Divergent Conversion of N-Acyl-isoxazol-5(2 H)-ones to Oxazoles and 1,3-Oxazin-6-ones Using Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00903

The fragmentation of N-acyl-isoxazol-5-ones using visible light photoredox catalysis has been disclosed. The catalyst-controlled divergent mechanisms, namely the oxidative and reductive quenching catalytic cycle, are utilized. Various oxazoles and 1,3-oxazin-6-ones are selectively obtained from the same isoxazol-5-one skeleton under mild conditions.

Full text of DOI:10.1021/acs.orglett.9b00903

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Conversion of N‑Acyl-isoxazol-5(2H)‑ones to Oxazoles
and 1,3-Oxazin-6-ones Using Photoredox Catalysis
Mingjing Mei, Devireddy Anand, and Lei Zhou*
School of Chemistry, Sun Yat-Sen University, 135 Xingang West Road, Guangzhou, 510275, China
S
* Supporting Information
ABSTRACT: The fragmentation of N-acyl-isoxazol-5-ones
using visible light photoredox catalysis has been disclosed. The
catalyst-controlled divergent mechanisms, namely the oxida-
tive and reductive quenching catalytic cycle, are utilized.
Various oxazoles and 1,3-oxazin-6-ones are selectively
obtained from the same isoxazol-5-one skeleton under mild
conditions.
soxazol-5-ones are five-membered heterocycles possessing
Scheme 1. N−O Bond Cleavage Enabled by Visible Light
Photoredox Catalysis
I
rich chemical reactivities.1 They may exist as a mixture of
three tautomeric forms, known as CH-form I, NH-form II, and
OH-form III (Figure 1).2 Because of the weak N−O bond
Figure 1. Tautomeric forms of isoxazol-5-ones.
(BDE, D0298 = 151 kcal mol−1) in their architecture,3 isoxazol-
5-ones are versatile building blocks in organic synthesis
through N−O bond cleavage and CO2 extrusion.4−7 Early
reports by Prager indicated that most of the isoxazol-5-ones
can be used as the precursors of imino carbene under flash
vacuum pyrolysis (FVP) conditions or irradiation with high-
energy UV light.4 Metal-catalyzed decarboxylation of isoxazol-
5-ones generates vinylmetal nitrenoid species,5 which has been
applied to prepare diverse aza-heterocycles, such as 1-
azabicyclo[3.1.0]hex-2-enes,5a pyridines,5c and 2H-pyrroles.5g
Nitrosative cleavage of isoxazol-5-ones is a well-established
route to access alkynes.6 The isoxazolone motif has also been
developed as a directing group in Rh-catalyzed ortho C−H
bond activation reaction.7 Despite these significant advances,
the reactivity manifolds of isoxazol-5-ones remain to be
explored.
There has been progress using a photoredox strategy to
generate alkyl radicals through single-electron reduction of N-
(acyloxy)-phthalimides (NHPI esters).8 This reduction results
in N−O bond cleavage followed by decarboxylation to release
CO2, an alkyl radical, and a phthalimide anion (Scheme 1a).
