N-Heterocyclic Carbene/Magnesium Cocatalyzed Radical Relay Assembly of Aliphatic Keto Nitriles

Article abstract of DOI:10.1021/acs.orglett.0c03883

An unprecedented N-heterocyclic carbene and magnesium cocatalyzed three-component acylcyanoalkylation of alkenes with cycloketone oxime esters and aldehydes is presented. This method displayed good scope generality, providing a transition-metal- and photoredox-free pathway to access various multifunctionalized aliphatic keto nitrile structures under mild reaction conditions. Moreover, this strategy is supposed to follow a radical relay mechanism via a single electron transfer event of a Mg/matched Breslow intermediate/oxime ester electron-donating acceptor (EDA) complex.

Full text of DOI:10.1021/acs.orglett.0c03883

pubs.acs.org/OrgLett
Letter
N‑Heterocyclic Carbene/Magnesium Cocatalyzed Radical Relay
Assembly of Aliphatic Keto Nitriles
†
†
Lei Chen, Shiyi Jin, Jian Gao, Tongtong Liu, Yuebo Shao, Jie Feng,* Kangyi Wang, Tao Lu,
and Ding Du*
Cite This: Org. Lett. 2021, 23, 394−399
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ABSTRACT: An unprecedented N-heterocyclic carbene and magnesium cocatalyzed three-component acylcyanoalkylation of
alkenes with cycloketone oxime esters and aldehydes is presented. This method displayed good scope generality, providing a
transition-metal- and photoredox-free pathway to access various multifunctionalized aliphatic keto nitrile structures under mild
reaction conditions. Moreover, this strategy is supposed to follow a radical relay mechanism via a single electron transfer event of a
Mg/matched Breslow intermediate/oxime ester electron-donating acceptor (EDA) complex.
1
0
liphatic compounds bearing multiple functional groups
represent key structures in many chemical frontier fields.
great interest among organic chemists. However, there are
3
A
limited NHC-catalyzed radical relay reactions for C(sp )−C
bond formation via olefin dicarbofunctionalization (Scheme
1b). Therefore, further discovery of novel radical relay
matched substrate pairs and reaction systems for C(sp )−C
For example, they are the basic skeletons for dual target
1
2
11
inhibitors, the chemical linkers for surfactants or polymers,
3
3
and the connectors for supported catalysts (Scheme 1a). The
traditional synthesis of such compounds usually required the
installation of each functional group in sequence, resulting in
extra workloads such as protection/deprotection procedures,
selectivity issues, and workup problems.
bond formation via olefin dicarbofunctionalization is in high
demand. To the best of our knowledge, three-component
acylcyanoalkylation of olefins has not been reported to date.
We noticed that cycloketone oxime esters are useful and
versatile intermediates in organic synthesis that serve as the
feedstock for the synthesis of functionalized nitriles via the
formation of nitrile alkyl radicals under TM catalysis or
photoredox conditions. Thus, in principle, the incorporation
of cyclobutanone oxime esters with alkenes and aldehydes
under NHC catalysis might enable the olefin acylcyanoalky-
lation reaction to afford diverse structurally interesting
aliphatic keto nitriles via the electron-donating acceptor
Multicomponent reactions (MCRs) have been recognized as
powerful tools to provide straightforward access to various
4
complex structures. Among them, the intermolecular
3
12
dicarbofunctionalization of olefins, installing an sp -alkyl
group and another carbon group into the substrates, represents
one of the most efficient MCR strategies to enable the
streamlined construction of aliphatic frameworks in a single
5
6
step. Regularly, transition metal (TM) catalysis, especially
7
8
Pd and more recently Ni catalysis, have been successfully
applied to these transformations (Scheme 1b). However, the in
situ-generated alkylmetal intermediates may undergo potential
side reactions such as β-H elimination and isomerization.
Despite the significant progress in TM-catalyzed reactions,
catalytic transition-metal-free dicarbofunctionalization, espe-
cially acylalkylation of alkenes, remains highly desired.
(
EDA) strategy (Scheme 1c). In particular, the newly formed
keto nitriles can allow various further transformations that
would be useful in synthetic and medicinal chemistry.
