Efficient dealkylation of aryl alkyl ethers catalyzed by Cu2O

DOI: 10.1016/j.tet.2018.03.070

Source and publish data:

Tetrahedron p. 2447 - 2453 (2018)

Update date:2022-08-10

Topics:

Authors:

Liu, Lingxian

Li, Zengguang

Chen, Changjun

Li, Huanrong

Xu, Lijin

Yu, Zhiyong

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Article abstract of DOI:10.1016/j.tet.2018.03.070

An efficient protocol for dealkylation of aryl alkyl ethers under the catalysis of inexpensive and easily reusable Cu₂O has been described. The phenol products were obtained in high yields, and a range of functional groups were well tolerated. The choice of solvent is critical to the catalysis, and CH₃OH proved to be the optimal choice. Mechanistic investigations showed that this reaction possibly proceeds via a single-electron transfer (SET) process.

Full text of DOI:10.1016/j.tet.2018.03.070

Accepted Manuscript

Efficient dealkylation of aryl alkyl ethers catalyzed by Cu O

Lingxian Liu, Zengguang Li, Changjun Chen, Huanrong Li, Lijin Xu, Zhiyong Yu

PII:

S0040-4020(18)30353-3

10.1016/j.tet.2018.03.070

TET 29410

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 18 January 2018

Revised Date: 22 March 2018

Accepted Date: 29 March 2018

Please cite this article as: Liu L, Li Z, Chen C, Li H, Xu L, Yu Z, Efficient dealkylation of aryl alkyl ethers

catalyzed by Cu O, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.070.

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Efficient Dealkylation of Aryl Alkyl Ethers

Catalyzed by Cu₂O

Leave this area blank for abstract info.

Lingxian Liu^{a, b}, Zengguang Li^b, Changjun Chen^a, Huanrong Li^{a, *}, Lijin Xu^{a, *}and Zhiyong Yu^a

^aDepartment of chemistry, Renmin University of China, Beijing 100872, P. R. China

^bCollege of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

¹Efficient Dealkylation of Aryl Alkyl Ethers Catalyzed by Cu₂O

Lingxian Liu^{a, b}, Zengguang Li^b, Changjun Chen^a, Huanrong Li^{a, *}, Lijin Xu^{a, *}and Zhiyong Yu^a

^aDepartment of chemistry, Renmin University of China, Beijing 100872, P. R. China

^bCollege of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

An efficient protocol for dealkylation of aryl alkyl ethers under the catalysis of inexpensive

and easily reusable Cu₂O has been described. The phenol products were obtained in high

yields, and a range of functional groups were well tolerated. The choice of solvent is critical to

the catalysis, and CH₃OH proved to be the optimal choice. Mechanistic investigations showed

that this reaction possibly proceeds via a single-electron transfer (SET) process.

Available online

Keywords:

Copper(I) oxide

alkyl aryl ethers

dealkylation

single-electron transfer

sodium methanoxide

overstoichiometric amounts of sodium tert-butoxide.^[10a]In

addition, Coe et al. described the application of stoichiometric

sensitive boron trichloride/tetra-n-butylammonium iodide as

combination reagent for the cleavage of primary alkyl aryl ethers

at very low temperature.^[10b]Considering the drawbacks of these

reports and the importance of phenol products, it is desirable to

develop a new and efficient method for selective dealkylation.

Herein, we would like to disclose an efficient copper (I)-

catalyzed deprotection of aryl alkyl ethers to the corresponding

phenol in moderate to excellent yields with high regio-selectivity

and broad functional group tolerabnce.

1. Introduction

The phenol skeleton has been widely observed in a variety of

important functional molecules, including natural products,

pharmaceuticals

and

agrochemicals.^[1]

For

example,

Multisianthol is found in the roots of mutisia homoeantha, and

displays modest activity against the human tumor cell lines SF-

295, HCT-8 and MDA-MB-435 ( Figure1, A );^[2]Aplgenin was

evaluated using mouse edema assay, showing good anti-

infammatory activities ( Figure 1, B );^[3]Dopamine plays an

essential role in the central nervous system by modulating a

variety of brain circuitries (Figure 1, C);^[4]Apomorphine may be

a potential treatment for Parkinson’s disease (Figure 1, D).^[5]

