Stereospecific 1,4-Metallate Shift Enables Stereoconvergent Synthesis of Ketoximes

Article abstract of DOI:10.1002/anie.201906057

Reported herein is a stereospecific 1,4-metallate rearrangement for single-geometry ketoxime synthesis from oxime chlorides and arylboronic acids. This strategy exhibits broad substrate scope with excellent stereoselectivity under mild reaction conditions. In comparison with the conventional approaches, each configuration of unsymmetric diaryl oximes, as well as the thermodynamically less stable Z isomer of aryl alkyl ketoximes can be selectively and exclusively obtained. The reactivities of unsymmetric diaryl oximes and the Z isomer of aryl alkyl oximes, a class of underexplored molecules, enables efficient access to the corresponding isoquinolines, isoquinoline N-oxides, and amides having a single configuration.

Full text of DOI:10.1002/anie.201906057

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Accepted Article
Title: Stereospecific 1,4-Metallate Shift Enables Stereoconvergent
Synthesis of Ketoximes
Authors: Qiuling Song, Kai Yang, Feng Zhang, Tongchang Fang, and
Guan Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906057
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10.1002/anie.201906057
Angewandte Chemie International Edition
RESEARCH ARTICLE
Stereospecific 1,4-Metallate Shift Enables Stereoconvergent
Synthesis of Ketoximes
Kai Yang, [a] Feng Zhang, [a] Tongchang Fang, [a] Guan Zhang, [b] Qiuling Song*[a, b]
Dedication ((optional))
Abstract: We herein report
a
stereospecific 1,4-metallate
nitroso species[14] as well as the reduction of nitro compounds,[15]
however, the proportion of E/Z-isomers depends on the nature
of substrates by thermodynamic control, which usually causes
rearrangement for single geometric ketoxime synthesis from oxime
chlorides and arylboronic acids, this strategy exhibits broad
substrate scope with excellent stereoselectivity under mild conditions. severe isolation problems to access a single geometric isomer
In comparison with the conventional approaches, two single
configurations of unsymmetric diaryl oximes and thermodynamically
less stable Z-isomer of aryl alkyl ketoxime can be selectively and
exclusively obtained. The reactivity of unsymmetric diaryl oximes or
Z-isomer of aryl alkyl oximes, a class of molecules underexplored,
enables efficient access to corresponding isoquinolines, isoquinoline
N-oxides and amides with one single configuration.
unless the two substituents of the ketoximes are distinct (Figure
1B). Thus, a pragmatic and universal direct stereoselective
synthesis of stereochemically pure ketoximes, especially
thermodynamically less stable ketoximes, remains an unsolved
challenge in modern chemical transformations.
Oximes, first disclosed in 19 century,[1] are well-known as the
starting materials of Beckmann rearrangement,[2] which ranks
one of the most important name reactions since it has been
successfully employed in the industrial production of
caprolactamthe key precursor of Nylon-6.[3] Based on the well-
studied mechanisms,[4] the rearrangement of ketoximes occurs
stereospecifically with the migration group anti to the hydroxyl
group, therefore unsymmetric non-stereospecific ketoximes will
undoubtedly lead to two amides which are inseparable (Figure
1A). Notably, asides from their use as the important industrial
starting blocks, oximes are ubiquitous structural motifs in drugs,[5]
bioactive molecules[6] and food additives.[7] Meanwhile, biological
evaluation experiments indicate that different isomers of
ketoximes showcase different bioactivities,[8] which makes
stereospecific synthesis of ketoximes crucial in both industry and
drug discovery. Moreover, oximes are widely used in metal-
involving transformations.[10] For instance, ketoximes can served
as directing groups in C-H activation,[11] like the Beckmann
rearrangment, non-stereospecific ketoximes would render a
mixture of two isomers.[12] Notwithstanding the wide applications
and high desire on the stereochemically pure ketoximes, the
synthetic strategies which could lead to only one single
geometric ketoxime are very rare,[13] which does not match the
significance of the single geometric ketoximes in chemical
syntheses, industrial applications as well as pharmaceutical
sciences.
Figure 1. Motivation and preparation of the single geometric ketoxime isomers.
