Electrochemical Oxidative Carbon-Atom Difunctionalization: Towards Multisubstituted Imino Sulfide Ethers

Article abstract of DOI:10.1002/anie.202011329

Ethers (C?O/S) are ubiquitously found in a wide array of functional molecules and natural products. Nonetheless, the synthesis of imino sulfide ethers, containing an N(sp²)=C(sp²)?O/S fragment, still remains a challenge because of it

Full text of DOI:10.1002/anie.202011329

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Accepted Article
Title: Electrochemical Oxidative One-Carbon Difunctionalization
Towards Multi-Substituted Imino Sulfide Ethers
Authors: Zhipeng Guan, Shuxiang Zhu, Siyuan Wang, Huamin Wang,
Siyuan Wang, Xingxing Zhong, Faxiang Bu, Hengjiang Cong,
and Aiwen Lei
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10.1002/anie.202011329
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Electrochemical Oxidative One-Carbon Difunctionalization:
Towards Multi-Substituted Imino Sulfide Ethers
Zhipeng Guan,[a] Shuxiang Zhu,[a] Siyuan Wang,[a] Huamin Wang,[a] Siyuan Wang,[a] Xingxing Zhong,[a]
Faxiang Bu,[a] Hengjiang Cong,[a] Aiwen Lei*[a]
Dedication ((optional))
[a]
Z. Guan, S. Zhu, S. Wang, H. Wang, S. Wang, X. Zhong, F. Bu, Prof. H. Cong, Prof. A. Lei
College of Chemistry and Molecular Sciences and The Institute for Advanced Studies (IAS), Wuhan University
Wuhan, 430072, Hubei (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Abstract: Ethers (C-O/S) are ubiquitously found in a wide array of
functional molecules and natural products. Nonetheless, the
synthesis of imino sulfide ethers, containing N(sp2)=C(sp2)–O/S
fragment, still remains a great challenge due to its sensitivity to acid.
Herein, we developed an unprecedented electrochemical oxidative
one-carbon difunctionalization of isocyanides, providing a series of
novel multi-substituted imino sulfide ethers. Under metal- and
external oxidant-free conditions, isocyanides could react smoothly
with simple and readily available mercaptans and alcohols.
Importantly, the procedure exhibited high stereoselectivities,
excellent functional group tolerance, good efficiency in large-scale
synthesis as well as further derivatization of products.
via two channels. In 2017, Lin’s group reported electrochemical
strategy for diazidation and dichlorination of alkenes to
synthesize a variety of vicinally 1,2-diazides and dichlorinated
compounds respectively.[12] Alternatively, an active intermediate-
free radical cation could be obtained through anodic oxidation.[13]
For example, Vincent’s group and our group achieved the
electrochemical dearomative 2,3-difunctionalization of indoles
forging C-C, C-O and C-N bonds.[14] Despite numerous
advances, these reported reactions involving difunctionalization
are limited in utility to between two different atoms of
unsaturated bonds. Access to difunctionalization of one-carbon
under such conditions still remains room for improvement.[15]
As far as we know, isocyanides, which not only could be
inserted into metal-carbon and metal-heteroatom bonds in
transition-metal-catalyzed system, but also react with
electrophiles, nucleophiles and radicals under suitable
conditions, are an important C1 synthons.[16] Recently, the
monofunctionalization of isocyanides have been reported to
synthesize carbodiimides by electrochemical oxidation (Scheme
1b).[17] In order to realize difunctionalization of isocyanides, we
hypothesized that isocyanides could afford imine radical when
attacked by radicals. And then, carbocation was generated
through an electron transfer from the imine radical, which could
be captured further by nucleophiles (Scheme 1c). Herein, we
reported an unpresented electrochemical oxidative one-carbon
difunctionalization of isocyanides via sequential addition of
simple mercaptans and alcohols. A series of multi-substituted
imine ethers were facilely obtained under mild condition, with S-
C(sp2)-O bonds forming. In addition, this strategy obviated the
need of sacrificial oxidizing reagents and additives, with
concomitant valuable hydrogen gas releases.