However, a ubiquitous protection group tactic through the

masking of the phenol moiety as its alkyl ethers is used widely

due to sensitive phenolic compounds in organic synthesis.^[6]

Therefore, the development of efficient methods for selective

dealkylation has been the topic of intense research for many

years, and still attracts considerable attention today.^[7]Although

many classical protocols for dealkylation of aryl alkyl ethers are

available, they are often limited by the lack of selectivity, poor

reaction efficiency, the use of sensitive or expensive reagents,

and the formation of undesired side products.^[8]In 2013,

Waghmode and his co-workers found that, in the presence of an

overstoichiometric amount of strong protic acid (47% HBr) and a

catalytic amount of phase-transfer catalyst (Aliqat-336), selective

cleavage of aryl methyl ethers could be achieved rapidly.^[9]In

2015, Loh and co-workers reported an efficient method to

Figure 1.

2. Results and discussion

Because of its low cost and toxicity, copper has been

extensively studied as catalysts in organic synthesis.^[11]Thus, we

set out to investigate the feasibility of copper-catalyzed

selectively dealkylate the alkyl aryl ether bond by using

———

¹Email: hrli@ruc.edu.cn (H. Li); 20050062@ruc.edu.cn (L.Xu)

Tetrahedron

ACCEPTED MANUSCRIPT

dealkylation of aryl alkyl ethers. We first tried the

FeCl₃·6H₂O

CH₃OH

DCE

CH₃ONa

185

demethylation of 1-chloro-2-methoxybenzene (1a) with copper

powder as the catalyst in MeOH at 185 C. To our delight, the

FeCl₂

ZnCl₂

AlCl₃

Cu₂O

none

reaction finished in 12 h, and the corresponding phenol 2a was

isolated in 83 % yield with the C-Cl bond intact (Table 1, entry

1). The yield of 2a could be improved to 96% when Cu₂O was

employed (Table 1, entry 2), but the yield decreased significantly

when the reaction was conducted at lower temperature (Table 1,

entries 5-7). It was noteworthy that no reation took place when

the reaction was carried out using other bases such as Na₂CO₃,

NaOAc, or NaOH (Table 1, entries 8-10). Both CuI and CuBr

also displayed comparable catalytic activity to afford 2a in 95%

yield (Table 1, entries 11-12).Other copper salts, such as Cu₂SO₄,

CuCl₂, CuBr₂, Cu(OH)₂and CuO, could also performed well to

deliver 2a in good yields (Table 1, entries 13-17 ). The desired

product 2a was only produced in low yields when using FeCl₃,

FeCl₃·6H₂O or FeCl₂as the catalysts (Table 1, entries 18-20).

Further optimization showed that other frequently used Lewis

acids, such as ZnCl₂and AlCl₃, displayed no catalytic activities

in this reaction (Table 1, entries 21-22). With Cu₂O as the

catalyst, a screening of different solvents was then carried out to

find the best reaction medium. Although the reaction can proceed

in ethanol and tert-butanol (Table 1, entries 3-4), it revealed that

MeOH is the optimal choice, and the reaction was totally

suppressed in other solvents, including DCE, toluene, THF,

dioxane, CH₃CN, DMF and DMSO (Table 1, entries 23-29). The

control experiment indicated that copper is crucial for this

reaction, and no reaction occurred in its absence (Table 1, entry

30).

toluene

THF

dioxane

CH₃CN

DMF

DMSO

CH₃OH

^aReaction conditions: 1a (1 mmol) , catalyst precursor (5 mol%), solvent (2.0

mL), base (3 equiv.), 12h.

^bIsolated yield. NR: No Reaction.

With the optimal reaction conditions in hand, dealkylation of a

wide variety of aryl alkyl ethers was explored. As shown in Table

2, both the substituted aryl methyl ethers (1b-1q) and aryl ethyl

ethers (1r-1v) underwent easy cleavage regardless of their

substitution pattern, delivering the corresponding phenols in good

to excellent yields. However, cleaving long chain alkyl ethers

proved to be difficult (1r-1v). No reaction occurred with both β–

ethoxynaphthalene (1v) and β–naphthol butyl ether (1z’) (Table 2,

entries 21 and 26). These results clearly demonstrated that the

current transformation is selective towards the cleavage of alkyl

C-O bonds. It is notable that a variety of functional groups

including Cl, Br, F, NO₂, CH₃CO-, -CHO, CN and -COOEt were

well compatible with this reaction (Table 2, entries 3-10). It

could be observed that the electronic nature of the substituents

showed no substantial effect to the reaction efficiency (Table 2,

entries 1-10). But the reaction is sensitive to the steric hindrance

as the bulky substrates gave lower yields (Table 2, entries 12-13).

