e is
due to the stacking of A-rings because of the hydrophobic effect and π-π interactions.
They showed that solvent molecules are located between the A-rings by comparison of
the measured and calculated electronic circular dichroism (ECD) spectra of 6e, which is
an oxidative condensate of 1e, in acetone and acetonitrile.24 When a large amount of
organic solvent is present, the interactions between the A-rings are obstructed, and the
regioselective effect is lost. In fact, when 1b was used for the oxidation reaction in 80%
aqueous dioxane solution, the 4b:6b ratio was 1.69:1; that is, the production of 6b was
considerably decreased. Therefore, the A-ring is crucial for the production of compound
6.
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Next, the oxidation reaction of 1c, which is used a model compound having an oxygen
atom corresponding to the 1-position of the C-ring of EGC was performed under the same
conditions as that of 1b. When the reaction mixture of 1c was subjected to HPLC analysis,
two main peaks were observed. Each product was isolated by HPLC, and various NMR
and MS analyses were performed. The products were 4c and 6c. From the NMR integrals,
the product ratio of 2C-4C and 2C-2C-type compounds was found to be 0.45:1 (Table 1,
Figure S1C). These results indicate that the oxygen atom at the 1-position of the C-ring,
as well as the presence of the A-ring, enhance the formation of the 2C-2C-type
compound.
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Table 1. Ratios of oxidation product of each compound as determined by NMR.
1
4 or 5* (2C-4C)
6* (2C-2C)
1a
1b
1c
1d
1.1
0.7
1
1
1
1
0.45
1.43
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1e
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*Ratio calculated from 1H-NMR measurements.
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The oxidation reactions of 1b and 1c, for which 2C-2C-type compounds were
predominantly formed, were followed using HPLC, and it was found that 2C-4C-type
compounds 4 and 5 were produced in the early stages of the reaction. However, 2C-2C-
type products were formed with increasing reaction time. In the presence of a large
excess of copper chloride, the reaction was rapid, and 4 and 5 were obtained as the main
products (Table 2). In contrast, when using less than one equivalent of copper chloride,
the reaction rate was slow, and the amount of 2C-2C-type compound 6 increased (Table
2). These results suggest that the 2C-2C and 2C-4C-type compounds are formed by
different routes. When the oxidant is used in high concentrations, as well as in the initial
stages of the reaction, condensation between the highly reactive o-quinones formed by
oxidation occurs because o-quinones are produced in large quantities (Scheme 3). On
the other hand, the reaction between o-quinone and hydroquinone increases as the
reaction time increases. Thus, we proposed that the formation of the 2C-4C bond involves
a reaction between o-quinones, which are oxides of 1, and the 2C-2C bonds are formed
by reactions between o-quinone and hydroquinone.
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Table 2. Oxidation product ratios depending on CuCl2 equivalents used.
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CuCl2 (eq)
4c*
0.7
6c*
1
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0.3
1
0.85
1.2
1
3
1
*Ratio calculated from 1H-NMR measurements.
The reaction mechanism for the formation of 2C-2C and 2C-4C-type compounds can
be regarded as a nucleophilic addition reaction to α,β-unsaturated ketones. That is, the
formation of 2C-4C bonds involves the direct addition (1,2-addition) to a ketone, whereas
the formation of the 2C-2C bonds involves a conjugate addition (1,4-addition) reaction. In
addition, in reactions of α,β- unsaturated ketones, direct and conjugate addition reactions
result in the kinetic and thermodynamic products, respectively. This is because the
addition reaction to the ketone is usually reversible, so the final product is the
thermodynamic conjugate addition product. However, 4 and 5 were obtained as products
because these compounds are relatively stable when two direct addition reactions occur
simultaneously (Scheme 3).
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OH
4
OH
O
O
O
OH
OH
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O
O
O
O
oxidation
2
OH
HO
HO
O
O
2
HO
O
X
C2-C4 type
4
OH
OH
OH
OH
O
OH
4
O
O
O
oxidation
H2O
2
OH
OH
O
OH
OH
H
OH
O
2
OH
6
OH
OH
Y
C2-C2 type
Scheme 3. Direct addition (1,2-addition) and conjugate addition (1,4-addition) reactions.
Next, the oxidation of 1d was carried out under the same conditions as those for 1b.
