Unusual transformation of 4-hydroxy/methoxybenzylic alcohols via C[sbnd]C ipso-substitution reaction using proton-exchanged montmorillonite as media

Article abstract of DOI:10.1016/j.tetlet.2020.152584

We present here proton-exchanged montmorillonite-mediated an unusual transformation of 4-hydroxy and 4-methoxybenzylic alcohols to form symmetrical benzylic ethers and diarylmethanes under mild conditions. Nuclear magnetic resonance spectroscopy and density functional theory calculations support a plausible mechanism, which includes a distinctive aromatic C[sbnd]C ipso-substitution reaction with a hydroxymethyl group as the C-based leaving group.

Full text of DOI:10.1016/j.tetlet.2020.152584

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Unusual transformation of 4-hydroxy/methoxybenzylic alcohols via C-C ipso-
substitution reaction using proton-exchanged montmorillonite as media
Xuan Chen, Yangfang Yun, Zezhong Dong, Yu Zhou, Fei Li, Nan Jiang,
Dongyin Chen
PII:
S0040-4039(20)31083-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152584
TETL 152584
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 August 2020
7 October 2020
18 October 2020
Please cite this article as: Chen, X., Yun, Y., Dong, Z., Zhou, Y., Li, F., Jiang, N., Chen, D., Unusual
transformation of 4-hydroxy/methoxybenzylic alcohols via C-C ipso-substitution reaction using proton-
exchanged montmorillonite as media, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152584
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Unusual transformation of 4-
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hydroxy/methoxybenzylic alcohols via C-C
ipso-substitution reaction using proton-
exchanged montmorillonite as media
Xuan Chen, Yangfang Yun, Zezhong Dong, Yu Zhou, Fei Li, Nan Jiang* and Dongyin Chen*
R1
R1
OR2
R1
R2O
R1
H-mont
OR2
R1
R1
O
Etherification
Path b
Path a
H
O
H
H
H
H2O
R1
R2O
R1
R2O
R1
OR2
R1
OH
HCH
C-C
O
R1
R1
substitutio
ipso
R1
R1
R1 = H, Me, i-Pr, t-Bu
R2 = H, Me
n
R2O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Unusual transformation of 4-hydroxy/methoxybenzylic alcohols via C-C ipso-
substitution reaction using proton-exchanged montmorillonite as media
Xuan Chena,‡, Yangfang Yuna,‡, Zezhong Donga, Yu Zhoua, Fei Lia, Nan Jianga,* and Dongyin Chena,b,
a Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. E-mail address: jiangnan@njmu.edu.cn (N. Jiang), chendongyin@njmu.edu.cn (D. Chen).
‡ These authors contributed equally to this work.
Article history:
Received
We present here proton-exchanged montmorillonite-mediated an unusual transformation of 4-
hydroxy and 4-methoxybenzylic alcohols to form symmetrical benzylic ethers and
Received in revised form
Accepted
Available online
diarylmethanes under mild conditions. Nuclear magnetic resonance spectroscopy and density
functional theory calculations support a plausible mechanism, which includes a distinctive
aromatic C-C ipso-substitution reaction with a hydroxymethyl group as the C-based leaving
group.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Proton-exchanged montmorillonite
Aromatic C-C ipso-substitution
Benzylic alcohol
Diarylmethane
Density functional theory
polymerization reaction [15]. As part of our ongoing research in
our laboratory, we first reported H-mont-mediated substrate
1. Introduction
Aromatic carbon-carbon ipso-substitution reaction is
a
specific double-bond isomerization [16], selective deprotection of
p-methoxybenzyl esters/ethers [17], and synthesis of heterocycle-
containing diarylmethanes via Friedel–Crafts alkylation reaction
[18]. Herein, we report H-mont-mediated transformation of 4-
hydroxy and 4-methoxybenzylic alcohols to form symmetrical
benzylic ethers and diarylmethanes under mild conditions.
Nuclear magnetic resonance (NMR) spectroscopy and density
functional theory (DFT) calculations are carried out to investigate
the mechanism. An unusual type of aromatic C-C ipso-
substitution reaction with a hydroxymethyl group as the C-based
leaving group is firstly described in detail.
particular case of electrophilic aromatic substitution (EAS)
reaction [1], which is commonly used to prepare alkyl- [2], vinyl-
[3], alkynyl- [4], biphenyl-
and carbonyl-
substituted
[5]
[6]
aromatics. As shown in Scheme 1, the most important
characteristic of this reaction is that a new Ar‒C bonding takes
place upon the attack of a carbon-based electrophile on the
aromatic compound, producing a cyclohexadienyl cation as the
intermediate of EAS along with a new Ar-C bond formation at
the expense of another Ar-C bond [1c]. The most generally used
C-based leaving groups include alkyl [6], carbinol [5], CN
,
[2,4]
[3,7]
carbonyl
groups in this ipso-substitution reaction. In order to
expand the range of application of this reaction, further studies
are still required to explore the diversity of leaving groups. On
the other hand, almost all these aromatic C-C ipso-substitution
reactions are catalyzed by transition-metal salts [8], Lewis acids [9]
and strong proton acids [10], but heterogeneous solid acid-
2. Results and discussion
During the past two decades, a series of similar experiments
and theoretical model have been performed on the formation of
both cyclic and linear oligomers of benzyl alcohol derivatives
with bentonite or proton acid [19]. In this thesis, we present an
unusual transformation of 4-hydroxy and 4-methoxybenzylic
alcohol derivatives to form symmetrical benzylic ethers and
diarylmethanes using H-mont as media (Table 1). Under the H-
mont-mediated reaction condition, benzylic alcohol derivatives
1a-1c and 1f-1h are rapidly transformed to the corresponding
symmetrical diarylmethanes 2a-2c and benzylic ethers 3f-3h,
respectively (Table 1, entries 1-3 and 6-8). When using benzylic
derivatives 1d-1e and 1i-1j as substrates, the desired products are
rarely produced, together with some unidentified cyclic and
linear oligomers (Table 1, entries 4-5 and 9-10). A closer
inspection of the results reveals that para- and meta-substituents
on the aromatic ring of these benzylic alcohols plays an
important role on the reaction rate, product ratio and yield. With
a hydroxy group in the para-position and two symmetric
mediated this transformation has received very little attention [11]
.
Therefore, more extensive exploration on this interesting reaction
is a very attractive but challenging task.
X
E
X
E
-X+
E
R
R
R
X = C-based leaving group ( alkyl, carbinol, CN, carbonyl, etc.)
E+ = C-based electrophile
Scheme 1. General mechanism of aromatic C-C ipso-substitution
reaction.
As
a
heterogeneous solid acid, proton-exchanged
montmorillonites (H-mont) has recently received much attention
due to its successful application in the carbosilylation reaction [12]
,
[14]
nucleophilic substitution reaction [13], addition reaction
and