Table 1

Optimization of reaction conditions. ^a

Entry

Catalyst

Solvent

CH₃OH

C₂H₅OH

t-BuOH

CH₃OH

Base

Temp.(^oC)

185

180

175

170

185

Yield(%)^[b]

CH₃ONa

Na₂CO₃

NaOAc

Cu₂O

CuBr

CuI

With an aim to demonstrate the general applicability of the

current catalytic system, we then turned our attention to the

selective dealkylation of polyalkylated aryl ethers. As shown in

Table 3, only the monodemethylated phenolic products were

generated under the standard reaction conditions (Table 3, entries

1, 3 and 5). When increasing the base loading to 6 equiv., a

mixture of the separable mono-demethylated phenolic product

and complete demethylated phenolic product could be isolated in

good yields (Table 3, entries 2, 4 and 6). Substrate 3d underwent

dealkylation to give the corresponding products, 4d and 4c’, in

low yields (Table 3, entries 7 and 8), but cleaving long chain

alkyl ethers, such as 1,2-diethoxybenzene, 1,2-dibutoxybenzene

and 1,4-dibutoxybenzene, failed. In the case of substrate 3e, only

monodemethylated phenolic product 4e was produced in a good

yield in the presence of 3 equiv. of base (Table 3, entry 9).

Increasing the base loading to 6 equiv. still resulted in the

exclusive formation of 4e in almost the same yield. In contrast,

subjecting 1,2,3-trimethoxybenzene to Loh’s reaction conditions

led to the generation of a mixture of 2,3-dimethoxy phenol (63%)

and 2,6-dimethoxy phenol (27%).^[10a]It’s of great interest that

the method can distinguish between different alkyl groups in the

same molecule (Table 3, entry 10).

NaOH

CH₃ONa

CuSO₄

CuCl₂

CuBr₂

Cu(OH)₂

CuO

Table 2

Dealkylation of alkyl aryl ethers.^a

FeCl₃

OR¹

ACCEPTED MANUSCRIPT

Reaction conditions: 1 (1 mmol) , Cu₂O (5 mol%), CH₃OH (2.0 mL),

CH₃ONa (3 equiv.), 185 °C, 12 h.

Cu₂O (5 mol%)/CH₃ONa (3.0 equiv.)

CH₃OH, 185 ^oC, 12 h

R²

^bIsolated yield.

Entry

Substrate

Product

Yield(%)

Table 3

Selective dealkylation of alkyl aryl ethers ^a

OR¹

OMe

Cu₂O (5 mol%)/CH₃ONa (3.0/6.0 equiv.)

CH₃OH, 185 ^oC, 12 h

OMe

OR²

Entry

Substrate

OMe

Product

OMe

1^a

OMe

, 74%

O₂N

OMe

2^b

OMe

, 53%

4a'

, 41%

OHC

OMe

3^a

OMe

, 83%

OMe

EtOOC

NO₂

4^b

OMe

, 50%

4b'

, 43%

OMe

5^a

MeO

EtO

MeO

OMe

, 88%

6^b

7^a

4c', 49%

OMe

4c, 43%

MeO

EtO

OMe

OEt

, 45%

OMe

8^b

EtO

OEt

, 30%

4c'

, 25%

MeO

BuO

MeO

BuO

9^a,b

, 86% (88%)

OEt

10^a

OMe

4f, 84%

^aReaction conditions: 3 (1 mmol) , Cu₂O (5 mol%), CH₃OH (2.0 mL),

CH₃ONa (3 equiv.),185 °C, 12 h.

OEt

^bReaction conditions: 3 (1 mmol) , Cu₂O (5 mol%), CH₃OH (2.0 mL),

CH₃ONa (6 equiv.),185 °C, 12 h.

O₂N

OEt

O₂N

^cIsolated yield.

