An efficient synthesis of oxazolines: Via a cascade reaction between azaoxyallyl cations and 1,2-benzisoxazoles

Article abstract of DOI:10.1039/c9ob01366k

A formal [3 + 2] cycloaddition reaction between the C and O terminals of azaoxyallyl cations formed in situ and 1,2-benzisoxazoles has been realized. This one-pot cycloaddition method provided an effective and practical pathway to synthesize oxazoline in good yields under mild conditions. The title products exhibited unique fluorescence properties.

Full text of DOI:10.1039/c9ob01366k

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DOI: 10.1039/C9OB01366K
COMMUNICATION
An Efficient Synthesis of Oxazolines via Cascade Reaction between
Azaoxyallyl Cations and 1, 2-Benzisoxazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Li Sun‡, Yi Liu‡, Yankai Wang, Yuanyuan Li, Zhiwen Liu, Tao Lu and Wenhai Li*
DOI: 10.1039/x0xx00000x
A formal [3+2] cycloaddition reaction between the C and O
terminals of the azaoxyallyl cations formed in situ and 1, 2-
benzisoxazoles has been realized. This one-pot cycloaddition
method provided an effective and practical pathway to s-
ynthesize oxazoline in good yields under mild conditions. The
titled products were observed unique fluorescent properties.
O
O
H
C(CH3)3
O
N
NH
O
N
F
F
N
H
N
O
O
O
OH
OC2H5
HN
O
C17H35
etoxazole
DDM-838
The oxazolines are important heterocyclic structure motifs in
bioactive natural products and pharmaceuticals1. For example,
the natural product DDM-8382 was obtained from
Mycobacterium tuberculosis, vulnibactin3 served as iron
chelators, and etoxazole4 exhibited a very strong ovicidal
activity against tetranycus urticae. In addition, they have also
found applications in synthetic chemistry as valuable ligands5
and exhibit tuneable luminescence properties6 (Fig.1). Due to
their biological and physical properties, oxazoline derivatives
have received increasing attention from organic and
pharmaceutical chemists. But developing more efficient,
versatile and simple synthesis methods is still necessary.
OH
O
OH
OH
O
N
N
OH
N
O
R
O
H
H
OH
N
N
N
O
O
novel luminophors
vulnibactin
Fig. 1 Some compounds containing oxazoline ring
In the past decade, α-halohydroxamates, a readily available
and stable precursor of azaoxyallyl cations, has been widely
developed as the key to new efficient synthesis of heterocyclic.
In pioneering work, Jeffrey7 et al. reported the intermolecular
[3 + 4]-cycloaddition reactions of the azaoxyallyl with furans
for the synthesis of heterocycles. Subsequently, a series of [3 +
3]-8 [3 +2]9 [3 + 1]-9k and [2 + 4]-10cycloaddition reactions
involved in situ formed azaoxyallyl cations were developed, in
which most of the C and N terminals of azaoxyallyl cations
were participated in the final bond formations. Only in few
cases, the cycloaddition products with the C and O terminals of
azaoxyallyl cations could be observed [Scheme 1 (1)].
On the other hand, 1, 2-benzisoxazoles was also used to
prepare various azaheterocycles based on the nucleophilicity
of nitrogen atoms in the molecule. For example, Tang11
proposed a [3 + 2]-cycloaddition reaction of Rh-catalyzed N-
sulfonyl-1, 2, 3-triazole with 1, 2-benzisoxazoles. Recently,
Liu12 reported that tert-butyl propiolates and 1, 2-
benzisoxazoles underwent [4 + 2]-cycloaddition by Au-catalysis
produce
2-(2-hydroxyphenyl)-6H-1,
3-Oxazine-6-one
derivatives [Scheme 1 (2)]. Inspired by these efforts, we
envisioned that the in situ formed azaoxyallyl cations could be
subjected to
a [3 + 2]-cyclization reaction with 1, 2-
benzisoxazoles. Surprisingly, X-ray crystallography (Fig. 2)
revealed that cycloaddition occurred through 1, 2-
benzisoxazoles with the C and O terminals of the azaoxyallyl
cations rather than with the C and N terminals [Scheme 1 (3)].
