A Facile Approach to Oximes and Ethers by a Tandem NO+-Initiated Semipinacol Rearrangement and H-Elimination

Article abstract of DOI:10.1002/anie.201807861

An efficient oximation method has been developed on the basis of NO⁺-initiated semipinacol rearrangement and subsequent proton elimination. The procedure enabled the rapid construction of a series of oximes and oxime ethers with spiro quaternary stereocenters from allylic silyl ethers. Additional features of this reaction include wide substrate tolerance as well as the commercial availability of the safe nitrosation reagent NOBF₄. The key N-heterotricyclic cores of three natural alkaloids, tuberostemoninol B, (+)-quebrachidine, and an insecticide, were also constructed efficiently by this method.

Full text of DOI:10.1002/anie.201807861

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Accepted Article
Title: A Facile Approach to Oximes and Ethers by a Tandem NO+-
Initiated Semipinacol Rearrangement and H-Elimination
Authors: Jia-Wei Dong, Tongmei Ding, Shu-Yu Zhang, Zhi-Min Chen,
and Yongqiang Tu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807861
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10.1002/anie.201807861
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A Facile Approach to Oximes and Ethers by a Tandem NO+-
Initiated Semipinacol Rearrangement and H-Elimination
Jia-Wei Dong, Tongmei Ding, Shu-Yu Zhang*, Zhi-Min Chen*, and Yong-Qiang Tu*
Abstract:
A
novel and efficient oximation method has been
traditionally using hydroxylamine or relatives have ever suffered
many times of explosions in the case of high temperature or in
the presence of reductive metal such as iron powder.[6] Thus
developing new and safe methods to rapidly prepare these
special and versatile oximes or ethers from relatively simple
substrate is still required.
developed based on NO+-initiated semipinacol rearrangement and
subsequent proton elimination, which enables rapid construction of a
series of oximes and oxime ethers with spirocycles and quaternary
stereocenters from allylic silyl ethers. Additional features of this
reaction include high efficiency in most cases, wide substrate
toleration as well as commercial availability of safe nitrosation
reagent NOBF4. Three vital N-heterotricyclic cores 6, 10 and 11
have also been constructed efficiently by use of this method, which
would access readily to the short synthesis of three natural alkaloids,
tuberostemoninol B, (+)-quebrachidine and insectside 12,
respectively.
Nitrosonium tetraflouroborate (NOBF4) is a safe, conveniently
handled and commercially available reagent. It has been widely
used as oxidant, radical initiator,[7] as well as nitrosation reagent,
although the last receives less attention.[8] With our longstanding
interest to the semipinacol rearrangement of allylic alcohols,[9-11]
we expect that NO+ species act both as an electrophile and a
nitrosation species to initiate a tandem nitrosation/semipinacol
rearrangement of allylic silyl ethers, which could possibly
It is a fact that most of the bioactive and pharmaceutical agents
belong to the nitrogen-containing organic molecules, among
generate
a
nitrosyl product. Delightedly, after careful
optimization of reaction conditions, we observed a novel and
very fast oximation reaction, producing the oxime or oxime ether
with spiro- and fused polycycles and quaternary stereocenters.
This unique transformation involves an initial NO+ addition to
C=C bond, then a semipinacol rearrangement and finally an
unexpected base-mediated proton elimination/transfer.[12] Thus
this method is of prominent significance in the field of synthetic
N-hetereo-chemistry because it not only introduces facilely the
N-atom to complex organic frameworks, but also creates
versatile =NOH group. Herein, we present this tandem reaction
and the rapid construction of three vital tricyclic cores 6, 10 and
11 for the synthesis of natural alkaloids.
which the N-heterocyclic compounds play
a
particularly
important part.[1a] For example, the alkaloids tuberostemoninol B,
(+)-quebrachidine and insectside 12 (Scheme 1) incorporate
three kinds of characteristic spiro- and fused polycyclic
frameworks
psychosedative, adrenergic and insecticidal biologically activities,
respectively.[1b-i]
Therefore, developing efficient and
and
exhibit
the
significant
antitussive
straightforward method to construct the N-heterocyclic organic
molecules is highly demanded both for fundamental and
practical research of synthetic organic and pharmaceutical
chemistry.[2,3] Oximes and their ethers (also named isoazolines)
are a large number of basic N-hetero- species present in many
bioactive compounds[4] and also the versatile building blocks for
synthesis of a number of bioactive N-heterocyclic compounds.