Synthetic chemistry plays an extremely important role in the
development of human society through the construction of target
molecules, which has been widely used from pharmaceutical to
materials science.[1] Molecule ethers (C-O/S) are not only
ubiquitously found in a wide array of functional molecules and
natural products, but also could be extensively considered as
valuable building blocks in synthetic chemistry because of the
relatively high reactivity of C-O/C-S bond and oxygen/sulfur
atoms electronegativity.[2] Over the past several years, a myriad
of prevalent and synthetically useful methods have been
developed by thermochemistry,[3] photochemistry[4] and
electrochemistry[5] respectively, providing a broader array of
ethers compounds. Nonetheless, imino ethers, the significant
skeletons in a wide array of pharmaceuticals and sugar
chemistry, [6] are hitherto far less explored than alkyl ethers, aryl
ethers as well as enol ethers owing to its sensitivity to acid.[7]
Furthermore, existing method for the synthesis of imino sulfide
ethers also needs toxic transition-metal catalysts, strong redox
agents or other harsh conditions.[8] Hence, exploiting an efficient
and mild strategy to expand the scope, structural diversity, as
well as functional group tolerance in the generation of imino
sulfide ethers is an appealing and challenging task for chemists.
Organic electrochemistry, utilizing electrons as traceless
reagents, is an attractive and sustainable synthetic technology
for molecules construction.[9] At the same time, the proton can
be reduced to hydrogen at the cathode, which can adress the
challenge of the deterioration of acid-sensitive products in the
reaction
system.[10]
Recently,
the
electrochemical
difunctionalization of unsaturated bonds has proven to be a
powerful tool, expanding applications of these compounds
enormously.[11] In this field, great progress has been achieved
Scheme 1. Electrochemical oxidative difunctionalization of the unsaturated
bonds.
1
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After reaction optimization, utilizing 4-fluorobenzenethiol (1,
0.3 mmol), ethyl 2-isocyanoacetate (2, 0.5 mmol), methanol (3,
1.0 mmol) as coupling partners, ethyl (E)-2-((((4-
smoothly to afford the corresponding imino sulfide ethers
compounds in excellent yields (8-11). Furthermore, thiophenols
containing one group or two groups in different position also
showed good reaction efficiency in this transformation (12-15).
Afterwards, we turned our attention to expand the scope from
aryl mercaptans to alkyl mercaptans (16-23). To our delight, the
electrochemical protocol was shown to be compatible with a
variety of alkyl mercaptans including those bearing dodecyl (17),
benzyl (19), cycloalkyl (22,23) and ester (20). In addition, allow
for storage and toxicity of thiophenol, methyl mercaptan, ethyl
mercaptan, the satisfactory yields were obtained with the use of
corresponding disulfides as substances under slightly modified
conditions (24-26).
fluorophenyl)thio)(methoxy)methylene)amino)acetate
4
could
been obtained with 80% isolated yield successfully (Table 1,
entry 1). While a lower methanol of 0.6 mmol showed slight
decrease in yield, increasing amount of methanol revealed a
dramatically lower amount of target compound (entries 2-3).
Adding HOAc or NaOAc to the system was found to be
detrimental to the reaction process (entries 4-5). The presence
of co-solvent, especially DMF, resulted in a sharp drop in yield
(entries 6-7). With an alternative cathode material such as
graphite rod or nickel plate, lower yields obviously were
observed in undivided cell (entries 8-9). As to the electric current,
15 mA showed a similar reactivity, while 5 mA was less effective
in promoting the product formation (entries 10-11). The reaction
was sensitive to air, and a half yield was only obtained (entry 12).
Control experiments indicated that was completely abolished
without electricity (entry 13).