Due to the highly negative reduction potentials of NHPI esters,
reductive conditions are often employed to promote their
single electron reduction where the excited photocatalyst is
converted into a higher reducing species prior to engaging in
SET with N-(acyloxy)-phthalimides (reductive quenching of
photocatalyst).9 Recently, the direct electron transfer between
excited photocatalyst and NHPI esters has been reported,
driven by the formation of hydrogen bonding to increase the
electron-acceptor strength of substrates (oxidative quenching
of photocatalyst).10 Stimulated by the structural analogy of N-
acyl-isoxazol-5-ones with NHPI esters, we wish to investigate
the chemical reactivity of isoxazol-5-one derivatives under
photoredox conditions. In contrast to numerous reports on the
homolytic cleavage of the N−O bond of isoxazol-5-ones,4 the
visible light-driven SET process for their fragmentation has
been less explored. If feasible, this new activation mode would
expand the applications of isoxazol-5-ones in aza-heterocycles
synthesis. Herein, we report a visible light-promoted
decarboxylative rearrangement of N-acyl-isoxazol-5-ones to
oxazoles with fac-Ir(ppy)3 as the photocatalyst. By switching
the photocatalyst to 4DPAIPN, 1,3-oxazin-6-ones were
obtained with complete selectivity from same isoxazol-5-one
skeleton (Scheme 1b). Notably, both oxazoles11 and 1,3-
Received: March 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxazin-6-ones12 are important heterocycles present in a wide
range of natural products and bioactive compounds, as
exemplified by antidiabetic agent AD-5061,11d antimycobacte-
rial texaline,11e and salinazinone A (Figure 2).12d,e Although
a b
,
Table 1. Optimization of Reaction Conditions
2a
3a
entry
photocatalyst
fac-Ir(ppy)3
base (equiv)
solvent
(%)
(%)
1
2
3
4
5
6
7
−
DMSO
DMF
THF
DCE
MeCN
dioxane
22
27
18
32
57
91
11
0
0
0
0
0
0
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ru(bpy)3Cl2
−
−
−
−
−
Figure 2. Representative biologically active molecules containing
oxazole or 1,3-oxazin-6-one motif.
numerous synthetic methods for the construction of these
heterocyclic skeletons have been developed in the past
decades,13,14 processes in which different products can be
obtained from identical substrates in synthetically meaningful
yields utilizing catalyst rather than substrate control are rare.
At the outset of this investigation, we chose N-benzoyl-4-
phenyl-isoxazol-5-one 1a as the model substrate, and its redox
potential was measured. Although the cyclic voltammetry
experiment indicates that 1a has a high negative reduction
potential (−1.50 V vs SCE), it is still possible to reduce this
compound using the strong reducing photoexcited Ir(ppy)3*
(E1/2IV/III* = −1.73 V vs SCE).15 To our delight, irradiating the
DMSO solution of 1a in the presence of fac-Ir(ppy)3 gave 2,5-
diphenyloxazole 2a in 22% yield (Table 1, entry 1). A brief
screen of solvents indicated 1,4-dioxane was the best choice, in
which the desired product 2a was obtained in 91% yields
0
iPr2NEt (1.2) dioxane
iPr2NEt (1.2) dioxane
15
11
14
19
0
8
9
Ir(ppy)2(dtbbpy)PF6 iPr2NEt (1.2) dioxane
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4DPAIPN
Eosin Y
iPr2NEt (1.2) dioxane
iPr2NEt (1.2) dioxane
iPr2NEt (1.2) DMSO
iPr2NEt (1.2) DMF
iPr2NEt (1.2) DCE
iPr2NEt (1.2) MeCN
0
0
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
4DPAIPN
−
0
21
25
31
58
66
50
0
0
0
60
66
0
0
0
0
NEt3 (1.2)
NnBu3 (1.2)
DBU (1.2)
DHP (1.2)
K2CO3 (1.2)
NEt3 (1.0)
NEt3 (2.0)
−
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
dioxane
MeCN
0
0
0
0
0
0
0
0
(Table 1, entries 2−6). Because Ir(ppy)3− is a higher reducing
III/II
species (E1/2
= −2.19 V vs SCE), we also examined the
reaction by adding iPr2NEt as an electron donor. Interestingly,
the yield of oxazole 2a sharply decreased to 11%, while 1,3-
oxazin-6-one 3a was observed in 15% yield (Table 1, entry 7).
Inspired by this result, the reaction conditions toward the
formation of 3a were screened. When Ru(bpy)3Cl2, Ir-
(ppy)2(dtbbpy)PF6, and 4DPAIPN were used as the photo-
catalysts, oxazole 2a was completely suppressed, albeit
affording 1,3-oxazin-6-one 3a in low yields (Table 1, entries
8−10). Organic dye Eosin Y was essentially ineffective for the
reaction (Table 1, entry 11). We thus sought to further
improve the yield of 3a with 4DPAIPN as the photocatalyst.