Particularly for example, the spirocyclic and quaternary
stereocenters oximes 3 and ethers 2 represent a special class
of vital structural motifs, which could rapidly be transformed to
diverse polycyclic bioactive alkaloids such as those in Scheme 1.
During the past decades, however, tremendous progresses
have been made for using ketones and hydroxylamine reagents
to synthesize oximes and ethers, and fewer other special
methods without ketone and hydroxylamine are available to
elaborate the complex and useful oximes and ethers like 2 and
3.[5] And on the other hand, some industrial operations
[*]
J.-W. Dong, Dr. T. Ding, Prof. Dr. S.-Y. Zhang, Prof. Dr. Z.-M.
Chen, Prof. Dr. Y.-Q.Tu
School of Chemistry and Chemical Engineering, and Shanghai
Key Laboratory for Molecular Engineering of Chiral Drugs,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, P. R. China
Scheme 1. Design of a NO+-mediated approach to oximes/ethers and its
E-mail: zhangsy16@sjtu.edu.cn
chenzhimin221@sjtu.edu.cn
application to synthesis of the key cores of natural products
tuyq@sjtu.edu.cn
Prof. Dr. Y.-Q.Tu
State Key Laboratory of Applied Organic Chemistry and College of
Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R.
Our study was commenced by employing 1h as a model
substrate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a
base in CH3CN solvent. Delightedly, in an initial nitrosation test
with NOBF4 at room temperature, we were pleased to obtain the
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10.1002/anie.201807861
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desired product 2h, albeit in 12% yield (Table 1, entry 1). When
the unprotected allylic alcohol 1h in stead of 1h was used, only
a proton-promoted rearrangement product was found without
NO participating (entry 2). This result indicated that protecting
the OH group of allylic alcohol substrate was necessary to
effective to this reaction and furnished good yield (84%) of 2h,
but only a moderate yield (54%) of 2i. The low yield of 2i was
possibly due to the poor solubility of 1i in nitrile, which led to a
much longer reaction time (8 hours) and thus resulted in de-
oximation of 2i to a spirocyclicdione by-product.
o
perform this reaction. Then decreasing the temperature to 0 C
Table 2. Substrate scope of NO+ promoted semipinacol rearrangement.[a]
significantly improved the yield to 43% (entry 3). When
temperature was further decreased to -30 oC, 2h could be
obtained in higher 78% yield (entry 4). Furthermore, the base
additive also played a key role in improvement of reaction
efficiency, thus more organic bases such as pyridine, imidazole
and 2,6-di-tert-butylpyridine (DTBP) were further tested, and
DTBP gave the best 82% yield (entry 7). In addition, inorganic
bases and other solvents were also tested. However, no better
result was obtained (See Supporting Information). As a result,
the condition of entery 7 was selected as the general optimal
procedure for the substrate scope investigation below.
Table 1. Optimization of NO+-promoted semipinacol rearrangement.[a]
entry
base
DBU
DBU
DBU
DBU
Py
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
T (oC)
r.t.
yield
12%
trace[b,c]
43%
78%
74%
55%
82%
1
2
3
4
5
6
7
r.t.
0
-30
-30
-30
-30
Imid
DTBP
[a] Reactions were conducted using: 1h (0.2 mmol), NOBF4 (0.25 mmol), base
(15 mol%), in solvent (2 mL) stirred for 5 min. at T oC under Ar. Isolated yield.
[b] Unprotected allylic alcohol 1h’ was used. [c] Proton-promoted
rearrangement product was obtained. Py = pyridine, Imid = imidazole. For
detail operation, also please see SI.