When the reaction mixture was subjected to HPLC analysis, multiple peaks were
observed in addition to the two main peaks. Each peak was isolated by HPLC and various
NMR and MS analyses were carried out. The two main products were 4d (2C-4C) and 6d
1
(2C-2C). Based on the H-NMR integrals, the product ratio of 2C-4C and 2C-2C-type
products is 1.43:1 (Table 1, Figure S1D). Despite having an oxygen atom like 1c, 1d
showed reactivity similar to that of 1b. Furthermore, when the rates of oxidation of 1a to
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1e were compared, the order was found to be 1a > 1d = 1b > 1e > 1c (Figure 2).
Compound 1d contains oxygen in the R-group substituent, but no enhancement effect of
the oxygen atom on the regioselectivity of the reaction was observed. Further, its
reactivity is similar to that of compound 1b, whose R-group substituent does not contain
oxygen.
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Figure 2. Rates of oxidation of A (1a and 1b), B (1b and 1d), C (1b and 1c), and D (1c
and 1e).
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The difference between compounds 1c and 1d is the distance from the oxygen atom to
the B-ring. The oxygen atom of 1c is closer to the B-ring than that in 1d. Thus, this oxygen
atom may affect the rate of the nucleophilic addition reaction at the B-ring.
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Next, we used DFT to study the reactivity and redox properties of the compounds
formed by oxidation and condensation. Concerning redox chemistry, a lower HOMO
energy indicates easier oxidation.25 The experimentally obtained oxidation rates for 1a–e
decrease in order 1a > 1b = 1d > 1c > 1e (Figure 2), and the calculated HOMO energies
of all hydroquinone compounds are 1a > 1b = 1d > 1e > 1c. Thus, the presence of the
oxygen atom at the 1-position of the C-ring increased the HOMO energy and reduced the
rate of oxidation (Table 3). The oxidation reaction can also be evaluated by the ionization
potential (I) and electrophilicity (ω). When the ionization energy is low, a compound is
easily oxidized.26 Further, when the electrophilicity of a compound is high, its oxidation is
harder.27 Thus, I and ω of the hydroquinone compounds were calculated and were found
to increase in order 1a < 1b = 1d < 1e < 1c (Table 3). These results indicate that 1c is
less susceptible to oxidation than the other compounds. Further, the calculations show
that 1a, 1b, and 1d are more likely to be oxidized and form o-quinones than 1c and 1e.
As shown in Table 3, the former tended to form 2C-4C-type products, whereas the latter
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tended to form 2C-2C-type products. On the basis of these results, if 1 is easily oxidized,
the probability of o-quinone formation increases, so that the reaction proceeds between
o-quinones to form 2C-4C-type products. On the other hand, if 1 is relatively difficult to
oxidize, the formation of o-quinone is less likely; thus, the reaction between the o-quinone
and hydroquinone proceeds to form 2C-2C-type products.
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Table 3. DFT calculated parameters for 1a to 1e.


EHOMO ELUMO
E
I
A

(eV
)

(eV)
(eV)
(eV)
(eV)
(eV)
(eV) (eV)
10.
0
1a
1b
1c
-5.58
0.389
5.97
5.58 -0.389 2.98 2.6
5.61 0.0955 2.76 2.85
5.82 0.0999 2.86 2.96
-0.435
-0.517
-0.517
11.
2
-5.61
-5.82
-0.0955 5.52
-0.0999 5.72
12.
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11.
2
1d
1e
-5.61
-5.75
-0.0914 5.52
5.61 0.0914 2.76 2.85
-0.517
-0.492
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-
0.0473
11.
8
0.0473
5.79
5.75
2.90 2.85
Next, the reaction enthalpies of the 1a–e (ΔrH(X-1) or ΔrH(Y-1)) and the differences
between the enthalpies of these products (ΔrH(X-1)-ΔrH(Y-1)) were calculated. Using these
values, we compared the thermodynamic stability of 4 and 6 and evaluated their reactivity.
Because the formation of 6 increased when the A-ring substituent was used, as well as
with the R substituents containing oxygen (see Table 1), we expected that 6 would be
more thermodynamically stable. Therefore, the changes in the thermodynamic stability of
6 with changes in the R-group substituent were investigated. Although it is not possible
to compare the enthalpies of the products directly, we compared the enthalpies of
products of X and Y, which are reaction intermediates of 4 and 6 having the same
molecular weight, to estimate their thermodynamic stabilities.
