In situ generation of nitrile oxides from copper carbene and tert -butyl nitrite: Synthesis of fully substituted isoxazoles

Article abstract of DOI:10.1039/c8ob01067f

Herein, we present a novel [3 + 2] cycloaddition reaction of β-keto esters with nitrile oxides, which were generated in situ from copper carbene and tert-butyl nitrite. This three-component reaction provides new methodology for the direct synthesis of fully substituted isoxazole derivatives, featuring mild reaction conditions, readily accessible starting materials and simple operation. The experimental studies and DFT calculations suggest that the reaction starts with the generation of the key intermediate nitrile oxides, followed by a [3 + 2] cycloaddition reaction of β-keto esters to give the final isoxazole products.

Full text of DOI:10.1039/c8ob01067f

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10.1039/C8OB01067F.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C8OB01067F
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In Situ Generation of Nitrile Oxides from Copper Carbene and tert-
Butyl Nitrite: Synthesis of Fully Substituted Isoxazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Rongxiang Chen, Abosede Adejoke Ogunlana, Shangwen Fang, Wenhao Long, Hongmei Sun,
Xiaoguang Bao* and Xiaobing Wan*
DOI: 10.1039/x0xx00000x
Herein, we present a novel [3+2] cycloaddition reaction of -keto esters with nitrile oxides, which is generated in situ from
copper carbene and tert-butyl nitrite. This three-component reaction provides a new methodology for the direct synthesis
of fully substituted isoxazole derivatives, featuring the mild reaction conditions, readily accessible starting materials and
operational simplicity. The experimental studies and DFT calculations suggest that the reaction starts with the generation
of the key intermediates nitrile oxides, followed by [3+2] cycloaddition reaction of -keto esters to give finnal isoxazoles.
www.rsc.org/
structural motifs in natural products and bioactive
compounds,11 which also serves as versatile precursors for
various synthetically useful transformations.12 Among the
Introduction
Nitrile oxides are valuable reactive intermediates as 1,3-dipole,
which could undergo [3+2]-dipolar cycloaddition to construct
various heterocycles.1 The most popular synthetic strategies
for them included the removal of hydrochloric acid from
unstable hydroxymoyl chlorides in presence of base,2 the
dehydration of nitroalkanes,3 the oxidation of oximes using
hypervalent iodine reagents as the strong oxidants.4 In 2015,
Xu et al. reported copper nitrate mediated cascade reaction
for the synthesis of isoxazolines through in situ generation of
nitrile oxides (Scheme 1a).5 Alternatively, the group of Yang
discovered that KNO3 could also serve as the precursor of
nitrile oxides with cascade sp3 C–H bond oxidative
functionalization (Scheme 1b).6 Recently, a radical-mediated
domino reaction by using tert-butyl nitrite towards isoxazoline
was developed by Patel (Scheme 1c).7 Although significant
progress have been made, the easy decomposability of
substrate or the need of the strong oxidants urge chemists to
develop a general and simple method for the generation of
nitrile oxides intermediates under mild reaction conditions.
The transition-metal-catalyzed chemical conversions of
diazo compounds have attracted intense attention in the past
few decades due to their versatile reactivity.8 As our
continuous interest in catalytic transformation of diazo
compounds,9 we herein reported that the in situ generation of
nitrile oxides from diazo compounds and tert-butyl nitrite,10
which subsequently underwent [3+2] cycloaddition reaction
various isoxazoles, 3,4-disubstituted isoxazoles present good
stability under thermal conditions.13 Unfortunately, traditional
synthetic methods usually suffered from some drawbacks such
as narrow substrate scope, poor chemo- and regioselectivities,
and/or difficult substrate preparation.14 In sharp contrast with
traditional method, our methodology was distinguished by the
mild reaction conditions, readily accessible starting materials
and operational simplicity.
with
-keto esters to deliver fully substituted isoxazoles
(Scheme 1d). Isoxazoles scaffolds are commonly significant Scheme 1 In situ generation of nitrile oxides.
Results and discussion
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
To initiate this study, ethyl benzoylacetate (1a), ethyl di-
azoacetate (2a, EDA), and tert-butyl nitrite ( ) were chosen as
China. E-mail: xgbao@suda.edu.cn, wanxb@suda.edu.cn.