In addition, to further demonstrate the synthetic utilities of this

protocol, we carried out the demethylation of bioactive estradiol

3-methyl ether (5a) under the standard conditions, and the

corresponding product estradiol (6a) was obatined in 92% yield

(Scheme1).

OBu

O₂N

OBu

O₂N

Scheme 1. Synthetic utilities for bioactive molecule.

1z'

Tetrahedron

ACCEPTED MANUSCRIPT

From the point view of green chemistry, the ability to recover

specie C and the radical B. The radical anion transfer from the

and reuse the catalyst should be taken into account. The

demethylation of 1-chloro-2-methoxybenzene (1a) with 5%

Cu₂O as the catalyst was then carried out in MeOH at 185 ^oC for

12 h in the presence of three equiv. of NaOMe. After the

experiment, Cu₂O catalyst was removed from the reaction

mixture by simple filtration, washed with methanol, dried at 100

ºC under vacuum for 1 h, then reused in further experiments

under the same conditions to those of the first run. It was found

that the Cu₂O catalyst could be recovered and reused at least

eight times in the reaction, and a conversion of 87% was still

obtained for the transformation in the eighth run (Figure 2).

specie C results in the formation of the intermediate D. The

intermediate D then undergoes scission of the radical anion,

delivering radical E and anion F, both of which are further

transformed to G and 2, respectively.

3. Conclusions

In conclusion, we have developed an efficient protocol for

selective dealkylation of aryl alkyl ethers into the corresponding

phenols under the catalysis of cheap and reusable Cu₂O. This

simple and general protocol tolerates a number of functional

groups, and is expected to be useful in organic synthesis. Further

study on the application of this protocol to the synthesis of

complex molecules is underway in our laboratory.

4. Experimental section

4.1. General

Unless otherwise noted, all the reactions were carried out in a

hydrothermal synthesis reactor with PTFE lining, and all

commercially available chemicals were used as received from

Aladdin, Sinopharm Chemical Reagent limited corporation or

Strem without further purification. ¹H NMR and ¹³C NMR

spectra were recorded on a Bruker Model Advance DMX 400 or

600 Spectrometer (¹H 400 MHz and ¹³C 100.6 MHz or H 600

MHz and ¹³C 150.9 MHz, respectively). Chemical shifts (δ) are

given in ppm and are referenced to residual solvent peaks, and

coupling constants (J) were reported in Hertz. GC/MS spectra

were recorded on a Thermo Trace DSQ II gas chromatography-

mass spectrometry instrument.

Figure 2. Catalyst recycling studies.

Next, the mechanism of this reaction was studied. To explore

whether this reaction involves the formation of free radical

species, radical trapping experiments with benzoquinone (BQ),

and 2, 6-tri-tert-butylphenol (2,6-DTBP) were conducted

(Scheme 2). The reaction was totally inhibited upon the addition

of 2.5 equiv. of BQ and 2,6-DTBP (Scheme 2, 1b and 1c).

4.2. General procedures for the reactions of dealkylation

of alkyl aryl ethers

To an oven-dried 25 mL hydrothermal synthesis reactor with

PTFE lining were sequentially added 1 (1 mmol), CH₃ONa (162

mg, 3 mmol), Cu₂O (7.16 mg, 5 mol%), and CH₃OH (2 mL) were

added. The hydrothermal synthesis reactor was sealed and placed

in an air blowing thermostatic oven set at specified temperature

for 12 h. Then the mixture was cooled to room temperature,

acidified to pH 4-5 with 4 M hydrochloric acid and diluted with

water (5 mL) to get a clear solution, extracted with ether (3X10.0

mL). The combined organic layers were dried (anhydrous

Na₂SO₄) and concentrated under reduced pressure, and the

residue was purified by column chromatography on silica gel

using a mixture of petroleum ether and ethyl acetate to give the

pure product.

OMe

Cu₂O (5 mol%)/CH₃ONa (3.0 equiv.)

(1b)

CH₃OH, 185 ^oC, 12 h

Benzoquinone, 2.5 eq.

OMe

Cu₂O (5 mol%)/CH₃ONa (3.0 equiv.)

(1c)

CH₃OH, 185 ^oC, 12 h

2,6-DTBP, 2.5 eq.

Scheme 2. The radical trapping experiments with benzoquinone and 2,6-

DTBP.

