Four-Component Reactions for the Synthesis of Perfluoroalkyl Isoxazoles

Article abstract of DOI:10.1021/acscatal.9b03189

A four-component strategy for the synthesis of the isoxazole skeleton is developed. The approach achieves the synthesis of perfluoroalkyl isoxazoles by using simple perfluoroalkyl reagents. In addition, the unprecedented 3-azido-5-arylisoxazole formation

Full text of DOI:10.1021/acscatal.9b03189

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Letter
Four-Component Reactions for the Synthesis of Perfluoroalkyl Isoxazoles
Yuanjin Chen, Liangkui Li, Xiao He, and Zhiping Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03189 • Publication Date (Web): 05 Sep 2019
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Four-Component Reactions for the Synthesis of Perfluoroalkyl Isox-
azoles
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Yuanjin Chen, Liangkui Li, Xiao He, and Zhiping Li*
Department of Chemistry, Renmin University of China, Beijing 100872, China
ABSTRACT: A four-component strategy for the synthesis of isoxazole skeleton is developed. The approach achieves the synthesis
of perfluoroalkyl isoxazoles by using simple perfluoroalkyl reagents. In addition, the unprecedented 3-azido-5-arylisoxazole
formation demonstrates Togni’s reagent as a C-1 unit to be used in the isoxazole formation. The advantages of the method include
readily available starting materials, structural diversity, and late-stage functionalization. Mechanistic studies support that the
transformation includes a tandem process of perfluoroalkylation-peroxidation of alkene, Kornblum-DeLaMare rearrangement,
elimination, substitution, N-O bond formation to give the isoxazoles.
KEYWORDS: multicomponent reaction, cobalt catalysis, isoxazoles, radical reaction, perfluoroalkylation, peroxidation, organic
peroxide
Multicomponent reactions (MCRs) achieve multi-bond for-
mation in a single procedure from readily available starting ma-
terials.[1] MCRs provide fast access to structurally complex and
functionally diverse compounds and thus have attracted much
attention from both academia and industry. Isoxazole is one of
prevalent motifs in the field of synthetic and medical chemis-
try.[2] Over the last three years, 33 isoxazole compounds have
been approved as drugs by FDA, which have entered the mar-
ket.[2a] Isoxazole can be employed as a directing group and as a
synthon that provides access to numerous N-heterocycles (such
as isoxazolines, 2-aminopyrroles, 2-aminoquinolines, 7-
acylindoles, imidazo[1,2-a]pyridines, etc.) and other functional
Scheme 1. Strategies for the Construction of Isoxazole Ring
groups (for example, as masked 1,3-dicarbonyl equivalents).[3]
Great efforts have been made to achieve efficient synthesis of
Organofluorinated molecules have numerous applications,
isoxazole derivatives.[4] The strategies for the construction of
including in medicinal chemistry, agrochemistry, and material
isoxazole ring are summarized in Scheme 1. Cycloisomeriza-
science because of the unique properties of fluorine. Neverthe-
tion and condensation present the straightforward access to
less, it is not surprising that the synthesis of fluorinated isoxa-
isoxazoles, in which C-O bond is formed (Strategy A). [3+2]
zoles depends on the developed methods using the synthesized
fluorinated substrates (Scheme 1, Strategies A and B).[7] To the
best our knowledge, simple perfluoroalkyl reagents have never
been used as a starting material for the construction the fluori-
nated isoxazole ring.[8]
Cycloaddition is arguably the most reliable method to synthe-
size isoxazoles (Strategy B). The isoxazole ring was also con-
structed by the formation of C-C, C-O and C-N bonds through
a four-component coupling of a terminal alkyne, hydroxyla-
mine, carbon monoxide, and an aryl iodide (Strategy C).[5]
Herein, we disclose a novel [2+1+1+1] annulation for the syn-
thesis of isoxazoles (Strategy D). This discovery is the first ex-
ample of the construction of four of the five bonds of the
isoxazole ring from four components.[6]
To address the challenge of new approaches for the synthesis
of perfluoroalkyl isoxazole, we commenced the study by the re-
action of perfluorobutyl iodide (1a), styrene (2a), sodium azide
(3), and tert-butyl hydroperoxide (70% in water, 4a) (Table 1).
3-Perfluoropropyl-5-phenyl isoxazole (5a) was obtained in 8%
yield by the use of Co(acac)2 as catalyst and DABCO as base in
MeCN (entry 1). This finding prompted us to further optimize
the reaction conditions of this four-component reaction. Critical
improvement was made by evaluating the reaction solvent (en-
tries 1-5). Despite lower yields of 5a were obtained in hexane
and THF (entries 2 and 3), the mixture of hexane and THF (1:1
and 4:1) improved the yields of 5a to 56% and 77% respectively
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(entries 4 and 5). These results might indicate that a cosolvent
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significant route for the synthesis of perfluorinated isoxazoles.