Electronic Supplementary Information (ESI)
DOI: 10.1039/x0xx00000x
available.
See
3
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model reactants for anticipated isoxazole formation reaction that β-keto ester bearing an allyl group dVeileiwveArrteicdle Ontlhinee
DOI: 10.1039/C8OB01067F
(Table 1). To our delight, the reaction proceeded smoothly to corresponding product 4s in 50% yield.
afford the desired isoxazole 4a in 33% yield in the presence of
CuI (7.5 mol%), Mg(OTf)2 (10 mol%) and DABCO (2.5 equiv) at Table 2 Scope of β-keto estersa
o
80 C for 12 hours (entry 1). Encouraged by this result, further
optimizations were done with a survey of copper salts (entries
2–5). We found that the best result was obtained by applying
Cu(OAc)2·H2O as the catalyst, leading to the product 4a in 80%
yield (entry 3). The replacement of Mg(OTf)2 with other
additives resulted in dramatically diminished yields of 4a
(entries 6-10). Notably, only trace amount of product 4a was
observed when other bases were used for this transformation
(entries 11-14). Control experiments indicated the catalyst,
additive, and base played crucial role for this isoxazole
formation reaction (entries 15-17).
Table 1 Optimization of the reaction conditionsa
aConditions:
Cu(OAc)2 H2O (7.5 mol%), DABCO (1.25 mmol), Mg(OTf)2 (10
1 (0.5 mmol), 2a (0.75 mmol), 3 (0.75 mmol),
·
mol%) and cyclohexane (3.0 mL).
Table 3 Scope of diazo compoundsa
aConditions: 1a (0.5 mmol), 2a (0.75 mmol),
3 (0.75 mmol, 1.5
equiv), catalyst (7.5 mol%), base (1.25 mmol), additive (10
mol%) and cyclohexane (3.0 mL) in a test tube. bIsolated yields.
Having established the optimized reaction conditions, we
next tested a variety of β-keto esters to assess the versatility of
this catalytic system (Table 2). Both electron-donating and
electron-withdrawing substituents on phenyl ring were well
accommodated, affording the desired products in moderate to
good yields (4b-4o). The substrate with the sterically hindered
also uneventfully underwent this transformation (4p), albeit in
lower yield. Halogen atoms, such as F, Cl, Br and I, did not
aConditions: 1a (0.5 mmol),
Cu(OAc)2 H2O (7.5 mol%), DABCO (1.25 mmol), Mg(OTf)2 (10
mol%) and cyclohexane (3.0 mL).
2 (0.75 mmol), 3 (0.75 mmol),
·
affect the reactivity of the substrates (4e-4h, 4k-4m), which
Next, we evaluated the generality of this methodology with
respect to the diazo compounds (Table 3). Representative α-
diazocarbonyl substrates with different substituents could
engage well in this reaction, providing the desired products in
satisfactory yields (5a-5g). The exact structure of 5d was
conclusively confirmed by the single crystal X-ray diffraction. It
is noteworthy that diazo reagents bearing an allyl group were
created the opportunity for further derivatizations. The exact
structure of 4f was conclusively confirmed by the single-crystal
X-ray diffraction. Naphthyl in substrate was also compatible to
the reaction conditions, leading to the corresponding product
4q in 68% yield. Moreover, heterocyclic substituted β-keto
ester 1r exhibited good reactivity under standard conditions,
furnishing the product 4r in moderate yield. It is also of note
2 | J. Name., 2012, 00, 1-3
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proved to be good reaction partners, leading to the nitrogen atom in
corresponding products 5e
3
to the carbene carbon would take place via
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DOI: 10.1039/C8OB01067F
-
5f in moderate yields. Diazo TS2 to afford INT2. Next, the dissociation of the copper
compound 2g with a heterocyclic skeleton also worked well catalyst would occur to yield the intermediate INT3. Thereafter,
t
and delivered the desired product 5g in 67% yield.