Received: November 24, 2020
Published: December 29, 2020
N-Heterocyclic carbenes (NHCs) have emerged as leading
organocatalysts, especially for the characteristic ability to access
9
umpolung reactivity of diverse aldehydes. In recent years,
NHC-catalyzed reactions via a radical process have evoked
©
2020 American Chemical Society
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Scheme 1. Overview of Dicarbofunctionalization of Olefins
and Our Working Hypothesis
Figure 1. Modifications of the conditions for NHC-catalyzed radical
relay acylcyanoalkylation of alkenes. Isolated yields are based on 3a.
and poor conversions were observed for both strong organic
and inorganic bases (Figure 1, lines 6 and 7). Additionally,
conducting the reaction under air or at room temperature was
found to be ineffective (Figure 1, lines 8 and 9). Finally, the
standard conditions were identified as those resulting in 71%
isolated yield (Figure 1, lines 8 and 9, and Tables S1−S5).
With the optimized conditions in hand, the substrate scope
was then investigated. The reactions of diverse olefins 2 with
1a and 3a were initially tested (Scheme 2). Excess olefins were
usually required to reach the best yields because of their high
volatility. Overall, substituted styrenes showed good tolerance,
with isolated yields ranging from 54% to 85% (4b−o).
Particularly, the reactions of sterically hindered 2-substituted
styrenes and 1-vinylnaphthalene proceeded smoothly to give
the corresponding products 4n−p in moderate yields. The
reaction of 4-vinylpyridine was also found to be feasible,
although with a slightly decreased yield (4q). Notably, the
intermolecular olefin acylalkylation has seldom been applied to
activated olefins such as acrylates because Michael addition
side reactions were prone to occur. Gratifyingly, the desired
products 4r−t were obtained in moderate yields for several
acrylates under 20 mol % NHC catalysis. However, phenyl
acrylate was not suitable for this protocol with low reaction
conversion, which might be explained by the lower reactivity
resulting from its conjugated structure and electronic effect
(4u). It was noteworthy that an acrylate bearing a
perfluorocarbon chain was also applicable to this method,
although with a lower yield. The obtained product 4v might
However, it was found that the reductive potentials of
cyclobutanone oxime esters were around −1.6 V vs SCE in
1
2d
MeCN,
while the reductive potentials of enolates
(
−
deprotonation of the Breslow intermediates) were around
13
0.95 to −0.97 V vs SCE in MeCN. It seems that the
enolates might not attain sufficient reductive potential for the
14
cyclic oxime esters. Since NHC/Lewis acid (LA) cocatalysis
has been widely used to enable numerous unconventional
transformations, we assumed that the electron transfer of this
theoretically mismatched species might occur with the
assistance of a Lewis acid. Herein we present a magnesium-
promoted NHC-catalyzed radical relay protocol to patch up
the potential gap between cycloketone oxime esters, aldehydes,
and alkenes, providing facile access to functionalized aliphatic
keto nitriles (Scheme 1c).
To start this work, cyclobutanone oxime ester 1a, styrene
2a), and 4-chlorobenzaldehyde (3a) were used as the model
substrates (Figure 1). No product was observed in the absence
of NHC catalyst A (Figure 1, line 1). The presence of
(
Mg(OTf) was also crucial to this MCR reaction, as otherwise
2
a low yield was observed (Figure 1, line 2). La(OTf) could
3
slightly enhance the reaction yield to 23% (Figure 1, line 3),
while other tested Lewis acids led to no acceleration (Table
S3). To our interest, the water content (2.0 equiv, 4600 ppm;
Table S5) was found to be another key factor for the success of
this reaction because using a super-dry solvent along with
molecular sieves (300 ppm; Table S5) or adding more water
16
have potential applications in fluorine chemistry. To further
demonstrate the utility of this protocol, some presynthesized
olefins bearing natural or bioactive fragments such as
cholesterol and estrone were then screened. To our delight,
they produced the desired products 4w and 4x in 28% and
60% yield, respectively.