With the general optimal condition (Table 1, entry 7) in hand,
we next explored the substrate scope with various allyl
substituted cyclobutyl ethers. The obtained results (Table 2)
indicated that a number of cyclobutyl silyl ether substrates of
both cyclic (6-to-8 membered) alkenes (1a-1i) and acyclic
ethylenes (1j-1y) could react under the general condition to give
[a] Reactions were conducted using: 1 (0.2 mmol), NOBF4 (0.25 mmol), DTBP
(0.03 mmol), in CH3CN (2 mL) stirred for 5 min at -30 oC under Ar. Isolated
yield. [b] 8 h. [c] Reaction for 5 mmol scale. For detail operation, also please
see SI.
the
hemiketal-type
oxime
ethers
2a-2y
in
high
diastereoselectivity (only a single diastereomer was found in
each example) with moderate to excellent yields. Firstly, seven
cyclic hexenyl (1a-1d), heptenyl (1e-1f) and octenyl (1g)
substrates with or without substitutes could react smoothly to
generate the structurally diverse and elaborated tri-to-tetra-cyclic
oxime ethers 2a-2g with moderate to high yields. Importantly,
some multi-cyclic products could be readily transformed to, or
exist widely in the bioactive oxime ethers.[4e,13] The relative
configuration of the ether products was determined by X-ray
crystallography of compound 2a.[14] Similarly, two O- and N-
hetero cyclohexenyl substrates 1h and 1i proved to be also
Subsequently, twenty acyclic ethylenyl cyclobutyl ether
substrates 1j-1y, some of which contained methyl or various
aryls at ethylene units and/or methyl at cyclobutyl rings, were
examined under the general optimal condition. Delightedly all
demonstrated to be tolerable to this reaction to generate the
oxime ethers as a single diastereomer. And most substrates,
which contained electron-withdrawing groups (1n-1t) or no
substituents at aryl (R1) (1j, 1u and 1x), or dialkyls (R3, R4) at
cyclobutyl part, could afford the corresponding products in
moderate to good yields (67-83%), despite few examples (1k-
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1m and 1y) with the electron-neutral methyl-phenyl (R1) or
methyl (R2) at ethylene moiety gave just the medium yields 47-
58%. Notably, these aryl-substituted and quaternary centers
containing oxime ethers possessed extensive utilities for
synthesis of advanced polycyclic N-hetero intermediates such as
6, 10 and 11 (Schemes 1 and 2). It should also be particularly
mentioned that substrate 1x with an ethyloxy rather than the
silyloxy reacted to give exceptional ethyl ketal-type oxime ether
acid (TFA) in dichloromethane (DCM) to give a spirocyclic
lactam 4 in good yield. Subsequent acylation of 4 with
chloroacetyl chloride, followed by intramolecular Reformatsky
cyclization gave the key core 6.[14] To our delight, the X-ray
diffraction showed that relative stereochemistry of 6 was
consistent with the natural tuberostemoninol B (Scheme 2a).
Secondly, we transformed the phenyl-substituted oxime ethers
(2i-v) shortly to a tricyclic core 10, which exited widespread in
2x instead of the hemiketal alcohols of all other examples above. the biologically active indole alkaloids, such as quebrachidine,
This fact suggested that during this tandem reaction process the
C-to-C migration was possibly concerted with the O-
addition/etherization forming a 5-membered cyclic oxime ether,
as illustrated in path A of Scheme 3 below. In contrast, however,
if the substrates 1z and 1aa with 5-membered cyclopentenyl
structures were subjected to this reaction, two open oxime
products 3a/3a and 3b/3b were afforded in good yields and
both incorporated two Z/E-diastereomers (3.3:1 and 3.0:1,
respectively) due to the large tension of the spiro- and fused- 5-
membered rings. This observation could be explained in a
stepwise process of semipinacol rearrangement and proton-
elimination/transfer, as illustrated in path B in Scheme 3.