Several solvents, such as DMSO, DMF, DCE and MeCN, were
screened for this transformation, and MeCN was found to be
the best one (Table 1, entries 12−15). Triethylamine was the
c
24
c
fac-Ir(ppy)3
4DPAIPN
−
0
0
0
0
25
NEt3 (2.0)
a
Reaction conditions: N-benzoyl-4-phenyl-isoxazol-5-one 1a (0.1
mmol), base (1.2 equiv), 5 mol % of 4DPAIPN or 1 mol % of
other photocatalysts, solvent (2 mL), 5 W blue LED, rt, 3 h. Yields
were determined using mesitylene as the internal standard. In the
dark; DHP = 1,4-dihydropyridine.
b
c
2a−n smoothly in 82−97% yields (Table 2, entries 1−14).
The reaction was not significantly affected by the substituent
on the benzoyl group; both electron-rich groups, such as
methyl, tert-butyl, methoxyl, phenyl, and electron-deficient
groups, such as halogen (F, Cl, Br), trifluoromethyl, ester, on
the different positions of the aromatic ring were well-tolerated.
2-Naphthoyl (1o), 2-furoyl (1p), and 2-thienoyl (1q) 4-
phenyl-isoxazol-5-ones were also suitable for the reaction,
producing oxazoles 2o, 2p, and 2q in the yields of 73%, 85%,
and 74%, respectively (Table 2, entries 15−17). For the
substrates 1r−t bearing a substituent (para-methyl, para- and
meta-chloro) on the aromatic ring attached to the C−C double
bond, the reactions led to 2,5-substituted oxazoles 2r−t in 81−
93% yields (Table 2, entries 18−20). 2,4-Diphenyl oxazole 2u
was successfully synthesized from N-benzoyl-3-phenyl-isoxa-
zol-5-one 1u (Table 2, entry 21). We were delighted to find
that the substituent on the 3-position of isoxazol-5-ones was
not limited to the aryl group, as exemplified by the formation
of 2-alkyl oxazoles 2v−y (Table 2, entries 22−25). Notably, a
cyclopropyl group could survive in this radical-based trans-
formation (Table 2, entry 25). The reaction also allows access
to 2,4,5-trisubstituted oxazoles 2z−2ab in excellent yields via
i
best base in comparison with Pr2NEt and NnBu3 (Table 1,
entries 16, 17), while the use of DBU, 1,4-dihydropyridine
(DHP), and inorganic base K2CO3 led to no conversion at all
(Table 1, entries 18−20). The optimal amounts of NEt3 were
also evaluated. We found the use of 1 equiv of NEt3 led to 3a
in a slightly diminished yield (Table 1, entry 21). Further
increasing the loading of NEt3 from 1.2 to 2 equiv, the yield
was almost identical (Table 1, entry 22). Finally, the control
experiments indicated that neither 2a nor 3a was detected
when the reaction was carried out in the absence of
photocatalyst or in the dark, and most of 1a remained
unreacted (Table 1, entries 23−25).
To demonstrate the generality of the present photoredox
reactions of N-acyl-isoxazol-5-ones, their decarboxylative
rearrangement to oxazoles was first examined. As shown in
Table 2, a series of N-benzoyl-4-phenyl-isoxazol-5-ones 1a−n
were converted to the corresponding 2,5-substituted oxazoles
B
DOI: 10.1021/acs.orglett.9b00903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope for the Formation of Oxazoles 2
b
entry
1
R1
R2
R3
2
yield (%)
c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeC6H4
p-ClC6H4
m-ClC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
Et
iPr
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
88(85)
82
86
90
91
92
95
96
86
90
90
97
95
91
73
85
74
82
81
93
60
71
75
77
87
90
97
91
98
36
41
p-MeC6H4
p-tBuC6H4
p-MeOC6H4
p-PhC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-CF3C6H4
p-CO2EtC6H4
m-MeC6H4
o-MeC6H4
(2,4-Me2)C6H3
(3,4,5-Me3)C6H2
2-naphthyl
2-furyl
2-thienyl
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeC6H4
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
1s
1t
1u
1v
1w
1x
2s
2t
2u
2v
2w
2x
1y
1z
H
cyclopropyl
Me
Et
Ph
Ph
Ph
2y
2z
benzyl
Me
npentyl
1aa
1ab
1ac
1ad
1ad
2aa
2ab
2ac
2ad
2ad
Me
p-CF3C6H4
Ph
Me
(CH2)4
d
30
31
Ph
Ph
H
H
e
Me
a
All the reactions were carried out using N-acyl-isoxazol-5-ones 1 (0.2 mmol), fac-Ir(ppy)3 (1 mol %) in 2 mL of 1,4-dioxane under the irradiation
b
c
d
e
of a 5 W blue LED at rt for 3 h. Isolated yields. Isolated yield of 2 mmol scale reaction in the parentheses. 20 mol % of HOAc was added. 20
mol % of Zn(OTf)2 was added.