Subsequently, the generality of aryl aldehydes was
investigated (Scheme 3). The substituents of the aryl
aldehydes were found to have a great impact on the reaction
yield. The yields varied widely from 41% to 73% (5a−n),
perhaps as a result of the varied reactivity and redox potential
(
i.e., 20 equiv) always gave inferior results (Figure 1, lines 4
15
and 5). Water may act as the activator for oxime esters, and
meanwhile, Mg(OTf) is prone to absorb moisture to form the
2
hydrated magnesium salt, which may affect the reactivity of
magnesium ions in organic solvent. Further screening of the
bases identified the weak base NaHCO as the optimal one,
3
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Scheme 2. Substrate Scope of Diverse Olefins
of the Breslow intermediates generated via the combination of
aryl aldehydes with the NHC. Overall, some of the para-
substituted benzaldehydes gave superior yields compared with
those bearing meta substituents (5a−c and 5f vs 5j−n). In
some cases, increasing the NHC precatalyst loading slightly
enhanced the reaction yields (5d and 5h−l). The more
sterically hindered 2-methylbenzaldehyde and 1-naphthalde-
hyde were inapplicable to this protocol (5o and 5p), while the
less sterically hindered 2-naphthaldehyde was tolerated to
afford product 5q in 44% yield. Next, several representative
heterocyclic aromatic aldehydes were examined. The reactions
of 2-furyl and 2-thienyl aldehydes proceeded smoothly to
afford the desired products 5r and 5s, both in 59% yield.
Decreased yields were obtained with nicotinaldehyde, benzo-
[
(
b]thiophene-2-carbaldehyde, and benzofuran-2-carbaldehyde
5t−v) because of poor conversion of the aldehyde substrates.
However, in the case of quinoline-2-carbaldehyde, the
undesired compound 5w′ derived from the two-component
coupling of the oxime ester with the aldehyde was obtained as
the major product. Moreover, aldehydes bearing bioactive
fragments were found to be suitable for this transformation.
Products 5x and 5y were obtained in lower yields because of
poor conversion of the aldehydes even when a higher catalyst
loading (20 mol %) was applied.
Next, we turned our attention to the scope of oxime esters
Scheme 4). Cyclobutanone oxime esters bearing substituted
(
Scheme 4. Substrate Scope of Cycloketone Oxime Esters
Scheme 3. Substrate Scope of Diverse Aryl Aldehydes
benzyl groups at the α-position (6a−h) were well-tolerated
under the optimal conditions, affording the corresponding
aliphatic keto nitriles in satisfactory yields but with poor
diastereoselectivity. α-Substituted cyclobutanone oxime esters
always exhibited excellent regioselectivity due to the tendency
to form more stable alkyl radicals. Besides α-substituted
cyclobutanone oxime esters, several other representative β-
substituted cycloketone oxime esters were also checked. To
our delight, β-methoxycarbonyl-substituted oxime ester,
oxetan-3-one oxime ester, and N-Boc-azetidin-3-one oxime
were also applicable under the optimal conditions, affording
products 6i, 6j, and 6k, respectively. Notably, the difficulty of
isolating the above products from the reaction mixture might
have a certain influence on the reaction yield. However, the
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coupling of thietan-3-one oxime ester led to a significantly
decreased yield because of the complexity of the reaction (6l).
It is noteworthy that the reaction of the oxime ester bearing a
menthol fragment worked equally well to introduce the
aliphatic chain with four functional groups in a single step
(
6m).
After exploring the substrate scope, we also tested the
feasibility of the reaction of a representative aliphatic aldehyde
z (Scheme 5a). Gratifyingly, the reaction of aldehyde 3z with
3
Scheme 5. Synthetic Applications
Figure 2. “On−off” experiment: tracking of the yields for different
reaction times with heating turned on or off every 20 min. All of the
1
yields were determined by H NMR spectroscopy using mesitylene as
the internal standard.
Scheme 6. Control Experiments
1
a and 3a did not perform well (Scheme 6a), and only a trace
amount of product 4a′ was observed along with a large
quantity of recovered aldehyde 3a. Additionally, the desired
three-component product was not observed when 2a was
replaced with 1,1-diphenylethene (2a′). Instead, a mixture of
two-component coupling products 8a and 8a′ was obtained
(Scheme 6b). Therefore, the role of styrene in this reaction
system was to capture nitrile alkyl radical IV to form the more
stable benzyl radical (intermediate VII in Scheme 7).