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Table 4. Enthalpy changes of compounds with substituents a–e.
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ΔrH(X-1)/(kcal mol-
ΔrH(X-1)  ΔrH(Y-1)/(kcal mol-
R
ΔrH(Y-1)/(kcal mol-1)
1
1
)
)
A
B
C
D
E
770.06
775.14
774.01
774.18
765.85
763.14
765.81
764.03
765.77
767.49
6.92
9.33
9.98
8.41
-1.65
*Structures of X and Y are given in Scheme 3.
In general, a lower value of ΔrH(X-1) or ΔrH(Y-1) indicates stability, and, thus, the oxidation
product is more easily generated. For compounds 1a–d, ΔrH(X-1) was greater than ΔrH(Y-
1), suggesting that intermediate Y was more thermodynamically stable (Table 4).
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Therefore, we speculate that the larger reaction enthalpy difference (ΔrH(X-1)  ΔrH(Y-1)
)
6
7
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9
between the products indicates a higher product ratio of 6. The values of ΔrH(X-1)  ΔrH(Y-
1) are very different for 1a and 1e, especially 1b, which contains an A-ring, and 1c, which
has an oxygen atom at the 1-position of the model C-ring, for which the values are very
high (Table 4). These results appear to confirm the results of previous studies concerning
the π-π stacking interactions of the A-ring, as well as the importance of the C-ring oxygen
atom, both of which may enhance the stability of 6. Further, we suggest that the
thermodynamically stable 1,4-addition reaction proceeds preferentially over the kinetically
dominant 1,2-addition. Like 1b and 1c, 1d also contains an A-ring and oxygen atom, but
the larger distance between the A- and B-rings results in greater flexibility. Possibly, the
increase in flexibility decreases the regioselectivity of the reaction between the B-ring,
and, thus, the products of 1,4-addition decrease. Concerning 1e, the thermodynamic
stability of the X intermediate is higher than that of the Y intermediate. This is probably
because the structure of 1e is significantly different from those of 1a–d.
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CONCLUSIONS
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We have found that the A-ring and the oxygen atom at the 1-position of the C-ring affect
the regioselectivity in the oxidative condensation of the catechin B-ring. Experimental
results and DFT calculations suggest that the HOMO energy of ring B which is affected
by the oxygen atom at 1-position of the C-ring, and the thermodynamic stability of the
product are all important. These results suggests that the whole catechin molecule is
involved in the reactivity of the B-ring and that the reaction is regioselective. Although
there have been many reports on the functionality of polyphenols including catechins,
there is significant scope for further investigation, and many compounds, for example,
high-molecular-weight polyphenols in fermented tea, remain uninvestigated. We believe
that the findings obtained here will contribute to the elucidation of the reaction mechanism
of the oxidation of tea catechins and the chemical structure of polymeric polyphenols.
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EXPERIMENTAL SECTION
Chemicals. EGCg was gifted by Nagara Science Co. (Gifu, Japan). EGC was prepared
from EGCg by enzyme reaction using a tannase.9 Dioxane and tetrahydrofuran (THF)
were purchased from FUJIFILM Wako pure Chemical Corporation (Osaka, Japan).
Deuterated dimethyl sulfoxide (DMSO-d6) and D2O were purchased from KANTO
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CHEMICAL Corporation (Tokyo, Japan). Acetone-d6 was purchased from ACROS
ORGANICS Corporation (Tokyo, Japan).
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General procedure for oxidative condensation
Compounds 1a to 1d were oxidatively condensed using the following method. First, 400
L of 30% dioxane aqueous solution was added to 2 mg (0.014 mmol) of 1a and stirred
until the solid dissolved. Then, 2.4 mg (0.014 mmol) of CuCl2·2H2O dissolved in 400 L
of 30% dioxane aqueous solution was added, and the mixture was stirred at room
temperature for 2 h. After the reaction had completed, the CuCl2·2H2O was removed
using a Diaion HP20SS resin column (Mitsubishi Chemical Co., Japan), which had been
washed with water, and all compounds were eluted with MeCN and concentrated. The
same procedure was performed for 1b–d. 1e was prepared by the same procedure as
above except that 30% THF aqueous solution was used.