With these issues in mind, we are interested in seeking a
mechanistically distinct strategy, without considering the
configuration of the starting materials and transition metals
involvement, to conveniently provide a general method for the
construction of single geometric ketoximes. At this point, nitrile
oxides catch our eyes, since ketoximes were reported to be
obtained when organometallic reagents or aromatic nucleophiles
reacted with them in the presence of Lewis acids.[16]
Unfortunately, the diversity and stereoselectivity of ketoxime
products was highly restricted owing to the instability of nitrile
oxides and the strong nucleophilicity of these organometallic
reagents. Given that the features of nitrile oxides, we postulated
that a weak electrophilic pairing with nitrile oxides which are
generated in situ as a nucleophile may solve this problem.
Arylboronic acids and their derivatives, stable and easy to
prepare, are not only widely used in transition-metal-catalyzed
Suzuki–Miyaura cross-coupling reactions,[17] but also can be
used to build C-C bonds under transition-metal-free conditions
due to its weak nucleophilicity.[18-20] In this scenario, we consider
that the boron “ate” complex of nitrile oxide might be a perfect
The prototypical ketoxime synthesis involves the condensation
of ketones with hydroxylamine[1a] or the tautomerization of C-
[a]
[b]
Dr. K. Yang, F. Zhang, T. Fang, Prof. Dr. Q. Song
Key Laboratory of Molecule Synthesis and Function Discovery,
Fujian Province University, College of Chemistry at Fuzhou
University, Fuzhou, Fujian, China, 350108
E-mail: qsong@hqu.edu.cn
G. Zhang, Prof. Dr. Q. Song
Institute of Next Generation Matter Transformation, College of
Materials Science Engineering at Huaqiao University
668 Jimei Boulevard, Xiamen, Fujian, China, 361021
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/anie.201906057
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RESEARCH ARTICLE
one which might lead to the stereochemically pure ketoximes via
a stereospecific 1,4-metallate shift (Figure 1C).[20] We envisioned
a process wherein a nitrile oxide would first be generated in situ
from dehydrochlorination of oxime chlorides that are readily to
prepare[21]. The 1,3-dipole of nitrile oxide would then attack the
electrophilic boron atom of arylboronic acids resulting in a boron
“ate”-complex,[22] which might undergo a stereospecific 1,4-
metalate shift forming ketoxime boronic acid complex.
Subsequent hydrolysis of ketoxime boronic acid complex
removes the boron acid part and highly stereoselective ketoxime
products might be resulted (Figure 1C). However, there are
several formidable challenges in this hypothesis: (1) the
stereocontrol of ketoximes; (2) low stereoselectivity by the
competition of direct nucleophilic arylation of nitrile oxide;[19j] (3)
the potential oxidation of arylboronic acids by nitrile oxides via
1,2-metallate shift of boron “ate”-complex;[23] (4) the instability of
thermodynamically less stable products. Herein, we describe a
novel, pragmatic and general method for stereoselective
synthesis of ketoximes, including thermodynamically less stable
ketoximes. This strategy goes smoothly under mild conditions
with simple operation, excellent stereoselectivity and broad
substrate scopes.
To our delight, our strategy was also applicable to alkyl oxime
chlorides. A series of Z-isomer alkyl aryl ketoximes (23 to 35),
which are thermodynamically less stable ones that were difficult
to obtain by conventional method, can be obtained from alkyl
oxime chlorides with excellent stereoselectivity. The chain length
of alkyl oxime chlorides had no effect on the stereoselectivity of
this transformation, providing corresponding Z-isomer ketoximes
23 to 25 in moderate yields. Other linear oxime chlorides
containing phenyl, 1-adamantyl and methoxy groups were also
capable substrates to obtain 26 to 28 with Z-configuration. Our
protocol worked efficiently with branched oxime chlorides as well
(29 to 31). The generality of α-cyclic oxime chloride was broad,
as products of α-cyclohexane (32), α-(methyl-4-formyl)
cyclohexane (33), α-piperidine (34), α-cyclopropane (35) and α-
cyclobutane oxime chloride (36) could all be obtained with high
stereoselectivity and cyclic rings intact, even for the strained
cyclopropane and cyclobutane. The structure of 2, 22 and 27
were unambiguously confirmed by X-ray diffraction analysis.[27]
Then we explored the scope of arylboronic acids and
heteroarylboronic acids (Figure 3). Electron-rich arylboronic
acids were proved to be very amenable to our protocol (37 to
47). Arylboronic acids bearing halogen substituents provided the
corresponding products in good yields with excellent
stereoselectivity (37 and 38). Aside from alkoxy substituents (37
to 43), arylboronic acids with methylthio and nitrogen
substituents reacted smoothly to afford product 44 to 47.
