Direct oxidative C(sp3)–H cyanation of secondary benzylic ethers

Article abstract of DOI:10.1016/j.cclet.2019.03.019

Current studies on the oxidative C–H functionalization of benzylic ethers for C–C forging process dominantly focus on primary ethers. The corresponding reaction of secondary ethers remains underdeveloped. Herein, a practical and efficient oxidative C–H cyanation of secondary benzylic ethers with TMSCN in the presence of DDQ is described. The metal-free process is well tolerated with a wide variety of electronically varied α-monosubstituted isochromans, facilely furnishing a library of isochromans bearing α-aryl α-cyano substituent patterns for further diversification and bioactive small molecule identification.

Full text of DOI:10.1016/j.cclet.2019.03.019

Accepted Manuscript
Title: Direct oxidative C(sp3)–H cyanation of secondary
benzylic ethers
Author: Zehua Wang Ying Mao Honghao Guan Min Cao Jing
Hua Lei Feng Lei Liu
PII:
S1001-8417(19)30114-7
DOI:
Reference:
https://doi.org/doi:10.1016/j.cclet.2019.03.019
CCLET 4855
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
7 February 2019
5 March 2019
12 March 2019
Please cite this article as: Z. Wang, Y. Mao, H. Guan, M. Cao, J. Hua, L. Feng, L.
Liu, Direct oxidative C(sp3)ndashH cyanation of secondary benzylic ethers, Chinese
Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.03.019
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Graphical Abstract
Direct oxidative C(sp3)–H cyanation of secondary benzylic ethers
Zehua Wanga, Ying Maob, Honghao Guana, Min Caoa, Jing Huac, Lei Fenga,, Lei Liua,b,*
a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
b School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
c State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi
Normal University, Guilin 541004, China
A practical and efficient oxidative C–H cyanation of secondary benzylic ethers with TMSCN in the presence of DDQ is
described for the first time. The metal-free process is well tolerated with a wide variety of electronically varied α-
monosubstituted isochromans for the synthesis of isochromans bearing α-aryl α-cyano substituent patterns.
Page 1 of 5

Communication
Direct oxidative C(sp3)–H cyanation of secondary benzylic ethers
a
b
a
a
c
a,
a,b,*

Zehua Wang , Ying Mao , Honghao Guan , Min Cao , Jing Hua , Lei Feng , Lei Liu
a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
b School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
c State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi
Normal University, Guilin 541004, China
ARTICLE INFO
ABSTRACT
Article history:
Current studies on the oxidative C–H functionalization of benzylic ethers for C–C forging
process dominantly focus on primary ethers. The corresponding reaction of secondary ethers
remains underdeveloped. Herein, a practical and efficient oxidative C–H cyanation of secondary
benzylic ethers with TMSCN in the presence of DDQ is described. The metal-free process is
well tolerated with a wide variety of electronically varied α-monosubstituted isochromans,
facilely furnishing a library of isochromans bearing α-aryl α-cyano substituent patterns for
further diversification and bioactive small molecule identification.
Received 7 February 2019
Received in revised form 6 March 2019
Accepted 7 March 2019
Available online
Keywords:
C–H functionalization
Cyanation
Oxidation
Secondary ether
Tertiary ether synthesis
Direct one step substitution of C–H bonds with C–C bonds represents an economic and efficient alternative to traditional approaches
depending on functional group transformations [1,2]. Among these, considerable efforts have been made in the oxidative C(sp3)–H
functionalization of benzylic ethers [3,4]. However, current studies predominantly focused on the functionalization of the methylene
C–H bond of primary benzylic ether for secondary ether construction [5]. The direct manipulation of the methine C–H bond in a
secondary benzylic ether for tertiary ether synthesis remains elusive, probably due to the increased steric hindrance of the substrate and
1,1-disubstituted oxocarbenium ion intermediate [6]. A bimolecular oxidative C–H functionalization of secondary benzylic ethers for
new C–C bond construction has never been reported to date.
The isochroman skeleton is present in a number of natural products and synthetic pharmaceuticals exhibiting a wide range of
biological activities [7]. In particular, such structural motif bearing two different substituents at the α-position has been demonstrated to
possess antioxidative, anticancer, antibacterial, antifungal, antiviral, and antidepressive activities [8]. On the other hand, the nitrile
group is also an important building block in numerous natural products and synthetic materials with important pharmaceutical activities
[9]. Moreover, the nitrile moiety also serves as a versatile handle for further carbon elongations and functional group transformations.
Accordlingly, direct bimolecular oxidative C–H cyanation of α-monosubstituted isochromans would be a highly desirable project to
pursue [10].
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) has been widely adopted as an efficient oxidant in the C–H functionalization of a
series of primary benzylic ethers. In this context, Shi and Wang disclosed a DDQ-mediated oxidative C–H cyanation of isochroman
substrates leading to corresponding secondary ethers [10b]. Accordingly, α-phenyl substituted isochroman 1a was facilely prepared
(the details are given in Supporting information) [11], and then subjected to the C–H functionalization with trimethylsilyl cyanide
(TMSCN) using DDQ as the oxidant for optimization (Scheme 1). A systematic investigation of the cyanation source, solvent, and
temperature identified that DDQ-mediated C–H cyanation of 1a with TMSCN proceeded smoothly in toluene at 80 °C for 1 h,
providing the expected tertiary ether 2a in 92% yield. No expected 2a was observed when KCN was used as the cyanation agent.
Scheme 1. Oxidative C–H cyanation of α-substituted isochroman 1a.
 Corresponding authors.
E-mail addresses: feng_lei@sdu.edu.cn (L. Feng); leiliu@sdu.edu.cn (L. Liu)
Page 2 of 5