When 4-tert-butylstyrene was subjected to the template TS3 to generate the key intermediate INT4 15
reaction, cyclopropanation product could be detected by GC- the enol isomer 1′ would undergo [3+2] cycloaddition with
MS (see Supplementary Information),8 suggesting that a INT4 via TS4 to afford a five-membered cycloadduct INT5
the elimination of BuOH that water assisted would follow via
.
Subsequently,
,
carbene intermediate was involved in this transformation. from which dehydration would take place to deliver the final
Some possible intermediates were prepared and applied to isoxazole product (Figure S1).
this reaction system. However, ethyl 2-nitroacetate (
2-(hydroxyimino)acetate ( ), ethyl-2-(hydroxyimino)-3-oxo-3- mechanistic findings and DFT calculations, we formulated a
phenylpropanoate ( ), and ethyl cinnamate ( ) could not plausible catalytic cycle as depicted in Scheme 3. Reaction of
6
), ethyl-
Based upon literature precedents, above mentioned
7
8
9
afford the desired product 4a under the standard reaction the diazo compound with the copper catalyst formed the
conditions (Scheme 2a-d), thus ruling out the possibility of copper carbene species I,8 which was attacked by tert-butyl
these compounds as the intermediates for this isoxazole nitrite to give intermediate II. The nitrile oxide III was
formation
diphenylethylene did not inhibit the formation of isoxazole 4a
suggesting that a radical process was not involved in current enol intermediate IV
reaction (Scheme 2e). Notably, hydroxymoyl chlorides 10, the cycloaddition with nitrile oxide III to deliver intermediate
precursor of nitrile oxide,2 reacted well with 1a in the presence Finally, the desired isoxazole product VI was produced through
of Et3N and provided product 4a in 81% yield, indicating that the dehydration of intermediate V 16
reaction.
The
radical
scavenger
1,1- generated through the decomposition of intermediate II
Meanwhile, β-keto ester was activated by Mg(OTf)2 to provide
which would undergo [3+2]
.
,
,
V.
.
nitrile oxide was the possible intermediate in this
transformation (Scheme 2f).
Scheme 3 Proposed reaction mechanism.
Conclusions
In summary, we have developed a new three-component
reaction to deliver isoxazole derivatives from simple β-keto
esters, diazo regents and tert-butyl nitrite catalyzed by copper
catalyst. Experimental studies and DFT calculations suggests
that this transformation undergoes through the in situ
generation of nitrile oxides from copper carbene and tert-butyl
nitrite; followed by the [3+2] cycloaddition with β-keto esters.
Further extensions to the trapping of nitrile oxides with other
reagents are currently underway in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Scheme 2 Preliminary mechanism research.
DFT calculations were carried out to shed light on the
mechanism of the formation of isoxazole (see Supplementary
Information for computational details). The activation of the
Acknowledgements
diazo substrate
2 with the Cu(OAc)2 catalyst could lead to the
A
Project Funded by the Priority Academic Program
generation of a copper carbene intermediate (INT1) with the
extrusion of nitrogen gas. The predicted free energy barrier for
this step via TS1 is 35.6 kcal/mol relative to separated copper
Development of Jiangsu Higher Education Institutions (PAPD),
NSFC (21572148, 21472134, 21272165).
catalyst and 2, affording the Cu-carbene specie in an exergonic
manner. Subsequently, the nucleophilic addition of the
Notes and references
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15 One may suggest that the decomposition of
3 mediated by
the Cu catalyst to release the NO radical cannot be ignored.
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endergonic by 44.7 kcal/mol, which is even higher than the
9
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DOI: 10.1039/C8OB01067F
In Situ Generation of Nitrile Oxides from Copper Carbene and tert-Butyl Nitrite: Synthesis of Fully
Substituted Isoxazoles
Rongxiang Chen, Abosede Adejoke Ogunlana, Shangwen Fang, Wenhao Long, Hongmei Sun,
Xiaoguang Bao and Xiaobing Wan
Org. Biomol. Chem., 2018, Volume, Page – Page
DOI: 10.1039/b000000x
Herein, a novel [3+2] cycloaddition reaction of β-keto esters with nitrile oxides, which is generated in situ
from copper carbene and tert-butyl nitrite, was well developed to give fully substituted isoxazoles.