Therefore, whether this reaction produced oxime or oxime ether
depended mainly on the substrate structures.
vincamajine and vincarine.[1c] Thus 2j was subjected to reduction
with NiCl2/NaBH4 to form a -amino alcohol 7. Selective acylation
of 7 using picolinic acid and isobutyl chlorocarbonate to
generate the versatile building block 8, which was recognized as
a bidentate-chelation group, enabling a series of transition
metal-catalyzed oxidative couplings.[15] For example, oxidation of
8 with Dess-Martin reagent, followed by a catalyzed oxidative
intramolecular C-N coupling to deliver the 3-spiro- indole
structure 10 (Scheme 2b),[3a] which could access to the
synthesis of natural quebrachidine. In addition, 8 could also be
readily transformed to a tricyclic benzofuran derivative 11
through intramolecular C-O coupling, which was the central
skeleton of insecticide 12 (Scheme 2c).[1d]
Scheme 3. Proposed mechanism for forming oxime ether 2 and oxime 3
Finally, a possible reaction mechanism was proposed based
on experimental results above and literatures about semipinacol
rearrangement.[9] As indicated in Scheme 3, the tandem reaction
generally involved an initial NO+ addition to C=C bond of
cycloalkene moiety of 1, then if the cycloalkene contained the
flexiable 6-to-8- membered rings, a concerted C-to-C migration
and O-addition/etherization process took place to form a 5-
membered cyclic oxime ether product (such as 2a-2y) after
proton was eliminated or transferred (path A).[12b,16] If the
cycloalkene moiety of 1 contained relative rigid 5-membered ring
(n = 5), however, reaction would took both path A (major) and B
(minor) to form the open-forms oxime products (such as 3a and
3b) as a mixture of Z,E-isomers. Because of its tension of three
spiro- and fused- 5-membered rings (n = 5), the hemiketal ether
type-product, if formed in path A, tended to take a ring-openning
Scheme 2. The synthetic utility for the efficient construction of natural products.
After establishing the oximation methodology above, we
further converted the products 2a and 2j as examples to the vital
intermediates for synthesis of the important bioactive natural
products, in order to demonstrate the powerful and versatile
synthetic values of our method (Scheme 2). Firstly, tricyclic
oxime ether 2a was employed successfully for rapid construction
of a tricyclic structure 6, the key and challenging core for
synthesis of tuberostemoninol B, which was difficult to achieve
via traditional α-functionalization of caprolactam.[1b] Thus 2a was
subjected to Beckmann rearrangement with trifluoroacetic
to generate the major Z-isomer. Otherwise in path B,
a
semipinacol rearrangement took place first and then proton was
eliminated and transferred to N=O to form the minor E-isomer.
In conclusion, an efficient NO+-promoted semipinacol
rearrangement to synthesize polycyclic oximes and oxime ethers
has been developed. This reaction exhibited good substrate
tolerance, and a series of spiro- and/or fused cyclic and -
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efficiently and rapidly. Two products as examples were
converted into useful vital intermediates such as spirocyclic
lactams, indolines and tricyclic benzofuran through simple
transformations. This protocol provides a new, convenient and
modular route for synthesis of the polycyclic N-hetero-
compounds in the synthetic N-heterocyclo-chemistry. Its
application in the total synthesis of natural products is underway
in our group.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21702135, 21290181) and State
Commission of Science Technology of China (2018ZX09711001-
005).
Keywords: Oxime, Oxime Ether, Nitrosonium, Semipinacol
Rearrangement, Quaternary Center
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10.1002/anie.201807861
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10.1002/anie.201807861
Angewandte Chemie International Edition
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Jia-Wei Dong, Tongmei Ding, Shu-Yu
Zhang*, Zhi-Min Chen*, and Yong-Qiang
Tu*
Page 1 – Page 5
A Facile Approach to Oximes and
Ethers by a Tandem NO+-Initiated
Semipinacol Rearrangement and H-
Elimination
A novel and efficient oximation method based on NO+-initiated semipinacol
rearrangement and subsequent proton elimination is described. This method
enables rapid construction of a series of oximes and oxime ethers with spirocycles
and quaternary stereocenters from allylic silyl ethers. Additional features of this
reaction include high efficiency in most cases, high diastereoselectivity, wide
substrate toleration as well as commercial availability of safe nitrosation reagent
NOBF4. Three vital N-heterotricyclic cores 6, 10 and 11 have also been constructed
efficiently by this method, which would access readily to the short synthesis of three
natural alkaloids, tuberostemoninol B, (+)-quebrachidine and insectside 12,
respectively.
This article is protected by copyright. All rights reserved.