Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime

Article abstract of DOI:10.1021/jacs.7b06523

We report realization of the first enantioselective Cope-type hydroamination of oximes for asymmetric nitrone synthesis. The ligand promoted asymmetric cyclopropene "hydronitronylation" process employs a Cu-based catalytic system and readily available starting materials, operates under mild conditions and displays broad scope and exceptionally high enantio- and diastereocontrol. Preliminary mechanistic studies corroborate a Cu^I-catalytic profile featuring an olefin metalla-retro-Cope aminocupration process as the key C-N bond forming event. This conceptually novel reactivity enables the first example of highly enantioselective catalytic nitrone formation process and will likely spur further developments that may significantly expedite chiral nitrone synthesis.

Full text of DOI:10.1021/jacs.7b06523

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Communication
Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-
Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime
Zhanyu Li, Jinbo Zhao, Baozhen Sun, Tingting Zhou,
Mingzhu Liu, Shuang Liu, Mengru Zhang, and Qian Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Aug 2017
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Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-
Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime
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Zhanyu Li, Jinbo Zhao,* Baozhen Sun, Tingting Zhou, Mingzhu Liu, Shuang Liu, Mengru Zhang, and
Qian Zhang*
Jilin Province Key Laboratory of Functional Organic Molecule Design & Synthesis, Department of Chemistry, Northeast
Normal University, Changchun, Jilin, China
Supporting Information Placeholder
ABSTRACT: We report realization of the first enantioselective
Copeꢀtype hydroamination of oximes for asymmetric nitrone
synthesis. The ligand promoted asymmetric cyclopropene
“hydronitronylation” process employs a Cuꢀbased catalytic system
and readily available starting materials, operates under mild
conditions and displays broad scope and exceptionally high
enantioꢀ and diastereocontrol. Preliminary mechanistic studies
corroborate
a
CuIꢀcatalytic profile featuring an olefin
metallaꢀretroꢀCope aminocupration process as the key CꢀN bond
forming event. This conceptually novel reactivity enables the first
example of highly enantioselective catalytic nitrone formation
process and will likely spur further developments that may
significantly expedite chiral nitrone synthesis.
synthetic potential of the oxime version of Copeꢀtype amination
remains essentially untapped. Although a substoichiometric
inorganic base was recently found to facilitate the process in favor
of forging fiveꢀmembered ring closure,27 lacking of a facile
intermolecular process and an efficacious catalytic strategy
amenable to stereochemical control pose significant challenges for
this otherwise powerful nitrone formation process. Based on our
longꢀstanding interest in development of efficient CꢀN bond
As a highly versatile linchpin in synthetic chemistry,1,2 nitrone has
found widespread applications in 1,3ꢀdipolar cycloaddition for
heterocycle and natural product synthesis.3 Its multifaceted
applications as spin trapping agents,4 bioorthogonal probes5 and
efficacious therapeutic agents6 also render nitrone a heavily
pursued synthetic target. Chiral nitrones also serve as important
building blocks in asymmetric synthesis.7 In stark contrast to their
versatile reactivity and prominent roles, routinely employed
methods to synthesize nitrones still rely heavily on traditional
strategies8ꢀ12(Scheme 1, iꢀiii). Although alternative strategies are
emerging at an increasing rate in the past decade,13 none holds the
prospect of enantiocontrol. The great majority of extant methods
to access chiral nitrones rely on stoichiometric reaction of chiral
precursors typically of natural origins,14,15 which significantly
thwarted the application of chiral nitrones in organic chemistry
and related fields. Coupling readily available oxime and
electronꢀneutral olefin, an appealing and the most straightforward
approach for the formation of Nꢀalkyl nitrone, also offers the
advantage of being amenable to asymmetric catalysis. However,
such a process remains undefined so far (Scheme 1, iv).
construction
strategies,28
we
envisioned
a
transitionꢀmetalꢀcatalyzed twoꢀstep process to address these
challenges, wherein a transitionꢀmetal capable of ligating both
oxime and olefin could first promote
a
retroꢀCope
aminometallation to afford cyclometallated species (the putative
“metallaꢀretroꢀCope” intermediate). Protonation of this
intermediate then regenerates the catalyst and releases the formal
olefin “hydronitronylation” product (Scheme 2, ii). Herein we
present studies that validate the hypothesis, i.e., by identification
of an earthꢀabundant CuIꢀbased catalytic system, we realized an
intermolecular
desymmetritive
“hydronitronylation”
of
cyclopropene under exceptionally mild conditions (Scheme 3).