1
a and 2a was also able to form the desired product 5z,
although in a lower yield, under the catalysis of the unique
NHC precursor B reported by Ohmiya’s group. Since keto-
alkylated nitriles represent a class of important synthetic
intermediates, investigation of the scaled-up reaction and
downstream applications using product 4a as the starting
material were then conducted (Scheme 5b). The reaction on a
17
1
8
3
mmol scale under the standard conditions gave rise to
product 4a with a slightly decreased yield (60%). Reduction of
a with NaBH afforded alcohol 7a in 95% yield. 4a could be
Scheme 7. Proposed Mechanism
4
4
also smoothly hydrolyzed to carboxylic acid 7b in a moderate
yield, which had the potential for late-stage assembly of
medicinal molecules, such as the PROTACs and dual-target
inhibitors. In this case, late-stage decoration of 7b with
NH OH using a peptide coupling reagent (PCR) led to
2
19
HDAC inhibitor skeleton 7c. Alternatively, the amidation of
acid 7b with amphetamine or phenethylamine afforded
potential PROTACs frameworks 7d and 7e in high yields.
20
The above-developed methods demonstrated a great potential
for further medicinal and biochemical uses.
Several control experiments were then carried out to clarify
the possible mechanism (Figure 2 and Scheme 6). An “on−off”
experiment was conducted with a model reaction via
intermittent heating (Figure 2). The reaction mixture was
heated to 60 °C for 20 min, and then heating was stopped for
another 20 min. Subsequently, this progression was repeated
for two cycles. As expected, the reaction proceeded faster
during the heating period and slowed down without heating.
The heat input might be the driving force to accelerate the
single electron transfer (SET) in the Mg/oxime ester/Breslow
intermediate EDA complex. However, it was found that in the
absence of 2a, the two-component reaction between substrates
However, in the case of 2a′, the more sterically hindered
tertiary benzyl radical generated upon the combination of the
nitrile alkyl radical with 2a′ may block the further interaction
with the Breslow enolate radical intermediate V in Scheme 7.
Thus, this “matched” radical reactivity might be another
important factor for the success of this reaction.
Finally, a proposed radical−radical coupling mechanism
based on the experimental results and the literature is
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Letter
1
3,21
illustrated in Scheme 7.
Initially, the deprotonated Breslow
Kangyi Wang − School of Science, State Key Laboratory of
Natural Medicines, China Pharmaceutical University,
Nanjing 210009, P. R. China
Tao Lu − School of Science, State Key Laboratory of Natural
Medicines, China Pharmaceutical University, Nanjing
210009, P. R. China
intermediate III is formed through combination of the
aldehyde and NHC-I under basic conditions. As mentioned
above, the Breslow enolate may not have enough reductive
potential to reduce the oxime esters. Therefore, Mg(OTf) is
supposed to have an important interaction with the cyclo-
2
butanone oxime ester and enolate III to produce sandwich-
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03883
1
4,22
type complex IV.
Next, the thermally controlled SET event
between the enolate and cyclobutanone oxime ester provides
NHC-bound radical V and nitrile alkyl radical VI, respec-
Author Contributions
†L.C. and S.J. contributed equally to this work.
2
3
tively. The nitrile alkyl radical is quickly captured by an
olefin, forming the more stable benzyl radical VII. Subsequent
radical−radical coupling between VII and V affords
intermediate VIII, which is further transformed to the final
product with the regeneration of the NHC for the next
catalytic cycle.
In summary, we have described an NHC/Mg-cocatalyzed
olefin acylcyanoalkylation protocol to access structurally
diverse multifunctionalized aliphatic nitrile molecules. The
proposed Mg/cycloketone oxime ester/Breslow intermediate
EDA complex might account for the observed reactivity.
Moreover, given the simple reaction manipulation, freedom
from transition metal and photoredox catalysts, and wide
substrates generality, the developed protocol might have
widespread use in the fields of molecule assembly, PROTACs,
and dual target inhibitor library synthesis.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21572270 and 21702232) and the “Double First-Class”
University Project (CPU2018-GY02 and CPU2018GY35) for
financial support.
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