Oxycyanation of Vinyl Ethers with 2,2,6,6-Tetramethyl-N-oxopiperidinium Enabled by Electron Donor-Acceptor Complex

Article abstract of DOI:10.1021/acs.orglett.7b03858

An efficient and mild oxycyanation of vinyl ethers with 2,2,6,6-tetramethyl-N-oxopiperidinium and TMSCN is described. The mechanistic studies indicated that the formation of an electron donor-acceptor complex and subsequent single-electron-transfer proces

Full text of DOI:10.1021/acs.orglett.7b03858

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Oxycyanation of Vinyl Ethers with 2,2,6,6-
Tetramethyl‑N‑oxopiperidinium Enabled by Electron Donor−
Acceptor Complex
Jia-Li Liu, Ze-Fan Zhu, and Feng Liu*
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences,
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China
*
S Supporting Information
ABSTRACT: An efficient and mild oxycyanation of vinyl ethers with
,2,6,6-tetramethyl-N-oxopiperidinium and TMSCN is described. The
2
mechanistic studies indicated that the formation of an electron donor−
acceptor complex and subsequent single-electron-transfer process could be
involved in the reaction.
itrile compounds not only can serve as synthons for
Scheme 1. EDA Complex-Enabled Vicinal
Difunctionalization of Electron-Rich Alkenes
N
preparation of carboxylic acids, amides, amines, alde-
1
hydes and ketones but also prevail in bioactive natural
2
products and pharmaceutical agents. Therefore, the develop-
ment of efficient cyanation methods has been of considerable
3
significance. While olefins are a class of versatile building
blocks in organic synthesis, direct cyanation of alkenes toward
4
functionalized nitriles still remains underexplored. Among
these methods, the vicinal oxycyanation of alkenes represents a
notable approach to introduce a cyano group as well as an
4
h−k
oxygen atom.
Despite the utility of these protocols to
achieve oxycyanation, the development of new methods to
meet various synthetic demands is still of great interest.
Alkene radical cations, as an open-shell species, show a
combination of free-radical and cation properties that would5
deliver an attractive manner of reactivity and selectivity.
Recent efforts from our laboratory have demonstrated that
vinyl azide could interact with 1-(chloromethyl)-4-fluoro-1,4-
+
2
,2,6,6-Tetramethyl-N-oxopiperidinium (TEMPO ), as one of
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Select6-
the oxoammonium salts which are widely used for the oxidation
of alcohols, might act as the “O ” source. Recently, a charge-
transfer (CT) complex TEMPO−ClO was identified by
Yamamoto and co-workers. In continuation of our research
interest in the transformation of electron-rich alkenes via alkene
radical cations, herein we report a novel and efficient protocol
for the oxycyanation of vinyl ethers by using TEMPO as the
electron acceptor and TMSCN as the cyanating reagent,
obtaining TEMPO-trapped 2-alkoxynitriles as the products
which are difficult to access by existing methods (Scheme 1).
We commenced our investigation on the reaction of the
substrate 1a with TEMPO ClO4 and TMSCN using dichloro-
methane (DCM) as the solvent. To our delight, the TEMPO-
fluor) to form an electron donor−acceptor (EDA) complex,
10
+
followed by single-electron transfer (SET) to generate an
alkene radical cation intermediate and subsequent fluorine
2
11
7b
atom transfer and nucleophilic cyanation (Scheme 1). On the
other hand, the use of EDA complex strategy in synthetic
7
6
chemistry is relatively less studied, while the physicochemical
+
properties of EDA complexes have been extensively inves-
8
tigated since the 1950s. Due to the mild and sustainable
properties of EDA complex-enabled reactions, the design and
development of novel methods for the synthesis of useful
molecules is highly desirable, and many groups have been
+
−
9
devoted to finding new reactions in recent years.
+
Inspired by the concept that the “F ” could form EDA
aggregate with electron-rich vinyl azide (Scheme 1), we
+
wondered that whether “O ” species would interact with
Received: December 11, 2017
electron-rich vinyl ether to give an EDA complex as well.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03858
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
trapped nitrile 2a was obtained in 53% yield (Table 1, entry 1).
An increase of the loading of TMSCN up to 6 equiv led to a
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
additive
time (h)
yield (%)
c
1
DCM
DCM
1
1
53
62
53
42
<5
76
10
46
28
56
73
75
78
75
74
2
3
4
5
6
7
8
CH CN
1
3
PhCH3
DMF
DCE
CHCl3
PhCl
THF
DCE
DCE
DCE
DCE
DCE
DCE
1
12
1
1
1
9
1
d
1
1
1
1
1
1
0
1
2
3
4
4 Å MS
Na CO (2 equiv)
1
1
2
3
Na PO (2 equiv)
1
3
4
K PO (2 equiv)
1
3
4
K CO (2 equiv)
1
2
3
e
5
K PO (2 equiv)
1.5
3
4
Figure 1. Optical absorption spectra recorded in acetonitrile in a 1 cm
path quartz cuvettes using a Shimadzu UV-2600 UV−vis spectropho-
a
+
−
1
a (0.20 mmol), TEMPO ClO (030 mmol), TMSCN (1.2 mmol),
4
b
c
solvent (2 mL). Isolated yield. TMSCN (4 equiv, 0.80 mmol).
+
tometer. (a) [1a] = 0.1 M, [TEMPO ] = 0.15 M. The combination of
d
e
Powdered molecular sieves (4 Å, 50 mg). In the dark.
+
1
a with TEMPO leads to absorption shift. (b) Stoichiometry of the
EDA complex in solution determined at 480 nm. The acetonitrile
+
solutions of 1a and TEMPO have a constant total concentration of
higher chemical yield (entry 2 vs entry 1). A survey of organic
solvents revealed that 1,2-dichloroethane (DCE) was the best
one (entries 2−9). To inhibit the formation of hydrolysis