This unprecedented example of asymmetric Copeꢀtype
hydroamination with oximes displays several remarkable features,
including starting material availability, ligand enabled baseꢀmetal
catalysis, broad substrate scope, as well as remarkably high
enantioꢀ and diastereocontrol. To our knowledge, this process also
constitutes the first example of highly enantioselective nitrone
formation process. Additionally, the role of nitrone as masked
amine renders the process a potential route to cyclopropyl amine,
Copeꢀtype
hydroamination,
a
distinct
subtype
of
hydroamination,16 has recently garnered much synthetic
interest.17ꢀ24 However, since the seminal reports by Bishop25 and
Grigg26 with their respective coworkers on the intramolecular
thermal annulation of oxime with pendant olefin (Scheme 2, i), the
an
important
pharmocophore.
Direct
cyclopropene
hydroamination without ringꢀopening is challenging and has just
been realized very lately with rareꢀearth metal catalysts.29
The initial scouting reaction was performed by reacting
3ꢀphenylꢀ3ꢀmethyl cyclopropene 1a with benzophenone oxime 2a
Scheme 1. Nitrone formation strategies.
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using CuCl/dppbz as catalyst in the presence of a base at room
temperature. We envisioned that a substoichiometric amount of
base might suffice to initiate the process due to the basicity of the
bearing meta-substituted 3ꢀaryl and spirocyclic skeleton all
delivered the
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Scheme 3. Cu-catalyzed intermolecular Cope-type
hydroamination of cyclopropene.
Scheme 2. Cope-type hydroamination of oxime for the
synthesis of nitrones.
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Table 1. Scope of cyclopropenea
putative Cu(I) intermediates to regenerate the reactive species.
Indeed, with only 30 mol % NaOtꢀBu, the desired product 3a was
isolated in 92% yield with full conversion being reached within 40
min in toluene at room temperature (Scheme 3, i). The control
experiment without ligand resulted in no productive conversion,
indicating of dramatic ligandꢀenabled reactivity (for detailed
optimization, see Table S1 in the Supporting Information). This
observation prompted us to evaluate the effect of stereochemical
induction with chiral ligands. After
a brief screening of
commercially available ligands, solvents and temperature, we
found the reaction with (R)ꢀDTBMSegPhos L6 delivered 3a in 95%
yield and 92% ee in THF at ꢀ50oC within 3 h. Remarkably, under
all conditions the product was obtained as the exclusive
diastereoisomer, suggesting of a very high diastereoselectivity
control. The reaction also demonstrated good tolerance of air and
moisture, as the reaction performed with minimal precautions
(performed under air, without drying glassware, in wet solvents)
still afforded product 3a in a good yield without erosion of
enantioselection (75%, 92% ee). The reaction is also easily scaled
up to 2 mmol, producing 3a in 98% yield with the same
enantioselectivity (Scheme 3, iii).
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv.),
CuCl (5 mol %), L6 (6 mol %) and NaOtꢀBu (30 mol %) in THF
(0.1 M).
An evaluation of the generality of the reaction by variation of
cyclopropenes with the optimized conditions (Table 1)
demonstrates the robustness of the current hydronitronylation
protocol. The great majority of examined 3ꢀarylꢀ3ꢀalkyl, 3,3ꢀdiaryl,
or 3,3ꢀdialkyl cyclopropenes uneventfully produced the
“hydronitronylation” products in high yields with excellent
enantioselectivities. The reactivity and enantioselectivity is
generally insensitive to electronic poperties of the aryl substituents
(3aꢀk). Slight decrease of enantioselectivities was observed for the
sterically encumbered analogues (3l and 3m). Single crystal Xꢀray
diffraction studies of 3n allowed for unequivocal determination of
its structure and absolute configurations (Fig. S8). Those of the
other products are assigned by analogy. Improved
enantioselectivities were observed with cyclopropenes bearing
3ꢀalkyl substituents beyond methyl (3o). The reaction of more
bulky iꢀPrꢀsubstituted cyclopropene, however, turned out sluggish.
3p was isolated in a mere 5% yield with NHC ligand L10, with a
reversed facial selectivity (Figs. S1ꢀS3), suggesting that
diastereocontrol originates from steric differentiation. Substrates
corresponding nitrone products in high yields and
enantioselectivities (3i-k, 3r). 3,3ꢀDiaryl cyclopropane delivered
the corresponding nitrone with a slightly reduced enantioselection
control at room temperature (3q). Notably, unsymmetrical
3,3ꢀdialkyl substituted nitrone 3s was obtained in a diatereomeric
ratio of 4/1 under the racemic reaction conditions with dppbz as
ligand. With the chiral ligand L6, however, the diastereomeric
ratio was improved to 18.6/1, with the major diastereomer being
formed in 96% ee (Figure S4). These results demonstrate that
ligand exerts a decisive role in both enantioꢀ and diastereocontrol
and overrides the substrate control.
