Base-Promoted [3+2]-Annulation of Oxime Esters and Aldehydes for Rapid Isoxazoline Formation

Article abstract of DOI:10.1002/adsc.201700730

A base-promoted [3+2]-annulation of ketoxime esters and aldehydes is disclosed for the facile and rapid synthesis of 3,5-disubstituted and 3,4,5-trisubstituted isoxazolines. The key to our success is the pivalate leaving group of the oxime substrates, combined with cesium carbonate as promoter. This chemistry allows the assembly of a vast array of isoxazoline derivatives under simple base conditions in a method complementary to the classic isoxazoline formation via [3+2]-dipolar cycloaddition of nitrile oxides and olefins. It also represents a new reaction pattern involving electrophilic amination/N–O bond substitution. (Figure presented.).

Full text of DOI:10.1002/adsc.201700730

Title: Base-Promoted [3+2]-Annulation of Oxime Esters and Aldehydes
for Rapid Isoxazoline Formation
Authors: Huawen Huang, Feifei Li, Zhenhua Xu, Jinhui Cai, Xiaochen
Ji, and Guojun Deng
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700730
Link to VoR: http://dx.doi.org/10.1002/adsc.201700730

10.1002/adsc.201700730
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Base-Promoted [3+2]-Annulation of Oxime Esters and
Aldehydes for Rapid Isoxazoline Formation
Huawen Huang,a* Feifei Li,a Zhenhua Xu,a Jinhui Cai,a Xiaochen Ji,a* and Guo-Jun
Denga
a
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of
Chemistry, Xiangtan University, Xiangtan, (China) Fax: (+86)0731-5829-2251; Tel: (+86)0731-5829-8280; e-mail:
hwhuang@xtu.edu.cn; xcji@xtu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A base-promoted [3+2]-annulation of ketoxime
esters and aldehydes is disclosed for the facile and rapid
synthesis of 3,5-disubstituted and 3,4,5-trisubstituted
isoxazolines. The key to our success is the pivalate leaving
group of oxime substrates, combined with cesium carbonate
as promoter. This chemistry allows the assembly of a vast
array of isoxazoline derivatives under simple base
conditions in a method complementary to the classic
isoxazoline formation via [3+2]-dipolar cycloaddition of
nitrile oxides and olefins. It also represents a new reaction
pattern involving electrophilic amination/N–O bond
substitution.
Scheme 1. Isoxazoline formation.
Keywords: Isoxazolines; [3+2]-annulation; Ketoxime
esters; Aldehydes; Cesium carbonate
Hydroxylamine derivatives have been widely applied
as versatile building blocks in organic synthesis with
respect to classic rearrangements,[7] electrophilic
aminations,[8] internal oxidant-based C–H activation,[9]
Isoxazoles represent an array of highly valuable five-
and among others.[10] In these transformations, the N–
O bond cleavage of hydroxylamine derivatives was
membered heterocycles, which compose numerous
biologically active molecules such as therapeutic
generally favored frequently with the assistance of
agents, veterinary products and agrochemicals.[1]
transition metal catalysis.[11] For example, catalytic
Specifically, isoxazoline has been widely found as key
electrophilic amination has been developed into a
unit in pharmaceuticals and other bio-active
fairly efficient and promising strategy in the C–N
compounds.[2] Its derivatives were also used as
formation reactions through N–O bond cleavage,[12] in
building blocks for the construction of β-amino acids,
which copper salts get the most attention and have
been employed in various aminations, including
γ-amino alcohols and other functional molecules.[3]
Isoxazoline compounds are generally accessed via
elegant stereoselective synthesis recently examplified
[3+2]-dipolar cycloaddition of nitrile oxides and
by Miura[12e,f] and Buchwald[12g-l] groups. Beyond the
olefins (Scheme 1a).[4] Despite the high efficiency in
well-demonstrated C–N bond formation through N–O
most cases, this method suffers from limitations: a)
bond cleavage of hydroxylamine derivatives, recently
nitrile oxides are typically prepared from sometimes
we and others disclosed copper-assisted N–N bond
unstable hydroxymoyl chlorides, or by the dehydration
formation from oxime acetates for the construction of
of nitroalkanes under frequently harsh conditions;[5]
pyrazoles.[13] To our knowledge, there is no example
and b) poor regioselectivity was usually observed
dedicating to another formal electrophilic amination:
when unbiased olefins were used, in which two
new N–O bond formation through N–O bond cleavage
of hydroxylamines. Herein, we present alternative
isoxazoline isomers could not be easily isolated.[6]
Given the importance of isoxazolines in organic
isoxazoline formation through [3+2]-annulation of
synthesis and medicinal chemistry, it is highly
ketoxime esters and aldehydes involving base-
desirable to develop complementary synthetic
promoted
eletrophilic
amination/N–O
bond
methods for multi-substituted isoxazolines from
simple and stable starting materials.
substitution (Scheme 1b). This isoxazoline formation