byproduct ketone, molecular sieves were added but did not
provide a better result (entry 10). Although the addition of an
inorganic base could not significantly improve the chemical
yield (entries 11−14), the TLC analysis showed that it was
cleaner (or had fewer byproducts) compared to the neutral
conditions (entry 6). It should be noted that the reaction
proceeded smoothly in the dark as well though the yield
dropped (entry 15).
0
.02 M but different donor/acceptor ratios.
Scheme 2. Control Experiments
In general, the EDA complex exhibits a charge-transfer (CT)
band, the bathochromic shift band, which lies within the visible
8
region in many cases. We performed UV−vis spectroscopic
+
measurements on 1a, TEMPO , and a combination of these
two components (Figure 1a). A noticeable absorption shift
which could be attributed to the formation of an EDA complex
was observed. Moreover, a Job’s plot was constructed to
evaluate the stoichiometry of the EDA complex between 1a and
Having established the above optimal reaction conditions, we
aimed to explore the scope of this mild oxycyanation protocol.
As shown in Figure 2, a series of differentially substituted
TEMPO-trapped nitriles were readily obtained in moderate to
excellent yields (2a−w). In most cases, conversion of vinyl
ether was completed within 2 h. This protocol could
accommodate a wide range of substituents on arenes regardless
of their electronic and/or steric properties (2a−n). For
example, the reactions of the substrates bearing electron-
withdrawing and electron-donating groups at the para positions
on the phenyl rings proceeded nicely, giving the corresponding
products in good yields (2c−i). In the examples of 2d and 2e,
the survived bromo and iodo atoms reserved the options for
further cross-coupling. It is of note that vinyl ethers containing
alkynyl (2p) or thienyl (2q) moiety were compatible with the
reaction conditions, providing the desired nitriles in satisfied
yields. This protocol could also be extended to nonterminal
vinyl ethers (2r,s), including cyclic substrate (2r), readily
+
12
TEMPO in solution (Figure 1b). The maximum absorbance
was obtained at a ratio of 1:1. These results indicate that vinyl
+
ether and TEMPO can form the CT complex through single-
electron transfer. To gain more insights about the mechanism
of this reaction, control experiments were conducted (Scheme
2
, eqs 1 and 2). In the presence of radical scavenger 4-oxo-
TEMPO, we detected the formation of 4-oxo-TEMPO-trapped
cyanation product 3 (Scheme 2, eq 1). To rule out the
possibility that 4-oxo-TEMPO could be involved in the
+
initiation step, the reaction of 1a without TEMPO was carried
out. As might be expected, 4-oxo-TEMPO only acted as the
radical scavenger (Scheme 2, eq 2). These results could support
the involvement of radical process in the EDA complex-enabled
oxycyanation.
B
DOI: 10.1021/acs.orglett.7b03858
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed Mechanism
excellent functional group tolerance. Further applications of
radical cations in organic synthesis are still ongoing in our
group.
Figure 2. Scope of vinyl ethers. (a) 5 mmol scale. (b) The dr value was
determined by H NMR spectroscopy of the crude product.
ASSOCIATED CONTENT
Supporting Information
1
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03858.
furnishing the desired products in high yields. Ethyl (2t) and
butyl (2u,v) ethers were also applicable for the oxycyanation.
Inparticular, the chemical yield was not compromised when a
sugar (diacetone-D-glucose) moiety was installed (2v vs 2u).
The reaction of alkyl vinyl ether also proceeded smoothly,
affording the desired product with excellent stereoselectivity in
acceptable yield (2w). Importantly, the reaction can be readily
scaled up without compromising the chemical yield, for
instance, affording 2a in 73% yield (5 mmol scale).
Experimental details, characterizations, and H, 19F, and
1
13
C NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: fliu2@suda.edu.cn.
■
*
The proposed mechanistic details of the transformation are
7
ORCID
depicted in Scheme 3. At first, an EDA aggregate A can be
+
formed between vinyl ether 1 and TEMPO on the basis of the
Feng Liu: 0000-0003-2669-5448
Notes
aforementioned experimental phenomena. The subsequent
single-electron transfer (SET) is activated thermally, providing
an alkene radical cation C within B, followed by a fast radical−
radical cross-coupling to form a C−O bond in solvent cage.
The final step involves a nucleophilic cyanation of carbocation
intermediate D, giving the desired oxycyanation product.
Alternatively, out-of-cage diffusion and following a radical
coupling pathway cannot be excluded.
In conclusion, we have described the first example of an
operationally simple protocol for the synthesis of TEMPO-
trapped 2-alkoxynitriles under transition-metal-free conditions.
The investigations indicated that an EDA complex-enabled
generation of open-shell radical cation and subsequent radical/
radical cross-coupling and nucleophilic cyanation could be
involved in the reaction. Moreover, this mechanistically
interesting reaction is efficient and widely applicable to a
range of vinyl ethers. This transformation also demonstrated
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science
Foundation of China (Grant No. 21302134) is acknowledged.
■
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DOI: 10.1021/acs.orglett.7b03858
Org. Lett. XXXX, XXX, XXX−XXX