2
Tetrahedron Letters
hindering alkyl groups in the meta-positions, the reaction
5
3g
3h
3j
i-Pr
Me
H
Me
Me
Me
76 (2g)
33 (2h)
12 (2j)
14
6
proceeds rapidly to give the corresponding diarylmethanes in 94-
96% yields, together with trace amounts of symmetrical benzylic
ethers (Table 1, entries 1-3). In contrast, with a methoxy group in
the para-position and two symmetric hindering alkyl groups in
the meta-positions, the benzylic ethers are the major products in
32-83% yields, while the diarylmethanes are obtained in only 11-
19% yields after the consumption of starting materials (Table 1,
entries 6-8). However, with hydrogen or methoxy groups in the
6c
7c
9.5
a
Reaction conditions: each substrate (0.366 mmol), H-mont (260
mg), CH2Cl2 (3 mL), 25 oC.
b Isolated yield.
c The linear and cyclic oligomers are the main byproduct.
two meta-positions, the cyclic and linear oligomers are the main
[19]
products as similarly described in previous research
entries 4-5 and 9-10).
(Table 1,
To investigate the reaction process, NMR technique was
utilized to monitor the conversion of 1a to 2a and 3a. As shown
in Fig. 1, the signal around 4.58 ppm is corresponding to the CH2
protons of 1a (Fig. 1a). After H-mont added to trigger this
Table 1 H-mont-mediated transformation of 4-hydroxy and 4-
methoxybenzylic alcohol derivatives.a
R1
R1
R2O
R1
R1
R2O
R1
1
(m)
reaction, the appearance of two new resonances in the H NMR
OH
O
H-mont
CH2Cl2, 25 o
+
(p)
R2O
OR2
OR2
spectrum around 3.83 and 4.45 ppm (Fig. 1b and 1c), are
corresponding to the CH2 protons of 2a and CH2OCH2 protons of
3a, respectively, which indicates the transformation of 1a into 2a
and 3a. As the reaction goes on, the signal of 4.45 ppm increases
to a peak then decreases until it disappeares completely.
Meanwhile, the signal of 3.83 ppm increases. It illustrates the
conversion of benzylic ethers 3a to diarylmethanes 2a under the
H-mont-mediated reaction condition. Moreover, a significant
signal around 9.72 ppm is observed (Fig. 1d and 1e), which is
possible to indicate the formation of aldehyde compounds.
C
R1
R1
R1
R1
R1
2
1
3
Time
(h)
Yield of
2 (%)b
96 (2a)
96 (2b)
94 (2c)
0 (2d)
Yield of
3 (%)b
Entry
Comp.
R1
R2
1
2
1a
1b
1c
1d
1e
1f
t-Bu
i-Pr
Me
H
H
0.67
0.83
0.5
0.5
5
0.67
1.5
2
trace (3a)
trace (3b)
trace (3c)
0 (3d)
3
H
4c
5c
6
OMe
H
H
H
5 (2e)
0 (3e)
t-Bu
i-Pr
Me
OMe
H
Me
Me
Me
Me
Me
11 (2f)
19 (2g)
11 (2h)
0 (2i)
83 (3f)
65 (3g)
32 (3h)
6 (3i)
In order to elucidate these observations described above, a
plausible mechanism is proposed as shown in Scheme 2. With 4-
hydroxybenzylic alcohol 1c as an example, it receives a proton
from H-mont to form p-quinone methide Ⅰ by losing a molecular
of H2O. Due to the p-hydroxy group as a secondary driving force
through electron delocalization, this process is easy and fast to
accomplish. The p-quinone methide Ⅰ is a strong electrophilic
species, which can be attacked by two different nucleophilic sites
of another benzylic alcohol 1c as shown in Scheme 2. It's worth
noting that the symmetrical benzylic ether 3c generates more
easily than the diarylmethane 2c in the early stage of this process.
To illustrate this phenomenon, density functional theory (DFT) at
B3LYP/6‒31G(d,p) level was employed to investigate and
compare the two possible reaction pathways in dichloromethane
(DCM) solvation. Fig. 3 exhibits the free energy variation along
the reaction pathway by using the energy sum of reactants
(benzylic alcohol 1c + p-quinone methide I) as a reference to
make the next transformation steps share an energy scale. The
theoretically calculated results are consistent with the
experimental phenomenon. The electrophilic p-quinone methide I
is attacked more easily by the oxygen atom of hydroxy group
(light blue) to give the symmetrical benzylic ether 3c (Scheme 2,
path a), and the energy barrier is 18.98 kcal/mol. In comparison,
the electrophilic I attacked by the carbon atom of benzene ring
(pink) is more slowly, to generate the cyclohexadienyl cation II
with a new Ar-C bond formation (Scheme 2, path b), and the
energy barrier is 27.84 kcal/mol. The structures of transition-state
TS-a and TS-b are shown in Fig. 2. Then, the electron
delocalization on the cyclohexadienyl cation Ⅱ promotes Ar-C
bond cleavage to give 2c with concomitant release of a
formaldehyde molecule, which is successfully captured by NMR
spectroscopy. This is an unusual aromatic C-C ipso substitution
reaction with a hydroxymethyl group as the C-based leaving
group. On the other hand, the oxygen atom that joins both units
as a bridge in 3c is an electronegative center, which can capture a
proton from H-mont. Then, the C-O ether bond cleaves assisting
by p-hydroxy function as the secondary driving force through
electron delocalization in a mild condition. At last, nucleophilic
aromatic carbon (pink) of 1c interacts with electrophilic p-
quinone methide Ⅰ to afford diarylmethane 2c through an unusual
aromatic C-C ipso substitution process. It’s interesting to
investigate the energetic variation with 4-methoxybenzylic
alcohol 1h as substrate. From Fig. S1, it can be seen that the
energy barrier from 1h + Ⅰ’ to 3h + H+ (path a’: 20.25 kcal/mol)
7
1g
1h
1i
8c
9c
10c
8
0.25
1j
12 (2j)
14 (3j)
a
Reaction conditions: each substrate (0.366 mmol), H-mont
(260 mg), CH2Cl2 (3 mL), 25 oC.
b Isolated yield.
c The linear and cyclic oligomers are the main byproducts.
Interestingly, process monitoring of above reactions using thin
layer chromatography (TLC) shows that benzylic ether 3 is
unstable under the H-mont-mediated reaction condition, which
can be converted into the corresponding diarylmethane 2 as the
reaction going on. To further confirm this phenomenon, the
above reactions were terminated by filtering H-mont during the
initial stage of reactions, and then a certain amount of benzylic
ethers 3a-3c, 3f-3h and 3j were prepared by flash
chromatograghy on silica gel. As shown in Table 2, benzylic
ethers 3a-3c and 3f-3g can be readily converted into the
corresponding diarylmethanes 2a-2c and 2f-2g in moderate to
good yields (72%-92%) under the H-mont-mediated reaction
condition. However, due to the generation of linear and cyclic
oligomers, benzylic ethers 3h and 3j can only give the desired
products 2h and 2j in low yields (12%-33%).
Table
2 H-mont-mediated transformation of symmetrical
benzylic ethers 3 into diarylmethanes 2.a
R1
R2O
R1
R1
R2O
R1
H-mont
O
CH2Cl2, 25 o
C
OR2
OR2
R1
R1
R1
R1
3
2
Time
(h)
Yield of 2
Entry
Comp.
R1
R2
(%)b
1
2
3
4
3a
3b
3c
3f
t-Bu
i-Pr
Me
H
H
87 (2a)
92 (2b)
86 (2c)
72 (2f)
0.67
0.83
0.25
9
H
t-Bu
Me

