Metal-Free Etherification of Aryl Methyl Ether Derivatives by C-OMe Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.8b01696

A general and efficient protocol was developed for the synthesis of aryl alkyl ethers through metal-free C-OMe bond cleavage under mild reaction conditions. This process displays a wide scope of methoxyarenes and alcohols, including primary, secondary, and tertiary alcohols, as well as natural products, pharmaceuticals, and biologically active alcohols. DFT calculations and experimental results simultaneously confirm that a potassium ion plays a critical role in the activation of methoxy group via binding with the nitrile and provide support for an S_NAr mechanism.

Full text of DOI:10.1021/acs.orglett.8b01696

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Etherification of Aryl Methyl Ether Derivatives by C−OMe
Bond Cleavage
Xueqiang Wang,†,* Chenchen Li,† Xia Wang,† Qingli Wang,† Xiu-Qin Dong,§ Abing Duan,‡,*
and Wanxiang Zhao*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha, Hunan 410082, China
‡College of Environmental Science and Engineering, Hunan University, Changsha, Hunan 410082, China
§Key Laboratory of Biomedical Polymers, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China
S
* Supporting Information
ABSTRACT: A general and efficient protocol was developed
for the synthesis of aryl alkyl ethers through metal-free C−
OMe bond cleavage under mild reaction conditions. This
process displays a wide scope of methoxyarenes and alcohols,
including primary, secondary, and tertiary alcohols, as well as
natural products, pharmaceuticals, and biologically active
alcohols. DFT calculations and experimental results simulta-
neously confirm that a potassium ion plays a critical role in the
activation of methoxy group via binding with the nitrile and
provide support for an SNAr mechanism.
fragrances, and cosmetics.2c Synthesis of aryl alkyl ethers has
ryl alkyl ethers are ubiquitous in biologically active agents
1
thus gained intense interest from synthetic chemists (Figure
Aand pharmaceutically important molecules,
such as
1b).3−6 Conventionally, aryl alkyl ethers are prepared via the
Williamson ether synthesis,3 in which phenol derivative is
coupled with an alkyl halide. However, tertiary alkyl halides
tend to undergo E2 elimination to yield alkenes instead of aryl
alkyl ethers in the presence of base.3b Alternatively, transition-
metal-catalyzed C−O bond formation reactions are one of the
most reliable methods to access ethers.4 In this context,
copper-mediated Ullmann ether synthesis and Chan−Evans−
Lam coupling represent useful protocols to prepare aryl alkyl
ethers, despite the drawbacks of using a stoichiometric amount
of copper and/or harsh reaction conditions.4a−h On the other
hand, palladium-catalyzed C−O bond formation has also
become a powerful approach for the synthesis of aryl alkyl
ethers, which have been developed intensively by Buchwald,
Hartwig, as well as other groups.4g−i,5 Additionally, nucleo-
philic aromatic substitution (SNAr) reactions offer a con-
venient access to aryl alkyl ethers as well.6 However, the scope
is limited to the arenes bearing strong electron-withdrawing
groups and with halides as the leaving groups.6 Nevertheless,
methods for halogenation generally suffer from harsh reaction
conditions and poor selectivity or require multistep synthesis.
On the other hand, aryl methyl ethers are ideal alternatives to
aryl halides for SNAr reactions in terms of not only
environmental friendliness but also synthetic accessibility and
febuxostat,1c butoxycaine,1d and duloxetine1e (Figure 1a). In
addition, they have emerged as synthetically valuable building
blocks in the synthesis of catalysts,2a functional materials,2b
Figure 1. (a) Representative drugs containing aryl alkyl ether. (b)
Aryl alkyl ether synthesis.
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01696
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 1. Reaction Scope
a
b
c
Conditions: 1 (0.5 mmol), R′OH (1.0 mmol), KOtBu (1.0 mmol), dioxane (0.5 mL). The substrate is piperonylonitrile. The reaction was
d
e
conducted at ambient temperature. Without alcohol. The reaction was conducted using 2.0 equiv of KHMDS at 60 °C.
reliability. However, few examples on nucleophilic aromatic
substitution of aryl methyl ethers are available, likely due to the
inertness of the C−O bond.7 To address this issue, at least two
strong electron-withdrawing groups are required to activate the
C−O bond.7a−c These drawbacks largely limit the applications
of the SNAr reaction in etherification. Therefore, we
questioned whether it is possible to develop an efficient and
practical method to produce aryl alkyl ethers from aryl methyl
ethers through the optimal combination of an electron-
withdrawing group and reaction conditions.