starts from readily available ketoxime esters and
1
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10.1002/adsc.201700730
Advanced Synthesis & Catalysis
aldehydes, obviates the need for environmentally
unfriendly and unstable halosubstrates,[14] and more
importantly provides an easy-handling and rapid
access to multi-substituted isoxazolines in a highly
chemoselective fashion.
12[f]
1f (Piv)
Cs2CO3
94
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), base
(0.4 mmol), DMSO (1.0 mL), 120 oC, 0.5 h.
[b] Yields are determined by GC analysis using dodecane as
the internal standard. ND means not detected.
[c] I2 (0.02 mmol, 10 mol%) was used.
Initially, acetophenone derived oxime acetate (1a)
and 2-chlorobenzaldehyde (2a) were chosen as the
model substrates to optimize the reaction conditions
(Table 1 and for more details see Supporting
Information). When the reaction was run in DMSO
with Li2CO3 base, the annulation product 3a was
detected in trace amount by GC-MS (Table 1, entry 1).
This result encouraged us to screen a series of
carbonate bases such as Na2CO3, K2CO3, and Cs2CO3.
Delightedly, the yield of 3a was improved with the
atomic number of alkali metals increased (entries 1–4),
and thereby Cs2CO3 was found to be the best base,[15]
affording 3a in 48% yield. Other bases including
organic amine bases were all inferior. Our attempts to
explore additives such as catalytic amount of iodine
and transition metal salts as well as base-equivalent
crown ether were all proved ineffective for the yield
improvement (entries 5–7). As observing significant
formation of free oxime from 1a with base treatment,
we suspected that varying the leaving group of oximes
to accommodate the N–O bond activation energy
could switch the chemoselectivity of this system. To
this end, a range of oxime carboxylates instead of 1a
were subjected to this system. While oxime benzoate
1d enhanced the yield to 68% (entry 10), isobutyrate
1e and pivalate 1f gave excellent yield of the desired
product (89% and 94%, respectively, entries 11,12).
This is probably due to the electron-donating effect of
these leaving groups which slightly strengthened the
ester group to avoid rapid collapse by base attack. By
comparison, much more stable free oxime (1b) and
oxime ether (1c) were recovered in nearly quantitive
amount in this system (entries 8,9). Notably, the
annulation completed within 10 min when using oxime
pivatate, which highlights the high efficiency of this
method to prepare isoxazolines.
[d] CuI (0.02 mmol, 10 mol%) was used.
[e] 18-Crown-6 (0.4 mmol) was used.
[f] Within10 min.
Under the optimized reaction conditions, 3a was
isolated in 88% yield. In the gram-scale reaction the
yield was also satisfactory (67%). Next the scope of
the optimized annulation process was initially
explored using aromatic ketoxime pivalates with 2-
chlorobenzaldehyde 2a in the presence of cesium
carbonate. In general, good to excellent yields were
observed when using a broad range of acetophenone
oxime pivalates bearing substituent at the benzene ring
(Scheme 2, 3b–3t). Among them halo-functionals
such as F, Cl, Br, and I were all tolerated well (3b–3d,
3g–3i, 3l–3o, 3s). In the cases of alkyl and alkoxyl-
groups, good yields of the corresponding isoxazolines
were achieved and steric hindrance proved
analogously not to be a strong factor in the annulation
reactivity. The oxime pivalate from naphthalenyl
ketone gave good yield of the product 3u.
Heteroaromatic ketoxime pivalates containing
pyridine, furan, and thiophen were also effective as
coupling partners to react with 2a, delivering
heteroaromatic isoxazolines 3v–3x in good yields.
The scope with respect to the aromatic aldehydes was
then investigated. Under the standard reaction
conditions, a broad range of substituted benzaldehydes
were successfully coupled with acetophenone oxime
ester 1f to give the respected 3,5-diaryl isoxazolines in
moderate to very good yields (Scheme 2, 4a–4s).
Specifically, halo-functionals (F, Cl, and Br), nitro
group (4i), and even alkynyl substituent (4o) were
compatible with this transformation. Notably,
compared with meta- and para-substituted
benzaldehydes as well as none-substituted
benzaldehyde, an ortho-substituent generally
enhanced the annulation process, probably due to the
neighboring group activation effect on the carbonyl
group. Also, heteroaromatic aldehydes bearing furan,
thiophene, and pyridine were all accommodated (4q–
4t), further demonstrating the broad functional-group
tolerance of this method. The annulation of pyridinyl
or thiophenyl oxime pivalates with halo-substituted
benzaldehydes afforded the desired isoxazoline
products 4u–4x in moderate yields. Unfortunately,
aromatic ketones such as acetophenone and 2,2,2-
trifluoro-1-phenylethanone instead of aldehydes
proved to be ineffective to the present system.
Table 1. Optimization of reaction conditions.[a]
Entry
1 (R)
Base
Yield[b]
1
2
3
4
1a (Ac)
1a (Ac)