OR¹

4.2.1 2-chlorophenol (2a). Light yellow liquid, H NMR (400

MHz, CDCl₃) δ 7.30 (d, J=9.4 Hz, 1 H), 7.15 (t, J=7.8 Hz,1 H),

work-up

R²

6.99 (d, J=6.9 Hz, 1 H), 6.84 (t, J=7.7 Hz, 1 H), 5.30 (s, 1 H); ¹³

NMR (100.6 MHz, CDCl₃) δ 151.42, 129.14, 128.46, 121.47,

120.02, 116.43; HRMS (ESI) calcd. for C₆H₅ClO [M+Na]⁺:

150.9927, found: 150.9924.

R¹

[Cu₂O]

Cu₂O

+ B

4.2.2 Phenol (2b).White solid, mp: 41-43 °C, H NMR (600

CH₃OR¹

MHz, CDCl₃) δ 7.21 (t, J=7.9, 2 H), 6.92 (t, J=7.4,1 H) 6.85-6.79

(m, 2 H), 5.79 (s, 1 H); ¹³C NMR (150.9 MHz, CDCl3) δ 155.37,

129.75, 120.94, 115.40; HRMS (ESI) calcd. for C₆H₆O [M+Na]⁺:

117.0316, found: 117.0310.

CH₃O^-

CH₃O

Scheme 3. The proposed reaction mechanism.

4.2.3 4-Methylphenol (2c). White solid, mp: 33-35 °C; ¹H NMR

(600 MHz, CDCl₃) δ 6.99 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.4 Hz,

2H), 5.21 (s, 1H), 2.24 (s, 3H); ¹³C NMR (150.9 MHz, CDCl₃)

δ153.10, 130.16, 115.32, 20.50; HRMS (ESI) calcd. for C₇H₈O

[M+Na]⁺:131.0413, found: 131.0409.

Based on our mechanistic investigation and previous

reports,^{[8m, 10a]}a preliminary description of proposed mechanism

can be revealed in Scheme 3. It is believed that this reaction goes

through a single-electron transfer (SET) to generate the radical

anion. The reaction of Cu₂O with anion CH₃O^-(A) generates

4.2.4 4-chlorophenol (2d). White solid, mp: 43-44 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.20-7.15 (m, 2H), 6.79-6.72 (m, 2H), 5.57

(s,1H);¹³C NMR (100.6 MHz, CDCl₃) δ 153.78, 129.59, 125.89,

116.72; HRMS (ESI) calcd. for C₆H₅ClO [M+Na]⁺: 150.9927,

found: 150.9921.

4.2.5 4-bromophenol (2e). White solid, mp: 64-66 °C; ¹H NMR

(600 MHz, CDCl₃) δ 7.33 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz,

2H), 5.01 (s, 1H); ¹³C NMR (150.9 MHz, CDCl₃) δ 154.58,

132.51, 117.23, 112.96; HRMS (ESI) calcd. for C₆H₅BrO

[M+Na]⁺: 194.9421, found: 194.9352.

4.2.6 4-fluorophenol (2f). White solid, mp: 44-46 °C; ¹H NMR

(400 MHz, CDCl₃) δ 6.95-6.88 (m, 2H), 6.81-6.74 (m, 2H), 5.82

(d, J=3.6 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 157.40,

151.11, 116.31, 116.17; HRMS (ESI) calcd. for C₆H₅FO

[M+Na]⁺: 135.0222, found: 135.0187.

7.37 (m, 3H), 7.29-7.17 (m, 1H), 6.76-6.69 (m, 1H), 5.46 (s,

ACCEPTED MANUSCRIPT

1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 151.3, 134.82, 127.75,

126.50, 125.90, 125.36, 124.44, 121.54, 120.81, 108.81; HRMS

(ESI) calcd. for C₁₀H₈O[M+Na]⁺: 167.0472, found: 167.0421.

4.2.16 2-Naphthol (2p). White solid, mp: 120-121 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.74 (t, J=8.6 Hz, 2H), 7.65 (d, J=8.2 Hz,

1H), 7.41 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.31 (ddd, J=8.1, 6.9, 1.2

Hz, 1H), 7.12 (d, J=2.5 Hz,1H), 7.08 (dd, J=8.8, 2.5 Hz, 1H),

5.19 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 153.27, 134.58,

129.84, 128.96, 127.75, 126.52, 126.36, 123.62, 117.72, 109.53;

HRMS (ESI) calcd. for C₁₀H₈O[M+Na]⁺: 167.0472, found:

167.0413.