The past decade has witnessed tremendous advances in
transition-metal-catalyzed (particularly nickel-catalyzed) C−
OMe bond cleavage of methoxyarenes8 for borylation,9a
silylation,9b amination,9c reduction9d−g and couplings with
organometallic reagents,9h−s although C−OMe cleavage
requires high activation energy. In contrast, metal-free C−
OMe bond activation is far less common and more
challenging,10 and few available examples are limited to the
SNAr reactions of methoxyarenes with nitro groups.7 Not
surprisingly, etherification of anisole analogues has been
B
DOI: 10.1021/acs.orglett.8b01696
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Letter
a
Scheme 2. Scope of Complex Alcohols
a
b
c
Conditions: 1 (0.5 mmol), R′OH (1.0 mmol), KOtBu (1.0 mmol), dioxane (0.5 mL). The reaction was performed at 80 °C. 1.0 mL of dioxane
d
was used. The reaction was conducted using 2.0 equiv of KHMDS at 60 °C.
virtually unexplored via transition-metal-catalyzed or metal-free
C−OMe bond scission. Traditionally, etherification of aryl
methyl ethers requires two-step routes, namely, demethylation
and alkylation.11 Taking into consideration the significance of
aryl alkyl ethers and enlightened by Ogata and Okano’s work
on the SNAr reactions of 2,4-dinitroanisoles with alcohols,12
herein we describe an efficient method to prepare aryl alkyl
ethers from methoxyarenes with a cyano group via C−OMe
bond cleavage.
reaction parameters, we found the best yield was obtained
when KOtBu was used as the base and 1,4-dioxane as the
solvent (see details in the Supporting Information). With the
optimal conditions determined, we then looked into the
substrate scope of this reaction. A series of o-methoxy aromatic
nitriles with different substituents at different positions reacted
smoothly with 2-propanol to afford the corresponding aryl
alkyl ethers in good to excellent yields (Scheme 1). Various
functional groups, including bromide (2ab), chloride (2ac),
trifluoromethyl (2ae), and nitrile (2af), are well tolerated. In
addition, the mild reaction conditions are compatible with a
range of heterocycles, such as dibenzofuran (2ah), furan (2ai),
We began our studies of alcohol exchange reactions with 2-
methoxybenzonitrile 1a as the model substrate and 2-propanol
as the nucleophile. After efforts toward the evaluation of
C
DOI: 10.1021/acs.orglett.8b01696
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Letter
thiophene (2aj), and pyridine (2ak). This is particularly
noteworthy as not only o-methoxy aromatic nitriles but also p-
methoxy aromatic nitriles successfully participated in this
etherificaton reaction, although the m-OMe is unreactive under
the standard conditions. The p-methoxy substrates bearing
trifluoromethyl and methoxy all worked well, yielding the
products 2am and 2an in 89% and 98% yields, respectively.
The hindered C−OMe bond could also efficiently undergo a
substitution reaction to form the product 2ao. Notably, the
isopropoxyl group can be incorporated into both the ortho- and
para-positions at the same time (2ap). Piperonylonitrile
reacted smoothly with 2-propanol to furnish the ring-opening
product 2aq in 85% yield. Naphthalenes are also suitable
substrates for this C−O bond cleavage and formation process
and proceeded smoothly at room temperature to give the
corresponding products 2ar and 2as in excellent yields.
Furthermore, we were also interested in evaluating the scope
of the alcohols for our protocol. As shown in Scheme 1, a
variety of alcohols were applicable to provide the aryl alkyl
ethers with high efficiency, including primary, secondary, and
tertiary alcohols. The mild conditions can tolerate a diverse set
of functional groups, including chloride (2av), alkyne (2ba),
and alkene (2bb). Pyrazole could also be well accommodated
in this reaction (2bc). It is worth noting that the chiral alcohol
(+)-2-butanol is a competent coupling partner for this
transformation (2av). Surprisingly, the bulky tert-butoxy can
act as the nucleophile to yield the tert-butyl ethers 2bh and 2bi
in the absence of the alcohol. Consequently, 2.0 equiv of
KHMDS was utilized as the base instead of the KOtBu to avoid
the incorporation of the tert-butoxy when tertiary alcohols
were employed (2bj−bl).
proposed that this alcohol-exchange reaction underwent an
SNAr mechanism. To further confirm this, we performed a
series of density functional theory (DFT) calculations using
the methoxybenzonitriles (include o-, m- and p-methoxyben-
zonitrile) as the aromatic substrates and alkali isoproxides
(MOiPr, including KOiPr, NaOiPr and LiOiPr) as the
nucleophiles (see the Supporting Information). We also
studied the position effect of the methoxy using the
methoxybenzonitriles and KOiPr. On the basis of the
calculation results, we conclude that the nature of the alkali-
metal ion of MOiPr and the substrates themselves have
profound effects in terms of reactivity.
That is to say, the o-methoxybenzonitrile is the more
reactive substrate than p-methoxybenzonitrile, while the m-
methoxybenzonitrile turns out not to be suitable for the
reaction with KOiPr. Combing the experimental and computa-
tional studies results, we believe that our metal-free ether-
ification of aryl methyl ethers by C−OMe bond cleavage
involves an SNAr-type (addition−elimination) mechanism.
