Silver-mediated radical cyclization: Construction of Δ2- isoxazolines from α-halo ketoximes and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/c4cc02084g

A novel route to Δ²-isoxazolines is presented via silver-mediated radical cyclization of α-halo ketoximes with 1,3-dicarbonyl compounds. This method is performed using a radical strategy, and represents a new example of silver-initiated generation of oxime radicals for the formation of the C(sp³)-O bonds. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02084g

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Silver-mediated radical cyclization: construction
of D2-isoxazolines from a-halo ketoximes and
1,3-dicarbonyl compounds†
Cite this: Chem. Commun., 2014,
50, 6906
Received 20th March 2014,
Accepted 1st May 2014
Yan-Yun Liu,a Xu-Heng Yang,a Ji Yang,a Ren-Jie Songa and Jin-Heng Li*ab
DOI: 10.1039/c4cc02084g
www.rsc.org/chemcomm
A novel route to D2-isoxazolines is presented via silver-mediated
radical cyclization of a-halo ketoximes with 1,3-dicarbonyl com-
pounds. This method is performed using a radical strategy, and
represents a new example of silver-initiated generation of oxime
radicals for the formation of the C(sp3)–O bonds.
Scheme 1 Synthesis of isoxazolines.
Isoxazoles, including D2-isoxazolines, are important and prevalent
heterocycles that occur in many natural products and pharmaceutical
molecules.1 In addition, isoxazoles are versatile intermediates with
significant applications in organic synthesis.2 For these reasons,
practical and selective construction of various isoxazole ring
systems remains a continuing active research area.3–6 Among the
existing methods, the majority relies heavily on the use of nitrile
oxides as reactants through 1,3-dipolar cycloaddition with unsatu-
rated compounds, such as alkenes, enols and alkynes.3–5 However,
these methods often suffer severely from a limited substrate scope,
unsatisfactory regioselectivity and/or harsh conditions because
nitrile oxides are needed to be in situ generated in the presence
of bases from either hydroximinoyl chlorides or oximes combined
with electrophilic halide reagents.3–6 In order to overcome these
disadvantages, exploration of new strategies for selectively acces-
sing isoxazoles is highly desirable and urgent.
the hydrogen-bond donor to improve the yields, they provided an
intriguing chance to utilize oxime radicals for the reaction design.7
Herein, we report a new radical cyclization of a-halo ketoximes
with 1,3-dicarbonyl compounds for selective synthesis of function-
alized D2-isoxazolines (Scheme 1); this radical cyclization is triggered by
silver salts8 and avoids the regioselectivity problem that usually occurs
in the existing methods. Moreover, the absence of silver salts resulted
in an increase of the length of the carbon chain, not D2-isoxazolines,
from a-halo ketoximes with 1,3-dicarbonyl compounds.
We began our study with the reaction between 2-chloro-1-
phenylethanone oxime (1a) and pentane-2,4-dione (2a) as the
model to optimize the reaction conditions (Table 1). In the
Table 1 Screening optimal conditionsa
Recently, the groups of Han6a and Alexanian6b independently
reported a new alkene radical difunctionalization route to isoxazoles
and D2-isoxazolines wherein the addition of an oxygen-centered
radical, produced from either unsaturated oximes or hydroxamic
acids, to an alkene resulted in direct assembly of the isoxazole
architectures, thus avoiding the in situ generation of nitrile oxides.
Although these studies were focused on the use of unsaturated
oximes or hydroxamic acids with a limited substrate scope, and
employed TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)/DEAD
(diethyl azodicarboxylate) as the radical initiator or PhSO2NH2 as
Entry
[Ag] (equiv.)
Base (equiv.)
Isolated yield (%)
1
2
3
Ag2CO3 (0.1)
Ag2CO3 (1)
Ag2CO3 (2)
Ag2CO3 (2.5)
—
Ag2CO3 (2)
Ag2CO3 (2)
AgNO3 (2)
AgOAc (2)
Ag2O (2)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (2)
—
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
9
63
80
79
0
50
Trace
6
4
5b
6
7
8
9
10
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082,
China. E-mail: jhli@hnu.edu.cn; Fax: +86731 8871 3642; Tel: +86731 8882 2286
b State Key Laboratory of Applied Organic Chemistry Lanzhou University,
Lanzhou 730000, China
16
19
a
Reaction conditions: 1a (0.3 mmol), 2a (2 equiv.), [M], base, and DMA
(N,N-diethylacetamide, 2 mL) at room temperature under an argon
b
atmosphere for 20 h. Another product, 5-(acetoxyimino)-5-phenylpentan-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc02084g
2-one (4aa), was isolated in 15% yield.