Other aromatic substrates including naphthyl and
heteroaromatic ring gave the desired products (5r-5t) in
medium to good yield. However, internal alkenes， aliphatic
alkenes and acrylate derivatives are not viable substrates under
the standard reaction conditions(5u-5w). At this point, we
assumed that the present transformation is affected by the steric
and electronic effects of alkenes. As examples of the application
to the late-stage modification of more complex molecules, we
were delighted to find that styrenes bearing the biologically
active scaffolds afforded the desired products in 61-70% yield
(5x-5z).
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2
3
4
5
6
7
8
is required for better efficiency and reactivity of the desired
transformation. A 51% yield of 5a was obtained in the absence
of catalyst (entry 6), suggesting that the cobalt catalyst im-
proves the reaction efficiency. Notably, the desired product 5a
was not observed in the absence of base (entry 7) and other
tested bases (entries 8-12). These results indicated that base
plays a key role in the present transformation. No improvement
in yield was recorded when Co(acac)2 was replace by Co(acac)3,
CoCl2, Cu(acac)2 as Fe(acac)2 (entries 13-16). When tert-butyl
hydroperoxide (5.5 M in decane, 4a) replaced tert-butyl hy-
droperoxide (70% in water), an 81% yield of 5a was achieved
(entry 17). It should be noted that cumene hydroperoxide 4b
was also applicable as oxygen source in this reaction (entry 18).
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Table 2. Scope of Alkenes 2a,b
Table 1. Evaluation of Reaction Conditionsa
5a
entry
catalyst
base
solvent
(%)b
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1
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
-
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
-
MeCN
2
hexane
25
3
THF
23
4
hexane/THFc
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
hexane/THFd
56
5
77
6
51
7
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)3
CoCl2
N.D.e
N.D.e
N.D.e
N.D.e
trace
trace
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8
NEt3
9
DBU
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12
13
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15
16
17f
18g
NaOH
Py
K2CO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
52
Cu(acac)2
Fe(acac)2
Co(acac)2
Co(acac)2
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63
81
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aReaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), 3a (1.5 mmol), 4a (70%
in water, 3.0 mmol), catalyst (10 mol %), base (1.5 mmol), solvent (2.0 mL),
80 ℃, 12 h, under N2, unless otherwise noted. bReported yields were based
1
c
d
on 2a and determined by H NMR using an internal standard. 1:1. 4:1.
eNot detected. f4a (5.5 M in decane). gCumene hydroperoxide 4b instead of
4a.
aReaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), 3 (1.5 mmol), 4a (5.5
M in decane, 3.0 mmol), Co(acac)2 (10 mol %), DABCO (1.5 mmol),
hexane/THF (4:1, 2.0 mL), 80 ℃ , 12 h, under N2. bIsolated yields.
chexane/THF (4:1, 4.0 mL).
With the optimized conditions in hand, we investigated the
scopes of the four-component method for the synthesis of the
fluorinated isoxazoles (Tables 2 and 3). First, we investigated
the reaction scope for alkene 2 by the use of 1a as a model
substrate (Table 2). Styrene derivatives with either electron-
donating or electron-withdrawing groups on the phenyl ring
reacted well with 1a, 3 and 4a, providing isoxazoles (5a-5p) in
good yields. Styrene derivatives 2n could be converted to the
corresponding perfluorinated isoxazole 5n[9] in 72% yield,
which shows antibacterial activities against escherichia coli and
staphylococcus albus.[10] 1,2,3,4,5-Pentafluoro-6-vinylbenzene
was also applicable to give the corresponding product (5q),
albeit in 43% yield. It is noteworthy that this method presents a
Next, our attention turned to the reaction scope for fluoroal-
kyl reagents 1 (Table 3). To our delight, other perfluoroalkyl
iodides (1) were also applicable under the standard reaction
conditions to furnish the corresponding products (5aa-5fa) in
good yields. It's worth mentioning that perfluorohexyl bromide
1c’ afforded the corresponding perfluoropentyl isoxazole prod-
uct 5ba in 55% yield, which is slightly lower than perfluoro-
hexyl iodide 1c did (76%). We were particularly interested in
examining the chemoselectivity of perfluoroalkyl iodides pos-
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sessing chlorine and bromine atoms under these conditions. Re-
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markably, it was found that the perfluoroalkyl iodides pos-
sessing chlorine and bromine atoms underwent this four-com-
ponent transformation in a selective manner to deliver chloro-
and bromo-substituted isoxazoles (5ga-5oa) in good to excel-
lent yields. Chloro-substituted difluoroalkyl isoxazoles are po-
tential herbicideand bromo-substituted difluoroalkyl isoxazoles
are potential difluoroalkyl reagents.[11] The structure of the
product (5na) was confirmed by X-ray crystallographic analy-
sis.[12]
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Table 3. Scope of Perfluoroalkyl Reagents 1a,b
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Scheme 2. Togni’s Reagent as CF3 Source
To obtain mechanistic insights, some control reactions were
carried out (Scheme 3). The desired transformation was se-
verely inhibited by radical scavengers, such as 2,2,6,6-tetra-
methylpiperidin-1-oxyl
(TEMPO),
2,6-di-tert-butyl-4-
methylphenol (BHT) and benzoquinone (BQ) (eq 1). The re-
sults indicated that the isoxazole formation most likely involves
radical step(s). We found that in the absence of sodium azide (3)
and DABCO (base), -difluoro peroxide (7)[16] and iodide (8)[17]
were afforded (eq 2). Notably, -fluoro ,-unsaturated ketone
(9) was obtained in the presence of DABCO and without 3 (eq
3). These results indicated that: (1) the formation of 8 is sup-
pressed in the presence of DABCO; (2) 7 might convert into 9.