The utility of this methodology is demonstrated through a
gram-scale reaction of 2-methoxy-1-naphthonitrile with
(+)-fenchol, which furnished the etheric product 2bs in nearly
quantitative yield (Figure 2a). We also carried out a one-pot
To further demonstrate the generality of our method, a
range of complex alcohols were subjected to the standard
reaction conditions, including natural products, pharmaceut-
icals, and biologically active molecules, and were all
successfully transformed to the corresponding aryl alkyl ethers
in good yields (Scheme 2). The terpenoids such as (−)-perillyl
alcohol and nerol were found to be compatible nucleophiles
(2bm and 2bn). Perphenazine used as antipsychotic drug also
proceeded smoothly to give the etherification product 2bo,
albeit in 32% yield. Additionally, a collection of secondaryna-
tural alcohols, such as (+)-menthol, (+)-fenchol, and
(−)-borneol, were excellent substrates for this transformation
(2bp−bt). We were pleased to find that nitrogen-containing
alcohols (N-Bn-pyrrolidinol and 3-quinuclidinol) provided the
etheric products in 55% (2bu) and 99% yields(2bv),
respectively. Upon applying our reaction conditions to
estradiol, abiraterone, cholesterol, oleanolic acid (methyl
ester), and vitamins D2 and D3, the desired products
(2bw−cb) were all successfully obtained. With regard to
bulky tertiary alcohols, (+)-cedrol and the alcohol derived
from estrone were also converted efficiently to the ethers 2cc
and 2cd. All of these results demonstrate the extraordinarily
broad applicability of our method and immense utilization
potentiality for late-stage modifications of complex molecules.
To gain insightful mechanistic information from this
transformation, a series of complementary experiments were
carried out. We first investigated the possibility of a radical
mechanism. In the presence of a radical scavenger such as
TEMPO and BHT, no significant change was observed in
terms of yield and reaction rate (see the Supporting
Information). These results might allow us to exclude the
possibility of a radical pathway. On the other hand, we
Figure 2. (a) Gram-scale reaction. (b) Iterative C−O bond
formation. (c) Synthesis of butoxycaine.
iterative C−O bond formation process from 2-fluoro-4-
methoxybenzonitrile. Treated with KOtBu, the C−F bond
underwent an SNAr reaction with (+)-fenchol. Without
purification, the reaction mixture was then subjected to 2.0
equiv of 2-propanol to form the product 2ce in 48% total yield
via C−OMe bond cleavage (Figure 2b). Thus, our protocol is
in principle capable of assembling any two different alcohols
through this sequential process. Finally, this method was also
applied in the synthesis of butoxycaine with high efficiency
D
DOI: 10.1021/acs.orglett.8b01696
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Letter
from readily available 4-methoxybenzonitrile in three steps
(Figure 2c).
Diversification of the cyano group in aryl alkyl ether 2bp is
shown in Figure 3. The C−CN bond could be easily reduced
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01696.
■
S
Experimental procedures, NMR spectra, and computa-
tional data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhaowanxiang@hnu.edu.cn.
*E-mail: wangxq@hnu.edu.cn.
*E-mail: duanabing@hnu.edu.cn.
ORCID
Xueqiang Wang: 0000-0003-1631-9158
Chenchen Li: 0000-0002-2956-7639
Wanxiang Zhao: 0000-0002-6313-399X
Notes
The authors declare no competing financial interest.
Figure 3. Diversification of product. Reaction conditions: (a)
ACKNOWLEDGMENTS
■
i
[RhCl(cod)]2 (5 mol %), P(OnBu)3 (10 mol %), Pr3SiH (2 equiv),
Financial support was provided by the National Natural
Science Foundation of China (Grant No. 21702056,
21605070), the National Program for Thousand Young
Talents of China, the Fundamental Research Funds for the
Central Universities, and the State Key Laboratory of
Analytical Chemistry for Life Science (Grant No.
SKLACLS1505).
ethylcyclohexane, 130 °C, 15 h. (b) B2(nep)2 (2 equiv), [RhCl-
(cod)]2 (5 mol %), Xantphos (20 mol %), DABCO (1 equiv),
toluene, 100 °C, 15 h. (c) DIBAL (1.1 equiv), toluene, 0 °C to rt. (d)
MeMgBr (1.2 equiv), Et2O, 0−60 °C, overnight. (e) KOH (aq),
EtOH, 80 °C. (f) NaOH (6 M), MeOH, 70 °C, 7 h.
REFERENCES
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nitrile underwent reduction, addition with Grignard reagent
and hydrolysis to provide the corresponding aldehyde, ketone,
carboxylic acid, and amide in moderate to excellent yields
(Figure 3c−f).
In summary, we have developed a highly efficient and
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methoxy arenes and alcohols. This reaction underwent a metal-
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of butoxycaine. Perfect consistency between the computational
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type pathway. This noteworthy transformation, employing
readily available reagents and possessing broad substrate scope
and functional group compatibility, is anticipated to find
applications in late-stage modifications of complex molecules,
especially in pharmaceuticals.
■
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