Measurement of the oxidation rates of 1a–e
For these experiments, 1a (1.5 mg, 0.0065 mmol), 1b (0.91 mg, 0.0065 mmol), and
CuCl2·2H2O (1.1 mg, 0.0065 mmol) were added to 400 L of 30% dioxane aqueous
solution, and the mixture was stirred at room temperature until the raw materials disappeared.
The reaction was monitored by HPLC every 30 min, and the remaining proportion of the model
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compound was evaluated by considering the peak area before reaction as 100%. The same
procedure was performed for 1b and 1d, 1d and 1c, and 1c and 1e. HPLC analysis of each
sample was carried out with a JASCO PU-2080 intelligent pump equipped with a JASCO
UV-2075 intelligent UV/VIS detector and Sugai U-620 column heater (Tokyo, Japan). The
HPLC conditions were as follows. The sample (5 L) was injected onto a COSMOSIL
C18 column (Cosmosil 5C18-MS-Ⅱ 4.6 mm I.D. × 150 mm, Nacalai Tesque Co., Ltd.,
Kyoto, Japan). The oven temperature was maintained at 35 °C. The eluents for the
compounds were as follows: for 1a and 1b, 25% acetonitrile, 0.5% formic acid, and 74.5%
water; for 1b and 1d, 42% acetonitrile, 0.5% formic acid, and 57.5% water; for 1c and 1d,
42% acetonitrile, 0.5% formic acid, 57.5% water; and, for 1c and 1e, 20% acetonitrile
0.5% formic acid 79.5% water. The flow rate was maintained at 1.0 mL/min, and the eluted
compounds were monitored at 254 nm.
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Determination of ratio of oxidation product formation by NMR
The oxidation product of 1a was dissolved in 0.2 mL of DMSO-d6 + 1 drop D2O, and 1H-
NMR measurements were performed. 1b–e were dissolved in 0.2 mL of acetone-d6 + 1
drop D2O and subjected to 1H-NMR measurements. 1H-NMR spectra were recorded on a
JEOL ECA 500 (JEOL, Japan) at 500 MHz and a JEOL ECA 600 (JEOL, Japan) at 600
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MHz. The product ratio was calculated by averaging the integrated values of the peaks
at 5.8–6.3 and 3.7–4.3 ppm (hydrogen atoms in the condensed B-ring) that did not overlap
with other peaks. When compound 1 was used, the integrals with respect to 4 and 5
represent 2H, so the integrated value was divided by 2 to obtain the product ratio. The
NMR data of each oxidation product can be found in the Supplementary Information.
MS spectra instrument
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Mass of all compounds were measured using JMS-700 (JEOL, Japan), AccuTOF
(JEOL, Japan), UPLC-QTOF-MS (Waters Xevo G2 QTOF, Waters, USA).
Compound 1c synthetic methods
A solution of 5-phenoxy-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-benzene crude
in anhydrous THF (12 ml) was added 1M TBAF in THF (1.02 ml) and stirred at room
temperature for 1h in argon conditions. After 1 hour, saturated saline was added, and the
mixture was extracted with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo. After concentration, Column
chromatography (EtOAc/n-hexane = 1:1) gave compound 1c as a white solid (80 mg,
38.8%, 2step).
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1H-NMR (600MHz, acetone-d6) δ (ppm): 7.26 (2H, t, 7.56Hz, C-5’, 7’), 6.96 (2H, d,
7.56Hz, C-4’, 8’), 6.90 (1H, t, 7.56Hz, C-6’), 6.50 (2H, s, C-2), 4.89 (2H, S, C-1’), 13C {1H}
NMR (150MHz, acetone-d6) δ (ppm): 159.8 (C-3’), 146.5 (C-4), 133.2 (C-3, 5), 130.1 (C-
5’, 7’), 129.3 (C-1), 121.3 (C-6’), 115.6 (C-4’ 8’), 107.6 (C-2), 70.3 (C-1), LCMS (ESI) m/z
: calcd for C13H12O4 231.0657 ; Found 231.0629 (M-H)-
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Compound 1d synthetic methods
A solution of 5-(3-phenoxypropyl)-1,2,3-tris(phenylmethoxy)-benzene (360 mg, 0.68
mmol) in MeOH/CH2Cl2 = 1:1 (1 ml) was added 10% Pd/C (36 mg) and stirred at room
temperature for 1h30min under conditions filled with hydrogen. After the reaction was
completed, the mixed solution was filtered through Celite to remove 10% Pd/C and
concentrated in vacuo. After concentration, Column chromatography (EtOAc/n-hexane =
2:3) gave compound 1d as a white solid (120 mg, 68.0%).