Compound 45 can be further converted into an anticancer
reagent.[28] Analogues with electron neutral para-tert-butyl, para-
methyl and para-trimethylsilyl groups gave moderate to good
yields (48 to 50). 2-Naphthalene, 1-naphthalene and
phenanthren-9-ylboronic acids gave the desired products in
moderate to good yields (51 and 53). Remarkably, our protocol
was efficient to heteroarylboronic acids as well, for instance, the
unprotected 5-indole, 2-indole, 3-carbazole, 2-pyrrole, 3-
thiophene and 3-benzo[b]thiophen boronic acids were all
amenable in this protocol, resulting in the formation of heteroaryl
ketoximes in a single configuration (54 to 59). More importantly,
arylboronic acids derived from bioactive molecules or drugs,
including clofibrate, δ-vitamin E and epiandrosterone, were
converted into the corresponding ketoximes with moderate
yields and excellent stereoselectivity (60 to 62). This convenient
transformation may provide a useful tool for the discovery of new
bioactive molecules. Regrettably, alkenyl and alkylboronic acids
cannot obtain the corresponding ketoximes.
Condition survey was carefully carried out (see the
Supplementary Information (SI) for details), the optimized
condition eventually emerged as 1 equiv of arylboronic acids,
1.5 equiv of oxime chlorides with 1.5 equiv of K3PO4 as base in
dichloromethane at 0 °C. With the optimized reaction conditions
in hand, the substrate scope of oxime chlorides in this
transformation was first explored (Figure 2). A wide range of aryl,
alkenyl and alkyl oxime chlorides were found applicable to this
reaction with excellent stereoselectivity. Methyl substituted aryl
oxime chlorides at different positions gave good to excellent
yields of the corresponding products (3 to 6, 73-95% yields),
remarkably, the steric hindrance of 2,4,6-trimethyl substitution
did not affect the efficiency of the reaction (6). Aryl oxime
chlorides with 4-phenoxy and 3-siloxy substituent furnished the
desired products 7 and 8 in 91% and 78% yields. The
pharmaceutically
relevant
difluoromethoxy[24]
and
trifluoromethoxy[25] groups were also well tolerated to obtain
corresponding products 9 and 10. 2-Naphth and 1-naphth oxime
chlorides were also suitable substrates for this transformation,
affording 11 and 12 in 90% and 56% yields respectively. (E)-2-
pyridylaryl ketoxime (13), a skeleton of many biologically active
molecules,[26] can be smoothly synthesized in 48% yield.
Functional groups, such as halogen (14-17), boronic ester (18)
or carboxylic ester (19), were tolerated well that are of utmost
value for further structural elaborations. We were pleased to find
that alkenyl oxime chlorides were capable substrates as well,
providing the desired products in moderate to excellent yields
(20 to 22, 51-93% yields).
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10.1002/anie.201906057
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Figure 2. Scope of stereoselective synthesis of ketoximes with oxime chlorides. Reaction conditions: oxime chlorides (0.3 mmol, 1.5 equiv), 1 (0.2
mmol, 1.0 equiv), K3PO4 (0.3 mmol, 1.5 equiv), 0 oC, 24 hours unless otherwise specified. The yields were isolated yields. The isomer ratios were
determined by 1H NMR. a Reaction run at -20 oC. b Reaction run at -30 oC. DCM = dichloromethane; TBS = tert-butyldimethylsilyl; pin = pinacol.
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Figure 3. Scope of stereoselective synthesis of ketoximes with arylboronic acids. Reaction conditions: oxime chlorides (0.3 mmol, 1.5 equiv),
o
arylboronic acids (0.2 mmol, 1.0 equiv) and K3PO4 (0.3 mmol, 1.5 equiv), N2 atmosphere, 0 C, 24 hours unless otherwise specified. The yields were
isolated yields. The isomer ratios were determined by 1H NMR. a Reaction run at -20 oC. b Reaction run at 15 oC. c Reaction run at -10 oC. TMS=
trimethylsilyl.
Figure 4. Synthetic application. A) Gram-scale synthesis of 32. B) Ketoximes as directing group in C-H activation. Conditions: (1) [RhCp*Cl2]2 (1 mol%),
and CsOAc (30 mol%) at CH3OH at 60 oC for 12 hours; (2) [RhCp*Cl2]2 (2.5 mol%) and AgSbF6 (6.8 mg, 10 mol%) at CH3OH at 60 oC for 12 hours. C)
Beckmann rearrangement. Conditions: PCl5 (2 equiv) in DCM at room temperature for overnight.