To verify the hypothesis,-difluoro peroxide (7) was subject to
1
the basic condition (eq 4). A 88% H NMR yield of 9 was ob-
tained, albeit with a 26% isolated yield (probably due to the de-
composition of 9 during the isolation). The results indicated that
9 comes from the deprotonation of 7 in the presence of base.
Furthermore, the reaction of 9 with 3 led to the isoxazole 5a in
93% yield (eq 5),[18,19] suggesting that the cyclization step to
form O-N bond is facile.
aReaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), 3 (1.5 mmol), 4a (5.5 M
in decane, 3.0 mmol), Co(acac)2 (10 mol %), DABCO (1.5 mmol),
hexane/THF (4:1, 2.0 mL), 80 ℃, 12 h, under N2, unless otherwise noted.
bIsolated yields. cPerfluorohexyl bromide 1c’ instead of perfluorohexyl
iodide 1c.
Furthermore, we envisioned that 3-fluoro-5-arylisoxazole
might be generated if a CF3 reagent was applied. To examine
the feasibility of this hypothesis, Togni’s reagent was tested as
CF3 source.[13] Surprisingly, 3-azido-5-arylisoxazoles (6) were
generated and 3-fluoro-5-arylisoxazoles were not observed in
these reactions (Scheme 2). These results indicated that two
fluorine atoms in the intermediate are substituted by two azido
groups before the formation of 6.[14] Considering the importance
of organic azides in the chemical biology, medicinal chemistry,
supramolecular chemistry and materials science,[15] the present
transformation might find its applications in these areas. This
study presents an intriguing example of five-component
reaction.
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Scheme 3. Control Reactions
Scheme 5. Experiments with the Addition of Deuterated
Water
1
Based on the above results, a tentative reaction mechanism
for the formation of the isoxazole (5a) is described in Scheme
4.[20] The SET reaction of perfluorobutyl iodide (1a) by Co(II)
affords perfluorobutyl radical A, which adds to styrene (2a) to
form the radical intermediate B. Radical coupling of B with tert-
butylperoxy radical delivers -difluoro peroxide (7). DABCO-
catalyzed Kornblum-DeLaMare rearrangement of 7 leads to the
carbonyl intermediate C,[21] which subsequently transforms into
-fluoro ,-unsaturated ketone (9) by DABCO-promoted
elimination of hydrofluoric acid. The substitution reaction of 9
with NaN3 (3) affords the vinyl azide D. There are two possible
pathways from D to the final isoxazole (5a): (1) The 3-exo-tet
cyclization of D’ (one of resonance structures of D) gives azir-
ine (E),[22] which is converted into 5a through azirine ring open-
ing and cyclization (Path A); (2) Alternatively, the 5-exo-tet cy-
clization of D’’ (one of resonance structures of D) directly leads
to 5a by relieving N2 (Path B).[23]
2
3
4
5
6
7
8
9
In conclusion, we have developed a new approach for the
synthesis of perfluoroalkyl isoxazoles through four-component
reactions. This protocol features the use of simple perfluoroal-
kyl reagents that enables the other three components to partici-
pate in the isoxazole formation. The method presents a practical,
atom-economic, one-pot procedure that delivers functional
isoxazoles without intermediate workup or solvent change. In
addition, the unprecedented 3-azido-5-arylisoxazole formation
demonstrates Togni’s reagent as a C-1 unit to be used in the
isoxazole formation. Mechanistic studies support that the trans-
formation includes a tandem process of perfluoroalkylation-pe-
roxidation of alkene, Kornblum-DeLaMare rearrangement,
elimination, substitution, N-O bond formation to give the isox-
azoles. We anticipate that the present results would likely offer
new designs for the synthesis of isoxazoles and other heterocy-
cles. Further investigation on the mechanism and the synthesis
of isoxazoles are underway in our laboratory.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available
free of charge via the Internet at http://pubs.acs.org.
Experimental procedures, characterization data, crystallography
data, and 1H NMR and 13C NMR for the compounds (PDF)
Crystallographic Information File for 5na (CIF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: zhipingli@ruc.edu.cn
ORCID:
Zhiping Li: 0000-0001-7987-279X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Scheme 4. Proposed Mechanism for the Formation of 5a
Financial support from the National Natural Science Foundation of
China (21672259).
Furthermore, we performed the following experiments with
the addition of deuterated water (D2O) under the standard
reaction conditions (Scheme 5). Both the normal product (5a)
and the deuterated product (5a-D) were obtained in a ratio of
1.5:1. These results indicate that -H of ketone 9 might partially
occur H/D exchange through the keto-enol tautomerism
eqilibriums (E-F and D-D’-D’’) in Scheme 4.
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