1a (Ac)
1a (Ac)
1a (Ac)
1a (Ac)
1a (Ac)
1b (H)
Li2CO3
Na2CO3
K2CO3
trace
12
35
48
32
31
46
trace
ND
68
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
5[c]
6[d]
7[e]
8
9
10
11
1c (Me)
1d (Bz)
1e (isobutyryl)
89
2
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10.1002/adsc.201700730
Advanced Synthesis & Catalysis
Scheme 3. Annulation with aliphatic oxime pivalates or
aliphatic aldehydes.
To further explore the versatility of this method, cyclic
ketoxime pivalates derived from cyclohexanone and
fused cyclohexanones were tested with the treatment
of aromatic aldehydes for the annulation (Scheme 4).
Those substrates generally afforded the polycyclic
products in moderate yields with around 1:1
stereoselectivity (6a, 6b, 6d–f). Notably, the fused
isoxazoline products could not be accessed by
traditional intermolecular [3+2]-dipolar cycloaddition.
When the reactions were performed with acyclic
propiophenone oxime esters, modest yields of the
desired trisubstituted isoxazolines were given,
accompanied by nearly 7:3 trans/cis selectivity (6c,
6g).
Scheme 2. Scope of aromatic ketoxime pivalates and
aromatic aldehydes. Isolated yield was given. [a] 10.0 mmol
scale reaction. [b] 5.0 mmol scale reaction.
Aliphatic ketoxime pivalates and aliphatic aldehydes
were then explored for the annulation reaction
(Scheme 3). Compared to aromatic substrates, these
reactants generally delivered the corresponding
products in moderate yields, even using excessive
aliphatic coupling partners. It should be noted that,
along with the relatively low reactivity of aliphatic
reactants, the low boil point of these products led to
certain yield attenuation in the postprocessing.
Remarkably, while 3-phenylisoxazole 5c could be
assembled through [3+2]-dipolar cycloaddition of
nitrile oxides and gas ethylene, the employment of
formaldehyde (aq) in this work is much easier and
safer for handling.
Scheme 4. Synthesis of trisubstituted isoxazolines. The dr
ratio (trans/cis) in parentheses was determined by 1H NMR.
Isoxazolines bearing benzofuran moiety have been
found active as protein tyrosine phosphatase (PTPase)
inhibitors.[2c] To examplify the application of the
present isoxazoline annulation, benzofuranyl ketone
pivalate
8
was prepared through four-step
transformation starting from commercially available
6,7-dihydrobenzofuran-4(5H)-one 7 (Scheme 5).
Under the standard reaction conditions, the annulation
of 8 with picolinaldehyde worked smoothly to give
benzofuranyl isoxazoline 9 in 60% yield (Scheme 5a).
Then with a DDQ-based oxidative system, isoxazoline
4a underwent dehydrogenation aromatization,
affording 3,5-diphenyl isoxazole 10 in modest yield
(Scheme 5b). The incorporation of a bromo substituent
3
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10.1002/adsc.201700730
Advanced Synthesis & Catalysis
in the product 4c allows for further synthetic
modification through Pd(0)-catalyzed Suzuki-Miyaura
(11) and Sonigashira coupling (12), which offer rapid
access to a broader range of functional molecules
(Scheme 5c,d).[16] Finally, 3-arylisoxazolines were
also used as building blocks to directing C–H
activation reactions.[17] In our preliminary attempt,
isoquinoline 13 was obtained through the Ru-
catalyzed C–H activation/annulation, in which β-
carbon elimination probably occurred as the key step
to generate the 2-methylisoquinoline product (Scheme
5e).
used as the reactants generated a range of isoxazoline-
fused heterocycles which could not be easily accessed
by previous methods. Most importantly, N–O bond
substitution involved in this reaction procedure
inspires other cases of new designation for N–O bond
formation under transition metal-free conditions.
Experimental Section
General procedure for the preparation of isoxazolines:
Oxime pivalate 1 (0.2 mmol, 1.0 equiv), aldehyde 2 (0.24
mmol, 1.2 equiv), and Cs2CO3 (0.4 mmol, 2.0 equiv) were
charged in a septum capped vial (10 mL). The solvent
DMSO (1.0 mL, 0.2 M) was added into the vial by syringe.
o
The reaction mixture was stirred at 120 C for 10 min. The
mixture was then allowed to cool down to room temperature
and flushed through a short column of silica gel with ethyl
acetate, and, after rotary evaporation the residue was
separated by column chromatography (petroleum
ether/EtOAc 100:1 to 50:1) to give the pure products.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21602187, 21502161, and 21572194),
Scientific Research Fund of Hunan Provincial Education
Department (16B251), and Hunan Provincial Natural Science
Foundation of China (2017JJ3299).
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10.1002/adsc.201700730
Advanced Synthesis & Catalysis
COMMUNICATION
Base-Promoted [3+2]-Annulation of Oxime Esters
and Aldehydes for Rapid Isoxazoline Formation
Adv. Synth. Catal. Year, Volume, Page – Page
Huawen Huang,* Feifei Li, Zhenhua Xu, Jinhui
Cai, Xiaochen Ji,* and Guo-Jun Deng
6
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