the photocatalytic decarboxylative rearrangement of isoxazol-5-
ones 1z−1ab (Table 2, entries 26−28). In addition, cyclohexyl
fused isoxazol-5-one 1ac could be converted to 2-phenyl-
tetrahydrobenzoxazole 2ac in 98% yield (Table 2, entry 29).
The rearrangement of N-acetyl-4-phenyl-isoxazol-5-one 1ad
under the optimal reaction conditions failed, presumably due
to its highly negative reduction potential (−1.97 V vs SCE).16
Therefore, we attempted to increase its electron-acceptor
strength by forming stronger hydrogen bonding. To our
delight, the desired product 1ad was obtained in 36% yield
when 20 mol % acetic acid was added, which was further
improved to 41% with Zn(OTf)2 as the additive (Table 2,
entries 30, 31).
isoxazol-5-ones. Switching the products from oxazoles to 1,3-
oxazin-6-ones 3g and 3h were also viable with 2-furoyl (1p)
and 2-thienoyl (1q) 4-phenyl-isoxazol-5-ones as the substrates.
Unfortunately, the attempt to convert 3-ethyl-isoxazol-5-one
1w to 3i was unsuccessful.
To understand the limitation of scope and the mechanism of
both transformations, the redox profiles of several representa-
tive isoxazol-5-ones were evaluated (Scheme 3). Except 1ad, all
of the examined isoxazol-5-ones were expected to undergo
SET reduction by Ir(III)* directly. In order to reduce 1ad,
HOAc was added to improve its electron-acceptor strength by
forming a stronger hydrogen bond. Due to the low reducibility
+
(E1/2PC /PC* = −1.28 V) of excited 4DPAIPN*,17 it has no
Next, the scope of nondecarboxylative rearrangement of N-
acyl-isoxazol-5-ones for the synthesis of 1,3-oxazin-6-ones 3
was investigated. The generality and efficiency of this
transformation are lower than the formation of oxazoles 2.
As shown in Scheme 2, 1,3-oxazin-6-ones 3a−f were isolated in
41−64% yields from the corresponding N-benzoyl-4-aryl-
ability to reduce any isoxazol-5-ones. In the presence of NEt3,
4DPAIPN* was reduced to the higher reducing species
4DPAIPN−. Therefore, the SET between 4DPAIPN− and 1a
was feasible. However, its reducibility is still not sufficient to
reduce the isoxazol-5-ones with higher negative reduction
potentials, such as 1w, 1ac, and 1ad. Considering the high
C
DOI: 10.1021/acs.orglett.9b00903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
According to the above observations and previous reports in
literature, a possible pathway for the overall processes was
proposed in Scheme 4. Visible-light-promoted decarboxylative
Scheme 2. Substrate Scope for the Formation of 1,3-Oxazin-
6-ones 3
a
Scheme 4. Plausible mechanism
a
All the reactions were carried out using N-acyl-isoxazolidin-5-ones 1
(0.2 mmol), 4DPAIPN (5 mol %), and NEt3 (1.2 equiv) in 2 mL of
dry MeCN under the irradiation of a 5 W blue LED at rt for 3 h;
b
isolated yields. Isolated yield of 2 mmol scale reaction in the
parentheses.