State Key Laboratory of Natural Medicines, Department of Organic Chemistry,
China Pharmaceutical University, Nanjing, 210009, P. R. China
E-mail: liwenghai@cpu.edu.cn
†Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, and 1H and 13C NMR charts. CCDC 1900697. For ESI and
crystallographic
DOI: 10.1039/x0xx00000x
‡These authors contributed equally to this work.
data
in
CIF
or
other
electronic
format
see
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Organic & Biomolecular Chemistry
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COMMUNICATION
Journal Name
(1) Some works of azaoxyallyl cations
Entry
1
2
3
4
5
6
7
8
Cat.
Base(equiv) Solvent
Yieldb,c(%)
View Article Online
T/℃,t/h
O
O
DOI:2105.,13039/C9OB0714366K
S
N
OR3
Et3N(2)
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
R4
R1 or R2
DMAP(2)
K2CO3(2)
Na2CO3(2)
NaHCO3(2)
CS2CO3(2)
NaOH(2)
KOH(2)
25,3
25,3
25,3
25,3
25,3
25,3
25,3
25,3
25,3
25,3
25,3
25,18
25,18
25,18
25,18
25,18
25,18
0,3
83
73
87
39
81
79
55
56
48
61
60
25
29
9
NR
NR
NR
83
5
34
71
70
81
65
[3+1]
R4
O
R2 or R1= H
O
S
R4
C
R1
OR3
N
R2
N
O
[3+2]
S
R1
OR3
R4
C
R2
N
N
path a
R5
O
N
O
R1
R2
C and N terminals
as reactive sites
OR3
R4
R4
N
N
O
[3+3]
9
CuI2
CuCl2
Na2CO3(2)
Na2CO3(2)
N
R5
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24e
25f
a
O
R1
R2
OR3
Base
-HX
O
Y
R1
R2
Cu(OTf)2 Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
Na2CO3(1)
Na2CO3(3)
Na2CO3(2)
Na2CO3(2)
Na2CO3(2)
OR3
N
H
X
Y
[3+4]
MeCN
Dioxane
THF
OR3
N
R3O
Cl
N
N
H
R1
R2
R1
path b
N
O
R4
C
Ph
N
O
R2
Toluene
DCM
DMF
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
[3+3]
N
R4
Ph
C and O terminals
as reactive sites
(2) Some works of Benzo[d]isoxazole
Ts
N
50,3
25,3
25,3
25,3
25,3
25,3
R
N
N
N
O
O
N
R
N
N
[Rh]
Ts
OH
OH
O
R
O
R
N
O
tBu
[Au]
The reactions were carried out with 1a (0.2 mmol), 2a (0.3
mmol), base (0.4 mmol) in solvent (1.0 mL) for 3h at room
temperature. b Isolated yields. c NR= no reaction. d 1 equiv of 2a
was used. e 2 equiv of 2a was used. f 1a:2a=1.5:1.
(3) This work
O
azaoxyallyl
cation
R1
R2
OR3
R3O
OR3
N
Base
-HX
N
H
N
X
R1
R1
R2
O
1
O
C
R2
[3+2]
N
R
• No metal-catalyzed
• Room temperature
OH
O
Initially,
we
selected
N-(benzyloxy)-2-bromo-2-
3
R
N
methylpropanamide 1a and 1, 2-benzisoxazoles 2a as model
substrates (Table 1). The only product 3aa was obtained under
the organic bases Et3N and DMAP in good yields 74% and 83%
in HFIP, respectively (Table 1 entry 1-2). Then K2CO3, Na2CO3
and other inorganic bases were tried, the best yield of 3aa
(87%) can be isolated by using Na2CO3 (Table 1 entry 3-8).