1H-NMR (500MHz, acetone-d6) δ (ppm): 7.26 (2H, t, 7Hz, C-7’, 9’), 6.92-6.89 (3H, m,
C-6’, 8’, 10’), 6.28 (2H, s, C-2, 6), 3.96 (2H, t, 6.5Hz, C-3’), 2.59 (2H, t, 7.5Hz, C-1’), 2.02-
1.97 (2H, m, C-2’), 13C {1H} NMR (125MHz, acetone-d6) δ (ppm):160.0 (C-5’), 146.6 (C-
3), 133.6 (C-1), 131.6 (C-4), 130.2 (C-7’, 9’), 121.2 (C-6’, 10’), 115.3 (C-8’), 108.1 (C-2,
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6), 67.5 (C-3’), 32.3 (C-1’), 31.8 (C-2’), LCMS (ESI) m/z : calcd for C15H16O4 259.0970 ;
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Found 259.0925 (M-H)-
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NMR chemical shift values and MS values of oxidation products of each model compound
4a: white solid 1H-NMR (600MHz, d6-DMSO) δ (ppm): 7.02 (2H, s, OH) 6.23 (2H, s, C-
6), 3.48 (2H, s, C-2), 2.20 (6H, s, C-7), 13C {1H} NMR (150MHz, d6-DMSO) δ (ppm): 198.6
(C-3), 193.8 (C-5), 161.8 (C-1), 126.0 (C-6), 88.3 (C-4), 62.6 (C-2), 25.5 (C-7), LCMS
(ESI) m/z : calcd for C14H12O6 275.0556 ; Found 275.0518 (M-H) –
5a: yellow solid 1H-NMR (600MHz, d4-MeOD) δ (ppm): 6.01 (2H, s, C-6), 3.02 (2H, s,
C-2), 1.89 (6H, s, C-7), 13C {1H} NMR (150MHz, d4-MeOD) δ (ppm): 197.5 (C-5), 160.2
(C-1), 128.3 (C-6), 105.3 (C-3), 85.9 (C-4), 65.6 (C-2), 24.7 (C-7), LCMS (ESI) m/z : calcd
for C14H14O7 293.0661 Found 293.0689 (M-H)-
1
6a: white solid H-NMR (600MHz, d4-MeOD) δ (ppm): 6.30 (1H, s, C-6’), 5.87 (1H, s,
C-6), 3.75 (1H, s, C-2), 2.31 (3H, s, C-7’), 2.08 (3H, s, C-7), 13C {1H} NMR (150MHz, d4-
MeOD) δ (ppm): 193.0 (C-5), 167.2 (C-1), 146.1 (C-5’), 143.2 (C-3’), 132.0 (C-4’), 126.2
(C-1’), 122.4 (C-6), 114.4 (C-6’), 111.1 (C-2’), 96.4 (C-4), 92.0 (C-3), 49.8 (C-2), 24.2 (C-
7), 19.0 (C-7’), LCMS (ESI) m/z : calcd for C14H14O7 293.0661 Found 293.0689 (M-H)-
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4b: white solid 1H-NMR (600MHz, d6-acetone) δ (ppm): 7.28-7.18 (10H, m, C-3’~8’),
6.19 (2H, s, C-5), 5.78 (2H, s, OH), 3.64 (2H, s, C-2), 3.06-2.83 (8H, m, C1’, 2’), 13C {1H}
NMR (150MHz, acetone-d6) δ (ppm): 197.8 (C-3), 193.8 (C-5), 165.1 (C-1), 141.2 (C-3’),
129.3 (C-5’), 129.2 (C-4’), 127.0 (C-6’), 126.1 (C-6), 89.7 (C-4), 63.2 (C-2), 40.6 (C-1’),
33.3 (C-2’), LCMS (ESI) m/z : calcd for C28H24O6 457.1651 Found 457.1628 (M+H)+
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1
5b: yellow solid H-NMR (600MHz, d6-acetone) δ (ppm): 7.31-7.12 (10H, m, C-3’~8’),
5.97 (2H, s, C-6), 3.24 (2H, s, C-2), 3.02-2.84 (2H, m, C1’, 2’), 2.67-2.61 (2H, m, C1’, 2’),
13