3
is lower than that from 1h + Ⅰ’ to intermediate II’ (path b’: 26.60
kcal/mol). These results indicate that in the case of 4-
methoxybenzylic alcohol as substrate, the kinetic product
formation is preferred, which is consistent with the
experimental phenomenon.
(a)
1a
CH2 of
0 min
(b)
3a
CH2OCH2 of
1 min
(c)
2a
CH2 of
5 min
(d)
20 min
(e)
O
60 min
H
H
Fig. 1 Real-time monitoring of the H-mont-mediated transformation of 1a to 2a and 3a by 1H NMR spectroscopy. Reaction conditions: 1a
o
1
1
(0.366 mmol), H-mont (260 mg), CDCl3 (6 mL), 25 C. (a) H NMR spectrum of 1a in CDCl3 without the addition of H-mont. (b) H NMR
spectrum of reaction mixture at 1.0 min after the addition of H-mont. A molar ratio of 1a:2a:3a is approximately 40:1:9. (c) 1H NMR spectrum
of reaction mixture at 5.0 min after the addition of H-mont. A molar ratio of 1a:2a:3a is approximately 2:2:5. (d) 1H NMR spectrum of reaction
mixture at 20 min after the addition of H-mont. A molar ratio of 1a:2a:3a is approximately 2:11:2. (e) 1H NMR spectrum of reaction mixture at
60 min after the addition of H-mont.
H-mont
Me
HO
Me
OH
H
H
H
H
H-mont
O
Me
HO
Me
Me
H2O
2c
H
H
H
O
Me
1c
H
H
Path a
HO
OH
Me
Me
Me
HO
Me
HO
Me
OH
Me
HO
Me
OH
TS-a
TS-b
O
H
OH
Me
Me
Me
Me
Me
Path b
1c
3c
I
II
Scheme 2. Proposed mechanism for H-mont-mediated transformation of benzylic alcohol 1c.
TS-a
TS-b
Fig. 2 The transition-state structures of TS-a and TS-b at the B3LYP/6-31+G(d,p) level of theory.