Since most of the reactions involved 1, 2-benzisoxazoles useing
catalysts, several Lewis acids were tried. Unfortunately, no
better result is produced (Table 1 entry 9-11). A brief screen of
solvents showed that toluene, DCM, and DMF were unsuitable
for this reaction, the yield of 3aa in TFE was only 60% (Table 1
entry 12-18). The temperature was then further evaluated and
high temperature only produced a trace amount of the 3aa
(Table 1 entry 19-20). Investigation on the feed ratios showed
that 1.5 equiv of 2a and 2 equiv of Na2CO3 were optimal (Table
1 entry 21-25).
After determining the optimized reaction conditions, we
next examined the scope of 1, 2-benzisoxazoles substituted at
aryl ring (Scheme 2). The corresponding [3 + 2]-cycloadducts
were isolated in good to excellent yields. It was noted that the
1, 2-benzisoxazoles with electron-withdrawing groups result in
higher yields. For example, the best yield of 3ab (91%) was
obtained. In addition, naphtha[2, 1-d]isoxazole was also
suitable for this reaction to give 3an in 80%. However, the 3-
substituted 1, 2-benzisoxazoles did not produce the
2
Scheme 1 Research background and assumptions
Fig. 2 X-ray crystallography of 3ao
Table 1 Optimization of reaction conditionsa
BnO
N
cat.(10 mol%)
O
O
N
base(eq.)
O
OBn
N
N
H
solvent
Br
OH
T/°
,
t/h
C
2a
1a
3aa
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
corresponding target products 3ap and 3aq. Then we turned
to study the substrate range of α-halohydroxamates.
In order to display the practicability of the experimental
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method. We carried out a gram scaDleOI:e1x0p.1e0r3i9m/Ce9nOtB0u1n3d66eKr
As shown in Scheme 3, acceptable yields were achieved optimized conditions [Scheme 4 (a)], 3aa was obtained in
when the benzyloxy group in α-halohydroxamates was 1.04g (80%) without significant loss. According to the previous
replaced by its structural analogues, such as methoxy, ethoxy, literature8b, c, 9c, h, j, 3aa could be an intermediate obtained by
allyloxy and tert-butoxy. However, no reaction occurred when rapid kinetic O-alkylation reaction, which may be rearranged
the -OR3 is changed from -OBn to -Bn. Fortunately, mono- into a thermodynamically favorable N-arylation product 4,
alpha-substituted N-(benzyloxy)-2-bromopropionamide can however, only oxazole 3aa was observed in our reaction. Even
successfully give product 3ag with desired yield at relative high if treated with TFA at room temperature for 3aa for 3 hours
reaction temperature (50℃, 33%).
without any rearranged product formation [Scheme 4(b)], it
finally implied that 3aa is a stable product of the cycloaddition
reaction involving the C-O terminal.
Scheme 2 Substrate scope of 1, 2-benzisoxazolessa,b,c
BnO
The possible reaction mechanisms are described in Scheme
5. At the beginning, azaoxyallyl cations were formed in situ
from N-(benzyloxy)-2-bromo-2-methylpropanamide. Then an
initial N-attack of 1, 2-benzisoxazole at azaoxyallyl cations to
yield intermediate A, this N-attack arises from the potent
nucleophilicity of the nitrogen atom. A subsequent cyclization
intermediate B, finally readily aromatized because dissociation
of the C−H proton from species B to give 3aa.
N
O
O
N
O
Na2CO3(2.0 eq)
HFIP, rt
OBn
N
R
N
R
H
Br
OH
3
1a
2
BnO
N
BnO
BnO
N
N
O
N
O
N
O
N
Scheme 3 Substrate scope of α-halohydroxamatesa,b,c
OH
OH
OH
R3O
N
Br
3ab
O
3ac
,78%
3aa
,87%
O
,91%
BnO
R1
O
R1
R2
OR3
Na2CO3(2.0 eq)
HFIP, rt
O
R2
BnO
BnO
N
H
N
N
N
N
N
X
OH
O
N
O
N
O
N
1
2a
3
Bn
MeO
N
EtO
OH
F
OH
Cl
OH
N
N
O
O
N
O
3ae
3ad
,85%
O
3af
,83%
,75%
N
N
BnO
BnO
BnO
OH
OH
, 65%
OH
3da
,60%
N
N
N
3ba
3ca
, NR
O
N
O
N
N
O
OH
tBuO
N
Br
OH
OH
BnO
O
N
N
3ah
3ai
,80%
,81%
3ag
,90%
O
N
O
O
BnO
BnO
BnO
N
N
N
N
N
OH
OH
3ga
, 33%
O
N
O
N
O
O
OH
3ea,
3fa
,76%
R
73%
N
3aj
R=Cl, ,87%
a Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Na2CO3 (0.4
mmol) in HFIP (1.0 mL) for 3 h at room temperature or 50℃. b
Isolated yields. c NR= no reaction.