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presence of a catalytic amount of Ag2CO3 (0.1 equiv.), the reaction of organic synthesis (product 3ae). However, the reactivity of 1,3-keto
oxime 1a with pentane-2,4-dione (2a) and 1 equiv. K2CO3 afforded ester 2f was lower in the presence of Ag2CO3 and K2CO3, providing
the expected isoxazoline 3aa in 9% yield (entry 1). Gratifyingly, the product 3af in 21% yield. After a series of trials, we were happy to
yield of isoxazoline 3aa was sharply enhanced to 63% yield when the discover that Cs2CO3 was a viable base for the reaction of 1,3-keto
reaction was performed at 1 equiv. of Ag2CO3 (entry 2), and to 80% ester 2f with oxime 1a, and the yield was enhanced to 83%. In light
yield using 2 equiv. of Ag2CO3 (entry 3). Identical results to those of 2 of the results, the Ag2CO3-mediated reactions of various 1,3-keto
equiv. of Ag2CO3 were observed at 2.5 of equiv. Ag2CO3 (entry 4). esters 2g–2o with oxime 1a were subsequently performed using the
However, the absence of Ag salts resulted in no detectable isoxazo- Cs2CO3 base (products 3ag–3ao). For example, a number of esters
line 3aa, and gave another product 4aa, 5-(acetoxyimino)-5-phenyl- 2g–2k, such as Et, i-Pr, Bn, CH2CH2OMe and allyl 3-oxobutanoates,
pentan-2-one, in 15% yield (entry 5). Screening revealed that the successfully furnished the corresponding products 3ag–3ak in
amount of K2CO3 affected the reaction (entries 3, 6 and 7): only 50% high yields. 1,3-Keto esters 2l–2o, with an ethyl, a n-propyl, an
yield of isoxazoline 3aa was obtained due to decomposition of more i-propyl or a phenyl group adjacent to the keto carbonyl group,
substrate 1a by increasing K2CO3 to 2 equiv. (entry 3 vs. entry 6), and were also consistent with the optimal conditions leading to pro-
no isoxazoline 3aa was observed without bases (entry 7).9 Among the ducts 3al–3ao in moderate to good yields. Gratifyingly, the reaction
effect of Ag salts, it turned out that the reaction using Ag2CO3 could be applied to 1,3-keto amide 2p (product 3ap). Unfortu-
provided the best results than those of the other Ag salts, such as nately, dimethyl malonate 2q was not suitable for the reaction
AgNO3, AgOAc and Ag2O (entries 8–10).
under the optimal conditions (Table 2, 3aq).
With the optimal conditions in hand, we decided to investigate
We next set out to exploit the scope of 2-haloethanone oximes 1
the scope of this transformation with a diverse set of 2-halo- in the presence of pentane-2,4-dione (2a), Ag2CO3 and K2CO3
ethanone oximes and 1,3-dicarbonyl compounds (Tables 2 and (Table 3). Gratifyingly, 2-bromo-1-phenylethanone oxime (1b) also
3). As shown in Table 2, a variety of 1,3-dicarbonyl compounds 2 displayed high activity and offered the desired product 3aa in 78%
reacting with 2-chloro-1-phenylethanone oxime (1a) were first yield. Subsequently, a number of 2-chloroethanone oximes 1c–1i
investigated. Initially, three 1,3-diketones 2b–2d were examined. were employed in the study because they are more stable (products
Heptane-3,5-dione (2b) still constructed the desired isoxazoline 3ca–3ia). The influence of the substituents on the aryl group of the
3ab in 60% yield. However, phenyl-containing 1,3-diketones 2c 1-arylethanone moiety was examined. The results indicated that
and 2d generated the corresponding C–C bond cleavage products several substituents, including Me, MeO, Cl, Br, CN and NO2, were
4ac and 4ad in good yields, and not the expected isoxazolines 3ac well-tolerated (products 3ca–3ha), and the order of the substituent
or 3ad.9 Interestingly, the optimal conditions were compatible with reactivity was electron-donating groups 4 electron-withdrawing
a nitrile group, thereby making this methodology more useful in groups. The reason might be that the electron-withdrawing groups
have a lower reactivity in the radical cyclization process. While
Table 2 Scope of 1,3-dicarbonyl compounds (2)a
oximes 1c and 1d with an electron-rich aryl group afforded the
target products 3ca and 3da in excellent yields, oximes 1g and 1h
with an electron-deficient aryl group resulted in the corresponding
products 3ga and 3ha in moderate yields. It is noteworthy that
2-chloro-1-(thiophen-3-yl)ethanone oxime (1i) is viable for the
reaction with pentane-2,4-dione (2a), Ag2CO3 and K2CO3,
Table 3 Scope of 2-haloethanone oximes (1)a
a
Reaction conditions: 1a (0.3 mmol), 2 (2 equiv.), Ag2CO3 (2 equiv.),
K2CO3 (1 equiv.) and DMA (2 mL) at room temperature in Ar for 20 h.
b
4-(Benzoyloxyimino)-1,4-diphenylbutan-1-one (4ac) was isolated in
77% yield. c 4-(Acetoxyimino)-1,4-diphenylbutan-1-one (4ad) was isolated in
66% yield. d Cs2CO3 (1 equiv.) instead of K2CO3 at 50 1C.
Reaction conditions: 1 (0.3 mmol), 2a (2 equiv.), Ag2CO3 (2 equiv.),
a
K2CO3 (1 equiv.) and DMA (2 mL) at room temperature in Ar for 20 h.
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Scheme 2 Possible mechanisms.
providing product 3ia in 75% yield. Importantly, halogen groups,
such as Cl or Br, were compatible with good yields, thereby
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converted into either oxime radical intermediate A or products 4
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In summary, we have illustrated the first example of silver-
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compounds for D2-isoxazoline synthesis. This tandem method is
realized through sequential nucleophilic replacement and radical
cyclization. Applications of the conceptually new radical strategy in
organic synthesis are currently underway in our laboratory.
This research was supported by the NSFC (No. 21172060)
and the Hunan Provincial Natural Science Foundation of China
(No. 13JJ2018).
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experiments (Scheme S2, ESI†), and (iv) recovery and reuse of the silver
salts (Scheme S2, ESI†) are summarized in the ESI†.
6908 | Chem. Commun., 2014, 50, 6906--6908
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