Scheme 3. Redox Profiles of Substrate and Photocatalyst
rearrangement of N-acyl-isoxazol-5-ones to oxazoles is
supposed to proceed through the oxidative quenching of
excited photocatalyst fac-Ir(ppy)3*. Single electron reduction
of 1a by Ir(III)* generates radical ion A, followed by β-scission
of the N−O bond to give intermediate B. The extrusion of a
CO2 molecule from B leads to vinyl radical C, which
subsequently undergoes intramolecular addition to form
oxazole radical anion D.18 Finally, single electron oxidation
of D by Ir(IV) gives oxazole 2a with regeneration of the
photocatalyst. In contrast, the formation of 1,3-oxazin-6-one 3a
is initiated by the reductive quenching of 4DPAIPN*. As
described in Scheme 3, the reductive potential of 4DPAIPN*
−
III/II
+
reducibility of Ir(ppy)3 (E1/2
= −2.19 V), we examined
(E1/2PC /PC*= −1.28 V vs SCE) is not sufficient to reduce 1a
the rearrangement of 3-ethyl-isoxazol-5-one 1w with fac-
Ir(ppy)3 as the photocatalyst and NEt3 as the electron
donor. Instead of the desired 1,3-oxazin-6-one product 3i, N-
acyl enamine 4 was obtained in 34% yield, indicating that the
decarboxylation of substrates without a phenyl group on the 4-
position was much faster than those bearing a phenyl group
(Scheme 3, eq 1). As a comparison, nondecarboxylative
product 3a and oxazole 2a were detected in yields of 39% and
3%, respectively, when the fac-Ir(ppy)3/NEt3 catalytic system
was applied to the rearrangement of 4-phenyl-isoxazol-5-one
1a (Scheme 3, eq 2).
(E1/2 = −1.50 V vs SCE) directly. Therefore, it has to be
PC/PC−
reduced to higher reducing species 4DPAIPN− (E1/2
=
−1.52 V vs SCE) by NEt3 prior to engaging in SET with 1a.
Instead of direct decarboxylation, intermediate B undergoes
hydrogen abstraction from E to give carboxylic acid G and
iminium ion F. Nucleophilic attack of iminium ion F by the
carbonyl oxygen of the amide ion G leads to intermediate H,
which undergoes a fast cyclization reaction to produce product
3a with elimination of a molecule of α-OH amine (path a).19
Alternatively, intramolecular proton transfer of G, followed by
D
DOI: 10.1021/acs.orglett.9b00903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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nucleophilic attack of the resulting carboxylate J to iminium
ion F, and cyclization also afford the desired 1,3-oxazin-6-one
3a (path b). Because carboxylate J is a more stable anion than
G and the conversion of the carboxyl OH to a good leaving
group is more common in organic synthesis, path b is probably
a major route to form 3a. As shown in Table 1, entry 19, the
use of 1,4-dihydropyridine (DHP) is essentially ineffective for
the reaction because its oxidation product pyridine is stable to
intermediate G. Therefore, we assume that NEt3 plays a
threefold role for the formation of 1,3-oxazin-6-ones: (1) as an
electron donor; (2) as a hydrogen donor; and (3) as the
precursor of the iminium ion to promote the cyclization.
In conclusion, we have developed a mild and convenient
approach to oxazoles and 1,3-oxazin-6-ones via visible-light-
promoted decarboxylative and nondecarboxylative rearrange-
ment of isoxazol-5-ones, respectively. The photocatalyst-
controlled divergent mechanisms, namely oxidative and
reductive quenching catalytic cycle, are utilized, and various
oxazoles and 1,3-oxazin-6-ones are selectively obtained from
the same isoxazol-5-one skeleton. Since isoxazol-5-ones are
readily prepared from β-keto esters and their equivalents,20
such a catalyst-controllable methodology is an important
addition to those previous reports on diversity-oriented
synthesis of N-heterocycles.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00903.
Experimental details, characterization data, NMR spectra
of all new products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhoul39@mail.sysu.edu.cn.
ORCID
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Lei Zhou: 0000-0002-8391-8452
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the funds from the National Basic Research
Program of China (Grant 2016YFA0602900), the National
Natural Science Foundation of China (Grant No. 21871300),
and the Natural Science Funds of Guangdong Province for
Distinguished Young Scholars (Grant 2016A030306029).
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