4.2.17 1-Bromo-2-naphthol (2q). Light yellow, mp: 84-85 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.05-7.99 (m, 1H), 7.75 (ddd,

J=17.2, 8.9, 4.7 Hz, 2H), 7.58-7.51 (m, 1H), 7.37 (ddd, J=8.1, 6.9,

1.1 Hz, 1H), 7.26-7.21 (m, 1H), 5.91 (s, 1H); ¹³C NMR (100.6

MHz, CDCl₃) δ 150.57, 132.29, 129.68, 129.30, 128.18, 127.80,

125.30, 124.11, 117.13, 106.12; HRMS (ESI) calcd. for

C₁₀H₇BrO[M+Na]⁺: 244.9578, found: 244.9538.

4.2.7 4-Nitrophenol (2g). Yellow solid, mp: 112-113 °C; H

NMR (600 MHz, CDCl₃) δ 8.18 (d, J=9.0, 2H), 6.94 (d, J=9.0,

2H), 6.21 (s, 1 H); ¹³C NMR (150.9 MHz, CDCl₃) δ 161.45,

141.63, 126.31, 115.73; HRMS (ESI) calcd. for C₆H₅NO₃

[M+Na]⁺: 162.0167, found: 162.0109.

4.2.18 2-methoxyphenol (4a). Light yellow liquid; H NMR

(400 MHz, CDCl₃) δ 7.04-6.97 (m, 1H), 6.97-6.87 (m, 3H), 5.97

(brs, 1H), 3.87 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 146.66,

145.65, 121.47, 120.23, 114.66, 110.84, 55.86; HRMS (ESI)

calcd. for C₇H₈O₂[M+Na]⁺: 147.0422, found: 144.0383.

4.2.8 4-Hydroxyacetophenone (2h). White solid, mp: 108-110

°C; H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 7.92-7.86 (m,

2H), 6.98-6.90 (m, 2H), 2.57 (s, 3H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 199.02, 161.69, 131.27, 129.34, 115.61, 26.23; HRMS

(ESI) calcd. for C₈H₇O₂[M+Na]⁺: 159.0422, found: 159.0401.

4.2.19 1,2-benzenediol (4a'). White solid, mp: 104-106 °C; H

NMR (400 MHz, CDCl₃) δ 6.89-6.84 (m, 2H), 6.84-6.78 (m, 2H),

5.24 (s, 2H); ¹³C NMR (100.6 MHz, CDCl₃) δ 143.46, 121.27,

115.50; HRMS (ESI) calcd. for C₆H₆O₂[M+Na]⁺: 133.0265,

found: 133.0261.

4.2.9 4-Hydroxybenzaldehyde (2i). Light yellow solid, mp: 113-

115 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.86 (s, 1H), 7.85-7.78 (m,

2H), 6.97 (dd, J=9.0, 2.2 Hz, 2H), 6.47 (s, 1H); ¹³C NMR (100.6

MHz, CDCl₃) δ 191.22, 161.36, 132.48, 129.78, 115.99. HRMS

(ESI) calcd. for C₇H₆O₂[M+Na]⁺: 145.0265, found: 145.0242.

4.2.20 3-methoxyphenol (4b). Light yellow liquid; H NMR

(400 MHz, CDCl₃) δ 7.14 (t, J=8.1 Hz, 1H), 6.70 (brs, 1H), 6.55-

6.45 (m, 3H), 3.77 (s, 3H); ¹³C NMR (100.6 MHz, CDCl₃) δ

160.68, 156.68, 130.28, 108.08, 106.43, 101.62, 55.34; HRMS

(ESI) calcd. for C₇H₈O₂[M+Na]⁺: 147.0422, found: 147.0397.

4.2.10 4-hydroxybenzonitrile (2j). White solid, mp: 111-113 °C;

¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 7.60 (d, J=8.8

Hz, 2H), 6.90 (d, J=8.8 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆)

δ 162.02, 134.60, 119.96, 116.83, 101.46. HRMS (ESI) calcd. for

C₇H₅NO [M+Na]⁺: 142.0269, found: 142.0245.