2.51-2.35 (4H, m, C1’, 2’), C {1H} NMR (150MHz, acetone- d6) δ (ppm): 195.7 (C-5),
160.9 (C-1), 140.2 (C-3’), 128.0 (C-5’), 127.6 (C-4’), 125.8 (C-6’), 125.7 (C-6), 103.6 (C-
3), 84.5 (C-4), 62.7 (C-2), 37.9 (C-1’), 31.5 (C-2’), LCMS (ESI) m/z : calcd for C28H26O7
513.1316 Found 513.1326 (M+K)+
1
6b: white solid H-NMR (600MHz, d6-acetone) δ (ppm): 7.28-7.14 (10H, m, C-3’’~8’’,
C3’’’~8’’’), 6.48 (1H, s, C-6’), 5.92 (1H, s, C-6), 4.09 (1H, s, C-2), 3.09-2.95 (2H, m, C1’,
2’), 2.85-2.60 (6H, m, C1’, 2’), 13C {1H} NMR (150MHz, acetone- d6) δ (ppm): 192.2 (C-5),
168.2 (C-1), 145.7 (C-4’), 142.7 (C-3’’,C-3’’’), 141.4 (C-1’), 131.7 (C-5’), 129.6 (C-3’),
129.0, 128.9, 128.8, 126.8, 126.5, 126.1(C-4’’~8’’, C-4’’’ ~8’’’), 120.9 (C-6), 113.6 (C-2’),
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109.6 (C-6’), 96.0 (C-4), 91.7 (C-3), 47.6 (C-2), 38.6 (C-1’’), 38.3 (C-2’’’), 35.3 (C-1’’’),
33.3 (C-2’’), LCMS (ESI) m/z : calcd for C28H26O7 513.1316 Found 513.1326 (M+K)+
4c: white solid 1H-NMR (600MHz, d6-acetone) δ (ppm): 7.32 (4H, dd, 7.56Hz, 8.22Hz,
C-5’), 7.05 (4H, d, 8.22Hz, C-4’), 6.99 (2H, t, 7.56Hz, C-6’), 6.42 (2H, s, C-6) 5.28-5.25
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(1H, d, 2.04Hz, C-1’), 5.05-5.02 (1H, d, 2.04Hz, C-1’), 3.76(2H, s, C-2), C {1H} NMR
(150MHz, acetone- d6) δ (ppm): 196.9 (C-3), 193.1 (C-5), 160.0 (C-1), 158.5 (C-3’), 130.5
(C-5’), 124.4 (C-6), 122.4 (C-4’), 115.6 (C-6’), 89.8 (C-4), 69.9 (C-1’), 60.1 (C-2), LCMS
(ESI) m/z : calcd for C26H20O8 459.1080 Found 459.1103 (M-H)-
6c: white solid 1H-NMR (600MHz, d6-acetone) δ (ppm): 7.28 (2H, dd, 7.56Hz, 8.22Hz,
C-5’’), 7.18 (2H, dd, 7.56Hz, 8.22Hz, C-5’’’), 6.99 (2H, d, 7.56Hz, C-4’’ ), 6.97 (1H, t,
7.56Hz, C-4’’’ ), 6.93 (1H, t, 7.56Hz, C-6’’), 6.80 (2H, d, 8.28Hz, C-6’’’), 6.70 (1H, s, C-6’),
6.23 (1H, s, C-6), 5.13 (1H, d, 10.32Hz, C-1’), 5.04 (1H, d, 10.98Hz, C-1’’), 4.99 (1H, d,
1.38Hz, C-1”’), 4.84 (1H, dd, 1.38Hz, 16.44Hz, C-1’’’), 4.19 (1H,s, C-2), 13C {1H} NMR
(150MHz, acetone- d6) δ (ppm): 191.4 (C-5), 163.2 (C-1), 159.6 (C-3’’), 158.6 (C-3’’’),
146.3 (C-5’), 143.0 (C-1’), 133.8 (C-4’), 130.3 (C-5’’,7’’, 5’’’, 7’’’), 125.1 (C-3’), 122.0 (C-
6’’’), 120.1 (C-6’’), 120.0 (C-6), 115.6 (C-4’’, 8’’), 115.4 (C-4’’’, 8’’’), 114.6 (C-2’), 111.1 (C-
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6’), 96.6 (C-4), 91.9 (C-3), 68.3 (C-1’’), 67.6 (C-1’’’), 44.9 (C-2), LCMS (ESI) m/z : calcd
for C26H22O9 477.1161 Found 477.1161 (M-H)-
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4d: white solid 1H-NMR (600MHz, d6-acetone) δ (ppm): 7.26 (4H, t, 7.8Hz, C-7’, 9), 6.91