Table 1. Optimization of the Electrochemical Oxidative Difunctionalization
Entry
1
Variation from standard conditions
no
Yield/%[a]
80[b]
71
Scheme 2. Scope of mercaptans. Standard conditions: thiolating agents (0.3
mmol), ethyl 2-isocyanoacetate (0.5 mmol), alcohol (1.0 mmol) nBu4NBF4 (0.5
mmol), MeCN (6 mL), C anode, Pt cathode, undivided cell, constant current =
[a]
2
3 (0.6 mmol)
10 mA, room temperature, N2, 2.5 h, isolated yield.
constant current = 10 mA, 2 h.
disulfide (0.15 mmol),
3
3 (1 mL)
45
4
HOAc (0.5 mmol)
NaOAc (0.5 mmol)
MeCN/DCE = 5 mL/1 mL
MeCN/DMF = 5 mL/1 mL
C(+) C(-)
60
Subsequently,
further
exploration
revealed
the
5
63
difunctionalization of isocyanides was amenable to alcohols
(Scheme 3). The reaction efficacy of this protocol showed little
dependence on the chain length of primary alcohols (27-30).
Similarly, the reaction proceeded effectively with other fatty
alcohols, such as sobutanol (31) and cyclobutanemethanol (32)
in 62% and 69% yields, respectively. The sensitive benzylic C-H
bonds of benzylic alcohols (33-37) and phenethyl alcohols (38-
42) were tolerated in this transformation, providing acceptable
yields. Remarkably, subtle C-I bond on benzene ring was also
compatible with this strategy (42). Alkoxy alcohols were well
tolerated, affording the corresponding products in the reaction
system (43, 44). Owing to importance of fluorine atom in drug
molecules, we tried to introduce fluorine atom into the imino
sulfide ethers compounds. To our delight, the targeted
molecules, containing monofluoride (45), difluoromethyl (46) and
trifluoromethyl (47) were successfully obtained under
electrochemical conditions. A substrate bearing a primary
chloroalkane was fully tolerated to deliver the desired product in
good yield (48). A range of functionality vicinal to alcohols such
as thiomethyl (49), thiomethylene (50), cyano (51), ester (52),
carbonyl (84) and tert-butyldimethylsilyloxy (53), were also
tolerated under standard condition. Compared with terminal alkyl
alkene and alkyne, thiophenol would preferentially react with
isocyanides to obtain a series of imino sulfide ethers along with
the additional double or triple bonds intact (54-57). Extending
6
60
7
18
8
28
9
C(+) Ni(-)
40
10
11
12
13
15 mA, 100 min
5 mA, 5 h
75
62
under air
50
no electric current
0
Standard conditions: 1 (0.3 mmol), 2 (0.5 mmol), 3 (1.0 mmol) nBu4NBF4 (0.5
mmol), MeCN (6 mL), C anode, Pt cathode, undivided cell, constant current =
10 mA, room temperature, N2, 2.5 h. [a] 19FNMR yield, 1-(4-fluorophenyl)ethan-
1-one as an internal standard. [b] isolated yield.
In an effort to explore the scope of difunctionalization of
isocyanides, we first sought to examine applicability with respect
to mercaptans (Scheme 2). Thiophenols bearing electron-
withdrawing groups (F, Cl, Br, CF3) were also well amenable to
this protocol, providing a set of products with 70-87% yields (4-
7). With an electron-donating group on aromatic ring, such as
Me, OMe, SMe, and tBu, thiophenols could be employed
2
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10.1002/anie.202011329
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the substrate range to contain secondary alcohols enable us to
construct C-S and C-O bonds with adjoining tertiary carbon
centers. Simple secondary alcohols could be used, representing
Next, the isocyanides coupling partner scope was considered
with both mercaptans and alcohols. Methyl isocyanoacetate was
tolerated, leading to the formation of imino sulfide ethers in with
a practical route to form imino sulfide ethers (58-61). Additionally, 72% yield (81). Analogously, no obvious negative effect was
this protocol was not limited to acyclic systems. Cyclic
secondary alcohols from four to twelve-membered rings,
containing heterocycle alcohol, were also suitable substrates
(62-66). When glycol is used as a substrate, the retention of one
hydroxyl group is particularly noteworthy, providing the
opportunity for further derivatization (67-71). Due to steric
hindrance effect, primary alcohol could react to form target
observed using TOSMIC as a substrate (82). Benzyl isocyanide
(85) and cyclohexyl isocyanides (86,87) were coupling partners,
which could react smoothly with glycols, and one of the hydroxyl
groups is retained. Gratifyingly, isocyanides containing steric
hindrance, could engage with thiophenols and alcohols to give
the corresponding compounds in moderate yields (83,84).