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The protocol shows equal stereoselectivity and efficiency at 5
gram scale (50 mmol, 250 times) with oxime chloride 65 and
boronic acid 1 (Figure 4A), and the product 32 was obtained by
a three-step reaction with one purification that further illustrated
the applicability of our approach. Unsymmetric diaryl oximes
with single isomer and Z-isomer of aryl alkyl ketoximes are rare
compounds whose reactivity needs further exploration. In this
context, we tried to explore the reactivity of ketoximes as
directing group in C-H activation (Figure 4B) and Beckmann
rearrangement (Figure 4C). In terms of C-H activation,
compound 2 reacted with diphenylacetylene (66) or diazo
compound 68 with Rh(III) catalyst lead to isoquinoline (67)[12] or
isoquinoline N-oxides (69)[29] as the single isomer, and these C-
H activations of unsymmetric diaryl oxime 2 occurs only on the
aromatic ring which is trans to the hydroxyl group. The
corresponding amides 70 and 71 can be exclusively accessed
through Beckmann rearrangement of diaryl oxime 2 and aryl
alkyl oxime 35 in the presence of PCl5. These results indicated
that no isomerization of unsymmetric diaryl oximes occurs
during the reactions.
reaction and our protocol (Figure 5A). Two single configurations
of diaryl oximes (73 and 74) can be exclusively obtained by the
changing of substrates under our standard conditions, while 1:1
ratio of E- and Z-isomers was obtained by the classical
approach due to the similarity of the two substituents of the
ketone 72. The E-isomer of ketoxime 77 was generally obtained
from the condensation reaction between aryl alkyl ketone and
hydroxylamine by the conventional methods, but our protocol
can surprisingly and exclusively afford thermodynamically less
stable Z-isomer of aryl alkyl ketoxime product 27 (Figure 5B). To
thoroughly understand this mechanism, control experiments
were conducted. Ketoxime 6 was obtained smoothly when nitrile
oxide 78 and arylboronic acid 1 was mixed up in the absence of
base, while no the corresponding ketoxime ether 80 was
obtained when oxime ether chloride 79 and arylboronic acid 1
were exposed under standard conditions, since oxime ether
chloride 79 could not be converted to nitrile oxide under basic
conditions, therefore no coordination between 79 and
arylboronic acid (Figure 5C). These results clearly demonstrated
that nitrile oxide is the key intermediate for this transformation,
thus validate our hypothesis (Figure 1C).
To evaluate the practicality of the protocol, we preformed the
comparison experiments between classical condensation
Figure 5. Comparison experiments and control experiments.
In summary, we have developed a direct stereoselective
synthesis of single geometric ketoximes between oxime
chlorides and arylboronic acids via stereospecific 1,4-metallate
rearrangement. This approach allowed the preparation for single
geometric diaryl oximes and thermodynamically less stable Z-
isomer of aryl alkyl oximes under mild conditions with simple
operation. Excellent stereoselectivity was observed for a broad
substrate scope with good functional group tolerance.
Furthermore, the reactivity of unsymmetric diaryl oximes or Z-
isomer of aryl alkyl oximes in C-H activation or Beckmann
rearrangement was explored. It provides a good opportunity for
the development of oxime chemistry and demonstrates a
promising approach to prepare single geometric ketoximes for
both chemical community as well as pharmaceutical sciences.
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RESEARCH ARTICLE
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Acknowledgements
Financial support from the National Natural Science Foundation
(21772046) and the Natural Science Foundation of Fujian
Province (2016J01064) are gratefully acknowledged.
Keywords: ketoximes • arylboronic acids • stereospecific • 1,4-
metallate shift • stereoconvergent
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10.1002/anie.201906057
Angewandte Chemie International Edition
RESEARCH ARTICLE
Communication
Kai Yang, Feng Zhang, Tongchang
Fang, Guan Zhang, Qiuling Song *
Page No. – Page No.
Stereospecific 1,4-Metallate Shift
Enables Stereoconvergent Synthesis
of Ketoximes
Stereoconvergent Synthesis of Ketoximes: A stereospecific 1,4-metallate
rearrangement for single geometric ketoxime synthesis from oxime chlorides and
arylboronic acids was developed, this strategy exhibits broad substrate scope with
excellent stereoselectivity under mild conditions.
This article is protected by copyright. All rights reserved.