4.2.21 1,3-benzenediol (4b'). White solid, mp: 110-111 °C; H

NMR (400 MHz, CDCl₃) δ 7.08 (t, J=8.1 Hz, 1H), 6.40 (dd,

J=8.1, 2.3 Hz, 2H), 6.35 (t, J=2.3 Hz, 1H), 4.78 (s, 2H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 156.80, 130.34, 107.89, 102.8; HRMS

(ESI) calcd. for C₆H₆O₂[M+Na]⁺: 133.0265, found: 133.0257.

4.2.11 ethyl 4-hydroxybenzoate (2k). White solid, mp: 116-118

°C; H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 7.82 (d,

J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H),

1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 165.99,

162.35, 131.78, 120.99, 115.70, 60.47, 14.64. HRMS (ESI) calcd.

for C₉H₁₀O₃[M+Na]⁺: 189.0528, found: 189.0509.

4.2.22 4-methoxyphenol (4c). Light yellow liquid; H NMR

(400 MHz, CDCl₃) δ 6.80–6.74 (m, 4H), 5.83 (s, 1H), 3.76 (s,

3H); ¹³C NMR (100.6 MHz, CDCl₃) δ 153.49, 149.49, 116.14,

114.96, 55.91; HRMS (ESI) calcd. for C₇H₈O₂[M+Na]⁺:

147.0422, found: 147.0407.

4.2.12 2-Nitrophenol (2l). Yellow solid, mp: 44-46 °C; H

NMR (400 MHz, CDCl₃) δ 10.55 (s, 1H), 8.08 (dd, J=8.5, 1.6 Hz,

1H), 7.56 (ddd, J=8.7, 7.2, 1.7 Hz, 1H), 7.15-7.11 (m, 1H), 6.97

(ddd, J=8.5, 7.2, 1.3 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ

155.08, 137.46, 133.67, 125.01, 120.16, 119.92; HRMS (ESI)

calcd. for C₆H₅NO₃[M+Na]⁺: 162.0167, found: 162.0149.

4.2.13 3,5-dimethylphenol (2m). White solid, mp: 64-66 °C; ¹H

NMR (600 MHz, CDCl₃) δ 6.57 (s, 1H), 6.45 (s, 2H), 4.93 (s,

1H), 2.25 (s, 6H); ¹³C NMR (150.9 MHz, CDCl₃) δ 155.39,

139.57, 122.59, 113.09, 21.25; HRMS (ESI) calcd. for

C₈H₁₀O[M+Na]⁺: 145.0629, found: 145.0587.

4.2.23 1,4-benzenediol (4c'). White solid, mp: 170-172 °C; H

NMR (600 MHz, DMSO) δ 8.59 (s, 2H), 6.56 (s, 4H); ¹³C NMR

(150.9MHz, DMSO) δ 149.71, 115.63; HRMS (ESI) calcd. for

C₆H₆O₂[M+Na]⁺: 133.0265, found: 133.0232.

4.2.24 4-ethoxyphenol (4d). White solid, mp: 64-66 °C; H

NMR (400 MHz, CDCl₃) δ 6.77(m, 4H), 5.47(s, 1H), 3.98(q,

J=7.00Hz, 2H), 1.39(t, J=7.00Hz, 3H) ; ¹³C NMR(100.6MHz,

CDCl3) δ 14.92, 64.36, 115.81, 116.14, 149.50, 152.87; HRMS

(ESI) calcd. C₈H₁₀NaO₂for [M+Na]⁺:161.0573, found:161.0822.

4.2.14 3,4-Methylenedioxyphenol (2n). White solid, mp: 63-65

°C; ¹H NMR (400 MHz, CDCl₃) δ 6.63 (d, J = 8.3 Hz, 1H), 6.42

(d, J = 2.5 Hz, 1H), 6.25 (dd, J = 8.3, 2.5 Hz, 1H), 5.88 (s, 2H),

5.40 (s, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 150.47, 148.21,

141.55, 108.19, 106.79, 101.13, 98.35; HRMS (ESI) calcd. for

C₇H₆O₃[M+Na]⁺: 161.0215, found: 161.0211.