We then turned to evaluate the scope with respect to oximes
(Table 2). Oximes derived from substituted benzophenone
afforded the products uneventfully in high yields and
enantiocontrol (3tꢀ3w). For Aryl alkyl ketone derived oximes, the
employment of more electronꢀrich ligand was necessary, and
MeOꢀBIPHEP derivative L7 as ligand achieved high efficiency
and excellent selectivity. Notably, for these substrates Eꢀproducts
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were formed as the predominant isomer (exemplified by the
To gain some mechanistic insights of the current
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crystal structure of 3x’ in Fig. S9) in high yields with good to high
E/Z ratios (varying from E/Z = 5/1 to exclusive E).30 Reactions of
propiophenone derived oximes bearing a variety of electronically
transformation, we performed some preliminary mechanistic
studies. Addition of radical inhibitor 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylꢀ
phenol (BHT) to the the optimized conditions (Scheme 3, i)
imparted negligible impact on the reaction efficiency (isolated
yield: 79%), while the reaction performed under an atmosphere of
O2 delivered the desired product 3a in a significantly lower yield
of 15%. The insensitivity to radical inhibitors and susceptibility to
oxygen suggest of a CuIꢀcatalytic profile, rather than the most
commonly invoked radical pathways involving single electron
distinct
hydronitronylation
substituents
afforded
with
the
high
corresponding
yields and
products
enantioselectivities (3xꢀ3ze, 59ꢀ99% yields, 95ꢀ98% ee).31
Substrates bearing electronꢀrich heteroaryl (3zg) and various
alkyls of different chain length and sterical requirements
(3zh-3zm) also had negligible effect on reactivity or selectivity.
Overall, the current hydronitronylation strategy demonstrated
remarkably wide scope, granting efficient access to ketonitrones
otherwise difficult to obtain from condensation of ketone with
hydroxyamines.32 Furthermore, the reaction works equally well
with aldoximes, affording a series of Zꢀproducts (see the crystal
sturcutre of 4f in Fig. S10) in high selectivities. The efficiency and
selectivities are unanimously high across a diverse range of
aldoximes bearing electronically distinct functional groups at 4ꢀ
and 3ꢀ positions of the phenyl group (4aꢀ4j, 89-99%, 80-> 99.9%
ee). Again, sterically encumbered 1ꢀnaphthyl as well as pyridyl
aldoximes worked equally efficiently with respect to both
efficiency and selectivity (4l-4n). The high reactivity of the latter
is remarkable considering usually strong catalyst poisoning caused
by ligation of pyridine to metal center.
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transfer (SET) between copper and oxime derivatives.33,34
A
comparative study revealed that oxime and oxime acetate
retrieved the same product in essentially identical yields and
enantioselectivities (Table S3), suggesting that oxime ester rapidly
hydrolyzes to oxime prior to coupling with cyclopropene.
Furthermore, when MeOD was used as exogenous proton source
in the reaction of oxime ester, product 3aꢀd was obtained in 93%
yield with 71% deuterium incorporation, indicating of the
intermediacy of cyclopropyl copper species (Scheme 4). The syn
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relationship of
D
(Ha) with Me in 3aꢀd was assigned
unequivocally by 2D NOESY studies of 3a combined with the
isotope labeling experiment. Taken together, these observations
corroborate a CuIꢀbased catalytic profile featuring a putative
innerꢀsphere cis aminocupration process (Figure 1). Similar to the
hypothesis outlined above (Scheme 2, ii), it is proposed that the
oxime ligated Cu(I) species engages cyclopropene to form
πꢀcomplex C, which undergoes migratory insertion to generate the
key cyclopropyl copper D (the metallaꢀretroꢀCope intermediate).
We propose that this process proceeds via a fiveꢀmembered
metallaꢀretroꢀCope transition state to forge the key CꢀN formation
(TS, Figure 1).35 Protonation D with oxime 1a (path a) or tꢀBuOH
(path b) releases the product 3a and regenerate the copper
intermediates B (path a) or L*CuOtꢀBu M (path b). In path b, M
might be protonated by oxime to regenerate oximeꢀligated copper
intermediates B to close the catalytic loop.
Table 2. Scope of oximes.
Scheme 4. Deuterium labeling experiment.
Figure 1. A plausible CuIꢀbased mechanistic profile.
We have presented the first example of intermolecular
Copeꢀtype hydroamination process of oximes using catalytic
earthꢀabundant copper salts with the promotion of chiral ligands,
allowing for a practical, straightforward access to valuable chiral
nitrones in high enantioꢀ and diastereoselectivities from readily
available starting materials. The CuIꢀcatalyzed process
demonstrated broad scope and remarkable ligandꢀdirected
stererocontrol, representing the first example of highly
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv.),
CuCl (5 mol %), L (5 mol %) and NaOtꢀBu (30 mol %) in toluene
(0.1 M).
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of the conceptually novel reactivity mode are expected to
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, analytical and spectral data (PDF)
Crystal data for 3n, 3x’ and 4f (CIF)
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AUTHOR INFORMATION
Corresponding Author
zhaojb100@nenu.edu.cn; zhangq651@nenu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from NNSFC (21402025, 21372041), the
Fundamental Research Funds for the Central Universities
(2412017FZ014), and Changbai Mountain Scholarship Program
are gratefully acknowledged.
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