Besides alkyl isocyanides, aryl isocyanide was also a suitable
compound over secondary alcohols (72) and tertiary alcohol (73). substrate for this strategy (88).
It is particularly noteworthy that three important food additives
including tetrahydrogeranol (74), tetrahydrofurfuryl alcohol (75)
and 3-phenyl-1-propanol (76) were smoothly converted to the
desired products in 45-78% yields. Moreover, natural products
and pharmaceuticals such as L-menthol (77), isosorbide (78),
androsterone (79), dihydrocholesterol (80) all underwent
functionalization smoothly.
Scheme 4. Scope of isocyanides. Standard conditions: thiolating agents (0.3
mmol), isocyanides (0.5 mmol), alcohol (1.0 mmol) nBu4NBF4 (0.5 mmol),
MeCN (6 mL), C anode, Pt cathode, undivided cell, constant current = 10 mA,
room temperature, N2, 2.5 h, isolated yield.
To further demonstrate the potential application of this
difunctionalization of isocyanides, a gram scale reaction was
performed with similar condition. Using 20 mA constant current,
a
good yield of the corresponding product was offered.
Considering the retention of one hydroxyl group, we introduced
pharmaceuticals and amino acid to obtained products, providing
an opportunity for new drug discovery.
Scheme 5. Gram scale synthesis and derivatization of product.
A series of mechanistic studies were carried out to investigate
this electrochemical oxidative mechanism. In the absence of
isocyanide, 4-fluorobenzenethiol (1) underwent dimerization to
afford 1,2-bis(4-fluorophenyl)disulfane with 82% isolated yield
(Scheme 6a). 1,2-diphenyldisulfane as a substance, 77% yield
was also obtained in the difunctionalization reaction (Scheme
6b). Under the standard conditions, when 2.0 equivalent of
TEMPO or BHT was added to the reaction, no imine ethers was
observed, revealing the existence of a sulfur radical (Scheme 6c
and 6d). In order to further explore this reaction mechanism,
Scheme 3. Scope of alcohol. Standard conditions: thiolating agent (0.3 mmol),
isocyanide (0.5 mmol), alcohol (1.0 mmol) nBu4NBF4 (0.5 mmol), MeCN (6 mL),
C
anode, Pt cathode, undivided cell, constant current = 10 mA, room
temperature, N2, 2.5 h, isolated yield. [a] disulfide (0.15 mmol), constant current
= 10 mA, 2 h.
3
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electron paramagnetic resonance (EPR) experiments was firstly
performed. A S-centred radical was quickly trapped by 5,5-
dimethyl-1-pyrroline N-oxide (DMPO) to form arelatively stable
radical (g = 2.0065, AN=13.70 G, AH = 11.95 G).
Acknowledgements ((optional))
This work was supported by the National Natural Science
Foundation of China (22031008, 21520102003), the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Universities
of China (111 Program) is also appreciated.
Dedicated to P.H. Dixneuf for his outstanding (or meaningful)
contribution to organometallic chemistry and catalysis.
Keywords: imino sulfide ethers • difunctionalization •
electrochemistry • isocyanides • carbon radical
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Scheme 6. Control experiments.
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Scheme 7. Proposed reaction mechanism.
In summary, we have developed a novel electrochemical
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available mercaptans and alcohols, forming S-C(sp2)-O bonds
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10.1002/anie.202011329
Angewandte Chemie International Edition
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We developed an unprecedented electrochemical oxidative one-carbon difunctionalization of isocyanides, providing a series of novel
multi-substituted imino sulfide ethers. Under metal- and external oxidant-free conditions, isocyanides could react smoothly with
simple and readily available mercaptans and alcohols.
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