4
Tetrahedron
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In summary, we investigate H-mont-mediated transformation
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symmetrical benzylic ethers 3 and diarylmethanes 2 under mild
conditions. It is worth highlighting that benzylic ethers 3 are
unstable under the H-mont-mediated reaction condition, which
could be converted into the corresponding diarylmethanes 2.
NMR spectroscopy and DFT calculations support a mechanistic
scheme involving a novel aromatic C-C ipso-substitution process
with a hydroxymethyl group as the C-based leaving group.
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This work was supported by the National Natural Science
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State Key Laboratory of Natural Medicines (No.
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Experimental procedures, computational details and copies of
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6.
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☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

5
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Unusual transformation of 4-
Leave this area blank for abstract info.
hydroxy/methoxybenzylic alcohols via C-C
ipso-substitution reaction using proton-
exchanged montmorillonite as media
Xuan Chen, Yangfang Yun, Zezhong Dong, Yu Zhou, Fei Li, Nan Jiang* and Dongyin Chen*
R1
R1
OR2
R1
R2O
R1
H-mont
OR2
R1
R1
O
Etherification
Path b
Path a
H
O
H
H
H
H2O
R1
R2O
R1
R2O
R1
OR2
R1
OH
HCH
C-C
O
R1
R1
substitutio
ipso
R1
R1
R1 = H, Me, i-Pr, t-Bu
R2 = H, Me
n
R2O