(6H, m, C-6’, 8’, 10’), 6.27 (2H, s, C-6), 4.03 (2H, t, 6Hz, C-3’), 3.66 (1H, s, C-2), 2.95-
2.80 (2H, m, C-1’), 2.18-2.00 (2H, m, C-2’), 13C {1H} NMR (150MHz, acetone- d6) δ (ppm):
198.1 (C-5), 193.9 (C-3), 165.5 (C-1), 159.8 (C-5’), 130.2 (C-7’), 125.9 (C-6), 121.4(C-6’),
115.3 (C-8’), 89.8 (C-4), 67.5 (C-3’), 63.2 (C-2), 35.9 (C-1’), 27.1 (C-2’), LCMS (ESI) m/z
: calcd for C30H28O8 515.1706 Found 515.1726 (M-H)-
6d: white solid 1H-NMR (600MHz, d6-acetone) δ (ppm): 7.24 (4H, t, 9Hz, C-7’, 9’), 6.95
(2H, d, 9.6Hz, C-8’), 6.90 (4H, d, 7.2Hz, 6’, 8’), 6.43 (1H, s, C-6’), 5.94 (1H, s, 6), 4.15-
3.95 (5H, m, C-2, C-3’’ ), 3.03-2.97 (1H, m, C-3’’, 3’’’), 2.72-2.66 (1H, m, C-3’’, 3’’’), 2.62-
2.57 (1H, m, C-3’’, 3’’’), 2.57-2.50 (1H, m, C-3’’, 3’’’), 2.19-2.02 (4H,m, C-2’’,2’’’), 13C {1H}
NMR (150MHz, acetone- d6) δ (ppm): 191.8 (C-5), 168.8 (C-6), 160.1 (C-5’’), 159.9 (C-
5’’’), 146.1 (C-6’), 143.0 (C-4’), 131.8 (C-5’), 130.3 (C-7’’, 9’’, 7’’’, 9’’’), 121.3 (C-6’’, 10’’
,6’’’, 10’’’), 115.4 (C-8’’,8’’’), 114.1 (C-2’), 109.7 (C-6’), 96.1 (C-4), 92.1 (C-3), 67.7 (C-3’’’),
67.3 (C-3’’), 47.7 (C-2), 33.2 (C-2’’’), 32.2 (C-1’’’), 29.3 (C-1’’) 27.3 (C-2’’), LCMS (ESI)
m/z : calcd for C30H30O9 533.1812 Found 533.1824 (M-H)-
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The Journal of Organic Chemistry
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Computational details
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CONFLEX 8 Rev.C (CONFLEX, Japan) was used to search the conformations of 1a–e
and the intermediates and products formed by their oxidative condensation.28,29 After
conformational searching using the MMFF94s force field, many initial conformers were
identified. All stable conformers with a population of over 1% were chosen. Selected
conformers were optimized in the gas phase using the semi-empirical PM6 method in
Gaussian16W (Gaussian, Japan).30-34 Next, the minimum energy conformer calculated
using the PM6 method was optimized in water using the polarizable continuum model at
the B3LYP/6-31G** level of theory in Gaussian16W. To determine that the optimized
reactants, intermediates, and products were true minima, frequency calculations at the
same level of theory as the optimization calculations were carried out. Finally, using the
obtained data, the thermodynamic parameters were obtained.
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ASSOCIATED CONTENT
Supporting Information
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