OH
OH
OH
R
3ak
=Br,
,85%
3al
R=CH3, ,83%
3an
3am
,80%
,77%
BnO
BnO
BnO
N
N
N
O
N
O
O
Br
Cl
N
N
H
Scheme 4. Related experiments
H
OH
BnO
N
OH
OH
Br
O
O
3ap
3ao
,ND
3aq
,ND
,90%
Na2CO3(2.0 eq)
HFIP,rt
O
OBn
N
N
N
(a)
H
Br
a Reaction conditions: 1a (0.2mmol), 2 (0.3 mmol), Na2CO3 (0.4
mmol) in HFIP (1.0 mL) for 3 h at room temperature. b Isolated
yields. c ND= no desired product was detected by TLC.
OH
1a
4.2mmol
2a
6.3mmol
3aa
1.04g,80%
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Journal Name
BnO
N
View Article Online
DOI: 10.1039/C9OB01366K
O
BnO
TFA
O
N
N
(b)
N
HFIP, rt,
Table 2. Emission properties of selected phenols
OH
OH
component
3aa
267
326
3ao
266
325
3ai
267
326
3aa
4
λ abs (nm)
λ em (nm)
Stokes shift (cm-1
)
18868
18868
20408
Scheme 5 Proposed mechanisms for the formation of 3aa
Scheme 6. Gram-Scale and Synthetic Transformations
BnO
BnO
HO
N
N
OBn
N
N
DABCO(0.1 eq)
CO2Et
Pd/C(0.1 eq)
H2,rt
O
N
O
2a
O
N
O
O
N
N
O
O
N
O
N
Base
OBn
CO2Et
N
O
OH
OH
yield=97%
H
BnO
HBr
Br
A
3aa
6,
yield=78%
5,
1a
BnO
N
O
O
N
N
OBn
N
O
Conclusions
H
OH
In summary, we have established a new [3+2]-cycloaddition
reaction between the C and O terminals of azaoxyallyl cations
with 1, 2-benzisoxazoles, which provides an effective and
practical approach for the synthesis of oxazoline derivatives. The
method has the characteristics of being gentle, simple and one-
step. Further research is currently being conducted in our
laboratory for the construction of drug molecules using in situ
formed azaoxyallyl cations.
3aa
B
To investigate the synthetic utility, the 3aa was treated with
H2/Pd in MeOH to afford oxime 5. The products can be readily
transformed into other interesting compounds due to the free
hydroxyl group. For example, O-Michael addition product 6
was released when 3aa was coupled with ethyl propiolate.
(Scheme 6; see also Table S6 in the Supporting Information).
Interestingly, we noted that the product may have the
ESIPT-based emission properties, and three selected phenols
3aa, 3ao and 3ai (Figure 3 and Table 2) were studied in
dichloromethane because of the presence of an intramolecular
hydrogen bond (H-bond) between the proton donor (–OH) and
the proton acceptor groups in close proximity to each other in
a molecule. The results of the graph show that the excitation
and emission spectra of this series of compounds overlap
declines, the Stokes shift is up to 20408 cm-1 , and the
resolution of fluorescence analysis is much higher.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the Double First-Class
(CPU2018GF02) for financial support. Project supported by
Program of Innovation and Entrepreneurship for
Undergraduates.
Notes and references
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4 | J. Name., 2012, 00, 1-3
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