The scope of oxidative C–H cyanation of α-substituted isochromans 1 was next investigated (Scheme 2). Characterization data of the
target compounds are presented in Supporting information. Isochromans bearing either electron-donating aryl groups (1b) or electron-
withdrawing ones (1e and 1f) at the α-position proved to be suitable components in good yields, though the latter exhibited an inferior
efficiency to the former. Substrates with a substituent at either the meta- (1c) or ortho-position (1d) on the α-aryl group were also well
compatible with the C–H cyanation process, though the latter provided a slightly decreased yield. The observation might be ascribed to
the increased steric hindrance of both the ether substrate and highly substituted oxocarbenium intermediate. Isochroman having a
heteroaryl moiety at the α-position was well tolerated, as demonstrated by the generation of 2-thiophenyl substituted 2g in 90% yield.
The substituent effect on the isochroman skeleton was next evaluated (Scheme 2). Electronically varied isochromans 1h-1m
participated in the oxidative C–H cyanation efficiently, furnishing respective tertiary ethers 2h-2m in 81%-94% yields. No expected
tertiary ether 2n was observed for α-alkyl substituted isochroman 1n.
Scheme 2. Scope of oxidative C–H cyanation of α-substituted isochromans. Reaction conditions: 1a (0.1 mmol), TMSCN (0.12 mmol), and
DDQ (0.11 mmol) in toluene (1.0 mL) at 80 °C for 1 h. The yield refers to isolated yield.
Under the standard oxidation conditions, a gram-scale C–H cyanation reaction of 1g proceeded in 85% yield, thus suggesting the
practicability of the method (Scheme 3).
Scheme 3. A gram-scale reaction.
Based on the existing mechanistic studies on DDQ-promoted ether oxidation, a mechanism for the C–H cyanation of secondary
benzylic ethers was proposed (Scheme 4) [12]. α-Monosubstituted isochroman 1 underwent an initial single electron transfer (SET) to
DDQ gave the radical cation 3 together with the DDQ radical anion 4. The radical cation 3 can either undergo a hydrogen atom transfer
(HAT) to 4 or a proton abstraction by 4 followed by another SET providing 1,1-disubstituted oxocarbenium intermediate 5. A
nucleophilic attack of TMSCN on to 5 yielded the expected tertiary ether 2.
Scheme 4. A proposed reaction mechanism.
In summary, we have developed a practical and efficient oxidative C–H cyanation of secondary benzylic ethers with TMSCN in the
presence of DDQ. The metal-free process is well tolerated with a wide variety of electronically varied α-monosubstituted isochromans,
facilely furnishing a library of isochromans bearing α-aryl α-cyano substituent patterns for further diversification and bioactive small
molecule identification.
Page 3 of 5

Acknowledgment
This work was financial supported by the National Natural Science Foundation of China (No. 21722204), Fok Ying Tung Education
Foundation (No. 151035), the Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal
University) (No. CHEMR2016-B09), and Guangxi Funds for Distinguished expert.
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