4.2.25 2,6-dimethoxyphenol (4e). White solid, mp: 53-55 °C ;

¹H NMR (400 MHz, CDCl₃) δ 6.80(dd, J=8.08, 8.64Hz, 1H),

6.58(d, J=8.32Hz, 2H), 5.51(s, 1H), 3,89(s, 6H); ¹³C NMR

(100.6MHz, CDCl₃) δ 56.27, 104.87, 119.08, 134.83, 147.25;

HRMS (ESI) calcd.C₈H₁₀NaO₃for [M+Na]⁺: 177.0522, found:

177.0511.

4.2.15 1-Naphthol (2o). White solid, mp: 95-97 °C; H NMR

(400 MHz, CDCl₃) δ 8.20-8.07 (m, 1H), 7.83-7.72 (m, 1H), 7.50-

Tetrahedron

2. Bianco GG, Ferraz HMC, Costa AM, Costa-Lotufo LV, Pessoa C, de

4.2.26 4-butoxyphenol (4f). White solid, mp: 65-66 °C; H

ACCEPTED MANUSCRIPT

Moraes MO, Schrems MG, Pfaltz A, Silva LF. J Org Chem. 2009; 74:

2561.

NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 6.82 – 6.60 (m, 4H),

3.83 (t, J=6.5 Hz, 2H), 1.64 (dq, J=8.4, 6.6 Hz, 2H), 1.41 (h,

J=7.4 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz,

DMSO-d₆) δ 151.97, 151.52, 116.12, 115.72, 67.96, 31.42, 19.25,

14.16. HRMS (ESI) calcd. for C₁₀H₁₄O₂[M+Na]⁺: 189.0891,

found: 189.0873.

3. Dao TT, Chi YS, Kim J, Kim HP, Kim S, Park H. Arch Pharm Res. 2003;

26: 345.

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10962.

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Yang M, Holm R, Mu H. International Journal of Pharmaceutics

(Amsterdam, Netherlands). 2016; 509: 499.

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2nd ed., John Wiley and Sons: New York, 1991; p145; (b) Bhatt MV,

Kulkami SU. Synthesis. 1983; 249; (c) Burwell RL. Chem Rev. 1954; 54:

615; (d) Maercker A. Angew Chem Int Ed. 1987; 26: 972; (e) Weissman

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Prep Proced Int 1996; 28: 371; (g) Cor-nella J, Zarate C, Martin R.

Chem Soc Rev. 2014; 43: 8081.

4.2.27

13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-

cyclopenta[a]phenanthrene-3,17-diol (6a). White solid, mp: 174-

175 °C; H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 7.03 (d,

J=8.44Hz, 1H), 6.50 (dd, J=2.56, 8.36Hz, 1H), 6.43 (d, J=2.48Hz,

1H), 4.51 (d, J=4.36Hz, 1H), 3.51 (m, 1H), 2.69 (m, 1H), 2.22(m,

1H), 2,05 (m, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 1.28 (m, 7H),

0.66 (s, 3H); ¹³C NMR (100.6MHz, DMSO) δ 11.66, 23.18,

26.47, 27.34, 29.55, 30.28, 36.97, 43.20, 43.92, 49.90, 80.45,

113.09, 115.30, 126.43, 130.81, 137.52, 155.26; HRMS (ESI)

calcd. C₁₈H₂₄O₂Na for [M+Na]⁺: 272.1776 , found: 272.1745.

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2531.

Acknowledgments

Financial support from the National Natural Science

Foundation of China (21172258 and 21372258), China

Scholarship Council (201706365015) and Renmin University of

China is greatly acknowledged.

References and notes

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Synthesis, 3rd ed., Wiley, New York, 1999; (b) Kocienski, P. J.

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RM, Stec M, Surapaneni S, Tamir R, Zhu J, Treanor JJ, Norman MH. J

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Woodworth GF, Morgan BP, Coe JW. J Org Chem. 1999; 64: 9719..

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2014; 12: 4747.

ACCEPTED MANUSCRIPT

Research Highlights

ꢀ The Cu₂O proved to be a highly efficient catalyst for selective dealkylation

of aryl alkyl ethers.

ꢀ The catalyst can be reused for 8 times without compromising the catalytic

activity.

ꢀ A variety of functional groups including Cl, Br, F, NO₂, CH₃CO- and -CHO

were well compatible with this reaction.

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